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High risk non-small cell lung cancer treated with active scanning proton beam radiotherapy and immunotherapy

Open AccessPublished:November 23, 2022DOI:https://doi.org/10.1016/j.adro.2022.101125

      Abstract

      Introduction

      : Non-small cell lung cancer (NSCLC) is a deadly malignancy that is frequently diagnosed in patients with significant medical comorbidities. When delivering local and regional therapy an exceedingly narrow therapeutic window is encountered, which oftentimes precludes patients from receiving aggressive curative therapy. Radiotherapy advances including particle therapy have been employed in effort to expand this therapeutic window. Here we report outcomes with the use of proton therapy with curative intent and immunotherapy to treat high risk patients diagnosed with NSCLC.

      Methods

      : Patients were determined to be "high risk" if they had severe underlying cardiopulmonary dysfunction, history of prior thoracic radiation therapy, and/or large volume or unfavorable location of disease. (e.g, bilateral hilar involvement, supraclavicular involvement). As such, patients were determined to be ineligible for conventional x-ray based radiotherapy and were treated with pencil beam scanning proton beam therapy (PBS-PBT). Patients that demonstrated excess respiratory motion (i.e. greater than 1 cm in any dimension noted on the 4D CT simulation scan) were deemed to be ineligible for PBT. Toxicity was reported using the Common Terminology Criteria for Adverse Events (CTACE) version 5.0. Overall survival and progression free survival were calculated using the Kaplan-Meier method.

      Results

      : A total of 29 patients diagnosed with high risk NSCLC were identified who were treated with PBS–PBT. The majority (55%) of patients were defined as high risk due to severe cardiopulmonary dysfunction. Most commonly, patients were treated definitively to a total dose of 6000 cGy (RBE) in 30 fractions with concurrent chemotherapy. Overall, there were a total of six acute grade 3 toxicities observed in our cohort. Acute high grade toxicities included: esophagitis (n = 4, 14%), dyspnea (n = 1, 3.5%), and cough (n = 1, 3.5%). No patients developed grade 4 or higher toxicity. The majority of patients went on to receive immunotherapy and high-grade pneumonitis was rare. Two-year progression free and overall survival was estimated to be 51% and 67%, respectively. COVID-19 was confirmed or suspected to be responsible for two patient deaths during the follow-up period. The majority of patients (n = 25, 86%) received chemotherapy, with 84% receiving it concurrently. Nearly all of these patients (n = 7) received concurrent chemotherapy and were evenly distributed between adenocarcinoma (n = 3) and squamous cell carcinoma (n = 4) histology.

      Conclusion

      : Radical PBS-PBT treatment delivered in curative fashion in a high-risk lung cancer patient cohort is feasible with careful multidisciplinary evaluation and rigorous follow-up.

