Stringent Control of Opioids: Sound Public Health Measures, but a Step Too Far in Palliative Care?

PURPOSE OF REVIEW: Opioids are the only class of drug with the proven ability to control severe pain. The introduction of stringent opioid prescribing restrictions has inevitably impacted upon the ability of those prescribing opioids for advanced life-limited disease to practice as previously and could limit the supply of adequate pain relief to patients with cancer. This review considers the evidence that symptom management of patients with advanced cancer contributes to the "opioid problem" and whether there is adequate recognition of the risks involved. RECENT FINDINGS: The literature suggests that the risk of opioid abuse is low in the palliative care population as is the risk of legal consequences for doctors prescribing opioids at the end of life. However, as many patients with cancer are living longer or surviving with chronic pain, palliative care physicians must be cognisant not only of the risks of long term opioid use but also of the risk of opioid misuse. Adherence to evidence or consensus-based guidelines is necessary to avoid inappropriate prescribing. In palliative care, it is appropriate not only to exercise a reasonable degree of opioid control and surveillance, primarily for the good of society, but also to ensure that the ability to treat pain in patients with advanced malignant disease is not compromised.

Overall survival of children and adolescents with mature B cell non-Hodgkin lymphoma who had refractory or relapsed disease during or after treatment with FAB/LMB 96: A report from the FAB/LMB 96 study group.

We determined the risk factors associated with poor survival in children and adolescents with de novo mature B cell non-Hodgkin lymphoma (B-NHL) who had refractory or relapsed disease during or after the French-American-British mature lymphoma B (FAB/LMB) 96 multi-agent chemotherapy. Among the 1 111 registered on study, 104 patients (9·4%) had refractory disease or disease relapse after first complete remission. Among these 104 patients, 28 (27%) patients had refractory disease and 76 (73%) had relapsed disease. The estimated 1- and 2-year overall survival (OS) (95% confidence interval) was 31·5% (23·3-41·0%) and 22·3% (15·3-31·4%), respectively. Prognostic analysis of OS using a Cox multivariate model showed that factors independently associated with OS included lactate dehydrogenase ≥2 upper normal limit [hazard ratio (HR) = 2·86 (1·57-5·2), P = 0·0006]; time to failure (>6 months) [HR = 0·59 (0·36-0·97), P = 0·038]; and failure in bone marrow [HR = 2·78 (1·65-4·68), P = 0·0001]. New therapeutic strategies are required to significantly reduce refractory disease and disease relapse in patients with newly diagnosed mature B-NHL and, more importantly, there is a critical need to develop novel retrieval approaches in patients with chemotherapy-resistant disease.

Do Australian adolescents' and young adults' experiences of cancer care influence their quality of life?

OBJECTIVE: To examine the relationship between the cancer care experiences of adolescents and young adults (AYAs) and their quality of life. METHODS: Two hundred and nine AYAs completed a cross-sectional, self-report survey distributed through the population-based cancer registries in 2 Australian states (New South Wales and Victoria). Eligible AYAs were 15 to 24 years old when diagnosed with any cancer (excluding early-stage melanoma) and were 3 to 24 months post-diagnosis. Questions examined whether particular care experiences occurred for the patient at different points in the cancer care pathway, including diagnosis, treatment, inpatient care, and at the end of treatment. Quality of life was assessed using the Functional Assessment of Cancer Therapy-General scale. RESULTS: Positive experiences of care at diagnosis, during treatment, during inpatient stays, and when finishing treatment were associated with higher functional, emotional, and social well-being. However, these associations generally became nonsignificant when communication and support experiences were included in the model. Inpatient experiences positively influenced emotional well-being over and above the effect of communication and support experiences. CONCLUSIONS: The results suggest that, for most AYAs' quality of life outcomes, positive experiences of age-appropriate communication and emotional support may underpin the effect of positive experiences of care throughout the cancer care pathway. The results support the need for communication and support tailored to an AYA audience, as recognised by recent Australian and international guidelines on the care of AYAs with cancer.

Opioid addiction and misuse in adult and adolescent patients with cancer.

