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Patient Preference for Radiotherapy Fractionation Schedule in the Palliation of Painful Bone Metastases

Thomas P. Shakespeare, Jiade J. Lu, Michael F. Back, Shen Liang, Rahul K. Mukherjee, Christopher J. Wynne

From the Radiotherapy Centre, The Cancer Institute, National University Hospital; and Clinical Trials and Epidemiology Research Unit, Ministry of Health, Singapore.

Address reprint requests to Tom Shakespeare, MD, Radiotherapy Centre, National University Hospital, 5 Lower Kent Ridge Rd, Singapore 119074; email: ThomasS{at}nuh.com.sg.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: The radiotherapeutic management of painful bone metastases is controversial, with several institutional and national guidelines advocating use of single-fraction radiotherapy. We aimed to determine patient choice of fractionation schedule after involvement in the decision-making process by use of a decision board.

Patients and Methods: Advantages and disadvantages of two fractionation schedules (24 Gy in six fractions v 8 Gy in one fraction) used in the randomized Dutch Bone Metastasis Study were discussed with patients using a decision board. Patients were asked to choose a fractionation schedule, to give reasons for their choice, and to indicate level of satisfaction with being involved in decision making.

Results: Sixty-two patients were entered. Eighty-five percent (95% confidence interval, 74% to 93%) chose 24 Gy in six fractions over 8 Gy in one fraction (P < .0005). Variables including age, sex, performance status, tumor type, pain score, and paying class were not significantly related to patient choice. Multiple fractionation was chosen for lower re-treatment rates (92%) and fewer fractures (32%). Single-fraction treatment was chosen for cost (11%) and convenience (89%). Eighty-four percent of patients expressed positive opinions about being involved in the decision-making process.

Conclusion: Decision board instruments are feasible and acceptable in an Asian population. The vast majority of patients preferred 24 Gy fractionated radiotherapy compared with a single fraction of 8 Gy. These results indicate the need for further research in this important area and serve to remind both clinicians and national or institutional policy makers of the importance of individual patient preference in treatment decision making.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PALLIATIVE RADIOTHERAPY accounts for a large proportion of the workload of radiotherapy departments, and palliation of pain caused by bone metastases is one of the most frequent indications.¹ There is controversy surrounding the optimal fractionation schedule and total dose of external beam radiotherapy, despite many randomized trials^2–19 and overviews^20–24 addressing the issue. Most of these studies demonstrate that lower doses of radiotherapy are equivalent to higher doses for the end point of pain response rates.^{2,4–9,11,13,14,16,17} However, several studies demonstrate higher re-treatment^{2,4,8–10,12,24} and fracture rates^2,4 in arms using shorter, low-dose schedules.

Despite these potential differences, many overviews,^22,23 authors,^25–29 national guidelines,^30,31 and institutional protocols^32,33 recommend the use of 8-Gy single-fraction radiotherapy for the majority of patients with painful bone metastases. This "evidence-based" approach is rationalized by arguing that any potential benefit of longer schedules of higher dose, in terms of re-treatment and fracture rates, is far outweighed by the cheaper cost and convenience for patients using a single fraction.^2,25,33 In our own institution, our protocol recommended a single fraction of 8 Gy for patients with Eastern Cooperative Oncology Group (ECOG) performance status 3 to 4, and a single-fraction or longer schedule for patients with ECOG performance status 1 to 2, at the physicians choice.

To date, however, the debate has revolved around what clinicians and expert panels believe is in the best interest of the patient. There have been no studies assessing what patients think about the relative pros and cons of single and multiple fractionation schedules, and what they would choose based on an informed discussion. There is reason to believe that what oncologists consider important is different from patients’ beliefs,^34,35 thus there is a need to ascertain the patients’ viewpoint.

