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. 2022 May 7;14(9):2324. doi: 10.3390/cancers14092324

Table 2.

Olfactory dysfunction: studies included in the review.

Author, Year, Country Study
Design		 Number of
Patients		 Sex Age, Mean and Range/
Standard
Deviation (Years)		 Tumor
(Site and Stage)
Treatments
Measurements		 Time of
Assessment		 Results
Ophir et al., 1988, Israel [44] Prospective n = 12 M: 9 (75%)
F: 3 (25%)		 54.8 (38–76) Nasopharynx (n = 9), pituitary gland (n = 7)
(stage NR)		 2D-RT (66 Gy)
No CT
Dose to olfactory area: 25–28 Gy (nasopharyngeal carcinoma), 18–22 Gy (pituitary adenoma)		 ODT (amyl acetate and eugenol) Before RT, within a week after RT end, 1, 3 and 6 months later
  • -

    ODT increased for both compounds by the end of treatment

  • -

    Worst olfactory ability: first week and 1 month after RT end

  • -

    At 6 months after RT termination, ODT baseline levels were not yet recovered
Sagar et al., 1991, UK [45] Retrospective Study group: n = 25
Control group: n = 40		 NR NR Nasopharynx, pituitary fossa, maxillary sinus (n = 25)
(stage NR)		 2D-RT (doses NR)
No CT
Dose to olfactory area: 50–75 Gy (study group)		 Self-reported smell (ad hoc questionnaire) During RT
  • -

    15 patients (60%) reported an alteration of smell from the first treatment fraction diminishing toward RT end and ceasing after RT

  • -

    Odor described as unpleasant and consistent with ozone
Hua et al., 1999,
China [46]		 Prospective Study group (n = 49):
  • -

    group 1 (awaiting RT): n = 24

  • -

    group 2 (after RT): n = 25

Control group:
n = 36		 Group 1
M: 16 (67%)
F: 8 (33%)
Group 2
M: 23 (92%)
F: 2 (8%)
Control group
M: 26 (72%)
F: 10 (28%)		 Group 1
40.9 (27–59)
Group 2
45.2 (28–60)
Control group
43.6 (28–67)		 Nasopharynx
(T1-T3)		 2D-RT (68–72 Gy)
CT: NR
Dose to olfactory area: NR		 ODT (N-butyl alcohol), Odour Quality Discrimination test (5 odorants), Odour Recognition Memory Test, Odour-Visual Matching test, Odour-Tactile Matching test, OI (10 odorants), Odour Function test (edibility, function and identity) Before RT (n = 24 NPC, group 1), after RT (n = 25 NPC, group 2) NPC patients with RT had olfactory impairments including ODT, odour-tactile cross-modality matching, verbal identification
of odours, recall and recognition of identity of odours
Ho et al., 2002,
China [47]		 Prospective n = 48 M: 23 (48%)
F: 25 (52%)		 46 (22–71) Nasopharynx
(stage I–IV)		 RT (n = 43) (doses NR)
CT-RT (n = 15
Dose to olfactory area: NR
  • -

    ODT, OI, and OD (Sniffin’ Sticks)

  • -

    Subjective hyposmia (VAS scale 0–100)

 Before RT, end of RT, 3, 6 and 12 months after RT
  • -

    Deterioration of ODT and TDI score at 12 months

  • -

    No changes in OD, OI and self-reported hyposmia (VAS) at 12 months
Hölscher et al., 2005, Germany [48] Prospective n = 44 M: 28 (64%)
F: 16 (36%)		 55 (11–81) Maxillary sinus (n = 10), oropharynx (n = 10), oral cavity (n = 5), paranasal sinus (n = 5), nasopharynx (n = 6), hypopharynx (n = 2), nasal cavity (n = 1), brain (n = 1), skin (n = 1), unknown primary (n = 1), other (n = 2)
(stage NR)		 3D-CRT (30–76 Gy) (n = 30)
CT-RT (n = 14)
Dose to olfactory area:
  • -

    OLF group (n = 22): >20 Gy (median 62.2 Gy, range 23.7–79.5 Gy)

  • -

    Non-OLF group (n = 22): <12 Gy (median 5.9 Gy, range 2.9–11.1 Gy)

