Effect of enprostil on the gastroduodenal mucosa of healthy volunteers.

Enprostil is a synthetic dehydro-prostaglandin E2 with gastroduodenal ulcer-healing and mucosal-protective properties. One hundred and three healthy volunteers were randomized to receive capsules of enprostil 35 micrograms b.d. (the clinically recommended dose), enprostil 70 micrograms b.d., or placebo b.d. All underwent endoscopic assessment of the gastroduodenal mucosa, scored using a 0-4 scale, at baseline and on Days 3, 7, 14, 21 and 28 of dosing. Mean and median maximum scores demonstrated a dose response, and the mean maximum scores were statistically significantly higher for both enprostil groups on each endoscopy day when compared with placebo. The majority of enprostil-treated subjects had petechial haemorrhages. The proportion of volunteers with small white-based mucosal breaks (erosions) was significantly higher for the fundus in the enprostil 70-microgram group on Days 21 and 28 when compared with placebo, but there were no significant differences between treatment groups for any area on the other study days. The 70-microgram dose was associated with significantly more gastrointestinal adverse events than the 35-microgram dose, which was similar to placebo. There were no significant differences between groups for large white-based mucosal breaks (ulcers). We conclude that oral enprostil produced gastric mucosal petechial haemorrhages, primarily in the fundus of the stomach. Gastric mucosal petechial haemorrhages are probably without clinical significance because they are very common in the general population (10-15%) and do not progress to erosions and ulcers.

Prolonged survival and effective palliation in patients with squamous cell carcinoma of the esophagus following endoscopic laser therapy.

Endoscopic laser therapy provides effective symptomatic palliation for patients with squamous cell carcinoma of the esophagus. To investigate whether this treatment also prolongs survival, a retrospective case-control study was performed. Ten patients with squamous cell carcinoma of the esophagus, diagnosed between 1983 and 1985, were treated with the neodymium: yttrium aluminum garnet laser (Cooper Lasersonics, Model 8000, Santa Clara, CA). Twenty patients with the same diagnosis observed between 1979 and 1984 served as age-matched controls. There was no significant difference in sex, race, location of the cancer, prior treatment, or dysphagia scores for the two groups. Laser therapy produced a significant improvement in the mean dysphagia score. Life table analysis demonstrated a median survival of 17.5 months for the patients treated with endoscopic laser therapy compared with 5.7 months for the control subjects (P less than 0.05). One-year survival after laser treatment was 75%, compared with 20% in the control group (P less than 0.05). These results suggest that endoscopic laser therapy is effective for prolonging survival and improving the quality of life in patients with squamous cell carcinoma of the esophagus.

Hypergastrinemia and colorectal carcinogenesis in the rat.

Our objective was to determine whether chronic hypergastrinemia enhances chemical induction of rat colorectal cancers. Forty-five rats were randomized to sham operation or antral exclusion. Following a 2-week postoperative recovery period all rats were treated with 1,2-dimethylhydrazine (10 mg/kg) intraperitoneally for 20 weekly doses. Seven weeks later, the rats were killed. Blood was assayed for gastrin by radioimmunoassay. Tumor number, location, size, weight and histology were determined. The 23 rats receiving antral exclusion were hypergastrinemic compared with the 22 sham operated rats. All hypergastrinemic rats developed tumors while only 72.7% of normogastrinemic rats developed tumors. Hypergastrinemia increased the number of tumors/rat, total tumor weight/rat and total tumor volume/rat.

Fecal skatole and indole and breath methane and hydrogen in patients with large bowel polyps or cancer.

The object of this study was to explore the use of fecal skatole and indole and breath methane and hydrogen as metabolic markers of the anaerobic colonic flora in patients with unresected large bowel cancer or polyps. Patients with descending or sigmoid colon cancer were more likely to be breath methane excretors than control subjects, patients with proximal colon cancer, and patients with rectal cancer. Control subjects excreting breath methane excreted less fecal skatole than breath methane excretors in the following groups: patients with adenomatous polyps, all patients with colorectal cancer, patients with proximal colon cancer, patients with descending and sigmoid colon cancer, and patients with rectal cancer. These data suggest that fecal skatole excretion equal to or greater than 100 micrograms/g feces might be useful to discriminate colorectal cancer patients from control subjects. Twenty-nine percent (8 of 28) of the cancer patients had both "high" skatole levels and breath methane excretion compared with only 2% (1 of 41) of the control subjects (P less than 0.01).

Cis-diaminodichloroplatinum (II) chemotherapy for advanced adenocarcinoma of the upper gastrointestinal tract.

