Chemotherapy for metastatic non-small-cell bronchogenic carcinoma: EST 2575, generation V--a randomized comparison of four cisplatin-containing regimens.

Between December 1979, and October 1981, the Eastern Cooperative Oncology Group (ECOG) compared four cisplatin-containing regimens in the treatment of patients with metastatic non-small-cell bronchogenic carcinoma (NSCBC). CBP (cyclophosphamide, bleomycin, and cisplatin) and AFP (doxorubicin, 5-fluorouracil, and cisplatin) had shown activity in generation II of this study (EST 2575). These were compared to MVP (mitomycin C, vinblastine, and cisplatin) and CAP (cyclophosphamide, doxorubicin, and cisplatin) which were reported efficacious in single institution studies. A total of 479 previously untreated patients with metastatic NSCBC (ECOG performance status 0, 1, or 2) were entered, and of these, 432 (90%) were evaluable. Although MVP resulted in a higher response rate (5 complete responses [CRs], 22 partial responses [PRs], 26% overall) than CBP (4 CRs, 18 PRs, 20% overall), AFP (0 CRs, 18 PRs, 17% overall), or CAP (1 CR, 23 PRs, 23% overall), the difference was not significant. Survival by treatment did not differ significantly. There were 45 life-threatening and six lethal complications of therapy. Although each of the above regimens offers a modest chance of inducing greater than 50% tumor shrinkage (17% to 26%, 21% overall) the effect that these responses have an overall median survival (21.6 to 23.7 weeks, 22.9 weeks overall) is unclear.

Randomized comparison of cyclophosphamide, imidazole carboxamide, and adriamycin versus cyclophosphamide and adriamycin in patients with advanced stage malignant mesothelioma: a Sarcoma Intergroup Study.

In 1980, a consensus chemotherapy intergroup study for advanced malignant mesothelioma was initiated based on a collaborative agreement among the Eastern Cooperative Oncology Group (ECOG), the Southwest Oncology Group (SWOG), and the Southeastern Cancer Study Group (SECSG). The purpose of the study was to evaluate cyclophosphamide (500 mg/m2 day 1), imidazole carboxamide (250 mg/m2 days 1 through 5), and doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) (50 mg/m2 day 1) v cyclophosphamide (500 mg/m2) and doxorubicin (50 mg/m2) in a randomized prospective clinical trial involving 76 fully evaluable patients with advanced stages II to IV malignant mesothelioma. A total of nine responses (12%) were documented, including three complete and six partial responses. There was no significant difference in response duration or survival between treatment arms. Leukopenia (greater than 2,000/microL) was observed in 46% of patients treated with the three-drug combination and 38% of patients receiving the two-drug combination. The variables of performance status 0-1 and the absence of prior chemotherapy/radiotherapy were significant with respect to favorable impact on survival. We conclude, based on the minimal benefit observed, that the combination of cyclophosphamide and doxorubicin with or without imidazole carboxamide does not warrant further investigation in patients with advanced-stage malignant mesothelioma.

A randomized trial of the four most active regimens for metastatic non-small-cell lung cancer.

Between October 1981 and June 1983, the Eastern Cooperative Oncology Group (ECOG) conducted a prospectively randomized trial (EST 1581) of the four most active chemotherapy regimens for metastatic non-small-cell lung cancer (NSCLC). Four hundred eighty-six good performance status patients (PS 0 or 1; 81%) were randomized to receive cyclophosphamide, doxorubicin, methotrexate, and procarbazine (CAMP); mitomycin, vinblastine, and cisplatin (MVP); etoposide and cisplatin (VP-P); or vindesine and cisplatin (VDA-P). All regimens were administered in the doses and schedules originally reported. Complete response (CR) plus partial response (PR) rates for the four regimens were CAMP, 17%; MVP, 31%; VP-P, 20%; and VDA-P, 25%. The response rate for MVP was significantly higher in patients with squamous and adenocarcinoma histologies, but there was no impact on median survival (overall, 24.5 weeks). The duration of response did not differ by treatment as previously suggested for VDA-P. There were 15 CRs (CAMP, one; MVP, six; VP-P, two; VDA-P, six), and 12 patients have survived more than 2 years. Toxicity was significant with 20 treatment-related deaths. CAMP was significantly less toxic than the other regimens (P less than .001). VDA-P demonstrated significantly more life-threatening (seven) and lethal (three) episodes of nephrotoxicity (P less than .001) despite an aggressive hydration program that in itself caused significant morbidity. Analysis of the toxicity data showed, however, that most of the severe toxicity occurred in the 19% of patients who were initially PS 2, suggesting that they are not appropriate candidates for trials of new agents or combinations. None of these regimens can be recommended as a standard therapy for metastatic NSCLC.

Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas.

This study addressed two major questions regarding therapeutic use of Adriamycin ([Adr] Adria Laboratories, Columbus, OH) in adult soft tissue sarcomas: the influence of dosing schedule and the value of adding imidazole carboxamide (DTIC) to Adr. Patients with objectively measurable metastatic soft tissue sarcomas were randomized to Adr 70 mg/m2 intravenously (IV) day 1 and every 3 weeks (94 patients); Adr 20 mg/m2 IV day 1, 2, and 3, and 15 mg/m2 IV day 8 and weekly thereafter (89 patients); and Adr 60 mg/m2 IV day 1 and DTIC 250 mg/m2 days 1 to 5, repeated every 3 weeks (92 patients). The regimens using Adr as a single agent resulted in an equivalent response frequency (18% and 16%) and survival (median, 8.0 and 8.4 months). DTIC significantly increased (P less than .02) the overall response frequency of Adr to 30%. However, DTIC did not influence survival (median, 8.0 months) or increase the number of complete responses. The toxicities of the two single-agent regimens differed: Adr weekly resulted in more stomatitis (P = .09) and less hematologic toxicity (P less than .05). DTIC resulted in substantially increased toxicity, primarily gastrointestinal (P less than .002); overall, 98% of patients receiving Adr-DTIC experienced moderate or worse toxicity. To decrease the potential for error in interpretation of treatment results, histopathological confirmation of diagnosis was undertaken by a panel of reference pathologists; pathology slides were submitted on 97% of entered patients. The on-study clinical diagnosis was affirmed in 199 of 316 patients (63%) with a final review. In 23% of patients, the panel agreed with the diagnosis of soft tissue sarcoma, but not with the type. In 14%, the panel concluded that a diagnosis of mesenchymal malignancy could not be affirmed. Final treatment results were based on the 275 pathologically confirmed, eligible patients. The most common histological subtype entered was leiomyosarcoma (99 patients). The response to Adr-DTIC of this subtype was higher (44%) than that of any other subtype. However, this difference alone was not responsible for the overall superiority of the combination. This confirmed that the combination of DTIC plus Adr adds to the response rate of Adr alone in soft tissue sarcomas. Whether the increased response frequency, without an impact on survival, is worth the significantly greater toxicity remains a subjective judgement that must be made within the context of the individual patient.

Prospectively randomized clinical trial of three intensive chemotherapy regimens for the treatment of advanced unfavorable histology non-Hodgkin's lymphoma.

Three hundred thirty-two eligible patients with advanced (Ann Arbor stage III or IV) non-Hodgkin's lymphoma of aggressive histologic subtype (Rappaport classification diffuse histiocytic [DH], diffuse poorly differentiated lymphocytic [DPDL], diffuse mixed [DM], or diffuse undifferentiated [DU]) were randomly assigned to receive induction chemotherapy with one of three intensive regimens in a clinical trial conducted by the Eastern Cooperative Oncology Group (ECOG) between 1978 and 1983. Chemotherapy regimens consisted of cyclophosphamide, vincristine, prednisone, and doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) (COPA) administered in 3-week cycles; cyclophosphamide plus doxorubicin plus prednisone beginning day 1, with vincristine plus bleomycin day 15 of each 3-week cycle (COPA + Bleo); or cyclophosphamide plus doxorubicin plus procarbazine beginning day 1, and bleomycin plus vincristine plus prednisone beginning day 15 of each 4-week cycle (CAP-BOP). The median patient follow-up from study entry for patients still alive is 5 years. The three regimens were not significantly different with respect to complete response (CR) rates (43% to 46%), time to progression of malignant disease (median, 1.0 to 1.7 years), or survival (5-year survival, 34% to 45%), although duration of complete remission appeared to be shorter in patients receiving COPA (P = .03). COPA + Bleo and CAP-BOP were significantly more toxic than the COPA regimen. This study did not demonstrate any substantial therapeutic advantage associated with the addition of a fifth or sixth chemotherapy drug, or with treatment administered on a more frequent administration schedule, compared with the COPA regimen in this population of patients with advanced diffuse non-Hodgkin's lymphoma. The relatively small proportion of long-term disease-free survivors treated with COPA underscores the need for prospective clinical trials of new and more effective treatments for patients with these potentially curable tumors.

