Advertisement

Clinical Outcomes After Proton Beam Therapy for Locally Advanced Non-Small Cell Lung Cancer: Analysis of a Multi-institutional Prospective Registry

Open AccessPublished:September 10, 2021DOI:https://doi.org/10.1016/j.adro.2021.100767

      Abstract

      Purpose

      For most disease sites, level 1 evidence is lacking for proton beam therapy (PBT). By identifying target populations that would benefit most from PBT, prospective registries could overcome many of the challenges in clinical trial enrollment. Herein, we report clinical outcomes of patients treated with PBT for locally advanced non-small cell lung cancer (LA-NSCLC).

      Methods and Materials

      Data were obtained from the multi-institutional prospective database of the Proton Collaborative Group (PCG). Inclusion criteria of our study were stage III de novo or recurrent LA-NSCLC, use of PBT, and availability of follow-up data. Overall survival (OS) time was calculated from the start of treatment until death or last follow-up. Kaplan-Meier curves were generated for groups of interest and compared with log-rank tests. Cox regression modeling was used to evaluate the multivariate association between selected covariates and OS.

      Results

      A total of 195 patients were included in the analysis. PBT was given with a median equivalent dose in 2 Gy fractions (EQD2) of 63.8 Gy (relative biological effectiveness). Pencil beam scanning was used in 20% of treatments. Treatment-related grade 3 adverse events were rare: 1 pneumonitis, 2 dermatitis, and 3 esophagitis. No grade 4 events were reported. Two cardiac-related grade 5 events occurred in patients with multiple risk factors. The median follow-up time for living patients was 37.1 months and the median OS was 19.0 months. On multivariate analysis, good performance status (hazard ratio, 0.27; [95% confidence interval, 0.15-0.46]; P < .0001), pencil beam scanning use (0.55; [0.31-0.97]; P = .04), and increased EQD2 (0.80; [0.71-0.90] - per 10 Gy increase; P = .0002) were associated with decreased mortality.

      Conclusions

      PBT appears to yield low rates of adverse events with an OS similar to other retrospective studies on PBT for LA-NSCLC. PBS use and increased EQD2 can potentially improve OS.

      Introduction

      Lung cancer is the most common cause of cancer-related deaths worldwide.

      Ferlay J, Ervik M, Lam F, et al. Global Cancer Observatory: Cancer today. Lyon, Fr Int Agency Res Cancer 2020. Available at: https://gco.iarc.fr/today. Accessed January 19, 2021.

      Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer, responsible for approximately 85% of cases.
      • Vyfhuis MAL
      • Onyeuku N
      • Diwanji T
      • et al.
      Advances in proton therapy in lung cancer.
      Radiation therapy (RT) is one of the cornerstones in the treatment of NSCLC.
      • Liao Z
      • Lee JJ
      • Komaki R
      • et al.
      Bayesian adaptive randomization trial of passive scattering proton therapy and intensity modulated photon radiation therapy for locally advanced non–small cell lung cancer.
      It is prescribed to approximately 60% of patients with locally advanced disease, often with concurrent platin-based chemotherapy.
      • Vyfhuis MAL
      • Onyeuku N
      • Diwanji T
      • et al.
      Advances in proton therapy in lung cancer.
      ,
      • Guberina M
      • Eberhardt W
      • Stuschke M
      • et al.
      Heart dose exposure as prognostic marker after radiation therapy for resectable stage IIIA/B non-small cell lung cancer: Secondary analysis of a randomized trial.
      Most RT treatments are photon-based, but the use of newer techniques such as proton beam therapy (PBT) is increasing.
      As PBT gains in accessibility for routine care, it is critical to assess its added value as a cancer treatment modality. Multiple studies have shown that the differences in physical properties of protons and photons result in an increased sparing of organs at risk (OARs).
      • Goitein M
      • Cox JD.
      Should randomized clinical trials be required for proton radiation therapy?.
      • Widder J
      • van der Schaaf A
      • Lambin P
      • et al.
      The quest for evidence for proton therapy: Model-based approach and precision medicine.
      • Chang JY
      • Jabbour SK
      • De Ruysscher D
      • et al.
      Consensus statement on proton therapy in early stage and locally advanced non–small cell lung cancer.
      • Langendijk JA
      • Lambin P
      • De Ruysscher D
      • Widder J
      • Bos M
      • Verheij M.
      Selection of patients for radiation therapy with protons aiming at reduction of side effects: The model-based approach.
      • Nichols RC
      • Huh SN
      • Henderson RH
      • et al.
      Proton radiation therapy offers reduced normal lung and bone marrow exposure for patients receiving dose-escalated radiation therapy for unresectable stage iii non-small cell lung cancer: A dosimetric study.
      In 2006, a study comparing dose-volume histograms of passively scattered proton therapy (PSPT) with 3-dimensional conformal RT (3D-CRT) and photon-beam intensity modulated RT (IMRT) highlighted a reduction in the dose to the OARs when using PSPT relative to 3D-CRT and IMRT, even after dose escalation.
      • Chang JY
      • Zhang X
      • Wang X
      • et al.
      Significant reduction of normal tissue dose by proton radiation therapy compared with 3-dimensional conformal or intensity modulated radiation therapy in stage I or stage III non-small cell lung cancer.
      Similar benefits were observed using intensity modulated proton therapy (IMPT), which has been replacing PSPT over the last years. A study comparing dosimetric data of IMPT with PSPT and IMRT reported a better sparing of OARs with IMPT compared with IMRT in the planning of 10 patients with stage IIIB NSCLC.
      • Zhang X
      • Li Y
      • Pan X
      • et al.
      Intensity modulated proton therapy reduces the dose to normal tissue compared with intensity modulated radiation therapy or passive scattering proton therapy and enables individualized radical radiation therapy for extensive stage IIIB non-small cell lung cancer.
      Furthermore, based on dosimetric analysis, IMPT seemed to allow safe dose escalation to a mean maximum tolerated dose of 74 Gy of relative biological effectiveness (RBE), compared with 63 Gy for IMRT, which could lead to an improvement in both local control and overall survival (OS).
      • Zhang X
      • Li Y
      • Pan X
      • et al.
      Intensity modulated proton therapy reduces the dose to normal tissue compared with intensity modulated radiation therapy or passive scattering proton therapy and enables individualized radical radiation therapy for extensive stage IIIB non-small cell lung cancer.
      Level 1 evidence in favor of PBT, however, is currently lacking for most cancers. NSCLC is no exception, as only 1 randomized controlled trial (RCT) comparing protons and photons has been performed. This study, published in 2018, compared PSPT with IMRT and showed no significant difference for the primary endpoints: rates of local failure were similar in both groups (10.9% for IMRT, 10.5% for PSPT), and rates of grade 3 or higher pneumonitis were 6.5% for IMRT and 10.5% for PSPT.
      • Liao Z
      • Lee JJ
      • Komaki R
      • et al.
      Bayesian adaptive randomization trial of passive scattering proton therapy and intensity modulated photon radiation therapy for locally advanced non–small cell lung cancer.
      However, unlike in the IMRT arm, rates of pneumonitis and local failure significantly decreased during the trial in the PSPT arm, going from 31.0% in the first half to 13.1% in the second half of the trial,
      • Vyfhuis MAL
      • Onyeuku N
      • Diwanji T
      • et al.
      Advances in proton therapy in lung cancer.
      ,
      • Liao Z
      • Lee JJ
      • Komaki R
      • et al.
      Bayesian adaptive randomization trial of passive scattering proton therapy and intensity modulated photon radiation therapy for locally advanced non–small cell lung cancer.
      suggesting a learning curve in the proton treatment. Several criticisms have been made regarding this study and its design, including the PBT technique used (PSPT rather than IMPT) and the high number of randomized patients not receiving treatment (partly due to insurance refusal).
      • Vyfhuis MAL
      • Onyeuku N
      • Diwanji T
      • et al.
      Advances in proton therapy in lung cancer.
      ,
      • Verma V
      • Chang JY.
      Controversies in dose-escalation for locally advanced non-small cell lung cancer and the role of proton beam therapy.
      ,
      • Rengan R
      • Redman M
      • Zeng J.
      Challenge of proving the value of proton therapy in an unselected patient population in the era of precision oncology: The fallacy of a one-size-fits-all strategy in radiation therapy for lung cancer.
      Prospective cohort studies recruiting patients treated with PBT could bring insight to guide the design of future randomized studies, helping to identify a subgroup that benefits more from PBT within the treated population. Using the Proton Collaborative Group (PCG) registry, a database gathering information from 16 centers across the United States, this study focused on patients with locally advanced NSCLC (de novo or recurrent stage III) treated with PBT and aimed to present the current clinical outcomes, such as adverse events (AEs) and OS.

