Year : 2016 | Volume
: 7 | Issue : 2 | Page : 37--41
Intensity-modulated radiotherapy in head and neck cancers: In which direction are we heading?
Punita Lal, Mranalini Verma, KJ Maria Das, Shaleen Kumar
Department of Radiotherapy, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
Department of Radiotherapy, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh
Radiotherapy (RT) is one of the treatment modalities, which most of the time used in the treatment of most head and neck cancers with/without chemotherapy either as a definitive treatment or adjuvant/postoperated or for symptoms palliation, but it is always accompanied by late sequelae such as xerostomia and dysphagia. These two major sequelae have a significant effect on patient«SQ»s quality of life even after cure of disease. However, with the advancement of modern techniques such as intensity-modulated RT (IMRT) which effectively spares the parotid glands has a significant effect, proven in randomized trials, for xerostomia as well as dysphagia. IMRT to spare dysphagia and aspiration related structure ( DARSs) has also been studied extensively. To improve the results further, nowadays, we focus on use of functional imaging at the time of RT planning and/or use of image guidance for the adaptation during RT treatment as well as focus on to reduce neurocognition effects of treatment by sparing brain.
|How to cite this article:|
Lal P, Verma M, Maria Das K J, Kumar S. Intensity-modulated radiotherapy in head and neck cancers: In which direction are we heading?
.J Radiat Cancer Res 2016;7:37-41
|How to cite this URL:|
Lal P, Verma M, Maria Das K J, Kumar S. Intensity-modulated radiotherapy in head and neck cancers: In which direction are we heading?
. J Radiat Cancer Res [serial online] 2016 [cited 2020 Jul 4 ];7:37-41
Available from: http://www.journalrcr.org/text.asp?2016/7/2/37/191702
Intensity-modulated radiotherapy (IMRT) is an advancement of three-dimensional (3D) conformal treatment technique that optimizes the radiation delivery to irregularly-shaped volumes, especially concave-shaped treatment volumes, by modulation of radiation beams. ,, In the last decade, various single- and multi-institution retrospective case series and randomized trials have been reported, therefore establishing its role especially in head and neck cancers (HNCs). ,,,,,,,,, Typically, in these tumors, different target volumes such as high-risk clinical target volume (CTV)-which includes the primary tumor and the involved nodes receives a higher radiation dose, low-risk target volume, i.e, elective nodal irradiation, and critical normal structures that need to be avoided, all coexist in proximity. IMRT technique has the ability to simultaneously deliver different radiation doses to these different CTVs (i.e, using simultaneous integrated boost [SIB] technique). Apart from SIB treatment, IMRT has several other potential advantages: (i) it allows for greater sparing of normal structures such as salivary glands, esophagus, optic nerves, brain stem, and spinal cord; , (ii) it allows treatment to be delivered in a single treatment phase without the requirement for matching additional fields to provide tumor boosts and therefore eliminates the need for electron fields to the posterior (Level V) neck nodes; (iii) it offers the possibility of higher radiation doses to regions of hypoxia within the gross tumor volume to further increase locoregional control (LRC); (iv) it allows re-irradiation of recurrent disease to tumoricidal doses. This is possible since both total dose and fraction size can be kept to minimum for structures such as spinal cord-a major dose-limiting critical serial organ at risk (OAR) in HNC patients. 
Various Methods to Deliver Intensity-modulated Radiotherapy
IMRT can be delivered by linear accelerator using either with static multi-leaf collimators (MLC) (step and shoot IMRT), dynamic MLCs, tomotherapy (TT) machines, or with volumetric modulated arc therapy (VMAT). ,,,,, TT delivers IMRT treatment in a continuous spiral arc fashion around target with an ability to take computed tomography (CT) images simultaneously for image guidance and matched-corrected treatment delivery.  VMAT, on the other hand, is a technique of delivering IMRT in arcs. IMRT-like distributions are created in a single or two rotations of the gantry by varying the gantry speed and dose rate during delivery. This is in contrast to the standard IMRT, which uses fixed gantry beams. Planning studies using VMAT/Rapid Arc™ demonstrate shorter planning and treatment time, lesser monitor units for treatment delivery, better dose homogeneity, and normal tissue sparing.  A multi-institutional study from the Netherlands by Holt et al. compared step and shoot IMRT with VMAT plans in oropharyngeal malignancies, and they reported significantly better sparing for almost all OARs with VMAT, with better dose conformity. 