The psychologic support of the cancer patient: a medical oncologist's viewpoint.

The cancer patient should not be treated differently from other patients. He has the right to good medical care and, especially, sympathetic and constructive psychologic support during all phases of diagnosis, surgery, radiotherapy, and chemotherapy, independent of disease extent or therapeutic response. After the physician has reevaluated his own concepts about cancer and death, he can effectively begin to treat and support his cancer patients. By understanding the individual psychologic problems of cancer patients and their families, a physician can develop an effective psychologic, as well as antineoplastic, treatment program. The family physician has the central role of introducing the cancer patient to his illness and to his oncologic physicians. The surgeon should discuss preoperatively the nature of a patient's problem and the proposed surgical treatment with its possible alterations of bodily function. Postoperatively, he and the family physician should develop a treatment program after appropriate consultation with oncologic subspecialists. If the radiotherapist is consulted and feels radiation therapy is indicated, he should outline his objectives and the possible side effects of therapy. Likewise, the medical oncologist should discuss the potential benefits and possible side effects of anticancer drugs if he feels they should be administered. No one way of supporting the cancer patient is superior. Each patient and his doctors have to develop individual relationships based on honesty, trust, and close communication. A continued commitment to the care of the patient with nurturing of hope and realistic goals is necessary, even when all antineoplastic treatment plans have failed. A satisfactory adjustment of the patient, his family, and the physician as he approaches death can be a natural and beneficial outgrowth of the doctor-patient relationship. Although much attention has been recently focused on the problems of the terminal patient, it is also important to realize that even cured cancer patients may need active psychologic support long after successful antineoplastic therapy has been terminated.

Effects of pulsatile intravenous insulin therapy on the progression of diabetic nephropathy.

The purpose of this study was to assess the effects of pulsatile intravenous insulin therapy (PIVIT) on the progression of diabetic nephropathy in patients with type 1 diabetes mellitus (DM). This 18-month multicenter, prospective, controlled study involved 49 type 1 DM patients with nephropathy who were following the Diabetes Control and Complications Trial (DCCT) intensive therapy (IT) regimen. Of these, 26 patients formed the control group (C), which continued on IT, while 23 patients formed the treatment group (T) and underwent, in addition to IT, weekly PIVIT. Blood pressure in all patients was maintained below 140/90 mm Hg on antihypertensive medication, preferentially using angiotensin-converting enzyme (ACE) inhibitors. All study patients were seen in the clinic weekly for 18 months, had monthly glycohemoglobin (HbA1c), and every 3 months, 24-hour urinary protein excretion and creatinine clearance (CrCl) determinations. The HbA1c levels declined from 8.61% +/- 0.33% to 7.68% +/- 0.31% (P = .0028) in the T group and from 9.13% +/- 0.36% to 8.19% +/- 0.33% (P = .0015) in the C group during the study period. CrCl declined significantly in both groups, as expected, but the rate of CrCl decline in the T group (2.21 +/- 1.62 mL/min/yr) was significantly less than in the C group (7.69 +/- 1.88 mL/min/yr, P = .0343). We conclude that when PIVIT is added to IT in type 1 DM patients with overt nephropathy, it appears to markedly reduce the progression of diabetic nephropathy. The effect appears independent of ACE inhibitor therapy, blood pressure, or glycemic control.

Randomized evaluation of combination chemotherapy vs. observation alone following response or stabilization after oophorectomy for metastatic breast cancer in premenopausal women.

