Intensity-modulated radiotherapy or volumetric-modulated arc therapy in patients with head and neck cancer: Focus on salivary glands dosimetry

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1 ORIGINAL ARTICLE Intensity-modulated radiotherapy or volumetric-modulated arc therapy in patients with head and neck cancer: Focus on salivary glands dosimetry Alexis Vallard, MD, 1 Jean-Baptiste Guy, MD, 1 Sylvie Mengue Ndong, MD, 1 Nicolas Vial, MD, 1 Romain Rivoirard, MD, 2 Pierre Auberdiac, MD, 3 Beno^ıte Mery, MD, 2 Julien Langrand Escure, MD, 1 Sophie Espenel, MD, 1 Coralie Moncharmont, MD, 1 Majed Ben Mrad, MD, 1 Peng Diao, MD, 1 Dominique Goyet, PhD, 4 Nicolas Magne, MD, PhD 1 * 1 Department of Radiotherapy, Lucien Neuwirth Cancer Institute, Saint-Priest en Jarez, France, 2 Department of Medical Oncology, Lucien Neuwirth Cancer Institute, Saint-Priest en Jarez, France, 3 Department of Radiotherapy, Claude Bernard Clinic, Albi, France, 4 Department of Medical Physics, Lucien Neuwirth Cancer Institute, Saint-Priest en Jarez, France. Accepted 17 December 2015 Published online 8 February 2016 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. Despite radiotherapy (RT) technical improvements, high salivary dysfunction rates are still reported in patients with head and neck squamous cell carcinoma (HNSCC). The purpose of the present study was to report salivary glands dosimetry with volumetricmodulated arc therapy (VMAT) and intensity-modulated RT (IMRT). Methods. Dosimetry of consecutive patients receiving IMRT or VMAT for proven HNSCC between 2007 and 2013 were retrospectively reviewed. Results. Data of 609 patients were studied. Mean dose, mean maximum dose, and mean percentage of salivary gland volume receiving at least 26 Gy (V26) of the contralateral parotid were Gy (range, Gy), Gy (range, Gy), and 40.92% (range, 0% to 100%), respectively. Mean and maximum dose on contralateral submandibular gland were Gy (range, Gy), and Gy (range, Gy), respectively. Conclusion. Target volume coverage still has to be prioritized over organs at risk (OAR) sparing with new RT techniques. Submandibular glands are not sufficiently taken into account in guidelines. VC 2016 Wiley Periodicals, Inc. Head Neck 38: , 2016 KEY WORDS: volumetric-modulated arc therapies, intensity-modulated radiotherapy, parotid gland, submandibular gland, dosimetry INTRODUCTION Radiotherapy (RT) is a cornerstone of 4 head and neck squamous cell carcinoma (HNSCC) treatments. 1,2 If disease control remains the first objective of RT, reaching a higher therapeutic ratio (or efficacy/toxicity ratio) is truly challenging. 3 Historically, 2D RT-induced constant toxicity, with limited efficacy because of ballistic uncertainty. Over the past 20 years, major technical improvements have been developed. Three-dimensional conformal RT allowed precise definition of tumor and organs at risk (OAR) volumes based on CT scans. Provisional dosimetry was adapted to patient anatomy and OAR could be spared. High rates related to RT acute and late toxicities were still reported because target volume coverage had to be prioritized over OAR sparing to maintain high locoregional control rates. Most common side effects were linked with salivary dysfunction induced by radiations: acute and late xerostomia, dysphagia, and acute mucositis. 4,5 Reduced secretion of parotid and submandibular glands saliva became a problem of primary interest because resulting mucositis, dental caries, oral pain, oral *Corresponding author: N. Magne, Department of Radiotherapy, Lucien Neuwirth Cancer Institute, 108 bis, avenue Albert Raimond, BP 60008, Saint-Priest en Jarez, France. nicolas.magne@icloire.fr infections, xerostomia, dysphagia, and undernourishment negatively impacted the patient s quality of life. 6 Acute and late xerostomia intensity was shown to be related to the delivered radiation doses to the salivary glands, particularly to the parotids and the submandibular glands. 