melphalan and Neoplasm-Metastasis

The management of melanoma in-transit metastases (IT-mets) is challenging. For many years, the absence of effective systemic therapy has prompted physicians to focus on regional therapies for melanoma confined to the limb. The introduction of isolated limb perfusion (ILP) and isolated limb infusion (ILI) has enabled effective delivery of cytotoxic drugs in an isolated circuit, so as to overcome systemic toxicity and maximize local response. Both techniques have evolved over years and both tumor necrosis factor (TNF)-alpha-based ILP and ILI have distinct indications. The development of new systemic treatment options for patients with melanoma in the past decade has shed a new light on melanoma therapy. The present manuscript focuses on the modern role of ILI and ILP in the treatment of patients with melanoma with in-transit metastases in the era of effective systemic therapy. The response and control rates of ILI/ILP are still superior to rates achieved with systemic agents. The extent of disease in patients with stage III disease, however, warrants effective systemic treatment to prolong survival. There is great potential in combining rapid response therapy such as ILI/ILP with systemic agents for sustainable response. Trial results are eagerly awaited.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Humans; Infusions, Intravenous; Melanoma; Melphalan; Neoplasm Metastasis; Skin Neoplasms; Survival Analysis; Treatment Outcome

Indications for treatment of melanoma in-transit metastases (ITMs) confined to the limb with isolated limb perfusion (ILP) are not well defined. This study reports the Groningen regional therapeutic perfusion experience with melphalan (M-ILP) and TNF-melphalan (TM-ILP) for ITMs, and reviews of the melanoma TNF-melphalan ILP literature. Between 1991 and 2012, 60 patients were treated with ILP. Patients with "small" ITMs received M-ILP (10-13 mg melphalan/L limb volume) and patients with "bulky" disease TM-ILP (1-4 mg TNF); 19 M-ILPs and 41 TM-ILPs were performed, 26 Stage IIIB, 31 Stage IIIB and 1 stage IV disease. Overall response after 57 ILPs was 90%; CR 27 (45%), PR 27 (45%), no response 3 (5%); after 9 M-ILPs CR 6 (32%) and 41 TM-ILPs CR 21 (51%, P = 0.124). For younger patients (<65 years) CR was 69% and for elderly patients 29% (P = 0.003). For low volume disease (<5 ITMs) CR was 75% and for high volume disease (≥5 ITMs) 41% (P = 0.038). After median follow-up of 15 months (range, 1-144) there was local recurrence or disease progression in 36 patients (60%). Positive lymph node status was associated with local progression, absence of CR and Stage IIIC disease; these were independent prognostic factors for progression to systemic disease. M-ILP is an effective regional treatment for melanoma ITMs, whereas for bulky disease TM-ILP should be the first choice. In-field progression-free survival after ILP is determined by the biological behavior of the ITMs and the patient's immune system.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Humans; Melanoma; Melphalan; Neoplasm Metastasis; Tumor Necrosis Factor-alpha

Isolated limb infusion (ILI) was developed as a simplified and minimally invasive alternative to isolated limb perfusion (ILP) to treat unresectable limb melanoma. A number of centers around the world have reported their results using this procedure. In this study a systematic review of reported ILI experiences was undertaken. A literature search was conducted according to the guidelines for systematic reviews in order to select eligible papers reporting limb toxicity and response rates following ILI using melphalan and actinomycin D to treat limb melanoma. A total of 576 patients from seven publications were included. Regional toxicity following ILI was low: no visible effect of the treatment or slight erythema or edema was observed in 79% of the patients, while considerable erythema and/or edema with blistering was experienced by 19%. In 2% there was a threatened or actual compartment syndrome. No procedure-related amputation was reported. Complete response occurred in 33% of the patients and partial response in 40%, an overall response rate of 73%. Stable disease and progressive disease were achieved in 14% and 13% of the patients, respectively. This first systematic review of ILI procedures using melphalan and actinomycin D indicates that regional toxicity was generally low, with satisfactory response rates. When comparing ILI and ILP, it must be borne in mind that ILI is often performed in significantly older patients and in patients with higher stages of disease, which decreases the likelihood of a favorable response.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Humans; Melanoma; Melphalan; Neoplasm Metastasis

For in-transit melanoma confined to the extremities, regional chemotherapy in the form of hyperthermic isolated limb perfusion and isolated limb infusion are effective treatment modalities carrying superior response rates to current standard systemic therapy. Despite high response rates, most patients will eventually recur, supporting the role for novel research aimed at improving durable responses and minimizing toxicity. Although the standard cytotoxic agent for regional chemotherapy is melphalan, alternative agents such as temozolomide are currently being tested, with promising preliminary results. Current strategies for improving chemosensitivity to regional chemotherapy are aimed at overcoming classic resistance mechanisms such as drug metabolism and DNA repair, increasing drug delivery, inhibiting tumor-specific angiogenesis, and decreasing the apoptotic threshold of melanoma cells. Concurrent with development and testing of these agents, genomic profiling and biomolecular analysis of acquired tumor tissue may define patterns of tumor resistance and sensitivity from which personalized treatment may be tailored to optimize efficacy. In this article rational strategies for treatment of in-transit melanoma are outlined, with special emphasis on current translational and clinical research efforts.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Bevacizumab; Disease Progression; Humans; Melanoma; Melphalan; Neoplasm Metastasis; Neoplasm Staging; Skin Neoplasms; Treatment Outcome

To study tumor therapeutic treatment modalities, whether from a clinical, preclinical, or fundamental point of view, the use of clinically relevant animal models is indispensable. Particularly when the treatment comprises a multitargeted approach, (e.g., both tumor cells and endothelial cells are targeted), the in vitro data will be of very limited value. Well-chosen animal models will provide conclusive data on the activity of the drug in the complex in vivo setting. Moreover, when the treatment targets the stromal compartment of the tumor rather than the tumor cells directly, insight into the mechanism of action is only possible when studied in vivo. This approach is of great importance for studies on the use of tumor necrosis factor-alpha (TNFalpha) in solid tumor therapy. Although TNFalpha has shown activity toward tumor cells in vitro directly, we and others have demonstrated that an important activity of this cytokine is directed toward the tumor vasculature. To elucidate the working mechanism of TNFalpha and to test possible treatment modalities, the animal models described here are crucial. In this chapter we will describe the use of specific animal models for efficacy studies, such as isolated limb perfusion and isolated liver perfusion in the rat.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Disease Models, Animal; Doxorubicin; Extremities; Humans; Liposomes; Liver Neoplasms, Experimental; Melphalan; Mice; Neoplasm Metastasis; Neoplasms, Experimental; Perfusion; Rats; Time Factors; Tumor Necrosis Factor-alpha

Isolated limb perfusion (ILP) with melphalan is effective against melanoma in-transit metastases but has failed in the treatment of limb-threatening extremity sarcomas. Tumor necrosis factor-alpha (TNF) has changed this situation completely. Now, ILP with TNF + melphalan is a very successful treatment to prevent amputation. In a multicenter European trial, ILP with TNF + melphalan resulted in a 76% response rate and a 71% limb salvage rate in patients with limb-threatening soft-tissue sarcomas, deemed unresectable by independent review committees, leading to approval of TNF in Europe. We have also reported on the success of this regimen against bulky melanomas, multifocal skin cancers, and drug-resistant bony sarcomas. High-dose TNF destructs tumor vasculature, and, most importantly, it enhances tumor-selective drug uptake (ie, melphalan and doxorubicin) by threefold to sixfold. Similar synergy is observed in well-vascularized liver metastases after isolated hepatic perfusion with TNF and melphalan. New (vasoactive) drugs and mechanisms of action and interaction with chemotherapy are in development. ILP is also a promising treatment modality for adenoviral vector-mediated gene therapy. Many clinical phase I/II evaluations in ILP are now underway.

Topics: Animals; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Forecasting; Humans; Melphalan; Neoplasm Metastasis; Rats; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

The mainstay of treatment of cutaneous melanoma is surgical excision. Excision of the primary disease, lymph node metastases, and in some instances, distant metastases is the only therapeutic strategy that leads to long-term disease-free survival with rare exceptions. Surgical treatment of melanoma can be divided into therapy of the primary lesion, treatment of the lymph nodes, treatment of distant metastases, and treatment of in-transit disease by regional administration of intravascular chemotherapeutics. The current recommendations for each of these four areas is discussed in this review.

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Humans; Lymph Node Excision; Lymphatic Metastasis; Melanoma; Melphalan; Neoplasm Metastasis; Skin Neoplasms

Recombinant tumor necrosis factor-alpha (rTNF alpha) has potent antitumor activity in experimental studies on human tumor xenografts. However, in humans, the administration of rTNF alpha is hampered by severe systemic side-effects. The maximum tolerated dose ranges from 350 to 500 mg/m2, which is at least 10-fold less than the efficient dose in animals. Isolation perfusion of the limbs (ILP) allows the delivery of high dose rTNF alpha in a closed system with acceptable side-effects. A protocol with triple-drug regimen was based on the reported synergism of rTNF alpha with chemotherapy, with interferon-gamma, and with hyperthermia. In melanoma-in-transit metastases (stage IIIA or AB) we obtained a 91% complete response, compared with 52% after ILP with melphalan alone. Release of nanograms levels of TNF alpha in the systemic circulation was evident but control of this leakage and appropriate intensive care resulted in acceptable toxicity. Angiographic, immunohistological, and immunological studies suggest that the efficacy of this protocol is due to a dual targeting: rTNF alpha activates and electively lyses the tumor endothelial cells while melphalan is mainly cytotoxic to the tumor cells. ILP with rTNF alpha appears to be a useful model for studying the biochemotherapy of cancer in man.

Topics: Animals; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Drug Administration Schedule; Drug Synergism; Hemodynamics; Humans; Interferon-gamma; Melanoma; Melphalan; Neoplasm Metastasis; Pilot Projects; Recombinant Proteins; Transplantation, Heterologous; Tumor Necrosis Factor-alpha

Although the optimal efficacy of cytotoxic therapy plateaued in the 1970s, no consensus yet exists regarding which cytotoxic combination to offer as first-line therapy for metastatic breast cancer. Comparison of a combination of CAF/CEF with other cytotoxic combinations reveals that an anthracycline-containing regimen not only increases response rate, but also improves time to progression and survival. Regarding appropriate duration of cytotoxic therapy, randomized trials indicate that therapy in excess of 6 months is beneficial. Although the main objective of cytotoxic therapy in patients with metastatic disease is to palliate symptoms at the least toxic cost, the finding that adjuvant cytotoxic therapy improves survival provides a clinical and ethical rational for continued research into new drugs and combinations in the hope that new strategies can be employed not only against metastatic breast cancer but may be applied with benefit also in the adjuvant situation.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cisplatin; Cyclophosphamide; Dactinomycin; Doxorubicin; Epirubicin; Etoposide; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Mitomycin; Mitoxantrone; Neoplasm Metastasis; Vincristine

Studies are described of high-dose therapy in metastatic breast cancer, early stage breast cancer, stage IV neuroblastoma, recurrent or bulky disease testicular cancer and Ewing's sarcoma. The outcome in these subgroups with conventional therapy is described for comparison. The results of these studies suggest that high-dose therapy with autologous marrow support increases the proportion of patients with long-term survival without evidence of disease. Newer supportive care and recurrent high-dose therapy cycles of non-cross resistant regimens may improve outcome further in these diseases and increase the application to more resistant tumors.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Child; Combined Modality Therapy; Cyclophosphamide; Humans; Melphalan; Neoplasm Metastasis; Neoplasms; Neuroblastoma; Prednisone; Prognosis; Remission Induction; Survival Rate; Transplantation, Autologous; Treatment Outcome; Vincristine

The paper critically reviews major accomplishments achieved with the use of chemotherapy in the treatment of various stages of breast cancer. In spite of innumerable clinical trials, there is no evidence that in advanced breast cancer the addition of more drugs, either in concomitant, sequential or alternating fashion, to known effective combinations, was able to significantly improve the incidence and the magnitude of objective response or its median duration or survival. The addition of endocrine therapy to chemotherapy has failed so far to improve the most important end-point, i.e. total survival. Second-line chemotherapy is only moderately effective for a fairly short period of time. Thus, in women with advanced breast cancer excessive tumor cell burden and permanent drug resistance remain the major obstacles to obtaining complete remission and long-term disease free survival. In the adjuvant setting, the initial trials with combination chemotherapy have achieved consistent results, particularly in women with minimal axillary node involvement. Unless a woman has undergone a surgical breast-saving procedure, postoperative radiotherapy does not appear to play an important therapeutic role, either with or without concomitant or sequential chemotherapy. Present results would suggest that in advanced breast cancer little progress can be expected in the near future. Therefore, medical oncologists should focus on the correct application of established drug regimens, using a sequential flow of hormonal manipulations and cytotoxic chemotherapy. In high-risk groups, full dose adjuvant polydrug therapy given for a relatively short period of time appears to be at present the only means able to significantly decrease the failure rate following local regional treatment. Present consistent achievements, which appear devoid of important delay morbidity (e.g. cancerogenesis, chronic organ damage) will require further clinical research to identify more effective and less toxic treatments.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Prognosis; Receptors, Estrogen; Research Design

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Neoplasm Metastasis; Time Factors

Topics: Adult; Aging; Castration; Chlorambucil; Cryptorchidism; Cyclophosphamide; Dysgerminoma; Humans; Male; Melphalan; Middle Aged; Mumps; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Testicular Neoplasms; Testis

Topics: Adolescent; Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Child; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Radiotherapy, High-Energy; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms

Topics: Adult; Alkylating Agents; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Child; Cyclophosphamide; Doxorubicin; Drug Combinations; Drug Therapy, Combination; Female; Fluorouracil; Humans; Immunotherapy; Leucovorin; Male; Melphalan; Methotrexate; Neoplasm Metastasis; Neoplasms; Osteosarcoma; Prednisone; Rhabdomyosarcoma; Testicular Neoplasms; Thiotepa; Vinblastine; Vincristine

Topics: Azygos Vein; Biopsy; Colchicine; Cytodiagnosis; Drug Therapy, Combination; Esophageal Neoplasms; Esophagoscopy; Humans; Melphalan; Neoplasm Metastasis; Radiography; Radionuclide Imaging; Surgical Procedures, Operative

Topics: Abdominal Neoplasms; Alkylating Agents; Animals; Antimetabolites; Antineoplastic Agents; Carcinoma, Basal Cell; Choriocarcinoma; Cyclophosphamide; Dactinomycin; Dysgerminoma; Female; Fluorouracil; Head; Head and Neck Neoplasms; Hodgkin Disease; Humans; Injections, Intra-Arterial; Leg; Melanoma; Melphalan; Methotrexate; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms; Nitrogen Mustard Compounds; Pregnancy; Sarcoma; Sarcoma, Ewing; Skin Neoplasms; Vinblastine; Wilms Tumor

High-risk neuroblastoma is characterized by poor long-term survival, especially for very high-risk (VHR) patients (poor response of metastases after induction therapy). The benefits of a tandem high-dose therapy and hematologic stem cell reinfusion (HSCR) have been shown in these patients. Further dose escalation will be limited by toxicity. It is thus important to evaluate the efficacy and tolerability of the addition of new agents such as I-MIBG (131Iode metaiodobenzylguanidine) to be combined with high-dose therapy in the consolidation phase. We report the feasibility of busulfan/melphalan (BuMel) after I-MIBG therapy with HSCR in patients with refractory or relapsed metastatic neuroblastoma. From November 2008 to March 2015, 9 patients received BuMel after I-MIBG therapy and topotecan. The main toxicity was digestive with only 1 patient developing grade 4 sinusoidal obstructive syndrome. Seven patients are alive at a median follow-up of 25 months. Among them, 2 are in ongoing complete remission and 1 in ongoing stable disease. These results suggest that BuMel with HSCR can be administered safely 2 months after I-MIBG therapy associated with topotecan for VHR patients. This strategy will be compared with tandem high-dose chemotherapy (thiotepa and busulfan-melphalan), followed by HSCR in the upcoming SIOPEN VHR Neuroblastoma Protocol.

Topics: 3-Iodobenzylguanidine; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Female; France; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Neoplasm Metastasis; Neuroblastoma; Risk Factors; Topotecan

In-transit metastases of melanoma occur in 5-8% of all melanoma patients. In case of extensive locoregional disease, Tumor necrosis factor-α and melphalan-based isolated limb perfusion (TM-ILP) had proven to yield excellent local control. Here, we report on repeat TM-ILP for locoregional recurrence after isolated limb perfusion. Between 1991 and 2013, 37 consecutive repeat TM-ILPs were analyzed in 32 different patients. Three patients underwent a third TM-ILP. During a median follow-up of 20 months after repeat TM-ILP, the overall response rate was 86%. Complete response (CR) was recorded after 24 TM-ILPs (65%). CR after first TM-ILP was a strong predictor for successful repeat TM-ILP in terms of clinical response and local recurrence. Local toxicity was mild (70% Wieberdink I-II). The local recurrence rate was 59%. Five-year overall survival was 35%. Repeat TM-ILP is a safe treatment modality in melanoma patients with recurrent in-transit metastases of melanoma. Those with a CR after first TM-ILP benefit the most from repeat TM-ILP.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Drug Administration Schedule; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Skin Neoplasms; Tumor Necrosis Factor-alpha

The 5-year overall survival rate of patients undergoing complete surgical resection of pulmonary metastases (PM) from colorectal cancer (CRC) and sarcoma remains low (20-50%). Local recurrence rate is high (48-66%). Isolated lung perfusion (ILuP) allows the delivery of high-dose locoregional chemotherapy with minimal systemic leakage to improve local control.. From 2006 to 2011, 50 patients, 28 male, median age 57 years (15-76), with PM from CRC (n = 30) or sarcoma (n = 20) were included in a phase II clinical trial conducted in four cardiothoracic surgical centers. In total, 62 ILuP procedures were performed, 12 bilaterally, with 45 mg of melphalan at 37°C, followed by resection of all palpable PM. Survival was calculated according to the Kaplan-Meier method.. Operative mortality was 0%, and 90-day morbidity was mainly respiratory (grade 3: 42%, grade 4: 2%). After a median follow-up of 24 months (3-63 mo), 18 patients died, two without recurrence. Thirty patients had recurrent disease. Median time to local pulmonary progression was not reached. The 3-year overall survival and disease-free survival were 57% ± 9% and 36% ± 8%, respectively. Lung function data showed a decrease in forced expiratory volume in 1 second and diffusing capacity of the alveolocapillary membrane of 21.6% and 25.8% after 1 month, and 10.4% and 11.3% after 12 months, compared with preoperative values.. Compared with historical series of PM resection without ILuP, favorable results are obtained in terms of local control without long-term adverse effects. These data support the further investigation of ILuP as additional treatment in patients with resectable PM from CRC or sarcoma.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Alkylating; Bone Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Combined Modality Therapy; Female; Humans; Lung Neoplasms; Male; Melphalan; Metastasectomy; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Osteosarcoma; Survival Rate; Young Adult

High-dose chemotherapy (HDC) followed by autologous stem cell rescue (ASCR) is the only curative treatment for metastatic retinoblastoma, but its feasibility in developing countries is unknown. We report 11 consecutive children (six unilateral) treated in three South-American middle-income countries with HDC-ASCR. One patient had metastatic retinoblastoma at diagnosis and the remaining ones had a metastatic relapse. Metastatic sites included BM=6, bone=4, orbit=5 and central nervous system (CNS)=4. All patients received induction with conventional chemotherapy achieving CR at a median of 5.7 months from the diagnosis of metastasis. Conditioning regimens included carboplatin and etoposide with thiotepa in six or with CY in four or melphalan in one patient. All patients engrafted after G-CSF-mobilized peripheral blood ASCR and no toxic deaths occurred. Two children received post-ASCR CNS radiotherapy. Seven children have disease-free survival (median follow-up 39 months). CNS relapse, isolated (n=3) or with systemic relapse (n=1), occurring at a median of 7 months after ASCT was the most common event. In the same period, five children with metastatic retinoblastoma did not qualify for HDC-ASCR and died. We conclude that HDC-ASCR is a feasible and effective treatment for children with metastatic retinoblastoma in middle-income countries.

Topics: Antineoplastic Agents; Carboplatin; Child, Preschool; Etoposide; Female; Humans; Infant; Male; Melphalan; Neoplasm Metastasis; Retinoblastoma; South America; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous

Patients with high-risk locally advanced/inflammatory and oligometastatic (≤3 sites) breast cancer frequently relapse or experience early progression. High-dose chemotherapy combined with peripheral stem cell rescue may prolong progression-free survival/relapse-free survival (PFS/RFS) and overall survival (OS). In this study, patients initiated high-dose chemotherapy with STAMP-V (carboplatin, thiotepa, and cyclophosphamide), ACT (doxorubicin, paclitaxel, and cyclophosphamide), or tandem melphalan and STAMP-V. Eighty-six patients were diagnosed with locally advanced/inflammatory (17 inflammatory) breast cancer, and 12 were diagnosed with oligometastatic breast cancer. Median follow-up was 84 months (range, 6-136 months) for patients with locally advanced cancer and 40 months (range, 24-62 months) for those with metastatic cancer. In the patients with locally advanced cancer, 5-year RFS and OS were 53% (95% CI, 41%-63%) and 71% (95% CI, 60%-80%), respectively, hormone receptors were positive in 74%, and HER2 overexpression was seen in 23%. In multivariate analysis, hormone receptor-positive disease and lower stage were associated with better 5-year RFS (60% for ER [estrogen receptor]/PR [progesterone receptor]-positive versus 30% for ER/PR-negative; P < .01) and OS (83% for ER/PR-positive versus 38% for ER/PR-negative; P < .001). In the patients with metastatic cancer, 3-year PFS and OS were 49% (95% CI, 19%-73%) and 73% (95% CI, 38%-91%), respectively. The favorable long-term RFS/PFS and OS for high-dose chemotherapy with peripheral stem cell rescue in this selected patient population reflect the relative safety of the procedure and warrant validation in defined subgroups through prospective, randomized, multi-institutional trials.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Female; Humans; Inflammatory Breast Neoplasms; Melphalan; Middle Aged; Neoplasm Metastasis; Paclitaxel; Peripheral Blood Stem Cell Transplantation; Survival Analysis; Thiotepa; Treatment Outcome

We evaluated the feasibility and efficacy of a reduced-intensity conditioning (RIC) regimen of fludarabine and melphalan to achieve rapid complete donor chimerism after allogeneic stem cell transplantation (SCT) in patients with metastatic solid tumors. Between January 1999 and January 2003, 8 patients with metastatic breast cancer (BC) and 15 with metastatic renal cell carcinoma (RCC) underwent allogeneic SCT after an RIC regimen of 5 days of fludarabine and 2 days of melphalan. Filgrastim-mobilized stem cells from HLA-identical related or unrelated donors were infused. Prophylaxis for graft-versus-host disease (GVHD) consisted of tacrolimus and methotrexate. All 22 evaluable patients had 100% donor chimerism at day 30 and at all measurement times thereafter. One patient died 19 days after SCT. Nine patients (39%) had grades II to IV acute GVHD and 10 patients (43%) had chronic GVHD. Five patients (22%) died of nonrelapse treatment-related complications. Treatment-related disease response was seen in 10 patients (45%), with 3 complete responses, 2 partial responses, and 5 minor responses. Fludarabine-melphalan is a feasible and effective RIC regimen for allogeneic SCT in metastatic BC and RCC. It induces rapid complete donor chimerism without the need for donor lymphocyte infusion. Tumor regression associated with GVHD is consistent with graft-versus-tumor effect.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Renal Cell; Female; Graft vs Host Disease; Graft vs Tumor Effect; Humans; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Peripheral Blood Stem Cell Transplantation; Remission Induction; Transplantation Chimera; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

Although high-dose chemotherapy (HDC) with stem cell rescue for the treatment of women with metastatic breast cancer (MBC) is currently a controversial strategy, we report the long-term outcomes of women undergoing high-dose therapy for MBC over the past 12 years while participating in a sequence of research studies transitioning between a single to a double intensification approach. Univariate and multivariate analyses provide a framework to understand the prognostic factors important for event-free and overall survival. Between May 1988 and April 1998, we enrolled 188 women with MBC into 3 trials of previously reported sequential transplantation strategies. Trial I (long induction/single transplantation) accepted 62 women in partial or complete response to an unspecified induction therapy and treated them with high-dose CTCb (cyclophosphamide, thiotepa, and carboplatin) supported by marrow or peripheral blood progenitor cells (PBPC). Trial II (long induction/double transplantation) accepted 68 women in partial or complete response to an unspecified induction therapy, and mobilized stem cells with 2 cycles of AF (doxorubicin and 5-fluorouracil) with granulocyte colony-stimulating factor (G-CSF). These women then received 1 cycle of high-dose single-agent melphalan followed 3 to 5 weeks later by CTCb, each with marrow or PBPC support. Trial III (short induction/double transplantation) enrolled 58 women prior to chemotherapy treatment for metastatic disease. Induction/mobilization consisted of 2 cycles given 14 days apart of doxorubicin and G-CSF. In contrast to trials I and II, patients with stable disease or better response to induction were eligible to proceed ahead with 2 cycles of HDC, 1 being CTCb and the other being dose escalated paclitaxel together with high-dose melphalan (TxM). These 2 HDC regimens were administered 5 weeks apart. TxM was given first in 32 patients and CTCb was given first in 26 patients. The median follow-up periods for trials I, II, and III were 98, 62, and 39 months from the initiation of induction chemotherapy and 92, 55, and 36 months from last high-dose therapy, respectively. The patient characteristics upon entry into these trials were similar. Important differences were that only those patients achieving a partial response or better to induction therapy were enrolled and analyzed for trials I and II, but all patients were analyzed on an intent-to-treat basis for trial III, including those who did not receive intensificat

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Carcinoma; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Estrogens; Female; Fluorouracil; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Life Tables; Melphalan; Methotrexate; Middle Aged; Multivariate Analysis; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Paclitaxel; Peripheral Blood Stem Cell Transplantation; Progesterone; Prognosis; Proportional Hazards Models; Remission Induction; Survival Analysis; Thiotepa; Time Factors; Treatment Outcome

