In a continuing search for agents effective in advanced breast cancer, nonrandomized studies by the Southwest Cancer Chemotherapy Study Group have shown a 29% response rate with BCNU, a 19% response rate with CCNU, and a 36% response rate with adriamycin. Following these leads, a randomized Phase I11 study has compared adriamycin (60-75 mg/m2 intravenously every 3 weeks) with the oral nitrosoureas, CCNU (100-130 mg/m2 orally every 6 weeks) and methyl CCNU (125-150 mg/mz orally every 6 weeks) in patients with advanced breast cancer, all of whom had already failed in at least one trial with conventional chemotherapeutic agents. The patients' age, menopausal status, sites of metastatic involvement, and extent of prior therapy were nearly identical in the three treatment groups. Ten inevaluable patients died within the first 2 weeks from tumor. For the remaining 100 patients, the response rate was: adriamycin 15/40 (38%); CCNU 4/20 (14%); and methyl CCNU 1/31 (3%). The median durations of response for adriamycin, CCNU, and methyl CCNU were 7, 3, and 1% months respectively. Patients receiving adriamycin had significantly superior survival from the start of chemotherapy, and the duration of survival of adriamycin responders (12+ months) was significantly superior (P < .001) to adriamycin non-responders (5 months). Metastatic lesions responding to adriamycin included skin and soft tissue (46% response rate), lungs (36%), liver (20%), and bones (19%) compared with only soft tissue and skin responses ( 12%) with the nitrosoureas. Myelosuppression was the doselimiting toxicity with all three regimens, but was less prominent with methyl CCNU, suggesting that the dose of this agent could have been higher. An exploration of adriamycin in patients without prior chemotherapy is presently ongoing, with a response rate that is currently in excess of 50% and equal to the response rate of a control population receiving a commonly used five-drug combination regimen. Adriamycin is an effective new agent in the therapy of breast cancer, and combination trials seem indicated. URING THE PAST SEVERAL YEARS, THE ing search for new chemotherapeutic agents D Southwest Cancer Chemotherapy Study active in advanced refractory breast carcinoma.Group (SWG) has been involved in a continu-In one of our first studies, utilizing the intra-
A case is described in which a platelet count of 6,000,000/mm3 occurred in association with adenocarcinoma of the lung and remitted following definitive radiotherapy of the primary lesion. Despite the magnitude of the platelet elevation, thrombohemorrhagic phenomena were not observed. Extreme thrombocytosis of this magnitude is rare in either primary or secondary disorders of thrombopoiesis. The occurrence of unexplained thrombocytosis demands the exclusion of malignancy.
A case of mycosis fungoides with universal plaque‐like, dermal infiltration and severe generalized exfoliation is described. This patient had been treated with topical nitrogen mustard, occlusive steroid dressings, total body electron beam therapy, total body orthovoltage superficial radiotherapy, and intensive combination chemotherapy (cyclophosphamide, vincristine, prednisone) during the 6‐year course of his disease, and had become refractory to all modalities. Bleomycin, a new antitumor antibiotic, was administered parenterally at a dose of 10 mg/m2 twice weekly. Over a period of 12 weeks a complete response was achieved and has been maintained 8+ months with a low dose weekly bleomycin and burst cyclophosphamide and prednisone therapy. Toxicity has been minimal. The postulated mechanism for the success of this drug in therapy of this disease entity is discussed.
Three hundred and ninety-eight patients with disseminated solid tumors other than breast cancer, were treated with a combination chemotherapy protocol utilizing cyclophosphamide, vincristine sulfate, methotrexate, 5-fluorouracil, and prednisone. Three hundred and eighty were evaluable (95.5%). Partial or complete tumor regressions were noted in 73 of 380 (19%) evaluable patients. Response to therapy was associated with a prolongation and survival. The largest tumor categories were lung, ovary, and gastrointestinal. The proportion of complete plus partial responses in evaluable lung cancer patients was 40/236 (17%), compared to 20/44 (45%) for ovarian cancer patients and 6/39 (15%) for gastrointestinal tumors. Of the patients who could be evaluated for toxicity, 47% had minimal or no toxicity, 51% had moderate to severe toxicity, and 2% had life threatening toxicity. Virtually all patients were treated and managed as outpatients.
Background: Angiogenesis plays a substantial role in breast cancer development as well as in triple negative breast cancer (TNBC). Sunitinib is an inhibitor of the tyrosine kinase receptors for VEGF, platelet-derived growth factor (PDGF), KIT, RET, and fms-like tyrosine kinase receptor-3 (FLT3). As monotherapy in heavily pretreated breast cancer patients (pts), sunitinib demonstrated a response rate of 15% in TNBC (11% of all pts) with stable disease or better in 16% of all pts. The combination of paclitaxel and carboplatin is ideally suited for further exploration as neoadjuvant chemotherapy for TNBC, based on the established preclinical and clinical sensitivity of TNBC to these cytotoxic agents. This open label, phase I/II trial was designed to evaluate the combination of sunitinib plus paclitaxel and carboplatin as neoadjuvant treatment for locally advanced breast cancer. The primary objective for the phase I portion was to determine the maximum tolerated dose (MTD); these results are presented. Methods: Women with histologically confirmed invasive triple-negative adenocarcinoma of the breast, (defined as <10% staining by IHC for ER/PR; IHC 0–1+ or FISH negative for HER2), with no evidence of metastatic disease and normal LVEF were eligible. All pts received sunitinib (days 1–28), paclitaxel (days 1, 8, 15), and carboplatin (day 1) in 28-day treatment cycles x6. Following 6 cycles, pts had definitive surgery. After ≥2 weeks and evidence of adequate wound healing, maintenance sunitinib 25mg PO daily was initiated to complete a total of 52 weeks. Three dose levels were evaluated as shown in the table below: Doses were escalated in sequential cohorts of pts using standard phase I methodology. MTD was defined as the highest dose level (DL) producing ≤1 dose limiting toxicities (DLTs) in a pt cohort. The MTD identified in the phase I portion of the study will be used in the phase II portion, which will evaluate the efficacy, safety, and tolerability of this combination in pts with locally advanced TNBC. Results: 15 women with TNBC were enrolled between 10/2009 and 2/2011 [median age 53 years (range: 40–78)]. Due to grade 3 neutropenia resulting in the inability to deliver cycle 1 day 15 paclitaxel in the first pt treated at both DLs 1 and 2, these DLs were expanded to 6 pts each. No additional cycle 1 DLTs were noted in the 5 additional pts at either DL. Three pts were accrued to DL 3; there were 2 DLTs noted among these pts (grade 3 febrile neutropenia; grade 3 neutropenia with cycle 2 day 1 treatment delay). However, due to the development of grade 3/4 neutropenia in subsequent cycles in 5 of 6 DL 2 pts, resulting in dose delays and requiring dose reductions, the MTD of this combination was defined as DL 1 (paclitaxel 70mg/m2 (Days 1, 8, 15); carboplatin AUC=5 (Day 1); sunitinib 25mg PO daily). Conclusions: The administration of sunitinib with paclitaxel plus carboplatin as neoadjuvant therapy is feasible with neutropenia defining the MTD of this combination. The phase II portion of this study is ongoing. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-29.
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