Systemic therapy timing and use in patients with advanced melanoma at the end of life: A retrospective cohort study.

Novel systemic therapies for advanced melanoma improve survival, but carry potential serious side effects and high costs. This study aimed to assess the timing and use of systemic therapies in the months before death. Patients diagnosed with advanced melanoma (July 2017-June 2020) who died before July 2020 were selected from the Netherlands Cancer Registry. We evaluated the timing of systemic therapies within 30 days and 3 months before death, and studied patient and tumor characteristics associated with systemic therapy use between diagnosis and death. Out of 1097 patients 68% received systemic therapy. Almost 25% and 10% started a new therapy within 90 days and within 30 days before death, respectively. Female sex, elevated LDH, BRAF mutation, poor ECOG performance status (≥3), and high comorbidity index reduced the odds of receiving immune therapy. Poor performance status and high comorbidity decreased the odds for both therapies. A considerable number of patients started systemic therapy shortly before death, emphasizing the importance of considering potential benefits and drawbacks through shared decision-making.

Brain metastases in adult patients with melanoma of unknown primary in the Netherlands (2011-2020).

BACKGROUND: Although patients with melanoma of unknown primary (MUP) have a better prognosis than similar-staged melanoma patients with known primary, the occurrence of brain metastases (BM) entails a serious complication. This study provides an overview of the incidence, treatment patterns, and overall survival (OS) of adult patients with BM-MUP in the Netherlands. METHODS: BM-MUP cases were retrieved from the Netherlands Cancer Registry. Patient, disease and treatment-related characteristics were summarised using descriptive statistics. Overall survival (OS) was calculated by the Kaplan-Meier method, and the impact of prognostic factors on OS was assessed using Cox proportional hazard regression analyses. RESULTS: Among 1779 MUP patients, 450 were identified as BM-MUP (25.3%). Of these patients, 381 (84.7%) presented with BM along with other metastases, while 69 (15.3%) had BM only. BM-MUP patients were predominantly male (68.2%), and had a median age of 64 years at diagnosis (interquartile range 54-71 years). Over time, the proportion of BM along other metastatic sites increased, and the occurrence of BM decreased (p = 0.01). 1-Year OS improved for the total population, from 30.0% (95% confidence interval (CI): 19.8-40.9%) in 2011-2012 to 43.6% (95%CI: 34.5-52.3%) in 2019-2020, and median OS more than doubled from 4.2 months (95%CI: 3.3-6.2 months) to 9.8 months (95%CI: 7.0-13.2 months). Patient's age, localisation of BM, presence of synchronous liver metastasis and treatment were identified as independent predictors of OS. CONCLUSION: Notwithstanding the progress made in OS for patients with BM-MUP in the past decade, their overall prognosis remains poor, and further efforts are needed to improve outcomes.

Seasonal variation in diagnosis of cutaneous invasive melanoma and cutaneous squamous cell carcinoma: A nationwide study in the Netherlands.

BACKGROUND: Currently, there is no study that has reported on the seasonal trends of skin cancer in the Netherlands. This study aimed to investigate seasonal variation in diagnosis of cutaneous melanoma (CM) and cutaneous squamous cell carcinoma (cSCC) focusing on different subgroups. METHODS: CM diagnosed from 2001 till 2019 and cSCCs from 2001 till 2015 were selected from the Netherlands Cancer Registry. The monthly distribution of CM and cSCC diagnoses were evaluated. Summer-to-winter ratios (SWRs) were calculated overall and stratified by patient and tumour characteristics. RESULTS: Significant increases in melanoma incidence were noted over the summer months (SWR 1.39 (CI 1.37-1.40)). This increase was less apparent for cSCCs, as higher incidence rates were observed in the months September-November (SWR 1.13 (CI 1.12-1.14)). The seasonal variation of CM was greater in women and younger people, in superficial spreading melanoma and lentigo maligna melanoma, for the extremities, in thinner lesions, and for stage I at diagnosis. The seasonal variation of cSCC was similar for both sexes, most marked in patients 45-69 and ≥ 70, and for the extremities. CONCLUSIONS: Our findings showed a pronounced seasonal variation in the diagnosis of CM with a peak in the summer months. For cSCC, no evident peak was observed, but an increase in diagnosis was noted in fall. Both CM and cSCC showed strong seasonal effects for the extremities.

