Cisplatin, etoposide, and ifosfamide salvage therapy for refractory or relapsing germ cell carcinoma.

Thirty patients with metastatic progressive germ cell carcinoma who failed to be cured with first-line cisplatin chemotherapy were treated with a salvage regimen consisting of cisplatin 20 mg/m2, etoposide 100 mg/m2, and ifosfamide 1.2 g/m2 (PEI) intravenously (IV), days 1 to 5 every 3 weeks. Ten patients (33%) were tumor-free at the end of therapy. Complete response (CR) was achieved with chemotherapy alone in four patients and with additional surgery in six patients (two necroses, two mature teratomas, two carcinomas). Six patients (20%) had normalization of tumor markers but unresectable residual disease (Rm-), and the remaining 14 patients (46%) failed to respond. Of 10 patients with CR, nine (90%) relapsed again (eight carcinomas, one mature teratoma). The median duration of CR was 3.5 months. The median survival of the whole group was 311 days (range, 110 to 996+). Currently, seven of 30 patients are alive, and five of them are without signs of progressive tumor. The response to prior cisplatin therapy predicted for response and survival after PEI salvage therapy. Of 14 patients with prior CR, eight (57%) achieved a second CR compared with one of 11 (9%) with prior unfavorable response (P = .039). The median survival for patients with prior favorable response was 400 days, compared with 251 days for patients with prior unfavorable response (P less than .001). Myelosuppression was dose-limiting, with leukopenia greater than grade 2 in 84% and thrombocytopenia greater than grade 2 in 51% of all cycles. This three-drug regimen can induce a second CR in one third of patients with relapsed or refractory germ cell carcinoma. Only those patients with prior favorable responses can expect to be cured by this salvage regimen, while patients with prior unfavorable response should be considered for alternative salvage approaches.     

High-dose carboplatin and etoposide with autologous bone marrow transplantation in refractory germ cell cancer: an Eastern Cooperative Oncology Group protocol.

PURPOSE: A phase II trial was undertaken to assess the feasibility, toxicity, and efficacy of high-dose carboplatin and etoposide with autologous bone marrow transplantation in patients with relapsed or refractory germ cell tumors. PATIENTS AND METHODS: Forty patients with recurrent germ cell cancer received carboplatin 500 mg/m2 and etoposide 400 mg/m2 given at 7, 5, and 3 days before marrow infusion. Autologous marrow infusion (day 0) was accomplished using one half of the bone marrow harvested before chemotherapy. Patients who achieved a complete or partial response with the first cycle of treatment received a second identical cycle of chemotherapy followed by infusion of the remaining cryopreserved bone marrow. RESULTS: Objective responses were obtained in 17 of the 38 patients (45%) assessable for response, including eight partial and nine complete remissions. Five of these patients remain in continuous complete remission with minimal follow-up of 1 year. Toxicity encountered was primarily hematologic, and five patients (13%) died of treatment-related complications. Significant toxicities often seen with high-dose cisplatin (ototoxicity, neurotoxicity, and renal toxicity) were manageable in this regimen of high-dose carboplatin. CONCLUSIONS: This trial confirms the curative potential of high-dose carboplatin and etoposide in highly refractory germ cell cancer.     

MTX-HOPE (methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide) as a low-dose salvage chemotherapy for recurrent or refractory non-Hodgkin's lymphoma

We conducted a clinical study of MTX-HOPE (day 1, methotrexate 20 mg per os (po); day 2, hydrocortisone 100 mg intravenous (iv), vincristine 1 mg iv; day 3,4 sobuzoxane 400 mg po; etoposide 25 mg po, repeating every 2 or 3 weeks) in 14 relapsed or refractory patients with non-Hodgkin's lymphoma. Ten responders were obtained 5 CR and 5 PR), and heavily treated patients were included in the responders. The median duration of over all survival which was estimated with Kaplan-Meier curve was 11.1 months (range, 2-18+ months), and the median duration of response was 6.9 months (range, 0.8+ -16.4+ months).Out of the 14 patients,eleven were treated with this regimen in an outpatient setting. Grade 4 neutropenia and thrombocytopenia were observed in 4 and 2 patients,and grade 3 GPT-elevation and stomatitis in two and one, respectively. This newly developed MTX-HOPE therapy may be a promising treatment option for such patients as are intolerable for high-dose chemotherapies with PBSC rescue or wish for outpatient therapy.     

