Introduction

Nasopharyngeal carcinoma (NPC) is a rare malignancy in western countries, which arises from the epithelium of the nasopharynx. In Europe, its prevalence is about 1.4 per 100,000 inhabitants [1, 2]. Epstein Barr virus (EBV) is, with smoke, alcohol, and wood dust-related occupations, among the well-known risk factors for this tumor. Prognosis and association with EBV differentiate NPC from the other head and neck neoplasms [3–5]. Most stage I–II tumors are successfully treated by radical radiotherapy (RT), while patients with locoregionally advanced disease (stage III-IV) are cured by combined chemoradiotherapy (CRT) approach [6]. These treatments are related to high acute and late toxicities with impairment of patients’ Quality of Life (QoL). Over the years, RT techniques evolved: Intensity Modulated Radiotherapy (IMRT), compared to the conventional bi-dimensional and tri-dimensional conformal RT (2D and 3D-CRT) achieved good tumor coverage, high tumor control rate, and effectively lowered the exposure dose of normal tissues around the tumor, reducing temporal lobe injury, xerostomia, hearing loss, trismus, cataract, retinitis, and damage to brain stem and optic chiasm. Traditionally, treatment evaluation has focused on objective measures like survival time, tumor recurrence, overall survival, or standardized toxicity [7–9], but few studies has evaluated a possible impact of treatment on health-related quality of life (HRQoL) and functional status (FS) in patients with head and neck cancer. Information from physician about expected HRQoL outcomes may help patients “to actively participate” in the medical decisions concerning their care [8]. There are a variety of QoL instruments (Patient-Reported Outcomes, PRO’s) available in the field of head and neck oncology. In this study, we used five questionnaires to retrospectively analyze QoL, FS, and their correlation to late toxicity, treatment, and patient-related parameters in long-term NPC survivors. [10–14]. The use of more questionnaires (each one focused on different aspects) allowed us to have a complete description of patients FS and QoL.

Materials and methods

Between January 1990 and December 2014, 56 patients with histologically proven NPC have consecutively been treated with RT alone or CRT at the Radiation Oncology Unit of the “San Donato Hospital” Arezzo. Patients stage was retrospectively defined according to the 7th edition of the International Union against Cancer (UICC) TNM classification from WHO [15]. The characteristics of the patients are shown in Table 1. Median dose was 70 Gy (range 60–70), using five fractions per week. In December 2014, at different time after therapy, 25 of 30 long-term NPC survivors completed five questionnaires on QoL and FS: FACT-NP (Functional Assessment of Cancer Therapy Nasopharyngeal Cancer Questionnaire), FACT-G (Functional Assessment of Cancer Therapy—General), XeQOLS (University of Michigan Xerostomia-Related Quality of Life Scale), PSS-HN (Performance Status Scale for Head and Neck Cancer), and EQ-5D-3L (Generic Multi-Attribute Instrument). The patients completed questionnaires during a medical visit. Late toxicity, evaluated in 25 NPC long survivors who responded to questionnaires, was scored according to Common Terminology Criteria for Adverse Event version 4.0 (CTCAE vs 4.0).

Table 1 Mean characteristics of 56 nasopharyngeal cancer cases
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FACT-NP is a questionnaire that comprises a core questionnaire, FACT-G, and an additional concerns subscale, NasoPharyngeal Cancer Score (NPCS). FACT-G is a 27-item measure that is classified into four subscales, and is used to assess physical, social/family, emotional, and functional well-being. The NPCS consists of additional items specific of patients with NPC, such as eating, swallowing, mouth dryness, appetite, taste, voice quality, communication, appearance, pain, neck movement, tinnitus, hearing, vision, smell, and nasal blockage. Patients indicated their responses according to the last 7 days. For FACT questions, answers in the negative must be reversed and a higher score represents a better QoL or FS. Items are rated on a 5-point Likert scale. The total FACT-NP score is the sum of FACT-G and NPCS [16].

