Older adults account for approximately 60% of new cancer diagnoses and 70% of cancer-related deaths, yet they remain consistently under-represented in clinical trials and are routinely assessed using performance status (PS) tools developed over seven decades ago. The Karnofsky Performance Status and Eastern Cooperative Oncology Group (ECOG) PS scales, while simple and widely adopted, fail to capture the multidimensional vulnerabilities that define physiologic aging. Studies show that 43%-69% of patients with good PS have geriatric assessment (GA)-identified deficits that independently predict treatment toxicity and survival. Comprehensive GA evaluates functional status, cognition, nutrition, comorbidity burden, polypharmacy, and social support-domains that PS entirely misses. Landmark randomized controlled trials, including GAP70+, GAIN, INTEGERATE, COACH, and PERI-OP, provide level 1 evidence that GA-guided interventions reduce grade 3-5 treatment toxicities by 10%-20% without affecting survival. These trials demonstrate two complementary mechanisms of benefit: treatment modification (dose attenuation and regimen selection) and intensive supportive care. Disease-specific evidence further supports GA integration, including colon, pancreatic, and lung cancers, hematologic malignancies, and surgical oncology. Practical screening tools, including the CARG score, CRASH score, Geriatric 8, and VES-13, can be completed in under 30 minutes and are feasible in routine practice. A proposed clinical algorithm integrates GA findings into treatment decision making alongside standard National Comprehensive Cancer Network, ASCO, and ECOG guidelines. Moving beyond chronologic age and PS toward an understanding of functional reserve is both an evidence-based imperative and an ethical obligation to the fastest growing and most vulnerable segment of the cancer population.

OBJECTIVE:To characterize age-related variations in germline pathogenic variants (gPVs) in patients with high-grade serous ovarian cancer (HGSOC). METHODS:Patients with HGSOC who underwent clinical tumor-normal sequencing of ≥76 genes from 1/1/2015-11/15/2022, were included. Clinical variables including age at diagnosis were collected. Logistic regression models were built to examine associations between gPV, age, and clinical variables. RESULTS:Of 1231 patients, median age at diagnosis was 63 years (range, 33-93); 163 patients (13 %) were diagnosed at age ≤ 49, 739 (60 %) between ages 50-69, and 329 (27 %) at age ≥ 70 years. gPVs were observed in 68 (42 %), 200 (27 %), and 52 patients (16 %) respectively, p < 0.001. Compared to patients diagnosed between ages 50-69, those diagnosed at age ≥ 70 were less likely to have a gPV (OR: 0.58; 95 % CI: 0.38-0.86) and those diagnosed at age ≤ 49 were more likely to have a gPV (OR: 1.78; 95 % CI: 1.18-2.68), after adjustment for genetic ancestry and NCI Comorbidity Index. Seven of 67 patients (10 %) diagnosed at age ≥ 80 years had a gPV, including 2 in OC-related genes (BRCA2, PALB2). Twelve of 21 patients (57 %) diagnosed at age ≤ 39 years had a gPV, all in OC-related genes. No differences in genetics follow-up or poly (ADP-ribose) polymerase inhibitor use were observed by age (p > 0.05). CONCLUSION:Although gPV rates varied by age with the highest rates observed in patients with early-onset OC, rates were high (≥10 %) in all age groups, with similar genetics follow-up and implementation of targeted therapies. Universal genetic testing is important for all patients with OC regardless of age.

PURPOSE:Several lines of treatment can be used sequentially in patients with metastatic colorectal cancer. We investigated the evolution of patient/tumor characteristics and their prognostic impact across treatment lines to develop an overall prognostic score (OPS). PATIENTS AND METHODS:Individual patient data from 48 randomized trials were analyzed. The end point was overall survival (from random assignment to death). Missing data were imputed. The complete data set was then separated into construction (80%) and validation sets (20%). The Cox's model was used to define risk groups for survival using the OPS. The discrimination capability was assessed in each treatment-line via bootstrapping to obtain optimism-corrected calibration and discrimination C-indices. Internal validation was done in the validation set. RESULTS:A total of 37,560 patients (26,974 in first-line [1L], 7,693 in second-line [2L], and 2,893 in third-line [3L]) were analyzed. Some clinical, biological, and molecular characteristics of patients/tumors included in therapeutic trials evolve over the lines. Seven independent prognostic variables were retained in the final multivariate model common to all lines: Eastern Cooperative Oncology Group performance status, hemoglobin, platelet count, WBC/absolute neutrophil count ratio, lactate dehydrogenase, alkaline phosphatase, and the number of metastatic sites. The OPS was used to define four patient subgroups with significantly different prognoses in 1L, 2L, and 3L, separately, with adequate C-indices: 0.65, 0.66, and 0.69 in the construction set and 0.65, 0.66, and 0.68 in the validation set, respectively. The OPS was not predictive, with 3L drugs (v placebo) or subsequent line (2L/1L or 3L/2L) extending survival in all prognostic groups. CONCLUSION:The same prognostic model using practical variables can be used before all treatment lines. The OPS could better stratify patients in future clinical trials and help to therapeutic decision in routine practice.

Programmed death-1 (PD-1) inhibitors are approved for therapy of gynecologic cancers with DNA mismatch repair deficiency (dMMR), although predictors of response remain elusive. We conducted a single-arm phase 2 study of nivolumab in 35 patients with dMMR uterine or ovarian cancers. Co-primary endpoints included objective response rate (ORR) and progression-free survival at 24 weeks (PFS24). Secondary endpoints included overall survival (OS), disease control rate (DCR), duration of response (DOR) and safety. Exploratory endpoints included biomarkers and molecular correlates of response. The ORR was 58.8% (97.5% confidence interval (CI): 40.7-100%), and the PFS24 rate was 64.7% (97.5% one-sided CI: 46.5-100%), meeting the pre-specified endpoints. The DCR was 73.5% (95% CI: 55.6-87.1%). At the median follow-up of 42.1 months (range, 8.9-59.8 months), median OS was not reached. One-year OS rate was 79% (95% CI: 60.9-89.4%). Thirty-two patients (91%) had a treatment-related adverse event (TRAE), including arthralgia (n = 10, 29%), fatigue (n = 10, 29%), pain (n = 10, 29%) and pruritis (n = 10, 29%); most were grade 1 or grade 2. Ten patients (29%) reported a grade 3 or grade 4 TRAE; no grade 5 events occurred. Exploratory analyses show that the presence of dysfunctional (CD8+PD-1+) or terminally dysfunctional (CD8+PD-1+TOX+) T cells and their interaction with programmed death ligand-1 (PD-L1)+ cells were independently associated with PFS24. PFS24 was associated with presence of MEGF8 or SETD1B somatic mutations. This trial met its co-primary endpoints (ORR and PFS24) early, and our findings highlight several genetic and tumor microenvironment parameters associated with response to PD-1 blockade in dMMR cancers, generating rationale for their validation in larger cohorts.ClinicalTrials.gov identifier: NCT03241745 .

10583 Background: Genetic testing is recommended for all patients with ovarian cancer (OC), particularly high-grade serous OC (HGSOC). However, emphasis is often placed on younger patients, and the germline landscape of elderly patients with HGSOC is not well studied. We sought to define germline pathogenic variants (gPV) in patients with HGSOC by age. Methods: Patients with HGSOC treated at our institution who underwent clinical tumor-normal sequencing from 1/1/2015 – 3/31/2022, inclusive of germline analysis of ≥76 genes were included. Clinical variables including age at diagnosis were collected. OC-related genes were defined as BRCA1, BRCA2, BRIP1, RAD51B, RAD51C, RAD51D, PALB2, ATM, MLH1, MSH2, MSH6,and PMS2. Logistic regression models were built to examine associations between presence of gPV and clinical variables. In patients with new gPV findings, rates of genetics follow-up were calculated. Results: Of 1,231 patients with HGSOC, median age at diagnosis was 63 years (range 33-93) with 163 (13%) patients diagnosed age ≤49, 739 (60%) diagnosed ages 50-69, and 329 (27%) diagnosed age ≥70 years. Age-related differences were observed in primary treatment (neoadjuvant vs. primary debulking), genetic ancestry, marital status, insurance type, and National Cancer Institute (NCI) comorbidity index, p<0.01.We observed gPV in 68/163 (42%) patients diagnosed age ≤49, 200/739 (27%) patients diagnosed ages 50-69, and 52/329 (16%) patients diagnosed age ≥70 years, p<0.001. OC-related gPV were found in 59/163 (36%) patients diagnosed age ≤49, 132/739 (18%) patients diagnosed ages 50-69, and 26/329 (7.9%) patients diagnosed age ≥70 years, p<0.001. Age was associated with gPV in univariate and multivariable (MV) models, even after adjustment for genetic ancestry and NCI comorbidity index. Compared to patients diagnosed ages 50-69 years, those diagnosed age ≥70 were less likely to have gPV (OR 0.58 95% CI 0.38-0.86) and those diagnosed at age ≤49 were more likely to have a gPV (OR 1.78 95% CI 1.18-2.68) in MV models. Among the 67 patients diagnosed age ≥80 years, 7 (10%) had gPV with only 2/7 in OC-related gPV ( BRCA2and PALB2) and the rest being of low/recessive/uncertain penetrance (N=1 FANCC,N=2 APC,N=1 BLM,N=1 CHEK2).In contrast, in the 21 patients diagnosed age ≤39 years, 12 (57%) had gPV with 2 patients having 2 gPV. All 21 patients had gPV in OC-related genes with 1 patient having both a BRCA1 and BRCA2 gPV and another having a BRCA1 and ERCC3 gPV. No differences in genetics follow-up were observed by age group in those with new gPV with 65% of patients diagnosed age ≥70 years having genetics follow-up for a new gPV. Conclusions: Although gPV vary by age in those with HGSOC with highest rates in those diagnosed younger than 50 years, rates are high (≥10%) with good genetics follow-up in all age groups. Our findings support genetic testing in all patients with EOC regardless of age given implications for treatment and family members.

