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 »  Introduction
 »  The Role of IMRT...
 »  Future Directions
 »  Conclusions
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SYMPOSIUM
Year : 2010  |  Volume : 47  |  Issue : 3  |  Page : 267-273
 

The role of intensity-modulated radiotherapy in head and neck cancer


Head and Neck Unit, The Institute of Cancer Research and The Royal Marsden Hospital, London and Surrey, United Kingdom

Date of Web Publication28-Jun-2010

Correspondence Address:
S A Bhide
Head and Neck Unit, The Institute of Cancer Research and The Royal Marsden Hospital, London and Surrey
United Kingdom
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.64719

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 » Abstract 

Intensity-modulated radiotherapy (IMRT) has been a significant technological advance in the field of radiotherapy in recent years. IMRT allows sparing of normal tissue while delivering radical radiation doses to the target volumes. The role of IMRT for parotid salivary gland sparing in head and neck cancer is well established. The utility of IMRT for pharyngeal constrictor muscle and cochlear sparing requires investigation in clinical trials. The current evidence supporting the use of IMRT in various head and neck subsites has been summarized. Sparing of organs at risk allows for dose-escalation to the target volumes, taking advantage of the steep dose-response relationship for squamous cell carcinomas to improve treatment outcomes in advanced head and neck cancers. However, dose-escalation could result in increased radiation toxicity (acute and late), which has to be studied in detail. The future of IMRT in head and neck cancers lies in exploring the use of biological imaging for dose-escalation using targeted dose painting.


Keywords: Intensity-modulated radiotherapy, head and neck cancer


How to cite this article:
Bhide S A, Kazi R, Newbold K, Harrington K J, Nutting C M. The role of intensity-modulated radiotherapy in head and neck cancer. Indian J Cancer 2010;47:267-73

How to cite this URL:
Bhide S A, Kazi R, Newbold K, Harrington K J, Nutting C M. The role of intensity-modulated radiotherapy in head and neck cancer. Indian J Cancer [serial online] 2010 [cited 2019 Dec 6];47:267-73. Available from: http://www.indianjcancer.com/text.asp?2010/47/3/267/64719



 » Introduction Top


Radiotherapy (RT) is an extremely effective treatment for head and neck cancer, both as a primary modality and as an adjuvant treatment following surgery. In early-stage disease, single modality radical RT can cure >90% of cancers in some tumor subsites (i.e., larynx). [1] In more advanced-stage disease, RT is usually used in combination with cisplatin chemotherapy, either as radical chemoradiotherapy [2],[3],[4] or in an adjunctive fashion after ablative surgery. [5] Conventional RT results in permanent xerostomia with its associated complications [6],[7],[8] and effects on quality of life (QOL). [9],[10] Intensity-modulated radiotherapy (IMRT) is an advanced approach to 3-D treatment planning and conformal therapy. It optimizes the delivery of irradiation to irregularly shaped volumes and has the ability to produce concavities in radiation treatment volumes. Typically for head and neck cancer, the clinical target volume 1 (CTV1), which includes the primary tumor and the involved nodes, receives a higher radiation dose as compared to the clinical target volume 2 (CTV2). The different doses to CTV1 and CTV2 can be delivered simultaneously, while sparing the parotid salivary glands and the spinal cord. In the head and neck region, IMRT has a number of potential advantages: (i) it allows for greater sparing of normal structures such as salivary glands, esophagus, optic nerves, brain stem and spinal cord, [11],[12] (ii) it allows treatment to be delivered in a single treatment phase without the requirement for matching additional fields to provide tumor boosts and eliminates the need for electron fields to the posterior (level II, V) neck nodes and (iii) it offers the possibility of simultaneously delivering higher radiation doses to regions of gross disease and lower doses to areas of microscopic disease [[Figure 1], the so-called simultaneous integrated boost, SIB-IMRT]. [13]

IMRT has been compared to 3DCRT in three randomized controlled trials. The two published trials included patients with nasopharyngeal cancer. [14],[15] The third trial (PARSPORT), in patients with oropharyngeal and hypopharyngeal cancers, has completed accrual but has not been reported. The current role of IMRT in head and neck cancer, which is summarized below, has mainly been defined on the basis of review of retrospective case series.


