Introduction

Testicular tumors are the most frequent malignant diseases in men aged between 15 and 35 [1]. Cisplatin-based combination chemotherapy and—if indicated—surgical removal of residual disease is the standard treatment for metastatic germ cell tumors. This treatment cures a vast majority of patients. Besides the achievements obtained through chemotherapy, there also exist adverse effects caused by the cytostatic active substances, such as possible changes of olfaction in patients. There are several studies indicating the presence of subjective decrease in the sense of smell in cancer patients treated with chemotherapy [2–4]. As the subjective rating of olfactory function has been shown to be notoriously inaccurate, it is necessary to measure olfactory function [5]. There are some studies which measured olfactory function psychophysically during versus after chemotherapy with inconclusive findings though [2–14]. However, chemosensory alterations, especially olfactory and taste distortions have been reported in cancer patients in general. These findings are important as they may lead to a reduced pleasure of eating, resulting in lower energy intake, weight loss, nausea enhancing malnutrition and eventually morbidity in cancer patients [15–18]. This can furthermore result in higher levels of distress and in consequence to a strong decrease in quality of life [2, 17], which is more severely perceived in younger patients with impaired sense of smell compared to older patients [19–21]. This is especially interesting for testicular cancer patients as this disease affects mostly younger males. Knowing about possible olfactory dysfunction in testicular tumor patients undergoing chemotherapy, physicians could strengthen screening for this pathology and could intensify help for the affected patients. Patients could benefit from flavor enhancement, chemosensory education, and nutritional information, as this has already been shown to be beneficial for older cancer patients [22]. In summary, there are several reasons why investigation of the sense of smell of cancer patients receiving chemotherapy is important. The aim of the present study was, therefore, to analyze olfactory function of testicular patients before, during and after cisplatinum based chemotherapy. In addition depression markers were recorded and analyzed, as well.

Materials and methods

The present study was performed at the Smell & Taste Clinic of the Department of Otorhinolaryngology at the “Technische Universität Dresden” (TU Dresden) and approved by the local ethics committee (EK204072009). Written informed consent was obtained from all participants.

Participants

A total of 28 patients, suffering from testicular tumors were prospectively evaluated for the present study. Only participants who finished the last follow-up (21 of 28 patients) and whose baseline olfaction was normosmic (TDI score >30.75) (17 of 21 patients) were considered appropriate for this study and statistically analyzed. All patients underwent either the BEP (cisplatin, etoposid, bleomycin) or VIP (etoposide + ifosfamide + cisplatin − under mesna protection) chemotherapy protocol. Patients with acute or chronic rhinosinustis, neurological and olfactory disorders were excluded. In addition none of them had co-morbidities that might affect olfaction such as hyper- or hypothyreoidism, liver or renal problems, or diabetes.

Study protocol

Olfactory function was assessed one day before (day 0), during (day 42), shortly after (day 90) and 6 months (day 180) after chemotherapy. Additionally, patients were asked to respond to a questionnaire to assess their subjective chemosensory symptoms (olfaction, phantosmia, parosmia) and depressive symptoms for the same dates.

Olfactory testing

Orthonasal olfactory function was measured by means of the validated extended Sniffin’ Sticks test battery (Burghart GmbH, Wedel, Germany) [23] which consists of three separate subtests: phenylethylalcohol (PEA) odor threshold (THR), odor discrimination (DIS), and odor identification (ID). Results of the three subtests are summed up for a composite TDI score. This validated test is based on pen-like odor-dispensing devices [24]. For odor testing the cap of the pen was removed for approximately 3 s and the felt-tip was presented approximately 2 cm in front of the subjects’ nostrils. Testing started with the threshold subtest, where 16 dilutions were used. The participants were presented a stick triplet, with one containing the odor (PEA-rose like smell) and the others containing solvent, propylene glycol, alone. Triplets were presented in increasing odor concentrations, starting with the lowest one. After identifying the correct (odor containing) pen twice in a presented triplet, a reversal of the staircase was started until the patient could no longer identify the odor containing pen. The threshold score was built from the mean of the last four out of seven staircase reversals.

