Phase II trial of acivicin in patients with advanced colorectal carcinoma.

Acivicin, an amino acid antibiotic, was administered to 36 adult patients with previously treated metastatic colorectal cancer. The starting dose for good-risk patients was 15 mg/m2/day day given as a short intravenous infusion on 5 consecutive days every 3 weeks. Patients previously treated with radiation therapy, mitomycin, or nitrosoureas and those with inadequate bone marrow reserve received 12 mg/m2 on the same schedule. In 33 evaluable patients, one partial response occurred. Sixteen patients had stable disease with a median time to disease progression of 15 weeks (range 9-27) and a median survival of 8 months. The median survival of the whole group was, however, less than 6 months. Myelotoxicity was mild and resulted in no significant complications. Nonhematological toxicity primarily consisted of nausea, vomiting, drowsiness, depression, and altered mentation. Acivicin given by this schedule is inactive at these dose levels in previously treated patients with colorectal carcinoma.

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).

Chemotherapy for primary adenocarcinoma of the small bowel.

The results of chemotherapy for patients with advanced adenocarcinoma of the small bowel treated at U. T. M. D. Anderson Hospital between 1950 and 1980 were analyzed. A total of 21 single-agent and multidrug chemotherapy regimens were given to 14 patients. 5-Fluorouracil, Adriamycin, mitomycin C, and nitrosourea compounds were the most commonly used chemotherapeutic agents. Fluoropyrimidines, used alone or in combination with the other agents mentioned above, resulted in objective tumor regression in 3 patients (1 partial and 2 minor responses); while 9 additional patients had stable disease. The partial response (PR) was obtained with ftorafur in a patient with supraclavicular lymphadenopathy and hepatic metastasis. Median duration of survival for patients treated with chemotherapy was 9 months. Results of this study show that adenocarcinoma of the small bowel appears to be somewhat less responsive to chemotherapeutic agents than adenocarcinoma arising in the stomach, as reported in the literature. Systematic evaluations of the efficacy of new antitumor agents is indicated to improve results of treatment for advanced small bowel adenocarcinomas.

Thrombocytopenia and gastrointestinal hemorrhage in the cancer patient: prevalence of unmasked lesions.

Some coagulation deficiencies are known to cause bleeding by unmasking existing gastrointestinal pathology, as opposed to directly causing mucosal blood loss. Characteristics and etiology of gastrointestinal hemorrhage associated with thrombocytopenia have not been analyzed. Our objectives were to correlate the distribution and cause of gastrointestinal bleeding, as diagnosed by fiberoptic endoscopy, with the severity of thrombocytopenia. One hundred thirty-three patients were divided into three groups, determined by platelet count at the time of bleeding (group A: less than 20,000/mm3; group B: 20,000 to 40,000/mm3; group C greater than 40,000/mm3). Results of 187 endoscopies revealed unifocal sources of blood loss in over 50% of each group, and diffuse mucosal oozing independent of gastrointestinal pathology was seen in only 1% of group C. The only significant difference (p = 0.04) comparing unifocal, multifocal, and diffuse sources of bleeding was observed between groups A and C, where in the distribution of multifocal or diffuse sources of bleeding was more common in group A. Esophagitis was more common and gastric ulceration less common in group A. No endoscopic complications occurred. Gastrointestinal bleeding associated with thrombocytopenia is most commonly due to co-existent gastrointestinal pathology as opposed to diffuse mucosal bleeding. Even when an inflammatory process, such as esophagitis or gastritis, affects a particular organ, bleeding is usually unifocal or multifocal as opposed to diffuse even in the presence of moderately severe thrombocytopenia.

Gastrointestinal hemorrhage in the cancer patient.

The usefulness of fiberoptic endoscopy, performed to identify the cause(s) of gastrointestinal bleeding in cancer patients was assessed by (1) identifying the clinical presentation of bleeding, (2) evaluating the safety and diagnostic yield of fiberoptic endoscopy, (3) determining the frequency distribution of causes of bleeding, and (4) evaluating the clinical course following acute gastrointestinal bleeding in a cancer patient population. Hematemesis, melena, and hematochezia were observed in decreasing order of frequency as manifestations of bleeding. Of 187 endoscopic procedures performed on 133 patients, 75% were bleeding from benign lesions with the majority due to gastric ulceration, gastritis, or duodenal ulceration. One third of patients with tumors involving the gastrointestinal tract were bleeding from another source. Mortality from major hemorrhage was 8%; 55% of patients were alive at the end of 2 years. Endoscopy was performed without complications and contributed to medical management, angiographic therapy, and surgical planning.

Collagenous colitis.

Collagenous colitis is a newly described entity that clinically manifests itself as watery diarrhea of long-standing duration. The main histopathologic characteristic is the presence of a collagen band immediately beneath the colonic surface epithelium. Ultrastructurally, the collagen is deposited beneath the basement membrane, which is intact. Pathogenetically, an aberrant function of the pericryptal fibroblastic sheath may be involved.

Trichosporon hepatitis.

A 33-yr-old Puerto Rican women was hospitalized for chemotherapy and multiple antibiotic treatment for relapse of acute myelomonocytic leukemia. While she was already receiving amphotericin for suspected Aspergillus infection, she developed hepatomegaly and abnormal liver enzymes with high serum bilirubin. The blood cultures were negative. Percutaneous liver biopsy revealed granulomatous fungal hepatitis identified by cultures as Trichosporon cutaneum. In spite of the continued administration of amphotericin, with the addition of 5-fluorocytosine, Trichosporon was later cultured from her blood, and she succumbed to fungemia and polymicrobial sepsis.

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 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.

Work in progress: hypotension and high-volume biliary excretion following external percutaneous transhepatic biliary drainage.

A review of 120 consecutive percutaneous transhepatic biliary drainage (PTBD) procedures performed for high-grade obstructive jaundice identified seven patients whose bile output exceeded normal volumes. Three patients required intense fluid therapy for intravascular volume depletion. No patient exhibited fever or bacteremia. Hypovolemia due to high-volume biliary drainage was considered responsible for severe hypotension. Hypovolemia secondary to large-volume biliary secretion may complicate PTBD. The pathophysiology of high-volume biliary drainage unrelated to initial decompression is uncertain.

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.

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.