      Methods and Materials

      Data collection

      The data used for this research are part of a larger observational study titled “Evaluation Tracking Project: A Prospective Chart Review of Patients Treated With Radiation Therapy” (National Clinical Trial 01255748). The study, led by the PCG, initially included only patients treated solely with PBT in the participating centers, but has since been opened to patients treated with any other radiation modality. All participants provided informed consent. This study was approved after review by the board of directors of the sponsor.
      The data set was extracted from the main electronic database on January 25, 2019, containing pseudonymized information on patients, their disease, prior and current treatments, and dosimetric and follow-up data collected until January 6, 2020. Only patients with NSCLC and treated with PBT were included, reaching a total of 444 patients. After exclusion of patients with conflicting diagnosis data (n = 4), lack of follow-up data (n = 92), and disease other than stage III at inclusion (n = 153), 195 patients remained in our study.
      Staging was defined according to the American Joint Committee on Cancer tumor, nodes, metastases system. The 7th edition was used for cancers diagnosed until December 31, 2017 (n = 190), and was replaced by the 8th edition thereafter (n = 5).

      Statistical methods

      All analyses were performed using SAS Statistical Software (Version 9.4). P values under .05 were considered statistically significant, and all tests were two-sided. No adjustment was done for multiple testing.
      Patient demographics and treatment characteristics were described using frequencies and percentages for categorical variables, while means, medians, ranges, and standard deviations (SD) were used for continuous variables.
      Treatment doses delivered to target volumes were standardized to an equivalent dose in 2 Gy fractions (EQD2) assuming an α/β ratio of 10.
      AEs were tabulated by grade according to the Common Terminology Criteria for Adverse Events v4.0 and entered during treatment and follow-up. Only the maximum grade reported was considered per patient and per event; baseline toxicities were not accounted for. AEs were classified as early (during treatment or <90 days posttreatment) or late (≥90 days posttreatment). Centers were contacted if additional information was needed regarding a severe AE.
      OS was estimated using the Kaplan-Meier method. Survival time was calculated from the start of treatment until death, and patients last known to be alive were censored at their date of last follow-up. The log-rank test was used to compare Kaplan-Meier curves for groups of interest.
      Cox regression modeling was used to measure the association between covariates of interest and overall mortality (failure for OS) using hazard ratios and 95% confidence intervals (CI). Univariate models applied for each variable of interest were used to identify relevant parameters for the multivariate model. A multivariate model was used using parameters that had P < .1 in their respective univariate model while also including patients’ age at consent.