 ODT, OI, and OD (Sniffin’ Sticks)
  • -

    Before and bi-weekly during RT for 6 weeks (n = 44)

  • -

    Long term evaluation for 10 OLF patients (34 weeks after RT) and 15 non

  • -

    OLF patients (39 weeks after RT)
  • -

    During RT: OD, but not ODT and OI, was significantly decreased 2–6 weeks after beginning of RT in the OLF group

  • -

    Long term evaluation: lower OI, but not ODT and OD, in OLF vs. non-OLF group

  • -

    Dose-effect relationship for OD (analyzing dose to olfactory epithelium) during RT, while after RT just a trend was found
Sandow et al., 2006, USA [49] Prospective Study group: n = 13
Control group: n = 5		 Study group
M: 10 (77%)
F: 3 (23%)
Control group
M: 3 (60%)
F: 2 (40%)		 Study group 51.6 (40–75)
Control group 47.9 (27–70)		 Oropharynx
(stage NR)		 3D-CRT (63–76 Gy)
CT-RT (cisplatin, n = 3)
Dose to olfactory area: NR		 OI (UPSIT) Before RT, 1, and 12 months after RT OI was unaffected by RT
Bindewald et al., 2007,
Germany [50]		 Cross-sectional n = 205 M: 190 (93%)
F: 15 (7%)		 64 (32–84) Larynx
(stage I–IV)		 Total laryngectomy (n = 20)
Total laryngectomy + RT (n = 72)
Partial laryngectomy (n = 77)
Partial laryngectomy + RT (n = 36) (doses NR)
CT: NR
Dose to olfactory area: NR		 Self-reported smell (EORTC QLQ-H&N35)
  • -

    5.7 (0.11–16.58) years after total laryngectomy

  • -

    4.5 (0.19–15.14) years after partial laryngectomy

 No differences in olfactory alterations between irradiated and non-irradiated patients
Rhemrev et al.,
2007, The Netherlands [51]		 Cross-sectional n = 72 M: 44 (61%)
F: 28 (39%)		 57 (33–79) Oral cavity, oropharynx
(stage I–IV)		 Surgery (n = 15)
Surgery + RT (n = 57) (66–70 Gy)
CT: NR
Dose to olfactory area: NR		 Self-reported smell (EORTC QLQ-H&N35) 43 (2–120) months after treatment Higher olfactory alterations in irradiated patients
Brämerson et al., 2013, Sweden [52] Prospective n = 71 M: 51 (72%)
F: 20 (28%)		 60.9 (35–86) Paranasal sinuses (n = 10), parotid gland/ear/facial skin (n = 8), oral cavity (n = 12), nasopharynx/larynx (n = 15), oropharynx (n = 26)
(stage NR)		 RT (n = 39) (doses NR)
CT-RT (platinum compounds, pyrimidine compounds and taxanes, n = 32)
Dose to olfactory area:
  • -

    Low RT dose (n = 56): <10 Gy (mean 2.2 Gy)

  • -

    High RT dose (n = 15): >10 Gy (mean 65.9 Gy)
  • -

    ODT, OI (SOIT)

  • -

    Subjective hyposmia

 Before RT and 20 (12–35) months after RT
  • -

    ODT and OI decreased after RT in both groups with a larger difference in the high-dose group

  • -

    After therapy, 40% and 7% reported subjective olfactory decline in high and low RT dose groups, respectively

  • -

    CT was not significantly different between high and low RT dose groups
Momeni et al.,
2013, USA [53]		 Cross-sectional n = 21 M: 15 (71%)
F: 6 (29%)		 57.9 (24–87) Oral cavity (n = 15),
esophagus (n = 2),
scalp (n = 2),
pharynx
(n = 1), paranasal
sinus (n = 1)
(stage NR)		 Surgery (n = 8)
Surgery + RT (n = 13) (doses NR)
CT: NR
Dose to olfactory area: NR		 Self-reported smell (EORTC QLQ-H&N35) 24 (18–48) months after treatment No differences in olfactory alterations between irradiated and non-irradiated patients
Oskam et al., 2013, The Netherlands [54] Prospective n = 80 M: 47 (59%)
F: 33 (41%)		 58 (23–74) Oropharynx (n = 42), oral cavity (n = 38)
(stage II–IV)		 Surgery + RT (doses NR)
CT: NR
Dose to olfactory area: NR		 Self-reported smell (EORTC QLQ-H&N35)
  • -

