Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Whether adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) might prevent peritoneal metastases after curative surgery for high-risk colon cancer is an ongoing debate. This study aimed to determine 5-year oncologic outcomes of the randomized multicenter COLOPEC trial, which included patients with clinical or pathologic T4N0-2M0 or perforated colon cancer and randomly assigned (1:1) to either adjuvant systemic chemotherapy and HIPEC (n = 100) or adjuvant systemic chemotherapy alone (n = 102). HIPEC was performed using a one-time administration of oxaliplatin (460 mg/m 2 , 30 minutes, 42°C, concurrent fluorouracil/leucovorin intravenously), either simultaneously (9%) or within 5-8 weeks (91%) after primary tumor resection. Outcomes were analyzed according to the intention-to-treat principle. Long-term data were available of all 202 patients included in the COLOPEC trial, with a median follow-up of 59 months (IQR, 54.5-64.5). No significant difference was found in 5-year overall survival rate between patients assigned to adjuvant HIPEC followed by systemic chemotherapy or only adjuvant systemic chemotherapy (69.6% v 70.9%, log-rank; P = .692). Five-year peritoneal metastases-free survival rates were 63.9% and 63.2% ( P = .907) and 5-year disease-free survival was 55.7% and 52.3% (log-rank; P = .875), respectively. No differences in quality-of-life outcomes were found. Our findings implicate that adjuvant HIPEC should still be performed in trial setting only.
Abstract Aim To report the long term results of the CROSS trial with a minimum follow-up of 10 years. Background Neoadjuvant chemoradiotherapy according to the Dutch randomised controlled ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) has become standard of care for patients with cancer of the oesophagus or oesophagogastric junction. Methods Patients with locally advanced resectable squamous cell carcinoma or adenocarcinoma of the oesophagus or oesophagogastric junction were randomised between neoadjuvant chemoradiotherapy (five weekly cycles of intravenous carboplatin [AUC 2 mg/mL per min] and intravenous paclitaxel [50 mg/m² of body-surface area]) with concurrent 41.4 Gy radiotherapy given in 23 fractions of 1.8 Gy, 5 days per week) plus surgery versus surgery alone. Primary endpoint was overall survival, defined from date of randomisation to date of all-cause death or to last day of follow-up. Analysis was by intention-to-treat. Results Between March 2004 and 2008, eight centres enrolled 368 patients. Some 178 were analysed in the chemoradiotherapy plus surgery group and 188 in the surgery alone group. After a median follow-up for surviving patients of 146.6 months (IQR 133.5-156.6), median overall survival was 49.0 months (95%CI 34.7-76.6) in the neoadjuvant chemoradiotherapy plus surgery group compared to 25.1 months (95%CI 19.1-39.4) in the surgery alone group, which was significantly different (HR 0.71 [95%CI 0.55-0.90]; log-rank p=0·005). Ten-year overall survival was 38% (95%CI 31%-45%) in the neoadjuvant chemoradiotherapy followed by surgery group compared to 26% (95%CI 20%-33%) in the surgery alone group (HR 0.69 [95%CI 0.54-0.89]). For patients with squamous cell carcinoma ten-year overall survival was 46% (95%CI 33%-64%) in the neoadjuvant chemoradiotherapy plus surgery group compared to 23% (95%CI 13%-40%) in the surgery alone group. For patients with adenocarcinoma ten-year overall survival was 36% (95%CI 29%-45%) in the neoadjuvant chemoradiotherapy plus surgery group compared to 26% (95%CI 20%-35%) in the surgery alone group. Conclusion Survival benefit of patients with locally advanced resectable squamous cell carcinoma or adenocarcinoma of the oesophagus or oesophagogastric junction receiving neoadjuvant chemoradiotherapy persists for at least 10 years compared to patients undergoing surgery alone.
