[Targeting HER2 in colorectal cancer]. / Cibler HER2 dans le cancer colorectal.

Among the molecular subgroups of interest in metastatic colorectal cancer (mCRC), innovations are underway for tumors with overexpression of HER2 (Human Epidermal Growth Factor Receptor 2). Overexpression of the HER2 protein concerns 2 to 5% of CRC at any stage mainly located in the distal colon and rectum. Diagnosis is based on immunohistochemistry, in situ hybridization with appropriate criteria for colorectal localization, and molecular biology (NGS: next-generation sequencing). Overexpression of HER2 is a predictive factor for resistance to treatments targeting EGFR which are indicated in the case where the tumor is wild-type RAS. It seems to be associated with a poor prognosis of mCRC with a higher risk of brain metastasis. Regarding treatments targeting HER2, no randomized controlled phase III has been published to date. However, several combinations have been evaluated in phase II with clinically meaningful objective response rates: trastuzumab-deruxtecan (45%), trastuzumab-tucatinib (46%), trastuzumab-pyrotinib (45%), trastuzumab-pertuzumab (30%) ou trastuzumab-lapatinib (30%). In this literature review, we present here the current state of knowledge on the diagnostic methods of HER2 overexpression in CRC, the main clinical, molecular and prognostic characteristics, and the efficacy results of the different therapeutic combinations for the patients with HER2 overexpressed mCRC. This justifies, despite the lack of marketing authorization in France and in Europe for agents targeting HER2 in CRC, the systematic evaluation of the HER2 status, as recommended in particular by the NCCN (National Comprehensive Cancer Network).

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.

Reevaluating Disease-Free Survival as an Endpoint vs Overall Survival in Stage III Adjuvant Colon Cancer Trials.

BACKGROUND: Disease-free survival (DFS) with a 3-year median follow-up (3-year DFS) was validated as a surrogate for overall survival (OS) with a 5-year median follow-up (5-year OS) in adjuvant chemotherapy colon cancer (CC) trials. Recent data show further improvements in OS and survival after recurrence in patients who received adjuvant FOLFOX. Hence, reevaluation of the association between DFS and OS and determination of the optimal follow-up duration of OS to aid its utility in future adjuvant trials are needed. METHODS: Individual patient data from 9 randomized studies conducted between 1998 and 2009 were included; 3 trials tested biologics. Trial-level surrogacy examining the correlation of treatment effect estimates of 3-year DFS with 5 to 6.5-year OS was evaluated using both linear regression (RWLS2) and Copula bivariate (RCopula2) models and reported with 95% confidence intervals (CIs). For R2, a value closer to 1 indicates a stronger correlation. RESULTS: Data from a total of 18 396 patients were analyzed (median age = 59 years; 54.0% male), with 54.1% having low-risk tumors (T1-3 and N1), 31.6% KRAS mutated, 12.3% BRAF mutated, and 12.4% microsatellite instability high or deficient mismatch repair tumors. Trial-level correlation between 3-year DFS and 5-year OS remained strong (RWLS2 = 0.82, 95% CI = 0.67 to 0.98; RCopula2 = 0.92, 95% CI = 0.83 to 1.00) and increased as the median follow-up of OS extended. Analyses limited to trials that tested biologics showed consistent results. CONCLUSIONS: Three-year DFS remains a validated surrogate endpoint for 5-year OS in adjuvant CC trials. The correlation was likely strengthened with 6 years of follow-up for OS.

Early-Onset Colorectal Adenocarcinoma in the IDEA Database: Treatment Adherence, Toxicities, and Outcomes With 3 and 6 Months of Adjuvant Fluoropyrimidine and Oxaliplatin.

PURPOSE: Early-onset (EO) colorectal cancer (CRC, age < 50 years) incidence is increasing. Decisions on optimal adjuvant therapy should consider treatment adherence, adverse events, and expected outcomes in a population with life expectancy longer than later-onset (LO) CRC (age ≥ 50 years). MATERIALS AND METHODS: Individual patient data from six trials in the International Duration Evaluation of Adjuvant Chemotherapy database were analyzed. Characteristics, treatment adherence, and adverse events in stage II or III EO-CRC and LO-CRC were compared. To reduce confounders of non-cancer-related deaths because of age or comorbidities, time to recurrence (3-year relapse-free rate) and cancer-specific survival (5-year cancer-specific mortality rate) were considered. RESULTS: Out of 16,349 patients, 1,564 (9.6%) had EO-CRC. Compared with LO-CRC, EO-CRC had better performance status (86% v 80%, P < .01), similar T stage (% T1-3/T4: 76/24 v 77/23, P = .97), higher N2 disease rate (24% v 22%, P < .01), more likely to complete the planned treatment duration (83.2% v 78.2%, P < .01), and received a higher treatment dose intensity, especially with 6-month regimens. Gastrointestinal toxicity was more common in EO-CRC; hematologic toxicity was more frequent in LO-CRC. Compared with LO-CRC, significantly worse cancer-specific outcomes were demonstrated especially in high-risk stage III EO-CRC: lower 3-year relapse-free rate (54% v 65%; hazard ratio [HR] 1.33; 95% CI, 1.14 to 1.55; P value < .001) and higher 5-year cancer-specific mortality rate (24% v 20%; HR 1.21; 95% CI, 1.00 to 1.47; P value < .06). In this subgroup, no difference was observed with 3 or 6 months of therapy, with equally poor disease-free survival rates (57% v 56%; HR 0.97; 95% CI, 0.73 to 1.29; P value = .85). CONCLUSION: Young age is negatively prognostic in high-risk stage III CRC and associated with significantly higher relapse rate; this is despite better treatment adherence and higher administered treatment intensity, suggesting more aggressive disease biology.

