- Email: [email protected]
First Clinical Report of Proton Beam Therapy for Postoperative Radiotherapy for Non–Small-Cell Lung Cancer
Accepted Manuscript First Clinical Report of Proton Beam Therapy for Post-Operative Radiotherapy for Non-Small Cell Lung Cancer Jill S. Remick, MD, Caitlin Schonewolf, MD, Peter Gabriel, MD, Abigail Doucette, MPH, William P. Levin, MD, John C. Kucharczuk, MD, Sunil Singhal, MD, Taine TV. Pechet, MD, Ramesh Rengan, MD PhD, Charles B. Simone, II, MD, Abigail T. Berman, MD PII:
S1525-7304(16)30385-0
DOI:
10.1016/j.cllc.2016.12.009
Reference:
CLLC 585
To appear in:
Clinical Lung Cancer
Received Date: 2 July 2016 Revised Date:
11 December 2016
Accepted Date: 13 December 2016
Please cite this article as: Remick JS, Schonewolf C, Gabriel P, Doucette A, Levin WP, Kucharczuk JC, Singhal S, Pechet TT, Rengan R, Simone II CB, Berman AT, First Clinical Report of Proton Beam Therapy for Post-Operative Radiotherapy for Non-Small Cell Lung Cancer, Clinical Lung Cancer (2017), doi: 10.1016/j.cllc.2016.12.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT First Clinical Report of Proton Beam Therapy for Post-Operative Radiotherapy for Non-Small Cell Lung Cancer Jill S. Remick MD1, Caitlin Schonewolf MD2, Peter Gabriel MD2, Abigail Doucette MPH2, William P. Levin MD2, John C. Kucharczuk MD3, Sunil Singhal MD3, Taine TV Pechet MD3, Ramesh Rengan MD PhD4, Charles B Simone II MD2, Abigail T. Berman MD2
Author Contributions:
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Corresponding Author: Abigail T. Berman [email protected] (215) 662-2428
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University of Maryland Department of Radiation Oncology 22 South Green St. Baltimore, MD 21202 2 University of Pennsylvania Department of Radiation Oncology Perelman Center for Advanced Medicine 3400 Civic Center Blvd. Philadelphia, PA 19104 3 University of Pennsylvania Department of Thoracic Surgery Perelman Center for Advanced Medicine 3400 Civic Center Blvd. Philadelphia, PA 19104 4 University of Washington Department of Radiation Oncology 1959 NE Pacific St. Mailstop Box 356049 Seattle, WA 98195
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Jill Remick, MD – data collection, figure and table design, manuscript writing, editing and revising. Caitlin Schonewolf MD – data collection, statistical work, figure design, paper editing and revisions. Peter Gabriel MD – statistical assistance, data mining, figure design. Abigail Doucette – data mining, statistical work. William P. Levin MD – assisted in editing and revisions. John C. Kucharczuk MD - assisted in editing and revisions. Sunil Singhal MD - assisted in editing and revisions. Taine TV Pechet MD - assisted in editing and revisions. Ramesh Rengan MD PhD - assisted in editing and revisions. Charles B Simone II MD - assisted in editing and revisions. Abigail T. Berman MD – primary advisor, literature review, writing and editing manuscript.
Conflicts of Interest There are no conflicts of interest to disclose.
Role of Funding Sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
ACCEPTED MANUSCRIPT Micro Abstract We investigated the survival outcomes and early toxicity profile of post-operative radiation therapy (PORT) with proton beam therapy (PBT) versus intensity modulated radiation therapy (IMRT) for non-small cell lung cancer in a cohort of 61 patients with positive microscopic margins and/or positive N2 lymph nodes. We found that post-operative PBT in locally-
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advanced NSCLC is well-tolerated and has similar excellent short-term outcomes when compared with IMRT.
Abstract
Background and Purpose: The characteristic Bragg peak of proton beam therapy (PBT) allows for sparing normal tissues
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beyond the tumor volume that may allow for decreased toxicities associated with PORT. Here we report the first
institutional experience with proton therapy for PORT in NSCLC patients and assess early toxicities and outcomes.
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Materials and Methods: We identified 61 consecutive patients treated from 2011-2014 that underwent PORT for locallyadvanced NSCLC for positive microscopic margins and/or positive N2 lymph nodes (stage III), with 27 patients receiving PBT and 34 receiving intensity modulated radiation therapy (IMRT).
Results: Median follow-up time was 23.1 months for PBT (2.3-42 months) and 27.9 months for IMRT (0.5-87.4 months). The median radiation dose was 50.4 Gy for PBT (50.4-66.6 Gy) and 54 Gy for IMRT (50.0-72.0 Gy). Grade 3 radiation
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esophagitis was observed in 1 and 4 patients in the PBT and IMRT groups, respectively. Grade 3 radiation pneumonitis was observed in 1 patient in each cohort. Dosimetric analysis revealed a significant decrease in the V5 and mean lung dose (p=0.001 and p=0.045, respectively). One-year median overall survival and local recurrence-free survival were 85.2% and
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82.4% (95% CI 72.8-99.7% and 70.5-96.2%, p=0.648) and 92.3% and 93.3% (82.5-100%, 84.8-100%, p=0.816) for PBT and IMRT cohorts, respectively.
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Conclusions: Post-operative PBT in NSCLC is well-tolerated and has similar excellent short-term outcomes when compared with IMRT. Longer follow-up is necessary to determine if PBT has a meaningful improvement over IMRT for PORT.
Key words: Non-small cell lung cancer (NSCLC), post-operative radiation therapy (PORT), proton beam therapy (PBT), intensity-modulated radiation therapy (IMRT)
Introduction
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ACCEPTED MANUSCRIPT Lung cancer continues to be the number one cause of cancer death in the United States with non-small cell lung cancer (NSCLC)* being the most common histologic variant.1 Surgery, with an anatomical lobectomy or pneumonectomy, is the standard of care for early-stage disease; patients with N2 nodal involvement should be treated with either definitive chemoradiation or multimodality therapy with surgery preceded by chemotherapy or chemoradiation.2 Post-operative
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radiation therapy is recommended for N2 NSCLC patients who receive neoadjuvant chemotherapy followed by surgery or with “surprise” N2 nodal involvement (discovered incidentally at surgery) or with gross or residual microscopic disease after surgical resection in otherwise healthy patients.3
The primary concern regarding post-operative radiation therapy (PORT) is the potential for toxicity in this patient
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population. In the PORT meta-analysis (PORT Meta-analysis Trialists Group), radiation-induced toxicity appeared to negate any therapeutic benefit of PORT, presumably due to the large field sizes and outdated radiation techniques that were
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used.4 However, the role of radiation therapy in decreasing local recurrence, irrespective of survival benefit, had been recognized even among studies included in the PORT meta-analysis.5-6 There has been more recent evidence with the use of modern radiotherapy techniques to support an increase in survival in N2 positive patients receiving PORT.7-9 Targeting radiation to smaller volumes and using modern techniques such as intensity-modulated radiation therapy (IMRT) has resulted in an improved therapeutic ratio.10-11 However, radiation-induced toxicity is still of concern, in
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particular lung damage manifested as pneumonitis or fibrosis and cardiac injury. The potential for toxicity is even greater with concurrent chemotherapy in the setting of positive margins.12 In contrast to photons utilized in traditional radiation therapy, proton beam therapy (PBT) consists of charged particles
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that can be delivered to a specific depth within tissue that is dependent upon its energy, creating the characteristic ‘Bragg peak’.13-14 Proton therapy has been shown in a dosimetric study to significantly reduce mean total lung V5, V10 and V20
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using dose escalation in comparison to 3D conformal radiotherapy and IMRT.15 In addition, variations in PBT techniques, such as intensity modulated proton therapy (IMPT) using pencil beam scanning (PBS), may offer potential benefits. Pencil beam scanning is a technique unique to protons that allows for 3D conformation by filling in layer by layer of the tumor target and thus obviates the need for other devices to modulate the beam shape.16 We have shown that intensity modulated proton therapy (IMPT) results in a significant dose reduction to spinal cord, lung and heart compared to passive scattering proton therapy (PSPT) and IMRT.17-19
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Common Abbreviations: Non-small cell lung cancer (NSCLC), post-operative radiation therapy (PORT), proton beam therapy (PBT), intensity-modulated radiation therapy (IMRT), pencil beam scanning (PBS), intensity modulated proton therapy (IMPT)
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ACCEPTED MANUSCRIPT In lung cancer, there is limited clinical data available that has correlated the dosimetric benefits of PBT to an improved therapeutic index. Chang et al. reported a phase II trial of stage III NSCLC patients treated with concurrent chemoradiation using dose escalated proton-beam therapy resulted in low rates of toxicity and an improved survival compared to their institutional experience with IMRT using photon therapy.20
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To date, there is no clinical study that has assessed the use of PBT for PORT in locally-advanced NSCLC. Here, we report the first institutional experience of PBT PORT in patients with N2 nodal involvement or microscopic residual disease after surgical resection and assess the toxicity profile and survival outcomes in comparison to IMRT.
