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A Phase 2 Trial of Alternative Volumes of Oropharyngeal Irradiation for De-intensification (AVOID): Omission of the Resected Primary Tumor Bed After Transoral Robotic Surgery for Human Papilloma Virus–Related Squamous Cell Carcinoma of the Oropharynx
Journal Pre-proof A Phase II Trial of Alternative Volumes of Oropharyngeal Irradiation for Deintensification (AVOID): Omission of the Resected Primary Tumor Bed Following Transoral Robotic Surgery for Human Papilloma Virus Related Squamous Cell Carcinoma of the Oropharynx Samuel Swisher-McClure, MD, John N. Lukens, MD, Charu Aggarwal, MD, Peter Ahn, MD, Devraj Basu, MD PhD, Joshua M. Bauml, MD, Robert Brody, MD, Ara Chalian, MD, Roger B. Cohen, MD, Alireza Fotouhi-Ghiam, MD, Geoffrey Geiger, MD, Jared Gershowitz, Virginia Livolsi, MD, Nandita Mitra, PhD, Kathleen Montone, MD, Jason Newman, MD, Eric Ojerholm, MD, Bert O’Malley, Jr., MD, Karthik Rajasekaran, MD, Erik Tan, Gregory Weinstein, MD, Alexander Lin, MD
PII:
S0360-3016(19)34057-X
DOI:
https://doi.org/10.1016/j.ijrobp.2019.11.021
Reference:
ROB 26049
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 23 August 2019 Revised Date:
29 October 2019
Accepted Date: 1 November 2019
Please cite this article as: Swisher-McClure S, Lukens JN, Aggarwal C, Ahn P, Basu D, Bauml JM, Brody R, Chalian A, Cohen RB, Fotouhi-Ghiam A, Geiger G, Gershowitz J, Livolsi V, Mitra N, Montone K, Newman J, Ojerholm E, O’Malley Jr. B, Rajasekaran K, Tan E, Weinstein G, Lin A, A Phase II Trial of Alternative Volumes of Oropharyngeal Irradiation for De-intensification (AVOID): Omission of the Resected Primary Tumor Bed Following Transoral Robotic Surgery for Human Papilloma Virus Related Squamous Cell Carcinoma of the Oropharynx, International Journal of Radiation Oncology • Biology • Physics (2019), doi: https://doi.org/10.1016/j.ijrobp.2019.11.021. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2019 Elsevier Inc. All rights reserved.
TITLE: A Phase II Trial of Alternative Volumes of Oropharyngeal Irradiation for De-intensification (AVOID): Omission of the Resected Primary Tumor Bed Following Transoral Robotic Surgery for Human Papilloma Virus Related Squamous Cell Carcinoma of the Oropharynx
Authors: Samuel Swisher-McClure MD*1, John N. Lukens MD*1, Charu Aggarwal MD3, Peter Ahn MD1, Devraj Basu MD PhD2, Joshua M. Bauml MD3, Robert Brody MD2, Ara Chalian MD2, Roger B. Cohen MD3, Alireza Fotouhi-Ghiam MD1, Geoffrey Geiger MD1, Jared Gershowitz1, Virginia Livolsi MD 5, Nandita Mitra PhD4, Kathleen Montone MD 5, Jason Newman MD2, Eric Ojerholm MD1, Bert O’Malley Jr. MD2, Karthik Rajasekaran MD2, Erik Tan1, Gregory Weinstein MD2, Alexander Lin MD1 * Denotes co-first authorship Author Affiliations: 1. Department of Radiation Oncology, University of Pennsylvania 2. Department of Otorhinolaryngology, University of Pennsylvania 3. Department of Medicine, Division of Hematology/Oncology, University of Pennsylvania 4. Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania 5. Department of Pathology and Laboratory Medicine, University of Pennsylvania Corresponding Author: Alexander Lin, M.D. Department of Radiation Oncology University of Pennsylvania Perelman School of Medicine
3400 Civic Center Boulevard, TRC 2 West Philadelphia, PA 19104 Phone: 215-662-2428 Fax: 215-349-5445 Email: [email protected]
Prior Presentation: None
Running head: AVOID trial in HPV related Oropharynx Cancer
ACKNOWLEDGEMENT
Author Contributions: Conception and design: Alexander Lin, Roger Cohen, Gregory Weinstein Collection and assembly of data: Alexander Lin, Samuel Swisher-McClure, Jared Gershowitz, Erik Tan Manuscript Writing: All authors Data analysis and interpretation: All authors Financial Support: Alexander Lin Provision of study materials or patients: Samuel Swisher-McClure, John N. Lukens, Charu Aggarwal, Peter Ahn, Joshua M. Bauml, Ara Chalian, Roger B. Cohen, Geoffrey Geiger, Jason Newman, Bert O’Malley Jr., Gregory Weinstein, Alexander Lin Final approval of manuscript: All authors
Disclaimer: The interpretation and reporting of these data are the sole responsibility of the authors. Funding: Supported by a Pilot Research Grant awarded through the Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine Potential Conflicts of Interest: Drs. Weinstein and O’Malley serve as paid consultants for Olympus medical. Dr. Newman serves as a paid consultant for Medtronic, Castle Biosciences, and Just Right Surgical. Dr. Aggarwal serves on advisory boards for Bristol Myers Squibb, Celgene, Roche, Genentech, and Astra Zeneca. Dr. Bauml reports grants and personal fees from Merck, grants and personal fees from Clovis, grants from Carevive Systems, grants from Novartis, grants from Bayer, grants and personal fees from Janssen, grants and personal fees from Astra Zeneca, grants and personal fees from Takeda, personal fees from BMS, personal fees from Celgene, personal fees from Boehringer Ingelheim, personal fees from Guardant Health, personal fees from Genentech.
