Exclusive Hyperfractionated Radiation Therapy and Reduced Boost Volume for Standard-Risk Medulloblastoma: Pooled Analysis of the 2 French Multicentric Studies MSFOP98 and MSFOP 2007 and Correlation With Molecular Subgroups.

PURPOSE: Medulloblastoma has recently been characterized as a heterogeneous disease with 4 distinct molecular subgroups: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4, with a new definition of risk stratification. We report progression-free survival, overall survival, and long-term cognitive effects in children with standard-risk medulloblastoma exclusively treated with hyperfractionated radiation therapy (HFRT), reduced boost volume, and online quality control, and we explore the prognostic value of biological characteristics in this chemotherapy-naïve population. METHODS AND MATERIALS: Patients with standard-risk medulloblastoma were enrolled in 2 successive prospective multicentric studies, MSFOP 98 and MSFOP 2007, and received exclusive HFRT (36 Gy, 1 Gy/fraction twice daily) to the craniospinal axis followed by a boost at 68 Gy restricted to the tumor bed (1.5 cm margin), with online quality assurance before treatment. Patients with MYC or MYCN amplification were not excluded at the time of the study. We report progression-free survival and overall survival in the global population, and according to molecular subgroups as per World Health Organization 2016 molecular classification, and we present cognitive evaluations based on the Wechsler scale. RESULTS: Data from 114 patients included in the MSFOP 98 trial from December 1998 to October 2001 (n = 48) and in the MSFOP 2007 from October 2008 to July 2013 (n = 66) were analyzed. With a median follow-up of 16.2 (range, 6.4-19.6) years for the MSFOP 98 cohort and 6.5 (1.6-9.6) years for the MSFOP 2007 cohort, 5-year overall survival and progression-free survival in the global population were 84% (74%-89%) and 74% (65%-81%), respectively. Molecular classification was determined for 91 patients (WNT [n = 19], SHH [n = 12], and non-WNT/non-SHH [n = 60]-including group 3 [n = 9], group 4 [n = 29], and not specified [n = 22]). Our results showed more favorable outcome for the WNT-activated subgroup and a worse prognosis for SHH-activated patients. Three patients had isolated extra-central nervous system relapse. The slope of neurocognitive decline in the global population was shallower than that observed in patients with a normofractionated regimen combined with chemotherapy. CONCLUSIONS: HFRT led to a 5-year survival rate similar to other treatments combined with chemotherapy, with a reduced treatment duration of only 6 weeks. We confirm the MSFOP 98 results and the prognostic value of molecular status in patients with medulloblastoma, even in the absence of chemotherapy. Intelligence quotient was more preserved in children with medulloblastoma who received exclusive HFRT and reduced local boost, and intelligence quotient decline was delayed compared with patients receiving standard regimen. HFRT may be appropriate for patients who do not consent to or are not eligible for prospective clinical trials; for patients from developing countries for whom aplasia or ileus may be difficult to manage in a context of high cost/effectiveness constraints; and for whom shortened duration of RT may be easier to implement.

Analysis of the StoRM cohort reveals physical activity to be associated with survival in metastatic breast cancer.

Benefits of physical activity are widely demonstrated for early stage cancers but few studies have focused on metastatic disease. The purpose of this study was to determine the impact of physical activity on survival in patients with metastatic breast cancer. We conducted a secondary analysis of the national, multicentric, non-randomized, prospective cohort SNPs to Risk of Metastasis (StoRM) study. The level of physical activity was self-reported at inclusion and divided into three categories of physical activity: light level, moderate level, and vigorous level. Overall, 833 patients (56.2%) completed the physical activity questionnaire at baseline on average physical activity during the previous year: 11.6% had a light level of physical activity, 69.0% achieved moderate levels of physical activity and 19.3% reported vigorous levels of physical activity. After adjustment for confounding, physical activity was not statistically significantly associated with overall survival in the whole population. Subgroup analysis identified that both vigorous and moderate physical activity were associated with statistically significantly improved overall survival compared to light physical activity level only in the HER2 positive subgroup (HR 0.23; 95% CI 0.07-0.70, p = 0.01 and HR 0.38; 95% CI 0.15-0.96, p = 0.04). Physical activity done during the previous year was associated with survival in HER2 positive metastatic breast cancer patients. These results suggest that overall survival in metastatic breast cancer patients could be improved through physical activity which should be considered as a complementary intervention for these individuals. The study showed that moderate/vigorous levels of physical activity were associated with better overall survival, and that these associations remained statistically significant in multivariate analysis in the HER2 positive subgroup. These results have clinical relevance and justify the recommendations for physical activity interventions in metastatic breast cancer.

