Phase I/II study of neoadjuvant bevacizumab, erlotinib and 5-fluorouracil with concurrent external beam radiation therapy in locally advanced rectal cancer.

BACKGROUND: To determine the maximal tolerated dose of erlotinib when added to 5-fluorouracil (5-FU) chemoradiation and bevacizumab and safety and efficacy of this combination in patients with locally advanced rectal cancer. PATIENTS AND METHODS: Patients with Magnetic resonance imaging (MRI) or ultrasound defined T3 or T4 adenocarcinoma of the rectum and without evidence of metastatic disease were enrolled. Patients received infusional 5-FU 225 mg/M2/day continuously, along with bevacizumab 5 mg/kg days 14, 1, 15 and 29. Standard radiotherapy was administered to 50.4 Gy in 28 fractions. Erlotinib started at a dose of 50 mg orally daily and advanced by 50 mg increments in the subsequent cohort. Open total mesorectal excision was carried out 6-9 weeks following the completion of chemoradiation. RESULTS: Thirty-two patients received one of three dose levels of erlotinib. Erlotinib dose level of 100 mg was determined to be the maximally tolerated dose. Thirty-one patients underwent resection of the primary tumor, one refused resection. Twenty-seven patients completed study therapy, all of whom underwent resection. At least one grade 3-4 toxicity occurred in 46.9% of patients. Grade 3-4 diarrhea occurred in 18.8%. The pathologic complete response (pCR) for all patients completing study therapy was 33%. With a median follow-up of 2.9 years, there are no documented local recurrences. Disease-free survival at 3 years is 75.5% (confidence interval: 55.1-87.6%). CONCLUSIONS: Erlotinib added to infusional 5-FU, bevacizumab and radiation in patients with locally advanced rectal cancer is relatively well tolerated and associated with an encouraging pCR.

Proliferating cell nuclear antigen and mitotic activity in rectal cancer: predictor of response to preoperative irradiation.

PURPOSE: This study examines the association between the pathologic response of rectal cancer after irradiation and its pretreatment proliferative state as assayed by proliferating cell nuclear antigen (PCNA) and mitotic activity. PATIENTS AND METHODS: Ninety patients with clinical stage T3 and T4 rectal cancer received preoperative irradiation followed by surgery. Pretreatment tumor biopsies were scored for PCNA activity (number of tumor cells staining immunohistochemically with an anti-PCNA monoclonal antibody) and the number of mitoses per 10 high-powered fields (hpf). Postirradiation surgical specimens were examined for extent of residual disease. RESULTS: The tumors of 33 of 90 patients (37%) exhibited marked pathologic downstaging (no residual tumor or cancer confined to the rectal wall) after preoperative irradiation. Two features were independently associated with the likelihood of marked pathologic regression after preoperative irradiation: lesion size and PCNA/mitotic activity. When stratified by tumor size, marked tumor regression occurred most frequently in smaller tumors with high PCNA/mitotic activity compared with larger tumors with lower PCNA/mitotic activity. Intermediate downstaging rates were seen for small or large tumors with moderate PCNA/mitotic activity. CONCLUSION: Tumor PCNA/mitotic activity predicts the likelihood of response to irradiation, which may aid in formulating treatment policies for patients with rectal cancer.

Postoperative radiation therapy for high-risk colon carcinoma.

PURPOSE: This study examines the experience of patients treated with postoperative radiation therapy after resection of high-risk colon carcinoma in an effort to assess the potential role of this modality in combination with current systemic therapies. PATIENTS AND METHODS: From 1976 to 1989, 203 patients received postoperative radiation therapy with and without concurrent fluorouracil (5-FU) chemotherapy following resection of modified Astler-Coller B2, B3, C2, and C3 colon tumors. Of the 203 patients, 30 (15%) were identified as having residual local tumor after subtotal resection, whereas 173 (85%) had no known residual disease. The 173 patients treated with adjuvant radiation therapy were compared with a historical control group of 395 patients undergoing surgery only. RESULTS: Three groups of patients who appeared to benefit from postoperative radiation were identified. Improved local control and recurrence-free survival rates were seen for patients with stage B3 and C3 colon carcinoma treated with postoperative radiation therapy compared with a similarly staged group of patients undergoing surgery only. Irradiated patients whose tumors had an associated abscess or fistula formation had improved local control and recurrence-free survival rates compared with a similar group of patients undergoing surgery only. There appears to be a subset of patients with residual local disease after subtotal resection that may be salvaged by high-dose postoperative radiation therapy. CONCLUSION: Selected groups of patients with colon carcinoma may benefit from postoperative radiation in addition to current systemic therapies. Integration of 5-FU and levamisole with postoperative radiation therapy should be considered for patients with (1) stage B3 and C3 lesions, (2) tumors associated with abscess or fistula formation, and (3) residual local disease after subtotal resection.

