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Purpose: Our objective was to evaluate operating characteristics, particularly specificity and positive predictive value (PPV), by mapping plasma miR371 expression to actual clinical events in patients with a history of germ cell tumor., Patients and Methods: One hundred eleven male patients with a history of or newly diagnosed germ cell tumors were evaluable. Biospecimens obtained before confirmed clinical events were analyzed for miR371 expression with blinding of providers and laboratory personnel to analytic results or clinical status, respectively. Cases (patients with clinically confirmed active germ cell malignancy [aGCM]) and controls (patients with no clinically confirmed aGCM) were assigned over the course of the management. Patients were assigned risk status (high, low, or moderate) based on the composite clinical picture at time points in management., Results: Considering all cases and controls and results of prospectively obtained biosamples analyzed for miR371 expression, 46 (35%) of 132 samples had clinically confirmed aGCM over the course of management; 44 (96%) of these 46 patients had plasma miR371 expression (true positives) with no false positives. Two (4%) of 46 patients had no miRNA expression despite pathologic confirmation of aGCM (false negatives). Plasma miR371 expression in confirmed aGCM had a specificity, sensitivity, positive predictive value, and negative predictive value of 100%, 96%, 100%, and 98%, respectively. Interpretation of sensitivity and negative predictive value is limited by modest follow-up. Specificity and sensitivity were 100% and 98%, 100% and 92%, and 100% and 97% in the low-, moderate-, and high-risk groups, respectively, with a median follow-up time of 15 months., Conclusion: Plasma miR371 expression predicts aGCM with high specificity and positive predictive value. Although other operating characteristics of miR371 await longer follow-up for more complete definition, the findings of a highly specific liquid biopsy strongly support moving forward with large-scale, real-world clinical trials to further define full operating characteristics and to identify clinical utility and areas of patient benefit.

Purpose: Previous studies suggested that serum levels of microRNA (miR)-371a-3p (so-called M371 test) have a much higher sensitivity and specificity than the classic markers of testicular germ cell tumors (GCTs) and are applicable toward both seminoma and nonseminoma. We sought to confirm the usefulness of this test as a novel biomarker for GCT., Patients and Methods: In a prospective, multicentric study, serum samples of 616 patients with testicular GCTs and 258 male controls were examined for serum levels of miRNA-371a-3p (miR levels) by quantitative polymerase chain reaction. The GCT population encompassed 359 patients with seminoma and 257 with nonseminoma; 371 had clinical stage I disease, 201 had systemic disease, and 46 had relapses. Paired measurements before and after orchiectomy were performed in 424 patients; 118 with systemic disease had serial measurements during treatment. miR levels were compared with those of β-human chorionic gonadotropin, α-fetoprotein, and lactate dehydrogenase., Results: For the primary diagnosis of GCT, the M371 test showed a sensitivity of 90.1%, a specificity of 94.0%, an area under the curve of 0.966 upon receiver operating characteristic analysis, and a positive predictive value of 97.2%. α-Fetoprotein, β-human chorionic gonadotropin, and lactate dehydrogenase had sensitivities of less than 50% in seminoma and slightly higher sensitivities in nonseminomas. miR levels were significantly associated with clinical stage, primary tumor size, and response to treatment. Relapses had elevated miR levels that subsequently dropped to normal upon remission. Teratoma did not express miR-371a-3p., Conclusion: The M371 test outperforms the classic markers of GCT with both a sensitivity and a specificity greater than 90%. All histologic subgroups, except teratoma, express this marker. The test could be considered for clinical implementation after further validation.

Purpose: To investigate relapse detection methods among children and adolescents with nongerminomatous malignant germ cell tumors (MGCTs) and to determine whether tumor markers alone might be sufficient for surveillance., Methods: We retrospectively reviewed all patients enrolled in a phase III, single-arm trial for low-risk and intermediate-risk MGCTs. The method used to detect relapse was assessed based on case report forms, tumor markers, imaging, and pathology reports. Relapses were classified into one of two categories on the basis of whether they were (1) detectable by tumor marker elevation or (2) not detectable by tumor markers., Results: A total of 302 patients were enrolled, and 284 patients had complete data for review. Seven patients had normal tumor markers at initial diagnosis, and none experienced a relapse. At a median follow-up of 5.3 years, 48 patients (16.9%) had experienced a relapse. After central review, 47 of 48 relapses (98%) were detected by tumor marker elevation. Of the 47 patients, 16 (33.3%) had abnormal tumor markers with normal/unknown imaging, 31 patients (64.6%) had abnormal tumor markers with abnormal imaging, and one patient (2.1%) had abnormal imaging with unknown marker levels at relapse., Conclusion: Tumor marker elevation is a highly sensitive method of relapse surveillance, at least among children and adolescents with tumor marker elevation at initial diagnosis. Eliminating exposure to imaging with ionizing radiation may enhance the safety of relapse surveillance in patients treated for MGCT.

