John H. Glick

Full dose versus attenuated dose daunorubicin, cytosine arabinoside, and 6-thioguanine in the treatment of acute nonlymphocytic leukemia in the elderly.

Between July 1, 1981 and November 1, 1982, 45 patients with acute nonlymphocytic leukemia (age, greater than or equal to 70 years) were randomly assigned to receive induction chemotherapy using either daunorubicin, cytosine arabinoside, and 6-thioguanine in full dosage (F DAT) or an attenuated schedule of the same drugs (At DAT) as part of an Eastern Cooperative Oncology Group controlled trial. Forty patients were deemed evaluable, 20 on each arm. The overall complete remission (CR) rate for all patients in both arms was 28% (11/40). There was no significant difference in CR rates between the two arms. There were 12 early deaths (less than 60 days) in the F DAT arm compared with only five early deaths on the At DAT arm (P = .05). Due primarily to this early death rate, the median survival for the F DAT group was 29 days v 159 days for the At DAT groups (P = .02). The range of survival of the patients in CR for the At DAT group given either one or two cycles of induction therapy was 121 to 414 days, while the survival range for the F DAT CR patients was 121-186 + days. The median survival for those not achieving CR was 14 days for the F DAT group v 80 days for the At DAT (P less than .02). Fifty-nine percent of the At DAT patients spent greater than 100 days out of the hospital v 12% for the F DAT group. Attenuated chemotherapy with lower doses of DAT is the preferred induction regimen for elderly patients with acute nonlymphocytic leukemia since it causes fewer early deaths, allows a better quality of life, and yields survival times as durable as intensive therapy.

WR-2721 protects against the hematologic toxicity of cyclophosphamide: a controlled phase II trial.

WR-2721 S-2-(3-aminopropylamino) ethyl phosphorothioic acid, is an organic thiophosphate compound that in the animal model selectively protects against the hematologic toxicity of cyclophosphamide by factors of 1.5 to 2.0. Preliminary data from our controlled phase I trial of WR-2721 and cyclophosphamide suggested that WR-2721 protected against cyclophosphamide-induced granulocytopenia. Since variable drug doses and infusion rates were used in these early studies, we initiated a controlled phase II trial using constant drug doses to establish more precisely WR-2721s level of protection. Initially, 21 patients received 1,500 mg/m2 of cyclophosphamide alone and were retreated 4 weeks later after hematologic recovery was complete with 740 mg/m2 of WR-2721 before the same dose of cyclophosphamide. With WR-2721 pretreatment, 19 of 21 (90%) patients had improved WBC and granulocyte counts. The mean WBC increased from 1,760/mL with cyclophosphamide alone to 2,500/mL with WR-2721 pretreatment (P less than .0005). The mean granulocyte count increased from 541/mL on cyclophosphamide to 1,247/mL with WR-2721 and cyclophosphamide (P less than .0005). Following cyclophosphamide administration alone, neutropenic fevers developed in three patients. No patient experienced a febrile episode following WR-2721 and cyclophosphamide administration. Platelet nadirs below 100,000/mL were only noted in two patients treated with cyclophosphamide alone. Objective partial responses were observed in four of 19 (21%) patients with measurable or evaluable disease. These data suggest that WR-2721 provides significant protection against cyclophosphamide-induced hematologic toxicity.

The significance of bone marrow involvement in non-Hodgkin's lymphoma: The Eastern cooperative oncology group experience

Data from four clinical trials conducted by the Eastern Cooperative Oncology Group (ECOG) were used to investigate the importance of bone marrow involvement as a prognostic factor in patients with non-Hodgkins lymphoma (NHL). A total of 502 patients, 275 with nodular, poorly differentiated lymphocytic lymphoma (NLPD) and 227 with diffuse histiocytic lymphoma (DHL) or diffuse mixed-cell lymphoma (DML), were included in this analysis. Patients were separated into four categories: stage III, stage IV with bone marrow involvement (stage IV-M), stage IV without marrow involvement (stage IV-O), and stage IV with bone marrow and other organ involvement (stage IV-OM). Among the DHL and DML patients, the incidence of marrow involvement was 23%. However, stage IV-M patients had a prognosis that is similar to stage IV-O and stage IV-OM and worse than stage III patients. In contrast, the incidence of involvement with NLPD was 59% and patients with stage IV-M had a survival not different than stage III and not worse than stage IV-O and stage IV-OM. The results suggest that the current emphasis on bone marrow biopsy(s) as a routine diagnostic staging procedure for patients with NHL should be reevaluated. The necessity for this procedure in stage III patients with NLPD is not apparent from our data. One can still justify a bone marrow biopsy in stage I and II patients and can confirm the complete clinical response when all nodes have regressed in more advanced disease.

