Institut Gustave Roussy Research Articles

Reply to Letter

Department of Surgical Oncology, Institut Gustave Roussy, Cancer Center, Villejuif, France, [email protected] Disclosure: The authors declare no conflict of interest or funding sources relevant to this letter.

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

PurposeTo evaluate prior compliance with guidelines in patients treated with salvage chemotherapy for advanced germ-cell tumours (GCT). Patients and methodsData 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. ResultsAmong 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. ConclusionGuidelines 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.

Preoperative imaging prior to breast reconstruction surgery: Benchmarking bringing together radiologists and plastic surgeons. Proposed guidelines

Prescription of preoperatory imaging assessment prior to planned breast reconstruction surgery (reduction or augmentation mastoplasty, correction of congenital breast asymmetry) is poorly codified. The objective of this study was to analyze the attitudes of French radiologists and plastic surgeons with regard to prescription of preoperative imaging in the framework of non-oncologic breast surgery. This is a descriptive and comparative observational study involving two groups, one consisting of 50 plastic surgeons (P) and the other of 50 radiologists (R) specialized in breast imaging. A questionnaire was handed out to radiologists during a conference on breast imaging at the Institut Gustave-Roussy in Paris (France) held on 17th December 2012. The same questionnaire was handed out to plastic surgeons at the National Congress of the French Society of Plastic and Reconstructive Surgery (SOFCPRE) held on 19th, 20th and 21st November 2012, also in Paris (France). The questionnaire focused on prescription of preoperative and postoperative imaging evaluation for non-oncologic breast surgery in patients with no risk factors for breast cancer or clinically identified indications. Forty-six percent of the plastic surgeons considered an imaging exam to be recent when it had been carried out over the previous 6 months, while 40% of the radiologists set the figure at 1 year. Clinical breast density exerted no influence on 92% of the plastic surgeons and 98% of the radiologists. A majority of the plastic surgeons would prescribe a preoperative exam regardless of age (57% for breast reduction, 61% for breast implant placement and 61% for surgical correction of asymmetry) while the radiologists would prescribe exams mainly for patients over 40 years (50% for reduction, 44% for augmentation, 49% for asymmetry correction). The plastic surgeons would prescribe either ultrasound or mammograms (59% for reduction, 72% for augmentation, 66% for asymmetry correction) while radiologists would usually prescribe mammograms (64%, 57%, 64%). Most of the radiologists, along with the plastic surgeons, did not think that postoperative examination is justified (58% of P and 62% of R for reduction, 56% P and 68% of R for augmentation, 52% of P and 64% of R for asymmetry correction). In 2012, there existed no French consensus on prescription of a preoperative imaging assessment in the framework of non-oncologic breast surgery in patients without risk factors for breast cancer. Active cooperation bringing together radiologists and plastic surgeons is likely to facilitate the harmonizing of their respective practices. In this paper, we propose guidelines that could help them to synchronize their efforts.

Prognostic value of flare-up phenomenon after discontinuation of sunitinib (SU) or pazopanib (PA) in metastatic renal cell carcinoma (mRCC).

