Japanese Journal of Clinical Oncology 33:336-340 (2003)
© 2003 Foundation for Promotion of Cancer Research
The Changes in Irradiated Salivary Gland Function of Patients with Head and Neck Tumors Treated with Radiotherapy
Department of Radiology, Sapporo Medical University, School of Medicine, Sapporo, Japan
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ABSTRACT |
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Background: To investigate and analyze changes in irradiated salivary gland function of patients with head and neck tumors treated with radiotherapy.
Methods: Thirty-seven patients with head and neck tumors, who received 40–70 Gy of irradiation to all major salivary glands, were analyzed. The weights of saliva secreted for 10 minutes at rest, and for 5 minutes with vitamin C stimulation, were measured. The salivary gland function was defined by the weight of saliva.
Results: With vitamin C stimulation, the weight of saliva in patients whose doses were 
50 Gy, was significantly higher than that of patients whose doses were 
58 Gy (2.48 ± 0.33 g vs. 0.73 ± 0.18 g, P = 0.0003). When doses administered to salivary glands were 50 Gy, the stimulated saliva secretion recovered over time, after irradiation. However, when the doses of irradiation were 58 Gy, there was no recovery in saliva secretion even after a few years. Multiple regression analysis showed that age and chemotherapy may not affect salivary gland function even years after radiotherapy.
Conclusion: When salivary glands were irradiated with doses 50 Gy, gradual recovery of salivary gland function was observed over time, whereas there was no significant recovery when the irradiation dose was >58 Gy.
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INTRODUCTION |
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Radiotherapy plays an important role in the treatment of head and neck tumors, not only in local tumor control, but also in conserving functions such as speech, chewing, and swallowing. Higher doses of radiation are needed for better local tumor control, however its toxicity to normal tissue limits dose escalation. One of the most common complications in patients with head and neck tumors treated with radiotherapy, is xerostomia, which is caused by irradiation of the salivary glands (1,2).
When salivary glands are irradiated, salivary flow is reduced considerably. If the irradiation doses are within certain limits, the salivary gland function gradually recovers, to some extent. However, the tolerance dose and the kinetics for recovery of salivary gland function are not adequately defined. We investigated and analyzed the changes in salivary gland function of patients with head and neck tumors post-radiotherapy.
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PATIENTS AND METHODS |
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Patients’ Characteristics
Patients’ characteristics are summarized in Table 1. In this study, from 1990 to 2001 we analyzed the salivary gland function of 37 patients with head and neck tumors, who received radical radiotherapy in our hospital, and achieved local tumor control. Of these 27 were males and 10 were females. Twenty-three had squamous cell carcinoma of the head and neck region, 13 had non-Hodgkin’s lymphoma, and one had solitary plasmacytoma. All patients received conventional radiotherapy (1.8–2 Gy/fraction daily, 5 times/week) with 60Co-
rays or 4MV X-rays, with parallel opposed lateral fields or anterior and posterior fields. Irradiation doses of 40 Gy were administered to all the major salivary glands. We reviewed the simulator film and confirmed that the major salivary glands, such as the parotid, submandibular, and the sublingual glands were included in the treatment fields. No patient had undergone surgery for the major salivary glands or was receiving any medication known to affect salivary gland function (e.g., tricyclic antidepressants, antihistamines with anticholinergic effects, or beta blockers). Chemotherapy was performed for 19 patients. Three courses of CHOP (cyclophosphamide, adriamycin, vincristine, and predonisone) were administered neoadjuvantly in 13 patients with non-Hodgkin’s lymphoma. Two courses of chemotherapy based on cisplatin and 5-FU, were administered either neoadjuvantly or concurrently in patients with nasopharyngeal cancer.
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To serve as a normal control, we also collected and weighed saliva from five normal healthy volunteers, and five laryngeal cancer patients treated with radiotherapy, but without irradiation of the salivary glands (non-irradiated group). Of these seven were males and three were females. Written and informed consent were obtained from each patient and volunteer in this study.
Salivary Gland Function Test
Patients refrained from eating or smoking 30 minutes prior to the test. Saliva was collected according to the following procedure: Two absorbent cotton balls were placed sublingually at the orifices of Wharton’s ducts for 10 minutes, and then the cotton balls that absorbed saliva were weighed. Subsequently, patients were instructed to chew a tablet of vitamin C (200 mg) to stimulate secretion of saliva. The weight of saliva secreted in 5 minutes was then determined. Salivary gland function was defined by the weight of saliva secreted in 10 minutes at rest and that in 5 minutes with vitamin C stimulation.
Statistical Methods
The two-sided unpaired t-test was used for comparison between normal controls and irradiated patients. Multiple regression analysis was used to examine significant predictors that affect salivary gland function, namely, age at radiotherapy, irradiation dose to salivary glands, combination with chemotherapy, and interval between termination of radiation and salivary gland function tests. All statistical computing was done in StatView version 4.58 (Abacus Concepts, Berkeley, CA).
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RESULTS |
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Irradiation Dose and Salivary Gland Function
Figure 1 shows the relationship between the irradiation dose to the salivary glands and the weight of saliva collected at rest. The weight of saliva secreted by the non-irradiated group ranged from 0.56 to 9.46 g/10 minutes (average, 2.77 g), and that of the irradiated group ranged from 0.04 to 2.04 g/10 minutes (average, 0.30 g). There was no difference in the weight of saliva among patients who received doses >40 Gy, indicating that spontaneous secretion of saliva from major salivary glands at rest was negligible with 40 Gy of irradiation.
