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BACKGROUND The authors conducted a randomized Phase III trial of three treatment regimens for patients with residual, nonmeasurable, intra-abdominal metastatic disease after undergoing resection for primary colorectal carcinoma. METHODS To be eligible for this study, patients had to be both free of other malignancies and capable of starting their therapy within 3–6 weeks after surgery. They were required to have an Eastern Cooperative Oncology Group performance status < 3; to be chemotherapy, radiation, and immunotherapy naive; to have adequate bone marrow, renal, and hepatic function; and to provide written, informed consent. The patients were divided into two cohorts: patients with no demonstrable hepatic metastasis (Group A) and patients with hepatic metastasis (Group B). RESULTS The 229 patients in Group A were randomized to receive either 5-fluorouracil (5-FU) (n = 116 patients) or 5-FU with levamisole (n = 113 patients). The median survival (15.4 months and 15.3 months, respectively, for Groups A and B) was virtually identical. The two groups also were similar in terms of time to treatment progression, which was 7.9 months for group that received 5-FU alone 7.7 months for the group that received levamisole with 5-FU. The 168 patients in Group B with hepatic metastasis underwent a three-way randomization: 5-FU alone (n = 60 patients), 5-FU with levamisole (n = 54 patients), and 5-FU with hepatic irradiation (n = 54 patients). The median overall survival for the three treatment arms were similar, with 17.3 months for the group that received 5-FU alone, 16 months for the group that received 5-FU with levamisole, and 14.4 months for the group that received hepatic irradiation in addition to 5-FU: The time to treatment failure was 6.7 months, 6.8 months, and 8.3 months, respectively, for the three groups. The toxicity experienced by patients was as expected with the regimens, and no differences were observed between any of the treatment groups. The primary toxicities were hematologic and gastrointestinal. There was one treatment-related death due to adult respiratory distress syndrome, which occurred on the first day of the fourth cycle of 5-FU and levamisole. Other Grade 4 toxicities included nine patients with Grade 4 leukopenia, one patient with Grade 4 sepsis, and one patient with Grade 4 gastrointestinal toxicity, including blood loss and diarrhea. CONCLUSIONS This study showed no treatment advantage for any of the combined modalities over 5-FU alone in this group of patients with intra-abdominal, nonmeasurable disease. Cancer 2001;91:1020–8. © 2001 American Cancer Society.

Background. The purpose of this study was to determine by randomized, controlled, double-blind evaluation whether therapy with the somatostatin analogue, octreotide, would delay tumor progression and improve survival of patients with metastatic colorectal carcinomas who were ambulatory with no significant symptoms. Methods. Two hundred sixty patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 and without symptoms related to colon cancer were randomized to receive 150 μg of octreotide subcutaneously three times daily or, initially, no treatment. After 91 patients were entered in the double-blind study, saline placebo injections were used for patients in the control arm. Results. The randomization culminated in balanced assignment of patients with respect to disease site(s), presence or absence of measurable or evaluable disease, and interval from diagnosis of metastasis to protocol entry. Steatorrhea and diarrhea, usually mildly severe, resulted more often from treatment than from the placebo. The major end points were time to progression and survival. Curves for both parameters overlapped in the blind and open trial segments. Conclusion. Octreotide at a dose of 150 μg given three times daily is not effective therapy for patients with advanced asymptomatic colon carcinoma. Cancer 1995;76:961–6.

