[MOL] More info. for breast cancer/For your files, save.

[lillian jennings <firefly@islc.net>]

Abstract

 Background: A large number of controversies about the
 management of breast cancer produce uncertainties for patients
 and physicians alike. In addition, questions are constantly raised
 about the true value of new approaches or treatments.
 Methods: The authors have conducted a critical review of the
 literature on several of these issues, and they present a balanced
 view that can be useful for clinical decision making.
 Results: Although new staging systems for ductal carcinoma in
 situ have been proposed, a consensus has not yet been reached
 regarding the criteria to allow tumor excision alone. The extent of
 benefit of the main adjuvant therapies is becoming better
 established, and improvement in outcomes may accrue from
 dose-intensive treatments and autologous stem cell or
 hematopoietic growth factor support.
 Conclusions: Progress in breast cancer management continues
 to evolve. Several new approaches either reduce morbidity or
 improve outcomes. [Cancer Control 4(3):226-235, 1997. ©
 1997 Moffitt Cancer Center & Research Institute]

    Introduction

 The presentations and management of patients with breast
 cancer have changed markedly over the last several decades. In
 the 1960s and earlier, patients were often hospitalized with
 recurrent disease and massive arm lymphedema years after their
 radical mastectomy and postoperative radiotherapy, and their
 responses to palliative hormones or chemotherapy were only
 temporary. Today, a significant percentage of patients present
 with noninvasive breast cancer detected mammographically, and
 even those who have invasive disease often have a small primary
 tumor with negative ipsilateral axillary lymph nodes. Despite this
 shift in clinical presentation, many controversies remain regarding
 management of women with early breast cancer, with more
 advanced local tumors, and with regional spread or metastases.
 This review highlights conventional treatment results and
 discusses some of the controversial issues surrounding these
 approaches. Table 1 presents an overview of the controversies
 associated with treating patients with breast cancer.

 The principal reason for the controversies is the lack of definitive
 outcome data on most of the newer promising methods that have
 been applied to a group of diseases, all with inherently long and
 variable natural histories. In the absence of well-controlled,
 prospectively randomized clinical trials of sufficient size to
 exclude a spurious positive result occurring by chance alone,
 most newer treatments being used today should be viewed as "a
 hope and a promise" rather than as accepted replacements for
 conventional approaches. When viewed in this context, the
 following discussions address unresolved issues on a particular
 disease aspect rather than true controversies in management.

    Surgical Issues

 Unresolved surgical issues include mastectomy indications,
 selection of lumpectomy alone, clinical relevance of
 comedonecrosis and nuclear grade, and the role of sentinel node
 biopsy in influencing the need for axillary dissection.

 Ductal Carcinoma In Situ

 The incidence of ductal carcinoma in situ (DCIS), particularly the
 type detected by microcalcifications in a mammogram, is
 increasing. In 1992, DCIS represented approximately 12% of all
 new breast cancer diagnoses and accounted for 40% of
 mammographically detected breast cancer.[1] Several
 controversial issues have arisen, including the identification of
 significant histopathologic features, the importance of surgical
 margins, the use of local treatment options, and the role for
 systemic therapy. Total mastectomy and lumpectomy with
 radiotherapy are the standard treatment options. Lumpectomy
 with radiotherapy with or without tamoxifen is under clinical
 evaluation. Axillary node involvement in DCIS is rare; thus, node
 dissection is rarely indicated.

 Overall, the long-term outlook for DCIS is excellent. While more
 than 98% of women are cured by total mastectomy, this may not
 be the most appropriate option for treatment of DCIS today.
 Several series from single institutions demonstrate that selected
 patients have a low ipsilateral recurrence rate following local
 excision alone. Pathologists debate over how to best identify
 low-risk DCIS lesions. Several pathologic staging systems have
 been developed and tested retrospectively, but consensus
 recommendations have not yet been reported. Part of the
 problem stems from the fact that there are several histologic
 subtypes of DCIS, including micropapillary, papillary, solid,
 cribriform, and comedocarcinoma. Comedocarcinoma is often
 more aggressive and is associated with a higher probability of
 microinvasion.

