Prognostic Impact of Early Treatment and Oxaliplatin Discontinuation in Patients With Stage III Colon Cancer: An ACCENT/IDEA Pooled Analysis of 11 Adjuvant Trials.

PURPOSE: Oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (CC) for 6 months remains a standard in high-risk stage III patients. Data are lacking as to whether early discontinuation of all treatment (ETD) or early discontinuation of oxaliplatin (EOD) could worsen the prognosis. MATERIALS AND METHODS: We studied the prognostic impact of ETD and EOD in patients with stage III CC from the ACCENT/IDEA databases, where patients were planned to receive 6 months of infusional fluorouracil, leucovorin, and oxaliplatin or capecitabine plus oxaliplatin. ETD was defined as discontinuation of treatment and EOD as discontinuation of oxaliplatin only before patients had received a maximum of 75% of planned cycles. Association between ETD/EOD and overall survival and disease-free survival (DFS) were assessed by Cox models adjusted for established prognostic factors. RESULTS: Analysis of ETD and EOD included 10,447 (20.9% with ETD) and 7,243 (18.8% with EOD) patients, respectively. Compared with patients without ETD or EOD, patients with ETD or EOD were statistically more likely to be women, with Eastern Cooperative Oncology Group performance status ≥ 1, and for ETD, older with a lower body mass index. In multivariable analyses, ETD was associated with a decrease in disease-free survival and overall survival (hazard ratio [HR], 1.61, P < .001 and HR, 1.73, P < .001), which was not the case for EOD (HR, 1.07, P = .3 and HR, 1.13, P = .1). However, patients who received < 50% of the planned cycles of oxaliplatin had poorer outcomes. CONCLUSION: In patients treated with 6 months of oxaliplatin-based chemotherapy for stage III CC, ETD was associated with poorer oncologic outcomes. However, this was not the case for EOD. These data favor discontinuing oxaliplatin while continuing fluoropyrimidine in individuals with significant neurotoxicity having received > 50% of the planned 6-month chemotherapy.

Conversion of non-inferiority margin from hazard ratio to restricted mean survival time difference using data from multiple historical trials.

The restricted mean survival time measure has gained a lot of interests for designing and analyzing oncology trials with time-to-event endpoints due to its intuitive clinical interpretation and potentially high statistical power. In the non-inferiority trial literature, restricted mean survival time has been used as an alternative measure for reanalyzing a completed trial, which was originally designed and analyzed based on traditional proportional hazard model. However, the reanalysis procedure requires a conversion from the non-inferiority margin measured in hazard ratio to a non-inferiority margin measured by restricted mean survival time difference. An existing conversion method assumes a Weibull distribution for the population survival time of the historical active control group under the proportional hazard assumption using data from a single trial. In this article, we develop a methodology for non-inferiority margin conversion when data from multiple historical active control studies are available, and introduce a Kaplan-Meier estimator-based method for the non-inferiority margin conversion to relax the parametric assumption. We report extensive simulation studies to examine the performances of proposed methods under the Weibull data generative models and a piecewise-exponential data generative model that mimic the tumor recurrence and survival characteristics of advanced colon cancer. This work is motivated to achieve non-inferiority margin conversion, using historical patient-level data from a large colon cancer clinical database, to reanalyze an internationally collaborated non-inferiority study that evaluates 6-month versus 3-month duration of adjuvant chemotherapy in stage III colon cancer patients.

Randomized Phase II Trial of Polyphenon E versus Placebo in Patients at High Risk of Recurrent Colonic Neoplasia.

Polyphenon E (Poly E) is a green tea polyphenol preparation whose most active component is epigallocatechin gallate (EGCG). We studied the cancer preventive efficacy and safety of Poly E in subjects with rectal aberrant crypt foci (ACF), which represent putative precursors of colorectal cancers. Eligible subjects had prior colorectal advanced adenomas or cancers, and had ≥5 rectal ACF at a preregistration chromoendoscopy. Subjects (N = 39) were randomized to 6 months of oral Poly E (780 mg EGCG) daily or placebo. Baseline characteristics were similar by treatment arm (all P >0.41); 32 of 39 (82%) subjects completed 6 months of treatment. The primary endpoint was percent reduction in rectal ACF at chromoendoscopy comparing before and after treatment. Among 32 subjects (15 Poly E, 17 placebo), percent change in rectal ACF number (baseline vs. 6 months) did not differ significantly between study arms (3.7% difference of means; P = 0.28); total ACF burden was also similar (-2.3% difference of means; P = 0.83). Adenoma recurrence rates at 6 months were similar by arm (P > 0.35). Total drug received did not differ significantly by study arm; 31 (79%) subjects received ≥70% of prescribed Poly E. Poly E was well tolerated and adverse events (AE) did not differ significantly by arm. One subject on placebo had two grade 3 AEs; one subject had grade 2 hepatic transaminase elevations attributed to treatment. In conclusion, Poly E for 6 months did not significantly reduce rectal ACF number relative to placebo. Poly E was well tolerated and without significant toxicity at the dose studied. PREVENTION RELEVANCE: We report a chemoprevention trial of polyphenon E in subjects at high risk of colorectal cancer. The results show that polyphenon E was well tolerated, but did not significantly reduce the number of rectal aberrant crypt foci, a surrogate endpoint biomarker of colorectal cancer.