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Materials and Methods
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Patient Selection and Study Design
This retrospective study was approved by our Institutional Review Board. In addition, patients treated with PBT were enrolled on an Institutional Review Board-approved proton registry study allowing prospective collection of toxicity and clinical outcomes. All patients underwent extensive informed consent of the risks and benefits of radiotherapy or no radiotherapy as well as the possible dosimetric benefits and unknown variables of proton therapy. A total of 61 consecutive
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patients at our single institution with operable NSCLC who were found to have post-operative N2 nodal involvement or positive margins were retrospectively evaluated. Of these 61 patients, 27 were treated with proton bean therapy (PBT) and 34 were treated with intensity-modulated radiation therapy (IMRT). Of the 27 patients treated with PBT, 22 received
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double scatter proton therapy (DS-PT) and 5 received intensity-modulated proton therapy (IMPT). Patients who received neoadjuvant concurrent proton/chemotherapy as part of an institutional protocol (n=20) and those who had palliative
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surgery (n=2) to alleviate symptomatic airway compression prior to radiation treatment were excluded from this analysis.
Treatment Simulation and Target Volume Delineation Patients were simulated in the supine position with arms extended above the head. To account for tumor motion, a four-dimensional (4D)-computed tomography (CT) simulation was performed (Siemens Sensation and/or Philips GEMINI TF) using Varian Real-time Position Management (RPM) system (Varian Medical System, Palo Alto, CA). All 10 respiratory-phase images and the reconstructed averages were transferred into Eclipse planning system version 11.0 and fused with pre-treatment imaging (Varian Medical Systems, Palo Alto, CA). CTV volume was delineated based on
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ACCEPTED MANUSCRIPT guidelines described elsewhere.21-22 CTV was defined to include the bronchial stump, lymph nodes that are positive according to the pathology report as well as the ipsilateral hilar lymph node region and the mediastinal pleura adjacent to the surgical bed. Additional nodal stations were included as part of CTV using LungART protocol as a guide and clinical discretion of the treating physician. An ITV was defined based on respiratory motion of the CTV, and then a 0.5 cm
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expansion of ITV was used to generate a PTV. Patients that had suspected or confirmed (based on surgeon report or PETCT) gross disease after surgical resection (n=5), a CTV was generated by expanding the iGTV for any primary disease by
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0.5 cm and for any nodal disease by 0.3 cm as per institutional protocol.
Treatment Planning and Delivery
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The average 4D-CT was used for plan optimization and dose calculation. PBT patients were treated with double scatter proton therapy (DS-PT) (n=22) or pencil beam scanning (PBS) (n=5). Fields were centered on the ITV, with beam angles optimized to maximize ITV coverage and minimize exposure to normal structures. Patients underwent a verification CT approximately twice over the course of radiation to detect anatomical changes potentially altering proton therapy. Range uncertainty in the conversion of CT images to stopping power (3%) and patient setup (3 mm) were accounted for in the distal and proximal margins of DS-PT. Lucite compensators were manufactured for each beam and multi-leaf collimators
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were used for shaping and conformality. Smearing was used in the DS-PT compensator design to incorporate internal organ motion and ensure target coverage along the beam direction. Dynamic IMRT was planned using 5-7 coplanar beams. Institutional target planning constraints for both proton and IMRT plans were as follows: 95% of the PTV to be covered by
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at least 95% of the dose, lung mean dose ≤20 Gy (and ≤8.5 Gy in pneumonectomy cases, n=4), lung V20≤35%, lung V5≤60%, heart maximum of 70 Gy, heart V45≤35%, heart V30≤50%, esophagus maximum of 74 Gy and V55<30%. Dose-
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volume histograms (DVHs) of the target and critical normal structures were analyzed retrospectively. Radiation prescription dose ranged from 50 Gy to 72 Gy with a median dose of 50.4 Gy and 54 Gy for the PBT and IMRT groups, respectively. Per institutional guidelines, 50.4-54 Gy is generally prescribed to a negative margin resection (R0), 59.4-61.2 Gy to microscopic residual (R1) and 66.6 Gy or greater for gross residual disease (R2). The radiation was given in once-daily 1.8 Gy fractions (fx). Two patients received a combination photon and proton plan. These patients were allocated to the cohort in which they received the majority of their prescribed dose, as a result, there was one combination plan in each cohort.
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Evaluation and Follow-up Patients were followed weekly during radiotherapy and again 1 month after completing treatment; patients were then
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followed every 3 months with a CT scan for 2 years and thereafter every 6 months. Toxicities were documented according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Toxicities were retrospectively evaluated using an institutional toxicity database in which toxicity grade is determined by the primary attending and recorded during each on-treatment-visit and subsequent follow up visits. The same CTCAEv 4.0 was used for both proton and photon
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cohorts. This database was supplemented by chart reviewing all on-treatment and follow up notes to corroborate the documented grade based on description of symptoms, physical exam and imaging findings. PET scans were performed if
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there was suspicion of recurrent disease.
Local failure was defined as recurrence of tumor at the primary site or within the neighboring lung parenchyma in order to account for both in-field and out-of-field recurrences. Regional failure was documented if recurrence occurred in a lymph node proven by biopsy or by a clear interval increase in FDG avidity on PET scan. Distant failure was defined by either intra- or extra-thoracic metastatic disease. Intra-thoracic metastatic disease included disease in the contralateral lung, presence of bilateral disease or pleural or pericardial fluid involvement. The timing of the recurrence was recorded based on
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the date of biopsy backdated to the date of image that showed clear evidence of abnormalities or just to the date of imaging
Statistical Analysis
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evidence alone in patients who did not undergo a biopsy at the time of recurrence.
Overall survival was defined from the start of radiation treatment to the date of last follow-up contact or death.
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Progression-free survival was measured from the start of radiation therapy to the date of last follow-up or disease progression. Survival curves were estimated by the Kaplan-Meier method. DVH comparisons between PBT and IMRT were carried out using a two-tailed Wilcoxon signed rank test, and statistical significance was defined as p <0.05.
Results
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ACCEPTED MANUSCRIPT The clinical characteristics of the 61 patients are shown in Table 1. Median length of follow-up was 23.1 months for PBT (range 2.3-42 months) and 27.9 months for IMRT (range 0.5-87.4). In addition, the median length of follow-up was 26.5 months (range, 0.5-87.4) for all patients and 31.3 months (range, 7.3-87.4) for living patients. There were 42 patients (69%) treated for N2 involvement (18 PBT and 24 IMRT). A total of 23 (38%) had a
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microscopic positive margin and 5 patients (8%) had a gross positive margin based off surgeon report (n=2), post-operative PET-CT (n=2) or unknown (n=1). Radiation treatment dose varied based on surgical margins and clinical discretion and ranged from 50 to 72 Gy with a median dose 50.4 Gy and 54 Gy for the PBT and IMRT groups, respectively. There were two patients who received a combination of photon and proton plans. One plan included 50.4 Gy IMRT followed by 16.2
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Gy proton boost for gross residual disease with the intent to reduce side effects. The second patient received 19.8 Gy IMRT followed by 34.2 Gy proton therapy, however, it was unclear as to why the patient was switched. The majority of
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patients received adjuvant chemotherapy with either sequential (19 and 20 patients) or concurrent chemotherapy (6 and 11 patients) in the proton and IMRT groups, respectively. The most common regimen was cisplatin/pemetrexed in 13 patients treated with protons and in 17 patients treated with IMRT.
Patterns of first failure are shown in Table 2. A total of 5 (8%) patients had an isolated local recurrence (proton n=3, IMRT n=2). In each cohort, one of these isolated failures was outside the radiation field. Regional failure alone was seen in
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1 patient in each cohort. Distant failure was the most common recurrence pattern occurring in 11 (41%) and 17 (50%) of patients in the proton and IMRT cohorts, respectively.
