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REVIEW ARTICLE
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Intensity-modulated radiation therapy in head-and-neck carcinomas: Potential beyond sparing the parotid glands


1 Department of Radiotherapy and Oncology, Regional Cancer Centre, Indira Gandhi Medical College, Shimla, Himachal Pradesh, India
2 Department of Radiotherapy and Oncology, PGIMER, Chandigarh, India

Correspondence Address:
Aman Sharma,
Department of Radiotherapy and Oncology, Regional Cancer Centre, Indira Gandhi Medical College, Shimla - 171 001, Himachal Pradesh
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_880_18

 > Abstract 


Head-and-neck cancer (HNC) is in close proximity to several critical structures. Intensity-modulated radiation therapy (IMRT) has the potential of generating highly conformal and concave dose distributions around complex target and is ideally suited for HNC treatment. Conventionally, the focus of IMRT for HNC patients has been on prevention of radiation-induced parotid dysfunction. In the present article, we review the potential of IMRT to reduce the risk of posttreatment aspiration and dysphagia and spare submandibular gland. We also discuss the impact of IMRT on overall survival and quality of life (QoL) for HNC patients. Small retrospective and prospective studies show that reducing dose to adjoining organs at risks is feasible and decreases the risk of posttreatment dysphagia and aspiration without compromising local control. IMRT is associated with improved QoL in several important domains including swallowing, dry mouth, sticky saliva, social eating, and opening of the mouth; however, improvement in global QoL is inconsistent. Delivery of IMRT for HNC is associated with improved survival at nasopharyngeal subsite. Small studies demonstrate improved treatment outcomes with swallowing-sparing IMRT. These results now need validation within the prospective multicenter randomized controlled trial setting.

Keywords: Dysphagia, head-and-neck cancer, intensity-modulated radiation therapy, submandibular gland sparing, swallowing-sparing intensity-modulated radiation therapy



How to cite this URL:
Sharma A, Bahl A. Intensity-modulated radiation therapy in head-and-neck carcinomas: Potential beyond sparing the parotid glands. J Can Res Ther [Epub ahead of print] [cited 2019 Dec 7]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=268781




 > Introduction Top


It is estimated that nearly three-fourth of head-and-neck cancer (HNC) patients, need curative radiotherapy (RT) either in a radical or in the postoperative setting.[1] RT is preferred nonsurgical treatment for HNC and is associated with high local control with 5-year survival >80% for early stage 1–2 diseases and achieves 60% locoregional control rate for Stage 3–4 tumors.[2] Throughout years, new RT technologies have emerged, and delivery of RT has evolved from two-dimensional (2D-RT) techniques, based primarily on X-ray images and manual calculations to three-dimensional (3D) techniques, based on computerized tomography images incorporating progressively complex computer algorithms and modern hardware tools.[3]

Intensity-modulated radiation therapy (IMRT) is a form of conformal RT that uses nonuniform radiation beam intensities to create a sharp dose gradient between target and surrounding normal tissues. Theoretically, it allows for better target coverage and has the potential to decrease complication rate. Apart from merits, IMRT has its inherent weakness, which includes increased risk of marginal miss, increases in cost, laborious and is expensive. IMRT delivers higher total body dose because of leakage through collimator and internal scatter as a result of increased beam-on time. It has been contemplated that the use of IMRT will increase the risk of radiation-induced malignancies from 1% to 1.75% in patients who survive 10 years and beyond.[4]


 > Intensity-Modulated Radiation Therapy In Head-And-Neck Cancer Top


HNC is in close proximity to several critical structures such as the spinal cord, brainstem, parotid glands, optic apparatus (eyes, optic nerves, and chiasm), lacrimal glands, cochlea, and mandible. Radiation tolerance of adjoining critical organs at risk (OARs) is generally lesser than the dose required to control HNC, IMRT has the potential of generating highly conformal and concave dose distributions around complex target volumes with steep dose gradients which makes it ideally suited for HNC treatment. Although IMRT delivery is limited by availability in many countries and regions of the world, but where available IMRT is quickly superseding older treatment techniques for HNC despite hypothetical concerns about dose inhomogeneity and exposure of larger volumes of normal tissues to lower doses.[4] Potential benefits associated with IMRT seem intuitive, Phase III data are now beginning to emerge and confirm that delivery of IMRT is associated with lower morbidity. Although data as regards to the development of radiation-induced malignancy with use of IMRT is still immature.


 > Xerostomia Reduction By Intensity-Modulated Radiation Therapy Top


Radiation-induced xerostomia is most commonly reported late side effect of RT. Inadvertent damage to major salivary glands often results in severe reduction of salivary flow and altered salivary composition, leading to irreversible and distressing oral complaints. Salivary gland dysfunction often manifests as reduced salivary flow rates, reduction in saliva pH, changes in electrolyte and immunoglobulin saliva composition, and increased cariogenic mouth flora.[5] While the exact mechanism of radiation-induced gland damage is unknown, it is hypothesized that radiation has direct cytotoxic effects on salivary tissue and causes indirect changes in vascular blood flow to the gland.

