Radiotherapy to the conserved breast, chest wall, and regional nodes: is there a standard?

ARTICLE IN PRESS The Breast (2003) 12, 475–482 0960-9776/$ - see front matter r 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0960-9776(03)00155-3

ORIGINAL ARTICLE

Radiotherapy to the conserved breast, chest wall, and regional nodes: is there a standard? Harry Bartelink Department of Radiotherapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands S U M M A R Y . Background: The role of radiotherapy in the treatment of breast cancer has changed considerable during the last two decades. It has now become the standard part of the breast-conserving procedure, as well as in patients who underwent mastectomy with T3+tumor and/or 4 or more positive lymphnodes in axilla. Methods: Improvements are seen in the postmastectomy radiotherapy area by delivering better treatment techniques herewith avoiding treatment of the heart and lungs in order to optimize the improvement of local control and the significant improvement in survival. Indications exist that the largest impact of postmastectomy radiotherapy on survival is mostly seen in patients with minimal tumorload, i.e. small tumors and/or 1or 2 positive lymphnodes. Results: In several clinical trials, it was shown that the relapse rate in the ipsilateral breast is reduced with a HR of 4 if whole breast irradiation is given after tumorectomy. The update of the Oxford meta-analysis demonstrated that this improvement in local control has also led to an improved survival in these patients. More information is recently gained on the required radiation dose in breast-conserving therapy. Especially patients less than 50 years of age have to be treated with a high radiation dose, 50+16 Gy boost, while a dose of 50 Gy in 5 weeks seems sufficient for patients older than 50 years, who have a microscopically complete excision. Further optimization of the radiotherapy technique is found in imaged guided approaches and intensity modulated radiotherapy. Combining these efforts allows for a more precise delivery of the radiation dose to a limited volume, so that the side effects like fibrosis will be reduced. Conclusions: Partial breast irradiation, instead of whole breast irradiation, is now being tested in a few randomized trials. Although this approach may be useful in certain patients groups, it still cannot be accepted as standard treatment, as no proper selection criteria exist and no long-term follow-up data have been presented. r 2003 Elsevier Ltd. All rights reserved. Keywords: Radiotherapy; Chemotherapy; Breast cancer; Postmastectomy

seen in both postmastectomy and breast-conserving therapy.

INTRODUCTION The purpose of this article is to summarize the possibility of radiotherapy in reducing the local recurrence rate and its positive impact on improved survival if proper modern radiotherapy techniques are applied. This impact of reduction in local recurrence on survival is especially seen in patients with a minimal tumor burden at time of diagnosis. A phenomenon

IMPROVEMENT IN LOCO-REGIONAL CONTROL AND SURVIVAL BY POSTOPERATIVE RADIOTHERAPY Over the many years that clinical randomized 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 of 0.6 by adding radiotherapy

Address correspondence to: H. Bartelink, Department of Radiotherapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Tel.: +31 20 512 2120; Fax: +31 20 669 1101; E-mail: [email protected]

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after any form of mastectomy. This occurred both in the old trials using orthovoltage equipment and in the recent clinical trials where modern megavoltage equipment has been used. Generally, a loco-regional recurrence rate of about 30% has been reduced to about 7– 10%. This gain in local control on its own is already a major benefit to patients by preventing symptoms from untreatable local progression. 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 unfavorable 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.1 In a recent update by the Early Breast Cancer Trialist’s Collaborative Group (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.2 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.3 The Danish and Vancouver trials have demonstrated that with modern radiotherapy the improved local control has been translated into a survival advantage of approximately 10% (Fig. 1). 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 of cardiovascular death caused by improper radiation techniques has not been seen up to now4,5 (Fig. 2).

