Association of cancer with functional decline at old age: a longitudinal study in Danish twins.

INTRODUCTION: There is evidence that older adults with cancer have a higher risk of functional decline than cancer-free older adults. However, few studies are longitudinal, and none are twin studies. Thus, we aimed to investigate the relationship between cancer and functional decline in older adult (aged 70+ years) twins. MATERIALS AND METHODS: Cancer cases in the Longitudinal Study of Aging Danish Twins were identified through the Danish Cancer Registry. Functional status was assessed using hand grip strength (6 years follow-up), and self-reported questions on mobility (10 years follow-up), and cut-offs were defined to assess functional decline. Cox regression models were performed for all the individual twins. In addition, we extended the analysis to discordant twin pairs (twin pairs with one having cancer and the other being cancer-free), to control to a certain extent for (unmeasured) shared confounders (genetic and environmental factors). RESULTS: The analysis based on individual twins showed that individual twins with cancer are at increased hazard of worsening hand grip strength (hazard ratio (HR) 1.37, 95% confidence interval (CI) 1.04, 1.80) than cancer-free twins. Among the discordant twin pairs, twins with cancer had a higher hazard of worsening hand grip strength (HR 3.50, 95% CI 1.15, 10.63) than cancer-free cotwins. In contrast, there was no evidence of a difference between the hazard of experiencing mobility decline for twins with cancer compared with cancer-free twins, in both individual twins and discordant twin pairs analyses. DISCUSSION: Cancer was associated with hand grip strength functional decline in old individual twins and discordant pairs. Our results strengthen the importance of comprehensive geriatric assessment in older adults with cancer, as well as the importance of routine assessment of functional status. Promoting physical activity through exercise training programmes could enable the prevention of functional decline in older adults with cancer.

FDG-PET/CT in high-risk primary breast cancer-a prospective study of stage migration and clinical impact.

PURPOSE: To investigate the clinical impact of FDG-PET/CT for staging and treatment planning in high-risk primary breast cancer. METHODS: Women with high-risk primary breast cancer were enrolled between September 2017 and August 2019 at Odense University Hospital, Denmark. Conventional mammography with/without MRI was performed before staging by FDG-PET/CT. We studied the accuracy of FDG-PET/CT for the detection of distant metastases, the effect on the change of treatment, and the prevalence of incidental findings. Biopsy and follow-up were used as a reference standard for the accuracy analysis. RESULTS: Of 103 women, 24 (23%) were diagnosed with distant metastases by FDG-PET/CT. Among these, breast surgery was omitted in 18 and could have been spared in six. Another sixteen (16%) patients were upstaged to more advanced loco-regional disease, leading to more extensive radiotherapy. Sensitivity and specificity for diagnosing distant metastases were 1.00 (95% confidence interval: 0.86-1.00) and 0.95 (0.88-0.99), respectively. Twenty-nine incidental findings were detected in 24 women (23%), leading to further examinations in 22 and diagnosis of eight (8/22, 36%) synchronous diseases: cancer (n = 4), thyroiditis (n = 2), aorta aneurysm (n = 1), and meningioma (n = 1). CONCLUSIONS: FDG-PET/CT had a substantial impact on staging and change of treatment in women with high-risk primary breast cancer, and further examination of incidental findings was considered clinically relevant. Our findings suggest that FDG-PET/CT should be considered for primary staging in high-risk primary breast cancer to improve treatment planning.

Immediate evaluation of global longitudinal strain at initiation of trastuzumab treatment in breast cancer patients.

