Jérôme Dauba

Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial.

BACKGROUND Platinum-based doublet chemotherapy is recommended to treat advanced non-small-cell lung cancer (NSCLC) in fit, non-elderly adults, but monotherapy is recommended for patients older than 70 years. We compared a carboplatin and paclitaxel doublet chemotherapy regimen with monotherapy in elderly patients with advanced NSCLC. METHODS In this multicentre, open-label, phase 3, randomised trial we recruited patients aged 70-89 years with locally advanced or metastatic NSCLC and WHO performance status scores of 0-2. Patients received either four cycles (3 weeks on treatment, 1 week off treatment) of carboplatin (on day 1) plus paclitaxel (on days 1, 8, and 15) or five cycles (2 weeks on treatment, 1 week off treatment) of vinorelbine or gemcitabine monotherapy. Randomisation was done centrally with the minimisation method. The primary endpoint was overall survival, and analysis was done by intention to treat. This trial is registered, number NCT00298415. FINDINGS 451 patients were enrolled. 226 were randomly assigned monotherapy and 225 doublet chemotherapy. Median age was 77 years and median follow-up was 30.3 months (range 8.6-45.2). Median overall survival was 10.3 months for doublet chemotherapy and 6.2 months for monotherapy (hazard ratio 0.64, 95% CI 0.52-0.78; p<0.0001); 1-year survival was 44.5% (95% CI 37.9-50.9) and 25.4% (19.9-31.3), respectively. Toxic effects were more frequent in the doublet chemotherapy group than in the monotherapy group (most frequent, decreased neutrophil count (108 [48.4%] vs 28 [12.4%]; asthenia 23 [10.3%] vs 13 [5.8%]). INTERPRETATION Despite increased toxic effects, platinum-based doublet chemotherapy was associated with survival benefits compared with vinorelbine or gemcitabine monotherapy in elderly patients with NSCLC. We feel that the current treatment paradigm for these patients should be reconsidered. FUNDING Intergroupe Francophone de Cancérologie Thoracique, Institut National du Cancer.

Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial

BACKGROUND Early chemotherapy might improve the overall outcomes of patients with metastatic non-castrate (ie, hormone-sensitive) prostate cancer. We investigated the effects of the addition of docetaxel to androgen-deprivation therapy (ADT) for patients with metastatic non-castrate prostate cancer. METHODS In this randomised, open-label, phase 3 study, we enrolled patients in 29 centres in France and one in Belgium. Eligible patients were older than 18 years and had histologically confirmed adenocarcinoma of the prostate and radiologically proven metastatic disease; a Karnofsky score of at least 70%; a life expectancy of at least 3 months; and adequate hepatic, haematological, and renal function. They were randomly assigned to receive to ADT (orchiectomy or luteinising hormone-releasing hormone agonists, alone or combined with non-steroidal antiandrogens) alone or in combination with docetaxel (75 mg/m(2) intravenously on the first day of each 21-day cycle; up to nine cycles). Patients were randomised in a 1:1 ratio, with dynamic minimisation to minimise imbalances in previous systemic treatment with ADT, chemotherapy for local disease or isolated rising concentration of serum prostate-specific antigen, and Glass risk groups. Patients, physicians, and data analysts were not masked to treatment allocation. The primary endpoint was overall survival. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00104715. FINDINGS Between Oct 18, 2004, and Dec 31, 2008, 192 patients were randomly allocated to receive ADT plus docetaxel and 193 to receive ADT alone. Median follow-up was 50 months (IQR 39-63). Median overall survival was 58·9 months (95% CI 50·8-69·1) in the group given ADT plus docetaxel and 54·2 months (42·2-not reached) in that given ADT alone (hazard ratio 1·01, 95% CI 0·75-1·36). 72 serious adverse events were reported in the group given ADT plus docetaxel, of which the most frequent were neutropenia (40 [21%]), febrile neutropenia (six [3%]), abnormal liver function tests (three [2%]), and neutropenia with infection (two [1%]). Four treatment-related deaths occurred in the ADT plus docetaxel group (two of which were neutropenia-related), after which the data monitoring committee recommended treatment with granulocyte colony-stimulating factor. After this recommendation, no further treatment-related deaths occurred. No serious adverse events were reported in the ADT alone group. INTERPRETATION Docetaxel should not be used as part of first-line treatment for patients with non-castrate metastatic prostate cancer. FUNDING French Health Ministry and Institut National du Cancer (PHRC), Sanofi-Aventis, AstraZeneca, and Amgen.

