Efficacy of single fraction conventional radiation therapy for painful uncomplicated bone metastases: a systematic review and meta-analysis

Introduction

Bone is a common metastatic site accounting for cancer-related pain (1,2). Radiation therapy (RT) is a well-accepted treatment for painful uncomplicated bone metastases (3). Many studies have documented the effect of single fraction (SF) and multiple fraction (MF) regiments, with the majority of them concluding that the SFRT was equally as effective as MFRT for pain relief (4-20). These findings have been reflected in the guidelines from Choosing Wisely Canada and United States, the national Choosing Wisely campaign and the American Society for Therapeutic Radiology and Oncology—they all recommend SFRT for uncomplicated bone metastases (21-23). A recent study by Conway et al demonstrated that SFRT yields similar improvement to MFRT in patient-reported outcomes for pain, function and symptom frustration in both the complicated and uncomplicated setting of bone metastases (1).

The optimal conventional external beam SFRT dose for maximum pain relief remains unknown. In trials that directly compared 8 and 4 Gy, the larger-dose arm produced statistically superior pain responses (24). Across all trials included, trial doses of 8 Gy or more consistently produced superior response rates when compared to doses less than 8 Gy. Taking into account that 8 Gy has been by far the most commonly administered dose; the final recommendation from a past review was the adoption of 8 Gy as the standard dose to be compared against in future studies due to its reproducible pain response rates (24).

The past review included studies up until September 2012 (24). Since then, several papers have been published documenting the outcome of SFRT (25,26). The aim of this systematic review was to include recently-published papers that detailed SFRT outcomes and to conduct a meta-analysis to portray pain response rates by dose.

Methods

Search strategy

A literature search was conducted in Ovid MEDLINE(R) (1946 to June 2016 week 3), Embase Classic & Embase (1947 to 2016 week 26) and Cochrane Central Register of Controlled Trials (May 2016). Keywords and subject headings such as “bone metastasis”, “radiotherapy” and “single fraction” were employed. The search was limited to English-language papers and excluded reviews and re-irradiation studies (Figure 1). Titles and abstracts of search results were screened to determine eligibility for full-text article review.

Figure 1 Database search strategies.

Eligibility for full-text articles review

References were included if they reported outcomes of conventional external beam radiotherapy in a population where SFRT was administered for the first time, in either a prospective or retrospective setting. Articles not clearly identifying patient populations, study designs or dose fractions were conservatively included for review. Studies were excluded if they were duplicates, combined radiotherapy with other concurrent local or systematic treatments, or employed hemi-body-, radiopharmaceutical- or stereotactic radiation therapy.

Articles selected for synthesis

Full-text articles were included in this review if they reported pain response. Reference lists of articles were also reviewed, and full-text articles of relevant papers were obtained and similarly analyzed. Discrepancies for final selections were resolved by authors via consensus.

Data abstraction

The primary endpoints were pain response. When possible, reported pain response was categorized into partial, complete and overall pain response as reported in each study. Pain response assessments closest to 1–2 months following SFRT were recorded, as this is a common time to evaluate response and also a clinically important time frame for assessment of re-treatment (24,27,28).

Partial response (PR) rates were recorded as defined by authors in their studies, and complete response (CR) was generally defined as absence of pain following SFRT; defined criteria for CR and PR, were noted when reported. Overall response (OR) was defined as an improvement in pain after radiotherapy, and usually a summation of PR and CR. When studies did not separately document PR and CR, the response rate was documented as OR. PR, CR and OR were both documented under the analyses of both Intention-To-Treat (ITT) and Evaluable Patients (EP). Response rates when documented using percentages were converted to ratios; when multiple ratios yielded the same percentage, the number with lower patient response was noted. When conflicting number of EP were presented (8), the larger-value of EP was taken into account. Under circumstances where EP was not documented, ITT was recorded as EP.

The secondary endpoints were the rates of re-treatment, spinal cord compression, pathological fracture and acute toxicities such as pain flare, nausea, vomiting and diarrhea. Average duration of pain flare was recorded. Additional information extracted from articles included the type of study, key eligibility criteria, dose, pain assessment tool, and time to pain response.

