[Radiotherapy for Bone Metastases].

Appropriate use of radiotherapy leads to a better patient care. Oncologists may wonder when to apply radiotherapy for painful bone metastases, what patients should particularly be offered radiotherapy, when to apply re-irradiation, when to apply radiotherapy to malignant spinal cord compression, or whether to apply radiotherapy to prevent symptoms. This paper aims to offer non-radiation oncologist physicians knowledge to help them better refer patients to radiation oncology.

Treatment response after palliative radiotherapy for bleeding gastric cancer: a multicenter prospective observational study (JROSG 17-3).

BACKGROUND: Palliative radiotherapy seems to be rarely performed for incurable gastric cancer. In this first multicenter study, we examined the effectiveness of palliative radiotherapy and investigated whether biologically effective dose (BED) is associated with survival, response, or re-bleeding. METHODS: Eligibility criteria included blood transfusion or hemoglobin levels < 8.0 g/dL. The primary endpoint was the intention-to-treat (ITT) bleeding response rate at 4 weeks. Response entailed all of the following criteria: (i) hemoglobin levels ≥ 8.0 g/dL; (ii) 7 consecutive days without blood transfusion anytime between enrollment and blood sampling; and (iii) no salvage treatment (surgery, endoscopic treatment, transcatheter embolization, or re-irradiation) for bleeding gastric cancer. Re-bleeding was defined as the need for blood transfusion or salvage treatment. RESULTS: We enrolled 55 patients from 15 institutions. The ITT response rates were 47%, 53%, and 49% at 2, 4, and 8 weeks, respectively. The per-protocol response rates were 56%, 78%, and 90% at 2, 4, and 8 weeks, respectively. Neither response nor BED (α/ß = 10) predicted overall survival. Multivariable Fine-Gray model showed that BED was not a significant predictor of response. Univariable Cox model showed that BED was not significantly associated with re-bleeding. Grades 1, 2, 3, and, ≥ 4 radiation-related adverse events were reported in 11, 9, 1, and 0 patients, respectively. CONCLUSIONS: The per-protocol response rate increased to 90% during the 8-week follow-up. The frequent occurrence of death starting shortly after enrollment lowered the ITT response rate. BED was not associated with survival, bleeding response, or re-bleeding.

Influence of pain duration on pain outcomes following palliative radiotherapy for painful tumors: the sooner the irradiation, the better?

PURPOSE: The influence of pre-radiotherapy pain duration on post-treatment outcomes was assessed. METHODS: Patients that received palliative radiotherapy were analyzed in a prospective observational study investigating curative and palliative radiotherapy. Brief Pain Inventory data were acquired at baseline and 1, 2, and 3 months after commencing irradiation. The pain response in terms of the index pain (i.e., pain caused by the irradiated tumors) was assessed using the International Consensus Endpoint. Patients were diagnosed with predominance of other pain (POP) if non-index pain of malignant or unknown origin was present and showed a higher pain score than the index pain. Competing risk analyses were performed in which deaths without the pain endpoints were considered as competing events. RESULTS: Of 229 patients analyzed, 123 (54%) experienced a pain response and 43 (19%) experienced POP. Multivariable analyses using the Fine-Gray model revealed that patients with shorter pain duration (< 1 month) had higher cumulative incidence of pain response (subdistribution hazard ratio, 2.43; 95% confidence interval [CI], 1.35-4.38) and POP (subdistribution hazard ratio, 4.22; 95% CI, 1.30-13.70) compared with patients with longer pain duration (≥ 4 months). For patients with a pain duration of less than 1 month, cumulative incidence of pain response was estimated to be 69% (95% CI, 53-85%) and cumulative incidence of POP was estimated to be 15% (95% CI, 3-28%) at 1­month follow-up. CONCLUSION: Commencing palliative radiotherapy earlier may improve the probability of patients achieving a pain response, although POP may be more frequent.

Palliative brachytherapy and external beam radiotherapy for dysphagia from esophageal cancer: a nationwide survey in Japan.

