Janet Wolter

Multinational Study of the Efficacy and Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing Metastatic Breast Cancer That Has Progressed After Chemotherapy for Metastatic Disease

PURPOSE Overexpression of the HER2 protein occurs in 25% to 30% of human breast cancers and leads to a particularly aggressive form of the disease. Efficacy and safety of recombinant humanized anti-HER2 monoclonal antibody as a single agent was evaluated in women with HER2-overexpressing metastatic breast cancer that had progressed after chemotherapy for metastatic disease. PATIENTS AND METHODS Two hundred twenty-two women, with HER2-overexpressing metastatic breast cancer that had progressed after one or two chemotherapy regimens, were enrolled. Patients received a loading dose of 4 mg/kg intravenously, followed by a 2-mg/kg maintenance dose at weekly intervals. RESULTS Study patients had advanced metastatic disease and had received extensive prior therapy. A blinded, independent response evaluation committee identified eight complete and 26 partial responses, for an objective response rate of 15% in the intent-to-treat population (95% confidence interval, 11% to 21%). The median duration of response was 9.1 months; the median duration of survival was 13 months. The most common adverse events, which occurred in approximately 40% of patients, were infusion-associated fever and/or chills that usually occurred only during the first infusion, and were of mild to moderate severity. These symptoms were treated successfully with acetaminophen and/or diphenhydramine. The most clinically significant adverse event was cardiac dysfunction, which occurred in 4.7% of patients. Only 1% of patients discontinued the study because of treatment-related adverse events. CONCLUSION Recombinant humanized anti-HER2 monoclonal antibody, administered as a single agent, produces durable objective responses and is well tolerated by women with HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Side effects that are commonly observed with chemotherapy, such as alopecia, mucositis, and neutropenia, are rarely seen.

A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast carcinoma

Anastrozole is a new oral aromatase inhibitor with highly potent and selective activity for the aromatase enzyme. In a Phase III trial, the efficacy and tolerability of anastrozole, given in doses of 1 and 10 mg orally once daily, and megestrol acetate, given in doses of 40 mg orally 4 times daily, were compared in 386 postmenopausal women with advanced breast carcinoma who progressed after tamoxifen therapy.

Adjuvant chemotherapy with and without tamoxifen in the treatment of primary breast cancer: 5-year results from the National Surgical Adjuvant Breast and Bowel Project Trial.

In this National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial, 1,891 women with primary operable breast cancer and positive axillary nodes were randomized between Jan, 1977 and May 1980 to receive L-phenylalanine mustard (L-PAM) and 5-fluorouracil (5-FU) either with or without tamoxifen (TAM)-PFT. This report presents life table probabilities, cumulative odds ratios, and P values for disease-free survival (DFS) and survival at yearly intervals through 5 years of observation (mean time on study, 72 months). When patients were examined overall without regard for any discriminant associated with outcome, ie, age, number of positive nodes, or tumor receptor status, there was a significant prolongation of DFS (P = .002), but not survival through the fifth postoperative year. The benefit was almost entirely restricted to those greater than or equal to 50 years with greater than or equal to 4 positive nodes. In that group there was a 66% greater chance of remaining disease free if PFT was received (P less than .001), and there was also a significant survival benefit (P = .02). The advantage from PFT was found to be associated with tumor estrogen receptor (ER) and progesterone receptor (PR) as well as patient age and nodal status. Overall there was a significant improvement in DFS from PFT in those having tumors with an ER or PR level greater than or equal to 10 femtomole (fmol) (P = .01 and .009, respectively). No significant benefit in DFS or survival has been observed in patients less than or equal to 49 years old related either to nodes or tumor receptor status. Survival continues to be adversely affected by TAM in those patients (less than or equal to 49 years old), particularly when their tumors have a PR of 0 to 9 fmol (P = .007). In patients greater than or equal to 50 years old with four or more positive nodes, a significant DFS benefit persisted through the fifth year of observation in those having tumor ER or PR levels greater than 10 fmol (P less than .001 and .002). The advantage was observed in patients 50 to 59 years old as well as those 60 to 70. Women in the older decade demonstrated some advantage from PFT when their tumor ER or PR was 0 to 9 fmol. The most likely explanation for this finding is analytical error in receptor analyses.(ABSTRACT TRUNCATED AT 400 WORDS)

A comparison of adriamycin versus vincristine and adriamycin, and cyclophosphamide versus vincristine, actinomycin‐D, and cyclophosphamide for advanced sarcoma

This randomized study, conducted by the Eastern Cooperative Oncology Group, compared Adriamycin (doxorubicin) (70 mg/m2) versus vincristine (1.4 mg/m2) and Adriamycin (50 mg/m2); and cyclophosphamide (750 mg/m2) versus vincristine (1.4 mg/m2), actinomycin‐D, (0.4 mg/m2), and cyclophosphamide (750 mg/m2) for treatment of metastatic mesenchymal malignancies. The respective response rate seen in 200 evaluable patients to the treatments were, 27, 19, and 11%. The response rate to Adriamycin was significantly better than the response to vincristine, actinomycin‐D, and cyclophosphamide (P = 0.03, two‐sided). The respective median survivals on the three treatments were 37, 34, and 41 weeks and were not significantly different. Moderate or severe vomiting occurred in 60% of patients receiving vincristine—cyclophosphamide—adriamycin, a greater frequency than in Adriamycin alone (P = .09 two‐sided). Severe or life‐threatening hematologic toxicity (leukocytes <2000, platelets <50,000) occurred in 30% of patients receiving the Adriamycin combination, a markedly increased frequency when compared to the other two regimens (P = 0.07, P = 0.02, two‐sided). This trial establishes that Adriamycin has a better response rate than the combination of vincristine—actinomycin‐D—cyclophosphamide in advanced sarcomas. The combination of vincristine, Adriamycin, and cyclophosphamide increased toxicity and did not add to the therapeutic effect achieved with Adriamycin alone.