In the context of a therapeutic opioid epidemic, particularly in the USA, where increasingly stringent screening for 'at risk' individuals and close monitoring of opioid prescription and use is strongly recommended, the issue of misuse within the cancer population must be addressed. Most patients with advanced cancer will have pain requiring opioid therapy at some stage during their disease course. In the majority, this will provide good pain relief with no short- or longer-term adverse sequelae. A subset will present with substance misuse issues that will influence management and prescribing practice. The potential ethical issues of limiting effective analgesia on the basis of addiction risk or history must be acknowledged. Both a judgemental or 'relaxed' approach to such patients is problematic. Ignoring the situation will not be in the patient's best interest, but an undue focus on this aspect may damage therapeutic relationships with clinicians and adversely affect a holistic approach to care. Clinical practitioners must be aware of the risk factors for opioid misuse and in patients who are not under palliative care consider screening prior to commencing opioids. Clinicians must be able to manage and monitor those identified as having an opioid misuse problem.

Childhood, adolescent and young adult non-Hodgkin lymphoma: state of the science.

The 5th International Symposium on Childhood, Adolescent and Young Adult (CAYA) Non-Hodgkin Lymphoma (NHL) was held in Varese, Italy, from 21-25 October 2015. This review represents a summary of the scientific sessions of this international symposium including childhood, adolescent and young adult (AYA) NHL in countries with limited socio-economic resources, AYA NHL, anaplastic large cell lymphoma, post-transplant lymphoproliferative disease, B-cell NHL, lymphoblastic lymphoma, T/natural killer cell NHL and immunological therapies in NHL. Most importantly, the new International Paediatric NHL Staging System (IPNHLSS) and International Paediatric NHL Response Criteria (IPNHLRC) were introduced during the symposium. The symposium brought together a multinational and multidisciplinary group of clinicians and basic scientists focused in this field of haematological malignancies.

Outcome and pathologic classification of children and adolescents with mediastinal large B-cell lymphoma treated with FAB/LMB96 mature B-NHL therapy.

Mediastinal large B-cell lymphoma (MLBL) represents 2% of mature B-cell non-Hodgkin lymphoma in patients ≤ 18 years of age. We analyzed data from childhood and adolescent patients with stage III MLBL (n = 42) and non-MLBL DLBCL (n = 69) treated with Group B therapy in the French-American-British/Lymphome Malins de Burkitt (FAB/LMB) 96 study. MLBL patients had a male/female 26/16; median age, 15.7 years (range, 12.5-19.7); and LDH < 2 versus ≥ 2 × the upper limit of normal, 23:19. Six MLBL patients (14%) had < a 20% response to initial COP (cyclophosphamide, vincristine, and prednisone) therapy. Central pathology revealed approximately 50% with classical features of primary MLBL. Five-year event-free survival for the stage III MLBL and non-MLBL DLBCL groups was 66% (95% confidence interval [CI], 49%-78%) and 85% (95% CI, 71%-92%), respectively (P < .001; 14%). The 5-year overall survival in the 42 MLBL patients was 73% (95% CI, 56%-84%). We conclude that MLBL in adolescent patients is associated with significantly inferior event-free survival compared with stage III non-MLBL DLBCL and can be of multiple histologies. Alternate treatment strategies should be investigated in the future taking into account both adult MLBL approaches and more recent biologic findings in adult MLBL.

Primary follicular lymphoma of the testis in children and adolescents.

This study reports 6 cases of primary follicular lymphoma of the testis (PFLT) in children and adolescents correlated with clinical presentation, pathologic features, treatment, and outcome. All 6 patients (age, 3 to 16 y; median, 4 y) had PFLT grade 3 with disease limited to the testis, completely resected and treated with 2 courses of chemotherapy (cyclophosphamide, vincristine, prednisone, doxorubicin). Event-free survival was 100% (follow-up: median, 73 mo; mean, 53 mo; range, 6 to 96 mo). In conclusion, clinical outcome in children and adolescents with PFLT is excellent with treatment including complete surgical resection and 2 courses of cyclophosphamide, vincristine, prednisone, doxorubicin.

Vincristine pharmacodynamics and pharmacogenetics in children with cancer: a limited-sampling, population modelling approach.

