- Email: [email protected]
Quality of Life after Local External Beam Radiation Therapy for Symptomatic Bone Metastases: A Prospective Evaluation
Volume 1, Number 3 • April 2004
original contribution
Key words: Anxiety, Global pain, Index pain, Pain, Palliative therapy Radiation treatment
Quality of Life after Local External Beam Radiation Therapy for Symptomatic Bone Metastases: A Prospective Evaluation Edward Chow, George Hruby, Lori Davis, Lori Holden, Trudi Schueller, Rebecca Wong, Charles Hayter, Ewa Szumacher, Andrew Loblaw, Cyril Danjoux
Abstract This study was designed to prospectively evaluate quality of life in patients treated with local external beam radiation therapy for symptomatic bone metastases. Patients with symptomatic bone metastases treated with palliative radiation therapy were followed with Edmonton Symptom Assessment Scale (ESAS) at baseline and at 1, 2, 4, 8, and 12 weeks after the delivery of radiation therapy. The ESAS evaluates 10 symptoms: global pain, index pain (pain at the irradiated site), fatigue, nausea, depression, anxiety, drowsiness, appetite, sense of well-being, and shortness of breath on a categorical score of 0 to 10 (0 = absence of symptom, 10 = worst possible symptom). At each follow-up interval, the difference for each domain of the ESAS was compared with the baseline score. A P value < 0.01 was considered significant. Five hundred and eighteen patients were analyzed in this study. For the entire cohort, there were statistically significant improvements with the delivery of palliative radiation therapy in global pain, index pain, anxiety, sense of wellbeing, and shortness of breath in ≥ 1 follow-up interval. Fatigue was reported to be slightly worse in the first 2 weeks following the radiation treatment. Global pain, index pain, anxiety, and sense of well-being showed consistent improvement with the radiation treatment regardless of which endpoint definitions were employed. Radiation therapy not only can palliate pain but also can improve quality of life.
in symptom domains.4,7,11 This study prospectively evaluates the change in commonly encountered symptoms and QOL after local external beam radiation therapy for symptomatic bone metastases.
Introduction Patients with bone metastases represent a large group of patients with advanced cancer. Palliative radiation therapy for this group of patients accounts for at least 20% of all treatments in a radiation therapy department.1 Randomized trials of palliative radiation therapy in the treatment of bone metastases have reported outcomes in terms of response rates and/or alterations in analgesic consumption.2-12 However, few trials have evaluated quality of life (QOL) or alterations
Patients and Methods Patients Patients with symptomatic bone metastases who received palliative radiation therapy were followed with the
Address for correspondence: Edward Chow, Department of Radiation Oncology, Toronto Sunnybrook Regional Cancer Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5 Fax: 416-217-1338; e-mail: [email protected]
Rapid Response Radiotherapy Program, Bone Metastases Site Group, Department of Radiation Oncology, Toronto Sunnybrook Regional Cancer Centre, University of Toronto
Submitted: Feb 4, 2004; Revised: Apr 1, 2004; Accepted: Apr 6, 2004 Supportive Cancer Therapy, Vol 1, No 3, 179-184, 2004 Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1543-2912, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
179
Supportive Cancer Therapy
Quality of Life After Radiation Therapy in Patients with Bone Metastases
Table 1
Statistical Analysis All statistical analyses were performed using the Statistical Analysis System. At each follow-up interval, the difference for each domain of the ESAS was compared with the baseline score. For each pair of variables, the paired t test was used to determine whether or not the difference was statistically significant. A P value of < 0.01 was considered significant because of multiple comparisons.
Baseline Edmonton Symptom Assessment Scale Scores Parameter
Mean ± SD (n)
Global Pain
4.6 ± 3.1 (509)
Index Pain
5.8 ± 2.9 (518)
Fatigue
5.1 ± 2.8 (496)
Nausea
1.6 ± 2.3 (498)
Results
From January 1999 to January 2002, a total of 534 patients with bone metastases received palliative radiation therapy. Sixteen patients were not able to score the pain and therefore were 2.6 ± 2.6 (475) Depression excluded from further analysis. Patient characteristics of the remaining 518 subjects, sites of irradiation, dose fractionations, 3.2 ± 2.9 (480) Anxiety and patient responses by pain score and/or analgesic consumption 3.7 ± 2.9 (485) Drowsiness and international consensus endpoints14,15 were reported in the companion paper. Table 1 reports the baseline ESAS Scores. 4.2 ± 3.3 (498) Appetite With the delivery of palliative radiation therapy for bone 4.4 ± 2.4 (468) Sense of Well-Being metastases, there were statistically significant improvements for the entire cohort in the following ESAS domains (the range of the 2.3 ± 2.5 (488) Shortness of Breath mean difference from the baseline): global pain (–0.9 to –1.4), index pain (–2.1 to –2.9), anxiety (–0.6 to –0.8), sense of wellEdmonton Symptom Assessment Scale (ESAS)13 before the being (–0.7 to –0.8), and shortness of breath (–0.5) in at least one delivery of radiation therapy and at 1, 2, 4, 8, and 12 weeks follow-up interval. Fatigue was reported to be slightly worse in afterwards. The ESAS is a validated patient-based assessment the first 2 weeks following radiation treatment (0.5-0.8; Table 2). that evaluates 10 symptoms: global pain, index pain (pain at Patients who achieved complete response when analyzed by the irradiated site), fatigue, nausea, depression, anxiety, international consensus endpoints7 appeared to show improvedrowsiness, appetite, sense of well-being, and shortness of ments in global pain (–1.5 to –1.9), index