INDICATIONS FOR POSTMASTECTOMY RADIOTHERAPY In an overview study of the literature, Recht6 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 loco-regional 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 N0 tumor with unfavorable histological signs or positive nodes and for patients with four 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. Nowadays, the most difficult question concerns whether patients with T1–2 and N1 still need postmastectomy radiotherapy, considering that in the Danish trials

Fig. 1 Impact of postmastectomy radiotherapy on local recurrence and survival in patient who all received adjuvant systemic treatment.34

ARTICLE IN PRESS Radiotherapy in the treatment of breast cancer

Cumulative incidence

0.08

Mortality No radiotherapy Radiotherapy

0.06

0.04

0.02

0 0

2

4

6

8

10

12

No radiotherapy 1521

1316

1052

866

645

340

154

1525

1322

1099

946

737

410

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Patients at risk Radiotherapy

Fig. 2 Cumulative mortality for ischaemic heart disease by radiotherapy group.4

the major benefit in survival is seen in this patient group (M. Overgaard, pers. Commun.). 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 tumor to the resection margins. Of importance is that for patients receiving neo-adjuvant chemotherapy the indication for postmastectomy should be based on the pretreatment tumor extension as suggested by the results of the MDAH.7 The treatment of the internal mammary lymph nodes is still a matter for debate. The finding of involvement of these lymph nodes of 10–25%8 in, and the impact of inadequate loco-regional 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.

REDUCTION OF SIDE EFFECTS FROM RADIOTHERAPY 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 pneumonitis can occur especially if a (too) large lung volume is irradiated. An increased

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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.9 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 10–15 years is needed. Nowadays, the use of modern radiotherapy equipment allows the radiation oncologist to reduce significantly the dose to the heart and lungs. Herewith major toxicity as radiation pneumonitis and cardiac damage can be prevented. Tangential photon irradiation combined with direct irradiation fields to treat the internal mammary lymph nodes may be replaced by a different technique with electrons or a combination of tangential beam irradiation with angled fields to treat the internal mammary lymph nodes. If a simple tangential field technique is used the amount of cardiac complications can be estimated 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 modern 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.10 Care should also be taken when using concomitant radiotherapy and chemotherapy, especially when anthracyclins, taxanes and/or Herceptin 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% to 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 tumor 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.

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COMBINATION AND TIMING OF CHEMOTHERAPY WITH POSTMASTECTOMY RADIOTHERAPY In many trials it has been shown that the combination of radiotherapy and systemic treatment in breast cancer has led to improved loco-regional local control compared to radiotherapy alone.11,12 As referred to earlier, adjuvant chemotherapy on its own is not able to reduce significantly the loco-regional recurrence rate in highrisk 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. Often the Boston paper is cited where the preliminary results demonstrated that chemotherapy given before radiotherapy improved the metastases-free survival.13,14 In the final publication with longer followup however no differences is seen whether chemotherapy is given before or after radiotherapy. Furthermore, up to now none of the meta-analyses have demonstrated a benefit of chemotherapy before or after standard local treatment. Therefore, 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.15–17 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 the literature and the concomitant combination may prove to be not that harmful if drugs such as anthracyclins, taxanes and Herceptin are excluded.

BREAST-CONSERVING THERAPY Several randomized clinical trials18–21 and a metaanalysis22 have shown similar survival rates after breast-conserving therapy and after mastectomy in patients with early breast cancer. The B-06 trial of the National Surgical Adjuvant Breast and Bowel Project

