Neoadjuvant FOLFOXIRI prior to chemoradiotherapy for high-risk ("ugly") locally advanced rectal cancer: study protocol of a single-arm, multicentre, open-label, phase II trial (MEND-IT).

BACKGROUND: The presence of mesorectal fascia (MRF) invasion, grade 4 extramural venous invasion (EMVI), tumour deposits (TD) or extensive or bilateral extramesorectal (lateral) lymph nodes (LLN) on MRI has been suggested to identify patients with indisputable, extensive locally advanced rectal cancer (LARC), at high risk of treatment failure. The aim of this study is to evaluate whether or not intensified chemotherapy prior to neoadjuvant chemoradiotherapy improves the complete response (CR) rate in these patients. METHODS: This multicentre, single-arm, open-label, phase II trial will include 128 patients with non-metastatic high-risk LARC (hr-LARC), fit for triplet chemotherapy. To ensure a study population with indisputable, unfavourable prognostic characteristics, hr-LARC is defined as LARC with on baseline MRI at least one of the following characteristics; MRF invasion, EMVI grade 4, enlarged bilateral or extensive LLN at high risk of an incomplete resection, or TD. Exclusion criteria are the presence of a homozygous DPD deficiency, distant metastases, any chemotherapy within the past 6 months, previous radiotherapy within the pelvic area precluding standard chemoradiotherapy, and any contraindication for the planned treatment. All patients will be planned for six two-weekly cycles of FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) prior to chemoradiotherapy (25 × 2 Gy or 28 × 1.8 Gy with concomitant capecitabine). A resection will be performed following radiological confirmation of resectable disease after the completion of chemoradiotherapy. A watch and wait strategy is allowed in case of a clinical complete response. The primary endpoint is the CR rate, described as a pathological CR or a sustained clinical CR one year after chemoradiotherapy. The main secondary objectives are long-term oncological outcomes, radiological and pathological response, the number of resections with clear margins, treatment-related toxicity, perioperative complications, health-related costs, and quality of life. DISCUSSION: This trial protocol describes the MEND-IT study. The MEND-IT study aims to evaluate the CR rate after intensified chemotherapy prior to concomitant chemoradiotherapy in a homogeneous group of patients with locally advanced rectal cancer and indisputably unfavourable characteristics, defined as hr-LARC, in order to improve their prognosis. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04838496 , registered on 02-04-2021 Netherlands Trial Register: NL9790. PROTOCOL VERSION: Version 3 dd 11-4-2022.

Improved response rate in patients with prognostically poor locally advanced rectal cancer after treatment with induction chemotherapy and chemoradiotherapy when compared with chemoradiotherapy alone: A matched case-control study.

INTRODUCTION: The addition of induction chemotherapy (ICT) to neoadjuvant chemoradiotherapy (CRT) has the potential to improve outcomes in patients with locally advanced rectal cancer (LARC). However, patient selection is essential to prevent overtreatment. This study compared the complete response (CR) rate after treatment with and without ICT of LARC patients with prognostically poor characteristics. METHODS: All LARC patients who were treated with neoadjuvant CRT, whether or not preceded by ICT, and who underwent surgery or were considered for a wait-and-see strategy between January 2016 and March 2020 in the Catharina Hospital Eindhoven, were retrospectively selected. LARC was defined as any T4 tumour, or a T2/T3 tumour with extramural venous invasion and/or tumour deposits and/or N2 lymph node status, and/or mesorectal fascia involvement (T3 tumours only). Case-control matching was performed based on the aforementioned characteristics. RESULTS: Of 242 patients, 178 (74%) received CRT (CRT-group) and 64 patients (26%) received ICT followed by CRT (ICT-group). In the ICT-group, 3 patients (5%) did not receive the minimum of three cycles. In addition, in this selected cohort, compliance with radiotherapy was 100% in the ICT-group and 97% in the CRT-group. The CR rate was 30% in the ICT-group and 15% in the CRT-group (p = 0.011). After case-control matching, the CR rate was 28% and 9%, respectively (p = 0.013). CONCLUSION: Treatment including ICT seemed well tolerated and resulted in a high CR rate. Hence, this treatment strategy may facilitate organ preservation and improve survival in LARC patients with prognostically poor characteristics.

