# Radiation Oncology/Toxicity/Heart

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
Consequences of Radiotherapy to the Heart
    See also: RT toxicity from Breast

## Pericardial Effusion

* MD Anderson; 2008 (2001-2003) PMID 18191334 -- "Risk factors for pericardial effusion in inoperable esophageal cancer patients treated with definitive chemoradiation therapy." (Wei X, Int J Radiat Oncol Biol Phys. 2008 Mar 1;70(3):707-14. Epub 2008 Jan 11.)
** Retrospective. 101 patients, inoperable esophageal CA, treated with concurrent chemo-RT. RT dose 45-50.4 Gy. Pericardium defined as 0.5 cm radial expansion to cardiac contour
** Outcome: crude rate 28%, median time-to-onset 5.3 months (1-17 months)
** Predictors: no clinical factors; dosimetric V30 >46%, mean dose >26 Gy
** Conclusion: High-dose RT to pericardium may increase risk of pericardial effusion

## Breast cancer

* Ruijin Hospital, Shanghai, China; 2024 PMID 39499199 -- "A randomized trial of early cardiotoxicity in breast cancer patients receiving postoperative IMRT with or without serial cardiac dose constraints" (Cao L, Int J Cancer. 2024 Nov 5.)
** Randomized. 199 patients. Postoperative breast RT after AC/T or HER2+ chemotherapy. Arm 1) cardiac safety with MHD <6 Gy, V30 <20%, V10 <50% vs Arm 2) standard MHD <8 Gy.
** Outcome" 1 year cardiac events cardiac arm 19$ vs standard 25%. LVEF 0% vs 2%, diastolic dysfunction 5% vs 9%.
** Conclusion: cardiac dose constraints help
* HERA HER2+ Trial; 2022 PMID 34986381 -- "Evaluation of Cardiotoxicity in HER-2-Positive Breast Cancer Patients Treated With Radiation Therapy and Trastuzumab" (Bachir B, Int J Radiat Oncol Biol Phys. 2022 May 1;113(1):135-142. doi: 10.1016/j.ijrobp.2021.12.159. Epub 2022 Jan 2.)
** Post hoc analysis. 3321 patients. HERA trial, mastectomy, adjuvant chemotherapy, adjuvant maintenance trastuzumab. PMRT as per clinical decision. Group 1) Trastuzumab + Left PMRT vs Group 2) Trastuzumab + Right PMRT vs Group 3) Trastuzumab and no PMRT. Median F/U 11 years
** Outcome: LVEF decline by echo 9.2% vs 9.0% vs 8.8% (NS). Cardiovascular events 1.1% vs 0.9% vs 0.6% (NS). On multivariate analysis, no difference between left and right PMRT
** Conclusion: PMRT does not significantly increase risk of cardiotoxicity in HER2+ patients treated with Herceptin
* Oxford; 2013 (1958-2001) PMID 23484825 -- "Risk of ischemic heart disease in women after radiotherapy for breast cancer." (Darby SC, N Engl J Med. 2013 Mar 14;368(11):987-98.)
** Case-control study. Pts treated in Sweden or Denmark.
*** Study population consisted of all women (ages < 75) with breast cancer who received RT (both right and left); excluded pts with metastatic dz at diagnosis or prior thoracic RT.
*** Cases (n=963) consisted of pts who had a major coronary event (MCE) -- MI, coronary revascularization, or death from ischemic heart disease -- that occurred after the diagnosis of breast cancer but before any recurrence or diagnosis of a 2nd malignancy.
*** Controls (n=1205) were selected at random from all pts in the study population; matched to country of residence, age at breast cancer diagnosis, and year of diagnosis. Had all received RT and had no recurrence of breast cancer and no 2nd cancer and no major coronary event before the index date.
*** Radiation dosimetry was estimated. Reconstructed the radiation plan (using a diagram or photograph of the original RT fields and the original dose plan when available) on a CT scan of a patient with typical anatomy. Constructed DVH for the whole heart and LAD artery. Computed equivalent doses (EQD2) in 2-Gy fractions, using an alpha/beta ratio of 2 Gy. Note: 3D planning dosimetry was not available for the treated patients.
** Major coronary events: 44% at < 10 yrs from ca diagnosis, 33% at 10-19 yrs, and 23% at 20 or more years. 54% of case pts died from ischemic heart disease.
** RT:
*** Lt-sided RT associated with higher rates of MCE (rate ratio = 1.32). No other association between MCE and other tumor characteristics or treatment factors, such as use of chemotherapy; trend for positive nodes (p=0.06, rate ratio 1.20).
*** Average mean heart dose: 6.6 Gy (left breast), 2.9 Gy (right breast), 4.9 Gy (overall). The rate of MCE increased by 7.4% for each increase of 1 Gy. The mean heart dose was a better predictor than the dose to the LAD.
*** For dose ranges (mean heart dose): < 2 Gy, 10% increase; 2-4 Gy, 30%; 5-9 Gy, 40%; 10 or more Gy, 116%.
** Patient-related factors: positive history of ischemic heart disease (rate ratio 6.67); also: circulatory disease, diabetes, COPD, current smoker, obesity, analgesic medication use.
** The percentage increase in risk of MCE is similar for women with and without ischemic heart disease. Absolute radiation-related risks are greater in those with preexisting cardiac risk factors.
*** Example: 50 yr old women with no cardiac risk factors. Mean heart dose: 3 Gy. Increase risk of death from ischemic heart disease from 1.9% to 2.4% (absolute increase of 0.5%). Increase risk of having at least one acute coronary event from 4.5% to 5.4% (increase of 0.9%).
** Conclusion: "Exposure of the heart to ionizing radiation during radiotherapy for breast cancer increases the subsequent rate of ischemic heart disease. The increase is proportional to the mean dose to the heart, begins within a few years after exposure, and continues for at least 20 years. Women with preexisting cardiac risk factors have greater absolute increases in risk from radiotherapy than other women."
* Uppsala University; 2012 (1970-2003) PMID 22203772 -- "Distribution of coronary artery stenosis after radiation for breast cancer." (Nilsson G, J Clin Oncol. 2012 Feb 1;30(4):380-6. Epub 2011 Dec 27.)
** Retrospective cohort. Linked breast cancer and coronary angiography registries. 199 patients. Two hotspots defined as proximal RCA and mid/distal LAD
** Outcome: Odds ratio for left-sided radiation for grade 3-5 stenosis LAD 4.4 (SS), grade 4-5 stenosis 7.2 (SS)
** Conclusion: Increase in stenosis in mid/distal LAD in irradiated left-sided breast cancer; risk increases for severe stenosis
* U Penn; 2007 (1977-1995) PMID 17634481 -- "Coronary artery findings after left-sided compared with right-sided radiation treatment for early-stage breast cancer." (Correa CR, J Clin Oncol. 2007 Jul 20;25(21):3031-7.)
** Retrospective. 961 patients with Stage I-II BCA, conventional tangents. Screened with stress tests and cardiac cath
** 10-year risk of CAD: right and left 7% (NS)
** 12-year risk of cath abnormalities: right 8% vs. left 59% (SS); 70% in LAD territory
** Conclusion: Left-sided RT as component of BCS causes increased risk of later coronary damage
* Duke; 2005 (1998-2001) PMID 16111592 — "The incidence and functional consequences of RT-associated cardiac perfusion defects." Marks LB et al. Int J Radiat Oncol Biol Phys. 2005 Sep 1;63(1):214-23.
** 114 pts. Breast cancer. Pts imaged with technetium 99m sestamibi or tetrofosmin pre- and post-RT.
** 42% incidence of perfusion defects at 24 months.
* Danish trials 82b/82c
** 1999: PMID 10543669 — "Morbidity and mortality of ischaemic heart disease in high-risk breast-cancer patients after adjuvant postmastectomy systemic treatment with or without radiotherapy: analysis of DBCG 82b and 82c randomised trials." Hojris I et al. Lancet. 1999 Oct 23;354(9188):1425-30.
*** No increased risk of ischemic heart disease at 12 yrs.

