CMAJ/JAMC Special supplement
Supplément spécial

 

Clinical practice guidelines for the care and treatment of breast cancer

This guideline has been superseded by a revised version issued Jan. 23, 2001. Copies previously printed or downloaded should be destroyed.

7. Adjuvant systemic therapy for women with node-negative breast cancer

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

This guideline has been peer reviewed.

Abstract

Objective: To assist patients with node-negative breast cancer and their physicians in arriving at optimal decisions regarding treatment.

Evidence: Based on systematic literature review using primarily CANCERLIT from 1983 and MEDLINE from 1980 to September 1996. Nonsystematic review continued up to June 1997.

Recommendations:

  • Before deciding whether to use adjuvant systemic therapy, the prognosis without adjuvant therapy should be estimated.
  • A patient's risk for recurrence can be categorized as low, intermediate or high on the basis of tumour size, histologic or nuclear grade, estrogen receptor (ER) status, and lymphatic and vascular invasion (LVI).
  • For each individual, the choice of adjuvant therapy must take into account the potential benefits and possible side effects. These must be fully explained to each patient.
  • Pre- and postmenopausal women who are at low risk of recurrence can be advised not to have adjuvant systemic treatment.
  • Women at high risk should be advised to have adjuvant systemic therapy. Chemotherapy should be recommended for all premenopausal women (less than 50 years of age) and for postmenopausal women (50 years of age or older) with ER-negative tumours. Tamoxifen should be recommended as first choice for postmenopausal women with ER-positive tumours. For this last group of patients, it is possible that further benefit may be obtained from the addition of chemotherapy to tamoxifen.
  • For women at intermediate risk with ER-positive tumours, tamoxifen should normally be the first choice. For those who decline tamoxifen, chemotherapy may be considered.
  • For most patients over 70 years of age who are at high risk, tamoxifen is recommended regardless of ER status. For some who are in robust good health, chemotherapy is a valid option.
  • There are 2 recommended chemotherapy regimens: (1) 6 cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF); (2) 4 cycles of Adriamycin and cyclophosphamide (AC).
  • Tamoxifen should normally be administered daily for 5 years.
  • Patients should be offered the opportunity of participating in therapeutic trials whenever possible.

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

The term "adjuvant systemic therapy" refers to all anticancer medications used after surgical treatment of patients with breast cancer. The 2 forms of adjuvant therapy considered here are chemotherapy (cytotoxic drugs) and hormonal therapy (usually the antiestrogen, tamoxifen). This guideline focuses on adjuvant systemic therapy for women in whom the axillary lymph nodes have been shown to be free of cancer (node-negative disease) (see guideline 4 on axillary dissection). Over half of all patients in whom breast cancer is diagnosed are node negative. Most women who present with node-negative disease are cured by surgery alone.

The use of adjuvant therapy for women in whom the cancer has spread to the axillary nodes (node-positive disease) is addressed in a separate guideline (guideline 8).

The decision to use adjuvant systemic therapy is taken after weighing the benefits of reducing the risk of recurrence against the undesirable side effects and risks of the therapy in question. Since the value placed on different health effects is subjective, the process of weighing potential benefits against potential adverse effects must, to the extent that she wishes to do so, be carried out by the woman herself. To this end, the necessary information, including the uncertainty, must be carefully communicated to the patient in a way that enables her to make a truly informed decision.

This guideline reviews the evidence concerning the risks and benefits of adjuvant systemic therapy for node-negative breast cancer with the objective of assisting patients and their doctors in arriving at optimal treatment decisions. When making the decision of whether or not to administer adjuvant therapy, 3 questions must be considered:

  • What is the prognosis for this patient without adjuvant therapy?
  • To what extent will the prognosis be improved by the treatment?
  • What are the adverse effects of the treatment?