 The selection of treatment also can be controversial when there
 is initial margin involvement by tumor. Reexcision is indicated if
 the margin is positive, and the total extent of disease is evaluated
 before proceeding with radiotherapy or mastectomy.
 Mastectomy has been the usual treatment choice for patients
 with persistent microscopic involvement of margins after local
 excision and for those with a diagnosis of DCIS and evidence of
 suspicious, diffuse microcalcifications. Two elements needing
 more precise definition are (1) the early identification of the
 woman who would best be treated with mastectomy and (2) the
 selection of the woman who can be treated adequately with local
 excision alone. The local recurrence rate for lesions smaller than
 25 mm with low nuclear grade and no evidence of
 comedonecrosis is only 2.3%. In comparison, the local
 recurrence rate for high-grade DCIS with comedonecrosis is
 33%.[2] Lagios et al[3] highlighted the importance of nuclear
 differentiation and the presence or absence of comedonecrosis in
 identifying women at higher risk of recurrence after local excision
 alone. Simpson and Page[4] emphasized the heterogeneous
 nature of DCIS and the need for clear surgical margins. For
 patients with DCIS treated with breast conservation, Silverstein
 et al[5] have proposed a prognostic classification consisting of
 three risk groups: non-high-grade DCIS without comedo-type
 necrosis, non-high-grade DCIS with comedo-type necrosis,and
 high-grade DCIS with or without comedo-type necrosis.

 Local excision plus radiation is often recommended for women
 who are not treated with total mastectomy for DCIS. In those
 women who have a recurrence after conservative therapy, their
 survival is comparable following salvage mastectomy. The
 National Surgical Adjuvant Breast and Bowel Project (NSABP)
 B-17 protocol involving 790 women reported that radiation
 reduced the occurrence of second ipsilateral breast cancers from
 16.4% to 7.0% overall. No survival advantage was observed,
 however, since most recurrences could be managed by salvage
 mastectomy.[6,7] Solin et al[8] reported a local failure rate of 19%
 after 12 years of follow-up following local excision plus
 radiation, including 55% with invasive cancer and 45% with
 DCIS. The cause-specific survival was 96% at 12 years.

 Thus, the optimal strategy for local management of DCIS
 remains unclear. The possible benefit of tamoxifen in DCIS
 treated by lumpectomy with or without radiation is being
 evaluated in the ongoing NSABP B-24 study.

 Lobular Carcinoma In Situ

 Lobular carcinoma in situ (LCIS) typically is diagnosed only after
 a biopsy is performed for another suspected breast abnormality.
 Its pattern may be focal but distributed throughout the breast,
 and LCIS is often bilateral. The chance of developing an invasive
 cancer is 25%. LCIS may be either infiltrating lobular or, more
 commonly, infiltrating ductal carcinoma. The management of
 patients with LCIS is controversial, with options ranging from no
 treatment after biopsy except follow-up by both physical
 examination and mammography to bilateral prophylactic
 mastectomies. There is no role for tamoxifen for LCIS.

 Invasive Breast Cancer

 The role of sentinel node biopsy and the identification of patients
 who routinely might not require axillary node dissection are
 unresolved surgical issues for early invasive breast cancer. These
 are discussed elsewhere in this issue.[9] Whether the highly
 specialized technique of selective lymphadenectomy can be
 widely applied by many different surgeons and whether its
 widespread use will impair survival rates achieved with axillary
 dissection remain unclear.

    Radiation Therapy Issues

 Several controversial topics related to indications for radiation
 therapy include its use in low-risk DCIS patients treated by
 lumpectomy, postmastectomy radiation therapy for
 node-positive breast cancer patients, and the timing of radiation
 and chemotherapy in patients who have undergone a partial
 mastectomy for invasive breast cancer. Discussions regarding
 radiation therapy issues are presented elsewhere in this
 issue.[10,11]

    Adjuvant Chemotherapy Issues

 Local therapies for breast cancer (eg, partial mastectomy,
 axillary node dissection and radiation to the remaining portion of
 the breast, modified radical mastectomy) are recognized and
 accepted. A number of chemotherapy issues have yet to be
 resolved, despite more than two decades of clinical trials in the
 modern era of adjuvant chemotherapy for breast cancer. Some
 of these issues include comparisons of cyclophosphamide,
 methotrexate, and fluorouracil (CMF) vs doxorubicin in adjuvant
 therapy and in metastatic disease; drug sequencing; dose
 considerations; and the introduction of promising new agents in
 node-positive patients.

