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Parotid-sparing Radiotherapy: Does it Really Reduce Xerostomia?
Clinical Oncology (2005) 17: 610–617 doi:10.1016/j.clon.2005.06.012
Original Article Parotid-sparing Radiotherapy: Does it Really Reduce Xerostomia? M. K. Ng*, S. V. Porcedduy, A. D. Milnerz, J. Corry*, C. Hornby*, G. Hope*, D. Rischinx, L. J. Peters* *Department of Radiation Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; yDepartment of Radiation Oncology, Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia; zCentre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; xDivision of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia ABSTRACT: Aims: Parotid-sparing radiotherapy (PSRT) was introduced for patients with selected head and neck cancer requiring bilateral upper-neck irradiation at our centre in 2000. The aim of this study was to compare the subjective degree of xerostomia in patients treated with PSRT between January 2000 and June 2003 with patients treated using conventional techniques (radiotherapy) over the same period. Materials and methods: Eligible patients were required to have completed treatment 6 months previously and be recurrence-free at the time of interview. PSRT was defined as conformal radiotherapy, in which the mean dose to at least one parotid gland was 33 Gy or less, as determined by the dose–volume histogram. Patients receiving radiotherapy were treated with standard parallel-opposed fields, such that both parotids received a minimum of 40 Gy. Xerostomia was assessed using a validated questionnaire containing six questions with a rating between 0 and 10. Lower scores indicated less difficulty with xerostomia. Results: Thirty-eight eligible patients treated with PSRT were identified: 25 with oropharyngeal cancer and 13 with nasopharyngeal cancer (NPC). The mean overall questionnaire score (Q1–5) for this group was 4.20 (standard error Z 0.33). Forty-four patients (24 oropharyngeal, 21 NPC) treated with radiotherapy over the same period were eligible. The mean overall questionnaire score (Q1–5) for this group was 5.86 (standard error Z 0.35). The difference in mean overall scores between the two groups of patients was statistically significant (P ! 0.001), as were the scores for four of the six individual questions. Conclusion: These results suggest that PSRT offers improved long-term xerostomia-related quality of life compared with conventional radiotherapy. Ng, M. K. et al. (2005). Clinical Oncology 17, 610–617 Ó 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Head and neck cancer, parotid, quality of life, radiotherapy, three-dimensional treatment planning, xerostomia Received: 15 February 2005
Revised: 17 June 2005 Accepted: 20 June 2005
Introduction
Xerostomia is the most frequently reported late side-effect after radiotherapy for head and neck malignancies, and a major cause of reduced quality of life [1,2]. Effective treatment options for xerostomia are poor. Patients generally find saliva substitutes unsatisfactory. They offer limited efficacy of short duration, and lack the protective roles of saliva [3]. Saliva stimulants, such as pilocarpine, have shown promising results [4–8], but have significant side-effects and can be costly. The alternative strategy is salivary gland protection. This can potentially be achieved medically by the use of
Author for correspondence: Dr Michael Ng, Department of Radiation Oncology, Peter MacCallum Cancer Centre, Locked Bag 1 A’Beckett Street, Melbourne, Victoria 8006, Australia. Tel: C61-3-9656-1111; Fax: C61-3-9656-1424; E-mail: [email protected] 0936-6555/05/000000C08 $35.00/0
radioprotectors. Amifostine has been shown to reduce chronic xerostomia in Phase III trials; however, the administration of the drug is cumbersome, requiring daily intravenous injections before each radiation fraction, and the possibility of tumour protection remains a clinical concern [9,10]. A recent randomised study of pilocarpine used during and after radiotherapy failed to demonstrate a beneficial effect on radiation-induced xerostomia [5]. Physical protection of salivary function by reduction of parotid radiation dose is another attractive alternative. Eisbruch et al. [11,12] showed that if the mean radiation dose threshold to the parotid glands was less than 26 Gy, parotid gland function recovers fully over 1–2 years. Marks et al. [13] reported a marked reduction in salivary flow in parotid glands receiving more than 40 Gy. More recently, the dose threshold to the parotid gland was reported to be 32 Gy [14]. Standard radiotherapy techniques to radical doses for head and neck cancer invariably deliver high dose to both parotid glands (O50 Gy).
Ó 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
PAROTID-SPARING RADIOTHERAPY AND XEROSTOMIA
In recent years, conformal radiation techniques using computed tomography image-based computer planning, such as three-dimensional conformal radiation therapy (3DCRT) and intensity-modulated radiotherapy (IMRT) have permitted sparing of salivary glands. A concern with the use of conformal techniques to spare the salivary glands is the risk of reduction in treatment outcome by under-dosing disease or geographical miss. However, several recent studies using 3-DCRT or IMRT in head and neck cancers have not demonstrated inferior locoregional tumour control [15–18]. Longitudinal studies investigating the use of these parotid-sparing radiotherapy techniques (PSRT) report improved salivary flow and self-reported xerostomiaspecific quality of life [12,14,18–22]. At this centre, PSRT has been used in selected patients for at least 4 years. Before this, patients with head and neck cancers requiring bilateral neck irradiation were treated with standard radiotherapy techniques, with both parotid glands receiving a mean dose of at least 40 Gy. In this study, we aimed to assess the quality of life (QOL) outcomes in patients treated with PSRT using a xerostomia-specific questionnaire [23], and compared them with patients who received high-dose radiation to both parotid glands.
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as ‘parotid sparing’ (%33 Gy to at least one parotid gland defined by the dose–volume histogram). These patients would have received high dose to both parotid glands with conventional parallel-opposed radiation fields. The dose threshold of 33 Gy was selected arbitrarily as the mid-point of the range reported in the literature of between 26 and 40 Gy [11–14]. Conventional Radiotherapy
The comparison non-parotid-sparing group, termed ‘radiotherapy’ was defined as patients who received standard bilateral neck irradiation delivering a high dose (O40 Gy) to both parotid glands. Most received in excess of 50 Gy. Our treatment policy was to offer PSRT to all patients whose disease volume made it technically feasible to spare at least one parotid gland with either IMRT or 3-DCRT. However, owing to workload constraints, not all eligible patients received PSRT. Because of limited availability, IMRT was generally reserved for patients with nasopharyngeal carcinoma. Radiotherapy Technique
This was an unmatched cohort study, with follow-up assessment of xerostomia-specific quality of life after treatment in head and neck cancer patients treated at the Peter MacCallum Cancer Centre from January 2000 to June 2003. Patients were retrospectively identified from the patient record information database.
All patients were immobilised in a cobex mask and treated with photons, electrons, or both, using linear accelerators (6–18 MV). Patients had a planning computed tomography scan for dosimetry purposes. The planning target volume (PTV) was designed to encompass the gross-tumour volume, with at least a 1.0 cm margin in patients treated radically. In postoperative patients, the PTV encompassed the site of resected disease by at least 1.5 cm margin. Doses were prescribed according to ICRU 50 criteria.
Eligibility Criteria
Parotid-sparing Radiotherapy
To be eligible, patients had to have (1) received radical or postoperative radiotherapy for oropharyngeal cancers or nasopharyngeal cancers (NPC); (2) had no previous head and neck radiotherapy; (3) required bilateral upper-neck irradiation; (4) received radiotherapy at least 6 months before the quality of life assessment; and (5) been disease free at the time of the questionnaire. Six months after radiotherapy was chosen as the minimum time to assess xerostomia. This allows for the resolution of acute mucositis and permits a better assessment of true late xerostomia. Only patients who were disease free at the time of the questionnaire were eligible to ensure there was no confounding effect to quality of life issues.