Method

To identify the relevant evidence for these guidelines, a systematic search of the databases MEDLINE (from 1980) and CANCERLIT (from 1983) was carried out through to September 1996, using the key words breast cancer, node-negative, adjuvant therapy and prognostic factors. References in review articles and textbooks were also used. A nonsystematic review of the literature on systemic adjuvant therapy for breast cancer and monitoring of major conferences on breast cancer was continued until May 30, 1997. Evidence was categorized into 5 levels.

The initial draft guidelines were successively reviewed and revised by a writing committee consisting of 6 members of The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer, by 10 expert external reviewers and by all members of the Steering Committee. The prefinal draft was then submitted to 11 secondary reviewers consisting of surgical, medical and radiation oncologists, nurses, family physicians and breast cancer survivors from all regions of Canada. After further revision, final approval was given by the Steering Committee. The final guidelines reflect a consensus of all these contributors.

Recommendations

Estimating prognosis without adjuvant therapy

  • Before deciding whether to use adjuvant systemic therapy, the prognosis without adjuvant therapy should be estimated.

In about 30% of women with node-negative breast cancer who are treated surgically without receiving adjuvant therapy, metastases will eventually develop (level III evidence).1 However, these are average estimates, and the prognosis for patients with lymph-node-negative disease can vary depending on the patient's age and various tumour characteristics.2 In addition, the estimate of 30% is based on the outcome of patients in the control (no treatment) arms of clinical trials. Also, one must keep in mind the possibility that the survival rate was influenced by preferential selection of patients for clinical trials based on poor prognostic features.

Historically, a number of features of the tumour have been used to identify patients at increased risk of recurrence. These include tumour size, histologic differentiation (grade) and hormone receptor status. In addition, the presence of lymphatic and vascular invasion and age younger than 35 years have also been found to be associated with an increased risk of recurrence. In recent years, many new predictors of outcome have been reported and are being evaluated for their prognostic value.3 These include ploidy, S-phase fraction, cathepsin D, heat shock proteins, and HER-2 neu oncogene overexpression. However, none of these factors has yet consistently been shown to add prognostic information to that associated with the more traditional factors of tumour size, histologic grade and hormone receptor status.4 In 1996 the American Society of Clinical Oncology recommended that these newer factors not be used to predict recurrence in routine clinical practice.5 In 1995 an international consensus panel meeting in St. Gallen concluded that the evaluation of risk of recurrence in patients with node-negative breast cancer be categorized on the basis of the patient's age, and on the size, grade and hormone receptor status of the tumour (level IV evidence).2

Tumour size and prognosis

In many studies the size of the tumour at the time of surgery has been found to be an important predictor of recurrence and survival in patients with node-negative breast cancer (level III evidence).6-15 In most of these studies, size was defined as the maximum diameter of the tumour as estimated from the pathologic specimen. The influence of size on prognosis appears to be a continuum, with tumours less than 1 cm in diameter having a very low risk, which gradually increases as the size of the tumour increases to 3 cm and over. For example, in the control (no adjuvant therapy) group of the International Breast Cancer Study Group trial, the 5-year disease-free survival was as follows: 88% for tumours less 1 cm in diameter, 84% for tumours of 1 cm in diameter, 69% for tumours 1.1 to 2 cm in diameter, 60% for tumours 2.1 to 3 cm in diameter, and 61% for tumours 3.1 to 5 cm in diameter.11

Fisher and colleagues reported on the influence of tumour size on outcome in 3 trials.16-18 In women with estrogen receptor (ER)-positive tumours, disease-free survival at 5 years for those with tumours less 2 cm in diameter was 75% compared with 67% for those with tumours 2 cm or greater in diameter. For patients with ER-negative tumours, disease-free survival was 72% for those with tumours less than 2 cm in diameter and 63% for those with tumours 2 cm or greater in diameter.

