Cisplatin-refractory Germ Cell Tumors Research Articles

Targeting of Deregulated Wnt/β-Catenin Signaling by PRI-724 and LGK974 Inhibitors in Germ Cell Tumor Cell Lines.

The majority of patients with testicular germ cell tumors (GCTs) can be cured with cisplatin-based chemotherapy. However, for a subset of patients present with cisplatin-refractory disease, which confers a poor prognosis, the treatment options are limited. Novel therapies are therefore urgently needed to improve outcomes in this challenging patient population. It has previously been shown that Wnt/β-catenin signaling is active in GCTs suggesting that its inhibitors LGK974 and PRI-724 may show promise in the management of cisplatin-refractory GCTs. We herein investigated whether LGK-974 and PRI-724 provide a treatment effect in cisplatin-resistant GCT cell lines. Taking a genoproteomic approach and utilizing xenograft models we found the increased level of β-catenin in 2 of 4 cisplatin-resistant (CisR) cell lines (TCam-2 CisR and NCCIT CisR) and the decreased level of β-catenin and cyclin D1 in cisplatin-resistant NTERA-2 CisR cell line. While the effect of treatment with LGK974 was limited or none, the NTERA-2 CisR exhibited the increased sensitivity to PRI-724 in comparison with parental cell line. Furthermore, the pro-apoptotic effect of PRI-724 was documented in all cell lines. Our data strongly suggests that a Wnt/β-catenin signaling is altered in cisplatin-resistant GCT cell lines and the inhibition with PRI-724 is effective in NTERA-2 CisR cells. Further evaluation of Wnt/β-catenin pathway inhibition in GCTs is therefore warranted.

Utility of a general molecular screening program in patients with GU malignancies: The ProfiLER trial experience.

528 Background: Advances in comprehensive tumor molecular pathology in genito-urinary (GU) tumors have driven development of targeted agents since ten years and changed the landscape of GU tumors treatment. We describe our experience with the institutional molecular trial ProfiLER. Methods: Retrospective review of patients with advanced genitourinary malignancies included in the prospective molecular profiling trial ProfiLER (NCT01774409) Tumor samples were analyzed by sequencing a 69 gene panel by next generation sequencing (NGS, Ion torrent PGM system) and whole genome array comparative genomic hybridization (Agilent platform). Clinical data were collected retrospectively. Cases were presented in a molecular board to drive prescription of molecular targeted therapy (MTT) according to the molecular abnormalities observed. Results: Between February 2013 and December 2018 156 adult patients were included, 42 had kidney cancer (including 32 clear cell carcinoma, 5 papillary type 2); 38 prostate cancer, 52 urothelial carcinoma including (16 upper tract), 12 cisplatin-refractory testicular germ cell tumor, 4 penile cancer, 3 adenocarcinoma of the urachus, 2 urethral carcinoma and 3 Leydig cell tumor. Median age at inclusion was 62 years (range 19, 80). Overall NGS and CGH failed in 11.5% of cases, and in 24% of prostate cancer cases.28.8% patients had at least one actionable target (n=45) with a recommended MTT. Only 17.8 % (n=8) patients actually received MTT corresponding to 5.1% of the total screened population. Only one patient had a clinical benefit from MTT. The most frequently initiated MTT were PIK3/AKT/mTOR pathway inhibitors (44,4%), FGRF/EGFR pathway inhibitors (13.3%) PARP inhibitors (8.7%) or cyclin kinase inhibitors (8.7%). The most frequent reasons for lack of MTT initiation were early death, ineligibility for clinical trials due to general condition. Conclusions: Non tumor-specific molecular profiling is feasible in GU cancers. However the use of targeted sequencing with a tumor type specific panel and at an earlier clinical stage may improve the proportion of MTT recommendations.