In patients receiving PSRT, the entire parotid gland was outlined bilaterally to enable the determination of the dose– volume histogram and optimisation of the treatment plan. PSRT was delivered using either IMRT or a 3-DCRT. In this series of patients, IMRT was most often delivered using 8–10 coplanar fields to treat the primary site and bilateral neck. Dose differential (maintaining the same field size) was used rather than a shrinking field technique. The planning software used was Varian CadplanÔ, with the optimisation being carried out on Varian HeliosÔ. The three-dimensional conformal parotid-sparing technique (unpublished) was developed at our institution because of the limited availability of IMRT. In most patients, a two-phase technique was used. Phase I was delivered using six coplanar fields: anterior, posterior, two posterior oblique and two opposed-lateral fields to deliver 50 Gy encompassing the gross tumour and electively treated neck nodes. The weighting of the fields was as follows: anterior (1.0), posterior (0.6), posterior obliques (1.0) and laterals (1.0). Phase II was designed to deliver 16–20 Gy to gross tumour, or 10 Gy to the site of resected disease in cases treated postoperatively, typically using two
Methods
Cohorts
Two patient groups were identified from the cohort. Parotid-sparing Radiotherapy
The parotid-sparing radiotherapy group, termed ‘PSRT’, was defined as patients who received radiotherapy planned
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to three fields. Field arrangements were designed to limit the mean dose to at least one parotid gland to 33 Gy or less. Both parotids are spared if this could be achieved without compromising coverage of the PTV. Conventional Radiotherapy
In most cases, patients were planned with orthogonalsimulation films. Treatment fields were drawn on the simulation films. Isodose distributions were generated and three-dimensional compensation (correcting for both missing tissue and tissue inhomogeneities) was used to achieve a dose homogeneity of G5%. The parotid dose–volume histogram was not routinely calculated for the radiotherapy patients, but a clinico-radiological assessment was made to demonstrate that both parotids would receive at least 40 Gy, and, in most cases, more than 50 Gy. Treatment was delivered using a two-phase technique. Phase I involved parallel-opposed fields up to 50 Gy to the gross tumour and electively treated neck nodes. Posterior electrons ‘strips’ were usually introduced after 40 Gy to restrict the spinal cord dose of 45 Gy or less. Phase II involved a field reduction to treat the gross disease with at least a 1.5 cm margin using either parallel opposed or oblique field arrangements. The lower neck was most commonly treated with an anterior 6 MV photon field with midline shielding. The dose for elective treatment was 50 Gy specified at 2 cm depth. Chemotherapy
Patients with oropharyngeal cancer treated with chemotherapy were treated either with the ‘chemoboost’ protocol described by Corry et al. [24] or were enrolled on a prospective randomised Phase II chemo-radiotherapy trial reported by Rischin et al. [25]. In patients with NPC, those with locally advanced disease received a chemoradiotherapy regimen described by Rischin et al. [26].
Xerostomia Assessment
The primary end point of this study was the xerostomiaspecific quality-of-life score calculated from a questionnaire. The questionnaire, also used in studies assessing pilocarpine [4,8], consists of a validated bank of six questions about the patient’s self-assessed mouth dryness and is shown in Fig. 1. Patients were asked to rate difficulty with items related to specific and general aspects of xerostomia on a scale of 0–10. Lower scores indicated less difficulty with xerostomia. Scores for each question were recorded, and an ‘overall questionnaire score’ was calculated for each patient, as the average of the six component scores. Ethics
The ethics committee of our centre approved this study. All patients were informed of the purpose of the study when contacted by investigators. Statistical Analysis
Patient, tumour and treatment characteristics of the patients completing the questionnaire were tabulated for all patients and separately for the PSRT and radiotherapy groups. Responses to individual xerostomia questions were compared between the PSRT and radiotherapy groups using the Mann–Whitney test. Box-&-whisker plots were used to graphically display the distribution of responses to the six xerostomia questions. In these plots, the box represents the inter-quartile range (middle 50% of scores), with a symbol (circle) showing the median score; the whiskers extend to the minimum and maximum scores. The overall questionnaire score was computed as the average score from all questions, and was compared between PSRT and radiotherapy groups using the standard twosample t test. The overall questionnaire score was compared between patient groups using either the two-sample t test
Question 1. During the last 3 days, overall, on a scale of 0 to 10, how dry was your mouth or tongue? 0 is not dry and 10 is very dry. Question 2. In general, during the daytime hours of the last 3 days, rate the feeling of your mouth and tongue on a scale of 0 to 10, with 0 is comfortable and 10 is extremely uncomfortable. Question 3. During the last 3 nights, due to the dryness of your mouth and tongue, how difficult was it to sleep? Consider such factors as how difficult it was for you to go to sleep, the duration and the quality of your sleep, and how often you woke up to drink or to urinate. On a scale of 0 to 10, 0 is easy and 10 is extremely difficult. Question 4. During the last 3 days, overall, due to the dryness of your mouth and tongue, how difficult was it to speak without drinking liquids? On a scale of 0 to 10, 0 is easy and 10 is extremely difficult. Question 5. During the last 3 days, overall, due to the dryness of your mouth and tongue, how difficult was it to chew and swallow food? On a scale of 0 to 10, 0 is easy and 10 is extremely difficult. Question 6. If you normally wear dentures, due to the dryness of your mouth and tongue, how difficult was it to wear dentures in the last 3 days? On a scale of 0 to 10, 0 is easy and 10 is extremely difficult.
Fig. 1 – Xerostomia questionnaire.
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PAROTID-SPARING RADIOTHERAPY AND XEROSTOMIA
(two groups) or analysis of variance (greater than two groups). Note that the Welch modified two-sample t test was used, when appropriate, for situations in which there were pronounced differences in group variances. The statistical analyses were carried out using S-plus software [27]. All tests were two-sided, and statistical significance was defined as P ! 0.05.
