melphalan and Wilms-Tumor

High-dose chemotherapy intensification and hematopoietic stem cell support remains a valuable treatment option for the rare patient with relapsed Wilms' tumor. We report a 22-year-old adult male with an initially diagnosed stage II Wilms' tumor, treated by nephrectomy followed by adjuvant chemotherapy. After 1 year, an intra-abdominal relapse was treated with salvage ifosfamide carboplatin etoposide chemotherapy followed by autologous hematopoietic stem cell mobilization. It was intended that he would receive two tandem cycles of high-dose chemotherapy; the first consisting of melphalan etoposide carboplatin; however, the patient did not return to receive the second cycle while in remission, but did return later with grossly relapsed disease. He was then treated with a novel preparative regimen incorporating high-dose topotecan (topotecan, melphalan and cyclophosphamide). This case confirms the feasibility of double high-dose chemotherapy with hematopoietic stem cell support in relapsed Wilms' tumor. A detailed discussion with an extensive review of the literature, regarding studies evaluating the role and indications of high-dose chemotherapy in Wilms' tumor is provided.

Topics: Adult; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carboplatin; Cyclophosphamide; Etoposide; Fatal Outcome; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Male; Melphalan; Paclitaxel; Radiography; Salvage Therapy; Topotecan; Transplantation, Autologous; Wilms Tumor; Young Adult

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

Limited information is available regarding the use of amifostine in pediatric hematopoietic stem cell transplant (HSCT) patients. Melphalan, carboplatin, etoposide +/- cyclophosphamide is a commonly used preparatory regimen in pediatric solid tumor HSCT. Therefore, we decided to determine the feasibility of the addition of amifostine (750 mg/m b.i.d. x 4 d) to melphalan (200 mg/m), carboplatin (1200 mg/m), and etoposide (800 mg/m) (level 1) and escalating doses of cyclophosphamide (3000 mg/m and 3800 mg/m, levels 2 and 3, respectively) followed by autologous HSCT. Thirty-two patients with a variety of pediatric solid tumors were studied. Seventeen patients were accrued at level 1, 9 at level 2, and 6 at level 3. Major toxicities during the administration of the preparatory regimen were hypocalcemia, emesis, and hypotension. Hypocalcemia required aggressive calcium supplementation during the conditioning phase. No dose limiting toxicities were encountered at level 3. Amifostine at 750 mg/m b.i.d. for 4 days can be administered with a double alkylator regimen consisting of melphalan (200 mg/m), cyclophosphamide (up to 3800 mg/m), carboplatin (1200 mg/m), and etoposide (800 mg/m) with manageable toxicities.

Topics: Adolescent; Adult; Amifostine; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Bone Neoplasms; Carboplatin; Central Nervous System Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Etoposide; Feasibility Studies; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Hypocalcemia; Kidney Neoplasms; Melphalan; Neoplasms; Neuroblastoma; Pilot Projects; Recurrence; Risk Factors; Sarcoma; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Wilms Tumor

Normalized glomerular filtration rate (nGFR) <60 mL/min/1.73 m(2) often precludes hematopoietic stem cell transplant (HSCT) in pediatric patients. Three patients with nGFR < 60 mL/min/1.73 m(2) enrolled on an institutional phase I trial of HSCT preparative therapy for advanced and recurrent solid tumors with escalating melphalan, ranging from 135 to 180 mg/m(2), thiotepa (600 mg/m(2)), and vincristine (2 mg/m(2)). An additional patient with low nGFR was treated with the same preparative therapy. None of the patients developed acute renal failure, excess toxicities during HSCT or delayed engraftment. These cases demonstrate that it is feasible and safe to perform HSCT in pediatric patients with low nGFR using melphalan- and thiotepa-based preparative therapy.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Combined Modality Therapy; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Hematopoietic Stem Cell Transplantation; Humans; Infant; Kidney Neoplasms; Melphalan; Neuroblastoma; Thiotepa; Transplantation, Autologous; Treatment Outcome; Wilms Tumor

