Impact of 18FFDG-PET/CT and Laparoscopy in Staging of Locally Advanced Gastric Cancer: A Cost Analysis in the Prospective Multicenter PLASTIC-Study.

BACKGROUND: Unnecessary D2-gastrectomy and associated costs can be prevented after detecting non-curable gastric cancer, but impact of staging on treatment costs is unclear. This study determined the cost impact of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18FFDG-PET/CT) and staging laparoscopy (SL) in gastric cancer staging. MATERIALS AND METHODS: In this cost analysis, four staging strategies were modeled in a decision tree: (1) 18FFDG-PET/CT first, then SL, (2) SL only, (3) 18FFDG-PET/CT only, and (4) neither SL nor 18FFDG-PET/CT. Costs were assessed on the basis of the prospective PLASTIC-study, which evaluated adding 18FFDG-PET/CT and SL to staging advanced gastric cancer (cT3-4 and/or cN+) in 18 Dutch hospitals. The Dutch Healthcare Authority provided 18FFDG-PET/CT unit costs. SL unit costs were calculated bottom-up. Gastrectomy-associated costs were collected with hospital claim data until 30 days postoperatively. Uncertainty was assessed in a probabilistic sensitivity analysis (1000 iterations). RESULTS: 18FFDG-PET/CT costs were €1104 including biopsy/cytology. Bottom-up calculations totaled €1537 per SL. D2-gastrectomy costs were €19,308. Total costs per patient were €18,137 for strategy 1, €17,079 for strategy 2, and €19,805 for strategy 3. If all patients undergo gastrectomy, total costs were €18,959 per patient (strategy 4). Performing SL only reduced costs by €1880 per patient. Adding 18FFDG-PET/CT to SL increased costs by €1058 per patient; IQR €870-1253 in the sensitivity analysis. CONCLUSIONS: For advanced gastric cancer, performing SL resulted in substantial cost savings by reducing unnecessary gastrectomies. In contrast, routine 18FFDG-PET/CT increased costs without substantially reducing unnecessary gastrectomies, and is not recommended due to limited impact with major costs. TRIAL REGISTRATION: NCT03208621. This trial was registered prospectively on 30-06-2017.

Referral patterns of GIST patients: data from a nationwide study.

BACKGROUND: This study compares the characteristics, referral and treatment patterns and overall survival (OS) of gastrointestinal stromal tumor (GIST) patients treated in reference and non-reference centers in the Netherlands. PATIENTS AND METHODS: This retrospective cohort study on patients diagnosed between 2016 and 2019, utilises data from the Netherlands Cancer Registry and the Dutch Nationwide Pathology Database. Patients were categorized into two groups: patients diagnosed in or referred to reference centers and patients diagnosed in non-reference centers without referral. RESULTS: This study included 1,550 GIST patients with a median age of 67.0 in reference and 68.0 years in non-reference centers. Eighty-seven per cent of patients were diagnosed in non-reference centers, of which 36.5% (493/1,352) were referred to a reference center. Referral rates were higher for high-risk (62.2% [74/119]) and metastatic patients (67.2% [90/134]). Mutation analysis was performed in 96.9% and 87.6% of these cases in reference and in non-reference centers (p < 0.01), respectively. Systemic therapy was given in reference centers versus non-reference in 89.5% versus 82.0% (p < 0.01) of high-risk and in 94.1% versus 65.9% (p < 0.01) of metastatic patients, respectively. The proportion of positive resection margins and tumor rupture did not differ between reference and non-reference centers. Median OS was not reached. CONCLUSION: A substantial amount of metastatic GIST patients in non-reference centers did not receive systemic treatment. This might be due to valid reasons. However, optimisation of the referral strategy of GIST patients in the Netherlands could benefit patients. Further research is needed to explore reasons for not starting systemic treatment in metastatic GIST patients.

Locoregional Failure During and After Short-course Radiotherapy Followed by Chemotherapy and Surgery Compared With Long-course Chemoradiotherapy and Surgery: A 5-Year Follow-up of the RAPIDO Trial.

