Abstract
Introduction:
Adjuvant immunotherapy (IO) following concurrent chemotherapy and photon radiation therapy confers an overall survival (OS) benefit for patients with inoperable locally advanced non-small cell lung carcinoma (LA-NSCLC); however, outcomes of adjuvant IO after concurrent chemotherapy with proton beam therapy (CPBT) are unknown. We investigated OS and toxicity after CPBT with adjuvant IO versus CPBT alone for inoperable LA-NSCLC.
Materials and Methods:
We analyzed 377 patients with LA-NSCLC who were prospectively treated with CPBT with or without adjuvant IO from 2009–2021. Optimal variable ratio propensity score matching (PSM) matched CPBT with CPBT+IO patients. Survival was estimated with the Kaplan-Meier method and compared with log-rank tests. Multivariable Cox proportional hazards regression evaluated the effect of IO on disease outcomes.
Results:
Median age was 70 years; 71 (20%) received CPBT+IO and 283 (80%) received CPBT only. After PSM, 71 CPBT patients were matched with 71 CPBT+IO patients. Three-year survival rates for CPBT+IO vs CPBT were: OS 67% vs 30% (P<0.001) and PFS 59% vs 35% (P=0.017). Three-year LRFS (P=0.137) and DMFS (P=0.086) did not differ. Receipt of adjuvant IO was a strong predictor of OS (HR 0.40, P=0.001) and PFS (HR 0.56, P=0.030), but not LRFS (HR 0.61, P=0.121) or DMFS (HR 0.61, P=0.136). There was an increased incidence of grade ≥3 esophagitis in the CPBT-only group (6% CPBT+IO vs 17% CPBT, P=0.037).
Conclusion:
This study, one of the first to investigate CPBT followed by IO for inoperable LA-NSCLC, showed that IO conferred survival benefits with no increased rates of toxicity.
INTRODUCTION
For 20 years, the standard therapy for inoperable locally advanced non-small cell lung carcinoma (LA-NSCLC) was definitive concurrent chemotherapy and photon radiation therapy (RT). In 2018, based on the findings from the landmark PACIFIC trial demonstrating an overall survival (OS) benefit from adding adjuvant durvalumab to standard chemotherapy and photon RT, the US Food and Drug Administration approved the adjuvant ICI durvalumab as a new standard of care in such cases.1,2 Nevertheless, RT-related cardiac and pulmonary toxicity remains a significant source of morbidity and mortality in LA-NSCLC survivors,3,4 and radiation-induced lymphopenia (RIL) attenuates the effectiveness of immune checkpoint inhibitors for these patients.5,6
Although an essential treatment for LA-NSCLC, RT can be technically challenging because of the proximity of pulmonary tumors to nearby critical organs. The most effective strategy for reducing toxicity is decreasing unnecessary irradiation of normal tissues by using advanced technology. Over the past 20 years, dose-conforming RT techniques such as intensity-modulated radiation therapy (IMRT) have shown promise for improving toxicity by better sparing of nearby normal tissues compared with the prior techniques of 2D and 3D RT.7–9 Specifically, a secondary analysis of RTOG 0617 showed that the reduction in radiation dose to the heart in patients given IMRT rather than 3D RT may lead to an OS benefit.8 The use of proton-beam therapy (PBT) over photon RT may offer further advantages because of the unique physical characteristics of proton particles that allow them to deposit all of their energy at a prespecified depth in tissue (the Bragg peak), thereby further sparing normal tissues.10 Indeed, we previously showed that intensity-modulated proton radiation therapy (IMPT) led to lower radiation dose to the lungs, heart, and esophagus than IMRT and passive scattered proton beam therapy (PSPT).11 IMPT was associated with lower rates of severe grade ≥3 cardiopulmonary toxicity compared with PSPT.12 Our group also showed that severe RIL was associated with greater radiation to the lung and spleen and that the use of PBT reduced the risk of RIL.13,14 Thus, PBT may be one strategy to mitigate the burden of RT-related toxicity in patients with NSCLC.
Although a survival benefit from immunotherapy and a potential toxicity benefit from PBT hold promise, little is known of the efficacy and safety of combining the two for patients with inoperable LA-NSCLC, as the PACIFIC trial involved photon RT rather than PBT. Prior studies have shown that immunotherapy is safe to administer after photon RT,15 but PBT has yet to be studied in this context even though immunotherapy and PBT are both known to have immunomodulatory effects.16–18 Thus, we undertook a study of patients with inoperable LA-NSCLC who were enrolled to one of two prospective protocols and received concurrent chemotherapy and PBT (CPBT) with or without adjuvant immunotherapy (IO) and compared OS and toxicity outcomes between the two groups.
