New Advances in Supportive Care: Chemoprotective Agents as Novel Opportunities in Geriatric Oncology.

PURPOSE OF REVIEW: To explore the effectiveness of trilaciclib and ALRN-6924 in the prevention of cancer chemotherapy-induced toxicity in older patients. New chemoprotective agents are necessary because age is the main risk factor for chemotherapy complications that account largely for the poorer outcome of cancer in the elderly. Trilaciclib and ALRN-6924 cause a reversible block of the proliferation of normal cells through cell cycle arrest (CCA). With this mechanism, they may prevent the toxicity of cycle-active cancer treatment including neutropenia, anemia, thrombocytopenia, lymphopenia, mucositis, and alopecia. RECENT FINDINGS: Myelopoietic growth factors may prevent neutropenia in the aged, but they may cause severe bone pain, may aggravate thrombocytopenia and anemia, and may cause myelodysplasia and acute leukemia as a late complication. The prevention of thrombocytopenia, anemia, mucositis, and alopecia is unsatisfactory at present. These complications may jeopardize the treatment outcome as they require a reduction of treatment dose/intensity and because many patients find the resulting symptoms intolerable. In three studies of patients with extensive disease small cell lung cancer (ES-SCLC), trilaciclib reduced the severity and duration of neutropenia and thrombocytopenia as well as the need for blood transfusions. In addition, it produced a significant expansion of T-cell clones. Trilaciclib received FDA approval for the prevention of chemotherapy-induced myelosuppression in patients with ES-SCLC. ALRN-6924 is currently studied in phase II study of ES-SCLC. In a phase IB of 38 patients, ALRN-6924 prevented myelosuppression to an extent comparable with trilaciclib. Both drugs proved as effective in patients 65 and older as they were in the younger ones. In an "ex vivo" study, ALRN-6924 protected the epithelial stem cells of hair follicles from taxanes and promised to prevent alopecia. The possibility that CCA of tumor cells may reduce the effectiveness of cycle-active chemotherapy is a major concern. For this reason, the use of trilaciclib, an inhibitor of CDK 4/6, should be limited to tumors with inactivated RB1, and the use of ALRN-6924, an inhibitor of P53, should be limited to tumors with inactivated P53. Chemotherapy-related toxicities limit dose intensity and contribute to significant morbidity and mortality in elderly cancer patients. Trilaciclib and ALRN-6924 are of particular interest to geriatric oncologists because of their novel mechanism of action. Ameliorating chemotherapy-induced toxicities holds the promise of transforming the practice of geriatric oncology by enabling chemotherapeutic regimens that are currently not feasible for this patient population. Specifically, these agents may prevent chemotherapy-induced neutropenia and thrombocytopenia, perhaps the most life-threatening complications of cytotoxic chemotherapy, thereby obviating the need for the use of rescue strategies such as hematopoietic growth factors. In addition, these agents offer the potential for broad tissue protection from other chemotherapy-related toxicities, including mucositis, diarrhea, and alopecia, which historically have been poorly managed. Importantly, by preventing a spectrum of chemotherapy-related toxicities, these agents may permit the administration of chemotherapy at full-dose intensity, prevent functional decline, and grant maintenance of resilience to older cancer patients. As a result, the successful prevention of chemotherapy-induced side effects may not only mitigate the costs of care but also improve patient outcomes and quality of life. Finally, chemoprotective strategies offer the opportunity to apply geriatric principles to clinical trials of cancer treatment. In particular, they may allow the testing of prolongation of "active life expectancy" as a major goal of clinical trials in elderly patients. They may also enable novel and more practical forms of clinical trials. By assessing the risk of chemotherapy-related toxicity with the Chemotherapy Risk Assessment Scale for High Age Patients (CRASH) or the Cancer and Aging Research Group (CARG) instruments, these agents may permit researchers to utilize patients as their own controls and endorse the approval of supportive care drugs based upon the risk profile of individual patients.

Intensive care-related loss of quality of life and autonomy at 6 months post-discharge: Does COVID-19 really make things worse?

