Summary Background Patients with peritoneal metastatic colorectal cancer have reduced overall survival compared with patients with metastatic colorectal cancer without peritoneal involvement. Here we ...further investigated the effect of the number and location of metastases in patients receiving first-line systemic chemotherapy. Methods We analysed individual patient data for previously untreated patients enrolled in 14 phase 3 randomised trials done between 1997 and 2008. Trials were included if protocols explicitly pre-specified and solicited for patients with peritoneal involvement in the trial data collection process or had done a formal peritoneum-focused review of individual pre-treatment scans. We used stratified multivariable Cox models to assess the prognostic associations of peritoneal metastatic colorectal cancer with overall survival and progression-free survival, adjusting for other key clinical-pathological factors (age, sex, Eastern Cooperative Oncology Group (ECOG) performance score, primary tumour location colon vs rectum, previous treatment, and baseline BMI). The primary endpoint was difference in overall survival between populations with and without peritoneal metastases. Findings Individual patient data were available for 10 553 patients. 9178 (87%) of 10 553 patients had non-peritoneal metastatic colorectal cancer (4385 with one site of metastasis, 4793 with two or more sites of metastasis), 194 (2%) patients had isolated peritoneal metastatic colorectal cancer, and 1181 (11%) had peritoneal metastatic colorectal cancer and other organ involvement. These groups were similar in age, ethnic origin, and use of targeted treatment. Patients with peritoneal metastatic colorectal cancer were more likely than those with non-peritoneal metastatic colorectal cancer to be women (565 41% of 1371 vs 3312 36% of 9169 patients; p=0·0003), have colon primary tumours (1116 84% of 1334 patients vs 5603 66%; p<0·0001), and have performance status of 2 (136 10% vs 521 6%; p<0·0001). We recorded a higher proportion of patients with mutated BRAF in patients with peritoneal-only (eight 18% of 44 patients with available data) and peritoneal metastatic colorectal cancer with other sites of metastasis (34 12% of 289), compared with patients with non-peritoneal metastatic colorectal cancer (194 9% of 2230; p=0·028 comparing the three groups). Overall survival (adjusted HR 0·75, 95% CI 0·63–0·91; p=0·003) was better in patients with isolated non-peritoneal sites than in those with isolated peritoneal metastatic colorectal cancer. Overall survival of patients with two of more non-peritoneal sites of metastasis (adjusted HR 1·04, 95% CI 0·86–1·25, p=0.69) and those with peritoneal metastatic colorectal cancer plus one other site of metastasis (adjusted HR 1·10, 95% CI 0·89–1·37, p=0·37) was similar to those with isolated peritoneal metastases. Compared with patients with isolated peritoneal metastases, those with peritoneal metastases and two or more additional sites of metastasis had the shortest survival (adjusted HR 1·40; CI 1·14–1·71; p=0·0011). Interpretation Patients with peritoneal metastatic colorectal cancer have significantly shorter overall survival than those with other isolated sites of metastases. In patients with several sites of metastasis, poor survival is a function of both increased number of metastatic sites and peritoneal involvement. The pattern of metastasis and in particular, peritoneal involvement, results in prognostic heterogeneity of metastatic colorectal cancer. Funding None.
To determine the prevalence and prognostic value of mismatch repair (MMR) status and its relation to BRAF mutation (BRAF(MT)) status in metastatic colorectal cancer (mCRC).
A pooled analysis of four ...phase III studies in first-line treatment of mCRC (CAIRO, CAIRO2, COIN, and FOCUS) was performed. Primary outcome parameter was the hazard ratio (HR) for median progression-free survival (PFS) and overall survival (OS) in relation to MMR and BRAF. For the pooled analysis, Cox regression analysis was performed on individual patient data.
The primary tumors of 3,063 patients were analyzed, of which 153 (5.0%) exhibited deficient MMR (dMMR) and 250 (8.2%) a BRAF(MT). BRAF(MT) was observed in 53 (34.6%) of patients with dMMR tumors compared with 197 (6.8%) of patients with proficient MMR (pMMR) tumors (P < 0.001). In the pooled dataset, median PFS and OS were significantly worse for patients with dMMR compared with pMMR tumors HR, 1.33; 95% confidence interval (CI), 1.12-1.57 and HR, 1.35; 95% CI, 1.13-1.61, respectively), and for patients with BRAF(MT) compared with BRAF wild-type (BRAF(WT)) tumors (HR, 1.34; 95% CI, 1.17-1.54 and HR, 1.91; 95% CI, 1.66-2.19, respectively). PFS and OS were significantly decreased for patients with BRAF(MT) within the group of patients with pMMR, but not for BRAF status within dMMR, or MMR status within BRAF(WT) or BRAF(MT).
Prevalence of dMMR and BRAF(MT) in patients with mCRC is low and both biomarkers confer an inferior prognosis. Our data suggest that the poor prognosis of dMMR is driven by the BRAF(MT) status.