Combination chemotherapy with vincristine and methotrexate for advanced refractory breast cancer.

Eighteen patients with advanced breast cancer refractory to combination chemotherapy with 5-FU, Adriamycin, Cytoxan (FAC) were treated with methotrexate 30 to 40 mg/m2 iv and vincristing 1.5 mg/m2 iv at weekly intervals. Of 17 evaluable patients, 4 (23%) achieved a partial remission with a median duration of remission of 6 months and a median survival of 10 months. In another seven of seventeen patients (41%) the disease remained stable. Toxicity was minimal.     

Residual tumor resection after high-dose chemotherapy in patients with relapsed or refractory germ cell cancer.

PURPOSE: To assess the role of residual tumor resection performed after high-dose chemotherapy (HDCT) in patients with relapsed or refractory germ cell tumors (GCT). PATIENTS AND METHODS: Between July 1987 and October 1999, postchemotherapy resections of residual tumors were performed in 57 patients who had been treated with HDCT for relapsed or refractory GCT and who had achieved a partial remission to this treatment. RESULTS: Complete resections of residual masses were achieved in 52 (91%) of 57 patients who were rendered disease free; in five (9%) of 57 patients, the resections were incomplete. Resection of a single site was performed in 39 (68%) of 57 patients, and the remaining 18 (32%) of 57 patients required interventions at two or more residual tumor sites. Necrosis was found in 22 (38%) of 57 patients, mature teratoma with or without necrosis was found in nine (16%) of 57 patients, and viable cancer with or without additional necrosis or mature teratoma was found in 26 (46%) of 57 patients. Viable cancer consisted either of residual germ cell or undifferentiated cancer in 22 (85%) of 26 patients, with additional non-GCT histologies in the remaining four patients. Patients with viable cancer had a significantly inferior outcome after surgery compared with patients with necrosis and/or mature teratoma even if all cancer was completely resected. Pulmonary lesions with a diameter of more than 2 cm were the only predictive variable for viable cancer in univariate analysis. CONCLUSION: Resections of all residual tumors should be attempted in patients with relapsed or refractory GCT and partial remissions after HDCT.     

The role of ifosfamide plus cisplatin-based chemotherapy as salvage therapy for patients with refractory germ cell tumors

A prospective study of four cycles of etoposide with ifosfamide and cisplatin (VIP) chemotherapy was conducted in 42 germ cell tumor (GCT) patients who were refractory to cisplatin with etoposide/vinblastine-based therapy. Forty patients were evaluable for response. Ten patients (25%) had a complete response: seven to chemotherapy alone and an additional three patients after surgical resection of viable GCT. With a median follow-up of 15 months, four complete responders relapsed, and six patients (15%) remain in remission. Hematologic and nephrotoxicity were moderately severe. Durable complete responses with VIP as second salvage were achieved and suggests that ifosfamide adds efficacy to standard first-salvage therapy. The observed nephrotoxicity and myelotoxicity are considerations in the design of ifosfamide-cisplatin-based regimens. Hematopoietic growth factors may be useful in ameliorating myelotoxicity. The early use of ifosfamide-based chemotherapy may reduce the nephrotoxicity exacerbated by prior cisplatin. A trial of VIP as first salvage after a relapse from a complete response to platinum-based induction therapy is warranted. The modest proportion of patients who achieve a durable remission to VIP as second salvage emphasizes the need for more efficacious salvage therapy for patients who do not achieve a durable complete response.     

Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients.

