Interleukin-6 Family of Cytokines in Cancers.

Nine soluble ligands [interleukin-6 (IL-6), interleukin-11 (IL-11), leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine, interleukin-27 (IL-27), and interleukin-31] share the ubiquitously expressed transmembrane protein-glycoprotein-130 beta-subunit (gp130) and thus form IL-6 family cytokines. Proteins that may be important for cancerogenesis, CT-1, IL-11, IL-27, LIF, OSM, and CNTF, belong to the superfamily of IL-6. Cytokines such as IL-6, IL-11, and IL-27 are better investigated in comparison with other members of the same family of cytokines, eg, CT-1. Gp130 is one of the main receptors through which these cytokines exert their effects. The clinical implication of understanding the pathways of these cytokines in oncology is that targeted therapy to inhibit or potentiate cytokine activity may lead to remission in some cases.

A Randomized Placebo-Controlled Trial of the Anti-Nerve Growth Factor Antibody Tanezumab in Subjects With Cancer Pain Due to Bone Metastasis.

BACKGROUND: This phase III, randomized, double-blind, placebo-controlled, parallel-group study assessed the efficacy and safety of tanezumab in subjects with cancer pain predominantly due to bone metastasis receiving background opioid therapy. METHODS: Subjects were randomized (stratified by (1) tumor aggressiveness and (2) presence/absence of concomitant anticancer treatment) to placebo or tanezumab 20 mg. Treatment was administered by subcutaneous injection every 8 weeks for 24 weeks (3 doses) followed by a 24-week safety follow-up period. The primary outcome was change in daily average pain in the index bone metastasis cancer pain site (from 0 = no pain to 10 = worst possible pain) from baseline to week 8. RESULTS: LS mean (SE) change in pain at week 8 was -1.25 (0.35) for placebo (n = 73) and -2.03 (0.35) for tanezumab 20 mg (n = 72). LS mean (SE) [95% CI] difference from placebo was -0.78 (0.37) [-1.52, -0.04]; P = .0381 with α = 0.0478. The number of subjects with a treatment-emergent adverse event during the treatment period was 50 (68.5%) for placebo and 53 (73.6%) for tanezumab 20 mg. The number of subjects with a prespecified joint safety event was 0 for placebo and 2 (2.8%) for tanezumab 20 mg (pathologic fracture; n = 2). CONCLUSION: Tanezumab 20 mg met the primary efficacy endpoint at week 8. Conclusions on longer-term efficacy are limited since the study was not designed to evaluate the durability of the effect beyond 8 weeks. Safety findings were consistent with adverse events expected in subjects with cancer pain due to bone metastasis and the known safety profile of tanezumab. Clinicaltrials.gov identifier: NCT02609828.

Gastrointestinal fistula with thigh extension and intractable pain.

Spontaneous enterocutaneous fistulae are a rare complication in patients with cancer, especially following irradiation, chemotherapy or cytoreductive operations. They are associated with worse prognosis, higher costs of treatment and impaired quality of life. Proper recognition of the problem and fast implementation of selective therapy including water electrolyte resuscitation, infection control, nutritional support, control of output volume, proper wound care and, ultimately, surgical treatment in selected patients may result in better symptom relief and improved quality of life of patients. We describe a case of a patient with advanced rectal cancer and acute pain in the lateral aspect of thigh caused by the presumptive presence of an enterocutaneous fistula, in whom therapy with antibiotics and surgical incision enabled rapid pain relief and comfort of dying.

Midazolam and hydroxymidazolam plasma concentrations can be monitored with selected biochemical and physiological parameters of palliative care patients.

RATIONALE & OBJECTIVE: Midazolam is one of top three drugs used in palliative care. Its use increases in the last days of hospice patients' lives while safe dosage can be challenging. Equations currently used to estimate glomerular filtration rate, e.g: the Cockroft-Gault (eGFRCR) and the Modification of Diet in Renal Disease (eGFRMDRD) ones, do not generate precise calculations, especially in palliative patients exhibiting variations in body parameters. Our aim was to seek new relationships between mean midazolam (Mavg) and alfahydroxymidazolam (OH-Mavg) concentrations in plasma, and selected biochemical and physiological parameters of palliative patients, to enable optimal midazolam pharmacotherapy. STUDY DESIGN, PARTICIPANTS AND INTERVENTIONS: The pilot study included 11 Caucasians, aged 42-95, with advanced cancer disease, receiving midazolam in a hospice in-patient unit. We tested correlations among Mavg, BMI, eGFRMDRD, midazolam clearance (CL), OH-Mavg, bilirubin (Bil) and blood creatinine concentration (Cr). F test and leave-one out (LOO) validation was applied to verify the correlations' significance and predictive ability. RESULTS: We found ten statistically significant (p < 0.05) correlations related to midazolam pharmacokinetics and physiological factors. We formulated two equations with high degree of predictive ability, based on the eGFRMDRD→CL and the (Bil + BMI × Ln(Cr))→Mavg-(OH-Mavg) correlations. The limitations of the study mainly revolve around its pilot nature and the need to continue testing the results on a bigger population. No funding to disclose. CONCLUSIONS: The significance of correlations corresponding to the arithmetic expressions confirms that Bil, BMI, Ln(Cr) analyzed simultaneously report a series of processes on which midazolam metabolism depends. Two of ten correlations proposed came close to meet all LOO validation criteria. Current findings can help optimize midazolam treatment in palliative therapy.

