Prospective Study of Proton-Beam Radiation Therapy for Limited-Stage Small Cell Lung Cancer

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1 Original Article Prospective Study of Proton-Beam Radiation Therapy for Limited-Stage Small Cell Lung Cancer Jean-Claude M. Rwigema, MD 1,2 ; Vivek Verma, MD 3 ; Liyong Lin, PhD 1 ; Abigail T. Berman, MD, MSCE 1 ; William P. Levin, MD 1 ; Tracey L. Evans, MD 4 ; Charu Aggarwal, MD 4 ; Ramesh Rengan, MD, PhD 5 ; Corey Langer, MD 4 ; Roger B. Cohen, MD 4 ; and Charles B. Simone II, MD 6 BACKGROUND: Existing data supporting the use of proton-beam therapy (PBT) for limited-stage small cell lung cancer (LS- SCLC) are limited to a single 6-patient case series. This is the first prospective study to evaluate clinical outcomes and toxicities of PBT for LS-SCLC. METHODS: This study prospectively analyzed patients with primary, nonrecurrent LS-SCLC definitively treated with PBT and concurrent chemotherapy from 2011 to Clinical backup intensity-modulated radiotherapy (IMRT) plans were generated for each patient and were compared with PBT plans. Outcome measures included local control (LC), recurrencefree survival (RFS), and overall survival (OS) rates and toxicities. RESULTS: Thirty consecutive patients were enrolled and evaluated. The median dose was 63.9 cobalt gray equivalents (range, cobalt gray equivalents) in 33 to 37 fractions delivered daily (n 5 18 [60.0%]) or twice daily (n 5 12 [40.0%]). The concurrent chemotherapy was cisplatin/etoposide (n 5 21 [70.0%]) or carboplatin/etoposide (n 5 9 [30.0%]). In comparison with the backup IMRT plans, PBT allowed statistically significant reductions in the cord, heart, and lung mean doses and the volume receiving at least 5 Gy but not in the esophagus mean dose or the lung volume receiving at least 20 Gy. At a median follow-up of 14 months, the 1-/2-year LC and RFS rates were 85%/69% and 63%/ 42%, respectively. The median OS was 28.2 months, and the 1-/2-year OS rates were 72%/58%. There was 1 case each (3.3%) of grade 3 or higher esophagitis, pneumonitis, anorexia, and pericardial effusion. Grade 2 pneumonitis and esophagitis were seen in 10.0% and 43.3% of patients, respectively. CONCLUSIONS: In the first prospective registry study and largest analysis to date of PBT for LS-SCLC, PBT was found to be safe with a limited incidence of high-grade toxicities. Cancer 2017;123: VC 2017 American Cancer Society. KEYWORDS: intensity-modulated proton therapy, intensity-modulated radiotherapy, limited stage, proton therapy, small cell lung cancer. INTRODUCTION Radiation therapy (RT) is essential for the management of limited-stage small cell lung cancer (LS-SCLC). 1,2 When it is given with concurrent chemotherapy, RT can result in substantial toxicities, in part because of the anatomic proximity of frequently large-volume and centrally located disease to critical organs at risk (OARs), such as normal lung parenchyma, heart, and esophagus. The ability of proton-beam therapy (PBT) to reduce doses to these OARs has been described for locally advanced non small cell lung cancer (NSCLC), and dosimetric improvements have been demonstrated in comparison with intensity-modulated radiotherapy (IMRT) and 3-dimensional conformal RT. 3-5 The dosimetric benefits of PBT could lead to clinical toxicity reductions and even an improvement in overall survival (OS) 6 ; PBT is the focus of an ongoing phase 3 randomized trial comparing PBT and photons for locally advanced NSCLC (Radiation Therapy Oncology Group [RTOG] 1308). 7 There is no analogous literature on the use of PBT for small cell lung cancer (SCLC), a disease that presents some unique challenges to RT because of its often central location with large-volume disease. In fact, the current literature on PBT for LS-SCLC is limited to a single publication of a 6-patient case series. 8 Additional studies of the utility of PBT for SCLC are essential. We conducted a prospective institutional investigation assessing the safety and preliminary efficacy of PBT with concurrent chemotherapy for LS-SCLC. Corresponding author: Jean-Claude M. Rwigema, MD, Department of Radiation Oncology, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104; rwigema.jean@mayo.edu 1 Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; 2 Department of Radiation Oncology, Mayo Clinic, Scottsdale, Arizona; 3 Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska; 4 Division of Hematology/Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; 5 Department of Radiation Oncology, University of Washington Medical Center, Seattle, Washington; 6 Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland. DOI: /cncr.30870, Received: March 9, 2017; Revised: May 9, 2017; Accepted: May 30, 2017, Published online July 5, 2017 in Wiley Online Library (wileyonlinelibrary.com) 4244 Cancer November 1, 2017

