Multifraction Regimens Research Articles

Effect of Radiation Field Size and Dose on Local Control or Re-fracture Events after Post-Operative Radiation Following Intramedullary Nailing Procedures for Palliation of Bone Metastases

Pathologic fracture of long bones carries a heavy symptomatic burden in patients with metastatic malignancy. Standard therapy typically includes intramedullary nail placement to stabilize the bone, followed by palliative post-operative radiation therapy (PORT) to reduce the risk of re-fracture or local recurrence. The radiation dose and fields for this treatment approach have wide variation without uniform standards. We sought to estimate the distribution of PORT dose/fractionation, and field size, and estimate any potential association with the risk of re-fracture and/or local recurrence. We retrospectively analyzed patients treated at our institution with pathologic fractures of long bones, treated with intramedullary nailing of the femur, tibia, or humerus, followed by post-operative palliative radiation to that site. We stratified patients by radiation fractionation (single vs multi-fraction regimen) and by radiation field size (coverage of whole hardware [full-field] vs partial coverage of hardware [limited field]), to determine if these factors may be associated with the primary endpoint, which was defined as local re-fracture and/or local recurrence of disease within the long bone. Fisher’s exact test was used for statistical comparison due to the relative paucity of events. Eighty-six evaluable patients, treated between 2010 and 2017, were identified. Median patient age was 60 years. Median Karnofsky performance status was 70. Median follow up was 2.6 months (range, 2 weeks to 74 months). Radiation doses ranged from 8 – 30Gy, apart from one patient who received 45Gy in 3 Gy fractions. Thirty-six patients (42%) received 8 Gy in a single fraction, and fifty (58%) received multi-fraction treatment. Ten patients (12%) underwent limited field radiation, while 47 (55%) underwent full field radiation, and 29 (34%) were unevaluable for field size. Nine patients (10%) reached the primary endpoint of local recurrence and/or local refracture, consistent with historical comparison. On Fisher’s two-sided exact test, field size was not found to correlate with local recurrence/re-fracture (p=0.366). Local recurrence/re-fracture was also not significantly associated with multi-fraction radiation, compared to those who received 8 Gy in a single fraction, although was numerically worse in the multifraction group (p=0.073). Increased total dose beyond 8 Gy was not associated with improvement in local control. Similarly, irradiation of the entire hardware was not associated with improved rates of local control as compared to limited field radiation. Our findings suggest that single-fraction, limited-field palliative PORT may be sufficient to achieve adequate rates of local control, thereby allowing for expedient initiation of systemic therapy and minimal RT toxicity. Further evaluation is needed.

Phase III Multi-Center, Prospective Randomized Trial Comparing High Dose Single Fraction Radiation Therapy to a 3-Fraction SBRT Regimen in the Treatment of Oligometastatic Human Cancer

Pre-clinical and clinical evidence have shown that high single dose radiation therapy (SDRT) is associated with superior tumor control compared to multi-fraction (MF) regimens, due to SDRT’s ability to engage a microvascular response interfering with the ability to repair radiation damage to tumor cell DNA. The primary objective of this study was to compare local control rates with either a single dose of 24Gy versus 27Gy in three 9Gy fractions in patients with oligometastatic disease. A secondary objective was to compare toxicity outcomes between the two cohorts. A total of 174 patients were enrolled at three institutions. 155 patients (75 randomized to the SDRT and 80 to the MF regimen) were assessable for treatment-related toxicities having met protocol criteria. A total of 117 patients with 154 treated lesions, were evaluable for the local disease control end point. Eligibility criteria for enrollment included ≤5 metastatic lesions documented on imaging studies, and no prior radiation therapy to the treated site. Eligible lesions were limited to non-mobile targets (osseous or lymph node metastases). Potential candidates whose target lesions were adjacent to critical organs, precluding treatment with SDRT due to the risk of treatment-induced complications, were excluded. Patients were followed every 6 months for a minimum of 2 years, and imaging evaluation of the treated site at 12 and 24 months post-treatment was mandatory. Responses were measured using standard RECIST criteria. For the assessment of toxicity, a minimum follow-up of 6 months was required. Median follow up was 39 months (range, 11-85). Lesions treated with SDRT demonstrated a significantly lower incidence of local disease progression (LR) compared to those treated with MF (p<0.0005). The 3-year incidence of LR was 6.1% of the lesions compared to 23% for the SDRT and MF regimens, respectively. A reduction in distant metastatic (DM) progression was noted among those treated with SDRT compared to the MF regimen The 3-year incidence of DM progression was 4.1% compared to 17.5% for the SDRT and MF regimens, respectively(p<0.02). There was no significant difference in grade 3+ toxicity between the two arms (SDRT: 10.7%; MF: 5%; p=0.24). The specific incidence of grade 3+ pain, peripheral neuropathy and bone fractures for the SDRT regimen was 5.3%, 2.7% and 1.3%. The corresponding incidence for these toxicities for the MF regimen was 1.3%, 0% and 2.5%. No overall survival differences were observed between the arms. The study provides Level 1 evidence that SDRT was associated with superior tumor control outcomes compared to a standard 3-fraction regimen in a cohort of patients with oligometastatic osseous/nodal disease. SDRT was well tolerated, rendering comparable toxicity outcomes to a current standard-of-care hypofractionated SBRT treatment regimen.

