Adjuvant Hyperthermic Intraperitoneal Chemotherapy in Patients With Locally Advanced Colon Cancer (COLOPEC): 5-Year Results of a Randomized Multicenter Trial.

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/m2, 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 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.

Evaluation of National Surgical Practice for Lateral Lymph Nodes in Rectal Cancer in an Untrained Setting.

BACKGROUND: Involved lateral lymph nodes (LLNs) have been associated with increased local recurrence (LR) and ipsi-lateral LR (LLR) rates. However, consensus regarding the indication and type of surgical treatment for suspicious LLNs is lacking. This study evaluated the surgical treatment of LLNs in an untrained setting at a national level. METHODS: Patients who underwent additional LLN surgery were selected from a national cross-sectional cohort study regarding patients undergoing rectal cancer surgery in 69 Dutch hospitals in 2016. LLN surgery consisted of either 'node-picking' (the removal of an individual LLN) or 'partial regional node dissection' (PRND; an incomplete resection of the LLN area). For all patients with primarily enlarged (≥7 mm) LLNs, those undergoing rectal surgery with an additional LLN procedure were compared to those  undergoing only rectal resection. RESULTS: Out of 3057 patients, 64 underwent additional LLN surgery, with 4-year LR and LLR rates of 26% and 15%, respectively. Forty-eight patients (75%) had enlarged LLNs, with corresponding recurrence rates of 26% and 19%, respectively. Node-picking (n = 40) resulted in a 20% 4-year LLR, and a 14% LLR after PRND (n = 8; p = 0.677). Multivariable analysis of 158 patients with enlarged LLNs undergoing additional LLN surgery (n = 48) or rectal resection alone (n = 110) showed no significant association of LLN surgery with 4-year LR or LLR, but suggested higher recurrence risks after LLN surgery (LR: hazard ratio [HR] 1.5, 95% confidence interval [CI] 0.7-3.2, p = 0.264; LLR: HR 1.9, 95% CI 0.2-2.5, p = 0.874). CONCLUSION: Evaluation of Dutch practice in 2016 revealed that approximately one-third of patients with primarily enlarged LLNs underwent surgical treatment, mostly consisting of node-picking. Recurrence rates were not significantly affected by LLN surgery, but did suggest worse outcomes. Outcomes of LLN surgery after adequate training requires further research.

Perineal wound closure using gluteal turnover flap or primary closure after abdominoperineal resection for rectal cancer: study protocol of a randomised controlled multicentre trial (BIOPEX-2 study).

BACKGROUND: Abdominoperineal resection (APR) for rectal cancer is associated with high morbidity of the perineal wound, and controversy exists about the optimal closure technique. Primary perineal wound closure is still the standard of care in the Netherlands. Biological mesh closure did not improve wound healing in our previous randomised controlled trial (BIOPEX-study). It is suggested, based on meta-analysis of cohort studies, that filling of the perineal defect with well-vascularised tissue improves perineal wound healing. A gluteal turnover flap seems to be a promising method for this purpose, and with the advantage of not having a donor site scar. The aim of this study is to investigate whether a gluteal turnover flap improves the uncomplicated perineal wound healing after APR for rectal cancer. METHODS: Patients with primary or recurrent rectal cancer who are planned for APR will be considered eligible in this multicentre randomised controlled trial. Exclusion criteria are total exenteration, sacral resection above S4/S5, intersphincteric APR, biological mesh closure of the pelvic floor, collagen disorders, and severe systemic diseases. A total of 160 patients will be randomised between gluteal turnover flap (experimental arm) and primary closure (control arm). The total follow-up duration is 12 months, and outcome assessors and patients will be blinded for type of perineal wound closure. The primary outcome is the percentage of uncomplicated perineal wound healing on day 30, defined as a Southampton wound score of less than two. Secondary outcomes include time to perineal wound closure, incidence of perineal hernia, the number, duration and nature of the complications, re-interventions, quality of life and urogenital function. DISCUSSION: The uncomplicated perineal wound healing rate is expected to increase from 65 to 85% by using the gluteal turnover flap. With proven effectiveness, a quick implementation of this relatively simple surgical technique is expected to take place. TRIAL REGISTRATION: The trial was retrospectively registered at Clinicaltrials.gov NCT04004650 on July 2, 2019.

Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial.

BACKGROUND: Nearly a quarter of patients with locally advanced (T4 stage) or perforated colon cancer are at risk of developing peritoneal metastases, often without curative treatment options. We aimed to determine the efficacy of adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with locally advanced colon cancer. METHODS: This multicentre, open-label trial was done in nine hospitals that specialised in HIPEC in the Netherlands. Patients with clinical or pathological T4N0-2M0-stage tumours or perforated colon cancer were randomly assigned (1:1), with a web-based randomisation application, before resection of the primary tumour, to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy (experimental group) or to adjuvant systemic chemotherapy alone (control group). Patients were stratified by tumour characteristic (T4 or perforation), age (<65 years or ≥65 years), and surgical approach of the primary tumour resection (laparoscopic or open). Key eligibility criteria included age between 18 and 75 years, adequate clinical condition for HIPEC, and intention to start adjuvant systemic chemotherapy. Patients with metastatic disease were ineligible. Adjuvant HIPEC consisted of fluorouracil (400 mg/m2) and leucovorin (20 mg/m2) delivered intravenously followed by intraperitoneal delivery of oxaliplatin (460 mg/m2) for 30 min at 42°C, delivered simultaneously or within 5-8 weeks after primary tumour resection. In all patients without evidence of recurrent disease at 18 months, a diagnostic laparoscopy was done. The primary endpoint was peritoneal metastasis free-survival at 18 months, measured in the intention-to-treat population, with the Kaplan-Meier method. Adverse events were assessed in all patients who received assigned treatment. This study is registered with ClinicalTrials.gov, number NCT02231086. FINDINGS: Between April 1, 2015, and Feb 20, 2017, 204 patients were randomly assigned to treatment (102 in each group). In the HIPEC group, two patients withdrew consent after randomisation. In this group, 19 (19%) of 100 patients were diagnosed with peritoneal metastases: nine (47%) during surgical exploration preceding intentional adjuvant HIPEC, eight (42%) during routine follow-up, and two (11%) during diagnostic laparoscopy at 18-months. In the control group, 23 (23%) of 102 patients were diagnosed with peritoneal metastases, of whom seven (30%) were diagnosed by laparoscopy at 18-months and 16 during regular follow-up (therefore making them ineligible for diagnostic laparoscopy). In the intention-to-treat analysis (n=202), there was no difference in peritoneal-free survival at 18-months (80·9% [95% CI 73·3-88·5] for the experimental group vs 76·2% [68·0-84·4] for the control group, log-rank one-sided p=0·28). 12 (14%) of 87 patients who received adjuvant HIPEC developed postoperative complications and one (1%) encapsulating peritoneal sclerosis. INTERPRETATION: In patients with T4 or perforated colon cancer, treatment with adjuvant HIPEC with oxaliplatin did not improve peritoneal metastasis-free survival at 18 months. Routine use of adjuvant HIPEC is not advocated on the basis of this trial. FUNDING: Organization for Health Research and Development and the Dutch Cancer Society.

Hospital Teaching Status and Patients' Outcomes After Colon Cancer Surgery.

BACKGROUND AND OBJECTIVES: It is increasingly accepted that quality of colon cancer surgery might be secured by combining volume standards with audit implementation. However, debate remains about other structural factors also influencing this quality, such as hospital teaching status. This study evaluates short-term outcomes after colon cancer surgery of patients treated in general, teaching or academic hospitals. METHODS: All patients (n = 23,593) registered in the Dutch Colorectal Audit undergoing colon cancer surgery between 2011 and 2014 were included. Patients were divided into groups based on teaching status of their hospital. Main outcome measures were serious complications, failure to rescue (FTR) and 30-day or in-hospital mortality. Multivariate logistic regression models on these outcome measures and with hospital teaching status as primary determinant were used, adjusted for case-mix, year of surgery and hospital volume. RESULTS: Patients treated in teaching and academic hospitals showed higher adjusted serious complication rates, compared to patients treated in general hospitals (odds ratio 1.25 95% CI [1.11-1.39] and OR 1.23 [1.05-1.46]). However, patients treated in teaching hospitals had lower adjusted FTR rates than patients treated in general hospitals (OR 0.63 [0.44-0.89]). However, for all outcomes there was considerable between-hospitals variation within each type of teaching status. CONCLUSION: On average, patients treated in general hospitals had lower serious complication rates, but patients treated in teaching hospitals had more favorable FTR rates. Given the hospital variation within each hospital teaching type, it is possible to deliver excellent care regardless of the hospital teaching type.