Word Count of manuscript body: 2,174
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ABSTRACT: Purpose: This trial tested the safety and efficacy of a novel, de-intensified radiation therapy (RT) approach after initial surgical resection for patients with HPV associated OPSCC. Methods: This single arm phase II prospective clinical trial enrolled 60 patients at a single institution between May 2014-September 2017 with stage pT1-pT2 N1-3 HPV-associated OPSCC treated with transoral robotic surgery (TORS) and selective neck dissection (SND). Patients had favorable features at the primary site (negative surgical margins ≥2 mm, no perineural invasion, and no lymphovascular invasion) but required adjuvant therapy based on lymph node involvement. Surgeries were all performed at a high volume head and neck cancer center with expertise in TORS. Patients received post-operative RT to at-risk areas in the involved neck (60-66 Gy), and uninvolved neck (54 Gy). The resected primary site was treated as an
active avoidance structure in the treatment planning of postop RT. Concurrent chemotherapy was administered for patients with extranodal extension (ENE). Results: Median follow-up of the 60 patients enrolled was 2.4 years (range 8.5-53.8 months). A single patient recurred at the primary site, for 2-year local control of 98.3%. One patient (1.7%) developed a regional neck recurrence, and two patients (3.3%) developed distant metastases. Measured two-year local recurrence free survival was 97.9% (95% CI 86.1-99.7%). Overall survival was 100% at the time of analysis. The mean radiation dose to the primary site was 36.9 Gy [Standard Deviation (SD) 10.3 Gy]. Two patients (3.3%) experienced late soft tissue necrosis in the primary site surgical bed that resolved within 2 months. Feeding tube dependence rates were 0% during RT, 3.3% temporarily during follow-up, and 0% at last follow-up.
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Conclusions: De-intensified post-operative RT that avoids the resected primary tumor site and targets only the at-risk neck following TORS for selected patients with HPV-associated OPSCC may be safe and is worthy of further study. Trial Registration: National Institute of Health at Clinicaltrials.gov (XXXXX)
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INTRODUCTION: Human Papilloma Virus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC) is a disease of rising incidence and a distinctly favorable prognosis for which de-escalated treatment strategies are currently under intensive investigation. 1-3 Most U.S. patients with cT1-T2 OPSCC undergo primary surgery, 4 but adjuvant radiotherapy (RT) is usually indicated for lymph node involvement or other adverse pathologic features. Standard adjuvant RT targets the primary tumor site and the at-risk neck to doses of 50-66 Gy depending on risk factors.5-8 One strategy to de-intensify adjuvant RT is to reduce the dose. This is currently being studied in active clinical trials which reduce RT from 60 Gy to 50 Gy following surgery.9,10 Another strategy is to alter the RT targets. Novel RT volumes might irradiate only the neck while avoiding the primary tumor bed,11 with the rationale that recurrences are rare at the primary site following transoral robotic surgery (TORS) in selected favorable patients,12 and RT to the primary site can cause consequential late toxicity such as soft tissue necrosis.13 We believe that in HPV-associated oropharynx cancer where the primary site is cleanly resected (negative margin and no other local intermediate risk factors), active avoidance of adjuvant RT to the primary site will not compromise local control, and will yield a favorable toxicity profile. We conducted a prospective clinical trial to investigate this treatment strategy.
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METHODS AND MATERIALS Study Design This was a single arm Phase II clinical trial to evaluate disease recurrence and toxicity in patients with HPV-associated OPSCC following surgery and de-intensified RT, targeting the at-risk cervical lymph node regions only and avoiding the primary tumor operative bed. This trial was approved by XXXX Institutional Review Board and registered with the National Institute of Health at Clinicaltrials.gov (XXXXX). Patients Patients with completely resected non-metastatic p16+ OPSCC who required adjuvant RT were evaluated for trial eligibility. Eligible patients had pathologic T1-T2 tumors without adverse features on primary tumor pathology. Patients with perineural invasion, lymphovascular invasion, close margins (defined as < 2 mm), or positive margins were excluded since these factors would be expected to increase the risk of local recurrence if avoiding RT to this area. HPV status was determined by immunohistochemistry for p16 from the primary tumor. Tumors with strong and diffuse nuclear and cytoplasmic staining in at least 70% of cells were classified as p16 positive.14 The decision to administer post-operative RT +/- chemotherapy was based on lymph node involvement (AJCC 7th ed. stage pN1-3) and included patients with extranodal extension (ENE).15 Surgical pathology and laboratory testing was completed at the XXXX Department of Pathology and Laboratory Medicine. Treatment Procedures
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All treatment was delivered within XXXX, which is a high volume center for head and neck cancer and transoral robotic surgery. Pre-operatively, patients underwent imaging of the neck with computed tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomography-computed tomography (PET/CT). Additional pre-operative imaging included either chest CT, PET/CT, or chest x-ray. All patients underwent a direct laryngoscopy, panendoscopy, and primary tumor biopsy in order to confirm pathology and plan surgery. Surgery included ipsilateral/unilateral selective neck dissection and transoral robotic resection of the primary tumor.16 The transoral robotic surgical techniques used at our institution for oropharyngeal carcinomas have been well described previously.17,18 Of particular importance for this trial, collaborative pathologic analysis between the surgeon and the pathologist is critical in order to ensure accurate orientation and adequacy of surgical margins. Consistent definitions for positive (tumor on ink) or close (< 2mm) margins were used regardless of the laterality of the margin in question.
