Cancer Investigation, 10(6), 595-602 (1992)
Cancer Invest Downloaded from informahealthcare.com by University of Newcastle on 12/30/14 For personal use only.
Adjuvant Chemotherapy for Node-Negative Breast Cancer George W. Sledge, Jr., M.D. and Worta McCaskill-Stevens, M.D. Department of Medicine lndiana University School of Medicine Indianapolis, lndiana 46202
INTRODUCTION
rate of local and distant recurrence following local therapy for node negative breast cancer is decreased by both adjuvant combination cytotoxic chemotherapy and by adjuvant tamoxifen. The decision to use adjuvant treatment should follow a thorough discussion with the patient regarding the likely risk of recurrence without adjuvant therapy, the expected reduction in risk with adjuvant therapy, toxicities of therapy, and its impact on quality of life. . . . Patients with tumors less than or equal to 1 centimeter have an excellent prognosis and do not require adjuvant systemic therapy outside of clinical trials.
In May 1988, physicians throughout the United States received a mailing labeled “NCI CLINICAL ALERT: URGENT. ” This alert reported the preliminary results of three American trials evaluating the role of adjuvant therapy for axillary lymph node-negative breast cancer (1). Noting that all three trials suggested a benefit for patients receiving adjuvant therapy, the alert concluded: “Adjuvant hormonal or cytotoxic chemotherapy can have a meaningful impact on the natural history of Stage 1 breast cancer patients. . . . Outside of a trial setting, the hormonal and chemotherapy treatments described represent credible therapeutic options worthy of careful attention.” Subsequently, in June 1990, the National Institutes of Health Consensus Development Conference on Early Stage Breast Cancer took up the question of adjuvant therapy for node-negative breast cancer (2). Reviewing much the same data, its panelists concluded:
While not overtly contradictory, the clinical alert and the consensus panel statements differed in both tone and therapeutic recommendations. Of note, the consensus panel’s only specific recommendation regarding adjuvant therapy for node-negative patients was negative: small node-negative tumors should not be treated. Given this dissonance, what decisions should the individual clinician make when recommending therapy to his patient with node-negative breast cancer? In this and the following issue of Cancer Znvesrigation, the complex problem
The majority of patients with node negative breast cancer are cured by breast conservation treatment or total mastectomy and axillary dissection. The 595 Copyright 0 1992 by Marcel Dekker, Inc.
Sledge and McCaskill-Stevens
Cancer Invest Downloaded from informahealthcare.com by University of Newcastle on 12/30/14 For personal use only.
596
ADJUVANT CHEMOTHERAPY FOR NODE-NEGATIVE BREAST CANCER: THE CURRENT DATABASE
posed by node-negative breast cancer is discussed at length. This article will review the role of adjuvant chemotherapy in node-negative breast cancer. In evaluating the place of adjuvant therapy in nodenegative breast cancer patients, several questions need to be addressed: (1) What database are we working from in considering adjuvant therapy for node-negative breast cancer? (2) What are the results of currently available clinical trials? (3) How should these results be interpreted? (4) What price must the patient pay, in terms of both physical and financial cost, for the benefits obtained from adjuvant chemotherapy? (5) What questions remain to be answered with regard to adjuvant therapy for nodenegative breast cancer?
Although many oncologists think of adjuvant chemotherapy for node-negative breast cancer in terms of the work discussed in the National Cancer Institute’s Clinical Alert, the true database is simultaneously much broader and more complex. A representative, though undoubtedly incomplete, sample of node-negative adjuvant chemotherapy trials, shown in Table 1 (3-20), includes trials in which 5970 patients were entered. This table lists the regimens utilized, the entrance criteria employed, and the median follow-up time for the protocols.
Table 1
Trial Scandinavian
Adjuvant Chemotherapy Trials in Node-Negative Breast Cancer N Patient selection Randomization
Ref.
609
All N -
C vs. control
3,4
1137
All N -
C vs. control
19
Vienna
128
All N -
CFVM(-t a) vs. control
8,32
West Midlands Oncology Association
574
All N -
LMF vs. control
15,16
OSAKO
254
All N -
LMF + BCG vs. control
7
Wuerzberg
175
All N-
CMF vs. XRT
17
Cancer Research Campaign
Mastectomy Leningrad
46 1
All N -
T vs. TMF or CMF vs. control
18
1275
All N -
CMFl vs. control
14
Cardiff
52
N-ER-
AVC vs. control
20
Milan
90
N-ER-
CMF vs. control
9,lO
679
N-ER-
MF vs. control
11,13
536
N-ER-, >3 cm
Ludwig Trial V
NSABP B-13 Intergroup Total
N-ER+
CMFp vs. control
5970
+
N = number of patients; N - = node negative; ER - = estrogen receptor negative; ER = estrogen receptor positive; C = cyclophosphamide; F = 5-fluorouracil; V = vincristine; M = methotrexate; a = azimexon; L = leukeran; A = adriamycin (doxorubicin); T = thiotepa; I = leucovorin; p = prednisone; XRT = radiation therapy to chest wall and regional lymph nodes.