pain (–3.4 to –4.8), breath on a categorical scale of 0 to 10 (0 = absence of sympnausea (–0.9), anxiety (–0.9 to –1.3), and sense of well-being tom; 10 = worst possible symptom). Analgesic intake was (–1.2); whereas in partial responders, scores were global pain recorded at each follow-up. Ethics approval was obtained. (–1.8 to –2.3), index pain (–3.1 to –4.3), nausea (–1.0), anxiety (–1.6 to –2.2), appetite (–1.5), and sense of wellbeing (–0.9 to –1.8; Table 3). Table 2 Similarly, using the pain score alone as endpoint, the corresponding ESAS domains for Entire Population complete responders were global pain (–1.4 to –2.0), index pain (–3.8 to –5.2), anxiety Mean Difference From Baseline (Patients Evaluated) (–0.9), and sense of well-being (–1.3); and for Week 1 Week 2 Week 4 Week 8 Week 12 partial responders, global pain (–1.6 to –2.5), index pain (–4.0 to –4.4), nausea (–1.0), –1.2 (259) –1.4 (283) –1.2 (250) –1.2 (219) –0.9 (183) Global Pain anxiety (–1.2 to –1.3), sense of well-being (–0.8 to –1.5), and shortness of breath –2.1 (272) –2.8 (297) –2.9 (266) –2.9 (231) –2.7 (193) Index Pain (–0.7 to –0.8; Table 4). The equivalents using 0.8 (253) 0.5 (277) Fatigue integrated pain and analgesic consumption as endpoint are listed in Table 5, with global –0.6 (237) –0.8 (252) –0.7 (225) –0.7 (202) Anxiety pain (–1.6 to –2.6), index pain (–3.1 to –4.7), –0.7 (240) –0.8 (206) Sense of Well-Being and anxiety (–1.0) for combined complete response; and global pain (–1.6 to –2.1), Shortness of Breath –0.5 (254) index pain (–3.3 to –4.2), depression (–0.6), anxiety (–1.0 to –1.6), and sense of wellEntries only for those with significant paired t test (P < 0.01). being (–0.8 to –1.3) for integrated response.
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Edward Chow et al
Summarizing the various endpoint definitions, global pain, index pain, anxiety, and sense of well-being showed consistent improvement with radiation treatment (Table 6).
Table 3
International Consensus Endpoints Mean Difference From Baseline (Patients Evaluated)
Discussion
Week 1
Week 2
Week 4
Week 8
Week 12
Quality of life as an outcome measure is Complete Response increasingly being incorporated into trials in the palliative care setting. Four trials of localized –1.5 (44) –1.9 (65) –1.5 (63) –1.7 (56) Global pain palliative radiation therapy for bony metastases –3.4 (45) –4.2 (67) –4.5 (64) –4.8 (58) –4.0 (44) have examined this endpoint.4,7,11,16 Index pain In a randomized trial comparing 2 fractiona–0.9 (60) Nausea tion schedules (10 Gy in 1 fraction vs. 22.5 Gy in 5 fractions) in 280 patients, Gaze et al assessed –0.9 (38) –1.3 (57) –1.1 (59) Anxiety QOL and emotional status, and found no differ–1.2 (57) Sense of well-being ences in these measures when comparing single 4 to extended fractionation. The physicians in the Partial Response study completed the Spitzer QOL index17 –2.3 (80) –1.8 (77) –2.1 (64) –2.3 (51) Global pain according to the verbal description most closely reflecting the patient’s status. The Spitzer index –3.6 (87) –4.0 (82) –4.3 (70) –3.1 (51) –3.5 (54) Index pain contains 5 items relating to activity, daily living, health, support, and outlook, each rated from 0 to –1.0 (74) Nausea 2. The patients completed a Hospital Anxiety –1.7 (70) –2.2 (47) –1.6 (46) Anxiety and Depression (HAD) questionnaire to assess clinically significant levels of anxiety and depres–1.5 (49) Appetite sion. Assessments occurred at baseline, at 1 week –1.8 (61) –1.3 (41) Sense of well-being –0.9 (70) after completion of radiation therapy, at 3-4 weeks after, and then at 2-month intervals. Of 216 patients assessed post-treatment, the QOL Entries only for those with significant paired t test (P < 0.01). and HAD scores were available for 209 and 200 patients, respectively. and then at clinic visits 4, 8, 12, and 20 weeks after treatThe Gaze study found no association between initial QOL ment. With the exception of the initial and final visits, 2 parameters and the likelihood of achieving pain control. The clinic visits could be replaced by correspondence. The prevalence of anxiety and depression, as measured by the HAD authors reported that there was no difference in the relative scale, was reduced following treatment. The median HAD change in QOL at any stage between the 2 treatment arms. score was reduced from 6 before treatment to 5 after irradiaAt 4 weeks, approximately 34%, 20%, and 11% of patients tion. Before treatment, the prevalence of definite (HAD score in each arm achieved increases of ≥ 25%, 50%, and 75%, ≥ 11) and borderline (HAD score 7-10) anxiety and depression respectively, in their VAS QOL when compared with their were 49% and 39%, respectively. After treatment they were pretreatment status. However, the proportion of patients reduced to 35% and 32%, respectively. Quality of life as achieving complete well-being was only 7% in each arm. assessed by the Spitzer Index improved from a median preIn the largest reported randomized prospective trial for the treatment score of 6 (range, 0-10) to a median of 7 (range, 1-10) palliation of bone metastases (1157 patients evaluated) comafter radiation therapy. There was no difference in changes in paring 2 fractionation schemes, QOL assessment was one of HAD or QOL, according to the fractionation schedule. It must several endpoints.11 The study, conducted by Steenland and be noted that the physicians assessed QOL in this study, hence colleagues, used an extensive questionnaire comprising the the possibility of overestimation of post-treatment Spitzer Rotterdam Symptom Checklist18 and the EORTC QLQ scores. Nevertheless, there was a trend toward improvement in C30.19 In addition, overall QOL was measured using 5 patient self-rated anxiety and depression. EuroQOL questions on mobility, self care, usual activities, Nielsen examined global QOL using a visual analogue pain/discomfort, and anxiety/depression. The questionnaire scale (VAS) in a trial of single-dose 8 Gy versus 20 Gy in 4 (containing almost 60 questions) was filled out by the fractions.7 Two hundred and forty-one patients were enrolled patients at baseline, then weekly for 3 months, and then in this trial. The patients completed the pain and global monthly for up to 2 years. The analysis of repeated measures QOL evaluation forms on the first day of radiation treatment
