Abstract Background The role of chemotherapy in metastatic non castrate prostate cancer (mNCPC) is debated. Survival benefits of docetaxel (D) added to androgen-deprivation therapy (ADT) were shown ...in the CHAARTED trial in patients with metastatic high-volume disease (HVD). Objective To assess the impact of metastatic burden and to update overall survival (OS) data of the GETUG-AFU15 study. Design, setting, and participants Randomized phase 3 trial of ADT plus D versus ADT alone in 385 mNCPC patients; median follow-up of 7 yr. Outcome measurements and statistical analysis Primary end point was OS. Secondary end points were biochemical progression-free survival (bPFS) and radiographic progression-free survival (rPFS). Retrospective analysis was by tumor volume. Results and limitations After a median follow-up of 83.9 mo, median OS in the overall population was 62.1 mo (95% confidence interval CI, 49.5–73.7) and 48.6 mo (95% CI, 40.9–60.6) for ADT plus D and ADT arms, respectively (hazard ratio HR: 0.88 95% CI, 0.68–1.14; p = 0.3). Median OS in ADT plus D and ADT arms, respectively, was for HVD patients: 39.8 mo (95% CI, 28.0–53.4) versus 35.1 mo (95% CI, 29.9–43.6) (HR: 0.78 95% CI, 0.56–1.09; p = 0.14), for low-volume disease (LVD) patients; median was not reached (NR; 95% CI, 69.5–NR) and 83.4 mo (95% CI, 61.8–NR) (HR: 1.02 95% CI, 0.67–1.55; p = 0.9). For upfront metastatic patients, OS was 52.6 mo (95% CI, 43.3–66.8) and 41.5 mo (95% CI, 36.3–54.5), respectively (HR: 0.93 95% CI, 0.69–1.25; p = 0.6). The bPFS (HR: 0.73 95% CI, 0.56–0.94; p = 0.014) and rPFS (HR: 0.75 95% CI, 0.58–0.97; p = 0.030) were significantly longer in the ADT plus D arm. Limitations included the retrospective analysis of metastatic extent and the lack of statistical power to detect a significant difference in subgroups. Conclusions The post hoc analyses of the GETUG-AFU15 study demonstrated a nonsignificant 20% reduction in the risk of death in the HVD subgroup. Patients with LVD had no survival improvement with early D. Patient summary In this study, docetaxel added to castration did not improve survival in patients with metastatic hormone-sensitive prostate cancer, partly due to methodological issues. However, early chemotherapy should be discussed with all patients, given the data of three randomized trials including GETUG-AFU15.
Summary Background Poor prognosis germ-cell tumours are only cured in about half of patients. We aimed to assess whether treatment intensification based on an early tumour marker decline will improve ...progression-free survival for patients with germ-cell tumours. Methods In this phase 3, multicentre, randomised trial, patients were enrolled from France (20 centres), USA (one centre), and Slovakia (one centre). Patients were eligible if they were older than 16 years, had evidence of testicular, retroperitoneal, or mediastinal non-seminomatous germ cell tumours based on histological findings or clinical evidence and highly elevated serum human chorionic gonadotropin or alfa-fetoprotein concentrations that matched International Germ Cell Cancer Consensus Group poor prognosis criteria. After one cycle of BEP (intravenous cisplatin 20 mg/m2 per day for 5 days, etoposide 100 mg/m2 per day for 5 days, and intramuscular or intravenous bleomycin 30 mg per day on days 1, 8, and 15), patients' human chorionic gonadotropin and alfa-fetoprotein concentrations were measured at day 18–21. Patients with a favourable decline in human chorionic gonadotropin and alfa-fetoprotein continued BEP (Fav-BEP group) for 3 additonal cycles, whereas patients with an unfavourable decline were randomly assigned (1:1) to receive either BEP (Unfav-BEP group) or a dose-dense regimen (Unfav-dose-dense group), consisting of intravenous paclitaxel (175 mg/m2 over 3 h on day 1) before BEP plus intravenous oxaliplatin (130 