Cancer Invest Downloaded from informahealthcare.com by University of Newcastle on 12/30/14 For personal use only.
Adjuvant Chemotherapy for Node-Negative Breast Cancer Only prospective, randomized trials are included in this list, though it should be noted that innovative nonrandomized trials (such as that of the University of Arizona) have had an important influence on subsequent trial design (21). Even a cursory glance at such a list reveals several important observations. First, the entrance criteria employed for such trials can be divided into two distinct groups: those in which node-negative patients were entered without regard to any specific selection criteria, and those in which a specific effort was made to limit the trial to those node-negative patients at high risk for recurrence (e.g., the Intergroup trial, in which the presence of either a steroid-receptor-negative tumor or a steroid-receptor-positive tumor > 3 cm in diameter was required for entry into the study). Each of these approaches has obvious benefits and drawbacks. Studies in which all node-negative patients were entered are more representative of the entire node-negative population than trials limiting entry to certain high-risk subgroups. Conversely, such “broad entry” trials are less likely than “narrow entry” trials to show significant survival differences between treatment and control groups, given the dilution of their statistical base with large numbers of patients at low risk for early relapse. Second, it should be realized that subtle entry biases sneak into even the best-designed clinical trials. Physicians (and patients) may refuse to enter patients into a trial owing to perceptions regarding risk of relapse, benefits of therapy, and toxicity of therapy. Similarly, structural considerations may limit or affect entrance. To cite but one example of this, both the NSABP B-13 trial and the Intergroup trial required that steroid receptor determinations be determined by the dextran-coated charcoal methodology ( 5 , l l ) . Many node-negative tumors contain insufficient tumor sample to perform this assay, eliminating many smaller tumors from consideration for entry into the trial. Third, although some of the studies have relatively large numbers of patients, and some have relatively long follow-up times, many of the studies have either insufficient numbers of patients to detect a statistically significant difference in relapse-free survival or insufficient follow-up time to demonstrate a difference in overall survival. It should be remembered that one of the more important observations of the first (node-positive) generation of adjuvant therapy trials, namely the small, but real, benefit of adjuvant tamoxifen in postmenopausal patients, required the meta-analysis of a significant number of trials involving large numbers of patients followed
591
for relatively long periods before receiving general acceptance.
EFFECT OF ADJUVANT CHEMOTHERAPY ON RELAPSE AND SURVIVAL The results of adjuvant chemotherapy trials are shown in Table 2. With regard to relapse rate, the results are consistent and routinely demonstrate a lower likelihood of recurrence in treated patients compared to controls. Although the magnitude of this effect varies, and in many trials fails to reach statistical significance, in none of the trials did patients receiving therapy have a higher relapse rate than those not receiving adjuvant therapy. By our calculation, the total 0 - E (observed cases relapsing-expected number of relapses) for these trials (excluding the Vienna trial, where relapse-free survival data were not available in the published literature) was - 136.48, suggesting a substantial decrease in the total number of early relapses for patients receiving adjuvant chemotherapy. Furthermore, if one examines those trials showing the greatest effect of adjuvant therapy on relapse-free survival, it is evident that the most successful trials have two elements in common: they have selected patients for trial entry based on a perceived increase in risk of recurrence (e.g., ER negativity or increased tumor size), and they have utilized combination chemotherapy administered for multiple cycles. The former practice has the effect of eliminating those patients at lowest risk for early relapse. The use of multicycle combination chemotherapy, on the other hand, is likely to increase the magnitude of tumor cell kill and therefore improve relapse-free survival, as demonstrated in the meta-analysis of node-positive trials (22). As yet, most adjuvant chemotherapy trials have failed to demonstrate a statistically significant effect of treatment on overall survival. This is unsurprising in those trials in which the decrease in relapse rates is relatively small. Such trials lack statistical power to detect small differences in overall survival. More recent trials (e.g., NSABP B-13 and the Intergroup trial) in which differences in relapse-free survival are relatively large have had insufficient follow-up time-hence too few deathsto demonstrate statistically significant effects on survival. Though the Milan trial shows an impressive reduction in death rate among treated patients, it involved significantly fewer patients than either the Intergroup or NSABP trials and therefore is subject to the criticism that chance imbalances in known or unknown prognostic
Sledge and McCaskill-Stevens
598
Table 2 Effect of Adjuvant Chemotherapy on Survival: Trial Results F/U RFS (%) p value
Trial
Regimen
Scandinavian
c
20
Cancer Invest Downloaded from informahealthcare.com by University of Newcastle on 12/30/14 For personal use only.
