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Dosimetric advantages of intensity-modulated proton therapy for oropharyngeal cancer compared with intensity-modulated radiation: A case-matched control analysis
Medical Dosimetry ] (2016) ]]]–]]]
Medical Dosimetry journal homepage: www.meddos.org
Dosimetric advantages of intensity-modulated proton therapy for oropharyngeal cancer compared with intensity-modulated radiation: A case-matched control analysis Emma B. Holliday, M.D.,n Esengul Kocak-Uzel, M.D.,n† Lei Feng, M.S.,‡ Nikhil G. Thaker, M.D.,n Pierre Blanchard, M.D., Ph.D.,n David I. Rosenthal, M.D.,n G. Brandon Gunn, M.D., Ph.D.,n Adam S. Garden, M.D.,n and Steven J. Frank, M.D.n *Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; †Department of Radiation Therapy, Beykent University, Istanbul, Turkey; and ‡Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
A R T I C L E I N F O
A B S T R A C T
Article history: Received 11 November 2015 Accepted 20 January 2016
A potential advantage of intensity-modulated proton therapy (IMPT) over intensity-modulated (photon) radiation therapy (IMRT) in the treatment of oropharyngeal carcinoma (OPC) is lower radiation dose to several critical structures involved in the development of nausea and vomiting, mucositis, and dysphagia. The purpose of this study was to quantify doses to critical structures for patients with OPC treated with IMPT and compare those with doses on IMRT plans generated for the same patients and with a matched cohort of patients actually treated with IMRT. In this study, 25 patients newly diagnosed with OPC were treated with IMPT between 2011 and 2012. Comparison IMRT plans were generated for these patients and for additional IMRT-treated controls extracted from a database of patients with OPC treated between 2000 and 2009. Cases were matched based on the following criteria, in order: unilateral vs bilateral therapy, tonsil vs base of tongue primary, T-category, N-category, concurrent chemotherapy, induction chemotherapy, smoking status, sex, and age. Results showed that the mean doses to the anterior and posterior oral cavity, hard palate, larynx, mandible, and esophagus were significantly lower with IMPT than with IMRT comparison plans generated for the same cohort, as were doses to several central nervous system structures involved in the nausea and vomiting response. Similar differences were found when comparing dose to organs at risks (OARs) between the IMPT cohort and the case-matched IMRT cohort. In conclusion, these findings suggest that patients with OPC treated with IMPT may experience fewer and less severe side effects during therapy. This may be the result of decreased beam path toxicities with IMPT due to lower doses to several dysphagia, odynophagia, and nausea and vomiting– associated OARs. Further study is needed to evaluate differences in long-term disease control and chronic toxicity between patients with OPC treated with IMPT in comparison to those treated with IMRT. & 2016 American Association of Medical Dosimetrists.
Keywords: Proton radiotherapy IMPT Oropharyngeal carcinoma Dosimetric analysis Acute toxicity
Introduction The prevalence of human papilloma virus–associated oropharyngeal cancer (OPC) is rising in the United States and Europe; this type of cancer tends to affect young patients and those without traditional risk factors.1-3 Patients who develop this form of OPC typically have a better prognosis with survival rates ranging from
Reprint requests to Steven J. Frank, M.D., The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd Unit 1422, Houston, TX 77030. E-mail: [email protected] http://dx.doi.org/10.1016/j.meddos.2016.01.002 0958-3947/Copyright Ó 2016 American Association of Medical Dosimetrists
80% to 90%,4 meaning that survivors have the potential to live with side effects and complications of treatment for several decades. Radiotherapy, with or without chemotherapy, is the treatment of choice for most patients with early5,6 or advanced7,8 OPC because it allows organ preservation and avoids the morbidities associated with surgical procedures. Although the primary goal of radiotherapy for OPC is cancer control, sparing normal tissues from radiation-related toxicity is also considered when planning treatment. Studies of patients with head and neck cancer were among the first to show that use of intensity-modulated radiation therapy (IMRT) reduces dose to adjacent normal tissues, leading to reduced side effects such as xerostomia and improving patients' quality of
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life.9,10 Avoiding long-term toxicity is particularly important in OPC, as it is highly curable if durable local control is achieved.4 Although IMRT has an excellent track record for tumor control and survival for patients with OPC,11,12 IMRT seems to be associated with increased rates of certain types of toxicity related to dose deposited in the beam path.13,14 The charge and mass of protons allow lower exit doses than photons.15 Intensity-modulated proton therapy (IMPT) is a more conformal form of proton therapy delivery.16 The scanning beam nozzle permits the deposition of dose in discrete spots, which facilitates the delivery of IMPT.17 Thus, IMPT has the potential to further reduce dose to nontarget tissues and potentially lead to further gains in quality of life for patients with OPC if mucositis, dysphagia, dehydration, and weight loss can be minimized. The purpose of this study was to compare mean radiation doses to critical organs at risk (OARs) thought to be important in the development of nausea, vomiting, mucositis, and dysphagia for patients with OPC treated with IMPT or IMRT.
Methods and Materials IMPT cohort and data collection After institutional review board approval was obtained, a prospectively collected database of patients treated with proton therapy for head and neck malignancies at a single, tertiary referral cancer center was queried. Patients with OPC treated with definitive IMPT between 2011 and 2012 were identified. Patients with a history of head and neck radiation were excluded, as were patients treated after surgery. Variables extracted from the records included demographic, disease, and treatment information including sex, age, smoking history, primary site (tonsil or base of tongue), presenting stage (T and N categories), radiation, chemotherapy details.
IMPT planning details All patients underwent noncontrast computed tomography (CT) simulation for radiation treatment planning after fabrication of custom immobilization devices including a thermoplastic mask and bite block. An Eclipse proton therapy treatment planning system (version 8.9, Varian Medical Systems, Palo Alto, CA) was used to generate full-field IMPT plans in which patients were treated from the base of skull to the clavicle. Bilateral neck treatment consisted of left and right anterior oblique beams with a 151 to 201 couch kick plus a single posterior beam, and ipsilateral neck treatment consisted of 2 to 3 ipsilateral beam angles chosen such that the dose to the contralateral neck, salivary glands, oral cavity (OC), brainstem, and larynx was minimized. The treatment planning system then simultaneously optimized the spot intensities from all fields by using an optimization algorithm with the objective of covering 95% of the target volume with the prescribed dose while minimizing dose to the adjacent OARs. The primary clinical target volume (CTV1) was defined as gross disease plus up to a 1-cm margin. The dose prescribed to cover CTV1 ranged between 66 and 70 Gray (Gy) (or Gy relative biological effectiveness [RBE] for protons, assuming an RBE of 1.1) in 30 to 33 fractions depending on whether or not concurrent chemotherapy was administered. The CTV2 was defined as the high-risk nodal volume adjacent to gross disease in the neck, and 60 to 63 Gy or Gy(RBE) was given to cover this volume in 30 to 33 fractions. The CTV3 was defined as additional margin beyond CTV2 in the pharyngeal axis as well as uninvolved neck nodal stations believed to be at risk for subclinical disease, and 54 to 57 Gy or Gy(RBE) was given to cover this volume in 30 to 33 fractions. A simultaneous integrated boost technique was used to deliver the different dose levels to the volumes described. Although the planning target volume concept cannot be strictly applied with proton therapy,18 a 3 to 5–mm expansion was added to account for setup uncertainties. Daily orthogonal 2-dimensional kV x-ray images were compared with digitally reconstructed radiographs generated by the treatment planning system from simulation CT images to align the patient for image guidance. Chemotherapy was given at the discretion of the treating medical oncologist.