 » The Role of IMRT in Head and Neck Cancer Top


Parotid sparing

IMRT was first used to spare salivary gland tissue in head and neck cancer patients in Phase I/II studies performed at the University of Michigan (UM). The primary tumor, ipsilateral cervical lymph nodes and contralateral cervical lymph nodes up to and including the subdigastric nodes (lower level II) were treated. If the contralateral parapharyngeal space (upper part of level II) and parotid gland were judged to be at very low risk of harboring occult metastases, it was spared, as were the submandibular salivary glands. [10],[12] Unstimulated and stimulated salivary flow was measured from each parotid gland before and after RT and then at 3, 6 and 12 months. IMRT reduced the radiation dose to the contralateral parotid gland to 32% compared to 93% for the standard plans. Follow-up of these patients showed that spared parotid glands received a mean dose of 19.9 Gy and recovered 63% of their pre-treatment stimulated salivary flow rates at 1 year. This compared to only a 3% recovery for treated parotid glands, which received 57.5 Gy.

A mean dose threshold was found for both stimulated (26 Gy) and unstimulated (24 Gy) saliva flow rates, such that glands receiving a mean dose below or equal to the threshold showed substantial preservation of the saliva flow following RT, which may continue to improve over time. Subsequent studies from other institutions have established similar threshold doses. [11],[16],[17] Local control and disease-specific survival were equivalent to patients treated with conventional treatment. [18],[19],[20],[21],[22],[23]

The initial studies focused on the prevention of xerostomia and included patients with a mixture of head and neck cancer subsites. [11],[24] Single-center experiences with various head and neck subsites have been reported and have shown excellent treatment-related outcomes, with reduced incidence of xerostomia.

Prevention of late dysphagia

Late radiation damage to the structures involved in swallowing leads to dysphagia and dependence on assisted feeding. Several studies using chemoradiation (CRT) or altered radiation fractionation strategies have reported rates of 12-50% significant late dysphagia, i.e. feeding tube dependency at 1 year, which significantly affects the patient's QOL. [25],[26],[27],[28],[29],[30] Studies have reported that late dysphagia following treatment for head and neck cancer is dependent on the dose to the pharyngeal constrictors, particularly the superior constrictor. [31],[32],[33],[34] IMRT has the potential to prevent radiation-induced dysphagia by limiting the dose to the constrictors. The constrictors lie in close proximity to the parapharyngeal spaces and cervical lymph nodes areas. Therefore, constrictor sparing could result in a geographical miss. Long-term data on locoregional recurrence is required before the constrictor-sparing approach can be used in standard practice.

Oropharyngeal carcinoma

The critical structures when treating oropharyngeal cancers are the parotid salivary glands and the mandible. The role of IMRT in sparing the parotid glands has been described above. Radiation doses in excess of 60 Gy cause damage to the mandible and result in osteoradionecrosis. [35] The incidence of severe osteoradionecrosis after treatment to oropharyngeal cancer is 5-15%, depending on the dose to the mandible and factors such as dental hygiene. [36],[37] Studies have demonstrated that the dose to the mandible can be minimized without affecting the dose to the target volumes. [37],[38] [Table 1] summarizes the published reports of IMRT in oropharyngeal cancer.

