Safety and efficacy of using a single agent or a phase II agent before instituting standard combination chemotherapy in previously untreated metastatic breast cancer patients: report of a randomized study--Cancer and Leukemia Group B 8642.

PURPOSE: We undertook a prospective, randomized phase III trial to evaluate the safety and efficacy of using a phase II agent before initiating therapy with standard combination chemotherapy in metastatic breast cancer patients. PATIENTS AND METHODS: A total of 365 women with measurable metastatic breast cancer, previously untreated with chemotherapy for their metastatic disease, were randomized to receive either immediate chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) or up to four cycles of one of five sequential cohorts of single-agent drugs: trimetrexate, melphalan, amonafide, carboplatin, or elsamitrucin, followed by CAF. RESULTS: The toxicity of each single agent followed by CAF was comparable to that of CAF alone. The cumulative response rates for the single agent followed by CAF were not statistically different from those of CAF alone (44% v 52%; P = .24). However, in the multivariate analysis, patients with visceral disease had a trend toward lower response rates on the phase II agent plus CAF arm (P = .078). Although survival and response duration also were not statistically significantly different between the two study arms (P = .074 and P = .069, respectively), there was a suggestion of benefit for the CAF-only arm. CONCLUSION: The brief use of a phase II agent, regardless of its efficacy, followed by CAF resulted in response rates, toxicities, durations of response, and survival statistically equivalent to those seen with the use of CAF alone. These findings support the use of a new paradigm for the evaluation of phase II agents in the treatment of patients with metastatic breast cancer.

Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B.

BACKGROUND: About 65 percent of previously untreated adults with primary acute myeloid leukemia (AML) enter complete remission when treated with cytarabine and an anthracycline. However, such responses are rarely durable when conventional postremission therapy is administered. Uncontrolled trials have suggested that intensive postremission therapy may prolong these complete remissions. METHODS: We treated 1088 adults with newly diagnosed AML with three days of daunorubicin and seven days of cytarabine and randomly assigned patients who had a complete remission to receive four courses of cytarabine at one of three doses: 100 mg per square meter of body-surface area per day for five days by continuous infusion, 400 mg per square meter per day for five days by continuous infusion, or 3 g per square meter in a 3-hour infusion every 12 hours (twice daily) on days 1, 3, and 5. All patients then received four courses of monthly maintenance treatment. RESULTS: Of the 693 patients who had a complete remission, 596 were randomly assigned to receive postremission cytarabine. After a median follow-up of 52 months, the disease-free survival rates in the three treatment groups were significantly different (P = 0.003). Relative to the 100-mg group, the hazard ratios were 0.67 for the 3-g group (95 percent confidence interval, 0.53 to 0.86) and 0.75 for the 400-mg group (95 percent confidence interval, 0.60 to 0.94). The probability of remaining in continuous complete remission after four years for patients 60 years of age or younger was 24 percent in the 100-mg group, 29 percent in the 400-mg group, and 44 percent in the 3-g group (P = 0.002). In contrast, for patients older than 60, the probability of remaining disease-free after four years was 16 percent or less in each of the three postremission cytarabine groups. CONCLUSIONS: These data support the concept of a dose-response effect for cytarabine in patients with AML who are 60 years of age or younger. The results with the high-dose schedule in this age group are comparable to those reported in similar patients who have undergone allogeneic bone marrow transplantation during a first remission.

Acute leukemia and residential proximity to potential sources of environmental pollutants.

Possible associations between location of residence and acute leukemia risk were investigated in a study of 610 newly diagnosed patients, aged 18-79 y, and 618 population controls. There was an association between ever living within 5 miles (8 km) of an industrial plant and leukemia risk, with adjusted odds ratios (ORs) of 1.4 (95% confidence interval [95% CI] = 1.0-1.9) for all acute leukemias combined, 1.4 (95% CI = 1.0-2.0) for acute myeloid leukemia, and 1.7 (95% CI = 1.0-2.7) for acute lymphocytic leukemia. Odds ratios increased with decreasing distance from industrial sites, but a gradient with duration of residence was seen only among those less than age 60 who had lived within a mile of any industry. Suggestive associations were also observed for residence near specific industries, but the number of individuals living near any one industry was small.

A successful system of scientific data audits for clinical trials. A report from the Cancer and Leukemia Group B.