Results
During the study period, 160 patients received radical radiotherapy for oropharyngeal cancer and NPC of whom 82 met the eligibility criteria. Patient and Tumour Characteristics
Patient characteristics are shown in Table 1. Seventy-six per cent were men, and the median age was 55 years (range 25–83 years). The primary tumour site was oropharyngeal cancer in 59% of patients (n Z 48) and 41% for NPC (n Z 34). The predominant histological type was squamous-cell carcinoma in 62% of patients (n Z 51), and 83%
(n Z 68) of patients had a stage III–IV tumour. The median follow-up from the last day of radiotherapy treatment was 17 months (range 6–34 months). Treatment
Treatment data are shown in Table 2. Most patients received definitive radiotherapy, whereas 9% received adjuvant postoperative radiation. The median total tumour dose was 70 Gy given in 35 fractions. Seventy-eight per cent of patients received chemo-radiotherapy as part of the treatment; 84% of PSRT and 71% of radiotherapy patients were given chemotherapy. Thirty-eight patients were treated with PSRT (46%) and 44 patients received conventional non-PSRT (54%). Of these 38 PSRT patients, 10 patients were treated with IMRT and 28 patients were treated with 3-DCRT. Xerostomia Quality of Life
All patients were interviewed at least 6 months after completing radiotherapy. The median follow-up was longer in the radiotherapy group compared with the PSRT group:
Table 1 – Patient and tumour characteristics overall and for each cohort Overall N
Radiotherapy %
82
Total patients
76 24
Parotid-sparing radiotherapy
n
%
n
%
44
54
38
46
36 8
82 18
26 12
68 32
Sex
Male Female
62 20
Age (at presentation)
Median Range
55 25–83
Primary tumour site
Oropharyngeal wall Tonsil Base of tongue Vallecula Nasopharynx
8 28 11 1 34
10 34 13 1 41
4 12 7 0 21
9 27 16 0 48
4 16 4 1 13
11 42 11 3 34
Histological type
Squamous-cell carcinoma Adenocarcinoma Undifferentiated nasopharyngeal cancer (WHO3) Other
51 1 22 8
62 1 26 9
26 1 12 5
59 2 27 11
25 0 10 3
66 0 26 8
Histological grade at diagnosis
Well differentiated Moderately differentiated Poorly differentiated or undifferentiated Not stated
6 12 49 15
7 15 60 18
2 7 26 9
5 16 59 20
4 5 23 6
11 13 61 16
Overall stage*
1 2 2A 2B 3 4A 4B Unstageable
3 1 2 6 27 33 8 2
4 1 2 7 33 40 10 2
1 1 2 2 14 16 6 2
2 2 5 5 32 36 14 5
2 0 0 4 13 17 2 0
5 0 0 11 34 45 5 0
54 25–83
56 28–76
*AJCC Cancer Staging Manual, Sixth Edition, American Joint Committee on Cancer; Springer-Verlag New York, New York, 2002.
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Table 2 – Treatment details (including radiotherapy and chemotherapy) Overall N
Radiotherapy %
n
75 7
Total tumour dose
Median Range
70 58–74
70 60–74
70 58–70
Number of fractions
Median Range
35 29–37
35 30–37
35 29–35
Technique
Two-field More than three-field or multiple conformal Intensity-modulated radiotherapy
28 40 14
17
4
9
10
26
Chemotherapy
No chemotherapy Induction and concurrent chemotherapy for nasopharyngeal cancer* Chemoboosty Intermittent platinumz Weekly platinumx Tirapazamine regimenk
18 19
22 23
7 15
16 34
11 4
29 11
12 11 6 16
15 13 7 20
5 4 2 11
11 9 5 25
7 7 4 5
18 18 11 13
Mean Median Range
17.63 17 6–34
28 12
93 7
%
Radical Adjuvant
34 49
41 3
%
Radiotherapy intent
Follow-up (months)
91 9
n
Parotid-sparing radiotherapy
34 4
64 27
89 11
0 28
20.71 20 6–34
0 74
14.07 11 6–31
*Three induction cycles: epirubicin, cisplatin, 5-fluorouracil [5-FU] and concurrent cisplatin weeks 1 and 6 during radiation. yChemoboost: cisplatin 5-FU during last 2 weeks of radiation. zIntermittent platinum: cisplatin during weeks 1, 4 and 7 of radiation. xWeekly platinum: cisplatin weekly during radiation. kTirapazamine regimen: tirapazamine during weeks 1, 2, 3, 4 and 7 with cisplatin during weeks 1, 4 and 7 of radiation.
20 months (range 6–34 months) and 11 months (range 6–31 months), respectively. This is explained by the increased use of PSRT with each year and a larger proportion of patients being offered PSRT in the later years, limiting their available follow-up time. All 82 patients answered questions 1 to 5. However, for question 6, only 30 out of 82 patients responded (17 in the radiotherapy group, 13 in the PSRT group), as patients qualified to answer this question presumably must have worn dentures. Consequently, the overall questionnaire score was calculated from the average of questions 1–5 for all 82 patients and separately for the 30 patients with dentures (average of all six questions).
and PSRT [4.24]; P Z 0.344), but the difference was not significantly different. A trend was observed for lower overall questionnaire scores if both parotid glands were spared, compared with one gland (3.48 for both parotids vs 4.39 for one parotid only), but this was not statistically significant (P Z 0.269). The mean overall questionnaire score was significantly lower (P Z 0.027) for the 10 patients who received IMRT
Table 3 – Overall questionnaire score for radiotherapy and parotidsparing radiotherapy
Radiotherapy*
Overall Questionnaire Score
The mean overall questionnaire score (Q1–5) was 5.86 for the radiotherapy group and 4.20 for the PSRT group (Table 3). The lower questionnaire score in the PSRT group supported the finding that these patients had less xerostomia compared with the radiotherapy group (P ! 0.001). The difference was even more marked in the 34 patients with NPC in whom the mean overall questionnaire scores were 5.6 and 3.2 for radiotherapy and PSRT, respectively (P Z 0.0019). When the mean overall questionnaire was calculated with the addition of question 6 (n Z 30), scores remained lower in the PSRT group (radiotherapy [5.06],
Parotid-sparing radiotherapyy P valuez
Average Mean score 1–5 Standard deviation (n Z 82) Median Range
5.86 2.29 6.30 0–10
4.20 2.06 4.50 0.4–8
Average Mean score 1–6 Standard deviation (n Z 30) Median Range
5.06 2.61 6 0–9
4.24 1.79 4.50 0.5–6.83
!0.001
0.344
*Conventional radiotherapy. yParotid-sparing radiotherapy. zTwo-sample t test.
PAROTID-SPARING RADIOTHERAPY AND XEROSTOMIA
(2.98), compared with the 28 patients in the 3-DCRT group (4.63). Both parotid glands were spared in six out of 10 patients who received IMRT, compared with four out of 28 patients who received 3-DCRT. Additional variables that were not found to be significantly associated with xerostomia scores in this analysis included age, sex, chemotherapy and tumour site. Individual question scores have been summarised graphically in Fig. 2. The distribution of scores differs significantly between radiotherapy and PSRT groups for question 1, ‘dryness’ (P ! 0.001), question 3, ‘sleep’ (P ! 0.05), question 4, ‘speech’ (P ! 0.01) and question 5, ‘eating’ (P ! 0.01). Follow-up Effect and Overall Questionnaire Scores
It was previously noted that the median follow-up time was shorter in the PSRT group. A further analysis was carried out on the two groups. Each group was divided into two follow-up times: less than 12 months and greater than 12 months. There seemed to be no time effect on the mean overall questionnaire score. Within the PSRT group, no significant difference was observed between the follow-up periods and, similarly, in the radiotherapy group (Table 4). Discussion
Over the past two decades, major radio-therapeutic advances have been made in the treatment of head and neck malignancies. Improvements in diagnostic imaging, planning and treatment, availability of IMRT and the use of concurrent chemotherapy [28–30], have all potentially contributed to improved local regional control and survival. These aggressive treatments are not without considerable toxicity, and increasing attention is being directed at patient’s subsequent quality of life, particularly the affect of xerostomia. Our results suggest that PSRT may offer improved xerostomia-related quality of life compared with conventional radiotherapy. Using the validated questionnaire, significant differences were observed in the overall scores
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for questions 1–5, and for the individual questions 1, 3, 4, and 5 relating to sense of oral dryness and difficulty with sleep, speech and eating. Curiously, the overall score difference was not significant when question 6 (which relates to difficulty in wearing dentures) was included. This could be due to the relatively small number of patients (n Z 30) who answered question 6. Another possible explanation is that xerostomia does not have a significant effect on wearing dentures comfortably or that edentulous patients simply do not wear their dentures enough for them to perceive a problem related to xerostomia. More recent studies have not used denture-related questions in their questionnaires [12,14,20,22,31]. In our study, despite the improved xerostomia-specific quality of life in patients receiving PSRT, an objective improvement in salivary gland function cannot be asserted, as we did not measure salivary flows. However, we believe that subjective symptomatic self-assessment by the patient is a more meaningful criterion by which to assess the benefit of a change in treatment technique than actual salivary flow rates. Only one other study by Malouf et al. [31] has compared xerostomia between PSRT and conventional techniques. The results showed that PSRT was successful in preserving salivary flow compared with conventional non-PSRT techniques, although the numbers were not evenly balanced (patients receiving PSRT [n Z 88] vs patients receiving non-PSRT [n Z 11]). This study suffers from some problems inherent in most retrospective studies. There was no baseline questionnaire assessment, and there was a significant difference in follow-up time between the two groups. The median follow-up time was shorter in the PSRT group (11 months) than in the radiotherapy group (20 months). However, any bias would favour the radiotherapy group, and a median follow-up time of almost 12 months is likely to predict longer-term results fairly accurately. Eisbruch et al. [12] showed continuous improvement in salivary function during the 2 years after radiotherapy, and in glands that received a mean parotid dose less than 26 Gy, the salivary output returned to pre-radiotherapy levels usually by 1 year. Franzen et al. [32] noticed that
Fig. 2 – Box-plots for individual xerostomia questions: parotid-sparing radiotherapy (PSRT) vs radiotherapy (RT).