Survival for subgroups of patients with Wilms tumor (WT), such as those who suffer from relapse, is disappointing. Some patients' treatment plans include high-dose chemotherapy (HDT) with autologous hematopoietic cell transplantation (aHCT), although proof for its benefit is lacking. To increase the level of evidence regarding children with WT receiving aHCT as consolidation of first or second remission (after first relapse), we extracted relevant data from the European Blood and Marrow Transplantation Registry concerning 69 patients. Different HDT regimens were administered, mostly either melphalan-containing (n = 34) or thiotepa-containing (n = 14). For the whole population, 5-year overall survival (OS) and event-free survival (EFS) probabilities were 0.67 (±0.06) and 0.63 (±0.06), respectively (median observation time 7.8 years); for children transplanted in first remission, OS and EFS were 0.69 (±0.09) and 0.72 (±0.08). In univariate analysis, male gender and relapse in multiple sites were associated with lower OS probabilities. The use of a given pretransplant regimen (i.e. melphalan alone versus regimens with multiple drugs) did not seem to influence EFS/OS probability after aHCT, but significantly influenced platelet engraftment (more delayed with thiotepa). We here provide further data to improve the basis for future evidence-based clinical decision-making when using HDT and aHCT in relapsed/refractory WT.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Child; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Kidney Neoplasms; Male; Melphalan; Neoplasm Recurrence, Local; Transplantation, Autologous; Treatment Outcome; Wilms Tumor

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Chemoradiotherapy; Etoposide; Humans; Infant; Kidney Neoplasms; Lung Neoplasms; Male; Melphalan; Wilms Tumor

An increasing number of children with advanced malignancies have recently received high-dose chemotherapy (HDC) with hematopoietic stem cell transplantation (HSCT), followed by surgery. In this study, we reviewed our experience with surgery after HDC and autologous (auto) or allogeneic (allo) HSCT to elucidate the problems associated with this treatment and establish the optimum surgical management strategy.. We retrospectively reviewed the cases of 24 children with advanced malignancy treated with HDC and HSCT before tumor resection at our institution. The tumors included 18 neuroblastomas, 5 soft tissue sarcomas, 2 hepatoblastomas, and 1 Wilms tumor. The source of hematopoietic stem cells was auto-HSCT in 19 patients and allo-HSCT in 5 patients. To be able to undergo surgery, it was necessary that the patient's general condition, including hemostasis, should be fairly good and that the results of hematological examinations should include a white blood cell (WBC) count of>1,000/µL, hemoglobin level of>10 g/dL and platelet count of>5 × 10(4)/µL.. The mean duration before WBC recovery after HSCT was 14.5 ± 1.4 days after auto-HSCT and 23.8 ± 1.2 days after allo-HSCT, respectively (p<0.01). The mean duration before platelet recovery after HSCT was 46.5 ± 5.2 days for auto-HSCT and 48.6 ± 5.5 days for allo-HSCT (not significant [n.s.]). The mean interval between allo-HSCT and surgery was significantly longer (92.8 ± 6.2 days) than that between auto-HSCT and surgery (57.0 ± 3.9 days) (p<0.01), likely because of the use of steroids and immunosuppressants after HSCT. The tumors were completely resected in all cases without severe complications. All the patients treated with allo-HSCT had an acute graft versus host (aGVH) reaction at 2 to 3 weeks after HSCT, and specifically required the administration of steroids and immunosuppressants to prevent aGVH. The postoperative complications included paralytic ileus in two cases and a tacrolimus-associated encephalopathy in one case involving allo-HSCT. In half of the patients, the WBC count was not elevated after surgery, whereas the postoperative serum C-reactive protein (CRP) level was elevated in all cases.. Our data indicate that surgical treatment can be safely performed even after HDC with HSCT if attention is paid to myelosuppression and the adverse effects of both chemotherapeutic agents and immunosuppressants.

