Single Versus Conventional Fractionated Radiotherapy in the Palliation of Painful Bone Metastases

W. E. Hamouda¹; W Roshdy² and M. Teema²

Departments of ¹Radiation-oncology and ²Anaesthesia, Faculty of Medicine, Zagazig University

Abstract

Aim
To compare a single 8 Gy fraction with conventional regimen of 40 Gy in 20 fractions as a palliative treatment to patients with bone metastasis and reducing the treatment burden for both the patients and Hospital Staff.

Methods
One hundred and seven patients with painful localized bone metastases requiring palliative radiotherapy were entered into a prospective randomized trial comparing 8 Gy single fraction (SF group) with 40 Gy in 20 fractions, five fractions/week (CF group). The primary tumor was in the breast in (48.1%) of the patients, in the lung in (20.6%) in the prostate in (17.6%), and in other sites in (13.7%). Bone metastases were located in the spine (42.2%), pelvis (29.4%) limbs (21.6%), and other sites (6.8%). Pain relief was measured by visual analogue scale (VAS) and also by analgesic requirement. Evaluation was performed before and at 2 weeks then every 4 weeks for 24 weeks after treatment. A total of 102 patients were evaluable for response; 50 in the SF group and 52 in the CF group.

Results
There were no significant diferences in the frequency or duration of pain relief between the two study groups. In both groups, the maximum benefit was achieved at 8 weeks after treatment; 41 patients (82%) in SF group and (44%) of those in the CF group. The frequency of pain by ≥50% on VAS. Complete pain relief was reported in (44%) of those in the CF group. The frequency of pain relief did not differ between the two groups with respect to the primary tumor, the metastatic sites, and the performance status, but for patients as a whole, there was a significantly lower response rate for lung cancer patients (61.9%) in comparision to patients with breast (91.8%) and prostate (100%) cancer. The median duration of pain relief was 12 weeks in the SF group and 13.5 weeks in CF group. During follow-up, 7 patients (6 in SF group and one in CF group) had their bone metastases re-irradiated. Six of these re-irradiated patients also achieved pain relief.

Conclusions
This study indicates that a single fraction of 8 Gy is as effective as 40 Gy in 20 fractions for the palliation of painful bone metastases. Single fraction schedule may be preferred for patient convenience and an option for re-treatment in the case of recurrent pain.

Key words
Radiotherapy, Fractionation Schedules, Bone Metastasis, Pain.

Introduction

The skeleton is the most common organ to be affected by metastatic cancer, with bone metastases from carcinomas of the breast, prostate, and lung being the most frequent ⁽¹⁾.
Treatment of bone metastases is mainly palliative and the aims of treatment are to relieve pain, prevent development of pathological fractures, and to improve mobility and function. External beam radiotherapy provides excellent palliation for localized metastatic bone pain ^(2,3,4). To achieve this goal, a wide variety of dose fractionation schedules and a wide range of total doses have been employed in different radiotherapy departments.
Uncontrolled retrospective series ^(5,6) and prospective randomized trials ^{(7-9, 10-13)} provide much data about the different fractionation schedules, but there is no consensus about the best radiotherapy regimen. Some prospective randomized studies ^(7,12,14) supported the view that pain relief could be equally well achieved by 1 or 2 fractions of 8 Gy to 10 Gy or by 40-46 Gy in 20-23 fractions.
In this study, palliative radiotherapy of painful localized bone metastases with a single 8 Gy fraction was compared with conventional regimen of 40 Gy in 20 fractions.

Patients & Methods

Patients selection and pretreatment evaluation
Between March 1997 and December 2000, 102 patients with painful localized bone metastases referred to Radiation Oncology Unit and Pain Clinic at Zagazig University Hospitals were included. Patient selection criteria include the following: histological or cytological evidence of epithelial malignancy, radiogra-phic evidence of bone metastasis, no change in chemotherapy or hormonal therapy within 30 days, no previous radiotherapy to the treatment area, and no pathological fractures.

Pretreatment evaluation included patient history, clinical examination, and radiography of the painful bone metastasis. Pain intensity was assessed using visual analogue scale (VAS) graduated from 0 (no pain) to 10 (pain as bad as you can imagine) ⁽¹⁵⁾. Analgesic requirement was assessed using a four-point scale (0=no analgesic, 1=non-opiods, 2=weak opioids, 3=strong opioids) ⁽¹⁶⁾. The patient performance status (PS) was evaluated by using Eastern Cooperative Oncology Group (ECOG) scale ⁽¹⁷⁾.