Summary Background The best-known cause of intolerance to fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding ...DPD ( DPYD ), including DPYD *2A and c.2846A>T. Three other variants— DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A—have been associated with DPD deficiency, but no definitive evidence for the clinical validity of these variants is available. The primary objective of this systematic review and meta-analysis was to assess the clinical validity of c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity. Methods We did a systematic review of the literature published before Dec 17, 2014, to identify cohort studies investigating associations between DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A and severe (grade ≥3) fluoropyrimidine-associated toxicity in patients treated with fluoropyrimidines (fluorouracil, capecitabine, or tegafur-uracil as single agents, in combination with other anticancer drugs, or with radiotherapy). Individual patient data were retrieved and analysed in a multivariable analysis to obtain an adjusted relative risk (RR). Effect estimates were pooled by use of a random-effects meta-analysis. The threshold for significance was set at a p value of less than 0·0167 (Bonferroni correction). Findings 7365 patients from eight studies were included in the meta-analysis. DPYD c.1679T>G was significantly associated with fluoropyrimidine-associated toxicity (adjusted RR 4·40, 95% CI 2·08–9·30, p<0·0001), as was c.1236G>A/HapB3 (1·59, 1·29–1·97, p<0·0001). The association between c.1601G>A and fluoropyrimidine-associated toxicity was not significant (adjusted RR 1·52, 95% CI 0·86–2·70, p=0·15). Analysis of individual types of toxicity showed consistent associations of c.1679T>G and c.1236G>A/HapB3 with gastrointestinal toxicity (adjusted RR 5·72, 95% CI 1·40–23·33, p=0·015; and 2·04, 1·49–2·78, p<0·0001, respectively) and haematological toxicity (adjusted RR 9·76, 95% CI 3·03–31·48, p=0·00014; and 2·07, 1·17–3·68, p=0·013, respectively), but not with hand-foot syndrome. DPYD *2A and c.2846A>T were also significantly associated with severe fluoropyrimidine-associated toxicity (adjusted RR 2·85, 95% CI 1·75–4·62, p<0·0001; and 3·02, 2·22–4·10, p<0·0001, respectively). Interpretation DPYD variants c.1679T>G and c.1236G>A/HapB3 are clinically relevant predictors of fluoropyrimidine-associated toxicity. Upfront screening for these variants, in addition to the established variants DPYD *2A and c.2846A>T, is recommended to improve the safety of patients with cancer treated with fluoropyrimidines. Funding None.
Effective predictive biomarkers are needed to enable personalized medicine and increase treatment efficacy and survival for cancer patients, thereby reducing toxic side effects and treatment costs. ...Patient-derived organoids (PDOs) enable individualized tumour response testing. Since 2018, 17 publications have examined PDOs as a potential predictive biomarker in the treatment of cancer patients. We review and provide a pooled analysis of the results regarding the use of PDOs in individualized tumour response testing, focusing on evidence for analytical validity, clinical validity and clinical utility. We identify future perspectives to accelerate the implementation of PDOs as a predictive biomarker in the treatment of cancer patients.
A Trial within Cohorts (TwiCs) study design is a trial design that uses the infrastructure of an observational cohort study to initiate a randomized trial. Upon cohort enrollment, the participants ...provide consent for being randomized in future studies without being informed. Once a new treatment is available, eligible cohort participants are randomly assigned to the treatment or standard of care. Patients randomized to the treatment arm are offered the new treatment, which they can choose to refuse. Patients who refuse will receive standard of care instead. Patients randomized to the standard of care arm receive no information about the trial and continue receiving standard of care as part of the cohort study. Standard cohort measures are used for outcome comparisons. The TwiCs study design aims to overcome some issues encountered in standard Randomized Controlled Trials (RCTs). An example of an issue in standard RCTs is the slow patient accrual. A TwiCs study aims to improve this by selecting patients using a cohort and only offering the intervention to patients in the intervention arm. In oncology, the TwiCs study design has gained increasing interest during the last decade. Despite its potential advantages over RCTs, the TwiCs study design has several methodological challenges that need careful consideration when planning a TwiCs study. In this article, we focus on these challenges and reflect on them using experiences from TwiCs studies initiated in oncology. Important methodological challenges that are discussed are the timing of randomization, the issue of non-compliance (refusal) after randomization in the intervention arm, and the definition of the intention-to-treat effect in a TwiCs study and how this effect is related to its counterpart in standard RCTs.
Despite progress in the treatment of metastatic colorectal cancer (mCRC) in the last 15 years, it is still a condition with a relatively low 5-year survival rate. Panitumumab, a fully human ...monoclonal antibody directed against the epidermal growth factor receptor (EGFR), is able to prolong survival in patients with mCRC. Panitumumab is used in different lines of therapy in combination with chemotherapy, and as monotherapy for the treatment of wild-type (WT)
RAS
mCRC. It is administered as an intravenous infusion of 6 mg/kg every 2 weeks and has a
t
½
of approximately 7.5 days. Elimination takes place via two different mechanisms, and immunogenicity rates are low. Only
RAS
mutations have been confirmed as a negative predictor of efficacy with anti-EGFR antibodies. Panitumumab is generally well tolerated and has a manageable toxicity profile, despite a very high prevalence of dermatologic side effects. This article presents an overview of the clinical pharmacokinetics and pharmacodynamics of panitumumab, including a description of the studies that led to its approval in the different lines of therapy of mCRC.
