Postmastectomy radiation in patients with one to three positive axillary nodes receiving adjuvant chemotherapy: An unresolved issue

Postmastectomy Radiation in Patients With One to Three Positive Axillary Nodes Receiving Adjuvant Chemotherapy: An Unresolved Issue Barbara Fowble The rationale for postmastectomy radiation is based on the prevention of Iocoregional recurrence in the chest wall, regional lymphatics, or both. The randomized trials of postmastectomy radiation in patients with one to three positive nodes receiving adjuvant chemotherapy have shown a proportional reduction in Iocoregional recurrence rates of two thirds. The absolute benefit, however, varies with the magnitude of the risk in patients who do not receive radiation. The survival benefit from radiation is best explained by the prevention of an isolated Iocoregional recurrence, which could

serve as a source of fatal distant metastases and parallels the difference in the total incidence of distant metastases, The current dilemma is to identify patients with one to three positive nodes who have had an adequate axillary dissection and remain at substantial risk for a Iocoregional recurrence despite adjuvant chemotherapy. The routine use of postmastectomy radiation in all axillary node-positive patients requires further evaluation. Copyright 9 1999 by W.B. Saunders Company

he traditional rationale for postmastectomy radiation has been the prevention of recurrent disease in the chest wall, regional lymphatics (axillary, supraclavicular, and internal mammary nodes), or both. A meta-analysis of the early randomized trials of postmastectomy radiation demonstrated a two thirds reduction in locoregional recurrence with radiation when compared to surgery alone. 1 This benefit did not translate into a statistically significant improvement in survival?-6 In addition, radiation technique contributed to an increased incidence of non-breast cancer deaths resulting from cardiovascular disease, which offset any benefit in terms of breast cancer mortality. 1,7,8 These studies as well as the emergence of effective chemotherapy and hormonal therapy for axillary node-negative and axillary nodepositive breast cancer patients 9,1~ resulted in an almost complete reliance on surgery and systemic therapy without radiation to prevent locoregional recurrence as well as distant metastases. H,12 Subsequent studies, however, have identified patients with invasive cancers 5 cm or larger or with four or more positive axillary nodes as having a substantial risk of locoregional recurrence (20% to 30%) despite adjuvant chemotherapy. 13-21In addition, locoregional recurrence rates do not appear to be significantly influenced by the type of chemotherapy regimen, the

duration of treatment, the use of sequential or alternating regimens, or dose intensity. 22,23 The increasing recognition that systemic therapy alone does not effectively prevent locoregional recurrence in high-risk patients as well as the publication of two prospective, randomized trials demonstrating a survival benefit with radiation in premenopausal or perimenopausal women receiving cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy has resulted in a renewed interest in postmastectomy radiation. 24,25 Some investigators now recommend postmastectomy radiation in all axillary node-positive women, whereas others support its use primarily in high-risk women (ie, four or more positive nodes or primary tumor size -> 5 cm). 12,26y A commentary on the controversies and uncertainties generated by the British Columbia and Danish Breast Cancer Group trials as perceived by 12 radiation oncologists from the United States, Canada, and Europe has been published, ll There was general agreement among the authors that these studies supported the role of postmastectomy radiation in premenopausal or perimenopausal women with T3 primary tumors or those with four or more positive axillary nodes. Several radiation oncologists raised concern regarding the findings in women with T1 or T2 tumors and one to three positive nodes and their applicability to patients treated in the United States. The unquestioning acceptance of what were previously perceived as low-risk patients (T1 or T2 tumors with one to three positive nodes) as candidates for postmastectomy radiation requires further evaluation. This discussion focuses on postmastectomy locoregional recurrence rates in patients with T1 or

T

From the Department of Radiation Oncology,Fax Chase Cancer Center, Philadelphia, PA. Address reprint requests to Barbara Fowble, MD, Radiation Oncology, Fox Chase CancerCenter, 7701 BurholmeAvenue, Philadelphia, PA 19111. Cop.)~ght 9 1999 by W.B. Saunders Company 1053-4296/99/0903-0003510.00/0

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Seminars in Radiation Oncology, Vol 9, No 3 (July), 1999:pp 230-240

PostmastectomyRadiation in Patients With 1-3 Positive Nodes

T2 tumors and one to three positive nodes; factors that influence these rates; the results of prospective, randomized trials in this patient subgroup; and possible explanations for a survival benefit or lack thereof.

