Neurokinin-1 antagonist orvepitant for EGFRI-induced pruritus in patients with cancer: a randomised, placebo-controlled phase II trial.

OBJECTIVE: To evaluate the efficacy of orvepitant (10 or 30 mg given once daily, orally for 4 weeks), a neurokinin-1 receptor antagonist, compared with placebo in reducing the intensity of epidermal growth factor receptor inhibitor (EGFRI)-induced intense pruritus. DESIGN: Randomised, double-blind, placebo-controlled clinical trial. SETTING: 15 hospitals in Italy and five hospitals in the UK. PARTICIPANTS: 44 patients aged ≥18 years receiving an EGFRI for a histologically confirmed malignant solid tumour and experiencing moderate or intense pruritus after EGFRI treatment. INTERVENTION: 30 or 10 mg orvepitant or placebo tablets once daily for 4 weeks (randomised 1:1:1). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was change from baseline in mean patient-recorded numerical rating scale (NRS) score (over the last three recordings) at week 4. Secondary outcome measures were NRS score, verbal rating scale score, Skindex-16 and Leeds Sleep Evaluation Questionnaire at each study visit (baseline, weeks 1, 4, 8); rescue medication use; EGFRI dose reduction; and study withdrawal because of intense uncontrolled pruritus. RESULTS: The trial was terminated early because of recruitment challenges; only 44 of the planned 90 patients were randomised. All patients were analysed for efficacy and safety. Mean NRS score change from baseline to week 4 was -2.78 (SD: 2.64) points in the 30 mg group, -3.04 (SD: 3.06) points in the 10 mg group and -3.21 (SD: 1.77) points in the placebo group; the difference between orvepitant and placebo was not statistically significant. No safety signal was detected. Adverse events related to orvepitant (asthenia, dizziness, dry mouth, hyperhidrosis) were all of mild or moderate severity. CONCLUSIONS: Orvepitant was safe and well tolerated. No difference in NRS score between the orvepitant and placebo groups was observed at the week 4 primary endpoint. A number of explanations for this outcome are possible. TRIAL REGISTRATION NUMBER: EudraCT2013-002763-25.

Osteonecrosis of jaw beyond antiresorptive (bone-targeted) agents: new horizons in oncology.

INTRODUCTION: Osteonecrosis of the jaw (ONJ) is a clinically important, potentially painful and debilitating condition, which can affect the quality of life of cancer patients. Since 2003, ONJ appeared as a Bisphosphonate(BP)-related class effect, and the term Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) was widespread. AREAS COVERED: Under discussion in this review is the fact that ONJ cases have been reported after treatment including antiangiogenic agents and other "targeted therapy", with and without BPs. Consequently, the comprehensive term Medication-Related Osteonecrosis of the Jaw (MRONJ) has been introduced. The clinical aspects and the prognosis of ONJ associated with these new drugs are still less reported, but basing on their pharmacodynamics, they could be different from the well-known BRONJ. Accordingly, recommendations largely in use for BRONJ should be extended to these new forms, but critically applied and with respect to the individual risk assessment. EXPERT OPINION: There is a high risk of underdiagnoses for ONJ due to a lack of awareness, and too much restrictive or incomplete diagnostic criteria; at the same time, with regard to ONJ associated to the new non -antiresorptive agents, described here, we observe the strong need to improve the defining of any distinguished feature in their diagnosis, prevention and therapy.

Percutaneous Long Bone Cementoplasty for Palliation of Malignant Lesions of the Limbs: A Systematic Review.

PURPOSE: Percutaneous cementoplasty (PC) is rarely applied to long bone tumours, since cement is not considered to be sufficiently resistant to torsional forces. We reviewed the literature to understand the effects of percutaneous long bone cementoplasty (PLBC) in terms of analgesia, limb function and complications. MATERIALS AND METHODS: This study followed the Cochrane's guidelines for systematic reviews of interventions. Inclusion criteria were (1) prospective/retrospective studies concerning PC; (2) cohort including at least ten patients; (3) at least one patient in the cohort undergoing PLBC; (5) published in English; (6) results not published by the same author more than once. RESULTS: One thousand five hundred and ninety-eight articles were screened and 13 matched the inclusion criteria covering 196 PLBC patients. Pain improvement was high in 68.2% patients (σ = 0.2) and mild in 27.4% (σ = 0.2). Functional improvement was high in 71.9% patients (σ = 0.1) and mild in 6% (σ = 0.1). Use of PLBC correlated with pain reduction (P < 0.001). Secondary fractures occurred in 16 cases (8%, σ = 2.5); other complications in 2% cases. Percutaneous stabilisation (PS) was coupled with PLBC in 17% of cases without any subsequent fracture. PS was not associated with absence of secondary fracture (P = 0.08). CONCLUSION: PLBC is safe, offering good pain relief and recovery of impaired limb function. Secondary fractures are uncommon and PS may reduce their occurrence. However, no evidence is currently available to support PS plus PLBC as compared to PLBC alone.