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Quality of Life After Radiation Therapy in Patients with Bone Metastases
Three months after radiation therapy, 20 of 57 evaluable patients had reduced their analgesic Pain Score Alone intake, 17 reported no change in dose, and 20 had increased their analgesic requirement. The Mean Difference From Baseline (Patients Evaluated) global QOL was virtually unchanged, with a mean of 54 pretreatment and 52 at 3 months. Week 1 Week 2 Week 4 Week 8 Week 12 Given the advanced disease in this study population, there were likely other sites of pain outComplete Response side the irradiated fields. This may explain the –1.4 (56) –2.0 (84) –1.5 (83) –1.9 (75) Global pain lack of impact on QOL in this study. Our choice of symptom assessment was the –3.8 (58) –4.6 (88) –4.7 (86) –5.2 (80) –4.2 (61) Index pain ESAS, designed by Bruera and colleagues.13 It –0.9 (75) Anxiety consists of 9 100-mm VAS for pain, activity, nausea, depression, anxiety, drowsiness, –1.3 (71) Sense of well-being appetite, sense of well-being, and shortness of Partial Response breath (0 = best possible symptom, 100 = worst possible symptom). It is a simple and –2.2 (105) –2.1 (113) –2.2 (97) –1.6 (77) –2.5 (73) Global pain useful method for the assessment of palliative care patients, and can be used repeatedly in a –4.0 (112) –4.2 (121) –4.4 (105) –4.0 (80) –4.3 (80) Index pain very ill population. The ESAS was modified by –1.0 (76) Nausea Philip et al for their Australian study.21 They concluded that the modified ESAS has satis–1.3 (105) –1.2 (85) –1.2 (67) Anxiety factory concurrent face, construct, and criteri–1.5 (92) –1.0 (77) Sense of well-being –0.8 (93) on validity in addition to repeatability when compared with both the Rotterdam Symptom Shortness of breath –0.7 (102) –0.8 (110) Checklist and the Brief Pain Inventory. Chang compared the ESAS with the Functional Assessment Cancer Therapy (FACT) and the Memorial Symptom Assessment Scale Entries only for those with significant paired t test (P < 0.01). (MSAS) as well as with the Karnofsky performance status.22 The ESAS individual item and showed that no statistically significant differences in overall summary scores showed good internal consistency and correlatQOL were observed between the 2 fractionation schedules. ed appropriately with corresponding measures from the FACT Further details of the more specific domains of QOL, the and MSAS instruments. Individual items between the assessment of the various QOL instruments, and the impact instruments correlated well. Pain ratings in the ESAS, of local radiation therapy on QOL in this study are yet to be MSAS, and FACT correlated best with the “worst-pain” published. item of the Brief Pain Inventory. They confirmed that ESAS A single-arm trial by Fossa16,20 specifically examined the was a valid instrument. endpoint of QOL after palliative radiation therapy for men Paice and Cohen examined the validity of a verbally adminwith hormone refractory prostate cancer. In this trial, 31 istered 0-10 numeric, pain intensity, rating scale with the VAS patients were treated with the radioisotope 89Sr (strontium) using convergence methods.23 The correlation between the 2 and 106 received external beam radiation therapy. Of the latinstruments was strong and statistically significant (r = 0.847, ter group, 24 patients with poor performance status were treatP < 0.001). They concluded that a verbally administered 0-10 ed with single-fraction hemibody irradiation, and the remainnumeric rating scale provides a useful alternative to the VAS. der with fractionated treatments to localized fields. Only 19 of We employed the ESAS on an 11-point categorical scale (0 31 men treated with strontium and 54 of the 106 men receivto 10; 0 = best, 10 = worst) to facilitate telephone follow-up. ing external beam radiation therapy completed the 3-month The ESAS has been used extensively as a measurement tool in questionnaire. The 73 patients who completed the questionpalliative care services; our use of ESAS allows comparison of naire reported slight pain relief, with mean score decreasing patient symptom distress across studies. from 51 to 44. This is perhaps not surprising given that only Our study was in keeping with the findings of the Gaze 1 patient in the strontium arm and 8 patients in the external and Nielsen studies.4,7 Other than global and index pain, beam radiation therapy arm had < 6 hot spots on bone scan. In there were statistically significant improvements in patient fact, two thirds of the study population had ≥ 20 hot spots. anxiety and sense of well-being with palliative radiation
Table 4
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Volume 1, Number 3 • April 2004
Edward Chow et al
Table 5
Integrated Pain and Analgesic Consumption Mean Difference From Baseline (Patients Evaluated) Week 1
Week 2
Week 4
Week 8
Week 12
–1.6 (36)
–1.9 (41)
–2.6 (33)
–3.4 (38)
–4.1 (42)
–4.7 (35)
–3.4 (28)
Combined Complete Response Global pain Index pain
–3.1 (23)
–1.0 (37)
Anxiety Integrated Response Global pain
–2.1 (133) –1.9 (139) –1.7 (128)
–1.6 (98)
–1.7 (89)
Index pain
–3.3 (140) –4.1 (147) –4.2 (137) –4.1 (104)
–3.8 (92)
–0.6 (125)
Depression Anxiety
–1.0 (123) –1.6 (125) –1.0 (115)
–1.4 (97)
Sense of well-being
–0.9 (114) –1.3 (116) –1.0 (108)
–0.8 (90)
–1.1 (80)
Entries only for those with significant paired t test (P < 0.01).
