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BackgroundFirst-line therapeutic strategies for patients with BRAFV600E-mutated (BRAFmt) metastatic colorectal cancer (mCRC) mainly rely on subgroup analyses from randomized controlled trials (RCTs). We aimed to assess the prognostic and predictive impact of BRAFmt on the efficacy of targeted therapies with first-line chemotherapy.MethodsIndividual patient data from first-line RCTs with BRAF and KRAS status data in the ARCAD database were pooled. Progression-free survival and overall survival (OS) were assessed using Kaplan-Meier and Cox models. Outcomes were compared between treatment groups that were concurrently randomly assigned whenever possible.ResultsA total of 6391 patients from 10 RCTs were included: 573 BRAFmt (9.0%), 2059 KRASmt (32.2%), and 3759 double wild type (58.8%). BRAFmt mCRC patients experienced statistically significantly poorer OS than those with KRASmt (adjusted hazard ratio [HRadj] = 1.46, 95% confidence interval [CI] = 1.30 to 1.64) and patients with double wild-type tumors (HRadj = 2.14, 95% CI = 1.94 to 2.36). Anti-EGFR agents did not improve progression-free survival or OS of BRAFmt mCRC patients, based on 4 RCTs testing chemotherapy with or without anti-epidermal growth factor receptor (anti-EGFR) (HRadj = 0.96, 95% CI = 0.71 to 1.30; and HRadj = 0.85, 95% CI = 0.66 to 1.14, respectively).ConclusionsOur data suggest that the addition of anti-EGFR agents to chemotherapy is ineffective as first-line treatment for BRAFmt mCRC patients.

Colorectal cancer (CRC) biopsies underpin accurate diagnosis, but are also relevant for patient stratification in molecularly-guided clinical trials. The consensus molecular subtypes (CMS) and colorectal cancer intrinsic subtypes (CRIS) transcriptional signatures have potential clinical utility for improving prognostic/predictive patient assignment. However, their ability to provide robust classification, in pre-treatment biopsies from multiple regions or at different time points remains untested. In this study, we undertook a comprehensive assessment of the robustness of CRC transcriptional signatures, including CRIS and CMS, using a range of tumour sampling methodologies currently employed in clinical and translational research. These include analyses using (i) laser-capture microdissected CRC tissue, (ii) eight publically available rectal cancer biopsy data sets (n=543), (iii) serial biopsies (from AXEBeam trial, NCT00828672; n=10), (iv) multi-regional biopsies from colon tumours (n=29 biopsies, n=7 tumours) and (v) pre-treatment biopsies from the phase II rectal cancer trial COPERNCIUS (NCT01263171; n=44). Compared to previous results obtained using CRC resection material, we now demonstrate that CMS classification in biopsy tissue is significantly less capable of reliably classifying patient subtype (43% unknown in biopsy versus 13% unknown in resections, p=0.0001). In contrast, there was no significant difference in classification rate between biopsies and resections when using the CRIS classifier. Additionally, we demonstrated that CRIS provides significantly better spatially- and temporally- robust classification of molecular subtypes in CRC primary tumour tissue compared to CMS (p= 0.003 and p=0.02, respectively). These findings may have potential to inform ongoing biopsy-based patient stratification in CRC, enabling robust and stable assignment of patients into clinically-informative arms of prospective multi-arm, multi-stage clinical trials. Citation Format: Matthew Alderdice, Susan D. Richman, Simon Gollins, Peter Stewart, Chris Hurt, Richard Adams, Amy M. McCorry, Aideen Roddy, Dale Vimalachandran, Claudio Isella, Enzo Medico, Tim Maughan, Darrgh G. McArt, Mark Lawler, Philip D. Dunne. Prospective patient stratification into robust cancer-cell intrinsic subtypes from colorectal cancer biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5365.

The aim of palliative chemotherapy is to increase survival whilst maintaining maximum quality of life for the individual concerned. It is evident that the survival advantage offered by palliative chemotherapy for metastatic colorectal cancer has increased incrementally with the addition of each newly licensed therapeutic agent. More recently, advances in the field have led to the introduction of targeted monoclonal antibodies, whose benefits are documented in clinical trials and are acknowledged in their approval and licensing. Whilst we are continuing to explore the optimum use of the more traditional chemotherapy agents, with respect to both quantity and quality of life, these novel agents are battling to find their optimum place in the armamentarium. It is evident that a continuing add-one-in policy is likely to be detrimental to both patient and budget. Defining the positioning and duration of these combination therapies has become the subject of much debate and numerous current clinical trials. The Medical Research Council COIN trial is one of these trials, with a remit to explore further the optimum use of both standard agents and novel agents in the first-line setting for metastatic colorectal cancer.

