- Email: [email protected]
Review of internal mammary chain irradiation in breast cancer
The Breast (1999) 8, 245–250 © 1999 Harcourt Publishers Ltd
REVIEW ARTICLE
Review of internal mammary chain irradiation in breast cancer S. K. Vinod and S. C. Pendlebury Department of Radiation Oncology, Royal Prince Alfred Hospital, Sydney, Australia, 2050 S U M M A R Y. The aim was to assess the effectiveness of and indications for irradiation of the internal mammary chain (IMC) in the treatment of breast cancer based on a review of the literature. A computerized literature search was performed of the MEDLINE database from 1966 to March 1998. The data retrieved were ranked into levels of evidence as per convention. There was no Level I evidence found. Six randomized controlled trials and nine retrospective series were found pertaining to early stage breast cancer. Although some retrospective data suggested that IMC irradiation improved survival in mediocentral and axillary node-positive tumours, this was not supported by the randomized data. Two randomized trials were identified in high risk operable breast cancer. One of these showed a survival advantage to post-mastectomy irradiation, but the contribution of IMC irradiation to this could not be delineated. Based on the best current evidence, there is no advantage to elective IMC irradiation. The only indication is for positive IMC nodes where the management aim is palliative. The ongoing EORTC randomized trial may provide the definitive answer. © 1999 Harcourt Publishers Ltd
INTRODUCTION
als contributing most to this are ones which involved IMC irradiation especially with orthovoltage X-rays. His updated metaanalysis which included cause-specific mortality showed this excess to be primarily cardiac deaths, more obvious in left-sided tumours, adding support that there were adverse effects of radiation to the heart.6 However, for the more recent trials the excess mortality was no longer statistically significant and was offset by a reduction in breast cancer deaths. High doses to the myocardium in the treatment of Hodgkin’s disease has been shown to lead to late cardiac complications.7 Similarly in breast cancer, Rutqvist et al. have confirmed increased cardiac doses result in increased risk of ischaemic heart disease.8 Anthracycline based chemotherapy is increasing in popularity. This has been associated with significantly improved relapse-free and overall survival in premenopausal women with node-positive cancers.9 Data presented by the Early Breast Cancer Trialists Collaborative Group in 1998 support this.10 The role of anthracyclines will continue, thereby exacerbating potential cardiac morbidity from IMC irradiation. Pulmonary toxicity is also enhanced with IMC irradiation. When the breast, SCF and IMC are treated, the risk of radiation pneumonitis is 11.3% compared to 3.1% with omission of the IMC field.11 In light of both cardiac and pulmonary toxicity the routine use of IMC radiation had been discouraged.12 This review assesses the effectiveness of IMC irradiation based on best available evidence. This issue is addressed
The treatment of internal mammary chain nodes (IMC) in patients with breast cancer is controversial. Surgical series have shown that 19.1% of operable breast cancer patients harbour metastases at this site.1 The possible benefits of treatment are a reduced local recurrence rate and improved survival. Surgical trials randomized to dissection of the IMC or not have shown no survival advantage to IMC dissection at mature follow-up.2 In those who had modified radical mastectomy alone, the risk of isolated IMC relapse is low (2%) and elective treatment is unlikely to be clinically significant in reducing relapses.3 In radiotherapy series the value of IMC irradiation has been difficult to separate from that of the supraclavicular fossa (SCF), axilla, chest wall or breast. Elective nodal irradiation decreases local recurrence and although one trial has demonstrated improved survival, this has not been confirmed in a metaanalysis.4 The reservation about IMC irradiation has been toxicity. The first Cuzick metaanalysis, of trials started before 1975, showed a reduced survival, starting 15 years following treatment, for patients given chest wall radiation.5 The triAddress correspondence to: Shalini K. Vinod MBBS, Simpson Centre, Liverpool Health Service, Locked Bag 7103, Liverpool BA 1871, NSW Australia. Tel.: 612 9828 6542; Fax: 612 9828 6111; E-mail: [email protected]
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both in early stage and locally advanced breast cancer. The levels of evidence are summarized and indications for treatment proposed. METHODS A computerized literature search was performed of the MEDLINE database from 1966 to March, 1998. The search strategy used the keywords ‘internal mammary’, ‘breast cancer’, ‘breast neoplasm’, ‘radiotherapy’ and ‘radiation therapy’. The search was confined to papers or abstracts written in English. In addition references from identified papers were searched for relevant articles. It has been previously noted that such a search strategy is likely to retrieve only 60% of appropriate articles.13 Where data were updated or duplicated, the most recent publication was included. The inclusion criteria were studies that assessed the effect of internal mammary chain irradiation and reported outcome data in operable breast cancer. In most studies the effect of IMC irradiation alone could not be separated from supraclavicular fossa irradiation as the two sites were treated together. Irradiation of the axilla, chest wall or breast also had to be taken into account. Systemic therapy was not accounted for. Effectiveness was defined as a significant improvement in local control or survival. The articles were ranked into levels of evidence as per convention: Level 1 Evidence obtained from a systematic review of all relevant randomized controlled trials Level II Evidence obtained from at least one randomized controlled trial Level III Evidence from controlled trials without randomization, from cohort or case control studies, or from multiple time series with and without the intervention Level IV Opinions of respected authorities and expert committees. RESULTS This search strategy identified six randomized controlled trials and nine retrospective series in early stage breast cancer. Two randomized trials were found pertaining to high risk operable breast cancer. There was no Level I evidence found in answer to the effectiveness of IMC irradiation.
