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Differences in health related quality of life in the randomised ARTSCAN study; accelerated vs. conventional radiotherapy for head and neck cancer. A five year follow up

Radiotherapy and Oncology, Volume 118, Issue 2, February 2016, Pages 335 - 341

Abstract

Background and purpose

Health related quality of life (HRQoL) was assessed in the randomised, prospective ARTSCAN study comparing conventional radiotherapy (CF) with accelerated radiotherapy (AF) for head and neck cancer.

Material and methods

750 patients with squamous cell carcinoma (of any grade and stage) in the oral cavity, oro-, or hypopharynx or larynx (except T1–2, N0 glottic carcinoma) without distant metastases were randomised to either conventional fractionation (2 Gy/day, 5 days/week in 49 days, total dose 68 Gy) or accelerated fractionation (1.1 + 2.0 Gy/day, 5 days/week in 35 days, total dose 68 Gy). HRQoL was assessed with EORTC QLQ-C30, QLQ-H&N35 and HADS at baseline, at end of radiotherapy (eRT) and at 3 and 6 months and 1, 2 and 5 years after start of treatment.

Results

The AF group reported HRQoL was significantly lower at eRT and at 3 months for most symptoms, scales and functions. Few significant differences were noted between the groups at 6 months and 5 years. Scores related to functional oral intake never reached baseline.

Conclusion

In comparison to CF, AF has a stronger adverse effect on HRQoL in the acute phase.

Keywords: Health related quality of life, Accelerated radiotherapy, Head and neck cancer, Quality of life, Accelerated fractionation.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumours with a variable responsiveness to treatment. In the last decades efforts have been made to develop novel treatment modalities. Curative treatment is based on surgery and/or radiotherapy (RT). In recent years RT is commonly combined with concomitant chemotherapy. The side effects from radiotherapy often affect the patients’ health-related quality of life (HRQoL) [1] and [2]. Both acute and late side effects influence the results of patient-reported HRQoL that correlate to prognosis [3], [4], and [5]. Several studies of accelerated fractionated RT show an improved loco-regional tumour control (LRC) in treatment of HNSCC [6], [7], [8], and [9], while others do not [10], [11], [12], [13], [14], and [15]. In meta-analysis of 15 randomised trials comparing conventional RT with hyperfractionated and/or accelerated RT, the conclusion was that altered fractionation, hyperfractionation in particular, improves survival [16].

The altered fractionation schedules, including accelerated RT, generally seem to increase acute side effects [6], [7], [8], [9], [10], [11], [12], [13], [14], and [15]. In some cases more severe late side effects are encountered [6], but most trials report similar frequencies regardless of fractionation. A group of studies of altered fractionation with a reduced total dose, report a lower incidence of late side effects [11], [12], and [15]. In many cases the number of patients at risk is small after a long follow-up, which hampers statistical inference. Furthermore, patient-reported early and late effects are usually not carefully reported in most studies.

In the Swedish prospective multicentre ARTSCAN (Accelerated RadioTherapy of Squamous cell CArcinomas in the head and Neck) trial, accelerated fractionation (AF) was compared to conventionally fractionated (CF) RT. The primary physical tumour dose was the same in both treatment arms. Loco-regional control and survival after 2-years follow-up have been reported previously [17]. In the first report, doctor’s reported side effects showed increased frequency of acute reactions for AF, but late effects were similar in both study arms. The purpose of this paper was to longitudinally compare patient-reported HRQoL of AF (without reduction of total dose) with CF up to 5 years after RT.

Materials and methods

Between November 1998 and June 2006, 750 patients with M0 squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx (except glottic T1–2, N0) were randomised to receive either CF (2 Gy/day, total 68 Gy in 7 weeks) or AF (1.1 Gy + 2 Gy/ day, total 68 Gy in 4.5 weeks) either as single modality treatment or as preoperative RT.