Generating comparison IMRT plans The Pinnacle treatment planning system (version 9.0, Philips Radiation Oncology Systems, Fitchburg, WI) was used to generate optimal comparison IMRT plans for each of the patients in the IMPT cohort. The same target volumes were used, and a 3 to 5–mm planning target volume expansion was added to the CTV to account for setup uncertainties. A monoisocentric technique was typically used to match IMRT plans to low-neck anterior-posterior fields, and the plan was likewise
optimized with the objective of 95% target volume coverage as well as the same OAR constraints as were used for IMPT plan generation. Case-matching to form the IMRT cohort To identify suitable cases to form the matched cohort, an institutional database of 998 patients treated with definitive IMRT for OPC between 2000 and 2009 was queried. Patients from this database were matched in a 1:1 ratio with the 25 patients in the IMPT cohort. Matching was done sequentially based on the following variables believed to be most relevant to toxicity (in order): radiation laterality (ipsilateral vs bilateral), primary site (tonsil vs base of tongue), T-category, N-category, concurrent chemotherapy, induction chemotherapy, smoking status, sex, and age. Dosimetric analysis The original planning CT images for patients in both the IMPT and case-matched IMRT cohorts were exported into a commercial deformable registration or segmentation software (Velocity AI 2.8.1, Velocity Medical Solutions, Atlanta, GA). For each patient, OARs involved in the development of mucositis, xerostomia, and dysphagia, such as the anterior OC, posterior OC, esophagus, bilateral parotid and submandibular glands, inferior pharyngeal constrictor, middle pharyngeal constrictor, and superior pharyngeal constrictor were segmented manually by one physician and defined as described previously.19 The following central nervous system (CNS) OARs suspected to be involved in the nausea and vomiting response were also contoured: brainstem, cerebellum, whole brain, area postrema, dorsal vagal complex, nucleus ambiguus, solitary nucleus, medulla oblongata, pons, fourth ventricle, left vestibule, and right vestibule. The mean dose to each structure was collected and compared between the original IMPT plans and the comparison IMRT plans for each patient in the IMPT cohort. The mean dose to each structure was also compared between patients in the IMPT cohort and patients in the case-matched IMRT cohort. Statistical methods The χ2 test was used to evaluate differences in categorical variables, the Wilcoxon rank-sum test was used to evaluate difference in continuous numeric variables, and the Cochran Armitage trend test was used for between-group comparisons of ordinal variables. A p o 0.05 was considered statistically significant, and all tests were two-sided. Analyses were performed with JMP (Copyright 2013, 1998 to 2012, SAS Institute Inc., Cary, NC).
Results Patient, tumor, and treatment characteristics No significant differences were found between the 25 patients treated with IMPT and 25 case-matched patients treated with IMRT with regard to radiation laterality, tumor location, T-category, N-category, concurrent or induction chemotherapy, smoking status, or sex. Patients who had undergone IMPT were than patients who had undergone IMRT (median age 60 years [range 37 to 83] vs 55 [43 to 74]; p ¼ 0.046). Patient, tumor, and treatment characteristics are summarized in Table 1. Dosimetric comparison—IMPT plans vs comparison IMRT plans for the IMPT cohort Comparing the original IMPT plans with IMRT plans generated for the same 25 patients treated with IMPT for OPC revealed that mean doses to several OARs were significantly lower for IMPT. Mean dose to structures involved in the development of acute mucositis were particularly well spared: mean doses to the anterior OC, posterior OC, and esophagus were 8.3 ⫾ 5.9 Gy (RBE), 40.5 ⫾ 15.3 Gy(RBE), and 20.9 ⫾ 12.2 Gy(RBE) with IMPT compared with 31.0 ⫾ 7.2 Gy, 54.3 ⫾ 8.1 Gy, and 33.6 ⫾ 14.4 (p o 0.001, p o 0.001, and p ¼ 0.002, respectively). The Figure shows representative axial images from the IMPT plan used in the treatment of a patient with base of tongue carcinoma alongside a comparison IMRT plan generated for the same patient; the dose sparing to the anterior OC is well illustrated. Mean doses to the major salivary glands involved in the development of xerostomia were not significantly different between the IMPT plans and the comparison IMRT plans, but mean doses to structures
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Table 1 Patient characteristics for case-matching in order of priority assigned compared for patients with oropharyngeal cancer treated with intensity-modulated proton therapy compared with patients treated with photon-based intensity-modulated radiation therapy Characteristics
IMPT patients N ¼ 25
Matched IMRT patients N ¼ 25
Laterality of radiation; N (column %) Unilateral Bilateral
5 (20%) 20 (80%)
5 (20%) 20 (80%)
Location of tumor; N (column %) Tonsil Base of tongue
18 (72%) 7 (28%)
18 (72%) 7 (28%)
T-category; N (column %) 1 2 3 4
5 (20%) 16 (64%) 2 (8%) 2 (8%)
5 (20%) 16 (64%) 2 (8%) 2 (8%)
N-category; N (column %) 0 1 2a 2b 2c 3
1 (4%) 5 (20%) 2 (8%) 10 (40%) 5 (20%) 2 (8%)
1 (4%) 5 (20%) 2 (8%) 10 (40%) 5 (20%) 2 (8%)
Received concurrent chemotherapy; N (column %) Received neoadjuvant chemotherapy; N (column %)
13 (52%) 16 (64%)
15 (60%) 14 (56%)
Smoking status; N (column %) Current Former Never
5 (20%) 7 (28%) 13 (52%)
4 (16%) 6 (24%) 15 (60%)
Sex; N (column %) Male Female
23 (92%) 2 (8%)
21 (86%) 4 (16%)
Age in years; median (range)
60 (37-83)
55 (43-74)
p Value* 1.00
1.00
1.00
1.00
0.776 0.773 0.848
0.667
0.046
n The χ2 test was used to evaluate differences in categorical variables, the Wilcoxon rank-sum test was used to evaluate difference in continuous numeric variables, and the Cochran Armitage trend test was used for between-group comparisons of ordinal variables. p o 0.05 indicates significance and all tests were 2-sided.
involved in dysphagia, especially the inferior and middle pharyngeal constrictors, were also significantly different: 32.8 ⫾ 10.7 Gy(RBE) and 48.2 ⫾ 17.8 Gy(RBE) compared with 45.6 ⫾ 10.4 and 57.0 ⫾ 14.4 (p o 0.001 and p ¼ 0.046, respectively) (Table 2). With the exception of the right vestibule, doses to CNS structures involved in the nausea and vomiting response were all significantly lower with IMPT than with IMRT for this cohort (Table 3). Dosimetric comparison—IMPT cohort vs case-matched IMRT cohort Similar trends were seen when comparing mean dose to structures involved in the development of acute mucositis
between plans for patients treated with IMPT and patients in the case-matched cohort treated with IMRT. Mean doses to the anterior and posterior OC were lower with IMPT, but no significant difference was found in mean dose to the esophagus. Again, as was the case for the comparison IMRT cohort, no significant differences in dose were found between the major salivary glands involved in the development of xerostomia, nor were any differences found in the mean doses to structures involved in dysphagia (Table 2). Finally, mean doses to the CNS structures involved in the nausea and vomiting response were all significantly lower in the IMPT cohort than in the case-matched IMRT cohort (Table 3).
Fig. Panels A and B representative sagittal images from comparative intensity-modulated proton therapy (IMPT) and intensity-modulated photon therapy (IMRT) plans, respectively, for the same patient with oropharyngeal carcinoma. Panel C shows the excess radiation given with IMRT as opposed to IMPT for this patient. (Color version of the figure is available online.)
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Table 2 Dosimetric comparison of mean dose to central nervous system structures involved in the mucositis, xerostomia, and dysphagia for intensity-modulated proton therapy (IMPT) plans and intensity-modulated photon therapy (IMRT) plans generated for the same cohort of 25 patients treated with IMPT for oropharyngeal cancer Structures
Anterior oral cavity Posterior oral cavity Esophagus Lt. parotid gland Lt. SMG Rt. parotid gland Rt. SMG IPC MPC SPC
P value*†
Mean ⫾ SD (Gy(RBE)) Cohort of 25 patients treated with IMPT IMPT plans
Cohort of 25 Patients treated with IMPT IMRT plans
8.3 ⫾ 5.9 40.5 ⫾ 15.3 20.9 ⫾ 12.2 32.0 ⫾ 18.6 43.9 ⫾ 28.3 31.6 ⫾ 15.9 51.3 ⫾ 23.8 32.8 ⫾ 10.7 48.2 ⫾ 17.8 55.3 ⫾ 13.0
31.0 ⫾ 7.2 54.3 ⫾ 8.1 33.6 ⫾ 14.4 25.8 ⫾ 14.7 53.7 ⫾ 23.9 31.7 ⫾ 14.4 58.7 ⫾ 14.9 45.6 ⫾ 10.4 57.0 ⫾ 14.4 58.1 ⫾ 11.0
Mean ⫾ SD (Gy(RBE))
p Value*‡
Matched cohort of 25 patients treated with IMRT IMRT plans o 0.001 o 0.001 0.002 0.205 0.213 0.886 0.539 o 0.001 0.046 0.305
30.5 ⫾ 7.9 50.6 ⫾ 8.0 18.6 ⫾ 9.7 39.6 ⫾ 18.7 61.0 ⫾ 12.4 25.0 ⫾ 14.3 50.5 ⫾ 21.1 28.8 ⫾ 15.8 54.6 ⫾ 9.4 58.0 ⫾ 11.3
o 0.001 0.011 0.543 0.337 0.291 0.138 0.605 0.068 0.543 0.551
Gy ¼ Gray; IMPT ¼ intensity-modulated proton therapy; IMRT ¼ intensity-modulated photon therapy; IPC ¼ inferior pharyngeal constrictor; Lt. ¼ left; MPC ¼ middle pharyngeal constrictor; RBE ¼ relative biological effectiveness; Rt. ¼ right; SMG ¼ submandibular gland; SPC ¼ superior pharyngeal constrictor. n
† ‡
The Wilcoxon rank-sum test was used to evaluate difference in continuous numeric variables. Comparison of the IMPT plans and comparison IMRT plans for the same cohort of 25 patients treated with IMPT. Comparison of the IMPT plans for the cohort of 25 patients treated with IMPT compared to a case-matched cohort of 25 patients treated with IMRT.
