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.

Treatment Options in Late-Line Colorectal Cancer: Lessons Learned from Recent Randomized Studies.

Systemic treatment of metastatic colorectal cancer (mCRC) has improved considerably over the past 20 years. First- and second-line combinations of 5FU, oxaliplatin, and irinotecan, with or without anti-angiogenic and/or anti-EGFR antibodies, were approved shortly after the turn of the millennium. Further triumphs were not seen for almost 10 years, until the approval of initially regorafenib and shortly after trifluridine/tipiracil. A growing understanding of tumor biology through molecular profiling has led to further treatment options. Here, we review the most recent clinical data for late-line treatment options in mCRC, focusing on randomized trials if available. We include recommendations for options in unselected patients and therapies that should only be offered in patients with distinct tumor profiles (e.g., BRAF mutations, KRAS G12C mutations, HER2 amplification, deficient MMR, or NTRK gene fusions).

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.

Information provision to older patients receiving palliative chemotherapy: a quality study.

OBJECTIVES: Cancer treatment has become increasingly successful. However, prolonging and preserving life has become an important goal of therapy since many patients generally receive palliative chemotherapy. The perception of life changes when patients are informed, that no curative treatment is possible. This raises new dilemmas for patients with incurable cancer, but only sparse information is available about the thoughts of these patients.The aim of this study was to explore how older patients experience the information on absence of curative treatment options. METHODS: Qualitative interviews were performed in eleven older patients with incurable upper gastrointestinal cancer receiving first-line palliative chemotherapy. Median age was 74 (65-76) years. We used a qualitative approach to collect data through semistructured individual interviews conducted at the hospital or by telephone interviews by an experienced researcher. The thematic analysis was conveyed by Braun and Clarke. RESULTS: The interview findings were grouped around three main themes: hope of being cured, hearing but not comprehending, and desired milestones to reach. Further, it was determined that patients hid their feelings and avoided talking about the disease with the health professionals due to fear of being told the truth. CONCLUSIONS: Receiving information about their incurable cancer was an ongoing dilemma for the patients. Following the message, patients shared thoughts about reaching important milestones in life, spending time with their family or hope for a cure to be found.

Quality of Life in Vulnerable Older Patients with Metastatic Colorectal Cancer Receiving Palliative Chemotherapy-The Randomized NORDIC9-Study.

Quality of life data from randomized trials are lacking in older patients with metastatic colorectal cancer (mCRC). In the randomized NORDIC9-study, reduced-dose S1+oxaliplatin (SOx) showed superior efficacy compared to full-dose S1 monotherapy. We hypothesized that treatment with SOx does not result in inferior quality of life. Patients with mCRC aged ≥70 years and that were not a candidate for standard combination chemotherapy were included and randomly assigned to receive either S1 or SOx. The EORTC QLQ-C30 questionnaire was completed at baseline, after 9, and 18 weeks. The primary endpoint was global Quality of Life (QoL) at 9 weeks. For statistical analysis, a non-inferiority design was chosen applying linear mixed effects models for repeated measurements. The results were interpreted according to statistical significance and anchor-based, clinically relevant between-group minimally important differences (MID). A total of 160 patients aged (median (Interquartile range (IQR))) 78 years (76-81) were included. The QLQ-C30 questionnaire was completed by 150, 100, and 60 patients at baseline, at 9, and 18 weeks, respectively. The difference at 9 weeks in global QoL was 6.85 (95%CI-1.94; 15.65) and 7.37 (0.70; 14.05) in the physical functioning domain in favor of SOx exceeding the threshold for MID. At 18 weeks, the between-group MID in physical functioning was preserved. Dose-reduced combination chemotherapy may be recommended in vulnerable older patients with mCRC, rather than full-dose monotherapy.

Frailty screening for predicting rapid functional decline, rapid progressive disease, and shorter overall survival in older patients with gastrointestinal cancer receiving palliative chemotherapy - a prospective, clinical study.

