Painful vertebral metastases are a frequent manifestation of malignancies

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1 2892 COMMUNICATION Palliative Radiation Therapy for Painful Vertebral Metastases A Practice Survey Tejpal Gupta, M.D., D.N.B. Rajiv Sarin, M.D. Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, India. Painful vertebral metastases are a frequent manifestation of malignancies in their advanced stages and are a common cause of morbidity, causing pain, a reduction in mobility, and an impaired quality of life (QOL). External beam radiation therapy (RT) has long been recognized to be an effective treatment modality in the palliation of such painful bony metastases. 1 Although several randomized trials and two meta-analyses 2,3 published to date have addressed the issue of an optimal dose fractionation schedule for pain relief in patients with bony metastases, to our knowledge none of these studies has been conducted for spinal irradiation alone. In addition, the majority of these trials are confounded by widespread heterogeneity in the prescription parameters to the spine, thereby resulting in large variations of dose at depth (region of interest) and making comparisons difficult. Nearly 500 patients with bone metastases are referred annually to the Tata Memorial Hospital (TMH), the apex oncology training institute and the most comprehensive cancer care center in India. The choice of fractionation for such palliative RT is likely to have logistic, financial, and resource implications, particularly for busy centers with long waiting times, and is in need of urgent reappraisal. Because the spine is the most common site of such painful bony metastases, we conducted a survey of the patterns of practice for palliative spinal irradiation. The primary aim of the current study was to assess the practice patterns for palliative spinal RT that are most prevalent among the radiation oncologists of India in general and compare these patterns with the practice at our institution. The authors thank Dr Supriya Chopra. Address for reprints: Tejpal Gupta, M.D., Department of Radiation Oncology, Tata Memorial Hospital, Dr. Ernest Borges Road, Parel, Mumbai India; Fax: (011) , Attn: Dr. Tejpal; tejpalguptarediffmail.com Received August 6, 2004; revision received August 31, 2004; accepted August 31, 2004 MATERIALS AND METHODS This was a questionnaire-based survey performed in two phases. The questionnaire was a single page (Fig. 1), and was formatted to be simple to understand and easy to complete to ensure high return rates. In the first phase, all radiation oncologists at TMH, including consultants, registrars, and postgraduates, were served the questionnaire personally. They were required to complete and return it immediately without any cross-consultation. In the second phase, radiation oncologists from all over India who were attending the 24th Annual Conference of the Association of Radiation Oncologists of India (AROI) at Bangalore between November 21 24, 2002 were handed 2004 American Cancer Society DOI /cncr Published online 8 November 2004 in Wiley InterScience (

2 RT for Vertebral Metastases/Gupta and Sarin 2893 FIGURE 1. Questionnaire for palliative spinal irradiation. AP- PA: anteroposterior posteroanterior; Gy: grays; fx: fractions. the same questionnaire at the Conference Registration/ Reception desk. They were requested to provide the same information and return the questionnaire to the desk after completion. The chi-square test was used to compare proportions. SPSS software (version 10.0; SPSS, Inc., Chicago, IL) was used for analysis. RESULTS In the first phase of the survey (conducted in May 2002), a total of 40 questionnaires were circulated among the radiation oncologists at TMH, all of which were duly returned after completion. Because one of the respondents is also a coauthor of the current study, his reply was not considered for the final analysis. In the second phase (conducted in November 2002), a set of 200 questionnaires was sent to the AROI Conference for circulation among the attending delegates. A total of 160 of these were able to be delivered to the AROI delegates, and 43 of these 160 questionnaires were returned to the Conference Registration/ Reception desk after completion. One of these was ineligible (double-entry), thereby giving a total of 81 respondents, which formed the database for the current analysis. This rate of completion of 81 of 200 questionnaires (40.5%) correlated well with previously reported return rates for post-based or -based surveys. 4,5,6,7 The key observations from the survey are summarized in a tabular form (Table 1). Approximately 78% of the respondents stated that they always use a direct posterior field for palliative RT to the spine (with the exception of the cervical spine), with only 22% reporting the occasional use of an alternative beam arrangement. There was no difference noted in this regard between the TMH respondents and the AROI respondents.

