|Year : 2011 | Volume
| Issue : 3 | Page : 289-295
Whole saliva physico-biochemical changes and quality of life in head and neck cancer patients following conventional radiation therapy: A prospective longitudinal study
MS Tiwana1, MK Mahajan1, B Uppal2, G Koshy3, J Sachdeva1, HN Lee1, SD Talole4
1 Department of Radiation Oncology, Christian Medical College and Hospital, Ludhiana, India
2 Department of Biochemistry, Christian Medical College and Hospital, Ludhiana, India
3 Department of Oral Pathology and Microbiology, Christian Medical College and Hospital, Ludhiana, India
4 Department of Medical Records, Biostatistics and Epidemiology, Tata Memorial Hospital, Parel, Mumbai, India
|Date of Web Publication||14-Sep-2011|
M S Tiwana
Department of Radiation Oncology, Christian Medical College and Hospital, Ludhiana
Source of Support: None, Conflict of Interest: None
Background: We investigated the physico-biochemical changes in saliva and its relation to quality of life (QOL) in head and neck cancer patients following conventional radiation therapy (RT). Materials and Methods: 53 consecutive head and neck cancer patients underwent conventional RT using telecobalt photons. We analyzed objective sialometry and sialochemical parameters of salivary gland function and a physician reported Oral Assessment Protocol to assess the patients' QOL during (baseline, 3 and 6 weeks) and post RT (3 and 6 months). Statistical analysis was done using SPSS software (version 15.0; SPSS, Inc., Chicago, IL, USA). Results: Stimulated salivary flow rates had shown a consistent decline during and in post-RT analysis (P < 0.001). A significant correlation was seen between mean salivary flow rates at 6 months post-RT and mean salivary electrolytes and amylase levels during the same period (P < 0.001). Mean global QOL scores had significantly worsened during RT and were still significantly poorer at 6 months than initial pre-RT levels (P < 0.001). Further, significant correlation was established between salivary pH values with global QOL scores at 6 months (P = 0.05). Conclusions: Radiation-induced hyposalivation invariably persists and correlates with poor global QOL scores seen during and following conventional RT. Post RT, there is a trend for biochemical reversal toward pre-irradiation levels suggesting a subsiding inflammation or a probable functional recovery.
Keywords: Head-neck cancer, quality of life, radiation therapy, saliva, xerostomia
|How to cite this article:|
Tiwana M S, Mahajan M K, Uppal B, Koshy G, Sachdeva J, Lee H N, Talole S D. Whole saliva physico-biochemical changes and quality of life in head and neck cancer patients following conventional radiation therapy: A prospective longitudinal study. Indian J Cancer 2011;48:289-95
|How to cite this URL:|
Tiwana M S, Mahajan M K, Uppal B, Koshy G, Sachdeva J, Lee H N, Talole S D. Whole saliva physico-biochemical changes and quality of life in head and neck cancer patients following conventional radiation therapy: A prospective longitudinal study. Indian J Cancer [serial online] 2011 [cited 2018 Aug 21];48:289-95. Available from: http://www.indianjcancer.com/text.asp?2011/48/3/289/84918
| » Introduction|| |
The ultimate aim of managing head-neck cancer is to maximize treatment efficacy without increasing the toxicity. Head and neck squamous cell cancer (HNSCC) management involves newer approaches like induction chemotherapy, altered fractionation radiation with chemotherapy, intensity modulated radiation therapy (IMRT) and the use of biologically targeted drugs to achieve this goal.  However, despite following strict radiotherapy planning and adopting modern techniques, so as to confine the radiation to the tumor and minimize the dose to normal tissues, invariably some normal tissue is included in target volume to cover microscopic spread beyond the visible limits of the tumor.  Because of the location of the primary tumors, the target volume invariably includes the salivary glands, oral cavity, and mandible in the treatment portals.  As a result, changes induced by exposure to radiation occur in these critical tissues, leading to mucositis, hyposalivation, radiation-induced caries, taste loss, trismus, soft tissue necrosis and osteoradionecrosis.  