 Based on an overview analysis[12] of 75,000 patients enrolled in
 133 randomized clinical trials, postoperative systemic adjuvant
 therapy for breast cancer suggests that a survival advantage
 occurs in premenopausal patients treated with CMF
 chemotherapy for six months and in postmenopausal women
 treated with tamoxifen for at least two years. CMF provides a
 25% reduction in mortality at 10 years, or 12 additional lives
 saved for every 100 patients treated, and tamoxifen results in a
 20% reduction in mortality, with 10 additional lives saved for
 every 100 patients treated. Oophorectomy is also effective in
 premenopausal patients. These results for node-positive patients
 confirm recommendations from two earlier National Institutes of
 Health Consensus Development Conferences,[13,14] but no
 therapeutic recommendations for node-negative women were
 given in a later conference.[15] This meta-analysis has been
 updated with 15-year results (Table 2).[16] Formal presentations
 of the data indicate an overall annual reduction in mortality risk
 by chemotherapy of 18% ± 3%, including a 27% reduction in
 mortality for node-negative patients and a 14% reduction for
 node-positive patients. Patients 50 years of age or older had an
 11% reduction in mortality, and those who were 70 years of age
 or older had no benefit from chemotherapy. In contrast, women
 50 years of age or older who were estrogen receptor
 (ER)-positive had a 27% ± 5% mortality reduction with
 tamoxifen, and those under age 50 years had a 14% ± 3%
 overall reduction. There is no beneficial effect from tamoxifen in
 estrogen receptor-poor patients of any age, but tamoxifen plus
 chemotherapy leads to an additional 12% reduction in mortality
 for patients with ER-positive tumors. Oophorectomy affords a
 16% ± 5% mortality reduction in women under 50 years of age
 but has no effect in patients who are 50 years of age or older.

 CMF vs Doxorubicin-Based Regimens

 CMF is considered the "gold standard" for adjuvant combination
 chemotherapy, but other familiar combinations may offer similar
 therapeutic benefit, although not all have been compared with an
 untreated control group in prospective, randomized trials. These
 include cyclophosphamide plus doxorubicin (CA),
 cyclophosphamide, doxorubicin, and fluorouracil (CAF), and
 cyclophosphamide, methotrexate, fluorouracil, vincristine, and
 prednisone (CMFVP). CA may be given with or without
 tamoxifen.

 Although CMF is the "gold standard" for premenopausal women
 whose prognostic risk assessment make them candidates for
 chemotherapy, many cooperative group protocols are using
 CAF or CA as the control arm, and many patients not on trial
 are treated with a doxorubicin-based combination. While most
 oncologists would agree that six cycles of CMF are as effective
 as 12 cycles, many issues are unclear. Is a regimen of
 intravenous CMF every three weeks equivalent to the original
 CMF reported by Bonadonna et al[17]? Is cyclophosphamide
 necessary? Is methotrexate plus fluorouracil just as effective? Is
 CAF or CA superior to CMF? Does sequencing of CMF with
 an anthracycline make a difference in long-term outcome, and is
 this a better strategy than using any single combination?

 Published data comparing the efficacy of CMF with
 doxorubicin-based chemotherapy for metastatic disease and as
 adjuvant therapy are inconclusive. While studies often
 demonstrate a more favorable response rate in metastatic
 disease with the anthracycline regimen, it is unclear whether this
 is due to the types (bone/visceral vs soft tissue) and numbers of
 patients studied, the study design (intravenous vs oral
 cyclophosphamide), the number of various drugs and dosages in
 each arm, the length of follow-up, or other factors.[18] In adjuvant
 therapy, most of the same issues apply. The Cancer and
 Leukemia Group B (CALGB) study reported a positive effect
 when doxorubicin was substituted for methotrexate in the
 "Cooper regimen" (CMFVP).[19] A recent report with a 16-year
 median follow-up compared CMF with cyclophosphamide,
 doxorubicin, fluorouracil, and vincristine (CAFV) and showed
 significant overall and disease-free survival with CAFV.[20]
 Unfortunately, this trial does not resolve the question since there
 were several variables between the two arms, including doses of
 cyclophosphamide and fluorouracil, routes of cyclophosphamide
 (intravenously in CAFV and orally in CMF), use of radiotherapy
 in only 55% of the total 249 patients, and unexplained
 differences in outcome related to menopausal status and the
 number of involved nodes. A newer trial with a five-year
 follow-up shows no difference between CMF and CAF if given
 in equitoxic doses.[21]

