Adriamycin and Cytoxan in the treatment of inoperable lung cancer.

The results of a clinical trial involving 599 patients with inoperable squamous cell, large cell anaplastic, and adenocarcinoma of the lung are summarized. Patients were randomized to initial therapy with Cytoxan (CTX) (cyclophosphamide), or to one of two schedules of Adriamycin (doxorubicin) 50, or 75 mg/m2 IV every three weeks, or to a combined regimen of ADR and CTX. Upon disease progression, CTX patients were randomized to one of the two ADR schedules, while ADR patients were randomly assigned to CTX alone, or in combination with Cisdiamminedichloroplatinum (Cis-Platinum) 15 mg/m2 IV every three weeks. No statistically significant response or survival differences were observed between the two dose schedules of Adriamycin for any of the cell types studied. The two dose levels did, however, differ with respect to toxicity. There were some response and survival differences among the various cell types in the comparison of low-dose Adriamycin and Cytoxan: (1) patients with adenocarcinoma treated with low-dose Adriamycin tended to survive longer (P = 0.04) than those treated with Cytoxan; and (2) patients with large cell carcinoma receiving Cytoxan experienced a greater tumor response rate than those receiving low dose Adriamycin (P = 0.03). Because of the difficulties involved in distinguishing these two cell types on pathologic examination, the evidence of apparent treatment differences should not be regarded as definitive. During the period when Adriamycin plus Cytoxan was open to patient entry 61 evaluable patients received that regimen, 21 received low-dose Adriamycin and 22 received Cytoxan. Because relatively few patients received the latter two regimens, comparisons of these treatments with Adriamycin plus Cytoxan lack statistical power. However, there is no suggestion in the available data that Adriamycin plus Cytoxan increased survival either in the overall population or in the subset of patients with squamous histology. Initial performance status, metastatic disease symptoms, primary disease symptoms, and weight loss were significantly correlated to survival time, and are recommended as stratification factors in future studies.

Comparison of induction chemotherapies for metastatic breast cancer. An Eastern Cooperative Oncology Group Trial.

Patients with advanced breast carcinoma and no prior chemotherapy were prospectively evaluated to assess the induction capabilities of cyclophosphamide, methotrexate and 5-fluorouracil (CMF), Adriamycin and vincristine (AV), and CMF plus prednisone (CMFP). The crossover responsiveness from CMF or CMFP to AV and of AV to CMF were also assessed. A disproportionate randomization led to 166 analyzable cases on AV, 79 on CMF were also assessed. A disproportionate randomization led to 166 analyzable cases on AV, 79 on CMF and 86 on CMFP induction. One hundred and twelve patients were evaluated on crossover. Induction response rates were similar with 56% on AV, 57% on CMF and 63% on CMFP. Crossover response rates ranged from 32% to 41%. CMFP and AV were superior to CMF in terms of response duration (P = 0.05), and CMFP was superior to either in terms of time to treatment failure (P = 0.04), and survival (P = 0.03). Treatment failures occurred in only the on-study organ sites of disease in 73% of the patients and did not appear to be related to the response achieved. CMF was associated with more thrombocytopenia than either AV or CMFP (P = 0.03). AV was associated with fewer infections than CMFP (P = 0.02), less diarrhea than CMFP (P = 0.04), more emesis than CMF (P = 0.02), and more neurologic toxicity than either CMF or CMFP (P less than 0.0001). There was also more emesis with CMF than with CMFP (P = 0.006). CMFP was associated with greater delivery of CMF than was the CMF regimen despite a similar day 1 leukocyte distribution. These results strongly suggest that CMF(P) and AV are clinically noncross-resistant regimens, that AV and CMF are essentially equivalently active induction regimens, and that CMFP is superior to CMF and AV.

Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group.

The prognostic effect of weight loss prior to chemotherapy was analyzed using data from 3,047 patients enrolled in 12 chemotherapy protocols of the Eastern Cooperative Oncology Group. The frequency of weight loss ranged from 31 percent for favorable non-Hodgkin's lymphoma to 87 percent in gastric cancer. Median survival was significantly shorter in nine protocols for the patients with weight loss compared to the patients with no weight loss. Chemotherapy response rates were lower in the patients with weight loss, but only in patients with breast cancer was this difference significant. Decreasing weight was correlated with decreasing performance status except for patients with pancreatic and gastric cancer. Within performance status categories, weight loss was associated with decreased median survival. The frequency of weight loss increased with increasing number of anatomic sites involved with metastases, but within categories of anatomic involvement, weight loss was associated with decreased median survival. These observations emphasize the prognostic effect of weight loss, especially in patients with a favorable performance status or a limited anatomic involvement with tumor.

A randomized comparison of two dosage schedules of methyl CCNU: three-week versus six-week treatments.

Two dose schedules of methyl CCNU were compared for drug effect and toxicity. One hundred thirteen patients were stratified by tumor site, performance status, and prior chemotherapy and randomized to 100 mg/m2 q 3 wk or 200 mg/m2 q 6 wk orally. Response rates were similar (12% vs. 18%, respectively, in the major tumor sub-types studied) and survival was equivalent. Hematologic toxicity, however, was significantly different, with earlier time to the most severe blood count depressions, more frequent occurrence of severe depression, and a larger percentage of patients requiring dosage reduction on the 6-week regimen. We conclude that the 3-week regimen is superior due to its improved tolerance and is recommended especially for combination drug therapy.

Phase II study of vinblastine, methyl-CCNU, and medroxyprogesterone in advanced renal cell cancer.

One hundred and sixty-five patients with advanced renal cell cancer were evaluable for combination or single-agent therapy with methyl-CCNU, vinblastine, and medroxyprogesterone. A low order or response was observed, and these agents were not proven effective as treatment for metastatic renal cell cancer. Performance status and a relatively long symptom-free interval from primary tumor to metastatic disease were found to be the most prognostically significant factors for survival.

