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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.

Purpose: Management of locally recurrent colorectal adenocarcinoma represents a significant challenge. Many of these tumors adhere to or invade into vital pelvic structures rendering surgery or external beam radiotherapy (EBRT) as palliative treatment. Therefore, a treatment approach was developed to evaluate the role of high-dose-rate intraoperative brachytherapy (HDR-IORT) and surgery as a component of therapy in the management of locally recurrent colorectal cancer. This is an update of our preliminary report with longer follow-up and larger patient numbers., Methods and Materials: Between January 1992 and September 1998, 74 patients with locally recurrent rectal cancer were treated with surgery and HDR-IORT. Additional EBRT was given to 29 patients, and 33 patients received 5-fluorouracil based chemotherapy. All patients underwent complete gross resection, and 21 of 74 had positive microscopic margin. The dose of HDR-IORT ranged from 10 to 18 Gy., Results: With a median follow-up of 22 months, the 5-year local control, distant metastasis disease-free, disease-free, and overall survival rates were 39%, 39%, 23%, and 23%, respectively. The only predictor of improved local control was a negative margin of resection with a 5-year local control rate of 43%, compared to 26% in those with positive margin (p = 0.02). For overall survival, a negative microscopic margin (p = 0.04) and the use of IORT + EBRT (p = 0.04) were significant predictors of improved survival. The incidence of peripheral neuropathy was 16%., Conclusion: The results with HDR-IORT in this group of patients are encouraging. Further improvements in local and distant control are still needed.

Background: To determine the local control, survival, and functional outcome of local excision plus postoperative therapy for patients with rectal cancer., Methods: A total of 39 patients underwent a local excision (2 with snare excision of a T1 polyp and 37 with full-thickness local excision) followed by postoperative radiation therapy +/- 5-FU-based chemotherapy. The median follow-up was 41 months, and 11 patients had positive margins., Results: The 5-year actuarial colostomy-free survival was 87% and overall survival was 70%. Crude local failure increased with T stage: 0% T1, 24% T2, and 25% T3. Of the 8 patients (21%) who developed local failure, 5 underwent salvage APR and were locally controlled. Actuarial local failure at 5 years was 31% for T2 disease and 27% for the total patient group. In the 32 patients with an intact sphincter, 94% had good to excellent sphincter function., Conclusion: Although local failure in patients with T2 tumors has increased since our prior report, the survival, sphincter function, and local salvage rates are acceptable. Local excision and postoperative therapy remains a reasonable alternative to APR in selected patients.

Purpose: To determine the outcome of neoadjuvant chemotherapy followed by concurrent chemotherapy plus high-dose radiation therapy in patients with local/regional squamous cell carcinoma of the esophagus., Methods and Materials: Forty-five patients with clinical Stage T1-4N0-1M0 squamous cell carcinoma were entered on a prospective single-arm study, of which 38 were eligible. Patients received 3 monthly cycles of 5-FU (1000 mg/m2/24 h x 5 days) and cisplatin (100 mg/m2 day 1; neoadjuvant segment) followed by 2 additional monthly cycles of 5-FU (1000 mg/m2/24 h x 5 days) and cisplatin (75 mg/m2 day 1) plus concurrent 6480 cGy (combined modality segment). The median follow-up in surviving patients was 59 months., Results: For the 38 eligible patients, the primary tumor response rate was 47% complete, 8% partial, and 3% stable disease. The first site of clinical failure was 39% local/regional and 24% distant. For the total patient group, there were 6 deaths during treatment, of which 9% (4/45) were treatment related. The median survival was 20 months. Actuarial survival at 3 years was 30%, and at 5 years, 20%., Conclusion: This intensive neoadjuvant approach does not appear to offer a benefit compared with conventional doses and techniques of combined modality therapy. However, high dose radiation (6480 cGy) appears to be tolerable, and is being tested further in Intergroup Trial INT 0123.