Predictors of Early Death Risk in Older Patients Treated With First-Line Chemotherapy for Cancer

PURPOSE Objective factors for making choices about the treatment of elderly patients with cancer are lacking. This investigation aimed to help physicians select appropriate treatments through the identification of factors that predict early death (< 6 months) after initiation of chemotherapy treatment. PATIENTS AND METHODS Previously untreated patients greater than 70 years of age who were scheduled for first-line chemotherapy for various types of cancer were included. Baseline abbreviated comprehensive geriatric assessment (aCGA), including the Mini-Mental State Exam, Timed Get Up and Go (GUG), Activities of Daily Living (ADL), Instrumental Activities in Daily Living (IADL), Mini Nutritional Assessment (MNA), Geriatric Depression Scale (GDS15), and comorbidities index (Cumulative Index Rating Scale-Geriatric), was carried out. Prognostic factors of early death were sought from aCGA results and traditional oncology measures. RESULTS A total of 348 patients were included across 12 centers in Southwest France (median age, 77.45 years; ratio of men to women, 1.47; advanced disease, 65%). Abnormal aCGA scores were observed for 18.1% of patients on the ADL, 73.0% of patients on the IADL, 24.1% of patients on the GUG, 19.0% of patients on the MMS, 44.0% of patients on the GDS15, and 64.9% of patients on the MNA. Advanced disease (odds ratio [OR], 3.9; 95% CI, [1.58 to 9.73]), a low MNA score (OR 2.77; 95% CI, [1.24 to 6.18]), male sex (OR, 2.40; 95% CI, [1.2 to 4.82]), and long GUG (OR, 2.55; 95% CI, [1.32 to 4.94] were associated with higher risk of early death. CONCLUSION In patients greater than 70 years of age with cancer, advanced disease, a low MNA score, and poor mobility predicted early death. We recommend that the MNA and GUG, performed by a trained nurse, be maintained as part of routine pretreatment workup in these patients to identify at-risk patients and to inform the decision-making process for chemotherapy.

Functional Decline in Older Patients With Cancer Receiving First-Line Chemotherapy

PURPOSE To determine factors associated with early functional decline during first-line chemotherapy in older patients. PATIENTS AND METHODS Patients age ≥ 70 years receiving first-line chemotherapy for cancer were prospectively considered for inclusion across 12 centers in France. Functional decline was defined as a decrease of ≥ 0.5 points on the Activities of Daily Living (ADL) scale between the beginning of chemotherapy and the second cycle. Factors associated with functional decline were sought from pretreatment abbreviated comprehensive geriatric assessment, including ADL, Instrumental ADL (IADL), Mini-Nutritional Assessment (MNA), Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS15), and Timed Get Up and Go (GUG) test, and from comorbidities (Cumulative Illness Rating Scale-Geriatrics), MAX2 index, and baseline biologic and clinical information. RESULTS Of 364 included patients, 50 experienced functional decline (16.7%; median, 0.5 points). Abnormal preadmission performance status, IADL, GDS15, MMSE, GUG, and MNA were associated with increased likelihood of functional decline (univariate analysis). In the multivariate model adjusted for baseline ADL and MAX2 index, high baseline GDS (odds ratio [OR], 2.16; 95% CI, 1.09 to 4.30; P = .03) and low IADL scores (OR, 2.87; 95% CI, 1.06 to 7.79; P = .04) were independently associated with increased risk of functional decline. CONCLUSION Our results outline associations between baseline depression, instrumental dependencies, and early functional decline during chemotherapy for older patients. ADL should be sequentially evaluated early during treatment. Baseline evaluation of GDS15 and IADL may be proposed to anticipate this event.

Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-label, phase 3 trial

BACKGROUND The combination of an anti-VEGF or an anti-EGFR-targeted monoclonal antibody with chemotherapy has shown clinical activity in patients with metastatic colorectal cancer. However, combining both anti-VEGF and anti-EGFR antibodies with chemotherapy in first-line treatment resulted in adverse outcomes. We assessed whether the combination of erlotinib, an EGFR tyrosine kinase inhibitor, with bevacizumab could increase the efficacy of maintenance therapy in patients with unresectable metastatic colorectal cancer. METHODS This randomised, open-label, phase 3 study was undertaken in 49 centres in France, Austria, and Canada. Eligible patients were aged 18-80 years with histologically confirmed, unresectable metastatic colorectal cancer, WHO performance status 0-2, had received no previous therapy for metastatic disease, and had adequate organ function. Patients without disease progression after bevacizumab-based induction therapy were randomly assigned (1:1) by a minimisation technique to bevacizumab (7·5 mg/kg every 3 weeks) or bevacizumab plus erlotinib (150 mg once daily) as maintenance therapy until progression. All patients were stratified by centre, baseline performance status, age, and number of metastatic sites. The primary endpoint was progression-free survival on maintenance therapy analysed by intention to treat. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00265824. FINDINGS Between Jan 1, 2007, and Oct 13, 2011, 700 eligible patients were enrolled; following induction treatment, patients without disease progression were randomly assigned to bevacizumab (n=228) or bevacizumab plus erlotinib (n=224). At the final analysis, median follow-up was 51·0 months (IQR 36·0-60·0) in the bevacizumab group and 48·3 months (31·5-61·0) in the bevacizumab plus erlotinib group. In the primary analysis (after 231 progression-free survival events), median progression-free survival from randomisation was 5·1 months (95% CI 4·1-5·9) in the bevacizumab plus erlotinib group compared with 6·0 months (4·6-7·9) in the bevacizumab group (stratified hazard ratio [HR] 0·79 [95% CI 0·60-1·06]; p=0·11; unstratified HR 0·76 [0·59-0·99]; p=0·043). In the final analysis, median progression-free survival from randomisation was 5·4 months (95% CI 4·3-6·2) in the bevacizumab plus erlotinib group compared with 4·9 months (4·1-5·7) in the bevacizumab group (stratified HR 0·81 [95% CI 0·66-1·01], p=0·059; unstratified HR 0·78 [0·68-0·96], p=0·019). At the final analysis, median overall survival from maintenance was 24·9 months (95% CI 21·4-28·9) in the bevacizumab plus erlotinib group and 22·1 months (19·6-26·7) in the bevacizumab group (stratified HR 0·79 [95% CI 0·63-0·99], p=0·036; unstratified HR 0·79 [0·64-0·98], p=0·035). The most frequent grade 3-4 adverse events were skin rash (47 [21%] of 220 patients in the bevacizumab plus erlotinib group vs none of 224 patients in the bevacizumab alone group), diarrhoea (21 [10%] vs two [<1%]), and asthenia (12 [5%] vs two [<1%]). INTERPRETATION Maintenance bevacizumab plus erlotinib might be a new non-chemotherapy-based maintenance option for the first-line treatment of patients with unresectable metastatic colorectal cancer after bevacizumab-based induction therapy. FUNDING GERCOR and F Hoffmann-La Roche.

Nutritional Advice in Older Patients at Risk of Malnutrition during Treatment for Chemotherapy: A Two-Year Randomized Controlled Trial

Objective We tested the effect of dietary advice dedicated to increase intake in older patients at risk for malnutrition during chemotherapy, versus usual care, on one-year mortality. Method We conducted a multicentre, open-label interventional, stratified (centre), parallel randomised controlled trial, with a 1∶1 ratio, with two-year follow-up. Patients were aged 70 years or older treated with chemotherapy for solid tumour and at risk of malnutrition (MNA, Mini Nutritional Assessment 17–23.5). Intervention consisted of diet counselling with the aim of achieving an energy intake of 30 kCal/kg body weight/d and 1.2 g protein/kg/d, by face-to-face discussion targeting the main nutritional symptoms, compared to usual care. Interviews were performed 6 times during the chemotherapy sessions for 3 to 6 months. The primary endpoint was 1-year mortality and secondary endpoints were 2-year mortality, toxicities and chemotherapy outcomes. Results Between April 2007 and March 2010 we randomised 341 patients and 336 were analysed: mean (standard deviation) age of 78.0 y (4·9), 51.2% male, mean MNA 20.2 (2.1). Distribution of cancer types was similar in the two groups; the most frequent were colon (22.4%), lymphoma (14.9%), lung (10.4%), and pancreas (17.0%). Both groups increased their dietary intake, but to a larger extent with intervention (p<0.01). At the second visit, the energy target was achieved in 57 (40.4%) patients and the protein target in 66 (46.8%) with the intervention compared respectively to 13 (13.5%) and 20 (20.8%) in the controls. Death occurred during the first year in 143 patients (42.56%), without difference according to the intervention (p = 0.79). No difference in nutritional status changes was found. Response to chemotherapy was also similar between the groups. Conclusion Early dietary counselling was efficient in increasing intake but had no beneficial effect on mortality or secondary outcomes. Cancer cachexia antianabolism may explain this lack of effect. Trial Registration ClinicalTrials.gov NCT00459589

