Maria Gry Gundgaard Kier

Germ Cell Cancer and Multiple Relapses: Toxicity and Survival

PURPOSE A small number of patients with germ cell cancer (GCC) receive more than one line of treatment for disseminated disease. The purpose of this study was to evaluate late toxicity and survival in an unselected cohort of patients who experienced relapse after receiving first-line treatment for disseminated disease. METHODS From the Danish Testicular Cancer database, we identified all patients who received more than one line of treatment for disseminated disease. Information about late toxicity and mortality was obtained by means of linkage to national registers. Prognostic factors for relapse and death were identified and compared with the International Prognostic Factors Study Group (IPFSG) classification. RESULTS In total, 268 patients received more than one line of treatment for disseminated GCC. Approximately half of patients (n=136) died as a result of GCC. The 132 remaining patients, compared with patients treated with only orchiectomy, had an increased risk for a second cancer (hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.5), major cardiovascular disease (HR, 1.9; 95% CI, 1.0 to 3.3), pulmonary disease (HR, 2.0; 95% CI, 1.0 to 3.8), GI disease (HR, 7.3; 95% CI, 3.6 to 14.8), renal impairment (HR, 8.3; 95% CI, 3.0 to 23.2), neurologic disorders (HR, 6.3; 95% CI, 3.1 to 12.6), and death as a result of other causes (HR, 2.6; 95% CI, 1.6 to 4.2). In large part, the IPFSG classification was confirmed in our population; however, we could not confirm the primary site and the level of human chorionic gonadotropin as independent factors. We identified increasing age as a possible new prognostic factor for treatment failure after second-line treatment (HR, 1.2 per 10 years; 95% CI, 1.2 to 15). CONCLUSION Patients with GCC who survive after more than one line of treatment for disseminated disease have a highly increased risk of late toxicity and death as a result of causes other than GCC. Therefore, they should be candidates for life-long follow-up. The IPFSG classification was confirmed in this unselected population.

Pulmonary Function in Patients With Germ Cell Cancer Treated With Bleomycin, Etoposide, and Cisplatin

PURPOSE For patients with germ cell cancer, various pulmonary toxicity risk factors have been hypothesized for treatment with bleomycin, etoposide, and cisplatin (BEP). Because existing studies have shortcomings, we present a large, unselected cohort of patients who have undergone close monitoring of lung function before, during, and after treatment with BEP to disclose valid pulmonary toxicity risk factors. PATIENTS AND METHODS All patients who were treated with BEP at Rigshospitalet, Copenhagen, Denmark, from 1984 to 2007, were included. Pulmonary function tests (PFTs) that measured the diffusing capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume in 1 second, and forced vital capacity were performed systematically before, during, and after treatment with BEP for 5 years of follow-up. According to local protocol, bleomycin was discontinued if hemoglobin-corrected DLCO (DLCOc) decreased ≥ 25% compared with pretreatment value. Covariates of possible importance were evaluated with a multiple regression analysis for pretreatment PFTs and with a mixed model for follow-up PFTs. Bleomycin was adjusted on the basis of PFT results and was thus omitted as covariate. RESULTS Overall, 565 patients were evaluated with a PFT before or after treatment with BEP. During BEP, 15 patients died of progressive disease or toxicity, including one patient from bleomycin-induced pneumonitis. Post-treatment DLCOc decreased significantly, with a rebound during follow-up. Forced expiratory volume in 1 second and forced vital capacity remained unchanged after BEP but increased significantly to levels above pretreatment during follow-up. International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic group, mediastinal primary, pulmonary metastases, and smoking all significantly influenced baseline PFT results. Pulmonary surgery, pulmonary embolism, IGCCCG poor prognosis, and smoking influenced PFT during follow-up. Mediastinal primary, pulmonary metastases, age, or doses of cisplatin and etoposide had no influence on follow-up PFT, and renal function did not influence PFT. CONCLUSION After 5 years of follow-up, pulmonary impairment in patients with germ cell cancer who were treated with BEP was limited. Exceptions were patients treated with pulmonary surgery, those who suffered pulmonary embolism, and those in the IGCCCG poor prognostic group.

