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Sarah Darby, Paul McGale, Richard Peto, Fredrik Granath, Per Hall, and Anders Ekbom
Research pointers: Mortality from cardiovascular disease more than 10 years after radiotherapy for breast cancer: nationwide cohort study of 90 000 Swedish women
BMJ 2003; 326: 256-257 [Full text]
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[Read Rapid Response] Increased cardiovascular deaths following radiotherapy over 10 years ago - nothing new
Adrian N Harnett   (14 February 2003)
[Read Rapid Response] cardiac mortality and breast radiotherapy
Ian H kunkler   (15 February 2003)
[Read Rapid Response] The mortality from cardiovascular disease from breast cancer radiotherapy will become history
Simon S Lo, Kevin Albuquerque, M.D., FRCS, Assistant Professor   (21 August 2003)

Increased cardiovascular deaths following radiotherapy over 10 years ago - nothing new 14 February 2003
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Adrian N Harnett,
Consultant Clinical Oncologist
Norfolk and Norwich University Hospital, Colney Centre, Colney Lane, Norwich, Norfolk, NR4 7UY

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Re: Increased cardiovascular deaths following radiotherapy over 10 years ago - nothing new

The early breast cancer trials collaborative group reported long-term follow-up of patients treated by radiotherapy for breast cancer and showed an increased mortality rate from cardiovascular events (1). This is widely known and accepted in oncology. However, it is related to what would now be considered as poor radiotherapy techniques and poor fractionation schedules. Indeed, more recent reports have shown not only the established two-thirds reduction in local recurrence when radiotherapy is used after mastectomy, but also an overall survival benefit of around 9% (2,3,4). In addition, Overgaard has shown no excess cardiac deaths in patients followed up for over 10 years4. As a result, many patients who have had a mastectomy will now also receive post-operative radiotherapy. Current radiotherapy practice demands high precision. Patients are positioned with their arms raised above the head on the couch which alters the position of the soft tissues to be irradiated and reduces or excludes the heart from the radiation field. Additional shielding of the heart can be employed and in centres that have provision of conformal radiotherapy, the radiation fields can be shaped to avoid the heart.

I therefore find it surprising that a study from Sweden was recently published in this journal which does not provide any new information and refers to outmoded radiotherapy (5).

I also find it surprising that the substantial hazard in cardiovascular mortality reported is calculated from unpublished data suggesting around 30% of women with early breast cancer received radiotherapy.

Adrian N Harnett
Consultant in Clinical Oncology
Norfolk & Norwich University Hospital

1. Early Breast Cancer Trialists’ Collaborative Group: Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: An overview of the randomised trials. Lancet 355:1757- 1770, 2000

2. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 337:949-955, 1997

3. Ragaz J, Jackson SM, Le N, et al: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 337:956-962, 1997

4. Overgaard M, Jensen M-J, Overgaard J, et al: Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant Tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 353:1641-1648, 1999

5. Mortality from cardiovascular disease more than 10 years after radiotherapy for breast cancer: nationwide cohort study of 90,000 Swedish women

Competing interests:   None declared
cardiac mortality and breast radiotherapy 15 February 2003
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Ian H kunkler,
Consultant and Senior Lecturer in Clincal Oncology
Western General Hospital, Crewe Road, Edinburgh, EH4 2XU

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Re: cardiac mortality and breast radiotherapy

Sir,

The headline on the front cover of the BMJ (Ist Feb) ‘ cardiovascular mortality after radiotherapy for breast cancer’ would lead the reader to suppose that the study (1) described the relationship between adjuvant irradiation for breast cancer and cardiac mortality.The actual report of a cohort of nearly 90,000 women reported from the Swedish Cancer registry with data on laterality of breast cancer and cardiac mortality presents only estimates of the use of adjuvant radiotherapy (30%) from regional Swedish registries in the 1970s and 1980s. The authors are rightly modest in their claims about the elevated mortality ratio (left vs right) of 1.10 because of the wide confidence limits for the observed ratio. This study, as the metanalyses of trials of postoperative loco-regional irradiation for early breast cancer, treat radiotherapy as a uniform intervention.This takes no account of the volume of heart irradiated, preexisting cardiac morbidity or dose and fractionation or the use of potentially cardiotoxic antracycline containing adjuvant chemotherapy. Radiotherapy techniques have evolved to reduce cardiac irradiation. Three dimensional CT planning allows the irradiated volume of the heart to be measured. Beam configurations can be modified to minimise myocardial irradiation.

The combined analysis of the pre and postmenopausal trials of Danish Breast Cooperative Group has already shown that electron based techniques for minimising transmitted dose to the heart are effective in avoiding radiation induced cardiac toxicity (3). However the techniques adopted in these trials are very labour intensive and not widely practised. The recent introduction of intensity modulated radiotherapy allows the shaping of the irradiated volume to minimise cardiac irradiation. However as yet there are no long term follow up data confirming the reduction in radiation induced mortality. This technique is likely to become more widely adopted. What are needed are large prospective cohort studies linking cancer registry data, detailed description of the parameters of radiotherapy, irradiated cardiac volume, use of antracycline based chemotherapy, cancer control and cardiovascular morbidity and mortality. Only then will the specific cardiac risks of adjuvant irradiation be accurately assessed.

1.Darby S, McGale P, Peto R. Mortality from cardiovascular disease more than 10 years after radiotherapy for breast cancer: nationwide cohort study of 90,000 Swedish women. BMJ 326: 256-7.

2.Early breast cancer trialists' collaborative group (EBCTCG). Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 2000; 355: 1757-1770.

3.Hojris I, Overgaard M, Christensen JJ, Overgaard J. Morbidity and mortality of ischemic heart disease in 3083 high-risk breast cancer patients given adjuvant systemic therapy treatment with or without postmastectomy irradiation: analysis of DBCG 82b and 82c randomised trials. Lancet 1999; 354: 1425-1430.

