Endocrine therapy in advanced high-grade ovarian cancer: real-life data from a multicenter study and a review of the literature.

BACKGROUND: In women, ovarian cancer is the eighth most frequent cancer in incidence and mortality. It is often diagnosed at advanced stages; relapses are frequent, with a poor prognosis. When platinum resistant, subsequent lines of chemotherapy are of limited effect and often poorly tolerated, leading to quality of life deterioration. Various studies suggest a hormonal role in ovarian carcinogenesis, with a rationale for endocrine therapy in these cancers. PATIENTS AND METHODS: This multicenter, retrospective study assessed the use of endocrine treatment for high-grade ovarian epithelial carcinomas treated between 2010 and 2020. RESULTS: Eighty-one patients with ovarian cancers were included. The median duration of platinum sensitivity was 29 months. We observed a 35% disease control rate with endocrine therapy, and 10% reported symptom improvement. For 19 patients (23.5%), the disease was stabilized for more than 6 months. Median overall survival from diagnosis was 62.6 months. Regarding endocrine therapy predictive factors of response, in a multivariate analysis, 3 factors were statistically significant in favoring progression-free survival: platinum sensitivity (P = .021), an R0 surgical resection (P = .020), and the indication for hormone therapy being maintenance therapy (P = .002). CONCLUSION: This study shows real-life data on endocrine therapy in ovarian cancer. As it is a low-cost treatment with many advantages such as its oral administration and its safety, it may be an option to consider. A perspective lies in the search for cofactors to aim as future therapeutic targets to improve the effectiveness of hormone treatment by means of combination therapy.

PD-L1 expression and its prognostic value in metastatic papillary renal cell carcinoma: Results from a GETUG multicenter retrospective cohort.

INTRODUCTION: Papillary renal cell carcinoma (pRCC) is a rare and aggressive cancer with no specifically established therapeutic strategy in the metastatic setting. Combinations of tyrosine kinase and immune checkpoint inhibitors (ICI) are a promising option. We aimed to study the immune landscape of metastatic pRCC, and its interactions with angiogenesis pathways, to search for potential therapeutic targets. METHODS: The expression of immune markers (PD-L1, PD-1, PD-L2, LAG-3) and angiogenic pathways (CAIX, c-MET), was analyzed by immunohistochemistry on 68 metastatic pRCC retrieved from a retrospective multicenter GETUG cohort. Our primary endpoint was to estimate the prevalence of PD-L1 expression and its prognostic impact in metastatic pRCC. Secondary endpoints included the evaluation of other immune markers (PD-1, PD-L2, and LAG-3) and their association with PD-L1. We also assessed angiogenic markers and their association with PD-L1. RESULTS: Overall, 27.9 % of tumors were PD-L1 positive. PD-L2 was more frequently expressed (45.6 %), PD-1 and LAG-3 were positive in 17.6 % and 19.1 % respectively. None of these markers was correlated with PD-L1 expression. 66 % (45/68) expressed at least one immune marker, and 43 % (29/68) were "double-positive", as they expressed both immune and angiogenic markers. OS was significantly shorter for patients with PD-L1 positive pRCC. A multivariate analysis confirmed a significant association between PD-L1 expression and shorter overall survival (HR = 4.0, p = 0.01). CONCLUSION: These results reinforce clinical data on the expected benefit of ICI in metastatic pRCC treatment, as PD-L1 expression is a factor of poor prognosis in this multicenter cohort.

Impact of First Line Antiangiogenic Therapy Duration on Nivolumab Outcome in Metastatic Renal Cell Carcinoma Patients Treated in the GETUG-AFU 26 NIVOREN.

BACKGROUND: In metastatic renal clear cell carcinoma (ccRCC), vascular endothelial growth factor receptor (VEGFR) and immune checkpoint are 2 main therapeutic targets. We investigated the impact of duration exposure to antiangiogenic on immunotherapy clinical outcomes in metastatic ccRCC. METHODS: Patients from NIVOREN trial who received nivolumab after only 1 prior antiangiogenic therapy were included. Response rate, clinical benefit, progression free survival (PFS) and overall survival (OS) were prospectively analyzed depending on the duration of the first line (< 6 months, ≥6 months) and exploratory in patients with long first line exposure (≥18 months). The circulating levels of 8 plasma proteins and cytokines at baseline were collected and compared according to first line antiangiogenic duration. RESULTS: Among 354 patients, 127 (36%) and 227 (64%) patients had received first line antiangiogenic for < 6months and ≥ 6months respectively. Respective duration of first line therapy was not associated with objective response to nivolumab (20.5% vs. 23.9%, P = .50), or PFS (HR 0.92; P = .421). Median OS was respectively 16.6 and 31.3 months in the <6 and ≥6 months subgroups respectively. Adjusted on international metastatic renal cell carcinoma database consortium risk, age and metastatic site, OS was longer in patients with longer treatment duration in the first line setting (HR 0.73; P = .017). Duration of first line VEGFR TKI was independent from circulating levels of 8 proteins and cytokines at nivolumab baseline. CONCLUSION: Nivolumab activity in second line is independent from first-line duration of VEGFR TKI. However, first line VEGFR TKI duration ≥ 6 months is associated with longer OS.

