Radiotherapy and Oncology, 22 (1991) 133-139
(c) 1991 Elsevier Science Publishers B.V. All rights reserved. 0167-8140/91/$03.50
133
RADION 00895
Parotid gland function following accelerated and conventionally fractionated radiotherapy M. D. Leslie and S. D i s c h e Marie Curie Research Wing, Mount Vernon Centrefor Cancer Treatment, Mount Vernon Hospital, Northwood, Middlesex, U.K.
(Received 14 January 1991, revision received 3 July 1991, accepted 5 August 1991)
Key words: Parotid function; Accelerated fractionation; CHART; Radiotherapy
Summary The function of the parotid glands in patients treated by three different schedules of radiotherapy was studied 9 months or more after its conclusion. All had received radiotherapy for a malignancy confined to one side of the head and neck :region and only the gland on the side of the lesion was in the treatment volume; the contralateral gland acted as an internal control. Saliva was selectively collected from the parotid glands and the stimulated flow rate and pH of the saliva determined. Flow rates were expressed in each case as a percentage of that of the contralateral ("untreated") gland. Twelve glands that had received conventionally fractionated radiotherapy to a dose of 60-66 Gy showed a mean percentage flow of 20% and a significant fall in the pH of the saliva produced. Six glands that had received C H A R T and eight conventionally fractionated radiotherapy to a dose of 35-40 Gy showed mean percentage flows of 57 and 65%, respectively, with only slight and non-significant falls in saliva pH. The results show that in the treatment of squamous cell carcinoma in the head and neck the use of C H A R T can lead to considerably less late change in the function of the parotid gland.
Introduction Irradiation of salivary glands during the treatment of head and neck cancer may lead to an alteration in the amount and quality of the saliva produced. As a consequence of this, patients suffer dryness of mouth with oral discomfort, altered taste acuity and dental decay [19]. The normal human salivary glands produce over a litre of saliva per day [ 14]. Ninety percent of salivary secretion is produced by three pairs of major glands: the parotid, the submandibular, and the sublingual glands with the remainder coming from numerous minor salivary glands distributed throughout the oral cavity [ 11 ]. The parotid and submandibular glands are the main contributors to salivary secretion, the sublingual glands contribute only 2-5 To of total salivary flow [ 14]. Under resting conditions the flow from the submandibular glands is at least as great as that from the parotids, however, under conditions of stimulation (e.g. eating or drinking) the parotid glands become the main contribu-
tors [19,23]. In humans, the parotid glands consist entirely of serous acini producing a clear watery product virtually devoid of mucin. The submandibular and sublingual glands contain mucous and serous acini whilst the minor salivary glands are predominantly mucous secretors [ 11,14,19]. The serous acini are considered to be the most sensitive to ionising radiation [19,24] and it is the loss of their watery product that results in the thick tenacious secretions observed during and after a course of radiotherapy [19]. Dryness of mouth is most marked when both parotid glands are fully included in the treatment volume [24]. No measure is available to increase salivary flow and management is often unsatisfactory largely relying on saliva substitutes [6,24]. Falls in resting saliva flow from the human parotid gland have been detected as early as 24 h after a single dose of 2.25 Gy [23]. The stimulated flow falls by 50~o at the end of the first week of radiotherapy when a dose of about 10 Gy has been given [17] and continues to decline throughout a course of treatment, often to levels that are barely measurable [9]. The early effects of
Address for correspondence: M. D. Leslie, Marie Curie Research Wing, Mount Vernon Centre for Cancer Treatment, Mount Vernon Hospital,
Northwood, Middlesex HA6 2RN, U.K.
134 radiotherapy on salivary tissue are also manifested by a rise in the blood amylase that can be detected within hours of a dose of radiotherapy [ 12]. This possibly reflects the interphase death that the serous cells of the parotid gland undergo in responses to radiotherapy [251. Late effects of radiotherapy on parotid gland function with decreased production of saliva have been demonstrated up to 7 years following radiotherapy [18]. Marks et al. [15] found no measurable salivary flow after stimulation from 24 parotid glands that had received irradiation to a dose of 60 Gy or more from 5 to 47 months previously. In addition, it has been shown that the pH of the saliva produced falls [ 15] resulting in an altered oral microflora that is highly cariogenic
[21. Patients with head and neck cancer treated with continuous hyperfractionated accelerated radiotherapy (CHART) appear to show less dryness of mouth than patients with comparable tumours treated by conventionally fractionated radiotherapy [ 13]. This study has investigated the function of the parotid gland
following conventionally fractionated radiotherapy at two dose levels and after CHART. Patients and methods
The patients included had been treated by radiotherapy for a malignancy confined to one side of the head and neck region. In all cases, radiotherapy was given using a unilateral technique employing anterolateral and posterolateral fields. This resulted in the parotid gland on the ipsilateral side being encompassed in the treatment volume and a dose less than 25~o of that prescribed being delivered to the contralateral gland. All patients were treated with radiotherapy as the sole treatment modality and at the time of testing all were in complete remission and at least 9 months after radiotherapy. All patients were treated on a 5 MV Linear accelerator. Three groups of patients were studied (Table I): - T w e l v e treated with conventionally fractionated radiotherapy for a squamous cell carcinoma received
TABLE I Summary of patients details. No.