MATERIALS AND METHODS
Patients
This study included patients diagnosed with LA-NSCLC who were prospectively consecutively treated on two protocols with CPBT either using IMPT or PSPT, with or without adjuvant IO, at a single institution from January 2009 through December 2021. Patients provided informed consent to enroll either on a protocol specifically designed to assess normal tissue effects (CliniclTrial.gov registration: NCT00991094) or a prospective randomized clinical trial (CliniclTrial.gov registration: NCT00915005).19 All treatments, disease and toxicity outcome data were prospectively collected. These two studies were approved by the institutional review board. Inclusion criteria were histologic diagnosis of adenocarcinoma, squamous cell carcinoma, or NSCLC not otherwise specified; clinical stage II-IIIB disease (AJCC Version 7); mediastinal recurrence after surgical resection for which the recommended treatment was concurrent chemoradiation; PBT given either as passive scattered proton therapy (PSPT) or IMPT; and a definitive-intent radiation dose at least 60 cobalt-Gray equivalent (CGE) to the planning target volume (PTV). Patients were excluded if PBT was given as post-operative treatment, re-irradiation, or without concurrent chemotherapy. Patients were excluded if they developed disease progression or died within six weeks following radiation therapy completion and before the opportunity to begin IO (n=23).
Treatment and interventions
Treatment consisted of definitive PSPT or IMPT with concurrent chemotherapy, with or without induction or adjuvant chemotherapy, and with or without adjuvant IO. Concurrent chemotherapy most often consisted of weekly intravenous (IV) infusions of carboplatin plus paclitaxel. Adjuvant IO was most often durvalumab (n=60); 11 patients were treated with other IO agents (atezolizumab [n=7], pembrolizumab [n=3], and nivolumab [n=1]). The PSPT and IMPT treatment planning process is described elsewhere.12 Briefly, each patient underwent standard RT planning procedures that included 4D CT simulation scanning for motion assessment. The gross tumor was contoured as the internal gross tumor volume (iGTV). The clinical target volume (CTV) was defined as the iGTV with a 7–8 mm expansion, excluding anatomic boundaries. A 5-mm expansion was then added to the CTV to create the final PTV. The prescribed dose to the PTV was 60 CGE. Elective nodal irradiation was not used in either group.
Patient evaluation
All patients underwent standard pretreatment disease-staging evaluation. During CPBT, patients were evaluated weekly in a radiation clinic. After treatment completion, patients were followed with surveillance imaging and physical examination every 3 months for 2–3 years, and then every 6 months thereafter.
Toxicity was assessed by the treating physician and scored according to the Common Terminology Criteria for Adverse Effects version 4.0. All clinically meaningful (grade ≥3) cardiac and pulmonary toxic effects were reviewed with a dedicated cardiologist and pulmonologist to confirm toxicity type and severity. Interval PET-CT scans and biopsy of suspicious lesions were obtained at the discretion of the treating physician.
Study endpoints
The primary endpoints were OS, distant metastasis-free survival (DMFS), local-regional recurrence-free survival (LRFS), and progression-free survival (PFS). Local recurrence was defined as treatment failure within the PTV plus a 1 cm margin or less; regional recurrence as the development of new intrathoracic disease outside the local recurrence region; and distant recurrence as development of new disease outside the thorax. Disease progression was defined as the presence of a local, regional, or distant recurrence identified on imaging (CT, PET/CT, or magnetic resonance imaging [MRI]) and confirmed on pathology review. The time to failure was calculated from the date of CPBT completion to the date of the imaging study showing progression. The date of death was extracted from the medical record or from online obituary records. The time to death was calculated from the date of CPBT completion to the date of death.