    Before treatment, 6 and 12 months after treatment

  • -

    Long term evaluation: 9.2 (8–11) years (n = 27)

 No statistically significant difference in taste/smell score among evaluations over time, but a deterioration was present after treatment
Jalali et al.,
2014, Iran [55]		 Prospective n = 54 M: 26 (48%)
F: 28 (52%)		 49 (22–86) Nasopharynx (n = 24), oropharynx (n = 6), paranasal sinus (n = 12), brain (n = 9), skin (n = 3)
(stage NR) 		RT (n = 30)
CT-RT (n = 24)
12 patients with previous surgery
Total RT dose: 50.1 Gy (range: 30–66 Gy)
Dose to olfactory area: 334 μC (IQR 162–2068 μC)		 ODT (N-butanol) Before RT, during RT (2,4, 6 weeks), and after RT (3 and 6 months)
  • -

    ODT deteriorated during and after RT

  • -

    No difference between ODT of patients according to radiation region or CT

  • -

    The median cumulative local radiation for olfactory impairment (i.e., ODT ≤5) was 154 μC (IQR, 58–905 μC).

  • -

    ODT significantly decreased 2–6 weeks after initiation of RT with cumulative dose of >135 μC
Veyseller et al.,
2014, Turkey [56]		 Cross-sectional Study group: n = 24
Control group: n = 14		 Study group
M: 14 (56%)
F: 10 (44%)
Control group
M: 5 (36%)
F: 9 (64%)		 Study group 48.7 ± 11.4
Control group 48.8 ± 7.0		 Nasopharynx
(stage I–IV)		 CT-RT (68–72 Gy):
  • -

    2D-RT + cisplatin (n = 8)

  • -

    2D-RT + cisplatin and docetacel (n = 16)

Dose to olfactory area: NR
  • -

    ODT and OI (CCCRC test)

  • -

    Olfactory bulb volume (MRI scan)

 66 (14–218) months after RT
  • -

    Lower ODT and OI in the NPC group compared to the control group

  • -

    Lower mean olfactory bulb volume in the NPC compared to the control group

  • -

    No significant differences in the olfactory bulb volume between different CT regimens
Riva et al.,
2015, Italy [57]		 Cross-sectional Study group: n = 30
Control group: n = 30		 Study group
M: 24 (80%)
F: 6 (20%)
Control group
M: 20 (67%)
F: 10 (33%)		 Study group 53.5 (37–75)

Control group
52.3 (42–76) 		Nasopharynx
(stage I–IV)		 CT-RT (cisplatin-based regimens):
  • -

    2D-RT/3D-CRT (n = 10): 70.2 Gy

  • -

    IMRT (n = 20): 69–70 Gy

Dose to olfactory area: NR
  • -

    ODT, OI, OD (Sniffin’sticks)

  • -

    Subjective reduced or altered smell

 59 (24–124) months after RT
  • -

    Higher percentage of reduced, but not altered, smell in study group

  • -

    No differences for subjective hyposmia among radiation techniques

  • -

    Higher ODT and TDI, but not OI and OD, in the control group compared to study group

  • -

    No difference in ODT, OI and OD among radiation techniques
Landström et al., 2015, Sweden [58] Prospective n = 19 M: 12 (63%)
F: 7 (37%)		 56.6 (20–78) Oral cavity (n = 18), oropharynx (n = 1)
(stage I–IV)		 ECT (bleomycin) (n = 6)
ECT (bleomycin) + RT (57.8 Gy) (n = 13)
Dose to olfactory area: NR		 Self-reported smell (EORTC QLQ-H&N35) Before treatment, and 12 months after treatment No differences in problems with senses from baseline to 12 months after treatment
Haxel et al., 2015, Germany [59] Prospective n = 33 M: 25 (76%)
F: 8 (24%)		 61.6 (44–85) Oropharynx (n = 20), larynx (n = 8), hypopharynx (n = 5)
(stage NR)		 CT (cisplatin, 5-fluorouracil and docetaxel)
No RT
Dose to olfactory area: NA		 ODT, OI, OD (Sniffin’sticks) Before and immediately after first, second and third CT cycle
  • -

