[Show abstract][Hide abstract] ABSTRACT: High-dose chemotherapy (HDCT) is an effective salvage treatment for germ-cell tumors (GCTs) patients. In the first salvage setting, 30%-70% of patients may achieve durable remissions. Even when HDCT is administered as subsequent salvage treatment, up to 20% of patients may still be definitively cured. However, patients with refractory/relapsed disease still have a very poor long-term prognosis, requiring earlier intervention of HDCT.
Annals of Oncology 06/2014; 25(9). DOI:10.1093/annonc/mdu198 · 7.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Les tumeurs du testicule sont les cancers les plus fréquents de l’homme jeune. Depuis les années 1970, les tumeurs germinales métastatiques sont devenues le paradigme des cancers curables par l’utilisation de la chimiothérapie comportant le cisplatine et la chirurgie des masses résiduelles. Le pronostic des patients est défini par la classification internationale IGCCCG qui permet d’adapter la quantité de chimiothérapie nécessaire afin d’aboutir à la guérison. Dans les formes graves, l’adaptation précoce de la chimiothérapie en fonction de la décroissance des marqueurs sériques a fait la preuve de son efficacité. Malgré ces traitements, environ 20 % des patients rechutent et nécessitent un traitement de seconde ligne soit à doses standard, soit sous forme d’une intensification avec autogreffe. Le suivi des patients en rémission complète est important, à la fois pour détecter précocement les rechutes, mais également pour dépister un cancer du testicule controlatéral, pour accompagner un souhait de paternité si nécessaire et favoriser une resocialisation optimale.
Testicular tumours are the most common form of cancer in young men. Since the 1970s, metastatic germ cell tumours have become the curable cancer paradigm through the use of cisplatin-based chemotherapy and surgical removal of the residual mass. The prognosis for patients is defined using the International IGCCCG classification, which enables the appropriate amount of chemotherapy therapy to be administered in order to achieve recovery. In the most serious forms, early adaptation of the chemotherapy regimen based on the decreasing levels of serum markers has been shown to be effective. Despite these treatments, approximately 20% of patients relapse and require a second line treatment, either at a standard dose or at an intensified level with a stem cell transplant. Follow-up of patients in complete remission is important, not only for the early detection of any relapses, but also to screen for testicular cancer in the other side, associated with the potential desire to father a child, and favours the best possible social rehabilitation of the patient.
[Show abstract][Hide abstract] ABSTRACT: The standard treatment for patients with metastatic GCT relapsing after first-line chemotherapy is based on a cisplatin and ifosfamide-containing 3-drug regimen, which usually yields a complete response (CR) rate <50%. As gemcitabine consistently displayed activity in patients with advanced GCT and as synergy with cisplatin was reported, we integrated this drug into the salvage triplet regimen and assessed its activity in this phase II study.
The GIP regimen consisted in gemcitabine 1000 mg/m(2) day 1 and 5, ifosfamide 1200 mg/m(2)/d day 1-5, cisplatin 20 mg/m(2)/d, day 1-5, G-CSF 263 µg/d day 7-15, repeated every 3 weeks for 4 cycles. Eligibility criteria were that patients had favorable prognostic factors to conventional-dose salvage chemotherapy including a testis primary tumor and a previous complete response (CR) to first-line chemotherapy for metastatic disease. The primary endpoint was the CR rate and a two-stage Simon design was used.
37 patients were accrued and 29 (78%) achieved a favorable response, including a CR in 20 (54%) and a partial response with normalization of tumor markers (PRm-) in 9 (24%). With a median follow-up of 53 months (13-81), the 2-year overall survival rate is 73% (57%-84%) and the continuous progression-free survival rate is 51% (35%-66%). Myelosuppression was the main toxicity including febrile neutropenia in 8 (22%) patients and 18 (50%) cases required platelet infusion. No grade 3-4 peripheral neurotoxicity or renal toxicity occurred. Two patients died of treatment-related toxicity, one of them with cancer progression.
In a multicenter context, four cycles of the GIP regimen achieved a high CR rate in patients with relapsed testicular GCT. The GIP regimen avoided severe neurotoxicity and yielded a high survival rate.