OBJECTIVE: To report on data collected during on-site audits of source documents in the Cancer and Leukemia Group B (CALGB). DESIGN: A retrospective review of audit reports in four audit cycles. SETTING: A cooperative group of institutions conducting clinical trials in cancer treatment. PARTICIPANTS: Patients taking part in clinical trials at collaborating CALGB institutions, members of the CALGB Data Audit Committee, and group chairmen of CALGB. MAIN OUTCOME MEASURE: The results of 691 institutional audits conducted by the CALGB in 1982 through 1992 with comparisons of main CALGB institutions vs affiliates. RESULTS: In four full reviews of all participating institutions in the CALGB, 3787 patients have had their on-site medical records compared with data submitted to the CALGB Data Management Center. Compliance with federal regulations for oversight by an institutional review board improved from a deficiency rate of 28.0% among the main institutions and 49.6% of the affiliate institutions in the first audit cycle to respective figures of 13.3% and 28.2% in the fourth cycle. Consent form deficiencies also dropped overall from 18.5% in the first cycle to 3.9% in the fourth. Patient eligibility was verified by auditors in 94.5%, and assessment of tumor changes in response to treatment was verified in 96.4% in the fourth cycle; both figures were only slightly lower in the first cycle. Two instances of scientific impropriety were discovered for a rate of only 0.28% of all audits. Both occurred prior to 1984, and none have occurred since. Major protocol deviations in drug dosing have held steady at about 11% over four audit cycles. Over the 11-year period of audits, three main institutions and 96 affiliate institutions have discontinued CALGB membership due solely, or at least partly, to unfavorable audit results. CONCLUSION: Scientific improprieties have occurred very rarely in clinical trials conducted by the CALGB. Protocol compliance in assessing patient eligibility and tumor responses has been high. Attention to administrative matters of consent forms, institutional review board approval, and ancillary data submission has measurably improved in the CALGB, which is at least partly due to the pressure from this on-site peer review of investigator performance.

A randomized clinical trial comparing melphalan/prednisone with or without interferon alfa-2b in newly diagnosed patients with multiple myeloma: a Cancer and Leukemia Group B study.

PURPOSE: This clinical trial was designed to compare the effectiveness of the standard melphalan and prednisone regimen to that of melphalan, prednisone, and interferon in patients with untreated multiple myeloma. PATIENTS AND METHODS: Between October 1985 and March 1988, 278 patients were accrued to a multi-institutional, randomized clinical trial. Responding patients were treated for 2 years before termination of therapy. RESULTS: After a median follow-up of 23 months, the overall remission rate for the melphalan/prednisone treatment group was 44% compared with 33% for the group receiving melphalan/prednisone/interferon alfa-2b. The durations of response and survival were identical for the two treatment groups. Median survival was 3.17 years on melphalan/prednisone treatment and 3.0 years on melphalan/prednisone/interferon alfa-2b treatment. Both hematologic and nonhematologic toxicities were greater in the melphalan/prednisone/interferon alfa-2b treatment group, but were usually of a mild or moderate degree and did not interfere with the completion of therapy. The frequency of deaths in the two treatment groups attributable to the treatment itself was similar. CONCLUSION: This study shows no advantage to the concomitant delivery of interferon alfa-2b with standard melphalan and prednisone as initial treatment for patients with multiple myeloma.

ras oncogene activation and occupational exposures in acute myeloid leukemia.

BACKGROUND: Epidemiologic studies of acute myeloid leukemias (AMLs) show small increases in risk of disease associated with certain occupations and chemical exposures. PURPOSE: This study was designed to determine whether the presence of mutationally activated ras oncogenes in AML are associated with occupational and chemical exposures. METHODS: We interviewed 62 patients with newly diagnosed AML (or their next-of-kin), all of whom were enrolled in a national multicenter clinical trial, and 630 healthy control subjects. DNA extracted from patients' pretreatment bone marrow samples was amplified by using the polymerase chain reaction and probed with allele-specific oligonucleotides for activating point mutations at the 12th, 13th, and 61st codons of three protooncogenes: H-ras (also known as HRAS), K-ras (also known as KRAS2), and N-ras (also known as NRAS). RESULTS: Patients with ras mutation-positive AML had a higher frequency (six of 10 patients) of working 5 or more years in an a priori high-risk occupation than did patients with ras mutation-negative AML (eight of 52; odds ratio [OR] = 6.8; 95% confidence interval [CI] = 1.3-36). Patients with ras mutation-positive AML were more likely than patients with ras mutation-negative AML to have breathed chemical vapor on the job (OR = 9.1; 95% CI = 1.3-64) or to have had skin contact with chemicals (OR = 6.9; 95% CI = 1.3-37). When ras-positive patients were compared with healthy control subjects, the ORs for occupation and occupational exposures remained elevated, while patients with ras mutation-negative AML showed no increased risk when compared with control subjects. CONCLUSION: Activation of ras proto-oncogenes may identify an etiologic subgroup of AML caused by occupation and chemical exposure. IMPLICATION: Disease etiology may be better understood if epidemiologic measures of exposure are integrated with molecular assays of the genetic defects responsible for cancer initiation and promotion.