BACKGROUND: Global longitudinal strain (GLS) is recommended to detect subclinical changes preceding reduced left ventricular ejection fraction (LVEF) in trastuzumab related cardiotoxicity. Since the possibility to detect signs of acute myocardial deterioration at treatment initiation is not clarified, the objective of this study was to assess changes in GLS and biomarkers within the first 2 weeks of trastuzumab treatment. METHODS: In a prospective cohort study, 45 patients with non-metastatic breast cancer (age 54, LVEF 62.8%, GLS -19.9%, 40% hypertension) scheduled for trastuzumab treatment were included. Echocardiography and measurement of troponin and NT-proBrain-Natriuretic-Peptide were conducted before initiation of trastuzumab, at days 3, 7, and 14 and after 3, 6, and 9 months. RESULTS: A significant deterioration in LVEF from 62.8% (SD±3.6) to 58.4% (SD±4.1) (p < 0.0001), GLS from -19.9 (SD±2.1) to -18.1 (SD±2.5) (p = 0.004), s' (p < 0.0001), e' septal (p = 0.008), and s' RV (p < 0.0001) occurred at 9 months and was preceded by significant changes in these parameters within the first 14 days. After 14 days, 12 patients (27%) had a ≥10% deterioration in GLS, which was associated with significantly lower LVEF at 55.2% (SD±4.1) at 9 months compared to patients with < 10% early deterioration in GLS (LVEF = 59.5% (SD±3.5) (p = 0.001)). No difference in plasma concentrations of biomarkers was observed between the two groups. CONCLUSION: In this study deteriorations in key echocardiographic parameters within normal limits were detected during the first 2 weeks of trastuzumab treatment, and an early ≥10% deterioration in GLS was associated with a lower LVEF at 9 months.

Incidence of hypothyroidism after treatment for breast cancer-a Danish matched cohort study.

BACKGROUND: Breast cancer survivors (BCS) may have increased risk of hypothyroidism, but risk according to treatment modality is unclear. We estimated the incidence of hypothyroidism in women with breast cancer, and according to cancer treatment. METHODS: Using nationwide registries, we identified all Danish women aged ≥ 35 years diagnosed with non-metastatic breast cancer (1996-2009). We matched up to five cancer-free women (controls) for each BCS. We excluded women with prevalent thyroid disease. Cancer treatment was chemotherapy with or without radiotherapy (RT) targeting the breast/chest wall only, or also the lymph nodes (RTn). We identified hypothyroidism using diagnostic codes, and/or levothyroxine prescriptions. We calculated the cumulative incidence, incidence rates (IR) per 1000 person-years, and used Cox regression to estimate hazard ratios (HR) and associated 95% confidence intervals (CIs) of hypothyroidism, adjusting for comorbidities. RESULTS: We included 44,574 BCS and 203,306 matched controls with 2,631,488 person-years of follow-up. BCS had a slightly higher incidence of hypothyroidism than controls [5-year cumulative incidence, 1.8% (95%CI = 1.7-1.9) and 1.6% (95%CI = 1.5-1.6), respectively]. The overall IR was 4.45 (95%CI = 4.25-4.67) and 3.81 (95%CI = 3.73-3.90), corresponding to an adjusted HR = 1.17 (95%CI = 1.11-1.24). BCS who received RTn with chemotherapy (HR = 1.74, 95%CI = 1.50-2.02) or without chemotherapy (HR = 1.31, 95%CI = 1.14-1.51) had an elevated risk of hypothyroidism compared with matched controls and compared with BCS who underwent surgery alone [HR = 1.71, 95%CI = 1.45-2.01 and HR = 1.36, 95%CI = 1.17-1.58, respectively]. CONCLUSIONS: BCS have an excess risk of hypothyroidism compared with age-matched controls. BCS and those working in cancer survivorship settings ought to be aware that this risk is highest in women treated with radiation therapy to the lymph nodes and chemotherapy.

Statin use and breast cancer recurrence in postmenopausal women treated with adjuvant aromatase inhibitors: a Danish population-based cohort study.

PURPOSE: To examine the association between statin use and risk of breast cancer recurrence in a national Danish cohort of postmenopausal breast cancer patients receiving aromatase inhibitors (AI) in the adjuvant setting. PATIENTS AND METHODS: We enrolled all postmenopausal patients diagnosed with stage I-III estrogen receptor positive breast cancer during the years 2007-2017, assigned adjuvant AI treatment, and registered in both the Danish Breast Cancer Group database and the Danish Cancer Registry. We ascertained incident statin exposure (≥ 1 prescription post-diagnosis) from the Danish National Prescription Registry and modeled statins as a time-varying exposure lagged by 6 months. Follow-up began 7 months after diagnosis and continued to the first event of recurrence, death, emigration, 5 years elapsed, or 25th September 2018. We estimated incidence rates of recurrence at 5 years and used Cox regression models to compute crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CI), comparing statin exposure with non-exposure. RESULTS: We enrolled 14,773 eligible patients. During the 5 years of follow-up, there were 32 recurrences in 3163 person-years of follow-up among statin-exposed patients, and 612 recurrences in 45,655 person-years among unexposed patients (incidence rate per 1000 person-years: 10.12 [95% CI 6.92-14.28] and 13.40 [95% CI 12.36-14.51], respectively). In multivariable models, any statin exposure was associated with a reduced rate of 5-year breast cancer recurrence (adjusted HR 0.72 [95% CI 0.50-1.04]). Considering only lipophilic statins as exposure the results were similar (adjusted HR 0.70 [95% CI 0.48-1.02]). CONCLUSIONS: Statin use was associated with a reduced risk of breast cancer recurrence among postmenopausal patients diagnosed with early stage breast cancer who received adjuvant AI therapy.