Age
Sex
Primary site
Histology
Radiotherapy (Gy/fractions/days)
Time till testing (yrs)
01 02 03 04 05 06 07 08 09 10 11 12
54 68 67 72 75 63 78 79 74 55 67 63
M M M M F M M M M F F F
Tonsil Tonsil Tonsil Retromolar Retromolar Tonsil Tonsil Tonsil Tonsil Retromolar Palate Buccal
SCC SCC SCC SCC SCC SCC SCC SCC SCC SCC SCC SCC
66/33/49 60/30/45 64/32/46 60/30/43 64/32/51 64/32/49 64/32/48 64/32/49 64/32/49 65/32/57 60/30/43 64/32/44
1.8 2.3 2.2 1.6 3.8 1.0 2.8 3.5 6.4 7.5 5.0 8.2
13 14 15 16 17 18 19 20
44 70 70 55 51 60 62 54
M M F M F M M M
Tonsil Tonsil Tonsil Parotid Tonsil Tonsil Tonsil Tonsil
NHL NHL NHL HD NHL NHL NHL NHL
40/22/29 40/20/27 40/20/26 35/17/18 40/20/26 40/20/26 40/20/26 40/20/27
1.4 5.4 3.2 9.0 4.4 2.1 5.9 8.0
21 22 23 24 25 26
71 76 67 58 52 72
M M F M F M
Tonsil Tonsil Palate Retromolar Retromolar Alveolus
SCC SCC SCC SCC SCC SCC
54/36/12 54/36/12 54/36/12 54/36/12 54/36/12 54/36/12
4.1 3.0 1.8 1.4 1.0 0.8
HD = Hodgkins lymphoma; NHL = non-Hodgkins lymphoma; SCC = squamous cell carcinoma.
Group 1 Conventional 60-66 Gy
Group 2 Conventional 35-40 Gy
Group 3 CHART
135 between 60 and 66 Gy minimum tumour dose in 30-33 fractions over 6 - 7 weeks. Eight treated with conventionally fractionated radiotherapy for lymphoma received between 35 and 40 Gy minimum tumour dose in 17-22 fractions over 3.5-4.5 weeks. - Six treated with C H A R T for squamous cell carcinoma received 54 Gy minimum tumour dose in 36 fractions over 12 consecutive days treating three times a day using an individual dose increment of 1.5 Gy. In addition, 20 other head and neck cancer patients were studied prior to receiving radiotherapy to establish the normal range of parotid function encountered in this population. All patients freely gave their informed consent for the study.
Collection of saliva This was carried out in a quiet room, patients having refrained from eating or smoking for at least one hour
prior to testing. No patient was receiving any medication known to interfere with salivary gland function. Lashley cups [22] were used to collect saliva simultaneously from both parotid glands. These small round plastic cups (Fig. la) have an inner and outer chamber, each being attached to fine bore plastic tubing. The inner chamber is placed over the opening of Stensen's duct (Fig. lb) and suction applied to the outer chamber from a 20 ml syringe provides the vacuum to hold the device firmly on the buccal mucosa of the cheek whilst saliva is collected from the inner chamber (Fig. 2). Stimulation of saliva flow was achieved by applying three drops of 2~o citric acid to the dorsum of the tongue at intervals of 2 min and collection was carried out for 10 rain. Saliva volume and pH were determined and flow rate expressed as millilitres of saliva per gland per minute. In the few cases where dislodgement of cups occurred it was possible to successfully repeat the procedure. Results
The procedure of saliva collection from the parotid glands proved relatively simple to perform and caused no discomfort or trauma to the patients. Figure 3 shows
Fig. l(a) Lashley cup for collection ofparotid saliva; (b) Lashley cup in place over Stensen's duct.
Fig. 2. Simultaneous collection of saliva from both parotid glands.
136 Right Parotid
Flow Rote rnl/min
Left Porotid O
0.7'
•-0,7 0
0.B
E
-A 0.B
0.5
0
v OA
a -a
• 00 • •
o
O
o
0-~
0.5
03
0.2
0.4
0.4 0.7 ¸
0.3
0.3
0.6.
0.5'
0-2.
[]
04'
o
0.2
o
0.3"
[] []
02'
0.1
o
[]
o
[]
[] •
0
o
•
0.1 0.1
•
0.0 ;
=," 2
0
Fig. 3. Parotid flow rates in 20 patients with head and neck cancer prior to radiotherapy demonstrating the normal variation in flow between individuals and the correlation of flow rates between glands in the same individual.
--i
;
100.0"1°.
rl 8 0 , 0 "1.o
o
o
the results obtained from the control group of 20 head and neck cancer patients studied prior to undergoing radiotherapy. A range of flow rates from 0.23 to 0.63 ml/min was obtained showing the relatively wide variation in function as previously reported [ 1]; however, there was only a small variation seen between both glands in the same individual. The flow rates from the contralateral ("untreated") glands of the three groups of patients studied following radiotherapy are given in Fig. 4a. Rates of flow from 0.30 to 0.68 ml/min were obtained. The pattern and range are similar to that obtained from our control group and furthermore no differences can be seen between the patients of the three treatment groups. In Fig. 4b, the flow rates from the ipsilateral ("treated") parotid glands of the three groups are shown. These are reduced in all cases as compared with the corresponding contralateral glands with rates from 0.0 to 0.6 ml/min being obtained. In each case the flow rate of the ipsilateral gland was expressed as a percentage of the flow rate from the contralateral gland (Fig. 4c). This removes the effect of the normal variation in flow between individuals and the contrallateral gland acts as an internal control. The greatest falls in flow were seen in glands treated by conventionally fractionated radiotherapy to a dose of 6 0 - 6 6 Gy. In 4 of the 12 ipsilateral glands there was no detectable function
6 0 O*/*'
13 o
8°o
o o
4 0 0"1.. []
•
20 O*/*,
O,0"/,
-~. . . .
