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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 6  |  Page : 1196-1201

Objective and subjective assessment of xerostomia in patients of locally advanced head-and-neck cancers treated by intensity-modulated radiotherapy


1 Department of Radiotherapy, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Radiotherapy, CRI, Himalayan Institute of Medical Sciences, SRHU, Dehradun, Uttarakhand, India

Date of Web Publication28-Nov-2018

Correspondence Address:
Vipul Nautiyal
Assistant Professor, Department of Radiotherapy, CRI, Himalayan Institute of Medical Sciences, SRHU, Dehradun, Uttarakhand
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_200_17

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 > Abstract 


Background: Parotid-sparing intensity-modulated radiotherapy (IMRT) effectively reduces xerostomia in head-and-neck cancer (HNC). Changes in the salivary output at 1 year were studied and correlation with quality of life (QOL) changes in patients of locally advanced HNC (LAHNC) was drawn.
Materials and Methods: Between October 2009 and October 2011, 20 patients of LAHNC were treated with IMRT using simultaneous integrated boost technique. High-risk clinical target volume (CTV) was given a dose of 66 Gy/30 fr, intermediate-risk CTV 60 Gy/30 fr, and low-risk CTV 54 Gy/30 fr. The saliva flow rate was estimated for 5 min at rest (unstimulated) and after using lemon drops (stimulated) for the next 5 min, at baseline (pretreatment), and 3, 6, and 12 months following treatment. Evaluation of patients' perception of dry mouth was done using EORTC-QLQ-C30 and HN35 questionnaires at the same time points.
Results: Baseline unstimulated and stimulated salivary flow rates were 0.659 ml/min and 1.69 ml/min, respectively. At 3 months, a significant reduction in unstimulated (0.346 ml/min) and stimulated (0.80 ml/min) flow rate was observed. Unstimulated flow rate continued to decrease further till 6 months (0.295 ml/min), but slight improvement was seen in stimulated flow rate (0.91 ml/min). At 12 months, minimal recovery was observed in both unstimulated (0.362 ml/min) and stimulated flow rates (1.09 ml/min). EORTC-QOL questionnaire mean scores for dryness and stickiness of saliva were 10 and 15 at baseline and increased to 36 and 25, respectively, at 3 months. At 6 months, symptom score for dryness further increased to 45 and then decreased to 33 at 12 months. Stickiness score remained static from 3 to 12 months. Salivary flow rate correlated well with dry mouth (P < 0.05) but not with the perception of sticky saliva (P = 0.82) at 6 months and beyond.
Conclusions: Both salivary flow rate and xerostomia-related questions worsened at 3 months even with IMRT and showed a similar pattern of recovery.

Keywords: Head-and-neck cancer, intensity-modulated radiotherapy, xerostomia


How to cite this article:
Lal P, Nautiyal V, Verma M, Yadav R, Maria Das K J, Kumar S. Objective and subjective assessment of xerostomia in patients of locally advanced head-and-neck cancers treated by intensity-modulated radiotherapy. J Can Res Ther 2018;14:1196-201

How to cite this URL:
Lal P, Nautiyal V, Verma M, Yadav R, Maria Das K J, Kumar S. Objective and subjective assessment of xerostomia in patients of locally advanced head-and-neck cancers treated by intensity-modulated radiotherapy. J Can Res Ther [serial online] 2018 [cited 2019 Sep 21];14:1196-201. Available from: http://www.cancerjournal.net/text.asp?2018/14/6/1196/228635




 > Introduction Top


Nearly 1½ L of saliva is produced daily in our oral cavity, of which 20% (watery) is contributed from the parotid salivary glands (at rest), 70% (moderately viscous) from both submandibular salivary glands, 5% (viscous) from a pair of sublingual salivary glands, and remaining 5% from lingual and other minor salivary glands. Saliva contains mucins and glycoproteins that lubricate the food, assist in swallowing, and also protect the oral mucosa. It also contains IgA, the first immunologic defense against bacteria and viruses, lysozyme which attacks on wall of bacteria, lactoferrin which binds iron and is bacteriostatic, and proline-rich proteins that protect tooth enamel and bind toxic tannins. To sum up, saliva helps in digestion, swallowing, and keeping the mouth wet which helps in speech. It also maintains oral cavity pathogen-free and serves as a solvent for the molecules that stimulate the taste buds. This is why patients suffering from xerostomia have a higher than normal incidence of dental caries and distaste for food. Buffers in the saliva help maintain the oral pH at about 7.0 and it also helps neutralize gastric acid when the gastric juice is regurgitated into the esophagus.

