Journal of ISSN: 2373-633XJCPCR

Cancer Prevention & Current Research
Research Article
Volume 1 Issue 3 - 2014
Pilocarpine and Prevention of Radiation Induced Xerostomia in HNSCC
Atri R*, Dhull AK and Kaushal V
Department of Radiation Oncology, BD Sharma Post Graduate Institute of Medical Sciences, India
Received: October 28, 2014 | Published: December 06, 2014
*Corresponding author: Rajeev Atri, Department of Radiation Oncology, BD Sharma Post Graduate Institute of Medical Sciences Rohtak, Haryana, India, Tel: 919354180865; Email: @
Citation: Atri R, Dhull AK, Kaushal V (2014) Pilocarpine and Prevention of Radiation Induced Xerostomia in HNSCC. J Cancer Prev Curr Res 1(3): 00018. DOI: 10.15406/jcpcr.2014.01.00018

Abstract

Stated Purpose:To evaluate the efficacy and safety of concomitant pilocarpine with radiation therapy for the prevention of radiation induced xerostomia in Head & Neck cancer.
Material & methods: A prospective, randomized, study was carried out on sixty treatment naive histopathologically proven patients of squamous cell carcinoma of head and neck. All the patients received 64Gy/32Fraction/6.2wks with and without pilocarpine. The study group received concomitant Pilocarpine hydrochloride 5.0 mg four times a day, starting three days prior to start of radiotherapy, continued for 3-months. Patients were evaluated at four points for xerostomia using subjective and objective scale. The Zimmermans Xerostomia Questionnaire and Visual Analogue Scale were used for evaluation of results. The statistical analysis was done by Paired sample T test and Mann-Whiteny U-Test.
Results:The average Zimmerman Xerostomia scores of the pilocarpine group as compared to the control group were: First assessment - 100mm Vs 100mm; Second assessment - 48mm Vs 37mm; Third assessment - 57mm Vs 41mm; Fourth assessment - 62 Vs 44mm. The average LENT SOMA grades for the study group and the control group along with SEM respectively were: First assessment 1 Vs 1; Second assessment 2.7 (SEM-8.510X10-2) Vs 3 (SEM -0.000); Third assessment 2.3 (SEM -0.1150) Vs 2.5 (SEM -9.285X10-2); Fourth assessment 2.3 (SEM - 0.1150) Vs 2.5 (SEM -9.285X10-2). The RTOG Salivary Gland Morbidity Scores for the study group and the control group respectively were: First assessment – 0 Vs 0; Second assessment - 1.8 Vs 2 (p Value-0.595); Third assessment - 1.6 Vs 1.8 (p Value -0.094); Fourth assessment - 1.6 Vs 1.8 (p Value-0.054).
Conclusion: The objective assessment of xerostomia done by these scales were favorable in the study group as compared to the control group signifying that concomitant pilocarpine preserved better salivary gland function.
Keywords:Pilocarpine; Prevention of Radiation induced Xerostomia; Concomitant pilocarpine with radiation therapy

Abbreviations

HNSSC: Head and Neck Squamous Cell Carcinoma; HNC: Head and Neck Cancer; KPS: Karnofsky Performance Status; Zn: Zinc; Mn: Manganese; Fe: Ferric; WDSCC: Well Differentiated Squamous Cell Carcinoma; MDSCC: Moderately Differentiated Squamous Cell Carcinoma; PDSCC: Poorly Differentiated Squamous Cell Carcinoma; M:F Ratio: Male: Female Ratio; SD: Standard Deviation; SEM: Standard Error of Mean

Introduction

Radiotherapy alone, or in combination with surgery or chemotherapy, is the main modality used in the treatment of head and neck cancer. For cure, radiation doses more than 60Gy are needed though the tolerance of normal organs e.g. salivary gland varies between 32Gy (TD5/5) to 46Gy (TD50/5) [1]. Out of all the radiation reactions, xerostomia, the subjective sensation of dry mouth is one of the commonest and most troublesome. It may be an inconvenience when mild, or a debilitating condition when severe. The decreased salivary flow causes chronic oral discomfort and functional problems. Xerostomia is the main clinical effect that interferes with nutrition, use of dentures and oral hygiene. It predisposes patients to oral candidiasis and dental problems e.g. dental caries [1-3].
Pilocarpine has been used for prevention and treatment of radiation-induced xerostomia with variable success. The present prospective, randomized, study was carried out to evaluate the efficacy and safety of concomitant pilocarpine with radiation therapy for the prevention of radiation induced xerostomia in patients receiving radical radiotherapy for head and neck cancer.

