Copyright ©The Author(s) 2019.
World J Clin Oncol. Jan 10, 2019; 10(1): 1-13
Published online Jan 10, 2019. doi: 10.5306/wjco.v10.i1.1
Table 1 Pilocarpine and Cevimeline
AuthorType of studynInterventionXerostomia symptomsSalivary FunctionToxicity
Burlage et al[34], 2008Double-blind, randomized, placebo-controlled trial170PC during RT vs placeboLENT SOMA: no difference at 1 yr; Patient-reported xero: significantly lower scores in pilocarpine group at 12 mo only if mean parotid dose > 40 GyParotid 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], 2001Prospective non-randomized study49PC 5 mg TID during RT and for 1 yr vs no PCNo significant difference in visual analogue scale between groupsDynamic salivary scintigraphy: no SS differences between groupsNA
Valdez et al[36], 1993Double-blind, randomized, placebo-controlled trial9PC 5 mg four times daily for 3 mo during RT vs placeboSignificantly 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], 2007Open-label prospective single-arm study255Cevimeline for 1 yr 45 mg TID orallyUsed 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)NA20.4% G3 AE, most common was sweating; 7.1% severe AE, one possibly attributed to study drug (miscarriage)
Table 2 Amifostine: Xerostomia
AuthorType of studynInterventionXerostomia symptomsEffect Size
Bardet et al[46], 2011Phase III randomized trial291Amifostine IV vs SCRTOG grading: G2+ xero significantly higher in SC at 1 yr, but not at 2-3 yr37% IV vs 62% SC
Haddad et al[45], 2009Phase II randomized trial58SC amifostine 500 mg daily (for median 28 doses) no amifostineCTCAE: no significant difference in Gr2+ xero (minimum follow up 26 mo)41% both arms
Law et al[44], 2007Phase II prospective nonrandomized trial20SC 500 mg amifostine 30-60 min before RTG2 xero 42% at 12 mo, 29% at 18 mo; no G3+ xero. G3+ mucositis in 30% of pts.
Anné et al[43], 2007Phase II single arm multicenter trial54SC amifostineRTOG scoring: G2+ xero = 56%; late G2+ in 45% ; G3+ acute 33%
Jellema et al[23], 2006Phase II randomized trial91No amifostine vs 200 mg/m2 IV daily (3 wk) vs 5 wkRTOG 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 xeroLate 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], 2006Phase III randomized placebo-controlled trial132IV amifostine 300 mg/m2 days 1-5 and 21-25, 200 mg/m2 on other days vs placeboRTOG criteria: no significant difference in G2+ acute or late xero39% amifostine vs 34% placebo (acute); 39% amifostine vs 24% placebo (late)
Wasserman et al[42], 2005Phase III randomized trial303IV amifostine 200 mg/m2 15-30 prior to each RT fraction vs no amifostineRTOG scoring: significantly lower G2+ xero in amifostine group on longitudinal analysis20% vs 36% at 24 mo
Thorstad et al[47], 2004Pilot clinical trial27Amifostine concurrent with RT (500 mg SC daily)not reportedNA
Antonadou et al[40], 2002Randomized controlled trial50Amifostine 300 mg/m2 15-30 min prior to RT (daily) vs no amifostineRTOG/EORTC scoring: significantly lower xero in amifostine group at 18 mo (G1+)30.4% vs 4.5%
Brizel et al[39], 2000Phase III multiinstitutional randomized trial303Amifostine 200 mg/m2 15-30 min prior to each RT tx vs no amifostineRTOG 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], 1998Phase II randomized trial39Amifostine IV 500mg prior to carboplatin (days 1-5 and 21-25) vs no amifostineAcute G2 xero, G3 mucositis, and G3 thrombocytopenia all significantly decreased with amifostine; at 12 mo, trend toward xero improvement with amifostineXero: G2 100% vs 12% (acute); 55% vs 17% (late; P = 0.05)
Table 3 Amifostine: Salivary function, quality of life, toxicity
AuthorSalivary ProductionQOLToxicity
Bardet et al[46], 2011No difference in unstimulated and stimulated salivary flow rate =No difference in patient-reported salivary function or Gr 2+ xeroNo 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], 2009No 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], 2007NANAG2 weight loss for all pts, Gr2 or less N/V in 7 pts (35%). No grade 3+ amifostine-related AEs.