The one-year median overall survival and local recurrence-free survival were 85.2% and 82.4% (95% CI 72.8-99.7%
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and 70.5-96.2%) and 92.3% and 93.3% (82.5-100%, 84.8-100%) for PBT and IMRT cohorts, respectively (Figure 1). At two years, the overall survival for the proton cohort was 77.8% (95% CI 63.6-95.2%) compared to 73.2% (CI 59.6-89.9%) in the IMRT cohort. Local recurrence-free survival at two years was similar for PBT and IMRT (93.1% and 85.7%,
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respectively). Overall survival (p=0.648) and local recurrence free survival (p=0.816) was not significantly different between the two cohorts. Of the 9 deaths in the proton cohort, 4 were related to sepsis or pneumonia complicated by respiratory failure, 1 was due to lymphangitic carcinoma leading to respiratory failure and 4 were not well documented. Seven of the 9 patients had metastatic disease at the time of death. Of the 18 deaths in the IMRT group, 4 were related to respiratory failure (3 of these patients had documented lung progression and/or pleural effusion), 1 patient died of urosepsis and 1 patient died of metastatic breast cancer. Cause of death was not well described or unknown in the remaining 12 patients, although, 14 out of 18 of these patients had documented metastatic disease.
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ACCEPTED MANUSCRIPT Dosimetric results are shown in Table 3. There was a significant reduction in the mean dose to the lung (p=0.45) and V5 (p=0.001) and max dose to the spinal cord (p=0.010) in the proton group compared to the IMRT group (Figure 2). The toxicity profile is shown in Table 4. There were no grade 4 or 5 toxicities observed. There was 1 patient in each cohort (PBT and IMRT) who experienced grade 3 radiation pneumonitis. The one patient in the PBT group was treated with
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sequential chemotherapy (cisplatin/pemetrexed) followed by double-scatter proton therapy to 50.4 Gy in 1.8 Gy per fraction and had a mean lung dose of 13.5 Gy, V5 of 40% and V20 of 29%. The second patient in the IMRT cohort was treated with sequential chemotherapy (cisplatin/pemetrexed) followed by IMRT to 61.2 Gy in 1.8 Gy fractions and had a mean lung dose of 10.3 Gy, V5 of 28.3% and V20 of 18.7%. Grade 3 esophagitis was observed in 1 and 4 patients in the proton and
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IMRT cohorts, respectively. One of these patients in the IMRT cohort was treated to 72 Gy in 1.8 Gy fractions with N2 disease and undocumented margin status and had a max and mean dose to the esophagus of 53.4 Gy and 33.2 Gy,
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respectively. Interestingly, one of these patients was treated with a combined plan of 50.4 Gy IMRT followed by a proton boost of 16.2 Gy (included in the IMRT cohort) and had a max esophageal dose of 67.9 Gy with mean of 29 Gy. The other two patients in the IMRT cohort that experienced grade 3 esophagitis were treated to 50.4 Gy in 1.8 Gy fractions and had a max dose of 54.3 Gy and 47.3 Gy, respectively. The only patient to develop grade 3 esophagitis in the proton cohort received 66.6 Gy in 1.8 Gy fractions and had a max esophageal dose of 66.6 Gy. The grade 2 acute esophagitis rate was
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decreased with proton beam therapy (5 and 10 patients in proton and IMRT arm, respectively).
Discussion
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In this first clinical report of proton beam therapy for post-operative treatment of NSCLC, we found that proton therapy was well-tolerated in comparison to IMRT and was associated with similar excellent outcomes at an early initial
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time point.
The role of post-operative radiation therapy (PORT) has been historically controversial due to earlier studies with poor patient selection and outdated radiotherapy techniques.4 However, there has been more recent evidence to support a significant survival benefit with the use of PORT in this setting.7-8 A retrospective review of the National Cancer Database revealed an absolute 5-year OS benefit of 6.1% in patients with N2 involvement who received 45-54Gy, which was significantly higher compared to those that did not undergo PORT.23 Another review of this database by Wang et al. found improved survival with PORT regardless of nodal stage in patients with incompletely resected stage II or III N0-2 disease.24 Lastly, Robinson et al. showed a survival benefit of PORT across all nodal stages, suggesting an important role of radiation therapy that has long been doubted.9
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ACCEPTED MANUSCRIPT In addition to the excellent evidence of modern PORT, the Lung Adjuvant Radiotherapy Trial (ART), a Phase III study comparing post-operative conformal radiotherapy to no post-operative radiotherapy in patients with completely resected non-small cell lung cancer and mediastinal N2 involvement, is currently enrolling in Europe.25 In this study, which included patients with N2 disease and/or positive margins, we found post-operative proton
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radiation therapy with a mean follow up of 23.1 months and a median dose of 50.4 Gy after surgical resection resulted in a one-year overall survival of 85.2% and one year local recurrence-free survival of 92.3%, which was comparable to patients treated with IMRT.
Proton beam therapy, due to its characteristic Bragg peak, has the potential to deliver the most conformal PORT and
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may increase the therapeutic ratio by allowing for decreased early and late toxicities.26-27 Dosimetric studies in both standard and dose-escalated settings have shown that proton plans offer a significant reduction in normal lung V20 and
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mean lung dose compared to 3-D XRT or IMRT.28 There are several studies that have attempted to translate these findings to the clinical setting. For example, dose escalated proton therapy to 74 Gy and concurrent chemotherapy for stage III unresectable lung cancer was observed to have a median survival of 29.4 mos. The treatment was well-tolerated and remarkable for no severe grade 4 or 5 treatment related complications.20 This is in contrast to a recent large randomized trial that revealed a potential survival detriment with dose escalated photon therapy to 74 Gy.29
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The toxicity profile of proton PORT in our study was notable for absence of grade 4 or 5 treatment-related adverse event. Grade 3 radiation pneumonitis was fortunately uncommon (3-4%) in both cohorts and grade 2 was less in the proton cohort (1 versus 3). There was a trend toward decreased rate of esophagitis symptoms in the proton cohort, with grade 3
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toxicity observed in 1 versus 4 patients and grade 2 toxicity observed in 5 versus 10 patients in the PBT and IMRT cohorts, respectively. Dosimetric parameters were notable for a significant reduction in mean and V5 dose to the lung with proton therapy, which could explain the reduced rate of radiation pneumonitis in this cohort. Interestingly, however, esophageal
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constraints did not appear significantly different despite the reduced grade 2 and 3 esophagitis symptoms observed in the proton cohort. Further assessment of dose and location of tumor in relation to esophageal toxicity is needed to potentially separate out those in which a clinical benefit is derived. We have only reported on the acute and sub-acute toxicities in this manuscript given the median follow-up of 26.5 months; however, we anticipate that proton therapy will have even more sparing in regard to late adverse effects including lung fibrosis, cardiac toxicity, and/or secondary malignancies, and we will monitor for these late toxicities in this patient cohort. There is an increasing realization that cardiac dose may be a significant contributor to death from intercurrent disease. RTOG 0617 found on multivariable analysis that increasing heart dose predicted for worse overall survival in
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ACCEPTED MANUSCRIPT locally-advanced NSCLC.29 Therefore, in PORT, where the therapeutic ratio is even narrower, and where a greater proportion of the dose is centrally directed, the reduction in heart dose by proton therapy will likely be of significant benefit. Proton therapy does not come without its challenges. Protons are highly sensitive to tissue density deviations,
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particularly in lung cancer patients who commonly acquire anatomical changes throughout the course of their treatment.17 Consequently, proton plans may require adaptive re-planning during the course of treatment, in addition to careful evaluation of the 4D images that should be performed with any simulation. Although this may play less of a role with minimal to no gross tumor burden after surgical resection, postoperative normal tissue changes must be monitored. One
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study investigated mediastinal motion by placing small gold fiducial markers (0.35 × 5 mm) in the mediastinal lymph nodes of 51 patients with NSCLC, and carried out a 4D planning CT and daily 4D CBCT during RT (66Gy in 24 fractions). They
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found that margins could be reduced by 10% (left-right), 27% (cranial-caudal), and 10% (anteroposterior) if carina registration replaced bony anatomy registration.30 Given that on-board imaging for proton therapy is currently based on bony anatomy in most centers, it is important to consider how to account for interfraction setup error. Furthermore, IMPT is particularly sensitive to motion changes, and significant concerns arise regarding the interplay effect, or the interference between target motion and dynamic pencil beam scanning. There are several ways to account for
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this, including WET (water equivalent thickness) analysis method as put by forth by Mori et al.31; beam-specific PTV (BSPTV), such as analyses by Park et al.32 or Lin et al.33 distal and proximal water-equivalent treatment margins (WETM) converted to geometric treatment margins (GTM). Also, “worst-case scenarios” analysis can be performed with multi-field
proton therapy.
