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© 2000 American Society for Clinical Oncology Second Malignancies After Treatment of Early-Stage Breast Cancer: Lumpectomy and Radiation Therapy Versus MastectomyFrom the Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT. Address reprint requests to Bruce G. Haffty, MD, Department of Therapeutic Radiology, Yale University School of Medicine, PO Box 208040, New Haven, CT 06520-8040; email bruce.haffty{at}yale.edu
PURPOSE: To determine the risk of second malignancies after lumpectomy and radiation therapy (LRT), and to compare it with that in a similar cohort of early-stage breast cancer patients undergoing mastectomy without radiation (MAST). PATIENTS AND METHODS: Between January 1970 and December 1990, 1,029 breast cancer patients at our institution underwent LRT. A cohort of 1,387 breast cancer patients who underwent surgical treatment by mastectomy (MAST), and who did not receive postoperative radiation during the same time period, served as a comparison group. Second malignancies were categorized as contralateral breast versus nonbreast. In the cohort of patients undergoing LRT, a detailed analysis was carried out with respect to age, disease stage, smoking history, radiation therapy technique, dose, the use of chemotherapy or hormone therapy, and other clinical and/or pathologic characteristics. RESULTS: As of March 1999, the median follow-up was 14.6 years for the LRT group and 16 years for the MAST group. The 15-year risk of any second malignancy was nearly identical for both cohorts (17.5% v 19%, respectively). The second breast malignancy rate at 15 years was 10% for both the MAST and LRT groups. The 15-year risk of a second nonbreast malignancy was 11% for the LRT and 10% for the MAST group. In the subset of patients 45 years of age or younger at the time of treatment, the second breast and nonbreast malignancy rates at 15 years were 10% and 5% for patients undergoing LRT versus 7% and 4% for patients undergoing mastectomy (P, not statistically significant). In the detailed analysis of LRT patients, second lung malignancies were associated with a history of tobacco use. There were fewer contralateral breast tumors in patients undergoing adjuvant hormone therapy, although this did not reach statistical significance. The adjuvant use of chemotherapy did not significantly affect the risk of second malignancies. CONCLUSION: There seems to be no increased risk of second malignancies in patients undergoing LRT using modern techniques, compared with MAST. Continued monitoring of these patient cohorts will be required in order to document that these findings are maintained with even longer follow-up periods. With nearly 15 years median follow-up periods, however, these data should be reassuring to women who are considering LRT as a treatment option.
CONSERVATIVE SURGERY (CS) with radiation therapy (RT) offers early-stage breast cancer patients local control and survival rates equivalent to those offered by treatment with mastectomy. As the follow-up duration of conservatively managed patients increases, however, the relative long-term risks of radiation must be addressed. Second malignancies pose one important potential long-term complication of treatment. Radiation is a known carcinogen. Radiation carcinogenesis, however, is felt to be a stochastic process. Second malignancies may arise not only from therapeutic but also from diagnostic doses of irradiation. Although radiation carcinogenesis is not felt to require a threshold dose, the likelihood of developing a second malignancy seems to increase with higher doses of radiation. The severity of radiation-induced malignancies, however, is not felt to be dose-dependent.1 Many studies report an excess risk of second cancers in patients who have received radiation. Second malignancies after therapeutic doses of radiation have been reported in patients with a variety of malignancies, including pediatric malignancies, Hodgkin’s disease, germ cell tumors, and breast cancer.2-19 In a study by Boice et al,20 an excess risk of contralateral breast cancers in patients younger than 45 years of age was directly attributed to radiotherapy. However, many patients in that review were treated with antiquated techniques that are no longer routinely used. The purpose of this study was to compare the risks of second malignancies in a modern cohort of early-stage breast cancer patients treated by CS+RT, compared with a similar cohort of patients treated by mastectomy alone without adjuvant radiation. Both breast and nonbreast second malignancies will be addressed, as well as confounding factors such as smoking, use of adjuvant systemic therapy such as tamoxifen and/or chemotherapy, and radiotherapy treatment techniques.
