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Japanese Journal of Clinical Oncology Advance Access originally published online on June 23, 2005
Japanese Journal of Clinical Oncology 2005 35(7):375-379; doi:10.1093/jjco/hyi108
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© 2005 Foundation for Promotion of Cancer Research

Importance of the Initial Volume of Parotid Glands in Xerostomia for Patients with Head and Neck Cancers Treated with IMRT

Yasumasa Nishimura1, Kiyoshi Nakamatsu1, Toru Shibata1, Shuichi Kanamori1, Ryuta Koike1, Masahiko Okumura2 and Minoru Suzuki3

1 Department of Radiation Oncology and 2 Central Radiological Service, Kinki University School of Medicine, Osaka-Sayama, Osaka and 3 Radiation Oncology Research Laboratory, Research Reactor Institute, Kyoto University, Sennan-gun, Osaka, Japan

For reprints and all correspondence: Yasumasa Nishimura, Department of Radiation Oncology, Kinki University School of Medicine, Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan. E-mail: ynishi{at}med.kindai.ac.jp

Received March 16, 2005; accepted May 8, 2005


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Objective: Our aim was to evaluate predictors of xerostomia in patients with head and neck cancers treated with intensity-modulated radiation therapy (IMRT).

Methods: Thirty-three patients with pharyngeal cancer were evaluated for xerostomia after having been treated with IMRT. All patients were treated with whole-neck irradiation of 46–50 Gy by IMRT, followed by boost IMRT to the high-risk clinical target volume to a total dose of 56–70 Gy in 28–35 fractions (median, 68 Gy). For boost IMRT, a second computed tomography (CT-2) scan was done in the third to fourth week of IMRT. Xerostomia was scored 3–4 months after the start of IMRT.

Results: The mean doses to the contralateral and ipsilateral parotid glands were 24.0 ± 6.2 and 30.3 ± 6.6 Gy, respectively. Among the 33 patients, xerostomia of grades 0, 1, 2 and 3 was noted in one, 18, 12 and two patients, respectively. Although the mean dose to the parotid glands was not correlated with the grade of xerostomia, the initial volume of the parotid glands was correlated with the grade of xerostomia (P = 0.04). Of 17 patients with small parotid glands (≤38.8 ml) on initial CT (CT-1), 11 (65%) showed grade 2 or grade 3 xerostomia, whereas only three (19%) of 16 patients with larger parotid glands showed grade 2 xerostomia (P < 0.05). The mean volume of the parotid glands on CT-1 was 43.1 ± 15.2 ml, but decreased significantly to 32.0 ± 11.4 ml (74%) on CT-2 (P < 0.0001).

Conclusions: Initial volumes of the parotid glands are significantly correlated with the grade of xerostomia in patients treated with IMRT. The volume of the parotid glands decreased significantly during the course of IMRT.

Key Words: IMRT • xerostomia • parotid glands • head and neck cancer


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Xerostomia is the most common late toxic effect of radiation therapy (RT) in patients with head and neck cancers. Decreased saliva output affects every aspect of life, including speech, nutrition, taste, sleep, mastication and deglutition (1–5). Xerostomia also affects aspects of patients' health-related quality of life (QOL), such as pain, emotion and communication (4). Thus, QOL after RT is largely related to xerostomia in survivors.

Recent technological advances have led to the successful clinical use of intensity-modulated RT (IMRT), an advanced form of conformal RT. The initial clinical results of IMRT have been encouraging. IMRT reduces late salivary toxicity without compromising tumor control in patients with head and neck cancers (1,6–9).

To evaluate the predictors of xerostomia in patients with head and neck cancers treated with IMRT, we compared dosimetric parameters of the parotid glands with the grade of xerostomia.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 References
 
Since December 2000, 33 patients with head and neck cancers who were treated with whole-neck RT by IMRT were evaluated for xerostomia. Informed written consent for IMRT was obtained from all patients. Patient and tumor characteristics are shown in Table 1. Of the 33 patients, 13 had nasopharyngeal cancer, 10 had oropharyngeal cancers and 10 had hypopharyngeal cancers. Except for one non-Hodgkin's lymphoma of the nasopharynx, the remaining 32 tumors were squamous cell carcinomas.


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  		Table 1. Patient and tumor characteristics

 
For 17 patients with hypopharyngeal or oropharyngeal cancer, unilateral or bilateral neck dissection was performed before the start of IMRT. For one patient with tonsil cancer, simple tonsillectomy was performed without neck dissection. Of the 18 patients treated surgically before IMRT, 11 underwent laser coagulation of primary tumors, and four patients with tonsil cancer underwent simple tonsillectomy, only biopsy of primary tumors was done for the remaining three patients. No patients underwent potentially curative surgery or total laryngectomy before IMRT.

Twenty-three patients were treated with concurrent chemoradiation therapy. Concurrent cisplatin (60–80 mg/m2, 2–3 times) was given to 10 patients with nasopharyngeal cancers, and weekly docetaxel (15 mg/m2) was given to 13 patients with orohypopharyngeal cancers (10). No concurrent chemotherapy was given to one patient with malignant lymphoma, five patients of 70 years or older and four patients who refused chemotherapy.

SIMULATION AND TREATMENT PLANNING
All patients were immobilized with a thermoplastic mask covering the head, neck and shoulders (Type-S thermoplastic based system, MED-TEC, Orange City, IA). Treatment-planning computed tomography (CT) scans were obtained with contrast medium at 5 mm slice intervals from the head through the aortic arch. For all patients, treatment-planning CT was done before IMRT (CT-1) and in the third or fourth week of IMRT for boost IMRT (CT-2).

Treatment planning for IMRT was done by inverse planning with commercial treatment-planning systems (Cadplan Helios,Varian Associates, Palo Alto, CA; Eclipse, Varian Medical Systems International Inc., Baden, Switzerland). The IMRT beam arrangements consisted of five or seven co-planar beams. Typically, seven beam angles of 60–75, 105–115, 135–150, 180, 210–225, 245–255 and 285–300° were used.

TARGET DEFINITION AND DOSE SPECIFICATION
Following the recommendations of the International Commission on Radiation Units report 50 and report 62 (11,12), the gross tumor volume (GTV) and the clinical target volume (CTV) were determined with axial CT images. For patients undergoing neck dissection or tonsillectomy before IMRT, the tumor bed of metastatic lymph nodes or primary tumors was regarded as high-risk CTV. For all patients, bilateral submandibular (level Ib) and jugular chain (level II–IV) lymph nodes were included in the initial CTV. Margins of 3–5 mm for treatment set-up and internal organ motion error were added to the CTV to determine the planning target volume (PTV). For planning organ at risk volume, a margin of 3 mm was added to the spinal cord. For the parotid glands, no margin was added in treatment planning. In the present analysis, all parotid glands were re-contoured by a single physician (Y.N.) to exclude observer variability on contouring the parotid glands, and the net volume and dosimetric parameters of the parotid glands could be determined with a re-calculated dose–volume histogram.

All patients were treated with whole-neck irradiation of 46–50 Gy in 23–25 fractions. The upper and middle regions of the neck were irradiated with IMRT based on CT-1, and the lower region of the neck was irradiated with the conventional anterior–posterior technique. After whole-neck irradiation, boost IMRT was given to the PTV for GTV and high-risk CTV on the basis of CT-2 to a total dose of 56–70 Gy in 28–35 fractions (median, 68 Gy). The daily prescribed dose to the PTV was 2.0 Gy.

The prescribed dose was normalized at a point in the PTV so that the 95% volume of the PTV received the prescribed dose (D95), and the dose to 10% volume (D10) of the PTV was <110% of the prescribed dose to the PTV. When the prescribed dose to the PTV for the GTV was 70 Gy in 35 fractions, the maximum dose constraints used in the inverse planning for the spinal cord, brain, ipsilateral parotid gland and contralateral parotid gland were 40, 50, 25–30 and 20–25 Gy, respectively.

TREATMENT DELIVERY AND QUALITY ASSURANCE
Treatment was delivered using dynamic multileaf collimation with a Clinac-600C accelerator (Varian Associates) equipped with a 40 leaf dynamic multileaf collimator. Beam energy of 4 MV X-rays was used. The daily treatment time was 15–20 min.