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optimization IMPT.34 Future studies that explore motion management will be needed to address these unique challenges in
Our study is not without limitations. Although this is the first study of its kind and has a median follow-up of just over
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2 years, this length of time is not adequate to examine the late effects of radiotherapy, which we plan to subsequently report. In addition, our comparison with proton therapy and IMRT is robust as it included all consecutive patients treated with either modality during the time frame and did not exclude any subjects; however, it is not a randomized comparison of proton therapy and IMRT, and as such there may be selection bias. The retrospective nature of this study is also subject to misclassification bias. For instance, while CTCAE v4.0 was utilized, it is uncertain whether it was applied uniformly across all treating physicians. Another limitation of our study is variation in clinical target volume delineation among different clinicians which has been previously reported to be as high as threefold.35 However, we believe these inconsistencies are reduced with the adoption of more uniform contouring
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ACCEPTED MANUSCRIPT guidelines.21-22 Lastly, our study included patients receiving post-operative radiotherapy for either N2 disease or N0 with positive margins; the latter patients may have overall less toxicity from radiotherapy as the field size is smaller and therefore they may have less potential benefit from proton radiotherapy. To our knowledge, this is the first clinical study looking at post-operative radiation therapy in the treatment of lung
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cancer for patients with mediastinal (N2) nodal disease or following positive margin resection. Our study is notable for PORT with PBT being very well-tolerated and having similar survival as compared to conventional IMRT . These findings should be encouraging for future research aimed at identifying unique clinical characteristics, investigating motion
Table 1-4: see attachment in excel spreadsheet format.
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mitigation strategies and using dose escalation to further optimize proton beam therapy in this unique patient population.
format).
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Figure 1: Kaplan-Meier survival curves. Please see attached Figure 1_Survival curves.pdf file (also included in ppt
Figure 2: Dose-volume histograms. Please see attached Figure 2_DVH.pdf file (also included in ppt format). NOTE: color print is required for figure 2.
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with three-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(4):1087-1096. 16.
Lomax AJ, B Böhringer T, Bolsi A, et al. Treatment planning and verification of proton therapy using spot scanning: initial experiences. Med Phys. 2004; 31(11):3150-7.
17.
Berman AT, Teo BK, Dolney D, et al. An in-silico comparison of proton beam and IMRT for postoperative radiotherapy in completely resected stage IIIA non-small cell lung cancer. Radiat Oncol. 2013;8:144.
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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 radiotherapy for extensive stage IIIB non-small-cell lung cancer: a virtual clinical study. Int J Radiat Oncol Biol Phys.77(2):357-366. Kesarwala AH, Ko CJ, Ning H, et al. Intensity-modulated proton therapy for elective nodal irradiation and
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involved-field radiation in the definitive treatment of locally advanced non-small-cell lung cancer: a dosimetric study. Clin Lung Cancer. 2015;16(3):237-244. 20.
Chang JY, Komaki R, Lu C, et al. Phase 2 study of high-dose proton therapy with concurrent chemotherapy for
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unresectable stage III nonsmall cell lung cancer. Cancer. 2011;117(20):4707-4713.
Le Péchoux C. Phase III study comparing post-operative conformal radiotherapy to no post-operative radiotherapy
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in patients with completely resected non-small cell lung cancer and mediastinal N2 involvement (Lung ART Protocol IGR 2006/1202). 22.
Chapet O, Kong FM, Quint LE, et al. CT-based definition of thoracic lymph node stations: an atlas from the University of Michigan. Int J Radiat Oncol Biol Phys. 2005;63(1):170-178.
23.
Corso CD, Rutter CE, Wilson LD, Kim AW, Decker RH, Husain ZA. Re-evaluation of the role of postoperative
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radiotherapy and the impact of radiation dose for non-small-cell lung cancer using the National Cancer Database. J Thorac Oncol. 2015;10(1):148-155. 24.
Wang EH, Corso CD, Rutter CE, et al. Postoperative Radiation Therapy Is Associated With Improved Overall
2734. 25.
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Survival in Incompletely Resected Stage II and III Non-Small-Cell Lung Cancer. J Clin Oncol. 2015;33(25):2727-
Le Pechoux C, Dunant A, Pignon JP, et al. Need for a new trial to evaluate adjuvant postoperative radiotherapy in
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non-small-cell lung cancer patients with N2 mediastinal involvement. J Clin Oncol. 2007;25(7):e10-11. Berman AT, James SS, Rengan R. Proton Beam Therapy for Non-Small Cell Lung Cancer: Current Clinical Evidence and Future Directions. Cancers (Basel). 2015;7(3):1178-1190. 27.
Simone CB, 2nd, Rengan R. The use of proton therapy in the treatment of lung cancers. Cancer J. 2014;20(6):427432.
28.
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(4):252-257.
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Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB nonsmall-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015;16(2):187-199. Schaake EE, Rossi MM, Buikhuisen WA, et al. Differential motion between mediastinal lymph nodes and primary
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tumor in radically irradiated lung cancer patients. Int J Radiat Oncol Biol Phys. 2014;90(4):959-966. 31.
Mori S, Dong L, Starkschall G, Mohan R, Chen GT. A serial 4DCT study to quantify range variations in charged particle radiotherapy of thoracic cancers. J Radiat Res. 2014;55(2):309-319.
Park PC, Cheung JP, Zhu XR, et al. Statistical assessment of proton treatment plans under setup and range
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uncertainties. Int J Radiat Oncol Biol Phys. 2013;86(5):1007-1013.
Lin L, Kang M, Huang S, et al. Beam-specific planning target volumes incorporating 4D CT for pencil beam
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scanning proton therapy of thoracic tumors. J Appl Clin Med Phys. 2015;16(6):5678. 34.
Lomax AJ. Intensity modulated proton therapy and its sensitivity to treatment uncertainties 1: the potential effects of calculational uncertainties. Phys Med Biol. 2008;53(4):1027-1042.
Spoelstra FO, Senan S, Le Pechoux C, et al. Variations in target volume definition for postoperative radiotherapy
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2010;76(4):1106-1113.
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in stage III non-small-cell lung cancer: analysis of an international contouring study. Int J Radiat Oncol Biol Phys.
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35.
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Table 1. Clinical Characteristics IMRT (n=34)
number of patients (%)
p-value
Age Median age, yrs (range)
65 (38-77)
63 (38-80)
p=0.56
14 (52) 13 (48)
14 (41) 20 (59)
p=0.21
20 (74) 7 (26)
26 (76) 8 (23)
p=0.78
2 (7) 18 (67) 1 (4) 6 (22)
7 (20) 27 (79) 0 0
p<0.001
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p=0.84
22 (65) 12 (35)
p=0.50
9 (33) 18 (67)
10 (29) 24 (71)
p=0.66
8 (30) 19 (70)
7 (21) 27 (79)
p=0.23
12 (44)
18 (53)
p=0.43
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17 (63) 10 (37) 19 (70) 8 (30)
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Male Female Smoking History Yes No Tumor Histology Squamous Adenocarcinoma Large Cell Other AJCC Clinical Stage IA-IIB IIIA or higher Tumor Size T1-2 T3-4 Nodal Involvement N0-1 N2 AJCC Pathologic Stage IA-IIB IIIA or higher Margin Status R0
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Sex
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Proton (n=27)
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11 (32) 4 (12)
15 (55) 3 (11) 7 (26) 2 (7) 0
16 (47) 2 (6) 11 (32) 4 (12) 1 (3)
p=0.42
2 (7) 19 (70) 6 (22)
4 (12) 20 (59) 11 (32)
p=0.19
13 (48)
17 (50)
p=0.38
3 (11)
7 (21)
4 (15)
4 (12)
5 (18)
6 (18)
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4 (3-6) 3 (2-4)
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3 (2-4)
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12 (44) 1 (4)
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R1 R2 Radiation dose 5000-5040 5400 5940-6120 6660 7200 Chemotherapy Neoadjuvant Sequential Concurrent Type of chemotherapy Cisplatin/pemetrexed Carboplatin/paclitaxel Other cisplatin based regimen Other carboplatin based regimen Average Chemotherapy Cycles (range) Neoadjuvant Sequential Concurrent
3 (2-4) 4 (2-4) 5 (4-7)
p=0.51
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IMRT
3 1 0 11
2 1 1 17
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Site of Failure Local (isolated) Regional (isolated) Local + Regional Distant
ACCEPTED MANUSCRIPT Table 3. Dose Contraints for Organs At Risk Proton (n=27) Dose constraint
IMRT (n=34)
Mean (median)
p-value
Lung 11.2 (12) 23.8 (25.5) 32.3 (34.4)
12.7 (13.4) 23.9 (26.5) 44.9 (50.5)
0.045 (0.061) NS 0.001 (<0.001)
Max 74 Gy V55 < 30%
55.9 (55.0) 3.87
55.9 (54.3) 6
NS NS
Max 70 Gy V45 < 35% V30 < 50%
48.4 (55.2) 10.3 (9.6) 15.7 (14.7)
47.5 (52.9) 9.6 (4.8) 18.6 (16.5)
Max 50 Gy
35.7 (38.0)
Esophagus
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Cord
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NS NS NS
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Heart
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Mean < 20 V20 < 35% V5 < 60%
42.0 (44.3)
0.010 (0.005)
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Table 4. Acute Toxicity after Post-operative Proton Beam Therapy and IMRT Acute Toxicity Grade* Proton (n=27) IMRT (n=34) number of patients (%)
2
3
2
3
0 3 (11) 5 (18) 1 (4)
0 0 0 1 (4)
1 (3) 6 (18) 5 (15) 3 (9)
1 (3) 0 0 1 (3)
5 (18) 3 (11) 0 0 0 1 (4)
1 (4) 0 0 0 0 0
10 (29) 8 (23) 3 (9) 1 (3) 2 (6) 5 (15)
4 (12) 0 1 (3) 0 0 0
9 (26) 6 (18) 1 (3) 4 (12)
3 (9) 1 (3) 1 (3) 0
Other Fatigue Anorexia Dehydration Dermatitis
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Esophagitis: dysphagia and/or odynophagia Dyspepsia Nausea Vomiting Diarrhea Constipation
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Hoarseness Cough Dyspnea Radiation pneumonitis Gastrointestinal
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Lung
6 (22) 6 (22) 0 10 (37)
0 0 0 0
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*Toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE), version 4.