Previous malignant disease in the head and neck region, surgery other than diagnostic procedures, age under 18, inability to understand the information about treatment, expected non-compliance and chemotherapy closer than three months before randomisation excluded patients from the study.

Approval of the study was granted by the Ethical Review Board in Umeå. All included patients signed an informed written consent. So far, as stated in the previous reports by Zackrisson et al. [17] and [18], there were 349 patients eligible for evaluation in the CF group and 352 in the AF. Fig. 1 shows the inclusion of patients in the ARTSCAN study.

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Fig. 1 Trial profile.

Patients who lost locoregional control were included in the HRQoL study until relapse of the disease was confirmed.

Instruments for measuring quality of life

The HRQoL data were collected using The European Organization for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 (version 2 and version 3) [19] and the EORTC Head and Neck cancer module (H&N35). These instruments have been extensively validated [19], [20], and [21]. All scores were linearly transformed so that all scales ranged from 0 to 100 according to the EORTC scoring manual [22]. In case of missing data, if two of three items from the scale had been answered, the missing values were replaced with the average of the respondent’s score for this time point.

The cancer-specific QLQ-C30 questionnaire includes 30 questions organised into five functional scales (physical, role, emotional, cognitive, and social) and three symptom scales (nausea/vomiting, pain, and fatigue). It also includes a global health/QoL scale and six single additional symptom items (constipation, diarrhoea, loss of appetite, insomnia, dyspnoea, and financial difficulties). Higher scores on functional and global health/QoL scales indicate a higher level of functioning, while a higher score on the symptom scales or single items indicate greater symptoms or problems.

The QLQ-H&N35 was used for measuring symptoms and problems specific for head and neck cancer and treatment side effects. The questionnaire includes 35 questions organised into seven symptom scales (local pain, swallowing, senses, speech, social eating, social contact, sexuality), six single symptom items (problems with: teeth, opening the mouth, dry mouth, sticky saliva, coughing and feeling ill), and five yes–no questions (use of painkillers, nutritional supplements, feeding tube, loosing or gaining weight). Higher scores indicate more or more serious symptoms/problems. For the yes/no questions the scores indicate the percentage of yes answers.

The Hospital Anxiety and Depression Scale (HADS) [23] gives a measure for depression (7 items) and anxiety (7 items) in patients with somatic disease. It was used to assess psychological distress. The range for both scales is 0–21. Scores 8–10 indicate possible, and scores >10 indicate a probable depression or anxiety disorder. The scale has good criterion validity and discriminant validity for patients with physical illnesses and shows good sensitivity and specificity for psychological distress in cancer patients [24] and [25].

Data collection

Patients’ HRQoL was measured before start of treatment (baseline), after completion of RT (eRT) and at 3 months, 6 months, 1 year, 2 years and 5 years after start of treatment. The patient completed the first questionnaire at the hospital, the following were sent by mail to the patient with a postage-paid, pre-addressed envelope. If the patient failed to reply, one reminder was sent.

Statistical analysis

To test the difference between the two treatment groups the scores from the EORTC QLQ-C30 and QLQ-H&N35 were reported. To accommodate the repeated nature of the data, a linear mixed-effects model was constructed with treatment and time-effect interactions as fixed effects, and a patient-specific random effect. This model was applied to the data from all randomised patients. Score estimates and standard errors were obtained from the model. The test consisted of a general test for no differences between the two treatment arms at all time points using an overall F-test statistic at a 0.05 level of significance.

For the back to baseline part, scores from the EORTC QLQ-C30 and QLQ-H&N35 were reported as mean values and comparisons within treatment groups were performed with the non-parametric Mann–Whitney test to evaluate changes over time. All reported p values are based on the two-sided hypothesis with p < 0.05 considered to indicate statistical significance.

A final summary descriptive statistic was the percentage of patients reporting a change from baseline of >10-points at any time point. Differences of at least 10 points (on a 0–100 scale) were chosen because these correspond to the minimum clinically meaningful change in the HRQoL parameter [26].

