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Low Post-treatment Quality of Life and the High Incidence of Pain are Common and Significantly Exacerbated in Depressed Head and Neck Patients Treated with Definitive Accelerated Radiotherapy

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27 September 2023

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Abstract
(1) Background: The goal of the study was to evaluate psychological tolerance and health-related quality of life (QOL) in head and neck (HN) cancer patients treated with definitive accelerated radiotherapy (DART); (2) Methods: Seventy-six recurrence-free patients eligible for the study, who were treated with DART in the CAIR-2 phase III clinical study (median of follow-up=47 months), completed EORTC QLQ-C30 with H&N35 module, Hospital Anxiety and Depression Scale (HADS) and Visual–Analog Scales (VAS) of pain in HN and the neck / arm area.; (3) Results: The most dominating symptoms measured with QLQ-C30 were: fatigue (44/100), sleeplessness (39/100), financial problems (38/100) and pain (32/100). Within H&N35 the highest scores were reported on the subscales of sticky saliva (60/100), mouth dryness (65/100) and increased intake of painkillers (50/100). Pain (VAS) was reported by 87% (HN area) and 78% (shoulder) of the patients, with a mean score of 3/10. One-third reported depressive mood (HADS≥15 points) with an average score of 12.5/42 p. The depressed group, who smoked more as compared to non-depressed before DART (96% vs 78%) and required steroids treatment (85% vs 58%) during DART, also scored significantly worse on 23 of 35 subscales of QLQ-C30 and H&N35 and experienced more intense pain (VAS). Women, and less advanced patients scored better in several aspects of the quality of life; (4) Conclusions: Patients treated with DART struggle with low quality of life and persisting treatment-related symptoms including constant pain. HNC survivors, especially those, who are depressed, may require additional psychosocial, rehabilitation and medical intervention programs..
Keywords: 
Subject: Medicine and Pharmacology  -   Oncology and Oncogenics

1. Introduction

Most quality-of-life studies of head and neck cancer survivors showed that the patients are struggling with distress, depression, pain and a large variety of persisting cancer-related symptoms. Quality of life domains like the global quality of life, pain, eating and speech problems [1,2,3,4] were associated with survival in HN. Shorter overall survival is also present in the case of pre-existing depression or depressive states [5,6].
The 3-40% prevalence of depression after treatment of HNC was noted in various studies [7]. Depression and distress were found during the first year after treatment [8] and also during the long time of follow-up [9,10,11]. The advanced disease, being unmarried, and helpless/hopeless coping strategies were predictors of depressed mood in the head and cancer [12]. More depressive symptoms in HNC survivors were also found in groups with moderate to severe dysphagia [13] and in patients with a gastrostomy tube [14].
Persisting or worsening treatment-related symptoms after treatment of HNC were reported in various prospective studies [15,16,17,18,19]. In a large cross-sectional study of 640 HNC cancer survivors (median of follow-up 4,3 years) dry mouth, sticky saliva and teeth problems were the most severe symptoms reported by the patients [20]. Intimacy problems and sexual dysfunctions were reported by 25% of patients after primary HNC treatment [21].
Modification of the standard radiotherapy (once a day for five days a week, fractionation dose of 1.8 to 2 Gy, for five to seven weeks) in head and neck cancer patients entails an increase in the severity of acute (observed during and shortly after treatment) radiation-induced toxicities, mainly mucositis. However, in most reports, the incidence and intensity of late complications (xerostomia, tissue fibrosis, taste impairment) remain similar in patients after standard radiotherapy and those treated with the use of various ways of modifying standard treatment (hyperfractionation, accelerated fractionation, accelerated hyperfractionation) [22,23,24,25,26].
Meta-analysis of 6515 head and neck cancer patients from 15 different studies who were treated with different types of altered fractionated radiotherapy showed that it can improve both survival and locoregional control [25]. Although hyperfractionated or accelerated radiotherapy with or without total dose reduction gained a lot of scientific attention, there are only a few studies that explored the detailed quality of life and/or psychological tolerance of altered fractionated radiotherapy using various measurement tools.
Several existing studies on hyperfractionated radiotherapy using different measurement methods showed no differences in most dimensions of QOL after treatment between conventionally and hyperfractionated groups [11,27,28,29]. The longitudinal study comparing accelerated versus conventional radiotherapy in 750 HNC patients showed the worse quality of life in the AR group at the end of radiotherapy, with most differences observed three, several at and six months and five years later. Oral functions have never reached the baseline level in both groups [30]. Detailed quality of life in definitive accelerated radiotherapy was also described in another two studies [31,32] but they were difficult to analyse due to group heterogeneity (several patients received chemotherapy or/and had neck dissection.
Noteworthy, the late toxicities of radiotherapy can be assessed by using various scales, such as LENT/SOMA, RTOG/EORTC, and NCI-CTC. Therefore, the observed severity of late complications may vary depending on the selected reporting method [33 Denis et al. 2003]. Subscales in the above-mentioned scales do not consider psychological and socio-economic factors. After all, the quality of life after radiotherapy is a result not only of the observed morphological or functional defects but also of accompanying diseases (somatic and mental), lifestyle (nutrition, smoking), or the already mentioned aspects related to the economic status of patients.
Although there are a few publications on detailed quality of life after hyperfractionated radiotherapy of HNC patients, up till now no such publications are focused exclusively on Definitive Accelerated Radiotherapy in HNC without any chemotherapy or surgery. There are no QOL studies concerning further psychological evaluation that would be more detailed than basic QOL in HNC patients treated with DART. The purpose of the study was to examine the quality of life and psychological tolerance of patients who were treated with definitive accelerated radiotherapy.

