CMAJ/JAMC Special supplement
Supplément spécial

 

Clinical practice guidelines for the care and treatment of breast cancer

8. Adjuvant systemic therapy for women with node-positive breast cancer

The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer:

This guideline has been peer reviewed.

This guideline has been superseded by a revised version issued Mar. 6, 2001. Copies previously printed or downloaded should be destroyed.

Abstract

Objective: To facilitate the choice of systemic adjuvant therapy for women with node-positive breast cancer.

Evidence: Systematic review, using MEDLINE from 1976 and CANCERLIT from 1983 to December 1996. Nonsystematic review continued through June 1997.

Recommendations:

  • Chemotherapy should be offered to all premenopausal women with stage II breast cancer.
  • Acceptable treatments regimens are those using cyclophosphamide, methotrexate and 5-fluorouracil (CMF) or doxorubicin (Adriamycin) and cyclophosphamide (AC). Cyclophosphamide, epirubicin and 5-fluorouracil (CEF) may be shown in the future to result in better disease-free survival than CMF. Personal choice, quality of life and costs also influence this choice.
  • Systemic adjuvant chemotherapy should begin as soon as possible after the surgical incision has healed.
  • The recommended duration of therapy is at least 6 cycles (6 months) for CMF or CEF, and at least 4 cycles (2 to 3 months) for AC.
  • The recommended CMF regimen consists of 14 days of oral cyclophosphamide with intravenous methotrexate and 5 fluorouracil (5-FU) on days 1 and 8. This is repeated every 28 days for 6 cycles.
  • Potential toxic effects should be fully discussed with patients.
  • When possible, patients should receive the full standard dosage. No recommendations about high-dose chemotherapy can yet be made.
  • Ovarian ablation is effective in premenopausal women with estrogen receptor-positive tumours. However, chemotherapy has been better studied and is considered the intervention of choice. Ovarian ablation should be recommended to women who decline chemotherapy.
  • In the future, a small benefit may be shown for the combination of ovarian ablation plus chemotherapy in women with node-positive, estrogen receptor-positive cancers. At present there is insufficient evidence for this to be recommended.
  • Tamoxifen should not be recommended as the sole treatment for premenopausal women with node-positive tumours.
  • Routine use of tamoxifen after chemotherapy in premenopausal women cannot yet be recommended.
  • Before recommending hormonal therapy in premenopausal women, both the long-term side effects and its effects on recurrence must be considered.
  • Postmenopausal women with stage II, estrogen receptor-positive cancer should be offered adjuvant tamoxifen.
  • The recommended duration of tamoxifen therapy is 5 years.
  • No other hormonal intervention apart from tamoxifen can be recommended for postmenopausal patients.
  • Women with estrogen receptor-negative tumours who are fit to receive chemotherapy (generally younger than 70 years) should be offered CMF or AC. There is no proof that tamoxifen adds any benefit to chemotherapy. Tamoxifen alone may be of value.
  • Women with estrogen receptor-positive tumours may gain a small additional benefit from taking chemotherapy in addition to tamoxifen. This is an option for a motivated, well-informed patient.
  • Patients should be offered the opportunity to participate in clinical trials whenever possible.

Validation: The authors' original text was revised by a writing committee, primary and secondary reviewers, and by The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. The final document reflects a consensus of all these contributors.

Sponsor: The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer was convened by Health Canada.

Completion date: July 1, 1997

Approximately 50% of patients with palpable breast cancer will prove to have axillary lymph-node involvement at surgery (pathologic stage II).1 These women are at high risk of subsequent systemic relapse and death from metastatic breast cancer, even though investigations done at the time of diagnosis, such as routine blood counts, liver function tests and chest radiographic examinations, may reveal no evidence of cancer.

Before the advent of adjuvant systemic therapy, the 10-year survival for patients with axillary lymph-node involvement ranged from 25% to 48%.2-6 Patients with 1 to 3 positive nodes had a 10-year survival of approximately 40% to 60%, and patients who had 4 or more involved lymph nodes had a 10-year survival of approximately 25%.3-6

Intervention with anticancer chemotherapy or hormonal therapy has been studied extensively over the past 20 years. Adjuvant systemic therapy with the use of multidrug chemotherapy or hormone therapy has been shown to prolong disease-free and overall survival in patients with stage II breast cancer, both in randomized clinical trials7-15 and in population-based studies.16 However, many women still succumb to progressive breast cancer, and there are many unanswered questions about how best to plan optimal adjuvant systemic treatment at acceptable levels of toxicity.

Recommendations for pre- and postmenopausal women are grouped separately. Premenopausal women are defined as all women whose last menstrual period was within 12 months before the diagnosis of breast cancer. Also, age less than 50 years has been used as a surrogate for premenopausal status.11 "Adjuvant systemic therapy" refers to the use of cytotoxic drugs (chemotherapy), endocrine manipulation by ovarian ablation or use of drugs such as tamoxifen (hormonal therapy).

Method

The authors conducted a systematic review of the published literature using MEDLINE between 1976 and Dec. 31, 1982, and both MEDLINE and CANCERLIT for the years 1983 to December 1996. The terms used were: breast neoplasms, invasive breast adenocarcinoma, adjuvant, chemotherapy, hormonal therapy, premenopausal node-positive and postmenopausal node-positive, randomized studies, and high doses. The search was restricted to English language articles. Additional articles were identified by reviewing references in retrieved reports. Nonsystematic review of the literature was continued through June 1997. The quality of the evidence on which conclusions are based is categorized into 5 levels.

The draft guideline document was iteratively reviewed and revised as follows: by a writing committee consisting of 5 members of the Steering Committee, by 3 expert external reviewers, and by 11 secondary reviewers selected from across Canada consisting of family physicians, nurses, breast cancer survivors, medical and radiologic oncologists and surgeons with expertise in breast cancer. After further revision, final approval was given by all members of the Steering Committee. The guidelines reflect a consensus of all these contributors.

Recommendations (Table 17,17)

The following information and recommendations are presented in 4 sections:

  1. chemotherapy for premenopausal women,
  2. adjuvant endocrine therapy for premenopausal women,
  3. adjuvant hormonal therapy for postmenopausal women, and
  4. chemotherapy or chemotherapy plus tamoxifen for postmenopausal women.

Adjuvant chemotherapy for premenopausal women

  • Chemotherapy should be offered to all premenopausal women with stage II breast cancer.

Chemotherapy has been shown to prolong recurrence-free and overall survival in premenopausal patients with stage II breast cancer, both in randomized clinical trials (level I evidence)7-15 and in population-based studies (level III evidence).16 The benefits of treatment vary according to age, estrogen receptor (ER) status, tumour size and the number of involved nodes. The Early Breast Cancer Trialists' Collaborative Group overview of 133 randomized trials involving 75 000 women constitutes level I evidence for several interventions.11 From this analysis, it can be estimated that in patients of all ages, polychemotherapy that is taken for at least 1 month (usually up to 1 year) can be expected to result in an absolute improvement in 10-year survival of 6.8% (SD 1.6%) in patients with node-positive cancer. The major benefits can be expected during the first 5 years of follow-up. For premenopausal women under the age of 50 years, the crude death rate was reduced from 37% to 31%.11

A proportional reduction in risk applies uniformly to patients with varying risk factors. However, the absolute risk and absolute benefit increase with the extent of lymph-node involvement since with increasing involvement more patients are at risk and a greater number stand to benefit from systemic therapy.

The subanalyses of patients given chemotherapy indicated that prolonged polychemotherapy, usually with cyclophosphamide, methotrexate and 5-fluorouracil (5-FU) (CMF), was more effective than brief pre- or perioperative chemotherapy. The data in the overview did not answer the question of whether prolonged chemotherapy should begin before or after surgery.

Prolonged polychemotherapy was, in general, better than prolonged single-agent therapy. Reassuringly, prolonged polychemotherapy for 12 to 24 months did not prove superior to shorter regimens, such as a 6-month course of CMF or a 3-month course of doxorubicin (Adriamycin) and cyclophosphamide (AC).

In addition to influencing survival, there is level III evidence based on a retrospective case review that chemotherapy may also significantly reduce the rate of local recurrence in patients who have undergone breast-conserving surgery followed by radiotherapy.18

  • Acceptable treatments regimens are those using cyclophosphamide, methotrexate and 5-fluorouracil (CMF) or doxorubicin (Adriamycin) and cyclophosphamide (AC). Cyclophosphamide, epirubicin and 5-fluorouracil (CEF) may result in better disease-free survival than CMF. Personal choice, quality of life and costs also influence this choice.