Materials and Methods

From March 2003 to July 2004, a prospective randomized study was carried out on sixty treatment naïve patients of head & neck cancer, suitable for radical radiotherapy. All these patients had histopathologically proven squamous cell carcinoma of head & neck region. Excluded from the study were, patients of early head & neck cancer suitable only for brachytherapy, patients on palliative radiotherapy, patients who had received radiotherapy or chemotherapy earlier, patients planned to receive concurrent chemoradiation, patients having distant metastasis, patients having Karnofsky Performance Status < 70, pregnant or lactating females and the patients having contraindications to the use of pilocarpine ( e.g. glaucoma etc.)
The patients were staged according to AJCC - 2002 staging system [4]. The sixty patients were divided in two groups of 30 patients each by draw of lots. All the patients were planned to receive a total target radiation absorbed dose of 64 Gy/32Fraction/6.2wks (2Gy/Fraction, 5 days/week) on a Telecobalt machine. The study (Pilocarpine) group comprised of randomly selected thirty patients who, in addition to above radical radiotherapy received tablet Pilocarpine hydrochloride 5.0 mg four times a day, starting three days prior to start of radiotherapy and continued for 3-months. Control group comprised of randomly selected thirty patients who received the similar radical external radiotherapy without concomitant pilocarpine. The radiation reactions were graded according to RTOG criteria [5] and tumor control was assessed using WHO criteria [6].
Patients were evaluated for xerostomia using Zimmerman [7] Xerostomia Questionnaire for subjective assessment and LENT SOMA Scale for objective assessment [8]. The Zimmerman Xerostomia Questionnaire includes parameters like dryness of mouth and tongue, comfort status of mouth and tongue; sleep impairment attributed to dryness of mouth, speech impairment attributed to dryness of mouth and difficulty in denture wearing. It utilizes a Visual Analogue Scale for subjective documentation of xerostomia. The Zimmermans Xerostomia status was assessed at four points in time: before start of treatment, the day radiotherapy was completed, at 3Ë—months, and at 6Ë—months.
LENT SOMA scale for objective assessment of xerostomia includes following parameters: normal moisture, scant saliva, absence of moisture, stickiness of saliva, presence of coated mucosa etc. It was used in the present study for objective evaluation of the radiation induced xerostomia. The LENT SOMA scale status was assessed at four points in time: before start of treatment, the day radiotherapy is completed, at 3Ë—months, and at 6Ë—months.

Results

The radiation reactions in study and control group respectively were as follows: cutaneous radiation reactions; Grade I- 2(7%) vs 1(3%), Grade II-25 (83%) vs 27 (87%), Grade III- 3(10%) vs 3(10%); Mucosal radiation reactions; Grade I- 1(3%) vs 0(0%), Grade II-19 (64%) vs 20 (67%), Grade III- 10(33%) vs 10(33%). Complete response in the study and the control group respectively was as follows: Stage II-5/6 (83%) vs 2/2 (100%); Stage III-8/14 (57%) vs 7/12 (58%); Stage IV-1/10 (10%) vs 2/16 (12.5%). Partial response in the study and the control group respectively was as follows: Stage II-16 (17%) vs 0/2 (0%); Stage III-6/14 (43%) vs 5/12 (42%); Stage IV-8/10 (80%) vs 12/16 (75%). No response in the study and the control group respectively was as follows: Stage IV-1/10 (10%) vs 2/16 (12.5%).
Zimmerman Xerostomia scores for various parameters in the pilocarpine group as compared with control group respectively have been shown in (Table 1). Higher the Zimmerman Xerostomia Score on a scale of 0-100, better is the salivary gland function. The average Zimmerman Xerostomia score for all parameters (dryness of mouth and tongue, comfort status of mouth and tongue, sleep impairment, speech impairment and difficulty in chewing and swallowing) combined (Figure 1), of the pilocarpine group as compared to the control group was as follows: First assessment - 100mm vs 100mm; Second assessment - 48mm vs 37mm; Third assessment - 57mm vs 41mm; Fourth assessment - 62 vs 44mm. There was overall trend of better salivary gland function in study group as compared to control group. The average Zimmerman Xerostomia score variation with stage was as follows: Stage II; 77.2mm vs 66.2mm, Stage III; 66.2mm vs 49.3mm, Stage IV; 55.2mm vs 43.6mm. The average Zimmerman scores were better in stage II patients and were worst in stage IV patients in both the study and the control group.
Objective LENT SOMA scale for assessment of xerostomia is divided into four grades: grade-1 normal moisture; grade-2 scant saliva; grade-3 absence of moisture, stickiness of saliva; grade-4 absence of moisture, coated mucosa. Lower the LENT SOMA grade on a scale of 1-4, better is the salivary gland function. The average LENT SOMA grades as measured at the time of various assessments for the study group and the control group along with Standard Error of Mean (SEM) respectively were as follows: First assessment 1Vs 1; Second assessment 2.7 (SEM-8.510X10-2) Vs 3 (SEM -0.000); Third assessment 2.3 (SEM -0.1150) Vs 2.5 (SEM -9.285X10-2); Fourth assessment 2.3 (SEM - 0.1150) Vs 2.5 (SEM -9.285X10-2). The LENT SOMA grades were maximum at the time of completion of radiotherapy which improved to some extent in both groups at 6–months. Table 2 & 3 shows that xerostomia grade was higher in control group as compared to pilocarpine group, signifying that better salivary gland function was preserved with use of pilocarpine.

