Lise Eckhoff

Chemotherapy-induced peripheral neuropathy in patients treated with taxanes and platinum derivatives

Abstract Background. Chemotherapy with taxanes and platinum compounds has resulted in substantial survival benefits both in adjuvant and metastatic settings. However, as a side effect, such chemotherapy may cause peripheral neuropathy (CIPN) which may result in discontinuation of treatment, and if it persists after treatment completion, has a negative impact on quality of life (QoL). Results. Symptoms of CIPN are sensory, like pain, numbness, and tingling, typically located in the hands and feet. For oxaliplatin, there is an acute form of CIPN, resulting in paraesthesias in the mouth and throat during or shortly after the infusion triggered by exposure to cold. Risks factors for CIPN include preexisting neuropathy, either from treatment with other neurotoxic agents, or from comorbid conditions. The incidence of CIPN is related to dose per cycle, cumulative dose, and duration of infusion. While cisplatin-induced neuropathy is irreversible, CIPN induced by taxanes may persist for several years in about 30% of patients. Evidence from the literature is suggestive that CIPN is likely to be negatively associated with QoL. No agents have been identified to be recommended for the prevention of CIPN. For treatment of CIPN, the best available data supports a moderate recommendation for treatment with duloxetine and evidence is inconclusive regarding the use of tricyclic antidepressants (such as nortriptyline), gabapentin, and a compounded topical gel containing baclofen, amitriptyline HCL, and ketamine. Conclusion. Research is still needed to predict which patients are at high risk of developing CIPN during treatment and in whom CIPN will persist after completion of chemotherapy.

Persistence of docetaxel-induced neuropathy and impact on quality of life among breast cancer survivors

BACKGROUND This study evaluates persistence and severity of docetaxel-induced neuropathy (peripheral neuropathy (PN)) and impact on health related quality of life in survivors from early-stage breast cancer. METHODS One thousand and thirty-one patients with early-stage breast cancer, who received at least one cycle of docetaxel and provided information on PN during treatment, completed questionnaires on PN as an outcome (Common Toxicity Criteria (CTC) scores, European Organisation for Research and Treatment of Cancer Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC CIPN20) and EORTC Quality of Life Questionnaire (QLQ)-C30) after 1-3years. FINDINGS Upon completion of docetaxel treatment, 241 patients (23%) reported PN, grades 2-4. PN persisted for 1-3years among 81 (34%) while PN regressed to grades 0-1 among 160 (66%). Among 790 patients (77%) without PN, 76 (10%) developed PN 1-3years later while 714 (90%) stayed free from PN. Significant risk factors for persistent PN were age ⩾55 (p=0.001), maximum grade of PN during docetaxel treatment (p<0.0001), persistent muscle and joint pain (p<0.0001), stomatitis (p=0.047) and fatigue (p=0.001). Persistent PN had a significant negative correlation with health-related quality of life (HRQOL), functional scales and symptom scales. INTERPRETATIONS Overall, 15% of breast cancer survivors treated with docetaxel report PN 1-3years after treatment with a significant negative impact on HRQOL.

Persistent pain, sensory disturbances and functional impairment after adjuvant chemotherapy for breast cancer: Cyclophosphamide, epirubicin and fluorouracil compared with docetaxel + epirubicin and cyclophosphamide

Abstract Background. Taxanes used in adjuvant therapy for breast cancer are neurotoxic, and thereby being a potential risk factor for persistent pain after breast cancer treatment (PPBCT) and sensory disturbances. The purpose was to compare patients treated with cyclophosphamide, epirubicin and fluorouracil (CEF) and cyclophosphamide and epirubicin + docetaxel (CE + T) in relation to PPBCT, sensory disturbances, peripheral sensory disturbances and functional impairment. Material and methods. A comparative nationwide cross-sectional questionnaire study on two cohorts treated with CEF respectively CE + T, based on the Danish Breast Cancer Cooperative Groups database. Inclusion criteria: women treated with chemotherapy as adjuvant treatment for primary breast cancer, age 18–69 years, without recurrence. Results. One thousand two hundred and forty-one patients allocated to CEF in 2005–2006 and 1652 patients allocated to CE + T in 2007–2008 were included. Six hundred and sixty-four (53%) with CEF and 861 (53%) patients with CE + T reported pain. In the multivariate analysis including available risk factors, CE + T did not confer an increased risk of PPBCT, OR 0.95 (95% CI 0.81–1.11), p = 0.52, compared to CEF. Patients treated with CE + T had a lower risk of sensory disturbances in the area of surgery compared with CEF, OR 0.75 (95% CI 0.62–0.90), p = 0.002. More CE + T patients reported peripheral sensory disturbances in the hands, OR 1.56 (95%CI 1.27–1.92), p < 0.0001, and in the feet, OR 2.0 (95% CI 1.66–2.42) p < 0.0001, compared to CEF. There was no difference in functional impairment (p = 0.62). Conclusion. Docetaxcel as adjuvant treatment for breast cancer does not increase the risk of PPBCT, sensory disturbances in the surgical area or functional impairment, but increase risk for peripheral sensory disturbances.

