Douglas Wong

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.

Preoperative combined modality therapy for clinically resectable uT3 rectal adenocarcinoma

PURPOSE To determine the acute toxicity, outcome, and sphincter preservation rates in patients with clinically resectable uT3 adenocarcinoma of the rectum treated with preoperative combined modality therapy. METHODS AND MATERIALS A total of 72 patients were treated from 12/90-7/98 with preoperative 50.4 Gy plus 2 cycles of concurrent 5-fluorouracil (5-FU) and leucovorin (LV) bolus daily x 5 followed by sharp or total mesorectal excision and 4 cycles of postoperative 5-FU and LV. RESULTS Individual Grade 3+ toxicities during preoperative therapy included diarrhea, 11%; bowel movements, 9%; leukopenia, 18%; tenesmus, 1%; and thrombocytopenia, 1%. Total Grade 3+ toxicity was 28%. The pathologic complete response (CR) rate was 13%, and an additional 9% had a clinical CR for a total CR rate of 22%. Of the 35 patients who were judged clinically by their operating surgeon to require an abdominoperineal resection (APR) and were therefore treated with the goal of sphincter preservation, 89% were able to undergo sphincter-preserving surgery. Of the 21 patients eligible for analysis, 81% had good to excellent sphincter function. The 3-year actuarial patterns of failure were 2% local, 8% abdominal, and 13% distant. The 3-year actuarial survival was 95%. CONCLUSIONS Our data confirm our preliminary reports of encouraging rates of acute toxicity, local control, survival, sphincter preservation and function with preoperative combined modality therapy. It is an alternative approach for the treatment of uT3 clinically resectable rectal cancer.

T3N0 rectal cancer: results following sharp mesorectal excision and no adjuvant therapy☆

Adjuvant chemoradiation therapy following resection of T3N0 rectal cancer is recommended in order to reduce the incidence of local recurrence and improve survival. However, recent experience with rectal cancer resection utilizing sharp dissection and total mesorectal excision has resulted in a reduction in local recurrence rates to as low as 5% without adjuvant treatment. The purpose of this study was to determine if rectal cancer resection utilizing sharp mesorectal excision alone is adequate treatment for local control of T3N0 rectal cancer. Between July 1986 and December 1993, 95 patients with T3N0M0 rectal cancer underwent resection with sharp mesorectal excision and did not receive any adjuvant therapy. Various prognostic factors were analyzed for their association with local recurrence and survival. Seventy-nine patients had a low anterior resection, 10 of whom had a coloanal anastomosis, and 16 had an abdominoperineal resection. The median follow-up was 53.3 months. Six patients had local recurrence, 12 had distant recurrence, and three had local and distant recurrences. The overall local recurrence rate was 9% crude and 12% 5-year actuarial. The overall crude recurrence rate was 22%. The 5-year disease-specific survival rate was 86.6% with an overall survival of 75%. Postoperative complications occurred in 18 patients (19%). Five patients (6%) had a documented anastomotic leak. Perioperative mortality was 3%. No technical factors, including type of resection (low anterior vs. abdominoperineal), location of tumor, or extent of resection margin, were significant for determining local recurrence. The only histopathologic marker significant for determining local recurrence was lymphatic invasion (P <0.04). Sharp mesorectal excision with low anterior resection or abdominoperineal resection for T3N0M0 rectal cancer results in a local recurrence rate of less than 10% without the use of adjuvant therapy. Therefore, in select patients with T3N0M0 rectal cancer, the standard use of adjuvant therapy for local control may not be justified.

Signet-ring cell carcinoma of the colon and rectum: A matched control study

PURPOSE: There is little information comparing signet-ring cell carcinoma to common non-signet-ring cell colon and rectal cancers. The aim of this study was to better define the clinicopathologic differences between these two distinct entities. METHODS: Using a prospective database of 5,350 surgical patients with rectal cancers operated on at Memorial Sloan-Kettering Cancer Center between 1986 and 1997, 46 patients with signet-ring cell carcinoma were identified. Signet-ring cell carcinoma lesions were those in which signet-ring cells constituted more then 50 percent of the tumor. Six patients who presented with recurrent disease were excluded from the study. Control patients were matched for age, gender, TNM stage, primary site, procedure, and adjuvant therapy. Age, primary site of the tumor, stage at presentation, and survival times of patients with signet-ring cell carcinoma were also compared with 3,371 patients with primary non-signet-ring cell rectal cancers. Survival was calculated using Kaplan-Meier survival estimates. RESULTS: Mean age of the signet-ring cell carcinoma group was 59±12 years and median age was 61 (range, 20–91) years. Male-to-female ratio was 1.1:1. Lymphatic and peritoneal spread was more common among the signet-ring cell carcinoma group. Approximately one-third of signetring cell carcinoma patients presented with metastatic disease. Mean survival time of the signet-ring cell carcinoma group was 45.4 months (95 percent confidence interval, 26.9–63.8) compared with 78.5 months (95 percent confidence interval, 62.0–94.9) for the control patients group;P=0.02 by the log-rank test. The cumulative survival curve of patients with signet-ring cell carcinoma resembles that of patients with poorly differentiated rectal cancers. CONCLUSIONS: Patients with signet-ring cell carcinoma of the colon and rectum have a worse prognosis compared with matched controls with the same stage of disease.