OBJECTIVE: To analyze risk and patterns of locoregional failure (LRF) in patients of the RAPIDO trial at 5 years. BACKGROUND: Multimodality treatment improves local control in rectal cancer. Total neoadjuvant treatment (TNT) aims to improve systemic control while local control is maintained. At 3 years, LRF rate was comparable between TNT and chemoradiotherapy in the RAPIDO trial. METHODS: A total of 920 patients were randomized between an experimental (EXP, short-course radiotherapy, chemotherapy, and surgery) and a standard-care group (STD, chemoradiotherapy, surgery, and optional postoperative chemotherapy). LRFs, including early LRF (no resection except for organ preservation/R2 resection) and locoregional recurrence (LRR) after an R0/R1 resection, were analyzed. RESULTS: Totally, 460 EXP and 446 STD patients were eligible. At 5.6 years (median follow-up), LRF was detected in 54/460 (12%) and 36/446 (8%) patients in the EXP and STD groups, respectively ( P =0.07), in which EXP patients were more often treated with 3-dimensional-conformed radiotherapy ( P =0.029). In the EXP group, LRR was detected more often [44/431 (10%) vs. 26/428 (6%); P =0.027], with more often a breached mesorectum (9/44 (21%) vs. 1/26 (4); P =0.048). The EXP treatment, enlarged lateral lymph nodes, positive circumferential resection margin, tumor deposits, and node positivity at pathology were the significant predictors for developing LRR. Location of the LRRs was similar between groups. Overall survival after LRF was comparable [hazard ratio: 0.76 (95% CI, 0.46-1.26); P =0.29]. CONCLUSIONS: The EXP treatment was associated with an increased risk of LRR, whereas the reduction in disease-related treatment failure and distant metastases remained after 5 years. Further refinement of the TNT in rectal cancer is mandated.

Surgical Techniques and Related Perioperative Outcomes After Robot-assisted Minimally Invasive Gastrectomy (RAMIG): Results From the Prospective Multicenter International Ugira Gastric Registry.

OBJECTIVE: To gain insight in global practice of RAMIG and evaluated perioperative outcomes using an international registry. BACKGROUND: The techniques and perioperative outcomes of robot-assisted minimally invasive gastrectomy (RAMIG) for gastric cancer vary substantially in literature. METHODS: Prospectively registered RAMIG-cases for gastric cancer (≥10 per center) were extracted from 25 centers in Europe, Asia and South-America. Techniques for the resection, reconstruction, anastomosis and lymphadenectomy were analyzed, and related to perioperative surgical and oncological outcomes. Complications were uniformly defined by the Gastrectomy Complications Consensus Group. RESULTS: Between 2020-2023, 759 patients underwent total (n=272), distal (n=465) or proximal (n=22) gastrectomy (RAMIG). After total gastrectomy with Roux-en-Y-reconstruction, anastomotic leakage rates were 8% with hand-sewn (n=9/111) and 6% with linear stapled anastomoses (n=6/100). After distal gastrectomy with Roux-en-Y (67%) or Billroth-II-reconstruction (31%), anastomotic leakage rates were 3% with linear stapled (n=11/433) and 0% with hand-sewn anastomoses (n=0/26). Extent of lymphadenectomy consisted of D1+ (28%), D2 (59%) or D2+ (12%). Median nodal harvest yielded 31 nodes [IQR 21-47] after total and 34 nodes [IQR 24-47] after distal gastrectomy. R0-resection rates were 93% after total and 96% distal gastrectomy. Hospital stay was 9 days after total and distal gastrectomy, and was 3 days shorter without perianastomotic drains versus routine drain placement. Postoperative 30-day mortality was 1%. CONCLUSIONS: This large multicenter study provided a worldwide overview of current RAMIG-techniques with their respective perioperative outcomes. These outcomes demonstrated high surgical quality, set a quality standard for RAMIG and can be considered an international reference for surgical standardization.

Cumulative 5-year Results of a Randomized Controlled Trial Comparing Biological Mesh With Primary Perineal Wound Closure After Extralevator Abdominoperineal Resection (BIOPEX-study).