Radiation Treatment Planning Patients were simulated for RT using CT with mask immobilization. Clinical target volumes (CTV) for RT were defined as follows: CTV-1 included the ipsilateral lymph node levels II, III, and IV and any other involved lymph node stations; CTV-2 generally included the ipsilateral level V, lateral retropharyngeal nodal stations, and the contralateral level II, III, and IV; CTV-3 included areas of pathologic ENE if applicable. Treatment of the ipsilateral IB station was generally omitted from treatment if surgically dissected and pathologically negative. All CTVs were expanded uniformly by 3 mm to create Planning Target Volumes (PTV). The dose prescription for PTV-1, PTV-2, and PTV-3 were 60 Gy, 54 Gy, and 63-66 Gy respectively in 30-
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33 treatment fractions. RT target volumes included selective nodal regions of the bilateral neck in all study patients. The primary tumor site was defined as the TORS operative bed and was contoured as an avoidance structure for RT planning. The mean dose to the primary site was kept as low as reasonably achievable without compromising adjacent PTV coverage. Radiotherapy was planned and delivered using either Intensity Modulated Radiation Therapy (IMRT) or proton beam therapy using Intensity Modulated Proton Therapy (IMPT); allocation was typically determined by insurance coverage of proton therapy. Target volumes were the same for proton therapy and IMRT. Concurrent Systemic Therapy All patients with extra nodal extension (ENE) in this study (21.7%, n=13) received concurrent systemic therapy per the discretion of the medical oncologists.15 Systemic therapy administered consisted of weekly Cisplatin (40 mg/m2) in 9 patients, high dose cisplatin (100 mg/m2 every 3 weeks) in 2 patients, and cetuximab (400 mg/m2 loading dose and 250 mg/m2 weekly) in 2 patients. Patient Evaluation and Follow-up Patients were evaluated weekly during RT and followed after therapy at 3, 6, 12, 18, and 24 months. Follow-up included physical exam, nasopharyngolaryngoscopy, and cross-sectional imaging of the neck and chest. Follow-up beyond two years continued per standard of care.19 Local recurrence was defined as tumor recurrence identified radiographically or on clinical exam within the oral cavity, nasopharynx, oropharynx, larynx, or hypopharynx. Regional recurrence
7
was defined as failure within the lymph nodes or soft tissue of the neck. Distant failure was defined as progression outside of the head and neck. All disease recurrences were confirmed by biopsy. Patient toxicity was assessed using the NCI Common Terminology Criteria for Adverse Events (CTCAE v4.0). Patients completed health related quality of life questionnaires (EORTC QLQH&N35)20 at enrollment, the end of RT, and each protocol-specified follow-up visit. Statistical Analysis The primary endpoint was 2-year primary site local control. Secondary endpoints included 2year regional control, local recurrence free survival, distant metastasis free survival, progression free survival, and overall survival. Target accrual for the study was 60 patients which provided 78% power to detect a 2-yr local recurrence rate of 17.5%, assuming a null rate of 5%, using a one-tailed exact binomial test with type I error rate 10%. This estimate was based upon observed local control rates ranging from 85-100% following transoral surgery with or without adjuvant RT in HPV-associated OPSCC.12,16,21-24 A planned interim analysis for safety was conducted in July 2016 when 30 patients had been enrolled. This showed no local failures, and continued accrual was deemed safe. Patient characteristics were tabulated using descriptive statistics. Patient follow-up was measured in days from the end of RT to last follow-up. Patient survival was calculated using the KaplanMeier method. Cumulative incidence of severe toxicity including soft tissue necrosis and feeding tube dependency were calculated. Comparisons of primary tumor site radiation dose were made using the t test. All p-values were based on two-sided testing with an alpha of 0.05. Statistical analysis was completed using Stata version 12.1.
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RESULTS Patient Characteristics and Treatment Variables Table 1 displays characteristics of the study population. The trial enrolled 60 patients between May 2014 and September 2017 (Figure 1). Median patient age at diagnosis was 57 years (range 34-84). Most patients were men with a pT1 primary tumor of the palatine tonsil, generally with a limited history of tobacco use. The majority of patients had multiple positive neck nodes. Concurrent chemotherapy was used in 21.7% of cases, all due to presence of ENE in the neck. Radiotherapy technique was evenly split between IMRT and IMPT. One patient was identified as having gross disease in the contralateral neck at RT simulation and received 70.4 Gy in 32 fractions to the area of gross disease while avoiding the primary site. All other patients completed RT as outlined previously. The mean radiation dose to the primary tumor site was 36.9 Gy [Standard Deviation (SD) 10.3 Gy]. An illustrative patient example is shown in Figure 2. The mean radiation doses to the primary tumor site according to location were: tonsil 37.8 Gy, SD 9.6 Gy; glossotonsillar sulcus 38.7 Gy, SD 9.8 Gy; base of tongue 35.4 Gy, SD 11.5 Gy. Mean radiation dose to the primary site was statistically significantly lower with IMPT compared to IMRT (33.9 Gy, SD 11.1 Gy vs. 39.6 Gy, SD 8.9 Gy p=0.03). Box plots of radiation dose to the primary tumor site are in Figure 3. Disease Outcomes The median patient follow-up was 2.4 years (range 8.5-53.8 months). One patient (1.7%) developed a local tumor recurrence at the base of tongue 20 months after completion of RT,
9
yielding a two-year local control rate of 98.3%. This patient underwent salvage surgery and was disease free at last follow-up 5 months after re-resection. Patient overall survival was 100%. Survival curves for local recurrence free survival, regional recurrence free survival, distant metastasis free survival, and progression fee survival are displayed in Figure 4. There was one patient (1.7%) who developed a regional failure in the neck located within the radiation target volume. This patient underwent a salvage neck dissection without additional therapy. There were two patients (3.3%) with distant failure. Measured 2-year local recurrence free survival, regional recurrence free survival, distant metastasis free survival, and progression free survival were 97.9% (95% CI 86.1-99.7%), 97.9% (95% CI 86.3-99.7%), 96.2% (95% CI 85.5-99.0%), and 92.1% (95% CI 80.2-97.0%) respectively. Treatment toxicity No patients required a feeding tube during RT. During follow-up, two patients (3.3%) required feeding tubes (Related to surgery for local recurrence, and soft tissue necrosis respectively). Both these patients subsequently had feeding tubes removed. Soft tissue necrosis within the TORS site operative bed occurred in 2 patients (3.3%), both at 3 months following RT. The mean RT dose to the primary site was higher in the patients who developed soft tissue necrosis compared to patients without soft tissue necrosis (45.8 Gy, range 43.9-47.8 vs. 36.6 Gy, range 14.0-55.1 Gy, p=0.21). Both instances of soft tissue necrosis resolved following dietary modification, oral hygiene, and pain management. One case was treated with hyperbaric oxygen.
