Palliative Single Versus Fractionated Radiotherapy for Bone Metastases

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1 Med. J. Cairo Univ., Vol. 78, No. 1, March: , Palliative Single Versus Fractionated Radiotherapy for Bone Metastases REHAM SAFWAT, M.D.*; AMANY ALBASMY, M.D.**; MOHAMAD ESSAWI, M.D.*** and KHALED ALSHAHHAT, M.D.w The Department of Radiation Oncology, Zagazig University* & AL-Azhar University w ; the Departments of Epidemiology, National Cancer Institute (NCI)** and Anesthesiology***, Cairo University. Abstract Background and Objective: The debilitating pain that occurs in many patients with advanced malignancies is primarily produced by bone metastases. In 75% of patients with bone metastases (BM) pain is the dominant symptom. Radiotherapy is often used to treat painful metastatic lesions to bone. There has been controversy over the most effective method of delivering radiotherapy for this purpose. One relatively standard approach is to deliver 30 Gy in 10 treatment fractions. However, this if often inconvenient to patients and their families and some have advocated shorter courses of radiotherapy. In addition to being more inconvenient, longer courses of radiotherapy are much more expensive than a single dose. Although single- and multiple-fraction radiotherapy are thought to provide equal palliation. Several schedules of short and long fractionation XRT are used in clinical practice, with hypofractionated treatment being even more attractive for practical reasons. Objective: The aim of this study is to compare single fraction 8 Gys with the standard treatment course of 30 Gys/10 fractions/2 weeks regarding factors impacting on quality of life (QoL) in terms of improved pain, mobility, analgesia scores, and performans status in patients with multiple uncomplicated BM. Outcome Measures: The primary endpoints were pain by visual analogue score (VAS), four-point categorical pain scale, and analgesic consumption. Patients and Methods: Sixty patients with bone metastases from known primary sites divided into 2 groups each of 30 patients balanced in age, sex, and type of malignancy, to be treated with one of two RT regimens. The primary tumor was in the breast in 36.6% of patients, in the prostate in 25% of patients, in the lung in 21% of patients and in other locations in 16.6% of patients. Evaluation was performed before and 4, 8, and 12 weeks after completion of treatment. Of 60 eligible patients, 30 were randomized to the 8 Gys arm, and 30 were randomized to the 30Gys arm. Results: Overall, the treatment was well tolerated. Overall response rate was seen in (48/60) 81.6% of cases, whereas Correspondence to: Dr. Reham Safwat, Dept. of Radiation Oncology, Zagazig University, Zagazig, Egypt. complete response was seen in 28.3% (17/60) of cases and partial response in 51.6% (32/60). Complete and partial response rates were 26.6% and 50%, respectively with an overall response rate (ORR) is 76.6%, in the 8 Gys arm, compared with 30% and 53.3%, respectively, with an ORR of 83.3% in the 30 Gys arm (p>0.5). At 3 months, 26.6% of patients in the 8 Gys arm and 30% of patients in the 30 Gys arm no longer used narcotic medications. Pathologic fractures occurred within the treatment field of 6.6% and 3.3% of patients in the 8 Gy and 30 Gy arms, respectively. Significantly more patients in the 8 Gys arm were re-treated compared with the 30 Gys arm (1-year re-treatment rates: 13.3% versus 3.3%, p<0.001). Conclusion: At 3 months, a single dose of 8 Gys is equivalent to 30 Gys in providing pain and narcotic to patients with painful bone metastasis. There was a higher re-treatment rate, but less acute toxicity, among patients in the 8 Gy arm compared with the 30 Gy arm. Key Words: Bone metastases (BM) Debilitating pain Single Vs Fraction Visual analogue score (VAS). Introduction BONE metastases is a major complication of many solid tumors as prostate, lung, breast and thyroid cancers [1,2]. Although bone metastases often start clinically silent, yet they may lead to serious sequalae as pain, fractures, and hypercalcemia [3]. These complications usually impact on the performance status (PS) and quality of life (QoL) of the patient. Most patients experiencing bone pain eventually require opiates which can significantly alter the patient QoL [4]. Management of bone metastases presents a challenge to oncologists. Its current management includes RT, chemotherapy, hormone therapy, surgery, and supportive therapy either alone or in combination [5]. In most cases the treatment intent is palliative, when treatment goals are pain, preservation of mobility and 189

