melphalan and Carcinoma--Small-Cell

This clinical practice guideline, based on a systematic review, evaluates chemotherapy options for patients with relapsed small cell lung cancer (SCLC).. Relevant randomized trials and meta-analyses were identified through a systematic search of the literature. External feedback was obtained from practitioners in Ontario, and the guideline was approved by the provincial lung cancer disease site group.. Six randomized trials met the eligibility criteria and were included for review. One randomized phase III trial of oral topotecan versus no treatment in patients receiving best supportive care found topotecan to have a significant benefit in terms of 6-month survival and quality of life. A randomized phase III trial compared outcomes of carboplatin in patients receiving a combination of etoposide and cisplatin (EP) and found no significant improvement associated with carboplatin, although it was associated with significantly higher grade 3/4 thrombocytopenia. Two randomized trials directly compared chemotherapy regimens (intravenous [i.v.] topotecan versus cyclophosphamide, doxorubicin, and vincristine (CAV); and bis-chloro-ethylnitrosourea, thiotepa, vincristine, and cyclophosphamide (BTOC) versus EP), but these trials found no significant differences in terms of disease response or survival. I.v. topotecan was associated with significantly higher toxicities (grade 4 thrombocytopenia and grade 3/4 anemia) and greater improvement in patient-reported symptoms compared with CAV. Two randomized trials of topotecan-treated patients comparing route of administration (i.v. versus oral) found no significant differences in terms of disease response, survival, or quality of life, although oral administration was associated with increased grade 3 or 4 diarrhea in both trials.. Evidence on the clinical benefit of second-line therapy in SCLC is limited. Topotecan is the most studied agent in this population; it has a response and survival benefit in comparison with placebo, but it also has greater toxicity in comparison with CAV. To date, significant differences in terms of response and survival are not evident in studied chemotherapy options.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Clinical Trials, Phase III as Topic; Etoposide; Female; Humans; Infusions, Intravenous; Lomustine; Lung Neoplasms; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Ontario; Practice Guidelines as Topic; Prognosis; Randomized Controlled Trials as Topic; Salvage Therapy; Survival Analysis; Topotecan

The available evidence suggests that if benefit is to be obtained from high dose chemotherapy regimens, it will be in patients whose tumours are either untreated or still responding to conventional therapy. In each of the diseases discussed in this chapter the optimum timing of the treatment regimen has still to be determined. Effective regimens have been found but it is probable that further improvements can be made. In small cell lung cancer initial high dose therapy followed by non-cross-resistant regimens may prove effective. In glioma studies with high dose therapy before irradiation are awaited and may offer the best means of exploiting this approach to treatment. In breast cancer some impressive responses have occurred but the category of patient likely to benefit has not yet been defined. In melanoma high dose treatment is likely to benefit only those patients with probable minimal disease after surgery.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Transplantation; Breast Neoplasms; Carcinoma, Small Cell; Carmustine; Cell Separation; Cisplatin; Colonic Neoplasms; Cyclophosphamide; Etoposide; Glioma; Humans; Lung Neoplasms; Male; Melanoma; Melphalan; Neoplasms; Testicular Neoplasms; Whole-Body Irradiation

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

Experimental, and more recently, clinical data have suggested the influence of hemostasis in the spread of malignant disease.. To complete research in this type of coagulation and cancer, a multicentric randomized clinical trial was performed, including 303 patients with small cell lung cancer (SCLC), treated by the addition of aspirin at 1 g/day (a dosage at which aspirin is considered to be a platelet aggregation inhibitor) to combined chemotherapy.. Survival was not increased in the aspirin-treated group (P = 0.90). The analysis according to the extent of disease (limited or extensive disease) did not modify that conclusion.. This result does not confirm the hypothesis that, in SCLC, aspirin (a platelet aggregation inhibitor) reduces metastasis formation and local tumor thrombogenesis.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Aspirin; Carcinoma, Small Cell; Cyclophosphamide; Doxorubicin; Etoposide; Female; Humans; Lomustine; Lung Neoplasms; Male; Melphalan; Middle Aged; Platelet Aggregation; Prednisone; Survival Rate