These oral sequelae, especially late toxicity like xerostomia, may cause substantial problems during and after radiation therapy (RT) and are major causes of decreased quality of life (QOL).  It is an even more pertinent issue to radiation oncology centers in developing nations which have a limitation to advanced conformal techniques involved in sparing of critical normal tissues. Certainly, clinical benefits have been reported from studies incorporating sparing of major salivary glands which unequivocally demonstrate an improved symptom of xerostomia over time.  Most of the studies document physical decrease, but the changes in biochemical composition of saliva like altered viscosity, pH, protein and electrolyte concentrations equally affect the oral health which may necessitate an adjustment or an interruption of radiation treatment schedule. ,
The extent to which radiation induces biochemical alteration in saliva and its impact on QOL has not been well documented. To determine the magnitude and whether the radiation-induced salivary physico-biochemical variation will affect the QOL, a prospective study of these parameters has been carried out in patients given RT for head and neck cancer. The primary objective of the study was to analyze the physical and biochemical parameters of whole saliva in these patients during and post RT. Secondly, the QOL was estimated during the same period and any possible correlation to the measured primary objectives was noted and rationalized.
| » Materials and Methods|| |
The prospective study was conducted on 53 consecutive head and neck cancer patients treated at our hospital between March 2003 and May 2005. The study presented is a part of dissertation approved by the Institutional Review Board of our hospital.
All the patients underwent complete dental evaluation, oral treatment and prophylaxis prior to start of treatment and during the course of RT, and followed till the last follow-up assessment of the protocol patient. Detailed oral examinations and treatment were done at the Department of Dentistry at our hospital. The patients were maintained on daily fluoride applications and use of oral rinse preparations composed chiefly of carboxymethyl cellulose and pure glycerine in a normal saline base, to maintain an optimal oral hygiene.
As per the institutional practice, patients of head and neck cancer planned for radical treatment were managed with concurrent chemo-radiation protocols. Patients were given external beam radiotherapy with Theratron 80R® Cobalt-60 at 80 cm source to surface distance (SSD). A total tumor dose of 60-70 Gy was prescribed in 30-35 fractions over 6-7 weeks as per the protocol. They received primary RT fields covering all major salivary glands. Target volume was defined and dose homogenization was achieved with individualized wedges and compensators using aluminum blocks. Due to limited infrastructure, critical organ volumes and sparing beyond the conventional planning were not incorporated into the two-dimensional simulation process. Concomitant chemotherapy, where indicated, used cisplatin infusion at 50 mg/m2 on days 1, 22 and 42, and 5-fluorouracil (5-FU) at 500 mg twice weekly during the RT period.
Objective assessment of salivary gland function
Sialometry and sialochemistry were done at 0, 3 and 6 weeks of treatment and at 3 and 6 months in the follow-up period. Every attempt was undertaken to prohibit usage of any salivary stimulant or xerostomia inducing agent, unless medically indicated. Patients were recruited only after a medical evaluation ruled out any connective tissue disorder or endocrine ailment which would otherwise alter the normal salivary gland function.
No intake of food or oral stimulus was permitted for 90 min before saliva collection. Unstimulated whole saliva was collected in a graduated glass tube with gradation of 0.1 ml during a 5-min period. Stimulated whole saliva was collected by applying two to three drops of 2% citric acid solution over dorsum of the tongue bilaterally at 30-second intervals for a 2-min period, followed by a 5-min collection period during which gustatory stimulation was maintained. Flow rate for the whole saliva was recorded as ml/min and this constituted the physical evaluation of whole saliva.
