Detailed analysis of metastatic colorectal cancer patients who developed cardiotoxicity on another fluoropyrimidine and switched to S-1 treatment (subgroup analysis of the CardioSwitch-study).

BACKGROUND AND PURPOSE: The CardioSwitch-study demonstrated that patients with solid tumors who develop cardiotoxicity on capecitabine or 5-fluorouracil (5-FU) treatment can be safely switched to S-1, an alternative fluoropyrimidine (FP). In light of the European Medicines Agency approval of S-1 in metastatic colorectal cancer (mCRC), this analysis provides more detailed safety and efficacy information, and data regarding metastasectomy and/or local ablative therapy (LAT), on the mCRC patients from the original study. MATERIALS AND METHODS: This retrospective cohort study was conducted at 12 European centers. The primary endpoint was recurrence of cardiotoxicity after switch. For this analysis, safety data are reported for 78 mCRC patients from the CardioSwitch cohort (N = 200). Detailed efficacy and outcomes data were available for 66 mCRC patients. RESULTS: Data for the safety of S-1 in mCRC patients were similar to the original CardioSwitch cohort and that expected for FP-based treatment, with no new concerns. Recurrent cardiotoxicity (all grade 1) with S-1-based treatment occurred in 4/78 (5%) mCRC patients; all were able to complete FP treatment. Median progression-free survival from initiation of S-1-based treatment was 9.0 months and median overall survival 26.7 months. Metastasectomy and/or LAT was performed in 33/66 (50%) patients, and S-1 was successfully used in recommended neoadjuvant/conversion or adjuvant-like combination regimens and schedules as for standard FPs. INTERPRETATION: S-1 is a safe and effective FP alternative when mCRC patients are forced to discontinue 5-FU or capecitabine due to cardiotoxicity and can be safely used in the standard recommended regimens, settings, and schedules.

Palliative medical cancer treatment of the elderly.

Due to demographic changes the incidence of older patients with cancer will increase. The complexity of systemic treatment of cancer is also evolving. Older patients with cancer are underrepresented in clinical trials and do often not represent the older population treated in real-world setting. Knowledge on how to treat older patients with cancer is sparse and mostly based on pooled analyses from larger trials including older fit patients. Only few randomised trials include older patients with frailty. Clinical trials dedicated to older or frail patients with cancer are still an unmet need, as argued in this review.

Epigenetic and inflammatory markers in older adults with cancer: A Young International Society of Geriatric Oncology narrative review.

The number of adults aged ≥ 65 years with cancer is rapidly increasing. Older adults with cancer are susceptible to treatment-related acute and chronic adverse events, resulting in loss of independence, reduction in physical function, and decreased quality of life. Nevertheless, evidence-based interventions to prevent or treat acute and chronic adverse events in older adults with cancer are limited. Several promising blood-based biomarkers related to inflammation and epigenetic modifications are available to identify older adults with cancer who are at increased risk of accelerated aging and physical, functional, and cognitive impairments caused by the cancer and its treatment. Inflammatory changes and epigenetic modifications can be reversible and targeted by lifestyle changes and interventions. Here we discuss ways in which changes in inflammatory and epigenetic pathways influence the aging process and how these pathways can be targeted by interventions aimed at reducing inflammation and aging-associated biological markers. As the number of older adults with cancer entering survivorship continues to increase, it is becoming progressively more important to understand ways in which the benefit from treatment can be enhanced while reducing the effects of accelerated aging.

A randomized phase II study of full dose gemcitabine versus reduced dose gemcitabine and nab-paclitaxel in vulnerable patients with non-resectable pancreatic cancer (DPCG-01).

BACKGROUND: According to current evidence, the best treatment for fit patients with non-resectable pancreatic cancer (PC) is combination chemotherapy, whereas frail patients are recommended gemcitabine (Gem) monotherapy. Randomized controlled trials in colorectal cancer and a post-hoc analysis of gemcitabine and nab-paclitaxel (GemNab) in PC suggest, however, that reduced dose of combination chemotherapy may be feasible and more efficient compared to monotherapy in frail patients. The aim of this study is to investigate whether reduced dose GemNab is superior to full dose Gem in patients with resectable PC, who are not candidates for full dose combination chemotherapy in first line. METHODS: The Danish Pancreas Cancer Group (DPCG)-01 trial is a national multicenter prospective randomized phase II trial. A total of 100 patients in ECOG performance status 0-2 with non-resectable PC, not candidate for full dose combination chemotherapy in first line, but eligible for full dose Gem, will be included. Patients are randomized 1:1 to either full dose Gem or GemNab in 80% of recommended dose. The primary endpoint is progression-free survival. Secondary endpoints are overall survival, overall response rate, quality of life, toxicity and rate of hospitalizations during treatment. The correlation between blood inflammatory markers, including YKL-40 and IL-6, circulating tumor DNA, and tissue biomarkers of resistance to chemotherapy and outcome will be explored. Finally, the study will include measures of frailty (G8, modified G8, and chair-stand-test) to assess whether scoring would enable a personalized allocation to different treatments or indicates a possibility for interventions. DISCUSSION: Single-drug treatment with Gem has for frail patients with non-resectable PC been the main treatment option for more than thirty years, but the impact on outcome is modest. If improved results and sustained tolerability with reduced dose combination chemotherapy can be shown, this could change the future practice for this increasing group of patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05841420. Secondary Identifying No: N-20210068. EudraCT No: 2021-005067-52. PROTOCOL VERSION: 1.5, 16-MAY-2023.

Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer.

BACKGROUND: In a previous phase 3 trial, treatment with trifluridine-tipiracil (FTD-TPI) prolonged overall survival among patients with metastatic colorectal cancer. Preliminary data from single-group and randomized phase 2 trials suggest that treatment with FTD-TPI in addition to bevacizumab has the potential to extend survival. METHODS: We randomly assigned, in a 1:1 ratio, adult patients who had received no more than two previous chemotherapy regimens for the treatment of advanced colorectal cancer to receive FTD-TPI plus bevacizumab (combination group) or FTD-TPI alone (FTD-TPI group). The primary end point was overall survival. Secondary end points were progression-free survival and safety, including the time to worsening of the Eastern Cooperative Oncology Group (ECOG) performance-status score from 0 or 1 to 2 or more (on a scale from 0 to 5, with higher scores indicating greater disability). RESULTS: A total of 246 patients were assigned to each group. The median overall survival was 10.8 months in the combination group and 7.5 months in the FTD-TPI group (hazard ratio for death, 0.61; 95% confidence interval [CI], 0.49 to 0.77; P<0.001). The median progression-free survival was 5.6 months in the combination group and 2.4 months in the FTD-TPI group (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.54; P<0.001). The most common adverse events in both groups were neutropenia, nausea, and anemia. No treatment-related deaths were reported. The median time to worsening of the ECOG performance-status score from 0 or 1 to 2 or more was 9.3 months in the combination group and 6.3 months in the FTD-TPI group (hazard ratio, 0.54; 95% CI, 0.43 to 0.67). CONCLUSIONS: Among patients with refractory metastatic colorectal cancer, treatment with FTD-TPI plus bevacizumab resulted in longer overall survival than FTD-TPI alone. (Funded by Servier and Taiho Oncology; SUNLIGHT ClinicalTrials.gov number, NCT04737187; EudraCT number, 2020-001976-14.).

Interventions to improve nutritional status for older patients with cancer - a holistic approach is needed.

PURPOSE OF REVIEW: Older adults with cancer frequently experience malnutrition and sarcopenia resulting in lower treatment efficacy, increased risk of toxicities and healthcare costs, lower quality of life and shorter survival. Improving nutritional status in this rapidly growing population is an urgent need globally. We reviewed randomized controlled trials from the last 18 months focusing on nutritional status and applying multimodal interventions in older adults with cancer. RECENT FINDINGS: Several randomized controlled trials have been reported recently elucidating the impact of nutritional interventions as a part of multimodal interventions through different stages of cancer care. Although multimodal interventions rarely demonstrate survival benefit, they improve several important aspects of cancer care, including patient-centred endpoints such as physical functioning, adherence, patient satisfaction and quality of life. SUMMARY: Multimodal interventions including nutrition have the potential to improve patient-centred outcomes in older adults with cancer during the continuum of care, from prehabilitation to palliative care. Early, integrated supportive care applying the right intervention in the right setting at the proper time along with personalized antitumor treatment is the cornerstone of optimal holistic cancer care.

Trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer ineligible for intensive therapy (SOLSTICE): a randomised, open-label phase 3 study.