Purpose
We explored differences in survival between primary tumor locations, hereby focusing on the role of metastatic sites in synchronous metastatic colorectal cancer (mCRC).
Methods
Data for ...patients diagnosed with synchronous mCRC between 1989 and 2014 were retrieved from the Netherlands Cancer registry. Relative survival and relative excess risks (RER) were analyzed by primary tumor location (right colon (RCC), left colon (LCC), and rectum). Metastatic sites were reported per primary tumor location. Survival was analyzed for metastatic sites combined and for single metastatic sites.
Results
In total, 36,297 patients were included in this study. Metastatic sites differed significantly between primary tumor locations, with liver-only metastases in 43%, 54%, and 52% of RCC, LCC, and rectal cancer patients respectively (
p
< 0.001). Peritoneal metastases were most prevalent in RCC patients (33%), and lung metastases were most prevalent in rectal cancer patients (28%). Regardless of the location of metastases, patients with RCC had a worse survival compared with LCC (RER 0.81, 95% CI 0.78–0.83) and rectal cancer (RER 0.73, 95% CI 0.71–0.76). The survival disadvantage for RCC remained present, even in cases with metastasectomy for liver-only disease (LCC: RER 0.66, 95% CI 0.57–0.76; rectal cancer: RER 0.84, 95% CI 0.66–1.06).
Conclusions
This study showed significant differences in relative survival between primary tumor locations in synchronous mCRC, which can only be partially explained by distinct metastatic sites. Our findings support the concept that RCC, LCC and rectal cancer should be considered distinct entities in synchronous mCRC.
Parametric distributions based on individual patient data can be used to represent both stochastic and parameter uncertainty. Although general guidance is available on how parameter uncertainty ...should be accounted for in probabilistic sensitivity analysis, there is no comprehensive guidance on reflecting parameter uncertainty in the (correlated) parameters of distributions used to represent stochastic uncertainty in patient-level models. This study aims to provide this guidance by proposing appropriate methods and illustrating the impact of this uncertainty on modeling outcomes.
Two approaches, 1) using non-parametric bootstrapping and 2) using multivariate Normal distributions, were applied in a simulation and case study. The approaches were compared based on point-estimates and distributions of time-to-event and health economic outcomes. To assess sample size impact on the uncertainty in these outcomes, sample size was varied in the simulation study and subgroup analyses were performed for the case-study.
Accounting for parameter uncertainty in distributions that reflect stochastic uncertainty substantially increased the uncertainty surrounding health economic outcomes, illustrated by larger confidence ellipses surrounding the cost-effectiveness point-estimates and different cost-effectiveness acceptability curves. Although both approaches performed similar for larger sample sizes (i.e. n = 500), the second approach was more sensitive to extreme values for small sample sizes (i.e. n = 25), yielding infeasible modeling outcomes.
Modelers should be aware that parameter uncertainty in distributions used to describe stochastic uncertainty needs to be reflected in probabilistic sensitivity analysis, as it could substantially impact the total amount of uncertainty surrounding health economic outcomes. If feasible, the bootstrap approach is recommended to account for this uncertainty.
PURPOSEFatigue is a common problem among colon cancer patients and typically increases during chemotherapy. Exercise during chemotherapy might have beneficial effects on fatigue. To investigate the ...short- and long-term effects of an exercise program in colon cancer patients during adjuvant treatment, the Physical Activity During Cancer Treatment study was conducted.
METHODSIn this multicenter randomized controlled trial, 33 colon cancer patients undergoing chemotherapy (21 men and 12 women) were randomly assigned to either a group receiving an 18-wk supervised exercise program (n = 17) or to usual care (n = 16). The primary outcome was fatigue as measured by the Multidimensional Fatigue Inventory and the Fatigue Quality List. Secondary outcomes were quality of life, physical fitness, anxiety, depression, body weight, and chemotherapy completion rate. Outcome assessment took place at baseline, postintervention (18 wk) and at 36 wk.
RESULTSIntention-to-treat mixed linear model analyses showed that patients in the intervention group experienced significantly less physical fatigue at 18 wk and general fatigue at 36 wk (mean between group differences, −3.2; 95% confidence interval CI, −6.2 to −0.2; effect size ES, −0.9 and −2.7; 95% CI, −5.2 to −0.1; ES, −0.8, respectively), and reported higher physical functioning (12.3; 95% CI, 3.3–21.4; ES, 1.0) compared with patients in the usual care group.
CONCLUSIONThe Physical Activity During Cancer Treatment trial shows that an 18-wk supervised exercise program in colon cancer patients during chemotherapy is safe and feasible. The intervention significantly reduced physical fatigue at 18 wk and general fatigue at 36 wk. Considering the number of patients included in the present study, replication in a larger study population is required.
PDF