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DISCUSSION We conducted a single arm phase II prospective clinical trial to investigate the safety and effectiveness of de-intensified adjuvant RT following surgery for HPV-associated OPSCC. Novel RT targets included the at-risk neck while avoiding the primary tumor site. The study required low-risk features at the primary site, defined as pT1-pT2 tumors resected to negative margins, and no perineural invasion or lymphovascular invasion. Surgeries were all performed by highly experienced TORS surgeons at a single high volume head and neck cancer center. We observed excellent 2-year local control of 98.3%, and favorable toxicity compared to previous reports.16,25,26 Our study is the first prospective trial to report patient outcomes following RT to the neck alone while avoiding treatment to the primary tumor site. Standards of care for postoperative RT in resected OPSCC have included RT dose to the primary tumor site between 6066 Gy.6-8 Our results suggest this approach may be safe and is worthy of further study. Although adjuvant therapy plays an important role in oncologic care for patients with resected OPSCC, head and neck RT is associated with significant toxicities.27 Prior analyses have suggested that avoiding RT to the primary tumor site after surgery might not significantly reduce dose to the primary tumor site or other normal tissues.28,29 In contrast we measured a mean dose to the primary tumor site of 36.9 Gy, which is approximately a 40% reduction from the standard prescription dose of 60 Gy. Lower radiation doses in this functionally critical area of the head and neck could reduce treatment related toxicities such as dysphagia, dysgeusia, or xerostomia.30 However, definitive conclusions regarding the comparative toxicities of this approach cannot be made from the current trial given the non-randomized design. Another recently published trial evaluated aggressive RT dose reductions to the primary tumor site as well as the neck in HPV positive OPSCC following surgery using 30-36 Gy given in
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twice daily fractions with concurrent docetaxel.31 Although the measured mean dose to the primary tumor site in both that trial and the current study may seem comparable; the distinction between dose reduction and dose avoidance to the primary tumor site should be noted. In the trial by Ma et al., a relatively uniform dose was prescribed to the primary tumor site along with concurrent docetaxel, while in our study the dose to the primary tumor site was heterogeneous and a measured mean dose of 36 Gy reflects higher dose along the lateral aspects of the tumor bed adjacent to lymph node targets receiving 60 Gy and much lower doses in the medial aspects of the primary tumor site. Thus, both trials seek to address distinct questions in terms of deintensified adjuvant treatment for these patients. Toxicity outcomes in this trial were favorable. Two patients (3.3%) required temporary feeding tubes, and no patients had feeding tubes at last follow-up. Prior reports of transoral surgery for OPSCC have reported 18-40% of patients requiring feeding tubes during or after treatment.32,33 We observed very low rates of soft tissue necrosis in the primary tumor site operative bed (3.3%) following RT when compared to prior studies which have reported this in 8-28% of patients.13,34 Reducing the frequency of this complication is an important step towards mitigation of toxicity in this patient population. Patient-reported quality of life outcomes were collected as part of this trial and will be analyzed in future reports. Our study has important limitations to consider. First, the trial enrolled a relatively small number of patients and current follow-up is 2.4 years. It will be important to confirm findings in larger patient groups and with longer follow-up. Second, although the toxicity outcomes compare favorably to historical controls, the non-randomized study precludes direct comparison and definitive conclusions regarding comparative toxicity. Third, all patients had treatment at a single institution and surgeries were performed by highly experienced TORS surgeons which may limit
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generalizability. Importantly, prior analyses of patient outcomes following TORS alone performed at our institution for early stage HPV positive primary tumors had shown very low rates of local recurrence.12 Finally, although RT avoided the primary tumor site the measured radiation dose to this area was a mean of 37 Gy. It is important to acknowledge the possible therapeutic effects of these RT doses for patients with OPSCC. CONCLUSIONS In conclusion, de-intensified post-operative RT selectively targeting only the neck and avoiding treatment to the primary tumor site after TORS at a high volume center may be safe and is worthy of further study. The current trial provides important prospective evidence to guide deintensified RT planning and future trial design in patients with favorable risk surgically treated HPV-associated OPSCC.
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FIGURE LEGENDS: Figure 1. Consort Diagram Figure 2. Illustrative Example Radiation Treatment Plan: Study patient with a pT1N2a (AJCC 7th ed.) p16+ squamous cell carcinoma arising from the left base of tongue. The primary site operative bed is shown in violet. The left neck is CTV 6000 and right neck is CTV 5000. The measured mean dose to the operative bed is 14 Gy. Dose color wash set at 50 Gy (left) and 20 Gy (right).
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Figure 3. Measured Radiation Dose to the Primary Tumor Site for all study patients (A), and according to primary tumor location (B), and radiation treatment modality (C) Figure 4. Kaplan-Meier Curves of local recurrence free survival, regional recurrence free survival, distant metastasis free survival, and progression free survival
Table 1: Patient Characteristics of the Study Cohort
Age at diagnosis (years) Sex Male Female Primary Tumor Location Tonsil Base of Tongue Overlapping/Glossotonsillar sulcus Pathologic AJCC Tumor Stage (7th ed.) pT1 pT2 Pathologic AJCC Nodal Stage (7th ed.) pN2a pN2b pN2c* pN3 Primary tumor diameter (mm) Presence of ENE Yes No Number of Lymph Nodes Involved Maximum Diameter of Involved Lymph Nodes (mm) Tobacco use history Number of Pack Years Reported Never Smokers Receipt of Concurrent Chemotherapy Yes No Adjuvant RT Technique Proton Beam Therapy (PBT) IMRT Combination (IMRT/PBT) Management of the Neck Unilateral selective neck dissection Bilateral selective neck RT
All Patients (n=60) Percent (n) or Median (range) 57 (34-84) 83.3% (50) 16.7% (10) 48.3% (29) 40% (24) 11.7% (7) 73.3% (44) 26.7% (16) 41.7% (25) 55% (33) 1.7% (1) 1.7% (1) 12 (2-37) 21.7% 78.3% 2 (1-23) 38 (13-62) 2 (0-100) 53% (32) 21.7% (13) 78.3% (47) 45% (27) 53.3% (32) 1.7% (1) 100% (60) 100% (60)
Abbreviations: AJCC (American Joint Commission on Cancer), ENE (Extra-nodal extension), RT (radiation Therapy), IMRT (Intensity Modulated Radiation Therapy) * One patient identified with gross disease in the contralateral neck at RT simulation and received 70.4 Gy in 32 fractions to the area of gross disease while avoiding the primary site
1
Study CONSORT Diagram
Screened and Enrolled (n=60)
Received treatment per protocol (n=60)
Lost to follow-up (give reasons) (n=0) Discontinued intervention (n=0)
Analysed (n= 60) Excluded from analysis (n=0)
Measured Radiation Dose to Primary Tumor Site by Anatomic Location
10
C
Measured Radiation Dose to Primary Tumor Site by RT Modality
60
60
B
Primary Site Radiation Dose (mean, Gy) 20 30 40 50
Primary Site Radiation Dose (mean, Gy) 20 40 50 30
Measured Radiation Dose to Primary Tumor Site
10
10
Primary Site Radiation Dose (mean, Gy) 20 30 40 50
60
A
Tonsil
Base of Tongue
Glossotonsillar Sulcus
Proton Therapy
IMRT
2
60
57
38
Regional recurrence free survival (%) 0.25 0.50 0.75 1.00
3
4
5
16
4
0
Distant Metastasis Free Survival
Number at risk
0
1
2
60
57
39
Years
3
4
5
16
4
0
3
4
5
16
4
0
Progression Free Survival
Progression free survival (%) 0.25 0.50 0.75 0.00
0.00 Number at risk
Years
0.00
1
Distant Metastasis free survival (%) 0.25 0.50 0.75 1.00
Number at risk
0
Regional Recurrence Free Survival
1.00
0.00
Local recurrence free survival (%) 0.25 0.50 0.75 1.00
Local Recurrence Free Survival
0
1
2
60
56
37
Years
3
4
5
16
4
0
Number at risk
0
1
2
60
56
36
Years
PII:
S0360-3016(19)34057-X
DOI:
https://doi.org/10.1016/j.ijrobp.2019.11.021
Reference:
ROB 26049
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 23 August 2019 Revised Date:
29 October 2019
Accepted Date: 1 November 2019
Please cite this article as: Swisher-McClure S, Lukens JN, Aggarwal C, Ahn P, Basu D, Bauml JM, Brody R, Chalian A, Cohen RB, Fotouhi-Ghiam A, Geiger G, Gershowitz J, Livolsi V, Mitra N, Montone K, Newman J, Ojerholm E, O’Malley Jr. B, Rajasekaran K, Tan E, Weinstein G, Lin A, A Phase II Trial of Alternative Volumes of Oropharyngeal Irradiation for De-intensification (AVOID): Omission of the Resected Primary Tumor Bed Following Transoral Robotic Surgery for Human Papilloma Virus Related Squamous Cell Carcinoma of the Oropharynx, International Journal of Radiation Oncology • Biology • Physics (2019), doi: https://doi.org/10.1016/j.ijrobp.2019.11.021. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2019 Elsevier Inc. All rights reserved.