We read Lee and colleagues' systematic review on geriatric assessments (GA) in cancer clinical trials [ [1] Lee W. Cheng S.J. Grant S.J. et al. Use of geriatric assessment in cancer clinical trials: a systematic review. J Geriatr Oncol. 2022; 13: 20220509https://doi.org/10.1016/j.jgo.2022.04.014 Abstract Full Text Full Text PDF Scopus (8) Google Scholar ] with great interest. This study provides a comprehensive review of how the GA has been adopted and adapted for use in existing cancer clinical trials. We wish to discuss gaps and next steps on topics highlighted by Lee et al. using recent solutions proposed during the 2021 National Academies of Sciences, Engineering, and Medicine (NASEM) workshop on improving the evidence base for older adults with cancer which brought together geriatric oncology experts from within and across the clinical research and regulatory strata (see Table 1). Table 1NASEM improving the evidence base for treatment decision making for older adults with cancer virtual workshop 2021 adapted recommendations. ⁎ Adapted from: Moderators Summaries of Issues and Solutions. Improving the Evidence Base for Treatment Decision Making for Older Adults with Cancer: A Virtual Workshop. The National Academies of Sciences, Engineering, and Medicine, 2021. ▪Optimize Eligibility oRequire implementation of modernized eligibility criteria as standard practice oUtilize standardized GA measures to design trials for vulnerable/frail older adults oInclude geriatric oncology experts on therapeutic development and study design teams oConduct separate, adequately powered studies with eligibility limited to older or frail adults (when possible) ▪Patient Preferences as Endpoints oConduct older adult-specific trials with emphasis on treatment tolerance and geriatric-focused endpoints oDevelop and validate new endpoints that better define clinical benefit in older or more frail adults ▪Innovate and Leverage Technology oIncorporate a standardized set of core GA measures (minimum data set) into all treatment trials enrolling older adults oLeverage local trial/practice sites to use web- and app-based tools for symptom assessment oExtend geroscience to the nonclinical investigation of anticancer agent efficacy and toxicity Adapted from: Moderators Summaries of Issues and Solutions. Improving the Evidence Base for Treatment Decision Making for Older Adults with Cancer: A Virtual Workshop. The National Academies of Sciences, Engineering, and Medicine, 2021. Open table in a new tab

Cancer is a disease of aging with nearly 60% of all cancer diagnoses and 70% of all cancer deaths occurring among older adults over the age of 65 years [1]. Older adults with cancer continue to be underrepresented in cancer clinical trials resulting in significant knowledge gaps regarding the management of older adults with cancer, including how to adapt and personalize conventional treatment strategies for older patients [2]. Severe and potentially life-threatening chemotherapy toxicities remain common in older adults with advanced cancer, as approximately over half of older patients experience grade 3–5 chemotherapy toxicities [3,4].

Results. We included a total of 3686 patients, with 620 patients (16.8%) >= 70 years. OS was 37.2 months in older compared to 45.0 months in younger patients (HR 1.21, 95% CI, 1.09-1.34, p < 0.001). Older patients had an increased risk of cancer-specific-death (HR 1.16, 95% CI, 1.04-1.29) as well as non-cancer related deaths (HR 2.78, 95% CI, 2.00-3.87). Median PFS was 15.1 months in older compared to 16.0 months in younger patients (HR 1.10, 95% CI, 1.00-1.20, p = 0.056). In the carboplatin/paclitaxel arm, older patients were just as likely to complete therapy and more likely to develop grade >= 2 peripheral neuropathy (35.7 vs 19.7%, p < 0.001). Risk of other toxicities remained equal between groups. Conclusions. In women with advanced EOC receiving chemotherapy, age >= 70 was associated with shorter OS and cancer specific survival. Older patients receiving carboplatin and paclitaxel reported higher rates of grade >= 2 neuropathy but were not more likely to suffer from other chemotherapy related toxicities. Clintrials.gov: NCT00011986 (c) 2023 Elsevier Inc. All rights reserved.

The field of geriatric oncology has made significant progress in recent decades, but there are still missed opportunities in important areas of research. One issue is the underrepresentation of older patients, especially those aged 75 years and older, in clinical trials. This has resulted in a lack of high-quality data for the care of this population, and the American Society of Clinical Oncology has called for an increase in the evidence base for older patients with cancer. The second missed opportunity is the chance to gather important knowledge from older patients participating in clinical trials, such as medications, social support, insurance, and financial information. These data can be easily collected and incorporated into the trial design to enhance the information available to researchers and clinicians. The third missed opportunity is the chance to robustly analyze and report clinical trial data for the benefit of geriatric oncology research. Many trials only report a median age and range, which is a disservice to both the participants and the patients who will be treated based on the study results. To advance geriatric oncology research, the necessary data need to be collected, analyzed, and reported through appropriate representation of older patients, collection of essential information, and thorough analysis and communication of results. Clinical trial design needs to include geriatric baseline parameters, and Cancer Therapy Evaluation Program (CTEP) has modified its template to include these parameters.

AbstractIntroductionIn the National University Cancer Institute, Singapore (NCIS), 2 pilot programs providing (i) surgical prehabilitation before cancer surgery and (ii) geriatric oncology support for older adults planned for chemotherapy and/or radiotherapy were merged to form the Geriatric Oncology Longitudinal End to eNd (GOLDEN) program in 2019 to support patients from the time of their cancer diagnosis, through their treatment process, to cancer survivorship.Methods and MaterialsOlder adults aged ≥65 years were enrolled in either surgical prehabilitation, the geriatric medical oncology (GO) arm, or both. All patients undergo a geriatric assessment. We assessed if patients had a change in treatment plans based on GOLDEN recommendations, and the impact on patient related outcomes.ResultsThere were 777 patients enrolled in the GOLDEN program over 2 years; 569 (73%) were enrolled in surgical prehabilitation, 308 (40%) were enrolled in the GO arm, with 100 (12.8%) enrolled in both. 56.9% were females. Median age was 73. Lower gastrointestinal (51.2%) and hepatobiliary cancers (24.1%) were the most common cancer types. 43.4% were pre-frail and 11.7% were frail. Of the 308 patients in the GO arm, 86.0% had geriatric syndromes, while 60.7% had a change in their treatment plans based on GOLDEN recommendations. 31.5% reported an improved global health status, while 38.3% maintained their global health status. 226 (73%) responded that they had benefited from the GOLDEN.ConclusionMore than half of the population was either pre-frail or frail. Amongst those in the GO arm, the majority had geriatric syndromes and had a change in their treatment plans based on GOLDEN recommendations. Majority reported either improvement or maintenance in global health status, with most feeling they have benefited from the program. Further evaluation of the longitudinal geriatric hematology-oncology program for cancer-related outcomes and sustainability should be carried out.

5041 Background: Optimal carboplatin dosing (CPRx) for patients (pts) with renal dysfunction or low creatinine (Cr) values in the setting of malnutrition and ascites is unknown. Multiple methods have been utilized to estimate Cr clearance (CrCl) but these perform differently in pts with abnormal Cr values. We sought to determine 1) the relationship between adverse events (AE) and baseline CrCl used for CPRx; 2) the effect on CPRx of using Cockcroft-Gault (CG) +/- the NCI/CTEP recommended limits (CGL), Modification of diet in renal disease (MDRD) or Jelliffe Formula (J) renal function estimates. Methods: Retrospective data were drawn from pts treated on GOG 182, a phase III trial of carboplatin doublet vs triplet or sequential doublet combinations in stage III/IV EOC. For patient safety, the protocol was amended to assign the lower limit of Cr at 0.6mg/dl for CPRx. Area under the receiver operating characteristic curve (AUC) was used to describe associations between CrClJ and various AE. Sensitivity and positive predictive values (PPV) described the AE rate in pts with CrClJ <60ml/min. CPRx for each pt was calculated using J, CG, CGL and MDRD. Results: 3830 evaluable pts had a mean age 58.7yrs, mean BMI 26.8kg/m2 and mean baseline CrClJ 81.9ml/min (range 23.4-239). The AUC statistics (range 0.52-0.64) show that the log(CrClJ) was not a good predictor of grade ≥3 AE (anemia, thrombocytopenia, febrile neutropenia, auditory, renal, metabolic, neurologic). A cutoff value of CrClJ <60 ml/min would have deemed 15% of pts treated on GOG182 ineligible. The range of PPV for the above AEs in pts with CrClJ <60 ml/min was 1.8-15%. Using CG, CGL, MDRD instead of J for CPRx would have resulted in >10% decrease in CPRx in 21%, 32% and 12% of pts, respectively. Using CG, CGL, MDRD instead of J for CPRx would have resulted in >10% increase in CPRx in 45%, 9.6% and 5.2% of pts, respectively. Conclusions: Our data do not support excluding patients with CrClJ <60ml/min from clinical trials. The new GOG guidelines replacing J with CGL affect CPRx. The clinical significance of this change with regards to toxicity, particularly in pts with abnormally low Cr values, is yet to be determined.

