Treatment of testicular cancer and the development of secondary malignancies.

1995 ◽  
Vol 13 (1) ◽  
pp. 283-292 ◽  
Author(s):  
C Bokemeyer ◽  
H J Schmoll
Keyword(s):  
Testicular Cancer ◽  
Germ Cell ◽  
Solid Tumors ◽  
Alkylating Agents ◽  
Cell Cancer ◽  
Germ Cell Tumors ◽  
Elevated Risk ◽  
High Dose ◽  
Secondary Neoplasia ◽  
Increased Risk

PURPOSE Secondary neoplasia represents one of the worst possible long-term complications of therapy for testicular cancer, frequently leading to death in patients cured of the primary malignancy. The frequency and importance of secondary malignant disease will be reviewed. METHODS The international literature was screened for reports concerning secondary solid cancers or leukemias in patients treated with chemotherapy or radiotherapy for malignant germ cell tumors. RESULTS Patients with testicular germ cell tumors appear to have a twofold significantly increased risk (range, 0.7 to 3.4) for the development of secondary neoplasia. Apart from contralateral testicular cancers, which are not treatment-related, a largely elevated inherited risk for secondary cancers in patients with germ cell tumors seems unlikely. Radiotherapy is associated with a two- to threefold increased risk for secondary solid tumors (range, 1.3 to 7.5). A three- to sevenfold increased risk seems to exist for the development of solid tumors arising in the previous irradiation ports, such as stomach, pancreatic, bladder, and renal cell cancer, and sarcomas. To date, no significantly elevated risk for secondary solid tumors was observed after chemotherapy, even including regimens with alkylating agents, eg, cisplatin and ifosfamide. However, the risk associated with chemotherapy needs to be reexamined when the median follow-up of studies will exceed more than 10 years. An increased relative risk for secondary leukemias after chemotherapy (range, 1.3 to 3.4) has been reported in three of eight studies with more than 300 patients. Four large studies indicate a significantly elevated risk (range, 15 to 25) for the use of conventional-dose etoposide (< 2 g/m2 cumulative dose); however, with a 5-year cumulative incidence of less than 0.5% of all patients, this risk seems small. Concerning high-dose etoposide regimens (> 2 g/m2), further studies are necessary. CONCLUSION Treatment for testicular cancer is associated with a small, but clearly identifiable, risk for secondary solid tumors that can be attributed to radiotherapy, and for secondary leukemia mainly associated with the use of chemotherapy. The frequency of secondary neoplasia observed is rather low, and in the light of the high cure rate, the risk for the individual patient appears negligible and should not alter current treatment strategies for metastatic testicular cancer.

Salvage Treatment With Paclitaxel, Ifosfamide, and Cisplatin Plus High-Dose Carboplatin, Etoposide, and Thiotepa Followed by Autologous Stem-Cell Rescue in Patients With Relapsed or Refractory Germ Cell Cancer

2001 ◽  
Vol 19 (1) ◽  
pp. 81-88 ◽  
Author(s):  
O. Rick ◽  
C. Bokemeyer ◽  
J. Beyer ◽  
J. T. Hartmann ◽  
N. Schwella ◽  
...  
Keyword(s):  
Stem Cell ◽  
Germ Cell ◽  
Tumor Progression ◽  
Stable Disease ◽  
Multiorgan Failure ◽  
Cell Cancer ◽  
Germ Cell Tumors ◽  
Salvage Treatment ◽  
High Dose ◽  
Salvage Regimen

