Harvey G. Moore

Rate of Pathologic Complete Response with Increased Interval between Preoperative Combined Modality Therapy and Rectal Cancer Resection

INTRODUCTIONRecent data suggest a favorable prognosis for rectal cancer patients with a pathologic complete response to preoperative combined modality therapy. Prolongation of the interval between preoperative combined modality therapy and surgery (RT-surgery interval) as a means of increasing pathologic complete response rate has not been fully examined.METHODSOne hundred and fifty-five rectal cancer patients undergoing preoperative pelvic external beam radiation therapy and 5-fluorouracil-based chemotherapy followed by rectal resection were identified. All patients had endorectal ultrasound prior to combined modality therapy. Final pathology reports were reviewed for ypT and ypN stage and margin status. Medical records were reviewed for sphincter preservation, operative time, estimated blood loss, hospital stay, and morbidity (overall, anastomotic, and perineal).RESULTSA pathologic complete response (ypT0N0) occurred in 24 patients (15 percent). Median RT-surgery interval was 44 (range, 15-206) days. A pathologic complete response occurred in 19 percent of patients with an interval >44 days, vs. 12 percent in those with an interval ≤44 days (P = 0.27). Downstaging by three stages occurred more frequently in the long-interval group (15 percent vs. 6 percent, P = 0.11). The rates of sphincter preservation, positive margins, estimated blood loss, and operative time were not significantly different. Overall morbidity was similar between groups.CONCLUSIONSOur results demonstrate a trend toward increased pathologic complete response rate and downstaging with increased RT-surgery interval. However, sphincter preservation is not increased. Until prospective analyses are conducted assessing the impact of prolonged RT-surgery interval on long-term outcome, the benefit of a prolonged interval between the completion of preoperative combined modality therapy and surgery remains unclear.

Adequacy of 1-cm Distal Margin After Restorative Rectal Cancer Resection With Sharp Mesorectal Excision and Preoperative Combined-Modality Therapy

Background: Preoperative combined-modality therapy (CMT) for rectal cancer allows a sphincter-sparing procedure in some individuals who would otherwise require an abdominoperineal resection. To further define the subset of rectal cancer patients suitable for this approach, we determined the adequacy of a distal margin of ≤1 cm in patients with locally advanced rectal cancer requiring preoperative CMT.Methods: Ninety-four consecutive patients, status post curative low anterior resection for rectal cancer after preoperative CMT, were identified from the prospective Colorectal Service Database. Distal margin length, tumor grade, tumor-node-metastasis stage, presence of lymphovascular and perineural invasion, and tumor distance from the anal verge were examined for their effect on recurrence and survival. Median follow-up was 44 months.Results: Distal margin length ranged from .1 to 9.5 cm (median, 2.0 cm) and did not correlate with local recurrence (hazard ratio, 1.1; P = .34) or recurrence-free survival (hazard ratio, 1.1; P = .29) by univariate analysis. Kaplan-Meier estimates of recurrence-free survival and local recurrence at 3 years for the ≤1 cm versus >1 cm and the ≤2 cm versus >2 cm groups were not significantly different. Groups were well matched for other clinicopathologic variables.Conclusions: Our data suggest that for patients with locally advanced rectal cancer undergoing resection and preoperative CMT, distal margins ≤1 cm do not seem to compromise oncological outcome.

Patterns of Morphologic Alteration in Residual Rectal Carcinoma Following Preoperative Chemoradiation and their Association with Long-term Outcome