Competing interests:   none
The mortality from cardiovascular disease from breast cancer radiotherapy will become history 21 August 2003
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Simon S Lo,
Assistant Professor of Radiation Oncology
Loyola University Medical Center, Maywood, IL 60153, USA,
Kevin Albuquerque, M.D., FRCS, Assistant Professor

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Re: The mortality from cardiovascular disease from breast cancer radiotherapy will become history

The mortality from cardiovascular disease from breast cancer radiotherapy in the past resulted from the lack of knowledge of the cardiac toxicity from radiation therapy and the lack of technologic capability to optimally protect the heart. The traditional radiation therapy techniques have resulted in significant risks for cardiac deaths (1). It has been shown in multiple studies including the current one that patients with left-sided tumors treated with radiation therapy stand a higher risk for cardiac deaths (2-4). In the recent few decades, there have been a lot of new advances in the management of breast cancer including radiation therapy for breast cancer. Two modern large randomized trials utilized the comprehensive nodal irradiation approach with promising results. However, controversy exists as to whether internal mammary chain (IMC) irradiation is necessary. Some groups recommended IMC irradiation only for those with pathologically proven positive IMC because the benefits have to be balanced against the risk of cardiac toxicity (5). Sentinel lymph node mapping may provides an opportunity to evaluate the IMC in early stage breast cancer. Pathologic confirmation of the internal mammary nodes that show increased uptake may help select patients who are most likely to benefit from irradiation of these nodes (5). This risk-adapted approach is still investigational.

Modern radiation therapy techniques also help decrease the risk of cardiac toxicity. Marks et al. described a customized "partly wide" tangential fields for the treatment of internal mammary nodes in an attempt to decrease the amount of heart included in the radiation field (6). The superiorly located internal mammary nodes, which are those at highest risk for involvement, are treated selectively using this technique. With the advent of CT simulation, one will be able to design shaped fields to shield the left ventricle. Dose-volume histograms can be utilzed to assess the dose delivered to the heart, so the risk of toxicity can be estimated and this is balanced against disease control. Intensity- modulated radiation therapy for breast cancer has become more popular in the recent years and may be able to reduce doses delivered to the heart (7). Moderate deep inspiration breath hold method using an active breathing control device can potentially decrease heart doses (8).

In this modern era of breast cancer treatment, most women with breast cancer who are eligible for breast conservating surgery will receive lumpectomy followed by radiation therapy. Partial breast irradiation utilizing brachytherapy for selected candidates has become more popular in the recent years. Multiple groups have reported promising preliminary results (9-10). This approach will limit the radiation only to the lumpectomy site and hence the heart is spared from radiation toxicity.

REFERENCES:

1. Cuzick J, Stewart H, Rutqvist L, Houghton J, Edwards R, Redmond C, Peto R, Baum M, Fisher B, Host H, et al. Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol. 1994 Mar;12(3):447-53.

2. Sarah Darby, Paul McGale, Richard Peto, Fredrik Granath, Per Hall, and Anders Ekbom. Research pointers: Mortality from cardiovascular disease more than 10 years after radiotherapy for breast cancer: nationwide cohort study of 90 000 Swedish women. BMJ, Feb 2003; 326: 256 - 257.

3. Paszat L, Mackillop WJ, Groome PA, Boyd C, Schulze K, Holowaty E. Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the surveillance, epidemiology and end-results cancer registries. J Clin Oncol 1998; 16: 2625-2631.

4. Rutqvist LE, Johansson H. Mortality by laterality of the primary tumour among 55 000 breast cancer patients from the Swedish Cancer Registry. Br J Cancer 1990; 61: 866-868.

5. Freedman GM, Fowble BL, Nicolaou N, Sigurdson ER, Torosian MH, Boraas MC, Hoffman JP. Should internal mammary lymph nodes in breast cancer be a target for the radiation oncologist? Int J Radiat Oncol Biol Phys. 2000 Mar 1;46(4):805-14. Review.

6. Marks LB, Hebert ME, Bentel G, Spencer DP, Sherouse GW, Prosnitz LR. To treat or not to treat the internal mammary nodes: a possible compromise. Int J Radiat Oncol Biol Phys. 1994 Jul 1;29(4):903-9.

7. Krueger EA, Fraass BA, Pierce LJ. Clinical aspects of intensity- modulated radiotherapy in the treatment of breast cancer. Semin Radiat Oncol. 2002 Jul;12(3):250-9. Review.

8. Remouchamps VM, Vicini FA, Sharpe MB, Kestin LL, Martinez AA, Wong JW. Significant reductions in heart and lung doses using deep inspiration breath hold with active breathing control and intensity-modulated radiation therapy for patients treated with locoregional breast irradiation. Int J Radiat Oncol Biol Phys. 2003 Feb 1;55(2):392-406.

9. Arthur DW, Koo D, Zwicker RD, Tong S, Bear HD, Kaplan BJ, Kavanagh BD, Warwicke LA, Holdford D, Amir C, Archer KJ, Schmidt-Ullrich RK. Partial breast brachytherapy after lumpectomy: low-dose-rate and high-dose -rate experience. Int J Radiat Oncol Biol Phys. 2003 Jul 1;56(3):681-9.

10.Baglan KL, Martinez AA, Frazier RC, Kini VR, Kestin LL, Chen PY, Edmundson G, Mele E, Jaffray D, Vicini FA. The use of high-dose-rate brachytherapy alone after lumpectomy in patients with early-stage breast cancer treated with breast-conserving therapy. Int J Radiat Oncol Biol Phys. 2001 Jul 15;50(4):1003-11.

Competing interests:   None declared