Most patients in the overview analysis were treated with CMF.11 A variety of CMF variants were reported, including both oral and intravenous cyclophosphamide regimens. In general, most of the regimens lasted 12 months, since these were early studies carried out before 1985. Studies that have reported on the use of CMF together with a variety of other drugs including doxorubicin have not shown any consistent evidence of additive benefit.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-11 study compared melphalan (phenylalanine mustard) and 5-FU (PF) to melphalan, doxorubicin and 5-FU (PAF) in patients under 50 years of age and those aged 50 to 59 years with negative progesterone receptors. This study reported a significant recurrence-free and overall survival benefit at 6 years in those taking PAF.19 A French trial compared patients taking CMF with those taking cyclophosphamide, Adriamycin, 5-FU and vincristine (CAFV). After an average follow-up of 15 years, subset analysis indicated that premenopausal, node-positive patients in the CAFV arm showed improved overall survival (73%) compared with those in the CMF group (58%, p = 0.0025) and improved disease-free survival (73% for the CAFV patients versus 58% for the CMF group, p = 0.002).20

The recent National Cancer Institute of Canada comparison of CEF (cyclophosphamide, epirubicin and 5-FU) compared with oral CMF has yielded encouraging evidence of improved event-free survival with CEF. Although these results are categorized as level I evidence, the data are still relatively new, and this is a single trial.21 It is possible that ongoing but still unpublished analysis may also reveal improved overall survival.

In contrast, the NSABP B-12 study comparing melphalan, 5-FU and tamoxifen (PFT) with PAF plus tamoxifen (PAFT) in patients over 50 years of age with positive progesterone receptors found no differences in outcome (level II evidence).19 Also, a Milan study comparing CMF for 12 cycles with CMF for 8 cycles followed by doxorubicin for 4 cycles did not detect any differences (level II evidence).22

The NSABP B-15 study compared the effectiveness of 3 regimens in patients under 50 years old and those aged 50 to 59 years with progesterone receptor-negative tumours: (a) 4 cycles of AC administered every 3 weeks for 2 to 3 months; (b) 6 cycles of CMF; and (c) 4 cycles of AC, followed (after a 6-month rest period) by 6 cycles of CMF.17 No difference in outcome was detectable at 3 years, demonstrating that a 2- to 3-month course of AC is equivalent to a 6-month course of oral CMF (level I evidence).

  • Systemic adjuvant chemotherapy should begin as soon as possible after the surgical incision has healed.

Although there are no studies evaluating the effect of a delay in initiating combination chemotherapy, current practice is guided by the presumption that a prolonged delay is not in the best interests of the patient (level IV evidence). Most clinical trials have insisted on the initiation of therapy before 12 weeks. In practice, most women begin treatment 4 to 6 weeks after their surgery. For patients who are candidates for radiotherapy, the optimal sequencing of chemotherapy and irradiation has not been defined. Most centres administer chemotherapy first. Some administer both concurrently, but this may increase the chance of toxic effects, especially when an anthracycline-containing regimen is used (level III evidence). This issue is considered in guideline 6.

  • The recommended duration of therapy is at least 6 cycles (6 months) for CMF or CEF, and at least 4 cycles (2 to 3 months) for AC.

CMF regimens of 6 months' duration are as effective as longer regimens of 12 to 24 months (level I evidence). The NSABP B-15 study demonstrated 4 cycles of intravenous AC at 3-weekly intervals is equivalent to 6 cycles of oral CMF given at 4-weekly intervals (level I evidence).17

An early study from the Dana-Farber Cancer Clinic that compared 5 cycles of AC (15 weeks) to 10 cycles of AC (30 weeks) in patients with node-positive breast cancer did not detect any differences at 9 years.23 Also, the Milan groups have reported no difference in outcome between 6 or 12 courses of CMF.24 The Eastern Cooperative Oncology Group compared 4 months of CMF plus prednisone and tamoxifen (CMFPT) to 12 months of the same chemotherapy in postmenopausal patients and found no difference. However, this last result may be attributable to the lack of much benefit from CMF in postmenopausal patients who also receive adjuvant tamoxifen. In contrast, the Ontario Clinical Oncology Group compared a 12-week regimen of CMF plus vincristine and prednisone (CMFVP) plus doxorubicin and concurrent tamoxifen with a 36-week regimen of CMFVP in node-positive patients, and reported increased relapse-free and overall survival in patients taking the longer-duration treatment.25 Although this is classified as level I evidence, both the duration of therapy and the chemotherapy regimens differed, making it difficult to determine which factor influenced the outcome.

  • The recommended CMF regimen consists of 14 days of oral cyclophosphamide with intravenous methotrexate and 5-fluorouracil (5-FU) on days 1 and 8. This is repeated every 28 days for 6 cycles.

There has been no randomized comparison between intravenously and orally administered cyclophosphamide when used as adjuvant therapy. A European study (EORTC) that compared these regimens in patients with metastases demonstrated a higher response rate, better duration of response and longer survival in those receiving oral rather than intravenous CMF (level II evidence).26 It should be noted, however, that the oral regimen was more dose-intensive.

  • Potential toxic effects should be fully discussed with patients.

A major factor in the choice between these regimens is the patient's quality of life and satisfaction with the treatment. Some fatigue is common with all chemotherapy regimens. Patients may prefer to take the brief, 3-month AC regimens rather than the 6-month CMF program with the aim of reducing disruption of their normal working and family lives and having a briefer side effects.

CMF frequently causes mild to moderate nausea and vomiting.27 These symptoms are usually transient and can be effectively controlled with medication. With respect to oral CMF, chemotherapy is administered for 84 days over a 6-month period, so nausea may be more protracted. Four cycles of intravenous AC (1 every 3 weeks) may cause more severe but briefer nausea and vomiting.

AC and CEF cause complete but temporary hair loss; oral CMF causes some hair loss in 70% of patients and severe loss in 40%. Each of these regimens may cause mild, transient irritation of the mucous membranes of the mouth, throat and eyes and, rarely, chemical cystitis.28

All regimens cause transient myelosuppression, and there is an increased risk of infection, which, fortunately, is uncommon.27 Fatal toxicity in the Early Breast Cancer Trialists' reports varied from 0.1% to 1.0%.11 Anthracycline-containing chemotherapy is limited by severe dose-related cardiotoxicity. With doxorubicin, toxicity presenting as heart failure is uncommon (± 1%) when the total cumulative dose is kept below 300 mg/m2.29,30 The frequency of toxicity increases with increasing dose and age of the patient. Epirubicin likewise causes heart failure at higher doses but only very rarely at cumulative doses below 1000 mg/m2.31 Cardiac damage, when it occurs, is not rapidly reversible.32 Ovarian failure causing an early menopause is common, especially in older premenopausal patients. Weight gain during treatment may occur in 14% of patients on CMF regimens.28 Follow-up of patients on standard CMF regimens has not revealed a significant increase in drug-induced neoplasms.33,34 However, a worrisome incidence of acute nonlymphocytic leukemia has been reported after use of combinations of anthracyclines and alkylating agents.21,35

  • When possible, patients should receive the full standard dosage. No recommendations about high-dose chemotherapy can yet be made.

No randomized studies of high-dose chemotherapy supported by autologous bone marrow transplantation, peripheral blood stem cell support or colony stimulating factors have yet been completed. Although there are some phase 1 studies suggesting that very high-dose chemotherapy with stem cell support may be beneficial, the treatments have been in selected patients and the numbers are small.19,36-39 Evidence of benefit for the higher-dose regimens is not yet strong enough to recommend this approach as standard therapy. Data from phase 2 studies in patients with metastases have not yet demonstrated superior outcomes compared with conventional chemotherapy.40

Dose intensity has been addressed in a trial by the Cancer and Leukemia Group B (CALGB), involving 1572 women, half of whom were premenopausal.41 This trial compared 3 different dose regimens of 4 to 6 courses of CAF. It showed that the moderate- and high-dose regimens were more effective than the low-dose regimen, but also that there was no difference between the 2 higher doses (level I evidence). However, even the highest dose regimen in this study is comparable to conventional CAF chemotherapy and does not, in fact, represent a true "high-dose" regimen. This study suggests, therefore, that there is a threshold dose effect, below which chemotherapy is less effective and above which no further benefit is obtained. The results should be interpreted as indicating that, when possible, patients should receive the full dosage of their standard regimen since there may be some erosion of benefit at lower doses. The study should not be interpreted to indicate that a higher dose intensity will necessarily convey an additional benefit.

This is consistent with the findings reported by Bonadonna and Valagussa in 1981.42 In this landmark study, 20 years of follow-up of 386 women (half of whom were premenopausal) who received oral CMF showed that only those who received at least 85% of the planned dose benefited from adjuvant chemotherapy (level I evidence). These data tend to support delivery of full doses, when possible.