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Table 4 – Overall questionnaires scores (Q1–5) and time of follow-up after radiotherapy for parotid-sparing radiotherapy and radiotherapy group Follow-up
Group
n
Mean
Standard deviation
Median
Range
P value*
!12 months O12 months
Parotid-sparing radiotherapy Parotid-sparing radiotherapy
20 18
4.17 4.23
1.92 2.27
4.2 4.8
0.8–7.6 0.4–8.0
0.926
!12 months O12 months
Radiotherapy Radiotherapy
8 36
6.08 5.82
2.30 2.32
6.5 6.2
2.4–9.0 0.0–10.0
0.777
*Two-sample t test.
irradiation of the parotid to doses of 40–50 Gy caused generally reversible changes with restored salivary gland function within 6–18 months after completing radiotherapy. Of note, the follow-up period of the pilocarpine studies ranged from 3 to 12 months [4–8]. We used the xerostomia-specific questionnaire for our study, as it formed part of the assessment tool that led to FDA approval of pilocarpine in radiation-induced xerostomia. Patients who participated in this study coped well with answering the questionnaire. The participation rate was 100%, and patients were eager to discuss their symptoms and its treatment further. Other studies since have used the same questionnaire [14,23]. Of note, Chao et al. [14] used the same questionnaire in assessing xerostomia in patients receiving PSRT, and found a strong correlation between the questionnaire score and the salivary flow rate. They stated that the results implied that salivary function sparing would provide better quality of life. Potential biases in our study relate to patients possibly knowing that they had been treated using parotid-sparing techniques (which may affect their perception of xerostomia) and the tendency for patients to adapt with time to the affect of reduced saliva. The latter consideration would, however, have favoured the radiotherapy group, as their median follow-up time was longer. Other potential confounders not recorded in this study were post-treatment smoking and medications that may aggravate xerostomia. The PSRT used at our centre involved either IMRT or 3DCRT. Although IMRT is preferable, it is not available at all centres for a variety of reasons. The three-dimensional conformal technique we have developed provides an acceptable alternative for PSRT. However, the use of conformal techniques to reduce the dose to the parotid glands can result in an increase of integral dose and delivery of higher doses to the submandibular glands and the oral cavity. The submandibular glands produce about 30% of the total saliva volume under stimulation but, at rest, may account for 90% of total saliva [33]. The minor salivary glands in the mucosal membranes of the oral cavity account for lubrication of the oral mucosa [32] and produce 7–8% of total saliva [34]. Dose–volume relationships of the oral cavity, a surrogate for dose to the minor salivary glands, and submandibular DVH, has been shown to be an independent factor in predicting xerostomia scores [12]. During the study period, we did not routinely record the dose–volume histogram data for the submandibular glands or for the oral cavity, but it is likely that the extra dose to
these structures with 3-DCRT reduced the benefit of parotid sparing. We are currently conducting a prospective study comparing PSRT with conventional radiotherapy with documentation of dose to the submandibular glands and oral cavity to further investigate this point. References 1 Harrison LB, Zelefsky MJ, Pfister DG, et al. Detailed quality of life assessment in patients treated with primary radiotherapy for squamous cell cancer of the base of the tongue. Head Neck 1997;19:169–175. 2 Bjordal K, Kaasa S, Mastekaasa A. Quality of life in patients treated for head and neck cancer: a follow-up study 7 to 11 years after radiotherapy. Int J Radiat Oncol Biol Phys 1994;28:847–856. 3 Porter SR, Scully C, Hegarty AM. An update of the etiology and management of xerostomia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;97:28–46. 4 LeVeque FG, Montgomery M, Potter D, et al. A multicenter, randomized, double-blind, placebo-controlled, dose-titration study of oral pilocarpine for treatment of radiation-induced xerostomia in head and neck cancer patients. J Clin Oncol 1993;11:1124–1131. 5 Warde P, O’Sullivan B, Aslanidis J, et al. A Phase III placebocontrolled trial of oral pilocarpine in patients undergoing radiotherapy for head-and-neck cancer. Int J Radiat Oncol Biol Phys 2002;54:9–13. 6 Horiot JC, Lipinski F, Schraub S, et al. Post-radiation severe xerostomia relieved by pilocarpine: a prospective French cooperative study. Radiother Oncol 2000;55:233–239. 7 Valdez IH, Wolff A, Atkinson JC, Macynski AA, Fox PC. Use of pilocarpine during head and neck radiation therapy to reduce xerostomia and salivary dysfunction. Cancer 1993;71:1848–1851. 8 Johnson JT, Ferretti GA, Nethery WJ, et al. Oral pilocarpine for postirradiation xerostomia in patients with head and neck cancer. N Engl J Med 1993;329:390–395. 9 Brizel DM, Wasserman TH, Henke M, et al. Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol 2000;18:3339–3345. 10 Buntzel J, Glatzel M, Kuttner K, Weinaug R, Frohlich D. Amifostine in simultaneous radiochemotherapy of advanced head and neck cancer. Semin Radiat Oncol 2002;12:4–13. 11 Eisbruch A, Ten Haken RK, Kim HM, Marsh LH, Ship JA. Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys 1999;45:577–587. 12 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. 13 Marks JE, Davis CC, Gottsman VL, Purdy JE, Lee F. The effects of radiation of parotid salivary function. Int J Radiat Oncol Biol Phys 1981;7:1013–1019. 14 Chao KS, Deasy JO, Markman J, 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;49:907–916. 15 Dawson LA, Anzai Y, Marsh L, et al. Patterns of local-regional recurrence following parotid-sparing conformal and segmental
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21 22 23
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intensity-modulated radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 2000;46:1117–1126. Chao KS, Ozyigit G, Tran BN, Cengiz M, Dempsey JF, Low DA. Patterns of failure in patients receiving definitive and postoperative IMRT for head-and-neck cancer. Int J Radiat Oncol Biol Phys 2003;55: 312–321. Bussels B, Maes A, Hermans R, Nuyts S, Weltens C, Van Den Bogaert W. Recurrences after conformal parotid-sparing radiotherapy for head and neck cancer. Radiother Oncol 2004;72:119–127. Munter MW, Karger CP, Hoffner SG, et al. Evaluation of salivary gland function after treatment of head-and-neck tumors with intensitymodulated radiotherapy by quantitative pertechnetate scintigraphy. Int J Radiat Oncol Biol Phys 2004;58:175–184. Liem IH, Olmos RA, Balm AJ, et al. Evidence for early and persistent impairment of salivary gland excretion after irradiation of head and neck tumours. Eur J Nucl Med 1996;23:1485–1490. Henson BS, Inglehart MR, Eisbruch A, Ship JA. Preserved salivary output and xerostomia-related quality of life in head and neck cancer patients receiving parotid-sparing radiotherapy. Oral Oncol 2001;37: 84–93. Eisbruch A, Ship JA, Martel MK, et al. Parotid gland sparing in patients undergoing bilateral head and neck irradiation: techniques and early results. Int J Radiat Oncol Biol Phys 1996;36:469–480. 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. Zimmerman RP, Mark RJ, Tran LM, Juillard GF. Concomitant pilocarpine during head and neck irradiation is associated with decreased posttreatment xerostomia. Int J Radiat Oncol Biol Phys 1997;37:571–575. Corry J, Rischin D, Smith JG, et al. Radiation with concurrent late chemotherapy intensification (‘chemoboost’) for locally advanced head and neck cancer. Radiother Oncol 2000;54:123–127.