Treatment Methods
Eligible patients were randomized to receive either 8 Gy given as a single fraction (SF group) or 40 Gy given in 20 daily fractions, 5 fractions/week (CF group). All patients were treated using Cobalt-60 teletherapy unit. A single direct field or parallel opposing fields were used as best suited for the part of the body being treated. The dose was prescribed to the appropriate depth in single fields and to the midplane in opposed fields. The treated field encompassed osseous lesions plus 2-cm margin and for spine metastases one unaffected vertebral body on each side. A maximum field size of 150 cm2 was allowed where spinal cord or bowel was included in the field, or 200 cm2 for more peripheral sites.

Treatment Evaluation
Planned assessments were done at 2 weeks and every 4 weeks for 24 weeks after treatment. On each occasion both the VAS and the analgesic score were noted. A response (pain relief) was defined as a ≥50% reduction in pain score compared to the initial score on VAS. Complete response (CR) was defined as achievement of a score 0 on VAS. Duration of pain relief was defined as the time from the date of response to the date of pain progression.

Statistical Analysis
Data were analyzed using Student’s t-test, chi-square or Fisher’s exact test. Duration of pain relief was estimated by the Kaplan-Meier method and compared by log-rank test. A P-value of <0.05 was considered significant ⁽¹⁸⁾.
 

Results
 

Patients Characteristics
A total of 107 patients were included in the study. Two patients in SF group and 3 patients in CF group were excluded because of early death and the analysis was consequently based on 102 patients. Of these 50 were in SF group and 52 in CF group. The treatment was completed as planned in the two treatment groups.

[Table 1].
shows pretreatment characteristics in the two treatment groups. There was a good balance in all respects between the two groups, and no statistically significant differences were apparent. Of the 102 patients, there were 59 females (57.8%) and 43 males (42.2%) with a mean age of 61±14.5 years (range 35 to 85). Eighty-two patients (80.4%) had ECOG performance status 0-2. Pain intensity score range from 5 to 7 and was reported in 38 patients (37.3%) and from 8 to 10 in 47 patients (46%). Forty-nine (48.1%) patients had breast cancer, 21 (20.8%) lung, 18 (17.6%) prostate and 14 (13.7%) other cancers. Metastatic sites were in the spine (42.2%), pelvis (29.4%), limbs (21.6%) and in other sites (6.8%).

Response
Pain relief at the post-treatment intervals studied and as measured by VAS is shown in [Table 2].
The frequency of pain relief did not differ significantly between the SF group and the CF group. In the two groups, the maximum benefit was achieved at 8 weeks after treatment; 42 of 50 patients (84%) in SF group and 46 of 52 patients (88.5%) in CF group experienced a reduction in their pain by >50% at 8 weeks after treatment, complete pain relief was reported in 23 (46%) in the SF group and in 25 patients (48.1%) in the CF group.

Pain relief at 8 weeks did not differ between the two groups with respect to the primary tumor, the metastatic sites, and the performance status [Table 3].
However, for patients as a whole, there was a significantly lower response rate for lung cancer patients (61.9%) in comparison to patients with breast (91.8%) and prostate (100%) cancers. Metastases in the limbs seemed to be the least responsive (72.7%) in comparison to (93.3%) in the pelvis and (90.6%) in the spines. Patients with ECOG performance status score 0-2 achieved (89%) pain relief in comparison to (75%) for those with score 3. But, these differences were statistically non-significant.

The analgesic requirements for both groups before and 8 weeks after treatment are shown in [Table 4].
There was no significant difference between the two groups either before or after treatment. There was however, a significant reduction in the analgesic use in both arms of the trial after treatment.

At 8 weeks after radiotherapy, 14 patients (8 in SF group and 6 in CF group) did not obtain pain relief. Non steroidal analgesics up to morphine sulphate tablets (MST, 30 mg) were used to control pain in 14 patients. Four of them required epidural medication in the form of bupivacaine 0.5% (2-3 ml) plus morphine sulphate (2-3 mg) through tunneled epidural catheter. One non-responsive patient with rib metastasis has been controlled by neurolytic intercostal nerve block using phenol 10% in saline.

There was no significant difference in the duration of pain relief between the two study groups; 12 weeks and 13.5 weeks in SF group and CF group, respectively. At last follow-up, there was still pain relief in (52.6%) for the SF group and (59.5%) for the CF group.
During follow-up, 7 patients (6 in SF group and one in CF group) had their bone metastases reirradiated with 8 Gy single fraction. Six of them also achieved pain relief.

Toxicity
Treatment related acute morbidity was very modest and included mainly anorexia, erythema, nausea, vomiting and tiredness. No late adverse effects were noted. Three patients in SF group and 6 patients in CF group developed pathological fracture of the irradiated sites.