Early breast cancer: Level II evidence The earliest paper was published in 1980 by the Cancer Research Campaign Working Party.14 Two thousand eight
hundred patients with clinical stage I or II breast cancer were randomized between a simple mastectomy and a simple mastectomy and radiation to the chest wall, IMC, SCF and axilla. However, 557 patients were excluded owing to protocol violations and deviations and this creates potential bias. There was a significant advantage to the radiotherapy group with local recurrence-free survival but not overall survival. A subgroup analysis of medial tumours showed no survival benefit with radiotherapy. The NSABP-04 trial randomized 1665 women with operable breast cancer.15 Patients who had clinically positive axillary nodes were randomized between a radical mastectomy or simple mastectomy and regional nodal irradiation (IMC, SCF, and axilla). The node-negative patients underwent radical mastectomy, simple mastectomy, or simple mastectomy and regional nodal irradiation. At ten years there was no difference between any of the groups with respect to disease-free survival or overall survival. Regional nodal irradiation did not confer a benefit over mastectomy alone in either node-negative or node-positive tumours. A subgroup analysis was performed of medial and central tumours.16 Surgical series have demonstrated that these sites have a higher incidence of IMC metastases, so a possible benefit may exist with IMC treatment.17 NSABP-04 showed that tumour location did not affect survival. A comparison was made, of patients with similar tumour location and axillary nodal status, between those who underwent a radical mastectomy and those who had a total mastectomy and nodal irradiation. There was no reduction in distant failure or mortality with radiotherapy. Similar findings were observed in the comparison between the total mastectomy group vs total mastectomy and nodal irradiation. Despite two putative sources of dissemination (IMC and axilla) treatment of these areas had no advantage. This trial was instrumental in revealing that nodal status was a marker for distant metastases rather than a cause of them. The Oslo study of 1115 patients was carried out in two phases.18 In the first, women were randomized post-radical mastectomy to observation or radiotherapy with 200 kv X-rays (DXRT) to the axilla, IMC, SCF and chest wall. In the second phase, radiation was delivered with Co60 and chest wall radiotherapy was omitted. The adjuvant radiotherapy was found to decrease locoregional recurrences but did not impact on survival. In patients with stage II medial and central tumours there was a trend toward improved survival with Co60 as opposed to DXRT. However, these results have to be viewed with caution as this was a subgroup analysis containing a small number of patients. This trial also revealed a significant excess of non-breast cancer deaths in the Co60 group, and this may negate any potential survival benefit with radiotherapy. The Stockholm trial compared preoperative radiotherapy (IMC/SCF/axilla/breast), postoperative radiotherapy (IMC/
Review of internal mammary chain irradiation in breast cancer 247 SCF/axilla/chest wall) and modified radical mastectomy alone.19 The addition of radiotherapy significantly reduced local recurrence but at ten years no difference in survival was seen. In the initial report a significant survival benefit was seen for the preoperative patients when compared to the surgery alone arm.20 This was thought to be due to a higher dose delivered to the IMC in the preoperative and not the postoperative setting. However, longer follow-up has shown no difference in survival between the three groups. In the axillary node-positive patients receiving irradiation, there was a significant reduction in the incidence of distant metastases, suggesting that with greater patient numbers and longer follow-up an association between local control and survival may become apparent. The only trial to look at the possible benefit of adjuvant IMC irradiation alone (without treatment to the SCF or axilla) was carried out in Finland.21 Two hundred and seventy women underwent breast conservation surgery and axillary dissection for Stage I and II breast cancer. All received adjuvant breast irradiation but were randomized between IMC observation or IMC irradiation. At a median follow-up of 2 years there was no significant difference in relapse between the two groups. However, the primary endpoint was toxicity and follow-up is short. The most recent trial is the Canadian trial which randomized premenopausal women who had positive axillary nodes to postmastectomy irradiation (IMC, SCF, axilla, chest wall) or observation.22 Local recurrences were reduced by 56% and breast cancer specific survival was increased by 29% (P=0.05). There was a non-significant 8% increase in overall survival in the radiotherapy arm.
Summary In these 6 randomized studies of early stage breast cancer the addition of radiotherapy has consistently reduced the rate of local recurrence. However, the actual benefit of IMC treatment is unknown as sites of relapse were not reported. From surgical series isolated IMC relapses occur in less than 5% of cases. There were no trials which found a significant advantage in overall survival, even when the subgroup of medial and central cancers were looked at. Only one trial has reported a cancer specific survival and shown a significant improvement.22 The limitations of these trials in showing a possible survival benefit are that radiotherapy related deaths could have negated any survival benefit owing to breast cancer. The most likely cause of treatment mortality is IMC irradiation of left-sided tumours resulting in high cardiac doses. It is well recognized that the position of the IMC may vary between individuals. A lack of radiology based planning leads to the possibility of geographical misses, which could also explain the apparent lack of a survival benefit.
