Introduction

Cancer as a cause of premature mortality is more in the developed countries as compared to the developing countries; a price that west pays for its urbanization. Contrary to this, head and neck squamous cell cancer (HNSCC) is more common in the developing countries like India. Maharashtra, where the native language is Marathi, reported the highest incidence of oral cancer in India.1 Literature reported urban-rural difference in HNSCC survival from developed countries is variable,23 while in India, survival of rural HNSCC patients is poor as compared to their urban counterpart.4 According to the World Bank collection of development indicators, 64% of the total Indian population is rural.5 Rural population and rural area hinder the quality of oncology care.4

Despite advances in treatment modalities, the survival in HNSCC has reached a plateau.6 Hence, the quality of survival has gained an increasing importance. Health-related quality of life (QOL) is the difference between patient's expectations and experience7 and is better answered by patients themselves. QOL questionnaire (QLQ) is one of the ways to measure QOL. QOL is now viewed as a primary endpoint measure for quality of management and care in oncology practice as it reflects patient's discernment of an impact of cancer diagnosis and treatment on their daily living.8 The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) is the most widely used self-reported questionnaire in oncology.9

HNSCC itself and side effects of its treatment are bound to have measurable impact on patient's QOL. Depending on the site, size, stage, and treatment, HNSCC can cause varying degrees of structural deformations, and functional handicaps compromising well-being, self-esteem, and social integration.10 Treatment-induced side effects like facial disfigurement, speech, and swallowing changes cannot be concealed. This can further result in social withdrawal and avoidance of potentially helpful support systems.11 Cure at the cost of morbidity reflecting in a poor QOL is not acceptable. The disease itself and its treatment affect patients' social, psychological, and functional aspects, which need to be measured to implement the problem-directed interventions. QOL is sparsely studied in rural HNSCC patients,1213141516 with further scarcity of “real-world scenario.” Hence, this study was planned with an aim to evaluate the difference in QOL before (pre-) and at first follow-up after radiotherapy (RT) (post-RT) in patients of HNSCC at a rural tertiary cancer care center (RTCCC).

Materials and Methods

Ethical consideration: This before and after type of analytical study commenced after an institutional ethics committee (IEC) approval and was conducted in accordance with the ethical standards of IEC and the Helsinki Declaration of 1975, as revised in 2000.17 Informed written consent in a vernacular language was obtained from all the study participants.

Study subjects: All consecutive newly diagnosed, nonmetastatic, histopathology-proven, HNSCC patients of oral cavity (OC), oropharynx (OPX), hypopharynx, and larynx registered at the department of radiation oncology of a RTCCC from June 2019 to January 2022 were evaluated for the study. Marathi language speaking adult patients of either sex with Eastern Cooperative Oncology Group performance status of ≤ 2,18 treated with curative intent, accompanied by responsible caregiver, and consenting for the study were included. Patients with known acquired or congenital head-neck deformity, second primary head-neck cancer, or unable to interview were excluded.

Study tools: QOL was assessed using a translated and validated Marathi version of EORTC QLQ. A core questionnaire EORTC QLQ-C30 (version3.0)10 and head-neck specific EORTC QLQ-H&N4319 were used. EORTC QLQ-C30 is divided into three parts—a global health status (single item), function scales (5 multiple items), and a symptom scale (3 multiitem and 6 single-item scales). Thus, it includes a total of 15 item scales. EORTC QLQ-H&N43 is the supplementary head-neck specific questionnaire to be employed in conjunction with the core questionnaire. It incorporates 12 multiitem and 7 single-item scales. Thus, a total of 19 item scales are evaluable. Score calculation was done as per the EORTC guidelines20 for core questionnaire and as per the EORTC QLQ-H&N43 scoring manual received from the EORTC QOL unit, EORTC Data Centre, Brussels, Belgium. The score ranges from 0 to 100. High score of function scale represents high/healthy (better) level of functioning, high score of global health status represents high (better) QOL, while high score of symptom scale represents high (worse) level of symptomatology or problem. Calculation and interpretation of all item scales of EORTC QLQ-H&N43 are similar to the symptom scale of EORTC QLQ-C30 (version3.0).