Purpose: To describe treatment results in a large cohort with stage I nonseminoma germ cell cancer (NSGCC) treated in a surveillance program., Patients and Methods: From January 1, 1984, to December 31, 2007, 1,226 patients with stage I NSGCC, including high-risk patients with vascular invasion, were observed in a surveillance program., Results: The relapse rate after orchiectomy alone was 30.6% at 5 years. Presence of vascular invasion together with embryonal carcinoma and rete testis invasion in the testicular primary identified a group with a relapse risk of 50%. Without risk factors, the relapse risk was 12%. Eighty percent of relapses were diagnosed within the first year after orchiectomy. The median time to relapse was 5 months (range, 1 to 308 months). Early relapses were mainly detected by increase in tumor markers, and late relapses were detected by computed tomography scans. Relapses after 5 years were seen in 0.5% of the whole cohort or in 1.6% of relapsing patients. The majority of relapses (94.4%) belonged to the good prognostic group according to the International Germ Cell Cancer Collaborative Group classification. The disease-specific survival at 15 years was 99.1%., Conclusion: A surveillance policy for patients with stage I NSGCC is a safe approach associated with an excellent cure rate and an overall low treatment burden despite a high relapse rate in a small group of patients. We recommend surveillance for patients with stage I NSGCC with immediate systemic treatment at relapse. Clearly defined risk factors for relapse are presented if an option of risk-adapted treatment is preferred., (© 2014 by American Society of Clinical Oncology.)

Purpose: To assess longitudinal long-term alterations of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in testicular cancer survivors (TCSs)., Patients and Methods: In all, 307 TCSs treated from 1980 to 1994 provided blood samples after orchiectomy but before further treatment, at Survey I (SI; 1998-2002), and Survey II (SII; 2007-2008). Levels of sex hormones were categorized according to quartiles and reference range (2.5 and 97.5 percentiles) of 599 controls for each decadal age group. TCSs were categorized according to treatment: surgery, radiotherapy (RT), or chemotherapy (CT). The risk of higher (LH) or lower (testosterone) levels was assessed with χ(2) test (FSH) or ordinal logistic regression analysis and expressed as odds ratios (ORs) with 95% CIs., Results: Risk of lower testosterone and higher LH and FSH levels was significantly increased for TCSs at all time points after RT or CT. At SII, ORs were 3.3 (95% CI, 2.3 to 4.7) for lower testosterone categories and 5.2 (95% CI, 3.5 to 7.9) for RT and CT. ORs for increased LH and FSH were 4.4 (95% CI, 3.1 to 6.5) and 18.9 (95% CI, 11.0 to 32.6) for RT, respectively, and 3.6 (95% CI, 2.4 to 5.3) and 14.2 (95% CI, 8.3 to 24.4) for CT, respectively. The cumulative platinum dose was significantly associated with risk of higher LH levels at both surveys and higher FSH at SI. In total, half the TCSs had at least one of three sex hormone levels outside the reference range at SII., Conclusion: Long-term TCSs are at risk of premature hormonal aging. Our findings may pertain to cancer survivors in general, underlining the importance of extended follow-up.

Purpose: Cisplatin-induced neurotoxicity and ototoxicity (NTX) are important adverse effects after chemotherapy for testicular cancer (TC). Although serum platinum is measurable years after therapy, its impact on NTX has not been evaluated., Patients and Methods: In all, 169 cisplatin-treated survivors of TC provided blood samples at Survey I and reported NTX during Survey I (1998-2002) and Survey II (2007-2008). Serum platinum was quantified by inductively coupled plasma mass spectrometry. Patient-reported outcomes were evaluated with the Scale for Chemotherapy-Induced Neurotoxicity (SCIN), regarding the extent of symptom bother as 0, "not at all"; 1, "a little"; 2, "quite a bit"; or 3, "very much." Summing the six symptom scores yielded a total SCIN score of 0 to 18. Categorizing total SCIN scores into quartiles yielded similar-sized groups with increasing symptoms. Multivariate ordinal logistic regression analyses evaluated associations between NTX and long-term serum platinum levels, adjusting for cisplatin dose, dosing schedule, and age., Results: At Survey I, a significant four- to five-fold association with total SCIN score emerged for the highest serum platinum quartile (odds ratio [OR], 4.69; 95% CI, 1.82 to 12.08). Paresthesias and Raynaud's syndrome (hands and feet) showed significant two- to four-fold increased risks with the highest platinum quartile. At Survey II, total SCIN score remained significantly associated with the highest platinum quartile (OR, 4.28; 95% CI, 1.36 to 13.48). Paresthesias (hands and feet) and tinnitus showed significant three- to four-fold increased risks for the highest platinum quartile. Cumulative cisplatin dose was not associated with total SCIN score or individual SCIN symptoms in multivariate analyses., Conclusion: Here we document a significant relationship between increasing levels of residual serum platinum and NTX severity after adjusting for initial cisplatin dose.

Purpose: To provide recommendations on appropriate uses for serum markers of germ cell tumors (GCTs)., Methods: Searches of MEDLINE and EMBASE identified relevant studies published in English. Primary outcomes included marker accuracy to predict the impact of decisions on outcomes. Secondary outcomes included proportions of patients with elevated markers and statistical tests of elevations as prognostic factors. An expert panel developed consensus guidelines based on data from 82 reports., Results: No studies directly compared outcomes of decisions with versus without marker assays. The search identified few prospective studies and no randomized controlled trials; most were retrospective series. Lacking data on primary outcomes, most Panel recommendations are based on secondary outcomes (relapse rates and time to relapse)., Recommendations: The Panel recommended against using markers to screen for GCTs, to decide whether orchiectomy is indicated, or to select treatment for patients with cancer of unknown primary. To stage patients with testicular nonseminomas, the Panel recommended measuring three markers (alpha-fetoprotein [AFP], human chorionic gonadotropin [hCG], and lactate dehydrogenase [LDH]) before and after orchiectomy and before chemotherapy for those with extragonadal nonseminomas. They also recommended measuring AFP and hCG shortly before retroperitoneal lymph node dissection and at the start of each chemotherapy cycle for nonseminoma, and periodically to monitor for relapse. The Panel recommended measuring postorchiectomy hCG and LDH for patients with seminoma and preorchiectomy elevations. They recommended against using markers to guide or monitor treatment for seminoma or to detect relapse in those treated for stage I. However, they recommended measuring hCG and AFP to monitor for relapse in patients treated for advanced seminoma.