What has Already been Achieved?
The major benefit of IMRT in HNC is parotid gland sparing as was witnessed in the initial phase I/II studies conducted at the University of Michigan.  Unstimulated and stimulated salivary flow rates from each parotid gland were measured before and after radiotherapy (RT) at repeated time interval during follow-up. Dose distribution-wise, it was seen that when parotid glands received a mean dose of 20 Gy, 63% recovery of the salivary flow rates at 12 months was seen. In comparison, there was only a 3% recovery for parotid glands, which received a mean dose 57 Gy. , Severe xerostomia, i.e, salivary output <25% of the baseline values, was seen when the mean dose threshold exceeded 26 Gy for stimulated and 24 Gy for unstimulated saliva flow rates. Subsequent studies from other institutions have established similar threshold doses for the xerostomia. ,,
The multicenter study (PARSPORT trial) from the UK compared parotid-sparing IMRT with the standard RT in patients with oropharyngeal and hypopharyngeal cancers. The result showed nearly 50% reductions (74% vs. 38% and 83% vs. 29%) in rate of Grade 2 or more xerostomia in the IMRT arm as compared to the standard RT arm at 12 and 24 months, following treatment. Two-year progression-free survival remained the same (80% vs. 78%), and no patient had recurrence in the spared parotid tissue in IMRT arm. The estimated 2-year overall survival (OS) also remained same (78% vs. 76%) with the use of IMRT as compared to standard RT.  This study reiterated the previous phase II experiences that the benefit with IMRT was only in terms of parotid gland sparing while the local control and long-term results have remained the same. ,,,
The multicenter, prospective French study GORTEC 2004-03 also reported similar results in 208 HNC patients treated with IMRT as compared to conventional RT (CRT), i.e, 86% LRC and 87% OS at 2 years with nearly 3-fold less Grade 2 or more xerostomia (24% vs. 8.5%). This was achieved as the mean dose to the spared parotid gland was kept ≤28 Gy. 
A comparative study by Gupta et al. on 60 laryngopharyngeal cancers got the same results and showed only 59% patients had Radiation Therapy Oncology Group Grade 2 or worse acute salivary gland toxicity in IMRT arm versus 89% in 3D conventional RT (CRT) arm.  Patients in IMRT arm had significantly better quality of life (QOL) in comparison to 3D-CRT arm, measured with EORTC QOL questionnaire (QOL-C30 and HN-35) at various time intervals.  Further long-term results suggested that lesser patients in IMRT arm have Grade ≥2 xerostomia as well as long-term weight loss with no difference in disease-related outcomes. 
A study by Anand et al. on 19 HNC patients by sparing contralateral parotid gland (mean dose was 26.85 Gy) with IMRT showed that 9/19 patients at 13 months follow-up had no symptoms of xerostomia (Grade 1), 8 had only Grade 2, i.e, mild dryness of the mouth, and only 2 had Grade 3 xerostomia.  The same results repeated on 62 locally advanced HNC patients treated by IMRT and having Grade 0 xerostomia in 61.5%, Grade 1 in 31.5%, and Grade 2 in only 7% of patients at 6 months, following treatment with a median follow-up of 19 months; 2-year actuarial LRC and OS were 77% and 74%, respectively. 
A study by Nangia et al. using compensator-based IMRT on 18 HNCs showed that with contralateral parotid mean dose <35 Gy in 13 patients had Grade 1 xerostomia only. 