Results

A total of 635 articles were identified from the database search, and with an additional 39 articles included from reference lists, 674 papers were reduced to 417 records after duplicates (n=257) were removed. Ninety two full-text articles were assessed for eligibility, with 31 identified for potential quantitative synthesis (Figure 2). Ultimately 27 studies that reported the appropriate endpoints were included in this review (Figure 2). Twenty-three (4-9,16,25,29-43) and 3 (25,44,45) studies reported about pain response and pain flare, respectively, while one paper (46) documented both. When compared with the last review (24), four published before 2012 (35,39,41,43) and five additional papers published after 2012 (16,25,32,37,40) have been included in the current review. Studies included in the prior review that was written in languages other than English were not included, to be consistent with the search strategy with language-limitation.

Figure 2 PRISMA flow diagram.

There were four studies reporting on 4 Gy from 1988–2015, 3 studies on 6 Gy from 1995–2002, 23 studies on 8 Gy from 1986–2015 and 1 study on 10 Gy published in 1997. Of the 24 studies that documented pain response, 1 (16) was a retrospective study, 1 (39) was an observational study, and the remaining 22 (4-9,25,29-38,40-43,46) were prospective studies. Only three studies (36-38) compared head-to-head different SFRT doses, while other studies reviewed SFRT vs. MFRT (4-9,16,25,29-34,38,41,46) or just SFRT alone (34,39,40,42). Key eligibility criteria varied slightly in each study; in general, enrolled patients were consenting adults with proven malignancy and pain due to metastatic disease (Table 1).

Table 1 Background information of studies detailing pain
Full table

Studies differed in their employed assessment tool for pain response—one relied on physician consult and a patient diary (7), while others used numerical point scales (5,6,8,16,29-31,34,36,37,39,41-43,46), Brief Pain Inventory (35,37) or Visual Analog Scale (4,25,32,39,40). The majority of studies measured pain response within 1 month (4-6,9,16,25,29,31-34,36-40,43,46), with a few studies noting response after 6 weeks (42), 2 months (41), 3 months (35) or 6 months (7). CR and PR was reported in all but three studies (7,42), with study-specific criteria for CR and PR noted in Table 2. While some studies contained 10–20 patients (7,16,32,42), others featured a study population in excess of 300 patients (8,9,35,37). PR ranged from 14% (6) to 62% (33), CR from 4% (42) to 39% (45) and OR from 24% (6) to 81% (5,7) (Table 2).

Table 2 Pain response by study
Full table

ITT analysis

10 Gy had the highest overall OR of 81%. 6, 8 and 4 Gy had 74%, 60% and 54% OR rates respectively. CR was also highest for 10 Gy at 37%. 6 Gy seconded at 30% while 8 and 4 Gy had 22% and 21% respectively. The highest PR rate was 6 Gy (44%), followed by 10 Gy (43%), 8 Gy (38%) and 4 Gy (32%) (Table 3).

Table 3 Pain response by dose
Full table

EP analysis

10 Gy registered the highest overall OR of 84%. 6, 8 and 4 Gy had 81%, 72% and 66% rates respectively. CR was also highest for 10 Gy at 39%. 6 Gy had 33%, while 8 and 4 Gy had 27% and 26% respectively. 6 Gy had the highest PR rate (48%), with 10, 4 and 8 Gy reported at 45%, 40% and 38% (Table 3).

Adverse events

Sixteen studies (4,6-9,25,32-34,36-38,41-43,46) reported the incidence of re-treatment, 7 on the occurrence of spinal cord compression (6,8,9,32,38,43,46), 11 on the frequency of pathological fracture (4,6-9,25,32,35,38,43,46) and 9 on acute toxicities (5,7,9,16,30,33,35,38,39). Re-treatment varied from 9% (36) to 44% (38), while spinal cord compression and pathological fracture spanned 2% (6,8,9) to 8% (38) and 0% (6,7) to 16% (25), respectively. Acute toxicities, when specified, were reported as hematologic (30,35), lung (30,35), central nervous system (CNS) (30,35,39), gastrointestinal (GI) (30,35), nausea (5,7,9,16,38), vomiting (5,7,9,38), diarrhea (7,38) and fatigue/tiredness (5) (Table 4).

Table 4 Prospectively-evaluated rates of re-treatment, spinal cord compression, pathological fractures, and acute toxicities by study
Full table

When analyzed by dosage, 4 Gy had the highest incident of re-treatment (28%), followed by 6 Gy (23%) and 8 Gy (21%). Similarly, 4 Gy had the highest incidence of spinal cord compression and pathological fracture (7% and 6%, respectively) compared to 6 Gy (4% for both) and 8 Gy (3% and 4%, respectively). Nausea and vomiting were reported together in the 4, 6 and 10 Gy setting, with the higher dose of 10 Gy reporting the most incidence at 40%. Nausea and vomiting were separately reported in the 8 Gy setting at 52% and 30%, respectively. Diarrhea occurred more frequently in the 4 Gy (13%) than 6 Gy (11%) (Table 5). However, the information of the radiation area was not detailed enough in the publications to allow further analysis of the gastro-intestinal side effects.