The impact of the COVID-19 pandemic on keratinocyte carcinoma in the Netherlands: Trends in diagnoses and magnitude of diagnostic delays.

BACKGROUND: The COVID-19 pandemic impacted Dutch society and the healthcare system. Focus switched to care for COVID-19 patients, thereby altering care for non-COVID patients. Non-urgent medical visits were cancelled or postponed and patients were reluctant to visit healthcare services. OBJECTIVES: This study aimed to investigate the impact of the COVID-19 pandemic on trends in diagnoses of keratinocyte carcinoma (cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC)) and to assess the magnitude of diagnostic delays. METHODS: The number of cSCC and BCC diagnoses in each month of 2020 was compared to the expected number of diagnoses for these months, using data from the Netherlands Cancer Registry. Expected diagnoses for 2020 were used as a reference to take the yearly increase in keratinocyte carcinoma incidence into account and were calculated by extrapolating the trends observed in 2017-2019. Comparisons were further stratified by age, sex and region. Estimates of diagnostic delays were calculated and corrected for the influence of excess mortality due to the pandemic on keratinocyte carcinoma incidence. RESULTS: The number of cSCC and BCC diagnoses substantially decreased when compared to the number of diagnoses expected from March to May 2020 (cSCC -29%, BCC -50%). These decreases were observed across all age groups, both sexes, and all regions. From June to September the number of cSCC and BCC diagnoses was higher than expected, after which it slightly dropped below expected in October to December. In total, 2020 keratinocyte carcinoma diagnoses continued to trail those expected, with a backlog of around 1150 cSCCs and 11 767 BCCs remaining at the end of the year. CONCLUSION: Diagnosis of keratinocyte carcinoma was suboptimal during the COVID-19 pandemic, due to diagnostic delays likely resulting from both patient and health system-related delay. Further studies will need to determine the effects of these diagnostic delays on outcomes.

A nationwide study of the incidence and trends of first and multiple basal cell carcinomas in the Netherlands and prediction of future incidence.

BACKGROUND: Basal cell carcinoma (BCC) is the most frequently diagnosed malignancy worldwide and an ever increasing annual incidence is observed. However, nationwide registries of BCCs are very rare, and often extrapolation of the data has been necessary to estimate the absolute number of diagnoses. As of September 2016, all histopathologically confirmed BCCs are registered in the Netherlands, due to developments in automatic notification and import in the Netherlands Cancer Registry. This offers the unique possibility to assess the nationwide population-based incidence of first and multiple BCCs. OBJECTIVES: To assess the nationwide incidence and trends of first and multiple BCCs in the Netherlands and to predict incidence rates up to 2029. METHODS: All patients with histopathologically confirmed BCC between 2001 and 2019 were selected from the population-based Netherlands Cancer Registry. Age-standardized incidence rates were calculated and trends were analysed with use of the estimated annual percentage change. Prediction of BCC incidence rates up to 2029 was based on a regression model. RESULTS: In total, 601 806 patients were diagnosed with a first BCC over the period 2001-2019. The age-standardized incidence rates for both men and women with a first BCC increased over these years, from 157 to 304 and from 124 to 274 per 100 000 person-years, respectively. For male and female patients aged 30-39 years, decreases in annual incidences of -3·6% and -3·0%, respectively, were found in recent years. For patients aged 50 years or older an ever increasing trend was found. One-quarter of the patients with a first primary BCC developed one or more subsequent BCCs within 3 years. Increases in incidence of 30·4% (male) and 25·3% (female) are expected in the next 10 years. CONCLUSIONS: BCC incidence has doubled over the past two decades. Trends have seemed to stabilize in recent years for patients aged < 50 years. This might be a first sign of a decreasing trend. The incidence continues to rise in patients aged 50 years and older. In the next decade a further increase in BCC incidence is expected.