Duration of Adjuvant Doublet Chemotherapy (3 or 6 months) in Patients With High-Risk Stage II Colorectal Cancer.

PURPOSE: As oxaliplatin results in cumulative neurotoxicity, reducing treatment duration without loss of efficacy would benefit patients and healthcare providers. PATIENTS AND METHODS: Four of the six studies in the International Duration of Adjuvant Chemotherapy (IDEA) collaboration included patients with high-risk stage II colon and rectal cancers. Patients were treated (clinician and/or patient choice) with either fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) and randomly assigned to receive 3- or 6-month treatment. The primary end point is disease-free survival (DFS), and noninferiority of 3-month treatment was defined as a hazard ratio (HR) of < 1.2- v 6-month arm. To detect this with 80% power at a one-sided type one error rate of 0.10, a total of 542 DFS events were required. RESULTS: 3,273 eligible patients were randomly assigned to either 3- or 6-month treatment with 62% receiving CAPOX and 38% FOLFOX. There were 553 DFS events. Five-year DFS was 80.7% and 83.9% for 3-month and 6-month treatment, respectively (HR, 1.17; 80% CI, 1.05 to 1.31; P [for noninferiority] .39). This crossed the noninferiority limit of 1.2. As in the IDEA stage III analysis, the duration effect appeared dependent on the chemotherapy regimen although a test of interaction was negative. HR for CAPOX was 1.02 (80% CI, 0.88 to 1.17), and HR for FOLFOX was 1.41 (80% CI, 1.18 to 1.68). CONCLUSION: Although noninferiority has not been demonstrated in the overall population, the convenience, reduced toxicity, and cost of 3-month adjuvant CAPOX suggest it as a potential option for high-risk stage II colon cancer if oxaliplatin-based chemotherapy is suitable. The relative contribution of the factors used to define high-risk stage II disease needs better understanding.

Clinical Outcomes in Patients With Colon Cancer With Microsatellite Instability of Sporadic or Familial Origin Treated With Adjuvant FOLFOX With or Without Cetuximab: A Pooled Analysis of the PETACC8 and N0147 Trials.

PURPOSE: The microsatellite instability (MSI) or deficient mismatch repair (dMMR) phenotype is usually regarded as a single biologic entity, given the absence of comparative analyses regarding prognosis and response to chemotherapy between sporadic and familial dMMR cancers. PATIENTS AND METHODS: Patients with stage III colon cancers were randomly assigned to FOLFOX (leucovorin, fluorouracil, and oxaliplatin) with or without cetuximab in 2 large adjuvant phase III trials (N = 5,577). Among patients with MSI and KRAS exon 2 wild-type (WT) tumors, the prognostic and predictive impacts of sporadic versus familial dMMR cancers and BRAF V600E mutational status were determined. Multivariable Cox proportional hazards models were used to assess disease-free survival (DFS) by treatment arm, adjusting for age, sex, tumor grade, Eastern Cooperative Oncology Group performance status, pT/pN stage, and primary tumor location. RESULTS: Among patients with MSI status with complete data for dMMR mechanism analysis (n = 354), 255 (72%) had sporadic (BRAF mutation and/or MLH1 methylation) and 99 (28%) had familial tumors (BRAF WT and unmethylated MLH1 or loss of MSH2/MSH6/PMS2 protein expression). A large proportion of dMMR sporadic tumors were mutated for BRAF (n = 200). In patients treated with FOLFOX, DFS did not differ statistically by dMMR mechanism, whereas in patients treated with FOLFOX plus cetuximab, those with sporadic tumors had worse DFS than those with familial cancers (multivariable hazard ratio, 2.69; 95% CI, 1.02 to 7.08; P = .04). Considering the predictive utility, the interaction between treatment and dMMR mechanism was significant (P = .03). Furthermore, a nonsignificant trend toward a deleterious effect of adding cetuximab to FOLFOX was observed in patients with BRAF-mutant but not BRAF WT tumors. CONCLUSION: The addition of cetuximab to adjuvant FOLFOX was associated with shorter DFS in patients with sporadic dMMR colon cancer. Additional studies are needed to validate these results in metastatic disease.

