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In Reply:

H. Lee Moffitt Cancer Center and Research Institute, Cambridge, MA

Candace Correa

University of Michigan, Ann Arbor, MI

Harold Litt, Wei-Ting Hwang, Victor Ferrari, Lawrence Solin

University of Pennsylvania Medical Center, Philadelphia, PA

Thank you for your interest in our study. We are gratified that you chose to discuss this important topic using our article at your residents’ journal club. We will attempt to address your questions below. We also refer you to our previously published articles, which contain some additional relevant information on the study cohort and on our radiation techniques.^1,2

First, the original potential study cohort included consecutive patients with unilateral stage I or II invasive breast cancer treated at our institution between 1977 and 1995. We chose the end year of 1995 in order to ensure a minimum of 10 years of potential follow-up for the study. Out of this original group of consecutively treated patients, we excluded patients who were lost to follow-up or dead within 2 years of diagnosis, and those with pre-existing cardiac disease at the time of breast cancer diagnosis. The exclusion of patients with less than 2 years of follow-up was because such patients would have had little opportunity to manifest any cardiac toxicity related to radiation, whether simply lost to follow-up or dead as a result of metastatic disease. As such, we do not believe these exclusions would bias the results by omitting any cases of radiation-induced cardiac toxicity. The group with pre-existing cardiac disease was considered more likely to have subsequent cardiac events than the healthy patients, and therefore may have introduced a confounding effect into the analysis. They were the subject of a separate report that was presented at the 2006 American Society of Therapeutic Radiology and Oncology meeting.³

Second, details of our radiation treatment technique have been previously published.¹ In the whole group of 961 patients, a tumor bed boost was used in all patients to a median dose of 18 Gy. The majority were treated with an electron field (83%) while iridium implants were used as a boost technique in 16% of patients. In our previous study, we did not examine the effect of boost technique on the risk of cardiac disease.² Among the study cohort undergoing cardiac testing, all 82 patients were treated with electron boost (median dose, 18 Gy). Therefore, we could not examine the effect of the boost dose or technique on the incidence of cardiac test abnormalities, so we cannot specifically address the question regarding the relative safety of the two boost techniques. Interestingly, a recent report from Paszat et al⁴ did examine the impact of boost volume in left-sided breast cancer patients, using either anterior photon or electron fields, but not brachytherapy. These authors did not find that larger boost areas were associated with an increased risk of myocardial infarction (adjusted hazard ratio = 1.02). Studies of partial breast irradiation including interstitial brachytherapy compared with external-beam techniques have shown similarly low heart doses among compared techniques.⁵

Third, it was not the practice at the University of Pennsylvania during the study period to routinely treat uninvolved internal mammary nodes (IMN), which is why so few patients in the study had IMN fields. When an IMN field was used, it was at the discretion of the treating physician, the most common reason being an inner quadrant tumor location.

Fourth, we screened all 961 patients for subsequent cardiac tests to evaluate for coronary artery disease, and this report examines only those patients who had cardiac testing after irradiation, which was typically ordered in response to a symptomatic event. Given that this was a retrospective study, it was only feasible to collect data on symptomatic patients, as these were the only patients presenting for cardiac testing. We were not actively screening patients with cardiac testing for subclinical disease. We agree that asymptomatic ischemic changes may be present in women previously irradiated for breast cancer, particularly for left-sided disease, and these may be associated with an increased risk of future symptomatic cardiac disease. Understanding of the prevalence of such subclinical findings and associated risk factors may indeed allow for appropriate interventions at an earlier time point. We plan to conduct a prospective study in breast cancer survivors to address that study question.

Fifth, the acceptable parameters for heart dose are not well understood, and are evolving as clinical data for the risk of late cardiac toxicity is analyzed in the era of three-dimensional (3D) treatment planning, but few series have an appropriately long follow-up period with contemporary 3D planning to assess the impact of modifications in technique. In most studies with adequate follow-up, including ours, radiation treatment was performed during the era of two-dimensional treatment planning with fluoroscopic simulation; therefore, actual heart dose volume histograms are not available to correlate with outcomes. We have examined the association of the technical field parameters with the development of cardiac abnormalities in left-sided cancer patients post-treatment.⁶ These data showed that cardiac test abnormalities were present in a significantly higher-than-expected number of patients compared with the predicted incidence (P < .05), and that cardiac test abnormalities were associated with a larger central lung distance, representative of the volume of intrathoracic normal tissue exposure. In a similar study, Borger et al⁷ showed that left-sided irradiation was associated with a greater risk of cardiovascular disease than right-sided, but they were unable to find any correlation with cardiovascular disease, and increasing maximum heart distance as measured from two-dimensional simulation films. In a virtual comparison of heart doses seen using five different post-mastectomy irradiation techniques, Krueger et al⁸ found a mean heart dose of 2.91 Gy for standard tangents, and 3.31 Gy for partially wide tangents, which include the IMNs, with higher doses for older techniques. Gyenes et al⁹ calculated the proportion of heart included in the 50% isodose line among 100 patients treated for left-sided breast cancer who underwent computed tomography–based 3D planning. The mean irradiated heart volume receiving 25 Gy was 5.7%.