Receiving radiotherapy (RT) to the face and neck region is the most common cause of xerostomia. This is due to unavoidable irradiation of the salivary glands. Conventional RT (CRT) unnecessarily irradiates the parotid glands in head-and-neck cancer (HNC) patients since RT is usually delivered by two opposed lateral fields. Intensity-modulated RT (IMRT) has the potential to reduce the dose to the adjacent normal tissue without compromising the dose to the tumor-bearing region. In fact, parotid gland sparing is the most important endpoint, in which the IMRT scores over conventional technique.[1],[2],[3],[4],[5],[6],[7],[8],[9]

Xerostomia is the most debilitating side effect after irradiation of the head-and-neck region[10],[11],[12] and has a significant adverse effect on health-related quality of life (QOL).[13],[14] Radiation induces a decrease in the salivary output and a change in the salivary composition, resulting in the sense of a dry mouth and sticky saliva.[15],[16] Salivary dysfunction may result in considerable additional morbidity, including severe oral discomfort, problems with speaking, dysphagia, and increased incidence of caries and mucosal infections.[16] After 1 year of completion of treatment, saliva flow rate from unirradiated and low-dose irradiated volumes of parotid gland start to compensate and increase the baseline flow rate. Despite an objective increase in flow rate, the patient's subjectivity for dryness and stickiness may not improve.

In a study by Eisbruch et al., the dose, irradiated volumes, and salivary output from the parotid glands through 1 year after RT were correlated.[9] A threshold effect was found at around a mean dose of 26 Gy.[9] It has been seen that dosimetric sparing of parotid gland does translate into subjective and objective improvement in the salivary gland function.[17] Objective assessment of parotid gland sparing is done by quantitative assessment of stimulated and unstimulated saliva.

Subjective assessment is done using health-related QOL questionnaires such as EORTC-HN35. QOL questionnaires have been utilized for several years in the follow-up of patients with HNC, and impaired QOL has been reported until years after RT.[18],[19] Following RT, xerostomia-related QOL scores may or may not follow the salivary flow rates.[10],[20]

We performed a prospective study in patients with HNC receiving RT using IMRT technique with the aim to assess the salivary flow rate and QOL, before and after RT, and most importantly to correlate the subjective perception of dryness with objective saliva flow measurements, up to 12 months following completion of treatment.


 > Materials and Methods Top


A prospective study was carried out from August 2009 to October 2011. The study was approved by the Institutional Ethics Committee. Informed consent was taken from all patients.

Previously untreated, histology-proven, AJCC Stage III and IV HNC patients with Karnofsky performance scale of 80 or more were included. All patients were counselled for oro-dental hygiene and nutrition. Patients who received chemotherapy were excluded from the study. All these patients were treated with IMRT using simultaneous integrated boost (SIB) technique. High-risk clinical target volume (CTV) (covering gross tumor with margins) was given a dose of 66 Gy/30 fr (at 2.2 Gy/fraction), intermediate-risk CTV (encompassing the entire anatomical compartment) 60 Gy/30 fr (at 2.0 Gy/fraction), and low-risk CTV (for subclinical disease) 54 Gy/30 fr (at 1.8 Gy/fraction). All of them were treated by 1 week of acceleration using SIB-IMRT technique delivery by 6 MV photons from a linear accelerator. Five fractions were delivered in a week over 6 weeks. During RT, patients were seen by a radiation oncologist at least once a week. Subjective recording of treatment toxicity (according to the Radiation Therapy Oncology Group criteria) and weight loss was done at weekly intervals by the oncologists. Patients were followed up at regular interval once the treatment was complete.