All analyses were performed according to the intention-to-treat principle using the statistical programme PASW Statistics 22.

All available questionnaires filled in by correctly included patients with their active consent were included in the analysis.

Results

The patient and disease characteristics are summarised in Table 1.

Table 1 Characteristics of the patient populations.

CF AF
n = 349 n = 352 p
Age-years Mean 61.7 61.8 0.939
Range 30–86 26–89
 
Sex Male 257 (74%) 265 (75%) 0.635
Female 92 (26%) 87 (25%)
 
Karnofsky index Mean 92.4 92.0 0.697
Range 60–100 50–100
 
Tumour stage 0.471
T1 42 (12%) 49 (14%)
T2 133 (38%) 120 (34%)
T3 101 (29%) 90 (26%)
T4 73 (21%) 93 (26%)
 
Site 0.944
Larynx n (%) 72 (21) 71 (20)
Hypopharynx n (%) 58 (17) 61 (17)
Oris n (%) 50 (14) 48 (14)
Oropharynx n (%) 169 (48) 172 (49)

CF – conventional fractionation.

AF – accelerated fractionation.

No significant differences between groups were reported at baseline with respect to Karnofsky index, age, gender distribution, T-stage and tumour site or results from the questionnaires.

The response rate, shown also as the percentage of the tumour free survivors for every time point, is presented in Table 2.

Table 2 Number of completed questionnaires.

Follow-up CF AF
n = 367 n = 366
Completed (n) Eligible (n) Completed (n) Eligible (n)
Baseline 344 (94%) 367 339 (93%) 366
End of RT 314 (87%) 360 313 (88%) 355
3 months 289 (84%) 346 284 (84%) 340
6 months 258 (80%) 321 261 (85%) 308
1 year 220 (79%) 280 231(82%) 281
2 years 183 (80%) 109 192 (78%) 247
5 years 134 (74%) 182 138 (79%) 174

CF – conventional fractionation, AF – accelerated fractionation, RT – radiotherapy.

The results of EORTC QLQ-C30 and EORTC H&N35 are summarised in Supplementary Table S1. The AF group reported significantly worse HRQoL in the acute phase (i.e. either at eRT or at three months) for the majority of functions and symptoms. The differences between the two groups were significant for 22 of 33 scales at eRT, for 19 after 3 months, and for five after 6 months, Table S1. Fig. 2 illustrates the results over time for some of the scales and symptoms.

gr2

Fig. 2 Trends and differences in HRQoL reported by the accelerated fractionation (AF) and conventional fractionation (CF) groups at all time-points. Higher value on Global health/QoL refers to better HRQoL. Higher value on the symptom score refers to more symptom/worse function. For feeding tube the value is percentage “Yes”. Only significant p-values are reported.

Some symptoms never showed any significant differences between the groups (problems with teeth, dry mouth, coughing, dyspnoea and sleeping). The use of nutritional supplements was also at the same level over time in both groups. The only difference after the 6-month follow-up was detected at the 5-year follow up, when the AF group reported better role function, Table S1.

The number of patients reporting at least one change of >10 points after the baseline are summarised for some of the scores in Table 3. The most frequently reported, clinically relevant deterioration symptom was problems with swallowing at eRT among the AF patients 261/302, 86.4%. The corresponding number for the CF patients was 220/309, 71.2%.