Efficacy of Difluoromethylornithine and Aspirin for Treatment of Adenomas and Aberrant Crypt Foci in Patients with Prior Advanced Colorectal Neoplasms.

Difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, was shown to act synergistically with a NSAID for chemoprevention of colorectal neoplasia. We determined the efficacy and safety of DFMO plus aspirin for prevention of colorectal adenomas and regression of rectal aberrant crypt foci (ACF) in patients with prior advanced adenomas or cancer. A double-blinded, placebo-controlled trial was performed in 104 subjects (age 46-83) randomized (1:1) to receive daily DFMO (500 mg orally) plus aspirin (325 mg) or matched placebos for one year. All polyps were removed at baseline. Adenoma number (primary endpoint) and rectal ACF (index cluster and total) were evaluated at a one year colonoscopy. ACF were identified by chromoendoscopy. Toxicity was monitored, including audiometry. Eighty-seven subjects were evaluable for adenomas or ACF modulation (n = 62). At one year of treatment, adenomas were detected in 16 (38.1%) subjects in the DFMO plus aspirin arm (n = 42) versus 18 (40.9%) in the placebo arm (n = 44; P = 0.790); advanced adenomas were similar (n = 3/arm). DFMO plus aspirin was associated with a statistically significant reduction in the median number of rectal ACF compared with placebo (P = 0.036). Total rectal ACF burden was also reduced in the treatment versus the placebo arm relative to baseline (74% vs. 45%, P = 0.020). No increase in adverse events, including ototoxicity, was observed in the treatment versus placebo arms. While adenoma recurrence was not significantly reduced by one year of DFMO plus aspirin, the drug combination significantly reduced rectal ACF number consistent with a chemopreventive effect.

Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study.

BACKGROUND: Regorafenib confers an overall survival benefit in patients with refractory metastatic colorectal cancer; however, the adverse event profile of regorafenib has limited its use. Despite no supportive evidence, various dosing schedules are used clinically to alleviate toxicities. This study evaluated the safety and activity of two regorafenib dosing schedules. METHODS: In this randomised, multicentre, open-label, phase 2 study done in 39 outpatient cancer centres in the USA, adults aged 18 years or older with histologically or cytologically confirmed advanced or metastatic adenocarcinoma of the colon or rectum that was refractory to previous standard therapy, including EGFR inhibitors if KRAS wild-type, were enrolled. Eligible patients had an Eastern Cooperative Oncology Group performance status of 0-1 and had no previous treatment with regorafenib. Patients were randomly assigned (1:1:1:1) into four groups with two distinct regorafenib dosing strategies and two clobetasol usage plans, stratified by hospital. Regorafenib dosing strategies were a dose-escalation strategy (starting dose 80 mg/day orally with weekly escalation, per 40 mg increment, to 160 mg/day regorafenib) if no significant drug-related adverse events occurred and a standard-dose strategy (160 mg/day orally) for 21 days of a 28-day cycle. Clobetasol usage plans (0·05% clobetasol cream twice daily applied to palms and soles) were either pre-emptive or reactive. After randomisation to the four preplanned groups, using the Pocock and Simon dynamic allocation procedures stratified by the treating hospitals, we formally tested the interaction between the two interventions, dosing strategy and clobetasol usage. Given the absence of a significant interaction (p=0·74), we decided to pool the data for the pre-emptive and reactive treatment with clobetasol and compared the two dosing strategies (dose escalation vs standard dose). The primary endpoint was the proportion of evaluable patients (defined as those who were eligible, consented, and received any protocol treatment) initiating cycle 3 and was analysed per protocol. Superiority for dose escalation was declared if the one-sided p value with Fisher's exact test was less than 0·2. This trial is registered with ClinicalTrials.gov, number NCT02368886. This study is fully accrued but remains active. FINDINGS: Between June 2, 2015, and June 22, 2017, 123 patients were randomly assigned to treatment, of whom 116 (94%) were evaluable. The per-protocol population consisted of 54 patients in the dose-escalation group and 62 in the standard-dose group. At data cutoff on July 24, 2018, median follow-up was 1·18 years (IQR 0·98-1·57). The primary endpoint was met: 23 (43%, 95% CI 29-56) of 54 patients in the dose-escalation group initiated cycle 3 versus 16 (26%, 15-37) of 62 patients in the standard-dose group (one-sided p=0·043). The most common grade 3-4 adverse events were fatigue (seven [13%] patients in the dose-escalation group vs 11 [18%] in the standard-dose group), hand-foot skin reaction (eight [15%] patients vs ten [16%] patients), abdominal pain (nine [17%] patients vs four [6%] patients), and hypertension (four [7%] patients vs nine [15%] patients). 14 patients had at least one drug-related serious adverse event: six patients in the dose-escalation group and eight patients in the standard-dose group. There was one probable treatment-related death in the standard-dose group (myocardial infarction). INTERPRETATION: The dose-escalation dosing strategy represents an alternative approach for optimising regorafenib dosing with comparable activity and lower incidence of adverse events and could be implemented in clinical practice on the basis of these data. FUNDING: Bayer HealthCare Pharmaceuticals.