Purpose: Primary unresectable and locally advanced recurrent rectal cancer presents a significant clinical challenge. Local failure rates are high in both situations. Under such circumstances, there is a significant need to safely deliver tumoricidal doses of radiation in an attempt to improve local control. For this reason, we have incorporated a new approach utilizing high dose rate intraoperative radiation therapy (HDR-IORT)., Methods and Materials: Between 11/92-12/96, a total of 112 patients were explored, of which 68 patients were treated with HDR-IORT, and 66 are evaluable. The majority of the 44 patients were excluded for unresectable disease or for distant metastases which eluded preoperative imaging. There were 22 patients with primary unresectable disease, and 46 patients who presented with recurrent disease. The histology was adenocarcinoma in 64 patients, and squamous cell carcinoma in four patients. In general, the patients with primary unresectable disease received preoperative chemotherapy with 5-fluorouracil (5-FU) and leucovorin, and external beam irradiation to 4500-5040 cGy, followed by surgical resection and HDR-IORT (1000-2000 cGy). In general, the patients with recurrent disease were treated with surgical resection and HDR-IORT (1000-2000 cGy) alone. All surgical procedures were done in a dedicated operating room in the brachytherapy suite, so that HDR-IORT could be delivered using the Harrison-Anderson-Mick (HAM) applicator. The median follow-up is 17.5 months (1-48 mo)., Results: In primary cases, the actuarial 2-year local control is 81%. For patients with negative margins, the local control was 92% vs. 38% for those with positive margins (p = 0.002). The 2-year actuarial disease-free survival was 69%; 77% for patients with negative margins vs. 38% for patients with positive margins (p = 0.03). For patients with recurrent disease, the 2-year actuarial local control rate was 63%. For patients with negative margins, it was 82%, while it was 19% for those with positive margins (p = 0.02). The disease-free survival was 47% (71% for negative margins and 0% for positive margins) (p = 0.04). Prospective data gathering indicated that significant complications occurred in approximately 38% of patients and were multifactorial in nature, and manageable to complete recovery., Conclusion: HDR-IORT using our technique is versatile, safe, and effective. The local control rates for primary disease compare quite well with other published series, especially for patients with negative margins. For patients with recurrent disease, locoregional control and survival are especially encouraging in patients with negative resection margins. Further follow-up is needed to see whether these encouraging data will continue.

Background: To determine if preoperative radiation therapy allows sphincter preservation in the treatment of rectal cancer., Methods: Thirty six patients with the diagnosis of invasive, resectable, primary adenocarcinoma of the rectum limited to the pelvis were enrolled on a Phase I/II trial of preoperative radiation therapy plus low anterior resection/coloanal anastomosis. By preoperative assessment, all patients had invasive tumors (5,T2; 31,T3) involving the distal half of the rectum and clinically required an abdominoperineal resection. The median tumor size was 3.8 cm [range: 1.5-7 cm] and the median distance from the anal verge was 4 cm [range: 3-7 cm]. The whole pelvis received 46.80 Gy followed by a 3.60 Gy boost to the primary tumor bed. The median follow-up was 56 months [range: 4-121 months]., Results: Of the 35 patients who underwent resection, 5 (14%) had a complete pathologic response and 27 (77%) were able to successfully undergo a low anterior resection/coloanal anastomosis. The incidence of local failure was crude: 17% and 5-year actuarial: 21%. The 5-year actuarial survival was 64%. Analysis of sphincter function using a previously published scale was performed at the time of last follow-up in the 27 patients who underwent a low anterior resection/coloanal anastomosis. Function was good or excellent in 85%. The median number of bowel movements/day was 2 (range: 0-8)., Conclusions: Our data suggest that preoperative radiation therapy allows sphincter preservation in 77% of selected patients who would otherwise require an abdominoperineal resection, and 85% have good to excellent sphincter function. Given the moderate local failure rate, we now routinely use preoperative combined modality therapy plus postoperative chemotherapy for patients with clinical T3 disease.

Purpose: The Patterns of Care Rectal Cancer Committee was formed to develop consensus recommendations for patients with adenocarcinoma of the rectum limited to the pelvis., Methods and Materials: The Committee was composed of a multidisciplinary group of oncologists, and clinical scenarios were chosen to address most of the major treatment controversies in the combined modality treatment of rectal cancer. A literature search was then conducted and the major articles were identified. A modified Delphi technique was used to arrive at consensus. Serial surveys were conducted by distributing questionnaires to the Committee members to consolidate expert opinion. Voting was conducted using a scoring system and opinions were unified to the highest degree possible., Results: Consensus voting was performed for 4 clinical scenarios. Acceptability ratings for treatment were grouped into 3 broad categories: not acceptable, acceptable, and most acceptable. Based on the treatment options, a decision tree was developed that reflects the consensus of the committee., Conclusion: These options may help guide treatment decisions in rectal cancer.