OBJECTIVE: To determine long-term outcomes of a randomized trial (BIOPEX) comparing biological mesh and primary perineal closure in rectal cancer patients after extralevator abdominoperineal resection and preoperative radiotherapy, with a primary focus on symptomatic perineal hernia. SUMMARY BACKGROUND DATA: BIOPEX is the only randomized trial in this field, which was negative on its primary endpoint (30-day wound healing). METHODS: This was a posthoc secondary analysis of patients randomized in the BIOPEX trial to either biological mesh closure (n = 50; 2 dropouts) or primary perineal closure (n = 54; 1 dropout). Patients were followed for 5 years. Actuarial 5-year probabilities were determined by the Kaplan-Meier statistic. RESULTS: Actuarial 5-year symptomatic perineal hernia rates were 7% (95% CI, 0-30) after biological mesh closure versus 30% (95% CI, 10-49) after primary closure (P = 0.006). One patient (2%) in the biomesh group underwent elective perineal hernia repair, compared to 7 patients (13%) in the primary closure group (P = 0.062). Reoperations for small bowel obstruction were necessary in 1/48 patients (2%) and 5/53 patients (9%), respectively (P = 0.208). No significant differences were found for chronic perineal wound problems, locoregional recurrence, overall survival, and main domains of quality of life and functional outcome. CONCLUSIONS: Symptomatic perineal hernia rate at 5-year follow-up after abdominoperineal resection for rectal cancer was significantly lower after biological mesh closure. Biological mesh closure did not improve quality of life or functional outcomes.

Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial.

BACKGROUND: Systemic relapses remain a major problem in locally advanced rectal cancer. Using short-course radiotherapy followed by chemotherapy and delayed surgery, the Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation (RAPIDO) trial aimed to reduce distant metastases without compromising locoregional control. METHODS: In this multicentre, open-label, randomised, controlled, phase 3 trial, participants were recruited from 54 centres in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, and the USA. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, had a biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocarcinoma, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for chemotherapy, and could be assessed for staging within 5 weeks before randomisation. Eligible participants were randomly assigned (1:1), using a management system with a randomly varying block design (each block size randomly chosen to contain two to four allocations), stratified by centre, ECOG performance status, cT stage, and cN stage, to either the experimental or standard of care group. All investigators remained masked for the primary endpoint until a prespecified number of events was reached. Patients allocated to the experimental treatment group received short-course radiotherapy (5 × 5 Gy over a maximum of 8 days) followed by six cycles of CAPOX chemotherapy (capecitabine 1000 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1, and a chemotherapy-free interval between days 15-21) or nine cycles of FOLFOX4 (oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin [folinic acid] 200 mg/m2 intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m2 intravenously and fluorouracil 600 mg/m2 intravenously for 22 h on days 1 and 2, and a chemotherapy-free interval between days 3-14) followed by total mesorectal excision. Choice of CAPOX or FOLFOX4 was per physician discretion or hospital policy. Patients allocated to the standard of care group received 28 daily fractions of 1·8 Gy up to 50·4 Gy or 25 fractions of 2·0 Gy up to 50·0 Gy (per physician discretion or hospital policy), with concomitant twice-daily oral capecitabine 825 mg/m2 followed by total mesorectal excision and, if stipulated by hospital policy, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4. The primary endpoint was 3-year disease-related treatment failure, defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death, assessed in the intention-to-treat population. Safety was assessed by intention to treat. This study is registered with the EudraCT, 2010-023957-12, and ClinicalTrials.gov, NCT01558921, and is now complete. FINDINGS: Between June 21, 2011, and June 2, 2016, 920 patients were enrolled and randomly assigned to a treatment, of whom 912 were eligible (462 in the experimental group; 450 in the standard of care group). Median follow-up was 4·6 years (IQR 3·5-5·5). At 3 years after randomisation, the cumulative probability of disease-related treatment failure was 23·7% (95% CI 19·8-27·6) in the experimental group versus 30·4% (26·1-34·6) in the standard of care group (hazard ratio 0·75, 95% CI 0·60-0·95; p=0·019). The most common grade 3 or higher adverse event during preoperative therapy in both groups was diarrhoea (81 [18%] of 460 patients in the experimental group and 41 [9%] of 441 in the standard of care group) and neurological toxicity during adjuvant chemotherapy in the standard of care group (16 [9%] of 187 patients). Serious adverse events occurred in 177 (38%) of 460 participants in the experimental group and, in the standard of care group, in 87 (34%) of 254 patients without adjuvant chemotherapy and in 64 (34%) of 187 with adjuvant chemotherapy. Treatment-related deaths occurred in four participants in the experimental group (one cardiac arrest, one pulmonary embolism, two infectious complications) and in four participants in the standard of care group (one pulmonary embolism, one neutropenic sepsis, one aspiration, one suicide due to severe depression). INTERPRETATION: The observed decreased probability of disease-related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting. Therefore, the experimental treatment can be considered as a new standard of care in high-risk locally advanced rectal cancer. FUNDING: Dutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network.

