Patterns of practice in the prescription of palliative radiotherapy for the treatment of bone metastases at the Rapid Response Radiotherapy Program between 2005 and 2012.

OBJECTIVE
We examined whether patterns of practice in the prescription of palliative radiation therapy for bone metastases had changed over time in the Rapid Response Radiotherapy Program (rrrp).


METHODS
After reviewing data from August 1, 2005, to April 30, 2012, we analyzed patient demographics, diseases, organizational factors, and possible reasons for the prescription of various radiotherapy fractionation schedules. The chi-square test was used to detect differences in proportions between unordered categorical variables. Univariate logistic regression analysis and the simple Fisher exact test were also used to determine the factors most significant to choice of dose-fractionation schedule.


RESULTS
During the study period, 2549 courses of radiation therapy were prescribed. In 65% of cases, a single fraction of radiation therapy was prescribed, and in 35% of cases, multiple fractions were prescribed. A single fraction of radiation therapy was more frequently prescribed when patients were older, had a prior history of radiation, or had a prostate primary, and when the radiation oncologist had qualified before 1990.


CONCLUSIONS
For patients with bone metastasis, a single fraction of radiation therapy was prescribed with significantly greater frequency.


INTRODUCTION
Bone metastases are a common complication of advanced cancer 1 and can progress to spinal cord compression, cauda equina syndrome, and pathologic fracture 2 .Radiation therapy has been used for the palliation of painful bone metastases, with partial responses seen in 50%-80% of patients and one third of patients achieving complete pain relief after treatment 3 .
Numerous randomized trials have examined various dose fractionation schedules in palliative radiation therapy for bone metastasis  . For ncomplicated bone metastases, the most recent meta-analysis continues to report that single-fraction treatment provides pain relief equal to that achieved using a multiple-fraction treatment schedule 3 .An evidence-based clinical practice guideline from the American Society for Radiation Oncology recommends a single fraction as being more convenient for patients and their caregivers 2 .
The Rapid Response Radiotherapy Program (rrrp) was established to provide timely palliative radiation therapy for symptom relief in patients with metastatic or locally advanced cancer 28 .The present retrospective study examined whether patterns of practice in prescribing palliative radiation therapy to patients seen in the rrrp with bone metastases changed over time from 2005 to 2012.for all patients with bone metastases who received palliative radiation therapy between August 1, 2005, and April 30, 2012.That time period was selected to update a previous study in the rrrp that reviewed patients treated for bone metastases between 1999 and July 31, 2005 29 .The primary outcome for the present study was the treatment schedule prescribed, including fractionation and dose.Secondary outcomes included an analysis of factors that may have influenced the prescribed treatment schema, including patient, organizational, and disease factors.A further analysis was conducted to determine the reasons that multiple-or single-fraction treatment schedules were prescribed.
Ten factors were hypothesized to influence the choice of dose fractionation schedule.Of those 10 factors, 6 were patient or demographic factors: age, sex, Karnofsky performance status (kps), whether the patient had previously received radiation, where the patient had come from (for example, hospital, home, nursing home), and whether the patient arrived by ambulance.Another 3 factors pertained to the disease: primary cancer site, reason for referral, and irradiated site.The 10th factor was an organizational factor: the number of years the treating radiation oncologist had been certified for independent practice by the Royal College of Physicians and Surgeons of Ontario.

Statistical Analyses
Descriptive statistics are summarized as percentages and as means or medians with standard deviations and ranges for continuous variables.The dose fractionation schedules were categorized as single-fraction (that is, 8 Gy in 1 fraction) or multiple-fraction [that is, 20 Gy in 5 fractions (20 Gy/5), 30 Gy in 10 fractions (30 Gy/10), or others].To determine whether the use of single-fraction radiotherapy changed over time, a chi-square test was used to detect differences in the proportions of unordered categorical variables including sex, primary cancer site, previous radiation, whether the patient arrived by ambulance, where the patient had come from, the first site of radiation therapy, and reasons for referral across time.Continuous variables such as age and kps were tested across time using an analysis of variance.
Univariate logistic regression analyses were conducted to search for demographic and clinical characteristics significantly associated ( p < 0.05) with the prescription of a single-fraction treatment schedule, based on the first site of radiation.The outcome of the model was a binary variable (1 or 0) for single-or multiple-fraction treatment schedules.A multiple logistic regression analysis was also used to examine the effect of year of treatment (2012 being the referent year) on the use of a single-fraction treatment schedule, after adjusting for all other independent variables (that is, sex, age, primary cancer site, and so on).Odds ratios and 95% confidence intervals were estimated for each covariate.Multi-collinearity was assessed using variance inflation factors.The Hosmer-Lemeshow goodness-of-fit test was used to determine if the data fitted the specified model.
The final procedure conducted was a simple Fisher exact test to determine whether any referral reason was significantly associated with the prescription of 20 Gy/5, 30 Gy/10, and other multiple-fraction schedules.All analyses were conducted using the Statistical Analyses System (SAS version 9.2 for Windows: SAS Institute, Cary, NC, U.S.A.).