The present study was conducted to determine which fractionation schedule patients would choose given the small potential benefits of higher-dose multiple fractionation, when compared with the lower cost and convenience of a single fraction. Our study uses a decision board instrument based on the results of the largest randomized study assessing radiotherapy fractionation for painful bone metastases, which was conducted by the Dutch Bone Metastasis Study (DBMS) group.² As far as we are aware, ours is the first report to assess the use of a decision board instrument for palliative radiotherapy, or in an Asian population.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The primary end point of the study was to determine what proportion of patients with painful bone metastases would choose 8 Gy of radiotherapy in one fraction compared with 24 Gy in six fractions, and whether there were significantly more patients choosing one schedule over the other. Secondary end points were to explore potential patient characteristics and other factors that might influence this decision, to document the main reasons behind the patient’s decision, and to determine how Singaporean patients viewed being involved in the decision-making process.

The study received institutional ethics board approval. The instrument used was a decision board instrument based on the study by the DBMS group (Fig 1). Our pilot study confirmed instrument validity and reproducibility.³⁶ The decision board tool was found to have good inter- and intraobserver reliability (Cohen’s kappa statistic 0.83 for both measures). Face validity was confirmed by circulating the instrument to radiation oncologists in Singapore (four physicians), Australia (three physicians), Canada (one physician), and the United Kingdom (one physician) for comment before designing the final tool. The final decision board was deemed sound by all nine radiation oncologists consulted, which included all radiation oncologists who were to administer the instrument. It should be noted that the decision board was administered by the four radiation oncologists working in Singapore, who made up the full consultant workforce employed in the National University Hospital Radiotherapy Centre at the time of the study.

View larger version (63K): [in this window] [in a new window]   Fig 1. Decision board instrument used to aid patient decision making for choice of radiotherapy fractionation schedule.

The sample population consisted of patients with painful bone metastases consulted by radiation oncologists at the National University Hospital, Singapore. Eligibility criteria followed exactly the entry criteria in the DBMS,² to aid comparability of results. The eligibility criteria were as follows: patients with painful bone metastases from a solid tumor, excluding malignant melanoma and renal cell carcinoma; pain score of at least 2 when consulted (when scored from 0 to 10); any performance status; painful bone metastasis treatable in one target volume; no prior irradiation of the painful area; no pathological fracture in the area being irradiated that required fixation; no spinal cord compression; and no cervical spine metastases requiring irradiation

After obtaining informed consent, patients were counseled by their treating consultant regarding the relative advantages and disadvantages of 8 Gy in one fraction compared with 24 Gy in six fractions, using the decision board instrument as a visual aid. Time was allowed for the patient and family to ask questions and clarify any points, and a subsequent consultation was allowed if patients were unable to decide at the initial interview. After patients had decided on the schedule, they were asked, without prompting, why this decision was made (with multiple reasons allowed for). These data was collected to help validate the decision-making process and confirm comprehension. In addition, patients were asked their opinion about being involved in the decision-making process.

Statistical Analyses
All statistical analyses were performed using SPSS version 11.0 (SPSS Inc., Chicago, IL). Fisher’s exact test was used to evaluate possible associations between a patient’s decision and the following characteristics: patient age, sex, race, ECOG performance status, paying class, time from diagnosis to consultation, prior radiotherapy, tumor type, site of metastasis, pain score, and consultant advising the patient. Backward stepwise logistic regression was undertaken using a level of 0.10 to assess the main effect of the variables.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
From September 2000 to August 2002, 62 patients were eligible and entered onto the study. Patient characteristics are listed in Table 1. Our accrual rate of 2.6 eligible patients per month was slightly higher than that of the DBMS group (which averaged 2.3 patients per institution per month). No patient refused entry onto our study.

The patients who chose 24 Gy in six fractions did so for the reasons of re-treatment rates alone in 64%, fracture rates alone in 4%, and both re-treatment and fracture rates in 28%. Patients who chose single-fraction radiotherapy did so for cost (11%) and convenience (89%). No patient chose the 8-Gy regimen for reasons of both cost and convenience. Two (4%) of the 53 patients choosing multiple fractionation schedules did so for reasons not supported by the discussion. One of these patients chose the longer schedule because it was perceived as being "better" (without being able to explain why), and one patient chose six fractions, as they believed they would see the doctor more frequently during treatment (an issue not discussed in the consultation). Thus, 60 of 62 patients (97%) used information within the decision board to arrive at their choice, supporting the comprehension and validity of this instrument.