Older adults remain at higher risk for severe COVID-19 infection outcomes and, although the development of vaccines has changed the course of the disease, immunosenescence can result in lower vaccine immunogenicity [[1]Collier D.A. Ferreira I.A.T.M. Kotagiri P. et al.Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2.Nature. 2021; 596: 417-422Crossref PubMed Scopus (342) Google Scholar]. Older patients with solid tumours or haematologic malignancies receiving anti-cancer treatment are often immunocompromised and unable to provide an adequate immune response to COVID-19 vaccination [2Barriere J. Chamorey E. Adjtoutah Z. et al.Impaired immunogenicity of BNT162b2 anti-SARS-CoV-2 vaccine in patients treated for solid tumors.Ann Oncol. 2021; 32: 1053-1055Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 3Herishanu Y. Avivi I. Aharon A. et al.Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia.Blood. 2021; 137: 3165-3173Crossref PubMed Scopus (430) Google Scholar, 4Kuderer N.M. Choueiri T.K. Shah D.P. et al.COVID-19 and Cancer ConsortiumClinical impact of COVID-19 on patients with cancer (CCC19): a cohort study.Lancet. 2020; 395: 1907-1918Abstract Full Text Full Text PDF PubMed Scopus (1157) Google Scholar, 5Grivas P. Khaki A.R. Wise-Draper T.M. et al.Association of clinical factors and recent anticancer therapy with COVID-19 severity among patients with cancer: a report from the COVID-19 and Cancer consortium.Ann Oncol. 2021; 32: 787-800Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar], which may lead to worse COVID-19 clinical outcomes [6Dai M. Liu D. Liu M. et al.Patients with cancer appear more vulnerable to SARS-CoV-2: a multicenter study during the COVID-19 outbreak.Cancer Discov. 2020; 10: 783-791Crossref PubMed Scopus (1062) Google Scholar, 7Shah V. Ko Ko T. Zuckerman M. et al.Poor outcome and prolonged persistence of SARS-CoV-2 RNA in COVID-19 patients with haematological malignancies; King’s college hospital experience.Br J Haematol. 2020; 190: e279-e282Crossref PubMed Scopus (74) Google Scholar, 8Yang K. Sheng Y. Huang C. et al.Clinical characteristics, outcomes, and risk factors for mortality in patients with cancer and COVID-19 in Hubei, China: a multicentre, retrospective, cohort study.Lancet Oncol. 2020; 21: 904-913Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar, 9Robilotti E.V. Babady N.E. Mead P.A. et al.Determinants of COVID-19 disease severity in patients with cancer.Nat Med. 2020; 26: 1218-1223Crossref PubMed Scopus (400) Google Scholar, 10Giannakoulis V.G. Papoutsi E. Siempos I.I. Effect of cancer on clinical outcomes of patients with COVID-19: a meta-analysis of patient data.JCO Glob Oncol. 2020; 6: 799-808Crossref PubMed Scopus (128) Google Scholar]. Today, several drugs are available for the treatment of COVID-19 infection, with the best treatment option for each individual patient determined by their therapeutic indication, efficacy, availability, feasibility of administration, safety, and prevalence of infection variants. Older adults with cancer represent a vulnerable population. The impact of geriatric syndromes, comorbidities, immunosuppression, increased risk of side effects, and drug-drug interactions due to polypharmacy and/or oncological treatment, must be considered in the risk-benefit balance influencing the choice of COVID-19 treatments [[11]Elkrief A. Hennessy C. Kuderer N.M. et al.Geriatric risk factors for serious COVID-19 outcomes among older adults with cancer: a cohort study from the COVID-19 and cancer consortium.Lancet Healthy Longev. 2022; 3: e143-e152Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar]. The SIOG COVID-19 Working Group continues to advocate for the optimal management of older adults with cancer during the pandemic era. Therefore, we reviewed the data on currently available COVID-19 treatments mainly in outpatients setting and their potential use among older adults with cancer. The COVID-19 pandemic has triggered an unprecedented acceleration in drug development. Patients with mild to moderate COVID-19 infection, considered to be at higher risk for COVID-19 adverse outcomes, may benefit from different therapies. High-risk groups for SARS-CoV-2 complications and death are defined according to age, vaccination status, immune status, and the presence of risk factors for clinical progression [[12]COVID-19 Treatment Guidelines Panel Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health, 2023https://www.covid19treatmentguidelines.nih.gov/Google Scholar]. Age alone is a key risk factor, but comorbidities, often prevalent among older adults, may further increase the risk of COVID-19 disease progression and poor outcomes [[13]Battisti N.M.L. Mislang A.R. Cooper L. et al.Adapting care for older cancer patients during the COVID-19 pandemic: recommendations from the International Society of Geriatric Oncology (SIOG) COVID-19 working group.J Geriatric Oncol. 2020; 11: 1190-1198Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar]. Although older individuals may derive significant benefits from novel COVID-19 treatments, studies published to date mostly included very selected populations. Currently, therapeutic strategies for COVID-19 involve antiviral agents (often administered at early stages of the disease), steroids, and immunotherapeutic agents. For non-hospitalised adults affected by mild or moderate COVID-19 at high risk of disease progression, ritonavir-boosted nirmatrelvir or remdesivir are considered first-line treatment options [[12]COVID-19 Treatment Guidelines Panel Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health, 2023https://www.covid19treatmentguidelines.nih.gov/Google Scholar]. The protease inhibitor nirmatrelvir is combined with the strong cytochrome P450 (CYP) 3A4 inhibitor and pharmacokinetic boosting agent ritonavir. Coadministration of ritonavir is required to increase nirmatrelvir concentrations to the target therapeutic range [[14]Owen D.R. Allerton C.M.N. Anderson A.S. et al.An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for the treatment of COVID-19.Science. 2021; 374: 1586-1593Crossref PubMed Scopus (672) Google Scholar]. The Evaluation of Protease Inhibition for COVID-19 in High-Risk patients (EPIC-HR) phase 2–3 trial [[15]Hammond J. Leister-Tebbe H. Gardner A. et al.Oral nirmatrelvir for high-risk, nonhospitalized adults with COVID-19.N Engl J Med. 2022; 386: 1397-1408Crossref PubMed Scopus (703) Google Scholar] demonstrated the efficacy of oral nirmatrelvir associated to ritonavir within three days after the onset of symptoms. Authors reported an 89.1% relative risk reduction in COVID-19–related hospitalizations or deaths from any cause by day 28 compared to placebo among unvaccinated, non-hospitalised adults at high risk for progression to severe disease. In this study, 12% of the patients were aged ≥65 years and efficacy was supported by subgroup analyses (age, coexisting health conditions, etc). Fewer serious adverse events occurred in the population treated with nirmatrelvir plus ritonavir. Dysgeusia and diarrhoea are potentially dangerous events in older adults and occurred more frequently in ritonavir-boosted nirmatrelvir patients compared with placebo (6% versus 0.3% and 3% versus 2%, respectively). Ritonavir-boosted nirmatrelvir use involves a high risk of drug-drug interactions with concomitant medications that may increase the risk of toxicities. CYP3A4 inhibition occurs rapidly after initiating ritonavir, with maximum inhibition occurring within 48 h. After ritonavir is discontinued, 70% to 90% of CYP3A4 inhibition resolves within two to three days. The time to resolution of inhibition varies based on the patient's age and resolution may take longer in older adults [[12]COVID-19 Treatment Guidelines Panel Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health, 2023https://www.covid19treatmentguidelines.nih.gov/Google Scholar,[16]Katzenmaier S. Markert C. Riedel K.D. et al.Determining the time course of CYP3A inhibition by potent reversible and irreversible CYP3A inhibitors using a limited sampling strategy.Clin Pharmacol Ther. 2011; 90: 666-673Crossref PubMed Scopus (91) Google Scholar]. Ritonavir is also a well-known strong combined inhibitor of p-glycoprotein, therefore it can interact with oral anticoagulants and drug-drug interaction management is required. In this real-world series of 72 patients co-prescribed nirmatrelvir-ritonavir and an oral anticoagulant, recommended drug-drug interaction management strategies for apixaban, rivaroxaban, and warfarin seemed effective at minimizing adverse events [[17]Vazquez S.R. Wilson A.S. Witt D.M. Management of potential drug-drug interactions with nirmatrelvir-ritonavir and oral anticoagulants: a case series.J Thromb Thrombolysis. 2022; 54: 583-586Crossref PubMed Scopus (1) Google Scholar]. Also, a careful evaluation is required in older patients with cancer because of the risk of potential interactions with myelosuppressive agents and the risk of increasing concentrations of concomitant medications, including certain chemotherapeutic agents [[12]COVID-19 Treatment Guidelines Panel Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health, 2023https://www.covid19treatmentguidelines.nih.gov/Google Scholar]. Ritonavir-boosted nirmatrelvir should be used with caution in patients with pre-existing liver disease and is not recommended in the context of severe hepatic impairment. Dose reductions are also required in patients with moderate renal impairment. However, limited data are available for patients with advanced kidney disease. Regardless, older patients with cancer and renal failure are at high risk for COVID-19 morbidity and mortality and should not be excluded from treatment. Alternative antiviral options may be considered and a discussion between the physician and the patient about the potential risks and benefits of this drug is necessary prior to administering an adapted dose of nirmatrelvir/ritonavir [[18]Hiremath S. McGuinty M. Argyropoulos C. et al.Prescribing Nirmatrelvir/ritonavir for COVID-19 in advanced CKD.Clin J Am Soc Nephrol. 2022; 17: 1248-1249Google Scholar]. Intravenous remdesivir is approved for mild to moderate COVID-19 in patients at high risk of disease progression [[12]COVID-19 Treatment Guidelines Panel Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health, 2023https://www.covid19treatmentguidelines.nih.gov/Google Scholar,[19]Remdesivir Food and Drug Administration.https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214787Orig1s000lbl.pdfDate: 2020Google Scholar]. Benefits of combining dexamethasone and remdesivir have been reported in different studies, although data in older individuals are limited [ [20]Benfield T. Bodilsen J. Brieghel C. et al.Improved survival among hospitalized patients with coronavirus disease 2019 (COVID-19) treated with Remdesivir and dexamethasone. A Nationwide population-based cohort study.Clin Infect Dis. 2021; 73: 2031-2036Crossref PubMed Scopus (46) Google Scholar,[21]Wong C.K.H. Lau K.T.K. Au I.C.H. et al.Optimal timing of remdesivir initiation in hospitalized COVID-19 patients administered with dexamethasone.Clin Infect Dis. 2021; : ciab728Google Scholar]. The double blind, randomised, placebo-controlled, Adaptive COVID-19 Treatment Trial (ACTT) trial [[22]Beigel J.H. Tomashek K.M. Dodd L.E. et al.Remdesivir for the treatment of COVID-19—final report.N Engl J Med. 2020; 383: 1813-1826Crossref PubMed Scopus (4445) Google Scholar] evaluated remdesivir in unvaccinated, hospitalised adults with COVID-19. The study demonstrated a benefit on clinical recovery (7 versus 9; recovery rate ratio 1.45, 95% confidence interval [CI] 1.18–1.79) and mortality (hazard ratio [HR] for death 0.30, 95%CI 0.14–0.64) in patients requiring low-flow oxygen therapy. No significant benefit was shown in patients requiring high-flow oxygen (HFO) or non-invasive ventilation (NIV) (recovery rate ratio 1.09, 95%CI 0.76–1.57). Mean age was 58.9 years and 35% of patients were aged ≥65 years old. Half of the patients had more than two coexisting conditions, most commonly hypertension (50.2%), obesity (44.8%), and type 2 diabetes (30.3%). Only 8% (N = 80) had malignant neoplasms. The efficacy of remdesivir in hastening recovery did not vary according to prespecified age categories. Serious adverse events were similar between arms (25% versus 32%) [[22]Beigel J.H. Tomashek K.M. Dodd L.E. et al.Remdesivir for the treatment of COVID-19—final report.N Engl J Med. 2020; 383: 1813-1826Crossref PubMed Scopus (4445) Google Scholar]. A subsequent retrospective study compared survival outcomes in 34,230 patients treated with remdesivir within two days of hospitalisation versus patients who were not. In the remdesivir group, 8% of the patients were aged ≥85, 19% were 75–84, and 25% were 65–74 years old. About 8% had cancer and were immunosuppressed, 78% cardiovascular disease, 40% obesity, and 42% diabetes. Remdesivir initiation upon hospital admission was associated with improved survival [[23]Mozaffari E. Chandak A. Zhang Z. et al.Remdesivir treatment in hospitalized patients with COVID-19: a comparative analysis of in-hospital all-cause mortality in a large multicenter observational cohort.Clin Infect Dis. 2021; : ciab875Google Scholar]. Another prospective, observational study (median age 69 years) showed that among hospitalised patients affected by COVID-19 pneumonia who required oxygen supplementation, early (<5 days from symptom onset) remdesivir might reduce progression. Patients admitted within the first five days of symptom onset were older and had a higher prevalence of comorbidities and frailty [[24]Falcone M. Suardi L.R. Tiseo G. et al.Early use of remdesivir and risk of disease progression in hospitalized patients with mild to moderate COVID-19.Clin Ther. 2022; 44: 364-373Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. The phase 3, randomised, controlled, open-label DisCoVeRy trial [[25]Ader F. Bouscambert-Duchamp M. Hites M. et al.Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial.Lancet Infect Dis. 2022; 22: 209-221Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar], included unvaccinated, hospitalised patients with moderate or severe COVID-19. Although remdesivir delayed worsening of respiratory symptoms, the study showed no clinical and mortality benefit for treated patients. Median age was 64 years, 74% had one or more coexisting conditions and 8% had cancer. Remdesivir has also been tested in the ambulatory setting. The double-blind, placebo-controlled PINETREE study included non-hospitalised patients with COVID-19 at high risk for disease progression and demonstrated that three consecutive days of remdesivir resulted in a 87% relative reduction in the risk of hospitalisation or death (0.7% versus 5.3%; HR 0.13, 95%CI 0.03–0.59; p = 0.008). The study population of 562 patients included 30% aged ≥60 years, among whom 60% were affected by diabetes, 55% by obesity, and 45% by hypertension, with only 5.3% (N = 30) having a diagnosis of cancer [ [26]Gottlieb R.L. Vaca C.E. Paredes R. et al.Early remdesivir to prevent progression to severe COVID-19 in outpatients.N Engl J Med. 2022; 386: 305-315Crossref PubMed Scopus (517) Google Scholar]. Remdesivir may be associated with gastrointestinal toxicity, elevated transaminase levels, prolonged prothrombin time without change in the international normalized ratio, and hypersensitivity reactions [[19]Remdesivir Food and Drug Administration.https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214787Orig1s000lbl.pdfDate: 2020Google Scholar]. Remdesivir is available in two formulations (concentrated solution and lyophilized powder) containing sulfobutylether beta-cyclodextrin sodium (SBECD), which is eliminated by the kidneys and may result in toxicity in patients with renal impairment. Importantly, while some clinical trials excluded patients with an estimated glomerular filtration rate (eGFR) <50 mL/min, other studies involved an eGFR cutoff of <30 mL/min [[27]Pettit N.N. Pisano J. Nguyen C.T. et al.Remdesivir use in the setting of severe renal impairment: a theoretical concern or real risk?.Clin Infect Dis. 2021; 73: e3990-e3995Crossref PubMed Scopus (31) Google Scholar,[28]Ackley T.W. McManus D. Topal J.E. et al.A valid warning or clinical lore: an evaluation of safety outcomes of remdesivir in patients with impaired renal function from a multicenter matched cohort.Antimicrob Agents Chemother. 2021; 65 (e02290–20)Crossref Scopus (34) Google Scholar]. Nonetheless, remdesivir may be considered also for patients with an eGFR of <30 mL/min if the potential benefits outweigh the risks [[29]Adamsick M.L. Gandhi R.G. Bidell M.R. et al.Remdesivir in patients with acute or chronic kidney disease and COVID-19.J Am Soc Nephrol. 2020; 31: 1384-1386Crossref PubMed Scopus (115) Google Scholar]. A study by Kanai et al. [[30]Kanai O. Fujita K. Nanba K. et al.Safety of remdesivir for patients 80 years of age or older with coronavirus disease 2019 (COVID-19).Drugs Aging. 2021; 38: 1067-1074Crossref PubMed Scopus (6) Google Scholar] suggested that remdesivir's safety profile was comparable in hospitalised patients older or younger than 80 years, with no significant differences in the incidence of liver dysfunction, renal dysfunction, and asthenia between both groups. Systemic glucocorticoids are recommended for the treatment of patients with COVID-19 requiring supplemental oxygen [[12]COVID-19 Treatment Guidelines Panel Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health, 2023https://www.covid19treatmentguidelines.nih.gov/Google Scholar]. The multicentre, open-label, Randomised Evaluation of COVID-19 Therapy (RECOVERY) study [[31]Horby P. Lim W.S. Emberson J.R. et al.RECOVERY Collaborative GroupDexamethasone in hospitalized patients with Covid-19.N Engl J Med. 2021; 384: 693-704Crossref PubMed Scopus (6108) Google Scholar], showed that dexamethasone may reduce mortality in hospitalised patients with COVID-19 requiring supplemental oxygen, without significant survival differences between younger and older adults. Participants' mean age was 66 years and 56% of study population had one or more comorbidities (diabetes in 24%), without a report regarding the number of patients with cancer included. Gallay et al. [[32]Gallay L. Tran V.T. Perrodeau E. et al.Fourteen day survival among older adults with severe infection with severe acute respiratory syndrome coronavirus 2 treated with corticosteroid: a cohort study.Clin Microbiol Infect. 