A Multicenter Maintenance Study of Oral Pilocarpine Tablets for Radiation-Induced Xerostomia

ABSTRACT: Two hundred sixty-five patients with headand neck cancer who had previously participated in either a fixed-dose,dose-titration, or dose-ranging trial of oral pilocarpine hydrochloridetablets were enrolled in a 36-month multicenter maintenance studyto evaluate the long-term safety and efficacy of oral pilocarpinefor the treatment of radiation-induced xerostomia. In this open-labelstudy, the initial drug dose was 5.0 mg tid, with possible adjustmentsfrom 2.5 to 10.0 mg tid or bid. Efficacy was evaluated by subjectivemeasures of oral function. Safety evaluations were based on self-reportof symptoms (or of adverse effects), various examinations, andlaboratory tests. There was significant improvement in all criteriaof oral function. Sweating was the most frequent adverse experience(55%). Less frequent side effects, mild to moderate in nature,included increased urinary frequency, lacrimation, and rhinitis.Side effects usually diminished within hours after the cessationof therapy. We conclude that oral pilocarpine at these doses effectivelyand safely reduces the symptoms of radiation-induced xerostomia.[ONCOLOGY 10{Suppl):16-20, 1996]

Introduction

Xerostomia, or oral dryness, results from salivary gland dysfunction.Underlying causes include chronic diseases, such as Sjögren'ssyndrome, sarcoidosis, and diabetes. Drugs, such as antidepressants,anticholinergics, and antihypertensives, also may result in xerostomia,as can chronic graft-vs-host disease, and use of certain chemotherapeuticagents. Radiation therapy to the head and neck region is particularlydetrimental to salivary function, with the majority of patientssuffering long-term xerostomia.

Loss of the normal amount and consistency of saliva frequentlyleads to enhanced formation of caries, recurrent candidiasis,and chronic oral pain and burning. Xerostomia also has a profoundimpact on patients' quality of life. Persistent dryness impairsthe ability to speak, chew, and swallow, and necessitates frequentsips of liquids. Taste is impaired, and sleep is often interrupted.Patients complain of difficulty wearing dentures. Current managementwith artificial saliva, sialogogues, and fluoride treatment isinadequate.

Pilocarpine hydrochloride, a cholinergic parasympathomimetic agentthat primarily affects muscarinic receptors, has been shown toincrease saliva and improve functioning with acceptable side effects[1-7]. Its effectiveness and acceptability, however, have mainlybeen demonstrated for brief periods of use. The goal of this trialwas to assess the efficacy and safety of long-term pilocarpinehydrochloride use for the treatment of radiation-induced xerostomia.

Patients and Methods

Patients were eligible for the study if they had participatedin a prior study of oral pilocarpine (fixed-dose, dose-titration,or dose-ranging study). To be eligible for the current study,patients had to have head and neck cancer and be 18 years or older.They must have received at least 4,000 cGy of radiation to thehead and neck region at least 4 months prior to study entry andalso have significant xerostomia of at least 4 months' duration,presence of at least one parotid gland, and at least some residualsalivary gland function, as documented at the end of the priorstudy. If patients were of childbearing potential, a negativepregnancy test was required. All patients signed an informed consentform.

Patients were ineligible for the study if they had a life expectancyof less than 6 months, cancer treatment was anticipated duringthis study, or they had used drugs that could result in a drymouth (eg, anticholinergics, tricyclic antidepressants, antihistamines,beta blockers), ophthalmic pilocarpine, or any investigationalagent within 30 days.

The study was a multicenter, maintenance trial, and there wasopen-label distribution of the study drug, pilocarpine hydrochloridetablets. The starting dose for all patients was 5.0 mg tid. Investigatorshad the prerogative to adjust doses to between 2.5 and 10.0 mgtid or bid to achieve maximum efficacy with acceptable side effects.The duration of the study was 36 months.

Efficacy of oral pilocarpine for radiation-induced xerostomiawas assessed by subjective measures.

Subjective Assessment

At study entry and each visit, patients were asked to judge theirown condition, as measured by three forms of subjective assessment:

Part One--First, patients were asked five questions relatedto functioning during the 3 days prior to the visit. They scoredtheir condition from one extreme to the other using a visual analogscale (VAS), which was converted to an absolute number rangingfrom 0 to 100 (where 0 represents worse and 100, better). Thefollowing questions were asked:

• During the last 3 days, your mouth or tongue was: very dryto not dry.
• During the daytime hours of the last 3 days, the feeling ofyour mouth and tongue was: extremely uncomfortable to comfortable.
• During the last 3 nights due to dryness of your mouth andtongue, how difficult was it to sleep (very difficult to easy)?
• During the last 3 days due to dryness, how difficult was itto speak without drinking liquids (very difficult to easy)?
• During the last 3 days due to dryness, how difficult was itto chew and swallow food (very difficult to easy)?