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25 Rischin D, Peters L, Fisher R, et al. Tirapazamine, cisplatin, and radiation versus fluorouracil, cisplatin, and radiation in patients with locally advanced head and neck cancer: a randomized phase II trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02). J Clin Oncol 2005;23:79–87. 26 Rischin D, Corry J, Smith J, Stewart J, Hughes P, Peters L. Excellent disease control and survival in patients with advanced nasopharyngeal cancer treated with chemoradiation. J Clin Oncol 2002;20:1845–1852. 27 S-plus 2000. Seattle, WA: Mathsoft Inc, 1999. 28 Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 1998;16: 1310–1317. 29 Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-analysis of chemotherapy on head and neck cancer. Lancet 2000;355:949–955. 30 Calais G. Radiation and concomitant chemotherapy after surgery for breast cancer: Arcosein study [in French]. Cancer Radiother 1998;2: 469–474. 31 Malouf JG, Aragon C, Henson BS, Eisbruch A, Ship JA. Influence of parotid-sparing radiotherapy on xerostomia in head and neck cancer patients. Cancer Detect Prev 2003;27:305–310. 32 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;28:457–462. 33 Dawes C. Rhythms in salivary flow rate and composition. Int J Chronobiol 1974;2:253–279. 34 Dawes C, Wood CM. The contribution of oral minor mucous gland secretions to the volume of whole saliva in man. Arch Oral Biol 1973; 18:337–342.
Original Article Parotid-sparing Radiotherapy: Does it Really Reduce Xerostomia? M. K. Ng*, S. V. Porcedduy, A. D. Milnerz, J. Corry*, C. Hornby*, G. Hope*, D. Rischinx, L. J. Peters* *Department of Radiation Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; yDepartment of Radiation Oncology, Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia; zCentre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; xDivision of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia ABSTRACT: Aims: Parotid-sparing radiotherapy (PSRT) was introduced for patients with selected head and neck cancer requiring bilateral upper-neck irradiation at our centre in 2000. The aim of this study was to compare the subjective degree of xerostomia in patients treated with PSRT between January 2000 and June 2003 with patients treated using conventional techniques (radiotherapy) over the same period. Materials and methods: Eligible patients were required to have completed treatment 6 months previously and be recurrence-free at the time of interview. PSRT was defined as conformal radiotherapy, in which the mean dose to at least one parotid gland was 33 Gy or less, as determined by the dose–volume histogram. Patients receiving radiotherapy were treated with standard parallel-opposed fields, such that both parotids received a minimum of 40 Gy. Xerostomia was assessed using a validated questionnaire containing six questions with a rating between 0 and 10. Lower scores indicated less difficulty with xerostomia. Results: Thirty-eight eligible patients treated with PSRT were identified: 25 with oropharyngeal cancer and 13 with nasopharyngeal cancer (NPC). The mean overall questionnaire score (Q1–5) for this group was 4.20 (standard error Z 0.33). Forty-four patients (24 oropharyngeal, 21 NPC) treated with radiotherapy over the same period were eligible. The mean overall questionnaire score (Q1–5) for this group was 5.86 (standard error Z 0.35). The difference in mean overall scores between the two groups of patients was statistically significant (P ! 0.001), as were the scores for four of the six individual questions. Conclusion: These results suggest that PSRT offers improved long-term xerostomia-related quality of life compared with conventional radiotherapy. Ng, M. K. et al. (2005). Clinical Oncology 17, 610–617 Ó 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Head and neck cancer, parotid, quality of life, radiotherapy, three-dimensional treatment planning, xerostomia Received: 15 February 2005
Revised: 17 June 2005 Accepted: 20 June 2005
Introduction
Xerostomia is the most frequently reported late side-effect after radiotherapy for head and neck malignancies, and a major cause of reduced quality of life [1,2]. Effective treatment options for xerostomia are poor. Patients generally find saliva substitutes unsatisfactory. They offer limited efficacy of short duration, and lack the protective roles of saliva [3]. Saliva stimulants, such as pilocarpine, have shown promising results [4–8], but have significant side-effects and can be costly. The alternative strategy is salivary gland protection. This can potentially be achieved medically by the use of
Author for correspondence: Dr Michael Ng, Department of Radiation Oncology, Peter MacCallum Cancer Centre, Locked Bag 1 A’Beckett Street, Melbourne, Victoria 8006, Australia. Tel: C61-3-9656-1111; Fax: C61-3-9656-1424; E-mail: [email protected] 0936-6555/05/000000C08 $35.00/0
radioprotectors. Amifostine has been shown to reduce chronic xerostomia in Phase III trials; however, the administration of the drug is cumbersome, requiring daily intravenous injections before each radiation fraction, and the possibility of tumour protection remains a clinical concern [9,10]. A recent randomised study of pilocarpine used during and after radiotherapy failed to demonstrate a beneficial effect on radiation-induced xerostomia [5]. Physical protection of salivary function by reduction of parotid radiation dose is another attractive alternative. Eisbruch et al. [11,12] showed that if the mean radiation dose threshold to the parotid glands was less than 26 Gy, parotid gland function recovers fully over 1–2 years. Marks et al. [13] reported a marked reduction in salivary flow in parotid glands receiving more than 40 Gy. More recently, the dose threshold to the parotid gland was reported to be 32 Gy [14]. Standard radiotherapy techniques to radical doses for head and neck cancer invariably deliver high dose to both parotid glands (O50 Gy).