7,8 Selective radioprotective agents, such as amifostine (Ethyol; Medimmune, Gaithersburg, MD), were developed and proved efficacy in reducing related 3Dconformal RT acute and late xerostomia. 9,10 However, because of limited tolerance and new RT techniques development, radioprotective drugs were gradually abandoned. Intensity-modulated radiotherapy (IMRT) with inverse treatment planning brought major advantages. OAR could be more effectively spared and dose to target volumes could be delivered with higher accuracy thanks to highly conformal dose painting. Regarding toxicity, IMRT showed superiority over 3D-conformal RT with similar locoregional control rates, 11,12 and is now considered to be the standard of care in HNSCC management. Volumetric-modulated arc therapy (VMAT) was recently developed and might solve some IMRT issues, with shortened treatment duration. VMAT showed superiority over IMRT in terms of target coverage and OAR sparing in dosimetric studies In spite of all these improvements related to RT, treating salivary dysfunction is still the daily routine of radiation oncologists, with 20% of acute 1028 HEAD & NECK DOI /HED JULY 2016

2 REAL LIFE SALIVARY DOSIMETRY WITH IMRT/VMAT or late xerostomia and dysphagia in prospective and retrospective studies. 20,21 We investigated the dosimetric causes of such high toxicity rates induced by state of the art RT techniques (IMRT and VMAT) in head and neck malignancies. The purpose of the present study was to report real-life salivary glands provisional dosimetry of patients with HNSCC receiving at least VMAT or IMRT as part of the global management of care. MATERIALS AND METHODS A retrospective study was conducted at Lucien Neuwirth Comprehensive Cancer Care Center (public hospital, France) and at Claude Bernard clinic (private medical clinic, France). The institutional review board of the Comprehensive Cancer Care Center approved the study, which was conducted in compliance with the Helsinki Declaration. Patient population Planning and dosimetric parameters of consecutive patients receiving IMRT of VMAT for histologically proven HNSCC between 2007 and 2013 were retrospectively reviewed. Mean (Dmean) and maximum (Dmax) dose values for salivary glands were reported. The percentage of salivary gland volumes receiving at least 26 Gy (V26) or 39 Gy (V39) were reported. Patient characteristics (age, sex), tumor characteristics (histology, location, staging), and prior treatment history (primary surgery) were also studied. Tumors were classified according to the American Joint Committee on Cancer seventh edition. 22 All patient cases were discussed in multidisciplinary head and neck tumor board meetings before treatment initiation. Radiotherapy Planning-CT scan was performed with the patient immobilized in the supine position using a thermoplastic mask covering the head and shoulders. CT images were acquired from the top of the vertex to carina, without contrast agent infusion. Treatment planning was based on the CT scan with slice thickness of 2.5 mm. All VMAT and IMRT plans were contoured and calculated using Eclipse treatment planning system (Varian Medical Systems, Palo Alto, CA). Volumes definition Gross tumor volume (GTV), clinical tumor volume (CTV), planning tumor volume (PTV), and OAR were delineated based on the planning CT. PTV extent was based on physical examination, video laryngoscopy, and review of available diagnostic imaging. GTV was defined by the primary tumor volume and involved cervical lymph nodes. Involved lymph nodes were suspected on abnormal enlargement on CT imaging or abnormal uptake of radiolabeled [18F]-2-fluorodeoxyglucose on positron emission tomography/ct imaging All treatment plans were prescribed to at least 2 dose levels: a high dose (HD) and a low (or elective) dose (ED). The CTV receiving the high dose (CTV HD ) was defined as GTV plus a margin of 1 cm. Postresection CTVs were generated using margins, as defined in literature The CTV receiving an elective dose (CTV ED ) was defined as uninvolved