Adherence to treatment guidelines and survival in older women with early-stage breast cancer in Denmark 2008-2012.

Objectives: The aims of this study were to compare patients 70 years or older with younger patients, to examine whether Danish patients with early-stage breast cancer aged 70 years or more received treatment according to guidelines, the reasons for deviating from the guidelines, and to analyze whether such deviations affected survival.Methods: From the Danish Breast Cancer Cooperative Group (DBCG) database we identified 23,247 women diagnosed with early-stage breast cancer in Denmark from 2008 to 2012. 17,391 were aged less than 70 years and 5856 were 70+ years. We reviewed medical charts of 441 patients aged 70+ years from Funen (a region of Denmark) to ascertain whether treatment was given according to the guidelines of DBCG and if not, the reason for deviating. Overall survival was analyzed by Cox proportional hazards models.Results: Up to age 80 years most women (94%) had surgery according to guidelines, decreasing to 41% in women aged 85+ years, the main reason for omitting surgery being patients' requests. Patients with breast cancer over the age of 80 years did not have an excess mortality compared with the general population in Funen. Compared with women who had surgery according to guidelines, women who did not have surgery had a significantly higher risk of dying with a hazard ratio (HR) of 8.38 (95% Confidence Intervals (CI) 4.46-15.8) if they were less than 80 years and HR = 2.56 (95% CI 1.63-4.01) if they were 80 years or more (p = .003 for interaction).Conclusions: Adherence to treatment according to guidelines decreases with increasing age, mainly for patients aged 80+ years. Our results suggest that surgery is important for the survival of patients aged less than 80 years.

Hypothyroidism and the risk of breast cancer recurrence and all-cause mortality - a Danish population-based study.

BACKGROUND: Hypothyroidism may occur as a late effect of breast cancer-directed treatment, particularly after radiotherapy, but little is known whether hypothyroidism affects the prognosis after breast cancer. We investigated the association between hypothyroidism and breast cancer recurrence, and all-cause mortality. METHODS: In this population-based cohort study, we used national medical registries to identify all Danish women 35 years or older diagnosed with stage I-III, operable breast cancer between 1996 and 2009. Hypothyroidism was defined as hospital diagnoses ascertained via diagnostic codes, or as prescriptions for levothyroxine. Two analytic models were used: (i) hypothyroidism present at the time of the breast cancer diagnosis (prevalent) and (ii) hypothyroidism diagnosed during follow-up as a time-varying exposure lagged by 1 year (incident). Breast cancer recurrence was defined as any local, regional, or distant recurrence or contralateral breast cancer. All-cause mortality included death from any cause in any setting. We used Cox regression models accounting for competing risks to compute adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer recurrence and all-cause mortality. RESULTS: The study cohort included 35,463 women with breast cancer with 212,641 person-years of follow-up. At diagnosis, 1272 women had hypothyroidism and 859 women developed hypothyroidism during follow-up. In total, 5810 patients developed recurrent breast cancer. Neither prevalent nor incident hypothyroidism was associated with breast cancer recurrence (adjusted HRprevalent 1.01, 95% CI 0.87-1.19; adjusted HRincident 0.93, 95% CI 0.75-1.16, respectively). Furthermore, no differences were seen for all-cause mortality for prevalent or incident hypothyroidism (adjusted HRprevalent 1.02, 95% CI 0.92-1.14, and HRincident 1.08, 95% CI 0.95-1.23, respectively). Stratification by menopausal status, oestrogen receptor status, chemotherapy, or radiotherapy did not alter the estimates. CONCLUSIONS: Hypothyroidism present at diagnosis or during follow-up was not associated with breast cancer recurrence or all-cause mortality in women with breast cancer. Our findings provide reassurance to patients and their physicians that hypothyroidism is unlikely to impact on the clinical course of breast cancer or survival.

