Prospective Assessment of Patient-Rated Symptoms Following Whole Brain Radiotherapy for Brain Metastases

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1 18 Journal of Pain and Symptom Management Vol. 30 No. 1 July 2005 Original Article Prospective Assessment of Patient-Rated Symptoms Following Whole Brain Radiotherapy for Brain Metastases Edward Chow, MBBS, Lori Davis, PhD, Lori Holden, MRT (T), May Tsao, MD, and Cyril Danjoux, MD Rapid Response Radiotherapy Program, Toronto Sunnybrook Regional Cancer Center, University of Toronto, Toronto, Ontario, Canada Abstract To prospectively assess patient-rated symptoms in patients with brain metastases treated with whole brain radiotherapy, these patients were asked to rate their symptoms on the Edmonton Symptom Assessment Scale (ESAS) before, and 1, 2, 4, 8, and 12 weeks following the radiation treatment. ESAS evaluates pain, fatigue, nausea, depression, anxiety, drowsiness, appetite, sense of well-being, and shortness of breath on a scale of 0 10 (0 absence of symptom and 10 worst possible symptom). Patients with a language barrier or significant cognitive impairment were excluded. The mean difference of ESAS symptoms at each follow up were compared with baseline and P 0.01 was considered statistically significant. One hundred seventy patients (102 female and 68 male) were included between January 1999 and January Their median age was 66 years (range 33 84) and the median Karnofsky performance score (KPS) at baseline was 60 (range 20 90). The most common primary cancer sites were lung (99; 58%), breast (32; 19%), gastrointestinal (16; 9%), unknown (14; 8%) and others (9; 6%). One-third had significant weight loss ( 10% over the last 6 months). All patients were prescribed dexamethasone at varying doses during radiotherapy. The dose fractionations were 20 Gy in 5 fractions, 138 (81%); 30 Gy in 10 fractions, 7 (4%); and others, 25 (15%). The baseline mean SD for ESAS scores were: pain , fatigue , nausea , depression , anxiety , drowsiness , appetite , sense of well-being , and shortness of breath For the entire cohort, after the delivery of palliative radiotherapy for brain metastases, there were statistically significant deteriorations in the mean differences from the baseline for the following ESAS domains: fatigue 1.0 to 1.8; drowsiness 1.2 to 1.8; and appetite 2.2 to 2.4. The data demonstrate that certain parameters of quality of life worsen after whole Address reprint requests to: Edward Chow, MBBS, MSc, FRCPC, Department of Radiation Oncology, Toronto Sunnybrook Regional Cancer Center, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada. Accepted for publication: February 14, U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved /05/$ see front matter doi: /j.jpainsymman

2 Vol. 30 No. 1 July 2005 Symptoms Following Whole Brain Radiotherapy 19 brain radiotherapy. J Pain Symptom Manage 2005;30: U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Brain metastases, quality of life, external beam radiation Introduction Approximately 20 40% of cancer patients will develop brain metastases during the course of their illness. Brain metastases cause significant impact on both quality and duration of survival. Whole brain radiotherapy with steroids has been commonly employed in the treatment of most patients, especially those with multiple brain metastases. 1 For patients with a single brain metastasis and good performance status, surgical resection is also recommended prior to radiotherapy. 2,3 Many clinical trials have focused on defining the optimal radiation dose fractionation, the effectiveness of radiation combined with radiosensitizers and the use of radiosurgery The commonly employed endpoints in these studies include survival, tumor response, performance status, and observer-rated symptoms. Patient-rated symptoms have not been well documented. The objective of this prospective study was to assess patientrated symptoms using the Edmonton Symptom Assessment Scale (ESAS) 19 following whole brain radiotherapy in the treatment of brain metastases. Methods Patients with brain metastases who received palliative radiotherapy were followed with the Edmonton Symptom Assessment Scale (ESAS) before the delivery of radiotherapy and at 1, 2, 4, 8, and 12 weeks afterwards. The ESAS is a validated patient-based assessment that evaluates nine symptoms: global pain, fatigue, nausea, depression, anxiety, drowsiness, appetite, sense of well-being, and shortness of breath. Each item is scored on a categorical scale of 0 10 (0 absence of symptom; 10 worst possible symptom). Patients with a language barrier or significant cognitive impairment were excluded. All the patients were prescribed dexamethasone at varying doses during the radiotherapy. The steroid dose was slowly tapered off after radiation by the treating palliative care doctors. The exact steroid doses were not captured. Statistical Analysis All statistical analyses were performed using the Statistical Analysis System (SAS). At each follow-up interval, the difference for each domain of the ESAS was compared to the baseline score. In order to assess the changes from baseline, a mixed model approach was taken. This is advantageous over the standard repeated measures approach because the mixed model can accommodate missing data as well as withinsubject error that is correlated. SAS Proc Mixed was used for the analysis. Three covariance structures were considered to account for the within-subject error (unstructured, compound symmetry, and first order autoregressive) and the first order autoregressive structure gave the best fit of the data. A P-value of less than 0.01 was considered significant due to multiple comparisons. Non-parametric survival analysis was performed in order to assess whether survival could be better understood in relation to the covariates listed in Table 1, namely, sex, primary cancer sites (lung, other), age at radiation (split Table 1 Patient Characteristics n (%) Sex Male 68 (40) Female 102 (60) Age at radiation, yrs Median 66 Range Primary sites Lung 99 (58) Breast 32 (19) Gastrointestinal 16 (9) Unknown 14 (8) Others 9 (6) Weight loss 10 % over the last 6 months 56 (33) Karnofsky Performance Score at first visit Median 60 Range 20 90