Annals of Oncology 03/2014; 25(5). DOI:10.1093/annonc/mdu099 · 7.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The randomized, double-blind phase III AFFIRM trial demonstrated that enzalutamide, an oral androgen receptor inhibitor, significantly prolonged overall survival (OS) [median 18.4 versus 13.6 months (hazard ratio, HR) 0.63 (95% confidence interval, CI, 0.53-0.75); P < 0.001] compared with placebo in patients with metastatic castration-resistant prostate cancer who received prior docetaxel chemotherapy.
A post hoc analysis was carried out to assess the efficacy and safety of enzalutamide on outcomes in younger (<75 years) and elderly (≥75 years) patients in the AFFIRM population. Statistics are presented by age group (<75 years, ≥75 years) for efficacy outcomes of OS, radiographic progression-free survival (rPFS), time to prostate-specific antigen (PSA) progression, PSA response, and safety.
OS was significantly improved with enzalutamide over placebo in patients <75 years [median not yet reached versus 13.6 months; HR 0.63 (95% CI 0.52-0.78), P < 0.001] and in patients ≥75 years [median 18.2 versus 13.3 months; HR 0.61 (95% CI 0.43-0.86), P = 0.004], respectively. rPFS was similarly improved in both the younger [HR 0.45 (95% CI 0.38-0.53), P < 0.001] and elderly patient cohorts [HR 0.27 (95% CI 0.20-0.37), P < 0.001] relative to placebo, as were time to PSA progression and PSA response. Adverse events (AEs) were similar between the two enzalutamide age groups, with the exception of an increase in patients ≥75 years in the rates of all grade peripheral edema (22.1% versus 12.5%), fatigue (39.7% versus 31.6%), and diarrhea (26.6% versus 19.6%). The overall grade ≥3 AE rates were low with no major difference in frequency or severity between age groups or treatment arms. Five patients were reported with seizure events; three patients <75 years and two patients ≥75 years.
Enzalutamide significantly improves outcomes in both younger (<75 years) and elderly patients (≥75 years), with comparable safety and tolerability.
Annals of Oncology 02/2014; 25(2):429-34. DOI:10.1093/annonc/mdt571 · 7.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Patients with high-risk gestational trophoblastic neoplasia (GTN) need multi-agent chemotherapy to be cured. The most common regimen is etoposide (E), methotrexate (M) and actinomycin D (A), alternating weekly with cyclophosphamide (C) plus vincristine (O) (EMA/CO). Cisplatin (P) is a very active drug, but it is usually restricted to second-line therapies. Herein, we report the results of a cisplatin-based therapy: APE (actinomycin D, cisplatin, and etoposide).
Patients and methods
The efficacy and safety of APE for high-risk GTN (defined by Institut Gustave-Roussy (IGR) criteria and/or an International Federation of Gynaecology and Obstetrics (FIGO) score >6) are reported. Patients with brain metastasis or placental-site trophoblastic tumour were excluded.
Between 1985 and 2013, 95 patients were treated with APE for high-risk GTN: 59 patients as first-line, 36 as ⩾2nd-line therapy. There was 94.7% complete remission, though five patients relapsed. One patient died from GTN after multiple lines of chemotherapy. The five-year overall survival rate (median follow-up 5.7 years) was 97% (95% confidence interval (CI): 91–99%). No death from toxicity occurred. Long-term, six grade-1 neuro-toxicities, three grade-1 and two grade-2 oto-toxicities, and one grade-1 renal toxicity were recorded. One patient developed AML-M4 after APE and EMA/CO. Thirty-four of 35 women, who wished to become pregnant, succeeded and all had at least one live birth.
With a 97% long-term overall survival rate, limited long-term toxicity, and an excellent reproductive outcome, APE could be regarded as an alternative option to EMA/CO as a standard therapy for high-risk GTN.
[Show abstract][Hide abstract] ABSTRACT: Background:
Visceral disease, non-nodal soft-tissue metastases predominantly involving the lung and liver, is a negative prognostic factor in patients with metastatic castration-resistant prostate cancer (mCRPC). An exploratory analysis of COU-AA-301 assessed whether abiraterone acetate (AA) improved overall survival (OS) in mCRPC patients with visceral disease progressing post docetaxel.
