Clinical Controversies: Proton Therapy for Thoracic Tumors Dirk De Ruysscher, MD, PhD,* and Joe Y. Chang, MD, PhD Photon and proton therapy techniques have both improved dramatically over the past decade. As a result, high radiation doses can be delivered while sparing organs at risk. However, in many series, older proton techniques have been compared with contemporary photon techniques, hampering a fair comparison. By virtue of their physical properties and because of modern 4-dimensional and imaging evolution, protons show theoretical superiority compared with photons. Current nonrandomized studies suggest that protons may indeed spare organs at risk much better that the best available photon techniques, leading to fewer side effects and the possibility for safe dose escalation. This is the basis for ongoing randomized trials. Semin Radiat Oncol 23:115-119 2013 Elsevier Inc. All rights reserved. *Radiation Oncology, University Hospitals Leuven/KU Leuven, Leuven, Belgium. Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX. The authors declare no conflicts of interest. Address reprint requests to Dirk De Ruysscher, MD, PhD, Radiation Oncology, University Hospitals Leuven/KU Leuven, Leuven, Belgium. E-mail: dirk.deruysscher@uzleuven.be Lung cancer is the most important cause of death in most developed countries. 1 Most patients are 65 years of age and bear multiple comorbidities. 2 Moreover, as most lung cancers are diagnosed at an advanced stage, they have a high incidence of local tumor failure, whether treated with surgery, radiotherapy (RT), or combined modalities. 3,4 Distant metastases remain the most common cause of death. The combination of large tumor volumes in the chest, often invading critical vital organs such as the lungs, the large blood vessels, and the esophagus in patients with impaired organ function, poses a formidable challenge. In the past decades, the addition of chemotherapy to radical RT with or without surgery has improved the long-term survival of patients with non small-cell lung cancer (NSCLC). However, in stage III locally advanced NSCLC or small-cell lung cancer, the 5-year survival rates still remain at 20%-25%. 3,4 A significant proportion of patients, especially the old and frail, are not suitable for aggressive treatments because of assumed toxicity. 2 Although the combination of radiotherapy with targeted agents bears a lot of potential for the future, they are at present of no proven value for patients with stage III NSCLC. 5 Because of the curative potential and the noninvasive character of RT in lung cancer patients, higher radiation doses may lead to improvement of local control and overall survival, 3,6 a concept that has fueled research in RT with photons and protons. Photon Therapy Presently, photon therapy is the most used beam quality and is being used with increasing sophistication and with accompanying imaging. In the past decade, major advances have been made in photon calculation algorithms, treatment delivery, and quality assurance. 7 After the era of 3-dimensional conformal RT (3D-CRT), intensity-modulated RT (IMRT) and 4D treatment planning and execution have been introduced in standard practice together with the routine application of kilovolt cone-beam computed tomography scans, making image- and dose-guided RT possible. 7 These technical evolutions have made it possible to deliver standard doses of 60-70 Gy to the target volumes while sparing normal tissues. Individualized, isotoxic schedules allow the delivery of high biological doses with or without chemotherapy. 8-10 For early disease, stereotactic techniques such as stereotactic body RT or stereotactic ablative RT (SBRT or SABR) have led to local tumor control rates of 90% in early-stage NSCLC, with few side effects. 11 As is the case for most advances in engineering, computers, and software, the new techniques were introduced with a strong technical emphasis and basis. The suggestion was made that higher radiation doses would result in better local tumor control, 12 and that reduction of the dose to the organs at risk (OARs) would lessen side effects. 13 However, randomized trials demonstrating improvement in survival and reduction in side effects are lacking. It has been argued that 1053-4296/13/$-see front matter 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semradonc..11.010 115
116 D. De Ruysscher and J.Y. Chang phase III trials are not necessary when differences between treatments are very large (eg, odds ratios of 10). 14 There remains a large range of uncertainty in the relation between dose and toxicity and the real value of radiation dose escalation in photon treatment of lung cancer. One example is the recent debate about the result of RadioTherapy Oncology Group (RTOG) 0617, which randomized patients with stage III lung cancer to standard or high-dose radiation therapy, with concurrent chemotherapy where the higher dose did not improve outcomes. 15 The benchmark measure for local efficacy of RT in NSCLC treated with photon therapy is freedom from local tumor progression, with rates of 90% for stage I NSCLC treated with SABR and 70% for stage III NSCLC at 2 years. Five-year survival rates in stage I NSCLC patients depend on the patient selection. 16,17 Because many patients were inoperable because of medical comorbidities, long-term survival remains low because patients typically died of comorbidities even if their early-stage lung cancer had been controlled by SABR. However, in series that included patients considered operable, a 5-year survival rate of 60%-70%, comparable with surgery, was reported. 