therapy. There was a slight worsening of fatigue scores immediately after the delivery of radiation therapy in the entire cohort. Measures may be employed to overcome this transient period of worsening fatigue. Further studies are required to correlate the clinical significance with the statistical significance of the ESAS symptoms. Most treatment interventions have associated side effects. It is vitally important to document whether the interventions have an impact on QOL while attempting to palliate specific symptoms. Though external beam radiation therapy is a local treatment, studies including ours have shown it can improve patient QOL too.
Acknowledgements The authors thank Melissa Mulder and Danielle Nywening for secretarial support. This study was supported by Michael and Karen Goldstein Cancer Research Fund and Toronto Sunnybrook Regional Cancer Centre Radiation Program Fund.
References
Table 6
Global Pain
Index Pain
Fatigue
Nausea
Depression
Anxiety
Drowsiness
Appetite
Sense of Well-Being
Shortness of Breath
Statistical Significance in Edmonton Symptom Assessment Scale Domains
Entire Population
⻫
⻫
⻫
–
–
⻫
–
–
⻫
⻫
CR (International Consensus)
⻫
⻫
–
⻫
–
⻫
–
–
⻫
–
PR (International Consensus)
⻫
⻫
–
⻫
–
⻫
–
⻫
⻫
–
CR (Pain Score Alone)
⻫
⻫
–
–
–
⻫
–
–
⻫
–
PR (Pain Score Alone)
⻫
⻫
–
⻫
–
⻫
–
–
⻫
⻫
Combined Complete Response
⻫
⻫
–
–
–
⻫
–
–
–
–
Integrated Response
⻫
⻫
–
–
⻫
⻫
–
–
⻫
–
Entries only for those with significant paired t test (P < 0.01).
183
1. Maher EJ, Dische S, Grosch E, et al. Who gets radiotherapy? Health Trends 1990; 22:78-83. 2. Blitzer PH. Reanalysis of the RTOG study of the palliation of symptomatic osseous metastasis. Cancer 1985; 55:1468-1472. 3. 8 Gy single fraction radiotherapy for the treatment of metastatic skeletal pain: randomised comparison with a multifraction schedule over 12 months of patient follow-up. Bone Pain Trial Working Party. Radiother Oncol 1999; 52:111-121. 4. Gaze MN, Kelly CG, Kerr GR, et al. Pain relief and quality of life following radiotherapy for bone metastases: a randomised trial of two fractionation schedules. Radiother Oncol 1997; 45:109-116. 5. Hoskin PJ, Price P, Easton D, et al. A prospective randomised trial of 4 Gy or 8 Gy single doses in the treatment of metastatic bone pain. Radiother Oncol 1992; 23:74-78. 6. Jeremic B, Shibamoto Y, Acimovic L, et al. A randomized trial of three single-dose radiation therapy regimens in the treatment of metastatic bone pain. Int J Radiat Oncol Biol Phys 1998; 42:161-167. 7. Nielsen OS, Bentzen SM, Sandberg E, et al. Randomized trial of single dose versus fractionated palliative radiotherapy of bone metastases. Radiother Oncol 1998; 47:233-240. 8. Niewald M, Tkocz HJ, Abel U, et al. Rapid course radiation therapy vs. more standard treatment: a randomized trial for bone metastases. Int J Radiat Oncol Biol Phys 1996; 36:1085-1089. 9. Price P, Hoskin PJ, Easton D, et al. Prospective randomised trial of single and multifraction radiotherapy schedules in the treatment of painful bony metastases. Radiother Oncol 1986; 6:247-255.