Mood and clinical status in patients with multiple myeloma.

Two hundred ninety patients with a recent diagnosis of multiple myeloma were studied psychologically at the time of initial treatment. Physician- and patient-completed psychosocial scales were correlated with physical variables used to measure tumor load and physical status. A logistic regression model was used to analyze objective response to treatment. Indirect measures of response to treatment were obtained, and factors influencing survival duration were studied using a Cox regression model. If physical variables were controlled, there were no significant correlations between psychologic scores on entry and response to treatment or survival duration. Thus, the notion that mood influences disease outcome once the disease process has begun in patients with multiple myeloma is not supported by this data set.

A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B.

Between 1982 and 1986, 326 evaluable patients with acute myeloid leukemia (AML) were randomized to receive cytarabine (Ara-C) at 200 mg/m2 (A200) or 100 mg/m2 (A100) for induction and maintenance therapy. Cycle 1 of induction therapy consisted of 7 days of continuous intravenous (IV) Ara-C and 3 days of i.v. daunorubicin (DNR); cycle 2, if needed, consisted of 5 days of Ara-C and 2 days of DNR. Complete responders (CR) then received monthly subcutaneous (SC) Ara-C at the respective doses (A100 or A200) with 6-thioquanine (6TG) at months 1 and 5, with vincristine (VCR) and prednisone at months 2, 4, 6, and 8, and with DNR at months 3 and 7. Complete response rates were 58% (A100) and 64% (A200) (P = .29). Median survival was 46 weeks (A100) and 38 weeks (A200) (P = .64); 5-year survival was 10% (A200) and 8% (A100). Median time to remission was 6.7 weeks (A200) and 8.1 weeks (A100) (P = .18). Median disease-free survival was 41 weeks (A200) and 44 weeks (A100) (P = .86). Deaths were attributed to therapy-related toxicities in 21% (A200) and 13% (A100) (P = .05). The 5-year survival was 15% for patients with performance status (PS) 0, 8% for PS 1 to 2, and 2% for PS 3 to 4, 18% for patients less than 40 years, 8% for ages 40 to 59, and 3% for age 60 or greater. Stratification of data by age and PS suggested that A200 may improve survival in patients less than 60 years with a good PS 0 (P = .05). This trial does not support the superiority of A200 over A100 in the treatment of AML.

Pentostatin in chronic lymphocytic leukemia: a phase II trial of Cancer and Leukemia group B.

We conducted a phase II trial of deoxycoformycin (pentostatin [DCF]) in chronic lymphocytic leukemia (CLL). Eligibility criteria included age greater than 18 years, Cancer and Leukemia Group B (CALGB) performance status 0 to 2, lymphocyte count greater than or equal to 15,000 cells/microL, international stage B or C disease (multiple lymph nodes involved and/or hemoglobin [Hgb] less than 11 g and/or platelets less than 100,000/microL) and no more than one prior treatment regimen. DCF dose was 4 mg/m2 intravenously (IV) weekly for 3 weeks and then every 2 weeks. There were 39 eligible patients (35 men and four women; median age, 63 years; median time from diagnosis to study entry, 3 years). Of these 39 patients, 31% were stage B and 33% had no prior treatment. Median laboratory values at entry were Hgb 10.5 g, WBC 96,100/microL, and platelets 93,500/microL. Nodal involvement was present in 90%, splenomegaly in 81%, and hepatomegaly in 47%. Patients received a median of nine DCF injections, with a range of four to 26. Three patients were not evaluable for response. Overall, 3% achieved a complete response (CR), 23% a partial response (PR), 28% showed clinical improvement (CI), and 38% had stable disease (SD). Associated toxicities (grade 2 or worse) observed were infections (52%), worsening of thrombocytopenia (26%) or anemia (33%), nausea and vomiting (31%), rash or pruritus (20%), and stomatitis (8%). We conclude that DCF is an active agent in CLL with acceptable toxicity.

