DNA/RNA content and proliferative fractions of colorectal carcinomas: a five-year prospective study relating flow cytometry to survival.

In our prospective study, flow cytometric analysis of cellular DNA and RNA content was performed on unfixed fresh specimens of colorectal adenocarcinoma taken from 176 patients. Of the 176 tumors, 113 (64%) were aneuploid. There was no correlation between aneuploidy and tumor stage, grade, location, or size. After a median follow-up of 5.6 years, no correlation between DNA or RNA content and patient survival was found. DNA content alone was not an independent prognostic factor when the colorectal carcinomas were segregated by curable and incurable stages. However, normal mucosa, diploid tumors, and aneuploid tumors showed progressively higher proliferation and higher RNA and DNA indices. Proliferative fraction--defined as the percentage of cells in S + G2 and M phases of the cell cycle--was significantly related to ploidy and to Dukes' stage. Despite these correlations, we did not detect a significant influence of proliferative fraction on survival when patients were segregated above or below the mean proliferative fraction for all tumors. More accurate methods of identifying the proliferative fraction of tumor cells are currently being pursued. While the role of flow cytometry in the evaluation and management of patients with colorectal carcinoma is still undefined for a number of other cellular parameters, it seems unlikely that DNA index, RNA index, or the proliferative fractions calculated from the DNA histogram, will, of themselves, represent independent prognostic factors.

Reduced capacity for DNA repair synthesis in patients with or genetically predisposed to colorectal cancer.

Peripheral resting mononuclear leukocytes were compared for their capacities to repair DNA lesions induced by a 1-hour exposure to a standardized 10-microM dose of N-acetoxy-N-2-fluorenylacetamide (N-AcO-2-FAA). Leukocytes from the following 3 groups were studied: 39 control subjects, 40 patients after colonic resection because of colorectal cancer (disease-free at the time of this study), and 28 individuals with a hereditary predisposition to colorectal cancer. Although the level of N-AcO-2-FAA that bound to mononuclear leukocyte DNA was the same for the various population groups, the level of N-AcO-2-FAA-induced unscheduled DNA synthesis (UDS) was significantly reduced in the mononuclear leukocytes of individuals who had had colorectal cancer or a genetic predisposition for the disease. These findings indicate that a deficiency in mononuclear leukocyte DNA repair synthesis is associated with the development of colorectal cancer in these populations. Our observation of this nonspecific UDS deficiency (relating to colorectal cancer) was not explained by experimental variations among the sampled groups with regard to individual differences in lymphocyte heterogeneity, age, sex, smoking habits, or blood pressure.

Combined modality therapy of rectal cancer: decreased acute toxicity with the preoperative approach.

PURPOSE: We compared the combined radiation therapy (RT) plus chemotherapy segments of two separate parallel phase I trials to determine if combined pelvic RT, fluorouracil (5-FU), and high-dose leucovorin (LV) had less acute toxicity when delivered preoperatively versus postoperatively in patients with rectal cancer. PATIENTS AND METHODS: Patients with unresectable disease received preoperative RT plus LV and 5-FU followed by surgery and postoperative LV and 5-FU. Patients with resectable disease received identical doses, techniques, and schedules of RT and LV and 5-FU except all therapy was delivered postoperatively. On day 1, patients received LV and 5-FU times one cycle. RT began on day 8. A second cycle of LV and 5-FU was given concurrently with the fourth week of RT. RESULTS: Although more patients (75% v 32%; P = .02) received the higher dose level of 5-FU (250 mg/m2), significantly fewer experienced acute grade 3 to 4 toxicity with preoperative versus postoperative therapy (13% v 48%; P = .045). There was no grade 3 to 4 myelosuppression in either group. The two grade 3 toxicities in the preoperative group were gastrointestinal. The grade 3 toxicities in the postoperative group included seven gastrointestinal and two genitourinary; four patients had a grade 4 toxicity. CONCLUSION: Given the high incidence of grade 3 to 4 toxicity also reported in the postoperative combined modality adjuvant randomized trials, future adjuvant trials should explore the preoperative approach.

Enhancement of radiation-induced downstaging of rectal cancer by fluorouracil and high-dose leucovorin chemotherapy.