Apart from xerostomia, another important potential benefit by IMRT is - prevention of late dysphagia - radiation-related toxicities of the structures involved in swallowing lead to dysphagia as late sequelae. Several studies using chemoradiation (CRT) or altered radiation fractionation strategies have reported significant late dysphagia rate of around 12-50% at 1 year after completion of treatment. This degree of dysphagia significantly affects the QOL in HNC patients. Use of IMRT technique has shown a significant reduction in late dysphagia-related difficulties. ,, Studies have reported that it is the dose to the pharyngeal constrictor muscles, particularly the superior constrictor that is a predictive factor for late dysphagia. , IMRT has the potential to prevent radiation-induced dysphagia by limiting the dose to the constrictors and supraglottic larynx-another dysphagia and aspiration-related structure (DARS). ,, A prospective study by Feng et al. on selected oropharyngeal cancers attempted constrictor-sparing IMRT and tried to minimize the dose to these muscles (by not treating the medial retropharyngeal nodes). They reported that at median follow-up of 36 months, the survival outcomes were equivalent to historical controls, but patient reported that QOL parameters were much better.  A prospective study by Jeffrey et al. in advanced oropharyngeal malignancies (treated by swallowing structures and salivary gland sparing chemo-IMRT) evaluated long-term (more than 6 years median follow-up) health-related QOL (HRQOL) by a validated patient-reported instrument (University of Washington QOL questionnaire). They reported that these patients had stable or improved HRQOL in nearly all domains compared with both before the treatment and at 2 years after treatment. Moderate to severe swallowing difficulty was seen in only 5% and enteral feeding dependence in 2% cases in this study. 
A study by Anand et al. on 62 locally advanced HNC patients showed a major favorable impact on chronic dysphagia, i.e, Grade 0 dysphagia at 6 months in 77% patients, Grade 1 in 10.5%, and Grade 2 in only 12% cases. None of them had dependence on an alternative route for feeding within 8 weeks of treatment. 
Anatomically, the constrictor muscles lie in proximity to the parapharyngeal spaces and retropharyngeal lymph nodes areas. Moreover, therefore, constrictor muscle sparing could result in a geographical miss in these regions. In fact, it has been advised that constrictor muscles sparing IMRT should be considered in select situations only, excluding the posterior pharyngeal wall and positive retropharyngeal node tumors. Moreover, long-term data on locoregional recurrence are required before constrictor muscle sparing approach can be used in standard practice.
What has to Achieve Further?
Other late sequelae that have been of concern and attempt have been made to reduce their incidence by using IMRT are:
Cochlea sparing to avoid tinnitus (a study by Lee et al. investigated the side effects of RT for 422 inner ears among 211 patients with HNC and suggested that the mean dose to the cochlea should be <32 Gy to maintain the incidence of Grade 2+ tinnitus toxicity <20% in IMRT) Hippocampal sparing to reduce effect on decline in cognitive function (Dunlop et al. planned hippocampus sparing IMRT in ten HNC patients and found significant reduction in the probability of radiation-induced neurocognitive function decline associated with significantly reduced dose to the bilateral hippocampi Carotid vessel sparing in early glottic cancer to prevent carotid atherosclerosis to reduce risk of neurological sequelae, such as stroke and transient ischemic attack. , Zumsteg et al. studied the use of IMRT for carotid-sparing (CS) in early-stage laryngeal carcinoma among early-stage laryngeal carcinoma patients including 282 CRT and 48 CS-IMRT patients and found no difference in local failure and advocate further prospective evaluation of CS-IMRTOptic apparatus sparing IMRT. IMRT can be further refined and optimized by making use of advances in the imaging techniques at the time of treatment delivery, i.e, image-guided RT. Tumors that are small lying next to critical structures such as optic apparatus greatly benefit with image guidance-making adequate dose delivery possible. Since daily reproducibility is checked using image guidance, it is possible to give tighter planning target volume margins without compromising the dose to the target and exceeding dose to the critical structures.
Theoretically, when radiation dose is increased, it might improve the outcomes. This has to carry out without actually increasing the normal tissue toxicity to the dose-limiting structures in the vicinity. Advances in the IMRT have been explored by attempting selective dose escalation based on the biological activity of tumors. This is possible by integrating positron emission tomography (PET) scanning that enables biological imaging of tumors. Initial studies have shown that [(18)-F] fluoro-2-deoxy-D-glucose PET (FDG-PET) highlights the proliferating areas of the tumor and therefore may possibly benefit with higher radiation doses.  FDG-PET-guided dose escalation may be feasible with IMRT techniques when higher dose are delivered to the hypoxic regions within the tumors that are likely to be radioresistant and increasing the radiation dose might help overcome the radioresistance. ,, However, follow-up data for outcomes and toxicity from larger studies using PET-guided dose escalation are required before this approach can be used in the standard clinical practice.