Unresectable colorectal liver metastases are a significant clinical problem. Isolated hepatic perfusion (IHP) is a regional treatment technique that delivers high dose chemotherapy, biologic agents, and hyperthermia via a completely isolated vascular recirculating perfusion circuit as a means of regionally treating liver tumors. This study presents our results of IHP with tumor necrosis factor (TNF) plus melphalan or IHP with melphalan alone followed by infusional floxuridine (FUDR) and leucovorin in patients with advanced or refractory unresectable hepatic colorectal metastases.. Fifty-one patients with unresectable colorectal hepatic metastases underwent a 60-minute IHP with 1.5 mg/kg melphalan and hyperthermia (39 degrees C to 40 degrees C). Thirty-two patients received IHP with 1 mg TNF with melphalan and 19 patients had IHP with melphalan alone followed by monthly hepatic intra-arterial infusional (HAI) FUDR (0.2 mg/kg/day) and leucovorin (15 mg/M(2)/day) for 14 days monthly for up to 12 months. Twenty-six patients failed 1 or more previous treatment regimens for established hepatic metastases and 27 had greater than 25% hepatic replacement (PHR) by tumor. Patients were monitored for response, toxicity, and survival.. There was 1 perioperative death (2%), and only 2 patients (4%) had measurable perfusate leak during IHP (both less than 4%). In the 32 patients treated with IHP alone there were no detectable systemic TNF or melphalan levels during perfusion. The overall objective radiographic response rate (all partial [PR]) was 76% (38 of 50 assessable patients) with a median duration of 10.5 months (range, 2 to 21 months). Twenty-four of 31 patients (77%) had a PR after IHP alone and 14 of 19 (74%) after IHP with postperfusion HAI. Median duration of response was 8.5 months after IHP alone and 14.5 months after IHP and HAI; median survival was 16 and 27 months, respectively. There were 18 PRs in 26 patients (69%) whose prior therapy had failed and 18 PRs in 27 patients (67%) with PHR of 25 or greater.. IHP can be performed with acceptably low morbidity and has significant antitumor activity in patients with unresectable hepatic metastases from colorectal cancer including those with refractory disease or PHR of 25 or greater. HAI appears to prolong the duration of response after IHP, and this combined treatment strategy deserves additional clinical evaluation as a therapeutic modality in this setting.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Floxuridine; Humans; Hyperthermia, Induced; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Radiography; Survival Analysis; Tumor Necrosis Factor-alpha

To determine whether consolidation therapy with high-dose melphalan, etoposide, and total-body irradiation (TBI) with autologous stem-cell support would improve the prognosis for patients with newly diagnosed metastatic Ewing's sarcoma (ES).. Thirty-two eligible patients with newly diagnosed ES metastatic to bone and/or bone marrow were enrolled onto this study. Treatment was initially comprised of five cycles of induction chemotherapy (cyclophosphamide, doxorubicin, and vincristine alternating with ifosfamide and etoposide) and local control. Peripheral-blood stem-cell collection was performed after the second cycle of chemotherapy, with delay if the bone marrow was persistently involved. If patients had a good response to initial therapy, they proceeded to consolidation therapy with melphalan, etoposide, TBI, and stem-cell support.. Of the 32 eligible patients, 23 proceeded to high-dose therapy consolidation. Of the nine patients who did not proceed to consolidation, four were secondary to progressive disease and two were secondary to toxicity. Three patients died from toxicity during the high-dose phase of the therapy. The majority of the patients who underwent high-dose consolidation therapy experienced relapse and died with progressive disease. Two-year event-free survival (EFS) for all eligible patients is 20%. The 2-year post-stem-cell reconstitution EFS for the subset of 23 patients who received consolidation therapy is 24%. Analysis of peripheral-blood stem-cell collections by molecular techniques for minimal residual disease showed contamination of at least some samples by tumor cells in all three patients with available data.. Consolidation with high-dose melphalan, etoposide, TBI, and autologous stem-cell support failed to improve the probability of EFS in this cohort of patients with newly diagnosed metastatic ES.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Child, Preschool; Disease Progression; Dose-Response Relationship, Drug; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Melphalan; Neoplasm Metastasis; Prognosis; Sarcoma, Ewing; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation

Two cycles of high-dose chemotherapy with stem cell support (HDC) may increase the total dose delivered and dose intensity. A brief induction phase and different non-cross-resistant agents for each HDC cycle were used to avoid drug resistance. Twenty-six women with metastatic BC had induction and stem cell mobilization with two cycles of doxorubicin/G-CSF given every 14 days. Patients with stable disease or better after induction received HD CTCb followed by HD melphalan and dose-escalated paclitaxel. At 475 mg/m(2) of paclitaxel by 24-h infusion, dose-limiting transient peripheral sensory neuropathy was encountered. No toxic deaths occurred. Complete and near complete response after completion of therapy was achieved in 22 (85%) of 26 patients. The median EFS was 38 months. The median OS has not yet been reached. At a median follow-up of 33 (25-43) months, actuarial EFS and OS were 54% (95% confidence interval (CI), 39-69%) and 69% (95% CI, 56-79%), respectively. This double transplant approach lasts only 14 weeks and is feasible, safe, and tolerable. Whilst selection biases may in part contribute to favorable EFS and OS, a randomized comparison of standard therapy vs double transplant in both metastatic and locally advanced breast cancer is warranted.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Paclitaxel; Remission Induction; Survival Rate; Treatment Failure; Treatment Outcome

This study was designed to estimate the partial and complete response rates (CR and PR) of two novel drug pairs (vincristine and melphalan vs. ifosfamide and etoposide) and to improve overall survival of previously untreated patients with metastatic rhabdomyosarcoma.. One hundred twenty-eight patients were randomly assigned to phase II window therapy consisting of vincristine and melphalan (VM-containing regimen) or ifosfamide and etoposide (IE-containing regimen). Brief window therapy (12 wks) was immediately followed-up by vincristine, dactinomycin, and cyclophosphamide (VAC), chemotherapy, surgery, and irradiation, with continuation of either VM or IE in patients with initial response. Major endpoints were initial CR and PR rates after the phase II window phase of therapy, failure-free survival (FFS), and survival.. Patients who received the VM-containing regimen experienced significantly more anemia, neutropenia, thrombocytopenia, and had more cyclophosphamide dose reductions. The initial PR and CR rates were not significantly different for patients treated with either regimen (VM, 74%; IE, 79%; P = 0.428). However, FFS and overall survival (OS) at 3 years were significantly better with the IE-containing regimen (FFS: 33% vs. 19%; P = 0.043; OS: 55% vs. 27%; P = 0.012).. Although the VM-containing regimen produced a high response rate, inclusion of melphalan appeared to limit the cyclophosphamide dose that could be administered, and ultimately, this regimen was associated with a significantly worse outcome than was the IE-containing regimen. Also, the IE-containing regimen was associated with a gratifyingly high survival rate at 3 years (55%), which is significantly higher than has been observed on any previous Intergroup Rhabdomyosarcoma Study Group regimen for similar patients. We believe that this promising outcome indicates that this drug pair merits further randomized testing in metastatic rhabdomyosarcoma.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bronchiolitis Obliterans; Chemotherapy, Adjuvant; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Dactinomycin; Disease-Free Survival; Etoposide; Female; Follow-Up Studies; Humans; Ifosfamide; Infant; Kidney Diseases; Life Tables; Male; Melphalan; Neoplasm Metastasis; Radiotherapy, Adjuvant; Remission Induction; Rhabdomyosarcoma; Sepsis; Soft Tissue Neoplasms; Survival Analysis; Treatment Outcome; Vincristine

We report hereby the results of the french multicentric randomized PEGASE 04 protocol established to evaluate the impact on survival of high-dose chemotherapy over conventional chemotherapy for MBC patients.. Inclusion criteria were: age < or = 60 year, PS < 2, adenocarcinoma initially metastatic or in first relapse, chemosensitive disease. Randomization was done after 4-6 courses of conventionnal chemotherapy between high-dose (Mitoxantrone, 45 mg/m2, Cyclophosphamide: 120 mg/kg, Melphalan: 140 mg/m2), and the pursuit of the same conventionnal chemotherapy. Between 09/92 and 12/96, 61 chemosensitive patients were enrolled: 29 were referred to standard chemotherapy, 32 to intensive therapy. At randomization, 13 pts (21.3%) were in complete response and 48 in partial response.. The median progression-free survivals were 20 and 35.3 months in the standard and intensive groups (p=0.06). The relapse rates were respectively 79.3% vs 50.8% at 3 years and 90.8% vs 90.7% at 5 years. The median overall survivals were 20 and 43.4 months, with an overall survival rate of 18.5% vs 29.8% at 5 years (p=0.12).. The CMA regimen could prolong the progression-free survival of MBC patients, however without any significant impact on overall survival.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Female; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Remission Induction; Survival Analysis; Transplantation, Autologous

Dose-intensive chemotherapy appears to be important in the treatment of patients with recurrent solid tumors. Expanding upon our prior experience, we report the results of our most recent approach to administering dose-intensive therapy using four cycles of moderately high-dose chemotherapy with hematopoietic cell support for patients with metastatic breast cancer. This outpatient therapy includes high-dose melphalan, thiotepa, and paclitaxel for two cycles followed by mitoxantrone, thiotepa, and paclitaxel for two cycles, with each cycle supported with autologous peripheral blood progenitor cells (PBPCs). Between December 1994 and June 1996, 16 patients with recurrent or refractory breast cancer were enrolled in this prospective study. They had received a median of two previous chemotherapy regimens, with a median of nine prior cycles of chemotherapy. For mobilization of autologous PBPCs, patients received cyclophosphamide, 4 g/m2, followed by granulocyte colony-stimulating factor (G-CSF). PBPCs were collected by apheresis. Each day's collection was divided into four equal fractions, and each fraction was infused after each cycle of combination therapy. Cycles 1 and 2 consisted of melphalan, 80 mg/m2, thiotepa, 300 mg/m2, and paclitaxel, 200 mg/m2. Cycles 3 and 4 were comprised of mitoxantrone, 30 mg/m2, and thiotepa and paclitaxel at the same doses as in the first two cycles. The cyclophosphamide infusion was administered in the hospital, whereas all subsequent infusions of chemotherapy and PBPCs were performed on an outpatient basis. The first seven patients were randomized to receive alternate cycle G-CSF or placebo on day +1 of each cycle. Including the initial pulse of cyclophosphamide, 67 (84%) of a planned 80 total courses of chemotherapy were delivered. Of the planned 64 cycles of high-dose combination chemotherapy, 52 cycles (81%) were delivered. Treatment was discontinued for progressive disease (one patient) or morbidity (five patients). Twelve of 16 patients completed at least three cycles of therapy. Nine patients completed all four cycles. One death resulted from fungal sepsis. In 20 cycles delivered to the first seven patients, day +1 G-CSF versus placebo was administered, with a median WBC recovery of 10 versus 13 days, respectively (P = 0.048 in cycle 1). The median duration of response was almost 9 months, and the median survival was 18 months after therapy. With a median follow-up of 1.5 years and longest follow-up of 4.2 years, two pa

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Feasibility Studies; Female; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Paclitaxel; Recurrence; Thiotepa; Transplantation, Autologous; Treatment Outcome

Sequential high-dose chemotherapy may increase the threshold dose of CD34+ cells necessary for rapid and successful hematologic recovery. There are limited data regarding the pharmacodynamics and threshold CD34+ cell dose required for engraftment following high-dose paclitaxel. To determine the dose of CD34+ PBPC sufficient for rapid engraftment, 65 women with metastatic breast cancer undergoing a sequential high-dose paclitaxel, melphalan, and cyclophosphamide, thiotepa, and carboplatin (CTCb) chemotherapy regimen were evaluated. The intertreatment interval was a median of 27 days. Paclitaxel was escalated from 400 to 825 mg/m2, infused continuously (CI) over 24 h on day -4 with PBPC reinfusion on day 0. Following marrow recovery, 90 mg/m2/day of melphalan was given over 30 min on days -2 and -1, with PBPC reinfusion on day 0. On recovery, patients received CTCb on days -7 to -3, with PBPC reinfusion on day 0. G-CSF was administered after each cycle until WBCC recovery. For paclitaxel, an ANC >0.5 x 10(9)/L occurred at a median of 6 days (range 0-7 days) after PBPC reinfusion. The median nadir platelet count was 63 x 10(9)/L (range 6 x 10(9)/L-176 x 10(9)/L). Eight patients (12%) had platelet nadir <20 x 10(9)/L, and all recovered their counts to >20 x 10(9)/L on day 7. There was no clinical difference in days to engraftment between women receiving <2 or > or =2 x 10(6) CD34+ PBPC/kg following paclitaxel. All patients recovered neutrophil and platelet counts within 7 days after reinfusion of > or =1 x 10(6) CD34+ cells/kg and G-CSF. The data suggest that a paclitaxel dose of 825 mg/m2 is not myeloablative. For melphalan, median days to ANC >0.5 x 10(9)/L was 10 days (range 9-15), and platelet recovery to >20 x 10(9)/L was 13 days (range 0-28) after PBPC reinfusion. Median time to engraftment was more rapid in patients receiving > or =2 x 10(6) CD34+/kg versus <2 x 10(6)CD34+/kg, for both neutrophils (11 days versus 10 days, p = 0.05) and platelets (14 days versus 12 days, p < 0.01). Ninety-eight percent of patients infused with > or =2 x 10(6) CD34+/kg engrafted within 21 days. Following CTCb in this sequential regimen, a dose of > or =2 x 10(6) CD34+ cells/kg provided for significantly more rapid neutrophil engraftment than <2 x 10(6) CD34+ cells/kg (9 days versus 10 days,p = 0.01), but a dose > or =3 X 10(6) CD34+ cells/kg is necessary for reliable, rapid, and sustained neutrophil and platelet engraftment by day 21.

Topics: Adult; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Breast Neoplasms; Carboplatin; Combined Modality Therapy; Cyclophosphamide; Female; Graft Survival; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Paclitaxel; Thiotepa; Transplantation, Autologous

To determine the maximum-tolerated dose (MTD) of cyclophosphamide (CTX) when administered with fixed doses of carboplatin, etoposide, and melphalan (CEM) followed by autologous hematopoietic stem-cell transplantation (HSCT) in children with recurrent or high-risk solid tumors as a consolidation chemotherapy, and to make preliminary observations on efficacy.. Twenty-seven patients with solid tumors between the ages of 2 and 21 years were enrolled. Twenty of 27 had recurrent disease, whereas seven were treated in first remission. Nine were treated with melphalan 50 mg/m2/d for 4 days, carboplatin 300 mg/m2/d for 4 days as a continuous infusion (CI), and etoposide 200 mg/m2/d for 4 days as a CI (level I). CTX 750 mg/m2/d for 4 days was added to this regimen for the next 18 patients (level II). Seven of nine patients at level I and four of 18 at level II received bone marrow (BM) only, while two of nine at level I and 14 of 18 at level II received BM plus peripheral-blood stem cells (PBSC).. The median time to reach an absolute neutrophil count (ANC) greater than 500/microl was 12.5 and 10 days for patients who received BM only and BM plus PBSC, respectively. Three cases of grade 3 mucositis, one Candida sepsis, and two transient hypoxemias were the main nonfatal toxicities. No toxic mortality was observed among level I patients. Three of 18 (16%) level II patients, all in second CR, died of transplant-related complications. Median follow-up is 29 months. Nine died of progressive disease (one second malignancy), six relapsed and are alive with disease, and nine are in continuous CR. Among the 15 PNET/Ewing's sarcoma patients, seven are in continuous CR (three of nine in second CR/VGPR, four of six in first CR/VGPR).. The addition of CTX 3 g/m2 to CEM followed by autologous HSCT as a consolidation therapy resulted in 16% toxic mortality in children with recurrent or high-risk solid tumors. Further CTX dose escalation was aborted. No common nonhematologic toxicity was identified. The event-free survival (EFS) of 66% +/- 19% at 3 years for patients with metastatic PNET/Ewing's sarcoma in first remission is encouraging. However, this is based on only six patients. Both level I and II need further exploration in high-risk pediatric solid tumors in first remission.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carboplatin; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Drug Administration Schedule; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Neoplasm Metastasis; Neoplasm Recurrence, Local; Survival Analysis; Transplantation, Autologous

The acute-phase response and anaemia of chronic disease are characterized by hypoferraemia associated with an increased ferritin synthesis, which might be mediated by the activated cytokine cascade.. We examined the prolonged effects of isolated limb perfusion (ILP) with recombinant human tumour necrosis factor alpha (rTNF), recombinant human interferon gamma (rIFN-gamma) and melphalan on interleukin (IL) 6 and acute-phase protein levels, iron status and serum transferrin receptor (sTfR) levels in 12 patients with melanoma or sarcoma. Patients were treated with ILP during 90 min after pretreatment with rIFN-gamma during 2 days.. After ILP, leakage of TNF resulted in systemic peak levels at 3 min followed by an increase in IL-6 with maximum levels at 4h. C-reactive protein (CRP) rose at 4 h to peak levels at day 2, whereas alpha 1-antitrypsin and alpha 1-acid glycoprotein increased to maximum levels at day 3. Albumin and transferrin levels decreased after ILP and recovered after day 2. Serum iron and sTfR levels decreased during pretreatment and after ILP to minimum levels at 8 h and day 1 respectively. This was associated with an increase in serum ferritin levels, which paralleled CRP values.. Our data point to a central role for the cytokine network in the modulation of iron metabolism in the acute-phase response and anaemia of chronic disease. TNF, possibly via induction of IL-6, and IFN-gamma induce hypoferraemia, which may in part result from a decrease in tissue iron release based on a primary stimulation of ferritin synthesis. The fall in sTfR levels may reflect an impaired erythroid growth and/or TfR expression mediated by TNF and IFN-gamma.

Topics: Acute-Phase Proteins; Adult; Aged; alpha 1-Antitrypsin; Anemia; C-Reactive Protein; Chemotherapy, Cancer, Regional Perfusion; Female; Ferritins; Humans; Interferon-gamma; Interleukin-6; Iron; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Orosomucoid; Receptors, Transferrin; Recombinant Proteins; Sarcoma; Serum Albumin; Time Factors; Transferrin; Tumor Necrosis Factor-alpha

Dose-intensive treatment followed by ABMT is currently used in different approaches to treat breast cancer patients. An active non cross-resistant regimen combining cyclophosphamide (C), mitoxantrone (M) and melphalan (A) (CMA), was developed as the conditioning regimen before ABMT. The purpose of this phase II study was to evaluate this protocol and the duration of its effect in metastatic patients, who responded to chemotherapy. Criteria for inclusion included histologically documented breast cancer, age < 55 years and the first detection of measurable metastatic lesions. Following first-line chemotherapy in responding patients, histologically negative bone marrow was collected and cryopreserved. Then, intensification with cyclophosphamide (120 mg/kg), mitoxantrone (60 mg/m2), and melphalan (140 mg/m2) was followed by ABMT. Sixty-one metastatic breast cancer patients with a mean age of 40 years were included. Sites of measurable metastases included: liver 24, lung 14, central nervous system four, pleura three, skin six, and chest wall six, nodes eight and bone marrow one. Nineteen patients had lesions in two or more sites, and 22 had bone involvement. The response of 60 patients could be evaluated: before ABMT 31 were in clinical complete response (CR), 22 in partial response > 50% (PR), and seven had new progression. After ABMT, 36 patients were in CR, 16 in PR, one progressed and one was stable. Seven (11.5%) toxic deaths occurred. Mean time for hematological recovery was 32.5 days, without hematopoietic growth factors. Median survival was 33 +/- 9.4 months from the start of therapy, and 25.7 +/- 4.6 months from the date of ABMT. Median event-free survival was 20 months from the start of therapy, and 13 +/- 2 months from ABMT. With a median follow-up of 51 months, probability of actuarial survival, measured from the beginning of initial chemotherapy, was 36%, and event-free survival was 18%. In metastatic breast cancer responding to chemotherapy, high-dose consolidation with CMA and ABMT resulted in a median survival of 33 months. These results lay the ground work for evaluation in a randomized trial in metastatic breast cancer.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Melphalan; Middle Aged; Mitoxantrone; Neoplasm Metastasis

High-dose chemotherapy produces high complete remission (CR) rates and some survival advantage in patients with metastatic breast cancer (BC). A current issue is the possibility that these patients may have an even better prognosis with multiple high-dose treatments. In this study, we evaluated the feasibility of a four-step, high-dose sequential chemotherapy (HDSC) with double autologous hematopoietic progenitor-cell rescue. We also tested the hypothesis that peripheral-blood progenitor cells (PBPCs) harvested following a single recruitment with cyclophosphamide (CY) and granulocyte-macrophage colony-stimulating factor (GM-CSF) allow the safe administration of the whole HDSC with closely timed repeated courses of several non-cross-resistant agents.. The treatment plan included CY 7 g/m2, followed by GM-CSF 5 to 7 micrograms/kg/d administered by continuous intravenous (i.v.) infusion on days 2 to 14; PBPCs with or without bone marrow (BM) harvest; mitoxantrone (NOV) 60, 75, or 90 mg/m2 plus melphalan (L-PAM) 140 to 180 mg/m2 with hematopoietic rescue; methotrexate (MTX) 8 g/m2 plus vincristine (VCR) 1.4 mg/m2; and etoposide (VP-16) 1.5 g/m2 plus carboplatin (PP) 1.5 g/m2 with hematopoietic rescue.. All 15 patients enrolled completed the entire treatment and there were no toxic deaths. Hematologic reconstitution was good at each step. The median number of days with an absolute neutrophil count (ANC) less than 100/microL and platelet count less than 20,000/microL were 8 and 3, respectively, after NOV plus L-PAM, and 7 and 4, respectively, after VP-16 plus PP. The main non-hematologic toxicity was mucositis, while organ toxicity was mild and reversible.. This regimen is feasible, with acceptable toxicity. GM-CSF and PBPCs have a pivotal role, as they hasten hematologic reconstitution, abate toxicity, and allow rapid recycling.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Combined Modality Therapy; Cyclophosphamide; Etoposide; Feasibility Studies; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Methotrexate; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Neutropenia; Remission Induction; Thrombocytopenia; Vincristine

The analysis was undertaken to determine if the time to progression and survival for women with breast cancer treated with high-dose chemotherapy after a conventional-dose induction therapy differs significantly for women younger and older than 40 years of age. All patients treated in phase II or III protocols of high-dose chemotherapy for breast cancer are included in this analysis. Women were treated on one of six protocols: four sequential phase II protocols for metastatic breast cancer involving cyclophosphamide at a dose of 6000 mg/m2, thiotepa at 500 mg/m2, and carboplatin at 800 mg/m2 (CTCb) chemotherapy; one phase II study of CTCb chemotherapy for stage III or inflammatory breast cancer; and a Cancer and Leukemia Group B phase III study of cyclophosphamide, carmustine, and cisplatin for women with more than 10 involved lymph nodes after primary therapy. Eligibility criteria for the patients with metastatic disease included histologically documented breast cancer, at least a partial response to conventional dose therapy, no prior pelvic radiotherapy, cumulative doxorubicin of less than 500 mg/m2, and physiologic age of 18-55 years. Patients with inadequate renal, hepatic, pulmonary, and cardiac function or tumor involvement of marrow or central nervous system were excluded. Of 99 registered patients, three (3%) died of toxicity. There were no toxic deaths in protocols for stage II and III disease, and to date none of these patients have relapsed. Thus, there are no differences by age for these studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bone Marrow Transplantation; Breast Neoplasms; Carboplatin; Carmustine; Cyclophosphamide; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Salvage Therapy; Survival Analysis; Thiotepa; Treatment Outcome

Topics: Aged; Drugs, Investigational; Female; Humans; Infusions, Intravenous; Kidney Neoplasms; Male; Melphalan; Middle Aged; Neoplasm Metastasis

MMM (mitomycin 7-8 mg/m2 i.v.) every 6 weeks; mitoxantrone 7-8 mg/m2 i.v. every 3 weeks; methotrexate 35 mg/m2 i.v. every 3 weeks) is a new combination chemotherapy regimen for advanced breast cancer. It has been compared in two complementary randomized trials with CMF (cyclophosphamide 100 mg orally, days 1-14; methotrexate 35 mg/m2 i.v. days 1 and 8; 5-fluorouracil 1 g i.v. days 1 and 8; courses repeated at 28-day intervals) and VAC (vincristine 1.4 mg/m2 every 3 weeks, anthracycline 30 mg/m2 every 3 weeks, cyclophosphamide 400 mg/m2 every 3 weeks) in patients with advanced metastatic breast cancer. In the first trial, which involved 227 patients, 53% of patients receiving MMM and 49% receiving VAC responded to treatment. There was no significant difference between treatment groups in median response duration or survival. Incidence of neuropathy, alopecia, and nausea and vomiting was significantly higher in patients receiving VAC. Hematologic toxicity was greater in the MMM group. In the second trial, which involved 120 patients, 51% of patients receiving MMM and 60% receiving CMF responded to treatment. Again, there was no significant difference between treatment groups in median response duration or survival. Both regimens were well tolerated with a low incidence of alopecia and serious nausea and vomiting, and there were no significant differences in toxicity. Significant reductions in serial left ventricular ejection fractions occurred in 4 patients given CMF and in 2 given MMM. MMM is an effective, well-tolerated regimen for advanced breast cancer, with toxicity similar to that of CMF and less than that of an anthracycline-containing regimen.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cisplatin; Cyclophosphamide; Dactinomycin; Female; Fluorouracil; Humans; Melphalan; Menopause; Methotrexate; Middle Aged; Mitomycin; Neoplasm Metastasis; Neoplasm Staging; Vincristine

Studies are described of high-dose therapy in metastatic breast cancer, early stage breast cancer, stage IV neuroblastoma, recurrent or bulky disease testicular cancer and Ewing's sarcoma. The outcome in these subgroups with conventional therapy is described for comparison. The results of these studies suggest that high-dose therapy with autologous marrow support increases the proportion of patients with long-term survival without evidence of disease. Newer supportive care and recurrent high-dose therapy cycles of non-cross resistant regimens may improve outcome further in these diseases and increase the application to more resistant tumors.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Child; Combined Modality Therapy; Cyclophosphamide; Humans; Melphalan; Neoplasm Metastasis; Neoplasms; Neuroblastoma; Prednisone; Prognosis; Remission Induction; Survival Rate; Transplantation, Autologous; Treatment Outcome; Vincristine

Ninety-three patients with stage I primary cutaneous malignant melanoma of the lower limb were treated by wide local excision and hyperthermic isolated regional perfusion with melphalan (L-phenylalanine dihydrochloride) in a prospective non-randomized study between 1976 and 1982. Eighteen patients (19.4%) developed recurrent melanoma. Nine had recurrent regional disease, one with in transit metastases and eight with positive regional nodes. Nine patients developed distant metastases. No patient had locally recurrent disease. This series confirmed the close correlation between tumour microstaging, melanoma recurrence and survival. Seventy-nine per cent of patients were disease-free at 5 years. Males had deeper lesions (mean 4.56 mm) and increased recurrence (33%) than females (mean 3.36 mm and 13%). Superficial spreading melanoma had the most favourable prognosis of the three histological types. Overall survival was 83% (female 86%; males 64%) at 5 years. Significant morbidity occurred in two patients with deep vein thrombosis. Adjuvant therapy using hyperthermic regional perfusion provides improved local and intransit control of limb melanoma.