Between January 1970 and December 1990, 1,029 early stage (stage I and II) breast cancer patients underwent CS+RT at Yale New Haven Hospital. This group of patients served as the primary patient population for this study. During the same time period, a similar cohort of 1,387 patients with localized operable breast cancer underwent mastectomy without adjuvant postoperative radiotherapy (MAST). This group of mastectomy patients served as the comparison group for this current study. To select surgically treated patients with a similar stage of disease and prognosis as the conservatively treated cohort, patients with more advanced disease treated by mastectomy with postoperative radiation were excluded from analysis. Although this is not a prospective comparison, the surgically treated group had a similar follow-up duration and pathologic size as the conservatively treated group. As listed in Table 1, the patients in the surgically treated group had a lower 10-year survival rate, which is likely a reflection of the higher percentage of patients in the age group of patients 45 years of age and older. We acknowledged the obvious limitations in comparing these populations retrospectively by ensuring that both cohorts had a similar risk period with respect to the development of second malignancies.
Radiation oncology charts and tumor registry data were retrospectively reviewed in all patients undergoing CS+RT, and tumor registry data were reviewed in all patients treated by MAST. Patient, demographic, pathologic, and treatment parameters were all entered into a computerized database. Any patient identified as having developed a second malignancy was recorded as such. The site and date of diagnosis of second malignancy was then confirmed on the basis of anatomic pathology reports. For the study presented here, second malignancies were classified as second breast malignancies or as nonbreast malignancies. Second breast primary tumors were restricted to the development of new contralateral breast cancers, whether invasive or noninvasive. However, lobular carcinoma-in-situ of the contralateral breast was excluded. In addition, ipsilateral tumors were scored as recurrences and, therefore, were not considered second primary tumors, regardless of disease-free interval or location within the breast. Second nonbreast malignancies were subdivided into skin, soft tissue, lung, head and neck, gastrointestinal, gynecologic, genitourinary, or other site of origin. Among patients undergoing CS+RT, a detailed analysis was performed with respect to several prognostic factors, including age, T stage, nodal status, estrogen receptor/progesterone receptor status, histology, use of adjuvant chemotherapy and/or hormonal therapy, margin status, and method of tumor detection. The smoking histories of these patients were also recorded. Tobacco consumption was scored as heavy if smoking continued during RT and mild or moderate if smoking ceased before RT. The technique of radiation delivery and doses of RT used were also recorded (Table 2). All patients underwent treatment of the breast by use of tangential fields with the routine use of both medial and lateral wedges. Regional nodal radiation was delivered at the discretion of the practicing radiation oncologist, as has been previously described.21 The majority of patients underwent separate fields for coverage of both the supraclavicular and the internal mammary lymph nodes. The median dose to the intact breast was 48 Gy and was 46 Gy to the regional lymph nodes, using 2 Gy per fraction. Patients routinely received boost doses of radiation, bringing the tumor bed dose to 60 to 64 Gy.
Survival was determined by the life-table method. Survival was calculated from the date of diagnosis to the date of death or date last seen. Patients were analyzed for overall survival, distant metastasis–free survival, breast relapse–free survival, second malignancy–free survival, second breast malignancy–free survival, and second nonbreast malignancy–free survival. All tests for statistical significance were performed using the  2 method for categorical variables and the Mantel-Haenszel statistic for survival curves.
The median follow-up period for the entire cohort of patients was 14.6 years for patients undergoing CS+RT and 16 years for patients undergoing MAST. All patients had a minimum assessable follow-up period of 9 years. CS+RT patient characteristics are listed in Table 3. Overall survival, breast relapse–free survival, and distant metastasis–free survival for the entire cohort of patients undergoing CS+RT are depicted in Fig 1.
All second malignancies identified are shown in Tables 4, 5, and 6. There were no statistically significant differences in the incidence of second malignancies between CS+RT patients and MAST patients. As expected, contralateral breast malignancy was the most common second malignancy identified in both groups. Among nonbreast second malignancies, gastrointestinal malignancies, followed by gynecologic malignancies, were the next most common second primary tumors in both groups.