PURPOSE: To evaluate the efficacy and toxicity of sequential, dose-intensified chemotherapy with paclitaxel/ifosfamide and carboplatin/etoposide administered plus peripheral blood-derived stem-cell (PBSC) support for patients with germ cell tumors (GCT) who have unfavorable prognostic features in response to conventional-dose salvage programs. Carboplatin was dose escalated by target area under the curve (AUC; in [milligrams per milliliter] x minutes) among patient cohorts, and pharmacokinetic studies were performed for comparison. PATIENTS AND METHODS: Thirty-seven previously treated patients who had cisplatin-resistant GCT and unfavorable prognostic features for response to conventional-dose salvage therapy were treated. Two cycles of paclitaxel 200 mg/m(2) plus ifosfamide 6 g/m(2) were given 2 weeks apart with leukapheresis, followed by three cycles of carboplatin plus etoposide given 14 to 21 days apart with reinfusion of PBSCs. The dose of etoposide was 1, 200 mg/m(2), and the carboplatin target AUC ranged among cohorts from 12 to 32 (mg/mL) x min. Pharmacokinetic studies of carboplatin were performed for comparison of target to measured AUC. RESULTS: Twenty-one patients (57%) achieved a complete response and an additional two patients (5%) achieved a partial response with normal tumor markers; therefore, 23 (62%) achieved a favorable response. Eight patients relapsed, and 15 (41%) of the favorable responses remained durable at a median follow-up of 30 months. Myelosuppression was the major toxicity; 58% of carboplatin/etoposide cycles were associated with hospitalization for nadir fever. The AUC of carboplatin measured in serum was lower than the target AUC; this may be related to underestimation of the glomerular filtration rate used in the dosing formula. CONCLUSION: Dose-intense therapy with sequential, accelerated chemotherapy of paclitaxel/ifosfamide and carboplatin/etoposide administered with PBSC support was relatively well tolerated. The durable complete response proportion was substantial in patients with unfavorable prognostic features for achieving durable complete response to conventional-dose salvage programs. Optimal dosing of carboplatin in the high-dose setting warrants further investigation.     

Efficacy of first-line bleomycin, etoposide, and cisplatin chemotherapy for peripheral blood stem cell mobilization in patients with germ cell cancer

Background We assessed the efficacy of first-line bleomycin, etoposide, and cisplatin (BEP) chemotherapy for the mobilization of peripheral blood stem cells (PBSC) in patients with testicular cancer, and analyzed the predictive factors indicating the optimal time of PBSC harvest. Patients and Methods A total of 29 aphereses, performed during first-line BEP chemotherapy between 1994 and 1996 for 10 patients with metastatic germ cell cancer were analyzed. The predictive value for the optimal time of PBSC harvest was determined by analysis of the correlation between the rate of each cellular component in peripheral blood, and the number of CD34-positive cells harvested. Results The median number of CD34-positive cells obtained at a single apheresis was 11.2×10⁶/kg (range, 0.14 to 47.9×10⁶/kg), and the median cumulative number of CD34-positive cells collected during first-line BEP chemotherapy per patient was 31.9×10⁶/kg (range, 9.7 to 75.5×10⁶/kg). The percentage of immature leukocytes (myelocytes plus metamyelocytes) was significantly correlated with the number of harvested CD34-positive cells. Conclusion Adequate amounts of CD34-positive cells can be harvested during first-line BEP chemotherapy for patients with germ cell cancer. The monitoring of the percentage of immature leukocytes might be useful in ascertaining the optimal time of apheresis.     

Cisplatin and etoposide salvage therapy and resection of the residual tumor in pretreated germ cell testicular cancer

Thirty-two consecutive patients with pretreated germinal testis cancer received three to four inductions of cisplatin and etoposide therapy (PE). Patients not pretreated, or only partially pretreated with bleomycin (B), also received this drug for a maximum of 12 doses. Sixteen patients underwent secondary surgery for the removal of residual masses. Twelve (37.5%) entered complete remission (CR) with chemotherapy alone, and an additional 9 cases (28%) were rendered tumor-free by surgery. The 21 disease-free patients (65.5%) received two further inductions and no maintenance. Toxicity was moderate, and 1 of the 16 patients who underwent surgery died postoperatively of pulmonary embolism. After a median follow-up period of 26 months (range, 9-60), 2 patients have died in CR and 15 (47%) are currently alive and have been continuously disease-free. The major determinant of tumor response was prior therapy. Eleven of 14 (78%) patients who were not pretreated with cisplatin achieved a continuous disease-free status versus only 4 of the 18 pretreated patients (22%, P less than 0.01). In this set of cases, complete responders to prior PVB therapy did better than incomplete responders treated for tumor progression. It can be concluded that normal-dose PE +/- B therapy, followed by surgical resection of the residual tumor, is a satisfactory salvage therapy in patients not pretreated with cisplatin and is also active in complete responders to prior PVB therapy.     