Statistical analysis
Patients were grouped as receiving CPBT or CPBT+IO. The estimation was defined as the average treatment effect of treated (i.e., CBPT+IO). The primary comparative analyses were done based on propensity score matching (PSM) using optimal variable ratio.20–22 Propensity scores were calculated by multivariable logistic regression model, including age, race, sex, disease stage, tumor histology and volume, performance status, receipt of induction chemotherapy, radiation technique, and total delivered dose. The match tolerance was set at 0.025. The match ratios were between 1–4. The average treatment effect for patients treated with adjuvant IO was estimated after matching. Initially, 178 CPBT patients were matched with 71 CPBT+IO patients, and then weighted to 71 patients by the inverse of match ratios. After PSM, both treatment groups had equal number of patients (n=71) and were compared for treatment effect. The matched population was well-balanced in demographic and tumor characteristics with standard mean difference (SMD) <0.25 (Supplementary Figure S1, Table 1). Patient, disease, and treatment characteristics were compared using Pearson’s chi-square for categorical variables and two-sided t tests for continuous variables. Survival times were estimated with the Kaplan-Meier survival function and compared by the log-rank test. Multivariable Cox proportional hazards regression was used to evaluate the effect of adjuvant IO on disease outcomes, with adjustment for clinical covariates. A P value of less than 0.05 was considered to indicate statistical significance. All analyses were done with SAS 9.4 (SAS Institute Inc., Cary, NC, USA).
Table 1.
Patient, disease, and treatment characteristics of the study population (n=354).
| Variables | Total (n=354) | CPBT+IO (n=71) | CPBT | |||
|---|---|---|---|---|---|---|
|
| ||||||
| All (n=283) | P * | PSM (n=71) | P# | |||
|
| ||||||
| Age, median, years (range) | 70 (33–89) | 71 (53–86) | 69 (33–89) | 0.010 | 70 (47–89) | 0.794 |
| Sex | 0.380 | 0.887 | ||||
| Female | 161 (45%) | 29 (41%) | 132 (47%) | 28 (40%) | ||
| Male | 193 (55%) | 42 (59%) | 151 (53%) | 43 (60%) | ||
| Race | 0.021 | 0.586 | ||||
| White | 316 (89%) | 58 (82%) | 258 (91%) | 60 (85%) | ||
| Other | 38 (11%) | 13 (18%) | 25 (9%) | 11 (15%) | ||
| Histology Type | 0.569 | 0.931 | ||||
| Adenocarcinoma | 180 (51%) | 36 (51%) | 152 (50%) | 34 (48%) | ||
| Squamous cell carcinoma | 137 (39%) | 30 (42%) | 119 (39%) | 31 (44%) | ||
| Others | 37 (10%) | 5 (7%) | 34 (11%) | 6 (8%) | ||
| GTV, median, cm3 (range) | 79.6 (2.2–790.9) | 73.6 (3.4–636.1) | 83.7 (2.2–790.9) | 0.793 | 86.4 (11.1–647.7) | 0.477 |
| Tumor location | 0.212 | 0.329 | ||||
| Left | 164 (44%) | 37 (52%) | 126 (41%) | 27 (38%) | ||
| Right | 184 (49%) | 31 (44%) | 153 (50%) | 38 (54%) | ||
| Mediastinum | 18 (5%) | 1 (1%) | 17 (6%) | 3 (4%) | ||
| Two locations | 11 (3%) | 2 (3%) | 9 (3%) | 3 (4%) | ||
| Clinical stage | 0.298 | 0.993 | ||||
| I, II | 54 (15%) | 6 (8%) | 48 (17%) | 6 (8%) | ||
| IIIA | 145 (41%) | 29 (41%) | 116 (41%) | 33 (46%) | ||
| IIIB, IIIC | 137 (39%) | 32 (45%) | 105 (37%) | 29 (41%) | ||
| IV/Recurrent | 18 (5%) | 4 (6%) | 14 (5%) | 3 (5%) | ||
| ECOG | 0.836 | 0.191 | ||||
| 0–1 | 327 (92%) | 66 (93%) | 261 (92%) | 61 (86%) | ||
| 2–3 | 27 (8%) | 5 (7%) | 22 (8%) | 10 (14%) | ||
| Smoking status | 0.771 | 0.868 | ||||
| Previous | 260 (73%) | 52 (73%) | 208 (74%) | 50 (71%) | ||
| Current | 49 (14%) | 8 (11%) | 41(14%) | 9 (13%) | ||
| Never | 35 (10%) | 9 (13%) | 26 (9%) | 8 (11%) | ||
| Unknown | 10 (3%) | 2 (3%) | 8 (3%) | 4 (5%) | ||
| RT technique | <0.001 | 0.663 | ||||
| PSPT | 292 (82%) | 44 (62%) | 248 (88%) | 47 (65%) | ||
| IMPT | 62 (18%) | 27 (38%) | 35 (12%) | 25 (35%) | ||
| Delivered RT dose | <0.001 | 0.435 | ||||
| 60–66Gy | 159 (45%) | 52 (73%) | 107 (38%) | 48 (67%) | ||
| >66Gy | 195 (55%) | 19 (27%) | 176 (62%) | 23 (33%) | ||
| Chemotherapy | ||||||
| Induction chemotherapy | 78 (22%) | 9 (13%) | 69 (24%) | 0.033 | 11 (15%) | 0.671 |
| Adjuvant chemotherapy | 66 (19%) | 0 (0%) | 66 (23%) | - | 17 (24%) | - |
Note: P-values computed by Pearson Chi-square or T-test in CPBT+IO vs *CPBT original cohort or #CPBT PSM cohort.