Preoperative radiation (RT) and chemotherapy improve outcome in patients with locally advanced rectal adenocarcinoma and, therefore, have been used increasingly in patient management. The histopathologic alterations in postirradiated rectal adenocarcinoma and their prognostic significance have not been fully characterized. In this study, detailed analyses of morphologic alterations of stromal and tumor cells were performed in a series of 66 posttreatment rectal carcinomas, and the pathologic findings were correlated with long-term outcome. All tumors were locally advanced, with a bulky and/or tethered tumor or endorectal ultrasound or magnetic resonance imaging evidence of T3-4 and / or N1 disease. All patients were treated at one institution with preoperative RT to the pelvis (at least 4500 cGy) with or without concurrent 5-fluorouracil (5-FU)-based chemotherapy 4 to 7 weeks prior to surgical resection. Pathologic assessment showed some treatment response in all patients. Nine patients (13.4%) had complete response, and 8 (11.9%) had near-complete response (> 95% of the tumor replaced by fibroinflammatory tissue). Salient morphologic features included marked fibrosis with or without prominent inflammatory cells replacing neoplastic glands; lack of active tumor necrosis; increased mucin production and mucin pools; marked cytoplasmic eosinophilia, often in combination with marked nuclear atypia but without active mitoses in tumor cells showing treatment effect; endocrine tumor phenotype; and retention of mucosal adenoma in the presence of tumor regression within the bowel wall. With a median follow-up of 69 months, the estimated 5-year recurrence-free survival (RFS) for the entire group was 79%. By univariate analysis, the residual tumor stage (P < 0.05) and reduction of pretreatment T stage (P = 0.002) significantly correlated with RFS, as did pN stage (P = 0.002) and lymphovascular invasion (P = 0.008). The extent of treatment response did not correlate with RFS (P = 0.4). However, patients with a treatment response ≥ 95% seemed to fare better than those with a treatment response <95% (marginally significant difference in RFS, P = 0.057). Univariate and multivariate analyses identified the following morphologic patterns that were significantly associated with a reduced RFS independent of other risk factors: a fibrotic-type stromal response with minimal inflammatory infiltrates (P = 0.001) and absence of surface ulceration (P = 0.026). Our study represents the first detailed morphologic assessment of rectal carcinomas that have been subjected to long course preoperative RT and chemotherapy. Our results demonstrate distinct morphologic features in treated rectal carcinomas that are prognostically relevant.

Attenuated familial adenomatous polyposis : an evolving and poorly understood entity

PURPOSE: Familial adenomatous polyposis is a well-described, autosomal dominant, inherited syndrome characterized by diffuse polyposis of the colon and rectum as well as various upper gastrointestinal and extraintestinal manifestations. A subset of patients present with fewer colorectal polyps, later age of onset of polyps and cancer, and a predilection toward involvement of the proximal colon. This variant of familial adenomatous polyposis is known as attenuated familial adenomatous polyposis. The purpose of this review is to summarize current knowledge regarding this poorly understood entity and propose guidelines for diagnosis, surveillance, and surgical management. METHODS: The MEDLINE database was searched from 1985 onward using the keywords, “attenuated familial adenomatous polyposis,” “AFAP,” “adenomatous polyposis coli gene,” and “APC gene.” Additional articles were identified through the reference sections of retrieved papers. All papers that pertained to attenuated familial adenomatous polyposis or mutations in the APC gene producing an attenuated phenotype were included. RESULTS: Attenuated familial adenomatous polyposis is transmitted in an autosomal dominant fashion. Several distinct mutations within the APC gene have been associated with an attenuated phenotype, but variability of disease expression within kindreds possessing identical mutations makes classification difficult. Polyps are diagnosed at a mean age of 44 years, with cancer diagnosed at a mean of 56 years of age. Frequent involvement of the proximal colon necessitates the use of colonoscopy for surveillance, and infrequent involvement of the rectum supports the role of a total abdominal colectomy and ileorectal anastomosis. CONCLUSIONS: Although currently recognized as a distinct clinical entity, attenuated familial adenomatous polyposis may be part of a spectrum of disease that includes familial adenomatous polyposis and is caused by different mutations within the APC gene. Because of its unique characteristics, yet apparent overlap with familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, increased awareness of attenuated familial adenomatous polyposis should improve diagnosis, surveillance, and treatment strategies in this unique subset of familial polyposis syndromes.

Clinical Examination Following Preoperative Chemoradiation for Rectal Cancer Is Not a Reliable Surrogate End Point

PURPOSE Clinical assessment of rectal cancer response to preoperative combined-modality therapy (CMT) using digital rectal examination (DRE) has been proposed as a means of assessing efficacy of therapy. However, because the accuracy of this approach has not been established, we conducted a prospective analysis to determine the operating surgeons ability to assess response using DRE. PATIENTS AND METHODS Ninety-four prospectively accrued patients with locally advanced rectal cancer (T3/4 or N1) were evaluated with DRE and sigmoidoscopy in order to determine the following tumor characteristics: size, location, mobility, morphology, and circumference. Following preoperative CMT (50.40 Gy with fluorouracil-based chemotherapy) and under general anesthesia, the same surgeon estimated tumor response based on changes in these tumor characteristics, assessed via DRE. Percent pathologic tumor response was determined prospectively by a single pathologist using whole mount sections of the resected cancer. RESULTS Clinical assessment using DRE underestimated pathologic response in 73 cases (78%). In addition, DRE was able to identify only 3 of 14 cases (21%) with a pathologic complete response. There were no clinical overestimates of response. None of the clinicopathologic tumor characteristics examined had a significant impact on DRE estimation of response. CONCLUSION Clinical examination underestimates the extent of rectal cancer response to preoperative CMT. Given the inaccuracy of DRE following preoperative CMT, it should not be used as a sole means of assessing efficacy of therapy nor for selecting patients following CMT for local surgical therapies.