      Results

      Demographics

      A total of 195 patients were included in the analyses (Table 1). The median age was 70 years (range, 48-93). The majority of the tumors treated were located in the upper lobes (64%) and were right-sided (55%). The majority of patients had stage IIIA disease (51%), and 28% (n = 55) of the patients had recurrent stage III disease. Patients received concurrent chemotherapy in 64% of cases (n = 125).
      Table 1Patient and disease characteristics (n = 195)
      Characteristicn(%)Characteristicn(%)
      Age at consent (years)Tumor location
       Median70.0 Left lower lobe16(8.2)
       Minimum48.0 Left upper lobe56(28.7)
       Maximum93.0 Left lung, other2(1.0)
      Sex Main bronchus10(5.1)
       Female90(46.2) Right lower lobe23(11.8)
       Male104(53.3) Right middle lobe7(3.6)
       Undifferentiated1(0.5) Right upper lobe68(34.9)
      Race Right lung, other9(4.6)
       Asian3(1.5) Lung, NOS4(2.1)
       Black14(7.2)Histologic type
       White165(84.6) Adenocarcinoma82(42.1)
       Other3(1.5) Squamous78(40.0)
       Missing10(5.1) NSCLC NOS35(18.0)
      ECOG performance statusAJCC stage at original diagnosis
       082(42.1) IIIA100(51.3)
       179(40.5) IIIB39(20.0)
       222(11.3) IIIC1(0.5)
       31(0.5) IIIA recurrent35(18.0)
       Missing11(5.6) IIIB recurrent20(10.3)
      Smoking history
       No19(9.7)Clinical T-stage
       Current smoker26(13.3) T02(1.0)
       Past smoker149(76.4) T129(14.9)
       Missing1(0.5) T256(28.7)
      Concurrent chemotherapy T338(19.5)
       No70(35.9) T448(24.6)
       Yes125(64.1) TX2(1.0)
      Prior thoracic radiation
      For this cancer
       Missing20(10.3)
       No145(74.4)Clinical N-stage
       Yes50(25.6) N017(8.7)
      Prior surgery
      For this cancer
       N116(8.2)
       No159(81.5) N2105(53.8)
       Yes36(18.5) N337(18.9)
      Prior chemotherapy
      For this cancer
       Missing20(10.3)
       No110(56.4)
       Yes85(43.6)
      Abbreviations: AJCC = American Joint Committee on Cancer; ECOG = Eastern Cooperative Oncology Group; NOS = not otherwise specified; NSCLC = non-small cell lung cancer.
      low asterisk For this cancer

      Radiation treatment

      Most patients were treated with PBT as the sole RT technique (93%) (Table 2). Reasons for using another treatment modality (most often IMRT) were, among others, PBT as a boost after IMRT or temporary substitution (eg, machine downtime). The median time from diagnosis to treatment was 1.8 months.
      Table 2Radiation treatment characteristics (n = 195)
      Characteristicn(%)CharacteristicGy (RBE)
      Only protonsCumulative dose
      Cumulative proton dose when protons were used alone (n = 182)
       Yes182(93.3) Mean61.2
       No13(6.7) Median61.0
      Any PBS Minimum10.1
       Yes39(20.0) Maximum80.1
       No156(80.0) Standard deviation12.9
      Start of RT (year)Cumulative dose EQD2
      Cumulative proton dose when protons were used alone (n = 182)
       20102(1.0) Mean61.8
       20114(2.1) Median63.8
       201222(11.3) Minimum10.1
       201342(21.5) Maximum80.1
       201436(18.5) Standard deviation12.9
       201530(15.4)
       201620(10.3)
       201730(15.4)
       20189(4.6)
      Number of treatment plans
       1129(66.2)
       252(26.7)
       312(6.2)
       42(1.0)
      Abbreviations: EQD2 = equivalent dose in 2 Gy fractions; PBS = pencil beam scanning; RBE = relative biological effectiveness; RT = radiation therapy.
      low asterisk Cumulative proton dose when protons were used alone (n = 182)
      Uniform scanning was the most frequent proton modality, used in 80% of patients, whereas 20% of patients received pencil beam scanning (PBS). Sixty-six patients (34%) were treated with two or more treatment plans, often for a boost dose.
      The mean proton dose, when it was the only treatment modality, was 61.2 Gy (RBE) (SD, 12.9), or an EQD2 of 61.8 Gy (RBE) (SD, 12.9). Fractions of 2 Gy were used for 71.8% of patients.

      Adverse events

      Table 3 summarizes the most typical AEs after PBT for LA-NSCLC (esophagitis, pneumonitis, and dermatitis), together with other severe AEs. Six grade 3, no grade 4, and two grade 5 AEs were reported.
      Table 3Early and late treatment toxicities (n = 195)
      Adverse eventGrade 1Grade 2Grade 3Grade 4Grade 5All grades
      Early
       Cardiac events----11
       Dermatitis102402--144
       Esophagitis43543--100
       Pneumonitis-21--3
       Total early toxicities145966-1248
      Late
       Cardiac events----11
       Dermatitis1----1
       Esophagitis12---3
       Pneumonitis34---7
       Total late toxicities56--112
      Grade 2 or higher acute dermatitis occurred in 42 patients (21.5%), 2 of which (1.0%) were grade 3 events. Grade 2 or higher acute esophagitis affected 57 patients (29.2%), with 3 (1.5%) grade 3 events. Grade 2 late pneumonitis occurred in 4 patients (2.1%), with no grade 3 or higher events. There was also 1 case (0.5%) of grade 3 early pneumonitis.
      Regarding the 2 patients (1%) with grade 5 toxicities, neither of them had received prior thoracic radiation. The first patient suffered from a cardiac arrest after 16 of 34 fractions (32 Gy). This patient's tumor invaded into the heart and great vessels. He had considerable cardiac history, including myocardial infarction, and had received concurrent chemotherapy (unknown drugs). The mean heart dose (MHD) was kept at 12.23 Gy (RBE) for the 34 planned fractions.
      The second patient died of a myocardial infarction 10 months after the end of his treatment. He had been treated with concurrent cisplatin and etoposide and had multiple cardiovascular risk factors, including diabetes and a history of carotid stenosis. He had received a MHD of 9.31 Gy (RBE).

