Adjuvant Therapy In Postmenopausal Patients Research Articles

Bone Safety Profile of Steroidal Aromatase Inhibitor in Comparison to Nonsteroidal Aromatase Inhibitors in Postmenopausal Women with Breast Cancer: A Network Meta-Analysis

Background and Objectives: Aromatase inhibitors (AIs) provide an alternative to tamoxifen as an adjuvant therapy for postmenopausal patients with breast cancer (BC). Large trials resulted better outcomes with AIs. Adjuvant therapy with AIs reduced the risk of relapse compared with tamoxifen. Systemic therapies for BC can interfere with bone turnover, either by affecting gonadal steroid hormone production or by inhibiting peripheral aromatization into estrogen. We aimed to evaluate the safety profile of bone-related events by comparing 3 AIs with tamoxifen and a placebo. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were used for network meta-analyses (NMAs). Searches were performed using PubMed, Embase/Medline, Cochrane, and Ovid databases. Randomized controlled trials comparing tamoxifen and placebo or other AIs to steroidal or nonsteroidal AIs in patients with BC reporting bone-related safety events were included in NMA. NMA in a Bayesian approach was performed using R software (ver 3.2), Gemtc package. Results: Seventeen studies reporting 4 different bone-related endpoints were included. Although there was no statistical significance, treatment with exemestane lowered the incidence of bone pain (odds ratio [OR] vs. anastrozole and letrozole: 0.63, 0.54), fracture episodes (OR vs. anastrozole and letrozole: 0.84, 0.80), and osteoporosis (OR vs. anastrozole and letrozole: 0.85, 0.73) compared with letrozole and anastrozole. Reduction in bone mineral density was lesser in exemestane than in anastrozole (mean reduction in hip: 1.05; lumbar spine: 1.25). Treatment ranking with the surface under the cumulative ranking curve showed that exemestane was found to reduce the incidence of bone-related adverse events. Conclusion: A lower incidence of bone-related safety events was observed in patients treated with exemestane.

Abstract P4-14-11: No impact of osteoporosis or bisphosphonate use for osteoporosis on breast cancer outcome: A sub-study of the DATA trial

Abstract Background: The phase III DATA study (NCT00301457) investigates the efficacy of 6 versus 3 years of adjuvant anastrozole after an initial 2-3 year treatment with tamoxifen in postmenopausal women with breast cancer. A reduced bone mineral density (BMD) is associated with a lower risk of breast cancer. Bisphosphonates as adjuvant therapy in postmenopausal patients have been shown to prevent (distant) breast cancer recurrences. In this planned side-study of the DATA trial we assessed the relationship between osteoporosis and distant recurrence free survival (DRFS), and evaluated the effect of bisphosphonate use for reduced BMD in general on DRFS. Methods: Decisions on BMD measurements and bisphosphonate use in the DATA study were left to the treating physician. We registered all BMD measurements and start of bisphosphonate-use. BMD was measured by a dual-energy x-ray absorptiometry (DEXA) scan of the lumbar spine/hip. We used a landmark of 3 years beyond the start of anastrozole, to create 3 different groups by BMD values based on DEXA scans made before the landmark and before a DRFS event (normal T score >-1.0, osteopenia T score <-1.0, osteoporosis T score <-2.5). Kaplan Meier methodology was used for analyzing the DRFS for these groups. The events ending a period of DRFS were defined according to the STEEP criteria. For analyzing the relationship between bisphosphonate use and DRFS, overall bisphosphonate use was integrated as a time dependent covariate. Results: Of the 1860 DATA patients, 1142 (65.5% in the 6-year arm and 62.9% in the 3-year arm) had a DEXA scan within the first 3 years after randomization. A normal BMD was diagnosed in 436 (38.2%) patients, osteopenia in 565 (49.5%), and osteoporosis in 141 (12.3%). Of the latter group, 112 (80.9%) used bisphosphonates. In the total study population (n=1860), bisphosphonates were overall used over time before a DRFS event in 226 patients (24.2%) in the 6-year arm and 201 patients (21.7%) in the 3-year arm. During the study, only 46 patients used bisphosphonates without a diagnosis of osteopenia/osteoporosis. After a median follow up of 5.0 years from the landmark (interquartile range 4.3-5.7), osteoporosis (n=141) did not have a significant impact on DRFS when compared with the group without osteoporosis (normal/osteopenia (n=1001)) (HR 1.19, p=0.24 in the 6-year arm and HR=0.79, P=0.56 in the 3-year arm, P interaction=0.45). Neither when compared with only the group with a normal BMD (n=436) (HR=1.15, p=0.72 in the 6-year arm and HR=0.67, p=0.34 in the 3-year arm, P interaction=0.35). Within the group with osteoporosis, bisphosphonate use did not lead to a better DRFS (HR=1.47, P=0.72 in the 6-year arm and HR 0.65, P=0.61 in the 3-year arm, P interaction=0.55). Bisphosphonate use in general was also not associated with DRFS (HR 1.31, P=0.13 in the 6-year arm and HR 0.88, P=0.52 in the 3-year arm, P interaction=0.14). Conclusion: In this DATA sub-study, we observed no association between the presence of osteoporosis before the landmark of 3 years after the start of anastrozole and DRFS. However, as most patients with early osteoporosis also were treated with bisphosphonates this may have influenced the results. At the conference additional analyses will be presented. Citation Format: van Hellemond IE, Smorenburg CH, Peer PG, Swinkels AC, Seynaeve CM, van der Sangen MJ, Kroep JR, de Graaf H, Honkoop AH, Erdkamp FL, van den Berkmortel FW, de Roos WK, Linn SC, Imholz AL, de Boer M, Tjan-Heijnen VC. No impact of osteoporosis or bisphosphonate use for osteoporosis on breast cancer outcome: A sub-study of the DATA trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-14-11.

Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: A Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline.

Purpose To make recommendations regarding the use of bisphosphonates and other bone-modifying agents as adjuvant therapy for patients with breast cancer. Methods Cancer Care Ontario and ASCO convened a Working Group and Expert Panel to develop evidence-based recommendations informed by a systematic review of the literature. Results Adjuvant bisphosphonates were found to reduce bone recurrence and improve survival in postmenopausal patients with nonmetastatic breast cancer. In this guideline, postmenopausal includes patients with natural menopause or that induced by ovarian suppression or ablation. Absolute benefit is greater in patients who are at higher risk of recurrence, and almost all trials were conducted in patients who also received systemic therapy. Most studies evaluated zoledronic acid or clodronate, and data are extremely limited for other bisphosphonates. While denosumab was found to reduce fractures, long-term survival data are still required. Recommendations It is recommended that, if available, zoledronic acid (4 mg intravenously every 6 months) or clodronate (1,600 mg/d orally) be considered as adjuvant therapy for postmenopausal patients with breast cancer who are deemed candidates for adjuvant systemic therapy. Further research comparing different bone-modifying agents, doses, dosing intervals, and durations is required. Risk factors for osteonecrosis of the jaw and renal impairment should be assessed, and any pending dental or oral health problems should be dealt with prior to starting treatment. Data for adjuvant denosumab look promising but are currently insufficient to make any recommendation. Use of these agents to reduce fragility fractures in patients with low bone mineral density is beyond the scope of the guideline. Recommendations are not meant to restrict such use of bone-modifying agents in these situations. Additional information at www.asco.org/breast-cancer-adjuvant-bisphosphonates-guideline , www.asco.org/guidelineswiki , https://www.cancercareontario.ca/guidelines-advice/types-of-cancer/breast .

Abstract P2-13-04: Superior efficacy of anastrozole to tamoxifen as adjuvant therapy for postmenopausal patients with hormone-responsive breast cancer. Efficacy results of long-term follow-up data from N-SAS BC 03 trial