During radiotherapy with IMRT, routine quality assurance (QA) was crucial. To verifiy the leaf motion of each beam, various QA performances were done. Details of QA procedures at our hospital have been described elsewhere (13).

ASSESSMENT OF XEROSTOMIA
Xerostomia was scored according to the subjective assessment of Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late salivary gland toxicity. Slight dryness not affecting QOL correlated with grade 1 toxicity, and moderate dryness requiring a water bottle correlated with grade 2 toxicity. Severe dryness causing a profound change in QOL was grade 3. Xerostomia was scored when acute mucositis subsided 3–4 months after the start of IMRT. Thereafter, xerostomia was scored every 2–3 months, up to 24 months of treatment. In the present analysis, the xerostomia score after 3–4 months of treatment was used as an end-point.

DOSIMETRIC PARAMETERS OF THE PAROTID GLANDS
For all patients, dose–volume histograms were calculated for CT-1 and CT-2. The volumes of the parotid glands on CT-1 and CT-2 and the mean radiation doses to the contralateral and ipsilateral parotid glands were calculated for each patient. The mean doses to a parotid gland on CT-1 and CT-2 were added together to obtain the mean dose for the entire treatment.


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 References
 
The mean dose to the contralateral parotid gland could be reduced to 24.0 ± 6.2 Gy by IMRT. The mean dose to the ipsilateral parotid gland was 30.3 ± 6.6 Gy. In the 33 patients, xerostomia of grades 0, 1, 2 and 3 were noted in one, 18, 12 and two patients, respectively. Correlations between the grade of xerostomia and various dosimetric parameters were analyzed by the Spearman rank correlation with correction for ties. The mean dose to the contralateral parotid gland was not significantly correlated with the grade of xerostomia (Fig. 1, P = 0.129). Similarly, no significant correlation was noted for the mean dose to the bilateral parotid glands (P = 0.287). On the other hand, the initial volume of the parotid glands was significantly correlated with the grade of xerostomia (Fig. 2, P = 0.040).



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  		Figure 1. No significant correlation was noted between xerostomia score at 3–4 months and the mean dose to the contralateral parotid gland.

 


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  		Figure 2. Correlation between xerostomia score at 3–4 months and the initial volume of the parotid glands.

 
Table 2 shows the xerostomia score according to the initial parotid gland volume. Of the 17 patients with smaller parotid glands with volumes equal to or less than the median volume (38.8 ml) on CT-1, nine had grade 2 xerostomia and two had grade 3 xerostomia (65%), whereas only three (19%) of 16 patients with larger parotid glands had grade 2 xerostomia (P < 0.05: {chi}2 test with Yates' correction). The mean doses to the contralateral parotid gland did not differ between patients with smaller (25.3 ± 7.6 Gy) or larger parotid glands (22.6 ± 3.7 Gy).


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  		Table 2. Xerostomia according to the initial volume of the parotid glands

 
Interestingly, parotid glands regressed significantly during the course of IMRT. Figure 3 shows the changes in the parotid volume between CT-1 and CT-2 for each patient. The mean ± SD and median of parotid gland volumes had decreased significantly from CT-1 (43.1 ± 15.2 and 38.8 ml) to CT-2 obtained after 3–4 weeks of IMRT [32.0 ± 11.4 ml (74%) and 30.4 ml; P < 0.0001, paired t-test]. The regression rate of parotid glands was not significantly correlated with the grade of xerostomia (P = 0.186).



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  		Figure 3. Changes in parotid volume between CT-1 and CT-2 for each patient. The mean volume of the bilateral parotid glands was significantly higher on CT-1 (43.1 ± 15.2 ml) than on CT-2 (32.0 ± 11.4 ml; P < 0.0001, paired t-test).

