Affiliations of authors: Department of Radiation Oncology, Boston University Medical Center, Boston, MA (LK); Central Ohio Radiation Oncology, Columbus, OH (LB)
Correspondence to: Lisa Kachnic, MD, Department of Radiation Oncology, Boston University Medical Center, 88 East Newton St., EB 11, Boston, MA 02118 (e-mail: lisa.kachnic{at}bmc.org).
Bone metastases are a common manifestation of distant relapse from many types of solid malignancies, especially from cancers of the lung, breast, and prostate. Patients with a broad spectrum of solid cancers often develop painful bone metastases to the spine, pelvis, and extremities during the course of their disease (1). The goals of palliative treatment of bone metastases are pain relief, function preservation, and maintenance of skeletal integrity. Local-field external-beam radiation therapy is one well-recognized and effective palliative modality, with up to 80% of patients experiencing some improvement in their pain (2). Consensus statements from the National Comprehensive Cancer Network on Cancer Pain, the Second Workshop on Palliative Radiotherapy and Symptom Control, and the Ontario Guidelines for Palliative Pain advocate the use and efficacy of radiation therapy in palliating painful bone metastases (35).
There is continued debate over the appropriate fractionation scheme for the most effective regimen of palliative radiation therapy to treat bone metastases. To date, more than 40 different radiation therapy fractionation schedules have been reported in the literature, with 30 Gy in 10 fractions being the most common in the United States, 20 Gy over five fractions being the most common in Canada, and single fractions of 8 Gy being the most common in some European countries (such as Great Britain) (68). Despite a considerable body of evidence from randomized trials supporting the use of a single fraction of 8 Gy for radiation therapy (including the two largest trials, the Dutch Bone Metastasis Study and the Bone Pain Trial Working Party Study [BPTWG]), there has been a reluctance to adopt single fractionation as standard practice, even in the interest of patient convenience and cost effectiveness (9,10).
More than 20 years ago, the Radiation Therapy Oncology Group (RTOG) first reported in their trial RTOG 7402 that low-dose, short-course radiation therapy schedules were as effective as high-dose, longer-treatment programs in achieving pain relief from bone metastases (11). However, many aspects of this earlier randomized effort were criticized, including the inclusion of a heterogeneous group of primary cancer sites, the use of physician assessment of pain, and the fact that narcotic relief and the incidence of radiation therapy re-treatment were not taken into consideration. Moreover, different conclusions from this trial could be reached depending on the endpoint used to analyze pain relief (12). Perhaps, it has been this poor consensus on endpoint definition (lack of standard definitions for complete and partial pain relief), as well as a discrepancy in pain relief assessment (physician versus patient assessment), that have increased the reluctance of radiation oncologists to use single-fractionation radiation therapy schemes for the palliation of bone pain. However, there may also be a financial influence driving the continued use of longer radiation therapy palliative programs. In a study of the practice patterns for the treatment of bone metastases among European radiotherapy centers, fewer radiation therapy fractions were used by centers financed on a per-case basis than on fee-for-service basis. Fee-for-service centers were more likely to use custom blocking and administer a longer radiation therapy treatment course and higher total dose (13).
In 1999, the Dutch Bone Metastasis Study group reported (9) on a randomized trial of 1171 patients that compared 8 Gy in a single fraction with 24 Gy in six fractions. The BPTWG also reported (10) their study results of 765 patients who were randomly assigned to 8 Gy in a single fraction versus a multifraction schedule (either 20 Gy in five fractions or 30 Gy in 10 fractions). In this issue of the Journal, Hartsell et al. (14) report the results of RTOG trial 9701 that compared the efficacy of 8 Gy in a single radiation therapy fraction to 30 Gy in 10 fractions for the treatment of painful bone metastases. Although no trial can be perfect, care was taken by the RTOG investigators to incorporate criticisms of the previous trials in the design of their current study.
In RTOG 9701, only patients with breast or prostate cancer with an expected survival of 3 months or more were eligible. This study design provided for a homogeneous group of patients whose potential for long-term survival would allow sufficient follow-up to document the durable efficacy of the two treatments. This design is in contrast to that of the Dutch Bone Metastases trial and the BPTWG, which targeted bone metastases from many primary cancer sites and did not include prognosis as an early eligibility criterion.
Because determining the response to radiation therapy is a function of the trial's primary endpoint and of the instrument selected to measure it, the RTOG chose a sensitive, widely used patient-oriented pain scale that has been validated for the multi-institutional randomized trial setting: the Brief Pain Inventory (BPI) (15,16). The BPI asks patients to rate their pain for the last week on a scale of 010 at its "worst," "least," "average," and "now." Patients are also asked to estimate the pain relief that they are receiving from their pain treatment (in percent), to locate areas of pain on a human figure, and to estimate the cause of their pain (cancer disease, cancer treatment, or noncancer). The Dutch trial also used a pain scale of 010 (although it is unclear which instrument was used and whether the instrument was validated), but patients were asked only to describe their worst pain over the previous week. The BPTWG measurement was likewise vaguely described in their report (10) but appears to be only a 4-point pain scale.
