Is tamoxifen effective in prevention of breast cancer?
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Anticarcinogenic Agents↗
Biomedical subjects
K I Pritchard
Publications and source records attributed to K I Pritchard.
GnRH analogues and ovarian ablation: their integration in the adjuvant strategy.
Ovarian ablation, either by surgery or radiation, has been clearly shown to be an effective adjuvant therapy for pre-menopausal women following breast cancer surgery. The 1995 Oxford Overview confirmed this effect in trials of ovarian ablation compared to no other systemic adjuvant therapy. In trials of chemotherapy plus ovarian ablation compared to the same chemotherapy alone, however, the addition of ovarian ablation, although tending to add benefit, did not achieve a statistically significant positive effect. Data exist from a variety of randomized trials of adjuvant chemotherapy suggesting that pre-menopausal women who become amenorrhoeic after chemotherapy achieve a better outcome than those who continue to menstruate. These data are not consistent among all trials, however. There are few trials that compare ovarian ablation directly to chemotherapy, but those few that exist, as well as indirect comparisons, suggest that the effects of ovarian ablation, particularly in estrogen-receptor-positive women, are similar in magnitude to those of chemotherapy. Several large trials comparing chemotherapy to the LH-RH analogue Zoladex (goserelin) and studying the addition of Zoladex to adjuvant chemotherapy will be available by 1999 or 2000 and will provide considerable additional information on this matter.
Breast Neoplasms↗
Estrogen/hormone replacement therapy and the etiology of breast cancer.
ERT/HRT is clearly of use in relieving menopausal symptoms such as hot flashes and genitourinary changes. ERT/HRT also clearly reduces the risks of osteoporotic fracture, of cardiovascular events and deaths, and of developing colon cancer. ERT and, perhaps even more, HRT are, however, associated with an increased risk of developing breast cancer. This effect becomes more marked with long-term use (> or = 10 years); ERT/HRT use for more than 10 years is also associated with an increase in deaths from breast cancer. Because the underlying mortality risk for the average woman is, however, much greater from cardiovascular disease (approximately 22%) than from breast cancer (approximately 3.3%), the reduction in risk of cardiovascular death associated with ERT/HRT (from 22% to 15%) much outweighs the increase in risk of death from breast cancer (from 3.3% to 4.1%). Thus, overall, the average woman will gain more year(s) of life than she will lose by taking ERT/HRT. Even for a woman with a high risk of breast cancer and a low risk of cardiovascular disease, there will still be a net, although lower, gain in year(s) of life. Thus, the use of ERT/HRT would seem well worth considering for a well woman at the time of menopause.
Breast Neoplasms↗
Progress of clinical oncology guidelines development using the Practice Guidelines Development Cycle: the role of practitioner feedback.
PURPOSE: To present an update on the development of oncology practice guidelines (PGs) using the Practice Guidelines Development Cycle (Cycle), and to present the results of surveys of oncologists on the first 10 guidelines from the Cancer Care Ontario Practice Guidelines Initiative. METHODS: Practitioners' opinions about guidelines in development were sought using a mail survey method with systematic follow-up. Practitioners were identified by cancer center representatives. Survey packages included evidence-based recommendations (EBRs) and a one-page, nine-item feedback questionnaire. Data were collected between February 1995 and February 1996. RESULTS: Nine hundred fourteen surveys that pertained to 10 guidelines were mailed to 423 practitioners in Ontario. Practitioners included 112 medical oncologists/hematologists, 34 radiation oncologists, 195 surgeons, and 82 practitioners from other medical specialities. One hundred practitioners were located in cancer centers and 323 had community-based practices. The overall response rate by practitioner was 72% and by survey questionnaire, 70%. For the five questionnaire items that assessed guideline quality, approval ratings ranged from 86% to 92%. For the 10 recommendations, 77% ( 63% to 82%) of respondents agreed that the EBR could be approved as a PG. Response and approval rates were consistent across medical specialities and locations of practice. CONCLUSION: The process of obtaining practitioner feedback in the development of PGs is both feasible and useful. The high response rates to the survey indicate that it is possible to obtain broad participation in evidence-based guidelines development throughout Ontario. The changes made to the EBRs in response to feedback suggest that practitioners' opinions can be valuable in shaping evidence-based guidelines.
Evidence-Based Medicine↗
Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group.