Very Long-Term Complete Remission Can Be Achieved in Men With High-Risk Localized Prostate Cancer and a Very High PSA Value: An Analysis of the GETUG 12 Phase 3 Trial.

INTRODUCTION: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Abigene, a Prospective, Multicentric Study of Abiraterone Acetate Pharmacogenetics in Metastatic Castration-Resistant Prostate Cancer.

Abiraterone acetate (AA) is the first-in-class of drugs belonging to the second-generation of agents inhibiting androgen neosynthesis in advanced prostate cancer. A cumulative experience attests that germinal gene polymorphisms may play a role in the prediction of anticancer agent pharmacodynamics variability. In the present prospective, multicentric study, gene polymorphisms of CYP17A1 (AA direct target) and the androgen transporter genes SLCO2B1 and SLCO1B3 (potential modulators of AA activity) were confronted with AA pharmacodynamics (treatment response and toxicity) in a group of 137 advanced prostate cancer patients treated in the first line by AA. The median follow-up was 56.3 months (95% CI [52.5-61]). From multivariate analysis, rs2486758 C/C (CYP17A1) and PSA (≥10 ng/mL) were associated with a shorter 3-year biological PFS (HR = 4.05, IC95% [1.46-11.22]; p = 0.007 and HR = 2.08, IC95% [1.31-3.30]; p = 0.002, respectively). From a multivariate analysis, the rs743572 (CYP17A1) and performance status were independently associated with significant toxicity (OR = 3.78 (IC95% [1.42-9.75]; p = 0.006 and OR = 4.54; IC95% [1.46-13.61]; p = 0.007, respectively). Host genome characteristics may help to predict AA treatment efficacy and identify patients at risk for toxicity.

Frontline immune checkpoint inhibitor-based combination therapy in metastatic renal cell carcinoma patients with poor performance status.

BACKGROUND: Immune checkpoint inhibitor-based combination therapy (ICI-based combination) is a new standard of care for metastatic clear cell renal cell carcinoma (mRCC) in the frontline setting. Patients with poor performance status (PS) (≥2) were excluded from pivotal trials. Hence, the activity and safety of ICI-based combination therapy in this group of patients is still unknown. METHODS: We performed a multicentre retrospective study of PS ≥2 mRCC patients who received frontline ICI-based combination, either nivolumab-ipilimumab (NI) or pembrolizumab-axitinib (AP). Patients' characteristics, clinical outcomes, and toxicity were collected. We analysed overall response rate (ORR), median progression-free survival (mPFS), median overall survival (mOS) and grade ≥3 adverse events (G ≥ 3AEs). The association between the predictive biomarker IPI (immune prognostic index) and ORR/PFS/OS was also evaluated. RESULTS: We identified 70 mRCC patients with PS ≥2 treated with ICI-based combination across 14 institutions between October 2017 and December 2021, including 45 and 25 patients were treated with NI and AP, respectively. Median age at diagnosis was 63 years, 51 (73%) were male, only 17 (24%) had prior nephrectomy, 50 (71%) had synchronous metastatic disease at diagnosis, and 16 (23%) had brain metastases. Sixty-one (87%) and 9 (13%) patients had ECOG (Eastern Cooperative Oncology Group) PS 2 and 3, respectively, and 25 (36%) and 45 (64%) patients were intermediate and poor International Metastatic RCC Database Consortium (IMDC) risk, respectively. Among all, 91% were clear cell RCC, 7 patients had sarcomatoid features. At the time of the analysis (median follow-up 11.1 months), 41% patients were dead. Median PFS and mOS in the entire cohort were 5.4 months and 16.0 months, respectively; ORR was 31%. No significant differences in ORR, PFS, OS, or G ≥3AEs were seen between NI and AP. The intermediate and poor IPI groups were significantly associated with reduced ORR and shorter PFS. CONCLUSION: We report the first cohort of PS ≥2 mRCC patients treated with frontline ICI-based combination therapy. The survival outcomes in our cohort were inferior to that reported in pivotal trials. No significant differences in ORR, PFS, OS or toxicity were seen between NI and AP. Prospective real-world studies are needed to confirm these results.