Intraoperative electron beam radiation therapy for primary locally advanced rectal and rectosigmoid carcinoma.

To improve local control and survival in patients with primary locally advanced rectal and rectosigmoid carcinoma, intraoperative electron beam radiation therapy (IORT) has been used with a combination of moderate- to high-dose preoperative radiation therapy and surgical resection. Sixty-five patients underwent resection with the intention of using IORT if areas at high risk for local recurrence were apparent at surgery. For 20 patients undergoing complete resection with IORT, the 5-year actuarial local control and disease-free survival (DFS) was 88% and 53%, respectively. The results for 22 patients with pathologically documented residual carcinoma were less satisfactory with a 5-year actuarial local control and DFS of 60% and 32%, respectively. In this latter group, local control and DFS correlated with the extent of residual disease: patients with only microscopic disease had a 5-year actuarial local control and DFS of 69% and 47%, respectively, whereas for patients with macroscopic disease, these figures were 50% and 17%, respectively. For 18 patients undergoing complete resection without IORT or additional postoperative radiation therapy, the 5-year actuarial local control and DFS was 67% and 53%, respectively. Because local failure will occur in at least 30% of patients undergoing partial resection with or without IORT as well as patients undergoing complete resection of advanced tumors without IORT, additional postoperative radiation therapy should be considered.

Patterns of failure following local excision and local excision and postoperative radiation therapy for invasive rectal adenocarcinoma.

The clinical course of 40 patients undergoing conservative surgical excision and 26 patients undergoing local excision and postoperative radiation therapy of rectal carcinoma was reviewed. Surgical procedures were transanal excision (55 patients), Kraske procedure (ten patients), and fulguration (one patient). The five-year actuarial survival, disease-free survival, and local control of all 66 patients were 70%, 77%, and 63%, respectively. For patients undergoing local excision alone, the prognostic features of lesion size greater than 3 cm, poorly differentiated histology, invasion into muscularis propria or deeper, moderate to marked stromal fibrosis, vascular or lymph vessel invasion, fragmented resection, and positive resection margins were associated with a local failure rate of 20% or greater. Of the 26 patients receiving postoperative radiation therapy, four patients have developed local failure. For subgroups of patients with small rectal carcinomas confined to the mucosa, local excision may be a reasonable alternative to abdominoperineal resection. For tumors with deeper invasion but limited to the bowel wall, local excision plus pelvic irradiation can be offered to preserve anorectal function.

Tumor proliferation in rectal cancer following preoperative irradiation.

PURPOSE: This study examines the effect of preoperative irradiation on tumor proliferation in rectal cancer. PATIENTS AND METHODS: One hundred twenty-two patients with locally advanced rectal cancer received 45 to 50 Gy of preoperative irradiation followed by surgery. Pretreatment tumor biopsies and postirradiation surgical specimens were scored for proliferative activity by assaying the extent of Ki-67 and proliferating-cell nuclear antigen (PCNA) immunostaining and the number of mitoses per 10 high-power fields (hpf). Preirradiation and postirradiation proliferative activity was determined and correlated to clinical outcome. RESULTS: There was an overall reduction in the tumor proliferative activity of rectal cancer after irradiation compared with its preirradiation state. Decreases in the activity of all three markers of tumor proliferation (Ki-67 and PCNA immunostaining, and mitotic counts) were observed in irradiated tumors compared with pretreatment biopsies. Postirradiation tumor proliferative activity was associated with pathologic tumor stage. A high level of proliferative activity was observed in tumors downstaged to the rectal wall (T1-2) compared with tumors that retained transmural penetration (T3-4). Multivariate analysis indicated that postirradiation proliferative activity and stage were independently associated with survival following surgery. Patients with tumors that exhibited elevated proliferative activity postirradiation had improved survival compared with patients with tumors that showed less proliferative activity. CONCLUSION: Moderate- to high-dose preoperative irradiation decreases both the tumor size and proliferative activity of rectal cancers. Elevated postirradiation tumor proliferative activity correlates strongly with improved survival. This may aid in identifying high-risk patients following preoperative irradiation and surgery.