;
~
~
;o
Years Since Rodiotheropy
Fig. 4(a) Flow rates in contralateral parotid glands; (b) flow rates in ipsilateral parotid glands; (c)flow rate of ipsilateral glands expressed as a percentage of the flow from the corresponding contralateral glands: 60-66 Gy (11), 35-40 Gy (C)), CHART (D).
and in the other 8 the percentage flow of the ipsilateral gland, as compared to the contralateral gland, did not exceed 41 ~o and the mean percentage flow of the whole group was 2 0 ~ (SE 4.7). A more modest impairment of function was seen in those glands treated either by conventionally fractionated radiotherapy to a dose of 35-40 Gy or by CHART. Percentage flow was greater than 50~o for all 8 cases treated to a dose of 35-40 Gy and for 5 of the 6 C H A R T cases.The mean percentage flows were 65~o (SE 5.8) and 57~o (SE 6.4), respectively. Only three patients (cases 3, 5 and 11) complained of any dryness of mouth. All were in the group treated by conventionally fractionated radiotherapy to a dose of 6 0 - 6 6 Gy and the flow rate from the ipsilateral gland
137 TABLE II Changes in pH of parotid saliva following radiotherapy. Treatment group
Conventional 60-66 Gy
Conventional 35-40 Gy
CHART 54 Gy
No, of patients
8*
8
6
7.23 (7.19-7.31 ) 7.42 (7.36-7.50) p < 0.005
7.36 (7.28-7.47) 7.41 (7.29-7.47) NS
7.34 (7.29-7.44) 7.42 (7.31-7.49) NS
pH mean (range) Ipsilateral Contralateral Difference
* Four cases had insufficient flow to measure pH.
was unrecordable in two and just detectable in the third with a flow rate of 0.06 ml/min. The secretions from the contralateral glands in these cases were at the lower range of normal being 0.32, 0.39 and 0.30 ml/min, respectively. Over the period studied, 9 months to 9 years after radiotherapy, there was no evidence for a recovery of function in the group given conventionally fractionated radiotherapy to 60-66 Gy. If the two other groups are pooled there is a suggestion of a slight degree of recovery with time. Only serial study in individual cases will show if this is a reality.
CONVENTIONAL CHART 35-40Gy
54Gy
CONVENTIONAL 60-66Gy
pH 7.50-
7.40-
pH
I
© I
- 7.50
I
- 7.40
1
I
7.30IP
i
- 7.30
7.20-
7,20
7.10-
,7.10
7.00
7.00
Fig. 5. pH (mean and range) of parotid saliva following radiotherapy. Ipsilateral glands (O), contralateral glands (©).
Results for the pH values of the parotid saliva are given in Table II and are illustrated in Fig. 5. Following irradiation by conventionally fractionated radiotherapy to a dose of 60-66 Gy there is a significant fall (p < 0.005) in the mean pH of saliva from the ipsilateral parotid glands (7.23) as compared to that from the contralateral glands (7.42). In the cases irradiated to a dose of 35-40 Gy and in those treated by CHART, a small fall in mean pH was observed but in neither group did this reach statistical significance. Discussion
In the treatment of head and neck cancer by radiotherapy the major salivary glands are inevitably included in the treatment volume. Tumour site, stage and the need for nodal irradiation will determine which salivary glands are included. The risk of dryness of mouth can be reduced if during treatment planning the volume of salivary tissue irradiated can be minimised [ 19]. If only the submandibular and sublingual glands are included in the treatment volume and not both parotids, most patients note little or no difference in the quality and quantity of their saliva [ 19]. If the radiotherapist can spare even a portion of one parotid from the treatment beam this may help to reduce morbidity [15]. Mira et al. [16] suggest that it is necessary to exclude more than 50~o of both parotids from the treatment volume to prevent severe dryness when the rest of the major glands are included. When the major portion of the parotid gland is irradiated with conventionally fractionated radiotherapy to doses of 60 Gy or more, reduction in salivary flow is usually found when measured months or years following treatment [ 3,7,15 ]. Marks et al. [ 15 ] studied the stimulated salivary flow from parotid glands that had received radiotherapy from 5 to 47 months previously. Measurable quantities of saliva were obtained
138 from 20~o of glands receiving 40-60 Gy and from none that had received a dose of more than 60 Gy. A doseresponse effect was demonstrated with salivary flow progressively falling with increasing dose of radiation. However, Eneroth et al. [7] have reported one patient whose parotid gland was functioning well 9 years after radiotherapy to a dose of 65 Gy. The reduction in function of the parotid gland is related to the volume of glandular tissue treated and the dose achieved [6]. However, other factors such as anatomical variation, the use of high energy apparatus which will spare superficially placed salivary tissue and variable degrees of function prior to radiotherapy [8] could all serve to influence the degree of functional impairment observed. This study has investigated the late effects of radiotherapy on the function of the parotid gland as assessed by salivary flow rate and alteration in pH of the saliva produced. Our results confirm the dose-response effect described by Marks et al. [15] with significant difference in salivary flow being seen between glands treated to a dose of 35-40 Gy compared to those receiving 60-66 Gy. We were, however, able to demonstrate some function, albeit reduced in 67~o of our cases treated to a dose of more than 60 Gy. This difference may reflect the repeated stimulation with citric acid used in our collection procedure