Supportive Cancer Therapy
Quality of Life After Radiation Therapy in Patients with Bone Metastases
10. Rasmusson B, Vejborg I, Jensen AB, et al. Irradiation of bone metastases in breast cancer patients: a randomized study with 1 year followup. Radiother Oncol 1995; 34:179-184. 11. Steenland E, Leer JW, van Houwelingen H, et al. The effect of a single fraction compared to multiple fractions on painful bone metastases: a global analysis of the Dutch Bone Metastasis Study. Radiother Oncol 1999; 52:101-109. 12. Tong D, Gillick L, Hendrickson FR. The palliation of symptomatic osseous metastases: final results of the Study by the Radiation Therapy Oncology Group. Cancer 1982; 50:893-899. 13. Bruera E, Kuehn N, Miller MJ, et al. The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care 1991; 7:6-9. 14. Chow E, Wong R, Hruby G, et al. Prospective patient-based assessment of effectiveness of palliative radiotherapy for bone metastases. Radiother Oncol 2001; 61:77-82. 15. Chow E, Wu JS, Hoskin P, et al. International consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases. Radiother Oncol 2002; 64:275-280. 16. Fossa SD. Quality of life after palliative radiotherapy in patients with hormone-resistant prostate cancer: single institution experience. Br J
Urol 1994; 74:345-351. 17. Spitzer WO, Dobson AJ, Hall J, et al. Measuring the quality of life of cancer patients: a concise QL-index for use by physicians. J Chronic Dis 1981; 34:585-597. 18. de Haes JC, Olschewski M, Fayers P. Measuring the quality of life of cancer patients with the Rotterdam Symptom Checklist (RSCL): a manual. Groningen: Northern Centre for Healthcare Research series no. 9, 1996. 19. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993; 85:365-376. 20. Fossa SD, Aaronson NK, Newling D, et al. Quality of life and treatment of hormone resistant prostate cancer. The EORTC Genito-Urinary Group. Eur J Cancer Clin Oncol 1990; 26:1133-1136. 21. Philip J, Smith WB, Craft P, et al. Concurrent validity of the modified Edmonton Symptom Assessment System with the Rotterdam Symptom Checklist and the Brief Pain Inventory. Support Care Cancer 1998; 6:539-541. 22. Chang VT, Hwang SS, Feuerman M. Validation of the Edmonton Symptom Assessment Scale. Cancer 2000; 88:2164-2171. 23. Paice JA, Cohen FL. Validity of a verbally administered numeric rating scale to measure cancer pain intensity. Cancer Nurs 1997; 20:88-93.
184
original contribution
Key words: Anxiety, Global pain, Index pain, Pain, Palliative therapy Radiation treatment
Quality of Life after Local External Beam Radiation Therapy for Symptomatic Bone Metastases: A Prospective Evaluation Edward Chow, George Hruby, Lori Davis, Lori Holden, Trudi Schueller, Rebecca Wong, Charles Hayter, Ewa Szumacher, Andrew Loblaw, Cyril Danjoux
Abstract This study was designed to prospectively evaluate quality of life in patients treated with local external beam radiation therapy for symptomatic bone metastases. Patients with symptomatic bone metastases treated with palliative radiation therapy were followed with Edmonton Symptom Assessment Scale (ESAS) at baseline and at 1, 2, 4, 8, and 12 weeks after the delivery of radiation therapy. The ESAS evaluates 10 symptoms: global pain, index pain (pain at the irradiated site), fatigue, nausea, depression, anxiety, drowsiness, appetite, sense of well-being, and shortness of breath on a categorical score of 0 to 10 (0 = absence of symptom, 10 = worst possible symptom). At each follow-up interval, the difference for each domain of the ESAS was compared with the baseline score. A P value < 0.01 was considered significant. Five hundred and eighteen patients were analyzed in this study. For the entire cohort, there were statistically significant improvements with the delivery of palliative radiation therapy in global pain, index pain, anxiety, sense of wellbeing, and shortness of breath in ≥ 1 follow-up interval. Fatigue was reported to be slightly worse in the first 2 weeks following the radiation treatment. Global pain, index pain, anxiety, and sense of well-being showed consistent improvement with the radiation treatment regardless of which endpoint definitions were employed. Radiation therapy not only can palliate pain but also can improve quality of life.
in symptom domains.4,7,11 This study prospectively evaluates the change in commonly encountered symptoms and QOL after local external beam radiation therapy for symptomatic bone metastases.
Introduction Patients with bone metastases represent a large group of patients with advanced cancer. Palliative radiation therapy for this group of patients accounts for at least 20% of all treatments in a radiation therapy department.1 Randomized trials of palliative radiation therapy in the treatment of bone metastases have reported outcomes in terms of response rates and/or alterations in analgesic consumption.2-12 However, few trials have evaluated quality of life (QOL) or alterations
Patients and Methods Patients Patients with symptomatic bone metastases who received palliative radiation therapy were followed with the
Address for correspondence: Edward Chow, Department of Radiation Oncology, Toronto Sunnybrook Regional Cancer Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5 Fax: 416-217-1338; e-mail: [email protected]
Rapid Response Radiotherapy Program, Bone Metastases Site Group, Department of Radiation Oncology, Toronto Sunnybrook Regional Cancer Centre, University of Toronto
Submitted: Feb 4, 2004; Revised: Apr 1, 2004; Accepted: Apr 6, 2004 Supportive Cancer Therapy, Vol 1, No 3, 179-184, 2004 Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1543-2912, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
179
Supportive Cancer Therapy
Quality of Life After Radiation Therapy in Patients with Bone Metastases
Table 1
Statistical Analysis All statistical analyses were performed using the Statistical Analysis System. At each follow-up interval, the difference for each domain of the ESAS was compared with the baseline score. For each pair of variables, the paired t test was used to determine whether or not the difference was statistically significant. A P value of < 0.01 was considered significant because of multiple comparisons.