In a 10-year follow-up of 382 women with node-negative breast cancer, Rosen and colleagues found that primary tumours 1 cm or smaller in diameter were associated with a recurrence rate of 7% and a cancer-related death rate of 5%. For tumours 1.1 to 2.0 cm in diameter, the recurrence rate was 21% and the cancer-related death rate was 15%.13 In a similar study, at a mean follow-up of 13.5 years, Quiet and colleagues reported disease-free survival rates of 79% for those with tumours less than 2 cm in diameter and 64% for those with tumours 2 cm or more in diameter.19

In a trial conducted in Ontario, over 800 women with node-negative breast cancer who had undergone lumpectomy were randomized to receive or not receive breast irradiation.7 Tumour size was an independent predictor of mortality. For women with tumours 2 cm or greater in diameter compared to those with tumours less than 2 cm in diameter, the relative risk of death was 1.4 (p = 0.03). Data from the Memorial Sloan-Kettering Cancer Center indicate that women with node-negative tumours less than 3 cm in diameter have a lower relapse rate (28%) than those with tumours 3 to 5 cm in diameter (39%, p = 0.06).20

In summary, tumour size at the time of surgery is an important independent prognostic factor. Although no precise size can be identified that differentiates high risk from low risk of recurrence or death, many studies have used a diameter of 2 cm as a cutoff point.

Histologic and nuclear grade and prognosis:

An association between grade and outcome has been reported in a number of studies. Depending on the study, either histologic or nuclear grade, or both, have been evaluated.7,11,15,21 There is a high degree of concordance between histologic grade and nuclear grade.21

Although there is some interaction between grade and other variables, multivariate analyses show grade to be an important independent predictor. The National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted an analysis of 950 patients with node-negative breast cancer who did not receive adjuvant systemic therapy in trial B-06.18,21 The 5-year disease-free survival of patients with good nuclear grade (well differentiated and moderately well differentiated) was 80% compared with 64% for patients with poor grade (poorly differentiated) (p < 0.01). With regard to histologic grade, the 5-year disease-free survival related to good histologic grade was 83% versus 67% for those with poor histologic grade (p < 0.01). In the Cox model, good nuclear grade was an independent predictor of disease-free survival (good grade RR = 0.76, p = 0.01).

In the radiotherapy trial conducted in Ontario in women with node-negative breast cancer, nuclear grade was an independent predictor of mortality.7 For those with tumours of poor nuclear grade (grade III) versus all others, the relative risk was 2.0, p = 0.0001.

In a trial conducted by the International Breast Cancer Study Group, women with node-negative breast cancer were randomized to receive perioperative adjuvant chemotherapy or no adjuvant treatment.11 In the 388 patients in the control group, the 5-year disease-free survival of those with histologic grade I tumours was 89%, grade II tumours 65% and grade III tumours 60%. In a Cox model the relative risk of recurrence for grade III compared with grade I was 1.74 (p = 0.02).

Several different grading systems have been reported in published series, but in Canada most pathologists use a modification of the Bloom Richardson grading system to evaluate the histologic grade.22 This grading system is based on tubule formation, nuclear pleomorphism and mitotic index. Each score is added to give a combined score of 3 to 9: 3 to 5 points indicates grade I or well differentiated, 6 to 7 points indicates grade II or moderately differentiated, and 8 to 9 points indicates grade III or poorly differentiated. Since a pathologist's subjective judgement is involved when reporting on grade, there is potential concern regarding reproducibility. However, several studies have shown a high degree of interobserver agreement when evaluating histologic grade.23,24

In summary, the prognosis of patients with grade I tumours is considered good whereas those with grade III tumours is considered poor. It is unclear whether patients with grade II tumours have an intermediate prognosis or should be grouped prognostically according to grade I or grade III tumours.11,22

Hormone receptor status and prognosis

The influence of hormone receptor status on outcome is weaker than that of tumour size or histologic or nuclear grade and has been demonstrated less consistently.25 A follow-up of 8530 women from the San Antonio database showed a small but statistically significant increase (9%) in disease-free survival at 5 years for patients with ER-positive tumours compared with those having ER-negative tumours (level III evidence).25,26 Indirect comparison of the control groups of the NSABP B-13 and B-14 trials also suggests a slightly better survival and disease-free survival for women with ER-positive tumours than those with ER-negative tumours (level III evidence).16,17 The use of estrogen and progesterone receptor status to predict recurrence was recommended by the American Society of Clinical Oncology in 1996.5 Also, the prognostic value of ER status based on immunohistochemical techniques is now accepted.27

Age and prognosis

A patient's age appears to correlate with outcome. Patients younger than 35 years appear to have, on average, a poorer prognosis than older patients, and this has been used as a prognostic indicator.2,14,28,29 However, the relationship is poorly defined and difficult to distinguish from the influence of menopausal status and other tumour features. At present, there is insufficient evidence to justify the incorporation of age as an independent prognostic factor.