2. Materials and Methods

This is a cross-sectional survey of HNC patients with follow-ups longer than 12 months. All patients included in this study took part in the CAIR-2 phase III clinical trial [34] guided in the Ist Radiotherapy Department, Comprehensive Cancer Center Marie Skłodowska-Curie Institute of Oncology Gliwice Branch. All patients with squamous cell carcinoma of head and neck in Stage T(2-4)N(0-1)M(0) received two definitive radiation treatments: accelerated fractionation 7 days a week including weekends (CAIR) or 7 fractions 5 days a week (Concomitant Boost, CB). Fractionation parameters remained within the ranges: 66.6-72 Gy of the total dose, 37-40 fractions and 37-40 days. Most of the patients had received conformal radiotherapy (2D – 14%, 3D – 45%, IMRT-25%, 3D+IMRT-16%), see Table 1.
Due to results showing that weekend breaks have no impact on treatment outcome if radiotherapy is accelerated [34], with the same dose and treatment time, the quality of life scores of CB and CAIR groups were analysed as one DART group altogether. For patients’ initial characteristics see Table 1.
Out of 184 patients who were treated with DART in the years 1995-2006, 24 of them were deceased at the time of the study. All the patients who agreed to take part in the study signed the written consent and agreed to fill out the set of psychological and QOL tests. Seventy-eight patients were sent back or brought filled questionnaires. Two patients were excluded from the study because of secondary cancers. The follow-up time median was 47 months after completing the treatment varying from 12 to 158 months (ibid.).
Observer-based scoring systems like the DAHANCA toxicity score or CTCAE are not recognizing many symptoms of HN patients contrary to the quality of life scales which refer to their own complaints [35]. Therefore detailed QOL research in head and neck cancer requires the usage of patient-based surveys, especially in clinical trials. Quality of life research on head and neck cancer may be currently measured with 13 measurement tools designed exclusively for HNC patients [36]. Researchers are also using general quality-of-life questionnaires like for example the EORTC QLQ-C30 for cancer patients or SF-36 for the general population.
Instruments selected for this study are well-known tools measuring the quality of life, pain and psychological status of patients. Health-related quality of life of HNC patients was measured with the EORTC QLQ-C30 with head and neck module H&N35 [37,38]. Scores of QLQ-C30 and H&N35 range from 0 to 100. The higher are scores on functional subscales of QLQ-C30, the better the patient's functioning. Scores of H&N35 are symptom scales, so a higher result means that the symptom is more severe.
Baseline T and N status and patient’s gender were used as independent data to compare the intergroup differences in QOL and treatment-related data. Quality-of-life outcomes of the DART group were compared to the results of 640 HNC patients with a similar median follow-up [20] who completed QLQ-C30 and H&N35 and were treated with different types of radiotherapy with doses ranging from 54 to 79 Gy. A subgroup of 359 patients (67%) received the dose>70,2 GY, 371 patients were treated by 2DRT and 269 patients by conformal RT (3DCRT: 127 patients, IMRT: 142 patients). The clinically significant differences – of 10 points and more [38] between the groups in all QLQ-C30 subscales were analysed.
Two VAS scales, ranging from 0 to 10 points [40] were used to evaluate pain intensity in the head/neck area and, separately, in the shoulder area.
Depression and anxiety were examined with HADS - Hospital Anxiety and Depression Scale [41, 42]. HAD scale is recognized as a sensitive instrument to screen for depressive symptomatology in HNC [43] Sum of anxiety and depression subscales was also examined, 15 points are the cut-off score for recognizing major depression in HNC patients (ibid.). Patient’s QOL and VAS outcomes, initial characteristics including age, gender, marital status, education, smoking, TNM, presence of cancer symptoms before diagnosis, time from diagnosis to treatment ZUBROD, dose, irradiation method, corticosteroids and analgesics intake, dysphagia (see tab1) were analysed using the HADS cut-off score. Data were analysed with the non-parametric method – the Mann-Whitney U test.

3. Results

Patients reached the highest scores in role (85/100), social (79/100) and cognitive functioning (73/100) subscales. Fatigue (44/100), insomnia (39/100) and financial problems (38/100) were the most severe symptoms of QLQ-C30 reported by the patients. Out of the scores of H&N35, mouth dryness (65/100), sticky saliva (61/100) and painkillers intake (50/100) were the most severe symptoms, see Table 2. As compared to the large HNC survivors group who completed radiotherapy with similar time of the follow-up [20], DART group scored worse significantly worse with 10 points or more - a clinically significant difference, [39] in physical, emotional and financial functioning, the intensity of fatigue, insomnia, sexuality, dry mouth, sticky saliva and coughing.
Inter-group differences were analysed in all treatment-related, biological, QOL, and psychosocial variables (see tab 1) using such grouping factors as gender, T and N stage and cut off score for the depression (clinically relevant overall HADS score ≥15 points). All statistically significant results are presented in Table 3. Results for all groups are presented as means, not medians, due to the character of single-item questions of QLQ-C30 and H&N35 modules where the median is always 1 or 0.
Women initially lost less weight during radiotherapy as compared to men. They reported a lower frequency of pain in the head and neck area measured by the H&N35 subscale (p<0,05), fewer swallowing problems (p<0,01), and fewer problems with eating in the public (p<0,05). Men reported also more severe appetite loss (p<0,05) and more problems with sticky saliva (p<0,05, Table 3).
Two groups of 42 patients with T2 and 34 patients with T3 and T4 categories were analysed. Patients with a more advanced T category reported significantly worse cognitive functioning (p<0,05), more problems with opening the mouth (p<0,01), with speech (p<0,02) and also with social eating (p<0,02). They also reported more frequent pain in the head and neck area (p<0,05). Patients with N0 advancement (n=52) were compared to the N1 group (n=24). Nodal advancement was associated with worse cognitive functioning (p<0,05), problems with the opening mouth (p<0,02) and feeling senses (p<0,01), trouble with social eating (p<0.01) and dysphagia (p<0,05) during the treatment (see Table 3).
The intensity of pain in the head and neck (HN) area scored 3.4 on the VAS scale (1-3 points pain on 0-10 VAS is considered a weak pain). The pain in the shoulder area both scored 2,9. Only 10 patients (13%) didn't report any pain. That suggests that the majority of patients experienced some kind of HN pain. A very intense HN pain (7-10p) was reported by 10% of patients. Pain in the shoulder was reported by 78% of patients. In most cases, the intensity of pain was weak or moderate (see Table 4).
The analysis revealed a low average level of depression and anxiety in the whole group (below 8 points - 6/21p and 7/21p respectively). The clinically significant level of overall HADS score (15 points and more, [37] signifying possible major depression was reached by 27% of patients. The mean result was 12.25 points – below the cut-off score (Table 4).
Comparing the depressed group (27%) to the non-depressed has revealed many significant differences within variables like smoking before treatment, corticosteroids intake during and directly post-treatment, quality of life data, emotional states and traits and pain. They reported worse social, emotional and cognitive functioning and lower global health status. The intensity and frequency of pain were greater in the depressed group. Treatment-related symptoms except the pain were also more frequent in the depressed group including fatigue, insomnia, appetite loss, swallowing, speech, social eating and contact, mouth opening, mouth dryness, sticky saliva, deterioration of sexuality, coughing, painkillers intake and weight loss, scoring worse in 23 subscales out of 35 in QLQ-C-30 and H&N35. The depressed were smoking before DART and they had to take corticosteroids during and right after DART more often than non-depressed. Patients' initial biological characteristics and medical status 3,5y after the survey timeline didn't differ in both subgroups. Statistically significant differences are listed in Table 5.

