2016 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting.

PURPOSE: This review summarizes the recommendations for the prophylaxis of acute and delayed nausea and vomiting induced by multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting as agreed at the MASCC/ESMO Antiemetic Guidelines update meeting in Copenhagen in June 2015. METHODS: A systematic literature search using PubMed from January 01, 2009 through January 06, 2015 with a restriction to papers in English was conducted. RESULTS: There were three phase III randomized trials in patients undergoing high-dose chemotherapy and stem cell transplant and eight single arm non-randomized clinical studies (single in patients undergoing transplantation and one in patients receiving multiple-day chemotherapy treatment). We used a total of two randomized clinical trials in this guideline update. For patients receiving treatment for breakthrough chemotherapy-induced nausea and vomiting, a phase III randomized trial investigating the use of olanzapine versus metoclopramide in patients receiving highly emetogenic chemotherapy and a second single arm study looking at the effectiveness of olanzapine were identified. CONCLUSIONS: It was concluded that for patients receiving high-dose chemotherapy with stem cell transplant, a combination of a 5-HT3 receptor antagonist with dexamethasone and aprepitant (125 mg orally on day 1 and 80 mg orally on days 2 to 4) is recommended before chemotherapy. For patients undergoing multiple-day chemotherapy-induced nausea and vomiting, a 5-HT3 receptor antagonist, dexamethasone, and aprepitant, are recommended before chemotherapy for the prophylaxis of acute emesis and delayed emesis. For patients experiencing breakthrough nausea and vomiting, the available evidence suggests the use of 10 mg oral olanzapine, daily for 3 days. Mild to moderate sedation in this patient population (especially elderly patients) is a potential problem with this agent.

Phase II study of fosaprepitant + 5HT3 receptor antagonist + dexamethasone in patients with germ cell tumors undergoing 5-day cisplatin-based chemotherapy: a Hoosier Cancer Research Network study.

PURPOSE: A phase III study adding aprepitant to a 5HT3 receptor antagonist (5HT3-RA) plus dexamethasone in germ cell tumor (GCT) patients treated with 5-day cisplatin combination chemotherapy demonstrated a significant improvement in complete response (CR) (J Clin Onc 30:3998-4003, 2012). Fosaprepitant has demonstrated non-inferiority compared to aprepitant in single-day cisplatin chemotherapy and is approved as a single-dose alternative. This single-arm phase II study is the first clinical trial evaluating fosaprepitant in patients receiving multi-day cisplatin regimen. METHODS: GCT patients receiving a 5-day cisplatin combination chemotherapy were enrolled. Fosaprepitant 150 mg was given IV on days 3 and 5. A 5HT3-RA days 1-5 (days 1, 3, and 5, if palonosetron) plus dexamethasone 20 mg days 1 and 2 and 4 mg po bid days 6, 7, and 8 was administered. Rescue antiemetics were allowed. The primary objective was to determine the CR rate-no emetic episodes or use of rescue medications. Accrual of 64 patients was planned with expected CR > 27 %. RESULTS: Sixty-five patients were enrolled of whom 54 were eligible for analysis. Median age was 33. Fifty-one patients received bleomycin, etoposide, and cisplatin (BEP) chemotherapy. CR was observed in 13 (24.1 %) patients (95 % Agresti-Coull binomial C.I. 14.5 %, 37.1 %). CONCLUSION: The data in this phase II study, in contrast to our prior phase III study, appears to indicate a lower CR rate with the substitution of fosaprepitant for aprepitant. It is unknown whether the substitution of fosaprepitant for aprepitant provides the same benefit in multi-day cisplatin that was achieved with single-day cisplatin. Trial registration Clinical trial information NCT01736917.

Salvage therapy with high-dose chemotherapy and peripheral blood stem cell transplant in patients with primary mediastinal nonseminomatous germ cell tumors.

