Treatment of metastatic germ cell tumors with etoposide and cisplatin as first line chemotherapy

PURPOSE: The efficacy and toxicity of two-drug therapy (etoposide and cisplatin, EP) in patients with metastatic germ cell tumors were investigated. PATIENTS AND METHODS: Between December 1996 and November 1999, 18 patients with metastatic germ cell tumors (6 seminomas and 12 non-seminomas, Stage II 8, Stage IIIA 2, Stage IIIB 6, Stage IIIC 2) were treated by 3-5 cycles of induction chemotherapy regimen (EP). Etoposide and cisplatin were administrated in doses of 100 mg/m2 and 20 mg/m2, respectively, on days 1 to 5 and then repeated from day 21. After tumor markers obtained normal levels, one or two additional cycles of EP were continued. Patients showing evidence of residual tumor mass underwent debulking surgery as early as possible. RESULTS: At the end of EP therapy, 4 (22%) of the 18 patients achieved complete remission and 14 patients (78%) showed partial remission. Seven patients of partial remission were treated by excision of residual abnormalities: 6 had pathologically necrotic debris in the resected specimen and 1 had teratoma, and these 7 patients all achieved complete remission. Four other patients achieving partial remission were followed without surgical excision and have had no evidence of disease progression. Remaining three patients achieving partial remission received salvage chemotherapy with or without adjunctive surgery, resulted in complete remission in 2 patients and partial remission in 1 patient. EP demonstrated to have less treatment-related toxicity compared with that of EBP. Follow up studies ranging from 12 to 47 months (median, 29.6) showed that one patient experienced a relapse from complete remission at 13 months and was salvaged by chemotherapy and surgery. Finally, thirteen patients (72%) who achieved complete remission are alive and disease-free and 5 patients (28%) showing partial remission are alive with negative tumor markers and no evidence of relapse. CONCLUSION: These results suggests that EP is an efficacious and less toxic first line regimen for good-prognosis patients with metastatic germ cell tumors.     

Treatment results of VIP (etoposide, ifosfamide and cisplatin) chemotherapy as a first-line therapy in metastatic germ cell tumors

PURPOSE: We investigated the effectiveness and toxicity of VIP therapy as a first-line chemotherapy for patients with metastatic germ cell tumor. PATIENTS AND METHODS: From March 1994 to October 1997, we treated 16 patients with VIP therapy consisting of etoposide (100 mg/m2), ifosfamide, (1.2 g/m2) and cisplatin (20 mg/m2), all of which were generally given daily for 5 consecutive days every 3 weeks. Of the 16 patients, 6 were classified into a good, 5 into an intermediate, and 5 into a poor prognostic group according to the International Germ Cell Consensus Classification. RESULTS: Thirteen patients (81%) achieved complete response with VIP alone or VIP plus surgery. Three-year survival rate was 100% in good and intermediate prognostic group, while 40% in poor prognostic group. Although all patients had Grade 3 or higher myelosuppression, the treatment was well tolerated and no patient died of treatment-related complications. CONCLUSIONS: VIP appears to be an effective and safe regimen as an induction chemotherapy for good and intermediate risk patients with germ cell tumor. However, more intensive regimen may be necessary for poor-risk patients.     

Short-course etoposide, bleomycin and cisplatin in the treatment of metastatic germ cell tumours. Appraisal of its potential as adjuvant chemotherapy for stage 1 testis tumours

Prompted by recent reports of the increasing incidence of late relapses in Stage 1 patients with both malignant teratoma and seminoma on surveillance, a low toxicity regimen combining etoposide, bleomycin and cisplatin [EBCi(3)] with prolonged infusion of bleomycin, given daily for 3 days, has been developed for possible use as adjuvant treatment. Forty of 44 patients treated remain free of disease with a median follow-up of 21 months and actuarial disease free survival at 2 years of 91%. There have been no respiratory problems attributable to bleomycin lung toxicity in this study compared with four (3 associated with patient deaths) seen in 91 previously treated patients. The relatively low toxicity and high efficacy of this regime indicate that it may be suitable as adjuvant treatment.     

