Cetuximab versus methotrexate in first-line treatment of older, frail patients with inoperable recurrent or metastatic head and neck cancer (ELAN UNFIT): a randomised, open-label, phase 3 trial.

BACKGROUND: At present, there is no established standard treatment for frail older patients with recurrent or metastatic head and neck squamous cell carcinoma. We aimed to compare the efficacy and safety of cetuximab to those of methotrexate (the reference regimen) in this population. METHODS: This randomised, open-label, phase 3 trial was done at 20 hospitals in France. Patients aged 70 years or older, assessed as frail by the ELAN Geriatric Evaluation, with recurrent or metastatic head and neck squamous cell carcinoma in the first-line setting and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were eligible for inclusion. Patients were randomly assigned (1:1) to receive cetuximab 500 mg/m2 intravenously every 2 weeks or methotrexate 40 mg/m2 intravenously every week, with minimisation by ECOG performance status, type of disease evolution, Charlson Comorbidity Index score, serum albumin concentration, and geriatrician consultation. To avoid deterministic minimisation and assure allocation concealment, patients were allocated with a probability of 0·80 to the treatment that most reduced the imbalance. Treatment was continued until disease progression or unacceptable toxicity, whichever occurred first. The primary endpoint was failure-free survival (defined as the time from randomisation to disease progression, death, discontinuation of treatment, or loss of 2 or more points on the Activities in Daily Living scale, whichever occurred first) and was analysed in the intention-to-treat population. 151 failures expected out of 164 patients were required to detect a hazard ratio (HR) of 0·625 with 0·05 alpha error, with 80% power. A futility interim analysis was planned when approximately 80 failures were observed, based on failure-free survival. Safety analyses included all patients who received at least one dose of the study drug. This study is registered on ClinicalTrials.gov (NCT01884623) and was stopped for futility after the interim analysis. FINDINGS: Between Nov 7, 2013, and April 23, 2018, 82 patients were enrolled (41 to the cetuximab group and 41 to the methotrexate group); 60 (73%) were male, 37 (45%) were aged 80 years or older, 35 (43%) had an ECOG performance status of 2, and 36 (44%) had metastatic disease. Enrolment was stopped for futility at the interim analysis. At the final analysis, median follow-up was 43·3 months (IQR 30·8-52·1). At data cutoff, all 82 patients had failure; failure-free survival did not differ significantly between the groups (median 1·4 months [95% CI 1·0-2·1] in the cetuximab group vs 1·9 months [1·1-2·6] in the methotrexate group; adjusted HR 1·03 [95% CI 0·66-1·61], p=0·89). The frequency of patients who had grade 3 or worse adverse events was 63% (26 of 41) in the cetuximab group and 73% (30 of 41) in the methotrexate group. The most common grade 3-4 adverse events in the cetuximab group were fatigue (four [10%] of 41 patients), lung infection (four [10%]), and rash acneiform (four [10%]), and those in the methotrexate group were fatigue (nine [22%] of 41), increased gamma-glutamyltransferase (seven [17%]), natraemia disorder (four [10%]), anaemia (four [10%]), leukopenia (four [10%]), and neutropenia (four [10%]). The frequency of patients who had serious adverse events was 44% (18 of 41) in the cetuximab group and 39% (16 of 41) in the methotrexate group. Four patients presented with a fatal adverse event in the cetuximab group (sepsis, decreased level of consciousness, pulmonary oedema, and death of unknown cause) as did two patients in the methotrexate group (dyspnoea and death of unknown cause). INTERPRETATION: The study showed no improvement in failure-free survival with cetuximab versus methotrexate. Patients with an ECOG performance status of 2 did not benefit from these systemic therapies. New treatment options including immunotherapy should be explored in frail older patients with recurrent or metastatic head and neck squamous cell carcinoma, after an initial geriatric evaluation, such as the ELAN Geriatric Evaluation. FUNDING: French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC and the Ligue Contre le Cancer), GEMLUC, GEFLUC, and Merck Santé. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Prevalence of Four Sarcopenia Criteria in Older Patients with Cancer, and Their Predictive Value for 6-Month Mortality: The NutriAgeCancer National Prospective Cohort Study.