Laryngeal and hypopharyngeal cancer

Concurrent chemoradiation is now the standard of care as an organ-sparing approach in the treatment of stage III and IV squamous cell carcinomas (SCCs) of the larynx and the hypopharynx. [43],[44],[45] The overall survival at 5 years for stage III and IV laryngeal cancers using the most aggressive chemoradiation approaches is only 50-60%. Escalation of radiation dose may improve outcomes in this group of patients taking advantage of the steep dose-response relationships for SCCs. Using the SIB-IMRT technique, a higher dose can be delivered to the tumor while keeping the dose to the organ at risks (OARs) within tolerance. The initial results from a Phase I dose-escalation study using IMRT in patients with SCC of the larynx/hypopharynx have recently been reported. [46] The patients were initially treated with a standard dose equivalent of 63 Gy in 28 fractions (2.25 Gy/fraction). Subsequently, the dose was escalated to 67.2 Gy in 28 fractions (2.4 Gy/fraction). Acute radiation toxicity was comparable to standard RT and recovered over time. After 2 years of follow-up, only 5% of the patients had grade 2 xerostomia. The 2-year disease-specific survival (DSS) was 73% and 84% for the standard and escalated dose patients, respectively. There was no other significant late toxicity of note. Although the patient numbers are small and the follow-up short, the results are encouraging and justify further investigation. [47]

Nasopharyngeal cancer

Clinical target volumes for tumors of the nasopharynx lie in close proximity to the optic nerves, optic chiasm, orbit, pituitary gland and the brain stem. In addition, the parotid glands and the cochlea receive a significant radiation dose. Radical treatment of nasopharyngeal cancers frequently requires treatment of multiple cervical lymph node areas, which entails radiation delivery using large-field portals, treatment field matching and use of electrons to keep the spinal cord dose below 48 Gy. Radiation delivery using the SIB-IMRT technique enables delivery of a single-phase treatment while sparing the organs at risk. Two phase III randomized controlled trials investigating parotid gland sparing using IMRT for patients with nasopharyngeal cancer have been reported in the literature. [14],[15] Pow et al. randomized 51 patients to receive either IMRT or conventional RT. Eighty-three percent of the patients in the IMRT group had recovered parotid salivary flow versus 9.5% in the conventional group at 1 year. The global QOL was significantly better in the IMRT group versus the conventional group. [15] In a similar study, Kam et al. randomized 60 patients. The primary endpoint of observer-assessed xerostomia score was significantly better for the IMRT group as were the secondary endpoints of parotid and whole salivary flow rates. However, there was no statistically significant difference in the patient-reported xerostomia score. [14] Reports of single-institution retrospective studies reporting on outcomes and xerostomia rates have been summarized in [Table 2].

Paranasal sinus tumors

Tumors of the nasal cavity and the paranasal sinuses lie in close proximity to vital structures like the optic nerves, orbit, optic chiasm, pituitary gland and brain stem. IMRT enables delivery of adequate doses to these tumors while minimizing the dose to these OARs. Ombs et al. and Daly et al. have reported on the outcomes and toxicity, with IMRT as the primary treatment for this site. [51],[52] There were no incidences of grade 3 late-radiation toxicities affecting the OARs in either of the studies. The local control rates were 62% at 2 years in the study by Daly et al. and 81% at 3 years in the study by Combs et al. The overall survival rates were 45% (5 years) and 80% (3 years), respectively. Two studies have been reported using IMRT for post-operative RT (PORT) for the tumors of paranasal sinuses. [53],[54] There were no reported grade 3 toxicities and late-radiation toxicities, with satisfactory tumor control rates.

Parotid tumors

Radiation to the post-operative (after parotidectomy for malignant parotid tumors) parotid bed results in damage to the cochlea as it lies within the high-dose volume. This results in sensori-neural hearing loss, especially at higher frequencies. The literature review suggests a significant effect of RT on the auditory apparatus, especially hearing (incidence, 40-60%). [55],[56] The sensori-neural hearing loss that results after RT is permanent. Sensori-neural hearing loss has been shown to result in significant cognitive impairment, depression and reduction in functional status. [57]

Planning studies indicate that the dose to the cochlea can be reduced with the use of IMRT. [58] This might reduce the incidence of sensori-neural hearing loss. IMRT needs to be evaluated in the setting of a randomized controlled trial comparing it against standard 3D-conformal RT with sensori-neural deafness as the primary end point. A phase III study of cochlear sparing IMRT is now open and recruiting (Co-Star).