Premenopausal patients with progressive measurable metastatic breast cancer who demonstrated either stable or responsive disease 12 weeks following oophorectomy were randomized either to receive cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) combination chemo-therapy (20 patients) or to continue under observation alone (14 patients). Since the study began in 1974, data on receptor status were not required for entry into the study. Stratification for randomization was based on the nature of the oophorectomy response (stable vs. response), dominant metastatic site (visceral vs. osseous vs. soft tissue), and disease-free interval (greater than 2 years vs. lesser than 2 years). Three (21%) of the 14 patients under observation alone continued to improve whereas 6 of 18 (33%) of the patients given CMF improved further, an insignificant difference. The median time to failure from oophorectomy was 17.5 months for the CMF group and 6.1 months for the observation group (p = 0.01). Using a multivariate proportional hazards model, visceral disease (p = 0.05) and breast involvement (p = 0.001) were also associated with significantly shorter times to failure. After the randomization, the fraction of observation patients progressing within 8 weeks was significantly greater than that of the CMF patients (5/14 vs. 0/21, p = 0.01). With 9 of the 14 observation patients and 11 of the 20 CMF patients dead, the estimated median survivals are similar at 40.4 and 41.3 months, respectively. We conclude that the addition of CMF chemotherapy to patients with stable-disease or objective response following oophorectomy significantly increases the median duration to treatment failure, whereas there appears to be no survival advantage for such therapy.

A randomized phase II study of m-AMSA (NSC 249992) and neocarzinostatin (NSC 157365) in non-small cell bronchogenic carcinoma. An Eastern Cooperative Group Study.

Eighty-nine patients with advanced non-small cell bronchogenic carcinoma were treated with either m-AMSA 120 mg/m2 intravenously every 3 weeks or neocarzinostatin 2.0 mg/m2 intravenously daily X 5 every 4 weeks. There were no responses in 40 evaluable patients who received m-AMSA and three partial responses (7.5%) in 40 patients who received neocarzinostatin. Two patients receiving m-AMSA had drug-related deaths. For m-AMSA the major toxicities were hematologic, while for neocarzinostatin the major toxicities were hematologic, gastrointestinal, and fever. We conclude that m-AMSA is inactive while neocarzinostatin has minimal activity in non-small cell bronchogenic carcinoma.

Pulsatile intermittent intravenous insulin therapy for attenuation of retinopathy and nephropathy in type 1 diabetes mellitus.

Many hormones are secreted in a pulsatile fashion that is more efficient than continuous secretion when tested in vivo. A trial of multiple daily insulin doses with or without the addition of weekly pulsatile insulin infusion therapy was designed to determine if deterioration of renal and retinal function could be blunted. Sixty-five study subjects were evaluated prospectively in 7 centers. Thirty-six patients were randomly allocated to the infusion group and 29 to the standard therapy group. Mean serum creatinine was 1.6 mg/dL in both groups. Subjects were excluded if clearance was less than 30 mL/min. There were no significant differences between the groups with respect to age, duration of diabetes, sex distribution, glycohemoglobin, blood pressure, angiotensin-converting enzyme inhibitor use, proteinuria, or baseline diabetic retinopathy (DR) severity level (all eyes exhibited DR; 8 were deemed technically not amenable to evaluation). Progression of DR was noted in 31.6% of 57 patients (32.3% treated, 30.8% control; P = 1.0) with both eyes evaluable. For patients with 12 or more months of follow-up, 27.9% of 43 patients demonstrated progression of DR (32.0% treated, 22.2% control; P = .57). There were no significant differences between study groups with respect to progression or marked progression, nor was there any influence of duration of follow-up. Progression of DR was noted in 18.8% of 122 eyes that could be adequately evaluated (17.9% of 67 treated, 20% of 55 controls; P = .39). Serum creatinine increased to 1.7 mg/dL in the treatment group and to 1.9 mg/dL in the control group (P = .03). Statistically significant preservation of renal function by pulsatile insulin infusion was not matched by a statistically significant prevention of DR progression compared with standard diabetes care. Inadequate statistical power or duration of the study, or lack of further benefit of pulsatile insulin infusion on the retina in the presence of angiotensin-converting enzyme inhibition may be responsible.

Glycosylated albumin and transferrin: short-term markers of blood glucose control.