Abbreviations: PSM, propensity score match; CPBT, concurrent chemotherapy with proton beam therapy; IO, immunotherapy; GTV, gross tumor volume; SCC, squamous cell carcinoma; Adeno, adenocarcinoma; ECOG, performance status score developed by the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network; PSPT, passive scattered proton therapy; IMPT, intensity-modulated proton radiation therapy.
RESULTS
A total of 354 patients with inoperable LA-NSCLC were included in the study (Figure 1); patient, disease, and treatment characteristics for all patients are shown in Table 1. All patients were treated with definitive CPBT (total radiation dose ≥60 Gy). The median patient age was 70 years; most were white (89%), previous or current smokers (87%), had stage III disease (80%) and good performance status (ECOG score 0–1, 92%). More patients were treated with PSPT (82%) than with IMPT (18%). A total of 71 patients (20%) received CPBT plus IO and 283 (80%) did not receive IO (CPBT-only). Patients in the CPBT+IO group were older (median age 71 vs 69 years, P=0.010), less white ethnic (82% vs 91%, P=0.021), received less induction chemotherapy (13% vs 24%, P=0.033), and more received IMPT (38% vs 12%, P<0.001) than in the CPBT-only group. The CPBT+IO group also included more patients treated with 60–66 Gy than the CPBT-only group (73% vs 38%, P<0.001). In PSM cohort (n=142), patients’ age, race, induction chemotherapy, radiation technique, total tumor dose, and other characteristics were well balanced without significant differences between treatment groups (Table 1).
Figure 1.
CONSORT diagram. Abbreviations: NSCLC, non-small cell lung cancer; CPBT, concurrent chemotherapy with proton beam therapy; IO, immunotherapy.
The median follow-up time for the entire cohort was 20 months (interquartile range [IQR]: 10–39 months); 14 months for the CPBT+IO group (IQR: 8–30 months) and 22 months for the CPBT-only group (IQR: 10–39 months). Kaplan-meier survival estimates for all survival outcomes in PSM cohort were plotted in Figure 2. In PSM cohort, the median survival time for all patients was 33 months, and the 3-year OS rate was 45% (Table 2). Median survival time in the CPBT+IO group was not reached (but exceeded 36 months) and was 21 months in the CPBT-only group (Table 2 and Figure 2A). The 3-year survival rates for the CPBT+IO group vs. the CPBT-only group were: OS 67% vs 30% (P<0.001) and PFS 59% vs 35% (P=0.017). Three-year LRFS (71% vs 54%, P=0.137) and DMFS (72% vs 58%, P=0.086) did not differ (Table 2). The median survival time, survival rates and survival plots for the total population are shown in Supplementary Table S1 and Figure S2.
Figure 2.
Kaplan-Meier survival estimates of disease outcomes in propensity score–matched cohort, stratified by receipt of immunotherapy. Abbreviations: IO, immunotherapy; OS, overall survival; LRFS, locoregional-free survival; DMFS, distant metastasis-free survival; PFS, progression-free survival.
Table 2.
