Joseph R. Bateman

5-fluorouracil given once weekly: Comparison of intravenous and oral administration

One hundred seven patients with disseminated adenocarcinoma were randomized to receive 5‐Fluorouracil (5‐FU) by vein, Group A (52 patients), or by mouth, Group B (55 patients). Dosage for both groups was 15 mg/kg body weight given once weekly. Clinically useful response rate was 21% for Group A (IV) and 40% for Group B (oral). Duration of response and mean cumulative dose to beginning response were comparable in both groups. Slight differences were observed in toxicities in the 2 groups. G.I. toxicity was more frequent in Group B (oral) and hematologic toxicity was more common in Group A (IV).

Randomized phase II clinical trial of adriamycin, methotrexate, and actinomycin-d in advanced measurable pancreatic carcinoma. A gastrointestinal tumor study group report

Sixty‐six patients with advanced pancreatic carcinoma were randomized to receive single agent chemotherapy with either adriamycin, methotrexate, or actinomycin‐D using conventional dose, route and schedule of administration. All patients had measurable lesions which were used for objective assessment of response. For adriamycin, 2 of 25 patients (8%) evidenced a partial response (2 of 15 (13%) previously untreated patients). One of 25 patients treated with methotrexate and one of 28 who received actinomycin‐D responded. The duration of responses ranged from 43–64 days for those patients with no chemotherapy prior to study entry. The median survival of patients who received adriamycin as initial treatment was 12 weeks compared to 8 weeks for methotrexate and 6 weeks for actinomycin‐D therapy.

Streptozotocin in the treatment of cancer: phase II study.

Streptozotocin (NSC‐85998) was administered to 53 patients at a dose of 1 to 2 g/m2 weekly. Response to therapy could be evaluated in 39 patients. Responses exceeding 50% in magnitude of tumor reduction were noted in three patients; responses of 25–50% were noted in an additional four patients. Responses were noted in two of four patients with islet cell carcinoma, one of four patients with malignant carcinoid, one of two patients with carcinoma of the lung, one of two patients with squamous carcinoma of the oral cavity, one patient with synovial sarcoma, and one patient with adenocarcinoma of the gallbladder. Renal toxicity was manifested by azotemia in 21 patients and by proteinuria in 28 patients. Elevation of serum glucose occurred in seven patients, but clinical diabetes did not develop. Nausea and vomiting occurred in 40 patients. Hematologic toxicity was noted in four patients.

Treatment of cancer with weekly intravenous 5-fluorouracil. Study by the Western Cooperative Cancer Chemotherapy Group (WCCCG)†

5‐Fluorouracil (5‐FU) has usually been administered by rapid intravenous injection of 15 mg/kg daily for 3‐5 days and 7.5 mg/kg every 2 or 3 days to toxicity, repeated monthly (antitumor response about 10‐30%). Drug morbidity and mortality have been excessive. Modifications of this course have shown similar response rates but decreased toxicity and mortality. In the present WCCCG study, 548 patients with disseminated cancer were treated weekly with 5‐FU, without a loading dose, by rapid intravenous injection, beginning at 15 mg/kg/week for one month, and increased to 20 mg/kg/week (if necessary) to levels producing mild toxicity or an antitumor effect. Of the 339 patients now evaluated for response, 6 had complete responses, 54 had decreases in tumor size > 50%, and 34 had decreases in tumor size of 25‐50%. The response rates > 50% (I‐B and I‐C) for adenocarcinoma of the breast, stomach, and colon were 37.8%, 28.6%, and 16%, respectively. Of the 430 patients evaluated for toxicity, 62 manifested no toxicity, and 368 patients had mild‐to‐severe toxicity. There were 8 drug‐related deaths in patients who received 5‐FU in dosages higher than those allowed in the protocol. There were no drug deaths in patients who received 5‐FU as stipulated by the protocol.

Immunohistochemical localization of carcinoembryonic antigen (CEA), CEA-S, and nonspecific cross-reacting antigen (NCA) in carcinomas of lung.

Antisera to carcinoembryonic antigen (CEA), to a physicochemical subset of CEA, namely CEA‐S, and to nonspecific cross‐reacting antigen (NCA) were used for the immunohistochemical localization of these antigens in human bronchogenic carcinomas using a triple layer immunoperoxidase technique. The study is based on an analysis of tumors from 130 patients. CEA, CEA‐S, and NCA were all identified in the membrane and/or cytoplasm of neoplastic cells, and a good correlation between the antigens was observed in a majority of tumors. The presence or absence of these tumor‐associated glycoproteins appeared to be correlated with the histologic type of the tumors, especially in small cell anaplastic carcinoma and adenocarcinoma, and the degree of histologic differentiation of adenocarcinomas correlated positively with these tumor‐associated antigens. Data from this group of patients suggest that analysis of tissue CEA at the time of biopsy or surgical resection may facilitate a more objective interpretation of serial plasma CEA assays.