Re-Irradiation in Patients with Recurrent Rectal Cancer is Safe and Feasible.

BACKGROUND: There is no consensus yet for the best treatment regimen in patients with recurrent rectal cancer (RRC). This study aims to evaluate toxicity and oncological outcomes after re-irradiation in patients with RRC in our center. Clinical (cCR) and pathological complete response (pCR) rates and radicality were also studied. METHODS: Between January 2010 and December 2018, 61 locally advanced RRC patients were treated and analyzed retrospectively. Patients received radiotherapy at a dose of 30.0-30.6 Gy (reCRT) or 50.0-50.4 Gy chemoradiotherapy (CRT) in cases of no prior irradiation because of low-risk primary rectal cancer. In both groups, patients received capecitabine concomitantly. RESULTS: In total, 60 patients received the prescribed neoadjuvant (chemo)radiotherapy followed by surgery, 35 patients (58.3%) in the reRCT group and 25 patients (41.7%) in the long-course CRT group. There were no significant differences in overall survival (p = 0.82), disease-free survival (p = 0.63), and local recurrence-free survival (p = 0.17) between the groups. Patients in the long-course CRT group reported more skin toxicity after radiotherapy (p = 0.040). No differences were observed in late toxicity. In the long-course CRT group, a significantly higher cCR rate was observed (p = 0.029); however, there was no difference in the pCR rate (p = 0.66). CONCLUSIONS: The treatment of RRC patients with re-irradiation is comparable to treatment with long-course CRT regarding toxicity and oncological outcomes. In the reCRT group, less cCR was observed, although there was no difference in pCR. The findings in this study suggest that it is safe and feasible to re-irradiate RRC patients.

Effect of Extending the Original CROSS Criteria on Tumor Response to Neoadjuvant Chemoradiotherapy in Esophageal Cancer Patients: A National Multicenter Cohort Analysis.

BACKGROUND: Extending the original criteria of the Chemoradiotherapy for Oesophageal Cancer followed by Surgery Study (CROSS) in daily practice may increase the treatment outcome of esophageal cancer (EC) patients. This retrospective national cohort study assessed the impact on the pathologic complete response (pCR) rate and surgical outcome. PATIENTS AND METHODS: Data from EC patients treated between 2009 and 2017 were collected from the national Dutch Upper Gastrointestinal Cancer Audit database. Patients had locally advanced EC (cT1/N+ or cT2-4a/N0-3/M0) and were treated according to the CROSS regimen. CROSS (n = 1942) and the extended CROSS (e-CROSS; n = 1359) represent patients fulfilling the original or extended CROSS criteria, respectively. The primary outcome was total pCR (ypT0N0), while secondary outcomes were local esophageal pCR (ypT0), surgical radicality, and postoperative morbidity and mortality. RESULTS: Overall, CROSS and e-CROSS did not differ in total or local pCR rate, although a trend was observed (23.2% vs. 20.4%, p = 0.052; and 26.7% vs. 23.8%, p = 0.061). When stratifying by histology, the pCR rate was higher in the CROSS group compared with e-CROSS in squamous cell carcinomas (48.2% vs. 33.3%, p = 0.000) but not in adenocarcinomas (16.8% vs. 16.9%, p = 0.908). Surgical radicality did not differ between groups. Postoperative mortality (3.2% vs. 4.6%, p = 0.037) and morbidity (58.3% vs. 61.8%, p = 0.048) were higher in e-CROSS. CONCLUSION: Extending the CROSS inclusion criteria for neoadjuvant chemoradiotherapy in routine clinical practice of EC patients had no impact on the pCR rate and on radicality, but was associated with increased postoperative mortality and morbidity. Importantly, effects differed between histological subtypes. Hence, in future studies, we should carefully reconsider who will benefit most in the real-world setting.