RESULTS
During the study period, 2549 courses of radiation therapy were administered in the rrrp to patients with bone metastases.A single fraction of radiation therapy was prescribed in 65% of cases, and multiple fractions were prescribed in the remaining 35% (Figure 1).Of the 888 courses of radiation therapy in patients receiving multiple fractions, 738 courses used a prescription of 20 Gy/5, and 75 courses used 30 Gy/10.The most commonly irradiated sites were the spine (46%) and the limbs, hip, and skull (35% combined, Table i).
Median age of the patients was 70 years (range: 27-101 years), and 57% were men.The median kps was 60 (range: 10-100).Overall, 29% were hospital inpatients, and 23% arrived at the rrrp by ambulance.Prior radiation therapy (not necessarily to the same site) had been administered in 48% of patients before they received radiation therapy for their bone metastases.In terms of primary cancer site, 26% of the patients had a lung primary; prostate (25%) and breast (22%) primaries were the next most frequent.The most common reasons for referral to the rrrp were bone pain (83%), spinal cord compression, postoperative radiation therapy, and others (Table ii).
A significant difference in the prescription of a single fraction of radiation therapy occurred over time ( p = 0.036).Patients receiving a single fraction were significantly older ( p < 0.0001, Table iii).Patients with prostate cancer were most likely to receive a single fraction.In addition, compared with patients receiving radiation therapy for the first time, those with a prior history of radiation had 1.55 times the odds of receiving a single fraction.In contrast, women, inpatients, and patients arriving at the rrrp by ambulance were less likely to receive a single fraction of radiation therapy.A single fraction was less frequently used in the spine than in other sites ( p < 0.0001), being less frequently administered to patients referred for spinal cord compression, impending cord compression, cauda equina syndrome, or pathologic fracture ( p < 0.0001).Lastly, radiation oncologists certified from the year 1990 onward were more likely to prescribe multiple-fraction treatment schedules.

Current OnCOlOgy-VOlume 20, number 5, OCtOber 2013
Copyright © 2013 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).
In the multiple logistic regression analyses, the likelihood of using single-fraction radiation did not significantly change over time (p = 0.30) after adjustment for other parameters.There was no collinearity present; variance inflation factors ranged from 1.02 to 3.78.The results of the Hosmer-Lemeshow goodness-of-fit test did not demonstrate any evidence of gross lack of fit for the model ( p = 0.62).
Reasons for treating bone metastases with multiple fractions were also examined based on common fractionation schedules: 20 Gy/5, 30 Gy/10, and others (Table iv).The most common reasons for prescribing 20 Gy/5 included impending cord compression (17%), postoperative radiation therapy (16%), and cord or nerve root compression (16%).In comparison, the most common reasons for prescribing 30 Gy/10 included the presence of primary renal cell cancer (36%), postoperative radiation therapy (14%), and impending cord compression (13%).The Fisher exact test revealed a few significant correlations between the reason for referral to the rrrp and the prescription of common multiple fractionation schedules (Table v).A dose fractionation schedule of 20 Gy/5 was more likely to be prescribed for patients referred for spinal cord compression.In addition, patients referred for an impending fracture were more likely to be prescribed 30 Gy/10.