The subgroup analyses were performed retrospectively. Prospective stratification by site would have been a more accurate way of determining a beneficial effect of IMC irradiation. The Canadian study showed an improvement in breast cancer specific survival. However it is difficult to elucidate which components of radiotherapy are responsible for the benefit seen. Previous studies (NSA BP-A04) have shown treatment of the axilla as not impacting on survival. Local breast cancer: Level III and IV evidence Arriagada has performed a retrospective analysis of patients with operable (≤ 7cm) and node-positive breast cancer who were treated at the Institut Gustave–Roussy.23 All patients had a modified radical mastectomy and radiation to the chest wall, SCF and axilla. The 1195 patients were divided into four groups based on the extent of IMC treatment – no IMC treatment (n=135), IMC dissection only (n=102), IMC radiotherapy only (n=523), and IMC dissection and radiotherapy (n=435). In the three groups who had IMC treatment the risks of death and metastasis were the same. When these groups were combined and compared to the no IMC treatment group there was a trend toward improved survival in the treated arms (P=0.06). In subgroup analysis this reached statistical significance for medial tumours (10-year survival 58% vs 48%, P=0.05) only. He concluded that treatment of the IMC was beneficial in improving survival in axillary node-positive medial tumours. However, this was based on a subgroup analysis of a retrospective study. Furthermore, different treatment policies were adopted over sequential time periods and the possibility exists for staging biases. At the J. Bordet Institute there has been a similar change in policy of IMC treatment with time.24 Prior to 1974 the IMC was treated with a single anterior field to a dose of 27.5 Gy. From 1974 onwards the IMC was boosted to 40 Gy for medial cancers. Seven hundred and eighty-seven patients were reviewed, all of whom had surgery and postoperative radiation to the chest wall and nodal regions. Survival was correlated significantly with the higher dose to the IMC. However, there is no mention of the distribution of prognostic factors between the two groups and the association may be spurious. Montague and Fletcher have looked at the MDA experience.25 Of 1111 patients, 301 had a radical mastectomy alone, 368 had a radical mastectomy followed by radiation of the SCF and IMC, and 442 had preoperative radiation to the SCF, IMC, and axilla followed by a radical mastectomy. Axillary nodal positivity was 12%, 64% and 29% respectively. Despite this difference there was no difference seen in 10-year survival rates. This was interpreted as being a result of IMC and SCF radiation. Again this study is limited owing to retrospective data collection and the omission
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of other prognostic factors between the groups which may have impacted on survival rates. There have been three studies which have looked at IMC radiation in node-negative patients with operable breast cancer. Chahbazian published a series of 225 patients of whom 136 had radical mastectomy alone and 89 had additional radiotherapy to the IMC and SCF.26 When analyzed by tumour site, the radiotherapy group showed a significant survival advantage in medial tumours, but not lateral ones. Similarly, Roseman reviewed 134 patients of whom 118 had surgery alone and 17 postoperative radiation to the IMC and SCF.27 In medial tumours radiotherapy decreased local recurrences and improved disease-free survival. Overall survival was not mentioned. A case control study by Cappellini of 128 patients showed no significant difference in recurrence or survival.28 These conclusions were based on small numbers of patients in comparison to the large randomized trials. A study by Rubin has identified actual IMC recurrences.29 Over a ten-year period 16 out of 230 patients had an IMC recurrence. It is unclear whether these were isolated recurrences or not. Of these patients only 32% had received prior radiotherapy suggesting that IMC radiation does decrease local recurrence. Contemporary series have not suggested a benefit to irradiation of the IMC. A retrospective review of 183 mediocentral tumours by Shiba showed no difference in overall survival at 10 years.30 Similarly Schmolling found that IMC radiotherapy did not impact on survival rates of the 411 patients analyzed at the University of Bonn.31
Summary The early retrospective series suggest an improvement in survival with IMC radiation especially in medial tumours with positive axillary nodes. However, there are many uncontrolled factors which may bias the results. The patient numbers are also much smaller than in the randomized trials. The more contemporary series do not support the value of IMC treatment.
Locally advanced breast cancer Many of the early breast cancer series have included patients with locally advanced disease provided they were operable. There have been two randomized trials which have specifically looked at this group. At the Karolinska Institute 427 postmenopausal women with high risk breast cancer (T>30 mm or node-positive) were randomized postmastectomy to radiotherapy alone, radiotherapy and tamoxifen, chemotherapy alone, and chemotherapy and tamoxifen.32 The radiotherapy volume
included the chest wall, axilla, SCF and IMC. The addition of radiotherapy significantly reduced local failure and improved relapse-free survival. There was a trend toward reduced distant metastases (P=0.06) but no difference in survival. Overgaard has recently updated the Danish data on 1708 premenopausal women with T3, T4 or node-positive breast cancer.4 All patients had a mastectomy and were than randomized to chemotherapy alone or in combination with radiotherapy to the chest wall, axilla, SCF and IMC. This is the only randomized study to have shown a significant survival advantage. At 10 years 45% of the chemotherapy alone group and 54% of the radiotherapy group were alive (P<0.001). Summary In these two trials post-mastectomy radiation was delivered to the chest wall and all nodal regions. It is difficult to assess the contribution of IMC radiation alone to these results.
DISCUSSION In early stage breast cancer, the randomized data available show no significant survival benefit with the addition of IMC radiotherapy. The group expected to benefit is the medial tumours which have been demonstrated to have an increased incidence of IMC metastases in surgical series.17 Yet subgroup analyses in three of these studies failed to demonstrate a significant benefit.14,16,18 The radiotherapy planning techniques used may also impact on results. IMC lymph nodes vary in position. Individual localization using ultrasound or CT is needed to ensure adequate coverage. The apparent lack of benefit could be due to geographical misses, especially in the older trials. The Canadian trial is the only one which shows an improvement in cause-specific survival but there is still no overall survival benefit.22 One explanation is that the mortality from toxicity of radiotherapy cancels out the reduction in deaths from breast cancer. Certainly the 1994 Cuzick metaanalysis supports this.6 The mortality is mainly owing to cardiac disease which is a consequence of the dose received from IMC radiation. This was most evident in the Stockholm and Oslo trials. Surgical series of IMC treatment support the lack of survival benefit for treating IMC nodes. The International Cooperative Trial compared radical mastectomy and extended radical mastectomy in 1453 patients.2 At 10-year follow-up there was no difference in either relapse-free or overall survival. There is only one trial which has looked at the addition of IMC radiotherapy without the SCF or axilla.21 Although this was primarily a toxicity study, to date there has been no difference in relapse rates.