VP-16 plus ifosfamide plus cisplatin as salvage therapy in refractory germ cell cancer

Forty-eight evaluable male patients with germ cell tumors (GCT) failing to be cured with first-line therapy were treated with VP-16 (75 mg/m2), ifosfamide (1.2 g/m2), and cisplatin (20 mg/m2) (VIP), all given daily for 5 consecutive days every 3 weeks. All patients either achieved an unresectable partial remission as their best response to induction chemotherapy (Group A), relapsed from complete remission (CR) less than or equal to 2 months after induction therapy (Group B), or had received cisplatin plus VP-16 as previous salvage therapy (Group C). Nine (19%) had extragonadal GCT, and 37 (77%) had advanced disease. Twenty-three (48%) of the patients had greater than or equal 2 prior treatment regimens. Sixteen of 48 (33%) achieved CR with VIP treatment alone or following surgical excision of residual disease. Six of 22 (27%), three of seven (43%), and seven of 19 (37%) patients from groups A, B, and C, respectively, attained a CR. The median survival time of all patients was 7 months (range 0 to 28+) with seven patients remaining continuously free of disease (four patients greater than 1 year). Myelosuppression was significant with a median WBC nadir of 900/mm2 and platelet nadir of 24,000/mm2. Fourteen (26%) had granulocytopenic fever, and renal insufficiency developed in 15%. VIP combination chemotherapy demonstrates activity in this highly unfavorable population of patients with germ cell tumors. The actual contribution of ifosfamide in this regimen is unclear, but these results compare favorably to our experience with similar patients treated with cisplatin plus VP-16 alone. Further studies with VIP as initial salvage therapy for patients with GCT are planned.     

Effective chemotherapy for esophageal cancer with methotrexate, bleomycin, and cis-diamminedichloroplatinum II

Ten patients with squamous cancer of the esophagus were treated with an outpatient regimen combining cis-diamminedichloroplatinum (II), methotrexate and bleomycin. Nine of these had metastatic disease or recurrence after radiotherapy. Objective responses were noted in 50%, regardless of performance status or metastatic site. None of three patients with prior radiation therapy responded, however. Median duration of response was six months. Responders survived a median of eight months versus five months for nonresponders. Three patients had severe hematologic toxicity. A single patient with massive disease confined to the esophagus had an excellent response to six weeks of chemotherapy before radical irradiation. He is disease-free after two years but is paraplegic from radiation myelitis. This chemotherapy program is an effective palliative therapy for metastatic esophageal cancer. Its safety and efficacy as part of the initial treatment of local disease should be further investigated.     

Efficacy of high-dose methotrexate,ifosfamide, etoposide and dexamethasone salvage therapy for recurrent or refractory childhood malignant lymphoma

BackgroundChildren with recurrent or refractory malignant lymphoma generally have a poor prognosis. There is a need for new active drug combinations for this high-risk group of patients.Patients and methodsThis study evaluated the activity and toxicity of the methotrexate, ifosfamide, etoposide and dexamethasone (MIED) regimen for childhood refractory/recurrent non-Hodgkin’s lymphoma (NHL) or Hodgkin’s lymphoma (HL). From 1991 through 2006, 62 children with refractory/recurrent NHL (n = 24) or HL (n = 38) received one to six cycles of MIED. Based on MIED response, intensification with hematopoietic stem cell transplantation (HSCT) was considered.ResultsThere were 10 complete (CR) and 5 partial responses (PR) among the 24 children with NHL [combined response rate, 63%; 95% confidence interval (CI) 38% to 73%]. There were 13 CR and 18 PR among the 37 assessable children with HL (combined response rate, 84%; 95% CI, 68% to 94%). Although 59% courses were associated with grade IV neutropenia, treatment was well tolerated and without toxic deaths.ConclusionsMIED is an effective regimen for refractory/recurrent childhood malignant lymphoma, permitting a bridge to intensification therapy with HSCT.     