Purpose: The metabolic syndrome may be an important risk factor for cardiovascular disease in long-term survivors of testicular cancer (TC). We investigated the associations between hormone levels and the metabolic syndrome in these men., Patients and Methods: We included TC patients cured by orchidectomy and cisplatin-based chemotherapy, stage I TC patients after orchidectomy only, and healthy men of comparable age. Presence of the metabolic syndrome was determined using guidelines from the National Cholesterol Education Program Adult Treatment Panel III. Thyroid-stimulating hormone, follicle-stimulating hormone (FSH), inhibin B, luteinizing hormone (LH), total testosterone, sex-hormone-binding globulin, free testosterone, estradiol, dehydroepiandrosterone sulfate, and insulin-like growth factor 1 were determined in blood. Cortisol metabolite excretion was measured in urine., Results: Eighty-six chemotherapy patients (median follow-up, 7 years) were compared with 44 stage I patients and 47 controls. LH and FSH were higher, and inhibin B and total and free testosterone were lower in chemotherapy patients than controls. Adrenal and thyroid hormone production were unaffected. Chemotherapy patients with the metabolic syndrome (n = 22; 26%) had a higher body mass index (BMI) pretreatment, a larger BMI increase during follow-up, lower total testosterone, and higher urinary cortisol metabolite excretion than those patients without the metabolic syndrome. BMI and insulin were associated with the metabolic syndrome, while total testosterone and urinary cortisol metabolite excretion were associated with BMI., Conclusion: We found gonadal dysfunction, but normal adrenal and thyroid function. Through its association with BMI, testosterone may play a role in the development of the metabolic syndrome in long-term TC survivors.

Purpose: The prognostic relevance of the rate of decline of serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) during the first 3 weeks of chemotherapy for nonseminomatous germ cell tumors (NSGCT) was studied in the context of the International Germ Cell Cancer Collaborative Group (IGCCCG) classification., Patients and Methods: Data from 653 patients prospectively recruited in clinical trials were studied. Tumor markers were obtained before chemotherapy and 3 weeks later. Decline rates were calculated using a logarithmic formula and expressed as a predicted time to normalization (TTN). A favorable TTN was defined when both AFP and HCG had a favorable decline rate, including cases with normal values., Results: The median follow-up was 50 months (range, 2 to 151 months). Tumor decline rate expressed as a predicted TTN was associated with both progression-free survival (PFS; P <.0001) and overall survival (OS; P <.0001). The 4-year PFS rates were 64% and 38% in patients from the poor-prognosis group who had a favorable and an unfavorable TTN, respectively. The 4-year OS rates were 83% and 58%, respectively. This effect was independent from the initial tumor marker values, the primary tumor site, and the presence of nonpulmonary visceral metastases: tumor marker decline rate remained a strong predictor for both PFS (hazard ratio = 2.5; P =.01) and OS (hazard ratio = 4.6; P =.002) in patients from the IGCCCG poor-prognosis group in multivariate analysis., Conclusion: Early predicted time to tumor marker normalization is an independent prognostic factor in patients with poor-prognosis NSGCT and may be a useful tool in the therapeutic management of these patients.

Purpose: To assess the risk of cardiovascular morbidity and cardiac risk factors in long-term survivors of testicular cancer according to treatment received., Patients and Methods: All resident male patients registered in the United Kingdom between 1982 and 1992 attending for follow-up were eligible for recruitment. Patients completed a current health questionnaire and underwent clinical review, along with hematologic, biochemical, and hormonal profiles. For patients not under routine review, follow-up information was sought from their general practitioner and mortality data were sought from the Office of National Statistics. Descriptive analysis was performed on all variables and comparisons were made among patients treated by orchidectomy and follow-up only, chemotherapy alone (C), radiotherapy alone (RT), and radiotherapy and chemotherapy (C/RT)., Results: Data on cardiovascular events were available on 992 patients. After a median follow-up of 10.2 years, 68 events had been reported, including 18 deaths. After adjusting for age, increased risk for cardiac events was seen after C (relative risk [RR] = 2.59; 95% confidence interval [CI], 1.15 to 5.84; P =.022), RT (RR = 2.40; 95% CI, 1.04 to 5.45; P =.036), and C/RT (RR = 2.78; 95% CI, 1.09 to 7.07; P =.032). There were no significant differences in cardiac risk factors. On multivariate analysis, age, treatment group, free thyroxine, protein, and magnesium levels were associated with cardiovascular disease., Conclusion: In long-term survivors of testicular cancer, we observed a two-fold or greater risk of developing cardiovascular disease. This was not due to increases in cardiac risk factors, which suggests a direct or indirect treatment effect. These data support the continued research into the minimization of treatment in good-prognosis testicular cancer.