There is sufficient and robust evidence that parotid-sparing IMRT reduces dose to parotid glands, aids recovery of saliva flow, and reduces xerostomia.[6],[7],[8],[9],[10],[11],[12],[13],[14] However, despite better salivary flow rates, improvement in patient-reported xerostomia scores is only modest. Grade 2 or higher xerostomia is still experienced by 30%–40% of patients.[6],[7],[8],[9],[10],[11],[12]

The submandibular gland (SMG) is rich in mucin and is the main source of saliva at resting conditions. SMG accounts for almost 95% of salivary flow during a 24-h period. It has been reported that restricting the mean dose in one SMG to <39 Gy has improved salivary flow and correlated with favorable rates of patient- and observer-rated xerostomia. We hereby discuss potential methods to reduce dose to SMG, so as to further reduce the sensation of xerostomia experienced by patients.

Salivary gland transfer

In the year 2000, salivary gland transfer (SGT) was introduced as a novel method to prevent xerostomia by transferring one SMG to the submental region. SGT preserves SMG function and prevents the development of radiation-induced xerostomia.[15] SGT can prevent xerostomia in as high as 83% of patients.[15] Patients subjected to SGT have higher unstimulated (75% vs. 11%) and stimulated (86% vs. 8%) salivary flow rates as compared to patients without SGT. SGT appears to be highly effective in preventing the incidence of xerostomia in patients receiving RT for HNC.[16]

Submandibular gland-sparing intensity-modulated radiation therapy

Alternative to SGT, SMG may be spared by IMRT. Although the cellular makeup of SMG and parotid gland is different, the radiosensitivity is comparable and restricting the mean dose in one SMG to <39 Gy improves salivary flow and correlated with favorable rates of patient- and observer-rated xerostomia.[14],[17],[18] For HNC patients it is difficult to spare SMG, as it may sometimes directly abut the primary tumor or at other times lie within the lymph node region to be irradiated. Although technically demanding, it is possible to spare at least one SMG (when contra-lateral level 1 lymph node station is not to be irradiated). At present, there are no randomized trials evaluating clinical outcomes of SMG-sparing IMRT or comparing SGT with SMG-sparing IMRT, but several studies have evaluated the effectiveness of SMG-sparing IMRT.[18],[19],[20],[21],[22] Data in these studies have been briefly summarized in [Table 1]. Preliminary results within these series suggest that sparing of contralateral SMG with IMRT is safe, feasible, decreases xerostomia, and does not increase chances of locoregional failure. In the largest study on SMG-sparing IMRT included 114 patients of oropharyngeal carcinoma out of which 67% received contralateral SMG IMRT.[22] The SMG could be spared to a mean dose of 30.7G, and this resulted in a significant reduction of late Grade 2+ xerostomia (6% vs. 41% at 1 year, 3% vs. 36% at 2 years) when compared to nonSMGspared group.[22]
Table 1: Studies evaluating submandibular gland-sparing intensity-modulated radiation therapy

Click here to view



 > Posttreatment Risk Of Aspiration And Dysphagia Top


Among the most profound effects of RT for HNC is the impact on ability to eat and drink. The introduction of combination chemo-RT and altered fractionation RT schedules for HNC have improved disease control at the cost of higher rates of treatment-induced toxicity. It is recognized that organ-preserving regimes do not necessarily result in functional swallowing preservation. The main late sequel after treatment intensification has been increasing rates and severity of long-term dysphagia.[23] Severe swallowing disturbances lead to nutritional deficiency, weight loss, prolonged parenteral or gastric tube feeding, higher risk for aspiration, anxiety, and depression, and diminished health-related quality of life (HRQoL).[24],[25],[26] In fact, swallowing dysfunction after curative conformal RT (CRT) has a strong negative impact on HRQoL, which is even more than xerostomia.

In normal swallowing, there is no aspiration and minimal residue, while a pathologic swallowing dysfunction is characterized by penetration (bolus entering laryngeal vestibule without passing vocal folds) or aspiration (bolus entering the subglottic region). Normally, pathologic swallowing is defined in terms of the amount and incidence of penetration and aspiration and is associated with an increased risk of aspiration pneumonia or airway obstruction.

