Phase III quality-of-life study results: impact on patients’ quality of life to reducing xerostomia after radiotherapy for head-and-neck cancer—RTOG 97-09
Fisher J, International Journal of Radiation Oncology*Biology*Physics - 01 July 2003 (Vol. 56, Issue 3, Pages 832-836)  

It is documented that cumulative radiation doses ranging from 22.2 to 54 Gy injures the parenchyma of the salivary gland, causing fibrosis and secretory hypofunction. This effect is dose related and can be permanent, resulting in a condition known as postirradiation xerostomia.

Head-and-neck patients with postirradiation xerostomia produce little or no saliva (hyposalivation/xerostomia). Radiation-induced xerostomia remains an acute and common chronic complication of irradiation to the head and neck. Xerostomia can significantly increase dental caries and compromise mucosal integrity, resulting in oral pain, loss of taste, sleep disturbance, and difficulty with chewing and swallowing. These manifestations can further lead to predisposition to severe oral disease, nutritional deficiencies, and an overall decline in QOL. Before 1993, treatment for postirradiation xerostomia was ineffective. The use of mouthwashes and saliva substitutes often was abandoned by patients and replaced with increased water consumption.

Pilocarpine, a cholinergic parasympathomimetic agent, acts as an agonist primarily at the muscarinic receptors . Early trials from 1964 to 1971 resulted in recognition of pilocarpine as a salivary stimulant. Several clinical trials in 1993 demonstrated statistically significant improvement for postirradiation xerostomia. A prospective, randomized, placebo-controlled trial of 207 patients with postirradiation xerostomia by Johnson  found that pilocarpine improved salivary production and relieved the symptoms of xerostomia. LeVeque  in their multicenter, randomized, double-blind, placebo-controlled study of pilocarpine in another 207patients demonstrated similar results, concluding that pilocarpine produces clinically significant symptomatic treatment of postirradiation xerostomia. The Food and Drug Administration currently approves pilocarpine for the treatment of radiation-induced xerostomia.

Assuming the relief of a symptom is valued because of its benefit to a patient’s function and well-being, an intervention’s effectiveness for minimizing or preventing morbidity should have a positive impact on the QOL. Thus, the objectives for this QOL study were to determine the impact xerostomia has on patients receiving irradiation to the head and neck, and to determine the impact of symptom relief with pilocarpine on patients’ QOL.

Patients were 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 University of Washington head-and-neck QOL tool before RT and 3 and 6 months after RT. Patients were randomized to receive pilocarpine 5 mg or placebo q.i.d.

Results

The primary clinical objective of Radiation Therapy Oncology Group (RTOG) 97-09 was to determine whether the concomitant use of pilocarpine was able to preserve salivary flow in head-and-neck cancer patients receiving curative RT. Patients were randomized to pilocarpine 5 mg q.i.d. or placebo. A total of 249 patients was randomized between March 1998 and January 2000. Of these, 214 were eligible for QOL analysis. Patients were evenly distributed between arms by race, gender, tobacco use, tumor site, T stage (50% T2-T3), and salivary function. A Karnofsky performance status of 90% was more common in the pilocarpine arm. Twenty percent of the patients on the pilocarpine arm and 29% of the patients on the placebo arm were taking nutritional supplements. The placebo arm patients had greater mouth pain and chewing difficulties. Compliance for the QOL tool at 3 and 6 months was 65% and 50%, respectively. Despite statistically significant (p = 0.047 and p = 0.049, respectively) preservation of salivary function in the pilocarpine arm, patients on the pilocarpine arm reported difficulties with swallowing (75%), activity (80%), hyposalivation (64%), and taste (81%). No difference was noted between arms at 3 months in mucositis scores, with both arms demonstrating increased requirement for oral nutrients.

Discussion

This study assumed that the concomitant use of pilocarpine would prevent or minimize radiation-induced xerostomia and demonstrate a positive impact for maintaining or improving patients’ QOL. Concomitant use of pilocarpine did in fact maintain and protect unstimulated salivary flow. However, the analysis of the QOL data demonstrated that maintaining salivary flow did not have a positive impact on the QOL outcome for patients taking pilocarpine. No difference was found between arms by patient assessment for dryness or salivary consistency. Both arms at 3 and 6 months by patient assessment experienced similar levels of salivary dysfunction. These results are difficult to comprehend. One explanation is that all people react to change and in this study they all reacted to change similarly. It did not make any difference how small the change was, it equally affected both groups negatively. This is the fundamental definition for QOL, “ a patient’s appraisal of and satisfaction with their current level of functioning as compared to what they perceive to be possible or ideal”. Although salivary functioning was statistically better for the pilocarpine patients, it was not “perceived to be ideal.”