Axitinib in first-line for patients with metastatic papillary renal cell carcinoma: Results of the multicentre, open-label, single-arm, phase II AXIPAP trial.

INTRODUCTION: Papillary renal cell carcinoma (PRCC) represents 10%-15% of renal carcinomas. No standard treatments exist for metastatic PRCC (mPRCC) patients. Axitinib is indicated as second-line treatment in metastatic clear cell renal carcinoma, and we aim to assess the efficacy of this vascular endothelial growth factor receptor inhibitor in front line for mPRCC. METHODS: This French multicentre phase II study AXIPAP enrolled untreated mPRCC patients, with measurable disease, Eastern Cooperative Oncology Group performance status ≤ 1 and adequate organ functions. PRCC had to be confirmed by histology expert central review. Axitinib was administered orally 5 mg twice daily. Primary end-point was progression-free rate at 24 weeks (24w-PFR) by central review. RESULTS: Fifty-six patients were screened, and 44 included (13 type 1, 30 type 2 and 1 non-specified). The median follow-up was 32.0 (13.1-39.9) months. The 24w-PFR was 45.2% (95% confidence interval [CI], 32.6% to +∞), the objective response rate was 28.6% (95% CI, 15.7%-44.6%) (type 1: 7.7%; type 2: 35.7%). The overall median progression free survival was 6.6 months (95% CI, 5.5-9.2), 6.7 months (95% CI, 5.5-9.2) and 6.2 months (95% CI, 5.4-9.2) for type 1 and 2, respectively. Median overall survival was 18.9 months (95% CI, 12.8-not reached). Adverse events were as expected; grade 3-4 treatment-related adverse events were rare except hypertension (27%). CONCLUSIONS: Axitinib demonstrated encouraging efficacy in mPRCC patients, especially in type 2 PRCC. Toxicity was manageable. Axitinib appears as an interesting option for first-line treatment and to be worth further investigation in combination with immunotherapy in these patients. Expert pathology review should be recommended in this setting. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02489695.

Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): a 112-month follow-up of a phase 3, randomised trial.

BACKGROUND: Radiotherapy is the standard salvage treatment after radical prostatectomy. To date, the role of androgen deprivation therapy has not been formally shown. In this follow-up study, we aimed to update the results of the GETUG-AFU 16 trial, which assessed the efficacy of radiotherapy plus androgen suppression versus radiotherapy alone. METHODS: GETUG-AFU 16 was an open-label, multicentre, phase 3, randomised, controlled trial that enrolled men (aged ≥18 years) with Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed adenocarcinoma of the prostate (but no previous androgen suppression or pelvic radiotherapy), stage pT2, T3, or T4a (bladder neck involvement only) and pN0 or pNx according to the tumour, node, metastasis (TNM) staging system, whose prostate-specific antigen (PSA) concentration increased from 0·1 ng/mL to between 0·2 ng/mL and 2·0 ng/mL after radical prostatectomy, without evidence of clinical disease. Patients were assigned through central randomisation (1:1) to short-term androgen suppression (subcutaneous injection of 10·8 mg goserelin on the first day of irradiation and 3 months later) plus radiotherapy (3D conformal radiotherapy or intensity modulated radiotherapy of 66 Gy in 33 fractions, 5 days a week for 7 weeks) or radiotherapy alone. Randomisation was stratified using a permuted block method (block sizes of two and four) according to investigational site, radiotherapy modality, and prognosis. The primary endpoint was progression-free survival in the intention-to-treat population. This post-hoc one-shot data collection done 4 years after last data cutoff included patients who were alive at the time of the primary analysis and updated long-term patient status by including dates for first local progression, metastatic disease diagnosis, or death (if any of these had occurred) or the date of the last tumour evaluation or last PSA measurement. Survival at 120 months was reported. Late serious adverse effects were assessed. This trial is registered on ClinicalTrials.gov, NCT00423475. FINDINGS: Between Oct 19, 2006, and March 30, 2010, 743 patients were randomly assigned, 374 to radiotherapy alone and 369 to radiotherapy plus goserelin. At the time of data cutoff (March 12, 2019), the median follow-up was 112 months (IQR 102-123). The 120-month progression-free survival was 64% (95% CI 58-69) for patients treated with radiotherapy plus goserelin and 49% (43-54) for patients treated with radiotherapy alone (hazard ratio 0·54, 0·43-0·68; stratified log-rank test p<0·0001). Two cases of secondary cancer occurred since the primary analysis, but were not considered to be treatment related. No treatment-related deaths occurred. INTERPRETATION: The 120-month progression-free survival confirmed the results from the primary analysis. Salvage radiotherapy combined with short-term androgen suppression significantly reduced risk of biochemical or clinical progression and death compared with salvage radiotherapy alone. The results of the GETUG-AFU 16 trial confirm the efficacy of androgen suppression plus radiotherapy as salvage treatment in patients with increasing PSA concentration after radical prostatectomy for prostate cancer. FUNDING: The French Health ministry, AstraZeneca, la Ligue Contre le Cancer, and La Ligue de Haute-Savoie.