Purpose: A recent clinical trial in patients with resected node-positive colon cancer demonstrated a clear survival advantage for patients treated with adjuvant 5-fluorouracil and levamisole. This finding led to interest in development of a Phase III trial comparing 5-fluorouracil and levamisole with 5-fluorouracil, levamisole, and radiation therapy in colon cancer patients at high risk for local recurrence. A prospective evaluation of 5-fluorouracil, levamisole, and radiation therapy was undertaken with the goal of establishing a satisfactorily tolerated regimen. Methods and Materials: Fifteen patients were studied who had locally advanced or locally recurrent upper abdominal gastrointestinal cancer (11 patients) or large bowel cancer confined to the pelvis (4 patients). The tumor and regional lymph nodes received 45 Gy in 25 fractions. Patients with pelvic tumors subsequently were treated with a radiation boost of 5.4–9 Gy in 3–5 fractions. Systemic therapy consisted of 5-fluorouracil, 450 mg/m 2 , given intravenously for 3 consecutive days during the first and last weeks of radiation therapy. Levamisole, 50 mg, given orally 3 times daily was used for 3 consecutive days concurrent with initiation of radiation therapy and 5-fluorouracil, at the beginning of the third week of radiation therapy, and concurrent with the final 3-day course of 5-fluorouracil. Results: Therapy was generally well tolerated. In two patients, ≥ grade 3 nonhematologic toxicity developed and consisted of transient small bowel obstruction in one and severe nausea and vomiting related to levamisole administration in another. One patient experienced grade 3 hematologic toxicity with a leukocyte count nadir of 1,600 cells/μL. Conclusions: These results are similar to the toxicity profile reported elsewhere for radiation therapy and 5-fluorouracil. The addition of levamisole to radiation therapy and 5-fluorouracil does not appear to increase toxicity significantly.

BACKGROUND Modest activity for doxorubicin has been detected repeatedly for the therapy of advanced hepatocellular carcinoma. Variable activity in this disease also has been documented for alpha-interferon. Preclinical data indicated the possibility that alpha-interferon could enhance or add to the cytotoxic effect of doxorubicin. METHODS The authors evaluated the use of alpha-interferon at a dose of 12 x 10(6) units/m2/day for 5 days given by intramuscular injection plus doxorubicin 25-40 mg/m2 given intravenously on day 3 (both repeated every 4 weeks) for the treatment of advanced hepatocellular carcinoma. RESULTS Among 31 eligible patients treated, there was only one instance of objective tumor regression. The median survival for all patients was 10 months. Both hematologic and nonhematologic toxicity were significant but tolerable to the patients. CONCLUSIONS The 3% response rate indicated that, by the method used, the addition of alpha-interferon to doxorubicin does not improve the clinical effectiveness. This combination cannot be recommended for further study.

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.

We report the fourth case of cerebral demyelinating disease associated with 5-fluorouracil and levamisole hydrochloride therapy for adenocarcinoma of the colon. The initial manifestations included subacute progressive decline in mental status, ataxia, dysarthria, and diplopia. Magnetic resonance imaging of the head demonstrated multifocal enhanced lesions in the white matter. The patient experienced improvement, without corticosteroid treatment, from 2 weeks to 4 months after cessation of chemotherapy.

The study was a Phase II randomized study to evaluate the efficacy of new agents for the treatment of advanced gastric carcinoma. Patients were randomized to receive single agent chemotherapy with mitoxantrone, etoposide, aclacinomycin-A or spirogermanium. The patients were stratified by prior use of chemotherapy, prior doxorubicin use and ECOG performance status. Patients with a history of cardiac disease or prior doxorubicin exceeding a dose of 400 mg/m2 were restrictively randomized to sopirogermanium or etoposide only. One hundred and fourteen patients were registered for the study. Among 98 evaluable patients there were only two partial responses (both in the etoposide arm), and one complete response in the mitoxantrone arm. The median survival on the study was 3.3 months. One hundred and six patients were analyzable for toxicity. There were four treatment-related deaths and four life-threatening toxicities. Because of low response rates and relatively high toxicities the studied compounds were not deemed worth further investigation for advanced gastric cancer.

Because prolonged estrogen therapy can initiate hepatic adenomas, and estrogen receptors (ER) are found in 33% of hepatocellular carcinomas, a Phase II study of antiestrogen therapy was initiated in patients with hepatocellular carcinoma. Tamoxifen (20 mg twice a day) was administered to 33 patients who had biopsy proven and measurable hepatocellular carcinoma and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. No patient had a complete or partial antitumor response; eight patients had stable disease ranging from 5 to 13 months. The median survival time for all patients was 6 months from the initiation of tamoxifen therapy. Four patients have continuing long-term survival of 18+, 22+, and 39+ months.