Figure 2 depicts second breast malignancy–free survival in all patients. At 15 years, the risk of contralateral breast cancers was 10% of each cohort. Nonbreast second malignancies developed in 11% of CS+RT patients at 15 years, compared with 10% of MAST patients (Fig 3).
Among patients 45 years of age or younger at the time of treatment, the 15-year risk of contralateral breast malignancy was 10% for CS+RT patients versus 7% for MAST patients (Fig 4; P = not statistically significant [NS]). The 15-year risk of nonbreast second malignancy in patients  45 years of age at the time of treatment was 5% in the CS+RT group, compared with 4% in the MAST group (Fig 5). None of these differences was statistically significant.
Overall survival was decreased if a patient developed a second malignancy (Fig 6). The 15-year survival rate was 69% for patients not developing a second malignancy versus 55% for those developing a second malignancy (P = .05).
Second malignancies were associated with a history of smoking. Patients who continued to smoke at the time of radiation had a 20% risk of developing a second malignancy by 15 years, compared with 16% for nonsmokers (P = .07). Lung malignancies were particularly associated with tobacco consumption. The 15-year risk of developing a lung cancer after CS+RT was 0.26% for nonsmokers, 4.7% for patients with a smoking history before RT, and 6% for patients who continued to smoke at the time of radiation (P = .06). Although, as expected, treatment with adjuvant hormonal therapy (HT) showed a trend toward decreasing the risk of contralateral breast malignancies, the effect of HT on contralateral breast cancer was not statistically significant. The 15-year risk of a contralateral breast malignancy was 10.4% in patents who did not receive adjuvant HT, compared with 7.7% in patients who did receive adjuvant HT (P = NS). Patients who received adjuvant chemotherapy had a 15-year risk of 7% for the development of a second nonbreast malignancy, compared with a 12% risk for patients who did not receive adjuvant chemotherapy (P = NS). Adjuvant chemotherapy also did not seem to significantly increase the risk of developing hematologic malignancies or second breast malignancies. Radiation therapy technique, such as the use of a separate supraclavicular field, had no influence on the risk of second breast or nonbreast malignancies. Patients in whom the internal mammary lymph nodes were intentionally targeted manifested a trend toward a higher risk of developing a second malignancy. Patients who had their internal mammary nodes targeted had a longer follow-up period. Although this may, in part, account for the higher rate of second malignancies, the actuarial 15-year rate of second malignancies was slightly higher in the patients who received RT to the internal mammary field (19% v 15%, P = .097).
In the data presented, which has a median follow-up duration of nearly 15 years, patients who received therapeutic doses of irradiation after breast-conserving surgery did not seem to have an increased risk of second malignancies, compared with patients treated surgically without irradiation. The number of neither contralateral breast nor nonbreast second malignancies seem to be increased in patients who received RT. With modern techniques, this result seems to hold even for women 45 years of age or younger at the time of treatment. There are obvious limitations in the interpretation of the retrospective study design that must be acknowledged, however. Although the difference is not statistically significant, patients 45 years of age or younger who underwent MAST had a 3% lower 15-year risk of developing a contralateral breast cancer than did patients who underwent CS+RT (7% v 10%, respectively). In a study by Boice et al,20 RT was implicated as increasing the relative risk of contralateral breast cancer by a factor of 1.19 in women under the age of 45.20 However, older treatment techniques may have been responsible for the excess risk reported. Further follow-up and other studies using modern RT techniques such those reported here are certainly warranted to clarify this issue. Patients who received RT in our series routinely underwent treatment using both medial and lateral wedges. Although the use of medial wedges has been shown to increase scatter radiation to the contralateral breast,22 this factor apparently did not significantly increase the risk of contralateral breast cancer in patients in this series, compared with similar patients who underwent MAST without radiation. Modern megavoltage equipment may be responsible for the lessened impact of wedges on the incidence of contralateral breast cancer. Other case-control studies23-25 and randomized trials26-30 have also failed to reveal an increased risk of contralateral breast cancer due