MP10-01 SURGICAL MANAGEMENT OF PATIENTS WITH ADVANCED GERM CELL TUMORS FOLLOWING SALVAGE CHEMOTHERAPY WITH PACLITAXEL, IFOSFAMIDE AND CISPLATIN (TIP) OR PACLITAXEL PLUS IFOSFAMIDE FOLLOWED BY HIGH DOSE CARBOPLATIN AND ETOPOSIDE WITH STEM CELL SUPPORT (TICE): MEMORIAL SLOAN KETTERING CANCER CENTER (MSKCC) EXPERIENCE.

INTRODUCTION AND OBJECTIVES: The role of surgery for cisplatin-refractory or relapsed germ cell tumors (GCT) following salvage chemotherapy continues to evolve. We report our institutional experience with surgical management of patients following TIP or TICE salvage chemotherapy. METHODS: Data was reviewed on a heterogeneous group of 181 cisplatin-refractory or relapsed patients who received TIP or TICE salvage chemotherapy between 1994 and 2011 at MSKCC. We report clinicopathologic and outcomes data on 131 patients who underwent subsequent surgical management. Predictors of non-teratomatous viable GCT and disease-specific survival (DSS) were analyzed. Median follow-up was 7.3 years. RESULTS: 10-year DSS for this cohort was 73% (95% CI, 64%80%). Of the 112 patients who underwent post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND), 56 (50%) were found to have fibrosis, 30 (27%) had non-teratomatous residual viable disease and 26 (23%) had teratoma only on final pathology. On univariate analysis the risk of finding viable, non-teratomatous residual disease was decreased by (OR < 1): TIP or TICE as salvage regimen vs other regimens (OR 0.1, 95% CI, 0.03-0.43; p< 0.005), surgery within three months of salvage chemotherapy (OR 0.26, 95% CI, 0.08-0.79; p1⁄40.017) and lower clinical stage at diagnosis (stage < IIC vs III, OR 0.37, 95% CI, 0.15-0.90, p1⁄40.028). CONCLUSIONS: Our data suggests that patients with cisplatinrefractory or relapsed GCT who received TIP or TICE as salvage chemotherapy regimen have lower risk of finding non-teratomatous viable disease at resection compared to patients who received other regimens. Surgical resection of all residual disease following salvage chemotherapy should be performed whenever feasible.

Preclinical and clinical activity of sunitinib in patients with cisplatin-refractory or multiply relapsed germ cell tumors: a Canadian Urologic Oncology Group/German Testicular Cancer Study Group cooperative study

BackgroundThe objective of the study was to investigate the activity of sunitinib in a cell line model and subsequently in patients with cisplatin-refractory or multiply relapsed germ cell tumors (GCT). MethodsThe effect of sunitinib on cell proliferation in cisplatin-sensitive and cisplatin-refractory GCT cell lines was evaluated after 48-h sunitinib exposure by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, and IC50 (concentration that causes 50% inhibition of growth) doses were determined. Sunitinib was subsequently administered at a dose of 50 mg/day for 4 weeks followed by a 2-week break to 33 patients using a Simon two-stage design. ResultsSunitinib demonstrated comparable dose-dependent growth inhibition in cisplatin-sensitive and cisplatin-resistant cell lines, with IC50 between 3.0 and 3.8 μM. Patient characteristics were as follows: median of 2 (1–6) cisplatin-containing regimens; high-dose chemotherapy 67%; late relapse 33%; and cisplatin refractory or absolute cisplatin refractory 54%. Toxic effects included fatigue (39%), anorexia (21%), diarrhea (27%), mucositis (45%), nausea (33%), hand–foot syndrome (12%), dyspepsia (27%), and skin rash (18%). No unexpected side-effects were observed. Thirty -two of 33 patients were assessable for response. Three confirmed partial responses (PRs) and one unconfirmed PR were seen for a total response rate of 13%. Median progression-free survival (PFS) was 2 months, with a 6-month PFS rate of 11%. ConclusionsSunitinib shows in vitro activity in cisplatin-resistant GCT cell lines. Modest clinical activity in heavily pretreated GCT patients was observed.

