Norman D. Nigro

An evaluation of combined therapy for squamous cell cancer of the anal canal

Carcinoma of the anal canal develops in the area of the dentate line and is referred to as cloacogenic, transitional, basaloid, epidermoid, and squamous cell cancer. For years, the accepted treatment for these lesions has been abdominoperineal resection. The use of preoperative radiation and chemotherapy was begun by our group in 1972. By 1975, it became apparent that radiation and chemotherapy alone appeared effective enough so that radical operation was not done routinely. An evaluation of the results in 104 patients, 44 of whom were treated by us (the rest of the data was collected by questionnaire), suggests that radiation and chemotherapy alone are at least as effective as radical surgery in most patients with this disease.

Combined therapy for cancer of the anal canal

Nineteen patients with squamous-cell cancer of the anal canal have been treated with combined chemotherapy and radiation therapy, followed by appropriate surgery. The authors are convinced that the combined therapy is effective enough to avoid abdominoperineal resection if disappearance of the lesion is proven by adequate examination and biopsy. Although they believe cancers 5 cm or less in maximum diameter are generally adequately managed in this manner, experience is still too limited to justify, a recommendation, to change currently accepted management.

The effect of bile on the induction of experimental intestinal tumors in rats

THERE IS a STRONG EPIDEMIOLOGIC evidence that a dietary factor plays an impor tant role in the etiology of cancer of the colon.1 One of the food elements that is suspected is animal fat. A currently popula r theory is that a high level of dietary fat results in increased quantities of bile salts in the gut. There is an associated change in the bacterial flora of the colon which acts on these biliary compounds, and possibly with other dements in the gut, to form carcinogenic agents that act on intestinal epithelium.2 I t has recently been shown that increased bile acid secretion by the liver enhances intestinal tumor format ion in rats on certain carcinogens.3 T h e objective of our study was to determine the effect of diverting bile f rom the proximal half to the distal half of the small intestine on intestinal tumor formation in rats given azoxymethane subcutaneously.

Cancer of the anal canal. Model for preoperative adjuvant combined modality therapy

An analysis of preoperative multimodality adjuvant therapy with 5-fluorouracil, mitomycin-C, and radiation therapy revealed that 38 of 45 patients (84 percent) treated were rendered free of cancer after chemotherapy/radiation therapy. No recurrence of tumor has been noted in those patients rendered free of disease by the preoperative treatment. Seven patients (15 percent) with residual macroscopic or microscopic cancer after preoperative therapy have had recurrence, all in distant sites. These seven patients have died from the disease. The prognosis for patients in this series depended on the success of the preoperative therapy in eradicating all tumor prior to surgery. Mitomycin-C and 5-fluorouracil are cytotoxic for local disease and for microscopic distant disease as well. Abdomino-perineal resection is unnecessary for patients whose primary tumor is eradicated by the preoperative therapy. The role of the relatively low dose of radiation therapy needs to be further defined.

A rat model for studying colonic cancer: Effect of cholestyramine on induced tumors

SummaryDimethylhydrazine, azoxymethane, and methylazoxymethanol are highly efficient intestinal carcinogens in the rat. Azoxymethane is the best, producing tumors in all rats. The lesions occurred in significant numbers in the small intestine when given at high dosage levels over a period of six months or more. The tumors tend to occur more in the proximal halves of both segments of the intestine.When the animals are fed a 2 per cent cholestyramine diet, there is a marked increase in the tumor yield and the increase is, for the most part, in the large intestine, especially its distal half. Investigations of the mechanisms whereby cholestyramine enhances tumor formation in the large intestine of the rat are continuing.We conclude that the rat given azoxymethane subcutaneously at weekly intervals while on a 2 per cent cholestyramine diet is an excellent experimental model for studies of colonic cancer.

Combined therapy for cancer of the anal canal: a follow-up report.

SummaryWe believe this preoperative combined therapy is highly effective in treating squamous-cell carcinoma of the anal canal, and that a subsequent larger cooperative study with controls is indicated. This pilot study suggests that some individuals may be spared abdominoperineal resection when treated in the manner described.