Salvage chemotherapy with methotrexate,etoposide and actinomycin D in men with metastatic nonseminomatous germ cell tumors with a choriocarcinoma component: A preliminary report

The objective of the present study was to assess the use of salvage chemotherapy using methotrexate, etoposide and actinomycin D (MEA) in men with nonseminomatous germ cell tumor (NSGCT) with a choriocarcinoma component. Nine patients were included. They had initially received bleomycin, etoposide and cisplatin, and high‐dose ifosfamide, carboplatin and etoposide as induction chemotherapies. However, they failed to achieve the normalization of β‐human chorionic gonadotropin (β‐HCG). Therefore, MEA therapy (methotrexate: 450 mg/body on day 1, actinomycin D: 0.5 mg/body on days 1–5, etoposide: 100 mg/body on days 1–5) was subsequently administered. After MEA therapy (median: 3 cycles), serum β‐HCG was normalized in five of the nine patients. Of these five, three achieved long‐term disease‐free survival and one died of disease unrelated to NSGCT, whereas the remaining patient developed disease recurrence and died of disease progression. All four patients who failed to achieve the normalization of β‐HCG died of disease progression. Although several severe toxicities greater than grade 3, which were mainly associated with bone marrow suppression, occurred in all patients, there was no treatment‐related death. Considering the current outcomes, MEA regimen could be an attractive option as a salvage chemotherapy for metastatic NSGCT patients with a choriocarcinoma component showing resistance to intensive conventional chemotherapies.     

Low dose bleomycin with etoposide and cisplatin for metastatic testicular teratoma.

Thirty-nine men with metastatic testicular teratoma were treated with a combination of bleomycin, etoposide and cisplatin (BEP). Unlike the usual regimen of these 3 agents, bleomycin and cisplatin were given on day 1 only of the cycle, with etoposide for 3 days. Thirty patients (77%) are alive and disease-free after a median follow-up of 31 months--24/25 (96%) with disease confined to lymph nodes but only 6/14 (43%) patients with lung involvement. Modified BEP chemotherapy is a well tolerated alternative to standard BEP chemotherapy for small volume nodal disease; it minimises in-patient time, hospital visits and the risk of bleomycin lung toxicity. However, omission of the weekly doses of bleomycin and shortening of the administration schedule of cisplatin and etoposide may be detrimental in patients with more extensive disease, for whom more intensive therapy may be necessary.     

BEP (bleomycin, etoposide, cisplatinum) chemotherapy as an induction therapy of advanced extragonadal germ cell tumor]

Five patients with advanced extragonadal germ cell tumor (EGGCT) were treated with cisplatinum + vinblastine + bleomycin (BVP) or cisplatinum + etoposide + bleomycin (BEP) chemotherapy as an induction therapy. All patients had high levels of tumor markers and multiple distant metastasis in poor nutritious conditions. Two patients given BVP therapy died 6 and 9 months after the chemotherapy. By contrast, three patients given BEP therapy achieved complete remission and were surviving longer than one year without any evidences of disease. Granulocytopenic fever was seen soon after the first course of BEP therapy. Prophylactic granulocyte-colony stimulating factor (G-CSF) treatment, enabled two of them to receive full dose chemotherapy without any fever attacks. In conclusion, BEP chemotherapy is effective to EGGCT as well as far advanced testicular tumors and G-CSF treatment is useful for achievement of induction chemotherapy to advanced germ cell tumors.     

One cycle of bleomycin, etoposide and cisplatin plus two cycles of etopeside and cisplatin chemotherapy in selected patients with low-volume stage II nonseminomatous germ cell tumor of the testis

OBJECTIVE: To assess the feasibility of bleomycin omission from second and third cycles of bleomycin, etoposide and cisplatin (BEP) chemotherapy in low-volume stage II nonseminomatous germ cell tumor patients who achieve a normal tumor marker level after the first cycle of treatment. MATERIALS AND METHODS: Out of 59 nonseminomatous testicular cancer patients with low-volume retroperitoneal disease, serum markers normalized after the first cycle of treatment in 30 cases. 12 patients completed 3BEP (group 1; years 1994-1998) and other 18 patients received etoposide and cisplatin (EP) as second and third cycles of chemotherapy (group 2; years 1998-2004). RESULTS: All patients from each group achieved complete response with chemotherapy alone or by subsequent resection of teratoma or necrosis. There was no relapse with active cancer after the treatment. All patients remained disease-free during the median follow-up period of 97 and 48 months for groups 1 and 2 respectively. CONCLUSIONS: One cycle of BEP plus two cycles of EP chemotherapy was as effective as three standard cycles of BEP. The regimen can be suggested as a less toxic therapeutic alternative in these selected patients. More cases, however, in a prospective randomized setting are required to further verify these data.     