3 2894 CANCER December 15, 2004 / Volume 101 / Number 12 TABLE 1 Summary of Key Observations of the Survey Question Survey question TMH (n 39) AROI Overall (n 42)* a (n 81) 1 Preferred RT fields for spine Direct posterior always 32 (82%) 33 (74%) 63 (78%) Others 7 (18%) 9 (26%) 18 (22%) 2 RT dose prescription (posterior field) Variable depth for different levels 33 (85%) 33 (80%) 66 (83%) Same depth always 6 (15%) 8 (20%) 14 (17%) 3 Median depth (for those prescribing at same depth regardless of spinal level) 4 cm 4 cm 4 cm 4 Median depth as per spinal level Upper dorsal 4 cm 4 cm 4 cm Lower dorsal 5cm 4cm 5cm Lumbar 5cm 5cm 5cm Sacral 5cm 5cm 5cm 5 A) Most preferred fractionation Single fx 14 (36%) 5 (12%) 19 (24%) Fractionated 25 (64%) 36 (88%) 61 (76%) B) Preferred length of fractionation Shorter ( 10 fx) 21 (54%) 12 (29%) 33 (41%) Longer ( 10 fx) 18 (46%) 29 (71%) 47 (59%) C) Correlation with experience 6 yrs using single fx 5 (21%) 1 (8%) 6 (16%) 6 yrs using single fx 9 (60%) 4 (14%) 13 (30%) 6 Willingness to change fractionation Cord compression 24 (62%) 21 (50%) 45 (56%) Soft tissue mass 23 (59%) 21 (50%) 44 (55%) 7 If willing to change fractionation, change to prolonged or short? Protracted ( 10 fx) Protracted ( 10 fx) Protracted ( 10 fx) 8 Median no. of years in oncology 5 yrs 10 yrs 6.5 yrs TMH: Tata Memorial Hospital; AROI: Association of Radiation Oncologists of India; RT: radiation therapy; fx: fraction. a One respondent from the Association of Radiation Oncologists of India did not reply to Questions 2 and 5. Approximately 17% of the respondents stated that they always prescribed at the same depth regardless of the spinal level. The most common depths of prescription were 4 cm (35%), 5 cm (30%), 3 cm (15%), and at the surface (15%). Once again, there was no significant difference noted in this regard between the TMH and AROI cohorts. However, this is in sharp contrast to the practice reported among Canadian radiation oncologists, 14 44% of whom prescribe at the same depth, with the common prescriptions being either Dmax (55%) or 5 cm (35%). For those respondents who varied their depth of radiation according to the spinal level (83%), the depth varied from the surface, to Dmax, to 3 7 cm to the midplane of an anteroposterior-posteroanterior field as per the spinal level. This finding correlates well with the reported practice of the Canadian radiation oncologists. 14 Fractionation Patterns One respondent did not reply to the question concerning preferred fractionation. Overall, 61 respondents (76%) preferred a fractionated course of radiation with only 19 respondents (24%) opting for a single fraction as the most preferred treatment regimen for patients with painful vertebral metastases. Shortcourse RT ( 10 fractions) was preferred by 33 respondents (41%) whereas 47 respondents (59%) preferred a protracted course of radiation ( 10 fractions). Although fractionated RT remained the most preferred regimen, TMH respondents were more willing to use either single-fraction or short-course RT in comparison with their AROI counterparts. Fourteen TMH respondents (36%) used single-fraction RT as the most preferred regimen, compared with only 5 respondents from the AROI cohort (12%). This difference was found to be statistically significant (P 0.018). Short-course RT ( 10 fractions) was preferred by 21 respondents (54%) and 12 respondents (29%), respectively, from the TMH and AROI cohorts, with the difference being statistically significant (P 0.04). This finding correlates well with the results of a Canadian survey 14 in which 26% and 48% of the respondents, respectively, chose 8 grays (Gy) per single

4 RT for Vertebral Metastases/Gupta and Sarin 2895 fraction and 20 Gy per 5 fractions as the preferred treatment regimen. It also concurs with the survey of radiation oncologists from Australia and New Zealand, in which the radiation oncologists recommended a single fraction in 42%, 28%, and 15%, respectively, of patients with bone metastases from primary tumors of the lung, prostate, and breast. 