Cisplatin-based Chemotherapy For Testicular Cancer Research Articles

CEREBRAL VENOUS SINUS THROMBOSIS IN PATIENTS WITH METASTATIC TESTICULAR CANCER DURING CHEMOTHERAPY: REPORTS OF TWO CASES

Cerebral venous sinus thrombosis (CVT) is rare but sometimes develops in association with malignant neoplasm. We report two cases of CVT that occurred during cisplatin-based chemotherapy for testicular cancer. A 46-year-old man with stage IIA non-seminomatous germ cell tumour was treated with conventional doses of etoposide and cisplatin (EP). On day 11 of the third treatment course, he developed a systemic seizure. Brain computed tomography (CT) and magnetic resonance (MR) imaging could not detect the cause. Enhanced chest-pelvic CT revealed pelvic thrombosis. Administration of phenytoin for epilepsy of unknown cause and heparin for thrombosis was started. He had completed 4 courses of EP therapy without seizure recurrence. After re-evaluating the brain CT images retrospectively, we found high density of superior sagittal sinus (SSS) and strongly suspected CVT. Another patient was a 47-year-old man with stage IIIB seminomatous germ cell tumour treated with bleomycin, etoposide, and cisplatin (BEP) therapy. On day 11 of the second treatment course, he developed a systemic seizure. Brain CT revealed subarachnoid haemorrhage localised in the right parietal lobe. CT venography revealed a filling defect in the superior sagittal sinus (SSS). MR venography revealed a SSS stenosis. We diagnosed the cause of the seizure as CVT and started administration of anticoagulant therapy. After the thrombus had diminished, chemotherapy was restarted and another 2 courses of BEP therapy was completed.

Thromboembolic events after high-intensity training during cisplatin-based chemotherapy for testicular cancer.

4551 Background: Physical activity (PA) is believed to reduce acute side-effects as deconditioning, fatigue and nausea during chemotherapy and enhance post-treatment physical and psychosocial recovery. The national multicenter randomized TAST-trial (clinicaltrial.gov: NCT02577172) aimed to determine the effect of high-intensity training (HIT) during chemotherapy for testicular cancer (TC) on acute and post-treatment physical- and psychosocial outcomes. Methods: Patients aged 18 – 60 years with newly diagnosed metastatic TC, planned for 3 or 4 cisplatin-based chemotherapy cycles in combination with etoposide (EP) or etoposide plus bleomycin (BEP), were randomized to HIT during 9 or 12 weeks of chemotherapy or to one lifestyle counseling session (LCS) during first cycle. The HIT included two supervised endurance interval sessions per week, of which 10-15 minutes per session at 85 – 95 % of peak heart rate. The intensity, duration and number of the intervals were predetermined, but adjusted in accordance to the patients’ daily condition. Thromboembolic (TE) complications were registered consecutively. Results: Among the first 9 patients randomized to HIT, 33% (3 patients aged 22, 30 and 44 years) developed severe TE complications; 2 cases of pulmonary embolism (respectively at day 9 and 7 of BEP cycle 2) and 1 myocardial infarction (at day 7 of BEP cycle 3). Common for these patients were non-seminoma TC, clinical stage IIA, good prognosis group and no known risk factors for TE events. TE complications were not observed among the 10 patients randomized to the LCS. Conclusions: Since TC patients within good prognosis group are expected to have about 5 % risk of TE complications during or shortly after cisplatin-based chemotherapy, we cannot exclude that the HIT may have contributed to the unexpected high number of TE events. Until possible mechanisms explaining our observations have been explored, we discourage high-intensity endurance training during cisplatin-based chemotherapy for TC. These observations led to closure of the TAST-trial after inclusion of 19 of 94 planned patients. Clinical trial information: NCT02577172.

High risk vascular fingerprint in patients treated with cisplatin-based chemotherapy for testicular cancer.

e15556 Background: Metastatic TC (mTC) can be cured with cisplatin-based chemotherapy (CT). This comes at the price of increased risk for premature cardiovascular disease (CVD). We investigated ris...

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.

Longitudinal changes in cardiac function after cisplatin-based chemotherapy for testicular cancer