BACKGROUND: Trifluridine-tipiracil plus bevacizumab has shown efficacy in previous phase 2 studies including patients with unresectable metastatic colorectal cancer. We aimed to investigate first-line trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab in patients with unresectable metastatic colorectal cancer ineligible for intensive treatment. METHODS: In this open-label, randomised, phase 3 study, we enrolled patients aged 18 years and older with histologically confirmed metastatic colorectal cancer, ineligible for full-dose doublet or triplet chemotherapy and curative resection across 25 countries and regions. Participants were randomly allocated (1:1) to trifluridine-tipiracil plus bevacizumab or capecitabine plus bevacizumab until disease progression or unacceptable toxicity using an interactive web response system, stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1 vs 2), primary tumour location (right vs left colon), and the main reason for not being a candidate for intensive therapy (clinical condition vs non-clinical condition). The primary endpoint was investigator-assessed progression-free survival, defined as the time from randomisation to radiological progression or death from any cause, in the intention-to-treat population. Safety was assessed in all patients having taken at least one dose of the study drug. The trial is ongoing, findings presented here are those of the primary analysis of progression-free survival, conducted after 629 events had occurred. This study is registered with ClinicalTrials.gov, NCT03869892. FINDINGS: Between March 21, 2019, and Sept 14, 2020, 856 patients (54% male, 46% female) were randomly assigned to trifluridine-tipiracil plus bevacizumab (n=426) or capecitabine plus bevacizumab (n=430). After a median follow-up of 16·6 months (95% CI 16·5-17·1), the hazard ratio for progression-free survival for trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab was 0·87 (0·75-1·02; p=0·0464; protocol-defined significance level of p=0·021 not met). Investigator-assessed median progression-free survival was 9·4 months (95% CI 9·1-10·9) with trifluridine-tipiracil plus bevacizumab versus 9·3 months (8·9-9·8) with capecitabine plus bevacizumab. The most common grade 3 and higher treatment-emergent adverse events were neutropenia (220 [52%] of 423 patients in the trifluridine-tipiracil plus bevacizumab group vs six [1%] of 427 in the capecitabine plus bevacizumab group), decreased neutrophil count (78 [18%] vs four [<1%]), anaemia (60 [14%] vs 16 [4%]), and hand-foot syndrome (none vs 61 [15%]). Nine deaths (five in the trifluridine-tipiracil plus bevacizumab group and four in the capecitabine plus bevacizumab group) were treatment related. INTERPRETATION: First-line trifluridine-tipiracil plus bevacizumab was not superior to capecitabine plus bevacizumab in this population. As expected, the safety profile differed between the two treatments, but there were no new safety concerns. Trifluridine-tipiracil plus bevacizumab represents a feasible alternative to capecitabine plus bevacizumab in this population. FUNDING: Servier International Research Institute, Suresnes, France.

Prognostic value of baseline functional status measures and geriatric screening in vulnerable older patients with metastatic colorectal cancer receiving palliative chemotherapy - The randomized NORDIC9-study.

INTRODUCTION: Appropriate patient selection based on functional status is crucial when considering older adults for palliative chemotherapy. This pre-planned analysis of the randomized NORDIC9-study explored the prognostic value of four functional status measures regarding progression-free survival (PFS) and overall survival (OS) in vulnerable older patients with metastatic colorectal cancer (mCRC) receiving first-line palliative chemotherapy. MATERIALS AND METHODS: Patients ≥70 years of age with mCRC not candidates for standard full-dose combination chemotherapy were randomized to receive full-dose S1 or reduced-dose S1 + oxaliplatin. At baseline, functional status was assessed using ECOG performance status (ECOG PS), frailty phenotype, Geriatric 8 (G8), and Vulnerable Elderly Survey-13 (VES-13). Multivariable regression models were applied and C-statistics were estimated. RESULTS: In total, 160 patients with a median age of 78 years (IQR: 76-81) were included. While in univariate analyses, ECOG PS, frailty phenotype, and VES-13 were statistically significantly associated with differences in OS between subgroups, G8 was not (HR = 1.55, 95%CI: 0.99-2.41, p = 0.050). In multivariable analyses adjusted for age, sex, body mass index, and treatment allocation, we found significant differences between subgroups for all applied tools and with C-statistics in the moderate range for ECOG PS and VES-13. Concerning PFS, statistically significant differences were observed between subgroups of ECOG PS, G8, and VES-13 both in uni- and multivariable analyses, but not for frailty phenotype. DISCUSSION: In this Nordic cohort of vulnerable older patients with mCRC, baseline ECOG PS, frailty phenotype, G8, and VES-13 showed prognostic value regarding overall survival, and moderate predictive value of models based on ECOG PS and VES-13 was demonstrated.

The Prognostic Value of Pre-Treatment Circulating Biomarkers of Systemic Inflammation (CRP, dNLR, YKL-40, and IL-6) in Vulnerable Older Patients with Metastatic Colorectal Cancer Receiving Palliative Chemotherapy-The Randomized NORDIC9-Study.

