Overcoming barriers to timely recognition and treatment of cancer cachexia: Sharing Progress in Cancer Care Task Force Position Paper and Call to Action.

Cachexia is a life-threatening disorder affecting an estimated 50-80% of cancer patients. The loss of skeletal muscle mass in patients with cachexia is associated with an increased risk of anticancer treatment toxicity, surgical complications and reduced response. Despite international guidelines, the identification and management of cancer cachexia remains a significant unmet need owing in part to the lack of routine screening for malnutrition and suboptimal integration of nutrition and metabolic care into clinical oncology practice. In June 2020, Sharing Progress in Cancer Care (SPCC) convened a multidisciplinary task force of medical experts and patient advocates to examine the barriers preventing the timely recognition of cancer cachexia, and provide practical recommendations to improve clinical care. This position paper summarises the key points and highlights available resources to support the integration of structured nutrition care pathways.

Efficacy and Safety of Oral NEPA (Netupitant/Palonosetron), the First Fixed-Combination Antiemetic, in Patients With Gynecological Cancers Receiving Platinum-Based Chemotherapy.

OBJECTIVE: Patients with gynecological cancers are at high risk for chemotherapy-induced nausea and vomiting (CINV) after platinum-based chemotherapy (CT). NEPA (300-mg netupitant, 0.50-mg palonosetron) is the first oral fixed-combination antiemetic. Pivotal trials demonstrated the superiority of oral NEPA over intravenous palonosetron in preventing CINV after highly emetogenic (anthracycline-cyclophosphamide-based [AC] and cisplatin-based [non-AC]) CT. This post hoc subset analysis considered patients with gynecological cancer receiving cisplatin- or carboplatin-based CT from 1 pivotal trial and from 1 multicycle safety trial to evaluate the efficacy of oral NEPA in preventing CINV. METHODS: Single-dose NEPA was given before CT in combination with dexamethasone. The efficacy end points for the acute (0-24 hours), delayed (25-120 hours), and overall (0-120 hours) CINV phases after CT included complete response (CR; no emesis, no rescue medication) and no significant nausea (<25 mm on a 0- to 100-mm visual analog scale). Safety was also assessed. RESULTS: For cisplatin-induced CINV, NEPA achieved high CR rates (acute phase: >90%; delayed, overall phases: ≥85%). For carboplatin-induced CINV, NEPA was also highly effective, with high acute, delayed, and overall CR rates (cycle 1: >75%; cycles 2-4: >95%). No significant nausea rates were more than 90% and more than 80% in the acute and delayed phases, respectively, for patients receiving cisplatin or carboplatin. NEPA was well tolerated. CONCLUSIONS: Results suggest that oral NEPA is effective and safe in preventing CINV in patients with gynecological cancers treated with cisplatin- or carboplatin-based CT. Single fixed-combination NEPA is a convenient option for CINV prevention in high-risk CINV patients.

Prevention of chemotherapy-induced nausea: the role of neurokinin-1 (NK1) receptor antagonists.

Chemotherapy-induced nausea (CIN) has a significant negative impact on the quality of life of cancer patients. The use of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists (RAs) has reduced the risk of vomiting, but (except for palonosetron) their effect on nausea, especially delayed nausea, is limited. This article reviews the role of NK1RAs when combined with 5-HT3RA-dexamethasone in CIN prophylaxis. Aprepitant has not shown consistent superiority over a two-drug (ondansetron-dexamethasone) combination in nausea control after cisplatin- or anthracycline-cyclophosphamide (AC)-based highly emetogenic chemotherapy (HEC). Recently, dexamethasone and dexamethasone-metoclopramide were demonstrated to be non-inferior to aprepitant and aprepitant-dexamethasone, respectively, for the control of delayed nausea after HEC (AC/cisplatin), and are now recognized in the guidelines. The potential impact of the new NK1RAs rolapitant and netupitant (oral fixed combination with palonosetron, as NEPA) in CIN prophylaxis is discussed. While the clinical significance of the effect on nausea of the rolapitant-granisetron-dexamethasone combination after cisplatin is not conclusive, rolapitant addition showed no improvement in nausea prophylaxis after AC or moderately emetogenic chemotherapy (MEC). NEPA was superior to palonosetron in the control of nausea after HEC (AC/cisplatin). Moreover, the efficacy of NEPA in nausea control was maintained over multiple cycles of HEC/MEC. Recently, NK1RAs have been challenged by olanzapine, with olanzapine showing superior efficacy in nausea prevention after HEC. Fixed antiemetic combinations (such as NEPA) or new antiemetics with a long half-life that may be given once per chemotherapy cycle (rolapitant or NEPA) may improve patient compliance with antiemetic treatment.

