Reza-Thierry Elaidi

Negative impact of bone metastasis on outcome in clear-cell renal cell carcinoma treated with sunitinib

BACKGROUND The aim of our study was to determine whether the presence of bone metastases affects outcomes in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) receiving sunitinib. PATIENTS AND METHODS We reviewed the charts of all patients in four academic centers in Belgium and France who started first-line sunitinib (50 mg/day; 4 weeks on and 2 weeks off) between January 2005 and December 2008. Data were collected on known prognostic factors for metastatic renal cell carcinoma and metastatic sites. Response and progression were evaluated by computed tomography scan (according to RECIST). RESULTS Two hundred twenty-three patients were identified. With a median follow-up of 40 months, median progression-free survival (PFS) and median overall survival (OS) were significantly shorter in patients with bone metastases than in those without: respectively, 8.2 versus 19.1 months (P<0.0001) and 19.5 versus 38.5 months (P<0.0001). On multivariate analysis, taking on account platelet count, Eastern Cooperative Oncology Group performance status, number of metastatic sites, neutrophil count, corrected serum calcium, time from diagnosis to systemic treatment, and the presence of bone metastases, bone metastasis was the independent variable most significantly associated with poor PFS (P<0.0001) and OS (P=0.001). CONCLUSION The presence of bone metastases in m-ccRCC patients has a significant and clinically relevant negative impact on outcome on sunitinib.

Sequential therapy with targeted agents in patients with advanced renal cell carcinoma: Optimizing patient benefit

Multiple targeted agents are now available for the treatment of patients with metastatic renal cell carcinoma (mRCC). Although targeted agents offer improvements over previous treatments and significantly prolong progression-free survival, most patients eventually experience disease progression. For these patients, sequential treatment with multiple lines of therapy may afford sustained clinical benefit. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFr-TKIs) are recommended as first-line therapy for most patients with mRCC. Current clinical practice guidelines uniformly recommend treatment with the mammalian target of rapamycin (mTOR) inhibitor everolimus after initial VEGFr-TKI failure. Recent results of the AXIS phase 3 trial demonstrated improved efficacy with second-line axitinib compared with sorafenib in patients who progressed on a variety of first-line therapies, including the VEGFr-TKI sunitinib. Available clinical evidence, individual patient profile, and toxicity concerns should be carefully evaluated when deciding whether to administer an mTOR inhibitor or a second VEGFr-TKI after progression on a first-line VEGFr-TKI. In patients who progress on a VEGFr-TKI and an mTOR inhibitor, retrospective analyses indicate that treatment with a second VEGFr-TKI in the third-line setting provides additional clinical benefit. Recent results from a prospective phase 1/2 trial indicate that third-line therapy with the investigational TKI, dovitinib, may have promising efficacy in patients who progress on a VEGFr-TKI and an mTOR inhibitor; a phase 3 trial of dovitinib versus sorafenib in this patient population is ongoing. This review discusses and evaluates current clinical evidence for sequential therapy with targeted agents in patients with mRCC.

Everolimus (RAD001): an mTOR inhibitor for the treatment of metastatic renal cell carcinoma

The recent introduction of drugs that inhibit angiogenesis or the mTOR has provided new options for the treatment of metastatic renal cell carcinoma, a disease which often has a poor prognosis. Chemotherapy and cytokine therapy are largely ineffective. The 5-year survival rate is under 10%. Everolimus, an immunosuppressive drug widely used for the prevention of allograft rejection and an mTOR inhibitor, is one of the latest drugs undergoing clinical trials in metastatic renal cell carcinoma. It has been tested in patients with progressive disease after therapy with tyrosine kinase receptor inhibitors (sunitinib, sorafenib or both), which interfere with signaling pathways, such as the VEGF pathway. Clinical efficacy results (progression-free survival) for everolimus are promising and the safety profile is good.

Prostate-specific antigen flare induced by cabazitaxel-based chemotherapy in patients with metastatic castration-resistant prostate cancer

BACKGROUND A prostate-specific antigen (PSA) flare occurs in about 15% of metastatic castration-resistant prostate cancer (mCRPC) patients receiving docetaxel. This flare has no standard definition. Its impact on treatment efficacy is unclear. We sought to evaluate the incidence and characteristics of PSA flare on cabazitaxel, and its impact on survival. METHODS Multicentre retrospective review of consecutive patients treated with cabazitaxel second-line chemotherapy for mCRPC. Collection of baseline characteristics, disease history and PSA levels before and during cabazitaxel therapy. Overall survival (OS) and radiological/clinical progression-free survival (PFS) for patient groups corresponding to different definitions of PSA flare estimated by the Kaplan-Meier method and compared using the log-rank test. RESULTS Overall, 125 patients were included. Median PFS and OS were 6.5 and 13.3 months, respectively. Depending upon the definition used, flare incidence ranged from 8.3% to 30.6%. The flare lasted <2.6 months. A PSA flare followed by a ⩾ 50% decrease was associated with a median PFS and OS of 11.2 and 25.2 months, respectively. Median PFS and OS for a ⩾ 30% rather than ⩾ 5 0% decrease were 10.4 and 16.5 months. These outcomes were not significantly different from those in patients with immediate PSA decreases of ⩾ 50% or ⩾ 30% from baseline, but were significantly better than in patients experiencing no PSA decrease (p = 0.006 and 0.015, respectively, for OS). CONCLUSION The PSA response to cabazitaxel, with or without initial flare, was associated with a strong survival benefit. The taxane-induced flare during the first 12 weeks of therapy can be ignored when evaluating PSA response.