Median overall survival time and 3-year survival rates in propensity score matched population (n=142).
| Endpoints | Total (n=142) | CPBT+IO (n=71) | CPBT (n=71) | P |
|---|---|---|---|---|
|
| ||||
| Median OS (95% CI) | 33 (25–41) months | Not reached | 21 (16–27) months | <0.001 |
| 3-year OS (95% CI) | 45 (36–53) % | 67 (49–80) % | 30 (21–38) % | <0.001 |
| 3-year LRFS (95% CI) | 63 (53–71) % | 71 (55–82) % | 54 (42–65) % | 0.137 |
| 3-year DMFS (95% CI) | 65 (55–73) % | 72 (55–83) % | 58 (47–68) % | 0.086 |
| 3-year PFS (95% CI) | 47 (38–56) % | 59 (43–72) % | 35 (25–45) % | 0.017 |
Note: P-values computed by log-rank test.
Abbreviations: Concurrent chemotherapy with proton beam therapy (CPBT), immunotherapy (IO), overall survival (OS), locoregional-free survival (LRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS).
Univariable and multivariable regression analysis for survival outcomes in the PSM cohort are listed in Supplementary Table S2 and Table 3. Multivariable regression confirmed that receipt of adjuvant IO was a strong predictor of OS (HR 0.40, 95% CI 0.23–0.69, P=0.001) and PFS (HR 0.56, 95% CI 0.34–0.95, P=0.030) with adjustment of clinical covariables, however receipt of adjuvant IO was not associated with LRFS (HR 0.61, 95% CI 0.32–1.14, P=0.121) or DMFS (HR 0.61, 95% CI 0.32–1.17, P=0.136). Greater GTV volume was a predictor of worse OS, LRFS, DMFS, and PFS (P<0.05). In addition, smoking was associated with LRFS.
Table 3.
Multivariable cox regression analysis for disease outcome in propensity score matched patients (n=142).
| Variables | OS | LRFS | DMFS | PFS | ||||
|---|---|---|---|---|---|---|---|---|
| HR (95%CI) | P | HR (95%CI) | P | HR (95%CI) | P | HR (95%CI) | P | |
| Immunotherapy | 0.40 (0.23–0.69) | 0.001 | 0.61 (0.32–1.14) | 0.121 | 0.61 (0.32–1.17) | 0.136 | 0.56 (0.34–0.95) | 0.030 |
| Age | 1.04 (1.00–1.08) | 0.052 | 0.99 (0.95–1.03) | 0.552 | 0.99 (0.95–1.04) | 0.639 | 1.00 (0.97–1.04) | 0.874 |
| Sex | ||||||||
| Males vs Females | 1.18 (0.69–2.01) | 0.731 | 0.80 (0.41–1.56) | 0.518 | 1.31 (0.63–2.72) | 0.472 | 0.99 (0.55–1.79) | 0.979 |
| Race | ||||||||
| White vs Others | 0.65 (0.33–1.27) | 0.206 | 0.97 (0.46–2.03) | 0.936 | 0.51 (0.26–1.02) | 0.058 | 0.71 (0.39–1.26) | 0.241 |
| Histology | ||||||||
| Adeno | 1 | 1 | 1 | 1 | ||||
| SCC | 0.93 (0.58–1.48) | 0.761 | 1.08 (0.60–1.93) | 0.801 | 0.63 (0.33–1.20) | 0.157 | 0.74 (0.48–1.16) | 0.190 |
| Others | 1.21 (0.58–2.53) | 0.613 | 1.79 (0.52–6.16) | 0.353 | 1.00 (0.27–3.70) | 0.998 | 0.93 (0.30–2.85) | 0.893 |
| Clinical Stage | ||||||||
| Stage II | 1.29 (0.54–3.09) | 0.565 | 1.67 (0.55–5.09) | 0.368 | 0.54 (0.18–1.61) | 0.266 | 1.32 (0.52–3.37) | 0.558 |
| Stage IIIA | 1 | 1 | 1 | 1 | ||||
| Stage IIIB, IIIC | 1.12 (0.69–1.81) | 0.662 | 1.28 (0.63–2.60) | 0.497 | 1.45 (0.66–3.16) | 0.355 | 1.32 (0.73–2.38) | 0.366 |
| Recurrent | 3.21 (0.78–13.21) | 0.106 | 3.62 (0.83–15.77) | 0.087 | 0.98 (0.19–5.06) | 0.984 | 2.40 (0.62–9.22) | 0.204 |
| Tumor location | ||||||||
| Right | 1 | 1 | 1 | 1 | ||||
| Left | 0.79 (0.50–1.23) | 0.295 | 1.39 (0.76–2.56) | 0.290 | 1.36 (0.68–2.73) | 0.384 | 1.47 (0.90–2.38) | 0.123 |
| Mediastinal | 0.86 (0.40–1.83) | 0.692 | 0.40 (0.10–1.63) | 0.203 | 1.58 (0.58–4.34) | 0.371 | 1.50 (0.64–3.50) | 0.352 |