      Keywords

      Introduction

      The lung cancer mortality rate has declined substantially in recent years owing in large part to improved treatment options1. Despite these advances, lung cancer continues to be the leading cause of cancer-related death in the United States making up approximately 25% of all cancer fatalities2. A unique challenge in the treatment of Non-Small Cell Lung Cancer (NSCLC) is the narrow therapeutic window in high risk patients. Delivering aggressive concurrent chemoradiation therapy in patients who, on average are quite elderly and have significant cardiopulmonary dysfunction is challenging3,4. The fragility of such patients is most notably manifested by the survival detriment observed with dose escalation in RTOG 0617, which serves as a cautionary tale5. Nevertheless, RTOG 0617 demonstrated several critical factors implicit in modern radiotherapy management of NSCLC. First, lung dose, specifically V20 Gy, is significantly associated with severe pulmonary toxicity6. Second, heart dose is correlated with overall survival6. Third, intensity modulated radiation therapy (IMRT) can improve upon the aforementioned dose volume histogram (DVH) parameters and optimize clinical outcomes6. Hence, it is postulated that advanced proton therapy techniques may translate to further clinical improvement.
      Proton beam therapy (PBT) has shown the ability to reduce cardiopulmonary radiation exposure as compared to IMRT by numerous dosimetric studies7–12. Clinical results have been reported by multiple institutional series and have explored oncologic and toxicity outcomes of concurrent PBT chemoradiation for LA-NSCLC13–17. However, the majority of publications to date have utilized passive scatter PBT as opposed to pencil beam scanning (PBS) systems and to our knowledge none have reported treatment planning utilizing Monte Carlo algorithms exclusively. Moreover, with improvements in systemic therapy, particularly immunotherapy, in the localized and metastatic setting, the therapeutic landscape of NSCLC has dramatically changed18–20. The majority of patients with NSCLC receiving chemoradiation will now go on to receive immunotherapy, either as consolidation or upon disease progression. With the addition of immunotherapy, there are concerns regarding an increased risk of overlapping side effects, particularly pneumonitis, in this patient population. However, little data exists in this space for those receiving PBT32.
      Despite the significant aforementioned advances in the management of NSCLC in the modern era, these improvements can be reduced by the effects of a global pandemic. The cardiopulmonary frailty of high risk NSCLC patients especially while undergoing immunosuppressive or immunostimulatory therapy places them in arguably the highest risk COVID-19 category, which has been demonstrated in a recent meta-analysis21. In this manuscript, we review the outcomes of patients diagnosed with high risk NSCLC treated with PBS-PBT followed by immunotherapy.

      Materials and Methods

      Patient eligibility

      This single institutional review of consecutive patients treated with NSCLC was approved by the local Institutional Review Board (IRB#: 2017-0695). All patients were evaluated by a multidisciplinary thoracic oncology team which included radiation oncology, interventional pulmonology, medical oncology, and thoracic surgery. All patients underwent diagnostic tests including CT scan, PET/CT scan, MRI or CT scan of the brain, and pulmonary function tests. All patients underwent bronchoscopy and endobronchial ultrasound for biopsy of the primary mass and lymph node sampling. Patients were staged utilizing the AJCC 8th edition staging system. Patients with implanted cardiac devices were not PBT candidates based on institutional practice. Patients were determined to be "high risk" if they had severe underlying cardiopulmonary dysfunction, history of prior thoracic radiation therapy, and/or large volume or unfavorable location of disease (e.g, bilateral hilar involvement, supraclavicular involvement).

      Simulation and contouring

      All patients underwent computed tomography (CT)-based radiation treatment planning simulation with accompanied 4-dimensional computed tomography (4D-CT) for assessment of respiratory motion (GE LightSpeed RT16). Respiratory motion management in the form of abdominal compression was utilized in cases of excess motion, which was assessed at the time of simulation. A contrast CT scan was also obtained at the time of simulation and fused with the primary simulation CT scan. Diagnostic imaging including CT and/or PET/CT was fused with the simulation CT scan to assist in target volume delineation. Patients that demonstrated excess respiratory motion (i.e. greater than 1 cm in any dimension noted on the 4D CT simulation scan) were deemed to be ineligible for PBT. Target volume contours were generated using previously defined definitions from the RTOG 1308 protocol33. Elective nodal radiation was not incorporated for any definitive treatment. Organs at risk (OAR) were contoured and included lungs, heart, esophagus, spinal cord, brachial plexus, proximal bronchial tree, and skin (3 mm).