Outcomes from Second-Line Therapy in Long-Term Responders to First-Line Tyrosine Kinase Inhibitor in Clear-Cell Metastatic Renal Cell Carcinoma

BACKGROUND Although sequential targeted therapy is standard in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC), the choice of drugs and optimal administration sequence have yet to be established. The objective of this study was to explore whether it is preferable to rechallenge a long-term responder to a first-line tyrosine kinase inhibitor (TKI) with a TKI or whether to switch to a mammalian target of rapamycin inhibitor (mTORi); to determine whether second-line treatment response depends on duration of first-line response (TD1). PATIENTS AND METHODS Retrospective multicenter study (2004-2011) of 241 consecutive mRCC patients (clear-cell histology) who received a first-line TKI for ≥6 months followed by a second-line TKI (n = 118) or mTORi (n = 123). END POINTS Progression-free survival (PFS) and time-to-treatment failure (TTF) on second-line therapy. Multivariable full-model: second-line drug, TD1, ECOG-PS before first- and second-line, best objective response (first-line), Fuhrman grade, number of metastatic sites, and presence of bone metastases. Adjustment covariable: International mRCC Database Consortium (IMDC) risk score. Multiple propensity score and missing data methods were used. Any correlation between first-line and second-line PFS was investigated using censored quantile regression models (CQRM). RESULTS Sequence effect in the overall cohort was in favor of the TKI-TKI sequence over the TKI-mTORi sequence on using TD1 as continuous covariable (HR ≈ 0.75 for PFS and TTF). TKI-TKI superiority was attributed in large part to the 11-22 month (TD1) subgroup of patients which displayed significantly better outcomes [HR ≈ 0.5; median PFS (months): 9.4 (5.9-12.2) versus 3.9 (3.0-5.5), P = 0.003; TTF(months): 8.0 (5.5-11.0) versus 3.6 (3.0-4.6), P = 0.009]. Upon full CQRM, long-term second-line responders were more likely to have received a second TKI than an mTORi and to have been long-term responders to first-line TKI. CONCLUSIONS m-ccRCC patients who remained on first-line TKI between 11 and 22 months benefited from a TKI rechallenge rather than from second-line mTORi.

Efficacy of cabazitaxel and its relationship with predictors of poor response to second hormonal therapies (2d HT) in metastatic castration-resistant prostate cancer (mCRPC).

137 Background: Potential predictors of low response to 2d HT including new agents have been recently identified: high Gleason score, rapid progression with first androgen deprivation therapy (ADT), chemotherapy lines >1 and low baseline testosterone (T) levels. We evaluated the influence of these factors on the efficacy of cabazitaxel (C), a new taxane developed to overcome docetaxel (D) resistance. METHODS Records of 84 consecutive mCRPC pts (median 67 yrs) treated with C for disease progression on D or after D were retrospectively collected in 8 French centers. Baseline characteristics, disease history, PSA response, overall survival (OS) and radiological or clinical progression-free survival (PFS) were collected. RESULTS At C initiation, 84% of pts were ECOG 0-1, 59% had pain and 24% received ≥2 prior chemotherapy lines. Metastases were located in bone (93%), lymph nodes (49%) and visceral/soft tissues (9%). Gleason score was 8-10 in 47%, median time to progression with first ADT was 20 months and median T was 0.1 ng/ml. Median number of C cycles received was 6 (range 2-14). Efficacy of C was not influenced by Gleason score, response duration to first ADT, prior number of chemo lines, or baseline T (table). Main grade ≥ 3 toxicities were neutropenia (32%), anaemia (17%), thrombocytopenia (8%), diarrhoea (6%), and febrile neutropenia (5%). There was no grade ≥3 peripheral neuropathy and no toxic death. CONCLUSIONS This retrospective study suggests that C is effective and shows an acceptable safety profile. Efficacy was not influenced by predictors of poor response to 2d HT (high Gleason, short response to first ADT, Number of chemo lines, low T levels). If these results are confirmed in further investigations, cabazitaxel could be proposed whatever the baseline characteristics of mCRPC pts. [Table: see text].

Retrospective registry evaluating the PSA flare phenomenon with cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC).

