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Background: Results of epidemiologic studies suggest that there is limited evidence for the association between cigarette smoking and risk of colorectal cancer. Cigarette smoking has been shown to increase the risk of colorectal adenomatous polyps, which are recognized as precursors of colorectal cancer, while few studies have examined the association between alcohol consumption and the development of adenomatous polyps. Purpose: We examined the association between cigarette smoking, alcohol consumption, and the presence of colorectal adenomatous polyps. Methods: Analyses were based on data from a case-control study of dietary and other lifestyle factors for colorectal adenomatous polyps. We assessed the risk of adenomatous polyps associated with total number of years of smoking, number of cigarettes smoked per day, and pack-years of smoking for past and current smokers separately. We also assessed the joint association between cigarette smoking and alcohol consumption on the risk of adenomatous polyps. Results: Current smokers who smoked more than 20 pack-years were at significantly higher risk of adenomatous polyps compared with never smokers (odds ratio [OR] = 2.56; 95% confidence interval [CI] = 1.28-5.14). Past smokers also had an increased risk of having adenomatous polyps, but no clear trend was observed for pack-years of smoking. Alcohol consumption was positively associated with risk of adenomatous polyps. Compared with nondrinkers, the strongest risk was observed for individuals who consumed 2.31-9.46 g alcohol per day (OR = 2.23; 95% CI = 1.29-3.83), and a decrease in risk was observed for individuals who consumed 9.47-67.36 g alcohol per day (OR = 1.63; 95% CI = 0.92-2.88). Among current smokers, a joint effect was observed for individuals who smoked and drank compared with those who never smoked and were not current drinkers (OR = 4.21; 95% CI = 1.88-9.41). For past smokers, a significant joint effect of smoking and current alcohol consumption was also observed, but the risk was not as strong as that for current smokers (OR = 2.61; 95% CI = 1.40-4.87). Conclusions: These data provide further evidence of the positive association between cigarette smoking and the development of colorectal adenomatous polyps. The combination of cigarette smoking and alcohol consumption increased the risk of adenomatous polyps. Implications: Future research should focus on the understanding of the role of cigarette smoking and alcohol consumption as these two factors relate to the evolution of colorectal adenomatous polyps and subsequent carcinogenesis.

Background. Since the 1970s, work in several disciplines (toxicology, pharmacology, clinical medicine, epidemiology) increasingly has suggested that aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) may reduce the occurrence or progression of colorectal cancers and polyps and perhaps of other gastrointestinal tumors. The potential application of these findings for chemoprevention of such cancers in man now deserves serious consideration. Methods. An interdisciplinary workshop was held by the American Cancer Society in March 1994 to review the current knowledge of NSAIDs and cancer and to seek a consensus on future research directions, particularly concerning the possibility of randomized prevention trials in human populations. Results. A wide-ranging review was conducted of past and current research regarding (1) NSAIDs' effects in experimental animal cancer models; (2) clinic experience in NSAID treatment, particularly in familial polyposis; (3) pharmacologic studies regarding the enzymatic and metabolic actions of NSAIDs; and (4) epidemiologic observations on the relationship of aspirin/NSAID usage to colorectal cancer occurrence in human populations. Conclusions. Combined evidence from different research disciplines strongly supports the notion that aspirin and other NSAIDs act to prevent the development or progression of certain human gastrointestinal cancers, especially colorectal cancer. Consequently, the workshop recommended that randomized prevention trials be undertaken. For various logistic reasons, such trials probably should focus on NSAID effects on the occurrence and progression of colorectal polyps rather than on carcinoma itself. Continued research also is needed to clarify further the pharmacologic, clinical, and epidemiologic nature of NSAIDs' influences on human carcinogenesis. Cancer 1994; 74:2885-8.

Background. Hepatic arterial infusion chemotherapy (HAIC) of liver metastases of colon cancer with an implantable pump is associated with liver and gastrointestinal complications. Methods. The authors retrospectively studied the clinical features and gastric histopathology of nine patients who received HAIC and had gastritis develop and in whom biopsy specimens were available. Results. Gastritis was heralded in these patients by epigastric pain and tenderness, nausea, vomiting, weakness, and anorexia. In seven patients, 18 gastric ulcers were endoscopically detected. Mucosal damage developed despite prophylactic antiulcer therapy and healed only upon cessation of HAIC. These observations suggest that the predominant drug given, floxuridine, was the responsible toxic agent. Seventeen biopsy specimens were reviewed, and all exhibited varied histologic evidence of inflammation, reactive glandular changes, and cell necrosis. These mucosal changes were present even in tissues obtained from patients without ulcers. In addition, floxuridine-induced glandular atypia was noted in eight biopsy samples from six patients. The crowded glands were distorted and lined by large cells that included bizarre forms with pleomorphic nuclei. Conclusions. Gastric injury in HAIC appeared analogous to the general features encountered in reactive gastritis resulting from chemical irritants. The glandular atypia is peculiar to HAIC, and although the changes were morphologically alarming, in this clinical situation care should be exercised not to interpret floxuridine-induced atypia as carcinoma.