A phase II study of cis-diaminodichloroplatinum (II) (cis-DDP) was carried out in 55 patients with advanced adenocarcinoma of the upper gastrointestinal tract. The drug was given at a dose of 100 mg/m2 i.v. over 2h every 3-4 weeks, with hydration and mannitol diuresis. There were 3 partial responses (6%) among 51 evaluable patients (esophagus 12, stomach 16, pancreas 14, liver 6, and biliary 3). Toxicity was moderate with cumulative nephrotoxicity being the most serious side effect. Myelosuppression was noted in 25% of patients, all having had prior therapy with mitomycin C and nitrosoureas. Activity of cis-DDP as a single agent against adenocarcinoma of the upper gastrointestinal tract in our patient population was minimal.

Comparison of colon cleansing methods in preparation for colonoscopy.

Colonoscopy cleansing regimens were evaluated in 197 patients randomized in two study phases to one of four methods: group 1 (64 patients), 3-day clear liquid diet; group 2 (40 patients), 3-day minimum-residue diet; group 3 (44 patients), 1-day minimum-residue diet; group 4 (49 patients), Golytely. Groups 1-3 also received laxatives and enemas before colonoscopy. Physician assessment by endoscopists unaware of the method of colon cleansing favored group 4 (p less than 0.001), with good to excellent preparations achieved in 69% of group 1, 80% of groups 2 and 3, and 92% of group 4. Group 4 patients also experienced less abdominal distress (p less than 0.01). Breath hydrogen and methane levels were measured in groups 3 and 4 both before and after preparation. The decrease in pre- to postprep levels of hydrogen and methane were not significantly different between the groups and postprep gas concentrations were below combustible levels in both groups. There were no clinically significant differences between the four groups for any of the other measured hematologic or biochemical parameters. It is concluded that Golytely is a safe, effective method of colon cleansing, well tolerated by patients.

Comparison of effects of pentagastrin and gastrin on rat colon mucosa.

The trophic effect of chronic endogenous hypergastrinemia is compared with that of short term injected pentagastrin on colon mucosa of rats. Hypergastrinemia was achieved by antral exclusion. Pentagastrin (2 mg/kg) was administered to a group of sham operated rats every 12 hr for 48 hr prior to sacrifice. Normogastrinemic antrectomized and sham operated animals were studied as controls. Tissue content and synthesis of DNA, RNA, and protein were all markedly increased by both endogenous gastrin and exogenous pentagastrin. The stimulation by gastrin was significantly stronger than that of pentagastrin at the chosen schedule of administration.

Phase II clinical evaluation of intravenous 4'-(9-acridinylamino)methanesulfon-m-anisidide in colorectal cancer.

Thirty-five patients with measurable metastatic colorectal cancer received 4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA) on a 3-day intravenous schedule repeated every 3 weeks. There were 17 previously untreated patients and 18 patients who had disease progression on several regimens containing 5-fluorouracil. Good-risk patients received an initial daily AMSA dose of 40 mg/m2; poor-risk patients received an initial daily dose of 30 mg/m2. There were no complete or partial remissions. Ten patients achieved disease stabilization, 24 had disease progression and one patient was lost to follow-up. The most common toxicity associated with AMSA therapy was myelosuppression, with a greater effect on neutrophils than platelets. Median (range) lowest neutrophils and platelet counts X 10(3)/mm3 were 1.2 (0-5.0) and 209 (50-413), respectively. Myelosuppression was pronounced in patients with abnormalities of liver function. Other toxicities were negligible, although one patient developed an episode of cardiac arrhythmia which may have been secondary to AMSA therapy.

Phase II evaluation of 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea (PCNU, NSC 95466) in patients with metastatic colorectal cancer.

Thirty-two patients with measurable metastatic colorectal cancer refractory to 5-fluorouracil-containing regimens received PCNU (1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea, NSC 95466) on a single-day I.V. schedule administered every 6 weeks. Good-risk patients received PCNU at the starting dose of 100 mg/m2, while patients who had received radiotherapy or myelosuppressive drugs such as mitomycin C received an initial dose of 75 mg/m2. There were two partial remissions. Fifteen patients including four with minor tumor regression had disease stabilization. The dose-limiting toxicity was myelosuppression, with thrombocytopenia being more severe than neutropenia. The myelosuppression occurred late in the treatment cycle (days 25-32), was more severe with repeated treatments, and was more severe in patients who had a poor bone marrow reserve. Other toxicities were mild and infrequent. PCNU administered by the single-dose I.V. schedule as used in this study has very modest antitumor activity against colorectal cancer in humans.