and other trials demonstrated that after microscopically complete excision, irradiation of the whole breast with a dose of 50 Gy reduced the rate of recurrence in the ipsilateral breast from 35% to 10%.2,20,23–25 However, little was known about the effect of irradiation of the breast at doses higher than 50 Gy. The results of a large EORTC trial in early breast cancer patients provide important data for optimizing breast-conserving therapy. A near 50% reduction of the local recurrence rate was obtained by delivering an extra radiation dose of 16 Gy to the tumor bed in patients with early breast cancer. The relative reduction of the hazard of local recurrence to 0.59 was obtained by delivering an extra radiation dose of 16 Gy, given in 8 fractions to the original tumor bed after a microscopically complete lumpectomy and postoperative whole breast irradiation to 50 Gy. The results of this trial also confirm previous findings that younger patients have an increased risk of local recurrence. It is remarkable to see that the relative and absolute benefits of the boost dose are a function of age; the largest benefit is seen in young patients. This highly significant impact of age on local recurrence for the whole patient population is shown in (Fig. 3). In a separate multi-variate analysis, young age appeared to be the single most important prognostic factor for local recurrence. The improved local control rate by giving a higher radiation dose leads to a major question: which patient subgroups require this boost dose? In our study, a subgroup analysis for prognostic factors used in stratification, demonstrated that the largest clinical benefit was observed in patients younger than 40 years; at 5 years the local recurrence rate was reduced from 19.5% to 10.2%. The relative reduction in local recurrence with the higher radiation dose was reduced slightly for older patients from 54% in patients younger than 40 years, to 38% in patients between 41 and 50 years. In patients between 51 and 60 this percentage was 36%, and 32% for patients over 60 years (Fig. 4). Moreover, the clinical relevance became less with increasing age as they already gained a very high local control rate with whole breast irradiation to a dose of 50 Gy. An arbitrary cut-off age limit for patients requiring the boost may therefore be 50 years, since the gain in local control above this age will be limited. This large randomized trial demonstrated that a higher radiation dose significantly reduced the number of local recurrences after breast-conserving therapy, while only slightly reducing the cosmetic outcome. The clinical benefit of the extra radiation dose was greatest in young patients, clearly indicating that for patients younger than 50 years whole breast irradiation to 50 Gy should be followed by a boost dose of 16 Gy. The large size of this trial warrants the use of these

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Fig. 3 Survival free of local recurrence according to age for the entire cohort.35

Fig. 4 Cumulative incidence of recurrence of tumor in the ipsilateral breast after whole-breast irradiation at 50 Gy, with or without an additional dose to the tumor bed, according to age.35

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results to establish reference guidelines in the management of these patients with regard to the optimal dose level given to the surgical tumor bed.

WHOLE BREAST IRRADIATION Irrefutable evidence exists that postoperative radiotherapy to the whole breast significantly reduces the ipsilateral breast recurrence rate, as shown in numerous phase III trials (Table 1). Although each individual trial did not show improved overall survival, one may predict that long-term follow-up will show that improved local control will also lead to an improved survival rate, as has been shown in a meta-analysis22 and some recent trials aimed at evaluating the benefit of postmastectomy radiotherapy as mentioned earlier.2,23

PARTIAL BREAST IRRADIATION The preliminary results of partial breast irradiation given as intra-operative radiotherapy (IORT)5 or brachytherapy26 where a single or multiple fractions in a short period are given to the tumor bed are at first glance an appealing approach. The main advantage of partial breast irradiation is the avoidance of 5 weeks external irradiation in selected patients with early breast cancer. It is correctly argued that whole breast irradiation is not needed for all patients. Currently, however, selection criteria deciding which patients will or will not require whole breast irradiation are lacking. Before adapting this treatment policy outside clinical trials, one has to question the safety of this approach. The patient population with early breast cancer is characterized by both an excellent local control and life expectancy. For example in a recent trial by the EORTC involving

Table 1

18,30

IBTR (%)

NSABP B-0631 (lumpectomy) Scottish Cancer Trials32 (lumpectomy) Uppsala-Orebro33 (segment excision) Ontario29 (lumpectomy) Milan 324 (quadrantectomy) a

With RTa

Hazard ratio

Years follow-up

Without RTa

12

35

9

4.1

6

24

6

4.2

10

24

8.5

3.1

8

35

11

4.0

9

24

6

4.5

RT is whole breast irradiation.