to ipsilateral breast RT. Breast cancer patients are at an inherently higher risk of developing second malignancies.31 Therefore, any series implicating RT as a carcinogen should use a control arm of similar cancer patients who do not receive RT. In the study presented here, we attempted to provide a control population of patients who were treated at the same institution, in a similar era with a similar spectrum of disease and follow-up, but who did not receive RT. The nearly identical risk of second malignancies in the irradiated group is reassuring but, as noted above, must be interpreted cautiously. Longer follow-up and continued monitoring of these patients will be required to confirm the validity and stability of these results. Radiation carcinogenesis may take over 20 years.32 Although our median follow-up period was respectable, at nearly 15 years, this may still not have been long enough to detect a difference in the incidence of second malignancies between the two groups of patients. Our plan is to continue to monitor these two cohorts of patients to assure the stability of these findings with even longer follow-up. Although the RT technique did not seem to influence the risk of second malignancies, there were slightly more second malignancies at 15 years in patients who underwent intentional targeting of the internal mammary lymph nodes. It should be noted, however, that follow-up was longer in the internal mammary–treated group and that the actuarial difference in second malignancies at 15 years was not statistically significant. A recent review on the carcinogenic effects of RT for breast cancer suggested that selective use regional nodal irradiation may limit radiation-induced secondary malignancies.33 In light of the controversial issues surrounding the use of internal mammary RT,34-36 the potential benefit of internal mammary RT on disease-free survival37,38 needs to be weighed against all potential risks, including cosmetic issues, cardiopulmonary toxicity, and second malignancies. This issue is clearly worthy of further investigation. As expected, smoking increased the risk of developing second malignancies. Smoking particularly increased the risk of second lung malignancies. Furthermore, persistent smoking at the time of radiation seemed to carry the highest risk of developing a second lung malignancy. This may represent the fact that patients who continued tobacco use were simply heavier smokers than patients who quit smoking before RT. However, the possibility that RT enhances the carcinogenic effects of smoking cannot be excluded, especially since standard tangential fields routinely include 1 to 3 cm of lung tissue. Therefore, this result may also have clinical implications for counseling patients on smoking cessation before RT. Other studies confirm the additive carcinogenic effects of RT and smoking on the development of secondary lung cancers.39-41 Patients who underwent HT had a trend toward developing decreased contralateral breast malignancies. Although statistical significance was not achieved, the relatively small numbers of patients in this study who were treated with HT limited the study’s power to detect a statistically significant difference. This finding is, however, consistent with several trials reported by the National Surgical Adjuvant Breast and Bowel Project.42-44 Chemotherapy did not adversely affect the rate of second malignancies. Interestingly, the number of hematologic malignancies also did not seem to be increased. It should be noted, however, that the majority of patients undergoing chemotherapy in our series received cyclophosphamide, methotrexate, and fluorouracil, which may not be significantly associated with leukemia.45 Chemotherapy also did not increase the risk of second solid tumors including contralateral breast cancers. In summary, with a median follow-up period of nearly 15 years after treatment for early-stage breast cancer, there seems to be no increased risk of second malignancies in patients undergoing lumpectomy followed by therapeutic doses of irradiation using modern techniques, compared with surgically treated patients. This observation holds even in the subset of patients under the age of 45 at the time of treatment. Although the difference was not statistically significant, adjuvant HT seemed to lower the risk of a contralateral breast cancer, and smoking increased the risk of a second lung malignancy. Chemotherapy had no adverse effect on the rate of second malignancy. Continued monitoring of these patient cohorts will be required to document that these findings are maintained throughout an even longer-term follow-up period. With nearly 15 years median follow-up, however, these data should be reassuring to women considering lumpectomy followed by irradiation as a treatment option.