'Old' and 'new' drugs for the treatment of cancer pain.

INTRODUCTION: More than 20 years ago the World Health Organization (WHO) published the booklet 'Cancer Pain Relief', including the fundamentals and clear principles, which was summarized in five simple sentences: 'by mouth', 'by the clock', 'by the ladder', 'for the individual' and 'attention to detail'. Over the years, several modifications to the analgesic ladder have been proposed, as the addition of two further steps, related to the switch of opioid and/or non-invasive route of administration, and to the use of invasive approaches, or again the skip of the second step; nevertheless the educational value and benefits related to the worldwide dissemination are of paramount importance. AREAS COVERED: To date, all the guidelines are inspired by the strategy of WHO; below some of the most important international guidelines published in the last two years are compared, particularly as regards the criteria of choice of opioids for moderate/severe pain. EXPERT OPINION: The discussion on the role of the second step of the WHO analgesic ladder is still open. The challenge for new formulations of 'old' opioids will be to better manage cancer pain, with more tailored efficacy and possibly less side effects.

Serum VEGF levels as predictive marker of bisphosphonate-related osteonecrosis of the jaw.

Recent studies have been reported that angiogenesis suppression may play a role in developing bisphosphonate-related osteonecrosis of the jaw (B-ONJ). According to these evidence we evaluated the role of VEGF as predictive marker of B-ONJ onset. Of the 81 patients, 6 developed B-ONJ following bisphosphonate treatment. These patients showed a strongest decrease in VEGF circulating levels at day 7 and at day 21 after the first administration. These data demonstrated for the first time that the anti-angiogenic properties of bisphosphonates are directly linked to B-ONJ pathogenesis and serum VEGF levels could represent an effective early predictive marker.

Current knowledge and future directions on bisphosphonate-related osteonecrosis of the jaw in cancer patients.

BACKGROUND: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe adverse event of long-term use of bisphosphonates that heavily affects the quality of life of cancer patients. OBJECTIVE: To review epidemiologic data, pathobiology, risk factors, diagnosis and management of BRONJ. METHODS: Articles were identified by searching the PubMed and MEDLINE databases and recent meetings abstracts. RESULTS/CONCLUSION: BRONJ pathobiology is thought to be related to bisphosphonate-induced suppression of normal bone remodeling and impairment of bone blood flow. Dental extractions, daily masticatory traumas, oral infections, chemotherapy and antiangiogenic drugs can also play an active role. Collaboration between oncologists and dentists is essential to prevent BRONJ. A conservative approach based on pain control, oral rinses, antibiotics and limited debridement represents the current management. Optimization of therapy based on reduction of bisphosphonate doses or exposure time, newer bisphosphonates and biomolecular agents could favorably impact on BRONJ incidence.

Management of pain in elderly patients receiving infusion of zoledronic acid for bone metastasis: a single-institution report.

GOALS OF WORK: Bone metastases are a common cause of morbidity in elderly patients with solid tumors and myeloma. We studied the safety and the effect of a new bisphosphonate, zoledronic acid (ZA), on pain and on quality of life (QoL) in elderly patients with bone metastases. MATERIALS AND METHODS: From January 2004 to December 2005, we have enrolled elderly patients with bone metastasis for receiving ZA administration. Visual analog scale (VAS) and Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire were used to assess potential benefits of ZA therapy. RESULTS: Eighty-six patients were included; the median age was 75.5 years. Before starting treatment, the mean VAS was 6.8 (+/-0.24), after three infusions 5.4 (+/-0.3), and after six courses 4.5 (+/-0.3) with a significant improvement of bone pain. Moreover, we found a statistically significant improvement of QoL measured by FACT-G questionnaire after six courses (p = 0.010). Median baseline and final value of serum creatinine were 0.73 and 0.72 mg/dl, respectively (p = 0.11); creatinine clearance was also normal for most patients. Osteonecrosis of the jaw was diagnosed in one patient who received a prolonged ZA treatment. CONCLUSIONS: These data confirm the benefits of ZA on pain and QoL also in elderly patients with bone metastasis from solid tumors.