Control
0s (%)
p value
52 39.5
Cancer Invest Downloaded from informahealthcare.com by University of Newcastle on 12/30/14 For personal use only.
Adjuvant Chemotherapy for Node-Negative Breast Cancer George W. Sledge, Jr., M.D. and Worta McCaskill-Stevens, M.D. Department of Medicine lndiana University School of Medicine Indianapolis, lndiana 46202
INTRODUCTION
rate of local and distant recurrence following local therapy for node negative breast cancer is decreased by both adjuvant combination cytotoxic chemotherapy and by adjuvant tamoxifen. The decision to use adjuvant treatment should follow a thorough discussion with the patient regarding the likely risk of recurrence without adjuvant therapy, the expected reduction in risk with adjuvant therapy, toxicities of therapy, and its impact on quality of life. . . . Patients with tumors less than or equal to 1 centimeter have an excellent prognosis and do not require adjuvant systemic therapy outside of clinical trials.
In May 1988, physicians throughout the United States received a mailing labeled “NCI CLINICAL ALERT: URGENT. ” This alert reported the preliminary results of three American trials evaluating the role of adjuvant therapy for axillary lymph node-negative breast cancer (1). Noting that all three trials suggested a benefit for patients receiving adjuvant therapy, the alert concluded: “Adjuvant hormonal or cytotoxic chemotherapy can have a meaningful impact on the natural history of Stage 1 breast cancer patients. . . . Outside of a trial setting, the hormonal and chemotherapy treatments described represent credible therapeutic options worthy of careful attention.” Subsequently, in June 1990, the National Institutes of Health Consensus Development Conference on Early Stage Breast Cancer took up the question of adjuvant therapy for node-negative breast cancer (2). Reviewing much the same data, its panelists concluded:
While not overtly contradictory, the clinical alert and the consensus panel statements differed in both tone and therapeutic recommendations. Of note, the consensus panel’s only specific recommendation regarding adjuvant therapy for node-negative patients was negative: small node-negative tumors should not be treated. Given this dissonance, what decisions should the individual clinician make when recommending therapy to his patient with node-negative breast cancer? In this and the following issue of Cancer Znvesrigation, the complex problem
The majority of patients with node negative breast cancer are cured by breast conservation treatment or total mastectomy and axillary dissection. The 595 Copyright 0 1992 by Marcel Dekker, Inc.
Sledge and McCaskill-Stevens
Cancer Invest Downloaded from informahealthcare.com by University of Newcastle on 12/30/14 For personal use only.
596
ADJUVANT CHEMOTHERAPY FOR NODE-NEGATIVE BREAST CANCER: THE CURRENT DATABASE
posed by node-negative breast cancer is discussed at length. This article will review the role of adjuvant chemotherapy in node-negative breast cancer. In evaluating the place of adjuvant therapy in nodenegative breast cancer patients, several questions need to be addressed: (1) What database are we working from in considering adjuvant therapy for node-negative breast cancer? (2) What are the results of currently available clinical trials? (3) How should these results be interpreted? (4) What price must the patient pay, in terms of both physical and financial cost, for the benefits obtained from adjuvant chemotherapy? (5) What questions remain to be answered with regard to adjuvant therapy for nodenegative breast cancer?
Although many oncologists think of adjuvant chemotherapy for node-negative breast cancer in terms of the work discussed in the National Cancer Institute’s Clinical Alert, the true database is simultaneously much broader and more complex. A representative, though undoubtedly incomplete, sample of node-negative adjuvant chemotherapy trials, shown in Table 1 (3-20), includes trials in which 5970 patients were entered. This table lists the regimens utilized, the entrance criteria employed, and the median follow-up time for the protocols.
Table 1
Trial Scandinavian
Adjuvant Chemotherapy Trials in Node-Negative Breast Cancer N Patient selection Randomization
Ref.
609
All N -
C vs. control
3,4
1137
All N -
C vs. control
19
Vienna
128
All N -
CFVM(-t a) vs. control
8,32
West Midlands Oncology Association
574
All N -
LMF vs. control
15,16
OSAKO
254
All N -
LMF + BCG vs. control
7
Wuerzberg
175
All N-
CMF vs. XRT
17
Cancer Research Campaign
Mastectomy Leningrad
46 1
All N -
T vs. TMF or CMF vs. control
18
1275
All N -
CMFl vs. control
14
Cardiff
52
N-ER-
AVC vs. control
20
Milan
90
N-ER-
CMF vs. control
9,lO
679
N-ER-
MF vs. control
11,13
536
N-ER-, >3 cm
Ludwig Trial V
NSABP B-13 Intergroup Total
N-ER+
CMFp vs. control
5970
+
N = number of patients; N - = node negative; ER - = estrogen receptor negative; ER = estrogen receptor positive; C = cyclophosphamide; F = 5-fluorouracil; V = vincristine; M = methotrexate; a = azimexon; L = leukeran; A = adriamycin (doxorubicin); T = thiotepa; I = leucovorin; p = prednisone; XRT = radiation therapy to chest wall and regional lymph nodes.
