Circumferential Margin Status Research Articles

Systematic analysis of accuracy in predicting complete oncological resection in pancreatic cancer patients - proposal of a new simplified borderline resectability definition

Background: Borderline resectability in pancreatic cancer (PDAC) is currently debated. Methods: Patients undergoing pancreatic resections for PDAC were identified from a prospectively maintained database. As new borderline criteria, the presence of any superior mesenterico-portal vein alteration (SMPV) and perivascular stranding of the superior mesenteric artery (SMA) was evaluated in preoperative imaging. The accuracy of established radiological borderline criteria as compared to the new borderline criteria in predicting R status (sensitivity/negative predictive value) and overall survival was assessed. Results: 118 patients undergoing pancreatic resections for PDAC from 2013 to 2018 were identified. Forty-three (36.4%) had radiological perivascular SMA stranding and 55 (46.6%) had SMPV alterations. Interrater reliability was 90% for SMA stranding and 87% for SMPV alterations. The new borderline definition including SMPV alterations and perivascular SMA stranding was the best predictor of conventional R status (p = 0.040, sensitivity 53%, negative predictive value 81%) and Leeds/Wittekind circumferential margin status (p = 0.050, sensitivity 73%, negative predictive value 79%) as compared to established borderline resectability definition criteria. Perivascular SMA stranding qualified as an independent negative prognostic parameter (HR 3.066, 95% CI 1.078–5.716, p = 0.036). Conclusion: The radiological evaluation of any SMPV alteration and perivascular SMA stranding predicts R status and overall survival in PDAC patients, and may serve to identify potential candidates for neoadjuvant therapy.

Prognosis and Circumferential Margin in Patients with Resected Hilar Cholangiocarcinoma.

Resection margin status is a known prognosticator in patients who undergo resection for hilar cholangiocarcinoma. However, the influence of an isolated positive circumferential margin on clinical outcome is unclear. Patients with resected de novo hilar cholangiocarcinoma from two European hepatobiliary centres (Medical University of Vienna and Aintree University Hospital, 2006-2016) were classified according to resection margin status (negative, surgically positive, isolated circumferentially positive) and investigated with respect to overall survival (OS), recurrence-free survival (RFS) and recurrence pattern. Eighty-three (48 male/35 female) patients were enrolled. The median age was 64years (range 33-80). The median follow-up was 21.7months (range 0.3-92.4). Forty (48%) patients had negative resection margins, 25 (30%) had an isolated positive circumferential margin and 18 (22%) had a positive surgical margin. The 5-year OS rates in patients with negative, isolated positive circumferential and positive surgical resection margins were 47%, 33% and 0%, respectively. Median OS was 45.6, 32.7 and 14.5months, respectively (log rank, P = 0.011). Upon multivariable Cox regression analysis, resection margin status and lymph node status remained statistically significant (P < 0.05). No difference with respect to RFS and recurrence pattern was found between the groups (P > 0.05). Our data show that these three resection margin types were associated with different clinical outcomes. Circumferential margin status may therefore serve as a novel prognostic biomarker.

Systematic Analysis of Accuracy in Predicting Complete Oncological Resection in Pancreatic Cancer Patients—Proposal of a New Simplified Borderline Resectability Definition

Background: Borderline resectability in pancreatic cancer (PDAC) is currently debated. Methods: Patients undergoing pancreatic resections for PDAC were identified from a prospectively maintained database. As new borderline criteria, the presence of any superior mesenterico-portal vein alteration (SMPV) and perivascular stranding of the superior mesenteric artery (SMA) was evaluated in preoperative imaging. The accuracy of established radiological borderline criteria as compared to the new borderline criteria in predicting R status (sensitivity/negative predictive value) and overall survival was assessed. Results: 118 patients undergoing pancreatic resections for PDAC from 2013 to 2018 were identified. Forty-three (36.4%) had radiological perivascular SMA stranding and 55 (46.6%) had SMPV alterations. Interrater reliability was 90% for SMA stranding and 87% for SMPV alterations. The new borderline definition including SMPV alterations and perivascular SMA stranding was the best predictor of conventional R status (p = 0.040, sensitivity 53%, negative predictive value 81%) and Leeds/Wittekind circumferential margin status (p = 0.050, sensitivity 73%, negative predictive value 79%) as compared to established borderline resectability definition criteria. Perivascular SMA stranding qualified as an independent negative prognostic parameter (HR 3.066, 95% CI 1.078–5.716, p = 0.036). Conclusion: The radiological evaluation of any SMPV alteration and perivascular SMA stranding predicts R status and overall survival in PDAC patients, and may serve to identify potential candidates for neoadjuvant therapy.

