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Originally published as JCO Early Release 10.1200/JCO.2005.02.8738 on April 17 2006 © 2006 American Society of Clinical Oncology. Study of Failure Pattern Among High-Risk Breast Cancer Patients With or Without Postmastectomy Radiotherapy in Addition to Adjuvant Systemic Therapy: Long-Term Results From the Danish Breast Cancer Cooperative Group DBCG 82 b and c Randomized Studies
From the Department of Experimental Clinical Oncology, Department of Oncology, Aarhus University Hospital, Aarhus, Denmark Address reprint requests to Hanne M. Nielsen, MD, Department of Experimental Clinical Oncology, Aarhus University Hospital, Noerrebrogade 44, bygn 5, 2, 8000 Aarhus C, Denmark; e-mail: hmn{at}oncology.dk
Purpose Postmastectomy radiotherapy (RT) in high-risk breast cancer patients can reduce locoregional recurrences (LRRs) and improve disease-free and overall survival. The aim of this analysis was to examine the overall disease recurrence pattern among patients randomly assigned to receive treatment with or without RT. Patients and Methods A long-term follow-up was performed among the 3,083 patients from the Danish Breast Cancer Cooperative Group 82 b and c trials, except in those already recorded with distant metastases (DM) or contralateral breast cancer (CBC). The end points were LRR, DM, and CBC, and the follow-up continued until DM, CBC, emigration, or death. Information was selected from medical records, general practitioners, and the National Causes of Death Registry. The median potential follow-up time was 18 years. Results The 18-year probability of any first breast cancer event was 73% and 59% (P < .001) after no RT and RT, respectively (relative risk [RR], 0.68; 95% CI, 0.63 to 0.75). The 18-year probability of LRR (with or without DM) was 49% and 14% (P < .001) after no RT and RT, respectively (RR, 0.23; 95% CI, 0.19 to 0.27). The 18-year probability of DM subsequent to LRR was 35% and 6% (P < .001) after no RT and RT, respectively (RR, 0.15; 95% CI, 0.11 to 0.20), whereas the probability of any DM was 64% and 53% (P < .001) after no RT versus RT, respectively (RR, 0.78; 95% CI, 0.71 to 0.86). Conclusion Postmastectomy RT changes the disease recurrence pattern in high-risk breast cancer patients; fewer patients have LRR as first site of recurrence, and overall fewer patients have DM.
Postmastectomy radiotherapy (RT) in high-risk breast cancer (BC) patients can reduce locoregional recurrences (LRR) and improve disease-free and overall survival.1-4 In meta-analysis of RT randomization trials, including only trials that also applied systemic therapy (most of them also used modern RT equipment to an appropriate dose and target volume5,6), both a significant reduction in LRR and an improvement in overall survival were seen in patients receiving RT. Three hypotheses have been introduced in relation to the natural history of BC. The first hypothesis (the Halstedian hypothesis, first described in 1894) argues that tumor spreads from the primary site either by direct permeation or through the lymph nodes and then to distant sites, which means that patients can be cured by a sufficient locoregional treatment.7,8 The second hypothesis (the systemic hypothesis introduced in 1980 by Fisher9) argues that the disease has already given rise to distant spread at the time of clinical presentation, and that the primary lymph node involvement only serves as a marker, not a source of distant spread. However this hypothesis was not consistent with the natural history of BC, as shown by Koscielny et al10 in 1984, given that the probability of DM is strongly correlated with tumor size in patients receiving locoregional treatment without chemotherapy. A third hypothesis (the spectrum hypothesis, introduced in 1994 by Hellmann11) suggests, "metastases are a function of tumor growth and progression. Lymph node involvement is of prognostic importance not only because it indicates a more malignant biology, but also because persistent disease in the lymph nodes can be the source of distant spread."11 In the Danish Breast Cancer Cooperative Group (DBCG) 82 b and c trials, only first site of BC events were recorded originally. Given that the no-RT group had an increased risk of LRR and thereby was excluded from registration of further recurrence, patients randomly assigned to RT more often were recorded with distant metastases (DM) than patients randomly assigned to no RT.1,3 Long-term follow-up information is needed to assess whether RT had any protective effect against DM when subsequent disease recurrences, or failures, also are recorded. The aim of this analysis was to examine the overall failure pattern among high-risk BC patients randomly assigned to RT or no RT in addition to systemic therapy.
