Carlo DeAngelis

Dexamethasone for the Prophylaxis of Radiation-induced Pain Flare after Palliative Radiotherapy for Symptomatic Bone Metastases: a Phase II Study

AIMS Pain flare occurs in over one-third of patients receiving palliative radiotherapy for bone metastases. A single dose of dexamethasone can decrease the incidence of pain flare during the first 2 days immediately after radiotherapy. We conducted a phase II prospective study to investigate the prophylactic role of prolonged dexamethasone. MATERIALS AND METHODS Patients with bone metastases treated with a single 8Gy were prescribed 8mg dexamethasone just before palliative radiotherapy and for 3 consecutive days after treatment. Worst pain score and analgesic consumption data were collected at baseline and daily for 10 days after treatment. Analgesic consumption was converted into a total daily oral morphine equivalent dose in the analysis. Pain flare was defined (a priori) as a two-point increase in worst pain on an 11-point numeric rating scale compared with baseline with no decrease in analgesic intake, or a 25% increase in analgesic intake with no decrease in worst pain score. To distinguish pain flare from progressive disease, we required that the worst pain score and analgesic intake returned to baseline levels after the increase/flare. RESULTS Forty-one patients were evaluable (32 men, nine women). Their median age was 67 years. The overall incidence of pain flare was 9/41 (22%) within 10 days after the completion of radiotherapy. Most (55%) of these pain flares occurred on day 5. Absence of pain flare was 34/41(83%) and 39/41 (95%) for days 1-5 and 6-10 after the completion of radiotherapy, respectively. CONCLUSION Dexamethasone is effective in the prophylaxis of radiotherapy-induced pain flare after palliative radiotherapy for bone metastases. Randomised studies are needed to confirm this finding.

Spironolactone Pharmacokinetics and Pharmacodynamics in Patients With Cirrhotic Ascites

The intent of this study was to identify pharmacokinetic and pharmacodynamic characteristics for spironolactone (SP) and its metabolites (canrenone, 6 beta-hydroxy-7 alpha-thiomethylspirolactone, 7 alpha-thiomethylspirolactone) in cirrhotics under steady state conditions. Nine cirrhotics with ascites participated in the study. Serial blood samples were drawn and urine was collected over a 26-hour period. Using a reverse-phase high performance liquid chromatography (HPLC) method, all samples were analyzed for SP, canrenone, 6 beta-hydroxy-7 alpha-thiomethylspirolactone, and 7 alpha-thiomethylspirolactone concentrations. Parent compound and metabolite urinary excretion rates as well as maximal concentrations and time at which these are observed were calculated. The apparent median terminal elimination rate constants (associated half-lives) were 0.0767 h-1 (9.04 hours) for SP, 0.0055 h-1 (126 hours) for 6 beta-hydroxy-7 alpha-thiomethylspirolactone, 0.029 h-1 (23.9 hours) for 7 alpha-thiomethylspirolactone and 0.012 h-1 (57.8 hours) for canrenone. SP metabolism is impaired in cirrhosis; terminal half-lives of SP and metabolites appear to be increased when compared with values reported in the literature for normals. When assuming a linear model, clearance-effect relationship estimates are best correlated with 7 alpha-thiomethylspirolactone and canrenone. Further research is required to identify specific pharmacokinetic and pharmacodynamic parameters for SP and its metabolites in this patient population.

Prophylaxis of radiation-induced nausea and vomiting using 5-hydroxytryptamine-3 serotonin receptor antagonists: a systematic review of randomized trials.