Topics: Adult; Aged; Biopsy; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials as Topic; Combined Modality Therapy; Female; Humans; Hyperthermia, Induced; Leg; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Prospective Studies; Skin; Skin Neoplasms

Fifty consecutive patients with recurrent and metastatic endometrial carcinoma were treated with melphalan, 5-fluorouracil, and medroxyprogesterone acetate with or without tamoxifen as first-line chemotherapy. The objective response rate was 48%, with 20% complete responses. The estimated median progression-free survival time was only five months (0.5 to 65 months) with estimated two- and five-year progression-free survival rates of 16 and 13%, respectively. The estimated median progression-free survival time was 24 months for complete responders; the progression-free survival times were significantly longer than the survival times (median = four months) for all other patients (P = .0002). Whether or not the addition of cytotoxic chemotherapy to progesterone hormonal therapy for metastatic endometrial carcinoma lengthens survival time is still open to question.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Female; Fluorouracil; Humans; Medroxyprogesterone; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prospective Studies; Random Allocation; Tamoxifen; Thrombocytopenia; Uterine Neoplasms

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Female; Fluorouracil; Humans; Male; Melphalan; Menopause; Methotrexate; Neoplasm Metastasis; Prednisone; Random Allocation; Vincristine

The paper critically reviews major accomplishments achieved with the use of chemotherapy in the treatment of various stages of breast cancer. In spite of innumerable clinical trials, there is no evidence that in advanced breast cancer the addition of more drugs, either in concomitant, sequential or alternating fashion, to known effective combinations, was able to significantly improve the incidence and the magnitude of objective response or its median duration or survival. The addition of endocrine therapy to chemotherapy has failed so far to improve the most important end-point, i.e. total survival. Second-line chemotherapy is only moderately effective for a fairly short period of time. Thus, in women with advanced breast cancer excessive tumor cell burden and permanent drug resistance remain the major obstacles to obtaining complete remission and long-term disease free survival. In the adjuvant setting, the initial trials with combination chemotherapy have achieved consistent results, particularly in women with minimal axillary node involvement. Unless a woman has undergone a surgical breast-saving procedure, postoperative radiotherapy does not appear to play an important therapeutic role, either with or without concomitant or sequential chemotherapy. Present results would suggest that in advanced breast cancer little progress can be expected in the near future. Therefore, medical oncologists should focus on the correct application of established drug regimens, using a sequential flow of hormonal manipulations and cytotoxic chemotherapy. In high-risk groups, full dose adjuvant polydrug therapy given for a relatively short period of time appears to be at present the only means able to significantly decrease the failure rate following local regional treatment. Present consistent achievements, which appear devoid of important delay morbidity (e.g. cancerogenesis, chronic organ damage) will require further clinical research to identify more effective and less toxic treatments.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Prognosis; Receptors, Estrogen; Research Design

Topics: Adult; Aged; Clinical Trials as Topic; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fluorouracil; Humans; Infusions, Parenteral; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Rectal Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Neoplasm Metastasis; Time Factors

The purpose of this study was to determine the efficacy of single and multiple drug chemotherapeutic regimens in the treatment of patients with advanced or recurrent, Stage III and IV, ovarian epithelial carcinoma. Patients were randomly assigned to one of four treatment regimens postoperatively, or at the time of recurrence: Regimen I--Melphalan (MEL) 0.2 mg/kg/day for five days every four weeks; regimen II--MEL as in Regimen I plus 5-fluorouracil (FU) 15 mg/kg/day for five days every four weeks; regimen III--MEL and FU as in regimen II plus dactinomycin (AC) 0.5 mg daily for five days every four weeks; and regimen IV--Cytoxan (CY) 7 mg/kg/day, FU 8 mg/kg/day and AC 0.5 mg/day for five days every four weeks. Four hundred and twenty-seven patients were in the study, 314 of whom are evaluable for progression-free interval (PFI), survival, and toxicity: 102 in regimen I, 80 in regimen II, 83 in regimen III, and 49 in regimen IV. Of these, 293 were considered evaluable for response. Because of excessive toxicity, entry of patients to regimen IV was discontinued midway through the study. The overall toxicity was quite high but was most severe in regimen II and IV where 16 toxicity deaths were recorded. The complete and partial response rate with Melphalan alone was 29.2%. This response rate was not enhanced by the addition of FU or FU and AC and not substantially different than the response rate of AC, FU, and CY.

Topics: Cyclophosphamide; Dactinomycin; Drug Therapy, Combination; Erythrocyte Count; Female; Fluorouracil; Humans; Melphalan; Neoplasm Metastasis; Neoplasm Recurrence, Local; Ovarian Neoplasms; Platelet Count; Prognosis; Time Factors

Topics: Antineoplastic Agents; BCG Vaccine; Breast Neoplasms; Carcinoma; Clinical Trials as Topic; Colonic Neoplasms; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Mycobacterium bovis; Neoplasm Metastasis; Postoperative Care; Semustine; Vincristine

The results of chemotherapy in 24 patients with extramedullary plasmacytoma are reported. Complete regressions, including disappearance of monoclonal paraprotein and healing of bone lesions, were seen in 12 of 20 (60%) patients with disseminated disease. Extramedullary plasmacytoma responds better to chemotherapy than myeloma, and treatment should be pursued with vigour until all signs of disease have disappeared. Sensitivity to single-agent chemotherapy may vary, and if treatment fails with one agent, others should be tried.

Topics: Adult; Aged; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Plasmacytoma; Prednisone; Radiography

The addition of levamisole, administered in adjunctive manner between the cycles of conventional high dose chemotherapy in patients with hormone resistant end state breast cancer substantially improved the survival of treated patients. Analysis of this double-blind study in 60 such patients suggests that improvement in remission status and survival is related to better tolerability of such cytotoxic therapy as regards both specific and nonspecific cytotoxicity. This improved tolerability enabled patients to receive higher doses of cytotoxic drugs over a shorter time period resulting in an improved remission rate and ultimate survival.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorouracil; Humans; Levamisole; Melphalan; Menopause; Methotrexate; Middle Aged; Neoplasm Metastasis

The age adjusted death rate for ovarian cancer has remained unchanged for the past 20 years. Recent data obtained by staging ovarian cancer patients with lymphangiography and peritoneoscopy demonstrated that many patients with apparently localized disease actually have occult dissemination within the abdomen. These new staging techniques plus the determination of the histologic grade of anaplasia may permit a more precise determination of a patient's prognosis and therefore better design of therapeutic stategy. Radiotherapeutic techniques are being adapted to attempt to treat some areas of occult disease. Numerous single chemotherapeutic agents are capable of producing objective tumor responses. Preliminary data suggest that combination chemotherapy can increase the objective response rate above that seen with single agents. Longer follow-up is necessary to determine whether combination chemotherapy can prolong survival.

Topics: Alkylating Agents; Altretamine; Antimetabolites, Antineoplastic; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Laparoscopy; Lymphatic Metastasis; Lymphography; Melphalan; Neoplasm Metastasis; Ovarian Neoplasms

Topics: Adenocarcinoma, Mucinous; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leukopenia; Lymphatic Metastasis; Mastectomy; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prospective Studies; Thrombocytopenia

Chemotherapy once relegated to end stage patients has markedly improved with the use of combinations. Response rates with single agents have improved from 15 to 35%, to 50 to 70%, using combinations with an increase in complete response rates to about 25%. A series of four studies completed by the Eastern Cooperative Oncology Group over the past eight years typifies the improvement in response rates achieved by combinations as compared to single agents. Survival gain can be demonstrated for responders vs non-responders; however with current combinations, there is an apparent plateau in response rates (55 to 60%), durations of response (eight months) and survival for responders (18-22 months) as compared to survival of non-responders (six to eight months). Further improvement in response rates may occur by searching for new agents, combining hormonal and immunostimulation with chemotherapy or by sequencing non-crossresistant combinations. However, since most patients with breast cancer present with local or regional disease but go on to die of disseminated cancer, major improvements in survival are most likely to occur by treating this neoplasm as a systemic disease through cobmining effective local therapy with systemic treatments.

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Estrogens, Conjugated (USP); Female; Fluorouracil; Humans; Melphalan; Methotrexate; Neoplasm Metastasis; Prednisone; Vincristine

Topics: Adult; Aged; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Division; Cell Survival; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Lymphatic Metastasis; Mammary Neoplasms, Experimental; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Recurrence; Research Design

A randomized trial of Adriamycin (A) in combination with melphalan (M), (MA therapy), and in combination with M plus cyclophosphamide (C) (MAC therapy), was initiated in 40 evaluable patients with metastatic breast cancer. Twenty-two patients demonstrated an objective response to therapy: 9/20 to the MA regimen, and 13/20 to the MAC regimen. For the 22 responders, median duration of response is not yet achieved for either complete or partial responders, at 10 and 9 months, respectively. The addition of the two alkylating agents to Adriamycin was superior to the single alkylating agent addition, both in total response rate and in completeness of response. Maintenance therapy, after achieving the maximum cumulative dose of Adriamycin, was provided by cyclophosphamide plus methotrexate and 5-fluorouracil (CMF). In 19 patients completing induction and entering maintenance therapy, only one relapse has developed with maximun follow-up at 15 months.

Topics: Adult; Aged; Bone Neoplasms; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Remission, Spontaneous; Skin Neoplasms; Time Factors

A prospective randomized clinical trial was undertaken in 184 patients with metastatic breast carcinoma to compare single drug chemotherapy with L-phenylalanine mustard (L-PAM) and intermittent combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluourouracil (CMF). All patients had not been previously treated with cytotoxic drugs and all had objectively measurable visceral of soft tissue disease. Of the 93 patients who received CMF, 49 (53%) achieved a complete (14 patients) or partial (35 patients) regression of measurable tumor, for a median duration of 25 weeks. Eighteen of the 91 patients (20%) treated with L-PAM responded, for a median duration of 13 weeks. The toxicity was primarily hematologic, and greater in the CMF group, which also received more cycles of therapy because of the higher rate and duration of response. The overall survival of CMF-treated patients was superior to that of the single drug group. The differences were even greater when the patients were subclassified according to the presence of liver involvement or nonambulatory performance status. The superior antitumor effect of CMF over L-PAM suggests that it may be a more effective drug regimen to be used as an adjuvant to primary therapy.

Topics: Adult; Aged; Antineoplastic Agents; Boston; Breast Neoplasms; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Prospective Studies

The therapeutic effects of adriamycin and of melphalan in patients with advanced carcinoma of the ovary were tested in a prospective randomized study. Complete and partial remission occurred in eight of 19 patients treated with adriamycin and in four of 20 patients given melphalan. The difference, however, is not statistically significant. The median duration of complete and partial remissions was slightly longer after treatment with melphalan than with adriamycin. The number of cycles required to produce the initial regression state was less in the patients in the group given adriamycin as compared with those in the group treated with melphalan. No cross resistance was observed between the two drugs. These data indicate that, in patients with carcinoma of the ovary, the therapeutic efficacy of adriamycin is competitive with that of the most effective conventional agents, such as melphalan.

Topics: Adenocarcinoma; Carcinoma; Clinical Trials as Topic; Doxorubicin; Drug Evaluation; Endometriosis; Female; Humans; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Melphalan; Neoplasm Metastasis; Ovarian Neoplasms; Remission, Spontaneous

Topics: Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Melphalan; Methotrexate; Neoplasm Metastasis; Prednisone; Vincristine

Isolated limb infusion (ILI) is used to treat in-transit melanoma metastases confined to an extremity. However, little is known about its safety and efficacy in octogenarians and nonagenarians (ON).. ON patients (≥ 80 years) who underwent a first ILI for American Joint Committee on Cancer seventh edition stage IIIB/IIIC melanoma between 1992 and 2018 at nine international centers were included and compared with younger patients (< 80 years). A cytotoxic drug combination of melphalan and actinomycin-D was used.. Of the 687 patients undergoing a first ILI, 160 were ON patients (median age 84 years; range 80-100 years). Compared with the younger cohort (n = 527; median age 67 years; range 29-79 years), ON patients were more frequently female (70.0% vs. 56.9%; p = 0.003), had more stage IIIB disease (63.8 vs. 53.3%; p = 0.02), and underwent more upper limb ILIs (16.9% vs. 9.5%; p = 0.009). ON patients experienced similar Wieberdink limb toxicity grades III/IV (25.0% vs. 29.2%; p = 0.45). No toxicity-related limb amputations were performed. Overall response for ON patients was 67.3%, versus 64.6% for younger patients (p = 0.53). Median in-field progression-free survival was 9 months for both groups (p = 0.88). Median distant progression-free survival was 36 versus 23 months (p = 0.16), overall survival was 29 versus 40 months (p < 0.0001), and melanoma-specific survival was 46 versus 78 months (p = 0.0007) for ON patients compared with younger patients, respectively.. ILI in ON patients is safe and effective with similar response and regional control rates compared with younger patients. However, overall and melanoma-specific survival are shorter.

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Australia; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Female; Humans; Length of Stay; Lower Extremity; Male; Melanoma; Melphalan; Neoplasm Metastasis; Neoplasm Staging; Neoplasm, Residual; Progression-Free Survival; Skin Neoplasms; Treatment Outcome; Tumor Burden; United States; Upper Extremity

Isolated limb infusion (ILI) is a minimally-invasive procedure for delivering high-dose regional chemotherapy to treat melanoma in-transit metastases confined to a limb. The aim of this international multi-centre study was to identify predictive factors for toxicity and response.. Data of 687 patients who underwent a first ILI for melanoma in-transit metastases confined to the limb between 1992 and 2018 were collected at five Australian and four US tertiary referral centres.. After ILI, predictive factors for increased limb toxicity (Wieberdink grade III/IV limb toxicity, n = 192, 27.9%) were: female gender, younger age, procedures performed before 2005, lower limb procedures, higher melphalan dose, longer drug circulation and ischemia times, and increased tissue hypoxia. No patient experienced grade V toxicity (necessitating amputation). A complete response (n = 199, 28.9%) was associated with a lower stage of disease, lower burden of disease (BOD) and thinner Breslow thickness of the primary melanoma. Additionally, an overall response (combined complete and partial response, n = 441, 64.1%) was associated with female gender, Australian centres, procedures performed before 2005, lower limb procedures and lower actinomycin-D doses. On multivariate analysis, higher melphalan dose remained a predictive factor for toxicity, while lower stage of disease and lower BOD remained predictive factors for overall response.. ILI is safe and effective to treat melanoma in-transit metastases. Predictive factors for toxicity and response identified in this study will allow improved patient selection and optimization of intra-operative parameters to increase response rates, while keeping toxicity low.

Topics: Age Factors; Aged; Aged, 80 and over; Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Australia; Chemotherapy, Cancer, Regional Perfusion; Creatine Kinase; Dactinomycin; Dose-Response Relationship, Drug; Female; Humans; Ischemia; Lower Extremity; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Sex Factors; Skin Neoplasms; Time Factors; Tourniquets; United States; Upper Extremity

To investigate the outcome and safety data of chemosaturation with percutaneous hepatic perfusion (CS-PHP) of melphalan in patients with liver-dominant metastatic uveal melanoma.. This is a HIPAA compliant, IRB approved, retrospective study. A total of 28 CS-PHPs were performed in 16 individual patients (six men and ten women, median age 63.1 years [range 49.1 to 78.7 years], one to six CS-PHP procedures per patient) for treatment of liver-dominant metastatic uveal melanoma between June, 2015 and December, 2018. All patients received cross-sectional imaging at baseline and during follow-up. CS-PHP was performed with the Hepatic CHEMOSAT® Delivery System (Delcath Systems, Inc., NY, USA) facilitating extracorporeal filtration of hepatic blood for melphalan removal. Ideal body weight-adjusted melphalan doses were administered into the hepatic arteries. Serious adverse events (SAE), progression-free survival based on response criteria in solid tumors, and overall survival were noted. Survival data were analyzed using Kaplan-Meier estimates.. Partial response after first CS-PHP was observed in nine patients (60%), stable disease in five patients (33%) and progressive disease in one patient (7%). Median overall survival was 27.4 months (95% CI 4.1 to 35.4 month) after first CS-PHP. Median progression-free survival was 11.1 months after first CS-PHP (95% CI 4.9 to 23.6 months). SAEs were observed in the majority of patients with most SAEs limited to grades one and two. Thirteen SAEs of grades three and four were observed in seven individual patients. No grade five SAE was observed.. CS-PHP is an efficacious and safe treatment for patients presenting with liver-dominant metastatic uveal melanoma.

Topics: Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Liver Circulation; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Uveal Neoplasms

Pelvic Melanoma relapse occurs in 15% of patients with loco regional metastases, and 25% of cases do not respond to new target-therapy and/or immunotherapy. Melphalan hypoxic pelvic perfusion may, therefore, be an option for these non-responsive patients. Overall median survival time (MST), stratified for variables, including BRAF V600E mutation and eligibility for treatments with new immunotherapy drugs, was retrospectively assessed in 41 patients with pelvic melanoma loco regional metastases. They had received a total of 175 treatments with Melphalan hypoxic perfusion and cytoreductive excision. Among the 41 patients, 22 (53.7%) patients exhibited a wild-type

Topics: Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Cohort Studies; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Pelvic Neoplasms; Pelvis; Proto-Oncogene Proteins B-raf; Retrospective Studies; Survival Analysis

Data on isolated limb perfusion (ILP) in elderly melanoma patients are scarce. We aimed to evaluate the efficacy and safety of ILP in our institutional cohort of melanoma patients.. We performed retrospective analysis of stage IIIB/C melanoma patients who underwent ILP for melanoma in-transit metastases (ITMs) in our institution between 2000 and 2016. Normothermic ILP was performed with either melphalan or melphalan and tumor necrosis factor. Baseline and treatment characteristics, locoregional progression-free survival (LPFS) and melanoma-specific survival (MSS) were assessed and prognostic factors for response, recurrence, and survival were analyzed using univariable and multivariable analysis.. Overall, 91 patients were included in this study. Based on the median age of 70 years, we split patients into younger and elderly groups. No differences in response rates were observed between age groups, with an overall response rate of 81% and complete response (CR) rate of 47%. LPFS did not differ between age groups, and median LPFS was 16 months for patients with a CR. Median MSS was 38 months and differed between younger (45 months) and elderly patients (18 months). Toxicity was generally mild and did not differ between age groups. Two patients (2.2%) suffered Wieberdink IV toxicity, while no patients required amputation because of severe toxicity. CR was prognostic for improved LPFS and MSS, while patients >70 years of age and patients with stage IIIC disease had a higher risk of melanoma-specific death.. Because of its safety profile and high CR rates, ILP is a viable option for patients with bulky or multiple melanoma ITMs, including elderly (>70 years of age) patients.

Topics: Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Follow-Up Studies; Humans; Male; Melanoma; Melphalan; Neoplasm Metastasis; Neoplasm Recurrence, Local; Patient Safety; Retrospective Studies; Survival Rate; Treatment Outcome

Cytokines are the communicators of immune system and are involved in all immune responses. The aim of this study was to assess the correlation among plasma cytokines, patient and tumor characteristics, and clinical outcome in chemonaive testicular germ-cell tumor (TGCT) patients.. This study included 92 metastatic chemotherapy-naive TGCT patients treated with platinum-based chemotherapy from July 2010 to March 2014. Plasma was isolated before first administration of chemotherapy, and the concentration of 51 plasma cytokines were analyzed using multiplex bead arrays.. At a median follow-up of 33.2 months (range, 0.1-54.8 months), 10.9% of patients experienced disease progression, and 7.6% died. Several cytokines were associated with different baseline clinicopathologic features. Elevated plasma levels of interferon (IFN)-α2, interleukin (IL)-2Rα, IL-16, hepatocyte growth factor (HGF), and monocyte chemotactic protein (MCP)-3 were significantly associated with worse progression-free survival and overall survival (OS). Moreover, elevated levels of stem-cell growth factor (SCGF)-β were also associated with worse OS. Patients with elevated levels of all 6 cytokines experienced significantly worse outcomes compared to patients who had fewer than 6 cytokines elevated (hazard ratio = 12.06; 95% confidence interval, 7.39-19.49; P = .002 for progression-free survival, and hazard ratio = 39.65; 95% confidence interval, 25.03-62.18; P < .00001 for OS, respectively). Results were independent of International Germ Cell Cancer Collaborative Group criteria.. We found a correlation among progression free-survival, OS, and circulating cytokines in TGCT. This suggests the existence an association between plasma cytokines and baseline clinicopathologic features in TGCT. Plasma cytokines could be used for identification of high-risk patients who are candidates for new therapeutic approaches.

Topics: Cytokines; Disease Progression; Disease-Free Survival; Humans; Immunoglobulin G; Male; Melphalan; Neoplasm Metastasis; Neoplasms, Germ Cell and Embryonal; Organoplatinum Compounds; Prognosis; Prospective Studies; Testicular Neoplasms; Translational Research, Biomedical

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Hodgkin Disease; Humans; Male; Melphalan; Neoplasm Metastasis; Podophyllotoxin; Programmed Cell Death 1 Receptor; Remission Induction; Salvage Therapy

We have studied the feasibility and efficacy of intensified R-MegaCHOP-ESHAP-BEAM therapy in high-risk aggressive B-cell lymphomas. Altogether 105 patients (19-64 years) with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBL) or follicular lymphoma grade 3 (FL3) with an age-adjusted International Prognostic Index of 2-3 were recruited. Treatment consisted of three cycles of high-dose R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), followed by three cycles of R-ESHAP (rituximab, etoposide, methylprednisolone, cytarabine, cisplatin) and high-dose consolidation with BEAM (BCNU, etoposide, cytarabine, melphalan) and autologous stem cell transplant. The 5-year progression-free survival (PFS) was 72% (DLBCL 60%, PMBL 89%) and overall survival (OS) was 74% (DLBCL 61%, PMBL 89%) after a median follow-up of 85 months. However, an independent prognostic factor was age only, with patients ≤ 45 years having 5-year PFS 90% and patients > 45 years having PFS 54%. PMBL had better prognosis than DLBCL/FL3 in patients > 45 years (PFS, 88% vs. 48%), but not in younger patients (PFS, 91% vs. 94%).

Topics: Adult; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cisplatin; Consolidation Chemotherapy; Cyclophosphamide; Cytarabine; Disease Progression; Doxorubicin; Etoposide; Female; Humans; Induction Chemotherapy; Lymphoma, B-Cell; Male; Melphalan; Methylprednisolone; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Podophyllotoxin; Prednisone; Prognosis; Rituximab; Treatment Outcome; Vincristine; Young Adult

L-type amino acid transporter 1 (LAT1), an isoform of amino acid transport system L, transports branched or aromatic amino acids essential for fundamental cellular activities such as cellular growth, proliferation and maintenance. This amino acid transporter recently has received attention because of its preferential and up-regulated expression in a variety of human tumors in contrast to its limited distribution and low-level expression in normal tissues. In this study, we explored the feasibility of using LAT1 inhibitor as a new therapeutic agent for human malignant melanomas (MM) using canine spontaneous MM as a model for human MM. A comparative study of LAT expression was performed in 48 normal tissues, 25MM tissues and five cell lines established from MM. The study observed LAT1 mRNA levels from MM tissues and cell lines that were significantly (P<0.01) higher than in normal tissues. Additionally, MM with distant metastasis showed a higher expression than those without distant metastasis. Functional analysis of LAT1 was performed on one of the five cell lines, CMeC-1. [(3)H]l-Leucine uptake and cellular growth activities in CMeC-1 were inhibited in a dose-dependent manner by selective LAT1 inhibitors (2-amino-2-norbornane-carboxylic acid, BCH and melphalan, LPM). Inhibitory growth activities of various conventional anti-cancer drugs, including carboplatin, cyclophosphamide, dacarbazine, doxorubicin, mitoxantrone, nimustine, vinblastine and vincristine, were significantly (P<0.05) enhanced by combination use with BCH or LPM. These findings suggest that LAT1 could be a new therapeutic target for MM.

Topics: Amino Acids, Cyclic; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dogs; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Large Neutral Amino Acid-Transporter 1; Melanoma; Melphalan; Neoplasm Metastasis; Pilot Projects

Despite recent advances in melanoma therapy, disseminated melanoma still lacks effective treatment, and recurrence of the tumor frequently occurs, even after high-dose chemotherapy. The mechanisms responsible for this chemoresistance or for the formation of new relapses remain poorly understood. Using a human 'model', in which the isolated limb is perfused with high doses of the chemotherapeutic melphalan (ILP), we identified a five-gene set (ATF3, CYR61, IER5, IL6, and PTGS2) of stress-induced genes that was consistently upregulated after ILP in all in-transit metastatic melanoma samples as well as in three melphalan-treated melanoma cell lines. Early post-ILP relapses retained these elevated expressions, whereas the expression of these genes returned to their original levels in late post-ILP recurrences. In addition, we identified upregulation of these genes in the A375 cell line's side population (SP) and melanospheres, established methods to enrich for candidate cancer stem cells (CSCs), which are considered chemoresistant and tumorigenic, and thus proposed to be responsible for tumor relapse. Our data identify an immediate and short-term upregulation of early stress-responsive genes that are potentially linked to chemoresistance and CSCs.

Topics: Aged; Aged, 80 and over; Cell Line, Tumor; Chemotherapy, Cancer, Regional Perfusion; Dose-Response Relationship, Drug; Extremities; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes, Neoplasm; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Oligonucleotide Array Sequence Analysis; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; Side-Population Cells; Skin Neoplasms

The Italian Sarcoma Group and the Scandinavian Sarcoma Group designed a joint study to improve the prognosis for patients with Ewing's family tumors and synchronous metastatic disease limited to the lungs, or the pleura, or a single bone.. The study was opened in 1999 and closed to the enrollment in 2008. The program consisted of intensive five-drug combination chemotherapy, surgery and/or radiotherapy as local treatment, and consolidation treatment with high-dose busulfan/melphalan plus autologous stem cell rescue and total-lung irradiation.. During the study period, 102 consecutive patients were enrolled. The median follow-up was 62 months (range 24-124). The 5-year event-free survival probability was 0.43 [standard deviation (SD) = 0.05] and the 5-year overall survival probability was 0.52 (SD = 0.052). Unfavorable prognostic factors emerging on multivariate analysis were a poor histological/radiological response at the site of the primary tumor [relative risk (RR) = 3.4], and incomplete radiological remission of lung metastases after primary chemotherapy (RR = 2.6). One toxic death and one secondary leukemia were recorded.. This intensive approach is feasible and long-term survival is achievable in ∼50% of patients. New treatment approaches are warranted for patients responding poorly to primary chemotherapy.