4. Discussion

The experience of persisting pain dominates among other symptoms despite using painkillers and coming to follow-up visits. A large majority of DART-treated patients reported pain in the head/neck and shoulder area (87% and 78% respectively). Other studies on quality of life in HNC also showed that pain and other treatment-related symptoms are persisting or worsening during follow-ups longer than 1 year [15,17,18,19]. The pain in the DART group both in the HN area and arm and shoulder after cancer treatment persisted or possibly deteriorated over the years after the treatment. A meta-analysis of 82 studies evaluating pain in HNC patients treated according to various schemes estimated the incidence of any pain in 57% of patients before treatment and 42% after the treatment [44]. This result shows a much better outcome than the results of DART patients, where intensification of pain in the head and neck area concerned almost all of the examined patients. The intensity of pain in the analysed DART group was also found to be higher than in another study of the severity of pain in patients with HNC before and after radiation treatment with VAS up to 24 months after the treatment [45].
Persisting treatment–related symptoms are consistent with already existing research on QOL in H&N. Patients scored high on QOL dimensions such as functioning in the role, social and cognitive areas. Fatigue, insomnia and financial difficulties were the most common symptoms from QLQ-C30 subscales reported by patients treated with DART. Sticky saliva, mouth dryness and painkillers intake had the highest scores out of all subscales from the H&N35 module. Generally, the patients were functioning better in social, emotional and cognitive dimensions as compared to treatment-related ailments.
As compared to a large sample of HNC survivors from the Leung et al. study (see tab. ) with a similar median of follow-up but with several different irradiation types [20], DART patients reported worse functioning in most analysed QoL dimensions except for global health status, social functioning and mouth opening. DART patients scored significantly worse – with more than 10 points [39] on subscales of physical functioning, emotional functioning, fatigue, pain, insomnia, and financial difficulties. The largest, clinically relevant differences within treatment-specific symptoms (H&N35) between DART and the other group were found on subscales evaluating sticky saliva, dry mouth, coughing, and diminished sexuality.
These results might be corresponding to a quality of life study comparing accelerated fractionation to conventional by Nyqvist et al [30]. The reduction of the treatment time resulting in dose intensification is directly related to persistently low quality of life outcomes.
Reasons for gender differences in quality of life and psychological outcome remain unclear. Different QoL studies present contradictory results while comparing the QoL of men and women treated for HNC [46, 47]. Inter-group differences depending on T and N status seem to be mostly associated with more intensive treatment in case of more advanced disease.
Although the mean results on depression, anxiety or overall HADS score were below the clinically relevant score, one-third (27 % of the patients) scored more than 15 points of the major depression cut-off score. That shows that one-third of this group had a poor psychological outcome. Results comparing depressed and non-depressed groups revealed many significant differences in quality of life subscales, emotional states and pain. Deterioration of quality of life and increased pain are linked to depression in cancer. [48,49,50].
More common corticosteroid intake during DART in the depressed group suggests that their treatment caused more intensive symptoms of acute mucositis and might have been more difficult to bear. Previous intake of corticosteroids by cancer patients is linked to depressive symptomatology following such treatment. [51].
The depressed DART group significantly admitted more often to smoking before the treatment. Prevalence of depressive symptoms is also often related to fear of recurrence in head and neck cancer survivors which might be one of the possible reasons [52,53]. Level of cigarette consumption was a predictor of psychological distress 15 months after treatment in head and neck cancer survivors. Smoking was also linked to baseline distress and fear of recurrence [54].
A review of existing research on the comorbidity of pain and depression showed that pain and depression occur simultaneously in approximately 35% of patients (22-49%) [55]. A longitudinal study examining the relationship between the occurrence of pain and mood disorders in cancer patients also showed the interdependence of both symptoms. Patients responding well to analgesic treatment (61%) had significantly lower HADS scores within a few weeks, unlike people who had no improvement in pain [56]

5. Conclusions

All results from this cross-sectional study allow drawing limited conclusions only. Nevertheless, patients treated with DART struggle with low quality of life and persisting treatment-related symptoms including constant pain. Pain and multifaceted psychological and somatic ailments dominate the profile of self-rated quality of life.
The intensity of distress/depression strongly affects patients’ perception and reception of post-treatment symptoms and general functioning. Both facts are consistent with the quality of life research on HNC survivors after different kinds of treatment. The presence of depression in DART co-exists with intensive post-treatment oral symptoms, weight loss, and lower QOL. The level of self-rated depression and distress might be the factor distinguishing between the patient who can receive standard and the one who needs non-standard, more intensive care. Screening for distress/depression should become part of conventional follow-up visits after DART. HNC survivors, who are depressed, may require additional psychosocial, physiotherapeutic and medical intervention programmes.

