Poor-risk Germ Cell Tumors Research Articles

MP81-20 IRINOTECAN AND NEDAPLATIN AS SALVAGE THERAPY FOR PATIENTS WITH ADVANCED GERM CELL TUMOR FOLLOWING INTENSIVE TREATMENT WITH CISPLATIN-BASED COMBINATION CHEMOTHERAPIES

You have accessJournal of UrologySexual Function/Dysfunction: Penis/Testis/Urethra: Benign Disease & Malignant Disease II1 Apr 2016MP81-20 IRINOTECAN AND NEDAPLATIN AS SALVAGE THERAPY FOR PATIENTS WITH ADVANCED GERM CELL TUMOR FOLLOWING INTENSIVE TREATMENT WITH CISPLATIN-BASED COMBINATION CHEMOTHERAPIES Masatomo Nishikawa, Hideaki Miyake, and Masato Fujisawa Masatomo NishikawaMasatomo Nishikawa More articles by this author , Hideaki MiyakeHideaki Miyake More articles by this author , and Masato FujisawaMasato Fujisawa More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2073AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To analyze the clinical outcomes of the irinotecan plus nedaplatin (IN) regimen in patients with advanced germ cell tumors (GCTs) refractory to cisplation-based combination chemotherapies. METHODS This study included a total of 20 consecutive advanced GCT patients who were categorized into intermediate- or poor-risk GCT groups according to the International Germ Cell Consensus Classification, and were judged to show refractory or relapsed disease after BEP (bleomycin, etoposide and cisplatin) and TIP (cisplatin, ifosfamide and paclitaxel) therapies. All 20 patients subsequently received IN therapy (irinotecan, 100 mg/m2 on days 1 and 15; nedaplatin, 100 mg/m2 on day 1) every 4 weeks. RESULTS Following a median of 3 cycles of IN, 9 patients (45%) achieved the normalization of serum tumor markers. In addition, surgical resection of the residual tumors following IN was performed in 5 patients, of whom 4 were pathologically diagnosed with no viable cancer cells. At a median follow-up of 9 months, 11 patients (55%) were alive, including 7 (35%) with no evidence of disease, whereas the remaining 9 (45%) died of disease progression. The median duration of overall survival after the introduction of IN in these 20 patients was 13.4 months. Severe hematological toxicities were observed in all patients, but were manageable. Although fatal treatment-related interstitial pneumonia occurred in 1 patient, other non-hematological toxicities were generally tolerable. CONCLUSIONS Considering the markedly unfavorable characteristics of the included patients with advanced GCT who were intensively treated with cisplatin-based combination chemotherapies, IN could be regarded as having promising therapeutic activity with an acceptable toxicity profile. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1060 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Masatomo Nishikawa More articles by this author Hideaki Miyake More articles by this author Masato Fujisawa More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The Changing Landscape of Intermediate- and Poor-Risk Germ Cell Tumors: Do We Need to Reclassify Patients With Metastatic Germ Cell Tumors?

The Changing Landscape of Intermediate- and Poor-Risk Germ Cell Tumors: Do We Need to Reclassify Patients With Metastatic Germ Cell Tumors?

Irinotecan and nedaplatin as salvage therapy for patients with advanced germ cell tumors following intensive treatment with cisplatin-based combination chemotherapies.

To analyze the clinical outcomes of the irinotecan plus nedaplatin (IN) regimen in patients with advanced germ cell tumors (GCTs) refractory to cisplatin-based combination chemotherapies. This study included a total of 20 consecutive advanced GCT patients who were categorized into intermediate- or poor-risk GCT groups according to the International Germ Cell Consensus Classification, and were judged to show refractory or relapsed disease after bleomycin, etoposide and cisplatin and cisplatin, ifosfamide and paclitaxel therapies. All 20 patients subsequently received IN therapy (irinotecan 100 mg/m(2) on days 1 and 15; nedaplatin 100 mg/m(2) on day 1) every 4 weeks. Following a median of 3 cycles of IN, 9 patients (45 %) achieved normalization of serum tumor markers. In addition, surgical resection of the residual tumors following IN was performed in 5 patients, of whom 4 were pathologically diagnosed with no viable cancer cells. At a median follow-up of 9 months, 11 patients (55 %) were alive, including 7 (35 %) with no evidence of disease, whereas the remaining 9 (45 %) died of disease progression. The median duration of overall survival after the introduction of IN to these 20 patients was 13.4 months. Severe hematological toxicities were observed in all patients, but were manageable. Although fatal treatment-related interstitial pneumonia occurred in 1 patient, other non-hematological toxicities were generally tolerable. Considering the markedly unfavorable characteristics of the included patients with advanced GCT who were intensively treated with cisplatin-based combination chemotherapies, IN could be regarded as having promising therapeutic activity with an acceptable toxicity profile.

