Cardiotoxicity during long-term trastuzumab use in patients with HER2-positive metastatic breast cancer: who needs cardiac monitoring?

PURPOSE: Patients with HER2-positive metastatic breast cancer (MBC) usually receive many years of trastuzumab treatment. It is unknown whether these patients require continuous left ventricular ejection fraction (LVEF) monitoring. We studied a real-world cohort to identify risk factors for cardiotoxicity to select patients in whom LVEF monitoring could be omitted. METHODS: We included patients with HER2-positive MBC who received > 1 cycle of trastuzumab-based therapy in eight Dutch hospitals between 2000 and 2014. Cardiotoxicity was defined as LVEF < 50% that declined > 10%-points and was categorized into non-severe cardiotoxicity (LVEF 40-50%) and severe cardiotoxicity (LVEF < 40%). Multivariable Cox and mixed model analyses were performed to identify risk factors associated with cardiotoxicity. Additionally, we explored the reversibility of cardiotoxicity in patients who continued trastuzumab. RESULTS: In total, 429 patients were included. Median follow-up for cardiotoxicity was 15 months (interquartile range 8-31 months). The yearly incidence of non-severe + severe cardiotoxicity in the first and second year was 11.7% and 9.1%, respectively, which decreased thereafter. The yearly incidence of severe cardiotoxicity was low (2.8%) and stable over time. In non-smoking patients with baseline LVEF > 60% and no cardiotoxicity during prior neoadjuvant/adjuvant treatment, the cumulative incidence of severe cardiotoxicity was 3.1% after 4 years of trastuzumab. Despite continuing trastuzumab, LVEF decline was reversible in 56% of patients with non-severe cardiotoxicity and in 33% with severe cardiotoxicity. CONCLUSIONS: Serial cardiac monitoring can be safely omitted in non-smoking patients with baseline LVEF > 60% and without cardiotoxicity during prior neoadjuvant/adjuvant treatment.

Radiological complete remission in HER2-positive metastatic breast cancer patients: what to do with trastuzumab?

PURPOSE: Patients with HER2-positive metastatic breast cancer (MBC) treated with trastuzumab may experience durable tumor response for many years. It is unknown if patients with durable radiological complete remission (rCR) can discontinue trastuzumab. We analyzed clinical characteristics associated with rCR and overall survival (OS) in a historic cohort of patients with HER2-positive MBC and studied the effect of stopping trastuzumab in case of rCR. METHODS: We included patients with HER2-positive MBC treated with first or second-line trastuzumab-based therapy in eight Dutch hospitals between 2000 and 2014. Data were collected from medical records. We used multivariable regression models to identify independent prognostic factors for rCR and OS. Time-to-progression after achieving rCR for patients who continued and stopped trastuzumab, and breast cancer-specific survival were also evaluated. RESULTS: We identified 717 patients with a median age of 53 years at MBC diagnosis. The median follow-up was 109 months (IQR 72-148). The strongest factor associated with OS was achievement of rCR, adjusted hazard ratio 0.27 (95% CI 0.18-0.40). RCR was observed in 72 patients (10%). The ten-year OS estimate for patients who achieved rCR was 52 versus 7% for patients who did not achieve rCR. Thirty patients with rCR discontinued trastuzumab, of whom 20 (67%) are alive in ongoing remission after 78 months of median follow-up since rCR. Of forty patients (58%) who continued trastuzumab since rCR, 13 (33%) are in ongoing remission after 68 months of median follow-up. Median time-to-progression in the latter group was 14 months. CONCLUSIONS: Achieving rCR is the strongest predictor for improved survival in patients with HER2-positive MBC. Trastuzumab may be discontinued in selected patients with ongoing rCR. Further research is required to identify patients who have achieved rCR and in whom trastuzumab may safely be discontinued.

Trends in incidence and predictions of cutaneous melanoma across Europe up to 2015.

BACKGROUND: Melanoma is a significant health problem in Caucasian populations. The most recently available data from cancer registries often have a delay of several months up to a few years and they are generally not easily accessible. OBJECTIVES: To assess recent age- and sex-specific trends in melanoma incidence and make predictions for 2010 and 2015. METHODS: A retrospective registry-based analysis was performed with data from 29 European cancer registries. Most of them had data available from 1990 up to 2006/7. World-standardized incidence rates (WSR) and the estimated annual percentage change (EAPC) were computed. Predictions were based on linear projection models. RESULTS: Overall the incidence of melanoma is rapidly rising and will continue to do so. The incidence among women in Europe was generally higher than in men. The highest incidence rates were seen for Northern and north-western countries like the UK, Ireland and the Netherlands. The lowest incidence rates were observed in Portugal and Spain. The incidence overall remained stable in Norway, where, amongst young (25-49 years) Norwegian males rates significantly decreased (EAPC -2.8, 95% CI -3.6; -2.0). Despite a low melanoma incidence among persons above the age of 70, this age group experienced the greatest increase in risk during the study period. CONCLUSIONS: Incidence rates of melanoma are expected to continue rising. These trends are worrying in terms of disease burden, particularly in eastern European countries.

Burden of disease due to cutaneous melanoma has increased in the Netherlands since 1991.

BACKGROUND: The burden of disease, describing loss of health and death due to a disease, has not been fully studied for melanoma in the general population over time. OBJECTIVES: To determine the burden of disease due to melanoma in the Netherlands. METHODS: Age- and sex-specific incidence data from all patients with melanoma in the Netherlands between 1991 and 2010 were obtained from the Netherlands Cancer Registry. Melanoma-specific mortality and life expectancy data were obtained from Statistics Netherlands. Melanoma duration was calculated using the DISMOD software from the World Health Organization. The years of life lived with disability (YLD) and years of life lost (YLL) due to melanoma were calculated using Dutch disability weights, incidence and mortality of melanoma, and the life expectancy from the general population. The number of disability-adjusted life-years (DALYs) was estimated by adding YLD and YLL. RESULTS: The world-standardized incidence rates of melanoma have more than doubled for both men (7·1 per 100 000 inhabitants in 1991 to 17·0 in 2010) and women (9·4 per 100 000 inhabitants in 1991 to 19·8 in 2010). Likewise, the burden of melanoma to society has increased rapidly. The YLD for men increased from 4795 (1991-4) to 12 441 (2007-10), and for women from 7513 (1991-4) to 16 544 (2007-10). In 2007-10 the total YLL due to melanoma was 30 651 for men and 26 244 for women compared with 17 238 and 16 900, respectively, in 1991-4. The DALYs increased by 96% for men, from 22 033 (1991-4) to 43 092 (2007-10), and by 75% for women, from 24 413 (1991-4) to 42 788 (2007-10). CONCLUSIONS: Melanoma is becoming a great burden to Dutch society.

Melanoma patients receive more follow-up care than current guideline recommendations: a study of 546 patients from the general Dutch population.

BACKGROUND: Follow-up of melanoma patients has been a continuing issue for discussion in the past years partly due to ever increasing incidence of this disease, as well as the lack of agreement regarding the reasons for, and the frequency of follow-up. Patients' perspectives are often not included in this continuing discussion on follow-up of melanoma patients. OBJECTIVE: To examine to what extent follow-up was experienced, according to the guideline of 2005, by physicians and melanoma patients in a Dutch population from the south-east area of the Netherlands. The patient's perspective and satisfaction over said follow-up shall also be taken into account. METHODS: Follow-up among melanoma survivors was investigated and compared with the recommendations of the current Dutch national guideline. All 699 melanoma patients registered at the Eindhoven Cancer Registry (between 1998 and 2008), and treated in 3 regional hospitals, were contacted via postal mail. The survey questioned about treatment, symptoms, impact on daily life and follow-up. Patients with multiple melanomas (n = 16) were excluded. RESULTS: Response rate was 80%, 418 patients were still under surveillance for their melanoma. The average time since diagnoses was 4 years, 71% had stage I melanoma. Almost 80% of patients with a Breslow thickness <1 mm, reported more frequent follow-up visits than the guideline recommends. Only 5% of the patients wanted to reduce their follow-up frequency. Eighty percent of patients were under supervision of a dermatologist: physical examination (25%), lymph node palpation (11%) and/or scar inspection (20%) did not regularly occur. These proportions were significantly higher among other specialism. CONCLUSION: Follow-up frequency was higher than recommended by the current melanoma guideline in a large group of patients, mainly those with lower Breslow thickness.

A systematic review of health-related quality of life in cutaneous melanoma.

Melanoma can be considered an emerging chronic disease that may considerably affect patients' lives. The authors systematically reviewed the available literature on health-related quality of life (HRQOL) and melanoma. Of reviews and the selected studies, reference lists were hand-searched. The quality of the eligible studies was appraised based on 14 previously published criteria. Of the 158 abstracts, 44 articles were appraised, resulting in 13 selected studies written in English (published between 2001 and 2008). Most studies assessed patients from specialised centres with varying, but relatively advanced, disease stages. The most commonly used instruments were the SF-36 and EORTC QLQ-C30. Recently, a melanoma-specific HRQOL questionnaire [FACT-Melanoma (FACT-M)] was introduced for clinical trial purposes. It showed that approximately one-third of melanoma patients experienced considerable levels of distress, mostly at the time of diagnosis and following treatment. Systemic therapies affected HRQOL negatively in the short term, but to a lesser extent in the long term. Health status and patients' psychological characteristics are associated with higher levels of HRQOL impairment. The authors found that the impact of melanoma on patients' HRQOL is comparable to that of other cancers. Accurately assessing HRQOL impairment in melanoma patients is pivotal, as it may affect disease management, including therapy and additional counselling, future preventive behaviour and perhaps even prognosis.