Funding

This study did not receive any funding.

Author Contributions

Conceptualization: K.S. and A.H.; methodology and software: K.S. and A.H.; validation: A.H., D.K.B., A.W., K.S.; formal analysis: A.H., D.K.B., A.W., K.S.; investigation: K.S. and A.H.; resources: K.S. and A.H.; data curation: A.H. ; writing—original draft preparation: A.H..; writing—review and editing: A.W., K.S., D.K.B ; visualization: A.H. and D.K.B..; supervision: K.S. and A.W. All authors have read and agreed to the published version of the manuscript.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Acknowledgments

There was no support given.

Conflicts of Interest

All authors declare that they have no conflict of interest.

References

  1. Oskam IM, Verdonck-de Leeuw IM, Aaronson NK, Kuik DJ, de Bree R, Doornaert P, Langendijk JA, Leemans CR. Quality of life as predictor of survival: a prospective study on patients treated with combined surgery and radiotherapy for advanced oral and oropharyngeal cancer. Radiother Oncol. 2010 Nov;97(2):258-62. [CrossRef]
  2. Scharpf J, Karnell LH, Christensen AJ, Funk GF. The role of pain in head and neck cancer recurrence and survivorship. Arch Otolaryngol Head Neck Surg. 2009 Aug;135(8):789-94. [CrossRef]
  3. Karvonen-Gutierrez CA, Ronis DL, Fowler KE, Terrell JE, Gruber SB, Duffy SA. Quality of life scores predict survival among patients with head and neck cancer. J Clin Oncol. 2008 Jun 1;26(16):2754-60. [CrossRef]
  4. Morton RP, Davies AD, Baker J, Baker GA, Stell PM. Quality of life in treated head and neck cancer patients: a preliminary report. Clin Otolaryngol Allied Sci. 1984 Jun;9(3):181-5. [CrossRef]
  5. Van der Elst S, Bardash Y, Wotman M, Kraus D, Tham T. The prognostic impact of depression or depressive symptoms on patients with head and neck cancer: A systematic review and meta-analysis. Head Neck. 2021 Nov;43(11):3608-3617. [CrossRef]
  6. Jansen F, Verdonck-de Leeuw IM, Cuijpers P, Leemans CR, Waterboer T, Pawlita M, Penfold C, Thomas SJ, Waylen A, Ness AR. Depressive symptoms in relation to overall survival in people with head and neck cancer: A longitudinal cohort study. Psychooncology. 2018 Sep;27(9):2245-2256. [CrossRef]
  7. Lee Y , Chien Ch , Fang F , Lin P, Prevalence and Risk Factors of Depression in Patients With Head and Neck Cancer: A Literature Review International Journal of Head and Neck Science 3(3): 140-151, 2019 . [CrossRef]
  8. Hammerlid E, Ahlner-Elmqvist M, Bjordal K, Biörklund A, Evensen J, Boysen M, Jannert M, Kaasa S, Sullivan M, Westin T. A prospective multicentre study in Sweden and Norway of mental distress and psychiatric morbidity in head and neck cancer patients. Br J Cancer. 1999 May;80(5-6):766-74. [CrossRef]
  9. Pourel N, Peiffert D, Lartigau E, Desandes E, Luporsi E, Conroy T. Quality of life in long-term survivors of oropharynx carcinoma. Int J Radiat Oncol Biol Phys. 2002 Nov 1;54(3):742-51. [CrossRef]
  10. Singer S, Danker H, Dietz A, Hornemann B, Koscielny S, Oeken J, Matthäus C, Vogel HJ, Krauss O. Screening for mental disorders in laryngeal cancer patients: a comparison of 6 methods. Psychooncology. 2008 Mar;17(3):280-6. [CrossRef]
  11. Bjordal K, Kaasa S. Psychological distress in head and neck cancer patients 7-11 years after curative treatment. Br J Cancer. 1995 Mar;71(3):592-7. [CrossRef]
  12. Kugaya A, Akechi T, Okamura H, Mikami I, Uchitomi Y. Correlates of depressed mood in ambulatory head and neck cancer patients. Psychooncology. 1999 Nov-Dec;8(6):494-9. [CrossRef]
  13. Nguyen NP, Frank C, Moltz CC, Vos P, Smith HJ, Karlsson U, Dutta S, Midyett A, Barloon J, Sallah S. Impact of dysphagia on quality of life after treatment of head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2005 Mar 1;61(3):772-8. [CrossRef]
  14. El-Deiry MW, Futran ND, McDowell JA, Weymuller EA Jr, Yueh B. Influences and predictors of long-term quality of life in head and neck cancer survivors. Arch Otolaryngol Head Neck Surg. 2009 Apr;135(4):380-4. [CrossRef]
  15. Abendstein H, Nordgren M, Boysen M, Jannert M, Silander E, Ahlner-Elmqvist M, Hammerlid E, Bjordal K. Quality of life and head and neck cancer: a 5 year prospective study. Laryngoscope. 2005 Dec;115(12):2183-92. [CrossRef]
  16. Chaukar DA, Walvekar RR, Das AK, Deshpande MS, Pai PS, Chaturvedi P, Kakade A, D'Cruz AK. Quality of life in head and neck cancer survivors: a cross-sectional survey. Am J Otolaryngol. 2009 May-Jun;30(3):176-80. [CrossRef]
  17. Nordgren M, Abendstein H, Jannert M, Boysen M, Ahlner-Elmqvist M, Silander E, Bjordal K, Hammerlid E. Health-related quality of life five years after diagnosis of laryngeal carcinoma. Int J Radiat Oncol Biol Phys. 2003 Aug 1;56(5):1333-43.
  18. Nordgren M, Jannert M, Boysen M, Ahlner-Elmqvist M, Silander E, Bjordal K,Hammerlid E. Health-related quality of life in patients with pharyngeal carcinoma: a five-year follow-up. Head Neck. 2006 Apr;28(4):339-49. [CrossRef]
  19. Nordgren M, Hammerlid E, Bjordal K, Ahlner-Elmqvist M, Boysen M, Jannert M.,Quality of life in oral carcinoma: a 5-year prospective study. Head Neck. 2008Apr;30(4):461-70. [CrossRef]
  20. Wan Leung S, Lee TF, Chien CY, Chao PJ, Tsai WL, Fang FM. Health-related quality of life in 640 head and neck cancer survivors after radiotherapy using EORTC QLQ-C30 and QLQ-H&N35 questionnaires. BMC Cancer. 2011 Apr 12;11:128.
  21. Low C, Fullarton M, Parkinson E, O'Brien K, Jackson SR, Lowe D, Rogers SN.Issues of intimacy and sexual dysfunction following major head and neck cancer treatment. Oral Oncol. 2009 Oct;45(10):898-903. [CrossRef]
  22. Fu KK, Pajak TF, Trotti A, Jones CU, Spencer SA, Phillips TL, Garden AS, Ridge JA, Cooper JS, Ang KK. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys. 2000 Aug 1;48(1):7-16. [CrossRef]
  23. Overgaard J, Hansen HS, Specht L, Overgaard M, Grau C, Andersen E, Bentzen J, Bastholt L, Hansen O, Johansen J, Andersen L, Evensen JF. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet. 2003 Sep 20;362(9388):933-40. [CrossRef]
  24. Skladowski K, Maciejewski B, Golen M, Pilecki B, Przeorek W, Tarnawski R. Randomized clinical trial on 7-day-continuous accelerated irradiation (CAIR) of head and neck cancer - report on 3-year tumour control and normal tissue toxicity. Radiother Oncol. 2000 May;55(2):101-10.
  25. Bourhis, J., Lapeyre M., Tortochaux J., Rives M., Aghili M., Bourdin S., Benhamou, E. (2006). Phase III randomized trial of very accelerated radiation therapy compared with conventional radiation therapy in squamous cell head and neck cancer: a GORTEC trial. Journal of clinical oncology, 24(18), 2873-2878. [CrossRef]
  26. Denis F, Garaud P, Bardet E, Alfonsi M, Sire C, Germain T, Bergerot P, Rhein B, Tortochaux J, Oudinot P, Calais G. Late toxicity results of the GORTEC 94-01 randomized trial comparing radiotherapy with concomitant radiochemotherapy for advanced-stage oropharynx carcinoma: comparison of LENT/SOMA, RTOG/EORTC, and NCI-CTC scoring systems. Int J Radiat Oncol Biol Phys. 2003 Jan 1;55(1):93-8. [CrossRef]
  27. Griffiths GO, Parmar MK, Bailey AJ. Physical and psychological symptoms of quality of life in the CHART randomized trial in head and neck cancer: short-term and long-term patient reported symptoms. CHART Steering Committee. Continuous hyperfractionated accelerated radiotherapy. Br J Cancer. 1999 Dec;81(7):1196-205. [CrossRef]
  28. Hammerlid E, Mercke C, Sullivan M, Westin T. A prospective quality of life study of patients with laryngeal carcinoma by tumor stage and different radiation therapy schedules. Laryngoscope. 1998 May;108(5):747-59. [CrossRef]
  29. Ringash J, Lockwood G, O'Sullivan B, Warde P, Bayley A, Cummings B, Kim J, Sellmann S, Waldron J. Hyperfractionated, accelerated radiotherapy for locally advanced head and neck cancer: quality of life in a prospective phase I/II trial. Radiother Oncol. 2008 May;87(2):181-7. [CrossRef]
