An Educational Need Regarding Treatment-Related Infertility and Fertility Preservation: a National Survey Among Members of the Dutch Society for Medical Oncologists.

Cancer diagnosis and treatment may influence reproductive planning and impact fertility in patients of reproductive age. Although guidelines have been established in the past decade, education, practice, and attitudes of medical oncologists regarding fertility preservation remain undecided. A nationwide survey was performed among members of the Dutch Society for Medical Oncology. Demographics, practice, knowledge, and barriers were measured regarding information provision of fertility preservation towards cancer patients of childbearing age. From 392 members, 120 oncologists completed the questionnaire (30.6%). Majority of oncologists was convinced it is their responsibility to discuss impact of cancer treatment to fertility (93.2%), yet 68.3% discussed the subject often or always (n = 82). Oncologists employed in district general hospitals were less likely to discuss fertility (p = 0.033). On average, 44.6% of reproductive men and 28.9% of reproductive women is referred to fertility specialists. Half of the respondents declared to possess sufficient knowledge regarding fertility preservation (n = 57, 47.5%). Poor prognosis (53%), unlikely survival (43.1%), and high chances on fertility recovery (28.7%) were identified as barriers to discussing fertility preservation. Among oncologists, impact of cancer treatment on fertility is a well-accepted responsibility to counsel. Despite, self-reported knowledge regarding fertility preservation is strongly varying. In practice, fertility is discussed to some extent, influenced by several barriers and depending on prognosis and type of hospital. Patients benefit from knowledge improvement among oncology care providers concerning fertility effects of cancer treatment. Education during medical school, residency, and among practicing oncologists may raise awareness, together with enhancement of referral possibilities.

Sexual and fertility-related adverse effects of medicinal treatment for cancer; a national evaluation among medical oncologists.

BACKGROUND: Anti-cancer drugs commonly adversely affect fertility and sexual function. Despite this, patients report a lack of counselling of these potential adverse effects. The aim was to determine Dutch oncologists' knowledge about the adverse effects of various cancer drugs on fertility and sexual function. METHODS: A cross-sectional survey was sent to members of the Dutch Society for Medical Oncology (n = 433). The survey questions included various cancer drugs' adverse effects on fertility, ovulation, spermatogenesis, and sexual function. RESULTS: One hundred and five of 392 oncologists responded (26.8%). Oncologists were more aware of the adverse effects on fertility compared to sexual function. Drugs that were mostly believed to negatively affect fertility were cisplatin (n = 81, 80.2%), epirubicin (n = 78, 78.0%) and cyclophosphamide (n = 80, 77.7%). Regarding sexual function, most mentioned drugs were tamoxifen (n = 67, 65.7%), GnRH-agonists (n = 64, 63.4%) and cisplatin (n = 58, 57.4%). Oncologists with expertise in urology possessed more awareness regarding sexuality-related adverse effects (cisplatin p = 0.038, etoposide p = 0.025, ifosfamide p = 0.06, vinblastine p = 0.000). CONCLUSION: Results revealed that oncologists have different beliefs about possible sexual and fertility-related adverse effects concerning medication resources and literature. Based on our results, oncologists do not possess sufficient knowledge to inform patients about sexual and fertility-related adverse effects.

Discussing Sexual Health in the Medical Oncologist's Practice: Exploring Current Practice and Challenges.

Sexuality is a significant quality-of-life concern for many cancer patients. Patients may be disadvantaged if they are not informed and not offered sexual health care. We sought to reveal oncologists' current practice and opinions concerning sexual counselling. The aim of this study was to explore the knowledge, attitude and practice patterns of Dutch medical oncologists regarding treatment-related sexual dysfunction. Questionnaires were sent to 433 members of the Dutch Society of Medical Oncology. The majority (81.5%) of the 120 responding medical oncologists (response rate 30.6%) stated they discussed sexual function with fewer than half of their patients. At the same time, 75.8% of the participating oncologists agreed that addressing sexual function is their responsibility. Sexual function was discussed more often with younger patients and patients with a curative treatment intent. Barriers for avoiding discussing sexual function were lack of time (56.1%), training (49.5%) and advanced age of the patient (50.4%). More than half (64.6%) stated they had little knowledge about the subject and the majority (72.9%) wanted to acquire additional training in sexual function counselling. Medical oncologists accept that sexual function counselling falls within their profession, yet they admit to not counselling patients routinely concerning sexual function. Only in a minority of cases do medical oncologists inform their patients about sexual side effects of treatment. Whether they counsel patients is related to how they view patient's prognosis, patient's age, and self-reported knowledge. Findings indicate there is a role for developing education and practical training.