Safety and efficacy of NEPA, an oral fixed combination of netupitant and palonosetron, in older patients.

OBJECTIVES: Prevention of chemotherapy-induced nausea and vomiting is critical in older patients with cancer. NEPA is an oral fixed combination of netupitant 300mg, a new NK1 receptor antagonist (RA), and palonosetron 0.5mg, a pharmacologically distinct 5-HT3 RA. This retrospective analysis evaluated the efficacy and safety of NEPA in older patients. METHODS: Patients aged ≥65 and ≥70years from one phase II and two phase III trials were considered. Chemotherapy-naive patients with malignant tumors were treated with anthracycline-cyclophosphamide (AC), non-AC-based moderately emetogenic chemotherapy (non-AC MEC), or highly emetogenic chemotherapy (HEC). Following single-dose NEPA, patients received oral dexamethasone on day 1 (AC and non-AC MEC) or days 1-4 (HEC). Efficacy was evaluated through complete response (CR) in cycle 1. Safety was evaluated by AEs and ECGs. Data were summarized by descriptive statistics. RESULTS: Overall, 214 patients were ≥65years and 80 were ≥70years. A higher CR was observed in older patients versus the total population; in the acute phase >90% of patients ≥65years experienced CR. Efficacy was maintained over multiple cycles of chemotherapy. No significant nausea rates were generally higher in the older patients versus total population. Similar rates of AEs in the first treatment cycle were reported for patients ≥65years, ≥70years, and total population (72.9% vs 67.5% vs 70.0%, respectively). No cardiac safety concerns were raised. CONCLUSION: NEPA is highly effective in older patients receiving MEC or HEC regimens. NEPA is also well tolerated, demonstrating suitability for use in older patients who may have comorbidities.

Cancer and chemotherapy-induced nausea and vomiting: a focus on olanzapine.

PURPOSE OF THE REVIEW: The purpose of review is to critically present the evidence supporting the use of olanzapine, an atypical antipsychotic, as an antiemetic for cancer and chemotherapy-induced nausea and vomiting (CINV). RECENT FINDINGS: Two phase III clinical studies demonstrated superior efficacy of olanzapine in comparison with the neurokinin-1 receptor antagonists (NK1RA) for substance P (aprepitant, fosaprepitant) in the prevention of nausea after highly emetogenic chemotherapy. Olanzapine is inexpensive and the replacement of NK1RA with olanzapine can reduce the costs of the prevention of CINV. The addition of olanzapine to aprepitant-containing combination regimens for the prevention of CINV was also investigated, and has the potential to further improve the prevention of CINV after highly emetogenic chemotherapy or moderately emetogenic chemotherapy, without substantial increase in costs. In the treatment of uncontrolled ('breakthrough') CINV, olanzapine was more effective than metoclopramide. Existing clinical data also support the use of olanzapine to relieve a cluster of gastrointestinal symptoms in patients with advanced cancer (chronic nausea, vomiting, and anorexia). When used in cancer patients, olanzapine is well tolerated, with sedation being the major dose-limiting side effect. SUMMARY: Existing data from clinical trials justify further research of the role of olanzapine in the prevention of CINV. Olanzapine may be used instead of or in addition to NK1RA in the preventive antiemetic regimens. Olanzapine-containing preventive regimens may provide better nausea control after chemotherapy. When used instead of NK1RA it may also provide substantial reduction in costs of CINV prevention. In patients with advanced cancer, olanzapine was effective against a cluster of gastrointestinal symptoms (nausea, vomiting, and anorexia). The use of olanzapine as an antiemetic for CINV, or to relieve nausea, vomiting, and anorexia in palliative care is currently off-label.

A Multifaceted Approach to Improve the Availability and Accessibility of Opioids for the Treatment of Cancer Pain in Serbia: Results From the International Pain Policy Fellowship (2006-2012) and Recommendations for Action.

