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© 2003 American Society for Clinical Oncology The Role of Irradiation of the Internal Mammary Lymph Nodes in High-Risk Stage II to IIIA Breast Cancer Patients After High-Dose Chemotherapy: A Prospective Sequential Nonrandomized StudyFrom the Bone Marrow Transplant Service, Department of Oncology and Radiotherapy, Chaim Sheba Medical Center, Tel Hashomer; Oncology Unit Meir Hospital, Sapir Medical Center, Kfar Saba, Israel; and Bank of Cyprus Oncology Center, Nicosia, Cyprus. Address reprint requests to Salomon M. Stemmer, MD, Institute of Oncology, Rabin Medical Center, Beilinson Campus, Petach Tiqwa, Israel 49100; email: sstemmer{at}barak-online.net.
Purpose: This phase II single-institution prospective, nonrandomized trial investigates high-dose adjuvant chemotherapy and locoregional radiotherapy in patients with breast cancer. We compared the outcome of patients in this study treated with radiotherapy fields including the internal mammary nodes (IMN) to a group of patients who did not receive IMN irradiation. Patients and Methods: 100 patients with high-risk stage II–III breast cancer received doxorubicin-based adjuvant chemotherapy followed by high-dose chemotherapy, stem-cell support, and locoregional radiotherapy. The radiotherapy included electron-beam irradiation to the IMN. For 20 months during the study, no electron-beam facility was available and we were unable to deliver the IMN irradiation as planned to 33 patients. The remaining 67 patients (32 treated before and 35 treated after this period) received IMN irradiation. Patients with receptor-positive tumors received tamoxifen for 5 years. Results: At a median follow-up of 77 months for all of the patients, disease-free survival (DFS) was significantly prolonged in patients receiving IMN radiation compared to those without IMN radiation (73% v 52%; P = .02). A trend was seen for overall survival (OS; 78% v 64%; P = .08). Cox regression multivariate analysis found IMN radiotherapy to be significant both for DFS and OS. Estrogen receptor positivity was also significant for DFS. There was no treatment related mortality. Conclusion: In patients with high-risk stage II to III breast cancer, the inclusion of the IMN in the radiotherapy field was associated with a statistically significant increase in DFS and a borderline increase in OS.
EARLY EXPERIENCE with high-dose chemotherapy followed by autologous bone marrow transplantation for high-risk primary breast cancer patients showed that omission of locoregional radiotherapy results in a high incidence of local recurrence.1 Locoregional radiotherapy is therefore routinely offered to these patients. For patients who have a T2 or T3 primary and metastases to four or more axillary nodes, the American Society of Clinical Oncology consensus statement recommends treating both the breast or chest wall and the regional nodes, both in patients undergoing breast preservation and in patients who have undergone mastectomy.2 The role of irradiation to the internal mammary nodes (IMN) chain remains controversial, although both randomized studies that showed a survival benefit for breast cancer patients who received systemic chemotherapy and radiotherapy after mastectomy included the IMN in the radiotherapy field.3,4 Previously, we reported the initial results of our phase II study of high-risk breast cancer patients treated with high-dose chemotherapy and autologous stem-cell transplantation followed by locoregional radiotherapy and we demonstrated the safety of this approach.5 This study was conducted at the time when there was considerable enthusiasm for intensive adjuvant chemotherapy and stem-cell support for high-risk stage II to III breast cancer patients, but before the recent disappointing results of prospectively randomized studies became available.6 Long-term survival data of these randomized studies are still awaited, but the pendulum may be swinging away from the exclusively negative attitude of several years ago.7–10 We report here survival data from our study comparing a group of 67 patients who received IMN irradiation to a group of 33 patients who did not receive IMN irradiation. The study was not randomized but since patient selection to receive or not receive IMN irradiation was not influenced by either physician- or patient-related bias, and the two groups were well matched for known prognostic features, a direct comparison between the two groups seems justified. Historically, a majority of high-risk patients relapse in the first 2 to 3 years after adjuvant therapy.11 In the present study, with a minimum follow-up of 52 months for surviving patients and a median follow-up of 77 months from diagnosis, the data show a disease-free survival (DFS) advantage and a trend to overall survival (OS) benefit for patients whose radiotherapy fields included the internal mammary nodes.