    TDI score decrease during the second CT cycle was significant

  • -

    Older patients (>55 years) were more susceptible to decreasing TDI score during first and second CT cycles

  • -

    TDI score reached almost their initial levels after 3 weeks of recovery time
Wang et al.,
2015, Taiwan [16]		 Prospective n = 41 M: 31 (76%)
F: 10 (24%)		 45 (29–77) Nasopharynx
(stage I–IV)		 IMRT (70–76.8 Gy):
  • -

    IMRT alone (n = 2)

  • -

    Concurrent CT-RT (n = 2)

  • -

    induction CT + IMRT (n = 37)

Dose to olfactory area: NR
  • -

    OI (UPSIT)

  • -

    Self-reported smell (SNOT-22)

 Before and 12 months after RT
  • -

    Significant decrease in UPSIT score after RT

  • -

    The change in SNOT-22 scores was not significant, but the scores for item “loss of smell or taste” significantly increased after RT

  • -

    UPSIT scores negatively correlated with total and ethmoid Lund-Mckay scores
Alvarez-Camacho et al.,
2016, Canada [60]		 Prospective n = 160 M: 126 (79%)
F: 34 (21%)		 58.9 ± 11.9 Pharynx (n = 88), larynx (n = 36), oral cavity (n = 18), salivary glands (n = 11), nasal cavity and paranasal sinuses (n = 6), soft tissue (n = 1)
(stage I–IV)		 Surgery (n = 7)
Surgery + RT (60 Gy) (n = 59)
Surgery + CT-RT (cisplatin or carboplatin) (n = 86)
Surgery + RT + cetuximab (n = 8)
Dose to olfactory area: NR		 Self-reported smell (CCS) Before treatment, end of treatment and at 2.5 months follow-up
  • -

    Smell perception was significantly impaired at the end of treatment, with a partial recovery at 2.5 months follow-up

  • -

    CCS (including taste and smell) was a significant predictor of overall quality of life, social-emotional, physical and overall functions at UW-QoL
Galletti et al.,
2016, Italy [61]		 Cross-sectional Study group: n = 9
Control group: n = 9		 Study group
M: 9 (100%)
Control group
M: 9 (100%)		 Study group
55 ± 9.96
Control group
52.56 ± 8.56		 Nasopharynx

(stage III–IV)		 Induction CT (cisplatin and fluorouracil) + concurrent CT-RT (cisplatin, 60–69 Gy)
Dose to olfactory area: NR
  • -

    Olfactory event-related potential testing

  • -

    Subjective hyposmia (VAS scale 0–10, and 6-item Hyposmia Rating Scale)

44.77 ± 25.93 months after treatment
  • -

    Significant differences in latency and amplitude of olfactory event-related potentials between patients and controls (worse in patients)

  • -

    Significant negative correlation between olfactory event-related potentials and the 6-item Hyposmia Rating Scale

  • -

    Significant positive correlation between olfactory event-related potentials and the VAS scale
Badr et al., 2017, USA [62] Cross-sectional n = 93 M: 73 (78%)
F: 20 (22%)		 61.5 (39–88) Oral cavity (n = 26), oropharynx (n = 67)
(stage I–IV)		 RT (n = 3) (doses NR)
CT-RT (n = 22)
Surgery + RT (n = 32)
Surgery + CT-RT (n = 36)
Dose to olfactory area: NR		 Self-reported smell (Vanderbilt Head and Neck Symptom Survey version 2.0) Within 3 months of RT end (7% of participants), within 3–6 months (23%), within 6–9 months (24%) and within 9–12 months (46%)
  • -

    Younger patients (<60 years) reported more smell problems than older patients (>60 years)