Incidence and survival of cutaneous melanoma in Belgium and the Netherlands from 2004 to 2016: striking differences and similarities of two neighbouring countries.

BACKGROUND: Cutaneous melanoma (CM) is a multifactorial disease, with both environmental and genetic factors involved. The incidence of CM has risen rapidly during the last decades, making it a growing public health problem. OBJECTIVES: The purpose of this retrospective study was to compare incidence and survival data of CM between two neighbouring countries, Belgium (BE) and the Netherlands (NL). METHODS: Data were collected by the Belgian Cancer Registry (BCR) and the Netherlands Cancer Registry (NCR) from 1 January 2004 until 31 December 2016. Mucosal melanoma, in situ CM and melanoma in children from 0 to 14 years were excluded. Age-standardized incidence rates were calculated using the World Standard Population (WSR) per 100 000 persons. Five-year relative survival ratios were calculated using the Ederer II methodology. RESULTS: Total number of CM was higher in NL (63 789) compared with BE (27 679). The WSR was 1.5 times higher in NL compared with BE (27.7 vs. 18.6/100 000/year). The WSR of stage IV tumours was higher in BE than in NL (0.3 vs. 0.2/100 000/year). Five-year relative survival of stage IV tumours was higher in BE compared with NL (27.2% vs. 13.7%). CONCLUSIONS: Incidence of CM was higher in NL, indicating a higher risk of CM diagnosis. Stage IV tumours were relatively more frequent in BE for both sexes, while relative survival of stage IV tumours was higher in BE. As geographical location and latitude of both neighbouring countries are almost identical, other factors like differences in behaviour, follow-up and/or treatment may explain these differences.

Opportunities for improving the efficiency of keratinocyte carcinoma care in primary and specialist care: Results from population-based Dutch cohort studies.

BACKGROUND: High incidence rates of keratinocyte carcinoma (KC) in Western countries put pressure on healthcare systems. The aim of this study was to describe clinical practice in order to identify areas for improvement. METHODS: A random selection of patients from the Integrated Primary Care Information database who consulted their general practitioner (GP) for suspicious or confirmed KC (n = 1597) was made in the analysis. For secondary care, 1569 patients with histologically confirmed KC were randomly selected from the Netherlands Cancer Registry. All patients were diagnosed between 2009 and 2013 and followed up until 2016. Details on diagnosis, treatment and care during follow-up were described. RESULTS: Among 942 patients who consulted their GP, KC was included in the working or differential diagnosis, but two-thirds (629) were not KC. If the GP suspected KC, the GP directly referred to a medical specialist in most cases (548 of 942). In half (470 of 967) of all confirmed KCs, a skin malignancy was not described in the initial working or differential diagnosis of the GP. The medical specialist treated the first primary KC in 86% (1369 of 1596) by excision, 4% (69 of 1596) by Mohs surgery and 10% (158 of 1596) by another treatment. Although follow-up is not recommended for low-risk basal cell carcinoma, 83% (29 of 35) received follow-up care. In contrast, 82% (60 of 73) patients with squamous cell carcinoma received less follow-up than recommended. CONCLUSIONS: Strengthening the diagnostic pathway for KC in primary care and reduction of low-value follow-up visits in secondary care seem potential areas for improving the efficiency of KC care.

Sex matters: men with melanoma have a worse prognosis than women.