UP-03.111 TIN Therapy as Salvage Chemotherapy for Cisplatin Refractory Germ Cell Tumors

The aim of this study was to investigate the efficacy and safeness of paclitaxel (PTX) in combination with ifosphamide (IFM) and nedaplatin (CDGP)(TIN therapy) as salvage chemotherapy for CDDP refractory GCT.

Brief Report: Phase II Multicenter Study of Temozolomide in Patients with Cisplatin-Resistant Germ Cell Tumors

Purpose: To determine the activity and toxicity of temozolomide in a phase II multicenter trial in patients diagnosed with relapsed or cisplatin-refractory germ cell tumors. Patients and Methods: During a recruitment period of 30 months, 20 patients received temozolomide 150 mg/m²/day p.o. for 5 days every 4 weeks, escalating to 200 mg/m²/day if grade II toxicity was not observed in the first cycle. Eligibility criteria were tumor progression or relapse after previous cisplatin and ifosfamide-containing chemotherapy, creatinine clearance of >40 ml/min, and a performance status of 0–2. Results: The median age was 38 years (range 27–56). Seventeen patients had nonseminomatous tumors, and 3 had seminomatous tumors. Six of the patients had extragonadal primary tumors (3 retroperitoneal and 3 mediastinal). The median number of prior cisplatin-containing cycles was 11 (range 7–20). Eight patients received prior high-dose chemotherapy and 14 were refractory or absolutely refractory to cisplatin. A total of 45 cycles were administered. Two partial responses lasting 9 and 3.5 months (overall response rate 10%, 95% CI 1.2–31.7) were observed. One of these responses was seen in a patient with a cisplatin-refractory tumor that had previously been treated with high-dose chemotherapy. The median time to progression and the median overall survival were 1.5 and 3.1 months, respectively. Grade III hematological toxicity consisted of thrombocytopenia in 2 patients and anemia in 1 patient. No grade IV toxicity was observed. Conclusions: Temozolomide had some activity in heavily pretreated patients resistant to cisplatin-based chemotherapy.

Salvage chemotherapy with paclitaxel, gemcitabine, and nedaplatin (TGN) for cisplatin refractory heavily treated germ cell tumors.

e15089 Background: Only 20-30% of patients with cisplatin (CDDP) refractory germ cell tumor (GCT) will remain continuously disease free with salvage chemotherapy. The present study investigated the chemotherapy with paclitaxel (PTX) in combination with gemcitabine (GEM) and nedaplatin (CDGP), which is a derivative of CDDP, as salvage chemotherapy for CDDP refractory GCT. Methods: Between Jan 2003 and Dec 2010, 16 patients with CDDP refractory GCT were enrolled. All patients were male, with mean age 33 (range: 19-51). Median number of previous chemotherapy was 12 (range: 9-26) cycles. The combination chemotherapy consisted of PTX: 210 mg/m2 on day 1, CDGP 100 mg/m2 on day 2 and GEM: 1000mg/m2 on day 1 and 8 every three weeks. Results: A median of 4 cycles (range: 2-10) of TGN therapy was administered to 16 patients. Grade 3/4 toxicities were reported as follows: neutropenia: 100%, thrombocytopenia: 92%, anemia: 71%. No treatment related death was observed. Response rate was 56.3% (CR: 0 %, PRm-: 25%, PRm+: 31.3%, NC: 0%, PD: 43.7%). Unfortunately, no patients achieved a no evidence of disease status with a median duration of follow-up of 15 months (2-80 months). Six patients (37.5%) remain alive with disease. However, 10 patients (62.5%) died of the disease. Conclusions: This study demonstrates that combination chemotherapy with PTX, GEM and CDGP showed moderate anticancer activity for patients with CDDP refractory GCT without severe adverse events. These findings suggest that TGN therapy might be one of the options of salvage chemotherapy for CDDP refractory GCT and may be assessed as second or third line therapy.