Adjuvant endocrine treatment for premenopausal women

  • Ovarian ablation is effective in premenopausal women with estrogen receptor-positive tumours. However, chemotherapy has been better studied and is considered the intervention of choice. Ovarian ablation should be recommended to women who decline chemotherapy.

Review of clinical trials provides evidence for the efficacy of ovarian ablation in preventing recurrence and premature death in premenopausal patients with early, node-positive breast cancer (level I evidence). Ovarian ablation (either by surgery or radiotherapy) in premenopausal, node-positive patients has been used as adjuvant therapy for over 30 years. Its benefit has been demonstrated in the Early Breast Cancer Trialists' Collaborative Group overview analysis.11 The most recent overview analysis included a properly randomized trial comparing ovarian ablation to no ovarian ablation in the absence of chemotherapy in 696 node-positive women. It found that those receiving ovarian ablation had an absolute reduction of recurrence at 15 years of 13.4% (SD 3.8%) and a reduction in deaths of 12.5% (SD 3.9%) (level I evidence).43

Four trials comparing ovarian ablation to no oblation were not included in the overview.44-47 The Christie and Malmo trials randomized patients by date of birth. The Christie trial included 403 patients with positive nodes. Although distant spread was significantly reduced at 15 years in the group receiving ovarian ablation (p < 0.05), survival was not significantly prolonged (level I evidence, but note quasirandomization).44 The smaller Malmo study showed no difference in recurrence or survival between the groups, even in the premenopausal, node-positive subgroup (level II evidence).45 The 2 other trials were excluded because recent follow-up information could not be obtained.46,47

In comparison with this evidence of the efficacy of ovarian ablation, the benefits of combination cytotoxic chemotherapy have been evaluated in larger numbers of patients and have been more amply demonstrated.48 At present, chemotherapy remains the standard of care for premenopausal patients with positive nodes.

Apart from permanent castration with surgery or radiation, temporary ovarian ablation can be achieved with luteinizing hormone releasing hormone (LHRH) agonists. LHRH agonists have theoretic appeal in that the endocrine intervention is finite and reversible, and the long-term morbidity of permanent ovarian dysfunction is avoided. Goserelin has been shown to have a response rate similar to that of oophorectomy in premenopausal women with metastatic breast cancer.49 However, no randomized trials of medical castration versus chemotherapy in patients early breast cancer have yet been published.

Thus, although the efficacy of ovarian ablation has been established in premenopausal patients with early, node-positive breast cancer, definitive evidence of its superiority over CMF chemotherapy is lacking. For patients who are ER positive and who refuse chemotherapy, a hormonal intervention should be offered, either ovarian ablation or tamoxifen. In a randomized trial, no significant difference between the outcomes of these interventions was found. However, the trial was not of sufficient size to definitely establish their equivalence (level II evidence).50 At present, medical castration with LHRH agonists should not be recommended outside of a clinical trial.

  • In the future, a small benefit may be shown for the combination of ovarian ablation plus chemotherapy in women with node-positive, estrogen receptor-positive cancers. At present there is insufficient evidence for this to be recommended.

There is suggestive evidence that the addition of ovarian ablation to chemotherapy may confer added benefit. In the recent overview analysis at 15 years' follow-up, among 550 women under 50 years of age at entry with ER-positive tumours (mixed nodal status), ablation plus chemotherapy appeared to be more effective than chemotherapy alone in terms of recurrence-free survival and overall survival. However, neither benefit was statistically significant.43

The International Breast Cancer Study Group (Ludwig II) trial was included in the 1992 overview10 and has since been published.11 This study involved a 15-year follow-up of 327 premenopausal patients with 4 or more involved nodes. Overall, there was no difference in outcome between those who had oophorectomy before chemotherapy with CMF and prednisone (CMFP) and those treated with CMFP alone. However, in the ER-positive subgroup of 107 patients, those who had oophorectomy tended to have both an improved disease-free survival (23% [SD 5%]) compared with those who had CMFP alone (15% [SD 5%], p = 0.13) and an improved overall survival (41% [SD 7%]) compared with the CMFP group (30% [SD 7%], p = 0.12). This is in spite of the fact that 70% of patients were rendered permanently amenorrheic from CMFP alone (level II evidence). The Southwest Oncology Group recently published the results of a trial comparing CMF, vincristine and prednisone (CMFVP) with oophorectomy followed by CMFVP in 314 premenopausal, node-positive patients. The 7-year survival rates were 71% for the oophorectomy and CMFVP group and 73% for the CMFVP-only group (level II evidence).51

These data suggest that larger studies may show a slightly improved disease-free survival when oophorectomy is added to chemotherapy. Confirmatory studies are being done with temporary medical castration, but no conclusions can yet be made.

  • Tamoxifen should not be recommended as the sole treatment for premenopausal women with node-positive tumours.

The overview analysis demonstrated that in patients of all nodal categories and ER subgroups who were under the age of 50 years, tamoxifen alone compared with no adjuvant treatment significantly reduced the annual odds of recurrence by 12% (SD 4%) but did not have a significant effect on mortality (6% [SD 5%]).11 Further subgroup analysis produced several results. In all node-positive women under the age of 50 years, tamoxifen conferred an 11% (SD 4%) reduction in the annual odds of recurrence and an insignificant reduction on the annual odds of mortality (5% [SD 5%]). In those women less than 50 years old who were ER-positive, tamoxifen's protective effect was more pronounced, conferring a 19% (SD 6%) reduction in annual odds of recurrence and a 13% (SD 8%) reduction in mortality. For women under the age of 50 years who were ER-negative, the impact of tamoxifen was a statistically insignificant increase in annual odds of mortality (5% [SD 9%]). However, since polychemotherapy alone conferred a greater net benefit, polychemotherapy is considered standard treatment for premenopausal patients with positive nodes.

It is important to examine whether tamoxifen alone has ever been shown to be superior or equivalent to chemotherapy in this population of premenopausal, node-positive patients and whether tamoxifen in addition to chemotherapy is of additive benefit. Only 2 trials have prospectively compared chemotherapy alone to tamoxifen alone in premenopausal patients, and the results are contradictory. In the trial of the Italian Cooperative Group for Chemohormonal Therapy of Early Breast Cancer (GROCTA), 504 node-positive, ER-positive patients were randomized into 3 groups: tamoxifen for 5 years, 6 courses of intravenous CMF followed by 4 courses of epirubicin or a combination of both regimens.52 There were 237 patients in the premenopausal subgroup. In this subgroup, no significant differences were seen between the tamoxifen-only patients and the chemotherapy-only patients with respect to disease-free survival or overall survival, suggesting that tamoxifen is as effective as chemotherapy in premenopausal patients (level II evidence). However, patients taking tamoxifen alone had an excess of locoregional relapse in the first and third years after treatment, which the authors speculate may be attributable to the possible hyperestrogenic effect of tamoxifen in premenopausal patients.

The results of the Gynecological Adjuvant Breast Group (GABG) study from Germany53 contradict those of the GROCTA study. In that large, randomized, controlled trial, a subgroup of 331 patients less than 50 years old who were deemed "low-risk" (1 to 3 positive nodes and steroid receptor-positive) were randomized to receive intravenous CMF versus tamoxifen for 2 years. Disease-free and overall survival were significantly prolonged in the CMF group. (Total relapse rates were 51.1% for the tamoxifen group compared with 15.7% for the CMF group, and total deaths were 20.4% for the tamoxifen group compared with 4.3% for the CMF group.) Confidence intervals were not given (level I evidence).

  • Routine use of tamoxifen after chemotherapy in premenopausal women cannot yet be recommended.

It is highly unlikely that tamoxifen taken for 2 years or less adds substantially to the benefits of chemotherapy alone for premenopausal women. A recent abstract reports that in one trial, longer treatment with tamoxifen resulted in an improvement in disease-free survival but not overall survival.54

The question here is not whether tamoxifen can replace chemotherapy, but whether tamoxifen adds any benefit to chemotherapy in the premenopausal patient population. The overview included an indirect estimate of the additive effect of tamoxifen and standard chemotherapy.11 Based on the data of 6362 women younger than 50 years, there was a small but statistically significant reduction in the annual odds of recurrence (7% [SD 4%]) but not of death (3% [SD 5%]). This is considered level I evidence. However, the average duration of tamoxifen in these trials was 1.6 years, a duration not considered optimal by current standards. Furthermore, when the ER-positive subgroup was analysed separately, no advantage was found between chemotherapy plus tamoxifen over chemotherapy alone.11 These estimates include patients in both nodal categories. However, several of the individual studies included in the meta-analysis did consider node-positive women under the age of 50 years separately. These results are summarized briefly as follows.