BACKGROUND: In Europe, one of the highest melanoma incidences is found in the Netherlands. Like in several other European countries, females are more prone to develop melanoma as compared to males, although survival is worse for men. OBJECTIVE: To identify clinicopathological gender-related differences that may lead to gender-specific preventive measures. METHODS: Data from the Dutch Nationwide Network and Registry of Histopathology and Cytopathology (PALGA) were retrieved from patients with primary, cutaneous melanoma in the Netherlands between 2000 and 2014. Patients initially presenting as stage I, II and III without clinically detectable nodal disease were included. Follow-up data were retrieved from the Netherlands Cancer Registry. Gender-related differences were assessed, and to compare relative survival between males and females, multivariable relative excess risks (RER) were calculated. RESULTS: A total of 54.645 patients were included (43.7% men). In 2000, 41.7% of the cohort was male, as compared to 47.3% in 2014 (P < 0.001). Likewise, in 2000, 51.5% of the deceased cohort was male compared to 60.1% in 2014 (P < 0.001). Men had significantly thicker melanomas at the time of diagnosis [median Breslow thickness 1.00 mm (interquartile range (IQR): 0.60-2.00) vs. 0.82 mm (IQR: 0.50-1.50) for females] and were significantly older at the time of diagnosis, more often had ulcerated melanomas and melanomas localized on the trunk or head and neck. Over time, survival for females improved while that of men decreased (P < 0.001). RER for dying was 1.37 (95% CI: 1.31-1.45) for men in multivariable analysis. CONCLUSION: There are evident clinicopathological differences between male and female melanoma patients. After multivariable correction for all these differences, relative survival remains worse for men. Clinicians as well as persons at risk for melanoma should be aware of these differences, as awareness and prevention might lead to a lower incidence and mortality of melanoma. This indicates the need of prevention campaigns integrating and targeting specific risk profiles.

Trends in incidence of thick, thin and in situ melanoma in Europe.

BACKGROUND: We analysed trends in incidence for in situ and invasive melanoma in some European countries during the period 1995-2012, stratifying for lesion thickness. MATERIAL AND METHODS: Individual anonymised data from population-based European cancer registries (CRs) were collected and combined in a common database, including information on age, sex, year of diagnosis, histological type, tumour location, behaviour (invasive, in situ) and lesion thickness. Mortality data were retrieved from the publicly available World Health Organization database. RESULTS: Our database covered a population of over 117 million inhabitants and included about 415,000 skin lesions, recorded by 18 European CRs (7 of them with national coverage). During the 1995-2012 period, we observed a statistically significant increase in incidence for both invasive (average annual percent change (AAPC) 4.0% men; 3.0% women) and in situ (AAPC 7.7% men; 6.2% women) cases. DISCUSSION: The increase in invasive lesions seemed mainly driven by thin melanomas (AAPC 10% men; 8.3% women). The incidence of thick melanomas also increased, although more slowly in recent years. Correction for lesions of unknown thickness enhanced the differences between thin and thick cases and flattened the trends. Incidence trends varied considerably across registries, but only Netherlands presented a marked increase above the boundaries of a funnel plot that weighted estimates by their precision. Mortality from invasive melanoma has continued to increase in Norway, Iceland (but only for elder people), the Netherlands and Slovenia.

Trends in surgery for screen-detected and interval breast cancers in a national screening programme.

BACKGROUND: This population-based study aimed to evaluate trends in surgical approach for screen-detected cancer versus interval breast cancer, and to determine the factors associated with positive resection margins. METHODS: Screening mammograms of women aged 50-75 years, who underwent biennial screening in a Dutch breast-screening region between 1997 and 2011, were included. Patient and tumour characteristics were compared between women who underwent mastectomy or breast-conserving surgery (BCS) for screen-detected or interval cancer, and women with a negative or positive resection margin after BCS. RESULTS: Some 417,013 consecutive screening mammograms were included. A total of 2224 screen-detected and 825 interval cancers were diagnosed. The BCS rate remained stable (mean 6.1 per 1000 screened women; P = 0.099), whereas mastectomy rates increased significantly during the study from 0.9 (1997-1998) to 1.9 (2009-2010) per 1000 screened women (P < 0.001). The proportion of positive resection margins for invasive cancer was 19.6 and 7.6 per cent in 1997-1998 and 2009-2010 respectively (P < 0.001), with significant variation between hospitals. Dense breasts, preoperative magnetic resonance imaging, microcalcifications, architectural distortion, tumour size over 20 mm, axillary lymph node metastasis and treating hospital were independent risk factors for mastectomy. Interval cancer, image-guided tumour localization, microcalcifications, breast parenchyma asymmetry, tumour size greater than 20 mm, lobular tumour histology, low tumour grade, extensive invasive component and treating hospital were independent risk factors for positive resection margins. CONCLUSION: Mastectomy rates doubled during a 14-year period of screening mammography and the proportion of positive resection margins decreased, with variation among hospitals. The latter observation stresses the importance of quality control programmes for hospitals treating women with breast cancer.