Ó 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
PAROTID-SPARING RADIOTHERAPY AND XEROSTOMIA
In recent years, conformal radiation techniques using computed tomography image-based computer planning, such as three-dimensional conformal radiation therapy (3DCRT) and intensity-modulated radiotherapy (IMRT) have permitted sparing of salivary glands. A concern with the use of conformal techniques to spare the salivary glands is the risk of reduction in treatment outcome by under-dosing disease or geographical miss. However, several recent studies using 3-DCRT or IMRT in head and neck cancers have not demonstrated inferior locoregional tumour control [15–18]. Longitudinal studies investigating the use of these parotid-sparing radiotherapy techniques (PSRT) report improved salivary flow and self-reported xerostomiaspecific quality of life [12,14,18–22]. At this centre, PSRT has been used in selected patients for at least 4 years. Before this, patients with head and neck cancers requiring bilateral neck irradiation were treated with standard radiotherapy techniques, with both parotid glands receiving a mean dose of at least 40 Gy. In this study, we aimed to assess the quality of life (QOL) outcomes in patients treated with PSRT using a xerostomia-specific questionnaire [23], and compared them with patients who received high-dose radiation to both parotid glands.
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as ‘parotid sparing’ (%33 Gy to at least one parotid gland defined by the dose–volume histogram). These patients would have received high dose to both parotid glands with conventional parallel-opposed radiation fields. The dose threshold of 33 Gy was selected arbitrarily as the mid-point of the range reported in the literature of between 26 and 40 Gy [11–14]. Conventional Radiotherapy
The comparison non-parotid-sparing group, termed ‘radiotherapy’ was defined as patients who received standard bilateral neck irradiation delivering a high dose (O40 Gy) to both parotid glands. Most received in excess of 50 Gy. Our treatment policy was to offer PSRT to all patients whose disease volume made it technically feasible to spare at least one parotid gland with either IMRT or 3-DCRT. However, owing to workload constraints, not all eligible patients received PSRT. Because of limited availability, IMRT was generally reserved for patients with nasopharyngeal carcinoma. Radiotherapy Technique
This was an unmatched cohort study, with follow-up assessment of xerostomia-specific quality of life after treatment in head and neck cancer patients treated at the Peter MacCallum Cancer Centre from January 2000 to June 2003. Patients were retrospectively identified from the patient record information database.
All patients were immobilised in a cobex mask and treated with photons, electrons, or both, using linear accelerators (6–18 MV). Patients had a planning computed tomography scan for dosimetry purposes. The planning target volume (PTV) was designed to encompass the gross-tumour volume, with at least a 1.0 cm margin in patients treated radically. In postoperative patients, the PTV encompassed the site of resected disease by at least 1.5 cm margin. Doses were prescribed according to ICRU 50 criteria.
Eligibility Criteria
Parotid-sparing Radiotherapy
To be eligible, patients had to have (1) received radical or postoperative radiotherapy for oropharyngeal cancers or nasopharyngeal cancers (NPC); (2) had no previous head and neck radiotherapy; (3) required bilateral upper-neck irradiation; (4) received radiotherapy at least 6 months before the quality of life assessment; and (5) been disease free at the time of the questionnaire. Six months after radiotherapy was chosen as the minimum time to assess xerostomia. This allows for the resolution of acute mucositis and permits a better assessment of true late xerostomia. Only patients who were disease free at the time of the questionnaire were eligible to ensure there was no confounding effect to quality of life issues.
In patients receiving PSRT, the entire parotid gland was outlined bilaterally to enable the determination of the dose– volume histogram and optimisation of the treatment plan. PSRT was delivered using either IMRT or a 3-DCRT. In this series of patients, IMRT was most often delivered using 8–10 coplanar fields to treat the primary site and bilateral neck. Dose differential (maintaining the same field size) was used rather than a shrinking field technique. The planning software used was Varian CadplanÔ, with the optimisation being carried out on Varian HeliosÔ. The three-dimensional conformal parotid-sparing technique (unpublished) was developed at our institution because of the limited availability of IMRT. In most patients, a two-phase technique was used. Phase I was delivered using six coplanar fields: anterior, posterior, two posterior oblique and two opposed-lateral fields to deliver 50 Gy encompassing the gross tumour and electively treated neck nodes. The weighting of the fields was as follows: anterior (1.0), posterior (0.6), posterior obliques (1.0) and laterals (1.0). Phase II was designed to deliver 16–20 Gy to gross tumour, or 10 Gy to the site of resected disease in cases treated postoperatively, typically using two
Methods
Cohorts
Two patient groups were identified from the cohort. Parotid-sparing Radiotherapy
The parotid-sparing radiotherapy group, termed ‘PSRT’, was defined as patients who received radiotherapy planned
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to three fields. Field arrangements were designed to limit the mean dose to at least one parotid gland to 33 Gy or less. Both parotids are spared if this could be achieved without compromising coverage of the PTV. Conventional Radiotherapy
In most cases, patients were planned with orthogonalsimulation films. Treatment fields were drawn on the simulation films. Isodose distributions were generated and three-dimensional compensation (correcting for both missing tissue and tissue inhomogeneities) was used to achieve a dose homogeneity of G5%. The parotid dose–volume histogram was not routinely calculated for the radiotherapy patients, but a clinico-radiological assessment was made to demonstrate that both parotids would receive at least 40 Gy, and, in most cases, more than 50 Gy. Treatment was delivered using a two-phase technique. Phase I involved parallel-opposed fields up to 50 Gy to the gross tumour and electively treated neck nodes. Posterior electrons ‘strips’ were usually introduced after 40 Gy to restrict the spinal cord dose of 45 Gy or less. Phase II involved a field reduction to treat the gross disease with at least a 1.5 cm margin using either parallel opposed or oblique field arrangements. The lower neck was most commonly treated with an anterior 6 MV photon field with midline shielding. The dose for elective treatment was 50 Gy specified at 2 cm depth. Chemotherapy
Patients with oropharyngeal cancer treated with chemotherapy were treated either with the ‘chemoboost’ protocol described by Corry et al. [24] or were enrolled on a prospective randomised Phase II chemo-radiotherapy trial reported by Rischin et al. [25]. In patients with NPC, those with locally advanced disease received a chemoradiotherapy regimen described by Rischin et al. [26].
Xerostomia Assessment
The primary end point of this study was the xerostomiaspecific quality-of-life score calculated from a questionnaire. The questionnaire, also used in studies assessing pilocarpine [4,8], consists of a validated bank of six questions about the patient’s self-assessed mouth dryness and is shown in Fig. 1. Patients were asked to rate difficulty with items related to specific and general aspects of xerostomia on a scale of 0–10. Lower scores indicated less difficulty with xerostomia. Scores for each question were recorded, and an ‘overall questionnaire score’ was calculated for each patient, as the average of the six component scores. Ethics
The ethics committee of our centre approved this study. All patients were informed of the purpose of the study when contacted by investigators. Statistical Analysis
Patient, tumour and treatment characteristics of the patients completing the questionnaire were tabulated for all patients and separately for the PSRT and radiotherapy groups. Responses to individual xerostomia questions were compared between the PSRT and radiotherapy groups using the Mann–Whitney test. Box-&-whisker plots were used to graphically display the distribution of responses to the six xerostomia questions. In these plots, the box represents the inter-quartile range (middle 50% of scores), with a symbol (circle) showing the median score; the whiskers extend to the minimum and maximum scores. The overall questionnaire score was computed as the average score from all questions, and was compared between PSRT and radiotherapy groups using the standard twosample t test. The overall questionnaire score was compared between patient groups using either the two-sample t test
Question 1. During the last 3 days, overall, on a scale of 0 to 10, how dry was your mouth or tongue? 0 is not dry and 10 is very dry. Question 2. In general, during the daytime hours of the last 3 days, rate the feeling of your mouth and tongue on a scale of 0 to 10, with 0 is comfortable and 10 is extremely uncomfortable. Question 3. During the last 3 nights, due to the dryness of your mouth and tongue, how difficult was it to sleep? Consider such factors as how difficult it was for you to go to sleep, the duration and the quality of your sleep, and how often you woke up to drink or to urinate. On a scale of 0 to 10, 0 is easy and 10 is extremely difficult. Question 4. During the last 3 days, overall, due to the dryness of your mouth and tongue, how difficult was it to speak without drinking liquids? On a scale of 0 to 10, 0 is easy and 10 is extremely difficult. Question 5. During the last 3 days, overall, due to the dryness of your mouth and tongue, how difficult was it to chew and swallow food? On a scale of 0 to 10, 0 is easy and 10 is extremely difficult. Question 6. If you normally wear dentures, due to the dryness of your mouth and tongue, how difficult was it to wear dentures in the last 3 days? On a scale of 0 to 10, 0 is easy and 10 is extremely difficult.