Purpose: We report the local control and survival of two Phase I dose escalation trials of combined preoperative 5-fluorouracil (5-FU), low-dose leucovorin (LV), and radiation therapy followed by postoperative LV/5-FU for the treatment of patients with locally advanced and unresectable rectal cancer., Methods and Materials: A total of 36 patients (30 primary and 6 recurrent) received two monthly cycles of LV/5-FU (bolus daily x 5). Radiation therapy (50.40 Gy) began on day 1 in the 25 patients who received concurrent treatment and on day 8 in the 11 patients who received sequential treatment. Postoperatively, patients received a median of four monthly cycles of LV/5-FU., Results: The resectability rate with negative margins was 97%. The complete response rate was 11% pathologic and 14% clinical for a total of 25%. The 4-year actuarial disease-free survival was 67% and the overall survival was 76%. The crude local failure rate was 14% and the 4-year actuarial local failure rate was 30%. Crude local failure was lower in the four patients who had a pathologic complete response (0%) compared with those who either did not have a pathologic complete response (16%) or who had a clinical complete response (20%)., Conclusion: Our preliminary data with the low-dose LV regimen reveal encouraging downstaging, local control, and survival rates. Additional follow-up is needed to determine the 5-year results. The benefit of downstaging on local control is greatest in patients who achieve a pathologic complete response.

Purpose: To determine if preoperative radiation therapy allows sphincter preservation in the treatment of rectal cancer., Methods and Materials: Thirty patients with the diagnosis of invasive, resectable, primary adenocarcinoma of the rectum limited to the pelvis were enrolled on a Phase I/II trial of preoperative radiation therapy plus low anterior resection/coloanal anastomosis. By preoperative assessment, all patients had invasive tumors (2: T2 28:T3) involving the distal half of the rectum and required an abdominoperineal resection. The median tumor size was 4 cm (range: 1.5-6 cm) and the median distance from the anal verge was 4 cm (range: 3-7 cm). The whole pelvis received 46.8 Gy followed by a 3.60 Gy boost to the primary tumor bed. The median follow-up was 43 months (range: 6-82 months)., Results: Of the 29 patients who underwent resection, 3 (10%) had a complete pathologic response and 24 (83%) were able to successfully undergo a low anterior resection/colonanal anastomosis. The incidence of local failure was crude: 17% and 4-year actuarial: 23%. The 4-year actuarial survival was 75%. One patient developed a partial disruption of the anastomosis and two developed rectal stenosis. Analysis of sphincter function using a previously published scale was performed at the time of last follow-up in 22 of the 24 patients who underwent a low anterior resection/coloanal anastomosis. Function was good or excellent in 77%. The median number of bowel movements/day was two (range: 1-6)., Conclusions: This technique may be an alternative to an abdominoperineal resection in selected patients. Continued follow-up is needed to determine if this approach ultimately has similar local control and survival rates as an abdominoperineal resection.

Purpose: We performed a Phase I trial to determine the maximum tolerated dose of combined pre-operative radiation (5040 cGy) and 2 cycles (bolus daily x 5) of 5-FU and low dose LV (20 mg/m2), followed by surgery and 10 cycles of post-operative LV/5-FU in patients with unresectable primary or recurrent rectal cancer., Methods and Materials: Twelve patients were entered. The initial dose of 5-FU was 325 mg/m2. 5-FU was to be escalated while the LV remained constant at 20 mg/m2. Chemotherapy began on day 1 and radiation on day 8. The post-operative chemotherapy, was not dose escalated; 5-FU: 425 mg/m2 and LV: 20 mg/m2. The median follow-up was 14 months (7-16 months)., Results: Following pre-operative therapy, the resectability rate with negative margins was 91% and the pathologic complete response rate was 9%. For the combined modality segment (preoperative) the incidence of any grade 3+ toxicity was diarrhea: 17%, dysuria: 8%, mucositis: 8%, and erythema: 8%. The median nadir counts were WBC: 3.1, HGB: 8.8, and PLT: 153,000. The maximum tolerated dose of 5-FU for pre-operative combined LV/5-FU/RT was 325 mg/m2 with no escalation possible. Therefore, the recommended dose was less than 325 mg/m2., Conclusions: Since adequate doses of 5-FU to treat systemic disease could not be delivered until at least 3 months (cycle 3) following the start of therapy, we do not recommend that this 5-FU, low dose LV, and sequential radiation therapy regimen be used as presently designed. However, given the 91% resectability rate we remain encouraged with this approach.

