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© 1999 American Society for Clinical Oncology Impact of Consolidation Radiotherapy in Patients With Advanced Breast Cancer Treated With High-Dose Chemotherapy and Autologous Bone Marrow RescueFrom the Department of Radiation Oncology, Division of Medical Oncology, Bone Marrow Transplant Group, Duke University Medical Center, Durham, NC. Address reprint requests to Dennis L. Carter, MD, 1003 Loudon Road, Latham, NY 12110; email carter{at}radonc.duke.edu
PURPOSE: To examine the impact of consolidation radiotherapy (RT) after high-dose chemotherapy with autologous bone marrow rescue (HDC) in patients with advanced breast cancer. PATIENTS AND METHODS: Between 1988 and 1994, 425 patients with metastatic or recurrent breast cancer received doxorubicin, fluorouracil, and methotrexate (AFM) induction chemotherapy in a single-institution prospective trial. One hundred patients who achieved a complete response were randomized to receive HDC (cyclophosphamide, cisplatin, carmustine), with autologous bone marrow rescue immediately after AFM, or to observation, with HDC to be administered at next relapse. Seventy-four of the 100 became eligible for RT; 53 received consolidation RT (HDC RT+ and 21 did not (HDC RT-). The assignment of RT was not randomized. The RT+ and RT- groups were similar with regard to number of involved sites, the fraction of patients with only local-regional disease, age, and interval since initial diagnosis. Local control at previously involved sites and distant sites was assessed with extensive radiologic and clinical evaluations at the time of first failure or most recent follow-up. The impact of RT on failure patterns, event-free survival, and overall survival was evaluated. RESULTS: Sites of first failure were located exclusively at previously involved sites in 28% of RT+ patients versus 62% of RT- patients (P < .01). Event-free survival at 4 years was 31% and 21% in the RT+ and RT- groups, respectively (P = .02). Overall survival at 4 years was 30% and 16% in the RT+ and RT- groups, respectively (P = .20). CONCLUSION: Patients with advanced breast cancer who were treated with HDC without RT failed predominantly at the initial sites of disease. The addition of RT appeared to reduce the failure rate at initial disease sites and may improve event-free and overall survival. Our observations await verification in a trial in which assignment to RT is randomized.
PATIENTS WITH LOCALLY and/or regionally recurrent or metastatic breast cancer generally have a poor prognosis with conventional treatment. On the basis of laboratory and clinical data that suggest a dose-response curve for systemic chemotherapy,1-3 high-dose chemotherapy with autologous bone marrow rescue (HDC) has been used in these patients.4-6 Radiation therapy (RT) of breast cancer is well known to improve outcome when used in the adjuvant setting. Modern randomized trials have demonstrated improved local control, event-free survival (EFS), and overall survival (OS) with the addition of adjuvant RT after mastectomy in patients with locally advanced cancer or involvement of axillary lymph nodes.7-19 In the presence of metastatic cancer, local control has less impact on long-term outcome because of the inability to control distant disease. Therefore, despite the frequent use of RT in breast cancer for the adjuvant treatment of local-regional disease, metastatic cancer has not traditionally been treated with RT unless patients were symptomatic or at high risk for morbid events in the absence of treatment. However, investigators of HDC quickly realized that (1) these patients predominantly failed at the initial sites of disease, and (2) RT was generally successful in controlling the disease at these locations.20-22 Therefore, maximizing long-term EFS and OS after HDC likely requires that control be achieved at initial sites with the proper use of RT. Similarly, because more effective or more aggressive systemic therapy is better able to control distant disease, control at the initial sites with the addition of RT may have a greater impact on long-term outcome. In 1988, a prospective randomized trial to assess the impact of the timing of HDC in advanced breast cancer patients was initiated.23 In the 1988 study, patients who achieved a complete response (CR) after induction doxorubicin, fluorouracil, and methotrexate (AFM) therapy were randomized to receive HDC either immediately after induction AFM therapy or at the time of the first relapse. After HDC, patients still in CR were intended to receive consolidation RT. Seventy-two percent of those eligible received RT and 28% did not, providing an opportunity to assess the impact of consolidation RT on local control, event-free survival, and overall survival.