| Two locations | 0.30 (0.09–1.03) | 0.056 | 0.06 (0.00–0.92) | 0.044 | 0.74 (0.18–3.09) | 0.677 | 0.37 (0.10–1.40) | 0.144 |
| GTV | 1.003 (1.001–1.005) | 0.006 | 1.002 (1.000–1.005) | 0.024 | 1.003 (1.001–1.006) | 0.017 | 1.002 (1.000–1.004) | 0.046 |
| ECOG | ||||||||
| 2–3 vs 0–1 | 1.23 (0.60–2.52) | 0.571 | 0.65 (0.24–1.77) | 0.402 | 1.76 (0.50–6.19) | 0.376 | 1.44 (0.54–3.79) | 0.465 |
| Smoke | ||||||||
| Never | 1 | 1 | 1 | 1 | ||||
| Previous | 0.81 (0.32–2.07) | 0.658 | 0.41 (0.17–1.00) | 0.050 | 0.51 (0.16–1.65) | 0.264 | 0.53 (0.29–1.19) | 0.124 |
| Current | 1.04 (0.37–2.94) | 0.942 | 0.16 (0.04–0.67) | 0.012 | 1.07 (0.26–4.34) | 0.930 | 0.61 (0.21–1.77) | 0.361 |
| Induction chemotherapy | 0.76 (0.39–1.48) | 0.418 | 1.88 (0.73–4.77) | 0.182 | 0.88 (0.37–2.08) | 0.770 | 1.45 (0.67–3.14) | 0.345 |
| Radiation dose | ||||||||
| >66Gy vs 60–66Gy | 1.13 (0.89–1.43) | 0.318 | 1.15 (0.85–1.56) | 0.367 | 1.20 (0.85–1.67) | 0.301 | 1.18 (0.81–1.99) | 0.231 |
| RT Technique | ||||||||
| PSPT vs IMPT | 0.69 (0.43–1.10) | 0.119 | 0.70 (0.36–1.38) | 0.306 | 0.49 (0.26–0.93) | 0.029 | 0.67 (0.41–1.10) | 0.113 |
| MLD | 1.05 (1.00–1.11) | 0.064 | 1.03 (0.96–1.10) | 0.488 | 1.04 (0.97–1.16) | 0.313 | 1.04 (0.99–1.11) | 0.138 |
Abbreviations: HR, hazard ratio; CI, confidence interval; SCC, squamous cell carcinoma; Adeno, adenocarcinoma; ECOG, performance status score developed by the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network; PSPT, passive scattered proton therapy; IMPT, intensity-modulated proton radiation therapy.
Univariable and multivariable regression analysis results for survival outcomes in the total population were similar with the results of PSM cohort. The results are listed in Supplementary Table S3 and S4.
Treatment-related toxicities of the lung, esophagus, heart, and lymphocytes in PSM cohort are shown in Supplementary Table S5 and Figure 3. No significant differences were found in grade ≥2 or ≥3 pulmonary toxicity (pneumonia, pneumonitis, pulmonary fibrosis, pleural effusion) between groups (grade ≥2: 54% CPBT+IO vs 53% CPBT, P=0.967; grade ≥3: 20% CPBT+IO vs 30% CPBT, P=0.159). In the CPBT-only group, two patients experienced grade 5 pneumonitis or pneumonia. One patient in the CPBT+IO group experienced grade 5 pneumonia. No significant differences were found in grade≥2 or ≥3 cardiac toxicity (pericardial effusion, myocardial infarction, ischemia, pericarditis, arrhythmia, cardiac arrest, heart failure) between groups (grade ≥2: 32% CPBT+IO vs 36% CPBT, P=0.617; grade ≥3: 9% CPBT+IO vs 7% CPBT, P=0.754). In the CPBT-only group, one patient experienced grade 4 heart failure. In the CPBT+IO group, one patient experienced grade 4 myocardial infarction and one had grade 4 pericardial effusion. There was no significant difference found in grade ≥2 esophagitis (68% CPBT+IO vs 78% CPBT, P=0.162), however there was an increased incidence of grade ≥3 esophagitis in the CPBT-only group (6% CPBT+IO vs 17% CPBT, P=0.037) (Figure 3). The incidence of severe (grade ≥3) lymphopenia was 72% vs 82% in CPBT+IO vs CPBT and there was no difference in the incidence and severity of lymphopenia between treatment groups (P=0.154).