3 20 Chow et al. Vol. 30 No. 1 July 2005 Table 2 Baseline ESAS Scores (mean SD) Pain Fatigue Nausea Depression Anxiety Drowsiness Appetite Sense of well-being Shortness of breath at median), Karnofsky Performance Status (KPS) score, and weight loss (yes, other). Results From January 1999 to January 2002, a total of 170 patients with brain metastases received whole brain palliative radiotherapy. There were 102 female and 68 male patients. Their median age was 66 years and median KPS score prior to radiotherapy was 60. The most common primary sites were lung, breast, and gastrointestinal. One-third of the patients had significant weight loss, which was defined as 10% over the last 6 months (Table 1). The dose fractionations employed were 20 Gy in 5 fractions, 138 (81%); 30 Gy in 10 fractions, 7 (4%); and others, 25 (15%). The baseline mean ESAS scores with standard deviations, and those during follow-up, are listed in Tables 2 and 3, respectively. Twentythree patients were lost to follow-up after the radiation treatment. They were censored at their last day of treatment. The number of patients who completed the ESAS at 1, 2, 4, 8, and 12 weeks was 73, 71, 60, 40, and 33, respectively. Thirty-two (19%), 34 (20%), and 25 (15%) died in the first, second, and third months following the delivery of radiotherapy, respectively. The median survival of the entire cohort was 8 weeks (range 1 172) (Figure 1). Of the 101 patients who had a KPS 70 at the time of radiotherapy, the median survival was 5 weeks (range 1 79) (Figure 2). Twenty-eight patients with age below 60 years had KPS 70. Their median survival was 18 weeks (range 1 75) (Figure 3). For the entire cohort, after the delivery of palliative radiotherapy for brain metastases, there was statistically significant deterioration in the mean difference from the baseline for the following ESAS domains: fatigue (range ); drowsiness (range ); and appetite (range ) (Table 4). Univariate statistics (log-rank test) showed that KPS was the most predictive factor for survival (P ), followed by weight loss (P 0.04), sex (P 0.07), primary cancer site (P 0.14), and age at radiation (P 0.24). A forward stepwise selection sequence, in which KPS was followed by weight loss, was not found to significantly improve the model. Thus, KPS was the most highly significant factor in predicting survival among our patients. Discussion Our choice of symptom assessment was the Edmonton Symptom Assessment Scale (ESAS), designed by Bruera and colleagues. 19 It is a simple and useful method for the assessment of palliative care patients, and can be done repeatedly in a very ill population. The ESAS was modified by Philip et al. for their Australian study. 20 They concluded that the modified ESAS has satisfactory face, construct, and criterion validity in addition to repeatability when compared with both the Rotterdam Symptom Checklist and the Brief Pain Inventory. 20 Table 3 ESAS Scores (mean SD) at Follow-Up Week 1 Week 2 Week 4 Week 8 Week 12 Pain Fatigue Nausea Depression Anxiety Drowsiness Appetite Sense of well-being Shortness of breath