Sex and Adverse Events of Adjuvant Chemotherapy in Colon Cancer: An Analysis of 34 640 Patients in the ACCENT Database.

BACKGROUND: Adjuvant chemotherapy is a standard treatment option for patients with stage III and high-risk stage II colon cancer. Sex is one of several factors responsible for the wide inter-patient variability in drug responses. Amalgamated data on the effect of sex on the toxicity of current standard adjuvant treatment for colorectal cancer are missing. METHODS: The objective of our study was to compare incidence and severity of major toxicities of fluoropyrimidine- (5FU or capecitabine) based adjuvant chemotherapy, with or without oxaliplatin, between male and female patients after curative surgery for colon cancer. Adult patients enrolled in 27 relevant randomized trials included in the ACCENT (Adjuvant Colon Cancer End Points) database, a large, multi-group, international data repository containing individual patient data, were included. Comparisons were conducted using logistic regression models (stratified by study and treatment arm) within each type of adjuvant chemotherapy (5FU, FOLFOX, capecitabine, CAPOX, and FOLFIRI). The following major toxicities were compared (grade III or IV and grade I-IV, according to National Cancer Institute Common Terminology Criteria [NCI-CTC] criteria, regardless of attribution): nausea, vomiting, nausea or vomiting, stomatitis, diarrhea, leukopenia, neutropenia, thrombocytopenia, anemia, and neuropathy (in patients treated with oxaliplatin). RESULTS: Data from 34 640 patients were analyzed. Statistically significant and clinically relevant differences in the occurrence of grade III or IV nonhematological {especially nausea (5FU: odds ratio [OR] = 2.33, 95% confidence interval [CI] = 1.90 to 2.87, P < .001; FOLFOX: OR = 2.34, 95% CI = 1.76 to 3.11, P < .001), vomiting (5FU: OR = 2.38, 95% CI = 1.86 to 3.04, P < .001; FOLFOX: OR = 2.00, 95% CI = 1.50 to 2.66, P < .001; CAPOX: OR = 2.32, 95% CI = 1.55 to 3.46, P < .001), and diarrhea (5FU: OR = 1.35, 95% CI = 1.21 to 1.51, P < .001; FOLFOX: OR = 1.60, 95% CI = 1.35 to 1.90, P < .001; FOLFIRI: OR = 1.57, 95% CI = 1.25 to 1.97, P < .001)} as well as hematological toxicities (neutropenia [5FU: OR = 1.55, 95% CI = 1.37 to 1.76, P < .001; FOLFOX: OR = 1.96, 95% CI = 1.71 to 2.25, P < .001; FOLFIRI: OR = 2.01, 95% CI = 1.66 to 2.43, P < .001; capecitabine: OR = 4.07, 95% CI = 1.84 to 8.99, P < .001] and leukopenia [5FU: OR = 1.74, 95% CI = 1.40 to 2.17, P < .001; FOLFIRI: OR = 1.75, 95% CI = 1.28 to 2.40, P < .001]) were observed, with women being consistently at increased risk. CONCLUSIONS: Our analysis confirms that women with colon cancer receiving adjuvant fluoropyrimidine-based chemotherapy are at increased risk of toxicity. Given the known sex differences in fluoropyrimidine pharmacokinetics, sex-specific dosing of fluoropyrimidines warrants further investigation.

Impact of the IDEA Collaboration Study Results on Clinical Practice in France for Patients With Stage III Colon Cancer: A National GERCOR - PRODIGE Survey.