compared with the single application of "sour grape drops" which they used. The three of our patients who did complain of dryness of mouth are of particular interest. In two there was no measurable function from the ipsilateral gland and in the third it was barely detectable. In addition, the flow from the contralateral glands was in all three cases at, or close to, the lower end of the normal range. This combination would seem to explain the symptom of dryness in these patients. A fall in saliva pH following radiotherapy results in an altered oral microflora that contributes to dental decay [2]. The absence of a significant fall in pH of parotid saliva after CHART may result in less dental decay in our patients following the treatment of squamous cell carcinoma in the head and neck region. This may mean that a more conservative approach to
dental extractions prior to radiotherapy can be adopted when treating with CHART. Dental problems may be of the same low incidence as after radiotherapy to the head and neck region for lymphomas. Following CHART, there is therefore less impairment of parotid gland function as compared with that after conventionally fractionated radiotherapy to doses of 60-66 Gy. This confirms our clinical impression that following CHART for squamous cell cancer in the head and neck there is less than expected dryness of mouth [13]. The function of the parotid gland following CHART is, in fact, more comparable to that seen when conventionally fractionated radiotherapy is given to the much lower dose of 35-40 Gy. With the exception of spinal cord [4,5] CHART has been followed by reduced late radiation change in all other normal tissues [13]. This reduction in the incidence of late changes after CHART was predicted radiobiologically on the basis of the low dose per fraction employed [ 10]. Using the "two regimen" comparison of Thames et al. [26] it would appear from our data showing similar parotid function after CHART and conventionally fractionated radiotherapy to a dose of 35-40 Gy that the c~//~ratio for this endpoint is in the low range. Therefore, the functional unit in question has a fractionation sensitivity akin to late responding tissues. In pilot studies CHART appeared to give greater tumour control in head and neck and bronchial carcinoma when comparison was made with patients treated with conventional radiotherapy [20,21]. This study provides evidence that CHART gives the further benefit of reduced late change in a normal tissue - the parotid gland.
Acknowledgements We would like to thank Dr. M. I. Saunders, Professor P. Wardman and Dr. M. Joiner for their help and advice. Also, Dr. E. Grosch, Dr. D. Fermont, Dr. R. Ashford, Dr. M. I. Saunders, Dr. J. Maher and Dr. A. Makepeace for allowing us to study patients under their c are.
References 1 Becks, H. and Wainwright, W.W. Rate of flow of resting saliva of healthy individuals. J. Dent. Res. 22: 391, 1943. 2 Brown, R. L., Dreizen, S., Handler, S. and Johnston, D.A. Effect of radiation induced xerostomia on human oral microflora. J. Dent. Res. 54: 740-750, 1975. 3 Cheng, V. S. T., Downs, J., Herbert, D. and Aramany, M. The function of the parotid gland following radiation therapy for head and neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 7: 253-258, 1981.
4 Dische, S. and Saunders, M.I. Continuous hyperfractionated accelerated radiotherapy (CHART): an interim report on late morbidity. Radiother Oncol. 16: 67-74, 1989. 5 Dische, S. Accelerated treatment and radiation myelitis. (Editorial) Radiother Oncol. 20: 1-2, 1991. 6 Dreizen, S., Daly, T. E., Drane, J. B. and Brown, L.R. Oral complications of cancer radiotherapy. Postgrad. Med. 61: 85-92, 1977. 7 Eneroth, C. M., Henrikson, C.O., and Jakobsson, P. A, The
139
8
9
10 11 12
13
14 15
16
17
effect of irradiation in high doses on parotid glands. Acta Otolaryngol. 71: 349-356, 1971. Eneroth, C. M., Henrikson, C.O. and Jakobsson, P.A. Preirradiation qualities of a parotid gland predicting the grade of functional disturbance by radiotherapy. Acta Otolaryngol. 74: 436-444, 1972. Eneroth, C. M., Henrikson, C. O. and Jakobsson, P.A. Effect of fractionated radiotherapy on salivary gland function. Cancer 30: 1147-1153, 1972. Fowler, J.F. Non-standard fractionation in radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 10: 755-759, 1984. Herrera, J. L., Lyons, M. F. and Johnson, L.F. Saliva: its role in health and disease. J. Clin. Gastroenterol. 10: 569-578, 1988. Kashima, H.K., Kirkham, W.R. and Andrews, R.J. Postirradiation sialadenitis: a study of the clinical features, histopathologic changes and serum enzyme variations following irradiation of human salivary glands. Am. J. Roentgenol. 94: 271-291, 1965. Lartigau, E., Saunders, M. I., Dische, S., Warburton, M. and Des Rochers, C. A comparison study of late radiation change after continuous hyperfractionated accelerated radiotherapy (CHART). Radiother Oncol. 20: 139-148, 1991. Lavelle, C. L.B. Saliva. In: Applied Oral Physiology, 2nd edn. pp. 128-141. Wright, 1988. Marks, J. E., Davis, C. C., Gottsman, V. L., Purdy, J. E. and Lee, F. The effects of radiation on parotid salivary function. Int. J. Radiat. Oncol. Biol. Phys. 7: 1013-1019, 1981. Mira, J.G., Wescott, W.B., Starcke, E.N. and Shannon, I.L. Some factors influencing salivary function when treating with radiotherapy, lnt. J. Radiat. Oncol. Biol. Phys. 7: 535-541, 1981. Mossman, K. L., Shatzman, A. R. and Chencharick, J.D. Effects of radiotherapy on human parotid saliva. Radiat. Res. 88: 403-412, 1981.