In the Eastern Cooperative Oncology Group 5177 Trial, 553 premenopausal patients with positive axillary nodes were randomly assigned to receive CMF, CMF with prednisone (CMFP), or CMFP plus tamoxifen (CMFPT) for 1 year.55 All steroid receptor subgroups were included. There was no significant difference in time to relapse or overall survival between treatment groups in the ER-positive subgroup (level II evidence).

In another study of similar design, Ingle and colleagues of the North Central Clinical Trials Group showed no difference in disease-free or overall survival once imbalances in prognostic factors were corrected.56 Likewise, there was no difference between treatment groups in the ER-positive subgroup (level II evidence).

The GROCTA trial showed a trend in the premenopausal subgroup for superior event-free and overall survival in the group that received both hormonal and chemotherapy (22% mortality) compared with the chemotherapy group (33% mortality, p = 0.13) (level II evidence).52,57

The GABG trial randomized high-risk patients (women with 4 or more positive nodes or negative steroid receptors) to 8 cycles of AC, with or without tamoxifen, for 2 years.53 There were 212 women under the age of 50 years included in this subgroup. No difference in disease-free or overall survival was seen, even in the ER-positive subset (level II evidence).

Mauriac and colleagues58 investigated the addition of tamoxifen to CMF for 2 years in node-positive, ER-positive women. In the premenopausal subgroup of 126 patients, again no difference was seen in disease-free or overall survival (level II evidence).

In the NSABP B-09 trial, 1891 node-positive patients were randomized to receive l-phenylalanine mustard (l-PAM) plus 5-FU, with or without tamoxifen, for 2 years.12 No significant disease-free or overall survival benefit was seen in women under the age of 50 years. In fact, there was a small decrease in overall survival in the ER-negative subgroup (p = 0.007) (level I evidence).

An Italian study (GUN 2) trial also investigated the addition of tamoxifen to CMF in 125 node-positive premenopausal women.59 Although a trend to improved disease-free survival was seen, no significant improvement in overall survival was demonstrated. No analyses were done according to ER status (level II evidence).

The Case-Western Group investigated the addition of tamoxifen to CMF, with or without BCG (Bacille Calmette-Guérin) immunotherapy, in 311 patients with node-positive breast cancer.60 Only 94 of these patients were premenopausal. Tamoxifen had no added benefit over chemotherapy alone for premenopausal patients with ER-positive tumours (level II evidence).

It should be noted that in these trials tamoxifen was used for a relatively short period (1 to 2 years) compared with current usage (approximately 5 years).

Since the overview was conducted, only 1 additional trial investigating the hypothesis that tamoxifen adds significant benefit has been published.39 In this trial, 533 premenopausal node-positive women were randomized to 12 months of induction chemotherapy/hormonal therapy with either CMFPT or an alternating regimen that also contained doxorubicin and fluoxymesterone (Halotestin). Subsequent randomization was to 4 years of maintenance tamoxifen versus no treatment. Patients were stratified according to the number of involved nodes and by ER status. Median follow-up was 4.6 years for maintenance tamoxifen. The results showed a statistically significantly longer time to relapse in favour of the group taking maintenance tamoxifen (72% disease-free) versus the no-treatment group (63% disease-free, p = 0.05). The effect was seen in both ER subgroups (level I evidence). However, at the time of reporting there was no improvement in overall survival (level II evidence). A confirmatory study conducted by the National Cancer Institute of Canada is under way to investigate whether tamoxifen taken for 5 years adds any benefit to standard chemotherapy in node-positive and high-risk node-negative women.48

As already mentioned, the overview demonstrated that oophorectomy is approximately equivalent to chemotherapy in reducing the proportional odds of mortality for premenopausal women. However, comparison between groups failed to show that tamoxifen-containing regimens significantly decreased mortality in this subgroup (level III evidence).11 Only one study directly compared tamoxifen to oophorectomy as adjuvant treatment.50 Among the 373 premenopausal patients entered, there was no significant difference in 10-year overall survival (63% for the tamoxifen group versus 56% for the radiation oophorectomy group) (level II evidence). The authors conclude that tamoxifen can be considered a viable alternative to irradiation-induced menopause.

  • Before recommending hormonal therapy in premenopausal women, both the long-term side effects and its effects on recurrence must be considered.

Adverse effects: The long-term adverse consequences of menopause include osteoporosis and an increase in cardiovascular deaths.61 However, the overview analysis did not demonstrate any excess nonbreast-cancer-related mortality in the oophorectomy subgroup.11 Detrimental side effects of tamoxifen include an increased incidence of thromboembolism (1.3% versus 0.1% for the control group, p < 0.001)62 and endometrial cancer.61,63-65 In terms of absolute risk, in the NSABP B-14 study the rates of endometrial cancer were 0.16% per year for the tamoxifen group and 0.02% per year for the control group (level III evidence).63 Use of tamoxifen has been reported to be associated with increased risk of cataract (posterior subcapsular opacities) in the B-14 trial and increased likelihood of undergoing cataract surgery in the Breast Cancer Prevention Trial.66

Beneficial effects: Tamoxifen is associated with beneficial effects apart from its ability to improve disease-free survival in patients with primary breast cancer. Specifically, the overview showed a statistically significant reduction in the absolute frequency of contralateral breast cancer (2% in the control group versus 1.3% in patients receiving tamoxifen) and in the frequency of vascular deaths (level I evidence).11 Finally, in a recent randomized, controlled trial, the use of tamoxifen prevented bone mineral loss in the spine and was associated with significantly decreased indices of bone turnover in postmenopausal patients with breast cancer (level I evidence).67

The relative impact of each of these adverse and beneficial effects on survival has been recently studied.68 The authors showed a survival advantage to adjuvant tamoxifen apart from its effect on recurrence of the primary breast cancer (level III evidence). Although tamoxifen's profile of beneficial effects is compelling, there is not yet enough evidence to recommend it over ovarian ablation.

Adjuvant hormonal therapy for postmenopausal women

  • Postmenopausal women with stage II, estrogen receptor-positive cancer should be offered adjuvant tamoxifen.

Tamoxifen, when used as systemic adjuvant therapy in postmenopausal women with stage II breast cancer, decreases the risk of recurrence and mortality (level I evidence). The benefit is greatest in women with ER-positive disease.11

Tamoxifen is the only form of adjuvant systemic therapy that has been adequately evaluated in women over 70 years of age and is the only form of systemic adjuvant therapy recommended at this time in this age group outside a clinical trial setting.

Many randomized, controlled clinical trials have been conducted to assess the role of adjuvant tamoxifen in the treatment of breast cancer. The larger trials are summarized with reference to postmenopausal patients with node-positive disease.

The NATO (Nolvadex Adjuvant Trial Organization) trial randomized 1285 patients aged 75 years or younger with stage I, II or III breast cancer to receive either tamoxifen (10 mg twice a day, orally for 2 years) or no further therapy after mastectomy and axillary node sampling between 1977 and 1981.69 Node-positive patients received regional radiation therapy, 89% of patients were postmenopausal and 47% of patients had negative axillary nodes; 324 patients were known to have ER-positive tumours, and the ER status was unknown in 606 patients. Selection criteria were not satisfied in 151 patients, causing withdrawal from analysis. Thus, the analysis was based on 564 patients treated with tamoxifen and 567 patients in the no-treatment group. At a median follow-up of 66 months there was a significant reduction in the risk of recurrence for tamoxifen-treated patients (relative risk [RR] = 0.64, 95% confidence interval [CI] = 0.53-0.77) (level I evidence). The effect of treatment was independent of menopausal and ER status.70

The Scottish Trial assessed 1312 patients with breast cancer under 80 years of age, between 1978 and 1984, who were randomized after mastectomy to receive tamoxifen (20 mg/d, orally, for 5 years) or tamoxifen upon relapse; 242 patients were premenopausal and 1070 patients were postmenopausal. Axillary lymph nodes were negative in 751 patients. Tumours were ER-positive in 524 patients and the ER status was unknown in 570 patients. Improvement in both disease-free survival (p = 0.0001) and overall survival (p = 0.002) was noted in the adjuvant tamoxifen group (level I evidence).71

In the Christie Hospital adjuvant tamoxifen trial, 588 postmenopausal patients were randomized to receive oral tamoxifen 20 mg daily for 1 year or no further treatment (73% of the postmenopausal patients in the control group were given tamoxifen on relapse).50 Only 26% of patients had clearance of axillary lymph nodes. At 7 years' follow-up there was a statistically significant difference in disease-free survival favouring tamoxifen-treated patients. However, the 10-year analysis did not show evidence of statistically significant improvement in disease-free survival or overall survival (level II evidence).