Objective assessment of saliva flow rate was done by quantifying whole saliva over 5 min at baseline and 3, 6, and 12 months post-RT. Detailed procedure of saliva collection (both stimulated and unstimulated) is mentioned in our previous published work.[21] Parotid flow rates and QOL measurements were taken at the same time points. Comparison was done between subjective (QOL) and objective assessment (whole saliva). Follow-up measurements were compared with baseline data.

Subjective evaluation of patients' perception of dry mouth and stickiness was done by EORTC-QLQ HN35 manual version 3.0. Permission from EORTC office was taken for the same after Hindi translation and validation. Patients were apprised about the questionnaire, due permission sought, and were advised to fill it independently. Question number 11 and 12 were specifically pertaining to dryness of mouth. For each parameter studied, for instance dryness of mouth in this study, a formula was used for calculating symptom score. Raw scores (RSs); RS = (I1 + I2 + I3+… +In)/n. Symptom scales (SSs): The values ranged from 1 to 4; SS = ([RS − 1]/range) × 100. All the scores were measured in the 0–100 scale. A high score for the SS represents a low QOL.

Statistical analysis

Differences between mean scores of subjective and objective assessment of xerostomia between same and different group were tested with unpaired t-test and paired t-test or nonparametric tests when appropriate. Logistic regression analyses were performed to study the association correlation between objective assessment (salivary flow rate) and subjective assessment (stickiness and dryness) at 3, 6, and 12 months after completion of RT. All analyses were performed using SPSS for Windows (version 6; SPSS Inc., Chicago, IL, USA).


 > Results Top


This study included 20 patients moderately advanced HNC (Stage III and resectable, i.e., Stage IVa patients). The median follow-up of this study is 12 months. [Table 1] depicts demographic characteristics of all patients. All patients received RT alone using SIB-IMRT technique. Dose prescription to high-risk planning target volume (PTV) was 66 Gy in 30 fractions with a dose rate of 2.2 Gy per fraction in 6-week time, while low-risk PTV was prescribed to a dose of 54 Gy in 30 fractions at the dose rate of 1.8 Gy per fraction. Modest acceleration of 1 week was an integral part of SIB boost. Dosimetric parameters, i.e., PTV coverage and mean dose to contralateral (C/L) and ipsilateral (I/L) parotid glands were studied using dose–volume histogram criteria. Mean D95 for PTV is 97%. Mean volume to the right and left parotid is 25.44 cc and 25.17 cc, respectively. A mean dose of 31 Gy and 25 Gy for the I/L and C/L parotid gland, respectively, was documented. The mean percent volume of the parotid glands receiving ≥30 Gy (V30) was 47% and 39% for the right and left parotid gland, respectively. The mean percent volume of the parotid glands receiving ≥45 Gy (V45) was 32% and 24% (right and left parotid glands, respectively) [Table 2].
Table 1: Demographic characteristics of patients

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Table 2: Dose-volume histogram parameters for parotid glands

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Acute toxicity in the form of mucositis, dysphagia, etc., was assessed and documented at weekly intervals while the patients were on the treatment. Grade II acute mucositis in 11 patients and 9 patients had grade III mucositis. None of the patients had significant weight loss (>10% of body weight) during RT. Out of 20 patients, five patients required nasogastric tube feeding by the 4th week of RT, due to increasing degree of dysphagia (grade III and above) [Table 3].
Table 3: Maximum score for mucositis during radiotherapy treatment as per the radiation therapy oncology group scoring criteria (n=20)

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At present, of these 20 patients, eight are alive, seven lost to follow-up, and five are dead. Out of 8 live patients, six are doing well while two had locoregional recurrence [Table 4]. Out of five dead patients, three died after locoregionally failure, one developed metastasis in the lung, while one succumbed because of aspiration pneumonia after 32 months of follow-up with locally no evidence of disease. Three patients were fine at the time of the last follow-up, and subsequently, they were lost to follow-up, while four were lost to follow-up after developing regional failures.
Table 4: Status at last follow-up