Univariate analysis demonstrated that patient decision making did not seem to be significantly affected by any patient factors analyzed (P > .1 for all variables), except possibly sex (P = .08). We also found that a high proportion (ranging from 67% to 94%) of patients in our study chose the multiple-fraction schedule regardless of which consultant administered the tool, with no statistically significant differences (P = .4). Multivariate analysis found that only sex might associate with the patient’s decision; however, this did not reach conventional statistical significance (P = .07). In particular, tumor type (after adjusting for the confounding variable, sex) was not associated with patient choice.

Most patients (84%) expressed positive views about being involved in decision making, with 11% of patients expressing neutral views, and 3% of patients expressing either negative views or preferences for doctors making the decision for them. In one patient (2%), there was no recorded indication of the patient’s views.

Although the use of the decision board instrument was a theoretical exercise, patients were mostly (82%) treated according to their choice. The most common reasons for altering management were the presence of a visible and distressing mass (four patients) and the histology of sarcoma (three patients). In both of these situations, patients were treated with 30 Gy over 10 fractions at the discretion of the oncologist.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
There have been a number of randomized studies that have compared low-dose short-course radiotherapy with more prolonged or higher dose schedules.^2–19 Most of these studies,^{2,4–9,11,13,14,16,17} and several overviews,^20–23 have shown that the proportion of patients obtaining pain relief seems to be no different between schedules, and that overall survival, quality of life, and toxicity seem to be equivalent. However, there are several randomized studies,^15,18,19 a reanalysis¹⁰ of a previously reported negative study,³ and an overview²⁴ finding that higher doses of radiotherapy result in better pain relief. This has resulted in proponents for^1,10,24 and against^2,15,23,25 higher-dose fractionated schedules.

Given the conflicting opinions on initial pain relief as an end point, our study was conducted based on the following premise: if no difference exists for this end point, what would patients choose based on a discussion of other end points? Two secondary end points that have been studied are re-treatment rates and fracture rates. Several randomized studies^{2,4,8–10,12} and an overview²⁴ demonstrated higher re-treatment rates for lower-dose palliative radiotherapy. The largest reported randomized study of 1,171 patients by the DBMS group² found that, although survival, quality of life, pain relief, and overall toxicity were the same, there was a significantly higher re-treatment rate in the single-fraction arm (25% v 7%), with rates varying by primary site. An additional finding was that there was a statistically significantly higher fracture rate in the single-treatment arm (4% v 2%).

Some have questioned whether re-treatment rates are truly higher in single-fraction arms, due to a greater readiness to re-treat after lower doses.^2,12 Unfortunately, there is no valid way to either prove or disprove this theory due to the lack of placebo control and double-blinding in randomized studies performed to date. It is well established that biases in subjective end points, such as pain assessment or decision to offer re-treatment, occur in randomized trials in which there is lack of blinding and placebo control.^37–40 Indeed, we are not alone in questioning the quality of radiotherapy dose-fractionation randomized studies for palliation of bone pain. Others have identified problems such as inadequate radiotherapy planning and techniques,²⁴ poor reporting of toxicity,^20–22 lack of standardized end points,^24,41–43 loss of surviving patients to follow-up resulting in censoring problems,²⁴ inability to obtain original data for overviews,²⁴ and inability to combine data from randomized studies,²¹ resulting in the absence of a true meta-analysis. Thus, claims of "Level 1 evidence" for the use of low-dose or single-fraction schedules^23,30 are somewhat misleading. Perhaps the most balanced evaluation of the evidence is found in the conclusions of one consensus meeting on the treatment of bone metastases,⁴⁴ which stated that "the relationships between radiotherapy dose and response duration in terms of pain relief and bone healing are poorly defined and require further investigation."