A nomogram for predicting survival and retroperitoneal lymph node dissection treatment in patients with resected testicular germ cell tumors.

BACKGROUND AND OBJECTIVES: To build nomogram incorporating potential prognostic factors for predicting survival outcomes of testicular germ cell tumors (TGCT) patients after resection of the primary tumor. METHODS: Data of TGCT patients from the Surveillance, Epidemiology, and End Results database (2010-2016) who underwent resection of the primary tumor were collected. Overall survival (OS) and cancer-specific survival (CSS) were analyzed by using Cox regression models, nomogram, Kaplan-Meier method, and log-rank test. RESULTS: We identified 7272 TGCT patients. Age at diagnosis, histology, tumor size, American Joint Committee on Cancer (AJCC) staging system, and number of metastases sites were independent prognostic factors and were integrated into nomograms. The nomograms had higher C-indexes for both OS and CSS compared with the AJCC 7th staging system (0.881 vs 0.831 and 0.895 vs 0.856, respectively). Moreover, the new stratification of risk groups based on the nomograms showed a more significant distinction between Kaplan-Meier curves for survival outcomes than the AJCC staging system. Retroperitoneal lymph node dissection was associated with statistically improved survival probability in the nomogram middle-risk group in resected TGCT patients. CONCLUSION: The novel nomogram-based staging system could provide satisfactory risk stratification and survival prediction ability beyond traditional AJCC staging systems.

Development and validation of a model to predict outcomes of colon cancer surveillance.

PURPOSE: Clinical trials suggest that intensive surveillance of colon cancer (CC) survivors to detect recurrence increases curative-intent treatment, although any survival benefit of surveillance as currently practiced appears modest. Realizing the potential of surveillance will require tools for identifying patients likely to benefit and for optimizing testing regimens. We describe and validate a model for predicting outcomes for any schedule of surveillance in CC survivors with specified age and cancer stage. METHODS: A Markov process parameterized based on individual-level clinical trial data generates natural history events for simulated patients. A utilization submodel simulates surveillance and diagnostic testing. We validate the model against outcomes from the follow-up after colorectal surgery (FACS) trial. RESULTS: Prevalidation sensitivity analysis showed no parameter influencing curative-intent treatment by > 5.0% or overall five-year survival (OS5) by > 1.5%. In validation, the proportion of recurring subjects predicted to receive curative-intent treatment fell within FACS 95% CI for carcinoembryonic antigen (CEA)-intensive, computed tomography (CT)-intensive, and combined CEA+CT regimens, but not for a minimum surveillance regimen, where the model overestimated recurrence and curative treatment. The observed OS5 fell within 95% prediction intervals for all regimens. CONCLUSION: The model performed well in predicting curative surgery for three of four FACS arms. It performed well in predicting OS5 for all arms.

A Phase II Randomized Trial of Panitumumab, Erlotinib, and Gemcitabine Versus Erlotinib and Gemcitabine in Patients with Untreated, Metastatic Pancreatic Adenocarcinoma: North Central Cancer Treatment Group Trial N064B (Alliance).