2 Protons for Small Cell Lung Cancer/Rwigema et al MATERIALS AND METHODS Patients and Workup This study examined the outcomes of patients at a single institution who were enrolled in an institutional review board approved registry study assessing prospectively the clinical outcomes of and toxicities in patients with LS- SCLC treated with PBT. For this analysis, we excluded patients with recurrent disease receiving PBT reirradiation (n 5 5), patients receiving postoperative radiation (n 5 1), and enrolled patients who did not receive therapy (n 5 1). Thus, a total of 30 consecutive patients who were definitively treated with PBT for primary LS- SCLC were included in the analysis. The workup for all patients included histological confirmation of SCLC, systemic staging with positron emission tomography (PET)/ computed tomography (CT), and brain magnetic resonance imaging. RT Patients underwent 4-dimensional CT simulation with a wing board and custom body molds for immobilization. Patients were instructed to breathe normally throughout the simulation. An initial free-breathing scan was first obtained. CT images from 8 different breathing phases (100% inspiration through 100% expiration) were collected and transferred to treatment planning software (Eclipse; Varian Medical Systems, Palo Alto, California) for target delineation. The gross tumor volume (GTV) was defined as all gross disease determined from bronchoscopy, CT scanning (node short-axis diameter > 1 cm), PET scanning (standard uptake value > 3), or pathological nodal sampling. Separate GTVs were contoured for the primary tumor and nodal metastases. To account for intrafractional motion, an internal gross target volume was created for each GTV via the expansion of the GTV based on the tumor excursion seen on 4-dimensional CT simulation. An 8-mm margin was added to the primary tumor GTV to account for microscopic disease to create internal clinical target volumes (ictvs). For nodal stations involved with the tumor, the entire nodal level was included in the ictv, and an additional 3- to 5-mm margin was added to the involved nodal station. Elective nodal irradiation was not administered. To account for patient setup uncertainties, an isotropic 5-mm margin was added to each ictv to define planning target volumes (PTVs) for the primary tumor and nodal ictvs, which were then combined to create the final PTVs. For each patient, a clinical backup IMRT plan was created with either RapidArc techniques (Varian Medical Systems) or, more commonly, static IMRT. These plans prioritized conformality and minimization of the lung volume receiving at least 20 Gy (V 20 ), although in all cases, a lung volume receiving at least 5 Gy (V 5 ) constraint was applied in an attempt to minimize contralateral lung volumes receiving low doses. Patients were treated either twice daily with 45 Gy in 30 twice daily fractions or once daily with 59.4 to 66.6 Gy in 33 to 37 daily fractions at the discretion of the treating radiation oncologist, with the choice mainly driven by patient preference and/or the distance from the patient s home to the treatment facility. For proton plans, doses were prescribed in cobalt gray equivalents corrected with the accepted relative biologic effectiveness value of Treatment planning used double-scattering, uniform-scanning, or pencil beam scanning intensitymodulated proton therapy (IMPT) techniques. For double-scattering and uniform-scanning plans, beam range compensators were designed to account for the properties of the proton beam and range uncertainties by providing proximal and distal margins with respect to each PTV. Blocking was designed to create a lateral margin with respect to each PTV, with margins individualized for each patient according to formulas by Moyers et al. 10 For IMPT, single-field uniform-dose optimization was used, and beam-specific PTVs were created similarly to PTVs in the literature. 