Advantages of Proton Therapy in Non-Small Cell Lung Cancers

Abstract

The advantage of proton therapy over conventional radiotherapy is enormous, with many clinical advantages. In this review, we summarized the important literature in the advantages of Proton Therapy in Non-small Cell Lung Cancers.

Introduction

Proton therapy for cancer was first proposed by Robert R. Wilson, a physicist in 1946.¹ In the following years, rapid developments took place that recognized the rationale of proton therapy and established it as a form of therapeutic option in certain forms of cancer.² Currently, proton therapy is being considered as a major tool in the armamentarium for the oncoradiologist. The advantage of proton therapy over conventional X-rays is enormous, with undoubted clinical advantages.³ Although adequate amounts of radiation through X-rays can kill cancer cells, adjacent healthy tissues also get damaged because of the spreading pattern of radiation. On the contrary, proton radiation has the ability to specifically invade only the genetic material of cells to which they are directed. This leads to cell death, when cancer cells are targeted.⁴ This process is made possible by the deposition of energy at the Bragg peak near the end of the range of the proton beam, allowing for escalation of the target dose which is the ideal dose profile for the tumor, and negligible amount of energy beyond the peak. This is because for a given dose to the target volume, protons deposit substantially less dose outside the target volume.^5
–7 So if the Bragg peak is placed depending on the depth of the tumor⁸ and even when high doses are given, the precision for maximum doses at the peak allows for maximal energy to the tumor with minimal damage to adjacent healthy tissues which fall beyond the peak. So as to cover a tumor volume, multiple Bragg peaks (spread out Bragg peaks, SOBP) produce a uniform dose distribution that is able to cover the entire target volume but avoiding dose delivery to distal structures.^5,9,10

More than 53,000 patients with intracranial pediatric tumors, ocular tumors, chordomas, chondrosarcomas, hepatocellular, and prostate cancers have been treated at various proton therapy centers worldwide, with proton therapy.¹¹ The clinical outcomes of proton beam therapy in terms of local control confirm its efficacy in these cancers.^6,11,12 The advantage is that the radiation oncologists can maintain set dose constraints and deliver an escalated radiation dose to the target volume, and maintain the dose so that radiation exposure to normal tissue remains low enough so as not to produce any harmful effect.⁵ Proton facilities aim to deliver therapeutic doses of proton beams to tumor sites anywhere in the human body. Proton therapy can be delivered utilizing either passive scattering, uniform scanning, or spot scanning/pencil-beam scanning. Optimal treatment remained a concern with early techniques. To optimize treatment, the relative biological effectiveness (RBE) generic value of 1.1 has been suggested to be reasonable, in both in vivo and in vitro studies. Proton therapy uses a generic RBE, which is applied to all treatments independent of dose/fraction, position in the SOBP.¹³ The product of the absorbed dose and RBE is called the RBE-weighted absorbed dose with the special unit of gray (Gy), although proton therapy centers often use the annotation of CGE, GyE, or Gy(E) to indicate the RBE-weighted absorbed dose.¹¹ Both these units will be used in this article.

Intensity Modulated Proton Therapy

Intensity modulated proton therapy (IMPT), as the name suggests, has the ability to offer an intense stream of protons in a three-dimensional field throughout the clinical target volume with improved dose distribution compared to conventional proton therapy.¹⁴ This process further delivers the exact dose to the target tumor, further reducing errors of the conventional proton therapy. However, IMPT is sensitive to setup errors, and treatment planning becomes vital to minimize these errors. Recent research points out that IMPT must be robustly optimized to derive the best possible outcome on clinical target volume, and negate errors or uncertainties for the treatment planner. Researchers have now found a way by getting around the uncertainties by a worst-case robust optimization method where delivery of the lowest doses within the clinical target volume and the highest dose outside, can spare normal tissues while being effective against the tumour.¹⁵ Others suggest a multicriteria optimization framework for robust planning that takes less than 5 minutes setup on a standard computer, making it very easy for the treatment planner.¹⁶

The present article outlines clinical evidence of the potential advantages with beams of protons delivering radiotherapy in non-small-cell lung cancers (NSCLCs).