One hundred consecutive women with histologically proven American Joint Committee on Cancer (AJCC) high-risk stage II to IIIA breast carcinoma12 who were treated at the Chaim Sheba Medical Center between January 1994 and October 1998 were entered onto a prospective study with a treatment protocol comprising induction chemotherapy followed by high-dose chemotherapy with autologous stem-cell support and consolidated with locoregional radiotherapy and tamoxifen for receptor-positive breast cancer patients. The radiotherapy protocol included treatment of the breast or chest wall with tangential 6 to 8 MV photon beams, treatment of axilla and supraclavicular nodes with an anterior 6 to 8 MV photon beam, and treatment of the internal mammary nodes with an anterior 9 to 12 MeV electron beam. The first consecutive 32 patients received radiotherapy as planned. From January 1996 when our high-energy linear accelerator was removed until October 1997 when its replacement was fully commissioned, we had no capability of delivering electron-beam irradiation to the IMN. To avoid radiation to the heart and to limit the volume of lung tissue irradiated, we decided not to treat the IMN with alternative radiation techniques and to completely omit IMN irradiation during this period. All 33 patients treated during these 22 months received identical radiotherapy to the patients treated before and after this period, except for the omission of the internal mammary field. All 35 patients treated from October 1997 when the new linear accelerator was fully activated until the end of the study received internal mammary irradiation. The end points of the current study include DFS, OS, and toxicity for patients receiving IMN radiation (67 patients) and not receiving IMN radiation (33 patients). The feasibility, safety, toxicity, and local control rates of this approach have been reported previously.5
Eligibility criteria included age Three to 5 weeks after the last cycle of adjuvant chemotherapy, autologous peripheral stem cells were collected primed by granulocyte colony-stimulating factor (Neupogen; Amgen Biologicals, Thousand Oaks, CA; 5 µg/kg subcutaneously daily). The cells were collected on days 5, 6, and additionally on day 7 if necessary. The number of cells required for consolidation with high-dose chemotherapy was 5 x 108 mononuclear cells/kg and 2.5 x 106 CD34-positive cells/kg. A reserve stem-cell collection was preserved and stored. All patients received high-dose chemotherapy with the Stamp V protocol as previously described.13 Cyclophosphamide (1500 mg/m2 continuous infusion per day for a total of 96 hours), carboplatin (200 mg/m2 continuous infusion per day for a total of 96 hours), and thiotepa (125 mg/m2 continuous infusion per day for a total of 96 hours), were given on days -7 to -3. Stem cells were reinfused on day 0 and granulocyte colony-stimulating factor was administered the same day and continued until engraftment was achieved. Radiotherapy was planned after recovery from the high-dose chemotherapy and within 70 days of stem-cell transplant. Our radiotherapy technique has been described previously.5 In brief, radiotherapy was delivered to the whole breast or to the chest wall via medial and lateral tangential fields, with the posterior edge of the fields aligned to prevent divergence into the lungs. We aimed to include a maximum of 1.5 cm of lung as measured at the midpoint of the tangential fields (central lung distance) although in exceptional cases it was necessary to allow a central lung distance of up to 2 cm to treat the breast adequately. A bolus comprising 0.5 cm water-equivalent material was applied three times a week for patients receiving chest wall irradiation after mastectomy. The supraclavicular and upper axillary lymph nodes were treated via an anterior field angled 15° laterally to avoid irradiating the upper esophagus and spinal cord. Tangential and supraclavicular fields were treated to a dose of 50.4 Gy in 1.8 Gy daily fractions and delivered with 6 to 8 MV photons. In the group of patients whose treatment included the IMN nodes, the entire internal mammary chain was treated with a direct anterior electron beam whose energy ranged from 9 to 12 MeV depending on the depth of the nodes which are usually situated up to 1 cm deep to the sternum. A lateral x-ray of the sternum was performed with a guide wire placed on the skin above the sternum. The distance