LESSONS LEARNED: Dual epidermal growth factor receptor (EGFR)-directed therapy with erlotinib and panitumumab in combination with gemcitabine was superior to gemcitabine and erlotinib, but the clinical relevance is uncertain given the limited role of gemcitabine monotherapy.A significantly longer overall survival was observed in patients receiving the dual EGFR-directed therapy.The dual EGFR-directed therapy resulted in increased toxicity. BACKGROUND: Gemcitabine is active in patients with advanced pancreatic adenocarcinoma. The combination of erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, and gemcitabine was shown to modestly prolong overall survival when compared with gemcitabine alone. The North Central Cancer Treatment Group (now part of Alliance for Clinical Trials in Oncology) trial N064B compared gemcitabine plus erlotinib versus gemcitabine plus combined EGFR inhibition with erlotinib and panitumumab. METHODS: Eligible patients with metastatic adenocarcinoma of the pancreas were randomized to either gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle with erlotinib 100 mg p.o. daily (Arm A) or the same combination with the addition of panitumumab 4 mg/kg on days 1 and 15 of a 28-day cycle (Arm B). The primary endpoint of the trial was overall survival. Secondary endpoints included progression-free survival, the confirmed response rate, and toxicity. Comparison between arms for the primary endpoint was done with a one-sided log-rank test, and a p value less than .20 was considered statistically significant. Response rate comparison was done with Fisher's exact test. All other reported p values are two-sided. RESULTS: A total of 92 patients were randomized, 46 to each arm. The median overall survival was 4.2 months in Arm A and 8.3 months in Arm B (hazard ratio, 0.817; 95% confidence interval [CI], 0.530-1.260; p = .1792). The progression-free survival was 2.0 months in Arm A and 3.6 months in Arm B (hazard ratio, 0.843; 95% CI, 0.555-1.280; p = .4190). A partial confirmed response was seen in 8.7% of patients on Arm A and 6.5% on Arm B (p = .9999). No patients had a complete response. Grade 3 and higher nonhematologic toxicities were more common in patients on Arm B compared with those on Arm A (82.6% vs. 52.2%; p = .0018). CONCLUSION: Dual EGFR-directed therapy resulted in a significant prolongation of overall survival in patients with advanced adenocarcinoma of the pancreas but was associated with substantially increased toxicities. Dual EGFR-directed therapy in combination with gemcitabine alone cannot be recommended for further study, as single-agent gemcitabine is no longer considered an appropriate therapy for otherwise fit patients with metastatic pancreatic cancer.

Feasibility of Implementing the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events in a Multicenter Trial: NCCTG N1048.

Purpose The US National Cancer Institute (NCI) Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) was developed to enable patient reporting of symptomatic adverse events in oncology clinical research. This study was designed to assess the feasibility and resource requirements associated with implementing PRO-CTCAE in a multicenter trial. Methods Patients with locally advanced rectal cancer enrolled in the National Cancer Institute-sponsored North Central Cancer Treatment Group (Alliance) Preoperative Radiation or Selective Preoperative Radiation and Evaluation before Chemotherapy and Total Mesorectal Excision trial were asked to self-report 30 PRO-CTCAE items weekly from home during preoperative therapy, and every 6 months after surgery, via either the Web or an automated telephone system. If participants did not self-report within 3 days, a central coordinator called them to complete the items. Compliance was defined as the proportion of participants who completed PRO-CTCAE assessments at expected time points. Results The prespecified PRO-CTCAE analysis was conducted after the 500th patient completed the 6-month follow-up (median age, 56 years; 33% female; 12% nonwhite; 43% high school education or less; 5% Spanish speaking), across 165 sites. PRO-CTCAE was reported by participants at 4,491 of 4,882 expected preoperative time points (92.0% compliance), of which 3,771 (77.2%) were self-reported by participants and 720 (14.7%) were collected via central coordinator backup. Compliance at 6-month post-treatment follow-up was 333 of 468 (71.2%), with 122 (26.1%) via backup. Site research associates spent a median of 15 minutes on PRO-CTCAE work for each patient visit. Work by a central coordinator required a 50% time commitment. Conclusion Home-based reporting of PRO-CTCAE in a multicenter trial is feasible, with high patient compliance and low site administrative requirements. PRO-CTCAE data capture is improved through centralized backup calls.

Duration of Adjuvant Chemotherapy for Stage III Colon Cancer.

BACKGROUND: Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures. METHODS: We performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12. RESULTS: After 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority). CONCLUSIONS: Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.).

Role of Deficient DNA Mismatch Repair Status in Patients With Stage III Colon Cancer Treated With FOLFOX Adjuvant Chemotherapy: A Pooled Analysis From 2 Randomized Clinical Trials.