Fertility preservation counselling in Dutch Oncology Practice: Are nurses ready to assist physicians?

Cancer and its treatments may result in impaired fertility, which could cause long-term distress to cancer survivors. For eligible patients, fertility preservation (FP) is available to secure future reproductive potential. Many physicians, however, feel inhibited about discussing FP. Oncology nurses may serve as an initiator for discussing the subject and provide additional support. Our aim was to investigate their knowledge about FP, the way they apply this, and possible barriers to discussing FP with patients of reproductive age. A questionnaire was administered via mail, Internet and the Dutch Oncology Nursing Congress. Four hundred and twenty-one oncology nurses participated, a third of whom (31.1%) had "sufficient" knowledge of FP. Twenty-eight per cent of participants reported that they "never/hardly ever" discussed FP; 32.2% "almost always/always." FP discussions were more frequently performed by graduate nurses, academic nurses, experienced nurses and nurses with sufficient knowledge. Reasons for not discussing FP were a "lack of knowledge" (25.2%), "poor prognosis" (16.4%) and "lack of time" (10.5%). In conclusion, several obstacles may result in FP not being routinely discussed, specifically a lack of knowledge. Yet nurses feel responsible for addressing the issue, indicating that assistance with FP discussions should be encouraged. Educational training about FP is recommended.

Chemotherapy for testicular cancer induces acute alterations in diastolic heart function.

BACKGROUND: After treatment with cisplatin-based chemotherapy for testicular cancer (TC), patients have higher prevalence of cardiovascular complications after long-term follow up. Little is known about acute cardiovascular effects of cisplatin-based chemotherapy. The aim of this study was to explore acute effects of chemotherapy on cardiac function in patients treated for TC. METHODS: Fourteen TC patients (age 34.6 ± 12.3 years) were studied before and 3 months after start with cisplatin-based chemotherapy. Cardiac function was assessed with magnetic resonance imaging. Fasting glucose and insulin levels were measured and insulin sensitivity, reflected by the quantitative insulin sensitivity index (Quicki index), was calculated. RESULTS: Left ventricular (LV) end-diastolic volume and LV stroke volume (SV) significantly decreased from 192 ± 27 to 175 ± 26 ml (P<0.05) and 109 ± 18 to 95 ± 16 ml (P<0.05), respectively. The ratio of early and atrial filling velocities across the mitral valve, a parameter of diastolic heart function, decreased after chemotherapy from 1.87 ± 0.43 to 1.64 ± 0.45 (P<0.01). Metabolic parameters were unfavourably changed, reflected by a decreased Quicki index, which reduced from 0.39 ± 0.05 to 0.36 ± 0.05 (P<0.05). CONCLUSION: Chemotherapy for TC induces acute alterations in diastolic heart function, paralleled by unfavourable metabolic changes. Therefore, early after chemotherapy, metabolic treatment may be indicated to possibly reduce long-term cardiovascular complications.

Prevalence of the metabolic syndrome and cardiovascular disease risk in chemotherapy-treated testicular germ cell tumour survivors.