Bevacizumab (Bev) with or without erlotinib as maintenance therapy, following induction first-line chemotherapy plus Bev, in patients (pts) with metastatic colorectal cancer (mCRC): Efficacy and safety results of the International GERCOR DREAM phase III trial.

LBA3500^ Background: Therapy targeting VEGF or EGFR demonstrated clinical activity in combination with chemotherapy (CT) in mCRC but monoclonal antibodies cannot be associated. The DREAM trial compares a maintenance therapy (MT) with bev +/- EGFR tyrosine kinase inhibitor erlotinib (E) after a first-line Bev-based induction therapy (IT) in pts with mCRC. METHODS Pts with previously untreated and unresectable mCRC were eligible. After a Bev-based IT with FOLFOX or XELOX or FOLFIRI, pts without disease progression were randomized to MT between Bev alone (Bev 7.5 mg/kg q3w; arm A) or Bev+E (B 7.5 mg/kg q3w, E 150 mg/day continuously; arm B). Pts were treated until progression or unacceptable toxicity. The primary endpoint was PFS on MT. RESULTS The study enrolled 700 pts from 01/2007 to 11/2011 in 3 countries (France, Canada, Austria). 446 (63.7%) pts were randomized for MT (arm A, N=224; arm B, N=222). Among the 446 randomized pts, IT regimen was FOLFOX-Bev in 265 pts (59.4%), XELOX-Bev in 135 pts (30.3%), and FOLFIRI-Bev in 46 pts (10.3%). Baseline characteristics of randomized pts were (arm A/B): ECOG PS 0, 60% in both arms; normal LDH level 47%/49%; normal alkaline phosphatase level 48%/50%; synchronous metastasis 83%/82%. The median no of MT cycles was 6 in both arms. With a median follow-up of 31.0 months, 327 PFS events were observed. Median MT-PFS were 4.6 m in arm A vs 5.8 m in arm B (HR 0.73 [95%CI: 0.59-0.91], P=.005). Median PFS from inclusion were 9.2 m vs 10.2 m. During MT, in arm A vs arm B, grade 3-4 diarrhea (<1% vs 9%) and grade 3 skin toxicity (0% vs 19%) were the main differences in toxicity. Severe adverse events from randomization related to B or E were 6 in arm A and 7 in arm B. Overall survival is not mature. CONCLUSIONS The addition of erlotinib to bevacizumab after induction therapy significantly improves the duration of maintenance PFS, following induction with first-line chemotherapy plus bevacizumab, in patients with unresectable metastatic colorectal cancer.

Prognostic Factors for Survival in Noncastrate Metastatic Prostate Cancer: Validation of the Glass Model and Development of a Novel Simplified Prognostic Model