1. Hall EJ: Radiation carcinogenesis, in: Radiobiology for the Radiologist (ed 4). Philadelphia, PA,J.B. Lippincott, 1994, pp 323-350 2. Kimball Dalton VM, Gelber RD, Li F, et al: Second malignancies in patients treated for childhood acute lymphoblastic leukemia. J Clin Oncol 6:2848-2853, 1998
3.
Walter AW, Hancock ML, Pui CH, et al: Secondary brain tumors in children treated for acute lymphoblastic leukemia at St Jude Children’s Research Hospital. J Clin Oncol 16:3761-3767, 1998 4. Bauman GS, Venkatesan VM, Ago CT, et al: Postoperative radiotherapy for stage I/II seminoma: Results for 212 patients. Int J Radiat Oncol Biol Phys 42:313-317, 1998[Medline] 5. Le Vu B, de Vathaire F, Shamsaldin A, et al: Radiation dose, chemotherapy and risk of osteosarcoma after solid tumours during childhood. Int J Cancer 77:370-377, 1998[Medline] 6. Salloum E, Doria R, Schubert W, et al: Second solid tumors in patients with Hodgkin’s disease cured after radiation or chemotherapy plus adjuvant low-dose radiation. J Clin Oncol 14:2435-2443, 1996[Abstract]
7.
Doria R, Holford T, Farber LR, et al: Second solid malignancies after combined modality therapy for Hodgkin’s disease. J Clin Oncol 13:2016-2022, 1995 8. Scaradavou A, Heller G, Sklar CA, et al: Second malignant neoplasms in long-term survivors of childhood rhabdomyosarcoma. Cancer 76:1860-1867, 1995[Medline]
9.
Boivin JF, Hutchison GB, Zauber AG, et al: Incidence of second cancers in patients treated for Hodgkin’s disease. J Natl Cancer Inst 87:732-741, 1995 10. Peters MH, Sonpal IM, Batra MK: Breast cancer in women following mantle irradiation for Hodgkin’s disease. Am Surg 61:763-766, 1995 (review)[Medline] 11. Brady MS, Farfein CF, Petrek JA, et al: Post-treatment sarcoma in breast cancer patients. Ann Surg Oncol 1:66-72, 1994[Medline]
12.
Inskip PD, Stovall M, Flannery JT: Lung cancer risk and radiation dose among women treated for breast cancer. J Natl Cancer Inst 86:983-988, 1994 13. Mark RJ, Poen J, Tran LM, et al: Postirradiation sarcomas: A single-institution study and review of the literature. Cancer 73:2653-2662, 1994[Medline]
14.
Del Mastro L, Garrone O, Guenzi M, et al: Angiosarcoma of the residual breast after conservative surgery and radiotherapy for primary carcinoma. Ann Oncol 5:163-165, 1994 15. van Leeuwen FE, Lkokman WJ, Hagenbeek A, et al: Second cancer risk following Hodgkin’s disease: A 20-year follow-up study. J Clin Oncol 12:312-325, 1994[Abstract] 16. Pitcher ME, Davidson TI, Fisher C, et al: Post irradiation sarcoma of soft tissue and bone. Eur J Surg Cancer 20:53-56, 1994 17. Giacchetti S, Raoul Y, Wibault P, et al: Treatment of stage I testis seminoma by radiotherapy: Long-term results—a 30-year experience. Int J Radiat Oncol Biol Phys 27:3-9, 1993[Medline]
18.
Bokemeyer C, Schmoll HJ: Secondary neoplasms following treatment of malignant germ cell tumors. J Clin Oncol 11:1703-1709, 1993 19. Taghian A, de Vathaire F, Terrier P, et al: Long-term risk of sarcoma following radiation treatment for breast cancer. Int J Radiat Oncol Biol Phys 21:361-367, 1991[Medline] 20. Boice JD Jr, Harvey EB, Blettner M, et al: Cancer of the contralateral breast after radiotherapy for breast cancer. N Engl J Med 326:781-785, 1992[Abstract] 21. Haffty BG, Fischer D, Fischer JJ: Regional nodal irradiation in the conservative treatment of breast cancer. Int J Radiat Oncol Biol Phys 19:859-865, 1990[Medline] 22. Fraass BA, Roberson PL, Lichter AS: Dose to the contralateral breast due to primary breast irradiation. Int J Radiat Oncol Biol Phys 11:485-497, 1983
23.