 Many other adjuvant chemotherapy issues remain unresolved.
 Should chemotherapy be different in node-positive vs
 node-negative women or in premenopausal vs postmenopausal
 women? Can newer agents (eg, the taxanes, vinorelbine,
 platinum, topoisomerase-I inhibitors) replace or be incorporated
 into conventional adjuvant chemotherapy? Many early reports
 suggesting a divergence in the natural history of a particular
 disease subset by a new treatment approach seem to pale with
 longer follow-up as survival curves merge.

 Node-Positive Breast Cancer Patients

 Unresolved issues regarding the management of node-positive
 breast cancer include the identification of better treatment
 programs for premenopausal women, the use of postmenopausal
 chemotherapy, and the role of high-dose strategies for high-risk
 patients, using either bone marrow transplant or peripheral blood
 stem cell support following ablative doses of chemotherapy or
 colony-stimulating factor (CSF) support after dose-intensive
 regimens. Clinical trials addressing these areas are underway to
 assess both efficacy and toxicity, since recent findings have noted
 an increased incidence of endometrial cancer after tamoxifen use
 and acute leukemia or myelodysplasia after high-dose
 cyclophosphamide treatment. One Intergroup trial (INT0101) in
 premenopausal, receptor-positive, node-positive patients is
 comparing CAF chemotherapy alone for six cycles to sequential
 CAF followed by goserelin acetate for five years to sequential
 CAF followed by combined tamoxifen and goserelin acetate for
 five years. Another Intergroup trial (INT0100) in the same type
 of postmenopausal patients is comparing standard adjuvant
 tamoxifen alone for five years to sequential CAF for six cycles
 followed by tamoxifen to concurrent chemoendocrine CAF plus
 tamoxifen for six cycles, then tamoxifen to a total of five years.
 Thus, the control arms are CAF chemotherapy for the
 premenopausal trial and tamoxifen for the postmenopausal trial,
 but both studies involve patients who are ER-positive. A trial
 (S9313) for patients with up to three positive nodes is evaluating
 CA in high doses given together or sequentially. Doxorubicin
 sequence may be an important determinant of outcome. As
 noted recently,[22] four cycles of doxorubicin preceding eight
 cycles of CMF was more effective than alternating CMF for two
 cycles and doxorubicin for one cycle for 12 courses.

 New Agents

 New chemotherapeutic agents are now available for breast
 cancer treatment. The most mature of these are the taxanes,
 paclitaxel and docetaxel, but vinorelbine and the camptothecans,
 topotecan and irinotecan, also have activity in metastatic breast
 cancer. The taxanes have shown impressive single-agent activity
 in treating metastatic disease, as first-line chemotherapy as well
 as in patients previously treated with an anthracycline.[23]
 Paclitaxel is being evaluated as a sequential treatment in a trial
 (C9344) for node-positive patients who are receiving CA, with
 doxorubicin given at either standard or dose-escalated levels.
 Gianni et al[24] reported that the combination of 125 to 200
 mg/m2 of paclitaxel given over three hours with 60 mg/m2 of
 doxorubicin as first-line chemotherapy for metastatic breast
 cancer achieves response rates as high as 94%, including a
 complete response rate of 40%, but is associated with
 congestive heart failure in 24% of patients receiving more than
 360 mg/m2 of cumulative doxorubicin. The latter issue precludes
 wide acceptance of this dosage schedule in the adjuvant setting
 for most subsets of patients, but other similarly effective dosage
 schedules might not have this toxicity profile. Trials are being
 conducted that use different schedules, limit the total dose of
 doxorubicin, add a cardioprotectant such as dexrazoxane, and
 use different drugs such as cisplatin. Results of an Eastern
 Cooperative Oncology Group trial (EST 1193) will soon be
 reported that involves 739 patients with metastatic breast cancer.
 This trial compares three regimens: (1) eight cycles of 60 mg/m2
 of doxorubicin, (2) eight cycles of 175 mg/m2 of single-agent
 paclitaxel given over 24 hours, and (3) the combination of eight
 cycles of 50 mg/m2 of doxorubicin plus 150 mg/m2 of paclitaxel
 per 24 hours plus G-CSF on days 3 through 12 for
 hematopoietic support. The relative response rates, toxicities,
 and survival results are critical issues to be scrutinized in
 assessing the potential role of paclitaxel in earlier disease.