Salvage therapy with high-dose chemotherapy (HDCT) and bone marrow transplant (BMT) or peripheral blood stem cell transplant (PBSCT) has curative potential in patients with recurrent germ cell tumor. However, patients with primary mediastinal nonseminomatous germ cell tumors (PMNSGCTs) have had poor results with any form of salvage chemotherapy including HDCT. We switched from BMT to PBSCT in 1996. One hundred sixteen of 184 patients (63%) with recurrent or refractory germ cell tumors treated from 1996 to 2004 were alive and continuously disease-free. PMNSGCTs were excluded from that study because of poor results in the patient population with HDCT and BMTs. In 2006, we resumed treating patients with recurrent PMNSGCT with 2 consecutive courses of HDCT consisting of carboplatin 700 mg/m(2) × 3 plus etoposide 750 mg/m(2) × 3 and each followed by an infusion of autologous peripheral-blood hematopoietic stem cells with a second course 3 to 4 weeks later. Twelve patients were treated: 11 as initial salvage chemotherapy and 1 as fourth-line therapy. Eight of the 12 patients had major thoracic resections at the time of the relapse after initial chemotherapy. Three of the 12 patients achieved complete remission (CR; 10, 15, and 50 months' duration). One patient remains continuously with no evidence of disease (NED) at 50 months. An additional patient is currently NED at 52 months with HDCT and subsequent surgery. Median survival for the 12 patients was 11 months (range, 4-52 months). Results with tandem transplant for recurrent PMNSGCT remain poor compared to primary testis cancer, but durable CR and probable cure can be achieved in a small subset of patients with PMNSGCT. In our opinion, salvage surgical resection if anatomically feasible is the preferred option for patients with PMNSGT progressing after initial chemotherapy.

Perceptions of masculinity and self-image in adolescent and young adult testicular cancer survivors: implications for romantic and sexual relationships.

OBJECTIVE: To examine adolescent and young adult (AYA) testicular cancer survivors' subjective understanding of the impact of cancer in adolescence and young adulthood, with a particular emphasis on romantic and sexual relationships. METHODS: Twenty-one AYA testicular cancer survivors, aged 18 to 34 years, were recruited from outpatient testicular cancer follow-up clinics and completed a semi-structured qualitative interview that assessed the impact of testicular cancer on their romantic and sexual relationships. RESULTS: Four themes were identified that reflected survivors' understanding of the impact of cancer in adolescence and young adulthood: (1) embarrassment leads to delays in care-seeking, (2) testicular cancer makes you feel different from others, (3) being different from others makes you damaged goods, and (4) cancer disclosure is difficult. CONCLUSIONS: As these themes represent important components of being in a romantic/sexual relationship, either currently or in the future, AYA testicular cancer survivors would benefit from the development of tailored interventions focused on improving these relevant domains.

High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors.

BACKGROUND: Metastatic testicular tumors that have not been successfully treated by means of initial chemotherapy are potentially curable with salvage chemotherapy. METHODS: We conducted a retrospective review of 184 consecutive patients with metastatic testicular cancer that had progressed after they received cisplatin-containing combination chemotherapy. We gave 173 patients two consecutive courses of high-dose chemotherapy consisting of 700 mg of carboplatin per square meter of body-surface area and 750 mg of etoposide per square meter, each for 3 consecutive days, and each followed by an infusion of autologous peripheral-blood hematopoietic stem cells; the other 11 patients received a single course of this treatment. In 110 patients, cytoreduction with one or two courses of vinblastine plus ifosfamide plus cisplatin preceded the high-dose chemotherapy. RESULTS: Of the 184 patients, 116 had complete remission of disease without relapse during a median follow-up of 48 months (range, 14 to 118). Of the 135 patients who received the treatment as second-line therapy, 94 were disease-free during follow-up; 22 of 49 patients who received treatment as third-line or later therapy were disease-free. Of 40 patients with cancer that was refractory to standard-dose platinum, 18 were disease-free. A total of 98 of 144 patients who had platinum-sensitive disease were disease-free, and 26 of 35 patients with seminoma and 90 of 149 patients with nonseminomatous germ-cell tumors were disease-free. Among the 184 patients, there were three drug-related deaths during therapy. Acute leukemia developed in three additional patients after therapy. CONCLUSIONS: Testicular tumors are potentially curable by means of high-dose chemotherapy plus hematopoietic stem-cell rescue, even when this regimen is used as third-line or later therapy or in patients with platinum-refractory disease.

Fluoxetine versus placebo in advanced cancer outpatients: a double-blinded trial of the Hoosier Oncology Group.

