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The consensus molecular subtype (CMS) classification divides colon tumors into four subtypes holding promise as a predictive biomarker. However, the effect of adjuvant chemotherapy on recurrence free survival (RFS) per CMS in stage III patients remains inadequately explored. With this intention, we selected stage III colon cancer (CC) patients from the MATCH cohort (n = 575) and RadboudUMC (n = 276) diagnosed between 2005 and 2018. Patients treated with and without adjuvant chemotherapy were matched based on tumor location, T- and N-stage (n = 522). Tumor material was available for 464 patients, with successful RNA extraction and CMS subtyping achieved in 390 patients (surgery alone group: 192, adjuvant chemotherapy group: 198). In the overall cohort, CMS4 was associated with poorest prognosis (HR 1.55; p = .03). Multivariate analysis revealed favorable RFS for the adjuvant chemotherapy group in CMS1, CMS2, and CMS4 tumors (HR 0.19; p = .01, HR 0.27; p < .01, HR 0.19; p < .01, respectively), while no significant difference between treatment groups was observed within CMS3 (HR 0.68; p = .51). CMS subtyping in this non-randomized cohort identified patients with poor prognosis and patients who may not benefit significantly from adjuvant chemotherapy.
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BACKGROUND: Encorafenib-cetuximab has been approved for pretreated BRAFV600E-mutated metastatic colorectal cancer (mCRC) patients based on efficacy demonstrated in the randomized phase III BEACON trial. The aim of this real-world effectiveness study is to improve knowledge on the generalizability of trial results. METHODS: This population-based real-world study includes all mCRC patients in the Netherlands treated with encorafenib-cetuximab since approval. Individual patient data and pathology reports were collected. Overall survival (OS) was compared to BEACON and subgroup analyses were conducted for patients who would have been eligible and ineligible for BEACON. RESULTS: 166 patients were included with a median follow-up time of 14.5 months. Median OS was 6.7 months (95% CI:6.0-8.3) and differed from BEACON (9.3 months; 95% CI:8.0-11.3, p-value 0.002). Thirty-six percent of real-world patients would have been ineligible for the BEACON trial. Trial ineligible subgroups with symptomatic brain metastases and WHO performance status ≥2 had the poorest median OS of 5.0 months (95% CI:4.0-NR) and 3.9 months (95% CI:2.4-NR). CONCLUSION: This real-world cohort of mCRC patients treated with encorafenib-cetuximab showed a clinically relevant efficacy-effectiveness gap for OS. The chance of survival benefit from encorafenib-cetuximab in patients with brain metastases and/or WHO performance status ≥2 is negligible as neither efficacy nor effectiveness has been demonstrated.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carbamatos , Cetuximab , Neoplasias Colorretais , Mutação , Proteínas Proto-Oncogênicas B-raf , Sulfonamidas , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/mortalidade , Proteínas Proto-Oncogênicas B-raf/genética , Carbamatos/uso terapêutico , Carbamatos/administração & dosagem , Feminino , Masculino , Cetuximab/administração & dosagem , Cetuximab/uso terapêutico , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Pessoa de Meia-Idade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso de 80 Anos ou mais , Países Baixos/epidemiologia , Adulto , Metástase Neoplásica , Resultado do TratamentoRESUMO
BACKGROUND: The incidence of T1 colorectal cancer (CRC) has increased with the implementation of CRC screening programs. It is unknown whether the outcomes and risk models for T1 CRC based on non-screen-detected patients can be extrapolated to screen-detected T1 CRC. This study aimed to compare the stage distribution and oncologic outcomes of T1 CRC patients within and outside the screening program. METHODS: Data from T1 CRC patients diagnosed between 2014 and 2017 were collected from 12 hospitals in the Netherlands. The presence of lymph node metastasis (LNM) at diagnosis was compared between screen-detected and non-screen-detected patients using multivariable logistic regression. Cox proportional hazard regression was used to analyze differences in the time to recurrence (TTR), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival. Additionally, the performance of conventional risk factors for LNM was evaluated across the groups. RESULTS: 1803 patients were included (1114 [62%] screen-detected), with median follow-up of 51 months (interquartile range 30). The proportion of LNM did not significantly differ between screen- and non-screen-detected patients (12.6% vs. 8.9%; odds ratio 1.41; 95%CI 0.89-2.23); a prediction model for LNM performed equally in both groups. The 3- and 5-year TTR, MFS, and CSS were similar for patients within and outside the screening program. However, overall survival was significantly longer in screen-detected T1 CRC patients (adjusted hazard ratio 0.51; 95%CI 0.38-0.68). CONCLUSIONS: Screen-detected and non-screen-detected T1 CRCs have similar stage distributions and oncologic outcomes and can therefore be treated equally. However, screen-detected T1 CRC patients exhibit a lower rate of non-CRC-related mortality, resulting in longer overall survival.