Adaptation of RT during the 6-7-week long course of IMRT is yet another area which is being extensively studied. During the period of RT, significant volumetric and anatomical changes occur in the parotid glands as well as gross tumor. Both the tumor and parotid glands tend to shrink and relatively shift their position leading to significant dose violation from the originally generated plan (nearly 10-25% variation from the original plan). , Beltran et al. were one of the initial workers in the field and they evaluated the effect of these anatomical and volumetric changes by doing repeat planning CT scan at the 15 th and 25 th day of RT and compared the original IMRT plans with the new CT-based IMRT plans for remaining fractions. They reported that if patients are not replanned, parotid gland mean dose increased by 6% and the spinal cord increased by 4%.  Castelli et al. evaluated the dose distribution changes by doing weekly CT scans and reported that if no replanning is done, then parotid glands receive excess dose in nearly 60% of cases.  Unfortunately, adaptive RT studies on HNC have been limited to small trials with less number of patients and therefore need larger studies to effectively prove a point and identify the patient's subgroup that is likely to be benefit with adaptive RT. Moreover, adaptation is a laboratory intensive process, especially in resourced constrained overburdened centers within the country and therefore must be explored judiciously.
Intensity-modulated proton therapy (IMPT) is another emerging investigational area of IMRT which may further reduce the side effects of RT. Proton beam with its unique physical dose characteristics, i.e, Bragg-peak and scattered Bragg-peak, has the ability to treat the target and spare the normal tissue beyond the tumor since there is no exit dose. This dose distribution strategy serves as IMRT, if available. Hans Paul et al. compared IMPT with IMRT (using photon beams) in pharyngeal malignancies. They reported that the swallowing organs sparing proton therapy has the potential to substantially higher reduction of the risk of swallowing dysfunction.  Proton therapy facilities however are still confined to limited centers across the globe and need further experience to bring it to routine clinical practice.
The radiation dose distribution to the mandible is rarely considered with IMRT, and the potential risks of ORN are not well characterized for this modality. A study by Parliament et al. on ten patients found that significantly higher mandible doses were received in cases of oral cavity as opposed to other sites with IMRT. Efforts to optimize IMRT to further reduced doses to the mandible should be considered. Another study by Owosho et al. compared between IMRT and proton beam radiation therapy (PBRT) and found that PBRT has effective tissue sparing capability compared to IMRT translating to less radiation-related toxicity. ,
To sum up, IMRT has become the standard of care for HNC patients with a well-established role in parotid glands sparing and reducing xerostomia related QOL. However, for dysphagia structures sparing, we need further studies to identify the select situations where it might be useful using IMRT. The future of head and neck RT lies in optimally using IMRT and possibly using biological imaging and exploring the option of dose escalation. Adaptive IMRT may help us in future to maximize the therapeutic ratio in these tumors. Proton beam therapy, based on its physical characteristics, sounds promising, however, its translation into clinical benefit, needs further assessment.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
