Carl W. Langberg

Cardiovascular Risk Factors and Morbidity in Long-Term Survivors of Testicular Cancer: A 20-Year Follow-Up Study

PURPOSE To evaluate the prevalence of cardiovascular risk factors and long-term incidence of cardiovascular disease (CVD) in survivors of testicular cancer (TC). METHODS Overall, 990 men treated for unilateral TC (1980 to 1994) were included in this national follow-up study (2007 to 2008). They were categorized into four treatment groups: surgery (n = 206), radiotherapy only (RT; n = 386), chemotherapy only (n = 364), and combined RT/chemotherapy (n = 34). Age-matched male controls from the general population (ie, NORMs) were included (n = 990). Survivors of TC who were diagnosed with CVD before or within 2 years after the TC diagnosis were excluded from analyses of CVD end points. RESULTS Median observation time was 19 years (range, 13 to 28 years). All cytotoxic treatment groups had significantly increased prevalences of antihypertensive medication, and survivors in the RT and RT/chemotherapy groups had higher prevalences of diabetes (RT: odds ratio [OR], 2.3; 95% CI, 1.5 to 3.7; RT/chemotherapy: OR, 3.9; 95% CI, 1.4 to 10.9) compared with NORMs. Overall 74 survivors of TC (8.0%) experienced atherosclerotic disease during follow-up. Increased risks for atherosclerotic disease were observed in age-adjusted Cox regression analyses after any cytotoxic treatment when compared with surgery only (RT: hazard ratio [HR], 2.3; 95% CI, 1.04 to 5.3; chemotherapy: HR, 2.6; 95% CI, 1.1 to 5.9; RT/chemotherapy: HR, 4.8; 95% CI, 1.6 to 14.4). Treatment with cisplatin, bleomycin, and etoposide (BEP) alone had a 5.7-fold higher risk (95% CI, 1.9 to 17.1 fold) for coronary artery disease compared with surgery only and a 3.1-fold higher risk (95% CI, 1.2 to 7.7 fold) for myocardial infarction compared with NORMs. CONCLUSION Treatment with infradiaphragmatic RT and/or cisplatin-based chemotherapy, particularly the BEP regimen, increases the long-term risk for CVD in survivors of TC.

Risk-Adapted Treatment in Clinical Stage I Nonseminomatous Germ Cell Testicular Cancer: The SWENOTECA Management Program

PURPOSE To offer minimized risk-adapted adjuvant treatment on a nationwide basis for patients with clinical stage 1 (CS1) nonseminomatous germ-cell testicular cancer (NSGCT). The aim was to reduce the risk of relapse and thereby reducing the need of later salvage chemotherapy while maintaining a high cure rate. PATIENTS AND METHODS From 1998 to 2005, 745 Norwegian and Swedish patients were included into a prospective, community-based multicenter Swedish and Norwegian Testicular Cancer Project (SWENOTECA) management program. Treatment strategy depended on the presence or absence of vascular tumor invasion (VASC). VASC-positive patients were recommended brief adjuvant chemotherapy (ACT) with bleomycin, etoposide, and cisplatin (BEP), whereas VASC-negative patients could choose between ACT and surveillance. RESULTS At a median follow-up of 4.7 years, there have been 51 relapses. On surveillance, 41.7% of VASC+ patients relapsed, compared with 13.2% of VASC- patients. After one course of BEP, 3.2% of VASC+ and 1.3% of VASC- patients relapsed. The toxicity of adjuvant BEP was low. Eight patients have died, none died from progressive disease. CONCLUSION One course of adjuvant BEP reduces the risk of relapse by approximately 90% in both VASC+ and VASC- CS1 NSGCT, and may be a new option as initial treatment for all CS1 NSGCT. One course of adjuvant BEP for VASC+ CS1 reduces the total burden of chemotherapy compared with surveillance or two courses of BEP. SWENOTECA currently recommends one course of BEP as standard treatment of VASC+ CS1 NSGCT, whereas both surveillance and one course of BEP are options for VASC- CS1 NSGCT.