Purpose: To evaluate the prognostic value of metastases, extension into bone, and alpha-fetoprotein (AFP) elevation in children with malignant sacrococcygeal germ cell tumors (GCTs) prospectively collected in two cooperative Maligne Keimzelltumoren (MAKEI) protocols (83/86 and 89)., Patients and Methods: Between October 1983 and October 1995, 76 of 210 registered patients with sacrococcygeal primaries presented either with pure yolk sac tumor, embryonal carcinoma (EC), or yolk sac tumor and EC mixed with immature and mature teratoma elements. Stages T1 and T2 disease were diagnosed in 15 and 61 children, respectively, 41 patients had metastases, and 35 children presented with extension into bone. At diagnosis, 22 children had an AFP elevation of less than 10,000 ng/mL. Thirty-six children showed an AFP level between 10,000 and 100,000 ng/mL, and 12 patients had values of greater than 100,000 ng/mL. Five patients died of complication during treatment and were excluded from further evaluation. Seventy-one patients could be analyzed., Results: The 5-year relapse-free survival rate (RFS, Kaplan-Meier) was 0.76 +/- 0.03 (54 of 71 patients; median observation time, 54 months after diagnosis). The RFS of patients with and without metastases was different, but not significantly so (0.71 v 0.82). The outcome of patients with extension into bone (n = 31) and without this extension (n = 40) was 0.71 versus 0.80 (RFS, 5 years). Above-normal AFP level had no prognostic significance (P =.52)., Conclusion: In children with malignant sacrococcygeal GCTs treated with an intensive, short-interval, platinum-based regimen, the stage, extent of metastases, extension into bone, and AFP level had no prognostic significance.

Purpose: To determine the effect of radiotherapy in doses 14 to 20 Gy on eradication of carcinoma-in-situ (CIS) testis and on the Leydig cell function., Patients and Methods: Forty-eight patients presented with unilateral testicular germ cell cancer and CIS of the contralateral testis. The CIS-bearing testis was treated with daily irradiation doses of 2 Gy, 5 days a week, to a cumulative dose of 20 Gy (21 patients), 18 Gy (three patients), 16 Gy (10 patients), and 14 Gy (14 patients)., Results: All patients treated at dose levels 20 Gy to 16 Gy achieved histologically verified complete remission without signs of recurrence of CIS after an observation period of more than 5 years. One of 14 patients treated at dose level 14 Gy had a relapse of CIS 20 months after irradiation. Leydig cell function was examined before and regularly after radiotherapy in 44 of 48 patients. The levels of testosterone were lower after radiotherapy than before. Testosterone showed a stable decrease for more than 5 years after treatment (3.6% per year) without dose dependency. The levels of luteinizing hormone and follicle-stimulating hormone were increased after radiotherapy. The need of androgen substitution therapy was similar at all dose levels., Conclusion: Testicular irradiation is a safe treatment at dose level 20 Gy (10 x 2 Gy). Decrease of dose to 14 Gy (7 x 2 Gy) might lead to risk of relapse of CIS. Impairment of hormone production without clinically significant dose dependency is seen in the dose range 14 to 20 Gy.

Purpose: The prognostic significance of the rate of decline of the serum tumor marker alpha-fetoprotein (AFP) and human chorionic gonadotrophin (HCG) during the first two cycles of chemotherapy in germ cell tumor (GCT) patients was initially reported by us, but its value has been debated. We re-examined this issue in the context of the International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification system and investigated the role of including in the analysis patients whose markers normalized early., Patients and Methods: One hundred eighty-nine GCT patients with elevated AFP/HCG marker values treated with platinum-based chemotherapy between 1986 and 1998 were included in this analysis. Patients were classified as good, intermediate, or poor risk by the IGCCCG criteria and as having satisfactory or unsatisfactory marker decline. Risk and marker decline were correlated with response, event-free survival, and overall survival., Results: Satisfactory marker decline predicted improved complete response (CR) proportion and event-free and overall survival (P <.0001). The CR proportion, 2-year event-free, and 2-year overall survival rates for patients with a satisfactory and unsatisfactory marker decline were 92% versus 62%, 91% versus 69%, and 95% versus 72%, respectively. Marker decline remained a significant variable for all three end points when adjusted for risk (P <.01) with the outcome differences most pronounced in the poor-risk group., Conclusion: The rate of marker decline during chemotherapy has prognostic value independent of risk and may play a significant role in the management of poor-risk patients. It is appropriate to include patients whose markers normalized early.

Purpose: To determine whether long-term survivors of metastatic testicular cancer have an increased risk of cardiovascular morbidity more than 10 years after chemotherapy., Patients and Methods: Eighty-seven patients treated with cisplatin-containing chemotherapy before 1987 who were in remission for at least 10 years and whose ages were