DISCUSSION
Our previous study of the rrrp between 1999 and 2005 revealed that in 65% of palliative radiation therapy cases, a single fraction was prescribed, and that in 35%, multiple fractions were prescribed 29 , findings identical to those in the present study.Furthermore, in both time periods, a single fraction was more likely to be prescribed for patients with a prostate cancer primary or for older patients, and by radiation oncologists with a greater number of years of certification for independent practice.This time, we also analyzed the physician-dictated notes that were transcribed after each rrrp clinic to further examine the reasons that radiation oncologists prescribed multiple fractions of radiation therapy.That analysis had not been conducted in the earlier study, and it revealed that dose fractionation schedules of 20 Gy/5 and 30 Gy/10 were commonly prescribed for complicated bone metastases: for example, in cord compression or pathologic fracture requiring postoperative radiation therapy.Several studies examining radiation therapy used to treat spinal cord compression revealed that no specific treatment schedules proved to be more advantageous than others 30 .Fractionated treatment schedules such as 30 Gy/10 and 20 Gy/5 are typically administered to manage spinal cord compression in patients receiving only radiation therapy 2,31,32 .
A dose fractionation schedule of 30 Gy/10 was specifically more commonly prescribed in patients with a primary renal cell cancer.Studies have suggested that metastatic renal cell cancers often require higher doses of radiation therapy because they are typically more radioresistant 33 .In bony metastatic renal cell cancer, Halperin and Harisiadis 34 used dose fractionation schedules with a total dose ranging from 30 Gy to 60 Gy.They showed that a total dose ranging between about 30 Gy and 40 Gy controlled bone pain within normal tissue tolerance and that higher doses were not necessary for achieving bone pain palliation in this patient population.Another prospective study conducted by Lee et al. 35 also revealed that a dose of 30 Gy/10 for patients with renal cell cancer metastatic to bone resulted in significant relief from local symptoms.Those findings reflect the rationale behind the prescription of 30 Gy/10 in patients with a primary renal cell cancer attending the rrrp.
Our study also revealed that patients with prostate cancer were commonly prescribed a single fraction of radiation therapy.That finding reflects the results of an international pattern-of-practice survey conducted by Fairchild et al. 36 , in which one scenario described a patient with hormone-refractory prostate cancer.The most common dose fractionation schedule selected for that scenario by the radiation oncologists surveyed was 8 Gy in 1 fraction.Fairchild et al. also demonstrated that Canadian radiation oncologists were significantly more likely to prescribe a single fraction of radiation therapy.The same patterns were reflected among radiation oncologists in the United Kingdom, Australia, and New Zealand.Members of the American Society for Radiation Oncology were less likely to prescribe a single fraction of radiation therapy.The authors speculated that such differences could potentially be attributed to financial compensation 36 .
Protracted dose fractionation schedules have been found to be more commonly prescribed in countries that offer financial compensation based on the number of fractions administered than in countries-such as Canada-that do not use any sort of financial incentive 37,38 .Radiation oncologists certified from 1990 onward were more likely to prescribe multiple fractions of radiation therapy to patients, which accords with the findings of the previous rrrp study 29 .
The age of the patient also appeared to be a significant factor: older patients had a 1.02 greater chance of receiving a single fraction of radiation therapy.A British study by Crellin et al. 39 made similar findings and concluded that radiation oncologists who typically prefer prescribing a single fraction of radiation therapy for bone metastases tend to prescribe multiple fractions in younger patients (≤40 years of age).Similarly, radiation oncologists who prefer prescribing multiple fractions of radiation therapy typically prescribe a single fraction in older patients (≥70 years of age).

CONCLUSIONS
In this updated review of patterns of practice in the rrrp for 2005-2012, most radiation therapy for bone metastases continued to be delivered in a single fraction, which accords with established practice guidelines 2,30 .

table i
Cases of radiation therapy for bone metastases, including fractionation and site of radiation, overall and by year

Variable
First radiation sites

figure 1
figure 1 Prescription of single and multiple fractions of palliative radiation therapy for bone metastases administered in the Rapid Response Radiotherapy Program over time.

a
By chi-square test for categorical variables and by analysis of variance for age and kps.

e402 Current OnCOlOgy-VOlume 20, number 5, OCtOber 2013
Boldface type indicates significance (p<0.05).Copyright © 2013 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).Karnofsky performance status was not collected in 2005; and therefore patients with missing values were excluded from the multiple regression analysis.
Current OnCOlOgy-VOlume 20, number 5, OCtOber 2013Copyright © 2013 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).na = not available.

table iv
Reasons for prescribing multiple treatments, by dose fractionation schedule a By the simple Fisher exact test.