4 Vol. 30 No. 1 July 2005 Symptoms Following Whole Brain Radiotherapy 21 Fig. 1. Survival of cancer patients with brain metastases, entire cohort. Chang et al. compared the ESAS with the Functional Assessment Cancer Therapy (FACT) and the Memorial Symptom Assessment Scale (MSAS), as well as the KPS. They confirmed that ESAS was a valid instrument. 21 Paice and Cohen examined the validity of a verbally administered 0 10 numeric (pain intensity) rating scale with the VAS using convergence methods. 15 The correlation between the two was strong and statistically significant (r 0.847, P 0.001). They concluded that a verbally administered 0 10 numeric rating scale provides a useful alternative to the VAS. 22 We employed the ESAS using an 11-point categorical scale (0 10, 0 absence of symptom, 10 worst possible symptom) to facilitate telephone follow-up. The ESAS has been used extensively as a measurement tool in palliative care services; our use of ESAS allows comparison of patient symptom distress across studies. Our study was limited by the high attrition rate observed in most palliative studies. Patients with short survival and profound deterioration of health were lost to subsequent follow-up. This no doubt has an impact on the interpretation of our results. For those who were alive and well enough to conduct a telephone interview, Fig. 2. Survival of cancer patients with brain metastases, at KPS 70. Fig. 3. Survival of cancer patients with brain metastases, KPS 70 and age at radiation 60. there was statistically significant deterioration in fatigue, drowsiness, appetite, and sense of well-being. Our results were also limited by the incomplete data on steroid doses at the time of follow-up. We also did not systematically record neurological symptoms and mental status before and after the radiation treatment, as it was difficult to collect the information by telephone follow-up. Bezjak et al. prospectively followed 75 patients with brain metastases treated with whole brain radiotherapy. They employed observer ratings of neurological symptoms, patient-rated symptoms, performance status, neurological functional status, cognitive function, and quality of life. At 1 month, 55% of patients had progressed or died, 23% were stable, and only 19% showed an improvement or resolution of presenting symptoms. Patient-rated symptoms were worsened at 1 month in comparison to the baseline data. 23,24 The benefits of whole brain radiotherapy in brain metastases patients with poor performance status, extensive active extracranial disease, and anticipated short survival have been questioned. The magnitude of benefit using whole brain radiotherapy above dexamethasone alone in this subset of patients remains uncertain. There has been a proposal of a trial of dexamethasone alone versus radiotherapy and dexamethasone in patients with poor performance status and anticipated short survival. 25 In certain patient subgroups, such as those patients with poor performance status and progressive extracranial disease, treatment interventions may fail to achieve benefits and have associated side effects. It is vitally important to document if interventions have an impact on quality of life and improve patient symptoms, especially in the palliative setting.

5 22 Chow et al. Vol. 30 No. 1 July 2005 Table 4 Differences of Mean from Baseline Using Mixed Model Mean Difference from Baseline Week 1 Week 2 Week 4 Week 8 Week 12 Fatigue Drowsiness Appetite Statistically significant, where P In patients with relatively indolent or inactive extracranial disease, the use of radiation to treat brain metastases may be beneficial to improve or maintain quality of life and/or neurologic symptoms. Treatment also may allow for reduced dexamethasone requirements. There have been studies, including ours, employing patient-rated symptom assessment, which documents symptom deterioration after whole brain radiotherapy. The statistically significant differences in the symptom domains in our study require further studies to confirm clinical significance. Further work is required in this area to document the benefits of palliative radiotherapy in patients with poor performance and short survival. It is important that studies employing the use of therapy in the treatment of brain metastases measure quality of life outcomes. In the spectrum of patients with brain metastases, quality of life may deteriorate despite intervention in certain patient subsets and may improve in other patient subsets. Acknowledgments The authors thank Melissa Frost for secretarial support. This study was supported by the Michael and Karen Goldstein Cancer Research Fund and the Toronto Sunnybrook Regional Cancer Center Radiation Program Fund. References 1. Loeffler JS, Patchell RA, Sawaya R. Treatment of metastatic cancer. In: Devita VT, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology, 5th ed. Philadelphia: Lippincott-Raven Publishers, Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990;322: Patchell RA, Tibbs PA, Regine WF, et al. Postoperative radiotherapy in the treatment of single metastases to the brain. JAMA 1998;280(17): Antonadou D, Coliarakis N, Paraskevaidis M, et al. Whole brain radiotherapy alone or in combination with tenazolamide for brain metastases. A phase III study [abstract]. Int J Radiat Oncol Biol Phys 2002;54: Borgelt G, Gelber R, Kramer S, et al. The palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1980;6: Borgelt G, Gelber R, Larson M, et al. Ultra-rapid high dose irradiation schedules for the palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1981;7: Chatani M, Matayoshi Y, Masaki N, Inoue T. Radiation therapy for brain metastases from lung carcinoma. Prospective randomized trial according to level of lactate dehydrogenase. Strahlenther Onkol 1994;170: Eyre HJ, Ohlsen JD, Frank J, et al. Randomized trial of radiotherapy versus radiotherapy plus metronidazole for the treatment of metastatic cancer to brain. J Neurooncol 1984;2: Haie-Meder C, Pellae-Cosset B, Laplanche A, et al. Results of a randomized clinical trial comparing two radiation schedules in the palliative treatment of brain metastases. Radiother Oncol 1993;26: Harwood AR, Simpson WJ. Radiation therapy of cerebral metastases: a randomized prospective clinical trial. Int J Radiat Oncol Biol Phys 1977;2: Komarnicky LT, Phillips TL, Martz K, et al. A randomized phase III protocol for the evaluation of misonidazole combined with radiation in the treatment of patients with brain metastases. (RTOG- 7916). Int J Radiat Oncol Biol Phys 1991;20: Kurtz JM, Gelber R, Brady LW, et al. The palliation of brain metastases in a favorable patient population: a randomized clinical trial by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1981;7: Mehta MP, Rodrigus P, Teerhaard C, et al. Results from the phase III trial of motexafin gadolinium

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