but at risk of bilateral cervical lymph node disease plus a margin of 3 mm. Uninvolved node regions at risk were delineated using the Radiation Therapy Oncology Group consensus guidelines. An intermediate CTV (CTV INT ) could be defined in case of infiltrative (endophytic) tumor, or positive margins resection, and included CTV HD. PTVs (PTV HD, PTV ED, and PTV INT ) were defined as CTVs (CTV HD, CTV ED, and CTV INT ) plus a margin of 3 mm. Segmented OAR were the parotid glands, submaxillary glands, larynx, spinal cord, brainstem, cerebellum, brachial plexus, inner ears, thyroid, anterior half of the tongue, infield skin, temporomandibular joints, and mandible. If the radiation oncologist considered that dose constraints for salivary glands were impossible to comply with (ie, when the CTV was adjacent to salivary glands), salivary glands could be not delineated before RT course. In this situation, OAR were retrospectively delineated and doses delivered to salivary glands were a posteriori calculated. Dose prescription RT could be performed using standard integrated boost with the following schemes: for patients with unresected tumor, the PTV HD was prescribed a total dose of 70 Gy in 35 fractions at 2 Gy per fraction. The PTV ED was prescribed 56 Gy in 35 fractions using 1.6 Gy per fraction. The PTV INT was prescribed 60 to 66 Gy in 35 fractions at 1.7 to 1.9 Gy per fraction. For patients receiving postoperative radiation, the primary tumor bed and involved nodes (PTV HD ) were prescribed a total dose of 66 Gy in 33 fractions at 2 Gy per fraction. The PTV ED was prescribed 56 Gy in 33 fractions at 1.7 Gy per fraction. The PTV INT was prescribed 60 to 66 Gy in 33 fractions at 1.8 to 2 Gy per fraction. If RT was performed without standard integrated boost, the following doses were prescribed: for patients with unresected tumor, the PTV HD was prescribed a total dose of 66 to 70 Gy in 30 to 35 fractions at 2 to 2.2 Gy per fraction. The PTV INT was prescribed 60 to 66 Gy in 30 to 33 fractions at 2 to 2.2 Gy per fraction. The PTV ED was prescribed 50 Gy in 25 fractions. For patients receiving postoperative radiation, the PTV HD was prescribed a total dose of 66 Gy in 33 fractions at 2 Gy per fraction. The PTV INT was prescribed 60 to 66 Gy in 30 to 33 fractions at 2 Gy per fraction. The PTV ED was prescribed 50 Gy in 25 fractions. Intensity-modulated radiotherapy planning and dosimetry IMRT plans were generated using 7 to 10 nonparallel and noncoplanar fields of 6 MV photons with the dynamic or sliding window technique. Optimization and dose calculations were processed with Eclipse version 8.1. The PTVs were reduced to 3 mm below the skin surface. Treatment plans were optimized according to dose limits for OAR and constraints for volume coverage specified by the International Commission on Radiation Units and Measurements 83 report (ie, the PTV should receive 95% to 107% of the prescribed dose, and PTV coverage should be higher than 95%). Dose calculation HEAD & NECK DOI /HED JULY

3 VALLARD ET AL. TABLE 1. Patient and tumor characteristics. Characteristics Whole set of patients Public hospital Private medical clinic No. of patients Mean age (range), y 60.8 (18 93) 59.9 (18 91) 64 (34 93) Sex, no. (%) Male 500 (82) 385 (82) 115 (84) Female 109 (18) 87 (18) 22 (16) Tumor classification, no. (%) T1 73 (12) 56 (11.9) 17 (12.4) T2 186 (30.5) 143 (30.3) 43 (31.4) T3 169 (27.8) 133 (28.2) 36 (26.3) T4 128 (21) 87 (18.4) 41 (29.9) Unknown 53 (8.7) 53 (11.2) 0 Lymph node classification, no. (%) N0 149 (24) 108 (23) 41 (30) N1 134 (22) 111 (24) 23 (16.8) N2 225 (37) 157 (33) 68 (49.6) N3 48 (8) 43 (9) 5 (3.6) Unknown 53 (9) 53 (11) 0 Metastasis classification, no. (%) M0 537 (88) 402 (85) 135 (99) M1 19 (3) 17 (4) 2 (1) Unknown 53 (9) 53 (11) 0 Primary tumor location, no. (%) Oropharynx 226 (37) 163 (35) 63 (46) Hypopharynx 135 (22) 110 (23) 25 (18) Larynx 96 (16) 80 (17) 16 (12) Oral cavity 82 (13) 63 (13) 19 (14) Sinus/nasal fossae 41 (7) 31 (7) 10 (7) Nasopharynx 29 (5) 25 (5) 4 (3) TNM classification was based on American Joint Committee on Cancer seventh edition. 