Efficacy and tolerability of TIP (paclitaxel, ifosfamide and cisplatin) incorporated into induction chemotherapy for patients with intermediate- or poor-risk metastatic germ cell tumors.

The objective of this study was to analyze the clinical outcomes of TIP (paclitaxel, ifosfamide and cisplatin) incorporated into induction chemotherapy for patients with metastatic germ cell tumor (GCT) characterized by unfavorable clinical features. This study included 37 patients, who were categorized into intermediate- or poor-risk GCT according to the International Germ Cell Consensus Classification (IGCCC). All 37 patients received two cycles of bleomycin, etoposide and cisplatin (BEP) followed by several cycles of TIP. Following treatment with TIP, 25 patients achieved the normalization of serum tumor markers. In addition, surgical resection of the residual tumors following TIP was performed in 17 patients who were pathologically diagnosed with no viable cancer cells. At a median follow-up of 36 months, 31 patients were alive, including 27 with no evidence of disease, whereas the remaining six died of disease progression. The 5-year disease-free survival (DFS) and overall survival (OS) rates in these 37 patients were 72.9 and 85.3%, respectively. Despite the lack of a significant predictor of OS, univariate analysis identified the presence of a choriocarcinoma element and IGCCC as significant predictors of DFS, of which only the presence of a choriocarcinoma element appeared to be independently associated with DFS. In this series, treatment-related death did not occur, although 27 patients had at least one adverse event corresponding to grade 3 ≤. Collectively, it would be of worth to pursue the significance of the early incorporation of TIP into induction chemotherapy for patients with intermediate- or poor-risk metastatic GCT in the future.

872TiP - Anzup 1302: a Randomised Phase 3 Trial of Accelerated Versus Standard Bep Chemotherapy for Patients with Intermediate and Poor-Risk Metastatic Germ Cell Tumours (P3Bep)

ABSTRACT Background: Bleomycin, Etoposide, Cisplatin (BEP) administered 3-weekly x 4 remains standard 1st line chemotherapy for intermediate- and poor-risk metastatic germ cell tumours (GCTs). High-dose chemotherapy and more complex regimens (eg VIP, T-BEP) have failed to improve cure rates and are more toxic. Accelerating regimens of standard chemotherapy by giving them 2-weekly rather than 3-weekly has improved cure rates in other cancers where more complex or higher-dose regimens failed. Aim: To determine if accelerated BEP is superior to standard BEP as 1st line chemotherapy for intermediate and poor risk metastatic GCTs. Trial design: Open-label, randomised, stratified 2-arm multicentre, 2 stage, phase 3 clinical trial. The primary endpoint for stage I of the trial (n = 150) is complete response rate, and for the complete trial (n = 500) is progression-free survival (PFS). A sample size of 150 and 500 patients gives >80% power to detect a 20% improvement in response rates and 7% absolute improvement in 2yr PFS, respectively. Participants: Males aged 16-45years with intermediate or poor-risk metastatic GCTs for 1st line chemotherapy. Planned expansion to include children aged 11+ and females. Regimen: Participants are randomised 1:1 to “standard BEP” or “accelerated BEP”: Timing of BEP accelerated vs standard Week 1 2 3 4 5 6 7 8 9 10 11 12 Standard EP EP EP EP B B B B B B B B B B B B Accelerated EP EP EP EP B B B B B B B B B B B B E-Etoposide 100mg/m2 D1-5; P-Cisplatin25mg/m2 D1-5; B-Bleomycin 30000 IU weekly; Peg G-CSF 6mg s/c given on D6 post EP in both arms Assessments: Weekly during BEP. Initial response assessment at 30-day safety assessment. Final response assessment at 6 months from randomisation or after all post-chemotherapy intervention is completed. Follow-up 3-monthly for 2 years from randomisation, then 6-monthly to 5 years, then annually. Tissue and blood collection for translational substudies Current status: In start-up phase or open to recruitment at 25 sites in Australia & New Zealand. International trial groups invited to participate. Email: p3bep@ctc.usyd.edu.au Webstite: http://www.anzup.org.au/ Disclosure: All authors have declared no conflicts of interest.