Acute myocardial infarction during combined chemotherapy with bleomycin, etoposide and cisplatin for testicular cancer

We report a case of acute myocardial infarction during combined chemotherapy with bleomycin, etoposide and cisplatin for testicular cancer. A 30-year-old smoker without any history of ischemic heart disease complained of sudden chest pain on the ninth day of his third course of chemotherapy. An electrocardiogram showed ST segment elevation in II, III and aVF. Emergency coronary angiography revealed total occlusion of the right coronary artery by a thrombus, which was removed by coronary atherectomy.     

Treatment of patients with metastatic germ cell tumors relapsing after high-dose chemotherapy

With the use of cisplatin-based combination chemotherapy, metastatic testicular germ cell tumors can be cured in 70–80% of patients. Patients refractory to cisplatin-based chemotherapy have a very poor prognosis. Several mechanisms have been discussed for the development of platinum resistance such as a decreased intracellular concentration of the drug, increased repair of the drug induced damage, or an altered apoptotic response to this damage. Various chemotherapeutic agents have been evaluated in intensively pretreated or cisplatin-refractory patients. Neither the antracyclines nor vinorelbine, bendamustine, topotecan, nor biological agents such as suramin and retinoic acid have demonstrated clinical activity. Paclitaxel has been evaluated at different doses and schedules and yielded a response rate of 21% (range 11–30%) with individual patients achieving complete remissions. This has led to the inclusion of paclitaxel in salvage regimens in combination with cisplatin and/or ifosfamide. Two recent studies have evaluated gemcitabine in refractory germ cell tumors, demonstrating a response rate of 17% (95% CI: 7–28%) in 52 intensively pretreated patients, two-thirds of whom had relapsed after previous high-dose chemotherapy plus autologous stem cell transplantation. The nonhematologic toxicity of weekly gemcitabine at doses of 1000–1250 mg/m² was tolerable and hematologic side effects included thrombocytopenia in approximately 20% of patients. Ongoing studies in refractory germ cell tumors performed by the German Testicular Cancer Study Group (GTCSG) are evaluating oxaliplatin, a platinum derivative with incomplete cross-resistance to cisplatin. Future trials combining new active agents may make it possible to test the use of alternating treatment strategies in patients with “poor prognostic” disease or as salvage treatment. It is hoped that the increase in knowledge of the molecular mechanism of testicular cancer may lead to the development of new therapeutic options.     

Multiple liver metastases of a suprasellar germ cell tumor treated with combined chemotherapy of cisplatin and etoposide

A 23-year-old man was admitted with progressively disturbed vision and easy fatigability. CT scans demonstrated an enhanced mass in the sellar region. Physical and endocrinological examinations revealed atrophy of both optic nerves, temporal field cuts in both eyes, and panhypopituitarism. Concentrations of human chorionic gonadotropin (HCG) in the serum and cerebrospinal fluid were 12 and 33IU/L, respectively. On November 11, 1987, the tumor was partially removed using the transsphenoidal approach. The histological diagnosis was germinoma with syncytiotrophoblastic giant cells. Following postoperative craniospinal irradiation (whole brain, 30Gy; local, 18Gy; spinal canal 28Gy), CT scans showed no residual tumor and the HCG levels decreased until they were undetectable. Eighteen months later, the patient complained of abdominal pain. His serum HCG level had increased to 2,554 IU/L. CT scans of the abdomen revealed multiple low density areas in the liver. Chest X-ray was negative. A Ga scintigram disclosed only liver metastasis. Administration of a chemotherapy was started on June 26, 1989. Cisplatin and etoposide in doses of 20mg and 40mg respectively were given for 5 consecutive days in one course. Following four courses of the combined chemotherapy, the tumor entirely disappeared on CT scans and the HCG level returned to normal. The patient is now able to work well without evidence of recurrence. Multiple liver metastases of an intracranial germ cell tumor had been fatal in previous reports. This may be the first case with liver metastases in which the victim is still alive. The present case indicates that combined chemotherapy with cisplatin and etoposide is effective for extraneural metastases of an intracranial germ cell tumor.     

Phase II trial of first-line chemotherapy with gemcitabine,etoposide, and cisplatin for patients with advanced urothelial carcinoma

