Clinical Studies of Nonpharmacological Methods to Minimize Salivary Gland Damage after Radioiodine Therapy of Differentiated Thyroid Carcinoma: Systematic Review

Table 1

Authors, country, year of publication	Study design	Assessment methods and times	Radioiodine activity	Statistical analysis	Results	Jadad^1 score
Nakada et al., Japan, 2005 [9]	105 participants receiving ^131I therapy in control group were given 1-2 lemon candies immediately after iodine consumption and then every 2-3 hours for 5 days; 125 participants in experimental group had the same intervention, but starting 24 hours after iodine ingestion; Allocation was not randomized; each study group’s members were recruited consecutively during different periods	Questionnaire and VAS; Salivary gland scintigraphy with Tc-pertechnetate during hospitalization and after 1–6 months for 24-month duration	3.66 GBq versus 5.55 GBq between two groups	Chi-squared test, -test; ()	Sialadenitis incidence in Group A = 63.8% and in Group B = 36.8% (); Taste dysfunction incidence in Group A = 39.0% and in Group B = 25.6% (); Dry mouth incidence in Group A = 23.8% and in Group B = 11.2% (); Dry mouth in Group A = 14.3% and 5.6% in Group B ()	1
Liu et al., China, 2010 [13]	72 participants receiving ^131I therapy; Patients sucked vitamin C lozenge (100 g) every 4 hours for 6 days starting either 1 hour (), 5 hours (), 13 hours (), or 25 hours () after ^131I consumption	Salivary gland scintigraphy with Tc-pertechnetate; 1, 2, 3, 4, 5, 13, 25, and 48 hours after ^131I	3.7 GBq	Chi-squared and Kruskal-Wallis test ()	Salivary gland cumulative activities from the first 24 hours after ^131I administration accounted for 86.08%  ±  7.89%; No statistically significant differences among the 4 groups; Vitamin C had limited effect in all groups	3
Fallahi et al., Iran, 2013 [14]	36 participants receiving ^131I therapy; 19-patient experimental group was given 800 IU vitamin E/day for 1 week before radioiodine administration, as well as the 4 weeks afterwards; 17-patient control group was given a placebo according to the same regimen	Salivary gland scintigraphy with Tc-pertechnetate; was performed on the day of RAIT as well as 6 months later (follow-up); Salivary gland excretion function was measured	3700–5550 MBq	Mann-Whitney test; Fisher’s Exact test; Wilson Signed-Rank test	Experimental group: no statistical difference before versus after iodine; Control group: decline in the amount of the parotid gland uptake after iodine; In the experimental group, there was a change in the first minute uptake ratio in the right parotid gland and the excretion function of the left parotid gland suffered less damage; Salivary gland excretion experimental group = 7.9% versus 26.5% for control group, with more than 15% absolute decrease in the experimental group ()	3
Kulkarni et al., USA, 2014 [15]	9 participants awaiting ^131I therapy: prospective pilot study	2 salivary gland scans performed over 8 days; One salivary gland scintigraphy done with lemon juice (SSwLJ) after ^123I administration; Second salivary scintigraphy done without lemon juice (SSwoLJ), again after ^123I administration; Examine the potential absorbed dose in parotid glands with the use of TAC	37 MBq–185 MBq (^123I); (dose of iodine given only for the purpose of scintigraphy and not for therapy)	Descriptive statistics; Wilcoxon Signed-Rank sum test	37% decrease in radiation absorbed dose in salivary glands; Mean TAC = 70749.4 (SD = 53516.5, median = 51258) for SSwoLJ; Mean TAC = 43638.6 (SD = 310227.7, median = 29887) for SSwLJ; Area under TAC = 27110.8 (SD = 25808.8, median = 16669) for SSwoLJ; Significantly higher for SswoLJ	2