Phase II clinical evaluation of AZQ in colorectal cancer.

Thirty patients with measurable metastatic colorectal cancer refractory to 5-fluorouracil-containing regimens, received AZQ (1,4-cyclohexadiene-1,4-dicarbamic acid, 2,5-bis(1-aziridinyl)3,6,dioxo,diethylester, NSC 182986) on a 5-day intravenous schedule administered every 4 weeks. Good risk patients received AZQ at the starting daily dose of 8 mg/m2, while patients who had had therapy with radiation or myelosuppressive drugs such as mitomycin C or a nitrosourea compound received an initial daily dose of 6 mg/m2. There were no complete or partial remissions. Only one of 27 evaluable patients had objective tumor regression. Five additional patients had disease stabilization. The dose-limiting toxicity was myelosuppression, with thrombocytopenia being more severe than neutropenia. The myelosuppression occurred late in the treatment cycle (day 20), was more severe with repeated treatments, and was more severe in patients who had poor bone marrow reserves. AZQ administered by the 5-day dose schedule as used in this study is not effective against colorectal cancer.

Breath methane excretion in patients with unresected colorectal cancer.

The objective of our study was to verify or refute the observation that patients with unresected colorectal cancer are more likely to be breath methane excretors than the general population. Intracolonic heme had no effect on breath methane excretion of 11 normal volunteers given oral hemoglobin. Laxative-enema colonoscopy preparation had a profound effect on the subsequent measurement of breath methane. Three of 4 volunteer methane excretors became nonexcretors, and 2 remained nonexcretors for 21 days and 7 months, respectively. No significant difference was found in the frequency and the amount of breath methane excretion in 55 patients with unresected colorectal cancer and in 99 control subjects. However, 13 patients with unresected descending or sigmoid colon cancers were almost twice as likely to be breath methane excretors as 38 patients with colorectal cancer at other sites.

Phase I--II study of the combination of 5-FU, doxorubicin, mitomycin, and semustine (FAMMe) in the treatment of adenocarcinoma of the stomach, gastroesophageal junction, and pancreas.

One hundred and fifteen patients with advanced gastrointestinal cancer (stomach cancer, 42 patients; gastroesophageal junction cancer, ten; pancreatic cancer, 32; and other upper gastrointestinal cancers, 31) were treated with a combination chemotherapy regimen consisting of 5-FU, doxorubicin, mitomycin, and semustine (methyl-CCNU) (FAMMe). Of the 31 patients with stomach cancer who were evaluable for response and had had no previous chemotherapy, 12 (39%) achieved complete or partial remission. One of eight (12%0 patients with gastroesophageal junction cancer and five of 23 (22%) patients with pancreatic cancer achieved a partial remission. The median duration of survival for all patients with adenocarcinoma of the stomach was 7.1 months. The median duration of survival for responding patients with stomach cancer was 13.6 months, and the median survival for nonresponding patients was 6.1 months. FAMMe chemotherapy was generally well-tolerated and can be administered in adequate doses without producing prohibitive myelosuppression. The starting dose should be reduced for patients greater than or equal to 70 years old or for patients who have received pelvic or vertebral radiation therapy. FAMMe is effective against advanced gastric cancer; however, because this was not a randomized comparative study of the relative effectiveness of FAMMe and FAM (5-FU, doxorubicin, and mitomycin), no recommendation for the use of one regimen instead of the other for advanced adenocarcinoma of the stomach can be made. FAMMe chemotherapy cannot recommended for advanced adenocarcinoma of the pancreas and gastroesophageal junction.

Sequential phase II studies of chemotherapy for colorectal cancer with 5-fluorouracil and vindesine with or without methyl-1,3 cis(2 chloroethyl)-1-nitrosourea.

Vindesine, a newer vinca alkaloid, has been demonstrated to have activity against colorectal cancer during phase I studies. This report describes the results of two phase II trials in which vindesine was administered with 5-fluorouracil (5-FU) or in combination with 5-FU and methyl-1,3 cis(2 chloroethyl)-1-nitrosourea (MeCCNU). One of 16 patients (6%) given 5-FU-vindesine, and 4 of 31 (13%) patients in the 5-FU-vindesine-MeCCNU group achieved partial response (PR). Stable disease was observed in 50% of the 5-FU vindesine and 48% of the 5-FU-vindesine-MeCCNU group. In each treatment group, survival of respondents and those with stable disease was statistically superior (p less than 0.02) to that of those with progressive disease; there was no difference however, in overall survival between the two treatment groups and no enhancement of survival compared to published reports of results with 5-FU alone. No chemotherapy-related deaths occurred and both treatment regimens were well tolerated. Myelosuppression, which occurred with equal (50%) frequency in both regimens, was the major dose-limiting toxicity. MeCCNU increased the incidence of gastrointestinal toxicity. Vindesine neurotoxicity occurred in approximately 4% of the evaluable courses in each group. Combination therapy with 5-FU vindesine with or without MeCCNU in the dosages administered did not significantly increase the activity of 5-FU. Further evaluation of vindesine will require dosage modification.