 Dose Delivery and Effects

 Dose schedule is an unresolved issue with paclitaxel. The
 NSABP B-26 protocol is studying the issue of three-hour vs
 24-hour administration of paclitaxel in metastatic breast cancer.
 No comparative trials in breast cancer have been reported that
 address the remaining questions concerning other dosage
 schedules. The dose of paclitaxel presents another issue, since
 early reports suggest a dose-response effect. CALGB trial
 C9342 is evaluating paclitaxel dosages in 300 patients who will
 receive 175 mg/m2, 210 mg/m2, and 250 mg/m2, all given over
 three hours, but results have not yet been reported. The NSABP
 plans a sequential CA-to-paclitaxel study as well as a
 preoperative or postoperative docetaxel trial following
 preoperative CA.

 The delivery of effective doses is an important issue in therapy
 and may effect overall outcome. Arbitrary dose reduction may
 result in poorer outcomes,[25] and retrospective analyses suggest
 that increasing dose intensity improves response rates in
 metastatic breast cancer and freedom from relapse in stage II
 patients.[26] Despite these findings, issues regarding the role of
 high-dose therapy in both metastatic breast cancer and in treating
 patients with a high risk of recurrence remain unresolved.[27] The
 number of women who have received bone marrow or
 peripheral blood stem cell transplants as treatment for breast
 cancer has risen significantly over the last five years.
 Approximately 2,000 patients with breast cancer are treated
 annually with high-dose regimens, according to a national
 Transplant Registry.[28] Two national trials currently underway
 restrict entry to women with 10 or more positive nodes, and
 another protocol for women with four to nine nodes has just
 begun. A retrospective comparison between results from
 transplantation and chemotherapy suggests benefit from this
 high-dose approach but, to date, no data have been derived in a
 prospective, randomized fashion to clarify which, if any, breast
 cancer patients will benefit most from this procedure.

 Various selection factors -- such as age, performance status,
 organ function, exclusion criteria, and prior response to treatment
 -- can influence outcomes and can lead to erroneous conclusions
 regarding the relative merits of two treatments when not
 compared prospectively.[29] Even premenopausal women with
 good performance status and ER-positive first-recurrence stage
 IV disease survive an average of five years when treated with
 CAF and oophorectomy.[30] Thus, a comparison of conventional
 adjuvant chemotherapy vs high-dose chemotherapy and
 autologous bone marrow or peripheral blood stem cell
 transplantation as adjuvant intensification therapy following
 conventional adjuvant chemotherapy, as in the national trial
 (INT0121), is justified. This complements an earlier trial
 (C9082) in which high-dose cyclophosphamide, platinum,
 1,3-bis(2-Chlorethyl)-1-nitrosourea (BCNU), and autologous
 bone marrow transplantation is compared with standard doses of
 the same agents as consolidation to adjuvant CAF. A recent
 randomized trial[31] of 90 South African patients compared bone
 marrow transplantation to "conventional" chemotherapy for
 metastatic disease and suggested a benefit from transplantation.
 The interpretation of the trial is clouded, however, by the small
 number of patients studied, the use of an atypical "standard"
 chemotherapy arm (cyclophosphamide, mitoxantrone, and
 vincristine), and the use of tamoxifen in responding patients.
 More confusion regarding the role of high-dose therapy in
 metastatic breast cancer resulted following an analysis of 423
 patients that compared immediate vs delayed high-dose
 chemotherapy after conventional chemotherapy with
 doxorubicin, fluorouracil, and methotrexate. The results showed
 a benefit in disease-free survival with immediate high-dose
 therapy but, paradoxically, an overall survival benefit from
 delayed high-dose consolidation with combination alkylating
 agents and autologous cellular support.[32]