PURPOSE: To determine if fluorouracil (5-FU) plus high-dose leucovorin (LV) enhances local response in patients receiving preoperative radiation therapy (RT) for adenocarcinoma of the rectum, we compared the degree of downstaging in patients receiving preoperative RT with or without chemotherapy. PATIENTS AND METHODS: For this comparison, three groups of patients who were treated with identical doses and techniques of preoperative pelvic RT (total dose of 5,040 cGy) were examined. Group 1 included 20 patients with unresectable disease who received combined RT and LV/5-FU. Group 2 included 11 patients with unresectable disease who received preoperative RT. Group 3 included 21 patients with invasive, resectable, primary disease who received preoperative RT. RESULTS: Patients with unresectable disease who received LV/5-FU had a higher rate of pathologic complete response (20% v 0%) and a lower incidence of positive nodes (30% v 64%) compared with those who did not receive chemotherapy. Even when the most favorable group of patients was included (group 3), patients who received LV/5-FU still had a higher complete response rate (20% v 6%) and a lower incidence of positive nodes (30% v 53%) compared with those who received RT without LV/5-FU. Of those patients with initially unresectable disease, the resectability rate was higher in those who received LV/5-FU compared with those who did not receive LV/5-FU (90% v 64%). Patients who received LV/5-FU experienced slightly more grade 1 to 2 fatigue, stomatitis, nausea, and grade 3 diarrhea, tenesmus, and dysuria. CONCLUSIONS: Despite the fact that patients who received chemotherapy (group 1) had more advanced disease compared with those with resectable disease (group 3), the addition of LV/5-FU increased the resectability and downstaging rates. The ultimate impact of a complete response as well as a decrease in the incidence of pelvic nodes on local control and survival remains to be determined. However, given the enhancement of down-staging in patients with unresectable rectal cancer, we are encouraged by the combined modality approach.

Liver resection for colorectal metastases.

PURPOSE: More than 50,000 patients in the United States will present each year with liver metastases from colorectal cancers. The current study was performed to determine if liver resection for colorectal metastases is safe and effective and to evaluate predictors of outcome. MATERIALS AND METHODS: Data for 456 consecutive resections performed between July 1985 and December 1991 in a tertiary referral center were analyzed. RESULTS: The perioperative mortality rate was 2.8%, with a mortality rate of 4.6% for resections that involved a lobectomy or more. The median hospital stay was 12 days and only 9% of patients were admitted to the intensive care unit. The 5-year survival rate is 38%, with a median survival duration of 46 months. By univariate analysis, nodal status of the primary lesion, short disease-free interval before detection of liver metastases, carcinoembryonic antigen (CEA) level greater than 200 ng/mL, multiple liver tumors, extrahepatic disease, large tumors, or positive resection margin was predictive of poorer outcome. Sex, age greater than 70 years, site of primary tumor, or perioperative transfusion was not predictive of outcome. By multivariate analysis, positive margin, size greater than 10 cm, disease-free interval less than 12 months, multiple tumors, and extrahepatic disease were independent predictors of poorer outcome. Short disease-free interval or multiple tumors were nevertheless associated with a 5-year survival rate greater than 24%. CONCLUSION: Liver resection for colorectal metastases is safe and effective therapy and currently represents the only potentially curative therapy for metastatic colorectal cancer. The only absolute contraindication to resection is extrahepatic disease. A randomized trial to examine efficacy of surgical resection cannot ethically be performed. Liver resection should be considered standard therapy for all fit patients with colorectal metastases isolated to the liver.

Phase I/II trial of pre-operative radiation therapy and coloanal anastomosis in distal invasive resectable rectal cancer.

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.

Sphincter preservation with preoperative radiation therapy and coloanal anastomosis.

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.

Local control with pre-operative radiotherapy alone versus "sandwich" radiotherapy for rectal carcinoma.

Forty-nine patients with primary adenocarcinoma of the rectum, clinically localized to the pelvis were treated with pre-op radiotherapy (RT) 1500 cGy/5 fx with AP/PA fields, followed by immediate curative resection. Patients staged as Astler-Coller B2, C1, or C2 were considered for post-op RT, 4140 cGy/23 fxs with a 4-field technique. There were 47 evaluable patients in this non-randomized study. Two groups of patients were analyzed, namely pre-op RT only (24 patients) and combined pre- and post-op ("sandwich") RT (23 patients). Two patients with pre-op RT only were considered inevaluable for recurrence because they died NED at 1 and 7 mo. All patients have been followed for greater than 1 year; 77% have been followed for greater than 2 yr. There has been only one local recurrence (LR), surprisingly in a Stage A pre-op RT patient who had no residual tumor in the final operative specimen. In the pre-op group which included 10 B2s, and 1 C2, 1500 cGy in 5 days (equivalent to 1940 cGy by the NSD formulation) was associated with no local recurrence. No distant metastases (DM) have developed in this group. In the "sandwich" RT group, which included 3 B2s, 1 C1, 17 C2s, and 1 D (localized to the pelvis, i.e. ovary), there were no LRs and 7 DMs (1 B2 and 6 C2s). Actuarial survival is 92% in the pre-op RT group at 2 and 3 yr, and 82% in the "sandwich" group at 2 and 3 yr. There have been no serious early or late complications related to RT in our pre-op group. The use of 1500 cGy in 5 days as pre-op RT with immediate surgery may prove, upon longer follow-up, to be sufficient for increasing local control, with minimum morbidity, in patients with B2 disease. Patients with C2 disease are being controlled locally with the "sandwich" regimen, but it is not clear whether pre-op RT alone may be adequate in this group as well. We are now addressing this question in a randomized study.