Review of internal mammary chain irradiation in breast cancer 249 In locally advanced breast cancer, randomized data show both a significant decrease in local recurrence and improvement in overall survival with the addition of postmastectomy radiotherapy. The radiotherapy volume included the chest wall, SCF, axilla and IMC. The value of IMC radiation per se remains uncertain and cannot be answered from these trials. Another reason to deliver IMC radiation would be to decrease local recurrences. However, isolated IMC recurrences are rare and so the benefit of prophylactic treatment is likely to be small and clinically insignificant.3 The small possible gains with IMC irradiation must be balanced against the increase in toxicity, specifically cardiac and pulmonary, which have been well documented in the literature.8,11 There are potential deficiencies in a review such as this. In identification of the trials there may be publication bias, English language bias and MEDLINE bias. The trials are heterogeneous, cover a long time span and have utilized different radiotherapy techniques and so may not be truly comparable. The systemic therapy used has changed and so the relevance of older trials to current practice may be questioned. The emerging technology of sentinel node sampling is providing a new challenge to the decision regarding treatment of IMC nodes. Medial tumours which drain to the IMC raise the question of a possible advantage to treating this nodal group. There remains, however, an absence of proven benefit against a substantial risk of toxicity. The EORTC is currently conducting a Phase III trial investigating the role of internal mammary and medial supraclavicular lymph node irradiation in Stage I to III breast cancer.33 Patients with positive axillary nodes or mediocentral tumours are eligible for randomization. This trial includes the first three intercostal spaces for the IMC but can be extended to the fifth intercostal space for lowermedial quadrant tumours. Radiological localization is mandatory for planning purposes. The prescribed dose is 50Gy in 25 daily fractions with the planning target volume extending to a depth of 4 cm. A mixture of photons and electrons is used. This trial may provide the definitive answer to the question of IMC irradiation.
2.
3. 4.
5. 6. 7. 8.
9.
10. 11.
12. 13. 14. 15.
16.
17. 18.
CONCLUSIONS Based on best current evidence (Level II) there is no advantage to elective irradiation of the IMC. The only indication is therapeutic for clinically or radiologically positive lymph nodes where the management aim is palliative. References 1. Veronesi U, Cascinelli N, Greco M et al. Prognosis of breast cancer
19.
20.
21.
patients after mastectomy and dissection of internal mammary nodes. Ann Surg 1985; 202: 702–707. Lacour J, Le M, Caceres E, Koszarowski T, Veronesi U, Hill C. Radical mastectomy versus radical mastectomy plus internal mammary dissection. Ten year results of an international cooperative trial in breast cancer. Cancer 1983; 51: 1941–1943. Veronesi U, Valagussa P. Inefficacy of internal mammary node dissection in breast cancer surgery. Cancer 1981; 47: 170–175. Overgaard M, Hansen P S, Overgaard J et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997; 337: 949–955. Cuzick J, Stewart H, Peto R et al. Overview of randomised trials of postoperative adjuvant radiotherapy in breast cancer. Cancer Treat Rep 1987; 71: 15–29. Cuzick J, Stewart H, Rutqvist L et al. Cause- specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 1994; 12: 447–453. Pihkala J, Saarinen U M, Lundstrom U et al. Myocardial function in children and adolescents after therapy with anthracyclines and chest irradiation. Eur J Cancer 1996; 32: 97–103. Rutqvist L E, Lax I, Fornander T, Johansson H. Cardiovascular mortality in a randomised trial of adjuvant radiation therapy versus surgery alone in primary breast cancer. Int J Radiat Oncol Biol Phys 1992; 22: 887–896. Levine M N, Bramwell V H, Pritchard K I et al. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. J Clin Oncol 1998; 16: 2651–2658. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer. Lancet 1998; 352: 930–942. Halverson K J, Taylor M E, Perez C A et al. Regional nodal management and patterns of failure following conservative surgery and radiation therapy for Stage I and II Breast Cancer. Int J Radiat Oncol Biol Phys 1993; 26: 593–599. Harris J R, Hellman S. Put the ‘hockey stick’ on ice. Int J Radiat Oncol Biol Phys 1988; 15: 497–499. Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic reviews. BMJ 1994; 309: 1286–1289. Cancer Research Campaign Working Party. Cancer Research Campaign (King’s/Cambridge) Trial for early breast cancer. A detailed update at the tenth year. Lancet 1980 July: 55–60. Fisher B, Redmond C, Fisher E R et al. Ten year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N Engl J Med 1985; 312: 674–681. Fisher B, Wolmark N, Redmond C et al. Findings from NSABP Protocol B-04. Comparison of radical mastectomy with alternative treatments. II. The clinical and biological significance of medialcentral breast cancers. Cancer 1981; 48: 1863–1872. Haagensen C D, Bhonslay S B, Guttman R J et al. Metastases of carcinoma of the breast to the periphery of the regional lymph node filter. Ann Surg 1969; Feb: 174–190. Host H, Brennhord I O, Loeb M. Postoperative radiotherapy in breast cancer – long term results from the Oslo Study. Int J Radiation Oncology Biol Phys 1986; 12: 727–732. Wallgren A, Arner O, Bergstrom J et al. Radiation therapy in operable breast cancer. Results from the Stockholm Trial on adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 1986; 12: 533–537. Strender L E, Wallgren A, Arndt J et al. Adjuvant radiotherapy in operable breast cancer. Correlation between dose in internal mammary nodes and prognosis. Int J Radiat Oncol Biol Phys. 1981; 7: 1319–1325. Kaija H, Maunu P. Tangential breast irradiation with or without internal mammary chain irradiation: results of a randomized trial. Radiother Oncol 1995; 36: 172–176.
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22. Ragaz J, Jackson S M, Le N et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 1997; 337: 956–962. 23. Arriagada R, Le M G, Mouriesse H et al. Long-term effect of internal mammary chain treatment. Results of a multivariate analysis of 1195 patients with operable breast cancer and positive axillary nodes. Radiother Oncol 1988; 11: 213–222. 24. Regnier R, Nguyen T H, Balikdjian D, Lustman-Marechal J, Darquennes H & Henry J. Experience of telecobalt Therapy in operable breast cancer at J. Bordet Institute. Int J Radiat Oncol Biol Phys 1982; 8: 1517–1523. 25. Montague E D, Fletcher G H. The curative value of irradiation in the treatment of nondisseminated breast cancer. Cancer 1980; 46: 995–998. 26. Chahbazian C, del Regato J A, Wilson J F. Postoperative radiation therapy for ‘Early’ Carcinoma of the Breast. Cancer 1978; 42: 1126–1128. 27. Roseman J M, James A G. The significance of the internal mammary nodes in medially located breast Cancer. Cancer 1982; 50: 1426–1429. 28. Cappellini M, Ciatto S, Mungai R. Post-operative radiotherapy in node negative breast cancer. A retrospective case-control study. Tumori 1981; 67: 443–445.