In the Cancer Research Campaign Adjuvant Breast Trial, patients under 75 years of age with stage I or II breast cancer were randomized to 1 of 4 treatment groups: oral tamoxifen 20 mg daily for 2 years, perioperative cyclophosphamide, tamoxifen plus cyclophosphamide or control. Between 1980 and 1985, 1912 patients were recruited to either tamoxifen or control group. At a median follow-up of 7.8 years there was a statistically significant improvement in disease-free survival for postmenopausal patients who received tamoxifen compared with the control (RR = 0.72, CI = 0.57-0.87, p < 0.001) (level I evidence). For patients over 50 years of age, the RR was 0.68 (CI = 0.58-0.81, p < 0.001). The improvement in disease-free survival was apparent in both node-negative and node-positive patients. There was a trend toward a reduction in the incidence of contralateral breast cancer in postmenopausal patients receiving tamoxifen, although it did not reach statistical significance (p = 0.08).72

The Danish trial (DBCG77C) considered postmenopausal patients with high-risk features, including tumour size greater than 5 cm, positive axillary nodes, or invasion of skin or fascia. After total mastectomy, 1716 patients were randomized to radiotherapy or radiotherapy plus tamoxifen 30 mg daily for 1 year. At 7 years median follow-up of patients under 70 years of age, disease-free survival in the radiotherapy group was 33% compared with 38% in the radiotherapy plus tamoxifen group (p = 0.007) (level I evidence). For the same age group, overall survival in the radiotherapy group was 42% compared with 50% in radiotherapy plus tamoxifen group (p = 0.03) (level I evidence). For patients over 70 years of age there was no statistically significant improvement in disease-free or overall survival (level II evidence); the characteristics of patients in this age group were not described. ER determinations were available for only 20% of patients.73

The overview analysis conducted by the Early Breast Cancer Trialists' Collaborative Group evaluated 40 randomized tamoxifen trials that included 29 892 women (Table 2).11 Indirect comparisons between trials of tamoxifen versus no tamoxifen for patients aged 50 to 59 years (of any nodal status) resulted in a reduction of both the crude recurrence rate (41% for the control group versus 33% for the tamoxifen group) and mortality (29% for the control group versus 25% for the tamoxifen group) (level III evidence).

  • The recommended duration of tamoxifen therapy is 5 years.

There is level I evidence that tamoxifen when given for 2 years is less effective than when given for 5 years.74 There is also level I evidence that a 10-year course of tamoxifen is no more effective than a 5-year course of this therapy.75,76 Since the level of toxicity is relatively low, most centres continue tamoxifen for 5 years (level IV evidence) (see also guideline 7).

  • No other hormonal intervention apart from tamoxifen can be recommended for postmenopausal patients.

Although tamoxifen is the hormonal treatment of choice for postmenopausal women with node-positive breast cancer11 there are theoretic reasons for considering sequential or alternating types of endocrine treatment.77 An ongoing trial in Scandinavia is exploring the use of alternating tamoxifen and medroxyprogesterone acetate versus tamoxifen alone in postmenopausal patients. Also, 2 studies (described below) have investigated the use of high-dose medroxyprogesterone acetate (HD-MPA) concurrently with chemotherapy as adjuvant treatment for breast cancer.78,79

In a French trial, node-positive patients received CMF with or without HD-MPA for 5 months. Patients in the HD-MPA group were able to receive higher doses of chemotherapy than with those in the control group. However, although postmenopausal patients receiving CMF with HD-MPA did better with respect to relapse-free survival, premenopausal patients taking both CMF and HD-MPA did significantly worse with respect to both relapse-free and overall survival (level II evidence).78 In the Netherlands trial, node-positive patients showed no disease-free or overall survival advantage when a 6-month course of HD-MPA was added to cyclophosphamide, CAF chemotherapy. However, in the subgroup of women over the age of 55 years, there was a significant disease-free survival advantage (p = 0.002) and a trend toward better overall survival (level II evidence).79 In both trials, HD-MPA ameliorated the nausea and vomiting but was associated with significant weight gain.

A recent study investigated the use of adjuvant aminoglutethimide in postmenopausal patients.80 In this study, 354 node-positive women were randomized to aminoglutethimide 250 mg 4 times daily, orally, for 2 years, or placebo. No survival benefit was seen (level I evidence).

Chemotherapy and chemotherapy plus tamoxifen in postmenopausal women

  • Women with estrogen receptor-negative tumours who are fit to receive chemotherapy (generally younger than 70 years) should be offered CMF or AC. There is no proof that tamoxifen adds any benefit to chemotherapy. Tamoxifen alone may be of value.

  • Women with estrogen receptor-positive tumours may gain a small additional benefit from taking chemotherapy in addition to tamoxifen. This is an option for a motivated, well-informed patient.

Many clinical trials have assessed the role of adjuvant chemotherapy or chemotherapy plus hormonal therapy for women with node-positive breast cancer (level I evidence). The following is a summary of these trials as they pertain to postmenopausal women.

Chemotherapy versus no adjuvant therapy for postmenopausal women:

In the 1973 to 1975 trial of Bonadonna and associates,34 using CMF, 386 women between 26 and 75 years of age (including 201 postmenopausal women) were randomized after mastectomy to CMF for 12 cycles or to no further therapy. For the postmenopausal patients, after 20 years of follow-up there was no significant difference in disease-free or overall survival between the adjuvant CMF and no-treatment groups (level II evidence). Bonadonna and Valagussa42 reported that they feel the difference in premenopausal versus postmenopausal results is due to "the low dose of chemotherapy that many postmenopausal patients received."

More than 20 trials have assessed chemotherapy versus no additional therapy in women with node-positive breast cancer. To date, no randomized trial assessing this question has shown a statistically significant improvement in overall survival in postmenopausal patients with node-positive breast cancer after adjuvant chemotherapy. However, most of these trials assessed relatively small numbers of postmenopausal women and may therefore have failed to detect a modest but significant benefit.

In the overview analysis, those who received adjuvant chemotherapy showed a benefit, with estimated overall 10-year rates for recurrence 8.7% lower and mortality 6.8% lower than for those who received no adjuvant chemotherapy.11 In postmenopausal patients, chemotherapy was associated with an absolute reduction in 10-year mortality of 5% (SD 2%). Very few patients in these clinical trials were more than 70 years of age.

Thus, the meta-analysis demonstrated a modest benefit with chemotherapy in postmenopausal women. However, because the benefit is small, it must be weighed against the side effects and risks and discussed with the patient. Other than in clinical trials, adjuvant chemotherapy is given less frequently to women older than 70 years.

Chemotherapy versus tamoxifen plus chemotherapy for postmenopausal women:

The Eastern Cooperative Oncology Group conducted a randomized trial in which 265 postmenopausal patients with node-positive breast cancer were randomized into 3 groups: CMFP for 12 cycles, CMFP for 12 cycles plus tamoxifen for 1 year, and no adjuvant therapy.81 There was no statistically significant difference between the 3 groups with respect to disease-free or overall survival (level II evidence). However, subset analysis of patients with ER-negative tumours showed an improvement in disease-free survival in the CMFP plus tamoxifen group (45% [CI 29%-68%] compared with the CMFP group (34% [CI 20%-57%]) (level I, subset, evidence).

NSABP B-09 is a clinical trial involving 1891 women with node-positive breast cancer, 58% of whom were 50 years of age or older, who were randomized after mastectomy to receive l-PAM plus 5-FU (l-PAM/5-FU) or the same mixture plus tamoxifen (l-PAM/5-FU/TAM).13 There was a statistically significant increase in disease-free survival with the triple regimen but no difference in overall survival. Subgroup analysis showed no benefit for patients who were "tamoxifen nonresponsive"; that is, aged less than 50 years, with estrogen or progesterone-receptor (PR) levels under 10 fmol, or age between 50 and 59 years, with PR levels under 10 fmol.

In the overview analysis, indirect comparisons are made between trials of tamoxifen plus chemotherapy versus the same chemotherapy alone.11 In 8135 women aged 50 years and over who were randomized in these trials, the reduction in annual odds of recurrence or prior death for patients treated with chemotherapy plus tamoxifen was 28% (SD 3%). The reduction in annual odds of death from any cause was 20% (SD 4%) (level III evidence).

Chemotherapy plus tamoxifen versus tamoxifen alone for postmenopausal women:

In the NSABP B-16 trial, women over the age of 50 years with node-positive tumours were randomized to tamoxifen (389 patients) or AC plus tamoxifen (385 patients) for 5 years.82 At 7 years' follow-up there was a statistically significant improvement in outcome in favour of the combined therapy: disease-free survival was 62% for those taking combined therapy compared with 49% for those taking tamoxifen alone, and overall survival was 74% for the group taking combined therapy compared with 65% for those taking tamoxifen alone. In this trial, 2 deaths of patients in the combination-therapy group (AC plus tamoxifen) were possibly therapy-related (level I evidence).