Haloperidol in palliative care: Indications and risks.

Individual response to medication depends on several factors (age, gender, body weight, general clinical condition, genetics, diet, hydration status, comorbidities, co-administered drugs and their mode of administration, smoking, alcohol overuse, environmental factors, e.g. sunlight) that may contribute to adverse drug reactions even at therapeutic doses. Patients in palliative care are at increased risk of these reactions. Unwanted drug effects diminish the quality of life and may lead to a suboptimal dying process. Haloperidol is one of the three most commonly used drugs in palliative care and the most commonly employed typical antipsychotic. It has also been recommended for inclusion into the palliative care emergency kit of home care teams. As such, it is important to be fully conversant with the indications, benefits, and risks of haloperidol, especially in the context of palliative care.

Midazolam: Safety of use in palliative care: A systematic critical review.

PURPOSE: The undesired effects of midazolam can be life-threatening. This paper delineates the findings related to the pharmacokinetics, adverse effects and drug-drug interactions as well as associated therapeutic implications for safe midazolam use. METHODS: A systematic review of literature was conducted. RESULTS: The pharmacokinetics of midazolam depends on hepatic and renal functions, fat tissue mass, route and duration of administration, as well as potential drug-drug interactions. Palliative care patients constitute a high-risk group prone to side effects of drugs, due to polytherapy and multi-organ failure. CONCLUSION: Midazolam is one of three most frequently administered drugs in palliative care. The indications for its use include anxiety, dyspnea, seizures, vomiting refractory to treatment, agitation, myoclonus, status epilepticus, restlessness, delirium, pruritus, hiccups, insomnia, analgosedation, palliative sedation and preventing or counteracting undesired effects of ketamine.

Managing metastatic bone pain: New perspectives, different solutions.

Bone metastases are the most frequent cause of cancer-induced bone pain (CIBP). Although palliative radiotherapy and pharmacotherapy conducted according to World Health Organization (WHO) analgesic ladder are the treatment of choice for CIBP reduction, these methods are not always successful, especially with regard to alleviation of incidental pain. Antiresorptive drugs (bisphosphonates) are able to inhibit bone destruction (loss), proliferation of cancer cells and angiogenesis, but their prolonged use may lead to a spectrum of adverse effects. In this paper, types of bone metastases, their complications, as well as diagnostic and therapeutic implications are presented. Moreover, the paper discusses presently used CIBP treatment methods and research directions for future methods, with special focus on bone metastases.

Efficacy and safety of tanezumab in the treatment of pain from bone metastases.

Patients with metastatic bone cancer report life-altering pain. Nerve growth factor is involved in pain signaling. Tanezumab, a nerve growth factor monoclonal antibody, has demonstrated efficacy in chronic pain. Placebo-controlled parent (NCT00545129; study 1003) and noncontrolled open-label extension (NCT00830180; study 1029) studies evaluated efficacy and safety of tanezumab in patients with painful bone metastases taking daily opioids. Patients in study 1003 received a single intravenous injection of 10 mg tanezumab or placebo and were followed up to 16 weeks. Efficacy analyses included change from baseline in daily average and worst pain at week 6 on an 11-point numeric rating scale. At week 8, patients could enroll in study 1029 and receive 4 infusions of 10 mg tanezumab at 8-week intervals with follow-up to 40 weeks. Safety assessments included adverse events and physical and neurologic examinations. Overall, 59 patients were randomized and treated (placebo, n = 30; tanezumab, n = 29). At the primary endpoint of study 1003, least squares mean (SE) difference in change from baseline in daily average pain vs placebo was -0.26 (0.45; P = 0.569). Post hoc analyses suggested that tanezumab had greater efficacy in patients with lower baseline opioid use and/or higher baseline pain. Mean (SE) pain scores in study 1029 were reduced through week 40 compared with study 1029 or 1003 baselines (-0.21 [0.76] and -1.27 [0.68], respectively). Adverse event incidence of study 1003 was similar between groups. Although the primary endpoint was not achieved, tanezumab may provide additional sustained analgesia in patients with metastatic bone pain taking daily opioids. Additional larger studies are warranted.

Treatment of acute, severe epigastric/chest pain in a patient with stomach cancer following gastrectomy: A case report.