Following surgery for Stages T3-4N0-2M0 primary and recurrent resectable rectal cancer limited to the pelvis, 25 patients have been entered on a Phase I trial of pelvic radiation therapy (RT) [5040 cGy] and 12 cycles of postoperative 5-FU and high dose Leucovorin (LV) chemotherapy. 5-FU was escalated 50 mg/m2 while the LV remained constant at 200 mg/m2. The initial doses of 5-FU were: combined-RT/chemotherapy = 200 mg/m2 and post-RT chemotherapy = 325 mg/m2. The median F/U was 25 months (range: 13-36). Two maximum tolerated doses (MTD's) have been determined, one for combined-RT/chemotherapy and one for post-RT chemotherapy. The MTD for combined-RT/chemotherapy was 250 mg/m2; therefore, the recommended dose of 5-FU is 200 mg/m2. The MTD for post-RT chemotherapy was 375 mg/m2; therefore, the recommended dose of 5-FU is 325 mg/m2. The dose limiting toxicities were diarrhea, tenesmus, frequent bowel movements, dysuria, and myelosuppression. For the nine patients who received 5-FU at the recommended dose level the median low counts were WBC 3.5 (2.2-4.0), HGB 10.3 (9.0-12.3), and PLT (x 1000) 167 (133-280), and the incidence of any grade greater than or equal to 3 toxicity was 22% diarrhea, 17% tenesmus, and 22% frequent bowel movements. The recommended dose of combined-RT/chemotherapy as used in this protocol was relatively well tolerated. However, optimal doses of 5-FU cannot be delivered until the fourth postoperative month. Therefore, despite the encouraging results reported with high dose LV in patients with advanced disease, we do not recommend that high dose LV be used with combined RT and 5-FU in the treatment regimen as presently designed.

A total of 22 patients with the diagnosis of invasive, resectable, primary adenocarcinoma of the rectum limited to the pelvis were enrolled on a Phase I/II trial of pre-operative radiation therapy+low anterior resection/coloanal anastomosis. By pre-operative assessment, all patients had invasive tumors involving the distal half of the rectum and required an abdominoperineal resection. The median tumor size was 4 cm (1.5-6 cm) and the median distance from the anal verge was 4 cm (3-7 cm). The whole pelvis received 4680 cGy followed by a 360 cGy boost to the primary tumor bed. The median follow-up was 29 months (10-60 months). Of the 21 patients who underwent resection, 10% had a complete pathologic response and 90% were able to successfully undergo a low anterior resection/coloanal anastomosis. The incidence of local failure as a component of failure was crude: 23% and 4-year actuarial: 32%. The 4-year actuarial survival was 61%. No patients experienced Grade 3 or 4 toxicity while receiving radiation therapy, and 6% developed a partial disruption of the anastomosis. Of the patients who underwent a low anterior resection/coloanal anastomosis, 89% had a good or excellent functional result. This technique may be an alternative to an abdominoperineal resection in selected patients. Further follow-up is needed in order to determine if this approach ultimately has similar local control and survival rates as an abdominoperineal resection.