The Ludwig group study (Ludwig III) evaluated 463 postmenopausal patients with node-positive breast cancer aged 65 years and under after mastectomy and axillary clearance (33% were ER-positive, 18% ER-negative and 49% ER status unknown).83 Patients were randomized to 3 groups: CMF for 12 cycles plus prednisone plus tamoxifen for 1 year (CMFpT), prednisone and tamoxifen (pT) or no adjuvant therapy. At a median follow-up of 9 years the disease-free survival was 41% for the CMFpT group, 31% for the pT group, and 19% for the no-treatment control group (p < 0.0001).84 The overall survival was shown to be 53% for the CMFpT group, 41% for the pT group and 38% for the control group (p = 0.08) (level I evidence).

The National Cancer Institute of Canada Clinical Trials Group conducted a trial in which 706 postmenopausal patients with node-positive and ER- or PR-positive breast cancer received either tamoxifen for 2 years, or tamoxifen for 2 years plus CMF for 8 cycles, given concurrently.48 There was no difference in disease-free or overall survival between the 2 groups (level II evidence). Toxicities, including infection, nausea and vomiting, mucositis, diarrhea, leukopenia, thrombocytopenia and thromboembolism were each significantly more common in the group taking CMF plus tamoxifen (level I evidence).

The overview analysis provides comparisons between trials of prolonged chemotherapy plus tamoxifen versus tamoxifen alone in the 3932 women who were randomized in these studies. Women 50 years of age and over with node-positive disease who received polychemotherapy and tamoxifen had an absolute reduction in 10-year mortality of 12% (SD 2%) compared with those who received tamoxifen alone.

In a subsequent meta-analysis of the same data, the outcomes were considered in terms of quality-adjusted time (i.e., without symptoms or toxicity). Within 7 years of follow-up for patients who received chemotherapy in addition to tamoxifen, the modest benefit in terms of relapse-free and overall survival just balanced the "costs" in term of acute side effects.85

Two recent trials have compared tamoxifen to tamoxifen plus chemotherapy. In the Intergroup trial, postmenopausal women with node-positive, ER-positive tumours were randomized to tamoxifen alone, CMF followed by tamoxifen or CAF plus tamoxifen. There was a statistically significant improvement in the 4-year disease-free survival in favour of CAF plus tamoxifen (79%) compared with tamoxifen alone (72%). There was no difference in overall survival.86

In the International Breast Cancer Study Group trial, postmenopausal women with node-positive, ER-positive tumours were randomized using a factorial design to receive tamoxifen alone, tamoxifen plus early CMF, tamoxifen plus delayed CMF or tamoxifen plus early and delayed CMF.87 The addition of chemotherapy to tamoxifen was associated with a significant (24%) reduction in recurrence compared with tamoxifen alone. There was no difference in overall survival (level I evidence).

Clinical trials

  • Patients should be offered the opportunity to participate in clinical trials whenever possible.

As frequently noted above, the knowledge base for many of the interventions involved in the treatment of breast cancer often either does not exist or is extremely weak. These particular areas of uncertainty, where recommendations must, at present, be based on level III, IV or V evidence, can only be eliminated by well-designed, randomized, controlled trials. Improvement in the care of future patients with breast cancer is thus dependent on the participation of sufficient numbers of patients in such trials. Physicians treating patients with breast cancer should therefore be aware of currently available trials and should give patients the chance to participate.

Contributing authors

 Authors of initial guideline document: Susan E. O'Reilly, MB BCh, The British Columbia Cancer Agency -- Vancouver Cancer Centre, Vancouver; Sharon J. Allan, MD, The British Columbia Cancer Agency -- Vancouver Island Cancer Centre, Victoria, BC; Tamara N. Shenkier, MD, The British Columbia Cancer Agency -- Vancouver Cancer Centre, Vancouver; Karen A. Gelmon, MD, The British Columbia Cancer Agency -- Vancouver Cancer Centre, Vancouver

Writing Committee: Mark N. Levine, MD, Hamilton Regional Cancer Centre, Hamilton, Ont.; Ivo A. Olivotto, MD, British Columbia Cancer Agency -- Vancouver Cancer Centre, Vancouver; Anthony L.A. Fields, MD, Cross Cancer Institute, Edmonton; David M. Bowman, MD, Manitoba Cancer Treatment and Research Foundation, Winnipeg; Françoise Bouchard, MD, Health Canada, Ottawa; Maurice McGregor, MD (Chair), Royal Victoria Hospital, Montreal

Primary reviewers: Drs. J. Jolivet, K.I. Pritchard and S. Verma

Secondary reviewers: Drs. G.A. Arjane, J. Ayoub, P.E. Champion, M.L. Davis and S. Hicks, Ms. J. Hiller, and Drs. J. Hiscock, S.K. Liem, M.F. Mohamed, E.M. Tomiak and E. Warner