PURPOSE: To determine the relative efficacy of an intensive cyclophosphamide, epirubicin, and fluorouracil (CEF) adjuvant chemotherapy regimen compared with cyclophosphamide, methotrexate, and fluorouracil (CMF) in node-positive breast cancer. PATIENTS AND METHODS: Premenopausal women with node-positive breast cancer were randomly allocated to receive either cyclophosphamide 100 mg/m2 orally days 1 through 14; methotrexate 40 mg/m2 intravenously (i.v.) days 1 and 8; and fluorouracil 600 mg/m2 i.v. days 1 and 8 or cyclophosphomide 75 mg/m2 orally days 1 through 14; epirubicin 60 mg/m2 i.v. days 1 and 8; and fluorouracil 500 mg/m2 i.v. days 1 and 8. Each cycle was administered monthly for 6 months. Patients administered CEF received antibiotic prophylaxis with cotrimoxazole two tablets twice a day for the duration of chemotherapy. RESULTS: The median follow-up was 59 months. One hundred sixty-nine of the 359 CMF patients developed recurrence compared with 132 of the 351 CEF patients. The corresponding 5-year relapse-free survival rates were 53% and 63%, respectively (P = .009). One hundred seven CMF patients died compared with 85 CEF patients. The corresponding 5-year actuarial survival rates were 70% and 77%, respectively (P = .03). The rate of hospitalization for febrile neutropenia was 1.1% in the CMF group compared with 8.5% in the CEF group. There was one case of congestive heart failure in a patient who received CMF compared with none in the CEF group. Acute leukemia occurred in five patients in the CEF group. CONCLUSION: The results of this trial show the superiority of CEF over CMF in terms of both disease-free and overall survival in premenopausal women with axillary node-positive breast cancer.
Adult↗
Ovarian ablation as adjuvant therapy for early-stage breast cancer.
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Adult↗
Phase II study of dexverapamil plus anthracycline in patients with metastatic breast cancer who have progressed on the same anthracycline regimen.
The purpose of this study is to evaluate whether metastatic breast cancer that has progressed on an anthracycline-containing drug regimen will subsequently respond to that identical regimen if dexverapamil, a modulator of P-glycoprotein-mediated drug resistance, is given concomitantly. Eligible patients received 180 mg/m2 dexverapamil every 6 h for 15 doses with the anthracycline administered 30 min after the seventh dose. Blood for dexverapamil levels was drawn before and 30 min after this dose. When possible, biopsies were obtained to measure mdr-1 expression by reverse transcription-PCR and by image cytometry. Of the 21 patients entered onto the trial, 20 were evaluable for response. There were two partial responses (10%) that both lasted for 6 months, and two additional patients had stable disease. Seven patients had asymptomatic cardiotoxicity consisting of hypotension (24%), bradycardia (5%), or prolongation of the P-R interval (14%). Two patients developed acute congestive heart failure, one on dexverapamil and one 10 days after stopping it. Dexverapamil did not seem to increase anthracycline toxicity. The median trough dexverapamil plus norverapamil level on day 3 was 1110 ng/ml (range, 186-3385 ng/ml), and the median peak level was 2164 ng/ml (range, 964-8382 ng/ml). There was poor correlation between reverse transcription-PCR and image cytometry for the level of mdr-1 expression. Because dexverapamil has been shown to affect doxorubicin pharmacokinetics subsequent to the initiation of this trial, it cannot be concluded that the responses seen were necessarily due to P-glycoprotein inhibition. Additional studies are necessary to determine whether mdr-1 modulators can reverse clinical drug resistance in breast cancer patients. The intrinsic cardiotoxicity of dexverapamil makes it less suitable for such studies than several other available agents.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Attitudes of Canadian oncology practitioners toward psychosocial interventions in clinical and research settings in women with breast cancer.
The aim of this study was to survey Canadian oncology practitioners' attitudes toward psychosocial concerns and issues in women with breast cancer. Surveys were mailed to 351 medical, radiation and surgical oncologists and 375 oncology nurses. Standard questionnaires assessed attitudes towards psychosocial issues in women with primary and metastatic breast cancer and evaluated the practitioners' willingness to refer women to psychosocial intervention trials in the presence and absence of competing drug trials. Responses were obtained from 74% of those surveyed. Respondents reported being aware of the common occurrence of psychosocial problems in women with metastatic breast cancer, however, physicians were less likely than nurses to offer these women psychosocial support on a prophylactic basis (p < 0.0001) and they expressed greater concern than nurses about scientific validity of (p = 0.0003), and potential psychological damage from (p = 0.005), psychosocial support groups. Nurses were more likely than physicians to favour a study investigating group psychosocial support over competing drug studies (p < or = 0.003) in the metastatic setting. Physicians were less likely than nurses to deal with weight problems prophylactically in women with primary breast cancer (p = 0.0009) and they expressed greater concern over scientific validity of psychosocial interventions addressing weight than nurses (p = 0.0008); nurses were more concerned about excessive expectations of patients regarding potential benefits of such interventions (p < 0.0001). Regardless, nurses were more likely than physicians to favour a psychosocial intervention study focused on weight management over drug studies in pre- (p = 0.0006) and postmenopausal women (p = 0.05) with primary breast cancer. Canadian oncology practitioners are aware of the common occurrence of psychosocial distress in women with breast cancer. Physicians and nurses assigned differing priorities to psychosocial interventions in both clinical and research situations.