HEPATOFLUO: A prospective monocentric study assessing the benefits of indocyanine green (ICG) fluorescence for hepatic surgery.

BACKGROUND AND OBJECTIVES: Fluorescence imaging using indocyanine green (ICG) is undergoing extensive development. This study aimed to assess the merits of ICG in regard to hepatic surgery. METHODS: Patients with liver lesions that required a resection were eligible. They received an injection of ICG the day before the surgery. Step 1 allowed assessment of use of the medical device under surgical conditions. Steps 2 and 3 assessed the capacity of the MD to detect known tumorous lesions and to spot a predefined area of the liver following injection of ICG into the portal vein (ICGp). RESULTS: The 1st step allowed for validation of the MD use with three patients. Between 04-2013 and 04-2015, 45 pts were included (40 eligible) in steps 2 and 3. All of the tumorous lesions (95/119) exhibited fluorescence. Four new metastasis were detected in 3 pts, and two missing metastases in 1 pt. False positive were 22%. The maximal depth for detection by fluorescence was 13 mm. Injection of ICGp allowed the corresponding anatomical area to be identified in 16/20 patients. CONCLUSION: This study confirmed that intraoperative fluorescence is a helpful and relevant tool for the liver surgeon (NCT 01738217).

Patterns of locoregional failure in locally advanced non-small cell lung cancer treated with definitive conformal radiotherapy: Results from the Gating 2006 trial.

PURPOSE: To determine the patterns of locoregional failure (LRF) in patients with locally advanced non-small cell lung cancer treated with definitive radiotherapy (RT). PATIENTS AND METHODS: One hundred and fifty-four patients from the Gating 2006 prospective randomized trial were treated with conformal RT with or without respiratory motion management. For patients with a LRF as first event, treatment planning with simulation CT, pre-treatment 18FDG PET-CT and post-treatment images demonstrating recurrence were registered and analyzed. Measurable LRF was contoured (rGTV) and classified as in-field, marginal, or out-of-field. RESULTS: Median follow-up was 27.8 months. Forty-eight patients presented with LRF. One-year and 2-year locoregional disease-free survival rates were 77% (95% CI 70-83) and 72% (95% CI 64-79) respectively. 79% of the patients with LRF as first event relapsed within the RT field (55% isolated), 30% had marginal LRF component. Isolated out-of-field failure occurred in only 3% of all patients. The regions of highest FDG-uptake on pre-treatment PET-CT were located within the recurrence in 91% of patients with in-field LRF. CONCLUSION: In-field failure was the most common pattern of failure. Escalated dose RT with high-dose fractions guided by PET parameters warrants further investigation.

Utility of post-therapy brain surveillance imaging in the detection of primary central nervous system lymphoma relapse.

BACKGROUND: The optimal follow-up strategy for primary central nervous system lymphoma (PCNSL) patients after first-line therapy is unclear. The goal of this study is to determine the utility of planned brain surveillance imaging in the detection of relapse in a retrospective cohort of PCNSL patients. METHODS: Patients were consecutive PCNSL cases treated in Leon Berard Cancer Centre, Lyon, France, from 1985 to 2011. Histology was diffuse large B-cell lymphoma in 94%. Patients were treated by methotrexate (92%) and cytarabine (63%) based-chemotherapy followed by radiotherapy for 108 patients (51%). Clinical records were reviewed for details at relapse and relationship to planned imaging. The imaging follow-up strategy was performed according to each treating physicians. RESULTS: Among 209 PCNSL patients, 127 complete response patients entered in post-treatment observation and 63 (50%) subsequently relapsed. Among the 125 evaluable patients, the majority of relapses (N = 49, 80%) was asymptomatic and identified before the planned brain imaging. Surveillance imaging detected relapses before symptoms in 12 patients who entered in post-therapy observation (10%). The median number of brain imaging during the follow-up was 7 (0-13). A total of 819 MRI/CT-scan were performed leading to the detection of 12 asymptomatic relapses. The one year OS rates were 41% and 58% for symptomatic and non-symptomatic relapses, respectively (P = 0.21). CONCLUSION: The majority of PCNSL relapses occurred outside planned follow-up with no difference in patient outcome between symptomatic and asymptomatic relapses. The role of brain imaging for the detection of relapses in the follow-up of PCNSL patients remains to be clarified.

Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial.