The authors of the DBMS do comment on the difficulty of interpreting the information about re-treatment rates. However, they argue that, even if re-treatment rates truly differ, the benefits of multiple fractionation (in terms of lower re-treatment and fracture rates) are minor compared with the cost and convenience to patients of a single fraction. They support this by stating that, for patients requiring re-treatment, the efficacy of subsequent radiotherapy is high. They conclude that most patients should be treated with a single fraction of 8 Gy. An accompanying editorial echoes this conclusion,²⁵ with several overviews,^20–24 institutional protocols,^32,33 and national guidelines³⁰ advocating the use of single-fraction radiotherapy for the majority of patients with painful bone metastases. Others believe that the increased requirement for re-treatment justifies the use of multiple-fraction schedules.¹⁰

It is interesting that participants in the debate about advantages and disadvantages of the various radiotherapy options do not seem to directly involve patients in the issue. This is somewhat surprising given the fact that physicians and patients often do not agree on what is important,^34,35 as we have also demonstrated. One effective way to aid patients in the decision-making process is by use of visual aids such as decision boards. Although decision boards, to our knowledge, have not previously been reported in the palliative radiotherapy setting, they have been used successfully in several other areas of cancer management.^45–51

After involving patients in decision making through the use of a decision board, we found that a high proportion (85%) of patients preferred multiple-fraction radiotherapy. This was despite the fact that our instrument was based on the DBMS, and highlighted the finding that there were no differences in initial pain relief, quality of life, or survival. Patients preferred multiple-fraction schedules despite the higher cost and added inconvenience of this choice. Both re-treatment rates and risk of bone fracture were important factors for patients choosing the longer schedule. The latter was somewhat surprising to us, given the small absolute differences in fracture rates between the single- and multiple-fraction arms (4% v 2%, respectively). Once again, this highlights the differences between what patients and their treating clinicians find important. The small proportion of study participants who chose the 8-Gy single-fraction regimen did so primarily for convenience alone, with cost being a much lesser issue (affecting only one patient’s decision). This was also an interesting finding, taking into consideration that there were considerable cost differences of up to $916 Singapore dollars (approximately $515 US dollars). It is uncertain whether patients would still prefer multiple-fraction radiation where the extra cost is substantially higher, as may be the case in countries such as the United States; there is a need to repeat our study in such health care systems.

Another interesting finding was that factors such as patient age, pain score, performance status, and primary tumor site did not seem to influence choice. For example, patient preference did not seem to differ significantly by ECOG score, with 87% of ECOG 1 to 2 and 80% of ECOG 3 to 4 preferring multiple fractionation (Table 1). Of course, larger numbers would be required to confirm these findings. The lack of a difference between tumor type is particularly relevant, as quoted risks of re-treatment were quite variable depending on tumor type. The DBMS found re-treatment rates for lung cancer ranging from 5% (in the arm with 24 Gy in six fractions) to 32% (in the 8-Gy arm), and that of prostate ranging from 11% (with 24 Gy) to 22% (with 8 Gy). These differences were not statistically assessed in the DBMS; however, they were included in our decision board to determine whether patient’s choice may be influenced by level of re-treatment rate. We did not break risks down by treatment site, as this could not be combined with risks by primary site in the decision board. Whether patient preference would vary depending on site of palliative radiotherapy is unknown. Multivariate analysis revealed that only sex might be associated with patient choice, although this was not conventionally statistically significant (P = .07). Anecdotally, female patients seemed to have greater family input in the decision-making process, and it is possible that issues of patient inconvenience might be viewed differently by third parties. It was also interesting that patient preferences were not significantly influenced by the individual radiation oncologist administering the decision board. Larger studies would be required to confirm any small, statistically significant differences in patient subgroups, or between consultants. However the relevance of any such differences would seem to be of little clinical relevance, as the majority of patients in all subgroups in our study chose multiple-fraction radiotherapy (Table 1).

