RTOG Protocol No: 9709	Protocol Status:
	Opened:	March 17, 1998
	Closed:	February 1, 2000

Title: A Phase III Study to Test the Efficacy of the Prophylactic Use of Oral Pilocarpine to Reduce Hyposalivation and Mucositis Associated with Curative Radiation Therapy in Head and Neck Cancer Patients

Patient Population:
- Confirmed histopathologic diagnosis of oral or oropharyngeal squamous cell carcinoma
- Karnofsky Performance Score > 60
- Age > 18
- No prior radiotherapy to the head and neck
- Primary tumor in oral cavity or oropharynx
- Planned irradiation of oral cavity or oropharynx at 1.8-2.0 Gy/day or 1.2 Gy/bid > 6 hours apart to 60-70 Gy five days a week for 6-7 weeks.
- Signed study-specific consent form

Objective:

1. To determine if prophylactic use of pilocarpine can shelter unstimulated and stimulated whole salivary flow by objective measurement (sialometry).

2. To determine if prophylactic use of pilocarpine can moderate xerostomia as measured by subjective means.

3. To determine whether prophylactic use of pilocarpine can reduce the grade and duration of radiation-induced mucositis in the same patient group.

4. To evaluate quality of life outcomes between patients receiving pilocarpine to patients receiving placebo.

5. To evaluate the impact of xerostomia on patients receiving irradiation to the head and neck.

Schema:

S		R
	RT Fractionation		Double-Blinded Randomization
T		A
	1. Standard (once daily)		Pilocarpine Tablets, 5mg
R	2. Hyperfractionated	N	vs.
			Placebo Tablets
A		D
T		O	Both arms begin 3 days
			prior to irradiation, one tablet four times a
I		M	a day for three months.* See Section 7.2.
F		I	Irradiation will be given at 1.8 to 2 Gy
			once a day or 1.2 Gy b.i.d > 6 hours apart.
Y		Z	Total Dose: 60-70 Gy over 6-7 weeks.
		E
			* After three months, all patients will receive non blinded pilocarpine for an additional three months.

Study Chairs:	Francis LeVeque, D.D.S.	Total Patients Entered: 249
	Charles Scarantino, M.D. (Radiation Oncology)
	Jackie Fisher, R.N. (Quality of Life)

Reference: Fisher J, Scott C, et al. Phase III Quality Of Life (QOL) Study: Reduction In Hyposalivation Does Not Improve QOL For Head And Neck (H&N) Cancer Patients Post Radiation Therapy (P-RT). RTOG 9709. J Clin Oncol 21:356a, 2002.

Purpose: To determine if the prevention of hyposalivation following curative radiation therapy (RT) for H&N cancer improves patients QOL.

Method: Patients were required to receive at least 50 Gy to 50% of the volume of the major salivary glands; provide unstimulated and stimulated saliva samples and complete the Univ. of Washington H&N QOL tool (HNSS) prior to RT, and 3 mo., and 6 mo. p-RT. Patients were randomized to receive, Pilocarpine (P), 5mg qid or placebo.

Results: 249 patients were randomized between 3/98 to 1/00, 246 were eligible for analysis for QOL. Patients were evenly distributed between arms by race, gender, tobacco use, tumor site and T-stage (50% T2/T3) and salivary function. KPS 90% was more common in P arm. 20% of patients on P arm and 29% patients on placebo arm were on oral supplements. Use of oral supplements related to activity, employment, eating and mucosal complaints. Placebo arm patients had greater mouth pain and chewing difficulties. Compliance for HNSS was 75% at 3 mo. and 50% at 6mo. There was no difference between treatment arms in any of the HNSS (taste impairment, activity, pain) at 3 mo. or 6mo.despite statistically significant (p=.047 and p=0.049 respectively) preservation of salivary function in the P arm with continued functional loss in the placebo arm. Patients on P arm reported difficulties with swallowing (75%), activity (80%), hyposalivation (64%) and taste (81%). There was no difference between arms at 3 mo. in mucositis scores with both arms demonstrating increased requirement for oral nutrients.

Conclusion: The objective prevention of hyposalivation did not affect patients' assessment of salivary function or QOL most likely due to the greater impact mucositis plays in QOL post- rt.

Reference: Scarantino C, et al. A Phase III Study on the Concurrent Use of Oral Pilocarpine to Reduce Hyposalivation and Mucositis Associated with Radiation Therapy In Head And Neck Cancer Patients. Final Results of RTOG 97-09. Int J Radiat Oncol Biol Phys 51:85-86, 2001.

Purpose: Radiation therapy (RT) continues to play a major role in the management of head and neck (H&N) cancer. Two of the major treatment morbidities are acute mucositis and acute and chronic xerostomia. The former can affect tolerance and result in treatment breaks, while the latter is largely permanent and can significantly impact the quality of life (QOL) of many patients. Pilocarpine (P), a cholinergic agonist that acts to stimulate salivary glands, is an approved therapy for post radiation xerostomia The primary objective of this study is to determine whether the concomitant use of P is able to preserve salivary flow in H&N cancer patients receiving curative RT.

Methods and Materials: Selected patients were required to have at least 50% of the volume of the major salivary glands receive at least 50Gy. They agreed to provide stimulated and unstimulated samples of saliva (measured in ml/min) prior to, 3 mo and 6 mo after initiation of RT and complete the Univ. of Washington H&N QOL forms. The study was conducted from 3/98 to 1/00. Patients were randomized to receive P at 5 mg qid or placebo. 249 patients were registered of whom 244 were eligible for analysis. Patients were evenly distributed to both arms in terms of race, gender, tobacco use, tumor site, and T-stage (.50%T2/T3). KPS of at least 90% was more common in P group. Following 3mo of drug/placebo patients were allowed to take open label P.

Results: Toxicities from P were mild. Mucositis scores were similar in both groups- 43% on both arms experienced ulceration. At 3 months following the initiation of RT, the average reduction in unstimulated salivary flow was statistically different in P group -1.1 ml/min vs. -1.7 placebo (p< 0.047). At 6mo,with over 50% of placebo patients switching to P, there was a difference in unstimulated flow, but not statistically significant (p= .09). More than 50% of P pts stopped P at 3mo and when compared to placebo that never received P, they had > 50% better salivary flow (p=0.088). Changes in salivary flow were not correlated with QOL. 31% of patients on P reported normal salivary flow vs. 25% on placebo at 3 months. Eating and taste were impaired in 78% and 90%, respectively at three months.

Conclusions: The significant difference in unstimulated salivary flow advocates for the concomitant use of oral P to decrease radiation associated xerostomia. Oral P did not influence the onset or grade of mucositis. Patients could not distinguish xerostomia from mucositis and their affect on QOL, thus, having the latter (mucositis) results in no improvement in QOL.