BACKGROUND: The IDEA collaboration showed that the type and duration of adjuvant chemotherapy in stage III colon cancer (CC) could be adjusted according to the schedule of chemotherapy and the level of risk. We aimed at evaluating the implementation of IDEA's results in real-life practice for stage III CC. MATERIAL AND METHODS: All clinicians registered in the French oncology cooperative groups GERCOR, FFCD, and UNICANCER GI mailing lists were invited to participate to an online anonymized nationwide survey from January 30, 2019 to March 31, 2019. Proportions were compared using the χ2 test. RESULTS: A total of 213 physicians answered the survey. Of these, 173 (81%) considered that 3 months of adjuvant chemotherapy was the new standard of care for low-risk (pT1-3/N1) stage III CC, and 99% considered that 6 months remained the standard of care for high-risk (pT4 and/or pN2) stage III CC. In patients under 70 years, capecitabine and oxaliplatin (CAPOX) for 3 months was prescribed by 74% of the participants in low-risk CC, whereas 6 months of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) was preferred for high-risk CC in 94% of cases. For patients over 70 years with good performance status and no comorbidities, 172 (81%) physicians prescribed oxaliplatin-based chemotherapy for low-risk CC (3 months, 144 of 172%; 88%), and 200 (94%) physicians prescribed oxaliplatin-based adjuvant chemotherapy for high-risk CC (6 months, 199 of 200%; 99.5%). CONCLUSIONS: The IDEA results have been practice-changing as French physicians have implemented 3 months of CAPOX for patients with low-risk stage III CC, substituting from 6 months of FOLFOX, which remains the preferred regimen for high-risk patients.

Microsatellite Instability in Patients With Stage III Colon Cancer Receiving Fluoropyrimidine With or Without Oxaliplatin: An ACCENT Pooled Analysis of 12 Adjuvant Trials.

PURPOSE: In patients with stage III colon cancer (CC) whose tumors demonstrate microsatellite instability (MSI), the efficacy of adjuvant fluoropyrimidine (FP) with or without oxaliplatin has not been clearly demonstrated and the prognostic value of MSI remains uncertain. MATERIALS AND METHODS: Individual patient data from the ACCENT database were used to evaluate the effect of FP with or without oxaliplatin on disease-free survival (DFS) and overall survival (OS) among patients with MSI stage III CC and the prognostic value of MSI in patients treated with FP plus oxaliplatin, by stratified Cox models adjusted for demographic and clinicopathological factors. RESULTS: MSI status was available for 5,457 patients (609 MSI, 11.2%; 4848 microsatellite stable [MSS], 88.8%) from 12 randomized clinical trials (RCTs). Oxaliplatin significantly improved OS of MSI patients from the two RCTs testing FP with or without oxaliplatin (n = 185; adjusted hazard ratio [aHR] = 0.52, 95% CI, 0.28 to 0.93). Among the 4,250 patients treated with FP plus oxaliplatin (461 MSI and 3789 MSS), MSI was associated with better OS in the N1 group compared with MSS (aHR = 0.66; 95% CI, 0.46 to 0.95) but similar survival in the N2 population (aHR = 1.13; 95% CI, 0.86 to 1.48; P interaction = .029). The main independent prognosticators of MSI patients treated with FP plus oxaliplatin were T stage (aHR = 2.09; 95% CI, 1.29 to 3.38) and N stage (aHR = 3.57; 95% CI, 2.32 to 5.48). Similar results were observed for DFS in all analyses. CONCLUSION: Adding oxaliplatin to FP improves OS and DFS in patients with MSI stage III CC. Compared with MSS, MSI patients experienced better outcomes in the N1 group but similar survival in the N2 group.

Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials.