BACKGROUND: International guidelines recommend brachytherapy for patients with dysphagia from esophageal cancer, whereas brachytherapy is infrequently used to palliate dysphagia in some countries. To clarify the availability of palliative treatment for dysphagia from esophageal cancer and explain why brachytherapy is not routinely performed are unknown, this study investigated the use of brachytherapy and external beam radiotherapy for dysphagia from esophageal cancer. METHODS: Japanese Radiation Oncology Study Group members completed a survey and selected the treatment that they would recommend for hypothetical cases of dysphagia from esophageal cancer. RESULTS: Of the 136 invited facilities, 61 completed the survey (44.9%). Four (6.6%) facilities performed brachytherapy of the esophagus, whereas brachytherapy represented the first-line treatment at three (4.9%) facilities. Conversely, external beam radiotherapy alone and chemoradiotherapy were first-line treatments at 61 and 58 (95.1%) facilities, respectively. In facilities that performed brachytherapy, the main reason why brachytherapy of the esophagus was not performed was high invasiveness (30.2%). Definitive-dose chemoradiotherapy with (≥50 Gy) tended to be used in patients with expected long-term survival. CONCLUSIONS: Few facilities routinely considered brachytherapy for the treatment of dysphagia from esophageal cancer in Japan. Conversely, most facilities routinely considered external beam radiotherapy. In the future, it will be necessary to optimize external beam radiotherapy.

Improvement in pain interference after palliative radiotherapy for solid and hematologic painful tumors: a secondary analysis of a prospective observational study.

BACKGROUND: We previously demonstrated that patients with painful hematologic tumors were more likely to experience pain response after palliative radiotherapy (RT) than those with painful solid tumors. However, it is unknown whether change in pain interference differs between these two tumor types. In the present study, we carried out a secondary analysis of our previous prospective observational study to investigate this matter. METHODS: From patients undergoing palliative RT to treat painful tumors, Brief Pain Inventory data were collected at the start of RT and at the 1-, 2-, and 3- month follow-ups. The Mann-Whitney U test was used to compare changes in pain interference score from baseline between the two groups. RESULTS: Of the 237 patients, 203 (86%) had solid and 34 (14%) had hematologic index tumors planned to receive RT. At baseline, the groups did not differ significantly in terms of pain score, analgesic use, or pain interference score. At the 1-, 2-, and 3-month follow-ups, the changes in pain interference score from baseline did not differ significantly between the two groups. In both groups, all seven pain interference items, other than sleep in patients with hematologic tumors at the 2-month follow-up, were significantly improved (P < 0.05). CONCLUSIONS: The two groups showed comparable benefit from RT in terms of improvement in pain interference. Patients with tumor-related pain should be offered the option of palliative RT, irrespective of whether the painful tumor is solid or hematologic.

Predictors of acute hematologic toxicity attributable to palliative radiotherapy: Analysis of patient characteristics and bone marrow dose-volume parameters.

PURPOSE: As predictors of hematologic toxicity (HT) after palliative radiotherapy (RT) have been studied insufficiently, we explored predictors of leukopenia, neutropenia, and thrombocytopenia attributable to palliative RT. METHODS: We retrospectively assessed patients with various solid tumors who had received palliative RT at our institution. Excluded from our study were patients who had undergone chemotherapy from one month before to one month after the start of RT. To measure the bone marrow dose, all bones were delineated, and the absolute volume of bone marrow that had received 5, 10, 20, and 30 Gy was recorded. Univariate and multivariate logistic regression analysis was performed to identify variables associated with leukopenia, neutropenia, or thrombocytopenia of grade 2 or higher (HT2+). RESULTS: Of 68 patients, 17 (25%) developed HT2+. Grade ≥ 2 leukopenia developed in 13 patients (19%), neutropenia in 8 (12%), and thrombocytopenia in 6 (9%). Only one patient experienced ≥ grade 3 toxicity. The median baseline and nadir white blood cell count (WBC) was 6.950 and 4.650x109/l, respectively; the absolute neutrophil count (ANC) was 5.236 and 3.307x109/l, respectively, and the platelet count was 249 and 177.5x109/l, respectively. Multivariate analysis revealed that female gender and a lower baseline WBC and ANC were significant independent predictors of HT2+. No bone marrow dose-volume parameter was a significant predictor of HT2+. CONCLUSIONS: Overall, HT was relatively mild. Female gender and lower baseline WBC and ANC may be predictors of HT elicited by palliative RT.