OBJECTIVES: A growing number of older patients with cancer require well-founded clinical decision-making. Frailty screening is suggested as a service to improve outcomes in vulnerable older patients with cancer. This prospective study examined the value of frailty screening to predict rapid functional decline, rapid progressive disease (PD) and shorter overall survival (OS) in older patients with gastrointestinal cancer receiving palliative chemotherapy. MATERIALS AND METHODS: Patients aged ≥70 years were screened for frailty in an oncologic department after clinical decision but before starting palliative chemotherapy. Screening was repeated at first response evaluation after approximately two months of chemotherapy. Frailty screening tools included performance status (PS), Charlson Comorbidity Index, G-8 using two different cut-offs (G814,G811), VES-13, Timed-Up-and-Go, Handgrip strength and falls. RESULTS: A total of 170 patients were included, median age was 75.5 (70-88) years and 65.9% were male. The frequency of frailty varied from 14% to 74% according to the chosen frailty tool. In multivariate analysis G814 predicted OS (HR 1.5; 95%CI 1.0-2.4), whereas G811 predicted PD (OR 2.4; 1.1-5.6) and OS (HR 2.1; 1.4-2.9). VES-13 predicted functional decline (OR 3.5; 1.0-11.6), PD (OR 3.5; 1.5-8.4) and OS (HR 1.7; 1.2-2.4). Timed-Up-and-Go predicted OS (HR 1.8; 1.1-2.7). Handgrip strength and falls predicted functional decline (OR 4.5; 1.1-19 and OR 6.1; 1.4-25.8, respectively). PS predicted PD (OR 6.2; 2.6-14.7) and OS (HR 2.2; 1.5-3.2). CONCLUSION: VES-13 was useful for predicting all three endpoints of interest. Frailty tools covering domains of functioning and nutrition are suggested for older patients with advanced gastrointestinal cancer.

TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial.

BACKGROUND: TAS-102 (trifluridine-tipiracil) has shown a significant overall survival benefit compared with placebo in patients with chemorefractory metastatic colorectal cancer. Inspired by the encouraging results of a small phase 1-2 study, C-TASK FORCE, which evaluated the combination of TAS-102 plus bevacizumab in patients with chemorefractory metastatic colorectal cancer, we aimed to compare the efficacy of TAS-102 plus bevacizumab versus TAS-102 monotherapy in patients receiving refractory therapy for metastatic colorectal cancer . METHODS: This investigator-initiated, open-label, randomised, phase 2 study enrolled patients (aged ≥18 years) with metastatic colorectal from four cancer centres in Denmark. The main inclusion criteria were histopathologically confirmed metastatic colorectal cancer refractory or intolerant to a fluoropyrimidine, irinotecan, oxaliplatin, and cetuximab or panitumumab (only for RAS wild-type), and WHO performance status of 0 or 1. Previous therapy with bevacizumab, aflibercept, ramucirumab, or regorafenib was allowed but not mandatory. Participants were enrolled and randomly assigned (1:1) in block sizes of two, four, or six by a web-based tool to receive oral TAS-102 (35 mg/m2 twice daily on days 1-5 and 8-12 every 28 days) alone or combined with intravenous bevacizumab (5 mg/kg on days 1 and 15) until progression, unacceptable toxicity, or patient decision to withdraw. Treatment assignment was not masked, and randomisation was stratified by institution and RAS mutation status. The primary endpoint was investigator-evaluated progression-free survival. All analyses were based on intention to treat. This trial is registered with EudraCT, 2016-005241-23. FINDINGS: From Aug 24, 2017, to Oct 31, 2018, 93 patients were enrolled and randomly assigned to TAS-102 (n=47) or TAS-102 plus bevacizumab (n=46). The clinical cut-off date was Feb 15, 2019, after a median follow-up of 10·0 months (IQR 6·8-14·0). Median progression-free survival was 2·6 months (95% CI 1·6-3·5) in the TAS-102 group versus 4·6 months (3·5-6·5) in the TAS-102 plus bevacizumab group (hazard ratio 0·45 [95% CI 0·29-0·72]; p=0·0015). The most frequent grade 3 or worse adverse event was neutropenia (18 [38%] of 47 in the TAS-102 monotherapy group vs 31 [67%] of 46 in the TAS-102 plus bevacizumab group). Serious adverse events were observed in 21 (45%) patients in the TAS-102 group and 19 (41%) in the TAS-102 plus bevacizumab group. No deaths were deemed treatment related. INTERPRETATION: In patients with chemorefractory metastatic colorectal cancer, TAS-102 plus bevacizumab, as compared with TAS-102 monotherapy, was associated with a significant and clinically relevant improvement in progression-free survival with tolerable toxicity. The combination of TAS-102 plus bevacizumab could be a new treatment option for patients with refractory metastatic colorectal cancer and could be a practice-changing development. FUNDING: Servier.