Topics: Adolescent; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Etoposide; Female; Humans; Ifosfamide; Lung Neoplasms; Male; Melphalan; Myeloablative Agonists; Neoplasm Metastasis; Prognosis; Sarcoma, Ewing; Stem Cell Transplantation; Vincristine; Young Adult

Three pediatric patients with infratentorial metastatic non-epithelial malignant brain tumors were successfully treated by radical surgical resection followed by aggressive radiochemotherapy. One patient with neuroblastoma and two with rhabdomyosarcoma were successfully treated by first line multimodal treatments, but developed infratentorial metastasis after several months of remission. All patients revealed intracranial metastases manifesting as rapidly progressing neurological symptoms caused by mass effect in the posterior fossa. Radical surgical resection was performed without morbidity. The patients were then treated by adjuvant radiochemotherapy with or without autologous peripheral blood stem cell transplantation, resulting in complete remission. Two patients developed extracranial recurrences 4 months after the treatments for intracranial metastases. One patient was treated by second high-dose chemotherapy with allogeneic cord blood transplantation, again resulting in complete remission. Another patient was treated by second chemotherapy and maintaining stable disease. The other patient maintained complete remission. All three patients were alive without neurological deficit for 8, 11, and 12 months after diagnosis of brain metastasis. Patients with infratentorial brain metastases of highly malignant pediatric non-epithelial tumors are in a severe clinical state, but still can have longer and useful lives with aggressive multimodal treatments combined with radical surgical resection.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Camptothecin; Carboplatin; Chemotherapy, Adjuvant; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Dactinomycin; Doxorubicin; Etoposide; Humans; Ifosfamide; Infant; Infratentorial Neoplasms; Irinotecan; Melphalan; Neoplasm Metastasis; Neuroblastoma; Rhabdomyosarcoma; Thiotepa; Topotecan; Vincristine

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Hyperthermia, Induced; Infusion Pumps; Infusions, Intra-Arterial; Male; Melanoma; Melphalan; Neoplasm Metastasis

The aim is to analyse a modified standardised HILP procedure regarding the response rates, local recurrences and complication rates.. 152 patients (101 females, 51 males) with an average age of 62 years and locoregionally metastasised malignant melanoma underwent HILP using melphalan and dactinomycin between 1992 and 2007. Using M.D. Anderson's classification at the time of the perfusion 51 patients presented in stage IIIA, 43 patients in stage IIIAB and 58 patients in stage IV. If indicated, lymph node dissection was performed simultaneously just before perfusion of the extremity.. Complete remission was observed in 91 (62.7%) of 145 patients, partial remission in 26 (17.9%) patients. 28 (19.3%) patients showed no response. The overall response rate was 80.7% (117 of 145 patients). Severe complications (Wieberdink IV/V) were seen in eight cases. The average recurrence-free survival was 17 months. The median survival was 39 months; the five-year overall survival rate was 38%. The overall survival rate was significantly influenced by the stage of the disease.. HILP is an efficient therapy for multiple or recurrent in-transit metastases of malignant melanoma of the lower extremities. The efficiency increased by improving the technique of the perfusion. Long-term survival can be observed in patients without regional lymph node metastases or distant metastases.

Topics: Adult; Aged; Aged, 80 and over; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Extremities; Female; Humans; Hyperthermia, Induced; Kaplan-Meier Estimate; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Skin Neoplasms; Treatment Outcome

In-transit metastatic melanoma, which typically presents as multifocal lesions, provides a unique setting to evaluate the utility of gene signatures for defining optimal regional therapeutic strategies and assessing the efficacy of treatment. The goal of this study was to determine whether a single multifocal lesion is representative of residual tumor burden in terms of gene expression signatures predictive of response to therapy. Using microarray-based gene expression profiling, we examined 55 in-transit melanoma lesions across 29 patients with multifocal disease. Principal component analysis, unsupervised hierarchical clustering, one-way ANOVA, binary regression analysis, and gene signatures predictive of oncogenic pathway activation were used to compare patterns of gene expression across all multifocal lesions from a patient. Patterns of gene expression were highly similar (P < 0.006; average r = 0.979) across pretreatment lesions from a single patient compared with the significantly different patterns observed across patients (P < 0.05). The findings presented in this study show that individual melanoma tumor nodules in patients with multifocal disease harbor similar patterns of gene expression and a single lesion can be used to predict response to chemotherapy, evaluate the activation status of oncogenic signaling pathways, and characterize other aspects of the biology of an individual patient's disease. These results will facilitate the use of gene expression profiling in melanoma regional therapy clinical trials to not only select optimal regional chemotherapeutic agents but to also allow for a more rational identification of candidates for specific targeted therapies and evaluation of their therapeutic efficacy. Mol Cancer Ther; 9(4); 779-90. (c)2010 AACR.

Topics: Aged; Aged, 80 and over; Cell Line, Tumor; Dacarbazine; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Intracellular Space; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Regression Analysis; Signal Transduction; Temozolomide; Transcription, Genetic

The aims of the study were: (1) to determine toxicity, response rate, local-regional control, and survival in the entire population of the perfused patients; (2) to compare toxicity, response, and survival among patients who underwent melphalan-based perfusion with or without low-dose tumor necrosis factor (TNF); and (3) to identify factors that predict a complete response and survival.. A total of 53 patients with extensive in-transit metastases (47%) underwent perfusion with melphalan, and 59 (53%) also received low-dose TNF.. No difference was observed between the 2 drug regimens for what concerns local toxicity (P = 1.0). The tumor complete response rate was higher in patients treated with TNF (60.3% versus 41.5%, P = .036), in particular in the case of locally advanced tumors (66.7% versus 30%, P = .049). The presence of lymph node metastases had a negative influence on the tumor response rate (P = .003). Median time to local progression and survival were 19.6 and 34.5 months, respectively. Long-term complete response was achieved in 68% of the patients with initial CR (39 of 57 patients). The tumor response after perfusion was the only prognostic factor for local control and survival (P < .0001 and P = .002, respectively).. In the case of locally advanced disease, the addition of low-dose TNF to melphalan-based isolated limb perfusion appears safe and particularly useful. The presence of lymph node metastases is associated with decreased response rates. A sustained complete response was obtained in about one-third of the patients.

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Remission Induction; Skin Neoplasms; Survival Analysis; Treatment Outcome; Tumor Necrosis Factor-alpha

The treatment of malignant melanoma or sarcomas on a limb using extremity perfusion with tumour necrosis factor (TNF-alpha) and melphalan can result in a high degree of systemic toxicity if there is any leakage from the isolated blood territory of the limb into the systemic vascular territory. Leakage is currently controlled by using radiotracers and heavy external probes in a procedure that requires continuous manual calculations. The aim of this work was to develop a light, easily transportable system to monitor limb perfusion leakage by controlling systemic blood pool radioactivity with a portable gamma camera adapted for intraoperative use as an external probe, and to initiate its application in the treatment of MM patients.. A special collimator was built for maximal sensitivity. Software for acquisition and data processing in real time was developed. After testing the adequacy of the system, it was used to monitor limb perfusion leakage in 16 patients with malignant melanoma to be treated with perfusion of TNF-alpha and melphalan.. The field of view of the detector system was 13.8 cm, which is appropriate for the monitoring, since the area to be controlled was the precordial zone. The sensitivity of the system was 257 cps/MBq. When the percentage of leakage reaches 10% the associated absolute error is +/-1%. After a mean follow-up period of 12 months, no patients have shown any significant or lasting side-effects. Partial or complete remission of lesions was seen in 9 out of 16 patients (56%) after HILP with TNF-alpha and melphalan.. The detector system together with specially developed software provides a suitable automatic continuous monitoring system of any leakage that may occur during limb perfusion. This technique has been successfully implemented in patients for whom perfusion with TNF-alpha and melphalan has been indicated.

Topics: Disease-Free Survival; Equipment Design; Extremities; Gamma Cameras; Humans; Melanoma; Melphalan; Monitoring, Intraoperative; Neoplasm Metastasis; Radionuclide Imaging; Reproducibility of Results; Sarcoma; Survival Analysis; Technetium; Tumor Necrosis Factor-alpha

Isolated limb perfusion (ILP) is a surgical technique that enables the administration of high-dose chemotherapy while minimizing serious systemic side effects. The clinical value and indications are well established for skin and soft tissue tumors on limbs. For skin tumors, this technique is mainly indicated for melanoma with in-transit metastasis. For soft tissue tumors--sarcoma and osteosarcoma--it is useful as a palliative technique to reduce the tumoral mass. Limb perfusion can also be an option in other tumors, such as advanced stage squamous cell carcinoma or Merkel cell carcinoma. We present a case report of a 68-year-old man with Merkel cell carcinoma on the right tibiotarsical region, with in-transit metastasis throughout the whole lower limb. Regional chemotherapy involving ILP with melphalan and tumor necrosis factor-alpha (TNFalpha) was performed in order to avoid amputation; the primary tumor was not excised. A steady regression of the disease was observed, with complete resolution of all visible in-transit metastases at the 45th day post-perfusion. However, systemic metastasis leading to fatal outcome occurred 4 months later. Although there was no change in the patient's prognosis, ILP was able to avoid limb amputation as it controlled local-regional disease and produced complete regional remission. The addition of TNFalpha to melphalan in ILP appears to produce greater efficacy in the treatment of patients with bulky tumors or a large number of in-transit metastases.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Fatal Outcome; Follow-Up Studies; Humans; Immunohistochemistry; Limb Salvage; Lower Extremity; Male; Melphalan; Neoplasm Metastasis; Neoplasm Staging; Palliative Care; Risk Assessment; Skin Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

Both patients with soft tissue sarcoma (STS) and patients with melanoma have limited treatment possibilities once the tumor has metastasized systemically. In patients with extremity STS or bulky melanoma in-transit metastases, the local tumor burden may be so problematic that, even in patients with systemically metastasized disease, an amputation may be inevitable. Isolated limb perfusion (ILP) has proven to be an excellent, local, limb-saving treatment option in patients with locally advanced extremity tumors. In this study, the authors investigated the palliative value of the ILP procedure to avoid amputation in patients who had Stage IV STS and melanoma.. From 1991 to 2003, of 339 tumor necrosis factor alpha (TNF)-based ILPs, 51 procedures were performed for either Stage IV STS (n = 37 patients) or Stage IV melanoma (n = 14 patients). All patients underwent an ILP with TNF and melphalan of the upper limb (n = 4 patients) or the lower limb (n = 47 patients) with 26-140 mg melphalan and 2-4 mg TNF.. The overall response in patients with Stage IV STS was 84%, and their median survival was 12 months after ILP. Limb salvage was achieved in 36 of 37 patients, with 1 patient undergoing amputation due to treatment toxicity. In the patients with Stage IV melanoma, the complete response rate was 43%. All patients with melanoma preserved their limb during a median survival of 7 months.. TNF-based ILP is an excellent procedure that provided tumor control and limb salvage for the short survival of patients with metastasized, very bulky, limb-threatening tumors of the extremity.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amputation, Surgical; Antineoplastic Agents, Alkylating; Arm; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Leg; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Palliative Care; Recombinant Proteins; Sarcoma; Tumor Necrosis Factor-alpha

The prognosis of patients with metastatic retinoblastoma is poor with conventional chemotherapy and radiation. Since retinoblastoma is highly chemosensitive, dose-escalation of chemotherapeutic agents with stem cell support should be promising. We report our experience with high-dose chemotherapy (HDC) and autologous stem cell transplantation (SCT) in patients with metastatic retinoblastoma. Five patients with metastatic retinoblastoma underwent HDC with autologous SCT following conventional chemotherapy and local radiation therapy. Stem cells (bone marrow in four and peripheral blood stem cells in one) were collected after marrow involvement was cleared. Melphalan was a key drug in all patients, and was administered in combination with other agents such as cisplatin, cyclophosphamide, carboplatin or thiotepa. Three patients are currently alive disease-free at 113, 107 and 38 months, respectively, from the time of SCT. They had no central nervous system (CNS) involvement. The two patients who died of disease had CNS involvement. No long-term sequelae of HDC have been noted. Our treatment strategy using HDC appears to be effective for treating metastatic retinoblastoma without CNS involvement.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Cells; Carboplatin; Central Nervous System; Child, Preschool; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Dose-Response Relationship, Drug; Eye Neoplasms; Female; Humans; Infant; Male; Melphalan; Neoplasm Metastasis; Nervous System Neoplasms; Prognosis; Retinoblastoma; Stem Cell Transplantation; Stem Cells; Thiotepa; Time Factors; Treatment Outcome

Locoregional treatments like photodynamic therapy (PDT), radiofrequency ablation (RFA) or hepatic artery infusion (HAI) of chemotherapeutics may be applied for unresectable colorectal liver metastases. We evaluated the effect of these treatments on the immune response in a rat colon tumour liver metastases model.. Wag/Rij rats were inoculated at day 0 with CC531 tumour cells at two sites in the liver. At day 15, one of two tumours was treated with RFA or PDT, or the liver was treated by HAI. Twelve days later (day 27), rats were rechallenged locally with CC531 cells in the liver or systemically with CC531 cells in the femoral vein. At day 42, tumour growth in liver and lungs was determined.. RFA, PDT and HAI were very effective in liver tumour eradication, but following RFA or PDT there was no inhibitory effect on untreated nearby liver tumours. Outgrowth after local rechallenge was, however, significantly inhibited in RFA-, PDT- and HAI-treated rats, whereas all control rats showed outgrowth of a third liver tumour. After systemic rechallenge, control rats developed lung metastases whereas treated rats did not, but this difference was not statistically significant.. These results show that following PDT, RFA and HAI resistance to local and possibly systemic tumour rechallenge is increased. This may be partly due to the induction or enhancement of a cellular immune response.

Topics: Animals; Antibodies; Catheter Ablation; Colonic Neoplasms; Disease Models, Animal; Disease Progression; Infusion Pumps, Implantable; Liver Neoplasms; Male; Melphalan; Neoplasm Metastasis; Photochemotherapy; Porphyrins; Rats; Rats, Inbred Strains

The patient is a 74-year-old woman first diagnosed with a peripheral cutaneous T-cell lymphoma (PCTCL) in April of 1994. Initially she presented with subcutaneous indurated areas in the right forearm, scapula, and submadibular region. After chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), she went into remission for 2 years before relapse of her PCTCL localized to the right lower extremity. Persistent isolated disease in the extremity since then led to numerous chemotherapy regimens and localized radiation therapy. Due to dramatic limb threatening progression of the disease in 2001, she underwent isolated hyperthermic limb perfusion with melphalan (1-phenylalanine mustard). Although limb preservation could not be achieved, this treatment resulted in complete clinical and pathological regression of the lesions of the perfused extremity.

Topics: Aged; Amputation, Surgical; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Female; Humans; Hyperthermia, Induced; Lower Extremity; Lymphoma, T-Cell, Cutaneous; Melphalan; Neoplasm Metastasis; Neoplasm Recurrence, Local; Skin Neoplasms

The aim of this study is to describe the experience with 100 TNF-based ILP for locally advanced melanoma and to determine prognostic factors for response, time to local progression, and survival.. One hundred TNF-based ILPs were performed between 1991 and 2003 in 87 patients for whom local control by surgery of in-transit melanoma metastases was impossible. In total, 62 iliac, 33 femoral, and 5 axillary ILPs were performed in mild hyperthermic conditions with 2 to 4 mg of TNF and 10 to 13 mg of melphalan per liter of limb volume.. Overall response was 95%, with 69% complete response, 26% partial response, and 5% no change. Complete response rate differed significantly for patients with IIIA disease versus IIIAB and IV. Local and systemic toxicity was mild to moderate in almost all cases, with no treatment-related death and one treatment-related amputation. Five-year overall survival was 32%; local progression occurred in 55% after a median of 16 months. In complete response patients, 5-year survival was 42% with local progression in 52% at a median of 22 months. Response rate and survival were significantly influenced by stage of disease; (local progression free) survival was influenced by response rate.. TNF-based ILP results in excellent response rates in this patient population with unfavorable characteristics. Response on ILP predicts outcome in patients and reflects aggressiveness of the tumor.

Topics: Antineoplastic Agents, Alkylating; Axillary Artery; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Femoral Artery; Humans; Iliac Artery; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Prognosis; Skin Neoplasms; Survival Rate; Time Factors; Tumor Necrosis Factor-alpha

Preliminary randomized studies have failed to show a survival benefit of high-dose chemotherapy with alkylators in advanced breast cancer. Idarubicin is an active agent in breast cancer and is suitable for dose escalation. We designed a dose finding study with escalating high-dose idarubicin (HD-Ida) followed by fixed high-dose thiotepa+melphalan (HD-TM) with peripheral blood progenitor cells (PBPC) in MBC patients with stable disease or in partial response after six courses of induction chemotherapy with gemcitabine 1000 mg/m(2) days 1 and 4, epirubicin 90 mg/m(2) day 1, taxol 175 mg/m(2) day 1 (GET). Aims of the study were to identify the maximum tolerated dose (MTD) of idarubicin, to evaluate the cardiac safety and activity of HD-Ida and HD-TM after GET and to study the pharmacokinetic profile of idarubicin and idarubicinol. A total of 14 patients were treated. Idarubicin was administered as a 48 h continuous i.v. infusion at the following dose levels: 40 mg/m(2) (three patients), 50 mg/m(2) (three patients), 60 mg/m(2) (five patients) and 70 mg/m(2) (three patients). Mucositis was the dose-limiting toxicity and the MTD was 60 mg/m(2). C(max) of Idarubicin and idarubicinol were 7.7+/-2.0 and 26.3+/-9.7 ng/ml at 40 mg/m(2) and increased to 14.8+3.0 and 47.4+12.6 ng/ml at 70 mg/m(2). AUCt(0-264) of idarubicin and idarubicinol increased from 423.2+/-111.6 and 2581+/-606 hng/ml at 40 mg/m(2) to 732.8+/-140.2 and 4590+/-1258 hng/ml at 70 mg/m(2). Conversion rates after HD-Ida and HD-TM were 28.6 and 38.5%, respectively. No episodes of cardiac toxicity were observed. We conclude that HD-Ida followed by HD-TM is feasible and devoid of cardiac toxicity. Moreover, the activity of HD-Ida after a epirubicin-containing regimen suggests incomplete cross-resistance between the two drugs.

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Daunorubicin; Deoxycytidine; Disease Progression; Disease-Free Survival; Dose-Response Relationship, Drug; Epirubicin; Female; Humans; Idarubicin; Melphalan; Middle Aged; Neoplasm Metastasis; Paclitaxel; Remission Induction; Taxoids; Thiotepa; Time Factors; Transplantation Conditioning; Treatment Outcome

This study was conducted to evaluate the efficacy of high-dose thiotepa, melphalan and carboplatin (TMCb) regimen in 27 patients undergoing autologous stem cell transplantation (ASCT) for metastatic breast cancer. A total of 27 patients with stage IV breast cancer underwent ASCT following thiotepa (500 mg/m(2)), melphalan (100 mg/m(2)) and carboplatin (1200-1350 mg/m(2)). Of 27 patients, 17 had refractory relapse, eight had responding relapse, and two had no evidence of disease (NED) at the time of transplant. In all, 11 patients had only bone disease, nine had bone plus visceral disease, three had only visceral disease, and two had locoregional recurrent disease. The median time from diagnosis to transplant was 1081 days (range 180-2341). Staging for evaluation of response was performed 4-6 months after transplantation. Five patients were not evaluable (NE) for response because of NED at transplant (n=2) or early death due to transplant-related complications (n=3) (two of viral pneumonia and one of regimen-related toxicity) occurring at a median of 4 days (range 11-46) post-transplant. One of the two patients who was NED at the time of transplant is still NED on day 760 post-transplant. Seven of 15 refractory (47%) and 5/7 (71%) responsive patients with evaluable disease achieved a complete response of all measurable disease or all soft-tissue disease with at least improvement in bone lesions. Of 27 patients (37%),(10) are alive and progression-free, a median of 582 days (range 410-1380) after treatment, 6/17 (35%) with refractory disease and 4/10 (40%) with responsive disease. The probability of progression-free survival (PFS) for all patients was 0.50. The probabilities of PFS at 2 years for patients with refractory (n=17) and responsive (n=10) disease were 0.42 and 0.60, respectively. PFS at 2 years for the 14 patients who were NED or achieved CR/PR(*) following-HDC was 0.67. PFS at 2 years for patients who did not achieve CR/PR(*) following-DHC was 0.33. These preliminary data suggest that high-dose TMCb followed by autologous stem cell transplantation is an effective regimen for patients with advanced breast cancer and may be comparable to some previously used regimens.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Disease-Free Survival; Female; Graft Survival; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Peripheral Blood Stem Cell Transplantation; Retrospective Studies; Thiotepa; Transplantation, Autologous; Treatment Outcome

Isolated limb perfusion (ILP) with high-dose chemotherapy and tumor necrosis factor is being tested in clinical trials as a treatment for locally advanced extremity melanoma. The authors investigated the ability of F-18 fluorodeoxyglucose positron emission tomography (FDG PET) to determine the true extent of disease in patients with this condition, whose distribution of lesions differs from that seen in previous studies.. Nine patients with locally advanced melanoma were selected for imaging of the entire body and extremities using FDG PET from a group of participants in a clinical trial of ILP with melphalan +/- tumor necrosis factor. Scans were obtained without attenuation correction. Post-treatment scans were obtained in three patients 1 month after ILP. The findings in the FDG-PET scans were compared with those of a standard protocol (SP) that included anatomic images and physical examinations.. Eighty lesions (74 malignant, 6 benign) were detected with FDG PET and the SP combined. Only malignant lesions were detected by both methods in the perfused limbs. Of the malignant lesions, FDG PET detected 65 lesions (sensitivity rate, 88%). In contrast, 48 lesions were detected with the SP (sensitivity rate, 65%). Twenty-six malignant lesions were seen only with FDG PET (35%), whereas nine malignant lesions were seen only with SP (12%). The six benign lesions included three false-positive mediastinal lymph nodes in one patient. The accuracy rates of FDG PET and the SP were 83% and 65%, respectively. These results are comparable to those seen in previous studies with patients who had disease confined primarily to the torso. All post-therapy FDG-PET scans showed a reduction in the number of visualized limb lesions, and diffuse uptake throughout the perfused limbs. The diffuse uptake correlated with post-therapy limb inflammation.. Non-attenuation-corrected FDG PET is more sensitive than the SP in detecting the extent of disease in candidates for ILP. The FDG uptake associated with post-therapy inflammation may reduce the contrast resolution of this technique and must be evaluated further.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Drug Therapy, Combination; Female; Fluorodeoxyglucose F18; Humans; Image Processing, Computer-Assisted; Likelihood Functions; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Radiopharmaceuticals; Sensitivity and Specificity; Tomography, Emission-Computed; Tumor Necrosis Factor-alpha; Whole-Body Counting

Twenty-six patients with breast cancer who had relapsed after previously receiving high-dose chemotherapy and autologous hematopoietic cell support received a second course of high-dose cytoreductive therapy and autologous hematopoietic cell support as salvage therapy. Several different high-dose therapy regimens were employed for the second transplant, including a radiolabeled immunoconjugate. Two patients died of treatment-related complications. The remaining 24 patients relapsed a median of 126 (range 22-635) days after salvage transplant. All have since died. The median survival after salvage transplant was 362 (range 31-931) days. We conclude that second courses of high-dose therapy as salvage treatment are generally well-tolerated but their efficacy is modest. Alternative treatment strategies are needed for these patients.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Carmustine; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Life Tables; Melphalan; Middle Aged; Neoplasm Metastasis; Paclitaxel; Salvage Therapy; Survival Analysis; Treatment Outcome

The management of locally advanced soft-tissue sarcomas (STS) of the extremities in patients who present with regional and/or distant metastases at the time of diagnosis remains an unsolved problem. The recently introduced hyperthermic isolated limb perfusion (HILP) with tumour necrosis factor (TNF)-alpha and melphalan has been shown to be an effective limb-saving treatment modality, but is it feasible to use this approach with palliative intent? Nine patients, five men and four women, mean age 41 (range 21-75) years with locally advanced extremity STS and regional (n = 3) or distant (n = 6) metastases at the time of diagnosis, underwent a palliative HILP with TNF-alpha and melphalan. Resection of the residual tumour mass was performed, if possible, 6-8 weeks after HILP. Treatment-related morbidity, local recurrences and the limb salvage rate were scored during follow-up. The median follow-up period was 9 (range 3-39) months (seven deaths, but six were due to metastatic disease). Treatment-related morbidity was seen after 3 of the 10 perfusions performed (30%) and consisted of superficial wound infections (n = 2), blow out of the external iliac artery followed by an iliac thrombosis (n = 1). Two patients showed local recurrences after HILP followed by resection of the residual tumour mass, and one patient showed local progression after two perfusions without resection. Limb salvage was achieved in 8 patients (89%). Therefore, HILP with TNF-alpha and melphalan for locally advanced extremity STS in patients with disseminated disease is feasible. The local management of locally advanced extremity STS should be the same whether the intent is curative or palliative, as the local control improves the quality of life.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Arm; Chemotherapy, Cancer, Regional Perfusion; Feasibility Studies; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Leg; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Palliative Care; Salvage Therapy; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

Eighteen patients with poor risk Ewing's sarcoma (including 11 patients with metastatic disease at presentation) received consolidation therapy of busulphan and melphalan with autologous stem cell rescue. There were nine females. The median age at diagnosis was 14.2 years (range 2.75-30 years). There was one early death due to cytomegalovirus pneumonitis. One patient developed a single generalised convulsion during busulphan therapy. Severe renal toxicity was not encountered. One patient developed veno-occlusive disease of the liver (VOD) which eventually resolved. With a median follow up of 2 years, 13 patients survive including six with initial metastatic disease. We conclude that high-dose busulphan/melphalan is well-tolerated and should be evaluated for efficacy in a larger series of patients with high risk Ewing's sarcoma.