IMPORTANCE: The prognostic impact of DNA mismatch repair (MMR) status in stage III colon cancer patients receiving FOLFOX (folinic acid, fluorouracil, and oxaliplatin) adjuvant chemotherapy remains controversial. OBJECTIVE: To determine the association of MMR status with disease-free survival (DFS) in patients with stage III colon cancer treated with FOLFOX. DESIGN, SETTING, AND PARTICIPANTS: The evaluated biomarkers for MMR status were determined from prospectively collected tumor blocks from patients treated with FOLFOX in 2 open-label, phase 3 randomized clinical trials: NCCTG N0147 and PETACC8. The studies were conducted in general community practices, private practices, and institutional practices in the United States and Europe. All participants had stage III colon adenocarcinoma. They were enrolled in NCCTG N0147 from February 2004 to November 2009 and in PETACC8 from December 2005 to November 2009. INTERVENTIONS: Patients in the clinical trials were randomly assigned to receive 6 months of chemotherapy with FOLFOX or FOLFOX plus cetuximab. Only those patients treated with FOLFOX alone were included in the present study. MAIN OUTCOMES AND MEASURES: Association of MMR status with DFS was analyzed using a stratified Cox proportional hazards model. Multivariable models were adjusted for age, sex, tumor grade, pT/pN stage, tumor location, ECOG (Eastern Cooperative Oncology Group) performance status, and BRAF V600E mutational status. RESULTS: Among 2636 patients with stage III colon cancer treated with FOLFOX, MMR status was available for 2501. Of these, 252 (10.1%) showed deficient MMR status (dMMR; 134 women, 118 men; median age, 59 years), while 2249 (89.9%) showed proficient MMR status (pMMR; 1020 women, 1229 men; median age, 59 years). The 3-year DFS rates in the dMMR and pMMR groups were 75.6% and 74.4%, respectively. By multivariate analysis, patients with dMMR phenotype had significantly longer DFS than those with pMMR (adjusted hazard ratio, 0.73; 95% CI, 0.54-0.97; P = .03). CONCLUSIONS AND RELEVANCE: The deficient MMR phenotype remains a favorable prognostic factor in patients with stage III colon cancer receiving FOLFOX adjuvant chemotherapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00079274 for the NCCTG N0147 trial and EudraCT identifier: 2005-003463-23 for the PETACC8 trial.

Personalizing Survival Predictions in Advanced Colorectal Cancer: The ARCAD Nomogram Project.

Background: Estimating prognosis on the basis of clinicopathologic factors can inform clinical practice and improve risk stratification for clinical trials. We constructed prognostic nomograms for one-year overall survival and six-month progression-free survival in metastatic colorectal carcinoma by using the ARCAD database. Methods: Data from 22 674 patients in 26 randomized phase III clinical trials since 1997 were used to construct and validate Cox models, stratified by treatment arm within each study. Candidate variables included baseline age, sex, body mass index, performance status, colon vs rectal cancer, prior chemotherapy, number and location of metastatic sites, tumor mutation status (BRAF, KRAS), bilirubin, albumin, white blood cell count, hemoglobin, platelets, absolute neutrophil count, and derived neutrophil-to-lymphocyte ratio. Missing data (<11%) were imputed, continuous variables modeled with splines, and clinically relevant pairwise interactions tested if P values were less than .001. Final models were internally validated via bootstrapping to obtain optimism-corrected calibration and discrimination C-indices, and externally validated on a 10% holdout sample from each trial (n = 2257). Results: In final models, all included variables were associated with overall survival except for lung metastases, and all but total white cell count associated with progression-free survival. No clinically relevant pairwise interactions were identified. Final nomogram calibration was good (C = 0.68 for overall and C = 0.62 for progression-free survival), as was external validity (concordance between predicted >50% vs < 50% probability) and actual (yes/no) survival (72.8% and 68.2% concordance, respectively, for one-year overall and six-month progression-free survival, between predicted [>50% vs < 50% probability] and actual [yes/no] overall and progression-free survival). Median survival predictions fell within the actual 95% Kaplan-Meier confidence intervals. Conclusions: The nomograms are well calibrated and internally and externally valid. They have the potential to aid prognostication and patient-physician communication and balance risk in colorectal cancer trials.

North Central Cancer Treatment Group N0543 (Alliance): A phase 2 trial of pharmacogenetic-based dosing of irinotecan, oxaliplatin, and capecitabine as first-line therapy for patients with advanced small bowel adenocarcinoma.