Purpose: To obtain information about preorchiectomy gonadal function in patients with testicular germ cell cancer to improve the clinical management of fertility and other andrologic aspects in these men., Patients and Methods: In group 1, a group of 83 consecutive patients with testicular germ cell cancer (TGCC) investigated before orchiectomy, semen analysis was carried out in 63 patients and hormonal investigations, including measurement of follicle-stimulating hormone, luteinizing hormone (LH), testosterone, estradiol, sex hormone-binding globulin (SHBG), inhibin B, and human chorionic gonadotropin (hCG), in 71 patients. Hormone levels in patients with elevated hCG (n = 41) were analyzed separately. To discriminate between general cancer effects and specific effects associated with TGCC, the same analyses were carried out in a group of 45 consecutive male patients with malignant lymphoma (group 2). Group 3 comprised 141 men employed in a Danish company who served as controls in the comparison of semen parameters. As a control group in hormone investigations, 193 men were selected randomly from the Danish National Personal Register to make up group 4., Results: We found significantly lower sperm concentration (median, 15 x 10(6)/mL; range, 0 to 128 x 10(6)/mL) and total sperm count (median, 29 x 10(6)/mL; range, 0 to 589 x 10(6)) in patients with testicular cancer than in patients with malignant lymphomas (sperm concentration: median, 48 x 10(6)/mL; range, 0.04 to 250 x 10(6)/mL; sperm count: median, 146 x 10(6); range, 0.05 to 418 x 10(6)) (P < .001 and P < .001) and healthy men (sperm concentration: median, 48 x 10(6)/mL; range, 0 to 402 x 10(6)/mL; sperm count: median, 162 x 10(6); range, 0 to 1253 x 10(6)) (P < .001 and P < .001). FSH levels were increased in men with testicular cancer (median, 5.7 IU/L; range, 2.0 to 27 IU/L) compared with both men with malignant lymphomas (median, 3.3 IU/L; range, 1.01 to 12.0 IU/L) and healthy controls (median, 4.1 IU/L; range, 1.04 to 21 IU/L)(P = .001 and P = .007, respectively). Surprisingly, we found significantly lower LH in the group of men with TGCC (median, 3.6 IU/L; range, 1.12 to 11.9 IU/L) than in healthy men (median, 4.7 IU/L; range, 1.3 to 11.9 IU/L) (P = .01). We could not detect any differences between men with testicular cancer and men with malignant lymphomas and healthy men with regard to serum levels of testosterone, SHBG, and estradiol. Men with testicular cancer who had increased hCG levels had significantly lower LH and significantly higher testosterone and estradiol than those without detectable hCG levels., Conclusion: Spermatogenesis is already impaired in men with testicular cancer before orchiectomy. Neither local suppression of spermatogenesis by tumor pressure nor a general cancer effect seems to fully explain this impairment. The most likely explanation is preexisting impairment of spermatogenesis in the contralateral testis in men with testicular cancer. The question of whether also a pre-existing Leydig cell dysfunction is present in men with testicular cancer could not be answered in this study because the tumor seems to have a direct effect on the Leydig cells. Men with testicular cancer had low LH values as compared with controls. We speculate that increased intratesticular level of hCG also in men without measurable serum hCG may play a role by exerting LH-like effects on the Leydig cells, causing increased testosterone and estrogen levels and low LH values in the blood.

Purpose: To determine the therapeutic results in advanced germ cell tumor (GCT) patients with initial human chorionic gonadotropin (hCG) elevation greater than 50,000 mIU/mL and to document the levels of hCG decline and subsequent plateau and outcome of this patient population., Patients and Methods: We conducted a retrospective review of 41 patients who presented to Indiana University (IU) with hCG levels greater than 50,000 mIU/mL between December 1976 and August 1996. All patients had received cisplatin-containing regimens and were monitored with serial hCG levels., Results: Twenty-two of 41 (53.7%) patients continuously show no evidence of disease (NED) and eight additional patients (19.5%) are currently NED with salvage therapy. Only two of 41 patients had a normal hCG level at the start of the fourth and final course of cisplatin combination chemotherapy. Eight additional patients showed normalized hCG levels 1 month later. Seven of these 10 are continuously NED and three are currently NED with salvage therapy. Thirty-one patients had an abnormal hCG greater than 1 month after they completed primary chemotherapy; 15 of these patients (48%) are continuously NED despite no further therapy and five additional patients (16%) are currently NED with salvage therapy. Overall, there was an initial rapid decline in hCG followed by a plateau after the first two courses of therapy., Conclusion: Less than 10% of patients who present with hCG levels greater than 50,000 mIU/mL will have a normal hCG at the institution of the fourth and final course of chemotherapy. However, 22 of 41 (53.7%) are continuously NED despite no further therapy. We feel that the optimal strategy for such patients is monthly observation with initiation of salvage therapy if and when there is serologic progression.

Purpose: Testicular intraepithelial neoplasia ([TIN], so-called carcinoma in situ of the testis) is hypothesized to be the precursor of testicular germ cell neoplasms. According to previous studies, it can be detected by testicular biopsy. Since patients with a unilateral testicular tumor are at high risk of a second testicular tumor, it seemed feasible to examine the prevalence of contralateral TIN in patients with testicular germ cell cancer and correlate it with the known prevalence of bilateral testicular tumors. The aim was to provide more evidence for the role of TIN as the preinvasive stage of testicular cancer., Patients and Methods: Nineteen hundred fifty-four consecutive patients with a unilateral testicular germ cell tumor underwent contralateral biopsy. All specimens were examined immunohistologically., Results: TIN was observed in 4.9% (95% confidence interval [CI], 3.95% to 5.91%). Testicular atrophy and a history of undescended testis were more frequently observed in patients with contralateral TIN, but only atrophy was shown to be independently associated by multivariate analysis. Patients with testicular atrophy have a 4.3-fold increased risk of having contralateral TIN. Sixty-four percent of TIN cases were found in normal testes. Patients with TIN were significantly younger than those without (P < .0017). Three patients developed a second testicular tumor despite a negative biopsy for TIN., Conclusion: The prevalence of contralateral TIN corresponds well to the known prevalence of bilateral testicular tumors. Testicular atrophy is a strong indicator for the presence of TIN, but approximately 60% of TIN cases occur without atrophy. The present data are in accordance with the theory that TIN is an early step in the histogenesis of testicular germ cell neoplasms.

