Predicting Benefit From FOLFOXIRI Plus Bevacizumab in Patients With Metastatic Colorectal Cancer.

PURPOSE: Patient outcomes may differ from randomized trial averages. We aimed to predict benefit from FOLFOXIRI versus infusional fluorouracil, leucovorin, and oxaliplatin/fluorouracil, leucovorin, and irinotecan (FOLFOX/FOLFIRI), both plus bevacizumab, in patients with metastatic colorectal cancer (mCRC). METHODS: A Cox model with prespecified clinical, molecular, and laboratory variables was developed in 639 patients from the TRIBE2 trial for predicting 2-year mortality. Data from the CHARTA (n = 232), TRIBE1 (n = 504), and CAIRO5 (liver-only mCRC, n = 287) trials were used for external validation and heterogeneity of treatment effects (HTE) analysis. This involves categorizing patients into risk groups and assessing treatment effects across these groups. Performance was assessed by the C-index and calibration plots. The C-for-benefit was calculated to assess evidence for HTE. The c-for-benefit is specifically designed for HTE analysis. Like the commonly known c-statistic, it summarizes the discrimination of a model. Values over 0.5 indicate evidence for HTE. RESULTS: In TRIBE2, the overoptimism-corrected C-index was 0.66 (95% CI, 0.63 to 0.69). At external validation, the C-index was 0.69 (95% CI, 0.64 to 0.75), 0.68 (95% CI, 0.64 to 0.72), and 0.65 (95% CI, 0.65 to 0.66), in CHARTA, TRIBE1, and CAIRO5, respectively. Calibration plots indicated slight underestimation of mortality. The c-for-benefit indicated evidence for HTE in CHARTA (0.56, 95% CI, 0.48 to 0.65), but not in TRIBE1 (0.49, 95% CI, 0.44 to 0.55) and CAIRO5 (0.40, 95% CI, 0.32 to 0.48). CONCLUSION: Although 2-year mortality could be reasonably estimated, the HTE analysis showed that clinically available variables did not reliably identify which patients with mCRC benefit from FOLFOXIRI versus FOLFOX/FOLFIRI, both plus bevacizumab, across the three studies.

Adjuvant chemotherapy in patients with clinically node-negative but pathologically node-positive rectal cancer in the Netherlands: A retrospective analysis.

INTRODUCTION: Accurate clinical staging of rectal cancer is hampered by suboptimal sensitivity of MRI in the detection of regional lymph node metastases. Consequently, some patients may be understaged and have been withheld neoadjuvant (chemo)radiotherapy in retrospect. Although Dutch guidelines do not advocate adjuvant chemotherapy (ACT) in rectal cancer, some of these clinically understaged patients receive ACT according to local policy. We aim to assess the benefit of ACT in these patients. METHODS: Population-based data from patients with clinically node-negative (cN0) but pathologically node-positive (pN+) rectal cancer that underwent total mesorectal excision (TME) without neoadjuvant treatment between 2008 and 2018 were obtained from the Netherlands Cancer Registry. Missing data were handled by multiple imputation. Stabilised inverse probability treatment weighting (sIPTW) was used to balance clinical characteristics. Overall survival (OS) was compared in ACT and non-ACT patients. RESULTS: Of 34,724 patients, 13,861 had cN0 disease of whom 3016 were pN+ (21.8%). 1466 (48.6%) of these patients underwent upfront TME and were included. Median follow-up was 84 months (95% confidence interval [CI] 76-97) versus 79 months (95% CI 77-81) in patients that did (n = 290, 19.8%) and did not (n = 1176, 80.2%) receive ACT, respectively. After sIPTW adjustment, ACT was associated with improved OS (hazard ratio 0.70; 95% CI 0.49-0.99; p = 0.04). The estimated 5-year OS rate was 74.2% versus 65.3%, respectively. CONCLUSION: In this population-based cohort of patients with cN0 but pN+ rectal cancer who underwent upfront TME, ACT was associated with a significant OS benefit. These data support to discuss ACT in this population.

Long-Term Safety Data on S-1 Administered After Previous Intolerance to Capecitabine-Containing Systemic Treatment for Metastatic Colorectal Cancer.

