Prospective evaluation of impact of adaptive radiotherapy on quality of life in patients with locally advanced head and neck cancers

Introduction

Intensity-modulated radiation therapy (IMRT) helps in focused irradiation of the target volume and sparing normal head and neck organs such as the oral cavity, larynx, spinal cord, and salivary gland (1). It spares the parotids and reduces the incidence of severe xerostomia (2,3). During the course of radiation treatment, changes in patient anatomy may occur either due to tumor regression, shrinkage of parotids, weight reduction, or due to postoperative oedema subsides, and it varies from patient to patient (4). Hence, to assist further in improving the therapeutic outcome, various advanced techniques have been introduced; one of them is combining multiple images like CT, MRI, and PET to assist in delineating treatment volumes (5). Inter- or intra-fractional anatomy changes from the planning image set may misjudge the dose conformity in delivered dose distribution. The solution to this problem is repeated imaging during the course of radiation and adapting the plan to the new anatomical variations whenever the anatomical changes seem unacceptable to continue treatment (6,7).

When evaluating the treatment and care of cancer patients, information about local control and survival is often supplemented with data from health-related quality of life (HRQoL) surveys for treatment impact on QoL of these patients (8). HRQoL can measured by questionnaires developed by the Quality of Life Group of the European Organization for Research and Treatment of Cancer (EORTC). The Quality of Life Questionnaire (QLQ)-C30 and QLQ-H&N35 are valid, precise, and apt for head and neck cancer (HNC) patients from diverse populations (9). Adaptive replanning is usually considered for patients who have tumor shrinkage, weight loss, and/or anatomic changes during the radiation treatment.

There is a paucity of studies on adaptive radiotherapy from India because of logistical and technical difficulties (10,11). It has been perceived in the literature that the dose to the organs at risk (OARs) is decreased in adaptive radiotherapy, leading to a reduction in toxicity. IMRT improves QoL by reducing doses to OARs, and we further hypothesized that adaptive radiotherapy will improve QoL in patients with HNC.

The present study was planned to evaluate the baseline QoL and changes in QoL at subsequent intervals in HNC patients undergoing IMRT/Chemo-IMRT with mid-treatment adaptive replanning. We present this article in accordance with the TREND reporting checklist (available at https://tro.amegroups.com/article/view/10.21037/tro-23-40/rc).

Methods

Patient selection

The period of conduct for the current prospective study was January 2021–August 2022. Patients with age ≤70 years who had locally advanced non-nasopharyngeal head and neck squamous cell carcinoma (HNSCC) were eligible based on histological evidence, presenting to Radiation Oncology Outpatient department (OPD). Individuals having distant metastases or recurrence after surgery for any type of HNC were not included in the study. Eligible patients were illustrated in detail about the purpose of the study and registered in the study after informed consent was obtained.

The participants had the choice of exiting the study at any point during the study period. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The institutional ethics committee of All India Institute of Medical Sciences (Rishikesh) approved the study (AIIMS/IEC/21/226), and informed consent was taken from all individual participants. The study is registered with CTRI/2021/09/036821 (www.ctri.nic.in).

To detect a paired difference at an effect size of 0.5 and α of 0.05, 34 paired samples (before and after treatment) were required when testing by the paired t-test. The sample size was determined using G-Power software. With an attrition rate of 20%, the sample size 40 was determined.

Treatment planning

Using five clamp thermoplastic head and neck casts, patients were immobilized while lying supine. Non-ionic contrast was injected intravenously at a dose of 1.5 mL/kg, and pictures were obtained from the vertex to the tracheal bifurcation using simulated computed tomography with a 2.5 mm slice thickness. The images were exported to the Treatment Planning System (ECLIPSE 16.1). Following the guidelines recommended by the Radiation Therapy Oncology Group (RTOG), contouring was performed on the following organs: brain stem, optic chiasma, optic nerves, eyeball, lens, parotid gland, spinal cord, mandible, glottic larynx, and target volumes included gross tumor volume (GTV), clinical target volume (CTV) and planning target volume (PTV).

IMRT dose prescription and dose constraints

A total dose of 66–70 Gy equivalent radiation therapy was delivered in 33–35 fractions, 5 fractions per week. Guidelines by QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic) were used to evaluate OARs dose constraints.

Treatment delivery and re-scan

Patients were treated on HALCYON v3, with daily imaging done before treatment delivery. Repeat CT simulation was done at the 20^th fraction of treatment. Rigid and Deformable Image Registration was used to re-align the new scan to the old scan, and re-planning was done with dose calculation. The PTV margin was changed if OARs were intruding into the PTV. Initial PTV was edited only if extended outside body contour. Reoptimisation of a new plan (Pnew) was done to generate a plan similar to the original plan. Lateral neck diameter (LND) was measured at the cervical 1 (C1) vertebra level in the initial and the re-scan CT scan (12). A new plan (Pnew) was executed at mid-treatment.