Purpose This study addressed whether age is prognostic for overall survival (OS) or progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC). Patients and Methods A total of 20,023 patients from 24 first-line clinical trials in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were analyzed. Primary age effects and interactions with age, sex, performance status (PS), and metastatic site were modeled using Cox proportional hazards stratified by treatment arm within study. Results Of total patients, 3,051 (15%) were age ≤ 50 years. Age was prognostic for both OS (P < .001) and PFS (P < .001), with U-shaped risk (ie, highest risk was evident in youngest and oldest patients). Relative to patients of middle age, the youngest patients experienced 19% (95% CI, 7% to 33%) increased risk of death and 22% (95% CI, 10% to 35%) increased risk of progression. The oldest patients experienced 42% (95% CI, 31% to 54%) increased risk of death and 15% (95% CI, 7% to 24%) increased risk of progression or death. This relationship was more pronounced in the first year of follow-up. Age remained marginally significant for OS (P = .08) when adjusted for PS, sex, and presence of liver, lung, or peritoneal metastases, and age was significant in an adjusted model for PFS (P = .005). The age effect did not differ by site of metastatic disease, year of enrollment, type of therapy received, or biomarker mutational status. Conclusion Younger and older age are associated with poorer OS and PFS among treated patients with mCRC. Younger and older patients may represent higher-risk populations, and additional studies are warranted.

Summary Background In the Medical Research Council (MRC) COIN trial, the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to standard chemotherapy in first-line treatment of advanced colorectal cancer with the aim of assessing effect on overall survival. Methods In this randomised controlled trial, patients who were fit for but had not received previous chemotherapy for advanced colorectal cancer were randomly assigned to oxaliplatin and fluoropyrimidine chemotherapy (arm A), the same combination plus cetuximab (arm B), or intermittent chemotherapy (arm C). The choice of fluoropyrimidine therapy (capecitabine or infused fluouroracil plus leucovorin) was decided before randomisation. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and C is described in a companion paper. Here, we present the comparison of arm A and B, for which the primary outcome was overall survival in patients with KRAS wild-type tumours. Analysis was by intention to treat. Further analyses with respect to NRAS, BRAF , and EGFR status were done. The trial is registered, ISRCTN27286448. Findings 1630 patients were randomly assigned to treatment groups (815 to standard therapy and 815 to addition of cetuximab). Tumour samples from 1316 (81%) patients were used for somatic molecular analyses; 565 (43%) had KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367; arm B, n=362), overall survival did not differ between treatment groups (median survival 17·9 months [IQR 10·3–29·2] in the control group vs 17·0 months [9·4–30·1] in the cetuximab group; HR 1·04, 95% CI 0·87–1·23, p=0·67). Similarly, there was no effect on progression-free survival (8·6 months [IQR 5·0–12·5] in the control group vs 8·6 months [5·1–13·8] in the cetuximab group; HR 0·96, 0·82–1·12, p=0·60). Overall response rate increased from 57% (n=209) with chemotherapy alone to 64% (n=232) with addition of cetuximab (p=0·049). Grade 3 and higher skin and gastrointestinal toxic effects were increased with cetuximab (14 vs 114 and 67 vs 97 patients in the control group vs the cetuximab group with KRAS wild-type tumours, respectively). Overall survival differs by somatic mutation status irrespective of treatment received: BRAF mutant, 8·8 months (IQR 4·5–27·4); KRAS mutant, 14·4 months (8·5–24·0); all wild-type, 20·1 months (11·5–31·7). Interpretation This trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer. Cetuximab increases response rate, with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours. The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases cannot be recommended. Funding Cancer Research UK, Cancer Research Wales, UK Medical Research Council, Merck KGgA.