Purpose: To develop a statistical model that predicts the histology (necrosis, mature teratoma, or cancer) after chemotherapy for metastatic nonseminomatous germ cell tumor (NSGCT)., Patients and Methods: An international data set was collected comprising individual patient data from six study groups. Logistic regression analysis was used to estimate the probability of necrosis and the ratio of cancer and mature teratoma., Results: Of 556 patients, 250 (45%) had necrosis at resection, 236 (42%) had mature teratoma, and 70 (13%) had cancer. Predictors of necrosis were the absence of teratoma elements in the primary tumor, prechemotherapy normal alfa-fetoprotein (AFP), normal human chorionic gonadotropin (HCG), and elevated lactate dehydrogenase (LDH) levels, a small prechemotherapy or postchemotherapy mass, and a large shrinkage of the mass during chemotherapy. Multivariate combination of predictors yielded reliable models (goodness-of-fit tests, P > .20), which discriminated necrosis well from other histologies (area under the receiver operating characteristic (ROC) curve, .84), but which discriminated cancer only reasonably from mature teratoma (area, .66). Internal and external validation confirmed these findings., Conclusion: The validated models estimate with high accuracy the histology at resection, especially necrosis, based on well-known and readily available predictors. The predicted probabilities may help to choose between immediate resection of a residual mass or follow-up, taking into account the expected benefits and risks of resection, feasibility of frequent follow-up, the financial costs, and the patient's individual preferences.

Purpose: To determine whether the initial regression rates of serum tumor marker concentration (alpha-fetoprotein [AFP] and beta-human chorionic gonadotrophin [HCG]) were important prognostic factors after chemotherapy for germ cell tumors., Patients and Methods: The analysis was confined to patients with at least two precise marker assay results between days 7 and 22 from start of platinum-based combination chemotherapy, with at least 7 days between markers. One hundred eighty-three patients were eligible and marker half-life (MHL) was evaluated for AFP in 142 and for HCG in 111 cases. MHL was calculated from the following formula: MHL = Ln1/2/G, where G was the gradient of the marker slope on a plot of Ln marker concentration versus time. MHL was regarded as prolonged if more than 3 days for HCG or more than 7 days for AFP., Results: The median AFP MHL was 6 days (range, 2.7 to 237) and the median HCG MHL was 2.6 days (range, 1.7 to 37.5). Forty-nine of 142 patients (35%) had a prolonged AFP MHL; 39 of 111 patients (35%) had a prolonged HCG-MHL. A prolonged MHL did not identify relapse after front-line chemotherapy. The positive predictive value of MHL tests in identifying patients who progressed after front-line therapy was 18% for HCG, 20% for AFP, and 18% for either marker. A prolonged MHL did indicate a higher risk of mortality (hazards ratio [HR], 2.4; P = .016), but again the positive predictive value of this test was only 23%., Conclusion: Early evaluation of MHL by this method does not predict patients at higher risk of progression after front-line chemotherapy, and also is a poor guide to long-term prognosis.

Purpose: To investigate the efficacy of chemotherapy and to assess the relationship between selected pretreatment characteristics and survival in patients with advanced seminoma., Patients and Methods: One hundred forty-two patients with advanced seminoma treated with platinum-based chemotherapy were the subject of this study. Treatment regimens included cisplatin, vinblastine, bleomycin, cyclophosphamide, and dactinomycin (VAB-6) (45 patients), a six-cycle regimen of VAB-6 alternating with etoposide and cisplatin (two patients), cisplatin and etoposide (60 patients), and etoposide and carboplatin (35 patients)., Results: One hundred thirty of 140 (93%) assessable patients treated with platinum-based therapy achieved a favorable response (complete response or a partial response with negative serum tumor markers). One hundred twenty-five patients (88%) are alive and 120 (86%) remain progression-free at a median follow-up duration of 43 months. Fifty-seven of 60 patients (95%) who were treated with cisplatin and etoposide achieved a favorable response; 55 (92%) remain progression-free. The relative risks of death or of an event (death or relapse) related to human chorionic gonadotropin (HCG) elevation were 1.8 (P = .04) and 1.96 (P = .001), respectively. The relative risks of death or of an event associated with lactate dehydrogenase (LDH) elevation were 2.6 (P = .05) and 2.7 (P = .02), respectively. All 19 patients with a mediastinal primary tumor site achieved a complete response, and 18 of 19 (95%) remain progression-free., Conclusion: Four cycles of cisplatin and etoposide is highly effective therapy for seminoma and is the standard therapy at our center. Elevation of the serum markers HCG and LDH were of prognostic significance, while an extragonadal primary tumor site was not associated with an adverse prognosis. Studies of tumor biology, including genetic analysis, are ongoing to determine other parameters that may correlate with response and survival.

Purpose: The study was designed to determine prospectively the prevalence of fasting serum lipid abnormalities in patients who were treated with cisplatin-based chemotherapy for germ cell tumors. We unexpectedly had demonstrated hypercholesterolemia in 20 of 30 nonfasting patients in a prior study of long-term toxicity of chemotherapy for germ cell tumors. The present study was designed to explore this phenomenon further., Patients and Methods: Seventeen unselected patients with biopsy-proven germ cell tumors, who underwent cisplatin-based chemotherapy and who had no prior history of cardiac disease nor known hypercholesterolemia, were studied. In addition to the standard staging tests, blood was drawn for a pretreatment fasting lipid screen, which included cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and apolipoproteins A1, B, and (a). Repeat samples were drawn 24 hours after the administration of cisplatin and at intervals of 6 to 24 months after the completion of treatment., Results: Seven of 17 patients (41%) had higher than desirable levels of total serum cholesterol and low-density lipoprotein cholesterol. Two of them had normal levels before treatment, four had preexisting hypercholesterolemia that increased further, and one patient had an elevated pretreatment level that did not alter. Absolute increases in serum cholesterol were noted in 14 of 17 patients. No consistent patterns of change beyond the reference ranges were found for other serum lipids., Conclusions: We have confirmed our initial observation that serum cholesterol increases in patients who received cisplatin-containing chemotherapy regimens for germ cell tumors. Further studies will be necessary to define whether other lipid abnormalities occur and the biologic significance of these findings.