Prescription of Evidence-Based Single Fraction Radiation Therapy for Bone Metastases Can be Increased in a Meaningful and Sustained Way on a Population Level Using Quality Assurance Data

There is ample evidence that a single fraction of radiation therapy (SFRT) is as equally efficacious as more costly and potentially morbid multi-fraction regimens. In our large provincial program, we previously demonstrated that a multi-pronged educational and audit intervention increased the use of SFRT in all regional cancer centers the year following. However, other investigators have demonstrated interventions focused on guideline dissemination were only associated with a transient one year change in prescribing practices, and therefore we sought to determine if our use of SFRT also returned to baseline or persisted. Several province-wide interventions were implemented in 2012 to increase the use of SFRT, including an audit of prescribing practices of individual physicians (anonymized) and center averages (non-anonymized) and subsequent presentation of these results to leaders and oncologists. After individual patient chart review, we subsequently compared the use of SFRT in all patients treated with bone metastases in our provincial program from 2007-2011 (pre-intervention) and 2013-2016 (post-intervention), and performed comparison across all six provincial cancer centers. Prior to the intervention, the rates of SFRT in 2007, 2008, 2009, 2010, and 2011 were 51, 51, 48, 49, and 48, while the rates post intervention in 2013, 2014, 2015, and 2016 were 60, 60, 57, and 54% (p <0.001). In the most recent year of this study (2016), 4 of the 6 provincial centers prescribed in a relatively narrow range (45, 48, 53, and 54%). However, there was little change in the center with the lowest use of SFRT (26% to 25%) or in the center with the highest use of SFRT (73% to 75%). Our audit and educational based intervention resulted in a lasting change in practice. A small trend toward decreasing SFRT in recent years was observed, though rates were still above our pre-intervention level and well above international comparisons. Our provincial rate is similar to a previously published recommended benchmarks rate of 60%, though we continue to see significant variation by center, suggesting further room for improvement in provincial standardization. With the potential of emerging evidence in support of stereotactic ablative radiation therapy for select populations of patients with bone metastases, future benchmark rates of SFRT use should be readdressed, though our data suggest programmatic comparison and dissemination of SFRT prescribing practices can achieve a population based SFRT utilization rate of over 50%.

The influence of fractionated radiotherapy on the stability of spinal bone metastases: a retrospective analysis from 1047 cases

BackgroundThe effect of radiotherapy, in particular the application of different multi-fraction schedules in the management of unstable spinal bone metastases (SBM), is incompletely understood. This study aims to compare the radiological response regarding various dose and fractionation schedules of radiotherapy in the palliative treatment of SBM.MethodsWe retrospectively assessed 1047 patients with osteolytic SBM, treated with palliative radiotherapy at our department between 2000 and 2015. Lung cancer (40.2%), breast (16.7%) and renal cancer (15.2%) were the most common solid tumors in this study. Different common multi-fraction regimen (5x4Gy, 10x3Gy, 14 × 2.5Gy and 20x2Gy) were compared with regard to radiological response and recalcification at 3 and 6 months after radiotherapy. The Taneichi score was used for classification of osteolytic SBM.ResultsMedian follow up was 6.3 months. The median overall survival (OS) in the short-course radiotherapy (SCR) group using less than 10 treatment fractions was 5.5 months vs. 9.5 months in the long-course radiotherapy (LCR) group using in excess of 10 fractions (log rank p < .0001). Overall survival (OS) in the SCR group after 3 and 6 months was 66.8 and 49.1%, respectively vs 80.9 and 61.5%, respectively in the LCR group.17.6% (n = 54/306) and 31.1% (n = 89/286) of unstable SBM were classified as stable in the SCR group at 3 and 6 months post radiotherapy, respectively (p < .001 for both). In the LCR group, 24.1% (n = 28/116) and 34.2% (n = 38/111) of unstable SBM were stabilized after 3 and 6 months, respectively (p < .001 for both).ConclusionsOur study shows no significant difference in stabilization achieving recalcification rates between multi-fraction schedules (SCR vs. LCR) in the palliative management of unstable SBM. Both groups with multi-fraction regimen demonstrate a stabilizing effect following 3 and 6 months after radiotherapy.