Trophic effects of gastrin on colorectal neoplasms in the rat.

This study was designed to determine the effect of gastrin on colorectal neoplasms in the rat. Multiple colon and rectal cancers were induced in each of 57 rats with methylazoxymethanol. Animals were randomly assigned to groups: (1) antral exclusion, (2) antrectomy, (3) sham, or (4) sham with subsequent pentagastrin injections. Resulting tumors were analyzed for concentration and synthesis of DNA, RNA, and protein. The number of tumors per rat and distribution of tumors within the colons did not vary among groups. Antrectomy did not alter the gastrin level, and tumors developing in these animals did not differ from those of sham controls. Antral exclusion markedly raised serum gastrin levels. Both chronic endogenous hypergastrinemia and administration of exogenous pentagastrin significantly increased tumor synthesis and concentration of DNA, RNA, and protein. We conclude that gastrin exerts a trophic effect on colorectal neoplasms in rats. This biological phenomenon suggests a tumor regulatory role for the hormone.

Chemotherapy for colorectal cancer with a combination of PALA and 5-FU.

Fifty-one previously untreated patients with advanced, measurable colorectal cancer were randomized to receive single doses of PALA and 5-FU either weekly (24 patients) or daily for 5 days every 4 weeks (27 patients). In both schedules the daily dose of PALA was administered iv over 1 hour, while the dose of 5-FU was administered iv over 30 minutes, starting 3 hours after completion of the PALA dose. Doses of both drugs were changed simultaneously, based on toxic effects. Partial responses were seen in four of 24 evaluable patients receiving the weekly regimen and in three of 26 patients receiving the 5-day regimen. Skin rash, mucositis, and diarrhea were the dose-limiting toxic effects in both treatment regimens. These toxic effects were more common and severe at higher doses and on the weekly schedule. Myelosuppression was mild and moderate, the doses and schedules used in this study did not significantly increase the activity of 5-FU. Further evaluation of these doses and schedules for activity against colorectal cancer is not warranted.

5-fluorouracil, Adriamycin, and mitomycin-C (FAM) chemotherapy for advanced adenocarcinoma of the pancreas.

Thirty-nine patients with advanced metastatic adenocarcinoma of the pancreas were treated with a combination of 5-fluorouracil, Adriamycin, and mitomycin-C (FAM). Twenty-seven of these patients had measurable disease, and ten (37%) achieved a partial response. An additional three patients had evidence of disease stabilization. The median survival period of responding patients was 12 months, compared with 3.5 months for nonresponders (P < 0.01). The median survival period for all patients was 6 months. Moderate myelosuppression constituted the treatment-limiting toxicity. The FAM combination is an active and well-tolerated regimen for pancreatic cancer and may have an application in the management of patients with less advanced disease.

Effect of dioctyl sodium sulfosuccinate feeding on rat colorectal 1,2-dimethylhydrazine carcinogenesis.

The 1,2-dimethylhydrazine (DMH) rodent model for colorectal carcinogenesis was used to explore the effect of dietary dioctyl sodium sulfosuccinate (DSS) on carcinogenesis. Inbred male F344 rats were divided into two groups of 84 each and fed the following diets: ground chow and 5% corn oil (control group) and ground chow, 5% corn oil, and 1% DSS (experimental group). All rats received high-dose DMH base, 20 mg/kg/week sc for 20 weeks. Twenty rats per group were killed after 3, 4, 5, and 6 months. Duodenum, small intestine, colon, and rectum were dissected out. Each tumor was measured for size and location and evaluated histologically. The percentage of rats bearing tumors in the control and experimental groups did not differ significantly. In each rat there were fewer gastrointestinal tumors in the DSS-fed group of all histologic types combined, at all organ sites, at 5 and 6 months. This difference between the control and DSS-fed rats reached the level of statistical significance for tumors of the duodenum, colon, and rectum and for total gastrointestinal tumors at the 5th month.