      Survival

      The median OS of all patients was 19.0 months (95% CI [14.2-22.5]; range, 0.69-71.8) (Fig 1). The median follow-up time of living patients was 37.1 months (range, 2.4-82.4). The 1, 3, and 5-year OS were 60%, 32%, and 20%, respectively.
      Fig 1
      Figure 1Survival probability for all patients.
      There was no statistically significant difference in OS by clinical stage of the disease (log-rank P = .46): median OS was 18.1 months (95% CI [11.1-26.1]) for stage IIIA, 19.2 months ([9.4-36.9]) for stage IIIB/C, and 19.0 months ([12.0-29.6]) for patients treated for recurrent disease. Patients with a history of prior radiation had a median OS of 16.0 months ([9.6-29.6]) compared with 19.6 months ([14.2-26.1]) for patients who did not (P = .15).
      Patients who received concurrent chemotherapy had a significantly higher median OS (20.6 months [16.0-28.0]) than those who did not receive it (12.9 [7.2-19.8]; P = .03) (Fig 2). Patients with performance status (PS) in the categories 0 and 1 of the Eastern Cooperative Oncology Group (ECOG) classification had a longer OS (21.1 months; [16.3-30.0]) compared with patients in categories 2 or 3 (7.0 months; [3.9-11.3]) (P < .0001).
      Fig 2
      Figure 2Survival probability by concurrent chemotherapy status.
      On univariate analysis, 6 parameters were significantly associated with better OS: female or undifferentiated gender, tumors located in the upper lobes, ECOG PS of 0/1, increased cumulative dose (EQD2), concurrent chemotherapy, and use of PBS.
      On multivariate analysis, ECOG PS, cumulative dose (EQD2), and use of PBS remained statistically significant (Table 4).
      Table 4Multivariate Cox regression analysis for overall mortality
      VariableHR95% CIP value
      Age at consent (years).52
       Per 1 year increase0.99(0.97-1.01)
      Sex09
       Female/undifferentiatedReference
       Male1.38(0.95-2.00)
      Tumor location.07
       OtherReference
       Upper lobes0.71(0.49-1.03)
      ECOG score< .0001
      Statistical significance
       0Reference
       11.33(0.90-1.97)
       2/33.75(2.17-6.48)
      Cumulative dose (EQD2).0002
      Statistical significance
       Per 10 Gy increase0.80(0.71-0.90)
      Any PBS use.04
      Statistical significance
       NoReference
       Yes0.55(0.31-0.97)
      Concurrent chemotherapy.07
       NoReference
       Yes0.70(0.48-1.02)
      Abbreviations: CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; EQD2 = equivalent dose in 2 Gy fractions; HR = hazard ratio; PBS = pencil beam scanning.
      low asterisk Statistical significance
      In a subsequent stratified analysis by total EQD2, OS was higher in the group receiving ≥60 Gy versus <60 Gy (P = .03). In a univariate analysis restricted to patients who received ≥60 Gy (n = 153), the association between EQD2 dose and survival was no longer statistically significant (hazard ratio, 0.83; [0.59-1.17]; P = .29).