Cancer is the second leading cause of death in Serbia, and at least 14,000-16,000 patients experience moderate-to-severe cancer pain every year. Cancer pain relief has been impeded by inadequate availability of opioid analgesics and barriers to their accessibility. In 2006, a Serbian oncologist was selected as an International Pain Policy Fellow. The fellow identified barriers to opioid availability in Serbia and implemented an action plan to address the unavailability of oral morphine, attitudinal and knowledge barriers about opioids, and barriers in the national opioid control policy, in collaboration with the government, local partners, and international experts, including those from the World Health Organization. Collaborative efforts resulted in availability of immediate-release oral morphine, registration of controlled-release hydromorphone, and reimbursement of oral methadone for cancer pain; numerous educational activities aimed at changing inadequate knowledge and negative attitudes toward opioids; recognition of opioids as essential medicines for palliative care in a new National Palliative Care Strategy; and recognition of the medical use of opioids as psychoactive-controlled substances for the relief of pain included in a new national law on psychoactive-controlled substances, and the development of recommendations for updating regulations on prescribing and dispensing opioids. An increase in opioid consumption at the institutional and national levels also was observed. This article outlines a multifaceted approach to improving access to strong opioids for cancer pain management and palliative care in a middle-income country and offers a potential road map to success.

A Review of NEPA, a Novel Fixed Antiemetic Combination with the Potential for Enhancing Guideline Adherence and Improving Control of Chemotherapy-Induced Nausea and Vomiting.

Combination antiemetic regimens targeting multiple molecular pathways associated with emesis have become the standard of care for prevention of chemotherapy-induced nausea and vomiting (CINV) related to highly and moderately emetogenic chemotherapies. Antiemetic consensus guidelines from several professional societies are widely available and updated regularly as new data emerges. Unfortunately, despite substantial research supporting the notion that guideline conformity improves CINV control, adherence to antiemetic guidelines is unsatisfactory. While studies are needed to identify specific barriers to guideline use and explore measures to enhance adherence, a novel approach has been taken to improve clinician adherence and patient compliance, with the development of a new combination antiemetic. NEPA is an oral fixed combination of a new highly selective NK1 receptor antagonist (RA), netupitant, and the pharmacologically and clinically distinct 5-HT3 RA, palonosetron. This convenient antiemetic combination offers guideline-consistent prophylaxis by targeting two critical pathways associated with CINV in a single oral dose administered only once per cycle. This paper will review and discuss the NEPA data in the context of how this first combination antiemetic may overcome some of the barriers interfering with adherence to antiemetic guidelines, enhance patient compliance, and offer a possible advance in the prevention of CINV for patients.

Incidence of delayed nausea and vomiting in patients with colorectal cancer receiving irinotecan-based chemotherapy.

PURPOSE: This study sought to prospectively determine the frequency of delayed nausea and vomiting with irinotecan-based chemotherapy following day 1 prophylaxis with a 5-HT3 receptor antagonist and dexamethasone. METHODS: Patients with colorectal cancer aged ≥ 18 years with ECOG performance status ≤ 2 receiving irinotecan alone, combined with cetuximab or as part of a standard folinic acid, 5- fluorouracil, irinotecan (FOLFIRI) regimen for the first time were eligible. All patients received a 5-HT3 receptor antagonist and dexamethasone 8 mg on day 1 prior to irinotecan. No routine prophylaxis for delayed emesis was given. Antiemetic outcome was recorded in patient-completed diaries for the 120-h study period after irinotecan administration. Primary endpoint was frequency of delayed (24-120 h) emesis. RESULTS: Forty-four patients were enrolled, and all are evaluable. The median age was 61 (39-79) years; the male-female ratio was 37:7. Four patients (9%) experienced vomiting or retching during the delayed period. Three patients (7%) vomited during the first 24 h after irinotecan. The overall no emesis rate was 89% (39/44). Fifteen patients (34%) experienced delayed nausea (mildin 11 patients, moderate in four patients). Six patients (14%) took rescue antiemetics during the delayed period. Delayed and overall complete response (no emesis or use of rescue antiemetics) rates were 82% and 77% respectively. CONCLUSIONS: The use of a 5-HT3 antagonist and dexamethasone prior to irinotecan results in excellent control of nausea and vomiting (CR 86%) during the 24 h after chemotherapy. Without further antiemetic treatment, most patients (82%) will not experience delayed emesis or require rescue antiemetics. Routine prophylaxis for delayed emesis following irinotecan does not appear to be warranted.

Improving the availability and accessibility of opioids for the treatment of pain: the International Pain Policy Fellowship.