2 190 Palliative Single Versus Fractionated Radiotherapy function, preservation of quality of life and if possible, prolongation of survival. Only in exceptional cases the treatment goal is curative [6]. Over many years, radiation therapy (RT) had been the main indication that proved to be effective in the treatment of pain of osseous metastases [7]. At least 75% of patients achieve pain following RT and about half of them stay free from pain [8]. However, there is no consensus regarding doses or fractionations required to achieve these results [9]. There have been many randomized trials addressing the issue of optimal fractionation schedules and total dose of external beam radiotherapy. Many of them have shown that lower doses of radiotherapy are equivalent to higher doses for the end point of pain response rates [10]. Despite evidence from trials, some authors still believe that a higher total dose provides better pain of longer duration than a single fraction [11]. The measurement of pain has always been a problem for researchers and clinicians working in palliative studies. Although several scales are currently available, it remains unclear which of these provides the most precise measurement because of the subjective nature of this experience [12-14]. The purpose of this study was to compare single fraction RT with multiple fraction RT in the palliative treatment of painful bone metastases where metastatic disease constitute a significant proportion of our total cancer workload in RT departments, as >50% of the patients present in advanced stage disease and ultimately develop metastases. Patients and Methods Out of the 60 Cancer patients treated between Sept. "2007 to January" 2010 in our Radio therapy department. There were 48 men and 12 women. The age of the patients ranged from 30 to 72 years, majority being 40 to 70 years of age. In 16.6%, the primary site of malignancy could not be identified. Breast (36.6%), prostate (25%), and lung (2 1 %) are the commonest sites of primary malignancy (Table 1). 75% patients had solitary site involvement whereas 25% patients had multiple bone metastases. Radiological study revealed lytic nature of the involved site in 75% of cases and only 25% being sclerotic. The spine was involved in 41.6% of patients, whereas extremity bones were involved in 38.3% of cases (Table 1). Patients, who fulfilled the inclusion criterias were randomly allocated in two different treatment groups-group A, 8 Gys single fraction and Group B, 30 Gys in 10 fractions. Inclusion criterias were: 1 - Cytologically or histologically proven malignant disease with painful bone metastases in single or multiple sites without pathological fracture. 2- Patients had a life expectancy of at least three months. 3- No history of previous radiotherapy on the treatment site. 4- No history of Chemotherapy or Hormone therapy within the last 8 weeks. 5- Patient able to determine subjectively the amount of pain. All patients below 18 years of age, patients with clinical or radiological evidence of cord or cauda equina compression, and patients with bone metastases who received irradiation or hormonal treatment, bisphosphonates or chemotherapy within 8 weeks prior to study were excluded. Changes in systemic therapies and analgesic requirements were recorded before and during the period of study. Pre-treatment and post-treatment assessment: Evaluation included complete history taking, clinical examination including performance status (PS), pain scale, mobility, previous or current medication, the type and dose of analgesia. Routine blood investigations, radiological examination and bone scanning were mandatory. severity was scored on a 4-point graded scale and visual analogue scale (VAS) [15]. After treatment completion patients were followed up weekly for 4 weeks and then bi-weekly till the end of follow-up at 12 weeks. Assessment looked at the patient's general condition, performance status, pain intensity, analgesic consumption, and side effects. Patients who developed new painful metastases remained on-study and these events were treated appropriately. acute side effects like nausea, vomiting, diarrhea, lassitude and skin reactions were evaluated on 0 (none) to 4 (maximum) scale were noted during treatment and on each follow-up according to the Toxicity criteria of the Radiation Therapy Oncology Group (RTOG). Analgesic intake were evaluated on (none, nonopioids, weak opioids and strong opioids). assessment in this study was done by the Radiation Oncologist, Clinical response was defined as a decrease of 25% of the initial score before starting treatment reflecting an improvement in pain, mobility, performance status and decrease of analgesia or by a of pain at least by one category e.g. severe to moderate (4 to 3) or mod-