Serum was collected from children with type 1 diabetes mellitus before and 10 days after attending a camp session in which blood glucose concentrations were carefully controlled. Glycosylated and nonglycosylated proteins were separated, and levels of albumin and transferrin were determined on each of these fractions. Glycosylated hemoglobin was also determined and ranged from 4.6% to 14.6% (mean +/- SEM 8.1% +/- 0.2%). Mean initial glycosylated albumin in 73 children was 16.4% +/- 0.6%, which was elevated compared with the mean of levels in 20 nondiabetic controls (8.7% +/- 0.3%) and correlated well with levels of glycosylated hemoglobin (r = 0.71). After 10 days mean glycosylated albumin fell to 14.6% +/- 0.5% (P less than 0.00001), near the predicted final value of 13.4% if control had been ideal. Initial levels of glycosylated transferrin in 44 of these children ranged from 4.5% to 22.3% (11.4 +/- 0.6%) and was significantly higher than the mean of 3.8% +/- 0.3% in 20 nondiabetic controls. Mean final glycosylated transferrin fell to 8.2% +/- 0.3% (P less than 0.00001), near the predicted final mean of 7.0% +/- 0.2%. The mean of each subject's blood glucose determinations performed throughout the study period correlated with final levels of both glycosylated albumin (r = 0.55, P less than 0.001) and glycosylated transferrin (r = 0.54, P less than 0.001). Both glycosylated albumin and glycosylated transferrin appear to be reliable markers of short-term glycemic control; glycosylated transferrin (half-life 8 days) was more sensitive than glycosylated albumin over this 10-day period.

An effective low-dose adriamycin regimen as secondary chemotherapy for metastatic breast cancer patients.

Sixty breast cancer patients with hormone-resistant metastatic disease who had progressed after chemotherapy with low-dose cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) or with L-phenylalanine mustard underwent treatment with a low-dose Adriamycin regimen,i.e., 20 mg/m2, intravenously on days 1 and 8 every 28 days. Two percent of patients had complete responses; 25%, partial responses; 38%, stabilization; and 35%, progression. The time to progression for the responders was similar to that of the stabilized patients, while the responders and stabilized patients survived significantly longer than did the progressors. Responses were seen in nodal, hepatic, dermal/subcutaneous, bone, pulmonary, and peritoneal metastases. The toxicity was mild: 18% of patients had leukocyte counts of less than 3,000/mm3; 10% had platelet counts of less than 90,000/mm3, 22% experience vomiting; and 33% had hair loss. No patient experienced local venous/subcutaneous toxicity or heart failure. Since this regimen of low-dose Adriamycin appears to be as effective as, but less toxic than, the secondary standard-dose of Adriamycin at 60--75 mg/m2 every three weeks, a randomized trial of low-dose Adriamycin vs. standard-dose Adriamycin should be conducted in metastatic breast cancer patients who have previously undergone chemotherapy.

Progestin therapy for advanced ovarian cancer: a phase II Eastern Cooperative Oncology Group trial.

PIP: This is the report of results from a phase 2 trial of high-dose progestin therapy for treatment of ovarian cancer. 19 women received 1000 mg of Depo Provera (medroxyprogesterone acetate) weekly by intramuscular injection for at least 8 weeks and longer if there was no evidence of tumor progression. None of the women in the study was responding any longer to surgery, radiation therapy, or conventional cytotoxic chemotherapy. Response was measured as: 1) regression if there was at least a 50% decrease in the area of measurable lesion; or 2) disease progression as at least a 25% increase over the original measurements or the appearance of new lesions. Based on these criteria, there were no responses in the 19 women. Only 1 patient remained stable (3 months). Median survival time was 2 months with 75% of the patients dying within 4 months. 1 patient suffered severe vomiting and another experienced bleeding; there was no other toxicity. It is concluded that progestin therapy does not have a beneficial effect and its use in ovarian cancer patients should be limited to those with endometrioid histology.^ieng

Phase II study of mitolactol in chemotherapy-refractory metastatic breast cancer.

Thirty-eight evaluable patients with metastatic breast cancer refractory to hormonal therapy and multiple chemotherapy regimens were treated with mitolactol at a dose of 130 mg/m2/day orally for 10 days every 6 weeks. Only one patient, with nodal and chest wall metastases, had a sustained complete regression; two patients had stable disease; and 35 patients had disease progression. The toxicity, which was primarily hematologic, was acceptable.