A prospective pathologic analysis using whole-mount sections of rectal cancer following preoperative combined modality therapy: implications for sphincter preservation.

Objective:The aims of this study were to use a comprehensive whole-mount pathologic analysis to characterize microscopic patterns of residual disease, as well as circumferential and distal resection margins, in rectal cancer treated with preoperative CMT; and to identify clinicopathologic factors associated with residual disease. Summary Background Data:Recent studies have shown that preoperative combined modality therapy (CMT) for rectal cancer enhances rates of sphincter preservation. However, the efficacy of preoperative CMT in conjunction with a total mesorectal excision (TME)-based resection, in terms of resection margins using whole-mount sections, has not been reported. Furthermore, since patterns of residual disease and extent of distal spread following preoperative CMT are largely unknown, intraoperative determination of distal rectal transection remains a surgical challenge. Methods:We prospectively accrued 109 patients with endorectal ultrasound (ERUS)-staged, locally advanced rectal cancer (T2–T4 and/or N1), located a median distance of 7 cm from the anal verge, requiring preoperative CMT, and undergoing a TME-based resection. Comprehensive whole-mount pathologic analysis was performed, with particular emphasis on extent of residual disease, margin status, and intramural tumor extension. Clinicopathologic factors associated with residual disease were identified. Results:A sphincter-preserving resection was feasible in 87 patients (80%), and in all 109 patients, distal margins were negative (median, 2.1 cm; range, 0.4–10 cm). Intramural extension beyond the gross mucosal edge of residual tumor was observed in only 2 patients (1.8%), both ≤0.95 cm. There were no positive circumferential margins (median, 10 mm; range, 1–28 mm), although 6 were less than or equal to 1 mm. On multivariate analysis, residual disease was observed more frequently in distally located tumors (distance from anal verge <5 cm) (P = 0.03). Conclusion:Our comprehensive pathologic analysis suggests that, following preoperative CMT and a TME-based resection, distal margins of 1 cm may provide for complete removal of locally advanced rectal cancer. Although residual cancer following preoperative CMT was more likely in the setting of distally located tumors, occult tumor beneath the mucosal edge was rare and, when present, limited to less than 1 cm. Our results extend the indications for sphincter preservation, as distal resection margins of only 1 cm may be acceptable for rectal cancer treated with preoperative CMT.

Colorectal cancer pelvic recurrences: determinants of resectability.

PURPOSEThis study was designed to identify preoperative and intraoperative features of locally recurrent colorectal cancer that predict R0 resection in patients scheduled for attempted complete resection followed by intraoperative radiation therapy.METHODSReview of a prospective data base identified 119 patients brought to the intraoperative radiation therapy suite for planned complete resection of locally recurrent rectal (n = 101) and colon (n = 18) cancer between January 1994 and November 2000. R0 resection was achieved in 61 patients. This group was compared with patients in which an R1 (n = 38), R2 (n = 7), or palliative procedure (n = 13) was performed. Variables evaluated included: tumor location, features of the primary tumor, and preoperative findings on computed tomography, magnetic resonance imaging, and history/physical. Tumor location was established by review of operative/pathologic reports and classified as axial (anastomotic/perineal), anterior (bladder/genitourinary organs), posterior (presacral), or lateral (pelvic sidewall).RESULTSWhen recurrence was confined to the axial location only, or axial and anterior locations, R0 resection was achieved significantly more often than when other locations were involved (P < 0.001, P = 0.003, respectively). When a lateral component was present, R0 resection was achieved significantly less often than when there was no lateral component (P = 0.002). For patients with available preoperative computed tomography and/or magnetic resonance imaging results (n = 70), the finding of lateral tumor involvement was associated with R0 resection significantly less often than when lateral disease was not identified (P = 0.004).CONCLUSIONSPelvic recurrences confined to the axial location, or axial and anterior locations, are more likely to be completely resectable (R0) than those involving the pelvic sidewall. Efforts to enhance preoperative identification and imaging of these patients are clearly justified.