Kim et al., Republic of Korea, 2012 [16]	60 participants initially divided into 2 equal groups; The patients in the 1st group received parotid gland (PG) massage; 18 of them were classified as group Hyper-Mas (hyperthyroidism) and 12 as group Euthy-Mas (normal thyroid function); PG massage 20 times over 1 min; The patients in the 2nd group did not receive PG massage; 19 were classified as group Hyper-Mas (hyperthyroidism) and 11 as group Euthy-No Mas (normal thyroid function)	Salivary scans (ROIs); Total counts of both PGS and accumulation were calculated	185 MBq of Tc-99m pertechnetate	Mean ± SD, -test, and Fisher exact test	PG counts and accumulation ratios; PG count on first image; Group Hyper-Mas = 7563.7 ± 2962.4; Group Hyper-noMas = 8618.7 ± 3173.8; PG count on second image; Group Hyper-Mas = 7615.0 ± 3010.0; Group Hyper-noMas = 9188.0 ± 3152.8; Accumulation ratio (%); Group Hyper-Mas = 0.7 ± 3.2; Group Hyper-noMas = 7.4 ± 3.8; No statistical difference between group Euthy-Mas and group Euthy-noMas	2
Hong et al., Republic of Korea, 2014 [17]	44 participants; Total thyroidectomy followed by ^131I therapy; Group A and Group B; A salivary scan two hours after ^123I administration. One minute later, patients in Group A were scanned again for control, received one-minute massage, and were scanned for the third time; Patients in Group B were scanned for control two minutes after the first scan, received two-minute massage, and were scanned for the third time	Three salivary scans, ROIs, and; and	18.5 Mbq ^123I orally	-test, -test to compare and	The mean value of is significantly lower than for patients in both groups (); No significant difference between () and () in the two groups	2
Jentzen et al., Germany, 2010 [23]	Two studies, with 10 participants in each study; In the first study, ten patients were given lemon slices about 20 minutes after administration of ^124I; they chewed on them over the first day (stimulation group); In the second study, patients were not given lemon slices (nonstimulation group)	Both studies used six PET scans at 0.5, 1, 2, 4, 48, and ≥96 h and one PET/CT scan (ROIs) at 24 h after the administration of radioiodine; Blood samples were collected at about 2, 4, 24, 48, and 96 h	^131I in the first study and ^124I in the second study (22.6–30.5 MBq)	Kolmogorov-Smirnov test; Mean ± standard deviation; Mann-Whitney test; Pearson’s and Spearman’s correlation coefficients were used	ODpA was 0.23 Gy/GBq in the nonstimulation group and 0.32 Gy/GBq in the stimulation group; Average blood uptake similar in the stimulation and nonstimulation groups	2
Jentzen et al., Germany, 2014 [18]	patients awaiting radioiodine therapy after total thyroidectomy. Those patients were given tasteless gum about 20 minutes after swallowing a 23 MBq ^124I capsule	Three PET/CT scans 4, 24, and ≥96 h after the consumption of ^124I were performed	23 MBq ^124I capsule	Statistical analysis was performed using the mean, the median, and the SD and the Mann-Whitney test as well as	The current study showed that patients who chewed on lemon slices had a higher blood flow increase than the patients who chewed gum (). Patients who chewed gum had a little higher blood flow increase than the nonstimulation patients (). However, chewing tasteless gum immediately after administering ^124I did not significantly reduce the absorbed dose to the salivary glands; therefore, it cannot be considered effective ()	2

SSwoLJ: salivary gland scintigraphy without lemon juice; SSwLJ: salivary gland scintigraphy with lemon juice; TAC: time-activity curve; : changes in the uptake of ¹²³I at control; : changes in the uptake of ¹²³I at massage; ODpAs: organ absorbed doses.
¹The Jadad scale grades 3 methodological qualities, with scores for each quality combined to produce an overall score of 0 to 5 points, with 0 being the lowest quality score and 5 being the highest. The parameters assessed include randomization (maximum of 2 points), blinding (maximum of 2 points), and participant exclusion (maximum of 1 point).