Topics: Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Child; Child, Preschool; Drug Administration Schedule; Female; Hematopoietic Stem Cell Transplantation; Hepatoblastoma; Humans; Infant; Kidney Neoplasms; Liver Neoplasms; Male; Melphalan; Neoadjuvant Therapy; Neoplasms, Complex and Mixed; Neuroblastoma; Perioperative Care; Retrospective Studies; Sarcoma; Thiotepa; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Wilms Tumor

High-dose chemotherapy (HDC) with autologous stem-cell rescue (ASCR) is a treatment option for pediatric patients with relapsed nephroblastoma. We present long term results of 9 patients treated between 1993 and 2013 at our center.. Reinduction therapy was carried out according to GPOH and SIOP recommendations. The conditioning regimen consisted of carboplatin (1 200 mg/m²), etoposide (800 mg/m² or 40 mg/kg) and melphalan (180 mg/m²). Purging of the grafts with immunomagnetic CD34 positive selection was performed in 5 patients.. 8 of 9 Patients (90%) are alive without evidence of disease after a median follow-up of 8.5 years. Leukocyte engraftment occurred after a median of 10 days (range 8-12). Median numbers of 667/µl CD3+, 329/µl CD4+, 369/µl CD8+T cells and 949/µl B cells were reached after 180 days. No negative impact of CD34 selection was observed. No transplantation-related death occurred. Acute toxicity comprised mucositis III°-IV° in all and veno-occlusive disease in one patient. Long term effects probably related to treatment occurred in 3/7 evaluable patients and comprised hearing impairment, reduced renal phosphate reabsorption, mild creatinine elevation and hypothyroidism (n=1, each).. Thus, in our experience HDC with ASCR is an effective treatment of recurrent or refractory nephroblastoma with acceptable side effects. However, a randomized trial proving its efficiency with a high level of evidence is needed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Combined Modality Therapy; Dactinomycin; Disease-Free Survival; Dose-Response Relationship, Drug; Doxorubicin; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Kidney Neoplasms; Male; Melphalan; Neoplasm Recurrence, Local; Transplantation Conditioning; Vincristine; Wilms Tumor

High-dose chemotherapy and hematopoietic stem cell support remains a valuable treatment option for the rare patient population with relapsed Wilms' tumor. Here we report the case of a 22-year-old male patient treated with two cycles of high-dose chemotherapy at relapse after nephrectomy and adjuvant chemotherapy; the first cycle with melphalan--etoposide--carboplatin and the second with a novel preparative regimen incorporating high-dose topotecan (topotecan--cyclophosphamide--melphalan). A detailed discussion and literature review pertaining to that case is provided.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Chemotherapy, Adjuvant; Cyclophosphamide; Dose-Response Relationship, Drug; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Kidney Neoplasms; Male; Melphalan; Nephrectomy; Topotecan; Wilms Tumor; Young Adult

Wilms tumor relapses are infrequent, occurring in approximately 15% of favorable histology patients. Very few cases of late recurrent relapse exist in the literature. Long-term survival after autologous stem cell rescue ranges from 40% to 73%, but there are very few reports of patients transplanted in their third complete response. We report a late recurrent relapse of Wilms tumor successfully treated with high-dose chemotherapy and autologous stem cell rescue in his third complete response who remains disease free 15 months posttransplant.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child, Preschool; Combined Modality Therapy; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Kidney Neoplasms; Male; Melphalan; Neoplasm Recurrence, Local; Salvage Therapy; Wilms Tumor

To investigate whether high-dose therapy with hematopoietic stem-cell rescue (HSCR) will improve survival for patients with relapsed Wilms' tumor.. Thirteen children with relapsed Wilms' tumor were treated with one or two cycles of high-dose chemotherapy (HDT) followed by autologous HSCR. Twelve of 13 patients received reinduction chemotherapy before HDT and HSCR. The median age at diagnosis was 4.8 years, and the median time to relapse was 12 months. The histology was favorable in 12 of 13 patients. The ablative regimens included: (1) thiotepa (TT)/cyclophosphamide (CTX)/carboplatin (CP; n = 2); (2) TT/CTX (n = 5); (3) TT/etoposide (ETP; n = 1); and (4) CP/ETP/CTX (n = 1). Four patients received two cycles of HDT and HSCR. Cycle 1 consisted of CP/ETP/CTX, and melphalan/CTX were used in cycle 2.. Seven of 13 patients are alive without evidence of disease, with a median follow-up of 30 months. The 4-year estimated event-free survival (EFS) rate is 60% (95% CI, 0.40 to 6.88), and the overall survival (OS) at 4 years is 73% (95% CI, 0.40 to 6.86). There was no transplant-related mortality. All patients engrafted to an absolute neutrophil count 500/microL at a median of 13 days (range, 8 to 62 days) and had an unsustained platelet count > 20.0 micro at a median of 16 days (range, 10 to 202 days).. Our results suggest that HDT with HSCR is an effective treatment for patients with Wilms' tumor who experience relapse.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Cyclophosphamide; Dose-Response Relationship, Drug; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Kidney Neoplasms; Male; Melphalan; Neoplasm Recurrence, Local; Survival Analysis; Thiotepa; Transplantation, Autologous; Treatment Outcome; Wilms Tumor