448 Background: SU and PA are VEGFR inhibitors, approved for the treatment of mRCC. Cessation of treatment has been reported to induce flare-up, with increased tumor growth rate (TGR). We aimed to investigate this phenomenon and its prognostic role in mRCC. Methods: Patients who discontinued first line SU or PA with available data about CT scans performed before (t-1), at the time of discontinuation (t0) and after (t+1), were included in this analysis. TGR was evaluated as the difference between the sum of longest diameters (SLD) of the target lesions during the interval time between the CTs (TGR1=SLD0–SLD-1/t0-t-1 and TGR2=SLD+1-SLD0/t+1-t0) and expressed in cm/month. Flare-up was evaluated as the difference between the TGRs. Median overall survival was evaluated from t0 (OS0) to death by the Kaplan-Meier method and correlation with variables was evaluated with Cox model. Results: Sixty-three patients treated from Oct 2006 to Nov 2012 at the Institut Gustave Roussy were eligible. Median age was 57.1 y, 81% were males, 89% had SU and 11% PA. Heng prognostic groups were good in 33% and intermediate in 67% of the pts. Median OS0 was 24.1 months (95%CI, 8.3 – 40.0). Major reasons for discontinuation were durable partial/complete response (16%), severe toxicity (22%) and progression of disease (62%). The median TGR1 and TGR2 were 0.2 and 0.7 cm/month, respectively (p=0.001), no correlation was found (p=0.33) and no differences were found between SU and PA in TGR1 (p=0.95) and TGR2 (p=0.53). Median flare-up was 0.5 cm/month (IQR: 0.1 – 1.2); in pts who discontinued for response, toxicity, or PD it was 0.1 (IQR: -0.2 – 0.6), 0.5 (IQR; 0.2 – 2.0) and 0.8 (0.1 – 1.7), respectively. At the univariate analysis flare-up was a prognostic factor for OS0 (HR: 1.13, 95%CI: 1.02 – 1.24; p=0.018). When compared to Heng criteria in the multivariate analysis, it was confirmed to be an independent prognostic factor: each increase of 1 cm in flare-up increases the risk of death by 11% (HR: 1.11, 95%CI: 1.00 – 1.23; p=0.048). Conclusions: Flare-up is an independent prognostic factor present in patients affected by mRCC who discontinued SU or PA. This is independent by the reason for discontinuation and the type of therapy.

Observatoire des tumeurs malignes rares gynécologiques

The observatory of gynecological rare tumors (TMRG) has been initially created for ovarian rare neoplasms (TMRO). Because of the similarities between ovarian and other gynecological tumors, this observatory has been then extended to all gynecological rare tumors. The recognition by INCa of three national expert centers (centre Léon-Bérard, hôpitaux de Paris, institut Gustave-Roussy) in rare gynecological cancers and a network of regional expert centers in 2010, expend the experience of the website "Observatoire francophone des tumeurs rares de l'ovaire". The major goals of this gynecology rare tumors experts network, are to promote systematic second opinion for initial diagnostic by experts in gynecopathology, systematic multidisciplinary advice by surgeons and medical oncologist experts, to disseminate clinical guidelines dedicated to rare gynecological tumors, to promote specific fundamental and translational research within clinical trials dedicated to rare tumors. At the end, we would like to improve benefit in term of survival and/or fertility for all these potential young patients.

High‐dose busulfan–thiotepa with autologous stem cell transplantation followed by posterior fossa irradiation in young children with classical or incompletely resected medulloblastoma

The aim of the study is to evaluate the outcome of young children with high risk localized medulloblastomas (newly diagnosed classical or incompletely resected) treated by high-dose busulfan-thiotepa with autologous stem cell rescue (ASCT) followed by focal radiation therapy (RT). Between September 1994 and January 2010, 19 children younger than 5 years old at diagnosis fulfilling the above inclusion criteria were treated at the Institute Gustave Roussy. After conventional chemotherapy, they received busulfan at a dose of 600 mg/m(2) and thiotepa at a dose of 900 mg/m(2) followed by ASCT. Focal RT was delivered at least 70 days after ASCT. The median follow-up was 40.5 months (range, 14.5-191.2 months). The 3-year event-free survival (EFS) and OS were 68% (95% CI 45-84%) and 84% (95% CI 61-94%), respectively. Acute toxicity consisted mainly in hepatic veno-occlusive disease (6/19 patients) and bone marrow aplasia (all patients). No toxic death occurred. The Full Scale Intellectual Quotient tended to decrease over time at a mean rate of 0.9 point per year from the date of diagnosis. This intensive treatment resulted in a high overall survival rate in young children with newly diagnosed non-metastatic classic or incompletely resected MB. In spite of a high incidence of hepatic veno-occlusive disease (32%), the acute toxicity was manageable. Delayed neuropsychological side effects remain main concerns. These results should to be confirmed in a larger cohort.

Prof. Jean Armand: personalized medicine in France and the niche in future international cooperation.