For the purposes of the ongoing Radiation Therapy Oncology Group/National Surgical Adjuvant Breast and Bowel Project randomized trial comparing whole-breast to partial-breast irradiation techniques, the heart dose constraints have been defined as follows: left sided, less than 5% of whole heart may receive less than 40% of prescribed dose; right sided, less than 5% of whole heart may receive 5% of prescribed dose. It is our current practice to perform 3D computed tomography–based planning on all breast cancer patients receiving radiation, to assess dose volume histogram measurements of the heart and bilateral lungs, and to minimize the volume of heart irradiated as much as possible. This requires individualized treatment planning, often involving the use of heart blocks, segmental field-in-field technique, or occasionally the use of intensity-modulated radiation therapy to achieve the best treatment plan with respect to minimal heart dose in each individual patient. Although the impact of 3D planning will have to be assessed after adequate follow-up times have elapsed, the anticipated benefit will be a additional reduction in radiation-induced late cardiac mortality and morbidity.

Sixth, as discussed, none of the patients who underwent cardiac testing were treated with a brachytherapy boost; therefore, we cannot comment on the relative benefit or risk of brachytherapy technique compared with external-beam techniques. There is an emerging dosimetric literature regarding the use of brachytherapy for partial breast irradiation, but with limited follow-up for outcomes. In fact, some brachytherapy techniques may expose volumes of cardiac tissue to higher maximum doses and at accelerated fractionation schemes,¹⁰ and therefore these approaches should be used cautiously. Heart dose parameters are likely to be highly dependent on patient anatomy and tumor location, again emphasizing the need for individualized treatment planning.

Seventh, the body of literature for accelerated partial-breast irradiation (APBI) suffers from lack of follow-up, and, similar to other institutions, we do not have sufficient follow-up data on patients treated with APBI to assess long-term normal tissue toxicity. Few institutions have greater than 5- year follow-up using interstitial techniques, but all other APBI techniques all have shorter follow-up only. Such brief follow-up times are inadequate for the assessment of late cardiac toxicity, which does not manifest itself until 10 years or more after treatment.² We are awaiting the results of several randomized trials in the United States and elsewhere. However, it should be noted that the study design of these trials generally is intended to test the equivalence of APBI with whole-breast irradiation with respect to local control and survival, not its superiority. APBI may allow reduced heart volume exposures in some patients compared to whole breast treatment, but its use must be considered in the context of emerging clinical trial data and appropriate selection, so that patients are not subjected to an increased risk of local recurrence and death from breast cancer.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Santiago R, Harris EE, Hwang W-T, et al: Similar long-term results of breast conservation treatment for stage I and II invasive lobular carcinoma compared to invasive ductal carcinoma of the breast: The University of Pennsylvania experience. Cancer 103:2447-2454, 2005[CrossRef][Medline]

2. Harris EE, Correa C, Hwang W-T, et al: Late cardiac mortality and morbidity in early-stage breast cancer patients after breast-conservation treatment. J Clin Oncol 24:4100-4106, 2006[Abstract/Free Full Text]

3. Gutt R, Hwang W-T, Solin LJ, et al: Cardiac morbidity and mortality after breast conservation treatment in early stage breast cancer patients with pre-existing cardiac disease. Int J Radiat Oncol Biol Phys 66:S106-107, 2006

4. Paszat LF, Vallis KA, Benk VMA, et al: A population based case cohort study of the risk of myocardial infarction following radiation therapy for breast cancer. Radioth Oncol 82:294-300, 2007[CrossRef]

5. Patel RR, Becker SJ, Das RK, et al: A dosimetric comparison of accelerated partial breast irradiation techniques: Multicatheter interstitial brachytherapy, three-dimensional conformal radiotherapy, and supine versus prone helical tomotherapy. Int J Radiat Oncol Biol Phys 68:935-492, 2007[Medline]

6. Correa CR, Harris EE, Das IJ, et al: Prediction of cardiac test abnormalities and diagnoses from tangential beam treatment parameters in primary radiotherapy for left-side breast cancer. Proceedings Radiological Society of Northern America, November 28-December 3, 2004, Chicago, IL

7. Borger JH, Hooning MJ, Boersma LJ, et al: Cardiotoxic effects of tangential breast irradiation in early breast cancer patients: The role of irradiated heart volume. Int J Radiat Oncol Biol Phys 69:1131-1138, 2007[Medline]

8. Krueger EA, Schipper MJ, Koelling T, et al: Cardiac chamber and coronary artery doses associated with postmastectomy radiotherapy techniques to the chest wall and regional nodes. Int J Radiat Oncol Biol Phys 60:1195-1203, 2004[CrossRef][Medline]

9. Gyenes G, Gagliardi G, Lax I, et al: Evaluation of irradiated heart volumes in stage I breast cancer patients treated with postoperative adjuvant radiotherapy. J Clin Oncol 15:1348-1353, 1997[Abstract/Free Full Text]

10. Khan AJ, O’Farrell D, Hansen JL, et al: Normal tissue dose for accelerated partial breast irradiation: A comparative phantom study. Int J Radiat Oncol Biol Phys 69:S215, 2007

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Harris, E. E. R. Articles by Solin, L. Search for Related Content PubMed Articles by Harris, E. E. R. Articles by Solin, L. Related Articles Related Correspondence Social Bookmarking                            What's this?