Adult Wilms' tumor (AWT) is a very rare and aggressive malignancy, and little information is available on effective therapy in adults. Although mutations in WT1 have been found in 10% to 15% of childhood Wilms' tumor patients, to date WT1 mutations in AWT patients have not been described. The authors describe a 47-year-old man with relapsed AWT and a novel germline alteration in intron 1 of WT1: IVS1-6 C-->A. This alteration may reduce the splicing efficiency for exon 2 and possibly results in exon skipping. The effective salvage chemotherapy contained ifosfamide, carboplatin, and etoposide and was followed by a high-dose chemotherapy that contained melphalan, carboplatin, and etoposide. Both chemotherapy regimens showed moderate treatment-related toxicity. This report is the first that indicates that adult nephroblastoma patients also may carry WT1 germline mutations.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Dose-Response Relationship, Drug; Etoposide; Genes, Wilms Tumor; Germ-Line Mutation; Humans; Kidney Neoplasms; Male; Melphalan; Middle Aged; Salvage Therapy; Stem Cell Transplantation; Transplantation, Autologous; Treatment Outcome; Wilms Tumor

Children with Wilms tumor who have a particular risk of failure at relapse or at primary diagnosis were treated with high-dose chemotherapy (HDC) and autologous peripheral blood stem cell rescue in order to improve their probability of survival. From April 1992 to December 1998, 23 evaluable patients received HDC within the German Cooperative Wilms Tumor Studies. Nineteen were given melphalan, etoposide and carboplatin (MEC); the others received different regimens. The dose of carboplatin was adjusted according to renal function. Indications for HDC were high-risk relapse in 20 patients, bone metastases in two patients and no response in one patient. Fourteen of 23 patients are alive after a median observation time of 41 months, 11 of 14 in continuous complete remission, three in CR after relapse post HDC. The estimated survival and event-free survival for these patients are 60.9% and 48.2%. Twelve children relapsed after HDC; nine of them died within 12 months and three are surviving from 20 to 33 months after relapse. The main toxicities were hematologic, mucositis and renal (tubular dysfunction; intermittent hemodialysis in one patient). There were no toxic deaths. About half of the children suffering from Wilms tumor with very unfavorable prognostic factors survive disease-free after HDC for over 3 years. Besides hematological toxicity, mucositis and infections, renal function is at risk during HDC. With dose adjustment on glomerular filtration rate, however, no permanent renal failure was observed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Etoposide; Female; Germany; Hematologic Diseases; Humans; Ifosfamide; Infant; Kidney Diseases; Kidney Neoplasms; Life Tables; Lung Neoplasms; Male; Melphalan; Peripheral Blood Stem Cell Transplantation; Prognosis; Stomatitis; Survival Analysis; Thiotepa; Transplantation, Autologous; Wilms Tumor

In children with bilateral Wilms' tumor, the therapy should aim at maximal preservation of renal parenchyma and function. Local radiotherapy may give rise to second malignant neoplasms and may impair renal function. We present a therapeutic strategy without any irradiation. Three children were diagnosed with bilateral Wilms' tumor at ages from 6 months to 5 years. Each patient had a massive tumor with local stage III on one side; one had pulmonary metastases. The therapeutic strategy was first to obtain tissue for histology by percutaneous needle biopsy, to administer pre-operative chemotherapy until desired tumor shrinkage, and then to perform kidney-sparing resective surgery. After a period of conventional chemotherapy, the patients were consolidated with high-dose (HD) melphalan and ABMT. Renal parenchyma spared post-surgery (right/left) was 0%/70%, 60%/40% and 40%/60% of the original kidney volumes. The toxicity of the ABMT procedure was mild, the patients engrafted promptly, and were discharged on days +14 to +27. All patients survive disease-free, 3 years 4 months to 4 years 5 months post-transplant. Our program resulted in good preservation of renal parenchyma and normal function, and we consider the risk of this ABMT program smaller than the late consequences of local radiotherapy for children with bilateral Wilms' tumor. The therapeutic strategy described merits further evaluation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Dactinomycin; Doxorubicin; Drug Administration Schedule; Female; Humans; Infant; Kidney Neoplasms; Male; Melphalan; Pilot Projects; Rhabdomyoma; Vincristine; Wilms Tumor