References

  1. Harris JR, Hellman S. Natural history of breast cancer. In: Henderson IG, Kinne DM, editors. Breast diseases. Philadelphia: JB Lippincott; 1991. p. 165-80.
  2. Ferguson DJ, Meier P, Karrison T, Dawson PJ, Straus FH, Lowenstein FE. Staging of breast cancer and survival rates: an assessment based on 50 years of experience with radical mastectomy. JAMA 1982;248:1337-41.
  3. Fisher B, Slack NH, Katrych D, Wolmark N. Ten-year follow-up results of patients with carcinoma of the breast in a co-operative clinical trial evaluating surgical adjuvant chemotherapy. Surg Gynecol Obstet 1975;140:528-34.
  4. Haagensen CD. Treatment of curable carcinoma of the breast. Analysis of 716 consecutive patients. Int J Radiat Oncol Biol Phys 1977;2:975-80.
  5. Schottenfeld D, Nash AG, Robbins GF, Beattie EJ Jr. Ten-year results of the treatment of primary operable breast carcinoma. A summary of 304 patients evaluated by the TNM system. Cancer 1976;38:1001-7.
  6. Valagussa P, Bonadonna G, Veronesi U. Patterns of relapse and survival following radical mastectomy. Analysis of 716 consecutive patients. Cancer 1978;41:1170-8.
  7. Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Bambilla C, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 1976;294:405-10.
  8. Bonadonna G, Valagussa P, Rossi A, Tancini G, Brambilla C, Zambetti M, et al. Ten-year experience with C.M.F.-based adjuvant chemotherapy in resectable breast cancer. Breast Cancer Res Treat 1985;5:95-115.
  9. Bonadonna G, Zambetti M, Valagussa P. Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes. Ten year results. JAMA 1995;273:542-7.
  10. Castiglione-Gertsch M, Johnsen C, Goldhirsch A, Gelber RD, Rudenstam CM, Collins J, et al. The International (Ludwig) Breast Cancer Study Group Trials 1-1V: 15 years follow-up. Ann Oncol 1994;5:717-24.
  11. Systemic treatment of early breast cancer by hormonal, cytotoxic or immune therapy. 133 randomized trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Early Breast Cancer Trialists' Collaborative Group. Lancet 1992;339:1-15,71-85.
  12. Fisher B, Redmond C, Brown A, Fisher ER, Wolmark N, Bowman D, et al. Adjuvant chemotherapy with and without tamoxifen in the treatment of primary breast cancer: 5-year results from the National Surgical Adjuvant Breast and Bowel Project trial. J Clin Oncol 1986;4:459-71.
  13. Henderson IC. Adjuvant systemic therapy for early breast cancer. Cancer 1994;74(1 Suppl):401-9.
  14. Richards MA, O'Reilly SM, Howell A, George WD, Fentiman IS, Chaudary MA, et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with axillary node-positive breast cancer: an update of the Guy's/Manchester trial. J Clin Oncol 1990;8:2032-9.
  15. Rivkin SE, Green S, Metch B, Glucksberg H, Gad-el-Mawla N, Constanzi JJ, et al. Adjuvant CMFVP versus melphalan for operable breast cancer with positive axillary nodes: 10-year results of a Southwest Oncology Group Study. J Clin Oncol 1989;7:1229-38.
  16. Olivotto IA, Bajdik CD, Plenderleith IH, Coppin CM, Gelmon KA, Jackson SM, et al. Adjuvant systemic therapy and survival after breast cancer. N Engl J Med 1994;330:805-10.
  17. Fisher B, Brown A, Dimitrov N, Poisson R, Redmond C, Margolese RG, et al. Two months of doxorubicin-cyclophosphamide with and without interval re-induction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-non-responsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 1990;8:1483-96.
  18. Rose MA, Henderson IC, Gelman R, Boyages J, Gore SM, Come S, et al. Premenopausal breast cancer patients treated with conservative surgery, radiotherapy and adjuvant chemotherapy have a low risk of local failure. Int J Radiat Biol Phys 1989;17:711-7.
  19. Fisher B, Redmond C, Wickerham DL, Bowman D, Schipper H, Wolmark N, et al. Doxorubicin-containing regimens for the treatment of stage II breast cancer: The National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol 1989;7:572-82.
  20. Misset J-L, di Palma M, Delgado M, Plagne R, Chollet P, Fumoleau P, et al. Adjuvant treatment of node-positive breast cancer with cyclophosphamide, doxorubicin, fluorouracil, and vincristine versus cyclophosphamide, methotrexate, and fluorouracil: final report after a 16-year median follow-up duration. J Clin Oncol 1996;14:1136-45.
  21. Levine M, Bramwell V, Bowman D, Norris B, Findlay D, Warr KI, et al. A clinical trial of intensive CEF versus CMF in premenopausal women with node positive breast cancer [abstract]. Proc Annu Meet Am Soc Clin Oncol 1995;14:A103.
  22. Moliterni A, Bonadonna G, Valagussa P, Ferrari L, Zambetti M. Cyclophosphamide, methotrexate, and fluorouracil with and without doxorubicin in the adjuvant treatment of resectable breast cancer with one to three positive axillary nodes. J Clin Oncol 1991;9:1124-30.
  23. Shapiro CL, Henderson I, Gelmon R, Harris J, Canellos G, Frei E. A randomized trial of 15 vs. 30 weeks of adjuvant chemotherapy in high risk breast cancer patients: results after a median follow-up of 9.1 years [abstract]. Proc Annu Meet Am Soc Clin Oncol 1991;10:A44.
  24. Tancini G, Bonadonna G, Valagussa P, Marchini S, Veronesi U. Adjuvant CMF in breast cancer: comparative 5-year results of 12 versus 6 cycles. J Clin Oncol 1983;1:2-10.
  25. Levine MN, Gent M, Hryniuk WM, Bramwell V, Abu-Zahra, De Pauw S, et al. A randomized trial comparing 12 weeks versus 36 weeks of adjuvant chemotherapy in stage II breast cancer. J Clin Oncol 1990;8:1217-25.
  26. Engelsman E, Klijn JC, Rubens RD Wildiers J, Beex LV, Nooij MA, et al. "Classical" CMF versus a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer. An EORTC Breast Cancer Co-operative Group Phase III Trial (10808). Eur J Cancer 1991;27:966-70.
  27. Henderson IC, Shapiro CL. Adjuvant chemotherapy: an overview. In: Powles TJ, Smith IE, editors. Medical management of breast cancer. London: Martin Dunetz; 1991. p. 197-215.
  28. Osborne CK, Clark GM, Ravdin PM. Adjuvant systemic therapy of primary breast cancer. In: Harris JR, Lippman ME, Morrow M, Hillman S, editors. Diseases of the breast. Philadelphia: J.B. Lippincott; 1996. p. 569-71.
  29. Buzdar AU, Marcus C, Smith TL, Blumenschein GR. Early and delayed clinical cardiotoxicity of doxorubicin. Cancer 1985;55:2761-5.
  30. Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rosencweig M, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979;91:710-7.
  31. Nielsen D, Jensen JB, Dombernowsky P, Munck O, Fogh G, Brynjolf I, et al. Epirubicin cardiotoxicity. A study of 135 patients with advanced breast cancer. J Clin Oncol 1990;8:1806-10.
  32. Jensen BV, Nielsen SL, Skovsgaard T. Treatment with angiotensin-converting-enzyme inhibitor for epirubicin-induced dilated cardiomyopathy. Lancet 1996;347:297-9.
  33. Bonadonna G, Rossi A, Valagussa P, Banfi A, Veronesi U. The CMF program for operable breast cancer with positive axillary nodes: updated analysis on the disease free interval, site of relapse and drug tolerance. Cancer 1977;39:2904-15.
  34. Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med 1995;332:901-6.
  35. DeCillis A, Anderson S, Wickerham DL, Brown A, Fisher B. Acute myeloid leukemia (AML) in NSABP B-25 [abstract]. Proc Annu Meet Am Soc Clin Oncol 1995;14:A92.
  36. Abeloff MD. High-dose adjuvant chemotherapy for high-risk breast cancer. Recent Results Cancer Res 1993;127:177-83.
  37. de Graaf H, Willemse PH, de Vries EG, Sleijfer DT, Mulder PO, van der Graaf WT, et al. Intensive chemotherapy with autologous bone marrow transfusion as primary treatment in women with breast cancer and more than five involved axillary lymph nodes. Eur J Cancer 1994;30A:150-3.
  38. Peters WP, Ross M, Vredenburgh JJ, Meisenberg B, Marks LB, Winer E, et al. High-dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. J Clin Oncol 1993;11:1132-43.
  39. Tormey D, Gray R, Abeloff MD, Roseman DL, Gilchrist KW, Barylak EJ, et al. Adjuvant therapy with a doxorubicin regimen and long-term tamoxifen in premenopausal breast cancer patients: an Eastern Cooperative Oncology Group Trial. J Clin Oncol 1992;10:1848-56.
  40. Antman K, Ayash L, Elias A, Wheeler C, Hunt M, Eder JP, et al. A phase II study of high-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy. J Clin Oncol 1992; 10:102-10.
  41. Wood WC, Budman DR, Korzun AH, Cooper MR, Younger J, Hart RD, et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 1994;330:1253-9.
  42. Bonadonna G, Valagussa P. Dose-response effect of adjuvant chemotherapy in breast cancer. N Engl J Med 1981;304:10-5.
  43. Ovarian ablation in early breast cancer: overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 1996;348:1189-96.
  44. Cole MP. A clinical trial of artificial menopause in carcinoma of the breast. In: Namer M, Lalanne CM, editors. Hormones and breast cancer. Paris: Éditions INSERM; 1975. p. 143-150.
  45. Tengrup I, Nittby LT, Landberg T. Prophylactic oophorectomy in the treatment of carcinoma of the breast. Surg Gynecol Obstet 1986;162:209-14.
  46. Ravdin RG, Lewison EF, Slack NH, Dao TL, Gardner B, Slate D, et al. Results of a clinical trial concerning the worth of prophylactic oophorectomy for breast cancer. Surg Gynecol Obstet 1970;131:1055-64.
  47. Nevinny HB, Nevinny D, Rosoff CB, Hall TC, Muench H. Prophylactic oophorectomy in breast cancer therapy. Am J Surg 1969;117:531-6.