      Discussion

      As the PCG registry enrolls patients without restrictive criteria, unlike interventional trials, the population studied in the present paper presented several differences in terms of demographics. The median age of 70 years (range, 48-93) seems higher than in the only RCT comparing photons to protons (66 years; range, 33-85)
      • Liao Z
      • Lee JJ
      • Komaki R
      • et al.
      Bayesian adaptive randomization trial of passive scattering proton therapy and intensity modulated photon radiation therapy for locally advanced non–small cell lung cancer.
      and in the Radiation Therapy Oncology Group (RTOG) 0617 trial, comparing standard (60 Gy) to high dose (74 Gy) radiochemotherapy (64 years; range, 38-83).
      • Bradley JD
      • Paulus R
      • Komaki R
      • et al.
      Standard-dose versus high-dose conformal radiation therapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small cell lung cancer (RTOG 0617): A randomized, 2-by-2 factorial P.
      An older population may be one of the factors associated with poorer survival, a reason why these patients are often excluded from prospective studies. Yet, age was not found to be a significant parameter related to mortality in our analysis, possibly due to the limited sample size.
      PBT has been shown to be safe and effective for previously irradiated patients with recurring NSCLC.
      • Chao H-H
      • Berman AT
      • Simone CB
      • et al.
      Multi-institutional prospective study of reirradiation with proton beam radiation therapy for locoregionally recurrent non–small cell lung cancer.
      • McAvoy SA
      • Ciura KT
      • Rineer JM
      • et al.
      Feasibility of proton beam therapy for reirradiation of locoregionally recurrent non-small cell lung cancer.
      • Badiyan SN
      • Rutenberg MS
      • Hoppe BS
      • et al.
      Clinical outcomes of patients with recurrent lung cancer reirradiated with proton therapy on the Proton Collaborative Group and University of Florida Proton Therapy Institute prospective registry studies.
      In our cohort, a high percentage of patients (26%) had received thoracic radiation before this treatment. Care must be applied when interpreting these results as patients might have been selected for a new RT based on PS. Although previous radiation data (site, fractionation, dose, and dates) were available for most reirradiated patients, cumulative dose to target volumes and OARs were not quantifiable as the degree of overlap between past and current treatment was unknown.
      The overall low rate of high-grade AEs, even in patients with prior radiation, is in favor of good tolerance of the PBT treatment, in line with previous reports.
      • Badiyan SN
      • Rutenberg MS
      • Hoppe BS
      • et al.
      Clinical outcomes of patients with recurrent lung cancer reirradiated with proton therapy on the Proton Collaborative Group and University of Florida Proton Therapy Institute prospective registry studies.
      Previously irradiated patients and patients with recurrent disease had similar OS as other subgroups. These findings could be due to the limited statistical power of small sample sizes. Another explanation could be that the selection process for reirradiating a patient with PBT might exclude patients who had early metastatic disease, therefore selecting more indolent tumors.
      AEs in the mediastinum were limited to 6 grade 3 events, but 2 grade 5 also occurred. The implication of PBT in the grade 5 cardiac events cannot be excluded. However, considering the substantial medical history of the patients, the chemotherapy received concurrently, and the relatively low mean dose of radiation reaching the heart, it is very difficult to isolate 1 factor as directly causal. Nevertheless, if PBT played a role in those events, it would probably also have been the case with conventional RT. Cardiac-related mortality after RT has been frequently studied in the past years. In 2013, Darby et al
      • Darby SC
      • Ewertz M
      • McGale P
      • et al.
      Risk of ischemic heart disease in women after radiation therapy for breast cancer.
      showed a linear correlation between the MHD and the risk of major coronary events in patients with breast cancer, starting soon after treatment completion and regardless of their cardiac history. In lung cancer, the possible effect on mortality of high heart doses gained attention after the results of the RTOG 0617 trial,
      • Bradley JD
      • Paulus R
      • Komaki R
      • et al.
      Standard-dose versus high-dose conformal radiation therapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small cell lung cancer (RTOG 0617): A randomized, 2-by-2 factorial P.
      where the high-dose arm showed a significantly lower OS than the standard-dose arm (20.3 vs 28.7 months); heart V5 and V30 were found to be predictive factors of shorter OS. Similar results were reported in a study using the contouring guidelines of RTOG 0617; heart V50 ≥ 25% was associated with shorter OS and increased cardiac toxicity.
      • Speirs CK
      • DeWees TA
      • Rehman S
      • et al.
      Heart dose is an independent dosimetric predictor of overall survival in locally advanced non–small cell lung cancer.
      In contrast, a European study (using data from the Essen-Paris-Tübingen trial) was not able to confirm heart V5 as an independent predictor of OS.
      • Guberina M
      • Eberhardt W
      • Stuschke M
      • et al.
      Heart dose exposure as prognostic marker after radiation therapy for resectable stage IIIA/B non-small cell lung cancer: Secondary analysis of a randomized trial.
      In comparison with photon-based RT, PBT reduces the mean dose to the heart and could therefore be used for dose-escalation while limiting cardiac-related mortality.
      • Liao Z
      • Lee JJ
      • Komaki R
      • et al.
      Bayesian adaptive randomization trial of passive scattering proton therapy and intensity modulated photon radiation therapy for locally advanced non–small cell lung cancer.
      ,
      • Zhang X
      • Li Y
      • Pan X
      • et al.
      Intensity modulated proton therapy reduces the dose to normal tissue compared with intensity modulated radiation therapy or passive scattering proton therapy and enables individualized radical radiation therapy for extensive stage IIIB non-small cell lung cancer.
      Minimizing cardiac events seems even more important considering the improvements in OS of patients with LA-NSCLC treated with Durvalumab.
      • Antonia SJ
      • Villegas A
      • Daniel D
      • et al.
      Overall survival with Durvalumab after chemoradiotherapy in stage III NSCLC.
      Further studies should explore the factors linked to a lower cardiac dose, as such patients could potentially benefit from dose-escalation.
      Our analysis showed that with PBT, a higher cumulative EQD2 could lead to an increased OS. It is consistent with theoretical principles that PBT allows for dose-escalation while limiting the dose to OARs and hence improving OS.
      • Vyfhuis MAL
      • Onyeuku N
      • Diwanji T
      • et al.
      Advances in proton therapy in lung cancer.
      ,
      • Zhang X
      • Li Y
      • Pan X
      • et al.
      Intensity modulated proton therapy reduces the dose to normal tissue compared with intensity modulated radiation therapy or passive scattering proton therapy and enables individualized radical radiation therapy for extensive stage IIIB non-small cell lung cancer.
      ,
      • Choi JI
      • Simone II CB
      Breaking the dose ceiling: Proton therapy for locally advanced non-small cell lung cancer.
      However, treatment doses were heterogeneous, and some patients received EQD2s inferior to the standard 60 Gy, used, for example, in the RTOG 0617 trial.
