Germ Cell Tumors Pts Research Articles

Large retroperitoneal lymph nodes (RPLN) as a novel risk factor for venous thromboembolism (VTE) in germ cell tumor (GCT) patients (pts) receiving first-line chemotherapy (chemo).

4535 Background: VTE causes substantial morbidity and mortality in GCT pts. The Khorana model is a validated predictive model that stratifies VTE risk in cancer pts receiving chemo; Khorana score ≥3 (K3) identifies pts at high risk. Many GCT pts have bulky RPLN that can cause venous stasis in the lower limbs. This study examines the incidence of VTE in GCT pts and assesses large RPLN as a novel predictor of VTE risk. Methods: Retrospective data from the Princess Margaret Hospital GCT database was complemented by review of medical records. GCT pts receiving 1st line chemo between 2000-2010 were included. Pts diagnosed with VTE prior to chemo and pts receiving thromboprophylaxis (TP) were excluded. Pts diagnosed with VTE during or within 3 months of completing chemo were identified. Large RPLN were defined as having maximal diameter ≥5cm. Odds ratios for VTE risk with large RPLN and K3 were calculated. Discriminatory accuracy (DA) of each predictor was calculated using area under the receiver operating characteristic curves (AUROC). An external cohort from London Regional Cancer Program, with similarly collected data, was used to validate results. Results: In the test cohort 21 (10%) of 216 pts developed VTE. Both large RPLN (OR 6.2, p<0.001) and K3 (OR 11.8, p<0.001) were significantly associated with VTE. Positive predictive value (PPV) was lower for large RPLN compared to K3 (21% v 44%, p<0.014) but sensitivity was greater (71% v 40%, p=0.001), while DA showed no difference (AUROC 0.73 v 0.67, p=0.46). In the validation cohort 10 (9%) of 111 pts developed VTE. There was a non significant trend for associations between VTE and both large RPLN (OR 2.54, p=0.16) and K3 (OR 4.5, p=0.13). When compared to K3, sensitivity was greater for large RPLN (60% v 20%, p=0.003), but there was no difference in PPV (14% v 29%, p=0.25) or DA (AUROC 0.61 v 0.57, p=0.72). Conclusions: VTE occurs in 1 in 10 GCT pts receiving curative chemotherapy. Large RPLN is a novel and clinically applicable predictor of VTE risk, although prospective validation would be beneficial. Randomized controlled trials of TP in GCT pts should be considered in pts at high risk of VTE, identified by large RPLN or K3.

Bone metastases in patients with relapsed/refractory germ cell tumors (GCT) undergoing first salvage chemotherapy: A retrospective analysis of a large international database.

4597 Background: Bone metastases (mets) are rare events in GCT patients (pts) and data on characteristics, risk factors, treatment and outcome in these pts are largely missing. Methods: A subgroup of 104 ptswith bone metsfrom the IPFSG database was analyzed. All patients experienced unequivocal relapse/progression after > 3 cycles of cisplatin-based chemotherapy and received conventional-dose (CDCT) or high-dose salvage chemotherapy (HDCT). Results: 104 / 1594 pts presented with bone mets (6,5%) at first relapse. Histology was pure seminoma in 26%, and non-seminoma in 74%. At initial diagnosis, 54% of pts had presented with "poor risk" according to IGCCCG. Overall response rate (ORR; CR+PR) to 1st-line chemotherapy was 89%. Median PFS after primary treatment was 3 months (range 0 - 140). Bone mets at first relapse were accompanied by abdominal, lung, mediastinal, liver and brain mets in 54%, 48%, 28%, 36%, and 14%, respectively. Tumor marker profiles were heterogeneous (elevation of AFP / ß-HCG: 51% / 37%). Salvage treatment was CDCT in 34%, and HDCT in 66% of pts. ORR to salvage chemotherapy was 68% for the total cohort, and 43% vs. 81% for CDCT vs. HDCT (p<.01). For the total cohort, 2y-PFS and 5y-OS were 24% and 16%, respectively. 2y-PFS and 5y-OS were significantly higher in pts after HDCT compared to CDCT (2y-PFS 29% vs. 14%, p=.01; 5y-OS 19% vs. 9%, p=.04). Conclusions: Pts relapsing with bone mets after platinum-based CTX were characterized by "poor risk" disease at initial diagnosis, but characteristics at first relapse were heterogeneous. Treatment response and outcome was improved in pts with HDCT compared to CDCT. Further prospective evaluation of characteristics and treatment approaches in GCT pts with bone mets is warranted.