from the skin to the posterior edge of the sternum was measured and the electron energy was chosen to treat to a depth of 1 cm below the sternum. The IMN electron field dose was calculated at the 90% isodose line. This electron field overlapped the tangential field by 6 to 8 mm to prevent underdose at the field junction. Patients who underwent breast-preserving surgery received a further 14 Gy boost to the tumor bed in daily fractions of 2 Gy using 6 to 12 MeV electrons. During the period when electrons were not available, cobalt-60 was used to deliver the boost to the tumor bed. All patients received a total dose of 64.4 Gy. Toxicity was recorded according to the National Cancer Institute Common Toxicity Criteria. Radiotherapy was delivered without interruption unless the patient developed more than grade 2 skin toxicity or other major organ toxicity. The treatment was continued provided the hemoglobin level was more than 10 mg/dL, platelets were more than 30,000/µL, and leukocytes were more than 1500/µL with an absolute neutrophil count more than 500/µL. When hemoglobin decreased to less than 10 mg/dL, irradiated RBCs were transfused. Patients who were hormone receptor-positive received tamoxifen (20 mg/d) for 5 years after completing radiotherapy. No prophylactic antibiotic therapy was given in the period after the stem-cell transplant.
Statistical Analysis
The DFS and OS curves for all patients were calculated using the Kaplan-Meier product limit method, applied from the day of diagnosis and end of radiotherapy. Possible differences in the survival curves between the two subgroups were examined using the log-rank test. When multivariate Cox regression analysis was performed, the regression coefficients were estimated by maximum likelihood criteria, and their difference was determined by Wald’s test. The Cox regression coefficients were transformed to be the relative risks (RR) by exponentiation. The analysis was performed for the full model, where the effect of IMN irradiation was controlled for all the confounders (Table 2  ). All tests were performed using SPSS statistical analysis software version 11 (SPSS Inc, Chicago IL).
At a median follow-up of 77 months (range, 52 to 111 months) from diagnosis (69 months from the end of radiotherapy) for all the study patients, there was no treatment-related mortality.
There was no difference between the two groups (internal mammary radio-therapy v no internal mammary ratio-therapy) with regard to all the evaluated prognostic parameters, including age, tumor size, number of positive axillary lymph nodes, receptor status, dose-intensity, and treatment schedule (Table 1 All patients received the planned treatment as described earlier. Three patients in the no IMN irradiation group had delay of less than 5 days in starting radiotherapy, and five patients in the group treated to the IMN had delays of 3 to 20 days (median, 7 days) after recovery from high-dose chemotherapy. A further 10 patients, three patients in the no IMN irradiation group (one due to toxicity) and seven patients in the group treated to IMN (five due to toxicity) had treatment interruptions of up to 7 days during the radiotherapy. Ten patients (three patients in the no IMN irradiation group and seven patients in the group treated to IMN) received RBC transfusion during the radiation treatment. Leukocyte and platelet toxicity during radiotherapy was not life threatening, and blood counts thereafter returned to normal. Patients whose radiotherapy encompassed the IMN experienced a greater incidence of skin toxicity. Grade 2 skin toxicity occurred in 15% of patients not receiving IMN irradiation and 22% of patients receiving IMN irradiation. Grade 3 skin toxicity occurred in 6% and 10%, respectively. Radiation pneumonitis was seen in two patients who received IMN irradiation. There was no long-term organ toxicity or secondary leukemia. Only one patient in each group had a locoregional relapse as first site of metastatic disease. Eighteen (27%) of the 67 patients who received internal mammary radiotherapy relapsed and 15 died. The DFS for this group is 73% and OS is 78%. One patient died 5 years posttransplant with progressive neurological disease after developing an autoimmune-like thrombocytopenia that was controlled with steroids and low-dose cyclophosphamide. A brain biopsy was not diagnostic. No evidence of metastatic breast cancer was detected at her death.