Preoperative chemoradiotherapy may improve the radical resection rate for resectable or borderline resectable pancreatic cancer, but the overall benefit is unproven.In this randomized phase III trial in 16 centers, patients with resectable or borderline resectable pancreatic cancer were randomly assigned to receive preoperative chemoradiotherapy, which consisted of 3 courses of gemcitabine, the second combined with 15 × 2.4 Gy radiotherapy, followed by surgery and 4 courses of adjuvant gemcitabine or to immediate surgery and 6 courses of adjuvant gemcitabine. The primary end point was overall survival by intention to treat.Between April 2013 and July 2017, 246 eligible patients were randomly assigned; 119 were assigned to preoperative chemoradiotherapy and 127 to immediate surgery. Median overall survival by intention to treat was 16.0 months with preoperative chemoradiotherapy and 14.3 months with immediate surgery (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P = .096). The resection rate was 61% and 72% (P = .058). The R0 resection rate was 71% (51 of 72) in patients who received preoperative chemoradiotherapy and 40% (37 of 92) in patients assigned to immediate surgery (P < .001). Preoperative chemoradiotherapy was associated with significantly better disease-free survival and locoregional failure-free interval as well as with significantly lower rates of pathologic lymph nodes, perineural invasion, and venous invasion. Survival analysis of patients who underwent tumor resection and started adjuvant chemotherapy showed improved survival with preoperative chemoradiotherapy (35.2 v 19.8 months; P = .029). The proportion of patients who suffered serious adverse events was 52% versus 41% (P = .096).Preoperative chemoradiotherapy for resectable or borderline resectable pancreatic cancer did not show a significant overall survival benefit. Although the outcomes of the secondary end points and predefined subgroup analyses suggest an advantage of the neoadjuvant approach, additional evidence is required.
We conducted a population-based study to establish the incidence, treatment and overall survival over time of patients with small bowel adenocarcinoma.All patients diagnosed with small bowel adenocarcinoma in the Netherlands between 1999 and 2013 were included (n = 1775). Age-standardized incidence rates were calculated per 100 000 person-years using the European standardized population rate. The influence of patient and tumor characteristics on the administration of chemotherapy was analyzed by means of a multivariable logistic regression analysis. The Cochran-Armitage trend test was conducted to evaluate trends in treatment and survival and the Cox proportional hazards model was used to identify prognostic factors of overall survival.The incidence of small bowel adenocarcinomas increased, mainly due to an almost twofold increase of duodenal adenocarcinomas. Patients with locoregional duodenal tumors were less likely to undergo surgery (58%), towards 95% of the locoregional jejunal and ileal tumors (p < 0.0001). The use of chemotherapy doubled for adjuvant (7-15%) and palliative chemotherapy (19-37%). Median overall survival of patients with locoregional disease increased from 19 to 34 months (p = 0.0006), whereas median overall survival of patients with metastatic disease remained 4-5 months. Favorable prognostic factors for prolonged survival in locoregional disease, identified by multivariable survival analysis, included age <60 years, tumor stage I or II, diagnosis in 2009-2013, surgical treatment and chemotherapy. Favorable prognostic factors for prolonged survival in metastatic disease were age <50 years, jejunal tumors, surgical treatment and chemotherapy.Small bowel adenocarcinomas are rare tumors with an increasing incidence. The administration of adjuvant and palliative chemotherapy doubled, but median overall survival only increased for patients with locoregional disease. Given the rarity and dismal prognosis, it is important to develop international studies to determine the optimal treatment for these patients.
Malignancies of the peritoneal cavity are associated with a dismal prognosis. Systemic chemotherapy is the gold standard for patients with unresectable peritoneal disease, but its intraperitoneal effect is hampered by the peritoneal-plasma barrier. Intraperitoneal chemotherapy, which is administered repeatedly into the peritoneal cavity through a peritoneal implanted port, could provide a novel treatment modality for this patient population. This review provides a systematic overview of intraperitoneal used drugs, the performed clinical studies so far, and the complications of the peritoneal implemental ports. Several anticancer drugs have been studied for intraperitoneal application, with the taxanes paclitaxel and docetaxel as the most commonly used drug. Repeated intraperitoneal chemotherapy, mostly in combination with systemic chemotherapy, has shown promising results in Phase I and Phase II studies for several tumor types, such as gastric cancer, ovarian cancer, colorectal cancer, and pancreatic cancer. Two Phase III studies for intraperitoneal chemotherapy in gastric cancer have been performed so far, but the results regarding the superiority over standard systemic chemotherapy alone, are contradictory. Pressurized intraperitoneal administration, known as PIPAC, is an alternative way of administering intraperitoneal chemotherapy, and the first prospective studies have shown a tolerable safety profile. Although intraperitoneal chemotherapy might be a standard treatment option for patients with unresectable peritoneal disease, more Phase II and Phase III studies focusing on tolerability profiles, survival rates, and quality of life are warranted in order to establish optimal treatment schedules and to establish a potential role for intraperitoneal chemotherapy in the approach to unresectable peritoneal disease.