Adult↗
Phase I studies of fluorouracil, doxorubicin and vinorelbine without (FAN) and with (SUPERFAN) folinic acid in patients with advanced breast cancer.
PURPOSE: The Breast Cancer Site Group of the National Cancer Institute of Canada - Clinical Trials Group (NCIC-CTG) undertook two parallel phase I studies to determine the maximum tolerated dose (MTD) and recommended phase II dose of vinorelbine in combination with doxorubicin and fluorouracil (with or without folinic acid) in metastatic breast cancer. METHODS: Cohorts of five patients were to receive: (a) fluorouracil 500 mg/m2 and doxorubicin 50 mg/m2 on day 1 only and escalating doses of vinorelbine (15, 20, 25, 30 mg/m2) on days 1, 8 and 15 every 3 weeks (FAN regimen), or (b) fluorouracil 340 mg/m2 and folinic acid 200 mg/m2 on days 1, 2, 3, 4 and 5, doxorubicin 40 mg/m2 on day 1 only and escalating doses of vinorelbine (15, 20, 25, 30 mg/m2) on day 1 and again on day 5 every 4 weeks (SUPERFAN regimen). Eligibility included measurable or evaluable metastatic breast cancer and having received neither previous chemotherapy for metastatic disease nor anthracycline-containing adjuvant therapy. RESULTS: Of 26 and 12 patients enrolled in the FAN and SUPERFAN regimens, 26 and 12 were evaluable for toxicity and 21 and 9 for response, respectively. Median ages were 60.3 years (41-71 years) and 64.2 years (51-73 years). Both regimens required amendment after the first cohort with an original day- 15 vinorelbine dose omitted from the FAN regimen and more prolonged nadir granulocyte counts allowed. Myelosuppression was dose limiting. MTDs in the FAN and SUPERFAN regimens were vinorelbine 25 mg/m2 and 20 mg/m2. Other toxicities included mucositis, septicemia and febrile neutropenia. Peripheral neuropathy and constipation were mild. Of the 21 FAN patients evaluable for response, 3 (14%) had complete responses and 7 (33%) had partial responses, for an overall response rate of 48%; 9 (43%) had stable disease and 2 (9%) had progressive disease as their best response. Of the nine SUPERFAN patients evaluable for response, none had a complete response. There were two (22%) with partial responses, and six (67%) had stable disease and one (11%) had progressive disease as their best response. CONCLUSIONS: The SUPERFAN regimen was too toxic to pursue even at the lowest dose. The recommended phase II starting dose for the FAN regimen was vinorelbine 20 mg/m2. Although these were phase I studies response rates in evaluable patients were less than expected and toxicity did not allow the use of as much vinorelbine in the combinations as had been anticipated. The limited response data from our study would imply that combining vinorelbine with more toxic agents may not enhance response rates and may defeat the advantage of tolerability, especially in elderly patients.
Adult↗
Liver metastases: can our understanding of their biology and prognostic value contribute to a strategy for optimum therapeutic management?
Breast cancer is most likely to recur in soft tissue, liver, lungs and bone. The development of visceral disease, in particular liver disease, carries a poorer prognosis than the development of soft tissue or bony disease. Traditionally, liver metastases were believed to respond more poorly to hormonal approaches than other metastatic sites; although many studies of hormonal agents document a response in liver metastases in at least a proportion of the patients treated. Chemotherapeutic agents are generally considered the first-line of approach for women who have developed liver metastases from breast cancer, however. No well designed randomised studies have yet been carried out to compare the effects of various chemotherapeutic approaches using response in liver as a specific outcome. Many practitioners believe, even if this belief is not well documented in studies, that anthracyclines are more likely to produce shrinkage of liver metastases than some of the more traditional regimens such as cyclophosphamide/methotrexate/5-fluorouracil. More recently, it has been suggested from phase II data that liver metastases may respond more rapidly and completely to some of the newer agents such as the taxoids. Even in the setting of very aggressive chemotherapy, however, liver metastases retain their poor prognosis. Both disease characteristics and systemic adjuvant therapy have been linked to the site of recurrence of disease and considerable research into the molecular mechanisms mediating the distribution of metastases has been carried out. Despite the poor prognosis for patients with liver metastases, many new avenues are currently being explored to better understand and control this situation and, perhaps, to lead to the development of new treatment strategies for patients with this disease.