      • Bradley JD
      • Paulus R
      • Komaki R
      • et al.
      Standard-dose versus high-dose conformal radiation therapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small cell lung cancer (RTOG 0617): A randomized, 2-by-2 factorial P.
      This was due to either a low prescription dose or treatment interruption. When excluding patients who received <60 Gy from our analysis, the association was no longer significant. Studies with larger and more homogeneous cohorts are warranted to determine whether, unlike with photons, increased proton dose can improve OS.
      IMPT, one of the optimization strategies for the delivery of PBS,
      • Chang JY
      • Zhang X
      • Knopf A
      • et al.
      Consensus guidelines for implementing pencil-beam scanning proton therapy for thoracic malignancies on behalf of the PTCOG Thoracic and Lymphoma Subcommittee.
      improves the dose distribution compared with PSPT, similarly to the improvement of IMRT relative to 3D-CRT. This provides better tumor conformality and healthy tissue sparing, with consequent improved local control and lower AE rates.
      • Chang JY
      • Jabbour SK
      • De Ruysscher D
      • et al.
      Consensus statement on proton therapy in early stage and locally advanced non–small cell lung cancer.
      ,
      • Chang JY
      • Zhang X
      • Knopf A
      • et al.
      Consensus guidelines for implementing pencil-beam scanning proton therapy for thoracic malignancies on behalf of the PTCOG Thoracic and Lymphoma Subcommittee.
      However, PBS also has limitations: more sensitive to setup and range uncertainties, motion, and interplay effect than PSPT or IMRT, PBS makes treatment planning more difficult.
      • Chang JY
      • Zhang X
      • Knopf A
      • et al.
      Consensus guidelines for implementing pencil-beam scanning proton therapy for thoracic malignancies on behalf of the PTCOG Thoracic and Lymphoma Subcommittee.
      ,
      • Inoue T
      • Widder J
      • van Dijk LV
      • et al.
      Limited impact of setup and range uncertainties, breathing motion, and interplay effects in robustly optimized intensity modulated proton therapy for stage III nonsmall cell lung cancer.
      Nonetheless, a study by Inoue et al
      • Inoue T
      • Widder J
      • van Dijk LV
      • et al.
      Limited impact of setup and range uncertainties, breathing motion, and interplay effects in robustly optimized intensity modulated proton therapy for stage III nonsmall cell lung cancer.
      showed that robust optimization of IMPT plans limits the effect of the aforementioned factors. PBS is slowly becoming the modality of choice for PBT, but it has been implemented more recently than PSPT. This could potentially introduce a difference in our study groups (cohort effect).
      PBS use was also correlated with improved survival in our study. Our novel finding is promising, as more PBT centers are adopting these delivery techniques despite their challenges. It should also encourage the conduction of clinical trials using the latest available technologies, such as PBS, as they could improve local control and survival. In their RCT, Liao et al
      • Liao Z
      • Lee JJ
      • Komaki R
      • et al.
      Bayesian adaptive randomization trial of passive scattering proton therapy and intensity modulated photon radiation therapy for locally advanced non–small cell lung cancer.
      did not evaluate PBS but reported no differences in local failure between PSPT and IMRT.
      In 2017, Chang et al
      • Chang JY
      • Verma V
      • Li M
      • et al.
      Proton beam radiation therapy and concurrent chemotherapy for unresectable stage III non–small cell lung cancer.
      evaluated the use of PBT in 64 patients with unresectable stage III NSCLC from a single-arm phase II study and reported 16% grade 2 and 12% grade 3 late pneumonitis. In the RTOG 0617 trial, Bradley et al
      • Bradley JD
      • Paulus R
      • Komaki R
      • et al.
      Standard-dose versus high-dose conformal radiation therapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small cell lung cancer (RTOG 0617): A randomized, 2-by-2 factorial P.
      reported AEs separately for 4 treatment groups (60 vs 74 Gy, with or without Cetuximab); grade 2 late pneumonitis rates ranged from 1% to 8%, whereas grade 3 ranged from 0% to 2%. The late pneumonitis rates in our study were low. Although these are similar to those reported by Bradley et al, an under-reporting of the late AEs such as pneumonitis cannot be ruled out as a factor influencing our findings. The nature of the PCG registry and of prospective registries as a whole could account for this limitation. As patients enter follow-up, centers sometimes fail to update the registry with follow-up information. This can lead to a bias in the number of late AEs. Regarding acute esophagitis, Chang et al also found 28% grade 2 and 8% grade 3, whereas Bradley et al reported rates of 24% to 30% for grade 2 and 6% to 19% for grade 3, similar to our results.
      In terms of survival, the median OS of 19 months is slightly superior to the OS described by Higgins et al
      • Higgins KA
      • O'Connell K
      • Liu Y
      • et al.
      National Cancer Database analysis of proton versus photon radiation therapy in non-small cell lung cancer.
      in their retrospective analysis, comparing protons with photons. In their subset of 193 patients with stage II/III NSCLC, the median OS (from start of radiation) was 17.4 months for PBT, not significantly different from IMRT and 3D-CRT (17.2 and 15.2 months, respectively). Analyses of prospective registries are often limited by a short follow-up of living patients (13.6 months in our initial analyses). After the aforementioned update, the median follow-up was increased to 37.1 months for living patients, giving more robustness to our results. Yet, compared with the largest prospective series studying PBT on stage III patients, our follow-up and OS are considerably inferior.
      • Chang JY
      • Verma V
      • Li M
      • et al.
      Proton beam radiation therapy and concurrent chemotherapy for unresectable stage III non–small cell lung cancer.
      With a median follow-up of 79.6 months for living patients, Chang et al reported a median OS of 26.5 months for the 64 patients who received PBT at 74 Gy (RBE) concurrently with chemotherapy. The OS in our study is also inferior to that reported for both groups by Bradley et al.
      • Bradley JD
      • Paulus R
      • Komaki R
      • et al.
      Standard-dose versus high-dose conformal radiation therapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small cell lung cancer (RTOG 0617): A randomized, 2-by-2 factorial P.
      This could be due to the difference in populations, as registries like the one from our study often recruit all patients without the strict exclusion criteria of RCT.
      In the future, such cohort studies may become increasingly important, due to the difficulties of conducting RCTs. As an example, at least 2 phase II proton studies have been prematurely closed in recent years, partly due to poor accrual.
      • Hoppe BS
      • Henderson R
      • Pham D
      • et al.
      A phase 2 trial of concurrent chemotherapy and proton therapy for stage III non-small cell lung cancer: Results and reflections following early closure of a single-institution study.
      ,
      • Nantavithya C
      • Gomez DR
      • Wei X
      • et al.
      Phase 2 study of stereotactic body radiation therapy and stereotactic body proton therapy for high-risk, medically inoperable, early stage non-small cell lung cancer.
      Some authors have raised awareness about the problem of lack of clinical equipoise getting in the way of well-conducted RCTs.
      • Goitein M
      • Cox JD.