|1||Eisbruch A, Marsh LH, Martel MK, Ship JA, Ten Haken R, Pu AT, et al. Comprehensive irradiation of head and neck cancer using conformal multisegmental fields: Assessment of target coverage and noninvolved tissue sparing. Int J Radiat Oncol Biol Phys 1998;41:559-68.|
|2||Eisbruch A, Ship JA, Martel MK, Ten Haken RK, Marsh LH, Wolf GT, et al. Parotid gland sparing in patients undergoing bilateral head and neck irradiation: Techniques and early results. Int J Radiat Oncol Biol Phys 1996;36:469-80.|
|3||Feng M, Eisbruch A. Future issues in highly conformal radiotherapy for head and neck cancer. J Clin Oncol 2007;25:1009-13.|
|4||Butler EB, Teh BS, Grant WH 3 rd , Uhl BM, Kuppersmith RB, Chiu JK, et al. Smart (simultaneous modulated accelerated radiation therapy) boost: A new accelerated fractionation schedule for the treatment of head and neck cancer with intensity modulated radiotherapy. Int J Radiat Oncol Biol Phys 1999;45:21-32.|
|5||Chao KS, Deasy JO, Markman J, Haynie J, Perez CA, Purdy JA, et al. A prospective study of salivary function sparing in patients with head-and-neck cancers receiving intensity-modulated or three-dimensional radiation therapy: Initial results. Int J Radiat Oncol Biol Phys 2001;49:907-16.|
|6||Lee N, Xia P, Fischbein NJ, Akazawa P, Akazawa C, Quivey JM. Intensity-modulated radiation therapy for head-and-neck cancer: The UCSF experience focusing on target volume delineation. Int J Radiat Oncol Biol Phys 2003;57:49-60.|
|7||Yao M, Dornfeld KJ, Buatti JM, Skwarchuk M, Tan H, Nguyen T, et al. Intensity-modulated radiation treatment for head-and-neck squamous cell carcinoma - the University of Iowa experience. Int J Radiat Oncol Biol Phys 2005;63:410-21.|
|8||Chao KS, Low DA, Perez CA, Purdy JA. Intensity-modulated radiation therapy in head and neck cancers: The Mallinckrodt experience. Int J Cancer 2000;90:92-103.|
|9||de Arruda FF, Puri DR, Zhung J, Narayana A, Wolden S, Hunt M, et al. Intensity-modulated radiation therapy for the treatment of oropharyngeal carcinoma: The memorial Sloan-Kettering cancer center experience. Int J Radiat Oncol Biol Phys 2006;64:363-73.|
|10||Al-Mamgani A, Mehilal R, van Rooij PH, Tans L, Sewnaik A, Levendag PC. Toxicity, quality of life, and functional outcomes of 176 hypopharyngeal cancer patients treated by (chemo) radiation: The impact of treatment modality and radiation technique. Laryngoscope 2012;122:1789-95.|
|11||Toledano I, Graff P, Serre A, Boisselier P, Bensadoun RJ, Ortholan C, et al. Intensity-modulated radiotherapy in head and neck cancer: Results of the prospective study GORTEC 2004-03. Radiother Oncol 2012;103:57-62.|
|12||Kam MK, Leung SF, Zee B, Chau RM, Suen JJ, Mo F, et al. Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients. J Clin Oncol 2007;25:4873-9.|
|13||Pow EH, Kwong DL, McMillan AS, Wong MC, Sham JS, Leung LH, et al. Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: Initial report on a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys 2006;66:981-91.|
|14||Sulman EP, Schwartz DL, Le TT, Ang KK, Morrison WH, Rosenthal DI, et al. IMRT reirradiation of head and neck cancer-disease control and morbidity outcomes. Int J Radiat Oncol Biol Phys 2009;73:399-409.|
|15||Dawson LA, Jaffray DA. Advances in image-guided radiation therapy. J Clin Oncol 2007;25:938-46.|
|16||Vanetti E, Clivio A, Nicolini G, Fogliata A, Ghosh-Laskar S, Agarwal JP, et al. Volumetric modulated arc radiotherapy for carcinomas of the oro-pharynx, hypo-pharynx and larynx: A treatment planning comparison with fixed field IMRT. Radiother Oncol 2009;92:111-7.|
|17||Verbakel WF, Cuijpers JP, Hoffmans D, Bieker M, Slotman BJ, Senan S. Volumetric intensity-modulated arc therapy vs. conventional IMRT in head-and-neck cancer: A comparative planning and dosimetric study. Int J Radiat Oncol Biol Phys 2009;74:252-9.|