Salivary constituents were analyzed in stimulated samples with adequate volume. The pH, total protein, sodium, potassium, chloride and amylase concentrations were the biochemical parameters analyzed, which required a detailed laboratory analysis in the biochemistry department. The pH was estimated using Universal pH Indicator strip with a range of 2-10, although the sampling being done in an open system was considered as a limitation. Total proteins (g/l) were analyzed on Hitachi 902 Automated Analyzer based on colorimetric assay. Amylase (U/l) assessment was done using kits from ACCUREX® ; sample was fed through Aspirator of Erba Chem 5 plus (TRANS ASIA®) and result was estimated in 3 min. Electrolytes (mmol/l), i.e., sodium (Na+), potassium (K+) and chloride (Cl−), were analyzed on Easy Light Plus® (ISE) analyzer directly.
Physician-reported oral assessment protocol
After a detailed literature search of xerostomia-specific and general head and neck cancer QOL instruments and discussions with Head and Neck Oncology unit, a detailed oral assessment protocol questionnaire was developed as specified in [Table 1]. ,, However, the protocol was not validated at the inception of this study in our institute. Though a uniform consensus is favored toward adoption of patient reported instrument for assessment of treatment sequelae following RT, we felt it otherwise, considering our patients' level of education and understanding. ,
The Oral Assessment Protocol comprised both subjective and objective parameters relating to the status of mucous membranes, asking about difficulties in swallowing, nidus of infection if any, oro-dental health, physical assessment of salivary secretion and levels of comfort. The questionnaire was filled before RT, every week during the course of RT, and at 3 and 6 months of follow-up. Each item score was added at the time of analysis, and the sum global score was transformed linearly to produce the final summary scores ranging between 0 and 16. A higher mean global score corresponds to worsening of QOL for the patient, which is quite expected during the course of RT.
The objective sialometry and sialochemical variation, and global oral assessment scores over the different time intervals were analyzed graphically and through application of repeated measures of analysis of variance (one-way ANOVA post-hoc range tests). Assuming equal variance, multiple comparison Bonferroni test was used and the group means were considered significant at an alpha level of 0.05. Additionally, "t" test was used for binary variable statistical assessment.
Any correlation between the objective salivary gland function and global scores was examined graphically and also using Pearson correlation coefficient (r). In assessing these relationships, if a nonlinear relationship appeared to have a better fit, regression analysis was done using the global scores as the dependent variable. Statistical analysis was done using SPSS software (version 15.0; SPSS, Inc., Chicago, IL, USA).
| » Results|| |
The patient and treatment-related characteristics have been highlighted in [Table 2]. The mean sialometric flow rates and sialochemical variables have been tabulated in [Table 3]. A total of 50 (93%) patients at 6 weeks and 42 (79%) patients at 6 months were available for final analysis.
|Table 3: Mean values of sialometry and sialochemical variables, and mean global QOL scores pre, during and after radiotherapy|
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Stimulated salivary flow rates had shown a consistent decline during and post RT analysis as depicted in [Figure 1]. At 6 weeks of RT, there was a statistically significant reduction in mean flow rates in comparison to the baseline estimates (P < 0.001). Post RT at 3 and 6 months, the salivary flow rates showed a further significant reduction (P < 0.001). However, the flow rates did not decrease statistically between 3 and 6 months. Salivary flow reduction at 6 weeks and 6 months were 41.2 and 82.4%, respectively, in relation to baseline flow rates. At 6 months, 39% of the evaluable patients had a salivary flow rate of less than 0.01 ml/min.
|Figure 1: Mean salivary electrolyte concentrations over the study period|
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During RT, the mean pH values of stimulated saliva indicated a trend toward having a more acidic nature, with significant decline at 6 weeks of radiation (P < 0.05). Post RT at 3 months, the mean pH levels showed a reversal to alkaline form, though not significant statistically. There was a significant rise in pH of saliva between 6 weeks of evaluation and post-RT analysis at 6 months (P < 0.05). At 6 months, the saliva attained near baseline mean pH values [Table 3].
At 6 weeks of RT, mean salivary total proteins had decreased from pre-irradiation levels, though not significantly (P = 0.12). Post RT at 6 months, the total proteins did recover toward pre-radiation levels, but again not significantly. Salivary mean amylase levels drastically reduced at 6 weeks of RT (P = 0.07). The post-RT amylase concentration in saliva was higher than the pre-irradiation levels, though not statistically impressive (P = 0.95).