BACKGROUND: Testicular cancer patients have an increased risk for cardiovascular disease (CVD), which might be related to the increased prevalence of the metabolic syndrome (MetS) in this group of patients. METHODS: We assessed the prevalence of MetS and calculated the 10-year CVD risk in a cohort of 255 testicular germ cell tumour survivors (median age, 38.7 years; interquartile range, 31-48) at a mean of 7.8 years after anti-cancer treatment, and compared these with data obtained from 360 healthy men. RESULTS: Survivors had an age-adjusted increased risk for MetS of 1.9 compared with that of healthy controls. The risk for MetS was highest in survivors treated with combination chemotherapy (CT) 2.3 (Adult Treatment Panel of the National Cholesterol Education Program classification) and 2.2 (International Diabetes Federation classification). The risk of MetS was especially increased in survivors with testosterone levels in the lowest quartile (OR, 2.5). Ten-year cardiovascular risk as assessed by the Framingham Risk Score (3.0%) and Systemic Coronary Risk Evaluation (1.7%) algorithms was low, independent of treatment, and was comparable to controls. CONCLUSION: Testicular germ cell tumour survivors have an increased prevalence of MetS, with hypogonadism and CT treatment being clear risk factors for the development of the syndrome. The increased prevalence of MetS was not associated with an increased 10-year cardiovascular risk.

Quantitative ultrasound of the calcaneus (QUS): A valuable tool in the identification of patients with non-metastatic prostate cancer requiring screening for osteoporosis.

Non-metastatic prostate cancer (PCa) patients are at increased risk for osteoporosis and fractures mainly due to androgen deprivation therapy (ADT)-associated hypogonadism, but this remains largely underdiagnosed and untreated. In this study, we examine the value of pre-screening calcaneal QUS in identifying patients who should be referred for screening for osteoporosis using dual-energy X-Ray absorptiometry (DXA). In a single-center retrospective cross-sectional cohort study, we analysed data on DXA and calcaneal QUS measurements systematically collected between 2011 and 2013 in all non-metastatic PCa patients attending our Uro-Oncological Clinic at the Leiden University Medical Center. Receiver operating characteristic curves were used to assess the positive (PPV) and negative (NPV) predictive values of QUS T-scores of 0, -1.0, and - 1.8 in identifying DXA-diagnosed osteoporosis (T-scores ≤ - 2.5 and ≤ -2) at lumbar spine and/or femoral neck. Complete sets of data were available in 256 patients, median age 70.9 (53.6-89.5) years; 93.0 % had received local treatment, 84.4 % with additional ADT. Prevalence of osteoporosis and osteopenia was respectively 10.5 % and 53 %. Mean QUS T-score was -0.54 ± 1.58. Whereas PPV at any QUS T-score was <25 %, precluding the use of QUS as surrogate for DXA in screening for osteoporosis, QUS T-scores of -1.0 to 0.0 had a NPV of ≥94.5 % for DXA T-scores ≤ 2.5 and ≤ -2 at any site, confidently identifying patients least likely to have osteoporosis, thereby significantly reducing the number of patients requiring DXA screening for diagnosing osteoporosis by up to two-third. Osteoporosis screening is a significant unmet need in non-metastatic prostate cancer patients treated with ADT, and QUS may represent a valuable alternative pre-screening strategy to overcome logistics, time demands, and economic barriers encountered with current strategies for osteoporosis screening in these patients. Summary: Osteoporosis and associated increased fracture risk are common in non-metastatic prostate carcinoma, mainly due to androgen deprivation therapy, but these often remain underdiagnosed and untreated. We demonstrate that QUS is a safe, less costly pre-screen tool that reduces by up to two-third the number of patients requiring referral for DXA for osteoporosis screening.

Determination of the size distribution of blood microparticles directly in plasma using atomic force microscopy and microfluidics.

Microparticles, also known as microvesicles, found in blood plasma, urine, and most other body fluids, may serve as valuable biomarkers of diseases such as cardiovascular diseases, systemic inflammatory disease, thrombosis, and cancer. Unfortunately, the detection and quantification of microparticles are hampered by the microscopic size of these particles and their relatively low abundance in blood plasma. The use of a combination of microfluidics and atomic force microscopy to detect microparticles in blood plasma circumvents both problems. In this study, capture of a specific subset of microparticles directly from blood plasma on antibody-coated mica surface is demonstrated. The described method excludes isolation and washing steps to prepare microparticles, improves the detection sensitivity, and yields the size distribution of the captured particles. The majority of the captured particles have a size ranging from 30 to 90 nm, which is in good agreement with prior results obtained with microparticles immediately isolated from fresh plasma. Furthermore, the qualitative shape of the size distribution of microparticles is shown not to be affected by high-speed centrifugation or the use of the microfluidic circuit, demonstrating the relative stable nature of microparticles ex vivo.