Effect of selenium on azoxymethane-induced intestinal cancer in rats fed high fat diet

The effects of selenium supplementation on azoxymethane-induced intestinal cancer were studied in male Sprague- Dawley rats given 8 weekly injections of azoxymethane (8 mg/kg body wt), and fed a 30% beef fat diet. Selenium-supplemented groups received 8 ppm H2SeO3 in drinking water. Blood selenium levels of supplemented rats increased rapidly the first 9 weeks of the experiment, followed by a plateau significantly higher than that for non-selenium controls. There was a significantly increase in liver and intestinal selenium levels in supplemented groups. The average number of intestinal tumors was 6.5 in the control group, and 3.1 in the selenium-supplemented group. There was a significant reduction in tumor incidence in the proximal half of the colon of selenium-treated rats. There was also increased concentration of tissue selenium in the proximal half of the colon of these rats.

THE FORCE OF CHANGE IN THE MANAGEMENT OF SQUAMOUS-CELL CANCER OF THE ANAL CANAL

International Society of University Colon and Rectal Surgeons. In the past, these articles have been published as they were received. In this issue, we have p u t together a number of these articles and, in the future, will place articles f rom this meeting in one issue. We are doing this in an attempt to more clearly define the source of these articles for the readers. The Editorial Board hopes you will f i nd this helpful.

The essential fatty acid requirement for azoxymethane-induced intestinal carcinogenesis in rats

The essential fatty acid requirement for the development of intestinal carcinogenesis was determined and compared to the overall essential fatty acid status of the animals as measured by the triene/tetraene ratio in the plasma, liver and colon. To induce tumors, male Sprague-Dawley rats were given two weekly injections (20 mg/kg body wt) of azoxymethane. Two weeks after the last injection, the rats were divided into groups of 25 and given one of six diets containing various levels of essential fatty acids (as linoleate). The diets contained 5% total fat and were prepared by mixing safflower oil (high essential fatty acids, beef fat (low essential fatty acids), and medium chain triglyceride oil (no essential fatty acids). One group of rats was fed a 20% beef fat diet. The range of essential fatty acids was from <0.03% to 1.28% (w/w). Twenty-six weeks after the first azoxymethane injection, the animals were killed and intestinal tumor incidence and multiplicty were determined. Samples of plasma, liver and colon were also taken for measurement of the triene/tetraene ratio by gas chromatography.Large bowel tumor incidence showed a dependence on the essential fatty acid content of the diet. The results were as follows: (percent essential fatty acids: percent tumor incidence) Group A (1.28∶ 72.4), Group B (0.60∶ 73.3), Group C (0.11∶ 55.2), Group D (0.08∶ 39.3), Group E (<0.03∶ 37.9) and Group F, which was fed 20% beef fat, (0.34∶ 88.5). These data suggest the essential fatty acid requirement for colon tumorigenesis is much lower than values previously reported for tumorigenesis in the breast and pancreas. The plasma and liver triene/tetraene ratios showed clear-cut essential fatty acid deficiency (ratio >0.4) in Groups D and E, although no clinical symptoms were evident. In all dietary groups, the triene/tetraene ratio in the colon was lower than 0.3. In addition in the colon, the percentage of fatty acids present as 20 carbon polyunsaturated fatty acids was lower than in the plasma and liver. These data suggest the colon possesses low levels of the fatty acid desaturase and elongase needed for conversion of linoleate to 20 carbon fatty acids, and therefore, that the colonic requirement for essential fatty acids may be low. Furthermore, in the absence of other clinical symptoms, the reduced tumorigenesis observed in the groups fed low essential fatty acids suggests the essential fatty acid requirement of tumor tissue may be higher than that of normal colon mucosa.

Inhibition of azoxymethane-induced intestinal cancer by disulfiram.

Sprague--Dawley rats, both intact and colostomized animals, were given 24 weekly injections of azoxymethane. Rats were fed either Rat Purina Chow or the same diet plus 0.25% disulfiram. In the intact animals, disulfiram reduced tumors from an average of 6.3 to 0.95. The number of rats developing tumors was reduced from 100% to 60%. In colostomized animals, the reduction was from an average of 5.0 to 0.13. Marked inhibition occurred even in the defunctionalized colon. The results suggest that disulfiram blocks the metabolism of azoxymethane to methylazoxymethanol, and also that the inhibitor may act systemically.