3 Reham Safwat, et al. 191 erate to mild (3 to 2) or ^!50% reduction of pain by visual analogue scale. Complete pain indicates absence of pain in treatment site. Performance status was evaluated according to the Karnofsky score scale (16). A pre-irradiation pain assessment was done followed by pain assessment performed weekly i.e. 1, 2, 3, 4 weeks after completion of radiation and again on eighth and twelveth week after radiation. was measured by a 4 point scale with numbers from 1 to 4. Mild (2) Moderate (3) None (1) Severe (4) Therapeutic regimen: Gp-A patients received 8 Gys in single fraction and Gp-B patients received 30 Gys in 10 fractions. Both groups were started on RT within a week of randomization. All patients received appropriate treatment delivered by LA 4-1 0MV photons. The number of fields ranged from 1 to 3 in most of the patients using single or two parallel opposing fields and sometimes up to 6 fields were used as dicatated by the needs of each case. In general, the policy was to use a field encompassing the painful areas with a generous margin. Supplementary treatment for relieving distressing symptoms was given on required basis. Treatment with chemotherapy and/or hormonal therapy was allowed, but all changes in the treatment were registered. Statistical analysis: Data were entered, checked and analyzed using the SPSS Software system (version 11.0; Chicago, IL). Duration of response and survival were estimated by use of the Kaplan-Meier method. Differences were analyzed using the log-rank test: A comparison of pain and QoL scores was performed using the Mann-Whitney test. Statistical significance was claimed for p<0.05. Results Each of 30 patients, were balanced in age, sex, type of malignancy and number of bone metastatic sites and have shown no significant difference regarding any of these clinical features (Table 1). Factors impacting on quality of life (QoL) as pain, analgesia consumption, mobility and performance status were assessed before and at 1,2,3 and 4 weeks after radiation therapy according to the established scoring system and again at eighth and twelfth weeks after treatment. No significant difference ( p<0.50) was observed in the speed of onset of for the two treatment arms (Table 4) which was 63.3% in Gr. A (SF) and 70% in Gr. B (MF) 4 weeks after completion of irradiation. both complete and partial though marginally better with multiple fraction regime (Gr. B) were however not significantly better (p<0.50) than single fraction regime (Table 3). Significantly more patients in the 8 Gy arm were re-treated compared with the 30 Gy arm (1- year re-treatment rates: 13.3% versus 3.3%, p<0.001). Even when stratified by the number of painful treatment sites, treatment site weightbearing status, pretreatment pain score, or bisphosphonate use, differences in response between the two treatment groups were not significant. The overall response was 76.6% in the 8 Gy arm and 83.3% in the 30 Gy arm. Complete response and partial response rates were 26.6% and 50% in the 8 Gy arm, 30% and 53.3% in the 30 Gy arm. Acute toxicity was of 36.6% in the 8 Gys arm and of 30% in the 30 Gys arm. These differences were not statistically significant. The retreatment rate was 13.3 vs 3.3% in the 8 Gy and 30 Gy arms, respectively, this difference were statistically significant. At 3 months, 26.6% of patients in the 8 Gy arm and 30% of patients in the 30 Gy arm no longer used narcotic medications. Pathologic fractures occurred within the treatment field of 6.6% and 3.3% of patients in the 8 Gy and 30 Gy arms. The incidence of complete pain as defined in this study protocol is shown in Table (4). Here also no significant difference ( p>0.50) between the two treatment arms could be noted. At 4 weeks the difference in pain was 8% (95% CI 7, 20%) and at 8 weeks the difference was about 10% (95% CI 3, 28%), which are both in favor of 3 Gy x10. Approximately 23.3% (8 Gy x1) and 16.6% (3 Gy x10) of the patients, respectively, did not obtain pain (i.e. ^! 100% residual pain. Acute toxicity: This was generally higher in group I but the difference was not statistically significant Mild nausea (Grade I) was the main early toxicity (36.6% in Group I vs. 30% in Group II) in both the treatment groups (Table 3). (Grade I-2) diarrhea was noticed in two patients in multiple fraction and