High-Dose-Rate Brachytherapy Boost for Localised Prostate Cancer: Comparison of a Single 12.5 Gy Fraction to a Multi-fraction Regimen of 19 Gy in 2 Fractions, A Single Institution Experience

High-Dose-Rate Brachytherapy Boost for Localised Prostate Cancer: Comparison of a Single 12.5 Gy Fraction to a Multi-fraction Regimen of 19 Gy in 2 Fractions, A Single Institution Experience

Programmatic Comparison and Dissemination of an Audit of Single-fraction Radiation Therapy Prescribing Practices for Bone Metastases is Associated with a Meaningful and Lasting Change in Practice on a Population Level

There is ample evidence that single-fraction radiation therapy (SFRT) is as efficacious as more costly and morbid multifraction regimens. We previously demonstrated that an audit-based intervention increased the use of SFRT in all regional cancer centers the following year. However, other investigators have demonstrated that interventions were only associated with a transient 1-year change in prescribing practices. We sought to determine whether our intervention resulted in a more lasting impact. In 2012, we performed an audit of the prescribing practices of individual physicians, which was then presented to leaders and oncologists as an intervention to increase SFRT. We compared the use of SFRT between 2007 to 2011 (preintervention) and 2013 to 2016 (postintervention) in all 31,192 patients treated in our provincial program. The use of SFRT increased from 49.2% to 58.9% postintervention (P < .001). Rates from 2007 to 2011 were 51%, 51%, 48%, 49%, and 48%, respectively, whereas the postintervention rates from 2013 to 2016 were 60%, 62%, 59%, and 56%, respectively. Postintervention, half of the centers prescribed SFRT in a relatively narrow range (55%-58%). However, across all centers, there was still a broad range, with the lowest and highest users at 35% and 81%, respectively, although the lowest-using center still showed a significant increase (26% to 35%; P < .001). Our audit and education-based intervention resulted in a lasting and meaningful 10% change in practice. Our provincial rate is similar to that of a previously recommended benchmark rate of 60%, but we continue to see significant variation by center, suggesting further room for improvement in provincial standardization. With emerging evidence in support of ablative radiation therapy for select populations of patients with bone metastases, future benchmark rates of SFRT should be readdressed. However, our data suggest that programmatic comparison and dissemination of SFRT prescribing practices can achieve a population-based SFRT utilization rate near 60%.

One- vs. Three-Fraction Pancreatic Stereotactic Body Radiation Therapy for Pancreatic Carcinoma: Single Institution Retrospective Review.

Early reports of stereotactic body radiation therapy (SBRT) for pancreatic ductal adenocarcinoma (PDAC) used single fraction, but eventually shifted to multifraction regimens. We conducted a single institution review of our patients treated with single- or multifraction SBRT to determine whether any outcome differences existed. Patients treated with SBRT in any setting for PDAC at our facility were included, from 2004 to 2014. Overall survival (OS), local control (LC), regional control (RC), distant metastasis (DM), and late grade 3 or greater radiation toxicities from the time of SBRT were calculated using Kaplan-Meier estimation to either the date of last follow-up/death or local/regional/distant failure. We identified 289 patients (291 lesions) with pathologically confirmed PDAC. Median age was 69 (range, 33-90) years. Median gross tumor volume was 12.3 (8.6-21.3) cm3 and planning target volume 17.9 (12-27) cm3. Single fraction was used in 90 (30.9%) and multifraction in 201 (69.1%) lesions. At a median follow-up of 17.3 months (IQR 10.1-29.3 months), the median survival for the entire cohort 17.8 months with a 2-year OS of 35.3%. Univariate analysis showed multifraction schemes to have a higher 2-year OS 30.5% vs. 37.5% (p = 0.019), it did not hold significance on MVA. Multifractionation schemes were found to have a higher LC on MVA (HR = 0.53, 95% CI, 0.33-0.85, p = 0.009). At 2 years, late grade 3+ toxicity was 2.5%. Post-SBRT CA19-9 was found on MVA to be a prognostic factor for OS (HR = 1.01, 95% CI, 1.01-1.01, p = 0.009), RC (HR = 1.01, 95% CI 1.01-1.01, p = 0.02), and DM (HR = 1.01, 95% CI, 1.01-1.01, p = 0.001). Our single institution retrospective review is the largest to date comparing single and multifraction SBRT and the first to show multifraction regimen SBRT to have a higher LC than single fractionation. Additionally, we show low rates of severe late toxicity with SBRT.