Jean-Pierre Armand MD, MSc, certified in Medical Oncology, is senior consultant at Institute Gustave Roussy and Institute Curie in Paris (Figure 1). He was the General Director of the Institute Claudius Regaud the comprehensive cancer center in Toulouse and was in charge of the construction of a new cancer center (institute universitaire cancer) in a European research hub created in the Toulouse cancer campus. He is an active member of the Medical Oncology Community. Previously Head of Early Clinical New Drugs Programs and Medical Director Research and development at the Institute Gustave-Roussy, Villejuif, Prof. Armand is involved in Phase I II and III studies for the treatment of solid tumors. Prof. Armand is active at ESMO, EORTC and at EMEA French agency (AFSSAPS). In CSCO 2013 in Xiamen, China, professor Armand gave a presentation on personalized medicine in France and here we are honored to have an interview with Prof. Armand to detail the recent update in drug development.

Does KRAS mutational status predict chemoresistance in advanced non-small cell lung cancer (NSCLC)?

BackgroundClinical implications of KRAS mutational status in advanced non-small cell lung cancer (NSCLC) remain unclear. To clarify this point, we retrospectively explored whether KRAS mutations could impact tumor response, and disease control rate (DCR) to first-line platinum-based chemotherapy (CT) as well as progression-free survival (PFS) or overall survival (OS). MethodsBetween June 2009 and June 2012, 340 patients with advanced (stage IIIB/IV) NSCLC were reviewed in a single institution (Institut Gustave Roussy). Two hundred and one patients had a biomolecular profile and received a platinum-based first-line CT. Patients with an unknown mutational status or with actionable alterations were excluded. We retained two groups: patients with KRAS mutated tumor (MUT) and patients with wild-type KRAS/EGFR (WT). Multivariate analyses with Cox model were used. Survival curves were calculated with Kaplan–Meier method. ResultsOne hundred and eight patients were included in the analysis: 39 in the MUT group and 69 in the WT group. Baseline radiological assessment demonstrated more brain (P=0.01) and liver (P=0.04) metastases in MUT patients. DCR was 76% for MUT vs. 91% for WT group (P=0.03), regardless of the type of platinum-based CT (use of pemetrexed or not). Although no statistically significant differences were found, shorter PFS (4.9 vs. 6.0 months; P=0.79) and OS (10.3 vs. 13.2 months; P=0.40) were observed for patients with KRAS mutated tumors in univariate analysis. ConclusionsKRAS mutant tumors had a lower DCR after the first-line platinum-based CT, but this difference did not translate in PFS or OS. The presence of KRAS mutations may confer a more aggressive disease, with greater baseline incidence of hepatic and cerebral metastases.

Comparative study analyzing survival and safety of bevacizumab/carboplatin/paclitaxel and cisplatin/pemetrexed in chemotherapy-naïve patients with advanced non-squamous bronchogenic carcinoma not harboring EGFR mutation

PurposeThe majority of Egyptian patients with lung cancer present at a late stage of the disease. Bevacizumab/carboplatin/paclitaxel, as well as cisplatin plus pemetrexed, are both standard regimens for advanced non-squamous bronchogenic cancer. This study compares both regimens, in terms of efficacy and toxicity profile, in Egyptian patients.Patients and methodsThis is a randomized Phase II study comparing toxicity profile and survival in 41 chemotherapy-naïve patients with stage IIIB or IV non-squamous NSCLC, with an ECOG performance status of 0 to 2. The epidermal growth factor receptor (EGFR) mutation detection was performed prior to treatment of all patients. Patients in the first group received: bevacizumab 7.5 mg/m2 on Day 1 and Day 15; carboplatin area under the curve-5 on Day 1; and paclitaxel 60 mg/m2 on Day 1, Day 8, and Day 15 every 4 weeks. In the second group, patients received cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 every 3 weeks.ResultsThe combination of bevacizumab/carboplatin/paclitaxel demonstrated higher Grade III–IV toxicity than cisplatin/pemetrexed regarding sensory/motor neuropathy (P = 0.06), DVT (P = 0.23), proteinuria (P = 0.23), and hypertension (P = 0.11), as well as Grade II alopecia (P = 0.001); however, no significant difference in toxicities between both arms was recorded regarding nausea and vomiting (P = 0.66), hematological toxicity, febrile neutropenia (P = 1) and fatigue (P = 0.66). Progression-free survival was similar for both treatment arms with a median of 6 months (P = 0.978). Overall median survival was comparable in both arms, 16.07 months versus 16.01 months (P = 0.89).ConclusionBevacizumab/carboplatin/paclitaxel and cisplatin/pemetrexed provided meaningful and comparable efficacy in advanced non-squamous bronchogenic carcinoma not harboring EGFR mutation. No significant difference in toxicity was observed between both treatment arms, apart from bevacizumab/carboplatin/paclitaxel-related risks as DVT, hypertension, proteinuria, sensory/motor neuropathy, and alopecia.