Impact of Novel Hormonal Agents (Abiraterone, Enzalutamide) on the Development of Visceral and/or Brain Metastases in Patients With Bone-metastatic Castration-resistant Prostate Cancer.

INTRODUCTION: The overall survival (OS) of metastatic castration-resistant prostate cancer (mCRPC) patients has improved since 2011 with the use of novel hormonal agents (NHAs). The incidence of brain metastases (mets) has been reported to increase since 2004 with the use of docetaxel, but not the incidence of visceral mets. Our objective was to study whether the use of NHAs increases the risk of developing visceral or brain mets (VBMs). PATIENTS AND METHODS: mCRPC patients with mets limited to bone (bmCRPC), treated at Tours University Hospital between 2007 and 2015, were included retrospectively. The primary endpoint was to determine whether treatment with NHAs was associated with an increased incidence of VBMs. Secondary endpoints included the search for putative predictive factors to develop VBMs. RESULTS: On 187 bmCRPC patients included, 65 developed VBMs. VBM incidence increased in bmCRPC patients alive after 2011, compared to patients who died before (39.7 vs. 24.6%, P = .04). Meanwhile, their median OS increased from 16.3 months to 28.5 months (P = .01). The longer was the treatment with NHAs, the lower was the risk of VBMs (HR = 0.96, 95% CI [0.94; 0.99]), whereas age < 70 years (HR = 3.33, 95% CI [1.50; 7.40]) and low PSA level at diagnosis (HR = 1.58, 95% CI [1.16; 2.15]) increased this risk. CONCLUSION: Though retrospective, our results showed an increased incidence of VBMs in bmCRPC patients after 2011. However, this was not associated with NHA exposure duration. The role of NHA exposure remains unclear and needs further investigation.

Everolimus or sunitinib as first-line treatment of metastatic papillary renal cell carcinoma: A retrospective study of the GETUG group (Groupe d'Etude des Tumeurs Uro-Génitales).

BACKGROUND: 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. MATERIAL AND METHODS: 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). RESULTS: 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. CONCLUSION: Sunitinib and everolimus had similar efficacy in first-line treatment of patients with mpRCC.

Sunitinib Alone or After Nephrectomy for Patients with Metastatic Renal Cell Carcinoma: Is There Still a Role for Cytoreductive Nephrectomy?

BACKGROUND: The CARMENA trial in patients with metastatic renal cell carcinoma (mRCC) demonstrated that treatment with sunitinib alone was noninferior to cytoreductive nephrectomy (CN) followed by sunitinib (nephrectomy⬜sunitinib). OBJECTIVE: The objective of this study was to provide updated overall survival (OS) outcomes of CARMENA and assess whether some subgroups may still benefit from upfront CN. DESIGN, SETTING, AND PARTICIPANTS: CARMENA was a phase III trial in 450 patients with mRCC enrolled from 2009 to 2017. INTERVENTION: Patients in the intention-to-treat population received nephrectomy⬜sunitinib (standard of care [SOC]; n = 226) or sunitinib alone (n = 224). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary endpoint was OS, assessed using an updated data cut-off (October 2018; median OS event-free follow-up, 36.6 mo). Patients were reclassified by risk using International Metastatic RCC Database Consortium (IMDC) criteria. RESULTS AND LIMITATIONS: Sunitinib alone was noninferior to nephrectomy⬜sunitinib (hazard ratio [HR], 0.97; 95% confidence interval, 0.79⬜1.19; p = 0.8) and demonstrated longer median OS (19.8 mo vs 15.6 mo, respectively). For patients with two or more IMDC risk factors, OS was significantly longer with sunitinib alone than with nephrectomy⬜sunitinib (31.2 mo vs 17.6 mo, respectively; HR, 0.65; p = 0.03). For patients with one IMDC risk factor, OS was longer for nephrectomy⬜sunitinib versus sunitinib alone although not significantly (31.4 mo vs 25.2 mo; HR, 1.30; p = 0.2). The post hoc nature of the subgroup analyses may limit their interpretation. CONCLUSIONS: Sunitinib alone was noninferior compared with nephrectomy⬜sunitinib, suggesting that CN should not be considered SOC in patients with mRCC requiring systemic treatment. Certain subgroups, including patients with one IMDC risk factor, may still benefit from upfront CN. PATIENT SUMMARY: We assessed the survival of patients with metastatic kidney cancer in a clinical trial. Patients treated with sunitinib on its own had the same survival as patients who had surgery before sunitinib treatment. We conclude that surgery may not be necessary for some patients with metastatic kidney cancer.