One Versus 3 Fraction Pancreatic SBRT for Pancreatic Adenocarcinoma: Single Institution Retrospective Review

Early reports of Stereotactic Body Radiation Therapy (SBRT) for pancreatic carcinoma used a single fraction regimen, but subsequent clinical experience switched to multi-fraction regimens. We therefore conducted a single institution review of patients treated with single or multi-fraction SBRT to determine if there were differences in outcome based on fractionation. We conducted a retrospective review of patients treated between 2004 and 2014. Overall survival (OS), local control (LC), regional control (RC), and late toxicity were our primary endpoints. Statistical analysis was performed using IBM SPSS Statistics Version 23. P-values less than 0.05 were deemed significant for both univariate (UVA) and multivariate analysis (MVA). We identified 289 patients with 291 lesions who had pathologically confirmed pancreatic adenocarcinoma. Median age was 69 (33-90) years. Median gross tumor volume (GTV) was 12.3 cm3 (range 8.6-21.3) and planning tumor volume (PTV) 17.9 cm3 (range 12–27). Single fraction was used in 90 (30.9%) and multifraction in 201 (69.1%) lesions. At a median follow-up of 17.3 months (IQR 10.1-29.3 months), the median survival for the entire cohort 17.8 months with a 2-year OS of 35.3%. While univariate analysis showed multi-fraction schemes to have a higher 2-year OS 30.5% vs. 37.5% (P = 0.019), it did not hold significance on multivariate analysis. Multi-fractionation schemes were found to have a higher 2-year LC (69.7% vs 56.8%) on MVA [HR = 0.53, 95% CI (0.33-0.85), P = 0.009]. Fractionation scheme on univariate analysis did not affect regional control (P = 0.541) or distant metastasis (P = 0.226). At 2 years, late grade 2+ toxicity was 7.8% and late grade 3+ toxicity was 3.5%. Post-SBRT CA19-9 was found on MVA to be a prognostic factor for OS [HR = 1.01, 95% CI (1.01-1.01), P = 0.009], RC [HR = 1.01, 95% CI (1.01-1.01), P = 0.02] and DM [HR = 1.01, 95% CI (1.01-1.01), P = 0.001]. This single institution retrospective review shows multi-fraction regimens SBRT had a higher LC than single fractionation regimens. While multi-fraction regimens had a higher OS on univariate, this did not hold true on MVA. We showed low rates of late grade 2+ and grade 3+ toxicity with SBRT. Post-SBRT CA19-9 was found to be significant factor for OS, RC, and DM. This single institution report is the largest retrospective series showing multi-fraction regimens SBRT is associated with a higher LC than single fractionation regimens.

Stereotactic spine radiosurgery: Review of safety and efficacy with respect to dose and fractionation.

Background:Stereotactic body radiotherapy (SBRT) is an emerging treatment option for spinal metastases with demonstrated efficacy in the upfront, postoperative, and re-treatment settings, as well as for tumor histologies considered radioresistant. Uncertainty exists regarding the optimal dose and fractionation schedule, with single and multifraction regimens commonly utilized.Methods:A literature search of the PubMed and Medline databases was conducted to identify papers specific to spine SBRT and the effect of varying dose/fractionation regimens on outcomes. Bibliographies of relevant papers were searched for further references, and international spine SBRT experts were consulted.Results:Local control rates generally exceed 80% at 1 year, while high rates of pain control have been attained. There is insufficient evidence to suggest superiority of either single or multiple fraction regimens with respect to local control and pain control. Low rates of toxicity have been reported, assuming strict dose constraints are respected. Radiation myelopathy may be the most morbid toxicity, although the rates are low. The risk of vertebral compression fracture appears to be associated with higher doses per fraction such as those used in single-fraction regimens. The Spinal Instability Neoplastic Score should be considered when evaluating patients for spine SBRT, and prophylactic stabilisation may be warranted. Pain flare is a relatively common toxicity which may be mediated with prophylactic dexamethasone. Because of the treatment complexity and potentially serious toxicities, strict quality assurance should occur at the organizational, planning, dosimetric, and treatment delivery levels.Conclusion:Both single and multifraction regimens are safe and efficacious in spine SBRT for spinal metastases. There may be advantages to hypofractionated treatment over single-fraction regimens with respect to toxicity. Ongoing investigation is underway to define optimal dose and fractionation schedules.