Clinicopathological factors associated with positive circumferential margins in rectal cancers

Positive circumferential resections are associated with local disease recurrence and reduced survival in rectal cancer. We studied a cohort of consecutive rectal cancer resections to assess for clinicopathological differences and survival in patients with positive and negative circumferential margins. Rectal cancers were identified from a retrospective histopathology database of colorectal resections performed at five western Sydney hospitals from 2010 to 2016. Univariate and multivariate analysis with binary logistic regression were performed on histopathology data matched with survival times from the New South Wales Registry of Births Deaths and Marriages. A total of 502 rectal cancer patients were identified including 66 (13.1%) with involved circumferential margins. Patients with positive and negative circumferential margins had a similar distribution of age, gender and use of neoadjuvant radiotherapy. Tumours with involved circumferential margin comprised 98.5% T3 and T4 disease of which 51.5% received neoadjuvant radiotherapy. These were significantly associated with metastatic disease, increasing tumour size, circumferential and perforated tumours on univariate analysis. Multivariate analysis identified abdomino-perineal resection (odds ratio (OR) 3.35; P = 0.003), en-bloc multivisceral resection (OR 2.56; P = 0.032), T4 stage (OR 6.99; P < 0.001), perineural (OR 5.61; P < 0.001) and vascular invasion (OR 2.46; P = 0.022) as independent risk factors. Five-year survival was significantly worse for patients with involved circumferential margins (26% versus 69%; P < 0.001). Circumferential margin status reflects not only technical success but also aggressive disease phenotypes which require adjuvant therapy. Further work is needed to determine whether omission of radiotherapy has had an effect on long-term outcomes in some of our at-risk patients.

Robotic Versus Laparoscopic Minimally Invasive Surgery for Rectal Cancer: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

The aim of this study was to evaluate the safety and efficacy of elective rectal resection for rectal cancer in adults by robotic surgery compared with conventional laparoscopic surgery. Technological advantages of robotic surgery favor precise dissection in narrow spaces. However, the evidence base driving recommendations for the use of robotic surgery in rectal cancer primarily hinges on observational data. We searched MEDLINE, Embase, and CENTRAL for randomized controlled trials (until August 2016) comparing robotic surgery versus conventional laparoscopic surgery. Data on the following endpoints were evaluated: circumferential margin status, mesorectal grade, number of lymph nodes harvested, rate of conversion to open surgery, postoperative complications, and operative time. Data were summarized as relative risks (RR) or weighted mean differences (WMDs) with 95% confidence intervals (95% CIs). Risk of bias of studies was assessed with standard methods. Five trials were eligible, including 334 robotic and 337 laparoscopic surgery cases. Meta-analysis showed that RS was associated with lower conversion rate (7.3%; 4 studies, 544 participants, RR 0.58; 95% CI 0.35-0.97, P = 0.04, I = 0%) and longer operating time (MD 38.43 minutes, 95% CI 31.84-45.01: P < 0.00001) compared with laparoscopic surgery. Perioperative mortality, rate of circumferential margin involvement (2 studies, 489 participants, RR 0.82, 95% CI 0.39-1.73), and lymph nodes collected (mean 17.4 Lymph Nodes; 5 trials, 674 patients, MD -0.35, 95% CI -1.83 to 1.12) were similar. The quality of the evidence was moderate for most outcomes. Evidence of moderate quality supports that robotic surgery for rectal cancer produces similar perioperative outcomes of oncologic procedure adequacy to conventional laparoscopic surgery. Robotic surgery portraits lower rate of conversion to open surgery, while operating time is significantly longer than by laparoscopic approach.