Postmastectomy Locoregional Recurrence Rates of T1-T2 Breast Cancer With One to Three Positive Axillary Nodes Locoregional recurrence rates after mastectomy in patients receiving adjuvant chemotherapy are not well documented, especially for certain prognostic subgroups. Tables 1 and 2 present data from retrospective series as well as prospective, randomized trials comparing different chemotherapy regimens for women with one to three positive axillary nodes. The term isolated Iocoregional recurrence refers to, in general, a first site of failure in the chest wall or axillary, supraclavicular, or internal m a m m a r y nodes without the simultaneous presence of distant metas-

Table 1.

Postmastectomy Locoregional Recurrence Rates in Patients With One to Three Positive Axillary Nodes Receiving CMF

Chemotherapy Randomized Trials SEG~8 Milan 29 NCCTGI 7 TI

Percentageof Isolated (Total) No. Locoregional Interval Pts Recurrence Reported (y) 302 141 342 146

T2

196

ER < I0

110

ER >- 10

193

IBCSG6:~ 491 ECOG 14 3t0 GABG 18 138 -<49 y 70 >-50 y 68 Retrospective Series Fisher et al4~ 120 Rao et aP 6 53 Stefanik et al ~5 52 Lee 13 33

9 (11) 7 8* 6 17 10 18 14 19 5 17 8 7 10 4 16 8t 6 9 9 (9)

10 median 8 3 3 8 3 8 3 8 3 8 4 median 3 6 6 6 6.4 median 5.2 median 5 4.4 median

*CFP .T. + tamoxifen. tChest wall only with modifications CMF. Abbreviations: CMF, cyclophosphamide, 5-fluorouracil, prednisone; ER, estrogen receptor; C, cyclophosphamide; M, methotrexate; F, 5-fluorouracil.

231

Table 2. Postmastectomy I_ocoregional Recurrence Rates in Patients With One to Three Positive Nodes Receiving Doxorubicin-Based Regimens

Chemotherapy Randomized Trials

No. Pts

Percentage of Isolated (Total) Interval Chemo- Locoregional Reported therapy Recurrence (y)

M. D. Anderson64 125 FAC Milan '~6 243 CMF---* A Retrospective Series Sykes et a119 98 AC

7 5 (8)* 10

5 5 median 2.9 median

*47% breast conservation therapy. Abbreviations: F, 5-fluorouracil; A, doxorubicin (Adriamycin); C, cyclophosphamide; M, methotrexate.

tases. The term total tocoregional recurrence includes patients who present with simultaneous distant metastases. A distinction between the two terms has therapeutic implications. Prevention of an isolated locoregional recurrence has the potential for a survival benefit. Prevention o f a locoregional recurrence associated with distant metastases may improve quality of life but not survival. For patients with one to three positive nodes receiving CMF, isolated locoregional recurrence rates range from 4% to 19%. In the study reported by Pisansky et a117 from the North Central Cancer Treatment Group, patients with T I or T2 tumors receiving CFP_+T (cyclophosphamide, 5-fluorouracil, prednisone, with or without tamoxifen) had a 17% and 18% 8-year locoregional recurrence rate. The estrogen receptor status did not significantly influence these rates. In contrast with a 10-year median follow-up, Velez-Garcia et a128from the Southeastern Cancer Group (SEG) reported a 9% isolated locoregional recurrence rate in 302 women with one to three positive axillary nodes. The Milan trial of CMF also reported a relatively low locoregional recurrence rate (7% at 8 years), although the majority of patients had undergone a radical mastectomy39 The use of doxorubicin-based regimens has been associated with postmastectomy locoregional recurrence rates of 10% of less in patients with one to three positive axillary nodes (Table 2). A concern related to these studies is the relative absence of 10-year data, especially for the doxorubicinbased regimens. Pisansky et a117 reported that 60% of all locoregional recurrences were seen within 3 years, with 90% by 6.5 years in patients receiving CFP+__T. Therefore, the 10-year rates could be estimated to be