Low and Intermediate Risk Prostate Cancer Treated with Single Fraction 19 Gy High Dose Rate Brachytherapy as Monotherapy: Outcomes Comparison to Multi-Fraction Regimens

Low and Intermediate Risk Prostate Cancer Treated with Single Fraction 19 Gy High Dose Rate Brachytherapy as Monotherapy: Outcomes Comparison to Multi-Fraction Regimens

Stereotactic Body Radiation Therapy for Oligometastatic Prostate Cancer

To review outcomes of patients with oligometastatic prostate cancer (PCa) treated with stereotactic body radiation therapy (SBRT) and to identify variables associated with local failure. We retrospectively reviewed records of patients treated with SBRT for oligometastatic PCa. Metastasis control (ie, control of the treated lesion, MC), biochemical progression-free survival, distant progression-free survival, and overall survival were estimated with the Kaplan-Meier method. Sixty-six men with 81 metastatic PCa lesions, 50 of which were castrate-resistant, were included in the analysis. Lesions were in bone (n=74), lymph nodes (n=6), or liver (n=1). Stereotactic body radiation therapy was delivered in 1 fraction to 71 lesions (88%), at a median dose of 16Gy (range, 16-24Gy). The remaining lesions received 30Gy in 3 fractions (n=6) or 50Gy in 5 fractions (n=4). Median follow-up was 16months (range, 3-49months). Estimated MC at 2years was 82%. Biochemical progression-free survival, distant progression-free survival, and overall survival were 54%, 45%, and 83%, respectively. On multivariate analysis, only the dose of SBRT was significantly associated with MC; lesions treated with 16Gy had 58% MC, and those treated with ≥18Gy had 95% MC at 2years (P≤.001). At 2years, MC for lesions treated with 18Gy (n=21) was 88%. No patient treated with ≥18Gy in a single fraction or with any multifraction regimen had local failure. Six patients (9%) had grade 1 pain flare, and 2 (3%) had grade 2 pain flare. No grade 2 or greater late toxicities were reported. Stereotactic body radiation therapy for patients with oligometastatic prostate cancer provided optimal metastasis control and acceptable toxicity with doses ≥18Gy. Biochemical progression-free survival was 54% at 16months with the inclusion of SBRT in the treatment regimen. Stereotactic body radiation therapy should be considered in patients with castration-refractory, oligometastatic prostate cancer who have limited options for systemic therapy.

Osseous Pseudoprogression in Vertebral Bodies Treated with Stereotactic Radiosurgery: A Secondary Analysis of Prospective Phase I/II Clinical Trials

Osseous pseudoprogression on MR imaging can mimic true progression in lesions treated with spine stereotactic radiosurgery. Our aim was to describe the prevalence and time course of osseous pseudoprogression to assist radiologists in the assessment of patients after spine stereotactic radiosurgery. A secondary analysis of 2 prospective trials was performed. MRIs before and after spine stereotactic radiosurgery were assessed for response. "Osseous pseudoprogression" was defined as transient growth in signal abnormality centered at the lesion with a sustained decline on follow-up MR imaging that was not attributable to chemotherapy. From the initial set of 223 patients, 37 lesions in 36 patients met the inclusion criteria and were selected for secondary analysis. Five of the 37 lesions (14%) demonstrated osseous pseudoprogression, and 9 demonstrated progressive disease. There was a significant association between single-fraction therapy and the development of osseous pseudoprogression (P = .01), and there was a significant difference in osseous pseudoprogression-free survival between single- and multifraction regimens (P = .005). In lesions demonstrating osseous pseudoprogression, time-to-peak size occurred between 9.7 and 24.4 weeks after spine stereotactic radiosurgery (mean, 13.9 weeks; 95% CI, 8.6-19.1 weeks). The peak lesion size was between 4 and 10 mm larger than baseline. Most lesions returned to baseline size between 23 and 52.4 weeks following spine stereotactic radiosurgery. Progression on MR imaging performed between 3 and 6 months following spine stereotactic radiosurgery should be treated with caution because osseous pseudoprogression may be seen in more than one-third of these lesions. Single-fraction spine stereotactic radiosurgery may be associated with osseous pseudoprogression. The possibility of osseous pseudoprogression should be incorporated into the prospective criteria for assessment of local control following spine stereotactic radiosurgery.

Utilization of single-fraction radiotherapy for the treatment of bone metastases before and after the “Choosing Wisely” campaign.