Management of Seminomatous Testicular Cancer: A Binational Prospective Population-Based Study From the Swedish Norwegian Testicular Cancer Study Group

PURPOSE A binational, population-based treatment protocol was established to prospectively treat and follow patients with seminomatous testicular cancer. The aim was to standardize care for all patients with seminoma to further improve the good results expected for this disease. PATIENTS AND METHODS From 2000 to 2006, a total of 1,384 Norwegian and Swedish patients were included in the study. Treatment in clinical stage 1 (CS1) was surveillance, adjuvant radiotherapy, or adjuvant carboplatin. In metastatic disease, recommended treatment was radiotherapy in CS2A and cisplatin-based chemotherapy in CS2B or higher. RESULTS At a median follow-up of 5.2 years, 5-year cause-specific survival was 99.6%. In CS1, 14.3% (65 of 512) of patients relapsed following surveillance, 3.9% (seven of 188) after carboplatin, and 0.8% (four of 481) after radiotherapy. We could not identify any factors predicting relapse in CS1 patients who were subjected to surveillance only. In CS2A, 10.9% (three of 29) patients relapsed after radiotherapy compared with no relapses in CS2A/B patients (zero of 73) treated with chemotherapy (P = .011). CONCLUSION An international, population-based treatment protocol for testicular seminoma is feasible with excellent results. Surveillance remains a good option for CS1 patients. No factors predicted relapse in CS1 patients on surveillance. Despite resulting in a lower rate of relapse than with adjuvant carboplatin, adjuvant radiotherapy has been abandoned in the Swedish and Norwegian Testicular Cancer Project (SWENOTECA) as a recommended treatment option because of concerns of induction of secondary cancers. The higher number of relapses in radiotherapy-treated CS2A patients when compared with chemotherapy-treated CS2A/B patients is of concern. Late toxicity of cisplatin-based chemotherapy versus radiotherapy must be considered in CS2A patients.

Quantitative Apparent Diffusion Coefficients in the Characterization of Brain Tumors and Associated Peritumoral Edema

Background: Conventional magnetic resonance (MR) imaging has a number of limitations in the diagnosis of the most common intracranial brain tumors, including tumor specification and the detection of tumoral infiltration in regions of peritumoral edema. Purpose: To prospectively assess if diffusion-weighted MR imaging (DWI) could be used to differentiate between different types of brain tumors and to distinguish between peritumoral infiltration in high-grade gliomas, lymphomas, and pure vasogenic edema in metastases and meningiomas. Material and Methods: MR imaging and DWI was performed on 93 patients with newly diagnosed brain tumors: 59 patients had histologically verified high-grade gliomas (37 glioblastomas multiforme, 22 anaplastic astrocytomas), 23 patients had metastatic brain tumors, five patients had primary cerebral lymphomas, and six patients had meningiomas. Apparent diffusion coefficient (ADC) values of tumor (enhancing regions or the solid portion of tumor) and peritumoral edema, and ADC ratios (ADC of tumor or peritumoral edema to ADC of contralateral white matter, ADC of tumor to ADC of peritumoral edema) were compared with the histologic diagnosis. ADC values and ratios of high-grade gliomas, primary cerebral lymphomas, metastases, and meningiomas were compared by using ANOVA and multiple comparisons. Optimal thresholds of ADC values and ADC ratios for distinguishing high-grade gliomas from metastases were determined by receiver operating characteristic (ROC) curve analysis. Results: Statistically significant differences were found for minimum and mean of ADC tumor and ADC tumor ratio values between metastases and high-grade gliomas when including only one factor at a time. Including a combination of in total four parameters (mean ADC tumor, and minimum, maximum and mean ADC tumor ratio) resulted in sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of 72.9, 82.6, 91.5, and 54.3% respectively. In the ROC curve analysis, the area under the curve of the combined four parameters was the largest (0.84), indicating a good test. Conclusion: Our results suggest that ADC values and ADC ratios (minimum and mean of ADC tumor and ADC tumor ratio) may be helpful in the differentiation of metastases from high-grade gliomas. It cannot distinguish high-grade gliomas from lymphomas, and lymphomas from metastases. ADC values and ADC ratios in peritumoral edema cannot be used to differentiate edema with infiltration of tumor cells from vasogenic edema when measurements for high-grade gliomas, lymphomas, metastases, and meningiomas were compared.

Proton magnetic resonance spectroscopy in the distinction of high-grade cerebral gliomas from single metastatic brain tumors.