Table 3 Clinically relevant deterioration from baseline in a few chosen scales.

eRT 3 months 1 year 5 years
CF AF CF AF CF AF CF AF
n = 309 n = 302 n = 287 n = 277 n = 217 n = 226 n = 134 n = 137
S ⩾ 10 % S ⩾ 10 % S ⩾ 10 % S ⩾ 10 % S ⩾ 10 % S ⩾ 10 % S ⩾ 10 % S ⩾ 10 %
Swallowing 220 71.2 261 86.4 144 50.2 185 66.8 100 46.1 97 42.9 58 43.3 58 42.3
Pain, local 217 70.2 230 76.2 146 50.9 164 59.2 57 26.3 61 27.0 35 26.1 38 27.7
Senses 254 82.2 244 80.8 214 74.6 187 67.5 138 63.6 135 59.7 65 48.5 66 48.2
Fatigue 28 9.1 18 6.0 41 14.3 39 14.1 58 26.7 74 32.7 44 32.8 51 37.2
Role function 204 66.0 221 73.2 168 58.5 178 64.3 68 31.3 79 35.0 41 30.6 28 20.4
Global health/QoL 189 61.2 219 72.5 157 54.7 160 57.8 61 28.1 70 31.0 31 23.1 32 23.4
Dry mouth 224 72.5 211 69.9 213 74.2 213 76.9 176 79.7 170 75.2 105 78.4 104 75.9
Social eating 232 75.1 240 79.5 173 60.3 186 67.1 100 46.1 103 45.6 49 36.6 49 35.8

n: Patients are evaluable if they have a valid baseline, at least one follow-up assessment and they are on-treatment at the time-point of interest.

S ⩾ 10: Number of patients reporting scores of at least 10 points difference to the score reported at baseline, indicating a clinically relevant deterioration of the symptom.

CFb – conventional fractionation.

AF – accelerated fractionation.

HADS demonstrated no significant differences between the two groups in anxiety and depression level (Table 4), except for a higher level of probable depression in the CF group at the 5-year follow up.

Table 4 Frequency of probable cases on HADS depression and anxiety scale scores.

Symptom/follow-up CF (%) AF (%) p
Depression
Baseline 18 16 0.467
End of RT 17 19 0.139
3 months 19 21 0.800
6 months 18 21 0.681
1 year 21 17 0.189
2 year 21 14 0.189
5 year 24 13 0.039
 
Anxiety
Baseline 20 21 0.476
End of RT 16 19 0.801
3 months 16 20 0.379
6 months 16 12 0.060
1 year 15 14 0.427
2 year 15 16 0.564
5 year 12 13 0.991

CF – conventional fractionation.

AF – accelerated fractionation.

There was a pattern similar for both treatment groups: 11 of the scales, symptoms and functions, returned to baseline levels at the 1-year follow-up. The use of a feeding tube became indistinguishable from baseline after the 2-year follow-up in both groups. The symptom items “feeling ill” and “weight loss” fell to baseline levels for both groups at six months, as did the pain scale of QLQ-C30. Six symptoms related to functional oral intake did not return to baseline levels in either CF or AF.

Differences in returning to baseline levels between the groups were noted for 9 scales. For 6 of these the CF group was at baseline faster, i.e. coughing, use of painkillers, nutritional supplements, emotional and cognitive function and financial problems. The AF group recuperated faster for nausea/vomiting, sleeping disturbances and diarrhoea.

The global QoL scale reached baseline level at the 1-year follow-up for the AF group, while the CF group was already significantly above the baseline at the 1-year follow-up. The AF group was significantly over the baseline level at the 2-year follow-up.

Social eating reached baseline level at the 5-year follow-up for both groups. At the 5-year follow up five differences related to baseline were still seen. The AF group reported better than baseline regarding problems with speech, social functioning, gaining weight and diarrhoea. The CF group reported significantly less local pain than at baseline. At five years both groups reported significantly better function than baseline for 12 scales, at baseline levels for 10, and significantly worse than baseline level for 6 of the scales, symptoms and functions.

Discussion

When assessing the efficacy for different treatment regimens, survival is regarded as the most important outcome. For the patient, the cost in terms of side effects and lowered HRQoL is also very important and should always be evaluated together with survival benefits and locoregional tumour control when decision about treatment modality is made.

In this randomised study two radiotherapy regimens were compared with regard to the patients’ reported HRQoL. The main HRQoL differences were found in the acute phase and showed a more reduced HRQoL in the AF group.