BACKGROUND: Oxaliplatin in combination with either 5-fluorouracil or capecitabine is commonly used as first-line therapy for patients with small bowel adenocarcinoma. The addition of irinotecan improves survival in other gastrointestinal tumors but at the cost of hematologic toxicity. The authors performed a phase 2 cooperative group study (North Central Cancer Treatment Group N0543, Alliance) using genotype-dosed capecitabine, irinotecan, and oxaliplatin (gCAPIRINOX), with dosing assigned based on UDP glucuronosyltransferase family 1 member A1 (UGT1A1) genotype to test: 1) whether the addition of irinotecan would improve outcomes; and 2) whether UGT1A1 genotype-based dosing could optimize tolerability. METHODS: Previously untreated patients with advanced small bowel adenocarcinoma received irinotecan (day 1), oxaliplatin (day 1), and capecitabine (days 2-15) in a 21-day cycle and were dosed with gCAPIRINOX according to UGT1A1*28 genotypes (6/6, 6/7, and 7/7). RESULTS: A total of 33 patients (17 with the 6/6 genotype, 10 with the 6/7 genotype, and 6 with the 7/7 genotype) were enrolled from October 2007 to November 2013; 73% were male, with a mean age of 64 years (range, 41-77 years). Location of the primary tumor included the duodenum (58%), jejunum (30%), and ileum (9%). The regimen yielded a confirmed response rate of 37.5% (95% confidence interval, 21%-56%), with a median progression-free survival of 8.9 months and a median overall survival of 13.4 months. Neither hematologic toxicity (grade ≥3 in 52.9%, 30.0%, and 33.3%, respectively, of the 6/6, 6/7, and 7/7 genotype groups) nor tumor response rate (41.2%, 33%, and 33%, respectively) were found to differ significantly by UGT1A1 genotype. CONCLUSIONS: UGT1A1 genotype-directed dosing (gCAPIRINOX) appears to be feasible with favorable rates of hematologic toxicity compared with prior 3-drug studies in unselected patients. Larger studies would be needed to determine the regimen's comparability to oxaliplatin and capecitabine (CapeOx) alone or if response/toxicity differs among patients with different UGT1A1 genotypes. Cancer 2017;123:3494-501. © 2017 American Cancer Society.

Association of DNA Mismatch Repair and Mutations in BRAF and KRAS With Survival After Recurrence in Stage III Colon Cancers : A Secondary Analysis of 2 Randomized Clinical Trials.

IMPORTANCE: The association of biomarkers with patient survival after recurrence (SAR) of cancer is poorly understood but may guide management and treatment. OBJECTIVE: To determine the association of DNA mismatch repair (MMR) status and somatic mutation in the B-Raf proto-oncogene (c.1799T>A [V600E]; BRAFV600E) or exon 2 of the KRAS proto-oncogene (KRAS) in the primary tumor with SAR in patients with stage III colon carcinomas treated with adjuvant chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: Patients with resected stage III colon cancers were randomized to adjuvant FOLFOX (folinic acid [leucovorin calcium], fluorouracil, and oxaliplatin) chemotherapy with or without cetuximab (North Central Cancer Treatment Group N0147 trial) or adjuvant FOLFOX chemotherapy with or without bevacizumab (National Surgical Adjuvant Breast and Bowel Project C-08 trial). Associations of biomarkers with SAR were analyzed using Cox proportional hazards models adjusted for clinicopathologic features and time to recurrence (data collected February 10, 2004, to August 7, 2015). MAIN OUTCOMES AND MEASURES: The primary study outcome was survival after recurrence of cancer. A secondary outcome measure was the effect of the site of the primary tumor on the association of biomarkers with SAR. RESULTS: Among 871 patients with cancer recurrence in the N0147 trial (472 men [54.2%] and 399 women [45.8%]; mean [SD] age, 57.8 [11.2] years) and 524 in the C-08 trial (269 men [51.3%] and 255 women [48.7%]; mean [SD] age, 57.0 [11.7] years), multivariable analysis revealed that patients whose tumors had deficient vs proficient MMR had significantly better SAR (adjusted hazard ratio [AHR], 0.70; 95% CI, 0.52-0.96; P = .03). Patients whose tumors harbored mutant BRAFV600E (AHR, 2.45; 95% CI, 1.85-3.25; P < .001) or mutant KRAS (AHR, 1.21; 95% CI, 1.00-1.47; P = .052) had worse SAR compared with those whose tumors had wild-type copies of both genes, although only results for BRAFV600E achieved statistical significance. Significant interactions were found for MMR (P = .03) and KRAS (P = .02) by primary tumor site for SAR. Improved SAR was observed for patients with deficient MMR tumors of the proximal vs distal colon (AHR, 0.57; 95% CI, 0.40-0.83; P = .003), and worse SAR was observed for tumors of the distal colon with mutant KRAS in codon 12 (AHR, 1.76; 95% CI, 1.30-2.38; P < .001) and codon 13 (AHR, 1.76; 95% CI, 1.08-2.86; P = .02). CONCLUSIONS AND RELEVANCE: In patients with recurrence of stage III colon cancer, deficient MMR was significantly associated with better SAR, and this benefit was limited to primary tumors of the proximal colon. Mutations in BRAFV600E were significantly associated with worse SAR, and worse SAR for BRAFV600E or KRAS mutant tumors was more strongly associated with distal cancers. These biomarkers have implications for patient management at recurrence. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00079274 and NCT00096278.

Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database.

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.

Clinical Utility of Metrics Based on Tumor Measurements in Phase II Trials to Predict Overall Survival Outcomes in Phase III Trials by Using Resampling Methods.