Bernstein J, Thompson WD, Risch N, et al: Risk factors predicting the incidence of second primary breast cancer among women diagnosed with a first primary breast cancer. Am J Epidemiol 136:925-936, 1992
24.
Storm HH, Andersson M, Boice JD Jr, et al: Adjuvant radiotherapy and risk of contralateral breast cancer. J Natl Cancer Inst 84:145-150, 1992 25. Basco VE, Coldman AJ, Elwood FM, et al: Radiation dose and second cancer. Br J Cancer 52:319-325, 1985[Medline] 26. Veronesi U, Banfi A, Salvadori B, et al: Breast conservation is the treatment of choice in small breast cancer: Long-term results of a randomized trial. Eur J Cancer 26:668-670, 1990 27. Fisher B, Bauer M, Margolese R, et al: Five-year results of a randomized trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med 312:665-673, 1985[Abstract]
28.
Jacobson JA, Danforth DN, Cowan KH, et al: Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 332:907-911, 1995
29.
Arriagada R, Le MG, Rochard F, et al: Conservative treatment vs mastectomy in early breast cancer: Patterns of failure with 15 years of follow-up data. J Clin Oncol 14:1558-1564, 1996 30. Sarrazin D, Le MG, Arriagada R, et al: Ten-year results of a randomized trial comparing conservative treatment to mastectomy in early breast cancer. Radiother Oncol 14:177-184, 1989[Medline] 31. Harvey EB, Brinton LA: Second cancer following cancer of the breast in Connecticut. Natl Cancer Inst Monogr 68:99-112, 1985 32. Committee on the Biological Effects of Ionizing Radiation:Health Effects of Exposure to Low Levels of Ionizing Radiation (Beir V). Washington, DC,National Research Council, 1990 33. Neugut AI, Weinberg MD, Ahsan H, et al: Carcinogenic effects of radiotherapy for breast cancer. Oncology 13:1245-1252, 1999[Medline] 34. 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[Medline] 35. Marks LB, Hardenbergh P, Prosnitz LR: Mounting evidence for post mastectomy locoregional radiation therapy. Oncology 13:1123-1135, 1999 (review)[Medline] 36. Fowble B, Hanlon A, Freedman G, et al: Internal mammary node irradiation does not decrease distant metastases or improve survival in stage I and II breast cancer. Proc Am Soc Ther Radial Oncol 45:158, 1999 (abstr 24)
37.
Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk pre-menopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 337:949-955, 1997
38.
Ragaz J, Jackson SM, Le N, et al: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 337:956-962, 1997
39.
van Leeuwen FE, Klokman WJ, Stovall M, et al: Roles of radiotherapy and smoking in lung cancer following Hodgkin’s disease. J Natl Cancer Inst 87:1530-1537, 1995 40. Inskip PD, Boice JD Jr: Radiotherapy-induced lung cancer among women who smoke. Cancer 73:1541-1543, 1994 (editorial)[Medline] 41. Neugut AI, Murray T, Santos J, et al: Increased risk of lung cancer after breast cancer radiation therapy in cigarette smokers. Cancer 73:1615-1620, 1994[Medline]
42.
Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 90:1371-1388, 1998 43. Fisher B, Costantino J, Redmond C, et al: A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 320:479-484, 1989[Abstract] 44. Fisher B, Dignam J, Wolmark N, et al: Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 353:1993-2000, 1999[Medline]
45.
Valagussa P, Moliterni A, Terenziani M, et al: Second malignancies following CMF-based adjuvant chemotherapy in resectable breast cancer. Ann Oncol 5:803-808, 1994 Submitted November 29, 1999; accepted February 22, 2000.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