Documentation of analgesic use is an integral component of any palliative treatment study. The RTOG, BPTWG, and Dutch studies all recorded the use of narcotics after treatment. However, the primary endpoint of the RTOG trial also incorporated the level of narcotic use. A complete response in the RTOG trial was zero pain on the BPI and complete cessation of narcotic use at 3 months. In contrast, neither the Dutch trial, which reported on the mean pain scores of both arms, nor the BPTWG, whose primary endpoint was long-term pain relief, took into account the use of narcotics in their primary endpoint. Furthermore, an attempt was made in the RTOG trial to assess possible confounding effects of systemic therapy by documenting the previous use of chemotherapy and bisphosphonates, and by stratifying for bisphosphonate use. Neither the Dutch trial nor the BPTWG trial commented on such confounding effects. Overall, the RTOG trial made a valiant effort to avoid the criticisms leveled by previous bone metastasis trials.
In terms of the primary endpoint results, there was no difference in complete response rates between the two arms in RTOG 9701 (17% in the 30-Gy arm and 15% in the 8-Gy arm) and partial response rates (49% and 50%, respectively). In the Dutch and BPTWG trials, there were also no differences in response rates between the single-fraction arm and arms with protracted radiation therapy. In the Dutch study, there was a 71% overall response (a decrease of at least 2 points on the pain scale), and a 35% complete response rate (no pain, independent of analgesic consumption). In the BPTWG trial, there was a 78% overall response, with a 57% complete response rate (no pain, independent of analgesic use). Given the difference in primary endpoint definitions among these three trials, the magnitude of complete pain responses appears similar. The lower absolute complete response rate in RTOG 9701 likely reflects their stringent endpoint definition requiring both zero pain on the BPI and zero narcotic use. Use of the stringent endpoint is unrealistic in a patient population with multiple causes for pain, including cancer sites other than the index site. However, it should be noted that at 3 months, 33% of patients required no analgesics. Interestingly, the results of the RTOG trial also showed that acute grade 24 toxicity was statistically significantly lower with single-fraction treatment rather than with protracted radiation therapy (7% versus 17%, respectively; P = .002), despite 51% of the patients receiving radiation to some part of the spine. Late toxicity (pathologic fractures) was equivalent in both arms (5% in the 8-Gy arm and 4% in the 30-Gy arm).
Although single-fraction radiation therapy appears to be as efficacious as multiple-fraction radiation therapy in these three randomized trials, the reported incidence of radiation therapy re-treatment rates in the single-fraction arm may be of concern to some oncologists. The re-treatment rate in the RTOG trial was twice as high in the single-fraction arm (18%) as in the multiple-fraction arm (9%). Re-treatment was not allowed before 4 weeks after the end of treatment, unless the pain level went up by 2 points on the BPI worst pain scale. It can then be assumed that re-treatment was administered to patients with persistent or increasing pain. Although these events were counted as treatment failures in the primary analysis of the RTOG study, nonetheless, there remained no statistically significant difference in the treatment failure rates of the two arms. Higher re-treatment rates were also reported in the Dutch Study with single-fraction therapy (24%) than with multiple-fraction therapy (6%) (P = .001). In a reanalysis of the Dutch data, the response rate after initial treatment was not predictive for re-treatment (17). Re-treatment for nonresponders was successful in 66% of the single-fraction group and in only 33% of the multiple-fraction group (P = .24). In the BPTWG study, a statistically significantly higher re-treatment rate was associated with the single-fraction arm (23%) than with the multiple-fraction arm (10%) (P<.001). Again, further analysis detected that there was no association between the initial pain outcome and the re-treatment rate. Therefore, the higher re-treatment rates with a single 8-Gy fraction may reflect only the increased willingness of both the patient and the physician to retreat after single-fraction radiotherapy compared with that after multiple-fraction radiotherapy. An international trial initiated by the National Cancer Institute of Canada (NCIC SC20) is examining the efficacy of radiation therapy re-treatment of bone metastases.
In conclusion, three very large randomized trialsthe Dutch Bone Metastases Study with 1171 patients, the BPTWG with 765 patients, and the RTOG trial reported in this issue with 898 patientshave all demonstrated that single-fraction radiation therapy is sufficient to achieve palliation of painful bone metastases. It remains to be seen if this approach will become standard of care in the United States. The outcome may distinguish whether radiation oncologists in the United States practice evidence-based or remuneration-based medicine.
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