OBJECTIVE: To compare old patients hospitalized in ICU for respiratory distress due to COVID-19 with old patients hospitalized in ICU for a non-COVID-19-related reason in terms of autonomy and quality of life. DESIGN: Comparison of two prospective multi-centric studies. SETTING: This study was based on two prospective multi-centric studies, the Senior-COVID-Rea cohort (COVID-19-diagnosed ICU-admitted patients aged over 60) and the FRAGIREA cohort (ICU-admitted patients aged over 70). PATIENTS: We included herein the patients from both cohorts who had been evaluated at day 180 after admission (ADL score and quality of life). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 93 COVID-19 patients and 185 control-ICU patients were included. Both groups were not balanced on age, body mass index, mechanical ventilation, length of ICU stay, and ADL and SAPS II scores. We modeled with ordered logistic regression the influence of COVID-19 on the quality of life and the ADL score. After adjustment on these factors, we observed COVID-19 patients were less likely to have a loss of usual activities (aOR [95% CI] 0.47 [0.23; 0.94]), a loss of mobility (aOR [95% CI] 0.30 [0.14; 0.63]), and a loss of ADL score (aOR [95% CI] 0.30 [0.14; 0.63]). On day 180, 52 (56%) COVID-19 patients presented signs of dyspnea, 37 (40%) still used analgesics, 17 (18%) used anxiolytics, and 14 (13%) used antidepressant. CONCLUSIONS: COVID-19-related ICU stay was not associated with a lower quality of life or lower autonomy compared to non-COVID-19-related ICU stay.

Changes in the Use of Comprehensive Geriatric Assessment in Clinical Trials for Older Patients with Cancer over Time.

BACKGROUND: The objective of this study was to describe the implementation of comprehensive geriatric assessment (CGA) in clinical trials dedicated to older patients before and after the creation of the International Society of Geriatric Oncology in the early 2000s. SUBJECTS, MATERIALS, AND METHODS: All phase I, II, and III trials dedicated to the treatment of cancer among older patients published between 2001 and 2004 and between 2011 and 2014 were reviewed. We considered that a CGA was performed when the authors indicated an intention to do so in the Methods section of the article. We collected each geriatric domain assessed using a validated tool even in the absence of a clear CGA, including nutritional, functional, cognitive, and psychological status, comorbidity, comedication, overmedication, social status and support, and geriatric syndromes. RESULTS: A total of 260 clinical trials dedicated to older patients were identified over the two time periods: 27 phase I, 193 phase II, and 40 phase III trials. CGA was used in 9% and 8% of phase II and III trials, respectively; it was never used in phase I trials. Performance status was reported in 67%, 79%, and 75% of phase I, II, and III trials, respectively. Functional assessment was reported in 4%, 11%, and 13% of phase I, II, and III trials, respectively. Between the two time periods, use of CGA increased from 1% to 11% (p = .0051) and assessment of functional status increased from 3% to 14% (p = .0094). CONCLUSION: The use of CGA in trials dedicated to older patients increased significantly but remained insufficient. IMPLICATIONS FOR PRACTICE: This article identifies the areas in which research efforts should be focused in order to offer physicians well-addressed clinical trials with results that can be extrapolated to daily practice.

[Prehabilitation, therapeutic innovation]. / La préhabilitation, innovation thérapeutique.

The concept of prehabilitation emerged in the United States in the 1940s to maintain the performance of American soldiers notably through good nutrition and sport. It was then a question of optimising the patient's health status in a pre-treatment situation and reducing surgical stress. The specific collaborative programme Proadapt, comprising multiprofessional expertise, was put in place for elderly patients in 2016.

Impact of geriatric assessment for the therapeutic decision-making of breast cancer: results of a French survey. AFSOS and SOFOG collaborative work.