29. Rubin P, Bunyagidj S, Poulter C. Internal mammary lymph node metastases in breast cancer: detection and management. Am J Roentgenol Radium Ther Nucl Med 1971; 111: 588–598. 30. Shiba, E, Miyauchi K, Kobayashi T, Takai S, Mori T. Radical mastectomy with parasternal node dissection or radiation to the parasternal region for breast cancer of medial or central location. Surg Today 1992; 22: 124–127. 31. Schmolling J, Maus B, Rezek D et al. Breast preservation versus mastectomy – recurrence and survival rates of primary breast cancer patients at the UFK Bonn. Eur J Gynaecol Oncol 1997; 18: 29–33. 32. Rutqvist L, Cedermark B, Glas U et al. Randomised trial of adjuvant tamoxifen combined with postoperative radiation therapy or adjuvant chemotherapy in postmenopausal breast cancer. Cancer 1990; 66: 89–96. 33. Bartelink H, Borger J, Fourquet A et al. Phase III randomized trial investigating the role of internal mammary and medial supraclavicular lymph node irradiation in stage I-III breast cancer. Protocol 22922. EORTC Cooperative Group for Radiotherapy. May 1996.
REVIEW ARTICLE
Review of internal mammary chain irradiation in breast cancer S. K. Vinod and S. C. Pendlebury Department of Radiation Oncology, Royal Prince Alfred Hospital, Sydney, Australia, 2050 S U M M A R Y. The aim was to assess the effectiveness of and indications for irradiation of the internal mammary chain (IMC) in the treatment of breast cancer based on a review of the literature. A computerized literature search was performed of the MEDLINE database from 1966 to March 1998. The data retrieved were ranked into levels of evidence as per convention. There was no Level I evidence found. Six randomized controlled trials and nine retrospective series were found pertaining to early stage breast cancer. Although some retrospective data suggested that IMC irradiation improved survival in mediocentral and axillary node-positive tumours, this was not supported by the randomized data. Two randomized trials were identified in high risk operable breast cancer. One of these showed a survival advantage to post-mastectomy irradiation, but the contribution of IMC irradiation to this could not be delineated. Based on the best current evidence, there is no advantage to elective IMC irradiation. The only indication is for positive IMC nodes where the management aim is palliative. The ongoing EORTC randomized trial may provide the definitive answer. © 1999 Harcourt Publishers Ltd
INTRODUCTION
als contributing most to this are ones which involved IMC irradiation especially with orthovoltage X-rays. His updated metaanalysis which included cause-specific mortality showed this excess to be primarily cardiac deaths, more obvious in left-sided tumours, adding support that there were adverse effects of radiation to the heart.6 However, for the more recent trials the excess mortality was no longer statistically significant and was offset by a reduction in breast cancer deaths. High doses to the myocardium in the treatment of Hodgkin’s disease has been shown to lead to late cardiac complications.7 Similarly in breast cancer, Rutqvist et al. have confirmed increased cardiac doses result in increased risk of ischaemic heart disease.8 Anthracycline based chemotherapy is increasing in popularity. This has been associated with significantly improved relapse-free and overall survival in premenopausal women with node-positive cancers.9 Data presented by the Early Breast Cancer Trialists Collaborative Group in 1998 support this.10 The role of anthracyclines will continue, thereby exacerbating potential cardiac morbidity from IMC irradiation. Pulmonary toxicity is also enhanced with IMC irradiation. When the breast, SCF and IMC are treated, the risk of radiation pneumonitis is 11.3% compared to 3.1% with omission of the IMC field.11 In light of both cardiac and pulmonary toxicity the routine use of IMC radiation had been discouraged.12 This review assesses the effectiveness of IMC irradiation based on best available evidence. This issue is addressed
The treatment of internal mammary chain nodes (IMC) in patients with breast cancer is controversial. Surgical series have shown that 19.1% of operable breast cancer patients harbour metastases at this site.1 The possible benefits of treatment are a reduced local recurrence rate and improved survival. Surgical trials randomized to dissection of the IMC or not have shown no survival advantage to IMC dissection at mature follow-up.2 In those who had modified radical mastectomy alone, the risk of isolated IMC relapse is low (2%) and elective treatment is unlikely to be clinically significant in reducing relapses.3 In radiotherapy series the value of IMC irradiation has been difficult to separate from that of the supraclavicular fossa (SCF), axilla, chest wall or breast. Elective nodal irradiation decreases local recurrence and although one trial has demonstrated improved survival, this has not been confirmed in a metaanalysis.4 The reservation about IMC irradiation has been toxicity. The first Cuzick metaanalysis, of trials started before 1975, showed a reduced survival, starting 15 years following treatment, for patients given chest wall radiation.5 The triAddress correspondence to: Shalini K. Vinod MBBS, Simpson Centre, Liverpool Health Service, Locked Bag 7103, Liverpool BA 1871, NSW Australia. Tel.: 612 9828 6542; Fax: 612 9828 6111; E-mail: [email protected]
245
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both in early stage and locally advanced breast cancer. The levels of evidence are summarized and indications for treatment proposed. METHODS A computerized literature search was performed of the MEDLINE database from 1966 to March, 1998. The search strategy used the keywords ‘internal mammary’, ‘breast cancer’, ‘breast neoplasm’, ‘radiotherapy’ and ‘radiation therapy’. The search was confined to papers or abstracts written in English. In addition references from identified papers were searched for relevant articles. It has been previously noted that such a search strategy is likely to retrieve only 60% of appropriate articles.13 Where data were updated or duplicated, the most recent publication was included. The inclusion criteria were studies that assessed the effect of internal mammary chain irradiation and reported outcome data in operable breast cancer. In most studies the effect of IMC irradiation alone could not be separated from supraclavicular fossa irradiation as the two sites were treated together. Irradiation of the axilla, chest wall or breast also had to be taken into account. Systemic therapy was not accounted for. Effectiveness was defined as a significant improvement in local control or survival. The articles were ranked into levels of evidence as per convention: Level 1 Evidence obtained from a systematic review of all relevant randomized controlled trials Level II Evidence obtained from at least one randomized controlled trial Level III Evidence from controlled trials without randomization, from cohort or case control studies, or from multiple time series with and without the intervention Level IV Opinions of respected authorities and expert committees. RESULTS This search strategy identified six randomized controlled trials and nine retrospective series in early stage breast cancer. Two randomized trials were found pertaining to high risk operable breast cancer. There was no Level I evidence found in answer to the effectiveness of IMC irradiation.