As in all geographically localized studies, care must be used when extrapolating results to different patient populations. The sample in our study consisted of Asian patients, who traditionally are not given extensive opportunities to be involved in decision making.⁵² Discussion with this patient group is almost exclusively a collaborative effort involving the patient plus a number of family members. An important finding of our study was that no patient refused participation, and an overwhelming 84% of patients expressed positive views about being involved in the decision-making process. As far as we are aware, decision board instruments have not previously been studied in patients in Asian medical systems. Our study was a successful example of the feasibility of involving such patients in the use of decision boards. The validity of our decision board model was sound, although an interesting area for further research would be to determine whether other models are also valid. For example, in the design of such an instrument, varying the amount of input by physicians, patients, and other stakeholders may affect the validity in unknown ways. Likewise, framing risks in absolute percentages or in descriptive terms (such as "likely," "unlikely," or "rare") may also affect validity.

There are several other factors that may affect extrapolation of our results. By virtue of the small size of Singapore, the vast majority of patients included in this study live within 20 km of the radiotherapy center. In addition, the cost structure of radiotherapy as defined in our study may not apply to other centers within Singapore or other countries, which may potentially influence results if varying magnitudes of cost difference exist. Also, our usual departmental policy that patients be consulted, simulated, and have treatment commence on separate days may also differ between centers. Thus, the results of our study do require confirmation in Asian, as well as other, patient groups.

In addition, there are competing preferences that must be taken into consideration when determining fractionation schedules. Radiation oncologists may prefer single or multiple fractionation schedules based on their own synthesis of the literature. These preferences may be partially based on end points not included in this study such as fractionation of re-treatment, site of metastasis, or presence of other symptoms. Our decision board by design does not incorporate all possible end points that could be included. For example, the issue of fractionation of re-treatment after initial palliative radiotherapy was not included, as it was not included in the DBMS. Incorporation of these other end points into a single decision board would be an area for further research; however, care must be taken to avoid bias in determining which end points from the various studies should be included.

Decision makers in institutions and health care systems may also have differing preferences in view of costs to the payer (as opposed to cost to the patient, which we have studied) as well as resource utilization. The latter may be important in a situation in which prolongation of palliative therapy might delay the start of definitive or adjuvant treatment for other patients. Thus, it is possible that patients, physicians, and policy makers in institutions and health care systems may have conflicting preferences as to what fractionation schedule is the most appropriate for an individual patient with painful bone metastases. Identifying potential differences is an area ripe for further investigation, as are studies investigating how differing preferences might be prioritized or combined.

Despite these potential limitations, it is clear that a substantial proportion of patients in our study preferred a longer course of radiotherapy to a higher dose, if this results in a lower rate of re-treatment and fracture. Because there is conflicting evidence as to whether these differences truly exist, and there is no valid way to either prove or disprove this theory with current evidence, further studies are warranted. In particular, it would seem that there is a need for a large, double-blind, placebo-controlled, randomized trial of single- versus multiple-fraction irradiation for the treatment of painful bone metastases. Although some have stated that placebo control and double-blinding are not possible in radiotherapy studies,^20,21 there is ample evidence that this can be achieved using "sham" irradiation.^53–56 Such a study investigating the palliation of bone metastases would greatly strengthen existing randomized evidence and treatment guidelines.

Thus, it is evident that there is a need for further research into patient preferences for palliative radiation of painful bone metastases. In particular, investigation of the most appropriate way to prioritize or combine treatment preferences of patients, physicians, and institutional and national policy makers is warranted. In addition, we believe there is a need to conduct a large double-blind, placebo-controlled, randomized trial for palliative radiotherapy in the management of painful bone metastases. The results of our study also serve to remind both clinicians and policy makers of the importance of considering individual patient preference in treatment decision making.

	NOTES

 
Awarded the Novartis Prize for Best Scientific Research (Poster Category), Royal Australian and New Zealand College of Radiologists 53^rd Annual Scientific Meeting, Adelaide, Australia, October 3–6, 2002.

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Submitted October 21, 2002; accepted February 27, 2003.

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