Neoadjuvant chemoradiation for locally advanced rectal cancer with fluoropyrimidine alone or intensified with oxaliplatin: A systematic review and meta-analysis.

678 Background: Improved outcomes have been demonstrated with the use of neoadjuvant fluoropyrimidine-based chemoradiotherapy and total mesorectal excision for locally advanced rectal cancer. The addition of oxaliplatin in the adjuvant setting has also resulted in improved disease-free survival (DFS). A meta-analysis was performed to evaluate DFS and overall survival (OS) with the addition of oxaliplatin to standard neoadjuvant chemoradiation for locally advanced rectal cancer. Methods: A systematic literature review was performed. Randomized-controlled trials (RCTs) comparing the addition of oxaliplatin in the neoadjuvant setting (oxaliplatin group) to fluoropyrimidine-based chemoradiation (standard group) were included. The primary outcomes were DFS and OS; secondary outcomes were short-term surgical results, morbidity, and mortality. Results were combined using meta-analysis via linear mixed-effects models. Calculations were performed using R. Results: Of 73 studies identified, 4 reported DFS (n=3829) and 3 reported OS (n=2680). There was no difference in DFS between the standard and oxaliplatin groups amongst RCTs [HR 0.90 (0.64-1.26), p=0.5313]. There was no difference in OS [HR 0.93 (0.59-1.47), p=0.9894]. There was no significant heterogeneity between RCTs for primary outcomes. There was also no difference in pathologic complete response rate [OR 0.93 (0.77-1.14), p=0.4923), resection margin (R0) status [OR 1.01 (0.59-1.72), p=0.9846], circumferential resection margin status [OR 0.84 (0.50-1.41), p=0.5079], sphincter saving surgery rate [OR 0.87 (0.74-1.03), p=0.1103], grade 3-4 toxicity [OR 1.60 (0.88-2.92), p=0.1251], and 60-day mortality [OR 1.27 (0.50-3.25), p=0.6148]. There was significant heterogeneity between RCTs for R0 status, circumferential margin status, and grade 3-4 toxicity. Adjuvant treatment varied across studies. Conclusions: There are no short-term or long-term survival benefits with the addition of oxaliplatin to fluoropyrimidine-based chemoradiation in the neoadjuvant setting for locally advanced rectal cancer.

Rectal cancer threatening or affecting the prostatic plane: is partial prostatectomy oncologically adequate? Results of a multicentre retrospective study.

The management of rectal cancer threatening or affecting the prostatic plane is still under debate. The role of preoperative chemo radiotherapy and the extent of prostatectomy seem to be key points in the treatment of these tumours. The aim of the present study was to evaluate the pathological circumferential margin status and the local recurrence rate following different therapeutic options. A multicentre, retrospective study was conducted of patients with rectal cancer threatening or affecting the prostatic plane, but not the bladder, judged by magnetic resonance imaging (MRI). The use of preoperative chemoradiotherapy and the type of urologic resection were correlated with the status of the pathological circumferential resection margin (CRM) and local recurrence. A consecutive series of 126 men with rectal cancer threatening (44) or affecting (82) the prostatic plane on preoperative staging and operated with local curative intent between 1998 and 2010 was analysed. In patients who did not have chemoradiotherapy but had a preoperative threatened anterior margin the CRM-positive rate was 25.0%. In patients who did not have preoperative chemoradiotherapy but did have an affected margin, the CRM-positive rate was 41.7%. When preoperative radiotherapy was given, the respective CRM infiltration rates were 7.1 and 20.7%. In patients having preoperative chemoradiotherapy followed by prostatic resection the rate of CRM positivity was 2.4%. Partial prostatectomy after preoperative chemoradiotherapy resulted in a free anterior CRM in all cases, but intra-operative urethral damage occurred in 36.4% of patients who underwent partial prostatectomy, resulting in a postoperative urinary fistula in 18.2% of patients. Preoperative chemoradiation is mandatory in male patients with a threatened or affected anterior circumferential margin on preoperative MRI. In patients with preoperative prostatic infiltration, prostatic resection is necessary. In this group of patients partial prostatectomy seems to be oncologically safe.