Background. A Phase II clinical trial was conducted to evaluate the efficacy of intravenous fluorouracil (5-FU) and subcutaneous recombinant interferon-alpha-2b (rIFN-[alpha]-2b) in the treatment of hepatocellular carcinoma (HCC) and to define factors that might be predictive of a response to treatment. Methods. Twenty-nine patients were registered on the protocol. 5-FU was administered as a continuous intravenous (IV) infusion (dose = 750 mg/[m.sup.2]) for 5 consecutive days. rIFN-[alpha]-2b was administered subcutaneously (SC) (dose = 5 X [10.sup.6] um/[m.sup.2]) once a day on days 1, 3, and 5 of the 5-FU infusion. The treatment was repeated at 14-day intervals. Responses were assessed at the end of one course of therapy, which was equivalent to four treatments. Results. Of the 28 patients evaluable for response, 5 (18%) had a partial response, and 1 (4%) had a minor response. Responses lasted from more than 2 to more than 24 months (median, 11.5 months). Ten (36%) patients experienced no response, and 12 (43%) had progressive disease. The 6 responders were part of a group of 16 patients who had pretreatment levels of serum alpha-fetoprotein (AFP) of 50 ng/ml or less and a group of 8 whose tumors involved 50% or less of the liver parenchyma. Mucositis, which occurred in 54% of the patients, was the most common toxicity associated with the treatment regimen. Diarrhea and dermatitis were observed in 16% and 17% of the patients, respectively; fatigue, thrombo-cytopenia, granulocytopenia, neurologic toxicity, and nausea and vomiting were not commonly seen. Conclusions. The regimen of IV 5-FU and SC rIFN-[alpha]-2b was well tolerated and induced durable partial response in 31% (5 of 16) of patients with HCC who had low levels of serum AFP and in those with 50% or less of liver replacement. In contrast, the treatment regimen was ineffective in patients with HCC who had high levels of serum AFP or extensive liver disease.

Background. Mitoxantrone is an anthraquinone derivative that has demonstrated encouraging preclinical and clinical activity against a variety of human carcinoma cell lines and malignancies. Three Phase 11 studies of systemically administered mitoxantrone in patients with colorectal carcinoma failed to demonstrate any therapeutic activity, as did four Phase II studies of intravenous mitoxantrone in hepatocellular carcinoma. Two additional trials demonstrated limited activity when administered intravenously to patients with hepatocellular carcinoma. However, because this drug exhibits a steep dose-response curve, a Phase I-II trial of mitoxantrone by hepatic arterial infusion was initiated. Methods. Patients with hepatocellular carcinoma and metastatic colorectal carcinoma with liver only or liver-predominant disease were eligible for therapy. All patients underwent the placement of a percutaneous hepatic arterial catheter before each course of therapy, and the first cohort of patients was treated at 10 mg/[m.sup.2]/ course on day 1 on a 28-day cycle. Dosages were escalated in increments of 2 mg/[m.sup.2]/course based on side effects and tolerance. Results. Twenty-eight patients with bidimensionally measurable unresectable, liver-predominant disease were entered into this trial. The therapy was well tolerated, with only 5 courses of 55 being complicated by neutropenia and none associated with fever. Only one patient required a dosage reduction on the basis of toxicity (neutropenia). No complete or partial responses were observed. Conclusion. These data are consistent with a lack of therapeutic activity of mitoxantrone when administered by hepatic arterial infusion for the treatment of hepatocellular carcinoma or metastatic colorectal cancer.