A) PBT
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B) IMRT
Figure 1. Kaplan-Meier survival curves. One year median overall survival (left) and local recurrencefree survival (right) were 85.2% and 82.4% (95% CI 72.8-99.7% and 70.5-96.2%) and 92.3% and 93.3% (82.5-100% and 84.8-100%) for PBT (A) and IMRT (B), respectively. The overall survival (p=0.648) and local recurrence free survival (p=0.816) were not significantly different between the two groups.
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Figure 2. Dose-volume histograms. The maximum and V55 dose of the esophagus were not significantly different between PBT (orange) and IMRT (blue) (p=0.994 and p=0.417), however, both the mean and V5 dose were significantly lower in PBT (orange) compared to IMRT (blue) for Lung-GTV (bottom) (p=0.045 and p=0.001).
S1525-7304(16)30385-0
DOI:
10.1016/j.cllc.2016.12.009
Reference:
CLLC 585
To appear in:
Clinical Lung Cancer
Received Date: 2 July 2016 Revised Date:
11 December 2016
Accepted Date: 13 December 2016
Please cite this article as: Remick JS, Schonewolf C, Gabriel P, Doucette A, Levin WP, Kucharczuk JC, Singhal S, Pechet TT, Rengan R, Simone II CB, Berman AT, First Clinical Report of Proton Beam Therapy for Post-Operative Radiotherapy for Non-Small Cell Lung Cancer, Clinical Lung Cancer (2017), doi: 10.1016/j.cllc.2016.12.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT First Clinical Report of Proton Beam Therapy for Post-Operative Radiotherapy for Non-Small Cell Lung Cancer Jill S. Remick MD1, Caitlin Schonewolf MD2, Peter Gabriel MD2, Abigail Doucette MPH2, William P. Levin MD2, John C. Kucharczuk MD3, Sunil Singhal MD3, Taine TV Pechet MD3, Ramesh Rengan MD PhD4, Charles B Simone II MD2, Abigail T. Berman MD2
Author Contributions:
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Corresponding Author: Abigail T. Berman [email protected] (215) 662-2428
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University of Maryland Department of Radiation Oncology 22 South Green St. Baltimore, MD 21202 2 University of Pennsylvania Department of Radiation Oncology Perelman Center for Advanced Medicine 3400 Civic Center Blvd. Philadelphia, PA 19104 3 University of Pennsylvania Department of Thoracic Surgery Perelman Center for Advanced Medicine 3400 Civic Center Blvd. Philadelphia, PA 19104 4 University of Washington Department of Radiation Oncology 1959 NE Pacific St. Mailstop Box 356049 Seattle, WA 98195
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1
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Jill Remick, MD – data collection, figure and table design, manuscript writing, editing and revising. Caitlin Schonewolf MD – data collection, statistical work, figure design, paper editing and revisions. Peter Gabriel MD – statistical assistance, data mining, figure design. Abigail Doucette – data mining, statistical work. William P. Levin MD – assisted in editing and revisions. John C. Kucharczuk MD - assisted in editing and revisions. Sunil Singhal MD - assisted in editing and revisions. Taine TV Pechet MD - assisted in editing and revisions. Ramesh Rengan MD PhD - assisted in editing and revisions. Charles B Simone II MD - assisted in editing and revisions. Abigail T. Berman MD – primary advisor, literature review, writing and editing manuscript.
Conflicts of Interest There are no conflicts of interest to disclose.
Role of Funding Sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
ACCEPTED MANUSCRIPT Micro Abstract We investigated the survival outcomes and early toxicity profile of post-operative radiation therapy (PORT) with proton beam therapy (PBT) versus intensity modulated radiation therapy (IMRT) for non-small cell lung cancer in a cohort of 61 patients with positive microscopic margins and/or positive N2 lymph nodes. We found that post-operative PBT in locally-
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advanced NSCLC is well-tolerated and has similar excellent short-term outcomes when compared with IMRT.
Abstract
Background and Purpose: The characteristic Bragg peak of proton beam therapy (PBT) allows for sparing normal tissues
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beyond the tumor volume that may allow for decreased toxicities associated with PORT. Here we report the first
institutional experience with proton therapy for PORT in NSCLC patients and assess early toxicities and outcomes.
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Materials and Methods: We identified 61 consecutive patients treated from 2011-2014 that underwent PORT for locallyadvanced NSCLC for positive microscopic margins and/or positive N2 lymph nodes (stage III), with 27 patients receiving PBT and 34 receiving intensity modulated radiation therapy (IMRT).
Results: Median follow-up time was 23.1 months for PBT (2.3-42 months) and 27.9 months for IMRT (0.5-87.4 months). The median radiation dose was 50.4 Gy for PBT (50.4-66.6 Gy) and 54 Gy for IMRT (50.0-72.0 Gy). Grade 3 radiation
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esophagitis was observed in 1 and 4 patients in the PBT and IMRT groups, respectively. Grade 3 radiation pneumonitis was observed in 1 patient in each cohort. Dosimetric analysis revealed a significant decrease in the V5 and mean lung dose (p=0.001 and p=0.045, respectively). One-year median overall survival and local recurrence-free survival were 85.2% and
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82.4% (95% CI 72.8-99.7% and 70.5-96.2%, p=0.648) and 92.3% and 93.3% (82.5-100%, 84.8-100%, p=0.816) for PBT and IMRT cohorts, respectively.
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Conclusions: Post-operative PBT in NSCLC is well-tolerated and has similar excellent short-term outcomes when compared with IMRT. Longer follow-up is necessary to determine if PBT has a meaningful improvement over IMRT for PORT.