PIP: Patients with metastatic renal cell cancer have an overall 5-year survival rate of only 28% to 40% in spite of aggressive surgical treatment. A prospective randomized study conducted by the Eastern Cooperative Oncology Group used methyl--CCNU (meCCNU), vinblastine, and meCCNU-medroxyprogesterone acetate (MPA) to treat 165 patients with advanced renal cancer. The antitumor activity of the single-agent and/or combination therapy is analyzed. Patients were classified (as to grade of anaplasia of tumor; age; performance status; primary site of metastatic disease; and previous treatment with a progestational agent) and randomly assigned to various treatment protocols as described. Crossover randomization to one of alternate single-agent or combination regimens was carried out after failure with initial therapy. 2 meCCNU regimens were associated with severe hematologic toxicity, vinblastine regimens with neurotoxicity. All regimens except the vinblastine-MPA resulted in substantial vomiting. Response rate is low (11%) with each regimen. There were no statistically significant differences in treatment variables or factors among the various regimens. Patients capable of normal activity had a significantly higher response rate and longer survival period than nonambulatory or poor performance status patients. A relatively long symptom-free interval from primary tumor to metastatic disease was also associated with better survival rate. More than 50% of patients exhibited disease progression with 3 months of initiating the regimens.

Comparison of intensive versus moderate chemotherapy of lymphocytic lymphomas: a progress report.

In an Easter Cooperative Oncology Group trial, Cytoxan-prednisone (CP) Induction was compared to BCNU-prednisone (BP) in 273 patients with lymphocytic lymphoma. Response rates were comparable, with 21% achieving complete response and 40%, partial response. Patients with a nodular pattern responded better. Maintenance phase comparing cyclic intensive therapy (BCVP) with intermittent chlorambucil revealed the superiority of BCVP as demonstrated by improvement of the quality of response and somewhat longer remissions. The value of the Rappaport classification in the evaluation of lymphoma chemotherapy results is discussed. It is suggested tha NHL be separated into "favorable" and "unfavorable" groups, based on the presence or absence of nodularity and treatment schedules devised accordingly.

Cyclophosphamide and CCNU in the treatment of inoperable small cell carcinoma and adenocarcinoma of the lung.

Two hundred and fifty-eight patients with small cell carcinoma and 185 patients with adenocarcinoma were centrally randomized to receive either cyclophosphamide (1000 mg/m2 every 3 weeks) iv or cyclophosphamide (700 mg/m2 every 3 weeks) iv plus CCNU (70 mg/m2 every 6 weeks) orally. Those patients who were initially treated with the single agent were then treated with CCNU (130 mg/m2 every 6 weeks) at the time of cyclophosphamide failure. Objective tumor regression occurred more frequently with the combination regimen in patients with small cell carcinoma (43% vs 22%, P = 0.002), but no difference in response rates was apparent in patients with adenocarcinoma. In both cell types patients survived somewhat longer following treatment with the combination. The overall incidence of severe toxicity was equal for the two regimens in both cell types; however, the therapeutic index of the combination was superior to that of the single agent in small cell carcinoma. Severe drug toxicity was more frequent in small cell carcinoma patients with extensive disease, and survival was reduced in both cell types with extensive disease. Survival was better for ambulatory patients in both cell types and women survived longer than men. In women with small cell carcinoma, ambulatory status also was associated with a higher incidence of tumor regression. In patients with small cell carcinoma those who had prior lung surgery survived longer than those without prior surgery. Previous radiation therapy was associated with a reduced incidence of objective regression in men with small cell carcinoma. In both cell types patients with tumor regression lived longer than nonresponders; however, objective disease stability was associated with improved survival only in patients with adenocarcinoma. Stratification in future studies should consider extent of disease, performance status, sex, and prior therapy.

Phase II study of cis-dichlorodiammineplatinum(II) (NSC-119875) in combination with cyclophosphamide (NSC-26271) in the treatment of human malignancies.

The effectiveness of cis-dichlorodiammineplatinum(II) in the treatment of human malignancies is evaluated. The first stage of our investigation consisted of a phase I study to determine toxicity. In the second stage attempts were made to reduce toxicity by varying the modes of administration, and the third stage comprised studies of combination chemotherapy including cis-dichlorodiammineplatinum(II). A total of 74 patients have been treated, 20 of whom received the combination of cis-dichlorodiammineplatinum(II) and cyclophosphamide. Major toxic effects included vomiting, mild leukopenia and thrombocytopenia, decreased creatinine clearance, audiologic toxic effects, hyperuricemia, and nephrotoxicity. Measurable regression of tumors was seen in 18 of the 74 patients and ten of the 18 patients who responded had been given the combination of cis-dichlorodiammineplatinum(ii) and cyclophosphamide.

Estrogen and estrogen receptors of breast cancer.

Human breast cancer can be divided into a group that contains specific receptor sites for estrogen and a group without such specific estrogen-binding sites. The presence of specific estrogen receptors in some tumors indicating hormonal dependency has been shown to be of predictive value for endocrine treatment. This would greatly improve therapeutic planning for patients with breast cancer. Tumor tissue from 52 patients was investigated for content of both cytosol estrogen and estrogen receptor. In addition, the total tumor estrogen was also determined in 14 of these tumors. The results of this investigation show two distinct groups: one group containing both estrogen receptor and estrogen and a second group with no receptor but with measurable amount of estrogen. Tumors with estrogen receptors have higher tissue levels of estrogen than tumors without specific estrogen receptor. Even in the absence of estrogen recptor, however, most tumor tissue examined contained a measurable amount of estrogen.