Background: Brain metastases and primary high-grade gliomas, including glioblastomas multiforme (GBM) and anaplastic astrocytomas (AA), may be indistinguishable by conventional magnetic resonance (MR) imaging. Identification of these tumors may have therapeutic consequences. Purpose: To assess the value of MR spectroscopy (MRS) using short and intermediate echo time (TE) in differentiating solitary brain metastases and high-grade gliomas on the basis of differences in metabolite ratios in the intratumoral and peritumoral region. Material and Methods: We performed MR imaging and MRS in 73 patients with histologically verified intraaxial brain tumors: 53 patients with high-grade gliomas (34 GBM and 19 AA) and 20 patients with metastatic brain tumors. The metabolite ratios of Cho/Cr, Cho/NAA, and NAA/Cr at intermediate TE and the presence of lipids at short TE were assessed from spectral maps in the tumoral core, peritumoral edema, and contralateral normal-appearing white matter. The differences in the metabolite ratios between high-grade gliomas/GBM/AA and metastases were analyzed statistically. Cutoff values of Cho/Cr, Cho/NAA, and NAA/Cr ratios in the peritumoral edema, as well as Cho/Cr and NAA/Cr ratios in the tumoral core for distinguishing high-grade gliomas/GBM/AA from metastases were determined by receiver operating characteristic (ROC) curve analysis. Results: Significant differences were noted in the peritumoral Cho/Cr, Cho/NAA, and NAA/ Cr ratios between high-grade gliomas/GBM/AA and metastases. ROC analysis demonstrated a cutoff value of 1.24 for peritumoral Cho/Cr ratio to provide sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of 100%, 88.9%, 80.0%, and 100%, respectively, for discrimination between high-grade gliomas and metastases. By using a cutoff value of 1.11 for peritumoral Cho/NAA ratio, the sensitivity was 100%, the specificity was 91.1%, the PPV was 83.3%, and the NPV was 100%. Conclusion: The results of this study demonstrate that MRS can differentiate high-grade gliomas from metastases, especially with peritumoral measurements, supporting the hypothesis that MRS can detect infiltration of tumor cells in the peritumoral edema.

Relationship Between Intestinal Fibrosis and Histopathologic and Morphometric Changes in Consequential and Late Radiation Enteropathy

Intestinal fibrosis is a marked feature of late radiation enteropathy. This study assessed the time dose fractionation relationships of radiation-induced fibrosis in order to elucidate possible pathogenetic mechanisms. In 290 male Sprague-Dawley rats, a loop of small bowel was transposed to the left side of the scrotum. Three weeks later, the transposed segment was irradiated with either single dose or various fractionated regimens. The animals were observed for radiation-induced intestinal complications and killed in groups, 2 and 26 weeks after completion of irradiation. A semiquantitative histopathologic radiation injury score, morphometry of the submucosa, submucosal arterioles, intestinal surface area, and relative collagen content were used as endpoints. Fibrosis, measured by collagen assay and radiation injury score, increased with total dose, increasing fraction size and reduction in overall treatment time. This paralleled the results of morphometric assessment of mucosal surface area. Differences in vascular morphometry were only statistically significant in response to changes in total dose and fraction size and not with changes in overall treatment time. We conclude that fibrosis increases with increasing observation time, increasing fraction size, increasing total dose, and reduction of interfraction interval. Consequential injury, occurring as a result of disruption of mucosal integrity, seems to be an important mechanism for development of intestinal fibrosis. In contrast, vascular injury is relatively independent of this mechanism.

TOLERANCE OF RAT SMALL INTESTINE TO LOCALIZED SINGLE DOSE AND FRACTIONATED IRRADIATION

The tolerance of rat small intestine to localized single-dose and fractionated irradiation was assessed. In 168 rats, bilateral orchiectomy was performed and a loop of small intestine was transposed to the left part of the scrotum. Beginning 3 weeks postoperatively, single dose (18-24 Gy) or fractionated (4.2 Gy or 5.6 Gy per fraction) x-irradiation was delivered to the transposed intestine. The animals were observed for complications, and groups of animals were killed 2 and 26 weeks after completion of irradiation for assessment of injury. Mortality (i.e. the occurrence of lethal intestinal complications) and a semiquantitative histopathologic scoring system were used as endpoints to assess the degree of radiation injury. The most frequent intestinal complications were enterocutaneous fistula formation and intestinal obstruction. Logistic regression analysis ov complications data was used to estimate LD50 values and the alpha/beta ratio. There was good correlation between histopathologic scores and the incidence of lethal complications. The estimated LD50 values were 22.1 +/- 0.5 Gy, 37.0 +/- 4.4 Gy and 51.0 +/- 5.3 Gy for the single dose regimen and the fractionated regimens of 5.6 Gy and 4.2 Gy respectively. The estimated alpha/beta ratio was 10.7 +/- 2.4 Gy. The goodness of fit of the linear-quadratic isoeffect model to our data was satisfactory. Our results indicate that acute mucosal damage may be pathogenetically involved in the development of intestinal complications.

