Hink Boer

Long-Term and Late Effects of Germ Cell Testicular Cancer Treatment and Implications for Follow-Up

Germ cell testicular cancer (TC) represents a malignancy with high cure rates. Since the introduction of cisplatin-based chemotherapy in the late 1970s, the 5-year survival rate has increased considerably, and it is currently above 95%. Because TC is usually diagnosed before the age of 40 years, these men can expect to live for another 40 to 50 years after being successfully treated. This success, however, is hampered by an increased risk of long-term and late effects of treatment. Secondary malignant neoplasms and cardiovascular disease represent the most common potentially life-threatening late effects, typically occurring more than 10 years after treatment. Other long-term effects include pulmonary toxicity, nephrotoxicity, neurotoxicity, decreased fertility, hypogonadism, and psychosocial problems. The incidence and time to onset of these various adverse effects vary according to treatment type and intensity. There is still little knowledge about underlying mechanisms and genetic susceptibility of the various adverse effects. Apart from treatment burden, it is not yet possible to identify patients who are at high risk for certain late effects after TC treatment. In this clinical review, we present the current status regarding different somatic and psychosocial long-term late effects after treatment for TC, based on Medline searches and our own research. Moreover, we postulate recommendations for general medical evaluations that should begin after treatment is completed and continue during follow-up.

Long-term Exposure to Circulating Platinum is Associated with Late Effects of Treatment in Testicular Cancer Survivors

Cisplatin is an essential part of testicular cancer treatment. We investigated whether long-term exposure to circulating platinum (Pt) plays a role in the development of late effects in survivors. We assessed Pt decay in samples collected 1–13 years after chemotherapy. Renal function is a strong determinant of exposure to Pt. Higher exposure to Pt is associated with an increased prevalence of adverse effects hypogonadism and hypertension.

Growth Differentiation Factor 15 (GDF-15) Plasma Levels Increase during Bleomycin- and Cisplatin-Based Treatment of Testicular Cancer Patients and Relate to Endothelial Damage

Introduction Chemotherapy-related endothelial damage contributes to the early development of cardiovascular morbidity in testicular cancer patients. We aimed to identify relevant mechanisms of and search for candidate biomarkers for this endothelial damage. Methods Human micro-vascular endothelial cells (HMEC-1) were exposed to bleomycin or cisplatin with untreated samples as control. 18k cDNA microarrays were used. Gene expression differences were analysed at single gene level and in gene sets clustered in biological pathways and validated by qRT-PCR. Protein levels of a candidate biomarker were measured in testicular cancer patient plasma before, during and after bleomycin-etoposide-cisplatin chemotherapy, and related to endothelial damage biomarkers (von Willebrand Factor (vWF), high-sensitivity C-Reactive Protein (hsCRP)). Results Microarray data identified several genes with highly differential expression; e.g. Growth Differentiation Factor 15 (GDF-15), Activating Transcription Factor 3 (ATF3) and Amphiregulin (AREG). Pathway analysis revealed strong associations with ‘p53’ and ‘Diabetes Mellitus’ gene sets. Based on known function, we measured GDF-15 protein levels in 41 testicular patients during clinical follow-up. Pre-chemotherapy GDF-15 levels equalled controls. Throughout chemotherapy GDF-15, vWF and hsCRP levels increased, and were correlated at different time-points. Conclusion An unbiased approach in a preclinical model revealed genes related to chemotherapy-induced endothelial damage, like GDF-15. The increases in plasma GDF-15 levels in testicular cancer patients during chemotherapy and its association with vWF and hsCRP suggest that GDF-15 is a potentially useful biomarker related to endothelial damage.