Fig. 1 – Xerostomia questionnaire.
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PAROTID-SPARING RADIOTHERAPY AND XEROSTOMIA
(two groups) or analysis of variance (greater than two groups). Note that the Welch modified two-sample t test was used, when appropriate, for situations in which there were pronounced differences in group variances. The statistical analyses were carried out using S-plus software [27]. All tests were two-sided, and statistical significance was defined as P ! 0.05.
Results
During the study period, 160 patients received radical radiotherapy for oropharyngeal cancer and NPC of whom 82 met the eligibility criteria. Patient and Tumour Characteristics
Patient characteristics are shown in Table 1. Seventy-six per cent were men, and the median age was 55 years (range 25–83 years). The primary tumour site was oropharyngeal cancer in 59% of patients (n Z 48) and 41% for NPC (n Z 34). The predominant histological type was squamous-cell carcinoma in 62% of patients (n Z 51), and 83%
(n Z 68) of patients had a stage III–IV tumour. The median follow-up from the last day of radiotherapy treatment was 17 months (range 6–34 months). Treatment
Treatment data are shown in Table 2. Most patients received definitive radiotherapy, whereas 9% received adjuvant postoperative radiation. The median total tumour dose was 70 Gy given in 35 fractions. Seventy-eight per cent of patients received chemo-radiotherapy as part of the treatment; 84% of PSRT and 71% of radiotherapy patients were given chemotherapy. Thirty-eight patients were treated with PSRT (46%) and 44 patients received conventional non-PSRT (54%). Of these 38 PSRT patients, 10 patients were treated with IMRT and 28 patients were treated with 3-DCRT. Xerostomia Quality of Life
All patients were interviewed at least 6 months after completing radiotherapy. The median follow-up was longer in the radiotherapy group compared with the PSRT group:
Table 1 – Patient and tumour characteristics overall and for each cohort Overall N
Radiotherapy %
82
Total patients
76 24
Parotid-sparing radiotherapy
n
%
n
%
44
54
38
46
36 8
82 18
26 12
68 32
Sex
Male Female
62 20
Age (at presentation)
Median Range
55 25–83
Primary tumour site
Oropharyngeal wall Tonsil Base of tongue Vallecula Nasopharynx
8 28 11 1 34
10 34 13 1 41
4 12 7 0 21
9 27 16 0 48
4 16 4 1 13
11 42 11 3 34
Histological type
Squamous-cell carcinoma Adenocarcinoma Undifferentiated nasopharyngeal cancer (WHO3) Other
51 1 22 8
62 1 26 9
26 1 12 5
59 2 27 11
25 0 10 3
66 0 26 8
Histological grade at diagnosis
Well differentiated Moderately differentiated Poorly differentiated or undifferentiated Not stated
6 12 49 15
7 15 60 18
2 7 26 9
5 16 59 20
4 5 23 6
11 13 61 16
Overall stage*
1 2 2A 2B 3 4A 4B Unstageable
3 1 2 6 27 33 8 2
4 1 2 7 33 40 10 2
1 1 2 2 14 16 6 2
2 2 5 5 32 36 14 5
2 0 0 4 13 17 2 0
5 0 0 11 34 45 5 0
54 25–83
56 28–76
*AJCC Cancer Staging Manual, Sixth Edition, American Joint Committee on Cancer; Springer-Verlag New York, New York, 2002.
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Table 2 – Treatment details (including radiotherapy and chemotherapy) Overall N
Radiotherapy %
n
75 7
Total tumour dose
Median Range
70 58–74
70 60–74
70 58–70
Number of fractions
Median Range
35 29–37
35 30–37
35 29–35
Technique
Two-field More than three-field or multiple conformal Intensity-modulated radiotherapy
28 40 14
17
4
9
10
26
Chemotherapy
No chemotherapy Induction and concurrent chemotherapy for nasopharyngeal cancer* Chemoboosty Intermittent platinumz Weekly platinumx Tirapazamine regimenk
18 19
22 23
7 15
16 34
11 4
29 11
12 11 6 16
15 13 7 20
5 4 2 11
11 9 5 25
7 7 4 5
18 18 11 13
Mean Median Range
17.63 17 6–34
28 12
93 7
%
Radical Adjuvant
34 49
41 3
%
Radiotherapy intent
Follow-up (months)
91 9
n
Parotid-sparing radiotherapy
34 4
64 27
89 11
0 28
20.71 20 6–34
0 74
14.07 11 6–31
*Three induction cycles: epirubicin, cisplatin, 5-fluorouracil [5-FU] and concurrent cisplatin weeks 1 and 6 during radiation. yChemoboost: cisplatin 5-FU during last 2 weeks of radiation. zIntermittent platinum: cisplatin during weeks 1, 4 and 7 of radiation. xWeekly platinum: cisplatin weekly during radiation. kTirapazamine regimen: tirapazamine during weeks 1, 2, 3, 4 and 7 with cisplatin during weeks 1, 4 and 7 of radiation.
20 months (range 6–34 months) and 11 months (range 6–31 months), respectively. This is explained by the increased use of PSRT with each year and a larger proportion of patients being offered PSRT in the later years, limiting their available follow-up time. All 82 patients answered questions 1 to 5. However, for question 6, only 30 out of 82 patients responded (17 in the radiotherapy group, 13 in the PSRT group), as patients qualified to answer this question presumably must have worn dentures. Consequently, the overall questionnaire score was calculated from the average of questions 1–5 for all 82 patients and separately for the 30 patients with dentures (average of all six questions).
and PSRT [4.24]; P Z 0.344), but the difference was not significantly different. A trend was observed for lower overall questionnaire scores if both parotid glands were spared, compared with one gland (3.48 for both parotids vs 4.39 for one parotid only), but this was not statistically significant (P Z 0.269). The mean overall questionnaire score was significantly lower (P Z 0.027) for the 10 patients who received IMRT
Table 3 – Overall questionnaire score for radiotherapy and parotidsparing radiotherapy
Radiotherapy*
Overall Questionnaire Score
The mean overall questionnaire score (Q1–5) was 5.86 for the radiotherapy group and 4.20 for the PSRT group (Table 3). The lower questionnaire score in the PSRT group supported the finding that these patients had less xerostomia compared with the radiotherapy group (P ! 0.001). The difference was even more marked in the 34 patients with NPC in whom the mean overall questionnaire scores were 5.6 and 3.2 for radiotherapy and PSRT, respectively (P Z 0.0019). When the mean overall questionnaire was calculated with the addition of question 6 (n Z 30), scores remained lower in the PSRT group (radiotherapy [5.06],
Parotid-sparing radiotherapyy P valuez
Average Mean score 1–5 Standard deviation (n Z 82) Median Range
5.86 2.29 6.30 0–10
4.20 2.06 4.50 0.4–8
Average Mean score 1–6 Standard deviation (n Z 30) Median Range
5.06 2.61 6 0–9
4.24 1.79 4.50 0.5–6.83
!0.001
0.344
*Conventional radiotherapy. yParotid-sparing radiotherapy. zTwo-sample t test.