Breast Neoplasms↗
An individual patient-based meta-analysis of tamoxifen versus ovarian ablation as first line endocrine therapy for premenopausal women with metastatic breast cancer.
We performed a meta-analysis of randomized trials comparing tamoxifen to ovarian ablation carried out either by surgery or irradiation as first-line hormonal therapy for pre-menopausal women with metastatic breast cancer. Patients in all trials included were required to have measurable disease and to be currently menstruating or within 1 year of cessation of menses, and to have estrogen receptor (ER) positive or unknown disease (ER negative women were admitted to one of the studies). Individual patient data were obtained from the four studies identified and the results updated to June 1992. A total of 220 eligible patients were enrolled in the four trials. There was no difference in overall response rate between tamoxifen and oophorectomy across the four trials (p = 0.94, Mantel-Haenszel test). The odds reduction for progression was 14% +/- 12% and for mortality 6% +/- 13% in favour of tamoxifen, results which were not statistically significant (p = 0.32 and 0.72, respectively). Although the design of all four studies included a cross-over to the other therapy, only 54/111 patients receiving ovarian ablation and 34/109 patients receiving tamoxifen as primary therapy actually crossed over to the other arm at the time of disease progression. Response to initial treatment with tamoxifen was predictive of subsequent response to ovarian ablation (p < 0.05), and response to initial therapy with ovarian ablation was predictive of subsequent response to tamoxifen (p < 0.05). Support curves based on log-likelihood ratios revealed that this meta-analysis provides moderate evidence rejecting a 14% advantage for ovarian ablation compared to tamoxifen in terms of odds of disease progression. A 25% advantage for ovarian ablation with respect to odds of death is also rejected with moderate evidence. We conclude that the efficacy of tamoxifen appears to be similar to that of ovarian ablation by surgery or irradiation as first-line therapy for premenopausal, ER positive metastatic breast cancer, and is unlikely to be substantially inferior.
Adult↗
A randomized crossover trial of tamoxifen versus ovarian ablation for metastatic breast cancer in premenopausal women: a report of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial MA.1.
We concluded a randomized crossover trial comparing tamoxifen 40 mg daily with ovarian ablation for treatment of metastatic breast cancer in premenopausal women. Objective responses (complete response (CR) plus partial response (PR)) were observed in 5/20 patients treated initially with tamoxifen and in 3/19 patients initially treated with ovarian ablation (p = 0.69). Seven additional patients were stable (SD) on tamoxifen while five additional patients were stable after ovarian ablation, for CR + PR + SD rates of 12/20 (60%) for tamoxifen and 8/19 (42%) for ovarian ablation (p = 0.34). Median time to disease progression was 184 days for tamoxifen and 126 days for ovarian ablation (p = 0.40, logrank test, odds ratio for progression 0.71). Overall survival times were also similar: a median of 2.35 years for tamoxifen and 2.46 years for ovarian ablation (p = 0.98, logrank test, odds ratio for death 1.07). Side effects from tamoxifen included hot flashes and menstrual abnormalities. With one exception, these toxicities were not sufficient to require dose reduction. In this small study, tamoxifen was associated with similar response rates, response durations, and survival times to those observed with ovarian ablation.
Adult↗
Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer.
Breast cancer is the second leading cause of cancer death in North American women. There is considerable need for reliable prognostic markers to assist clinicians in making management decisions. Although a variety of factors have been tested, only tumor stage, grade, size, hormone receptor status, and S-phase fraction are used on a routine basis. The cell cycle is governed by a family of cyclin-dependent kinases (cdks), which are regulated by associated cyclins and by phosphorylation. p27Kip1, a cyclin-dependent kinase inhibitor, regulates progression from G1 into S phase by binding and inhibiting cyclin/cdks. p27Kip1 protein levels and/or activity are upregulated by growth inhibitory cytokines including transforming growth factor-beta (TGF-beta) and, thus, provide an important link between extracellular regulators and the cell cycle. Loss of p27Kip1, a negative cell-cycle regulator, may contribute to oncogenesis and tumor progression. However, p27Kip1 mutations in human tumors are extremely rare. We have demonstrated by immunohistochemistry that p27Kip1 protein levels are reduced in primary breast cancers and that this is associated with tumor progression in both in situ and invasive lesions. This was confirmed by western analysis, reflected in increased G1/S-phase cyclin-dependent kinase activities and shown to be regulated posttranscriptionally by in situ hybridization. Furthermore, on multivariate analysis, low p27Kip1 is a predictor of reduced disease-free survival. This simple and reliable immunohistochemical assay may become a routine part of breast cancer evaluation and may influence patient management.