232

Barbara Fowble

20% to 25% higher than the 5-year rates presented in Tables 1 and 2 (ie, in the range of 10% to t5%). The absence of long-term data has prompted others to evaluate locoregional control rates in patients receiving adjuvant chemotherapy after mastectomy. The Eastern Cooperative Oncology Group (ECOG) completed an analysis of 2,016 premenopausal and postmenopausal women entered into four randomized trials evaluating CMF with or without prednisone or tamoxifen and an alternating regimen including doxorubicin,a~ The total cumulative incidence of a locoregional recurrence in women with one to three positive nodes was 12.9% at 10 years. Theriault et a127 also reported an 11% crude locoregional recurrence rate in 409 axillary node-positive women younger than 50 years of age who received 5-fluorouracil, doxorubicin (Adriamycin [Pharmacia & Upjohn, Kalamazoo, MI]), cyclophosphamide (FAC) chemotherapywith a median follow-up of 13.7 years. In the past, the magnitude of the risk of locoregional recurrence after mastectomyinfluenced recommendations for postoperative radiation. A risk of 20% to 30% was considered by most radiation oncologists as sufficient enough to justify radiation even in the absence of a statistically significant survival benefit. A risk of 10% to 15% generally did not result in a recommendation for postmastectomy radiation given the potential for morbidity. Knowledge of the longterm risk of locoregional recurrence in women with T1 or T2 tumors and one to three positive axillary nodes is becoming increasingly important if recommendations for postmastectomy radiation are to continue to be based primarily on the absolute benefit of reducing this pattern of failure.

Factors Influencing the Risk of Postmastectomy Locoregional Recurrence in Patients Receiving Adjuvant Chemotherapy Factors that influence the risk of a postmastectomy locoregional recurrence in patients receiving chemotherapy may be divided into three categories: clinical, pathological, and treatment related. One factor that is not frequently considered is the definition of a locoregional recurrence. Surgical series often define a locoregional recurrence as one in the operative site only (ie, chest wall or axilla). The exclusion of supraclavicular recurrences from the definition of a locoregional recurrence decreases the reported rate by 20% to 30% because the second most common site of such a recurrence after mastectomy is the supracla-

vicular region.3133Similarly, if the definition includes patients who present with simultaneous distant metastases, the reported rate is 20% higher because 20% of patients receiving chemotherapy who experience a locoregional recurrence have simultaneous distant metastases. 24,34,35 A clinical factor that may influence locoregional recurrence rates is patient age. Young age has been associated with an increased risk of tocoregional recurrence in some series] 6 but not others. ~4,3GIn the Gynecologic Adjuvant Breast Group study,36 women 49 years old or younger with one m three positive nodes had a lower postmastectomy locoregional recurrence rate when compared to women 50 years old or older (4% versus 16%). The single pathological factor that may influence locoregional recurrence rates in patients with T1 or T2 tumors and one to three positive nodes is the status of the mastectomy resection margin. Freedman et a137reported a 28% cumulative incidence of a chest wall recurrence in women 50 years old or younger with zero to three positive axillary nodes and a close (<-5 ram) or positive margin. The cumulative incidence at 8 years was 24% for T2 tumors compared to 7% for T1 tumors. Pisansky et al t7 found no correlation with tumor size (T1 versus T2) and locoregional recurrence rates in patients with one to three positive nodes unrelated to margin status. Estrogen receptor negativity has been found to correlate with locoregional recurrence rates in patients receiving doxorubicin-based regimens19; however, Pisansky et a117found no such correlation in patients receiving CFP + T (Table 1). Treatment-related factors that may influence locoregional recurrence rates include the adequacy of the axillary dissection; the type of mastectomy; and the chemotherapy regimen, duration, or intensity. Axillary recurrences have been correlated with the number of axillary nodes removed and examined34,3a-4~ In the NSABP B04 trial, patients with clinically negative axillae who had no axillary nodes removed at the time of a total mastectomy had a 21% axillary recurrence rate. 5 In contrast, the axillary recurrence rate was less than 1% for patients who had 10 or more nodes removed. 38Eighty-four percent of these patients had primary tumors 5 cm or smaller. Axillary recurrence rates in patients with histologically negative axillary nodes range from 8% to 16% when an axillary sampling is performed compared to 3% for an axillary dissection.41,42 For patients with histologically positive axillary nodes, axiUary recurrence rates range from 12% to 29% with