TITLE: A Phase II Trial of Alternative Volumes of Oropharyngeal Irradiation for De-intensification (AVOID): Omission of the Resected Primary Tumor Bed Following Transoral Robotic Surgery for Human Papilloma Virus Related Squamous Cell Carcinoma of the Oropharynx
Authors: Samuel Swisher-McClure MD*1, John N. Lukens MD*1, Charu Aggarwal MD3, Peter Ahn MD1, Devraj Basu MD PhD2, Joshua M. Bauml MD3, Robert Brody MD2, Ara Chalian MD2, Roger B. Cohen MD3, Alireza Fotouhi-Ghiam MD1, Geoffrey Geiger MD1, Jared Gershowitz1, Virginia Livolsi MD 5, Nandita Mitra PhD4, Kathleen Montone MD 5, Jason Newman MD2, Eric Ojerholm MD1, Bert O’Malley Jr. MD2, Karthik Rajasekaran MD2, Erik Tan1, Gregory Weinstein MD2, Alexander Lin MD1 * Denotes co-first authorship Author Affiliations: 1. Department of Radiation Oncology, University of Pennsylvania 2. Department of Otorhinolaryngology, University of Pennsylvania 3. Department of Medicine, Division of Hematology/Oncology, University of Pennsylvania 4. Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania 5. Department of Pathology and Laboratory Medicine, University of Pennsylvania Corresponding Author: Alexander Lin, M.D. Department of Radiation Oncology University of Pennsylvania Perelman School of Medicine
3400 Civic Center Boulevard, TRC 2 West Philadelphia, PA 19104 Phone: 215-662-2428 Fax: 215-349-5445 Email: [email protected]
Prior Presentation: None
Running head: AVOID trial in HPV related Oropharynx Cancer
ACKNOWLEDGEMENT
Author Contributions: Conception and design: Alexander Lin, Roger Cohen, Gregory Weinstein Collection and assembly of data: Alexander Lin, Samuel Swisher-McClure, Jared Gershowitz, Erik Tan Manuscript Writing: All authors Data analysis and interpretation: All authors Financial Support: Alexander Lin Provision of study materials or patients: Samuel Swisher-McClure, John N. Lukens, Charu Aggarwal, Peter Ahn, Joshua M. Bauml, Ara Chalian, Roger B. Cohen, Geoffrey Geiger, Jason Newman, Bert O’Malley Jr., Gregory Weinstein, Alexander Lin Final approval of manuscript: All authors
Disclaimer: The interpretation and reporting of these data are the sole responsibility of the authors. Funding: Supported by a Pilot Research Grant awarded through the Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine Potential Conflicts of Interest: Drs. Weinstein and O’Malley serve as paid consultants for Olympus medical. Dr. Newman serves as a paid consultant for Medtronic, Castle Biosciences, and Just Right Surgical. Dr. Aggarwal serves on advisory boards for Bristol Myers Squibb, Celgene, Roche, Genentech, and Astra Zeneca. Dr. Bauml reports grants and personal fees from Merck, grants and personal fees from Clovis, grants from Carevive Systems, grants from Novartis, grants from Bayer, grants and personal fees from Janssen, grants and personal fees from Astra Zeneca, grants and personal fees from Takeda, personal fees from BMS, personal fees from Celgene, personal fees from Boehringer Ingelheim, personal fees from Guardant Health, personal fees from Genentech.
Word Count of manuscript body: 2,174
1
ABSTRACT: Purpose: This trial tested the safety and efficacy of a novel, de-intensified radiation therapy (RT) approach after initial surgical resection for patients with HPV associated OPSCC. Methods: This single arm phase II prospective clinical trial enrolled 60 patients at a single institution between May 2014-September 2017 with stage pT1-pT2 N1-3 HPV-associated OPSCC treated with transoral robotic surgery (TORS) and selective neck dissection (SND). Patients had favorable features at the primary site (negative surgical margins ≥2 mm, no perineural invasion, and no lymphovascular invasion) but required adjuvant therapy based on lymph node involvement. Surgeries were all performed at a high volume head and neck cancer center with expertise in TORS. Patients received post-operative RT to at-risk areas in the involved neck (60-66 Gy), and uninvolved neck (54 Gy). The resected primary site was treated as an
active avoidance structure in the treatment planning of postop RT. Concurrent chemotherapy was administered for patients with extranodal extension (ENE). Results: Median follow-up of the 60 patients enrolled was 2.4 years (range 8.5-53.8 months). A single patient recurred at the primary site, for 2-year local control of 98.3%. One patient (1.7%) developed a regional neck recurrence, and two patients (3.3%) developed distant metastases. Measured two-year local recurrence free survival was 97.9% (95% CI 86.1-99.7%). Overall survival was 100% at the time of analysis. The mean radiation dose to the primary site was 36.9 Gy [Standard Deviation (SD) 10.3 Gy]. Two patients (3.3%) experienced late soft tissue necrosis in the primary site surgical bed that resolved within 2 months. Feeding tube dependence rates were 0% during RT, 3.3% temporarily during follow-up, and 0% at last follow-up.
