Adjuvant trials of aromatase inhibitors: determining the future landscape of adjuvant endocrine therapy.

This review will discuss the role of aromatase inhibitors (AIs) in the adjuvant setting, and will summarize major strategies behind individual adjuvant trials using aromatase inhibitors. Studies with the third generation AIs including anastrozole, letrozole and exemestane, have shown better outcome and improved therapeutic ratio over second line hormonal approaches (i.e. progestins or aminoglutethimide) and, more recently, over tamoxifen also. These promising results have led recently to testing of AIs in the adjuvant setting for postmenopausal patients. Most trials now in progress are evaluating the role of new AIs versus tamoxifen (T) given x 5 years, which in most institutions is currently the standard hormonal adjuvant therapy for breast cancer. Three adjuvant approaches are being tested. First is the use of AI+T x 5 years in combination versus each agent alone, as reflected in the recently completed ATAC trial. Second is a sequential approach T first x 2-3 years followed by AIs x 2-3 years, or the other way round; and third, T x 5 years followed by AIs for additional 5 years (i.e. total duration of adjuvant hormones of 10 years). Many patients in the above trials will survive their first cancer. Hence, the non-oncological outcomes known to be affected by hormones are of rising importance. Therefore, the assessment of lipids as surrogates for cardiovascular morbidity, and of bone mineral status, as a marker for osteoporosis/bone fractures, is an important component of these trials. Also discussed in this review are proposals for future studies of AIs with focus on hormone resistance, such as early alteration of multiple hormonal agents or their intermittent use, the impact of the new generation of SERMs or 'pure' antiestrogens on activity of AIs, and the rising importance of AIs interacting with biologicals, cytokines or hormone modulators.

A decision analysis of the effect of avoiding axillary lymph node dissection in low risk women with invasive breast carcinoma.

BACKGROUND: Evidence that avoiding axillary lymph node dissection (AxD) strikes an appropriate balance between morbidity and recurrence risk in patients with invasive breast carcinoma generally is anecdotal and without a formally quantified basis. The current study presents a decision analysis of the difference in 5-year disease free survival (DFS) rate between treatment scenarios with and without routine AxD. METHODS: To derive quantitative estimates of the effect of avoiding AxD on 5-year DFS, the authors examined outcomes for women undergoing 2 treatment scenarios: AxD or no AxD with adjuvant therapy decisions based on risk factors in the primary tumor. Eligible patients belonged to 2 lymph node metastases risk groups: low (patients without palpable lymph nodes and lymphatic or vascular invasion [LVI] negative tumors < or = 0.5 cm in greatest dimension) and moderate (patients with mammographically detected, LVI negative tumors, between 0.6-2.0 cm in greatest dimension or patients with palpable LVI negative tumors between 0.6-1.0 cm in greatest dimension with nonpalpable lymph nodes). Along with observed data regarding treatment and recurrence, the authors employed estimates of the efficacy of chemotherapy, tamoxifen, and regional radiation therapy derived from published randomized trials to estimate the 5-year DFS rate for treatment scenarios with and without AxD. RESULTS: Patients in the low risk group had a 5% risk of lymph node metastases. In these women, eliminating AxD and treating no patients with chemotherapy and/or tamoxifen resulted in a < 1% decrease in the 5-year DFS rate. Patients in the moderate risk group had a 10% risk of lymph node metastases. Eliminating AxD and treating only those women with Grade 3 tumors > 1 cm in greatest dimension with chemotherapy and/or tamoxifen resulted in a 1.8% decrease in the 5-year DFS rate. However, if all patients in this group were treated with chemotherapy and/or tamoxifen and no AxD, the 5-year DFS rate increased by 2.7%. CONCLUSIONS: In patients with a low risk of lymph node metastases, it was estimated that eliminating AxD may result in only minimal changes in the estimated 5-year DFS rate.

Status of aromatase inhibitors in relation to other breast cancer treatment modalities.

Aromatase is one of the key enzymes possibly linked with the perpetuation or even initiation of breast cancer. Modulation of its activity by the new generation inhibitors has resulted in increased responses and improved therapeutic ratio compared with those of parent aromatase inhibitors. More recent trials have shown promising results with regard to improved therapeutic ratio compared with what is seen with presently accepted second-line hormonal approaches. Present data and laboratory research indicate that new aromatase inhibitors have the potential to play an important role as adjuvants, and possibly in the prevention of human breast cancer. It is probable that it may be as adjuvants that their real therapeutic strength in terms of a beneficial impact on survival may be realized. The absence of estrogen agonist activity of new aromatase inhibitors on lipid and bone metabolism calls for more clinical studies having late mortality in breast cancer survivors as the ultimate outcome objective; in this regard, interaction of new aromatase inhibitors with new selective estrogen receptor modulators looks promising. Achievement of these outcomes, and understanding of interactions with other therapies, await the termination of present trials and the start of new initiatives.