Radiation-induced Liver Injury after 3D-conformal Radiotherapy for Hepatocellular Carcinoma: Quantitative Assessment Using Gd-EOB-DTPA-enhanced MRI.

Focal liver reaction (FLR) appears in the hepatobiliary-phase images of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-DTPA-enhanced MRI) following radiotherapy (RT). We investigated the threshold dose (TD) for FLR development in 13 patients with hepatocellular carcinoma (HCC) who underwent three-dimensional conformal radiotherapy (3D-CRT) with 45 Gy in 15 fractions. FLR volumes (FLRVs) were calculated based on planning CT images by referring to fused hepatobiliary- phase images. We also calculated the TD and the irradiated volumes (IVs) of the liver parenchyma at a given dose of every 5 Gy (IVdose) based on a dose-volume histogram (DVH). The median TD was 35.2 Gy. The median IV20, IV25, IV30, IV35, IV40, and IV45 values were 371.1, 274.8, 233.4, 188.6, 145.8, and 31.0 ml, respectively. The median FLRV was 144.9 ml. There was a significant difference between the FLRV and IV20, IV25, and IV45 (p<0.05), but no significant differences between the FLRV and IV30, IV35, or IV40. These results suggest that the threshold dose of the FLR is approx. 35 Gy in HCC patients who undergo 3D-CRT in 15 fractions. The percentage of the whole liver volume receiving a dose of more than 30-40 Gy (V30-40) is a potential candidate optimal DVH parameter for this fractionation schedule.

Dosimetric Predictors of Treatment-related Lymphopenia induced by Palliative Radiotherapy: Predictive Ability of Dose-volume Parameters based on Body Surface Contour.

BACKGROUND: Radiation-related lymphopenia has been associated with poor patient outcome. Our aim was to identify predictors of lymphopenia after palliative radiotherapy, with a focus on dose-volume parameters. PATIENTS AND METHODS: To retrospectively assess patients with various cancers who had undergone palliative radiotherapy, we delineated three organs at risk: the volume enclosed by the body surface contour (body A), the volume left after excluding air, pleural effusion, ascites, bile, urine, and intestinal content (body B), and the volume of the bone marrow (BM). We then noted the absolute volume of the three organs at risk that had received 5-30 Gy, and assessed the predictive value for post-treatment lymphopenia of grade 3 or higher (LP3+). RESULTS: Of 54 patients, 23 (43%) developed LP3+. Univariate logistic regression analysis showed that body A V5, body A V10, body B V5, body B V10, the number of fractions, and splenic irradiation were significant predictors of LP3+ (p < 0.05). By multivariate analysis, body A V5, body A V10, body B V5, body B V10, and the number of fractions retained significance (p < 0.05). BM dose-volume parameters did not predict lymphopenia. CONCLUSIONS: Higher body A and body B dose-volume parameters and a larger number of fractions may be predictors of severe lymphopenia after palliative radiotherapy.

Influence of the treatment schedule on the physicians' decisions to refer bone metastases patients for palliative radiotherapy: a questionnaire survey of physicians in various specialties.

We investigated whether the treatment schedule influences physicians' decisions to refer their patients for radiotherapy. We presented a questionnaire to 104 physicians in various specialties at three hospitals. It included three hypothetical patients with uncomplicated painful bone metastasis: patients with an expected life span of one year (case 1), 6 months (case 2), and 2 months (case 3). The physicians were asked whether they would refer their patients for radiotherapy when a radiation oncologist presented three different treatment schedules: a short (8 Gy/1 fraction/1 day)-, a medium (20 Gy/5 fractions/1 week)-, and a long (30 Gy/10 fractions/2 weeks) schedule. We used Cochran's Q-test to compare the percentage of physicians across the three schedules and a mixed-effect logistic model to identify predictors of the selection of only the one-day schedule. Of the 104 physicians, 68 (65%) responded. Of these, 37 (54%), 27 (40%), and 26 (38%) chose to refer patients for radiotherapy when the short-, medium-, and long schedules, respectively, were proposed in case 1 (p = 0.14). These numbers were 44 (65%), 29 (43%), and 15 (22%) for case 2 (p < 0.001), and 59 (87%), 12 (18%), and 1 (1%) for case 3 (p < 0.001). Hypothetical patient and the physicians' years of practice and perspective regarding side effects were independently predictive of the selection of only the one-day schedule. In conclusion, the treatment schedule influenced the physicians' decisions to refer patients for radiotherapy.

