Dose-reduced first cycle of chemotherapy for prevention of life-threatening acute complications in nonseminomatous germ cell tumor patients with ultra high tumor markers and/or poor performance status.

PURPOSE: Patients with metastatic nonseminomatous germ cell tumors (mNSGCT) and a high tumor burden or a poor performance status at initial diagnosis are at risk from potentially life-threatening early complications during or after the first chemotherapy cycle. The outcomes with dose-reduced first cycle of chemotherapy in this population of patients are not well established. METHODS: We performed a retrospective analysis of patients with mNSGCT and International Germ Cell Cancer Collaborative Group (IGCCCG) poor risk features. All patients received cisplatin and etoposide-based combinations as first-line treatment. Ultra high tumor marker levels were defined as α-fetoprotein ≥ 100,000 ng/ml or human chorionic gonadotropin ≥ 200,000 mIU/ml. Before 2005, the first treatment cycle was administered at a full dose in our center. After 2005, we used an abbreviated course of cisplatin and etoposide (EP) for the first cycle, followed by subsequent full-dose administration. RESULTS: From 1987 to 2012, 265 patients with poor risk features according to IGCCCG received first-line chemotherapy. Among them, 63 out of 265 (24%) patients had ultra high tumor marker levels and/or ECOG performance status of 3-4. Dose reduction of the first chemotherapy cycle was associated with a significant decrease of life-threatening complications from 76 to 44% (p = 0.01), but not with the overall survival (HR 0.99, 95% CI 0.44-2.26). CONCLUSIONS: Dose reduction of the first EP cycle by 40-60% in the subgroup of poor risk patients with ultra high tumor marker levels and/or ECOG performance status 3-4 is associated with significantly lowered acute complication rates but not with overall survival.

Nuclear Protein of the Testis Midline Carcinoma Masquerading as a Primary Mediastinal Seminoma.

Nuclear protein of the testis (NUT) midline carcinomas are rare aggressive carcinomas characterized by chromosomal rearrangements that involve the gene encoding the NUT. This article reviews the clinicopathologic features and the differential diagnosis of these malignancies.

Chemotherapy intensification in patients with advanced seminoma and adverse prognostic factors.

PURPOSE: The aim of our study was to identify factors which influence survival in patients with disseminated seminoma in the good prognostic group according to IGCCCG, as well as to evaluate the impact of treatment intensification in patients with negative prognostic factors. METHODS: We analyzed the database of the patients with metastatic seminoma who had received treatment at our department from 1986 to 2005. Inclusion criteria were as follows: morphologically verified seminoma; favorable prognosis according to IGCCCG; modern chemotherapy regimen (EP ± bleomycin); AFP level <15 IU/ml; and HCG level <300 mIU/ml. The primary endpoint was overall survival (OS). RESULTS: With median follow-up 83 months, 5-year OS rate was 91% in 206 patients. Only three negative prognostic factors were associated with OS: retroperitoneal lymph nodes >5 cm (p < 0.01), pulmonary metastases (p < 0.01) and LDH level ≥ 2.25 × ULN (p = 0.01). In view of the obtained data, we have changed our treatment approach since 2005. In case of any negative prognostic factors, we administered an intensified CT regimen--4BEP or 3BEP + 1EP. Prospective phase of the study included 34 patients with unfavorable prognosis. We observed an increase of 5-year OS rate in the intensified CT group in comparison with the standard CT group in patients with unfavorable prognostic from 85 to 100%. CONCLUSION: Administration of 4 cycles of induction CT (4BEP or 3BEP + 1EP) in patients with metastatic seminoma who have LDH level ≥ 2.25 ULN, and/or retroperitoneal lymph nodes >5 cm and/or pulmonary metastases results in decreased disease progression rate and significant gain in OS.

Prognostic factors and efficacy of different chemotherapeutic regimens in patients with mediastinal nonseminomatous germ cell tumors.

PURPOSE: Patients (pts) with mediastinal nonseminomatous germ cell tumors (MNGCT) are belonged to poor prognostic group by IGCCCG. We retrospectively studied the prognostic factors and efficacy of different chemotherapeutic regimen in pts with MNGCT. METHODS: We analyzed data on 61 pts with MNGCT. Conditional induction chemotherapy BEP was performed in 38 %, TBEP-in 28 %, CBOP-in 28 %, accelerated (two weekly) version of BEP-in 6 % pts. Based on similar efficacy of CBOP and TBEP regimens, we combines pts with CPOB and TBEP regimen in one group-55.8 % and different variants of BEP regimen in the second group-44.2 %. Multivariate Cox regression analysis was performed to determine independent factors, which influenced on overall survival. RESULTS: We revealed the following independent negative prognostic factors: age ≥ 24 years (p = 0.07), size of the primary mediastinal tumor ≥19 cm (p = 0.03). Median overall survival (OS) has not been reached, and 2-year OS was 66 % in pts with good prognosis (age < 24 years and/or size of mediastinal tumor < 19 cm) versus 15 months and 40 % in pts with poor prognosis (p = 0.03). Objective marker negative response was revealed more often in pts with CPOB/TBEP group: 26/34 (76.5 %) versus 14/27 (52 %), p = 0.08. Median OS was also higher in pts with CPOB/TBEP group: nonreached versus 15 months (p = 0.01). CONCLUSION: CPOB and TBEP regimen were significantly associated with better outcome in pts with MNGCT. Age ≥ 24 years and size of the primary mediastinal tumor ≥ 19 cm were found as independent negative prognostic factors.