BACKGROUND: Vincristine is a key component of many childhood cancer treatment regimens. Pharmacodynamic parameters such as clinical efficacy and toxicity may be influenced by polymorphisms of CYP3A. AIM: The aim of this study was to document CYP3A5 genotype, vincristine pharmacokinetics (PK) and neurotoxicity profile for 50 children with cancer and determine whether, in a population of Australian children, the CYP3A5 genotype influenced the pharmacodynamics of vincristine as reflected by peripheral neurotoxicity. METHODS: Blood for PK analysis was collected after any single dose of vincristine and assayed using high performance liquid chromatography with tandem mass spectrometry detection. CYP3A5*3 and CYP3A5*6 genotype was determined using gel-electrophoresis or automated microfluidic electrophoresis. Neurotoxicity was determined by physical examination. RESULTS: The median age of children sampled was 6.5 years (range 1-16.25). Half the patients received concurrent corticosteroids for acute lymphoblastic leukaemia. Six patients (12%) had experienced grade 3 or 4 neurotoxicity. The median clearance, area under the curve and Cmax of vincristine was 482 mL/min/m(2) (range 132-698), 49.7 mcg/L.h (16.5-143.1) and 3.5 mcg/L (1.0-31.2), respectively. In contrast to prediction, all but three children were homozygous for wild-type CYP3A5*3. No CYP3A5*6 polymorphisms were identified. CONCLUSIONS: No correlation was identified between vincristine clearance, vincristine neurotoxicity, age, sex or concomitant steroid therapy. The limited sampling methodology proved acceptable to patients and families and would be suitable for larger scale studies including a wider range of genotypic variants and more detailed prospective evaluation of neurotoxicity.

Treatment and Outcomes for Central Nervous System Tumors in Australian Adolescents and Young Adults: A Population-Based National Study.

Purpose: While central nervous system (CNS) tumors account for only 10% of adolescent and young adult (AYA) cancers, they are the leading cause of cancer death in this age group. Using national data for Australia, we describe the presentation, treatment, and survival for AYAs diagnosed with CNS tumors. Methods: A population-based study of 15-24 year-olds diagnosed with CNS tumors (low- and high-grade glioma [LGG, HGG], medulloblastoma [MB], primitive neuroectodermal tumors [PNET], ependymoma [EP]) or other (e.g., low-grade neuronal tumor) between 2007 and 2012. Clinical details were extracted from hospital medical records for each patient. Treatment centers were classified as pediatric or adult services. Results: Two hundred seventy-five patients (129 LGG, 77 HGG, 23 MB, 10 PNET, 19 EP, 17 other) were identified, with 17% treated at pediatric hospitals. Symptoms (headache [53%], nausea [31%]) were present for a median of 3 weeks before consulting a health professional. Of LGG patients, 15% had radiotherapy (RT) and 12% chemotherapy (CT). Of HGG patients, 81% had RT and 75% CT. All MB and PNET were managed with surgery, and 74% of MB and 80% of PNET had both RT and CT. Treatment did not differ by treatment center type. Five-year survival for LGG and EP was over 80%, but was 42% for HGG and 20% for PNET. Conclusions: This national, population-based study indicates similar treatment for AYA patients with CNS tumors between pediatric and adult services. Poor outcomes for HGG and PNET patients highlight the need for clinical trials of novel approaches for these tumors.

Prevalence of QTc Prolongation in Patients With Advanced Cancer Receiving Palliative Care-A Cause for Concern?

CONTEXT: Medications commonly used for symptom control along with other known risk factors have the potential to prolong ventricular repolarization as measured by the QT interval (the time from the start of the Q wave to the end of the T wave) on a standard electrocardiogram (ECG). OBJECTIVES: To document the prevalence of a prolonged QT interval corrected for heart rate (QTc) interval in the palliative/oncology setting, compare automatic ECG QTc measurements with manual readings and identify any correlation between QTc prolongation and the use of drugs or other risk factors. METHODS: A convenience sample of consecutive patients with cancer, admitted under or known to the palliative/supportive care teams in two metropolitan hospitals, and willing to provide an ECG recording and basic demographic information including QTc risk factors were included. Both automated and manually calculated QTc intervals were recorded. Multivariable analysis was used to determine risk factors independently associated with prolonged QTc intervals. RESULTS: Of the 389 participants, there was a significant difference in mean QTc between sites using automated but not manual calculations. Manual readings were therefore used with predetermined cutoffs of 0.44 seconds (males) and 0.46 seconds (females). Seventy-two (18.5%) of the participants had a prolonged QTc with six (1.5%) having a prolongation of >0.50 seconds. At-risk drugs were being taken by 218 participants (56.0% of total cohort). Factors shown to be associated with QTc prolongation included age, gender, performance status, and hypocalcemia. No specific medication was associated with increased risk. CONCLUSION: Although almost 20% of patients receiving palliative care had prolongation of QTc, the possibility of serious consequences appeared to be low despite the frequent occurrence of risk factors.