Study Population and Treatment Details of the two DBCG trials have been described elsewhere.1,3 In brief, 3,083 high-risk BC patients after total mastectomy and partial axillary dissections were included. A median of seven lymph nodes was removed from the axilla. The patients had no evidence of DM, had no history of cancer, had unilateral BC, and were age younger than 70 years. All patients were at high risk of recurrence because of a tumor size larger than 5 cm, and/or positive axillary nodes, and/or invasion of the skin or pectoral fascia. The adjuvant systemic therapy to the premenopausal patients consisted of a combination of cyclophosphamide 600 mg/m2 of body-surface area, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 (CMF) given intravenously every 4 weeks to a total of eight cycles for patients randomly assigned to RT, and nine cycles for patients randomly assigned to no RT.1 The chemotherapy and RT were delivered using a sandwich technique, with the RT interpolated after the first cycle of CMF. The postmenopausal women received tamoxifen 30 mg daily for 1 year.3 The RT in the DBCG 82 b and c trials was intended to cover the chest wall and regional lymph nodes including the axillary, supra/infraclavicular, and ipsilateral internal mammary nodes. Of the 1,538 patients randomly assigned to receive RT, 1,341 (87%) were treated with megavoltage RT with the prescribed dose 50 Gy in 25 fractions, five fractions per week or 48 Gy in 22 fractions, four fractions per week. Orthovoltage RT was delivered to 120 patients (8%) with the prescribed dose of 36 Gy in 20 fractions, five fractions per week. Finally, 77 patients (5%) had no RT or did not complete RT.12
Follow-Up For patients alive with no relapse the first 10 years after treatment, a short questionnaire considering recurrence status was send to their general practitioner. If necessary, relevant hospital medical records were requested. Information was collected from medical records, death certificates, or general practitioners for patients who died more than 10 years after mastectomy but with no relapse the first 10 years, patients with first recurrence as an LRR, patients with another cancer within 10 years after mastectomy, and patients who died within 10 years after mastectomy, but with discrepancy between the National Causes of Death Registry and the DBCG registry. No long-term follow-up was performed for patients with DM or contralateral breast cancer (CBC) as first recurrence and patients who died from other causes than BC within the first 10 years after mastectomy (when in agreement with the National Causes of Death Registry and the DBCG registry). Follow-up was continued until DM, CBC, emigration, or death. Nine patients were lost to follow-up because of emigration; otherwise, the follow-up was complete.
End Points DM was defined as any failure outside the ipsilateral mammary region and the regional lymph nodes. Histopathologic or cytologic confirmation of DM was not performed routinely and often the diagnosis of DM was based on clinical or radiologic findings. The diagnosis of CBC was based on the finding of a clinically evident malignant tumor in the opposite breast, and often was based on cytological confirmation; thus no histopathologic comparison was done routinely with the original BC tissue sample. For CBC and DM within the same month, the patient was recorded as DM. Metastases in the contralateral axilla were recorded as DM if there was no clinical evidence of CBC. Any first BC event was defined as one of following: LRR alone, simLRR-DM, DM, or CBC.
Statistical Analysis Median time to event in the two groups was compared using the Wilcoxon-Mann-Whitney test. Hazard rates for 2-year periods were calculated as the number of DM divided by the time the patients were at risk of DM in these 2-year time intervals. Level of significance was chosen as 5% and all P values were two-tailed. The treatment effect was evaluated in accordance with the intention-to-treat principle. The patients were included in their randomization group, irrespective of whether they completed the planned treatment. The length of the follow-up time to an event was measured from the date of mastectomy. The evaluation date for recurrences and survival was November 15, 2004, which resulted in a median potential follow-up time of 216 months (range, 180 to 264 months). Calculations were done using SPSS Version 11.5 for Windows (SPSS Inc, Chicago, IL).
Crude Failure Pattern The overall failure pattern in the two randomization groups is shown in Figure 1. At the time of evaluation, 30% of patients in the RT group were alive with no evidence of recurrence ever, compared with 19% of the patients in the no-RT group. In particular, the frequency of LRR alone differed between the two groups, with 30% of the patients in the no-RT group and 5% of the patients in the RT group having an LRR alone as the first site of failure. In addition, simLRR-DM was more common in the no-RT group. Conversely, DM as the first site of failure was most common in the RT group, with 41% of the patients having a DM as first site of failure in the RT group compared with 28% of the patients in the no-RT group. Of the patients with LRR alone, 17% (79 of 456) in the no-RT group and 20% (16 of 79) in the RT group had no subsequent DM or CBC. Any DM was seen in 59% (919 of 1,545) in the no-RT group and 50% (768 of 1,538) in the RT group. Total CBC was seen in 5% (81 of 1,545) in the no-RT group and 6% (89 of 1,538) in the RT group. Of the patients in the no-RT group, 61% (937 of 1,545) had died with recurrence or CBC and 12% (191 of 1,545) had died without recurrence. In the RT group, 50% (775 of 1,538) had died with recurrence or CBC and 13% (207 of 1,538) had died without recurrence.