Lymphatic and vascular invasion (LVI) and prognosis

In several studies of patients with node-negative disease, a relationship has been found between invasion of lymphatic and blood vessels and increased recurrence or reduced survival.10,11,13,15,20,30-34 In 4 studies, invasion was found to be an independent prognostic factor by multivariate analysis.9,12,28,35 However, not all studies have found such an association, and its practical value as a prognostic factor is diminished by the fact that it can be difficult to evaluate and may have poor reproducibility.36-38

In summary, there is good evidence that small tumour size (less than 1 cm diameter), low nuclear grade (grade 1) and ER positivity are favourable prognostic factors. In contrast, large tumour size (greater than 2 cm diameter), high nuclear or histologic grade (grade III), ER negativity, and lymphatic and vascular invasion are unfavourable prognostic factors.

  • A patient's risk for recurrence can be categorized as low, intermediate or high on the basis of tumour size, histologic or nuclear grade, estrogen receptor (ER) status, and lymphatic and vascular invasion (LVI).

In the following classification, the risk of recurrence associated with certain combinations of features can be estimated with some confidence on the basis of level III evidence. The risk associated with other combinations, which have not been adequately studied, must be based on level V evidence. With this proviso, patients can be categorized somewhat arbitrarily into 3 levels of risk as outlined below.

Low risk

A low-risk category is defined by tumour diameter of 1 cm or less with all prognostic factors favourable (grade I, ER positive, no LVI). There are many oncologists who would also include in this category a patient with a tumour less than 2 cm in size and all other factors favourable. The risk of recurrence at 10 years associated with this low-risk category is less than 10% (level III evidence).1,2,20

High risk

A patient with a tumour more than 3 cm in diameter, irrespective of any other factors, should be considered at high risk (level III evidence). In addition, a patient with a tumour more than 1 cm in diameter, associated with any other unfavourable prognostic feature (grade III, ER negative or LVI) should also be considered at high risk for recurrence (level V evidence). For those in the high-risk category, the risk of recurrence within 5 to 10 years is at least 20% and in some circumstances as high as 50%.1-3,7

Intermediate risk

There are insufficient data on the natural history of tumours with other combinations of risk factors to predict outcome. On the basis of level V evidence, patients in the intermediate risk category face a probability of recurrence at 10 years of 10% to 20%.2,3

Adjuvant systemic therapies

Chemotherapy:There is good evidence that chemotherapy will result in a small but definite increase in disease-free and overall survival of patients with node-negative breast cancer. Several randomized trials in which chemotherapy was specifically evaluated in node-negative patients have each demonstrated a benefit (level I evidence). These are summarized below.

In the Milan trial, 90 patients with node-negative breast cancer and ER-negative tumours were randomized to receive a 9-month course of intravenous cyclophosphamide, methotrexate and 5-fluorouracil (CMF) or no treatment.39 At 7 years, disease-free survival was significantly increased in the treated patients (85%) compared with the control group (42%, p = 0.0001), and the same was found with regard to overall survival (86% in treated patients versus 58% in the control group, p = 0.006). However, in this trial the outcome of the patients in the control group was much poorer than is usually observed; thus, these findings should be generalized with caution.

