Post-mastectomy radiotherapy: recommended standards H. Bartelink Department of Radiotherapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands Introduction The local recurrence rate after mastectomy in breast cancer patients varies significantly in reported series; in some publications from 2% to even more than 50% at 10 years. The reasons for these differences can be found in patient selection and the surgical method and technical skills of the surgeon. For example, a low recurrence percentage can be obtained by combining a good surgical procedure with the exclusion of patients for radical mastectomy by following strict inoperability criteria. For this purpose, the following criteria are often used: fixation of the tumour and/or lymph nodes to the chest wall, inflammatory breast cancer, and in some institutes a positive axillary apex biopsy. In 1949 Ralston Paterson and colleagues in Manchester started probably the first randomized clinical trial in the world investigating the potential of radiotherapy in improving local control and indirectly survival [1]. They randomized patients after mastectomy between no radiotherapy and post-mastectomy radiotherapy. For this purpose 1461 patients were entered in this trial. He and his colleagues demonstrated that radiotherapy was able to reduce significantly the amount of local recurrences thereby preventing patients dying from symptoms of uncontrolled local disease. Unfortunately long term follow up showed that the potential gain in survival was diminished by an excess of radiotherapy-related cardiovascular complications. It would be unfair to criticize the trial design according to current standards and the radiation technique used but a few remarks should be made here. For example, the randomization was based on the patient's date of birth (odd or even), so the surgeon would know beforehand in which arm the patient would be randomized. He may have therefore decided not to select patients for the trial if they had a high risk of local recurrence knowing that they would be randomized to no further treatment. Instead he may have referred these patients for radiotherapy, leading to unbalanced treatment arms. The major reason for the excess of cardiovascular deaths seen in this trial was the equipment available at that time. The patients were treated with orthovoltage equipment using a technique that delivered a high dose to a large part of the heart with higher fraction doses. A reduction of the local recurrence rate, by a factor of 0.6, by post-mastectomy radiotherapy has now been confirmed by many trials. It took until recently for it to be demonstrated that improvement in local control could result in about 10% improved survival rate [2-4]. These results became available with the publication of the long term follow up data from a few major trials started after 1975. These trials have shown a gain that can be reached by careful selection of high-risk patients for radiotherapy and through the execution of meticulous radiotherapy techniques, avoiding over dosage of radiation to the heart. The impact of improved local control on the survival rate shown by these trials suggests that distant metastases may arise from recurrent local disease, stressing the need for adequate local treatment. The purpose of this lecture is to discuss the indications for post-mastectomy radiotherapy, the technique used and the avoidance of complications and also the interaction with adjuvant chemotherapy. Indications for post-mastectomy radiotherapy In an overview study of the literature, Recht [5] showed that the local recurrence rate in T3 or N4+ patients varied between 14 and 46%, despite receiving adjuvant chemotherapy, thus underlining the need for postoperative radiotherapy in these cases. Considering indications for postoperative radiotherapy one should always bear in mind the balance between the gain in local control and survival and the disadvantages of radiotherapy (see below). There is a general consensus that a locoregional recurrence rate of 20% at 10 years or more justifies postoperative radiotherapy. This percentage (or even higher) is frequently seen for patients with a microscopically incomplete resection, a T3 NO tumour with unfavourable histological signs or positive nodes and for patients with 4