Appropriate patient selection for palliative chemotherapy is crucial in patients with metastatic colorectal cancer (mCRC). We investigated the prognostic value of C-reactive protein (CRP), derived neutrophil-to-lymphocyte ratio (dNLR), Interleukin (IL)-6, and YKL-40 on progression-free survival (PFS) and overall survival (OS) in the NORDIC9 cohort. The randomized NORDIC9-study included patients ≥70 years with mCRC not candidates for standard full-dose combination chemotherapy. Participants received either full-dose S1 (Teysuno) or a dose-reduced S1 plus oxaliplatin. Blood samples were collected at baseline and biomarkers were dichotomized according to standard cut-offs. Multivariable analyses adjusted for age, sex, ECOG performance status, and treatment allocation; furthermore, C-statistics were estimated. In total, 160 patients with a median age of 78 years (IQR: 76−81) were included between 2015 and 2017. All investigated biomarkers were significantly elevated in patients with either weight loss, ≥3 metastatic sites, or primary tumor in situ. In multivariable analyses, all markers showed significant association with OS; the highest HR was observed for CRP (HR = 3.40, 95%CI: 2.20−5.26, p < 0.001). Regarding PFS, statistically significant differences were found for CRP and IL-6, but not for dNLR and YKL-40. Applying C-statistics, CRP indicated a good prognostic model for OS (AUC = 0.72, 95%CI: 0.67−0.76). CRP is an easily available biomarker, which may support therapeutic decision-making in vulnerable older patients with mCRC.

Chemotherapy and gene expression profiling in older early luminal breast cancer patients: An International Society of Geriatric Oncology systematic review.

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.

The Evolution of Geriatric Oncology and Geriatric Assessment over the Past Decade.

Cancer is predominantly a disease of aging, and older adults represent the majority of cancer diagnoses and deaths. Older adults with cancer differ significantly from younger patients, leading to important distinctions in cancer treatment planning and decision-making. As a consequence, the field of geriatric oncology has blossomed and evolved over recent decades, as the need to bring personalized cancer care to older adults has been increasingly recognized and a focus of study. The geriatric assessment (GA) has become the cornerstone of geriatric oncology research, and the past year has yielded promising results regarding the implementation of GA into routine cancer treatment decisions and outcomes for older adults. In this article, we provide an overview of the field of geriatric oncology and highlight recent breakthroughs with the use of GA in cancer care. Further work is needed to continue to provide personalized, evidence-based care for each older adult with cancer.

Gastroesophageal adenocarcinoma in older adults: A comprehensive narrative review of management by the Young International Society of Geriatric Oncology.

Gastroesophageal adenocarcinoma is a disease of older adults with very poor survival rates. Its incidence has risen dramatically across the world in recent decades. Current treatment approaches for older adults are based largely on extrapolated evidence from clinical trials conducted in younger and fitter participants than those more commonly encountered in clinical practice. Understanding how to apply available evidence to our patients in the clinic setting is essential given the high morbidity of both curative and palliative treatment. This review aims to use available data to inform the management of an older adult with gastroesophageal adenocarcinoma.

Association of patient-reported outcomes and ovarian cancer recurrence.

BACKGROUND: The vast majority of patients with advanced ovarian cancer experience disease recurrence after primary treatment. OBJECTIVE: To explore the diagnostic accuracy of repeated measurement of patient-reported outcomes and quality-of-life scores in relation to ovarian cancer recurrence. METHODS: Patients with ovarian cancer were recruited to the PROMova study by the end of their primary treatment at eight centers in Denmark. The purpose of the PROMova study was to explore the applicability of repeated use of patient-reported outcomes, which consisted of the European Organization for Research and Treatment of Cancer generic questionnaire and the ovarian specific questionnaire. The patient-reported outcomes were completed 3, 6, 9, 12, and 15 months after enrollment or until recurrence. The 3-month interval between completions was the period in which recurrence was assessed. Imaging and the biomarker CA125 were used as reference modality for recurrence. Mixed effects logistic regression was used to investigate the association between mean patient-reported outcome scores and recurrence. Receiver operating curves were used to establish cut-off scores. The diagnostic accuracy of patient-reported outcomes, including sensitivity, specificity, and positive and negative predictive values was estimated based on the Youden index. For combined scales, diagnostic accuracy was investigated based on multivariate analysis. RESULTS: The analysis included 196 patients with an overall recurrence rate of 50.5% and an overall mean time to recurrence of 302 days. With imaging as reference, patients with recurrence reported significantly lower global health, worse physical functioning, and more abdominal symptoms preceding recurrence. With CA125 as reference, global health, physical and emotional functioning were impaired. Despite the worsening of a number of symptoms prior to recurrence whichever reference modality was applied, the patient-reported outcome scores did not provide adequate diagnostic accuracy. CONCLUSION: Repeated use of patient-reported outcomes during surveillance of ovarian cancer was not of diagnostic value. Future efforts should be directed at improving the administration of patient-reported outcomes as well as exploring the potential of using these outcomes as an indicator of clinical relevance.