18 Mossman, K. L., Shatzman, A. and Chencharick, J. Long term effects of radiotherapy on taste and salivary function in man. Int. J. Radiat. Oncol. Biol. Phys. 8: 991-997, 1982. 19 Parsons, J.T. The effect of radiation on normal tissues of the head and neck. In: Management of Head and Neck Cancer, a MultidisciplinaryApproach, pp. 176-178. Editors: R. R. Million and N. J. Cassisi, J. B. Lippincott and Co, Philadelphia, 1984. 20 Saunders, M. I., Dische, S., Hong, A., Grosch, E. J., Fermont, D. C., Ashford, R. F. U. and Maher, E.J. Continuous hyperfractionated accelerated radiotherapy in locally advanced carcinoma of the head and neck region. Int. J. Radiat. Oncol. Biol. Phys. 17: 1287-1293, 1989. 21 Saunders, M. I. and Dische, S. Continuous hyperfractionated accelerated radiotherapy (CHART) in non-small cell carcinoma of the bronchus. Int. J. Radiat. Oncol. Biol. Phys. 19:1211-1215, 1990. 22 Shannon, I. and Chauncey, H. A parotid fluid collection device with improved stability characteristics. J. Oral. Ther. Pharm. 4: 93-97, 1967. 23 Shannon, I. L., Trodahl, J. N. and Starcke, E.N. Radiosensitivity of the human parotid gland. Proc. Soc. Exp. Biol. Med. 157: 50-53, 1978. 24 Silverman, S. Radiation effects. In: Oral Cancer, pp. 70-78. New York American Cancer Society, 1985. 25 Stephens, C., Kian Ang, K., Schultheiss, T.E., King, G.K., Brock, W. A. and Peters, L.J. Target cell and mode of radiation injury in rhesus salivary glands. Radiother Oncol. 7: 165-174, 1986. 26 Thames, H. D., Bentzen, S. M., Turesson, I., Overgaard, M. and Van den Bogaert, W. Time-dose factors in radiotherapy: a review of the human data. Radiother Oncol. 19: 219-235, 1990.
(c) 1991 Elsevier Science Publishers B.V. All rights reserved. 0167-8140/91/$03.50
133
RADION 00895
Parotid gland function following accelerated and conventionally fractionated radiotherapy M. D. Leslie and S. D i s c h e Marie Curie Research Wing, Mount Vernon Centrefor Cancer Treatment, Mount Vernon Hospital, Northwood, Middlesex, U.K.
(Received 14 January 1991, revision received 3 July 1991, accepted 5 August 1991)
Key words: Parotid function; Accelerated fractionation; CHART; Radiotherapy
Summary The function of the parotid glands in patients treated by three different schedules of radiotherapy was studied 9 months or more after its conclusion. All had received radiotherapy for a malignancy confined to one side of the head and neck :region and only the gland on the side of the lesion was in the treatment volume; the contralateral gland acted as an internal control. Saliva was selectively collected from the parotid glands and the stimulated flow rate and pH of the saliva determined. Flow rates were expressed in each case as a percentage of that of the contralateral ("untreated") gland. Twelve glands that had received conventionally fractionated radiotherapy to a dose of 60-66 Gy showed a mean percentage flow of 20% and a significant fall in the pH of the saliva produced. Six glands that had received C H A R T and eight conventionally fractionated radiotherapy to a dose of 35-40 Gy showed mean percentage flows of 57 and 65%, respectively, with only slight and non-significant falls in saliva pH. The results show that in the treatment of squamous cell carcinoma in the head and neck the use of C H A R T can lead to considerably less late change in the function of the parotid gland.
Introduction Irradiation of salivary glands during the treatment of head and neck cancer may lead to an alteration in the amount and quality of the saliva produced. As a consequence of this, patients suffer dryness of mouth with oral discomfort, altered taste acuity and dental decay [19]. The normal human salivary glands produce over a litre of saliva per day [ 14]. Ninety percent of salivary secretion is produced by three pairs of major glands: the parotid, the submandibular, and the sublingual glands with the remainder coming from numerous minor salivary glands distributed throughout the oral cavity [ 11 ]. The parotid and submandibular glands are the main contributors to salivary secretion, the sublingual glands contribute only 2-5 To of total salivary flow [ 14]. Under resting conditions the flow from the submandibular glands is at least as great as that from the parotids, however, under conditions of stimulation (e.g. eating or drinking) the parotid glands become the main contribu-
tors [19,23]. In humans, the parotid glands consist entirely of serous acini producing a clear watery product virtually devoid of mucin. The submandibular and sublingual glands contain mucous and serous acini whilst the minor salivary glands are predominantly mucous secretors [ 11,14,19]. The serous acini are considered to be the most sensitive to ionising radiation [19,24] and it is the loss of their watery product that results in the thick tenacious secretions observed during and after a course of radiotherapy [19]. Dryness of mouth is most marked when both parotid glands are fully included in the treatment volume [24]. No measure is available to increase salivary flow and management is often unsatisfactory largely relying on saliva substitutes [6,24]. Falls in resting saliva flow from the human parotid gland have been detected as early as 24 h after a single dose of 2.25 Gy [23]. The stimulated flow falls by 50~o at the end of the first week of radiotherapy when a dose of about 10 Gy has been given [17] and continues to decline throughout a course of treatment, often to levels that are barely measurable [9]. The early effects of
Address for correspondence: M. D. Leslie, Marie Curie Research Wing, Mount Vernon Centre for Cancer Treatment, Mount Vernon Hospital,
Northwood, Middlesex HA6 2RN, U.K.