Influence of specific comorbidities on survival after early-stage breast cancer.

BACKGROUND: While comorbidity indices are useful for describing trends in survival, information on specific comorbidities is needed for the clinician advising the individual breast cancer patient on her treatment. Here we present an analysis of overall survival, breast cancer-specific mortality, and effect of medical adjuvant treatment among breast cancer patients suffering from 12 major comorbidities compared with breast cancer patients without comorbidities. MATERIAL AND METHODS: The study population was identified from the Danish Breast Cancer Cooperative Group and included 59,673 women without prior cancer diagnosed with early-stage breast cancer in Denmark from 1990 to 2008 with an estimated median potential follow-up of 14 years and 10 months. Information on comorbidity and causes of death was derived from population-based registries. Multivariable proportional hazards regression models were used to assess the effect of comorbidities on mortality, all-cause and breast cancer specific, using patients without comorbidity as reference. RESULTS: At breast cancer diagnosis, 16% of patients had comorbidities and 84% did not. Compared with the latter, the risk of dying from all causes was significantly increased for all types of comorbidity, but the risk of dying from breast cancer was significantly increased only for peripheral vascular disease, dementia, chronic pulmonary disease, liver, and renal diseases. Comorbidities diagnosed within 5 years of breast cancer diagnosis correlated with a greater risk of dying than comorbidities diagnosed more than 5 years before breast cancer diagnosis. With a few exceptions, the effect of adjuvant treatment on breast cancer mortality was similar among patients with and without comorbidity. CONCLUSION: Breast cancer mortality was not significantly elevated for patients with prior myocardial infarction, congestive heart failure, cerebrovascular disease, connective tissue disease, ulcer disease, and diabetes. The similar effect of adjuvant treatment in patients with and without comorbidity underlines the importance of adhering to guideline therapy.

A phase II study of combined ridaforolimus and dalotuzumab compared with exemestane in patients with estrogen receptor-positive breast cancer.

PURPOSE: Combining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor (ER)-positive advanced breast cancer, especially in high proliferation tumors (Ki67 > 15%). METHODS: This randomized, multicenter, international, phase II study enrolled postmenopausal women with advanced ER-positive breast cancer previously treated with a nonsteroidal aromatase inhibitor (NCT01234857). Patients were randomized to either oral ridaforolimus 30 mg daily for 5 of 7 days (once daily [qd] × 5 days/week) plus intravenous dalotuzumab 10 mg/kg/week or oral exemestane 25 mg/day, and stratified by Ki67 status. Due to a high incidence of stomatitis in the ridaforolimus-dalotuzumab group, two sequential, nonrandomized, reduced-dose cohorts were explored with ridaforolimus 20 and 10 mg qd × 5 days/week. The primary endpoint was progression-free survival (PFS). RESULTS: Median PFS was 21.4 weeks for ridaforolimus 30 mg qd × 5 days/week plus dalotuzumab 10 mg/kg (n = 29) and 24.3 weeks for exemestane (n = 33; hazard ratio = 1.00; P = 0.5). Overall survival and objective response rates were similar between treatment arms. The incidence of drug-related, nonserious, and serious adverse events was higher with ridaforolimus/dalotuzumab (any ridaforolimus dose) than with exemestane. Lowering the ridaforolimus dose reduced the incidence of grade 3 stomatitis, but overall toxicity remained higher than acceptable at all doses without improved efficacy. CONCLUSIONS: The combination of ridaforolimus plus dalotuzumab was no more effective than exemestane in patients with advanced ER-positive breast cancer, and the incidence of adverse events was higher. Therefore, the combination is not being further pursued.

Validity of Danish Breast Cancer Group (DBCG) registry data used in the predictors of breast cancer recurrence (ProBeCaRe) premenopausal breast cancer cohort study.

