Class of 2013 Abstract / Specific Aims: To describe the outcomes of olanzapine in the treatment of refractory chemotherapy-induced nausea and vomiting (CINV). Methods: Data were collected regarding demographic information, chemotherapy regimen, CINV prophylaxis, rescue antiemetics, and olanzapine usage for subjects, age 18-79, who were admitted to the University of Arizona Medical Center for chemotherapy and received at least one dose of olanzapine for CINV between January 2008 and January 2012. The primary outcome measure was the number of rescue antiemetics required following the first dose of olanzapine (greater than 10 doses was considered treatment failure). Comparisons using chi square to determine if differences existed with respect to the level of chemotherapy emetogenicity and demographic information were conducted. Main Results: No statistical difference between chemotherapy regimens of high versus low-to-moderate emetogenicity was seen (P=0.79). However, 7 of 10 (70%) subjects receiving highly emetogenic chemotherapy achieved success and 15 of 23 (65%) subjects receiving low-to-moderately emetogenic chemotherapy achieved success. No statistical differences appeared when evaluating usage of 1 versus 2 or more prophylactic antiemetics (P=0.77), men versus women (P=0.08), and age over 50 versus 50 years or younger (P<0.99). Conclusion: This study demonstrated a trend towards greater emetic control with the addition of olanzapine in patients failing first-line antiemetic pharmacotherapy. Additionally, a trend towards greater emetic control was seen in women. The rates of success among all groups may suggest benefit to adding olanzapine to subjects experiencing refractory CINV. Due to the limited sample size and retrospective methodology of the study, the use of olanzapine in refractory CINV merits further research with large, prospective studies directly comparing addition of olanzapine to other appropriate antiemetics.

No description available.

Background: Cannabis has been legalized in Canada since October 2018 and shown to be effective for chemotherapy-induced nausea (CIN). Purpose: Guided by the Ottawa Model of Research use, the aim was to determine factors influencing oncology nurses discussing cannabis use with patients experiencing CIN. Part I: A literature review to identify oncology nurses’ practices, knowledge, and attitude toward providing guidance on cannabis use for patients with CIN. Twelve articles were included. Results showed that health care professionals were hesitant to provide guidance for patients on using cannabis for medical purposes. But no studies specifically focus on nurses and CIN. Part II: A descriptive, cross-sectional study was conducted using survey methods. Twenty-five Canadian oncology nurses responded to the survey. Half (n=11) correctly answered the knowledge question about the effectiveness of cannabis. Most (n=18) did not feel confident providing guidance on use of cannabis for CIN. The top three barriers identified are social stigma, lack of knowledge, and lack of support in the workplace. Conclusion: Few Canadian oncology nurses discuss cannabis use for CIN. Identified barriers need to be addressed for oncology nurses to be prepared to discuss use of cannabis for CIN.

No description available.

Background: Chemotherapy Induced Peripheral Neuropathy (CIPN) is a debilitating neuropathy caused by commonly used chemotherapeutics. Clinically, the problem of CIPN is compounded by difficulties with diagnosis and limited treatment options. The pathophysiology of CIPN remains elusive, with current mechanistic postulates focused mainly on the peripheral nervous system. However, animal and human models of non-CIPN neuropathic conditions have shown the brain to be central to the development and maintenance of painful neuropathy. Moreover, evidence suggests that aberrant activity in key regions of the brain and brainstem could denote individual vulnerability for chronic pain states. The impact of the brain on CIPN development is unknown. Assessment of drug efficacy using brain imaging can provide sensitive readouts and is increasingly used in clinical trials. Aims: Firstly, to prospectively explore the structure and function of the brain in cancer patients prior to chemotherapy administration, using functional magnetic resonance imaging (fMRI), in order to determine whether baseline differences exist between patients who progress to CIPN as compared to those who do not. Secondly, to develop a pilot study using fMRI to investigate a topical treatment for CIPN, in order to assess the feasibility of setting up a study with this kind of design. Methods: To address the first aim of this thesis a prospective cohort study (the CIPN fMRI Study) was developed. Cancer patients scheduled to receive neurotoxic chemotherapy treatment including oxaliplatin, carboplatin, carbotaxol, or cisplatin, were recruited from three NHS trusts in Scotland, to undergo a high resolution (3 tesla) functional MRI scan, at a single time point prior to commencement of chemotherapy. During the scan structural, resting state and functional data were collected. Functional data involved the presentation of punctate stimuli (using a 256mN von Frey filament), above the patients’ right medial malleolus. While receiving the punctate stimuli, patients viewed images that had neutral or positive emotional content or a baseline coloured image with no content. Sample size was based on previously successful pain fMRI studies and pragmatic estimates. Acute CIPN was defined clinically by common toxicity criteria as necessitating a chemotherapy dose reduction or cessation. Data were analysed using FMRIB’s Software Library (FSL) version 5, 2015. Standard data pre-processing (brain extraction, registration, B0 unwarping, motion correction, and denosiing with FIX) was carried out. Structural analysis was conducted using FIRST. Resting state analysis utilised FSL’s MELODIC tool, and a non-parametric group comparison was made following a dual regression approach. FEAT was used for both first and second level functional analyses. Group comparisons were made using a mixed effects analysis (z threshold 2·3 and 2, regions considered significant at p < 0·05, cluster corrected). The group was split by sex to explore known sex differences in pain processing. To address the second aim of this thesis, a pilot fMRI randomised controlled trial (MINT3 Study) was designed. Approvals from ethics and research and development were sought and obtained. Data collection forms were developed. An fMRI experiment was proposed and a single pilot scan was conducted and analysed. Results: 30 patients were recruited for the CIPN fMRI study (mean age 60·4 years, 95% Confidence Interval: 57.4-63.4, 17 women). Two patients had lung cancer, nine had gynecological malignancies and 18 had colorectal cancer. 17 patients developed acute CIPN. Structural analysis showed that patients who developed CIPN had a smaller volume of the Nucleus Accumbens (NAc). Resting state analysis did not show clear differences between those who developed CIPN and those who did not. Finally, functional analysis showed that patients who did not develop CIPN had greater activation in the superior frontal gyrus when viewing positive emotional images as compared to those who did progress to CIPN. Region of interest analysis showed that female patients who developed CIPN had greater activity in their mesencephalic pontine reticular formation (MPRF). Male patients who progressed to CIPN had decreased activity in their thalamus. Feasability of the MINT3 study set up and fMRI paradigm was assessed. Interpretation Differences in brain structure and function are evident between patients who developed CIPN and those who did not. Crucially, the regions identified, in particular the NAc, have been postulated to denote a vulnerability for progression to pain states. Although the findings need further confirmation they suggest a paradigm shift in terms of CIPN as a clinical problem. Specifically, it appears that certain individuals can be considered as having increased risk of CIPN development prior to chemotherapy administration. This risk relates to the baseline structure, and function of their brains. Finally, the set up of the MINT3 fMRI study showed that this kind of study design is acceptable in terms of ethical and R&D approvals and a single healthy volunteer pilot.