2021; 27: 1145-1150Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar] supported the use of corticosteroids in patients aged ≥80 years with severe COVID-19, with improved overall survival at day 14. In this study, corticosteroids were prescribed less often in patients with lower level of independence at baseline, as measured by the Group Iso Ressource score. Low autonomy was reported in 14% of the patients in the treatment group and 21% in the control group (Groupe Iso Ressource score 1/2). Among 131 patients receiving corticosteroids, 17% developed adverse events, including hyperglycaemia, heart failure, confusion, and infection. The COronavirus disease in Very elderly Intensive care Patients (COVIP) study [[33]Jung C. Wernly B. Fjølner J. et al.Steroid use in elderly critically ill COVID-19 patients.Eur Respir J. 2021; 58: 2100979Crossref PubMed Scopus (33) Google Scholar] included 3082 critically ill patients with COVID-19 aged ≥70 years. Univariate rates of 30-day mortality were higher in patients receiving corticosteroids (53% versus 42%; adjusted odds ratio [aOR] 1.16, 95%CI 1.28–2.02; p < 0.001) and this treatment remained associated with increased 30-day mortality after multivariable adjustment (aOR 1.60, 95%CI 1.26–2.04; p < 0.001). The benefit/risk ratio of systemic corticosteroid use in older adults remains unclear in the context of potential adverse events, such as delirium, hyperglycaemia, falls, immunosuppression, secondary infections, opportunistic fungal infections, reactivation of latent infections, gastrointestinal bleeding, and/or neuromuscular weakness. In addition, dexamethasone may reduce the efficacy of concomitant CYP3A4 substrates. These drug-related adverse effects may be more severe in older patients, especially in those with a cancer diagnosis who are also immunocompromised. Monoclonal Antibodies (mAbs) may reduce the risk of COVID-19 progression and death, particularly if ritonavir-boosted nirmatrelvir and remdesivir are not available or clinically appropriate, but few data are available in older adults [[12]COVID-19 Treatment Guidelines Panel Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health, 2023https://www.covid19treatmentguidelines.nih.gov/Google Scholar]. Bebtelovimab or tixagevimab plus cilgavimab are authorised for SARS-CoV-2 pre-exposure prophylaxis in individuals who may have an inadequate immune response to COVID-19 vaccination or are ineligible for vaccination and who have not been exposed to the infection. These could include older patients with cancer and/or haematological malignancies undergoing anticancer treatment. While the TACKLE study [[34]Montgomery H. Richard Hobbs F.D. Padilla F. et al.Efficacy and safety of intramuscular administration of tixagevimab-cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind, placebo-controlled trial.Lancet Respir Med. 2022; S2213-2600: 00180-00181Google Scholar] showed a statistically and clinically significant protection against progression to severe COVID-19 or death in unvaccinated individuals, only 13% (N = 116) were aged ≥65 years, limiting generalizability to older adults. Some mAbs are not effective against COVID-19 variants, so the prevalence of resistant variants should be considered in decision-making [[35]Hoffmann M. Krüger N. Schulz S. et al.The omicron variant is highly resistant against antibody-mediated neutralization: implications for control of the COVID-19 pandemic.Cell. 2022; 185: 447-456.e11Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar]. The Blocking Viral Attachment and Cell Entry with SARS-CoV-2 Neutralizing Antibodies (BLAZE-1) phase 3 trial [[36]Dougan M. Nirula A. Azizad M. et al.The BLAZE-1 investigators. Bamlanivimab plus Etesevimab in mild or moderate Covid-19.N Engl J Med. 2021; 385: 1382-1392Crossref PubMed Scopus (393) Google Scholar] showed that among high-risk outpatients, bamlanivimab plus etesevimab was associated with a lower incidence of hospitalisation and death compared with placebo. The trial included 1035 patients with one or more risk factors for severe COVID-19 (age ≥ 65 years; body-mass index ≥35; and coexisting conditions), with 31% aged ≥65 years. Adverse events were similar between groups, and no patients discontinued treatment due to toxicity. In a retrospective study including 429 patients aged ≥65 years with mild to moderate SARS-CoV-2, treatment with bamlanivimab or casirivimab/imdevimab was associated with a lower risk of hospitalisation [[37]Sobolewski K.A. Smoke S. Brophy A. et al.Real-world evaluation of the impact of two anti-SARS-CoV-2 monoclonal antibody regimens on COVID-19 hospitalizations in older adults.Med Virol. 2022; 94: 2493-2499Crossref PubMed Scopus (1) Google Scholar]. Sotrovimab also reduced the incidence of all-cause hospitalisation and death among patients with mild to moderate COVID-19. In this series of 520 patients, 20% were aged ≥65 years [[38]Gupta A. Gonzalez-Rojas Y. Juarez E. et al.Effect of sotrovimab on hospitalization or death among high-risk patients with mild to moderate COVID-19: a randomized clinical trial.JAMA. 2022; 327: 1236-1246Crossref PubMed Scopus (121) Google Scholar]. Potential side effects include hypersensitivity, nausea, rash, dizziness, diarrhoea, and hypertension. As the Omicron variant has become dominant, the COVID-19 Treatment Guidelines Panel recommends against the use of bamlanivimab plus etesevimab, casirivimab plus imdevimab or sotrovimab for the treatment of COVID-19 disease [[12]COVID-19 Treatment Guidelines Panel Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health, 2023https://www.covid19treatmentguidelines.nih.gov/Google Scholar]. In December 2021, molnupiravir was authorized for the treatment of adults with mild to moderate COVID-19 infection at high risk of progression to severe disease, within five days of symptom onset and for whom alternative antiviral therapies are unaffordable or clinically inappropriate [[39]Food and Drug Administration Fact Sheet for Healthcare Providers: Emergency Use Authorization for Molnupiravir.2021Google Scholar]. Data from the phase 3 MOVe-OUT trial [[40]Bernal A. Gomes da Silva M. Musungaie D. el al. Molnupiravir for Oral treatment of Covid-19 in nonhospitalized patients.N Engl J Med. 2022; 386: 509-520Crossref PubMed Scopus (768) Google Scholar] showed that molnupiravir reduced the risk of hospitalisation or death in at-risk, unvaccinated adults with COVID-19. The analysis included 1433 participants, of whom 17% were aged ≥60 years. Among the participants, 74% had a body mass index ≥30 and 16% were affected by diabetes. Only 29 patients, representing 2% of the entire sample, had any active cancer. Serious adverse events (diarrhoea, nausea, and dizziness) were less frequent in the molnupiravir group. No drug-drug interactions were observed. Severely immunocompromised adults, such as patients affected by haematological malignancies receiving anticancer treatment, may have prolonged SARS-CoV-2 replication potentially leading to rapid viral evolution. In this setting, a single antiviral agent may be associated with the development of variants resistant to antivirals [[12]COVID-19 Treatment Guidelines Panel Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health, 2023https://www.covid19treatmentguidelines.nih.gov/Google Scholar]. However, the role of combined antiviral therapy in severely immunocompromised patients is still unclear and more research is warranted. The anti-interleukin (IL)-6 monoclonal antibody tocilizumab has been utilised for hospitalised patients with COVID-19 infection requiring supplemental oxygen or ventilatory support. The RECOVERY study [[41]RECOVERY Collaborative GroupTocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.Lancet. 2021; 397: 1637-1645Abstract Full Text Full Text PDF PubMed Scopus (1015) Google Scholar] randomised 4116 patients with progressive COVID-19 to tocilizumab versus standard care. Tocilizumab was associated with a lower 28-day mortality compared to standard care alone (Tocilizumab: 31%; standard care: 35%; rate ratio 0–85; 95%CI 0–76–0-94; p = 0–0028). The mean age was 64 years, including 11% of patients aged >80 years in the tocilizumab group and 12% in standard care. No differences in comorbidities were found between both groups. A Spanish single-centre retrospective observational study [[42]Duarte-Millan M.A. Mesa-Plaza N. Guerrero-Santillan M. et al.Prognostic factors and combined use of tocilizumab and corticosteroids in a Spanish cohort of elderly COVID-19 patients.J Med Virol. 2022; 94: 1540-1549Crossref PubMed Scopus (12) Google Scholar], documented a survival benefit in hospitalised patients aged >80 years with tocilizumab plus corticosteroids (HR 0.09, 95%CI: 0.01–0.74), with no benefits seen in patients receiving corticosteroids alone (HR 0.95, 95%CI 0.53–1.71). COVID-19 convalescent plasma (CCP) is authorised for use in immunocompromised patients. A randomised, double-blind, placebo-controlled trial of 160 non-hospitalised older patients showed that early administration of CCP to mildly ill older patients reduced disease progression. The study was conducted in 160 immunocompetent older adults affected by one or more comorbidities. Participants' mean age was 77 years, 45% were aged 65–74 years, and 55% were ≥ 75 years. No imbalances in baseline characteristics were found between CCP and placebo groups [[43]Libster R. Perez Marc G. Wappner D. et al.Early high-titer plasma therapy to prevent severe COVID-19 in older adults.N Engl J Med. 2021; 384: 610-618Crossref PubMed Scopus (575) Google Scholar]. Serious adverse reactions were infrequent and consistent with those of plasma infusions for other indications. Most clinical trials were completed before the appearance of circulating SARS-CoV-2 variants, so data regarding the use of CCP against variants are not available [[12]COVID-19 Treatment Guidelines Panel Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health, 2023https://www.covid19treatmentguidelines.nih.gov/Google Scholar]. Trials that evaluated colchicine in outpatients with COVID-19 failed to reach the efficacy endpoint of reducing hospitalizations and death [[44]Tardif J.C. Bouabdallaoui N. L’Allier P.L. et al.Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.Lancet Respir Med. 2021; 9: 924-932Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar], or the time of recovery from COVID-19 [[45]Dorward J. Yu L. Hayward G. et al.Colchicine for COVID-19 in the community (PRINCIPLE): a randomised, controlled, adaptive platform trial.Br J Gen Pract. 2022; : e450-452Google Scholar]. In addition, more gastrointestinal adverse events were reported in patients receiving colchicine. Due to the lack of specific data, fluvoxamine should not be used as a preferred option for older adults with cancer. Regarding ivermectin, more data are needed to evaluate the use of this drug in the treatment of COVID-19 [[12]COVID-19 Treatment Guidelines Panel Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health, 2023https://www.covid19treatmentguidelines.nih.gov/Google Scholar]. Relative to the disease burden of COVID-19 among older adults, especially those with cancer, this population is underrepresented in most clinical trials of COVID-19 therapeutics, and evidence for making strong recommendations is lacking. In light of this limited evidence, the SIOG COVID-19 Working Group recommends following existing guidelines for other populations of older adults, and prioritizing treatments based on their availability, efficacy, and safety profile (Table 1). The following recommendations mainly concern outpatients.Table 1Recommendations of the SIOG COVID-19 working group on the use of COVID-19 drugs in older adults and in older patients with cancer.COVID-19 Therapeutics and RecommendationsSpecific Considerations in Older Adults with CancerRitonavir-boosted nirmatrelvir is recommended for the early treatment of non-hospitalised older adults with cancer affected by mild or moderate COVID-19 at high risk of disease progression who do not require supplemental oxygen, particularly dose who have not completed an approved vaccination schedule.•Monitoring of gastrointestinal side effects is required.•Pharmaceutical analysis of patient concomitant medications and potential drug-drug interactions, especially in polypharmacy, is requested before prescribing treatment. (https://www.covid19druginteractions.org/checker)•Particular attention is required in older adults with cancer because of the risk of interactions with immunosuppressants and of increasing concentrations of concomitant chemotherapeutic agents.•Adapted dosing is required in patients affected by moderate kidney disease. In severe disease category, evaluation of treatment risk/benefit is requested.•Particular attention is required in patients affected by liver diseases. Treatment is not recommended in severe hepatic impairment.•Treatment is available in oral form. An evaluation of cognitive function, social support, and ability to adhere to treatment is recommended before starting therapy in older adults with cancer.Remdesivir is recommended for the early treatment of non-hospitalised older adults with cancer with mild or moderate COVID-19 at high risk of disease progression who do not require supplemental oxygen or for whom minimal supplemental oxygen is required, particularly those who have not completed an approved vaccination schedule.Remdesivir might be co-prescribed with systemic corticosteroids for the treatment of hospitalised older adults with cancer and COVID-19 who require high-flow device supplemental oxygen or non-invasive ventilation.•Monitoring of gastrointestinal side effects is required.•Evaluation of liver function and prothrombin time tests is required before starting and during treatment.•Adapted dose is required in patients affected by moderate kidney disease. In severe disease category, evaluation of treatment risk/benefit is required.•The feasibility of administering parenteral medications in the outpatient setting must be considered. An evaluation of the patient's ability to obtain transportation and of social support is recommended.Treatment with corticosteroids is recommended for hospitalised older adults with cancer and COVID-19 who require supplemental oxygen, high-flow oxygen, non-invasive ventilation, or mechanical ventilation.•The use of corticosteroids in the older adults and in older patients with cancer may be associated with side effects such as delirium and falls. The risk/benefit decision must be evaluated for each individual patient, and evidence-based geriatric interventions should be implemented early.•Pharmaceutical analysis of patient's concomitant medications and potential drug-drug interactions, especially in polypharmacy, is required before prescribing treatment.•Close inpatient monitoring of potential side effects, especially in patients affected by geriatric syndromes, coexisting conditions, solid tumour and/or haematological malignancies, and polypharmacy.•Careful monitoring of secondary infections, opportunistic fungal infections, reactivation of latent infections, is necessary in older patients with cancer, particularly those who are receiving immunosuppressants.Monoclonal antibodies should not be the first option for the treatment of older adults with cancer and COVID-19, due to the lack of older-adult specific data and the low effectiveness against newer COVID-19 strains. Monoclonal antibodies could be utilized in cases where other more effective therapies are not available, particularly in those who have not completed an authorized vaccination schedule or who may not have an appropriate antibody response.Due to the lack of older adult specific data and the availability of other antiviral agents with improved results, monoclonal antibodies should not be a preferred option for older adults with cancer.Molnupiravir should not be the first option for the treatment of non-hospitalised older adults with cancer affected by mild or moderate COVID-19. This treatment could be considered in cases were alternative antiviral therapies are not accessible or clinically appropriate.Due to the lack of older adult specific data, the under-representation of patients with cancer in clinical trials, and the availability of other antiviral agents demonstrating better outcomes, molnupiravir should not be used as a preferred option for older adults with cancer.Tocilizumab should be considered in hospitalised older adults with cancer and COVID-19 who require supplemental oxygen, high-flow oxygen, non-invasive ventilation, or mechanical ventilation.Due to the lack of older adult specific data and the under-representation of patients with cancer in clinical trials, tocilizumab should not be the preferred treatment in older adults with cancer and should only be utilized in conjunction with other treatments.Although COVID-19 convalescent plasma is authorized for patients with COVID-19 affected by immunocompromising conditions or receiving immunosuppressive treatment, data regarding its effectiveness is scarce.Available data on effectiveness do not allow to make a recommendation regarding the use of convalescent plasma in older adults with cancer. 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Abstract Background We evaluated the time to progression (TTP) and survival outcomes of second-line therapy for metastatic colorectal cancer among adults aged 70 years and older compared with younger adults following progression on first-line clinical trials. Methods Associations between clinical and disease characteristics, time to initial progression, and rate of receipt of second-line therapy were evaluated. TTP and overall survival (OS) were compared between older and younger adults in first- and second-line trials by Cox regression, adjusting for age, sex, Eastern Cooperative Oncology Group Performance Status, number of metastatic sites and presence of metastasis in the lung, liver, or peritoneum. All statistical tests were 2-sided. Results Older adults comprised 16.4% of patients on first-line trials (870 total older adults aged >70 years; 4419 total younger adults aged ≤70 years, on first-line trials). Older adults and those with Eastern Cooperative Oncology Group Performance Status >0 were less likely to receive second-line therapy than younger adults. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariable analysis (odds ratio = 1.11, 95% confidence interval = 1.02 to 1.21, P = .01). Older and younger adults enrolled in second-line trials experienced similar median TTP and median OS (median TTP = 5.1 vs 5.2 months, respectively; median OS = 11.6 vs 12.4 months, respectively). Conclusions Older adults were less likely to receive second-line therapy for metastatic colorectal cancer, though we did not observe a statistical difference in survival outcomes vs younger adults following second-line therapy. Further study should examine factors affecting decisions to treat older adults with second-line therapy. Inclusion of geriatric assessment may provide better criteria regarding the risks and benefits of second-line therapy.

