Survival and patient-reported outcomes of real-world high-risk stage II and stage III colon cancer patients after reduction of adjuvant CAPOX duration from 6 to 3 months

Aim: Adjuvant chemotherapy has been advised for high-risk stage II and III colon cancer since 2004. After the IDEA study showed no clinically relevant difference in outcome, reduction of adjuvant CAPOX duration from 6 to 3 months was rapidly adopted in the Dutch treatment guideline in 2017. This study investigates the real-world impact of the guideline change on overall survival (OS) and patient-reported outcomes (PROs). Methods: Patients with high-risk stage II (pT4 +) and III (pN+) colon cancer were selected from the Netherlands Cancer Registry, based on surgical resection and adjuvant CAPOX before (2015–2016) versus after (2018–2019) the guideline change. Both groups were compared on OS, using multivariable Cox regression, and on PROs. Results: Patients treated before (n = 2330) and after (n = 2108) the guideline change showed similar OS (HR 1.02; 95 %CI [0.89–1.16]), also in high-risk stage III (pT4/N2, HR 1.06 [0.89–1.26]). After the guideline change, 90 % of patients were treated for 3 months with no inferior OS to those still receiving 6 months (HR 0.89 [0.66–1.20]). PROs 2 years after CAPOX completion, available for a subset of patients, suggest a lower neuropathy (n = 366; 26.2 [21.3–31.1] to 16.5 [14.4–18.6]) and better quality of life (n = 396; 80.9 [78.6–83.2] to 83.9 [82.8–84.9]), but no significant difference in workability (n = 120; 31.5 [27.9–35.1]) to 35.3 [33.8–36.7]), with reduction from 6 to 3 months of CAPOX. Conclusion: This real-world study confirmed that shorter adjuvant CAPOX did not compromise OS and may improve PROs, complementing the IDEA study and supporting 3 months of adjuvant CAPOX in daily clinical practice

Use of preventive medication and supplements in general practice in patients in their last year of life: a Retrospective cohort study

Background: Several preventive medications and supplements become inappropriate in the last phase of life due to increased risk of adverse events caused by changed pharmacokinetics, drug-drug interactions, and changed care goals. Information on these preventive medication and supplements use in patients with a life-limiting illness in the home-care setting is limited. The primary aim of this study was to assess the use of four different groups of preventive drugs and supplements, which are inappropriate in adult patients with a life-limiting illness, living at home in the last year of life. The secondary aims were to assess reasons for discontinuing these drugs as documented in the general practitioners’ patient file and whether these reasons affected the time between medication discontinuation and death. Methods: We performed a retrospective cohort study using the routine primary care database of the Julius General Practitioners’ Network of the University Medical Centre Utrecht, a database consisting of routine care data from GPs from the city of Utrecht and its vicinity. Patients in the homecare setting with a life-limiting illness, diagnosed at least one year before death, were included. Descriptive analyses were used to describe the study population and the frequency of starting, using, and discontinuing medication and supplements in the last year of life. Results: A total of 458 of 666 included patients (69%) used at least one preventive drug in the last year of life. Vitamins were used by 36% of the patients, followed with 35% using cholesterol-lowering medication, 24% using calcium supplements and 9% using bisphosphonates. Bisphosphonates were discontinued by 70% of the users, calcium supplements by 61%, vitamins by 56% and cholesterol-lowering medication by 48% of the users, with a median interval between day of discontinuation and death of 119, 60, 110 and, 65 days, respectively. The median time between medication or supplement discontinuation and death was longest in patients with side effects and who had medication reviews. Conclusion: Many patients in their last phase of life in the home-care setting use inappropriate medication and supplements. Timely medication review may contribute to optimise medication use in the last year of life

Survival of Patients with Deficient Mismatch Repair Versus Proficient Mismatch Repair Metastatic Colorectal Cancer Receiving Curative-Intent Local Treatment of Metastases in a Nationwide Cohort

BACKGROUND: It is unclear whether curative-intent local therapy of metastases is of similar benefit for the biological distinct subgroup of patients with deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC) compared with proficient mismatch repair (pMMR) mCRC. PATIENTS AND METHODS: In this nationwide study, recurrence-free (RFS) and overall survival (OS) were analyzed in patients with dMMR versus pMMR mCRC who underwent curative-intent local treatment of metastases between 2015 and 2018. Subgroup analyses were performed for resection of colorectal liver metastases (CRLM) and cytoreductive surgery ± hyperthermic intraperitoneal chemotherapy (CRS ± HIPEC). Multivariable regression was conducted. RESULTS: Median RFS was 11.1 months [95% confidence interval (CI) 8.5-41.1 months] for patients with dMMR tumors compared with 8.9 months (95% CI 8.1-9.8 months) for pMMR tumors. Two-year RFS was higher in patients with dMMR versus pMMR (43% vs. 21%). Results were similar within subgroups of local treatment (CRLM and CRS ± HIPEC). Characteristics differed significantly between patients with dMMR and pMMR mCRC; however, multivariable analysis continued to demonstrate dMMR as independent factor for improved RFS [hazard ratio (HR): 0.57, 95% CI 0.38-0.87]. Median OS was 33.3 months for dMMR mCRC compared with 43.5 months for pMMR mCRC, mainly due to poor survival of patients with dMMR in cases of recurrence in the preimmunotherapy era. CONCLUSION: Patients with dMMR eligible for curative-intent local treatment of metastases showed a comparable to more favorable RFS compared with patients with pMMR, with a clinically relevant proportion of patients remaining free of recurrence. This supports local treatment as a valuable treatment option in patients with dMMR mCRC and can aid in shared decision-making regarding upfront local therapy versus immunotherapy