A retrospective analysis of patients with poor-risk germ cell tumor (PRGCT) treated at Indiana University from 1990 to 2011.

4557 Background: Based on the International Germ Cell Cancer Collaborative Group (IGCCCG), PRGCT represents 14% of germ cell tumors with a 5-year survival of only 48% and 5-year PFS of 41%. PRGCT i...

A retrospective analysis of patients with poor-risk germ cell tumor (PRGCT) treated at Indiana University from 2000 to 2010.

4557 Background: PRGCT represents 14% of germ cell tumors, with 2-year PFS of 50%. PRGCT is defined by primary mediastinal non-seminomatous germ cell tumor (PMNSGCT), non-pulmonary visceral metastasis (NPVM), AFP > 10,000 or hCG > 50,000. This analysis attempts to identify subsets of patients with more or less favorable outcomes among the poor risk groups. Methods: Retrospective analysis of all patients with testicular cancer seen at Indiana University (IU) from 2000-2010. 291 patients with PRGCT identified of whom 79 received initial therapy at IU. We analyzed the following variables: primary site testis/retroperitoneal (T/RP) vs. PMNSGCT, pulmonary vs. NPVM, and the amplitude of serum tumor markers. We identified groups of patients according to the level of tumor marker elevation with cutoff points of AFP 20,000 and hCG 200,000. Results: Mean age 29, mean AFP 8,283, mean hCG 185,667. 24% had PMNSGCT, 48% NPVM, 11% AFP>20,000, and 25% hCG>200,000. When hCG was analyzed as a continuous variable, every 10,000 unit increase in hCG caused the hazard of progression to increase by 1% (p value 0.01). Patients with NPVM had significantly worse PFS. NPVM with elevated hCG had worse outcome than NPVM with normal hCG. This did not correlate as well with AFP. PFS was worse with NPVM than elevated pre-chemotherapy tumor markers. Multiple different criteria for poor risk disease carried significantly worse impact on PFS and OS when compared to having a single criterion for poor risk disease. Conclusions: Our data indicate that patients with NPVM or more than one criteria for PRGCT have a worse outcome compared to other PRGCT subgroups. [Table: see text]

Paclitaxel, ifosfamide, and cisplatin (TIP) efficacy for first-line treatment of patients (pts) with intermediate- or poor-risk germ cell tumors (GCT).

4501 Background: Durable progression-free survival (PFS) rates for pts with intermediate- and poor-risk GCT approximate only 75% and 50%, respectively with standard BEP. This multicenter phase II study investigated first-line TIP in this population. Methods: Pts age ≥18 with untreated, IGCCCG intermediate- (LDH modified to ≥3x upper limit of normal) or poor-risk GCT were eligible. Pts received 4 cycles of TIP every 21 days, consisting of paclitaxel 120mg/m2 days 1-2; ifosfamide 1200mg/m2 days 1-5; and cisplatin 20mg/m2days 1-5, followed by G-CSF and levofloxacin for neutropenic fever prophylaxis. The primary endpoint was the complete response (CR) rate; secondary endpoints included PFS and toxicity. A Simon’s 2-stage design required a CR in ≥11/18 pts to proceed to stage 2, where with ≥27/41 CRs overall, the regimen would be considered active and worthy of further study. Results: Of 44 men (median age 27) enrolled; 38 had nonseminoma and 6 seminoma; 29 were poor-risk and 15 intermediate-risk. Primary site was testis in 30, mediastinum in 11, and retroperitoneum in 3. 42 pts had elevated markers and 14, 6, and 1 had liver, bone, and brain metastasis, respectively. The trial met its primary endpoint; of 41 evaluable pts, 28 achieved a CR (see Table) and 6 pts (5 with seminoma) achieved a partial response with negative markers (PR-). Two pts relapsed. With a median follow-up of 2.2 years, estimated 3-year PFS was 79% and 3-year overall survival (OS) 98% (see Table). There were no treatment-related deaths. Grade 3/4 toxicities were primarily hematologic and 6 (14%) pts developed neutropenic fever. Conclusions: TIP demonstrates promising efficacy and is well-tolerated in intermediate- and poor-risk GCT pts. A randomized trial of TIP vs. BEP has been initiated to compare efficacy. Clinical trial information: NCT00470366. [Table: see text]