The treatment of acute chest pain can be a challenge in palliative care. Firstly, because acute chest pain is a symptom of a paucity of diseases, which makes diagnosis difficult and time consuming, while there is also a time constraint, due to the extreme suffering of the patient. Secondly, the condition of a patient with advanced cancer disease and co-morbidities does not always allow for required diagnostic procedures. The present report describes a case of acute, severe epigastric/chest pain in a patient with dynamic disease progression, who was receiving palliative care. This study also demonstrates that the pathophysiology of pain in a terminal patient may determine the treatment strategy. The patient in the present case was a 41-year-old male, who had previously undergone gastrectomy for stomach cancer, followed by postoperative chemotherapy. The patient was treated with palliative chemotherapy for metastases to the lungs, liver and lymph nodes, which led to the development of iatrogenic peripheral neuropathy. The patient was subsequently admitted to the Palliative Medicine In-patient Unit of the University Hospital of Lord's Transfiguration (Poznan, Poland) with the complaint of acute epigastric and chest pain. An electrocardiogram, echocardiogram, chest and abdomen computerized tomography scan, esophagoduodenoscopy and laboratory analyses were performed to determine the source of the pain. The patient was treated with morphine sulfate, metoclopramide, midazolam, diazepam, acetaminophen, ketamine, hyoscine butylbromide, propofol, dexamethasone and amoxycillin, and received parenteral nutrition. As the source of pain remained unclear, a second esophagoduodenoscopy was performed to determine a diagnosis, resulting in pain relief. Thus, in the present case, esophagoduodenoscopy was diagnostic and therapeutic. Furthermore, although the treatment of acute chest pain may be a challenge in palliative care, the present study indicates that pain treatment should be adjusted to anatomical, pathophysiological and pharmacological factors, and may pose risks due to the unavoidable parenteral co-administration of multiple agents with strong therapeutic effects.

Bupivacaine administered intrathecally versus rectally in the management of intractable rectal cancer pain in palliative care.

BACKGROUND: Unacceptable adverse effects, contraindications to and/or ineffectiveness of World Health Organization step III "pain ladder" drugs causes needless suffering among a population of cancer patients. Successful management of severe cancer pain may require invasive treatment. However, a patient's refusal of an invasive procedure necessitates that clinicians consider alternative options. OBJECTIVE: Intrathecal bupivacaine delivery as a viable treatment of intractable pain is well documented. There are no data on rectal bupivacaine use in cancer patients or in the treatment of cancer tenesmoid pain. This study aims to demonstrate that bupivacaine administered rectally could be a step in between the current treatment options for intractable cancer pain (conventional/conservative analgesia or invasive procedures), and to evaluate the effect of the mode of administration (intrathecal versus rectal) on the bupivacaine plasma concentration. CASES: We present two Caucasian, elderly inpatients admitted to hospice due to intractable rectal/tenesmoid pain. The first case is a female with vulvar cancer, and malignant infiltration of the rectum/vagina. Bupivacaine was used intrathecally (0.25-0.5%, 1-2 mL every 6 hours). The second case is a female with ovarian cancer and malignant rectal infiltration. Bupivacaine was adminstered rectally (0.05-0.1%, 100 mL every 4.5-11 hours). METHODS: Total bupivacaine plasma concentrations were determined using the high-performance liquid chromatography-ultraviolet method. RESULTS: Effective pain control was achieved with intrathecal bupivacaine (0.077-0.154 mg·kg(-1)) and bupivacaine in enema (1.820 mg·kg(-1)). Intrathecal bupivacaine (0.5%, 2 mL) caused a drop in blood pressure; other side effects were absent in both cases. Total plasma bupivacaine concentrations following intrathecal and rectal bupivacaine application did not exceed 317.2 ng·mL(-1) and 235.7 ng·mL(-1), respectively. Bupivacaine elimination was slower after rectal than after intrathecal administration (t½= 5.50 versus 2.02 hours, respectively). LIMITATIONS: This study reports two cases only, and there could be inter-patient variation. CONCLUSION: Bupivacaine in boluses administered intrathecally (0.25%, 2 mL) provided effective, safe analgesia in advanced cancer patients. Bupivacaine enema (100 mg·100 mL(-1)) was shown to be a valuable option for control of end-of-life tenesmoid cancer pain.

The pilot study assessing efficacy and versatility of novel therapy for neoplastic ulceration: clinical and microbiological aspects.