Cyclocreatine, an analog of creatine, is an efficient substrate for creatine kinase, but its phosphorylated form is a poor phosphate donor in comparison with creatine phosphate. Cyclocreatine was not very cytotoxic upon 24 h of exposure of human SW2 small-cell lung cancer cells to concentrations of up to 5 mM. However, combinations of cyclocreatine (0.5 mM, 24 h) with each of four antitumor alkylating agents, cis-diamminedichloroplatinum(II), melphalan, 4-hydroperoxycyclophosphamide, and carmustine, resulted in additive to greater-than-additive cytotoxicity toward exponentially growing SW2 cells. The greatest levels of synergy were seen at higher concentrations of 4-hydroperoxycyclophosphamide and carmustine as determined by isobologram analysis. In vivo cyclocreatine (0.5 or 1 g/kg) was more effective if given i.v. rather than i.p. The longest tumor-growth delays, up to 10 days, were produced by extended regimens of cyclocreatine. Cyclocreatine was an effective addition to therapy with standard anticancer agents including cis-diamminedichloroplatinum(II), cyclophosphamide, Adriamycin, or 5-fluorouracil. No additional toxicity was observed when 10 days of cyclocreatine treatment was given with full standard-dose regimens of each drug. The resultant increases in tumor-growth delay were 1.7- to 2.4-fold as compared with those obtained for each of the drugs alone. These results indicate that cyclocreatine may be an effective single agent and an effective addition to combination chemotherapy regimens.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Carcinoma, Small Cell; Carmustine; Cell Division; Cell Survival; Cisplatin; Creatinine; Cyclophosphamide; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Humans; Injections, Intraperitoneal; Injections, Intravenous; Lung Neoplasms; Mammary Neoplasms, Experimental; Melphalan; Rats; Rats, Inbred F344; Tumor Cells, Cultured

A 44-year-old woman had small cell carcinoma of the esophagus complicated by liver and lymph node metastases. She was treated with aggressive combination chemotherapy, followed by autologous bone marrow transplantation and adjuvant radiation therapy. (The authors believe this to be the first use of autologous bone marrow transplantation for treatment of this condition.) This regimen resulted in apparent complete regression of the disease as documented by computed tomography and endoscopic study. Three years later, she again experienced general malaise and was found to have extensive recurrent disease in the lung, bone, and liver. Her condition deteriorated rapidly, and she died within 1 month. A review of the literature reveals that this patient survived longer than any others who have had this rare but aggressive tumor. The authors suggest that this form of therapy should be considered for future patients.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carboplatin; Carcinoma, Small Cell; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Esophageal Neoplasms; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Humans; Liver Neoplasms; Lymphatic Metastasis; Melphalan; Prognosis; Radiotherapy Dosage; Transplantation, Autologous; Vincristine

We have studied alterations in glutathione (GSH) levels and glutathione-S-transferase (GST) activity in a series of in vitro derived multidrug resistant and cisplatin resistant sublines of the human lung cancer lines NCI-H69 (small cell), COR-L23 (large cell) and MOR (adenocarcinoma). We have also investigated the effects of ethacrynic acid, a putative inhibitor of GSTs, on levels of GSH and GST activity and on cellular sensitivity to melphalan and to cisplatin. Neither GSH content nor GST activity were significantly greater in the resistant sublines compared with their respective parental lines. The only effects of treating with ethacrynic acid at doses of 1 microgram ml-1 and 3 micrograms ml-1 for 2 h were a reduction in GSH content in the cisplatin resistant subline H69/CPR at the 3 micrograms ml-1 dose, and an increase to over 140% of control at 1 microgram ml-1 and 3 micrograms ml-1 in the MOR parental line (MOR/P) and at 1 microgram ml-1 in the multidrug resistant subline MOR/R. Exposure of parental line COR-L23/P to 3 micrograms ml-1 and 6 micrograms ml-1 of ethacrynic acid for 24 h, however, increased the GSH content to over 300% and 500% of control respectively. Variable effects of ethacrynic acid on GST activity were seen in these cell lines. Doses of 1 microgram ml-1 and 3 micrograms ml-1 reduced activity to 59% and 48% of control respectively in multidrug resistant subline H69/LX4. On the other hand, activity was increased in the cisplatin resistant subline H69/CPR (to 146% and 218% of control) and in MOR/P (to 117% and 137% of control) by 1 microgram ml-1 and 3 micrograms ml-1 respectively of ethacrynic acid. Addition of ethacrynic acid (3 micrograms ml-1) to treatment of the cell lines with melphalan or with cisplatin did not alter the dose-response curves to these agents.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cisplatin; Drug Interactions; Drug Resistance; Drug Screening Assays, Antitumor; Ethacrynic Acid; Glutathione; Glutathione Transferase; Humans; Lung Neoplasms; Melphalan; Tumor Cells, Cultured