134 radiotherapy on salivary tissue are also manifested by a rise in the blood amylase that can be detected within hours of a dose of radiotherapy [ 12]. This possibly reflects the interphase death that the serous cells of the parotid gland undergo in responses to radiotherapy [251. Late effects of radiotherapy on parotid gland function with decreased production of saliva have been demonstrated up to 7 years following radiotherapy [18]. Marks et al. [15] found no measurable salivary flow after stimulation from 24 parotid glands that had received irradiation to a dose of 60 Gy or more from 5 to 47 months previously. In addition, it has been shown that the pH of the saliva produced falls [ 15] resulting in an altered oral microflora that is highly cariogenic
[21. Patients with head and neck cancer treated with continuous hyperfractionated accelerated radiotherapy (CHART) appear to show less dryness of mouth than patients with comparable tumours treated by conventionally fractionated radiotherapy [ 13]. This study has investigated the function of the parotid gland
following conventionally fractionated radiotherapy at two dose levels and after CHART. Patients and methods
The patients included had been treated by radiotherapy for a malignancy confined to one side of the head and neck region. In all cases, radiotherapy was given using a unilateral technique employing anterolateral and posterolateral fields. This resulted in the parotid gland on the ipsilateral side being encompassed in the treatment volume and a dose less than 25~o of that prescribed being delivered to the contralateral gland. All patients were treated with radiotherapy as the sole treatment modality and at the time of testing all were in complete remission and at least 9 months after radiotherapy. All patients were treated on a 5 MV Linear accelerator. Three groups of patients were studied (Table I): - T w e l v e treated with conventionally fractionated radiotherapy for a squamous cell carcinoma received
TABLE I Summary of patients details. No.
Age
Sex
Primary site
Histology
Radiotherapy (Gy/fractions/days)
Time till testing (yrs)
01 02 03 04 05 06 07 08 09 10 11 12
54 68 67 72 75 63 78 79 74 55 67 63
M M M M F M M M M F F F
Tonsil Tonsil Tonsil Retromolar Retromolar Tonsil Tonsil Tonsil Tonsil Retromolar Palate Buccal
SCC SCC SCC SCC SCC SCC SCC SCC SCC SCC SCC SCC
66/33/49 60/30/45 64/32/46 60/30/43 64/32/51 64/32/49 64/32/48 64/32/49 64/32/49 65/32/57 60/30/43 64/32/44
1.8 2.3 2.2 1.6 3.8 1.0 2.8 3.5 6.4 7.5 5.0 8.2
13 14 15 16 17 18 19 20
44 70 70 55 51 60 62 54
M M F M F M M M
Tonsil Tonsil Tonsil Parotid Tonsil Tonsil Tonsil Tonsil
NHL NHL NHL HD NHL NHL NHL NHL
40/22/29 40/20/27 40/20/26 35/17/18 40/20/26 40/20/26 40/20/26 40/20/27
1.4 5.4 3.2 9.0 4.4 2.1 5.9 8.0
21 22 23 24 25 26
71 76 67 58 52 72
M M F M F M
Tonsil Tonsil Palate Retromolar Retromolar Alveolus
SCC SCC SCC SCC SCC SCC
54/36/12 54/36/12 54/36/12 54/36/12 54/36/12 54/36/12
4.1 3.0 1.8 1.4 1.0 0.8
HD = Hodgkins lymphoma; NHL = non-Hodgkins lymphoma; SCC = squamous cell carcinoma.
Group 1 Conventional 60-66 Gy
Group 2 Conventional 35-40 Gy
Group 3 CHART
135 between 60 and 66 Gy minimum tumour dose in 30-33 fractions over 6 - 7 weeks. Eight treated with conventionally fractionated radiotherapy for lymphoma received between 35 and 40 Gy minimum tumour dose in 17-22 fractions over 3.5-4.5 weeks. - Six treated with C H A R T for squamous cell carcinoma received 54 Gy minimum tumour dose in 36 fractions over 12 consecutive days treating three times a day using an individual dose increment of 1.5 Gy. In addition, 20 other head and neck cancer patients were studied prior to receiving radiotherapy to establish the normal range of parotid function encountered in this population. All patients freely gave their informed consent for the study.