 Node-Negative Breast Cancer Patients

 The routine use of adjuvant chemotherapy in all node-negative
 breast cancer patients remains controversial. Since it became
 known that a significant number of patients with node-negative
 breast cancer have disease recurrence, several prospective,
 randomized trials were designed to evaluate adjuvant
 chemotherapy in node-negative breast cancer. The first, which
 was organized by the Eastern Cooperative Oncology Group
 (EST1180), studied CMF with prednisone (CMFP) for six
 cycles in patients whose primary tumor was either ER-negative
 or greater than 3 cm.[33] The second trial was conducted by the
 NSABP for ER-negative patients using methotrexate and
 fluorouracil with leucovorin rescue.[34] A third trial, the European
 perioperative adjuvant trial, using CMFP was reported by the
 Ludwig Breast Cancer Study Group.[35] All three trials
 demonstrated improvement in disease-free survival after five
 years of follow-up. In the NSABP study, premenopausal and
 postmenopausal patients benefited. An improvement in survival
 was seen at five years in the subset of postmenopausal
 ER-negative women treated with CMFP, and an overall survival
 benefit was seen at eight years in those women treated with
 CMFP. An additional five to 10 years of follow-up will be
 required to evaluate fully the long-term impact of these trials.
 CMFP and nonalkylating-agent chemotherapy using only
 methotrexate and fluorouracil confer a benefit in disease-free
 survival only for node-negative, ER-negative premenopausal
 patients, whereas tamoxifen does the same and may provide a
 survival advantage for node-negative, ER-positive
 postmenopausal women.

 Most would agree that women with poor prognostic features
 (eg, tumor size greater than 2 cm, high nuclear grade, tumor
 necrosis) are reasonable candidates for adjuvant chemotherapy.
 Those women expressing high levels of HER-2/neu might even
 require high-dose chemotherapy.[36] However, those with more
 favorable prognostic features (eg, tumor size less than 1 cm,
 diploid tumors, an S-phase fraction less than 10%) probably
 would not benefit from adjuvant chemotherapy since their overall
 prognosis is excellent. Conversely, for ER-positive,
 node-negative premenopausal breast cancer patients, adjuvant
 tamoxifen may be as useful as chemotherapy if they have good
 prognostic factors. ER status is not a good discriminant in
 node-negative patients, however, since the difference in
 disease-free survival between ER-positive and ER-negative
 patients at 10 years is only approximately 5%. Primary tumor
 size may be the most important factor in both ER-positive and
 -negative women, as noted in NSABP B-13 and B-14
 node-negative trials. Flow cytometry or image analysis for
 determining diploid or aneuploid pattern and proportion of
 S-phase fraction or molecular markers (eg, epidermal growth
 factor receptor, HER-2/neu oncogene expression, p53 tumor
 suppressor gene expression) may offer potential in the future for
 identifying high-risk node-negative patients who would benefit
 from adjuvant therapy, but presently their use remains promising
 at best. Progesterone receptor is most helpful in node-positive
 patients. Thus, unresolved issues about adjuvant therapy for
 node-negative women with invasive breast cancer range from the
 selection of low-risk women who will not benefit from any
 systemic postoperative treatment (as suggested by Rosner and
 Lane[37]) to identification of node-negative patients with
 unfavorable prognostic features that indicate a higher risk of
 relapse, where more aggressive adjuvant chemotherapy might be
 indicated.

    Hormonal Therapy Issues

 Early results from a trial by the Nolvadex Adjuvant Trial
 Organization[38] in early breast cancer suggested a benefit from
 postoperative tamoxifen irrespective of nodal, menopausal, or
 ER status. Subsequently, the Scottish Trial[39] using five years of
 postoperative adjuvant tamoxifen suggested improved
 disease-free and overall survival benefit in node-negative patients
 treated with tamoxifen. The NSABP B-14 trial[40] in
 node-negative, ER-positive patients showed benefit in delaying
 treatment failure at five years in both premenopausal and
 postmenopausal patients. A meta-analysis by the Early Breast
 Cancer Trialists' Collaborative Group of premenopausal and
 postmenopausal women with stage I or II carcinoma supports
 the benefit of tamoxifen at 20 mg daily for at least two years or
 perhaps longer.[41] Recent evidence suggests that ER-negative
 women benefit little from tamoxifen. In addition, there is a
 decreased incidence of contralateral breast cancer and
 cardiovascular mortality in women treated with tamoxifen.
 Unresolved issues regarding hormonal therapy include treatment
 of node-negative patients, the duration of tamoxifen treatment,
 ovarian ablation, and chemoendocrine therapy.