Background. Elderly and frail patients with cancer, although often treated with chemotherapy, are under-represented in clinical trials. We designed FOCUS2 to investigate reduced-dose chemotherapy options and to seek objective predictors of outcome in frail patients with advanced colorectal cancer. Methods. We undertook an open, 2 × 2 factorial trial in 61 UK centres for patients with previously untreated advanced colorectal cancer who were considered unfit for full-dose chemotherapy. After comprehensive health assessment (CHA), patients were randomly assigned by minimisation to: 48-h intravenous fluorouracil with levofolinate (group A); oxaliplatin and fluorouracil (group B); capecitabine (group C); or oxaliplatin and capecitabine (group D). Treatment allocation was not masked. Starting doses were 80% of standard doses, with discretionary escalation to full dose after 6 weeks. The two primary outcome measures were: addition of oxaliplatin ([A vs B] + [C vs D]), assessed with progression-free survival (PFS); and substitution of fluorouracil with capecitabine ([A vs C] + [B vs D]), assessed by change from baseline to 12 weeks in global quality of life (QoL). Analysis was by intention to treat. Baseline clinical and CHA data were modelled against outcomes with a novel composite measure, overall treatment utility (OTU). This study is registered, number ISRCTN21221452. Findings. 459 patients were randomly assigned (115 to each of groups A–C, 114 to group D). Factorial comparison of addition of oxaliplatin versus no addition suggested some improvement in PFS, but the finding was not significant (median 5·8 months [IQR 3·3–7·5] vs 4·5 months [2·8–6·4]; hazard ratio 0·84, 95% CI 0·69–1·01, p=0·07). Replacement of fluorouracil with capecitabine did not improve global QoL: 69 of 124 (56%) patients receiving fluorouracil reported improvement in global QoL compared with 69 of 123 (56%) receiving capecitabine. The risk of having any grade 3 or worse toxic effect was not significantly increased with oxaliplatin (83/219 [38%] vs 70/221 [32%]; p=0·17), but was higher with capecitabine than with fluorouracil (88/222 [40%] vs 65/218 [30%]; p=0·03). In multivariable analysis, fewer baseline symptoms (odds ratio 1·32, 95% CI 1·14–1·52), less widespread disease (1·51, 1·05–2·19), and use of oxaliplatin (0·57, 0·39–0·82) were predictive of better OTU. Interpretation. FOCUS2 shows that with an appropriate design, including reduced starting doses of chemotherapy, frail and elderly patients can participate in a randomised controlled trial. On balance, a combination including oxaliplatin was preferable to single-agent fluoropyrimidines, although the primary endpoint of PFS was not met. Capecitabine did not improve QoL compared with fluorouracil. Comprehensive baseline assessment holds promise as an objective predictor of treatment benefit. Funding. Cancer Research UK and the Medical Research Council.

The hypoxic cell radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole) are under evaluation as single agents (Phase III) and in combination (Phase I). Ro 03-8799 produces an acute, transient central nervous system syndrome, whereas SR 2508 causes cumulative, peripheral neurotoxicity; both effects are dose-limiting. Pharmacokinetic studies have shown the importance of area under the plasma drug concentration versus time curve (AUC) in predicting the risk of peripheral neuropathy. Most patients have very similar pharmacokinetic parameters. This study reports 2/25 patients receiving 0.75 g/m2 Ro 03-8799 plus 2.0 g/m2 SR 2508 who showed significant discrepancies in drug handling. One patient exhibited a markedly elevated AUC and prolonged t1/2 beta for SR 2508 and this was associated with an unusually rapid onset of peripheral neuropathy. A second patient showed normal handling of SR 2508 but prolonged values for both t1/2 alpha and t1/2 beta for Ro 03-8799 and unusually low levels of its N-oxide metabolite. In addition a low peak Ro 03-8799 concentration combined with a very high volume of distribution was found in this patient, leading to a normal AUC value and toxicity profile. Both patients exhibited a relatively low creatinine clearance. The mechanisms which may underlie these findings are discussed, and the importance of pharmacokinetic monitoring in the use of these agents is emphasized.

A case report is presented of intra-mural gallbladder carcinoma discovered incidentally after laparoscopic cholecystectomy who subsequently developed abdominal wall recurrence at the epigastric exit port, and axillary lymph node metastases. Possible preventative steps for tumour dissemination and a management plan if incidental carcinoma is diagnosed is discussed. The use of a non-porous retrieval bag, early recognition of the carcinoma and excision of the exit wound are advocated.