No grouping according to survival, site, gender, or age was done is this study because there were no differences between the groups from the beginning, and the main objective for the study was to identify difference in HRQoL between the two treatment arms.

The frequency of surgery and neck dissection post radiotherapy was not significantly different between the two groups [17]. This stresses that the differences in HRQoL between the groups were related to the given radiotherapy.

During the follow-up, two periods could be identified, an acute phase dominated by reduced HRQoL, and a late phase characterised by recovery. In the acute phase, patients in the AF group had a significantly greater burden of side effects from treatment during the first three months. The greatest differences for the patients in the AF group were more pain and greater use of painkillers. They also reported greater difficulties in swallowing and greater need for a feeding tube. After termination of radiotherapy they were also more fatigued and reported lower physical and global health than patients in the CF group. Opening mouth and eating socially were also more troublesome for patients in the AF group than for the CF patients immediately post-treatment.

In studies comparing two treatment regimens the early time points chosen for answering questionnaires influence the HRQoL outcome. In the present study the 3-month time point was almost two months post-treatment for the AF group and only slightly more than one month after termination of radiotherapy for the CF group. This strengthens the significant differences in HRQoL at three months. It shows that the AF group did not only experience more negative impact on their HRQoL but also possibly for a longer time after treatment. For the physician it is crucial to be aware of the course of side effects of radiotherapy and its impact on HRQoL to adequately inform the patient before and during treatment. It is also critical to know what problems are expected and which might be warning signs for recurrence of disease.

To our knowledge there is only one earlier large-scale study comparing HRQoL in patients receiving conventional or accelerated RT [27]. In the prospective randomised CHART study, comparing CF (2 Gy, 6 weeks, total 60 Gy) to hyperfractionated accelerated continuous RT (1.5 Gy, three times a day, 12 consecutive days, total 54 Gy) the HRQoL of 615 patients was evaluated with a modified Rotterdam Symptom checklist. The results are partly in line with the findings in the present study; pain was a problem in the accelerated regimen and HADS did not show any difference initially.

The results of the present study confirm some of the observations made from the HARDWINS study [28] and [29]. In that prospective dose-escalation study, a total of 169 (171) patients were given hyperfractionated accelerated RT. Three different treatment schedules were used; 1.5, 1.55 and 1.6 Gy fractions, given twice daily, five days a week for four weeks up to 60, 62 and 64 Gy, respectively. HRQoL was evaluated using FACT H&N at baseline (n = 148) and at 6 and 12 months post treatment. The largest differences between the two radiation modalities shown in the present study, i.e. the acute reactions, noted at the end of treatment and at three months after start of treatment, were not evaluated in the HARDWINS study.

The GORTEC study [30] was a prospective randomised study that compared CF (2 Gy fractions, 48 days, total 70 Gy) to very AF (2 + 2 Gy fractions, 22 days, total 63 Gy) and including 266 patients. Feeding tube use was observed in 89% of the patients in the AF group and in 41% in the CF group. In the present study there was also a difference between the groups. Feeding tube use at eRT for the AF group was 64%, and for the CF group it was 42%.

The RTOG 9003 study [10] was a prospective randomised study comparing CF (2 Gy, 35 days over 7 weeks) to hyperfractionated, split accelerated- and continuous accelerated fractionated RT (1.8 Gy daily, 6 weeks, last 12 days + 1.5 in the afternoon, total 72 Gy). Among the disease-free survivors at one year after treatment, 13% of the patients in the continuous accelerated fractionated group had used a feeding tube, which is about the same as in the present study, 15%.

The benefit for the patient treated with AF – a shorter treatment period – seems to be offset by the more severe acute radiation reaction and the treatment of the side effects which might demand more and longer hospitalisation. In the GORTEC trial [30], hospitalisation occurred more frequently in the AF group, but the stays were significantly shorter. An earlier study also showed more frequent hospitalisation in the AF group, but the total number of hospital days was about the same in the CF group [31]. A subsequent paper from the same study explained: “mucosal reactions were more severe, occurred earlier and settled faster in the AF arm” [15].