BACKGROUND: Cancer management in the elderly is often considered as suboptimal, highly variable, and rarely evidence-based. Data are needed to understand decision-making processes in this population. MATERIALS AND METHODS: A survey was performed in France to describe decision-making in gynaecologic patients over 70. It followed a three-step method: (1) 101 representative physicians questioned about treatment decision criteria; (2) simplified individual data were collected; (3) as well as detailed data patients receiving chemotherapy. This analysis refers to breast cancer subgroup of patients. RESULTS: Main decision criteria were performance status, comorbidities, and renal function. In adjuvant setting, the main concern was life expectancy, whereas it was quality of life in metastatic setting. Of the 631 patients entered in the simplified analysis, 41% had been evaluated by a geriatrician, 67% received chemotherapy. In the detailed analysis, patients older than 75 were more likely to receive a monochemotherapy and to be treated with weekly/divided dose. In adjuvant setting, respectively, 19, 55, and 26% of the patients were treated with regimen validated in the elderly, validated in a younger population, and not validated. A G-CSF was prescribed in 48% of the patients, as primary prophylaxis in 78 and in 41% of patients with a risk of febrile neutropenia < 10%. CONCLUSION: Geriatric covariates become an increasing concern in the decision-making process. This survey also suggests an insufficient use of validated chemotherapy regimens. To date, age remains a risk factor for heterogeneity in oncologic practice justifying a persistent effort for elaborating and disclosing specific recommendations.

Is There an Age Threshold for Holding Off on Testing Novel Therapies?

PURPOSE OF REVIEW: We will review the reasons that explain the poor accrual of elderly patients to clinical trials, then we will discuss the relevance of an age threshold for holding off on testing novel therapies. RECENT FINDINGS: Little progress has been made in enrolling elderly patients in clinical trials. Reasons to hold off on testing novel therapies in elderly patients are mainly explained by exclusion criteria and industrials' reluctance to include elderly patients for fear of negative results. No age threshold should exist for testing novel therapies as long as well-designed clinical trials are developed and requested by regulatory authorities. Furthermore, clinical trials assessing novel anticancer therapies such as targeted therapies or immune checkpoint inhibitors should be developed in elderly patients regardless of age as these therapies may present a favorable benefit-risk profile compared to chemotherapy which is often more toxic and at risk of geriatric deconditioning.

Toxicity of Cancer Therapies in Older Patients.

PURPOSE OF THE REVIEW: In clinical practice, older patients are often undertreated due to underrepresentation in clinical trials and fear of toxicity. Our objective was therefore to review toxicities that are specific to older cancer patients, to review risk factors in order to help physicians guide their decisions, and to review interventions that can be implemented in routine clinical practice to prevent toxicity induced by cancer therapies. RECENT FINDINGS: On the whole, reviews report similar number and frequency as well as similar grade 3 or 4 adverse events between subjects older and younger than 65 years. Yet patients included in clinical trials are often not representative of real-life patients and are often fit older cancer patients. Moreover, tolerance to the additive impact of multiple adverse effects is different between older and younger patients. And specific symptoms such as stomatitis may cause a series of consequences such as dehydration, denutrition, renal insufficiency, and adverse events of renally excreted drugs. Older patients are at high risk of toxicity due to many factors but mainly due to the prevalence of frailty in this population that has been estimated to be around 40% increasing the risk of chemotherapy intolerance. As a consequence, interventions must be implemented according to altered domains of comprehensive geriatric assessment in order to improve anticancer tolerance. These interventions are reviewed here.

Age Nutrition Chirugie (ANC) study: impact of a geriatric intervention on the screening and management of undernutrition in elderly patients operated on for colon cancer, a stepped wedge controlled trial.

BACKGROUND: Undernutrition prior to major abdominal surgery is frequent and increases morbidity and mortality, especially in older patients. The management of undernutrition reduces postoperative complications. Nutritional management should be a priority in patient care during the preoperative period. However undernutrition is rarely detected and the guidelines are infrequently followed. Preoperative undernutrition screening should allow a better implementation of the guidelines. METHODS/DESIGN: The ANC ("Age Nutrition Chirurgie") study is an interventional, comparative, prospective, multicenter, randomized protocol based on the stepped wedge trial design. For the intervention, the surgeon will inform the patient of the establishment of a systematic preoperative geriatric assessment that will allow the preoperative diagnosis of the nutritional status and the implementation of an adjusted nutritional support in accordance with the nutritional guidelines. The primary outcome measure is to determine the impact of the geriatric intervention on the level of perioperative nutritional management, in accordance with the current European guidelines. The implementation of the intervention in the five participating centers will be rolled-out sequentially over six time periods (every six months). Investigators must recommend that all patients aged 70 years or over and who are consulting for a surgery for a colorectal cancer should consider participating in this study. DISCUSSION: The ANC study is based on an original methodology, the stepped wedge trial design, which is appropriate for evaluating the implementation of a geriatric and nutritional assessment during the perioperative period. We describe the purpose of this geriatric intervention, which is expected to apply the ESPEN and SFNEP recommendations through the establishment of an undernutrition screening and a management program for patients with cancer. This intervention should allow a decrease in patient morbidity and mortality due to undernutrition. TRIAL REGISTRATION: This study is registered in ClinicalTrials.gov NCT02084524 on March 11, 2014 (retrospectively registered).