Erratum to: Lenalidomide in patients with cisplatin-refractory and multiply relapsed germ cell tumors

The online version of the original article can be found under doi:10.1007/s00432-009-0677-2.K. Oechsle ( &) · C. Bokemeyer · F. HoneckerDepartments of Oncology, Hematology, Bone Marrow Transplantation and Pneumology, University Medical Center Eppendorf, Martinistr. 52, 20246 Hamburg, Germanye-mail: k.oechsle@uke.hamburg.de

Salvage chemotherapy with paclitaxel and gemcitabine plus nedaplatin (TGN) as part of multidisciplinary therapy in patients with heavily pretreated cisplatin-refractory germ cell tumors

We investigated the efficacy and toxicity of a regimen consisting of paclitaxel and gemcitabine plus nedaplatin, a derivative of cisplatin (TGN) in patients with heavily pretreated cisplatin-refractory germ cell tumors (GCTs). Fifteen patients with advanced GCTs were treated with the TGN regimen. The combination chemotherapy consisted of paclitaxel (210 mg/m(2)) on day 1 and gemcitabine (1000 mg/m(2)) on days 1 and 8 in combination with nedaplatin (100 mg/m(2)) on day 2 every 3 weeks. Patients enrolled in this study had been heavily pretreated with a median of 12 platinum-containing cycles (range, 7 to 26 cycles). Most of the regimens had included paclitaxel and ifosfamide plus cisplatin or nedaplatin (TIP/TIN) chemotherapy. The median follow-up period of the present study was 15 months. Patients received 2-11 cycles of the TGN combination chemotherapy. Six patients received the treatment combined with other therapeutic modalities; 2 patients received radiation therapy for retroperitoneal lymph node metastasis, 1 patient had cyber-knife radiosurgery for brain metastasis and 3 patients had radiofrequency ablation for liver and lung metastasis. Seven (46.7%) of the 15 patients achieved an objective response; 6 had marker-negative partial responses (PRs) and 1 had a marker-positive PR. Two (13%) of the 7 patients with PRs achieved a disease-free status after chemotherapy combined with RT and followed by surgical resection. However, 10 patients died of the disease and 3 patients are still alive with the disease. The TGN regimen alone had limited efficacy in this patient population, with severe but manageable toxicities. However, TGN chemotherapy may offer a chance of cure for some heavily pretreated cisplatin-refractory (TIP/TIN-refractory) patients as part of multidisciplinary therapy.

Long-term outcome of salvage high-dose chemotherapy in patients with germ cell tumor with poor prognostic features

Objective High-dose chemotherapy (HDCT) represents an option as salvage treatment for patients with resistant/refractory germ cell tumor (GCT). The objective of this retrospective analysis was to evaluate the long-term results of a single-center experience with salvage HDCT for GCT patients, and to validate the prognostic model proposed by Einhorn and colleagues [9]. Materials and methods Between 1986 and 2003, 100 GCT patients received salvage HDCT consisting of high-doses of carboplatin, etoposide ± cyclophosphamide, or ifosfamide. Twenty-four patients underwent a second HDCT cycle, and in 1 case, a third cycle was given with a median interval time of 6 weeks (range, 5–10). Results With a median follow-up of 8 years (range, 3–17); 6 of 32 (19%) patients with resistant GCT and 1 of 19 (5%) patients with cisplatin-refractory disease have been continuously disease-free, while none of the 16 patients with absolutely cisplatin-refractory GCT were alive at 1 year from HDCT treatment. In the PBPC era, HDCT appeared to be inapplicable in 32% of patients, mainly due to progressive disease during the induction/mobilizing phase. The prognostic model by Einhorn et al. for tandem HDCT did categorize our patients treated with a single HDCT cycle or low-dose intensity regimens in a very similar manner, but with inferior overall results. Conclusions Long-term results with a single HDCT cycle or a low dose-intensity multicycle HDCT regimen remained poor in patients with adverse prognostic features. The tandem HDCT regimen represents a major option for refractory GCTs and relapsed tumors in third-line or later therapy, while a single course of HDCT should be abandoned for these patients.