8 H. Bartelink Table 1 Indications for postoperative chest wall irradiation Incomplete resection (micro- or macroscopic) 4 or more positive lymph nodes T3 tumours with grade 2 or 3 and/or vascular invasion T3 N+ tumours Diffusely growing tumours in more than one quadrant Table 2 Indications for postoperative irradiation of the axilla 4 or more positive nodes in 2 levels or 50% of the nodes are positive More than one palpable lymph node metastases of more than 2cm Margin of surgery less than 5 mm Extra nodal spread at the border of surgical specimen or more positive lymph node metastases (N4+). The indications for postoperative irradiation of the chest wall and axilla should be considered separately since the recurrence rate in the axilla is much lower than on the chest wall (Tables 1 and 2). Nowadays, the most difficult question concerns whether patients with Tl-2 and Nl still need postmastectomy radiotherapy, considering that in the Danish trials the major benefit in survival is seen in this patient group. The indications for post-mastectomy radiotherapy should therefore be discussed in a multidisciplinary team including the pathologist, the surgeon and the radiation oncologist. They should consider the surgical technique such as the adequacy of the axillary dissection and pathological factors associated with a high local recurrence rate such as vascular invasion and extra nodal spread together with the proximity of the tumour to the resection margins. The treatment of the internal mammary lymph nodes is still a matter for debate. The finding of involvement of these lymph nodes of 20-25% in, for example, the Milan experience and the impact of inadequate locoregional treatment on survival suggests that elective irradiation of these nodes may be of benefit to patients with an increased risk of internal mammary lymph node metastases. For this purpose a major EORTC trial is presently underway to investigate the benefit of irradiation of these lymph nodes. Acute side effects seen after radiotherapy are mainly skin reactions varying from redness to moist desquamation at the end of treatment Six weeks to 6 months after treatment, radiation pneumonia's can occur especially if a (too) large lung volume is irradiated. An increased incidence of radiation pneumonitis has been reported in patients receiving both radiotherapy and tamoxifen, although this has to be confirmed in a larger patient population [6]. Late side effects such as fibrosis and arm edema are seen mostly 2 years or more after the end of treatment. For evaluation of cardiovascular side effects a follow-up of 10 to 15 years is needed. Nowadays, the use of modern radiotherapy equipment allows the radiation oncologist to reduce significantly the dose to the heart and lungs. Tangential photon irradiation combined with direct irradiation fields to treat the internal mammary lymph nodes (technique A) (Fig. 1) may be replaced by a different technique with electrons or a combination of tangential beam irradiation with angled fields to treatment the internal mammary lymph nodes (technique B) (Fig. 2). If a simple tangential field technique is used the amount of cardiac complications can be estimated -15-10 Fig. 1. Transverse slice through the middle of the breast showing the external contour, heart and lungs (technique A): note low dose region between the internal mammary fields and the tangential fields. Field outlines and 95% and 50% isodose lines are shown m. Reduction of side effects from radiotherapy -is Fig. 2. Transverse slice through the middle of the breast showing the external contour, heart and lungs (technique B). Field outlines and 95% and 50% isodose lines are shown [7].
Post-mastectomy radiotherapy: recommended standards by measuring the heart volume on the simulator film in case of left-sided breast cancer. In cases exceeding a limited volume (heart volume distance more than 1 cm) a different technique should be selected. A more modem way is to use intensity modulated radiotherapy (IMRT). With this approach the beams are angled and shaped according to the patient's contour, carefully avoiding critical normal tissues while being able to deliver curative doses to the chest wall, axilla and internal mammary lymph nodes [7]. Care should also be taken when using concomitant radiotherapy and chemotherapy, especially when anthracyclins, taxoids and/or trastuzumab are given. Due to limited follow-up, it is not known at this moment whether the combination of anthracyclins will later result in an increased rate of cardiovascular problems as seen in patients with small cell lung cancer. Another disadvantage of postoperative radiotherapy in breast cancer is the risk of arm edema, which can increase from 2-5% after mastectomy and axillary dissection alone to 20-30% when radiotherapy is added. Reduction of the risk of arm edema can be obtained by not exceeding the daily radiation dose of 2.5 Gy. Instructions to patients on how to prevent arm infections and their immediate