In a trial conducted by the Ludwig group, 1275 women with node-negative breast cancer were randomized to receive a 1-month course of adjuvant CMF or no treatment.40 The 5-year disease-free survival rate was slightly but significantly improved in the chemotherapy group, at 74% compared with 68% for the control group (p = 0.02). In the NSABP B-13 trial, 679 patients with node-negative breast cancer and ER-negative tumours were randomized to receive sequential methotrexate and fluorouracil (MF), or no treatment.17 At 4 years, disease-free survival in the chemotherapy group was 80% compared with 71% in the no-treatment group (p = 0.003).

In the Intergroup trial, 406 women with either ER-negative tumours or tumours larger than 3 cm in diameter were randomized to receive either CMF with prednisone (CMFP) or no treatment.41 There was a statistically significant increase in the 3-year disease-free survival in the chemotherapy group, at 84% compared with 69% for the control group (p = 0.0001).

In 1990 the Early Breast Cancer Trialists' Collaborative Group conducted a meta-analysis of 44 trials to evaluate adjuvant polychemotherapy in 18 000 women with early-stage breast cancer.1 Although different chemotherapy regimens were used in the trials, CMF was among the more common ones. In over 4900 patients with node-negative breast cancer, the relative reduction in the risk of recurrence was 26% (SD 7%) and the relative reduction in mortality was 18% (SD 8%). The absolute disease-free survival at 5 years was 75% for patients who received chemotherapy and 67% for the control group (p < 0.00001). At 10 years these values were 61.5% for the chemotherapy patients and 54.5% for the control group (p < 0.0001). The overall survival at 10 years was 67.2% for the chemotherapy patients and 63.2% for the nontreated patients (p = 0.03). For the combined group of patients with node-negative and node-positive cancer, chemotherapy was associated with a risk reduction for recurrence and mortality in all age groups, although the effect was greatest in women younger than 50 years of age. No effect was observed in women over 70 years old, but the number of patients in this group was relatively small.

Tamoxifen

There is good evidence that tamoxifen will result in a small but definite increase in disease-free and overall survival in patients with node-negative breast cancer. There is level I evidence that ovarian ablation, whether induced by surgery or radiotherapy, is associated with significant improvement in recurrence-free and overall survival in women who are under the age of 50 years at the time of treatment.42 Although ovarian ablation is now rarely used, a number of trials have evaluated tamoxifen in women with node-negative breast cancer.

In the NATO trial there were 300 women with node-negative disease who received tamoxifen and 305 women who received no treatment.43 At a median 5.6 years there were 80 recurrences in the tamoxifen group and 107 in the control group, a benefit comparable to the statistically significant difference observed in the combined node-negative and node-positive population.43

In the Scottish study of 747 women with node-negative disease, there was a statistically significant difference in disease-free survival in favour of tamoxifen at 5 years (relative risk reduction of 0.6, p = 0.0001).44 In the NSABP B-14 trial, 2844 women with node-negative, ER-positive tumours were randomized to receive tamoxifen for 5 years or no treatment.16 The disease-free survival rate with tamoxifen was 82% compared with 72% in the control group (p < 0.000005). In both the NSABP and Scottish trials no difference was detected in overall survival between treatment groups.

The Early Breast Cancer Trialists' Collaborative Group analysed the data from over 35 000 women enrolled in 54 clinical trials.1 In over 12 000 women with node-negative disease, the relative reduction in the risk of recurrence associated with tamoxifen was 25% (SD 4%) and the relative reduction in mortality was 17% (SD 5%). Disease-free survival rates at 5 years were 83.5% for the tamoxifen group and 77.3% the control group (p < 0.00001). The corresponding rates at 10 years were 68.1% with tamoxifen and 63.1% without treatment, the difference being significant at the same level. The overall survival rates at 10 years were 74.5% for the tamoxifen group compared with 71% for the control group (p = 0.0002). In patients with node-negative disease, on subgroup analysis by age, tamoxifen was associated with a reduction in the risk of recurrence in women both under and over 50 years of age. A survival benefit was detected only in the over-50 age group. No benefit regarding recurrence or survival was detected in women with ER-negative tumours.