Phase II trial of paclitaxel, ifosfamide, and cisplatin (TIP) for previously untreated patients (pts) with intermediate- or poor-risk germ cell tumors (GCT).

336 Background: Durable progression-free survival (PFS) rates for pts with intermediate- and poor-risk GCT approximate only 75% and 50%, respectively with standard BEP chemotherapy. This phase II study investigated first-line TIP in this population. Methods: Pts age ≥18 with previously untreated poor-risk or modified intermediate-risk (LDH ≥3x upper limit of normal [ULN]) GCT were eligible. Four cycles of TIP were given every 21 days, consisting of paclitaxel 120mg/m2 on days 1-2; ifosfamide 1200mg/m2 (with mesna support) on days 1-5; and cisplatin 20mg/m2on days 1-5. Peg-filgrastim was given on day 6 and levofloxacin on days 7-13 for prevention of neutropenic fever. The primary endpoint was the complete response (CR) rate; secondary endpoints included PFS and toxicity. A Simon’s two-stage design was used: if ≥11 CRs were observed in the first 18 pts, a total of 41 evaluable pts would be accrued with the trial considered positive if ≥27 CRs were achieved. Results: Of 44 men (median age 27 [range 18-56]) enrolled; 38 had nonseminoma and 6 had seminoma; 29 were poor-risk and 15 intermediate-risk. Primary site was testis in 30, mediastinum in 11, retroperitoneum in 3. Most pts had lung (n=31) and abdomen/pelvis (n=29) metastasis, and 14, 6, and 1 had liver, bone, and brain metastasis, respectively. Markers were elevated in 42 pts. Forty pts received all 4 TIP cycles; 3 pts were withdrawn after 2 cycles for allergic reactions to paclitaxel and were inevaluable for response, and 1 pt completed only 3 cycles in order to undergo surgery for growing teratoma syndrome (evaluable). Of 41 evaluable pts, 29 (72%, 90% CI: 60% – 78%) achieved a CR and 5 (all seminoma) achieved a PR with negative markers (PR-); 7 pts had incomplete responses and 2 pts relapsed from PR- or CR. With a median follow-up of 2.1 years, estimated 1-year PFS was 79% (95% CI: 64% – 89%) and 3-year overall survival 97% (95% CI: 83% – 100%). There were no toxic deaths. Grade 3/4 toxicities were primarily hematologic but only 7 (16%) pts developed neutropenic fever. Conclusions: TIP demonstrated promising efficacy and was tolerable in intermediate- and poor-risk GCT pts. A randomized trial of TIP versus BEP is being planned. Clinical trial information: NCT00470366.

High-dose chemotherapy and stem cell transplantation for advanced testicular cancer

High-dose chemotherapy (HDCT) with autologous stem cell support has been studied in both the salvage and first-line setting in advanced germ cell tumor (GCT) patients with poor-risk features. While early studies reported significant treatment-related mortality, introduction of peripheral blood stem cell transplantation, recombinant growth factors and better supportive care have decreased toxicity; and in more recent reports treatment-related deaths are observed in <3% of patients. Two to three cycles of high-dose carboplatin and etoposide is the standard backbone for HDCT, given with or without additional agents including ifosfamide, cyclophosphamide and paclitaxel. Three large randomized Phase III trials have failed to show a benefit of HDCT over conventional-dose chemotherapy (CDCT) in the first-line treatment of patients with intermediate- or poor-risk advanced GCT, and to date the routine use of HDCT has been reserved for the salvage setting. Several prognostic models have been developed to help predict outcome of salvage HDCT, the most recent of which applies to both CDCT and HDCT in the initial salvage setting. Patients that relapse after HDCT are usually considered incurable, and additional therapy is provided with palliative intent.