First Site of Failure The probability of any first BC event (LRR, simLRR-DM, DM, or CBC) was significantly reduced among patients in the RT group (P < .001; Fig 2). The median time to any first BC event was 3.9 and 7.9 years (P < .001) after no RT and RT, respectively. The 18-year probability of LRR (with or without DM) or LRR alone was significantly lower in the RT group (Fig 3). About half of the LRRs appeared within 2 years after mastectomy, although the risk of developing LRR continued to persist in 18 years follow-up after mastectomy.
Table 1 lists the site of first LRR alone and first simLRR-DM. The frequency of all sites of LRR was lower with RT than without. Chest wall failures were the most common type of LRR, with involvement of this site in 55% (321 of all 586 LRRs) in the no-RT group and 70% (106 of all 152 LRRs) in the RT group. Axillary failures were especially pronounced among patients in the no-RT group, with involvement of this site in 43% (254 of 586). In the RT group, the axilla was involved in 24% of the LRRs (36 of 152). In the no-RT group, chest wall and axillary failures most commonly occurred without simultaneous DM, whereas supra/infraclavicular failures were associated as often with DM. Overall, 22% of the patients with LRR in the no-RT group appeared with simultaneous DM, whereas 48% of the patients with LRR in the RT group also had DM at the time of diagnosis of LRR.
DM Table 2 lists the 18-year probabilities of DM. The 18-year probability of DM subsequent to LRR was 35% and 6% (P < .001) after no RT and RT, respectively. The 18-year probability of any DM was 64% and 53% (P < .001) after no RT and RT, respectively (Fig 4. The median time to DM was 6.5 years in the no-RT group and 12.3 years in the RT group (P = .04). In the no-RT group, DM after LRR and DM as first site of failure were equally common, whereas in the RT group, DM occurred most often as the first site of failure (Table 2).
To assess if the risk of DM was time dependent in the two randomization groups, the hazard rates for 2-year time interval were calculated (Fig 5). The DM hazard rates were at all times increased among patients randomly assigned to no-RT compared with patients randomly assigned to RT. In both randomization groups, the DM hazard rate decreased with time after mastectomy, but even 18 years after mastectomy, a small risk of DM was present in both groups.
The six most common sites of first DM are listed in Table 3. Bone metastases were most often part of the first DM; the 18-year probability of bone metastases was 40% and 32% (P = .003) after no RT and RT, respectively. In addition, the 18-year probabilities of lung metastases, CNS metastases, and skin metastases outside the ipsilateral chest wall were significantly lower in the RT group.
Megavoltage RT Versus Orthovoltage RT To examine if there was a dose-response relationship in the failure pattern, the first sites of recurrence are listed in Table 4 in the megavoltage versus orthovoltage RT group. The groups were not comparable according to all primary tumor variables because significantly more patients in the megavoltage group were lymph node positive (P < .001). Conversely, significantly more patients in the orthovoltage group had invasion of the deep fascia (P < .001). The Kaplan-Meier estimates should be interpreted accordingly. LRR as first site of recurrence (with or without DM) was more frequent among the orthovoltage-irradiated patients compared with the megavoltage-irradiated patients (P = .01). The 18-year probability of LRR was 12% and 20% (P = .04) after megavoltage and orthovoltage RT, respectively (Fig 6A). The 18-year probability of any DM was 52% and 55% (P = .63) after megavoltage and orthovoltage RT, respectively (Fig 6B).