11 Patients were treated with 2 or 3 beams for all PBT plans. Both IMRT and PBT plans were optimized to achieve at least 95% PTV coverage by at least 95% of the prescription dose. For IMRT plans, dose objectives were created for PTVs and OARs. Inverse treatment planning (Varian Medical Systems) was used to optimize plans to minimize doses to critical structures by increasing OAR constraints while maintaining optimal coverage on target volumes and dose homogeneity. Planning for PBT and IMRT plans was performed to achieve maximum doses to the spinal cord that were less than 36 Gy for twice daily fractionation and less than 50 Gy for daily regimens. For the heart, the volume receiving at least 45 Gy (V 45 ) was <35%, and the constraint for the volume receiving at least 30 Gy was <50%. Lung constraints included a mean < 20 Gy, a V 5 value < 60%, and a V 20 value < 35%. The esophageal constraints were a mean < 34 Gy and a V 45 value < 30%. Treatment and Follow-Up All patients were treated with concurrent chemotherapy for a total of 4 cycles. Chemotherapy consisted of cisplatin (60-80 mg/m 2 ) or carboplatin (Area under the curve 5-6) with etoposide ( mg/m 2 ) administered in 3-week Cancer November 1,

3 Original Article TABLE 1. Patient Clinical Characteristics and Treatment Course Parameter Value Age at diagnosis, median (range), y 68 (57-81) Sex, Female 21 (70.0) Male 9 (30.0) Race, White 26 (86.7) African American 4 (13.3) ECOG performance status at diagnosis, 0 12 (40.0) 1 15 (50.0) 2 2 (6.7) 3 1 (3.3) Smoking history, median (range), pack-y 41 ( ) Persistent smoking at consultation, Yes 8 (26.7) No 22 (73.3) Pulmonary function tests, median (range) FEV 1, L 1.8 ( ) DLCO, % 65 (22-133) Prior malignancy, NSCLC 5 (16.7) Breast cancer 3 (10.0) Bladder cancer 3 (10.0) Cervical cancer 1 (3.3) Colon cancer 1 (3.3) Prior thoracic RT, Yes 2 (6.7) No 28 (93.3) AJCC clinical T stage (7th ed.), T1 12 (40) T2 13 (43.3) T3 5 (16.7) AJCC clinical N stage (7th ed.), N0 2 (6.7) N1 8 (26.7) N2 17 (56.7) N3 3 (10.0) Pre-RT PET SUV max, median (range) Tumor 11.4 ( ) Node 8.8 (baseline to 47.1) Chemotherapy, Cisplatin/etoposide 21 (70.0) Carboplatin/etoposide 9 (30.0) Timing of RT during chemotherapy, Cycle 1 3 (10.0) Cycle 2 26 (86.7) Cycle 3 1 (3.3) Thoracic RT, Fractionation Twice daily 12 (40.0) Once daily 18 (60.0) Prescription dose 45 CGEs 12 (40.0) 59.4 CGEs 1 (3.3) 61.2 CGEs 2 (6.7) 66.6 CGEs 15 (50.0) RT technique DS 26 (86.7) IMPT 1 (3.3) US 3 (10.0) Abbreviations: AJCC, American Joint Committee on Cancer; CGE, cobalt gray equivalent; DLCO, diffusing capacity of the lungs for carbon monoxide; DS, double scattering; ECOG, Eastern Cooperative Oncology Group; FEV 1, forced expiratory volume in 1 second; IMPT, intensity-modulated proton therapy; NSCLC, non small cell lung cancer; PET, positron emission tomography; RT, radiation therapy; SUV max, maximum standard uptake value; US, uniform scattering. cycles. Dose reductions in chemotherapy, if needed, were performed at the discretion of the medical oncologist. All radiation fields were treated daily under daily imaging guidance with kilovoltage-kilovoltage (KV-KV) imaging or cone-beam CT scans. 12 Weekly verification scans were performed to allow for adaptive replanning if necessary (>5% change in dose-volume histogram indicators to target volumes or critical serial structures) to maintain precise treatment delivery. 13 Patients were monitored at least weekly while on treatment. Only 2 patients required photon treatment, and both cases resulted from machine downtime. Both of these patients were treated with 37 total fractions, with one receiving 1 IMRT fraction (2.7%) and the other receiving 9 fractions (24.3%). Toxicities were prospectively assigned at the time of ontreatment visits and subsequent follow-up visits according to the Common Terminology Criteria for Adverse Events (version 4.0). After the completion of chemoradiotherapy (CRT), patients underwent repeat neuroimaging and a PET/CT scan or CT scan of the chest and abdomen at 2 to 8 weeks for an assessment of responses to CRT with the Response Evaluation Criteria in Solid Tumors. Twentyseven patients (90%) received photon-based prophylactic cranial irradiation at a dose of 25 Gy in 10 fractions at a median of 6 weeks (range, 4-12 weeks) after the completion of chemotherapy; the remaining 3 patients died of pulmonary emboli, emphysema, or bacterial pneumonia before prophylactic cranial irradiation was delivered. Patients underwent PET/CT or CT chest surveillance every 3 months for the first 2 years after PBT, every 4 months during year 3, every 6 months during year 4, and then annually. Statistical Analysis Statistics were performed with SPSS Statistics software (version 21; IBM, Armonk, New York); all tests were 