The variation in salivary electrolytes did show a positive correlation at 6 weeks (P<0.01). However, salivary flow rates and sialochemical parameters did not depict any significant correlation at 6 weeks assessment. Mean salivary electrolyte Na+ and Cl− levels had increased during and post RT at 6 weeks and 3 months, respectively [Figure 1]. However, a mean increase of 23.28 mEq/l in salivary Na+ concentration was significant at 6 weeks in comparison to baseline values Post RT at 6 months, both Na+ and Cl− strived toward pre-radiation baseline concentrations, but were not statically significant (P = 1.0). Mean K+ concentration had decreased by 7.60 mEq/l at 6 weeks of RT (P < 0.05). A further significant fall of 8.15 mEq/l was noticed at 6 months post-RT (P < 0.05) [Figure 1]. A significant correlation was seen between mean salivary flow rates at 6 months post-RT and mean salivary electrolytes and amylase levels during the same period (P < 0.001).
| » Physician-Reported oral Assessment Protocol and Global Quality of Life Scores|| |
Mean global scores had significantly worsened during RT assessment (P < 0.001). Although the quality of assessment global scores showed a trend of recovery post RT at 6 months, they were still significantly poorer than initial pre-radiation therapy levels (P < 0.001). Each item on the Oral Assessment Protocol [Table 1] was independently analyzed during and post RT. [Figure 2] shows the individual variation of each item on this protocol over the study period. During RT at 6 weeks, mucosa state, discomfort levels, xerostomia symptoms and difficulty in chewing had worsened significantly (P < 0.001). However, at 6 months, these symptoms barring xerostomia had recovered significantly in comparison to assessment at 6 weeks (P < 0.001). Symptoms related to oral dryness had slightly progressed to worsening at 6 months in comparison to evaluation at 6 weeks of RT, although at nonsignificant levels (P = 1.0). The variation of mean global scores of each item on the Oral Assessment Protocol during the study period is depicted in [Figure 3]. A strong correlation was established between salivary pH values with global QOL scores at 6 months (P = 0.05) [Figure 3].
|Figure 2: Distribution of each item on the Oral Assessment Protocol over the study period, presented as mean global scores|
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|Figure 3: Mean values line plot for global QOL scores, pH and stimulated salivary flow rates|
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| » Discussion|| |
Researchers have extensively studied the salivary gland function in patients with established radiation-induced xerostomia. ,, However, we analyzed the whole salivary physical and biochemical parameters during the course and following curative RT doses delivered through conventional cobalt-based teletherapy unit. Additionally, we made an attempt to understand the relation of QOL parameters not only to the physical attributes but also to the relatively undocumented biochemical salivary variables.
In our study, stimulated salivary flow rates demonstrated a significant decline, shift to more acidic pH, higher salinity, falling proteins and amylase concentrations at 6 weeks of RT. It is consistent with the reported reduction of 83.3% in stimulated saliva flow after 6 weeks of radiotherapy, further decreasing to 93.4% 3 months post-radiotherapy.  The decrease in salivary flow rates is histologically confirmed by showing that the parenchyma and supporting connective tissues exhibit an initial acute inflammation followed by a progressive loss of secretory acini, fibrosis and atrophy.  Additionally, the salivary electrolyte changes in our study concur with established studies. ,, The hypothesis related to the rise in salivary sodium and chloride concentrations is that radiation reduces the resorption ability of salivary gland tubuli.  Furthermore, the shift to acidic pH is supported by the reduced buffering capacity of saliva as a result of radiation injury. , The fall in salivary total proteins is consistent with results showing the decline during irradiation phase. ,, The fall in proteins and amylase levels during RT possibly correlates with the decreasing salivary flow rates. Salivary amylase has an acinar cell origin and reflects the overall functional integrity of the salivary glands.  Hence, a fall in amylase levels in our study suggests an acute radiation-induced acinar cell injury.
