Long-term outcomes of interventions for radiation-induced xerostomia: A review

Table 1 Pilocarpine and Cevimeline

Author	Type of study	n	Intervention	Xerostomia symptoms	Salivary Function	Toxicity
Burlage et al[34], 2008	Double-blind, randomized, placebo-controlled trial	170	PC during RT vs placebo	LENT SOMA: no difference at 1 yr; Patient-reported xero: significantly lower scores in pilocarpine group at 12 mo only if mean parotid dose > 40 Gy	Parotid flow rate complication probability (PFCP): at 1 yr, no diff between arms (except in subset of pts with > 40 Gy mean parotid dose-reduced loss of flow in pilocarpine group)	2 patients didn't complete treatment, excessive sweating for PC and suspected AE for placebo pt; 1 G2 excessive sweating
Mateos et al[35], 2001	Prospective non-randomized study	49	PC 5 mg TID during RT and for 1 yr vs no PC	No significant difference in visual analogue scale between groups	Dynamic salivary scintigraphy: no SS differences between groups	NA
Valdez et al[36], 1993	Double-blind, randomized, placebo-controlled trial	9	PC 5 mg four times daily for 3 mo during RT vs placebo	Significantly fewer subjective oral symptoms in pilocarpine group on survey during treatment; no difference at 1 yr (25% in both arms)	Salivary flow rate (resting and stimulated): smaller losses in stim function in PC group at 3 mo (SS)	none reported
Chambers et al[37], 2007	Open-label prospective single-arm study	255	Cevimeline for 1 yr 45 mg TID orally	Used mean global eval. score (0-3), at final eval. 59.2% improved, 37.3% no change, 3.5% worse compared with first visit (P < 0.0001 change from baseline to visit 8)	NA	20.4% G3 AE, most common was sweating; 7.1% severe AE, one possibly attributed to study drug (miscarriage)

PC: Pilocarpine; G: Grade; AE: Adverse event; xero: Xerostomia; pts: Patients.

Table 2 Amifostine: Xerostomia

Author	Type of study	n	Intervention	Xerostomia symptoms	Effect Size
Bardet et al[46], 2011	Phase III randomized trial	291	Amifostine IV vs SC	RTOG grading: G2+ xero significantly higher in SC at 1 yr, but not at 2-3 yr	37% IV vs 62% SC
Haddad et al[45], 2009	Phase II randomized trial	58	SC amifostine 500 mg daily (for median 28 doses) no amifostine	CTCAE: no significant difference in Gr2+ xero (minimum follow up 26 mo)	41% both arms
Law et al[44], 2007	Phase II prospective nonrandomized trial	20	SC 500 mg amifostine 30-60 min before RT	G2 xero 42% at 12 mo, 29% at 18 mo; no G3+ xero. G3+ mucositis in 30% of pts.
Anné et al[43], 2007	Phase II single arm multicenter trial	54	SC amifostine	RTOG scoring: G2+ xero = 56%; late G2+ in 45% ; G3+ acute 33%
Jellema et al[23], 2006	Phase II randomized trial	91	No amifostine vs 200 mg/m2 IV daily (3 wk) vs 5 wk	RTOG scoring: significant difference in late G2+ xero at 6 mo between arms; no difference in xero at 12 mo or 24 mo; no dif in acute xero	Late G2+ xero 74% vs 67% vs 52%
				EORTC QLQ-H and N35: significantly higher mean xerostomia score in no amifostine group
Buentzel et al[41], 2006	Phase III randomized placebo-controlled trial	132	IV amifostine 300 mg/m2 days 1-5 and 21-25, 200 mg/m2 on other days vs placebo	RTOG criteria: no significant difference in G2+ acute or late xero	39% amifostine vs 34% placebo (acute); 39% amifostine vs 24% placebo (late)
Wasserman et al[42], 2005	Phase III randomized trial	303	IV amifostine 200 mg/m2 15-30 prior to each RT fraction vs no amifostine	RTOG scoring: significantly lower G2+ xero in amifostine group on longitudinal analysis	20% vs 36% at 24 mo
Thorstad et al[47], 2004	Pilot clinical trial	27	Amifostine concurrent with RT (500 mg SC daily)	not reported	NA
Antonadou et al[40], 2002	Randomized controlled trial	50	Amifostine 300 mg/m2 15-30 min prior to RT (daily) vs no amifostine	RTOG/EORTC scoring: significantly lower xero in amifostine group at 18 mo (G1+)	30.4% vs 4.5%
Brizel et al[39], 2000	Phase III multiinstitutional randomized trial	303	Amifostine 200 mg/m2 15-30 min prior to each RT tx vs no amifostine	RTOG scoring: significantly higher G2+ xero (acute and late) in control vs amifostine; higher dose required to cause G2 xero in amifostine pts (60 Gy vs 42 Gy);	78% vs 51% (acute); 57% 43% (1 yr)
Büntzel et al[38], 1998	Phase II randomized trial	39	Amifostine IV 500mg prior to carboplatin (days 1-5 and 21-25) vs no amifostine	Acute G2 xero, G3 mucositis, and G3 thrombocytopenia all significantly decreased with amifostine; at 12 mo, trend toward xero improvement with amifostine	Xero: G2 100% vs 12% (acute); 55% vs 17% (late; P = 0.05)