XeQOLS consists of 15 items and measures impact of salivary gland dysfunction and xerostomia on the four major domains of oral health-related QoL: physical, personal/psychological, social functioning, and pain/discomfort issues. Patients answered to questions by checking the box that describes best how true each statement was during the last 7 days (not at all, a little, somewhat, quite a bit, very much), with 1–5 scale. Higher scores represent greater degree of symptoms [17].

The PSS-HN is a validated clinician-rated instrument designed to evaluate performance in areas of functioning. It consists of three subscales assessing normality of diet, understability of speech, and eating in public. Each is rated from 0 to 100, with higher scores indicating a better performance [11].

The EQ-5D-3L descriptive system comprises the following five areas: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has three levels: no problems (level 1), some problems (level 2), and extreme problems (level 3) [18].

In this study, we analyzed if late toxicity was affected by different predictive factors (age, gender, stage, time elapsed from the end of treatment, RT techniques, and associated chemotherapy) and if it was significantly related to questionnaire scores about QoL and FS.

Statistical analysis

The Kaplan–Meier method was used to calculate the disease-specific survival (DSS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), progression free survival (PFS), and overall survival (OS) rates. DSS was measured from the end of RT to the date of death due to NPC or to the last follow-up evaluation. LRRFS and DMFS were measured from the date of the end of RT to the date of the first observation of locoregional recurrence or distant metastasis, respectively. PFS was measured from the date of the end of RT to the date of the first observation of locoregional recurrence or distant metastasis or death due to NPC. OS was evaluated from the date of the end of RT to the date of death or to the last follow-up. The log-rank test was used to compare the survival curves. The non-parametric Mann–Whitney U test was used for QoL questionnaires analysis according to late toxicity; the categorical data were analyzed using χ 2 test with Yate’s correction. All calculations were performed using IBM-SPSS® version 22.0 (IBM Corp., Armonk, NY, USA, 2013). A two-sided p value < 0.05 was considered significant.

Results and analysis

Survival and toxicity

Patients’ features are summarized in Table 1. Male:female ratio was equal to 3.5:1; age ranged between 18–83 years (median 52.5). Median follow-up was 85 months (range 13–304). At the time of the analysis, no patient was lost to follow-up, 23 (41.1%) died from disease, 3 (5.4%) died from other causes, and 30 (53.5%) were alive. Twenty-nine of them were disease-free and 1 patient had locoregional relapse. In 23 dead patients, 10 (43.5%) had locoregional relapse, 10 (43.5%) had distant metastasis, and 3 (13%) had both locoregional recurrence and distant metastases. In IMRT group, no recurrence was observed after an average follow-up of 30 months. In female patients, no metastasis was recorded. Five and ten-year DSS, LRRFS, DMFS, PFS, and OS are reported in Table 1. Age <50 years was related to better DSS (p = 0.009), LRRFS (p = 0.0004), and PFS (p = 0.042), while dose >66 Gy was related to better LRRFS (p = 0.012) and PFS (p = 0.048); gender (female) was associated with better DMFS and PFS (p = 0.033 and p = 0.038 respectively), as shown in Figs. 1 and 2. Concomitant chemotherapy showed a trend towards better locoregional control (p = 0.07) but not better metastasis-free survival. No significant association between tumor stage, time elapsed from the end of treatment, and outcome was observed. Table 2 shows the frequency of the late toxicity by type and grade. Grade 1–2 late toxicities were predominantly xerostomia (60%) and hearing loss (32%). No G4 late toxicity was observed; G3 late toxicity occurred in only three patients: one impaired vision, one sensory neuropathy, and one subcutaneous fibrosis. All cases of neuropathy occurred in patients treated in the pre-IMRT era. IMRT had a downward trend of related effects like neuropathy, otitis, and hypothalamic dysfunction (p = 0.06). We analyzed if different predictive factors influenced late toxicity. Only female gender was related to fibrosis (p < 0.01).