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
References
 
In the present study, IMRT reduced the radiation dose to the parotid glands in patients with pharyngeal cancers, and resulted in a sparing of salivary function. Although the mean dose to the contralateral parotid gland was reduced to 24.0 ± 6.2 Gy, xerostomia of grade 2–3 was still noted in 14 (42%) of the 33 patients evaluated. To evaluate the predictors of xerostomia, dosimetric parameters of the parotid glands were compared with the grade of xerostomia. Many investigators have demonstrated a correlation between mean dose to the parotid gland and a reduction in stimulated saliva output or xerostomia-related QOL scores (1,4,6,14). Mean radiation doses reported to cause significant salivary reduction range from 26 to 39 Gy (1,2).

In the present study, however, the mean dose to the parotid glands was not correlated with the xerostomia score. Possible reasons for this finding are that all patients received bilateral neck irradiation with IMRT and that the mean doses to the contralateral parotid gland were, except in one patient, within a relatively narrow range (16–33 Gy, with a mean of 24.0 Gy) (Fig. 1). Concurrent chemotherapy given for 23 patients (70%) may also affect the degree of xerostomia, although the incidence of grade 2, 3 xerostomia was not affected by concurrent chemotherapy in the present study.

In addition to the relatively uniform dose to the contralateral parotid gland, the xerostomia score as an end-point was not more accurate than a more complicated xerostomia-specific questionnaire or measurement of saliva from the stimulated parotid gland to evaluate its function (1,4,6,14). In the present study, the xerostomia score in patients who needed to carry a water bottle or artificial saliva was classified as grade 2.

An important finding of this study was that the initial volume of the parotid glands is significantly correlated with the grade of xerostomia (Fig. 2 and Table 2). Several investigators have also noted the importance of parotid gland volume. Amosson et al. (6) analyzed the dosimetric predictors of xerostomia in patients with head and neck cancer treated with IMRT and demonstrated that patients reporting xerostomia had a significantly higher contralateral parotid volume receiving >25 Gy than did patients reporting adequate saliva. Eneroth et al. (15) have reported that large parotid glands have better pre-irradiation function, which is extinguished at much higher RT doses than is that of small parotid glands. It is very likely that the absolute volume of the parotid glands reflects the reserve of saliva output and becomes a predictor of xerostomia in parotid-sparing IMRT.

The volume of the parotid glands decreased significantly during the course of IMRT (Fig. 3). Recently, a similar finding has been reported by Barker et al. (16). They measured the volume and position of the parotid glands by serial CT examinations during RT for head and neck cancer, and found that parotid glands decreased in volume (0.6%/day of initial volume) and shifted medially. In the present study, parotid glands regressed to 74% of the initial volume at the third to fourth week of the treatment, which is very similar to the results reported by Barker et al. (16).

The radiosensitivity of the parotid glands is apparently high. In the first week of conventional RT for head and neck cancer, after only 10 Gy has been delivered, salivary output declines by 60–90% (2,5). Experiments with rhesus salivary glands have shown acute degeneration and interphase cell death of serous cells 24 h after irradiation with 2.5–15 Gy (17). In addition, fractionation had no significant sparing effect on parotid gland function (17). The CT-2 for boost IMRT was performed at the third or fourth week of RT. At that time, accumulated mean doses to the parotid glands were 10–15 Gy. This small RT dose can cause significant loss of serous acini and reduce parotid volume.

To evaluate the dose–volume histograms of parotid glands, the change in parotid volume during IMRT should be considered. When only CT scans obtained before RT are used for treatment planning, the dosimetric parameters for the parotid gland may not be sufficiently accurate. As the gross tumor volumes also decreased significantly during the course of fractionated RT (16), serial imaging and sequential IMRT boost planning may be necessary, although it is an expensive and time-consuming strategy.

In conclusion, the initial volume of the parotid glands is a predictor for xerostomia, and parotid volume regresses significantly during IMRT.