Renal impairment and late toxicity in germ-cell cancer survivors

BACKGROUND Treatment with bleomycin-etoposide-cisplatin (BEP) impairs renal function and increases the risk of late cardiovascular disease (CVD) and death. We investigated the influence of BEP on glomerular filtration rate (GFR) and assessed the importance of GFR changes on CVD and death in a large cohort of germ-cell cancer survivors. PATIENTS AND METHODS BEP-treated patients (N = 1206) were identified in the Danish DaTeCa database, and merged with national registers to identify late toxicity. GFR were measured (51Cr-EDTA clearance) before and after treatment and at 1, 3 and 5-year follow-up. The influence of BEP on GFR was evaluated with a linear mixed model. Risk factors for late toxicity were identified by a landmark analysis adjusting for covariates. The cohort was compared with the background population with standardized hospitalization/mortality rates. RESULTS GFR changed (ΔGFR) -11.3%, -15.4% and -25.9% after three, four and five+ cycles of BEP. For patients with impaired renal function before treatment the changes were 4.3%, 0.0% and -12.8%, respectively. During follow-up a significant rebound of GFR was documented. Compared with the background population, all patients, irrespective of renal function, had an increased risk of CVD and death. This risk depended on chronic kidney disease stage before treatment but not after treatment. ΔGFR had no influence on risk of late toxicity [death: hazard ratio (HR) 1.06, P = 0.50; CVD: HR 0.97, P = 0.61]. CONCLUSIONS Renal function after BEP is closely related to number of cycles, but the changes in GFR are partly reversible and have no impact on risk of CVD or death.BACKGROUND Treatment with bleomycin-etoposide-cisplatin (BEP) impairs renal function and increases the risk of late cardiovascular disease (CVD) and death. We investigated the influence of BEP on glomerular filtration rate (GFR) and assessed the importance of GFR changes on CVD and death in a large cohort of germ-cell cancer survivors. PATIENTS AND METHODS BEP-treated patients (N = 1206) were identified in the Danish DaTeCa database, and merged with national registers to identify late toxicity. GFR were measured (51Cr-EDTA clearance) before and after treatment and at 1, 3 and 5-year follow-up. The influence of BEP on GFR was evaluated with a linear mixed model. Risk factors for late toxicity were identified by a landmark analysis adjusting for covariates. The cohort was compared with the background population with standardized hospitalization/mortality rates. RESULTS GFR changed (ΔGFR) -11.3%, -15.4% and -25.9% after three, four and five+ cycles of BEP. For patients with impaired renal function before treatment the changes were 4.3%, 0.0% and -12.8%, respectively. During follow-up a significant rebound of GFR was documented. Compared with the background population, all patients, irrespective of renal function, had an increased risk of CVD and death. This risk depended on chronic kidney disease stage before treatment but not after treatment. ΔGFR had no influence on risk of late toxicity [death: hazard ratio (HR) 1.06, P = 0.50; CVD: HR 0.97, P = 0.61]. CONCLUSIONS Renal function after BEP is closely related to number of cycles, but the changes in GFR are partly reversible and have no impact on risk of CVD or death.

Testosterone deficiency in testicular cancer survivors – a systematic review and meta‐analysis