Antihyperlipidemic effect of Acanthopanax senticosus (Rupr. et Maxim) Harms leaves in high-fat-diet fed mice.

BACKGROUND: Metabolic syndrome is a major risk factor for a variety of obesity-related diseases. Recently, the effects of functional foods have been investigated on lipid metabolism as a means to reduce lipid content in the blood, liver and adipose tissues associated with carnitine O-palmitoyltransferase (CPT) activity. Acanthopanax senticosus (Rupr. et Maxim) Harms (AS) is a medicinal herb possessing a wide spectra of functions including antioxidant, anti-inflammatory and anti-fatigue actions. Despite much research being focused on the cortical roots of AS, little information is available regarding its leaves, which are also expected to promote human health, for example by improving abnormal lipid metabolism. Here, we explored whether AS leaves affect lipid metabolism in mice fed a high-fat diet. RESULTS: The administration of AS to BALB/c mice fed a high-fat diet significantly decreased plasma triglycerides (TG). CPT activity in the liver of these mice was significantly enhanced by AS treatment. CONCLUSION: These findings indicate that AS leaves have the potential to alleviate increase in plasma TG levels due to high-fat diet intake in mice, possibly by increasing mitochondrial fatty acid ß-oxidation, especially via CPT activation. Consequently, daily intake of AS leaves could promote beneficial health effects including the prevention of metabolic syndrome. © 2015 Society of Chemical Industry.

[Potential uncertainty about image registration in thoracic image-guided radiotherapy].

PURPOSE: Although image-guided radiotherapy (IGRT) is widely used to determine and correct daily setup errors, the additional interpretation for image registration would provide another error. We evaluated the uncertainty in image registration in IGRT. METHOD: The subjects consisted of 12 consecutive patients treated with IGRT for thoracic esophageal cancer. Two radiation therapists had consensually achieved daily 3D registration between planning computed tomography (CT) and cone beam CT (CBCT). The original data sets of image registration in all fractions except for boost irradiations with a change in the isocenter positions were selected for evaluation. There were 20 to 32 data sets for each patient: a total of 318 data sets. To evaluate daily setup errors, the mean 3D displacement vector was calculated for each patient. To assess the reproducibility of image registration, two other radiation therapists reviewed the data sets and recorded geometric differences as uncertainty in the image registration. RESULTS: The mean 3D displacement vector for each patient ranged from 4.9 to 15.5 mm for setup errors and 0.7 to 2.2 mm for uncertainty in image registration. There was a positive correlation between the 3D vectors for setup error and uncertainty in image registration (r = 0.487, p = 0.016). CONCLUSION: Although IGRT can correct the setup errors, potential uncertainty exists in image registration. The setup error would disturb the image registration in IGRT.

[Development of a quality assurance phantom for brachytherapy: the feasibility of daily check with the phantom].

PURPOSE: We developed a quality assurance (QA) phantom to enable easy confirmation of radiation source output measurements of a high dose rate (192)Ir intracavitary brachytherapy unit in gynecology. The purpose of this study was to evaluate the feasibility of daily checks using the QA phantom. METHODS AND MATERIALS: The QA phantom was designed with tough water phantoms to hold a Farmer-type ionization chamber, with semiconductor detectors used as in vivo dosimeters to measure rectal dose, and three transfer tubes for gynecology. To test the reliability of our QA phantom for the detection of abnormalities in source output or semiconductor detectors, we applied different doses. RESULTS: Variations due to different settings of the QA phantom were within 2%. The temporal variations were less than 2% and 5% in the Farmer-type ionization chamber and semiconductor detectors, respectively. Interobserver variations were below 3%. CONCLUSIONS: With tolerance levels of 2% and 5% for a Farmer-type ionization chamber and semiconductor detectors, respectively, a QA phantom is potentially useful for easily detecting abnormalities by applying daily checks of the brachytherapy unit.