DPYD-guided fluoropyrimidine dosing improves patient safety in carriers of DPYD variant alleles. However, the impact on treatment outcome in these patients is largely unknown. Therefore, progression-free survival (PFS) and overall survival (OS) were compared between DPYD variant carriers treated with a reduced dose and DPYD wild-type controls receiving a full fluoropyrimidine dose in a retrospective matched-pair survival analysis.Data from a prospective multicenter study (ClinicalTrials.gov identifier: NCT02324452) in which DPYD variant carriers received a 25% (c.1236G>A and c.2846A>T) or 50% (DPYD*2A and c.1679T>G) reduced dose and data from DPYD variant carriers treated with a similarly reduced dose of fluoropyrimidines identified during routine clinical care were obtained. Each DPYD variant carrier was matched to three DPYD wild-type controls treated with a standard dose. Survival analyses were performed using Kaplan-Meier estimates and Cox regression.In total, 156 DPYD variant carriers and 775 DPYD wild-type controls were available for analysis. Sixty-one c.1236G>A, 25 DPYD*2A, 13 c.2846A>T, and-when pooled-93 DPYD variant carriers could each be matched to three unique DPYD wild-type controls. For pooled DPYD variant carriers, PFS (hazard ratio [HR], 1.23; 95% CI, 1.00 to 1.51; P = .053) and OS (HR, 0.95; 95% CI, 0.75 to 1.51; P = .698) were not negatively affected by DPYD-guided dose individualization. In the subgroup analyses, a shorter PFS (HR, 1.43; 95% CI, 1.10 to 1.86; P = .007) was found in c.1236G>A variant carriers, whereas no differences were found for DPYD*2A and c.2846A>T carriers.In this exploratory analysis, DPYD-guided fluoropyrimidine dosing does not negatively affect PFS and OS in pooled DPYD variant carriers. Close monitoring with early dose modifications based on toxicity is recommended, especially for c.1236G>A carriers receiving a reduced starting dose.
Abstract Background Short-chain fatty acids (SCFA) and branched-chain fatty acids (BCFA) are produced by the gut microbiota and are considered to fulfill crucial physiological roles. Previous pre-clinical studies also indicated bi-directional interactions between gut bacteria and the chemotherapeutic capecitabine or its metabolite 5-FU. However, evidence from clinical studies in this field of research is scarce. This study investigated the effect of three cycles of capecitabine on fecal SCFA and BCFA levels and their associations with tumor response, nutritional status, physical performance, chemotherapy-induced toxicity, systemic inflammation, and bacterial abundances in patients with colorectal cancer (CRC). Methods Forty-four patients with metastatic or unresectable CRC, scheduled for treatment with capecitabine (± bevacizumab), were prospectively enrolled in a multicentre cohort study. Patients collected a fecal sample and completed a questionnaire before (T1), during (T2), and after (T3) three cycles of capecitabine. Tumor response (based on CT/MRI scans), nutritional status (MUST score), physical performance (Karnofsky Performance Score), and chemotherapy-induced toxicity (CTCAE) were recorded. Additional data on clinical characteristics, treatment regimen, medical history, and blood inflammatory parameters were collected. Fecal SCFA and BCFA concentrations were determined by gas chromatography-mass spectrometry (GC-MS). Gut microbiota composition was assessed using 16S rRNA amplicon sequencing. Results Fecal levels of the SCFA valerate and caproate decreased significantly during three cycles of capecitabine in our patient population. Furthermore, baseline levels of the BCFA iso-butyrate were associated with tumor response. Nutritional status, physical performance, and chemotherapy-induced toxicity were not statistically significantly associated with SCFA or BCFA. Baseline SCFA correlated positively with blood neutrophil counts. At the three sampling timepoints, we identified associations between SCFA and BCFA and the relative abundance of bacterial taxa on family level. Conclusions The present study provided the first indications for a role of SCFA and BCFA during treatment with capecitabine as well as implications and recommendations for further research. More knowledge in this field will contribute to the evidence-based design of interventions targeting the gut microbiota and/or SCFA/BCFA production to optimize chemotherapy efficacy. Trial registration The current study was registered in the Dutch Trial Register (NTR6957) on 17/01/2018 and can be consulted via the International Clinical Trial Registry Platform (ICTRP).