2
Conclusions: De-intensified post-operative RT that avoids the resected primary tumor site and targets only the at-risk neck following TORS for selected patients with HPV-associated OPSCC may be safe and is worthy of further study. Trial Registration: National Institute of Health at Clinicaltrials.gov (XXXXX)
3
INTRODUCTION: Human Papilloma Virus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC) is a disease of rising incidence and a distinctly favorable prognosis for which de-escalated treatment strategies are currently under intensive investigation. 1-3 Most U.S. patients with cT1-T2 OPSCC undergo primary surgery, 4 but adjuvant radiotherapy (RT) is usually indicated for lymph node involvement or other adverse pathologic features. Standard adjuvant RT targets the primary tumor site and the at-risk neck to doses of 50-66 Gy depending on risk factors.5-8 One strategy to de-intensify adjuvant RT is to reduce the dose. This is currently being studied in active clinical trials which reduce RT from 60 Gy to 50 Gy following surgery.9,10 Another strategy is to alter the RT targets. Novel RT volumes might irradiate only the neck while avoiding the primary tumor bed,11 with the rationale that recurrences are rare at the primary site following transoral robotic surgery (TORS) in selected favorable patients,12 and RT to the primary site can cause consequential late toxicity such as soft tissue necrosis.13 We believe that in HPV-associated oropharynx cancer where the primary site is cleanly resected (negative margin and no other local intermediate risk factors), active avoidance of adjuvant RT to the primary site will not compromise local control, and will yield a favorable toxicity profile. We conducted a prospective clinical trial to investigate this treatment strategy.
4
METHODS AND MATERIALS Study Design This was a single arm Phase II clinical trial to evaluate disease recurrence and toxicity in patients with HPV-associated OPSCC following surgery and de-intensified RT, targeting the at-risk cervical lymph node regions only and avoiding the primary tumor operative bed. This trial was approved by XXXX Institutional Review Board and registered with the National Institute of Health at Clinicaltrials.gov (XXXXX). Patients Patients with completely resected non-metastatic p16+ OPSCC who required adjuvant RT were evaluated for trial eligibility. Eligible patients had pathologic T1-T2 tumors without adverse features on primary tumor pathology. Patients with perineural invasion, lymphovascular invasion, close margins (defined as < 2 mm), or positive margins were excluded since these factors would be expected to increase the risk of local recurrence if avoiding RT to this area. HPV status was determined by immunohistochemistry for p16 from the primary tumor. Tumors with strong and diffuse nuclear and cytoplasmic staining in at least 70% of cells were classified as p16 positive.14 The decision to administer post-operative RT +/- chemotherapy was based on lymph node involvement (AJCC 7th ed. stage pN1-3) and included patients with extranodal extension (ENE).15 Surgical pathology and laboratory testing was completed at the XXXX Department of Pathology and Laboratory Medicine. Treatment Procedures
5
All treatment was delivered within XXXX, which is a high volume center for head and neck cancer and transoral robotic surgery. Pre-operatively, patients underwent imaging of the neck with computed tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomography-computed tomography (PET/CT). Additional pre-operative imaging included either chest CT, PET/CT, or chest x-ray. All patients underwent a direct laryngoscopy, panendoscopy, and primary tumor biopsy in order to confirm pathology and plan surgery. Surgery included ipsilateral/unilateral selective neck dissection and transoral robotic resection of the primary tumor.16 The transoral robotic surgical techniques used at our institution for oropharyngeal carcinomas have been well described previously.17,18 Of particular importance for this trial, collaborative pathologic analysis between the surgeon and the pathologist is critical in order to ensure accurate orientation and adequacy of surgical margins. Consistent definitions for positive (tumor on ink) or close (< 2mm) margins were used regardless of the laterality of the margin in question.
Radiation Treatment Planning Patients were simulated for RT using CT with mask immobilization. Clinical target volumes (CTV) for RT were defined as follows: CTV-1 included the ipsilateral lymph node levels II, III, and IV and any other involved lymph node stations; CTV-2 generally included the ipsilateral level V, lateral retropharyngeal nodal stations, and the contralateral level II, III, and IV; CTV-3 included areas of pathologic ENE if applicable. Treatment of the ipsilateral IB station was generally omitted from treatment if surgically dissected and pathologically negative. All CTVs were expanded uniformly by 3 mm to create Planning Target Volumes (PTV). The dose prescription for PTV-1, PTV-2, and PTV-3 were 60 Gy, 54 Gy, and 63-66 Gy respectively in 30-
6
33 treatment fractions. RT target volumes included selective nodal regions of the bilateral neck in all study patients. The primary tumor site was defined as the TORS operative bed and was contoured as an avoidance structure for RT planning. The mean dose to the primary site was kept as low as reasonably achievable without compromising adjacent PTV coverage. Radiotherapy was planned and delivered using either Intensity Modulated Radiation Therapy (IMRT) or proton beam therapy using Intensity Modulated Proton Therapy (IMPT); allocation was typically determined by insurance coverage of proton therapy. Target volumes were the same for proton therapy and IMRT. Concurrent Systemic Therapy All patients with extra nodal extension (ENE) in this study (21.7%, n=13) received concurrent systemic therapy per the discretion of the medical oncologists.15 Systemic therapy administered consisted of weekly Cisplatin (40 mg/m2) in 9 patients, high dose cisplatin (100 mg/m2 every 3 weeks) in 2 patients, and cetuximab (400 mg/m2 loading dose and 250 mg/m2 weekly) in 2 patients. Patient Evaluation and Follow-up Patients were evaluated weekly during RT and followed after therapy at 3, 6, 12, 18, and 24 months. Follow-up included physical exam, nasopharyngolaryngoscopy, and cross-sectional imaging of the neck and chest. Follow-up beyond two years continued per standard of care.19 Local recurrence was defined as tumor recurrence identified radiographically or on clinical exam within the oral cavity, nasopharynx, oropharynx, larynx, or hypopharynx. Regional recurrence
7
was defined as failure within the lymph nodes or soft tissue of the neck. Distant failure was defined as progression outside of the head and neck. All disease recurrences were confirmed by biopsy. Patient toxicity was assessed using the NCI Common Terminology Criteria for Adverse Events (CTCAE v4.0). Patients completed health related quality of life questionnaires (EORTC QLQH&N35)20 at enrollment, the end of RT, and each protocol-specified follow-up visit. Statistical Analysis The primary endpoint was 2-year primary site local control. Secondary endpoints included 2year regional control, local recurrence free survival, distant metastasis free survival, progression free survival, and overall survival. Target accrual for the study was 60 patients which provided 78% power to detect a 2-yr local recurrence rate of 17.5%, assuming a null rate of 5%, using a one-tailed exact binomial test with type I error rate 10%. This estimate was based upon observed local control rates ranging from 85-100% following transoral surgery with or without adjuvant RT in HPV-associated OPSCC.12,16,21-24 A planned interim analysis for safety was conducted in July 2016 when 30 patients had been enrolled. This showed no local failures, and continued accrual was deemed safe. Patient characteristics were tabulated using descriptive statistics. Patient follow-up was measured in days from the end of RT to last follow-up. Patient survival was calculated using the KaplanMeier method. Cumulative incidence of severe toxicity including soft tissue necrosis and feeding tube dependency were calculated. Comparisons of primary tumor site radiation dose were made using the t test. All p-values were based on two-sided testing with an alpha of 0.05. Statistical analysis was completed using Stata version 12.1.