In a recent abstract, Fisher and colleagues reported the results of NSABP B-20 trial in which 2363 women with ER-positive, node-negative breast cancer were randomized to receive tamoxifen, tamoxifen plus MF or tamoxifen plus CMF. There was a statistically significant improvement in 5-year disease-free survival in favour of chemotherapy plus tamoxifen over tamoxifen alone: the disease-free survival rates were 84% with tamoxifen alone, 89% with tamoxifen plus MF and 90% with tamoxifen plus CMF.45

Adverse effects of adjuvant systemic therapy.

Adjuvant chemotherapy frequently causes acute adverse effects (level III evidence).

Nausea, vomiting and diarrhea are common.46 The nausea and vomiting are generally well controlled with antiemetics.47 Fatigue is also a common accompaniment of all chemotherapy regimens. Some weight gain may occur in approximately 14% of those on CMF regimens.48 Complete but temporary alopecia occurs in approximately 40% of patients receiving CMF48 and in virtually all patients receiving Adriamycin.49 In the NSABP B-15 study, anthracycline-containing chemotherapy (Adriamycin) was associated with more vomiting and more frequent and more complete alopecia than CMF regimens, but the latter caused more nausea.49 Febrile neutropenia occurs infrequently and may require hospitalization in 1% to 2% of patients.50 Permanent amenorrhea occurs in approximately 70% of patients but is less common in younger than older women.51,52 Venous thromboembolism, which can be life-threatening and require anticoagulant therapy, may occur in from 2% to 7% of patients.48,53 There is a risk of cardiac injury with anthracycline-based chemotherapy, but clinically important toxicity is rare (below 1%) with conventional adjuvant doses.49,54,55 In a review of 133 randomized trials, fatal toxicity varied from 0.1% to 1.0%.1

All chemotherapy is potentially leukemogenic. In a recent review of a series of adjuvant trials in Milan involving CMF, 3 cases of leukemia were observed in 2465 patients (the cumulative absolute risk at 15 years was 0.23%).56 The NSABP has recently reported 2 cases of leukemia in 1562 patients within 18 months of starting treatment with standard-dose Adriamycin and cyclophosphamide (AC).57 Monitoring of these patients is continuing. If such therapies are leukemogenic the level of risk must be low.

Tamoxifen is associated with relatively few severe side effects (level II evidence)

About 20% of women taking tamoxifen experience severe hot flashes, which abate with time.48 Tamoxifen probably causes occasional depression, but evidence regarding this complication is conflicting (level IV evidence).58 A more serious complication, venous thromboembolism, is slightly increased in those taking tamoxifen (1.3%) compared with those not taking it (0.1%) (level I evidence).18 Use of tamoxifen has also been reported to be associated with an increased risk of cataract ("posterior subcapsular opacities") in the B-14 study and with an increased risk of cataract surgery in the BCPT trial.59 In general, for most complications, the risk of toxicity is increased by the concurrent use of chemotherapy with tamoxifen in postmenopausal women.60

Several studies have reported a small but significant increase in the risk of endometrial cancer (level I evidence).61-63 In the NSABP B-14 study, after 5 to 8 years of follow-up, the annual risk of endometrial cancer for women who received tamoxifen was 1.6/1000 compared with 0.2/1000 for those who did not.61 Thus, women taking tamoxifen should be warned to report any vaginal bleeding promptly. In none of these trials was any increase in the incidence of other solid tumours detected.61-63

Choosing adjuvant therapy: factors predictive of benefit.

Menopausal status and ER status influence the response to systemic adjuvant therapy:

Postmenopausal status is defined as starting 1 year after the last period or, where menopausal status cannot be determined, after the age of 50 years. Most evidence concerning the influence of ER and menopausal status (or age) on response to therapy is based on studies in women with metastatic breast cancer or node-positive disease (see guideline 8). Previously untreated patients with stage IV breast cancer have at least a 50% chance of responding to tamoxifen if the ER status is positive, compared with a less than 10% response rate if the ER status is negative (level I evidence).64

Evidence based on studies of women with node-negative disease is more sparse. In the overview analysis, chemotherapy was associated with a risk reduction for recurrence and mortality in all age groups, but the greatest effect was in the women who were under 50 years of age. Conversely, the greatest effect of tamoxifen was found in women over 50 years of age.1

Evidence of a relationship between tamoxifen response and estrogen receptor status in patients with stages I and II breast cancer comes from the overview analysis.1 For patients with node-negative and node-positive disease who were receiving tamoxifen, there was an 11% (SD 5%) reduction in the odds of death in those with ER-poor tumours, compared with a 21% (SD 3%) reduction in those with ER-positive tumours.