From March 1981 to November 1987, 87 patients with histologically confirmed pancreatic adenocarcinoma, unresectable but confined to the pancreatic region, were randomized to two treatments. The standard treatment was 40-50 Gy external-beam radiation therapy (RT) to gross tumor plus potential microscopic tumor with a 5 Gy boost to gross tumor plus a 1.5-2.0 cm margin, using multiple fields and 5-fluorouracil (5-FU) 500 mg/m2/d intravenously by rapid infusion. The 5-FU was given each of the initial 3 days of each of three 20 Gy radiation courses. The experimental treatment used identical radiation fields, but the two Gy daily radiation fractions were administered in a continuous course to a total dose of 50 Gy. Hycanthone was administered 60 mg/m2 intravenously within 2 to 4 hr during each day of the 5-day course of infusions during the first and fifth weeks of radiation therapy. There was no statistically significant difference between treatment arms in survival (p = 0.82) or disease-free survival (p = 0.27). Seven percent of hycanthone-treated patients demonstrated hepatic toxicity which was usually mild in nature. There was, however, one death due to hepatic toxicity.

We observed a 45% response rate from the combination of VP-16, bleomycin, and cisplatin among 20 patients with nonsquamous cell head and neck cancer. The regressions were partial and typically occurred within 1 to 2 months of commencing treatment. The median response duration for responding patients was 3 months. Median survival of responders was 8 months, similar to that of all study participants. Gastrointestinal and hematologic sequelae were predictable and manageable. This regimen may provide some transient palliation for selected patients with these neoplasms, but no substantive impact on survival.

Thirty-one patients with disseminated malignant melanoma received intramuscular recombinant leukocyte A interferon (rIFN-alpha A), 50 X 10(6) 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-alpha A. 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-alpha A has some antitumor activity accompanied by difficult side effects in patients with disseminated malignant melanoma.

33 patients with advanced adenocarcinoma of the colon or rectum were treated with isophosphamide given intravenously at a dose of 4 g/m2 every 3 weeks. Patients receiving the full dose in a

This radomized 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 times 5 was found to produce comparable G.I., mucocutaneous, and hematologic side effects to a dose of 13.5 mg/kg day times 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 less than 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.

Twenty-two patients were given progressively increasing doses of Cytembena to determine toxicity patterns and to establish a dosage which produces definite but clinically tolerable toxicity when the drug is given by intravenous injections in a 5-day intensive course. Toxicity consisted primarily of nausea, vomiting, arm pain, and transiently decreased renal function. At higher doses, an "autonomic-storm" phenomenon was observed consisting of hypertension, tachycardia, tachypnea, hyperperistalsis, frequent explosive defecation, facial flushing and paresthesias, and chest pain with accompanying ischemic EKG changes. There was no evidence of mucocutaneous, hepatic, or hematologic toxic effects. Toxicity was dose-related, first being recognized at a daily dose of 300 mg/m2 and becoming clinically intolerable at a daily dose of 475 mg/m2. No permanent damage was observed in any of the organ systems monitored. An acceptable treatment regimen for most patients is 400 mg/m2/day for 5 days. Patient discomfort can be reduced by dividing each day's dose into two intravenous injections given at an interval of at least 6 hours. Coronary artery disease and impaired renal function should be contraindications to Cytembena therapy, and caution should be employed in the patients with significant impairment of liver function. Two of 22 patients, both with far-advanced carcinoma and previous chemotherapy failures, showed a favorable objective response to Cytembena therapy. Phase II studies to assess the magnitude of the drug's antineoplastic activity seem warranted.