  30. Nyqvist J, Fransson P, Laurell G, Hammerlid E, Kjellén E, Franzén L, Söderström K, Wickart-Johansson G, Friesland S, Sjödin H, Brun E, Ask A, Nilsson P, Ekberg L, Björk-Eriksson T, Nyman J, Lödén B, Lewin F, Reizenstein J, Lundin E, Zackrisson B. 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. Radiother Oncol. 2016 Feb;118(2):335-41. [CrossRef]
  31. Allal AS, Dulguerov P, Bieri S, Lehmann W, Kurtz JM. Assessment of quality of life in patients treated with accelerated radiotherapy for laryngeal and hypopharyngeal carcinomas. Head Neck. 2000 May;22(3):288-93.
  32. Allal AS, Nicoucar K, Mach N, Dulguerov P. Quality of life in patients with oropharynx carcinomas: assessment after accelerated radiotherapy with or without chemotherapy versus radical surgery and postoperative radiotherapy. Head Neck.2003 Oct;25(10):833-9; discussion 839-40. [CrossRef]
  33. Denis F, Garaud P, Bardet E, Alfonsi M, Sire C, Germain T, Bergerot P, Rhein B, Tortochaux J, Oudinot P, Calais G. Late toxicity results of the GORTEC 94-01 randomized trial comparing radiotherapy with concomitant radiochemotherapy for advanced-stage oropharynx carcinoma: comparison of LENT/SOMA, RTOG/EORTC, and NCI-CTC scoring systems. Int J Radiat Oncol Biol Phys. 2003 Jan 1;55(1):93-8. [CrossRef]
  34. Skladowski K, Hutnik M, Wygoda A, Golen M, Pilecki B, Przeorek W, Rutkowski T, Lukaszczyk-Widel B, Heyda A, Suwinski R, Tarnawski R, Maciejewski B. Radiation-free weekend rescued! Continuous accelerated irradiation of 7-days per week is equal to accelerated fractionation with concomitant boost of 7 fractions in 5-days per week: report on phase 3 clinical trial in head-and-neck cancer patients. Int J Radiat Oncol Biol Phys. 2013 Mar 1;85(3):741-6. [CrossRef]
  35. Jensen K, Bonde Jensen A, Grau C, The relationship between observer-based toxicity scoring and patient assessed symptom severity after treatment for head and neck cancer. A correlative cross sectional study of the DAHANCA toxicity scoring system and the EORTC quality of life questionnaires, Radiotherapy and Oncology 78 (2006) 298–305. [CrossRef]
  36. Murphy BA, Ridner S, Wells N, Dietrich M. Quality of life research in head and neck cancer: a review of the current state of the science. Crit Rev Oncol Hematol. 2007 Jun;62(3):251-67. [CrossRef]
  37. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JCJM, Kaasa S, Klee MC, Osoba D, Razavi D,Rofe PB, Schraub S, Sneeuw KCA, Sullivan M, Takeda F.The European Organisation for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology.Journal of the National Cancer Institute 1993; 85: 365-376.
  38. Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition).Published by: European Organization for Research and Treatment of Cancer,Brussels 2001.
  39. Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol. 1998 Jan;16(1):139-44. [CrossRef]
  40. De Walden-Gałuszko K, Majkowicz M, Psychologiczno-kliniczna ocena bólu przewlekłego wskazania dla lekarzy pierwszego kontaktu oraz poradni przeciwbólowych i paliatywnych, Akademia Medyczna w Gdańsku, 2003,Gdańsk.
  41. Majkowicz M. Praktyczna ocena efektywności opieki paliatywnej — wybrane techniki badawcze. W: Ocena jakości opieki paliatywnej w teorii i praktyce. De Walden-Gałuszko, K., Majkowicz M. (red.). Akademia Medyczna Gdańsk, Zakład Medycyny Paliatywnej, Gdańsk 2000: 21–42.
  42. Zigmond AS, Snaith RP The Hospital Anxiety And Depression Scale. Acta Psychiatr Scand 1983 , 67:361-70.
  43. Katz MR, Kopek N, Waldron J, Devins GM, Tomlinson G. Screening for depression in head and neck cancer. Psychooncology. 2004 Apr;13(4):269-80. [CrossRef]
  44. MacFarlane TV, Wirth T, Ranasinghe S, Ah-See KW, Renny N, Hurman D. Head andNeck Cancer P ain: Systematic Review of Prevalence and Associated Factors. J Oral Maxillofac Res. 2012 Apr 1;3(1):e1. eCollection 2012.
  45. Chaplin JM, Morton RP. A prospective, longitudinal study of pain in head and neck cancer patients. Head Neck. 1999 Sep;21(6):531-7. [CrossRef]
  46. Hammerlid E, Taft C. Health-related quality of life in long-term head and neck cancer survivors: a comparison with general population norms. Br J Cancer. 2001 Jan;84(2):149-56. [CrossRef]
  47. de Graeff A, de Leeuw JR, Ros WJ, Hordijk GJ, Blijham GH, Winnubst JA. Long-term quality of life of patients with head and neck cancer. Laryngoscope. 2000 Jan;110(1):98-106. [CrossRef]
  48. Parker PA, Baile WF, de Moor C, Cohen L, 2003,.Psychosocial and demographic predictors of quality of life in a large sample of cancer patients. Psychooncology. 2003 Mar;12(2):183-93. [CrossRef]
  49. Kroenke K, Theobald D, Wu J, Loza JK, Carpenter JS, Tu W. The association of depression and pain with health-related quality of life, disability, and health care use in cancer patients. J Pain Symptom Manage. 2010 Sep;40(3):327-41. [CrossRef]
  50. Brown LF, Kroenke K, Theobald DE, Wu J, Tu W. The association of depression and anxiety with health-related quality of life in cancer patients with depression and/or pain. Psychooncology. 2010 Jul;19(7):734-41. [CrossRef]
  51. Breitbart W, Stiefel F, Kornblith AB, Pannullo S, Neuropsychiatric disturbance in cancer patients with epidural spinal cord compression receiving high dose corticosteroids: A prospective comparison study. Psycho-Oncology, Volume 2, Issue 4, pages 233–245, December 1993.
  52. Llewellyn CD, Weinman J, McGurk M, Humphris G. Can we predict which head and neck cancer survivors develop fears of recurrence? J Psychosom Res. 2008 Dec;65(6):525-32. [CrossRef]
  53. Humphris GM, Rogers S, McNally D, Lee-Jones C, Brown J, Vaughan D, Fear of recurrence and possible cases of anxiety and depression in orofacial cancer patients. Int J Oral Maxillofac Surg. 2003 Oct;32(5):486-91.
  54. Humphris GM, Rogers SN. The association of cigarette smoking and anxiety, depression and fears of recurrence in patients following treatment of oral and oropharyngeal malignancy. Eur J Cancer Care (Engl). 2004 Sep;13(4):328-35. [CrossRef]
  55. Laird BJ, Boyd AC, Colvin LA, Fallon MT. Are cancer pain and depression interdependent? A systematic review. Psychooncology. 2009 May;18(5):459-64. [CrossRef]
  56. Jack L, Scott A, Colvin L, Laird B, Fallon M, Pain and depression in cancer patients: a longitudinal study, BMJ Support Palliat Care 2011;1:A11. [CrossRef]
Table 1. Initial patients and treatment characteristics.
Table 1. Initial patients and treatment characteristics.
Patients & treatment characteristics
CAIR-2 phase III clinical trial participants
Deceased at the time of the study
Eligible for the study
Patients who filled QOL tests
Tests included into study
Response rate
184pts
24
160
78 (2 excluded due to secondary cancer)
76
48%
Age Median: 64 y
Gender men - 70%,
women - 30%
Marital status married - 79%,
widowed - 13%,
single - 6,7%,
divorced -1,3%
Education and overall years of education) primary school (8y) – 20%,
secondary school (11y) – 39%,
high school (12y) – 33%,
master’s degree (16y) – 8%
Smoking tobacco before DART 84%
Cancer symptoms before diagnosis median: 5,5 months (1–84)
Time from diagnosis to treatment median: 49 days (15–188)
Tracheostomy before DART 0
Feeding tube during DART 4%
Neck dissection or surgery before DART 0
ZUBROD status before DART
ZUBROD status after DART
0 – 80%, 1 – 18.7%, 2 – 1.3 %,
0 – 70%, 1 – 28.7%, 2 –1.3%
Weight loss during the treatment Mean = -2,4kg (-12,3kg +7,9kg)
Analgesics type during and after DART no analgesics – 3%,
regional - 9%,
NSAIDs+tramadol - 72%,
opiates - 16%
Analgesics intake (days) median: 21 days (5-173)
Dysphagia during and after DART no dysphagia - 41%,
mixed food - 51%,
liquids only - 8%
Dysphagia (days median: 20 days (6-189)
Corticosteroids intake during and directly after DART 68%
Corticosteroids intake (days) median: 20 days (1-50)
Length of follow-up Median: 47 months (12-158)
TNM classification
T
N