Non-transferrin bound iron measurement is influenced by chelator concentration.

Release of non-protein bound iron plays an important role in the toxicity inflicted by chemotherapy in cancer patients. Since large variations have been described for different methods measuring non-transferrin bound iron (NTBI), we aimed to obtain more accurate values. After binding to the chelator nitrilotriacetic acid disodium salt (NTA) and ultrafiltration, the NTBI can be measured spectrophotometrically by the addition of thioglycolic acid (TGA) and baptophenanthroline disulfonic acid (BPT). Results demonstrated that NTBI values increased with NTA concentration. In samples incubated with 80 mM NTA, >5-fold higher NTBI values were found compared to using 10 mM NTA. Optimal concentration of NTA was established by additions of iron to serum with known latent iron-binding capacity (LIBC). Iron addition curves showed that NTBI could be measured starting from the LIBC of the serum with optimal yield after incubation with 4 mM NTA in 5 mM Tris-HCl pH 6.5, with 3mM TGA and 6.2 mM BPT for the colour reaction. The results showed excellent correlation with 195 samples measured also by HPLC. For the spectrophotometric method, significantly higher NTBI values were measured in patient samples with maximal iron saturation compared to patients with lower iron saturation.

Evaluation of biomarkers for cardiotoxicity of anthracyclin-based chemotherapy.

INTRODUCTION: The clinical assessment of the myocardial damage caused by anthracyclin (ANT)-therapy is difficult. Therefore a study was performed to evaluate non-invasive markers of anthracyclin-induced cardiac effects, with emphasis on course-to-course variation. METHODS: Eligible for study participation were patients, without known cardiologic abnormalities who did not use cardiotoxic medication (except for ANT-therapy), who had previously completed at least three cycles of anthracyclin-containing chemotherapy (n = 14) and patients who were ANT-naïve and who were scheduled to receive doxorubicin-containing chemotherapy (n = 12). Seven patients in this last group also completed at least three cycles and were available for follow-up assessments; thus a total population of 21 patients (12F/9M) completed at least three courses ANT-chemotherapy. In these patients blood samples and ECG-recordings were taken within 6 months after completion of ANT-therapy. In 12 patients (10F/2M) assessments were also done before, immediately afterwards and at 24 h after each course of ANT. RESULTS AND CONCLUSIONS: In the patients who completed chemotherapy, NT-proBNP was 277% (n = 21; 95% CI: 86-661%, P < 0.001) higher compared to healthy volunteers. During the first course NT-proBNP rose 269% (n = 12; 167-409%, P < 0.0001) at 24 h post-administration. The linear corrected QT (QTcL) directly after the first administration of ANT increased by 9.56 ms (n = 12; 3.85-15.27, P < 0.001) and this prolongation was still present at 24 h, 11.48 ms (n = 12; 5.61-17.34, P < 0.0001). Both NT-proBNP and QTcL returned to baseline before the start of the next course and a similar pattern was observed during each course. NT-proBNP and QTcL may be useful markers for course-to-course evaluation of anthracyclin-induced cardiotoxicity.

[Guideline 'Renal cell carcinoma']. / Richtlijn 'Niercelcarcinoom'.