Discussion Prior work done by our group has shown IMPT to be a safe and well-tolerated method for treating patients that leads to low rates of acute toxicity.16 In an effort to propose a mechanism for the lesser acute toxicity from IMPT, we evaluated mean dose to several adjacent OARs and found that, compared with IMRT plans, IMPT plans involved delivering lower mean doses to the OC and several CNS structures involved in the nausea and vomiting response, such as the area postrema, subthalamic nucleus, and whole brain.14,20 Many dosimetric studies have shown that proton therapy can deliver lower doses to surrounding OARs in the head and neck compared with photon-based radiation techniques.21-27 For OPC specifically, dosimetric studies have shown the potential for proton therapy to reduce quality-of-life-threatening side effects such as mucositis, xerostomia,28 and dysphagia.29 However, few
previously published comparative studies have evaluated the potential advantages of the IMPT technique of proton therapy delivery for OPC. Most proton centers coming into operation have IMPT capability. Therefore, these results are timely, as few institutions may be treating OPC with a passive scatter proton technique in the future. Dosimetric analyses comparing proton and photon dose distributions and OARs are often criticized for comparing optimized IMPT plans generated by expert dosimetrists with IMRT plans that are generated purely for the purposes of a comparative study, often quickly and with less attention to detail. That is why we designed this analysis to have 2 comparison arms. We first compared doses delivered to OARs for the first 25 patients with OPC treated with IMPT at our institution and comparison IMRT plans generated by dosimetrists with particular expertise in head and neck IMRT planning, who used the same objectives for target
Table 3 Dosimetric comparison of mean dose to central nervous system structures involved in the nausea-vomiting response for intensity-modulated proton therapy (IMPT) plans and intensity-modulated photon therapy (IMRT) plans generated for the same cohort of 25 patients treated with IMPT for oropharyngeal cancer Structures
Brainstem Cerebellum Whole brain Area postrema Dorsal vagal complex Nucleus ambiguus Solitary nucleus Medulla oblongata Pons Lt. vestibule Rt. vestibule Fourth ventricle
p Value*†
Mean ⫾ SD (Gy(RBE)) Cohort of 25 patients treated with IMPT IMPT plans
Cohort of 25 patients treated with IMPT IMRT plans
7.7 ⫾ 3.7 12.6 ⫾ 4.3 2.3 ⫾ 1.1 14.6 ⫾ 9.0 17.5 ⫾ 8.7 19.1 ⫾ 9.9 15.4 ⫾ 8.5 19.6 ⫾ 9.8 5.8 ⫾ 3.6 7.6 ⫾ 6.5 7.4 ⫾ 4.1 6.8 ⫾ 8.5
14.4 ⫾ 6.4 18.8 ⫾ 4.8 3.1 ⫾ 0.9 24.5 ⫾ 7.2 26.3 ⫾ 7.3 27.6 ⫾ 7.9 26.0 ⫾ 7.6 27.5 ⫾ 7.2 9.2 ⫾ 3.9 11.7 ⫾ 5.3 8.6 ⫾ 3.3 11.4 ⫾ 5.4
Mean ⫾ SD (Gy(RBE))
p Value*‡
Matched cohort of 25 patients treated with IMRT IMRT plans o 0.001 o 0.001 0.006 o 0.001 o 0.001 0.001 o 0.001 0.005 0.003 0.010 0.240 o 0.001
18.6 ⫾ 8.8 18.9 ⫾ 7.6 4.4 ⫾ 3.8 30.7 ⫾ 6.5 31.5 ⫾ 6.3 33.3 ⫾ 6.3 31.2 ⫾ 8.7 32.4 ⫾ 6.9 12.7 ⫾ 6.5 16.4 ⫾ 10.4 11.8 ⫾ 6.8 17.6 ⫾ 8.6
o 0.001 o 0.001 0.003 o 0.001 o 0.001 o 0.001 o 0.001 o 0.001 0.002 0.004 0.013 o 0.001
Gy ¼ Gray; IMPT ¼ intensity-modulated proton therapy; IMRT ¼ intensity-modulated photon therapy; Lt. ¼ left; RBE ¼ relative biological effectiveness; Rt. ¼ right. n
† ‡
The Wilcoxon rank-sum test was used to evaluate difference in continuous numeric variables. Comparison of the IMPT plans and comparison IMRT plans for the same cohort of 25 patients treated with IMPT. Comparison of the IMPT plans for the cohort of 25 patients treated with IMPT compared to a case-matched cohort of 25 patients treated with IMRT.
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coverage and normal tissue avoidance. To corroborate our findings in that treatment plan comparison study, we then identified a case-matched cohort of patients with OPC actually treated with IMRT and compared OAR doses with those of our patients with OPC treated with IMPT. Most of our findings remained consistent across the 2 comparison groups. Namely, IMPT delivered a lower mean dose to the OC and CNS structures than did either the generated IMRT comparison plans or the actual IMRT plans for the case-matched control cohort. The significant reduction in mean dose to the esophagus, middle constrictor muscles, and inferior constrictor muscles in IMPT plans compared with the generated IMRT comparison plans, however, was not seen in the case-matched control IMRT cohort. This discrepancy underscores the reality that, no matter how diligently one generates an excellent comparison IMRT plan, more care may be taken when generating a plan intended to actually treat a patient. Curiously, we did not see lower mean doses to the parotid or submandibular glands with IMPT compared with either comparison group. However, recent evidence suggests that using IMPT with a reduced spot size for patients with OPC may help to reduce the normal tissue complication probability for salivary gland dysfunction and xerostomia even further.30 We also did not see a significant difference in dose to the pharyngeal constrictors between IMPT and IMRT plans, a finding that other groups have demonstrated when comparing IMPT with IMRT plans for OPC.29 We further found that IMPT delivered a significantly lower mean dose to CNS structures thought to be involved in radiationinduced nausea and vomiting.14,20 However, it is difficult to gauge whether this statistical significance is clinically significant, as many of the CNS structures evaluated do not have wellestablished dose constraints. Although further studies are needed to evaluate the significance of these differences in mean dose, these findings do suggest that IMPT can achieve the “as low as reasonably achievable” principle for CNS structures while maintaining excellent target coverage. In contrast to the relatively small absolute differences in dose to CNS structures, we demonstrated that IMPT could result in a reduction in absolute dose to the OC dose of nearly 25 Gy relative to either IMPT comparison group (Table 2). To put this into perspective, a dental x-ray contributes about 0.002 mSv, which is the equivalent of 0.002 mGy. Therefore, the dose to the OC saved by using IMPT over IMRT is equivalent to 12,500,000 dental x-rays. The Figure shows comparative IMPT and IMRT plans for the same patient with OPC and illustrates the “unnecessary radiation” that can be avoided through the use of IMPT. The ability to reduce OC dose with IMPT is likely the most important factor in reducing acute toxicity and associated morbidity. Patients receiving radiotherapy with or without chemotherapy for the treatment of OPC often develop acute oral pain and odynophagia that have serious medical consequences, and mucositis is typically the main cause of odynophagia and resulting reductions in oral intake. A systematic review comparing IMRT vs 2-dimensional and 3-dimensional radiation therapy showed a trend toward superiority of IMRT for acute mucositis,31 and our results suggest that it may be possible to reduce dose to the OC even further by using IMPT. In combination with mucositis, dysphagia, nausea and vomiting can also contribute to weight loss, dehydration, and poor nutritional status. Significant weight loss during treatment is a predictor of poor outcomes, and dehydration and poor oral intake are responsible for most hospital admissions during treatment.32 When patients cannot meet their hydration and nutritional needs orally, alternative methods such as gastrostomy (feeding) tubes are considered. In one study of patients with nasopharyngeal cancer, IMPT was associated with an approximately 50% reduction in the need for