T2 - 53%, T3 - 23%,T4 - 24%,
N0 - 69%, N1 - 31%
Location: hypopharynx - 8%,
oropharynx - 25%,
larynx - 53%
oral cavity- 14%
Technique
Fraction schedule
Total dose
No of fractions/days
2D - 14%, 3D - 45%, IMRT - 25%, 3D+IMRT - 16%
1.8Gy/fx
66.6-72 Gy
37-40 fractions and 37-40 days
Table 2. Results of QLQ-C30 and H&N35 of DART survivors with a follow-up median of 47 months compared with 640 HNC survivors with a similar median of follow-up who had various radiotherapy treatments from Leung et al [20].
Table 2. Results of QLQ-C30 and H&N35 of DART survivors with a follow-up median of 47 months compared with 640 HNC survivors with a similar median of follow-up who had various radiotherapy treatments from Leung et al [20].
QLQ-C30 and H&N 35
Subscales (range 0-100)
DART survivors
n=76 (sexuality scale n=63)
median of follow-up: 47m.
Leung et al, 2011g
n=640
median of follow-up 51m
Clinically significant difference - 10 points or more between the means
Mean (sd) Median Mean (sd) Median
QLQ-C30 Functional scales:
Global health status
Physical functioning
Role functioning
Emotional functioning
Cognitive functioning
Social functioning
QLQ-C30 Symptom scales:
Fatigue FA
Nausea and vomiting NV
Pain PA
Dyspnea DY
Insomnia
Appetite loss AP
Constipation CO
Diarrhea DI
Financial difficulties FI