122 Background: PSA initial flare followed by a decrease is documented in up to 18% of mCRPC patients (pts) treated with docetaxel (D). There is no standard definition of this phenomenon, and its significance in terms of treatment efficacy and prognosis remains unclear. We evaluated the PSA flare incidence and characteristics with cabazitaxel (C), a new taxane developed to overcome D resistance, and its impact on outcome. METHODS A retrospective review of 84 consecutive pts (median 67 yrs) treated with C for mCRPC progressing during or after D was conducted in 8 French centers. Baseline characteristics, disease history, PSA values before and during C, overall survival (OS) and radiological or clinical progression-free survival (PFS) were collected. RESULTS At C initiation, most pts (84%) were ECOG 0-1, 59.5% had pain and 23.8% received ≥2 chemotherapy lines. Metastases were located in bone (92.9%), lymph nodes (48.8%) and visceral/soft tissues (9.5%). Median number of C cycles was 6 (range 2-14). Median OS and PFS from first C cycle were 16.4 and 6.7 months, respectively. Flare incidence, PFS and OS varied with the definition used (table). Definition [3] seems to us the most clinically relevant, and showed a close estimate of PFS compared to pts with immediate PSA decrease from baseline. We recommend to use this definition in clinical practice. CONCLUSIONS PSA flare occurred in 16% pts treated with C and was associated with as good outcome as immediate responders. C should not be withdrawn prematurely in case of isolated initial PSA rise. This finding supports the PCWG 2 recommendation that early rise (prior to 12 weeks) with cytotoxics should be ignored in determining PSA response. [Table: see text].

What is the best treatment option for second line in long responders to the first-line TKI in metastatic renal cell carcinoma (mRCC) patients (pts): TKI-TKI or TKI-mTORi? A European retrospective study.

375 Background: The question regarding the benefit of a TKI rechallenge versus switch to an mTOR inhibitor (mTORi) in mRCC pts who responded to a previous line of TKI remains unanswered and is a common dilemma in clinical practice. We report results of a retrospective study to address this question. METHODS This study retrospectively investigated Duration of Treatment (DT), best radiological response (OR) and predictive factors in pts treated with either TKI-TKI or TKI-mTORi sequences for clear-cell mRCC. Eligibility criteria: 1 TKI in 1st line (L1) followed by another TKI or mTORi as 2nd line (L2). Prior immunotherapy was allowed but not intermediate lines with other drugs. Pts characteristics and Hengs prognostic factors were collected at each line initiation. Response (resp) was classified with regard to DT and OR using 2 different definitions: def1 = Non Responders (NR): < 4months (m) + PD; Short-Term responders (STR): [4-6]m + SD/PR, Long-term Responders (LTR): >6m + SD/PR, and def2 = NR: < 4m + PD, STR: [4-12]m + SD/PR, LTR: >12m + SD/PR. RESULTS 127 pts from 7 European centers were retrospectively analyzed. Based on def1, resp to L1 was: LTR=93, STR=20, NR=14; among LTR pts, 54 received a L2=TKI and 39 a L2=mTORi. Based on def2, resp to L1 was: LTR=59, STR=53, NR=15; among LTR pts, 35 received a L2=TKI and 24 a L2=mTORi. Whether def1 or def2, resp (L1 and L2) was never related to Hengs score. Among LTR pts at L1, 26 out of 54 were LTR after L2=TKI vs 18 out of 39 after L2=mTORi (p=0.85, Z-test) for def1 and 9 out of 35 were LTR after L2=TKI vs 6 out of 24 after L2=mTORi (p=0.95) for def2 (see table). For both def1 and def2, median DT was 7.2m and 6.9m for L2=TKI and L2=mTORi, respectively (p=0.86 and p=0.95, Log-Rank). CONCLUSIONS Results suggest that long-term responders on 1st line TKI could benefit both from TKI and mTORi as 2nd line and there is no evidence to favor one sequence over the other. [Table: see text].

1510PANEMIA AS AN EXPLANATORY FACTOR FOR FATIGUE IN PATIENTS TREATED WITH CHEMOTHERAPY

ABSTRACT Aim: Fatigue (F) and anemia (A) are common adverse reactions in patients (pts) treated with chemotherapy. The relationship between fatigue and anemia is complex and still unexplained. This study aimed to investigate the time dependant relationship between hemoglobin (Hb) levels and patients reported fatigue. Methods: Patients (pts) included in the PROCHE program between 2008 and 2011 at the Georges Pompidou hospital (Paris, France) were eligible. Pts were contacted before each chemotherapy (CT), and data for F (patients reported outcome according to CTC-NCI grading: 0=none, 1=mild, 2=moderate, 3=severe, 4=3+long-term condition) and A (hemoglobin (Hb) level (g/dl): 0= >12, 1=[10-12[, 2=[10-8], 3=[9; 8[ and 4= Results: 5585 records of F and Hb were collected at the same time point in 661 pts who had at least 1 F and 1 Hb assessments. Median age=64.9y, sex-ratio=1.1, most frequent tumor type (%): lung: 25, breast: 21, urogenital: 21, gynecological: 13, H&N: 12. Localized disease=467 (70.6%), metastatic=194 (29.4%). Median number of cycles received=4 (IQR: 4). Median follow-up was 26.7m (25.5-27.9). Patients reported F grade (%): 0=24.7, 1=45.2, 3=24.2, >3=5.9. Hb (g/dl)(%): >12=31.5, [10-12[=53.7, Conclusion: This study confirmed through internal and external validation the longitudinal relationship between fatigue and anemia over the chemotherapy period. Anemia was found to be the main explanatory factor of fatigue. Disclosure: All authors have declared no conflicts of interest.