Study methodology: Consecutive eligible patients were enrolled in the study and were offered with the Marathi language version of EORTC QLQ-C30 (version 3)10 and EORTC QLQ H&N4319 pre-RT. The purpose of the study was briefly explained to each participant. Patients completed the EORTC QLQ and filled the answers on their own (module) or with the help of an investigator (schedule); either because of illiteracy problem or technical difficulties like unavailability of spectacles. In the schedule subgroup, investigator read the questions aloud and noted the respondent's responses. Treatment was delivered as per the discretion of the treating physician while respecting the evidence; using three-dimensional conformal RT (3DCRT), intensity-modulated RT (IMRT), or combination of both to a dose ranging from 1.1 Gy/fraction twice a day to 2.5 Gy/fraction per day. Patients completing the planned RT and reporting for first physical follow-up visit (6–18 weeks after RT conclusion) were reserved with the EORTC QLQ. The patients completing both the pre- and post-RT QLQ were analyzed further.

Staging of HNSCC was done as per the American Joint Committee of Cancer staging manual (8th edition).21 P-16 immunohistochemistry was not done and hence all patients of OPX were staged as human papillomavirus or P-16 negative. Socioeconomic status was noted according to the modified Prasad's classification.22 Clinical and treatment details were collected from the prospectively maintained hospital records. Treatment toxicity was accessed as per the Common Terminology Criteria for Adverse Events version 5.023 and treatment response was accessed according to the Response Evaluation Criteria for Solid Tumors (RECIST-1.1) keeping in mind the limitations for postsurgery and RT.24

Statistical analysis: Considering the primary outcome as difference in QOL, before (pre-RT) and at first follow-up after RT (post-RT), and as per the literature review,202526 the sample size calculated was 100 in each arm. An α-error of 5% and β-error of 20% were considered.2025 The mean and standard deviation (SD) values of global health quality at pre-RT (mean [X1] = 53.80, SD1 = 21.60])] and at first follow-up post-RT (mean [X2] = 65.29, SD2 = 26.26) observed by Karimi et al, were referred.26 Sample size was calculated using the following formula:

Sample size (n) = (Z_1–α/2 + Z_1–β)² *(SD₁² + SD₂²)/(X₁–X₂)²

= 7.84 * (21.60)² + (26.26)²/(53.80–65.29)² = 66.87

Considering the heterogeneity of head and neck subsites, 1.5 times the calculated value was finalized as a sample size in each arm, that is, 66.87 × 1.5 = 100. Thus, 100 patients each in pre- and post-RT group were considered.

Statistical analysis was done using Graph-Pad, Instat-3 (California Inc) statistical software to derive a conclusion. Effect size (ES) for QOL items were calculated as it depicts clinically significant difference and was interpreted as trivial effect (0–0.19), small effect (0.2–0.49), medium effect (0.5–0.79), and large effect (≥ 0.8). Minimal important change (MIC) (difference in mean of 5 to 15 for EORTC QLQ-C30, and for EORTC QLQ-H&N43 the difference of –3 to –14 was considered as improvement, and the difference of 8 to 16 was considered as deterioration for swallowing scale)2728 was noted.

Appropriate sample size was calculated to take care of random errors. Consecutive patients were evaluated to avoid selection bias. All the study participants were evaluated by single investigator to reduce an investigator bias. The questionnaires were checked for missed items/no response and readministered then and there to take care of no-response bias.

Results

Patient selection: A total of 364 HNSCC patients registered during the study period were evaluated. Note that 210 eligible enrolled patients completed the pre-RT QLQ. A total of 100 patients who completed both the pre- and post-RT QLQ were included in the study, analyzed, and reported further. Fig. 1 depicts the selection of study participants.

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Fig. 1: Selection of study participants.