PostmastectomyRadiation in Patients With 1-3 Positive Nodes

an axillary sampling compared to 3% for a dissection. 4L43Wilking et aP 9 reported a 6% axillary recurrence rate in patients with 1 to 3 positive axillary nodes who had 1 to 4 nodes examined compared to 1% for 10 or more nodes examined. The type of mastectomy (ie, radical versus modified radical mastectomy) has been reported to influence postmastectomy locoregional recurrence rates in the absence of chemotherapy for T3 tumors but not T1 or T2 tumors. 44,45 In the ECOG analysis of patients treated with CMFP_+T, the type of mastectomy did not influence locoregional recurrence rates.14 In a review, postmastectomy locoregional recurrence rates in axiUary node-positive women were not found to be significantly diminished with the use of multiagent chemotherapy when compared to a single agent, the duration of chemotherapy, the use of doxorubicin-based regimens, sequential versus alternating regimens, or dose intense regimens. 22 For patients with one to three positive axillary nodes in the Milan trials, 12 months of CMF was equivalent to 6 months in terms oflocoregional recurrence rates. 29 In the SEG trial, the isolated locoregional recurrence rates at 10 years was 12% for patients with one to three positive nodes who received 6 cycles of CMF compared to 5% for those who received 12 cycles38 The Milan trial of sequential CMF also demonstrated no difference in locoregional recurrence rates for patients with one to three positive nodes when comparing these two regimens. 46 Two studies have also failed to demonstrate a decrease in postmastectomy locoregional recurrence rates with variations in the dose of CMF. 14,15 Similarly, three additional studies have failed to demonstrate a significant impact on locoregional recurrence rates with dose intense regimens. 47-49 Therefore, the two factors

233

most likely to have an impact on locoregional recurrence rates in patients with T1 or T2 tumors and one to three positive axillary nodes are the adequacy of the axillary dissection and the status of the mastectomy resection margin.

Results of Prospective, Randomized Trials of Adjuvant Chemotherapy With or Without Radiation in Patients with One to Three Positive Axillary Nodes Thirteen prospective, randomized trials have evaluated the role of postmastectomy radiation in axillary node-positive patients receiving adjuvant chemotherapy. Six of these trials 24,34,35,5~ have reported results for the subgroup of patients with one to three positive nodes (Tables 3 and 4). The addition of radiation decreased the incidence oflocoregional recurrence in the four trials in which this information was reported with a similar proportional reduction of two thirds. The magnitude of the risk of recurrence in patients who did not receive radiation varied considerably. An unexpected finding from the British Columbia and Danish trials was the relatively high total locoregional recurrence rate in premenopausal patients with one to three positive axillary nodes receiving CMF without radiation. With a median follow-up of 9.5 years, the Danish trial reported a crude total locoregional recurrence rate of30%fl 4 Isolated locoregional recurrence rates were not presented; however, it was stated that 21% of the patients who received CMF alone and experienced a locoregional failure had simultaneous distant metastases. Therefore, the crude isolated locoregional rate recurrence could be estimated at 24%. In the British Columbia trial, the 10- and 15-year actuarial rates of survival free of

Table3.

Postmastectomy Locoregional Recurrence Rates in Patients With One to Three Positive Axillary Nodes: Prospective, Randomized Trials Comparing Adjuvant Chemotherapy With or Without Radiation Percentageof Isolated (Total) LocoregionalRecurrence Total No. Pts CMF Regimens Premenopausal women British Columbia25 Danish 24 All patients Dana Farber52 Doxorubicin Regimens University of Arizona51

Chemotherapy

Chemotherapy and XR T

Interval Reported(y)

183 1,061

(33) (30)

(I 0) (7)

15 actuarial 9.5 median

83

5

2

4.4 median

87

11

0

5 actuarial

Abbreviations:CMF,cyclophosphamide,methotrexate,5-fluorouracil;XRT, radiation.

234

BarbaraFowble

Table 4. Results of Prospective, Randomized Trials Evaluating Postmastectomy Radiation in Patients with One to Three Positive Axillary Nodes Receiving Adjuvant Chemotherapy

CMF Regimens British Columbia (pre) 25 Danish (pre) 24 Glasgow35 Pre Post Dana Farber 52 Doxorubicin Based University of Arizona51

No. Pts

Absolute Reduction LocoregionalRecurrence With Radiation

Percentage of Overall Survival Chemotherapy Chemotherapy and X R T

183 1,061 141 NS NS 83

23% 23% NS NS NS 3%

48* (+ 16) 54 (+8) 68t (+8) 84t (-6) 61? (+ 12) 85 (-8)