Abstract Background: Aromatase inhibitors have been shown to be superior to tamoxifen as adjuvant therapy in postmenopausal patients with hormone-responsive breast cancer. Here we report the efficacy results of long-term follow-up data from N-SAS BC 03 trial (UMIN CTRID: C000000056), in which anastrozole was compared to tamoxifen in hormone-responsive postmenopausal early breast cancer patients who had taken tamoxifen for 1—4 years out of a total of 5 years of treatment as adjuvant therapy. Patients and methods: Out of a total of 706 recruited patients, 696 patients (tamoxifen group, n=345; anastrozole group, n=351) were used as the full analysis set for the present study. The log-rank test was used to compare the two groups in terms of disease-free survival (DFS) and relapse-free survival (RFS), Kaplan-Meier estimates were calculated. The treatment effects were estimated by Cox's proportional hazard model and were expressed as hazard ratios, with associated 95% confidence intervals (CIs). Results: After a median follow-up of 76.1 months, (range: 1.3–110 months), the unadjusted hazard ratio was 0.87 (95%Cl 0.60–1.26; log-rank p = 0.457) for DFS and 0.77 (95%Cl 0.49–1.22; log-rank p = 0.266) for RFS, both in favor of anastrozole. The estimated hazard ratio (95%CIs) for DFS and for RFS until each time point (right censored data) was as follows: until 30 months: 0.54 (0.30–0.98) and 0.48 (0.23–0.98), until 42 months; 0.65 (0.40–1.06) and 0.53 (0.29–0.97), until 54 months: 0.77 (0.50–1.19) and 0.63 (0.37–1.06), until 66 months: 0.82 (0.55–1.24) and 0.72 (0.44–1.17), until 78 months: 0.83 (0.57–1.23) and 0.73 (0.46–1.17), respectively. The hazard ratios (95%CIs) for DFS and for RFS until 36 months were 0.72 (95%Cl 0.43–1.22) and 0.58 (95%Cl 0.30–1.12), and those after 36 months were 1.06 (95%Cl 0.62–1.81) and 0.98 (95%Cl 0.51–1.88), respectively. Conclusion: Superior efficacy of anastrozole to tamoxifen in the Japanese population was suggested over a long-term follow-up period. It was the greatest early after switching from tamoxifen and then decreased thereafter. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-13-04.

Phase III randomized trial of toremifene versus tamoxifen for Japanese postmenopausal patients with early breast cancer

Toremifene, a selective estrogen receptor modulator, is used as adjuvant therapy for postmenopausal patients with breast cancer in Japan. For Japanese patients, however, only limited data are available on the efficacy and safety profile of toremifene. To establish the long term efficacy and safety of toremifene for Japanese patients, we conducted a prospective, multicenter, randomized phase III trial comparing toremifene and tamoxifen. The subjects were postmenopausal Japanese patients who had undergone surgery for node-negative breast cancer. Toremifene or tamoxifen was administered for 2years. The primary endpoint was demonstration of the non-inferiority of toremifene compared with tamoxifen in respect of 5-year survival. Secondary endpoints were cumulative overall survival, cumulative disease-free survival, effects on lipid profiles, and adverse events. A total of 253 patients were enrolled. The baseline characteristics of the two treatment groups were well-balanced. Median follow-up was 66.5months. Five-year survival was similar for toremifene and tamoxifen (97.0 vs. 96.9%; 90% confidence interval -3.9 to 4.1), indicating that toremifene is not inferior to tamoxifen for postmenopausal Japanese patients with early breast cancer. Cumulative overall survival and cumulative disease-free survival were also very similar for toremifene and tamoxifen (97.5 vs. 97.3%, log-rank test P=0.9458; 88.4 vs. 90.6%, log-rank test P=0.3359, respectively). Adverse events in both groups were similar and mostly mild or moderate. Thus, both are equally effective and well tolerated. Our results suggest that the efficacy and safety of toremifene and tamoxifen are equivalent for postmenopausal Japanese patients with early breast cancer.