Results concerning treatment of Testicular Germ Cell Cancer (TGCC) and subsequent risk of testosterone deficiency are conflicting. To systematically evaluate and estimate the risk of testosterone deficiency (TD) in TGCC‐patients according to treatment to optimize follow‐up and for prevention of late effects related to hypogonadism. We performed a critical review of PubMed in January 2015 according to the Preferred Reporting Items for Systematic Review and Meta‐analysis (PRISMA) statement. Twelve publications were selected for inclusion in this analysis. Eleven studies evaluated the risk of TD in TGCC‐patients treated with standard chemotherapy (CT) and the odds ratio for TD was 1.8 (95% CI) (1.3–2.5), (p = 0.0007). Seven studies evaluated the risk of TD in TGCC‐patients treated with non‐conventional therapy and the odds ratio for TD was 3.1 (95% CI) (2.0–4.8), (p < 0.0001). Six studies evaluated the risk of TD in TGCC‐patients treated with infradiaphragmatic radiotherapy (RT), and the odds ratio for TD was 1.6 (95% CI) (1.0–2.4), (p = 0.03). In all treatment groups the risk of TD was compared with TGCC‐patients treated with orchiectomy alone. There was no indication of heterogeneity between studies in the three treatment groups. Strong evidence exists that standard CT, non‐conventional therapy and infradiaphragmatic RT are associated with an increased risk of TD in TGCC‐patients when compared with orchiectomy alone. The risk of testosterone defficiency appears to be highest in patients treated with non‐conventional therapy.

Surveillance versus adjuvant radiotherapy for patients with high-risk stage I seminoma

The optimal treatment strategy for patients with clinical stage I (CS‐1) seminoma is controversial. The objective of the current study was to evaluate the outcomes for patients considered to be at high risk of disease recurrence with a tumor size ≥6 cm. Patients were treated with either adjuvant radiotherapy (RT) or followed with surveillance.

Second Malignant Neoplasms and Cause of Death in Patients With Germ Cell Cancer: A Danish Nationwide Cohort Study.

Importance Patients given systemic treatment for testicular germ cell cancer (GCC) are at increased risk for a second malignant neoplasm (SMN). Previous studies on SMN and causes of death lacked information on the exact treatment applied or were based on patients receiving former treatment options. Objective To evaluate the treatment-specific risks for SMN and death in a nationwide population-based cohort of patients with GCC treated with current standard regimens. Design, Setting, and Participants This study examined a Danish nationwide cohort of 5190 men with GCC who entered the Danish Testicular Cancer database between January 1, 1984, and December 31, 2007. Treatment results were compared with a randomly sampled, age-stratified, population-based control group. Cases of gonadal and extragonadal primary were included in the nationwide cohort. The treatments were surveillance only; retroperitoneal radiotherapy (RT); bleomycin, etoposide, and cisplatin (BEP); or more than 1 line of treatment (MTOL). Main Outcomes and Measures Cumulative incidence and hazard ratios (HRs) for SMN and death calculated by the Cox proportional hazards model were compared with those of age-matched controls. Results The study population comprised 2804 patients with seminoma and 2386 with nonseminoma. The median follow-up was 14.4 years (interquartile range, 8.6-20.5 years). The 20-year cumulative incidence of SMN with death as a competing risk was 7.8% (surveillance), 7.6% (BEP), 13.5% (RT), 9.2% (MTOL), and 7.0% (controls). We found no increased risk for SMN after surveillance, while the HRs were 1.7 (95% CI, 1.4-2.0), 1.8 (95% CI, 1.5-2.3), and 3.7 (95% CI, 2.5-5.5), respectively, after BEP, RT, and MTOL. Mortality owing to non-GCC causes was decreased after surveillance, but increased by 1.3 times after BEP and RT and by 2.6 times after MTOL. Excess mortality due to SMN was found after BEP (HR, 1.6; 95% CI, 1.2-2.2), RT (HR, 2.1; 95% CI, 1.5-2.9), and MTOL (HR, 5.8; 95% CI, 3.6-9.6). Conclusions and Relevance We found no increased risk for SMN or death among patients undergoing surveillance only. The risks for SMN and death due to SMN were increased after BEP alone, RT alone, and MTOL. Approaches to define patients who might benefit from less intensive treatment are needed.