Acute dysphagia starts and progressively increases during CRT, while late dysphagia and aspiration are usually observed months to years later. Acute dysphagia tends to resolve shortly after treatment; late swallowing disturbances are irreversible and often progressive in time. Swallowing function may be impaired due to a number of normal tissue changes, including edema, neuropathy, and fibrosis. Acute toxicities such as mucositis and edema commonly disrupt normal swallowing during treatment but improve substantially within months following treatment. In contrast, neuropathy and fibrosis of the oral, laryngeal, and pharyngeal musculature may develop and persist long after completion of the treatment. These late effects ultimately impair the range of motion of key swallowing structures and have been implicated as the primary mechanisms of long-term dysphagia in HNC survivors. Late dysphagia after CRT returns to normal in <10% of patients, one-third of the patients show a decrease in the severity of dysphagia, whereas in nearly half percent of patients severity of dysphagia remains unchanged, and it may worsen with the passage of time in 20% of cases.[23] At a follow-up period of >5-year, as high as 66% of cases may require gastrostomy to prevent pneumonia or for nutritional supplementation.[27]

Factors influencing late dysphagia and dysphagia and aspiration-related structures

The incidence of late dysphagia depends on treatment modality (RT alone vs. CRT), irradiated volume, RT dose, and fractionation, and overall treatment duration it also depends on tumor site and stage, patient age, pretreatment weight loss, pretreatment dysphagia, and smoking are among other factors affecting the rates of treatment-induced swallowing disturbances.[28],[29],[30],[31] Clinical parameters independent associated with dysphagia, included T3–T4, bilateral neck irradiation, weight loss prior to radiation, oropharyngeal and nasopharyngeal tumors, accelerated RT, and concomitant chemoradiation.[31] Based on these parameters, patients can be stratified into three risk groups with a rate of dysphagia of 5%, 24%, and 46% for low-risk, intermediate-risk, and high-risk category, respectively.[31]

Sparing of dysphagia and aspiration-related structures by intensity-modulated radiation therapy from high-dose radiation gradient

Radiation-induced damage to anatomical structures that result in the development of dysphagia includes pharyngeal constrictor muscles (PCM), upper esophageal sphincter, cricopharyngeus muscle, cervical esophagus, glottis, supraglottic larynx, and base of tongue.[31],[32] Prominent studies evaluating dysphagia and dose–volume relationship of these adjoining critical structures have been briefly highlighted in [Table 2].[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44] Dose–volume parameters suggest that reducing the mean dose below 50 Gy and decreasing V50 of these structures may be helpful in reducing dysphagia and aspiration. After a dose of 55 Gy to dysphagia aspiration-related structures (DARS), there is possibly a steep dose–effect relationship, with an increase in the probability of dysphagia of 19% with every additional 10 Gy.[36] The mean dose received by PCM appears to be the most important dosimetric predictor of late swallowing disturbances.[43] There is worsened swallowing and aspiration in patients with mean doses to PCM of 61–64 Gy, and mean doses to the supraglottic larynx of 48–54 Gy as compared to mean dose of 52–55 Gy and 36–38 Gy, respectively, to these structures.[43] As compared with 3D plans, standard IMRT reduces V50 of pharyngeal constrictors by 10%, and dysphagia optimized IMRT reduces these volumes further by an additional 10% on average.[32]
Table 2: Studies evaluating dysphagia and swallowing-sparing intensity-modulated radiation therapy

Click here to view


One of the seminal study prospectively aimed to reduce dysphagia with IMRT demonstrated that this technique is safe and achieves high tumor control rates (3-year disease-free and locoregional recurrence-free survivals 88% and 96%, respectively).[44] At 1-year posttreatment, observer-rated dysphagia was absent or minimal in all patients except four. Results within the study suggested that long-term patient-reported, observer-rated, and objective measures of swallowing were only slightly worse than pretherapy measures, representing a potential improvement compared with previous studies.

Single-arm studies have shown that sparing of swallowing structures translate to better functional outcomes.[44],[45],[46],[47],[48],[49] At present, no published randomized trial has addressed the impact of swallowing-sparing IMRT with standard IMRT. The ongoing DARS trial is the only phase III randomized trial comparing swallowing-sparing IMRT with standard IMRT.[50] The primary endpoint of the trial is to evaluate the difference in mean MD Anderson Dysphagia Inventory composite score, measured at 12-month post IMRT.

Time and resources issues with submandibular gland sparing and dysphagia aspiration-related structures

Delivery of IMRT is demanding and labor intensive procedure. One of the most important issues of IMRT is correct and accurate delineation of target and normal adjoining OAR. Delineation of SMG and DARS adds further workload to the radiation oncologist. Delivery of swallowing-sparing IMRT is challenging in terms of achieving specified dose-volume constraints to SMG and DARS, while maintaining dose homogeneity and conformity to the target and other adjoining structures. Furthermore, during the treatment course, there could be discrepancies between planned and delivered dose to target and normal tissue due to tumor regression or patient's weight loss. This often takes added efforts and time, if the decision for replanning is taken to achieve desired results.