Between 1988 and 1994, 425 patients with locally and/or regionally advanced (American Joint Committee on Cancer stage T4, N3, M1, or X) or distant metastatic disease received induction AFM therapy as outlined in Fig 1. Eligibility criteria included premenopausal or perimenopausal status, no previous chemotherapy for inoperable or metastatic disease (adjuvant chemotherapy was acceptable, provided the total cumulative doxorubicin dose was < 250 mg/m2), objective measurable disease, Cancer and Leukemia Group B toxicity criteria performance status of 0 or 1, radiographic absence of brain metastasis,  three positive lesions on bone scan, and absence of pelvic or marrow involvement. It was required that RT to all bony areas be considered feasible by the enrolling physician. Because the objective response of bone disease is difficult to assess accurately, patients with only bone disease were excluded from this study. The last two patients entered onto the study started treatment just as the study was closing. They are included in the analysis. Their exclusion would not alter the results.
After AFM therapy, patients were eligible for randomization if they achieved a clinical CR (absence of tumor on physical examination, bone marrow biopsy, and imaging studies); had no serious medical illnesses precluding general anesthesia, bone marrow harvesting, and HDC; had a lung functional vital capacity and forced expiratory volume at 1 second Of the randomized patients considered to have a CR, 25 of 100 actually were partial responders after AFM therapy, converted to CR with surgery or RT, and were included in this study. The four patients who converted to CR with RT all received RT for incompletely responding local-regional involvement. The remaining 21 patients converted to CR with surgery and also had predominantly local-regional disease, with only four that had disease at distant sites (liver and lung nodules). Any patient who required radiation to obtain a CR was analyzed in the RT group. After AFM therapy, 107 patients were scored as having a CR. Seven patients were not randomized because of insurance company refusal to pay (four patients), patient refusal to be randomized (two patients), and initial misclassification as having no response to induction AFM therapy (one patient). The remaining 100 patients were randomized either to immediate HDC (I-HDC) or to observation with HDC delayed until the time of next relapse (D-HDC). One patient refused HDC immediately after randomization to I-HDC and was evaluated in the observation arm for the purposes of this review. The median follow-up duration was 4 years (range, 0.93 years to 7.3 years) for all CR patients. The treatment schema is outlined in Fig 1. Forty-eight patients were included in the I-HDC arm. Forty-seven patients in the I-HDC arm received immediate HDC as planned. One other patient was diagnosed with extensive metastases immediately after randomization to I-HDC but before receiving HDC and was not treated. There were fifty-two patients in the observation arm (51 assigned patients plus one crossover patient). Four of these 52 received RT immediately and were excluded from the analysis. Of the remaining 48 patients, five have not relapsed and remain without evidence of disease. Forty-three relapsed after AFM therapy alone, 42 of whom then received D-HDC. The one other patient relapsed with brain metastasis and was not eligible for HDC. Of the 91 patients treated with either immediate or delayed HDC, 17 were excluded from the analysis of consolidation RT. Ten of the 17 had chemotherapy-related deaths soon after HDC. Five other patients had persistent clinical disease after HDC (in the delayed group). Two of the four patients who received RT immediately after randomization to observation were subsequently treated with HDC and, as noted above, were excluded from further analysis. Thus, of the initial 107 patients who had a CR, 100 were randomized, 91 received HDC, and 74 were potentially eligible for consolidation RT after HDC. These 74 patients form the basis of this report. Fifty-three received RT; 21 did not. The reasons for omitting RT in these 21 patients were nonfatal chemotherapy toxicity (eight patients), patient refusal (four patients), disease sites that were previously irradiated and recommendation for no additional RT by the treating physician (five patients), physician preference (three patients), and only site of disease resected (one patient). These 74 patients were evaluated with regard to patterns of failure, EFS, and OS. Follow-up details after HDC were not specified in the protocol, but patients were generally observed by use of frequent aggressive clinical and radiologic evaluation. Patterns of failure were assessed at the time of first failure. Additional follow-up after first failure was not included for the analysis of patterns of failure because subsequent treatment methods varied. Failure was evaluated for five sites: local-regional soft tissue, mediastinum, lung, bone, and liver. The majority of patients had local-regional disease before treatment (Table 1). For the purpose of evaluating local-regional involvement, any patient who had disease involving the breast, chest wall, axilla, supraclavicular fossa, internal mammary lymph nodes, or cervical lymph nodes was considered to have local-regional disease.