A phase I-II study of bi-weekly paclitaxel as first-line treatment in metastatic breast cancer.

BACKGROUND: Single-agent bi-weekly paclitaxel was studied as first-line metastatic treatment for breast cancer in a phase I-II trial. PATIENTS AND METHODS: Thirty-eight women with metastatic breast cancer were enrolled. Thirty-seven are evaluable for toxicity, 35 for response. RESULTS: The MTD was defined at 160 mg/m2 q two weeks with dose limiting toxicity in two patients consisting of hematological toxicity (1) and neurotoxicity (2). Twenty patients were treated at 150 mg/m2, the recommended dose. Response rates were two CRs and nine PRs (overall 61%) at the RD of 150 mg/m2 and three CRs and 11 PRs for an overall RR of 67% for the two top doses. CONCLUSIONS: The good drug tolerance, response rates, and convenience over weekly treatment suggest this may be a worthwhile regimen.

Prediction of axillary lymph node involvement of women with invasive breast carcinoma: a multivariate analysis.

BACKGROUND: The increasing use of systemic therapy for women with lymph node negative breast carcinoma and earlier stage of disease at mammographic detection raises questions regarding the need for routine axillary lymph node dissection. Predictive modeling for lymph node involvement may be one way to reduce the need for axillary lymph node dissection and its morbidity. METHODS: A multivariate analysis of 12 factors predictive of axillary lymph node involvement was conducted in a population-based cohort of 4312 women with invasive breast carcinoma diagnosed between January 1, 1993 and December 31, 1996. RESULTS: Clinical palpability, lymphatic or vascular invasion, lesion size, margin status, histology, and patient age were independent predictors of axillary lymph node involvement. The model correctly identified lymph node status in 76.6% of cases. Model accuracy and fit were equally high when applied to randomly selected halves of the study subjects. Approximately 32.0% of the patients in the study sample (1363/4312) were identified as having an extremely high (91%; n = 1102) or low (10%; n = 261) risk of lymph node involvement. In a second analysis, a clinically useable, three-variable model identified a very low risk group of patients (n = 147) with a 4.8% risk of lymph node metastasis and a high risk group of patients (n = 1008) with a 74.2% risk of lymph node metastasis. Greater than 90% of subjects in the high risk group received adjuvant systemic therapy even if they were lymph node negative pathologically. CONCLUSIONS: A clinically useable, three-variable model employing tumor and lymph node palpability, size, and lymphatic or vascular invasion can identify women with invasive breast carcinoma in whom axillary lymph node dissection is very unlikely to alter recommendations regarding adjuvant systemic therapy.

Survival impact of adjuvant tamoxifen on competing causes of mortality in breast cancer survivors, with analysis of mortality from contralateral breast cancer, cardiovascular events, endometrial cancer, and thromboembolic episodes.

PURPOSE: This study provides estimates of the effect of tamoxifen treatment on mortality from four conditions known to be affected by tamoxifen in women who survive their breast cancer: contralateral breast cancer, cardiovascular events, endometrial cancer, and thromboembolic events. These estimates are in addition to tamoxifen's impact on primary breast cancer mortality. METHODS: The effects of tamoxifen were calculated by the use of the published relative risk (RR) rates of the four conditions as affected by adjuvant tamoxifen and their application to the respective Canadian age-specific mortality rates for the same conditions. The final mortality impact of tamoxifen was expressed as net mortality difference between users and nonusers of tamoxifen. RESULTS: At 10 years of follow-up, the sum of avoided deaths (contralateral breast cancer, cardiovascular events) and excess deaths (uterine cancer, thromboembolic episodes) resulted in an overall (net) mortality reduction because of tamoxifen use, with 3 to 41 avoided deaths per 1,000 tamoxifen-treated patients who were 50 to 80 years of age. With the follow-up projected until the age of 90 years, the numbers of avoided late deaths attributed to tamoxifen ranged from 38 to 56 per 1,000 patients. CONCLUSION: Our calculations that pertain to late breast cancer survivors indicate that there is a more substantial mortality reduction as a result of deaths avoided from contralateral breast cancer and cardiovascular events, despite the moderately increased mortality from endometrial cancer and thromboembolic episodes. The overall tamoxifen-associated mortality reduction occurs, in different magnitudes, in patients of all ages from 50 to 80 years at diagnosis of the primary breast cancer.

Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer.