7 However, it contrasts sharply with the American Society for Therapeutic Radiology and Oncology (ASTRO) survey, 4 wherein protracted RT was used by 90% of the respondents in 96% of cases. Next, the choice of fractionation was correlated with experience. We chose 6 years as the cutoff value because it was close to the median value for the entire group. In addition, it would differentiate between respondents in training (residents) and established oncologists (consultants). Single-fraction RT was used by 13 respondents (30%) and 6 respondents (16%), respectively, as the preferred regimen of respondents with 6 years and 6 years experience, with the difference found to be nonsignificant (P 0.19). Similarly, there was no significant difference noted with regard to the length of RT (shorter vs. longer) based on years of experience, with 37% and 46%, respectively, of respondents preferring short-course RT in the 2 treatment arms. A further subset analysis of the selection of fractionation based on the institutional cohort and experience also was performed. There was a significant difference (P 0.019) found in the TMH cohort, with more experienced oncologists (consultants) preferring single-fraction radiation (60%) compared with only 21% in the lesser experienced group (residents). This difference became nonsignificant when correlated with the length of fractionation. In the group of respondents with 6 years of experience, 67% preferred a shorter course of RT compared with 46% in the group of respondents with 6 years of experience (P 0.3). Within the AROI cohort, there were no such differences noted with regard to the preferred fractionation based on the number of years of experience, possibly because all of the respondents reported using a single fraction sparingly. These differences in the choice of fractionation could be the result of physician reluctance to believe that shorter fractionation schedules are as effective as longer ones for pain control in patients with osseous metastases. This could stem from the differences in training as also was pointed out by Crellin et al. 6 or because of the perception that, because it is less expensive, single-fraction RT must be inferior. 15 These differences were borne out by the ASTRO survey, 4 in which the tendency to use longer fractionation was more pronounced in private practice than in a university setting and in respondents trained in an earlier era. A second reason for this could be that a number of AROI respondents may have engaged in private practice, in which financial considerations dictate the choice of fractionation rather than evidence-based medicine. Although not specifically examined, it may have been interesting to determine whether a private practice or a general hospital patient would receive the same fractionation within the same institute. Overall, 56% and 54% of the respondents, respectively, were willing to change their RT fractionation in the presence of a soft tissue mass or cord compression in favor of fractionated RT. AROI respondents were more reluctant to change fractionation (50%), possibly because the majority of them already were using a protracted course of RT. Of the 19 respondents who used single-fraction RT as the most preferred regimen, 69% were willing to use fractionated RT in the presence of a soft tissue mass or cord compression. Of the 61 respondents for whom fractionated RT was the preferred regimen, 51% and 49%, respectively, were willing to change fractionation in the case of soft tissue masses and cord compression. These findings correlate well with the Canadian survey, wherein the respondents avoided single-fraction RT for cord compression. 14 DISCUSSION Vertebral metastases are a common occurrence in cancer patients and adversely affect their QOL. External beam RT is reported to provide excellent palliation in the vast majority of patients but to our knowledge the optimal dose fractionation and prescription parameters have not been well defined to date and remain controversial, with several systematic reviews 8-10 reaching contradictory conclusions. Despite two meta-analyses 2,3 having proven that single-fraction RT is as good as fractionated RT for pain relief in patients with bone metastases, there is continued reluctance for its use in the clinical setting. 7 Although the majority of investigators 11,12 agree, to our knowledge there is no consensus regarding the optimal dose for singlefraction RT. 13 The International Bone Metastases Consensus Working Party recently issued their consensus statement regarding palliative RT endpoints for future clinical trials in patients with bone metastases 16 to promote consistency in reporting. For patients with vertebral metastases, they advocate prescribing to the midvertebral body of a single posterior field and to the mid-plane of an anteroposterior-posteroanterior field. Barton et al. 14 also addressed this issue of the prevalent heterogeneity of prescription parameters, demonstrating that the dose received by the vertebrae at