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Patient characteristics: Note that 100 patients who completed both the pre- and post-RT QLQ were included in the study. Median age of patients was 53 years (range: 30–78 years) and man to woman gender ratio was 4.56:1. Detailed patient characteristics are depicted in Table 1.

Patients received either radical (45) or adjuvant (55) RT to a dose ranging from 46 Gy/19# to 72 Gy/36# over 3.5 to 7 weeks with 6 MV photons. Treatment and treatment response details are given in Table 2. Note that 1, 2, 1, and 1% patients had more than grade II skin, xerostomia, trismus, and neck edema as a RT toxicity.

Pre- versus post-RT QOL: For EORTC QLQ-C30, large ES was observed for financial difficulty (FI) (ES = 0.98), while medium ES was observed for pain (PA) (ES = 0.69), insomnia (SL) (ES = 0.59), constipation (Con) (ES = 0.41), and emotional functioning (EF) (ES = –0.62). MIC was observed for dyspnea (DY) (ES = –0.41), fatigue (FA) (ES = 0.42), loss of appetite (AP) (ES = 0.38), cognitive functioning (CF) (ES = –0.49), and social functioning (SF) (ES = –0.32).

For EORTC QLQ-H&N43, large ES was observed only for deterioration, that is, dry mouth and sticky saliva (DR) (ES = –1.75), problems with senses (SE) (ES = –1.31), and problems with skin (SK) (ES = –1.38). Swelling in the neck (SN) (ES = –0.40) showed deterioration with small ES. Medium ES for improvement was observed for pain in mouth (PM) (ES = 0.53) and fear of progression (AX) (ES = 0.75). Improvement with trivial and small ES was observed with speech (SP) (ES = 0.17), sexuality (SX) (ES = 0.17), shoulder pain (SH) (ES = 0.16), weight loss (WL) (ES = 0.16), problems with wound healing (WO) (ES = 0.13), and neurological problems (NE) (ES = 0.23), respectively.

Global health status improved significantly after treatment showing large ES (ES = –0.84). Thus, at short-term follow-up, majority of parameters showed improvement except for treatment-related side effects (Fig. 2). The detailed ES difference in pre- and post-RT QOL parameters is depicted in Table 3.

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Fig. 2: Comparison between pre- and postradiotherapy quality of life (N = 100).

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Discussion

Majority of Indian HNSCC patients presents in locally advanced stage of disease29 resulting in poor treatment outcome and prognosis. Even after treatment majority of them are lost to follow-up. Hence, the long-term results are lacking.4 Eighty-two percent patients in the present study had locally advanced stage. Note that 65.24% (137) patients completed the planned treatment; out of which 75.91% (104) patients reported for physical follow-up.

The function of head and neck region is affected by the disease and the side effects of surgery, chemotherapy, concurrent chemoradiotherapy (CTRT), and/or RT. Extent of surgery negatively affects the QOL, especially in patients of OC.30 RT-related acute (mucositis, dysphagia, dermatitis) and late (xerostomia, speech, swallowing and voice changes, silent aspiration, osteoradionecrosis, laryngeal edema, sensory-neural hearing loss, skin fibrosis) toxicities result in increased morbidity and altered symptom scales of QOL during3132 and after treatment.33343536 Indirectly it affects the functional domains of QOL.31 Few late RT toxicities are permanent resulting in poor QOL in symptom scale even 3 years post-RT.36 MacDowell et al concluded that despite IMRT, survivors experience many physical symptoms negatively affecting QOL.37 It is difficult to spare the salivary glands completely so as the xerostomia. Posttreatment salivary function-related QOL is better with IMRT with equal survival as compared to two-dimensional or 3DCRT.3839 Though prophylactic exercises may help to improve the organ function at no added cost,4041 IMRT, a significantly more costly RT modality is widely adopted,42 specially as a dysphagia aspiration-related structure sparing RT modality.43 Majority of QOL parameters of our study showed clinically significant improvement except for the QOL domains depicting the treatment toxicities. Thus, the QOL assessment helps to identify a subgroup requiring specific symptom-directed therapy. Presently, the MIC for head-neck specific questionnaire is exemplified for swallowing domain28 and the rest are under development. The clinically significant difference or change is gaining importance over the statistically significant difference. Future studies directed to reduce the treatment toxicities or improved functional outcome measured using QLQ evaluating the clinically significant difference are warranted.