4 192 Palliative Single Versus Fractionated Radiotherapy three patients with single fraction regime. Skin reaction (Grade I-2) erythema was also observed in some patients (6 in Group I and four in Group II). These treatment related early toxicities were never severe enough to cause interruption in treatment procedure. Table (1): Patient characteristics. Characteristic 8 Gy x1 N 5 Gy x4 N Included patients: Median age (Range) (Years) 62 (33-72) 59 (30-63) Sex: Male 25 (83.3) 23 (76.6) Female 5 (16.6) 7 (23.3) Karnofsky (Median) Site of primary tumor: Breast 10 (33.3) 12 (40) Prostate 8 (26.6) 7 (23.3) Lung 6 (20) 7 (23.3) Other 6 (20) 4 (13.3) Localization: Dorsal/lumbar spine 14 (46.6) 11 (36.6) Pelvis 6 (20) 6 (20) Hip/femur 5 (16.6) 6 (20) Other 5 (16.6) 7 (23.3) Systemic treatment: None 15 (50) 14 (46.6) Chemotherapy 2 (6.6) 3 (10) Endocrine 11 (36.6) 12 (40) Combination 2 (6.6) 1 (3.3) Table (2): Symptom characteristics prior to treatment. Characteristics 8 Gy x1 N Included patients Gy x4 N Non analgesics 6 (20) 2 (6.6) Weak analgesics 6 (23.3) 9 (30) Morphine 5 (16.6) 5 (16.6) Combination 13 (43.3) 14 (46.6) a Median (range). Table (3): Single dose radiotherapy vs. 10 fraction radiotherapy. Single dose radiotherapy 10 Fraction radiotherapy Number of Patients Grade 1-2 toxicities 36.6% 30% Grade 3-4 toxicities: 0 0 Late toxicities 4% 4% Complete response 26.6% 30% Partial response 50% 53.3% Narcotic-free 26.6% 30% Re-treatment rate 13.3% 3.3% Table (4): Frequency of pain a after radiotherapy as measured bya 4-point pain scale. Posttreatment (week) patients b Frequency of pain a 3 Gy x10 (n=30) patientsb patientsb > > >0.05 Table (5): Frequency of pain a after radiotherapy as measured bya VAS pain scale. Posttreatment (week) 8 Gy x1 (n=30) patients b Frequency of pain a 8 Gy x1 (n=30) 3 Gy x10 (n=30) > > >0.05 a: Defined at a 50% reduction in pain on the VAS. b: Number of patients filling out the forms at a given follow-up control. Discussion p value p value Bone metastases are a common problem in advanced metastatic cancer. More than 50% of patients with breast, prostate, and lung cancer will eventually develop bone metastasis. External beam radiation therapy is a very effective method of palliative treatment, with more than two-thirds of patients experiencing meaningful pain [1]. The major goal of palliative radiotherapy of bone metastases is to relieve pain and thereby improve mobility and function. Radiotherapy is generally very effective, giving response rates approaching 80%. In the current study, more than half of the patients obtained a 50% reduction in pain, whereas about 20% did not obtain any pain. We found no advantage of the fractionated treatment as compared to the single fraction treatment. Thus, our data support that in the majority of patients with painful bone metastases a single fraction of 8 Gy will be as effective as a more protracted fractionated treatment. similar conclusion has been obtained in a number of prospective trials [2-9]. As far as this endpoint is concerned, there is an abundance of data from multiple randomized trials and meta-analyses indicating that more complex prescriptions have no advantage over a single

5 Reham Safwat, et al Gy radiation treatment [10-14]. The report by Hartsell, et al. [17] of a prospective randomized study of patients with bone metastasis from prostate cancer and breast cancer comparing 8 Gy in one fraction versus 30 Gy in 10 Gy fractions, conducted by the Radiation Therapy Oncology Group, again confirms these results. In spite of the overwhelming evidence, however, the practice of prescribing fractionated, prolonged courses of radiotherapy continues [18]. What are the reasons for this practice? Practitioners prescribe radiation therapy with more than one objective. In addition to immediate pain, they are generally concerned with the duration of pain, prevention of fractures, and to some extent, treatment toxicity. The Hartsell study confirms a greater need for re-treatment following a single-fraction treatment, but fails to confirm differences in the risk of fractures, and shows higher toxicity for fractionated treatment. There is thus no reason to prescribe more than a single 8 Gy dose for patients with painful bone metastasis who are in the terminal phase of their disease and are unlikely to require retreatment, or to patients in significant pain where a single treatment is much more convenient [19]. In a review of radiotherapy for painful metastases [7] it was indicated that there may be formidable difficulties surrounding clinical trials in this patient group, such as patient selection, choice of end-points as well as definition of the precise contribution from radiotherapy to other cointerventions like analgesics and psycho-social support. The original report by Slotman, et al. [20] concluded that there was no relationship between the response and the number of fractions used. Subsequent reanalysis of the same data [21,22], however, did demonstrate an association between the number of fractions and the response. In contrast to the initial analysis, patients with solitary and multiple metastases were grouped together and analgesic requirements were included in the pain score. As regard time of