Reduced-dose combination chemotherapy (S-1 plus oxaliplatin) versus full-dose monotherapy (S-1) in older vulnerable patients with metastatic colorectal cancer (NORDIC9): a randomised, open-label phase 2 trial.

BACKGROUND: Older or vulnerable patients with metastatic colorectal cancer are seldom included in randomised trials. The multicentre NORDIC9 trial evaluated reduced-dose combination chemotherapy compared with full-dose monotherapy in older, vulnerable patients. METHODS: This randomised, open-label phase 2 trial was done in 23 Nordic oncology clinics and included patients aged 70 years or older with previously untreated metastatic colorectal cancer who were not candidates for full-dose combination chemotherapy. Patients were block randomised (1:1) using a web-based tool to full-dose S-1 (30 mg/m2 orally twice daily on days 1-14 every 3 weeks) followed by second-line treatment at progression with irinotecan (250 mg/m2 intravenously on day 1 every 3 weeks or 180 mg/m2 intravenously on day 1 every 2 weeks) or reduced-dose combination chemotherapy with S-1 (20 mg/m2 orally twice daily on days 1-14) and oxaliplatin (100 mg/m2 intravenously on day 1 every 3 weeks) followed by second-line treatment at progression with S-1 (20 mg/m2 orally twice daily on days 1-14) and irinotecan (180 mg/m2 intravenously on day 1 every 3 weeks). Use of bevacizumab (7·5 mg/kg intravenously on day 1 of each cycle) was optional. Treatment allocation was not masked and randomisation was stratified for institution and bevacizumab. The primary outcome was progression-free survival. Survival analyses were by intention to treat and safety analyses were done on the treated population. This trial is registered with EudraCT, number 2014-000394-39, and is closed to new participants. FINDINGS: From March 9, 2015, to Oct 11, 2017, 160 patients with a median age of 78 years (IQR 76-81) were randomly assigned to full-dose monotherapy (n=83) or reduced-dose combination chemotherapy (n=77). At data cutoff (Sept 1, 2018; median follow-up 23·8 months [IQR 18·8-30·9]), 81 (98%) patients in the full-dose monotherapy group and 71 (92%) patients in the reduced-dose combination group had progressed or died. Median progression-free survival was significantly longer with reduced-dose combination chemotherapy (6·2 months [95% CI 5·3-8·3]) than with full-dose monotherapy (5·3 months [4·1-6·8]; hazard ratio [HR] 0·72 [95% CI 0·52-0·99]; p=0·047). Toxicity was evaluated in 157 patients who received treatment. Significantly more patients in the full-dose monotherapy group (51 [62%] of 82 patients) experienced at least one grade 3-4 adverse event than in the reduced-dose combination group (32 [43%] of 75 patients; p=0·014). Grade 3-4 diarrhoea (12 [15%] vs two [3%]; p=0·018), fatigue (ten [12%] vs three [4%]; p=0·083), and dehydration (five [6%] vs none; p=0·060) were more frequent in the full-dose monotherapy group than in the reduced-dose combination group. Treatment-related deaths occurred in three patients during first-line treatment and three patients during second-line treatment (two in the full-dose monotherapy group vs one in the reduced-dose combination group in both cases). INTERPRETATION: Reduced-dose combination chemotherapy with S-1 and oxaliplatin for older, vulnerable patients with metastatic colorectal cancer was more effective and resulted in less toxicity than full-dose monotherapy with S-1. Reduced-dose combination chemotherapy could be a preferred treatment for this population. FUNDING: Taiho Pharmaceuticals, Nordic Group, the Danish Cancer Society, the Swedish Cancer Society, Academy of Geriatric Research (AgeCare), and Region of Southern Denmark.