245 Background: Multiple studies have demonstrated equivalence of single vs. multi-fraction regimens for palliation of uncomplicated bone metastases, but single fraction (SF) radiotherapy (RT) remains under-utilized in the United States. To increase physician and patient awareness of RT options for bone metastases, both AAHPM and ASTRO participated in the “Choosing Wisely” campaign. AAHPM recommended 8 Gy X 1 for uncomplicated bone metastases. ASTRO recommended against routine use of courses &gt; 10 fractions and supported strong consideration for the use of SF RT for patients with limited prognosis or transportation difficulties. To identify possible changes in prescribing patterns following “Choosing Wisely”, we evaluated utilization rates of SF (8 Gy x 1) for treatment of bone metastases via treatment requests submitted for preauthorization over a 3 year period. Methods: A proprietary web-based application (eviti Connect ) enables oncology providers to obtain real time automated precertification for patients insured by payers across the U.S. that utilize the platform. All preauthorization requests for RT of bone metastases were evaluated for the prescription of 8 Gy X 1. The overall rate of SF use was calculated as were quarterly rates within the study period. Results: From 6/1/11-6/30/14 7,524 requests were submitted; 658 were for bone metastases. Overall SF was used in 7.6 % of cases. Prior to Q4 of 2012 no prescriptions for 8 Gy X 1 were used. In 2013 SF was prescribed in 9.6% of cases (30/314): 2.8%, 7.3%, 7% and 20% for Q1, Q2, Q3, and Q4 respectively. During 2014 use of 8 Gy X 1 was 23.9% in Q1 and 19.5% in Q2. Protracted schedules &gt; 10 treatments were prescribed in 31% of cases, but decreased over the study period (from 40% prior to Q4 2012, to 28% in 2013, and to 23% in the first half of 2014). Conclusions: Within this unique dataset of working aged insured patients, utilization of 8 Gy X 1 for treatment of bone metastases has increased. Increases were most pronounced in 2013. This coincides with the announcement and dissemination of the “Choosing Wisely” initiatives. Longer follow-up is needed to determine if increased provider uptake of SF RT as a componant of patient-centered quality care persists.

Palliative Radiotherapy: Run With the Hare and Hunt With the Hounds

study on palliative radiotherapy in metastatic non–small-cell lung cancer. These population-based cohort data confirm the important role of radiotherapy in palliative care; more than 50% of patients received radiotherapy. The authors concluded that a substantial proportion of patients receive more treatments and at higher doses than what is supported by current evidence. There is a continued debate over the appropriate fractionation scheme for the most effective regimen of palliative radiation therapy. Meta-analysis and randomized clinical trials suggest that single-fraction radiotherapy offers more pain relief than fractionated schedules and reduces the travel and treatment costs. 2-5 All these studies evaluated treatment effect on pain relief and duration of response, yet this assessment remains difficult and subjective. In addition, it is difficult to identify which patients need radiation as a purely palliative approach. If we focus on a median survival after metastatic diagnosis of 20 weeks, as reported in this study, 1 a long radiation treatment period (4 to 6 weeks, the standard used in a radiation therapy curative approach) is a large proportion of a patient’s remaining lifetime; that being so, it is necessary to use shorter fraction schedules with a higher dose per fraction to achieve the outcome as soon as possible. These radiation schedules result in less troublesome acute adverse effects that lead to poor quality of life. Late radiation adverse effects are not considered, because they appear after 6 months. However, here too, it is necessary to differentiate between pain relief for solid tumors pushing on nociceptors and palliative treatment for tumors occluding a small anatomic space. In the first, radiosensitive host cells—including macrophages and osteoclasts, which respond to low doses of ionizing radiation by apoptosis—may be therapeutic targets. Roentgen therapy or single-beam megavoltage radiotherapy (used in most clinical trials) obtains pain relief despite underdosing, which suggests activity on an inflammatory response pathway. In the second, palliative response seems to be related to the degree of shrinkage of the tumor, so it is not surprising if an increase in survival is demonstrated in patients with locally advanced lung cancer with higher doses of radiotherapy. If 20% of patients remain alive at 15 months, then there is a fine line between a palliative and a curative treatment. There is sufficient time to develop late adverse effects, creating a detrimental effect on quality of life, considering that hypofractionation correlates to a higher rate of late effects. Furthermore, patients treated with a single radiation fraction have greater possibility of being retreated. Observed retreatment rates were higher with the use of a single fraction at 20% to 25% compared with 7% to 12% after multifraction regimens. 3,4 In these cases, the aim of radiotherapy is to obtain an effective response and also to minimize associated long-term tissue damage. To run with the hare and hunt with the hounds, radiation oncologists have used a moderately hypofractionated (30 Gy in 10 fractions) schedule to obtain acceptable acute and late adverse effects within an appropriate timescale. Considering all this, at the present time, there are no clear objective criteria to define which patients need purely palliative radiotherapy, and this may form the basis of reluctance to adopt single fractionation as standard practice.