  48. Pritchard KI, Paterson AHG, Fine S, Paul NA, Zee B, Shepherd LE, et al. 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. J Clin Oncol 1997;15:2302-11.
  49. Boccardo F, Rubagotti A, Perrotta A, Amoroso D, Balestrero M, De Matteis A, et al. Ovarian ablation versus goserelin with or without tamoxifen in pre-perimenopausal patients with advanced breast cancer: results of a multicentric Italian study. Ann Oncol 1994;5:337-42.
  50. Ribeiro G, Swindell R. The Christie Hospital adjuvant tamoxifen trial -- status at ten years. Br J Cancer 1988;57:601-3.
  51. Rivkin SE, Green S, O'Sullian J, Cruz AB, Abeloff MD, Jewell WR, et al. Adjuvant CMFVP versus adjuvant CMFVP plus ovariectomy for premenopausal, node-positive, and estrogen receptor-positive breast cancer patients; a Southwest Oncology Group Study. J Clin Oncol 1996;14:46-51.
  52. Boccardo F, Amoroso D, Rubagotti A, Sismondi P, De Sanctis C, Cappellini M, et al. Endocrine therapy of breast cancer. The experience of the Italian Cooperative Group for Chemohormonal Therapy of Early Breast Cancer (GROCTA). Ann NY Acad Sci 1993;698:318-29.
  53. Kaufmann M, Jonat W, Able U, Hilfrich J, Caffier H, Kreienberg R, et al. Adjuvant randomized trials of doxorubicin/cyclophosphamide versus doxorubicin/cyclophosphamide/tamoxifen and CMF chemotherapy versus tamoxifen in women with node-positive breast cancer. J Clin Oncol 1993;11:454-60.
  54. Dombernowsky P, Hansen PS, Mouridsen HT, Overgaard M, Rose C, Zedeler K. Randomized trial of adjuvant CMF + radiotherapy (RT) vs CMF alone vs + tamoxifen (TAM) in pre-and menopausal stage II breast cancer [abstract]. Ann Oncol 1994;5(8 Suppl):2.
  55. Tormey D, Gray R, Gilchrist K, Grage T, Carbone PP, Wolter J, et al. Adjuvant chemohormonal therapy with cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen compared with CMF for premenopausal breast cancer patients: an Eastern Cooperative Oncology Group Trial. Cancer 1990;65:200-6.
  56. Ingle JN, Everson LK, Wieand HS, Cullinan SA, Wold LE, Hagen JB, et al. Randomized trial to evaluate the addition of tamoxifen to cyclophosphamide, 5-fluorouracil, prednisone adjuvant therapy in premenopausal women with node-positive breast cancer. Cancer 1989;63:1257-64.
  57. Boccardo F, Rubagotti A, Bruzzi P, Cappellini M, Isola G, Nenci I, et al. Chemotherapy versus tamoxifen versus chemotherapy plus tamoxifen in node-positive, estrogen receptor-positive breast cancer patients: results of a multicentric Italian study. Breast Cancer Adjuvant Chemo-Hormone Therapy Cooperative Group. J Clin Oncol 1990;8:1310-20.
  58. Mauriac L, Durand M, Chauvergne J, Bonichon F, Avril A, Mage P, et al. Adjuvant trial for stage II receptor positive breast cancer: CMF vs. CMF plus tamoxifen in a single center. Breast Cancer Res Treat 1988;11:179-86.
  59. Bianco AR, De Placido S, Gallo C, Pagliarulo C, Marinelli A, Petrella G, et al. Adjuvant therapy with tamoxifen in operable breast cancer. 10 year results of the Naples (GUN) study. Lancet 1988;2:1095-9.
  60. Crowe JP Jr, Gordon NH, Shenk RR, Soegiarso RW, Hubay CA, Mansour EG, et al. Short-term tamoxifen plus chemotherapy: superior results in node-positive breast cancer. Surgery 1990;108:619-27.
  61. Shapiro CL, Recht A. Late effects of adjuvant therapy for breast cancer. J Natl Cancer Inst Monogr 1994;16:101-12.
  62. Fisher B, Redmond C. Systemic therapy in node-negative patients: updated findings from NSABP clinical trials. J Natl Cancer Inst Monogr 1992;11:105-16.
  63. Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM. Endometrial cancer and tamoxifen treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 1994;86:527-37.
  64. Fornander T, Rutqvist LE, Cedermark B, Glas U, Mattsson A, Silfversward C, et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1989;1:117-20.
  65. Rutqvist LE, Johansson H, Signomklao T, Johansson U, Fornander T, Wilking N. Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. J Natl Cancer Inst 1995;87:645-51.
  66. Wickerham DL. Ophthalmic toxicity associated with tamoxifen [letter to National Surgical Adjuvant Breast and Bowel Project trial members]. Alert Mar. 11, 1997.
  67. Love RR, Mazess RB, Barden HS, Epstein S, Newcomb PA, Jordan VC, et al. The effects of tamoxifen on bone mineral density in post menopausal women with breast cancer. N Engl J Med 1992;326:852-6.
  68. Ragaz J, Coldman A. Age-matched survival impact (SI) of adjuvant tamoxifen in long-term breast cancer survivors (LTBCS) taking into analysis breast contralateral breast cancer (CBC), cardiovascular events (CVE), uterine cancer (UC), and pulmonary emboli (PE) [abstract]. Proc Annu Meet Am Soc Clin Oncol 1995;14:112.
  69. Controlled trial of tamoxifen as single adjuvant agent in management of early breast cancer. Analysis at six years by Nolvadex Adjuvant Trial Organisation. Lancet 1985;1:836-40.
  70. Controlled trial of tamoxifen as a single adjuvant agent in the management of early breast cancer. 'Nolvadex' Adjuvant Trial Organisation. Br J Cancer 1988;57:608-11.
  71. Adjuvant tamoxifen in the management of operable breast cancer: the Scottish Trial. Report from the Breast Cancer Trials committee, Scottish Cancer Trials Office (MRC), Edinburgh. Lancet 1987;2:171-5.
  72. The effect of adjuvant tamoxifen: the latest results from the Cancer Research Campaign Adjuvant Breast Trial. Cancer Research Campaign Breast Cancer Trials Group. Eur J Cancer 1992; 28A:904-7.
  73. Mouridsen HT, Rose C, Overgaard M, Dombernowsky P, Panduro J, Thorpe S, et al. Adjuvant treatment of postmenopausal patients with high risk primary breast cancer. Results from the Danish adjuvant trials DBCG77C and DBCG82C. Acta Oncol 1988;27:699-705.
  74. Rutqvist LE. Randomized trial of 2 versus 5 years of adjuvant tamoxifen in postmenopausal early-stage breast cancer [abstract]. Proc Annu Meet Am Soc Clin Oncol 1996;15:A171.
  75. Fisher B, Dignam J, Wieand S, Wolmark N, Wickerham DL. Duration of tamoxifen (TAM) therapy for primary breast cancer: 5 vs 10 years (NSABP B-14) [abstract]. Proc Annu Meet Am Soc Clin Oncol 1996;15:A118.
  76. Stewart HJ, Forrest AP, Everington D, McDonald CC, Dewar JA, Hawkins RA, et al. Randomized comparison of 5 years of adjuvant tamoxifen with continuous therapy for operable breast cancer. The Scottish Cancer Trials Breast Group. Br J Cancer 1996;74:297-9.
  77. Rutqvist LE. Randomized adjuvant breast cancer trials in Sweden. Cancer 1994;74(3 Suppl):1156-9.
  78. Focan C, Beaudoin M, Salamon E, Dewasch G, Driesschaert P, Bopelle JP, et al. Influence of age, node involvement and CMF chemotherapy on the outcome of early breast cancer treated with high dose methoxyprogesterone acetate (HD-MPA) as adjuvant hormone therapy: five year results of a randomized trial. In: Salmon SE, editor. Adjuvant therapy of cancer VI. Proceedings of the Sixth International Conference on the Adjuvant Therapy of Cancer. Philadelphia: W.B. Saunders; 1990.
  79. Hupperets PS, Wils J, Volovics L, Schouten L, Fickers M, Bron H, et al. Adjuvant chemohormonal therapy with cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) with or without medroxyprogesterone acetate for node-positive breast cancer patients. Ann Oncol 1993;4:295-301.
  80. Jones AL, Powles TJ, Law M, Tidy A, Easton D, Coombes RC, et al. Adjuvant aminoglutethimide for postmenopausal patients with primary breast cancer: analysis at 8 years. J Clin Oncol 1992;10:1547-52.
  81. Taylor SG IV, Knuiman MW, Sleeper LA, Olson JE, Tormey DC, Gilchrist K, et al. Six-year results of the Eastern Cooperative Oncology Group trial of observation versus CMFP versus CMFPT in postmenopausal patients with node-positive breast cancer. J Clin Oncol 1989;7:879-89.
  82. Fisher B, Redmond C, Fisher E, Wolmark N. Systemic adjuvant therapy in treatment of primary operable breast cancer: National Surgical Adjuvant Breast and Bowel Project experience. Natl Cancer Inst Monogr 1986;1:35-43.
  83. Randomized trial of chemo-endocrine therapy, endocrine therapy, and mastectomy alone in postmenopausal patients with operable breast cancer and axillary node metastasis. Ludwig Breast Cancer Study Group. Lancet 1984;1:1256-60.
  84. Goldhirsch A, Castiglione M, Gelber RD. Adjuvant chemo-endocrine therapy in postmenopausal women with breast cancer and axillary-node metastases [letter]. Lancet 1990;335:1099-100.
  85. Gelber RD, Cole BF, Goldhirsch A, Rose C, Fisher B, Osborne CK, et al. Adjuvant chemotherapy plus tamoxifen compared with tamoxifen alone for postmenopausal breast cancer: meta-analysis of quality-adjusted survival. Lancet 1996;347:1066-71.
  86. Albain K, Green K, Osborne C, Cobau E, Levine J, Ingle J, et al. Tamoxifen (T) versus cyclophosphamide, Adriamycin and 5-FU plus either concurrent or sequential T in postmenopausal, receptor (+), node (+) breast cancer: a Southwest Oncology Group phase III Intergroup trial (SWOG-8814, INT-0100) [abstract]. Proc Annu Meet Am Soc Clin Oncol 1997;16:128a.
  87. Effectiveness of adjuvant chemotherapy in combination with tamoxifen for node-positive postmenopausal breast cancer patients. International Breast Cancer Study Group. J Clin Oncol 1997:15:1385-94.
Next: Guideline 9. Follow-up after treatment for breast cancer
Previous: Guideline 7. Adjuvant systemic therapy for women with node-negative breast cancer
[Table of Contents]
| CMAJ February 10, 1998 (vol 158, no 3) / JAMC le 10 février 1998 (vol 158, no 3) |
| CPG Infobase / Infobanque des GPC |