Management of poor-prognosis testicular germ cell tumors

Currently, the outcome of patients with intermediate-and poor-risk germ cell tumors at diagnosis is optimized by the use of risk-appropriate chemotherapy and post-chemotherapy surgical resection of residual masses. Currently, there is no role for high-dose chemotherapy in the first-line setting. Patients who progress on first-line chemotherapy or who relapse after an initial complete response also have a poor prognosis. In the setting of early relapse, the standard approach at most centers is conventional-dose, ifosfamide-based regimens and post-chemotherapy resection of residual masses. The treatment of patients with late relapse is complete surgical resection whenever feasible. Salvage chemotherapy for late relapse may be used prior to surgery in patients where a complete resection is not feasible. A complete surgical resection of all residual sites of disease after chemotherapy is critical for the prevention of relapse and the long-term survival of patients with advanced germ cell tumors.

Chemotherapy for patients with poor prognosis germ cell tumors

Germ cell tumors (GCTs) are the most common solid malignancy in young adult males. Approximately 28% of metastatic non-seminomatous GCTs have features that confer a poor prognosis, as defined by the International Germ Cell Consensus Classification. Five-year survival rates in poor prognosis GCTs remain about 50%. Despite numerous clinical trials testing a range of approaches, four cycles of bleomycin, etoposide, and cisplatin remain the standard of care for patients with poor-risk disease. Further improvements in the outcomes of patients with poor-risk GCTs might be achieved by incorporating targeted therapies into existing regimens, and by improving our understanding of the mechanism of cisplatin insensitivity.

Testicular Function in Poor-Risk Nonseminomatous Germ Cell Tumors Treated With Methotrexate, Paclitaxel, Ifosfamide, and Cisplatin Combination Chemotherapy

Our objective was to investigate the impact of methotrexate, paclitaxel, ifosfamide, and cisplatin (M-TIP) on long-term fertility in poor-risk nonseminomatous germ cell tumors (NSGCT). Thirty patients with poor-risk NSGCT (median age, 29 years; range, 17-62 years) were treated with methotrexate 250 mg/m(2) with folinic acid rescue (day 1) and paclitaxel 175 mg/m(2) (day 1), followed by ifosfamide 1.2 g/m(2) and cisplatin 20 mg/m(2) (days 2-6). Treatment consisted of 4 cycles of M-TIP administered every 3 weeks. Twenty-one patients were continuously disease-free at a median follow-up of 5.3 years (range, 0.9-8.4 years). Sperm count and hormonal analyses were examined prechemotherapy (30 patients) and postchemotherapy (21 patients). Counts were classified as follows: lower than 1 x 10(6)/mL, azoospermia; 1-20 x 10(6)/mL, oligospermia (OS); higher than 20 x 10(6)/mL, normospermia (NS). Patients were followed for a median of 2.3 years (range, 0.9-3.8 years) postchemotherapy. The prechemotherapy median luteinizing hormone (LH) serum levels were slightly above the upper normal limit, whereas the serum levels of follicle-stimulating hormone (FSH) and testosterone (T) were within the reference interval. Eleven (52.3%) patients had NS prechemotherapy. Among the patients with NS, 72.7% still had NS following chemotherapy. Overall, 17 of 21 (80.9%; 33.3% OS and 47.6% NS) patients had recovery of spermatogenesis after treatment. The median FSH serum levels were significantly elevated at least 1 year postchemotherapy when compared with the pretreatment levels. Eighteen months after the completion of chemotherapy the median FSH levels had returned to the reference limits. Serum LH and T levels were unaffected by chemotherapy. Prior to chemotherapy 4 of 30 patients had fathered 5 children. Since completion of chemotherapy, 5 patients have fathered 5 children. The majority of men with poor-risk germ cell tumors who were treated with the M-TIP regimen demonstrated recovery spermatogenesis after treatment, and Leydig cell function was unaffected.