Key words: Non-small cell lung cancer (NSCLC), post-operative radiation therapy (PORT), proton beam therapy (PBT), intensity-modulated radiation therapy (IMRT)
Introduction
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ACCEPTED MANUSCRIPT Lung cancer continues to be the number one cause of cancer death in the United States with non-small cell lung cancer (NSCLC)* being the most common histologic variant.1 Surgery, with an anatomical lobectomy or pneumonectomy, is the standard of care for early-stage disease; patients with N2 nodal involvement should be treated with either definitive chemoradiation or multimodality therapy with surgery preceded by chemotherapy or chemoradiation.2 Post-operative
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radiation therapy is recommended for N2 NSCLC patients who receive neoadjuvant chemotherapy followed by surgery or with “surprise” N2 nodal involvement (discovered incidentally at surgery) or with gross or residual microscopic disease after surgical resection in otherwise healthy patients.3
The primary concern regarding post-operative radiation therapy (PORT) is the potential for toxicity in this patient
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population. In the PORT meta-analysis (PORT Meta-analysis Trialists Group), radiation-induced toxicity appeared to negate any therapeutic benefit of PORT, presumably due to the large field sizes and outdated radiation techniques that were
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used.4 However, the role of radiation therapy in decreasing local recurrence, irrespective of survival benefit, had been recognized even among studies included in the PORT meta-analysis.5-6 There has been more recent evidence with the use of modern radiotherapy techniques to support an increase in survival in N2 positive patients receiving PORT.7-9 Targeting radiation to smaller volumes and using modern techniques such as intensity-modulated radiation therapy (IMRT) has resulted in an improved therapeutic ratio.10-11 However, radiation-induced toxicity is still of concern, in
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particular lung damage manifested as pneumonitis or fibrosis and cardiac injury. The potential for toxicity is even greater with concurrent chemotherapy in the setting of positive margins.12 In contrast to photons utilized in traditional radiation therapy, proton beam therapy (PBT) consists of charged particles
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that can be delivered to a specific depth within tissue that is dependent upon its energy, creating the characteristic ‘Bragg peak’.13-14 Proton therapy has been shown in a dosimetric study to significantly reduce mean total lung V5, V10 and V20
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using dose escalation in comparison to 3D conformal radiotherapy and IMRT.15 In addition, variations in PBT techniques, such as intensity modulated proton therapy (IMPT) using pencil beam scanning (PBS), may offer potential benefits. Pencil beam scanning is a technique unique to protons that allows for 3D conformation by filling in layer by layer of the tumor target and thus obviates the need for other devices to modulate the beam shape.16 We have shown that intensity modulated proton therapy (IMPT) results in a significant dose reduction to spinal cord, lung and heart compared to passive scattering proton therapy (PSPT) and IMRT.17-19
*
Common Abbreviations: Non-small cell lung cancer (NSCLC), post-operative radiation therapy (PORT), proton beam therapy (PBT), intensity-modulated radiation therapy (IMRT), pencil beam scanning (PBS), intensity modulated proton therapy (IMPT)
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ACCEPTED MANUSCRIPT In lung cancer, there is limited clinical data available that has correlated the dosimetric benefits of PBT to an improved therapeutic index. Chang et al. reported a phase II trial of stage III NSCLC patients treated with concurrent chemoradiation using dose escalated proton-beam therapy resulted in low rates of toxicity and an improved survival compared to their institutional experience with IMRT using photon therapy.20
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To date, there is no clinical study that has assessed the use of PBT for PORT in locally-advanced NSCLC. Here, we report the first institutional experience of PBT PORT in patients with N2 nodal involvement or microscopic residual disease after surgical resection and assess the toxicity profile and survival outcomes in comparison to IMRT.
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Materials and Methods
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Patient Selection and Study Design
This retrospective study was approved by our Institutional Review Board. In addition, patients treated with PBT were enrolled on an Institutional Review Board-approved proton registry study allowing prospective collection of toxicity and clinical outcomes. All patients underwent extensive informed consent of the risks and benefits of radiotherapy or no radiotherapy as well as the possible dosimetric benefits and unknown variables of proton therapy. A total of 61 consecutive
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patients at our single institution with operable NSCLC who were found to have post-operative N2 nodal involvement or positive margins were retrospectively evaluated. Of these 61 patients, 27 were treated with proton bean therapy (PBT) and 34 were treated with intensity-modulated radiation therapy (IMRT). Of the 27 patients treated with PBT, 22 received
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double scatter proton therapy (DS-PT) and 5 received intensity-modulated proton therapy (IMPT). Patients who received neoadjuvant concurrent proton/chemotherapy as part of an institutional protocol (n=20) and those who had palliative
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surgery (n=2) to alleviate symptomatic airway compression prior to radiation treatment were excluded from this analysis.
Treatment Simulation and Target Volume Delineation Patients were simulated in the supine position with arms extended above the head. To account for tumor motion, a four-dimensional (4D)-computed tomography (CT) simulation was performed (Siemens Sensation and/or Philips GEMINI TF) using Varian Real-time Position Management (RPM) system (Varian Medical System, Palo Alto, CA). All 10 respiratory-phase images and the reconstructed averages were transferred into Eclipse planning system version 11.0 and fused with pre-treatment imaging (Varian Medical Systems, Palo Alto, CA). CTV volume was delineated based on
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ACCEPTED MANUSCRIPT guidelines described elsewhere.21-22 CTV was defined to include the bronchial stump, lymph nodes that are positive according to the pathology report as well as the ipsilateral hilar lymph node region and the mediastinal pleura adjacent to the surgical bed. Additional nodal stations were included as part of CTV using LungART protocol as a guide and clinical discretion of the treating physician. An ITV was defined based on respiratory motion of the CTV, and then a 0.5 cm
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expansion of ITV was used to generate a PTV. Patients that had suspected or confirmed (based on surgeon report or PETCT) gross disease after surgical resection (n=5), a CTV was generated by expanding the iGTV for any primary disease by
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0.5 cm and for any nodal disease by 0.3 cm as per institutional protocol.
Treatment Planning and Delivery
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The average 4D-CT was used for plan optimization and dose calculation. PBT patients were treated with double scatter proton therapy (DS-PT) (n=22) or pencil beam scanning (PBS) (n=5). Fields were centered on the ITV, with beam angles optimized to maximize ITV coverage and minimize exposure to normal structures. Patients underwent a verification CT approximately twice over the course of radiation to detect anatomical changes potentially altering proton therapy. Range uncertainty in the conversion of CT images to stopping power (3%) and patient setup (3 mm) were accounted for in the distal and proximal margins of DS-PT. Lucite compensators were manufactured for each beam and multi-leaf collimators
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were used for shaping and conformality. Smearing was used in the DS-PT compensator design to incorporate internal organ motion and ensure target coverage along the beam direction. Dynamic IMRT was planned using 5-7 coplanar beams. Institutional target planning constraints for both proton and IMRT plans were as follows: 95% of the PTV to be covered by
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at least 95% of the dose, lung mean dose ≤20 Gy (and ≤8.5 Gy in pneumonectomy cases, n=4), lung V20≤35%, lung V5≤60%, heart maximum of 70 Gy, heart V45≤35%, heart V30≤50%, esophagus maximum of 74 Gy and V55<30%. Dose-
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volume histograms (DVHs) of the target and critical normal structures were analyzed retrospectively. Radiation prescription dose ranged from 50 Gy to 72 Gy with a median dose of 50.4 Gy and 54 Gy for the PBT and IMRT groups, respectively. Per institutional guidelines, 50.4-54 Gy is generally prescribed to a negative margin resection (R0), 59.4-61.2 Gy to microscopic residual (R1) and 66.6 Gy or greater for gross residual disease (R2). The radiation was given in once-daily 1.8 Gy fractions (fx). Two patients received a combination photon and proton plan. These patients were allocated to the cohort in which they received the majority of their prescribed dose, as a result, there was one combination plan in each cohort.
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Evaluation and Follow-up Patients were followed weekly during radiotherapy and again 1 month after completing treatment; patients were then
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followed every 3 months with a CT scan for 2 years and thereafter every 6 months. Toxicities were documented according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Toxicities were retrospectively evaluated using an institutional toxicity database in which toxicity grade is determined by the primary attending and recorded during each on-treatment-visit and subsequent follow up visits. The same CTCAEv 4.0 was used for both proton and photon
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cohorts. This database was supplemented by chart reviewing all on-treatment and follow up notes to corroborate the documented grade based on description of symptoms, physical exam and imaging findings. PET scans were performed if
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there was suspicion of recurrent disease.
Local failure was defined as recurrence of tumor at the primary site or within the neighboring lung parenchyma in order to account for both in-field and out-of-field recurrences. Regional failure was documented if recurrence occurred in a lymph node proven by biopsy or by a clear interval increase in FDG avidity on PET scan. Distant failure was defined by either intra- or extra-thoracic metastatic disease. Intra-thoracic metastatic disease included disease in the contralateral lung, presence of bilateral disease or pleural or pericardial fluid involvement. The timing of the recurrence was recorded based on
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the date of biopsy backdated to the date of image that showed clear evidence of abnormalities or just to the date of imaging
Statistical Analysis
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evidence alone in patients who did not undergo a biopsy at the time of recurrence.
Overall survival was defined from the start of radiation treatment to the date of last follow-up contact or death.
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Progression-free survival was measured from the start of radiation therapy to the date of last follow-up or disease progression. Survival curves were estimated by the Kaplan-Meier method. DVH comparisons between PBT and IMRT were carried out using a two-tailed Wilcoxon signed rank test, and statistical significance was defined as p <0.05.