Harnessing the Potential of Real-World Evidence in the Treatment of Colorectal Cancer: Where Do We Stand?

Treatment guidelines for colorectal cancer (CRC) are primarily based on the results of randomized clinical trials (RCTs), the gold standard methodology to evaluate safety and efficacy of oncological treatments. However, generalizability of trial results is often limited due to stringent eligibility criteria, underrepresentation of specific populations, and more heterogeneity in clinical practice. This may result in an efficacy-effectiveness gap and uncertainty regarding meaningful benefit versus treatment harm. Meanwhile, conduct of traditional RCTs has become increasingly challenging due to identification of a growing number of (small) molecular subtypes. These challenges-combined with the digitalization of health records-have led to growing interest in use of real-world data (RWD) to complement evidence from RCTs. RWD is used to evaluate epidemiological trends, quality of care, treatment effectiveness, long-term (rare) safety, and quality of life (QoL) measures. In addition, RWD is increasingly considered in decision-making by clinicians, regulators, and payers. In this narrative review, we elaborate on these applications in CRC, and provide illustrative examples. As long as the quality of RWD is safeguarded, ongoing developments, such as common data models, federated learning, and predictive modelling, will further unfold its potential. First, whenever possible, we recommend conducting pragmatic trials, such as registry-based RCTs, to optimize generalizability and answer clinical questions that are not addressed in registrational trials. Second, we argue that marketing approval should be conditional for patients who would have been ineligible for the registrational trial, awaiting planned (non) randomized evaluation of outcomes in the real world. Third, high-quality effectiveness results should be incorporated in treatment guidelines to aid in patient counseling. We believe that a coordinated effort from all stakeholders is essential to improve the quality of RWD, create a learning healthcare system with optimal use of trials and real-world evidence (RWE), and ultimately ensure personalized care for every CRC patient

Prognostic value of Lynch syndrome, BRAF V600E, and RAS mutational status in dMMR/MSI-H metastatic colorectal cancer in a pooled analysis of Dutch and French cohorts.

BACKGROUND: Current knowledge on prognostic biomarkers (especially BRAF V600E /RAS mutations) in metastatic colorectal cancer (mCRC) is mainly based on mCRC patients with proficient mismatch repair (pMMR) tumors. It is uncertain whether these biomarkers have the same prognostic value in mCRC patients with deficient mismatch repair (dMMR) tumors. METHODS: This observational cohort study combined a population-based Dutch cohort (2014-2019) and a large French multicenter cohort (2007-2017). All mCRC patients with a histologically proven dMMR tumor were included. RESULTS: In our real-world data cohort of 707 dMMR mCRC patients, 438 patients were treated with first-line palliative systemic chemotherapy. Mean age of first-line treated patients was 61.9 years, 49% were male, and 40% had Lynch syndrome. BRAF V600E mutation was present in 47% of tumors and 30% harbored a RAS mutation. Multivariable regression analysis on OS showed significant hazard rates (HR) for known prognostic factors as age and performance status, however showed no significance for Lynch syndrome (HR: 1.07, 95% CI: 0.66-1.72), BRAF V600E mutational status (HR: 1.02, 95% CI: 0.67-1.54), and RAS mutational status (HR: 1.01, 95% CI: 0.64-1.59), with similar results for PFS. CONCLUSION: BRAF V600E and RAS mutational status are not associated with prognosis in dMMR mCRC patients, in contrast to pMMR mCRC patients. Lynch syndrome is also not an independent prognostic factor for survival. These findings underline that prognostic factors of patients with dMMR mCRC are different of those with pMMR, which could be taken into consideration when prognosis is used for clinical decision-making in dMMR mCRC patients and underline the complex heterogeneity of mCRC

The predictive ability of the 313 variant–based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Abstract: Purpose: To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. Methods: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. Results: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06–1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07–1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. Conclusion: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making

Potential of adaptive clinical trial designs in pharmacogenetic research, A simulation based on the IPASS trial