Evolution of Radiotherapy in Lung Cancer

Lung cancers are responsible for a high incidence, globally, of mortality and morbidity worldwide. Nearly 80% of all lung cancers are NSCLCs, for which different treatment modalities are now available according to the individual staging of the tumour.¹⁷ Medically inoperable NSCLCs present a significant challenge. When surgery is not an option, chemotherapy or a combined chemoradiation is the treatment of choice to increase chances of long-term survival. Chemotherapy might control distant metastasis but local control failure contributes to mortality of such patients with stage III unresectable NSCLC.¹⁸ It was subsequently understood that local control in NSCLC could be attained by maintaining higher doses of radiation. The concern was to save adjacent organs and tissues surrounding the tumor. Early results indicated that the dose to achieve significant probability of tumor control may be large (about 84 Gy) for longer (>30 months) local progression-free survival from a three-dimensional dose distribution of the tumor.¹⁹ A two-phase dose approach was tried where phase 1 would deliver 44 Gy and target a wide area, including nodes that might get affected, and phase 2 to the tumor itself keeping the total dose under 60 Gy.²⁰ Despite using computer assisted treatment planning to vary angles, or with additional use of three-dimensional conformal radiotherapy, ideal dosage and distribution could not be discharged.

Proton Therapy for Local Control and Survival

The fact that NSCLCs are moderately radiosensitive tumors, a higher dose escalation has been successfully achieved with proton therapy among patients with NSCLC.²¹ Although proton therapy has been used clinically for the past few decades, most published data have been single institution series. Early researchers pointed that conformal proton beam radiotherapy (small volume) for early stage inoperable NSCLC was safe and comparable to existing literature from treatment with photon radiotherapy.²² When a total tumor dose between 51 and 73.8 CGE was given, depending on individual patients cardiopulmonary status, the actuarial disease-free survival at 2 years for stage I patients was 86%, with local disease control of 87%. A study from Japan later evaluated 51 patients with various stages of NSCLC: 28 patients in Stage I, 9 in Stage II, 8 in Stage III, 1 in Stage IV, and 5 with recurrent disease, of which 33 patients had squamous cell carcinoma, 17 had adenocarcinoma, and 1 had large-cell carcinoma.²³ The median fraction and total doses given were 3.0 Gy (range 2.0–6.0 Gy), and 76.0 Gy (range 49.0–93.0 Gy), respectively. The overall survival (OS) was 29% for all patients. A significant difference in OS was noted among Stages IA and IB patients (70% for 9 Stage IA patients and 16% for 19 Stage IB patients, respectively (Stages IA vs. 1B: p<0.05). The 5-year in-field local control rate was much higher in patients with Stage IA when compared with those with Stage IB (89% vs. 39%, respectively) indicating that early stages of NSCLC could benefit from proton therapy. Although most patients suffered from acute lung toxicity as a result of proton therapy, late toxicity was unremarkable, suggesting that proton therapy could be a safe therapeutic technique in the treatment of early stages of NSCLC. A computed tomography (CT) imaging analysis further established that limited volume proton radiation produced a reduced incidence of lung injury severity when compared to CT images of patients who underwent a combination of photon and proton radiotherapy.²⁴ Results from a Japanese retrospective analysis conducted from November 2001 to July 2008, in 55 patients, has further emphasized the role of proton beam therapy for patients with medically inoperable Stage I NSCLC.²⁵ Yet another recent clinical evaluation, in which 52 patients with Stage I NSCLC were subjected to high-dose proton therapy protocol involving 80 GyE in 20 fractions, and 60 GyE in 10 fractions in a median follow-up period for living patients, was 35.5 months also established proton therapy safety and efficacy.²⁶ Notably, in this study, the local control rates for squamous cell carcinomas obtained by proton therapy were worse than those for adenocarcinoma suggesting that adenocarcinomas maybe better responsive to proton therapy. Larger tumors >5 cm in diameter that are not indicated for x-ray stereotactic radiotherapy, can be treated with proton therapy with possibly good local control. This is of value especially that even in patients with tumors >5 cm in diameter, no grade ≥3 toxicities developed, indicating the safety of proton therapy.