Adenocarcinoid tumor of the colon arising in preexisting ulcerative colitis

Patients with ulcerative colitis are at increased risk of developing adenocarcinoma of the colon. The authors describe a patient whose colonic neoplasm demonstrated histologic characteristics of both an adenocarcinoma and a carcinoid tumor and which was pathologically identical to a appendiceal adenocarcinoid. Because individual tumor cells stained positively for both mucin and argentaffin granules, the histologic picture is unique among the malignancies seen in patients with ulcerative colitis and cannot be explained as a composite of two independent neoplasms that have grown together. Since the tumor discussed seems to have originated from a single cell line, the theory that carcinoids develop from neural crest cells which have migrated to embryonic gut endoderm must be regarded with considerable doubt.

Nodular histiocytic lymphoma: Factors influencing prognosis and implications for aggressive chemotherapy

Twenty‐five patients with Stage III and IV nodular histiocytic lymphoma (NH), entered on three different Eastern Cooperative Oncology Group protocols from 1972–78, were analyzed for response and survival. A complete response (CR) rate of 44% was observed, with 40% partial responders (PR). Four of the 11 CRs are continuing in their original remission. Median survival for CRs was 52 months; for PRs it was 30 months. The six patients treated with cyclophosphamide‐prednisone had a median survival of 18 months versus 51 months for the 19 patients treated with more aggressive combination chemotherapy programs. No significant difference in survival was noted between those patients with both nodular and diffuse histology and those with a pure nodular pattern. The median survival of the 25 NH patients was 47 months and is similar to a group of 101 patients with nodular mixed lymphoma (NM) entered on the same ECOG protocols during this time. This survival is intermediate between the nodular lymphocytic poorly differentiated subtype and diffuse histiocytic lymphoma. It suggests that patients with NH histologies be treated with aggressive combination chemotherapy programs designed to achieve complete remission and prolonged disease‐free survival.

Phase II trial of tamoxifen in metastatic carcinoma of the prostate.

Fifty‐one patients with advanced metastatic carcinoma of the prostate were treated with the antiestrogen tamoxifen. Thirty‐eight of these patients were refractory to prior hormonal manipulation with estrogens and/or orchiectomy, and five (13%) achieved an objective response (partial regression or stable disease using the National Prostate Cancer Project criteria). Median survival of the responders was significantly longer than that of the nonresponders (P < 0.05). An additional 13 patients who had not previously received hormonal manipulation were treated with tamoxifen; one partial response and three disease stabilizations were noted. Response was separately evaluated for 15 patients with objectively measurable lesions using standard Phase II response criteria. Only 1/15 (7%) partial response and 3/15 (20%) disease stabilizations were documented. Subjective benefit in terms of significant pain relief was noted in 17/50 (34%) of patients. Toxicity was mild, but two possible “tumor flares” were noted. These results do not support the continued investigation of tamoxifen in advanced carcinoma of the prostate.

Alterations in oxygen transport following WR-2721

The toxicity of radiation and alkylating agent chemotherapy is in part related to free radical formation in DNA and associated proteins, which is enhanced by oxygen and other electron affinic compounds. During the Phase I clinical trials of WR-2721 and alkylating agent chemotherapy, venous blood samples were obtained prior to and immediately following the WR-2721 infusion. We have observed a marked increase in the oxygen saturation of venous blood following WR-2721 (430-910 mg/m2 at a rate of 15 mg/m2/minute). The mean venous PO2 (PvO2) rose from a baseline of 34.0 +/- 13.54 torr to a mean value of 54.60 +/- 12.47 torr (p less than 0.001). The percent venous oxygen saturation increased from 54.52 +/- 21.38% to 82.73 +/- 7.66%. The highest values generally occurred within the first 2 hours after the completion of the WR-2721 infusion. No significant differences were found between the pre and post WR-2721 values for either the venous pH, CO2, or bicarbonate levels. Despite increased PvO2, the patients heart rates, blood pressures, or respiratory rates did not change pre and post WR-2721. No apparent differences were noted in the effects of WR-2721 or PvO2 when given at doses of 740 or 910 mg/m2. However, when WR-2721 (418-1100 mg/m2) was administered over 15 minutes, the PvO2 increased in only 8/13 courses. We postulated that the marked increase in venous blood oxygen concentration was secondary to one of the following mechanisms: 1) Increased affinity of hemoglobin for oxygen, 2) microcirculatory shunting, or 3) decreased tissue requirements for oxygen. In 12 patients oxygen-hemoglobin dissociation curves and intracellular red cell pHs were obtained before and after 740-910 mg/m2 of WR-2721. Despite the significant increase in oxygenation of venous blood after WR-2721, there were no changes in either oxygen-hemoglobin dissociation or intracellular red cell pH to account for this increase. The oxygen consumption of peripheral blood granulocytes was measured prior to and following 15 courses of WR-2721. A marked decrease in granulocyte oxygen consumption was observed in 6/8 patients who had a significant increase in PvO2 and only 1/7 patients who had either a decrease or no change in PvO2 after WR-2721. Our preliminary investigations suggest that the increased venous blood oxygen content may be secondary to a reduction in normal tissue oxygen consumption. WR-2721 may afford protection by both decreasing oxygen consumption and delivery to normal tissues and increasing intracellular sulfhydryls.