Background Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting toxicity with significant sequelae impacting prognosis and quality of life. The natural history and pathophysiological mechanisms of CIPN are unclear. Equally, the lack of systematic approach to diagnosis and assessments contribute to difficulty identifying at risk patients with implications on symptom burden. Effective management of CIPN is also difficult due to limited treatment options. To try and address this challenging clinical problem, this thesis aimed to adopt a translational approach to: 1) characterisation and early identification of the development of CIPN in cancer patients receiving neurotoxic chemotherapy and 2) explore topical treatment options in patients with chronic peripheral neuropathic pain. Methodology In the CIPN study, a mixed cohort of colorectal, gynaecological and lung cancer patients receiving neurotoxic chemotherapy (platinum agents and taxanes) were assessed prospectively, at baseline (prior to initiating chemotherapy), during cycles (every 3 weeks) and post-treatment (every 3 months) for up to 12 months (cumulative 261 assessments). Comprehensive longitudinal clinical characterisation consisted of the integration of quantitative sensory testing (QST), objective measure of function (grooved pegboard test), patient-reported outcomes and in vivo confocal microscopy to provide insight into the clinical course and potential psychophysical biomarkers of CIPN during and after chemotherapy. In the pilot intervention study, patients with chronic, complex cancer treatment related peripheral neuropathic pain received a single application of high concentration 8% capsaicin patch. Assessments conducted at baseline, 4 weeks and 12 weeks included patient-reported outcomes and QST with an exploratory application of in vivo confocal microscopy in a case. Results In the CIPN study, 33 patients when compared to 33 age and gender matched healthy controls displayed thermal hyperalgesia, sensorimotor impairment and increased resting heart rate prior to initiating neurotoxic chemotherapy. Characterisation of somato-sensory profile demonstrated dysfunction of the various types of primary afferent nerves (Aβ, Aδ and C). Assessing the change over time from baseline to during cycles and post-treatment follow up, revealed signs and symptoms as early as cycle 2 with an increase in the later cycles and 3 months post-treatment follow up. A greater burden was observed at 12 months in comparison to baseline. Significant changes were observed in QST parameters indicating both small and large fibre deficits. Interesting associations were observed for example with tactile deficits in the upper and lower limb and patient-reported outcomes. The repeated measures model provided an opportunity to distil the relationship between subjective and objective measures of CIPN. The subclinical findings at baseline however did not translate to obvious predictors of CIPN development. The exploratory use of in vivo confocal microscopy (45 healthy controls, 9 patients) demonstrated correlation with current assessment tools (QST). Analysis from the pilot intervention study of 20 patients revealed clinically significant improvement in pain in a subset at 4 and 12 weeks post-treatment. Conclusion Overall the combination of subjective and objective measures utilised in the prospective characterisation of this mixed cohort of cancer patients provided a useful paradigm for qualifying and quantifying the trajectory of CIPN related peripheral nerve damage and symptom burden with additional contribution from the novel in vivo confocal microscopy work. In capturing the varied spectrum of phenotypes, this approach may provide insight into the complexities of the underlying neurobiological mechanisms. The baseline subclinical sensory, motor and autonomic nerve dysfunction implicate a cancer-mediated process possibly contributing to CIPN. Although the preliminary investigation of baseline predictors of CIPN was inconclusive, thermal pain threshold warrant further investigation. These findings highlight the need to further address prediction and risk stratification in larger studies. The exploratory intervention study suggests that patients with chronic neuropathic pain may receive some benefit in pain severity, function and mood with effect continuing at 12 weeks post-treatment. This research warrants further investigation in larger cohorts.