BACKGROUND: Validation studies of the Danish Breast Cancer Group (DBCG) registry show good agreement with medical records for adjuvant treatment data, but inconsistent recurrence information. No studies have validated changes in menopausal status or endocrine therapy during follow-up. In a longitudinal study, we validated DBCG data using medical records as the gold standard. MATERIAL AND METHODS: From a cohort of 5959 premenopausal women diagnosed during 2002-2010 with stage I-III breast cancer, we selected 151 patients - 77 estrogen-receptor-positive and 74 estrogen-receptor-negative - from three hospitals. We assessed the validity of DBCG registry data on patient, tumor, and treatment factors, and follow-up information on menopausal transition, changes in endocrine therapy, and recurrence. We computed positive predictive values (PPVs) with 95% confidence intervals (95%CI). RESULTS: Agreement was near perfect for tumor size, lymph node involvement, receptor status, surgery type, and receipt of radiotherapy, chemotherapy, or tamoxifen treatment. The PPV for a change in endocrine therapy in the DBCG was 96% (95%CI = 83, 100). The PPV for menopausal transition was 61% (95%CI = 42, 77). The PPV for DBCG-recorded recurrence was 100%. However, of 19 patients who had a recurrence documented in their medical record, 13 had the recurrence registered in DBCG. CONCLUSIONS: DBCG data are valid for most epidemiological studies of breast cancer treatment. Data on menopausal transition may be less valid, though this interpretation depends on the suitability of medical records for making this assessment. Although recurrence is missing for some, this would not bias most ratio measures of association.

Risk of ischemic heart disease in women after radiotherapy for breast cancer.

BACKGROUND: Radiotherapy for breast cancer often involves some incidental exposure of the heart to ionizing radiation. The effect of this exposure on the subsequent risk of ischemic heart disease is uncertain. METHODS: We conducted a population-based case-control study of major coronary events (i.e., myocardial infarction, coronary revascularization, or death from ischemic heart disease) in 2168 women who underwent radiotherapy for breast cancer between 1958 and 2001 in Sweden and Denmark; the study included 963 women with major coronary events and 1205 controls. Individual patient information was obtained from hospital records. For each woman, the mean radiation doses to the whole heart and to the left anterior descending coronary artery were estimated from her radiotherapy chart. RESULTS: The overall average of the mean doses to the whole heart was 4.9 Gy (range, 0.03 to 27.72). Rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per gray (95% confidence interval, 2.9 to 14.5; P<0.001), with no apparent threshold. The increase started within the first 5 years after radiotherapy and continued into the third decade after radiotherapy. The proportional increase in the rate of major coronary events per gray was similar in women with and women without cardiac risk factors at the time of radiotherapy. CONCLUSIONS: Exposure of the heart to ionizing radiation during radiotherapy for breast cancer increases the subsequent rate of ischemic heart disease. The increase is proportional to the mean dose to the heart, begins within a few years after exposure, and continues for at least 20 years. Women with preexisting cardiac risk factors have greater absolute increases in risk from radiotherapy than other women. (Funded by Cancer Research UK and others.).

Trends in breast cancer in the elderly in Denmark, 1980-2012.

BACKGROUND: Breast cancer is the most frequent malignancy among women worldwide and the second most common cause of cancer-related death in developed countries. The aim of the present analysis is to describe trends in incidence, mortality, prevalence, and relative survival in Denmark from 1980 to 2012 focusing on age, comparing persons aged 70 years or more with those aged less than 70 years. MATERIAL AND METHODS: Cancer of the breast was defined as ICD-10 code C50. Data derived from the NORDCAN database with comparable data on cancer incidence, mortality, prevalence and relative survival in the Nordic countries, where the Danish data were delivered from the Danish Cancer Registry and the Danish Cause of Death Registry with follow-up for death or emigration until the end of 2013. RESULTS: The proportion of patients diagnosed with breast cancer over the age of 70 years increased with time to 29% of women and 44% of men in 2012. Incidence rates increased with time and peaked around 2010 in all age groups except for those aged 90 years or more. Mortality rates were clearly separated by age with increasing mortality rates by increasing age group for both women and men. Relative survival increased over time in all age groups, but patients aged 70 years or more had a poorer relative survival than those aged less than 70 years. In 2012, 58 521 persons (all ages) were alive in Denmark after a diagnosis of breast cancer. CONCLUSION: Poorer survival of Danish breast cancer patients over the age of 70 years is likely to be due to inferior treatment and non-adherence to treatment guidelines. There is a need for clinical trials focusing on patients over the age of 70 years.

Trends in cancer in the elderly population in Denmark, 1980-2012.