A case-controlled study of 18-fluorodeoxyglucose positron emission tomography in the detection of pelvic recurrence in previously irradiated rectal cancer patients

BACKGROUND Although effective at detecting locally recurrent colorectal cancer, the accuracy of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) for detecting rectal cancer recurrence in an irradiated pelvis has not been systematically studied. STUDY DESIGN Records of surgically resected rectal cancer patients who underwent FDG-PET imaging at least 6 months after external beam radiation therapy (EBRT) were reviewed. Cases (n = 19) were defined as scans from patients in whom a pelvic recurrence was confirmed (histologically, n = 14, radiologic followup, n = 5). Controls (n = 41), defined as scans from patients without clinical or radiologic evidence of pelvic recurrence, were compared with cases for the time interval between completion of EBRT and FDG-PET imaging (RT/PET interval, mean 25.1 months versus 27.5 months, respectively), as well as EBRT dose (mean 5,084 cGy versus 5,062 cGy, respectively). All 60 FDG-PET scans were iteratively reconstructed and reinterpreted by a single nuclear medicine physician blinded to original FDG-PET interpretation and disease status. Certainty of disease was scored on a five-point scale (1 to 5), with scores greater than or equal to 4 considered positive. RESULTS FDG-PET correctly identified 16 of 19 recurrences, for a sensitivity of 84% and specificity of 88%. Overall accuracy was 87%. Positive predictive value was 76% and negative predictive value was 92%. Positive predictive value and accuracy improved in scans performed more than 12 months after EBRT. CONCLUSIONS Our preliminary data suggest that FDG-PET is an accurate modality for detecting pelvic recurrence of rectal cancer after full-dose EBRT. Its reliability appears to improve with time, perhaps because of resolution of early postradiation inflammation.

Residual mesorectal lymph node involvement following neoadjuvant combined-modality therapy: rationale for radical resection?

Background: In order to evaluate the impact of preoperative radiation and chemotherapy (combined modality therapy, or CMT) on primary rectal cancer and mesorectal lymph nodes (MLNs), middle and lower third rectal cancers were resected with total mesorectal excision (TME) and assessed for frequency of MLN retrieval and residual MLN involvement.Methods: Between 1990 and 2001, 187 consecutive patients underwent abdominoperineal resection (APR) or low anterior resection (LAR) for locally advanced (endorectal ultrasound [ERUS] stage, T3–4) mid and distal rectal cancer following preoperative CMT. Sphincter preservation was possible in 150 patients (80%). The mean number of retrieved MLNs was 10.6. Pre-CMT ERUS stage was compared with final pathologic stage.Results: Comparison of pre-CMT ERUS stage with pathologic stage revealed a decrease in T stage in 93 patients (49%), as well as a decrease in the percentage of individuals with positive MLNs, from 54% to 27% (P < .0001). The overall incidence of positive MLN involvement was 27%, and incidence paralleled pathologic T stage (pT): pT0 = 7%, pT1 = 8%, pT2 = 22%, pT3 = 37%, and pT4 = 67%.Conclusions: Following preoperative CMT, the incidence of residual MLN involvement remains significant and parallels increasing pT stage. Therefore, the standard of care for locally advanced distal rectal cancer should continue to include formal rectal resection (TME).

The safety of a pancreaticoduodenectomy in patients older than 80 years: risk vs. benefits

BACKGROUND A pancreaticoduodenectomy (PD) offers the only chance of a cure for pancreatic cancer and can be performed with low mortality and morbidity. However, little is known about outcomes of a PD in octogenarians. METHODS Differences in two groups of patients (Group Y, <80 and Group O, ≥80 year-old) who underwent a PD for pancreatic adenocarcinoma were analysed. Study end-points were length of post-operative stay, overall morbidity, 30-day mortality and overall survival. RESULTS There were 175 patients in Group Y (mean age 64 years) and 25 patients in Group O (mean age 83 years). Octogenarians had worse Eastern Cooperative Oncology Group (ECOG) Performance Status (PS ≥1: 90% vs. 51%) and American Society of Anesthesiology (ASA) score (>2: 71% vs. 47%). The two groups were similar in underlying co-morbidities, operative time, rates of portal vein resection, intra-operative complications, blood loss, pathological stage and status of resection margins. Octogenarians had a longer post-operative stay (20 vs. 14 days) and higher overall morbidity (68% vs. 44%). There was a single death in each group. At a median follow-up of 13 months median survival appeared similar in the two groups (17 vs. 13 months). CONCLUSIONS As 30-day mortality and survival are similar to those observed in younger patients, a PD can be offered to carefully selected octogenarians.