Fig. 1
figure 1

Correlation between DSS (up), LRRFS (middle), PFS (down), and age

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Fig. 2
figure 2

Correlation between LRRFS (left), PFS (right), and dose; b Correlation between DMFS (left), PFS (right), and gender

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Table 2 Late toxicity
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Questionnaires

Five patients refused to answer the questionnaires for personal reasons. Of the 25 patients who completed questionnaires, 19 were men and 6 women aged 49.6 (range 18–87); 8 patients were treated 1–4 years before compiling questionnaires and the remaining 17 received RT at least 4 years before. Table 3 shows the score summary of questionnaires. Table 4 reports the frequencies of problem levels subdivided according to the EQ-5D-3L dimensions: 72% of cases had not problems about their cancer, 16% of cases had some problems, and 12% had severe problems, more frequently pain, or discomfort. Patients aged <50 had significant better QoL according to FACT-G and PSS-HN scores (p < 0.03). Moreover, a trend toward improved QoL in patients treated with IMRT was showed by PSS-HN and EQ-5D-3L scores (p = 0.07 and p = 0.06, respectively) (Table 5). G1–2 late xerostomia was significantly related to lower PSS-HN and higher XeQOLS score (p < 0.009 and p < 0.002, respectively). Patients with G1–G2 xerostomia had also worse FACT-NP scores without reaching statistical significance. Hearing loss seemed to be related to worse PSS-HN score (p = 0.06) (Table 6).

Table 3 Summary of QoL and functional status
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Table 4 EQ-5D-3L dimension of health
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Table 5 Correlation between questionnaires and prognostic factors
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Table 6 Correlation between late toxicity and questionnaires
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Discussion

Inge et al. reported that, in NPC, sociodemographic parameters like younger age appeared to be preeminent predictors of both OS and DSS [19]. DSS, in our experience, was related to age (<50 years), LRRS to age and dose (>66 Gy), and PFS to age, gender (female), and dose. Fang et al. found that besides socio-economic levels, advances in RT technique played a significant role to improve QoL of NPC patients suggesting that QoL may be a prognostic indicator in NPC [20]. In our study, we used a combination of questionnaires, FACT-NP, FACT-G, XeQOLS, PSS-HN, and EQ-5D-3L, in patients with NPC to get more information about QoL and FS by disease-specific instruments. Our data suggested that patients aged <50 had a better QoL based on FACT-G and PSS-HN questionnaires. Some studies suggested that IMRT is associated with statistically significant improvement in several important QoL domain, including swallowing, dry mouth, and social eating [19, 21, 22]. Our study showed a trend between IMRT and better QoL according to PSS-HN and EQ-5D-3L questionnaires, without to reach statistical significance, probably due to the small number of patients analyzed. Bian et al. reviewed the published literature addressing the question of whether IMRT resulted in an improvement of QoL, especially xerostomia-related QoL. They found that IMRT improved QoL, but xerostomia-related items still had a significantly negative effect after 2 years from the end of treatment on survivors’ QoL [23]. Severe xerostomia, neuropathy, hearing loss, otitis, and hypothalamic dysfunction have a negative impact on QoL according to Tsai et al. [24]. In our study, patients with G1-G2 xerostomia had worse FACT-NP scores, while hearing loss was related to worse PSS-HN score.

Although this study has several limitations, because it includes a small number of patients with heterogeneous treatments, no pre-treatment QoL data are available and post-treatment evaluation to assess QoL and late toxicity were obtained at only one date for all patients, a very few data are reported on literature about QoL of NPC long-term survivors.

Conclusions

Our preliminary data on PROs measures suggest that negative predictors of QoL in NPC patients are age, techniques, xerostomia, and hearing loss. Better QoL is probably achieved with IMRT. Prospectively studies with a larger sample are needed to confirm our findings.