Toxicity assessment

Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE) criteria were used to grade acute radiation toxicity. Side effects occurring within 90 days of the start of radiotherapy were considered acute side effects.

QoL assessment

The EORTC QLQ-C 30 (v3) and EORTC QLQ-H&N35 were used to assess the QoL (13). QLQ-C30 (v3) has thirty items: five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea and vomiting), a global health status/QoL scale, and single items that evaluate extra symptoms (dyspnoea, loss of appetite, insomnia, constipation, and diarrhoea) that are frequently reported by cancer patients as well as financial concerns related to the disease. Thirty-five questions make up the EORTC QLQ-H&N35 module, which is HNC-specific. A multi-item measure called the Seven includes symptoms like pain, difficulty swallowing, speech, senses, difficulty eating in public, sexuality, and social interaction. Additionally, there are eleven single-item scales. The Global QoL scale has a 7-point response score, whereas the EORTC QLQ H&N 30 and 35 scales use a 4-point response (from “not at all” to “very much”). The results are transformed to a range of 0 to 100; the higher the scores, the better the function, whereas higher scores for symptoms indicate more symptom burden (14). There is also an available translation in Hindi for the QLQ-C30 and QLQ-H&N35.

EORTC QLQ-C 30 and EORTC QLQ-H&N35 questionnaires were given out at baseline, the day the treatment was finished, and then one, three, and six months later.

Statistical analysis

Data was analyzed using IBM SPSS 23.0 software. Normality was assessed by the Kolmogorov-Smirnov Z test. A paired t-test or Wilcoxon Signed Rank (Z) test was used to analyze quantitative data based on their normality. Spearman’s rho test was used for the assessment of co-relations. P<0.05 was considered a statistically significant result.

Results

From January 2021 to August 2022, as per the inclusion criteria, 40 patients were included. However, six patients defaulted for treatment, two before and four during treatment. Hence, 34 patients were included in the study. All the patients initially underwent a baseline radiation treatment planning scan for treatment, and during the course of treatment, a re-scan was taken at the 20^th fraction. The radiation dose planned by IMRT was 66–70 Gy in 30–33 fractions, along with concurrent chemotherapy weekly. Only one patient did not receive concurrent chemotherapy due to advanced age. All patients were replanned, and the new plan was executed at the 22^nd fraction. EORTC QLQ-H&N35 questionnaires were administered at baseline, on the day of treatment completion, and after one, three, and six months.

Patient characteristics

In this study, we analyzed 34 patients, 30 (88.2%) males. 25 (73.5%) patients were more than 50 years of age. Oropharyngeal site 18 (52.9%) was the most common location of primary disease. Carcinoma (followed by larynx (26.5%), oral cavity (14.7%), and hypopharynx (5.9%). 14 (41.2%) patients were in stage IVB, followed by IVA and III, 35.3% and 23%, respectively.

Dosimetric analysis

It was discovered that mean changes for volumetric changes in the GTV and the organ at risk were 5.81 cc, 10.95 cc, 4.93 cc, 0.9 cc, 43.9 cc, 46.9 cc and 26.1 cc for GTV-nodal, GTV-primary, left and right parotid volumes, LND, PTV-low risk, PTV-intermediate risk, and PTV high risk respectively and all were statistically significant P<0.001 (Figure 1). There were decreases in OAR dosages, but they were not statistically significant. The brain stem (Dmax =0.8), spinal cord (Dmax =0.3), right parotid (Dmean =0.2), and mandible (Dmax =0.6). On the other hand, the left parotid showed a higher dose (Dmean =2.3) (Figure 2).

Figure 1 Graphical representation of the volumetric changes in the tumour volumes (GTV, CTV, PTV) and the parotids. GTV, gross tumour volume; CTV, clinical target volume; PTV, planning target volume; GTVn, GTV of lymph nodes; GTVp, GTV of primary tumor; HR, high risk; IR, intermediate risk; LR, low risk.

Figure 2 Graphical representation of the dosimetric changes in the planning target volume and the organs at risk.

Acute toxicities

Mucositis grade 1, 2, and 3 toxicities were 67.5%, 29.5%, and 2% respectively. 91.2%, 8.8%, and 91.2% of patients had grade 1, and 8.8% had 2 dermatitis, respectively. 14.7% of patients had grade 1 pharyngitis.