Inter-operator variability in organs at risk delineation: Their effects on dose-volume histograms

Introduction As recommended by the ICRU report 83, while planning treatment in radiotherapy (RT), organs at risk (OAR) must be systematically delineated. As several studies have shown, interoperator variability implies differences in volume once rebuilt from computed tomography images. This work aims to evaluate the impact of this variability on dose-volume histograms (DVH). Materials and methods Using a treatment planning system (TPS) Isogray (Dosisoft®), three typical treatment plans, for 3 different pathologies, were performed: a case of carcinoma of the prostate in 3D conformational radiotherapy (3DCRT), one case of Hodgkin lymphoma Involved Field and in a case of breast carcinoma 3DCRT. To model changes in volumes of organs at risk induced by delineation, margins, implemented by the TPS were defined around reference delineations. These margins have been defined using results of several authors who have studied inter-operator variability in delineation. In addition, reference delineations were validated by two radiation oncologists from the Gustave Roussy Institute. The resulting DVH were analyzed to compare the dose-volume metrics for all treatment plans and all organs. Results Preliminary results relate to the D98%, D50% and D2%. Whatever the position of the OAR from the irradiated volume, defined by the 50% isodose of the prescribed dose, D50% of each organ at risk does not vary significantly with the volume in the volume range defined. D98% decreases of about 9% when delineation tends to overestimate the volume of interest at the maximum. However D2% increases of about 7% when delineation tends to overestimate volume of interest at the maximum. Conclusion Except for D50%, inter-operator variability in OAR delineation may induce a different interpretation of the DVH in the treatment planning process. These results have to be taken into account during the validation of a clinical treatment plan. In addition, to reduce inter-operator variability, this work recommends to define standardized protocols of delineation for each organ.

Antitumor activity in advanced cancer patients with thymic malignancies enrolled in early clinical drug development program (phase I trials) at Institut Gustave Roussy.

7604 Background: Thymic epithelial neoplasms (TENs) represent a rare entity with poor prognosis and limited systemic treatment options, particularly in advanced stages and/or in thymic carcinomas (TC). The aim of this study was to assess the clinical benefit, the efficacy and toxicities of agents for patients (pts) with a refractory TEN enrolled in Phase I trials. Methods: We reviewed retrospectively pts with advanced pretreated TEN enrolled in Phase I trials at the Institut Gustave Roussy (SITEP) between 1994 and 2012. Toxicities were reported and scored according to NCI CTCAE version 3.0. Efficacy was assessed using RECIST version 1.1. Results: Twenty-two treated pts were enrolled (14 with TC, 8 with thymomas). The median number of prior systemic therapies was 2 (1-8). The median age was 50 years (range 23-72), and 4 females were treated. Treatment received were mTOR inhibitor (mTORi) in 4 of pts, antiangiogenic agents (AA) in 11 pts, and other targeted therapies in 7 pts. The median follow-up time was 22.1 months (range, 1.25-77.79 months). Autoimmune associated disease (AID) was reported in 6 pts. 18% had grade III/IV toxicity, 54% grade I/II toxicity and no toxic death was reported. AID exacerbated in one patient. One patient experienced a complete response (CR) and 3 a partial response (PR); 16 pts had stable disease (median 6.6 months) and 2 had a progressive disease. Objective response rate (ORR) was 42%, 25.0% for thymoma and 21.4% for TC. The median overall survival was 54.5 months (95% CI 25-75.50 months), 54.5 for thymoma and 62 for TC. The median progression free survival (PFS) was 6.6 months (95% CI 1.35-11.59 months), 5.2 for thymoma and 6.9 for TC. Median PFS was 11.6 months for mTORi, 6.9 for AA, and 6.6 for other targeted therapies. Conclusions: Phase I trials appear as a sound therapeutic option in TENs pts progressing after standard treatments. Use of AA and mTORi seem to yield a good clinical response. Novel targeted therapies might be tested setting in a biology-oriented approach rather than a stochastical one. We are currently offering a molecular profiling in our patients (MOSCATO trial NCT01566019) for a better selection of appropriate Phase I trial.