  • For each individual, the choice of adjuvant therapy must take into account the potential benefits and possible side effects. These must be fully explained to each patient.

The evidence on which to base therapeutic choices is incomplete. In making decisions based on the available evidence, women must personally evaluate the potential gains and side effects of each option, which must be presented clearly so as to help patients make these difficult choices. At present, options are best given in terms of the absolute rather than the relative risk involved. Presentation of these options is demanding and requires time. Visual aids such as a "decision board" and written material may be useful in this process.65

Suggested therapeutic approaches according to risk category, age and ER status are summarized in the section that follows.

Recommended therapies.

  • Pre- and postmenopausal women who are at low risk of recurrence can be advised not to have adjuvant systemic treatment.

Patients in the low-risk category have a recurrence rate of less than 10% over 10 years. With an approximately 26% reduction in recurrence after therapy,1 they may expect a reduction in the absolute recurrence rate of between 1% and 2%. Thus, not more than 2 of every 100 women estimated to be at low risk of recurrence will benefit from treatment, which is a small benefit in relation to the potential toxicity. Therefore, systemic adjuvant therapy should not be recommended for such women (level IV evidence).2

  • Women at high risk should be advised to have adjuvant systemic therapy. Chemotherapy should be recommended for all premenopausal women (less than 50 years of age) and for postmenopausal women (50 years of age or older) with ER-negative tumours. Tamoxifen should be recommended as first choice for postmenopausal women with ER-positive tumours. For this last group of patients, it is possible that further benefit may be obtained from the addition of chemotherapy to tamoxifen.

It is estimated that adjuvant systemic therapy will reduce the 10-year recurrence rate by approximately 26%.1 Thus, for every 100 women with a background (untreated) recurrence rate of 20%, 5 may benefit from adjuvant systemic therapy. If the background rate were 50%, 13 women might benefit from such treatment. There are no trials that directly compare the efficacy of chemotherapy and tamoxifen in women with node-negative disease, but there is sufficient indirect evidence based on the overview and on the node-positive trials cited above to support these recommendations.

In a recent trial, as yet reported only in abstract form, in women with node-negative ER-positive tumours, the combination of chemotherapy plus tamoxifen was reported to result in a better disease-free survival than tamoxifen alone.45 Combined therapy may become the preferred option for such patients in the future.

In the overview analysis, chemotherapy was more effective in premenopausal women than postmenopausal women. Tamoxifen was also effective except in premenopausal women with ER-negative tumours.

  • For women at intermediate risk with ER-positive tumours, tamoxifen should normally be the first choice. For those who decline tamoxifen, chemotherapy may be considered.

Available evidence suggests that for women at intermediate risk, the benefit expected from chemotherapy is not substantially greater than that from tamoxifen, especially for women with ER-positive tumours. (In the absence of evidence, women with ER-poor tumours are usually treated as "high risk.") Since chemotherapy is associated with higher morbidity, tamoxifen is the recommended first-line therapy. Although it is possible that chemotherapy plus tamoxifen may be more effective,45 the small benefit does not justify the increased toxicity for patients other than those at high risk (level V evidence).

  • For most patients over 70 years of age who are at high risk, tamoxifen is recommended regardless of ER status. For some who are in robust good health, chemotherapy is a valid option.

There is little evidence to guide the choice of therapy for women over 70 years old. With increasing age or frailty, chemotherapy is less well tolerated. However, tamoxifen, which is well tolerated, can be recommended.