BACKGROUND: A prospective, pooled analysis of six randomised phase 3 trials was done to investigate disease-free survival regarding non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer; non-inferiority was not shown. Here, we report the final overall survival results. METHODS: In this prospective, pooled analysis of six randomised phase 3 trials, we included patients with stage III colon cancer aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0-1 recruited between June 20, 2007, and Dec 31, 2015, across 12 countries in the CALGB/SWOG 80702, IDEA France, SCOT, ACHIEVE, TOSCA, and HORG trials, who started any treatment (modified intention-to-treat). Patients in all trials were randomly assigned to 3 months or 6 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) every 2 weeks or capecitabine and oxaliplatin (CAPOX) in different doses and methods every 3 weeks, at the treating physician's discretion. The primary endpoint was disease-free survival (time to relapse, secondary colorectal primary tumour, or death due to all causes), and overall survival (time to death due to all causes) was the prespecified secondary endpoint. The non-inferiority margin for overall survival was set as a hazard ratio (HR) of 1·11. Pre-planned subgroup analyses included regimen and risk group. Non-inferiority was declared if the one-sided false discovery rate adjusted (FDRadj) p value was less than 0·025. FINDINGS: With median follow-up of 72·3 months (IQR 72·2-72·5), 2584 deaths among 12 835 patients were observed. 5064 (39·5%) patients received CAPOX and 7771 (60·5%) received FOLFOX. 5-year overall survival was 82·4% (95% CI 81·4-83·3) with 3 months of therapy and 82·8% (81·8-83·8) with 6 months of therapy (HR 1·02 [95% CI 0·95-1·11]; non-inferiority FDRadj p=0·058). For patients treated with CAPOX, 5-year overall survival was 82·1% (80·5-83·6) versus 81·2% (79·2-82·9; HR 0·96 [0·85-1·08]); non-inferiority FDRadj p=0·033), and for patients treated with FOLFOX 5-year overall survival was 82·6% (81·3-83·8) and 83·8% (82·6-85·0; HR 1·07 [0·97-1·18]; non-inferiority FDRadj p=0·34). Updated disease-free survival results confirmed previous findings (HR 1·08 [95% CI 1·02-1·15]; non-inferiority FDRadj p=0·25). Data on adverse events were not further recorded. INTERPRETATION: Non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer was not confirmed in terms of overall survival, but the absolute 0·4% difference in 5-year overall survival should be placed in clinical context. Overall survival results support the use of 3 months of adjuvant CAPOX for most patients with stage III colon cancer. This conclusion is strengthened by the substantial reduction of toxicities, inconveniencies, and cost associated with a shorter treatment duration. FUNDING: US National Cancer Institute.

Association of Bevacizumab Plus Oxaliplatin-Based Chemotherapy With Disease-Free Survival and Overall Survival in Patients With Stage II Colon Cancer: A Secondary Analysis of the AVANT Trial.

Importance: In the pivotal Bevacizumab-Avastin Adjuvant (AVANT) trial, patients with high-risk stage II colon cancer (CC) had 5-year and 10-year overall survival (OS) rates of 88% and 75%, respectively, with adjuvant fluorouracil and oxaliplatin-based chemotherapy; however, the trial did not demonstrate a disease-free survival (DFS) benefit of adding bevacizumab to oxaliplatin-based chemotherapy in stage III CC and suggested a detrimental effect on OS. The Long-term Survival AVANT (S-AVANT) study was designed to collect extended follow-up for patients in the AVANT trial. Objective: To explore the efficacy of adjuvant bevacizumab combined with oxaliplatin-based chemotherapy in patients with high-risk, stage II CC. Design, Setting, and Participants: This prespecified secondary end point analysis of the AVANT and S-AVANT studies included 573 patients with curatively resected high-risk stage II CC and at least 1 of the following criteria: stage T4, bowel obstruction or perforation, blood and/or lymphatic vascular invasion and/or perineural invasion, age younger than 50 years, or fewer than 12 nodes analyzed. The AVANT study was a multicenter randomized stage 3 clinical trial. Data were collected from December 2004 to February 2019, and data for this study were analyzed from March to September 2019. Intervention: Patients were randomly assigned to receive 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4), FOLFOX4 with bevacizumab, or capecitabine and oxaliplatin (XELOX) with bevacizumab. Main Outcomes and Measures: The primary end points of this secondary analysis were DFS and OS in patients with high-risk stage II CC. Results: The AVANT study included 3451 patients, of whom 573 (16.6%) had high-risk stage II CC (192 [33.5%] randomized to FOLFOX4 group; 194 [33.9%] randomized to FOLFOX4 with bevacizumab group; 187 [32.6%] randomized to XELOX with bevacizumab group). With a median (interquartile range) age of 57.0 (47.2-65.7) years, the study population comprised 325 men (56.7%) and 248 women (43.3%). After a median (interquartile range) follow-up of 6.9 (6.1-11.3) years, the 3-year DFS and 5-year OS rates were 88.2% (95% CI, 83.7%-93.0%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 group, 86.6% (95% CI, 81.8%-91.6%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 with bevacizumab group, and 86.7% (95% CI, 81.8%-91.8%) and 93.2% (95% CI, 89.6%-97.0%) in the XELOX with bevacizumab group, respectively. The DFS hazard ratio was 0.94 (95% CI, 0.59-1.48; P = .78) for FOLFOX4 with bevacizumab vs FOLFOX4 and 1.07 (95% CI, 0.69-1.67; P = .76) for XELOX with bevacizumab vs FOLFOX4. The OS hazard ratio was 0.92 (95% CI, 0.55-1.55; P = .76) for FOLFOX4 with bevacizumab vs FOLFOX4 and 0.85 (95% CI, 0.50-1.44; P = .55) for XELOX with bevacizumab vs FOLFOX4. Conclusions and Relevance: In this secondary analysis of data from the AVANT trial, adding bevacizumab to oxaliplatin-based chemotherapy was not associated with longer DFS or OS in patients with high-risk stage II CC. The findings suggest that the definition of high-risk stage II CC needs to be revisited. Trial Registration: ClinicalTrial.gov Identifiers: AVANT (NCT00112918); S-AVANT (NCT02228668).

