May 21, 2024

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Advanced Radiation Techniques Could Aid in Cardiac Sparing in Lung, Breast, and Esophageal Cancer Treatment

8 min read

Charles B. Simone II, MD, FASTRO, FACRO

Cardiac toxicities can be effectively reduced using advanced radiation techniques such as intensity-modulated radiation therapy (IMRT), which is preferred over 3-dimensional conformal radiation therapy (3DCRT) for patients with locally advanced lung, esophageal, and breast cancers, because of its ability to optimize cardiac sparing, according to Charles B. Simone II, MD, FASTRO, FACRO.1

During his presentation at the 2024 ACRO Summit, Simone added that, “Proton therapy can further reduce the dose to the heart over IMRT, potentially reducing major cardiac events and improving overall survival [OS].” Simone is a research professor and chief medical officer at the New York Proton Center, and a full member in the Department of Radiation Oncology at Memorial Sloan Kettering Cancer Center in New York.

Data published in the New England Journal of Medicine revealed that the rate of major coronary events increased by 7.4% (95% CI, 2.9-14.5; P < .001) for each increase of 1 Gy in mean radiation therapy dose to the heart with no threshold.2 Simone also cited data from an update released by the Danish Breast Cancer Cooperative Group, which revealed that the median mean heart dose for left-sided radiotherapy was 2.41 Gy compared with 0.68 Gy for right-sided.3 “That can lead to detrimental survival in these patients,” he noted.

General preventative strategies for coronary adverse effects (AEs) aim to manage modifiable cardiovascular risk factors, such as smoking cessation, exercise, and a healthy diet, with lifestyle changes. However, cardioprotective interventions are needed to address principal cardiac problems related to radiation. Radiation-related AEs include pericarditis, which is typically acute and develops within weeks of radiation therapy. Other toxicities believed to occur more than 10 years after radiation include cardiomyopathy, coronary artery disease leading to ischemia, valvular disease, conduction abnormalities, autonomic dysfunction, and vascular changes.1

“[We’ve seen that] patients who [receive] radiation in the postoperative setting [can have] better cancer control and cancer-specific survival, but a much higher rate of dying from cardiopulmonary complications,” Simone detailed. “That’s been the struggle that we’ve had in our field—how do we optimize radiation for the lung cancer population?”

Regarding the incidence of toxicities associated with postoperative radiotherapy (PORT), findings from a SEER analysis of 6148 patients with pN+ non–small cell lung cancer (NSCLC) following lobectomy/pneumonectomy from 1983 to 1993 revealed that PORT increased cardiac disease mortality by 30% (HR, 1.30; 95% CI, 1.04-1.61; P = .0193).4

“If you have a right upper lobe tumor, you’re not getting as much radiation to the heart, [but] anywhere else you’re getting a lot of radiation to the heart. Fortunately, we’re getting better over time with advanced treatment planning,” Simone said.

Examining the Impact of Radiation Dose on Cardiac Structures and the Benefits of IMRT

“IMRT is preferred over 3DCRT for locally advanced lung, esophageal, and breast cancers to optimize cardiac sparing,” Simone said in his presentation.1

The phase 3 RTOG 0617 trial (NCT00533949) comparing 3DCRT vs IMRT found that for a given PTV volume, IMRT was associated with lower heart doses (P < .05) in patients with stage III NSCLC. Fewer rates of grade 3 or higher pneumonitis were seen with IMRT (3.5%) vs 3DCRT (7.9%; adjusted P = .046). Additionally, IMRT was associated with higher compliance with full-dose consolidative chemotherapy but there was no difference is OS or progression-free survival (PFS) seen between arms.5

However, a survival advantage was observed for patients with stage III NSCLC (n = 2543) treated with at least 58 Gy and definitive chemoradiation either concurrent or sequential in the NCDB study; the median OS was 17.2 months with IMRT vs 14.6 months with 3DCRT.6

“Similar benefits with IMRT over 3DCRT [are observed] for [patients with] locally advanced breast cancer, especially for left-sided cases and/or when internal mammary nodes are being covered; esophageal cancer, especially middle and distal cases; [and] thymic [tumors], especially large and/or caudally located tumors and definitive cases,” Simone said.