16,17 Larger T2 and stage III-N2, stage III-N3, or T4 tumors have median survival rates of 2 years and 5-year survival rates of 20%-25% when treated with concurrent chemoradiotherapy with or without surgery. 3,7,18,19 Although small-cell lung cancer is considered very sensitive to chemotherapy and RT, local tumor progression is observed in at least 70% of patients. 4 Concurrent accelerated chemoradiotherapy resulted in median survival rates of 2 years and 5-year survival rates of 25%. 4 The rate of pulmonary side effects is more difficult to compare between series. Although standardized toxicity scoring systems such as the European Organization for Research and Treatment of Cancer/RTOG and the Common Terminology Criteria for Adverse Events have existed for many years, versions have changed significantly over time. Up to 40% of pulmonary symptoms may also occur in the absence of RT because of preexisting lung disease or infections. 20 Because of the temporary and fluctuating nature of pneumonitis, underreporting of pulmonary symptoms probably occurred in many published series. 20 Severe dyspnea classified as radiation pneumonitis is reported in 15%-30% of patients treated with high-dose RT for stage III lung cancer. Radiation esophagitis is another important and frequently occurring side effect of high-dose RT for lung cancer. 21 Acute grade 3-4 esophagitis is observed in approximately 5% of patients with stage III lung cancer treated with sequential chemoradiotherapy and in 20%- 30% of cases treated with concurrent chemotherapy and RT. The parameters associated with acute esophagitis are mean esophageal dose, maximal dose, several V x thresholds, and neutropenia. 22,23 Late esophageal damage is now increasingly reported in patients surviving longer and thus at risk for developing late radiation damage, with an actuarial incidence of 5%-10%. 22 Other side effects may include stenosis of the main bronchi, rib fractures, and increased hematological toxicity when RT is given together with chemotherapy. 22 As for all side effects, a relation is observed with dose volume radiation parameters; it is a reasonable assumption that a reduction of RT exposure should result in lower incidence of severe side effects. Proton Therapy Because of the complex anatomical relation between target volumes and OARs, proton therapy is a logical treatment approach to investigate in lung cancer 24,25 (Fig. 1). From a purely physics focused point of view, the dose distribution of protons is in most cases superior to that of photons, although the lateral dose fall-off is worse for protons at higher energies than for photons (refer to Engelsman, this issue) In contrast, a proton beam does not suffer from the lateral penumbra widening that a photon beam experiences in the lung, a great advantage for proton therapy. The technical challenges of adequately delivering protons to moving targets surrounded by tissues with large inhomogeneities are discussed elsewhere in this issue, but remain significant (refer to Engelsman et al, this issue) Specific challenges include dose algorithm uncertainties in inhomogeneous tissues, amplification of range uncertainties in low- Figure 1 Passive-scattering proton therapy spares more heart, esophagus, spinal cord, and contralateral lung, compared with 3-dimensional conformal radiotherapy and intensity-modulated radiotherapy in stage III non small-cell lung cancer. (Color version of figure is available online.)
Proton therapy for thoracic tumors 117 density lung tissue (in 0.25-density lung tissue, the uncertainties are amplified by 1/0.25 4, so a 5- mm range uncertainty in soft tissue becomes a 2-cm uncertainty in lung tissue), and range degradation effects. Although both passive-scattering and pencil-scanning technologies take advantage of the Bragg peak and hence reduce the radiation dose to the OARs, the conformality achieved with pencil-scanning methods like intensitymodulated proton therapy (IMPT) is in most cases superior to that of passive-scattering proton therapy (PSPT). However, the greater precision achieved with IMPT implies that there is less room for errors, which can be a disadvantage for mobile targets. IMPT is therefore not implemented for intrathoracic tumors in most facilities, although it may be used for a subset of tumors showing minimal motion ( 5 mm). Treatment planning studies consistently demonstrate that proton therapy allows for the delivery of higher tumor doses than photons while sparing normal tissues. Chang et al 26 generated 3D-CRT, IMRT, and PSPT plans in 25 patients with stage I-III NSCLC. In all cases, the radiation dose to the lungs, the spinal cord, the heart, and the esophagus and the integral dose was the lowest with proton beams. For a mean tumor dose of 63 Gy with photons, the mean V20 (lung) was 34.8%, compared with a mean proton dose of 74 cobalt Gray equivalent (CGE) to the tumor and a mean V20 (lung) of 31.6%. Zhang et al 27 conducted a virtual clinical study in patients with stage III NSCLC who could not receive 63 Gy with IMRT. While keeping the normal-tissue constraints the same, the tumor dose could be escalated from 63 Gy with photons to a mean maximum of 84.4 CGE (range, 79.4-88.4 CGE) with protons. A planning study of 25 consecutive NSCLC patients, stage IA-IIIB, performed by the Radiation Oncology Collaborative Comparison consortium demonstrated that PSPT resulted in the lowest dose to the OARs, while keeping the dose to the target at 70 Gy. 25 The integral dose was higher for 3D-CRT (59%) and IMRT (43%) than for PSPT. The mean lung dose was 18.9 Gy for 3D-CRT, 16.4 Gy for IMRT, and 13.5 Gy for PSPT. For 10 patients, dose escalation to 87 Gy was possible for all 3 modalities. In stage I NSCLC, protons also achieved lower doses to OARs than SBRT. 28-31 This may be of particular interest in centrally located tumors where currently used hypofractionated schedules such as 3 fractions of 18 Gy may lead to severe chronic toxicity such as bleeding, perforation, and stenosis. 