22 was performed in Eclipse with the pencil beam convolution algorithm using a calculation grid of 2.5 mm. Volumetric-modulated arc therapy planning and dosimetry VMAT plans were generated using 2 full arcs (21798 to 1808) of 6 MV photons in 1 clockwise direction. The collimator angle was typically set to a value between 108 and 308 (or alternatively between 3308 and 3508) to avoid tongue-and-groove effects, and to cover the entire PTV. Doses and volume coverage constraints to the PTVs and OAR were similar to the IMRT planning process. VMAT planning was performed in Eclipse version 8.5, using the AAA calculation algorithm, and the progressive resolution optimization algorithm. Resolution of control points within the arc was set to 48, to allow sufficient modulation and acceptable duration of the optimization. Statistical analysis No statistical test was performed, only a descriptive analysis of the results was realized. Mean values were given with their ranges or with SD (1/- SD). RESULTS Patient characteristics Dosimetry of 609 patients treated using IMRT or VMAT for HNSCC were analyzed. Four hundred seventy-two patients (77.5%) were treated at the public hospital and 137 patients (22.5%) were treated at the private medical clinic. At the time of RT, the median age was 60.8 years (range, years), with 500 men and 109 women. Most of the patients were initially staged T3 or T4 (n 5 297; 48.8%), N1 or N2 (n 5 359; 59%), and were metastases-free (n 5 537; 88%). Primary tumor locations were mainly the oropharynx (n 5 226; 37%), the hypopharynx (n 5 135; 22%), the larynx (n 5 96; 16%), and the oral cavity (n 5 82; 13%). Most of the patients experienced surgery before RT for tumor resection (n 5 374; 61%). Patient characteristics are reported in Table 1. Treatment characteristics A total of 423 patients (69%) and 186 patients (31%) were treated with IMRT and VMAT, respectively. VMAT was only performed at the public hospital. Mean duration of RT was days (range, days). Mean dose to the PTV HD and to the PTV ED was 65.6 Gy (range, Gy) and Gy (range, Gy), respectively. Treatments characteristics are summarized in Table 2. Salivary glands delineation Public hospital experience. Bilateral parotid and submandibular glands delineation was achieved before RT initiation in 108 of the 472 patients (23%). Delineation of bilateral parotids was initially completed in 420 of the 1030 HEAD & NECK DOI /HED JULY 2016

4 REAL LIFE SALIVARY DOSIMETRY WITH IMRT/VMAT TABLE 2. Treatment characteristics. Characteristics Whole set of patients Public hospital Private medical clinic No. of patients Primary surgery, no. (%) 374 (61) 341 (72) 33 (24) Technique, no. (%) IMRT 423 (69) 286 (61) 137 (100) VMAT 186 (31) 186 (39) 0 Standard integrated boost, no. (%) Yes 573 (94) 459 (97) 114 (83) No 36 (6) 13 (3) 23 (17) Mean dose to PTV HD, mean (range) (42 72) (45 72) (42 70) Mean dose to PTV ED, mean (range) (40 70) (40 70) ( ) Mean RT duration, d (range) (16 51) (16 51) (29 47) Abbreviations: IMRT, intensity-modulated radiotherapy; VMAT, volumetric-modulated arc therapy; PTV HD, planning target volume including primary tumor volume and involved cervical lymph nodes; PTV ED, planning target volume including uninvolved but at risk of disease bilateral cervical lymph nodes; RT, radiotherapy. 