2- tailed with significance defined as P <.05. Average doses for OARs with PBT and IMRT plans were compared with a paired t test. Analyses were intention-to-treat. Survival analyses were performed according to the Kaplan-Meier method. Local control (LC) was defined on the basis of the time interval from the initiation of therapy to the date of the local tumor recurrence. Recurrence-free survival (RFS) was defined from the start of radiation to disease progression, death, or last follow-up (whichever came first). LC and RFS were calculated actuarially and were detected with imaging. Pathological confirmation was attempted whenever feasible to confirm recurrence. OS was measured from the time of treatment initiation to death from any cause Cancer November 1, 2017

4 Protons for Small Cell Lung Cancer/Rwigema et al Figure 1. Illustrative treatment plan: (A) axial, (B) coronal, and (C) sagittal views of a proton-beam plan for a 74-year-old female patient with limited-stage small cell lung cancer with a small-volume primary tumor involving the right lower lobe as well as extensive right hilar and mediastinal nodal metastases and (D F) corresponding intensity-modulated radiotherapy plans. The planning tumor volume (PTV) is shown in cyan. Select percent isodose lines are indicated by the dose color legend. RESULTS Study Population and Treatment Characteristics Table 1 displays clinical and treatment characteristics of the study population. The majority of the patients were female (70%) and had an Eastern Cooperative Oncology Group performance status of 1 or 2 (57%; Table 1); the median age was 68 years. All patients had more than a 10 pack-year smoking history, and 27% were persistent smokers during treatment. Thirteen patients (43.3%) had a history of another malignancy (Table 1). Radiation dose fractionation and techniques and chemotherapy regimens are shown in Table 1. All patients except one began RT with either the first or second cycle of chemotherapy (Table 1). Three patients (10%) required adaptive planning because of tumor shrinkage, a need to reduce the spinal cord dose, or a changing anatomy related to decreasing pericardial fluid. Twenty-eight (93.3%) completed all 4 cycles of planned chemotherapy. Dosimetry Figure 1 displays a sample treatment plan using both PBT and IMRT. Proton plans achieved significantly improved dosimetry for the heart and spinal cord as well as improvements in V 5 and mean lung doses (Table 2). The mean doses to the esophagus and V 20 values of the lung were similar with the PBT and IMRT plans. Outcomes and Patterns of Failure After CRT, 27 patients were evaluable for the initial treatment response. Eleven of those patients (40.7%) experienced a complete response, 15 (55.6%) had a partial response, and 1 (3.7%) had stable disease. At a median follow-up of 14 months (range, 2-42 months), the 1- and 2-year LC rates were 85.0% and 68.6%, respectively (Fig. 2A), and the median RFS was 14.3 months, which corresponded to 1- and 2-year RFS rates of 63.0% and 42.0%, respectively (Fig. 2B). The median OS was 28.2 months, which corresponded to 1- and 2-year OS rates of 71.5% and 57.6%, respectively (Fig. 2C). Isolated local in-field failures occurred in only 2 patients (6.7%). Overall, 5 patients (16.7%) experienced recurrence in the field of irradiation, 6 patients (20%) experienced recurrence locoregionally outside the field of irradiation, and 7 patients (23.3%) experienced recurrence at distant sites. The first distant sites included the brain alone (n 5 2), liver and brain (n 5 1), liver and spine (n 5 1), contralateral lung and liver (n 5 1), adrenal Cancer November 1,

5 Original Article TABLE 2. Comparison of Median IMRT and Proton Therapy Dosimetry Values for the Cohort of Normal Patient Tissues Spinal Cord: Maximum (Range), Gy Lung Esophagus: Heart Mean (Range), V 5,% V 20, % Mean (Range), Gy Gy V 30,% V 45, % Mean (Range), Gy IMRT 37.5 ( ) 40.7 ( ) 28.1 ( ) 15.7 ( ) 20.8 ( ) 18.8 (0-84.4) 6.6 (0-48.1) 14.2 ( ) Proton 34 ( ) 34.9 ( ) 27.1 ( ) 14.2 ( ) 20.3 ( ) 7.9 (0-45.5) 3.9 (0-32) 5.2 ( ) P.004 < <.001 Abbreviations: IMRT, intensity-modulated radiotherapy; V n, volume receiving at least n grays. Figure 2. Kaplan-Meier survival curves for (A) local control, (B) recurrence-free survival, (C) and overall survival. glands and brain (n 5 1), and retroperitoneal nodes and contralateral lung (n 5 1). Hematologic Toxicities The majority of the patients tolerated systemic therapy with expected side effects. These included