BACKGROUND: How best to treat rising prostate-specific antigen (PSA) concentration after radical prostatectomy is an urgent clinical question. Salvage radiotherapy delays the need for more aggressive treatment such as long-term androgen suppression, but fewer than half of patients benefit from it. We aimed to establish the effect of adding short-term androgen suppression at the time of salvage radiotherapy on biochemical outcome and overall survival in men with rising PSA following radical prostatectomy. METHODS: This open-label, multicentre, phase 3, randomised controlled trial, was done in 43 French study centres. We enrolled men (aged ≥18 years) who had received previous treatment for a histologically confirmed adenocarcinoma of the prostate (but no previous androgen deprivation therapy or pelvic radiotherapy), and who had stage pT2, pT3, or pT4a (bladder neck involvement only) in patients who had rising PSA of 0·2 to less than 2·0 µg/L following radical prostatectomy, without evidence of clinical disease. Patients were randomly assigned (1:1) centrally via an interactive web response system to standard salvage radiotherapy (three-dimensional [3D] conformal radiotherapy or intensity modulated radiotherapy, of 66 Gy in 33 fractions 5 days a week for 7 weeks) or radiotherapy plus short-term androgen suppression using 10·8 mg goserelin by subcutaneous injection on the first day of irradiation and 3 months later. Randomisation was stratified using a permuted block method according to investigational site, radiotherapy modality, and prognosis. The primary endpoint was progression-free survival, analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00423475. FINDINGS: Between Oct 19, 2006, and March 30, 2010, 743 patients were randomly assigned, 374 to radiotherapy alone and 369 to radiotherapy plus goserelin. Patients assigned to radiotherapy plus goserelin were significantly more likely than patients in the radiotherapy alone group to be free of biochemical progression or clinical progression at 5 years (80% [95% CI 75-84] vs 62% [57-67]; hazard ratio [HR] 0·50, 95% CI 0·38-0·66; p<0·0001). No additional late adverse events occurred in patients receiving short-term androgen suppression compared with those who received radiotherapy alone. The most frequently occuring acute adverse events related to goserelin were hot flushes, sweating, or both (30 [8%] of 366 patients had a grade 2 or worse event; 30 patients [8%] had hot flushes and five patients [1%] had sweating in the radiotherapy plus goserelin group vs none of 372 patients in the radiotherapy alone group). Three (8%) of 366 patients had grade 3 or worse hot flushes and one patient had grade 3 or worse sweating in the radiotherapy plus goserelin group versus none of 372 patients in the radiotherapy alone group. The most common late adverse events of grade 3 or worse were genitourinary events (29 [8%] in the radiotherapy alone group vs 26 [7%] in the radiotherapy plus goserelin group) and sexual disorders (20 [5%] vs 30 [8%]). No treatment-related deaths occurred. INTERPRETATION: Adding short-term androgen suppression to salvage radiotherapy benefits men who have had radical prostatectomy and whose PSA rises after a postsurgical period when it is undetectable. Radiotherapy combined with short-term androgen suppression could be considered as a reasonable option in this population. FUNDING: French Ministry of Health, AstraZeneca, and La Ligue Contre le Cancer.

Impact of the introduction of rituximab in first-line follicular lymphoma: a retrospective study of 247 unselected patients referred to a single institution with a long-term follow-up.

Rituximab was approved in France in 2004, following randomized trials that demonstrated efficacy in newly diagnosed high tumour burden follicular lymphoma (FL). This retrospective study compared the management and outcome of FL in unselected patients treated in a single institution before and after rituximab approval. Two hundred and forty-seven adult patients were referred with first-line FL between 1996 and 2010 and are included in this study. The 103 pre-rituximab patients comprising cohort 1 were diagnosed between January 1996 and December 2003; cohort 2 includes the 144 patients diagnosed after the approval of rituximab between January 2004 and December 2010. Baseline clinical and biological data, type of therapy, treatment response, progression-free survival (PFS) and overall survival (OS) rates were compared. There were no statistically significant differences between the two cohorts with respect to baseline clinical and disease characteristics, including FL International Prognostic Index score. The major difference between the two cohorts is the use of rituximab in first line. Seventy-one per cent of patients in cohort 2 received rituximab (19% alone, 52% with chemotherapy) versus 10% in cohort 1 (2% alone, 8% with chemotherapy; p < 0.0001). The objective response rate (ORR) was significantly higher for cohort 2 (ORR 84% compared with 72% for cohort 1; p = 0.03). The PFS and OS rates were also significantly better: 3-year PFS 72% [95% confidence interval (CI) 64-80%] versus 55% (95% CI 45-64%), p = 0.0039 and 3-year OS 98% (95% CI 94-99%) versus 83% (95% CI 74-90%), p = 0.0007. Effect of period of study is significant when using multivariate analysis on PFS and OS and lactate dehydrogenase level (PFS and OS) and age (OS). These data from everyday practice confirm the benefit for patients with FL treated in the last decade through availability of rituximab in first line used alone or in association with various chemotherapy regimens.