 Additional unresolved issues in node-negative patients are the
 use of tamoxifen alone in premenopausal women, the role of
 surgical or medical castration alone or in combination with
 tamoxifen or chemotherapy, and the use of doxorubicin-based
 adjuvant chemotherapy regimens alone or with tamoxifen.
 Clinical trials evaluating these issues are currently underway. One
 Intergroup trial (INT0142) in premenopausal, node-negative,
 receptor-positive patients with a tumor size no greater than 3 cm
 is comparing tamoxifen alone for five years to tamoxifen plus
 ovarian ablation with monthly goserelin acetate with respect to
 outcome, menopausal and sexual issues, and quality of life. While
 this trial is designed to answer important therapeutic and
 quality-of-life issues, accrual to date has been poor.

 Tamoxifen Duration

 The duration of tamoxifen therapy remains an unresolved issue
 since the drug is widely used. Data from the NSABP B-14
 trial[42] involving 2,644 node-negative women showed no benefit
 from an additional five years of treatment, after patients had
 taken tamoxifen for five years. Two cohorts of patients were
 studied -- those prospectively randomized to receive either five
 or 10 years of tamoxifen, and those registered and eligible by
 having taken five years of tamoxifen who were randomized to
 five additional years or observation. Based on the results noted,
 the Data Safety Monitoring Committee recommended
 discontinuing adjuvant tamoxifen after five years. After a
 National Cancer Institute Clinical Alert publicizing this
 recommendation, opinions have ranged from full support of this
 recommendation to suggestions that it is premature to stop
 tamoxifen after five years based on the data presently available.
 This recommendation has inherently been extended to
 node-positive patients without adequate data to indicate benefit,
 no benefit, or even harm. A recent trial[43] suggested event-free
 and overall survival benefit in both node-negative and
 node-positive postmenopausal patients after six to eight years of
 follow-up who were treated with tamoxifen for five years
 compared with those treated for two years. Experimental work
 suggests that tamoxifen affects both cell proliferation and
 apoptosis and, with prolonged use (ie, greater than five years),
 resistance may develop or tamoxifen may actually stimulate
 tumor growth, but current clinical evidence suggesting a
 detrimental effect from prolonged tamoxifen is meager. An
 analysis[44] of two Eastern Cooperative Oncology Group trials in
 node-positive women -- EST 5181 for premenopausal patients
 and EST 4181 for postmenopausal patients -- both with a
 median follow-up in excess of 10 years, show benefit in patients
 randomly allocated to tamoxifen for five or more years following
 initial treatment with chemotherapy plus tamoxifen for 12 months.
 Two present large-scale trials, the worldwide ATLAS (Adjuvant
 Tamoxifen Long Against Short) involving 20,000 women and the
 United Kingdom's aTTom trial randomizing breast cancer
 patients to discontinue or continue more tamoxifen, hope to
 provide sufficient power to answer definitively the question of
 optimal tamoxifen duration.[45,46]

 Ovarian Ablation

 The role of ovarian ablation in premenopausal ER-positive
 patients needs clarification. Ovarian ablation in women under the
 age of 50 years produces a survival benefit comparable to that
 seen with adjuvant chemotherapy in premenopausal women,
 which raises the issue of the endocrine-related effects of
 chemotherapy vs cytotoxic effects as well as the possibility that
 both modalities might have additive effects. An additive effect of
 tamoxifen and cytotoxic chemotherapy in postmenopausal
 women also has been postulated.