Thirty patients with advanced head and neck cancer of diverse histologies received the combination of cis-diamminedichloroplatinum (CDDP) (100 mg/m2) and 5-fluorouracil (5-FU) (1,000 mg/m2/24 hours X 4 days) at 3-4 week intervals. Among all study participants, the median time to progression was 3.9 months and the median survival was 7.2 months. Among 20 patients with squamous cell carcinoma, we observed five objective regressions (25%). None of the responders had prior chemotherapy; four had extensive prior radiation therapy. Among 10 patients with non-squamous cell carcinoma neoplasms, we detected three objective responses (30%). Histopathology of the responding patients included poorly differentiated sarcoma, anaplastic carcinoma, and malignant mixed parotid tumor. Significant gastrointestinal toxicities included moderate-to-severe nausea (60%), vomiting (43%), and stomatitis (57%). Leukopenia (less than 4,000 cells/mm3) and thrombocytopenia (less than 130,000 cells/mm3) affected 78% and 41% of patients, respectively, without sepsis or hemorrhage.

Sixty-one of 76 patients entered on a prospective randomized trial of neocarzinostatin ( NCZ ) versus m-AMSA or doxorubicin were eligible for analysis. Among these 61 patients at least one episode of severe toxicity was documented in 39% of patients on NCZ and 58% on m-AMSA. Fifty-one of the 61 patients were previously untreated with chemotherapy. Among these 51 patients objective response was documented in two of 25 patients treated with NCZ , none of 17 treated with m-AMSA, and one of nine treated with doxorubicin. Among previously untreated North American and European (NA/E) patients the median survival times were: NCZ 11 weeks and m-AMSA 12 weeks. The data on South African (SA) patients with similar entrance criteria entered on earlier Eastern Cooperative Oncology Group trials were analyzed with that from the randomized trial and show that for SA patients the median survival times were: NCZ , 11 weeks (31 patients); m-AMSA, 13 weeks (33 patients); and doxorubicin, 15 weeks (29 patients).

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. Thi...

Four cases of primary gastric malignant lymphoma followed years later by adenocarcinoma of the stomach are described. Review of the literature revealed eleven other cases of these two lesions occurring in the same patient. In our four cases gastric adenocarcinoma developed many years after successful treatment of primary gastric lymphoma by partial gastrectomy. In three patients gastrectomy had been followed by radiation treatment to the upper abdomen. The relationship between the two tumors is discussed, including the possible role of treatment of the lymphoma in the development later of gastric adenocarcinoma. It is important to consider the possibility of the later development of a second primary gastric cancer in a patient who develops gastric symptoms, after successful treatment for primary gastric neoplasm.

Twenty-eight patients with measurable or evaluable, regionally advanced or metastatic head and neck cancer received the combination of cyclophosphamide (C), adriamycin (ADR), and a 24-hour infusion of cis-diamminedichloroplatinum (II) (P). Most patients had received extensive prior surgery and radiation therapy, but only two had prior chemotherapy. We observed a 46% response rate (13/28) which included five complete responders and eight partial responders. Nine of the 13 patients responded within the initial month of treatment. The median response duration for the 13 responding patients was 7.5 months. Moderate to severe nausea and vomiting, and alopecia were the most significant toxicities. Myelosuppression (WBC less than 4,100 cells/mm3) occurred in 90% of patients but there were no episodes of sepsis, nor did we detect any meaningful impairment in renal function.

Preclinical studies have demonstrated enhanced cytotoxic effects of 5-fluorouracil (5-FU) when given in conjunction with N-phosphonacetyl-L-aspartate (PALA) or thymidine in several murine systems. Early clinical studies have demonstrated significant delayed depletion of pyrimidine nucleotides in tumor biopsy specimens following systemic PALA administration and prolonged serum levels of 5-FU after thymidine administration. Each of these biochemical effects would be anticipated to augment the cytotoxic activity of 5-FU. A phase II trial of a timed sequential administration schedule of PALA, thymidine, and 5-FU was conducted in 37 patients with advanced measurable colorectal cancer. Ten of 37 patients (27%) experienced objective tumor responses with a median response duration of 22 weeks, and 18 patients (49%) had stable disease for a median duration of 20 weeks. Six of 13 patients (46%) with anaplastic histology and/or rapidly progressive tumors experienced high-quality tumor responses. Leukopenia and neurologic side effects were the primary toxicities, including one death caused by sepsis. This regimen has demonstrated striking alteration in the 5-FU dose-effect relationship and definite antitumor activity in patients with advanced colorectal cancer. Further trials in patients with anaplastic carcinomas of the colon or other anatomic sites should be considered.

