Particle Therapy in Non-Small Cell Lung Cancer

Zhongxing Liao; Charles B. Simone II


Transl Lung Cancer Res. 2018;7(2) 

In This Article

Abstract and Introduction


The finite range of proton beams in tissues offers unique dosimetric advantages that theoretically allow the dose to the target to be escalated while minimizing exposure of surrounding tissues and thereby minimizing radiation-induced toxicity. These theoretical advantages have led to widespread adoption of proton therapy around the world for a wide variety of tumors at different anatomic sites. Many treatment-planning comparisons have shown that proton therapy has substantial dosimetric advantages over conventional photon (X-ray) radiation therapy. However, given the typically significant difference in cost between proton therapy versus conventional photon therapy, strong evidence of proton therapy's clinical benefits in terms of toxicity and survival is warranted. Some findings from retrospective studies, single-arm prospective studies, and a very few randomized clinical trials comparing these modalities are beginning to emerge. In this review, we examine the available data on proton therapy for (non-small cell lung cancer NSCLC). We begin by discussing the unique challenges involved in treating moving targets with significant tissue heterogeneity and the technologic efforts underway to overcome these challenges. We then discuss the rationale for minimizing normal tissue toxicity, particularly pulmonary, cardiac, and hematologic toxicity, within the context of previously unsuccessful attempts at dose escalation for lung cancer. Finally, we explore strategies for accelerating the development of trials aimed at measuring meaningful clinical endpoints and for maximizing the value of proton therapy by personalizing its use for individual patients.


Thoracic malignancies such as non-small cell lung cancer (NSCLC) and esophageal cancer are complex and challenging to treat. They are often diagnosed at locally advanced stages and are not amenable to surgical resection. In such cases, radiation therapy, given with either concurrent or sequential chemotherapy, is often the treatment of choice. Unfortunately, most patients with locally advanced lung or esophageal cancer die of the disease; the median survival times even with treatment are only 16–28 months, and local recurrence accounts for 40–50% of failures. Although radiation dose escalation has been tested as a strategy to improve tumor control and patient survival, recent phase III randomized studies investigating dose intensification of thoracic irradiation showed that higher radiation doses conferred no benefit to patients with locally advanced NSCLC or esophageal cancer.[1,2] No differences were found in local control between the standard-dose and high-dose arms, and the higher-dose radiation had a detrimental effect on patient survival.

The fact that the cancer-related death rates for the standard-dose and high-dose groups in both studies were similar suggests that the higher death rate in the high-dose group was from non-cancer-related reasons, specifically treatment-related toxicity. The results of the Radiation Therapy Oncology Group (RTOG) 0617 trial showed that the radiation dose to the heart was an independent predictor of survival, confirming that exposing larger portions of the heart to higher thoracic radiation doses contributed to the higher death rates in the high-dose arm.[1] Several current reports have also linked therapy-induced lymphopenia during chemoradiation with poor survival for many types of tumors, including lung cancer, esophageal cancer, head and neck cancer, gastrointestinal cancer, and cervical cancer.[3–6]

The relevant organs at risk in the treatment of thoracic malignancies are the esophagus, lungs, heart, and bone marrow; other important structures or tissues include the brachial plexus, skin, spinal cord, and chest wall. In principle, the most effective strategy to reduce toxicity would be to reduce unnecessary irradiation of organs at risk by using advanced technologies, one example of which is proton beam therapy. Proton therapy offers substantial potential advantages over conventional photon therapy because of the unique depth-dose characteristics of protons, which can be exploited to reduce irradiation of normal tissues proximal and distal to the target volume so as to allow escalation of tumor doses while simultaneously sparing greater amounts of normal tissues; the expectation is that these effects would improve local tumor control and survival as well as reducing treatment-related toxicity and improving quality of life.

However, particle therapy (including proton therapy) is significantly more expensive than even the best available photon technology to date, and evidence demonstrating clinical benefit after proton therapy is increasingly demanded to justify the higher financial burden on the healthcare delivery system. Despite the high capital costs associated with charged particle therapy and the lack of level I evidence of clinical benefit from direct comparisons, the increasing demand for improved technology in cancer treatment, particularly proton therapy, is evidenced by the numbers of facilities being built worldwide. Currently, 76 particle therapy centers are in operation, 25 of which are proton centers in the United States, and many more are being planned (Particle Therapy Cooperative Group, By 2015, more than 154,000 patients worldwide had been treated with charged particle therapy ( Parallel with this increase in the numbers of facilities and the clinical use of particle therapy is the accumulation of knowledge about the physical uncertainties of particle therapy and methods of counteracting these uncertainties to ensure accurate planning and precise delivery of particle therapy.

In this review, we summarize the rationale for and challenges of using charged particles to treat thoracic cancers; we review the clinical experience to date on the use of proton therapy for locally advanced lung cancer and esophageal cancer; and we discuss future directions for use of proton therapy.