Characterization and diagnostic evaluation of chronic polyneuropathies induced by oxaliplatin and docetaxel comparing skin biopsy to quantitative sensory testing and nerve conduction studies

Chemotherapy‐induced peripheral neuropathy negatively affects the quality of life for many patients treated with oxaliplatin or docetaxel for gastrointestinal cancer or breast cancer. Symptoms can persist long after treatment and often include neuropathic pain. Our objective was to characterize the neuropathies with regard to symptoms, neurological signs and objective evidence of damage to the structure and function of the peripheral nerves. Furthermore, the diagnostic values of skin biopsy, quantitative sensory testing (QST) and nerve conduction studies (NCS) were compared.

TAXTOX – a retrospective study regarding the side effects of docetaxel given as part of the adjuvant treatment to patients with primary breast cancer in Denmark from 2007 to 2009

Abstract Background. In 2007 docetaxel was introduced as part of the adjuvant setting offered to high risk breast cancer patients in Denmark. Meta-analyses had shown that taxane-containing chemotherapy reduced the relative risk of relapse and death by 20–30%, apparently with moderate side effects. The treatment was given as three cycles of cyclophosphamide (600 mg/m2) and epirubicin (90 mg/m2) followed by three cycles of docetaxel (100 mg/m2). Because of an apparent high incidence of side effects, especially febrile neutropenia (FN) and non-hematologic side effects, the DBCG (The Danish Breast Cancer Cooperative Group) initiated a retrospective study of adverse reactions to the newly introduced regime and all patients were offered primary prophylaxis with growth factors (G-CSF) pr 1/1-2008. Material and methods. Two medical doctors examined available journals and nurse charts from the 13 oncology departments in Denmark, and graded all side effects according to NCI CTC version 2.0. To be enrolled, the patients should have received three cycles of EC and at least one cycle of docetaxel. The side effects were investigated before and after routine use of G-CSF. Results. One thousand one hundred and forty-three patients entered the study. In 2007 (before G-CSF) the incidence of FN was 25% and 90.6% of the patients completed the planned treatment. In 2008 (after the introduction of G-CSF) the incidence of FN was 10% and 94.5% completed the treatment. The incidence of non-hematological adverse events, in 2007 and 2008 combined, was for neuropathy 35%, mucositis 75%, muscle and joint pain 53%, skin rash 25% and fatigue 43% (all grades). Conclusion. The introduction of G-CSF was justified because of the high incidence of FN. However, it could not have been predicted after reviewing the published literature. The incidence of non-hematological adverse events had been reported in some, but not all adjuvant taxanes studies. In the future, focus should be more on the side effects, especially when introducing new toxic systemic regimes.

GWAS-based association between RWDD3 and TECTA variants and paclitaxel induced neuropathy could not be confirmed in Scandinavian ovarian cancer patients

GWAS-based association between RWDD3 and TECTA variants and paclitaxel induced neuropathy could not be confirmed in Scandinavian ovarian cancer patients

Docetaxel-induced neuropathy: A pharmacogenetic case-control study of 150 women with early-stage breast cancer

Abstract Background. Docetaxel is a highly effective treatment of a wide range of malignancies but is often associated with peripheral neuropathy. The genetic variability of genes involved in the transportation or metabolism of docetaxel may be responsible for the variation in docetaxel-induced peripheral neuropathy (DIPN). The main purpose of this study was to investigate the impact of genetic variants in GSTP1 and ABCB1 on DIPN. Material and methods. DNA was extracted from whole blood from 150 patients with early-stage breast cancer who had received adjuvant docetaxel from February 2011 to May 2012. Two polymorphisms in GSTP1 and three in ABCB1 were selected for the primary analysis, and a host of other candidate genes was explored and compared between 75 patients with clinician-reported DIPN grade ≥ 2 and 75 patients without DIPN. Results. Patients with the genetic variants GSTP1 rs1138272 C/T or T/T (114Ala/114Val or 114Val/114Val) genotype had an adjusted odds ratio of 3.82; 95% confidence interval 1.34–11.09 of developing DIPN. This result was confirmed in both analysis of cumulated docetaxel dose and haplotype analysis. None of the explorative genes investigated were significantly correlated with DIPN. Patients with a BMI ≥ 30 were five-fold more likely to have DIPN than patients with BMI < 25. Conclusion. We found that GSTP1 Ala114Val polymorphism is associated with occurrence of DIPN. This supports the theory that oxidative stress is involved in DIPN pathophysiology. If confirmed, this may be helpful in the risk assessment of DIPN and perhaps help to achieve better management of neurotoxicity.