Prognostic factors for overall survival in elderly patients with advanced ovarian cancer treated with chemotherapy: Results of a pooled analysis of three GINECO phase II trials.

BACKGROUND: The GINECO led three multicentric prospective phase II studies, Elderly Woman Ovarian Trials 1 (EWOT1), EWOT2, and EWOT3, to evaluate the impact of geriatric covariates on the outcome of elderly patients treated with six courses of first-line chemotherapy for FIGO stage IIIIV ovarian cancer. This pooled analysis was designed to evaluate the validity of the geriatric vulnerability parameters identified in EWOT3 (Falandry et al., 2013). PATIENTS AND METHODS: From 1997 to 2011, 266 patients were recruited: 83 in EWOT1, 72 in EWOT2, and 111 in EWOT3, which evaluated respectively a 4-weekly carboplatin-cyclophosphamide regimen, a 3-weekly standard carboplatin-paclitaxel doublet and a carboplatin monotherapy. All patients were analyzed in this pooled analysis for treatment completion, toxicity, and overall survival. RESULTS: The global treatment completion rate was 73% and ranged from 68% in EWOT2 to 74% in EWOT3. Toxicities were generally manageable: neutropenia was more frequent in EWOT2 and thrombopenia in EWOT1 and EWOT3. In multivariate analysis, covariates associated with decreased survival were: being "depressed" according to the investigators' assessment, hypoalbuminemia <35g/L, and FIGO stage IV. In addition, a Hospital Anxiety and Depression Scale (HADS) score>14 and Instrumental Activities of Daily Living (IADL) score<25 confirmed a deleterious impact in the EWOT2+EWOT3 population subanalysis. CONCLUSIONS: Despite moderate heterogeneity among the studies, this pooled analysis confirmed the deleterious effects on overall survival of emotional disorders ("depressed", as assessed by investigators or the HADS score), and decreased functionality (IADL score), in addition to FIGO stage.

The biology of aging and lymphoma: a complex interplay.

The probability to develop non-Hodgkin lymphoma grows with age. The biological links between aging and lymphoma are not well described in the literature, and different hypothesis may be raised to explain this complex relationship. First, the impact of chronological age favoring the accumulation of genetic alterations can contribute to the multisteps proces of lymphomagenesis. Then, the age-related defects in cancer protection and the age-related clonal restriction in hematopoietic stem cell may also promote lymphoma development. Finally, the senescent and immunosenescence phenotype might represent a key process explaining this link. In this review, we will explore the current available clinical data and their ability to apply to age-related regulation pathways.

Open-label uncontrolled pilot study to evaluate complementary therapy with Ruta graveolens 9c in patients with advanced cancer.

BACKGROUND: Patients with advanced metastatic disease are often treated aggressively with multiple lines of chemotherapy, even in the last month of life. The benefit of such an approach remains uncertain. The objective of the study was to investigate whether Ruta graveolens 9c homeopathic medicine can improve quality of life (QoL) and tumour progression in patients with advanced cancer. MATERIAL AND METHODS: This was a single-centre, open-label, uncontrolled, pilot study. Patients (>18-years, life-expectancy ≥3 months, performance status ≤2) with locally-advanced solid tumours or metastases, previously treated with all available standard anti-cancer treatments were recruited. Oral treatment consisted of two 1-mL ampoules of Ruta graveolens (9c dilution) given daily for a minimum of 8 weeks, or until tumour and/or clinical progression. Primary outcome was QoL measured using the EORTC QLQ-C30 questionnaire. Secondary outcome measures were anxiety/depression measured using the Hospital Anxiety and Depression Scale (HADS), WHO performance status (PS), tumour progression assessed using RECIST criteria and tumour markers, survival and tolerance. RESULTS: Thirty-one patients were included (mean age: 64.3 years). Mean duration of treatment was 3.3 months (median: 2.1). QoL global health status improved significantly between baseline and week 8 (P < 0.001) and week 16 (P = 0.035), but was at the limit of significance (P = 0.057) at the end of the study. There was no significant change in anxiety/depression or PS during treatment. Ruta graveolens 9c had no obvious effect on tumour progression. Median survival was 6.7 months [95%CI: 4.8-14.9]. Ruta graveolens 9c was well-tolerated. CONCLUSION: Some patients treated with Ruta graveolens 9c had a transitory improvement in QoL, but the effectiveness of this treatment remains to be confirmed in further studies.

Real-world experience with CDK4-6 inhibition in the old and oldest old with a diagnosis of breast cancer.

This study describes characteristics, toxicity and survival in old patients with HR+/HER2-breast cancer (BC) treated with CDK4/6 inhibitors. Retrospective observational study that included patients ≥ 75 years with HR+/HER2-BC treated with CDK4/6 inhibitors between 2017 and 2021. Patients' general and cancer-related data were collected. Comprehensive Geriatric Assessment scales were gathered. Adverse events reported before each cycle were included. At the end of the follow-up period, mortality was retrospectively registered from medical records. All 19 patients (94.7% women, median age 77.9 ± 10.1) were at risk of frailty (G8 ≤ 14) and malnutrition (MNA-SF ≤ 11). Most were independent (52.7% Lawton ≥ 6), had no cognitive impairment (89.5%, MMSE ≥ 24), poor physical performance (70%, SPPB < 8; 62.5% TUG ≥ 12'') and polypharmacy (72.2%). Almost half had stage IV disease (47.1%). Palbociclib+letrozole was the most frequently prescribed treatment (36.8%). All patients developed some toxicity (94.7% hematologic, 36.8% renal) but except one, grade ≤ 2. Over the 42-month follow-up period, 10 reported progression and 8 died. The median survival time was 19.9 ± 3.4 months. Five months after starting treatment, the probability of survival was 73%. At 30 months, 53% of patients survived. We found a high risk of frailty and drug toxicity in this small sample. Most patients presented hematologic toxicity but to a low degree. The probability of survival increases with treatment.

Clinical impact and cost-saving analysis of a comprehensive pharmaceutical care intervention in older patients with cancer.

BACKGROUND: Hospital admission and discharge are at high risk of drug-related problems (DRPs) in older patients with cancer. This study aimed to assess the clinical and economic impact of a comprehensive pharmaceutical care intervention (RECAP) to optimize drug therapy in patients with cancer ≥75 years admitted to oncology or geriatric wards. METHOD: RECAP intervention was defined as follows: at admission and discharge, hospital pharmacists conducted comprehensive medication reconciliation and review, identified relevant DRPs and provided optimization recommendations to prescribers; at discharge, pharmacists also provided patient education and shared information with primary care providers. The impact of the intervention was assessed by the rate of implementation of recommendations by the prescribers and the evolution of polypharmacy rate; a peer review of the clinical significance of DRPs was performed by an expert panel of geriatric oncologists and pharmacists. A cost saving analysis compared cost avoided through resolution of DRPs to cost of pharmacist's time. RESULTS: From January 2019 and August 2020, 201 patients were included (median age 80 [75-97] years), 68.7% with solid tumors. DRPs requiring optimization were identified in 70.9% of patients at admission (mean 1.7 DRP/patient) and 47.7% at discharge (0.9 DRP/patient). Most pharmacist recommendations (70.8%) were followed by prescribers, allowing the correction of 1.2 DRP/patient at admission and 0.7 DRP/patient at discharge. Half of resolved DRPs were rated as clinically significant. However, polypharmacy rate was not reduced at discharge. Cost comparison showed $7.2 avoided for $1 invested, with an estimated total net benefit of $354,822 (mean $1766 per patient). CONCLUSIONS: The RECAP model significantly reduces DRPs in hospitalized older patients with cancer. The model was cost saving, confirming the value of implementing it in routine practice.

Tailoring a specific medical leadership development program for faculty members: the Lyon-Ottawa experience.