Impact of transition from analog screening mammography to digital screening mammography on screening outcome in The Netherlands: a population-based study.

BACKGROUND: Full-field digital mammography (FFDM) has replaced screen-film mammography (SFM) in most breast screening programs. We analyzed the impact of this replacement on the screening outcome. PATIENTS AND METHODS: The study population consisted of a consecutive series of 60 770 analog and 63 182 digital screens. During a 1-year follow-up, we collected breast imaging reports, biopsy results and surgical reports of all the referred women. RESULTS: The referral rate and the cancer detection rate at FFDM were, respectively, 3.0% and 6,6‰, compared with 1.5% (P < 0.001) and 4.9‰ (P < 0.001) at SFM. Positive predictive values of referral and percutaneous biopsies were lower at FFDM, respectively, 21.9% versus 31.6% (P < 0.001) and 42.9% versus 62.8% (P < 0.001). Per 1000 screened women, there was a significant increase with FFDM versus SFM in the detection rate of low- and intermediate-grade ductal carcinoma in situ (DCIS) (+0.7), invasive T1a-c cancers (+0.9), invasive ductal cancers (+0.9), low-grade (+1.1), node-negative invasive cancers (+1.2), estrogen-receptor or progesterone-receptor-positive invasive cancers (respectively, +0.9 and +1.1) and Her2/Neu-negative (+0.8) invasive cancers. Mastectomy rates were stable at 1.1 per 1,000 screens. CONCLUSIONS: FFDM significantly increased the referral rate and cancer detection rate, at the expense of a lower positive predictive value of referral and biopsy. Extra tumors detected at FFDM were mostly low-intermediate grade DCIS and smaller invasive tumors, of more favorable tumor characteristics. Mastectomy rates were not increased in the FFDM population, while increased over-diagnosis cannot be excluded.

Inter-observer variability in mammography screening and effect of type and number of readers on screening outcome.

We prospectively determined the variability in radiologists' interpretation of screening mammograms and assessed the influence of type and number of readers on screening outcome. Twenty-one screening mammography radiographers and eight screening radiologists participated. A total of 106,093 screening mammograms were double-read by two radiographers and, in turn, by two radiologists. Initially, radiologists were blinded to the referral opinion of the radiographers. A woman was referred if she was considered positive at radiologist double-reading with consensus interpretation or referred after radiologist review of positive cases at radiographer double-reading. During 2-year follow-up, clinical data, breast imaging reports, biopsy results and breast surgery reports were collected of all women with a positive screening result from any reader. Single radiologist reading (I) resulted in a mean cancer detection rate of 4.64 per 1000 screens (95% confidence intervals (CI)=4.23-5.05) with individual variations from 3.44 (95% CI=2.30-4.58) to 5.04 (95% CI=3.81-6.27), and a sensitivity of 63.9% (95% CI=60.5-67.3), ranging from 51.5% (95% CI=39.6-63.3) to 75.0% (95% CI=65.3-84.7). Sensitivity at non-blinded, radiologist double-reading (II), radiologist double-reading followed by radiologist review of positive cases at radiographer double-reading (III), triple reading by one radiologist and two radiographers with referral of all positive readings (IV) and quadruple reading by two radiologists and two radiographers with referral of all positive readings (V) were as follows: 68.6% (95% CI=65.3-71.9) (II); 73.2% (95% CI=70.1-76.4) (III); 75.2% (95% CI=72.1-78.2) (IV), and 76.9% (95% CI=73.9-79.9) (V). We conclude that screener performance significantly varied at single-reading. Double-reading increased sensitivity by a relative 7.3%. When there is a shortage of screening radiologists, triple reading by one radiologist and two radiographers may replace radiologist double-reading.