Methotrexate-Etoposide-Ifosfamide Compared with Doxorubicin-Cisplatin-Ifosfamide Chemotherapy in Osteosarcoma Treatment, Patients Aged 18-25 Years.

Purpose: The French standard chemotherapy for osteosarcoma combines high-dose methotrexate (HDM) and etoposide-ifosfamide (EI) in children and adolescents, and API-AI (doxorubicin-cisplatin-ifosfamide) in adults. We herein present the results of M-EI and API-AI in 18- to 25-year-old patients. Methods: Patients, 18-25 years old, received either M-EI or API-AI regimens. M-EI comprised seven M and two EI doses preoperatively then M-EI in standard-risk patients (good histological response without metastasis) and five M-AP (methotrexate-doxorubicin-cisplatin) in high-risk patients (poor histological response, metastasis, and/or unresectable primary), postoperatively. API-AI comprised three API and two AI doses preoperatively, then two AI and two PI in standard-risk patients and five EI in high-risk patients, postoperatively. Results: We analyzed 95 patients 18-25 years of age: 55 received M-EI and 40 API-AI. The groups had similar baseline characteristics. Eighty-nine patients (94%) had surgery. Twenty-nine of 55 M-EI patients (60%) and 16/40 API-AI patients (41%) had good histological responses to preoperative chemotherapy. At 5 years, event-free survival was 50% (95% confidence interval [CI]: 39-60) and overall survival was 65% (95% CI: 54-74). Acute toxicity was similar, without treatment-related deaths. Conclusions: Survival outcomes with M-EI and API-AI were not significantly different. Tolerance was acceptable with both regimens. HDM is thus feasible for young adults. However, our study limitations preclude any definitive conclusions.

High-Dose Chemotherapy Compared With Standard Chemotherapy and Lung Radiation in Ewing Sarcoma With Pulmonary Metastases: Results of the European Ewing Tumour Working Initiative of National Groups, 99 Trial and EWING 2008.

PURPOSE: The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases. METHODS: From 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI (VAI plus WLI) by randomized assignment. The analysis was conducted as intention to treat. The estimates of the hazard ratio (HR), 95% CI, and P value were corrected for the three previous interim analyses by the inverse normal method. RESULTS: Of 543 potentially eligible patients, 287 were randomly assigned to VAI plus WLI (n = 143) or BuMel (n = 144). Selected patients requiring radiotherapy to an axial primary site were excluded from randomization to avoid excess organ toxicity from interaction between radiotherapy and busulfan. Median follow-up was 8.1 years. We did not observe any significant difference in survival outcomes between treatment groups. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for VAI plus WLI and BuMel patients, respectively, resulting in an HR of 0.79 (95% CI, 0.56 to 1.10; P = .16). For overall survival, the HR was 1.00 (95% CI, 0.70 to 1.44; P = .99). Four patients died as a result of BuMel-related toxicity, and none died after VAI plus WLI. Significantly more patients in the BuMel arm experienced severe acute toxicities than in the VAI plus WLI arm. CONCLUSION: In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.

Effect of Adding Docetaxel to Androgen-Deprivation Therapy in Patients With High-Risk Prostate Cancer With Rising Prostate-Specific Antigen Levels After Primary Local Therapy: A Randomized Clinical Trial.