Tamoxifen plus sequential CMF chemotherapy versus tamoxifen alone in postmenopausal patients with advanced breast cancer: A randomized trial

Eighty‐nine postmenopausal women with metastatic breast cancer, in whom estrogen receptors (ER) were positive or unknown, were treated on a controlled trial to determine the effectiveness of tamoxifen and to assess the therapeutic advantage of sequentially adding low‐dose cyclophosphamide‐methotrexate‐5‐fluorouracil (CMF) chemotherapy in tamoxifen responders. Patients with known ER negative status were not studied. After the initial 12 week treatment with tamoxifen alone, 59% of ER positive patients achieved complete or partial response as did 35% in whom ER were unknown. Response status further improved in 18% randomized to continue tamoxifen alone vs. 28% in whom CMF was added to tamoxifen. There were no statistically significant differences in time to the development of progressive disease or survival between the ER positive and ER unknown patients or between the tamoxifen and tamoxifen plus CMF groups. We conclude that inability to determine ER status should not prejudice against the use of tamoxifen in postmenopausal patients with advanced breast cancer. As yet, no benefit has been demonstrated from the addition of CMF chemotherapy in tamoxifen responders. Cancer 45:735‐741, 1980.

Chemotherapy for squamous cell carcinoma of the head and neck: a progress report.

This review highlights the most important recent advances in the chemotherapeutic management of patients with squamous cell carcinoma of the head and neck. Previous chemotherapy trials must be interpreted with caution in the absence of information concerning important prognostic variables, such as prior treatment, nutritional and performance status, and the heterogeneity of primary sites. In patients who have recurrent or metastatic disease, methotrexate, platinum, and bleomycin are three active drugs when used as single agents. There is no evidence that high dose methotrexate therapy is superior to more conventional weekly intravenous administration of methotrexate in the treatment of recurrent disease. Platinum is a new agent that has demonstrated activity against hematogenous as well as regional disease. In the absence of evidence of a dose-response curve for platinum, the lower dosage schedules that can be used with acceptable toxicity on an outpatient basis should be selected. Combination chemotherapy has resulted in a high proportion of objective responders and approximately 20 per cent complete remissions with any of several platinum containing regimens. However, the median duration of response remains short, and none of the combination drug programs has as yet been established to be superior to single agent chemotherapy in a randomized trial. Both single agent and combination chemotherapy programs have been used prior to initial surgery or radiation in patients with advanced inoperable but nonmetastatic disease. Despite dramatically higher response rates over those obtained with the same drugs used in recurrent disease, there is as yet no evidence that chemotherapy given in this manner has resulted in improved disease free or overall survival compared with local treatment alone. Similarly, the use of adjuvant chemotherapy following tumor clearance to eradicate potential micrometastatic disease is currently under investigation and cannot be recommended in the absence of a controlled trial. This article reviews the clinical trials currently in progress both for patients with recurrent squamous cell carcinoma of the head and neck and those with advanced local or regional disease.

Sequential cyclophosphamide‐prednisone and vincristine‐bleomycin (CPOB). An effective, schedule‐dependent treatment for advanced diffuse histiocytic lymphoma

In an Eastern Cooperative Oncology Group non‐Hodgkins lymphoma clinical trial, 90 patients with Stage III or IV diffuse histiocytic lymphoma (DHL) were treated with one of four chemotherapy regimens. All patients were previously untreated with chemotherapy, and careful restaging was required to document responses. Each treatment included cyclophosphamide, vincristine and prednisone (COP) plus Adriamycin (COPA), BCNU (BCVP) or bleomycin (COPB and CPOB). The two bleomycincontaining regimens differed only in the schedule of drug administration. CPOB‐treated patients received cyclophosphamide on day 1, prednisone on days 1 to 5 and vincristine and bleomycin on day 15 of each 21‐day cycle. COPB‐treated patients received the same four drugs in the same dosage; however, the schedule was changed so that vincristine and bleomycin were given on day 1. Treatment of responders was continued for 8 cycles. Those with a complete response (CR) were randomized to maintenance therapy with BCVP or no treatment. Treatment with CPOB yielded a CR rate of 55% compared to 25% for COPB (P = 0.07). In contrast to COPB, treatment with CPOB was associated with a significantly longer median duration of CR (26.5 versus 5.7 months; P < 0.05) and median survival (27.7 versus 11.2 months; P < 0.02). The CR rate was 31% for BCVP and 45% for COPA, and the median survivals were 10.7 months and 14.4 months, respectively. One half of the CPOB‐treated patients who achieved CR remained alive in continuous CR after 30 to 72 months. No advantage for maintenance therapy was observed. Myelotoxicity was greater with CPOB than COPB, but comparable to COPA. This trial demonstrated that the results of treatment of DHL with COP plus bleomycin were strikingly dependent upon the schedule of administration of bleomycin and vincristine. Bleomycin effectively combined with COP, as in CPOB, yielded results comparable to those obtained when Adriamycin was added to COP. CPOB appears to be an effective treatment for DHL that should be considered as an alternative to other regimens, particularly for patients who cannot receive Adriamycin.