Evidence for in vivo synergism between docetaxel and gemcitabine in patients with metastatic breast cancer.

BACKGROUND: The docetaxel and gemcitabine combination is active as salvage therapy in taxane-resistant/refractory patients with metastatic breast cancer (MBC). We conducted a phase II study to determine if this activity is due to an in vivo synergistic effect. PATIENTS AND METHODS: Women with measurable MBC, who were refractory or resistant to docetaxel monotherapy as first- or second-line treatment, were enrolled. Patients with progressive disease (PD) or stable disease (SD) after receiving at least four cycles of docetaxel received gemcitabine 900 mg/m(2) on days 1 and 8 plus docetaxel 100 mg/m(2 )on day 8, every 3 weeks. Granulocyte colony-stimulating factor could be used prophylactically in patients who experienced grade 3/4 neutropenia after the first cycle. RESULTS: Between January 1999 and March 2002, 173 courses of docetaxel and gemcitabine were administered to 50 patients. The median number of metastatic sites was two (range one to three). Forty-six percent of patients responded (three complete responses, 20 partial responses), whereas 28% had SD and 26% had PD. The median duration of response was 6.1 +/- 2.4 months. The median time to disease progression was 7.5 months (range 1-25) and the overall median survival was 15 months (range 3-57). Neutropenia was the only National Cancer Institute Common Toxicity Criteria grade 4 toxicity (in seven patients). Hematological grade 3 toxicities included neutropenia in 12 patients, thrombocytopenia in seven and anemia in one, while non-hematological toxicities were mild and manageable. CONCLUSIONS: The high overall response rate of the docetaxel plus gemcitabine combination after docetaxel failure in patients with MBC can be attributed to an in vivo synergism between the two drugs. These data warrant confirmation in a randomized study.

Treatment of operable breast cancer in the elderly: a randomised clinical trial EORTC 10850 comparing modified radical mastectomy with tumorectomy plus tamoxifen.

We have examined the outcome of older patients with operable breast cancer treated in a randomised trial by either standard surgery or less extensive surgery and tamoxifen. There were 236 participants aged >/=70 years, randomised to either modified radical mastectomy MRM (n=120) or wide local excision (WLE) and tamoxifen (T) 20 mg daily (n=116). Survival curves were estimated using the Kaplan-Meier method and multivariate analyses were performed using Cox's proportional hazards model. Endpoints were survival and time to first relapse or progression, loco-regional progression, time to distant progression and progression-free survival. No significant difference was seen in terms of progression-free survival, but there were significantly more loco-regional relapses in the WLE+T group. In contrast, there were more distant metastases in the MRM group, but with a similar overall survival in both groups. The results of this trial give cautious support for the use of WLE+T for selected older women.

Tamoxifen associated uterine pathology in breast cancer patients with abnormal bleeding.

The purpose of this study was to evaluate the underlying pathology in breast cancer patients treated with tamoxifen who present with abnormal bleeding. A total of 56 cases were studied and the histopathologic features of 50 curettage and 18 laparotomy specimens were reviewed. All patients were under tamoxifen treatment (10-40 mg daily) for a period ranging from 5 months to 15 years. Cervical and endometrial polyps were the most common finding in the D and C material (44%). Hyperplasia was the most frequent feature identified at hysterectomy, often combined with leiomyomas, adenomyosis and ovarian tumors. Five primary adenocarcinomas of the endometrium, most of them Stage I beta, Grade I minimally invading, were found as well. These data support the hypothesis that tamoxifen exerts a proliferative estrogen-like effect on the uterus. Abnormal bleeding in women under TAM treatment warrants prompt investigation and careful follow up of the patients.

Monocyte disorders associated with T cell defects in patients with solid tumors.

T cells proliferate in response to autologous monocytes in the autologous mixed lymphocyte reaction (AMLR). AMLR was found to be impaired in patients with advanced cancer (stages III and IV), whereas normal values were found in the early stages of the disease (stages I and II). Peripheral T lymphocytes from patients with advanced stages also exhibited a decreased ability to produce Interleukin-2 (IL-2) during an AMLR response, whereas production of IL-2 by T cells in stages I and II was comparable to that of normal donors. The impaired IL-2 production by T lymphocytes in the AMLR was associated with high concentrations of soluble interleukin-2 receptor (sIL-2R) in culture supernatants and reduced expression of membrane-bound interleukin-2 receptors (IL-2R) on the same AMLR-activated T lymphocytes. These abnormalities in T cells from cancer patients were demonstrated to be associated with dysfunctions of autologous monocytes. Thus monocytes from patients with advanced cancer exhibited diminished expression of HLA-DR antigens and produced low levels of Interleukin-1 beta (IL-1 beta) and Tumor Necrosis Factor a (TNFa). No changes were detected in the expression of HLA-A, -B, -C antigens. The results presented here demonstrate that decreased in vitro T cell responses may be attributed to monocyte dysfunctions in these patients and provide new information for a better understanding of the impaired T cell function in cancer patients.

Adjuvant androgen treatment of operable breast cancer--a 20 year analysis.

One hundred and fifty-five patients with carcinoma of the breast treated by mastectomy were randomised to receive no additional treatment or to receive adjuvant testosterone. After a minimum follow up of 15 years there is no difference in either relapse free survival or overall survival between the treated and control groups. Stratification by pathological nodal status showed no benefit either for those with negative or positive axillary lymph node involvement.

Sensory changes after treatment of operable breast cancer.

A study has been conducted to compare the nature and severity of post-operative sensory changes (sensory loss, paraesthesiae, and pain) among patients with breast cancer treated by either modified radical mastectomy or a conservative procedure (tumourectomy, axillary clearance, iridium implant, and external radiotherapy). There was a similar incidence of post-operative sensory loss in the two groups, reported by 82% of the mastectomy group and 77% of the iridium group, and an equivalent rate of improvement (76 and 80% respectively). Post-operative paraesthesiae occurred in 61% of the mastectomy group and 63% of the iridium group; maximum severity of paraesthesiae was similar as was the percentage improving. Among the mastectomy group 55% reported phantom breast sensation and 61% of the iridium group had post-operative breast pain. Improvement occurred in 58% of those with breast pain. These findings may have implications for the counseling of patients with breast cancer who are going to be treated by certain conservative procedures.