      Treatment planning and delivery

      Dose calculations and planning optimization were performed on the average phase of the simulation 4D-CT. Proton plans were generated utilizing RayStation version 8A (RaySearch Laboratories, Stockholm, Sweden). Beam angles were created to optimize target volume coverage, mitigate dose degradation due to motion or geometric changes, and minimize exposure of normal structures (Figure 1). Single field optimization was utilized for all PBT plans. All plans were optimized utilizing a Monte Carlo dose calculation algorithm, which has been very rarely utilized in prior publications for lung cancer PBT treatment. Apertures were created using the Adaptive Aperture multileaf collimator system (Mevion Medical Systems, Littleton, MA, USA).
      Figure 1
      Figure 1: 72-year-old female patient diagnosed with NSCLC of the left lower lobe, squamous cell carcinoma histology, clinical stage T3 NO MO, stage IIB. She was deemed medically inoperable due to significant pulmonary dysfunction (FEV1 of 37% and DLCO 31%) and was treated with PBT to a total dose of 6000 cGy in 30 fractions with concurrent chemotherapy. Color wash dose distribution is demonstrated for (a) 3D-CRT comparative plan, (b) IMRT comparative plan, and (c) PBT plan using Monte Carlo algorithm
      Planning overrides were utilized for artifact created by fiducial markers, if present. Quality assurance 4D-CT scans were obtained at regular intervals, typically every 1 to 2 weeks during treatment (Supplement). Proton beam therapy re-plans were performed on the 4D-CT scan average phase to ensure intrinsic anatomical changes during treatment did not significantly alter target coverage or OAR dose constraints. Replans were performed if target coverage or doses to OARs deviated from institutional standards. All patients were treated with standard fractionation. Patients were set up utilizing orthogonal kV imaging with gross set up to bony anatomy and subsequent final adjustment based on the bronchopulmonary tree with or without fiducial marker adjustment.

      Follow-up

      Patients were seen for weekly on treatment visits and acute toxicity was defined as that occurring within 90 days of treatment completion. Late toxicity was defined as that occurring greater than 90 days after radiotherapy completion. Toxicity was reported using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. All toxicities were radiation oncologist graded. Patients were typically followed using serial CT scans and multi-disciplinary clinical examination at 3-month intervals for the first two years and every 6 to 12 months thereafter.

      Statistical analysis

      The Kaplan-Meier method was used to calculate overall survival (OS) and progression free survival (PFS). All patients were included for the acute toxicity analysis. Patients who did not progress during treatment and were not lost to follow up were included in our survival and progression free survival analysis. Overall survival was defined as the time from the end of treatment to death from any cause. Progression free survival was defined as the time from the end of treatment to disease progression or death from any cause. Median follow-up was defined as time from the end of treatment to last clinical follow up or death. Local control was defined as any new or progressing disease within the radiation treatment field per RECIST version 1.1. Regional recurrence was defined as disease in the adjacent mediastinum or ipsilateral lobe (s) outside of the radiation field. Distant recurrence was defined as any recurrence not meeting the local or regional recurrence definition. All statistical analysis was performed using SPSS, version 24 (Armonk, NY).

      COVID-19 analysis

      We define the beginning of the COVID-19 pandemic as March 1st, 2020. All patients included in the COVID-19 portion of the analysis of the present study were either treated during the pandemic or seen in follow-up thereafter. We reviewed the following COVID-19 data for this patient cohort: Infection rate, severity of infection, and deaths rate (confirmed and suspected). We also reviewed the vaccination status of surviving patients.