87

11%

71:~ (+17)

P Value

Interval Reported(y)

64* 62 76t 78? 73? 77

.06 -.76 .40 .86 >.05

15 actuarial 10 actuarial 5 actuarial

88:~

<.05

5 actuarial

4.4 median

NOTE. Numbers in parentheses indicate the absolute difference in survival. *Survivalfree of systemicdisease. tCause-specificsurvival. :~Relapse-freesurvival. Abbreviations:CMF,cyclophosphamide,methotrexate, 5-fluorouracil;XRT, radiation;NS, not stated.

locoregional disease were 84% and 67% for patients who did not receive radiation. 25Although the 10-year rate is compatible with the estimates at this interval from Tables 1 and 2, the doubling of the rate between 10 and 15 years in the British Columbia trial suggests a late pattern of failure not previously described. The 30% total locoregional recurrence rate in the Danish trial for women receiving CMF may be explained, in part, by the axillary procedure performed. In this trial, the median number of axillary nodes examined was 7, and 45% of the recurrences were in the axilla. 53 In contrast, most other series have reported axillary recurrences to comprise 5% of the patients who experience a locoregional recurrence after mastectomy. 31-33The elimination of these axillary recurrences with an axillary dissection would translate into a locoregional recurrence rate of approximately 16% in the Danish trial in patients with one to three positive nodes. Similarly the median number of axillary nodes examined in the British Columbia trial was 11, and therefore the locoregional recurrence rate in this trial may also be a reflection of the surgery performed. The late pattern of failure between 10 and 15 years, however, remains unexplained. It is also possible that the use of an axillary sampling underestimated the number of positive axillary nodes, and, in fact, some of the women with one to three positive nodes may have actually had four or more positive nodes. Kiricuta and Tausch 54 developed a mathematical model based on 1,446 complete axillary dissections that assessed the prob-

ability of finding additional positive nodes after an axillary sampling of level I nodes. The authors calculated that the probability that the assessment of the axillary node status was correct for the clinical situation of two positive nodes at level I out of eight examined was only 29%. The probability of having four or more nodes positive was 41%. In the multiinstitutional study of sentinel node biopsy, 16% of patients with a single positive sentinel node had four or more positive nodes found on axillary dissection compared to 30% for two positive sentinel nodes and 60% for three positive sentinel nodes. 55 Therefore, there is a significant chance that an axillary sampling or sentinel node biopsy in node-positive patients would underestimate the actual number of positive nodes. Supraclavicular and chest wall recurrences have also been correlated with the number of positive axillary nodes. 13"21,40Patients with four or more positive nodes have a higher risk of a supraclavicular and chest wall recurrence than those with one to three positive nodes. Therefore, an inadequate axillary dissection in histologically node-positive women may result in an increased risk of axillary failure secondary to residual disease as well as an increased risk of supraclavicular and chest wall failure as a result of an underestimation of the number of positive nodes. In the Danish trial, the total locoregional recurrence rates decreased as the number of axillary nodes examined increased. Similar arguments may apply to some of the patients in the British Columbia trial because the median number of axillary nodes examined was 11. Kiricuta and Tausch 54 suggest that more

PostmastectomyRadiation in Patients With 1-3 PositiveNodes

than 13 nodes are required to assess accurately the extent of nodal positivity in patients with 1 to 3 positive level I nodes. Table 4 presents the survival results of the trials. Two of the five trials have reported an absolute improvement in overall or cause-specific survival with radiation of 8%. 24,35 The Dana Farber trial reported a lower overall survival in patients receiving radiation. 52 Both the British Columbia and the University of Arizona trials reported an improvement in distant disease-free survival or relapse-free survival.25,51 In an update of the British Columbia trial, presented by RagazJ at the 40th annual meeting of the American Society of Therapeutic Radiologists and Oncologists, there was no survival benefit with radiation in patients with one to three positive nodes who did not have extracapsular extension, and the benefit in those with extracapsular extension did not reach statistical significance. The Piedmont Oncology Association trial reported crude recurrence rates with a median follow-up of 11 years. 34 For patients with one to three positive nodes randomiz~l to radiation, recurrence rates were 50% for those receiving CMF and 47% for melphalan. In contrast, patients who received CMF or melphalan without radiation had a 25% or 39% recurrence rate. The total number of patients with one to three positive nodes in this trial was 84. The results of the British Columbia and Danish trials were obtained in premenopausal or perimenopausal women. The Glasgow trial reported a nonstatistically significant survival benefit with radiation only in postmenopausal women with one to three positive nodes. 35 Premenopausal women who received radiation had a lower survival. In the Piedmont Oncology Association trial, crude recurrence rates were higher for patients 50 years or younger as well as those older than age 50 who received radiation. 34 The number of patients in these trials is small except for the Danish trial, and the interval at which the results were reported was 5 years or less in three A