Patients with distant involvement generally had a solitary or limited volume of organ disease at initial evaluation. Patients who were suspected of having more than one area of involvement within a specific organ were still scored as having one site. Subsequent failure at any location within the same organ was considered to be a failure at that site. The goal of RT was to irradiate sites of involvement present before induction AFM chemotherapy. The study was designed to treat patients to tolerance doses in the range of 45 to 60 Gy (generally 45 Gy to bone, the spinal column, visceral organs, and uninvolved soft tissues and 60 Gy to previously involved or high-risk regional soft tissue). The actual doses ranged from 9 to 68 Gy, with 12 patients receiving less than 45 Gy and two patients receiving more than 60 Gy. All patients who received any RT were included in the RT group. All treatments were delivered at 1.8 to 2 Gy per fraction. For patients with local-regional involvement, the chest wall and supraclavicular fossa were typically treated, and the internal mammary nodes were occasionally included. For patients with distant disease, metastatic sites were typically treated to the prechemotherapy treatment volume, with a 2-cm margin. The entire organ (eg, lung or liver) was not treated. Nine patients received RT to some, but not all, initial sites of disease. In all nine cases, distant sites were not irradiated whereas regional sites were irradiated, at the preference of the patient or the treating physician. To avoid bias in favor of the RT group, these patients were included in the RT group. Patterns of failure after AFM therapy but before HDC are also reported for the observation group, who received AFM therapy only (48 patients) or AFM therapy in addition to RT (four patients). OS was measured from the date of transplant to the date of death or date of last follow-up for survivors. EFS was measured from the date of transplant to the date of progression or date of death, whichever occurred first. Patients who were alive and without disease progression were censored at the date of last follow-up. Survival curves were created using the Kaplan-Meier product limit method. Cox proportional hazards regression models were used to compare survival duration and time to progression for the independent variables, which were the following: disease-free interval, estrogen receptor status, age at randomization, number of metastatic sites, visceral versus nonvisceral sites of metastasis, menopause status (pre- v peri-/postmenopausal), race (white v others), prior hormone therapy (yes v no), performance status, any RT versus no RT, and randomization arm. Statistical significance refers to two-sided P values of less than .05.
In addition to the above analyses of patient outcome, site-specific failure rates were tallied at each site according to whether the particular site was irradiated, independent of whether another site in the same patient was irradiated. Failure rates at these sites were compared using the
Patient characteristics were similar among the patient groups with respect to the average number of involved sites, mean interval since initial diagnosis, mean age, and percentage of patients with local-regional only disease (Table 1). Patients who received RT after HDC had a 31% actuarial EFS at 4 years, compared with 21% in patients who received HDC without RT (P = .02) (Fig 2). The corresponding 4-year actuarial overall survival rates were 30% and 16%, respectively (P = .20) (Fig 3). For the overall group, only the timing of HDC (immediate HDC patients having done worse) and the use of consolidation RT (RT+ patients having done better) were predictive for EFS on univariate analysis. In multivariate models, however, no variables were significant for predicting EFS or OS.
The patterns of failure are shown in Table 2. The RT+ patients were less likely to fail only at initial sites (28%), compared with RT- patients (62%). Conversely, the RT+ patients were more likely to only fail at a new site (28%), compared with unirradiated patients (14%). Overall, the patients who received RT had a lower relapse rate and thus more frequently remain free of disease (36% v 19%).
Nine patients in the RT group received RT to some, but not all, initially involved sites. Four of the nine remain without evidence of disease. Two of the nine failed at a new site only. Three of the nine failed at initially involved sites: one regionally but outside the irradiated field (supraclavicular failure in a patient where the supraclavicular field was omitted) and two in unirradiated sites. Thus all failures in these nine patients occurred in unirradiated volumes.
Site-specific failure rates were lower at both local-regional and visceral sites if RT was given to these sites (Table 3).