A regimen utilizing 5-fluorouracil at a dose of 30–35 mg/kg as one single rapid injection was contrasted with a schedule of 5- fluorouracil administered rapidly, intravenously at a dose of 13.5 mg/kg/day for each of five successive days in a randomized clinical trial in 98 patients with various metastatic adenocarcinomas. Fifty-one of these patients had carcinoma whose primary site of origin was unknown. Nine of 50 patients had an objective regression on the 5-day schedule (8 of 25 with unknown primaries) contrasted with 1 of 48 (0 of 26 with unknown primaries) regressions utilizing a single injection technique. The toxicity encountered included myelosuppression in about 60% of patients in both groups but gastrointestinal side effects were statistically significantly less utilizing the single injection technique. In this group of patients, 5-fluorouracil as a single injection technique proved to be significantly inferior compared to the conventional 5-day course of this drug.

A clinical trial to determine the antitumor activity of recombinant interferon-gamma (rIFN-gamma) was conducted in 36 patients with advanced colorectal cancer. Severe constitutional symptoms were seen in the first five patients who received rIFN-gamma as a 2- to 4-hour intravenous infusion, and this method of administration was therefore abandoned. One transient partial tumor regression was observed in the 31 patients who received treatment by the intramuscular route of administration. Although a clinically tolerable regimen suitable for outpatient administration was developed, rIFN-gamma given in this dose and schedule had minimal antitumor effect for the treatment of advanced colorectal cancer. NK activity was depressed within 48 hours of rIFN-gamma administration but became significantly higher than normal controls or pretreatment levels during therapy despite disease progression, indicating discordance between augmentation of this immune parameter and tumor status. Serum CA 19-9 levels were unusually high and increased significantly more than CA 125 or CEA during rIFN-gamma treatment. This observation suggests that rIFN-gamma could augment localization of anti-CA 19-9 used to diagnostically image or therapeutically target a labeled chemotherapy agent to tumor in those patients expressing this antigen.

Sixteen patients with regionally advanced or disseminated nosquamous cell (NSC) head and neck cancer received a monthly combination chemotherapy regimen of cyclophosphamide (C), adriamycin (A), and cis-diamminedichloroplatinum (II) (P), or P, as a single agent administered by either bolus or 24-hour infusion technique. Fifteen patients had received extensive prior surgery and/or radiation therapy. Three patients had prior chemotherapy. A response rate of 50% was achieved (8/16); there were 2 complete regressions and 6 partial regressions. The estimated median time to progression (TTP) for the entire group of 16 patients was 6.0 months and the estimated median survival was 14.0 months. Seven of 8 responders have progressed, with a median TTP of 10.7 months. Virtually all patients experienced alopecia as well as nausea and vomiting, which was more pronounced with the bolus administration of P. Myelosuppression was tolerable; there was no clinically significant renal impairment.

Fifty-five patients with metastatic carcinomas of unknown primary site (50 adenocarcinomas) were randomized, after stratification, to treatment with either mitomycin and doxorubicin (MA) or mitomycin, doxorubicin, and cisplatin (MAP). There was a moderate but nonsignificant improvement in regression frequency (14 vs. 27%) and a slight but also nonsignificant worsening of survival (median 5.5 months vs. median 4.6 months) by the addition of cisplatin at 60 mg/m2 to the MA regimen.

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.