"Decision for adjuvant treatment in stage II colon cancer based on circulating tumor DNA:The CIRCULATE-PRODIGE 70 trial".

BACKGROUND: Adjuvant treatment for stage II colon cancer remains debated. Finding a tool to select patients at risk for disease recurrence may help the clinical decision. Circulating tumor DNA (ctDNA) has been reported recently as a potential predictive marker for disease recurrence. We thus aim to test its ability to better select stage II colon cancer patients for adjuvant therapy. METHODS: This national, phase III trial (NCT00002019-000935-15) conducted in more than 100 centers in France, plans to screen around 2640 patients in order to randomize (2:1; minimization method) 198 ctDNA positive patients. Patients aged 18 to 75 years with ECOG performance status ≤1 with R0 surgical resection of a pT3-T4aN0 colon or high rectum adenocarcinoma will be randomized within 63 days after curative-intent surgery, to adjuvant mFOLFOX6 (oxaliplatin 85 mg/m², leucovorin 400 mg/m², and 5-FU bolus 400 mg/m2 then 5FU Continuous infusion 2.4 g/m²) every two weeks for 12 cycles or observation. Patients will be followed for maximum 7 years. A gain of 17.5% in 3-yr disease free survival (DFS) is expected (42.5% in the experimental arm vs. 25% in the control arm; HR:0.62; α, 5% [two-sided log-rank test]; 1-ß, 80%). Secondary endpoints include 2-yr DFS, overall survival, and toxicity. Recruitement began End of January 2020.

Efficacy and Safety of Two Neoadjuvant Strategies With Bevacizumab in MRI-Defined Locally Advanced T3 Resectable Rectal Cancer: Final Results of a Randomized, Noncomparative Phase 2 INOVA Study.

BACKGROUND: Recurrence and distant metastases remain a significant issue in locally advanced rectal cancer (LARC). Several multimodal strategies are assessed in clinical trials. PATIENTS AND METHODS: Patients with mid/low magnetic resonance imaging-defined high-risk LARC were randomized to arm A (12-week bevacizumab + FOLFOX-4 then bevacizumab-5-fluorouracil [5-FU]-radiotherapy [RT] before total mesorectal excision [TME]) or arm B (bevacizumab-5-FU-RT then TME). Long-term efficacy and safety up to 5 years' follow-up are reported. No comparison between arms was planned. RESULTS: Overall, 91 patients (46 in arm A and 45 in arm B) were included. Main results have been presented previously. During the late follow-up period (> 4 weeks after surgery), 4 patients (8.7%) in arm A and 4 (8.9%) in arm B experienced grade 3/4 adverse events related to bevacizumab; the most frequent were 2 anastomotic fistulas (both in arm A) and abscesses (1 in arm A and 2 in arm B). At 5 years' follow-up, 9 (19.6%) and 11 (24.4%) patients in arms A and B developed a fistula in the year after surgery, and 2 (4.3%) in arm A at > 1 year after surgery. Most resolved before study end. Five-year disease-free survival was 70% and 64.3% in arms A and B, respectively. Five-year overall survival was 90.5% (95% confidence interval, 76.7, 96.3) in arm A and 72.7% (95% confidence interval, 56.0, 83.9) in arm B. CONCLUSION: Neoadjuvant bevacizumab + FOLFOX-4 may have the potential to increase survival outcomes when followed by bevacizumab-5-FU-RT and TME in LARC. Bevacizumab-5-FU-RT then TME was associated with a higher-than-projected rate of anastomotic fistulas. Further research of neoadjuvant strategies in LARC is encouraged.

Rationale and Design of the IROCAS Study: Multicenter, International, Randomized Phase 3 Trial Comparing Adjuvant Modified (m) FOLFIRINOX to mFOLFOX6 in Patients With High-Risk Stage III (pT4 and/or N2) Colon Cancer-A UNICANCER GI-PRODIGE Trial.