Screening for carcinoma in situ in the contralateral testicle in patients with testicular cancer: a population-based study

BACKGROUND Screening programmes for contralateral carcinoma in situ (CIS) testis in patients with unilateral germ-cell cancer (GCC) have never been evaluated. We investigated the effect of screening for contralateral CIS in a large nation-wide, population-based study. PATIENTS AND METHODS A contralateral single-site biopsy was offered to 4130 patients in whom GCC had been diagnosed in 1984-2007 (screened cohort); 462 patients in whom GCC was diagnosed in 1984-1988 comprised the unscreened cohort. Cases with CIS were offered radiotherapy. Initially CIS-negative biopsies in patients with metachronous GCC were revised according to todays standards. Risk for metachronous GCC was estimated using cumulative incidence and the Cox proportional hazards model. RESULTS In the screened cohort, contralateral CIS was found in 181 (4.4%) patients. The cumulative incidence of metachronous GCC after 20 years was 1.9% in the screened cohort and 3.1% in the unscreened cohort (P = 0.097), hazard ratio (HR) for the unscreened cohort: 1.59 (P = 0.144). Expert revision with contemporary methodology of CIS-negative biopsy samples from patients with metachronous cancer revealed CIS in 17 out of 45 (38%) cases. Decreased risks for metachronous GCC were related to older age at diagnosis (HR 0.52 per 10 years, P < 0.001) and chemotherapy (HR 0.35, P = 0.002). Limitations include the small number of patients in the unscreened cohort and the retrospective study design. CONCLUSIONS Our evaluation of a national population-based screening programme for contralateral CIS in patients with testicular cancer showed no significant difference in the risk for metachronous GCC between a screened and an unscreened cohort. Single-site biopsy including modern immunohistochemistry does not identify all cases of CIS.

Late Relapses in Stage I Testicular Cancer Patients on Surveillance

BACKGROUND Comprehensive data on late relapse (LR) and very LR (VLR) in patients with clinical stage I (CS-1) testicular cancer followed on surveillance are missing. These data are essential for planning optimal follow-up. OBJECTIVE Assess incidence and outcome of LR (>2 yr) and VLR (>5 yr) in a large cohort of CS-1 surveillance patients, and examine differences in the clinical characteristics of patients with early relapse (ER), LR, and VLR. DESIGN, SETTING, AND PARTICIPANTS CS-1 surveillance patients diagnosed between 1984 and 2007 were identified from the retrospective Danish Testicular Cancer (DaTeCa) database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We estimated survival and relapse probabilities and compared the results using log-rank tests and Cox regression analyses. We compared differences in patient characteristics by using χ(2), Fisher exact, and Mann-Whitney tests. RESULTS AND LIMITATIONS Our study included 3366 (2000 seminoma and 1366 nonseminoma) patients. Median follow-up was 15 yr. Five-year conditional risk of LR was 5.0% and 2.1% for seminoma and nonseminoma patients, respectively. There were no significant differences in disease-specific or overall survival when comparing the LR(VLR) and ER patients by log-rank, but Cox regression adjusted for age showed a significant effect of time to relapse on survival for seminoma patients. Apart from significantly more ER nonseminoma patients with elevated human chorionic gonadotropin at relapse, there were no significant differences in patient characteristics at orchiectomy or relapse. Limitations include retrospective design and exclusion of patients who had been offered adjuvant therapy. CONCLUSIONS The risk of VLR is minimal, and the patients carry a good prognosis. Patient characteristics of CS-1 surveillance patients with LR(VLR) do not differ significantly from patients with ER. PATIENT SUMMARY We compared stage I testicular cancer surveillance patients with early relapse (ER) versus late relapse (LR; >2 yr). LR patients as a group did no worse than ER patients, although increased time to relapse was negatively associated with survival for seminoma patients.