Effects of abiraterone acetate and enzalutamide on muscle and adipose mass in men with metastatic castration-resistant prostate cancer (mCRPC).

5088 Background: Abiraterone acetate (AA) and enzalutamide (MDV3100), two androgen receptor-directed compounds, have been shown to improve survival for patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after Docetaxel.. Since these drugs might be used at an early-stage in the future, and skeletal muscle (SM) and adipose tissue (AT) are known to be prognosis parameters, the aim of this study was to evaluate the body composition changes in patients with mCRPC treated with AA and MDV3100. Methods: Patients included in AFFIRM (n=62 treated with MDV3100 and placebo n=28) and COU-AA-301 (n=24 treated with AA+Prednisone (P)10mg/day and placebo+P n= 13) trials at the Institute Gustave Roussy were included in the analysis. Cross-sectional areas (cm2) of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and SM were assessed by computed tomography imaging at 3rd lumbar vertebra and were indexed for height (cm2/m2) with Slice-O-Matic software V4.3 at baseline, 3, 6 and 12 months of treatment. The data from patients treated with AA or MDV3100 were compared to placebo-patients and tissues changes were compared to baseline. We used the validated sarcopenic definitions as SM index less than 52.4 (cm2/m2). Results: For all cohort, median age was 69 years (range: 48-83), median weight was 79 kg (range: 47-150) and median BMI was 25.9 kg/m2(range: 18-46). At inclusion, 74 patients (58%) were overweight or obese (BMI>24.9 kg/m2), and only 2 patients were underweight (BMI<18.5kg/m2). 97 patients (81%) were sarcopenic, and 56 (75%) of overweight or obese patients were sarcopenic. Over 3 months, the patients from the entire cohort lost muscle mass (mean change: 4.5±7.5% (» 0.7 kg of muscle)) (P=0.01) . A non significant loss of SAT -4.6±19.2% and a non significant increase of VAT (+10.7±50.3% ) were observed. A similar pattern was observed at 6 months. There was no significant difference between body composition changes in treated groups and placebo. Conclusions: Sarcopenia is highly prevalent in patients with advanced CRPC. Unexpectedly, no difference in body composition changes was observed between patients treated with MDV3100 or AA and placebo.

Use of tumor growth rate (TGR) to provide useful clinical information in phase I trials and reveal clear drug-specific profiles.