Methotrexate, paclitaxel, ifosfamide, and cisplatin in poor-risk nonseminomatous germ cell tumors

Objective The efficacy and tolerability of M-TIP was evaluated as first-line treatment for patients with poor-risk germ cell tumors (GCT), according to International Germ Cell Cancer Collaborative Group (IGCCCG) criteria. Patients and methods Thirty patients with poor-risk GCT were treated with M-TIP (methotrexate 250 mg/m 2 given as a 4-hour infusion with folinic acid rescue on day 1, paclitaxel 175 mg/m 2 given as a 3-hour infusion on day 1, followed by ifosfamide 1.2 g/m 2 given as a 2-hour infusion and cisplatin 20 mg/m 2 given as a 2-hour infusion on days 2 to 6) regimen for four cycles. Results Five (16.6%, 95% confidence interval [CI]: 2%–31%) patients achieved clinical complete response (cCR) with chemotherapy only, 15 (50%, 95% CI: 31–69%) patients pathologic complete response (pCR) (11 had necrosis/fibrosis and 4 had mature teratoma) and 3 (10%) patients surgical complete response (sCR) for an overall favorable response of 76.6%. Twenty-one patients are continuously disease-free at a median follow-up of 5.3 years (range 0.9–8.4+ years), resulting in a 5-year progression-free survival (PFS) rate of 66.6% (95% CI = 49%–85%) and a 5-year survival rate of 70% (95% CI = 53%–87%). Toxicity was generally mild except for myelotoxicity. Patients with febrile neutropenia were successfully treated with broad spectrum antibiotics and G-CSF support. Hematologic toxicity in this trial was ameliorated with the use of G-CSF. Neurotoxicity and nephrotoxicity were not a problem, since only 6.6% and 3.3% of patients developed sensory neuropathy and renal toxicity, respectively. Conclusion M-TIP is a highly effective (high proportion of patients achieved long-term disease-free status, lack of relapses) and well tolerated regimen for first-line treatment of poor-risk GCT patients. These results have to be compared with the standard BEP chemotherapy or more intensive regimens in multicentre randomized trials.

Recent developments in germ cell tumors of the testes

An overview on several important developments in testicular germ cell tumors in the past year is provided. Despite being highly treatable even in advanced stages, recent studies demonstrate that testicular germ cell tumor mortalities can vary significantly in different regions of the world, suggesting limited access to appropriate treatments in certain geographic regions. Several clinically relevant studies on the role of retroperitoneal lymph node dissection in early and advanced stages of disease, and chemotherapy, particularly high-dose chemotherapy in the first-line and salvage settings, were reported. Large databases on testicular cancer survivors were analyzed to further define potentially delayed toxicities of initial treatments for testicular germ cell tumors. Significant challenges for poor-risk germ cell tumors remain. Treatment paradigms and follow-up strategies for the different stages of testicular germ cell tumors continue to be defined and refined, as research in these areas continues.

Medical Treatment of Advanced Testicular Cancer

The medical treatment of advanced testicular germ cell tumors has changed over the past 30 years, with long-term survival now achieved in the majority of patients. Clinicians need to be familiar with the available treatment regimens for testicular cancer and their associated toxic effects. To review the treatments used for advanced testicular germ cell tumors and their associated short-term and long-term complications. A search was performed of all English-language literature (1966 to October 2007) within the MEDLINE database using the terms neoplasms, germ cell, or embryonal or testicular neoplasms restricted to humans, drug therapy, complications, and mortality. The Cochrane Register of Controlled Trials Databases (through October 2007) was also searched using the terms testicular cancer or germ cell tumors. Bibliographies were reviewed to extract other relevant articles. One hundred eighty-six articles were selected based on pertinence to advanced testicular cancer treatment, associated complications, and late relapses with an emphasis on randomized controlled trials. The treatment of advanced testicular germ cell tumors with cisplatin combination chemotherapy is based on risk stratification (good, intermediate, or poor prognosis) according to pretreatment clinical features of prognostic value. Clinical trials have demonstrated that approximately 90% of patients classified as having a good prognosis achieve a durable complete remission to either 4 cycles of etoposide and cisplatin or 3 cycles of cisplatin, etoposide, and bleomycin. Complete responses are achieved less frequently for patients with intermediate- and poor-risk germ cell tumors, in whom 4 cycles of bleomycin, etoposide, and cisplatin remains the standard of care. Second- and third-line programs, including high-dose chemotherapy, also have curative potential. Chronic toxicities associated with therapy include cardiovascular disease, infertility, and secondary malignancies. Late relapses may also occur. Clinical trials have led to evidence-based treatment recommendations for advanced testicular cancer based on risk stratification. Clinicians should be familiar with the potential complications of these therapies.