Baseline assessment upon entry to the prior study was comparedto data from the last evaluable visit using the two-group pairedt-test.

Part Two--In the next portion of the subjective evaluation,patients were asked the following questions related to their conditionimmediately before and after taking medication during the last3 days prior to their visit:

• Were your mouth and tongue more comfortable?
• Were your mouth and tongue less dry?
• Was it easier to speak without drinking?

Part Three--Finally, patients were asked to rank theirpresent condition of xerostomia from worse to better (using aVAS), as compared with their condition at the beginning of thestudy. Patients were asked whether their use of oral comfort agentsor activities was decreased, unchanged, or increased since thestart of study.

Safety Evaluation

In order to evaluate the safety of long-term oral pilocarpineuse, patients underwent the following at each visit: a physicalexamination, complete blood count, chemistry panel, and urinalysis.Each subject was scheduled for a clinic visit every 3 months forthe first year, and then at 6-month intervals. Each subject wascontacted by telephone once a month.

Adverse Experiences

A diary of adverse experiences was kept by each patient and reviewedby the nurse or physician investigator at each visit. An ECG wasperformed at month 9, and an ophthalmologic examination was performedat month 9 and study's end.

Results

Between November 1990 and December 1991, 265 patients were enrolledin the study from 59 sites. Complete data are available for 261of these patients, including 185 men and 76 women. Overall, themean age of these patients was 58 years (Table 1). In their priorstudy, 150 patients had received active drug and 115, placebo.

Follow-up assessment is based on 265 patients. Of the 129 patientswho discontinued the drug, the reasons are as follows: adverseexperience (48 patients), lack of efficacy (34), personal reasonsor noncompliance (27), and recurrent cancer (20).

Although the trial allowed the investigator to increase or decreasethe drug dosage, the majority of patients started with a doseof 5 mg, and 116 patients stayed at that dose throughout the trial(Table 2). Dose was escalated above 5 mg in 128 patients, andhad to be reduced in 9 individuals because of side effects.

Subjective Evaluation of Efficacy

When patients' baseline assessments were compared to their lastevaluable visit, patients reported a significant improvement infunctioning (using the VAS) during the last 3 days prior to theirvisit (Table 3). Dryness of the mouth and tongue improved froma mean baseline of 23.9 to 42.0 (P less than .01). Comfort ofthe mouth and tongue improved from 40.9 to 47.6 (P less than .01).Ability to sleep, as related to dryness of the mouth and tongue,changed from 47.9 to 57.1, ease of speaking from 33.8 to 47.1,and ability to eat/drink from 24.4 to 42.8 (P less than .01).There was no evidence of a significant decrease in therapeuticeffect over time.

Patients were asked to relate their condition immediately beforeand after taking medication during the last 3 days prior to theirvisit. The data from visit 2 are as follows: Of 188 patients,62% said that their mouth and tongue were more comfortable, 62%stated that their mouth and tongue were less dry, and 58% feltit was easier to speak without drinking (Table 4). Patients wereasked how the use of oral comfort agents or activities had changedsince the start of study. At their last evaluable visit, 31% statedthat the use of oral comfort agents had decreased, 66% felt thatuse of these agents had not changed, and 3% said that it had increased(N = 214) (data not shown). When patients rated their conditionof xerostomia at last study visit compared to their conditionat the beginning of the study, the mean patient VAS response was56.1 (N = 224; Figure 1).

Adverse Experiences

Table 5 lists the type and incidence of adverse experiences. Sweatingwas the most common side effect. Less frequent, mild to moderatetoxicities included flu-like syndrome, urinary frequency, rhinitis,headache, diarrhea, and increased lacrimation. Most side effectslessened within hours after the cessation of therapy. There wereno significant toxicities, as measured by the complete blood count,chemistry panel, ECG, urinalysis, or ophthalmic examination.

Discussion and Conclusions

Radiation therapy is highly successful in the treatment of lymphomasand solid tumors arising in the head and neck region. Unfortunately,the salivary glands often must be included in the radiation field,and patients face life-long xerostomia, which impacts negativelyon nutrition, dentition, sleep, speech, and enjoyment of eating.These deleterious effects result from poor or absent salivaryflow, as well as changes in the consistency of saliva. Attemptsto improve oral function and reduce the high rate of dental carieshave included fluoride and antifungal agents as needed. Palliativetherapies, such as oral rinses, saliva substitutes, salivary stimulants(hard candy or gum), and frequent sips of water, have proved inadequate.