Discussion

Pain is the usual presenting symptom in patients with bone metastases. Although the effectiveness of external beam irradiation in palliation of pain from osseous metastases is well established, the optimal fractionation schedule has not been determined.
A worthwhile pain relief is usually obtained in 70-90% of patients with localized bone metastases by using a variety of dose fractionation schemes and a wide range of total doses ⁽³⁾, suggesting a lack of correlation between pain relief and total dose or number of fractions. Several retrospective studies ^(2,4) have failed to correlate the probability of pain relief with total dose of radiation. Furthermore, single fractions of 4-15 Gy have been shown to be equally effective as 20-40 Gy given in multiple fractions ⁽⁵⁾. On the other hand, Arcangeli et al. ⁽⁶⁾ found the best results, in terms of pain relief and long-term pain control, in patients receiving a fractionated course of 40 Gy, given in daily fractions of 2-3 Gy.

A prospective randomized study reported by Price et al. ⁽¹²⁾ comparing the effect of a single fraction of 8 Gy and 30 Gy given in 10 daily fractions failed to reveal a dose-response relationship, showing similar response rates for both radiation regimes. Another prospective randomized study by Cole ⁽⁷⁾ comparing a single fraction of 8 Gy and 24 Gy given in 6 fractions supported the view that satisfactory pain relief can be accomplished by either radiation regimes. Nielson et al. ⁽¹⁰⁾ concluded that a single fraction of 8 Gy was as effective as 20 Gy in 4 fractions in relieving pain from bone metastases. Gaze et al.⁽⁸⁾ reported that a single 10 Gy treatment was as effective as 22.5 Gy in 5 fractions in the management of painful bone metastases.

In the present study, there was no significant difference in the frequency or duration of pain relief between the two study groups. Pain relief at 8 weeks after treatment was reported in (82%) of patients in SF (46% CR) and in (88.5%) of patients in CF group (48.1% CR). 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 more protracted fractionated treatment.The Radiation Therapy Oncology Group randomized study of various fractionation schedules in 1016 patients reported by Tong et al. ⁽¹⁴⁾ concluded that low-dose, short-courses treatment schedules were as effective as high dose, protracted treatment schedules. Subsequent reanalysis of the same data by Blitzer ⁽¹⁹⁾ , however, demonstrated that, the relief of pain was significantly related to the number of fractions and the total dose of radiation. In contrast to the initial analysis, patients with solitary and multiple metastases were grouped together and analgesic requirements were included in the pain score. Treatment is, however, much more difficult than that of radical treatment where concrete endpoint such as survival can be used. Because pain is a multidimensional concept, a wide variety of measures (pain intensity markers, pain relief scales, patients satisfaction scales and pain management indices) have been used to assess the quality of pain treatment ⁽²⁰⁾. This may result in substantial differences in reported adequacy of cancer pain treatment.

In the present study, adequacy of pain treatment was based on both patient-oriented measure (VAS) and pain medication (analgesic score). At 8 weeks after treatment, 47 patients (46.1%) achieved score 0 on VAS whereas only 28 patients (27.5%) achieved score 0 on analgesic score. This may be due to medications required to relieve pain from other causes.

In our series, the maximum benefit from palliative radiation in the two study groups was gained at 8 weeks. This may reflect the time needed for re-calcification ⁽¹¹⁾. Blitzer ⁽¹⁹⁾ reported that only 50% of the patients who were going to respond had relief of pain at 2-4 weeks after radiation. In a review of radiotherapy for painful bone metastases, McQuary et al. ⁽³⁾ reported that response rates evaluated at any time during the post-treatment follow-up were higher than that evaluated at a specific time interval after treatment. Pain relief obtained a long time after radiation may be related to cointerventions other than radiation.

Arcangeli et al. ⁽²¹⁾ demonstrated a more favorable outcome for breast and prostate cancer patients in comparison to patients with other primaries concerning pain relief. Similarly, our results show a possible relationship between the primary tumor and the likelihood of pain relief as shown by the significantly lower response in the lung with respect to breast and prostate cancer patients.

In the present study, patients receiving single fraction were more likely to have the same site re-irradiated than those receiving multifractions (6 in SF group and one in CF group). Six of the 7 re-irradiated patients also achieved pain relief. Both Mithal et al. ⁽²²⁾ and Sengeloy ⁽²³⁾ concluded that patients who have responded initially will have a similar probability of response after re-irradiation.
 

Conclusion

The results of this study indicate that a single fractions of 8 Gy is as effective as 40 Gy in 20 fractions in relieving pain from bone metastasis. 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 patients whose symptoms recur in the treated areas.

Reference

1. Ruben R.D. and Colman R.E. (1995): Bone metastases, in Abeloff MD, Armitage JO, lichter AS, (eds): Clinical Oncology. New York NY, Churchill Livingstone P. 642-665.

2. Janjan N.A. (1997): Radiation for bone metastases: Conventional techniques and the role of systemic radiopharmaceuticals. Cancer 80:1628-1645.