treatment with antibiotics if this occurs, will help to reduce the incidence of arm edema. In case of edema, physiotherapy will help to reduce the swelling of the arm. Limiting the extent of the radiation fields to only the chest wall and lower part of the axilla will be possible in patients with a T3-4 tumour with only involvement of the nodes located in the lower part of the axilla. This adaptation will probably not lead to an increased incidence of arm edema after irradiation of the axilla and supraclavicular nodes. cancer has led to improved locoregional local control compared to radiotherapy alone [9,10]. As referred to earlier, adjuvant chemotherapy on its own is not able to reduce significantly the locoregional recurrence rate in high risk breast cancer patients. A combination of both treatment modalities is therefore often required. There is frequent debate whether chemotherapy should be given first or radiotherapy. In the past, the argument has often been used that postoperative radiotherapy has had no impact on survival and could therefore be delayed. This must now be considered differently as the extent of improvement in survival appears to be similar to that of adjuvant chemotherapy in these patients. Furthermore, up to now none of the meta-analyses have demonstrated a benefit of chemotherapy before or after standard local treatment. So the correct answer will remain uncertain for a while until major trial results in this area become available. One is inclined therefore not to postpone radiotherapy until after chemotherapy but to give it concomitantly as a 'sandwich' scheme: between two courses of chemotherapy [11-13]. In general it has been shown that this combination is well tolerated and few adaptations have to be made. As mentioned earlier, there is some concern in administering radiotherapy and chemotherapy concomitantly especially if anthracyclins are used. This combination may lead to an increase in cardiovascular problems as seen in patients with small cell lung cancer when doxorubicin was used concomitantly with radiotherapy. However reliable data are lacking in de literature and the concomitant combination may prove to be not that harmful if drugs such as anthracyclins, taxoids and trastuzumab are excluded. Timing of interval radiotherapy and surgery No major trials have been published investigating the optimal time interval between radiotherapy and surgery in breast cancer apart from a few small studies with conflicting results. Most retrospective studies in breast conserving therapy suggest that the interval between surgery and radiotherapy should preferably not exceed 6 weeks [8] as, with longer interval, more recurrences have been observed. Combination and timing of chemotherapy with post-mastectomy radiotherapy In many trials it has been shown that the combination of radiotherapy and systemic treatment in breast Improvement in locoregional control and survival by postoperative radiotherapy Over the many years that clinical randomized clinical trials have been performed, investigating the potential of postoperative radiotherapy, it has appeared that this approach has led to a consistent significant reduction of local recurrences. This approach resulted in a reduction by a factor 0.6 by adding radiotherapy after any form of mastectomy. This occurred both in the old trials using orthovoltage equipment, and in the recent clinical trials where modem megavoltage equipment has been used. Generally a locoregional recurrence rate of about 30% has been reduced to about 7-10% (Table 3). This gain in local control on its own is already a major benefit to patients by preventing symptoms from untreatable local progres-
10 H. Bartelink Table 3 Locoregional recurrences in patients who all received chemotherapy ± radiotherapy [2] ^^~ No radotfwrapy Treatment RT + CMF CMF alone Locoregional recurrence 75 (9%) 277 (32%) sion. It is important to realize also that only local cure can be obtained in about half of the patients with a local recurrence after mastectomy. Such a recurrence is an unfavourable sign as it is also frequently followed by the appearance of distant metastases. The trials executed before 1975 have not shown a benefit in survival; in contrast even a negative effect has been observed in some trials, mainly due to an excess of cardiovascular deaths [14]. In a recent update by the EBCTCG these findings were confirmed, showing both moderate benefits during the first decade or two, and moderate hazards that grow progressively larger with longer follow-up. The benefits demonstrate the important principle that improved control of local disease in early breast