Risk of pneumonitis in breast cancer patients treated with radiation therapy and combination chemotherapy with paclitaxel.

BACKGROUND: Some chemotherapy (CT) drugs, including taxanes, may enhance the effectiveness of radiation therapy (RT). However, combining these therapies may increase the incidence of radiation pneumonitis, a lung inflammation. In a retrospective cohort study, we evaluated the incidence of radiation pneumonitis in breast cancer patients treated with RT and standard adjuvant CT by use of doxorubicin (Adriamycin) and cyclophosphamide, with and without paclitaxel. METHODS: Forty-one patients with breast cancer were treated with RT and adjuvant CT, including paclitaxel. Paclitaxel and RT (to breast-chest wall in all and lymph nodes in some) were delivered sequentially in 20 patients and concurrently in 21 patients. Paclitaxel was given weekly in some patients and every 3 weeks in other patients. The incidence of radiation pneumonitis was compared with that among patients in our database whose treatments did not include paclitaxel (n = 1286). The percentage of the lung volume irradiated was estimated. The Cox proportional hazards model was used to find covariates that may be associated with the observed outcomes. All P values were two-sided. RESULTS: Radiation pneumonitis developed in six of the 41 patients. Three patients received paclitaxel concurrently with RT, and three received it sequentially (P =.95). The mean percentage of lung volume irradiated was 20% in patients who developed radiation pneumonitis and 22% in those who did not (P =.6). For patients treated with CT including paclitaxel, the crude rate of developing radiation pneumonitis was 14.6% (95% confidence interval [CI] = 5.6% to 29.2%). For patients treated with CT without paclitaxel, the crude rate of pneumonitis was 1.1% (95% CI = 0.2% to 2.3%). The difference between the crude rates with or without paclitaxel is highly statistically significant (P<.0001). The mean time to develop radiation pneumonitis in patients treated concurrently with RT and paclitaxel was statistically significantly shorter in patients receiving paclitaxel weekly than in those receiving it every 3 weeks (P =.002). CONCLUSIONS: The use of paclitaxel and RT in the primary treatment of breast cancer should be undertaken with caution. Clinical trials with the use of combination CT, including paclitaxel plus RT, whether concurrent or sequential, must evaluate carefully the incidence of radiation pneumonitis.

Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer.

PURPOSE: Capecitabine is a novel, oral, selectively tumor-activated fluoropyrimidine carbamate. This large multicenter phase II trial tested the efficacy and safety of twice-daily oral capecitabine at 2,510 mg/m2/d given for 2 weeks followed by a 1-week rest period and repeated in 3-week cycles, in patients with paclitaxel-refractory metastatic breast cancer. PATIENTS AND METHODS: Patients were to have received at least two but not more than three prior chemotherapeutic regimens, one of which had to have contained paclitaxel given for metastatic disease. One hundred sixty-three patients were entered onto the study at 25 centers, and 162 patients received capecitabine. One hundred thirty-five patients had bidimensionally measurable disease, and 27 patients had assessable disease. RESULTS: The overall response rate was 20% (95% confidence interval, 14% to 28%). All responding patients were resistant to or had failed paclitaxel, and all had received an anthracycline. Three complete responses were seen, with complete response durations of 106, 109, and 194+ days. Median duration of response was 8.1 months, median survival time was 12.8 months, and the median time to disease progression was 93 days. The most common treatment-related adverse events were hand-foot syndrome, diarrhea, nausea, vomiting, and fatigue. Diarrhea (14%) and hand-foot syndrome (10%) were the only treatment-related adverse events that occurred with grade 3 or 4 intensity in more than 10% of patients. CONCLUSION: Capecitabine is an active drug in the treatment of paclitaxel-refractory metastatic breast cancer. It has a favorable toxicity profile with the added advantage of being an oral drug administered at home.

Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer.

PURPOSE: To determine the response rate and toxicity profile of trastuzumab administered concurrently with weekly vinorelbine in women with HER2-overexpressing advanced breast cancer. PATIENTS AND METHODS: Forty women with HER2-positive (+3 by immunohistochemistry, n = 30; +2 or positive, n = 10) breast cancer were enrolled onto a study of trastuzumab (4 mg/kg x 1, 2 mg/kg weekly thereafter) and vinorelbine (25 mg/m2 weekly, with dose adjusted each week for neutrophil count). Eighty-two percent of women had received prior chemotherapy as part of adjuvant (30%), metastatic (25%), or both (28%) treatment, including substantial portions of patients who had previously received either anthracyclines (20%), taxanes (15%), or both types (38%) of chemotherapy. RESULTS: Responses were observed in 30 of 40 patients (overall response rate, 75%, conditional corrected 95% confidence interval, 57% to 89%). The response rate was 84% in patients treated with trastuzumab and vinorelbine as first-line therapy for metastatic disease, and 80% among HER2 +3 positive patients. High response rates were also seen in women treated with second- or third-line therapy, and among patients previously treated with anthracyclines and/or taxanes. Combination therapy was feasible; patients received concurrent trastuzumab and vinorelbine in 93% of treatment weeks. Neutropenia was the only grade 4 toxicity. No patients had symptomatic heart failure. Grade 2 cardiac toxicity was observed in three patients. Prior cumulative doxorubicin dose in excess of 240 mg/m2 and borderline pre-existing cardiac function were associated with grade 2 cardiac toxicity. CONCLUSION: Trastuzumab in combination with vinorelbine is highly active in women with HER2-overexpressing advanced breast cancer and is well tolerated.

Breast cancer update.