Simone is involved in research with NRG Oncology that aims to standardize contouring and cardiac substructures. These efforts will evaluate the aortic valve, left atrium, left anterior descending coronary artery, left ventricle, pulmonary artery, right atrium, right coronary artery, right ventricle, and superior vena cava. Overall, the use of advanced techniques such as IMRT and proton therapy is a key area of investigation in the radiation field.1

“There is so much literature in this field—every day there’s new publication on what cardiac substructure matters and what dose we should consider and what’s associated with what,” Simone explained. “We don’t have enough data right now to [create] informed constraints, but it is something our field needs to do.”

Breaking it Down: Proton Therapy in Breast and Lung Cancers

Both the RADCOMP Consortium trial (NCT02603341) in breast cancer and the phase 3 RTOG 1308 study (NCT01993810) in lung cancer are evaluating outcomes with proton- vs photon-based therapy.1 Simone noted that the RADCOMP study needs 3 patients to complete accrual, but the RTOG 1308 study has completed accrual.

Adjuvant proton therapy demonstrated promising results vs IMRT according to data from a retrospective report of patients with NSCLC who received PORT (n = 136) in the form of proton beam therapy (PBT; n = 61) and IMRT (n = 75) therapy treated from 2003 to 2016. Regarding dosimetry, PBT lowered mean heart (P < .01; 2.0 Gy vs 7.4 Gy), heart V30 (P < .01; 2.6% vs 10.7%), mean lung (P = .042; 7.9 Gy vs 10.4 Gy), and lung V5 (P < .01; 23.4% vs 42.1%) in the PBT vs IMRT arms, respectively.7

In the PBT vs IMRT group, cardiac toxicities occurred in 4.9% vs 14.7% of patients, respectively. Grade 2 or higher esophagitis (23.0% with PBT vs 60.0% with IMRT), as well as grade 2 or higher pneumonitis (4.9% vs 17.3%), were noted. The total toxicity burden was lower with PBT vs IMRT (odds ratio, 0.35; 95% CI, 0.15-0.83; P = .017). Further, the median OS was 76 months with PBT compared with 46 months for IMRT.

“There’s a randomized trial already completed in locally advanced NSCLC out of The University of Texas MD Anderson Cancer Center and every single patient had a benefit with protons to the heart specifically. Huge reductions in dose to the heart [were observed],” Simone added.

Simone also noted that “…not all protons are created equal. Now, fortunately, proton single-arm centers are much cheaper, and we are seeing more centers opening in the community. And fortunately, most of those machines are going to exclusively administer IMPT [and not scattering proton therapy].”

Proton Therapy in Esophageal and Additional Malignancies

When protons or photons were administered following treatment with neoadjuvant chemoradiation in patients with esophageal cancer, PBT was associated with fewer pulmonary toxicities (P = .005), cardiac events (P = .047), and wound complications (P = .005) vs IMRT/3DCRT. Proton therapy also had a shorter mean length of stay of 9.3 days (95% CI, 8.2-10.3) vs 13.2 days (95% CI, 11.7-14.7) for 3DCRT vs 11.6 days for IMRT (95% CI, 10.9-12.7; P < .0001). The 90-day postop mortality rate was lower with proton therapy as well—rates were 0.9% vs 4.2% vs 4.3%, respectively (P = 0.264).8

“The uptake of IMRT has been dramatic for esophageal cancer, [especially] knowing the morbidity of these treatments [for this patient population],” Simone said.

A randomized phase 2 trial (NCT01512589) revealed that patients with definitive (n = 56) or resectable (n = 51) esophageal cancer who received PBT experienced fewer AEs than those treated with IMRT—the total toxicity burden was 2.3 times higher for IMRT (39.9; 95% highest posterior density interval [HPDI], 26.2-54.9) vs PBT (17.4; 95% HPDI 10.5-25.0)and the postoperative complication score was 7.6 times higher with IMRT (19.1; 95% HPDI, 7.3-32.3) vs PBT (2.5; 95% CI, 0.3-5.2). Mean hospitalization duration was 8 days with PBT vs 13 days with IMRT (P = .06) and 3 grade 5 toxicities occurred with IMRT vs 0 with PBT. Additionally, there was no difference in PFS or OS.9