Serum tumor marker (STM) decline rates during high-dose chemotherapy (HDCT) to predict outcome for germ cell tumor (GCT) patients (pts).

4532 Background: STM decline rates predict outcome for GCT pts during 1st-line conventional-dose chemotherapy. We investigated the importance of STM decline rates during salvage HDCT. Methods: HDCT included an initial low dose (LD) portion (1-2 cycles of paclitaxel plus ifosfamide [TI] + G-CSF) for stem cell collection followed by a high-dose (HD) portion (3 cycles of carboplatin + etoposide or TI + carboplatin). Eligible pts had elevated STM (AFP >15 and/or HCG >2.2) at the start of LD and completed ≥1 HD cycle. Slope and t1/2 were calculated for HCG and AFP for cycles 1-2 of LD and HD starting with the peak value during days (d) 1-6 of LD and HD to avoid interference from lysis. T1/2 for AFP ≤7d and HCG ≤3.5d were categorized as satisfactory (SAT); normalization within 7d was also considered SAT, regardless of t1/2. Pts with elevated AFP and HCG had to have adequate decline in both to be considered SAT. Progression-free (PFS) and overall survival (OS) were compared for SAT vs. unsatisfactory (UNSAT) pts using the log-rank test. Results: Of 117 pts (115 male, 105 nonseminoma), the most common primary sites were testis (81) and mediastinum (26). 93, 19, and 5 pts completed 3, 2, and 1 HD cycles, respectively. Overall, 19/117 had SAT decline during LD (19/77 for HCG; 7/57 for AFP). For LD, there was no significant difference in PFS or OS for SAT vs. UNSAT decline. For HD, 17/96 had SAT decline (11/59 for HCG; 9/47 for AFP). SAT overall decline (HCG and AFP) during HD predicted superior PFS (p=0.0025) and OS (p=0.0046) with 2-year (yr) PFS 0.88 (0.59, 0.97) vs. 0.37 (0.26, 0.47) and 3yr OS 0.82 (0.55, 0.94) vs. 0.37 (0.26, 0.48). SAT HCG decline alone also predicted superior PFS (p=0.0018) and OS (p=0.004) with 2yr PFS 0.91 (0.51, 0.99) vs. 0.32 (0.19, 0.46) and 3yr OS 0.91 (0.51, 0.99) vs. 0.35 (0.22, 0.50) whereas only a non-significant trend for improved PFS (p=0.14) and OS (p=0.16) was seen for AFP alone. Conclusions: STM decline rates during the HD portion of salvage HDCT predicts favorable PFS and OS, mostly driven by HCG. However, UNSAT STM decline does not exclude long-term PFS/OS. STM decline rates during the initial LD portion of HDCT programs do not predict outcome; thus, UNSAT LD decline should not prohibit subsequent HDCT.

Addition of darbepoetin alfa to sequential high-dose VIP chemotherapy for patients with advanced metastatic germ cell cancer.

e15026 Background: High-dose VIP chemotherapy plus ABSCT given as first line treatment might be a strategy in patient with advanced germ cell tumors (GCT) with poor prognosis. The objective of the trial was to investigate the addition of darbepoetin alfa to HD-VIP in order to reduce anemia/red blood cell (RBC) transfusions. Methods: This was a randomized, open-label multicenter phase 2 study conducted in 20 hospitals. Darbepoetin 2.25 mcg/kg weekly or 500 mcg Q3W s.c., started with high dose VIP (dose level 6) was applied in arm B (arm A: HD-VIP alone). The primary objective was freedom from blood transfusions (FFT). Secondary objectives included objective remission rate (ORR) after chemotherapy, 24 mos PFS and OS, median course of hemoglobin (Hb) levels during 3 HD-VIP cycles as well as drug safety. Results: Between 7/2003 and 11/2008 108 pts were allocated to the study, and 106 were included in the intention-to-treat (ITT) analysis. By March 2011 the median follow-up time after randomization was 20 mos. Localisation of primary was gonadal in 66%, retroperitoneal in 19% and mediastinal in 14%s. A favourable treatment outcome (CR/NED/PR m-) in conjunction with secondary surgery (n = 76 pts) was achieved in 58% of pts with no difference between arms A and B. Overall FFT occurred in 2 pts (4.2%) in arm A and 3 pts (5.6%) in arm B, and in 23%/15%/15% and 15%/17%/19% of pts during cycles 1-3, respectively. No differences in baseline Hb, severity of anemia, no of RBC transfusions and area under the curve of Hb levels during HD-VIP was observed. Pts assigned to darbepoetin had similar treatment toxicity compared to those assigned to HD-VIP alone. 24-mos OS in arm A was 86.3% compared to 67.8% (p=.064) in Arm B. 2-year RFS was 66.8% in arm A vs 55.5% in Arm B (p=0.45). Darbopoetin was generally well tolerated with 2 pts discontinuing treatment due to thrombosis. Since compliance to study protocol was generally poor (6 out of 55 pts never received study drug during HD-VIP) a per-protocol analysis is in preparation. Conclusions: Based on ITT analysis, the addition of darbepoetin alfa to the high dose regimen compared to HD-VIP alone does not appear to impact on FFT, ORR, and 2-year survival rate in poor prognosis GCT pts (NCT00204633).