Any malignancy, including tumors in the colon, usually presents systemically in the traditional way of all tumors and locally according to the specific function of the organ involved. Important clues may be missed if one does not realize that, for some unknown reason, the malignancy may mimic endocrine and other specialized body cells. Any atypical feature of these systemic manifestations should be viewed with suspicion and investigated completely to establish that it is not due to an underlying malignancy.

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.

Because 1,2:5,6-dianhydrogalactitol (NSC-132313 (DAG; the main conversion reaction product of the treatment of dibromodulcitol by mild akali or human serum) showed considerable antitumor activity in various mouse and rat tumor systems, a phase I study in 50 patients was conducted with five daily iv treatments repeated every 6 weeks. Thrombocytopenia was the dose-limiting toxicity. At a dose of 40 mg/m2/day for 5 days, the median platelet nadir was 31,000/mm3 and occurred on day 20; the plate count returned to normal within 8 days. At the same dose, the median white blood cell (WBC) nadir was 2,300/mm3 also on day 20-, the WBC count returned to normal within 7 days. Anemia, nausea, and vomiting were usually mild to moderate. No renal, hepatic, central nervous system, cardiac, or pulmonary toxicity was identified. Antitumor effects of DAG were observed in patients with renal, bladder, and small-cell lung cancers. An iv dose of 20-30 mg/m2/day for 5 consecutive days, repeated every 5-6 weeks, was recommended for phase II studies.

Thirty-three patients with advanced measurable gastric cancer were treated with a combination of mitomycin C and triazinate. Twenty-nine of these patients had failed prior chemotherapy. Nine patients (27%) had an objective tumor response (median duration, 10 weeks). Median survival of all patients treated was 21 weeks. This study demonstrates that carefully selected patients with advanced gastric cancer who have failed a trial of chemotherapy, but are still ambulatory and maintaining adequate nutrition are appropriate subjects for studies of new treatment regimens. Based on the observed objective tumor response rate and median patient survival, further studies of these drugs in combination for the treatment of advanced gastric cancer are indicated.

Bisantrene was administered by 72-h continuous infusion at a dosage level of 240 mg/m2 to 17 patients with metastatic breast cancer who had received only one prior chemotherapy regimen and no prior doxorubicin. Three patients (18%) achieved partial regressions lasting 51, 106, and 213 days. For all patients, the median time to disease progression was 83 days and median survival was 280 days. Eleven patients received doxorubicin after removal from protocol and were evaluable for response, and four (36%) achieved a partial regression. We conclude that bisantrene administered by the method we employed is not associated with substantial clinical benefit in this population of patients.

In most areas of the world the annual incidence of gastro-intestinal cancer is greater than that of any other organ system. It is estimated that 102,000 Americans will die of gastrointestinal cancer in 1975 (1).

A prospective evaluation of 149 patients with Dukes' B2 or C colorectal carcinoma, including periodic history, physical examination, chest radiograph, liver function tests, complete blood count, carcinoembryonic antigen (CEA) radioimmunoassay, barium enema, and endoscopic studies, has been underway since 1976. Thirty-four patients have had recurrence. This study suggests that the history and CEA are the most sensitive noninvasive methods with which to detect recurrent tumors but are unlikely to indicate recurrence at a therapeutically advantageous stage.

We evaluated the ability of polyacrylamide gel electrophoresis (PAGE) to measure protein band No. 1 (PB1) in serum as a means of discriminating between the sera of cancer patients and controls. Serum samples from 123 cancer patients, 155 subjects without clinically diagnosed cancer, and 6 members of families with a high incidence of cancer (total, 284) were obtained in Israel. An additional 214 serum samples from 80 cancer patients and 134 subjects without cancer were obtained from the Mayo Clinic-National Cancer Institute Serum Bank. Although a significantly higher proportion of serum specimens from cancer patients had positive results for PB1 by the PAGE method, the test at its current stage of development does not seem sufficiently discriminating for use in screening for cancer.