Collection of saliva This was carried out in a quiet room, patients having refrained from eating or smoking for at least one hour
prior to testing. No patient was receiving any medication known to interfere with salivary gland function. Lashley cups [22] were used to collect saliva simultaneously from both parotid glands. These small round plastic cups (Fig. la) have an inner and outer chamber, each being attached to fine bore plastic tubing. The inner chamber is placed over the opening of Stensen's duct (Fig. lb) and suction applied to the outer chamber from a 20 ml syringe provides the vacuum to hold the device firmly on the buccal mucosa of the cheek whilst saliva is collected from the inner chamber (Fig. 2). Stimulation of saliva flow was achieved by applying three drops of 2~o citric acid to the dorsum of the tongue at intervals of 2 min and collection was carried out for 10 rain. Saliva volume and pH were determined and flow rate expressed as millilitres of saliva per gland per minute. In the few cases where dislodgement of cups occurred it was possible to successfully repeat the procedure. Results
The procedure of saliva collection from the parotid glands proved relatively simple to perform and caused no discomfort or trauma to the patients. Figure 3 shows
Fig. l(a) Lashley cup for collection ofparotid saliva; (b) Lashley cup in place over Stensen's duct.
Fig. 2. Simultaneous collection of saliva from both parotid glands.
136 Right Parotid
Flow Rote rnl/min
Left Porotid O
0.7'
•-0,7 0
0.B
E
-A 0.B
0.5
0
v OA
a -a
• 00 • •
o
O
o
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03
0.2
0.4
0.4 0.7 ¸
0.3
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0.5'
0-2.
[]
04'
o
0.2
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0.3"
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02'
0.1
o
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o
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0
o
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0.1 0.1
•
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=," 2
0
Fig. 3. Parotid flow rates in 20 patients with head and neck cancer prior to radiotherapy demonstrating the normal variation in flow between individuals and the correlation of flow rates between glands in the same individual.
--i
;
100.0"1°.
rl 8 0 , 0 "1.o
o
o
the results obtained from the control group of 20 head and neck cancer patients studied prior to undergoing radiotherapy. A range of flow rates from 0.23 to 0.63 ml/min was obtained showing the relatively wide variation in function as previously reported [ 1]; however, there was only a small variation seen between both glands in the same individual. The flow rates from the contralateral ("untreated") glands of the three groups of patients studied following radiotherapy are given in Fig. 4a. Rates of flow from 0.30 to 0.68 ml/min were obtained. The pattern and range are similar to that obtained from our control group and furthermore no differences can be seen between the patients of the three treatment groups. In Fig. 4b, the flow rates from the ipsilateral ("treated") parotid glands of the three groups are shown. These are reduced in all cases as compared with the corresponding contralateral glands with rates from 0.0 to 0.6 ml/min being obtained. In each case the flow rate of the ipsilateral gland was expressed as a percentage of the flow rate from the contralateral gland (Fig. 4c). This removes the effect of the normal variation in flow between individuals and the contrallateral gland acts as an internal control. The greatest falls in flow were seen in glands treated by conventionally fractionated radiotherapy to a dose of 6 0 - 6 6 Gy. In 4 of the 12 ipsilateral glands there was no detectable function
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Years Since Rodiotheropy
Fig. 4(a) Flow rates in contralateral parotid glands; (b) flow rates in ipsilateral parotid glands; (c)flow rate of ipsilateral glands expressed as a percentage of the flow from the corresponding contralateral glands: 60-66 Gy (11), 35-40 Gy (C)), CHART (D).
and in the other 8 the percentage flow of the ipsilateral gland, as compared to the contralateral gland, did not exceed 41 ~o and the mean percentage flow of the whole group was 2 0 ~ (SE 4.7). A more modest impairment of function was seen in those glands treated either by conventionally fractionated radiotherapy to a dose of 35-40 Gy or by CHART. Percentage flow was greater than 50~o for all 8 cases treated to a dose of 35-40 Gy and for 5 of the 6 C H A R T cases.The mean percentage flows were 65~o (SE 5.8) and 57~o (SE 6.4), respectively. Only three patients (cases 3, 5 and 11) complained of any dryness of mouth. All were in the group treated by conventionally fractionated radiotherapy to a dose of 6 0 - 6 6 Gy and the flow rate from the ipsilateral gland
137 TABLE II Changes in pH of parotid saliva following radiotherapy. Treatment group
Conventional 60-66 Gy
Conventional 35-40 Gy
CHART 54 Gy
No, of patients
8*
8
6
7.23 (7.19-7.31 ) 7.42 (7.36-7.50) p < 0.005
7.36 (7.28-7.47) 7.41 (7.29-7.47) NS
7.34 (7.29-7.44) 7.42 (7.31-7.49) NS
pH mean (range) Ipsilateral Contralateral Difference
* Four cases had insufficient flow to measure pH.
was unrecordable in two and just detectable in the third with a flow rate of 0.06 ml/min. The secretions from the contralateral glands in these cases were at the lower range of normal being 0.32, 0.39 and 0.30 ml/min, respectively. Over the period studied, 9 months to 9 years after radiotherapy, there was no evidence for a recovery of function in the group given conventionally fractionated radiotherapy to 60-66 Gy. If the two other groups are pooled there is a suggestion of a slight degree of recovery with time. Only serial study in individual cases will show if this is a reality.