INTRODUCTION: The oral fluoropyrimidine S-1 has shown comparable efficacy to capecitabine in Asian and some Western studies on metastatic colorectal cancer. S-1 is associated with a lower incidence of hand-foot syndrome (HFS) and cardiac toxicity. We assessed the long-term tolerability of S-1 in patients who discontinued capecitabine for reasons of HFS or cardiac toxicity. PATIENTS AND METHODS: Patients with metastatic colorectal cancer who switched from capecitabine to S-1, given as monotherapy or in combination with other agents, were identified in a Dutch prospective cohort study (2016-2021). The incidence and severity of HFS, cardiotoxicity and other toxicities were assessed. RESULTS: Forty-seven patients were identified. The median duration of capecitabine treatment was 81 days (range 4-454). In 19 patients (40%) a dose reduction was applied prior to switch to S-1. Reasons for discontinuation of capecitabine were HFS in 36 (77%) patients, coronary artery vasospasms in 10 (21%) patients, and gastrointestinal toxicities in 1 patient (2%). The median number of S-1 cycles was 6 (range 1-36). The median time between last dose of capecitabine and first dose of S-1 was 11 days (range 1-49). After switch to S-1, all patients with prior HFS developed a lower grade or complete resolution of symptoms, and in all other patients symptoms did not recur. Other S-1-related adverse events were limited to grade 1-2. Six patients (13%) discontinued S-1 due to either known fluoropyrimidine-related or bevacizumab-related toxicities. Switch to S-1 did not appear to compromise treatment efficacy. CONCLUSION: S-1 is a valid alternative to capecitabine in case HFS or cardiotoxicity occurs.

Management of cytotoxic chemotherapy-induced hand-foot syndrome.

Improvements in systemic cancer treatments have resulted in more patients surviving for prolonged periods of time on treatment. This has made treatment-related toxicity and quality of life concerns increasingly relevant. Hand-foot syndrome (HFS) is a common skin reaction to systemic therapy that should be anticipated with chemotherapeutic treatments such as pegylated liposomal doxorubicin, docetaxel, and fluoropyrimidines. In this review we discuss current knowledge of the diagnosis, incidence, pathogenesis, and management of hand-foot syndrome (HFS). Although HFS is not life threatening, it can cause significant discomfort and impairment of function, especially in elderly patients, and may seriously impact quality of life. The incidence of HFS is dependent on the chemotherapeutic drug used, the treatment schedule, and the median duration of treatment. Effective measures for prevention and treatment of HFS include systemic and topical treatments, dose reductions, and switching to other drugs in the same class that are associated with lower rates of HFS. These approaches allow patients to continue cancer treatment while reducing negative impacts on quality of life. Awareness and early recognition are important to ensure timely treatment and avoidance of dose reductions or treatment discontinuation. We provide useful recommendations to guide the management of HFS in clinical practice.

Choosing the right strategy based on individualized treatment effect predictions: combination versus sequential chemotherapy in patients with metastatic colorectal cancer.

BACKGROUND: Translating results from randomized trials to individual patients is challenging, since treatment effects may vary due to heterogeneous prognostic characteristics. We aimed to demonstrate model development for individualized treatment effect predictions in cancer patients. We used data from two randomized trials that investigated sequential versus combination chemotherapy in unresectable metastatic colorectal cancer (mCRC) patients. MATERIAL AND METHODS: We used data from 803 patients included in CAIRO for prediction model development and internal validation, and data from 1423 patients included in FOCUS for external validation. A Weibull model with pre-specified patient and tumour characteristics was developed for a prediction of gain in median overall survival (OS) by upfront combination versus sequential chemotherapy. Decision curve analysis with net benefit was used. A nomogram was built using logistic regression for estimating the probability of receiving second-line treatment after the first-line monochemotherapy. RESULTS: Median-predicted gain in OS for the combination versus sequential chemotherapy was 2.3 months (IQR: -1.1 to 3.7 months). A predicted gain in favour of sequential chemotherapy was found in 231 patients (29%) and a predicted gain of >3 months for combination chemotherapy in 294 patients (37%). Patients with benefit from sequential chemotherapy had metachronous metastatic disease and a left-sided primary tumour. Decision curve analyses showed improvement in a net benefit for treating all patients according to prediction-based treatment compared to treating all patients with combination chemotherapy. Multiple characteristics were identified as prognostic variables which identify patients at risk of never receiving second-line treatment if treated with initial monochemotherapy. External validation showed good calibration with moderate discrimination in both models (C-index 0.66 and 0.65, respectively). CONCLUSIONS: We successfully developed individualized prediction models including prognostic characteristics derived from randomized trials to estimate treatment effects in mCRC patients. In times where the heterogeneity of CRC becomes increasingly evident, such tools are an important step towards personalized treatment.

Survival after whole brain radiotherapy for brain metastases from lung cancer and breast cancer is poor in 6325 Dutch patients treated between 2000 and 2014.