Topics: Adolescent; Adult; Anticonvulsants; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Busulfan; Child; Child, Preschool; Clonazepam; Combined Modality Therapy; Contraindications; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Male; Melphalan; Neoplasm Metastasis; Phenytoin; Remission Induction; Sarcoma, Ewing; Seizures; Survival Analysis; Transplantation Conditioning; Treatment Outcome

In an attempt to improve the poor prognosis of poor responders with stage IV neuroblastoma, a new combined high-dose chemotherapy conditioning regimen was tested. Event-free and overall survival, as well as the incidence of complications, were analysed. Twenty-five children aged 12-146 months at diagnosis entered this study. All were in complete remission (CR) at the time of high-dose chemotherapy. Two or three different protocols had been necessary for them to achieve a CR. High-dose chemotherapy consisted of a combination of busulfan (600 mg/m2), cyclophosphamide (4400 mg/m2) and melphalan (140 mg/m2). It was followed by autologous bone marrow transplantation (ABMT). The bone marrow graft was purged in vitro with mafosfamide. The probability of event-free survival (EFS) at 5 years post-ABMT was 34%, compared to < 8% in a historical series. Toxicity was severe but manageable and 2 complication-related deaths were observed. Veno-occlusive disease was the most frequent extrahaematopoietic complication encountered, but its outcome was always favourable. By using a very intensive conditioning regimen consisting of a combination of three alkylating agents, the EFS of poor responders with metastatic neuroblastoma was improved and similar to that of good responders. When compared with a previously published similar series of patients, the improvement in survival appears probably related to intensification of the conditioning regimen.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Female; Follow-Up Studies; Humans; Infant; Male; Melphalan; Neoplasm Metastasis; Neuroblastoma; Remission Induction; Treatment Outcome

In mice bearing immunogenic tumors, adding thymic humoral factor-gamma 2 (THF-gamma 2)1 immunotherapy as an adjunct to anticancer chemotherapeutic regimens not only potentiates the antitumor activity of each drug but also repairs tumor/chemotherapy-induced damage to T-cell populations and functions. The Lewis lung carcinoma (3LL) is a weakly immunogenic, highly metastatic tumor in C57BL/6 mice. To investigate whether the immunoregulatory octapeptide is also effective against a tumor that does not elicit an antitumor immune response, we assessed the effect of combination THF-gamma 2 immunotherapy and chemotherapy in 3LL-bearing mice. The results indicate that THF-gamma 2 combined with either Melphalan or 5-Fluorouracil was more effective in reducing metastatic load than either chemotherapeutic drug alone and was characterized by massive infiltration of lymphatic cells. The combined chemoimmunotherapy treatment also prolonged the survival time in all treated animals and repaired T-cell defects and impaired in vitro cellular immune response parameters, induced either by the tumor or by chemotherapy. THF-gamma 2 immunotherapy reversed the decrease in the number of bone-marrow myeloid colonies (GM-CFU) induced by chemotherapy treatment of tumor-bearing mice, supporting the hypothesis that THF-gamma 2 directly stimulates the proliferation of myeloid stem cells. The overall results imply, that when administered as an adjunct to chemotherapy, THF-gamma 2 immunotherapy is equally effective against immunogenic and nonimmunogenic tumors.

Topics: Animals; Drug Synergism; Drug-Related Side Effects and Adverse Reactions; Erythrocytes; Female; Fluorouracil; Granulocyte-Macrophage Colony-Stimulating Factor; Immune Sera; Immunity; Immunotherapy; Lipopolysaccharides; Lung Neoplasms; Male; Melphalan; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasms, Experimental; Oligopeptides; Thymus Hormones

Twenty-one percent of responding metastatic breast cancer patients remain progression-free a median 50 months following one intensification cycle of cyclophosphamide (6,000 mg/m2), thiotepa (500 mg/ m2), and carboplatin (800 mg/m2) (CTCb) with autologous bone marrow transplantation (ABMT). This trial studied whether the sequence of high-dose melphalan followed by CTCb resulted in improved disease response and duration.. Women with at least partial responses (PRS) to induction received melphalan (140 or 180 mg/ m2) with peripheral-blood progenitor cell (PBPC) and granulocyte colony-stimulating factor (G-CSF) support. They were monitored as outpatients. After recovery, patients were hospitalized for CTCb with marrow, PBPC, and G-CSF support.. Data on 67 women, at a median of 25 months from CTCb, were examined. After melphalan, 49 (73%) required admission for fever (89%), mucositis (35%), or infection (15%) (median stay, 8 days). All received CTCb. For the first 33 patients, the median days from start of melphalan to CTCb was 24. After liver toxicity (one death from venoocclusive disease [VOD]) developed in 11 patients during CTCb, the interval between intensifications was increased to 35 days without incident. Twenty-three patients (34%) are progression-free a median of 16 months post-CTCb. The median progression-free survival (PFS) and survival times for the whole group are estimated at 11 and 20 months, respectively.. Treatment with this sequence of high-dose melphalan followed by CTCb has not resulted in superior PFS to date, when compared with single-intensification CTCb. This report discusses factors related to patient selection, the role of induced drug resistance, and the schedule of administration of alkylating agenting that may adversely influence outcome.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Carboplatin; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Thiotepa; Transplantation, Autologous

We have recently demonstrated the importance of V beta 8+/CD8+ cells for the curative effectiveness of a suboptimal low dose (0.75 mg/kg) of melphalan (L-phenylalanine mustard; L-PAM) for mice bearing a large s.c. MOPC-315 tumor and extensive metastases. Here we show that staphylococcal enterotoxin B (SEB), which is known to selectively stimulate T cells expressing members of the TCR-V beta 8 gene family, substantially improved the curative effectiveness of the suboptimal dose of L-PAM for mice bearing a large MOPC-315 tumor. Moreover, treatment of mice with mAb F23.1 (anti-V beta 8) abrogated the in vivo therapeutic effect of SEB for low dose L-PAM-treated MOPC-315 tumor bearers (L-PAM TuB mice). Analysis of the effect of SEB on the tumor-infiltrating lymphocytes (TILs) demonstrated that the SEB-mediated therapeutic effect was associated with a significant increase in: 1) the percentage of V beta 8+ cells among the CD8+ T cells that accumulated in the s.c. tumor nodules, 2) the total number of V beta 8+/CD8+ cells present per tumor on day 4 after low dose L-PAM therapy, and 3) the ability of the TILs to lyse MOPC-315 tumor cells in vitro in a short term assay. Furthermore, treatment of mice with mAb F23.1 abolished the ability of SEB to render the TIL population of L-PAM TuB mice more cytotoxic in vitro for MOPC-315 tumor cells. Thus, the SEB-mediated improvement in the therapeutic outcome of low dose L-PAM therapy for mice bearing a large MOPC-315 tumor may be due in part to SEB-mediated increase in the contribution of the V beta 8+ T cells to tumor eradication through enhancement in the magnitude of the anti-MOPC-315 lytic activity exhibited by the TIL population.

Topics: Animals; CD8 Antigens; Cytotoxicity, Immunologic; Enterotoxins; Female; Immunity, Cellular; Lymphocytes, Tumor-Infiltrating; Melphalan; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Plasmacytoma; Survival Analysis

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Chemotherapy, Adjuvant; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Combined Modality Therapy; Dacarbazine; Dactinomycin; Evaluation Studies as Topic; Extremities; Humans; Hyperthermia, Induced; Incidence; Melanoma; Melphalan; Neoplasm Metastasis; Osteosarcoma; Rhabdomyolysis; Skin Neoplasms; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Transplantation; Breast Neoplasms; Cisplatin; Clinical Protocols; Combined Modality Therapy; Cyclophosphamide; Etoposide; Feasibility Studies; Genetic Therapy; Genetic Vectors; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Melphalan; Multiple Myeloma; Neoplasm Metastasis; Retroviridae; Transfection; Transplantation, Autologous; Whole-Body Irradiation

In order to examine in detail the sensitivity to chemotherapy of tumour cells at various organ sites and at various stages of metastasis, we have used a series of cell lines, all selected from sister subpopulations derived from a single mouse mammary tumour, which can be distinguished and quantitated from normal cells and from each other through growth in selective medium. For the studies described here, we used two lines, 4T07 and 66FAR, which will form colonies in vitro in medium containing 60 microM 6-thioguanine or 330 microM 2,6-diaminopurine, respectively. Both cell lines have similar sensitivity to the test chemotherapeutic agent, melphalan, in vitro. These two tumour cell lines were treated with melphalan in vivo, when growing either in lungs as experimental metastases at various times after cell injection or as palpable tumours growing subcutaneously. Responses to various doses of melphalan were measured by removing lungs or subcutaneous tumours and performing colony-forming assays in selective medium. The data indicate marked shifts in sensitivity as a function of metastatic stage. Analyses of dose-response curves show that both cell lines were similarly sensitive to melphalan at early times (45 min) after cell injection i.v. but became less sensitive at an intermediate time after injection (3 days). Differences between the two lines became apparent at later times after i.v. injection (by day 8 or 9) and in subcutaneous tumours, where a marked reduction in the shoulder of the dose response curve was seen in line 4T07, resulting in sensitivity equal to or greater than the of early times, whereas the dose response parameters of 66FAR remained at those of the intermediate time point. These results show that, in heterogeneous tumours, individual subpopulations of tumour cells may respond differently to chemotherapeutic agents at various disease stages. In vitro measures of tumour sensitivity do not predict these changes in in vivo sensitivity. Model systems similar to the one described here may yield information which will eventually be useful in maximising the efficacy of clinically relevant adjuvant chemotherapy regimens.

Topics: Animals; Cell Division; Dose-Response Relationship, Drug; Female; Lung Neoplasms; Male; Mammary Neoplasms, Experimental; Melphalan; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Skin Neoplasms; Tumor Cells, Cultured; Tumor Stem Cell Assay

Topics: alpha-MSH; Animals; Humans; Iodine Radioisotopes; Liver Neoplasms; Melanoma; Melanoma, Experimental; Melphalan; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Pilot Projects; Radionuclide Imaging; Receptors, Pituitary Hormone

From 1978 to 1990, 32 patients with Clark V melanoma were treated by wide excision of the primary and adjuvant regional isolated perfusion with melphalan. M.D. Anderson stage of disease was stage I in 22 and stage IIIb in 10 patients. Five-year survival rates were 58% and 27%, respectively. Seven patients developed a recurrence in the perfused limb [stage I, 2, stage IIIb, 5 patients (P = 0.03)], and 4 of 17 patients developed regional lymph node metastases. Of the well-known prognostic variables, only ulceration of the primary tumor significantly influenced survival (P = 0.03). We did not see any improvement in survival rates compared with literature data on nonperfused patients. In the absence of data on locoregional recurrence rates in nonperfused Clark V melanoma patients, we cannot say whether adjuvant perfusion diminished this risk. Therefore, the results of the prospective randomized EORTC/WHO trial in primary high-risk extremity melanoma have to be awaited.

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Evaluation Studies as Topic; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prognosis; Skin Neoplasms; Treatment Outcome

Forty-two patients with measurable recurrent melanoma of the lower limb were treated according to a double-perfusion schedule.. To assess the advantage of this schedule compared with that of a single-perfusion treatment, a retrospective study was done comparing the 42 patients with 45 patients who had undergone a single-perfusion procedure. Both groups were well balanced with respect to patient and tumor characteristics. For patients treated with a double schedule, the dose of melphalan given in the first perfusion was low (6 mg/l; 1 hour; normothermic conditions) to make it possible to perform a second perfusion (9 mg/l; 1 hour; normothermic conditions) with a planned short interval of 3-4 weeks. In the single-perfusion group, a normothermic perfusion with 10 mg melphalan/l was performed.. The toxicity did not differ between the two treatment modalities. The response rate was significantly higher in the double-perfusion group (90% versus 68%; P = 0.007) because of a higher complete remission rate (76% versus 48%; P = 0.006). In both groups, approximately half of the patients with complete remission experienced disease recurrence in the perfused area (50% versus 52%). No significant differences were seen in the two groups in the regional node recurrence rate (33% in the double-perfusion group versus 20% in the single-perfusion group), distant recurrence rate (50% in the double-perfusion group versus 58% in the single-perfusion group), and their corresponding recurrence-free intervals. The overall 3-year survival rate was 46% in both groups.. In the patient groups studied, the double-perfusion schedule shows a better complete remission benefit than does the single-perfusion procedure. No differences are seen in limb, regional node, and distant recurrence rates in the two groups. Thus, additional improvement of the perfusion methodology is warranted.

Topics: Adult; Aged; Drug Administration Schedule; Female; Humans; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Perfusion; Retrospective Studies

Topics: Cytokines; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Metastasis; Prednisone

We reported earlier that oncolysate retained in the excision wound of a local tumor inhibits growth of remote tumor in the rat. We further studied this effect on pulmonary metastasis. C57BL/6 mice were given B16 melanoma F10 cells subcutaneously into the gluteal area (Day 0) and then intravenously on Day 10. On Day 14, mice were divided into four groups. Group 1 received a sham operation and no further treatment. Tumors were excised in the remaining mice. Group 2 received tumor excision alone. Groups 3 and 4 received injections of freeze-lysed tumor cells (TC) and lysate modified (PTC) with a hapten, L-phenylalanine mustard (PhM), respectively, into excision wounds. On Day 24, metastases were assessed by determining metastatic burden. Average diameters of excised tumors in repeated experiments ranged from 8.7 to 10.9 mm. In repeat experiments, pulmonary metastatic burden increased by as much as 52 to 181% in the tumor excised group (Group 2) in comparison with those receiving sham surgery (Group 1). However, metastatic burden was always reduced in Group 3. An even greater reduction was seen in Group 4. To study the possible involvement of macrophages, the production of prostaglandin-E2 (PGE2) and cytotoxicity of macrophages in these animals were examined. It was found that tumor excision enhanced PGE2 production by macrophages and suppressed their cytotoxicity, while TC inoculation prevented both of these changes. An even greater prevention was observed with PTC inoculation. These results indicate an association among macrophage cytotoxicity, PGE2 production of macrophages, and metastasis. In order to clarify the mechanism for these reactions, we did experiments using adherent splenic macrophages from the four groups of animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cell Survival; Dinoprostone; Immunization; Lung Neoplasms; Macrophages; Male; Melanoma, Experimental; Melphalan; Mice; Mice, Inbred C57BL; Neoplasm Metastasis

A combination of mitomycin C, vindesine and melphalan was administered to 33 patients with heavily pretreated refractory breast cancer. The overall response rate was 27% with a mean duration of more than 10.2 months. A stabilization with a mean duration of 5.1 months was seen in 56% of cases, while 20% of patients progressed. Gastrointestinal toxicity, mostly grade 1 or 2 nausea/vomiting was seen in 85% of cases, grade 1 or 2 leukopenia in 60% of patients, and grade 1 or 2 thrombocytopenia in 42%. Considering the good compliance of this regimen and the poor prognosis of patients with refractory advanced breast cancer, this combination can be useful as a palliative treatment of breast carcinoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Melphalan; Middle Aged; Mitomycin; Mitomycins; Neoplasm Metastasis; Palliative Care; Vindesine

In a consecutive series of studies, 164 patients with symptomatic and/or visceral metastatic malignant melanoma were treated with single agent vindesine, high dose melphalan with autologous bone marrow transplantation (AMBT), high dose BCNU with ABMT or the BOLD (bleomycin, vincristine, CCNU and DTIC) combination. The high dose treatments and the combination chemotherapy resulted in significantly higher response rates but no prolongation of survival. Factors associated with longer survival included the absence of visceral metastases, the absence of bulky disease and good performance status. For all treatments, life table estimates of survival at 1 and 2 years were only 10% and 4% respectively.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Marrow Transplantation; Dacarbazine; Female; Humans; Lomustine; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Retrospective Studies; Vincristine; Vindesine

The use of isolated regional perfusion with melphalan as an adjuvant treatment for stage I melanoma of the extremity continues to be controversial. The present retrospective study evaluates the past 25 years' experience by comparing 227 perfused patients from Groningen with 238 matched controls from five hospitals in The Netherlands and Westphalia (West Germany). All patients underwent wide local excision for a primary extremity melanoma of 1.5 mm or greater in thickness. A proportional hazards regression analysis for recurrence of disease and survival identified the significant prognostic factors, of which, besides level of infiltration, ulceration, age and sex, tumour thickness was found to be the most important. Corrected for these factors, it was not possible to demonstrate a statistically significant effect for perfusion in terms of time to limb recurrence (p = 0.61), time to regional lymph node metastasis (p = 0.11), time to distant metastasis (p = 0.73), disease-free interval (p = 0.42), and survival (p = 0.90). No statistically significant differences were seen for adjuvant perfusion in any of the subgroups.

Topics: Adult; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Proportional Hazards Models; Regression Analysis; Retrospective Studies; Skin Neoplasms

Since systemic application of a high-dose chemotherapy is limited by the extent of intolerable toxicity and overall response rates so far are rather poor, the systemic mode of chemotherapy for metastatic melanoma appears to be of only limited benefit. On the other hand, results from isolated limb perfusion for satellitosis and in-transit metastasis suggest distinct dose-response correlations with tumoricidal properties of appropriate antineoplastic agents. This experience prompted the idea to pilot the anti-tumor action of a high-dose regimen confined to one hemibody compartment for targeted tumor therapy. After having standardized the surgical procedure this goal appeared to be achievable by expanding the perfused area and by simultaneously detoxifying toxic drug levels within the non-perfused compartment by venous filtration. Two initial causal experiences revealed impressive tumor regressions and are therefore reported on preceding subsequent evaluation within a controlled clinical trial being designed at different solid tumors.

Topics: Adult; Antineoplastic Agents; Catheters, Indwelling; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Dose-Response Relationship, Drug; Extremities; Female; Heart-Lung Machine; Hemofiltration; Humans; Infusions, Intra-Arterial; Male; Melanoma; Melphalan; Mitomycin; Mitomycins; Neoplasm Metastasis; Pilot Projects; Skin Neoplasms

Thirty-seven patients with widely metastatic malignant melanoma were treated with one of three chemotherapy regimens, incorporating high-dose dacarbazine (DTIC). The chemotherapy was followed by autologous bone marrow rescue which was harvested under local anesthesia in 25 of the patients. The three regimens comprised a 24-hour infusion of DTIC (Regimen A for patients less than 45 years of age, 4.3 to 10.5 g/m2; B, if greater than 45 years of age 2.7 to 4.0 g/m2; and later C, if greater than 45 years of age 7.0 to 8.0 g/m2). The second alkylating agent was given at +8 and +16 hours from the start of DTIC. The total doses of the melphalan ranged from 60 to 130 mg/m2 for Regimen A and 30 to 40 mg/m2 for Regimen B. Ifosfamide 5.0 to 8.0 g/m2 was given instead of melphalan in Regimen C. The response rates for the regimens were 81% (25% CR) for A, 27% (11% CR) for B, and 20% (with no complete responders) for Regimen C. There was no statistically significant difference between the three regimens for survival with a median value of 6 months. One of the 16 patients treated with the very high dose Regimen A died of septicemia and three of ten patients in Regimen C died within the first 2 weeks of treatment. There was statistically significant greater myelosuppression, stomatitis, and diarrhea in the very high dosage DTIC and melphalan (Regimen A) compared with the other two regimens. No significant difference in response rate or toxicity was observed for the different dosages escalated within each of the three regimens. Although hematologic and gastrointestinal toxicity were very severe, no unusual side effects were noted except for one episode of severe acute renal failure in the high-dose DTIC and melphalan, Regimen A. Responses occurred mainly in nonvisceral, nodal, and cutaneous sites and occasionally in pulmonary metastases. The Karnofsky performance improved 4 to 6 months after treatment notably with the high-dose DTIC and melphalan therapy. No survival benefit for the combination chemotherapy despite the high dosages was detected and such an approach currently cannot be recommended.

Topics: Adult; Aged; Alkylating Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Transplantation; Dacarbazine; Humans; Ifosfamide; Lung Neoplasms; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Skin Neoplasms

To augment the antitumor effect of high-dose melphalan and determine pharmacokinetics we conducted a phase I trial of escalating doses of high-dose IV melphalan with the chemosensitizer misonidazole for patients with advanced colorectal carcinoma. Fourteen patients with modified Dukes D adenocarcinoma of the colorectum were treated with a single course of melphalan (40-60 mg/m2 i.v. bolus q.d. X 3 days) and misonidazole (1-3 g/m2 p.o. q.d. X 3 days) followed by autologous bone marrow transplantation. Toxicity consisted of severe myelosuppression, moderate nausea and vomiting, and mild mucositis and diarrhea. One patient developed unexplained renal tubular acidosis, and a diffuse encephalopathy occurred in another patient. Three patients died within the first 30 days after the start of treatment, two due to tumor progression and one due to sepsis and disseminated intravascular coagulation-induced intracerebral hemorrhage. Six of 14 patients achieved a partial response, and the median response duration was 4 months (range 3-10 months). Analysis of misonidazole serum concentrations showed similar pharmacokinetics to those previously reported, suggesting no significant drug interaction with intravenous melphalan. Mean peak serum concentrations ranged from 81.8 micrograms/ml to 115.2 micrograms/ml at the second and third misonidazole dose levels, which approximate those known to provide effective chemosensitization with melphalan in animal models. In this phase I study, we showed that maximally tolerated doses of intravenous melphalan can safely be combined with oral misonidazole. In view of the large volumes of oral misonidazole required at the highest dose level, subsequent studies to determine the maximally tolerated dose of misonidazole should employ the intravenous form.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Colonic Neoplasms; Drug Administration Schedule; Drug Evaluation; Female; Humans; Male; Melphalan; Middle Aged; Misonidazole; Neoplasm Metastasis; Rectal Neoplasms; Remission Induction

A total of 23 patients were treated at five dose escalations with high-dose combination cyclophosphamide, cisplatin, and melphalan with autologous bone marrow support. The maximum tolerated doses of cyclophosphamide, cisplatin, and melphalan were 5,625, 180, and 80 mg/m2, respectively. The dose-limiting toxicity was cardiac toxicity. Objective tumor regression occurred in 14 of 18 evaluable cases, with a median duration of 3.5 months. Pharmacokinetic evaluation of melphalan in 20 patients revealed a dose-related increase in maximum plasma concentration (Cmax) and area under the curve (AUC). Perturbation of the melphalan plasma half-life and AUC, associated with severe toxicity, resulted when renal insufficiency occurred. The results suggest that high-dose combination cyclophosphamide, cisplatin, and melphalan produces frequent, rapid responses in breast cancer, melanoma, and sarcoma, although with significant extramedullary toxicity. The pharmacokinetics suggest that modification of the treatment schedule may result in a reduction of treatment-related toxicity.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Melanoma; Melphalan; Neoplasm Metastasis; Neoplasms; Sarcoma; Transplantation, Autologous

Eight patients with advanced malignant melanoma were treated with high-dose melphalan (80-90 mg/m2) and BCNU (600-800 mg/m2). In all patients autologous bone marrow preservation was performed prior to therapy. Bone marrow was stored for 48 h in a refrigerator at 10 degrees C and reinfused 48 h post-therapy. Three patients had a complete response (CR), 1 a partial response and 4 patients no response. Two patients with CR died 4 and 5 months after therapy. One had an interstitial pneumonitis and 1 patient died from unknown cause. The third patient had a relapse 12 months after therapy. Major side effects were severe nausea/vomiting and a mild mucositis. Two patients suffered from BCNU-related encephalopathy. All patients had a full hematologic reconstitution after 6 weeks. High-dose chemotherapy with autologous bone marrow support achieves a high response rate. Long-term disease-free survival, however, was not seen with this approach.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Skin Neoplasms

From 1975 to 1986, 26 patients with soft tissue tumors of the extremities underwent a total of 29 perfusions. The cytostatics used were doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH) (19 perfusions), melphalan (two perfusions), and a combination of these agents (eight perfusions). Before perfusion most patients had been treated by surgical excision(s), radiotherapy, or systemic chemotherapy. Of 17 patients perfused because of local inoperable tumor, four showed prolonged complete remission of the tumor mass, stable disease was seen in three, and ten showed progression. The complete remissions observed in three patients with aggressive fibromatosis and in one with lymphangiosarcoma occurred after perfusion with doxorubicin combined with melphalan. Doxorubicin added to the perfusate as the sole cytostatic was not effective. Local recurrence was observed in five of nine patients treated by adjuvant perfusion, always after dubiously radical tumor excision. Toxicity was high, especially in the first few years. Tissue necrosis necessitated amputation in three cases (in two after perfusion with doxorubicin and melphalan and in one after repeated perfusion with doxorubicin only). This complication was no longer seen after adjustment of the dosage and dose distribution of doxorubicin, but the morbidity after perfusion with doxorubicin remained considerable.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Child; Doxorubicin; Extremities; Female; Humans; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Remission Induction; Soft Tissue Neoplasms

Melphalan (MEL), an alkylating agent, has been modified to a derivative, N-acetylmelphalan (N-AcMEL), which can be conjugated to anticolon cancer monoclonal antibodies (MoAbs 30.6, I-1, and JGT) and used for immunochemotherapy. The final immunoconjugates possess potent cytotoxicity and specificity in preclinical studies. In a phase I clinical study, N-AcMEL-MoAb conjugates were administered via the hepatic artery to 10 patients, nine of whom had disseminated colorectal cancer (including the liver) and one of whom had Dukes' C colon cancer that had been resected. The selection of MoAb was based on the immunoperoxidase staining of the primary colon cancer tissue. Thus far doses of 1000 mg/m2 MoAb conjugated to 20 mg/m2 of N-AcMEL have been administered with no significant side effects, whereas MEL unconjugated to monoclonal antibodies would have caused myelosuppression in a proportion of patients at the same dosage. Serum antimouse antibody responses were noted in all of the patients; febrile reactions were noted with higher doses but were easily controlled with antipyretics, antihistamines and, if necessary, steroids. Serum sickness developed in one patient who was given a second course of treatment in the presence of human antimouse antibody, but the episode was self-limiting. Eight of the 10 patients had evaluable disease. Subjective improvement was noted in almost all of the patients examined, and 33%, or 3 of 9, of the treatments (nine courses of treatment in eight patients with evaluable disease; one of the patients had two courses of treatment) led to antitumor responses (minor response) by objective assessment with computed tomography of the liver. It is important to note that treatment with N-AcMEL-MoAb conjugates was safe at a dose of 20 mg/m2 of N-AcMEL, whereas the efficacy of such a form of treatment remains to be determined.