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feeding tubes compared with IMRT, and no patient receiving a mean dose o 26 Gy to the OC required a feeding tube.33 It stands to reason that patients with OPC may similarly benefit, and, indeed, preliminary findings also show an approximately 50% reduction in feeding tube insertion rates for patients with OPC undergoing IMPT compared with historical control patients treated with IMRT.34 Analyses are currently ongoing for a contemporary case-matched cohort study. This analysis is the first of its kind to compare dosimetric outcomes of patients with OPC treated with IMPT with comparison IMRT plans for the same cohort and with IMRT plans of casematched patients with OPC actually treated with IMRT. This dual comparison allows us to more confidently assert the actual and potential dosimetric benefits of IMPT for such patients. Another strength of this study is the breadth of OARs included in the dosimetric analysis, particularly the CNS structures involved in the nausea and vomiting response. Limitations to this analysis include the lack of clinical end points correlating with the observed dosimetric differences which complicate attempts to translate statistically significant differences to clinically significant ones. This question is being addressed in our studies of acute and chronic toxicity, functional swallowing outcomes,35 and feeding tube insertion rates.34
Conclusions Patients with OPC treated with IMPT have significantly lower doses to OARs, specifically those related to acute mucositis, nausea, and vomiting, than do patients treated with IMRT. Prospective trials enrolling patients with OPC will provide further information on oncologic control and toxicity end points for IMPT versus IMRT. References 1. Panwar, A.; Batra, R.; Lydiatt, W.M.; et al. Human papilloma virus positive oropharyngeal squamous cell carcinoma: A growing epidemic. Cancer Treat. Rev. 40(2):215–9; 2014. http://dx.doi.org/10.1016/j.ctrv.2013.09.006. 2. Deschler, D.G.; Richmon, J.D.; Khariwala, S.S.; et al. The “new” head and neck cancer patient-young, nonsmoker, nondrinker, and HPV positive: Evaluation. Otolaryngol. Head Neck Surg. 151(3):375–80; 2014. http://dx.doi.org/10.1177/ 0194599814538605. 3. Sturgis, E.M.; Ang, K.K. The epidemic of HPV-associated oropharyngeal cancer is here: Is it time to change our treatment paradigms? J. Natl. Compr. Cancer Netw. 9(6):665–73; 2011. 4. Ang, K.K.; Harris, J.; Wheeler, R.; et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N. Engl. J. Med. 363(1):24–35; 2010. http: //dx.doi.org/10.1056/NEJMoa0912217. 5. Selek, U.; Garden, A.S.; Morrison, W.H.; et al. Radiation therapy for early-stage carcinoma of the oropharynx. Int J Radiat Oncol Biol Phys 59(3):743–51; 2004. http://dx.doi.org/10.1016/j.ijrobp.2003.12.002. 6. Hicks, W.L.; Kuriakose, M.A.; Loree, T.R.; et al. Surgery versus radiation therapy as single-modality treatment of tonsillar fossa carcinoma: The Roswell Park Cancer Institute experience (1971-1991). Laryngoscope 108(7):1014–9; 1998. 7. Denis, F.; Garaud, P.; Bardet, E.; et al. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J. Clin. Oncol. 22(1):69–76; 2004. http://dx.doi.org/10.1200/ JCO.2004.08.021. 8. Calais, G.; Bardet, E.; Sire, C.; et al. Radiotherapy with concomitant weekly docetaxel for Stages III/IV oropharynx carcinoma. Results of the 98-02 GORTEC Phase II trial. Int. J. Radiat. Oncol. Biol. Phys. 58(1):161–6; 2004. 9. Kam, M.K.M.; Leung, S.-F.; Zee, B.; et al. Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients. J. Clin. Oncol. 25(31):4873–9; 2007. http: //dx.doi.org/10.1200/JCO.2007.11.5501. 10. Nutting, C.M.; Morden, J.P.; Harrington, K.J.; et al. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): A phase 3 multicentre randomised controlled trial. Lancet Oncol. 12 (2):127–36; 2011. http://dx.doi.org/10.1016/S1470-2045(10)70290-4. 11. Marta, G.N.; Silva, V.; de Andrade Carvalho, H.; et al. Intensity-modulated radiation therapy for head and neck cancer: Systematic review and meta-analysis. Radiother. Oncol. 110(1):9–15; 2014. http://dx.doi.org/10.1016/j.radonc.2013.11.010. 12. Beadle, B.M.; Liao, K.-P.; Elting, L.S.; et al. Improved survival using intensitymodulated radiation therapy in head and neck cancers: A SEER-Medicare analysis. Cancer 120(5):702–10; 2014. http://dx.doi.org/10.1002/cncr.28372.
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13. Rosenthal, D.I.; Chambers, M.S.; Fuller, C.D.; et al. Beam path toxicities to nontarget structures during intensity-modulated radiation therapy for head and neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 72(3):747–55; 2008. http://dx.doi. org/10.1016/j.ijrobp.2008.01.012. 14. Kocak-Uzel, E.; Gunn, G.B.; Colen, R.R.; et al. Beam path toxicity in candidate organs-at-risk: Assessment of radiation emetogenesis for patients receiving head and neck intensity modulated radiotherapy. Radiother. Oncol. 111 (2):281–8; 2014. http://dx.doi.org/10.1016/j.radonc.2014.02.019. 15. Kahn, F.M. The Physics of Radiation Therapy. 4th ed. Baltimore, MD: Lippincott Willaims & Wilkins.; 2009. 16. Frank, S.; Cox, J.D.; Gillin, M.; et al. Multifield optimization intensity modulated proton therapy for head and neck tumors: A translation to practice. Int. J. Radiat. Oncol. Biol. Phys. 89(4):846–53; 2014. 17. Zhu, X.R.; Poenisch, F.; Li, H.; et al. A single-field integrated boost treatment planning technique for spot scanning proton therapy. Radiat. Oncol. Lond. Engl. 9:202; 2014. http://dx.doi.org/10.1186/1748-717X-9-202. 18. Liu, W.; Zhang, X.; Li, Y.; et al. Robust optimization of intensity modulated proton therapy. Med. Phys. 39(2):1079–91; 2012. http://dx.doi.org/10.1118/ 1.3679340. 19. Schwartz, D.L.; Hutcheson, K.; Barringer, D.; et al. Candidate dosimetric predictors of long-term swallowing dysfunction after oropharyngeal intensitymodulated radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 78(5):1356–65; 2010. http://dx.doi.org/10.1016/j.ijrobp.2009.10.002. 20. Ciura, K.; McBurney, M.; Nguyen, B.; et al. Effect of brain stem and dorsal vagus complex dosimetry on nausea and vomiting in head and neck intensitymodulated radiation therapy. Med. Dosim. 36(1):41–5; 2011. http://dx.doi.org/ 10.1016/j.meddos.2009.11.002. 21. Steneker, M.; Lomax, A.; Schneider, U. Intensity modulated photon and proton therapy for the treatment of head and neck tumors. Radiother. Oncol. 80 (2):263–7; 2006. http://dx.doi.org/10.1016/j.radonc.2006.07.025. 22. Chera, B.S.; Malyapa, R.; Louis, D.; et al. Proton therapy for maxillary sinus carcinoma. Am. J. Clin. Oncol. 32(3):296–303; 2009. http://dx.doi.org/10.1097/ COC.0b013e318187132a. 23. Miralbell, R.; Crowell, C.; Suit, H.D. Potential improvement of three dimension treatment planning and proton therapy in the outcome of maxillary sinus cancer. Int. J. Radiat. Oncol. Biol. Phys. 22(2):305–10; 1992. 24. Miralbell, R.; Lomax, A.; Cella, L.; et al. Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors. Int. J. Radiat. Oncol. Biol. Phys. 54(3):824–9; 2002. 25. Yoon, M.; Ahn, S.H.; Kim, J.; et al. Radiation-induced cancers from modern radiotherapy techniques: Intensity-modulated radiotherapy versus proton therapy. Int. J. Radiat. Oncol. Biol. Phys 77(5):1477–85; 2010. http://dx.doi.org/ 10.1016/j.ijrobp.2009.07.011.