Radiation therapy for unresectable rectal cancer.

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.

Remote afterloading intraluminal brachytherapy in the treatment of rectal, rectosigmoid, and anal cancer: a feasibility study.

From 1981 to 1986, 28 patients (27 evaluable) were treated with intraluminal brachytherapy (ILBT) using a remote afterloading technique for persistent or recurrent anal, rectal and rectosigmoid cancers. Eighty-nine percent underwent previous surgery for colorectal cancer. Seventy-seven percent of the patients received external beam irradiation (ERT) as a part of the present treatment. Intraluminal brachytherapy was given with a 2 cm diameter cylinder and the dose per fraction ranged from 440 cGy to 840 cGy at 0.5 cm from the surface of the cylinder. Follow-up ranged from 1 to 74 months with a median of 12 months. Patients were divided into two groups. Group I consisted of 15 patients receiving elective ILBT; Group II: 13 patients with recurrent disease. Seventy-one percent of the patients in Group I and 39% of the patients in Group II achieved local control. The majority of patients tolerated treatment well with only transient reactions. However, three patients (11%) developed grade 3 (G3) complications requiring surgical intervention. Eight patients developed moderate complications--grade 2 (G2)--requiring only conservative treatment. This study has identified several factors which appear to influence the risk of developing complications with this combined treatment, using remote afterloading apparatus, among which are technique of previous external beam irradiation, treatment length, anatomical location, intraluminal brachytherapy fractionation, and total cumulative dose (ERT + ILBT). This experience suggests that intraluminal brachytherapy appears to be an acceptable form of treatment, as a boost to external beam radiation therapy, in the management of rectal and colorectal cancers.

Phase I trial of postoperative 5-FU, radiation therapy, and high dose leucovorin for resectable rectal cancer.

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.

High dose rate intraoperative radiation therapy (HDR-IORT) as part of the management strategy for locally advanced primary and recurrent rectal cancer.

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.

Pre-operative combined 5-FU, low dose leucovorin, and sequential radiation therapy for unresectable rectal cancer.

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.

Preoperative 5-FU, low-dose leucovorin, and radiation therapy for locally advanced and unresectable 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.

Tritiated-thymidine labeling of rectal epithelial cells in 'non-prep' biopsies of individuals at increased risk for colonic neoplasia.

Recent measurements have shown increased proliferation of colonic epithelial cells in individuals at heightened risk for cancer of the large intestine. This biomarker has facilitated measurements of the effects of nutritional intervention in studies that are attempting to inhibit tumor development in high-risk individuals. In this study, further measurements were made of the proliferation of rectal epithelial cells, when biopsies were removed from mucosa that had not previously been disturbed by any tapwater or other enema preparations. Progressive increases were found in the numbers of [3H]dThd-labeled epithelial cells in rectal crypts, and in labeling index profiles, in patients having previous sporadic adenomas or colon cancer, compared to individuals who had not developed colonic neoplasms. The most quiescent proliferative equilibrium was found in individuals without previous colonic disease. Findings indicated that 'non-prep' rectal biopsies obtained from the most accessible region of the large intestine, show modifications in the biomarker of cell proliferation paralleling colon cancer risk.

Intraoperative brachytherapy alone for incomplete resected recurrent rectal cancer.

In order to determine the impact of intraoperative brachytherapy alone in patients with recurrent rectal cancer who, due to prior pelvic radiation therapy, were ineligible to receive further external beam pelvic radiation, we retrospectively reviewed the records of 36 patients with recurrent rectal cancer who had gross residual disease remaining in the pelvis following biopsy alone or subtotal resection. The median follow-up was 24 months (6-81 months). The median survival was 27 months and the 4 year actuarial survival was 25%. There was a suggestion of lower survival in patients who underwent biopsy alone compared with those who underwent a subtotal resection (21% vs. 34%). The local failure (LF) rate was 22% as the only site of failure and 44% as a component of failure. There was a lower but non-significant LF rate in patients who underwent subtotal resection vs. biopsy alone (33% vs. 66%) and those with an 125I implant volume of less than 40 cm3 vs. greater than or equal to 40 cm3 (39% vs. 100%). Four patients (11%) developed treatment-related severe complications (without evidence of LF). Our data suggest that, although it is not clear that intraoperative brachytherapy impacts on the ultimate survival rate in this group of patients, it does offer reasonable local control with acceptable morbidity. Since local control, in and of itself is an important endpoint in the treatment of rectal cancer, we continue to recommend brachytherapy as part of an overall aggressive approach in patients who are unable to receive pelvic radiation therapy.