High Dose Thiotepa in Patients with Relapsed or Refractory Osteosarcomas: Experience of the SFCE Group.

Introduction. Osteosarcoma relapse has a poor prognosis, with less than 25% survival at 5 years. We describe the experience of the French Society of Paediatric Oncology (SFCE) with high dose (HD) thiotepa and autologous stem cell transplantation (ASCT) in 45 children with relapsed osteosarcoma. Patients and Methods. Between 1992 and 2004, 53 patients received HD thiotepa (900 mg/m(2)) followed by ASCT in 6 centres. Eight patients were excluded from analysis, and we retrospectively reviewed the clinical radiological and anatomopathological patterns of the 45 remaining patients. Results. Sixteen girls and 29 boys (median age, 15.9 years) received HD thiotepa after initial progression of metastatic disease (2), first relapse (26), and second or third relapse (17). We report 12 radiological partial responses and 9 of 31 histological complete responses. Thirty-two patients experienced further relapses, and 13 continued in complete remission after surgical resection of the residual disease. Three-year overall survival was 40%, and 3-year progression-free survival was 24%. Delay of relapse (+/- 2 years from diagnosis) was a prognostic factor (P = 0.011). No acute toxic serious adverse event occurred. Conclusion. The use of HD thiotepa and ASCT is feasible in patients with relapsed osteosarcoma. A randomized study for recurrent osteosarcoma between standard salvage chemotherapy and high dose thiotepa with stem cell rescue is ongoing.

A phase II trial of sunitinib in patients with renal cell cancer and untreated brain metastases.

BACKGROUND: The expanded access program and anecdotal cases suggested sunitinib is safe in RCC patients with BM and might have worthwhile activity. PATIENTS AND METHODS: In a phase II trial, patients with untreated BM received the standard regimen of sunitinib. The primary end point was objective response (OR) rate in BM after 2 cycles. An OR rate of 35% was prospectively defined as the minimum needed to warrant further investigation. According to Simon's optimal 2-stage design, at least 3 of the initial 15 patients had to have an OR for accrual to continue. RESULTS: Among 16 evaluable patients, 1 had a complete response outside the central nervous system (CNS). CNS disease was stabilized in 5 (31%). However, no BM showed an OR. Therefore, no further accrual took place. Median time to progression was 2.3 months and overall survival was 6.3 months. There was 1 toxic death, from peritonitis with gastric perforation. Three patients experienced at least 1 treatment-related grade 3 or greater toxicity but no neurological adverse events were attributable to sunitinib. CONCLUSION: Although tolerability was acceptable in RCC patients with previously untreated BM, sunitinib has limited efficacy in this setting.

Sorafenib and sunitinib for elderly patients with renal cell carcinoma.

BACKGROUND: Sunitinib and sorafenib are small-molecule tyrosine kinase inhibitors with known antitumor activity in advanced renal cell carcinoma. MATERIALS AND METHODS: We retrospectively assess the response and tolerance of elderly patients with renal cell carcinoma to these two agents. Data of patients aged ≥70years receiving sorafenib or sunitinib at the Centre Léon Bérard were analyzed. Forty-eight patients received sorafenib or sunitinib as a first line treatment, 8 received sorafenib followed by sunitinib and 4 received the reverse sequence. Objective responses (ORs), stable disease (SD), toxicity, overall survival (OS) and progression-free survival (PFS) were reported. RESULTS: Sorafenib and sunitinib achieved similar OR+SD rates (79% vs. 71% respectively). Median PFS was 6months in first-line sorafenib treated patients and 5months in the sunitinib group. Median OS was 16months in first-line sorafenib-treated patients and 15months in the sunitinib group. In patients receiving sorafenib followed by sunitinib, median PFS was 11.5months, and median OS was 13.1months. With the reverse sequence, median PFS was 8.1months and median OS was 15months. Treatment modifications were more frequent in sunitinib-treated patients, in first or second line (75% vs. 50%). Limitations are the retrospective design of the study and the small number of patients. CONCLUSION: First-line sunitinib and sorafenib seem equally efficient in elderly patients treated for advanced renal carcinomas, but sunitinib is less well tolerated. Sequential treatment with sorafenib followed by sunitinib seems to be better tolerated. These results should be confirmed in a larger prospective study.

Efficacy of pemetrexed as second-line therapy in advanced NSCLC after either treatment-free interval or maintenance therapy with gemcitabine or erlotinib in IFCT-GFPC 05-02 phase III study.