Is sterile exposure in perianal procedures necessary? A single-institution experience and results from a national survey.

BACKGROUND: Surgical site infections (SSI) are the most common postoperative complications. To minimize the risk of SSI, there is a strict asepsis policy in the operating theatre. The aim of this study was to evaluate the risk and cost-saving benefit of performing perianal surgery in a non-sterile setting. METHODS: All patients who had perianal surgery at our institution between January 2014 and December 2017 in a sterile (S) or non-sterile (NS) setting for an infectious or non-infectious cause were included. The primary outcome was the 30-day SSI rate. The secondary outcome was the reintervention rate. A questionnaire was sent to surgeons in the Netherlands to assess current policy with regard to asepsis in perianal procedures. Finally, a cost analysis was performed. RESULTS: In total, 376 patients were included. The rate of SSI in infectious procedures was 13% (S) versus 14% (NS, p = 0.853) and 5.1% (S) versus 0.9% (NS) in non-infectious procedures (p = 0.071). Reintervention rates in infectious procedures were 3.4% (S) versus 8.6% (NS, p = 0.187) and 1.3% (S) versus 0.0% (NS) in non-infectious procedures (p = 0.227). The questionnaire revealed that most surgeons perform perianal surgery in a sterile setting although they did not consider this useful. The potential national cost-saving benefit of a non-sterile setting is €124.61 per patient. CONCLUSIONS: This study suggests that it is safe to perform perianal surgery in a non-sterile setting with regard to the SSI and reintervention rate. Adjustment of the current practice will contribute to a reduction in healthcare expenses.

Impact of a history of metastases or synchronous metastases on survival in patients with locally recurrent rectal cancer.

AIM: Patients with locally recurrent rectal cancer (LRRC) frequently present with either synchronous metastases or a history of metastases. This study was conducted to evaluate whether LRRC patients without metastases have a different oncological outcome compared to patients with a history of metastases treated with curative intent or patients with potentially curable synchronous metastases. METHOD: All consecutive LRRC patients who underwent intentionally curative surgery between 2005 and 2017 in a large tertiary hospital were retrospectively reviewed and categorized as having no metastases, a history of (curatively treated) metastases or synchronous metastases. Patients with unresectable distant metastases were excluded from the analysis. RESULTS: Of the 349 patients who were analysed, 261 (75%) had no metastases, 42 (12%) had a history of metastases and 46 (13%) had synchronous metastases. The 3-year metastasis-free survival was 52%, 33% and 13% in patients without metastases, with a history of metastases, and with synchronous metastases, respectively (P < 0.001) A history of metastases did not influence overall survival (OS), but there was a trend towards a worse OS in patients with synchronous metastases compared with patients without synchronous metastases (hazard ratio 1.43; 95% CI 0.98-2.11). CONCLUSION: LRRC patients with a history of curatively treated metastases have an OS comparable to that in patients without metastases and should therefore be treated with curative intent. However, LRRC patients with synchronous metastases have a poor metastasis-free survival and worse OS; in these patients, an individualized treatment approach to observe the behaviour of the disease is recommended.

Age-related differences in morbidity and mortality after surgery for primary clinical T4 and locally recurrent rectal cancer.

AIM: Outcomes in elderly patients (≥75 years) with non-advanced colorectal cancer have improved. It is unclear whether this is also true for elderly patients with clinical T4 rectal cancer (cT4RC) or locally recurrent rectal cancer (LRRC). We aimed to compare age-related differences in morbidity and mortality after curative treatment for cT4RC and LRRC. METHODS: All cT4RC and LRRC patients without distant metastasis who underwent curative surgery between 2005 and 2017 in the Catharina Hospital (Eindhoven, The Netherlands) were included. Morbidity and mortality were evaluated based on age (<75 and ≥75 years) and date of surgery (2005-2011 and 2012-2017). RESULTS: Overall, 72 of 474 (15.2%) cT4RC and 53 of 293 (18.1%) LRRC patients were ≥75 years. No significant differences in the incidence of Clavien-Dindo I-IV complications were observed between age groups. However, in elderly cT4RC patients, cerebrovascular accidents occurred more frequently (4.2% vs. 0.5%, P = 0.03). Between 2005-2011 and 2012-2017, 30-day mortality improved from 7.5% to 3.1% and from 10.0% to 0.0% in elderly cT4RC and LRRC patients, respectively. The 1-year mortality during 2012-2017 was worse in elderly than in younger patients (28.1% vs. 6.2%, P = 0.001 for cT4RC and 27.3% vs. 13.8%, P = 0.06 for LRRC). In elderly cT4RC and LRRC patients, 44.4% and 46.2% died due to non-cancer-related causes, while only 27.8% and 23.1% died due to disease recurrence, respectively. CONCLUSION: Although the 30-day mortality in elderly cT4RC and LRRC patients improved after curative treatment, the 1-year mortality in elderly patients continued to be high, which requires more awareness for the elderly after hospitalization.

