M. Kusters

Patterns of local recurrence in rectal cancer; a study of the Dutch TME trial.

AIM OF THE STUDY In patients from the Dutch TME trial patterns of local recurrence (LR) in rectal cancer were studied. The purpose was to reconstruct the most likely mechanisms of LR and the effect of preoperative radiotherapy. METHODS 1417 patients were analyzed; 713 were randomized into preoperative radiotherapy and total mesorectal excision (RT + TME), 704 into TME alone. Of the 114 patients with LR, the subsites of LR were determined and related to tumor and treatment factors. RESULTS Overall 5-year LR-rate was 4.6% in the RT + TME group and 11.0% in the TME group. Presacral local recurrences occurred most in both groups. Radiotherapy reduced anastomotic LR significantly, except when after low anterior resection (LAR) distal margins were less than 5 mm. Abdominoperineal resection (APR) mainly resulted in presacral LR. Even after resection with a negative circumferential resection margin, LR-rates were high. Thirty percent of the patients had advanced tumors, which resulted in 58% of all LRs. Lateral LR comprised 20% of all LR. Presacral and lateral LR resulted in a poor prognosis, in contrast to anterior or anastomotic LRs with a relatively good prognosis. CONCLUSIONS RT reduces LR in all subsites and is especially effective in preventing anastomotic LR after LAR. APR-surgery mainly results in presacral LR, which may be prevented by a wider resection. In the TME trial many advanced tumors were included, rather requiring chemoradiotherapy instead of RT. Currently, with good imaging techniques, better selection can take place. Especially lateral LR might be a problem in the future.

Results of European pooled analysis of IORT-containing multimodality treatment for locally advanced rectal cancer: adjuvant chemotherapy prevents local recurrence rather than distant metastases

BACKGROUND The purpose of this study is to analyze the pooled results of multimodality treatment of locally advanced rectal cancer (LARC) in four major treatment centers with particular expertise in intraoperative radiotherapy (IORT). PATIENTS AND METHODS A total of 605 patients with LARC who underwent multimodality treatment up to 2005 were studied. The basic treatment principle was preoperative (chemo)radiotherapy, intended radical surgery, IORT and elective adjuvant chemotherapy (aCT). In uni- and multivariate analyses, risk factors for local recurrence (LR), distant metastases (DM) and overall survival (OS) were studied. RESULTS Chemoradiotherapy lead to more downstaging and complete remissions than radiotherapy alone (P < 0.001). In all, 42% of the patients received aCT, independent of tumor-node-metastasis stage or radicality of the resection. LR rate, DM rate and OS were 12.0%, 29.2% and 67.1%, respectively. Risk factors associated with LR were no downstaging, lymph node (LN) positivity, margin involvement and no postoperative chemotherapy. Male gender, preoperatively staged T4 disease, no downstaging, LN positivity and margin involvement were associated with a higher risk for DM. A risk model was created to determine a prognostic index for individual patients with LARC. CONCLUSIONS Overall oncological results after multimodality treatment of LARC are promising. Adding aCT to the treatment can possibly improve LR rates.

RADICALITY OF RESECTION AND SURVIVAL AFTER MULTIMODALITY TREATMENT IS INFLUENCED BY SUBSITE OF LOCALLY RECURRENT RECTAL CANCER

PURPOSE To analyze results of multimodality treatment in relation to subsite of locally recurrent rectal cancer (LRRC). METHOD AND MATERIALS A total of 170 patients with LRRC who underwent treatment between 1994 and 2008 were studied. The basic principle of multimodality treatment was preoperative (chemo)radiotherapy, intended radical surgery, and intraoperative radiotherapy. The subsites of LRRC were classified as presacral, posterolateral, (antero)lateral, anterior, anastomotic, or perineal. Subsites were related to radicality of the resection, local re-recurrence rate, distant metastasis rate, and cancer-specific survival. RESULTS R0 resections were achieved in 54% of the patients, and 5-year cancer-specific survival was 40.5%. The worst outcomes were seen in presacral LRRC, with only 28% complete resections and 19% 5-year survival (p = 0.03 vs. other subsites). Anastomotic LRRC resulted in the most favorable outcomes, with 77% R0 resections and 60% 5-year survival (p = 0.04). Generally, if a complete resection was achieved, survival improved, except in posterolateral LRRC. Local re-recurrence and metastasis rate were lowest in anastomotic LRRC. CONCLUSIONS Classification of the subsite of LRRC is a predictor of potentially resectable and consequently curable disease. Treatment of posterior LRRC imposes poor results, whereas anastomotic LRRC location shows superior results.

Patterns of local recurrence in locally advanced rectal cancer after intra-operative radiotherapy containing multimodality treatment

BACKGROUND AND PURPOSE The purpose of this study is to analyze the patterns of local recurrence (LR) after intra-operative radiotherapy (IORT) containing multimodality treatment of locally advanced rectal carcinoma (LARC). METHODS AND MATERIALS Two hundred and ninety patients with LARC who underwent multimodality treatment between 1994 and 2006 were studied. For patients who developed LR, the subsite was classified into presacral, postero-lateral, lateral, anterior, anastomotic or perineal. Patient and treatment characteristics were related to subsite of LR. RESULTS After 5years, 34 patients (13.2%) developed LR. The most prominent subsite of LR was the presacral subsite. 47% of the local recurrences occurred outside the IORT field. Most recurrences developed when IORT was given dorsally, while least occurred when IORT was given ventrally. Especially after dorsal IORT a high amount of infield recurrences were observed (6 of 8; 75%). In multi-variate analysis tumor distance of more than 5cm from the anal verge and a positive circumferential margin were associated with presacral local recurrence. CONCLUSIONS Multimodality treatment is effective in the prevention of local recurrence in LARC. IORT application to the area most at risk is feasible and seems effective in the prevention of local recurrence. Dorsal tumor location results in unfavourable oncologic results.