Purpose: At least one third of the patients with metastatic testicular cancer are rendered tumor-free by cisplatin-based chemotherapy. One may question, therefore, the routine use of postchemotherapy retroperitoneal lymph node dissection (RLND), especially if the residual masses are less than 20 mm in diameter. To define the role of such surgery, we analyzed the postchemotherapy histology in testicular cancer patients with minimal residual disease., Patients and Methods: Seventy-eight patients with advanced nonseminomatous testicular cancer underwent RLND after three to four cycles of cisplatin- or carboplatin-based chemotherapy. In all patients, the largest diameter of the residual retroperitoneal mass was less than 20 mm., Results: Complete fibrosis/necrosis was found in 51 patients, mature teratoma in 22, and vital malignant germ cell tumor in five. In two of the latter five patients, alphafetoprotein (AFP) had increased immediately before RLND. In the 76 patients with normal pre-RLND tumor markers, the presence of undifferentiated malignant teratoma (MTU) in the primary tumor and normal prechemotherapy tumor markers were independent parameters predicting complete fibrosis/necrosis, which was demonstrated in all 15 patients with these two pretreatment parameters., Conclusions: Postchemotherapy RLND can be omitted in patients with MTU in the primary tumor who have normal AFP/human chorionic gonadotropin (AFP/HCG) before chemotherapy and whose residual retroperitoneal mass is less than 20 mm in diameter. If the pre-RLND tumor markers are normal, RLND should be performed in all other patients with small residual masses, even in the presence of a normal computed tomography (CT) and particularly if regular follow-up of the patients is not guaranteed.

Between 1981 and 1986, 200 consecutive patients with metastatic nonseminomatous testicular cancer were entered into the Swedish Norwegian Testicular Cancer (SWENOTECA) project from 14 hospitals. The treatment plan was four chemotherapy cycles (cisplatin, vinblastine, and bleomycin) followed by surgical resection of residual tumor masses. After a median observation time of 75 months, the overall 5-year survival rate was 82%. In a univariate analysis, the following parameters influenced the prognosis significantly: the extent of the disease (Medical Research Council [MRC] grouping); the prechemotherapy levels of serum alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG), and lactate dehydrogenase (LDH); the patients' age; the presence of extrapulmonary hematogeneous metastases; and/or particularly large lymph node metastases. Patients fared better when more than 3 weeks elapsed between orchiectomy and start of chemotherapy as compared with those who were treated within this interval. The place of treatment (a large oncology unit v smaller units) also represented a significant prognostic factor for patients with large-volume (LV) and very-large-volume (VLV) disease combined. Multivariate analysis (Cox regression proportional hazards model) performed in all 193 assessable patients showed the following adverse prognostic factors: high-volume metastatic burden, age older than 35 years, prechemotherapy AFP greater than 500 micrograms/L and/or HCG greater than 1,000 U/L, and an interval between orchiectomy and start of chemotherapy of less than 3 weeks. The place of treatment also significantly influenced the final outcome. If patients with LV and VLV disease were combined, the presence of two of the following risk factors represented an additional prognostic factor: AFP greater than 1,000 micrograms/L, HCG greater than 10,000 U/L, liver metastases, brain metastases, bone metastases, retroperitoneal tumor greater than or equal to 10 cm, and mediastinal tumor greater than or equal to 5 cm.

Between 1981 and 1986, 279 consecutive patients with clinical stage I (CS1) nonseminomatous germ cell tumors (NSGCT) of the testis underwent pathological staging (PS) with retroperitoneal lymphadenectomy (RPLND). Patients with retroperitoneal metastases (PS2) received adjuvant chemotherapy. The median follow-up time after RPLND was 50 months (range, 30 to 90). Clinical and histopathologic features were registered prospectively and analyzed for association with risk of having PS2, relapse despite pathological stage 1 (PS1) or the combined risk of either event, metastatic disease (MET). Seventy-five (26.9%) of the patients had PS2 disease, and 30 (14.7%) of the 204 PS1 patients relapsed, indicating that at least 105 (37.6%) of this CS1 population had subclinical MET at the time of orchiectomy. Four (1.4%) of the 279 CS1 patients died of testicular cancer. Multivariate analyses showed several variables to be significantly associated with outcome for the CS1 patients; vascular invasion in primary tumor and normal preorchiectomy serum alpha-fetoprotein (Pre-AFP) level indicated PS2 disease. If Pre-AFP was excluded from the model, the absence of teratoma or yolk sac elements in the primary tumor became significant predictors of PS2. Vascular invasion, absence of teratoma, and a short interval between orchiectomy and RPLND indicated increased risk of relapse in PS1 patients. Vascular invasion, normal Pre-AFP, absence of teratoma elements, and a short orchiectomy to RPLND interval were predictive of MET. Our results indicate that prognostic factors useful for stratification of CS1 patients with NSGCT to different treatment options may be established.