|18||Stromberger C, Wlodarczyk W, Marnitz S, Jamil B, Budach V, Raguse JD, et al. Simultaneous integrated boost (SIB): RapidArc and tomotherapy plan comparison for unilateral and bilateral neck irradiation. Anticancer Res 2015;35:2991-7.|
|19||Chen J, Mok E, Wang L, Chen C, Le QT. Volumetric-modulated arc radiotherapy for skull-base and non-skull-base head and neck cancer: A treatment planning comparison with fixed Beam IMRT. Technol Cancer Res Treat 2013;12:11-8.|
|20||Holt A, Van Gestel D, Arends MP, Korevaar EW, Schuring D, Kunze-Busch MC, et al. Multi-institutional comparison of volumetric modulated arc therapy vs. intensity-modulated radiation therapy for head-and-neck cancer: A planning study. Radiat Oncol 2013;8:26.|
|21||Blanco AI, Chao KS, El Naqa I, Franklin GE, Zakarian K, Vicic M, et al. Dose-volume modeling of salivary function in patients with head-and-neck cancer receiving radiotherapy. Int J Radiat Oncol Biol Phys 2005;62:1055-69.|
|22||Bussels B, Maes A, Flamen P, Lambin P, Erven K, Hermans R, et al. Dose-response relationships within the parotid gland after radiotherapy for head and neck cancer. Radiother Oncol 2004;73:297-306.|
|23||Nutting CM, Morden JP, Harrington KJ, Urbano TG, Bhide SA, Clark C, et al. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): A phase 3 multicentre randomised controlled trial. Lancet Oncol 2011;12:127-36.|
|24||Toledano I, Graff P, Serre A, Boisselier P, Bensadoun RJ, Ortholan C, et al. Intensity-modulated radiotherapy in head and neck cancer: Results of the prospective study GORTEC 2004-03. Radiother Oncol 2012;103:57-62.|
|25||Mortensen HR, Jensen K, Aksglæde K, Behrens M, Grau C. Late dysphagia after IMRT for head and neck cancer and correlation with dose-volume parameters. Radiother Oncol 2013;107:288-94.|
|26||Feng FY, Kim HM, Lyden TH, Haxer MJ, Feng M, Worden FP, et al. Intensity-modulated radiotherapy of head and neck cancer aiming to reduce dysphagia: Early dose-effect relationships for the swallowing structures. Int J Radiat Oncol Biol Phys 2007;68:1289-98.|
|27||Mazzola R, Ricchetti F, Fiorentino A, Fersino S, Giaj Levra N, Naccarato S, et al. Dose-volume-related dysphagia after constrictor muscles definition in head and neck cancer intensity-modulated radiation treatment. Br J Radiol 2014;87:20140543.|
|28||Lee TF, Yeh SA, Chao PJ, Chang L, Chiu CL, Ting HM, et al. Normal tissue complication probability modeling for cochlea constraints to avoid causing tinnitus after head and neck intensity modulated radiation therapy. Radiat Oncol 2015;10:194.|
|29||Gupta T, Agarwal J, Jain S, Phurailatpam R, Kannan S, Ghosh-Laskar S, et al. Three-dimensional conformal radiotherapy (3D-CRT) versus intensity modulated radiation therapy (IMRT) in squamous cell carcinoma of the head and neck: A randomized controlled trial. Radiother Oncol 2012;104:343-8.|
|30||Rathod S, Gupta T, Ghosh-Laskar S, Murthy V, Budrukkar A, Agarwal J. Quality-of-life (QOL) outcomes in patients with head and neck squamous cell carcinoma (HNSCC) treated with intensity-modulated radiation therapy (IMRT) compared to three-dimensional conformal radiotherapy (3D-CRT): Evidence from a prospective randomized study. Oral Oncol 2013;49:634-42.|
|31||Ghosh-Laskar S, Yathiraj PH, Dutta D, Rangarajan V, Purandare N, Gupta T, et al. Prospective randomized controlled trial to compare 3-dimensional conformal radiotherapy to intensity-modulated radiotherapy in head and neck squamous cell carcinoma: Long-term results. Head Neck 2016;38 Suppl 1:E1481-7.|