472 patients (89%). Bilateral parotid glands had to be retrospectively delineated in 46 patients (9.7%): 16 nasal sinus (34.8%); 11 oropharyngeal (23.9%); 9 laryngeal (19.6%); 4 oral cavity (8.7%), 3 hypopharyngeal (6.5%), and 3 nasopharyngeal (6.5%) malignancies. A posteriori contralateral parotid delineation was required for 6 patients (1.3%). Submandibular glands had to be retrospectively delineated in 318 patients (67.4%): 116 oropharyngeal (36.4%); 71 hypopharyngeal (22.3%); 53 laryngeal (16.7%); 53 oral cavity (16.7%), 14 nasopharyngeal (4.4%); and 11 nasal sinus (3.5%) malignancies. For 20 of 318 patients (6.3%), only 1 submandibular gland (ipsilateral or contralateral) had to be retrospectively delineated. Private clinic experience. Bilateral parotid and submandibular glands delineation was performed before RT initiation in 51 of the 137 patients (37.2%). Bilateral parotids were initially delineated for all patients (n 5 137; 100%). Submandibular glands bilateral retrospective delineation had to be performed in 86 patients (62.8%): 42 oropharyngeal (48.8%); 20 hypopharyngeal (23.2%); 9 laryngeal (10.5%), 8 oral cavity (9.3%); 4 nasal sinus (4.7%); and 3 nasopharyngeal (3.5%) malignancies. Salivary glands dosimetry In the whole set of patients, mean (Dmean), maximum (Dmax), and mean V26 of the ipsilateral parotid were Gy (range, Gy), Gy (range, Gy), and 58.80% (range, 0% to 100%), respectively. Mean Dmean, mean Dmax and mean V26 of the contralateral parotid were Gy (range, Gy), Gy (range, Gy), and 40.92% (range, 0% to 100%), respectively. Mean Dmean, mean Dmax, and mean V39 of the ipsilateral submandibular gland were Gy (range, Gy), Gy (range, Gy), and 90.01% (range, 0% to 100%), respectively. Mean Dmean, mean Dmax, and mean V39 of the contralateral submandibular gland were Gy (range, Gy), Gy (range, Gy), and 79.37% (range, 0% to 100%), respectively. Detailed dosimetric parameters of each salivary gland are reported in Table 3. Regarding tumor primary location, highest Dmean on ipsilateral parotid were reported with oropharynx (37.75 Gy 1/ ), nasopharynx (36.34 Gy 1/ ), and oral cavity RT (34.72 Gy 1/ ). Highest Dmean on contralateral parotid were reported with nasopharynx (27.99 Gy 1/- 8.87), oropharynx (25.59 Gy 1/ ) and hypopharynx RT (23.67 Gy 1/- 7.17). Highest Dmean on the ipsilateral submandibular glands were TABLE 3. Salivary glands dosimetry. Whole set of patient, Public hospital, Private medical clinic, Salivary gland Dosimetric values mean (range) n mean (range) n mean (range) n Ipsilateral parotid gland Dmean, Gy ( ) ( ) ( ) Dmax, Gy ( ) ( ) (1 72.7) V26, % (0 100) (0 100) (0 100) Contralateral parotid gland Dmean, Gy (0 70.4) ( ) ( ) Dmax, Gy ( ) ( ) ( ) V26, % (0 100) (0 100) (0 100) Ipsilateral submandibular gland Dmean, Gy ( ) ( ) (0 70.7) Dmax, Gy (0 76.8) ( ) (0 72.1) V39, % (0 100) (0 100) (0 100) Contralateral submandibular gland Dmean, Gy ( ) ( ) (0 70.6) Dmax, Gy (0 75.8) ( ) (0 73.9) V39, % (0 100) (0 100) (0 100) Abbreviations: Dmean, mean dose; Dmax, maximum dose; V26, percentage of salivary gland volume receiving at least 26 Gy; V39, percentage of salivary gland volume receiving at least 39 Gy. HEAD & NECK DOI /HED JULY

5 VALLARD ET AL. TABLE 4. Salivary glands dosimetry. Primary tumor location, mean (1/- SD) Oral cavity Oropharynx Nasopharynx Nasal fossae/sinus Hypopharynx Larynx n 5 82 n n 5 29 n 5 41 n n 5 96 Ipsilateral parotid gland Dmean, Gy (1/ ) (1/ ) (1/ ) (1/ ) (1/- 8.92) (1/ ) Dmax, Gy (1/ ) (1/- 9.61) (1/ ) (1/ ) (1/ ) (1/ ) V26, % (1/ ) (1/ ) (1/ ) (1/ ) (1/ ) (1/ ) Contralateral parotid gland Dmean, Gy (1/ ) (1/ ) (1/- 8.87) 6.25 (1/- 8.59) (1/- 7.17) (1/- 9.47) Dmax, Gy (1/ ) (1/ ) (1/- 8.75) (1/ ) (1/ ) (1/ ) V26, % (1/ ) (1/ ) (1/ ) 3.18 (1/ ) (1/ ) (1/ ) Ipsilateral submandibular gland Dmean, Gy (1/ ) (1/- 9.50) (1/ ) 8.70 (1/ ) (1/ ) (1/ ) Dmax, Gy (1/ ) (1/- 8.19) (1/ ) (1/ ) (1/- 9.64) (1/ ) V39, % (1/ ) (1/ ) (1/ ) (1/ ) (1/ ) (1/ ) Contralateral submandibular gland Dmean, Gy (1/ ) (1/ ) (1/ ) 4.20 (1/ ) (1/ ) (1/ ) Dmax, Gy (1/ ) (1/ ) (1/ ) 6.80 (1/ ) (1/ ) (1/ ) V39, % (1/ ) (1/ ) (1/ ) 2.69 (1/ ) (1/ ) (1/ ) Abbreviations: Dmean, mean dose; Dmax, maximum dose; V26, percentage of salivary gland volume receiving at least 26 Gy; V39, percentage of salivary gland volume receiving at least 39 Gy. reported with oropharynx (62.43 Gy 1/- 9.50), hypopharynx (59.96 Gy 1/ ), and oral cavity RT (58.86 Gy 1/ ). Highest Dmean on contralateral submandibular gland were reported with hypopharynx (52.68 Gy 1/ ), nasopharynx (50.85 Gy 1/ ), and oropharynx RT (50.31 Gy 