For the DIS, 16 triplets were presented, with two pens containing the same odor and the third a different one, which was asked to be identified by the patient. The last subtest performed was the ID, where 16 pens with different odors were presented. Individuals were asked to choose the object that describes the odor the best through multiple forced choice from flash cards where the name of the objects were written.

Subjective assessment

On a 5 point Likert scale, patients rated their subjective olfactory function (complete loss, impaired sense of smell, normal, better than normal, excellent). Furthermore, they were asked whether they notice odors in absence of an odor source (phantosmia) or whether known odor sources exhibit an altered scent (parosmia).

Beck depression inventory

Patients were in addition asked to fill out the Beck Depression Inventory (BDI) test, which is a widely used, standardized and validated tool used for measuring depressive symptoms [25, 26]. The BDI consists of 21 questions in a 4-item forced choice manner. Answer possibilities were scored from 0 (= no stress present) to 3 points (= maximal stress present) resulting in a sum score between 0 and 63 points. A BDI score <11 reflects the norm, whereas a score between 11 and 17 points suggests a moderate manifestation of depressive symptoms and a score ≥18 indicates a relevant manifestation of depressive symptoms.

Statistical analysis

Statistical analysis was performed by means of SPSS 21.0 (SPSS Inc., Chicago, IL, USA). Repeated measures ANOVAs were performed. Greenhouse-Geisser corrected degrees of freedom were used when the sphericity assumption was infringed. Bonferroni tests were used for post hoc comparisons. p values of <0.05 were considered significant.

Results

The study population comprised a total of 17 patients, suffering from testicular cancer (3 seminoma patients, 1 recurrent seminoma and 13 nonseminoma patients), with a mean age of 31 years ± 10 years (range 18–60 years), which were prospectively included in the present study. Patients underwent in mean 2.47 cycles ± 0.5 (range 2–3 cycles) of chemotherapy.

Olfactory assessment

At baseline examination patients obtained a mean THR score of 10.40 ± 2.20, a mean DIS score of 12.82 ± 1.29, a mean ID score of 13.71 ± 1.52 and a mean TDI score of 36.93 ± 2.40.

Comparison of the olfactory scores revealed that THR scores were significantly lower on day 90 (8.0 ± 2.51) compared to baseline score (10.4 ± 2.20) (p = 0.014). Six months after chemotherapy olfactory threshold function had recovered almost completely (9.65 ± 3.26) (see Fig. 1). In addition, also TDI score decreased non-significantly under chemotherapy (day 0: TDI 36.93 ± 2.4 vs. day 42: TDI 35.69 ± 2.36)) and recovered after completion of therapy (day 180: TDI 36.76 ± 3.42). Odor identification and discrimination tests did not demonstrate significant changes over the study period (Table 2).

Fig. 1
figure 1

THR scores from day 0 until day 180 (from the left: day 0, day 42, day 90 and day 180)

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Ratings

At baseline examination, 16 patients rated their olfactory function as normal or better than normal. One patient reported about an impaired sense of smell. At follow-up examination on day 42 four patients and on day 90 one patient indicated an impaired sense of smell. At day 180 no patient indicated any impairment in the sense of smell.

At baseline 2 patients reported parosmia resp. 1 patient phantosmia. During the follow-up parosmia increased to 5 patients on day 42, whereas phantosmia remained almost stable. Regarding day 180 parosmia and phantosmia were on the baseline level (n = 1 resp. n = 0) again.

Beck depression inventory

Patients achieved an average BDI score of 5 ± 6.3 at day 0. The BDI score tended to increase on day 42 (7 ± 5.01) (Fig. 2).

Fig. 2
figure 2

BDI score on day 0 until day 180 (from the left starting with day 0, day 42, day 90 and day 180)

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Regarding the correlation between the depressive symptoms and olfactory function, a significant correlation between the BDI and TDI score was only seen on day 180 (p = 0.007). The subtest scores (THR, DIS, ID) did not correlate significantly with the BDI score.

