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.

The role of primary tumor resection (PTR) in synchronous patients with metastatic colorectal cancer (mCRC) who had unresectable metastases and few or absent symptoms of their primary tumor is unclear. Studying subgroups with low postoperative mortality may identify patients who potentially benefit from PTR.OBJECTIVE To determine the difference in 60-day mortality between patients randomized to systemic treatment only vs PTR followed by systemic treatment, and to explore risk factors associated with 60-day mortality.DESIGN, SETTING, AND PARTICIPANTS CAIRO4 is a randomized phase 3 trial initiated in 2012 in which patients with mCRC were randomized to systemic treatment only or PTR followed by systemic treatment with palliative intent. This multicenter study was conducted by the Danish and Dutch Colorectal Cancer Group in general and academic hospitals in Denmark and the Netherlands. Patients included between August 2012 and December 2019 with histologically proven colorectal cancer, unresectable metastases, and a primary tumor with few or absent symptoms were eligible.INTERVENTIONS Systemic treatment, consisting of fluoropyrimidine-based chemotherapy with bevacizumab vs PTR followed by fluoropyrimidine-based chemotherapy with bevacizumab. MAIN OUTCOMES AND MEASURESThe aim of the current analysis was to compare 60-day mortality rates in both treatment arms. A secondary aim was the identification of risk factors for 60-day mortality in the treatment arms. These aims were not predefined in the study protocol.RESULTS A total of 196 patients were included in the intention-to-treat analysis (112 [57%] men; median [IQR] age, 65 [59-70] years). Sixty-day mortality was 3% (95% CI, 1%-9%) in the systemic treatment arm and 11% (95% CI, 6%-19%) in the PTR arm (P = .03). In a per-protocol analysis, 60-day mortality was 2% (95% CI, 1%-7%) vs 10% (95% CI, 5%-18%; P = .048). Patients with elevated serum levels of lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, and/or neutrophils who were randomized to PTR had a significantly higher 60-day mortality than patients without these characteristics.CONCLUSIONS AND RELEVANCE Patients with mCRC who were randomized to PTR followed by systemic treatment had a higher 60-day mortality than patients randomized to systemic treatment. Especially patients randomized to the PTR arm with elevated serum levels of lactate dehydrogenase, neutrophils, aspartate aminotransferase, and/or alanine aminotransferase were at high risk of postoperative mortality. Final study results on overall survival have to be awaited.

Background Accurate detection of patients with minimal residual disease (MRD) after surgery for stage II colon cancer (CC) remains an urgent unmet clinical need to improve selection of patients who might benefit form adjuvant chemotherapy (ACT). Presence of circulating tumor DNA (ctDNA) is indicative for MRD and has high predictive value for recurrent disease. The MEDOCC-CrEATE trial investigates how many stage II CC patients with detectable ctDNA after surgery will accept ACT and whether ACT reduces the risk of recurrence in these patients. Methods/design MEDOCC-CrEATE follows the ‘trial within cohorts’ (TwiCs) design. Patients with colorectal cancer (CRC) are included in the Prospective Dutch ColoRectal Cancer cohort (PLCRC) and give informed consent for collection of clinical data, tissue and blood samples, and consent for future randomization. MEDOCC-CrEATE is a subcohort within PLCRC consisting of 1320 stage II CC patients without indication for ACT according to current guidelines, who are randomized 1:1 into an experimental and a control arm. In the experimental arm, post-surgery blood samples and tissue are analyzed for tissue-informed detection of plasma ctDNA, using the PGDx elio™ platform. Patients with detectable ctDNA will be offered ACT consisting of 8 cycles of capecitabine plus oxaliplatin while patients without detectable ctDNA and patients in the control group will standard follow-up according to guideline. The primary endpoint is the proportion of patients receiving ACT when ctDNA is detectable after resection. The main secondary outcome is 2-year recurrence rate (RR), but also includes 5-year RR, disease free survival, overall survival, time to recurrence, quality of life and cost-effectiveness. Data will be analyzed by intention to treat. Discussion The MEDOCC-CrEATE trial will provide insight into the willingness of stage II CC patients to be treated with ACT guided by ctDNA biomarker testing and whether ACT will prevent recurrences in a high-risk population. Use of the TwiCs design provides the opportunity to randomize patients before ctDNA measurement, avoiding ethical dilemmas of ctDNA status disclosure in the control group. Trial registration Netherlands Trial Register: NL6281/NTR6455 . Registered 18 May 2017, https://www.trialregister.nl/trial/6281