      Should randomized clinical trials be required for proton radiation therapy?.
      ,
      • Widder J
      • van der Schaaf A
      • Lambin P
      • et al.
      The quest for evidence for proton therapy: Model-based approach and precision medicine.
      ,
      • Bentzen SM.
      Randomized controlled trials in health technology assessment: Overkill or overdue?.
      The fact that PBT reduces the dose to the normal tissues has been widely accepted for many years now.
      • Goitein M
      • Cox JD.
      Should randomized clinical trials be required for proton radiation therapy?.
      ,
      • Chang JY
      • Jabbour SK
      • De Ruysscher D
      • et al.
      Consensus statement on proton therapy in early stage and locally advanced non–small cell lung cancer.
      ,
      • Zhang X
      • Li Y
      • Pan X
      • et al.
      Intensity modulated proton therapy reduces the dose to normal tissue compared with intensity modulated radiation therapy or passive scattering proton therapy and enables individualized radical radiation therapy for extensive stage IIIB non-small cell lung cancer.
      ,
      • Suit H
      • Kooy H
      • Trofimov A
      • et al.
      Should positive phase III clinical trial data be required before proton beam therapy is more widely adopted? No.
      Knowing that no radiation dose is beneficial to healthy tissues,
      • Goitein M
      • Cox JD.
      Should randomized clinical trials be required for proton radiation therapy?.
      ,
      • Suit H
      • Kooy H
      • Trofimov A
      • et al.
      Should positive phase III clinical trial data be required before proton beam therapy is more widely adopted? No.
      some clinicians find themselves in front of an ethical dilemma, refusing to randomize patients. Another factor limiting the recruitment of patients in RCTs comparing protons and photons is insurance denial, due to the higher cost of PBT.
      • Hoppe BS
      • Henderson R
      • Pham D
      • et al.
      A phase 2 trial of concurrent chemotherapy and proton therapy for stage III non-small cell lung cancer: Results and reflections following early closure of a single-institution study.
      ,
      • Nantavithya C
      • Gomez DR
      • Wei X
      • et al.
      Phase 2 study of stereotactic body radiation therapy and stereotactic body proton therapy for high-risk, medically inoperable, early stage non-small cell lung cancer.
      Nevertheless, some large RCTs are currently enrolling patients in the United States.
      • Chang JY
      • Jabbour SK
      • De Ruysscher D
      • et al.
      Consensus statement on proton therapy in early stage and locally advanced non–small cell lung cancer.
      Results from the RTOG 1308 trial, comparing proton to photon RT with concomitant platinum-based chemotherapy in patients with stage II to IIIB NSCLC, are expected in 2024, approximately ten years after its start.
      Radiation Therapy Oncology Group
      RTOG 1308: Comparing photon therapy to proton therapy to treat patients with lung cancer.
      With such a fast-changing technology, however, the RT techniques may be outdated by the time the results are published.
      • Widder J
      • van der Schaaf A
      • Lambin P
      • et al.
      The quest for evidence for proton therapy: Model-based approach and precision medicine.
      ,
      • Langendijk JA
      • Lambin P
      • De Ruysscher D
      • Widder J
      • Bos M
      • Verheij M.
      Selection of patients for radiation therapy with protons aiming at reduction of side effects: The model-based approach.
      This is well illustrated in this trial, where recruitment began with patients in the proton group being treated with PSPT, compared with IMRT in the photon group.
      • Verma V
      • Chang JY.
      Controversies in dose-escalation for locally advanced non-small cell lung cancer and the role of proton beam therapy.
      ,
      Radiation Therapy Oncology Group
      RTOG 1308: Comparing photon therapy to proton therapy to treat patients with lung cancer.
      The Netherlands’ model-based approach is one of the alternatives to RCTs.
      • Widder J
      • van der Schaaf A
      • Lambin P
      • et al.
      The quest for evidence for proton therapy: Model-based approach and precision medicine.
      ,
      • Langendijk JA
      • Lambin P
      • De Ruysscher D
      • Widder J
      • Bos M
      • Verheij M.
      Selection of patients for radiation therapy with protons aiming at reduction of side effects: The model-based approach.
      Another possibility (or rather supplement) would be the use of phase IV studies for RT, or radiovigilance, similar to what is done in pharmacovigilance, as mentioned by Bentzen
      • Bentzen SM.
      Randomized controlled trials in health technology assessment: Overkill or overdue?.
      : “The point here is that nonrandomized, or ‘observational,’ studies should be seen as a complement to, rather than a substitute for, randomized controlled trials of treatment outcome.”
      The limiting factor to the acceptance of PBT seems to be mainly financial; PBT is more expensive than even the most advanced forms of photon-based RT.
      • Goitein M
      • Cox JD.
      Should randomized clinical trials be required for proton radiation therapy?.
      ,
      • Suit H
      • Kooy H
      • Trofimov A
      • et al.
      Should positive phase III clinical trial data be required before proton beam therapy is more widely adopted? No.
      ,
      • Smith WP
      • Richard PJ
      • Zeng J
      • Apisarnthanarax S
      • Rengan R
      • Phillips MH.
      Decision analytical modeling for the economic analysis of proton radiation therapy for non-small cell lung cancer.
      A study published in 2018 estimated the cost of a 30-course PBT treatment with concurrent chemotherapy for stage III NSCLC to be 72% higher than IMRT.
      • Smith WP
      • Richard PJ
      • Zeng J
      • Apisarnthanarax S
      • Rengan R
      • Phillips MH.
      Decision analytical modeling for the economic analysis of proton radiation therapy for non-small cell lung cancer.
      More than physicians, health technology assessment experts are the ones who need evidence to evaluate whether the clinical benefit brought by PBT is worth the financial surplus.
      • Goitein M
      • Cox JD.
      Should randomized clinical trials be required for proton radiation therapy?.
      ,
      • Bentzen SM.
      Randomized controlled trials in health technology assessment: Overkill or overdue?.
      ,
      • Suit H
      • Kooy H
      • Trofimov A
      • et al.
      Should positive phase III clinical trial data be required before proton beam therapy is more widely adopted? No.
      Finally, it is important to put these financial costs into perspective. The cost of RT is a small part of the global budget for cancer care.
      • Goitein M
      • Cox JD.
      Should randomized clinical trials be required for proton radiation therapy?.
      ,
      • Bentzen SM.
      Randomized controlled trials in health technology assessment: Overkill or overdue?.
      Although it is true that the wider use of PBT would increase its share in the total cost, it would still be minimal compared with some modern drugs that can improve the OS by a few months in the palliative setting.
      • Goitein M
      • Cox JD.
      Should randomized clinical trials be required for proton radiation therapy?.
      ,
      • Rengan R
      • Redman M
      • Zeng J.
      Challenge of proving the value of proton therapy in an unselected patient population in the era of precision oncology: The fallacy of a one-size-fits-all strategy in radiation therapy for lung cancer.
      ,
      • Bentzen SM.
      Randomized controlled trials in health technology assessment: Overkill or overdue?.