Invited Commentary

The manuscript “Prognostic significance of positive circumferential resection margin in esophageal cancer: A systematic review and meta-analysis,” by Dr Wu and colleagues [1], addresses an important question for surgeons managing esophageal malignancies as it has therapeutic implications regarding adjuvant therapy as well as choice of operative approach. To assess whether the hazard for survival differs based on circumferential margin status after resection for esophageal cancer with curative intent, the authors performed a systematic review of the literature for studies that compared overall survival in patients with circumferential resection margin positive (CRM+) to survival in those with negative circumferential resection margin (CRM−).

Association of radiation therapy with overall survival in patients undergoing surgery for T3N0M0 adenocarcinoma of the rectum.

528 Background: The standard treatment for locally advanced rectal cancer is neoadjuvant chemoradiation followed by surgery, but many physicians question the benefit of multimodality therapy in patients with stage T3N0M0 disease. We aimed to determine the impact of radiation therapy (RT) on overall survival (OS) in this group of patients. Methods: We used the Surveillance, Epidemiology, and End Results database to identify patients undergoing surgery for T3N0M0 adenocarcinoma of the rectum from 2004 to 2010. The Kaplan-Meier method was used to compare OS for patients receiving RT vs. no RT, along with for pre-op vs. post-op RT among patients that received RT. Multivariable analysis (MVA) using a Cox proportional hazards model was performed to assess the association of RT with OS after adjusting for patient age, gender, race, tumor grade, carcinoembryonic antigen, type of surgery, and circumferential margin status. The analysis was repeated separately on patients that underwent total colectomy (TC) vs. sphincter-sparing surgery. Results: The cohort included 8,679 patients, including 4,705 who received RT and 3,974 who did not. Median age was 66 years. Five year OS was 76.5% in patients who received RT, compared to 60.0% in patients who did not receive RT (p &lt;0.001). Five year OS was 76.9% for patients receiving pre-op RT vs. 75.7% in patients receiving post-op RT (p = 0.247). In patients undergoing TC, five year OS was 74.7% for patients receiving RT, compared to 47.5% in patients not receiving RT (p &lt;0.001). In patients undergoing sphincter-sparing surgery, five year OS was 77.7% in patients receiving RT, compared to 62.9% in patients not receiving RT (p &lt;0.001). Use of RT was significantly associated with OS on MVA, both in the entire cohort (HR 0.70 [95% CI 0.60-0.81]; p&lt;0.001) and in subsets of patients undergoing TC (HR 0.55 [95% CI 0.38-0.79]; p=0.001) and sphincter-sparing surgery (HR 0.70 [95% CI 0.59-0.84]; p&lt;0.001). Conclusions: The use of RT is associated with superior OS in patients undergoing surgery for T3N0M0 adenocarcinoma of the rectum. This benefit is demonstrated in both the pre-op and post-op settings and applies to patients undergoing both TC and sphincter-sparing surgery.

Improved Outcomes for Rectal Cancer in the Era of Preoperative Chemoradiation and Tailored Mesorectal Excision: A Series of 338 Consecutive Cases

Neoadjuvant chemoradiation (CRT), tailored mesorectal excision, and intraoperative radiotherapy (IORT) have become the leading measures for rectal cancer treatment. The objective of this study was to evaluate early and long-term results of a multimodal treatment model for rectal cancer followed by curative surgery. Prospectively collected hospital records of 338 patients surgically treated for rectal cancer between January 1998 and December 2008 were retrospectively reviewed. Patients with high rectum level cancers and those with middle and low rectum cancers with clinical stage T1 to T2 underwent surgery, whereas those with T3 to T4 and N+ disease at the middle and low rectum received neoadjuvant CRT in 96.2 per cent of cases. Short-course neoadjuvant radiotherapy was not considered for neoadjuvant treatment. Postoperative major complications and mortality rates were 12.7 and 2.3 per cent, respectively. Overall 5-year disease-specific and disease-free survival were 80 and 73.1 per cent, respectively, whereas local recurrence rate was 6.1 per cent. At multivariate analysis, nodal status and circumferential margin status were independently associated with poor survival; local recurrence rates were independently affected by nodal and marginal status and tumor stage. The extent of mesorectal excision should be tailored depending on tumor location and the use of neoadjuvant chemotherapy, combined with IORT in advanced middle and low rectal cancer, leading to remarkable tumor downstaging with excellent prognosis in responding patients.