BACKGROUND: Age is the strongest risk factor for developing cancer. The aim of the present analysis is to give an overview of the trends in cancer incidence, mortality, prevalence, and relative survival in Denmark from 1980 to 2012 focusing on age, comparing persons aged 70 years or more with those aged less than 70 years. MATERIAL AND METHODS: Data derived from the NORDCAN database with comparable data on cancer incidence, mortality, prevalence and relative survival in the Nordic countries. The Danish data originate from the Danish Cancer Registry and the Danish Cause of Death Registry with follow-up for death or emigration until the end of 2013. RESULTS: Incidence and mortality rates of all sites, but non-melanoma skin cancer, were higher and relative survival was lower among persons aged 70 years or more than those aged less than 70 years. The age distribution (age group-specific percentages of total number of incident cases) remained constant over time while the percentage of persons dying from cancer decreased with time up to the age of 79 years but increased for those aged 80 years or more, in whom about a third of all cancer deaths occurred in 2012. In 2003-2007, the five-year relative survival was 48% for men aged 70-79 years, 38% for men aged 80-89 years, and 29% for men aged 90 years or more and the corresponding figures for women were 46%, 39%, and 36%, respectively. There was a substantial increase in the number of prevalent cancer cases aged 70 years or older, especially among those aged 90 years or more. CONCLUSION: An increase in elderly cancer patients is expected over the coming 20 years due to an increasing elderly population. Healthcare providers need to focus on developing specific strategies for treatment of elderly cancer patients in the future.

Change in bone mineral density during adjuvant chemotherapy for early-stage breast cancer.

PURPOSE: Adjuvant chemotherapy has been associated with loss of bone mineral density (BMD) either as a direct effect or due to glucocorticoids used as supportive care medication. A prospective cohort study was conducted to evaluate changes in BMD from baseline to right after completion of chemotherapy, i.e., 4 months. METHODS: Dual-imaging X-ray absorptiometry (DXA) was performed at baseline and after completing anthracycline- and taxane-based chemotherapy to measure BMD in the spine, hip, and forearm in early-stage breast cancer patients. High-dose prednisolone was used at three weekly intervals to reduce nausea and vomiting. Patients were advised a daily calcium/vitamin D supplement. Linear regression was used to assess mean percentage change in BMD and 95 % confidence intervals (95 % CI) according to doses of prednisolone, menopausal status, smoking, and BMI. RESULTS: Eight patients were excluded: seven because of initiation of bisphosphonate treatment due to osteoporosis at baseline, and one had non-interpretable DXA. The final cohort included 97 patients with a mean age of 53 years (range 34-72). Mean cumulative prednisolone dose was 1308 mg (95 % CI 1255; 1362). BMD increased 1.36 % (95 % CI 0.7; 2.0, p < 0.001) in the spine and 1.27 % (95 % CI 0.9; 1.7, p < 0.001) in the hip. Forearm BMD did not change. Postmenopausal women had increases in spine BMD of 2.35 % (95 % CI 1.1; 3.6, p < 0.001) compared to premenopausal women. The spine BMD of current smokers decreased 1.67 % (95 % CI -3.3; -0.1, p = 0.04) compared to never/former smokers. CONCLUSIONS: Adjuvant chemotherapy supplemented with prednisolone was not associated with loss of BMD. Postmenopausal women gained bone mass, whereas current smokers lost bone mass.

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

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.

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

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.

Automatic segmentation of the heart in radiotherapy for breast cancer.

BACKGROUND: The aim of this study was to evaluate two fully automatic segmentation methods in comparison with manual delineations for their use in delineating the heart on planning computed tomography (CT) used in radiotherapy for breast cancer. MATERIAL AND METHODS: Automatic delineation of heart in 15 breast cancer patients was performed by two different automatic delineation systems. Analysis of accuracy and precision of the differences between manual and automatic delineations were evaluated on volume, mean dose, maximum dose and spatial distance differences. Two sets of manual delineations were used in the evaluation: 1) a set prior to common delineation guidelines; and 2) a second set repeated with a common set of guidelines. RESULTS: Systematic differences between automatic and manual delineations were small for volume as well as dose. The uncertainty of the difference in volume was smaller than or similar to the inter-observer variation in manual delineations. For dose, the uncertainty was similar to manual delineations performed without common guidelines but slightly higher than the variation in manual delineations with common guidelines. Spatial differences between average manual and automatic delineations were largest at the base of the heart, where also large variations are observed in the manual delineations. Both algorithms could be improved slightly at the apex of the heart where the variation of automatic delineation was larger than for the manual delineations. CONCLUSION: Automatic delineation is an equal alternative to manual delineation when compared to the inter-observer variation. The reduction in precision of measured dose was small compared to other uncertainties affecting the estimated heart dose and would for most applications be outweighed by the benefits of fully automated delineations.