The definitive value of active-specific immunotherapy for experimental carcinoma of the colon.

Active-specific immunotherapy with concanavalin A or with neuraminidase-modified syngeneic tumor cells has been studied in an experimental model of colon cancer. Systemic immunotherapy with concanavalin A-modified tumor cells or with neuraminidase-modified tumor cells has resulted in up to 70 percent cure of rats receiving a lethal inoculum of tumor in a model tumor system which otherwise proved 80 percent lethal to untreated hosts. The possible mechanisms whereby neuraminidase or concanavalin A are effective cell-surface modifiers for active-specific immunotherapy are discussed. In vitro studies suggest markedly heightened antigenic recognition following immunization with concanvalin A-modified syngeneic tumor cells. These studies represent the first apparent evidence for the definitive value of systemic active-specific immunotherapy for the adjuvant treatment of large bowel cancer.

Potency, cure, and local control in the operative treatment of rectal cancer.

Impotence due to parasympathetic nerve injury is one of the most feared consequences of operations for treatment of rectal cancer. Sharp dissection along the parietal pelvic fascia where the parasympathetic nerves are located significantly reduces the incidence of pelvic failure. Autonomic nerve-preserving pelvic sidewall dissections, which combined the benefits of en bloc parietal pelvic dissection with nerve preservation, were performed in 42 men who were undergoing sphincter-preserving operations for treatment of rectal cancer. Thirty-three (86.7%) of the 38 evaluable patients have remained potent, and 29 (87.9%) of the 33 patients have normal ejaculation. Deliberate sacrifice of the inferior hypogastric plexus caused only minor sexual dysfunction. Cancer recurred locally in only one patient (with stage D cancer). Autonomic nerve-preserving pelvic sidewall dissection combines the benefits of curative resection and local control with reduced morbidity, and it preserves potency.

Late ovarian metastases in carcinoma of the colon and rectum.

We reviewed 63 patients with metachronous ovarian metastases from colorectal carcinoma to determine the natural history of this problem, and whether aggressive surgical treatment is beneficial. Ovarian metastases usually occurred in younger patients (mean age, 51 years) and in 55.5% of the patients, the metastases were part of diffuse intra-abdominal disease. The mean survival rate for all patients following surgery was 16.6 months. The survival rate did not correlate with menstrual status, interval to recurrence, or Dukes' stage of the original cancer. Ability to remove all gross disease at the time of oophorectomy was the major determinant of survival. Surviving patients who were rendered disease free surgically (n = 15) lived a mean of 48 months compared with 9.6 months for patients with localized, but unresectable disease (n = 9), and eight months for patients with diffuse disease (n = 35). Surgical attempts to remove all gross disease seem to result in significantly improved survival rates even though a cure is rare. Bilateral oophorectomy is warranted as part of the palliative treatment of women who are seen with stage D cancers to prevent the development of large symptomatic metastases that require further therapy.

Improved survival in epidermoid carcinoma of the anus in association with preoperative multidisciplinary therapy.

From 1972 to 1983, we treated 78 patients who had primary epidermoid carcinoma of the anus. Forty-four of these patients were treated by protocol, while 34 patients were not treated according to protocol. Protocol consisted of fluorouracil (750 mg/m for 5 days) and mitomycin (10 to 15 mg/m on day 1), followed sequentially by 3000 rad (30 Gy) over three weeks, followed by surgery. There were 20 local excisions and 29 abdominoperineal resections in the protocol group, and 11 local excisions and 14 abdominoperineal resections in the nonprotocol group. In the protocol group, 26 patients (59%) had no residual cancer in their operative specimens, while only ten (29.9%) of the nonprotocol patients had no remaining cancer. Four (11.7%) of the 34 nonprotocol patients had pathologically positive inguinal nodes, compared with only three (4.5%) of 44 protocol patients. Thirty-four (77%) of 44 protocol patients remained free of disease, while ten patients experienced local or pelvic recurrence. In contrast, only 17 (50%) of 34 patients in the nonprotocol group remained free of disease. Of 17 recurrences, five were at distant sites. The status at this writing of all patients in the protocol group was 32 (75%), with no evidence of disease, four alive with disease, and eight dead of or with disease. Of the untreated patients, only 11 (32%) remained without evidence of disease, two were alive with disease, and 19 were dead of or with disease. Smaller carcinoma size (less than 5 cm, 27 of 32 had no evidence of disease), younger age, female gender, and deep infiltration also predicted a statistically significant survival advantage after protocol treatment. Controlled, prospective, multi-institutional trials should stratify for these factors when comparing new treatment modalities.