Figure 3.
Incidence rates of grade ≥2 and grade ≥3 adverse events after propensity score matching, stratified by receipt of immunotherapy (IO). Abbreviations: CPBT, concurrent chemotherapy with proton beam therapy.
DISCUSSION
This study was the first to compare survival and toxicity outcomes in patients with inoperable LA-NSCLC who received vs. did not receive adjuvant IO after CPBT for patients with inoperable LA-NSCLC. Patients who received CPBT plus adjuvant IO had better OS and PFS than those treated with CPBT only, consistent with what has been reported from PACIFIC trial. Rates of grade ≥3 pulmonary and cardiac toxicity were low and similar between groups. These findings demonstrate favorable efficacy and no increased toxicity with the use of IO after CPBT, supporting additional testing of this regimen for other patients with inoperable LA-NSCLC.
One of the notable findings of this study was the median OS time, which had not been reached at the time of analysis but exceeded 36 months in the CPBT+IO group versus 21 months in the CPBT-only group in PSM cohort. These outcomes were inferior to the median OS times reported in the PACIFIC trial (47.5 and 29.1 months in the durvalumab and non-durvalumab arms).23 Several factors may explain this discordance. First, the median age of patients in the current study was 70 years vs 64 years in the PACIFIC study. The higher median age in the current study probably reflects greater insurance coverage of proton therapy by Medicare as compared with private insurers; consequently, patients aged 65 years or older were more likely to receive proton RT and be included in this analysis.24 Moreover, older adults are also more likely to have comorbid conditions, and both older age and worse performance status were associated with worse OS in PACIFIC.23,25 Also, the follow-up time in the current study was 14 months for the CPBT+IO group vs a median 34 months in PACIFIC.23 Thus, maturation of data from the current study may reveal median survival times that more closely corroborate those in the PACIFIC trial with this older patient population.
Notably, the current study demonstrated acceptable esophageal, pulmonary, and cardiac toxicity rates from the use of adjuvant IO after CPBT. The immunomodulatory characteristics of immunotherapy and proton RT16–18 underscore the importance of establishing the safety profile of this regimen. Because low-grade IO-related adverse events can still occur more than 1 year after treatment completion,26 it will be important to closely monitor these patients during the surveillance period; however, the current study provides some confidence in the low rates of grade 3 acute or long-term toxicity in patients who received CPBT followed by IO.
There was a higher incidence of grade 3 or greater esophagitis in the CPBT alone group in our PSM analysis; however, this is due to radiation-specific factors as opposed to an affect from IO. This finding is likely multi-factorial due to the more frequent utilization of of PSPT (as compared to IMPT) with higher doses (>66 Gy) prescribed in the PBT alone group. Additionally, it is possible that the presence of severe esophagitis may have precluded patients from receiving IO. By decreasing the radiation dose to nearby normal organs, more conformal radiation modalities, such as IMPT or intensity-modulated radiation therapy, have been shown to reduce the incidence of acute radiation-related toxicities as compared to 3D radiation techniques.12,27 Moreover, the location of the esophagus within the mediastinum and with close proximity to the lungs in combination with higher total radiation doses likely caused a greater volume of the esophagus to receive large radiation doses, which has also been associated with higher incidence of acute radiation-related toxicities.27 Further investigations are warranted to examine esophageal toxicities with different radiation modalities and total doses, especially given the lack of survival benefit seen with greater total radiation dose (>66 Gy) observed in this study.
Lymphopenia is caused by radiation-induced DNA damage in peripheral circulating and bone marrow lymphocytes, and occurs in 40%–70% of patients undergoing fractionated RT.28 This toxicity may impact the outcomes for patients receiving IO because lymphocytes are direct mediators of the antitumor response created by IO agents.29 Indeed, several prior investigations have demonstrated an association between RIL and inferior survival outcomes in LA-NSCLC even when body sites containing lymphocytes are treated to relatively low radiation doses.30,31 Treatment with proton RT translates to lower exit doses and less overall low dose to nearby organs, suggesting that PBT may mitigate the effect of radiation on lymphocytes and perhaps reduced the severity of RIL. In esophageal cancer, PBT has been shown to significantly reduce the risk of RIL compared with photon RT.32 The current report has not included details of RIL analysis due to limitation of space. We are currently performing comprehensive analysis focusing on RIL because currently no such comparison has been done for LA-NSCLC.