Older cancer patients have an elevated risk of sarcopenia. The aim was to estimate the prevalence of four criteria for sarcopenia case finding, assessment, diagnosis, and severity determination: abnormal strength, assistance with walking, rising from a chair, climbing stairs, and falls (SARC-F), low hand-grip strength (HGS), low arm circumference (AC, a muscle mass proxy), and low physical performance (PP). Sarcopenia (low HGS and AC) and severe sarcopenia (low HGS, AC, and PP) and their predictive values for 6-month mortality were estimated in the whole population and by metastatic status. We analyzed data from the NutriAgeCancer French nationwide study of cancer patients aged ≥70 referred for geriatric assessment before anti-cancer treatment. We performed Cox proportional hazards analysis for each criterion separately and all criteria combined. Overall, 781 patients from 41 geriatric oncology clinics were included (mean age: 83.1; females: 53%; main cancer types: digestive (29%) and breast (17%); metastases: 42%). The prevalence of abnormal SARC-F, low HGS, a low AC, low PP, sarcopenia, and severe sarcopenia were, respectively, 35.5%, 44.6%, 44.7%, 35.2%, 24.5%, and 11.7%. An abnormal SARC-F and/or low HGS, sarcopenia, and severe sarcopenia were associated with 6-month mortality in patients with metastases (adjusted hazard ratios [95% confidence interval]: 2.72 [1.34-5.49], 3.16 [1.48-6.75] and 6.41 [2.5-16.5], respectively). Sarcopenia was strongly predictive of 6-month mortality in patients with metastatic cancer.

Protein intake, weight loss, dietary intervention, and worsening of quality of life in older patients during chemotherapy for cancer.

Decreased health-related quality of life (HRQoL) is common in patients with cancer. We investigated the effects of dietary intervention and baseline nutritional status on worsening of HRQoL in older patients during chemotherapy. In this randomized control trial assessing the effect on mortality of dietary advice to increase dietary intake during chemotherapy, this post hoc analysis included 155 patients with cancer at risk of malnutrition. The effects of dietary intervention, baseline Mini Nutritional Assessment item scores, weight loss, and protein and energy intake before treatment on the worsening of HRQoL (physical functioning, fatigue) and secondary outcomes (Timed Up and Go test, one-leg stance time, depressive symptoms, basic (ADL), or instrumental (IADL) activities of daily living) were analyzed by multinomial regressions. Dietary intervention increased total energy and protein intake but had no effect on any examined outcomes. Worsening of fatigue and ADL was predicted by very low protein intake (< 0.8 g kg-1 day-1) before chemotherapy (OR 3.02, 95% CI 1.22-7.46, p = 0.018 and OR 5.21, 95% CI 1.18-22.73, p = 0.029 respectively). Increase in depressive symptomatology was predicted by 5.0-9.9% weight loss before chemotherapy (OR 2.68, 95% CI 1.10-6.80, p = 0.038). Nutritional intervention to prevent HRQoL decline during chemotherapy should focus on patients with very low protein intake along with those with weight loss.

Treatment of inoperable elderly head and neck cancer patients.

PURPOSE OF REVIEW: Elderly head and neck cancer (HNC) patients are very rarely enrolled in clinical trials, and even more so in dedicated trials in curative or palliative setting. As a result, no standards of treatment exist for this population and thus, adaptation of standard treatments is commonly used. RECENT FINDINGS: The choice between a monotherapy and a platinum-cetuximab combination is based on the performance status, which is not suitable and/or sufficient to evaluate the patient ability to receive a systemic treatment combined or not with radiotherapy. The evaluation of functional age using geriatric assessment is recommended. However, access to comprehensive geriatric assessment is limited in many centers, and the choice of the type of treatment is often not based on objective and reproducible criteria. As a result, fragile elderly HNC patients may be overtreated with a risk of increased toxicity and fit patients proposed for suboptimal treatment with a risk of failure of tumor control. SUMMARY: It is therefore crucial to develop and evaluate customized treatments by enrolling elderly HNC patients in dedicated therapeutics trials, such as the ELAN (Elderly Head and Neck Cancer) studies or new approaches involving promising immunotherapies. To administer the most suitable therapy, a simple and reproducible geriatric assessment could efficiently guide practitioners.

Adverse events need for hospitalization and systemic immunosuppression in very elderly patients (over 80 years) treated with ipilimumab for metastatic melanoma.

BACKGROUND: Checkpoint inhibitors are first-line therapies in melanoma, but safety in older adults has not yet been assessed. Ipilimumab improves survival, but immunologic-related adverse events (AEs) can be threatening, and its use in elderly people raises questions. AIM: To assess safety in a cohort of very elderly patients treated with ipilimumab. METHODS: All patients over 80 years treated with ipilimumab for melanoma were retrospectively included. AE occurrence, management, and outcome, as well as response rate at week 16 and overall survival were recorded, and compared to data for a group of younger patients treated in our institution during the same period. RESULTS: In the elderly group, 23 patients were included with a median age of 82 years [80-90]. AEs amounting to 23 occurred in 15 patients (65%) with 5 grade 3 (22%) and 1 grade 5 (opportunistic infection) AEs. Corticosteroids were required for five (22%) patients, additive immunosuppressive therapy for two, hospitalization for four, and definitive interruption of ipilimumab for three. Median overall survival was 14 months. In the younger group, 29 patients were included with a median age of 58 years. AEs occurred in 15/29 (52%) with 4 grade 3 (19%) and 1 grade 4 (7%). Median OS was 17 months. CONCLUSION: Serious AEs occurred in 80 + adults at the same rate as observed in our younger patients and as previously reported in younger populations. Ipilimumab can be an option in elderly patients, as patients may benefit from therapy and safety seems to be manageable.