PURPOSE: Phase II clinical trials inform go/no-go decisions for proceeding to phase III trials, and appropriate end points in phase II trials are critical for facilitating this decision. Phase II solid tumor trials have traditionally used end points such as tumor response defined by Response Evaluation Criteria for Solid Tumors (RECIST). We previously reported that absolute and relative changes in tumor measurements demonstrated potential, but not convincing, improvement over RECIST to predict overall survival (OS). We have evaluated the metrics by using additional measures of clinical utility and data from phase III trials. METHODS: Resampling methods were used to assess the clinical utility of metrics to predict phase III outcomes from simulated phase II trials. In all, 2,000 phase II trials were simulated from four actual phase III trials (two positive for OS and two negative for OS). Cox models for three metrics landmarked at 12 weeks and adjusted for baseline tumor burden were fit for each phase II trial: absolute changes, relative changes, and RECIST. Clinical utility was assessed by positive predictive value and negative predictive value, that is, the probability of a positive or negative phase II trial predicting an effective or ineffective phase III conclusion, by prediction error, and by concordance index (c-index). RESULTS: Absolute and relative change metrics had higher positive predictive value and negative predictive value than RECIST in five of six treatment comparisons and lower prediction error curves in all six. However, differences were negligible. No statistically significant difference in c-index across metrics was found. CONCLUSION: The absolute and relative change metrics are not meaningfully better than RECIST in predicting OS.

A phase I/II study of bortezomib in combination with paclitaxel, carboplatin, and concurrent thoracic radiation therapy for non-small-cell lung cancer: North Central Cancer Treatment Group (NCCTG)-N0321.

INTRODUCTION: Despite the advances in radiation techniques and chemotherapy, survival with current platinum-based chemotherapy and concomitant thoracic radiation remains dismal. Bortezomib, a proteasome inhibitor, modulates apoptosis and cell cycle through disruption of protein degradation. The combination of bortezomib and carboplatin/paclitaxel and concurrent radiation in unresectable stage III non-small-cell lung cancer was evaluated in this phase I/II study. METHODS: Patients with histologic or cytologic confirmed stage III nonmetastatic non-small-cell lung cancer who were candidates for radiation therapy were eligible. In the phase I portion, patients received escalating doses of bortezomib, paclitaxel, and carboplatin concomitantly with thoracic radiation (60 Gy/30 daily fractions) using a modified 3 + 3 design. The primary endpoint for the phase II portion was the 12-month survival rate (12MS). A one-stage design with an interim analysis yielded 81% power to detect a true 12MS of 75%, with a 0.09 level of significance if the true 12MS was 60% using a sample size of 60 patients. Secondary endpoints consisted of adverse events (AEs), overall survival, progression-free survival, and the confirmed response rate. RESULTS: Thirty-one patients enrolled during the phase I portion of the trial, of which four cancelled before receiving treatment, leaving 27 evaluable patients. Of these 27 patients, two dose-limiting toxicities were observed, one (grade 3 pneumonitis) at dose level 1 (bortezomib at 0.5 mg/m, paclitaxel at 150 mg/m, and carboplatin at area under the curve of 5) and one (grade 4 neutropenia lasting ≥8 days) at dose level 6 (bortezomib 1.2 mg/m, paclitaxel 175 mg/m, and carboplatin at area under the curve of 6). During the phase I portion, the most common grade 3 of 4 AEs were leukopenia (44%), neutropenia (37%), dyspnea (22%), and dysphagia (11%). Dose level 6 was declared to be the recommended phase II dose (RP2D) and the phase II portion of the study opened. After the first 26 evaluable patients were enrolled to the RP2D, a per protocol interim analysis occurred. Of these 26 patients, 23 (88%) survived at least 6 months (95% confidence interval [CI], 70-98%), which was enough to continue to full accrual per study design. However, due to slow accrual, the study was stopped after 27 evaluable patients were enrolled (6-phase I RP2D; 21-phase II). Of these 27 patients, the 12MS was 73% (95% CI, 58-92%), the median overall survival was 25.0 months (95% CI, 15.6-35.8), and the median progression-free survival was 8.4 months (95% CI, 4.1-10.5). The confirmed response rate was 26% (seven of 27; 95% CI, 11-46%), consisting of four partial responses and three complete responses. Grade 3+ and grade 4+ AEs occurred in 82% and 56% of patients, respectively. One patient experienced grade 5 pneumonitis that was possibly related to the treatment. Grade 3 and 4 hematological toxicities were observed in 82% and 56% patients, respectively. CONCLUSIONS: The addition of bortezomib to concurrent carboplatin/paclitaxel and radiation seemed to be feasible, although associated with increased hematological toxicities. A favorable median overall survival of 25 months suggests a potential benefit for this regimen.