Pain response in single-fraction 8-Gy radiotherapy for painful non-bone-metastasis tumors: a single-center retrospective study.

The effectiveness of single-fraction 8-Gy radiotherapy for painful bone metastases has been verified in numerous randomized controlled trials. However, few reports have described the effectiveness of single-fraction 8-Gy radiotherapy in painful tumors other than bone metastases. We conducted a retrospective analysis to evaluate the pain response to single-fraction 8-Gy radiotherapy in painful non-bone-metastasis tumors. We included patients who had received single-fraction 8-Gy radiotherapy for such tumors between January 2017 and December 2022, excluding those with brain metastases, hematological tumors and those who received re-irradiation. Pain response assessment was based on the best responses documented in the medical records and conducted by two radiation oncologists. A total of 36 eligible patients were included in this study. The irradiation sites included primary lesions in eight patients, lymph node metastases in eight, muscle metastases in seven, pleural dissemination in four, skin/subcutaneous metastases in four and other sites in five. Pain response was assessed in 24 patients after radiotherapy. Pain response rate was 88% in evaluable patients; 21 of the 24 patients experienced response. The median assessment date for pain response was 37 days (range: 8-156 days) after radiotherapy. Re-irradiation was performed in four patients (11%). Single-fraction 8-Gy radiotherapy seemed to be a promising treatment option for painful non-bone-metastasis tumors and warrants further investigation.

Radiation-Induced Myonecrosis: A Case Report of a Cervical Cancer Patient With a History of Systemic Lupus Erythematosus.

Radiation-induced myonecrosis is a rare but serious complication of radiation therapy. We present a case of a 49-year-old woman with systemic lupus erythematosus who developed radiation-induced myonecrosis after concurrent chemoradiation for cervical cancer. She underwent external-beam radiation therapy, weekly cisplatin chemotherapy (40 mg/m2), and intracavitary brachytherapy. One month later, she received one cycle of nedaplatin (80 mg/m2) and irinotecan (60 mg/m2). Two months after treatment, she experienced pain in the left inguinal region. An MRI revealed a mass in the left obturator externus muscle and right pectineus muscle suggestive of myonecrosis. A biopsy confirmed the diagnosis. She received hyperbaric oxygen therapy, and her symptoms improved. The masses resolved completely.

Radiation Therapy Oncology Group 8502 "QUAD shot" regimen using volumetric modulated arc therapy for incurable head and neck cancer.

OBJECTIVES: We aimed to evaluate the outcomes of the Radiation Therapy Oncology Group 8502 "QUAD shot" regimen using volumetric modulated arc therapy (VMAT) for incurable head and neck cancer (HNC). MATERIALS AND METHODS: We included 105 patients with HNC in the study, undergoing at least one QUAD shot regimen cycle. We planned the radiotherapy using VMAT with 6 MV photons. One QUAD shot cycle included 14.8 Gy in 4 fractions with at least 6-hour intervals over 2 consecutive days, repeated every 3-6 weeks up to 3 cycles. RESULTS: We completed 1, 2, and 3 cycles in 11 (10 %), 17 (16 %), and 77 (73 %) patients, respectively. We concurrently performed systemic therapy in 13 (12 %) patients. Tumor response was observed in 92 (88 %) patients and at least one symptom relief in 51 (71 %) of 72 patients. We observed an overall response (tumor response or symptom relief) in 98 (93 %) patients with all patients who completed 3 cycles achieving it. The median overall survival (OS) was 6.8 months. Our multivariate analysis revealed that non-squamous cell carcinoma (p < 0.001), T category of 0-2 (p = 0.021), and 3 QUAD shot cycles (p < 0.001) were independent prognostic factors of better OS. We observed Grade 3 toxicity in 2 (2 %) patients while no ≥ Grade 4 acute or ≥ Grade 3 late toxicity. CONCLUSIONS: The QUAD shot regimen using VMAT exerts appropriate palliative effect in patients with incurable HNC. Treatment with higher QUAD shot cycle number would be recommended for better treatment outcomes.