A Systematic Review and Meta-analysis on Omentoplasty for the Management of Abdominoperineal Defects in Patients Treated for Cancer.

OBJECTIVE: The objective of this systematic review and meta-analysis was to examine the effects of omentoplasty on pelviperineal morbidity following abdominoperineal resection (APR) in patients with cancer. BACKGROUND: Recent studies have questioned the use of omentoplasty for the prevention of perineal wound complications. METHODS: A systematic review of published literature since 2000 on the use of omentoplasty during APR for cancer was undertaken. The authors were requested to share their source patient data. Meta-analyses were conducted using a random-effects model. RESULTS: Fourteen studies comprising 1894 patients (n = 839 omentoplasty) were included. The majority had APR for rectal cancer (87%). Omentoplasty was not significantly associated with the risk of presacral abscess formation in the overall population (RR 1.11; 95% CI 0.79-1.56), nor in planned subgroup analysis (n = 758) of APR with primary perineal closure for nonlocally advanced rectal cancer (RR 1.06; 95% CI 0.68-1.64). No overall differences were found for complicated perineal wound healing within 30 days (RR 1.30; 95% CI 0.92-1.82), chronic perineal sinus (RR 1.08; 95% CI 0.53-2.20), and pelviperineal complication necessitating reoperation (RR 1.06; 95% CI 0.80-1.42) as well. An increased risk of developing a perineal hernia was found for patients submitted to omentoplasty (RR 1.85; 95% CI 1.26-2.72). Complications related to the omentoplasty were reported in 4.6% (95% CI 2.5%-8.6%). CONCLUSIONS: This meta-analysis revealed no beneficial effect of omentoplasty on presacral abscess formation and perineal wound healing after APR, while it increases the likelihood of developing a perineal hernia. These findings do not support the routine use of omentoplasty in APR for cancer.

Quality of Life, Sexual Functioning, and Physical Functioning Following Perineal Reconstruction with the Lotus Petal Flap.

BACKGROUND: Lotus petal flaps (LPF) may be used for the reconstruction of extralevator abdominoperineal defects that cannot be closed primarily. Limited data are available on how perineal reconstruction with the LPF impacts on patients' quality of life (QoL), sexual functioning, and physical functioning. METHODS: A cross-sectional study was performed following perineal reconstruction with the LPF. The QoL of patients having undergone LPF reconstruction was compared with a control group in which perineal defects were closed without flaps. Sexual and physical functioning (presence of perineal herniation and range of motion [ROM] of the hip joints) could only be evaluated in the LPF group. Psychometrically sound questionnaires were used. Physical functioning was evaluated subjectively with binary questions and objectively by physical examination. RESULTS: Of the 23 patients asked to participate, 15 (65%) completed the questionnaires and 11 (47%) underwent physical examination. In the control group, 16 patients were included. There were no significant differences in QoL between the LPF and control groups. Within the LPF group, 33% of patients were sexually active postoperatively compared with 87% preoperatively. No perineal herniation was found. The ROM of the hip joints was bilaterally smaller compared with the generally accepted values. CONCLUSIONS: Conclusions should be made with care given the small sample size. Despite a supposedly larger resection area in the LPF group, QoL was comparable in both groups. Nonetheless, reconstruction seemed to affect sexual function and physical function, not hampering overall satisfaction.

CRITICS-II: a multicentre randomised phase II trial of neo-adjuvant chemotherapy followed by surgery versus neo-adjuvant chemotherapy and subsequent chemoradiotherapy followed by surgery versus neo-adjuvant chemoradiotherapy followed by surgery in resectable gastric cancer.