The two radiosensitizers etanidazole and pimonidazole, currently in clinical phase 3 trials, have different toxicities. The former produces a peripheral neuropathy after cumulative doses and the latter presents an accurate but transient central nervous system syndrome after each dose. A strategy for improving on the maximum radiosensitization achievable using either drug alone, has been investigated in the study reported in this paper. Escalating doses of the two drugs were given together to determine toxicity up to a maximum of 15 doses of 2.0 g/m2 etanidazole and 0.75 g/m2 pimonidazole/dose. 25 neuropathies were seen in the total of 48 patients (48%). This included 6 grade 2 neuropathies (12.5%) or 15% of those receiving 9 or more infusions. There were no significant correlations between the incidence of neuropathy and various dose and AUC parameters for the 31 patients receiving 10 or more infusions. However, in the selected group of 26 patients planned to receive multiple doses of etanidazole at 2 g/m2/dose with pimonidazole at 0.75 g/m2, significant correlations were seen with the cumulative dose, with single and cumulative AUCs for pimonidazole and also for the cumulative dose and the cumulative AUC for etanidazole, but not its single AUC. In the light of these observations and the recent reports of higher peripheral neuropathy rates than previously reported in studies in the USA, it is concluded that it is not possible at this time to determine whether there is toxicity interaction between the two drugs. There remains the possibility that, on the basis of the combined drug dosage achieved, an increased therapeutic efficacy can be reached with either drug alone.

The hypoxic cell radiosensitizers Ro 03-8799 and SR 2508 have different clinical toxicities. The former produces an acute but transient central nervous system syndrome, whereas the latter produces cumulative peripheral neuropathy. Following single dose studies, an escalating multiple dose schedule using both drugs in combination showed no unexpected adverse reactions at lower doses. This study identifies the clinical tolerance and pharmacokinetics when doses in the region of the maximal tolerated dose are given to 26 patients receiving infusions of 0.75 g/m2 Ro 03-8799 and 2 g/m2 SR 2508 three times per week. At 15 doses, 3/4 patients experienced WHO grade 2 peripheral neuropathy, whereas at 12 doses 1/9 developed grade 2 and 6/9 developed grade 1 neuropathies. This represents a lower dose of SR 2508 than can be given alone suggesting that some interaction between the two drugs does exist in terms of chronic peripheral neurotoxicity. Pharmacokinetic studies show no adverse interactions between the two drugs and minimal inter-patient variation. From bivariate analysis, cumulative AUC for Ro 03-8799 has the most significant correlation with the development of peripheral neuropathy. Tumor drug concentrations normalized to the administered dose show mean values of 34 micrograms/g Ro 03-8799 and 76 micrograms/g SR 2508 30 minutes after infusion. These could be expected to produce a single dose sensitizer enhancement ratio of 1.5. The combination of the two sensitizers at the maximum tolerable dose may be expected to give an increased therapeutic efficacy over either drug alone.

Background: When cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim. Methods: COIN was a randomised controlled trial in patients with previously untreated advanced colorectal cancer. Patients received either continuous oxaliplatin and fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (arm B), or intermittent (arm C) chemotherapy. In arms A and B, treatment continued until development of progressive disease, cumulative toxic effects, or the patient chose to stop. In arm C, patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression, when the same treatment was restarted. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and B is described in a companion paper. Here, we compare arms A and C, with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy, with a predefined non-inferiority boundary of 1·162. Intention-to-treat (ITT) and per-protocol analyses were done. This trial is registered, ISRCTN27286448. Findings: 1630 patients were randomly assigned to treatment groups (815 to continuous and 815 to intermittent therapy). Median survival in the ITT population (n=815 in both groups) was 15·8 months (IQR 9·4–26·1) in arm A and 14·4 months (8·0–24·7) in arm C (hazard ratio [HR] 1·084, 80% CI 1·008–1·165). In the per-protocol population (arm A, n=467; arm C, n=511), median survival was 19·6 months (13·0–28·1) in arm A and 18·0 months (12·1–29·3) in arm C (HR 1·087, 0·986–1·198). The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary. Preplanned subgroup analyses in the per-protocol population showed that a raised baseline platelet count, defined as 400 000 per μL or higher (271 [28%] of 978 patients), was associated with poor survival with intermittent chemotherapy: the HR for comparison of arm C and arm A in patients with a normal platelet count was 0·96 (95% CI 0·80–1·15, p=0·66), versus 1·54 (1·17–2·03, p=0·0018) in patients with a raised platelet count (p=0·0027 for interaction). In the per-protocol population, more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects (72 [15%] vs 60 [12%]), whereas nausea and vomiting were more common on intermittent treatment (11 [2%] vs 43 [8%]). Grade 3 or worse peripheral neuropathy (126 [27%] vs 25 [5%]) and hand–foot syndrome (21 [4%] vs 15 [3%]) were more frequent on continuous than on intermittent treatment. Interpretation: Although this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival, chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer, offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life. Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break. Funding: Cancer Research UK.