In addition to the primary symptoms of dryness and salivary consistence, xerostomia can have an impact on a patient’s level of pain, and ability to eat, swallow, and taste. The results demonstrated similar outcomes in these domains, but this finding was most likely related to another underlying principle. As in previous head-and-neck clinical trials, the results of this study confirm the impact RT has on patients’ ability to eat, swallow, and taste after treatment. This is obvious when comparing the pretreatment norms with the 3- and 6-month posttreatment results. The question is which of the two morbidities, mucositis vs. xerostomia, had the most impact on these posttreatment dysfunctions. Mucositis produces similar dysfunctions as xerostomia. Patients with Grade 2 mucositis experience difficulties with swallowing, chewing, taste, pain, sleeping, and speaking, resulting in a progressive deterioration in their general well-being and QOL. Mucositis is self-limiting; however, with increasing use of dose-intensifying radiation regimens, clinicians are observing a prolonging of acute mucositis from weeks to several months after RT. The UW-QOL questionnaire asks patients to circle the statement that best describes their current level of function. They were not asked if this dysfunction was attributed to their lack of saliva, sore mouth, or altered taste. Even the most experienced clinician might experience difficulty deciphering whether a patient’s taste or swallowing difficulty was related more to their dry mouth or their Grade 2 mucositis. Validating the pure impact of xerostomia on this population was difficult because of the similarities between the two morbidities and the patients’ inability to delineate between cause and effect. The concomitant use of pilocarpine prevents radiation-induced xerostomia. It is unfortunate that the research effort to have a positive impact on patients’ QOL from this well-established morbidity of radiation-induced xerostomia was not realized by the head-and-neck patient population in this study. Future QOL trials for xerostomia intervention will need to be sensitive to the similar impact mucositis and xerostomia have on a patient’s oral integrity to better delineate which has the greater impact on QOL.

Conclusion

Objective prevention of hyposalivation did not affect patients’ assessment of salivary function or QOL because of the greater impact mucositis plays in QOL after RT.

A Phase III placebo-controlled trial of oral pilocarpine in patients undergoing radiotherapy for head-and-neck cancer
Warde P, International Journal of Radiation Oncology*Biology*Physics - 01 September 2002 (Vol. 54, Issue 1, Pages 9-13)

Purpose: To test the hypothesis that the use of oral pilocarpine during and after radiotherapy (RT) for head-and-neck cancer would reduce the symptoms of post-RT xerostomia.

Methods and Materials: One hundred thirty patients were randomized in a double-blind method to receive either pilocarpine (5-mg tablets) or placebo three times daily starting on Day 1 of RT and continuing for 1 month after treatment. The eligibility criteria included a planned dose of >50 Gy as radical or postoperative RT for head-and-neck cancer, with at least 50% of both parotid glands included in the treatment fields. The primary outcome measure was the severity of xerostomia as assessed by a patient-completed linear analog scale 3 months after RT. Secondary outcome measures included quality of life during therapy (as assessed by the McMaster University Head-and-Neck Questionnaire) and severity of mucositis during RT (as assessed using Radiation Therapy Oncology Group scales).

Results: No difference was observed between the pilocarpine-treated patients and the placebo group in the severity of xerostomia score as assessed by linear analog scale at baseline and 1, 3, and 6 months after treatment (repeated measures analysis, p = 0.92). No difference was apparent in the severity of mucositis during RT; 56.3% of patients receiving pilocarpine had Grade III/IV mucositis compared with 50.8% treated with placebo. No difference in quality of life was noted between the treatment groups during or after RT. The questionnaire score at 3 months after RT was 5.0 (SD 1.0). in the pilocarpine group and 4.9 (SD 0.9) in the placebo group.

Conclusion: We were unable to detect a beneficial effect of pilocarpine on RT-induced xerostomia when administered during RT for head-and-neck cancer.

The effect of pilocarpine and biperiden on salivary secretion during and after radiotherapy in head and neck cancer patients
Rode M, S International Journal of Radiation Oncology*Biology*Physics - 01 September 1999 (Vol. 45, Issue 2, Pages 373-378)

Normal salivation is an essential component of oral health due to its important contributions to oral defense mechanisms and digestive functions. When irradiating patients with head and neck carcinoma it is often impossible to avoid the irradiation of major salivary glands. During irradiation treatment, patients quickly note reduced production of saliva and increase in its viscosity. Lack of saliva may lead to dental caries and mucosal alterations.