This study had several strengths. To our knowledge, it is the first comparison of outcomes in patients who received vs. did not receive IO after proton RT for inoperable LA-NSCLC. By demonstrating the efficacy and safety of this regimen, this study provides justification for further exploring the use of adjuvant IO after CPBT because the PACIFIC trial did not include patients treated with proton RT. Moreover, the large numbers of patients in each group and the comprehensive PSM analysis to account for clinically meaningful factors provide confidence in our results and confirm our findings.
Conversely, this study had several limitations, first among them its non-randomized registrar nature to include consecutively treated patients reflecting real world experience rather than a prospective randomized trial. Most of the patients who received PSPT were from our reported randomized trial of PSPT and IMRT for NSCLC.19 As such, the CPBT-only and CPBT+IO groups differed in a few aspects; for example, more patients in the CPBT+IO group received IMPT rather than PSPT, which may have enhanced the survival benefit in the CPBT+IO group. This may be explained by CPBT+IO patients being treated more recently due to the approval of IO in 2018. In addition, IMPT became available for lung cancer patients at our institution in 2012 with limited accessibility which may have led to these CBPT+IO patients being treated with more advanced radiation technologies. However, our prior study showed no difference in survival outcomes in patients with LA-NSCLC treated with IMPT versus PSPT.12 Future investigations are needed with longer follow-up to evaluate survival differences between IMPT and PSPT in LA-NSCLC. Additionally, we did not control for comorbidities in our regression analysis, which may have revealed a contributor to the detrimental survival experienced by the CPBT-only group. However, patients in the CPBT-only group were significantly younger than those in the CPBT+IO group, suggesting that the OS difference was real. The fact that the survival curves began to separate immediately after completion of CPBT suggests that adjuvant IO has an early effect on distant metastasis, which would also translate to an OS benefit. Despite these differences between the CPBT-only and the CPBT+IO groups, our multivariable analysis and PSM analysis adjusted for these baseline differences and confirmed our main findings.
CONCLUSION
To our knowledge, this is the first study to compare survival and toxicity outcomes in patients with inoperable LA-NSCLC who received vs. did not receive adjuvant IO after definitive concurrent chemotherapy and proton RT from two prospective trials. Similar to the PACIFIC study, we found a survival benefit from adding adjuvant IO relative to chemotherapy and proton RT alone. We also found adjuvant IO to be associated with an acceptable toxicity profile, with similar pulmonary and cardiac toxicities between treatment groups. Detailed analyses and a report on RIL are underway. In summary, the findings from this study support the further exploration of adjuvant IO after proton RT for patients with inoperable LA-NSCLC.
Supplementary Material
HIGHLIGHTS.
In this study of 354 patients with inoperable locally advanced non-small cell lung carcinoma (LA-NSCLC) from two clinical trials, patients given concurrent chemotherapy with proton beam therapy (CPBT) followed by adjuvant immunotherapy (IO) had significantly better overall survival, distant metastasis-free survival, and disease-free survival than did patients given CPBT only.
Rates of severe (grade ≥3) pulmonary and cardiac toxicity were low and similar between groups.
Adjuvant IO after CPBT led to a survival benefit with an acceptable toxicity profile, justifying further use of this regimen in patients with inoperable LA-NSCLC.
Acknowledgements:
The authors thank Christine F. Wogan, MS, EL, from the Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, for editing the manuscript.
Funding:
This work was funded in part by the NATIONAL HEART, LUNG, AND BLOOD INSTITUTE grant R01HL157273, and the National Cancer Institute, National Institutes of Health by Cancer Center Support (Core) Grant P30 CA016672 to The University of Texas MD Anderson Cancer Center (PI: PW Pisters).
Footnotes
Disclaimers: The authors report no disclosures or conflicts of interest related to this work.
Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Data availability:
Research data is stored in an institutional repository and will be shared upon reasonable request to the corresponding author.
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Supplementary Materials
Data Availability Statement
Research data is stored in an institutional repository and will be shared upon reasonable request to the corresponding author.