Opioid analgesics are simultaneously indispensable medicines for the treatment of moderate to severe pain and are harmful when abused. The challenge for governments is to balance the obligation to prevent diversion, trafficking, and abuse of opioids with the equally important obligation to ensure their availability and accessibility for the relief of pain and suffering. Over the last 30 years, significant progress has been made toward improving access to opioids as measured by increasing global medical opioid consumption. However, this progress is marked by ongoing large disparities among countries, with most increases in medical opioid consumption attributed to high-income countries, not low- and middle-income countries (LMICs). The International Pain Policy Fellowship (IPPF) was developed by the Pain & Policy Studies Group, with the central goal of developing national leaders from LMICs and empowering them to improve availability and accessibility of opioids for the treatment of pain. To date, two classes of fellows have been selected, representing 17 fellows from 15 countries. Progress achieved by the leadership of three fellows from Sierra Leone, Colombia, and Serbia is highlighted in this paper. The fellows from each country were successful at initiating collaboration with relevant governmental bodies, national authorities, and professional societies, which resulted in a new supply of oral opioids in Sierra Leone and Serbia, and improvements in the distribution of already available opioids in Colombia. All fellows were instrumental in facilitating evaluation of national policy. The IPPF program empowers fellows with the necessary knowledge, skills, and guidance to improve the availability and accessibility of opioids for the treatment of pain.

Severe skin toxicity observed with the combination of capecitabine and weekly paclitaxel in metastatic breast cancer patients.

BACKGROUND: Skin toxicity has recently been recognized as a dose-limiting toxicity of antineoplastic therapy. DISCUSSION: We report severe skin toxicity observed in anthracycline-pretreated metastatic breast cancer patients receiving the combination of capecitabine and weekly paclitaxel.

[Slow release tramadol in the initial treatment of moderate to severe cancer pain: open, multicentric clinical trial].

INTRODUCTION: The analgesic efficacy of slow release tramadol in the titration phase of treatment of moderate to severe cancer pain has been demonstrated in clinical trials. OBJECTIVE: The aim of the study was to evaluate this treatment strategy in routine daily practice. METHOD: This was a prospective, non-randomized, open, multicentric, phase IV two-week study. Each patient received 100 mg slow release tramadol orally, twice a day. Patients were allowed to take 20 drops (50 mg) of tramadol as needed for breakthrough pain. The pain intensity and tramadol tolerability were recorded every day for the previous 24 hours, in the first week and at the end of the study. Pain relief and the impact of pain on sleep were evaluated on the 8th and 15th day. RESULTS: The study included 46 patients with metastatic malignant disease. The total of 46 patients completed the first week of treatment, and 33 patients completed the whole study. At the end of study, the intensity of pain was significantly reduced from 6.75 to 3.03 on numerical scale (NS 0-100) (p < 0.001). At the end of study, 60.6% of patients graded the severity of pain as maximally mild on a verbal scale. The pain relief significantly improved from 25.75 to 71.81 on a numerical scale (NS 0-100) (p < 0.001). The impact of pain on sleep was significantly reduced from 51.51% to 10.61% on a numerical scale (NS 0-100) (p < 0.001). There were no differences in the drowsiness/confusion, nausea, vomiting, dizziness, loss of appetite and constipation, from the beginning to the end of treatment. CONCLUSION: Tramadol slow release was effective in the titration phase of treatment of moderate to severe cancer pain with good tolerability.

Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study.

PURPOSE: To compare the effectiveness and side effects of methadone and morphine as first-line treatment with opioids for cancer pain. PATIENTS AND METHODS: Patients in international palliative care clinics with pain requiring initiation of strong opioids were randomly assigned to receive methadone (7.5 mg orally every 12 hours and 5 mg every 4 hours as needed) or morphine (15 mg sustained release every 12 hours and 5 mg every 4 hours as needed). The study duration was 4 weeks. RESULTS: A total of 103 patients were randomly assigned to treatment (49 in the methadone group and 54 in the morphine group). The groups had similar baseline scores for pain, sedation, nausea, confusion, and constipation. Patients receiving methadone had more opioid-related drop-outs (11 of 49; 22%) than those receiving morphine (three of 54; 6%; P =.019). The opioid escalation index at days 14 and 28 was similar between the two groups. More than three fourths of patients in each group reported a 20% or more reduction in pain intensity by day 8. The proportion of patients with a 20% or more improvement in pain at 4 weeks in the methadone group was 0.49 (95% CI, 0.34 to 0.64) and was similar in the morphine group (0.56; 95% CI, 0.41 to 0.70). The rates of patient-reported global benefit were nearly identical to the pain response rates and did not differ between the treatment groups. CONCLUSION: Methadone did not produce superior analgesic efficiency or overall tolerability at 4 weeks compared with morphine as a first-line strong opioid for the treatment of cancer pain.

The importance of clinical practice guidelines (CPGs) for the quality and development of supportive care in Central and Eastern European (CEE) countries.