Rectal cancer: the influence of tumor proliferation on response to preoperative irradiation.

PURPOSE: Regression of rectal carcinoma after preoperative irradiation is variable, likely reflecting differences in the physical and biologic properties of these tumors. This study examines the association between the pathologic response of rectal cancer after irradiation and its pretreatment proliferative state as assayed by the activity of the proliferative dependent antigens (Ki-67, PCNA) and mitotic counts. METHODS AND MATERIALS: One hundred and twenty-two patients with locally advanced rectal cancer received preoperative irradiation followed by surgery. Pretreatment tumor biopsies were scored for the extent of Ki-67 and PCNA immunostaining and the number of mitoses per 10 high-powered fields. Postirradiation surgical specimens were examined for extent of residual disease. RESULTS: The tumors of 38 of 122 patients (31%) exhibited marked pathologic downstaging (no residual tumor or cancer confined to the rectal wall) after preoperative irradiation. Two features were associated with the likelihood of marked pathologic regression after preoperative irradiation: tumor proliferative activity and lesion size. When stratified by lesion size, marked tumor regression occurred most frequently in smaller tumors with high Ki-67, PCNA, and mitotic activity compared to larger tumors with lower Ki-67, PCNA, and mitotic activity. Intermediate downstaging rates were seen for small or large tumors with moderate Ki-67, PCNA, and mitotic activity. CONCLUSION: Tumor Ki-67, PCNA, and mitotic activity predicts the likelihood of response to irradiation, which may aid in formulating treatment policies for patients with rectal cancer.

Preoperative irradiation for tethered rectal carcinoma.

Twenty-eight patients with resectable but tethered rectal carcinomas were treated with preoperative irradiation (EBRT) and surgical resection. The 5-year actuarial disease-free survival and local control rates of these 28 patients were 66 and 76%, respectively. Two patients have developed local failure only, 2 patients concurrent local failures and distant metastases, and 4 patients distant metastases only. All local failures occurred in areas of tumor adherence to unresectable structures (sacrum, pelvic side wall). Patients with tethered rectal tumors are at risk for local failure despite preoperative irradiation and surgical resection. To improve local control in this subset of patients, an intraoperative radiation therapy (IORT) boost is given to areas of tumor adherence at resection following EBRT.

Intraoperative radiation therapy for locally advanced recurrent rectal or rectosigmoid cancer.

BACKGROUND AND PURPOSE: To update and summarize the experience at the Massachusetts General Hospital of a treatment program of high-dose preoperative irradiation, surgical re-resection, and intraoperative radiation therapy (IORT) as a salvage treatment for patients with recurrent rectal or rectosigmoid carcinoma. PATIENTS AND METHODS: From June 1978 to February 1997, the records of 69 patients with locally recurrent rectal carcinomas or rectosigmoid carcinomas without metastases referred for consideration of IORT were reviewed. Forty-nine patients received IORT and local control and disease-free survival curves were calculated using the actuarial method of Kaplan-Meier. RESULTS: The 5-year overall survival, local control and disease-free survival rates of 49 patients receiving IORT were 27, 35, and 20%, respectively. Thirty-four patients who underwent a macroscopic complete resection had a significantly better 5-year overall survival than the remaining 15 patients with gross residual disease (33 vs. 13%, P=0.05, log rank). For those patients, local control and disease-free survival rates were 46 and 27%, respectively. Patients with a microscopic complete resection had a superior 5-year overall survival than partially resected patients (40 vs. 14%, P=0.0001, log rank). Chemotherapy had no significant influence on overall or disease-free survival. CONCLUSION: The current analysis shows the importance of a microscopic complete resection in a multi-modality approach with IORT for survival and local control. Salvage is rare for patients undergoing subtotal resection.

Predominant role of bile in modulation of early postresectional enteric hyperplasia.