EORTC OLQ-C 30

At baseline, the mean global health score of patients was 45.59. Functional scales were above 50 (physical functioning =82.94, role functioning =76.96, emotional functioning =79.41, cognitive functioning =89.22, social functioning =82.35). The mean scores for the symptom scales were: fatigue =26.47, nausea and vomiting =6.37, pain =39.22, dyspnoea =19.61, insomnia =21.57, appetite loss =16.67, constipation =10.78, diarrhoea =8.82 and financial difficulties =12.74.

Global QoL showed deterioration at treatment completion (P<0.001), but there was significant improvement at one month (P<0.001), three months (P=0.004), and six months (P<0.001). Physical functioning showed significant deterioration following treatment (P<0.001), which slightly improved at one month (P=0.03) and further at three and six months. However, it was not statistically significant. Role functioning deteriorated at the completion of treatment (P=0.001), which improved at one month (P=0.04), but there was no significant improvement at three months or six months. Emotional functioning decreased (P=0.003) following treatment compared to baseline; however, it progressively increased in the following months till six months, even though it was not statistically significant. Cognitive functioning deteriorated post-treatment (P=0.03), which increased in the following months, even though it was not statistically significant. Social functioning had decreased at the end of treatment (P=0.05), which had progressively increased at one, three, and six months (P=0.03).

Patients had significant fatigue at the end of treatment (P<0.001), which gradually decreased in the subsequent months. There was considerable nausea and vomiting after treatment (P<0.001), which gradually reduced at one, three, and six months. Patients had pain at baseline, which increased post-treatment (P=0.001) but gradually decreased at one, three (P=0.03) and six months (P=0.02). No significant change in dyspnoea was observed in patients during treatment. There was a considerable increase in insomnia at the end of treatment (P=0.01) and at one month (P=0.03), which gradually decreased at three and six months. Patients had significant appetite loss post-treatment (P<0.001), which gradually reduced at one (P=0.003), three and six months. Significant constipation was noted at the end of treatment (P<0.001), which gradually improved over time. No significant diarrhoea was reported; however, there was increased diarrhoea post-treatment, which eventually resolved over time. Patients had significant financial problems after treatment (P=0.01), with scores returning to levels comparable to baseline at 6 months (Table 1).

EORTC QLQ-H&N35

At baseline the mean scores for symptoms were: pain =29.66, difficulty in swallowing =22.79, sense of taste and smell =7.84, speech problems =18.3, issues with social eating =19.85, social contact =13.33, sexuality =21.57, teeth problems =8.82, difficulty in opening mouth =17.65, mouth being dry =8.82, saliva =13.73, cough =18.63, felt ill =32.35, took painkillers =94.12, took nutritional supplements =8.82.

Pain was increased in patients with a median score of 50 post-treatment (P<0.001), which decreased at one month (P=0.02) and further gradually. Patients had difficulty in swallowing, maximum noted after treatment (P<0.001), which gradually improved. There was a significant problem in the sense of taste and smell at the end of treatment (P<0.001), at one month (P<0.001), three months (P<0.001), and six months (P<0.001). Most patients had problems speaking after treatment (P<0.001), which gradually improved over time. Patients experienced trouble with social eating at the end of treatment (P<0.001) and one month (P=0.003), which gradually improved over time. Patients had trouble with social contact at the end of treatment (P<0.001) and at one month (P=0.02). Patients faced sexuality problems at the end of treatment (P=0.049). Patients had teeth issues post-treatment (P=0.02) and at one month (P=0.02). Problems with teeth showed initial worsening post-treatment and at one month, then returned to near-baseline levels by 6 months. Patients had issues with opening of mouth post-treatment (P=0.004), which gradually improved over time. There was significant dry mouth at the end of treatment at one month, three months, and six months (P<0.001). There was significant sticky saliva post-treatment (P<0.001), one month (P<0.001), three months (P=0.011), and six months (P=0.002). Patients had significant cough post-treatment (P=0.001) and at one month (P=0.01), which gradually improved. Most patients felt ill after treatment, which improved later (P=0.001). The majority of patients required painkillers at baseline, whose dependency gradually decreased over a period of time, lowest at three months (P=0.005) and at six months (P<0.001). Most patients took nutritional supplements post-treatment (P<0.001), and the requirement decreased in the succeeding months. None of the patients had a feeding tube inserted at baseline, but during the course of treatment, some patients got a feeding tube inserted (P=0.003). All patients had weight loss at baseline; some gradually regained weight at three months (P=0.02) and six months (P<0.001) (Table 2).