 Combined Chemoendocrine Therapy

 The use of combined chemoendocrine adjuvant therapy for
 breast cancer has been tested since the mid-1970s, but the
 optimal use of these modalities is still unresolved. Inconclusive
 and sometimes contradictory results have been noted in many
 reports of controlled trials using chemotherapy with concurrent
 or prolonged tamoxifen. The latest meta-analysis suggests a 12%
 benefit with combined treatment, but most individual
 node-positive trials have not reported an overall long-term
 survival advantage.[41] The Eastern Cooperative Oncology
 Group has not seen improved overall survival with CMFP plus
 tamoxifen given concurrently for 12 months in either
 premenopausal or postmenopausal node-positive patients. The
 NSABP B-16 trial reported a survival benefit in node-positive
 patients using doxorubicin plus tamoxifen compared to tamoxifen
 alone but with follow-up of only 3.4 years.[47] Two recent
 trials[48,49] using epirubicin-based combinations plus tamoxifen
 suggest an advantage with combined chemoendocrine therapy
 but show no significant overall survival benefit after three and one
 half and six years of follow-up. No survival advantage was noted
 in a recent neoadjuvant trial of chemoendocrine therapy in
 operable breast cancer, despite a clinical response rate of 83%
 but a pathologic complete response rate of only 11%.[50]

    Management of the Elderly

 Breast cancer in the elderly is a complex issue with unique
 features that extend beyond the individual characteristics of the
 cancer itself. Age alone impacts considerably on screening
 practices, diagnostic testing, and treatment patterns of many
 older cancer patients, including women with breast cancer.
 Compared with younger women, fewer older women have
 screening mammograms, have thorough diagnostic testing once a
 cancer is detected, or receive postoperative breast radiation
 following partial mastectomy. While conventional therapies are
 similarly effective for older women who are diagnosed with
 breast cancer, a number of unresolved issues remain, including
 surgical management of the axilla, the need for postoperative
 radiation following partial mastectomy, and the use of systemic
 chemotherapy and newer hormone therapies.

 While mastectomy for the older woman presents few issues, use
 of a more conservative procedure is associated with a number of
 issues. Traditionally, postoperative radiation is mandated as an
 adjunctive component to optimize local tumor control in the
 remaining breast and surrounding tissues, unless disabling
 comorbidities preclude an expected survival of reasonable
 length. Results with conservative surgery and radiation are
 equivalent to more extensive surgery in patients with local
 disease, including the elderly. However, the need for axillary
 dissection and postoperative radiation in all older women is being
 questioned. The requirement for radiation therapy is being
 studied in a randomized trial in which all patients will receive
 tamoxifen following lumpectomy if they are 70 years of age or
 older and have a primary tumor no greater than 3 cm with clear
 surgical margins and clinically negative axillary and
 supraclavicular nodes. Thus, the surgical issue of eliminating
 axillary dissection in some older patients, and the need for
 postoperative radiation in all older women with operable breast
 cancer treated conservatively, remain unresolved questions for
 some physicians.

 Systemic adjuvant therapy for elderly women with node-positive
 breast cancer is relatively straightforward since tamoxifen is
 clearly beneficial, reduces the number of contralateral breast
 cancers, and is well tolerated.[51] Issues on the quality of life of
 older patients are not well characterized in formal clinical trials,
 but the extended symptom-free time afforded tamoxifen-treated
 patients allows high-quality life and independence. Tamoxifen is
 the systemic treatment of choice for any elderly women with
 breast cancer. Toremifene has recently become available in the
 United States for adjuvant use as well. The use of purer
 antiestrogens such as droloxifene and raloxifene and aromatase
 inhibitors such as anastrozole, letrozole, and vorozole are being
 studied in metastatic disease and, if effective and tolerable, may
 have a place in the adjuvant therapy of breast cancer in the
 future, either alone or in combination with tamoxifen. These new
 hormones and other novel compounds potentially applicable to
 older patients are presented in Table 3.

 Chemotherapy for all older postmenopausal patients is
 controversial, despite the activity of CMF in older patients with
 metastatic disease. In such patients, CMF is equivalent but not
 superior to tamoxifen, provided that dose adjustments are made
 to accommodate the decline in renal function that accompanies
 aging. Chemotherapy represents another treatment option for the
 elderly who fail tamoxifen or other treatments. Additional agents
 that can be administered safely to the elderly are needed, as are
 clinical trials exploring biologic conjugates, inhibitors of
 angiogenesis, matrix metalloproteinase inhibitors, and other
 growth inhibitory compounds.


--
MZ�


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