Early breast cancer: Level II evidence The earliest paper was published in 1980 by the Cancer Research Campaign Working Party.14 Two thousand eight
hundred patients with clinical stage I or II breast cancer were randomized between a simple mastectomy and a simple mastectomy and radiation to the chest wall, IMC, SCF and axilla. However, 557 patients were excluded owing to protocol violations and deviations and this creates potential bias. There was a significant advantage to the radiotherapy group with local recurrence-free survival but not overall survival. A subgroup analysis of medial tumours showed no survival benefit with radiotherapy. The NSABP-04 trial randomized 1665 women with operable breast cancer.15 Patients who had clinically positive axillary nodes were randomized between a radical mastectomy or simple mastectomy and regional nodal irradiation (IMC, SCF, and axilla). The node-negative patients underwent radical mastectomy, simple mastectomy, or simple mastectomy and regional nodal irradiation. At ten years there was no difference between any of the groups with respect to disease-free survival or overall survival. Regional nodal irradiation did not confer a benefit over mastectomy alone in either node-negative or node-positive tumours. A subgroup analysis was performed of medial and central tumours.16 Surgical series have demonstrated that these sites have a higher incidence of IMC metastases, so a possible benefit may exist with IMC treatment.17 NSABP-04 showed that tumour location did not affect survival. A comparison was made, of patients with similar tumour location and axillary nodal status, between those who underwent a radical mastectomy and those who had a total mastectomy and nodal irradiation. There was no reduction in distant failure or mortality with radiotherapy. Similar findings were observed in the comparison between the total mastectomy group vs total mastectomy and nodal irradiation. Despite two putative sources of dissemination (IMC and axilla) treatment of these areas had no advantage. This trial was instrumental in revealing that nodal status was a marker for distant metastases rather than a cause of them. The Oslo study of 1115 patients was carried out in two phases.18 In the first, women were randomized post-radical mastectomy to observation or radiotherapy with 200 kv X-rays (DXRT) to the axilla, IMC, SCF and chest wall. In the second phase, radiation was delivered with Co60 and chest wall radiotherapy was omitted. The adjuvant radiotherapy was found to decrease locoregional recurrences but did not impact on survival. In patients with stage II medial and central tumours there was a trend toward improved survival with Co60 as opposed to DXRT. However, these results have to be viewed with caution as this was a subgroup analysis containing a small number of patients. This trial also revealed a significant excess of non-breast cancer deaths in the Co60 group, and this may negate any potential survival benefit with radiotherapy. The Stockholm trial compared preoperative radiotherapy (IMC/SCF/axilla/breast), postoperative radiotherapy (IMC/
Review of internal mammary chain irradiation in breast cancer 247 SCF/axilla/chest wall) and modified radical mastectomy alone.19 The addition of radiotherapy significantly reduced local recurrence but at ten years no difference in survival was seen. In the initial report a significant survival benefit was seen for the preoperative patients when compared to the surgery alone arm.20 This was thought to be due to a higher dose delivered to the IMC in the preoperative and not the postoperative setting. However, longer follow-up has shown no difference in survival between the three groups. In the axillary node-positive patients receiving irradiation, there was a significant reduction in the incidence of distant metastases, suggesting that with greater patient numbers and longer follow-up an association between local control and survival may become apparent. The only trial to look at the possible benefit of adjuvant IMC irradiation alone (without treatment to the SCF or axilla) was carried out in Finland.21 Two hundred and seventy women underwent breast conservation surgery and axillary dissection for Stage I and II breast cancer. All received adjuvant breast irradiation but were randomized between IMC observation or IMC irradiation. At a median follow-up of 2 years there was no significant difference in relapse between the two groups. However, the primary endpoint was toxicity and follow-up is short. The most recent trial is the Canadian trial which randomized premenopausal women who had positive axillary nodes to postmastectomy irradiation (IMC, SCF, axilla, chest wall) or observation.22 Local recurrences were reduced by 56% and breast cancer specific survival was increased by 29% (P=0.05). There was a non-significant 8% increase in overall survival in the radiotherapy arm.
Summary In these 6 randomized studies of early stage breast cancer the addition of radiotherapy has consistently reduced the rate of local recurrence. However, the actual benefit of IMC treatment is unknown as sites of relapse were not reported. From surgical series isolated IMC relapses occur in less than 5% of cases. There were no trials which found a significant advantage in overall survival, even when the subgroup of medial and central cancers were looked at. Only one trial has reported a cancer specific survival and shown a significant improvement.22 The limitations of these trials in showing a possible survival benefit are that radiotherapy related deaths could have negated any survival benefit owing to breast cancer. The most likely cause of treatment mortality is IMC irradiation of left-sided tumours resulting in high cardiac doses. It is well recognized that the position of the IMC may vary between individuals. A lack of radiology based planning leads to the possibility of geographical misses, which could also explain the apparent lack of a survival benefit.