  • -

    Smell disorders were predictors of depression and anxiety
Riva et al.,
2017, Italy [63]		 Cross-sectional Study group: n = 50
Control group: n = 50		 Study group
M: 43 (86%)
F: 7 (14%)
Control group
M: 40 (80%)
F: 10 (20%)		 Study group 68.76 (50–83)
Control group
67.54 (53–76)		 Larynx
(stage II–IV)		 Total laryngectomy + RT (n = 16)
Total laryngectomy + CT-RT (n = 4)
Dose to olfactory area: NR		 ODT, OI, OD (Sniffin’sticks) 61.96 (24–132)
Months after treatment
  • -

    Significant decrease of ODT, OI, OD, and TDI score in the study group

  • -

    No correlation between TDI score and RT, age, and follow-up time at multivariate analysis
Lilja et al.,
2018, Finland [64]		 Prospective n = 44 M: 29 (66%)
F: 15 (34%)		 56.2 (38–80) Oral cavity (n = 28), oropharynx (n = 13), hypopharynx (n = 3)
(stage II–IV)		 Surgery (n = 5)
Surgery + RT (n = 35)
Surgery + CT-RT (n = 4)
Dose to olfactory area: NR
  • -

    ODT (phenylethyl methyl ethyl carbinol)

  • -

    OD and OI (7 odours)

 Before treatment, and 6 weeks,
3, 6 and 12 months after treatment
  • -

    No differences in ODT between pre- and post-treatment scores

  • -

    Higher scores in the OD in the 6-week and 3-month tests compared with preoperative scores for the tumour side

  • -

    Higher scores in the OI in all post-treatment tests compared with preoperative scores
Riva et al.,
2019, Italy [15]		 Prospective n = 10 M: 10 (100%) 56.90 (39–72) Nasopharynx (n = 3),
oral cavity (n = 3),
parotid gland (n = 3),
primary unknown (n = 1)
(stage I–IV)		 Surgery (n = 8)
Concurrent CT-RT (54–70 Gy) (n = 5)
Induction CT + concurrent CT-RT (n = 1)
Dose to olfactory area:
  • -

    Mean dose (Dmean) to nasal cavities 13.59 ± 17.74 Gy

  • -

    Near maximum dose (D2%) to nasal cavities 26.73 ± 31.80 Gy
  • -

    ODT, OI, OD (Sniffin’sticks)

  • -

    NOSE scale and subjective reduced or altered smell

 Before (T0), at mid-course (T1), and at the end (T2) of RT, 1 and 3 months after RT (T3 and T4)
  • -

    Although olfactory function remained within the normal range at the evaluated times, a significant decrease in ODT, OD and TDI score was observed during RT, which returned to baseline levels after RT

  • -

    Not significant increase of NOSE total score at T2

  • -

    Near significant correlation between Dmean to nasal cavities and subjective hyposmia at T2 and between D2% to nasal cavities and dysosmia at T2
Epstein et al., 2020, USA [65] Prospective n = 10 M: 7 (70%)
F: 3 (30%)		 59.9 ± 7.0 Oropharynx (n = 9), oral cavity (n = 1)
(stage I–III)		 IMRT:
  • -

    alone (n = 1)

  • -

    CT-RT (platinum-based, n = 9)

Dose to olfactory area: NR		 OI (UPSIT) 4–6 weeks after starting of treatment (n = 6) and up to 2 years after treatment (n = 8) Decreased OI in 3 patients (33%) during treatment with smell recovery after treatment
Tyler et al.,
2020, USA [66]		 Cross-sectional n = 114 M: 68 (60%)
F: 46 (40%)		 55 (18–78) Nasopharynx (n = 61), paranasal sinuses (n = 29), nasal cavity (n = 24)
(stage I–IV)		 IMRT (n = 110) (66.6 ± 5.1 Gy)
3D-CRT (n = 4)
Surgery (n = 38)
CT:
  • -

    induction (n = 8)

  • -

    induction + concurrent (n = 58)

  • -

    concurrent (n = 12

  • -

    concurrent + adjuvant (n = 9)

Dose to olfactory area: NR		 Self-reported smell (EQ-5D VAS, MDASI-HN, ASBQ) 65 (12–154) months after treatment
  • -

    The most frequently reported high-severity items in ASBQ were difficulty with smell and nasal secretions

