Constance Thibault

Compliance with guidelines and correlation with outcome in patients with advanced germ-cell tumours

PURPOSE To evaluate prior compliance with guidelines in patients treated with salvage chemotherapy for advanced germ-cell tumours (GCT). PATIENTS AND METHODS Data concerning the initial management of patients requiring salvage chemotherapy for GCT at Institut Gustave Roussy between 2000 and 2010 were obtained and correlated with recommendations for treatment. Criteria of non-compliance were defined based on guidelines. Compliance with guidelines, predictive factors for non-compliance and the impact on outcome were analysed. RESULTS Among 82 patients treated in the salvage setting, guidelines to initial treatment were followed in only 41 cases (50%). The most common non-compliance criteria were non-adherence to the planned dose (16%), an inappropriate interval between first-line chemotherapy cycles (16%), the lack of post-chemotherapy surgery (16%) and a long interval to post-chemotherapy surgery (48%). Compliance with standard care was better in cancer centres than in other hospitals (private or public) (Odd Ratio (OR): 6.9, P = 0.001). A poor-risk status according to the International Germ Cell Cancer Collaborative Group (IGCCCG) was also predictive of compliance in univariate but not in multivariate analysis. No significant difference in outcome after salvage chemotherapy was observed. Patients relapsing after non-compliant first-line therapy tended to be more easily salvaged, which is consistent with the fact that their initial treatment was inadequate. Some of these relapses were therefore probably not due to true biologically refractory disease. CONCLUSION Guidelines for first-line treatment are adhered to in only half the patients requiring salvage chemotherapy. As the only predictive factor for non-compliance was the treating centre, centralisation of patients with GCT in well-trained hospitals should be recommended.

Relapses in metastatic germ-cell tumors and relationship to international guidelines compliance: A study from the Institut Gustave Roussy.

323 Background: Germ-cell tumors (GCT) are rare but highly curable cancers even in patients with metastatic spread. We aimed at assessing whether relapse after upfront treatment could be explained by low compliance with international guidelines. METHODS All patients (pts) who were referred to Institut Gustave Roussy from 2000 to 2010 with progression or relapse after treatment for metastatic GCT were included. International guidelines available at the time of diagnosis were used as reference. A list of noncompliant criteria defined as disagreement with the recommendations with a potential impact on outcome was set up. RESULTS 78 pts were included. According to the IGCCCG classification, 18 pts (23.1%) had good, 25 pts (32%) had intermediary and 34 pts (43.6%) had poor prognosis. The first-line chemotherapy administered consisted of PEB regimen (70.5%) , PE regimen (15.4%) or other regimen (12.8%). Most patients were treated in cancer centers (52.5%, n=41), whereas 26.9% and 17.9% pts were treated in private or public general hospitals, respectively. Only 50% pts received treatment according to guidelines recommendations. This percentage was significantly higher in cancer centres than in public hospitals (75.6% versus 28.6%, p< 0.001) or also when compared with private hospitals (75.6% versus 14,3%, p<0.001). The most frequent noncompliance criteria were: time to surgery for residual mass (over 6 weeks after the latest chemotherapy cycle)(20.3%) and respected chemotherapy schedule (20.3%). Other noncompliance findings were: inadequate chemotherapy dose (15.6%), number of cycles (12.5%), decision regarding residual disease (12.5%), chemotherapy regimen (6.3%), follow up (4.6%), type of surgery (3.1%), staging(1.6%), IGCCCG classification (1.6%), or decision regarding chemotherapy after residual mass surgery (1.6%). CONCLUSIONS This study suggests that the majority of relapse for metastatic GCT may be explained by a poor conformity to international guidelines and not only by aggressive tumor biology. These data represent a strong argument for treatment centralization in reference centers in patients with GCT.

Safety and efficacy of 2-weekly cabazitaxel in metastatic castration-resistant prostate cancer

To evaluate the safety and efficacy of a 2‐weekly cabazitaxel schedule in patients with metastatic castration‐resistant prostate cancer (mCRPC).