Twenty-five patients with evaluable histologically confirmed inoperable metastatic sarcomas were treated once every four weeks with cyclophosphamide, doxorubicin, and cisplatin in doses of 400, 40, and 60 mg/m2, respectively. Cyclophosphamide and doxorubicin were given by rapid intravenous injection followed immediately by cisplatin by slow intravenous infusion (2-6 hr) in 1 liter of 0.45% saline with mannitol added. Leukopenia, alopecia, and vomiting were common side effects and three patients refused further treatment because of vomiting following their initial courses. No drug-related deaths occurred and we removed no one from the study because of toxicity problems. Among the 9 patients who experienced objective tumor regression were 2 of 2 with hemangiosarcoma, 3 of 5 with malignant fibrous histiocytoma, 3 of 5 with osteosarcoma, and 1 of 1 with pleomorphic liposarcoma of bone. Although not therapeutically gratifying, these results appear to be better than any previously observed at our institution.

Forty-four patients with unresectable primary, residual, or recurrent colorectal carcinoma confined to the pelvis were randomized to treatment with split course megavoltage radiotherapy alone (5,000 rad given over 7 weeks) or in combination with the intradermal administration of the methanol extraction residue of BCG (MER) over an eight-month period. No improvement was observed in frequency of symptomatic palliation, interval to progression, or survival among patients receiving MER. Furthermore, there was no evidence of enhanced immunological status in patients receiving MER as compared to those receiving radiation alone. Although temporary pain relief was seen in 94% of patients with pretreatment pelvic or perineal pain, 37 patients (84%) have experienced subequent progressive malignant disease. Regional recurrences within the radiotherapy port were observed in 28 of 31 patients who were evaluable for analysis of pattern of sites of initial progression. Eleven of the 28 patients with local failure also had distant metastasis at the time of tumor progression. There was no discernible clinical value associated with MER treatment in combination with radiotherapy as employed in this study. The high frequency of pelvic recurrence following radiotherapy at the dose and schedule we employed highlights the need for more effective treatment strategies for this group of patients.

Thirty patients with disseminated malignant melanoma received the combination DTIC, BCNU, actinomycin D, and vincristine. The objective response rate was 17 percent concomitant with moderate-to-severe nausea and vomiting in 80 percent of patients. Hematologic toxicity was transient. In the dose and schedule that we used, the four-drug regimen does not offer meaningful benefit for patients with advanced melanoma.

Excerpt Managing patients with the carcinoid tumor, whose condition is sometimes complicated by the carcinoid syndrome, presents a difficult challenge. Surgical treatment is usually curative in ear...

A total of 25 patients with metastatic breast cancer who had failed one prior chemotherapy regimen and had not received prior treatment with doxorubicin were treated with menogaril (200 mg/m2 i.v. over 1 h) every 4 weeks. Four patients (16%) achieved partial regressions lasting a median of 46 days. The median time to progression for all patients was 60 days and the median survival was 264 days. Seventeen patients subsequently received doxorubicin after removal from protocol and six (35%) achieved objective regression. We conclude that menogaril administered by the method that we employed has marginal activity in women with metastatic breast cancer after failure of prior chemotherapy. Failure to respond to menogaril does not preclude response to subsequent treatment with doxorubicin.

The clinical antiemetic effect of benzquinamide by oral route at a dosage of 100 mg 3 times daily was evaluated by a controlled double-blind method in 183 studies of patients treated with 5-fiuorouracil. The incidence of nausea and vomiting in benzquinamide-treated patients was equal to that in placebo-treated patients and significantly higher than that in patients treated with prochlorperazine, 10 mg 3 times daily. Sedation was the only significant side effect observed. and this occurred at essentially equal rates in benzquinamide- and prochlorperazine-treated patients.

