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.

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

BACKGROUND: 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. METHODS: From the Danish Testicular Cancer database, the authors identified 473 patients with CS-1 seminoma with a tumor size ≥6 cm. Of these, 254 patients underwent adjuvant RT and 219 were followed with surveillance. Cumulative incidence function was applied to estimate the risk of disease recurrence, risk of second malignant neoplasm, and risk of receiving >1 line of treatment. Survival of the 2 groups was compared with the log-rank test and Cox model including age at diagnosis. RESULTS: No significant differences were found with regard to overall survival or risk of a second malignant neoplasm. Patients undergoing adjuvant RT received more treatments per patient than patients followed with surveillance, but there was no significant difference noted with regard to the risk of receiving >1 line of treatment. The 10-year cumulative incidence of disease recurrence was 32% versus 2.8%, respectively, for patients followed with surveillance and adjuvant RT. In patients followed with surveillance who developed disease recurrence, there was a high incidence of second recurrences after RT. CONCLUSIONS: The 10-year overall survival was found to be similar irrespective of primary treatment. Adjuvant RT was found to effectively reduce the rate of disease recurrence but resulted in the overtreatment of approximately two-thirds of the patients. The high incidence of second disease recurrences after RT in the patients followed with surveillance needs be addressed in future studies. Cancer 2017;123:1212-1218. © 2016 American Cancer Society.

Relapse and Mortality Risk of Stage I Testicular Cancer.

OBJECTIVES: - To assess the medical insurance risk for patients with stage I testicular cancer (TC), by calculating the overall mortality risk with and without relapse, and compare it to men from the Danish population. BACKGROUND: - Testicular cancer is the most common malignancy in young males. Outcomes of a Danish cohort of 3366 patients with stage I TC (1366 non-seminomas (NSTC) and 2000 Seminomas (STC)), were analyzed. METHOD: - The data were analyzed by the "illness-death" model. For the analysis of the transitions between diagnosis, relapse and death we adopted a parametric approach, where the relationship between the intensities and the effect of covariates were specified by Poisson regression models for NSTC and STC individually. RESULTS: - In the NSTC group, 422 patients relapsed. Six relapses (1.4%) occurred after 5 years of follow-up. In the STC group, 389 relapsed. The relapse rate after 5 years was 4.1%. The overall mortality analyses showed that the standardized mortality ratio (SMR) for men with NSTC without relapse, was slightly lower than in the matched general population of Danish men (SMR = 0.9). In STC patients without relapse, SMR was 0.80. Relapse raised the overall mortality by a factor 2.0 for NSTC and 1.5 for STC. CONCLUSIONS: - The fact that few relapses occur 5 years after diagnosis is an important finding for risk assessment in life insurance. It makes it possible to insure men diagnosed with stage I TC, who have not experienced relapse 5 years after diagnosis, on normal terms.

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.

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.

Reliability of estimated glomerular filtration rate in patients treated with platinum containing therapy.

Estimates of glomerular filtration rate (eGFR) are widely used when administering nephrotoxic chemotherapy. No studies performed in oncology patients have shown whether eGFR can safely substitute a measured GFR (mGFR) based on a marker method. We aimed to assess the validity of four major formulas based on PCr (Cockcroft-Gault, MDRD, Wright and CKD-EPI) in comparison to mGFR in an oncology setting. Patients included had disseminated germ cell cancer and received conventional chemotherapy: bleomycin, etoposide and cisplatin. The mGFR of the patients was compared to all estimates with focus on bias (median percentage error), precision (median absolute percentage error) and accuracy (p10 and p30). The precision of carboplatin dosage based on eGFR was calculated. Data on mGFR, eGFR, and PCr were available in 390 patients, with a total of ∼ 1,600 measurements. Median PCr and mGFR synchronically decreased after chemotherapy, yielding high bias and low precision of most estimates. Post-chemotherapy, bias ranged from -0.2% (MDRD after four cycles) to 33.8% (CKD-EPI after five cycles+), precision ranged from 11.6% (MDRD after four cycles) to 33.8% (CKD-EPI after five cycles+) and accuracy (p30) ranged from 37.5% (CKD-EPI after five cycles+) to 86.9% (MDRD after four cycles). Although MDRD appeared acceptable after chemotherapy because of high accuracy, this equation underestimated GFR in all other measurements. Before and years after treatment, Cockcroft-Gault and Wright offered best results. Precision of carboplatin dosage was low. In conclusion, bias, precision and accuracy were unacceptable in all equations due to a synchronous decrease of PCr and mGFR during chemotherapy.