PAROTID-SPARING RADIOTHERAPY AND XEROSTOMIA
(2.98), compared with the 28 patients in the 3-DCRT group (4.63). Both parotid glands were spared in six out of 10 patients who received IMRT, compared with four out of 28 patients who received 3-DCRT. Additional variables that were not found to be significantly associated with xerostomia scores in this analysis included age, sex, chemotherapy and tumour site. Individual question scores have been summarised graphically in Fig. 2. The distribution of scores differs significantly between radiotherapy and PSRT groups for question 1, ‘dryness’ (P ! 0.001), question 3, ‘sleep’ (P ! 0.05), question 4, ‘speech’ (P ! 0.01) and question 5, ‘eating’ (P ! 0.01). Follow-up Effect and Overall Questionnaire Scores
It was previously noted that the median follow-up time was shorter in the PSRT group. A further analysis was carried out on the two groups. Each group was divided into two follow-up times: less than 12 months and greater than 12 months. There seemed to be no time effect on the mean overall questionnaire score. Within the PSRT group, no significant difference was observed between the follow-up periods and, similarly, in the radiotherapy group (Table 4). Discussion
Over the past two decades, major radio-therapeutic advances have been made in the treatment of head and neck malignancies. Improvements in diagnostic imaging, planning and treatment, availability of IMRT and the use of concurrent chemotherapy [28–30], have all potentially contributed to improved local regional control and survival. These aggressive treatments are not without considerable toxicity, and increasing attention is being directed at patient’s subsequent quality of life, particularly the affect of xerostomia. Our results suggest that PSRT may offer improved xerostomia-related quality of life compared with conventional radiotherapy. Using the validated questionnaire, significant differences were observed in the overall scores
615
for questions 1–5, and for the individual questions 1, 3, 4, and 5 relating to sense of oral dryness and difficulty with sleep, speech and eating. Curiously, the overall score difference was not significant when question 6 (which relates to difficulty in wearing dentures) was included. This could be due to the relatively small number of patients (n Z 30) who answered question 6. Another possible explanation is that xerostomia does not have a significant effect on wearing dentures comfortably or that edentulous patients simply do not wear their dentures enough for them to perceive a problem related to xerostomia. More recent studies have not used denture-related questions in their questionnaires [12,14,20,22,31]. In our study, despite the improved xerostomia-specific quality of life in patients receiving PSRT, an objective improvement in salivary gland function cannot be asserted, as we did not measure salivary flows. However, we believe that subjective symptomatic self-assessment by the patient is a more meaningful criterion by which to assess the benefit of a change in treatment technique than actual salivary flow rates. Only one other study by Malouf et al. [31] has compared xerostomia between PSRT and conventional techniques. The results showed that PSRT was successful in preserving salivary flow compared with conventional non-PSRT techniques, although the numbers were not evenly balanced (patients receiving PSRT [n Z 88] vs patients receiving non-PSRT [n Z 11]). This study suffers from some problems inherent in most retrospective studies. There was no baseline questionnaire assessment, and there was a significant difference in follow-up time between the two groups. The median follow-up time was shorter in the PSRT group (11 months) than in the radiotherapy group (20 months). However, any bias would favour the radiotherapy group, and a median follow-up time of almost 12 months is likely to predict longer-term results fairly accurately. Eisbruch et al. [12] showed continuous improvement in salivary function during the 2 years after radiotherapy, and in glands that received a mean parotid dose less than 26 Gy, the salivary output returned to pre-radiotherapy levels usually by 1 year. Franzen et al. [32] noticed that
Fig. 2 – Box-plots for individual xerostomia questions: parotid-sparing radiotherapy (PSRT) vs radiotherapy (RT).
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Table 4 – Overall questionnaires scores (Q1–5) and time of follow-up after radiotherapy for parotid-sparing radiotherapy and radiotherapy group Follow-up
Group
n
Mean
Standard deviation
Median
Range
P value*
!12 months O12 months
Parotid-sparing radiotherapy Parotid-sparing radiotherapy
20 18
4.17 4.23
1.92 2.27
4.2 4.8
0.8–7.6 0.4–8.0
0.926
!12 months O12 months
Radiotherapy Radiotherapy
8 36
6.08 5.82
2.30 2.32
6.5 6.2
2.4–9.0 0.0–10.0
0.777
*Two-sample t test.
irradiation of the parotid to doses of 40–50 Gy caused generally reversible changes with restored salivary gland function within 6–18 months after completing radiotherapy. Of note, the follow-up period of the pilocarpine studies ranged from 3 to 12 months [4–8]. We used the xerostomia-specific questionnaire for our study, as it formed part of the assessment tool that led to FDA approval of pilocarpine in radiation-induced xerostomia. Patients who participated in this study coped well with answering the questionnaire. The participation rate was 100%, and patients were eager to discuss their symptoms and its treatment further. Other studies since have used the same questionnaire [14,23]. Of note, Chao et al. [14] used the same questionnaire in assessing xerostomia in patients receiving PSRT, and found a strong correlation between the questionnaire score and the salivary flow rate. They stated that the results implied that salivary function sparing would provide better quality of life. Potential biases in our study relate to patients possibly knowing that they had been treated using parotid-sparing techniques (which may affect their perception of xerostomia) and the tendency for patients to adapt with time to the affect of reduced saliva. The latter consideration would, however, have favoured the radiotherapy group, as their median follow-up time was longer. Other potential confounders not recorded in this study were post-treatment smoking and medications that may aggravate xerostomia. The PSRT used at our centre involved either IMRT or 3DCRT. Although IMRT is preferable, it is not available at all centres for a variety of reasons. The three-dimensional conformal technique we have developed provides an acceptable alternative for PSRT. However, the use of conformal techniques to reduce the dose to the parotid glands can result in an increase of integral dose and delivery of higher doses to the submandibular glands and the oral cavity. The submandibular glands produce about 30% of the total saliva volume under stimulation but, at rest, may account for 90% of total saliva [33]. The minor salivary glands in the mucosal membranes of the oral cavity account for lubrication of the oral mucosa [32] and produce 7–8% of total saliva [34]. Dose–volume relationships of the oral cavity, a surrogate for dose to the minor salivary glands, and submandibular DVH, has been shown to be an independent factor in predicting xerostomia scores [12]. During the study period, we did not routinely record the dose–volume histogram data for the submandibular glands or for the oral cavity, but it is likely that the extra dose to
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