Effects of Toremifene and Tamoxifen on Lipid Profiles in Post-menopausal Patients with Early Breast Cancer: Interim Results from a Japanese Phase III Trial

Toremifene and tamoxifen have been used for adjuvant therapy in post-menopausal patients with breast cancer in Japan. Dyslipidemias are common in post-menopausal women. However, limited data are available on the effects of these agents on lipid profiles in Japanese patients. The Japan Toremifene Cooperative Study Group has been conducting a Phase III randomized trial of post-menopausal patients with breast cancer. One of its secondary endpoints is to confirm the effects of these agents on serum lipid profiles. The subjects were post-menopausal Japanese patients who had undergone surgery for early breast cancer. Toremifene or tamoxifen was administered for 2 years. Lipid levels were measured before and up to 24 months after initiation. Compared with baseline, at 24 months, the toremifene group (n = 123) showed significantly decreased total cholesterol (P < 0.001) and low-density lipoprotein cholesterol levels (P < 0.001), and significantly increased high-density lipoprotein cholesterol levels (P < 0.001). Their triglyceride levels were not affected (P = 0.677). The tamoxifen group (n = 120) also showed significantly decreased total cholesterol (P < 0.001) and low-density lipoprotein cholesterol levels (P < 0.001); no significant changes occurred in high-density lipoprotein cholesterol (P = 0.297) or triglyceride levels (P = 0.120). Distinct differences between two selective estrogen receptor modulators on lipids were observed. Toremifene improved lipid profiles, particularly as an enhancer of high-density lipoprotein cholesterol. To a large extent, tamoxifen improved low-density lipoprotein cholesterol levels. The impact of these improved lipid profiles on the risk of cardiovascular diseases needs further confirmation.

Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial

Tamoxifen is standard adjuvant treatment for postmenopausal women with hormone-receptor-positive breast cancer. We assessed the benefit of adding chemotherapy to adjuvant tamoxifen and whether tamoxifen should be given concurrently or after chemotherapy. We undertook a phase 3, parallel, randomised trial (SWOG-8814, INT-0100) in postmenopausal women with hormone-receptor-positive, node-positive breast cancer to test two major objectives: whether the primary outcome, disease-free survival, was longer with cyclophosphamide, doxorubicin, and fluorouracil (CAF) given every 4 weeks for six cycles plus 5 years of daily tamoxifen than with tamoxifen alone; and whether disease-free survival was longer with CAF followed by tamoxifen (CAF-T) than with CAF plus concurrent tamoxifen (CAFT). Overall survival and toxicity were predefined, important secondary outcomes for each objective. Patients in this open-label trial were randomly assigned by a computer algorithm in a 2:3:3 ratio (tamoxifen:CAF-T:CAFT) and analysis was by intention to treat of eligible patients. Groups were compared by stratified log-rank tests, followed by Cox regression analyses adjusted for significant prognostic factors. This trial is registered with ClinicalTrials.gov, number NCT00929591. Of 1558 randomised women, 1477 (95%) were eligible for inclusion in the analysis. After a maximum of 13 years of follow-up (median 8.94 years), 637 women had a disease-free survival event (tamoxifen, 179 events in 361 patients; CAF-T, 216 events in 566 patients; CAFT, 242 events in 550 patients). For the first objective, therapy with the CAF plus tamoxifen groups combined (CAFT or CAF-T) was superior to tamoxifen alone for the primary endpoint of disease-free survival (adjusted Cox regression hazard ratio [HR] 0.76, 95% CI 0.64-0.91; p=0.002) but only marginally for the secondary endpoint of overall survival (HR 0.83, 0.68-1.01; p=0.057). For the second objective, the adjusted HRs favoured CAF-T over CAFT but did not reach significance for disease-free survival (HR 0.84, 0.70-1.01; p=0.061) or overall survival (HR 0.90, 0.73-1.10; p=0.30). Neutropenia, stomatitis, thromboembolism, congestive heart failure, and leukaemia were more frequent in the combined CAF plus tamoxifen groups than in the tamoxifen-alone group. Chemotherapy with CAF plus tamoxifen given sequentially is more effective adjuvant therapy for postmenopausal patients with endocrine-responsive, node-positive breast cancer than is tamoxifen alone. However, it might be possible to identify some subgroups that do not benefit from anthracycline-based chemotherapy despite positive nodes. National Cancer Institute (US National Institutes of Health).