Supportive care CPGs are intended to improve the quality of supportive care received by cancer patients. They hold potential benefits for health-care professionals, health-care organizations and patients. In order to provide an effective influence of CPGs on supportive care development in CEE countries their validity and successful implementation in clinical practice must be ensured. This would involve several important steps: (1) achievement of a consensus across Europe about what constitutes supportive care in cancer; (2) identification of supportive care priorities in CEE countries to be covered by the guidelines; and (3) searching existing CPGs relevant to previously identified priorities. Valid international CPGs could then be translated and adapted to local resources and circumstances in CEE countries and used to prepare national supportive care CPGs which could assist in the development of national supportive care standards. Skills, expertise and additional investment are required for local adaptation, dissemination and implementation of international supportive care CPGs.

Emesis: antiemetic effect of cyclophosphamide at central receptors of multitransmitter system in the cat.

The antiemetic and emetic actions of the anticancer drug cyclophosphamide injected intracerebroventricularly (i.c.v.) and intravenously (i.v.) through chronically implanted cannulae were investigated in unanaesthetized cats. Cyclophosphamide in single doses was injected into the cerebral ventricles and intravenously for 5 consecutive days. The antiemetic effect was regularly obtained, whereas the emetic effect was unpredictable and of low incidence. The antiemetic effect of i.c.v. and i.v. cyclophosphamide was assessed, when the neurotoxic (mydriasis, restlessness, emesis, ataxia, muscular weakness) signs subsided, against i.c.v. noradrenaline- and clonidine-induced emesis. Noradrenaline-induced emesis was dose-dependently and dose-independently inhibited with i.c.v. and i.v. cyclophosphamide. On the other hand, i.c.v. cyclophosphamide inhibited the clonidine-induced emesis in dose-independent manner, while i.v. injection of the anticancer drug had no significant effect on the emesis. The inhibition of emesis was consistently obtained and no significant differences in the antiemetic potency were found between 1 and 5 consecutive days of treatment with cyclophosphamide. However, the inhibition of noradrenaline-induced emesis was dose-dependent only after first administration of i.c.v. cyclophosphamide. It is assumed that noradrenaline acts at alpha-adrenoceptors within the area postrema and clonidine at alpha-adrenoceptors within and outside the area postrema as well as at muscarinic cholinoceptors, 5-hydroxytryptamine, dopamine and histamine H1 and H2 receptors, outside the area postrema, of multitransmitter system subserving the central regulation of emesis. It is suggested, therefore, that the antiemetic effect of cyclophosphamide at the receptors of the multitransmitter central emetic system is non-specific. In general, the antiemetic effect, even non-specific, of an anticancer drug could have practical implication. Namely, when a combination of two or more anticancer drugs are used for chemotherapy, the emesis could not occur if one of them could antagonize the emesis induced by other anticancer drug/s. Finally, cyclophosphamide injected i.c.v., but not i.v., evoked shortlasting emesis in about 20% of cats. Since the emesis was unpredictable and of low incidence it was not possible to study the mechanism/s and site/s of action of the anticancer drug.

Are Central Eastern European countries involved in clinical trials of supportive care?

Clinical trials are the most widely accepted tools in the search for more effective supportive care drugs/interventions. The aim of our study was to determine Central Eastern European countries' (CEEC) involvement and future interest in conducting supportive care clinical trials. Our study was a part of an ESMO/MASCC program launched to support the development of supportive care in CEEC. The study was designed as a mailed questionnaire survey within the ESMO CEE Task Force. It involves national representatives from 18 countries. The purpose of the questionnaire was to assess the involvement and interest in conducting clinical trials in 13 representative supportive care fields: antiemetic therapy, cancer pain control, infections/febrile neutropenia, mucositis, fatigue, hypercalcemia, dyspnea, anorexia/cachexia, psychosocial support, toxicity reducing agents, hematopoietic growth factors, communication/education and quality of life. A total of 15 completed questionnaires were returned (83.3%). CEEC were mainly involved in clinical trials of hematopoietic growth factors (7/15), quality of life (6/15), antiemetic therapy (5/15), and cancer pain control (4/15). Increased interest was observed in the trials of fatigue, dyspnea, psychosocial support, infections / febrile neutropenia, communication / education and toxicity reducing agents. Clusters of CEEC that are similar in terms of their previous involvement and future interest in supportive care trials were identified. Our survey may prove to be a significant first step for CEEC active involvement in multinational clinical trials, which are crucial for improving supportive care standards.