Baseline Edmonton Symptom Assessment Scale Scores Parameter
Mean ± SD (n)
Global Pain
4.6 ± 3.1 (509)
Index Pain
5.8 ± 2.9 (518)
Fatigue
5.1 ± 2.8 (496)
Nausea
1.6 ± 2.3 (498)
Results
From January 1999 to January 2002, a total of 534 patients with bone metastases received palliative radiation therapy. Sixteen patients were not able to score the pain and therefore were 2.6 ± 2.6 (475) Depression excluded from further analysis. Patient characteristics of the remaining 518 subjects, sites of irradiation, dose fractionations, 3.2 ± 2.9 (480) Anxiety and patient responses by pain score and/or analgesic consumption 3.7 ± 2.9 (485) Drowsiness and international consensus endpoints14,15 were reported in the companion paper. Table 1 reports the baseline ESAS Scores. 4.2 ± 3.3 (498) Appetite With the delivery of palliative radiation therapy for bone 4.4 ± 2.4 (468) Sense of Well-Being metastases, there were statistically significant improvements for the entire cohort in the following ESAS domains (the range of the 2.3 ± 2.5 (488) Shortness of Breath mean difference from the baseline): global pain (–0.9 to –1.4), index pain (–2.1 to –2.9), anxiety (–0.6 to –0.8), sense of wellEdmonton Symptom Assessment Scale (ESAS)13 before the being (–0.7 to –0.8), and shortness of breath (–0.5) in at least one delivery of radiation therapy and at 1, 2, 4, 8, and 12 weeks follow-up interval. Fatigue was reported to be slightly worse in afterwards. The ESAS is a validated patient-based assessment the first 2 weeks following radiation treatment (0.5-0.8; Table 2). that evaluates 10 symptoms: global pain, index pain (pain at Patients who achieved complete response when analyzed by the irradiated site), fatigue, nausea, depression, anxiety, international consensus endpoints7 appeared to show improvedrowsiness, appetite, sense of well-being, and shortness of ments in global pain (–1.5 to –1.9), index pain (–3.4 to –4.8), breath on a categorical scale of 0 to 10 (0 = absence of sympnausea (–0.9), anxiety (–0.9 to –1.3), and sense of well-being tom; 10 = worst possible symptom). Analgesic intake was (–1.2); whereas in partial responders, scores were global pain recorded at each follow-up. Ethics approval was obtained. (–1.8 to –2.3), index pain (–3.1 to –4.3), nausea (–1.0), anxiety (–1.6 to –2.2), appetite (–1.5), and sense of wellbeing (–0.9 to –1.8; Table 3). Table 2 Similarly, using the pain score alone as endpoint, the corresponding ESAS domains for Entire Population complete responders were global pain (–1.4 to –2.0), index pain (–3.8 to –5.2), anxiety Mean Difference From Baseline (Patients Evaluated) (–0.9), and sense of well-being (–1.3); and for Week 1 Week 2 Week 4 Week 8 Week 12 partial responders, global pain (–1.6 to –2.5), index pain (–4.0 to –4.4), nausea (–1.0), –1.2 (259) –1.4 (283) –1.2 (250) –1.2 (219) –0.9 (183) Global Pain anxiety (–1.2 to –1.3), sense of well-being (–0.8 to –1.5), and shortness of breath –2.1 (272) –2.8 (297) –2.9 (266) –2.9 (231) –2.7 (193) Index Pain (–0.7 to –0.8; Table 4). The equivalents using 0.8 (253) 0.5 (277) Fatigue integrated pain and analgesic consumption as endpoint are listed in Table 5, with global –0.6 (237) –0.8 (252) –0.7 (225) –0.7 (202) Anxiety pain (–1.6 to –2.6), index pain (–3.1 to –4.7), –0.7 (240) –0.8 (206) Sense of Well-Being and anxiety (–1.0) for combined complete response; and global pain (–1.6 to –2.1), Shortness of Breath –0.5 (254) index pain (–3.3 to –4.2), depression (–0.6), anxiety (–1.0 to –1.6), and sense of wellEntries only for those with significant paired t test (P < 0.01). being (–0.8 to –1.3) for integrated response.
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Summarizing the various endpoint definitions, global pain, index pain, anxiety, and sense of well-being showed consistent improvement with radiation treatment (Table 6).