1/ ). Data on salivary glands dosimetry are reported in Table 4, by tumor location. Levels of late xerostomia With a median follow-up of 4.2 years, late xerostomia was achievable in 334 patients (54.8%), as reported in the medical records. No grades 4 or 5 were documented. Grades 2 to 3 xerostomia were reported in 149 patients (44.6%). DISCUSSION RT is a cornerstone of HNSCC management. An important section of patients with HNSCC is expected to become long-time survivors, and is likely to develop symptoms related to RT late toxicities. The degree of xerostomia has been reported to depend on the radiation dose and on the salivary gland volume irradiated. 5,26 Salivary glands produce approximately 1 L/24 hours of saliva, 27 containing 2 types (serous and mucous) of protein secretions. The serous secretion includes ptyalin, a salivary amylase that can break down starch. The mucous secretion includes mucin, that gives saliva its lubricating and mucosa-protecting nature. 28 Major salivary glands (ie, parotid glands, submandibular glands, and sublingual glands) produce 90% of saliva, whereas minor salivary glands (a thousand tiny glands located throughout the oral cavity) produce only 10% of saliva but secrete a major part of mucins. Parotid glands only produce serous secretions, submandibular glands and sublingual glands produce serous and mucous secretions, and minor salivary glands produce only mucous secretions. So far, the exact reasons related to RT salivary dysfunction remain unclear, but effectively sparing salivary glands was expected to reduce acute and late toxicities. Promising RT techniques (VMAT and IMRT) have been recently developed and proved superiority over 3D-conformal RT regarding toxicities, without being totally convincing in prospective studies and real-life reports. 20,21 The present study demonstrates that IMRT and VMAT require a learning time to be optimally performed. In the overall population, only 26% (n 5 159) of the salivary glands were entirely segmented before RT initiation, and 66% (n 5 404) of the submandibular glands were not delineated. Bilateral parotids were not segmented in 10% of the public hospital s treatment plans. These insufficiencies highlight the primary importance of quality assurance and reporting, especially in a public hospital where the pressure induced by legal actions might be lower than in private medical centers. The present results also reflect the fact that OAR definitions should probably be updated, because submandibular glands and parotids functional anatomy are not taken into account. Submandibular glands play a leading role in the production of good quality saliva, as they secrete a significant part of saliva s lubricating agent (mucins). 6,28 So far, little is known about submandibular dose constraints HEAD & NECK DOI /HED JULY 2016

6 REAL LIFE SALIVARY DOSIMETRY WITH IMRT/VMAT The only available recommendations have been published in 2010 by the quantitative analysis of normal tissue effects in the clinic (QUANTEC) group and advise that one of the submandibular glands should be spared, with Dmean <35 Gy, to reduce xerostomia. 26 In 2011, the Radiation Therapy Oncology Group 1016 trial set the mean dose to the contralateral submandibular gland to a maximum of 39 Gy, without justification. The absence of the submandibular glands delineation in the present study directly induced a lack of protection. If ipsilateral submandibular glands received high-dose radiations, as might be anticipated (Dmean >56 Gy, Dmax >66 Gy, V39 >90%), doses on the contralateral submandibular were surprisingly close (Dmean >48 Gy, Dmax >61 Gy, V39 >79%). These findings suggest that the submandibular glands should be systematically delineated. Submandibular preservation with as low as reasonably achievable doses should be one of IMRT/VMAT dosimetry objectives. Regarding the parotid glands, the present study results reflect an attempt to respect the recent recommendations stating that one of the parotids should be spared with Dmean <20 Gy to prevent xerostomia. 