Pancreaticobiliary secretions modulate compensatory hyperplasia after proximal small-bowel resection. To investigate the individual contributions of bile and pancreatic juice, levels of nucleic acids in ileal mucosa of the rat were examined 48 hours after performance of jejunectomy with selective exclusion of bile or pancreatic juice. Exclusion of bile alone inhibited the postresectional increase in levels of RNA and DNA. Exclusion of pancreatic juice (but provision of bile) did not inhibit a rise in ileal RNA or DNA levels after jejunectomy. Presence of bile seems to be one of the major elements in the early stages of adaptive hyperplasia of the ileum.

Idiopathic intermittent gastroparesis and its surgical alleviation.

Five otherwise healthy young adults with a syndrome of recurrent intermittent gastric atony have been described. Symptomatic periods characterized by severe nausea, early satiety, and abdominal bloating alternated with asymptomatic intervals. During symptomatic phases upper gastrointestinal barium contrast radiographs demonstrated gastric dilatation with atony but without obstruction. At other times, the symptoms would disappear, and gastric size, motility, and emptying would appear normal. Upper gastrointestinal endoscopy confirmed gastric atony and showed no mucosal abnormalities or gastric outlet obstruction. No pathogenic factors were detected, and the gastroparesis was unassociated with any motility disorder of the esophagus, small bowel, or colon. Thus, it differed from other recognized forms of visceral pseudoobstruction. Because of failed medical treatment, four patients were treated with antrectomy, gastrojejunostomy, and truncal vagotomy to allow passive emptying of the stomach by gravity. All four surgically treated patients improved greatly. Idiopathic intermittent gastroparesis is a distinct clinical syndrome that can be successfully treated by surgical means in severe cases.

Indications for adjuvant radiotherapy in extrapelvic colonic carcinoma.

Although the value of postoperative radiotherapy has been demonstrated for subsets of patients with rectal carcinoma, the efficacy of postoperative radiation therapy for colonic carcinoma (above the peritoneal reflection) is much less clear. Recent studies examining the failure patterns of colonic carcinoma following resection indicate that local failure increases as a function of bowel mobility, disease extension through bowel wall, and lymph node involvement. Retrospective series reporting the results of postoperative irradiation suggest that postoperative radiation therapy to the tumor bed may be beneficial for patients with Stage B3, C2 and C3 disease with limited nodal involvement. Randomized prospective trials are required to further evaluate the efficacy of such adjuvant radiotherapy.

Adjuvant postoperative radiation therapy for rectal adenocarcinoma.

From October 1975 to August 1988, 261 patients at high risk for local recurrence after curative resection of rectal carcinoma underwent high-dose postoperative irradiation. Patients received 45 Gy by a 4-field box usually followed by a boost to 50.4 Gy or higher when small bowel could be excluded from the reduced field. Since January 1986, patients also received 5-fluorouracil (5-FU) for 3 consecutive days during the first and last week of radiotherapy. Five-year actuarial local control and disease-free survival decreased with increasing stage of disease; patients with Stage B2 and B3 disease had local control rates of 83% and 87% and disease-free survivals of 55% and 74%, respectively. In patients with Stage C1 through C3 tumors, local control rates ranged from 76% to 23%, and disease-free survivals ranged from 62% to 10%, respectively. For patients with Stage C disease, disease-free survival decreased progressively with increasing lymph node involvement, but local control was independent of the extent of lymph node involvement. For each stage of disease, local control and disease-free survival did not correlate with the dose of pelvic irradiation. Preliminary data from this study suggest a trend toward improved local control for patients with Stage B2, C1, and C2 tumors who receive 5-FU for 3 consecutive days during the first and last weeks of irradiation compared with patients who do not receive 5-FU. Current prospective randomized studies are addressing questions regarding the optimum administration of chemotherapy with pelvic irradiation for patients following resection of rectal carcinoma.

Complications of abdominal stoma surgery.

PURPOSE: This study was undertaken to review and summarize the complications of ileostomy and colostomy creation and subsequent closure. METHODS: The English-language medical literature for at least the past 15 years was reviewed comprehensively. RESULTS: Complications of surgery for the creation of end, loop, and "end loop" stomas are presented. Technical factors, which might influence complication rates, are discussed. Optimal management of ostomy complications is presented, especially for peristomal hernias. Similarly, techniques and complications for stoma closure are analyzed. CONCLUSIONS: Stoma creation is not a trivial undertaking; careful surgical technique minimizes complications (which are relatively frequent), and promotes good ostomy function. Peristomal hernias are difficult to cure permanently. The morbidity of ileostomy and colostomy closure is also appreciable.