      Results

      Patient and tumor characteristics

      A total of 29 patients with high risk NSCLC were consecutively treated from 2018 to 2020 with thoracic PBS-PBT. The median age of the cohort was 70 years (range: 49-86 years). A significant proportion of patients, 24%, required supplemental oxygen prior to treatment due to severe baseline pulmonary disease. The most common diagnosed histology was adenocarcinoma (n = 14). Over half of the cohort was diagnosed with unresectable locally advanced NSCLC staged IIIB-C. Most patients were considered high risk due to severe cardiopulmonary dysfunction (n = 16, 55%) and/or tumor location or size (n = 13, 45%). A notable proportion were considered high risk due to prior thoracic radiation therapy (n = 7, 24%) all for metachronous non-related malignancies. Of note, the median dose of the previous RT course was 6000cGy (range: 3000-7380 cGy). The median volume of disease as measured by PTV was 471 cc (45 – 1286 cc). Table 1 illustrates patient and tumor characteristics (Dosimetric data can be found in Supplmentary Table 1). Figure 1 illustrates comparative radiotherapy plans for a patient treated in our cohort with underlying severe pulmonary disease.
      Table 1Patient and cancer characteristics
      Patient numberPercentage
      Age
      ≤70 years1448%
      >70 years1552%
      Gender
      Female1759%
      Male1241%
      ECOG
      01862%
      11034%
      214%
      Tobacco use (pack-years)
      ≤10414%
      10-30724%
      ≥301862%
      Oxygen dependent
      No2276%
      Yes724%
      Stage (AJCC 8th edition)
      IA/B27%
      IIB27%
      IIIA931%
      IIIB1138%
      IIIC414%
      IV13%
      Histology
      Adenocarcinoma1449%
      Squamous cell carcinoma1034%
      Undifferentiated311%
      Large cell Carcinoma13%
      Spindle cell Carcinoma13%
      The vast majority of patients were treated with definitive intent (n = 26, 90%). Patients were treated to a median total dose of 6000 cGy (RBE) in 30 fractions (4500 – 6600 cGy RBE). The majority of patients (n = 25, 86%) received chemotherapy, with 84% receiving it concurrently. During treatment, 28% of patients (n = 8) had geometric target volume changes that significantly altered coverage and/or OAR dose constraints necessitating a PBT re-plan. Nearly all of these patients (n = 7) received concurrent chemotherapy and were evenly distributed between adenocarcinoma (n = 3) and squamous cell carcinoma (n = 4) histology. Interestingly, none of the patients who required a re-plan went on to develop local or regional disease recurrence, perhaps reflective of the rapid treatment response identified during treatment. Table 2 lists specific treatment characteristics. Supplementary figure demonstrates radiotherapy changes seen during radiation treatment (i.e. 3-week QA-CT scan) as well as 2 years following treatment completion.
      Table 2Treatment characteristics
      Patient numberPercentage
      Radiation approach
      Definitive2690%
      Adjuvant27%
      Neoadjuvant13%
      Chemotherapy approach
      None414%
      Sequential517%
      Concurrent2069%
      Reason for PBT*
      Comorbidities1655%
      Reirradiation724%
      Adjacent OAR1345%
      PBT re-plan required
      No2172%
      Yes828%
      Immunotherapy regimen
      Durvalumab1365%
      Pembrolizumab420%
      Nivolumab210%
      Ipilimumab/Nivolumab15%
      *Multiple reasons for PBT per patient were possible

      Acute PBT toxicity

      Overall, there were a total of six acute grade 3 toxicities observed in our cohort. Acute high grade toxicities included: esophagitis (n = 4, 14%), dyspnea (n = 1, 3.5%), and cough (n = 1, 3.5%). Notably, all patients who experienced grade 3 esophagitis received concurrent chemotherapy and had either bilateral mediastinal disease or disease directly invading the mediastinum. No patient experienced any grade 4 or higher acute toxicity. The most common low grade toxicities (≤ grade 2) included fatigue (n = 27, 15%), esophagitis (n = 22, 12%), and radiation dermatitis (n = 19, 10%). Detailed acute toxicity information is shown in Table 3.
      Table 3Acute toxicity (CTCAE version 5.0)
      Grade 1Grade 2Grade 3Grade 4
      Dermatological
      Radiation dermatitis12 (41%)7 (24%)00
      Skin hyperpigmentation10 (34%)2 (7%)
      Pulmonary
      Cough14 (48%)4 (14%)1 (3%)
      Pleural effusion3 (10%)1 (3%)00
      Dyspnea11 (38%)5 (17%)1 (3%)0
      Voice alteration6 (21%)7 (24%)0
      Atelectasis4 (14%)1 (3%)00
      Wheezing4 (14%)5 (17%)00
      Chest wall pain5 (17%)3 (10%)0
      Gastrointestinal
      Esophagitis4 (14%)18 (62%)4 (14%)0
      Weight loss8 (28%)4 (14%)0
      Anorexia11 (38%)5 (17%)00
      Fatigue
      Fatigue16 (55%)11 (38%)0