Topics: Adult; Antibodies, Monoclonal; Antineoplastic Agents; Carcinoembryonic Antigen; Carcinoma; Colorectal Neoplasms; Drug Evaluation; Female; Humans; Immunohistochemistry; Immunotoxins; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Tomography, X-Ray Computed

In spite of the better results observed during the last decades and particularly due to earlier diagnosis and earlier surgical excision, malignant melanoma remains a tumour with a disconcerting course. This relative therapeutic impotence explains the variety of treatments used, including chemotherapy, radiotherapy, immunotherapy, etc. Surgical excision after chemotherapy under hyperthermic regional perfusion with extracorporeal circulation is an original method which has been applied for more than 3 decades with conflicting results but which may prove useful in several circumstances. The principle of regional perfusion using cytostatic drugs injected into the regional arterial blood flow resulted from a study by Klopp et al. in 1950. This technique was developed in practice by Creech et al. in 1957, and it was improved about 10 years later by additional hyperthermia, an idea suggested by Cavaliere et al. and by Stehlin. In Strasbourg, we have been using this method since January, 1982. Indications for perfusion are melanoma of the limbs with Breslow thickness greater than or equal to 0.85 mm, but from 1984 onwards these indications have been limited to patients with high-risk tumours such as melanoma with a Breslow thickness greater than or equal to 1.5 mm. Such melanomas are situated on the upper limb below the brachial insertion of the deltoid muscle, and on the lower limb below the upper third portion of the thigh. The technique consists of regional chemotherapy of the limb using extracorporeal circulation with hyperthermic perfusion. Melphalan is the drug used, and its dosage is based on body-weight: 1.4 mg/kg for the lower limb, and 0.9 mg/kg for the lower limb. Melphalan is introduced in the perfusion when the subcutaneous temperature near the tumour reaches 38 degrees C. The temperature of the limb is maintained at 40-42 degrees C for 45 minutes. At completion of the perfusion a wash-out is performed, and the tumour is excised with a 3 cm margin. From January, 1982 to January, 1987, 68 patients with malignant melanoma were treated by this method. Perfusion could not be performed in 5 patients because the small caliber of the vessel did not allow sufficient perfusion flow rate. No lethal complication occurred, and morbidity was very low.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adult; Aged; Combined Modality Therapy; Extracorporeal Circulation; Extremities; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Injections, Intra-Arterial; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local

The use of isolated regional perfusion in an adjuvant setting for stage I melanoma of the extremity continues to be controversial. The present retrospective study evaluates the past 20 years' experience by comparing 227 perfused patients from Groningen with 238 matched controls from five hospitals in The Netherlands and Westphalia (a region of West Germany bordering the Netherlands). All patients underwent wide local excision for a primary extremity melanoma of 1.5 mm or greater in thickness. A proportional hazards regression analysis for recurrence of disease and survival identified the significant prognostic factors, of which tumor thickness was the most important. Corrected for these factors, it was not possible to demonstrate a statistically significant effect for perfusion in terms of time to limb recurrence (P = .61), time to regional lymph node metastasis (P = .11), time to distant metastasis (P = .73), disease-free interval (P = .42), and survival (P = .90). No statistically significant differences were seen for adjuvant perfusion in any of the subgroups.

Topics: Adult; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Perfusion; Retrospective Studies; Skin Neoplasms

Although human tumor xenografts have been extensively used for preclinical evaluation of antitumor agents, most of this work has utilized subcutaneous or subrenal capsule assays based on change in tumor size. To obtain experimental models more reflective of the human clinical situations, we have developed several metastatic models that are based on and complement a panel of cell strains used in large-scale in vitro drug screening. One melanoma and four lung tumors produced metastatic lesions in the lung within 60 days following subcutaneous, intraperitoneal, or intrasplenic inoculation of BALB/C athymic nude mice. Several tumors also produced liver lesions, and one lung tumor strain showed metastasis to the brain. The metastatic lesions histologically resembled the tumors that grew at the inoculation site. In vitro and in vivo cell strains were rederived from the metastatic lesions. These systems may provide practical models for experimental drug and immunotherapeutic trials.

Topics: Animals; Antineoplastic Agents; Cell Line; Female; Melphalan; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Transplantation, Heterologous

At no stage of tumor growth are thymocytes from MOPC-315 tumor bearers capable of bringing about the generation of enhanced antitumor cytotoxicity when added to immunization cultures of syngeneic normal spleen cells and "autochthonous" tumor cells. However, by Day 7 after low-dose melphalan [L-PAM (L-phenylalanine mustard)] therapy of mice bearing a large (greater than or equal to 20 mm) s.c. MOPC-315 tumor, their thymocytes exhibit such activity and it persists for at least 17 additional days. The ability of thymocytes from L-PAM-treated MOPC-315 tumor bearers to bring about the generation of enhanced antitumor cytotoxicity when added to immunization cultures of normal spleen cells and MOPC-315 tumor cells is evident over a 10-fold range of responder/stimulator cell ratios, and requires the presence of the thymocytes within the first day after initiation of the 5-day immunization cultures. In addition, immunization cultures containing normal spleen cells and thymocytes from L-PAM-treated MOPC-315 tumor bearers exhibit enhanced antitumor cytotoxicity by Day 4 after culture initiation that persists for at least 3 additional days. Thymocytes from L-PAM-treated MOPC-315 tumor bearers are able to bring about the generation of enhanced antitumor cytotoxicity only in response to stimulation with autochthonous tumor cells but not in response to stimulation with unrelated allogeneic EL4 tumor cells. The apparent specificity of the enhanced antitumor immune reactivity of thymocytes from L-PAM-treated MOPC-315 tumor bearers is not the result of extensive metastasis of tumor cells to the thymus. In fact, no tumor cells were found in the thymuses of MOPC-315 tumor bearers with methods that can detect 1 X 10(3) tumor cells, indicating that if MOPC-315 tumor cells metastasize at all into the thymus, the thymuses of mice bearing a large MOPC-315 tumor contain fewer than 1 X 10(3) tumor cells. Thus, thymocytes from mice which are engaged in the eradication of a large MOPC-315 tumor display enhanced antitumor immunity in response to stimulation with the autochthonous tumor cells. Such thymocytes may prove important to the outcome of low-dose L-PAM therapy for mice bearing a large MOPC-315 tumor, since the low-dose chemotherapy requires the contribution of T-cell-dependent antitumor immunity for its therapeutic effectiveness.

Topics: Animals; Antigens, CD; Cytotoxicity, Immunologic; Immunization; Melphalan; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neoplasms, Experimental; Receptors, Fc; T-Lymphocytes; Thymus Gland; Time Factors

Fifty-nine patients received 61 courses of cyclophosphamide, cisplatin, and carmustine combined. The phase I study consisted of seven dose escalations. Dose levels 5 and 6 also included the attempted addition of melphalan at 40 and 80 mg/m2. The maximum tolerated dose for the three-drug combination was 5620 mg/m2 of cyclophosphamide, 165 mg/m2 of cisplatin, and 600 mg/m2 of carmustine. The dose-limiting toxic effect was fatal veno-occlusive disease of the liver in two of five patients treated at the highest dose level. Veno-occlusive disease of the liver was fatal in two of 40 patients treated at Dose level 4, the maximum tolerated dose. The median time to recovery of polymorphonuclear leukocyte counts to greater than 500/microliters and platelet counts to transfusion independence greater than 20,000/microliters was 19 and 22 days, respectively, after marrow reinfusion. Other toxic effects observed included postdischarge pulmonary toxicity, which appeared to respond to prednisone therapy. Thus, this combination of alkylating agents can be combined at close to the transplant dose of each individual agent. The response rate was high despite considerable prior treatment in most patients. Of 16 evaluable patients with breast cancer, 15 responded (six complete responses). Of six evaluable patients with sarcoma, six responded (one complete response). While patients with melanoma had had no prior treatment, 11 of 17 patients responded (65%). There are currently three patients who are disease-free. Two patients with melanoma were rendered disease-free by excisional biopsy of the only remaining nodule after good partial response, and a patient with metastatic breast cancer remains disease-free after a complete response at 36+ months.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Carmustine; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Drug Evaluation; Female; Hematologic Diseases; Humans; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasms; Statistics as Topic

WHT/Ht mice were transplanted s.c. with NC carcinoma, and the tumours were excised after 2 weeks. The mice were treated orally throughout the experiments with prednisolone 500 micrograms kg-1 or mepacrine 3.6 mg kg-1, starting the day after tumour transplantation or, with prednisolone, the day after tumour excision. In some experiments the mice were also treated with the cytotoxic drugs methotrexate 2 mg kg-1 and melphalan 1.4 mg kg-1. The excised tumours were weighed; some of them, and samples of serum, were extracted for prostanoids which were measured by radioimmunoassay. The chemotherapy lengthened the survival of the mice, but prednisolone or mepacrine had little or no effect on survival, metastasis, the response to chemotherapy, tumour size or the formation of tumour prostanoids.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Female; Male; Mammary Neoplasms, Experimental; Melphalan; Methotrexate; Mice; Mice, Inbred Strains; Neoplasm Metastasis; Neoplasm Transplantation; Prednisolone; Prostaglandins E; Quinacrine; Thromboxane B2

Antitumor and antimetastatic effects of an official extract of Rhodiola rosea were established in experiments on inbred and noninbred mice and rats with transplantable NK/Ly tumor, Ehrlich's adenocarcinoma, melanoma B16 and Lewis lung carcinoma. Application of the said preparation to sarcolysin-treated animals was followed by an increase in survival.

Topics: Animals; Carcinoma, Ehrlich Tumor; Drug Evaluation, Preclinical; Lymphoma, Non-Hodgkin; Male; Melanoma, Experimental; Melphalan; Mice; Mice, Inbred Strains; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Transplantation; Neoplasms, Experimental; Plant Extracts; Rats; Rats, Inbred Strains; Sarcoma 180; Time Factors

Both B16 melanoma and Lewis lung carcinoma growing in C57/Bl mice spontaneously metastasize to the lungs and other organs. When the tumors are grown in the mouse tail to a specific volume and amputated, the spontaneously disseminated tumor cells can then be independently treated. The effects of a single dose of cyclophosphamide (200 mg/kg), cis-platinum (6 mg/kg) and melphalan (10 mg/kg) on the appearance of pulmonary and other metastases were measured. The cis-platinum treatment was shown to reduce the number and incidence of metastases of both tumors at various times after treatment. The antimetastatic effectiveness of cis-platinum against these two tumors was increased when 2.4 mg/kg was administered each day for five consecutive days after amputation of the primary. Cyclophosphamide, when administered at two-thirds maximum tolerated dose, had a small promoting effect on the number and incidence of pulmonary metastases of Lewis lung carcinoma, whereas, applied in the same dose, it had efficacy in the treatment of disseminated B16 melanoma and inhibited appearance of both pulmonary and lymph-node metastases. When melphalan was administered in single- and multiple-dose regimens, the number and incidence of metastases of both tumors increased at various times after primary tumor amputation. These data suggest that melphalan can promote the growth of disseminated tumor cells in both the lungs and other sites and that some systemic chemotherapies may result in promotion instead of suppression of metastatic disease.

Topics: Cisplatin; Cyclophosphamide; Drug Administration Schedule; Humans; Lung Neoplasms; Lymphatic Metastasis; Melanoma, Experimental; Melphalan; Neoplasm Metastasis; Neoplasms, Experimental

Patients with regional metastases of malignant melanoma (75 with Stage IIIA soft tissue metastases, 124 with Stage IIIB nodal metastases and 75 with Stage IIIAB soft tissue and nodal metastases) treated by regional perfusion between 1957 and 1982 were retrospectively studied to identify prognostic factors relating to survival. In patients with Stage IIIB disease, the melanoma specific cumulative survival rates at five years was 72 per cent for one, 33 per cent for two to three and 20 per cent for four or more positive lymph nodes. In patients with Stage IIIAB disease, those with one node had a better survival rate at five years than those with multiple nodes (45 versus 25 per cent). In patients with Stage IIIA melanoma, two groups were identified based upon the results of prior treatment--those with and without prophylactic lymph node dissection (PLND) at the time of primary therapy. The factors associated with decreased survival rates in patients with PLND were: 1, increasing age; 2, presence of subcutaneous or both subcutaneous and dermal metastases, and 3, treatment at normothermic temperatures or earlier date of treatment. No significant factors were found in the group without PLND; however, the survival time was similar to that for patients with Stage IIIAB and one positive node (45 per cent at five years). Knowledge of these factors is important in assessing the prognosis and establishing randomization criteria for prospective studies evaluating various forms of therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Lymphatic Metastasis; Male; Melanoma; Melphalan; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Soft Tissue Neoplasms

Twenty-nine patients were treated with 31 courses of high-dose combination cyclophosphamide, cisplatin, and carmustine (BCNU) with and without melphalan with autologous bone marrow support. Toxicity was dose related. The maximum tolerated dose for cyclophosphamide, cisplatin, and BCNU in this combination in mg/m2 was 5,625, 165, and 600, respectively. Further dose escalation was precluded by the development of multiple organ toxicity, including venoocclusive disease, refractory thrombocytopenia, and hypertension. Melphalan added to the three-drug combination produced excessive renal and gastrointestinal toxicity. Objective tumor regression occurred in 21 of 25 evaluable cases. The results suggest that selected alkylating agents can be combined in full or nearly full doses before nonmyelosuppressive dose-limiting toxicity precludes further escalation.

Topics: Adult; Alkylating Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carcinoma; Carmustine; Cisplatin; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Evaluation; Drug Tolerance; Female; Humans; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Sarcoma

We have devised a method utilizing a monoclonal antibody-toxin conjugate (LICR-LON-Fib75/abrin A-chain) for ridding bone marrow of infiltrating breast cancer cells to rescue patients with autologous bone marrow following high dose therapy. Initially we examined the activity of this conjugate in vitro. Five of seven human breast cancer cell lines were killed following exposure at 10(-8) M for 2 h; this concentration only reduced bone marrow colony formation to 83% (range, 50-100%) of control bone marrow. We then examined the pattern of bone marrow recovery after high dose melphalan (200 mg/m2) in patients with advanced breast cancer who were in remission following combination chemotherapy. To do this we compared the time of recovery of the blood count in three patients who received treated marrow and seven who received untreated marrow. Mean time to recovery of the peripheral white count (greater than 1.5 X 10(9)/liter) was 16.7 days (treated) and 18.3 days (untreated), respectively. Mean time to recovery of peripheral platelet count (greater than 50 X 10(9)/liter) was 23.7 days (treated) and 18.9 days (untreated), respectively. Patients continued in remission for 1-greater than 14 mo after high dose melphalan, and remission duration was similar in patients who received treated (6.2 mo) and untreated (7.3 mo) bone marrow. These findings indicate that treatment of bone marrow with LICR-LON-Fib75/abrin A-chain conjugate does not significantly impair bone marrow recovery, and it is, therefore, possible to rescue breast cancer patients with bone marrow that has been cleansed of infiltrating cancer cells. This may have an application in patients with poor-risk primary breast cancer who have micrometastases and who may benefit from intensive therapy, but it has minimal application in patients with more advanced disease.

Topics: Abrin; Antibodies, Monoclonal; Bone Marrow; Bone Marrow Transplantation; Breast Neoplasms; Cell Line; Female; Humans; Melphalan; Neoplasm Metastasis; Tumor Stem Cell Assay

Colon carcinoma, the second leading cause of cancer-related deaths in the United States, is resistant to chemotherapy in a large majority of cases. Single-agent and combination chemotherapy have failed to prolong survival. New approaches are clearly needed. In experimental models, a steep dose-response curve for colorectal cancer has been demonstrated using various agents. The hematopoietic toxicity of high-dose therapy with these drugs can be circumvented by autologous bone marrow transplantation. We investigated the use of high-dose melphalan with autologous bone marrow rescue in 20 patients with metastatic colon carcinoma. Each patient received melphalan, 180 mg/m2 intravenously (IV), followed eight hours later by bone marrow infusion. Median duration of granulocytopenia (less than 500 neutrophils/microL) was twelve days (range, 5 to 35 days), while transfusion-dependent thrombocytopenia (less than 20,000 platelets/microL) had a median duration of eight days (range, 3 to 23 days). Time to bone marrow engraftment was not affected by prior 5-fluorouracil therapy. Nausea and vomiting occurred in 14 patients but was generally short lived. Mild stomatitis, esophagitis, and diarrhea were common. Severe gastrointestinal (GI) side effects did not occur. One treatment-related death occurred secondary to intramural tumor necrosis, which resulted in massive lower GI bleeding. Complete responses were observed in three patients (15%) and partial responses in six patients (30%), for an overall response rate of 45%. Median survival was 198 days in this group of patients with extensive disease. High-dose melphalan therapy for metastatic colon carcinoma, when used with autologous bone marrow transplantation, appears to achieve a high response rate with tolerable toxicity. Further investigation is needed to define the role of this therapy in the care of advanced colon carcinoma.

Topics: Adult; Aged; Bone Marrow Transplantation; Colonic Neoplasms; Combined Modality Therapy; Drug Evaluation; Gastrointestinal Diseases; Hematologic Diseases; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Tomography, X-Ray Computed

A clinical evaluation of peptichemio (40-45 mg/m2/day for 3 days every 3-4 weeks) was conducted in 32 patients with advanced breast cancer, 28 of whom were evaluable for both toxicity and response. The overall response rate was 18% (one complete remission and four partial remissions), with a median duration of 4 months (range, 2-6). The major side effects were cumulative myelotoxicity, phlebitis, mild nausea, and vomiting. A posttreatment heparin infusion was used to prevent phlebitis.

Topics: Breast Neoplasms; Drug Administration Schedule; Drug Evaluation; Female; Hematologic Diseases; Heparin; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Peptichemio; Thrombophlebitis

Three cases of advanced epithelial ovarian carcinoma Stage III-IV which could not be submitted to classical surgical and oncological treatment (BSO-TH) are presented. After a year of chemotherapy a complete remission was observed. Myometrial and myocervical micrometastases were found in a specimen from the hysterectomy, carried out during second-look, that was negative. These micrometastases, when they are present, apparently show a different chemosensitivity, as compared with other metastasis localization. The causes of this phenomenon are analyzed.

Topics: Female; Humans; Hysterectomy; Melphalan; Neoplasm Metastasis; Ovarian Neoplasms

The effect of known chemotherapeutic programs in patients with breast cancer who developed metastasis during or after adjuvant chemotherapy with L-PAM plus 5-FU (PF) were studied. Thirteen patients failed while receiving adjuvant therapy at 3-22 months from the time therapy started. Three patients failed 6-28 months after 2 years of therapy. Thirteen patients received PF followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) at the time of progression on PF. Of these, ten received Adriamycin and vincristine (AV) at the time of progression on CMF. The response to CMF was 7%. No patient responded to AV after progression on CMF. Two of three patients treated with AV after failure on PF did respond, but both for only 6 months. This suggests that adjuvant therapy may render the tumor less responsive to further chemotherapy. Since most patients failed while on adjuvant therapy, this may indicate a poor prognosis regardless of the agents used.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Prognosis; Tamoxifen; Vincristine

Exposure of MOPC-315 cells from the primary tumor nodule to a low concentration (0.5 nmol/ml) of melphalan (L-phenylalanine mustard; L-PAM) rendered the tumor cells capable of bringing about the generation of a potent primary antitumor cytotoxic response. Accordingly, the level of antitumor cytotoxicity generated by normal spleen cells immunized in vitro with L-PAm-treated tumor cells was at least five-fold greater than the level generated in response to untreated tumor cells. The marked superiority of L-PAM-treated tumor cells over untreated tumor cells in bringing about the generation of antitumor cytotoxicity was evident over a wide range of responder to stimulator cell ratios. The higher level of antitumor cytotoxicity exhibited by normal spleen cells immunized with L-PAM-treated tumor cells as compared with untreated tumor cells was not merely the result of direct drug-mediated tumoricidal activity, thereby reducing the number of tumor cells present which can act as cold target cell inhibitors during the 51Cr release assay. This is apparent from the observation that the level of antitumor cytotoxicity generated in response to a given percentage of stimulator tumor cells pretreated with 0.5 nmol L-PAM/ml, a drug concentration associated with retention of 60% tumor cell proliferative capacity, is substantially greater than that generated in response to less than half that percentage of untreated stimulator tumor cells. Moreover, stimulator tumor cells exposed to a fully antiproliferative concentration of L-PAM brought about the generation of a higher level of antitumor cytotoxicity than stimulator tumor cells exposed to mitomycin C at a concentration which inhibited the proliferation of the tumor cells to the same extent as the L-PAM. A low concentration of L-PAM which was effective in rendering isolated tumor cells from the primary tumor nodule capable of bringing about the generation of antitumor cytotoxicity was also effective in inducing the appearance of potent antitumor immune potential in tumor bearer splenic cells containing metastatic tumor cells.

Topics: Animals; Cell Division; Cytotoxicity, Immunologic; Immunity, Cellular; Melphalan; Mice; Mitomycin; Mitomycins; Neoplasm Metastasis; Neoplasms, Experimental; Spleen

The pharmacokinetics of isolated limb perfusion were studied to see what melphalan concentrations were achieved and how effective the isolation was. Twenty-eight patients received 32 limb perfusions with heat and melphalan for locally recurrent or level V melanoma. Melphalan was given 0.75 mg/kg for axillary/popliteal or 1.2 mg/kg for femoral perfusions with heat (perfusate 42 degrees C, limb 40 degrees C) for 1 hour. Melphalan concentratives were measured by high-performance liquid chromatography in seven patients. Peak perfusate melphalan concentrations were 6.1 to 115 mg/ml, which was one to two logs higher than peak systemic concentratives of melphalan. Isolation of the perfusate circuit from the systemic circulation was better for axillary and popliteal perfusions than for femoral perfusions (P less than 0.05). Complete responses were seen in 81% of evaluable patients; long-term local control was achieved in most patients, although many developed hematogenous metastases. Toxicity included erythema and edema in all, mild leukopenia in two, neuropathy in two, and amputation was required in one patient. Improvements in surgical technique include regional anesthesia to reduce vasospasms and transcutaneous measurement of fluorescein to measure leak. Perfusion with heat and melphalan remains the treatment of choice for in-transit metastases from melanoma.

Topics: Chemotherapy, Cancer, Regional Perfusion; Extravasation of Diagnostic and Therapeutic Materials; Extremities; Female; Hot Temperature; Humans; Kinetics; Male; Melanoma; Melphalan; Neoplasm Metastasis; Skin Neoplasms

Nine children with poor-prognosis malignancies--seven with advanced neuroblastoma and two with metastatic Ewing's sarcoma--were given high doses of melphalan (HDM), 150 mg/m2 (3 patients) and 180 mg/m2 (6 patients), as a 'late intensification' agent combined with noncryopreserved autologous bone marrow transplants. Melphalan levels in the plasma decreased biphasically, with mean half-lives of 6.6 min and 3.0 h. At the time of marrow reinfusion (12-21 h after HDM) the melphalan plasma level was generally below 0.1 microgram/ml. The renal contribution to melphalan clearance was low, a mean of 5.8% of the injected dose being found in patients' urine over the 12 h following HDM administration. No significant difference was seen in pharmacokinetic parameters between patients undergoing and not undergoing forced diuresis.

Topics: Child; Child, Preschool; Dose-Response Relationship, Drug; Half-Life; Humans; Infant; Kinetics; Male; Melphalan; Neoplasm Metastasis; Neuroblastoma; Sarcoma, Ewing

The human tumor colony-forming assay was used to compare chemosensitivity among tumor cells within a primary tumor, between primary tumor and metastases, and between different metastases. No significant differences in cloning efficiency were found in any of the three comparison studies. However, considerable differences in chemosensitivities were observed between different parts of the same tumor and between the primary tumor and metastases. Two different parts of the same tumor were comparably assayed for nine primary tumors. In nine paired samples which allowed in vitro drug sensitivity testing, there was no satisfactory correlation of sensitivity to cytostatic drugs. Cell suspensions were prepared from 28 primary tumors and from metastases taken from the same patient. In 14 paired samples which formed sufficient colonies for determination of drug effect, the data showed no satisfactory correlation of chemosensitivity between a primary tumor and its metastases. Both tumor samples from different metastatic sites of the same patient formed sufficient colonies in seven of eight instances. In the seven paired samples, there was strong association of chemosensitivity (p less than 0.005). The results indicate that the reported discrepancies of in vitro and in vivo results in clinical trials using the tumor colony-forming assay for predicting resistance or sensitivity to cytostatic drugs may be due to therapeutic heterogeneity among tumor colony-forming units within a primary tumor and between a primary tumor and its metastases.

Topics: Antineoplastic Agents; Bleomycin; Cell Division; Cell Survival; Cells, Cultured; Cisplatin; Doxorubicin; Fluorouracil; Humans; Kinetics; Male; Melphalan; Mitomycin; Mitomycins; Neoplasm Metastasis; Neoplasms

Fifty-seven patients with metastatic breast carcinoma have been treated with mitomycin C (10 mg/m2 IV 6-weekly), melphalan (6 mg/m2 PO X 3 days, 3-weekly), and methotrexate (35 mg/m2 IV 3-weekly) to assess the efficacy and toxicity of this regimen. Of 48 evaluable patients 19 (40%) responded for a median period of 5 months and 12 (25%) had stabilisation of disease. Of the 12 patients previously treated with adriamycin only one responded, whereas 18 of the 36 patients without previous chemotherapy responded. Although healing of bone metastases was infrequent control of hypercalcaemia was commonly seen. Generally the treatment was well tolerated and treatment was stopped in only five patients because of toxicity. Cumulative marrow toxicity was observed but was not a significant problem in the first 6 months of treatment. Mitomycin C, melphalan, and methotrexate (MMM) appears to provide an effective, well tolerated chemotherapy combination for metastatic breast carcinoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Evaluation; Female; Gastrointestinal Diseases; Hematologic Diseases; Humans; Melphalan; Methotrexate; Middle Aged; Mitomycin; Mitomycins; Neoplasm Metastasis; Palliative Care

Topics: Antineoplastic Combined Chemotherapy Protocols; Arm; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Doxorubicin; Female; Hot Temperature; Humans; Leg; Male; Melanoma; Melphalan; Neoplasm Metastasis; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms

Topics: Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Hyperthermia, Induced; Melanoma; Melphalan; Neoplasm Metastasis; Skin Neoplasms

Eleven patients with metastatic thyroid cancer received combination chemotherapy with doxorubicin, bleomycin, vincristine, and melphalan. Six of 11 patients responded, two with a minor response, three a partial, and one with a complete response. Most responses were brief (2-3 months), but the patient with a complete response is alive and free of disease at 60+ months. Toxicity was moderate and predominantly hematologic. Thyroid carcinoma is a moderately sensitive neoplasm with occasional prolonged responses to chemotherapy.

Topics: Adult; Aged; Bleomycin; Doxorubicin; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Thyroid Neoplasms; Vincristine

A combination of AMSA and peptichemio was evaluated in patients with advanced breast cancer refractory to conventional chemotherapy. Of 33 evaluable patients, five patients (15%) achieved partial remission, two patients (6%) had less-than-partial remission, nine patients (27%) had stable disease, and seventeen patients (52%) had progressive disease. The median duration of response was 6 months (range: 3-8 months). The median duration of stable disease was 5 months (range: 2-7 months). Myelosuppression was the dose-limiting toxicity. This combination of AMSA and peptichemio did not result in an improved response rate or duration of remission compared to the previous experience with single-agent therapy with either of these agents.