BackgroundCross-sectional studies showed that treatment with cisplatin chemotherapy for testicular cancer is associated with an increased incidence of cardiac dysfunction. We investigated longitudinal progression of and contributing factors to cardiac dysfunction in testicular cancer survivors. Patients and methodsCardiac assessments were carried out before 10 months (range 7–15 months) and 6.9 years (range 4.9–9.7 years) after start of cisplatin-based chemotherapy, consisting of echocardiography [systolic function (left ventricular ejection fraction, LVEF), diastolic function (myocardial tissue velocities; tissue velocity imaging of early diastole, TVI Et)] and plasma biomarkers (N-Terminal pro brain natriuretic peptide, NT-proBNP; galectin-3). ResultsIn 37 patients [median age 34 years (range 24–51 years)], the incidence of abnormal TVI Et increased from 0% at baseline and 4.5% at 10 months (in 27 patients) to 16.7% at 6.9 years post-chemotherapy (P = 0.03). One patient developed LVEF <50%; no other systolic abnormalities occurred. Hypertension, obesity and age were associated with larger decreases in TVI Et. Changes in NT-proBNP and galectin-3 were not related to echocardiographic abnormalities. ConclusionsIn this longitudinal cohort study, we observed a gradual decline in diastolic parameters after cisplatin-based chemotherapy for testicular cancer, whereas the rate of systolic dysfunction remains low. The association of larger declines in diastolic parameters with hypertension and obesity stresses the need to monitor and treat cardiovascular risk factors.

Changes in circulating endothelial cells (CECs) during treatment with cisplatin-based chemotherapy for testicular cancer

e16009 Background: Chemotherapy (CT)-induced endothelial damage is an important pathogenic factor for cardiovascular morbidity in testicular cancer (TC) patients (pts). Therefore, we studied early markers of endothelial damage as predictors of cancer treatment-related cardiovascular morbidity. Methods: We prospectively assessed markers of endothelial damage in TC pts treated at the University Medical Center Groningen, before, during, 4 weeks and one year after completion of standard CT (3 or 4 three weekly cycles with bleomycin, etoposide and cisplatin). The number of circulating endothelial cells (CECs), identified by CD146+, CD105+ and CD45− using the CellSearch system, and plasma levels of von Willebrand Factor (vWF) were measured. Results: 30 TC pts were included (median age 34 years, range 20–47). Before start of CT, CECs were not associated with disease stage or leukocyte count. The number of CECs progressively increased over the 9–12 week CT period [baseline: median (range) 25/mL (6–137); maximum number during CT: 134/mL (28–320; p&lt;0.001); 4 weeks after completion of CT: 66/mL (18–316; p=0.005)]. One year post treatment, CECs were not different from baseline [N= 10; 13/mL (6–31; p=0.263)]. vWF levels also progressively increased during CT [baseline: median 105% (range 50–377); maximum level during CT: 289% (175–464; p&lt;0.001); 4 weeks after completion of CT: vWF 124% (56–274; p=0.149)]. One year after CT, vWF levels were 115% (61–184; p=0.285). During CT, numbers of CECs and vWF levels correlated positively (r=0.283; p&lt;0.001), whereas maximum CECs increase and maximum vWF increase were not associated (r=0.098; p=0.605). Two pts had a cerebral infarction during CT. In one pt, vWF increased before the event; in both pts CECs increased directly afterwards. Conclusions: During CT for disseminated TC, CECs and vWF progressively increased during consecutive cycles. CECs remained increased 4 wks after completion of CT, whereas vWF returned to baseline levels. The magnitude of changes was not equal in every pt. Therefore, both CECs and vWF might be early predictive markers for chemotherapy-induced cardiovascular toxicity, and may serve as intermediate endpoint in intervention studies. [Table: see text]

Disturbed diastolic cardiac function one year after cisplatin-based chemotherapy for testicular cancer

5088 Background: Chemotherapy-induced cardiovascular effects are increasingly observed in testicular cancer (TC) survivors. Early signs of cardiovascular damage after cisplatin-based treatment are important to estimate subclinical cardiac dysfunction. We prospectively investigated changes in cardiac function within the first year after chemotherapy for disseminated TC. Methods: In TC patients (pts) treated at the University Medical Center Groningen we performed echocardiography before start of Bleomycin, Etoposide and Cisplatin chemotherapy and one year later. Systolic left ventricular function was estimated by Wall Motion Score Index (WMSI, normal =1.00); diastolic function by Tissue Velocity Index (TVI, available in 19 pts) and E/A ratio. Diastolic dysfunction was defined as TVI <8cm/s and/or E/A-ratio <1. Concomitantly cardiovascular risk factors (CRF) were assessed, including 24-hour ambulatory blood pressure (BP). Results: 42 TC pts (median age 28 years, range 18–50) were assessed pre- and post treatment. The median interval was 10 months (range 6–15). Diastolic dysfunction was present in 9 pts pre-treatment (E/A-ratio <1 n=7, TVI <8 n=1, both n=1), CRF in these 9 pts consisted of obesity (n=5) and hypertension (n=3). One year later pre-treatment diastolic dysfunction persisted in 5 pts, new dysfunction developed in 2 pts (E/A-ratio <1 n=4, TVI <8 n=2, both n=1). CRF in these 7 pts were hypercholesterolemia (n=2) and obesity (n=1). Compared with pre-treatment the median E/A ratio did not change (1.38 ± 0.46 Vs 1.35 ± 0.037; p=0.259), whereas median TVI decreased after treatment (12.0 ± 3.2 Vs 10.4 ± 2.9 cm/s; p=0.002). The median WMSI did not change (1.00 ± 0.04 Vs 1.00 ± 0.12; p=0.273). BP did not change (systolic 130 ± 11.6 Vs 122 ± 10.8; p=0.082; diastolic 74 ± 9.6 Vs 68 ± 11.4; p=0.140). Systolic BP and age correlated with TVI pre- and post treatment. Conclusions: One year after cisplatin-based treatment, TC-survivors have a significant decrease in TVI, suggesting an impaired diastolic function of the heart. Systolic parameters and BP did not change. The prognostic significance of this disturbed diastolic function 1 year after chemotherapy for future cardiovascular morbidity is not clear yet. No significant financial relationships to disclose.