3010 Background: The evaluation of treatment response by RECIST does not take into account the tumor growth kinetics along the treatment sequence and may induce misleading information regarding the evaluation of the drug activity. TGR incorporates the time between the tumor evaluations and allows for a dynamic and quantitative evaluation of the tumor kinetics. How TGR is modified along the introduction of experimental therapeutics and is associated with outcome in phase I patients remains unknown. Methods: Medical records from all patients (n=304) prospectively treated at Institut Gustave Roussy in 19 phase I trials between 2009 and 2011 were analyzed. TGR was computed both during the pre-treatment period (REFERENCE) and between baseline and first evaluation (EXPERIMENTAL). TGR is defined as: log 10 (Vt/V0)/dt and is represented as a percentage increase of tumor volume per month for clinical relevance. The associations between TGR, RECIST, the most commonly used prognostic scores (ECOG, RMH score, PFS ratio) and the outcome (OS, PFS) were computed (multivariate analysis). The effect of treatment, prognostic scores, histology, and the number of previous treatment lines on TGR were assessed. Results: Overall, we observed a reduction of TGR between the REFERENCE vs. EXPERIMENTAL periods (11.5 vs. 1.5, P<.0001). Although most of the patients were classified as stable disease (57%) or progressive disease (28%) by RECIST at the first evaluation, 88% and 69% of them exhibited a decrease in TGR, respectively. TGR reveals clear drug specific profiles along the 19 experimental regimens tested, allowing for an early evaluation of the drug activity. The TGR decrease was associated with both PFS (P=.004) and OS (P=.001) and remained significant even after adjustment to the other prognostic scores for phase I patients. Conclusions: Adding TGR assessment in phase I patients is simple and provides clinically relevant information: (i) It allows for an early and precise assessment of the tumor growth, (ii) It reveals drug-specific profiles, suggesting its potential use for the early assessment of drug activity, (iii) TGR is independently associated with prognosis in phase I patients.

Safety and tolerability in patients over age 75 included in phase I: The Institut Gustave Roussy experience.

9556 Background: Safety and tolerability of anti-cancer therapy in elderly people (>=75 years, EP) is of major interest since they represent 31% of US patients diagnosed with cancer. However proportion of EP recruited is only 9% in clinical trials and probably less in phase I trials, which aim to determine the recommended phase II dose. Our objective was to evaluate the safety of phase I trials in EP. Methods: Patients treated from 2007 to 2012 at Institut Gustave Roussy in phase I trials, in which patients aged over 75 years had been included. Population was divided into two groups: EP or patients aged < 75 years (YP). Time to occurrence of first high toxicity (any grade 3-4 adverse event (AE) or dose-limiting toxicity DLT) and overall survival were estimated using Kaplan-Meier method. Conditional Cox proportional hazards model was used to compare occurrence of AE in a sub population of patients aged >= 75 years matched with patients aged <75 years of same Royal Marsden Hospital (RMH) score (Albumin, LDH, Number of metastatic site) and protocol. Results: In the 33 EP and the 161 YP, 20(60%) and 100(62%) grade 3-4 AEs and 1(3%) and 18(11%) DLTs occurred. The median time to occurrence of high toxicity were 2 months (95%CI=1-4) and 2 months (95%CI=1-2). The median overall survival were 22 months (95%CI=11-non estimable) (EP) and 13 months (95%CI =10-16) (YP). Twenty-seven patients aged >=75 years could be matched: age over 75 years was not associated with higher risk of neither high toxicity (HR=0.85, 95%CI=[0.45 ; 1.61], p=.62) nor death (HR=1.03, 95%CI=[0.47;2.24], p=.94). Conclusions: No impact of age over 75 years on occurrence of neither high toxicity nor death was identified. Patients above 75 years are good candidates for phase I trials.

Efficacy of docetaxel chemotherapy in metastatic prostate cancer (mPC) patients (pts) experiencing early castration resistance (CR).