The subgroup analyses were performed retrospectively. Prospective stratification by site would have been a more accurate way of determining a beneficial effect of IMC irradiation. The Canadian study showed an improvement in breast cancer specific survival. However it is difficult to elucidate which components of radiotherapy are responsible for the benefit seen. Previous studies (NSA BP-A04) have shown treatment of the axilla as not impacting on survival. Local breast cancer: Level III and IV evidence Arriagada has performed a retrospective analysis of patients with operable (≤ 7cm) and node-positive breast cancer who were treated at the Institut Gustave–Roussy.23 All patients had a modified radical mastectomy and radiation to the chest wall, SCF and axilla. The 1195 patients were divided into four groups based on the extent of IMC treatment – no IMC treatment (n=135), IMC dissection only (n=102), IMC radiotherapy only (n=523), and IMC dissection and radiotherapy (n=435). In the three groups who had IMC treatment the risks of death and metastasis were the same. When these groups were combined and compared to the no IMC treatment group there was a trend toward improved survival in the treated arms (P=0.06). In subgroup analysis this reached statistical significance for medial tumours (10-year survival 58% vs 48%, P=0.05) only. He concluded that treatment of the IMC was beneficial in improving survival in axillary node-positive medial tumours. However, this was based on a subgroup analysis of a retrospective study. Furthermore, different treatment policies were adopted over sequential time periods and the possibility exists for staging biases. At the J. Bordet Institute there has been a similar change in policy of IMC treatment with time.24 Prior to 1974 the IMC was treated with a single anterior field to a dose of 27.5 Gy. From 1974 onwards the IMC was boosted to 40 Gy for medial cancers. Seven hundred and eighty-seven patients were reviewed, all of whom had surgery and postoperative radiation to the chest wall and nodal regions. Survival was correlated significantly with the higher dose to the IMC. However, there is no mention of the distribution of prognostic factors between the two groups and the association may be spurious. Montague and Fletcher have looked at the MDA experience.25 Of 1111 patients, 301 had a radical mastectomy alone, 368 had a radical mastectomy followed by radiation of the SCF and IMC, and 442 had preoperative radiation to the SCF, IMC, and axilla followed by a radical mastectomy. Axillary nodal positivity was 12%, 64% and 29% respectively. Despite this difference there was no difference seen in 10-year survival rates. This was interpreted as being a result of IMC and SCF radiation. Again this study is limited owing to retrospective data collection and the omission
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of other prognostic factors between the groups which may have impacted on survival rates. There have been three studies which have looked at IMC radiation in node-negative patients with operable breast cancer. Chahbazian published a series of 225 patients of whom 136 had radical mastectomy alone and 89 had additional radiotherapy to the IMC and SCF.26 When analyzed by tumour site, the radiotherapy group showed a significant survival advantage in medial tumours, but not lateral ones. Similarly, Roseman reviewed 134 patients of whom 118 had surgery alone and 17 postoperative radiation to the IMC and SCF.27 In medial tumours radiotherapy decreased local recurrences and improved disease-free survival. Overall survival was not mentioned. A case control study by Cappellini of 128 patients showed no significant difference in recurrence or survival.28 These conclusions were based on small numbers of patients in comparison to the large randomized trials. A study by Rubin has identified actual IMC recurrences.29 Over a ten-year period 16 out of 230 patients had an IMC recurrence. It is unclear whether these were isolated recurrences or not. Of these patients only 32% had received prior radiotherapy suggesting that IMC radiation does decrease local recurrence. Contemporary series have not suggested a benefit to irradiation of the IMC. A retrospective review of 183 mediocentral tumours by Shiba showed no difference in overall survival at 10 years.30 Similarly Schmolling found that IMC radiotherapy did not impact on survival rates of the 411 patients analyzed at the University of Bonn.31
Summary The early retrospective series suggest an improvement in survival with IMC radiation especially in medial tumours with positive axillary nodes. However, there are many uncontrolled factors which may bias the results. The patient numbers are also much smaller than in the randomized trials. The more contemporary series do not support the value of IMC treatment.
Locally advanced breast cancer Many of the early breast cancer series have included patients with locally advanced disease provided they were operable. There have been two randomized trials which have specifically looked at this group. At the Karolinska Institute 427 postmenopausal women with high risk breast cancer (T>30 mm or node-positive) were randomized postmastectomy to radiotherapy alone, radiotherapy and tamoxifen, chemotherapy alone, and chemotherapy and tamoxifen.32 The radiotherapy volume
included the chest wall, axilla, SCF and IMC. The addition of radiotherapy significantly reduced local failure and improved relapse-free survival. There was a trend toward reduced distant metastases (P=0.06) but no difference in survival. Overgaard has recently updated the Danish data on 1708 premenopausal women with T3, T4 or node-positive breast cancer.4 All patients had a mastectomy and were than randomized to chemotherapy alone or in combination with radiotherapy to the chest wall, axilla, SCF and IMC. This is the only randomized study to have shown a significant survival advantage. At 10 years 45% of the chemotherapy alone group and 54% of the radiotherapy group were alive (P<0.001). Summary In these two trials post-mastectomy radiation was delivered to the chest wall and all nodal regions. It is difficult to assess the contribution of IMC radiation alone to these results.