Anné et al[43], 2007NAPBQ: mean score 8.5 baseline, 6.1 at 4 wk, 7.5 at 1 yrNausea, 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], 2006NAQLQ-C30, QLQ-H and N35: no differences in sticky saliva or other QOL dataSignificantly higher N/V in amifostine groups; 28% of patients discontinued amifostine early
Buentzel et al[41], 2006not assessed: fewer than one-third in each arm had salivary assessment at 1 yrNA42% G3+ toxicity (amifostine) vs 20% (placebo) (SS)
Wasserman et al[42], 2005no 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 monot enough to analyze
Thorstad et al[47], 2004not reportednot reportedreasons for discontinuing amifostine: nausea (33%), rash (15%), fever (7%), other (11%)
Antonadou et al[40], 2002NANASS 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], 2000Whole 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], 1998NANANo significant difference in N/V between groups; hypotension 40% amifostine arm (max drop 20 mmHg)
Table 4 Submandibular gland transfer: Xerostomia
AuthorStudy designnInterventionXerostomia symptomsEffect size
Zhang et al[31], 2014Randomized controlled trial65Submandibular transfer vs controlSignificantly 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 groupXerostomia 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], 2012Phase III randomized controlled trial69Submandibular transfer vs oral PCEORTC QLQ H and N35: significantly worse dry mouth and sticky saliva at 1 yr in PC group vs submandibular transfer at 1 yrDry mouth score 42.6 vs 85.8; sticky saliva score 37.2 vs 66.7
Liu et al[50], 2011Prospective non-randomized controlled trial70Submandibular transfer vs controlAt 5 yr, significantly higher mod-to-severe xerostomia in control group; significantly better VAS in transfer group vs controlMod-to-severe xerostomia 78.6% vs 12.9%
Seikaly et al[49], 2004Phase II prospective non-randomized38Submandibular gland transfer vs controlUW-QOL: significantly better xerostomia symptoms (amount and consistency) at 2 yr83% vs 0% reporting normal amount of saliva
Jha et al[48], 2003Phase II prospective single arm76submandibular gland transferUW-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)-
Table 5 Submandibular gland transfer: Salivary function, quality of life, toxicity
AuthorSalivary functionQuality of lifeToxicity
Zhang et al[31], 2004Transfer 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 groupNo surgical death or complications occurred in transfer group
Rieger et al[51], 2012NANANot reported
Liu et al[50], 2011Significantly better trapping and excretion (scintigraphy) in transfer group at 5 yr; Significantly higher mean weight of unstimulated saliva in transfer group at 5 yrTransfer 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 scaleNo 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], 2004Significantly higher stimulated and unstimulated saliva in transfer group at 16 moNANo surgical complications from submandibular transfer
Jha et al[48], 2003stimulated and unstimulated saliva decrease gradually, then increase at 16 mo (graphical)NANo surgical complications
Table 6 Other
AuthorType of studySample sizeInterventionXerostomia symptomsSalivary functionQuality of lifeToxicity
Wong et al[54], 2015Phase III randomized controlled trial148ALTENS vs oral PC (5 mg TID for 12 wk)NABasal WSP and stimulated WSP: no sig differenceXeQOLs: 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], 2009randomized controlled trial19Hyperbaric O2 (30 sessions at 2.5 ATA with O2 breathing for 90 min daily, 5 d a week) vs controlVisual analogue scale dry mo better on O2 (SS)NAEORTC QLQ-C30 and H and N35; Sticky saliva better on O2 (SS) and less dry mouth on O2 (SS)NA
Blom et al[53], 1996randomized placebo-controlled trial38acupuncture vs placebo (superficial acupuncture)NAsalivary flow rate: no dif. between groups; both groups showed increased flow rates after treatmentNo specific endpointsTiredness, small haematomas at acupuncture sites