Simone noted that there are less data on proton therapy in patients with lymphoma, but regarding data on thymic tumors there was an “…80.7% predicted decrease in the rate of major coronary events with proton vs IMRT.”10

Further Examination of Advanced Techniques

A nonrandomized comparison of 2 prospective cohorts of patients with stage II to IIIB and limited stage IV (solitary brain metastases) cancer found that intensity-modulated proton therapy (IMPT) had lower mean lung, heart, and esophagus doses vs passive scattering proton therapy (PSPT) and concurrent chemotherapy. Patients treated with IMPT (n = 53) also experienced a longer median OS of 36.2 months compared with 23.9 months for those treated with PSPT (n = 86; P = .09).11

“Additional means to reduce cardiac morbidity are needed [and] current investigations with radioprotectors and FLASH [are] ongoing,” Simone noted. He added that radioprotectors may serve to prevent cardiac toxicities and FLASH radiotherapy also has the potential to widen the therapeutic window. “Across multiple preclinical models, FLASH can achieve a protective effect on normal tissues and reduce both acute and late toxicities compared with conventional dose rate radiotherapy,” he said.

Editor’s Note: Dr Simone disclosed a professional relationship with the National Institutes of Health; he has received grants as well as honorarium and serving in a consulting role for Varian Medical System.

References

  1. Simone II CB. Treatment planning techniques, dose constraints, and advanced modalities to reduce the risks of cardiac toxicities. Presented at: The Radiation Oncology Summit: ACRO 2024; March 13-16, 2024; Orlando, Florida.
  2. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368(11):987-98. doi:10.1056/NEJMoa1209825
  3. Laugaard Lorenzen E, Christian Rehammar J, Jensen MB, Ewertz M, Brink C. Radiation-induced risk of ischemic heart disease following breast cancer radiotherapy in Denmark, 1977-2005. Radiother Oncol. 2020;152:103-110. doi:10.1016/j.radonc.2020.08.007
  4. Lally BE, Detterbeck FC, Geiger AM, et al. The risk of death from heart disease in patients with nonsmall cell lung cancer who receive postoperative radiotherapy: analysis of the Surveillance, Epidemiology, and End Results database. Cancer. 2007;110(4):911-7. doi:10.1002/cncr.22845
  5. Chun SG, Hu C, Choy H, et al. Impact of intensity-modulated radiation therapy technique for locally advanced non-small-cell lung cancer: a secondary analysis of the NRG Oncology RTOG 0617 randomized clinical trial. J Clin Oncol. 2017;35(1):56-62. doi:10.1200/JCO.2016.69.1378
  6. Jegadeesh N, Liu Y, Gillespie T, et al. Evaluating intensity-modulated radiation therapy in locally advanced non-small-cell lung cancer: results from the National Cancer Data Base. Clin Lung Cancer. 2016;17(5):398-405. doi:10.1016/j.cllc.2016.01.007
  7. Boyce-Fappiano D, Nguyen QN, Chapman BV, et al. Single institution experience of proton and photon-based postoperative radiation therapy for non-small-cell lung cancer. Clin Lung Cancer. 2021;22(5):e745-e755. doi:10.1016/j.cllc.2021.02.002
  8. Lin SH, Merrell KW, Shen J, et al. Multi-institutional analysis of radiation modality use and postoperative outcomes of neoadjuvant chemoradiation for esophageal cancer. Radiother Oncol. 2017;123(3):376-381. doi:10.1016/j.radonc.2017.04.013
  9. Lin SH, Hobbs BP, Verma V, et al. Randomized phase IIB trial of proton beam therapy versus intensity-modulated radiation therapy for locally advanced esophageal cancer. J Clin Oncol. 2020;38(14):1569-1579. doi:10.1200/JCO.19.02503
  10. Vogel J, Berman AT, Lin L, et al. Prospective study of proton beam radiation therapy for adjuvant and definitive treatment of thymoma and thymic carcinoma: Early response and toxicity assessment. Radiother Oncol. 2016;118(3):504-9. doi:10.1016/j.radonc.2016.02.003
  11. Gjyshi O, Xu T, Elhammali A, et al. Toxicity and survival after intensity-modulated proton therapy versus passive scattering proton therapy for NSCLC. J Thorac Oncol. 2021;16(2):269-277. doi:10.1016/j.jtho.2020.10.013

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