5 2896 CANCER December 15, 2004 / Volume 101 / Number 12 depth could vary by as much as 50% with changes in prescription depth and energy. They suggest the anterior spinal canal as a suitable prescription point for the direct posterior field in the absence of detailed spinal imaging. Both meta-analyses of fractionation in bone metastases 2,3 concluded that there is no significant difference in complete and overall pain relief between single fraction and multifraction palliative RT for patients with uncomplicated bony metastases. These seminal publications should go a long way toward discouraging the ad hoc prescription parameters prevalent for palliative spinal irradiation. CONCLUSIONS This survey highlights the patterns of practice for palliative spinal RT that are prevalent among the radiation oncologists of India in general and the TMH in particular. It also demonstrates the widespread heterogeneity regarding the optimal dose fractionation and prescription parameters for palliative spinal RT. Institute (place of training and work) and years of experience were found to be factors that significantly affected the choice of fractionation. This heterogeneity could have an effect on the dose received at depth with implications for the reporting of outcome measures and the comparison of results. The continued reluctance to use single-fraction RT and the preference for fractionated RT demonstrated by the respondents in general and the AROI oncologists in particular is indeed worrisome, particularly with its attendant implications in terms of machine availability, waiting times for therapy, patient and caregiver convenience, and human and financial resources. REFERENCES 1. Hoskin PJ. Radiotherapy in the management of bone pain. Clin Orthop. 1995;(312): Sze WM, Shelley MD, Held I, et al. Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy a systematic review of randomised trials. Clin Oncol (R Coll Radiol). 2003;15: Wu JSY, Wong R, Johnston M, et al. Meta-analysis of dose fractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys. 2003;55: Ben-Josef E, Shamsa F, Williams AO, et al. Radiotherapeutic management of osseous metastases: a survey of current patterns of care. Int J Radiat Oncol Biol Phys. 1998;40: Coia LR, Owen JB, Maher EJ, et al. Factors affecting treatment patterns of radiation oncologists in the United States in the palliative treatment of cancer. Clin Oncol (R Coll Radiol). 1992;4: Crellin AM, Marks A, Maher EJ, et al. Why don t British radiotherapists give single fractions of radiotherapy for bone metastases? Clin Oncol (R Coll Radiol).1989;1: Roos DE. Continuing reluctance to use single fractions of radiotherapy for metastatic bone pain: an Australian & New Zealand practice survey and literature review. Radiother Oncol. 2000;56: Ben-Josef E, Shamsa F, Yousef E, et al. External beam radiotherapy for painful osseous metastases: pooled data dose response analysis. Int J Radiat Oncol Biol Phys. 1999;45: McQuay HJ, Collins S, Caroll D, et al. Radiotherapy for the palliation of painful bone metastases. Cochrane Database Syst Rev. 2000;2:CD Ratnatharathorn V, Powers WE, Moss WT, et al. Bone metastasis: review and critical analysis of random allocation trials of local field treatment. Int J Radiat Oncol Biol Phys. 1999;44: Bentzen SM, Hoskin P, Roos D, et al. Fractionated radiotherapy for metastatic bone pain: evidence based medicine or? Int J Radiat Oncol Biol Phys. 2000;46: 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: Chander SS, Sarin R. Single fraction radiotherapy for bone metastases: are all questions answered? Radiother Oncol. 1999;52: Barton R, Robinson G, Gutierrez E, et al. Palliative radiation for vertebral metastases: the effect of variation in prescription parameters on the dose received at depth. Int J Radiat Oncol Biol Phys. 2002;52: Rose CM, Kagan R. The final report of the expert panel for the radiation oncology bone metastases work group of the American College of Radiology. Int J Radiat Oncol Biol Phys. 1998;40: Chow E, Wu JSY, Hoskin P, et al. International consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases. Radiother Oncol. 2002;64: