Maree Colosimo

Nutraceuticals and chemotherapy induced peripheral neuropathy (CIPN): A systematic review

Chemotherapy induced peripheral neuropathy [CIPN] is a common significant and debilitating side effect resulting from the administration of neurotoxic chemotherapeutic agents. These pharmaco-chemotherapeutics can include taxanes, vinca alkaloids and others. Moderate to severe CIPN significantly decreases the quality of life and physical abilities of cancer patients and current pharmacotherapy for CIPN e.g. Amifostine and antidepressants have had limited efficacy and may themselves induce adverse side effects. To determine the potential use of nutraceuticals i.e. vitamin E, acetyl-L-carnitine, glutamine, glutathione, vitamin B6, omega-3 fatty acids, magnesium, calcium, alpha lipoic acid and n-acetyl cysteine as adjuvants in cancer treatments a systematic literature review was conducted. Revised clinical studies comprised of randomized clinical trials that investigated the anti-CIPN effect of nutraceuticals as the adjuvant intervention in patients administered chemotherapy. Twenty-four studies were assessed on methodological quality and limitations identified. Studies were mixed in their recommendations for nutraceuticals. Currently no agent has shown solid beneficial evidence to be recommended for the treatment or prophylaxis of CIPN. The standard of care for CIPN includes dose reduction and/or discontinuation of chemotherapy treatment. The management of CIPN remains an important challenge and future studies are warranted before recommendations for the use of supplements can be made.

Genetic association study of CYP1A1 polymorphisms identifies risk haplotypes in nonsmall cell lung cancer.

Lung cancer remains a leading cause of disease globally, with smoking being the largest single cause. Phase I enzymes, including cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1), are involved in the activation of carcinogens, such as polycyclic aromatic hydrocarbons, to reactive intermediates that are capable of binding covalently to DNA to form DNA adducts, potentially initiating the carcinogenic process. The aim of the present study was to investigate the association of CYP1A1 gene polymorphisms and haplotypes with lung cancer risk. A case–control study was carried out on 1,040 nonsmall cell lung cancer (NSCLC) cases and 784 controls to investigate three CYP1A1 variants, CYP1A1*2A (rs4646903; thymidine to cytosine substitution at nucleotide 3801 (3801T>C)), CYP1A1*2C (rs1048943; 2455A>G; substitution of isoleucine 462 with valine (exon 7)) and CYP1A1*4 (rs1799814; 2453C>A; substitution of threonine 461 with asparagine (exon 7)) using PCR restriction fragment length polymorphism methods. The CYP1A1*2A and CYP1A1*2C variants were significantly over-represented in NSCLC cases compared with controls, whereas the CYP1A1*4 variant was under-represented. CYP1A1 haplotypes (in allele order CYP1A1*4, CYP1A1*2C, CYP1A1*2A) CGC and CGT were associated with an increased risk of lung cancer, whereas AAT was associated with decreased lung cancer risk in this population. The present study has identified risk haplotypes for CYP1A1 in NSCLC and confirmed that CYP1A1 polymorphisms are a minor risk factor for NSCLC.

Risk of non-small cell lung cancer and the cytochrome P4501A1 Ile462Val polymorphism

ObjectiveThe Ile462Val substitution in the cytochrome P450 1A1 gene (CYP1A1) results in increased enzymatic activity. Preliminary data suggesting a link between this polymorphism and lung cancer risk in Caucasians are inconsistent, reflecting small sample sizes and the relatively low frequency of the variant.MethodsThe data set consisted of 1050 primary non-small cell lung cancer cases and 581 controls, a large homogenous population designed specifically to address previous inconsistencies. Patients were genotyped using a PCR-RFLP technique.ResultsCarriers of the valine allele, CYP1A1*2C, (Ile/Val or Val/Val genotypes) were significantly over-represented in non-small cell lung cancer compared to controls (OR=1.9; 95% CI=1.2–2.9; p=0.005) when adjusted for confounders, particularly in women (OR=4.6; 95% CI=1.7–12.4; p=0.003). The valine variant was statistically significantly over-represented in cases of lung cancer younger than the median age (64 years) (OR=2.5; 95% CI=1.3–4.8; p=0.005) and cases with less than the median cumulative tobacco-smoke exposure (46 pack-years) (OR=2.4; 95% CI=1.3–4.7; p=0.007).ConclusionsThese new data establish an association between the CYP1A1 Ile462Val polymorphism and the risk of developing non-small cell lung cancer, especially among women.

Gene expression of lung squamous cell carcinoma reflects mode of lymph node involvement

Tumour, node, metastasis staging is essential for lung cancer management. However, similarly staged cancers may have markedly different prognoses, indicating that stage cannot completely explain tumour behaviour. While ipsilateral hilar node involvement is designated N1, the current authors hypothesised that primary tumours involving nodes by direct extension are biologically distinct from those involving nodes through lymphatic metastasis. Microarrays were used to investigate the gene expression profiles of 59 primary lung squamous cell carcinomas, comparing N0 tumours (n = 35), N1 tumours by direct extension (N1d; n = 8), and N1/N2 tumours by lymphatic metastasis (N1/N2m; n = 16). Hierarchical clustering using 125 genes differentially expressed between N0 and N1/N2m tumours found N1d tumours clustered with N0 tumours. Class prediction modelling found the expression profiles of all eight N1d tumours were more similar to N0 than to N1/N2m tumours. The present study demonstrates for the first time that N1 tumours directly invading hilar nodes are genomically different to those that metastasise via lymphatics. Independent reports suggest that tumours with direct, rather than metastatic node involvement have better outcomes. Consequently, the data suggest that there is a need to re-evaluate the N1 staging definition in lung cancer. This is relevant for prognosis prediction and also for clinical management, particularly in selecting those patients most likely to benefit from adjuvant chemotherapy.

Chemotherapy-induced peripheral neuropathy (CIPN) and vitamin B12 deficiency

Chemotherapy-induced peripheral neuropathy (CIPN) continues to be a major concern for oncological practise considering the increasing number of cancer survivors and the lack of standardised prevention or treatment [1]. The incidence of CIPN depends on the chemotherapy agent administered but is estimated to occur in one third of all patients undergoing chemotherapy [2, 3]. The prevalence of CIPN has been estimated to be 68.1 % the first month after the administration of neurotoxic chemotherapy agents and 60 % 3 months post chemotherapy treatment. Patients were found to still have 30% prevalence 6 months or more after chemotherapy according to the results published in a systematic review conducted in 2014 [4]. Patients experiencing moderate to severe CIPN report a reduced quality of life [5], chronic discomfort [6] and disruption of physical abilities for general life activities which can be temporary or permanent [5]. Currently in clinical practise, CIPN is assessed using the common toxicity scales; however, these rely heavily on the patient’s subjective reports rather than quantitative testing [7]. CIPN is a potentially rescindable side effect although reversibility may be dependent on early detection or identification and modification of chemotherapy treatment [7]. Permanent CIPN has still been reported, especially sensory symptoms in the lower extremities among patients treated with oxaliplatin up to 11 years after treatment [8]. Early differential diagnosis and prevention of permanent CIPN need to be a priority for extending the quality of life of cancer patients. Patients with a previous history of a vitamin B12 deficiency have been identified as a predisposing condition that may increase the risk of developing CIPN [5]. However, patients who have had no previous history of a vitamin B12 deficiency may not be tested before chemotherapy commences for vitamin B12 status. Moreover, a potential vitamin B12 deficiency may develop during chemotherapy administration [9] that can therefore potentially predispose the patient to developing and/ or delaying the development of CIPN. We present a clinical case of a cancer patient who developed CIPN and was found to be vitamin B12 deficient after completing a chemotherapy regimen. Upon vitamin B12 administration, the severity of CIPN decreased that allowed the patient increased functional ability in daily activities including the ability to walk.

Herbal medicines and chemotherapy induced peripheral neuropathy (CIPN): a critical literature review

ABSTRACT Background: Chemotherapy induced peripheral neuropathy [CIPN] is a common significant and debilitating side-effect resulting from the administration of neurotoxic chemotherapeutic agents. These pharmaco–chemotherapeutics can include taxanes, vinca alkaloids, platinum analogues, and others. Moderate to severe CIPN significantly decreases the quality of life and physical abilities of cancer patients and current pharmacotherapy for CIPN e.g. Amifostine, and antidepressants have had limited efficacy and may themselves induce adverse side-effects. Methods: To determine the potential use of herbal medicines as adjuvants in cancer treatments, a critical literature review was conducted by electronic and manual search on nine databases. These include PubMed, the Cochrane Library, Science Direct, Scopus, EMBASE, MEDLINE, Google Scholar, and two Chinese databases CNKI and CINAHL. Thirty-four studies were selected from 5614 studies assessed and comprising animal studies, case reports, retrospective studies, and minimal randomized clinical trials investigating the anti-CIPN effect of herbal medicines as the adjuvant intervention in patients administered chemotherapy. The thirty-four studies were assessed on methodological quality and limitations identified. Results: Studies were mixed in their recommendations for herbal medicines as an adjuvant treatment for CIPN. Conclusion: Currently no agent has shown solid beneficial evidence to be recommended for the treatment or prophylaxis of CIPN. Given that the number of cancer survivors is increasing, the long-term side effects of cancer treatment, is of major importance.

B Vitamin Complex and Chemotherapy-Induced Peripheral Neuropathy

Purpose of ReviewThe purpose of this mini review is to evaluate the literature on B vitamins and chemotherapy-induced peripheral neuropathy.Recent FindingsOne hundred and five journal articles were evaluated and nine manuscripts were included. There was one in vitro, one was an animal and seven were human studies. The in vitro study was a safety study on vitamin B6 and oxaliplatin which was not directly related to CIPN. The animal study evaluated vitamin B3 on paclitaxel administration with positive results. The human studies varied using a vitamin B complex, vitamin B12 only and vitamin B6.SummaryChemotherapy-induced peripheral neuropathy (CIPN) continues to plague patients and the medical fraternity. Currently, there are still no conclusive protective or treatment options. B vitamins have been found to play a role in CIPN prevention, but further studies are required to ascertain possible protection and treatment options.

Chemotherapy-induced peripheral neuropathy management.

154 Background: Neurological complications such as chemotherapy-induced peripheral neuropathy (CIPN) and neuropathic pain are frequent side-effects of neurotoxic chemotherapy agents. An increasing survival rate and frequent administration of adjuvant chemotherapy treatments involving neurotoxic agents makes it imperative that accurate diagnosis, prevention and treatment of these neurological complications be implemented to minimize the burden experienced by patients undergoing these treatments. METHODS To determine the potential use of pharmaceuticals, nutraceuticals and herbal medicines as adjuvants in cancer treatments a critical literature review was conducted by electronic and manual search on nine databases. These include PubMed, the Cochrane Library, Science Direct, Scopus, EMBASE, MEDLINE, Google Scholar and two Chinese databases CNKI and CINAHL. Thirty studies were selected for pharmaceutical agents, twenty-four studies for nutraceuticals and thirty-four studies for herbal medical trials. Seven acupuncture trials were also identified in relation to CIPN management. Data was collated and organised into chemotherapy drugs, agents trialled, number of participants, results and recommendations. RESULTS For pharmaceutical agents, amifostine has possible ototoxicity protection for children in cisplatin and duloxetine as a treatment option for pain. For nutraceuticals, vitamin E was found to have protective abilities for cisplatin ototoxicity, omega 3 fatty acids for taxane administration and vitamin B6 and lipoic acid for oxaliplatin CIPN. In herbal medicine, Goshajinkigan showed great promise for oxaliplatin-IPN protection. Vitamin B12 deficiencies have also been found to increase the onset and severity of CIPN. CONCLUSIONS Currently, no pharmaceutical, nutraceutical or complementary agent has been found to be completely beneficial in preventing or treating CIPN. It is suggested clinicians identify the best option from the research to assist patients in both possible prevention and treatment of CIPN. In addition, research has found that a vitamin B12 deficiency may potentiate moderate to severe CIPN presentation and testing of this vitamin is suggested.