The large number of excellent presentations on breast cancer at this year's ASCO meeting reflects the enormous interest in clinical trials of this common disease. In the reports of adjuvant hormonal therapy, the most interesting included Abstract 273 by Boccardo et al., who reported that postmenopausal women with estrogen receptor positive (ER(+)) cancers who had already completed three years of tamoxifen experienced better overall survival if treated with two years of subsequent aminoglutethimide (a first-generation aromatase inhibitor) rather than another two years of tamoxifen. This whets our appetite for studies currently under way to define the role of third-generation aromatase inhibitors in the adjuvant setting. A report by FISHER: from the National Surgical Adjuvant Breast and Bowel Project B-23 study (Abstract 277) provided confirmation of what is rapidly becoming accepted, that the addition of tamoxifen to chemotherapy does not benefit breast cancer patients with negative lymph nodes who have ER(-) cancers. In premenopausal women, another report of the benefit of hormonal therapy, this time by the French Adjuvant Study Group using complete hormonal blockade with a luteinizing hormone-releasing hormone agonist and tamoxifen (Abstract 279) showed that hormonal therapy can be at least as good as, if not better, than six cycles of 5-fluorouracil 500 mg/m(2), epirubicin 50 mg/m(2), cyclophosphamide 500 mg/m(2) in terms of disease-free survival and overall survival. Among the papers on adjuvant chemotherapy, a controversial paper from the German Adjuvant Breast Cancer Group reported that three cycles of CMF (a dose-intense regimen with all three drugs being given on days 1 and 8) were as good as six cycles (Abstract 283). Another report, from the International Breast Cancer Study Group, raised the controversial question of whether there really is much added benefit from the addition of chemotherapy to tamoxifen in postmenopausal women with negative lymph nodes if their tumors have ERs (Abstract 281). A second study (the first was the CALGB study reported at ASCO in 1998) showing a benefit to the addition of Taxol to an anthracycline-based adjuvant regimen, was reported from the M.D. Anderson Cancer Center (Abstract 285), giving further impetus to the inclusion of Taxol in standard adjuvant treatment. Finally, there were a number of interesting presentations on HER-2. Reported here are three of these, all addressing the effect of HER-2 overexpression on the response to hormonal therapy. Taken together, they uphold the emerging concern that women with ER(+) cancers may not benefit significantly from endocrine treatment if the tumors also overexpress HER-2. Observations such as these will afford us the ability to predict more accurately which women will benefit from specific treatments.

Breast cancer.

Several interesting aspects of breast cancer were covered at this year's American Society of Clinical Oncology meeting. Sentinel lymph node (SN) mapping is now in widespread use, in concert with the general trend toward trying to decrease the morbidity of breast cancer surgery. With every advance, however, comes new challenges, and there was a timely presentation from Giuliano's group addressing the controversial issue of how to interpret the presence of cells in the SN seen only with keratin stains but not by routine hematoxylin and eosin stains. Two abstracts addressed the issue of whether for certain women with invasive breast cancer radiation therapy could be omitted after lumpectomy. Another interesting topic related to hormonal issues in the adjuvant treatment of premenopausal women. An analysis from the ZIPP-TRIAL reported on bone marrow density studies in young women given two years of ovarian suppression in the adjuvant setting: it seems that the loss of bone density may be reversible and, more interestingly, may be prevented with concurrent tamoxifen. Two other presentations looked at the prognostic significance of drug-induced amenorrhea in young women treated with adjuvant chemotherapy and at the efficacy of ovarian suppression during chemotherapy in preserving fertility. In an unpublicized presentation, Mary-Claire King presented very interesting results from the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial suggesting that tamoxifen may be an effective chemopreventive drug for women with BRCA2, but not BRCA1, mutations. Two important presentations re-analyzed the outcome of the pivotal trials using Herceptin to treat metastatic breast cancer and nicely show that FISH analysis of HER-2 overexpression is a more accurate indicator of response to Herceptin than immunohistochemical staining. Finally, there were two interesting presentations related to tamoxifen resistance which may be relevant clinically, pertaining to subsequent raloxifene use and the interaction of the estrogen receptor and EGF receptor pathways, respectively.

Collagenase secretion accompanying changes in cell shape occurs only in the presence of a biologically active cytokine.

We have investigated the relationship between collagenase production, cell shape and stimulatory factors in cell culture. In a homogeneous culture of primary rabbit corneal stromal cells, shape change induced by a variety of agents was not effective in stimulating collagenase secretion. Only in the presence of a biologically active cytokine or phorbol myristate acetate was a correlation seen between changes in cell shape (induced by a second agent) and collagenase secretion by these primary cells. Cell shape changes were not, however, necessary for collagenase secretion, since certain concentrations of endotoxin or lactalbumin hydrolysate effected secretion of the enzyme in the absence of morphological changes. With passaged cells or mixed cell cultures, where cell shape change did correlate with collagenase secretion without the addition of an exogenous agent, the production of an effective cytokine (autocrine or paracrine) was demonstrated. Thus cell shape change seems to be neither universally necessary nor sufficient for the stimulation of collagenase secretion. It is proposed that the function of cytokines may be more immediately related to gene expression in this system than is change in the shape of the cell. The hypothesis is presented that cell shape changes may render the target cells receptive to cytokines, perhaps by replacing the need for a natural cytokine cofactor. It is also demonstrated here that the use of passaged cells, mixed cell cultures containing endogenous cytokine-secreting cells or tissue culture additives can profoundly affect the interpretation of the effect of various agents on collagenase secretion, and may lead to observations that are not directly relevant to cell function in vivo.