INTRODUCTION: Neoplastic ulcers are chronic and, most often, irreversible lesions caused by proliferation of tumor cells infiltrating and damaging skin tissues. The treatment of neoplastic ulcers is a very difficult and time-consuming process. So, is very important to find methods of controlling this type of chronic wounds. AIM: To evaluate the efficiency of monitored treatment of neoplastic ulcers by means of providing moist wound environment dressings and antiseptic to the group of patients with an advanced stage of tumor, with particular focus on the impact of the treatment applied on the clinical condition of the ulcers; to evaluate the impact of the treatment applied on the dynamics of bacterial flora in neoplastic ulcers, with particular focus on the presence of alarm pathogens; to conduct a risk analysis of the occurrence of local and systemic complications during treatment. MATERIAL AND METHODS: This was a prospective pilot clinical study of 30 patients with malignant ulcers, 13 male and 17 female aged from 24 to 92 years treated with octenidine antiseptic and dressing set for 3 weeks. The wounds were clinically assessed for the changes of amount of necrotic tissue, exudate level and type, malodour and pain level during treatment. At the baseline and after 3 weeks of treatment, the wounds were swabbed for microbiological assessment. RESULTS: The used scheme of treatment is efficient and brings clinical improvement in all treated ulcers. During the 3-week treatment, reduction of necrotic tissue, decrease in the level of exudate, pain and malodour was observed in all patients (p < 0.05). High activity of octenidine against Gram(-) and Gram(+) bacteria was observed. The use of octenidine dihydrochloride correlated with a progressing eradication of multiresistant strains and alarm pathogens (p < 0.001). No serious adverse effects or significant symptoms of intolerance of the applied treatment were observed.

Clinical efficacy and safety of once-daily dosing of a novel, prolonged-release oral morphine tablet compared with twice-daily dosing of a standard controlled-release morphine tablet in patients with cancer pain: a randomized, double-blind, exploratory crossover study.

CONTEXT: Recently, a new oral prolonged-release formulation of morphine sulfate for once-daily dosing has been developed based on an injection-molded matrix (abuse-deterrent, prolonged-release erodible matrix [ADPREM]). OBJECTIVES: The objective of this double-blind, randomized, exploratory crossover study was to assess the efficacy and safety of once-daily ADPREM compared with twice-daily controlled-release morphine (CRM; MST ContinusNapp Pharmaceuticals, Cambridge, UK). METHODS: Thirty-eight adult cancer pain patients participated in the study, which consisted of a run-in period for stabilization and two consecutive fixed-dose treatment periods of two weeks' duration each. Rescue medication, immediate-release morphine sulfate, was available during the entire study for treatment of breakthrough pain (BTP). RESULTS: There was no difference between the treatments in use of rescue medication. The medians of the average number of rescue doses per day were 1.0 and 0.7 during the ADPREM and CRM treatment periods, respectively, with an estimated median difference of 0.07 dose/day (95% confidence interval: -0.21, 0.29). Likewise, no differences between treatments were found for the number of BTP episodes per day or morning and evening ratings of pain intensity (current, average, minimum, and maximum). Median assessment of the drugs was "good" for both treatments, and neither of the treatments was preferred. Steady-state trough concentrations of morphine and its metabolites in plasma before morning dosing were similar after either treatment period. The adverse events were as expected in an opioid-treated cancer population and showed no differences between ADPREM and CRM. CONCLUSION: In this study, dosing with ADPREM at intervals of 24 hours was therapeutically equivalent to CRM dosed at intervals of 12 hours.

Efficacy and safety of transdermal buprenorphine: a randomized, placebo-controlled trial in 289 patients with severe cancer pain.

Strong opioids are recommended for treating severe cancer pain in the advanced stages of the disease. Few data are available concerning the efficacy of buprenorphine in cancer pain. We compared transdermal buprenorphine 70 microg/h (BUP TDS) to placebo in an enriched design study. Opioid-tolerant patients with cancer pain requiring strong opioids in the dose range of 90-150 mg/d oral morphine equivalents entered a two-week run-in phase, during which they were converted to BUP TDS. Patients who could be stabilized on BUP TDS were randomized to BUP TDS or placebo patch for a two-week maintenance phase. Rescue medication (buprenorphine sublingual tablets 0.2mg) was allowed as required. Response was defined as a mean pain intensity of <5 (0-10 scale) and a mean daily buprenorphine sublingual tablet intake of < or =2 tablets during the maintenance phase. Of 289 patients who entered the run-in phase, 100 discontinued treatment due to lack of efficacy or adverse events; 189 patients continued treatment in the maintenance phase (94 BUP TDS, 95 placebo), of whom 31 discontinued treatment (7 BUP TDS, 24 placebo). A significant difference in the number of treatment responders was observed: 70 BUP TDS (74.5%, 65.7-83.3) vs. 47 placebo (50%, 39.9-60.1) (P=0.0003). This result was supported by a lower daily pain intensity, lower intake of buprenorphine sublingual tablets and fewer dropouts in the BUP TDS group. The incidence of adverse events was slightly higher for BUP TDS. In conclusion, BUP TDS 70 microg/h is an efficacious and safe treatment for patients with severe cancer pain.