Unemployment among breast cancer survivors.

AIM: Though about 20% of working age breast cancer survivors do not return to work after treatment, few studies have addressed risk factors for unemployment. The majority of studies on occupational consequences of breast cancer focus on non-employment, which is a mixture of sickness absence, unemployment, retirement pensions and other reasons for not working. Unemployment in combination with breast cancer may represent a particular challenge for these women. The aim of the present study is therefore to analyze the risk for unemployment in the years following diagnosis and treatment for breast cancer. METHOD: This study included 14,750 women diagnosed with breast cancer in Denmark 2001-2009 identified through a population-based clinical database and linked with information from Danish administrative population based registers for information on labour market affiliation, socio-demography and co-morbid conditions. Multivariable analyses were performed by Cox's proportional hazard models. RESULTS: Two years after treatment, 81% of patients were still part of the work force, 10% of which were unemployed. Increasing duration of unemployment before breast cancer was associated with an adjusted HR = 4.37 (95% CI: 3.90-4.90) for unemployment after breast cancer. Other risk factors for unemployment included low socioeconomic status and demography, while adjuvant therapy did not increase the risk of unemployment. CONCLUSIONS: Duration of unemployment before breast cancer was the most important determinant of unemployment after breast cancer treatment. This allows identification of a particularly vulnerable group of patients in need of rehabilitation.

Effects of comprehensive geriatric assessment-guided interventions on physical performance and quality of life in older patients with advanced cancer: A randomized controlled trial (PROGNOSIS-RCT).

INTRODUCTION: Older patients with frailty starting oncological treatment are at higher risk of experiencing declining physical performance, loss of independence, and quality of life (QoL). This study examines whether comprehensive geriatric assessment (CGA)-guided interventions added to standard oncological care can prevent declining physical performance and QoL in older patients with frailty initiating palliative treatment. MATERIALS AND METHODS: Patients aged ≥70 years, with a Geriatric-8 score of ≤14, initiating palliative oncological treatment were enrolled in an open label randomized controlled trial and randomized 1:1 to receive either CGA-guided interventions in addition to oncological standard care or oncological care alone. Baseline characteristics, physical performance measures, and QoL questionnaires were retrieved before group allocation. CGA was performed using a fixed set of domains and validated tests by a geriatrician-led team. The primary endpoint, physical performance, was measured by the 30-s chair stand test (30s-CST) at three months. Additional outcomes included 30s-CST at six months, handgrip strength test, and QoL. Outcomes were analyzed using linear mixed regression models. The trial was registered at clinicaltrials.org (NCT04686851). RESULTS: From November 1, 2020 to May 31, 2022, 181 patients were included; 88 in the interventional arm and 93 in the control arm. Median age was 77 (interquartile range [IQR] 73-81) years, 69% were male, median Geriatric-8 score was 12 (IQR 10-13), 69% had a Performance Status of 0-1, and the median 30s-CST was 9 (IQR 5-11) repetitions. The between-group difference in 30s-CST at three months was 0.67 (95%CI: -0.94 - 2.29) and 1.57 (95%CI: -0.20 - 3.34) at six months, which were not statistically significant. Subgroup analysis including participants with a baseline Geriatric-8 of 12-14 found borderline significant between-group differences in 30s-CST scores at three and six months of 2.04 (95% confidence interval [CI]: -0.07 - 4.2, P = 0.06) and 2.25 (95%CI: 0.01-4.5, P = 0.05), respectively. No within-group or between-group differences in the summary score or the Elderly Functional Index score (measuring QoL) were found. DISCUSSION: This study did not find significant between-group differences in the 30s-CST in older patients receiving palliative care. However, a tendency towards improved physical performance was seen in the least frail. These patients may represent a target group wherein CGA interventions provide particular benefit.