An important study from an apex urban Indian cancer institute concluded that there is substantial deterioration in QOL after curative-intent head–neck irradiation that gradually improves over time. IMRT results in clinically meaningful and statistically better QOL scores for some domains compared to 3DCRT at several time points with comparable disease outcomes. This could support widespread adoption of IMRT in routine clinical practice.3839 At the same time, Kumar and Bhaskar concluded that cobalt brachytherapy and teletherapy are best for the developing nations like India and highly conformal RT should be used in trail setting.44 Quality training of oncology professionals and regular quality check are necessary,45 specially when using higher technology. Risk (financial toxicity) and benefits (majority presenting in locally advance stage) of highly conformal therapy needs to be considered and individualized treatment should be offered.

QOL domains affected in rural HNSCC patients showed geographical variation. Adamowicz et al observed poor QOL in emotional domain in rural HNSCC survivors from America.13 Physical domain of QOL was affected in Australian literature.14 European studies showed poor QOL in both physical and emotional domains.1215 These differences could be because of QOL assessment at different time points of patient's cancer life (e.g., as a cancer patient or as a cancer survivor). We could identify a single cross-sectional study from rural India evaluating the QOL in 50 HNSCC patients admitted in hospital and undergoing various forms of treatment (neoadjuvant chemotherapy /RT/CTRT). QOL instrument used by the author was World Health Organization QOL scale. Authors concluded poor QOL of patients which was dependent on patient's socioeconomic status.16 None of the studies compared pre- versus post-RT QOL difference.

Rural-urban disparities were observed in diagnostic and therapeutic facilities in India which affected the stage at presentation and survival of HNC patients,4 and hence the QOL. Note that 83% patients of the present study were rural residents while 17% were from small town (taluka place). Reverse was the picture described in western literature; 26.3% were rural residents and majority of the patients were insured.46 No urban-rural difference in stage at presentation or survival was observed by Mukherjee et al among the HNSCC patients of south eastern America.47

Multimodality treatment and technological advances have helped improve the survival48 which along with the tumor or disease control has almost reached a plateau. Hence, the QOL assessment is important. Though QOL improves after treatment in certain domains, treatment-related side effects limit the better QOL outcome. Thus, there is need to increase the benefit-to-risk ratio by timely interventions, and QOL assessment helps to identify the subgroup of patients in need of symptom-directed interventions. QOL is multidimensional and all dimensions should be considered simultaneously, because of potential tradeoffs between them. Physical, social, and emotional well-being along with development and activity are important dimensions of QOL.49 QLQ, that is, subjective assessment, in patient's own language should be incorporated in clinical studies for better understanding and timely addressing the patient's problems. With the help of advancement in information technology and artificial intelligence, patient-friendly QLQ needs to be designed considering the literacy and understandability issues of rural patients.

There were few shortcomings of this study. QOL itself means a quality which is quantified while score calculation of EORTC QLQ. Hence, the limitations of qualitative study, that is, informer bias, cannot be ruled out. Patient's perception and attitude about QLQ and their physical and emotional status at the time of attempting QLQ may affect the outcome. These are the major limitations of any QOL study. The coronavirus disease pandemic and local transport constraints affected the patients' physical follow-up. The study group could have been more homogenous in terms of patient (age, gender, socioeconomic status, literacy level), disease (head-neck subsite, stage), and treatment (3DCRT/IMRT, dose-fractionation schedules, extent of surgery, and postsurgery recovery) characteristics.

Conclusion

There is considerable improvement in QOL in HNSCC patients after RT; especially in financial and emotional domains and except for the treatment-related toxicity domains. Future studies with large number of patients with relatively uniform characteristics and long-term follow-up will direct the trend of change in QOL after treatment.