RT could not be given in 18 cases of severe chemotherapy toxicity (the upper two rows in Table 4). Most of these patients were in the I-HDC arm. Of the 53 patients in the RT group, RT was discontinued prematurely (final dose < 45 Gy) in eight patients: thrombocytopenia in four and pneumonitis in four (third row in Table 4). These eight patients were evenly distributed between the I- and D-HDC arms. Overall, HDC treatment-related toxicities that limited the use of RT resulted from thrombocytopenia (12 patients), neutropenia (five patients), pneumonitis (seven patients), encephalopathy (one patient), and hepatitis (one patient).
After RT, one fatal complication occurred. Death in this patient occurred 78 days after HDC and 18 days after completion of RT (dose, 18 Gy) to the chest wall and supraclavicular fossa. At the time of autopsy, she was found to have diffuse bilateral pulmonary injury and sepsis. Although these findings are consistent with the toxicities observed with HDC, this patient is included in the RT+ group for analysis of EFS and OS. In the observation group, 39 of 48 (81%) patients failed only at previously involved sites after AFM therapy alone (before HDC). An additional four patients failed at new sites, and five patients remain free of disease. Among the four patients in the observation group who received RT after AFM therapy, two failed at initial sites, one failed at a new site, and one remains free of disease.
The prognosis for patients with metastatic breast cancer is poor. The favorable subset of stage IV patients described in this article had predominantly local-regional disease and were responsive to induction chemotherapy. Even so, most failed rapidly after HDC. The 39% 4-year survival in the overall group might represent an improvement in outcome in these women, but phase III data comparing patients treated with HDC and a similar group treated only with conventional chemotherapy are incomplete. Putting aside this issue for the moment, however, our interest was in improving the efficacy of HDC. In the great majority of instances, overt metastases or local-regional recurrence after mastectomy are markers for occult disease at other sites. If chemotherapy is capable of sterilizing multiple occult sites of disease, but not clinically apparent sites of disease, then the administration of the consolidation RT to sites that were clinically apparent before chemotherapy might sterilize residual disease at these sites, prolong the interval to relapse, and improve survival.24,25 Thus increased control with RT at initially involved sites might result in more long-term survivors, as is conceptually shown in Fig 4. A similar rationale has been advanced for the use of consolidation RT in the treatment of advanced malignant lymphomas26,27 and neuroblastomas.28,29
In the study presented here, consolidation RT was planned for all patients after HDC. For a variety of reasons, 21 of 74 patients did not receive the planned RT, providing the opportunity for an initial nonrandomized evaluation of this hypothesis. The data suggest a potential benefit of consolidation RT. The patterns of failure were altered, with fewer failures at initial sites of disease (28% in the RT patients, compared with 62% in those who did not receive RT). More significantly, however, the overall number of failures appeared to be reduced, with an EFS of 31% at 4 years in the irradiated patients, compared with 21% for those who did not receive RT (P = .02). Overall survival may also have been influenced, with the 4-year OS being 30% in the RT patients, compared with 16% in those treated with only HDC (P = .20). The allocation of RT was not made on a random basis. Although our groups appear to be reasonably balanced in terms of prognostic variables (Table 1), confirmation in a prospective phase III trial is necessary before this hypothesis can be completely accepted. The value of HDC itself in advanced breast cancer remains undefined. Comparisons to historical controls have suggested a benefit,30 but phase III data are sparse. Bezwoda et al6 reported a single, small, randomized comparison of HDC to standard chemotherapy for initial therapy of metastatic breast cancer, demonstrating improved response rates and prolonged duration of response and survival with the use of HDC. This study has been criticized for the poor results obtained in the control arm, which had a very low CR rate of 4% and an OS rate of only 5% at 14 months. The use of consolidation RT is not described in the report by Bezwoda et al. Phase III trials of HDC in the adjuvant setting for patients with advanced breast cancer are ongoing (Cancer and Leukemia Group B 9082/Southwest Oncology Group 91-14, Eastern Cooperative Oncology Group 2190 and Philadelphia Bone Marrow Transplant Group-01). HDC remains a treatment associated with substantial complications. In the study presented here, the absence of peripheral stem cells and the use of very high-intensity chemotherapy likely resulted in a greater mortality rate than has been observed in more recent