Sixteen (49%) of the 33 patients who did not receive internal mammary radiotherapy relapsed and 12 died. DFS for this group was 52% and OS was 64% (Fig 1A
Using the log-rank test, a significant difference in DFS from date of diagnosis (P = .02) and a trend toward improvement in OS (P = .08) were observed in the group of patients receiving IMN irradiation. Similar results were seen for DFS and OS from end of therapy (median follow-up, 69 months).
A Cox regression multivariate analysis (Table 2
We have shown that inclusion of the internal mammary chain in the radiation field after surgical resection and high-dose chemotherapy was associated with an increased DFS and a trend toward increasing OS in high-risk breast cancer patients. There was no influence on locoregional recurrences and a clinically insignificant increase in skin toxicity. This was a single institution, prospective, nonrandomized study in which the decision on whether to treat or not to treat the internal mammary nodes was dictated by temporal factors, beyond the control of either physician or patient (eg, the lack of electron beam irradiation facilities for part of the period under study). All patients received the same intensive chemotherapy regimen (induction chemotherapy followed by high-dose chemotherapy), and the treatment period for patients who received IMN irradiation spanned the period of those who did not receive IMN irradiation. The patients were well matched for other prognostic factors. Although our study is not randomized, the forced, unbiased circumstances of the treatment selection justify a direct comparison between the two treatment groups. The aims of locoregional irradiation after resection and adjuvant systemic therapy for breast cancer is to reduce recurrences in the treated area and also to increase survival.3,4 The incidence of pathologically identified metastases to the IMN in patients with positive axillary nodes who undergo dissection of the IMN nodes ranges from 30% to 70% depending on the site and size of the primary tumor.14 On the other hand, the incidence of clinically significant IMN recurrence is small and therefore the role of internal mammary chain irradiation remains controversial.15,16 Fisher examined the patterns of recurrence in 320 axillary node-positive patients who did not receive adjuvant radiation after surgery. Of the 114 patients with locoregional recurrence, only one occurred in the internal mammary chain.17 An additional argument against irradiation of the internal mammary nodes is the evidence that radiotherapy techniques used in older series resulted in a high incidence of cardiotoxicity.18,19 A number of retrospective studies investigating the role of IMN irradiation in breast cancer have reached conflicting conclusions. Some of the negative studies included a high proportion of early-stage patients who are at low risk of recurrence. These patients have little to gain from IMN irradiation but have the same risk of cardiotoxicity as the entire cohort. One of the largest available retrospective studies reviewed 984 women treated with breast conservation and radiotherapy between 1970 and 1990.20 In the mid-1980s the treatment policy was changed, and routine irradiation of the IMN was no longer used. No benefit in local control or survival for the group receiving IMN irradiation was found, but in this study only 17% of all the patients had positive axillary nodes. In addition, patients receiving IMN irradiation were treated in an earlier period than patients who did not receive IMN irradiation. Other retrospective studies supporting the use of IMN irradiation have identified high-risk tumor related factors patients most likely to benefit from inclusion of the IMN in the irradiated volume. These factors include involvement of axillary nodes,21,22 inner quadrant or central primary tumors23,24 and both medial location and tumor size.25,26 Women undergoing mastectomy who receive radiotherapy to the chest wall and lymphatic drainage including the IMN have a significant survival benefit compared to women receiving no radiotherapy at all. A MEDLINE survey (key words: breast randomized internal mammary radiation) revealed only a single small study which randomized patients to receive or not receive IMN irradiation, and this study has until now only reported early toxicity data but no outcome data.27 