Phase II study of everolimus (E) in refractory germ cell tumors (GCTs).

TPS4677 Background: GCTs represent a model for the cure of cancer. Nonetheless, a small proportion of patients (pts) develop disease recurrence. Because of insufficient results in the treatment of relapsed GCTs, evaluation of new treatments is a priority. Loss of the tumor suppressor gene PTEN (phosphatase and tensin homolog) marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive GCTs. In the testis, PTEN was abundantly expressed in germ cells whereas it was virtually absent from 56% of seminomas as well as from 86% of embryonal carcinomas and virtually all teratomas. On the contrary, ITGCN intensely expressed PTEN, indicating that loss of PTEN expression is not in early event in GCTs development, but is associated with disease progression. PTEN inactivation is associated with dysregulation of PI3K/Akt pathway and increased mTOR signalling. We hypothesize that dysregulation of PI3K/Akt pathway due to PTEN inactivation in GCTs suggests that these pts could have greater benefit from mTOR inhibition. Methods: In December 2011, National Cancer Institute of Slovakia launched an one arm, two-staged phase II study aimed to evaluate the efficacy and toxicity of E in pts with refractory GCTs. The primary objective is to determine the efficacy of E in patients with refractory GCTs. Secondary objectives includes favourable response rate, time to progression and safety. The pts with radiological and/or serological proof of relapsed GCTs, who were not amenable to be cured by chemotherapy or surgery and who failed at least two platinum-based regimens or one platinum regimen in case of platinum-refractory disease or primary mediastinal non-seminomatous GCTs were eligible. All other standard inclusion and exclusion criteria for study of salvage treatment in refractory GCTs pts were applied. E will be administered at a dose of 10mg daily until progression or unacceptable toxicity. Assuming a response rate of clinical interest of ≥40%, a minimal response rate of 20%, a probability of 5% for rejecting an active drug, and a probability of 20% to further evaluate an ineffective drug, 18 pts will be enrolled into the first cohort. If <4 responses will be observed, the study will be terminated, otherwise, it will be continued with a second cohort of 20 pts.

Large retroperitoneal lymph nodes (RPLN) as a predictor for venous thromboembolism (VTE) in patients (pts) with germ cell tumor (GCT) receiving first-line chemotherapy (chemo).

332 Background: VTE causes significant morbidity and mortality in GCT pts. While an existing and validated predictive model identifies VTE risk in chemo pts with any cancer (Khorana model), a predictive model specific to GCT does not exist. Many GCT pts present with bulky RPLN that produce venous stasis in the lower extremities. The objective of this study was to explore the association between large RPLN and VTE in GCT pts receiving chemo and compare large RPLN as a predictor for VTE in GCT pts to the non-GCT specific Khorana model. Methods: Clinical data from our institutional GCT database was complemented by review of radiology, pharmacy and medical records. All GCT pts receiving 1st line chemo between 1-Jan-00 and 31-Dec-10 were included. Large RPLN were defined as ≥5cm in maximal diameter. Factors used in the Khorana model (baseline BMI, hemoglobin, white cell count and platelets) were collected. We compared the predictive accuracy of large RPLN versus Khorana score ≥3 using receiver operator characteristic (ROC) curve statistical analyses. Results: The cohort consisted of 260 GCT pts, median age 31.5 years, predominantly testis primary (235, 90%) and good risk (171, 66%). 17 (7%) developed VTE prior to the start of chemo. 19 (7%) were given prophylactic anticoagulation, none of whom developed VTE. Of the remaining 224 pts, 20 (9%) developed VTE during chemo. In a univariate analysis, large RPLN was strongly associated with VTE (OR 7.74, p<0.001), as were Khorana score ≥3 (OR 9.81, p<0.001) and hospital admission during chemo (OR 3.96, p=0.004). ROC curve analyses demonstrated large RPLN was a significant individual predictor for VTE (AUC 0.588, p=0.03), however, Khorana score ≥3 was a better predictor (AUC 0.664, p=0.02). Adding large RPLN to create a modified Khorana score provided marginal gains (AUC 0.682, p=0.02). Conclusions: Although large RPLN at diagnosis predicts for VTE in GCT pts, the Khorana predictive model is superior. Given the high rate of VTE in GCT pts receiving chemo, we recommend prophylactic anticoagulation for pts at increased risk, including pts with Khorana score ≥3, pts requiring hospital admission or pts with large RPLN.