Phase II trial of amsacrine in patients with multiple myeloma.

Seventy-four previously treated patients with multiple myeloma were treated with Amsacrine (m-AMSA) 120 mg/m2 every 3 weeks. A good response was observed in two patients (3%), and improvement was seen in three patients (4%). Severe toxicity was observed in 33% of patients who received three or more courses of treatment. This dose and schedule of m-AMSA in multiple myeloma is usually ineffective.

Inhibitory effect of disodium EDTA upon the growth of Staphylococcus epidermidis in vitro: relation to infection prophylaxis of Hickman catheters.

Granulocytopenic patients with an intravascular catheter are at increased risk for infection with Staphylococcus epidermidis. During the intervals when the catheters are not being used for infusions, it is customary to maintain patency of the catheter lumen with a solution containing heparin. We show that heparin does not inhibit the growth of S. epidermidis isolated from the catheter of an infected patient. A 20-mg/ml solution of disodium EDTA, a chelating agent which effectively anticoagulates blood at this concentration, was shown to be bactericidal for an initial inoculum of 10(3) CFU of staphylococci per ml in 24 h. Vancomycin, an antibiotic which is often employed to treat Staphylococcus infections, was also bactericidal for initial inocula of 10(3) CFU/ml at doses of 6.7 micrograms/ml, a drug concentration in the therapeutic range. When 10(3) staphylococci per ml were cultured in the presence of catheter segments and disodium EDTA or vancomycin, subcultures of the catheters showed minimal or no growth, respectively. In contrast, when cultured with heparin alone, subcultures showed abundant growth. In view of its low cost, effectiveness as an anticoagulant, and bactericidal activity, EDTA should be studied as a replacement for heparin solutions for the maintenance of intravenous catheters in granulocytopenic patients.

Melphalan and prednisone plus total bone marrow irradiation as initial treatment for multiple myeloma.

Patients who have received radiation to localized areas of marrow eventually regenerate marrow in the irradiated area, if the dose is 2,400 centigrays (cGy) or less. This trial was designed to deliver a radiation dose of 1500 cGy to all marrow containing sites in patients with multiple myeloma, a technique we refer to as total bone marrow irradiation, or TBMI. Patients with previously untreated myeloma received 12 weeks of melphalan (L-PAM) and prednisone (pred) therapy. Four weeks later, sequential irradiation was administered using the 3-2 technique with rest periods to permit recovery from radiation-induced cytopenia. This was followed by electron beam irradiation of the rib and skull fields. Following completion of TBMI, patients were untreated until relapse. Twenty patients were entered. At entry 5, 8, and 7 patients had low, intermediate and high tumor cell loads, respectively. Two patients had a serum Ca in excess of 12 mg/dl; 3 had an increased creatinine. The median performance (ECOG) was 1. At week 16, immediately prior to TBMI, 5 of the 20 patients fulfilled the Myeloma Task Force criteria for response and 5 others had improved. Six patients did not begin the radiation therapy portion of the protocol. Three had rapidly progressive disease, one persistent leukopenia, one refused radiation therapy and one was withdrawn by his physician. Only 6 of the fourteen patients receiving the radiation treatment phase of the protocol were able to tolerate the intended course of 1500 cGy to all areas. Eight other patients received lower doses. Patients completing the radiation phase of the protocol failed to have further reductions in M-protein or improvement in other parameters beyond those obtained on the chemotherapy phase of the protocol. The median duration of response and survival was 12.0 and 42 months, respectively. We suggest possible reasons for the disappointing results of this trial and conclude that this approach to the primary treatment of myeloma holds little promise.

Vincristine and prednisone prolong the survival of patients receiving intravenous or oral melphalan for multiple myeloma: Cancer and Leukemia Group B experience.