Cyclophosphamide (NSC 26271) versus the combination of adriamycin (NSC 123127), 5-fluorouracil (NSC 19893), and cyclophosphamide in the treatment of metastatic prostatic cancer. A randomized trial

Twenty‐seven patients with a diagnosis of metastatic adenocarcinoma of the prostate were treated in a randomized, prospective trial with either Cyclo‐phosphamide or a combination of Adriamycin, 5‐Fluorouracil, and Cyclo‐phosphamide. Doses were either Cyclophosphamide alone (800‐1200 mg/m2 iv q 3 weeks) or Cyclophosphamide (150‐200 mg/m2 po Day 3‐6) plus 5‐FU (400‐500 mg/m2 iv Day 1,8) plus Adriamycin (30‐50 mg/m2 iv Day 1) given as a 4 week treatment cycle. Patients with compromised bone marrow reserve initially received the lower dose level. Objectively stable disease as defined by a modification of the National Prostatic Cancer Project criteria was seen in 53% of the 15 Cyclophosphamide treated patients and in 50% of the 12 combination treated patients. Survival was not significantly different in the two arms. However, the survival of patients responding to Cyclophosphamide was significantly longer than that of patients responding to the combination (median 18.6 months versus 8.1 months, p < 0.05). Gastrointestinal and hematologic toxicity was moderate with both regimens. Therefore, in the present study, Cyclophosphamide alone was as effective as the combination of Cyclophosphamide, 5‐FU and Adriamycin for patients with disseminated prostatic carcinoma. The moderate hematologic toxicity noted with both regimens suggests further evaluation of drug combinations utilizing higher dosages of active agents in this disease. Cancer 42:2546–2552, 1978.

clinical experience with procarbazine in Hodgkin's disease, reticulum cell sarcoma, and lymphosarcoma

Seventy‐two patients with Hodgkins diseasereticulum cell sarcomalymphosarcomaand various other malignant neoplasms were treated with the methylhydrazine derivative procarbazine hydrochloride (Matulane, NSC‐77213). Response to therapy could be evaluated in 50 patients. Favorable responses occurred in 22 of 33 evaluable patients with Hodgkins disease2 of 5 patients with reticulum cell sarcomaand 2 of 5 patients with lymphosarcoma. All of the responders had previously shown resistance to at least 2 other antitumor agents. Toxic effects of therapy included leukopeniathrombocytopenianauseavomitingstomatitislethargyataxiaand alopecia. Median time to start of response was 21 days; median cumulative dose to start of response was 51.3 mg/kg. Responses lasted a median of 98 days (range: 34‐322 days). Procarbazine is a useful agent in advanced lymphomas.

Dosimetry and preliminary human studies of 18F-5-fluorouracil

The relative distribution, metabolism and kinetics of 18F containing compounds, following administration of 18F-5-fluorouracil, has been proposed as a prognostic aid in predicting response to 5-fluorouracil chemotherapy. Because 18F has a relatively short physical half-life (t1/2 = 110 min), and the distribution and kinetics of the radiolabeled 5-fluorouracil need to be studied over periods of time that range over several half-lives of the radionuclide, significant quantities of the labeled drug must be administered in order to obtain good counting statistics. The distribution of 18F, following injection of 18F-5-fluorouracil to rats and mice, has been well documented in our previous work. It appears that the distribution of 18F in humans, following administration of 18F-5-fluorouracil is similar to that in rats. We calculated the radiation dose according to the MIRD technique for the eleven main target organs for a reference man. The critical organs, according to these calculations, are the bladder wall, the kidney and the liver, receiving a radiation dose of 729, 184 and 114 mrad per mCi injected, respectively.

Adriamycin and methyl‐CCNU combination therapy in hepatocellular carcinoma: Clinical and pharmacokinetic aspects

Twenty‐one patients with unresectable hepatocellular carcinoma (hepatoma) were treated with Adriamycin (15–45 mg/m2 q 21 D) and methyl‐CCNU (75–150 mg/m2 q 63 D) with dosage adjusted for hepatic dysfunction. Objective response frequency was 14% with all responses occurring in patients with normal pretreatment bilirubin levels. Median survival of all patients was 87 days. Initial bilirubin levels greater than 2 mg/dl predicted for decreased survival (median 30 days vs. 115 days, P < 0.05). Only moderate hematologic toxicity was observed. Plasma profiles of Adriamycin and adriamycinol were determined during 11 courses of Adriamycin administration in seven of these patients. Despite moderately elevated transaminase levels (all cases) and bilirubin levels (three cases), plasma Adriamycin profiles in hepatoma patients were not elevated (terminal half‐life of 30 hours) and were indistinguishable from that of non‐hepatoma patients with normal liver functions. However, delayed appearance of peak levels and prolongation of terminal half‐lives were routinely observed for adriamycinol, a major metabolite of Adriamycin. This resulted in a significant increase in the CXT (concentration X time) ratio of adriamycinol/Adriamycin in hepatoma patients compared with non‐hepatoma patients (2.36 ± 2.12 vs 0.76 ± 0.31, P < 0.05). We conclude that the combination of relatively mild toxicity and normal Adriamycin disposition indicates unusual tolerance to Adriamycin therapy for patients with hepatoma and cirrhosis. As a result, severe dosage adjustments of Adriamycin may not be indicated for all such patients having only moderate hepatic dysfunction.

Long-Term Survival Following Levamisole or Placebo Adjuvant Treatment of Colorectal Cancer: A Western Cancer Study Group Trial

In 1976, the Western Cancer Study Group initiated a prospectively randomized, double-blind trial of an 18-month adjuvant program comparing levamisole with placebo treatment following surgical resection in patients with colorectal adenocarcinoma. After stratification for site of disease (colon vs. rectum) and stage (B vs. C), 78 patients were entered. The levamisole schedule was 2.5 mg/kg/day given on days 1 and 2 of each week. The median follow-up of entered patients is now 7.5 years. Toxic effects of treatment were minimal. However, no long-term survival advantage was associated with levamisole compared to placebo administration in this population with resected large-bowel adenocarcinoma.