Impact of renal impairment and granulocyte colony stimulating factor (GCSF) on bleomycin-induced pneumonitis (bleo lung), febrile neutropenia (FN), and survival in patients (pts) with germ cell tumor (GCT) treated with chemotherapy (chemo).

328 Background: Use of GCSF and the development of renal impairment in GCT pts receiving chemo are common, but their effect on toxicity and survival is unclear. This study examines the impact of GCSF and renal impairment on bleo lung, FN and survival, in GCT pts receiving 1st line chemo. Methods: Clinical data from our institutional GCT database was complemented by review of radiology, pharmacy and medical records. All GCT pts receiving 1st line chemo between 1-Jan-00 and 31-Dec-10 were included. Pts receiving at least one GCSF dose were identified. Renal impairment during chemo was defined as any serum creatinine above the institutional upper limit of normal. Bleo lung was graded (G1-5) using CTCAE criteria. FN was defined as temperature ≥38C and neutrophil count <1.0. Results: The cohort consisted of 260 GCT pts, median age 31.5 years, 171 (66%) had IGCCCG good risk disease, 42 (16%) intermediate, and 41 (16%) poor, while 6 (2%) received adjuvant chemo. 159 (61%) received GCSF and 49 (19%) developed renal impairment. 212 (82%) received BEP of which 73 (34%) developed bleo lung (56 pts G1 asymptomatic, 13 pts G2, 4 pts ≥G3). Renal impairment was associated with bleo lung in univariate (OR 2.87, p=0.008) and multivariate (OR 2.69, p=0.01) analyses. GCSF was associated with increasing severity of bleo lung (OR 1.86, p=0.045) but this was not significant in a multivariate analysis (OR 1.72, p=0.08). FN occurred in 33 (13%) of 260 pts. Renal impairment (OR 3.91, p=0.001) was associated with FN. Primary GCSF prophylaxis reduced FN (OR 0.26, p=0.001), however, 8 (7%) of 112 patients developed FN in spite of GCSF prophylaxis. Survival analyses demonstrated GCSF and renal impairment did not impact progression free or overall survival (OS), however, bleo lung was associated with poorer OS in a multivariable Cox proportional hazards analysis (HR 2.85, p=0.029). Conclusions: Our findings demonstrate both renal impairment and GCSF are risk factors for bleo lung, while renal impairment itself is also a risk factor for FN. Additionally, we identify bleo lung as a significant poor prognostic factor for OS.

Association of CD4 lymphopenia with survival in patients with advanced cancer.

e21145 Background: Lymphopenia (lyp) is associated with an increased risk of toxicity and early death after cytotoxic chemotherapy (CT) in cancer patients (pts) and is also a prognostic factor for overall survival (OS) and progression free survival (PFS) in lymphoma, breast, and sarcoma pts. We report here the impact of CD4 lyp on patient survival after 10 years. Methods: 220 HIV negative pts treated in 2C dept in the Centre L.Bérard (Lyon, France) were included in this study from 04/99 to11/00. 98 (45%) had lymphoma or myeloma, 58 (26%) sarcoma, 21 (9%) breast cancer and 43 (19%) for other cancers. Two groups of diseases: 1) chemocurable diseases (NHL or germ cell tumors), 2) seldom chemocurable disease (advanced carcinomas and sarcomas). Phenotypic analysis of peripheral blood lymphocyte (ly) subsets on d1 of CT was determined using flow cytometry. Prognostic factors were analyzed univariate and multivariate analysis using Cox model. Results: With a minimum follow-up of 10 years in the entire group, age>60, PS >1, stage, tumor type, baseline ly <700/uL, CD4 count<450/uL CD8<400/uL correlated to OS in univariate analysis. Using Cox model, age, PS, stage, tumor type, use of high-risk CT, and ly subsets independently correlated to OS. In lymphoma pts, baseline ly count<700/uL, CD4 count<450/uL, CD56 count <100/uL were independent prognostic factors for OS and PFS using Cox model. In sarcoma pts, baseline ly count <700/uL, CD4 count <450/uL and CD8 count <400/uL were independent risk factors for OS and PFS in multivariate analysis. In pts with seldom chemocurable diseases (advanced carcinomas and sarcomas), all pts with total ly < 400/ uL or CD4 ly < 200/ uL died within 18 months (median: 6 mos). In lymphoma and germ cell tumor pts, all pts but one with ly< 200/ uL or CD4 lymphocytes < 100/ uL relapsed and died. Conclusions: Peripheral blood lymphocyte subsets prior to initiation of CT is a strong predictor of OS and PFS in this series. All pts with advanced breast carcinoma or sarcoma and CD4 count<200/uL had a very short term survival.