Palonosetron plus dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving multiple-day cisplatin chemotherapy for germ cell cancer

The aims of this study were to assess the safety and antiemetic efficacy of multiple-day dosing of palonosetron plus dexamethasone in patients receiving highly emetogenic multiple-day cisplatin-based chemotherapy for germ cell tumors. Forty-one men undergoing 5-day cisplatin-based chemotherapy for testicular cancer received palonosetron 0.25 mg IV once daily 30 min before chemotherapy on days 1, 3, and 5 plus IV dexamethasone 20 mg before chemotherapy on days 1 and 2, and 8 mg PO bid on days 6 and 7 and 4 mg bid on day 8. Safety and efficacy were assessed in 24-h intervals for 9 days. Efficacy endpoints included emesis, intensity of nausea and its interference with patient functioning, and rescue antiemetic use. A subset of patients (n = 11) was studied for electrocardiograph effects and pharmacokinetic evaluation. This multiple-day antiemetic regimen was safe, with headache and constipation the most common treatment-related adverse events, mostly mild. Neither adverse events nor electrocardiographic changes appeared to increase in frequency, duration, or intensity over time despite a 1.42-fold systemic accumulation of palonosetron with repeated doses. The majority of patients had no emesis at any time throughout days 1-5 (51%) or days 6-9 (83%), had no moderate-to-severe nausea, and did not require rescue medication. Most patients reported that nausea had no significant effect on daily functioning on days 1-4 (72%) and days 5-9 (85%). Palonosetron on days 1, 3, and 5, along with a regimen of dexamethasone, was safe and well tolerated and effectively controlled both nausea and emesis in patients undergoing 5-day cisplatin-based chemotherapy for testicular cancer.

Spermatogenesis After Cancer Treatment: Damage and Recovery

Treatment with cytotoxic chemotherapy and radiotherapy is associated with significant gonadal damage in men, and alkylating agents are the most common agents implicated. The vast majority of men receiving procarbazine-containing regimens for the treatment of lymphomas are rendered permanently infertile, whereas treatment with doxorubicin hydrochloride (Adriamycin), bleomycin, vinblastine, and dacarbazine appears to have a significant advantage, with a return to normal fertility in the vast majority of patients. Cisplatin-based chemotherapy for testicular cancer results in temporary azoospermia in most men, with a recovery of spermatogenesis in about 50% of the patients after 2 years and 80% after 5 years. The germinal epithelium is very sensitive to radiation-induced damage, with changes to spermatogonia following as little as 0.2 Gy. Testicular doses of less than 0.2 Gy had no significant effect on FSH levels or sperm counts, whereas doses between 0.2 and 0.7 Gy caused a transient dose-dependent increase in FSH and reduction in sperm concentration, with a return to normal values within 12-24 months. No radiation dose threshold has been defined above which permanent azoospermia is inevitable; however, doses of 1.2 Gy and above are likely to be associated with a reduced risk of recovery of spermatogenesis; the time to recovery, if it is to occur, is also likely to be dose dependent.

Effect of cancer therapy on pituitary-testicular axis.

Treatment with cytotoxic chemotherapy and radiotherapy is associated with significant gonadal damage in men. Alkylating agents, such as cyclophosphamide and procarbazine, are the most common agents implicated. The vast majority of men receiving procarbazine-containing regimens for the treatment of lymphomas are rendered permanently infertile. Treatment with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) appears to have a significant advantage in terms of testicular function, with a return to normal fertility in the vast majority of patients. Cisplatin-based chemotherapy for testicular cancer results in temporary azoospermia in most men with a recovery of spermatogenesis in about 50% after 2 years and 80% after 5 years. There is also evidence of chemotherapy-induced Leydig cell impairment in a proportion of these men, although this appears to be of no clinical significance in the majority of patients. The germinal epithelium is very sensitive to radiation-induced damage with changes to spermatogonia following as little as 0.1 Gy, and permanent infertility after fractionated doses of 2 Gy and above, whereas clinically significant Leydig cell impairment occurs rarely with doses of less than 20 Gy.