No prospectively randomized study reporting the specific contribution of IMN irradiation to local control and survival has been published. An ongoing European Organization for Research and Treatment of Cancer (EORTC) study randomizing women with either positive axillary nodes or medial/central tumors to receive radiation including or excluding the internal mammary chain is planned to accrue more than 5000 patients.28 This study may definitively answer the question whether IMN node irradiation increases the survival of breast cancer patients but will require several years to complete accrual and several more years until the results mature. It should be noted that patients in this study were treated in the era when CT simulation was not routinely available. Currently accepted techniques require actual visualization of the depth of the IMN nodes. Our study is unique in including only patients who are at a particularly high-risk of recurrent disease due to multiple axillary metastases or with a large primary tumor with involvement of four or more axillary lymph nodes. All patients were treated with high-dose chemotherapy and stem-cell support. If chemotherapy can eradicate distant small microscopic disease, the addition of irradiation to nodal areas with a larger burden of microscopic disease may prevent subsequent systemic reseeding. In our opinion, the cohort of patients included in this study are those at highest risk of developing metastatic disease and may therefore be most likely to show an early benefit from a positive effect of internal mammary irradiation. In this high-risk group, any such effect is likely to be apparent after a relatively short follow-up because relapse tends to occur within 24 to 36 months from therapy. In our study, radiation to the internal mammary chain was associated with a significantly increased DFS and borderline improvement in OS, as shown with multivariate Cox analysis. These results, albeit in a relatively small cohort of patients, support the notion that nodal irradiation may influence survival without having any clear clinical effect on locoregional recurrence. This idea is supported by the discrepancy between the high incidence of pathological metastases to the internal mammary nodes compared to the low incidence of clinical manifestation of such metastases. We conclude that until data from prospectively randomized studies mature, patients with high-risk locoregional breast cancer might benefit from IMN irradiation. The large ongoing EORTC trial whose results will only be available in several years may give a definitive answer regarding the delivery of internal mammary irradiation and may also clarify which groups of breast cancer patients (stage and site of disease) are likely to benefit from this treatment.
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4. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 337:949–955, 1997 5. Stemmer SM, Pfeffer MR, Rizel S, et al: Feasibility and low toxicity of early radiotherapy after high-dose chemotherapy and autologous stem cell transplantation for patients with high-risk stage II–III and locally advanced breast carcinoma. Cancer 91:1983–1991, 2001[CrossRef][Medline] 6. Peters WP, Rosner G, Vredenburgh J, et al: A prospective, randomized comparison of two doses of combination alkylating agents (AA) as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes (LN): Preliminary results of CALGB 9082/SWOG 9114/NCIC MA-13. Proc Am Soc Clin Oncol 18:1a, 1999 (abstr 2) 7. Rodenhuis S, Bontenbal M, Beex LVAM, et al: Randomized phase III study of high-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin in operable breast cancer with 4 or more axillary lymph nodes. Proc Am Soc Clin Oncol 19:74a, 2000 (abstr 286) 8. Zander AR, Kröger W, Kröger N, et al: High-dose chemotherapy with autologous hematopoietic stem-cell support (HSCS) vs. standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: First results of a randomized trial. Proc Am Soc Clin Oncol 21:xa, 2002 (abstr 1658) 9. Antman KH: Overview of the six available randomized trials of high-dose chemotherapy with blood or marrow transplant in breast cancer. J Natl Cancer Inst Monogr 30:114–116, 2001