BACKGROUND: Although radical surgery remains the cornerstone of cure in resectable gastric cancer, survival remains poor. Current evidence-based (neo)adjuvant strategies have shown to improve outcome, including perioperative chemotherapy, postoperative chemoradiotherapy and postoperative chemotherapy. However, these regimens suffer from poor patient compliance, particularly in the postoperative phase of treatment. The CRITICS-II trial aims to optimize preoperative treatment by comparing three treatment regimens: (1) chemotherapy, (2) chemotherapy followed by chemoradiotherapy and (3) chemoradiotherapy. METHODS: In this multicentre phase II non-comparative study, patients with clinical stage IB-IIIC (TNM 8th edition) resectable gastric adenocarcinoma are randomised between: (1) 4 cycles of docetaxel+oxaliplatin+capecitabine (DOC), (2) 2 cycles of DOC followed by chemoradiotherapy (45Gy in combination with weekly paclitaxel and carboplatin) or (3) chemoradiotherapy. Primary endpoint is event-free survival, 1 year after randomisation (events are local and/or regional recurrence or progression, distant recurrence, or death from any cause). Secondary endpoints include: toxicity, surgical outcomes, percentage radical (R0) resections, pathological tumour response, disease recurrence, overall survival, and health related quality of life. Exploratory endpoints include translational studies on predictive and prognostic biomarkers. DISCUSSION: The aim of this study is to select the most promising among three preoperative treatment arms in patients with resectable gastric adenocarcinoma. This treatment regimen will subsequently be compared with the standard therapy in a phase III trial. TRIAL REGISTRATION: clinicaltrials.gov NCT02931890 ; registered 13 October 2016. Date of first enrolment: 21 December 2017.

Pretreatment identification of patients likely to have pathologic complete response after neoadjuvant chemoradiotherapy for rectal cancer.

PURPOSE: In selected patients, a wait-and-see strategy after chemoradiotherapy for rectal cancer might be feasible provided that the probability of pathologic complete response (pCR) is high. This study aimed to identify clinical parameters associated with pCR. Furthermore, we attempted to identify subgroups with increased probability of pCR that might aid in clinical decision making. METHODS: A total of 6444 patients that underwent surgical resection of a single primary carcinoma of the rectum after neoadjuvant chemoradiotherapy (nCRT) between January 2009 and December 2016 in the Netherlands were included in the study. Data on the outcome variable, pCR, and potential covariates were retrieved from a nationwide database. The variables included in the analysis were selected based on previous studies and were analyzed using univariate and multivariate logistic regression analyses. RESULTS: pCR was observed in 1010 patients (15.7%). Pretreatment clinical tumor stage and signs of obstruction were independently associated with pCR. Nodal stage and presence of metastatic disease decreased chances of pCR significantly. The best response rate was observed in patients diagnosed with a non-obstructive, well-/moderately differentiated adenocarcinoma of the lower rectum with no clinical apparent nodal or distant metastatic disease (pCR ratio 18.8%). The percentage of patients demonstrating pCR decreased in case of symptoms of pretreatment obstruction or poorly differentiated tumors (pCR ratio of 11.8 and 6.7%, respectively). CONCLUSION: This nationwide study confirms several of the previously reported clinical predictors of pCR.

Biological Mesh Closure of the Pelvic Floor After Extralevator Abdominoperineal Resection for Rectal Cancer: A Multicenter Randomized Controlled Trial (the BIOPEX-study).

OBJECTIVE: To determine the effect of biological mesh closure on perineal wound healing after extralevator abdominoperineal resection (eAPR). BACKGROUND: Perineal wound complications frequently occur after eAPR with preoperative radiotherapy for rectal cancer. Cohort studies have suggested that biological mesh closure of the pelvic floor improves perineal wound healing. METHODS: Patients were randomly assigned to primary closure (standard arm) or biological mesh closure (intervention arm). A non-cross-linked porcine acellular dermal mesh was sutured to the pelvic floor remnants in the intervention arm, followed by a layered closure of the ischioanal and subcutaneous fat and skin similar to the control intervention. The outcome of the randomization was concealed from the patient and perineal wound assessor. The primary endpoint was the rate of uncomplicated perineal wound healing defined as a Southampton wound score of less than 2 at 30 days postoperatively. Patients were followed for 1 year. RESULTS: In total, 104 patients were randomly assigned to primary closure (n = 54; 1 dropouts) and biological mesh closure (n = 50; 2 dropouts). Uncomplicated perineal wound healing rate at 30 days was 66% (33/50; 3 not evaluable) after primary closure, which did not significantly differ from 63% (30/48) after biological mesh closure [relative risk 1.056; 95% confidence interval (CI) 0.7854-1.4197; P = 0.7177). Freedom from perineal hernia at 1 year was 73% (95% CI 60.93-85.07) versus 87% (95% CI 77.49-96.51), respectively (P = 0.0316). CONCLUSIONS: Perineal wound healing after eAPR with preoperative radiotherapy for rectal cancer was not improved when using a biological mesh. A significantly lower 1-year perineal hernia rate after biological mesh closure is a promising secondary finding that needs longer follow-up to determine its clinical relevance.