GONADAL DAMAGE FROM CHEMOTHERAPY AND RADIOTHERAPY

Treatment with cytotoxic chemotherapy and radiotherapy is associated with significant gonadal damage in men and women. Alkylating agents such as cyclophosphamide and procarbazine are the most common agents implicated. The vast majority of men receiving procarbazine-containing regimens for the treatment of lymphomas become permanently infertile. Cisplatin-based chemotherapy for testicular cancer results in temporary azoospermia in most men, with a recovery of spermatogenesis in about 50% after 2 years and in 80% after 5 years. There is also evidence of Leydig cell impairment in a proportion of these men, although the clinical significance of this is not clear. The germinal epithelium is very sensitive to radiation-induced damage, with changes to spermatogonia occurring following as little as 0.1 Gy and permanent infertility after fractionated doses of 2 Gy and above. Cytotoxic-induced premature ovarian failure is age- and drug-dependent and ensues in approximately half of women treated with procarbazine-containing chemotherapy for lymphomas. High-dose chemotherapy, total body irradiation, and irradiation at an ovarian dose above 6 Gy usually result in permanent ovarian failure. The course of ovarian function after chemotherapy is variable, and late recovery occurs in some patients. Several methods of preserving gonadal function during potentially sterilizing treatment have been considered. Currently, sperm banking remains the only proven method in men, although hormonal manipulation to enhance the recovery of spermatogenesis and cryopreservation of testicular germ cells are possibilities for the future. Transposition of the ovaries to allow better shielding during radiotherapy is of use in some women, and the prospect of cryopreservation and reimplantation of ovarian tissue is promising.

Secondary Raynaud's phenomenon and other late vascular complications following chemotherapy for testicular cancer

182 patients treated with cisplatin-based chemotherapy for testicular cancer at Hannover University Medical School who were in complete remission (CR) for more than 1 year after therapy were randomly selected for the evaluation of late vascular toxicity. 90 patients with a mean age of 28 years (19-53) and a median follow-up of 57.9 months (15-159) participated in this examination. Patients were examined clinically and digital photoelectric pulse plethysmography (PP) and Doppler-flow of the digital arteries after cold exposure were performed. Thirty seven per cent of patients developed symptoms of Raynaud's phenomenon (RP) after chemotherapy, which were transient in 7%. PP proved to be highly diagnostic for RP with a sensitivity of 95% and a specificity of 100%. As significant risk factors for the development of RP, the cumulative dose of bleomycin (P < 0.05) and the use of bleomycin in combination with vinblastine (PVB-regimen) instead of etoposide (PEB-regimen) (P < 0.01) were found. A trend for an increased frequency of RP was observed in patients who received bleomycin as a bolus instead of continuous infusion. No significant correlation was seen with the cumulative or single doses of cisplatin, etoposide or vinblastine, serum magnesium levels during or after chemotherapy or a history of smoking. RP was not associated with the occurrence of neuro- or ototoxicity. All 7 patients with hypertensive blood pressure before chemotherapy developed RP. Furthermore, the median postchemotherapy diastolic blood pressure had increased by 8 mmHg compared to prechemotherapy values, leading to significant hypertension in 8 patients (> 20 mmHg increase). 2 patients developed major vascular events with myocardial infarctions at 4 years and 5 years after chemotherapy, respectively. No cerebral infarction was registered. In summary, RP is the main late vascular toxicity affecting one third of patients after curative chemotherapy for testicular cancer. However, the incidence of RP following PEB-therapy in contrast to PVB-therapy appears to be lower. Major vascular events seem to be rare. The prospective evaluation of late toxicity should be part of current chemotherapy treatment for testicular cancer, and long-term follow-up of surviving patients is recommended.

Osteogenic sarcoma: MR signal abnormalities of the brain in asymptomatic patients treated with high-dose methotrexate.

The advent of lesions with high signal intensity in periventricular white matter was incidentally observed on T2-weighted images in one patient who underwent magnetic resonance (MR) imaging of the brain after administration of high-dose methotrexate (HDMTX) for osteogenic sarcoma. Twenty-one additional symptom-free patients who had been treated with the same regimen and 10 patients who had undergone cisplatin-based chemotherapy for testicular cancer also underwent examination. Fourteen of the patients with osteosarcoma showed high-signal-intensity lesions in white matter on T2-weighted images. The interval between the last course of chemotherapy and MR imaging was a factor in this finding, as 12 of 14 patients who underwent examination within 2 years after chemotherapy had a positive finding, as opposed to two of eight patients who underwent examination later. The patients with testicular cancer had normal MR images. The occurrence of MR imaging abnormalities in asymptomatic patients treated with HDMTX for osteogenic sarcoma may be subclinical evidence of treatment-related central nervous system toxicity.