PURPOSE To systematically review the effectiveness and safety of 5-hydroxytryptamine-3 receptor antagonists (5-HT3 RAs) compared with other antiemetic medication or placebo for prophylaxis of radiation-induced nausea and vomiting. METHODS AND MATERIALS We searched the following electronic databases: MEDLINE, Embase, the Cochrane Central Register of Controlled Clinical Trials, and Web of Science. We also hand-searched reference lists of included studies. Randomized, controlled trials that compared a 5-HT3 RA with another antiemetic medication or placebo for preventing radiation-induced nausea and vomiting were included. We excluded studies recruiting patients receiving concomitant chemotherapy. When appropriate, meta-analysis was conducted using Review Manager (v5) software. Relative risks were calculated using inverse variance as the statistical method under a random-effects model. We assessed the quality of evidence by outcome using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS Eligibility screening of 47 articles resulted in 9 included in the review. The overall methodologic quality was moderate. Meta-analysis of 5-HT3 RAs vs. placebo showed significant benefit for 5-HT3 RAs (relative risk [RR] 0.70; 95% confidence interval [CI] 0.57-0.86 for emesis; RR 0.84, 95% CI 0.73-0.96 for nausea). Meta-analysis comparing 5-HT3 RAs vs. metoclopramide showed a significant benefit of the 5-HT3 RAs for emetic control (RR 0.27, 95% CI 0.15-0.47). CONCLUSION 5-Hydroxytryptamine-3 RAs are superior to placebo and other antiemetics for prevention of emesis, but little benefit was identified for nausea prevention. 5-Hydroxytryptamine-3 RAs are suggested for prevention of emesis. Limited evidence was found regarding delayed emesis, adverse events, quality of life, or need for rescue medication. Future randomized, controlled trials should evaluate different 5-HT3 antiemetics and new agents with novel mechanisms of action such at the NK(1) receptor antagonists to determine the most effective drug. Delayed nausea and vomiting should be a focus of future study, perhaps concentrating on the palliative cancer population.

A Multicenter Assessment of the Adequacy of Cancer Pain Treatment Using the Pain Management Index

PURPOSES Determine adequacy of management of pain secondary to bone metastases by physicians referring to specialized outpatient palliative radiotherapy (RT) clinics in Canada; compare geographic differences in adequacy of pain management and pain severity between these cohorts; compare results with published international literature. METHODS Prospectively collected data from three participating centers were used to calculate the Pain Management Index (PMI) by subtracting the patient-rated pain score at time of initial clinic visit from the analgesic score. Scores were 0, 1, 2, and 3 when patients reported no pain (0), mild (1-4), moderate (5-6), or severe pain (7-10), respectively, on the Edmonton Symptom Assessment System or Brief Pain Inventory. Analgesic scores of 0, 1, 2, and 3 were assigned for no pain medication, nonopioids, weak opioids, and strong opioids respectively. A negative PMI suggests inadequate pain management. RESULTS Overall incidence of negative PMI and moderate to severe pain was 25.1% and 70.9% respectively for 2011 patients. Comparing the three participating centers, the incidence of negative PMI was 31.0%, 20.0%, and 16.8% (p < 0.0001), and severe pain was 55.5%, 48.2% and 43.4% (p < 0.0001), these correlated with a negative PMI. Patients referred to our clinics were less likely to be undertreated for their pain when compared to study results from international countries. CONCLUSION Geographic differences in adequacy of analgesic management for painful bone metastases exist between Canadian specialized outpatient palliative RT clinics and between centers globally. Investigating reasons for these differences may provide insight into solutions to improve quality of life for these patients.

Elderly Patients With Painful Bone Metastases Should be Offered Palliative Radiotherapy

PURPOSE To investigate the efficacy of palliative radiotherapy (RT) in relieving metastatic bone pain in elderly patients. METHODS AND MATERIALS The response to RT for palliation of metastatic bone pain was evaluated from a prospective database of 558 patients between 1999 and 2008. The pain scores and analgesic intake were used to calculate the response according to the International Bone Metastases Consensus Working Party palliative RT endpoints. Subgroup analyses for age and other demographic information were performed. RESULTS No significant difference was found in the response rate in patients aged >or=65, >or=70, and >or=75 years compared with younger patients at 1, 2, or 3 months after RT. The response was found to be significantly related to the performance status. CONCLUSION Age alone did not affect the response to palliative RT for bone metastases. Elderly patients should be referred for palliative RT for their painful bone metastases, regardless of age, because they receive equal benefit from the treatment.

Cut points for mild, moderate, and severe pain among cancer and non-cancer patients: a literature review

Defining cut points (CPs) for varying levels of pain intensity is important for assessing changes in patients functional status, and guiding the development and evaluation of treatment options. We aimed to summarize CPs identified in the literature for mild, moderate, and severe pain on the numeric rating scale (NRS), and recommend optimal CPs for cancer and non-cancer patients. We searched MEDLINE and EMBASE (inception to May 2015) for studies that used CPs to classify pain intensity on the NRS among patients with cancer or non-cancer conditions leading to acute or chronic pain. A CP was defined as the upper bound of a mild or moderate pain category. Of 1,556 identified articles, 27 were included for review. Among patients with cancer pain, mild-moderate pain CPs ranged from 1 to 4 (mean, 3.5±1.08), with CP4 being the most recommended CP (80%). For moderate-severe pain, CPs ranged from 4 to 7 (mean, 6.2±0.92), and CP6 (50%) was the optimal CPs. Among patients with non-cancer pain, mild-moderate pain CPs ranged from 2 to 5 (mean, 3.62±0.78), and CP4 was the most frequently used CP (52.9%). For moderate-severe non-cancer pain, CPs ranged from 4 to 8 (mean, 6.5±0.99), and CP6 (41.2%) was the most frequently recommended CP. A wide range of CPs for mild, moderate, and severe pain categories were identified in the literature among both cancer and non-cancer patient populations. Further studies are needed to delineate more accurate and precise CPs for pain intensity.