5075 Background: mPC pts experiencing a short period of sensitivity to initial androgen deprivation therapy (ADT) have an unfavourable prognosis and lower probability of response to 2nd-line endocrine therapy suggestive of androgen receptor (AR) pathway-independent mechanisms of resistance. Recent studies have shown that docetaxel may kill PC cells through AR targeting. We thus investigated whether docetaxel may have efficacy in pts with early CR. Methods: Two independent prospective databases (Institut Gustave Roussy and Institut Jean Godinot) of mCRPC pts were analyzed. Early CR was defined as progression within the first year of ADT. The primary endpoint was time to progression (TTP) on docetaxel. Secondary criteria were clinical benefit (decrease in 2 points on a 0-to-10-pain-scale or in dose or type of pain medication), PSA response (decrease > 50% in PSA serum level) and overall survival (OS). Pts with early CR were compared to pts with sensitivity to initial ADT > 1 year (t-test for quantitative data, χ-2 test or Fischer’s exact test for qualitative data, Logrank test for TTP and OS). Results: 188 pts were selected for analysis. A higher frequency of unfavourable prognostic factors in pts with early CR as compared with others pts was observed with a median PSA serum level of 81 ng/dl (4-8000) vs 35 ng/dl (4-4260) (p=5.10-5), presence of visceral metastasis in 11% vs 2% of pts (p=0.01) and Gleason score ≥ 8 in 63% vs 41% of pts respectively (p=0.001). Clinical benefit and PSA response on docetaxel were observed in 84% vs 89% of pts (p=0.45) and 67% vs 81% of pts (p=0.10) respectively. Median TTP was 6.1 months (95%CI=6-7.5) vs 7.8 months (95%CI=7-8.3) (p=0.04). Median OS was 22.4 months (95%CI=17.1–28.6) vs 36.1 months (95%CI=26.3–42.4) (p=0.002). Conclusions: mPC pts experiencing early CR have more unfavourable baseline prognostic factors, shorter TTP on docetaxel and shorter OS as compared with pts experiencing time to CR > 1 year. However, similar clinical and biological benefits from docetaxel chemotherapy were observed in this subset of pts. Since they have lower probability of response to second-line endocrine therapy, docetaxel appears as the best option after progression on initial ADT.

Prognostic factors and outcome of undifferentiated endometrial sarcoma treated by multimodal therapy

ObjectiveTo describe the natural history, prognostic factors, and optimal treatment modalities of undifferentiated endometrial sarcoma (UES). MethodsA retrospective review was conducted of 30 patients with UES treated at Institut Gustave-Roussy, France, between January 1978 and December 2008. Clinical and pathologic variables, treatment modalities, and outcomes were assessed. ResultsDisease was advanced in most cases: FIGO stage III–IV in 70% of patients. Overall, 29 patients (96.7%) underwent hysterectomy as part of the initial surgical treatment; however, only 18 (60.0%) attained complete macroscopic resection. The incidence of pelvic and/or para-aortic lymph-node involvement at primary surgery or first recurrence was 44.4%. Median postoperative follow-up was 5 years; progression-free survival (PFS) and overall survival (OS) were 9.7 and 23 months, respectively. No differences in OS and PFS were observed by staging subgroup (FIGO vs the American Joint Committee on Cancer). Only postoperative pelvic radiotherapy with or without brachytherapy correlated with improved PFS (19.1 vs 6.5 months; P=0.04) and OS (54.5 vs 16.7 months; P=0.01) in a univariate analysis. ConclusionNeither staging system was optimal for risk stratification. Multimodal therapy was recommended after surgery.

Update on the treatment of non-small-cell lung cancer: focus on the cost-effectiveness of new agents

BackgroundThe incidence of lung cancer and the cost of drug treatment have increased dramatically in the last decade. This article examines the costs of new target agents, such as tyrosine kinase inhibitors (TKIs) and anti-angiogenic drugs.MethodsThis study uses PubMed research to focus on the topics of lung cancer, economics, and new targeted therapies.ResultsThe published papers only addressed TKIs and anti-angiogenic antibodies. For gefitinib, the results favored a clinical-based selection, despite the low number of studies. Erlotinib was studied in second line and as a maintenance treatment (with the studies reaching opposite conclusions in terms of cost-effectiveness). Economic analyses were not in favor of bevacizumab, but the studies on this topic were very heterogeneous.ConclusionThe economic impact of a drug depends on the health care system organization. Future clinical trials must include economic analyses, particularly with TKIs in the first line.