Mithramycin treatment of hypercalcemia

An experience with Mithramycin in the treatment of hypercalcemia of malignancy is reported. Mithramycin given by direct, single, intravenous injection of 25 μg/kg was effective in lowering serum calciums within 24 to 48 hours in the majority of patients studied. The duration of this effect has been quite variable, but repeated doses of single injections have proven to be successful in most cases treated. The potential clinical usefulness of this agent in the treatment of hypercalcemia is apparent. It is reasonable to continue such studies on a long‐term basis. Such studies are currently in progress.

A pilot study of the Functional Living Index-Cancer (FLIC) Scale for the assessment of quality of life for metastatic lung cancer patients. An Eastern Cooperative Oncology Group study.

Quality of life is an important factor in the assessment of cancer therapy, but it is difficult to define and measure. The Functional Living Index-Cancer (FLIC) was designed specifically for cancer patients under treatment. The Eastern Cooperative Oncology Group (ECOG) mounted a pilot study to assess the feasibility and sensitivity of the patient-oriented FLIC scale for assessment of quality of life. The results of this study show that the FLIC scores correlate with the functional status of patients on treatment: high scores on the FLIC prior to therapy were found to correlate with good performance status (p = 0.0001), and decreases in the FLIC score during therapy correlated with a decline in performance status (p = 0.0001), with poor performance status (p = 0.0002), and <5% recent weight loss (p = 0.004). However, there was poor compliance to completion of the instrument, indicating a need for future research into this aspect of assessing quality of life in the cooperative group setting.

Results with methyl-CCNU and DTIC in metastatic melanoma

This report is the result of an Eastern Cooperative Oncology Group (ECOG) study. Four hundred and 15 patients with inoperable metastatic malignant melanoma, excluding those with cutaneous metastases only, were randomized to one of three drug treatments: DTIC alone, methyl‐CCNU alone, or the combination DTIC plus methyl‐CCNU. Responses were seen in 14% of DTIC patients (19/127), 15% of methyl‐CCNU patients (18/119) and 14% of DTIC plus methyl‐CCNU patients (18/122). Duration of response was the same (14 weeks) for all three treatment groups. There was no difference among the treatments in achieving complete responses. Survival was improved significantly for responders (50 weeks) compared with nonresponders (15 weeks) regardless of treatment regimen. Toxicities were generally tolerable. DTIC caused significantly more gastrointestinal toxicity than methyl‐CCNU. Methyl‐CCNU caused significantly more bone marrow toxicity than DTIC. There were three drug‐related deaths. All occurred in patients on combination DTIC plus methyl‐CCNU. Important pretreatment characteristics that favor response are ambulatory status, female, less than 50 years old, no prior chemotherapy and no liver or brain metastases. Patients with favorable characteristics combinations had a 30% response rate, while those with unfavorable characteristic combinations had only a 9% response rate.

Clinical study with bleomycin

Bleomycin is an antitumor antibiotic produced by Streptomyces verticillus. Seventy‐five patients with various neoplasms were studied using this drug. Fourteen out of 20 patients with epidermoid carcinoma of the head and neck region, 5 out of 14 cases of lymphoma including Hodgkins disease, 3 out of 6 patients with testicular tumors, and one patient with lymphangiosarcoma of the arm showed evidence of objective regression. Common side effects encountered were hyperthermic reactions, gastrointestinal disturbances, hyperkeratosis and vesiculation of fingers, alopecia, and stomatitis. Pulmonary fibrosis is a rare but serious complication. One patient in this series died of this complication. There was no evidence of bone marrow, liver, or renal toxicity. Bleomycin promises to be a useful therapeutic agent and merits further study.

Hormonal treatment for metastatic breast cancer. An eastern cooperative oncology group phase III trial comparing aminoglutethimide to tamoxifen

Background. Tamoxifen and aminoglutethimide are two hormone therapies reported to be effective palliative approaches for patients with metastatic breast cancer. The current trial was designed to evaluate their relative therapeutic effectiveness.

Therapy of malignant melanoma with an imidazole carboxamide and bis-chloroethyl nitrosourea

One hundred twelve evaluable patients with metastatic malignant melanoma were randomized to receive either a combination of DTIC 100 mg/m2/day × 5 days and BCNU 75 mg/m2/day × 2 days or DTIC 150 mg/m2/day × 5 days alone. The combination treatment yielded 12/61 responders as compared with 9/51 with DTIC alone. Responders survived significantly longer (7 months) than did nonresponders (3 months). Toxicity of both treatments was tolerable, but more frequent bone marrow suppression was encountered with DTIC‐BCNU combination. Patients were analyzed for relation between survival and the following: regional node dissection, length of the free interval, and positive urinary melanogens. Only the latter relation tended to be positive. We conclude that DTIC is the best agent for the therapy of melanoma with an expected response rate of 20%, and that its combination with BCNU does not add to its therapeutic effectiveness except in patients with central nervous system metastases.