Primary treatment

B

Pdmary

treatment

235

of the trials. Therefore, definitive conclusions regarding the benefit of radiation in this patient subgroup are somewhat tenuous. Based on data from the largest trial (Danish), however, a decrease in locoregional recurrence rates from 30% to 7% translates into an 8% improvement in overall survival at 10 years.

Explanations for a Survival Benefit with Postmastectomy Radiation The survival benefit from postmastectomy radiation has been attributed to the eradication of occult residual disease in the chest wall and regional lymphatics with the prevention of secondary fatal distant metastases, which could then arise from uncontrolled locoregional disease. 18,56 The ability of radiation to produce a survival benefit requires that occult residual disease be present and located within the radiation fields and that distant metastases are absent or minimal enough so as to be effectively controlled with systemic therapy. The impact of patterns of failure on outcome is shown in Fig 1. After a mastectomy and adjuvant chemotherapy, patients may experience no treatment failure or one that initially occurs in a locoregional site, distant site, or both. The total incidence of distant metastases is a summation of patterns C, D, and E. Because initial sites of failure are often the only pattern of failure reported, distant metastases occurring after an initial locoregional failure may not be documented. Postmastectomy radiation achieves a survival benefit primarily by affecting pattern C. Radiation has a minimal impact on survival if the magnitude of pattern C is small in patients who do not have radiation, if the magnitude of pattern E is large in radiation patients when compared to no radiation patients, or if locoregional recurrences can be successfully salvaged without resulting in distant metastases (pattern B). Arriagada et all8 using a competing risk approach Alive No evidence of disease P

Iocoregional

=.

recurrence C

Primary treatment

=' I o c o r e g i o n a l

= distant

recurrence

Figure 1. Patterns of failure after mastectomy and adjuvant chemotherapy.

Alive No evidence of disease

metastases

D

Primary treatment

='

Ioceregional recurrence + distant metastases

*

death

E

Primary treatment

p

distant m e t a s t a s e s

,

death

=,

death

236

Barbara Fowble

demonstrated that radiation in the Stockholm trial decreased the total incidence of distant metastases by initially decreasing locoregional recurrences as a first site of failure followed by a decrease in the distant metastases that appeared subsequent to this type of failure (pattern C). The cumulative incidence of distant metastases as a first site of failure was 16% for the no-radiation patients and 24% for the radiation patients (pattern E). The total 15-year cumulative incidence of distant metastases was 27% for both groups despite the fact that the 15-year cumulative rate of locoregional recurrence was decreased from 18% to 2% with radiation. The finding of an identical rate of total distant metastases is due to the higher initial rate of distant metastases in the radiation patients (pattern E) and the fact that not all patients with locoregional recurrence subsequently developed distant metastases (pattern B). In contrast, for axillary node-positive patients, radiation decreased locoregional recurrence rates from 37% to 10%, and the total 15-year cumulative incidence of distant metastases was 54% for radiation patients and 72% for those who did not receive radiation. The distant failure rate as the initial site of failure was 34% for the no-radiation group and 43% for the radiation group. The authors concluded that a 2% survival benefit at 10 years could be seen for axillary nodenegative patients with radiation compared to a 6% benefit for axillary node-positive patients. The greater numerical benefit in the node-positive group reflected a larger absolute benefit in terms of locoregional recurrence as well as the fact that more of the node-positive patients developed distant metastases after their initial locoregional failure than the nodenegative (ie, pattern C predominated over pattern B). In applying these principles to the Danish trial, the crude total locoregional recurrence rates were 30% and 7% without and with radiation for patients with one to three positive nodes. 24 For the overall group, 41% of the radiation patients who had a locoregional failure had simultaneous distant metastases (pattern D) compared to 21% of the CMF patients, and approximately 80% of patients who experienced an isolated locoregional failure developed subsequent distant metastases (pattern C). Distant metastases alone as first site of failure were reported in 23% of the CMF patients and 30% of the CMF and radiation patients (pattern E). Therefore, the total incidence of distant metastases in the CMF patients with one to three positive nodes can be estimated to be 48% and in the CMF and radiation