Salvage chemotherapy with irinotecan and nedaplatin for cisplatin refractory germ cell tumors

e16022 Background: Only 20 - 30 % of patients with cisplatin (CDDP) refractory germ cell tumor (GCT) will remain continuously disease-free with salvage chemotherapy. The present study investigated the combination chemotherapy with irinotecan (Ir) and nedaplatin (CDGP), the second generation derivative of CDDP developed in Japan, as salvage chemotherapy for CDDP-refractory GCT. Methods: Between June 1998 and December 2007, 39 CDDP refractory GCT patients treated with irinotecan and CDGP (IrN therapy) were assessed retrospectively. IrN therapy consisted of Ir: 100–150 mg/m2 on day 1, 15 or 200–300 mg/m2 on day 2, CDGP: 100 mg/m2 on day 1 every four weeks with oral administration of Chinese-herb ‘Hange-shashinto’ and sodium bicarbonate for diarrhea. After tumor marker normalization, residual masses were resected and chemotherapy was continued in the case of without marker normalization. Results: The median age was 31 years old (range; 17–48). The median number of cycles of prior chemotherapy was 6 (range; 2–30). The median number of cycles of IrN therapy was 3 (range: 1–9). The response rate was 30.8% ( CR: 0%, PRm−: 15.4%, PRm+: 15.4% ) and the outcome was no evidence of disease (NED) 46.2%, alive with disease (AWD) 25.6% and dead 28.2%, respectively. Twenty-five patients with IrN therapy as 2nd (17 cases) and 3rd (8 cases) line salvage therapy showed that the response rate was 48% (CR: 0%, PRm−: 16.0%, PRm+: 16.0, NCm−: 16.0%) and the outcome was as follows; NED 64%, AWD 16% and dead 20%, respectively. On the other hand, 14 pts who had the treatment as fourth-line or more showed less response rate (PR: 28.5%) and worse outcome (NED 14.2%). Major adverse events more than grade 3 were neutropenia and thrombocytopenia. These adverse events were manageable. Grade 4 diarrhea which was major adverse event of CPT-11 was observed in only one case and there was no treatment related death. Conclusions: This study demonstrates that combination chemotherapy with CPT-11 and CDGP showed significant anticancer activity for patients with CDDP-refractory GCT without severe adverse events. These findings suggest that salvage IrN therapy may be one of the options as second- or third-line therapy. No significant financial relationships to disclose.

Gemcitabine Plus Vinorelbine as an Effective Salvage Chemotherapeutic Regimen in Cisplatin-Refractory Germ Cell Tumor

Germ cell tumors (GCT) are the most common malignancies among male adolescents. Approximately 5% of GCTs are of extragonadal origin. Cisplatin-based chemotherapy is the standard first-line treatment for GCT. Patients who fail to respond to first-line treatment usually have poor outcomes. High-dose chemotherapy with stem cell support, paclitaxel, gemcitabine, and oxaliplatin are reported as effective salvage treatment. We report two patients with cisplatin-refractory, metastatic, nonseminomatous, and extragonadal GCT treated successfully with gemcitabine plus vinorelbine (GV). One patient achieved good partial remission and had a five-month progression-free period. Another patient is still alive with stable disease after 4 cycles of treatment. In heavily treated, cisplatin-refractory GCT patients, GV could be considered an effective chemotherapeutic regimen.

Combination chemotherapy with gemcitabine, oxaliplatin and paclitaxel in patients with cisplatin-refractory or relapsed germ cell tumors (gct)