      Conclusions

      This study confirms the safe use of PBT with low rates of AEs and promising OS in spite of the unselected population. Besides, the use of PBS and increased treatment dose (EQD2) have shown to be associated with an increased OS.
      With the difficulty to conduct RCTs and fast technological improvements, prospective registries such as the one created by the PCG will have great importance in the future. Nonetheless, it is essential that participating centers meticulously update follow-up information, without which survival and late AE reports will not reflect the clinical reality.

      Acknowledgments

      We would like to thank the PCG and its members for the access to the database as well as their support throughout the project.

      References

      1. Ferlay J, Ervik M, Lam F, et al. Global Cancer Observatory: Cancer today. Lyon, Fr Int Agency Res Cancer 2020. Available at: https://gco.iarc.fr/today. Accessed January 19, 2021.

        • Vyfhuis MAL
        • Onyeuku N
        • Diwanji T
        • et al.
        Advances in proton therapy in lung cancer.
        Ther Adv Respir Dis. 2018; 12175346661878387
        • Liao Z
        • Lee JJ
        • Komaki R
        • et al.
        Bayesian adaptive randomization trial of passive scattering proton therapy and intensity modulated photon radiation therapy for locally advanced non–small cell lung cancer.
        J Clin Oncol. 2018; 36: 1813-1822
        • Guberina M
        • Eberhardt W
        • Stuschke M
        • et al.
        Heart dose exposure as prognostic marker after radiation therapy for resectable stage IIIA/B non-small cell lung cancer: Secondary analysis of a randomized trial.
        Ann Oncol. 2017; 28: 1084-1089
        • Goitein M
        • Cox JD.
        Should randomized clinical trials be required for proton radiation therapy?.
        J Clin Oncol. 2008; 26: 175-176
        • Widder J
        • van der Schaaf A
        • Lambin P
        • et al.
        The quest for evidence for proton therapy: Model-based approach and precision medicine.
        Int J Radiat Oncol. 2016; 95: 30-36
        • Chang JY
        • Jabbour SK
        • De Ruysscher D
        • et al.
        Consensus statement on proton therapy in early stage and locally advanced non–small cell lung cancer.
        Int J Radiat Oncol. 2016; 95: 505-516
        • Langendijk JA
        • Lambin P
        • De Ruysscher D
        • Widder J
        • Bos M
        • Verheij M.
        Selection of patients for radiation therapy with protons aiming at reduction of side effects: The model-based approach.
        Radiother Oncol. 2013; 107: 267-273
        • Nichols RC
        • Huh SN
        • Henderson RH
        • et al.
        Proton radiation therapy offers reduced normal lung and bone marrow exposure for patients receiving dose-escalated radiation therapy for unresectable stage iii non-small cell lung cancer: A dosimetric study.
        Clin Lung Cancer. 2011; 12: 252-257
        • Chang JY
        • Zhang X
        • Wang X
        • et al.
        Significant reduction of normal tissue dose by proton radiation therapy compared with 3-dimensional conformal or intensity modulated radiation therapy in stage I or stage III non-small cell lung cancer.
        Int J Radiat Oncol Biol Phys. 2006; 65: 1087-1096
        • Zhang X
        • Li Y
        • Pan X
        • et al.
        Intensity modulated proton therapy reduces the dose to normal tissue compared with intensity modulated radiation therapy or passive scattering proton therapy and enables individualized radical radiation therapy for extensive stage IIIB non-small cell lung cancer.
        Int J Radiat Oncol. 2010; 77: 357-366
        • Verma V
        • Chang JY.
        Controversies in dose-escalation for locally advanced non-small cell lung cancer and the role of proton beam therapy.
        J Thorac Dis. 2018; 10: S1124-S1126
        • Rengan R
        • Redman M
        • Zeng J.
        Challenge of proving the value of proton therapy in an unselected patient population in the era of precision oncology: The fallacy of a one-size-fits-all strategy in radiation therapy for lung cancer.
        J Clin Oncol. 2018; 36: 2003-2004
        • Bradley JD
        • Paulus R
        • Komaki R
        • et al.
        Standard-dose versus high-dose conformal radiation therapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small cell lung cancer (RTOG 0617): A randomized, 2-by-2 factorial P.
        Lancet Oncol. 2015; 16: 187-199
        • Chao H-H
        • Berman AT
        • Simone CB
        • et al.
        Multi-institutional prospective study of reirradiation with proton beam radiation therapy for locoregionally recurrent non–small cell lung cancer.
        J Thorac Oncol. 2017; 12: 281-292
        • McAvoy SA
        • Ciura KT
        • Rineer JM
        • et al.
        Feasibility of proton beam therapy for reirradiation of locoregionally recurrent non-small cell lung cancer.
        Radiother Oncol. 2013; 109: 38-44
        • Badiyan SN
        • Rutenberg MS
        • Hoppe BS
        • et al.
        Clinical outcomes of patients with recurrent lung cancer reirradiated with proton therapy on the Proton Collaborative Group and University of Florida Proton Therapy Institute prospective registry studies.
        Pract Radiat Oncol. 2019; : 1-9
        • Darby SC
        • Ewertz M
        • McGale P
        • et al.
        Risk of ischemic heart disease in women after radiation therapy for breast cancer.
        N Engl J Med. 2013; 368: 987-998
        • Speirs CK
        • DeWees TA
        • Rehman S
        • et al.
        Heart dose is an independent dosimetric predictor of overall survival in locally advanced non–small cell lung cancer.
        J Thorac Oncol. 2017; 12: 293-301
        • Antonia SJ
        • Villegas A
        • Daniel D
        • et al.
        Overall survival with Durvalumab after chemoradiotherapy in stage III NSCLC.
        N Engl J Med. 2018; 379: 2342-2350
        • Choi JI
        • Simone II CB
        Breaking the dose ceiling: Proton therapy for locally advanced non-small cell lung cancer.
        J Thorac Dis. 2018; 10: 130-134
        • Chang JY
        • Zhang X
        • Knopf A
        • et al.
        Consensus guidelines for implementing pencil-beam scanning proton therapy for thoracic malignancies on behalf of the PTCOG Thoracic and Lymphoma Subcommittee.
        Int J Radiat Oncol. 2017; 99: 41-50
        • Inoue T
        • Widder J
        • van Dijk LV
        • et al.
        Limited impact of setup and range uncertainties, breathing motion, and interplay effects in robustly optimized intensity modulated proton therapy for stage III nonsmall cell lung cancer.
        Int J Radiat Oncol. 2016; 96: 661-669
        • Chang JY
        • Verma V
        • Li M
        • et al.
        Proton beam radiation therapy and concurrent chemotherapy for unresectable stage III non–small cell lung cancer.
        JAMA Oncol. 2017; 3e172032
        • Higgins KA
        • O'Connell K
        • Liu Y
        • et al.
        National Cancer Database analysis of proton versus photon radiation therapy in non-small cell lung cancer.
        Int J Radiat Oncol. 2017; 97: 128-137
        • Hoppe BS
        • Henderson R
        • Pham D
        • et al.
        A phase 2 trial of concurrent chemotherapy and proton therapy for stage III non-small cell lung cancer: Results and reflections following early closure of a single-institution study.
        Int J Radiat Oncol. 2016; 95: 517-522
        • Nantavithya C
        • Gomez DR
        • Wei X
        • et al.
        Phase 2 study of stereotactic body radiation therapy and stereotactic body proton therapy for high-risk, medically inoperable, early stage non-small cell lung cancer.
        Int J Radiat Oncol. 2018; 101: 558-563
        • Bentzen SM.
        Randomized controlled trials in health technology assessment: Overkill or overdue?.
        Radiother Oncol. 2008; 86: 142-147
        • Suit H
        • Kooy H
        • Trofimov A
        • et al.
        Should positive phase III clinical trial data be required before proton beam therapy is more widely adopted? No.
        Radiother Oncol. 2008; 86: 148-153
        • Radiation Therapy Oncology Group
        RTOG 1308: Comparing photon therapy to proton therapy to treat patients with lung cancer.
        ClinicalTrialsGov. 2013; (Available at:)
        • Smith WP
        • Richard PJ
        • Zeng J
        • Apisarnthanarax S
        • Rengan R
        • Phillips MH.
        Decision analytical modeling for the economic analysis of proton radiation therapy for non-small cell lung cancer.
        Transl Lung Cancer Res. 2018; 7: 122-133