PURPOSE: To determine whether fluoxetine improves overall quality of life (QOL) in advanced cancer patients with symptoms of depression revealed by a simple survey. PATIENTS AND METHODS: One hundred sixty-three patients with an advanced solid tumor and expected survival between 3 and 24 months were randomly assigned in a double-blinded fashion to receive either fluoxetine (20 mg daily) or placebo for 12 weeks. Patients were screened for at least minimal depressive symptoms and assessed every 3 to 6 weeks for QOL and depression. Patients with recent exposure to antidepressants were excluded. RESULTS: The groups were comparable at baseline in terms of age, sex, disease distribution, performance status, and level of depressive symptoms. One hundred twenty-nine patients (79%) completed at least one follow-up assessment. Analysis using generalized estimating equation modeling revealed that patients treated with fluoxetine exhibited a significant improvement in QOL as shown by the Functional Assessment of Cancer Therapy-General, compared with patients given placebo (P =.01). Specifically, the level of depressive symptoms expressed was lower in patients treated with fluoxetine (P =.0005), and the subgroup of patients showing higher levels of depressive symptoms on the two-question screening survey were the most likely to benefit from treatment. CONCLUSION: In this mix of patients with advanced cancer who had symptoms of depression as determined by a two-question bedside survey, use of fluoxetine was well tolerated, overall QOL was improved, and depressive symptoms were reduced.

Long-term survival with paclitaxel and gemcitabine for germ cell tumors after progression following high-dose chemotherapy with tandem transplant.

OBJECTIVES: Germ cell tumor patients progressing after high-dose chemotherapy (HDCT) have a dismal prognosis. A prior retrospective study of paclitaxel and gemcitabine enrolled 32 patients. All failed first-line chemotherapy and salvage therapy with HDCT. We now present long-term results. METHODS: Eligible patients received BEP or similar first-line chemotherapy and subsequent HDCT. They were treated with paclitaxel (100 mg/m) on days 1, 8, and 15 and gemcitabine (1000 mg/m) on days 1, 8, and 15 every 4 weeks for a maximum of 6 cycles. RESULTS: Ten of 32 (31%) had an objective response (4 partial remissions and 6 complete responses). Four patients (12.5% of total) have enjoyed long-term survival; 3 are continuously disease free for 64, 94, and 122 months. None of these 3 received subsequent chemotherapy or surgery. A fourth patient relapsed after 72 months, and has now reachieved remission for 36+ months after treatment with the same regimen. These patients had 2, 2, 2, and 4 prior therapies, respectively, and a rising serum human chorionic gonadotropin (69 and 138 mIU/mL), α-fetoprotein (525 ng/mL), or increasing intrathoracic metastases. Longest prior response ranged from 5 to 24 months. CONCLUSIONS: Paclitaxel and gemcitabine salvage chemotherapy can offer long-term survival and probable cure in relapsed/refractory germ cell tumor patients after HDCT. This is an appropriate regimen in a taxane-naive and gemcitabine-naive patient population. This is the first example of a nonplatinum curative chemotherapy regimen in patients progressing after HDCT.

Phase II clinical trial of oxaliplatin and bevacizumab in refractory germ cell tumors.

BACKGROUND: Salvage chemotherapy has curative potential in germ cell tumors (GCTs). However, novel therapies are still needed for patients failing to be cured with standard salvage chemotherapy. Bevacizumab in combination with chemotherapy has clinical activity in many solid tumors. This is the first study of bevacizumab with oxaliplatin in refractory GCT patients. PATIENTS AND METHODS: Patients with metastatic GCT with progressive disease after second-line or later salvage chemotherapy were eligible. Prior high-dose chemotherapy and paclitaxel and/or gemcitabine were required unless primary mediastinal nonseminomatous GCT or late relapse. Patients received oxaliplatin-85 mg/m and bevacizumab-10 mg/kg every 2 weeks for a maximum of 14 cycles. RESULTS: Twenty-nine patients were enrolled and evaluated. Nine patients were late relapses and 5 had primary mediastinal nonseminomatous GCT. Median number of prior chemotherapy regimens was 4. There was no grade 4 and only 1 grade 3 toxicity. Although the primary endpoint of 12 months disease-free survival was not achieved, 8 patients (27.6%) had objective response including 1 complete remission. Median duration of remission was 5 months (range, 4 to 22 mo). CONCLUSIONS: Oxaliplatin plus bevacizumab was well tolerated in heavily pretreated GCTs with manageable adverse events. There was modest clinical activity but only 1 patient achieved complete remission.

