Precision Cancer Care: Preserving Normal Tissue With Proton Therapy

Radiation therapy is a critical component of cancer care that is currently being used in approximately 50% of all patients with cancer.¹ For all treatment sites, there is a delicate balance between treating the cancer cells with a dose of radiation high enough to kill the entire tumor and minimizing the impact to surrounding normal tissue to reduce adverse effects (AEs).

Technology has progressed significantly, allowing for better targeting of conventional radiation treatment using x-rays or photons. Radiation therapy comes in many forms, including photons, radioactive sources or drugs, or particle therapy, such as proton beam radiation. Numerous studies have demonstrated benefits in terms of reducing toxicities associated with chemoradiotherapy treatments by treating patients with proton as opposed to photon radiation therapy, without compromising tumor control.²

Proton beam radiation therapy is unique compared with conventional or photon radiation therapy because there is no exit dose of radiation. With proton beam radiation therapy, the highest dose is delivered at the end of the beam (Bragg peak) and has a sharp falloff, which allows us to “paint” the target, minimizing radiation exposure to healthy tissues surrounding the tumor. Proton therapy can also be delivered on the millimeter scale using pencil beam scanning (PBS), which ensures precise treatment in the desired areas. Because of the sharp dose falloff, extra care must be taken during treatment to account for changes in the tumor, such as tissue swelling, tumor shrinkage, and/or a shift in its location due to weight loss during treatment, in the path of beam to ensure the Bragg peak remains in the target region. Thus, patients undergoing proton therapy may require additional scans and potential changes to their treatment plan over the course of their therapy to account for any anatomical changes.

Tackling Health Disparities

Despite advances in technology, equitable access to proton therapy is a challenge. A retrospective study by Nogueira et al of all patients in the National Cancer Database treated with proton beam therapy from 2004 to 2018 revealed that Black patients were less likely to be treated with proton beam therapy compared with White patients (OR, 0.67; 95% CI, 0.64-0.71).³

In August 2019, the New York Proton Center (NYPC) opened its doors in East Harlem as a consortium effort between 3 premier academic institutions in New York, New York: Montefiore Health System, Memorial Sloan Kettering Cancer Center, and Mount Sinai Health System. As the only proton beam treatment facility in the state of New York and one of the busiest proton centers in the country, the NYPC has treated nearly 5000 patients. Prior to the opening of the NYPC, individuals had to travel to New Jersey or Massachusetts, to receive this type of treatment, which was cost and time prohibitive.

Now through the NYPC, we are providing more patients with access to top-quality cancer care, particularly historically underrepresented populations, such as our Bronx community. Collaborative partnerships like the NYPC not only benefit people in the communities we serve, but they also make sense from an economic perspective. The expenditures for cancer treatment for a recurrent cancer are close to 6 times what we spend the first time around, and cure rates are more than 8 times lower.

Treatment Implications

Proton therapy was first approved by the FDA for human treatment in 1988. Only 1 center in the United States was providing this cutting-edge treatment before 2001. Since then, 44 other centers have opened across the country, with more in development.⁴

Due to the relative nascency of this technology and lack of robust clinical trials, the American Society for Radiation Oncology published preliminary guidelines for conditions that may necessitate proton beam therapy. Specific conditions listed in these recommendations include reirradiation, pediatric patients, ocular tumors, skull base tumors, malignant or benign primary central nervous system tumors, retroperitoneal sarcomas, advanced stage cancers of the head and neck, pelvic tumors with significant nodal disease, and patients requiring craniospinal irradiation. Additionally, primary cancers of the nasopharynx, nasal cavity, paranasal sinuses, esophagus, mediastinum, mesothelioma, hepatocellular, and intrahepatic biliary cancers are included.⁵

Ultimately, any patient for whom a plan with conventional photon therapy cannot be generated with acceptable radiation doses to surrounding tissues, which is relatively common for those with head and neck cancers, is recommended to receive proton beam therapy. The Department of Radiation Oncology at Montefiore Einstein Comprehensive Cancer Center (MECCC) routinely refers these cases to the NYPC under the care and supervision of their MECCC radiation oncologist. For example, we recently treated a young patient with classic Hodgkin lymphoma that abutted the left atrium of the heart. The tumor partially responded to initial chemotherapy but also required radiation therapy. Because of his young age and the proximity of the tumor to his heart, he was referred to NYPC where we generated a comparison plan using conventional radiation techniques, which clearly demonstrated that protons would reduce the radiation dose to the heart by approximately 50% and to the spinal cord by one-third. Although both photon and proton treatments would have treated this patient’s tumor with equal clinical efficacy, the advantage of proton treatment was that it could potentially reduce late toxicities, such as heart disease, spinal cord injury, and/or pulmonary toxicity.

Most patients we refer to the NYPC do not have metastatic disease, but there are some indications for proton therapy in the metastatic disease setting. For example, a patient with a history of locally advanced rectal cancer who had previously been treated with chemotherapy, radiation, and surgery developed a single, large metastasis in the liver 4 years later. After discussion with our colleagues and the patient, we referred him to the NYPC to deliver radiation therapy that could better spare his normal, uninvolved liver. He is now more than 1 year post treatment, and his tumor is shrinking without evidence of further disease. Another patient who had been diagnosed and treated for her primary cancer developed a solitary metastasis in her right nasal cavity 3 years later, which progressed through systemic therapy. She underwent surgical debulking, as the entire tumor was not able to be removed due to proximity to her brain and eyes, and she was recommended for postoperative radiation.