Single-nucleotide polymorphism in the 5-α-reductase gene (SRD5A2) is associated with increased prevalence of metabolic syndrome in chemotherapy-treated testicular cancer survivors

PURPOSE Chemotherapy-treated testicular cancer survivors are at risk for development of the metabolic syndrome, especially in case of decreased androgen levels. Polymorphisms in the gene encoding steroid 5-α-reductase type II (SRD5A2) are involved in altered androgen metabolism. We investigated whether single-nucleotide polymorphisms (SNPs) rs523349 (V89L) and rs9282858 (A49T) in SRD5A2 are associated with cardiometabolic status in testicular cancer survivors. METHODS In 173 chemotherapy-treated testicular cancer survivors, hormone levels and cardiometabolic status were evaluated cross-sectionally (median 5 years [range 3-20] after chemotherapy) and correlated with SNPs in SRD5A2. RESULTS The metabolic syndrome was more prevalent in survivors who were homozygous or heterozygous variant for SRD5A2 rs523349 compared to wild type (33% versus 19%, P = 0.032). In particular, patients with lower testosterone levels (<15 nmol/l) and a variant genotype showed a high prevalence of the metabolic syndrome (66.7%). Mean intima-media thickness of the carotid artery and urinary albumin excretion, both markers of vascular damage, were higher in the group of survivors homozygous or heterozygous variant for rs523349 (0.62 versus 0.57 mm, P = 0.026; 5.6 versus 3.1 mg/24 h, P = 0.017, respectively). No association was found between cardiometabolic status and SNP rs9282858 in SRD5A2. CONCLUSION Metabolic syndrome develops more frequently in testicular cancer survivors homozygous or heterozygous variant for SNP rs523349 in SRD5A2. Altered androgen sensitivity appears to be involved in the development of adverse metabolic and vascular changes in testicular cancer survivors and is a target for intervention.

Gedeelde zorg voor de late effecten

Overlevenden van kanker vormen een groeiende groep mensen in de bevolking en dus ook in de huisartsenpraktijk. Dit komt onder andere door een toename van het aantal patienten met kanker in een vergrijzende bevolking, en door vroegtijdige opsporing en betere en agressievere behandelingen. De ziekte en vooral ook de behandeling kunnen echter een aanzienlijke negatieve invloed hebben op het leven van de ‘genezen’ patient. In de afgelopen jaren is hier meer aandacht voor gekomen.

Late gevolgen van kankerbehandeling: gedeelde zorg

SamenvattingNuver J, Boer H, Bunskoek S, Siesling S, Berendsen AJ, Gietema JA. Late gevolgen van kankerbehandeling: gedeelde zorg. Huisarts Wet 2013;56(7):342-5. Veel nadelige effecten van behandelingen van kanker treden pas na jaren op. Voorbeelden zijn cardiotoxiciteit, metabool syndroom en osteoporose. Deze late effecten kunnen soms gunstig worden beïnvloed of worden voorkomen, als ze tijdig worden opgespoord. Patiënt en huisarts dienen betrokken te worden bij de zorg om deze potentiële late toxiciteit, door het ontwikkelen van een duidelijk nazorgplan voor elke overlever, waarin patiënt, huisarts en oncoloog ieder een eigen rol hebben. De huisarts is een belangrijke en logische speler in deze zogeheten shared care, gezien zijn generalistische achtergrond en zijn kennis van multimorbiditeit. Voor het slagen van shared care zijn wel betere richtlijnen nodig en is meer onderzoek vereist naar nut en frequentie van screening op de diverse late effecten.AbstractNuver J, Boer H, Bunskoek S, Siesling S, Berendsen AJ, Gietema JA. Late effects of cancer treatment: shared care. Huisarts Wet 2013;56(7):342-5. Many adverse effects of cancer treatment develop years after treatment completion. Late effects such as cardiotoxicity, metabolic syndrome, and osteoporosis can sometimes be prevented or reduced if they are detected early. This makes it important to continue to monitor patients after they have been discharged from secondary care. Shared care means that patients, general practitioners, and oncologists are jointly involved in the management of these late effects. To this end, a personalized care plan should be prepared that clearly describes each person’s role and which provides recommendations for screening and, if necessary, interventions. It would seem logical that general practitioners have a pivotal role in this because of their broad background and experience with multimorbidity and chronic illnesses. A precondition for successful shared care is the availability of better and more consistent aftercare protocols for various types of cancer treatment and better scientific support for the relevance of screening for late effects.