26. Weber, D.C.; Chan, A.W.; Lessell, S.; et al. Visual outcome of accelerated fractionated radiation for advanced sinonasal malignancies employing photons/protons. Radiother. Oncol. 81(3):243–9; 2006. http://dx.doi.org/10.1016/j. radonc.2006.09.009. 27. van de Water, T.A.; Bijl, H.P.; Schilstra, C.; et al. The potential benefit of radiotherapy with protons in head and neck cancer with respect to normal tissue sparing: A systematic review of literature. Oncologist 16(3):366–77; 2011. http://dx.doi.org/10.1634/theoncologist.2010-0171. 28. van de Water, T.A.; Lomax, A.J.; Bijl, H.P.; et al. Potential benefits of scanned intensity-modulated proton therapy versus advanced photon therapy with regard to sparing of the salivary glands in oropharyngeal cancer. Int. J. Radiat. Oncol. Biol. Phys. 79(4):1216–24; 2011. http://dx.doi.org/10.1016/j.ijrobp.2010. 05.012. 29. van der Laan, H.P.; van de Water, T.A.; van Herpt, H.E.; et al. The potential of intensity-modulated proton radiotherapy to reduce swallowing dysfunction in the treatment of head and neck cancer: A planning comparative study. Acta Oncol. Stockh. Swed. 52(3):561–9; 2013. http://dx.doi.org/10.3109/0284186X. 2012.692885. 30. van de Water, T.A.; Lomax, A.J.; Bijl, H.P.; et al. Using a reduced spot size for intensity-modulated proton therapy potentially improves salivary glandsparing in oropharyngeal cancer. Int. J. Radiat. Oncol. Biol. Phys. 82(2):e313–9; 2012. http://dx.doi.org/10.1016/j.ijrobp.2011.05.005. 31. Kouloulias, V.; Thalassinou, S.; Platoni, K.; et al. The treatment outcome and radiation-induced toxicity for patients with head and neck carcinoma in the IMRT era: A systematic review with dosimetric and clinical parameters. BioMed. Res. Int 2013:401261; 2013. http://dx.doi.org/10.1155/2013/401261. 32. Capuano, G.; Grosso, A.; Gentile, P.C.; et al. Influence of weight loss on outcomes in patients with head and neck cancer undergoing concomitant chemoradiotherapy. Head Neck 30(4):503–8; 2008. http://dx.doi.org/10.1002/ hed.20737. 33. Holliday, E.B.; Garden, A.S.; Rosenthal, D.I.; et al. Proton therapy reduces treatment-related toxicities for patients with nasopharyngeal cancer: A casematch control study of intensity-modulated proton therapy and intensitymodulated photon therapy. Int. J. Particle Ther. 2(1):19–28; 2015. 34. Frank, S.; Rosenthal, D.; Ang, K.; et al. Gastrostomy tubes decrease by over 50% with intensity modulated proton therapy (IMPT) during the treatment of oropharyngeal cancer patients: A case–control study. Int. J. Radiat. Oncol. Biol. Phys. 87(2):S144; 2013. 35. Hutcheson, K.; Lewin, L.; Garden, A.; et al. Early experience with IMPT for the treatment of oropharyngeal tumors: Acute toxicities and swallowing-related outcomes. Int. J. Radiat. Oncol. Biol. Phys. 87(2):S604; 2013.
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Dosimetric advantages of intensity-modulated proton therapy for oropharyngeal cancer compared with intensity-modulated radiation: A case-matched control analysis Emma B. Holliday, M.D.,n Esengul Kocak-Uzel, M.D.,n† Lei Feng, M.S.,‡ Nikhil G. Thaker, M.D.,n Pierre Blanchard, M.D., Ph.D.,n David I. Rosenthal, M.D.,n G. Brandon Gunn, M.D., Ph.D.,n Adam S. Garden, M.D.,n and Steven J. Frank, M.D.n *Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; †Department of Radiation Therapy, Beykent University, Istanbul, Turkey; and ‡Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
A R T I C L E I N F O
A B S T R A C T
Article history: Received 11 November 2015 Accepted 20 January 2016
A potential advantage of intensity-modulated proton therapy (IMPT) over intensity-modulated (photon) radiation therapy (IMRT) in the treatment of oropharyngeal carcinoma (OPC) is lower radiation dose to several critical structures involved in the development of nausea and vomiting, mucositis, and dysphagia. The purpose of this study was to quantify doses to critical structures for patients with OPC treated with IMPT and compare those with doses on IMRT plans generated for the same patients and with a matched cohort of patients actually treated with IMRT. In this study, 25 patients newly diagnosed with OPC were treated with IMPT between 2011 and 2012. Comparison IMRT plans were generated for these patients and for additional IMRT-treated controls extracted from a database of patients with OPC treated between 2000 and 2009. Cases were matched based on the following criteria, in order: unilateral vs bilateral therapy, tonsil vs base of tongue primary, T-category, N-category, concurrent chemotherapy, induction chemotherapy, smoking status, sex, and age. Results showed that the mean doses to the anterior and posterior oral cavity, hard palate, larynx, mandible, and esophagus were significantly lower with IMPT than with IMRT comparison plans generated for the same cohort, as were doses to several central nervous system structures involved in the nausea and vomiting response. Similar differences were found when comparing dose to organs at risks (OARs) between the IMPT cohort and the case-matched IMRT cohort. In conclusion, these findings suggest that patients with OPC treated with IMPT may experience fewer and less severe side effects during therapy. This may be the result of decreased beam path toxicities with IMPT due to lower doses to several dysphagia, odynophagia, and nausea and vomiting– associated OARs. Further study is needed to evaluate differences in long-term disease control and chronic toxicity between patients with OPC treated with IMPT in comparison to those treated with IMRT. & 2016 American Association of Medical Dosimetrists.
Keywords: Proton radiotherapy IMPT Oropharyngeal carcinoma Dosimetric analysis Acute toxicity
Introduction The prevalence of human papilloma virus–associated oropharyngeal cancer (OPC) is rising in the United States and Europe; this type of cancer tends to affect young patients and those without traditional risk factors.1-3 Patients who develop this form of OPC typically have a better prognosis with survival rates ranging from
Reprint requests to Steven J. Frank, M.D., The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd Unit 1422, Houston, TX 77030. E-mail: [email protected] http://dx.doi.org/10.1016/j.meddos.2016.01.002 0958-3947/Copyright Ó 2016 American Association of Medical Dosimetrists
80% to 90%,4 meaning that survivors have the potential to live with side effects and complications of treatment for several decades. Radiotherapy, with or without chemotherapy, is the treatment of choice for most patients with early5,6 or advanced7,8 OPC because it allows organ preservation and avoids the morbidities associated with surgical procedures. Although the primary goal of radiotherapy for OPC is cancer control, sparing normal tissues from radiation-related toxicity is also considered when planning treatment. Studies of patients with head and neck cancer were among the first to show that use of intensity-modulated radiation therapy (IMRT) reduces dose to adjacent normal tissues, leading to reduced side effects such as xerostomia and improving patients' quality of
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life.9,10 Avoiding long-term toxicity is particularly important in OPC, as it is highly curable if durable local control is achieved.4 Although IMRT has an excellent track record for tumor control and survival for patients with OPC,11,12 IMRT seems to be associated with increased rates of certain types of toxicity related to dose deposited in the beam path.13,14 The charge and mass of protons allow lower exit doses than photons.15 Intensity-modulated proton therapy (IMPT) is a more conformal form of proton therapy delivery.16 The scanning beam nozzle permits the deposition of dose in discrete spots, which facilitates the delivery of IMPT.17 Thus, IMPT has the potential to further reduce dose to nontarget tissues and potentially lead to further gains in quality of life for patients with OPC if mucositis, dysphagia, dehydration, and weight loss can be minimized. The purpose of this study was to compare mean radiation doses to critical organs at risk (OARs) thought to be important in the development of nausea, vomiting, mucositis, and dysphagia for patients with OPC treated with IMPT or IMRT.