One course of adjuvant BEP in clinical stage I nonseminoma mature and expanded results from the SWENOTECA group

BACKGROUND SWENOTECA has since 1998 offered patients with clinical stage I (CS I) nonseminoma, adjuvant chemotherapy with one course of bleomycin, etoposide and cisplatin (BEP). The aim has been to reduce the risk of relapse, sparing patients the need of toxic salvage treatment. Initial results on 312 patients treated with one course of adjuvant BEP, with a median follow-up of 4.5 years, have been previously published. We now report mature and expanded results. PATIENTS AND METHODS In a prospective, binational, population-based risk-adapted treatment protocol, 517 Norwegian and Swedish patients with CS I nonseminoma received one course of adjuvant BEP. Patients with lymphovascular invasion (LVI) in the primary testicular tumor were recommended one course of adjuvant BEP. Patients without LVI could choose between surveillance and one course of adjuvant BEP. Data for patients receiving one course of BEP are presented in this study. RESULTS At a median follow-up of 7.9 years, 12 relapses have occurred, all with IGCCC good prognosis. The latest relapse occurred 3.3 years after adjuvant treatment. The relapse rate at 5 years was 3.2% for patients with LVI and 1.6% for patients without LVI. Five-year cause-specific survival was 100%. CONCLUSIONS The updated and expanded results confirm a low relapse rate following one course of adjuvant BEP in CS I nonseminoma. One course of adjuvant BEP should be considered a standard treatment in CS I nonseminoma with LVI. For patients with CS I nonseminoma without LVI, one course of adjuvant BEP is also a treatment option.

Population-Based Study of Treatment Guided by Tumor Marker Decline in Patients With Metastatic Nonseminomatous Germ Cell Tumor: A Report From the Swedish-Norwegian Testicular Cancer Group

PURPOSE From 1995 to 2003, 603 adult patients from Sweden and Norway with metastatic testicular nonseminomatous germ cell tumor (NSGCT) were included prospectively in a population-based protocol with strict guidelines for staging, treatment, and follow-up. Patients with extragonadal primary tumor or previous treatment for contralateral testicular tumor were excluded. The basic strategy was to individualize treatment according to initial tumor marker response. METHODS Initial treatment for all patients was two courses of standard bleomycin, etoposide, and cisplatin (BEP), with tumor markers analyzed weekly. Good response was defined as a half-life (t(1/2)) for α-fetoprotein (AFP) of ≤ 7 days and/or for β-human chorionic gonadotropin (β-HCG) of ≤ 3 days. Patients with prolonged marker t(1/2) (ie, poor response) received intensification with addition of ifosfamide (BEP-if/PEI) in step 1. If poor response continued, the treatment was intensified with high-dose chemotherapy with stem-cell rescue as step 2. RESULTS Overall, 99% of all patients with metastatic testicular NSGCT in the population were included in the protocol. Median follow-up was 8.2 years. Seventy-seven percent of the patients were treated with BEP alone; 18% received intensification step 1%, and 5% received intensification step 2. Grouped according to International Germ Cell Consensus Classification, 10-year overall survival was 94.7% in good-prognosis patients, 90.0% in intermediate-prognosis patients, and 67.4% in poor-prognosis patients. CONCLUSION With detailed treatment protocols and a dedicated collaborative group of specialists, treatment results comparable to those reported from large single institutions can be achieved at national level. With the treatment principles used in Swedish-Norwegian Testicular Cancer Group study SWENOTECA IV, the survival of intermediate-prognosis patients is remarkable and close to that of good-prognosis patients.

Self-reported cognitive problems in testicular cancer patients: Relation to neuropsychological performance, fatigue, and psychological distress ☆

OBJECTIVE There is a concern about negative cognitive effects of systemic chemotherapy. We prospectively explored self-reported cognitive problems in testicular cancer patients (TCPs) treated with and without chemotherapy. METHODS One hundred and twenty-two TCPs were interviewed about concentration and memory problems shortly after orchidectomy but before any additional treatment (baseline), and then at a median of 1 year after end of treatment (follow-up). Symptoms of psychological distress, fatigue, and peripheral neurotoxicity were assessed by questionnaires, and patients also underwent neuropsychological testing. Self-reported cognitive problems were compared between three treatments groups: no chemotherapy, one cycle of chemotherapy, and multiple cycles of chemotherapy. Variables associated with an increase of self-reported cognitive problems from baseline to follow-up were explored. RESULTS Significantly larger proportions of TCPs in the two chemotherapy groups had an increase of self-reported cognitive problems from baseline to follow-up compared to the no-chemotherapy group. Increase of self-reported cognitive problems was significantly associated with psychological distress, fatigue, lower level of education, and Raynaud-like symptoms, but not with a decline in neuropsychological test performance. CONCLUSION In this explorative study of TCPs, an increase of self-reported cognitive problems from baseline to 1-year follow-up was associated with chemotherapy and with symptoms of fatigue and psychological distress at follow-up, while no significant association was found with a decline in neuropsychological test performance.