low hemoglobin levels (grade 2 [n 5 10] and grade 3 [n 5 7]), neutropenia (grade 3 [n 5 6], grade 4 [n 5 6], and febrile grade 4[n5 1]), thrombocytopenia (grade 1 [n 5 2], grade 2 [n 5 1], and grade 3 [n 5 3]), and lymphopenia (grade 2 [n 5 2], grade 3 [n 5 3], and grade 4 [n 5 10]). As a result of hematologic toxicities, 2 patients did not receive the final (fourth) cycle of chemotherapy, 4 patients experienced a delay of 1 week in the initiation of a cycle of chemotherapy, 4 patients required a chemotherapy dose reduction, and 1 patient was switched to weekly carboplatin alone after 1 cycle of carboplatin plus etoposide. Nonhematologic Toxicities Altogether, PBT was generally well tolerated, with the toxicities enumerated in Table 3. Grade 2 or higher pneumonitis were observed in 13.3% of the patients at a median of 5.2 months (range, months) from treatment initiation, and only 1 of these cases (3.3%) was a grade 3 event. Grade 2 esophagitis occurred in 13 patients (43.3%). Among patients treated with twice daily RT, 1 experienced grade 3 pericardial effusion, and 1 experienced grade 4 esophagitis. The only other grade 3 toxicity was anorexia in a patient treated with once daily RT. No other acute or late grade 3 or higher toxicities were observed. Qualitatively, toxicities seemed numerically increased in the twice daily group, although the low sample sizes precluded a formal statistical comparison. No patient required an RT treatment break because of toxicity. DISCUSSION In this first prospective report (and largest report to date) on the use of PBT for the treatment of LS-SCLC, PBT was found to be safe and effective in comparison with standard-of-care photon-based treatment. We first describe dosimetric advantages of PBT versus IMRT and then report patient outcomes, including toxicities, and we conclude with a description of patterns of failure. Our dosimetric figures (in both the PBT and IMRT groups), showing low radiation doses to the heart, lungs, and esophagus, are similar to those of numerous other publications on the use of PBT in the treatment of locally advanced NSCLC and other intrathoracic neoplasms. 4,14-19 Most notably, PBT decreased the lung volume receiving low doses and the mean dose but not the lung V 20 value. This could be explained not only by the decreased side scatter and unique Bragg peak associated with PBT but also by the fact that the vast majority of the patients 4248 Cancer November 1, 2017

6 Protons for Small Cell Lung Cancer/Rwigema et al TABLE 3. Nonhematologic Toxicity Profiles of the Patient Population Toxicity Grade 1, Grade 2, Grade 3, Grade 4, Grade 5, bid qd bid qd bid qd bid qd bid qd Total, Cough 8 (66.7) 6 (33.3) 0 (0) 1 (5.6) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 15 Dyspnea 3 (25.0) 5 (27.8) 3 (25.0) 3 (16.7) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 14 Pneumonitis 4 (33.3) 4 (22.2) 2 (16.7) 1 (5.6) 1 (8.3) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 12 Pleural effusion 0 (0) 3 (16.7) 0 (0) 2 (11.1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 5 Pericardial effusion 0 (0) 0 (0) 0 (0) 0 (0) 1 (8.3) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 Dermatitis 6 (50.0) 11 (61.1) 2 (16.7) 1 (5.6) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 20 Esophagitis 3 (25.0) 7 (38.9) 6 (50.0) 7 (38.9) 0 (0) 0 (0) 1 (8.3) 0 (0) 0 (0) 0 (0) 24 Fatigue 5 (41.7) 7 (38.9) 6 (50.0) 7 (38.9) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 25 Anorexia 5 (41.7) 4 (22.2) 3 (25.0) 1 (5.6) 0 (0) 1 (5.6) 0 (0) 0 (0) 0 (0) 0 (0) 14 Total Abbreviations: bid, twice daily fractionation (n 5 12); qd, once daily fractionation (n 5 18). received double-scattered PBT, which in itself does not guarantee higher conformality in comparison with advanced photon techniques (because of a relative lack of proximal dose shaping and treatment of these regions with the full prescribed dose). 20 Our observed rate of grade 2 or higher pneumonitis in this population with a heavy smoking history was relatively low, and perhaps this reflects the decreased lung radiation doses due to PBT. 21 Although heart doses were clearly lower because of the Bragg peak placement as well as the use of fewer beams, the value of any potential reduction in late cardiotoxicity in patients with a disease with a relatively poor prognosis is currently undefined. The finding of similar esophageal doses with PBT and IMRT in this series is likely related to the predominant use of double-scattered PBT and the fact that SCLC is more often a bulky, centrally located neoplasm with resulting anatomic apposition to the esophagus (likely on multiple sides) in comparison with NSCLC. Our survival figures (median OS, 28.2 months; 2- year OS, 57.6%) are numerically higher than those of both prior publications on photon-based chemoradiation and are most similar to those of the recently reported Concurrent ONce-daily VErsus twice-daily RadioTherapy (CONVERT trial). 