Comparison of comorbidity prevalence in oesophageal and gastric carcinoma patients: a population-based study.

OBJECTIVE: We investigated the distribution of serious comorbidity in patients with newly diagnosed oesophageal and gastric cancer between 1993 and 2001. Our special interest was comparing distal oesophageal and gastric cardia adenocarcinoma patients since a common origin of these tumours has been suggested. METHODS: Data on comorbidity (previous cancers, chronic obstructive pulmonary diseases, cardiovascular and cerebrovascular diseases, hypertension, ulcerative digestive tract diseases, liver diseases and diabetes) were derived from a population-based database in The Netherlands to compare risk factor profiles for 479 oesophageal squamous cell carcinomas, 339 distal oesophageal adenocarcinomas, 570 cardia adenocarcinomas and 1965 subcardia cancers. RESULTS: A comparable age and gender distribution was shown in distal oesophageal and cardia adenocarcinoma patients. After adjustment for age and gender, only the prevalence of previous cancers differed between adenocarcinomas of distal oesophagus and cardia [more frequent in distal oesophageal adenocarcinoma patients, odds ratio (OR) = 1.84, P = 0.01]. Ulcerative and liver diseases were more prevalent in oesophageal squamous cell carcinoma patients as compared with distal oesophageal adenocarcinoma patients (OR = 1.90, P = 0.02 and OR = 8.82, P = 0.04, respectively), whereas diabetes was more prevalent in the latter (OR = 0.56, P = 0.03). Cardia adenocarcinoma patients significantly more often had hypertension as compared with subcardia cancer patients (OR = 1.53, P = 0.001), whereas the latter more often suffered from previous cancers and ulcerative diseases (OR = 0.54, P = 0.0009 and OR = 0.25, P < 0.0001, respectively). CONCLUSIONS: In terms of comorbidity at diagnosis, cardia adenocarcinoma patients resemble distal oesophageal adenocarcinoma patients rather than gastric subcardia carcinoma patients, with likewise equal age and gender distribution.

Signs of impaired cognitive function in adolescents with marginal cobalamin status.

BACKGROUND: Lack of cobalamin may lead to neurologic disorders, which have been reported in strict vegetarians. OBJECTIVE: The objective of this study was to investigate whether cognitive functioning is affected in adolescents (aged 10-16 y) with marginal cobalamin status as a result of being fed a macrobiotic diet up to an average age of 6 y. DESIGN: Data on dietary intake, psychological test performance, and biochemical variables of cobalamin status were collected from 48 adolescents who consumed macrobiotic (vegan type) diets up to the age of 6 y, subsequently followed by lactovegetarian or omnivorous diets, and from 24 subjects (aged 10-18 y) who were fed omnivorous diets from birth onward. Thirty-one subjects from the previously macrobiotic group were cobalamin deficient according to their plasma methylmalonic acid concentrations. Seventeen previously macrobiotic subjects and all control subjects had normal cobalamin status. RESULTS: The control subjects performed better on most psychological tests than did macrobiotic subjects with low or normal cobalamin status. A significant relation between test score and cobalamin deficiency (P: = 0.01) was observed for a test measuring fluid intelligence (correlation coefficient: -0.28; 95% CI: -0.48, -0.08). This effect became more pronounced (P: = 0.003) within the subgroup of macrobiotic subjects (correlation coefficient: -0.38; 95% CI: -0.62, - 0.14). CONCLUSION: Our data suggest that cobalamin deficiency, in the absence of hematologic signs, may lead to impaired cognitive performance in adolescents.