The degree of radiation injury to salivary glands depends on the total dose and the proportion of gland that was irradiated. Histopathological studies of irradiated animals showed that acinar cells are the most radiosensitive glandular component. The excretory ducts are relatively insensitive, and the intercalated and striated ducts are of intermediate sensitivity. The serous acini of the parotid gland are apparently more radiosensitive than the seromucous acini of the submandibular, and much more than the mucous acini of the sublingual gland.

There were many attempts to mitigate the effects of irradiation on salivary glands. Some authors  report that pilocarpine given during the irradiation treatment helps to maintain some secretion of saliva. Others found that pilocarpine given after the completion of irradiation treatment improved the salivation . On the other hand, Ahlner reported that better salivation was achieved in animal experiments if the function of salivary glands had been inhibited during the irradiation. However, the number of patients receiving pilocarpine during the irradiation in these studies was small, and the studies where the salivary glands were inhibited during the irradiation were performed on experimental animals. Thus, the question how to alleviate the irradiation effects on salivary glands in patients irradiated for carcinoma of the head and neck remains unclear.

The aim of present research was to study the influence that parasympathicomimetic drug (pilocarpine) or parasympathicolytic drug (biperiden) may have on the salivation in patients irradiated for head and neck carcinoma.Purpose: The influence of parasympathicomimetic pilocarpine and anticholinergic biperiden on salivation in patients irradiated for malignant tumors of the head and neck region was assessed in a prospectively designed clinical study.

Methods and Materials: Sixty-nine patients, irradiated for head and neck cancer with salivary glands included in the irradiation fields, were randomly assigned into three groups (A, B, and C). Group A consisted of patients receiving pilocarpine, group B of those who were receiving biperiden during radiotherapy and pilocarpine for 6 weeks after its completion, while group C comprised patients not receiving any xerostomy prevention therapy during or after radiotherapy. The quantity of secreted unstimulated saliva was measured before the beginning of radiotherapy, after 30 Gy of irradiation, on completed irradiation, and 3, 6, and 12 months after completion of radiotherapy.

Results: Saliva secretion has been found to be the least affected by irradiation treatment in the group of patients receiving biperiden throughout the course of radiotherapy. Six months after completed irradiation, the differences in the quantity of secreted saliva between groups C and B as well as between groups A and B were statistically significant (P = 0.002 and 0.05 respectively). In patients receiving pilocarpine during radiotherapy, and those in the control group, further decrease in saliva secretion was observed. One year after completed therapy, the quantity of secreted saliva could only be measured in the patients receiving biperiden during radiotherapy: it amounted to 16% of the average quantity of saliva secreted before the beginning of irradiation.

Conclusion: It seems that the inhibition of saliva production during irradiation treatment and the stimulation after completed radiotherapy may contribute to the preservation of salivary gland function after therapy.

Concomitant pilocarpine during head and neck irradiation is associated with decreased posttreatment xerostomia
Zimmerman RP, Mark RJ, Tran LM, Juillard GF
International Journal of Radiation Oncology*Biology*Physics - 01 February 1997 (Vol. 37, Issue 3, Pages 571-575) Purpose: To retrospectively compare subjective postirradiation xerostomia scores of patients who received concomitant oral pilocarpine during radiotherapy for head and neck cancer and 3 months thereafter with those of similar cohorts who did not receive pilocarpine.

Methods and Materials: Subjective serostomia was assessed using a visual analog scale xerostomia questionnaire that measured oral dryness, oral comfort, difficulty with sleep, speech, and eating. The concomitant pilocarpine group had both paratid glands in the initial field treated to at least 45 Gy and received 5 mg pilocarpine hydrochloride four times per day (q.i.d.) beginning on the first day of radiotherapy and continuing for 3 months after completion of radiation. The control cohort had also received at least 45 Gy to both parotid glands and had not received pilocarpine at the time of evaluation. Scores on the visual analog scale were averaged and compared using the Student's t-test.

Results: Seventeen patients who received concomitant pilocarpine during head and neck irradiation and 18 patients who had not been treated with pilocarpine were available for follow-up. The mean intervals between completion of radiation and evaluation of xerostomia were 17 months and 16 months, respectively. Only one of the pilocarpine-treated patients was still taking pilocarpine at the time of evaluation. For each of the individual components of xerostomia scored on the visual analog scale, as well as the composite of all components, the group that had received oral pilocarpine during radiation had significantly less xerostomia ( for each).