Long-Term Outcome of Perianal Paget’s Disease

AbstractPURPOSE: Extramammary Paget’s disease of the perianal region is a rare finding that often results in delayed diagnosis and treatment. Although the natural history of the disease is not well characterized, it historically has been associated with other cancers. This study summarizes the history and treatment of all patients diagnosed with perianal Paget’s disease at a single institution. METHODS: Charts of all patients with a diagnosis of extramammary Paget’s disease of the perianal region confirmed or treated at Memorial Sloan-Kettering Cancer Center between 1950 and 2000 were reviewed. Patients with vulvar Paget’s disease or Bowen’s disease were excluded except when Paget’s disease of the perianal region was diagnosed first. Whenever possible, follow-up information was updated. Estimates of overall and disease-free survival were made by the method of Kaplan and Meier. RESULTS: Twenty-seven patients with a median age of 63 years were diagnosed with perianal Paget’s disease. Most patients (74 percent) were treated with wide excision. Local recurrence occurred in 37 percent of all patients treated and in 30 percent of patients (6/20) undergoing a wide excision as part of their treatment. An invasive component was identified in 44 percent of patients (12/27) with perianal Paget’s disease. Six patients (22 percent) required a colostomy as part of the treatment for their disease. Adjuvant chemoradiotherapy was used in 22 percent of patients (6/27) who had more aggressive disease. At a median follow-up of 67 months, 56 percent (15/27) had no evidence of disease, and two patients had died of metastatic disease. The overall and disease-free survival at five years was 59 and 64 percent, respectively, which decreased to 33 and 39 percent, respectively, by ten years. CONCLUSIONS: Perianal Paget’s disease is a rare finding even at a large referral center. The disease process is generally a prolonged one marked by frequent recurrences, and the treatment of first choice is wide excision. Patients with invasive malignancies require more extensive surgery. The role of chemoradiotherapy remains undefined in this disease.

124 I-huA33 Antibody PET of Colorectal Cancer

Humanized A33 (huA33) is a promising monoclonal antibody that recognizes A33 antigen, which is present in more than 95% of colorectal cancers and in normal bowel. In this study, we took advantage of quantitative PET to evaluate 124I huA33 targeting, biodistribution, and safety in patients with colorectal cancer. We also determined the biodistribution of 124I-huA33 when a large dose of human intravenous IgG (IVIG) was administered to manipulate the Fc receptor or when 124I-huA33 was given via hepatic arterial infusion (HAI). Methods: We studied 25 patients with primary or metastatic colorectal cancer; 19 patients had surgical exploration or resection. Patients received a median of 343 MBq (44.4–396 MBq) and 10 mg of 124I-huA33. Nineteen patients received the antibody intravenously and 6 patients via HAI, and 5 patients also received IVIG. Results: Ten of 12 primary tumors were visualized in 11 patients. The median concentration in primary colon tumors was 0.016% injected dose per gram, compared with 0.004% in normal colon. The PET-based median ratio of hepatic tumor uptake to normal-liver uptake was 3.9 (range, 1.8–22.2). Quantitation using PET, compared with well counting of serum and tissue, showed little difference. Prominent uptake in bowel hindered tumor identification in some patients. Pharmacokinetics showed that patients receiving IVIG had a significantly shorter serum half-time (41.6 ± 14.0 h) than those without (65.2 ± 9.8 h). There were no differences in clearance rates among the intravenous group, IVIG group, and HAI group, nor was there any difference in serum area under the curve, maximum serum concentration, or volume of distribution. Weak titers of human–antihuman antibodies were observed in 6 of 25 patients. No acute side effects or significant toxicities were associated with huA33. Conclusion: Good localization of 124I-huA33 in colorectal cancer with no significant toxicity has been observed. PET-derived 124I concentrations agreed well with those obtained by well counting of surgically resected tissue and blood, confirming the quantitative accuracy of 124I-huA33 PET. The HAI route had no advantage over the intravenous route. No clinically significant changes in blood clearance were induced by IVIG.