mg/m2 over 3 h on day 10; two cycles), followed by intravenous cisplatin (100 mg/m2 over 2 h on day 1), intravenous ifosfamide (2 g/m2 over 3 h on days 10, 12, and 14), plus mesna (500 mg/m2 at 0, 3, 7 and 11 h), and bleomycin (25 units per day, by continuous infusion for 5 days on days 10–14; two cycles), with granulocyte-colony stimulating factor (lenograstim) support. Centrally blocked computer-generated randomisation stratified by centre was used. The primary endpoint was progression-free survival and the efficacy analysis was done in the intention-to-treat population. The planned trial accrual was completed in May, 2012, and follow-up is ongoing. This study is registered with ClinicalTrials.gov , number NCT00104676. Findings Between Nov 28, 2003, and May 16, 2012, 263 patients were enrolled and 254 were available for tumour marker assessment. Of these 51 (20%) had a favourable marker assessment, and 203 (80%) had an unfavourable tumour marker decline; 105 were randomly assigned to the Unfav-dose-dense group and 98 to the Unfav-BEP group. 3-year progression-free survival was 59% (95% CI 49–68) in the Unfav-dose-dense group versus 48% (38–59) in the Unfav-BEP group (HR 0·66, 95% CI 0·44–1·00, p=0·05). 3-year progression-free survival was 70% (95% CI 57–81) in the Fav-BEP group (HR 0·66, 95% CI 0·49–0·88, p=0·01 for progression-free survival compared with the Unfav-BEP group). More grade 3–4 neurotoxic events (seven 7% vs one 1%) and haematotoxic events occurred in the Unfav-dose-dense group compared with in the Unfav-BEP group; there was no difference in grade 1–2 febrile neutropenia (18 17% vs 18 18%) or toxic deaths (one 1% in both groups). Salvage high-dose chemotherapy plus a stem-cell transplant was required in six (6%) patients in the Unfav-dose-dense group and 16 (16%) in the Unfav-BEP group. Interpretation Personalised treatment with chemotherapy intensification reduces the risk of progression or death in patients with poor prognosis germ-cell tumours and an unfavourable tumour marker decline. Funding Institut National du Cancer (Programme Hospitalier de Recherche Clinique).
A phase III, multicenter, randomized study compared conventional dosing of fluorouracil (FU) plus folinic acid with pharmacokinetically guided FU dose adjustment in terms of response, tolerability, ...and survival.
Two hundred eight patients with measurable metastatic colorectal cancer were randomly assigned to one of two arms: arm A (104 patients; 96 assessable), in which the FU dose was calculated based on body-surface area; and arm B (104 patients; 90 assessable), in which the FU dose was individually determined using pharmacokinetically guided adjustments. The initial regimen was 1,500 mg/m(2) FU plus 200 mg/m(2) folinic acid infusion during a continuous 8-hour period administered once weekly. FU doses were adjusted weekly in arm B based on a single-point measurement of FU plasma concentrations at steady state until the therapeutic range (targeted area under the curve 20-25 mg x h x L(-1)) previously established in other studies was reached.
An intent-to-treat analysis of the 208 patients showed the objective response rate was 18.3% in arm A and 33.7% in arm B (P = .004). Median overall survival was 16 months in arm A and 22 months in arm B (P = .08). The mean FU dose throughout treatment was 1,500 mg/m(2)/wk in arm A and 1,790 +/- 386 mg/m(2)/wk (range, 900 to 3,300 mg/m(2)/wk) in arm B. Toxic adverse effects were significantly more frequent and severe in arm A compared with arm B (P = .003).
Individual FU dose adjustment based on pharmacokinetic monitoring resulted in significantly improved objective response rate, a trend to higher survival rate, and fewer grade 3/4 toxicities. These results support the value of pharmacokinetically guided management of FU dose in the treatment of metastatic colorectal patients.