8
RESULTS Patient Characteristics and Treatment Variables Table 1 displays characteristics of the study population. The trial enrolled 60 patients between May 2014 and September 2017 (Figure 1). Median patient age at diagnosis was 57 years (range 34-84). Most patients were men with a pT1 primary tumor of the palatine tonsil, generally with a limited history of tobacco use. The majority of patients had multiple positive neck nodes. Concurrent chemotherapy was used in 21.7% of cases, all due to presence of ENE in the neck. Radiotherapy technique was evenly split between IMRT and IMPT. One patient was identified as having gross disease in the contralateral neck at RT simulation and received 70.4 Gy in 32 fractions to the area of gross disease while avoiding the primary site. All other patients completed RT as outlined previously. The mean radiation dose to the primary tumor site was 36.9 Gy [Standard Deviation (SD) 10.3 Gy]. An illustrative patient example is shown in Figure 2. The mean radiation doses to the primary tumor site according to location were: tonsil 37.8 Gy, SD 9.6 Gy; glossotonsillar sulcus 38.7 Gy, SD 9.8 Gy; base of tongue 35.4 Gy, SD 11.5 Gy. Mean radiation dose to the primary site was statistically significantly lower with IMPT compared to IMRT (33.9 Gy, SD 11.1 Gy vs. 39.6 Gy, SD 8.9 Gy p=0.03). Box plots of radiation dose to the primary tumor site are in Figure 3. Disease Outcomes The median patient follow-up was 2.4 years (range 8.5-53.8 months). One patient (1.7%) developed a local tumor recurrence at the base of tongue 20 months after completion of RT,
9
yielding a two-year local control rate of 98.3%. This patient underwent salvage surgery and was disease free at last follow-up 5 months after re-resection. Patient overall survival was 100%. Survival curves for local recurrence free survival, regional recurrence free survival, distant metastasis free survival, and progression fee survival are displayed in Figure 4. There was one patient (1.7%) who developed a regional failure in the neck located within the radiation target volume. This patient underwent a salvage neck dissection without additional therapy. There were two patients (3.3%) with distant failure. Measured 2-year local recurrence free survival, regional recurrence free survival, distant metastasis free survival, and progression free survival were 97.9% (95% CI 86.1-99.7%), 97.9% (95% CI 86.3-99.7%), 96.2% (95% CI 85.5-99.0%), and 92.1% (95% CI 80.2-97.0%) respectively. Treatment toxicity No patients required a feeding tube during RT. During follow-up, two patients (3.3%) required feeding tubes (Related to surgery for local recurrence, and soft tissue necrosis respectively). Both these patients subsequently had feeding tubes removed. Soft tissue necrosis within the TORS site operative bed occurred in 2 patients (3.3%), both at 3 months following RT. The mean RT dose to the primary site was higher in the patients who developed soft tissue necrosis compared to patients without soft tissue necrosis (45.8 Gy, range 43.9-47.8 vs. 36.6 Gy, range 14.0-55.1 Gy, p=0.21). Both instances of soft tissue necrosis resolved following dietary modification, oral hygiene, and pain management. One case was treated with hyperbaric oxygen.