5569 patients with early breast cancer, a 5-year breast recurrence rate of 4% and a 5 years survival of 92% was achieved with breast-conserving therapy.18 One is, therefore, entitled to wonder whether the partial breast irradiation is based upon clinical evidence, or whether this is a novel tool in search of a clinical application. Before applying this approach into routine clinical practice partial breast radiotherapy without proper patient selection criteria could lead to an unacceptable high local recurrence rate and maybe even to a worse prognosis. Veronesi et al.18 argue for partial breast irradiation on updated data of their own trial, where they randomized between quadrantectomy alone versus quadrantectomy and radiotherapy. In this trial, they showed that even after an extensive local excision (quadrantectomy) adjuvant radiotherapy still dramatically reduces the recurrence rate. One may suppose that the breast volume irradiated by partial breast irradiation will be equal to the volume of breast tissue removed by quadrantectomy. Can we reliably extrapolate the early results of breastconserving therapy for both local control and late side effects caused by radiotherapy? Many studies including the long-term follow-up data of the EORTC trial 10801,25 demonstrated that even after many years ipsilateral recurrences still occur. The data on local control in the Milan trial should, therefore, be considered preliminary. The acute complications after radiotherapy for early breast cancer are usually limited. However, in optimizing radiation treatment by dose escalation, one must always weigh the gain in local control against the increase in late side effects. Late side effects that may occur after IORT, as used by the authors, are fibrosis, telangiectasia, and necrosis. These all cause poor cosmesis. The incidence and severity of side effects increases with longer follow-up post radiotherapy as seen in EORTC trial 10801.26 These side effects are dependent on the total dose, the dose per fraction, and the irradiated volume. In a recent paper where a similar approach is used with iridium 192 implants,27 it was clearly shown that larger irradiated volume had significantly more tissue necrosis. The fraction size is another important parameter related to the incidence of late normal tissue complications after irradiation. Finally, what is the evidence that whole breast irradiation is necessary after local excision. Local irradiation to the tumor bed by electrons or iridium implant has been attempted previously in several small phase II trials. The Guy’s hospital was one of the first to report disappointing breast recurrence rates after local irradiation by performing iridium 192 implants during the tumorectomy.28 Others claim more favorable

ARTICLE IN PRESS Radiotherapy in the treatment of breast cancer results but have a relatively short follow-up period. The aforementioned Manchester trial randomized 708 patients and demonstrated that whole breast irradiation significantly reduced the recurrence rate in the breast to 13% from 25% for local electron irradiation.29 The long-term follow-up data of their recently started phase III trials on partial breast irradiation needs to be awaited. Since the biological effects of the large doses per fraction may result in significantly more late complications such as fibrosis and tissue necrosis. The natural spread of breast tumors may not be controlled with partial breast irradiation and result in an increased breast recurrence rate, as shown in several trials comparing lumpectomy versus lumpectomy and whole breast irradiation. The modest reduction in treatment resources may not be justified in a group with such excellent local control and survival as is obtained with the present standard breast-conserving treatment and adjuvant whole breast irradiation.

CONCLUSIONS Postmastectomy radiotherapy is able to reduce significantly the local recurrence rate and has a positive impact on survival if modern techniques are used. The impact on survival seems larger in patients with a limited tumor load at presentation. In breast conserving a higher local recurrence rate is observed in patients less than 50 years of age. However, this can be overcome by having a microscopically complete excision and by delivering a boost dose of 16 Gy.

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30. Bartelink H. Commentary on the paper ‘‘A preliminary report of intraoperative radiotherapy (IORT) in limited-stage breast cancers that are conservatively treated’’. A critical review of an innovative approach. Eur J Cancer 2001; 37(17): 2143–2146. 31. Fisher B, Anderson S, Redmond C K, Wolmark N, Wickerham D L, Cronin W M. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1995; 333: 1456–1461. 32. Forrest A P, Stewart H J, Everington E et al. Randomised controlled trial of conservation therapy for breast cancer: 6-year analysis of the Scottish trial. Scottish Cancer Trials Breast Group. Lancet 1996; 348: 708–713. 33. Liljegren G, Holmberg L, Bergh J et al. 10-Year results after sector resection with or without postoperative radiotherapy for stage I breast cancer: a randomized trial. J Clin Oncol 1999; 17: 2326–2333. 34. Whelan T J, Julian J, Wright J, Jadad A R, Levine M L. Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 2000; 18(6): 1220–1229. 35. Bartelink H, Horiot J C, Poortmans P, Struikmans H, Van den Bogaert W, Barillot I, Fourquet A, Borger J, Jager J, Hoogenraad W, Collette L, Pierart M. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001; 345(19): 1378–1387.