Screening lung Tumour tissue for whole genome sequencing

068-P12 LUNG ADENOCARCINOMA BIOMARKER SCREENING IN AN AUSTR`ALIAN POPULATION Ainge Allen H, Stone E, Plit Ml, Havryk A, Goldrick A, Field A, Mead S, Qiu M, Chou A, Morey A Department of Respiratory Medicine, St Vincent’s Hospital, Sydney, New South Wales/AUSTRALIA; Department of Anatomical Pathology, Sydpath, St Vincent’s Hospital, Sydney, New South Wales/AUSTRALIA Aims: The emergence of new targeted therapies and clinical trials in lung adenocarcinoma suggest that routine molecular biomarker testing is warranted to detected subtypes of adenocarcinoma which will benefit from new therapies. Australian data is still emerging. We aim to detect the incidence of treatment specific molecular subtypes of lung adenocarcinoma in the Australian population. Methods: This is a single centre prospective pilot study of patients with a histopathological diagnosis of adenocarcinoma who have been presented at a Lung Cancer multidisciplinary meeting. Formalin fixed paraffin embedded tissue of 22 tumour samples were submitted for targeted PCR-based EGFR and KRAS mutation analysis; and EGFR amplification, MET amplification and EML4-ALK rearrangement testing by in-situ hybridization. one sample had insufficient tissue for analysis. Results: So far 22 patients received a definite tissue diagnosis of lung adenocarcinoma, 8/22 with Stage III and 10/22 with Stage IV disease. 4/22 (19%) are positive for an EGFR mutation, with activating EGFR mutations in 3/22 (14%) and an EGFR mutation of uncertain clinical significance in one patient (5%). EGFR amplification was detected in 2/22 patients (9%), KRAS mutations were detected in 5/22 patients (23%) patients, of which none carried EGFR mutations. EML4-ALK translocation was seen in 2/22 patients (9%) and MET amplification in 1/22 (5%) patients. Conclusions: Preliminary results indicate that treatment specific molecular subtypes of lung adenocarcinoma occur more commonly in the Australia population than other Western populations. Though further investigation is required, routine molecular biomarker testing is warranted. Disclosure: This study was funded by an unrestricted grant from Roche.

P-120 Expression of cyclin D1 in bronchial epithelium of smokers

Cyclin Dl synthesis and activity levels peak in Gl, are tightly regulated during other phases of the cell cycle, and are critical in driving cells through the Gl restriction point, committing them to complete the cell cycle. Dysregulated expression of Cyclin Dl has been implicated in lung carcinogenesis. To determine whether altered expression of Cyclin Dl occurs in benign, tobacco-exposed bronchial epithelium as a precursor of invasive lung cancer we studied expression of Cyclin Di in anatomically mapped regions of proximal bronchus in 66 smokers undergoing lung resections mostly for primary lung cancer. Relative expression of Cyclin 01 by Taqman real-time PCR analysis was high i.e. >I000 fold arbitrary reference levels in at least one epithelial region (two to seven separate epithelial regions analysed per patient) in 18 of 66 current or ex-smokers (27%) and 0 of 6 never smokers. Morphological evaluation of flanking transverse sections available in 15 smokers with high levels of Cyclin Dl expression showed normal histology in 9 cases, metaplastic epithelium in 3, and dysplastic epithelium in 3 cases. In most patients high level expression was observed in only one of several epithelial segments analysed, however in one smoker with lung cancer all 3 segments expressed high levels of Cyclin Dl and multiple flanking sections were dysplastic in this case. There was no association between relative expression of Cyclin Dl in bronchial epithelium and genotype at the polymorphic locus A870G in exon 4 of CCNDI in these smokers. We have demonstrated that Cyclin Dl expression is focally high in the bronchial epithelium of a proportion of smokers undergoing lung resections, and that this is more likely related to local conditions in the respiratory tract than to genotypic determinants. Some areas of morphologically normal non-inflamed bronchus express high levels of Cyclin Dl and the altered expression in these cases may accompany focally increased cell turnover in otherwise normal epithelium. To determine the significance of this we plan to extend these studies by correlating bronchial Cyclin Di expression with proliferative indices.