Allan J. Schutt

TREATMENT OF THE MALIGNANT CARCINOID SYNDROME: EVALUATION OF A LONG-ACTING SOMATOSTATIN ANALOGUE

We studied the effects of a long-acting analogue of somatostatin (SMS 201-995, Sandoz) in 25 patients with histologically proved metastatic carcinoid tumors and the carcinoid syndrome. This drug was self-administered by subcutaneous injection at a dose of 150 micrograms three times daily. Flushing and diarrhea associated with the syndrome were promptly relieved in 22 patients. All 25 patients had an elevated 24-hour urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) (mean, 265 mg per 24 hours; range, 14 to 1079), which served as an objective indicator of disease activity. Eighteen of the 25 patients (72 percent) had a decrease of 50 percent or more in their urinary 5-HIAA levels, as compared with the pretreatment values. The median duration of this biochemical response was more than 12 months (range, 1 to greater than 18). Since no serious toxicity was observed, we conclude that SMS 201-995 may be appropriate for use as early therapy in patients with symptoms due to the carcinoid syndrome who have not responded to simpler measures.

Failure of High-Dose Vitamin C (Ascorbic Acid) Therapy to Benefit Patients with Advanced Cancer

One hundred and fifty patients with advanced cancer participated in a controlled double-blind study to evaluate the effects of high-dose vitamin C on symptoms and survival. Patients were divided randomly into a group that received vitamin C (10 g per day) and one that received a comparably flavored lactose placebo. Sixty evaluable patients received vitamin C and 63 received a placebo. Both groups were similar in age, sex, site of primary tumor, performance score, tumor grade and previous chemotherapy. The two groups showed no appreciable difference in changes in symptoms, performance status, appetite or weight. The median survival for all patients was about seven weeks, and the survival curves essentially overlapped. In this selected group of patients, we were unable to show a therapeutic benefit of high-dose vitamin C treatment.

A phase III trial on the therapy of advanced pancreatic carcinoma evaluations of the mallinson regimen and combined 5-fluorouracil, doxorubicin, and cisplatin

One hundred eighty‐seven patients with histologically proven advanced pancreatic adenocarcinoma were randomly assigned to therapy with 5‐fluorouracil (5‐FU) alone, to the Mallinson regimen (combined and sequential 5‐FU, cyclophosphamide, methotrexate, vincristine, and mitomycin C), or to combined 5‐FU, doxorubicin, and cisplatin (FAP). Patients with both measurable and nonmeasurable disease were included and the primary study end point was survival. Among 41 patients with measurable disease, objective response rates were 7% for 5‐FU alone, 21% for the Mallinson regimen, and 15% for FAP. The median interval to progression for each of the three regimens was 2.5 months. Survival curves intertwined with the median survival times for 5‐FU alone and the Mallinson regimen at 4.5 months and for FAP at 3.5 months. Compared with 5‐FU alone, both the Mallinson regimen and FAP produced significantly more toxicity. Neither the Mallinson regimen nor FAP can be recommended as therapy for advanced pancreatic carcinoma. Any chemotherapy for this disease should remain an experimental endeavor.

Combined 5-fluorouracil and radiation therapy as a surgical adjuvant for poor prognosis gastric carcinoma.

Sixty-two patients with resectable but poor-prognosis gastric carcinoma were randomized to either no surgical adjuvant therapy or treatment with 5-fluorouracil (15 mg/kg by rapid intravenous injection X 3) plus radiation (3,750 rad in 24 fractions) initiated 3 1/2 to six weeks postoperatively. Informed consent was obtained after randomization and only from the 39 randomized to treatment. Ten patients refused their treatment assignment. The five-year survival rate for patients randomized to treatment was 23%, and for those randomized to no treatment, 4% (P less than .05). Both the survival distributions and the alive-without-recurrence distributions were significantly different for the two groups (P = .024) and favored treatment assignment. When the treatment assignment group was broken down to those patients actually receiving treatment and those refusing, five-year survival rates were: treated, 20%; treatment refusal, 30%; controls, 4%; the three survival distributions were not significantly different. Thirty-nine percent of patients actually treated had a local-regional component of first clinical recurrence compared with 54% of those who received no treatment. This study does not establish 5-fluorouracil plus radiation as effective surgical adjuvant therapy for gastric cancer but suggests this approach as a possible fruitful area for continued research. This study also illustrates the potential problems that may be encountered in interpreting results when patients are randomized to a study before consent is obtained.

Treatment of the patient with adenocarcinoma of unknown origin

One hundred sixty‐two patients with adenocarcinoma of undertermined origin were treated with 213 chemotherapeutic regimens, primarily 5‐FU by intensive course. Objective response was obtained with 12% of these regimens and was maintained by a median time of 3.5 months and a mean of 9 months. Regimens producing a response rate of 15% or greater included 5‐FU alone, 5‐FU in combination with BCNU, and mitomycin C. Those patients achieving objective response had a significantly longer survival period than those failing to respond. Necropsy examinations revealed the greatest proportion of patients presenting with adenocarcinoma of unknown origin to have their primary neoplasms in the pancreas.