26 If not achievable, both parotids should be spared with Dmean <25 Gy. 26 Moreover, 26 Gy should not be delivered to more than 50% of the contralateral parotid (V26 <50%) In the overall population, the mean dose to the contralateral parotid was 24.5 Gy, and V26 was 40.9%. If V26 criteria could be reached, whatever the primary tumor s location, the Dmean exceeded the limit value to the contralateral parotid gland, except for the nasal fossae or sinus carcinoma. Sophisticated new RT techniques still do not allow optimal OAR sparing. In case of proximity between the tumor and salivary glands, target volume coverage still has to be prioritized over OAR sparing. Nevertheless, it has been shown that even when parotids were correctly spared, the salivary flow preservation was not correlated with an improvement of dry mouth sensation or of quality of life. 6 Apart from the lack of protection of the submandibular glands and their primary importance in making a lubricating saliva, some recent findings suggest the importance of the parotid stem cell areas that should be spared to allow better recovery of saliva production after RT. 35 Consequently, even optimized IMRT and VMAT still seem to be inadequate to efficiently protect salivary glands and prevent patients from salivary dysfunction. Amifostine is a selective radioprotector that has been shown to reduce xerostomia with 3D-conformal RT, 9,10 and increase the parotid and submandibular gland tolerance mean dose of approximately 9 Gy. 36 If IMRT or VMAT have been shown to allow better preservation of salivary function than amifostine associated with 3D-conformal RT, 37 the toxicity and safety profile of the association with IMRT/VMAT with amifostine has never been assessed. Given the disappointing dosimetric and clinical real-life results of IMRT and VMAT on salivary glands, the addition of concurrent amifostine might be interesting. A limitation of the present study was the poor reporting of data on xerostomia. Unfortunately, grade 1 xerostomia were not reported, although this side effect inevitably exists. Grades 2 to 3 were mixed, and might have been underreported because only half of data were available. Moreover, the present heterogeneous population was treated with various procedures, causing dose heterogeneity among comparable patients. Therefore, it is impossible to correlate xerostomia with RT doses in the present study, because of the too limited number of patients receiving comparable treatments with comparable cancer locations. However, a prospective study including patients with delineation and dosimetry based on QUANTEC recommendations should be initiated in the near future. Nutting et al 12 reported 83% of late xerostomia with 3Dconformal RT, and 29% with IMRT at a median followup of 24 months. With 44.6% of late xerostomia in the present study, one can conclude that VMAT, when performed in a learning process, gives suboptimal results. There is scope for progress, as always when an innovative technique is introduced in routine practice. The present study reflects real-life development of state of the art RT techniques in local hospitals. IMRT and VMAT require a learning time to be optimally performed, but probably will never be able to completely spare the salivary glands. Reporting real-life dosimetries and related toxicities is of primary interest to evaluate the real efficacy/toxicity ratio of recent RT techniques. The present results may enhance a better understanding of the daily encountered high rates of xerostomia. The question that amifostine places in association with IMRT/VMAT in patients with HNSCC should be addressed by a future pilot study. REFERENCES 1. [No authors listed]. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 1991;324: Lefebvre JL, Chevalier D, Luboinski B, Kirkpatrick A, Collette L, Sahmoud T. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. 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