SC: Subcutaneous; G: Grade; xero: Xerostomia; pts: Patients.

Table 3 Amifostine: Salivary function, quality of life, toxicity

Author	Salivary Production	QOL	Toxicity
Bardet et al[46], 2011	No difference in unstimulated and stimulated salivary flow rate =	No difference in patient-reported salivary function or Gr 2+ xero	No difference in compliance between arms (69% IV vs 71% SC). Acute toxicity 25% IV vs 27% SC (NS). SS higher rate of hypotension in IV arm; significantly higher skin rash and local pain in SC arm.
Haddad et al[45], 2009	No difference in unstimulated or stimulated saliva at all endpoints (up to 1 yr)	No difference in penetration, aspiration, and pharyngeal residue on swallow eval.	G3 mucositis in 75% (amifostine) and 70% (no amifostine); Gr3 skin toxicity in 12 patients in amifostine group (main reason for withholding amifostine)
Law et al[44], 2007	NA	NA	G2 weight loss for all pts, Gr2 or less N/V in 7 pts (35%). No grade 3+ amifostine-related AEs.
Anné et al[43], 2007	NA	PBQ: mean score 8.5 baseline, 6.1 at 4 wk, 7.5 at 1 yr	Nausea, emesis, injection site reaction most common G1-2; G3 dehydration 11%, rash 6%, weight decrease, mucositis, dyspnea, allergic reaction 4% each; one G4 anaphylaxis
Jellema et al[23], 2006	NA	QLQ-C30, QLQ-H and N35: no differences in sticky saliva or other QOL data	Significantly higher N/V in amifostine groups; 28% of patients discontinued amifostine early
Buentzel et al[41], 2006	not assessed: fewer than one-third in each arm had salivary assessment at 1 yr	NA	42% G3+ toxicity (amifostine) vs 20% (placebo) (SS)
Wasserman et al[42], 2005	no dif. in stimulated; unstimulated higher in amifosine group at 12 mo (SS)	PBQ: amifostine group had SS better mouth dryness at 12, 18, and 24 mo; better score for "use of oral comfort aids" with amifostine at 24 mo	not enough to analyze
Thorstad et al[47], 2004	not reported	not reported	reasons for discontinuing amifostine: nausea (33%), rash (15%), fever (7%), other (11%)
Antonadou et al[40], 2002	NA	NA	SS lower acute mucositis and acute dysphagia in amifostine group; in amifostine group, 1 pt had N/V, 3 pts had transient hypotension
Brizel et al[39], 2000	Whole saliva production higher in amifostine pts at 1 yr (SS)	PBQ: overall score favored amifostine at 1 yr (SS)	53% nausea and vomiting (5% of total administrations; 3% G3 N, 5% G3 V)); G3 N/V in 7% of pts; median weight loss higher in control group (SS); hypotension 15% (3% G3; < 1% of all doses); venous catheter complications 5%; infections 14%; clotting/vascular 3% (1 pt G4); allergic reaction 5%
Büntzel et al[38], 1998	NA	NA	No significant difference in N/V between groups; hypotension 40% amifostine arm (max drop 20 mmHg)

QOL: Quality of life; SC: Subcutaneous; G: Grade; AE: Adverse event; xero: Xerostomia; NA: Not available; PBQ: Patient benefit questionnaire; pts: Patients.