INTRODUCTION: Maintenance therapy in advanced non-small-cell lung cancer (NSCLC) might lead to resistance to subsequent treatments. IFCT-GFPC 0502 study showed a progression-free survival (PFS) benefit with gemcitabine or erlotinib maintenance compared with observation after cisplatin-gemcitabine chemotherapy. The trial included a pre-defined pemetrexed second-line therapy, allowing post-hoc assessment of its efficacy according to previous maintenance treatment or treatment-free interval. METHODS: Stage IIIB/IV NSCLC patients were randomized after four cycles of cisplatin-gemcitabine chemotherapy to either observation or to receive maintenance therapy with gemcitabine or erlotinib. Pemetrexed was given as second-line treatment on disease progression in all arms. PFS and overall survival (OS) were assessed from the beginning of pemetrexed therapy according to randomization arm. RESULTS: Of the 464 randomized patients, 360 (78 %) received second-line pemetrexed (130 [84%], 114 [74%], and 116 [75%] in observation, gemcitabine, and erlotinib arm, respectively). Median number of pemetrexed cycles was 3 (1-40) in all arms. Median PFS did not differ between gemcitabine and observation arms (4.2 versus 3.9 months, hazard ratio [HR] [95% confidence interval [CI] 0.81 [0.62-1.06]) or between erlotinib and observation arms (4.2 versus 3.9 months, HR 0.83 [0.64-1.09]). OS data showed a non-significant improvement with gemcitabine arm versus observation arm (8.3 versus 7.5 months, HR 0.81 [0.61-1.07]) or erlotinib arm versus observation arm (9.1 versus 7.5 months, HR 0.80 [0.61-1.05]). Results were similar for non-squamous patients. Grade 3 to 4 treatment-related adverse events (AEs) were comparable in all arms. CONCLUSIONS: Maintenance therapy with gemcitabine continuation or erlotinib does not seem to impair efficacy of second-line pemetrexed comparatively to administration after a treatment-free interval.

Neoadjuvant TPF in locally advanced head and neck cancer can be followed by radiotherapy combined with cisplatin or cetuximab: a study of 157 patients.

Neoadjuvant TPF (docetaxel, cisplatin, 5-fluorouracil), followed by radiotherapy or chemoradiotherapy with weekly carboplatin, increases overall survival and organ preservation. We assessed whether TPF could be used in routine practice and whether radiotherapy potentiated with cisplatin or cetuximab was feasible and could increase survival. We retrospectively reviewed 157 patients with advanced head and neck squamous cell carcinoma treated with TPF in four French institutions between May 2005 and March 2009. After induction, operable patients had undergone surgery and were irradiated, and potentiated in some cases with cetuximab or cisplatin. Most patients (79%) had been treated with organ preservation strategies. The two most common sites were the hypopharynx (34%) and the oropharynx (30%). The response rate to TPF was 84%, including 26% with a complete response. Radiotherapy had been provided to 144 (92%) patients (of whom 17 had received radiotherapy alone, 46 had received q3w cisplatin, 30 had received q1w cisplatin, and 37 had received cetuximab). Potentiation had been achieved as planned in 59, 63, and 62% of patients treated with q3w cisplatin, q1w cisplatin, and cetuximab, respectively. After a median follow-up of 39.9 months, the median overall survival was 43 months. No significant difference was observed in progression-free survival or overall survival according to the type of potentiation. This study confirms the efficacy and tolerability of TPF induction, followed by chemoradiation, with outcomes similar to those for patients irradiated without induction. The best potentiation of radiotherapy after induction has not yet been determined.

Clinical experience of bendamustine in relapsed or refractory Hodgkin lymphoma: a retrospective analysis of the French compassionate use program in 28 patients.

Limited data support the use of bendamustine in Hodgkin lymphoma (HL). This retrospective study evaluated the efficacy and toxicity of bendamustine in 28 patients with refractory HL or relapsed HL after autologous stem cell transplant (ASCT) used as part of a compassionate use program. The median number of therapies before bendamustine was 5 (3-8). ASCT and non-myeloablative allogeneic transplant were previously performed for 25 and six patients, respectively. The median number of bendamustine cycles administered was 3 (1-12). The objective response rate was 50% with complete response (CR) in 29% of patients. The median progression-free survival was 5.7 months, and 10.2 months in patients with CR. During the first six cycles, two patients had a febrile neutropenia and four patients had grade 3-4 thrombocytopenia. Bendamustine was effective in these highly pretreated patients with HL. It might be used earlier in the treatment strategy of HL and in combination with other active drugs.

Prognostic value of serum CA9 in patients with metastatic clear cell renal cell carcinoma under targeted therapy.