Continuous controversy about radiation oncologists’ choice of treatment regimens for bone metastases: should we blame doctors, cancer-related features, or design of previous clinical studies?

Recent studies from Italy, Japan and Norway have confirmed previous reports, which found that a large variety of palliative radiotherapy regimens are used for painful bone metastases. Routine use of single fraction treatment might or might not be the preferred institutional approach. It is not entirely clear why inter-physician and inter-institution differences continue to persist despite numerous randomized trials, meta-analyses and guidelines, which recommend against more costly and inconvenient multi-fraction regimens delivering total doses of 30 Gy or more in a large number of clinical scenarios. In the present mini-review we discuss the questions of whether doctors are ignoring evidence-based medicine or whether we need additional studies targeting specifically those patient populations where recent surveys identified inconsistent treatment recommendations, e.g. because of challenging disease extent. We identify open questions and provide research suggestions, which might contribute to making radiation oncology practitioners more confident in selecting the right treatment for the right patient.

1424P - Comparison of 8GY Single Fraction Radiotherapy Versus 20GY in Five Fractions or 30GY in 10 Fractions for the Treatment of Metastatic Bone Pain

ABSTRACT Introduction In 1974 the Radiation Therapy Oncology Group (RTOG) initiated a randomized clinical trial comparing various dose-fractionation schedules in the palliation of cancer metastatic to bone. The trial was closed in February of 1980 and results have been published in 1982, with the conclusion that: “low-dose short schedules are as effective as more aggressive protracted programs. Since that time, different radiotherapy schedules had been employed for palliation of bone metastasis: 40 Gy in 20 fractions, 30 Gy in 10 fractions and single fractions of 8 Gy, 6 Gy or 4 Gy. Several randomized prospective trials and meta-analyses have been reported showing the same results in pain relief when comparing single doses vs protracted treatments. Objectives The aim of this study was to compare the most common fractionation used in oncology to treat bone metastases which are 8Gy single fraction, 20Gy in five fractions and 30Gy in 10 fractions. Method A total dose of 120 patients who is known to have stage VI cancer with bone metastasis at King Hussein Medical Center between January 2007 and December 2009, were allocated to receive either 8Gy single fraction, 20Gy in five fractions or 30Gy in 10 fractions for the treatment of their pain. Patient recorded pain severity and analgesic requirements on questionnaire which was filled by the main investigator before treatment, at 2 weeks and at 1,2,3,4,5,6,8,10, and 12 months after radiotherapy. Pain relief was the primary endpoint of treatment benefit. Results There was no difference in the time to first improvement in pain, time to complete pain relief or in time to first increase in pain at any time up to 12 months after randomization, nor in the class of analgesic used. Retreatment was twice as common after 8Gy than after multifraction radiotherapy, although retreatment for residual or recurrent pain did not reflect a difference between the three groups in the probability of pain relief. Conclusion A single fraction of 8 Gy when used for the treatment of bone metastasis is as safe and effective as a multifraction regimen for the palliation of metastatic bone pain for at least 12 months. This may make it suitable alternative to the multifraction radiotherapy regimens. Keywords: Bone metastases; Radiotherapy; Pain relief; Palliation Disclosure All authors have declared no conflicts of interest.

Tumor Volume-Adapted Dosing in Stereotactic Ablative Radiotherapy of Lung Tumors

Current stereotactic ablative radiotherapy (SABR) protocols for lung tumors prescribe a uniform dose regimen irrespective of tumor size. We report the outcomes of a lung tumor volume-adapted SABR dosing strategy. We retrospectively reviewed the outcomes in 111 patients with a total of 138 primary or metastatic lung tumors treated by SABR, including local control, regional control, distant metastasis, overall survival, and treatment toxicity. We also performed subset analysis on 83 patients with 97 tumors treated with a volume-adapted dosing strategy in which small tumors (gross tumor volume <12 mL) received single-fraction regimens with biologically effective doses (BED) <100 Gy (total dose, 18-25 Gy) (Group 1), and larger tumors (gross tumor volume ≥12 mL) received multifraction regimens with BED ≥100 Gy (total dose, 50-60 Gy in three to four fractions) (Group 2). The median follow-up time was 13.5 months. Local control for Groups 1 and 2 was 91.4% and 92.5%, respectively (p = 0.24) at 12 months. For primary lung tumors only (excluding metastases), local control was 92.6% and 91.7%, respectively (p = 0.58). Regional control, freedom from distant metastasis, and overall survival did not differ significantly between Groups 1 and 2. Rates of radiation pneumonitis, chest wall toxicity, and esophagitis were low in both groups, but all Grade 3 toxicities developed in Group 2 (p = 0.02). A volume-adapted dosing approach for SABR of lung tumors seems to provide excellent local control for both small- and large-volume tumors and may reduce toxicity.