10. Gianni L: High-dose chemotherapy for breast cancer: Any use for it? Ann Oncol 13:650–652, 2002 11. Nikcevich DA, Vredenburgh JJ, Broadwater G, et al: Ten year follow-up after high-dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. Proc Am Soc Clin Oncol 22:415a, 2002 (abstr 1657) 12. Fleming ID, Cooper JS, Henson DE, et al (eds): American Joint Committee on Cancer Staging Manual (ed 5). Philadelphia, Lippincott Raven, 1997 13. Antman K, Ayash L, Elias A, et al: A phase II study of high-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy. J Clin Oncol 10:102–110, 1992[Abstract] 14. Handley RS: A surgeon’s view of the spread of breast cancer. Cancer 24:1232–1239, 1969 15. Kuske RR: Adjuvant chest wall and nodal irradiation: Maximize cure, minimize late cardiac toxicity. J Clin Oncol 16:2579–2582, 1998[Medline] 16. Freedman GM, Fowble BL, Nicolaou N, et al: Should internal mammary lymph nodes in breast cancer be a target for the radiation oncologist? Int J Radiat Oncol Biol Phys 46:805–814, 200 17. Fisher BJ, Perera FE, Cooke AL, et al: Long-term follow up of axillary node positive breast cancer patients receiving adjuvant systemic therapy alone: Patterns of recurrence. Int J Radiat Oncol Biol Phys 38:541–550, 1997[CrossRef][Medline] 18. Cuzick J, Stewart H, Ritqvist LE, et al: Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 12:447–453, 1994[Abstract] 19. Early Breast Cancer Trialists’ Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: An overview of the randomised trials. Lancet 355:1757–1770, 200 20. Obedian E, Haffty BG: Internal mammary nodal irradiation in conservatively-managed breast cancer patients: Is there a benefit? Int J Radiat Oncol Biol Phys 44:997–1003, 1999[CrossRef][Medline] 21. Montague ED, Fletcher GH: The curative value of irradiation in the treatment of nondisseminated breast cancer. Cancer 46:995–998, 1980 (suppl 4)[CrossRef][Medline] 22. Fletcher GH, McNeese MD, Oswald MJ: Long-range results for breast cancer patients treated by radical mastectomy and postoperative radiation without adjuvant chemotherapy: An update. Int J Radiat Oncol Biol Phys 17:11–14, 1989[Medline] 23. Chahbazian CM, del Regato JA, Wilson JF: Postoperative radiation therapy for "early" carcinoma of the breast. Cancer 42:1126–1128, 1978[CrossRef][Medline]
24. Zucali R, Mariani L, Marubini E, et al: Early breast cancer: Evaluation of the prognostic role of the site of the primary tumor. J Clin Oncol 16:1363–1366, 1998 25. Roseman JM, James AG: The significance of the internal mammary lymph nodes in medially located breast cancer. Cancer 50:1426–1429, 1982[CrossRef][Medline] 26. Le MG, Arriagada R, de Vathaire F, et al: Can internal mammary chain treatment decrease the risk of death for patients with medial breast cancers and positive axillary lymph nodes? Cancer 66:2313–2318, 199 27. Kaija H, Maunu P: Tangential breast irradiation with or without internal mammary chain irradiation: Results of a randomized trial. Radiother Oncol 36:172–176, 1995[CrossRef][Medline] 28. Lievens Y, Poortmans P, Van den Bogaert W: A glance on quality assurance in EORTC study 22922 evaluating techniques for internal mammary and medial supraclavicular lymph node chain irradiation in breast cancer. Radiother Oncol 60:257–265, 2001[CrossRef][Medline] Submitted September 19, 2002; accepted April 25, 2003. Related Correspondence
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
65 years and normal organ function including radionuclide cardiac scan (multigated angiogram [at rest and exercise] > 50%), carbon monoxide diffusing capacity (DLC) of the lungs greater than 60%, creatinine clearance greater than 60 mL/min, and normal liver function tests. All patients had a negative metastatic work-up that included brain, chest, abdominal, and pelvic CT scans, radionuclide bone scan, and bilateral bone marrow biopsies examined by hematoxylin and eosin stain. Informed consent was obtained from all patients. The protocol specified adjuvant chemotherapy with a doxorubicin-based regimen. Single-agent doxorubicin (75 mg/m2 every 3 weeks for a total of 4 cycles) was the preferred regimen used in 89 patients (88%). An additional 11 patients (11%) were referred for high-dose chemotherapy after adjuvant chemotherapy was initiated with doxorubicin combination chemotherapy. Surgery was performed by several surgeons, and included either lumpectomy and axillary lymph node dissection or mastectomy at the discretion of the patient and the referring surgeon. 
2 test for the comparison of categorical variables. 