While cancer chemotherapy continues to significantly contribute to the number of cancer survivors, exposure to these drugs can often result in chemotherapy-induced peripheral neuropathy (CIPN), a consequence of peripheral nerve fiber dysfunction or degeneration. CIPN is characterized by sensory symptoms in the hands and feet, such as numbness, burning, and allodynia, resulting in an overall decrease in quality of life. Paclitaxel (Taxol), a microtubule poison that is commonly used to treat breast, lung, and ovarian cancers, has been found to cause CIPN in 59-78% of cancer patients. There is currently no effective preventative or therapeutic treatment for this side effect, which can be a dose-limiting factor for chemotherapy or delay treatment. Our collaborators in the laboratory of Dr. M. Imad Damaj have shown that nicotine, a nicotinic acetylcholine receptor (nAChR) agonist, and R-47, an α7 nAChR silent agonist, can prevent and reverse paclitaxel-induced peripheral neuropathy in mice. With regard to cancer, this work demonstrates that nicotine and R-47 do not enhance A549 and H460 human non-small cell lung cancer cell viability, colony formation, or proliferation alone, and they do not attenuate paclitaxel-induced growth arrest, apoptosis, or DNA fragmentation. Most importantly, nicotine and R-47 do not increase the growth of A549 tumors or interfere with the antitumor activity of paclitaxel in tumor-bearing mice. These data suggest that targeting nAChRs may be a safe and efficacious approach for the prevention and treatment of CIPN in cancer patients.

Chemotherapy Induced Peripheral Neuropathy (CIPN) is a common problem among cancer patients who receive a wide range of chemotherapy. This problem causes a decline in quality of life and increased disabilities. CIPN assessment instruments are either subjective, objective, or a combination of both. So far, there is no agreement on the best way for assessment. The goal of this study was to explore the relationships among subjective and objective CIPN assessment instruments. Specifically, this study aimed to 1) evaluate the relationship between the Total Neuropathy Score-reduced (mainly objective) and patients’ function, as measured by the interference scale of the Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (subjective); and 2) evaluate the relationship between the Total Neuropathy Score-reduced and neuropathy symptom experience, as measured by the symptom experience scale of the Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (Subjective). To achieve those aims, a secondary data analysis for 56 participants who participated in a study entitled: Group Acupuncture for Treatment of Neuropathy from Chemotherapy was done. After Pearson correlations were calculated, the study found that there is a positive, weak relationship between the TNSr and the symptom experience scale of the CIPNAT(r=0.34). A positive, week relationship was found between the TNSr and the interference with activity scale of the CIPNAT(r=0.28). These results suggest that objective and subjective assessment are not highly correlated, and likely measure different aspects of CIPN. A comprehensive assessment approach is needed for decision making in the clinical oncology setting.

This study examined the association between neuropathy limitations and depression in chemotherapy patients currently on treatment with a taxane-based, platinum-based or plant alkaloid chemotherapy drug. The Overall Neuropathy Limitations Scale (ONLS) and the Beck Depression Inventory-Short Form (BDI-SF) were used to assess neuropathy limitations and depression in 24 chemotherapy patients with reported symptoms of peripheral neuropathy. Average age of patients was 65 years, 66.6% were female, and average number of chemotherapy cycles completed was 5.6. Of the 24 patients, 37.5% of patients were on a single agent taxane-based drug, 37.5% of patients were on a taxane-based drug with a platinum based drug, 16.6% of patients were on a plant alkaloid, and 8.3% were on a combination of a taxane-based and another non-neurotoxic chemotherapy drug. The scores on both the BDI-SF and ONLS were very low. The mean score on the BDI-SF was 4.1 with a standard deviation of 2.7. The mean score on the ONLS was 2.2 with a standard deviation of 1.5. The study showed a non-significant relationship between neuropathy limitations and depression in chemotherapy patients. These findings show no association between neuropathy limitations and depression. Although all of these patients had symptoms of peripheral neuropathy, they were not severe enough to interfere with daily activities. The lack of relationship was not unexpected given the low scores on both the BDI-SF and ONLS. Future research should re-evaluate this relationship with a larger, more diverse sample.

Published in Supportive Care in Cancer 2014;22(8):2161-6. DOI:10.1007/s00520-014-2182-7 / 京都大学 / 0048 / 新制・課程博士 / 博士(社会健康医学) / 甲第18548号 / 社医博第59号 / 新制||社医||8(附属図書館) / 31448 / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 武藤 学, 教授 佐藤 俊哉, 教授 千葉 勉 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM