Philip S. Schein

A comparison of combination chemotherapy and combined modality therapy for locally advanced gastric carcinoma

This controlled trial compared the survival of 90 patients with locally advanced gastric carcinoma treated with either chemotherapy alone (5‐FU and methyl‐CCNU) or external radiotherapy of 5000 rad combined with the same chemotherapy. The minimum period of followup is 4 years. During the initial 12 months, combined modality therapy was associated with an increased number of early deaths attributable to progression of tumor within the radiation field, or nutritional and hematologic complications. During the second to fourth years of followup, patients treated with combined radiation therapy have shown a significantly lower death rate compared to those treated with chemotherapy alone, with eight of 45 patients alive and disease‐free. Patients who received only chemotherapy, in contrast, have demonstrated a continued probability for tumor relapse and death, with three of 45 patients alive at 4 years. Palliative resection of the primary tumor was associated with an improved survival, independent of the form of postoperative therapy employed. It is possible that the superior late survival achieved with combined modality therapy in this program can be further improved with measures to decrease the toxicity of upper abdominal irradiation, and with the use of more effective forms of chemotherapy.

5-fluorouracil, adriamycin, and mitomycin-c (fam) combination chemotherapy in the treatment of advanced gastric cancer

Thirty‐six patients with advanced measurable gastric cancer were treated with a new combination chemotherapy program consisting of 5‐fluorouracil, Adriamycin and mitomycin‐C (FAM). Fifty percent of patients achieved an objective partial response. The median duration of remission was 9.5 months and the median survival for responding patients was 13.5 months, with 2 remaining alive at 14 and 26 months. The median survival for nonresponding patients was 3.0 months and all were dead by 6 months after initiation of therapy. The median survival of all 36 patients treated with FAM was 5.5 months. An analysis of possible prognostic variables including initial performance status, resectability of the primary gastric tumor and histologic differentiation of the neoplasm failed to account for differences in patient response and survival. The FAM regimen was well tolerated, and produced only moderate bone marrow suppression. These results demonstrate that some patients with advanced gastric cancer can be effectively palliated with FAM chemotherapy. Phase III trials are warranted to assess the effect of the FAM regimen on the survival of patients with advanced gastric cancer.

Phase II trial of streptozotocin, mitomycin-C and 5-fluorouracil (SMF) in the treatment of advanced pancreatic cancer

Ten of 23 patients with advanced measurable adenocarcinoma of the pancreas achieved an objective response after treatment with a regimen consisting of streptozotocin, mitomycin‐C and 5‐fluorouracil (SMF). The median duration of response is in excess of 7 months, and responding patients have lived significantly longer than patients with progressive disease (7.5+ months vs. 3 months). The SMF regimen was adequately tolerated. Principal toxicities included myelosuppression, which was generally mild, nausea and vomiting. There was reversible nephrotoxicity in the form of proteinuria in 30% of patients and persistent azotemia in 9% of patients.

Tetracycline and quinacrine in the control of malignant pleural effusions. A randomized trial.

Eighteen patients with advanced metastatic malignancy who had 21 pleural effusions requiring sclerosis for control were randomly allocated to intrapleural therapy with tetracycline or quinacrine. Tetracycline produced partial or complete control of the effusion in ten of 12 trials for a median duration of 6 months (range 1.5 to 22 months). Partial or complete control was obtained in nine of ten trials with quinacrine, for a median duration of 3 months (range 1 to 13 months). All complete responders who died achieved control of their effusions until their terminal admissions despite clinical evidence of overt systemic tumor progression in the intervening period. Single‐dose tetracycline therapy was accompanied by less fever (p < 0.04) and less pleuritic pain (p = 0.09) than quinacrine. Tetracycline is effective, well tolerated, easily administered, and should be considered as the initial therapy for malignant pleural effusions requiring pleural sclerosis.

Cachexia of malignancy. Potential role of insulin in nutritional management

Patients manifesting the syndrome of cachexia of malignancy exhibit an abnormal diabetic glucose tolerance. In our patients this has been correlated with a marked resistance to administered insulin, while insulin receptors on monocytes are normal. Lipolysis remains responsive to the effects of insulin. The oxidation of FFA, as a substrate for metabolism, has been reported to be increased, and the utilization of glucose as a metabolic fuel is reduced. Increased Cori cycle activity has been demonstrated, which produces an enhanced gluconeogenesis from lactate and amino acids; there is an expenditure of 6 ATP for the synthesis of each mole of glucose. An attempt to interrupt the Cori cycle in man, using hydrazine sulfate to inhibit the enzyme phosphoenolpyruvate carboxykinase, has not resulted in reproducible clinical benefit. However, successful treatment of the underlying tumor may produce a total reversal of the cachexia syndrome, suggesting that neoplasms have the potential to elaborate an, as yet, unidentified metabolic toxin. The use of insulin to counteract the reported abnormalities should be examined as a possible supportive measure in the total nutritional management of the cancer patient.

Carcinoembryonic Antigen: Its Role as a Marker in the Management of Cancer. A National Institutes of Health Consensus Development Conference

Excerpt A consensus development conference was held 29 September to 1 October 1980, at the National Institutes of Health, to address issues concerning the role of carcinoembryonic antigen (CEA) as ...

A phase II trial of high‐dose intravenous interferon alpha‐2 in advanced colorectal cancer

Twenty‐one patients with metastatic colorectal cancer were treated with high‐dose intravenous interferon alpha‐2 (30–50 × 106 units/m2) administered daily for 5 consecutive days. Courses of therapy were repeated every 2 to 3 weeks. No tumor responses were seen among 15 evaluable patients. In two subjects, disease remained stable for 3 and 7 months, respectively. Toxicity was substantial and a de‐escalation of dose was frequently required. Fevers, gastrointestinal symptoms, fatigue, leukopenia, and elevated serum transaminases were common. High‐dose interferon was found to be ineffective in the treatment of metastatic colorectal cancer. A daily dose of 50 × 106 units/m2 was greater than the maximum tolerated dose in this group of patients.

Efficacy of tetrahydrocannabinol in patients refractory to standard antiemetic therapy

SummaryOral delta-9-tetrahydrocannabinol (THC), 15 mg/m2, was compared to prochlorperazine (PCZ), 10 mg. for the control of cancer chemotherapy-related emesis. Thirty-six patients whose vomiting was refractory to standard antiemetic therapy were entered in this randomized comparative cross-over study. THC decreased nausea and vomiting in 23 of 36 (64%) patients compared to 1 of 36 receiving PCZ. THC efficacy was not dependent on the class of antineoplastic-agent inducing the emetic symptoms, age of patients or type of sensorial change experienced. Using the 15 mg/m2 dose, all patients experienced transient sensorial changes, characterized as a pleasant “high” in 19 or a variable state of dysphoria in 17 cases. This study confirms the usefulness of THC in patients whose chemotherapy-induced nausea and vomiting is refractory to other standard antiemetics. While excellent antiemetic control was achieved at the dosage 15 mg/m2, dysphoria was encountered at this dose level and we recommend that an initial dose of 5 mg/m2 which, if necessary, can be carefully increased to achieve maximum antiemetic benefit.

Tumor 5-fluorodeoxyuridylate concentration as a determinant of 5-fluorouracil response.

The antitumor activity of 5-fluoruoracil (5-FU) for two murine colonie adenocarcinomas was correlated with the concentration and the clearance of the active antimetabolite, 5-fluorodeoxyuridylate (FdUMP). Mice inoculated with a cell suspension of murine colonic adenocarcinomas 38 and 51 were treated with 5-FU (100 mg/kg i.p.) on 3 day post-transplantation. For mice bearing adenocarconoma 38, treatment with 5-FU was associated with a 97 per cent reduction in mean tumor weight a day 30 and a 77 per cent reduction at day 37 of tumor growth. In contrast, mice bearing colonic adenocarcinoma 51, treated with the same dose schedule of 5-FU did not demonstrate a reduction in the rate of tumor growth in vivo. Two hr after i.p. injection of 5-FU (100 mg/kg) the intracellular concentration of free FdUMP in the sensitive tumor 38 was 560 fmoles/μg of DNA. The active antimetabolite was maintained at a concentration in excess of 100 fmoles/μg of DNA for 72 hr. In contrast, the 2-hr free FdUMP concentration in the resistant tumor line 51 was 240 fmoles μg of DNA(P < 0.005), and a concentration in excess of 100 fmoles/μg of DNA was maintained for only 24 hr. There was no difference in the rate of progressive accumulation of the competitive metabolite, deoxyuridine monophosphate (dUMP), during the first 24 hr of the study. Two hr after i.p. injection of 5-FU (100 mh/kg), [3H] deoxyuridine ([3H]Udr) incorporation into DNA was reduced in both tumor lines to below 3 per cent of control. However, in the sensitive tumor, adeno-carcinoma 38, DNA synthesis was maximally inhibited for 72 hr, compared to 24 hr in the resistant adenocarcinoma 51. The reinitiation of DNA synthesis corresponded to the reduction of free FdUMP concentration to less than 100 fmoles/μg of DNA. There was no linear relationship between the FdUMP/ dUMP ratio and [3H]UdR incorporation into DNA in either tumor line. These data demonstrate that the peak tumor FdUMP concentration and the kinetics of its clearance correlated with the responsiveness of the two specific murine tumors to 5-FU. The measure of peak FdUMP level should be tested for its potential clinical application as a means of selecting patients with gastrointestinal and breast cancer to be treated with this agent.

Chemotherapy of pancreatic carcinoma

Cancer of the pancreas is the fourth leading cause of cancer death in the United States. Until recently, this tumor has not been the subject of a systematic evaluation of nonsurgical therapies. In particular, there have been remarkably few anticancer agents specifically studied for activity in pancreatic cancer, but at the present time 5‐fluorouracil, mitomycin‐C, streptozotocin, and Adriamycin have demonstrated single‐agent effectiveness. Despite the limited number of agents available for the development of combination chemotherapy, several programs have demonstrated an apparent improvement in response relative to single‐agent treatment. These include S‐FU and mitomycin‐C, SMF, and FAM; response rates of 30–43% have been reported for patients with advanced measurable pancreatic cancer. For the locally advanced stage of this disease, the combined modality approach of 5‐fluorouracil plus external irradiation has produced superior survivals when compared with radiation therapy used alone. Although chemotherapy of pancreatic cancer is a developing field, clinically meaningful responses correlated with improved patient survival can be obtained with existing regimens. Phase II trials of new anticancer agents remain a high priority research effort with the intent of identifying useful drugs for future regimens of combination chemotherapy.