ObjectivesThis study sought to examine the combination chemotherapy of gemcitabine, etoposide, and cisplatin (GEP) as a first-line treatment for advanced urothelial carcinoma (UC) to assess its antitumor activity and toxicity.Methods and materialsEligible patients with advanced UC had undergone no previous chemotherapy. Advanced UC was defined as unresectable or metastatic disease. Subsequent recurrent disease, either locally or distantly following primary radical surgery, was not excluded. GEP was recycled every 4 weeks. Etoposide and cisplatin were given on days 1 through 3 at doses of 60 mg/m² and 20 mg/m², respectively, and gemcitabine was given on days 1, 8, and 15 at a dose of 800 mg/m². The primary end point was objective response rate, and the secondary end points included progression-free survival, overall survival (OS), and toxicity.ResultsForty-two patients were enrolled and subsequently treated with GEP. Nineteen had visceral/bone metastases, 16 had disease restricted to the lymph nodes, and the remaining 7 had unresectable disease at the primary site. The median number of GEP courses was 4. Thirty of the 42 assessable patients (71.4%, 95% confidence interval [CI]: 56.4%–82.8%) demonstrated objective responses. At a median follow-up of 14.6 months, median progression-free survival and OS periods were 8.7 months (95% CI: 6.9–14.6 mo) and 16.2 months (95% CI: 13.1–25.4 mo), respectively. In the multivariate analysis, anemia and visceral/bone metastasis were significant pretreatment prognostic factors for OS. Grade 4 hematologic events were neutropenia (83.3%), thrombocytopenia (23.8%), and anemia (7.1%). There were no toxic deaths and no instances of severe nonhematologic toxicity.ConclusionsGEP as a first-line chemotherapy treatment was very active and moderately tolerable for advanced UC. Anemia and visceral/bone metastasis were important negative predictive factors of GEP for OS.     

Long-term results of first-line sequential high-dose carboplatin, etoposide and ifosfamide chemotherapy with peripheral blood stem cell support for patients with advanced testicular germ cell tumor

OBJECTIVE: Standard chemotherapy shows relatively low long-term survival in patients with poor-risk testicular germ cell tumor (GCT). First-line high-dose chemotherapy (HD-CT) may improve the result. High-dose carboplatin, etoposide, ifosfamide chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT) was investigated as first-line chemotherapy in patients with advanced testicular GCT. METHODS: Fifty-five previously untreated testicular GCT patients with Indiana 'advanced disease' criteria received three cycles of bleomycin, etoposide and cisplatin (BEP) followed by one cycle of HD-CT plus PBSCT, if elevated serum tumor markers were observed after three cycles of the BEP regimen. RESULTS: Thirty patients were treated with BEP alone, because the tumor marker(s) declined to normal range. Twenty-five patients received BEP and HD-CT. One patient died of rhabdomyolysis due to HD-CT. Three and six (13% and 25%) out of 24 patients treated with BEP and HD-CT achieved marker-negative and marker-positive partial responses, respectively. The other patients achieved no change. Fifteen (63%) are alive and 14 (58%) are free of disease at a median follow-up time of 54 months. Severe toxicity included treatment-related death (4%). CONCLUSIONS: HD-CT with peripheral stem cell support can be successfully applied in a multicenter setting. HD-CT demonstrated modest anticancer activity for Japanese patients with advanced testicular GCT and was well tolerated. This regimen might be examined for further investigation in randomized trials in first-line chemotherapy for patients with poor-risk testicular GCT.     

Prognosis of intracranial germ cell tumours: Effectiveness of chemotherapy with cisplatin and etoposide (CDDP and VP-16)

Summary A co-operative study for patients with intracranial germ cell tumours was performed to analyze their prognosis and the effectiveness of Cisplatin/Etoposide (CDDP/VP-16) chemotherapy.A total of 46 patients; 30 primary and 16 recurrent cases were registered from 15 participating neurosurgical institutions in Japan. Based on histological criteria and tumour markers, they were classified into three groups; germinoma, germinoma with syncytiotro-phoblastic giant cell (STGC), and non-germinomatous malignant tumour.Sixteen patients were treated with CDDP/VP-16 chemotherapy alone and the other 30 patients were treated by a combination of surgery and/or radiation in addition to chemotherapy. Eleven out of 13 patients (85%) with germinoma showed a complete (n=10) or partial (n=1) response to CDDP/VP-16 chemotherapy even if their tumours were recurrent and there was evidence of CSF dissemination. For the germinoma with STGC and non-germinomatous malignant tumour, a high response rate; 100% for the former and 78% for the latter, could also be achieved in both the primary and the recurrent cases except in those cases of immature teratoma. Their survival times were still different between them. Two-year survival was 50% in germinoma with STGC and 48% in non-germinoma, while it was 88% in germinoma cases.     

Vascular toxicity following vinblastine, bleomycin, and cisplatin therapy for germ cell tumours

Vascular toxicity following the use of vinblastine, bleomycin, and cisplatin (VBP) combination chemotherapy has been described. This report gives details of five patients who suffered acute life-threatening vascular events following such a chemotherapy regimen for germ cell tumours. In three of the cases no evidence of tumour was found at autopsy. Both acute and long-term vascular toxicity were seen. Large artery vascular disease may result from synergistic toxicity of the drugs comprising the regimen. These cases, with an additional sixteen collected from the literature, suggest that major vascular disease is a significant side-effect of the VBP regimen.     