Biomarkers, Tumor↗
Breast cancer patients' attitudes about rationing postlumpectomy radiation therapy: applicability of trade-off methods to policy-making.
PURPOSE: Along with evidence, clinical policies must take patients' values into account. Particularly where evidence is limited and where assumptions of utility-maximizing behavior may not be valid, new methods such as trade-off techniques (TOTs), which allow elicitation of patients' treatment alternatives, might be useful in policy formulation. We used TOTs to assess breast cancer patients' attitudes toward two clinical policies designed to ration adjuvant postlumpectomy breast radiation therapy. METHODS: Cross-sectional interviews were performed in a tertiary cancer center. A total of 102 patients were presented with information about the side effects and benefits associated with two hypothetical decisions: (1) willingness to receive treatment elsewhere to shorten the wait for radiation therapy, and (2) foregoing radiation therapy in the face of small marginal benefits. For each scenario, a TOT was used to identify the maximal acceptable wait time (MAWT) for therapy and the benefit threshold at which the patient would forego therapy. Associations of clinical and demographic factors with these decisions were determined by regression analysis. RESULTS: Patients would be willing to wait, on average, 7 weeks before wanting to leave their city for radiation therapy, less than the 13-week delay our patients actually faced. Older patients were less willing to wait (P = .013); 46% of patients would not give up radiation therapy, even in the face of no stated benefit. Willingness to give up radiation therapy was predicted by willingness to accept delay (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.05 to 3.37) and being employed (OR, 2.61; 95% CI, 1.08 to 6.54). Patients with larger tumors were less willing to give up radiation therapy (OR, 0.57; 95% CI, 0.31 to 0.97). CONCLUSION: Even in difficult decisions such as rationing postlumpectomy breast cancer radiation therapy, TOTs can inform policy formulation by indicating the distributions of patients' preferences.
Adult↗
Cyclophosphamide and fluorouracil combined with mitoxantrone versus doxorubicin for breast cancer: superiority of doxorubicin.
PATIENTS AND METHODS: We conducted a randomized, multicenter study of intravenous cyclophosphamide 500 mg/m2 plus fluorouracil 500 mg/m2 combined with either mitoxantrone (Novantrone, Lederle Cyanamid Canada Ltd, Willowdale, Ontario) 10 mg/m2 (CNF) or doxorubicin (Adriamycin, Adria Laboratories of Canada Ltd, Mississauga, Ontario) 50 mg/m2 (CAF) every 3 weeks in advanced breast cancer. RESULTS: The response rate in 249 randomized patients was 36% with CNF (44 of 121) and 48% with CAF (62 of 128) (P = .054), with complete remissions in 10 patients (8.3%) on CNF and in 13 (10.2%) on CAF. If only fully assessable patients are considered, the response rate was 48% (44 of 91) with CNF and 60% (62 of 103) with CAF (P = .098). At time of analysis, all except 10 patients (one CNF and nine CAF) had died. The median survival time with CAF was longer than with CNF (15.2 v 10.9 months; P = .003), and time to progression was also longer with CAF (5.3 v 3.2 months; P < .03). Survival differences remained significant (P = .006) if patients who failed to meet all eligibility criteria were excluded. Favorable prognostic factors for survival in a Cox regression model included good performance status (P < .0001); less than two organ systems involved by tumor (P < .0001); no involvement of lung, liver, or brain (P < .003); involvement of bone or bone marrow (P < .009), prior surgery for breast cancer (P < .006); being premenopausal (P < .03); > or = 3 years from diagnosis until randomization on this study (P < .03); and treatment with CAF (P < .03). Alopecia > or = grade 3 was reported in 55% of patients with CAF and 12% of patients with CNF (P < .001), while other > or = grade 3 toxicities did not differ significantly. Priestman-Baum quality-of-life assessment was comparable on the two study arms. CONCLUSION: In patients with advanced breast cancer, CAF was associated with longer survival than was CNF, with an increase in alopecia, but not in other toxicities.
Adult↗
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.
Antineoplastic Combined Chemotherapy Protocols↗
The clinical practice guideline: an evolving health care technology.
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Humans↗
Postmenopausal breast cancer: is the short-term pain worth the long-term gain?
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Antineoplastic Agents, Hormonal↗