5583 Background: EC and a subset of OVCA are associated with high rates of dMMR and are responsive to PD-1 blockade. It is unknown what additional biomarkers beyond dMMR may enrich for benefit in these patients (pts). Methods: This was an investigator-initiated, single-arm, phase II study. Eligible pts had recurrent EC or OVCA that met one of the following criteria: 1) dMMR, as determined by immunohistochemical loss of expression of 1+ MMR genes; 2) MSI-H, as determined by next generation sequencing (MSK-IMPACT); or 3) hypermutated, defined as 20+ non-synonymous somatic mutations. Pts received nivo 240mg IV every 2 weeks or 480mg IV every 4 weeks until toxicity or progression. The co-primary endpoints were 1) the progression-free survival (PFS) rate at 24 weeks (PFS24) and 2) the objective response rate (ORR) by RECIST v1.1. The study was designed using Simon’s two-stage design, with a sample size of 40 pts based on a promising ORR of 25% with a type I error rate of 0.025 and a type II error rate of 0.05. Overall survival (OS), PFS and duration of response (DOR) were calculated using the method of Kaplan-Meier. Adverse events (AEs) were graded per CTCAE and tabulated. Biomarker analyses on the available archival tissue were performed using multiplex immunofluorescence (mIF) labeling for CD8, PD-1, TOX, PD-1, PD-L1, and FoxP3. Quantification of immune phenotypes and interaction studies between CD8+ T cells and PD-L1+ cells was performed in HALO. Results: Between 9/2017 and 5/2021, 35 pts were enrolled; the study closed early due to slow accrual. The median duration of follow-up was 33.2 months. The median age was 64 years (range 36-87); 82% of pts were white, 54% had high grade EC, and 65% had confirmed MLH1 hypermethylation. The ORR was 57.1% (97.5% CI 39.4-100%) [37% PR, 20% CR]. The PFS24 was 62.9% and median PFS was 26.7 months (95% CI 4.9-NE). Neither median DOR nor OS was reached. OS at 1 year was 76.4% (95% CI 58.2-87.4%). The ORR in patients with MLH1 hypermethylation was 52%; 4 of 5 patients with confirmed germline MMR alterations had a response by RECIST. AEs were consistent with the reported literature. Notable treatment related AEs included Grade 4 myocarditis with associated grade 4 AV block, grade 2 extraocular paresis, grade 3 Type 1 diabetes mellitus, and grade 3 elevations in AST/ALT. On mIF analysis, PD-L1 expression did not distinguish responders from non-responders, though interaction between CD8+ T cells and PD-L1+ cells was associated with CR/PR. Increase in relative fraction of dysfunctional CD8+ T cells (characterized by CD8+TOX+PD-1+ phenotype) was also associated with CR/PR. Conclusions: Nivo is an effective and tolerable treatment option for patients with MMR-D/MSI-H or hypermutated EC or OVCA. Presence of dysfunctional CD8+ T cells in the tumors was associated with response, while expression of PD-L1 was not predictive. Clinical trial information: NCT03241745.