Table 5 Prospectively-evaluated rates of re-treatment, spinal cord compression, pathological fractures, and acute toxicities (nausea, vomiting, diarrhea) by dose
Full table

Pain flare documented across four studies (26,44-46) pertained to the 8 Gy dosage. Three different pain assessment tools were used—Brief Pain Inventory (26,44), Present Pain Intensity (45) and a 4-point categorical pain scale (46). Pain flare rates ranged from 10% (46) to 57% (45), with the overall combined rate being 25%. Gomez-Iturriaga et al. noted a mean pain flare duration of 3 days (26), while Loblaw et al. reported a median duration of 3 days (45) (Table 6).

Table 6 Pain flare
Full table

Discussion

This systematic review contains nine additional studies when compared with that of Dennis et al. (24), and also combined pain response rates reported by studies. Although the combined rates suggest that 10 and 6 Gy may produce superior OR and CR compared to 8 Gy, and 6 Gy may result in better PR than 8 Gy under EP, it is important to note that only a few studies document doses other than 8 Gy. The last study examining 6 Gy was from 2002 (34) and the only study examining 10 Gy was published in 1997 (5). The overall rates for doses other than 8 Gy need to be interpreted with caution especially in non-randomised studies. The three studies that did compare SFRT doses were conducted in 1992 (36), 1998 (38) and recently in 2015 (37). Hoskin et al. compared 4 and 8 Gy in 1992 and 2015, and concluded both times that 8 Gy produced superior pain response rates (36,37). Similarly, Jeremic et al. reported that 8 Gy had better pain response than 6 and 4 Gy SFRT (38). To date, there have been no trials comparing a single 8 Gy versus a single 10 Gy or higher.

There was a wide range of pain response rates in the heavily-studied 8 Gy arm, likely accounted for by the different criteria for pain response set out by each study. While CR generally had the same criteria (no pain following SFRT), the different parameters for PR may have led to different outcomes. Some studies noted PR as any improvement in pain scale (5,43,46), while others required at least a 2-point improvement on their pain scale and variable use of analgesics (41). Cultural influences could also have impacted the reporting of pain, with studies being conducted in different geographical locations (24).

The considerable amount of studies investigating 8 Gy SFRT and its accompanying overall lower rates of re-treatment, spinal cord compression and pathological fracture verifies the safety of administration. This reproducible data sets a standard for future SFRT doses to be compared against (24). 10 Gy has the highest response rates but with increased side effects in this review. Future efforts can be directed to confirm the efficacy of 10 Gy when compared with a single 8 Gy while minimizing the side effects of nausea and vomiting.

Pain flare was only well-documented in the 8 Gy SFRT setting, making it difficult to be compared to other doses. While Kirkbride and Aslanidis did present an abstract regarding pain flare in the 12 Gy SFRT, their results were never published in a paper (47). Although pharmaceutical responses have been examined to manage pain flare (48-50), clinicians should also examine whether there is a dose response with the occurrence of pain flare.

This review was not without limitations. It only included English papers, thereby missing out on other published studies (51,52) that comparably reported OR, CR and PR in a similar setting. Additionally, there was a lack of statistical analysis to determine if certain doses are significantly more efficacious than others. As a result, rankings of response rates based on a few percentage-points should be interpreted with great caution, taking into account heterogeneity of data and also lack of weighting of studies.

8 Gy SFRT was the most commonly administered dose for palliation of bone metastases. While 8 Gy SFRT cannot decisively be determined as the optimal dose for pain relief, studies that did directly compare different doses reported better pain responses for 8 Gy over 4 and 6 Gy (36,39). With extensive data supporting its efficacy and safety, 8 Gy SFRT should be the standard for all future comparable treatments, in an attempt to determine which dose produces the maximum benefit.

Acknowledgements

We thank the generous support of Bratty Family Fund, Michael and Karyn Goldstein Cancer Research Fund, Joey and Mary Furfari Cancer Research Fund, Pulenzas Cancer Research Fund, Joseph and Silvana Melara Cancer Research Fund, and Ofelia Cancer Research Fund.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

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