Combined chemotherapy with cisplatin and aclarubicin hydrochloride for metastatic brain tumors

Thirteen patients with metastatic brain tumors were treated by combined chemotherapy with cisplatin and aclarubicin hydrochloride. Initial response to this therapy was evaluated by the changes of tumor size on CT scan and clinical state during and after the treatment. The side effects and the causes of death were also studied. Nine cases demonstrated complete remission and 3 cases revealed partial response on CT scan. In short, over all response rate was 92%. Clinical state evaluated by Karnofsky scale was improved in 9 out of 13 cases. As the side effects, there were mild myelosuppression, nausea and vomiting, which didn't persist for a long time. The cause of death was mainly due to recurrence of primary lesion. The tissue concentration of aclarubicin hydrochloride was measured in 6 patients, of which mean value was 0.558 microgram/g at 15 min. The concentration was thought high enough to kill tumor cells.     

Impact of paclitaxel,cisplatin, and gemcitabine as first-line chemotherapy in cisplatin-fit and -unfit patients with advanced/metastatic urothelial carcinoma

PurposeThis study aimed to clarify the efficacy and toxicity of first-line combination treatment with paclitaxel, cisplatin, and gemcitabine (PCG) for advanced/metastatic urothelial carcinoma (UC) in cisplatin-unfit patients compared with cisplatin-fit patients.MethodsWe conducted a retrospective study of patients who received first-line PCG. Using international consensus criteria, patients were classified into cisplatin-fit and -unfit groups. Cisplatin-unfit patients received PCG with adjustment of the cisplatin dose after assessing 24-hour urinary creatinine clearance, without modifying the administration interval.ResultsFrom 2008 to 2017, 50 patients received first-line PCG, of whom 30 and 20 were classified into the cisplatin-fit and -unfit groups. After a median follow-up of 15.0 months, the median overall survival (OS) and progression-free survival (PFS) were 15.0 and 9.8 months in all patients, 15.0 and 10.0 months in the cisplatin-fit group, and 13.2 and 9.3 months in the cisplatin-unfit group, respectively. There was no significant difference in OS (hazard ratio [HR]: 1.33, 95% confidence interval [CI]: 0.69–2.54) or PFS (HR: 1.38, 95% CI: 0.74–2.55) between the groups. The overall response rate and complete response rate were 58% (95% CI: 43.2–71.8) and 32% (95% CI: 19.5–46.7) in all patients, and 55% (95% CI: 31.5–76.9) and 35% (95% CI: 15.4-59.2) in the cisplatin-unfit group, respectively. The common grade 3 of 4 adverse events experienced were neutropenia (78%), followed by thrombocytopenia (56%), anemia (46%), and febrile neutropenia (16%). The 24-hour urinary creatinine clearance did not differ significantly between the groups after one, two, or three courses of PCG.ConclusionsWe found no significant difference regarding OS and PFS between the cisplatin-fit patients with a full dose of cisplatin and -unfit patients with cisplatin-dose-adjusted chemotherapy. In select cisplatin-unfit patients, PCG with dose adjustment of cisplatin may be useful for treating advanced/metastatic UC without any significant adverse events or impaired renal function compared with cisplatin-fit patients with a full dose of cisplatin.     

Successful salvage chemotherapy with gemcitabine,etoposide and cisplatin for metastatic ureteral cancer: a case report

A 35-year-old man who had undergone nephroureterectomy and a single cycle of adjuvant MVAC chemotherapy for the left ureteral cancer was referred our clinic for the treatment of paraaortic lymph node metastases. Following histologic confirmation of transitional cell carcinoma by computed tomography (CT) guided biopsy, we treated him with combination chemotherapy consisting of ifosfamide, 5-fluorouracil, etoposide and cisplatin. After 5 cycles of chemotherapy complete remission was obtained. Six months later, however, metastases recurred in the left supraclavicular and paraaortic lymph nodes. Thus, we treated him with a new combination chemotherapy comprising gemcitabine, etoposide and cisplatin which was approved as a phase I study by the institutional review board. Although he was the first patient enrolled in the study and received the minimum dose of gemcitabine (level 1), complete remission was again achieved. Adjuvant radiotherapy of 40 Gy was given to the metastatic sites. He has been well without evidence of disease for 12 months.