Paclitaxel for metastatic germ-cell tumour

Inclusion of paclitaxel into the combination of high-dose sequential etoposide, ifosfomide, and cisplatin (VIP) chemotherapy with peripheral blood-derived haemopoetic stem-cell (PBSC) support produces a favourable response in patients with untreated metastatic germ-cell tumours (J Clin Oncol 2007; 25: 5742–47). “We tried to establish the maximal tolerable dose of paclitaxel [plus] high dose VIP, [and] assessed the toxicity, safety, response, and survival in order to improve the treatment of poor-risk germ-cell tumours”, says fi rst author Jorg Hartmann (Eberhard-Karls-University of Tuebingen, Germany). In a combined phase I/II study, researchers enrolled 53 patients with poor prognosis non-seminomatous germ-cell tumours. Initially, all patients received one cycle of standard-dose VIP plus granulocyte colony-stimulating factor to collect autologous PBSCs. Three cycles (range 2–4) of paclitaxel plus high-dose VIP with PBSC support was administered 21 days apart. Paclitaxel was administered in three dose levels (level 1: 135 mg/m2; level 2: 175 mg/m2; level 3: 225 mg/m2). Patients with brain metastasis received concomitant radiotherapy. Orchi dectomy was done in newly diagnosed patients and a residual mass, if present, was subsequently resected. Addition of paclitaxel resulted in doseindependent myelosuppression. The med ian duration of leucocytes <1000/μl and thrombocytes <25 000/μl was 6 and 4 days respectively. WHO grade 2 neurotoxicity and grade 3 encephalopathy were noted in two patients at dose levels 2 and 3. 2-year and 5-year survival was 77·6% (95% CI 65·4–89·9) and 75·2% (62·55–87·8%), respectively. “It is diffi cult to comment on the utility of adding paclitaxel to the highdose VIP regimen for poor-risk nonseminomatous germ-cell tumours in the absence of a randomised trial. Additionally, the value of high-dose VIP as opposed to conventional bleomycin, etoposide, and cisplatin is unproven in this setting”, says Guru Sonpavde (US Oncology Research, Webster, TX, USA). “Given the toxicity profi le with high-dose VIP plus paxlitaxel, and the profusion of novel biological agents, such as bevacizumab and sunitinib, another avenue may be to investigate the role of combining these novel biological agents with conventional chemotherapy in the frontline setting”, he adds. “Addition of paclitaxel up to a dose of 225 mg/m2 is feasible. Currently, effi cacy is being investigated in a larger number of patients in an expanded phase II study”, comments Hartmann.

Chemotherapy for Patients with Intermediate- and Poor-Risk Germ-Cell Tumors

Cisplatin-based combination chemotherapy yields cure rates >90% in patients with nonseminomatous germ-cell tumors that are classified by the International Germ Cell Cancer Collaborative Group (IGCCCG) as good risk. Unfortunately, patients with IGCCCG intermediate- and poor-risk tumors have cure rates of only 81% and 48%, respectively. These problematic subgroups of patients have been targeted for a variety of clinical approaches during the years, including cisplatin dose intensification, upfront ifosfamide therapy, and high-dose chemotherapy with stem-cell rescue. To date, …

High-dose chemotherapy in poor-risk germ cell tumours

Addition of high-dose chemotherapy (HDCT) to standard first-line treatment does not improve treatment response in patients with intermediate-risk or poor-risk metastatic germ cell tumours (GCT), according to results from a US multicentre randomised phase III study (J Clin Oncol 2007; 25: 247–56).

Poor-Prognosis Germ Cell Tumors: We Have Not Yet Crossed the Finish Line

Poor-Prognosis Germ Cell Tumors: We Have Not Yet Crossed the Finish Line