cohorts of patients treated with HDC. Twelve percent of transplant patients died secondary to complications from the chemotherapy; another 9% of patients could not be given consolidation RT because of prolonged toxicity from the chemotherapy. Tolerance of normal tissues to RT after HDC appeared to be reduced as well.31 Seventeen percent of our patients required cessation of RT before completion of the prescribed dose, mostly because of lung and/or hematologic toxicity, with one death occurring 18 days after RT was discontinued. This is clearly a greater frequency of toxicity than is generally reported after RT for metastatic disease or in the postmastectomy setting.32 The reason for this increased toxicity remains unclear. Possible explanations include the impact of treatments received before enrollment, use of a very intensive chemotherapy regimen, absence of peripheral stem cells in protocol, use of pulmonary-toxic carmustine in the HDC regimen, impact of timing of RT after HDC, and the irradiated volumes. Hematologic complications are expected to decrease because of the current use of peripheral stem cells. A review is underway to determine the risk factors for development of pneumonitis during RT in stage II through IV breast cancer patients who have previously been treated with HDC.33 The primary question addressed in this trial as initially designed was the value of immediate HDC, compared with HDC delayed until the time of relapse, as applied to a chemoresponsive group of patients with stage IV disease, all of whom experienced a CR with AFM therapy. As was recently reported,23 there was no overall survival benefit for immediate HDC, compared with delayed HDC. If one compares the 100 patients randomized to immediate versus delayed HDC, irrespective of whether or not they received consolidation RT, the survival was 34% at 3 years from the time of randomization in the immediate HDC patients, compared with 43% for the delayed HDC patients. A possible explanation for these results is that seven patients in the I-HDC arm were unable to receive consolidation RT because of persistent long-term toxicity from the chemotherapy, compared with only one patient in the D-HDC arm who was unable to receive radiation. Because RT appears to be of value in delaying or preventing relapse, this might provide a reasonable explanation for the difference in outcome between the two arms. Other groups have reported the use of consolidation RT in conjunction with HDC and autologous BMT therapy. Shah et al20 reviewed 46 patients with hormone-unresponsive metastatic breast carcinoma treated with HDC. Six of the 46 patients died of HDC-related complications. Twenty-two of the 46 patients had local-regional disease with partial or complete responses, 18 of whom subsequently received consolidation therapy. The authors reported a local control rate of 67% at initially involved sites, comparable with the rate our study. Mundt et al21 reported 31 patients with metastatic breast cancer who had a CR after treatment with HDC at the University of Chicago. Similar to our study, the Chicago report only included patients who had a CR to chemotherapy. Unlike our study, the majority of patients had distant disease at study entry. Consolidation RT was used in 14 patients, with the other 17 not receiving radiation (not randomized). The patterns of failure were similar to those in our study, with 11 of the 17 unirradiated patients (65%) failing at previous sites of involvement, compared with three of the 14 irradiated patients (21%). The addition of radiation did not seem to affect EFS, but the numbers of patients were small. In conclusion, patients with locally advanced/recurrent breast cancer or with limited metastatic disease treated with HDC and autologous bone marrow rescue appear to relapse primarily at disease sites that were present before chemotherapy. The administration of RT as consolidation treatment after chemotherapy reduces the risk of failure at these sites and appears to have a favorable impact on the overall risk of relapse. Consolidation RT may favorably influence long-term survival as well. Phase III trials in which irradiation is prospectively allocated will be necessary to confirm this hypothesis.
We thank Dr Edward C. Halperin for his guidance and assistance in the care of these patients, Dr Greg Sibley for his suggestions, Donald Berry and Robert Clough for their assistance with the statistical analysis and data collection, and Jane Hoppenworth for her assistance in the preparation of the manuscript.
L.B.M. is the recipient of American Cancer Society Career Development Award no. 92-53. The Duke Bone Marrow Transplant Group is supported by National Cancer Institute grant no. PO1 CA47741-04. Presented at the Thirty-Eighth Meeting of the American Society for Therapeutic Radiology and Oncology, Los Angeles, CA, October 27-30, 1996.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
80% of that predicted, diffusion lung capacity for carbon monoxide 
2 test (when n > 20) and Fisher's exact test (when n 