S-1 (Teysuno) and gemcitabine in Caucasian patients with unresectable pancreatic adenocarcinoma.

PURPOSE: Gemcitabine has been standard of care in advanced pancreatic adenocarcinomas (PC) for almost two decades. Randomized, primarily Japanese, studies have shown promising efficacy when combined with S-1 (GemS-1); however, no data are published in Caucasian patients. We report the first study with a combination of GemS-1 in an unselected cohort of Caucasian PC patients. METHODS: In this observational cohort study, we analyzed efficacy and toxicity prospectively. RESULTS: From July 2012 to July 2014, 64 patients received at least one cycle of GemS-1. 16 patients started therapy with gemcitabine and capecitabine (GemCap) but switched to GemS-1 after median 3 cycles of GemCap due to toxicity (hand-foot syndrome). 48 patients received GemS-1 as initial therapy. For the complete cohort, median age was 68 years (range 44-80); 22 patients (34%) had locally advanced PC; 42 patients (66%) had metastatic disease. Five patients had received prior adjuvant therapy with gemcitabine and 9 pts had received prior first-line therapy. The most common adverse event was fatigue (86%), however, only grade 3 in 3%. Five patients (8%) developed febrile neutropenia. Median PFS was 8.1 (95% CI 6.9-9.0) months and median OS was 11.7 (95% CI 10.7-13.1) months in the whole GemS-1 population. In the 48 patients starting with GemS-1, median PFS was 7.7 (95% CI 6.7-8.9) months and median OS was 11.5 (95% CI 9.7-12.3) months. CONCLUSIONS: The combination of gemcitabine and S-1 is safe and associated with promising efficacy in a Caucasian population; however, this needs to be confirmed in prospective clinical trials.

Randomized study comparing full dose monotherapy (S-1 followed by irinotecan) and reduced dose combination therapy (S-1/oxaliplatin followed by S-1/irinotecan) as initial therapy for older patients with metastatic colorectal cancer: NORDIC 9.

BACKGROUND: Metastatic colorectal cancer (mCRC) is a disease of older age, but there is a relative lack of knowledge about effects of chemotherapy in older patients as they are under-represented in clinical trials. Little data can guide whether the strategy in older mCRC patients should be a sequential full-dose monotherapy chemotherapy approach or a dose-reduced combination chemotherapy approach. The oral 5FU prodrug S-1 seems to have less side effects than capecitabine and should be an optimal drug for older patients, but few data are available. Improved geriatric assessments are needed to select which older patients should receive therapy. METHODS: The NORDIC 9 trial is a Nordic multicenter randomized phase II study comparing full dose monotherapy (S-1 30 mg/m2 twice daily days 1-14 every 3 weeks, followed by second line irinotecan 250-350 mg/m2 iv day 1 every 3 weeks or 180-250 mg/m2 iv day 1 every 2 weeks) with reduced dose combination therapy (S-1 20 mg/m2 days 1-14 + oxaliplatin 100 mg/m2 iv day 1 every 3 weeks, followed by second line S-1 20 mg/m2 days 1-14 + irinotecan 180 mg/m2 day 1 every 3 week) for older patients (≥70 years) with mCRC who are not candidates for full-dose standard combination therapy. Additional bevacizumab (7.5 mg/kg) is optional in first-line. Blood samples and tumor tissue will be collected to investigate predictive markers. Geriatric screening tools (G-8, VES-13, Timed-Up-and-Go and Handgrip strength), Charlson Comorbidty Index and quality of life (EORTC QLQ-C30) will be evaluated as predictors of efficacy and toxicity. The target sample size is 150 patients. The primary endpoint is progression-free survival and secondary endpoints are time-to-failure of strategy, overall survival, response rate, toxicity, and correlations between biomarkers, pre-treatment characteristics and geriatric assessments. DISCUSSION: The study will add knowledge on how to treat older mCRC patients who are not candidates for standard combination therapy. Furthermore it may provide understanding of efficacy and tolerability of chemotherapy in older cancer patients and thus offer a better chance for tailored treatment strategies in these patients. TRIAL REGISTRATION: EU Clinical Trial Register, EudraCT no. 2014-000394-39 . Registered 05 May 2014.