Cancer Invest Downloaded from informahealthcare.com by University of Newcastle on 12/30/14 For personal use only.
Adjuvant Chemotherapy for Node-Negative Breast Cancer Only prospective, randomized trials are included in this list, though it should be noted that innovative nonrandomized trials (such as that of the University of Arizona) have had an important influence on subsequent trial design (21). Even a cursory glance at such a list reveals several important observations. First, the entrance criteria employed for such trials can be divided into two distinct groups: those in which node-negative patients were entered without regard to any specific selection criteria, and those in which a specific effort was made to limit the trial to those node-negative patients at high risk for recurrence (e.g., the Intergroup trial, in which the presence of either a steroid-receptor-negative tumor or a steroid-receptor-positive tumor > 3 cm in diameter was required for entry into the study). Each of these approaches has obvious benefits and drawbacks. Studies in which all node-negative patients were entered are more representative of the entire node-negative population than trials limiting entry to certain high-risk subgroups. Conversely, such “broad entry” trials are less likely than “narrow entry” trials to show significant survival differences between treatment and control groups, given the dilution of their statistical base with large numbers of patients at low risk for early relapse. Second, it should be realized that subtle entry biases sneak into even the best-designed clinical trials. Physicians (and patients) may refuse to enter patients into a trial owing to perceptions regarding risk of relapse, benefits of therapy, and toxicity of therapy. Similarly, structural considerations may limit or affect entrance. To cite but one example of this, both the NSABP B-13 trial and the Intergroup trial required that steroid receptor determinations be determined by the dextran-coated charcoal methodology ( 5 , l l ) . Many node-negative tumors contain insufficient tumor sample to perform this assay, eliminating many smaller tumors from consideration for entry into the trial. Third, although some of the studies have relatively large numbers of patients, and some have relatively long follow-up times, many of the studies have either insufficient numbers of patients to detect a statistically significant difference in relapse-free survival or insufficient follow-up time to demonstrate a difference in overall survival. It should be remembered that one of the more important observations of the first (node-positive) generation of adjuvant therapy trials, namely the small, but real, benefit of adjuvant tamoxifen in postmenopausal patients, required the meta-analysis of a significant number of trials involving large numbers of patients followed
591
for relatively long periods before receiving general acceptance.
EFFECT OF ADJUVANT CHEMOTHERAPY ON RELAPSE AND SURVIVAL The results of adjuvant chemotherapy trials are shown in Table 2. With regard to relapse rate, the results are consistent and routinely demonstrate a lower likelihood of recurrence in treated patients compared to controls. Although the magnitude of this effect varies, and in many trials fails to reach statistical significance, in none of the trials did patients receiving therapy have a higher relapse rate than those not receiving adjuvant therapy. By our calculation, the total 0 - E (observed cases relapsing-expected number of relapses) for these trials (excluding the Vienna trial, where relapse-free survival data were not available in the published literature) was - 136.48, suggesting a substantial decrease in the total number of early relapses for patients receiving adjuvant chemotherapy. Furthermore, if one examines those trials showing the greatest effect of adjuvant therapy on relapse-free survival, it is evident that the most successful trials have two elements in common: they have selected patients for trial entry based on a perceived increase in risk of recurrence (e.g., ER negativity or increased tumor size), and they have utilized combination chemotherapy administered for multiple cycles. The former practice has the effect of eliminating those patients at lowest risk for early relapse. The use of multicycle combination chemotherapy, on the other hand, is likely to increase the magnitude of tumor cell kill and therefore improve relapse-free survival, as demonstrated in the meta-analysis of node-positive trials (22). As yet, most adjuvant chemotherapy trials have failed to demonstrate a statistically significant effect of treatment on overall survival. This is unsurprising in those trials in which the decrease in relapse rates is relatively small. Such trials lack statistical power to detect small differences in overall survival. More recent trials (e.g., NSABP B-13 and the Intergroup trial) in which differences in relapse-free survival are relatively large have had insufficient follow-up time-hence too few deathsto demonstrate statistically significant effects on survival. Though the Milan trial shows an impressive reduction in death rate among treated patients, it involved significantly fewer patients than either the Intergroup or NSABP trials and therefore is subject to the criticism that chance imbalances in known or unknown prognostic
Sledge and McCaskill-Stevens
598
Table 2 Effect of Adjuvant Chemotherapy on Survival: Trial Results F/U RFS (%) p value
Trial
Regimen
Scandinavian
c
20
Cancer Invest Downloaded from informahealthcare.com by University of Newcastle on 12/30/14 For personal use only.
Control
0s (%)
p value
52 39.5