Predictive factors for additional vascular procedures in patients with germ cell tumors (GCT) and residual tumor resection (RTR): A multicenter analysis of the German Testicular Cancer Study Groups (GTCSG).

e15050 Background: The aim of this analysis was to identify parameters to predict additional vascular procedures during RTR in a multicenter setting in patients (pts) with GCT after chemotherapy. Methods: A retrospective analysis was performed in 411 GCT pts who underwent RTR in multiple centers. 380 of 411 pts had a sufficient follow-up and were evaluable with complete data sets. The RTR database was queried for additional vascular procedures (cava resection, aortic prosthesis) and correlated to IGCCCG classification and residual tumor volume. The median age of patients was 32 yrs (14-67). 44% of patients initially had IGCCCG intermediate/poor prognosis features. Results: In 34 RTRs a vena cava resection was necessary. The necessity of vena cava resection was significantly correlated with initial IGCCCG classification (16.6% intermediate/poor vs. 4.5% good; p<0.001) but not with tumor size (9.2% residual tumor size <5cm vs. 17.2% residual tumor size >5cm; p=0.0624). In 5 patients an aortic resection and prosthesis during RTR was required. There was no significant correlation to IGCCCG (2.2% intermediate/poor vs. 0.7% good; p=0.2877) but to tumor size (0.6% residual tumor size <5cm vs. 4.5% residual tumor size >5cm; p=0.0340). Conclusions: The necessity for additional vascular procedures (cava resection, aortic prosthesis) during RTR is correlated to the residual tumor size and initial IGCCCG classification. Patients with high volume residual tumors (>5cm) and with IGCCCG intermediate/poor risk features can be initially identified as high risk patients for vascular procedures and therefore should be referred to specialized surgical centers with ad hoc possibility of vascular interventions.

Nonepithelial ovarian cancer: Outcomes after aggressive treatment with surgery and platinum-based chemotherapy.

e15548 Background: Nonepithelial ovarian malignancies account for approximately 10% of all ovarian cancers. Germ cell tumors (GCTs) represent 5% of all ovarian neoplasms and sex cord stromal tumors (SCSTs) are rare neoplasms that account for 3%–5% of them. The aim of this study was to review treatment outcomes in patients (pts) with malignant nonepithelial ovarian cancer in a single institution. Methods: Data from all pts with nonepithelial ovarian cancer sequentially diagnosed and treated at Instituto do Câncer do Estado de São Paulo (ICESP) from 1992 to 2006 were retrospectively reviewed. Results: 38 pts were identified. Median age was 52 y (22-82) for SCTCs and 20 y (12-49) for GCTs. Twelve pts (31.6%) had granulosa cell tumors, 8 (21.1%) immature teratomas, 7 (18.4%) dysgerminomas, 4 (10.5%) endodermal sinus tumors, 3 (7.9%) Sertoli–Leydig cell tumors and 1 (2.6%) embryonal carcinoma. Pts were staged according to FIGO system and 17 (54.8%) were classified as stage I, 3 (9.7%) stage II, 9 (29%) stage III, and 2 (6.5%) stage IV. Surgery was performed in all pts: pan-hysterectomy in 51.5% (17 pts) and unilateral salpingo-oophorectomy or oophorectomy for fertility preservation in 7 (21.2%) and 8 pts (24.2%), respectively; omentectomy in 19 pts (63.3%) and lymphadenectomy in 8 pts (27.6%). Considered as having a high recurrence risk, 37 pts (97.4%) received platinum-based chemotherapy: 17 GCT pts and 14 SCTC pts with adjuvant (n = 31, 83.8%) and 6 pts with palliative intent (n = 6, 16.2%). Twenty-eight pts (75.7%) received BEP regimen and 8 pts (21.6%) were treated with carboplatin and etoposide. At a median follow-up of 4.2 y, 7 pts (18.4%) experienced disease recurrence (3 GCTs and 4 SCTCs) and 24 pts (94.7%) remained alive. One death was observed among GCT pts. The 5-year overall survival rate was 95%. Conclusions: In this high-recurrence-risk group of nonepithelial ovarian cancers, aggressive treatment with surgery and platinum- based chemotherapy resulted in excellent survival outcomes. No significant financial relationships to disclose.