Effect of the timing of orchiectomy on survival in patients with metastatic germ cell tumors of testis.

OBJECTIVES: Classically, orchiectomy (OE) is the first step of treatment in patients with metastatic germ cell tumors (mGCTs) of testis. However, some patients have severe symptoms of disease, which require immediate beginning of chemotherapy (CT) followed by OE. This retrospective analysis was performed to find the effect of time constraints of delayed OE on survival in patients with mGCT. METHODS AND MATERIALS: We analyzed the data of 1,483 CT-naive patients with advanced mGCT of the testis treated in our Department from 1986 to 2009. Delayed OE was performed on 71 (4.8%) patients: seminoma in 8 patients (11.2%), nonseminomatous tumor in 50 patients (70.4%), and unknown tumor histology in 13 patients (18.4%). Twenty percent, 40%, and 40% of patients belonged to good, intermediate, and poor International Germ Cell Cancer Consensus Group prognostic groups, respectively. Median time from the beginning of the CT to OE was 18 (range, 1-250) days. OE was performed on 39 (55%), 21 (29.5%), and 11 (15.5%) patients during cycle 1, cycle 2 to completion of CT, and after the finishing of induction CT, respectively. Median follow-up time was 156 (range, 3-241) months. Etoposide and cisplatin-based CTs were received by 66 patients (93%). RESULTS: Three-year overall survival (OS) of all 1,483 patients was 75%. An excellent primary tumor response to CT was observed among the patients, who had delayed OE after completion of CT (n = 11): only mature teratoma (n = 4) and tumor necrosis (n = 7) were found. The 3-year OS in patients with delayed OE was 63%. OE performed after completion of CT was associated with better prognosis. The 3-year OS in patients with delayed OE performed during the cycle 1 (group 1) was 67%, cycle 2 to completion of CT (group 2) was 39%, and after finishing of CT (group 3) was 88% (groups 1 vs. 3: hazard ratio 3.7, 95% confidence interval 0.69-10.1, P = 0.15; groups 2 vs. 3: P = 0.01, hazard ratio 8.1, 95% confidence interval 1.32-18.,72). It seems that if OE had been performed during CT, the beginning of the successive cycle was delayed and dose intensity of CT was decreased. CONCLUSIONS: In case of severe symptoms of disease, which require an immediate start of CT, performing OE simultaneously with other surgeries after completion of induction CT was associated with better OS, when compared with performing OE during induction CT.

Late relapses (>2 years) in patients with stage I testicular germ cell tumors: predictive factors and survival.

OBJECTIVES: Late relapses (>2 years) after completion of chemotherapy are rare and often platinum-resistant. There are limited data concerning late relapses in chemotherapy-naïve patients with stage I germ cell tumors. This retrospective analysis was performed to compare the outcome between patients with stage I germ cell tumors, who had late (≥2 years) and early (≥3 months and <2 years) relapse after orchiectomy. METHODS AND MATERIALS: We analyzed data of 1,069 chemotherapy-naïve patients with advanced germ cell tumors of testis treated in our department from 1986 to 2008. All patients had cisplatin- and etoposide-based chemotherapy. We identified 169 (15.8%) patients with prior stage I disease, who had not received adjuvant treatment: 140 and 29 patients had early and late relapse, respectively. Among patients with late relapse, pure seminoma was revealed in 14 patients, and nonseminoma in 15 patients. Median follow-up time for 169 patients was 35 (range, 2-218) months. RESULTS: Patients with late relapse were older, 35 years (23-57) and had more frequent pure seminoma in primary tumor, 14/29 (48.3%), than patients with early relapse, 30 years (16-63) (P = 0.0008) and 46/140 (32,8%, P = 0.08), respectively. At the time of disease progression, both groups were very similar according to well-known prognostic factors including IGCCCG classification. The only difference was larger size of retroperitoneal lymph nodes in late (9 cm) than in early relapse (4 cm, P < 0.0001). The outcome in patients with late relapse was significantly worse than in patients with early relapse: complete response rate after induction chemotherapy was 20.7% (6/29) vs. 42.1% (59/140) (P = 0.01), 3-year progression-free survival 66% vs. 84% (P = 0.02, HR = 2.4, 95% CI 1.2-8.8) and 3-year overall survival, 72% vs. 88% (P = 0.04, HR = 2.4, 95% CI 1.05-10.25), respectively. In patients with pure seminoma, this difference in overall survival was even more significant: 65% vs. 91% (P = 0.04, HR = 3.8, 95% CI 1.06-32.4). CONCLUSIONS: Late relapses following stage I germ cell tumors were associated with seminoma, older age, and worse outcome after induction chemotherapy.