patients 36%. The overall survival benefit with radiation was 8%, which approximates the 12% estimated difference in total distant metastases. Some patients may still be alive with distant disease. The difference between patients with and without radiation in total distant metastases can be decreased if fewer patients develop distant disease after an isolated locoregional failure (pattern B more common than pattern C) and if more radiation patients have distant metastases as an initial site of failure (pattern E). It is difficult to apply these calculations to the remainder of the trials because sites of first and subsequent failure are not provided. For the Danish trial, however, the survival benefit appears to parallel the locoregional recurrence rate, which impacts on the total distant failure. It has been suggested that patients with one to three positive nodes may have a greater potential for a survival benefit with postmastectomy radiation than those with four or more positive nodes based on the premise that these patients are less likely to have micrometastatic disease at the inception and, if present, would more likely be controlled with systemic therapy (ie, less common pattern E). Patients with four or more positive nodes, however, have a higher incidence of locoregional recurrence after mastectomy and chemotherapy without radiation and are more likely to develop distant metastases after such a recurrence (ie, pattern C). 31'57'58Therefore, patients with four or more positive nodes should have a greater absolute benefit. Table 5 presents a comparison of survival results from the randomized trials for patients with one to three positive nodes and four or more positive nodes. Overall the absolute benefit or lack thereof is similar when comparing the two groups. The Arizona trial is the only one that suggests a greater absolute benefit in relapse-free survival in patients with one to three positive nodes. 51 Patients with four or more positive nodes in this trial, however, had a higher incidence of locoregional recurrence with radiation than without. In the Danish trial, the absolute survival benefit was greater in patients with four or more positive nodes. 24 As previously noted, the survival benefit in the patients with one to three positive nodes could be explained by the high locoregional recurrence rate in the patients who did not receive radiation. Wilking et aP 9 reported an improvement in survival in patients with one to three positive nodes as the number of axillary nodes examined increased. The 7-year survival was 45%, 65%, and 80% for patients with 1 to 3 positive nodes who had fewer than 5 nodes examined, 5 to 9

PostmastectomyRadiation in Patients With 1-3 PositiveNodes

237

Table 5. Survival Benefit in Postmastectomy Radiation Related to Number of Positive Axillary Nodes Percentageof OverallSurvival 1-3 PositiveNodes

Glasgow35 * All pts Premenopausal Postmenopausal Arizona51 t Dana Farber 5z Danish 24 British Columbia 25:[:

>-4PositiveNodes

Chemotherapy

Chemotherapy and XR T

P Value

Chemotherapy

Chemotherapy and X R T

P Value

68 (+8) 84 (-6) 61 (+ 12) 71 (+ 17) 82 (-2) 54 (+8) 49 (+ 14)

76 78 73 88 80 62 63

.76 .40 .86 <.05 .39 -.06

46 (+8) 54 (-5) 43 (+ 15) 59 ( - 13) 55 (-2) 20 (+12) 20 (+ 13)

54 49 58 46 53 32 33

.01 .04 .09 .95 .27

Interval Reported~) 5 actuarial

.05

5 actuarial 5 actuarial 10 actuarial 15 actuarial

NOTE. Numbers in parentheses indicate the absolute difference in survival. *Cause-specificsurvival. tRelapse-free survival. ~:Survivalfree of systemicdisease.

nodes examined, and 10 or more nodes examined. The improvement in survival was greater than the improvement in regional control and reflects a more accurate assessment of the extent of nodal positivity as the number of nodes examined increased. Similar findings were reported by Fisher and Slack. 59 The 5-year survival for patients with 1 to 3 positive nodes was 44% for 1 to 5 nodes examined, 58% for 6 to 10 nodes examined, and 68% for 11 to 15 nodes examined. Therefore, underestimating the number of positive axillary nodes with an axiUary sampling results in both an increase in locoregional recurrence and a decrease in survival. A new concept has been proposed by some investigators to explain the survival benefit with radiation in patients with one to three positive nodes in the British Columbia and Danish trials independent of the improvement in locoregional control. It has been suggested that the internal m a m m a r y nodes may function as sanctuary sites for metastases and, in the absence of a clinically evident recurrence in this region, serve as a source for distant dissemination. Clinical internal m a m m a r y recurrences are uncommon in patients with operable breast cancer treated with mastectomy and adjuvant chemotherapy. 14,53 According to this theory, treatment of the internal m a m m a r y nodes with radiation may not affect the clinical appearance of recurrent disease in this site but results in a decrease in distant metastases. It seems logical that this decrease in distant disease would appear as a decrease in distant metastases as first site of failure and not as a subsequent site because clinical evidence of an internal m a m m a r y node recurrence would not be required to precede