Optimal adjuvant regimens.

  • There are 2 recommended chemotherapy regimens: (1) 6 cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF); (2) 4 cycles of Adriamycin and cyclophosphamide (AC).

There are no completed clinical trials that have evaluated the commonly used anthracycline-containing regimens such as AC, or cyclophosphamide, Adriamycin and 5-fluorouracil (CAF) in women with node-negative breast cancer. AC is often used in patients with node-positive disease. The course of AC is shorter in duration and has a different toxicity profile than that of CMF. However, there is the concern of cardiomyopathy and leukemia with AC. Some patients with high-risk, node-negative disease have recurrence rates similar to patients with node-positive disease, for whom anthracycline-containing chemotherapy is normally offered. Thus, there is a rationale, without any direct supporting evidence, for the use of AC in women with high-risk, node-negative breast cancer (level V evidence).

  • Tamoxifen should normally be administered daily for 5 years.

There is level I evidence that therapy with tamoxifen should be continued for more than 2 years and not more than 5 years. The optimal duration between these limits is unknown. Since the level of toxicity is relatively low, most centres continue tamoxifen for 5 years (level IV evidence).

In a trial conducted by the Swedish Breast Cancer Cooperative Group, 3887 postmenopausal patients with node-positive or node-negative breast cancer were randomized to receive tamoxifen for either 2 years or 5 years. At a median follow-up of 5 years there was a significant improvement in both disease-free and overall survival in favour of the longer treatment. The survival at 10 years was 80% in the group who received tamoxifen for 5 years compared with 74% in the group who received tamoxifen for 2 years (p = 0.003).66

There is also level I evidence that no benefit can be expected for continuing tamoxifen treatment longer than 5 years. In the NSABP B-14 trial, 1172 women with node-negative, ER-positive tumours who had received tamoxifen for 5 years were randomized to continue tamoxifen for 5 more years or to stop treatment. There was no statistically significant difference in the 4-year disease-free survival (86% for 10-year tamoxifen versus 92% for 5-year treatment) nor in the overall survival (94% for 10-year tamoxifen versus 96% for 5-year treatment).67 The Scottish tamoxifen trial showed a similar outcome. In this trial, 342 postmenopausal women with node-positive breast cancer who had received tamoxifen for 5 years were randomized to receive tamoxifen for an additional 5 years or to stop therapy. At a median follow-up of 6.2 years, the disease-free survival of those who received tamoxifen for 5 years was 70% compared with 62% for those who received tamoxifen for 10 years.68

Clinical trials

  • Patients should be offered the opportunity of participating in therapeutic trials whenever possible.

As frequently noted, 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 the option of participation should be offered to patients.

Contributing authors

 Authors of initial guideline document: A. David Ginsburg, MD, Kingston Regional Cancer Centre, Kingston, Ont.; Mark N. Levine, MD, Hamilton Regional Cancer Centre, Hamilton, Ont.

Writing Committee: David M. Bowman, MD, Manitoba Cancer Treatment and Research Foundation, Winnipeg; Ivo A. Olivotto, MD, British Columbia Cancer Agency -- Vancouver Cancer Centre, Vancouver; Anthony L.A. Fields, MD, Cross Cancer Institute, Edmonton; Cameron D. Little, MD, College of Physicians & Surgeons of Nova Scotia, Halifax; Jacques Cantin, MD, Centre hospitalier de l'Université de Montréal, Montreal; Maurice McGregor, MD (Chair), Royal Victoria Hospital, Montreal

Primary reviewers: Drs. A. Goldhirsch, V. Bramwell, K. Gelmon, C. Bryce, S. Allan, B. Norris, J. Latreille, A.D.H. Paterson, E. Tomiak and G. Tremblay

Secondary reviewers: Dr. R. Baird, Ms. P. Becker, Drs. C. Butts, J.T. Dancey, R. Goel, B. Kvern, C. Milne and S. Narod, Ms. E. Nolan and Drs. W.H. Thurlow and R. Wong

References

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