In COU-AA-301, post-docetaxel mCRPC patients were randomized 2:1 to AA 1000 mg (n=797) or placebo (n=398) once daily, each with prednisone 5 mg b.i.d. The primary end point was OS; secondary end points included radiographic progression-free survival (rPFS), PSA response rate and objective response rate (ORR). Treatment effects in visceral disease (n=352) and non-visceral disease (n=843) subsets were examined using final data (775 OS events).
AA plus prednisone produced similar absolute improvement in median OS in patients with (4.6 months) and without (4.8 months) visceral disease versus prednisone; hazard ratios (HRs) were 0.79 (95% confidence interval (CI): 0.60–1.05; P=0.102) and 0.69 (95% CI: 0.58–0.83; P<0.0001), respectively. Treatment with AA plus prednisone significantly and comparably improved secondary endpoint outcomes versus prednisone in both the subsets: the HRs for rPFS were 0.60 (95% CI: 0.46–0.78; P=0.0002) and 0.68 (95% CI: 0.58–0.80; P<0.0001) in visceral and non-visceral disease subsets, respectively. PSA response rates were 28% versus 7% in the visceral disease subsets and 30% versus 5% in the non-visceral disease subsets (both P<0.0001), and ORRs were 11% versus 0% (P=0.0058) and 19% versus 5% (P=0.0010), respectively. The incidence of grade 3/4 adverse events was similar between the subsets and between the treatment arms in each subset. Adverse events related to CYP17 blockade were increased in the AA arms and were similar in patients with or without visceral disease.
AA plus prednisone provides significant clinical benefit, including improvements in OS and secondary end points, in post-docetaxel mCRPC patients with or without baseline visceral disease. The presence of visceral disease does not preclude clinical benefit from abiraterone.
Prostate cancer and prostatic diseases 10/2013; 17(1). DOI:10.1038/pcan.2013.41 · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Androgen receptor (AR) signalling remains critically important in metastatic castration-resistant prostate cancer (mCRPC) as confirmed by recent phase III trials, showing a survival advantage for abiraterone acetate and enzalutamide (MDV3100). The antitumour activity of abiraterone and prednisolone in patients pre-treated with enzalutamide is as yet unknown.Patients and methodsWe investigated the antitumour activity of abiraterone and prednisolone in patients with mCRPC who had progressed following treatment with docetaxel (Taxotere) and enzalutamide. Clinical data were retrospectively analysed for prostate-specific antigen (PSA) and RECIST responses, clinical benefit and survival.ResultsThirty-eight patients were included in the analysis. The median age was 71 years (range 52-84); metastatic sites included bone disease in 37 patients (97%), lymph nodes in 15 patients (39%) and visceral disease in 10 patients (26%). Abiraterone was well tolerated. Three patients (8%) attained a PSA response, defined as ≥50% decline in PSA confirmed after ≥4 weeks, while seven patients (18%) had a ≥30% PSA decline. The median progression-free survival (PFS) was 2.7 months (95% CI 2.3-4.1). Of the 12 patients assessable radiologically, only 1 (8%) attained a confirmed partial response.Conclusion
Abiraterone and prednisolone have modest antitumour activities in patients with mCRPC pretreated with docetaxel and enzalutamide.
Annals of Oncology 04/2013; 24(7). DOI:10.1093/annonc/mdt136 · 7.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Standard treatment options are limited for the management of non-metastatic castration-resistant prostate cancer (CRPC). This study, part of the ENTHUSE (EndoTHelin A USE) phase III programme, evaluated the efficacy and safety of the oral specific endothelin (ET)A receptor antagonist zibotentan vs placebo in patients with non-metastatic CRPC (non-mCRPC).
This was a multicentre, randomized, double-blind, phase III study. Patients (n=1421) with non-mCRPC and biochemical progression (determined by rising serum PSA levels) were randomized to receive zibotentan 10 mg or placebo once daily. Based on the lack of efficacy signal in another ENTHUSE phase III study, an interim analysis was performed to determine whether the study was likely to achieve the co-primary objectives of improved overall survival (OS) and progression-free survival (PFS).
Criteria for continuation of this study were not met. A total of 79 deaths and 293 progression events were recorded at final data cutoff. Zibotentan-treated patients did not significantly differ from placebo-treated patients for OS (hazard ratio (HR): 1.13; 95% confidence interval (CI): 0.73-1.76, P=0.589) or PFS (HR: 0.89; 95% CI: 0.71-1.12, P=0.330). The most commonly reported adverse events in zibotentan-treated patients were peripheral oedema (37.7%), headache (26.2%) and nasal congestion (24.9%); each occurred with >15% higher incidence than in the placebo group.