Background. Thirty-nine patients with advanced measurable metastatic colorectal carcinoma were entered in a clinical trial of recombinant alpha-2a-interferon (r [Alpha]-2a-IFN) and continuous-infusion 5-flourouracil (5-FU). Patients had not been treated previously with chemotherapy and had bidimensionally measurable disease. Methods. A course of therapy consisted of a 5-day continuous infusion of 5-FU, 750 mg/[m.sup.2]/day, with r [Alpha]-2a-IFN, 9 X [10.sup.6] IU, subcutaneously, on days 1, 3 and 5 of the 5-FU infusion. A course of therapy was repeated every 15 days, and patients were examined for response after receiving four courses of therapy. Results. One patient had a complete response, and 11 patients experienced partial responses, for an overall response rate of 31% (95% confidence interval [CI], 17-48%). The median duration of response was 7.5 months (range, 2-13 months). Fifty-two percent of the patients entered in this trial are alive at time of this writing, with a median follow-up duration of 12.2 months (range, 6-24 months). Grade 3-4 toxicities included mucositis (nine patients), diarrhea (two patients), granulocytopenia (two patients), and fatigue (three patients). Conclusion. This regimen of 5-FU with r [Alpha]-2a-IFN administration does not appear to be superior to previously published schedules of 5-FU with r [Alpha]-2a-IFN or to other methods that modulate 5-FU. Cancer 1993; 71:1214-8.

Background. Based on initial encouraging results of the combination of 5-fluorouracil (5-FU) with recombinant [alpha]-2a-interferon (r[apha]-2a-IFN) in the treatment of advanced colorectal carcinomas, a clinical trial was conducted using 5-FU with r[alpha]-2a-IFN in 49 patients with advanced pancreatic adenocarcinoma. Methods. Forty-nine patients who had bidimensionally measurable disease and had not been treated previously with chemotherapy were entered in the trial. Starting on day 1, 5-FU was administered as a continuous infusion at a dose of 750 mg/[m.sup.2]/day for 5 consecutive days. Starting on day 12, it was administered as an intravenous bolus of 750 mg/[m.sup.2] a week for 7 weeks. The r[alpha]-2a-IFN was administered subcutaneously at a dose of 9 X [10.sup.6] units three times a week during weeks 1-8. Results. Of the 46 patients evaluable for response, none had a complete response, and two had partial responses that lasted 14 and 28 weeks. The overall response rate was 4% (95% confidence interval, 1-15%). Fourteen patients had minor responses (median duration of response, 12 weeks). The median length of survival of all patients enrolled in this trial was 22 weeks. Grade 3-4 toxicities included oral mucositis in 19 patients, granulocytopenia in 16, fatigue in 8, and diarrhea in 3. One patient had severe ataxia and leg weakness. Another died of neutropenic sepsis.

Environmental and genetic factors play an important role in the cause and pathogenesis of colorectal cancer. In addition to nutritional aspects, other environmental factors include physical exercise, energy intake, obesity, and parity. Dietary components currently under study are dietary fiber, fat, fruits, vegetables, and calcium. Intermediate markers of colonic proliferation, including bromodeoxyuridine and proliferating cell nuclear antigen incorporation, are being used to evaluate the response of the colonic epithelium to putative chemopreventative agents.

Patients who have had extensive colitis for more than 10 years are at increased risk for colorectal cancer. The risk may be greatest for those whose onset of illness is in childhood. Management options for patients at increased risk include prophylactic colectomy or endoscopic surveillance. The object of surveillance is prevention of cancer by detecting premalignant lesions that predispose to cancer. A less desirable objective is the diagnosis of cancer at an early curable stage. Patients must be well informed about their risk for cancer, the limitations of endoscopic surveillance, and the availability of surgical alternatives. Current endoscopic and pathologic techniques focus on the detection of dysplasia, but newer biomarkers may offer greater sensitivity and specificity in the future. Cancer 1992; 70:1313-1316.

Patients with intestinal cancer may develop bowel obstructions. These patients, prior to being able to undergo preoperative chemotherapy or radiotherapy for definitive surgery, generally require a diverting colostomy (diversion of the intestine with creation of an artificial anus on the abdominal wall). Endoscopic laser treatment may provide an alternative to colostomy, in that it can be used to remove the tumor and reopen the lumen of the intestine. This can permit preoperative bowel preparation (enemas and other cleansing procedures) and possible preoperative administration of chemotherapy and radiotherapy. A retrospective review was undertaken of 37 patients with cancer of the distal sigmoid colon and rectum who underwent endoscopic laser recannulation. All patients underwent the procedure for purposes of palliation (relief of symptoms in the absence of cure) for advanced cancer. Patients underwent endoscopy of the colon and rectum using an illuminated optic instrument fitted with laser capability. There were 123 sessions performed, average of 2.5 per patient. During average follow-up of 31.5 weeks, 84 percent of the patients maintained patent (open) intestinal tracts. The majority of patients (62 percent) underwent radiotherapy, chemotherapy or surgery along with endoscopic laser therapy. Complications occurred in 3 of 123 procedures (2.5 percent) and there was one death. It is concluded that endoscopic laser therapy can be useful in reestablishing and maintaining an unobstructed intestine in patients who have advanced cancer of the sigmoid and rectum with obstruction. This palliative therapy may permit the administration of preoperative treatment such as chemotherapy or radiotherapy. (Consumer Summary produced by Reliance Medical Information, Inc.)