  • -

    Negative correlation between MDASI-HN and ASBQ sum score

  • -

    Positive correlation between EQ5D VAS score and ASBQ sum score
Gurushekar et al., 2020, India [67] Prospective n = 21 M: 16 (76%)
F: 5 (24%)		 42.62 (16–75) Nasopharynx
(n = 13) oropharynx (n = 4), oral cavity (n = 2), paranasal sinuses (n = 2)
(stage NR)		 CT-RT (n = 15)
Surgery + RT (n = 4)
RT (n = 2) (doses NR)
Dose to olfactory area: NR
  • -

    ODT and OI (CCCRC test)

  • -

    Self-reported smell (AHSP questionnaire)

  • -

    Mucociliary clearance time (saccharine test)

 Before RT, at mid-course of RT (n = 21), at the end of RT (n = 18), 3 months after RT (n = 13)
  • -

    OTD and OI showed significant reduction during RT with partial recovery at 3 months follow up

  • -

    No significant deterioration of smell by AHSP, although overall QOL significantly deteriorated

  • -

    Mucociliary clearance time prolonged in 72% of patients at the end of RT
Sharma et al.,
2020, Denmark [68]		 Cross-sectional n = 27 M: 17 (63%)
F: 10 (37%)		 67 (47–83) Nasal cavity (n = 19), paranasal sinuses (n = 8
(stage I–IV)		 IMRT (60–68 Gy):
  • -

    alone (n = 7)

  • -

    Surgery + RT (n = 20)

Concurrent CT (cisplatin, n = 6)
Dose to olfactory area: NR
  • -

    OI (Brief Smell Identification Test)

  • -

    Self-reported smell (SNOT-22)

 6.4 (1.6–11.1) years after RT
  • -

    Impaired olfactory function in 63% of patients (76% with surgery and RT versus 17% in RT alone)

  • -

    The risk of olfactory impairment increased with higher tumor stage
Alfaro et al., 2021, USA [69] Cross-sectional Study group: n = 40
Control group: n = 20		 Study group
M: 24 (40%)
F: 16 (60%)
Control group:
M: 11 (55%)
F: 9 (45%)		 Study group
63 ± 12
Control group 58 ± 14		 Oral cavity (n = 19), pharynx (n = 18), larynx (n = 3)
(stage I–IV)		 RT (alone or combined with surgery or CT, doses NR) (n = 40)
Concurrent CT (n = 24)
Dose to olfactory area: NR
  • -

    OI (UPSIT)

  • -

    Smell intensity (general Labeled Magnitude Scale)

 Between 6 months and 10 years after RT
  • -

    No differences in OI between study and control groups

  • -

    Lower smell intensity when tasting caffeine solutions in the study group

Abbreviations: 2D-RT, Two-dimensional Radiotherapy; 3D-CRT, Three-Dimensional Conformal Radiotherapy; ASBQ, Anterior Skull Base Inevntory; AHSP, Appetite, Hunger and Sensory Perception; CCCRC, The Connecticut Chemosensory Clinical Research Center test; CCS, Chemosensory Complaint Score; CT, Chemotherapy; CTCAE, Common Terminology Criteria for Adverse Events; CT-RT, Chemoradiotherapy; ECT, Electrochemotherapy; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life CoreQuestionnaire; EORTC QLQ-H&N35, EORTC Quality of Life Head and Neck Module 35; EQ-5D VAS, EuroQol Group-5 Dimension Visual Analogue Scale; F, Female; Gy, Gray; IMRT, Intensity Modulated Radiation Therapy; IQR, Inter-Quartile Range; M, Male; MDASI-HN, MD Anderson Symptom Inventory–Head and Neck; MRI, Magnetic Resonance Imaging; NA, Not Applicable; NOSE, Nasal Obstruction Symptom Evaluation; NPC, Nasopharyngeal carcinoma; NR, Not reported; OI, Odor identification; OD, Odor discrimination; ODT, Odor detection threshold; RT, Radiotherapy; SNOT, Sino-Nasal Outcome Test; SOIT, Scandinavian Odor Identification test; TDI, Threshold, discrimination and identification total score; UPSIT, University of Pennsylvania Smell Identification Test; UW-QoL, University of Washington Quality of Life Questionnaire; VAS, Visual Analog Scale.