The development of leadership skills has been the topic of several position statements over recent decades, and the need of medical leaders for a specific training was emphasized during the COVID-19 crisis, to enable them to adequately collaborate with governments, populations, civic society, organizations, and universities. However, differences persist as to the way such skills are taught, at which step of training, and to whom. From these observations and building on previous experience at the University of Ottawa, a team of medical professors from Lyon (France), Ottawa, and Montreal (Canada) universities decided to develop a specific medical leadership training program dedicated to faculty members taking on leadership responsibilities. This pilot training program was based on a holistic vision of a transformation model for leadership development, the underlying principle of which is that leaders are trained by leaders. All contributors were eminent French and Canadian stakeholders. The model was adapted to French faculty members, following an inner and outer analysis of their specific needs, both contextual and related to their time constraints. This pilot program, which included 10 faculty members from Lyon, was selected to favor interactivity and confidence in older to favor long-term collaborations between them and contribute to institutional changes from the inner; it combined several educational methods mixing interactive plenary sessions and simulation exercises during onescholar year. All the participants completed the program and expressed global satisfaction with it, validating its acceptability by the target. Future work will aim to develop the program, integrate evaluation criteria, and transform it into a graduating training.

Feasibility of a screening and prevention procedure for risks associated with dysphagia in older patients in geriatric units: the DYSPHAGING pilot study protocol.

BACKGROUND: Dysphagia, particularly sarcopenic dysphagia, is frequent in frail older patients. Sarcopenic dysphagia is a swallowing disorder caused by sarcopenia, corresponding to a loss of muscle mass and strength. It frequently leads to inhalation and to the decrease of food intake, leading the patient to enter a vicious circle of chronic malnutrition and frailty. The awareness of the major health impacts of sarcopenic dysphagia is recent, explaining a low rate of screening in the population at risk. In this context, methods of prevention, evaluation and intervention of sarcopenic dysphagia adapted to the most at-risk population are necessary. METHODS: The DYSPHAGING (dysphagia & aging) pilot study is a prospective, multicentre, non-comparative study aiming to estimate the feasibility of an intervention on allied health professionals using the DYSPHAGING educational sheet designed to implement a two-step procedure 'screen-prevent' to mitigate swallowing disorders related to sarcopenic dysphagia. After obtaining oral consent, patients are screened using Eating Assessment Tool-10 Score. In case of a score≥2, procedures including positional manoeuvres during mealtimes, food and texture adaptation should be implemented. The primary endpoint of the study is the feasibility of this two-step procedure (screening-prevention measures) in the first 3 days after patient's consent.The study will include 102 patients, with an expected 10% rate of non-analysable patients. Participants will be recruited from acute geriatric wards, rehabilitation centres and long-term care units, with the hypothesis to reach a feasibility rate of 50% and reject a rate lower than 35%. ETHICS AND DISSEMINATION: The study protocol was approved according to French legislation (CPP Ile-de-France VII) on 15 February 2023. The results of the primary and secondary objectives will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05734586.

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.

Adapted EXTREME regimen in the first-line treatment of fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (ELAN-FIT): a multicentre, single-arm, phase 2 trial.