Recent data suggest that cabazitaxel and docetaxel have similar activity but a different safety profile in the first-line metastatic castration-resistant prostate cancer (mCRPC) setting. In this ...randomized trial, men with mCRPC preferred cabazitaxel over docetaxel, mainly owing to less fatigue and better quality of life.
The taxanes docetaxel and cabazitaxel prolong overall survival for men with metastatic castration-resistant prostate cancer (mCRPC), with cabazitaxel approved in the postdocetaxel setting only. Recent data suggest they have similar efficacy but a different safety profile in the first-line mCRPC setting.
To assess patient preference between docetaxel and cabazitaxel among men who received one or more doses of each taxane and did not experience progression after the first taxane.
Chemotherapy-naïve patients with mCRPC were randomized 1:1 to receive docetaxel (75 mg/m2 every 3 wk × 4 cycles) followed by cabazitaxel (25 mg/m2 every 3 wk × 4 cycles) or the reverse sequence. Randomization was stratified by prior abiraterone or enzalutamide use.
The primary endpoint was patient preference, assessed via a dedicated questionnaire after the second taxane. Secondary endpoints included reasons for patient preference, prostate-specific antigen response, radiological progression-free survival, and overall survival. This clinical trial is registered at ClinicalTrials.gov as NCT02044354.
Of 195 men randomized, 152 met the prespecified modified intent-to-treat criteria for analysis. Overall, 66 patients (43%) preferred cabazitaxel, 40 (27%) preferred docetaxel, and 46 (30%) had no preference (p = 0.004, adjusted for treatment period effect). More patients preferred treatment period 1 (43%, 95% confidence interval CI 36–52%) versus period 2 (27%, 95% CI 20–34%). Patient preference for cabazitaxel was mainly related to less fatigue (72%), better quality of life (64%), and other adverse events (hair loss, pain, nail disorders, edema). Adverse events were consistent with the known safety profile of each drug.
A significantly higher proportion of chemotherapy-naïve men with mCRPC who received both taxanes preferred cabazitaxel over docetaxel. Less fatigue and better quality of life were the two main reasons driving patient choice.
Men with metastatic castration-resistant prostate cancer preferred cabazitaxel over docetaxel for chemotherapy, mainly because of less fatigue and better quality of life.
Serum prostate specific antigen (PSA) is a well-known prognostic parameter in men with prostate cancer. The treatment of men with very high PSA values and apparently no detectable metastases is not ...fully established.
Ancillary analysis from the GETUG 12 phase 3 trial. Patients with non-metastatic high-risk prostate cancer by bone and computerized tomography (CT) scan were randomly assigned to receive androgen deprivation therapy (ADT) and docetaxel plus estramustine or ADT alone. Relapse-free survival (RFS), clinical RFS, metastases-free survival (MFS), overall survival (OS), and prostate cancer-specific survival (PCSS) were estimated using the Kaplan–Meier method for different levels of PSA (50 ng/mL, 75 ng/mL, and 100 ng/mL). The relationship between PSA and outcomes was studied using residual-based approaches and spline functions.
The median follow-up was 12 years (range: 0-15.3). Baseline PSA (<50 ng/mL, n = 328; ≥50ng/mL, n = 85) was associated with improved RFS (P = .0005), cRFS (P = .0024), and MFS (P = .0068). The 12-year RFS rate was 46.33% (CI 40.59-51.86), 33.59% (CI 22.55-44.97), and 11.76% (1.96-31.20) in men with PSA values <50 ng/mL (n = 328), 50-100 ng/mL (n = 68), and ≥100 ng/mL (n = 17), respectively. Exploratory analyses revealed no deviation from the linear relationship assumption between PSA and the log hazard of events.
Men with apparently localized prostate cancer and a high baseline PSA value have a reasonable chance of being long-term disease-free when treated with curative intent combining systemic and local therapy.
In this report we looked at survival outcomes in men with localized prostate cancer and high baseline prostate specific antigen values. At a long follow-up we found that a significant proportion never experience cancer relapse when they received treatment with curative intent.