Quality of palliative radiotherapy assessed using quality indicators: a multicenter survey†.

We sought to identify potential evidence-practice gaps in palliative radiotherapy using quality indicators (QIs), previously developed using a modified Delphi method. Seven QIs were used to assess the quality of radiotherapy for bone metastases (BoM) and brain metastases (BrM). Compliance rate was calculated as the percentage of patients for whom recommended medical care was conducted. Random effects models were used to estimate the pooled compliance rates. Of the 39 invited radiation oncologists, 29 (74%) from 29 centers participated in the survey; 13 (45%) were academic and 16 (55%) were non-academic hospitals. For the QIs, except for BoM-4, the pooled compliance rates were higher than 80%; however, for at least some of the centers, the compliance rate was lower than these pooled rates. For BoM-4 regarding steroid use concurrent with radiotherapy for malignant spinal cord compression, the pooled compliance rate was as low as 32%. For BoM-1 regarding the choice of radiation schedule, the compliance rate was higher in academic hospitals than in non-academic hospitals (P = 0.021). For BrM-3 regarding the initiation of radiotherapy without delay, the compliance rate was lower in academic hospitals than in non-academic hospitals (P = 0.016). In conclusion, overall, compliance rates were high; however, for many QIs, practice remains to be improved in at least some centers. Steroids are infrequently used concurrently with radiotherapy for malignant spinal cord compression.

Relationship between the receptor occupancy profile and pleiotropic effects of angiotensin II receptor blockers.

AIM: To investigate whether (i) angiotensin receptor occupying profiles of angiotensin II receptor blockers (ARBs) vary among the drugs and (ii) such differences contribute to the degree of their pleiotropic effects. METHODS: In a randomized, three phase crossover study, nine hypertensive patients received repeated doses (each recommended starting dose for 7 days and then each maximum recommended dose for 20 days) of irbesartan, valsartan and candesartan. The time course profiles and trough level of receptor occupancy were determined on days 7 and 28, respectively. The pleiotropic effect related parameters were measured on days 0 and 28 in each trial. RESULTS: Of the pleiotropic effect related parameters investigated, urinary 8-isoprostane, fasting serum insulin and homeostasis model assessment of insulin resistance index were more suppressed after 4 weeks treatment with irbesartan than after candesartan and valsartan therapy, respectively. The maximum, area under the curve and trough values of receptor occupancy significantly differed between the ARBs [geometric mean (and 95% CI) of trough value 18.1 (12.9, 25.3) for irbesartan, 9.6 (6.0, 15.3) for valsartan and 5.5 (2.8, 10.8) for candesartan, respectively] and were negatively correlated with the change in urinary 8-isoprostane (r = -0.46 - -0.55, P < 0.05), but not the markers of insulin resistance (r = 0.02-0.15, P = 0.46-0.94). CONCLUSIONS: Our results demonstrate that the receptor occupying profiles are different among the ARBs. This class of drugs might have both receptor occupancy dependent and independent pleiotropic effects.

Dosing time-dependent effect of raloxifene on plasma plasminogen activator inhibitor-1 concentrations in post-menopausal women with osteoporosis.

Raloxifene, a selective oestrogen receptor modulator commonly used for the treatment of post-menopausal osteoporosis, affects the coagulation and fibrinolytic systems and consequently increases the risk of venous thromboembolism. Because both the coagulation and fibrinolytic systems exhibit circadian rhythms, the aim of the present study was to investigate the effects of dosing time of raloxifene on markers of coagulation and fibrinolysis, as well as on markers of bone metabolism. Thirty-nine post-menopausal patients with osteoporosis were randomly allocated to two groups: one received 60 mg raloxifene once daily in the morning, whereas the other received 60 mg raloxifene once daily in the evening, for 12 months. In both groups, the activity of coagulation Factors IX and XII was increased significantly after 12 months treatment compared with baseline. The activity of coagulation Factors II and V and levels of markers of bone metabolism (i.e. bone alkaline phosphatase and tartrate-resistant acid phosphatase 5b) decreased in both groups. The changes in these markers did not differ between the two groups. In contrast, the plasma concentration of plasminogen activator inhibitor (PAI)-1 increased in the group receiving the morning dose (mean change 40.9%; 95% confidence interval (CI) 9.4, 72.5), but not in the groups receiving the evening dose (mean change -0.3%; 95% CI -31.5, 30.9); these percentage changes differed significantly (P < 0.05). Because an elevated concentration of PAI-1 is known to be associated with the risk of venous thromboembolism, the findings of the present study suggest that the dosing time of raloxifene influences its safety. Further larger-scale studies are needed to determine the clinical usefulness of chronotherapy with raloxifene.