Origin of presacral local recurrence after rectal cancer treatment.

The objective of this study was to obtain detailed anatomical information about the lateral lymph nodes, in order to determine whether they might play a role in presacral local recurrence of rectal cancer after total mesorectal excision without lateral lymph node dissection.

Safety and effectiveness of SGM-101, a fluorescent antibody targeting carcinoembryonic antigen, for intraoperative detection of colorectal cancer: a dose-escalation pilot study

BACKGROUND Tumour-targeted fluorescence imaging has the potential to advance current practice of oncological surgery by selectively highlighting malignant tissue during surgery. Carcinoembryonic antigen (CEA) is overexpressed in 90% of colorectal cancers and is a promising target for colorectal cancer imaging. We aimed to assess the tolerability of SGM-101, a fluorescent anti-CEA monoclonal antibody, and to investigate the feasibility to detect colorectal cancer with intraoperative fluorescence imaging. METHODS We did an open-label, pilot study in two medical centres in the Netherlands. In the dose-escalation cohort, we included patients (aged ≥18 years) with primary colorectal cancer with increased serum CEA concentrations (upper limit of normal of ≥3 ng/mL) since diagnosis, who were scheduled for open or laparoscopic tumour resection. In the expansion cohort, we included patients (aged ≥18 years) with recurrent or peritoneal metastases of colorectal cancer, with increasing serum concentrations of CEA since diagnosis, who were scheduled for open surgical resection. We did not mask patients, investigators, or anyone from the health-care team. We assigned patients using a 3 + 3 dose design to 5 mg, 7·5 mg, or 10 mg of SGM-101 in the dose-escalation cohort. In the expansion cohort, patients received a dose that was considered optimal at that moment of the study but not higher than the dose used in the dose-escalation cohort. SGM-101 was administered intravenously for 30 min to patients 2 or 4 days before surgery. Intraoperative imaging was done to identify near-infrared fluorescent lesions, which were resected and assessed for fluorescence. The primary outcome was tolerability and safety of SGM-101, assessed before administration and continued up to 12 h after dosing, on the day of surgery, the first postoperative day, and follow-up visits at the day of discharge and the first outpatient clinic visit. Secondary outcomes were effectiveness of SGM-101 for detection of colorectal cancer, assessed by tumour-to-background ratios (TBR); concordance between fluorescent signal and tumour status of resected tissue; and diagnostic accuracy in both cohorts. This trial is registered with the Nederlands Trial Register, number NTR5673, and ClinicalTrials.gov, number NCT02973672. FINDINGS Between January, 2016, and February, 2017, 26 patients (nine in the dose-escalation cohort and 17 in the expansion cohort) were included in this study. SGM-101 did not cause any treatment-related adverse events, although three possibly related mild adverse events were reported in three (33%) of nine patients in the dose-escalation cohort and five were reported in three (18%) of 17 patients in the expansion cohort. Five moderate adverse events were reported in three (18%) patients in the expansion cohort, but they were deemed unrelated to SGM-101. No changes in vital signs, electrocardiogram, or laboratory results were found after administration of the maximum dose of 10 mg of SGM-101 in both cohorts. A dose of 10 mg, administered 4 days before surgery, showed the highest TBR (mean TBR 6·10 [SD 0·42] in the dose-escalation cohort). In the expansion cohort, 19 (43%) of 43 lesions were detected using fluorescence imaging and were not clinically suspected before fluorescent detection, which changed the treatment strategy in six (35%) of 17 patients. Sensitivity was 98%, specificity was 62%, and accuracy of fluorescence intensity was 84% in the expansion cohort. INTERPRETATION This study presents the first clinical use of CEA-targeted detection of colorectal cancer and shows that SGM-101 is safe and can influence clinical decision making during the surgical procedure for patients with colorectal cancer. FUNDING Surgimab.

Is There Any Reason to Still Consider Lateral Lymph Node Dissection in Rectal Cancer? Rationale and Technique

&NA; Nodal dissemination in locally advanced rectal cancer occurs mainly in two directions: upward and lateral. Lateral node involvement has been demonstrated; however, lateral lymph node dissection (LLND) is not routinely performed in Western countries and the focus is more on neoadjuvant treatment regimens. The main reasons for this are the high morbidity associated with the operation and the uncertain oncological benefit. There is, however, recent evidence that in selected cases, neoadjuvant treatment combined with total mesorectal excision only might not be sufficient. In this article, the historical developments in the East and the West, the current evidence regarding lateral nodal disease, and the surgical steps in the LLND are discussed.

Total Mesorectal Excision and Lateral Pelvic Lymph Node Dissection

In the treatment of rectal cancer, surgery is the principal therapeutic modality for cure. Over time, the surgical treatment of rectal cancer has undergone major developments, with differing pathways in the West and the East. In the West, total mesorectal excision (TME) has become the standard, often combined with neoadjuvant or adjuvant treatment. In the East, initiated by Japanese surgeons, the lateral lymph node dissection (LLND) has become the gold standard in cases of advanced rectal cancer, without the use of (neo)adjuvant treatment regimens. Both surgical treatment approaches and nerve-sparing methods are discussed, including analysis of oncologic outcomes (patterns of local recurrence), major complications rates (including anastomotic leakage), and comparison of Eastern and Western adjuvant treatment modalities, as well as future perspectives in surgical approaches to this disease.