Two years after the declaration of the COVID-19 pandemic by the World Health Organization (WHO), its effects continue to have a negative social and health impact. Despite the implementation of global vaccination campaigns which have successfully reduced hospitalizations and mortality rates in many regions of the world, there are still many unresolved issues and challenges to tackle before the pandemic is over. While 65% of the world's population has received at least one dose of the COVID-19 vaccine, vaccination coverage is still very low in many regions of the world, particularly in low- and middle-income countries (LMIC) [[1]Our World in Data Coronavirus (COVID-19) Vaccinations.https://ourworldindata.org/covid-vaccinations?country=~MEXGoogle Scholar]. Older adults, particularly those who are unvaccinated and those with comorbidities such as cancer, continue to be at significant risk of increased morbidity and mortality when contracting COVID-19 [[2]Elkrief A. Hennessy C. Kuderer N.M. Rubinstein S.M. Wulff-Burchfield E. Rosovsky R.P. et al.Geriatric risk factors for serious COVID-19 outcomes among older adults with cancer: a cohort study from the COVID-19 and cancer consortium.Lancet Healthy Longev. 2022; 3: e143-e152https://doi.org/10.1016/s2666-7568(22)00009-5Abstract Full Text Full Text PDF PubMed Google Scholar]. While early in the pandemic significant changes in the administration of anticancer therapies (including omitting and delaying therapy) were undertaken, in many parts of the world cancer care delivery has returned to the same level as before COVID-19 [[3]Battisti N.M.L. Mislang A.R. Cooper L. O'Donovan A. Audisio R.A. Cheung K.L. et al.Adapting care for older cancer patients during the COVID-19 pandemic: Recommendations from the International Society of Geriatric Oncology (SIOG) COVID-19 Working Group.J Geriatric Oncol. 2020; 11: 1190-1198https://doi.org/10.1016/j.jgo.2020.07.008Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar]. The emergence of the omicron variants of SARS-CoV-2, which show substantial resistance to vaccine-induced serum neutralizing activity, highlights the relevance of ongoing public health interventions, continued mass immunization, and booster campaigns targeting the most vulnerable members of society, including older adults with cancer [[4]Vanshylla K. Tober-Lau P. Gruell H. Munn F. Eggeling R. Pfeifer N. et al.Durability of omicron-neutralising serum activity after mRNA booster immunisation in older adults.Lancet Infect Dis. 2022; 22: 445-446https://doi.org/10.1016/S1473-3099(22)00135-9Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. In 2021, the International Society of Geriatric Oncology (SIOG) published an initial set of recommendations regarding COVID-19 vaccinations among older adults with cancer [[5]Mislang A.R. Soto-Perez-de-Celis E. Russo C. Colloca G. Williams G.R. O'Hanlon S. et al.The SIOG COVID-19 working group recommendations on the rollout of COVID-19 vaccines among older adults with cancer.J Geriatr Oncol. 2021; 12: 848-850https://doi.org/10.1016/j.jgo.2021.03.003Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar]. However, recent changes in the epidemiology of the disease and in data regarding COVID-19 vaccines require updated recommendations. As of April 2022, data for 34 COVID-19 vaccines have been successfully submitted for authorization by the WHO, 14 have been approved, and over 150 are currently under clinical development [[6]World Health Organization COVID-19 vaccine tracker and landscape.https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccinesGoogle Scholar]. As vaccinations and vaccine boosters are becoming increasingly available in most regions of the world, those at higher risk of adverse outcomes including hospitalization and/or death should continue to be prioritized. Older people have been grossly underrepresented in randomized clinical trials (RCT) of the COVID-19 vaccine [[7]Helfand B.K.I. Webb M. Gartaganis S.L. Fuller L. Kwon C.S. Inouye S.K. The exclusion of older persons from vaccine and treatment trials for coronavirus disease 2019-missing the target.JAMA Intern Med. 2020; 180: 1546-1549https://doi.org/10.1001/jamainternmed.2020.5084Crossref PubMed Scopus (51) Google Scholar]. In the same way, patients with cancer, comorbidities, or those receiving immunosuppressive therapy have been excluded. The only published RCT including patients with cancer was the BNT162b2 Pfizer/BioNTech mRNA vaccine trial, which recently reported a subgroup analysis of the 3813 patients with a history of cancer (median age 64 years, range 16–91 years), showing an efficacy of 92–94%, with only four cases reported among the 1802 participants who received the vaccine compared with 71 among those who received placebo [[8]Thomas S.J. Perez J.L. Lockhart S.P. Hariharan S. Kitchin N. Bailey R. et al.Efficacy and safety of the BNT162b2 mRNA COVID-19 vaccine in participants with a history of cancer: subgroup analysis of a global phase 3 randomized clinical trial.Vaccine. 2022; 40: 1483-1492https://doi.org/10.1016/j.vaccine.2021.12.046Crossref PubMed Scopus (15) Google Scholar]. This causes clinicians to make recommendations based on the risk-benefit ratio, on extrapolation of RCT data, on subgroup analyses, or on observational studies, particularly in the context of the emergence of novel variants. The efficacy of vaccines relies on an intact host response, which could be disrupted in people with myelosuppression due to cancer or its treatment, and in older adults (secondary to an age-related dysregulation and immune dysfunction commonly called immunosenescence), leading to potentially lower immunogenicity of vaccines in these population subgroups [[9]Crooke S.N. Ovsyannikova I.G. Poland G.A. Kennedy R.B. Immunosenescence and human vaccine immune responses.Immun Age. 2019; 16: 25https://doi.org/10.1186/s12979-019-0164-9Crossref PubMed Google Scholar]. A reduced magnitude and duration of immune responses among older adults after receiving mRNA and inactivated virus vaccines has also been reported, with reduced IgG levels, a lower proportion of specific memory B-cells, and a reduction in IL-2-producing T cells [[10]Collier D.A. Ferreira I.A.T.M. Kotagiri P. Datir P.R. Lim E.Y. Touizer E. et al.Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2.Nature. 2021; 596: 417-422https://doi.org/10.1038/s41586-021-03739-1Crossref PubMed Scopus (307) Google Scholar]. Humoral responses and T cell activation have been found to be significantly lower among older adults, and to have a sharper decline over time, highlighting the relevance of providing booster doses for this population [10Collier D.A. Ferreira I.A.T.M. Kotagiri P. Datir P.R. Lim E.Y. Touizer E. et al.Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2.Nature. 2021; 596: 417-422https://doi.org/10.1038/s41586-021-03739-1Crossref PubMed Scopus (307) Google Scholar, 11Brockman M.A. Mwimanzi F. Lapointe H.R. Sang Y. Agafitei O. Cheung P.K. et al.Reduced magnitude and durability of humoral immune responses to COVID-19 mRNA vaccines among older adults.J Infect Dis. 2021; 225: 1129-1140https://doi.org/10.1093/infdis/jiab592Crossref Scopus (28) Google Scholar, 12Bag Soytas R. Cengiz M. Islamoglu M.S. Borku Uysal B. Yavuzer S. Yavuzer H. Antibody responses to COVID-19 vaccines in older adults.J Med Virol. 2022; 94: 1650-1654https://doi.org/10.1002/jmv.27531Crossref PubMed Scopus (4) Google Scholar]. Likewise, patients with cancer seem more likely to develop a reduced immune response to COVID-19 vaccination. Vaccination effectiveness for preventing severe COVID-19 infections, although high, is lower among patients with cancer than among the general population, and even lower for those receiving active treatments and of advanced chronological age [[13]Embi P.J. Levy M.E. Naleway A.L. Patel P. Gaglani M. Natarajan K. et al.Effectiveness of 2-dose vaccination with mRNA COVID-19 vaccines against COVID-19-associated hospitalizations among immunocompromised adults - Nine States, January-September 2021.MMWR Morb Mortal Wkly Rep. 2021; 70: 1553-1559https://doi.org/10.15585/mmwr.mm7044e3Crossref PubMed Google Scholar,[14]Wu J.T.-Y. La J. Branch-Elliman W. Huhmann L.B. Han S.S. Parmigiani G. et al.Association of COVID-19 vaccination with SARS-CoV-2 infection in patients with cancer: A US nationwide veterans affairs study.JAMA Oncol. 2022; 8: 281-286https://doi.org/10.1001/jamaoncol.2021.5771Crossref PubMed Scopus (30) Google Scholar]. Real-world evidence shows that both patients aged ≥65 years and those with cancer have a higher risk of developing COVID-19 infections, and of adverse outcomes, despite vaccination [[15]Song Q. Bates B. Shao Y.R. Hsu F.C. Liu F. Madhira V. et al.Risk and outcome of breakthrough COVID-19 infections in vaccinated patients with cancer: real-world evidence from the national COVID cohort collaborative.J Clin Oncol. 2022 Mar 14; JCO2102419https://doi.org/10.1200/JCO.21.02419Crossref Scopus (27) Google Scholar]. Specifically, patients aged ≥65 with a diagnosis of cancer have an increased risk of adverse COVID-19-related outcomes (odds ratio [OR] 1.42, p = 0.01) than their younger counterparts [[15]Song Q. Bates B. Shao Y.R. Hsu F.C. Liu F. Madhira V. et al.Risk and outcome of breakthrough COVID-19 infections in vaccinated patients with cancer: real-world evidence from the national COVID cohort collaborative.J Clin Oncol. 2022 Mar 14; JCO2102419https://doi.org/10.1200/JCO.21.02419Crossref Scopus (27) Google Scholar]. Data from the United Kingdom shows that patients on moderate-to-high intensity chemotherapy are at increased risk of dying from COVID-19 despite being vaccinated (two doses) [[16]Hippisley-Cox J. Coupland C.A. Mehta N. Keogh R.H. Diaz-Ordaz K. Khunti K. et al.Risk prediction of COVID-19 related death and hospital admission in adults after covid-19 vaccination: National prospective cohort study.BMJ. 2021; 374n2244https://doi.org/10.1136/bmj.n2244Crossref Scopus (132) Google Scholar]. The exact timing of the vaccination during active chemo/immunotherapy does not seem to influence the efficacy of the vaccination significantly, except for patients undergoing stem cell-transplantation or receiving anti-CD20 therapies [[17]Thakkar A. Gonzalez-Lugo J.D. Goradia N. Gali R. Shapiro L.C. Pradhan K. et al.Seroconversion rates following COVID-19 vaccination among patients with cancer.Cancer Cell. 2021; 39: 1081-1090.e2https://doi.org/10.1016/j.ccell.2021.06.002Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar]. Importantly, booster doses of COVID-19 vaccine seem to be effective at increasing antibody titres, as well as improving immune response to variants of concern among patients with cancer, and thus this should be a priority population in booster campaigns [[18]Naranbhai V. St. Denis K.J. Lam E.C. Ofoman O. Garcia-Beltran W.F. Mairena C.B. et al.Neutralization breadth of SARS-CoV-2 viral variants following primary series and booster SARS-CoV-2 vaccines in patients with cancer.Cancer Cell. 2022; 40: 103-108.e2https://doi.org/10.1016/j.ccell.2021.12.002Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar,[19]Fendler A. Shepherd S.T.C. Au L. Wilkinson K.A. Wu M. Byrne F. et al.Adaptive immunity and neutralizing antibodies against SARS-CoV-2 variants of concern following vaccination in patients with cancer: the CAPTURE study.Nat Cancer. 2021; 2: 1305-1320https://doi.org/10.1038/s43018-021-00274-wCrossref PubMed Scopus (74) Google Scholar]. The SIOG COVID-19 Working Group advocates for continued prioritization of older adults with cancer in vaccination campaigns and boosters to protect this vulnerable group from the adverse outcomes of COVID-19, even in the absence of robust data, following the recommendations included in Table 1 [[5]Mislang A.R. Soto-Perez-de-Celis E. Russo C. Colloca G. Williams G.R. O'Hanlon S. et al.The SIOG COVID-19 working group recommendations on the rollout of COVID-19 vaccines among older adults with cancer.J Geriatr Oncol. 2021; 12: 848-850https://doi.org/10.1016/j.jgo.2021.03.003Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar].Table 1Updated SIOG COVID-19 Working Group recommendations for COVID-19 vaccinations among older patients with cancer.RecommendationRationaleA. For immediate actionPrioritize initial vaccination courses and vaccine boosters for individuals at disproportionate risk of death and other complications from COVID-19, including older patients with active or progressive cancer, or anticancer therapy at high risk for immunosuppression.Higher 30-day all-cause mortality from COVID-19 observed in patients with older age, comorbidities, active or progressive cancer [[20]Kuderer N.M. Choueiri T.K. Shah D.P. Shyr Y. Rubinstein S.M. Rivera D.R. et al.Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study.Lancet. 2020; 395: 1907-1918https://doi.org/10.1016/s0140-6736(20)31187-9Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar].Immune response to COVID-19 vaccines declines faster among older individuals and thus specific measures to boost vaccine responses in this population are warranted [[10]Collier D.A. Ferreira I.A.T.M. Kotagiri P. Datir P.R. Lim E.Y. Touizer E. et al.Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2.Nature. 2021; 596: 417-422https://doi.org/10.1038/s41586-021-03739-1Crossref PubMed Scopus (307) Google Scholar,[11]Brockman M.A. Mwimanzi F. Lapointe H.R. Sang Y. Agafitei O. Cheung P.K. et al.Reduced magnitude and durability of humoral immune responses to COVID-19 mRNA vaccines among older adults.J Infect Dis. 2021; 225: 1129-1140https://doi.org/10.1093/infdis/jiab592Crossref Scopus (28) Google Scholar].Administering at least one booster dose seems to be effective in increasing immune response among patients with cancer. Data regarding subsequent booster doses is currently missing or very limited [[18]Naranbhai V. St. Denis K.J. Lam E.C. Ofoman O. Garcia-Beltran W.F. Mairena C.B. et al.Neutralization breadth of SARS-CoV-2 viral variants following primary series and booster SARS-CoV-2 vaccines in patients with cancer.Cancer Cell. 2022; 40: 103-108.e2https://doi.org/10.1016/j.ccell.2021.12.002Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar,[19]Fendler A. Shepherd S.T.C. Au L. Wilkinson K.A. Wu M. Byrne F. et al.Adaptive immunity and neutralizing antibodies against SARS-CoV-2 variants of concern following vaccination in patients with cancer: the CAPTURE study.Nat Cancer. 2021; 2: 1305-1320https://doi.org/10.1038/s43018-021-00274-wCrossref PubMed Scopus (74) Google Scholar,[21]Bar-On Y.M. Goldberg Y. Mandel M. Bodenheimer O. Amir O. Freedman L. et al.Protection by a Fourth Dose of BNT162b2 against Omicron in Israel.N Engl J Med. 2022; https://doi.org/10.1056/NEJMoa2201570Crossref Scopus (146) Google Scholar].Implement the use of regulated vaccines and vaccine boosters in areas with high community transmission and with a high prevalence of variants of concern as soon as possible and without interrupting active treatment.Except for patients receiving anti CD-20 antibodies or undergoing stem cell transplantation (for whom a delay of at least three months after treatment may be appropriate) [[22]National Comprehensive Cancer Network Recommendations of the NCCN COVID-19 vaccination advisory committee version 2.0 03/10/2021.https://www.nccn.org/covid-19/pdf/COVID-19_Vaccination_Guidance_V2.0.pdfGoogle Scholar], patients receiving anticancer therapies such as chemotherapy, targeted, endocrine therapy, or immunotherapy seem to be able to mount appropriate immune responses, particularly after boosters [[17]Thakkar A. Gonzalez-Lugo J.D. Goradia N. Gali R. Shapiro L.C. Pradhan K. et al.Seroconversion rates following COVID-19 vaccination among patients with cancer.Cancer Cell. 2021; 39: 1081-1090.e2https://doi.org/10.1016/j.ccell.2021.06.002Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar].Persevere with community-based intervention strategies, such as physical distancing, hand hygiene, mask wearing, and use of personal protective equipment to mitigate transmission, even for patients and healthcare professionals that have already been vaccinated.Emerging COVID-19 variants, particularly omicron variants, are highly transmissible even among vaccinated individuals, and specifically among patients with cancer [[23]Araf Y. Akter F. Tang Y.D. Fatemi R. Parvez S.A. Zheng C. et al.Omicron variant of SARS-CoV-2: Genomics, transmissibility, and responses to current COVID-19 vaccines.J Med Virol. 2022; 94: 1825-1832https://doi.org/10.1002/jmv.27588Crossref PubMed Scopus (296) Google Scholar,[24]Pinato D.J. Aguilar-Company J. Ferrante D. Hanbury G. Bower M. Salazar R. et al.Outcomes of the SARS-CoV-2 omicron (B.1.1.529) variant outbreak among vaccinated and unvaccinated patients with cancer in Europe: results from the retrospective, multicentre, OnCovid registry study.Lancet Oncol. 2022 Jun 2; (S1470–2045(22)00273-X)https://doi.org/10.1016/S1470-2045(22)00273-XAbstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar].The timing and level of measures to contain the virus, such as travel restrictions, facilities shutdowns, and social distancing have impacted the incidence and mortality from COVID-19 [[25]Thu T.P.B. Ngoc P.N.H. Hai N.M. Tuan L.A. Effect of the social distancing measures on the spread of COVID-19 in 10 highly infected countries.Sci Total Environ. 2020; 742140430https://doi.org/10.1016/j.scitotenv.2020.140430Crossref PubMed Scopus (153) Google Scholar].Facilitate the availability of vaccines and boosters for older adults with cancer living in LMIC by means of negotiation of fair prices and by equitable distribution of the vaccine supply through international collaborations and partnerships.COVID-19 vaccines have been disproportionately utilized in high-income regions of the world [[1]Our World in Data Coronavirus (COVID-19) Vaccinations.https://ourworldindata.org/covid-vaccinations?country=~MEXGoogle Scholar].Increasing access in LMIC is in line with WHO recommendations for Let's #ACTogether for #VaccinEquity and the United Nations COVAX program.Ensure equitable and timely access to primary vaccination for older people within community, local, or national level.Achieving high and equitable global coverage with a COVID-19 primary vaccination series remains the highest priority and is fundamental to reducing COVID-19–related morbidity and mortality [[26]Mbaeyi S. Oliver S.E. Collins J.P. Godfrey M. Goswami N.D. Hadler S.C. et al.The advisory committee on immunization practices' interim recommendations for additional primary and booster doses of COVID-19 vaccines - United States, 2021.MMWR Morb Mortal Wkly Rep. 2021; 70: 1545-1552https://doi.org/10.15585/mmwr.mm7044e2Crossref PubMed Google Scholar].Prioritize older patients with cancer from socially and medically disadvantaged populations, including those with poor access to healthcare or from underrepresented racial/ethnic groups, in vaccination campaigns.Higher incidence and mortality from COVID-19 in racial/ethnic minorities likely related to underlying disparities in social determinants of health [[27]Moore J.T. Ricaldi J.N. Rose C.E. Fuld J. Parise M. Kang G.J. et al.Disparities in incidence of COVID-19 among underrepresented racial/ethnic groups in counties identified as hotspots during June 5–18, 2020–22 States, February–June 2020.MMWR Morb Mortal Wkly Rep. 2020; 69: 1122-1126https://doi.org/10.15585/mmwr.mm6933e1Crossref PubMed Scopus (0) Google Scholar].Governments, international organizations, and medical associations, including SIOG, should create and disseminate educational messaging and risk communication campaigns aimed at combating misinformation and convincing the public, older adults with cancer, and their caregivers of the value and safety of vaccination.COVID-19 vaccine hesitancy is a global phenomenon which is highly variable across countries, and which is related with lower education and awareness, as well as inefficient government efforts [[28]Shakeel C.S. Mujeeb A.A. Mirza M.S. Chaudhry B. Khan S.J. Global COVID-19 vaccine acceptance: A systematic review of associated social and behavioral factors.Vaccines. 2022; 10: 110Crossref Scopus (60) Google Scholar]. Tackling this hesitancy is necessary to increase vaccination rates.Ensure the availability of antiviral medications and monoclonal antibodies for non-hospitalized vaccinated older adults aged ≥65 with hematologic malignancies, for older adults with cancer aged ≥65 who have not been previously vaccinated, and for those aged ≥75 years regardless of vaccination status.Antiviral medications and monoclonal antibodies may decrease disease progression and hospitalization among ambulatory patients with COVID-19. Prioritization of their use is recommended by the National Institutes of Health [[29]COVID-19 Treatment Guidelines Panel. Coronavirus disease 2019 (COVID-19) treatment guidelines. National Institutes of Health. https://www.covid19treatmentguidelines.nih.gov/. Accessed April 15 2022.Google Scholar].We encourage our members to continue investigating the vaccines' long-term safety and efficacy in older adults with cancer (including booster shots), particularly in the emerging variants of concern.Populations included in phase III RCT were mostly younger individuals without comorbidities. "Real-world" evidence can further support the effectiveness COVID-19 vaccines among populations such as older adults with cancer, particularly with the emergence of novel, more transmissible, variants. "Real-world" evidence can also inform the incidence of COVID-19 infections after primary vaccination and support prioritizing the administration of booster doses in vulnerable populations [[2]Elkrief A. Hennessy C. Kuderer N.M. Rubinstein S.M. Wulff-Burchfield E. Rosovsky R.P. et al.Geriatric risk factors for serious COVID-19 outcomes among older adults with cancer: a cohort study from the COVID-19 and cancer consortium.Lancet Healthy Longev. 2022; 3: e143-e152https://doi.org/10.1016/s2666-7568(22)00009-5Abstract Full Text Full Text PDF PubMed Google Scholar].We encourage our members to prioritize investigations on the impact of previous COVID-19 infections, aging, physical activity, function, frailty, and various anticancer treatments on vaccine efficacy and adverse effects. Experts in geriatrics should be embedded in the planning of future studies regarding COVID-19 and cancer.Abbreviations: SIOG, International Society of Geriatric Oncology; LMIC, low- and middle-income counties; WHO, World Health Organization. Open table in a new tab Abbreviations: SIOG, International Society of Geriatric Oncology; LMIC, low- and middle-income counties; WHO, World Health Organization. Therefore, SIOG continues to stress the prioritization of initial vaccination and vaccine boosters among patients at higher risk of morbidity and mortality from COVID-19, specifically older adults with cancer, when implementing global and local vaccination plans. AM: Honoraria Janssen, MSD, Novartis. KPL: National Cancer Institute in the United States (R00CA237744), Wilmot Cancer Institute Research Fellowship Award. Receipt of consultation fees: Pfizer and Seattle Genetics; Receipt of honoraria: Pfizer. KLC: Consultancy: Roche. SML: National Cancer Institute Cancer Center Support Grant (P30CA008748). EB: Receipt of travel supports: Pfizer, Sandoz. Receipt of honoraria: Eli Lilly, Pfizer, Seagen. Receipt of consultation fees: Daiichi, Pfizer, Sandoz. RK: Speaker/ Advisory Board / Honoraria: AstraZeneca, Pfizer, MSD, BMS, Astellas, J&J, Eisai, Ipsen, Amgen, Merck. NMLB: Advisory board: Pfizer, Abbott, Sanofi; speaker fees: Abbovie, Pfizer, Roche, Sanofi; travel grants: Genomic Health, Pfizer, Lilly. MA: Honoraria from Pfizer. All authors contributed to the manuscript.