DISCUSSION In early stage breast cancer, the randomized data available show no significant survival benefit with the addition of IMC radiotherapy. The group expected to benefit is the medial tumours which have been demonstrated to have an increased incidence of IMC metastases in surgical series.17 Yet subgroup analyses in three of these studies failed to demonstrate a significant benefit.14,16,18 The radiotherapy planning techniques used may also impact on results. IMC lymph nodes vary in position. Individual localization using ultrasound or CT is needed to ensure adequate coverage. The apparent lack of benefit could be due to geographical misses, especially in the older trials. The Canadian trial is the only one which shows an improvement in cause-specific survival but there is still no overall survival benefit.22 One explanation is that the mortality from toxicity of radiotherapy cancels out the reduction in deaths from breast cancer. Certainly the 1994 Cuzick metaanalysis supports this.6 The mortality is mainly owing to cardiac disease which is a consequence of the dose received from IMC radiation. This was most evident in the Stockholm and Oslo trials. Surgical series of IMC treatment support the lack of survival benefit for treating IMC nodes. The International Cooperative Trial compared radical mastectomy and extended radical mastectomy in 1453 patients.2 At 10-year follow-up there was no difference in either relapse-free or overall survival. There is only one trial which has looked at the addition of IMC radiotherapy without the SCF or axilla.21 Although this was primarily a toxicity study, to date there has been no difference in relapse rates.
Review of internal mammary chain irradiation in breast cancer 249 In locally advanced breast cancer, randomized data show both a significant decrease in local recurrence and improvement in overall survival with the addition of postmastectomy radiotherapy. The radiotherapy volume included the chest wall, SCF, axilla and IMC. The value of IMC radiation per se remains uncertain and cannot be answered from these trials. Another reason to deliver IMC radiation would be to decrease local recurrences. However, isolated IMC recurrences are rare and so the benefit of prophylactic treatment is likely to be small and clinically insignificant.3 The small possible gains with IMC irradiation must be balanced against the increase in toxicity, specifically cardiac and pulmonary, which have been well documented in the literature.8,11 There are potential deficiencies in a review such as this. In identification of the trials there may be publication bias, English language bias and MEDLINE bias. The trials are heterogeneous, cover a long time span and have utilized different radiotherapy techniques and so may not be truly comparable. The systemic therapy used has changed and so the relevance of older trials to current practice may be questioned. The emerging technology of sentinel node sampling is providing a new challenge to the decision regarding treatment of IMC nodes. Medial tumours which drain to the IMC raise the question of a possible advantage to treating this nodal group. There remains, however, an absence of proven benefit against a substantial risk of toxicity. The EORTC is currently conducting a Phase III trial investigating the role of internal mammary and medial supraclavicular lymph node irradiation in Stage I to III breast cancer.33 Patients with positive axillary nodes or mediocentral tumours are eligible for randomization. This trial includes the first three intercostal spaces for the IMC but can be extended to the fifth intercostal space for lowermedial quadrant tumours. Radiological localization is mandatory for planning purposes. The prescribed dose is 50Gy in 25 daily fractions with the planning target volume extending to a depth of 4 cm. A mixture of photons and electrons is used. This trial may provide the definitive answer to the question of IMC irradiation.
2.
3. 4.
5. 6. 7. 8.
9.
10. 11.
12. 13. 14. 15.
16.
17. 18.
CONCLUSIONS Based on best current evidence (Level II) there is no advantage to elective irradiation of the IMC. The only indication is therapeutic for clinically or radiologically positive lymph nodes where the management aim is palliative. References 1. Veronesi U, Cascinelli N, Greco M et al. Prognosis of breast cancer
19.
20.
21.
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22. Ragaz J, Jackson S M, Le N et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 1997; 337: 956–962. 23. Arriagada R, Le M G, Mouriesse H et al. Long-term effect of internal mammary chain treatment. Results of a multivariate analysis of 1195 patients with operable breast cancer and positive axillary nodes. Radiother Oncol 1988; 11: 213–222. 24. Regnier R, Nguyen T H, Balikdjian D, Lustman-Marechal J, Darquennes H & Henry J. Experience of telecobalt Therapy in operable breast cancer at J. Bordet Institute. Int J Radiat Oncol Biol Phys 1982; 8: 1517–1523. 25. Montague E D, Fletcher G H. The curative value of irradiation in the treatment of nondisseminated breast cancer. Cancer 1980; 46: 995–998. 26. Chahbazian C, del Regato J A, Wilson J F. Postoperative radiation therapy for ‘Early’ Carcinoma of the Breast. Cancer 1978; 42: 1126–1128. 27. Roseman J M, James A G. The significance of the internal mammary nodes in medially located breast Cancer. Cancer 1982; 50: 1426–1429. 28. Cappellini M, Ciatto S, Mungai R. Post-operative radiotherapy in node negative breast cancer. A retrospective case-control study. Tumori 1981; 67: 443–445.
29. Rubin P, Bunyagidj S, Poulter C. Internal mammary lymph node metastases in breast cancer: detection and management. Am J Roentgenol Radium Ther Nucl Med 1971; 111: 588–598. 30. Shiba, E, Miyauchi K, Kobayashi T, Takai S, Mori T. Radical mastectomy with parasternal node dissection or radiation to the parasternal region for breast cancer of medial or central location. Surg Today 1992; 22: 124–127. 31. Schmolling J, Maus B, Rezek D et al. Breast preservation versus mastectomy – recurrence and survival rates of primary breast cancer patients at the UFK Bonn. Eur J Gynaecol Oncol 1997; 18: 29–33. 32. Rutqvist L, Cedermark B, Glas U et al. Randomised trial of adjuvant tamoxifen combined with postoperative radiation therapy or adjuvant chemotherapy in postmenopausal breast cancer. Cancer 1990; 66: 89–96. 33. Bartelink H, Borger J, Fourquet A et al. Phase III randomized trial investigating the role of internal mammary and medial supraclavicular lymph node irradiation in stage I-III breast cancer. Protocol 22922. EORTC Cooperative Group for Radiotherapy. May 1996.