Long-term effects of cisplatin on renal function were investigated in 34 patients with germ cell cancer observed for a median of 65 months (range, 43 to 97 months). All patients achieved a complete remission after treatment with cisplatin (median dose 583 mg/m2), vinblastine, and bleomycin. None of the patients relapsed during follow-up. During treatment the glomerular filtration rate (GFR) decreased by 18% (P less than .05). During follow-up kidney function recovered in ten patients and partly improved in eight patients. Changes in plasma creatinine did not consistently correspond to alterations in GFR. The mean increase in systolic blood pressure during follow-up did not differ from the increase seen in a group of age-matched healthy men. The mean increase in diastolic pressure, however, was significant (P less than .05), but was entirely due to hypertension observed in six patients. Renography of these patients was normal. We conclude that the decrease in GFR observed during treatment with cisplatin is partly reversible. Cisplatin-treated patients have an increased risk of developing hypertension years after treatment.

Twenty-four normotensive males in complete remission (CR) for 9+ to 54+ months after cisplatin-based chemotherapy for metastatic germ-cell tumors were evaluated for evidence of alterations in the renin-aldosterone axis and renal function. Abnormally high ambulatory plasma renin activity was seen in 14 of 19 patients with 24-hour urine sodium excretion greater than 50 mEq. This was correlated with elevated ambulatory plasma aldosterone (P = .009) and 24-hour urinary aldosterone excretion (P = .01). The mean serum magnesium value (1.34 +/- .05 mEq/L) was subnormal. Therapy resulted in an increase in serum creatinine during treatment (P less than .0001), an increase in BUN (P less than .01), and decrease in serum phosphorus (P less than .001). The relationship between the alterations in the renin-aldosterone axis and abnormal renal tubular function remains to be determined. In view of reports of cardiovascular toxicity after treatment for germ-cell tumors, and evidence individually linking both magnesium deficiency and increased plasma renin activity (PRA) to cardiovascular consequences, these abnormalities in renin and magnesium metabolism suggest that patients treated with cisplatin-based chemotherapy should be carefully observed for the development of delayed cardiovascular toxicities.

Forty-five patients with clinical stage I nonseminomatous germ cell tumor of the testis (NSGCTT) were entered in a prospective clinical trial to receive no treatment other than orchiectomy until clinical evidence of relapse. Of this group, 36 patients (80%) have been continuously free of disease for a median duration of 19.5 months after orchiectomy. Nine patients (20%) have relapsed, eight within seven months of orchiectomy. Seven of nine relapsing patients have been rendered free of disease with chemotherapy and/or surgery for a median duration of seven months (range, one to 33 months) after completion of treatment; the other two patients are presently under treatment although one has progressive disease. The relapse rate was higher in patients with embryonal carcinoma than in those with teratocarcinoma, 57% versus 17%. These preliminary results imply that the omission of routine lymphadenectomy or lymph-node irradiation in clinical stage I NSGCTT deserves further trial.

The effects of chemotherapy on endocrine function were assessed in 22 previously treated patients with germ-cell tumors and compared with the endocrine function of six previously untreated patients. Baseline and stimulated serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, thyroid-stimulating hormone (TSH), prolactin, and thyroxine (T4) were obtained. Baseline LH levels were elevated in both groups of patients, whereas basal FSH levels were significantly elevated only in treated patients (P less than .001). Following gonadotropin-releasing hormone (GnRH), levels of LH (P = .051) and FSH (P = .003) were greater in treated patients than in untreated control patients. No abnormalities of thyroid function or prolactin responsiveness were observed. Patients younger than 25 years of age at the time of treatment had lower serum levels of LH and FSH following chemotherapy than patients older than 25. Evidence for partial recovery of gonadal function was present with patients treated more than 18 months before study having lower levels of LH and FSH than those patients studied less than 18 months after treatment. These data demonstrate that frequent gonadal dysfunction exists in untreated patients with germ-cell tumors and that chemotherapy induces additional injury to both Leydig cells and the germinal epithelium. Further studies with long-term follow-up are necessary to define the pattern of gonadal recovery and to assess the potential sequelae of endogenous gonadotropin hypersecretion.

Fifty patients with clinical stage II nonseminomatous germ cell tumor of the testis (NSGCTT) were treated with primary chemotherapy followed by a retroperitoneal lymph node dissection (RPLND) in selected patients. The study population included 34 patients with retroperitoneal masses and elevated levels of serum biomarkers (alpha-fetoprotein [AFP] and beta-human chorionic gonadotropin [BHCG] ), five with needle aspiration biopsy-proven retroperitoneal metastases but normal levels of biomarkers, and 11 in whom there were rising levels of serum biomarkers but no radiographic evidence of retroperitoneal metastases. Forty-eight patients (96%) achieved a complete response (CR), with a mean disease-free survival of 132 weeks (range, 55 to 273 weeks). Two patients developed recurrent disease. One died and one achieved a second CR with further therapy (48 + weeks). Postchemotherapy RPLND was required in 11 patients (22%). Patients with embryonal carcinoma had a lower frequency of RPLND (8%) than patients with teratomatous elements in their primary tumor [36%, P = .014]. To reduce the frequency of double therapy (surgery +/- chemotherapy), we propose individualized therapy. Patients presenting with clinical stage II embryonal carcinoma of the testis should receive primary chemotherapy. Patients with clinical stage II NSGCTT and teratomatous elements in their primary tumor continue to require an RPLND. Those patients with intermediate volume disease (greater than 2 cm less than or equal to 5 cm in maximum diameter) may be treated with an RPLND only. Patients with higher volume teratomatous elements (greater than 5 cm less than or equal to 10 cm in maximum diameter) are likely to require the combination of chemotherapy and surgery.