Changes in QoL with time

There was a decrease in QoL C-30 and H&N 35 at the completion of treatment in comparison to baseline scores. QoL was evaluated at 1.3 and 6 months. An increment in the functioning scores was observed at the end of 6 months compared to baseline with maximum improvement in social and emotional function (6.36 and 6.34, respectively). C30 symptoms reduced at the end of 6 months except for fatigue (2.2) and loss of appetite (3.76), which might be due to taste alteration. QLC-HN35 symptoms also reduced except for sense problems (19.58), sticky saliva (27.13), and dryness of the mouth (33.12). Also, there was a decrease in the use of pain killers (−45.73) and weight loss (−45.16) (Table 3).

Discussion

“A patient’s appraisal of and satisfaction with their current level of functioning as compared to what they perceive to be possible or ideal” is the definition of QoL. The nature of QoL is multifaceted and individualized (15). Patients incur a functional deficit following radiotherapy, which can be measured using functional scales (e.g., EORTC QLQ-H&N35, Xerostomia questionnaires) (16).

Additionally, patients might have reviewed their goals and intentions for their lives as the disease progressed from diagnosis to treatment and follow-up. One of the most important facilitators of this adaptation process is response shift, which makes it challenging to evaluate changes in QoL data over time. Furthermore, patients might think that the cost of tumor control justifies the functional impairment they are experiencing. As a result, the global QoL score and functional outcomes (xerostomia, dysphagia, or feeding dependency) don’t always correlate (17).

A cross-sectional survey approach was employed in the largest study to date, in which post-radiotherapy QoL was assessed in 640 head-neck patients’ post-treatment. This design was utilized to determine the impact of technical advancements over time. Of 640 patients, 371 received X-ray-based conventional radiotherapy, 127 received three-dimensional radiotherapy, and 142 received advanced IMRT. In QLQ-C30, two scales, and in QLC-HN35, ten scales had significant differences (P<0.05) obtained using various techniques. IMRT considerably improves global QoL, physical functioning, and multidimensional scales compared to 2D-RT. Teeth, dry mouth, and sticky saliva were the three scales that showed better results in 3D-CRT as compared to 2D-RT. Although IMRT outpaced 3D-CRT on most scales, the difference was not statistically significant (18).

Rathod et al. compared 3D-CRT and IMRT for QoL results in HNC patients (19). At various time intervals, IMRT outperformed 3D-CRT in preserving several general and specific QoL domains of HNC. It is also important to mention that in IMRT, none of the QoL domains ever showed worsening. Immediate post-treatment (3 months), QoL ratings significantly declined in both arms. For the majority of areas, an improvement was observed in QoL scores gradually over time. While physical/cognitive functioning, xerostomia, weariness, and senses unveiled protracted recovery (>6 months), global QoL emotional/role functioning showed quick recovery (within six months). After radical head-neck irradiation, there was a substantial deterioration in QoL, which gradually improved after treatment completion.

Tribius et al. studied the changes in QoL scores at various intervals after the completion of radiotherapy treatment in HNC (20). They identified that improvement in QoL occurred after one year, with dryness of mouth and sticky saliva persisting for longer. In the present study, at the end of 6 months, there was an improvement in symptoms with functioning scales suggesting that adaptive radiotherapy might lead to early improvement in symptomatology, but this needs to be further validated in prospective comparative studies of adaptive versus non-adaptive IMRT QoL studies.

Yang et al. assessed the effect of replanning on the QoL of patients with nasopharyngeal carcinoma (NPC) during IMRT. They discovered that most QoL scales showed statistically and clinically significant improvements in patients undergoing IMRT replanning. Furthermore, it improved the locoregional control at two years in replanning (97.2%) compared to non-replanning (92.4%) strategies (21).

The limitations of our study are the number of patients and the absence of a comparative arm. There was a statistically significant deterioration of QoL scores at treatment completion, which gradually improved during the follow-up period. Patients who underwent a replanning had statistical improvements in global QoL, social functioning, role functioning, senses, speech, social contact, eating, and coughing. There was a statistically significant decrease in taking painkillers and nutritional supplements. Patients had substantial weight loss at baseline and during treatment and gradually gained weight at follow-up.

Conclusions

QoL of patients is seen to decrease post-treatment in patients undergoing radiation therapy. In adaptive radiotherapy, an initial decrement followed by subsequent significant improvements during follow-up have been documented in patients with HNC. However, the impact of adaptive replanning will need to be further defined with a longer follow-up and a larger patient sample.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the TREND reporting checklist. Available at https://tro.amegroups.com/article/view/10.21037/tro-23-40/rc

Data Sharing Statement: Available at https://tro.amegroups.com/article/view/10.21037/tro-23-40/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tro.amegroups.com/article/view/10.21037/tro-23-40/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The institutional ethics committee of All India Institute of Medical Sciences (Rishikesh) approved the study (AIIMS/IEC/21/226), and informed consent was taken from all individual participants. The study is registered with CTRI/2021/09/036821 (www.ctri.nic.in).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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