Bias due to statistical handling of death and reirradiation in the assessment of duration of response after palliative radiotherapy: a scoping review and analysis of clinical data.

OBJECTIVES: We investigated the influence of handling death and reirradiation on the estimation of duration of response (DOR). METHODS: First, we performed a scoping review on methods to assess DOR in palliative radiotherapy. Second, we performed three different analyses on a subgroup of patients from a previously published prospective study. The first analysis was a competing risks analysis considering relapse of pain as the event of interest and death and reirradiation as competing events (Analysis A). The second and third analyses were standard survival analyses where the event of interest was a composite outcome of relapse of pain, death, or reirradiation (Analysis B) and relapse of pain (Analysis C), respectively. RESULTS: Death was considered as an event of interest in less than half of the papers, while reirradiation was not considered in any of the studies. Competing risks analysis was not performed in any of the studies. In the analysis of clinical data, competing risks analysis showed that relapse of pain predominated as the cause of the end of response. Median DOR was correctly estimated to be 4.1 months in Analyses A and B, but was overestimated to be 8.1 months in Analysis C. CONCLUSIONS: Death and reirradiation should be treated as the events of interest that mark the end of response (as in Analyses A and B) to avoid overestimation of treatment efficacy and an invalid assumption of independent censoring. ADVANCES IN KNOWLEDGE: The definition of end of response remains inconclusive in the assessment of DOR. We recommend competing risks analysis (Analysis A), by which we can estimate cumulative incidence of each event type and evaluate the necessity of reirradiation.

Pain Response Rates After Conventional Radiation Therapy for Bone Metastases Assessed Using International Consensus Pain Response Endpoints: A Systematic Review and Meta-Analysis of Initial Radiation Therapy and Reirradiation.

Previous meta-analysis of conventional radiation therapy for painful bone metastases showed overall response (OR) rates of 72% to 75% (evaluable patients), 61% to 62% (intent-to-treat patients) for initial radiation therapy, and 68% for reirradiation (evaluable patients). However, the definition of pain response differed among the studies included. Hence, we conducted a systematic review and meta-analysis to determine the pain response rates assessed by the International Consensus Pain Response Endpoints (ICPRE) for both initial radiation therapy and reirradiation. The PubMed and Scopus databases were searched for articles published between 2002 and 2021. The inclusion criteria were (1) prospective studies or studies based on prospectively collected data and (2) studies in which pain response was assessed using ICPRE. Our primary outcomes of interest were the OR rates (sum of the complete and partial response rates) for both initial radiation therapy and reirradiation. Of the 6470 articles identified in our database search, 32 and 3 met the inclusion criteria for the analysis of initial radiation therapy and reirradiation, respectively. The OR rates of initial radiation therapy in evaluable patients (n = 4775) and intent-to-treat patients (n = 6775) were 60.4% (95% confidence interval [CI], 55.2-65.4) and 45.4% (95% CI, 38.7-52.4), respectively. The OR rates of reirradiation in evaluable patients (n = 733) and intent-to-treat patients (n = 1085) were 70.8% (95% CI, 15.7-96.9) and 62.2% (95% CI, 5.3-98.0), respectively. Subgroup analyses of initial radiation therapy including the comparison of randomized and nonrandomized studies showed no significant differences in any comparison, indicating similar response rates across different study designs. For initial radiation therapy, we determined the ICPRE-assessed response rates, which were lower than previously reported. The OR and complete response rates should be benchmarks for future randomized and nonrandomized studies. For reirradiation, the wide CIs demonstrate that the response rates based on ICPRE require further investigation.