CONVENTIONAL CHART 35-40Gy
54Gy
CONVENTIONAL 60-66Gy
pH 7.50-
7.40-
pH
I
© I
- 7.50
I
- 7.40
1
I
7.30IP
i
- 7.30
7.20-
7,20
7.10-
,7.10
7.00
7.00
Fig. 5. pH (mean and range) of parotid saliva following radiotherapy. Ipsilateral glands (O), contralateral glands (©).
Results for the pH values of the parotid saliva are given in Table II and are illustrated in Fig. 5. Following irradiation by conventionally fractionated radiotherapy to a dose of 60-66 Gy there is a significant fall (p < 0.005) in the mean pH of saliva from the ipsilateral parotid glands (7.23) as compared to that from the contralateral glands (7.42). In the cases irradiated to a dose of 35-40 Gy and in those treated by CHART, a small fall in mean pH was observed but in neither group did this reach statistical significance. Discussion
In the treatment of head and neck cancer by radiotherapy the major salivary glands are inevitably included in the treatment volume. Tumour site, stage and the need for nodal irradiation will determine which salivary glands are included. The risk of dryness of mouth can be reduced if during treatment planning the volume of salivary tissue irradiated can be minimised [ 19]. If only the submandibular and sublingual glands are included in the treatment volume and not both parotids, most patients note little or no difference in the quality and quantity of their saliva [ 19]. If the radiotherapist can spare even a portion of one parotid from the treatment beam this may help to reduce morbidity [15]. Mira et al. [16] suggest that it is necessary to exclude more than 50~o of both parotids from the treatment volume to prevent severe dryness when the rest of the major glands are included. When the major portion of the parotid gland is irradiated with conventionally fractionated radiotherapy to doses of 60 Gy or more, reduction in salivary flow is usually found when measured months or years following treatment [ 3,7,15 ]. Marks et al. [ 15 ] studied the stimulated salivary flow from parotid glands that had received radiotherapy from 5 to 47 months previously. Measurable quantities of saliva were obtained
138 from 20~o of glands receiving 40-60 Gy and from none that had received a dose of more than 60 Gy. A doseresponse effect was demonstrated with salivary flow progressively falling with increasing dose of radiation. However, Eneroth et al. [7] have reported one patient whose parotid gland was functioning well 9 years after radiotherapy to a dose of 65 Gy. The reduction in function of the parotid gland is related to the volume of glandular tissue treated and the dose achieved [6]. However, other factors such as anatomical variation, the use of high energy apparatus which will spare superficially placed salivary tissue and variable degrees of function prior to radiotherapy [8] could all serve to influence the degree of functional impairment observed. This study has investigated the late effects of radiotherapy on the function of the parotid gland as assessed by salivary flow rate and alteration in pH of the saliva produced. Our results confirm the dose-response effect described by Marks et al. [15] with significant difference in salivary flow being seen between glands treated to a dose of 35-40 Gy compared to those receiving 60-66 Gy. We were, however, able to demonstrate some function, albeit reduced in 67~o of our cases treated to a dose of more than 60 Gy. This difference may reflect the repeated stimulation with citric acid used in our collection procedure compared with the single application of "sour grape drops" which they used. The three of our patients who did complain of dryness of mouth are of particular interest. In two there was no measurable function from the ipsilateral gland and in the third it was barely detectable. In addition, the flow from the contralateral glands was in all three cases at, or close to, the lower end of the normal range. This combination would seem to explain the symptom of dryness in these patients. A fall in saliva pH following radiotherapy results in an altered oral microflora that contributes to dental decay [2]. The absence of a significant fall in pH of parotid saliva after CHART may result in less dental decay in our patients following the treatment of squamous cell carcinoma in the head and neck region. This may mean that a more conservative approach to
dental extractions prior to radiotherapy can be adopted when treating with CHART. Dental problems may be of the same low incidence as after radiotherapy to the head and neck region for lymphomas. Following CHART, there is therefore less impairment of parotid gland function as compared with that after conventionally fractionated radiotherapy to doses of 60-66 Gy. This confirms our clinical impression that following CHART for squamous cell cancer in the head and neck there is less than expected dryness of mouth [13]. The function of the parotid gland following CHART is, in fact, more comparable to that seen when conventionally fractionated radiotherapy is given to the much lower dose of 35-40 Gy. With the exception of spinal cord [4,5] CHART has been followed by reduced late radiation change in all other normal tissues [13]. This reduction in the incidence of late changes after CHART was predicted radiobiologically on the basis of the low dose per fraction employed [ 10]. Using the "two regimen" comparison of Thames et al. [26] it would appear from our data showing similar parotid function after CHART and conventionally fractionated radiotherapy to a dose of 35-40 Gy that the c~//~ratio for this endpoint is in the low range. Therefore, the functional unit in question has a fractionation sensitivity akin to late responding tissues. In pilot studies CHART appeared to give greater tumour control in head and neck and bronchial carcinoma when comparison was made with patients treated with conventional radiotherapy [20,21]. This study provides evidence that CHART gives the further benefit of reduced late change in a normal tissue - the parotid gland.
Acknowledgements We would like to thank Dr. M. I. Saunders, Professor P. Wardman and Dr. M. Joiner for their help and advice. Also, Dr. E. Grosch, Dr. D. Fermont, Dr. R. Ashford, Dr. M. I. Saunders, Dr. J. Maher and Dr. A. Makepeace for allowing us to study patients under their c are.
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8
9
10 11 12
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17
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