Characteristics

Patient Group

Pilocarpine Group

n=30

Control Group

n=30

Age (years)

Range

Mean

31- 80

51

±S.D-9.22

31- 70

50.9

±S.D-8.77

Gender

Male

Female

M:F Ratio

29

1

29:1

29

1

29:1

Karnofsky Performance status

>=70

30

30

Tumor stage

(AJCC-2002)

I

II

III

IV

0

6

14

10

0

2

12

16

Primary site

Floor of mouth

Tonsil

Base of tongue

Soft palate

4

9

17

0

4

3

22

1

Histopathology

WDSCC

MDSCC

PDSCC

7

22

1

4

25

1

Table 1: Patient Characteristics in Radical Radiotherapy for HNC.
Figure 1: Average Zimmerman Xerostomia Score (n=60) in Radical Radiotherapy for Head & Neck cancer.
Figure 2: Average LENT SOMA Grade in Radical Radiotherapy for Head & Neck Cancer.

 

First Assessment

Second Assessment

Third Assessment

Fourth Assessment

Zimmerman Xerostomia Score

PilocarpineGroup

(n=30)

Control Group

(n=30)

PilocarpineGroup

(n=30)

Control Group

(n=30)

Pilocarpine Group

(n=30)

Control Group

(n=30)

PilocarpineGroup

(n=30)

Control Group

(n=30)

 

Parameters

Mean

(mm) (SEM)

Mean

(mm) (SEM)

Mean

(mm) (SEM)

Mean

(mm) (SEM)

Mean

(mm) (SEM)

Mean

(mm) (SEM)

Mean

(mm) (SEM)

Mean

(mm) (SEM)

Dryness of mouth

100

100

48

(1.6089)

39

(1.6491)

57

(1.5365)

42

(1.6283)

62

(1.6574)

44

(1.6082)

p-value

 

P =0.000

P =0.000

P =0.000

Comfort status of mouth

100

100

43

(1.4015)

 

32

(1.4794)

50

(1.7234)

36

(1.4637)

58

(1.4762)

40

(1.4948)

p-value

 

P =0.000

P =0.000

P =0.000

Sleep impairment

100

100

60

(1.5796)

44

(1.6077)

64

(1.6811)

48

(1.6252)

70

(1.7237)

53

(1.5573)

p-value

 

P =0.000

P =0.000

P =0.000

Speech impairment

100

100

50

(1.6774)

42

(1.6344)

60

(1.6451)

50

(1.5967)

68

(1.5989)

68

(1.5989)

p-value

 

P =0.001

P =0.000

P = 1.000

Difficulty in eating

100

100

43

(1.4596)

27

(1.3561)

50

(1.6341)

30

(1.4158)

62

(1.5132)

33

(1.4700)

p-value

 

P =0.000

P =0.000

P =0.000

Table 2: Average Zimmerman Xerostomia Score in Radical Radiotherapy for HNC.
P value < 0.05 statistically significant for each group, the distance from left side of scale were measured in millimeters, and then averaged and compared

 

Maximum

Minimum

Median

Mode

SD (Standard Deviation)