INTRODUCTION:Our understanding of the biologic heterogeneity of endometrial cancer has improved, but which patients benefit from single-agent versus combination immune checkpoint blockade remains unclear. METHODS:We conducted a single-center, randomized, open-label, phase 2 study of durvalumab 1500 mg (Arm 1) versus durvalumab 1500 mg plus tremelimumab 75 mg every 4 weeks (Arm 2) in patients with endometrial carcinoma. The primary endpoints were overall response rate (ORR) and progression-free survival (PFS) at 24 weeks. Patients were stratified by mismatch repair (MMR) status and carcinosarcoma histology. Using a Simon two-stage minimax design, we determined 40 patients per arm would provide 90% power and Type 1 error of 10%. RESULTS:Eighty-two patients were enrolled; 77 were evaluable for toxicity (Arm 1: 38, Arm 2: 39) and 75 evaluable for efficacy (Arm 1: 37, Arm 2: 38). Patient were stratified by MMR status (Arm 1: 5, Arm 2: 4 were MMR-deficient). The ORR in Arm 1 was 10.8% (one-sided 90% CI: 4.8-100%); the ORR in Arm 2 was 5.3% (one-sided 90% CI: 1.4-100%). Since the primary endpoint of ORR was not met, 24-week PFS was not compared to historical controls per protocol specification. No new safety signals were identified. CONCLUSIONS:In these patients with predominantly MMR-proficient endometrial cancer, there was limited response with single-agent and combined immune checkpoint blockade. The pre-specified efficacy thresholds were not met for further evaluation. A deeper understanding of potential mechanisms of resistance to immunotherapy in MMR-proficient endometrial cancer is needed for the development of novel therapeutic approaches.