Treatment of Metastatic Islet Cell Carcinoma with a Somatostatin Analogue (SMS 201-995)

We used an octapeptide analogue of somatostatin, SMS 201-995, in dosages ranging from 150 to 450 micrograms/d administered subcutaneously in three daily doses for 1 to 16 months, to treat 22 patients with advanced malignant islet cell carcinomas. Of the 22 patients, there were 9 with gastrinomas; 3 with glucagonomas; 4 with insulinomas; 1 with ectopic production of parathyroid hormone; and 3 with mixed syndromes. The only biochemical marker in 1 patient was pancreatic polypeptide, and 1 patient had no demonstrable peptide production from the tumor. In 14 patients, dramatic decreases in the levels of circulating peptides (insulin, vasoactive intestinal polypeptide, gastrin, and glucagon) have been accompanied by major alleviations of symptoms. Steatorrhea appears to be the most significant toxicity. This analogue of somatostatin may be appropriate for use as early therapy in patients who have symptoms from syndromes related to islet cell carcinomas but in whom there is no immediate threat from tumor progression.

Phase II study of recombinant leukocyte A interferon (rIFN-αA) in disseminated malignant melanoma

Thirty‐one patients with disseminated malignant melanoma received intramuscular recombinant leukocyte A interferon (rIFN‐αA), 50 × 106 units/m2 three times weekly for a planned treatment duration of 3 months. Seven objective regressions (23%), which ranged in duration from 3 to 11.2+ months, were observed. Forty‐two percent of 12 patients who were fully active (Eastern Cooperative Oncology Group [ECOG] performance score, 0) responded compared to 11% of 19 patients with impairment of performance status (ECOG, 1–3). Prior chemotherapy did not influence response rate. For all patients the median time to progression and of survival was 2 months and 6 months, respectively. Four patients had partial regressions in soft tissue (3, 4.6 months), pulmonary (7 months), and prostatic lesions (3 months). The latter was biopsy‐proven and assessed by serial computerized tomography (CT) scans. Three had complete regressions of soft tissue disease (2 patients, 6.4 and 10+ months each), and liver involvement (11.2+ months). The major toxicities were moderate to severe fatigue (87%), anorexia (58%), and confusion (23%). Performance score deteriorated in 84% of patients during the time they were receiving rIFN‐αA. Among the 13 patients whose tumors did not progress for at least 12 weeks, 7 required dose reductions or termination of treatment due to toxicities. Hematologic and hepatic toxicity was transient and of little clinical significance. The study indicates that rIFN‐αA has some antitumor activity accompanied by difficult side effects in patients with disseminated malignant melanoma.

Delta-9-tetrahydrocannabinol as an antiemetic for patients receiving cancer chemotherapy. A comparison with prochlorperazine and a placebo.

The antiemetic activity and side-effects of delta-9-tetrahydrocannabinol (THC) were evaluated in 116 patients (median age 61 years) receiving combined 5-fluorouracil and semustine (methyl CCNU) therapy for gastrointestinal carcinoma. In a double-blind study, patients were randomized to receive THC, 15 mg orally three times a day, prochlorperazine, 10 mg orally three times a day, or placebo. The THC had superior antiemetic activity in comparison to placebo, but it showed no advantage over prochlorperazine. Central nervous system side-effects, however, were significantly more frequent and more severe with THC. With the dosage and schedule we used, and in our patient population of largely elderly adults, THC therapy resulted in an overall more unpleasant treatment experience than that noted with prochlorperazine or placebo. Although THC may have a role in preventing nausea and vomiting associated with cancer chemotherapy, this role must be more clearly defined before THC can be recommended for general use.

A phase II study of combined 5-fluorouracil, doxorubicin, and cisplatin in the treatment of advanced upper gastrointestinal adenocarcinomas.

In a phase II study of 67 patients with upper gastrointestinal carcinomas and measurable disease without previous chemotherapy, we have evaluated the combination of intensive course 5-fluorouracil (5-FU) (300 mg/m2/d for five days) doxorubicin (40 mg/m2 on day 1), and cisplatin (60 mg/m2 on day 1). Courses were repeated every 5 weeks. Among 26 patients with gastric carcinoma, a 50% regression rate was obtained with a median survival for all patients of 9 months. Among 29 patients with pancreatic carcinoma, the regression rate was 21% and the median survival was 4 months. Regressions were also observed in smaller numbers of patients with carcinomas of the gallbladder and ampulla of Vater, as well as in cholangiocellular carcinoma of the liver. Toxic reactions were usually clinically tolerable and consisted primarily of nausea, vomiting, stomatitis, diarrhea, leukopenia, and alopecia. Phase III studies are in progress to place the value of this experimental regimen into clinical perspective.

A double-blind comparison of intensive course 5-fluorouracil by oral vs. intravenous route in the treatment of colorectal carcinoma†

This randomized double‐blind study was designed to compare the therapeutic effectiveness of the oral and i.v. routes for 5‐FU administered in intensive courses to 100 patients with metastatic adenocarcinoma of the large bowel, treated to equivalent levels of toxicity. An oral dose of 20 mg/kg/day × 5 was found to produce comparable G. I., mucocutaneous, and hematologic side effects to a dose of 13.5 mg/kg/day × 5 by rapid i.v. injection. Courses were repeated at 5 weeks. Nine of 47, or 19.1%, treated by the oral route have shown objective response, compared to 14 of 53, or 26%, treated by the i.v. route. If malignant hepatomegaly is considered alone, the response rates are 8 of 23, or 34.8%, by the oral route, and 7 of 22, or 31.8%, by the i.v. route. The mean duration of response for the oral group, 11.1 weeks, was shorter than for the i.v. route, 20 weeks, a statistically significant (p < 0.02) difference. Serial serum 5‐FU levels after two doses of 5‐FU were determined by microbiological assay in 19 patients. For i.v. administration the curves were comparable among different patients as well as in the same patient. There was striking variability, however, for oral administration.