Pilocarpine Group

3

1

2

2

0.65

Control Group

3

2

2.5

3

0.51

Table 3: Objective Xerostomia Grade in Pilocarpine and Control Groups in Radical Radiotherapy for HNC.
The RTOG Salivary Gland Morbidity Scores as measured at the time of various assessments for the study group and the control group respectively were as follows: First assessment – 0 Vs 0; Second assessment - 1.8 Vs 2 (p Value-0.595); Third assessment - 1.6 Vs 1.8 (p Value -0.094); Fourth assessment - 1.6 Vs 1.8 (p Value-0.054).
The RTOG Salivary Gland Morbidity Scores were maximum at the time of completion of radiotherapy, which improved to some extent in both the groups at 6 months. The average recovery in grades was 0.2 in both the study and the control group between the second and the final assessment. However, in both the groups pretreatment values were not achieved.
The frequency and severity of known side effects of pilocarpine were specifically enquired and documented. The adverse effects were nonspecific symptoms such as nausea (5/30), palpitations (2/30), excessive lacrimation (4/30), rhinitis (4/30), urinary frequency (3/30) and sweating (11/30). These were generally of mild degree.

Discussion

Xerostomia is a major complication in patients who are receiving curative radiotherapy for head and neck cancer. Having no threshold dose, the magnitude depends both on the volume of salivary tissue irradiated and dose of radiation delivered. Xerostomia and its associated symptoms have a considerable, negative global impact, resulting in shame, anxiety, disappointments and verbal communication difficulties [1-3]. Treatment of radiation induced xerostomia calls for good hydration, optimal oral hygiene and prophylaxis of candidiasis. Therapeutic options are artificial saliva substitutes, mouth wetting agents and drugs like pilocarpine and amifostine [9]. However radiation induced xerostomia is better avoided than dealt with [10]. It has been shown that preemptive use of oral pilocarpine hydrochloride prior to and concurrent with therapeutic irradiation in head and neck cancer patients has a positive effect upon retention of a beneficial level of post irradiation salivary function with no jeopardy of tumor control [7-12]. Pilocarpine is being used for prevention and treatment of radiation-induced xerostomia with a good measure of success.
The mechanism of action of radiation induced xerostomia is unknown. The main damage to serous salivary tissue is because of intracellular leakage of proteolytic enzymes in secretary granules after radiation induced per-oxidative damage. It is noteworthy that pretreatment with atropine which inhibits salivation and leads to an increase in secretory granules found in acinar cells, resulted in increased radiation damage to salivary glands. Pilocarpine by depleting heavy metals such as Zn, Mn, and Fe found in secretary granules, leads to reduction in metal–catalyzed lipid peroxidation of lysosomal membranes and subsequent serous cell autolysis seen following radiation [13]. The improvement of xerostomia may also be due to stimulation of residual function of non-irradiated parts of parotid and other salivary glands/ minor salivary glands. As consistent with our findings, some studies have also suggested that stimulation of these salivary glands by pilocarpine is responsible for better salivary gland function in irradiated patients [14-16].
It is known that xerostomia begins within first week of radiotherapy. This has been the rationale to begin pilocarpine administration during radiotherapy Zimmerman et al. [7] showed that concomitant administration of pilocarpine with radical radiotherapy followed by continuation of pilocarpine for three months is adequate for favorable outcome in prevention and treatment of radiation induced xerostomia. Similar schedule of pilocarpine administration was followed in our study. Pilocarpine was well tolerated by all patients of study group and side effects were mild as reported in other studies [7-8,18-19]. Discontinuation of pilocarpine because of side effects was not required in any of the patients.
Several studies have shown significant improvement in radiation induced xerostomia when pilocarpine was given along with radiotherapy in HNC where whole of parotid glands received more than 45 Gy [7-12]. Our study has also shown improved subjective and objective xerostomia grades, which correlated positively, but results were not statistically significant. The average xerostomia scores were better in stage II patients and were worst in stage IV patients in both the study and the control group. This may be explained by the fact that radiation fields generally smaller in stage II patients, making sparing of salivary glands possible.
The possibility of tumor protection by pilocarpine is a valid concern that needs to be addressed. In in vitro studies, pilocarpine does not alter tumor cell killing by gamma irradiation [7]. The tumor response rate of radiation treatment was almost similar in both the groups in the present study. The present study agrees with previous in vitro studies where pilocarpine did not alter tumor cell kill by gamma irradiation.

Conclusion

In the present study the Pilocarpine given during and continued for three months after radiotherapy has shown to reduce symptoms of xerostomia during treatment and lower the degree of post radiation salivary dysfunction than that occurring in a similar cohort of patients who had not received pilocarpine

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