Table 3
International Consensus Endpoints Mean Difference From Baseline (Patients Evaluated)
Discussion
Week 1
Week 2
Week 4
Week 8
Week 12
Quality of life as an outcome measure is Complete Response increasingly being incorporated into trials in the palliative care setting. Four trials of localized –1.5 (44) –1.9 (65) –1.5 (63) –1.7 (56) Global pain palliative radiation therapy for bony metastases –3.4 (45) –4.2 (67) –4.5 (64) –4.8 (58) –4.0 (44) have examined this endpoint.4,7,11,16 Index pain In a randomized trial comparing 2 fractiona–0.9 (60) Nausea tion schedules (10 Gy in 1 fraction vs. 22.5 Gy in 5 fractions) in 280 patients, Gaze et al assessed –0.9 (38) –1.3 (57) –1.1 (59) Anxiety QOL and emotional status, and found no differ–1.2 (57) Sense of well-being ences in these measures when comparing single 4 to extended fractionation. The physicians in the Partial Response study completed the Spitzer QOL index17 –2.3 (80) –1.8 (77) –2.1 (64) –2.3 (51) Global pain according to the verbal description most closely reflecting the patient’s status. The Spitzer index –3.6 (87) –4.0 (82) –4.3 (70) –3.1 (51) –3.5 (54) Index pain contains 5 items relating to activity, daily living, health, support, and outlook, each rated from 0 to –1.0 (74) Nausea 2. The patients completed a Hospital Anxiety –1.7 (70) –2.2 (47) –1.6 (46) Anxiety and Depression (HAD) questionnaire to assess clinically significant levels of anxiety and depres–1.5 (49) Appetite sion. Assessments occurred at baseline, at 1 week –1.8 (61) –1.3 (41) Sense of well-being –0.9 (70) after completion of radiation therapy, at 3-4 weeks after, and then at 2-month intervals. Of 216 patients assessed post-treatment, the QOL Entries only for those with significant paired t test (P < 0.01). and HAD scores were available for 209 and 200 patients, respectively. and then at clinic visits 4, 8, 12, and 20 weeks after treatThe Gaze study found no association between initial QOL ment. With the exception of the initial and final visits, 2 parameters and the likelihood of achieving pain control. The clinic visits could be replaced by correspondence. The prevalence of anxiety and depression, as measured by the HAD authors reported that there was no difference in the relative scale, was reduced following treatment. The median HAD change in QOL at any stage between the 2 treatment arms. score was reduced from 6 before treatment to 5 after irradiaAt 4 weeks, approximately 34%, 20%, and 11% of patients tion. Before treatment, the prevalence of definite (HAD score in each arm achieved increases of ≥ 25%, 50%, and 75%, ≥ 11) and borderline (HAD score 7-10) anxiety and depression respectively, in their VAS QOL when compared with their were 49% and 39%, respectively. After treatment they were pretreatment status. However, the proportion of patients reduced to 35% and 32%, respectively. Quality of life as achieving complete well-being was only 7% in each arm. assessed by the Spitzer Index improved from a median preIn the largest reported randomized prospective trial for the treatment score of 6 (range, 0-10) to a median of 7 (range, 1-10) palliation of bone metastases (1157 patients evaluated) comafter radiation therapy. There was no difference in changes in paring 2 fractionation schemes, QOL assessment was one of HAD or QOL, according to the fractionation schedule. It must several endpoints.11 The study, conducted by Steenland and be noted that the physicians assessed QOL in this study, hence colleagues, used an extensive questionnaire comprising the the possibility of overestimation of post-treatment Spitzer Rotterdam Symptom Checklist18 and the EORTC QLQ scores. Nevertheless, there was a trend toward improvement in C30.19 In addition, overall QOL was measured using 5 patient self-rated anxiety and depression. EuroQOL questions on mobility, self care, usual activities, Nielsen examined global QOL using a visual analogue pain/discomfort, and anxiety/depression. The questionnaire scale (VAS) in a trial of single-dose 8 Gy versus 20 Gy in 4 (containing almost 60 questions) was filled out by the fractions.7 Two hundred and forty-one patients were enrolled patients at baseline, then weekly for 3 months, and then in this trial. The patients completed the pain and global monthly for up to 2 years. The analysis of repeated measures QOL evaluation forms on the first day of radiation treatment
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Quality of Life After Radiation Therapy in Patients with Bone Metastases
Three months after radiation therapy, 20 of 57 evaluable patients had reduced their analgesic Pain Score Alone intake, 17 reported no change in dose, and 20 had increased their analgesic requirement. The Mean Difference From Baseline (Patients Evaluated) global QOL was virtually unchanged, with a mean of 54 pretreatment and 52 at 3 months. Week 1 Week 2 Week 4 Week 8 Week 12 Given the advanced disease in this study population, there were likely other sites of pain outComplete Response side the irradiated fields. This may explain the –1.4 (56) –2.0 (84) –1.5 (83) –1.9 (75) Global pain lack of impact on QOL in this study. Our choice of symptom assessment was the –3.8 (58) –4.6 (88) –4.7 (86) –5.2 (80) –4.2 (61) Index pain ESAS, designed by Bruera and colleagues.13 It –0.9 (75) Anxiety consists of 9 100-mm VAS for pain, activity, nausea, depression, anxiety, drowsiness, –1.3 (71) Sense of well-being appetite, sense of well-being, and shortness of Partial Response breath (0 = best possible symptom, 100 = worst possible symptom). It is a simple and –2.2 (105) –2.1 (113) –2.2 (97) –1.6 (77) –2.5 (73) Global pain useful method