In the previous DBCG 82 b and c publications, only first site of failure was recorded, and an improved local control rate was found in patients randomly assigned to RT, but an increased frequency of DM as first site of failure also was observed. The current long-term follow-up shows that the probability of DM was increased among patients randomly assigned to no RT compared with patients randomly assigned to RT. These results indicate that secondary dissemination after LRR to a distant site has occurred in a high number of patients. The first site of treatment failure among high-risk BC patients receiving systemic therapy but no RT, and with a median number of 15 to 17 lymph nodes removed, has been examined in four large studies,13-16 with an identical failure pattern. In these studies, the 10-year actuarial risk (cumulative incidence) of LRR ± DM was approximately 20%, in contrast to our 10-year actuarial risk of LRR ± DM of 43% in the no-RT group (Fig 3). However, our data are more in agreement with the British Columbia Cancer Agency trial,2,4 in which a median of 11 nodes was removed and the 10-year LRR rate without RT was 16% (patients with one to three positive nodes) and 41% (patients with > three positive nodes). The Danish trials have been criticized previously for the suboptimal axillary surgery, with only a median of seven lymph nodes removed.17 In the no-RT group, 45% of LRRs alone involved the axilla (Table 2), compared with other studies that found involvement of the axilla in only 7% to 21%.18-22 However in our study, chest wall failures were most common, and were involved in 57% of the LRRs alone in the no-RT group; thus, in addition to the suboptimal axillary surgery, other factors might have influenced the high LRR risk in the Danish trials. Given that the risk of chest wall failures is related to T stage,16 it is possible that the T stage might, in general, be more advanced in the Danish trials compared with other large trials. In the Danish trials, data on tumor size were recorded routinely, whereas the precise T stage was not recorded. The other studies with lower risk of LRR than the Danish trials only included patients with pT1-3 or T1-3 tumors.13-15 The DBCG 82 b and c trials were nationwide, which suggests that all operable high-risk BC patients in Denmark could enter onto these trials. For this reason, the patient cohort was inhomogeneous, both with respect to the quality of the surgical procedures but also with respect to prognostic factors. The chemotherapy regimen consisted of CMF in the studies by Recht et al13 and Wallgren et al,15 whereas in the studies by Katz et al14 and Taghian et al16 the chemotherapy regimen included doxorubicin for almost all patients. The premenopausal patients in the 82 b trial also received CMF chemotherapy, but with less locoregional control than in the above-mentioned studies, suggesting that CMF chemotherapy was not effective in eradicating locoregional tumor burden when suboptimal surgery was performed in our high-risk patients. At present, more effective regimes are being used, which possibly would have improved also the locoregional control despite no RT.23 Likewise, the postmenopausal women in the 82 c trial received tamoxifen 30 mg irrespective of estrogen receptor (ER) status, and only for 1 year, which is not optimal treatment according to current knowledge. At present, the ER-negative patients would be offered chemotherapy and the ER-positive patients would be offered 5 years of tamoxifen instead of 1 year,24 or modern long-term systemic treatments with aromatase inhibitors.25 The benefit of RT on the total DM failure rate has been described previously in a detailed analysis of the Stockholm trial, in which 960 patients from 1971 to 1976 were randomly assigned to preoperative, postoperative, or no RT.26,27 However, their 15-year cumulative incidence rates of total DM were lower (45% and 37% in the no-RT and RT group, respectively) compared with 18-year actuarial probabilities of 64% and 53%, respectively, in this study. In the Stockholm trial, only one third of the patients were node positive, compared with nearly all of the patients in this study. However, the reduction in the risk of total DM due to RT was similar, with an RR of 0.80 in the Stockholm trial and an RR of 0.78 in this study. This supports the Halstedian hypothesis that patients can be cured by sufficient locoregional treatment, and rejects the systemic hypothesis that LRR is only a marker of DM, given that primary adjuvant RT actually resulted in a decreased risk of DM. We found a comparable number of patients with contralateral BC in the two randomization groups, which is also in agreement with other studies, which found a minimal risk of contralateral BC in patients with RT.28-30 This study used appropriate dose and target volume for most patients, given that 87% were treated by megavoltage RT, and few patients (< 1%) had clinically unacceptable RT treatments.12 In the DBCG 82 b and c trials, the median time from mastectomy to RT was 6.1 and 5.2 weeks for the pre- and postmenopausal women, respectively; the premenopausal patients were delayed due to the prior onset of chemotherapy. At present, RT is often delivered after chemotherapy, according to the results of a small randomization study that showed that postlumpectomy patients receiving chemotherapy before RT had a lower DM rate than patient receiving RT before chemotherapy.31 However, a recent update of these data showed that the 10-year actuarial DM rate was independent of the sequencing of RT and chemotherapy,32 although the optimal sequencing of RT and chemotherapy also depends on margin status and effectiveness of systemic therapies.33 Had the RT been delivered after chemotherapy in the DBCG 82 b trial, a delay of 9 months (nine cycles of CMF every 4 weeks) in the beginning of RT would have occurred. The 9-month actuarial risk of LRR alone among the premenopausal patients in the no-RT group was 5% (a total of 45 patients) compared with 0.7% in the RT group (a total of only six patients; odds ratio, 0.16; 95% CI, 0.06 to 0.42). This shows that the sequencing of RT and chemotherapy can change the LRR pattern in high-risk BC patients and therefore, consequently, might also change the distant failure pattern. Randomized trials are needed to answer the question about the sequencing of RT and chemotherapy definitively; in addition, the currently used systemic therapies presumably are more effective in decreasing the local tumor burden than CMF.