Topics: Adult; Aged; Aminoacridines; Amsacrine; Antineoplastic Agents; Breast Neoplasms; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Leukopenia; Melphalan; Middle Aged; Neoplasm Metastasis; Peptichemio; Thrombocytopenia

Unscheduled DNA synthesis (UDS) indicated by melphalan was studied in freshly collected tumor cells from human melanoma metastases. Comparative studies were done on human bone marrow blast cells. Significant levels of UDS comparable with those in myeloblasts were found in only two of eight melanoma cell populations. This difference between melanoma and blast cells was not related to different cellular uptake of melphalan. When UDS was induced by ultraviolet irradiation, significant levels of UDS were found in all melanoma and blast cell populations studied. Also, in a human melanoma cell line, high levels of UDS were found after exposure to ultraviolet irradiation, while treatment with melphalan did not result in detectable levels of UDS. Possible explanations for the divergent results of UDS in melphalan-exposed melanoma cells are discussed.

Topics: Bone Marrow; Cell Line; DNA Repair; DNA Replication; DNA, Neoplasm; Female; Humans; Hydroxyurea; Male; Melanoma; Melphalan; Neoplasm Metastasis; Ultraviolet Rays

From September 1969 through 1979, 68 patients with already locally metastasized malignant melanomas of the extremities were treated by hyperthermic regional perfusion and local excision(s). Of these, 53 patients could be evaluated after a follow-up of at least 2 years: 31 had been perfused with melphalan and 22 with melphalan in combination with actinomycin D. Local recurrence rates were about the same in both groups: 32 versus 33%. The same applied to the symptom-free interval between perfusion and local recurrence: about 12 versus about 13 months. Virtually all recurrences in both groups (90 versus 85%) were seen within 2 years. The interval between perfusion and systemic metastization was also roughly the same: about 25 versus about 23 months. These results indicate the need for better chemotherapeutics in order to achieve further improvement. The results of these perfusions were otherwise by no means disappointing, and hyperthermic regional perfusion is indicated in the treatment of patients with locally metastasized malignant melanomas.

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Drug Therapy, Combination; Extremities; Female; Hot Temperature; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local

As the observation times of current studies using adjuvant chemotherapy in the treatment of operable stage II breast cancer lengthen, the probability of significantly reducing the high risk of developing metastases associated with this stage of the disease is also increasing and should be reflected in improved cure rates. The theoretical basis, prerequisites and presently available results for adjuvant chemotherapy of breast cancer are discussed. Adjuvant combination chemotherapy provides better results than monochemotherapy with Alkeran. While earlier results suggested that adjuvant chemotherapy is especially effective in premenopausal women, newer studies and analyses indicate that appropriate dosage and consistent administration of chemotherapy are of decisive importance. Exact determination and documentation of the tumor stage, and especially the regional lymph node status, is the most important factor in determining the indication for adjuvant chemotherapy. Adjuvant chemotherapy is still best with many unsolved problems. These include the duration, necessary intensity based upon risk factors, and short- and long-term side effects.

Topics: Adult; Breast Neoplasms; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Lymphatic Metastasis; Melphalan; Menopause; Methotrexate; Middle Aged; Neoplasm Metastasis; Prednisone; Risk; Vincristine

The results of treatment of 110 out-patients with breast metastases, using various repeated schemes of chemotherapy, are discussed. The results and recommendations may be integrated with the procedures of selection of schemes of breast metastasis treatment. Good tolerance, virtual absence of side--effects and complications (e. g. persistent leukopenia) were observed. Integration of the new scheme with antibiotic treatment (carminomycin and adriamycin) is suggested.

Topics: Breast Neoplasms; Cyclophosphamide; Drug Evaluation; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Neoplasm Metastasis; Prednisolone; Time Factors; Vincristine

The results of the treatment of the prevalent form of Ewing's sarcoma in 85 children aged 3 to 16 years with various methods are presented. 21 patients were subjected to monochemotherapy with sarcolysine or cyclophosphamide. 26 patients received monochemotherapy with sarcolysine or cyclophosphamide in combination with irradiation of the metastases. Polychemotherapy in combination with radiotherapy was applied to 38 patients. The polychemotherapy in combination with radiotherapy was applied to 38 patients. The polychemotherapy included cyclophosphamide, vincristine, methotrexate, dactinomycin and carminomycin used in various combinations. The schemes of the polychemotherapy are presented. The best results were obtained with the use of the polychemotherapy in combination with radiotherapy: the index of the 3-year survival amounted to 38.5+/-14 per cent, while in the patients subjected to the monochemotherapy in combination with irradiation of the metastases it was equal to 3.8+/-3.7 per cent. After the monochemotherapy used alone all the children died by the 2nd year. It is concluded that patients with the prevalent form of Ewing's sarcoma should b subjected to systematic treatment. Polychemotherapy in combination with radiotherapy is shown to be promising.

Topics: Adolescent; Carubicin; Child; Child, Preschool; Cyclophosphamide; Daunorubicin; Drug Evaluation; Drug Therapy, Combination; Humans; Melphalan; Neoplasm Metastasis; Radiotherapy Dosage; Sarcoma, Ewing

It is reported on the symptomatology, diagnostics and therapy in a 54-year-old patient with a micromolecular plasmocytoma of kappa-type. Here particularly the impressionable improvement of the clinical picture after an intermitting impact therapy with melphalan (alkeran) - prednisolone in a period of treatment of approximately 2 years is emphasized.

Topics: Bence Jones Protein; Humans; Immunoglobulin kappa-Chains; Lumbar Vertebrae; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Osteolysis; Plasmacytoma; Prednisolone; Radiography

In a total of 1,828 determinations, urinary excretion of 5-S-Cysteinyldopa was studied over a period of three years in 384 patients treated for melanoma or with metastases of malignant melanoma. By serial investigations the excretion of 5-S-Cysteinyldopa was compared to the course of the disease. In the case of small and circumscribed metastases which could be eliminated by surgical treatment, the excretion of 5-S-Cysteinyldopa remained normal. When the disease became generalized, an increase of the urinary excretion of 5-S-Cysteinyldopa prior to the clinical manifestation of the metastases was observed in only four out of 26 cases. In the remaining cases, the increase of 5-S-Cysteinyldopa coincided with the manifestation of metastases, or the excretion of the substance became pathological when the metastases were already conspicuous. In five patients, the urinary excretion of 5-S-Cysteinyldopa remained normal inspite of widespread disease. Therefore, its diagnostic value seems to be similar to that of the "common" laboratory investigations the results of which are only pathological when the disease has already become generalized. Our investigations demonstrate that serial investigations of the urinary excretion of 5-S-Cysteinyldopa only rarely indicate melanoma metastases prior to their clinical manifestation. In cases of early metastasing melanoma, all common laboratory investigations are of limited value. BSR and GGT levels which become pathological very early in the course of the disease are so sensitive that slightly pathological levels may be ambiguous. In these cases, however, pathological levels of 5-S-Cysteinyldopa most probably will indicate a widespread disease.

Topics: BCG Vaccine; Cysteinyldopa; Dihydroxyphenylalanine; Female; Humans; Male; Melanoma; Melphalan; Neoplasm Metastasis; Skin Neoplasms

A transplantable non-immunogenic murine carcinoma of spontaneous origin, WHT Carcinoma N-C (Hewitt), was used to assess the effectiveness of melphalan (Ml) and/or methotrexate (Mx) for treatment of occult metastatic disease following surgical excision of primary tumors. Early surgical excision alone cured 66% of mice; later excision gave no cures. Maximum sublethal doses of chemotherapy rarely cured mice of metastases but did extend their survival time by up to 66% as compared with mice subjected to excision only. The influence of excision and chemotherapy on the frequency of local recurrence or pulmonary metastasis is discussed. Extrapulmonary metastases were 2.5 times more frequent in long-term than in short-term survivors, independently of treatment.

Topics: Animals; Drug Therapy, Combination; Female; Lung Neoplasms; Male; Mammary Neoplasms, Experimental; Melphalan; Methotrexate; Mice; Neoplasm Metastasis; Neoplasm Recurrence, Local

The experimental synergism of melphalan with DTIC and the ability of transfer factor to improve immunocompetence were the basis of an attempt to improve therapeutic results in disseminated malignant melanoma. Sixty-four evaluable patients with disseminated malignant melanoma were treated in a 21-day cycle as follows: DTIC 250 mg/M2 intravenously days 1 to 5, Connaught BCG 6 X 10(8) organisms on days 7, 12, and 17 by scarification, and transfer factor 1 unit (10(9) lymphocytes equivalent, from immunocompetent relatives of patients) subcutaneously on day 12, with or without L-PAM 30 mg/M2 on day 1. Twenty-nine patients received L-PAM and 35 did not. Remission rates of 17% and 23%, respectively, occurred in these groups. An additional 15 patients received DTIC-BCG and three doses of transfer factor on days 7, 12, and 17 and had a remission rate of 20%. Remission duration and survival were compared to historical controls of 111 patients treated with DTIC and 89 treated with DTIC-BCG. Median survival on DTIC-BCG-Transfer Factor was seven months compared to four months for DTIC (P = .003) but did not differ from DTIC-BCG. Addition of L-PAM did not improve remission duration or survival compared to DTIC-BCG but enhanced myelosuppression and immunosuppression. A 60% increase in delayed type hypersensitivity to recall antigens occurred in this study compared to 34% with DTIC-BCG (P = .005). Prognosis and immunocompetence were not directly related. In summary, in this study, (1) transfer factor therapy did not enhance the clinical effects of DTIC-BCG, although it augmented delayed type hypersensitivity to recall antigens; and (2) L-PAM was not additive to DTIC in the treatment of disseminated malignant melanoma and may have abrogated the effect of immunotherapy.

Topics: Adult; Aged; BCG Vaccine; Blood Cell Count; Dacarbazine; Drug Therapy, Combination; Female; Humans; Immunocompetence; Immunotherapy; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Prognosis; Skin Tests; Time Factors; Transfer Factor

The purpose of this study was to evaluate therapy with melphalan, 5-fluorouracil (5-FU), and medroxyprogesterone acetate combination (MFP) in women with metastatic or recurrent endometrial carcinoma not amenable to surgery or radiation therapy, as compared to progesterone therapy alone. Previously, the authors have treated 114 women with progesterone therapy and achieved a 15.8% objective response rate; 7.0% were complete responders. Thirteen women with documented recurrent or metastatic endometrial carcinoma were entered into the MFP study. Thirteen were evaluable for toxicity and 11 for response (2 had no measureable parameter). Treatment consisted of melphalan 0.2 mg/kg/day for 4 days every 4 weeks; 5-FU 15 mg/kg/day for 4 days every 4 weeks; and medroxyprogesterone acetate 1.0 g intramuscularly weekly. Two of the first 3 patients who were treated with this regimen developed severe thrombocytopenia (platelets, 25,000 and 17,000/mm3). Therefore, the remaining 10 patients received 5-FU at a dose of 10 mg/kg/day for 4 days every 4 weeks. Except for 1 patient who devloped thrombophlebitis, there was no other significant toxicity in the 90 courses of therapy received by the 13 women. Of the 11 women evaluable for respone, 6 (54.5%) responded (2 complete responders, 4 partial responders), 2 for stationary disease, and 3 progressed after having had stationary disease for 3, 6, and 9 months, respectively. Of special interest was that the 2 women with adenosquamous carcinoma responded and 1 additional patient with adenocarcinoma maintained a complete response with 5-FU therapy alone.

Topics: Adenocarcinoma; Antineoplastic Agents; Drug Therapy, Combination; Female; Fluorouracil; Humans; Medroxyprogesterone; Melphalan; Neoplasm Metastasis; Neoplasm Recurrence, Local; Uterine Neoplasms

Topics: Bone Neoplasms; Breast Neoplasms; Cyclophosphamide; Humans; Lymphoma; Melphalan; Multiple Myeloma; Neoplasm Metastasis; Palliative Care; Prednisone; Vincristine

Topics: Female; Humans; Medroxyprogesterone; Melphalan; Neoplasm Metastasis; Ovarian Neoplasms; Thiotepa

Topics: Adult; Antineoplastic Agents; Bone Marrow; Burns; Creatine Kinase; Electroencephalography; Etoposide; Female; Humans; Hyperthermia, Induced; L-Lactate Dehydrogenase; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasms; Peripheral Nervous System Diseases; Remission, Spontaneous; Tachycardia

Chemotherapy employed in the treatment of metastatic breast cancer effectively palliates the disease. Response rates to combination chemotherapy are high (greater than 50%); response durations, however, are still very short (less than 1 year). Future investigations must focus on the development of alternate maintenance regimens to improve response duration. Other areas for future study include the use of immunotherapy in conjunction with chemotherapy and the combination of chemotherapy and endocrine manipulation.

Topics: Antineoplastic Agents; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Prednisone; Vincristine

Eleven years have elapsed since we first added heat to regional perfusion for treatment of melanoma of the extremities. This report describes briefly our laboratory findings and our technique of hyperthermic perfusion and brings up to date the survival figures for the 165 patients (185 perfusions) which were originally reported in 1975 (Stehlin et al., Surg. Gynecol. Obstet., 122: 3--14, 1966). A dramatic increase in the survival rate is documented for those patients with recurrent melanoma confined to the extremities.

Topics: Chemotherapy, Cancer, Regional Perfusion; Extremities; Hot Temperature; Humans; Immunity; Melanoma; Melphalan; Neoplasm Metastasis; Recurrence; Skin Neoplasms

Topics: Acid Phosphatase; Aged; Drug Evaluation; Humans; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms; Remission, Spontaneous

A 46-year-old woman presented and IgG myeloma without metastases at the time of the diagnosis. A complete hematologic remission was achieved with melphalan and prednisone, but the patient then developed a polysymptomatic condition with myelomatous metastases in different organs. In some cases these were confirmed histologically (meninges, stomach, skin, and scalp); in others there was a strong clinical evidence (liver, oral mucosa, lymph nodes, and lumbar vertebra). There were manifestations of the disease in all of these sites, while complete hematologic remission was maintained. The meningeal metastasis was treated by surgery and irradiation with orbital penetration; the lymph nodes were irradiated, and COPP polychemotherapy was given to treat the rest of the metastatic localizations. In this way an apparently remission was achieved temporarily. The incidence of each one of the extraskeletal manifestations in this unusual case of myeloma is reviewed in the literature.

Topics: Female; Humans; Immunoglobulin G; Lymphatic Metastasis; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Metastasis; Prednisone

Report on the application of a dinitrochlorobenzene ointment of 61 postoperative melanoma patients exhibiting clinical stages I and II. After contact sensitization the erythemogenic threshold concentrations of DNCB were mostly found in the range of 0,05% and 0,1%. Patients with reactions at low concentrations of 0,01% and 0,05% DNCB were in the mean 8 years younger than those with reactions at 0,1% and 0,5%, but no connection to different stages of malignant melanoma could be evaluated. 3 melanoma patients suffering from skin metastases were treated by epifocal DNCB-application. One of them became clinically tumor free since more than 1 year, whereas the two other exhibiting multicentric and/or profound tumor growth did not respond. In a 82-year-old wife a superficial lentigo maligna melanoma disappeared by DNCB-application. In none of the 61 cases we observed a "tumor enhancement" after immunoprophylaxis or adjuvant immunotherapy with DNCB. The DNCB-method in malignant melanoma is yet in the experimental stage and is not recommended for general use in practice.

Topics: Adult; Aged; Dinitrochlorobenzene; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Nitrobenzenes; Postoperative Care; Skin Neoplasms

Topics: Breast Neoplasms; Female; Humans; Melphalan; Neoplasm Metastasis

A case of proved delayed recurrence of a granulosa cell tumor 18 years after initial diagnosis is presented. L-Phenylalanine mustard was given after radiation was refused for the unresectable mass. A prolonged complete remission was produced. The present status of palliative therapy of recurrent granulosa cell tumor is discussed with a request for the reporting of experiences with more patients treated with chemotherapy.

Topics: Female; Granulosa Cell Tumor; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Ovarian Neoplasms; Palliative Care; Remission, Spontaneous; Time Factors

7 patients with advanced malignant melanoma who were given cyclophosphamide (500 mg intravenously) 7 days before a high dose of melphalan (140 mg/m2) had a more rapid recovery of the peripheral white-cell count than did 4 patients who received melphalan alone. "Priming" by cyclophosphamide might be a practicable means of offsetting the bone-marrow toxicity of some chemotherapy regimens and it may permit higher doses of drugs to be given safely.

Topics: Blood-Brain Barrier; Bone Marrow; Bone Neoplasms; Cyclophosphamide; Drug Evaluation; Drug Therapy, Combination; Humans; Injections, Intravenous; Leukocyte Count; Leukocytes; Melanoma; Melphalan; Neoplasm Metastasis; Premedication; Skin Neoplasms

Topics: Adult; Bence Jones Protein; beta 2-Microglobulin; Bone Neoplasms; Fanconi Syndrome; Female; Humans; Immunoglobulin kappa-Chains; Immunoglobulin Light Chains; Lumbar Vertebrae; Melphalan; Neoplasm Metastasis; Plasmacytoma; Prednisone; Radiotherapy Dosage; Spinal Neoplasms; Vincristine

Topics: Breast Neoplasms; Cyclophosphamide; Female; Fluorouracil; Hormones; Humans; Immunotherapy; Mastectomy; Melphalan; Methotrexate; Neoplasm Metastasis

In a prospective phase II study, 25 patients with advanced (Duke's D) colorectal adenocarcinoma received 0.25 mg/kg of melphalan orally daily for 4 days every 28 days. There were 17 men and eight women. All patients had measurable areas of known malignant disease which served as objective indicators of the response to chemotherapy. All patients were evaluated for at least two cycles of therapy. Each patient had had previous treatment with 5-fluorouracil and, in addition, 24 of 25 patients had had treatment with methyl-CCNU; all patients had disease progression with both regimens. Toxicity consisted of mild gastrointestinal symptoms and transient leukopenia (wbc count less than 4000/mm3) in nine of 25 (36%) patients and thrombocytopenia (platelet count less than 100,000/mm3) in six of 25 (24%). One of 25 (4%) patients had an objective response for 12 weeks, 15 of 25 (60%) had disease progression, and nine of 25 (36%) remained stable for 2 months. We conclude that melphalan is ineffective for patients with metastatic colorectal carcinoma who have previously failed to respond to both 5-fluorouracil and methyl-CCNU.

Topics: Adenocarcinoma; Adult; Aged; Colonic Neoplasms; Drug Evaluation; Female; Fluorouracil; Humans; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Prospective Studies; Rectal Neoplasms; Semustine

Topics: Adenocarcinoma; Adult; Aged; Bone Marrow; Breast Neoplasms; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Recurrence

Topics: Animals; Antineoplastic Agents; Chlorambucil; Drug Synergism; Goats; Humans; Immunoglobulins; Immunotherapy; Melanoma; Melphalan; Neoplasm Metastasis; Nitrogen Mustard Compounds; Skin Neoplasms; Vincristine

Treatment for primary malignant tumors of bone, in the past several decades, has yielded uniformly poor results. Recent progress in chemotherapy and immunotherapy are detailed. An important advance in treating osteogenic sarcoma has been the application of adjuvant chemotherapy after initial amputation. CONPADRI-I and COMPADRI-II chemotherapy (a multiple drug approach) is discussed. Adriamycin in combination or alone has proved effective in treating osteogenic sarcoma. Ewing's tumor is showing increased survival rates from radiation therapy alone, as well as by use of systemic adjuvant chemotherapy combined with local radiation. Adjuvant triple chemotherapy with radiotherapy has resulted in pronounced improvement in survival. Chondrosarcomas are largely chemotherapy-resistant. Immunotherapy in bone tumors still is in the experimental stage and investigations with immunotherapy are preliminary. It appears, however, that the immunological status of a patient definitely relates to prognosis. Through increased sophistication in specific chemotherapy and magnitude of treatment, further advances in treatment of primary malignant bone tumors may be expected.

Topics: Amputation, Surgical; Bone Neoplasms; Cyclophosphamide; Doxorubicin; Humans; Immunity, Active; Immunity, Maternally-Acquired; Immunotherapy; Melphalan; Neoplasm Metastasis; Osteosarcoma; Postoperative Care; Sarcoma, Ewing; Vincristine

A 49-year-old man with multiple myeloma, IgA type, contracted cutaneous plasmocytomas. No deposits of immunoglobulin were found in the cutaneous tumor by direct immunofluorescence. The case is an unusual manifestation occurring in multiple myeloma.

Topics: Fluorescent Antibody Technique; Humans; Immunoglobulin A; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Metastasis; Skin Neoplasms

To estimate the leukemogenic potential of alkylating agents, we surveyed 70 institutions using these drugs for the frequency of second cancers in patients with advanced ovarian cancer. Thirteen cases of acute nonlymphocytic leukemia occurred among 5455 patients, as compared to 0.62 cases expected (relative risk = 21.0). All 13 had received alkylating agents. Nine also received radiotherapy. The relative risk for patients given chemotherapy was 36.1 and rose to 171.4 for those surviving for two years (rate = 13.75 per 1000 patients per year). To evaluate the role of therapy versus underlying disease, a historical control of 13,309 patients with ovarian cancer in the National Cancer Institute's End Results Program was analyzed. No excess of leukemia was noted in this group, even among 6596 women receiving radiation. The excess of acute nonlymphocytic leukemia, therefore, appears attribute to alkylating agents, although the effect may be enhanced by exposure to radiation, as previously suggested for Hodgkin's disease.

Topics: Acute Disease; Alkylating Agents; Altretamine; Chlorambucil; Cyclophosphamide; Female; Fluorouracil; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Neoplasm Metastasis; Ovarian Neoplasms; Risk; Thiotepa; Time Factors; Uracil Mustard

Metastatic tumor incidence in BALB/C X DBA/8F1 female mice was examined in the presence and absence of adjuvant chemotherapy. Following surgical removal of spontaneous mammary adenocarcinomas, phenylalanine mustard, adriamycin, and 5-fluorouracil (PAF) were administered at 4, 2, and 50 mg/kg, respectively, once a week for six injections. Recurring tumors and new tumors developing in other breasts over the next 6 months were noted and surgically removed to allow time for originally undetectable pulmonary metastases to develop or to regress completely. This regimen of PAF significantly decreased original tumor recurrences from 58% in controls to 36% in treated mice. New tumor development also was significantly reduced during the 5 weeks of PAF therapy and for 8 weeks thereafter. However, the incidence of pulmonary metastasis was unaffected by the chemotherapy, being 42% in controls and 37% in PAF-treated mice. About 30% of these metastases would have been undetectable at the time of original surgery. The findings stress the importance of developing agents and/or schedules that will specifically affect metastatic cells when administered early to minimal numbers of tumor cells. This system represents a stringent clinimimetic model for evaluating adjuvant chemotherapy in this regard.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Lung Neoplasms; Male; Mammary Neoplasms, Experimental; Melphalan; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary

Of 25 patients with estrogen-unresponsive prostatic adenocarcinoma submitted to multi-drug chemotherapy 6 had partial objective regression, 12 had objectively stable disease and 7 had progressive disease. The survival rates in the 3 groups were 63, 52 and 40 weeks, respectively.

Topics: Administration, Oral; Antineoplastic Agents; Drug Administration Schedule; Drug Evaluation; Drug Therapy, Combination; Estrogens; Fluorouracil; Follow-Up Studies; Humans; Injections, Intravenous; Male; Melphalan; Methotrexate; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms; Vincristine

16 patients with cutaneous or subcutaneous melanoma recurrence on an extremity were treated with regional perfusion with Melphalan. 18 perfusions were performed on 15 patients with stage II disease, that is with tumor growth restricted to an extremity including possible regional node metastases. All patients except two had new recurrences within the observation time. However, many of the patients had been treated surgically for recurrences once or several times previously. By comparing the length of the recurrence-free period following surgery alone with that following surgery plus perfusion in the same patients it was shown that perfusion treatment gave a significant extension of the recurrence-free time. Four perfusions were performed on patients in stage III, that is those with distant metastases. These perfusions gave a moderate or good temporary palliation as regards to tumor growths on the extremity. The traditional treatment for melanoma recurrences on an extremity has been surgical excision or less often amputation. An analysis of the literature shows that perfusion, usually combined with excision, seems to give definitely better results than surgical excision alone. There is evidence to suggest that perfusion treatment is even superior to amputation as regards survival; if so an immunological mechanism might be responsible for this effect.

Topics: Amputation, Surgical; Chemotherapy, Cancer, Regional Perfusion; Drug Evaluation; Evaluation Studies as Topic; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Skin Neoplasms

A patient with a progesterone-producing granulosa cell carcinoma is the basis of this report. Seven years after initial surgical therapy pelvic masses were palpated. At laparotomy the recurrence of tumor was confirmed, and many nonresectable metastases were discovered on the surface of the liver and on the mesentery of the bowel. An exceedingly high plasma progesterone level of 6270 pg/ml was obtained in the postoperative period. During 12 months of single agent chemotherapy with melphalan, serial plasma progesterone assays declined to 310 pg/ml. Complete tumor regression was subsequently confirmed by laparoscopy. Evaluation of progesterone levels in patients with granulosa cell tumors is recommended to determine the incidence of this finding and to further assess its value in following response to therapy.

Topics: Aged; Female; Granulosa Cell Tumor; Hormones, Ectopic; Humans; Hysterectomy; Melphalan; Neoplasm Metastasis; Ovarian Neoplasms; Progesterone

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Drug Therapy, Combination; Female; Humans; Lomustine; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Nitrosourea Compounds; Prednisone

Asaley is an L-leucine derivative of sarcolysin which is more active against some rodent tumors. Studies in the USSR demonstrated activity in patients with ovarian and breast carcinoma, Hodgkin's disease, and multiple myeloma. This study in 73 evaluable patients indicated that an appropriate oral dose for patients with adequate bone marrow is 800 mg/M2/day X 4 days at 5-6 week intervals. The most common toxicities were myelosuppression, nausea, and vomiting. Antitumor activity was observed in 2 of 24 evaluable patients with melanoma, and stabilization of previously progressive disease was observed in patients with adenocarcinoma of the colon, multiple myeloma, lymphoma, breast carcinoma, and thyroid carcinoma. Responses were minimal and of short duration but most of the patients had received extensive prior therapy.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Animals; Bone Marrow; Colonic Neoplasms; Drug Administration Schedule; Drug Evaluation; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Multiple Myeloma; Nausea; Neoplasm Metastasis; Neoplasms; Rats; Remission, Spontaneous; Vomiting

Serial carcinoembryonic antigen (CEA) assays were conducted in patients with endocrine-unresponsive prostatic adenocarcinoma who were being treated with multidrug chemotherapy. Changes in CEA correlated with the clinical status of the patient in 70 per cent of the determinations and were more accurate than acid phosphatase in monitoring the response to treatment.