onset of pain, analysis of results of our study revealed no significant difference between single fraction of 8 Gy and multiple fractions of 30 Gy in 10 fractions over 12 weeks (74% versus 78.2%). The picture is more or less the same in overall pain i.e. both complete and partial i.e 76.6% in Gr. I (SF) vs. 83.3% in Gr. II (MF). In this present trial we have analysed the results on the basis of a numerical pain scale. A simultaneous assessment of pain by scoring the consumption of analgesic before and after treatment is expected to improve the sensitivity of the measurement. However patient's self assessment of pain using a visual analogue scale should remain our ultimate goal. The present study also showed no significant difference in the percentage of patients not responding to irradiation therapy in the two protocol groups. (23.3% in single fraction vs 16.6% in multiple fraction). It is to be noted that inspite of large treatment fields in some patients no significant early toxicity was observed in both groups and side effects were generally mild to moderate in nature and well tolerated 36.6% versus 30% in group Iand II respectively. Reports of various studies [18] and results of the present prospective study indicate that there is no significant difference between speed of onset and overall incidence of pain following single or multiple fractions of irradiation in metastatic bone pain (Table 4). In fact, Hoegler [19] in a recent article in 1997 had advocated that a single dose of 800 cgy may provide pain control in nearly 80% of patients which is comparable to a more protracted treatment at a higher dose of radiation and comparable to our results. Both in the study by Hartsell, et al. [17] and in the present study, the initial radiotherapy influenced the choice of subsequent therapy if pain recurred or persisted. Patients receiving a single fraction were more likely to have the same site re-irradiated, 13.3% versus 3.3%, whereas more patients treated with fractionated radiotherapy tended to be retreated with analgesics. We did not evaluate pain after re-irradiation, but others have shown that patients who have responded initially will have a similar probability of response after reirradiation [23]. Another reason to interpret the presented results with caution is the possible influence from simultaneous systemic treatment [5]. In the present study, treatment with chemotherapy and/or endocrine treatment were allowed in order to minimize possible patient selection, however, only a minor proportion of patients experie-nced changes in systemic treatment during the follow-up period and there was no difference between the two groups. To increase accuracy most studies have accepted a mixture of tumour types and this may have obscured important differences between different

6 194 Palliative Single Versus Fractionated Radiotherapy tumors in response to radiation. Although current data indicate no correlation between the site of the primary tumour and the likelihood of pain [1-3,13,23], this may be because the question has never been properly addressed. In the present study, the majority of patients had their primary tumours in the breast, prostate or lung and the common sites treated were the spine and pelvis. This is consistent with the general population of patients with metastatic bone disease [15]. In the literature the reporting of adverse effects has generally been poor [12], but there are no obvious differences between the fractionation schedules studied, at least in the incidence of nausea, vomiting, diarrhoea and pathological fractures. Similarly, in the approximately 20% of patients surviving for more than 2 years no increase in late morbidity after single fraction irradiation has been reported [21-23]. In summary, the present study showed no statistically significant difference in pain after 8 Gy x1 as compared to 3 Gy x10. This was irrespective of the time of assessment and whether the VAS or the categorical pain scale was used. In view of the many other aspects involved in optimizing palliative radiotherapy, we feel that differences in efficacy of this order of magnitude are generally not clinically relevant. Thus, we conclude that single fraction schedules may be preferred for patient convenience without any major loss in palliative effect. The use of a single fraction could be of benefit by reducing the treatment burden for both the patient and the hospital staff and by allowing re-treatment in case of recurrent pain. Conclusion: Both single and multiple fraction radiation protocol are very effective in relieving bone pain for bone secondaries without any significant difference in response rate and early toxicities. 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