BACKGROUND: A standard treatment for fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) is yet to be established. In the previous EXTREME trial, few older patients were included. We aimed to evaluate the efficacy and tolerance of an adapted EXTREME regimen in fit, older patients with recurrent or metastatic HNSCC. METHODS: This single-arm, phase 2 study was done at 22 centres in France. Eligible patients were aged 70 years or older and assessed as not frail (fit) using the ELAN Geriatric Evaluation (EGE) and had recurrent or metastatic HNSCC in the first-line setting that was not eligible for local therapy (surgery or radiotherapy), and an Eastern Cooperative Oncology Group performance status of 0-1. The adapted EXTREME regimen consisted of six cycles of fluorouracil 4000 mg/m2 on days 1-4, carboplatin with an area under the curve of 5 on day 1, and cetuximab on days 1, 8, and 15 (400 mg/m2 on cycle 1-day 1, and 250 mg/m2 subsequently), all intravenously, with cycles starting every 21 days. In patients with disease control after two to six cycles, cetuximab 500 mg/m2 was continued once every 2 weeks as maintenance therapy until disease progression or unacceptable toxicity. Granulocyte colony-stimulating factor was systematically administered and erythropoietin was recommended during chemotherapy. The study was based on the two-stage Bryant and Day design, combining efficacy and toxicity endpoints. The primary efficacy endpoint was objective response rate at week 12 after the start of treatment, assessed by central review (with an unacceptable rate of ≤15%). The primary toxicity endpoint was morbidity, defined as grade 4-5 adverse events, or cutaneous rash (grade ≥3) that required cetuximab to be discontinued, during the chemotherapy phase, or a decrease in functional autonomy (Activities of Daily Living score decrease ≥2 points from baseline) at 1 month after the end of chemotherapy (with an unacceptable morbidity rate of >40%). Analysis of the coprimary endpoints, and of safety in the chemotherapy phase, was based on the per-protocol population, defined as eligible patients who received at least one cycle of the adapted EXTREME regimen. Safety in the maintenance phase was assessed in all patients who received at least one dose of cetuximab as maintenance therapy. The study is registered with ClinicalTrials.gov, NCT01864772, and is completed. FINDINGS: Between Sept 27, 2013, and June 20, 2018, 85 patients were enrolled, of whom 78 were in the per-protocol population. 66 (85%) patients were male and 12 (15%) were female, and the median age was 75 years (IQR 72-79). The median number of chemotherapy cycles received was five (IQR 3-6). Objective response at week 12 was observed in 31 patients (40% [95% CI 30-51]) and morbidity events were observed in 24 patients (31% [22-42]). No fatal adverse events occurred. Four patients presented with a decrease in functional autonomy 1 month after the end of chemotherapy versus baseline. During chemotherapy, the most common grade 3-4 adverse events were haematological events (leukopenia [22 patients; 28%], neutropenia [20; 26%], thrombocytopenia [15; 19%], and anaemia [12; 15%]), oral mucositis (14; 18%), fatigue (11; 14%), rash acneiform (ten; 13%), and hypomagnesaemia (nine; 12%). Among 44 patients who received cetuximab during the maintenance phase, the most common grade 3-4 adverse events were hypomagnesaemia (six patients; 14%) and acneiform rash (six; 14%). INTERPRETATION: The study met its primary objectives on objective response and morbidity, and showed overall survival to be as good as in younger patients treated with standard regimens, indicating that the adapted EXTREME regimen could be used in older patients with recurrent or metastatic HNSCC who are deemed fit with use of a geriatric evaluation tool adapted to patients with head and neck cancer, such as the EGE. FUNDING: French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC, and the Ligue Contre le Cancer), Sandoz, GEFLUC, and GEMLUC. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Senotherapy, cancer, and aging.

INTRODUCTION: We aimed to highlight the effects of senotherapy on the prevention and treatment of cancer in older individuals. The aim of senotherapy is to eliminate senescent cells. These cells express the senescence-associated secretory phenotype (SASP). With production of inflammatory cytokines, growth factors, and different type of proteases, the SASP is responsible for aging-associated disability and diseases. All mammalian cells experience senescence. The main agents of aging include fibroblasts and adipose cells. Senescent tumor cells may undergo genomic reprogramming and re-enter cell cycle with a stem cell phenotype. MATERIALS AND METHODS: We conducted a Medline search for the following key words: senotherapy, senolysis, senomorphic agents. We provide a narrative review of the finding. RESULTS: Different agents may eliminate senescent cells from cell cultures and murine models. These include metformin, rapamycin, desatinib, quercitin, fisetin, ruloxitinib, and BCL2 inhibitors. A randomized controlled study of metformin in 3,000 patients aged 65-79 without glucose intolerance aiming to establish whether senotherapy may prevent or reverse disability and aging associated diseases, including cancer, is ongoing. Senotherapy prolongs the life span and decreases the incidence of cancer in experimental animal models, as well as delays and reverses disability. Senescent tumor cells are found prior to treatment and after chemotherapy and radiation. These elements may be responsible for tumor recurrence and treatment refractoriness. DISCUSSION: Senotherapy may have substantial effects on cancer management including decreased incidence and aggressiveness of cancer, improved tolerance of antineoplastic treatment, and prevention of relapse after primary treatment. Senotherapy may ameliorate several complications of cancer chemotherapy.