5084 Background: Treatment of pts with cisplatin-refractory GCT remains a therapeutic challenge. The present phase II study investigates the toxicity and activity of triple combination of gemcitabine/oxaliplatin/paclitaxel (GOP) in pts with multiple relapse or cisplatin- refractory GCT. Patients and Methods: Between 04/03 - 10/06, 41 patients (pts) refractory to cisplatin-based chemotherapy or with relapse after high-dose chemotherapy plus autologous peripheral blood stem cell transplantation (PBSCT) received 800 mg/m2gemcitabine, 80 mg/m2 paclitaxel, both on days 1+8, and oxaliplatin 130 mg/m2 on day 1 of a three week cycle for at least 2 cycles. Treatment was continued until tumor progression or a maximum of 8 cycles. Results: Pts were pretreated with a median number of 2 previous lines of platin-based chemotherapy (range, 1 - 3) and 78 % had relapsed after either first- (39%) or second-line high-dose chemotherapy (39%) with PBSCT. Responses: 5% of the pts achieved a complete response (CR), 47% a partial response and 20% a disease stabilisation. 20% of the pts underwent a secondary complete tumor resection resulting in a total NED-rate of 22%. After a median follow up time of 5 months (mos) (0 - 20+) 17% of the pts are continuously disease-free with a median response duration of 8 mos (1–17+). Median progression free and overall survival was 3 mos (1–17+) and 6 mos (1–19+), respectively. Toxicity was acceptable. 51% of 150 cycles could be applied without dose modifications or delay. Leucocytopenia grade 3/4 was observed in 15%, anemia in 7%, and thrombocytopenia in 49% of the patients. Grade 3/4 nonhematologic toxicities (diarrhoea, nausea and neurotoxicity) occurred in one patient each (2%). Conclusion: The triple combination chemotherapy with gemcitabine, oxaliplatin and paclitaxel is feasible and effective in patients with cisplatin-refractory or multiply relapsed germ cell tumors exhibiting an overall response rate of &gt;50% and prolonged survival in about 20% of the pts. Despite a significant rate of grade 3/4 thrombocytopenia the overall toxicity profile is acceptable. No significant financial relationships to disclose.

Phase II Trial of ixabepilone in patients with cisplatin-refractory germ cell tumors

In a phase I study, ixabepilone, a novel non-taxane microtubule-stabilizing agent, demonstrated activity against both paclitaxel-sensitive and paclitaxel-refractory solid tumors. We conducted a phase II trial of this agent in patients with advanced germ cell tumors (GCT) who were resistant to conventional therapies. Patients with cisplatin-refractory GCT were enrolled in this single-institution, phase II trial. Ixabepilone was administered at a dose of 40 mg/m2 intravenously over 3 hours every 21 days. Dose modifications were planned according to a nomogram for adverse events. Responses were assessed every 6 weeks using tumor markers and radiographic imaging according to the Response Evaluation Criteria in Solid Tumors (RECIST). Patients who progressed (>or=20% increase in tumor size or rising serum tumor markers) were taken off protocol. Twenty-nine cycles of treatment were administered to 12 patients. The most common Grade 3/4 toxicities were leukopenia, lymphopenia, and neutropenia. One patient (8%) achieved a confirmed objective partial response but this patient had not received prior treatment with a taxane. Based on slow accrual and a lack of antitumor activity in patients previously treated with a taxane, the trial was closed after enrolling 12 patients. For patients who had previously received taxane therapy, ixabepilone was not efficacious in the treatment of cisplatin-refractory GCT.

An open-label, multicenter phase II trial of capecitabine in patients with cisplatin-refractory or relapsed germ cell tumors

The objective of this multicenter phase II trial was to evaluate the efficacy and tolerability of capecitabine in patients with cisplatin-refractory or relapsed germ cell tumors. Between March 2003-June 2004, 14 patients refractory to at least two regimens of cisplatin-based chemotherapy or with relapse after high-dose chemotherapy and autologous peripheral blood stem cell transplantation received 1250 mg/qm capecitabine orally twice daily for 14 days in 3-week cycles. Treatment was continued until tumor progression. All patients were heavily pretreated with a median number of four previous lines of chemotherapy (range, 2-11) and 86% had relapsed after high-dose chemotherapy with peripheral blood stem cell transplantation. No patient responded to study treatment. Nine patients (64%) had progressive disease after two cycles. Two patients already stopped treatment after one cycle, because of a clinically overt tumor progression. One patient died of his tumor progression at the end of the second cycle. Two patients received four cycles of capecitabine, as progression was less than 30%. The median survival time was 4 months (range, 0-10). The toxicity profile was favorable. Eighty-six percent of the cycles could be applied without dose modifications or delay. Grade III/IV toxicities (diarrhea and anorexia in one patient each) occurred in 7% of the cases. No hematotoxicity grade III/IV was observed. Neutropenia grade I/II was documented in 21%, anemia in 35% and thrombocytopenia in 14% of the patients. Capecitabine was well tolerated, but is not effective in heavily pretreated patients with cisplatin-refractory or relapsed germ cell tumors.