Incidence of late-relapse germ cell tumor and outcome to salvage chemotherapy.

PURPOSE: To define the incidence, clinical features, and outcome to salvage chemotherapy in patients with late-relapse germ cell tumor (GCT) after a complete response to first-line chemotherapy. PATIENTS AND METHODS: Two patient populations were examined. First, retrospective analysis of 246 patients treated on a clinical trial with salvage chemotherapy was performed; 29 patients with late-relapse GCT were identified and evaluated for treatment outcome and survival. Salvage regimens included paclitaxel, ifosfamide, and cisplatin, single agents, or a high-dose chemotherapy program. Second, the incidence of late relapse was assessed by retrospective analysis of 551 patients after a complete response (CR) to first-line chemotherapy. RESULTS: Twenty-nine patients received salvage chemotherapy on a clinical trial for late relapse GCT. The median survival was 23.9 months. At a median follow-up of 50.6 months, there were nine survivors. The chemotherapy regimens varied, but the only CRs were observed in patients treated with paclitaxel, ifosfamide, and cisplatin. Seven (50%) of 14 patients treated with paclitaxel, ifosfamide, and cisplatin achieved a continuous CR. Among the second population of 551 patients who had previously achieved a CR to a first-line chemotherapy trial, 17 were identified as having a late relapse (3%). The median time to relapse for these 17 patients was 7.8 years. CONCLUSION: Late-relapse GCT is uncommon and is associated with a poor prognosis resulting from a high degree of resistance to chemotherapy. Chemotherapy with paclitaxel, ifosfamide, and cisplatin followed by surgery may be effective in patients with late-relapse GCT who are not considered candidates for primary surgery.     

足叶乙甙联合铂类一线化疗后复发的小细胞肺癌二线化疗的临床研究

目的：本研究旨在分析敏感性复发及难治性复发的小细胞肺癌的二线化疗效果。方法：2003年1月-2006年3月经足叶乙甙联合铂类一线化疗后复发的小细胞肺癌（SCLC）共64例,其中敏感性患者复发31例,难治性患者复发33例。对难治性复发或敏感性复发时间少于6月者,采用紫杉类或伊立替康单药化疗;对敏感性复发时间大于6月者仍采用原一线方案或更改为紫杉类或伊立替康单药化疗。结果：64例患者进行了二线化疗,有57例患者可评价疗效,二线治疗总有效率22．8％,中位疾病进展时间（mTTP）15．1周,中位生存期（MST）7．2月。敏感性复发组及难治性复发组的有效率（CR＋PR）分别为37．9％和7．1％（P〈0．01）,mTTP分别为15．9周和10．4周（P〈0．05）,MST分别为9．0月和6．0月（P〈0．05）。骨髓抑制为二线化疗的主要不良反应,敏感性复发组及难治性复发组G3／4级白细胞减少发生率分别为41．9％和42．4％,G3／4级血小板减少发生率分别为22．6％和30．3％,两组不良反应无明显差异（P〉0．05）。结论：足叶乙甙联合铂类一线化疗后复发的小细胞肺癌采用二线化疗有部分病例仍有效,特别是对于敏感性复发的患者。     

Persistent gestational trophoblastic disease: results of MEA (methotrexate, etoposide and dactinomycin) as first-line chemotherapy in high risk disease and EA (etoposide and dactinomycin) as second-line therapy for low risk disease