3. McQuary H.J.; Carroll D. and Moore R.A. (1997): Radiotherapy for painful bone metastases: a systemic review. Clin. Oncol. 9:150-154.

4. Tordiglione M.; Luraghi R. and Antogoni, P. (1999): Role of palliative and symptomatic radiotherapy in bone metastases (abstr.). Radiol. Med. Torino. 97: 372-377.

5. Allen K.L.; Johnson T.W. and Hibbs G.C. (1976): Effective bone palliation as related to various treatment regimens. Cancer 37: 984-987.

6. Arcangeli G.; Micheli A.; Giannarelli D.; La Pasta O.; Tollis A.; Vitullo A.; Ghera S. and Benassi M. (1989): The responsiveness of bone metastases to radiotherapy: The effect of site, histology and radiation dose on pain relief. Radiother. Oncol. 14:95-101.

7. Cole D.J. (1989): A randomized trial of single treatment versus conventional fractionation in the palliative radiotherapy of painful bone metastases. Clin. Oncol. 1: 59:62.

8. Gaze M.N.; Kelly C.G.; Kerr G.R.; Cull A.S.; Cowie V.J.; Gregor A.; Howard G.C. and Rodger A. (1997): Pain relief and quality of life following radiotherapy for bone metastases: a randomized trial of two fractionation schedules. Radiother, Oncol. 5: 109-116.

9. Hoskin P.J.; Price P.; Eaton D.; Regan, J.; Austin D.; Palmer S. and Yarnold J.R.A. (1992): A prospective randomized trial of 4 Gy or 8 Gy single doses in the treatment of metastatic bone pain. Radiother. Oncol. 23: 74-78.

10. Nielson O.S.; Bentzen, S.M.; Sandberg, E.; Gadeberg, C.C. and Timothy A.R. (1998): Randomized trial of single dose versus fractionated palliative radiotherapy by bone metastases. Radiother. Oncol. 47: 233-240.

11. Niewald M.; Tkocz H.J.; Abel U.; Scheib T.; Walter K. Nieder C.; Schnabel K.; Baaerberich W.; Kubale R. and Fuchs M. (1996): Rapid course radiation therapy vs. more standard treatment: A randomized trial for bone metastases. Int. J. Radiat. Oncol. Biol. Phys. 36: 1085-1089.

12. Price P.; Hoskin P.J.; Easton D.; Austin A. Palmer S.G. and Yarnold J.R. (1986): Prospective randomized trial of single and multifraction radiotherapy schedules in the treatment of painful bony metastases. Oncol. 6: 247-255.

13. Rasmusson B.; Vejborg I. And Jensen A.B. (1995): Irradiation of bone metastases in breast cancer patients: a randomized study with one year follow-up. Radiother. Oncol. 34: 179-184.

14. Tong D.; Gillieh, I. And Hendrickson F.R. (1982): The palliation of symptomatic osseous metastases. Final results of the radiation therapy oncology Group. Cancer 50: 893-899.

15. Huskisson E.C. (1983): Visual analogue scale. In: Melzack R (ed). Pain measurement and assessment. Raven press, New York, PP 33-37.

16. Cleeland C.S.; Gonin R. and Hatfild A.K. (1994): Pain and its treatment in patients with metastatic cancer. N. Eng. J. Med. (330: 592-596.

17. Roland T. (1987): Systemic assessment of patients with cancer, in Handbook of cancer chemotherapy, 2nd ed., Little Brown Company, Boston-Toronto, P. 15-24.

18. Kirkwood B.R. (1989): Essentials of medical statistics. Blackwell Scientific publication.

19. Blitzer P.H. (1985): Reanalysis of the RTOG study of the palliation of symptomatic osseous metastases. Cancer 55: 1468-1472.

20. Jadad A.R. and Browman G.P. (1995): The WHO analgesic ladder for cancer pain management: Stepping up the quality of its evaluation. J.A.M.A. 274: 1870-1873.

21. Arcangeli G.; Giovinazzo G.; Saracoino B.; D’Angelo L.; Giannarelli D; Arcangeli G. and Micheli A. (1998): Radiation therapy in the management of symptomatic bone metastases: the effect of total dose and histology on pain relief and response duration. Int. J. Radiat. Oncol. Biol. Phys. 42: 1119-1126.

22. Mithal N.P.; Needham P.R. and Hoskin P.J. (1994): Retreatment with radiotherapy for painful bone metastases. Int. J. Radit. Oncol. Biol. Phys. 29: 1011-1014.

23. Sengelov L. (1998): Repeated irradiation of cancer patients (abstr.). Ugskr. Laeger. 160: 4610-4613.onadonna G, et al. Adjuvant cyclophospha- mide, methotrexate, and flouracil in node-positive breast cancer; the results of 20 Years of follow-up. N Engl J Med 1995; 332:901-906.