Discussion

The aim of the present study was to evaluate olfactory function of testicular cancer patients before, during and 6 months after platinum based chemotherapy by means of the validated and widely used Sniffin’ Sticks test [23]. As one major result of the present study it could be demonstrated that olfactory sensitivity decreases significantly under chemotherapy which is expressed as a significant increase in the odor threshold test at day 42 (Fig. 1; Table 2). Furthermore, a trend of decrease in TDI score could be seen. These findings are in accordance with Haxel et al., who enrolled 33 patients with malignancies in the head and neck region undergoing chemotherapy (cis-, carboplatin, 5-fluoruracil and docetaxel) for evaluation of the sense of smell. They could demonstrate a significant decrease in TDI score during the chemotherapy [8]. In addition, in a cohort of 87 cancer patients (breast cancer or gynecologic malignancies) undergoing various chemotherapy regimens (27% of those platinum containing) it could be demonstrated that olfactory function decreased significantly during chemotherapy but recovered almost completely after termination of the therapy [13]. These results were reaffirmed by a following study investigating 12 ovarian cancer patients receiving carboplatin containing chemotherapy [12]. In accordance with our results, in both studies [11, 12] odor identification of patients undergoing chemotherapy was hardly affected, whereas odor threshold score significantly decreased. These results were confirmed by other research investigating olfactory function of patients undergoing cisplatin containing chemotherapy protocols, that showed odor ID unaffected [7, 13].

However, the present study could show that olfactory sensitivity normalizes after completion of chemotherapy. A trend of improvement of THR and TDI scores was seen 6 months after chemotherapy (Table 1; Fig. 1). All patients presented a normal olfactory function after completing therapy. These results were confirmed by other studies [8, 11, 12]. This is not surprising as olfactory sensory cells are unique among the sensory cells of humans because they are capable for renewing.

Table 1 Clinical staging of included patients according to the TNM classification
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In contrast to the studies who demonstrated olfactory function affected by chemotherapy, other studies did not find any significant difference in psychophysically measured odor threshold scores of cancer patients receiving cisplatin or etoposide based chemotherapy regimens [7, 9]. However, they demonstrated that subjective pleasantness for food odors decreased [7]. Interview-based studies could extend these findings to the sense of smell, as patients reported a decreased olfactory function during chemotherapy [2–4]. In accordance with these results also in the present study patients reported an impaired olfactory function during chemotherapy. Regarding parosmia and phantosmia we found a trend of increasing parosmia during therapy. This was not found for phantosmia, which might be due to the relatively small number of evaluated patients. Nevertheless, humans are quite poor at rating their subjective olfactory acuity [5].

Olfactory dysfunctions are known to negatively influence pleasantness of eating and be associated with taste disturbances [15, 16, 18]. This may be particularly interesting in cancer patients, as this can result in reduced oral intake of food, which can support a decline in patient’s nutrition and in consequence patients’ quality of life. In line with this, research has recently shown that daily life of oesophagogastric cancer patients undergoing chemotherapy was impacted significantly when food-related changes were experienced [6].

In accordance to this, in this study a significant correlation was found between depressive symptoms and the TDI score after termination of chemotherapy (day 180). This is in line with other studies which demonstrated that olfactory impaired patients typically show signs of depression [26–30] (Tables 2, 3).

Table 2 Mean olfactory score obtained before, during and after chemotherapy
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Table 3 Subjective rating of olfactory function before, during and after chemotherapy
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The other way around, in a study of 518 cancer patients during chemotherapy, subjects reporting depressed mood were found to suffer more frequently from chemosensory changes during their chemotherapy [2]. In the studied population almost every fourth patient demonstrated a depressed mood after perceiving the diagnosis of testicular cancer. To conclude it is important to screen patients undergoing chemotherapy thoroughly for olfactory impairment to be able to better support them with matching food/diets and offering psychooncological support.

Conclusion

Patients undergoing cisplatin-based chemotherapy for germ cell tumors should be informed about possible transient olfactory impairment during/immediately after chemotherapy. Support of the patients by matching food and diets should be taken into consideration.