Improved Outcomes for Responders After Treatment with Induction Chemotherapy and Chemo(re)irradiation for Locally Recurrent Rectal Cancer.

BACKGROUND: Despite improvements in the multimodality treatment for patients with locally recurrent rectal cancer (LRRC), oncological outcomes remain poor. This study evaluated the effect of induction chemotherapy and subsequent chemo(re)irradiation on the pathologic response and the rate of resections with clear margins (R0 resection) in relation to long-term oncological outcomes. METHODS: All consecutive patients with LRRC treated in the Catharina Hospital Eindhoven who underwent a resection after treatment with induction chemotherapy and subsequent chemo(re)irradiation between January 2010 and December 2018 were retrospectively reviewed. Induction chemotherapy consisted of CAPOX/FOLFOX. Endpoints were pathologic response, resection margin and overall survival (OS), disease free survival (DFS), local recurrence free survival (LRFS), and metastasis free survival (MFS). RESULTS: A pathologic complete response was observed in 22 patients (17%), a "good" response (Mandard 2-3) in 74 patients (56%), and a "poor" response (Mandard 4-5) in 36 patients (27%). An R0 resection was obtained in 83 patients (63%). The degree of pathologic response was linearly correlated with the R0 resection rate (p = 0.026). In patients without synchronous metastases, pathologic response was an independent predictor for LRFS, MFS, and DFS (p = 0.004, p = 0.003, and p = 0.024, respectively), whereas R0 resection was an independent predictor for LRFS and OS (p = 0.020 and p = 0.028, respectively). CONCLUSIONS: Induction chemotherapy in addition to neoadjuvant chemo(re)irradiation is a promising treatment strategy for patients with LRRC with high pathologic response rates that translate into improved oncological outcomes, especially when an R0 resection has been achieved.

Outcomes of urinary diversion after surgery for locally advanced or locally recurrent rectal cancer with complete cystectomy; ileal and colon conduit.

INTRODUCTION: Surgery for locally advanced rectal cancer (LARC) or locally recurrent rectal cancer (LRRC) may require total pelvic exenteration with the need for urinary diversion. The aim of this study was to describe outcomes for ileal and colon conduits after surgery for LARC and LRRC. METHODS: All consecutive patients from two tertiary referral centers who underwent total pelvic exenteration for LARC or LRRC between 2000 and 2018 with cystectomy and urinary reconstruction using an ileal or colon conduit were retrospectively analyzed. Short- (≤30 days) and long-term (>30 days) complications were described for an ileal and colon conduit. RESULTS: 259 patients with LARC (n = 131) and LRRC (n = 128) were included, of whom 214 patients received an ileal conduit and 45 patients a colon conduit. Anastomotic leakage of the ileo-ileal anastomosis occurred in 9 patients (4%) after performing an ileal conduit. Ileal conduit was associated with a higher rate of postoperative ileus (21% vs 7%, p = 0.024), but a lower proportion of wound infections than a colon conduit (14% vs 31%, p = 0.006). The latter did not remain significant in multivariate analysis. No difference was observed in the rate of uretero-enteric anastomotic leakage, urological complications, mortality rates, major complications (Clavien-Dindo≥3), or hospital stay between both groups. CONCLUSION: Performing a colon conduit in patients undergoing total pelvic exenteration for LARC or LRRC avoids the risks of ileo-ileal anastomotic leakage and may reduce the risk of a post-operative ileus. Besides, there are no other differences in outcome for ileal and colon conduits.