A support brace for the endoscope.

The availability of an endoscopic support brace for use during gastrointestinal endoscopy is described.

Tube gastrostomy. Techniques and complications.

For prolonged gastrointestinal decompression or enteral nutrition, gastrostomies are preferable to nasogastric tubes. To assess the safety of tube gastrostomy, the authors reviewed 424 gastrostomies systematically selected from a total of 3,359 done from 1975 through 1980. Feeding gastrostomies composed 22% of the total; the remaining 78% were done for decompression. Complications were rare (6.6% major, 6.6% minor) and were not influenced by patients' age. Perioperative steroid therapy promoted laparotomy wound infections. External and internal leakage of stomach contents, as well as bleeding from the gastrostomy site, were independent of the method of gastrostomy and the type of catheter used. Feeding gastrostomies were more likely to leak internally than were decompression gastrostomies. Unless the gastrostomy site was sutured to the anterior abdominal wall, there was a 7% incidence of extravasation of stomach contents into the peritoneal cavity after removal of the tube. The low complication rate justifies use of gastrostomies as an alternative to prolonged nasogastric intubation. Problems are minimized by employing the Stamm technique with a straight catheter and anterior gastropexy.

Surgery for radiation injury to the large intestine. Variables influencing outcome.

PURPOSE: Surgery for colorectal radiation injury is technically difficult and often followed by complications. This study evaluates factors affecting outcome. METHODS: A retrospective 30-year review was carried out. Preoperative characteristics and operative variables were correlated with morbidity, mortality, and success in providing symptomatic relief. RESULTS: A total of 60 cases and 75 colon and rectal lesions were analyzed. After surgery, the morbidity rate was 65 percent, and the mortality was 6.7 percent. A successful outcome in providing symptomatic relief was achieved in 71.7 percent of cases. When comparing success after operations for the different lesions (stricture, 78.1 percent; hemorrhage, 64.3 percent; perforation, 100 percent; and fistula, 54.5 percent), the presence of a fistula was associated with symptomatic relief significantly less often than the remainder (P = 0.03). The type of operation had no effect on success rate: 72 percent for diversion, 66.7 percent for resection, and 83.3 percent for bypass. Morbidity and mortality rates were not significantly influenced by site of lesions, type of lesions, or choice of surgical operation. A permanent stoma was necessary in 70 percent of patients. CONCLUSIONS: The morbidity for surgical treatment of large bowel radiation injury is substantial, and largely unrelated to the type and location of the radiation lesion, as well as the type of operation. Success rates are reasonably high, but worst after fistula repair. The selection of therapy (medical, endoscopic, surgical) for radiation-induced colorectal lesions must take into account numerous factors and be highly individualized.

Treatment of recurrent colonic pseudo-obstruction by endoscopic placement of a fenestrated overtube. Report of a case.

The case of a 73-year-old man who developed acute colonic pseudo-obstruction (Ogilvie's syndrome) following chemotherapy for lymphoma is reported. Cecal dilatation resolved after a single colonoscopic decompression. Following his next course of chemotherapy, colonic dilatation again developed. The recurrence was treated successfully by introducing a fenestrated colonoscopic overtube transanally for continuous decompression. The literature concerning acute, colonic pseudo-obstruction is reviewed. The colonoscopic overtube is a convenient and effective treatment for recurrent colonic distention.

The freckle sign--an endoscopic feature of the cecum.

Mucosal spots, or "freckles," surrounding the appendiceal orifice are an endoscopic feature of the cecum. These are clusters of 1 to 2 mm round or oval slightly raised spots, each with a pale center and an erythematous border. They correlate microscopically with subepithelial and submucosal lymphoid follicles. The freckling pattern, identified in about one third of colonoscopies, was seen best with the videoendoscope and was identified more commonly in patients with systemic illness. Recognition of mucosal freckling around the appendiceal orifice helps identify the cecum and may be useful in the evaluation of cecal and appendiceal pathology.