   Acknowledgments
 
This study was partially supported by a Grant-in-Aid for Scientific Research (14570887, 17591300) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 References
 
1 Chao KS. Protection of salivary function by intensity-modulated radiation therapy in patients with head and neck cancer. Semin Radiat Oncol 2002;12(Suppl 1):20–5.[CrossRef][Medline]

2 Eisbruch A, Ship JA, Kim HM, Ten Haken RK. Partial irradiation of the parotid gland. Semin Radiat Oncol 2001;11:234–9.[Web of Science][Medline]

3 Franzen L, Funegard U, Ericson T, Henriksson R. Parotid gland function during and following radiotherapy of malignancies in the head and neck. A consecutive study of salivary flow and patient discomfort. Eur J Cancer 1992;28:457–62.[Medline]

4 Lin A, Kim HM, Terrell JE, Dawson LA, Ship JA, Eisbruch A. Quality of life after parotid-sparing IMRT for head-and-neck cancer: a prospective longitudinal study. Int J Radiat Oncol Biol Phys 2003;57:61–70.[CrossRef][Medline]

5 Mossman KL. Quantitative radiation dose–response relationships for normal tissues in man. II. Response of the salivary glands during radiotherapy. Radiat Res 1983;95:392–8.[CrossRef][Medline]

6 Amosson CM, Teh BS, Van TJ, Uy N, Huang E, Mai WY, et al. Dosimetric predictors of xerostomia for head-and-neck cancer patients treated with the smart (simultaneous modulated accelerated radiation therapy) boost technique. Int J Radiat Oncol Biol Phys 2003;56:136–44.[Medline]

7 Chao KS, Majhail N, Huang CJ, Simpson JR, Perez CA, Haughey B, et al. Intensity-modulated radiation therapy reduces late salivary toxicity without compromising tumor control in patients with oropharyngeal carcinoma: a comparison with conventional techniques. Radiother Oncol 2001;61:275–80.[CrossRef][Medline]

8 Chao KS, Deasy JO, Markman J, Haynie J, Perez CA, Purdy JA, et al. A prospective study of salivary function sparing in patients with head-and-neck cancers receiving intensity-modulated or three-dimensional radiation therapy: initial results. Int J Radiat Oncol Biol Phys 2001;49:907–16.[CrossRef][Web of Science][Medline]

9 Lee N, Xia P, Quivey JM, Sultanem K, Poon I, Akazawa C, et al. Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the UCSF experience. Int J Radiat Oncol Biol Phys 2002;53:12–22.[CrossRef][Web of Science][Medline]

10 Suzuki M, Nishimura Y, Nakamatsu K, Kanamori S, Koike R, Kawamoto M, et al. Phase I study of weekly docetaxel infusion and concurrent radiation therapy for head and neck cancer. Jpn J Clin Oncol 2003;33:297–301.[Abstract/Free Full Text]

11 International Commission on Radiation Units and Measurements (ICRU). Report number 50: prescribing, recording and reporting photon beam therapy. Bethesda, Maryland: ICRU;1993.

12 International Commission on Radiation Units and Measurements (ICRU). Report number 62: prescribing, recording and reporting photon beam therapy (supplement to ICRU Report 50). Bethesda, Maryland: ICRU;1999.

13 Suzuki M, Nakamatsu K, Kanamori S, Okumra M, Uchiyama T, Akai F, et al. Feasibility study of the simultaneous integrated boost (SIB) method for malignant gliomas using intensity modulated radiotherapy (IMRT). Jpn J Clin Oncol 2003;33:271–7.[Abstract/Free Full Text]

14 Eisbruch A, Kim HM, Terrell JE, Marsh LH, Dawson LA, Ship JA. Xerostomia and its predictors following parotid-sparing irradiation of head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001;50:695–704.[CrossRef][Web of Science][Medline]

15 Eneroth CM, Henrikson CO, Jakobsson PA. Pre-irradiation qualities of a parotid gland predicting the grade of functional disturbance by radiotherapy. Acta Otolaryngol 1972;74:436–44.[Medline]

16 Barker JL Jr, Garden AS, Ang KK, O'Daniel JC, Wang H, Court LE, et al. Quantification of volumetric and geometric changes occurring during fractionated radiotherapy for head-and-neck cancer using an integrated CT/linear accelerator system. Int J Radiat Oncol Biol Phys 2004;59:960–70.[CrossRef][Medline]

17 Stephens LC, Ang KK, Schultheiss TE, King GK, Brock WA, Peters LJ. Target cell and mode of radiation injury in rhesus salivary glands. Radiother Oncol 1986;7:165–74.[Medline]


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