## Hodgkin Disease

* Zurich, 2007 PMID 17512861 -- "Radiotherapy and the heart." (Bramkamp M, Lancet. 2007 May 19;369(9574):1762.)
** Case report. 47M with CAD, s/p mantle field to 40 Gy for HD in his teens

## Non-Hodgkin's Lymphoma

* SEER/Colorado; 2010 (1988-2004) PMID 19515509 -- "Cardiac mortality in patients with stage I and II diffuse large B-cell lymphoma treated with and without radiation: a surveillance, epidemiology, and end-results analysis." (Pugh TJ, Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3):845-9. Epub 2009 Jun 8.)
** SEER analysis. 15,454 patients, Stage I-II DLBCL, treated with anthracycline-based chemo, anti-CD20 antibody. RT given in 39%. Primary outcome cardiac-specific mortality (CSM). Median F/U 3 years
** Cardiac-specific mortality: 5-year RT+ 4.3% vs RT- 5.9%; 10-years 9.0% vs 10.8%; 15-years 13.8% vs 16.1% (HR 1.3, SS)
** Conclusion: Increased anthracycline exposure in patients treated only with chemo may result in increase in cardiac deaths

## Childhood disease

* INSERM; 2010 (1942-1986) PMID 20142603 -- "Role of cancer treatment in long-term overall and cardiovascular mortality after childhood cancer." (Tukenova M, J Clin Oncol. 2010 Mar 10;28(8):1308-15. Epub 2010 Feb 8.)
** Retrospective. 4,122 5-year survivors of childhood cancer in France and UK. Chemotherapy and RT info collected; RT heart dose estimate. Average F/U 27 years
** Outcome: Overall standardized mortality ratio 8.3 compared to general population. Cardiac death SMR 5.0, if anthracycline >360 mg/m2 RR 4.4 (SS), if RT dose 5-15 Gy RR 12.5, if RT dose >15 Gy RR 25. Linear relationship between heart dose and risk of cardiac mortality, estimated RR 60% at 1 Gy
** Conclusion: Relationship between RT dose to heart and long-term cardiac mortality