Persistent gestational trophoblastic disease is potentially fatal, but the majority of patients are cured with chemotherapy. Any developments in treatment are therefore being directed towards maintaining efficacy and reducing toxicity. We evaluated efficacy and toxicity of methotrexate, etoposide and dactinomycin (MEA) as first-line therapy for high risk disease and etoposide and dactinomycin (EA) as second-line therapy for methotrexate-refractory low risk disease in a retrospective analysis of 73 patients (38 MEA, 35 EA) treated since 1986 at a supra-regional centre. The median follow-up period was 5.5 years and the median number of cycles received was 7. The overall complete response rate was 85% (97% for EA, 75% for MEA). Of eight patients who failed to respond, four have since died and four were cured with platinum-based chemotherapy. Alopecia was universal. Grade II or worse nausea, emesis, or stomatitis was observed in 29%, 30% and 37% respectively. Fifty-one per cent experienced grade II/III anaemia, 8% grade II or higher thrombocytopenia and 64% grade III or IV neutropenia; in six cases this was complicated by sepsis. Fifty-four per cent of patients went on to have a normal pregnancy. No patient has developed a second malignancy. In conclusion, the MEA and EA chemotherapy regimens for persistent trophoblastic disease are very well tolerated, do not appear to affect future fertility and are associated with excellent, sustained complete response rates.     

Relapse-free and overall survival in patients with pathologic stage II nonseminomatous germ cell cancer treated with etoposide and cisplatin adjuvant chemotherapy.

PURPOSE: To assess the long-term relapse-free survival and overall survival of patients with stage II nonseminomatous germ cell tumor (NSGCT) who received two cycles of adjuvant etoposide and cisplatin (EP) after primary retroperitoneal lymph node dissection. PATIENTS AND METHODS: Eighty-seven patients with completely resected pathologic stage II NSGCT were treated with adjuvant EP chemotherapy. Adjuvant EP consisted of two cycles of etoposide (100 mg/m(2)) plus cisplatin (20 mg/m(2)) per day, administered days 1 to 5 at a 21-day interval. RESULTS: Ten patients (11%) had pN1 disease, 73 (84%) had pN2 disease, and four (5%) had pN3 disease. Eighty-six patients received two cycles of EP, and one patient received an additional two cycles of EP after a transient marker increase after his first cycle. Eighty-seven patients are alive, and 86 patients (99%) remain relapse-free at a median follow-up of 8 years (range, 0.9 to 13.5 years). CONCLUSION: Two cycles of adjuvant EP is highly effective in preventing relapse in patients with pathologic stage II pN1 and pN2 NSGCT. An alternative treatment strategy is surveillance with full-course chemotherapy at relapse. Because there is a higher risk of relapse for patients with pN2 disease, these patients are offered adjuvant chemotherapy.     

Cystosarcoma phyllodes. Effective therapy with cisplatin and etoposide chemotherapy

Cystosarcoma phyllodes is an unusual breast neoplasm that rarely metastasizes. Most series report chemotherapy, radiation, and hormonal therapy to be ineffective. Three patients were treated with cisplatin and etoposide combination chemotherapy with effective palliation in two patients. Radiation therapy was effective in controlling symptomatic metastasis in all three patients. Hormonal therapy was ineffective in two patients despite the presence of positive hormone receptors. Chemotherapy and radiotherapy may be more effective in the treatment of this tumor than has been reported, although there is no apparent role for hormonal therapy. Functional hormone receptors are probably not present.     

Treatment of refractory and relapsed non-Hodgkin's lymphoma with ifosfamide,methotrexate and etoposide

Summary The combination of ifosfamide, etoposide and methotrexate was evaluated in 22 patients with non-Hodgkin's lymphoma (NHL) whose disease had relapsed or was resistant to first-line adriamycin-containing treatment. Only 4 of the 22 patients underwent remissions, 3 of which were complete and 1, partial. Two of the complete remissions occurred in patients with high-grade histology who received IMVP-16 after first-line treatment had induced only a partial remission. Bone marrow suppression was the limiting toxicity of this regime, which may be of value in the salvage therapy of selected patients with NHL.     

High-dose epirubicin in chemotherapy refractory non-seminomatous germ cell cancer: a phase II study. EORTC Genito-Urinary Tract Cancer Co-operative Group. EORTC Early Clinical Trials Group.

Eighteen patients with progressive disseminated, platinum-resistant germ cell tumors were treated with epirubicin 135 mg/m2, every 3 weeks. One patient had stable disease, 17 developed progression. Myelosuppression was dose-limiting. One patient died of neutropenic septicemia. High-dose epirubicin is not active against platinum-resistant germ cell cancer.