58,6 (23,1)
68,9 (20,2)
85,7 (19,4)
62,9 (23,2)
73,1 (21,2)
80,1 (25)

43,6 (25,6) 8,9 (15,1)
32,40(28,4)
20,4 (26,2)
38,8 (33,8)
29,7 (26,9)
22,5 (28,2)
10,3 (15,3)
37,6 (38,8)


58,3
68,7
100
66,7
66,7
83,3

44,3
0
33,3
0
44,4
30
0
0
33,3


54.6 (19.9)
84.5 (16,5)
86,4 (21)
77,9 (20)
78,4 (19,8)
75,1 (24,2)

29,2 (20,04)
9.3 (17,5)
21,9 (22,4)
15,2 (21,16)
26,3 (25,9)
19,9 (24,6)
19,1 (23,7)
14 (19,9)
26,4 (27,1)


50
86.7
100.0
75.0
83.3
66.7

33.3
0.0
16.7
0.0
33.3
0.0
33.3
0.0
33.3


↑4
15,6
↓0,7
15
↓5,3
↑5

14,4
↑0,4
10,5
↓5,2
12,4
↓2,6
↓3,4
↓3,7
11,2
H&N35 (symptoms scales)
HN pain HNPA
Swallowing problems HNSW
Senses problems HNSE
Speech HNSP
Social eating HNSO
Social contact HNSC
Less sexuality HNSX
Teeth HNTE
Opening mouth HNOM
Dry mouth HNDR
Sticky saliva HNSS
Coughing HNCO
Feeling ill HNFI
H&N35 single items

Painkillers HNPK
Nutritional supplements HNNU
Feeding tube HNFE
Weight loss HNWL
Weight gain HNWG

28,2 (21,5)
26,7 (25,4)
31,2 (30,6)
28,9 (23,7)
28,7 (26,6)
19,6 (19,9)
38,6 (34,9)
26 (36,5)
27,4 (37,8)
64,8 (32,3)
60,7 (34,8)
42,7 (31)
36,5 (32,5)



50 (50)
18,9 (39,4)

0
24,3 (43)
36 (48,3)

25
16,7
33
22
25
13
33
0
0
66,7
66,7
33,3
33,3



50
0
0
0
0

19,1 (20,6)
30,2 (24,4)
26,9 (27,7)
28 (25,9)
28,5 (26,9)
20,4 (23,5)
26 (27,7)
38,9 (29,8)
32,8 (31,6)
48,3 (31)
40,7 (30,6)
29,3 (25,4)
29,3 (25,3)