Topics: Acid Phosphatase; Adenocarcinoma; Carcinoembryonic Antigen; Drug Therapy, Combination; Fluorouracil; Humans; Male; Melphalan; Methotrexate; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms; Vincristine

Topics: Antibodies, Neoplasm; Breast Neoplasms; Cell Division; Female; Humans; Immunity; Kinetics; Lymph Nodes; Lymphatic System; Melphalan; Neoplasm Metastasis; Research Design

Topics: Breast Neoplasms; Cyclophosphamide; Drug Evaluation; Drug Therapy, Combination; Female; Fluorouracil; Humans; Lymphatic Metastasis; Melphalan; Methotrexate; Neoplasm Metastasis; Prednisone; Time Factors; Vincristine

Excision of the primary and isolation-perfusion with 1-phenylalanine mustard was the treatment in 199 patients with invasive Stage I melanoma of the extremities with the goal of improving regional disease control and long-term survival. The determinant survival in patients followed 5-15 years was 83%; Berkson-Gage survivals were 98% at 2 years, 88% at 5 years, and 84% at 10 years. The site of first recurrence was determined in all 49 (25%) patients who failed treatment: three (2%) developed local recurrence, six (3%) developed intransit recurrence, 24 (13%) developed positive regional lymph nodes, 15 (8%) developed systemic metastases, and one developed local recurrence plus positive regional nodes. Of these 49 patients failing treatment, 15 (31%) are currently surviving with no evidence of disease after retreatment of the recurrence. These data are compared to historical controls in the literature. It is concluded that regional control rates are improved by perfusion and that survival has probably been improved. In 14 patients treated by perfusion without local excision, regional control and survival was poor. Single drug (L-PAM) perfusion with the techniques employed is effective in controlling regional subclinical disease, but the primary should be widely excised.

Topics: Adolescent; Adult; Age Factors; Aged; Arm; Chemotherapy, Cancer, Regional Perfusion; Child; Female; Foot; Humans; Leg; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Retrospective Studies; Sex Factors; Skin Neoplasms

Topics: Adolescent; Adult; Aged; Bone Neoplasms; Child; Child, Preschool; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Femoral Neoplasms; Follow-Up Studies; Frontal Bone; Humans; Humerus; Ilium; Male; Mandibular Neoplasms; Maxillary Neoplasms; Melphalan; Middle Aged; Neoplasm Metastasis; Osteosarcoma; Radiotherapy, High-Energy; Sacrum; Sphenoid Bone; Tibia; Vincristine

Recent advances in the use of chemotherapy for treatment of osteosarcoma have altered out pessimism in this disease. Results are presented from 3 groups of investigators using different agents as adjuvant chemotherapy following immediately upon amputation of the primary. The Roswell Park Memorial Institute began a regime, immediately after amputation, of adriamycin 30 mg/M2 for 3 doses and given every 4-6 weeks. This study was subsequently expanded in a cooperative group (ALGB) and the results on 20 patients analyzed. At 19 months approximately 75 per cent are free of any pulmonary metastases compared with 10-25 per cent expected from amputation alone. Similar results have been obtained by other Centers using different chemotherapeutic agents. In Boston Children's Hospital high dose Methotrexate with citrovorum factor is used. In 12 of these patients local control of the primary by surgery was obtained and of these only 1 developed pulmonary metastases during an observation time of 23 months. At the M. D. Anderson Hospital multi-drug combinations were used including Cyclophosphamide, Vincristine, L-Phenylalamine Mustard and Adriamycin. They reported a survival rate of 55 per cent (10 out of 18). All of these neoplastic agents have toxic side effects but when carefully used these effects are minimized and the quality of life is quite good. Many questions must be answered by future controlled long term follow-up studies.

Topics: Amputation, Surgical; Bone Neoplasms; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Humans; Lung Neoplasms; Melphalan; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Vincristine

A four-drug adjuvant chemotherapy regimen (CONPADRI-I) was utilized in the primary treatment of 18 children with osteogenic sarcoma. All patients had surgical amputation for the primary lesion. The children then received cyclophosphamide, vincristine, melphalan, and adriamycin in defined combinations intermittently over a 72-week period. Of the 18 patients, 10 (55%) remain free of disease 24 months or longer from time of amputation.

Topics: Adolescent; Adult; Amputation, Surgical; Antineoplastic Agents; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Heart; Humans; Leukopenia; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Osteosarcoma; Thrombocytopenia; Vincristine

Topics: Breast Neoplasms; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Neoplasm Metastasis; Prednisone; Prognosis; Vincristine

Our studies show that the malignant melanoma cell in human beings is more sensitive to the lethal effect of heat than its normal counterpart, the melanocyte. Malignant melanoma of the extremities presents unique problems; at times, local control can be extremely difficult. The addition of heat to regional perfusion with melphalan has dramatically improved the objective response of melanoma. Complications rise as the tempreature and duration of perfusion increase. These risks must be weighed carefully against the volume and extent of tumor. One hundred and eighty-five hyperthermic perfusions have been perfomed on 165 patients. When done with meticulous attention to details, this procedure is accompanied by minimal morbidity and mortality. Hyperthermic perfusion is currently the best treatment for recurrent melanoma of the extremities and has almost eliminated the necessity for amputation. Perfusion is recommended as a prophylactic measure for the more deeply invasive primary lesions. It reduces the incidence of regional recurrence. A retrospective statistical analysis of survival rates of patients treated with nonheated and heated perfusion for recurrent melanoma, State IIIA, was conducted. If the experience of the heated group continues, which from a clinical standpoint appears likely, then a striking advantage of heated perfusion over nonheated perfusion will be demonstrated. This superiority in survival rates for the heated group is now three to one or 300 per cent. The most reasonable explanation for the improvement in survival time of patients in State IIIA is stimulation of the immune response. As a result of our experience with heated perfusion of limbs, we are investigating the possibility that systemic hyperthermia may enhance the antitumor effects of various chemotherapeutic agents on melanoma.

Topics: Acute Kidney Injury; Age Factors; Aged; Cell Line; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Hot Temperature; Humans; Hyperthermia, Induced; Male; Melanocytes; Melanoma; Melphalan; Neoplasm Metastasis; Pulmonary Embolism; Recurrence; Sex Factors

Topics: Breast Neoplasms; Humans; Lymphatic Metastasis; Mastectomy; Melphalan; Neoplasm Metastasis; Neoplasm Recurrence, Local

Topics: Adult; Age Factors; Aged; Breast Neoplasms; Contraceptives, Oral, Hormonal; Family; Female; Humans; Mastectomy; Maternal Age; Medical Records; Melphalan; Menopause; Middle Aged; Neoplasm Metastasis; Parity; Pregnancy

The survival of melanoma patients is directly related to the involvement of regional nodes and to the microscopic level of invasion of the tumor. During the past 10 years, with the increased use of aggressive surgical therapy (wide local excision or re-excision of the primary tumor and prophylactic dissection of predictably involved regional nodes) the 5-year survival rate has more than doubled. The 5-year survival has doubled in those patients with regional lymph node involvement who were infused for 5 days with L-phenylalanine mustard. Perfusion of the lower extremities with L-phenylalanine mustard has been abandoned at Vanderbilt. The potential aggressiveness of a specific melanoma can be predicted, and thus an appropriate treatment may be planned.

Topics: Adolescent; Adult; Aged; Arm; Child; Female; Head; Humans; Leg; Male; Melanoma; Melphalan; Middle Aged; Neck; Neoplasm Metastasis; Retrospective Studies; Skin Neoplasms; Thorax

Although breast cancer presents as localized disease and is treated with local modalities, i.e. surgery and radiotherapy, patients die with metastatic disease. For patients with positive nodes, the recurrence rates are well known. It is this group of patients who should receive more aggressive treatment. Chemotherapeutic regimens are available that cause responses in patients with advanced disease in the range of 20% to 65%, with about 15% complete responses The current paper deals with the application of several chemotherapeutic regimens at the time of surgery in those patients at high risk. The preliminary results indicate a significant decrease in the recurrence rates. Additional studies combining chemotherapy and hormonal procedures are mentioned.

Topics: Breast Neoplasms; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prednisone

Differences in cytostatic sensitivity between subcutaneously transplanted Lewis lung carcinomas and metastases from them were studied in vitro. Sensitivity to vinblastine sulphate and melphalan was determined as the reduction of the incorporation of H3-thymidine into drug-treated cells compared with control cells. The main result of the present study is that tumor cells obtained from pulmonary metastases are more sensitive to cytostatic drugs in vitro than are the cells obtained from the corresponding subtaneous tumors. When cells from pulmonary metastases are transplanted subcutaneously, the sensitivity of the resulting tumor closely resembles that of other subcutaneous tumors. However, when the tumor cells have been passed through many cycles where the pulmonary metastases from subcutaneous tumors were re-transplanted subcutaneously and then allowed to metastasize again, a selection of tumor cells has apparently occurred: they have become more sensitive even when grown subcutaneously. Different explanations of this phenomenon are discussed.

Topics: Animals; Cells, Cultured; Lung Neoplasms; Melphalan; Mice; Mitosis; Neoplasm Metastasis; Neoplasms, Experimental; Vinblastine

The most common causes of treatment failure in patients with malignant melanoma treated by surgical therapy alone are local or regional recurrences. These are presumed to be due to occult metastasis present at the time of the initial treatment. In an effort to control this occult regional disease, 202 patients with Stage I malignant melanoma underwent isolation-perfusion with 1-phenylalanine mustard between the years 1960 and 1970. The 2-5 and 10-year determinate survival rates were 98%, 86% and 83%, respectively. In these patients, 2% developed local recurrences, 3% developed intransit metastasis, 18% developed positive regional lymph nodes and 6% developed disseminated disease, as their first evidence of recurrence. Over 40% of these patients were benefitted by further therapy. When regional perfusion is used, the question of prophylactic lymph node dissection need not arise. There was one surgical death in this series and only a few patients had symptomatology referable to their limbs beyond 3 months.

Topics: Adolescent; Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Child; Extremities; Female; Humans; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Postoperative Complications; Skin Neoplasms; Time Factors

In an attempt to improve the survival rates in women with advanced ovarian adenocarcinoma (abdominal spread), they were treated with sequential therapy. This consisted of operation followed by chemotherapy, second-look exploratory laparotomy, and finally whole-abdomen irradiation. Only those patients who had a complete clinical response to chemotherapy and subsequently underwent a second operation and irradiation were evaluated. Seventy-five per cent of the patients had recurrent cancer within the treated area after sequential therapy was completed. Morever, of four patients with no gross residual cancer after the second operation, three had cancer recurrences within the treated area. It is concluded that methods of treating advanced ovarian adenocarcinoma other than sequential therapy must be found.

Topics: Adenocarcinoma; Chlorambucil; Cyclophosphamide; Dactinomycin; Female; Fluorouracil; Laparotomy; Melphalan; Neoplasm Metastasis; Neoplasm Recurrence, Local; Ovarian Neoplasms

Topics: Adult; Antineoplastic Agents; Choriocarcinoma; Colchicine; Dactinomycin; Daunorubicin; Female; Flavonoids; Humans; Lung Neoplasms; Melphalan; Mercaptopurine; Methotrexate; Middle Aged; Mitomycins; Neoplasm Metastasis; Olivomycins; Pneumonectomy; Pregnancy; Uterine Neoplasms; Vinblastine

One hundred and sixteen human tumours were transplanted to thymectomized, irradiated, antilymphocyte serum-treated mice. In 12 cases the recipient mice died rapidly, presumably from infection. With the remaining 104 tumours, three-quarters grew to a varying extent, retaining the characteristic histological features of the primary tumours. Implant nodules varied widely in composition, from solid tumour and stroma to dense fibrous tissue without recognizable tumour cells. There was no relation between degree of malignancy and ability to grow, and also some benign tumours grew.In 44 cases, mice were treated with the drug or drugs most likely to be used in the patients and the effects on the implants were assessed histologically. Two tumours were largely destroyed and one showed marked metaphase arrest. Three other tumours showed lesser changes that were attributable to the drug but were of equivocal significance.There appeared to be differences in drug sensitivity between structurally different clones of the same tumour, and some tumours treated with two alkylating agents were damaged by one and not the other, suggesting that this model may have substantial discriminatory power. Assays such as this should not be used to guide treatment of the patient without prior validation. The practical and ethical difficulties of validation by clinical trial may be insurmountable, and an alternative approach to validation is proposed which does not raise these difficulties.

Topics: Animals; Chlorambucil; Cyclophosphamide; Dactinomycin; Disease Models, Animal; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Immunosuppression Therapy; Male; Melphalan; Methotrexate; Mice; Mice, Inbred CBA; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Ovarian Neoplasms; Thiotepa; Thymectomy; Transplantation, Heterologous; Triaziquone; Urinary Bladder Neoplasms; Vinblastine; Vincristine

Topics: Cervical Vertebrae; Cobalt Radioisotopes; Cyclophosphamide; Female; Humans; Hyperbaric Oxygenation; Male; Melanoma; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Radiography; Radioisotope Teletherapy; Radiotherapy Dosage; Vinblastine

Topics: Aged; Biopsy; Cyclophosphamide; Diagnosis, Differential; Frontal Bone; Humans; Immunoelectrophoresis; Immunoglobulin G; Iodine Radioisotopes; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Metastasis; Parietal Bone; Plasmacytoma; Prednisone; Skull Neoplasms; Thyroid Neoplasms; Thyroidectomy; Vincristine

Topics: Aged; Amputation, Surgical; Arm; Bone Neoplasms; Cartilage; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Female; Fibrosarcoma; Hemangiosarcoma; Humans; Leg; Liposarcoma; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Sarcoma

Topics: Adenocarcinoma, Mucinous; Cyclophosphamide; Cystadenocarcinoma; Dactinomycin; Drug Combinations; Female; Fluorouracil; Humans; Melphalan; Neoplasm Metastasis; Ovarian Neoplasms

Topics: Adult; Antibiotics, Antineoplastic; Antineoplastic Agents; Cyclophosphamide; Drug Therapy, Combination; Fibrosarcoma; Hemangiosarcoma; Humans; Leiomyosarcoma; Liposarcoma; Male; Melphalan; Neoplasm Metastasis; Neurilemmoma; Nitrogen Mustard Compounds; Sarcoma; Sarcoma, Synovial; Thiotepa

Topics: Animals; Benzyl Compounds; Brain; DDT; Electron Spin Resonance Spectroscopy; Free Radicals; Humans; Kinetics; Leukemia; Liver; Lung Neoplasms; Lymphocytes; Mathematics; Melphalan; Mercaptopurine; Mice; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Nitrosourea Compounds; Rats; Thiotepa; Time Factors

Topics: Adenocarcinoma; Fallopian Tube Neoplasms; Female; Humans; Lung Neoplasms; Melphalan; Middle Aged; Neoplasm Metastasis; Radiography

Topics: Bone Neoplasms; Child; Child, Preschool; Cyclophosphamide; Dose-Response Relationship, Radiation; Female; Humans; Lung Neoplasms; Male; Melphalan; Neoplasm Metastasis; Prognosis; Radiotherapy Dosage; Sarcoma, Ewing; Time Factors; Vinblastine

Topics: Adult; Aged; Arm; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Leg; Male; Mechlorethamine; Melanoma; Melphalan; Neoplasm Metastasis; Postoperative Complications; Skin Transplantation; Thiotepa

Topics: Adolescent; Amputation, Surgical; Female; Foot; Humans; Melanoma; Melphalan; Neoplasm Metastasis

Topics: Adult; Aged; Antineoplastic Agents; Chlorambucil; Colchicine; Cyclophosphamide; Cytarabine; Eye Neoplasms; Female; Floxuridine; Humans; Hydroxyurea; Idoxuridine; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Nitrosourea Compounds; Skin Neoplasms; Vinblastine; Vincristine; Vulvar Neoplasms

Topics: Adolescent; Amputation, Surgical; Anti-Bacterial Agents; Bone Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Child; Chondrosarcoma; Giant Cell Tumors; Hip; Humans; Lymphoma, Large B-Cell, Diffuse; Melphalan; Neoplasm Metastasis; Osteosarcoma; Radioisotopes; Sarcoma, Ewing; Shoulder; Vitamins

Topics: Adult; Cervix Uteri; Female; Fluorouracil; Humans; Imidazoles; Melanoma; Melphalan; Neoplasm Metastasis; Prognosis; Uterine Cervical Neoplasms

The presence of sex chromatin in a metastatic malignant melanoma from a male patient aged 26 who showed no evidence of any constitutional chromosome anomaly is described. A possible association between the apparently "female" origin of the tumour and the good response to therapy is considered.

Topics: Adult; Humans; Karyotyping; Male; Melanoma; Melphalan; Neoplasm Metastasis; Prognosis; Radioisotope Teletherapy; Sex Chromatin; Skin; Skin Neoplasms

Topics: Adolescent; Adult; Bone Marrow; Child; Child, Preschool; Dosage Forms; Female; Humans; Injections, Intravenous; Leukopenia; Male; Melphalan; Neoplasm Metastasis; Osteosarcoma; Thrombocytopenia; Time Factors

Topics: Adolescent; Adult; Autopsy; Child; Child, Preschool; Female; Humans; Male; Melphalan; Mitomycins; Neoplasm Metastasis; Osteosarcoma; Time Factors; Vincristine

Topics: Adolescent; Amines; Antineoplastic Agents; Child; Child, Preschool; Cyclophosphamide; Daunorubicin; Female; Humans; Hydroxyurea; Male; Melphalan; Neoplasm Metastasis; Nitrosourea Compounds; Osteosarcoma; Sarcoma, Ewing; Triazines; Uracil Mustard; Vincristine

Topics: Adult; Aortography; Child, Preschool; Cyclophosphamide; Dactinomycin; Female; Humans; Male; Melphalan; Mesenchymoma; Middle Aged; Neoplasm Metastasis; Nephrectomy; Prednisone; Radioisotope Teletherapy; Retroperitoneal Neoplasms; Urography

Topics: Adult; Antibiotics, Antineoplastic; Cyclophosphamide; Dactinomycin; Depression, Chemical; Dysgerminoma; Humans; Male; Melphalan; Methotrexate; Neoplasm Metastasis; Olivomycins; Teratoma; Testicular Neoplasms

Topics: Animals; Antibody Formation; Antineoplastic Agents; Asparaginase; Cytarabine; Dactinomycin; Drug Resistance; Drug Synergism; Escherichia coli; Immunization; Immunosuppressive Agents; Leukemia, Experimental; Melphalan; Mice; Mice, Inbred Strains; Neoplasm Metastasis; Neoplasm Transplantation; Podophyllin; Procarbazine; Time Factors; Vincristine

Topics: Animals; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Female; Leukopenia; Lung Neoplasms; Lymphoma, Non-Hodgkin; Melphalan; Mice; Neoplasm Metastasis; Ovarian Neoplasms; Peritoneal Neoplasms; Rats; Sarcoma 180; Sarcoma, Experimental; Thiotepa; Triazines

Topics: Adolescent; Adult; Dysgerminoma; Humans; Leukopenia; Lung Neoplasms; Lymphatic Metastasis; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Teratoma; Testicular Neoplasms; Vinblastine

Topics: Adolescent; Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Child; Dactinomycin; Female; Humans; Leg; Male; Mechlorethamine; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Prognosis; Skin Neoplasms

Topics: Adenocarcinoma; Ascitic Fluid; Busulfan; Chromosomes; Female; Humans; Karyotyping; Lymphatic Metastasis; Melphalan; Middle Aged; Neoplasm Metastasis; Ovarian Neoplasms; Peritoneal Neoplasms; Pleural Neoplasms

Topics: Adult; Aged; Bone Marrow Examination; Bone Neoplasms; Cerebrospinal Fluid Proteins; Cyclophosphamide; Female; Fractures, Spontaneous; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Metastasis; Plasma Cells; Polyradiculopathy; Radiography

Topics: Biopsy; Chemotherapy, Cancer, Regional Perfusion; Female; Hot Temperature; Humans; Melanoma; Melphalan; Methods; Middle Aged; Neoplasm Metastasis; Skin Neoplasms; Thermography

Topics: Bence Jones Protein; Blood Protein Electrophoresis; Bone Marrow Examination; Diagnosis, Differential; Female; gamma-Globulins; Humans; Infarction; Leukemia, Plasma Cell; Leukocytosis; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Metastasis; Plasma Cells; Prednisone; Spleen; Splenic Neoplasms; Splenic Rupture; Subarachnoid Hemorrhage; Thrombocytopenia

Topics: Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis

Topics: Animals; Chick Embryo; Culture Techniques; Female; Gonads; Humans; Liver Neoplasms; Male; Melphalan; Neoplasm Metastasis; Ovary; Stomach Neoplasms; Testis

Topics: Adult; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Leg; Melanoma; Melphalan; Neoplasm Metastasis; Skin Neoplasms

Topics: Adult; Breast Neoplasms; Carcinosarcoma; Female; Humans; Mastectomy; Melphalan; Neoplasm Metastasis; Toxins, Biological

Topics: Abdominal Neoplasms; Adenocarcinoma, Papillary; Aged; Alkylating Agents; Ascitic Fluid; Chromosomes; Female; Humans; Hydroxyprogesterones; Karyotyping; Melphalan; Methods; Neoplasm Metastasis; Neoplastic Cells, Circulating; Ovarian Neoplasms

Topics: Arm; Burns; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Edema; Femoral Neoplasms; Foot Diseases; Hemangiosarcoma; Hemoglobinuria; Hemolysis; Hot Temperature; Humans; Leg; Melanoma; Melphalan; Neoplasm Metastasis; Sarcoma; Sarcoma, Ewing; Sarcoma, Kaposi; Time Factors

Topics: Adult; Animals; Cell- and Tissue-Based Therapy; Female; Humans; Immunosuppressive Agents; Lymph Nodes; Lymphocyte Transfusion; Lymphocytes; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasms; Skin Neoplasms; Spleen; Swine; Transplantation, Heterologous; Transplantation, Homologous

Topics: Carcinoma, Squamous Cell; Diagnosis, Differential; Esophageal Neoplasms; Esophagus; Gastroenterostomy; Gastrostomy; Hematemesis; Humans; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasms, Nerve Tissue; Pyloric Stenosis; Radiography; Vagotomy; Vagus Nerve

Topics: Alkylating Agents; Bone Neoplasms; Cyclophosphamide; Dysgerminoma; Lymphatic Metastasis; Lymphoma, Large B-Cell, Diffuse; Male; Mechlorethamine; Melphalan; Neoplasm Metastasis; Testicular Neoplasms

Topics: Adrenalectomy; Aged; Antineoplastic Agents; Breast Neoplasms; Bronchial Neoplasms; Cortisone; Cyclophosphamide; Drug Synergism; Ethinyl Estradiol; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Hydrazines; Hypophysectomy; Kidney Neoplasms; Lung Neoplasms; Male; Melanoma; Melphalan; Mesothelioma; Methotrexate; Middle Aged; Nandrolone; Neoplasm Metastasis; Ovarian Neoplasms; Podophyllin; Sarcoma; Thiotepa; Vinblastine

Topics: Adenocarcinoma; Adenocarcinoma, Papillary; Cystadenoma; Female; Granulosa Cell Tumor; Humans; Melphalan; Neoplasm Metastasis; Ovarian Neoplasms

Topics: Child; Child, Preschool; Female; Humans; Male; Melphalan; Neoplasm Metastasis; Neuroblastoma

Topics: Antineoplastic Agents; Child; Child, Preschool; Cyclophosphamide; Female; Humans; Hydroxyurea; Infant; Male; Melphalan; Neoplasm Metastasis; Retinoblastoma; Uracil Mustard; Vincristine

Topics: Antineoplastic Agents; Chlorambucil; Cyclophosphamide; Dactinomycin; Fluorouracil; Humans; Hydrazines; Hydroxyurea; Lymph Node Excision; Lymphatic Metastasis; Melanoma; Melphalan; Methotrexate; Neoplasm Metastasis; Neoplasm Recurrence, Local; Perfusion; Vincristine

Topics: Adult; Cyclophosphamide; Dysgerminoma; Humans; Lung Neoplasms; Lymphatic Metastasis; Male; Melphalan; Mesothelioma; Middle Aged; Neoplasm Metastasis; Peritoneal Neoplasms; Radiotherapy Dosage; Sertoli-Leydig Cell Tumor; Teratoma; Testicular Neoplasms

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Cyclophosphamide; Female; Fluorouracil; Humans; Hydroxyurea; Mechlorethamine; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Progestins; Thiotepa; Urea; Uterine Cervical Neoplasms

Topics: Adolescent; Adult; Choriocarcinoma; Dysgerminoma; Female; Humans; Male; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Ovarian Neoplasms; Pregnancy; Teratoma; Testicular Neoplasms; Vincristine

Topics: Antineoplastic Agents; Catheterization; Floxuridine; Fluorouracil; Gastrointestinal Neoplasms; Hepatic Artery; Humans; Injections, Intra-Arterial; Liver Neoplasms; Melphalan; Methotrexate; Neoplasm Metastasis

Topics: Animals; Mannomustine; Melphalan; Neoplasm Metastasis; Neoplasms, Experimental; Rats

Topics: Animals; Lung Neoplasms; Lymphatic Metastasis; Melphalan; Neoplasm Metastasis; Neoplasm Transplantation; Rats; Sarcoma, Experimental; Tail; Thiotepa; Vitamin B 12

Topics: Blood; Cell Nucleus; Chemotherapy, Cancer, Regional Perfusion; Cytoplasm; Drug Therapy; Humans; Melanoma; Melphalan; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Thiotepa

Topics: Animals; Dactinomycin; Floxuridine; Leukemia; Melphalan; Mercaptopurine; Methotrexate; Mitomycins; Neoplasm Metastasis; Pyrimidines; Sarcoma, Experimental; Thiotepa

Topics: Animals; Antineoplastic Agents; Drug Synergism; Melphalan; Mice; Neoplasm Metastasis; Plants, Medicinal; Sarcoma, Experimental; Thiotepa

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Mechlorethamine; Melanoma; Melphalan; Neoplasm Metastasis; Neoplasms; Postoperative Complications; Surgical Procedures, Operative; Thiotepa; Toxicology; Wound Healing

Topics: Antineoplastic Agents; Cricetinae; Cyclophosphamide; Dactinomycin; Melphalan; Mice; Mitomycin; Mitomycins; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Pharmacology; Research; Sarcoma; Sarcoma, Experimental; Thiotepa

Topics: Antineoplastic Agents; Cytosine; Erythrocyte Count; Leukocyte Count; Melphalan; Neoplasm Metastasis; Neoplasms; Pyrimidines; Rats; Research; Sarcoma; Sarcoma, Experimental; Toxicology

Topics: Humans; Male; Melphalan; Neoplasm Metastasis; Neoplasms; Neoplasms, Germ Cell and Embryonal; Neoplasms, Second Primary; Testicular Neoplasms