Adjuvant chemotherapy consisting of 5-fluorouracil and semustine was given to 26 patients who had undergone resection (with curative intent) of hepatic metastatic lesions from a primary colorectal carcinoma. Our objective was to obtain preliminary observations regarding the effectiveness of this regimen for improving the long-term survival associated with hepatic resection alone in these patients (the overall 5-year survival after hepatic resection is 25% at our institution). At the time of analysis, the malignant disease had progressed in 19 of our patients, and 17 patients had died. For all patients who receive adjuvant chemotherapy, the median duration of survival is 34 months, and the estimated 5-year survival is 15%. Statistical analysis indicated no significant advantage in survival for the study patients in comparison with 26 control patients who were treated with hepatic resection only and were closely matched for prognostic factors. Because 5-fluorouracil plus semustine conferred no apparent beneficial effects as an adjuvant treatment in this exploratory study, we do not recommend a definitive randomized trial of this regimen.

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.

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.

The familiar malignancy of the gastrointestinal tract may present some difficulty in early diagnosis but is ultimately recognized by its local effect on the organ involved, as well as by symptoms from dysfunction of adjacent viscera. Adding another dimension to the problem of diagnosis of gastrointestinal malignancies is the unusual tumor that may or may not have local manifestations but predominantly presents systemic symptoms foreign to the accepted function of the cells of the gastrointestinal tract. These aberrant symptoms may be due to the production of abnormal hormones, cellular metabolites with generalized endocrine disturbances, immunologic reactions, or other metabolic abnormalities that are even less well understood. The size and duration of the primary tumor and the presence or absence of metastasis frequently have little or no correlation with the systemic presentation. A few genetic syndromes may make their appearance known with systemic features which, if recognized, may provide early diagnostic clues heralding the presence of an underlying gastrointestinal lesion carrying a high risk of future carcinoma.

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.

• Thirteen patients with functioning carcinoid syndrome and hepatic metastases were surgically treated. Localized hepatic metastases were resected in five patients, and diffuse hepatic metastases were treated with hepatic artery ligation in eight. There were no postoperative deaths, and follow-up ranged from six to 46 months. All patients were symptom-free after operation. In all patients with resection, levels of 5-hydroxyindoleacetic acid (5-HIAA) returned to normal or near normal, whereas in patients who underwent hepatic artery ligation, the average reduction in 5-HIAA level was 76%. Three patients died during the follow-up period—two of metastatic carcinoids and one without evidence of disease. The mean duration of response was 36 months for resection and 4.8 months for hepatic artery ligation. The addition of postoperative intra-arterial chemotherapy and sequential systemic chemotherapy may enhance the response to hepatic artery ligation. ( Arch Surg 1983;118:537-542)

Serum carcinoembryonic antigen (CEA) tests were performed on 36 patients with histologically proved locally recurrent or residual malignant disease after resection of colorectal carcinoma but with no clinical evidence of distant metastasis. Only nine patients (25%) had abnormal CEA levels of greater than 5 ng/ml despite the fact that most patients had had symptoms of recurrence for several months. Among the nine of our patients, none had CEA values greater than 5 ng/ml, and only three had levels greater than 2.5 ng/ml (3.4, 3.8, and 4.7 ng/ml). The CEA assay is not a sensitive test for early detection of recurrence of colorectal carcinoma. ( JAMA 239:1065-1066, 1978)

Serial carcinoembryonic antigen (CEA) measurements were evaluated in a group of 263 patients undergoing systemic chemotherapy for metastatic colorectal carcinoma. Initial CEA levels were not found to be of value in predicting the likelihood of subsequent tumor response. Although a general relation between serial CEA measurements and clinical tumor measurements was noted, these measurements were discordant in a substantial proportion of patients. Tumor measurements as an index of response to therapy were strongly correlated with survival, whereas changes in CEA values and patient survival were not correlated at a statistically significant level. Serial CEA measurements were perhaps of some value in predicting progression of malignant disease, and were roughly comparable to serum alkaline phosphatase assay in assessing response of liver metastasis to chemotherapy. Overall, serial CEA measurements added little to the standard clinical assessment of patients with advanced colorectal carcinoma receiving chemotherapy.