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Saliva estimation and assessment of QOL (objective and subjective assessment) at baseline were done in all patients, at 3 months after RT evaluation were possible in 16 patients, at 6 months after RT evaluation were in 12 patients, and at 12 months after RT evaluation were in 8 patients. Baseline unstimulated and stimulated salivary flow rates were 0.659 ml/min and 1.69 ml/min, respectively. At 3 months, a significant reduction in unstimulated (0.346 ml/min) (P = 0.046) and stimulated (0.80 ml/min) (P = 0.002) flow rate was observed. Unstimulated flow rate continued to decrease further till 6 months (0.295 ml/min) (P = 0.042), but slight improvement was seen in stimulated flow rate (0.91 ml/min) (P = 0.012). At 12 months, minimal recovery was observed in both unstimulated (0.362 ml/min) (P = 0.180) and stimulated flow rates (1.09 ml/min) (P = 0.191). EORTC-QOL-HN35 questionnaire mean scores for dryness and stickiness of saliva were 10 and 15 at baseline, and both these mean scores increased to 36 and 25, respectively, at 3 months (implying worsening of symptoms). At 6 months, symptom score for dryness further increased to 45 and then decreased to 33 at 12 months. Stickiness score remained static from 3 to 12 months. [Table 5] and [Figure 1] depict the unstimulated and stimulated salivary flow rate and EORTC-QOL questionnaire mean scores for dryness and stickiness of saliva at baseline and 3, 6, and 12 months. Salivary flow rate correlated well with dry mouth (P < 0.05) but not with perception of sticky saliva (P = 0.82), at 6 months and beyond. We also analysed average doses of I/L and C/L parotid glands and salivary flow rates according to the subsites (oropharynx and laryngopharynx). In oropharyngeal cancer, the mean dose to I/L parotid gland was 40 Gy as opposed to laryngopharynx primaries, where it was 27 Gy (P = 0.01). Average dose to C/L parotid gland and salivary flow rates (unstimulated as well as stimulated) were not significantly different in these two subsites [Table 6].
Table 5: Temporal changes during follow up in unstimulated and stimulated saliva flow rates and symptomatic scores using QLQ HN35 questionnaire

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Figure 1: Temporal changes in saliva flow rates. Unstimulated saliva flow rate and stimulated saliva flow rate and symptomatic scores for dryness (HNDR) and stickiness (HNSS) during follow-up at 3, 6, and 12 months after radiotherapy

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Table 6: Site-wise mean parotid dose and salivary flow rates

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 > Discussion Top


In this study, C/L parotid gland could be effectively spared from the permanent effect of radiation (with mean dose of 25 Gy). Objective assessment showed that saliva flow rate both unstimulated as well as stimulated saliva reduced to half of the baseline at 3 months following treatment. Unstimulated saliva flow rate further decreased at 6 months, while stimulated saliva flow rate showed slight improvement. At 12 months, both unstimulated and stimulated saliva flow rates showed improvement and the values reached up to half and three-fourth of the baseline values in unstimulated and stimulated saliva, respectively. Subjectively, EORTC-QLQ-HN35 score showed that patients perceived worsening of symptoms up to 1.5–3.5 times of baseline value at 3 months following treatment and continued to feel worse at 6 months (up to 4.5 times of baseline) and then started to show improvement by 12 months (returning back to 1.5–3 times of baseline).

RT of HNC patients cited xerostomia as the most prevalent long-term treatment side effect and as a major factor contributing to reduce QOL.[10],[18],[19],[20] Improvement of xerostomia over time was noted in both patient groups receiving parotid-sparing bilateral or unilateral neck RT. In a study by Eisbruch et al., the dose, irradiated volumes, and salivary output from the parotid glands through 1 year following RT were correlated.[9] A threshold effect was found around a mean dose of 26 Gy. Parotid glands receiving a lower mean dose showed a time-related recovery, whereas most glands receiving a higher dose produced no measurable salivary output and with no sign of recovery in the future. The results of this study suggested that the effort to spare the major C/L and I/L glands can gain meaningful improvement of both objective and subjective feeling of dryness of mouth with time. Eisbruch et al. observed significant recovery over time with parotid-sparing IMRT. A mean threshold dose for both unstimulated and stimulated parotid saliva flow rate to reduce the saliva to <:25% of the pretreatment level was 24 and 26 Gy, respectively. Portions of the glands receiving a lower mean dose showed time-related recovery, whereas most glands receiving a higher dose produced no measurable output and did not recover with time.[22]