Salvage chemotherapy with paclitaxel, ifosphamide and nedaplatin for cisplatin refractory germ cell tumors

4587 Background: Only 20–30 % of patients with cisplatin (CDDP) refractory germ cell tumor (GST) will remain continuously disease free with salvage chemotherapy. The present study investigated the chemotherapy with paclitaxel (TXL) in combination with ifosphamide (IFM) and nedaplatin (NDP), which is a derivative of CDDP, as salvage chemotherapy for CDDP refractory GCT. Methods: Between 2000 and 2005, 33 patients with CDDP refractory GCT were enrolled. All patients were male, with median age 30 (range: 17–45). Median number of previous regimens was 2 (range: 1–4). The combination chemotherapy consisted of TXL: 200 mg/m2 on day 1, NDP: 100 mg/m2 on day 2 and IFM: 1.2 g/m2 on day 2–6 every three weeks. Results: A median of 5 cycles was administered to 33 patients. Grade 3/4 toxicity were reported as follows: neutropenia: 90%, thrombocytopenia: 70%, anemia: 70%, nausea/vomiting: 90%, diarrhea: 6%, alopecia: 97%. No treatment related death was observed. Response rate was 82% (CR: 9%, PRm−: 67%, PRm+: 6%, NC: 6%, PD: 6 %). Nineteen (58%) patients achieved a no evidence of disease status with a median duration of follow-up of 18 months (7–60 months). Six patients (18%) remain alive with disease. However, 8 patients (24%) died of the disease. Conclusions: This study demonstrates that the chemotherapy with TXL in combination with IFM and NDP showed a significant anticancer activity for patients with CDDP refractory GCT. These findings suggest that the combination chemotherapy may be one of the options of salvage chemotherapy for CDDP refractory GCT. No significant financial relationships to disclose.

Weekly Gemcitabine, Paclitaxel, Oxaliplatin Combination Chemotherapy in Patients With Cisplatin-Refractory Germ Cell Tumor

Although the overall cure rate for advanced germ cell tumor (GCT) is high, the prognosis for patients with cisplatin-refractory GCT remains poor. Gemcitabine, paclitaxel, and oxaliplatin have shown significant activity as single agents in these patients. We investigated the activity and tolerance of a weekly gemcitabine, paclitaxel, oxaliplatin chemotherapy regimen. From September 2000 to February 2002, 9 patients with cisplatin-refractory GCT were treated with gemcitabine 800 mg/m2, paclitaxel 70 mg/m2, and oxaliplatin 50 mg/m2, days 1, 8, and 15, every 4 weeks. Only 1 patient stayed on schedule. In 7 patients, chemotherapy treatment was modified due to grade 3-4 hematological toxicity, whereas in another patient, who received high-dose chemotherapy 2 months before, chemotherapy was administered biweekly. In total, 21 cycles were administered with a median of 2 cycles for each patient. One patient achieved a partial remission lasting 5 months, 1 had disease stabilization for 5 months, whereas 7 had progressive disease. This chemotherapy regimen was not feasible in our patient population. Recently, oxaliplatin at full doses, but not as weekly administration, has appeared to possess activity in cisplatin-refractory GCT. Thus, we plan a phase II study protocol of the oxaliplatin and gemcitabine combination at full doses every 3 weeks.