NSABP B-42: A Clinical Trial to Determine the Efficacy of Five Years of Letrozole Compared with Placebo in Patients Completing Five Years of Hormonal Therapy Consisting of an Aromatase Inhibitor (AI) or Tamoxifen Followed by an AI in Prolonging Disease-Free Survival in Postmenopausal Women with Hormone Receptor—Positive Breast Cancer

Aromatase Inhibitors as Adjuvant Therapy Adjuvant hormonal therapy significantly improves disease-free and overall survival in patients with stage I, II, or III breast cancer and hormone receptor–positive tumors.1,2 For some time, 5 years of adjuvant tamoxifen has been the gold standard. However, recent results from studies evaluating the third generation aromatase inhibitors (AIs) as adjuvant therapy in postmenopausal women have challenged the primacy of tamoxifen for this group of patients.3-14 In patients with advanced-stage breast cancer, the third generation nonsteroidal AIs anastrozole and letrozole as well as the steroidal inactivator exemestane have been found superior to megestrol acetate as second-line therapy15-21 and at least equivalent (and possibly superior) to tamoxifen as first-line therapy.21-25 Based on these results, several clinical trials have evaluated or are currently evaluating AIs as adjuvant therapy in postmenopausal patients with early-stage breast cancer. In the adjuvant setting, AIs have demonstrated activity in 3 distinct clinical scenarios. In the first, an AI was compared with tamoxifen as initial adjuvant hormonal therapy in patients with resected operable breast cancer.3-5 The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial demonstrated that 5 years of anastrozole significantly improved disease-free survival (DFS) when compared with 5 years of tamoxifen.3,4 More recently, the BIG (Breast Intergroup) 1-98 trial also demonstrated similar benefit for 5 years of letrozole compared with 5 years of tamoxifen.5 In the second scenario, an AI was compared with tamoxifen in patients who had already received 2-3 years of adjuvant tamoxifen.6-10 In 3 randomized trials (the IES [Intergroup Exemestane Study] trial,6,7 the ABCSG [Austrian Breast and Colorectal Cancer Study Group]–8/ARNO [ArimidexNSABP B-42: A Clinical Trial to Determine the Efficacy of Five Years of Letrozole Compared with Placebo in Patients Completing Five Years of Hormonal Therapy Consisting of an Aromatase Inhibitor (AI) or Tamoxifen Followed by an AI in Prolonging Disease-Free Survival in Postmenopausal Women with Hormone Receptor–Positive Breast Cancer

Optimizing the use of aromatase inhibitors in adjuvant therapy for postmenopausal patients with hormone-responsive early breast cancer: current and future prospects

Five years of tamoxifen treatment after primary surgery has had a significant impact on outcomes for women with early breast cancer, but the third-generation aromatase inhibitors (AIs) are now challenging tamoxifen as the gold standard endocrine adjuvant treatment. Results from two large, phase III, early adjuvant studies have indicated that the AIs letrozole and anastrozole offer greater protection against recurrence than tamoxifen in upfront substitution strategies in the first 5 years after surgery. Similarly, changeover to an AI (exemestane or anastrozole) after 2-3 years of tamoxifen has been shown to offer greater protection against recurrence than 5 years of tamoxifen. More than 50% of early breast cancer recurrences occur five or more years after surgery. Letrozole has been shown to offer greater protection against recurrence than placebo in the 5 years after a standard course of tamoxifen. The safety implications of treatment with these potent AIs for 5 years or more are being closely monitored. Anticipated effects of estrogen deprivation on bone health may be treatable with bisphosphonates, and this strategy is under investigation. Effects on the cardiovascular system, and other estrogen-sensitive systems such as the central nervous system, are currently unclear and further results are awaited. Current evidence indicates that the third-generation AIs will improve outcomes for many women with early breast cancer.