Effect of Radiotherapy on Painful Bone Metastases: A Secondary Analysis of the NCIC Clinical Trials Group Symptom Control Trial SC.23

Importance Many studies that found improved quality of life (QOL) after radiotherapy of bone metastases have small sample sizes and do not use specific questionnaires. How soon after radiotherapy one can expect an improvement in QOL is unknown. Objective To investigate QOL at days 10 and 42 after radiotherapy with a bone metastases–specific QOL tool. Design, Setting, and Participants In this secondary analysis of the NCIC Clinical Trials Group Symptom Control Trial SC.23, a double-blind randomized clinical trial that investigated dexamethasone for the prophylaxis of pain flare after radiotherapy, patients were accrued from 23 Canadian centers from May 30, 2011, to December 11, 2014, and were followed up for 42 days after treatment. Participants referred for radiotherapy for bone metastases were required to have a pain score at the site(s) of treatment of at least 2 (range, 0-10). Interventions Patients were treated with a single 8-Gy radiotherapy dose for 1 or 2 bone metastases. Main Outcomes and Measures Patients reported their worst pain score and analgesic intake at baseline and days 10 and 42 after treatment. Pain response was assessed with International Bone Metastases Consensus Endpoint Definitions. Self-reported QOL was completed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Bone Metastases Module (QLQ-BM22) and the European Organisation for Research and Treatment of Cancer Quality of Life Core 15 Palliative (QLQ-C15-PAL) at the same time points. Results A total of 298 patients were accrued (median age, 68.8 [range, 32-94] years at day 10 and 68.0 [range, 34-90] years at day 42). A total of 122 patients (40.9%) responded to radiotherapy at day 10 and 116 patients (38.9%) at day 42. At day 10, compared with nonresponders, patients with a pain response had a greater reduction in pain (mean reduction, 17.0 vs 1.8; P = .002) and pain characteristics (mean reduction, 12.8 vs 1.1; P = .002), as well as greater improvements in functional interference (mean increase, 11.6 vs 3.6; P = .01) and psychosocial aspects (mean increase, 1.2 points in responders vs mean decrease of 2.2 points in nonresponders, P = .04). Comparing changes in QOL from baseline to day 42, responders had significantly greater improvements in the physical (mean increase, 6.2 vs −9.0; P < .001), emotional (mean increase, 12.3 vs −5.5; P < .001), and global domains (mean increase, 10.3 vs −4.5; P < .001) of the QLQ-C15-PAL compared with nonresponders. Conclusions and Relevance Forty percent of patients experienced pain reduction and better QOL at day 10 after radiotherapy with further improvements in QOL at day 42 in responders. A single 8-Gy radiotherapy dose for bone metastases should be offered to all patients, even those with poor survival. Trial Registration clinicaltrials.gov Identifier: NCT01248585

Update on the management of chemotherapy-induced nausea and vomiting – focus on palonosetron