      Immunotherapy characteristics

      The majority of eligible patients (20 out of 21) went on to receive immunotherapy either for consolidation or upon disease progression. The most common immunotherapy utilized was durvalumab (n = 13). Ineligibility for immunotherapy was documented for the following reasons: (1) radiation delivered without radical intent (n = 3), (2) contraindications due to systemic autoimmune diseases (n = 2), (3) early stage disease (n = 2), (4) targeted therapy utilized (n = 1), and (5) rapid disease progression (n = 1). Grade 2 or higher pneumonitis was identified in a total of seven patients, two of whom were found to have grade 3 toxicity. Grade 2 or higher pneumonitis occurred at a median of 3.75 months following completion of radiation. Of these cases, three were attributed to radiation, two were attributed to immunotherapy, and two had an unclear etiology (i.e. immunotherapy versus radiation). Of note, immunotherapy-related grade 3 thyroiditis and grade 3 colitis was identified in two additional patients.

      Late PBT Toxicity

      A total of seven high-grade (grade 3+) toxicities were observed in five patients. Nearly all of these toxicities (11.6%) were pulmonary and had the following distribution: Pneumonitis (n = 2), pleural effusion (n = 2), lung infection (n = 1), dyspnea (n = 1), and esophageal stricture (n = 1). No grade 4 or higher late toxicities were observed. High-grade pneumonitis was attributed to immunotherapy in one case and had an unclear etiology (i.e. immunotherapy versus radiation) in the other. The late grade 3 esophageal stenosis occurred in a patient who previously underwent a course of definitive thoracic irradiation, highlighting the risk of late normal tissue toxicity with re-irradiation. The most commonly observed low-grade (≤ grade 2) late toxicities were cough (n = 9, 35%), fatigue (n = 9, 35%), and chest wall pain (n = 8, 30%). Low-grade acute toxicities demonstrated a clear improvement over time with fatigue, esophagitis, and radiation dermatitis dissipating with longer follow-up. Of note, three patients were lost to follow-up shortly after completion of radiation treatment and were excluded from late toxicity and survival analysis. Late toxicity information is illustrated in Table 4.
      Table 4Late toxicity (CTCAE version 5.0)
      Grade 1Grade 2Grade 3Grade 4Grade 5
      Dermatological
      Radiation dermatitis1 (3%)0000
      Superficial soft tissue fibrosis1 (3%)0000
      Pulmonary
      Cough4 (14%)5 (17%)0
      Pneumonitis05 (17%)2 (7%)00
      Pneumothorax00000
      Lung infection2 (7%)1 (3%)00
      Pleural effusion3 (10%)02 (7%)00
      Dyspnea3 (10%)3 (10%)1 (3%)00
      Atelectasis3 (10%)1 (3%)000
      Wheezing1 (3%)0000
      Chest wall pain1 (3%)7 (24%)0
      Gastrointestinal
      Esophageal stricture001 (3%)00
      Anorexia3 (10%)0000
      Fatigue
      Fatigue9 (31%)1 (3%)0

      Oncologic outcomes

      With a median follow-up of 17.36 months, median overall survival and progression free survival has not been reached. The 1- and 2-year estimated progression free survival was 60% and 51%, respectively (Figure 3a). The 1- and 2-year estimated overall survival was 76% and 67%, respectively (Figure 3b). Notably, progression of disease was typically observed within the first six months, and for those patients who remained disease-free, control appeared to be durable with extended follow up. The predominant pattern of failure was distant progression with only one case of regional recurrence identified. A total of 10 patients died during the follow-up period. Cause of death distribution was as follows: Cancer progression (n = 4), COVID-19 or suspected COVID-19 (n = 2), cardiac arrest due to substance abuse (n = 1), cerebral hemorrhage (n = 1), respiratory failure (n = 1), and unknown (n = 1).