Aromatase Inhibitors as Adjuvant Therapy for Postmenopausal Patients With Early Stage Breast Cancer

Endocrine therapy of hormone receptor-positive breast tumors is widely used as palliative therapy for metastatic breast cancer and as adjuvant therapy for early stage breast cancer. Tamoxifen has been the definitive standard of hormonal therapies for the last 30 years because of its documented efficacy and reasonable safety profile. Based on encouraging results from trials utilizing the selective, third generation aromatase inhibitors (AIs) in metastatic breast cancer, a number of trials were designed to examine these agents as adjuvant therapies. Trials directly comparing AIs with tamoxifen have, to date, demonstrated superior disease-free-survival with AIs. Likewise, trials examining the use of AIs after tamoxifen have demonstrated better outcomes compared with tamoxifen alone. Additionally, letrozole has been demonstrated to result in superior disease-free-survival after 5 years of adjuvant tamoxifen, compared with no further therapy. In general, the AIs are tolerated at least as well as tamoxifen but decrease bone mineral density and increase osteoporosis due to their lack of estrogenic effects on bone. Based on the fact that AIs appear more effective at preventing contralateral breast cancers than tamoxifen, they are being examined as breast cancer preventives. Despite available data using the AIs as adjuvant therapies, many questions remain unanswered, and further trials will be needed to address these important issues.

Role of anastrozole in adjuvant therapy for postmenopausal patients

For the past 25 years tamoxifen has been the mainstay for adjuvant treatment of postmenopausal patients with hormone-sensitive breast cancer. However, tamoxifen has some safety and tolerability issues, and its partial estrogen-receptor agonist activity may have efficacy implications. Highly specific aromatase inhibitors, of which anastrozole was the first, were introduced in the 1990s and have emerged as a potentially better tolerated and more effective class of agents targeting hormonally responsive breast cancer. This article provides a review of the clinical pharmacology of anastrozole (1 mg once daily) and reviews the first results of the ongoing Arimidex, Tamoxifen, Alone or in Combination early breast cancer trial, initiated in 1996. This randomized, double-blind multicenter trial compared tamoxifen (20 mg once daily) with anastrozole (1 mg once daily) alone and the combination of anastrozole plus tamoxifen, as adjuvant endocrine treatment for postmenopausal patients with operable, invasive, early breast cancer. The results of the Arimidex, Tamoxifen, Alone or in Combination trial show anastrozole to be an effective and well tolerated endocrine option for early breast cancer and provide evidence for its potential role in chemoprevention.

Therapeutic Use of Bisphosphonates in Breast Cancer

Bisphosphonates are synthetic derivatives of phosphonate, a normal constituent of bone. These agents are potent inhibitors of osteoclastic resorption, and as such are being explored for the management of various pathological conditions including osteoporosis, hypercalcemia, bone metastases and certain aspects of cancer. Among the first agents to be developed in the class, clodronic acid has shown conflicting results with respect to its ability to reduce osseous metastases, while pamidronic acid reduced hypercalcemia effectively compared with placebo in patients with breast cancer and multiple myeloma. Recent exploratory studies have shown that the novel bisphosphonate zoledronic acid reduces hypercalcemia more effectively than pamidronic acid in patients with various malignancies. In a recent phase III trial designed to show equivalence, zoledronic acid was as effective as pamidronic acid in the number of skeletal-related events arising over a predefined period of time. Furthermore, a trend in radiation therapy delay was observed in the zoledronic acid group. Zoledronic acid appears to be an effective agent in reducing the complications from bone involvement in cancer patients and it has shown efficacy in the prevention of osteoporosis in healthy postmenopausal women. For these reasons, it is being investigated as an adjunct to adjuvant therapy for postmenopausal patients with early breast cancer treated with nonsteroidal aromatase inhibitors, because efficient and prolonged estrogen deprivation with the latter agents may result in an increased risk of bone degradation in some patients.

Regarding the dilemma of adjuvant therapy in postmenopausal patients with node-positive, estrogen receptor-positive breast cancer: are we better informed?

Regarding the dilemma of adjuvant therapy in postmenopausal patients with node-positive, estrogen receptor-positive breast cancer: are we better informed?

Adjuvant therapy of primary breast cancer. 4th International Conference on Adjuvant Therapy of Primary Breast Cancer St. Gallen, Switzerland.