Garden et al. have shown that doses of 35–45 Gy to at least 90% parotid reduced the salivary output to 10% of the baseline value by 6 weeks, but recovery up to 30% of the basal flow rate occurred during the 1st year.[23]

PARSPORT trial showed grade II or worse xerostomia at 12 months was significantly lower in the IMRT group than in the CRT group (25 [74%; 95% confidence interval (CI) 56–87] of 34 patients given CRT vs. 15 [38%; 95% CI 23–55] of 39 given IMRT, P = 0·0027). At 24 months, grade II or worse xerostomia was significantly less common with IMRT than with CRT (20 [83%; 95% CI 63–95] of 24 patients given CRT vs. 9 [29%; 14–48] of 31 given IMRT; P < 0·0001). At 12 and 24 months, significant benefits were seen in the recovery of saliva secretion with IMRT compared with CRT as were clinically significant improvements in dry mouth-specific and global QOL scores.[17]

As regards, the method of measurement in the present study was total saliva estimation from all the salivary glands together; however, techniques of salivary output by a single parotid gland using Lashley cups have been attempted by some studies.[9] Lashley cup method is considered robust, easy to use, noninvasive, and nonexpensive, simulating a physiological situation and showed the smallest variability for measuring the salivary flow rate from a single parotid gland.[22],[24] Salivary gland scintigraphy seems to be a good indicator of gland function, but it is an expensive test and requires hospital equipment. In our set up, we found it easiest, simple, and cheapest method to assess total salivary flow rate by simple quantification also because Lashley cups were not available.

In a previous study from the department, a significant reduction in both stimulated and unstimulated salivary flow rate was observed when conventional chemo-RT was used in HNCs. The study showed salivary flow rates fell to one-fourth of the baseline value, with minimal recovery at 12 months following completion of treatment.[21] However in the present study the salivary flow rate fell to half of the baseline value with minimal recovery after 12 months following completion of RT by IMRT technique. This fall and recovery of saliva correlated well with dry mouth (P < 0.05) but not with perception of sticky saliva (P = 0.82) at 6 months and beyond. Vergeer et al. also reported salivary functions in terms of stimulated whole salivary and parotid flow, as well as patient-rated xerostomia and sticky saliva (EORTC-QLQ-HN35) were significantly better after IMRT.[25]

Henson et al. found that the xerostomia-related QOL scores followed the general pattern of parotid flow rates, till 1 year of follow-up.[26] Parliament et al. reported an inverse correlation between the unstimulated and stimulated whole salivary flow and xerostomia-specific items at 1 month, which disappeared 3 months and 12 months after treatment.[27] Blanco et al. found a strong correlation between the stimulated salivary function and the QOL scores 6 months after RT and a nonsignificant trend toward improvement in the mean QOL scores. As regards the subjective scores, dry mouth as established early after RT could be defined as a complication. When the subjective score for xerostomia and sticky saliva is used, it is argued that the role of the minor salivary glands in xerostomia should be taken into account. Alterations in submandibular and/or sublingual function may have the greatest impact on the sensation of oral dryness. The mucins are not found in the parotid secretions and may be an important component for imparting a sense of wetness and comfort to chewing and swallowing.[28] However, more recent studies showed a normal unstimulated salivary flow in patients after surgical resection of the submandibular glands or delivery of high radiation doses.[27]

The strengths of the present study are that it is a prospective study representing all head-and-neck subsites. There are however a few limitations as well – salivary flow rate of both parotid glands was taken together, and therefore, individual contribution of each gland could not be determined. Patients number is less and therefore we are unable to analyze the effect of site, T and N stage on either objective or subjective saliva estimation.

We also found a strong correlation between stimulated/unstimulated saliva reduction and the change in QOL scores. It has been reported that xerostomia is a subjective symptom of oral dryness and does not always correlate with actual salivary gland flow rate.[29],[30] In contrast, we have found significant correlation of dryness with salivary flow rate but not with stickiness.


 > Conclusions Top


Sparing parotid glands translate into objective and subjective improvement of both xerostomia and QOL scores in patients with HNCs receiving radiation therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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