The three-drug combination of melphalan (M), etoposide (E), and carboplatin (C) followed by autologous stem-cell (ASC) rescue has been evaluated prospectively by the French Society of Pediatric Oncology (SFOP) in pediatric high-risk recurrent (HRR) Wilms' tumor (WT) patients with chemotherapy-responsive disease.. From October 1988 to October 1994, 29 patients with HRR WT were treated in nine SFOP centers. Two additional patients with stage IV anaplastic WT were consolidated in first complete response (CR) with the same regimen and have been studied separately. The regimen consisted of M 180 mg/m2 for 1 day, E 200 mg/m2/d for 5 days, and C at a daily targeted area under the concentration-time curve (AUC) of 4 mg x min/mL for 5 days. ASCs were reinfused 48 hours after M.. Twelve of 28 assessable patients with HRR WT are still in continuous CR at a median of 48.5 months (range, 36 to 96) after consolidation. Disease-free survival (DFS) and overall survival (OS) estimated by the Kaplan-Meier method at 3 years were 50%+/-17% and 60%+/-18%, respectively. Sixteen patients relapsed at a median of 8.5 months (range, 3 to 53) after consolidation. Toxicity data are available in 31 grafted patients. Grade III and IV toxicities included hematologic side effects (n=31), hemorrhage (n=8), mucositis (n=24), diarrhea (n=12), renal disorders (n=8), and pneumonitis (n=3).. The adverse prognostic factors (APF) used to select patients for this dose-intensive chemotherapy define children with very-poor-risk recurrent WT. Despite high treatment-related toxicity, about half of these patients remain disease-free at 3 years. Patient outcome is statistically better when high-dose chemotherapy (HDCT) is performed as early as the second CR or partial response (PR). Novel therapeutic approaches with innovative preparative regimens are warranted for the remaining high-risk patients.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Combined Modality Therapy; Disease-Free Survival; Etoposide; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Infant; Kidney Neoplasms; Male; Melphalan; Neoplasm Recurrence, Local; Wilms Tumor

The clinical and pathologic findings in a 53-year-old woman who developed a uterine adenosarcoma following an adenomyoma are described. During the interval between the diagnosis of adenomyoma and the subsequent diagnosis of adenosarcoma, the patient developed breast carcinoma and received adjuvant chemotherapy that included tamoxifen. The possible stimulatory effects of this drug upon the patient's pre-existing adenomyoma are discussed in view of reports of tamoxifen-associated endometrial carcinoma and uterine sarcomas developing in the setting of estrogen excess.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Cell Transformation, Neoplastic; Combined Modality Therapy; Doxorubicin; Endometriosis; Female; Fluorouracil; Humans; Melphalan; Menopause; Middle Aged; Tamoxifen; Uterine Neoplasms; Wilms Tumor

Topics: Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Female; Humans; Male; Melphalan; Neoplasm Recurrence, Local; Neuroblastoma; Sarcoma, Ewing; Transplantation, Autologous; Wilms Tumor

Topics: Asparaginase; Child; Cyclophosphamide; Cytosine; Daunorubicin; Doxorubicin; Drug Therapy, Combination; Hodgkin Disease; Humans; Infant; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphoma; Melphalan; Mercaptopurine; Methotrexate; Neoplasms; Nitrogen Mustard Compounds; Osteosarcoma; Prednisone; Procarbazine; Prognosis; Remission, Spontaneous; Rhabdomyosarcoma; Teniposide; Thioguanine; Vincristine; Wilms Tumor

Topics: Antineoplastic Agents; Asparaginase; Burkitt Lymphoma; Choriocarcinoma; Cyclophosphamide; Cytarabine; Dactinomycin; Daunorubicin; Female; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Melphalan; Mercaptopurine; Methotrexate; Prednisone; Pregnancy; Vincristine; Wilms Tumor