Can we predict toxicity and efficacy in older patients with cancer? Older patients with colorectal cancer as an example.

Colorectal cancer is a disease of the elderly. As older and frail patients are under-represented in clinical trials, most of the evidence available on treatment of older metastatic colorectal patients with cancer originates from pooled analyses of the older patients included in large prospective clinical trials and from community-based studies. The aging process is highly individual and cannot be based on the chronological age alone. It is characterised by a decline in organ function with an increased risk of comorbidity and polypharmacy. These issues can result in an increased susceptibility to the complications of both the disease and treatment. Therefore, evaluation of performance status and the chronological age alone is not sufficient, and additionally assessment must be included in the treatment decision process. In the present review, we will focus on clinical aspects of treating older and frail metastatic colorectal patients with cancer, but also on the present knowledge on how to select and tailor therapy for this particular group of patients. TRIAL REGISTRATION NUMBER: EudraCT 2014-000394-39, pre-results.

Experience with S-1 in older Caucasian patients with metastatic colorectal cancer (mCRC): Findings from an observational chart review.

BACKGROUND: An aging population will increase the number of older patients with metastatic colorectal cancer (mCRC). However, there is limited knowledge about treatment in older patients as they are under-represented in clinical trials. The oral fluoropyrimidine S-1 is associated with a lower rate of adverse events than capecitabine and may therefore be a suitable drug for elderly. However, data on the use of S-1 in Caucasian mCRC patients are lacking/scarce. MATERIAL AND METHODS: In the present study we evaluated safety and the efficacy of S-1 alone or in combination with oxaliplatin (SOx) or irinotecan (IRIS) in older mCRC patients. Patients who received at least one cycle of S-1 (first-line therapy), SOx (mainly first-line therapy) or IRIS (second-line therapy) were included. RESULTS: From June 2012 to December 2014, 71 older patients received ≥1 cycle of either S-1 (n = 9), SOx (n = 44) or IRIS (n = 18) for mCRC. Median age was 76 years and most patients had a WHO performance status of 0 (32%) or 1 (56%). All patients were evaluable for response and safety. In the SOx group, 18 (41%) and 20 patients (45%) had partial response (PR) and stable disease (SD), respectively (disease control rate 86%). Median progression-free survival (PFS) was 8.5 months and median overall survival (OS) was 18.5 months. In the S-1 group (median age 82 years), PR was 22%, median PFS 6.4 months and median OS 15.8 months. In the IRIS group, PR was 28%, median PFS 7.8 months and the median OS 16.5 months. In general, therapy was well tolerated; main non-hematological toxicities were fatigue and diarrhea. CONCLUSION: S-1 monotherapy, SOx and IRIS were well tolerated for older patients with mCRC and could become alternative regimens in older mCRC patients. These regimens are now further evaluated in the randomized ongoing NORDIC9 trial.