According to recent consensus reports (eg, St Gallen, National Institutes of Health), postmastectomy RT is indicated in high-risk patients with In conclusion, postmastectomy RT changes the failure pattern in high-risk BC patients; fewer patients have LRR as the first site of failure, and overall fewer patients have DM.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Overgaard M: Overview of randomized trials in high risk breast cancer patients treated with adjuvant systemic therapy with or without postmastectomy irradiation. Semin Radiat Oncol 9:292-299, 1999[CrossRef][Medline] 6. Whelan TJ, Julian J, Wright J, et al: Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 18:1220-1229, 2000 7. Halsted WS: The results of operations for cure of cancer of the breast performed at Johns Hopkins Hospital from June 1889 to January 1894. Johns Hopkins Bull 4:297-319, 1895 8. Halsted WS: The results of radical operations for the cure of carcinoma of the breast. Ann Surg 46:1-6, 1907[Medline] 9. Fisher B: Laboratory and clinical research in breast cancer: A personal adventure—The David A. Karnofsky Memorial Lecture. Cancer Res 40:3863-3874, 1980 10. Koscielny S, Tubiana M, Le MG, et al: Breast cancer: Relationship between the size of the primary tumour and the probability of metastatic dissemination. 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J Clin Oncol 16:2651-2658, 1998[Abstract] 24. Tamoxifen for early breast cancer: An overview of the randomised trials—Early Breast Cancer Trialists' Collaborative Group 1. Lancet 351:1451-1467, 1998 25. Henderson IC: Aromatase inhibitors in the management of early breast cancer: Optimizing the clinical benefit. Semin Oncol 31:31-34, 2004[Medline] 26. Rutqvist LE, Pettersson D, Johansson H: Adjuvant radiation therapy versus surgery alone in operable breast cancer: Long-term follow-up of a randomized clinical trial. Radiother Oncol 26:104-110, 1993[CrossRef][Medline] 27. Arriagada R, Rutqvist LE, Mattsson A, et al: Adequate locoregional treatment for early breast cancer may prevent secondary dissemination. J Clin Oncol 13:2869-2878, 1995[Abstract] 28. Storm HH, Andersson M, Boice JD Jr, et al: Adjuvant radiotherapy and risk of contralateral breast cancer. J Natl Cancer Inst 84:1245-1250, 1992 29. Obedian E, Fischer DB, Haffty BG: Second malignancies after treatment of early-stage breast cancer: Lumpectomy and radiation therapy versus mastectomy. J Clin Oncol 18:2406-2412, 2000 30. Gao X, Fisher SG, Emami B: Risk of second primary cancer in the contralateral breast in women treated for early-stage breast cancer: A population-based study. Int J Radiat Oncol Biol Phys 56:1038-1045, 2003[CrossRef][Medline] 31. Recht A, Come SE, Henderson IC, et al: The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 334:1356-1361, 1996 32. Bellon JR, Come SE, Gelman RS, et al: Sequencing of chemotherapy and radiation therapy in early-stage breast cancer: Updated results of a prospective randomized trial. J Clin Oncol 23:1934-1940, 2005 33. Bellon JR, Harris JR: Chemotherapy and radiation therapy for breast cancer: What is the optimal sequence? J Clin Oncol 23:5-7, 2005 34. Cheng JC, Chen CM, Liu MC, et al: Locoregional failure of postmastectomy patients with 1-3 positive axillary lymph nodes without adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 52:980-988, 2002[CrossRef][Medline] 35. Fodor J, Polgar C, Major T, et al: Locoregional failure 15 years after mastectomy in women with one to three positive axillary nodes with or without irradiation the significance of tumor size. Strahlenther Onkol 179:197-202, 2003[CrossRef][Medline] 36. Truong PT, Olivotto IA, Kader HA, et al: Selecting breast cancer patients with T1–T2 tumors and one to three positive axillary nodes at high postmastectomy locoregional recurrence risk for adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 61:1337-1347, 2005[CrossRef][Medline] 37. Koscielny S, Tubiana M: The link between local recurrence and distant metastases in human breast cancer. Int J Radiat Oncol Biol Phys 43:11-24, 1999[CrossRef][Medline] Submitted May 27, 2005; accepted March 1, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test was used for comparison of qualitative data. 
four positive nodes and/or T3 and T4 tumors. There is a general belief that the role of postmastectomy RT in women with one to three positive axillary lymph nodes is unclear, and this question is among the most debated among BC radiation oncologist. Therefore, several retrospective studies have tried to identify subgroups of patients with one to three positive nodes at increased risk of LRR to suggest who might benefit from RT.