Lobulitis is a frequent finding in prophylactically removed breast tissue from women at hereditary high risk of breast cancer.

The aim of this study was to investigate closely the nature of premalignant lesions that occur in prophylactically removed breast tissue from patients at hereditary high risk of breast cancer. Breast tissues obtained from 41 patients who underwent prophylactic mastectomy (pM) because of a hereditary high risk of breast cancer and control tissues from 82 age-matched healthy controls who underwent breast reduction surgery were screened for premalignant lesions. Premalignant and malignant lesions were more frequent (p = 0.0016) in pM samples (5/41) than in controls (1/82). Interestingly, lobulitis, defined as more than 100 lymphocytes and/or plasma cells per lobule in more than one section in morphologically normal lobules, was encountered in 21 of 41 (51%) pM patients, in contrast to only 8 of 82 (10%) controls (p < 0.0001). Preliminary observations indicate a predominance of T-cells in these infiltrates, in agreement with the already known frequent presence of lymphocytic infiltration in hereditary ductal in situ and infiltrating ductal/medullary carcinomas. This novel finding implies an immune reaction to an as yet unidentified antigen frequently present in women at hereditary high risk of breast cancer, possibly as part of an early carcinogenic event.

Clinical relevance of parasternal uptake in sentinel node procedure for breast cancer.

BACKGROUND AND OBJECTIVES: Preoperative lymphoscintigraphy contributes highly to the accuracy of the sentinel node procedure. Besides routing towards the axilla, in a number of patients additional parasternal focal accumulation may be observed. So far the clinical consequences of this parasternal uptake remains unclarified, i.e., whether any internal mammary lymph node uptake should be surgically biopsied. An analysis of all sentinel node procedures with parasternal uptake was performed. METHODS: Sixty-nine patients with scintigraphic parasternal uptake and with a minimal follow-up of 24 months, were selected from a prospective database. Tumor characteristics, treatment strategies, and recurrences of these patients were analyzed and subsequently matched against the present day indications for adjuvant treatment. RESULTS: During follow-up (median 41 months) only four (6%) patients developed systemic disease. Initially, three of these patients did not receive adjuvant chemotherapy. Two are alive without evidence of disease after treatment of these recurrences. Currently these patients would, initially, all have been eligible for chemotherapy based on tumor characteristics and age according to international guidelines. CONCLUSIONS: For the indication of adjuvant treatment, the status of the internal mammary lymph nodes was not relevant in our patients. Parasternal uptake is not an indication to extend the surgical procedure.

Ultrasound-guided lumpectomy of nonpalpable breast cancer versus wire-guided resection: a randomized clinical trial.

BACKGROUND: The wire-guided excision of nonpalpable breast cancer often results in tumor resections with inadequate margins. This prospective, randomized trial was undertaken to investigate whether intraoperative ultrasound (US) guidance enables a better margin clearance than the wire-guided technique in the breast-conserving treatment of nonpalpable breast cancers. METHODS: Patients with a preoperative histological diagnosis of nonpalpable breast cancer that could be visualized both with US and mammography were included. Patients were randomized to undergo either a wire-guided or a US-guided excision. Adequate margins were defined as >or=1 mm. RESULTS: Of 49 included patients, 23 were assigned to undergo wire-guided excision and 26 to undergo US-guided excision. One patient crossed over to US-guided excision after inadvertent wire displacement. Mean tumor diameter, specimen weight, and operating time were similar in both groups. The excision was adequate in 24 (89%) of 27 US-guided excisions and 12 (55%) of 22 wire-guide excisions (P =.007). CONCLUSIONS: US-guided excision seems to be superior to wire-guided excision with respect to margin clearance of mammographically detected and US-visible nonpalpable breast cancers. Patients do not have to undergo the unpleasant wire placement before surgery.