PURPOSE: To study feasibility and efficacy of a new salvage regimen in patients with relapsed and/or refractory germ cell tumors. PATIENTS AND METHODS: Between May 1995 and February 1997, 80 patients were entered onto a phase II study. Conventional-dose salvage treatment with three cycles of paclitaxel 175 mg/m2, ifosfamide 5 × 1.2 g/m2, and cisplatin 5 × 20 mg/m2 (TIP) was followed by one cycle of high-dose chemotherapy (HDCT) with carboplatin 500 mg/m2 × 3, etoposide 600 mg/m2 × 4, and thiotepa 150 to 250 mg/m2 × 3 (CET). In 23 patients, one additional cycle of paclitaxel 175 mg/m2 and ifosfamide 5 g/m2 (TI) was given immediately before TIP to improve stem-cell mobilization. RESULTS: Fifty-five (69%) of 80 patients responded to TIP, 24 (30%) of 80 patients had stable disease (n = 5) or tumor progression (n = 19), and one patient died. Only 62 (78%) of 80 patients received subsequent HDCT. Among those, 41 (66%) of 62 patients responded and 20 (32%) of 62 patients had stable disease (n = 3) or tumor progression (n = 17). One patient died after HDCT from multiorgan failure. Survival probabilities at 3 years were 30% for overall and 25% for event-free survival. Peripheral neurotoxicity with sensorimotor impairment grade 2 through 4 in 29%, paresthesias grade 2 through 4 in 24%, and skin toxicity grade 2 through 3 in 15% of patients were the most relevant side effects. CONCLUSION: Treatment with TIP followed by high-dose CET is feasible and can induce long-term remissions in 25% of patients with relapsed or refractory germ cell tumors. Peripheral nervous toxicity in approximately one third of patients is a disadvantage of this salvage strategy.

A randomized trial of standard chemotherapy v a high-dose chemotherapy regimen in the treatment of poor prognosis nonseminomatous germ-cell tumors.

1988 ◽  
Vol 6 (6) ◽  
pp. 1031-1040 ◽  
Author(s):  
R F Ozols ◽  
D C Ihde ◽  
W M Linehan ◽  
J Jacob ◽  
Y Ostchega ◽  
...  
Keyword(s):  
Germ Cell ◽  
Dose Regimen ◽  
Standard Therapy ◽  
Poor Prognosis ◽  
Cell Cancer ◽  
Germ Cell Tumors ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
High Dose Regimen ◽  
Disease Free

We performed a prospective randomized trial of a high-dose chemotherapy regimen v standard cisplatin-based chemotherapy in poor prognosis nonseminomatous germ-cell cancer patients. The high-dose regimen consisting of twice the standard dose of cisplatin (P), along with vinblastine (Ve), bleomycin (B), and the epipodophylotoxin etoposide (VP-16) (V) (PVeBV) was compared to the classic regimen with normal dose cisplatin, vinblastine, and bleomycin (PVeB). Eligibility criteria included large abdominal masses, liver metastases, multiple pulmonary metastases, brain metastases, marked elevations in serum tumor markers (alpha-fetoprotein greater than 1,000 ng/mL or the beta-subunit of human chorionic gonadotropin greater than 10,000 mIU), unfavorable histology (pure choriocarcinoma), or extragonadal germ-cell tumors. Fifty-two consecutive patients with poor prognostic features were randomized to receive either PVeBV or PVeB. The median follow-up is 4 years. Treatment with the high-dose regimen increased the complete remission rate (88% v 67%, P = .14) and was associated with a lower relapse rate (17% v 41%, P = .2). The median survival of patients receiving standard therapy was 30 months, while the median survival for patients receiving the high-dose regimen has not been reached. Actuarial 5-year survival for patients treated with the high-dose regimen is 78%, compared with 48% for patients receiving standard therapy (two-sided Mantel-Cox test = .06). Disease-free survival was also superior for patients randomized to PVeBV (P = .03). Sixty-eight percent of patients (23 of 34) randomized to PVeBV are alive and continuously disease-free, compared with 33% (six of 18) for PVeB (P = .02). The major difference in toxicity between the high-dose regimen and standard therapy was the severity of myelosuppression and the incidence of severe hearing loss. Ninety-one percent of patients treated with PVeBV had a WBC count less than 1,000/microL, compared with 50% of patients receiving PVeB (P less than .05). Hearing aids were recommended for 12 patients who received PVeBV and two who received PVeB. The increased effectiveness of the PVeBV regimen in poor prognosis germ-cell cancer patients may relate to the double-dose cisplatin, the addition of VP-16, or to a synergistic effect of these two drugs.

Secondary neoplasms following treatment of malignant germ cell tumors.