cancer implies, other things being equal, a moderate but definite reduction in the long-term risk of death from breast cancer [15]. If particular radiotherapy regimens (those that very strictly limit carotid and intrathoracic exposure) can be shown to yield most of the benefit while avoiding most of the hazard, 20 year survival could be improved in a wider range of patients [16]. The recent Danish and Vancouver trials have demonstrated that with modem radiotherapy the improved local control has been translated into a survival advantage of approximately 10% (Fig. 3). One may criticize some of these trials for having used rather low doses of chemotherapy. This diminishes the opportunity to further improve survival in these patients, although these trials may reflect the doses given in the large community. The negative impact 100 1 2 3 4 5 6 7 8 9 10 Years after Mastectomy Fig. 3. Kaplan Meier Estimates of overall survival among women treated with radiotherapy plus CMF and CMF alone [2]. 0 2 4 6 8 10 12 Years Fig. 4. Cumulative mortality for ischemic heart disease by radiotherapy group [17]. of cardiovascular death caused by improper radiation techniques has not been seen up to now [17,18] (Fig. 4). Recommended reading... Seminars in Radiation Oncology, Volume 9 (3), 1999: special issue on adjuvant therapy of breast cancer (LJ Pierce and M Overgaard, eds.) References 1 Paterson R, Russell M. Breast cancer evaluation of postoperative radiotherapy. J Fac Radiol 1959; 10: 75-180. 2 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 Group DCG 82b randomised trial. N Engl J Med 1997; 337: 949-955. 3 Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high-risk postmenopausal patients given adjuvant tamoxifen: Danish Breast Cancer Group DBCG 82c randomised trial. Lancet 1999; 353(9165): 1641-1648. 4 Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in node positive premenopausal women with breast cancer. N Engl J Med 1997; 337: 956-962. 5 Recht A. Locoregional failure rates in patients with involved axillary nodes after mastectomy and systemic therapy. Semin Radiat Oncol 1999; 9: 223-229. 6 Bentzen SM, Skoczylas JZ, Overgaard M, Overgaard J. Radiotherapy-related lung fibrosis enhanced by tamoxifen. J Natl Cancer Inst 1996; 88(13): 918-922. 7 Hurkmans CW, Bos L, Van der Horst A, et al: Estimation of cardiac and lung complications after breast cancer irradiation. Radiother Oncol 2000; in press. 8 Slotman BJ, Jeyer OW, Njo KH, et al. Importance of riming of radiotherapy in breast conserving treatment of early stage breast cancer. Radiother Oncol 1994; 30: 206-212. 9 Bartelink H, Rubens RD, Van der Schueren E, et al Hormonal therapy prolongs survival in irradiated locally advanced breast cancer, a European Organization for Research and Treatment of Cancer randomized phase DI trial. J din Oncol 1997; 15: 207-215. 10 Elkhuizen PH, Van Slooten HJ, Clahsen PC, et al. High local recurrence risk after breast-conserving therapy in node-nega-
Post-mastectomy radiotherapy: recommended standards 11 tive premenopausal breast cancer patients is greatly reduced by one course of perioperative chemotherapy: A European Organization for Research and Treatment of Cancer, Breast Cancer Cooperative Group Study. J Clin Oncol 2000; 18: 1075-1083. 11 Maririewicz DA, Schultz DJ, Haas JA, et al. The effects of sequence and type of chemotherapy and radiation therapy on cosmesis and complications after breast conservation therapy. Int J Radiat Oncol Biol Phys 1996; 35: 661-668. 12 Borger J, Bartelink H. Does the sequence of radiotherapy and chemotherapy in breast-conserving therapy influence outcome? Cancer J Sci Am 1996; 2: 19-20. 13 Thames HD, Buchholz TA, Smith CD. Frequency of first metastatic events in breast cancer implications for sequencing of systemic and local-regional treatment J Clin Oncol 1999; 17: 2649-2658. 14 Cuzick J, Stewart H, Rutqvist L, et al. Cause-specific mortality on long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 1995; 12: 447-453. 15 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 2000; 355(9217): 1757-1770. 16 Recht A, Bartelink H, Fourquet A, et al. Postmastectomy radiotherapy: questions for the twenty-first century. J Clin Oncol 1998; 16:2886-2889. 17 H0jris I, Overgaard M, Christensen JJ, et al. Morbidity and mortality of ischaemic heart disease in high-risk breast-cancer patients after adjuvant postmastectomy systemic treatment with or without radiotherapy: analysis of DBCG 82b and 82c randomised trials. Lancet 1999; 354: 1425-1430. 18 Kurtz JM. Radiotherapy for early breast cancer was a comprehensive overview of trials needed? Lancet 2000; 355(9217): 1739-1740.