Randomized, double-blind, placebo-controlled, phase III cross-over study evaluating the oral neurokinin-1 antagonist aprepitant in combination with a 5HT3 receptor antagonist and dexamethasone in patients with germ cell tumors receiving 5-day cisplatin combination chemotherapy regimens: a hoosier oncology group study.

PURPOSE: Aprepitant, a 5-HT3 receptor antagonist (5HT3-RA), and dexamethasone are standard antiemetic therapy for prevention of single-day, cisplatin-induced nausea and vomiting. We conducted a double-blind, placebo-controlled phase III cross-over study that compared aprepitant to placebo combined with standard antiemetic prophylaxis (a 5HT3-RA and dexamethasone) in patients receiving 5 days of cisplatin combination chemotherapy for testicular cancer. PATIENTS AND METHODS: Patients receiving two consecutive identical courses of a 5-day cisplatin-based chemotherapy were randomly assigned to aprepitant 125 mg on day 3 and 80 mg per day on days 4 through 7 or to placebo with the initial course and crossover to the opposite treatment with the second course. The primary objective was complete response (CR). Secondary end points were emetic episodes (acute and delayed), nausea measurement based on a visual analog scale (VAS), and patient-stated preference after the second study cycle. RESULTS: In all, 71 patients were screened for the study and 69 were evaluable. Thirty-five patients were randomly assigned to receive aprepitant and 34 to receive placebo for the first course. Forty-two percent achieved CR with aprepitant compared with 13% with placebo (P < .001). Eleven patients (16.2%) had at least one emetic episode during the aprepitant cycle versus 32 patients (47.1%) with placebo. Thirty-eight patients preferred the aprepitant cycle whereas 11 preferred placebo (P < .001). There was no statistical difference in VAS for nausea, but it was numerically superior with aprepitant. There was no toxicity with aprepitant compared with placebo. CONCLUSION: There was a significant improvement in CR rate with aprepitant combined with a 5HT3-RA and dexamethasone. Patient preference strongly favored the aprepitant cycle.

Salvage chemotherapy with high-dose carboplatin and etoposide with peripheral blood stem cell transplant in patients with relapsed pure seminoma.

PURPOSE: To evaluate rates of complete remission and overall survival for patients with relapsed pure seminoma treated with high-dose carboplatin and etoposide followed by peripheral blood stem cell transplant. PATIENTS AND METHODS: Forty-eight consecutive patients with relapsed pure seminoma who were treated with high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplant between May 1996 and June 2006 were retrospectively reviewed. Upon relapse (first, second, or third relapse) patients were given HDCT with carboplatin 700 mg/m(2) and etoposide 750 mg/m(2) for 3 consecutive days followed by infusion of peripheral blood stem cells. Here, we review both response and survival. RESULTS: Thirty-eight (79%) of 48 patients obtained a complete response (CR) with overall survival of 75%. Median follow-up of all patients was 45.6 months. Twenty-two (92%) of 24 patients in first relapse achieved CR and are still alive and continuously disease-free. Sixteen (67%) of 24 patients had HDCT as third- or fourth-line therapy with 67% CR and overall survival of 64%. There were 3 treatment-related deaths, all of which occurred as third- or fourth-line therapy. CONCLUSION: HDCT results in high rates of both CR and overall survival in patients with first or later relapsed pure seminoma germ cell tumors.

Long-term follow-up of Cisplatin combination chemotherapy in patients with disseminated nonseminomatous germ cell tumors: is a postchemotherapy retroperitoneal lymph node dissection needed after complete remission?

