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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.

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.

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.

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

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).

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.

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.

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.

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.

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.

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)

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.

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.