BACKGROUND: Radiotherapy after mastectomy to treat early breast cancer has been known since the 1940s to reduce rates of local relapse. However, the routine use of postoperative radiotherapy began to decline in the 1980s because it failed to improve overall survival. We prospectively tested the efficacy of combining radiotherapy with chemotherapy. METHODS: From 1978 through 1986, 318 premenopausal women with node-positive breast cancer were randomly assigned, after modified radical mastectomy, to receive chemotherapy plus radiotherapy or chemotherapy alone. Radiotherapy was given to the chest wall and locoregional lymph nodes between the fourth and fifth cycles of cyclophosphamide, methotrexate, and fluorouracil. RESULTS: After 15 years of follow-up, the women assigned to chemotherapy plus radiotherapy had a 33 percent reduction in the rate of recurrence (relative risk, 0.67; 95 percent confidence interval, 0.50 to 0.90) and a 29 percent reduction in mortality from breast cancer (relative risk, 0.71; 95 percent confidence interval, 0.51 to 0.99), as compared with the women treated with chemotherapy alone. CONCLUSIONS: Radiotherapy combined with chemotherapy after modified radical mastectomy decreases rates of locoregional and systemic relapse and reduces mortality from breast cancer.

Randomized trial of cyclophosphamide, methotrexate, and fluorouracil chemotherapy added to tamoxifen as adjuvant therapy in postmenopausal women with node-positive estrogen and/or progesterone receptor-positive breast cancer: a report of the National Cancer Institute of Canada Clinical Trials Group. Breast Cancer Site Group.

PURPOSE AND METHODS: By the mid 1980s, tamoxifen alone was considered standard adjuvant therapy for postmenopausal women with node-positive, estrogen receptor (ER)- or progesterone receptor (PgR)-positive breast cancer. From 1984 through 1990, 705 eligible postmenopausal women with node-positive, ER- or PgR-positive breast cancer were randomized to a National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) study that compared tamoxifen 30 mg by mouth daily for 2 years (TAM) versus TAM plus chemotherapy with all-intravenous cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 given every 21 days for eight cycles (CMF). RESULTS: There were no significant differences in overall survival, recurrence-free survival, locoregional recurrence-free survival, or distant recurrence-free survival between the two treatment arms. However, there was significantly greater severe toxicity, which included leukopenia (P < .0001), nausea and vomiting (P < .0001), and thromboembolic events (P < .0001), as well as significantly more mild or greater toxicity, which included thrombocytopenia (P = .04), anemia (P = .02), infection (P = .0004), mucositis (P = .0001), diarrhea (P = .0001), and neurologic toxicity (P = .006), in women who received TAM plus CMF. CONCLUSION: The addition of CMF to TAM adds no benefit and considerable toxicity in this group of women.

Interaction of tamoxifen's impact on overall net mortality and quality of life.

Tamoxifen has well-documented activity in reducing breast cancer mortality. In addition, it has several secondary effects that may have an overall impact on long-term survival, and that are of particular importance in patients surviving the primary breast cancer. To fully understand the therapeutic role of tamoxifen, it is important to take into account survival differences related to all conditions known to be affected by tamoxifen. The purpose of this report is twofold. First, it provides information on mortality rates for conditions other than primary breast cancer in patients who survive the primary breast cancer, and the effect of tamoxifen on these mortality rates. Second, it outlines the principal side effects of tamoxifen that can affect quality of life and briefly summarizes their management.

Phase I/II trial of biweekly paclitaxel and cisplatin in the treatment of metastatic breast cancer.

PURPOSE: To determine the maximum-tolerated dose of escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) administered biweekly with a fixed dose of cisplatin, to assess the toxicity, and to evaluate the activity of this combination in a phase I/II trial in metastatic breast cancer. PATIENTS AND METHODS: Twenty-nine women with metastatic breast cancer were enrolled; 27 were assessable for response and 29 for toxicity. All but two of the women had received prior adjuvant chemotherapy, with 23 receiving anthracyclines and six previous cisplatin. RESULTS: The initial starting dose of paclitxel 90 mg/m2 and cisplatin 60 mg/m2 became the phase II dose due to dose-limiting neutropenia. Responses were seen in 85% of assessable patients, with three patients (11%) achieving a complete response (CR) and 20 patients (14%) a partial response (PR), for an overall response rate of 85% (95% confidence interval [CI], 66% to 96%). The time to disease progression for patients who achieved a CR was 110 to 200 days, and for those with a PR, it was 96 to 377+ days, with a median time to progression of 7.1 months and a median response duration of 7.9 months. Sites of CR were skin, soft tissue, and lung, and all occurred in women with previous exposure to anthracyclines. Septic events were rare, with two grade 3 infections (7%), only one of which required hospital admission. There were no grade 4 nonhematologic toxicity and minimal grade 3 toxicity. A total of 251 chemotherapy cycles were given -- 16 with paclitaxel alone in five patients. Forty-five percent of patients required dose reductions, while 52% had delays due to neutropenia. CONCLUSION: Biweekly paclitaxel and cisplatin is an active combination in the treatment of metastatic breast cancer, including for patients with previous exposure to anthracyclines.