PURPOSE: Controversy arises regarding the optimal management of patients with nonseminomatous germ cell tumor (NSGCT) who achieve a serologic and radiographic complete remission (CR) to systemic chemotherapy. Some authors recommend postchemotherapy retroperitoneal lymph node dissection (PC-RPLND), whereas others omit surgery and observe these patients. In an attempt to address this question, we report the long-term follow-up of patients treated at Indiana University who were observed without PC-RPLND. PATIENTS AND METHODS: This is a retrospective analysis of patients with NSGCT who achieved a CR to first-line chemotherapy and were monitored without further therapy. CR was defined as normalization of serum tumor markers and resolution of radiographic disease (residual mass < 1 cm). RESULTS: One hundred forty-one patients were identified. Five patients (4%) had less than 2 years of follow-up. After a median follow-up of 15.5 years, 12 patients (9%) experienced relapse. Of these 12 patients, eight patients currently have no evidence of disease (NED), and four patients died of disease. The estimated 15-year recurrence-free survival (RFS) and cancer-specific survival rates were 90% and 97%, respectively. The estimated 15-year RFS for good-risk patients (n = 109) versus intermediate- or poor-risk patients (n = 32) was 95% and 73% (P = .001), respectively. Six patients (4%) experienced recurrence in the retroperitoneum, of whom two patients died of disease. Five patients had late relapse (range, 3 to 13 years), including two patients in the retroperitoneum. All five patients currently have NED. CONCLUSION: Patients obtaining a CR after first-line chemotherapy can be safely observed without PC-RPLND. Relapses are rare and potentially curable with further treatment.

Palonosetron plus dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving multiple-day cisplatin chemotherapy for germ cell cancer.

GOALS OF WORK: The aims of this study were to assess the safety and antiemetic efficacy of multiple-day dosing of palonosetron plus dexamethasone in patients receiving highly emetogenic multiple-day cisplatin-based chemotherapy for germ cell tumors. MATERIALS AND METHODS: Forty-one men undergoing 5-day cisplatin-based chemotherapy for testicular cancer received palonosetron 0.25 mg IV once daily 30 min before chemotherapy on days 1, 3, and 5 plus IV dexamethasone 20 mg before chemotherapy on days 1 and 2, and 8 mg PO bid on days 6 and 7 and 4 mg bid on day 8. Safety and efficacy were assessed in 24-h intervals for 9 days. Efficacy endpoints included emesis, intensity of nausea and its interference with patient functioning, and rescue antiemetic use. A subset of patients (n = 11) was studied for electrocardiograph effects and pharmacokinetic evaluation. MAIN RESULTS: This multiple-day antiemetic regimen was safe, with headache and constipation the most common treatment-related adverse events, mostly mild. Neither adverse events nor electrocardiographic changes appeared to increase in frequency, duration, or intensity over time despite a 1.42-fold systemic accumulation of palonosetron with repeated doses. The majority of patients had no emesis at any time throughout days 1-5 (51%) or days 6-9 (83%), had no moderate-to-severe nausea, and did not require rescue medication. Most patients reported that nausea had no significant effect on daily functioning on days 1-4 (72%) and days 5-9 (85%). CONCLUSIONS: Palonosetron on days 1, 3, and 5, along with a regimen of dexamethasone, was safe and well tolerated and effectively controlled both nausea and emesis in patients undergoing 5-day cisplatin-based chemotherapy for testicular cancer.

Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant.

PURPOSE: To determine long-term survival and potential cure with salvage chemotherapy with paclitaxel plus gemcitabine after progression after both cisplatin combination chemotherapy and subsequent high-dose chemotherapy with tandem transplantation. PATIENTS AND METHODS: One hundred eighty-four patients received salvage high-dose chemotherapy at Indiana University (Indianapolis, IN) from February 1996 to December 2004. After further evidence of progressive disease, 32 patients were subsequently treated with paclitaxel 100 mg/n2 over 1 hour plus gemcitabine 1,000 mg/m2 over 30 minutes, days 1, 8, and 15 every 4 weeks for a maximum of six courses. This is a retrospective review of this patient population. Patients were evaluated for response, duration of response, and survival. Patients were ineligible if they received prior paclitaxel or gemcitabine. RESULTS: Ten (31%) of 32 patients achieved objective response, including four partial remissions (2- to 6-month duration) and six complete responses (CRs). Four of these six CRs (12.5% of total patient population) are continuously disease free (NED) with paclitaxel plus gemcitabine alone (no postchemotherapy surgery) at more than 20, 40, 44, and 57 months from start of paclitaxel plus gemcitabine, respectively. One additional CR is currently NED more than 63 months after paclitaxel plus gemcitabine with two subsequent resections of carcinoma. CONCLUSION: Long-term disease-free survival is possible with paclitaxel plus gemcitabine in this patient population that progressed after high-dose chemotherapy, and had not received prior paclitaxel or gemcitabine.

Emetic potential of daily oral etoposide.