Chemoradiation in elderly esophageal cancer patients: rationale and design of a phase I/II multicenter study (OSAGE).

BACKGROUND: The management of elderly patients with cancer is a therapeutic challenge and a public health problem. Definitive chemoradiotherapy (CRT) is an accepted standard treatment for patients with locally advanced esophageal cancer who cannot undergo surgery. However, there are few reports regarding tolerance to CRT in elderly patients. We previously reported results for CRT in patients aged ≥75 years. Following this first phase II trial, we propose to conduct a phase I/II study to evaluate the combination of carboplatin and paclitaxel, with concurrent RT in unresectable esophageal cancer patients aged 75 years or older. METHODS/DESIGN: This prospective multicenter phase I/II study will include esophageal cancer in patients aged 75 years or older. Study procedures will consist to determinate the tolerated dose of chemotherapy (Carboplatin, paclitaxel) and of radiotherapy (41.4-45 and 50.4 Gy) in the phase I. Efficacy will be assessed using a co-primary endpoint encompassing health related quality of life and the progression-free survival in the phase II with the dose recommended of CRT in the phase I. This geriatric evaluation was defined by the French geriatric oncology group (GERICO). DISCUSSION: This trial has been designed to assess the tolerated dose of CRT in selected patient aged 75 years or older. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT02735057 . Registered on 18 March 2016.

Screening for vulnerability in older cancer patients: the ONCODAGE Prospective Multicenter Cohort Study.

BACKGROUND: Geriatric Assessment is an appropriate method for identifying older cancer patients at risk of life-threatening events during therapy. Yet, it is underused in practice, mainly because it is time- and resource-consuming. This study aims to identify the best screening tool to identify older cancer patients requiring geriatric assessment by comparing the performance of two short assessment tools the G8 and the Vulnerable Elders Survey (VES-13). PATIENTS AND METHODS: The diagnostic accuracy of the G8 and the (VES-13) were evaluated in a prospective cohort study of 1674 cancer patients accrued before treatment in 23 health care facilities. 1435 were eligible and evaluable. Outcome measures were multidimensional geriatric assessment (MGA), sensitivity (primary), specificity, negative and positive predictive values and likelihood ratios of the G8 and VES-13, and predictive factors of 1-year survival rate. RESULTS: Patient median age was 78.2 years (70-98) with a majority of females (69.8%), various types of cancer including 53.9% breast, and 75.8% Performance Status 0-1. Impaired MGA, G8, and VES-13 were 80.2%, 68.4%, and 60.2%, respectively. Mean time to complete G8 or VES-13 was about five minutes. Reproducibility of the two questionnaires was good. G8 appeared more sensitive (76.5% versus 68.7%, P =  0.0046) whereas VES-13 was more specific (74.3% versus 64.4%, P<0.0001). Abnormal G8 score (HR = 2.72), advanced stage (HR = 3.30), male sex (HR = 2.69) and poor Performance Status (HR = 3.28) were independent prognostic factors of 1-year survival. CONCLUSION: With good sensitivity and independent prognostic value on 1-year survival, the G8 questionnaire is currently one of the best screening tools available to identify older cancer patients requiring geriatric assessment, and we believe it should be implemented broadly in daily practice. Continuous research efforts should be pursued to refine the selection process of older cancer patients before potentially life-threatening therapy.

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.

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.

Agronomical factors influencing the legumin/vicilin ratio in pea (Pisum sativum L.) seeds.

BACKGROUND: Many research studies have investigated the impact of agronomical factors on the protein content of pea (Pisum sativum). This study aimed to establish if a correlation exists between protein content and legumin/vicilin (L/V) ratio in pea seeds and to identify agronomical factors that have an impact on this ratio. RESULTS: The L/V ratio was positively correlated with protein content (r = 0.58, P ≤ 0.01), but no linear regression was applicable (adjusted R(2) = 0.31). Both variety and cultivation year had a highly significant effect on the ratio (P < 0.001). The interaction between these two factors was also highly significant (P < 0.001), some varieties being less sensitive to climatic conditions than others. Cultivation location had a highly significant effect (P < 0.01). There was no interaction between variety and location. Seeding density had a highly significant effect on the ratio (P < 0.01), with a saturation effect above 60 seeds m(-2). CONCLUSION: Further studies should establish if a linear regression model can be applied to pea varieties independently. Varieties with a stable L/V ratio can prove to be useful in the food industry. Other agronomical factors (soil type and seeding density) should be considered for the production of pea seeds with a specific L/V ratio.