      COVID- 19 impact

      A total of 24 patients were included in our COVID-19 analysis. Of these, only two were found to have PCR documented COVID-19 infections. For those who were found to have COVID-19 infections, one patient required hospitalization and subsequently died of their infection, and the other patient recovered quickly. In addition, due to difficulty with respect to follow-up and availability of PCR testing during the initial phase of the pandemic, one further patient died at an outside hospital with a suspected COVID-19 infection but was never tested. Of the remaining 22 patients, six individuals died prior to the availability of the COVID-19 vaccine. A total of 16 patients were alive at the time of last follow-up with only nine being vaccinated.

      Discussion

      The present manuscript reports clinical outcomes for a high-risk lung cancer patient cohort at the intersection of novel advanced active scanning PBT in concert with immunotherapy delivered during the COVID-19 pandemic. The high-risk nature of our cohort reflects a more generalizable patient population that is often not reported upon in clinical trials. In the present study, over half of the cohort was diagnosed with unresectable stage IIIB-C disease. Furthermore, 24% of the patients required supplemental oxygen at baseline, 24% had prior thoracic irradiation, and over half carried a diagnosis of severe cardiopulmonary dysfunction. Elderly patients with severe cardiopulmonary disease typically represent the rule rather than the exception in the average lung cancer clinical encounter. Moreover, prior publications not surprisingly demonstrate that the risk of radiation-related toxicity can escalate as age and medical comorbidities increase22,23. As a consequence, these patients may be exquisitely sensitive to low doses of radiation to thoracic organs23. As such, many practitioners often recommend against aggressive definitive intent locoregional therapy in effort to avoid potential harm to the high-risk patient. Nevertheless, locoregional progression of lung cancer is strongly associated with morbidity, decreased quality of life, and is a leading cause of lung cancer related death24. Taken as a whole, it is critical to widen the therapeutic ratio in this patient population and one theoretical method of doing so is improved radiation technique such as the use of PBS-PBT.
      Fundamentally, it is the physical dose superiority afforded by the Bragg peak that makes PBT an attractive radiation option particularly when minimization of integral radiation dose exposure is critical. The use of PBT in the treatment of locally advanced NSCLC has been well reported in the literature and has prompted the randomized control trial, RTOG 1308, comparing PBT with IMRT 15–17,17. The vast majority of PBT lung cancer literature utilizes older passive scatter technology, whereas we describe the clinical results of modern PBS delivery in concert with Monte Carlo-based planning, which will likely become standard for thoracic PBT in the near future25. Despite improvements in conformality with PBS-PBT, it is critical to monitor tumor response during treatment, particularly in heterogeneous tissue such as the lung, to avoid target dose degradation and organ at risk overdosage. This is demonstrated by the fact that 28% of our cohort had geometric changes that required PBT re-plans during treatment. Ultimately, the comparative effectiveness of PBT versus x-ray based therapy will be determined by randomized trials with particular attention placed on PBT toxicity mitigation, which is all the more important for a high risk cohort such as that described in this manuscript.
      Without question the most meaningful therapeutic advance in lung cancer in the last several decades has been the development of immunotherapy. In cases of locally advanced NSCLC following curative treatment, the predominant pattern of failure has historically been distant, and the use of effective immunotherapy has yielded dramatic progression-free and overall survival improvements. However, concerns regarding overlapping toxicities with radiation therapy, specifically pneumonitis, persist and appear to be higher than was initially reported in the PACIFIC trial18,19,26. In the present study we identified limited severe radiation- and immunotherapy-related pneumonitis (n = 2) with five additional patients diagnosed with low-grade pneumonitis. Moreover, despite underlying comorbidities, the majority of patients who were eligible for immunotherapy went on to receive it following upfront radiation. It would appear with careful multidisciplinary evaluation and close follow-up, curative radical PBS-PBT in concert with immunotherapy in a high-risk cohort is feasible with manageable toxicity.
      In 2020, lung cancer patients simultaneously faced the deadliest cancer in America and the deadliest pandemic in modern history, oftentimes while immunosuppressed from antineoplastic treatment and handicapped by underlying medical comorbidities. As the COVID-19 pandemic initially flared, intense management decisions were made on the fly as our understanding of the virus evolved27,28. With little effective treatment identified early in the pandemic, oncologists sometimes faced the decision of minimizing viral exposure or offering curative lung cancer treatment29. As one of the first countries hit with COVID-19, Italy reported the consequences of the infection on radiation therapy with a 17% reduction in radiation treatments, but despite this drop nearly half of patients who were diagnosed with COVID-19 continued radiotherapy without interruption30.
      In contrast, data reported from the initial epicenter in the United States, New York City, the severity of COVID-19 infection in lung cancer patients was more grim with a 62% hospitalization rate and a 25% mortality rate in consecutive patients treated from March 12th, 2020 to May 6th, 2020 at Memorial Sloan-Kettering Cancer Center (MSKCC)31. Although, cancer specific factors did not seem to impact the severity of infection, patient-specifics factors such as smoking and pulmonary disease dramatically increased the risk of COVID-19 severity. Such comorbid factors placed the “high risk” patient population of the present study at a profound risk during the pandemic with 62% of patients having a greater than 30-pack-year smoking history and nearly one quarter on pre-treatment supplemental oxygen. In the present study, COVID-19 was responsible for one confirmed and one suspected death. Fortunately, the significant clinical impact seen at MSKCC during the peak in New York City was not observed in the present cohort in Washington DC. Nevertheless, it is concerning that of the remaining living 16 patients in the present study only half of this cohort has agreed to COVID-19 vaccination.
      Limitations of the present study include its retrospective nature, limited patient numbers, and heterogeneous cohort. It is difficult to remark on the oncologic outcomes of the present study relative to previously published literature given the heterogeneity of our patient population and lack of similar publications for high risk patients34. Certainly the high risk nature of this group poses significant limitations on life expectancy. Nevertheless, we included a wide range of lung cancer stages some of which would be expected to achieve long-term disease control. Thus, direct comparison to previously published PBT literature (i.e. Chang et al.) or modern radiotherapy followed by consolidative immunotherapy (i.e. PACIFIC trial) is challenging17,19. Moreover, the occurrence of the COVID-19 pandemic as a competing cause of mortality makes interpretation even more nebulous.