Summary Background Combining targeted treatments for renal cell carcinoma has been suggested as a possible method to improve treatment efficacy. We aimed to assess the potential synergistic or ...additive effect of the combination of bevacizumab, directed against the VEGF receptor, and temsirolimus, an mTOR inhibitor, in metastatic renal cell carcinoma. Methods TORAVA was an open-label, multicentre randomised phase 2 study undertaken in 24 centres in France. Patients aged 18 years or older who had untreated metastatic renal cell carcinoma were randomly assigned (2:1:1) to receive the combination of bevacizumab (10 mg/kg every 2 weeks) and temsirolimus (25 mg weekly; group A), or one of the standard treatments: sunitinib (50 mg/day for 4 weeks followed by 2 weeks off; group B), or the combination of interferon alfa (9 mIU three times per week) and bevacizumab (10 mg/kg every 2 weeks; group C). Randomisation was done centrally and independently from other study procedures with computer-generated permuted blocks of four and eight patients stratified by participating centre and Eastern Cooperative Oncology Group performance status. The primary endpoint was progression-free survival (PFS) at 48 weeks (four follow-up CT scans), which was expected to be above 50% in group A. Analysis was by intention to treat. The study is ongoing for long-term overall survival. This study is registered with ClinicalTrials.gov , number NCT00619268. Findings Between March 3, 2008 and May 6, 2009, 171 patients were randomly assigned: 88 to the experimental group (group A), 42 to group B, and 41 to group C. PFS at 48 weeks was 29·5% (26 of 88 patients, 95% CI 20·0–39·1) in group A, 35·7% (15 of 42, 21·2–50·2) in group B, and 61·0% (25 of 41, 46·0–75·9) in group C. Median PFS was 8·2 months (95% CI 7·0–9·6) in group A, 8·2 months (5·5–11·7) in group B, and 16·8 months (6·0–26·0) in group C. 45 (51%) of 88 patients in group A stopped treatment for reasons other than progression compared with five (12%) of 42 in group B and 15 (38%) of 40 in group C. Grade 3 or worse adverse events were reported in 68 (77%) of 88 patients in group A versus 25 (60%) of 42 in group B and 28 (70%) of 40 in group C. Serious adverse events were reported in 39 (44%) of 88, 13 (31%) of 42, and 18 (45%) of 40 patients in groups A, B, and C, respectively. Interpretation The toxicity of the temsirolimus and bevacizumab combination was much higher than anticipated and limited treatment continuation over time. Clinical activity was low compared with the benefit expected from sequential use of each targeted therapy. This combination cannot be recommended for first-line treatment in patients with metastatic renal cell carcinoma. Funding French Ministry of Health and Wyeth Pharmaceuticals.
Tasquinimod, a novel oral therapy targeting the tumor microenvironment, significantly improved progression-free survival (PFS) in a randomized, placebo-controlled phase II trial in men with ...metastatic castration-resistant prostate cancer (mCRPC). This phase III study was conducted to confirm the phase II results and to detect an overall survival (OS) benefit.
Men with chemotherapy-naïve mCRPC and evidence of bone metastases were assigned (2:1) to receive tasquinimod once per day or placebo until progression or toxicity. The primary end point was radiographic PFS (rPFS; time from random assignment to radiologic progression or death) per Prostate Cancer Working Group 2 criteria and RECIST 1.1. The study had 99.9% power to detect an rPFS hazard ratio (HR) of 0.6 with a two-sided alpha error of .05 and 80% power to detect a target HR of 0.8 for OS, the key secondary end point.
In all, 1,245 patients were randomly assigned to either tasquinimod (n = 832) or placebo (n = 413) between March 2011 and December 2012 at 241 sites in 37 countries. Baseline characteristics were balanced between groups: median age, 71 years; Karnofsky performance status ≥ 90%, 77.3%; and visceral metastases, 21.1%. Estimated median rPFS by central review was 7.0 months (95% CI, 5.8 to 8.2 months) with tasquinimod and 4.4 months (95% CI, 3.5 to 5.5 months) with placebo (HR, 0.64; 95% CI, 0.54 to 0.75; P < .001). Median OS was 21.3 months (95% CI, 19.5 to 23.0 months) with tasquinimod and 24.0 months (95% CI, 21.4 to 26.9 months) with placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). Grade ≥ 3 adverse events were more frequent with tasquinimod (42.8% v 33.6%), the most common being anemia, fatigue, and cancer pain.