Methods and Materials IMPT cohort and data collection After institutional review board approval was obtained, a prospectively collected database of patients treated with proton therapy for head and neck malignancies at a single, tertiary referral cancer center was queried. Patients with OPC treated with definitive IMPT between 2011 and 2012 were identified. Patients with a history of head and neck radiation were excluded, as were patients treated after surgery. Variables extracted from the records included demographic, disease, and treatment information including sex, age, smoking history, primary site (tonsil or base of tongue), presenting stage (T and N categories), radiation, chemotherapy details.
IMPT planning details All patients underwent noncontrast computed tomography (CT) simulation for radiation treatment planning after fabrication of custom immobilization devices including a thermoplastic mask and bite block. An Eclipse proton therapy treatment planning system (version 8.9, Varian Medical Systems, Palo Alto, CA) was used to generate full-field IMPT plans in which patients were treated from the base of skull to the clavicle. Bilateral neck treatment consisted of left and right anterior oblique beams with a 151 to 201 couch kick plus a single posterior beam, and ipsilateral neck treatment consisted of 2 to 3 ipsilateral beam angles chosen such that the dose to the contralateral neck, salivary glands, oral cavity (OC), brainstem, and larynx was minimized. The treatment planning system then simultaneously optimized the spot intensities from all fields by using an optimization algorithm with the objective of covering 95% of the target volume with the prescribed dose while minimizing dose to the adjacent OARs. The primary clinical target volume (CTV1) was defined as gross disease plus up to a 1-cm margin. The dose prescribed to cover CTV1 ranged between 66 and 70 Gray (Gy) (or Gy relative biological effectiveness [RBE] for protons, assuming an RBE of 1.1) in 30 to 33 fractions depending on whether or not concurrent chemotherapy was administered. The CTV2 was defined as the high-risk nodal volume adjacent to gross disease in the neck, and 60 to 63 Gy or Gy(RBE) was given to cover this volume in 30 to 33 fractions. The CTV3 was defined as additional margin beyond CTV2 in the pharyngeal axis as well as uninvolved neck nodal stations believed to be at risk for subclinical disease, and 54 to 57 Gy or Gy(RBE) was given to cover this volume in 30 to 33 fractions. A simultaneous integrated boost technique was used to deliver the different dose levels to the volumes described. Although the planning target volume concept cannot be strictly applied with proton therapy,18 a 3 to 5–mm expansion was added to account for setup uncertainties. Daily orthogonal 2-dimensional kV x-ray images were compared with digitally reconstructed radiographs generated by the treatment planning system from simulation CT images to align the patient for image guidance. Chemotherapy was given at the discretion of the treating medical oncologist.
Generating comparison IMRT plans The Pinnacle treatment planning system (version 9.0, Philips Radiation Oncology Systems, Fitchburg, WI) was used to generate optimal comparison IMRT plans for each of the patients in the IMPT cohort. The same target volumes were used, and a 3 to 5–mm planning target volume expansion was added to the CTV to account for setup uncertainties. A monoisocentric technique was typically used to match IMRT plans to low-neck anterior-posterior fields, and the plan was likewise
optimized with the objective of 95% target volume coverage as well as the same OAR constraints as were used for IMPT plan generation. Case-matching to form the IMRT cohort To identify suitable cases to form the matched cohort, an institutional database of 998 patients treated with definitive IMRT for OPC between 2000 and 2009 was queried. Patients from this database were matched in a 1:1 ratio with the 25 patients in the IMPT cohort. Matching was done sequentially based on the following variables believed to be most relevant to toxicity (in order): radiation laterality (ipsilateral vs bilateral), primary site (tonsil vs base of tongue), T-category, N-category, concurrent chemotherapy, induction chemotherapy, smoking status, sex, and age. Dosimetric analysis The original planning CT images for patients in both the IMPT and case-matched IMRT cohorts were exported into a commercial deformable registration or segmentation software (Velocity AI 2.8.1, Velocity Medical Solutions, Atlanta, GA). For each patient, OARs involved in the development of mucositis, xerostomia, and dysphagia, such as the anterior OC, posterior OC, esophagus, bilateral parotid and submandibular glands, inferior pharyngeal constrictor, middle pharyngeal constrictor, and superior pharyngeal constrictor were segmented manually by one physician and defined as described previously.19 The following central nervous system (CNS) OARs suspected to be involved in the nausea and vomiting response were also contoured: brainstem, cerebellum, whole brain, area postrema, dorsal vagal complex, nucleus ambiguus, solitary nucleus, medulla oblongata, pons, fourth ventricle, left vestibule, and right vestibule. The mean dose to each structure was collected and compared between the original IMPT plans and the comparison IMRT plans for each patient in the IMPT cohort. The mean dose to each structure was also compared between patients in the IMPT cohort and patients in the case-matched IMRT cohort. Statistical methods The χ2 test was used to evaluate differences in categorical variables, the Wilcoxon rank-sum test was used to evaluate difference in continuous numeric variables, and the Cochran Armitage trend test was used for between-group comparisons of ordinal variables. A p o 0.05 was considered statistically significant, and all tests were two-sided. Analyses were performed with JMP (Copyright 2013, 1998 to 2012, SAS Institute Inc., Cary, NC).
Results Patient, tumor, and treatment characteristics No significant differences were found between the 25 patients treated with IMPT and 25 case-matched patients treated with IMRT with regard to radiation laterality, tumor location, T-category, N-category, concurrent or induction chemotherapy, smoking status, or sex. Patients who had undergone IMPT were than patients who had undergone IMRT (median age 60 years [range 37 to 83] vs 55 [43 to 74]; p ¼ 0.046). Patient, tumor, and treatment characteristics are summarized in Table 1. Dosimetric comparison—IMPT plans vs comparison IMRT plans for the IMPT cohort Comparing the original IMPT plans with IMRT plans generated for the same 25 patients treated with IMPT for OPC revealed that mean doses to several OARs were significantly lower for IMPT. Mean dose to structures involved in the development of acute mucositis were particularly well spared: mean doses to the anterior OC, posterior OC, and esophagus were 8.3 ⫾ 5.9 Gy (RBE), 40.5 ⫾ 15.3 Gy(RBE), and 20.9 ⫾ 12.2 Gy(RBE) with IMPT compared with 31.0 ⫾ 7.2 Gy, 54.3 ⫾ 8.1 Gy, and 33.6 ⫾ 14.4 (p o 0.001, p o 0.001, and p ¼ 0.002, respectively). The Figure shows representative axial images from the IMPT plan used in the treatment of a patient with base of tongue carcinoma alongside a comparison IMRT plan generated for the same patient; the dose sparing to the anterior OC is well illustrated. Mean doses to the major salivary glands involved in the development of xerostomia were not significantly different between the IMPT plans and the comparison IMRT plans, but mean doses to structures
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Table 1 Patient characteristics for case-matching in order of priority assigned compared for patients with oropharyngeal cancer treated with intensity-modulated proton therapy compared with patients treated with photon-based intensity-modulated radiation therapy Characteristics
IMPT patients N ¼ 25
Matched IMRT patients N ¼ 25
Laterality of radiation; N (column %) Unilateral Bilateral
5 (20%) 20 (80%)
5 (20%) 20 (80%)
Location of tumor; N (column %) Tonsil Base of tongue
18 (72%) 7 (28%)
18 (72%) 7 (28%)
T-category; N (column %) 1 2 3 4
5 (20%) 16 (64%) 2 (8%) 2 (8%)
5 (20%) 16 (64%) 2 (8%) 2 (8%)
N-category; N (column %) 0 1 2a 2b 2c 3
1 (4%) 5 (20%) 2 (8%) 10 (40%) 5 (20%) 2 (8%)
1 (4%) 5 (20%) 2 (8%) 10 (40%) 5 (20%) 2 (8%)
Received concurrent chemotherapy; N (column %) Received neoadjuvant chemotherapy; N (column %)
13 (52%) 16 (64%)
15 (60%) 14 (56%)
Smoking status; N (column %) Current Former Never
5 (20%) 7 (28%) 13 (52%)
4 (16%) 6 (24%) 15 (60%)
Sex; N (column %) Male Female
23 (92%) 2 (8%)
21 (86%) 4 (16%)
Age in years; median (range)
60 (37-83)
55 (43-74)
p Value* 1.00
1.00
1.00
1.00
0.776 0.773 0.848
0.667
0.046
n The χ2 test was used to evaluate differences in categorical variables, the Wilcoxon rank-sum test was used to evaluate difference in continuous numeric variables, and the Cochran Armitage trend test was used for between-group comparisons of ordinal variables. p o 0.05 indicates significance and all tests were 2-sided.