We have derived sublines of three human lung cancer cell lines with acquired resistance to cisplatin. The cisplatin resistant sublines of NCI-H69 (small cell), COR-L23 (large cell), and MOR (adenocarcinoma) show 5.3 fold, 3.1 fold, and 3.8 fold resistance, respectively, determined in a 6-day MTT assay. Although the parent lines show a wide range of glutathione content per cell, the sublines each show similar values to their corresponding parent line. Radiation response curves have been obtained using a soft agar clonogenic assay. Values obtained for the parent lines (95% CL in parentheses) were: NCI-H69: Do = 0.99 Gy (0.87-1.16), n = 2.9 (1.6-5.2), GSH = 14 ng/10(4) cells; COR-L23: Do = 1.23 Gy (1.05-1.49), n = 1.3 (0.7-2.2), GSH = 47 ng/10(4) cells; MOR: Do = 1.66 Gy (1.48-1.88), n = 3.0 (1.9-4.8), GSH = 86 ng/10(4) cells. The cisplatin resistant variants of NCI-H69 and COR-L23 showed 31% and 63% increases, respectively, in Do compared to their parent lines, whereas no change in radiation response was seen in MOR. In this panel of lines, therefore, although there is a correlation between glutathione content and radiosensitivity of the parent cell lines, acquired resistance to cisplatin is not accompanied by increased glutathione content. However, two of the three cisplatin resistant lines do show a significantly reduced radiosensitivity.

Topics: Adenocarcinoma; Carcinoma; Carcinoma, Small Cell; Cisplatin; Dose-Response Relationship, Radiation; Drug Resistance; Glutathione; Glutathione Transferase; Humans; Lung Neoplasms; Melphalan; Radiation Tolerance; Tumor Cells, Cultured

Since 1980, 75 patients with small-cell lung cancer (SCLC) have been entered into four consecutive studies of high-dose chemotherapy using autologous bone marrow transplantation (ABMT) to assist haematological recovery. In the first study, 25 patients were treated with cyclophosphamide (160-200 mg/kg) as the sole chemotherapy; in the second (26 patients), the cycle of high-dose cyclophosphamide (with or without 800-1,200 mg/m2 etoposide) was repeated as induction treatment. In the first study, response was high [14 complete responses (CR), 7 partial responses (PR)] but was not increased by repeating the cycle (15 CR, 8 PR), and survival was slightly worse in the second trial. In the third study, 15 patients were treated with doxorubicin, vincristine and etoposide for two cycles and then with 200 mg/kg cyclophosphamide. Although high-dose cyclophosphamide increased the complete response rate, the additional responses were short-lived. In the final study, an attempt was made to increase the initial CR rate by combination chemotherapy using carboplatin (400-600 mg/m2), etoposide (120 mg/m2 x 4) and either high-dose cyclophosphamide (40 mg/kg x 4) or melphalan (140 mg/m2). Although all nine patients responded, none underwent a CR. The long-term survival (up to 7 years) does not appear to be different from that in comparably selected cases treated with conventional chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carboplatin; Carcinoma, Small Cell; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Etoposide; Follow-Up Studies; Humans; Lung Neoplasms; Melphalan; Organoplatinum Compounds; Prognosis; Radiotherapy Dosage; Remission Induction; Vincristine

Topics: Bone Transplantation; Carcinoma, Small Cell; Female; Humans; Lung Neoplasms; Male; Melphalan; Middle Aged

Nineteen patients were treated with high dose chemotherapy followed by an autologous bone marrow transplantation. The chemotherapy regimen was an association of BCNU, procarbazine, etoposide, melphalan. Six patients had a progressive disease; 4 short-term complete remissions were observed. In 13 responding patients, 6 maintained complete remissions were noted.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carcinoma, Small Cell; Carmustine; Combined Modality Therapy; Etoposide; Humans; Lung Neoplasms; Melphalan; Procarbazine