for the assessment of palliative care patients, and can be used repeatedly in a –4.0 (112) –4.2 (121) –4.4 (105) –4.0 (80) –4.3 (80) Index pain very ill population. The ESAS was modified by –1.0 (76) Nausea Philip et al for their Australian study.21 They concluded that the modified ESAS has satis–1.3 (105) –1.2 (85) –1.2 (67) Anxiety factory concurrent face, construct, and criteri–1.5 (92) –1.0 (77) Sense of well-being –0.8 (93) on validity in addition to repeatability when compared with both the Rotterdam Symptom Shortness of breath –0.7 (102) –0.8 (110) Checklist and the Brief Pain Inventory. Chang compared the ESAS with the Functional Assessment Cancer Therapy (FACT) and the Memorial Symptom Assessment Scale Entries only for those with significant paired t test (P < 0.01). (MSAS) as well as with the Karnofsky performance status.22 The ESAS individual item and showed that no statistically significant differences in overall summary scores showed good internal consistency and correlatQOL were observed between the 2 fractionation schedules. ed appropriately with corresponding measures from the FACT Further details of the more specific domains of QOL, the and MSAS instruments. Individual items between the assessment of the various QOL instruments, and the impact instruments correlated well. Pain ratings in the ESAS, of local radiation therapy on QOL in this study are yet to be MSAS, and FACT correlated best with the “worst-pain” published. item of the Brief Pain Inventory. They confirmed that ESAS A single-arm trial by Fossa16,20 specifically examined the was a valid instrument. endpoint of QOL after palliative radiation therapy for men Paice and Cohen examined the validity of a verbally adminwith hormone refractory prostate cancer. In this trial, 31 istered 0-10 numeric, pain intensity, rating scale with the VAS patients were treated with the radioisotope 89Sr (strontium) using convergence methods.23 The correlation between the 2 and 106 received external beam radiation therapy. Of the latinstruments was strong and statistically significant (r = 0.847, ter group, 24 patients with poor performance status were treatP < 0.001). They concluded that a verbally administered 0-10 ed with single-fraction hemibody irradiation, and the remainnumeric rating scale provides a useful alternative to the VAS. der with fractionated treatments to localized fields. Only 19 of We employed the ESAS on an 11-point categorical scale (0 31 men treated with strontium and 54 of the 106 men receivto 10; 0 = best, 10 = worst) to facilitate telephone follow-up. ing external beam radiation therapy completed the 3-month The ESAS has been used extensively as a measurement tool in questionnaire. The 73 patients who completed the questionpalliative care services; our use of ESAS allows comparison of naire reported slight pain relief, with mean score decreasing patient symptom distress across studies. from 51 to 44. This is perhaps not surprising given that only Our study was in keeping with the findings of the Gaze 1 patient in the strontium arm and 8 patients in the external and Nielsen studies.4,7 Other than global and index pain, beam radiation therapy arm had < 6 hot spots on bone scan. In there were statistically significant improvements in patient fact, two thirds of the study population had ≥ 20 hot spots. anxiety and sense of well-being with palliative radiation
Table 4
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Edward Chow et al
Table 5
Integrated Pain and Analgesic Consumption Mean Difference From Baseline (Patients Evaluated) Week 1
Week 2
Week 4
Week 8
Week 12
–1.6 (36)
–1.9 (41)
–2.6 (33)
–3.4 (38)
–4.1 (42)
–4.7 (35)
–3.4 (28)
Combined Complete Response Global pain Index pain
–3.1 (23)
–1.0 (37)
Anxiety Integrated Response Global pain
–2.1 (133) –1.9 (139) –1.7 (128)
–1.6 (98)
–1.7 (89)
Index pain
–3.3 (140) –4.1 (147) –4.2 (137) –4.1 (104)
–3.8 (92)
–0.6 (125)
Depression Anxiety
–1.0 (123) –1.6 (125) –1.0 (115)
–1.4 (97)
Sense of well-being
–0.9 (114) –1.3 (116) –1.0 (108)
–0.8 (90)
–1.1 (80)
Entries only for those with significant paired t test (P < 0.01).
therapy. There was a slight worsening of fatigue scores immediately after the delivery of radiation therapy in the entire cohort. Measures may be employed to overcome this transient period of worsening fatigue. Further studies are required to correlate the clinical significance with the statistical significance of the ESAS symptoms. Most treatment interventions have associated side effects. It is vitally important to document whether the interventions have an impact on QOL while attempting to palliate specific symptoms. Though external beam radiation therapy is a local treatment, studies including ours have shown it can improve patient QOL too.
Acknowledgements The authors thank Melissa Mulder and Danielle Nywening for secretarial support. This study was supported by Michael and Karen Goldstein Cancer Research Fund and Toronto Sunnybrook Regional Cancer Centre Radiation Program Fund.
References
Table 6
Global Pain
Index Pain
Fatigue
Nausea
Depression
Anxiety
Drowsiness
Appetite
Sense of Well-Being
Shortness of Breath
Statistical Significance in Edmonton Symptom Assessment Scale Domains
Entire Population
⻫
⻫
⻫
–
–
⻫
–
–
⻫
⻫
CR (International Consensus)
⻫
⻫
–
⻫
–
⻫
–
–
⻫
–
PR (International Consensus)
⻫
⻫
–
⻫
–
⻫
–
⻫
⻫
–
CR (Pain Score Alone)
⻫
⻫
–
–
–
⻫
–
–
⻫
–
PR (Pain Score Alone)
⻫
⻫
–
⻫
–
⻫
–
–
⻫
⻫
Combined Complete Response
⻫
⻫
–
–
–
⻫
–
–
–
–
Integrated Response
⻫
⻫
–
–
⻫
⻫
–
–
⻫
–
Entries only for those with significant paired t test (P < 0.01).
183
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