Each year, more than 1500 new cases of renal cell carcinoma are diagnosed in the Netherlands, and approximately 850 patients die due to this disease. The guideline 'Renal cell carcinoma' contains clinical practice recommendations on the diagnosis (imaging, pathological assessment, histopathological classification) and treatment (surgery, chemo-, immuno-, and radiotherapy) of renal cell carcinoma. For diagnostic imaging, chest and abdominal CT is recommended. Scintigraphy is not recommended. The term 'Grawitz tumour' is obsolete and should be replaced by 'renal cell carcinoma' with histological subtype specification according to the 2004 WHO classification. Laparoscopic radical nephrectomy is as effective as open surgery for localised tumours (T1 and T2) and possibly also for T3 tumours. The laparoscopic approach is associated with less morbidity due to the less invasive nature of this technique. This operation requires experience. In partial nephrectomy, a small margin of healthy tissue is sufficient. Frozen section examination of the resection edges does not appear to be required. In patients with metastatic renal cell carcinoma who are eligible for immunotherapy, removal of the tumour prolongs survival. Metastasectomy prolongs survival in patients with a solitary metastasis. Most currently available cytotoxic agents are ineffective against renal cell carcinoma. Interferon-alpha may have a role in the treatment of patients with renal cell carcinoma and favourable prognostic factors, given the survival advantage demonstrated with this agent in clinical trials. The guideline is available in English at www.oncoline.nl.

[Angiogenesis inhibitors for the systemic treatment of metastatic renal cell carcinoma: sunitinib, sorafenib, bevacizumab and temsirolimus]. / Angiogeneseremmers voor de systemische behandeling van gemetastaseerd niercelcarcinoom: sunitinib, sorafenib, bevacizumab en temsirolimus.

Treatment of patients with metastatic renal cell carcinoma is evolving rapidly due to the advent of novel targeted therapies. Improved knowledge of the underlying pathogenesis has led to the development of drugs that modulate the dominant signal transduction pathways for this disease, which results in inhibition of angiogenesis. Recent evidence indicates that the receptor tyrosine kinase inhibitor sunitinib prolongs progression-free survival compared with interferon-alpha, especially in patients with intermediate risk. Immunotherapy with interferon-alpha or high-dose interleukin-2 should still be considered for low-risk patients, particularly those with clear-cell tumours and metastases of the lung only. In patients who fail treatment with interferon-alpha, sorafenib has been shown to improve progression-free survival. High-risk patients may benefit from treatment with temsirolimus, which inhibits mammalian target of rapamycin (mTOR) kinase activity and has shown to improve overall survival. These angiogenesis inhibitors did not receive mention in the recently published guideline 'Renal cell carcinoma'.

Microparticle-associated tissue factor activity: a link between cancer and thrombosis?

BACKGROUND: Cancer, in particular mucinous adenocarcinoma, is associated with venous thromboembolism (VTE). Tissue factor (TF), initiator of coagulation, plays a central role in the paradigm that clotting and tumor growth form a vicious circle, in which hypercoagulability facilitates the aggressive biology of cancer and vice versa. Expression of TF in tumors is associated with poor differentiation and poor prognosis. PATIENT/METHODS: We investigated the association between clinically manifest VTE and procoagulant properties of circulating microparticles (MP) isolated from blood of unselected pancreatic and breast adenocarcinoma patients' consecutive subjects, who presented with ultrasound or CT-scan confirmed VTE, and healthy subjects. RESULTS: Patients with disseminated breast and pancreatic cancer had significantly increased levels of MP-associated TF activity compared with healthy controls, subjects with idiopathic acute VTE and non-metastatic cancer patients. Patients with both high MP-associated TF-activity and MP-associated epithelial mucin (MUC1) had a lower survival rate at 3-9 months follow-up than those with low TF-activity and no MUC1 expression: the likelihood of survival was 0.42 (95% CI: 0.19- 0.94) for an individual with these two predictor variables present, after adjustment for other factors (age cohort, type of cancer, VTE) in the Cox proportional hazards model. CONCLUSIONS: Our results suggest an important role for MP-associated TF and MUC1 in the pathogenesis of thrombosis in disseminated mucinous adenocarcinoma patients. Future studies should reveal the mechanism underlying the observed associations.

N-ras mutations in human cutaneous melanoma from sun-exposed body sites.