BACKGROUND The Glass model developed in 2003 uses prognostic factors for noncastrate metastatic prostate cancer (NCMPC) to define subgroups with good, intermediate, and poor prognosis. OBJECTIVE To validate NCMPC risk groups in a more recently diagnosed population and to develop a more sensitive prognostic model. DESIGN, SETTING, AND PARTICIPANTS NCMPC patients were randomized to receive continuous androgen deprivation therapy (ADT) with or without docetaxel in the GETUG-15 phase 3 trial. Potential prognostic factors were recorded: age, performance status, Gleason score, hemoglobin (Hb), prostate-specific antigen, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), metastatic localization, body mass index, and pain. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS These factors were used to develop a new prognostic model using a recursive partitioning method. Before analysis, the data were split into learning and validation sets. The outcome was overall survival (OS). RESULTS AND LIMITATIONS For the 385 patients included, those with good (49%), intermediate (29%), and poor (22%) prognosis had median OS of 69.0, 46.5 and 36.6 mo (p=0.001), and 5-yr survival estimates of 60.7%, 39.4%, and 32.1%, respectively (p=0.001). The most discriminatory variables in univariate analysis were ALP, pain intensity, Hb, LDH, and bone metastases. ALP was the strongest prognostic factor in discriminating patients with good or poor prognosis. In the learning set, median OS in patients with normal and abnormal ALP was 69.1 and 33.6 mo, and 5-yr survival estimates were 62.1% and 23.2%, respectively. The hazard ratio for ALP was 3.11 and 3.13 in the learning and validation sets, respectively. The discriminatory ability of ALP (concordance [C] index 0.64, 95% confidence interval [CI] 0.58-0.71) was superior to that of the Glass risk model (C-index 0.59, 95% CI 0.52-0.66). The study limitations include the limited number of patients and low values for the C-index. CONCLUSION A new and simple prognostic model was developed for patients with NCMPC, underlying the role of normal or abnormal ALP. PATIENT SUMMARY We analyzed clinical and biological factors that could affect overall survival in noncastrate metastatic prostate cancer. We showed that normal or abnormal alkaline phosphatase at baseline might be useful in predicting survival.

Evaluation of efficacy and safety of FOLFIRI for elderly patients with gastric cancer: A first-line phase II study

OBJECTIVE Current chemotherapy protocols for gastric cancer present high toxicity. The FOLFIRI regimen has shown promising results with elderly colorectal cancer patients and for gastric cancer patients but this is the first report on elderly gastric cancer patients. DESIGN In this multicenter non-randomized phase II trial, we administered the FOLFIRI chemotherapy protocol (irinotecan [180 mg/m(2)], fluorouracil [5-FU] [400 mg/m(2)] and folinic acid 400 mg/m(2) or 200mg/m(2) of l-folinic acid) to patients aged over 70 years with locally-advanced or metastatic gastric cancer combined with Comprehensive Geriatric Assessment (CGA). Responses were assessed at 2 months. RESULTS Forty-two patients received eight cycles of the FOLFIRI regimen, with 82.5% of patients showing disease control: 10 patients (26%) showing objective (partial or complete) responses and 23 (57.5%) showing stable disease. One-year overall survival (OS) was 41.5% [95%CI 26.5-56.0] and one-year progression-free survival (PFS) was 31.8% [95%CI 18.4-46.1%]. We observed 10 Grade 3/4 hematologic toxicities with one febrile neutropenia. CGA data demonstrated that geriatric functions were not altered by treatment and that nutritional status improved over treatment. CONCLUSIONS Results show excellent disease control and relatively high survival rates with limited toxicity similar to younger patients indicating that this regimen should be considered as a possible treatment in advanced gastric cancer of the elderly.

Second-line therapy in elderly patients with advanced nonsmall cell lung cancer

There is no dedicated study on second-line treatment for elderly patients with advanced nonsmall cell lung cancer (NSCLC). We report the results on second-line erlotinib therapy from our previously published phase III study comparing single-agent therapy with platinum-based doublet (carboplatin plus paclitaxel) therapy in 451elderly patients. Erlotinib was given to patients exhibiting disease progression or experiencing excessive toxicity during first-line therapy, until further progression or unacceptable toxicity. In total, 292 (64.7%) patients received erlotinib as second-line therapy. Initial performance status 0–1, stage IV NSCLC and an Activities of Daily Living score of 6 were independent factors for receiving erlotinib. Median (95% CI) overall survival was 4 (3.2–6.7) versus 6.8 (5.0–8.3) months in the single-agent and doublet arms, respectively (p=0.089). Performance status 0–1, never having smoked, adenocarcinoma and weight loss ≤5% were favourable independent prognostic factors of survival, whereas the randomisation arm had no significant impact. Among the 292 patients who received erlotinib, 60 (20.5%) experienced grade 3–4 toxic effects, the most frequent being rash. Erlotinib as second-line therapy is feasible, leading to efficacy results similar to those obtained in a previous randomised study that was not dedicated to elderly patients, with acceptable toxicity. Erlotinib is a feasible second-line therapy in elderly patients with advanced nonsmall cell carcinoma http://ow.ly/pz6ud