Not analysed
-
-
-
-
-
-

16.7
25.0
25.0
22.2
25.0
13.3
33.3
33.3
33.3
33.3
33.3



-
-
-
-
-

↓9,1
↓3,5
↓4,39
↓0,9
↓0,9
↓0,8
12,6
12,9
↑5,4
16,5
20
13,4
↓7,2



-
-
-
-
-
-
Table 3. Statistically significant differences in mood, pain, QoL and medical data depending on gender, T and N status.
Table 3. Statistically significant differences in mood, pain, QoL and medical data depending on gender, T and N status.
Variables Test type
(if relevant)
Grouping variable
vs mean/ median results for analyzed groups
p value
Mann- Whitney U-test


Appetite loss AP
Pain of H&N area – HNPA
Sticky saliva HNSS
Swallowing problems HNSW
Social eating HNSO
Weight loss during RT (kg)



Cognitive functioning CF
Opening mouth HNOM
Pain of H&N area – HNPA
Speech problems HNSP
Social eating HNSO


Cognitive functioning CF
Opening mouth HNOM
Senses problems HNSE
Social eating HNSO
Dysphagia during DART (mixed food or liquids only)


QLQ-C30
H&N35
H&N35
H&N35
H&N35
-



QLQ-C30 H&N35
H&N35
H&N35
H&N35


QLQ-C30 H&N35
H&N35
H&N35
-
Gender


<0,05
<0,05
<0,01
<0,05
<0,05
<0,05


<0,01
<0,01
<0,05
<0,05
<0,05


<0,05
<0,05
<0,01
<0,01
<0,05
men (M/ME) women (M/ME)
33 / 33,3
32 / 33,3
32 / 33,3
67/ 66,7
33 / 25
-2,9 / -2,7
23 / 0
20 / 16,7
16 / 8,3
47 / 33,3
20 / 16,7
-1,2 / -0,8
T-stage
T2 (M/ME) T3+T4 (M/Me)
78 / 83
17 / 0
23 / 25
25 / 22,2
23 / 16,7
66 / 66,7
42 / 33,3
35 33,3
34 / 33,3
37 / 33,3
N-stage
N0 (M/ME) N1 (M/ME)
77 / 83,3
18 / 16,7
24 / 16,7
23 / 16.7
58%
64 / 66,7
45 / 33,3
44 / 37,5
40 / 33,3
87%
Table 4. The mood (HADS) and intensity of the pain (VAS) in the DART group.
Table 4. The mood (HADS) and intensity of the pain (VAS) in the DART group.
Mood (HADS) Results Std dev Median/ quartiles
Depression (0-21p.)
Anxiety (0-21p.)
Sum of depression + anxiety
% of possible major depression outcomes (≥15 points)
mean=6
mean=7
mean=12,5
27%
4,53
4.41
8,37

5 (2-9)
6 (2.5-10)
10.5 (6-18)
Intensity of Pain (VAS, 0-10p.)
Pain of the head and neck area
no pain (0 points)
weak pain (1-3 p)
moderate pain (4-6p)
strong pain (7-10p)
mean=3.4
13%
37%
40%
10%
2,46 3(1-5)

Pain of the shoulder area
no pain (0 points)
weak pain (1-3 p)
moderate pain (4-6p)
strong pain (7-10p)
mean=2.9
22%
41%
32%
4,5%
2,44 3 (1-5)
Table 5. Significant differences between depressed and non-depressed group (Mann-Whitney’s U Test).
Table 5. Significant differences between depressed and non-depressed group (Mann-Whitney’s U Test).
Variables Test type Mean results for analyzed groups p value
Depressed group (27%) Non-depressed
(73%)
Pretreatment/treatment data
Smoking tobacco before RT
Steroids intake during RT

-
-

96%
85%

78%
58%

<0,05
<0,05
mean median mean median

Intensity of pain of head/neck (0-10)
Intensity of shoulder pain (0-10)

VAS
VAS

4,7
4,4

5
5

2,6
2

2
2

<0,001
<0,001
Functional scores (0-100)
Global health status QL2
Physical functioning PF
Emotional functioning EF
Cognitive functioning CF
Social functioning SF
Symptom scores (0-100)
Fatigue FA
Pain (frequency) PA
Dyspnea DY
Insomnia SL
Appetite loss AP
QLQ-C30
41,3
60
44,7
65,9
70,2

53,9
53,2
28
58,8
44,7

45
60
41,7
66,7
66,7

55,6
50
33,3
66,7
33,3

66,2
74,2
73,7
77,4
85

37,6/
20,9
15,9
27,5
21

66,7
80
75
83.3
100

33,3
16,7
0
33,3
33,3

<0,000001
<0,001
<0,000001
<0,05
<0,05

<0,01
<0,000001
<0,05
<0,001
<0,01
Symptom scores (0-100)
HN pain (frequency) HNPA
Swallowing problems HNSW
Speech HNSP
Social eating HNSC
Social contact HNSO
Less sexuality HNSX
Opening mouth HNOM
Dry mouth HNDR
Sticky saliva HNSS
Coughing HNCO
Feeling ill HNFI
Painkillers HNPK
Weight loss HNWL
H&N35
40,4
40,7
38,3
40,7
29,6
53,6
45,7
81,5
74,1
53,1
57,7
74,1
44,4

33,3
33,3
33,3
26,7
33,3
50
33,3
100
100
66,7
33,3
100
0

21
18,4
23,4
21,7
13,7
29,9
16,7
55
52,9
36,8
24,8
34,8
12,7/

16.7
8.3
22,2
6,7
16,7
16,7
0
33,3
33,3
33,3
33,3
0
0

<0,001
<0,001
<0,05
<0,01
<0,001
<0,05
<0,01
<0,01
<0,05
<0,05
<0,0001
<0,01
<0,01
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