Fasciocutaneous Lotus Petal Flap for Perineal Wound Reconstruction after Extralevator Abdominoperineal Excision: Application for Reconstruction of the Pelvic Floor and Creation of a Neovagina.

BACKGROUND: The extralevator abdominoperineal excision (ELAPE) procedure creates an extensive soft tissue defect of the pelvic floor. It has been suggested that primary reconstruction reduces the risk of wound infection and delayed wound healing in this high-risk area. Use of myocutaneous flaps or omentoplasty are associated with functional limitations and complications. We performed the perineal variant of the lotus petal flap, which was originally described for vulvar reconstruction. We aimed to verify if application of the lotus petal flap in pelvic floor reconstruction after ELAPE meets the goals of an ideal reconstruction. METHODS: We performed a retrospective study of 28 patients who underwent the lotus petal flap procedure for pelvic floor reconstruction after ELAPE between January 2011 and March 2014. RESULTS: Median age was 62.1 years and 78.6 % of patients were female. In most patients the tumor was preoperatively irradiated (89.3 %) and in 28.6 % of the reconstructions a biological mesh was applied. No total flap loss occurred. Six (21.4 %) patients had no complications, while 13 (46.4 %) patients had minor complications (Clavien-Dindo grade I-II). Reoperation (Clavien-Dindo grade IIIb) was performed in nine patients (32.1 %), three of whom required a second lotus petal flap reconstruction. Median time until wound healing was 14 weeks. No additional surgery was performed for aesthetic problems. CONCLUSIONS: Reconstruction of the pelvic floor after ELAPE using the fasciocutaneous lotus petal flap has limited major complications, but still with a high incidence of minor wound complications. This retrospective cohort study shows limited consequences on form and function.

Randomized controlled multicentre study comparing biological mesh closure of the pelvic floor with primary perineal wound closure after extralevator abdominoperineal resection for rectal cancer (BIOPEX-study).

BACKGROUND: Primary perineal wound closure after conventional abdominoperineal resection (cAPR) for rectal cancer has been the standard of care for many years. Since the introduction of neo-adjuvant radiotherapy and the extralevator APR (eAPR), oncological outcome has been improved, but at the cost of increased rates of perineal wound healing problems and perineal hernia. This has progressively increased the use of biological meshes, although not supported by sufficient evidence. The aim of this study is to determine the effectiveness of pelvic floor reconstruction using a biological mesh after standardized eAPR with neo-adjuvant (chemo)radiotherapy compared to primary perineal wound closure. METHODS/DESIGN: In this multicentre randomized controlled trial, patients with a clinical diagnosis of primary rectal cancer who are scheduled for eAPR after neo-adjuvant (chemo)radiotherapy will be considered eligible. Exclusion criteria are prior radiotherapy, sacral resection above S4/S5, allergy to pig products or polysorbate, collagen disorders, and severe systemic diseases affecting wound healing, except for diabetes. After informed consent, 104 patients will be randomized between standard care using primary wound closure of the perineum and the experimental arm consisting of suturing a biological mesh derived from porcine dermis in the pelvic floor defect, followed by perineal closure similar to the control arm. Patients will be followed for one year after the intervention and outcome assessors and patients will be blinded for the study treatment. The primary endpoint is the percentage of uncomplicated perineal wound healing, defined as a Southampton wound score of less than II on day 30. Secondary endpoints are hospital stay, incidence of perineal hernia, quality of life, and costs. DISCUSSION: The BIOPEX-study is the first randomized controlled multicentre study to determine the additive value of using a biological mesh for perineal wound closure after eAPR with neo-adjuvant radiotherapy compared to primary perineal wound closure with regard to perineal wound healing and the occurrence of perineal hernia. TRAIL REGISTRATION NUMBER: NCT01927497 (Clinicaltrial.gov).