Oral pilocarpine has been shown to be beneficial in several trialsof short-term use [1-7]. In a double-blind, placebo-controlledtrial, Fox et al [1] demonstrated an improvement in salivary flowand a decrease in oral dryness with oral pilocarpine, 5.0 mg bid.1No severe toxicity was reported. In another double-blind trial,Greenspan and Daniels [2] noted improved salivary flow and diminishedsymptoms in 9 of 12 patients treated with oral pilocarpine tabletsat a dose of 5.0 to 7.5 mg tid or qid.

Fox et al [3] confirmed these findings in a double-blind, placebo-controlledtrial using 5.0 mg oral pilocarpine tablets tid for 6 months.Subjective improvement was reported in 27 of 31 patients, and20 of those exhibited a measurable increase in unstimulated salivaryflow. Patients reported sweating, urinary frequency, and increasedlacrimation, but serious toxicities were not noted. Valdez etal [4], in a 3-month trial of oral pilocarpine in patients undergoingradiation, demonstrated a lower incidence of oral xerostomia symptomsin the active-treatment group compared with the placebo group.

Placebo-Controlled Trials of Oral Pilocarpine Tablets

Two large, multicenter, placebo-controlled clinical trials recentlyevaluated the safety and efficacy of oral pilocarpine hydrochloridetablets [6,7]. Efficacy was most clearly demonstrated in the fixed-dosetrial [6]. In this trial, a significantly greater number of pilocarpine-treatedpatients in both the 5- and 10-mg groups experienced improvementsin oral dryness and mouth comfort, as compared with those receivingplacebo. With respect to secondary response variables, pilocarpineimproved the ability to speak, mouth and tongue comfort, and theneed for oral comfort agents. Saliva production increased withpilocarpine, but the volume of saliva did not necessarily correlatewith symptomatic relief.

Results of the dose-titration trial [7] were similar to thoseseen in the fixed-dose trial. Sensations of oral dryness improvedwith pilocarpine, particularly at the 5- and 10-mg doses. As inthe fixed-dose trial, overall global improvement in the dose-titrationtrial was significantly better with pilocarpine than with placebo.Also, those receiving pilocarpine used significantly fewer oralcomfort agents than did those receiving placebo. At every visit,post-dose salivary production was significantly increased in pilocarpine-treatedpatients compared with those receiving placebo.

In both studies, adverse reactions associated with pilocarpinewere mild and typical of side effects seen with cholinergic agonists.The most common drug-related effect in the large, multicentertrials was sweating, which generally occurred 20 to 60 minutesafter dosing and was short lived. Side effects of pilocarpinealso appeared to be dose-related.

Maintenance Study of Oral Pilocarpine Tablets

Although the aforementioned trials demonstrated the short-termbenefit of oral pilocarpine with acceptable toxicity, it was anticipatedthat the need for this drug would be lifelong. Thus, the presentstudy was undertaken to evaluate long-term efficacy and safety.We demonstrated that oral pilocarpine hydrochloride is moderatelyeffective in reducing the symptoms of radiation-induced xerostomia,including dryness, oral discomfort, sleep disturbances, difficultywith speech, chewing, and swallowing. When given as a maintenancedrug, this effect can be maintained for up to 36 months. A startingdose of 5 mg tid appears to be optimal.

Side effects are tolerable, with sweating being the most commonadverse effect. Only 18% of patients discontinued the drug dueto adverse experiences. We conclude from this study that oralpilocarpine hydrochloride tablets can be safely used for the reliefand long-term management of xerostomia.

References:

1. Fox PC, van der Ven PF, Baum BJ et al: Pilocarpine for thetreatment of xerostomia associated with salivary gland dysfunction.Oral Surg Oral Pathol 61:243-248, 1986.

2. Greenspan D, Daniels TE: Effectiveness of pilocarpine in postirradiationxerostomia. Cancer 59:1123-1125, 1987.

3. Fox PC, Atkinson JC, Macynski A, et al: Pilocarpine for treatmentof salivary hypofunction-a six month trial (abstract). J DentRes 68:315, 1989.

4. Valdez IH, Wolff A, Atkinson JC, et al: Use of pilocarpineduring head and neck radiation therapy to reduce xerostomia andsalivary dysfunction. Cancer 71:1848-1851, 1993.

5. Fox PC, Atkinson JC, Macynski AA, et al: Pilocarpine treatmentof salivary gland hypofunction and dry mouth (xerostomia). ArchIntern Med 151:1149-1152, 1991.

6. Johnson JT, Ferretti GA, Nethery WJ, et al: Oral pilocarpinefor post-irradiation xerostomia in patients with head and neckcancer. N Engl J Med 329:390-395, 1993.

7. LeVeque FG, Montgomery M, Potter D, et al: A multicenter, randomized,double-blind, placebo-controlled, dose-titration study of oralpilocarpine for treatment of radiation-induced xerostomia in headand neck cancer patients.