Paclitaxel (T) plus ifosfamide (I) followed by high-dose carboplatin (C) and etoposide (E) with autologous stem cell support for patients (pts) with previously treated germ cell tumors (GCT): TI-CE results and prognostic factor analysis in 107 pts

5027 Background: Pts with incomplete response (IR) to first-line chemotherapy or relapsed primary mediastinal non-seminomatous GCT (NSGCT) have &lt;10% 3-year (yr) survival with conventional-dose salvage regimens (Cancer. 67:1305). The doses, schedule, and safety of TI-CE in this population were previously reported (J Clin Oncol. 25: 85). Efficacy and prognostic factor analysis are now presented. Methods: Phase I/II trial of TI-CE conducted in GCT pts with progressive disease following chemotherapy and unfavorable prognostic features (extragonadal primary site, IR to first-line therapy, or relapse/IR to ifosfamide/cisplatin-based conventional-dose salvage). Univariate and multivariate analyses of prognostic factors were performed. Einhorn (N Eng J Med. 357:340) and Beyer (J Clin Oncol. 14: 263) prognostic models were also assessed. Results: Of 107 pts, primary site was testis in 72, mediastinum (all NSGCT) in 21, and other in 14. 81 had 1 prior line of therapy and 26 had ≥2. 79 were platinum-refractory and 7 had late relapses. A complete response was achieved in 54 (50%) and partial response with negative markers in 8 (8%). 5-yr disease-free survival (DFS) was 47% and overall survival 52% with a median follow-up of 61 months (m). No relapses occurred after 2 yrs. 5/21 (24%) primary mediastinal NSGCT and 2/7 late relapses are continuously disease-free. On multivariate analysis, primary mediastinal site (p = 0.0002), ≥2 lines of prior therapy (p = 0.0005), baseline HCG &gt;1000 (p = 0.01), and lung metastases (p = 0.02) significantly predicted adverse DFS. By Beyer model, 79% were intermediate and 21% poor risk (0 good risk). DFS was better for intermediate than poor risk pts (p &lt; 0.002), with 2-year rates of 54% and 23%, respectively. By Einhorn model, 15% pts were good, 38% intermediate, and 47% poor risk; good/intermediate risk pts had superior DFS compared to poor risk pts (p &lt; 0.05) with DFS at 2 yrs of 69% vs. 44%. Conclusions: TI-CE is effective salvage therapy for GCT pts with poor prognostic features. Mediastinal primary site and ≥2 lines of prior therapy were most predictive of adverse DFS. Beyer &amp; Einhorn models can assist in predicting outcome. No significant financial relationships to disclose.

A phase II trial of high-dose chemotherapy (HDCT) supported by haematopoietic stem cell transplantation (HSCT) in patients (pts) with disseminated germ-cell tumors (GCTs) failing chemotherapy and with adverse prognostic factors: The TAXIF II protocol