There are also administrative or logistic aspects for accelerated fractionation. The fixed interval between fractions using AF requires that the first treatment must be given early to be followed by the second, which make initial commuting to the treatment centre difficult. On the other hand, this could be balanced by the shortened overall treatment time. Nothing in the present study pinpointed this effect on HRQoL.

The patients were followed with three different questionnaires for five years. One peculiar difference with respect to the questionnaires was noted. The QLQ-C30 emotional function scale consists of four questions asking the patient to evaluate tension, worry, irritation and depression. For the CF group, this remained stable during the acute phase whereas the AF group had a significant dip after RT was completed. HADS did not show this difference; it was stable although the questions seem similar. This may indicate that HADS is less sensitive for anxiety and depression in head and neck cancer patients early post treatment. Still, at the 5-year follow up, no difference was detected in QLQ-C30, while HADS showed a difference in probable depression cases.

As in a previous study [32], there was a difference between the pain scales of QLQ-C30 and H&N35. In the present study the former returned to baseline level faster than the latter. This is explained by the original questions. In QLQ-C30 general pain and limitations due to pain are sought after, whereas in the H&N35 the more specific pains in the mouth, jaw and pharynx are of interest.

Conclusion

In this study, which compared two radiotherapy fractionation regimens, conventional and accelerated, HRQoL was more reduced in the acute phase in the AF group. Few long-term differences were seen. With time HRQoL reached similar levels for both groups, with the exception of functional oral intake.

Funding

Swedish Cancer Society, Laryngfonden (Sweden), Lions Cancer Research Foundation at Umeå Universitet, the Cancer Research Foundation of Northern Sweden, Swedish Association for Otorhinolaryngology, Head and Neck Surgery.

The study sponsors had no involvement in the study or manuscript.

Conflict of interest statement

All individual authors agree on the submission of the article.

The question of conflicts of interest has been individually answered with “None” by all authors.

The study sponsors had no involvement in the study or manuscript.

Acknowledgments

This work was supported by grants from the Swedish Cancer Society, the Cancer Research Foundation of Northern Sweden, Laryngfonden (Sweden) and the Stockholm Cancer Society. The study was made possible by the commitment from the staff at all the participating centres in the ARTSCAN study: Umeå University Hospital, Lund University Hospital, Karolinska University Hospital, Stockholm, Sahlgrenska University Hospital, Göteborg, Örebro University Hospital, Karlstad Central Hospital, Linköping University Hospital, Gävle hospital, Ryhov County Hospital, Jönköping, Uppsala University Hospital.

Appendix A. Supplementary data

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Supplementary Table S1 Mean scores. SE and differences for EORTC QLQ-C30 and H&N35 function scales. Symptom scales and symptoms.

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Footnotes

a Department of Otolaryngology and Head and Neck Surgery, Skåne University Hospital, Lund, Sweden

b Department of Clinical Science Otolaryngology and Head and Neck Surgery, Umeå University, Sweden

c Department of Nursing, Umeå University, Sweden

d Department of Otolaryngology and Head and Neck Surgery, Uppsala University Hospital, Sweden

e Department of Otolaryngology and Head and Neck Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden

f Department of Oncology and Radiation Physics, Skåne University Hospital, Lund University, Sweden

g Department of Radiation Sciences, Oncology, Umeå University, Sweden

h Department of Oncology, Karolinska University Hospital, Stockholm, Sweden

i Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden

j Department of Clinical Oncology, Karlstad Central Hospital, Sweden

k Department of Oncology, Ryhov County Hospital, Jönköping, Sweden

l Department of Oncology, Örebro University Hospital, Sweden

Corresponding author at: Öron-näs-och halskliniken, Skånes Universitetssjukhus, Lasarettsgatan 21, 221 85 Lund, Sweden.


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