Post-RT analysis revealed progressive declining salivary flow rates, though not significantly between 3 and 6 months. Biochemical parameters showed a trend of reversal with an alkaline pH, less salinity, rising protein and amylase concentrations in relation to pre-irradiation levels, although not significant statistically. At 6 months, a significant correlation was seen between salivary flow rates and salivary electrolyte and amylase concentrations. A higher protein and amylase and elevated electrolytes post RT are attributed more to lower salivary volumes rather than a salivary gland recovery. Researchers have correlated similar findings to the role of chronic periductal inflammation.  Amylase itself serves as an indicator of protein synthesis in the acinar cells.  The fall in salivary total protein and amylase concentration could possibly further reflect the injury to salivary glandular tissue. This observation clinically correlates to the significant incidence of mucositis and candidiasis seen during the course of RT, as evident in our evaluation. Although a statistical correlation was ruled out, this reflects the biochemical relation to the clinical items on the QOL scale. Perhaps, a longer follow-up and larger patient population would further rationalize the statistical evaluation. After completion of RT, the rise in amylase and salivary total proteins, as seen in our study, serves as an indicator of reduction of acute inflammatory processes due to settling of radiation-induced reactions and the control of infections.
Global QOL significantly worsened through RT in our study but recovered post RT, although still significantly poorer than pre-irradiation levels. However, besides a persistent symptom of oral dryness at 6 months assessment, the remaining items on the Oral Assessment Protocol significantly improved than at 6-weeks mean scores.
Mucositis generally persists throughout radiotherapy and peaks at the end of the irradiation period, and continues for over 3 weeks after the treatment has ceased. 
Symptom of pain increases throughout the course of RT and persists following treatment and in some patients for 6-12 months.  The occurrence of radiation induced dysphagia, increased dental sensitivity and difficulty in chewing was due to the effects of hyposalivation. ,,,
Though the trend of physical and biochemical salivary variables closely follows the global QOL scores, a larger patient population, additional control group and a longer follow-up would probably establish adequate statistical power. Studies with a longer follow-up at 5 years have significantly correlated the recovery of salivary gland flow ratio to the recovery of dry mouth feeling, but the overall global QOL remained high.  But we must be aware of the fact that salivary gland injury and recovery from irradiation relies on time, radiation dose, residual salivary gland function and implementation of newer salivary gland sparing techniques like IMRT. , A few serious drawbacks of our study have been that whole saliva evaluation has limitation in its interpretation owing to contamination with oral mucosal constituents. Secondly, salivary flow rate and composition could be altered due to multifactorial causes, the prominent being patient's nutritional and hydration status, and also varies with the concurrent usage of chemotherapy drugs along with RT. These confounding factors need to be properly addressed in drafting future prospective studies addressing similar issues in head and neck cancer patients. Although the volume of salivary gland tissue exposed is an important determinant of salivary dysfunction and xerostomia, due to logistical and conventional teletherapy unit, we were not able to constrain the volume of major salivary gland included in our radiation portals.  With the conventional RT treatment in this study, 39% of the patients at 6 months had frank xerostomia with salivary flow at less than 0.1 ml/min. This study should serve as a guiding tool to radiation oncologists with limited resource settings wherein QOL for head-neck cancer patients is a concern.
Although the biochemical recovery starts at 3 months post RT, a persistent physical decreasing salivary volume overall reflects and determines the QOL of patients, essentially xerostomia related QOL. A longer fixed time period assessment would guide us to ascertain the conventional RT toxicity to the normal tissues, essentially salivary glands in head-neck cancer patients.
| » Conclusions|| |
Radiation-induced hyposalivation invariably persists and correlates with poor global QOL scores seen during and following conventional RT. Post RT, there is a trend for biochemical reversal toward pre-irradiation, suggesting a subsiding inflammation or a probable functional recovery. A possible relation of salivary biochemical parameters to QOL scores would probably reflect statistically in a larger patient population with a longer follow-up period.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]
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