Radium 223 dichloride for prostate cancer treatment

Prostate cancer is the most common malignant disease in men. Several therapeutic agents have been approved during the last 10 years. Among them, radium-223 dichloride (Xofigo®) is a radioactive isotope that induces irreversible DNA double-strand breaks and consequently tumor cell death. Radium-223 dichloride is a calcium-mimetic agent that specifically targets bone lesions. Radium-223 dichloride has been approved for the treatment of metastatic castration-resistant prostate cancer with symptomatic bone metastases, without known visceral metastases. In this review, first we summarize the interplay between prostate tumor cells and bone microenvironment; then, we discuss radium-223 dichloride mechanism of action and present the results of the available clinical trials and future developments for this new drug.

Les nouvelles thérapies dans le cancer de la prostate métastatique

Therapeutic arsenal in prostate cancer widens for several years. New hormonal therapies such as acetate abiraterone or enzalutamide were the first molecules to revolutionize the treatment of metastatic castration resistant prostate cancer. Several other treatments are on trial targeting different pathways: androgene pathway (TAK-007, ARN-509, ODM-201, TOK-001), immune system (sipuleucel, ipilimumab, PROSTVAC-V/F, tasquinimod), but also tumor cell (PARP inhibitor, cabozantinib). The treatment sequencing will therefore soon be problematic, raising the necessity to identify predictive markers of response to the new therapies.

Optimal cut-off for neutrophil-to-lymphocyte ratio: Fact or Fantasy? A prospective cohort study in metastatic cancer patients

This study assessed the prognostic value of pre-treatment neutrophil-to-lymphocyte ratio (NLR) in patients with metastatic solid tumors. Clinical and biological data for patients with metastatic solid tumors treated in an oncology outpatient department and prospectively followed by a call center (PROCHE program) between January 2008 and December 2011 were analyzed. All patients with an NLR value within 28 days before the first cycle of first-line of chemotherapy were included (cohort 1). To assess influence of chemotherapy line on NLR prognostic value, data from patients treated with later chemotherapy lines were also analyzed (cohort 2). Adjusted multivariate Cox regressions with or without non-linear and time-dependent effects were performed. Optimal NLR cut-off was investigated by time-dependent sensitivity analysis using several indices. There were 317 and 134 patients in cohorts 1 and 2, respectively. Elevated NLR was associated with worse survival (hazard ratio [HR] for death, 1.35 [95% confidence interval 1.19–1.54]; p<0.0001). The optimal NLR cut-off in cohort 1 was dependent on index used and time of assessment: HR values were non-significant at a cut-off of 3.0 (1.34 [0.99–1.32], but significant when the cut-off was 4.0 (1.53 [1.11–2.10]). NLR was linearly related to mortality risk; in subgroup analysis, no significant interaction was found with co-variables or tumor localization overall (cohorts 1+2). Pre-treatment NLR is a useful prognostic tool in patients with metastatic solid tumors, irrespective of primary tumor site, chemotherapy line, age, gender and performance status. However, using an NLR cut-off value for clinical decision-making requires extreme caution.

Patient-reported tolerability of adverse events in phase 1 trials

Background Phase I experts recommend revisiting dose-limiting toxicity (DLT) definition to include chronic and cumulative toxicities induced by new molecularly targeted therapies. Patient’s assessment of late toxicities’ tolerability is, however, unknown. Materials and methods A prospective survey on adverse events (AEs) tolerability on 23 National Cancer InstituteCommon Terminology Criteria for Adverse Event, Version 4 (NCI-CTCAE.v4) items was conducted at Gustave Roussy’s Phase I department. Patients’ maximum tolerability duration was recorded at baseline, during trial and at trial completion. Results were compared with the corresponding physicians’ survey. Results 52 patients enrolled in 27 Phase I trials between May 2014 and November 2015 completed 102 forms. At baseline, the most feared G2/G3 AEs were haematuria (74%), vomiting (71%) and hyperglycemia (64%)/dry mouth (94%), hyperglycemia (92%) and vomiting (92%). At trial completion, the most feared G2/G3 AEs were personality change (83.3%), haematuria (82%) and fever (80%)/dry mouth, fever and dizziness (100% each). Tolerability score did not differ over time. More previous treatments and occurrence of severe AEs were associated with better tolerability at study completion (p=0.0234 and p=0.0153, respectively, in multivariate analysis). Patient’s tolerability differed from physician’s assessment. Conclusion AEs considered intolerable by patients are toxicities that directly impact their quality of life and differ from those feared by physicians or included in DLT definition. Patient-reported tolerability of AEs may help in optimising drug development.