The standard approach to patients with unresectable rectal cancer is pre-op radiation therapy followed by surgery. To determine the impact of RT on local failure and survival, we present an analysis of our preliminary results of this approach in patients with unresectable rectal cancer. A total of 22 patients were analyzed (9 primary, 13 recurrent). The median follow-up was 22 months. There were two groups of patients. Group 1 included 12 patients with unresectable tumors in whom surgery was planned following pre-operative radiation therapy. Group 2 included 10 patients in whom no surgery was planned following radiation therapy due to extensive pelvic bone destruction. The whole pelvis received 4680 cGy followed by a boost of 360-1440 cGy. Six underwent brachytherapy. For the total patient group, the 3-year actuarial survival was 52% (Group 1: 91% vs Group 2: 30%). Patterns of failure as a component of failure were: local failure (or local progression): 50%, abdominal: 23%, and distant: 9%. The dose of pelvic radiation had no significant impact on the local failure rate (5040 cGy: 55% vs greater than 5700 cGy:45%). None of the seven patients with negative margins developed local failure compared with 73% of those with positive margins. The complete resection rate in Group 1 patients was 58%, and all are alive without local failure. Further follow-up will be needed to determine the ultimate local failure and survival rates.

We describe the use of a prosthetic maneuver to displace bowel from an implant site. The patient presented with a recurrent low grade fibrosarcoma which was grossly excised with positive microscopic margins in the right paravertebral area. For this reason we performed an Iridium-192 implant using afterloading catheters. Because of several dense adhesions, it was not possible to mobilize an omental sling over the implant site. To prevent the small bowel from lying on the catheters, we inserted a prosthetic breast tissue expander. This was expanded with saline and bacitracin solution and placed in the tumor bed overlying the catheters, thereby displacing the small bowel away from the sources. A postoperative CT scan with gastrograffin demonstrated that this procedure was effective. There were no complications. We conclude that such devices are suitable for use under these circumstances and can achieve the objective of decreasing the dose of radiation to the small bowel.

From January 1985 to December 1988, 10 patients with local/regional extrahepatic biliary system cancer (gallbladder: 2, Klatskin: 4, common bile duct: 4) underwent combined modality therapy. Laparotomy and biopsy or subtotal resection were performed in six patients and endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiogram, and biliary drainage in four patients. Patients initially received 5000 cGy to the tumor bed and primary nodal area. Eight received an additional 1500 cGy boost to the tumor bed. Chemotherapy (5-FU/mitomycin-C) was delivered at the beginning of each radiation treatment course. Four patients received an additional 1-4 cycles of maintenance chemotherapy and six received a boost with brachytherapy. The mean survival was 32 months and the median survival was 16 months. Five patients are currently NED at 16, 17, 17, 48, and 52 months. The overall 3-year actuarial survival was 50%. The cumulative incidence of failure as a component of failure was local/regional: 50%, abdominal: 40%, and distant: 10%. Of the five patients who developed failure, all developed a component of local/regional failure. Our data show that this approach is feasible and offers similar results to those reported in the literature. However, further follow-up will be needed to determine if this combined modality approach offers improved local control and survival rates compared with surgery or biliary bypass/drainage alone.

To assess whether lymphatic vessel invasion (LVI) is an independent prognostic factor in colorectal cancer, we retrospectively reviewed the records of 462 patients who underwent potentially curative surgery for carcinoma of the colon and rectosigmoid/rectum (rs/rectum) at the New England Deaconess Hospital from 1965-1978. Sixty-one patients were identified as having tumors with lymphatic vessel invasion (LVI+), and they were compared with the remaining group of 401 patients who had tumors without lymphatic vessel invasion (LVI-). The incidence of lymphatic vessel invasion was significantly increased in tumors with blood vessel invasion (24% vs. 5%, p = 0.000001). Patients with LVI+ tumors also had a significantly increased incidence of positive nodes (59% vs. 25%, p = 0.0004), the average number of positive nodes (4.8 vs. 2.2, p = 0.0003), and a lower 5-year survival rate (colon: 57% vs. 84%, p = 0.0001; rs/rectum: 38% vs. 71%, p = 0.004). There was a significant (p less than or equal to 0.05) increase in local (16% vs. 7%), abdominal (33% vs. 9%), and distant (13% vs. 4%) failure as a component of component of failure in patients with LVI+ colon cancer and a significant increase in abdominal (33% vs. 11%) and distant (13% vs. 8%) failure as a component of failure in patients with LVI+ rectosigmoid/rectal cancer. Proportional hazards analysis demonstrated that lymphatic vessel invasion was an independent prognostic factor for survival.