Oxaliplatin and irinotecan plus granulocyte-colony stimulating factor (G-CSF) as third-line treatment in relapsed or cisplatin-refractory germ-cell tumor (GCT) patients: A phase II study

4535 Background: Oxaliplatin is an active agent in patients with cisplatin-refractory GCT, while the combination of irinotecan with platinum compounds has also induced responses in such patients. Given the synergistic activity of the two agents, we investigated the efficacy and tolerability of their combination in patients with relapsed or cisplatin-refractory GCT. Methods: Eighteen patients with relapsed or cisplatin-refractory GCT were treated with oxaliplatin 85mg/m2 (days 1,15) and irinotecan 80mg/m2 (days 1,8,15) every 4 weeks for a maximum of 6 cycles. Results: All patients were assessable for response and toxicity. Seven patients (40%) achieved a favorable response (4 complete and 3 partial responses). One of the complete responders relapsed after 2.5 months and, despite treatment with high dose chemotherapy, he died 2 months later; the rest 3 patients are continuously disease-free for 11+, 14+ and 19+ months. The partial responders progressed subsequently and died after 2, 3 and 4.5 months, respec...

Oxaliplatin and irinotecan plus granulocyte-colony stimulating factor (G-CSF) as third-line treatment in relapsed or cisplatin-refractory germ-cell tumor (GCT) patients: A phase II study

4535 Background: Oxaliplatin is an active agent in patients with cisplatin-refractory GCT, while the combination of irinotecan with platinum compounds has also induced responses in such patients. Given the synergistic activity of the two agents, we investigated the efficacy and tolerability of their combination in patients with relapsed or cisplatin-refractory GCT. Methods: Eighteen patients with relapsed or cisplatin-refractory GCT were treated with oxaliplatin 85mg/m2 (days 1,15) and irinotecan 80mg/m2 (days 1,8,15) every 4 weeks for a maximum of 6 cycles. Results: All patients were assessable for response and toxicity. Seven patients (40%) achieved a favorable response (4 complete and 3 partial responses). One of the complete responders relapsed after 2.5 months and, despite treatment with high dose chemotherapy, he died 2 months later; the rest 3 patients are continuously disease-free for 11+, 14+ and 19+ months. The partial responders progressed subsequently and died after 2, 3 and 4.5 months, respec...

Induction of apoptosis by flavopiridol (FP) independent of a cell cycle arrest in germ cell tumor (GCT) cell lines

9712 Background: GCTs are highly sensitive to cisplatin-based chemotherapy. The inability to arrest the cell cycle at the G1/S-check-point due to a lack of retinoblastoma gene product (RB) has been suggested as an explanation. FP, an inhibitor of cyclin dependent kinases, causes cell cycle arrest or apoptosis depending on the relation of transcription factor E2F1 to RB. Methods: The effect of FP was evaluated in GCT-derived cell lines 2102EP, NT2, and NCCIT in comparison with other solid tumor cell lines (SKOV, MCF7, HeLa) using the MTT-assay. Cell cycle progression and induction of apoptosis were followed by flow cytometry and immunoblot analysis of PARP-cleavage. Results: FP did not affect cell cycle and proliferation of GCT cell lines at sublethal doses. Cell death occurred independent of cell cycle progression at doses well beneath plasma concentrations in clinical studies. The IC50 was 5fold lower for the GCT cell lines (60/60/70 nM) than for the other cell lines tested (350/280/300 nM). Sensitivity for FP did not correlate with that for cisplatin. Flow cytometry and immunoblot for PARP indicated apoptotic cell death induced by FP. Synergism between cisplatin or paclitaxel and FP was not observed. Conclusion: The data suggest significant antitumor activity of FP in GCT. GCT derived cell lines were far more responsive of FP than the cells derived from other solid tumor models. No cross resistance between FP and cisplatin was observed. In contrast to other cell lines tested, GCT derived cell lines did not show cell cycle arrest after exposure to FP, possibly due to the lack of RB-expression. However, already at low concentrations, apoptosis was induced unrelated to cell cycle progression. A clinical trial evaluating the single agent activity of FP in patients with cisplatin-refractory GCTs would be warranted. No significant financial relationships to disclose.