involved in dysphagia, especially the inferior and middle pharyngeal constrictors, were also significantly different: 32.8 ⫾ 10.7 Gy(RBE) and 48.2 ⫾ 17.8 Gy(RBE) compared with 45.6 ⫾ 10.4 and 57.0 ⫾ 14.4 (p o 0.001 and p ¼ 0.046, respectively) (Table 2). With the exception of the right vestibule, doses to CNS structures involved in the nausea and vomiting response were all significantly lower with IMPT than with IMRT for this cohort (Table 3). Dosimetric comparison—IMPT cohort vs case-matched IMRT cohort Similar trends were seen when comparing mean dose to structures involved in the development of acute mucositis
between plans for patients treated with IMPT and patients in the case-matched cohort treated with IMRT. Mean doses to the anterior and posterior OC were lower with IMPT, but no significant difference was found in mean dose to the esophagus. Again, as was the case for the comparison IMRT cohort, no significant differences in dose were found between the major salivary glands involved in the development of xerostomia, nor were any differences found in the mean doses to structures involved in dysphagia (Table 2). Finally, mean doses to the CNS structures involved in the nausea and vomiting response were all significantly lower in the IMPT cohort than in the case-matched IMRT cohort (Table 3).
Fig. Panels A and B representative sagittal images from comparative intensity-modulated proton therapy (IMPT) and intensity-modulated photon therapy (IMRT) plans, respectively, for the same patient with oropharyngeal carcinoma. Panel C shows the excess radiation given with IMRT as opposed to IMPT for this patient. (Color version of the figure is available online.)
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Table 2 Dosimetric comparison of mean dose to central nervous system structures involved in the mucositis, xerostomia, and dysphagia for intensity-modulated proton therapy (IMPT) plans and intensity-modulated photon therapy (IMRT) plans generated for the same cohort of 25 patients treated with IMPT for oropharyngeal cancer Structures
Anterior oral cavity Posterior oral cavity Esophagus Lt. parotid gland Lt. SMG Rt. parotid gland Rt. SMG IPC MPC SPC
P value*†
Mean ⫾ SD (Gy(RBE)) Cohort of 25 patients treated with IMPT IMPT plans
Cohort of 25 Patients treated with IMPT IMRT plans
8.3 ⫾ 5.9 40.5 ⫾ 15.3 20.9 ⫾ 12.2 32.0 ⫾ 18.6 43.9 ⫾ 28.3 31.6 ⫾ 15.9 51.3 ⫾ 23.8 32.8 ⫾ 10.7 48.2 ⫾ 17.8 55.3 ⫾ 13.0
31.0 ⫾ 7.2 54.3 ⫾ 8.1 33.6 ⫾ 14.4 25.8 ⫾ 14.7 53.7 ⫾ 23.9 31.7 ⫾ 14.4 58.7 ⫾ 14.9 45.6 ⫾ 10.4 57.0 ⫾ 14.4 58.1 ⫾ 11.0
Mean ⫾ SD (Gy(RBE))
p Value*‡
Matched cohort of 25 patients treated with IMRT IMRT plans o 0.001 o 0.001 0.002 0.205 0.213 0.886 0.539 o 0.001 0.046 0.305
30.5 ⫾ 7.9 50.6 ⫾ 8.0 18.6 ⫾ 9.7 39.6 ⫾ 18.7 61.0 ⫾ 12.4 25.0 ⫾ 14.3 50.5 ⫾ 21.1 28.8 ⫾ 15.8 54.6 ⫾ 9.4 58.0 ⫾ 11.3
o 0.001 0.011 0.543 0.337 0.291 0.138 0.605 0.068 0.543 0.551
Gy ¼ Gray; IMPT ¼ intensity-modulated proton therapy; IMRT ¼ intensity-modulated photon therapy; IPC ¼ inferior pharyngeal constrictor; Lt. ¼ left; MPC ¼ middle pharyngeal constrictor; RBE ¼ relative biological effectiveness; Rt. ¼ right; SMG ¼ submandibular gland; SPC ¼ superior pharyngeal constrictor. n
† ‡
The Wilcoxon rank-sum test was used to evaluate difference in continuous numeric variables. Comparison of the IMPT plans and comparison IMRT plans for the same cohort of 25 patients treated with IMPT. Comparison of the IMPT plans for the cohort of 25 patients treated with IMPT compared to a case-matched cohort of 25 patients treated with IMRT.
Discussion Prior work done by our group has shown IMPT to be a safe and well-tolerated method for treating patients that leads to low rates of acute toxicity.16 In an effort to propose a mechanism for the lesser acute toxicity from IMPT, we evaluated mean dose to several adjacent OARs and found that, compared with IMRT plans, IMPT plans involved delivering lower mean doses to the OC and several CNS structures involved in the nausea and vomiting response, such as the area postrema, subthalamic nucleus, and whole brain.14,20 Many dosimetric studies have shown that proton therapy can deliver lower doses to surrounding OARs in the head and neck compared with photon-based radiation techniques.21-27 For OPC specifically, dosimetric studies have shown the potential for proton therapy to reduce quality-of-life-threatening side effects such as mucositis, xerostomia,28 and dysphagia.29 However, few
previously published comparative studies have evaluated the potential advantages of the IMPT technique of proton therapy delivery for OPC. Most proton centers coming into operation have IMPT capability. Therefore, these results are timely, as few institutions may be treating OPC with a passive scatter proton technique in the future. Dosimetric analyses comparing proton and photon dose distributions and OARs are often criticized for comparing optimized IMPT plans generated by expert dosimetrists with IMRT plans that are generated purely for the purposes of a comparative study, often quickly and with less attention to detail. That is why we designed this analysis to have 2 comparison arms. We first compared doses delivered to OARs for the first 25 patients with OPC treated with IMPT at our institution and comparison IMRT plans generated by dosimetrists with particular expertise in head and neck IMRT planning, who used the same objectives for target
Table 3 Dosimetric comparison of mean dose to central nervous system structures involved in the nausea-vomiting response for intensity-modulated proton therapy (IMPT) plans and intensity-modulated photon therapy (IMRT) plans generated for the same cohort of 25 patients treated with IMPT for oropharyngeal cancer Structures
Brainstem Cerebellum Whole brain Area postrema Dorsal vagal complex Nucleus ambiguus Solitary nucleus Medulla oblongata Pons Lt. vestibule Rt. vestibule Fourth ventricle
p Value*†
Mean ⫾ SD (Gy(RBE)) Cohort of 25 patients treated with IMPT IMPT plans
Cohort of 25 patients treated with IMPT IMRT plans
7.7 ⫾ 3.7 12.6 ⫾ 4.3 2.3 ⫾ 1.1 14.6 ⫾ 9.0 17.5 ⫾ 8.7 19.1 ⫾ 9.9 15.4 ⫾ 8.5 19.6 ⫾ 9.8 5.8 ⫾ 3.6 7.6 ⫾ 6.5 7.4 ⫾ 4.1 6.8 ⫾ 8.5
14.4 ⫾ 6.4 18.8 ⫾ 4.8 3.1 ⫾ 0.9 24.5 ⫾ 7.2 26.3 ⫾ 7.3 27.6 ⫾ 7.9 26.0 ⫾ 7.6 27.5 ⫾ 7.2 9.2 ⫾ 3.9 11.7 ⫾ 5.3 8.6 ⫾ 3.3 11.4 ⫾ 5.4
Mean ⫾ SD (Gy(RBE))
p Value*‡
Matched cohort of 25 patients treated with IMRT IMRT plans o 0.001 o 0.001 0.006 o 0.001 o 0.001 0.001 o 0.001 0.005 0.003 0.010 0.240 o 0.001
18.6 ⫾ 8.8 18.9 ⫾ 7.6 4.4 ⫾ 3.8 30.7 ⫾ 6.5 31.5 ⫾ 6.3 33.3 ⫾ 6.3 31.2 ⫾ 8.7 32.4 ⫾ 6.9 12.7 ⫾ 6.5 16.4 ⫾ 10.4 11.8 ⫾ 6.8 17.6 ⫾ 8.6
o 0.001 o 0.001 0.003 o 0.001 o 0.001 o 0.001 o 0.001 o 0.001 0.002 0.004 0.013 o 0.001
Gy ¼ Gray; IMPT ¼ intensity-modulated proton therapy; IMRT ¼ intensity-modulated photon therapy; Lt. ¼ left; RBE ¼ relative biological effectiveness; Rt. ¼ right. n
† ‡
The Wilcoxon rank-sum test was used to evaluate difference in continuous numeric variables. Comparison of the IMPT plans and comparison IMRT plans for the same cohort of 25 patients treated with IMPT. Comparison of the IMPT plans for the cohort of 25 patients treated with IMPT compared to a case-matched cohort of 25 patients treated with IMRT.