distant metastases. First sites of failure were reported by four of the prospective, randomized trials evaluating postmastectomy adjuvant chemotherapy and radiation. 24,34,35,~t All of these trials included radiation to the internal m a m m a r y nodes either as a direct field 24 or within the chest wall tangential fields. 34 The incidence of distant metastases as a first site of failure was higher in patients who received radiation in each of the trials. In addition, the presence of internal m a m m a r y node metastases has been correlated with the number of positive axillary nodes and is significantly greater for patients with four or more positive nodes when compared to those with one to three positive nodes. 6~ It is also possible that subclinical disease in the internal m a m m a r y nodes can be eradicated by adjuvant chemotherapy without radiation in a manner similar to the downstaging of axillary nodes observed with neoadjuvant chemotherapy. 6~ Yamashita et a162 reported the results of a randomized trial in patients with biopsyproven internal m a m m a r y nodes receiving CMF. The addition of radiation after biopsy did not decrease the incidence of distant metastases when compared to no radiation or radical resection. The use of an inadequate axillary dissection in some of the patients in these trials resulted in an increased risk of axillary failure as well as the underestimation of the extent of nodal positivity (ie, patients with four or more positive nodes may have inadvertently been included in the group with one to three positive nodes). These high-risk patients would have experienced a greater risk of supraclavicular and chest wall failure as well as distant metastases and would have had a greater absolute benefit from

238

Ba~a~Fowb#

radiation. Therefore, it does not appear necessary to invoke the concept that radiation can affect survival w i t h o u t d i m i n i s h i n g clinical locoregional recurrences. T h e survival benefit from radiation in the British C o l u m b i a a n d D a n i s h trials in patients with one to three positive nodes can be a t t r i b u t e d to a decrease in locoregional recurrence rates a n d the p r e v e n t i o n of distant metastases that develop after this initial p a t t e r n of failure.

Summary T h e results of prospective, r a n d o m i z e d trials evaluating p o s t m a s t e c t o m y radiation a n d c h e m o t h e r a p y in p a t i e n t s with T1-T2 breast cancer with one to three positive axillary nodes have b e e n b o t h positive a n d negative. T h e largest trial has shown that a 23% absolute i m p r o v e m e n t in locoregional failure in these p a t i e n t s translates into a survival benefit of 8% at 10 years. At the p r e s e n t time, patients in this subgroup who a p p e a r to have a 25% to 30% risk of locoregional recurrence include those younger t h a n 50 years old with a close or positive m a s t e c t o m y resection m a r g i n or those who have had a n i n a d e q u a t e axillary dissection. A l t h o u g h the e x a m i n a t i o n of 10 or m o r e nodes has b e e n found to decrease the risk of a n axillary recurrence, the n u m b e r of axillary nodes r e q u i r e d to e n s u r e the accuracy of the assessment of the total n u m b e r of nodes positive is u n k n o w n . T h e i m p o r t a n c e of assessing the m a g n i t u d e of the risk of p o s t m a s t e c t o m y locoregional recurrence in p a t i e n t s receiving c h e m o t h e r a p y who have had a n a d e q u a t e axillary dissection has now emerged. Studies suggest a considerably lower risk t h a n that reported by the D a n i s h a n d British C o l u m b i a trials. If u l t i m a t e l y the risk in these patients is proven to be only 10% to 15% at 10 years, the addition of radiation could t r a n s l a t e into a 2% survival benefit, which probably would not justify its routine use. T h e clinical d i l e m m a r e m a i n s to identify patients with T1-T2 t u m o r s a n d one to three positive nodes whose risk of locoregional recurrence is significant e n o u g h to warr a n t radiation in terms of both locoregional control a n d survival.

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