IMPORTANCE: Androgen-deprivation therapy (ADT) plus docetaxel is the standard of care in hormone-naive metastatic prostate cancer but is of uncertain benefit in a nonmetastatic, high-risk prostate cancer setting. OBJECTIVE: To assess the benefit of ADT plus docetaxel in patients presenting with rising prostate-specific antigen (PSA) levels after primary local therapy and high-risk factors but no evidence of metastatic disease. DESIGN, SETTING, AND PARTICIPANTS: This open-label, phase 3, randomized superiority trial comparing ADT plus docetaxel vs ADT alone enrolled patients from 28 centers in France between June 4, 2003, and September 25, 2007; final follow-up was conducted April 12, 2017, and analysis was performed May 2 to July 31, 2017. Patients had undergone primary local therapy for prostate cancer, were experiencing rising PSA levels, and were considered to be at high risk of metastatic disease. Stratification was by prior local therapy and PSA-level doubling time (≤6 vs >6 months), and intention-to-treat analysis was used. INTERVENTIONS: Patients were randomly assigned to receive ADT (1 year) plus docetaxel, 70 mg/m2 (every 3 weeks [6 cycles]), or ADT alone (1 year). MAIN OUTCOMES AND MEASURES: The primary outcome was PSA progression-free survival (PSA-PFS). Secondary end points were PSA response, radiologic PFS, overall survival, safety, and quality of life. RESULTS: Overall, 254 patients were randomized (1:1) to the trial; median age, 64 years in the ADT plus docetaxel arm, 66 years in the ADT alone arm. At a median follow-up of 30.0 months, the median PSA-PFS was 20.3 (95% CI, 19.0-21.6) months in the ADT plus docetaxel arm vs 19.3 (95% CI, 18.2-20.8) months in the ADT alone arm (hazard ratio [HR], 0.85; 95% CI, 0.62-1.16; P = .31). At a median follow-up of 10.5 years, there was no significant between-arm difference in radiologic PFS (HR, 1.03; 95% CI, 0.74-1.43; P = .88). Overall survival data were not mature. The most common grade 3 or 4 hematologic toxic effects in the ADT plus docetaxel arm were neutropenia (60 of 125 patients [48.0%]), febrile neutropenia (10 [8.0%]), and thrombocytopenia (4 [3.0%]). There was no significant between-arm difference in overall quality of life. CONCLUSIONS AND RELEVANCE: Compared with ADT alone, combined ADT plus docetaxel therapy with curative intent did not significantly improve PSA-PFS in patients with high-risk prostate cancer and rising PSA levels and no evidence of metastatic disease. TRIAL REGISTRATION: French Health Products Safety Agency identifier: 030591; ClinicalTrials.gov identifier: NCT00764166.

Sunitinib Prior to Planned Nephrectomy in Metastatic Renal Cell Carcinoma: Angiogenesis Biomarkers Predict Clinical Outcome in the Prospective Phase II PREINSUT Trial.

Purpose: The PREINSUT study characterized factors predictive of response to sunitinib given before planned nephrectomy in patients with metastatic renal cell carcinoma (mRCC).Patients and Methods: This French multicenter, prospective, open-label, phase II trial (NCT00930345) included treatment-naïve patients with clear-cell mRCC. Patients received two cycles of sunitinib before nephrectomy. The primary objective was to evaluate the potential of circulating angiogenesis-related biomarkers measured before and on treatment for identifying responders based on primary renal tumor (PRT) size change. Secondary objectives were to evaluate the ability of biomarkers to predict progression-free survival (PFS) and overall survival (OS).Results: Thirty-two patients were enrolled. The median PFS was 4.5 months, and the median OS was 12.4 months. OS was significantly longer in responding patients (28.8 vs. 11.1 months; P = 0.03). Of 27 patients evaluable for PRT response, nine (33.3%) had a ≥10% decrease in PRT size. Baseline biomarkers significantly associated with outcome were endothelial progenitor cells (PRT response); vascular endothelial growth factor (VEGF)-A, stromal cell-derived factor-1 (SDF-1), soluble VEGF receptors (sVEGFR)1 and 2 (PFS); and SDF-1 and sVEGFR1 (OS). During treatment, changes in biomarkers associated with outcome were SDF-1 and platelet-derived growth factor (PDGF)-BB (PRT response), sVEGFR2 (PFS), and SDF-1 and sVEGFR1 (OS). There was no correlation between plasma sunitinib or its active metabolite steady-state trough concentrations and clinical outcome.Conclusions: Angiogenesis-related parameters that could reflect hypoxia seem to be associated with worse outcome in mRCC. As blood biomarkers are not subjected to tumor heterogeneity and allow longitudinal follow-up, circulating angiogenesis profile has a promising place in antiangiogenic therapy guidance. Clin Cancer Res; 24(22); 5534-42. ©2018 AACR.

Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma.