Adjuvant systemic therapy and survival after breast cancer.

BACKGROUND AND METHODS: We examined the effect of adjuvant systemic therapy on survival after breast cancer among the residents of the Canadian province of British Columbia. Data on survival were collected for all women in whom breast cancer was diagnosed in British Columbia during each of three calendar years chosen to represent different province-wide treatment recommendations: 1974, when no adjuvant systemic therapy was recommended; 1980, when adjuvant chemotherapy was recommended only for premenopausal women with node-positive disease; and 1984, when adjuvant chemotherapy was also recommended for premenopausal women with node-negative disease and lymphatic, vascular, or neural invasion and tamoxifen was recommended for postmenopausal women with involved lymph nodes or lymphatic, vascular, or neural invasion unless their tumors were negative for estrogen receptors. RESULTS: For women less than 50 years of age, disease-specific survival at seven years (i.e., with censoring of data on women who died from causes other than breast cancer) improved from 65.2 to 76.3 percent between 1974 and 1984 (P = 0.008), and overall survival improved from 64.8 to 74.6 percent (P = 0.02). For women from 50 through 89 years of age, disease-specific survival at seven years improved from 62.5 to 70.4 percent between 1980 and 1984 (P = 0.001), and overall survival improved from 53.9 to 58.3 percent (P = 0.05). The timing of the improvements in survival correlated with the introduction of adjuvant systemic therapy in each group. CONCLUSIONS: Survival among women with breast cancer improved significantly in a geographically defined population during the period when adjuvant systemic therapy became widely used.

Therapy-related acute myelogenous leukemia associated with 11q23 chromosomal abnormalities and topoisomerase II inhibitors: report of four additional cases and brief commentary.

We report 4 additional cases of therapy-related acute myelogenous leukemia (t-AML) with the translocation t(9;11)(p22q23). Chemotherapy for the primary malignancy (breast carcinoma in 2, non-Hodgkin's lymphoma in 2) included agents with topoisomerase II inhibitory activity (doxorubicin in 2; doxorubicin and etoposide in 1; doxorubicin, etoposide and mitoxantrone in 1) as well as alkylators. In agreement with previous reports, the leukemia was monoblastic (FAB M5 subtype) in all 4 patients, with only 1 having prior myelodysplasia, and the latency period from primary therapy was relatively short (24-48 months). All patients received potentially curative treatment for the leukemia which included allogeneic bone marrow transplantation in 3; however, all died (3 of t-AML and 1 of lymphoma). Therapy-related AML associated with exposure to agents with topoisomerase II inhibitory activity (epipodophyllotoxins and anthracyclines) is a distinct entity, the genetic basis and optimal treatment of which remain to be determined.

Relative operating characteristic analysis and group modeling for tumor markers: comparison of CA 15.3, carcinoembryonic antigen, and mucin-like carcinoma-associated antigen in breast carcinoma.

Relative operating characteristic (ROC) analysis was used to examine the clinical applicability of 3 breast carcinoma tumor markers, CA 15.3, carcinoembryonic antigen, and mucin-like carcinoma-associated antigen. Each tumor marker was quantitated in single serum samples collected from 100 normal blood donors, 60 patients with nonmalignant diseases, 33 women at high risk for breast carcinoma, 30 patients with malignancies other than breast carcinoma, and 158 breast carcinoma patients including 67 with no evidence of disease following surgery, 46 with a tumor burden less than 5 g, and 45 with a tumor burden greater than 5 g. These were used to construct models for early diagnosis among those at high risk for breast carcinoma, the influence of nonmalignant disease on early diagnosis, discrimination of breast carcinoma from other adenocarcinomas, detection of early recurrence, and assessment of change in tumor burden. For each model ROC data permitted the unbiased selection of the most appropriate critical values based on the interaction of sensitivity and specificity. ROC analysis indicated that in practice the assays were remarkably similar. While CA 15.3 generally performed best, there was significant variation among models. Optimal marker selection can thus depend on specific clinical application. In some cases ROC identified a combination of markers as superior to any single assay, but this was not statistically significant.

Psychosocial and Physical Effects of Adjuvant Chemotherapy: Survey of younger women with breast cancer.

Breast cancer patients younger than 55 completed a questionnaire on psychosocial factors and physical side effects shortly after diagnosis and 9 to 15 months after diagnosis. Those who had used adjuvant chemotherapy were more likely than those who had not to report physical side effects; there was little difference in psychosocial factors. Recent users were more likely than ex-users to report physical side effects, difficulties with domestic chores, and improvement in psychosocial factors.