In chemotherapy-naïve men with mCRPC, tasquinimod significantly improved rPFS compared with placebo. However, no OS benefit was observed.
BACKGROUND
Etoposide dosing is based on body surface area. We evaluated if further dose individualization would be required for high dose (HD) etoposide within the TI-CE (taxol, ifosfamide, ...carboplatin, and etoposide) protocol.
METHODS
Eighty-eight patients received 400 mg/m
2
/day of etoposide as a 1-hour IV infusion on 3 consecutive days over 3 cycles as part of a phase II trial evaluating efficacy of therapeutic drug monitoring (TDM) of carboplatin in the TI-CE HD protocol. Pharmacokinetic (PK) data were analyzed using population PK model on NONMEM to quantify inter- and intra-individual variabilities. Relationship between etoposide exposure and pharmacodynamic (PD) endpoints, and between selected genetic polymorphisms and tumor response or toxicity were evaluated.
RESULTS
The inter-patient, inter- and intra-cycle variabilities of clearance were 16%, 9% and 0.1%, respectively. The PK-PD relationship was not significant despite a trend toward higher etoposide exposure in patients responding to treatment. A significant correlation was found between exposure and extended neutropenia at cycle 3. A significant association between UGT1A1*28 polymorphism and late neutropenia was observed but needs further evaluation.
CONCLUSIONS
The present study suggests that neither
a priori
dose individualization nor dose adaptation using TDM is required validating body surface area dosing of etoposide in the TI-CE protocol.
Two phase II trials (NCT00688753 and NCT00541008) reported efficacy data of sunitinib and everolimus in first-line treatment of metastatic papillary renal cell carcinoma (mpRCC). Although most ...patients receive sunitinib or a mammalian target of rapamycin (mTOR) inhibitor in first- and second-line treatment, the optimal strategy remained unknown.
In 23 centres of the Groupe d’Etude des Tumeurs Urogénitales group, after centralised pathological review, we analysed retrospectively progression-free survival (PFS) of patients with mpRCC treated in first-line treatment (PFS-1) with sunitinib or everolimus (primary end-point), PFS in second-line treatment (PFS-2), overall survival (OS), objective response rate, disease control rate (DCR), overall sequence and prognostic factors for OS (secondary end-points).
One hundred thirty-eight patients (119 men and 19 women), median age 62.5 years, with mpRCC type 1 (n = 24) or non–type 1 (n = 114), received first-line sunitinib (n = 107) or everolimus (n = 31). With a median follow-up of 92 months, we found no significant difference between the treatment groups in terms of PFS-1 (5.5 versus 6.2 months) and DCR (69% versus 83%). Ninety-eight patients received a second-line treatment, 69% with mTOR inhibitors after sunitinib and 100% with tyrosine kinase inhibitors after everolimus, with similar DCR (64% versus 58%), median PFS-2 (3.4 versus 4.8 months) and OS (16.0 versus 20.3 months). No factor was prognostic for PFS-1, whereas leukocytosis, anaemia and the time from diagnosis to first systemic therapy < 1 year were prognostic for OS. We found no prognostic difference between both pRCC subtypes. The International Metastatic Renal Cell Database Consortium risk factors were prognostic for OS.
Sunitinib and everolimus had similar efficacy in first-line treatment of patients with mpRCC.
•This is the first study that compared retrospectively sunitinib and everolimus as first-line treatment in mpRCC patients.•Sunitinib and everolimus have similar efficacy in first-line treatment of mpRCCs.•The IMDC risk score is prognostic for overall survival in metastatic pRCCs.
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