22 Turrisi et al, 2 for example, observed 2-year OS rates of 41% and 47% in the once daily and twice daily arms of their study, respectively. The Cancer and Leukemia Group B (CALGB) study 23 reported a median OS of 22.4 months (2-year OS, 48%). The RTOG 0239 trial 24 found a 2-year OS rate of 37% (median OS, 19 months). When response rates were evaluated, the proportion of patients with a complete or partial response in our series was similar to the proportions in other works. 2,23,24 Likewise, patterns of failure were similar as well, with the majority of failures occurring distantly. We do note that our encouraging results were observed in a population of older patients with a slightly worse performance status in comparison with the published series. However, it is important to note that causation between PBT and the survival findings (especially in comparison with historical data) is not implied because these results may be explained by the increase in PET/CT staging, stage migration, and improved subsequent-line and supportive therapies. Indeed, survival is comparable to modern data such as those from the CONVERT trial. PBT in our study displayed an encouraging toxicity profile. With the exception of 1 patient (3%) receiving twice daily PBT, no subjects suffered from grade 3 or higher esophagitis. This result, in fact, compares favorably with seminal trials using older techniques (including large, 2-dimensional fields with elective nodal irradiation), 2 in which 33% and 16% of patients in the twice daily and once daily arms, respectively, developed grade 3 or higher esophageal adverse events. More contemporary data have found grade 3 esophageal toxicity rates of 16% to 18%, 23,24 and this is consistent with a 19% rate in the preliminary results of the CONVERT trial. 22 Similarly, our observation of a 13% rate of grade 2 or higher pneumonitis with only 1 instance of grade 3 or higher pneumonitis (3%) is also noteworthy. In CALGB 39808, although pneumonitis was not specifically mentioned, 5% of the patients developed grade 3 or higher dyspnea (none in the current study), 23 and this is similar to the 2% to 3% in the interim results of the CONVERT study. 22 RTOG 0239 displayed a 13% rate of grade 3 or higher acute pulmonary toxicities with additional late events. 24 Importantly, with doses comparable to those for locally advanced NSCLC with presumably comparable treatment volumes, our toxicity rates were similar to those of prior studies of concurrent PBT and chemotherapy for NSCLC. 16,25,26 Cancer November 1,

7 Original Article Although we chose IMRT as the photon modality with which a dosimetric comparison was made, the use of IMRT has been underreported for SCLC. Data show promise for the reduction of toxicities with IMRT, especially for high-volume disease. 14,27,28 Nevertheless, 3- dimensional conformal RT remains a commonly used modality for SCLC. 29 With extrapolation from NSCLC, the strongest evidence for IMRT in lung cancer with nodal metastases has come from a recent secondary analysis of the RTOG 0617 trial. 30 In that analysis, even though patients receiving IMRT had larger PTVs and PTV:lung ratios, IMRT patients experienced fewer cases of grade 3 or higher pneumonitis. Moreover, IMRT delivery correlated with lower cardiac doses, which were independently associated with survival in RTOG That PBT can achieve doses similar to or lower than those with IMRT is noteworthy and must be studied more thoroughly in the future, although extrapolation from NSCLC to SCLC is predictably problematic. It is also noted that according to the priorities of optimization (eg, target conformality vs low-dose areas to the contralateral lung), IMRT can produce plan variability. Because concurrent CRT has been shown to amplify toxicities, 2 potential clinical toxicity reduction with PBTmediated CRT may be noteworthy. Chemotherapy compliance was excellent in this study. As such, PBTmediated CRT may allow a higher proportion of patients to receive a full course of CRT with fewer RT treatment breaks or chemotherapy dose and/or cycle reductions. It is unclear, however, whether the proportion of patients who are not candidates for chemotherapy or concurrent CRT could also improve with PBT because of potential reductions in toxicities. PBT may also more safely allow dose escalation for LS-SCLC (to 70 Gy), as is being tested with photons in a current ongoing phase 3 trial. 