Prediction of Everolimus Toxicity and Prognostic Value of Skeletal Muscle Index in Patients With Metastatic Renal Cell Carcinoma

Micro‐Abstract Patients with metastatic renal cell carcinoma with a skeletal muscle index (SMI) in the highest tercile have better overall survival with everolimus therapy versus those with an SMI in the lowest tercile. Low SMI did not influence the toxicity of everolimus. Whether SMI provides additional prognostic value to the International Metastatic Database Consortium prognostic group criteria remains to be determined. Background: The objective of the study was to assess the prognostic role of skeletal muscle index (SMI) in metastatic renal cell carcinoma (mRCC) patients treated with everolimus, and its effect of on everolimus‐induced toxicity. Patients and Methods: Consecutive mRCC patients treated with everolimus between February 2007 and November 2014 underwent computed tomography scans at a single center performed by the same radiologist. SMI was assessed before everolimus treatment using the L3 cross‐sectional area. Overall survival (OS) was analyzed according to SMI value. Results were adjusted using the International Metastatic Database Consortium (IMDC) prognostic group, body mass index (BMI), and/or number of previous tyrosine kinase inhibitor lines (NPL). Results: One hundred twenty‐four mRCC patients (mean age, 60.21 years) were treated with everolimus as second‐ or third‐line (82.3%) or > third‐line (17.7%) therapy. Most patients (87.9%) had clear cell carcinoma. IMDC prognostic group was “favorable” (32.3%), “intermediate” (50%), or “poor” (17.7%). Median SMI was 40.75. OS was longer in patients from the highest versus lowest SMI tercile: 21.9 versus 10 months (P = .002). Continuous SMI at baseline was not significantly associated with OS after adjustment for IMDC prognostic group, BMI, or NPL but the highest versus lowest SMI tercile was an independent prognostic factor in multivariate analysis (P = .025). There was no difference in everolimus toxicity between SMI tercile groups. Conclusion: SMI was an independent prognostic factor for mRCC patients treated with everolimus. Whether this provides additional prognostic value to IMDC criteria needs to be confirmed in a larger cohort. SMI does not seem to be predictive of everolimus‐induced toxicity.

SynthèseLes nouvelles thérapies dans le cancer de la prostate métastatiqueNew therapies in metastatic castration resistant prostate cancer

Therapeutic arsenal in prostate cancer widens for several years. New hormonal therapies such as acetate abiraterone or enzalutamide were the first molecules to revolutionize the treatment of metastatic castration resistant prostate cancer. Several other treatments are on trial targeting different pathways: androgene pathway (TAK-007, ARN-509, ODM-201, TOK-001), immune system (sipuleucel, ipilimumab, PROSTVAC-V/F, tasquinimod), but also tumor cell (PARP inhibitor, cabozantinib). The treatment sequencing will therefore soon be problematic, raising the necessity to identify predictive markers of response to the new therapies.

Immunothérapie dans les cancers de la prostate

IMMUNOTHERAPY IN URO-ONCOLOGY Immunotherapy is moving forward in prostate cancer. The autologous vaccine, Sipuleucel-T has been the first vaccine to be approved by FDA. First results with GVAX, tasquinimob or anti-PD-1 have been disappointing. Ipilimumab seen to be more active at an earlier stage of prostate disease. Identifying predictive factor or surrogate markers of activity of immunotherapy and which agents are clinically effective alone or in combination with others therapies such as hormonal or bone targeted therapies are warranted.