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Neoplasias Colorretais , Detecção Precoce de Câncer , Metástase Linfática , Estadiamento de Neoplasias , Humanos , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/diagnóstico , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Detecção Precoce de Câncer/métodos , Países Baixos/epidemiologia , Fatores de Risco , Estudos Retrospectivos , Recidiva Local de Neoplasia , Modelos de Riscos Proporcionais , Colonoscopia/estatística & dados numéricos , Taxa de SobrevidaRESUMO
OPINION STATEMENT: 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.
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Neoplasias Colorretais , Humanos , Neoplasias Colorretais/terapia , Resultado do Tratamento , Incerteza , Ensaios Clínicos como AssuntoRESUMO
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.
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Neoplasias do Colo , Estadiamento de Neoplasias , Medidas de Resultados Relatados pelo Paciente , Humanos , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Neoplasias do Colo/tratamento farmacológico , Masculino , Feminino , Quimioterapia Adjuvante , Idoso , Pessoa de Meia-Idade , Países Baixos , Oxaliplatina/uso terapêutico , Oxaliplatina/administração & dosagem , Capecitabina/administração & dosagem , Capecitabina/uso terapêutico , Fatores de Tempo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso de 80 Anos ou mais , Sistema de RegistrosRESUMO
Real-world data are necessitated to counsel patients about the risk for recurrent disease after curative treatment of colorectal cancer. This study provided a population-based overview of the epidemiology of recurrent disease in patients with surgically resected stage II/III colorectal cancer.Patients diagnosed with stage II/III primary colorectal cancer between July and December 2015 were selected from the Netherlands Cancer Registry (N = 3,762). Cumulative incidence of recurrent disease was estimated, and multivariable competing risk regression was used to identify risk factors for recurrent disease in patients with primary colon and rectal cancer. Moreover, overall survival (OS) after diagnosis of recurrent colorectal cancer was estimated.Median clinical follow-up was 58 months (Q1-Q3: 22-62). Five-year cumulative incidence of recurrent disease was 21.6% [95% confidence interval (CI): 20.0-23.2] and 30.0% (95% CI: 28.3-33.5) for patients with primary colon and rectal cancer, respectively. Stage III disease and incomplete resection margin in patients with primary colon cancer and extramural vascular invasion in patients with primary rectal cancer were strongly (HR ≥ 2) associated with recurrent disease. Median OS of patients with distant, locoregional, or the synchronous combination of distant and locoregional recurrent disease was 29, 27, and 13 months, respectively (P < 0.001). Patients with distant recurrences limited to liver or lung showed a median OS of 46 and 48 months, respectively. The incidence of recurrent disease was higher in patients with rectal cancer than in patients with colon cancer, predominantly due to higher rates of distant recurrences. OS after recurrent disease was impaired, but subgroups of patients diagnosed with recurrent disease limited to one site showed statistically significantly longer OS. SIGNIFICANCE: Population-based data on recurrent colorectal cancer are rare, but crucial for counseling patients and their physicians. This large nationwide, population-based study provides an up-to-date overview of the epidemiology of recurrent disease in patients with stage II and III primary colon and rectal cancer treated with surgical resection.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Incidência , Estadiamento de Neoplasias , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Colorretais/epidemiologia , Neoplasias do Colo/epidemiologia , Neoplasias Retais/tratamento farmacológico , Fatores de RiscoRESUMO
Consensus Molecular Subtype (CMS) classification of colorectal cancer (CRC) tissues is complicated by RNA degradation upon formalin-fixed paraffin-embedded (FFPE) preservation. Here, we present an FFPE-curated CMS classifier. The CMSFFPE classifier was developed using genes with a high transcript integrity in FFPE-derived RNA. We evaluated the classification accuracy in two FFPE-RNA datasets with matched fresh-frozen (FF) RNA data, and an FF-derived RNA set. An FFPE-RNA application cohort of metastatic CRC patients was established, partly treated with anti-EGFR therapy. Key characteristics per CMS were assessed. Cross-referenced with matched benchmark FF CMS calls, the CMSFFPE classifier strongly improved classification accuracy in two FFPE datasets compared with the original CMSClassifier (63.6% versus 40.9% and 83.3% versus 66.7%, respectively). We recovered CMS-specific recurrence-free survival patterns (CMS4 versus CMS2: hazard ratio 1.75, 95% CI 1.24-2.46). Key molecular and clinical associations of the CMSs were confirmed. In particular, we demonstrated the predictive value of CMS2 and CMS3 for anti-EGFR therapy response (CMS2&3: odds ratio 5.48, 95% CI 1.10-27.27). The CMSFFPE classifier is an optimized FFPE-curated research tool for CMS classification of clinical CRC samples.