High-Dose Hypofractionated Proton Beam Radiotherapy

Hypofractionated technique utilizes computerized treatment planning and sophisticated beam delivery systems to deliver multiple noncoplanar beams to focal lung tissues. This allows for a highly conformal high-dose region to be treated as opposed to low doses reaching larger areas of lung tissues. Safety was further established in a prospective phase 2 clinical trial involving 68 subjects with clinical stage I NSCLC high-dose hypofractionated proton beam radiotherapy, with a follow-up median of 30 months.²⁷ In the multibeam treatment plan, used in this study, 51CGE in 10 fractions over 2 weeks to the initial 22 patients was given; the subsequent 46 patients received 60 CGE in 10 fractions over 2 weeks. None of the patients exhibited symptomatic radiation pneumonitis or late esophageal or cardiac toxicity. A significant improvement in local tumor control [T1(87%) vs. T2 tumors (49%)] was observed while the 3-year local control and disease-specific survival rates were 74% and 72%, respectively, indicating a positive trend towards improved survival. Factors, such as higher performance status (p=0.02), female gender (p=0.006), and smaller tumor sizes (p=0.012) were responsible for significantly improved survival. Preliminary result of a phase I/II Japanese clinical study also concluded with similar results indicating that hypofractionated high-dose proton beam therapy was a safe, feasible, and effective option for Stage I NSCLC.²⁸ This study included 21 patients, and the 2-year OS was 74%; cause-specific survival rate was 86%; local progression-free rate 95%; and, disease-free rate of 79%.

These potential advantages of reducing adverse events have also been noted in Stage III NSCLC.²⁹ This is especially significant since nearly half of patients with NSCLC present with locally advanced stage III and IV disease with a maximum OS of 2 years.³⁰ Despite dose escalation, proton treatment appears to reduce dose to normal tissues significantly, as evidenced by dose-volume histograms as compared to three-dimensional conformal or intensity modulated radiotherapy (IMRT).²¹ Although the percentage of dose per fraction is greater than 3 Gy and is significantly higher than the dose per fraction used in photon radiotherapy, there is an insignificant risk of secondary cancers in various organs, including the spinal cord, esophagus, bladder, and thyroid.³¹

However, a more advanced method of providing photon therapy was needed to treat Stage III tumors.

IMPT in NSCLC

The advantage of IMPT, defined as the simultaneous optimization of all Bragg peaks from all incident beams, is that this method increases dose conformality even further. This was thought to be ideal for advanced stages of NSCLC, and this fact was made evident by dose volume histograms of IMPT compared to those of IMRT and passive scattering proton therapy (PSPT) for the treatment of stage IIIB NSCLC in a virtual study.³² IMPT showed distinct advantage over IMRT and PSPT. IMPT was able to spare more lung, heart, spinal cord, and esophagus, even with dose escalation from 63 to 83.5 Gy, with a mean maximum-tolerated dose (MTD) of 74 Gy. Lung and esophageal toxicity can be morbid and lead to death. Dose escalation to 74 Gy may improve local control and possibly improve survival rates, but compromise tissues around IIIB tumors. Physical characteristics of proton beams and unique treatment planning advantage of IMPT over IMRT and PSPT may enable the use of ablative doses (>74 Gy) for stage IIIB NSCLC. Another factor to consider in treatment planning with IMPT is organ and tumor motion which in most cases (90%) is <1 cm, and for which four-dimensional (4-D) image-based motion management strategies have been evolved.³³ In Stage IIIB NSCLC, the tumor is more extensive and usually adherent to a mediastinal structure, and has much less tumor motion compared with Stage I disease. Dosimetric studies of proton therapy in the treatment of stage III NSCLC have already demonstrated improvement in dose conformality with lower doses to the surrounding tissues and low rates of toxicity in patients with stage III NSCLC, treated with proton therapy. This has been observed when compared with three-dimensional conformal radiotherapy, and IMRT.^21,34

Future Directions

The role of proton therapy for treatment of more advanced NSCLC that may also require concurrent chemotherapy is evolving. New technologies seem to emerge rapidly in radiation oncology, as in many other fields of modern medicine. Nevertheless, many randomized clinical trials, meta-analyses and systematic reviews are needed to assess and compare existing and upcoming technologies. It is important to keep costs for such facilities affordable so that clinical utilization can be made available to patients on a global scale for one of the most common cancers.

In conclusion, proton therapy, currently, appears to show great promise in the treatment of lung cancers. Protons, display unique dosimetric properties, may offer an opportunity to safely achieve both strategies of dose escalation to the primary tumor and adequate coverage of high-risk regional nodes. The benefits include escalating radiotherapy doses resulting in improved cure rates, with the additional advantage of causing minimal treatment related toxicity, sparing of normal, healthy tissues, and reduced incidence of radiation-induced secondary tumors. Furthermore, proton beam therapy has shown improvements in most dosimetric parameters for lung cancer patients.

Footnotes

Disclosure Statement

No financial conflicts of interest exist.

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