This trial was terminated early because of failure at interim analysis of the efficacy data to meet the defined criteria for continuation. Owing to the absence of demonstrable survival benefits in the ENTHUSE clinical studies, zibotentan is no longer under investigation as a potential treatment for prostate cancer.
Prostate cancer and prostatic diseases 02/2013; 16(2). DOI:10.1038/pcan.2013.2 · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The first ESMO Consensus Conference on prostate cancer was held in Zurich, Switzerland, on 17-19 November 2011, with the participation of a multidisciplinary panel of leading professionals including experts in methodological aspects. Before the conference, the expert panel prepared clinically relevant questions about prostate cancer in four areas for discussion as follows: diagnosis and staging, management of early localized disease, management of advanced localized disease and systemic disease. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the Consensus Conference, the panel developed recommendations for each specific question. The recommendations detailed here are based on an expert consensus after careful review of published data. All participants have approved this final update.
Annals of Oncology 01/2013; 24(5). DOI:10.1093/annonc/mds624 · 7.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Fatigue is a common, debilitating side-effect of prostate cancer and its treatment. Patient-reported fatigue was evaluated as part of COU-AA-301, a randomized, placebo-controlled, phase III trial of abiraterone acetate and prednisone versus placebo and prednisone in metastatic castration-resistant prostate cancer (mCRPC) patients after docetaxel chemotherapy. This is the first phase III study in advanced prostate cancer to evaluate fatigue outcomes using a validated fatigue-specific instrument.Patients and methodsThe Brief Fatigue Inventory (BFI) questionnaire was used to measure patient-reported fatigue intensity and fatigue interference with activities of daily life. All analyses were conducted using prespecified responder definitions of clinically meaningful changes.ResultsA total of 797 patients were randomized to abiraterone acetate and prednisone, and 398 were randomized to placebo and prednisone. Compared with prednisone alone, in patients with clinically significant fatigue at baseline, abiraterone acetate and prednisone significantly increased the proportion of patients reporting improvement in fatigue intensity (58.1% versus 40.3%, P = 0.0001), improved fatigue interference (55.0% versus 38.0%, P = 0.0075), and accelerated improvement in fatigue intensity (median 59 days versus 194 days, P = 0.0155).Conclusions
In patients with mCRPC progressing after docetaxel chemotherapy, abiraterone acetate and prednisone yielded clinically meaningful improvements in patient-reported fatigue compared with prednisone alone.
Annals of Oncology 11/2012; 24(4). DOI:10.1093/annonc/mds585 · 7.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In November 2011, the Third European Consensus Conference on Diagnosis and Treatment of Germ-Cell Cancer (GCC) was held in Berlin, Germany. This third conference followed similar meetings in 2003 (Essen, Germany) and 2006 (Amsterdam, The Netherlands) [Schmoll H-J, Souchon R, Krege S et al. European consensus on diagnosis and treatment of germ-cell cancer: a report of the European Germ-Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377–1399; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part I. Eur Urol 2008; 53: 478–496; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part II. Eur Urol 2008; 53: 497–513]. A panel of 56 of 60 invited GCC experts from all across Europe discussed all aspects on diagnosis and treatment of GCC, with a particular focus on acute and late toxic effects as well as on survivorship issues.
The panel consisted of oncologists, urologic surgeons, radiooncologists, pathologists and basic scientists, who are all actively involved in care of GCC patients. Panelists were chosen based on the publication activity in recent years. Before the meeting, panelists were asked to review the literature published since 2006 in 20 major areas concerning all aspects of diagnosis, treatment and follow-up of GCC patients, and to prepare an updated version of the previous recommendations to be discussed at the conference. In addition, ∼50 E-vote questions were drafted and presented at the conference to address the most controversial areas for a poll of expert opinions. Here, we present the main recommendations and controversies of this meeting. The votes of the panelists are added as online supplements.
Annals of Oncology 11/2012; 24(4). DOI:10.1093/annonc/mds579 · 7.04 Impact Factor