BACKGROUND: According to the IDEA trial, 6-month adjuvant chemotherapy should remain the treatment standard in stage III T4 or N2 colon cancer. The relatively poor survival in this high-risk subgroup-a 3-year disease-free survival (DFS) rate of 65%-and the potential synergistic efficacy of 5-fluorouracil (5-FU), oxaliplatin, and irinotecan suggest that FOLFIRINOX may be a regimen of particular interest in this setting. PATIENTS AND METHODS: This multicenter international phase 3 trial (ClinicalTrials.gov NCT02967289) being conducted in 49 centers in France and Canada plans to randomize (1:1; minimization method) 640 patients aged 18 to 70 years with Eastern Cooperative Oncology Group performance status ≤ 1. Randomization occurs within 42 days (with treatment initiated within 56 days) after curative-intent R0 surgical resection of a pT4N1 or pT1-4N2 colon adenocarcinoma. Patients will be randomized to receive adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 180 mg/m2, and 5-FU 2.4 g/m2 over 46 hours) or modified FOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU bolus 400 mg/m2, then 2.4 g/m2 over 46 hours) every 2 weeks for 24 weeks (12 cycles). Patients will be followed for 5 years after the end of adjuvant chemotherapy. A gain of 9% in 3-year DFS (primary end point) is expected (74% in the experimental arm vs. 65% in the control arm; α, 5% [2-sided log-rank test]; 1-ß, 80%). Secondary end points of this study include 2-year DFS, overall survival, and toxicity.

Impact of Combination Chemotherapy in Peritoneal Mesothelioma Hyperthermic Intraperitoneal Chemotherapy (HIPEC): The RENAPE Study.

BACKGROUND: The introduction of cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) improved the prognosis of selected patients with peritoneal mesothelioma (PM). OBJECTIVE: The objective of our study was to evaluate whether different HIPEC agents were associated with different outcomes in patients with PM. METHODS: From the RENAPE database, we selected all patients with histology-proven PM who underwent CRS + HIPEC from 1989 to 2014. Inclusion criteria were age ≤ 80 years, performance status ≤ 2, and no extraperitoneal metastases. RESULTS: Overall, 249 patients underwent CRS + HIPEC for PM. The HIPEC regimen included five chemotherapeutic agents (CAs), consisting of cisplatin, doxorubicin, mitomycin-C, oxaliplatin, and irinotecan. When considering all CAs (alone or in combination), there was no significant statistical difference in regard to postoperative overall survival (OS). However, OS was better when using two CAs (group 2 drugs) versus one CA (group 1 drug) (p = 0.03). The different CA regimens were equally distributed between the two groups. This association between OS and HIPEC agent, as well as a trend for better progression-free survival, were both observed in the two-drug group versus the one-drug group (p = 0.009) for patients undergoing complete cytoreductive surgery (CC-0) with an epithelioid subtype. CONCLUSIONS: This large study seems to show improved OS when combined CAs, especially with platinum-based regimens, are used for HIPEC in patients with PM, but needs to be confirmed by a randomized controlled trial.

Three Versus 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Patients With Stage III Colon Cancer: Disease-Free Survival Results From a Randomized, Open-Label, International Duration Evaluation of Adjuvant (IDEA) France, Phase III Trial.

Purpose Reduction of adjuvant treatment duration may decrease toxicities without loss of efficacy in stage III colon cancer. This could offer clear advantages to patients and health care providers. Methods In International Duration Evaluation of Adjuvant Chemotherapy (IDEA) France, as part of the IDEA international collaboration, patient with colon cancer patients were randomly assigned to 3 and 6 months of modified FOLFOX6 (mFOLFOX6: infusional fluorouracil, leucovorin, and oxaliplatin) or capecitabine plus oxaliplatin (CAPOX) by physician choice. The primary end point was disease-free survival (DFS), and analyses were descriptive. Results A total of 2,010 eligible patients received either 3 or 6 months of chemotherapy (modified intention-to-treat population); 2,000 (99%) had stage III colon cancer (N1: 75%, N2: 25%); 1,809 (90%) received mFOLFOX6, and 201 (10%) received CAPOX. The median age was 64 years, and the median follow-up time was 4.3 years. Overall, 94% (3 months) and 78% (6 months) of patients completed treatment (fluoropyrimidines ± oxaliplatin). Maximal grade 2 and 3 neuropathy rates were 28% and 8% in the 3-month arm and 41% and 25% in the 6-month arm ( P < .001). Final rates of residual neuropathy greater than grade 1 were 3% in the 3-month arm and 7% in the 6-month arm ( P < .001). There were 578 DFS events: 314 and 264 in the 3- and 6-month arms, respectively. The 3-year DFS rates were 72% and 76% in the 3- and 6-month arms, respectively (hazard ratio [HR], 1.24; 95% CI, 1.05 to 1.46; P = .0112). In the 3 and 6-month arms, respectively, for patients who received mFOLFOX6, the 3-year DFS rates were 72% and 76% (HR, 1.27; 95% CI, 1.07 to 1.51); for the T4 and/or N2 population, they were 58% and 66% (HR, 1.44; 95% CI, 1.14 to 1.82); and for the T1-3N1 population, they were 81% and 83% (HR, 1.15; 95% CI, 0.89 to 1.49). Conclusion IDEA France, in which 90% of patients received mFOLFOX6, shows superiority of 6 months of adjuvant chemotherapy compared with 3 months, especially in the T4 and/or N2 subgroups. These results should be considered alongside the international IDEA collaboration data.