AIM: Carbonic anhydrase 9 (CA9) has been found to be one of most powerful biomarkers for clear-cell renal cell carcinoma (RCC). The serum CA9 is detectable. The aim of this study was to evaluate the potential prognostic role of serum CA9 in patients with metastatic clear-cell RCC patients under targeted therapy. PATIENTS AND METHODS: Serum samples came from the randomized phase 2 TORAVA trial. All patients received a targeted therapy (arm A designed as experimental group: temsirolimus and bevacizumab combination; arm B: sunitinib; arm C: interferon-alfa and bevacizumab). Seventy cases of metastatic clear-cell RCC were analyzed. There were 49 males and 21 females. The age ranged from 33.5 to 79.1 years with a median of 61.2 years. Serum samples were collected before treatment. Serum CA9 was quantified by enzyme-linked immunosorbent assay (ELISA). The correlation of the serum CA9 levels with the clinical parameters, treatment response and overall survival was analyzed. Overall survival estimates were calculated using the Kaplan-Meier method and compared by the log-rank test. RESULTS: Serum concentrations of CA9 ranged between 0 and 897.3 pg/ml, with an average of 94.4±176.6 pg/ml. There was no association between serum CA9 and clinical parameters such as Eastern Cooperative Oncology Group (ECOG) Performance Status (p=0.367) or Motzer classification (p=0.431). The serum CA9 levels were lower in the response group (64.7±104.7 pg/ml) than the no-response group (108.2±203.8 pg/ml), but the difference was not statisticlly significant (p=0.366). For the patient group overall, the Kaplan-Meier survival curve showed that high serum CA9 levels were significantly associated with shorter overall survival (hazard ratio=2.65, 95% confidence interval=1.19-5.92, log-rank test p=0.0136). For the major group of patients treated with temsirolimus and bevacizumab, the Kaplan-Meier survival curve showed that high serum CA9 levels were significantly associated with shorter overall survival (p=0.0006). CONCLUSION: Serum CA9 levels may be of clinical interest to predict the outcome for patients under targeted therapy for metastatic clear-cell RCC. CA9 may be used to select patients with metastatic clear cell RCC for clinical trials.

Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer.

PURPOSE: This phase III study investigated whether continuation maintenance with gemcitabine or switch maintenance with erlotinib improves clinical outcome compared with observation in patients with advanced non-small-cell lung cancer (NSCLC) whose disease was controlled after cisplatin-gemcitabine induction chemotherapy. PATIENTS AND METHODS: Four hundred sixty-four patients with stage IIIB/IV NSCLC without tumor progression after four cycles of cisplatin-gemcitabine were randomly assigned to observation or to gemcitabine (1,250 mg/m(2) days 1 and 8 of a 3-week cycle) or daily erlotinib (150 mg/day) study arms. On disease progression, patients in all three arms received pemetrexed (500 mg/m(2) once every 21 days) as predefined second-line therapy. The primary end point was progression-free survival (PFS). RESULTS: PFS was significantly prolonged by gemcitabine (median, 3.8 v 1.9 months; hazard ratio [HR], 0.56; 95% CI, 0.44 to 0.72; log-rank P < .001) and erlotinib (median, 2.9 v 1.9 months; HR, 0.69; 95% CI, 0.54 to 0.88; log-rank P = .003) versus observation; this benefit was consistent across all clinical subgroups. Both maintenance strategies resulted in a nonsignificant improvement in overall survival (OS); patients who received second-line pemetrexed or with a performance status of 0 appeared to derive greater benefit. Exploratory analysis showed that magnitude of response to induction chemotherapy may affect the OS benefit as a result of gemcitabine maintenance. Maintenance gemcitabine and erlotinib were well tolerated with no unexpected adverse events. CONCLUSION: Gemcitabine continuation maintenance or erlotinib switch maintenance significantly reduces disease progression in patients with advanced NSCLC treated with cisplatin-gemcitabine as first-line chemotherapy. Response to induction chemotherapy may affect OS only for continuation maintenance.

Results of combined treatment of anaplastic thyroid carcinoma (ATC).

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is among the most aggressive human malignancies. It is associated with a high rate of local recurrence and with poor prognosis. METHODS: We retrospectively reviewed 44 consecutive patients treated between 1996 and 2010 at Leon Berard Cancer Centre, Lyon, France. The combined treatment strategy derived from the one developed at the Institut Gustave Roussy included total thyroidectomy and cervical lymph-node dissection, when feasible, combined with 2 cycles of doxorubicin (60 mg/m2) and cisplatin (100 mg/m2) Q3W, hyperfractionated (1.2 Gy twice daily) radiation to the neck and upper mediastinum (46-50 Gy), and then four cycles of doxorubicin-cisplatin. RESULTS: Thirty-five patients received the three-phase combined treatment. Complete response after treatment was achieved in 14/44 patients (31.8%). Eight patients had a partial response (18.2%). Twenty-two (50%) had progressive disease. All patients with metastases at diagnosis died shortly afterwards. Thirteen patients are still alive. The median survival of the entire population was 8 months. CONCLUSION: Despite the ultimately dismal prognosis of ATC, multimodality treatment significantly improves local control and appears to afford long-term survival in some patients. There is active ongoing research, and results obtained with new targeted systemic treatment appear encouraging.

Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial.

BACKGROUND: Combining targeted treatments for renal cell carcinoma has been suggested as a possible method to improve treatment efficacy. We aimed to assess the potential synergistic or additive effect of the combination of bevacizumab, directed against the VEGF receptor, and temsirolimus, an mTOR inhibitor, in metastatic renal cell carcinoma. METHODS: TORAVA was an open-label, multicentre randomised phase 2 study undertaken in 24 centres in France. Patients aged 18 years or older who had untreated metastatic renal cell carcinoma were randomly assigned (2:1:1) to receive the combination of bevacizumab (10 mg/kg every 2 weeks) and temsirolimus (25 mg weekly; group A), or one of the standard treatments: sunitinib (50 mg/day for 4 weeks followed by 2 weeks off; group B), or the combination of interferon alfa (9 mIU three times per week) and bevacizumab (10 mg/kg every 2 weeks; group C). Randomisation was done centrally and independently from other study procedures with computer-generated permuted blocks of four and eight patients stratified by participating centre and Eastern Cooperative Oncology Group performance status. The primary endpoint was progression-free survival (PFS) at 48 weeks (four follow-up CT scans), which was expected to be above 50% in group A. Analysis was by intention to treat. The study is ongoing for long-term overall survival. This study is registered with ClinicalTrials.gov, number NCT00619268. FINDINGS: Between March 3, 2008 and May 6, 2009, 171 patients were randomly assigned: 88 to the experimental group (group A), 42 to group B, and 41 to group C. PFS at 48 weeks was 29.5% (26 of 88 patients, 95% CI 20.0-39.1) in group A, 35.7% (15 of 42, 21.2-50.2) in group B, and 61.0% (25 of 41, 46.0-75.9) in group C. Median PFS was 8.2 months (95% CI 7.0-9.6) in group A, 8.2 months (5.5-11.7) in group B, and 16.8 months (6.0-26.0) in group C. 45 (51%) of 88 patients in group A stopped treatment for reasons other than progression compared with five (12%) of 42 in group B and 15 (38%) of 40 in group C. Grade 3 or worse adverse events were reported in 68 (77%) of 88 patients in group A versus 25 (60%) of 42 in group B and 28 (70%) of 40 in group C. Serious adverse events were reported in 39 (44%) of 88, 13 (31%) of 42, and 18 (45%) of 40 patients in groups A, B, and C, respectively. INTERPRETATION: The toxicity of the temsirolimus and bevacizumab combination was much higher than anticipated and limited treatment continuation over time. Clinical activity was low compared with the benefit expected from sequential use of each targeted therapy. This combination cannot be recommended for first-line treatment in patients with metastatic renal cell carcinoma. FUNDING: French Ministry of Health and Wyeth Pharmaceuticals.

Clinical characteristics and outcome of isolated extracerebral relapses of primary central nervous system lymphoma: a case series.

There is very limited data on isolated systemic relapses of primary central nervous system lymphomas (PCNSL). We retrospectively reviewed the clinical characteristics and outcome of 10 patients with isolated systemic disease among 209 patients with PCNSL mainly treated with methotrexate-based chemotherapy (CT) with or without radiation therapy (RT). Isolated systemic relapse remained rare (4.8%, 10/209 patients). Median time from initial diagnosis to relapse was 33 months (range, 3-94). Sites of relapse were mostly extranodal. Three patients presented with early extra-cerebral (EC) relapse 3, 5 and 8 months from the beginning of initial treatment, respectively, and 7 patients had later relapses (range, 17-94 months). Treatment at relapse included surgery alone, RT alone, CT with or without radiotherapy, or CT with autologous stem cell transplantation (ASCT). Median overall survival (OS) after relapse was 15.5 months (range, 5.8-24.5) compared to 4.6 months (range, 3.6-6.5) for patients with central nervous system (CNS) relapse (p = 0.35). In conclusion, isolated systemic relapses exist but are infrequent. Early EC relapse suggests the presence of systemic disease undetectable by conventional evaluation at initial diagnosis. Patient follow-up must be prolonged because systemic relapse can occur as late as 10 years after initial diagnosis. Whether EC relapses of PCNSL have a better prognosis than CNS relapses needs to be assessed in a larger cohort.