BACKGROUND: Cytoreductive nephrectomy has been the standard of care in metastatic renal-cell carcinoma for 20 years, supported by randomized trials and large, retrospective studies. However, the efficacy of targeted therapies has challenged this standard. We assessed the role of nephrectomy in patients with metastatic renal-cell carcinoma who were receiving targeted therapies. METHODS: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with confirmed metastatic clear-cell renal-cell carcinoma at presentation who were suitable candidates for nephrectomy to undergo nephrectomy and then receive sunitinib (standard therapy) or to receive sunitinib alone. Randomization was stratified according to prognostic risk (intermediate or poor) in the Memorial Sloan Kettering Cancer Center prognostic model. Patients received sunitinib at a dose of 50 mg daily in cycles of 28 days on and 14 days off every 6 weeks. The primary end point was overall survival. RESULTS: A total of 450 patients were enrolled from September 2009 to September 2017. At this planned interim analysis, the median follow-up was 50.9 months, with 326 deaths observed. The results in the sunitinib-alone group were noninferior to those in the nephrectomy-sunitinib group with regard to overall survival (stratified hazard ratio for death, 0.89; 95% confidence interval, 0.71 to 1.10; upper boundary of the 95% confidence interval for noninferiority, ≤1.20). The median overall survival was 18.4 months in the sunitinib-alone group and 13.9 months in the nephrectomy-sunitinib group. No significant differences in response rate or progression-free survival were observed. Adverse events were as anticipated in each group. CONCLUSIONS: Sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic renal-cell carcinoma who were classified as having intermediate-risk or poor-risk disease. (Funded by Assistance Publique-Hôpitaux de Paris and others; CARMENA ClinicalTrials.gov number, NCT00930033 .).

Brain Metastases from Adult Sarcoma: Prognostic Factors and Impact of Treatment. A Retrospective Analysis from the French Sarcoma Group (GSF/GETO).

BACKGROUND: Brain metastases (BM) from adult soft tissue or bone sarcomas are rare, and sparse data exist on their prognostic factors and management. SUBJECTS, MATERIALS AND METHODS: A retrospective study was conducted in 15 centers of the French Sarcoma Group, plus one Canadian and one Swiss center, to report on clinical, histological, and treatment characteristics and to identify predictive factors of outcome. RESULTS: Between 1992 and 2012, 246 patients with a median age of 50 years (range: 16-86) were managed for BM. BM included 221 cerebral and cerebellar metastases and 40 cases of meningeal sarcomatosis. The most frequent histopathological subtype was leiomyosarcoma (18.7%). Histological grade was high in 118 (48%) cases. Surgery of BM was carried out for 38 (15.5%) patients. Radiotherapy and chemotherapy were administered in 168 (68.3%) and 91 (37.0%) patients, respectively. Irrespective of treatment modality, BM were controlled in 113 patients (45.9%), including 31 partial responses (12.6%) and 18 complete responses (7.3%). The median overall survival from diagnosis of brain metastasis was 2.7 months (range: 0-133). In the multivariate analysis, the following parameters influenced overall survival: chemotherapy (hazard ratio [HR] = 0.38; 95% confidence interval [CI]: 0.26-0.48), surgery (HR = 0.40; 95% CI: 0.22-0.72), stereotactic radiotherapy (HR = 0.41; 95% CI: 0.19-0.90), whole-brain radiotherapy (HR = 0.51; 95% CI: 0.35-0.76), and grade (HR = 0.65; 95% CI: 0.43-0.98). CONCLUSION: BM of sarcomas are rare and associated with a dismal outcome. Multidisciplinary management with chemotherapy, radiation therapy, and surgery is associated with a better survival. IMPLICATIONS FOR PRACTICE: The incidence of brain and meningeal metastasis in bone and soft tissue sarcomas is estimated between 1% and 8%. Published data are derived from small retrospective case series, often in the pediatric population. A prognostic index is important to guide both clinical decision-making and outcomes research, but one such is lacking for adult sarcoma patients with brain metastases. The current study describes brain metastasis in a large cohort of sarcoma patients. This study, conducted within the French Sarcoma Group, describes the natural history of sarcoma brain metastasis and enables the proposal of strategic recommendations for subsequent clinical trials and for the management of such patients.

Anticancer Activity and Tolerance of Treatments Received Beyond Progression in Men Treated Upfront with Androgen Deprivation Therapy With or Without Docetaxel for Metastatic Castration-naïve Prostate Cancer in the GETUG-AFU 15 Phase 3 Trial.