A total of 589 patients with previously untreated multiple myeloma were randomized to receive daily oral melphalan, pulse-dose intravenous (IV) melphalan, carmustine (BCNU), or lomustine (CCNU). All patients received an initial tapering course of prednisone (Pred). During week 22 (day 154), patients were randomized to receive or not to receive additional therapy with vincristine (VCR) (1 mg/m2) and prednisone (0.6 mg/kg/d for seven days) at 8-week intervals. The influence of VCR/Pred was determined in 302 patients who remained on study beyond 22 weeks after initial therapy. VCR/Pred converted a significant percentage of nonresponders to responders in patients treated with melphalan (55% v 19%, P = .002), but not in patients treated with a nitrosourea (48% v 23%, P = .06). Survival beyond week 22 was significantly longer following the addition of VCR/Pred in patients receiving melphalan (median, 35.3 months v 27.0 months; P = .003) but not in patients receiving BCNU or CCNU (median, 28.1 months v 26.2 months; P = .91). These differences were seen both for oral and IV melphalan. A trend for beneficial effect of VCR/Pred was definitely seen in the good-risk patients (P = .03) but only suggestive for poor-risk patients (P = .12). Following adjustment for VCR/Pred effects, there were no differences in the survival of patients receiving any of the four initial treatments.

Distribution of the 124-kd antigen defined by monoclonal antibody AML-1-99 on normal and leukemic myeloid cells.

We have produced a monoclonal antibody (MoAb), AML-1-99, that defines a novel 124-kd protein antigen expressed on a subpopulation of monocytes and on the majority of hematopoietic progenitor cells of the granulocyte-monocyte (CFU-GM), erythroid, and mixed-lineage classes. AML-1-99 is lytic to bone marrow (BM)- and peripheral blood-derived progenitor cells in the presence of rabbit complement (C'). AML-1-99 is not toxic to progenitor cells in the absence of C', nor does it modify their growth when included in colony-forming cultures. Several leukemia cell lines, including HL-60, U937, KG-1a, and Daudi cells, express the antigen on the majority of cells. Freshly isolated leukemia cells from patients with acute myelogenous leukemia (AML) react variably with AML-1-99. Leukemia colony-forming cells from several AML patients express the antigen and could be eliminated by treatment with AML-1-99 and C'. Cell sorting and immune rosette techniques were successfully applied to normal BM and chronic myelocytic leukemia cell populations using AML-1-99 with the result that significant enrichment of CFU-GM could be accomplished. The pattern of reactivity of this MoAb and its apparent molecular weight suggests that AML-1-99 recognizes a newly defined myeloid-associated cell surface antigen.

Synergy between high-dose cytarabine and asparaginase in the treatment of adults with refractory and relapsed acute myelogenous leukemia--a Cancer and Leukemia Group B Study.

One hundred ninety-five adult patients with refractory or first relapse acute myelogenous leukemia (AML) were randomly assigned to receive high-dose cytarabine (HiDAC), 3 g/m2 as a three-hour intravenous (IV) infusion every 12 hours for four doses, followed by 6,000 IU/m2 asparaginase (ASNase) administered at hour 42, or HiDAC without ASNase. Treatment was repeated on day 8. The median patient age was 52 years. There was an overall superior complete remission (CR) rate for HiDAC/ASNase (40%) v HiDAC (24%), P = .02. Subset analysis according to prior response and age showed the following CR rates: 54% from HiDAC/ASNase treatment of refractory AML in patients less than 60 years, and 31% in patients greater than 60 years; CR from HiDAC in the same refractory groups were 18% (less than 60) and 0% (greater than 60); 37% from HiDAC/ASNase treatment of relapsed AML in patients less than 60 years, and 43% in patients greater than 60 years; CRs from HiDAC in the same relapsed groups were 33% (less than 60) and 21% (greater than 60). Toxicity in the two treatment arms was comparable and consisted primarily of leukopenia, thrombocytopenia, mild hepatic dysfunction, diarrhea, conjunctivitis and serositis, and hyperglycemia. There was only one case of transient cerebellar toxicity and no cutaneous toxicity. Median time to full hematologic recovery was 5 weeks. There was an overall survival benefit for patients treated with HiDAC/ASNase (19.6 weeks) compared with HiDAC (15.9 weeks), P = .046, primarily attributable to effects in refractory patients. Median time to failure for refractory patients who achieved CR was 38.5 weeks with HiDAC/ASNase, and 13.3 weeks for those treated with HiDAC. For relapsed patients in CR from HiDAC/ASNase the median time to failure was 17.7 weeks and 18.3 weeks for HiDAC. The overall 42% CR rate from HiDAC/ASNase v 12% from HiDAC in patients with refractory AML indicates that HiDAC/ASNase is not cross-resistant with standard-dose cytarabine (SDAC) and anthracyclines. We conclude that HiDAC/ASNase has substantial activity in poor-prognosis AML and that this combination warrants further trials in earlier stage disease.