10
DISCUSSION We conducted a single arm phase II prospective clinical trial to investigate the safety and effectiveness of de-intensified adjuvant RT following surgery for HPV-associated OPSCC. Novel RT targets included the at-risk neck while avoiding the primary tumor site. The study required low-risk features at the primary site, defined as pT1-pT2 tumors resected to negative margins, and no perineural invasion or lymphovascular invasion. Surgeries were all performed by highly experienced TORS surgeons at a single high volume head and neck cancer center. We observed excellent 2-year local control of 98.3%, and favorable toxicity compared to previous reports.16,25,26 Our study is the first prospective trial to report patient outcomes following RT to the neck alone while avoiding treatment to the primary tumor site. Standards of care for postoperative RT in resected OPSCC have included RT dose to the primary tumor site between 6066 Gy.6-8 Our results suggest this approach may be safe and is worthy of further study. Although adjuvant therapy plays an important role in oncologic care for patients with resected OPSCC, head and neck RT is associated with significant toxicities.27 Prior analyses have suggested that avoiding RT to the primary tumor site after surgery might not significantly reduce dose to the primary tumor site or other normal tissues.28,29 In contrast we measured a mean dose to the primary tumor site of 36.9 Gy, which is approximately a 40% reduction from the standard prescription dose of 60 Gy. Lower radiation doses in this functionally critical area of the head and neck could reduce treatment related toxicities such as dysphagia, dysgeusia, or xerostomia.30 However, definitive conclusions regarding the comparative toxicities of this approach cannot be made from the current trial given the non-randomized design. Another recently published trial evaluated aggressive RT dose reductions to the primary tumor site as well as the neck in HPV positive OPSCC following surgery using 30-36 Gy given in
11
twice daily fractions with concurrent docetaxel.31 Although the measured mean dose to the primary tumor site in both that trial and the current study may seem comparable; the distinction between dose reduction and dose avoidance to the primary tumor site should be noted. In the trial by Ma et al., a relatively uniform dose was prescribed to the primary tumor site along with concurrent docetaxel, while in our study the dose to the primary tumor site was heterogeneous and a measured mean dose of 36 Gy reflects higher dose along the lateral aspects of the tumor bed adjacent to lymph node targets receiving 60 Gy and much lower doses in the medial aspects of the primary tumor site. Thus, both trials seek to address distinct questions in terms of deintensified adjuvant treatment for these patients. Toxicity outcomes in this trial were favorable. Two patients (3.3%) required temporary feeding tubes, and no patients had feeding tubes at last follow-up. Prior reports of transoral surgery for OPSCC have reported 18-40% of patients requiring feeding tubes during or after treatment.32,33 We observed very low rates of soft tissue necrosis in the primary tumor site operative bed (3.3%) following RT when compared to prior studies which have reported this in 8-28% of patients.13,34 Reducing the frequency of this complication is an important step towards mitigation of toxicity in this patient population. Patient-reported quality of life outcomes were collected as part of this trial and will be analyzed in future reports. Our study has important limitations to consider. First, the trial enrolled a relatively small number of patients and current follow-up is 2.4 years. It will be important to confirm findings in larger patient groups and with longer follow-up. Second, although the toxicity outcomes compare favorably to historical controls, the non-randomized study precludes direct comparison and definitive conclusions regarding comparative toxicity. Third, all patients had treatment at a single institution and surgeries were performed by highly experienced TORS surgeons which may limit
12
generalizability. Importantly, prior analyses of patient outcomes following TORS alone performed at our institution for early stage HPV positive primary tumors had shown very low rates of local recurrence.12 Finally, although RT avoided the primary tumor site the measured radiation dose to this area was a mean of 37 Gy. It is important to acknowledge the possible therapeutic effects of these RT doses for patients with OPSCC. CONCLUSIONS In conclusion, de-intensified post-operative RT selectively targeting only the neck and avoiding treatment to the primary tumor site after TORS at a high volume center may be safe and is worthy of further study. The current trial provides important prospective evidence to guide deintensified RT planning and future trial design in patients with favorable risk surgically treated HPV-associated OPSCC.
13
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FIGURE LEGENDS: Figure 1. Consort Diagram Figure 2. Illustrative Example Radiation Treatment Plan: Study patient with a pT1N2a (AJCC 7th ed.) p16+ squamous cell carcinoma arising from the left base of tongue. The primary site operative bed is shown in violet. The left neck is CTV 6000 and right neck is CTV 5000. The measured mean dose to the operative bed is 14 Gy. Dose color wash set at 50 Gy (left) and 20 Gy (right).
17
Figure 3. Measured Radiation Dose to the Primary Tumor Site for all study patients (A), and according to primary tumor location (B), and radiation treatment modality (C) Figure 4. Kaplan-Meier Curves of local recurrence free survival, regional recurrence free survival, distant metastasis free survival, and progression free survival
Table 1: Patient Characteristics of the Study Cohort
Age at diagnosis (years) Sex Male Female Primary Tumor Location Tonsil Base of Tongue Overlapping/Glossotonsillar sulcus Pathologic AJCC Tumor Stage (7th ed.) pT1 pT2 Pathologic AJCC Nodal Stage (7th ed.) pN2a pN2b pN2c* pN3 Primary tumor diameter (mm) Presence of ENE Yes No Number of Lymph Nodes Involved Maximum Diameter of Involved Lymph Nodes (mm) Tobacco use history Number of Pack Years Reported Never Smokers Receipt of Concurrent Chemotherapy Yes No Adjuvant RT Technique Proton Beam Therapy (PBT) IMRT Combination (IMRT/PBT) Management of the Neck Unilateral selective neck dissection Bilateral selective neck RT
All Patients (n=60) Percent (n) or Median (range) 57 (34-84) 83.3% (50) 16.7% (10) 48.3% (29) 40% (24) 11.7% (7) 73.3% (44) 26.7% (16) 41.7% (25) 55% (33) 1.7% (1) 1.7% (1) 12 (2-37) 21.7% 78.3% 2 (1-23) 38 (13-62) 2 (0-100) 53% (32) 21.7% (13) 78.3% (47) 45% (27) 53.3% (32) 1.7% (1) 100% (60) 100% (60)
Abbreviations: AJCC (American Joint Commission on Cancer), ENE (Extra-nodal extension), RT (radiation Therapy), IMRT (Intensity Modulated Radiation Therapy) * One patient identified with gross disease in the contralateral neck at RT simulation and received 70.4 Gy in 32 fractions to the area of gross disease while avoiding the primary site
1
Study CONSORT Diagram
Screened and Enrolled (n=60)
Received treatment per protocol (n=60)
Lost to follow-up (give reasons) (n=0) Discontinued intervention (n=0)
Analysed (n= 60) Excluded from analysis (n=0)
Measured Radiation Dose to Primary Tumor Site by Anatomic Location
10
C
Measured Radiation Dose to Primary Tumor Site by RT Modality
60
60
B
Primary Site Radiation Dose (mean, Gy) 20 30 40 50
Primary Site Radiation Dose (mean, Gy) 20 40 50 30
Measured Radiation Dose to Primary Tumor Site
10
10
Primary Site Radiation Dose (mean, Gy) 20 30 40 50
60
A
Tonsil
Base of Tongue
Glossotonsillar Sulcus
Proton Therapy
IMRT
2
60
57
38
Regional recurrence free survival (%) 0.25 0.50 0.75 1.00
3
4
5
16
4
0
Distant Metastasis Free Survival
Number at risk
0
1
2
60
57
39
Years
3
4
5
16
4
0
3
4
5
16
4
0
Progression Free Survival
Progression free survival (%) 0.25 0.50 0.75 0.00
0.00 Number at risk
Years
0.00
1
Distant Metastasis free survival (%) 0.25 0.50 0.75 1.00
Number at risk
0
Regional Recurrence Free Survival
1.00
0.00
Local recurrence free survival (%) 0.25 0.50 0.75 1.00
Local Recurrence Free Survival
0
1
2
60
56
37
Years
3
4
5
16
4
0
Number at risk
0
1
2
60
56
36
Years