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.).

Nab-paclitaxel plus either gemcitabine or simplified leucovorin and fluorouracil as first-line therapy for metastatic pancreatic adenocarcinoma (AFUGEM GERCOR): a non-comparative, multicentre, open-label, randomised phase 2 trial.

BACKGROUND: Nab-paclitaxel plus gemcitabine has become a standard treatment regimen in patients with metastatic pancreatic adenocarcinoma; however, retrospective data suggest that gemcitabine might be inefficient in 50-60% of patients and thus not an optimum regimen in combination with nab-paclitaxel. We did a phase 2 trial to assess the activity and safety of a new regimen of nab-paclitaxel plus simplified leucovorin and fluorouracil. METHODS: We did a non-comparative, multicentre, open-label, randomised phase 2 trial in 15 hospitals and institutions in France. Eligible participants were previously untreated patients with metastatic pancreatic adenocarcinoma (previous adjuvant chemotherapy after curative intent resection was allowed if the interval between the end of chemotherapy and relapse was more than 12 months). Patients had to have at least one measurable lesion assessed by CT scan or MRI and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. We randomly assigned participants (1:2) centrally to 28-day cycles of either gemcitabine plus nab-paclitaxel or simplified leucovorin and fluorouracil plus nab-paclitaxel. The randomisation was by minimisation, stratified by centre and ECOG performance status. Drugs were administered in each cycle as follows: nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) as 30-min intravenous infusions on days 1, 8, and 15; leucovorin (400 mg/m2) as a 120-min intravenous infusion on days 1 and 15; and fluorouracil (400 mg/m2) as a 5-min bolus intravenous infusion followed by a 46-h continuous intravenous infusion of 2400 mg/m2 on days 1 and 15. Patients continued treatment until unacceptable toxicity, disease progression, or patient withdrawal. The primary endpoint was progression-free survival at 4 months in the first 72 assessable patients in the leucovorin and fluorouracil group, with a target of 50% for the regimen to be deemed sufficiently active to warrant further study. We did the primary analysis on the modified intention-to-treat (ITT) population, defined as all randomly assigned and assessable patients regardless of their eligibility and received treatments. This trial is registered at ClinicalTrials.gov, number NCT01964534. The trial has ended and we report the final analysis here. FINDINGS: Between Dec 12, 2013, and Oct 31, 2014, we randomly assigned 114 patients to treatment: 75 patients to the leucovorin and fluorouracil group and 39 to the gemcitabine group. One patient in the leucovorin and fluorouracil group did not have a 4-month assessment, and was thus excluded from the modified ITT analysis. Median follow-up was 13·1 months (95% CI 12·5-14·1). At 4 months, 40 (56%, 90% CI 45-66) of 72 patients in the leucovorin and fluorouracil group were alive and free from disease progression (21 [54%, 40-68] of 39 patients in the gemcitabine group were also alive and progression-free at 4 months). Grade 3-4 adverse events occurred in 33 (87%) of 38 patients in the gemcitabine group and in 56 (77%) of 73 patients in the leucovorin and fluorouracil group, with different toxicity profiles. The most common grade 3-4 adverse events in the leucovorin and fluorouracil group were neutropenia without fever (17 [23%]), fatigue (16 [22%]), paraesthesia (14 [19%]), diarrhoea (nine [12%]), and mucositis (seven [10%]); in the gemcitabine group they were neutropenia without fever (12 [32%]), thrombocytopenia (seven [18%]), fatigue (eight [21%]), anaemia (five [13%]), increased alanine aminotransferase and aspartate aminotransferase concentrations (five [13%] for both), and paraesthesia (four [11%]). Two participants died; one in the leucovorin and fluorouracil group from septic shock, and one in the gemcitabine group from diabetes compensation with acidosis; these deaths were deemed to be not related to treatment. Treatment-related serious adverse events occurred in 28 (38%) of 73 patients in the leucovorin and fluorouracil group and in 14 (37%) of 38 in the gemcitabine group. INTERPRETATION: Nab-paclitaxel plus simplified leucovorin and fluorouracil fulfilled the primary endpoint in that more than the required 50% of our study population were progression-free at 4 months, with a tolerable toxicity profile. This regimen thus deserves further assessment in a phase 3 trial. FUNDING: GERCOR (Groupe Coopérateur Multidisciplinaire en Oncologie) and Celgene through grants to GERCOR.

Genetic control of plasticity of oil yield for combined abiotic stresses using a joint approach of crop modelling and genome-wide association.