      Conclusion

      The present manuscript reports a high-risk lung cancer patient cohort at the juncture of novel advanced active scanning PBT in concert with immunotherapy. Modern PBS–PBT with Monte Carlo-based planning was delivered for curative intent. Close monitoring of tumor changes was required as 28% of cases required a PBT re-plan during treatment. Despite their high-risk status, the vast majority of patients went on to receive immunotherapy and only two cases of severe pneumonitis were identified. A total of six acute grade 3 toxicities were observed, most commonly esophagitis. Seven severe late toxicities were identified, most commonly pulmonary in origin. Infection with COVID-19 was confirmed or suspected to be responsible for two patient deaths during the follow-up period. Two-year progression free and overall survival was estimated as 51% and 67%, respectively. Radical PBT treatment delivered in curative fashion in a high-risk lung cancer patient cohort appears to be feasible with careful multidisciplinary evaluation with rigorous follow-up.Figure 2
      Figure 2
      Figure 2: a) Overall Survival and b) Progression Free Survival

      Role of funding source

      None.

      Authors’ contributions

      All authors were responsible for conception, design, data collection, analysis, interpretation, drafting, or critical revision of the manuscript. Final approval of the current manuscript and responsibility of accuracy was given by all authors.

      Meeting presentation

      None

      Data Sharing

      Research data are stored in an institutional repository and will be shared upon request to the corresponding author.

      Author Responsible for Statistical Analysis

      Jonathan W. Lischalk, MD
      Email: jonathan.lischalk@nyulangone.org

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      Conflicts of interests

      Brian T. Collins is a paid technical advisory committee member for Mevion medical systems. Stephen Liu is an advisor for AstraZeneca, Bristol-Myers Squibb and receives research funding from Lilly, Merck and Pfizer. The remaining authors have no competing interests.

      Acknowledgements

      Elizabeth Ballew contributed to the development and maintenance of institutional IRB. Anatoly Dritschilo, MD provided general support and guidance for the study.