Vincristine: Can its therapeutic index be enhanced?

Vincristine is one of the most widely used and more effective drugs in paediatric oncology. The dose-limiting toxicity of neuropathy, lack of proven neuroprotective measures and an incomplete understanding of the pharmacokinetics and pharmacogenetics of vincristine have limited its therapeutic potential. Recent advances in the understanding of vincristine pharmacokinetics and pharmacogenetics, and potential methods of preventing neurotoxicity are reviewed which could enable dose escalation and dose individualisation in order to enhance the therapeutic index.

Management of Sarcoma in Adolescents and Young Adults: An Australian Population-Based Study.

Background: While overall survival (OS) for cancer in adolescents and young adults (AYA) has improved, there has been little change in AYA survival for several types of sarcomas. Using national data for Australia we describe (1) the treatment centers caring for AYA sarcoma, (2) treatments provided, and (3) survival outcomes. Procedure: National population-based study assessing treatment of 15-24 year-olds diagnosed with soft tissue sarcoma (STS), bone sarcoma (BS), and Ewing family tumors (ET) between 2007 and 2012. Treatment details were abstracted from hospital medical records. Treatment centers were classified as pediatric or adult specialist AYA/sarcoma center, or other adult. Cox proportional hazard regression analyses examined associations between type of treatment center and OS. Results: Sixty-one hospitals delivered treatment to 318 patients (135 STS; 91 BS, 92 ET), with 9%, 22%, and 17% of STS, BS, and ET, respectively, treated at pediatric and 62%, 59%, and 71% at adult specialist hospitals. Of 18-24 year-olds, 82% of BS, 90% of ET, and 73% of rhabdomyosarcomas at adult specialist centers were on a trial or standard protocol, compared with 42%, 89%, and 100%, respectively, at nonspecialist adult hospitals. After adjusting for disease and patient characteristics, survival was not associated with treatment center type for any disease type. However, ET survival was poorer for patients not receiving a standard chemotherapy protocol. Conclusions: Around 10% of AYA sarcoma patients attending adult hospitals were not on a standard protocol. Poorer survival for ET patients not on a standard protocol highlights the importance of ensuring all patients receive optimal care.

Research priorities for childhood chronic conditions: a workshop report.

BACKGROUND: Chronic conditions are the leading cause of mortality, morbidity and disability in children. However, children and caregivers are rarely involved in identifying research priorities, which may limit the value of research in supporting patient-centred practice and policy. OBJECTIVE: To identify priorities of patients, caregivers and health professionals for research in childhood chronic conditions and describe the reason for their choices. SETTING: An Australian paediatric hospital and health consumer organisations. METHODS: Recruited participants (n=73) included patients aged 8 to 14 years with a chronic condition (n=3), parents/caregivers of children aged 0 to 18 years with a chronic condition (n=19), representatives from consumer organisations (n=13) and health professionals including clinicians, researches (n=38) identified and discussed research priorities. Transcripts were thematically analysed. RESULTS: Seventy-eight research questions were identified. Five themes underpinned participants' priorities: maintaining a sense of normality (enabling participation in school, supporting social functioning, promoting understanding and acceptance), empowering self-management and partnership in care (overcoming communication barriers, gaining knowledge and skills, motivation for treatment adherence, making informed decisions, access and understanding of complementary and alternative therapies),strengthening ability to cope (learning to have a positive outlook, preparing for home care management, transitioning to adult services), broadening focus to family (supporting sibling well-being, parental resilience and financial loss, alleviating caregiver burden), and improving quality and scope of health and social care (readdressing variability and inequities, preventing disease complications and treatment side effects, identifying risk factors, improving long-term outcomes, harnessing technology, integrating multidisciplinary services). CONCLUSION: Research priorities identified by children, caregivers and health professionals emphasise a focus on life participation, psychosocial well-being, impact on family and quality of care. These priorities may be used by funding and policy organisations in establishing a paediatric research agenda.

Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study.

High cure rates are possible in children with localized mature B-cell lymphoma (B NHL) using a variety of chemotherapeutic strategies. To reduce late sequelae, the duration and intensity of chemotherapy has been progressively reduced. The Lymphome Malins de Burkitt (LMB) 89 study reported long-term survival in almost all children with localized resected disease treated with two courses of COPAD (cyclophosphamide, vincristine, prednisolone and doxorubicin). This study was designed to confirm the effectiveness of this approach in a larger number of patients in a multinational co-operative study. The patient cohort was part of an international study (French-American-British LMB 96), which included all disease stages and involved three national groups. Patients in this part of the study had resected stage I or completely resected abdominal stage II disease. Following surgery, two courses of COPAD were given, without intrathecal (IT) chemotherapy. One hundred and thirty-two children were evaluable. Two of 264 (0.9%) courses were associated with grade IV toxicity (one stomatitis and one infection). With a median follow up of 50.5 months, the 4 year event-free survival is 98.3% and overall survival is 99.2%. Children with resected localized B-NHL can be cured with minimal toxicity following two courses of low intensity treatment without IT chemotherapy.

Role of FDG PET in the management of childhood lymphomas--case proven or is the jury still out?

Positron emission tomography (PET) is a novel non invasive functional imaging modality that is increasingly used for the primary staging of lymphomas and assessment of therapeutic response. This review evaluates the published reports of its use in childhood lymphomas, particularly in the primary staging, response assessment and monitoring after completion of treatment. Specific attention is focused on the clinical circumstances in which FDG PET is most likely to have an impact on management and some indications for its use in childhood lymphomas are suggested.

Palliative Care in Adolescents and Young Adults With Cancer-Why Do Adolescents Need Special Attention?

Meeting shortfalls in the provision of care to adolescents and young adults with cancer has focused largely on improving outcomes and psychosocial support. A significant percentage of adolescents and young adults with cancer will die of disease because of initial poor prognosis conditions or disease relapse. In adults, progress has been made in the concept of an integrated cancer/palliative care service. In pediatric oncology, the application of this philosophy of care has lagged behind somewhat. In the case of adolescents, particularly those with advanced cancer, the palliative care needs, in a broader sense than only end-of-life care, are often not adequately met, irrespective of whether treatment is delivered in a pediatric or adult cancer service. There are a number of age-specific aspects to palliative and supportive care for adolescents. Complex interactions between clinicians, parents, and patients potentially limit the young person's ability to influence care planning. The wide variation in real or perceived competency at this age, the developmental challenges in relation to behavior, communication, and coping strategy all require particular professional expertise that is not always available.

Impact of Opioid Therapy on Sleep and Respiratory Patterns in Adults With Advanced Cancer Receiving Palliative Care.

CONTEXT: In advanced cancer, abnormal sleep patterns may contribute to poor quality of life, but the impact of opioid-related sleep disorders has not been explored in detail in these patients. OBJECTIVE: To document sleep and respiratory patterns in patients with cancer, receiving a range of opioids, determine factors that contribute to severity of central or obstructive apnea, and to what extent these contribute to sleep disturbance. METHODS: Adults with advanced cancer admitted to a palliative care service underwent a sleep analysis by an unattended polysomnography. Total sleep time, apnea hypopnea index, central apnea index, obstructive apnea hypopnea index, arousal index, and oxygen desaturation were measured. Baseline assessment included body habitus, Mallampati score, comorbidity indices, concomitant medications, and the Berlin questionnaire. Epworth Sleepiness Scale, Stanford Sleepiness Scale, and Wu cancer fatigue scales were documented. RESULTS: Twenty-eight patients were studied, including 25 receiving opioids. In the latter group, the apnea hypopnea index was mildly abnormal in six patients and severely abnormal in 10 patients. Central apnea index and obstructive apnea hypopnea index were abnormal in nine and 17 patients, respectively. There was no significant correlation between opioid dose and polysomnographic results. CONCLUSION: In patients with advanced cancer receiving opioid analgesia, there was a high prevalence of respiratory disturbance, both central and obstructive, and deranged sleep patterns. Addressing sleep-disordered breathing in cancer patients has the potential to improve daytime drowsiness and quality of life.