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Neoplasias Colorretais , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/classificação , Neoplasias Colorretais/patologia , Inclusão em Parafina , Biomarcadores Tumorais/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Consenso , Fixação de Tecidos/métodos , Masculino , Perfilação da Expressão Gênica/métodos , Idoso , Pessoa de Meia-Idade , Prognóstico , Regulação Neoplásica da Expressão Gênica , FormaldeídoRESUMO
Background: Current patient selection for adjuvant chemotherapy (ACT) after curative surgery for stage II colon cancer (CC) is suboptimal, causing overtreatment of high-risk patients and undertreatment of low-risk patients. Postoperative circulating tumor DNA (ctDNA) could improve patient selection for ACT. Objectives: We conducted an early model-based evaluation of the (cost-)effectiveness of ctDNA-guided selection for ACT in stage II CC in the Netherlands to assess the conditions for cost-effective implementation. Methods: A validated Markov model, simulating 1000 stage II CC patients from diagnosis to death, was supplemented with ctDNA data. Five ACT selection strategies were evaluated: the current guideline (pT4, pMMR), ctDNA-only, and three strategies that combined ctDNA status with pT4 and pMMR status in different ways. For each strategy, the costs, life years, quality-adjusted life years (QALYs), recurrences, and CC deaths were estimated. Sensitivity analyses were performed to assess the impact of the costs of ctDNA testing, strategy adherence, ctDNA as a predictive biomarker, and ctDNA test performance. Results: Model predictions showed that compared to current guidelines, the ctDNA-only strategy was less effective (+2.2% recurrences, -0.016 QALYs), while the combination strategies were more effective (-3.6% recurrences, +0.038 QALYs). The combination strategies were not cost-effective, since the incremental cost-effectiveness ratio was 67,413 per QALY, exceeding the willingness-to-pay threshold of 50,000 per QALY. Sensitivity analyses showed that the combination strategies would be cost-effective if the ctDNA test costs were lower than 1500, or if ctDNA status was predictive of treatment response, or if the ctDNA test performance improved substantially. Conclusion: Adding ctDNA to current high-risk clinicopathological features (pT4 and pMMR) can improve patient selection for ACT and can also potentially be cost-effective. Future studies should investigate the predictive value of post-surgery ctDNA status to accurately evaluate the cost-effectiveness of ctDNA testing for ACT decisions in stage II CC.
Effectiveness and cost-effectiveness of circulating tumour DNA-guided selection for adjuvant chemotherapy in patients with stage II colon cancer Most patients with stage II colon cancer (CC) are cured by surgery. Therefore, guidelines recommend to only offer adjuvant chemotherapy to patients who have a tumor with high-risk features. However, current selection is suboptimal, leading to recurrence of cancer in 13% of low-risk patients and unnecessary administration of chemotherapy in some high-risk patients. Previous studies indicate that a biomarker, so-called circulating tumour DNA (ctDNA), could improve the selection of high-risk patients for adjuvant chemotherapy, as patients who have detectable ctDNA in their blood after surgery are likely to develop a recurrence. Despite its potential, implementation is still pending. Our study assessed the long-term effectiveness and costs associated with various ctDNA-guided strategies for selecting high-risk patients for adjuvant chemotherapy in stage II CC. We used an health-economic model to simulate a cohort of 1000 Dutch patients with stage II CC from diagnosis to death. Next, we compared the health outcomes and costs of the ctDNA-guided strategies to those when selection is based on the Dutch guideline. We found that a combination of the Dutch guideline and ctDNA was the most effective strategy, but not cost-effective. Additional analyses showed that ctDNA-guided selection were cost-effective if the costs of the ctDNA test were below 1500 euros, if the ctDNA test performed significantly better, or if patients with detectable ctDNA responded better to chemotherapy. Thus, while post-surgery ctDNA status is a good indicator for recurrence risk, specific criteria related to ctDNA test performance and costs, in addition to combining ctDNA with current high-risk features, should be met to achieve cost-effective implementation. Looking ahead, future studies should explore how patients with detectable ctDNA respond to chemotherapy for next assessments of the cost-effectiveness of ctDNA-guided strategies in selecting patients with stage II CC for adjuvant chemotherapy.
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INTRODUCTION: Follow-up care after treatment for colorectal cancer (CRC) is increasingly focused on health-related quality of life (HRQoL) and functional outcomes. The Assessment of Burden of ColoRectal Cancer (ABCRC)-tool is developed to measure these outcomes and support patient-oriented care. The tool comprises items assessing burden of disease and lifestyle parameters. It consists of a generic module combined with one of the three CRC specific modules. The objective of this study is to assess the construct validity and reliability of the items of the ABCRC-tool. METHODS: Patients who were receiving follow-up care after surgical CRC treatment were invited to complete the ABCRC-tool together with other validated patient-reported outcome measures (PROMs). Construct validity was assessed by testing expected correlations between items of the ABCRC-tool and domains of other PROMs and by examining predefined hypotheses regarding differences in subgroups of patients. Patients completed the ABCRC-tool twice, with 8 days apart, to evaluate its reliability. RESULTS: In total, 177 patients participated (64% male) with a mean age of 67 years (range 33-88). The colon, rectum and stoma module were completed by subsequently 89, 53 and 35 patients. Most items correlated as expected with anticipated domains of the EORTC QLQ-C30 or EORTC QLQ-CR29 (all p-values <0.05). Furthermore, the ABCRC-tool could discriminate between subgroups of patients. The intraclass correlation coefficient (ICC) was good (>0.70) for most items, indicating good reliability. CONCLUSION: The ABCRC-tool is a valid and reliable instrument that is ready for use in a clinical setting to support personalized follow-up care after CRC treatment.