Table 4 Submandibular gland transfer: Xerostomia

Author	Study design	n	Intervention	Xerostomia symptoms	Effect size
Zhang et al[31], 2014	Randomized controlled trial	65	Submandibular transfer vs control	Significantly lower incidence of xerostomia (RTOG/EORTC staging criteria) at 1 yr and 5 yr in transfer group vs control. Significantly lower VAS at 5 yr for transfer group	Xerostomia 18.7% vs 81.8% at 1 yr; 15.4% for transfer vs 76.9% at 5 yr; VAS 3.7 for transfer vs 5.8 for control
Rieger et al[51], 2012	Phase III randomized controlled trial	69	Submandibular transfer vs oral PC	EORTC QLQ H and N35: significantly worse dry mouth and sticky saliva at 1 yr in PC group vs submandibular transfer at 1 yr	Dry mouth score 42.6 vs 85.8; sticky saliva score 37.2 vs 66.7
Liu et al[50], 2011	Prospective non-randomized controlled trial	70	Submandibular transfer vs control	At 5 yr, significantly higher mod-to-severe xerostomia in control group; significantly better VAS in transfer group vs control	Mod-to-severe xerostomia 78.6% vs 12.9%
Seikaly et al[49], 2004	Phase II prospective non-randomized	38	Submandibular gland transfer vs control	UW-QOL: significantly better xerostomia symptoms (amount and consistency) at 2 yr	83% vs 0% reporting normal amount of saliva
Jha et al[48], 2003	Phase II prospective single arm	76	submandibular gland transfer	UW-QOL: 81% minimal or no xero at end of RT; 65% at 2 mo; 71% at 6 mo (in unshielded pts, 71% had severe xero at 6 mo)	-

VAS: Visual analogue scale; PC: Pilocarpine; xero: Xerostomia; UW-QOL: University of Washington quality of life scale; pts: Patients.

Table 5 Submandibular gland transfer: Salivary function, quality of life, toxicity

Author	Salivary function	Quality of life	Toxicity
Zhang et al[31], 2004	Transfer 1.39 g and 1.6 g saliva vs 0.66 and 0.68 g control at 1 yr and 5 yr, respectively. Significantly higher submandibular gland secretion in transfer group at 5 yr (radionuclide scintigraphy).	Significantly improved speech, chewing, swallowing, changes in eating habits, nighttime xero, need to wake up to drink frequently, sleep quality in transfer group	No surgical death or complications occurred in transfer group
Rieger et al[51], 2012	NA	NA	Not reported
Liu et al[50], 2011	Significantly better trapping and excretion (scintigraphy) in transfer group at 5 yr; Significantly higher mean weight of unstimulated saliva in transfer group at 5 yr	Transfer group improved significantly vs control in dry mouth, night rest, drink to speech, drink to eat, water intake, change in feeding pattern, tooth decay, and visual analogue scale	No major complications of surgery (one pt taken back 2 yr later for removal of wire used to mark borders of transferred gland due to pain)
Seikaly et al[49], 2004	Significantly higher stimulated and unstimulated saliva in transfer group at 16 mo	NA	No surgical complications from submandibular transfer
Jha et al[48], 2003	stimulated and unstimulated saliva decrease gradually, then increase at 16 mo (graphical)	NA	No surgical complications

xero: Xerostomia; NA: Not available.

Table 6 Other

Author	Type of study	Sample size	Intervention	Xerostomia symptoms	Salivary function	Quality of life	Toxicity
Wong et al[54], 2015	Phase III randomized controlled trial	148	ALTENS vs oral PC (5 mg TID for 12 wk)	NA	Basal WSP and stimulated WSP: no sig difference	XeQOLs: no difference at 15 mo. 83% ALTENS positive responders vs 62.8% PC, SS at 15 mo.	2 G3 events in PC (dry mouth, blurry vision) vs 1 G3 event in ALTENS (headache). 61.6% of PC had Grade 3 or less non-hematologic AEs vs 20.9% of ALTENS
Teguh et al[52], 2009	randomized controlled trial	19	Hyperbaric O2 (30 sessions at 2.5 ATA with O2 breathing for 90 min daily, 5 d a week) vs control	Visual analogue scale dry mo better on O2 (SS)	NA	EORTC QLQ-C30 and H and N35; Sticky saliva better on O2 (SS) and less dry mouth on O2 (SS)	NA
Blom et al[53], 1996	randomized placebo-controlled trial	38	acupuncture vs placebo (superficial acupuncture)	NA	salivary flow rate: no dif. between groups; both groups showed increased flow rates after treatment	No specific endpoints	Tiredness, small haematomas at acupuncture sites

ALTENS: Acupuncture like transcutaneous electrical nerve stimulation; NA: Not available; G: Grade; PC: Pilocarpine; AE: Adverse event; WSP: Whole salivary production; XeQOLs: Xerostomia quality of life scale.