Evaluation of Preoperative and Postoperative Radiotherapy on Long-Term Functional Results of Straight Coloanal Anastomosis

AbstractPURPOSE: Preoperative radiotherapy for rectal cancer avoids radiation to the reconstructed rectum and may circumvent the detrimental effects on bowel function associated with postoperative radiotherapy. We compared the long-term functional results of patients who received preoperative radiotherapy, postoperative radiotherapy, or no radiotherapy in conjunction with low anterior resection and coloanal anastomosis to assess the impact of pelvic radiation on anorectal function. METHODS: One hundred nine patients treated by low anterior resection and straight coloanal anastomosis for rectal cancer between 1986 and 1997 were assessed with a standardized questionnaire at two to eight years after resection. All radiotherapy was given to a total dose of 4,500 to 5,400 cGy with conventional doses and techniques. Most patients received concurrent 5-fluorouracil–based chemotherapy. RESULTS: There were 39 patients in the preoperative radiotherapy group, 11 patients in the postoperative radiotherapy group, and 59 patients in the no radiotherapy group. The postoperative radiotherapy group reported a significantly greater number of bowel movements per 24-hour period (P < 0.01) and significantly more episodes of clustered bowel movements (P < 0.02) than either the preoperative radiotherapy group or the no radiotherapy group. No significant difference in anal continence or satisfaction with bowel function was found among the three groups. CONCLUSION: In this study of straight (nonreservoir) coloanal anastomoses, postoperative pelvic radiotherapy had significant adverse effects on anorectal function, with higher rates of clustering and frequency of defecation than with preoperative radiotherapy. No differences in continence rates were demonstrated, perhaps because of the sample size of the compared groups. We attribute the adverse effects of postoperative radiotherapy to irradiation of the neorectum, which is spared when treatment is given preoperatively. The deleterious effects of adjuvant radiation on long-term anorectal function can be reduced by preoperative treatment.

Varying Features of Early Age-of-Onset "Sporadic" and Hereditary Nonpolyposis Colorectal Cancer Patients

PURPOSE: Although the criteria for clinical diagnosis of hereditary nonpolyposis colorectal cancer are not fully agreed on, young age seems to be a common trait. The purpose of this study is to identify clinicopathologic features of hereditary nonpolyposis colorectal cancer in early age-of-onset colorectal cancer patients stratified as a function of family cancer history. METHODS: Two hundred thirty consecutive colorectal cancer patients 40 years or older at time of diagnosis were registered into an ongoing database during a ten-year period. Accurate family history was obtainedvia medical records, telephone calls, and questionnaires on 146 patients. According to extent of family history of cancer, patients were stratified into seven groups: 1) fulfilling Amsterdam criteria, 2) fulfilling less strict criteria, 3) having at least one first-degree relative with colorectal cancer, 4) having at least one distant relative with colorectal cancer, 5) having at least one first-degree relative with any cancer, 6) having at least one distant relative with any cancer, 7) having no family history of cancer. RESULTS: Twenty-two of 146 patients fulfilled Amsterdam and less strict hereditary nonpolyposis colorectal cancer criteria (15 percent). These hereditary nonpolyposis colorectal cancer patients were significantly younger (31vs. 35 years;P=0.0003) and had more metachronous colorectal cancer (27 percentvs. 2 percent;P=0.007) and less colorectal cancer with nodal or metastatic spread than the non-hereditary nonpolyposis colorectal cancer patients (35 percentvs. 65 percent;P=0.01). CONCLUSION: Precise familial cancer assessment in early age-of-onset colorectal cancer increases the yield of hereditary nonpolyposis colorectal cancer diagnosis. Because of the frequent development of metachronous colorectal cancer and favorable prognosis, extensive rather than segmental surgery should be considered in early age-of-onset colorectal cancer patients belonging to hereditary nonpolyposis colorectal cancer families.

Primary adenocarcinoma of the anus treated with combined modality therapy.

AbstractPURPOSE: The purpose of this study was to determine the local control and survival of patients with adenocarcinoma of the anus who received combined modality therapy as a component of their treatment. METHODS: Thirteen patients with primary anal adenocarcinoma (T1: 1, T2: 4, T3: 3, T4: 5; and N0: 9, N1: 2, N2: 2) were treated between 1989 and 2001 in the Department of Radiation Oncology at Memorial Sloan Kettering Cancer Center. Three general treatment approaches were used that were based on physician and patient preference as well as tumor stage. These included preoperative combined modality therapy followed by abdominoperineal resection (n = 5), with four of the five receiving postoperative chemotherapy; local excision followed by postoperative radiation alone or combined modality therapy (n = 5); and abdominoperineal resection followed by postoperative combined modality therapy (n = 3). Two patients received brachytherapy. RESULTS: With a median follow-up of 19 months, the median survival was 26 months, the local failure rate was 37 percent, and the two-year actuarial survival was 62 percent. In the subset of eight patients treated with abdominoperineal resection and preoperative or postoperative radiation or combined modality therapy, local control was 63 percent, and three of eight are without evidence of disease. Of the five patients who underwent a local excision followed by postoperative radiation or combined modality therapy, the local control rate was 60 percent, with one of the local failures salvaged by abdominoperineal resection and one of five patients without evidence of disease. CONCLUSION: Although the experience is limited, our data suggest that the combination of abdominoperineal resection and combined modality therapy is a reasonable approach for this rare tumor.