Understanding the genetic basis of phenotypic plasticity is crucial for predicting and managing climate change effects on wild plants and crops. Here, we combined crop modelling and quantitative genetics to study the genetic control of oil yield plasticity for multiple abiotic stresses in sunflower. First, we developed stress indicators to characterize 14 environments for three abiotic stresses (cold, drought and nitrogen) using the SUNFLO crop model and phenotypic variations of three commercial varieties. The computed plant stress indicators better explain yield variation than descriptors at the climatic or crop levels. In those environments, we observed oil yield of 317 sunflower hybrids and regressed it with three selected stress indicators. The slopes of cold stress norm reaction were used as plasticity phenotypes in the following genome-wide association study. Among the 65 534 tested Single Nucleotide Polymorphisms (SNPs), we identified nine quantitative trait loci controlling oil yield plasticity to cold stress. Associated single nucleotide polymorphisms are localized in genes previously shown to be involved in cold stress responses: oligopeptide transporters, lipid transfer protein, cystatin, alternative oxidase or root development. This novel approach opens new perspectives to identify genomic regions involved in genotype-by-environment interaction of a complex traits to multiple stresses in realistic natural or agronomical conditions.

Efficacy of a sequential treatment strategy with GEMOX-based followed by FOLFIRI-based chemotherapy in advanced biliary tract cancers.

BACKGROUND: Gemcitabine (GEM)-platinum chemotherapy stands as first-line therapy for patients with recurrent/advanced biliary tract cancer (BTC), yielding progression-free survival (PFS) of 3.4-6.4 months. No standard second-line chemotherapy after GEM-platinum failure exists and data on survival benefit remain limited. MATERIAL AND METHODS: We retrospectively reviewed patients with recurrent/advanced BTC who received gemcitabine-oxaliplatin (GEMOX)-based chemotherapy followed by 5-fluorouracil-irinotecan (FOLFIRI)-based chemotherapy to evaluate the efficacy of the sequential treatment strategy. Overall survival (OS) and PFS were calculated by Kaplan-Meier method. RESULTS: Fifty-two patients were analyzed, 21 (40%) had intrahepatic, 14 (27%) had hilar/extrahepatic, and 17 (33%) had gallbladder cancer. Median age was 64 years (range 38-79 years). Prior curative intent resection of the primary tumor was performed in 23 (44.2%) patients and GEMOX adjuvant chemotherapy was given in 12 (23.1%) patients. After a median follow-up of 36.3 months, 47 (90.4%) patients completed the treatment strategy. First-sequence GEMOX and second sequence FOLFIRI achieved 4.8 months and 3.2 months median PFS, respectively. The global OS for the sequential chemotherapy was 21.9 months. The sequence of FOLFIRI resulted in a median OS of 8.4 months. CONCLUSION: The sequence of GEMOX-FOLFIRI is a potential treatment strategy for patients with recurrent/advanced BTC.

Feasibility of Capecitabine and Oxaliplatin Combination Chemotherapy Without Central Venous Access Device in Patients With Stage III Colorectal Cancer.

BACKGROUND: 5-Fluorouracil and leucovorin plus oxaliplatin (FOLFOX) or capecitabine plus oxaliplatin (XELOX) is a standard adjuvant treatment for patients with stage III colon cancer (CC). Capecitabine is an oral fluoropyrimidine, and administration of oxaliplatin does not necessarily require the insertion of a central venous access device (CVAD). We evaluated the feasibility of XELOX without a CVAD as adjuvant treatment in patients with stage III CC. PATIENTS AND METHODS: We retrospectively studied prospectively collected data from patients with stage III CC treated with XELOX in the International Duration Evaluation of Adjuvant Chemotherapy French trial. Patients were divided into 2 groups: those with a CVAD and those with peripheral venous access (PVA), including patients who had and had not had a CVAD at the first cycle of chemotherapy. Chemotherapy without a CVAD was considered feasible if the patient received all cycles of adjuvant therapy without it. RESULTS: A total of 203 patients were included: 86 (43%) in the PVA group and 116 (57%) in the CVAD group. Of the 85 patients in the PVA group (1 patient was not treated), 69 (81.2%) did not require the insertion of a CVAD. However, 16 (18.8%) required CVAD insertion owing to systematic delay of the initially planned CVAD before the second cycle of chemotherapy in 7, complications related to PVA usage in 5, a switch to the modified FOLFOX6 regimen in 2, and other reasons in 2. The oxaliplatin dose was similar in both groups regardless of the chemotherapy duration. XELOX without a CVAD was feasible for 81.2% of the patients for whom a CVAD had not been planned before chemotherapy and for 88.4% of patients for whom chemotherapy was planned without the use of a CVAD. CONCLUSION: XELOX chemotherapy without a CVAD is a feasible approach for treating patients with stage III CC in the adjuvant setting.