Results
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ACCEPTED MANUSCRIPT The clinical characteristics of the 61 patients are shown in Table 1. Median length of follow-up was 23.1 months for PBT (range 2.3-42 months) and 27.9 months for IMRT (range 0.5-87.4). In addition, the median length of follow-up was 26.5 months (range, 0.5-87.4) for all patients and 31.3 months (range, 7.3-87.4) for living patients. There were 42 patients (69%) treated for N2 involvement (18 PBT and 24 IMRT). A total of 23 (38%) had a
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microscopic positive margin and 5 patients (8%) had a gross positive margin based off surgeon report (n=2), post-operative PET-CT (n=2) or unknown (n=1). Radiation treatment dose varied based on surgical margins and clinical discretion and ranged from 50 to 72 Gy with a median dose 50.4 Gy and 54 Gy for the PBT and IMRT groups, respectively. There were two patients who received a combination of photon and proton plans. One plan included 50.4 Gy IMRT followed by 16.2
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Gy proton boost for gross residual disease with the intent to reduce side effects. The second patient received 19.8 Gy IMRT followed by 34.2 Gy proton therapy, however, it was unclear as to why the patient was switched. The majority of
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patients received adjuvant chemotherapy with either sequential (19 and 20 patients) or concurrent chemotherapy (6 and 11 patients) in the proton and IMRT groups, respectively. The most common regimen was cisplatin/pemetrexed in 13 patients treated with protons and in 17 patients treated with IMRT.
Patterns of first failure are shown in Table 2. A total of 5 (8%) patients had an isolated local recurrence (proton n=3, IMRT n=2). In each cohort, one of these isolated failures was outside the radiation field. Regional failure alone was seen in
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1 patient in each cohort. Distant failure was the most common recurrence pattern occurring in 11 (41%) and 17 (50%) of patients in the proton and IMRT cohorts, respectively.
The one-year median overall survival and local recurrence-free survival were 85.2% and 82.4% (95% CI 72.8-99.7%
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and 70.5-96.2%) and 92.3% and 93.3% (82.5-100%, 84.8-100%) for PBT and IMRT cohorts, respectively (Figure 1). At two years, the overall survival for the proton cohort was 77.8% (95% CI 63.6-95.2%) compared to 73.2% (CI 59.6-89.9%) in the IMRT cohort. Local recurrence-free survival at two years was similar for PBT and IMRT (93.1% and 85.7%,
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respectively). Overall survival (p=0.648) and local recurrence free survival (p=0.816) was not significantly different between the two cohorts. Of the 9 deaths in the proton cohort, 4 were related to sepsis or pneumonia complicated by respiratory failure, 1 was due to lymphangitic carcinoma leading to respiratory failure and 4 were not well documented. Seven of the 9 patients had metastatic disease at the time of death. Of the 18 deaths in the IMRT group, 4 were related to respiratory failure (3 of these patients had documented lung progression and/or pleural effusion), 1 patient died of urosepsis and 1 patient died of metastatic breast cancer. Cause of death was not well described or unknown in the remaining 12 patients, although, 14 out of 18 of these patients had documented metastatic disease.
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ACCEPTED MANUSCRIPT Dosimetric results are shown in Table 3. There was a significant reduction in the mean dose to the lung (p=0.45) and V5 (p=0.001) and max dose to the spinal cord (p=0.010) in the proton group compared to the IMRT group (Figure 2). The toxicity profile is shown in Table 4. There were no grade 4 or 5 toxicities observed. There was 1 patient in each cohort (PBT and IMRT) who experienced grade 3 radiation pneumonitis. The one patient in the PBT group was treated with
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sequential chemotherapy (cisplatin/pemetrexed) followed by double-scatter proton therapy to 50.4 Gy in 1.8 Gy per fraction and had a mean lung dose of 13.5 Gy, V5 of 40% and V20 of 29%. The second patient in the IMRT cohort was treated with sequential chemotherapy (cisplatin/pemetrexed) followed by IMRT to 61.2 Gy in 1.8 Gy fractions and had a mean lung dose of 10.3 Gy, V5 of 28.3% and V20 of 18.7%. Grade 3 esophagitis was observed in 1 and 4 patients in the proton and
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IMRT cohorts, respectively. One of these patients in the IMRT cohort was treated to 72 Gy in 1.8 Gy fractions with N2 disease and undocumented margin status and had a max and mean dose to the esophagus of 53.4 Gy and 33.2 Gy,
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respectively. Interestingly, one of these patients was treated with a combined plan of 50.4 Gy IMRT followed by a proton boost of 16.2 Gy (included in the IMRT cohort) and had a max esophageal dose of 67.9 Gy with mean of 29 Gy. The other two patients in the IMRT cohort that experienced grade 3 esophagitis were treated to 50.4 Gy in 1.8 Gy fractions and had a max dose of 54.3 Gy and 47.3 Gy, respectively. The only patient to develop grade 3 esophagitis in the proton cohort received 66.6 Gy in 1.8 Gy fractions and had a max esophageal dose of 66.6 Gy. The grade 2 acute esophagitis rate was
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decreased with proton beam therapy (5 and 10 patients in proton and IMRT arm, respectively).
Discussion
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In this first clinical report of proton beam therapy for post-operative treatment of NSCLC, we found that proton therapy was well-tolerated in comparison to IMRT and was associated with similar excellent outcomes at an early initial
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time point.
The role of post-operative radiation therapy (PORT) has been historically controversial due to earlier studies with poor patient selection and outdated radiotherapy techniques.4 However, there has been more recent evidence to support a significant survival benefit with the use of PORT in this setting.7-8 A retrospective review of the National Cancer Database revealed an absolute 5-year OS benefit of 6.1% in patients with N2 involvement who received 45-54Gy, which was significantly higher compared to those that did not undergo PORT.23 Another review of this database by Wang et al. found improved survival with PORT regardless of nodal stage in patients with incompletely resected stage II or III N0-2 disease.24 Lastly, Robinson et al. showed a survival benefit of PORT across all nodal stages, suggesting an important role of radiation therapy that has long been doubted.9
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ACCEPTED MANUSCRIPT In addition to the excellent evidence of modern PORT, the Lung Adjuvant Radiotherapy Trial (ART), a Phase III study comparing post-operative conformal radiotherapy to no post-operative radiotherapy in patients with completely resected non-small cell lung cancer and mediastinal N2 involvement, is currently enrolling in Europe.25 In this study, which included patients with N2 disease and/or positive margins, we found post-operative proton
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radiation therapy with a mean follow up of 23.1 months and a median dose of 50.4 Gy after surgical resection resulted in a one-year overall survival of 85.2% and one year local recurrence-free survival of 92.3%, which was comparable to patients treated with IMRT.
Proton beam therapy, due to its characteristic Bragg peak, has the potential to deliver the most conformal PORT and
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may increase the therapeutic ratio by allowing for decreased early and late toxicities.26-27 Dosimetric studies in both standard and dose-escalated settings have shown that proton plans offer a significant reduction in normal lung V20 and
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mean lung dose compared to 3-D XRT or IMRT.28 There are several studies that have attempted to translate these findings to the clinical setting. For example, dose escalated proton therapy to 74 Gy and concurrent chemotherapy for stage III unresectable lung cancer was observed to have a median survival of 29.4 mos. The treatment was well-tolerated and remarkable for no severe grade 4 or 5 treatment related complications.20 This is in contrast to a recent large randomized trial that revealed a potential survival detriment with dose escalated photon therapy to 74 Gy.29
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The toxicity profile of proton PORT in our study was notable for absence of grade 4 or 5 treatment-related adverse event. Grade 3 radiation pneumonitis was fortunately uncommon (3-4%) in both cohorts and grade 2 was less in the proton cohort (1 versus 3). There was a trend toward decreased rate of esophagitis symptoms in the proton cohort, with grade 3
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toxicity observed in 1 versus 4 patients and grade 2 toxicity observed in 5 versus 10 patients in the PBT and IMRT cohorts, respectively. Dosimetric parameters were notable for a significant reduction in mean and V5 dose to the lung with proton therapy, which could explain the reduced rate of radiation pneumonitis in this cohort. Interestingly, however, esophageal
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constraints did not appear significantly different despite the reduced grade 2 and 3 esophagitis symptoms observed in the proton cohort. Further assessment of dose and location of tumor in relation to esophageal toxicity is needed to potentially separate out those in which a clinical benefit is derived. We have only reported on the acute and sub-acute toxicities in this manuscript given the median follow-up of 26.5 months; however, we anticipate that proton therapy will have even more sparing in regard to late adverse effects including lung fibrosis, cardiac toxicity, and/or secondary malignancies, and we will monitor for these late toxicities in this patient cohort. There is an increasing realization that cardiac dose may be a significant contributor to death from intercurrent disease. RTOG 0617 found on multivariable analysis that increasing heart dose predicted for worse overall survival in
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ACCEPTED MANUSCRIPT locally-advanced NSCLC.29 Therefore, in PORT, where the therapeutic ratio is even narrower, and where a greater proportion of the dose is centrally directed, the reduction in heart dose by proton therapy will likely be of significant benefit. Proton therapy does not come without its challenges. Protons are highly sensitive to tissue density deviations,
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particularly in lung cancer patients who commonly acquire anatomical changes throughout the course of their treatment.17 Consequently, proton plans may require adaptive re-planning during the course of treatment, in addition to careful evaluation of the 4D images that should be performed with any simulation. Although this may play less of a role with minimal to no gross tumor burden after surgical resection, postoperative normal tissue changes must be monitored. One
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study investigated mediastinal motion by placing small gold fiducial markers (0.35 × 5 mm) in the mediastinal lymph nodes of 51 patients with NSCLC, and carried out a 4D planning CT and daily 4D CBCT during RT (66Gy in 24 fractions). They
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found that margins could be reduced by 10% (left-right), 27% (cranial-caudal), and 10% (anteroposterior) if carina registration replaced bony anatomy registration.30 Given that on-board imaging for proton therapy is currently based on bony anatomy in most centers, it is important to consider how to account for interfraction setup error. Furthermore, IMPT is particularly sensitive to motion changes, and significant concerns arise regarding the interplay effect, or the interference between target motion and dynamic pencil beam scanning. There are several ways to account for
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this, including WET (water equivalent thickness) analysis method as put by forth by Mori et al.31; beam-specific PTV (BSPTV), such as analyses by Park et al.32 or Lin et al.33 distal and proximal water-equivalent treatment margins (WETM) converted to geometric treatment margins (GTM). Also, “worst-case scenarios” analysis can be performed with multi-field
proton therapy.