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.

First-line chemotherapy for metastatic breast cancer in patients ≥75 years: a retrospective single-centre analysis.

Data on chemotherapy for elderly patients with metastatic breast carcinoma (MBC) are limited. We performed a 7-year retrospective analysis of MBC patients at our institution receiving first-line chemotherapy aged ≥75 years. Of 117 patients, 103 received monotherapy (67 capecitabine, 29 vinorelbine, 5 docetaxel, 2 liposomal doxorubicin) and 14 received polychemotherapy (12 anthracycline-based, 2 vinorelbine-gemcitabine). Chemotherapy demonstrated acceptable tolerability. Median progression-free survival (PFS) and overall survival (OS) from initiation of chemotherapy were 6.2 months and 13.8 months, respectively. At 2 years, 25% of patients were alive; however, 25% died within 3 months of beginning chemotherapy. Independent prognostic factors for longer PFS were good performance status, absence of visceral disease and capecitabine treatment. Good performance status and lack of visceral disease were also significant for OS. These results suggest that palliative chemotherapy should not be systematically excluded in this setting, but should be carefully discussed as it appears to be feasible with apparent benefit in selected patients.

Impact of liposomal doxorubicin-based adjuvant chemotherapy on autonomy in women over 70 with hormone-receptor-negative breast carcinoma: A French Geriatric Oncology Group (GERICO) phase II multicentre trial.

RATIONALE: Breast cancer is a disease of ageing. Functional independence in elderly patients, measured with the Katz activities of daily living (ADL) scale, predicts overall survival and the need for welfare support. Few prospective studies have examined the feasibility of adjuvant chemotherapy and its impact on autonomy in women over 70 years of age with high-risk breast cancer. This multicentre phase II trial was designed to assess the impact of adjuvant anthracycline-based chemotherapy on these patients' autonomy. DESIGN AND METHODS: In a two-stage Fleming design, women aged ≥70 years with histologically proven hormone-receptor-negative early breast cancer and a significant risk of recurrence (pN+ or "high risk" pN0) received 4 cycles of nonpegylated liposomal doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 3 weeks postoperatively, on an outpatient basis. The primary endpoint was the change in the ADL score during chemotherapy. Secondary endpoints include comprehensive geriatric, quality-of-life and acceptability assessments, tolerability, and long-term outcome. The results for the primary endpoint and other scales at completion of adjuvant chemotherapy are reported here, while long-term follow-up is not yet complete. RESULTS: Forty patients (median age 75 [70-82]) were enrolled between February 2006 and November 2007. Chemotherapy had no deleterious impact on ADL, cognition, mental status, or the frequency of comorbidities. In contrast, the number of patients at risk of malnutrition, based on the Mini Nutritional Assessment, more than doubled between baseline and the end of chemotherapy, rising from 15% to 38%. Quality-of-life deteriorated in terms of social and role functioning, likely owing to fatigue, loss of appetite, nausea and vomiting. Treatment acceptability was good. The main adverse effect was neutropenia, 15% of the patients experiencing febrile neutropenia. No cardiac toxicity or toxic deaths occurred. CONCLUSION: This study demonstrates the feasibility of an adjuvant chemotherapy regimen combining nonpegylated liposomal doxorubicin and cyclophosphamide in fit elderly women <85 years with breast cancer. Although chemotherapy had an impact on social and role functioning, autonomy was not impaired and toxicity was acceptable. Special attention should be paid to nutritional status before and after treatment.

Management of unfit patients with unfavourable non-Hodgkin's lymphomas.

Lymphoma is a malignant disease that often occurs in elderly patients. Although many treatment options are available, comorbidities and limitations of functional reserves limit their use in frail patients. Still, because of the high sensitivity of disease to these treatments, even reduced doses and schedules may allow long-term disease control or even cure. The question that remains is how to use these treatments while controlling risks. Fortunately, both biological and clinical researches allow for progress that will help clinicians improve treatment strategies. During the last years, interest for research in the elderly with lymphoma has increased. Most of it concerned fit patients but not only. Among those, availability of specific monoclonal antibodies, which improve treatment efficiency without significantly increasing toxicity, appears as a major step forward which should be further developed. Yet, recent data has also been published on other topics including trials on frail patients and specific biological data. Early evaluation of response is also among important topics which should be scrutinized. Overall, recently published results raise hopes for future management of our patients and more is expected soon.