5028 Background: HDCT using the etoposide-carboplatin ± ifosfamide regimen is able to circumvent resistance in GCT pts, even when used as third-line or later therapy (Lotz, Ann Onco.l 2005 / Einhorn, N Eng J Med. 2007). Pts whose relapses occur more than 4 w after CDDP-based CT are probably the best candidates for HDCT. Epirubicine (E) and paclitaxel (P) possess interesting activity in GCTs. Thiotepa (TTP) and P can be safely combined at HD with good efficacy. The ICE regimen is a well-known worldwide used regimen. Methods: Non-resistant/refractory GCTs pts failing CT and with adverse prognostic factors were planned to receive 2 cycles combining (mg/m2) E (100) and P (250), given on day 1 and 14 supported by filgrastim (F), followed by 3 consecutive HDCTs [1 course combining a 3-d combination of P (360) + TTP (720), followed by 2 ICE regimens (IFM, 12 g/m2, CBDCA, AUC 20, VP16, 1,500 mg/m2), given on 5 days with HSCT and F]. Inclusion criterias were mainly: radiologically and/or biologically mesurable disease, seminomatous GCT in relapse after 2 lines of CT (BEP/VeIP), non-seminomatous GCT in relapse after 1 or 2 lines of CT or in PR after 1 line of CT, primary mediastinal GCT in first relapse. Resistant / refractory pts were excluded. PBSC were collected after the first ± the second courses of EP (aim: 9x10E6 CD34+/kg BW). We report herein on the preliminary results of this multicentric study. Results: From 09/04 to 12/07, 45 pre-treated (BEP ± VeIP) pts with gonadal (89%) or extra-gonadal T (11%) were treated in second-line (27%), 3rd-line (44 %) or more (29 %). Thirty-five pts received 1 HDCT, 29 two HDCTs and 21 pts could receive the whole protocol. At the time of analysis (12/08), the final overall response rate was 47%, 10 pts were in continuous CR (median time, 8 m; range, 1–18), and 37 pts (82%) were alive at a median F/U of 9 m (range, 1–26). The 1-y survival rate was 90%. The 1-y PFS rate was 62%. One pt died of multi-organ failure and 7 died of disease progression. Conclusions: This HDCT program preceded by 2 semi-intensive cycles of E-P is highly effective in non-resistant/refractory pts with disseminated GCTS failing CT and with adverse prognostic factors. No significant financial relationships to disclose.

Outcome in 41 patients with late relapse germ cell tumors (GCT) treated with high-dose chemotherapy (HDCT)

5086 Background: The management of patients (pts) with late-relapse GCT and unresectable tumors or very high tumor markers is controversial. Methods: A total of 41 late-relapse pts were identified among a group of 216 pts with refractory or relapsed GCT who were treated in an open, prospective, randomized, multicenter phase III trial. Late relapse was defined as any relapse occurring more than 2 years after completion of initial chemotherapy for GCT. Treatment consisted of either one cycle cisplatin 100 mg/m2, etoposide 375 mg/m2 and ifosfamide 6 g/m2 (VIP) plus three cycles of high-dose carboplatin 1,500 mg/m2 and etoposide 1,500 mg/m2 (CE, arm A) or of three cycles of VIP plus one cycle high-dose carboplatin 2,200 mg/m2, etoposide 1,800 mg/m2 and cyclophosphamide 6,400 mg/m2 (CEC, arm B). Each HDCT was followed by reinfusion of autologous peripheral blood progenitor cells. Results: Overall 20 pts with late-relapse GCT received sequential HDCT and 21 pts single HDCT when the study was stopped due to excess treatment-related mortality in arm B; median time to late relapse in 41 pts was 5.4 years (range 2–18 years); 8/41 (20%) pts had seminomatous GCT, 32/41 (78%) pts had nonseminomatous GCT with or without teratoma; one pt (2%) had unknown GCT histology. No non-GCT histologies were included. The retroperitonum was most commonly involved in 30/41 (73%) pts. 29 of 41 (71%) pts had unresectable, multifocal disease and 20/41 (49%) pts also had very high markers. A complete remission to chemotherapy alone was achieved in 4/41 (10%) pts, 16/41 (39%) pts achieved a partial remission with negative tumor markers. The remaining 21/41 (51%) either had a transient or no response despite HDCT. Residual tumor resections were performed in 17/41 (41%) pts. Residual tumor histology was viable cancer in 8/17 (47%) pts, teratoma in 4/17 (24%) pts and necrosis in 5/17 (25%) pts. With a minimum follow-up of 1 year and a median follow-up of 3 years the estimated Kaplan-Meier rates are 17%, 20% and 32% for event-free, progression-free and overall survival. Conclusion: Treatment outcome after HDCT was inferior in late-relapse pts compared to the group of pts who relapsed within less than 2 years. Despite an overall poor prognosis, HDCT can still result in long-term remissions in selected late-relapse GCT pts. No significant financial relationships to disclose.