BACKGROUND: Androgen deprivation therapy (ADT) plus docetaxel is the standard of care in fit men with metastatic castration-naive prostate cancer (mCNPC) following results from GETUG-AFU 15, CHAARTED, and STAMPEDE. No data are available on the efficacy of treatments used for metastatic castration-resistant prostate cancer (mCRPC) in men treated upfront with ADT plus docetaxel for mCNPC. OBJECTIVE: To investigate the efficacy and tolerance of subsequent treatments in patients treated upfront with chemo-hormonal therapy for mCNPC. DESIGN, SETTING, AND PARTICIPANTS: Retrospective data from the GETUG-AFU 15 phase 3 trial were collected for treatments received for mCRPC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: For the first three lines of salvage treatment for mCRPC we investigated the biochemical progression-free survival, maximum prostate-specific antigen (PSA) decline, overall survival, and tolerance. RESULTS AND LIMITATIONS: Overall, 245 patients received at least one treatment for mCRPC. For docetaxel used in first-line, a PSA decline ≥50% was observed in 25/66 (38%) and in 4/20 patients (20%) who had received upfront ADT alone and ADT plus docetaxel (p=0.14). The median biochemical progression-free survival was 6.0 mo (95% confidence interval: 3.6-7.7) and 4.1 mo (95% confidence interval: 1.3-4.9), respectively. For docetaxel used in first- or second-line, a PSA decline ≥50% was observed in 36/80 (45%) and in 4/29 patients (14%) who had received upfront ADT alone and ADT plus docetaxel (p=0.07). PSA declines ≥50% were observed with bicalutamide in 12/28 (43%) and 4/23 patients (17%) who had received upfront ADT alone and ADT plus docetaxel. Among men treated upfront with ADT plus docetaxel who received abiraterone or enzalutamide for mCRPC, 10/19 patients (53%) achieved a PSA decline ≥50%. Few grade 3-4 events occurred. Study limitations include the observational design and retrospective characteristics of this analysis, without standardized therapeutic salvage protocols, and the limited number of patients in some of the treatment subgroups. CONCLUSIONS: Docetaxel rechallenge following progression to mCRPC after upfront ADT plus docetaxel for mCNPC was active only in a limited number of patients. Available data on abiraterone and enzalutamide support maintained efficacy in this setting. The lack of standardized therapeutic protocols for men developing mCRPC limits the comparability between patients. PATIENT SUMMARY: Rechallenging docetaxel at castration-resistance was active only in a limited number of patients treated upfront with chemo-hormonal therapy for metastatic castration-naive prostate cancer. Anticancer activity was suggested with abiraterone or enzalutamide in this setting.

Age and factors associated with access and time to post-operative adjuvant chemotherapy in colon cancer: a French epidemiological study.

BACKGROUND: Studies have shown the negative prognostic impact of increased time between colectomy and postoperative adjuvant chemotherapy (AC) in colon cancer (CC). Our aim was to investigate the role of age and non-organizational factors on access and time to AC. METHODS: All adult patients undergoing surgery for stage II or III CC in the "Région Centre-Val de Loire" in 2013, were selected. Time to AC and socio-demographic factors were collected. Logistic regression modeling was used to identify factors associated with access to AC, and a multivariate analysis performed to identify factors associated with time to AC. RESULTS: Among 404 stage II or III patients who underwent colectomy, 182 (45%; sex ratio 1.5; mean age 67.6 years; range 32-90) received AC. AC patients were younger than those without AC (67.6 vs. 77.9 years) and the difference was even greater for stage III patients (69.0 vs. 82.4). The median time to AC was 48 days, exceeding 42 days in 60% of cases. Living alone, postoperative morbidities, and emergency colectomy were independently associated with increased time to AC. Age and other factors were not associated with delayed AC. CONCLUSIONS: Emergency colectomy, postoperative morbidities, and living alone are associated with increased time to AC. Organizational measures to reduce the time to AC are therefore unlikely to have an impact. In contrast, age is not associated with increased time to AC, but to access to AC. Reasons for omitting AC in older patients requires further study.

Chemotherapy in hormone-sensitive metastatic prostate cancer: Evidences and uncertainties from the literature.

Data from the literature support with strong evidence the addition of docetaxel to androgen-deprivation therapy (ADT) for men with metastatic prostate cancer, and starting therapy for the first time. A meta-analysis of three randomized controlled trials showed a significant improvement of overall survival when ADT was combined with docetaxel when compared to ADT alone (HR=0.77; 95% CI: 0.68-0.87; p<0.0001). Consequently, combination therapy should be considered presently as the new standard of care, using 6 cycles of docetaxel, without prednisone. However, candidates for this upfront combination therapy in whom the balance between its side effects and benefits is favorable are still to be identified more precisely. Patients' stratification according to Gleason score, previous local treatment and age or performance status were shown to have a prognostic impact. The volume of metastases, as defined in the CHAARTED study for instance, could be an interesting predictive factor. However, data accumulated until now remain only hypothesis generating and further analysis and studies are needed to establish any potential discriminating factors. Several new efficient therapeutic options are now available in prostate cancer management and should be evaluated against a chemo-hormonal combination therapy. Other trials are warranted to establish the role of docetaxel in earlier stages of the disease, the combination with the new hormonal therapies as well as the best management options after docetaxel.

Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial.

BACKGROUND: Early risk-stratified chemotherapy is a standard treatment for breast, colorectal, and lung cancers, but not for high-risk localised prostate cancer. Combined docetaxel and estramustine improves survival in patients with castration-resistant prostate cancer. We assessed the effects of combined docetaxel and estramustine on relapse in patients with high-risk localised prostate cancer. METHODS: We did this randomised phase 3 trial at 26 hospitals in France. We enrolled patients with treatment-naive prostate cancer and at least one risk factor (ie, stage T3-T4 disease, Gleason score of ≥8, prostate-specific antigen concentration >20 ng/mL, or pathological node-positive). All patients underwent a staging pelvic lymph node dissection. Patients were randomly assigned (1:1) to either androgen deprivation therapy (ADT; goserelin 10·8 mg every 3 months for 3 years) plus four cycles of docetaxel on day 2 at a dose of 70 mg/m(2) and estramustine 10 mg/kg per day on days 1-5, every 3 weeks, or ADT only. The randomisation was done centrally by computer, stratified by risk factor. Local treatment was administered at 3 months. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was relapse-free survival in the intention-to-treat population. Follow-up for other endpoints is ongoing. This study is registered with ClinicalTrials.gov, number NCT00055731. FINDINGS: We randomly assigned 207 patients to the ADT plus docetaxel and estramustine group and 206 to the ADT only group. Median follow-up was 8·8 years (IQR 8·1-9·7). 88 (43%) of 207 patients in the ADT plus docetaxel and estramustine group had an event (relapse or death) versus 111 (54%) of 206 in the ADT only group. 8-year relapse-free survival was 62% (95% CI 55-69) in the ADT plus docetaxel and estramustine group versus 50% (44-57) in the ADT only group (adjusted hazard ratio [HR] 0·71, 95% CI 0·54-0·94, p=0·017). Of patients who were treated with radiotherapy and had data available, 31 (21%) of 151 in the ADT plus docetaxel and estramustine group versus 26 (18%) of 143 in the ADT only group reported a grade 2 or higher long-term side-effect (p=0·61). We recorded no excess second cancers (26 [13%] of 207 vs 22 [11%] of 206; p=0·57), and there were no treatment-related deaths. INTERPRETATION: Docetaxel-based chemotherapy improves relapse-free survival in patients with high-risk localised prostate cancer. Longer follow-up is needed to assess whether this benefit translates into improved metastasis-free survival and overall survival. FUNDING: Ligue Contre le Cancer, Sanofi-Aventis, AstraZeneca, Institut National du Cancer.

Trabectedin in patients with advanced soft tissue sarcoma: a retrospective national analysis of the French Sarcoma Group.

AIM: The French Sarcoma Group performed this retrospective analysis of the 'RetrospectYon' database with data of patients with recurrent advanced soft tissue sarcoma (STS) treated with trabectedin 1.5 mg/m(2) as a 24-h infusion every three weeks. METHODS: Patients who achieved non-progressive disease after six initial cycles could receive long-term trabectedin treatment until disease progression. RESULTS: Overall, 885 patients from 25 French centres were included. Patients received a median of four trabectedin cycles (range: 1-28). The objective response rate was 17% (six complete/127 partial responses) and 50% (n = 403) of patients had stable disease for a disease control rate of 67%. After a median follow-up of 22.0 months, median progression-free survival (PFS) and overall survival (OS) were 4.4 and 12.2 months, respectively. After six cycles, 227/304 patients with non-progressive disease received trabectedin until disease progression and obtained a significantly superior median PFS (11.7 versus 7.6 months, P<0.003) and OS (24.9 versus 16.9 months, P < 0.001) compared with those who stopped trabectedin treatment. Deaths and unscheduled hospitalisation attributed to drug-related events occurred in 0.5% and 9.4% of patients, respectively. CONCLUSION: The results of this real-life study demonstrate that treatment with trabectedin of patients with STS yielded comparable or improved efficacy outcomes versus those observed in clinical trials. A long-term treatment with trabectedin given until disease progression is associated with significantly improved PFS and OS.