Palliative radiotherapy in stage III/IV NSCLC: Dose, fractionation, and survival.

e18064 Background: Radiotherapy (RT) is frequently used to palliate the symptoms of advanced stage 3 and 4 NSCLC. A number of fractionation regimens are employed in the United Kingdom, although the optimal dose and fractionation remains unclear. Methods: A single-center, single-consultant practice in the United Kingdom was reviewed retrospectively (2003-2009). A total of 343 patients received palliative RT for stage 3 or 4 NSCLC either alone or as part of bimodality therapy with chemotherapy/TKI's. All patients were CT planned and treated with opposed photon fields. Four dose/fractionation regimens were examined. The inter-relationship with systemic therapy was reviewed, with the majority of patients receiving RT as consolidation following systemic therapy. Results: See Table. Conclusions: Significantly improved survival was observed in the multifraction regimens as compared to single-fraction treatments. A trend to improved survival over other regimens was observed in the 36Gy/12 fraction group. Significantly higher systemic therapy usage was noted in the 10 and 12 fraction regimens, a result primarily of better patient performance scores. The strong correlation with systemic therapy usage in improving outcomes may play a significant role when employed sequentially with RT. Regimen No. patients Mean age (yrs) Median survival (months) % receiving chemotherapy % receiving TKI % total receiving systemic therapy 10Gy single fraction 45 75.6 (58- 92) 4.0 (0-18) 6.7% 0% 6.7% 20Gy in 5 fractions (1 week) 176 70.5 (37- 93) 8.0 (0-77) 22.2% 3.9% 26.1% 30Gy in 10 fractions (2 weeks) 93 77.5 (39-94) 9.0 (0-47) 52.1% 10.7% 62.8% 36Gy in 12 fractions (2.5 weeks) 29 61.2 (43-78) 13.0 (3-43) 62.1% 10.3% 72.4% No significant financial relationships to disclose.

Treatment of painful bone metastases

Bone metastases are the most common cause of cancer-related pain. Radiotherapy is a safe and effective therapy and is well established for such a situation. A fractionation regimen with a short overall treatment time (< or =1 week) would be preferred if it was as effective as longer courses (2-4 weeks). Randomized clinical trials and meta-analyses have demonstrated that single-fraction radiotherapy with 1 x 8 Gy is as effective for pain relief as multi-fraction regimens such as 5 x 4 Gy in 1 week or 10 x 3 Gy in 2 weeks. Re-irradiation for recurrent pain in the irradiated region is required more often after single-fraction radiotherapy than multi-fraction radiotherapy; however, re-irradiation following single-fraction radiotherapy is safe and effective. Thus, 1 x 8 Gy is considered the standard regimen for uncomplicated painful bone metastases without pathological fractures or spinal cord compression. Multi-fraction radiotherapy results in significantly better remineralization of the osteolytic bone than single-fraction radiotherapy. Remineralization is important for preventing or treating pathological fractures. Multi-fraction long-course radiotherapy results in fewer recurrences of spinal-cord compression within the irradiated spinal region. Thus, long-course multi-fraction radiotherapy should be reserved for patients with a relatively favorable survival prognosis.

Randomized clinical trial with two palliative radiotherapy regimens in painful bone metastases: 30 Gy in 10 fractions compared with 8 Gy in single fraction

Background and purpose The aim was to demonstrate similar pain relief with two schedules of radiotherapy for painful bone metastases. Materials and methods A total of 160 patients were assigned to receive a single 8-Gy fraction or 30 Gy in 10 fractions. Pain intensity was measured on an ordinal pain scale of 0–10. Partial response was defined as a pain reduction of two points or more and complete response as a pain score of zero at the treated area. Response follow-up was at 3, 12, 24 and 48 weeks. Results The overall response was 75% in the 8-Gy arm and 86% in the 30-Gy arm. Complete response and partial response rates were 15% and 60% in the 8-Gy arm, 13% and 73% in the 30-Gy arm. Acute toxicity was of 18% in the 30-Gy arm and of 12% in the 8-Gy arm. These differences were not statistically significant. The re-treatment rate was 28% vs 2% in the 8-Gy and 30-Gy arms, respectively, these were statistically significant. Conclusions A single-fraction regimen of 8 Gy was as safe and effective as a multifraction regimen of 30 Gy for painful bone metastases in terms of pain relief.