Ultrasound-guided quantitative fluorescence molecular endoscopy for monitoring response in patients with esophageal cancer following neoadjuvant chemoradiotherapy.

PURPOSE: The ability to identify residual tumor tissues in patients with locally advanced esophageal cancer (EC) following neoadjuvant chemoradiotherapy (nCRT) is essential for monitoring the treatment response. Using the fluorescent tracer bevacizumab-800CW, we evaluated whether ultrasound-guided quantitative fluorescent molecular endoscopy (US-qFME), which combines quantitative fluorescence molecular endoscopy (qFME) with ultrasound-guided needle biopsy/single-fiber fluorescence (USNB/SFF), can be used to identify residual tumor tissues in patients following nCRT. PATIENTS AND METHODS: Eighteen patients received an additional endoscopy procedure the day before surgery. qFME was performed at the primary tumor site (PTS) and in healthy tissue to first establish the optimal tracer dose. USNB/SFF was then used to measure intrinsic fluorescence in the deeper PTS layers and in lymph nodes (LN) suspected for metastasis. Finally, the intrinsic fluorescence and the tissue optical properties, the absorption and the reduced scattering coefficient, were combined into a new parameter: omega. RESULTS: First, a dose of 25 mg bevacizumab-800CW allowed for clear differentiation between the PTS and healthy tissue, with a target-to-background ratio (TBR) of 2.98 (IQR: 1.86-3.03). Moreover, we found a clear difference between both the deeper esophageal PTS layers and suspected LN compared to healthy tissues, with TBR values of 2.18 and 2.17, respectively. Finally, our new parameter, omega, further improved the ability to differentiate between the PTS and healthy tissue. CONCLUSIONS: Combining bevacizumab-800CW with US-qFME may serve as a viable strategy for monitoring the response to nCRT in EC and may help stratify patients with respect to active surveillance versus surgery.

Oncological outcomes after a pathological complete response following total neoadjuvant therapy or chemoradiotherapy for high-risk locally advanced rectal cancer in the RAPIDO trial.

BACKGROUND: A pathological complete response (pCR) following chemoradiation (CRT) or short-course radiotherapy (scRT) leads to a favourable prognosis in patients with rectal cancer. Total neo-adjuvant therapy (TNT) doubles the pCR rate, but it is unknown whether oncological outcomes remain favourable and whether the same characteristics are associated with pCR as after CRT. METHODS: Comparison between patients with pCR in the RAPIDO trial in the experimental [EXP] (scRT, chemotherapy, surgery, as TNT) and standard-of-care treatment [STD] (CRT, surgery, postoperative chemotherapy depending on hospital policy) groups. Primary and secondary outcomes were time-to-recurrence (TTR), overall survival (OS) and association between patient, tumour, and treatment characteristics and pCR. RESULTS: Among patients with a resection within six months after preoperative treatment, 120/423 (28%) [EXP] and 57/398 (14%) [STD] achieved a pCR. Following pCR, 5-year cumulative TTR and OS rates in the EXP and STD arms were 8% vs. 7% (hazard ratio 1.04, 95%CI 0.32-3.38) and 94% vs. 93% (hazard ratio 1.41, 95%CI 0.51-3.92), respectively. Besides the EXP treatment (odds ratio 2.70, 95%CI 1.83-3.97), pre-treatment carcinoembryonic antigen (CEA) <5, pre-treatment tumour size <40 mm and cT2 were associated with pCR. Distance from the anal verge was the only characteristic with a statistically significant difference in association with pCR between the EXP and STD treatment (Pinteraction=0.042). pCR rates did not increase with prolonged treatment time. CONCLUSIONS: The doubled pCR rate of TNT compared to CRT results in similar oncological outcomes. Characteristics associated with pCR are the EXP treatment, normal CEA, and small tumour size.