32,33 In a prospective phase I/II study in patients with stage IA, IB, and selected stage II (T3N0M0) NSCLC treated with protons to a dose of 87.5 CGE delivered in 2.5-CGE fractions (biological effective dose [BED] 109.4 Gy, comparable with SABR BED dose using 48-50 Gy in 4 fractions regimen), no patient experienced grade 4 or 5 toxicity. 34 After a median follow-up time of 16 months, local control was achieved in 89% of the patients at 2 years. In another prospective study, similar findings were reported. 35 Although there are many publications on NSCLC treatment with protons, only a few have included at least 20 patients and have given results with a minimal follow-up of 2 years. 36 One prospective study (n 37) and 3 retrospective case studies (n 143) have been published. The majority only included early-stage patients. Although most of these studies were conducted in the era without positron emission tomography staging and modern imageguided techniques, the local tumor control, survival, and toxicity are comparable with those of current state-of-the art photon techniques. To make series comparable, current staging, target definition, and image guidance applied for IMRT should be compared with the same patient selection, including matching for prognostic factors and preparation for RT with protons. In a phase II trial, 44 patients with stage III NSCLC were treated with 74 CGE, with concurrent weekly carboplatin and paclitaxel and with current state-of-the-art imaging and protons RT repeated during the treatment process to determine the need for adaptive replanning. 37 The median overall survival time was 29 months, and no patient experienced grade 4 or 5 proton-related adverse events. The most common nonhematological grade 3 toxicities were dermatitis, esophagitis, and pneumonitis. Nine patients (21%) experienced local disease recurrence. These results are encouraging, promising local control, higher survival, and lower toxicities compared with similar studies results using photon-based concurrent chemoradiotherapy at 60 Gy or the same radiation dose of 74 Gy (RTOG 0617). This study, together with the superior dose distributions of protons and other clinical experiences, form the basis of an ongoing randomized trial conducted at MD Anderson Cancer Center. Image-guided adaptive conformal photon therapy is compared with image-guided PSPT for locally advanced NSCLC (NCT00915005), with 74 Gy of RT and concurrent chemotherapy in both arms. The primary end point of this study is time to grade 3 radiation pneumonitis/esophagitis or local control. The current concern regarding the apparent lack of benefit of dose escalation in locally advanced NSCLC points to a potential value of protons. In the phase III 2 2-factorial-design trial of the RTOG 0617, 15 patients with stage III NSCLC were treated with carboplatin paclitaxel chemotherapy and once-daily 2 Gy/fraction to a total dose of either 60 or 74 Gy, with or without cetuximab. At a planned interim analysis at 11 months median follow-up, the high-dose arm had worse survival (20.7 vs 21.7 months, P 0.02) and was closed. Although one explanation is that a higher dose of radiotherapy did not lead to more cell death than a lower dose, perhaps owing to a prolonged treatment time and therefore lower BED, this is contradicted by biological evidence and is not supported by SBRT data in NSCLC. Another possible explanation is that 74 Gy was too toxic when given with the photon techniques. If this were correct, proton therapy may offer an advantage, potentially allowing the safe delivery of higher doses within a short overall treatment time by allowing hypofractionation.
118 D. De Ruysscher and J.Y. Chang Conclusions Although systematic review of published proton results in lung cancer does not show clear superiority over photon RT, 36 more recent nonrandomized single-institutional studies suggest promise in terms of local control, survival, and toxicities. Proton therapy is a new RT modality, and further improvement is needed to optimize the treatment, particularly IMPT, motion management, volumetric image guidance, and adaptive RT. As dose distributions improve, it is reasonable to assume that when comparing the modern photon techniques with new and emerging proton techniques, protons may show a true benefit. This is being tested in prospective clinical studies, including ongoing randomized trials, with the aim of investigating the efficacy and safety of proton therapy and potentially its superiority. Such studies should be actively supported. References 1. Siegel R, Naishadham D, Jemal A: Cancer statistics,. CA Cancer J Clin 62:10-29, 2. 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