The Importance of Clinical Trials

Building on the activities taking place at the NYPC, MECCC participates in more than 20 open proton clinical trials, including investigator-initiated trials and national research group trials. We are also leveraging computational modeling to evaluate the benefits of treatment and potential AEs.

In 2019, we used an advanced computational model to evaluate treatment for people who have oropharyngeal cancer and determined that proton therapy improves quality-adjusted life years in these patients, mostly due to reductions in long-term complications such as difficulty or pain with swallowing and dry mouth. The benefit of proton therapy in this model was especially apparent in younger patients with minimal smoking history (no more than 10 years) whose oropharyngeal tumors were driven by human papillomavirus (HPV).⁶

A separate computer model was devised to determine the individual quality-of-life benefit and cost-effectiveness of proton therapy for patients with oropharyngeal cancer. Findings obtained with the model showed that patients whose tumors were HPV mediated and required radiation to both sides of the neck had the most cost-effective benefit with proton therapy when compared with those whose tumors were not HPV mediated or who only required radiation to 1 side of the neck.⁷

The NYPC is also studying a specific use of proton beam therapy, called FLASH proton therapy, which can further decrease the risks to surrounding normal tissue by manipulating the rate of dose delivery to ultrahigh rates more than 100 times that of conventional treatments, potentially decreasing normal tissue injury and/or increasing tumor control. Many studies utilizing FLASH proton therapy use transmission beams that minimize risk of potential uncertainty by placing the Bragg peak outside the body and utilize the entry pathway only for treatment. PBS Bragg peak FLASH utilizes the same technique described above that we use for our patient treatments, but with FLASH dose rates. This technique takes advantage of the lack of exit dose in proton beam therapy but requires a much more rigorous planning process. The NYPC team used novel planning techniques to compare radiation plans for patients undergoing reirradiation to the head and neck where doses delivered to normal tissues must be controlled to avoid serious AEs. The model revealed that PBS Bragg peak FLASH was better able to spare normal tissues from radiation than transmission FLASH or conventional proton beam radiation.⁸

To broaden the applications of this potentially revolutionary treatment, Montefiore-NYPC proton PBS Bragg peak FLASH landmark preclinical studies are being conducted to deliver curative doses of radiation to abdominal tumors while reducing serious toxicities in the gastrointestinal tract under the leadership of Chandan Guha , MBBS, PhD, associate director of innovation/tech transfer at MECCC, director of Einstein Institute of Oncophysics, and vice chair of the Department of Radiation Oncology at Albert Einstein College of Medicine. With the goal of eliminating unnecessary treatment AEs, we are focused on studying how to use proton beam therapy for not only precise cancer care today but to also redefine successful outcomes for anyone affected by cancer.

References

1. Baskar R, Lee KA, Yeo R, Yeoh KW. Cancer and radiation therapy: current advances and future directions. Int J Med Sci. 2012;9(3):193-199. doi:10.7150/ijms.3635

2. Baumann BC, Mitra N, Harton JG, et al. Comparative effectiveness of proton vs photon therapy as part of concurrent chemoradiotherapy for locally advanced cancer. JAMA Oncol. 2020;6(2):237-246. doi:10.1001/jamaoncol.2019.4889

3. Nogueira LM, Sineshaw HM, Jemal A, Pollack CE, Efstathiou JA, Yabroff KR. Association of race with receipt of proton beam therapy for patients with newly diagnosed cancer in the US, 2004-2018. JAMA Netw Open. 2022;5(4):e228970. doi:10.1001/jamanetworkopen.2022.8970

4. Hartsell WF, Simone CB II, Godes D, et al. Temporal evolution and diagnostic diversification of patients receiving proton therapy in the United States: a ten-year trend analysis (2012 to 2021) from the National Association for Proton Therapy. Int J Radiat Oncol Biol Phys. Published online December 30, 2023. doi:10.1016/j.ijrobp.2023.12.041

5. American Society for Radiation Oncology. Proton beam therapy (PBT). In: ASTRO Model Policies. American Medical Association;2022:1-21.

6. Brodin NP, Kabarriti R, Pankuch M, et al. A quantitative clinical decision-support strategy identifying which patients with oropharyngeal head and neck cancer may benefit the most from proton radiation therapy. Int J Radiat Oncol Biol Phys. 2019;104(3):540-552. doi:10.1016/j.ijrobp.2018.11.039

7. Brodin NP, Kabarriti R, Schechter CB, et al. Individualized quality of life benefit and cost-effectiveness estimates of proton therapy for patients with oropharyngeal cancer. Radiat Oncol. 2021;16(1):19. doi:10.1186/s13014-021-01745-1

8. Pennock M, Wei S, Cheng C, et al. Proton Bragg peak FLASH enables organ sparing and ultra-high dose-rate delivery: proof of principle in recurrent head and neck cancer. Cancers (Basel). 2023;15(15):3828. doi:10.3390/cancers15153828