Purpose Nausea and vomiting are major adverse effects of chemotherapy and can greatly impact patients’ quality of life. Although chemotherapy-induced nausea and vomiting (CINV) prevalence is high, treatment remains difficult. Palonosetron is a 5-hydroxytryptamine receptor antagonist (5-HT3RA) approved for treatment of CINV. The purpose of this review is to discuss existing and emerging therapeutic options, and examine studies focusing on palonosetron with regards to efficacy, pharmacology, tolerability, safety, and patient-derived outcomes. Methods A literature search was conducted using Ovid MEDLINE and EMBASE to identify relevant studies using palonosetron alone or in combination with other antiemetics. Studies were extracted if they included complete response (CR), complete control (CC), no nausea, no vomiting, and no rescue medications as an endpoint. Studies were also included if safety endpoints were examined. Results Palonosetron alone has been shown to improve CR and CC rates for patients receiving low, moderate, or high emetogenic chemotherapy. Rates were further improved with the addition of dexamethasone, a corticosteroid. Furthermore, the addition of neurokinin-1 receptor antagonists, such as netupitant markedly improved efficacy profiles compared to palonosetron alone. Aprepitant is an antiemetic that has exhibited positive results in combination with palonosetron. Recently, a new drug consisting of netupitant and palonosetron (NEPA) has demonstrated significantly more efficacious prevention of CINV. Regardless of the combination, palonosetron has been well tolerated. The most common adverse events were constipation, headache, fatigue, and dizziness, with the majority of patients describing them as only mild or moderate. Conclusion Palonosetron, alone or with other antiemetics, has improved CINV treatment due to its ability to significantly reduce delayed phases of CINV, compared to similar 5-HT3RAs. Palonosetron is both more effective than first generation 5-HT3RAs and safer, as it results in a smaller prolongation of the QTc interval, compared to other 5-HT3RAs.

Incidence of pain flare in radiation treatment of bone metastases: A literature review.

Purpose Pain flare is a temporary increase in pain and is a potential side effect of radiotherapy treatment. However, its incidence has been reported only in recent studies, and with great variability. A few studies have reported on the use of dexamethasone as a prophylactic agent in the prevention of pain flare. The objective of this study is to present a review of the available literature regarding the incidence of pain flare and use of dexamethasone as a preventative measure. Methods A literature search was conducted in PubMed using subject keywords including: “radiation therapy”, “stereotactic radiation therapy”, “bone metastases”, “pain flare”, and “dexamethasone”. The search was limited to English only but not restricted to any time period. Additionally, a search was also conducted in the American Society for Therapeutic Radiology and Oncology (ASTRO) 2014 book of published abstracts. Inclusion criteria were primary studies published with full text and/or abstracts only. Letters to the editor were excluded. Results A total of 11 studies were selected, two of which were abstracts published by ASTRO in 2014. Seven articles investigated pain flare and/or dexamethasone use for conventional external beam radiation therapy (EBRT) while the remaining four investigated stereotactic body radiation therapy (SBRT). Pain flare incidence ranged from 2 to 44% for EBRT and 10 to 68% in SBRT. The use of dexamethasone also showed to be effective in both the prophylaxis and treatment of pain flare. Conclusions Pain flare has been established as an acute toxicity of both EBRT and SBRT, although its incidence is widely variable due to differences in data collection. The use of dexamethasone in the prophylaxis of pain flare is efficacious. Future studies are required in order to both optimize the reporting of pain and the dexamethasone regimens in the prevention of pain flare.

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

BACKGROUND To assess the safety and clinical outcomes of bipolar radiofrequency ablation (RFA) assisted vertebroplasty (VP) and osteoplasty (OP) in pathological and insufficiency fractures. The insufficiency fractures were in patients who sustained demineralization secondary to cancer treatment. METHODS Patients referred for symptomatic malignant or insufficiency fractures for VP or OP from January 2011 to May 2015 were retrospectively reviewed. Bipolar RFA was performed (Osteocool RF ablation system, Baylis Medical) reaching a constant temperature of 70 ℃ over 7 to 15 minutes followed by cement injection. Clinical outcomes were evaluated by review of the electronic medical record (EMR). Radiological outcomes were assessed with CT. Pre and post procedural pain scores were also documented for the RFA subset, primarily to see if there were any adverse effects when using RFA on pain relief. RESULTS Twenty-six patients in the study were treated with the RFA assisted technique. These contributed to 4 OPs and 35 VP levels. Of these four VP levels were insufficiency fractures. All were technically successful without morbidity or mortality. Fifty-six patients were treated with a non RFA assisted technique. All these were VPs and 142 levels were treated in total. Two levels in this subset were insufficiency fractures. All were technically successful without morbidity or mortality. There was a significantly reduced rate of posterior and venous cement leaks when RFA was used prior to VP. There was no difference in the rate of leakage into the disc spaces when comparing RFA assisted to the conventional technique. Pain scores in the RFA assisted group decreased significantly post procedure with no unanticipated neuropathic events. CONCLUSIONS RFA assisted VP and OP using a bipolar device is safe and allows for controlled injection of cement into a preformed thermal cavity with a significant decrease in venous and posterior cement leaks. Rate of cement leakage into the disc spaces was unaffected.