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optimization IMPT.34 Future studies that explore motion management will be needed to address these unique challenges in
Our study is not without limitations. Although this is the first study of its kind and has a median follow-up of just over
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2 years, this length of time is not adequate to examine the late effects of radiotherapy, which we plan to subsequently report. In addition, our comparison with proton therapy and IMRT is robust as it included all consecutive patients treated with either modality during the time frame and did not exclude any subjects; however, it is not a randomized comparison of proton therapy and IMRT, and as such there may be selection bias. The retrospective nature of this study is also subject to misclassification bias. For instance, while CTCAE v4.0 was utilized, it is uncertain whether it was applied uniformly across all treating physicians. Another limitation of our study is variation in clinical target volume delineation among different clinicians which has been previously reported to be as high as threefold.35 However, we believe these inconsistencies are reduced with the adoption of more uniform contouring
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ACCEPTED MANUSCRIPT guidelines.21-22 Lastly, our study included patients receiving post-operative radiotherapy for either N2 disease or N0 with positive margins; the latter patients may have overall less toxicity from radiotherapy as the field size is smaller and therefore they may have less potential benefit from proton radiotherapy. To our knowledge, this is the first clinical study looking at post-operative radiation therapy in the treatment of lung
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cancer for patients with mediastinal (N2) nodal disease or following positive margin resection. Our study is notable for PORT with PBT being very well-tolerated and having similar survival as compared to conventional IMRT . These findings should be encouraging for future research aimed at identifying unique clinical characteristics, investigating motion
Table 1-4: see attachment in excel spreadsheet format.
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mitigation strategies and using dose escalation to further optimize proton beam therapy in this unique patient population.
format).
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Figure 1: Kaplan-Meier survival curves. Please see attached Figure 1_Survival curves.pdf file (also included in ppt
Figure 2: Dose-volume histograms. Please see attached Figure 2_DVH.pdf file (also included in ppt format). NOTE: color print is required for figure 2.
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Spoelstra FO, Senan S, Le Pechoux C, et al. Variations in target volume definition for postoperative radiotherapy
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in stage III non-small-cell lung cancer: analysis of an international contouring study. Int J Radiat Oncol Biol Phys.
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35.
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Table 1. Clinical Characteristics IMRT (n=34)
number of patients (%)
p-value
Age Median age, yrs (range)
65 (38-77)
63 (38-80)
p=0.56
14 (52) 13 (48)
14 (41) 20 (59)
p=0.21
20 (74) 7 (26)
26 (76) 8 (23)
p=0.78
2 (7) 18 (67) 1 (4) 6 (22)
7 (20) 27 (79) 0 0
p<0.001
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p=0.84
22 (65) 12 (35)
p=0.50
9 (33) 18 (67)
10 (29) 24 (71)
p=0.66
8 (30) 19 (70)
7 (21) 27 (79)
p=0.23
12 (44)
18 (53)
p=0.43
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17 (63) 10 (37) 19 (70) 8 (30)
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Male Female Smoking History Yes No Tumor Histology Squamous Adenocarcinoma Large Cell Other AJCC Clinical Stage IA-IIB IIIA or higher Tumor Size T1-2 T3-4 Nodal Involvement N0-1 N2 AJCC Pathologic Stage IA-IIB IIIA or higher Margin Status R0
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Sex
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Proton (n=27)
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11 (32) 4 (12)
15 (55) 3 (11) 7 (26) 2 (7) 0
16 (47) 2 (6) 11 (32) 4 (12) 1 (3)
p=0.42
2 (7) 19 (70) 6 (22)
4 (12) 20 (59) 11 (32)
p=0.19
13 (48)
17 (50)
p=0.38
3 (11)
7 (21)
4 (15)
4 (12)
5 (18)
6 (18)
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4 (3-6) 3 (2-4)
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3 (2-4)
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12 (44) 1 (4)
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R1 R2 Radiation dose 5000-5040 5400 5940-6120 6660 7200 Chemotherapy Neoadjuvant Sequential Concurrent Type of chemotherapy Cisplatin/pemetrexed Carboplatin/paclitaxel Other cisplatin based regimen Other carboplatin based regimen Average Chemotherapy Cycles (range) Neoadjuvant Sequential Concurrent
3 (2-4) 4 (2-4) 5 (4-7)
p=0.51
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IMRT
3 1 0 11
2 1 1 17
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Site of Failure Local (isolated) Regional (isolated) Local + Regional Distant
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IMRT (n=34)
Mean (median)
p-value
Lung 11.2 (12) 23.8 (25.5) 32.3 (34.4)
12.7 (13.4) 23.9 (26.5) 44.9 (50.5)
0.045 (0.061) NS 0.001 (<0.001)
Max 74 Gy V55 < 30%
55.9 (55.0) 3.87
55.9 (54.3) 6
NS NS
Max 70 Gy V45 < 35% V30 < 50%
48.4 (55.2) 10.3 (9.6) 15.7 (14.7)
47.5 (52.9) 9.6 (4.8) 18.6 (16.5)
Max 50 Gy
35.7 (38.0)
Esophagus
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Cord
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NS NS NS
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Heart
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Mean < 20 V20 < 35% V5 < 60%
42.0 (44.3)
0.010 (0.005)
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Table 4. Acute Toxicity after Post-operative Proton Beam Therapy and IMRT Acute Toxicity Grade* Proton (n=27) IMRT (n=34) number of patients (%)
2
3
2
3
0 3 (11) 5 (18) 1 (4)
0 0 0 1 (4)
1 (3) 6 (18) 5 (15) 3 (9)
1 (3) 0 0 1 (3)
5 (18) 3 (11) 0 0 0 1 (4)
1 (4) 0 0 0 0 0
10 (29) 8 (23) 3 (9) 1 (3) 2 (6) 5 (15)
4 (12) 0 1 (3) 0 0 0
9 (26) 6 (18) 1 (3) 4 (12)
3 (9) 1 (3) 1 (3) 0
Other Fatigue Anorexia Dehydration Dermatitis
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Esophagitis: dysphagia and/or odynophagia Dyspepsia Nausea Vomiting Diarrhea Constipation
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Hoarseness Cough Dyspnea Radiation pneumonitis Gastrointestinal
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Lung
6 (22) 6 (22) 0 10 (37)
0 0 0 0
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*Toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE), version 4.
A) PBT
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B) IMRT
Figure 1. Kaplan-Meier survival curves. One year median overall survival (left) and local recurrencefree survival (right) were 85.2% and 82.4% (95% CI 72.8-99.7% and 70.5-96.2%) and 92.3% and 93.3% (82.5-100% and 84.8-100%) for PBT (A) and IMRT (B), respectively. The overall survival (p=0.648) and local recurrence free survival (p=0.816) were not significantly different between the two groups.
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Figure 2. Dose-volume histograms. The maximum and V55 dose of the esophagus were not significantly different between PBT (orange) and IMRT (blue) (p=0.994 and p=0.417), however, both the mean and V5 dose were significantly lower in PBT (orange) compared to IMRT (blue) for Lung-GTV (bottom) (p=0.045 and p=0.001).