To the Editor We write regarding the article by van der Kruijssen et al, 1 which we discussed at CRAMSURG, a UK-based online journal club. We would like to congratulate the authors on years of work underlying the conduct and subsequent publishing of this multicenter, multinational randomized clinical trial addressing an important research question. We write to raise a number of issues discussed in our meeting. 1. Sixty-day mortality, the primary outcome of this article, is not listed in the original protocol 2 published in 2014. The primary outcome of the CAIRO4 trial was overall survival.Could the authors explain the decision to report on nonplanned outcomes, which is generally not recommended? These should always be reported in the context of primary results. 3 Performing such analysis without referring to the primary and planned secondary outcomes defeats the purpose of publishing an a priori study protocol. On the same note, we felt that the title was misleading as it appears to refer to the results of the CAIRO4 trial itself. 2. The lack of correction for multiple testing in this context is also controversial, needs explanation, and begs the question whether the results would remain statistically significant if this was done? 3. The sample size calculation reported in the CAIRO4 study protocol stated that planned recruitment was 360 patients. Only 196 patients are included in the current report.Given that the full results of the CAIRO4 trial have not yet been published, it would help to understand the reasons for the apparent under-recruitment. The original protocol 2 planned an interim analysis. Has such analysis taken place?If so, what were the findings and did this have any bearing on the reported sample size? 4. Finally, we feel that stoma formation rate should be mentioned in the main text. Stoma formation can significantly affect quality of life, which becomes particularly relevant in the context of untreatable metastatic disease 4,5 when no quality of life indicators are reported. According to supplemental online content, 14 stomas were formed of which 13 were colostomies.

<b><i>Introduction:</i></b> Uncertainty exists about a possible survival benefit of primary tumor resection (PTR) in synchronous metastatic colon cancer (mCC). Since sidedness of the primary tumor is regarded as an important prognostic factor, our objective was to study the interaction between PTR and sidedness in synchronous mCC. <b><i>Methods:</i></b> In this retrospective study, we used data from 2 first-line phase 3 randomized controlled trials (RCTs). A mixed Cox regression model was used to study the multiplicative interaction between PTR and sidedness. We adjusted for age, treatment arm, WHO performance status, number of affected organs by metastases, serum lactate dehydrogenase, and year of enrollment. <b><i>Results:</i></b> We found that PTR is associated with better survival in both right-sided (hazard ratio [HR] 0.59 [95% confidence interval 0.42–0.8 2]) and left-sided mCC (HR 0.70 [95% confidence interval 0.52–0.93]). The interaction between PTR and sidedness was not significant (<i>p</i> = 0.45). <b><i>Conclusion:</i></b> Our data suggest that the prognostic value of PTR is independent of sidedness. Validation of these results will be performed in ongoing RCTs.

Objectives: Location of the primary tumor has prognostic value and predicts the effect of certain therapeutics in synchronous metastatic colorectal cancer. We investigated whether the association between primary tumor resection (PTR) and overall survival (OS) also depends on tumor location.Methods: Data on synchronous metastatic colorectal cancer patients from the Netherlands Cancer Registry (n = 16,106) and Surveillance, Epidemiology, and End Results (SEER) registry (n = 19,584) were extracted. Cox models using time-varying covariates were implemented. Median OS for right-sided colon cancer (RCC), left-sided colon cancer, and rectal cancer was calculated using inverse probability weighting and a landmark point of 6 months after diagnosis as reference.Results: The association between PTR and OS was dependent on tumor location (P < 0.05), with a higher median OS of upfront PTR versus upfront systemic therapy in Netherlands Cancer Registry (NCR) of 1.9 (95% confidence interval: 0.9-2.8), 4.3 (3.3-5.6), and 3.4 (0.6-7.6) months in RCC, left-sided colon cancer and rectal cancer, respectively. In SEER data, the difference was 6.

We studied the prognostic value of primary tumor sidedness in metastatic colorectal cancer over time and across treatment lines. Population data on synchronous metastatic colorectal cancer patients were extracted from the Netherlands Cancer Registry and SEER database. Pubmed, EMBASE and Cochrane library were searched for prospective studies on metastatic colorectal cancer to conduct a meta‐analysis. Inclusion criteria consisted of metastatic disease, systemic treatment with palliative intent and specification of primary tumor location. Data were pooled using a random‐effects model. For the population‐based data, multivariable Cox models were constructed. The Grambsch‐Therneau test was conducted to evaluate the potential time‐varying nature of sidedness. Meta‐regression incorporating treatment‐line as variable was conducted to test the pre‐specified hypothesis that the prognostic value of sidedness varies over time. Analysis of 12 885 and 16 160 synchronous metastatic colorectal cancer patients registered in the Netherlands Cancer Registry and SEER database, respectively, indicated a time‐varying prognostic value of sidedness (P < .01). Thirty‐one studies were selected for the meta‐analysis (9558 patients for overall survival analysis). Pooled univariable hazard ratioleft‐sided/right‐sided for overall survival was 0.71 (95% CI: 0.65‐0.76) in 1st‐line, 0.76 (0.54‐1.06) in 2nd‐line and 1.01 (0.86‐1.19) in 3rd‐line studies. Hazard ratios were significantly influenced by treatment line (P = .035). The prognostic value of sidedness of the primary tumor in metastatic colorectal cancer patients treated with palliative systemic therapy decreases over time since diagnosis, suggesting that sidedness may not be a useful stratification factor in late‐line trials. This decrease in prognostic value should be taken into account when providing prognostic information to patients.

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