|32||Anand AK, Jain J, Negi PS, Chaudhoory AR, Sinha SN, Choudhury PS, et al. Can dose reduction to one parotid gland prevent xerostomia? - A feasibility study for locally advanced head and neck cancer patients treated with intensity-modulated radiotherapy. Clin Oncol (R Coll Radiol) 2006;18:497-504.|
|33||Anand AK, Chaudhoory AR, Shukla A, Negi PS, Sinha SN, Babu AA, et al. Favourable impact of intensity-modulated radiation therapy on chronic dysphagia in patients with head and neck cancer. Br J Radiol 2008;81:865-71.|
|34||Nangia S, Chufal KS, Arivazhagan V, Srinivas P, Tyagi A, Ghosh D. Compensator-based intensity modulated radiotherapy in head and neck cancer: our experience in achieving dosimetric parameters and their clinical correlation. Clin Oncol (R Coll Radiol) 2006;18:485-92.|
|35||Vainshtein JM, Moon DH, Feng FY, Chepeha DB, Eisbruch A, Stenmark MH. Long-term quality of life after swallowing and salivary-sparing chemo-intensity modulated radiation therapy in survivors of human papillomavirus-related oropharyngeal cancer. Int J Radiat Oncol Biol Phys 2015;91:925-33.|
|36||Dunlop A, welsh L, Nutting C, Harrington K, Bhide S, Newbold K. SU-E-T-198: Hippocampal sparing radiotherapy (HSRT) for patients with head and neck cancer (HNC) using intensity modulated radiation therapy (IMRT). Med Phys 2014;41:268.|
|37||Gujral DM, Shah BN, Chahal NS, Bhattacharyya S, Senior R, Harrington KJ, et al. Arterial stiffness as a biomarker of radiation-induced carotid atherosclerosis. Angiology 2016;67:266-71.|
|38||Zumsteg ZS, Riaz N, Jaffery S, Hu M, Gelblum D, Zhou Y, et al. Carotid sparing intensity-modulated radiation therapy achieves comparable locoregional control to conventional radiotherapy in T1-2N0 laryngeal carcinoma. Oral Oncol 2015;51:716-23.|
|39||Newbold K, Powell C. PET/CT in radiotherapy planning for head and neck cancer. Front Oncol 2012;2:189.|
|40||Madani I, Duthoy W, Derie C, De Gersem W, Boterberg T, Saerens M, et al. Positron emission tomography-guided, focal-dose escalation using intensity-modulated radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 2007;68:126-35.|
|41||Chao KS, Bosch WR, Mutic S, Lewis JS, Dehdashti F, Mintun MA, et al. A novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys 2001;49:1171-82.|
|42||Lee NY, Mechalakos JG, Nehmeh S, Lin Z, Squire OD, Cai S, et al. Fluorine-18-labeled fluoromisonidazole positron emission and computed tomography-guided intensity-modulated radiotherapy for head and neck cancer: A feasibility study. Int J Radiat Oncol Biol Phys 2008;70:2-13.|
|43||Beltran M, Ramos M, Rovira JJ, Perez-Hoyos S, Sancho M, Puertas E, et al. Dose variations in tumor volumes and organs at risk during IMRT for head-and-neck cancer. J Appl Clin Med Phys 2012;13:3723.|
|44||Castelli J, Simon A, Louvel G, Henry O, Chajon E, Nassef M, et al. Impact of head and neck cancer adaptive radiotherapy to spare the parotid glands and decrease the risk of xerostomia. Radiat Oncol 2015;10:6.|
|45||van der Laan HP, van de Water TA, van Herpt HE, Christianen ME, Bijl HP, Korevaar EW, 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 2013;52:561-9.|
|46||Parliament M, Alidrisi M, Munroe M, Wolfaardt J, Scrimger R, Thompson H, et al. Implications of radiation dosimetry of the mandible in patients with carcinomas of the oral cavity and nasopharynx treated with intensity modulated radiation therapy. Int J Oral Maxillofac Surg 2005;34:114-21.|
|47||Owosho AA, Yom SK, Han Z, Sine K, Lee NY, Huryn JM, et al. Comparison of mean radiation dose and dosimetric distribution to tooth-bearing regions of the mandible associated with proton beam radiation therapy and intensity modulated radiation therapy for ipsilateral head and neck tumor. Oral Surg Oral Med Oral Pathol Oral Radiol 2016. Available from: http://www.doi: 10.1016/j.oooo. 2016.07.003. [Published Online on 2016 Jul 19].|