Biological Mechanisms and Models for New Approaches to Adjuvant Therapy of Breast Cancer.- Patterns of Treatment Failure - Implications for New Treatment Approaches.- New Information on Drug Resistance: Implications for the Adjuvant Treatment of Breast Cancer.- Correlation of Dose Intensity and Prognosis in Adjuvant Chemotherapy: An Extended Controversy.- Dose Response for Adjuvant Chemotherapy of Breast Cancer: Experimental and Clinical Considerations.- Neoadjuvant (Pre- and Perioperative) Therapy.- Experimental Basis and Clinical Reality of Preoperative (Neoadjuvant) Chemotherapy in Breast Cancer.- Neoadjuvant Chemotherapy in the Conservative Management of Breast Cancer: A Study of 252 Patients.- Randomized Perioperative Therapy in Operable Breast Cancer: The Ludwig Trial V.- Is There a Role for Perioperative Adjuvant Cytotoxic Therapy in the Treatment of Early Breast Cancer?.- Problems of Rational Follow-up and Salvage Therapy.- Radiation Therapy in Prevention and Salvage of Local Relapse: Its Prognostic Implication.- Salvage Treatments in Relapsing Resectable Breast Cancer.- Time Course and Prognosis of Mammary Failure Following Breast-Conserving Therapy.- Detection of Recurrence: A Critical Assessment of Existing Methods and Programs.- Factors Associated with Local Recurrence as a First Site of Failure Following the Conservative Treatment of Early Breast Cancer.- Critical Review of Problems of Rational Follow-up and Salvage Therapy.- Adjuvant Therapy in Premenopausal Patients.- Endocrine Effects of Adjuvant Chemotherapy in Premenopausal Women: Suggestions for the Future.- The Milan Experience with Adjuvant Chemotherapy in Premenopausal Breast Cancer.- Adjuvant Chemo- and Endocrine Therapy Alone or in Combination in Premenopausal Patients (GABG Trial 1).- Scottish Adjuvant Breast Cancer Trials: Results in Pre-menopausal Patients.- Critical Review of Adjuvant Therapy in Premenopausal Patients.- Adjuvant Therapy in Postmenopausal Patients.- The Role of Adjuvant Endocrine Therapy in Primary Breast Cancer.- How to Improve Adjuvant Treatment Results in Postmenopausal Patients.- Adjuvant Chemo-Endocrine Therapy or Endocrine Therapy Alone for Postmenopausal Patients: Ludwig Studies III and IV.- Chemo- or Endocrine Adjuvant Therapy Alone or Combined in Postmenopausal Patients (GABG Trial 1).- Prognostic Factors and Treatment for Node-Negative Patients.- Prognosis in Breast Cancer.- Adjuvant Chemotherapy for Node-Negative Breast Cancer Patients.- Significant Survival Benefit of Node-Negative Breast Cancer Patients Treated with Adjuvant Chemotherapy: Seven-year Results.- Adjuvant Immunotherapy in Node-Negative Patients: Results of a Scandinavian Study.- Breast-Conserving Surgery and Adjuvant Radiotherapy.- Breast-Conserving Surgery and the Role of Adjuvant Radiotherapy: A Review.- New Trends in Breast Cancer Surgery.- Therapy of Early Breast Cancer: Preliminary Results of the German Breast Cancer Study.- Methodology of Adjuvant Trials and Interpretation of Results.- Methods for Assessing Treatment Efficacy in Trials for Adjuvant Therapy for Breast Cancer.- Overview of Adjuvant Radiotherapy for Breast Cancer.- Randomized Multicenter 2 x 2-Factorial Design Study of Chemo/Endocrine Therapy in Operable, Node-Positive Breast Cancer (Protocol 2).- Critical Review: Methodology of Adjuvant Trials and Interpretation of Results.- Quality of Life: Psychological Aspects of Adjuvant Therapy of Breast Cancer.- Adjuvant Therapies in Breast Cancer and Quality of Life: A Critical Review of the TWiST Concept.- Rehabilitation of Patients with Primary Breast Cancer: Assessing the Impact of Adjuvant Therapy.- Coping and Survival in Patients with Primary Breast Cancer: A Critical Analysis of Current Research Strategies and Proposal of a New Approach Integrating Biomedical, Psychological, and Social Variables.- Behavioral Side Effects of Adjuvant Chemotherapy.- Critical Review of Quality of Life: Psychosocial Aspects of Adjuvant Therapy in Breast Cancer.- Closing Summary and Outlook.