Second line treatment of metastatic renal cell carcinoma: The Institut Gustave Roussy experience with targeted therapies in 251 consecutive patients

BackgroundSequential treatment is currently the standard of care in metastatic renal cell carcinoma (mRCC). However, very little is known on how many patients (pts) can receive second line or further, and on how to predict those pts. The goal of this study was to evaluate these questions in a large series of pts treated in our institution. Patients and MethodsData from all mRCC patients treated at the IGR from 2005 to 2009 with first line targeted therapy (sunitinib (SU), sorafenib (SO), bevacizumab (B), temsirolimus or everolimus (pooled together as mammalian target of rapamycin – mTOR)) were analysed. Only patients with subsequent follow-up have been included in this analysis. Patients were defined as ‘non-eligible’ for second treatment if: they were (i) still on first line treatment, (ii) not showing progressive (durable stable disease or partial response or complete response) or (iii) if they refused a second line treatment. Results251 patients, median age 60years, median follow-up 20.2months were treated with targeted therapy with a median overall survival (OS) of 25.8months. Median OS with SU (127), SO (60) or B (61) were 26.3, 16.4 and 32.5months respectively. Only three patients received an mTOR inhibitor as first line. According to the eligibility criteria, the percentage of patients who received a second line was 59% (n=61/103), 52% (n=30/58) and 79% (n=38/48) for Su, So and B, respectively. Memorial Sloan-Kettering Cancer Centre (MSKCC) classification (P=0.02) and first line agent (P=0.001) were significant predictive factor for receiving a second line of treatment. Overall, patients receiving B were in better general condition, with 77% of performance status score (PS)=0 compared to SO (53%) and SU (48%) (P=0.005). Among the 131 patients who received a second line, the median OS from the start of second line treatment was 20.8months for a tyrosine kinase inhibitor (TKI) (n=98; 75%) and 16.6months for an mTOR (n=32; 42%) (P=0.12). Furthermore, the percentage of patients who received a third line was 56% (27/48), 28% (7/25) and 65% (13/20) for SU, SO and B, respectively. ConclusionThe median OS in patients treated with targeted therapies for mRCC in The Institut Gustave Roussy exceeds 2years. The use of second line varies from 52% to 79%. Further studies are needed to validate the MSKCC groups and first line therapy as predictive factor for second line treatment.

SP-0637: The role of the radiation technologist in the Brachytherapy (BT) Service at the Gustave Roussy Institute

SP-0637: The role of the radiation technologist in the Brachytherapy (BT) Service at the Gustave Roussy Institute

Long-term tolerance of neoadjuvant docetaxel/estramustine chemotherapy in patients with high-risk localized prostate cancer treated at IGR in the GETUG 12 phase III trial.

168 Background: The GETUG 12 phase III trial tested the adjunction of docetaxel-estramustine to standard treatment in 413 patients with high-risk prostate cancer (Eur J Cancer 2012, 48: 209-17). Patients in both arms received androgen deprivation therapy (ADT) for 3 years plus local treatment (radiotherapy: 87%, median dose: 74 Gy). Pts in the chemotherapy arm also received 4 cycles of docetaxel 70mg/m2 /3weeks + estramustine 10 mg/kg/d d1-5, repeated every 3 weeks. Immediate tolerance was acceptable with only 2% of febrile neutropenia and no toxic deaths. As the long-term impact of chemotherapy in this setting is unknown, long-term side effect assessment was undertaken in pts from GETUG 12 who were treated at the Institut Gustave Roussy (n=81). Methods: After pts had completed the planned 3 years of ADT, they were followed-up every 6 months. Data on weight, sexual function, serum testosterone, and cardiac complications were obtained prospectively, in parallel with efficacy data. Pts requiring salvage therapy for cancer progression were censored in this analysis. Results: The median follow-up is 71.6 months (range: 36- 108 months). The main long-term side effects are listed in the table below. 4 (4.9%) and 1(1.2%) cardiovascular events occurred in the ADT and the ADT + chemotherapy arm, respectively. Conclusions: Docetaxel-estramustine chemotherapy had no adverse long-term impact on serum testosterone, weight, and sexual function in patients with high-risk localized prostate cancer treated with ADT and radiotherapy. [Table: see text]