BACKGROUND: Chemotherapeutic agents are classified by their degree of emetogenicity. Highly and moderately emetogenic agents require antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. Intravenous etoposide is listed as having low emetic potential. However, oral etoposide is categorized as having moderate emetogenicity. Daily oral etoposide is used in refractory germ cell cancer patients. We prospectively evaluated the emetic potential of oral etoposide in this patient population. MATERIALS AND METHODS: Between August 2003 and February 2006, 16 patients with refractory germ cell cancer received single-agent, daily oral etoposide 50 mg/M(2) for 21 consecutive days every 4 weeks. All patients had progressed after cisplatin combination chemotherapy and had received high-dose chemotherapy with carboplatin plus etoposide (intravenously) with peripheral blood stem cell transplant. No patient received prophylactic antiemetics. Patients completed a six-question Multinational Association of Supportive Care in Cancer (MASCC) antiemetic tool during each day of etoposide during the first 21-day course. Nausea intensity and duration were recorded. Number of emetic episodes and any antiemetic medications were recorded. RESULTS: All 16 patients completed the six-question MASCC form. Eleven of 16 had no nausea or vomiting and two other patients had only minimal nausea, despite absence of any prophylactic antiemetics. Only two patients required antiemetic support. Two patients experienced emesis for a single episode. One patient had nausea on days 9-20 with a MASCC rating of 3-6, and one patient had continued mild nausea (MASCC rating 1-3) for all 21 days. CONCLUSIONS: Daily oral etoposide has a low probability of producing chemotherapy-induced nausea and/or vomiting and, in our opinion, does not require prophylactic antiemetics.

Phase II study of imatinib mesylate in chemotherapy refractory germ cell tumors expressing KIT.

OBJECTIVE: This phase II study was conducted to determine the activity of imatinib (gleevec) in heavily pretreated patients with KIT-positive metastatic germ cell tumor. MATERIALS AND METHODS: From June 2002 through April 2005, 18 patients with refractory germ cell tumors were tested for KIT expression by immunohistochemistry. All patients screened were deemed to be incurable with further standard chemotherapy or surgery. Six patients were eligible and treated with imatinib 600 mg/d orally. RESULTS: There were no complete or partial remissions. Five of 6 patients had progressive disease and 1 patient had stable disease with a >50% decline in serum alpha-fetoprotein for 3 months before developing further progression. CONCLUSION: In this small sample size, there was no evidence of significant antitumor activity of imatinib in patients with KIT-positive refractory germ cell tumors.

Phase II study of cisplatin plus epirubicin salvage chemotherapy in refractory germ cell tumors.

PURPOSE: Initial cisplatin (CIS) combination chemotherapy will cure 70% of patients with disseminated testicular cancer. This phase II clinical trial evaluated the combination of CIS plus epirubicin (CIS-EPI) in patients with metastatic germ cell tumors (GCT) not amenable to cure with standard salvage therapy. PATIENTS AND METHODS: Between March 2001 and August 2005, 30 patients with GCT, who had received at least one previous CIS-based regimen, were enrolled. All patients were males, with median age 36 (range, 24 to 45 years). Twenty-one patients (70%) had experienced late relapses (> 2 years). Patients received EPI 90 mg/m2 on day 1 and CIS 20 mg/m2 on days 1 to 5 every 3 weeks for maximum of four cycles. RESULTS: Nineteen (63%) of 30 patients received all four cycles. Toxicity was primarily hematologic: grade 3/4 neutropenia, four patients (one neutropenic fever); two patients had grade 3 thrombocytopenia, and five patients had grade 3/4 anemia. Nonhematologic toxicity was grade 3 acute renal failure in two patients; grade 3 electrolyte wasting in two patients; grade 3 nausea/vomiting in eight patients; grade 3 elevation of aminotransferases in one patient; and grade 3 diarrhea in one patient. There were no occurrences of severe mucositis, cardiotoxicity, or treatment-related deaths. Nine patients achieved a complete remission; seven of these patients remain without evidence of disease at 25+, 27+, 29+, 44+, 45+, 46+, and 48+ months. One patient remains alive with stable pulmonary nodules at 28+ months. CONCLUSION: CIS-EPI is an active regimen in metastatic GCT, with an acceptable toxicity profile. This regimen offers potential for long-term disease-free survival in this population.