Prognostic Factors and Treatment Results After Bleomycin, Etoposide, and Cisplatin in Germ Cell Cancer: A Population-based Study

BACKGROUND First-line treatment for patients with disseminated germ cell cancer (GCC) is bleomycin, etoposide, and cisplatin (BEP). A prognostic classification of patients receiving chemotherapy was published by the International Germ Cell Cancer Collaborative Group (IGCCCG) in 1997, but only a small proportion of the patients received BEP. OBJECTIVE To estimate survival probabilities after BEP, evaluate the IGCCCG prognostic classification, and propose new prognostic factors for outcome. DESIGN, SETTING, AND PARTICIPANTS Of a Danish population-based cohort of GCC patients (1984-2007), 1889 received first-line BEP, with median follow-up of 15 yr. Covariates evaluated as prognostic factors were age, year of treatment, primary site, non-pulmonary visceral metastases, pulmonary metastases, and tumor markers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Outcomes measured were 5-yr progression-free survival (PFS), 5-yr disease-specific survival (DSS), and 5-yr overall survival (OS) as calculated using the Kaplan-Meier method and the Cox proportional hazards model. RESULTS AND LIMITATIONS The 5-yr PFS, DSS, and OS were 87%, 95%, and 93%, respectively, for patients with seminomatous GCC (SGCC) and good prognosis. For nonseminomatous GCC (NSGCC) with good, intermediate, and poor prognosis, the 5-yr probabilities were 90%, 76%, and 55% for PFS; 97%, 87%, and 66% for DSS; and 95%, 85%, and 64% for OS, respectively. For SGCC patients, new adverse prognostic factors not included in the IGCCCG classification were higher age and lactate dehydrogenase ≥1.5 times the upper limit of normal. For NSGCC patients, higher age and pulmonary metastases were additional adverse prognostic factors. Treatment in earlier years was associated with higher mortality. Limitations include the small number of patients in the prognostic groups, and the inability to adjust for performance status and comorbidity. CONCLUSIONS Our study reveals improved survival for disseminated GCC throughout the study period. We propose new prognostic factors for outcome for validation in larger cohorts of patients. PATIENT SUMMARY In this study of testicular cancer patients, we evaluated prognostic factors for outcome and calculated survival after standard chemotherapy. We find that survival has improved over the years and we propose new prognostic factors for outcome for validation in larger patient cohorts.

Preorchiectomy Leydig Cell Dysfunction in Patients With Testicular Cancer

&NA; Leydig cell function was evaluated preorchiectomy in 561 patients with testicular cancer and compared with a cohort of age‐matched healthy men. Leydig cell dysfunction was found in 25% of patients and was associated with increasing tumor size. Total testosterone as well as calculated free testosterone was lower in patients than in healthy controls. Background: Little is known about preorchiectomy Leydig cell function in patients with testicular germ cell cancer (TGCC). The aim was to estimate the prevalence of preorchiectomy Leydig cell dysfunction and evaluate factors associated with this condition in a cohort of patients with TGCC. Patients and Methods: We evaluated luteinizing hormone (LH), total testosterone (TT), calculated free T (cFT), estradiol, and sex hormone–binding globulin (SHBG) preorchiectomy in 561 patients with TGCC and compared with 561 healthy controls. We calculated TT/LH and cFT/LH ratios and constructed bivariate charts of TT/LH and cFT/LH from the controls. Logistic regression analysis with an abnormal cFT/LH ratio as outcome and clinical stage, tumor size, age, histology, presence of contralateral germ cell neoplasia in situ (GCNIS), and bilateral tumors as covariates was performed. Results: In patients who were negative for human chorionic gonadotropin (hCG) (n = 374), TT (P = .004), cFT (P < .001), TT/LH ratio (P = .003), and cFT/LH ratio (P = .002) were lower than in controls. A total of 95 (25%) and 91 (24%) of hCG‐negative patients had abnormal values when using combined evaluation of TT/LH and cFT/LH, respectively. Increasing tumor size, contralateral GCNIS, and increasing age were associated with Leydig cell dysfunction. In patients positive for hCG (n = 187), all reproductive hormones except SHBG were different from controls (P < .001). Conclusion: Patients with TGCC are at increased risk of Leydig cell dysfunction before orchiectomy. Contralateral GCNIS, increasing age, and increasing tumor size are associated with Leydig cell dysfunction. We hypothesize that patients with preexisting Leydig cell dysfunction are at increased risk of testosterone deficiency following treatment.