A method based on detection of drug-induced cell cycle perturbation by flow cytometric DNA analysis has previously been described in Ehrlich ascites tumors as a way to estimate chemosensitivity. The method is extended to test human small-cell carcinoma of the lung. Three tumors with different sensitivities to melphalan in nude mice were used. Tumors were disaggregated by a combined mechanical and enzymatic method and thereafter have incubated with different doses of melphalan. After incubation the cells were plated in vitro on agar, and drug induced cell cycle changes were monitored by flow cytometric DNA analysis. Melphalan produced a dose-related S phase accumulation in the two sensitive tumors, whereas no changes in the cell cycle distribution were found in the resistant tumor. The size of S phase accumulation correlated to the chemosensitivity in vivo. For low concentrations of melphalan, the S phase accumulation was accompanied by G2 + M accumulation. The results indicate that the method may be extended to sensitivity testing of human solid tumors, including screening for new agents.

Topics: Animals; Carcinoma, Small Cell; Cell Cycle; DNA; Dose-Response Relationship, Drug; Drug Resistance; Flow Cytometry; Humans; Interphase; Lung Neoplasms; Melphalan; Mice; Mice, Nude; Neoplasm Transplantation

Four human small cell carcinomas of the lung grown in nude mice were exposed to melphalan. Two of the tumors were derived from subpopulations isolated by in vitro cloning from the same tumor biopsy. The chemosensitivity of the tumors was determined by calculating the specific growth delay. Drug-induced changes in the cell cycle were detected by flow cytometric DNA analysis. The specific growth delay of the tumors was very different with the greatest differences between the two subpopulations originating from the same tumor. Melphalan induced a dose-related S phase accumulation in three sensitive tumors, whereas no changes were seen in a resistant tumor. Furthermore, the amount of S phase accumulation reflected the sensitivity to melphalan. The results suggest that heterogeneity in chemosensitivity is an important reason for chemotherapy failures.

Topics: Animals; Carcinoma, Small Cell; Cell Cycle; Cell Line; DNA; Dose-Response Relationship, Drug; Drug Resistance; Flow Cytometry; Growth; Humans; Lung Neoplasms; Melphalan; Mice; Mice, Nude; Neoplasm Transplantation

Inherent and induced resistance was investigated in human small-cell lung cancer xenografts. Specimens from three patients were established in immune suppressed mice; the sensitivity of the xenografts to cyclophosphamide, MeCCNU and melphalan was determined using the growth delay end-point. Clinical chemosensitivity data were available in two cases and inherent differences in sensitivity were noted both in the xenografts and clinically. Radioactively labelled melphalan uptake studies were performed with these two xenografts. A number of different strategies to induce resistance were explored. Only one method proved to be successful and in only one of the xenografts; this was with cyclophosphamide. The induced resistant line was characterised in terms of the time course of its production, the degree of induced resistance, the growth rate, the cross-resistance pattern and stability of the phenotype; the possibility of altered antigenicity was also examined.

Topics: Alkylating Agents; Animals; Antineoplastic Agents; Carcinoma, Small Cell; Cyclophosphamide; Drug Resistance; Female; Humans; Lung Neoplasms; Melphalan; Mice; Mice, Inbred CBA; Semustine; Time Factors; Vincristine

The effect of melphalan on the growth of 4 different lines of human lung-tumour xenografts has been established. The oat-cell carcinoma was the most sensitive, whereas the adenocarcinoma was the most resistant. Two lines of large-cell anaplastic carcinomas were intermediate in sensitivity. The differences in sensitivity were not reflected in the gross uptake of drug into the tumours. There was, with the exception of the adenocarcinoma line, a marked decrease in uptake per g tumour with increasing tumour size. This was partly caused by a decrease in the vascular supply in the same tumours with increasing tumour size. Extravasation of plasma proteins increased with increasing tumour size in all tumours, but was much less pronounced in the adenocarcinoma than in the other tumour lines. The extracellular volume of the various tumour lines did not vary with tumour size.

Topics: Adenocarcinoma; Animals; Capillary Permeability; Carcinoma, Small Cell; Cell Line; Erythrocyte Volume; Extracellular Space; Humans; Lung Neoplasms; Male; Melphalan; Mice; Mice, Inbred CBA; Neoplasm Transplantation; Neoplasms, Experimental; Plasma Volume; Transplantation, Heterologous