Thyroid cancer

For patients with thyroid cancer considered at high risk of locoregional recurrence after thyroidectomy, external beam RT is used, sometimes in addition to radioiodine. With the present RT techniques, 32% do not obtain a complete response (CR), and, of those obtaining CR, 39% relapse within the radiation portals, especially in the thyroid bed. Techniques that enable safe dose escalation to the thyroid bed and/or nodal areas may be able to improve local control. Planning studies have shown that the maximal spinal cord dose can be reduced so that the dose to the thyroid bed can be escalated above the standard dose of 60 Gy and, possibly, to doses of 65-68 Gy. Moreover, the coverage of the thyroid and node target volume is also significantly improved with IMRT. [59] Preliminary results on acute toxicity from a study using IMRT for dose escalation in patients with thyroid cancer requiring external beam therapy have recently been reported. [60] The results on late toxicity and disease outcomes are awaited.

Squamous cell carcinoma with unknown primary

Typically, patients with squamous cell carcinoma with unknown primary (SCCUP) are treated with ipsilateral modified radical neck dissection (MRND) and PORT or chemoradiotherapy. There is a lack of consensus on the RT target volumes that should be treated after neck dissection. The most common RT techniques are either unilateral cervical lymph node irradiation to achieve local control in the ipsilateral neck or total mucosal irradiation (TMI) of the head and neck region with the aim of eradicating the primary and the microscopic neck disease. Treatment of the ipsilateral hemineck alone is of low toxicity and may achieve local control in the cervical nodes. Some groups recommend bilateral neck and total mucosal irradiation in this setting, claiming improved local control. [61],[62] With the conventional RT technique, this is at the price of significant acute toxicity and chronic morbidity, mainly xerostomia with its associated complications [6],[7],[8] and effects on QOL. [9],[10]

In a planning study, Bhide et al. showed that using the SIB-IMRT technique for TMI, 60 Gy in 30 Gy fractions or equivalent to the post-operative bed and 50 Gy in 25 fractions or equivalent (i.e., 54 Gy in 30 fractions) to the contralateral neck and the mucosal axis could be delivered in a single phase. The dose to the contralateral parotid gland was <26 Gy and the dose to the other OARs was within tolerance. [63] Three centers have reported their experience of using IMRT to deliver TMI for SCCUP. [64],[65],[66] The 2-year locoregional control and overall survival were 85-88% and 74-85%, respectively. The TMI was well tolerated. The results are summarized in [Table 3].


 » Future Directions Top


IMRT has become the standard of care for delivery of RT for head and neck cancer. The role of IMRT in salivary gland sparing is well established. IMRT can be further optimized, making use of advances in the imaging techniques, i.e. image-guided radiotherapy. Radiation dose escalation (taking advantage of the slope of the dose-response curves) could improve the outcomes in advanced head and neck cancers. Clinical trials that attempted to further intensify RT using hyperfractionation and/or acceleration have had to close prematurely or have the radiation schedule modified due to excessive acute toxicity. [67],[68] Selective dose escalation based on the biological activity of tumors might improve the outcomes without increasing the normal tissue toxicity. Positron emission tomography (PET) enables biological imaging of tumors. Initial studies using [(18)-F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), which highlights the proliferating areas of the tumor, have been reported. [69] These have shown that FDG-PET-guided dose escalation using IMRT is feasible. Hypoxic regions of the tumors are radioresistant and increasing the radiation dose might help overcome the radioresistance. PET scanning using two radioactive tracers, namely fluorine-18-labeled fluoromisonidazole (F-MISO) and Copper (II)-diacetyl-bis(N(4)-methylthiosemicarbazone) (Cu-ATSM) have been shown to highlight the hypoxic areas of the tumors. Preliminary studies escalating the radiation dose to the hypoxic areas have demonstrated the feasibility of this approach in terms of acute toxicity.[70],[71] The PET images could be fused with the planning computed tomography scans and these could be used for biological dose optimization (as opposed to the currently used DVH-based optimization) during inverse planning IMRT. 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 standard clinical practise.


 » Conclusions Top


The role of IMRT in salivary gland sparing is well established. The role of IMRT for constrictor sparing is less well established. The future of head and neck RT lies in optimally using IMRT for biologically based individualized patient treatment in order to maximize the therapeutic ratio.

 
 » References Top

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