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Figure 2 shows the relationship between the irradiation dose to the salivary glands and the weight of saliva collected with vitamin C stimulation. The weight of saliva secreted by the non-irradiated group with vitamin C stimulation ranged 2.22 to 21.79 g/5 minutes (average, 6.97 g), and that of the irradiated group ranged from 0.12 to 7.47 g/5 minutes (average, 1.77 g). With vitamin C stimulation, the weight of secreted saliva in 22 of 37 patients increased to over 1 g. In the group that received irradiation doses of 40–50 Gy, the weight of saliva in 19 of 22 patients also increased to over 1 g, with vitamin C stimulation. However, in the group that received irradiation doses
58 Gy, the weight of saliva in only three of 15 patients had increased to over 1 g, with vitamin C stimulation.
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Table 2 shows the relationship between irradiation dose and weight of saliva secreted at rest. The weight of saliva in the non-irradiated group was significantly higher than in the irradiated group (2.77 ± 0.95 g vs. 0.34 ± 0.12 g, P = 0.001). The weight of saliva at rest, in patients irradiated with doses
58 Gy appeared to be lower than in patients with doses of 40–50 Gy, although no significant difference was observed, which could be attributed to the small numbers of patients.
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Table 3 shows the relationship between irradiation dose and weight of saliva secreted with vitamin C stimulation, indicating that the weight of saliva in patients whose doses were 40–50 Gy was significantly higher than that of patients whose doses were
58 Gy (2.48 ± 0.33 g vs. 0.73 ± 0.18 g, P = 0.0003).
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Interval and Salivary Gland Function
Figure 3 shows the relationship between time after irradiation and the weight of saliva secreted after stimulation. When irradiation doses were 40–50 Gy, the stimulated saliva secretion tended to increase over time. However, when the doses were
58 Gy or more, there was no significant increase in saliva secretion, even after years.
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Multiple Regression Analysis
Table 4 shows the results of multiple regression analysis. The results of this analysis show that the irradiation dose to salivary glands (P = 0.023) and the interval between termination of radiation and salivary gland function test (P = 0.006), are significant predictors that affect salivary gland function. However, age at radiotherapy and combination with chemotherapy were not found to be significant predictors, and therefore may not affect salivary gland function even for years after radiotherapy.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Change In Salivary Gland Function after Radiotherapy
The serous cells of salivary glands (mainly parotid glands) are relatively sensitive to ionizing radiation, whereas the mucous cells are relatively resistant. When the salivary glands are irradiated, many patients observe a decrease in production of saliva and an increase in its viscosity within the first week of radiotherapy (1).
The early effects of radiotherapy result from interphase cell death of salivary serous cells, whereas late effects are determined by the ability to repopulate surviving stem cells (3–5). Emami et al. (6) estimated a TD 5/5 of 32 Gy and a TD 50/5 of 46 Gy following a partial or whole-organ irradiation of the parotid glands. However, these estimates were based on limited data in literature and the authors’ observations. Franzen et al. (7) noted that in patients receiving doses <52 Gy, all but one had a recovery of saliva secretion, which began 2 months after radiotherapy with a continuous improvement in the salivary flow for up to 18 months. Following administration of doses >64 Gy, parotid function was irreversibly diminished in the majority of the irradiated glands.
Our results also demonstrated that when the irradiation dose was 50 Gy, salivary gland function gradually recovered over time, whereas no significant recovery was observed when the dose was >58 Gy. These results indicate that the ability to produce saliva may be preserved when the salivary gland irradiation dose was 50 Gy, however, the function of the salivary glands is irreversibly damaged when the dose is >58 Gy.
We also found salivary gland function in patients treated with radiotherapy was not age or chemotherapy dependent. To the best of our knowledge there is no study that has documented age dependency and salivary gland function in radiotherapy.
Sparing Parotid Gland Dose Using IMRT
Two recently developed techniques that reduce xerostomia in patients irradiated for head and neck cancer are conformal radiotherapy (CRT) and intensity-modulated radiotherapy (IMRT), which can spare salivary gland tissue and enable the administration of a higher dose to the target (8–10).
Wu et al. presented examples of IMRT performed for four patients with head and neck tumors (10). Using nine to 15 beams from different angles, doses 60–70 Gy were administered to the primary tumors, whereas the percentage of parotid glands irradiated with a dose >32 Gy was reduced to 28–39%, which is sufficient for sparing salivary gland function. The use of radiation techniques such as CRT or IMRT to preserve salivary function seems promising, because our data demonstrated that doses 50 Gy could make the recovery of saliva secretion after radiotherapy possible.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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When salivary glands were irradiated with doses
40–50 Gy, gradual recovery of salivary gland function was observed over time, whereas there was no significant recovery when the irradiation dose was >58 Gy.
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FOOTNOTES |
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+ For reprints and all correspondence: Masanori Someya, Department of Radiology, Sapporo Medical University, School of Medicine, S1W16, Chuo-ku, Sapporo 060-8543, Japan. E-mail: someya{at}sapmed.ac.jp
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REFERENCES |
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Received March 24, 2003; accepted June 23, 2003
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