Stomach cancer is the eighth most common cause of cancer death in the US and was responsible for 13,700 deaths last year. The primary treatment is surgery, but the outlook is poor, and fewer than 20 percent of patients are likely to survive more than five years. Since many patients with stomach cancer relapse after apparently complete surgical removal of the cancer, a study was undertaken to evaluate the use of a regimen of chemotherapeutic treatment along with surgery. A total of 25 patients with previously untreated stomach cancer were given chemotherapeutic courses of etoposide, 5-fluorouracil, and cisplatin both before and after the surgical removal of their cancer. Six of the 25 patients had major responses to the preoperative chemotherapy, and 20 of 25 had subjective improvements including better appetite. At surgery, it was found that none of the 25 patients had a complete response to the chemotherapeutic treatment. In three cases, however, the only residual cancer was microscopic deposits. In seven patients, cancer spread was found at the time of surgery and so the surgery was potentially curative in only 18 cases. All seven patients with cancer spread were dead within 15 months. Of the remaining 18 patients, seven have died within an average follow-up period of just over two years. The side effects of the chemotherapy were only moderate, and there were no deaths attributed to this treatment, although one patient died of postoperative respiratory complications. This study indicates the feasibility of combining chemotherapy with surgical treatment for stomach cancer. Before a study is conducted to compare surgery with chemotherapy with surgery alone, it would seem appropriate to develop a chemotherapeutic regimen with a better response rate for this cancer. Based on comparisons with other forms of cancer, a suitable goal would be the development of an adjuvant chemotherapeutic protocol with a complete response rate of between 5 and 10 percent. (Consumer Summary produced by Reliance Medical Information, Inc.)

Colorectal cancer (cancer of the colon and rectum) is a leading cause of death in Western societies. Based on the results of several different studies performed on laboratory animals, it has been suggested that dietary fat may play a role in causing colon cancer. These studies showed that large amounts of fat can damage the cells in the colon and can alter the growth pattern of these cells, causing the cells to grow faster than normal. This type of abnormal cell growth, called hyperproliferation, occurs during the early stages of cancer. In animal studies, calcium supplements have been shown to inhibit colon cancer. It has been suggested that the calcium binds to dietary fat in the colon and prevents the fat from damaging the cells in the colon. A few studies, performed in humans, have reported that calcium supplements can reverse the hyperproliferation that is associated with the development of colon cancer. Others studies have reported that people who eat low-fat dairy products or calcium supplements have a lower risk of developing colon cancer. Based on the results of these studies, it is suggested that increasing the daily intake of calcium may reduce the risk of developing colon cancer. However, further studies are needed to confirm the results of these studies before a definite conclusion about the effectiveness of calcium in preventing colon cancer can be drawn. (Consumer Summary produced by Reliance Medical Information, Inc.)

A great deal of circumstantial evidence implicates estrogens in the development of some liver tumors. The precancerous changes of nodular hyperplasia (excessive cell growth) have been associated with oral contraceptives, as have adenomatous changes (characteristic of adenoma, a type of tumor). In one study, four-fifths of women under 50 years old with hepatoma (liver tumor), without cirrhosis, reported a history of estrogen exposure. Furthermore, laboratory analysis has revealed that carcinomas and adenomas of the liver possess estrogen receptors, albeit at lower concentrations than observed with breast or uterine cancer. It has been suggested that anti-estrogen therapy may benefit patients with some types of liver cancer. For this reason, 33 patients with hepatocellular carcinoma (liver cancer) were treated with tamoxifen, an anti-estrogen drug that has shown success in treating breast cancer. Eight patients remained stable and 25 showed evidence of disease progression within three months. None of the patients showed any response to the treatment, and half died within six months. The study provides no evidence to support the idea that anti-estrogen therapy may be effective in cases of hepatocellular carcinoma. (Consumer Summary produced by Reliance Medical Information, Inc.)