Robotic versus Laparoscopic Proctectomy for Rectal Cancer: A Meta-analysis

Robot-assisted laparoscopic surgery is being performed more frequently for the minimally invasive management of rectal cancer. The objective of this meta-analysis was to compare the clinical and oncologic safety and efficacy of robot-assisted versus conventional laparoscopic surgery. A search of the Medline and Embase databases was performed for studies that compared clinical or oncologic outcomes of conventional laparoscopic proctectomy with robot-assisted laparoscopic proctectomy for rectal cancer. The methodological quality of the selected studies was critically assessed to identify studies suitable for inclusion. Meta-analysis was performed by a random effects model and analyzed by Review Manager. Clinical outcomes evaluated were conversion rates, operation times, length of hospital stay, and complications. Oncologic outcomes evaluated were circumferential margin status, number of lymph nodes collected, and distal resection margin lengths. Eight comparative studies were assessed for quality, and seven studies were included in the meta-analysis. Two studies were matched case-control studies, and five were unmatched. A total of 353 robot-assisted laparoscopic surgery proctectomy cases and 401 conventional laparoscopic surgery proctectomy cases were analyzed. Robotic surgery was associated with a significantly lower conversion rate (P=0.03; 95% confidence interval 1-12). There was no difference in complications, circumferential margin involvement, distal resection margin, lymph node yield, or hospital stay (P=NS). Robot-assisted surgery decreased the conversion rate compared to conventional laparoscopic surgery. Other clinical outcomes and oncologic outcomes were equivalent. The benefits of robotic rectal cancer surgery may differ between population groups.

Circumferential Margin Involvement Is the Crucial Prognostic Factor after Multimodality Treatment in Patients with Locally Advanced Rectal Carcinoma

After preoperative (radio)chemotherapy, histologic determinants for prognostication have changed. It is unclear which variables, including assessment of tumor regression, are the best indicators for local recurrence and survival. A series of 201 patients with locally advanced rectal cancer (cT3/T4, M0) presenting with an involved or at least threatened circumferential margin (CRM) on preoperative imaging (<2 mm) were evaluated using standard histopathologic variables and four different histologic regression systems. All patients received neoadjuvant radiochemotherapy or radiotherapy. The prognostic value of all factors was tested with univariate survival analysis of time to local recurrence and overall survival. Local recurrence occurred in only 8% of the patients with a free CRM compared with 43% in case of CRM involvement (P < 0.0001). None of the four regression systems were associated with prognosis, not even when corrected for CRM status. However, we did observe a higher degree of tumor regression after radiochemotherapy compared with radiotherapy (P < 0.001). Absence of tumor regression was associated with increasing invasion depth and a positive CRM (P = 0.02 and 0.03, respectively). Assessment of CRM involvement is the most important pathologic variable after radiochemotherapy. Although tumor regression increases the chance on a free CRM, in cases with positive resection margins prognosis is poor irrespective of the degree of therapy-induced regression.

Does preoperative MRI influence the extent of surgical resection in conservative breast cancer surgery?

Abstract We assessed prospectively the impact of preoperative breast magnetic resonance (MRI) on the extent of surgical resection. Of 131 breast cancers treated with breast conservation over 18 months, 41 underwent preoperative MRI. Scans were shown to the operating surgeon to indicate the location of lesions and their local extent. Clinical information and histological assessment of wide local excision specimens were compared between those patients who underwent preoperative MRI and those who did not. There was no significant difference between the MRI group ( n =41) and no-MRI group ( n =90) in average specimen weight ( P = 0.72) or circumferential margin status ( P = 0.17). Logistic regression analysis demonstrated a positive correlation between margin status and patient age ( P = 0.045), younger patients being more likely to have involved margins, and a negative correlation with MRI status ( P = 0.006) these women having an MRI being more likely to have negative margins. Preoperative MRI does not currently influence the extent of surgical resection in breast conservation surgery.