31 Potential reductions in toxicities afforded by PBT could also play into its cost-effectiveness, a parameter associated with the controversy surrounding PBT for numerous neoplasms. 32 A systematic review demonstrated that on the basis of limited available data, PBT may be comparably cost-effective for locally advanced NSCLC. 33 Although such an analysis for LS-SCLC is currently lacking, the costs associated with grade 3 or higher esophagitis, which may be reduced with PBT, and potential reductions in cardiopulmonary toxicities may allow PBT to be cost-effective, and additional data are needed for such an analysis. This study has some notable limitations. Though prospectively enrolled and constituting the largest PBT experience for LS-SCLC, the overall study population was limited and heterogeneous. We included patients receiving both once daily and twice daily treatment as well as patients with an Eastern Cooperative Oncology Group performance status of 2 or 3 and patient who had received prior thoracic RT. Moreover, the previously reported crude toxicity rates could be underestimations of the true rates because of the competing risk of death. These findings are not generalizable to extensive-stage SCLC, the use of elective nodal irradiation, various other RT dose and fractionation regimens for LS-SCLC, or sequential CRT in patients not tolerating concurrent CRT or candidates for concurrent CRT. This is also true for advanced proton therapy techniques because only 1 patient received pencil beam scanning proton therapy. Although the magnitude of the benefit with proton therapy versus IMRT may have been greater for IMPT than double scattering, 11 double-scattering plans may be less susceptible to an interplay effect 34 or large dosimetric changes that may occur because of a potentially rapid tumor response, which can be achieved with chemoradiation for SCLC. As such, adaptive planning, though not critical for the majority of patients in this current investigation (with only 3 patients requiring replanning), is likely more imperative when patients are being treated with IMPT. Despite these limitations, for a malignancy for which virtually no data exist regarding the safety and efficacy of PBT, this work provides a platform on which to build future reports. Finally, we encourage further reporting of PBT experiences to verify the results and conclusions presented herein. In conclusion, PBT as part of a combined modality therapy for LS-SCLC is feasible and safe, with preliminary evidence showing encouraging efficacy in comparison with photon radiation. The clinical outcomes and toxicities were similar to those reported in contemporary photon-based studies, but the number of patients in our study was small. Additional comparative studies of PBT and photon therapy in LS-SCLC appear warranted. FUNDING SUPPORT No specific funding was disclosed. CONFLICT OF INTEREST DISCLOSURES The authors made no disclosure. AUTHOR CONTRIBUTIONS Jean-Claude M. Rwigema: Study concept; statistical and data analysis; writing, reading, and approval of the article; and responsibility for the overall content as guarantor. Vivek Verma: Study concept and writing, reading, and approval of the article. Liyong Lin: Writing, reading, and approval of the article. Abigail T. Berman: 4250 Cancer November 1, 2017

8 Protons for Small Cell Lung Cancer/Rwigema et al Writing, reading, and approval of the article. William P. Levin: Writing, reading, and approval of the article. Tracey L. Evans: Writing, reading, and approval of the article. Charu Aggarwal: Writing, reading, and approval of the article. Ramesh Rengan: Writing, reading, and approval of the article. Corey Langer: Writing, reading, and approval of the article. Roger B. Cohen: Writing, reading, and approval of the article. Charles B. Simone II: Study concept; writing, reading, and approval of the article; and responsibility for the overall content as guarantor. REFERENCES 1. Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med. 1992;327: Turrisi AT III, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999;340: Simone CB 2nd, Rengan R. 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