Evaluation of prognosis in relapsed germ cell tumors: Identification of patients who profit from high dose chemotherapy (HDCT)

4585 Background: To identify prognostic variables in patients (pts) with metastatic germ cell tumors (GCT) and relapse or progression after first-line chemotherapy (FLC). Methods: In our database of 257 GCT pts treated with HDCT, 176/257 (67.4%) pts with first relapse or progression were identified. All patients had received platinum-based FLC. As salvage treatment all pts had received 1–3 cycles of conventional-dose salvage chemotherapy (CDCT) followed by one cycle HDCT. First, pts were retrospectively classified according to a prognostic score developed for CDCT by Fossa et al. [Br J Cancer 1999,80:1392], based on variables present at the time of relapse. Thereafter, a multivariate analysis was performed to evaluate further risk factors. Results: After a median follow up of 9 years the event-free survival (EFS) and overall survival (OS) for all 176 patients was 34% and 38%, respectively. Patients with good (n= 100/176, 57%) and poor (n = 76/176, 43%) prognosis in accordance to Fossa et al. showed an EFS of 41% and 26% (p &lt; 0.01) and an OS of 47% and 26% (p &lt; 0.01). Thus, in contrast to the data of Fossa et al, long-term survival could be demonstrated even in the poor prognosis subset. In the multivariate analysis, the level of elevated tumor markers alfa-fetoprotein and human chorionic gonadotrophin (p &lt; 0.01), the presence of extrapulmonal visceral metastases (p &lt; 0.01) and refractoriness to cisplatin (p &lt; 0.01) adversely influenced OS after HDCT significantly. Based on these latter factors three different groups with increasingly poor OS could be identified: none factor (n = 39/176, 22%) 4 year OS of 59%, one factor (n = 78/176, 44%) 6 year OS of 42% and more than one factor (n = 59/176, 34%) 4 year OS of 17%. Conclusion: In pts with first relapse or progression after platinum-based FLC high serum tumor markers, presence of extrapulmonal visceral metastases and cisplatin refractoriness proved to be independent prognostic significance for OS after salvage HDCT. However, even in the poor prognosis subset long-term survival could be demonstrated. No significant financial relationships to disclose.

Salvage chemotherapy with high dose carboplatin + etoposide (HDCE) and peripheral blood stem cell transplant (PBSCT) in patients with germ cell tumors (GCT)

4549 Background: We began studies with HDCE for patients (pts.) with recurrent GCTs 20 years ago. During the past decade, better supportive care and use of PBSCT allowed outpatient therapy and more rapid hematopoietic recovery between the 2 courses of HDCE. Methods: Retrospective review of 184 consecutive pts. treated with HDCE at Indiana University from 2–96 to 12–04. Late relapse (&gt; 2 years from prior therapy) and primary mediastinal non-seminomatous germ cell tumor pts. were not offered HDCE. Cytoreduction with 0–2 courses of vinblastine + ifosfamide + cisplatin preceded HDCE. C dosage was 700 mg/M2 × 3 and E 750 mg/M2 × 3. A second course was given after hematologic recovery. Results: Toxicity was as previously described (JCO 18:3346, 2000). There were 3 drug- related mortalities. An additional 3 patients developed AML (2 fatal), and 1 glioma following CNS XRT for metastases. 11 pts. did not receive second course (8 due to progression or HDCE mortality). Median time to second course HDCE was 28 days (range 20 to 42). 116 of 184 pts. are alive and continuously (cont) NED (63%) with median followup 42 months (range 11 to 118). 113 (97%) of these are 12+ months NED. 5 additional pts. are currently NED with further therapy. Results are tabulated below. Conclusions: HDCE has a high cure rate with acceptable toxicity as salvage therapy for GCT pts. [Table: see text] [Table: see text]

25 P The role of a cytoreductive surgery in nonseminomatus germ cell tumor patients with small retroperitoneal mass after induction cemoterapy

We identify 64 nonseminomatos germ cell tumor pts, received 4 cycles of the induction chemoterapy with VAB-6, BEP or EP, who presented a residual retroperitoneal mass (RRM) < 2 cm (med. 1.0, range 0.4–2.0), measured by an abdomen CT scan and ultrasound. All pts were marker negative and underwent a retroperitoneal dissection. The correlation of pathologic findings with a size of RRM are presented in the table.HistologyNumberTumor size of pts (cm)<1.01.1-1.51.5-2.0Fibrosis/necrosis473359Mature teratoma16-313MalignancyI-0IRelapse31(14 mo)1(6mo)21(25mo) Fibrosis/necrosis was observed in all resected RRM < 1.0cm. Pts Wlth RRM > l.0cm frequetly had teratoma and I pt hed a mailgnacy Retroperitoneal relapses occurred in 3 pts. Our data suggests that surgery could be safely avoid in a marker negative pis who presented RRM < 10cm