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coverage and normal tissue avoidance. To corroborate our findings in that treatment plan comparison study, we then identified a case-matched cohort of patients with OPC actually treated with IMRT and compared OAR doses with those of our patients with OPC treated with IMPT. Most of our findings remained consistent across the 2 comparison groups. Namely, IMPT delivered a lower mean dose to the OC and CNS structures than did either the generated IMRT comparison plans or the actual IMRT plans for the case-matched control cohort. The significant reduction in mean dose to the esophagus, middle constrictor muscles, and inferior constrictor muscles in IMPT plans compared with the generated IMRT comparison plans, however, was not seen in the case-matched control IMRT cohort. This discrepancy underscores the reality that, no matter how diligently one generates an excellent comparison IMRT plan, more care may be taken when generating a plan intended to actually treat a patient. Curiously, we did not see lower mean doses to the parotid or submandibular glands with IMPT compared with either comparison group. However, recent evidence suggests that using IMPT with a reduced spot size for patients with OPC may help to reduce the normal tissue complication probability for salivary gland dysfunction and xerostomia even further.30 We also did not see a significant difference in dose to the pharyngeal constrictors between IMPT and IMRT plans, a finding that other groups have demonstrated when comparing IMPT with IMRT plans for OPC.29 We further found that IMPT delivered a significantly lower mean dose to CNS structures thought to be involved in radiationinduced nausea and vomiting.14,20 However, it is difficult to gauge whether this statistical significance is clinically significant, as many of the CNS structures evaluated do not have wellestablished dose constraints. Although further studies are needed to evaluate the significance of these differences in mean dose, these findings do suggest that IMPT can achieve the “as low as reasonably achievable” principle for CNS structures while maintaining excellent target coverage. In contrast to the relatively small absolute differences in dose to CNS structures, we demonstrated that IMPT could result in a reduction in absolute dose to the OC dose of nearly 25 Gy relative to either IMPT comparison group (Table 2). To put this into perspective, a dental x-ray contributes about 0.002 mSv, which is the equivalent of 0.002 mGy. Therefore, the dose to the OC saved by using IMPT over IMRT is equivalent to 12,500,000 dental x-rays. The Figure shows comparative IMPT and IMRT plans for the same patient with OPC and illustrates the “unnecessary radiation” that can be avoided through the use of IMPT. The ability to reduce OC dose with IMPT is likely the most important factor in reducing acute toxicity and associated morbidity. Patients receiving radiotherapy with or without chemotherapy for the treatment of OPC often develop acute oral pain and odynophagia that have serious medical consequences, and mucositis is typically the main cause of odynophagia and resulting reductions in oral intake. A systematic review comparing IMRT vs 2-dimensional and 3-dimensional radiation therapy showed a trend toward superiority of IMRT for acute mucositis,31 and our results suggest that it may be possible to reduce dose to the OC even further by using IMPT. In combination with mucositis, dysphagia, nausea and vomiting can also contribute to weight loss, dehydration, and poor nutritional status. Significant weight loss during treatment is a predictor of poor outcomes, and dehydration and poor oral intake are responsible for most hospital admissions during treatment.32 When patients cannot meet their hydration and nutritional needs orally, alternative methods such as gastrostomy (feeding) tubes are considered. In one study of patients with nasopharyngeal cancer, IMPT was associated with an approximately 50% reduction in the need for
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feeding tubes compared with IMRT, and no patient receiving a mean dose o 26 Gy to the OC required a feeding tube.33 It stands to reason that patients with OPC may similarly benefit, and, indeed, preliminary findings also show an approximately 50% reduction in feeding tube insertion rates for patients with OPC undergoing IMPT compared with historical control patients treated with IMRT.34 Analyses are currently ongoing for a contemporary case-matched cohort study. This analysis is the first of its kind to compare dosimetric outcomes of patients with OPC treated with IMPT with comparison IMRT plans for the same cohort and with IMRT plans of casematched patients with OPC actually treated with IMRT. This dual comparison allows us to more confidently assert the actual and potential dosimetric benefits of IMPT for such patients. Another strength of this study is the breadth of OARs included in the dosimetric analysis, particularly the CNS structures involved in the nausea and vomiting response. Limitations to this analysis include the lack of clinical end points correlating with the observed dosimetric differences which complicate attempts to translate statistically significant differences to clinically significant ones. This question is being addressed in our studies of acute and chronic toxicity, functional swallowing outcomes,35 and feeding tube insertion rates.34
Conclusions Patients with OPC treated with IMPT have significantly lower doses to OARs, specifically those related to acute mucositis, nausea, and vomiting, than do patients treated with IMRT. Prospective trials enrolling patients with OPC will provide further information on oncologic control and toxicity end points for IMPT versus IMRT. References 1. Panwar, A.; Batra, R.; Lydiatt, W.M.; et al. Human papilloma virus positive oropharyngeal squamous cell carcinoma: A growing epidemic. Cancer Treat. Rev. 40(2):215–9; 2014. http://dx.doi.org/10.1016/j.ctrv.2013.09.006. 2. Deschler, D.G.; Richmon, J.D.; Khariwala, S.S.; et al. The “new” head and neck cancer patient-young, nonsmoker, nondrinker, and HPV positive: Evaluation. Otolaryngol. Head Neck Surg. 151(3):375–80; 2014. http://dx.doi.org/10.1177/ 0194599814538605. 3. Sturgis, E.M.; Ang, K.K. The epidemic of HPV-associated oropharyngeal cancer is here: Is it time to change our treatment paradigms? J. Natl. Compr. Cancer Netw. 9(6):665–73; 2011. 4. Ang, K.K.; Harris, J.; Wheeler, R.; et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N. Engl. J. Med. 363(1):24–35; 2010. http: //dx.doi.org/10.1056/NEJMoa0912217. 5. Selek, U.; Garden, A.S.; Morrison, W.H.; et al. Radiation therapy for early-stage carcinoma of the oropharynx. Int J Radiat Oncol Biol Phys 59(3):743–51; 2004. http://dx.doi.org/10.1016/j.ijrobp.2003.12.002. 6. Hicks, W.L.; Kuriakose, M.A.; Loree, T.R.; et al. Surgery versus radiation therapy as single-modality treatment of tonsillar fossa carcinoma: The Roswell Park Cancer Institute experience (1971-1991). Laryngoscope 108(7):1014–9; 1998. 7. Denis, F.; Garaud, P.; Bardet, E.; et al. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J. Clin. Oncol. 22(1):69–76; 2004. http://dx.doi.org/10.1200/ JCO.2004.08.021. 8. Calais, G.; Bardet, E.; Sire, C.; et al. Radiotherapy with concomitant weekly docetaxel for Stages III/IV oropharynx carcinoma. Results of the 98-02 GORTEC Phase II trial. Int. J. Radiat. Oncol. Biol. Phys. 58(1):161–6; 2004. 9. Kam, M.K.M.; Leung, S.-F.; Zee, B.; et al. Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients. J. Clin. Oncol. 25(31):4873–9; 2007. http: //dx.doi.org/10.1200/JCO.2007.11.5501. 10. Nutting, C.M.; Morden, J.P.; Harrington, K.J.; et al. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): A phase 3 multicentre randomised controlled trial. Lancet Oncol. 12 (2):127–36; 2011. http://dx.doi.org/10.1016/S1470-2045(10)70290-4. 11. Marta, G.N.; Silva, V.; de Andrade Carvalho, H.; et al. Intensity-modulated radiation therapy for head and neck cancer: Systematic review and meta-analysis. Radiother. Oncol. 110(1):9–15; 2014. http://dx.doi.org/10.1016/j.radonc.2013.11.010. 12. Beadle, B.M.; Liao, K.-P.; Elting, L.S.; et al. Improved survival using intensitymodulated radiation therapy in head and neck cancers: A SEER-Medicare analysis. Cancer 120(5):702–10; 2014. http://dx.doi.org/10.1002/cncr.28372.
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