Conclusions: The use of 5 mg oral pilocarpine q.i.d. during radiotherapy for head and neck cancer and 3 months thereafter was associated with significantly less subjective xerostomia than that reported by a similar cohort of patients who had not received pilocarpine. The continued use of pilocarpine does not appear to be necessary to maintain this benefit in most patients.

Preservation of the rat parotid gland function after radiation by prophylactic pilocarpine treatment: radiation dose dependency and compensatory mechanisms
Roesink JM, Konings AWT, Terhaard CHJ, Battermann JJ, Kampinga HH, Coppes RP
International Journal of Radiation Oncology*Biology*Physics - 01 September 1999 (Vol. 45, Issue 2, Pages 483-489)

Purpose: To study the ability of a prophylactic pilocarpine administration to preserve the rat parotid gland function after unilateral irradiation with graded doses of X-rays. Radiotherapy of tumors in the head and neck region frequently involves the salivary glands in the irradiated volume. Exposing the salivary glands to radiation can result in severe side effects having a negative impact on the daily life of the patient. The consequences of irradiation-induced salivary gland injury are still very difficult to manage. The use of mouth rinses, saliva substitutes, and gustatory stimulants are often abandoned and replaced by repeated water consumption, generally offering only short-term relief of symptoms).

The muscarinic receptor agonist pilocarpine has been shown to produce clinically significant benefits for the symptomatic treatment of postradiation xerostomia when administered chronically. However, administration of pilocarpine to stimulate any residual function of the salivary gland after radiotherapy is useful to a limited extent: the gain in function ceases as soon as the administration of the sialogogue is stopped. This means that patients have to use this sialogogue for the rest of their lives.

Interestingly, histological studies on rat salivary glands have shown that prophylactic treatment with sialogogues has some radioprotective potential . The radioprotective effect of sialogogues on the morphology of the rat salivary gland consisted of attenuation of the irradiation-induced reduction in number of secretory granules, injury to the mitochondria and cell membrane (9, 10). We recently showed that pretreatment with pilocarpine also resulted in sparing of radiation-induced changes in rat salivary gland function. This is consistent with small clinical trials demonstrating that concomitant use of pilocarpine during head and neck irradiation was associated with decreased posttreatment xerostomia and that prolonged postirradiation use of pilocarpine was not always required. It was speculated that the sparing effect of pretreatment with pilocarpine might be due to stimulation of salivary gland tissue outside the radiation portal). This would suggest that the protective effectiveness of pilocarpine should decrease with increasing radiation dose and/or increasing irradiated salivary gland volume. Yet, the validity of this explanation is still completely unclear, especially in the light of our studies in rats that revealed a protective effect of a single pretreatment dose of pilocarpine against early function loss, even when both glands were completely irradiated . Therefore the effects of preirradiation treatment with a single dose of pilocarpine on rat parotid salivary gland function 0–30 days after X-rays were investigated in relation to radiation dose. Furthermore the effects of unilateral rat parotid gland radiation, using different radiation doses, on bilateral stimulated parotid saliva secretion were assessed to look at compensatory effects.

Methods: The right parotid gland of male albino Wistar rats was irradiated with single doses of X-rays (10–30 Gy, at 1.5 Gy min-1). Pilocarpine (4 mg/kg) was administered intraperitoneally, 1 hour prior to irradiation. Saliva samples of both left and right parotid gland were collected by means of miniaturized Lashley cups 4 days before and 3, 7, 10, and 30 days after irradiation. The parotid salivary flow rate (?l/min) was used as a parameter for the assessment of parotid gland function.

Results: Our data confirm that a single prophylactic treatment of pilocarpine can attenuate radiation-induced loss of gland function. Surprisingly, the effect of pilocarpine was not restricted to the irradiated gland only. Pilocarpine also enhanced the flow rate in the contralateral, nonirradiated gland. The latter effect was found for all doses above 10 Gy and became apparent around 7 days after the radiation treatment. The effectiveness of pilocarpine to attenuate function loss in the irradiated gland decreased with increasing dose and was lost after single doses of 30 Gy.

Conclusions: Our data provide direct evidence that increasing the compensatory potential of the nondamaged gland, at least in part, underlies the “radioprotective effect” of pilocarpine in case of unilateral radiation. The ability of pilocarpine to ameliorate the early radiation-induced impairment of the parotid gland function in the irradiated gland may therefore be dependent on the remaining number of functional cells, and thus on the volume of the gland that lies within the radiation portal.