 > Impact Of Intensity-Modulated Radiation Therapy On Quality Of Life Top


Patients diagnosed with cancer deal with various physical and psychosocial problems related to cancer and its treatment, including reduced physical fitness and function, reduced self-esteem, increased emotional distress and fatigue, all of which negatively affect the HRQoL. In addition to physical and psychosocial problems, patients with HNC are often confronted with oral dysfunction, dryness of mouth, swallowing, and speech problems.

Patient-reported outcomes are increasingly being used in clinical setting in addition to traditional outcome measures such as tumor control, overall survival, morbidity, and complications. There is evidence of a positive association between HRQoL and survival in cancer patients; patients with lower pretreatment HRQoL have reduced survival.[51],[52] A recently published study examined the association between pretreatment HRQoL and survival for 11 different cancers and found that for each cancer, the accuracy of survival increased by adding at least one HRQoL domain to clinical and demographic predictors such as age, performance status, and metastasis.[52] For HNC, physical functioning and social functioning were independently predictive for survival. In HNC patients, HRQoL declines after treatment but recovers to baseline levels, generally within 12 months; however, xerostomia-related HRQoL deficits may remain long term. Combined chemo-RT shows a trend toward worse HRQoL compared with RT alone, and IMRT yields better HRQoL compared with conventional or 3D conformal RT.[53]

IMRT in HNC is associated with improved quality of life (QoL) benefits, and there is statistically significant improvement with delivery of IMRT in several important QoL domains including swallowing, dry mouth, sticky saliva, social eating, and opening of the mouth at 3–12 months, although there is inconsistent improvement in global QoL with the use of IMRT.[10] Vergeer et al. in a prospective nonrandomized large cohort of 241 patients treated with 3D-conventional RT or IMRT reported a significant difference in functional scores on the European Organisation for Research and Treatment of Cancer (EORTC)Quality of life (QLQ)-H&N35 questionnaire and QoL scores on EORTC QLQ-C30 questionnaire.[54] In eight of the 12 functional subscales of the EORTC QLQ H and N35 (including dry mouth, sticky saliva, mouth opening, swallowing, and teeth problems), there was a statistically and clinically significant improvement in the IMRT group. In seven of the 15 QoL subscales of the EORTC QLQ-C30 (including global QoL score, role functioning, social functioning, fatigue, insomnia, and appetite loss), there was a statistically and clinically significant improvement in the IMRT group. However, other studies have failed to show improvement in global QoL.[10] The PARSPORT trial did not find any significant improvement in global QOL with use of IMRT, although there was significant improvement in subscale scores for the dry mouth with IMRT.[10] IMRT holds much promise as regard to sparing normal tissues, improving long-term salivary flow and reducing long-term functional deficits of RT; however, the early optimism that this would reflect an improvement in patient-reported QoL still remains unproven. The minimal impact that IMRT has had on patients' global QOL, thus far points out to further sparing of adjoining critical structures (e.g., SMGs, minor salivary glands in the oral cavity, and swallowing structures).


 > Impact Of Intensity-Modulated Radiation Therapy On Locoregional Control/Survival Top


IMRT has quickly taken over as the standard practice for HNC; however, tight margins and the opportunity for geographic miss are possible drawbacks to IMRT. Data from prospective trials and multiple single-institution reports indicate that locoregional control and survival achieved with IMRT is at par to with treatment outcomes achieved with the use of nonIMRT/conventional RT techniques.[8],[9],[10],[12],[13] A recently published meta-analysis also reported equivalent locoregional control and overall survival with the use of IMRT and nonIMRT techniques for HNC.[13]

Improved survival outcome with intensity-modulated radiation therapy

Almost all series show that delivery of IMRT may not improve survival; however, there are very few studies that point have shown improved survival for HNC patients. A recently published phase III trial that enrolled nasopharyngeal carcinoma patients, showed significant improvement in survival with the delivery of IMRT (5-year overall survival rate 80% vs. 67% for 2D-RT).[11] Similar results have been confirmed within the Surveillance, Epidemiology, and End Results database. Treatment with IMRT significantly improved the cause of specific survival (84% vs. 66%, P < 0.001) when compared to HNC patients treated with conventional RT.[55] All subgroups of HNC patients treated with IMRT had better cause-specific survival (CSS) than those treated with non-IMRT. On multivariable survival analyses, patients treated with IMRT were associated with better CSS (hazard ratio 0.72, 95% confidence interval: 0.59–0.90).


 > Conclusions Top


It is safe and feasible to spare SMG and “dysphagia- and aspiration-related” structures with IMRT. Delivery of swallowing-sparing IMRT translates to decrease the risk of posttreatment dysphagia and aspiration without increasing the risk of marginal recurrences. These findings now need to be validated in a multicenter prospective randomized trial setting. IMRT is associated with improved quality and has the potential to improve the global QoL. Delivery of IMRT is associated with improved survival at nasopharyngeal subsite.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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