Background: An adaptive clinical trial design that allows population enrichment after interim analysis can be advantageous in pharmacogenetic research if previous evidence is not strong enough to exclude part of the patient population beforehand.With this design, underpowered studies or unnecessary large numbers of patients given an inferior/harmful treatment can be avoided. Objectives: Aim of this study was to illustrate the potential benefits of an adaptive trial design using a simulation model based on empirical data. Methods: The simulation was based on data of the IPASS trial, a phase III trial in non-small-cell lung cancer patients, aimed to study the efficacy and safety of gefitinib. A subgroup analysis showed that the tumor response of patients positive for the EGFR mutation was 71.2% with gefitinib versus 47.3% with control, and 1.1% versus 23.5%, respectively, in the mutation-negative subgroup.We simulated two scenarios of an adaptive trial, one using the response rates of the IPASS trial and one assuming an equal response rate (20%) in mutation-negatives, which is a more realistic assumption when planning a trial. The conditional power was calculated to decide at interim analysis whether (1) to continue the trial with the whole population, (2) to continue with only mutation-positive patients, or (3) to stop due to futility. Results: The simulation showed that the overall ±-level was maintained at 2,5% (one-sided). The first scenario resulted in a probability of .91 to continue with only mutation-positive. Continuation with the whole population in this scenario resulted in the largest bias in the treatment effect estimates. Scenario 2 resulted in a probability of .54 to continue with the whole population and .38 to continue with only mutation- positive. Stopping the trial for futility in this scenario lead to the largest bias in the treatment effect estimates. Conclusions: We demonstrated that if an adaptive trial would have been performed in the case of gefitinib, continuation with an enriched population would have been very likely, which would have lead to a smaller trial, with less EGFR mutation-negative patients unnecessarily exposed to the drug

Potential of adaptive clinical trial designs in pharmacogenetic research, A simulation based on the IPASS trial

Background: An adaptive clinical trial design that allows population enrichment after interim analysis can be advantageous in pharmacogenetic research if previous evidence is not strong enough to exclude part of the patient population beforehand.With this design, underpowered studies or unnecessary large numbers of patients given an inferior/harmful treatment can be avoided. Objectives: Aim of this study was to illustrate the potential benefits of an adaptive trial design using a simulation model based on empirical data. Methods: The simulation was based on data of the IPASS trial, a phase III trial in non-small-cell lung cancer patients, aimed to study the efficacy and safety of gefitinib. A subgroup analysis showed that the tumor response of patients positive for the EGFR mutation was 71.2% with gefitinib versus 47.3% with control, and 1.1% versus 23.5%, respectively, in the mutation-negative subgroup.We simulated two scenarios of an adaptive trial, one using the response rates of the IPASS trial and one assuming an equal response rate (20%) in mutation-negatives, which is a more realistic assumption when planning a trial. The conditional power was calculated to decide at interim analysis whether (1) to continue the trial with the whole population, (2) to continue with only mutation-positive patients, or (3) to stop due to futility. Results: The simulation showed that the overall ±-level was maintained at 2,5% (one-sided). The first scenario resulted in a probability of .91 to continue with only mutation-positive. Continuation with the whole population in this scenario resulted in the largest bias in the treatment effect estimates. Scenario 2 resulted in a probability of .54 to continue with the whole population and .38 to continue with only mutation- positive. Stopping the trial for futility in this scenario lead to the largest bias in the treatment effect estimates. Conclusions: We demonstrated that if an adaptive trial would have been performed in the case of gefitinib, continuation with an enriched population would have been very likely, which would have lead to a smaller trial, with less EGFR mutation-negative patients unnecessarily exposed to the drug

Cytochrome P-450 2D6 and 2C19 polymorphisms and consumption of care in psychiatric practice

Background: Cytochrome P-450 2D6 (CYP2D6) and 2C19 (CYP2C19) are known to contain functional polymorphisms that can alter the metabolic rate of many antidepressants (AD) and antipsychotics (AP). Individuals with no metabolic activity and with increased activity may be at risk for an unsatisfactory drug response. Objectives: Aim of this study was to assess the influence of CYP2D6 and CYP2C19 phenotypes on the consumption of care in psychiatric patients. Methods: The study was conducted in a psychiatric hospital in the Netherlands, including all admissions from July 2001 until July 2010, of patients genotyped for (at least) the CYP2D6 ∗3 ∗4 and gene multiplication and CYP2C19 ∗2. Patients were classified as poor metabolizers (PM), ultrarapid metabolizers (UM), intermediate metabolizers (IM) and extensive metabolizers (EM). To study the consumption of care, several outcome measures were calculated for PM and UM and compared to EM. Results: 7377 admissions were analyzed, belonging to 3859 unique patients. The total duration of hospital stays with AP and/or AD treatment was longer for CYP2D6 UM than for CYP2D6 EM (66 versus 48 days,