What Happens When Proton Meets Randomization: Is There a Future for Proton Therapy?

The use of proton therapy has been a topic of debate for years. In the article that accompanies this editorial, Liao and colleagues report the first randomized study to assess the value of proton therapy compared with photon intensity-modulated radiotherapy (IMRT) in non–small-cell lung cancer (NSCLC). Completion of this study is not trivial because the evaluation of the benefit of a new technology rarely has been done during the century-long history of radiation oncology practice. A trial on the effectiveness of proton technology is particularly timely with the growing number of proton facilities in the United States and worldwide and its implication for value-based medicine. Is a randomized trial needed for an advanced radiation technology with a clear benefit in terms of radiation dosimetry, such as proton therapy? A consensus has not been reached in the field with regard to this question. Although some ask for clinical outcome data, somemay believe that a randomized trial is not needed because the dose to the tumor target can be increased, which means that higher tumor control probabilities and/or the dose to normal, nontumor-containing volumes can be decreased, thereby reducing the risks of normal tissue complications. Somemay even argue that conducting a trial to test the significance of such a treatment is unethical, like performing a randomized study to test the value of parachutes, because it will put patients at risk for unneeded radiation complications. Such beliefs have been reflected in the history of radiotherapy technology advancement. From the first uses of x-rays and radium for cancer treatment in the early 1900s, to kilovoltage (superficial) x-ray machines and the era of cobalt-60 and megavoltage two-dimensional treatment, to Linacbased three-dimensional conformal technology and the current widespread use of IMRT, technologies have been developed and implemented routinely in the clinic without randomized trials. Similar scientific and ethical arguments were made erroneously for surgical and medical oncology disciplines, such as for breast cancer, until randomized trials subsequently showed that radical mastectomy was not better than breast-conserving therapy and that high-dose chemotherapy with stem-cell rescue was not beneficial in metastatic breast cancer. Protons have been recognized for their physical dosimetric advantage in phantom andmodel studies as a result of the unique dose distribution described by the Bragg peak (sparing normal tissue distal to the target) and branded as “the sharpest scalpel for cancer treatment” shown in one advertisement. The concept of using protons for cancer therapy was first developed by Robert Wilson, PhD, early in 1946; the first patient was treated in 1954 in the Berkeley Radiation Laboratory; and the first fractionated treatment was performed in 1974. However, implementation in clinical practice has been slow mainly because of the high cost of building the machine and the corresponding facility (a multiroom proton center costs approximately 40 times more than a conventional megavoltage photon radiation or IMRT facility) as well as challenges in developing and implementing reliable dose-computation approaches. In addition, proton treatment and machine maintenance are much more expensive than photon therapy. Although 9,116 patients were treated with protons over 41 years at a joint program of Harvard Cyclotron Laboratory and the Massachusetts General Hospital before the cyclotron was shut down in 2002, hospital-based proton machines were not built until 1989 in the United Kingdom and 1990 in Loma Linda, California. Initially, protons were used mainly on fixed tumors, such as those in the base of the skull, and in pediatric patients. Could lung cancer, which presents a moving target with uncertainty of proton attenuation in low-density lung tissues, be treated effectively and cost-effectively? Comparative clinical outcome data are needed for patients and their families to choose a cancer treatment modality that is not readily available, for physicians tomake treatment recommendations, for investors/industry to determine where to spend resources, for insurance companies and government to make reimbursement policies, and for researchers to know how and where to focus their efforts. Thus, a randomized trial is needed to generate unbiased evidence for this extremely costly technology. The randomized trial reported by Liao and colleagues aimed to determine whether patients treated with proton therapy would have a lower risk of grade $ 3 radiation pneumonitis (RP) in locally advanced NSCLC. The study hypothesized a 10% reduction in grade $ 3 RP for the passive scattering proton therapy (PSPT) arm compared with the photon IMRTarmwithout compromise of local tumor control. No attempt was made in this study to improve tumor control; the rationale was only to decrease toxicity. In contrast to the largest retrospective study of patients from the National Cancer Database, this prospective randomized study failed to prove superiority of proton therapy. Instead, the PSPT arm had 10.5% grade $ 3 RP compared with only 6.5% in the IMRT arm, despite a significant reduction in low-dose volume in the dosimetric histograms for the PSPT arm. Significant dosimetric sparing of the heart and esophagus in the proton armwas found. The primary study outcomes of grade $ 3 RP and local failure were comparable with