BACKGROUND: Whole brain radiotherapy (WBRT) is considered standard of care for patients with multiple brain metastases or unfit for radical treatment modalities. Recent studies raised discussion about the expected survival after WBRT. Therefore, we analysed survival after WBRT for brain metastases 'in daily practice' in a large nationwide multicentre retrospective cohort. METHODS: Between 2000 and 2014, 6325 patients had WBRT (20 Gy in 4 Gy fractions) for brain metastases from non-small cell lung cancer (NSCLC; 4363 patients) or breast cancer (BC; 1962 patients); patients were treated in 15 out of 21 Dutch radiotherapy centres. Survival was calculated by the Kaplan-Meier method from the first day of WBRT until death as recorded in local hospital data registration or the Dutch Municipal Personal Records Database. FINDINGS: The median survival was 2.7 months for NSCLC and 3.7 months for BC patients (p < .001). For NSCLC patients aged <50, 50-60, 60-70 and >70 years, survival was 4.0, 3.0, 2.8 and 2.1 months, respectively (p < .001). For BC patients, survival was 4.5, 3.8, 3.2 and 2.9 months, respectively (p = .047). In multivariable analyses, higher age was related to poorer survival with hazard ratios (HR) for patients aged 50-60, 60-70 and >70 years being 1.05, 1.19 and 1.34, respectively. Primary BC (HR: 0.83) and female sex (HR: 0.85) were related to better survival (p < .001). INTERPRETATION: The survival of patients after WBRT for brain metastases from NSCLC treated in Dutch 'common radiotherapy practice' is poor, in breast cancer and younger patients it is disappointingly little better. These results are in line with the results presented in the QUARTZ trial and we advocate a much more restrictive use of WBRT. In patients with a more favourable prognosis the optimal treatment strategy remains to be determined. Prospective randomized trials and individualized prognostic models are needed to identify these patients and to tailor treatment.

Feasibility and effectiveness of trifluridine/tipiracil in metastatic colorectal cancer: real-life data from The Netherlands.

BACKGROUND: The RECOURSE trial showed clinical efficacy for trifluridine/tipiracil for refractory metastatic colorectal cancer patients. We assessed the feasibility and effectiveness of trifluridine/tipiracil in daily clinical practice in The Netherlands. METHODS: Medical records of patients from 17 centers treated in the trifluridine/tipiracil compassionate use program were reviewed and checked for RECOURSE eligibility criteria. Baseline characteristics, safety, and survival times were compared, and prespecified baseline characteristics were tested in multivariate analyses for prognostic significance on overall survival (OS). RESULTS: A total of 136 patients with a median age of 62 years were analyzed. Forty-three patients (32%) did not meet the RECOURSE eligibility criteria for not having received all prior standard treatments (n = 35, 26%) and/or ECOG performance status (PS) 2 (n = 12, 9%). The most common grade ≥3 toxicities were neutropenia (n = 44, 32%), leukopenia (n = 8, 6%), anemia (n = 7, 5%), and fatigue (n = 7, 5%). Median progression-free survival (PFS) and median OS were 2.1 (95% CI, 1.8-2.3) and 5.4 months (95% CI, 4.0-6.9), respectively. Patients with ECOG PS 2 had a worse median OS (3.2 months) compared to patients with ECOG PS 0-1 (5.9 months). ECOG PS, KRAS-mutation status, white blood cell count, serum lactate dehydrogenase, and alkaline phosphatase were prognostic factors for OS. CONCLUSIONS: Our data show that treatment with trifluridine/tipiracil in daily clinical practice is feasible and safe. Differences in patient characteristics between our population and the RECOURSE study population should be taken into account in the interpretation of survival data. Our results argue against the use of trifluridine/tipiracil in patients with ECOG PS 2. FUNDING: Johannes J.M. Kwakman received an unrestricted research grant from Servier.

Incidence of capecitabine-related cardiotoxicity in different treatment schedules of metastatic colorectal cancer: A retrospective analysis of the CAIRO studies of the Dutch Colorectal Cancer Group.

BACKGROUND: The frequency of capecitabine-related cardiotoxicity has been reported to be low but includes serious adverse events. We conducted a retrospective analysis of the incidence and severity of capecitabine-related cardiotoxicity in different regimens in the treatment of metastatic colorectal cancer in three randomised phase 3 studies. METHODS: We used data of cardiac events reported in the CAIRO, CAIRO2 and CAIRO3 studies of the Dutch Colorectal Cancer Group (DCCG) and analysed the incidence and severity of cardiac events in the different treatment regimens of the trials which all included the use of capecitabine. The following events were included: chest pain, newly diagnosed cardiac ischaemia/infarction, atrial fibrillation, other arrhythmias and heart failure, all graded according to National Cancer Institute Common Toxicity Criteria (NCI-CTC). RESULTS: A total of 1973 patients were included, who received a total of 2461 capecitabine-based lines of treatment. Overall, 5.9% of patients (n = 117) experienced at least one cardiac event, and 2.3% (n = 46) experienced at least one grade ≥3 event. Three patients had two cardiac events. The most frequently observed cardiac event was ischaemia/infarction (2.9%, n = 57), followed by arrhythmias (2.0%, n = 40, including atrial fibrillation in 10 patients), chest pain (0.8%, n = 16) and heart failure (0.4%, n = 7). The highest incidence of cardiac events was observed in patients treated with capecitabine in combination with oxaliplatin and bevacizumab (12%, n = 43). CONCLUSION: We observed capecitabine-related cardiotoxicity in 5.9% of patients, and severe cardiotoxicity in 2.3% of patients. Combination treatment with capecitabine, oxaliplatin and bevacizumab was associated with the highest risk of cardiotoxicity.