In 7 of 37 patients with cutaneous melanoma, mutations in the N-ras gene were found. The primary tumors of these seven patients were exclusively localized on body sites continuously exposed to sunlight. Moreover, the ras mutations were all at or near dipyrimidine sites known to be targets of UV damage. Two primary tumors were biclonal with respect to ras mutation. An active role for UV irradiation in induction of the mutations is suggested.

[New drugs; sunitinib and sorafenib]. / Nieuwe geneesmiddelen; sunitinib en sorafenib.

Sunitinib and sorafenib are both indicated for the treatment of advanced kidney carcinoma of the 'clear cell' type after failure of, or resistance to, other treatments. Both drugs inhibit the tyrosine-kinase activity of a number of growth factor receptors; sorafenib has an additional inhibitory effect on serine/threonine-kinase activity. This mechanism decreases signal transduction and results in an inhibition of tumour cell growth and angiogenesis. The adverse effects of the two drugs are different: sunitinib causes mainly fatigue and gastrointestinal discomfort, whereas sorafenib's most frequent adverse effects are diarrhoea, rash, the palmar-plantar erythrodysaesthesia syndrome, and hypertension.

Incidence of venous thrombosis in a large cohort of 66,329 cancer patients: results of a record linkage study.

BACKGROUND: The incidence of venous thrombosis (VT) for cancer patients is increased compared with patients without cancer, but estimations of the incidence for different types of cancer have rarely been made because of the low incidence of various types of cancer. Large registries offer an opportunity to study the risk of VT in large cohorts of cancer patients, which is essential in decisions on prophylactic anti-coagulant treatment. METHODS: This cohort study estimates the incidence of VT in cancer patients by using record linkage of a Cancer Registry and an Anticoagulation Clinic database in the Netherlands. Cumulative incidences in patients with different types of malignancies were estimated. We calculated relative risks (RRs) in relation to the presence of distant metastases and treatment. RESULTS: Tumors of the bone, ovary, brain, and pancreas are associated with the highest incidence of VT (37.7, 32.6, 32.1, and 22.7/1000/0.5 year). Patients with distant metastases had a 1.9-fold increased risk [RRadj: 1.9; 95% confidence interval (CI): 1.6-2.3]. Chemotherapy leads to a 2.2-fold increased risk (RR(adj): 2.2; 95% CI: 1.8-2.7) and hormonal therapy leads to a 1.6-fold increased risk (RRadj: 1.6; 95% CI: 1.3-2.1) compared with patients not using these treatment modalities. Patients with radiotherapy or surgery did not have an increased risk. CONCLUSIONS: We compared the overall incidences of VT in the first half year in our study to the risk of major bleeding as described in the literature. For patients with distant metastases, for several types of cancer, prophylactic anti-thrombotic treatment could be beneficial.

High risk of venous thrombosis in patients with pancreatic cancer: a cohort study of 202 patients.

To estimate the risk of venous thrombosis associated with pancreatic malignancies we followed a cohort of patients with pancreatic cancer (n = 202). We calculated incidence rates of venous thrombosis and compared this with population rates using a Standardised Morbidity Ratio (SMR). The effects of location, histology and treatment were assessed by Cox-modelling. The incidence of venous thrombosis was 108.3/1000 patient-years (95% confidence interval (CI) 64.4-163.8), 58.6-fold increased (SMR 58.6, 95% CI 36.9-92.9). Patients with a tumour of the corpus/cauda had a 2-fold increased risk compared with those with a tumour of the caput. Patients treated with chemotherapy had a 4.8-fold increased risk (HR(adj) 4.8, 95% CI 1.1-20.8), whereas radiotherapy did not increase the risk. In a postoperative period of 30 d, patients had a 4.5-fold increased risk of venous thrombosis (HR(adj) 4.5, 95% CI 0.5-40.9). The risk was 1.9-fold increased in the presence of distant metastases (HR(adj) 1.9, 95% CI 0.7-5.1). Anti-thrombotic prophylaxis seems warranted in the first month after surgery, during and after treatment with chemotherapy, and when distant metastases have been diagnosed.