Genomic risks for developing CIPN

Background: Oral mucositis (OM) is a common debiliating adverse effect following high dose chemotherapy prior to bone marrow transplantation. OM often interferes with food intake and lead to malnutrition, weight loss and impaired quality of life. These adverse effects may require intravenous morphine for pain alleviation, Although uncomfortable to the patient, oral cryotherapy with ice chips has been shown to reduce the grade and extent of OM. Purpose: The purpose of the present study is to evaluate whether an intraoral cooling device has the same effectiveness as ice chips when it comes to cooling the oral mucosa. Method: Five healthy volunteers (mean age 36.2 years) chewed ice under surveillance for 30 minutes. Before the start of and immediately after the termination of the ice chewing, the intraoral mucosal temperature was measured using a modified thermometer. The same protocol was used to asses the cooling efficacy obtained by the newly developed intraoral device. Results: No statistical significant differences in cooling of teh oral mucosa (p=0.12) were obtained. The mean surface temperature following cooling was 25.7 degrees Celcius with ice chips and 24.7 degrees Celcius with the cooling device. Conclucion: The cooling device is as effective as ice chips in terms of cooling the oral mucosa. The next step in this research is to use the cooling devise to establish the highest surface temperature of the oral mucosa, during infusion of chemotherapy, that will still result in prevention of oral mucositis.Introduction Lifestyle interventions might be useful in the management of adverse effects of androgen deprivation therapy (ADT) in men with prostate cancer. Objectives To examine the effects of dietary and exercise interventions on quality of life (QoL), metabolic risk factors and androgen deficiency symptoms in men with prostate cancer undergoing ADT. Methods CINAHL, Cochrane library, Medline and PsychINFO were searched to identify randomised controlled trials published from January, 2004 to October, 2014. Data extraction and methodological quality assessment was independently conducted by two reviewers. Meta-analysis was conducted using RevMan® 5.3.5. Results Of 2183 articles retrieved, 11 studies met the inclusion criteria and had low risk of bias.Nine studies evaluated exercise (resistance and/or aerobic and/or counselling) and three evaluated dietary supplementation. Median sample size =79 (33–121) and median intervention duration was 12 weeks (12–24). Exercise improved QoL measures (SMD 0.26, 95%CI −0.01 to 0.53) but not body composition, metabolic risk or vasomotor symptoms. Qualitative analysis indicated soy (or isoflavone) supplementation did not improve vasomotor symptoms; however, may improve QoL. Conclusions Few studies have evaluated the efficacy of lifestyle interventions in the management of adverse effects of ADT. We found inconclusive results for exercise in improving QoL and negative results for other outcomes. For soy-based products, we found negative results for modifying vasomotor symptoms and inconclusive results for improving QoL. Future work should investigate the best mode of exercise for improving QoL and other interventions such as dietary counselling should be investigated for their potential to modify these outcomes.

Persistent pain, sensory disturbances and functional impairment after adjuvant chemotherapy for breast cancer

Abstract Background Persistent pain after breast cancer treatment (PPBCT) is a considerable clinical problem affecting between 25 and 60% of breast cancer survivors [1]. Several risk factors have been proposed, among them nerve damage caused by adjuvant treatment [2]. Taxanes used in adjuvant therapy for breast cancer are neurotoxic, and thereby being a potential risk factor for PPBCT and sensory disturbances. However, the long term influence of taxanes on PPBCT is not well documented. Thus, the aim of this study was therefore to compare a nationwide cohort treated with cyclophosphamide and epirubicin + docetaxel (CE + T) versus a nationwide cohort treated with cyclophosphamide, epirubicin and fluoruracil (CEF), in order to assess differences in reporting of PPBCT, sensory disturbances in surgical area, symmetric peripheral sensory disturbances, and functional impairment. Methods A comparative nationwide cross-sectional questionnaire study on two cohorts treated with CEF respectively CE + T, based on the Danish Breast Cancer Cooperative Groups database. Inclusion criteria were identical i both cohorts: women treated with adjuvant chemotherapy for primary breast cancer, age 18–69 years, without recurrence. Exclusion criteria: bilateral or previous breast surgery, including reconstructive surgery. The same questionnaire [1] was used for both cohorts and contained detailed questions regarding pain intensity and frequency and sensory disturbances in the breast area, side of chest, axilla and arm, bilateral peripheral sensory disturbances in the hands and feet, and questions regarding daily activities. Results 1241 patients treated with CEF in 2005-2006 and 1652 patients treated with CE + T in 2007–2008 were included. 664 (54%) with CEF and 861 (53%) patients with CE+T reported PPBCT. In the multivariate analysis including available risk factors, CE + T did not increase risk of PPBCT, adjusted OR 0.95 (95%C10.81–1.11), p = 0.52, compared to CEF. Patients treated with CE + T had a lower risk of sensory disturbances in the area of surgery compared with CEF, adjusted OR 0.75 (95%C1 0.62–0.90), p = 0.002. More CE+T patients reported peripheral sensory disturbances in the hands, adjusted OR 1.56 (95%C11.27–1.92), p < 0.0001, and in the feet, adjusted OR 2.0 (95%C1 1.66–2.42), p < 0.0001, compared to CEF. There was no difference in functional impairment (p = 0.62). Conclusion Docetaxcel as adjuvant treatment for breast cancer does not increase the risk of PPBCT, sensory disturbances in the surgical area or functional impairment, but increase the risk for peripheral sensory disturbances.