BACKGROUND:The benefit of chemotherapy for older patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (EBC) is a key area of debate. Gene expression profiling (GEP) may identify patients deriving benefit, but their predictive role has not been established for older adults. We summarise evidence on efficacy, safety, and quality-of-life impacts of chemotherapy and on GEP use and impact in older HR-positive, HER2-negative EBC patients.METHODS:We conducted a literature search of PubMed and Embase on publications describing prospective studies evaluating chemotherapy in older adults with HR-positive, HER2-negative EBC and on publications describing retrospective and prospective studies evaluating GEP in older adults.RESULTS:Eight publications on chemotherapy use, including 2,035 older patients with EBC were selected. Only one trial evaluated chemotherapy survival benefits in older adults, showing no benefit. Of four studies comparing different regimens, only one showed the superiority of taxanes versus anthracyclines alone. Those investigating alternative regimens did not show improvements over standard regimens despite significant limitations. Five publications on GEP, including 445,323 older patients, were included and investigated Oncotype DX. Limited evidence shows that GEP aids treatment decisions in this population. GEP was offered less frequently to older versus younger patients. Higher Recurrence Score was prognostic for distant recurrence, but chemotherapy did not improve prognosis.CONCLUSIONS:In older patients with HR-positive, HER2-negative, chemotherapy survival benefits EBC are unclear and GEP is less used. Although its prognostic role is well established, its predictive role remains unknown.