1993 ◽  
Vol 11 (9) ◽  
pp. 1703-1709 ◽  
Author(s):  
C Bokemeyer ◽  
H J Schmoll
Keyword(s):  
Testicular Cancer ◽  
Germ Cell ◽  
Cumulative Incidence ◽  
Lymphoblastic Leukemia ◽  
Germ Cell Tumors ◽  
German Population ◽  
Secondary Neoplasms ◽  
Secondary Neoplasia ◽  
Malignant Germ Cell Tumors

PURPOSE The current study investigates the frequency and outcome of secondary malignancies in patients treated for testicular cancer at Hannover University Medical School between 1970 and 1990. PATIENTS AND METHODS One thousand twenty-five patients with a median follow-up duration of 61 months (range, 12 to 240) were included in the analysis. Follow-up was complete in 1,018 patients (99%). Histology was seminoma in 324 patients (38.7%) and nonseminomatous germ cell tumor in 624 patients (61.3%). At the time of median follow-up, 814 patients (79.9%) were alive. RESULTS Fourteen patients developed a secondary neoplasm (cumulative incidence, 1.38%; 95% confidence interval [CI], 0.75 to 2.30); 13 patients had solid tumors and one had secondary lymphoblastic leukemia with a t(4; 11) translocation including band 11q23. None of 224 patients on surveillance strategy (with or without retroperitoneal lymph node dissection [RPLND]) developed a second neoplasm, compared with four of 413 patients (0.97%; 95% CI, 0 to 1.9) after cisplatin-based chemotherapy (not significant) and nine of 332 patients (2.7%; 95% CI, 0.9 to 4.5) after radiotherapy (P = .02). The cumulative incidence of a secondary neoplasia of 1.76% (95% CI, 0.97 to 2.94) in patients treated by radiotherapy and/or chemotherapy was significantly higher compared with patients on surveillance protocols (P = .03). Chemotherapy containing standard-dose etoposide did not increase the risk of occurrence of secondary neoplasms. A significantly elevated relative risk of 7.53 (range, 3.4 to 14.3) compared with the male German population was only found for patients treated by radiotherapy. CONCLUSION Compared with patients who have other curable malignant tumors, an incidence of 1.38 of secondary neoplasms after a median follow-up duration of 61 months is low. The highest risk for secondary neoplasia after treatment of testicular cancer is associated with the use of radiotherapy. Following chemotherapy, no significantly elevated risk was observed. In conclusion, the benefits of curative treatment far outweigh the risk of secondary cancer in patients with malignant germ cell tumors.

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

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15026-e15026
Author(s):  
Joerg Thomas Hartmann ◽  
Bernd Metzner ◽  
Claudia Binder ◽  
Hans-Guenther Mergenthaler ◽  
Oliver Rick ◽  
...  
Keyword(s):  
Germ Cell ◽  
Darbepoetin Alfa ◽  
Poor Prognosis ◽  
Remission Rate ◽  
Cell Cancer ◽  
Germ Cell Tumors ◽  
Primary Objective ◽  
High Dose ◽  
Open Label ◽  
Similar Treatment

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).

High-dose chemotherapy as salvage treatment in germ cell tumors: a multivariate analysis of prognostic variables.

1996 ◽  
Vol 14 (10) ◽  
pp. 2638-2645 ◽  
Author(s):  
J Beyer ◽  
A Kramar ◽  
R Mandanas ◽  
W Linkesch ◽  
A Greinix ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Germ Cell ◽  
Germ Cell Tumors ◽  
The United States ◽  
High Dose Chemotherapy ◽  
Hematopoietic Progenitor Cell ◽  
Risk Category ◽  
High Dose ◽  
Prognostic Variables ◽  
Increased Risk

PURPOSE To identify prognostic variables for response and survival in male patients with relapsed or refractory germ cell tumors treated with high-dose chemotherapy (HDCT) and hematopoietic progenitor cell support. PATIENTS AND METHODS Three hundred ten patients treated with HDCT at four centers in the United States and Europe were retrospectively evaluated. Univariate and multivariate analysis of patient, disease, and treatment characteristics were used for comparisons of response rates and failure-free survival (FFS). RESULTS The actuarial FFS rate was 32% at 1, 30% at 2, and 29% at 3 years. Multivariate analysis identified progressive disease before HDCT, mediastinal nonseminomatous primary tumor, refractory or absolute refractory disease to conventional-dose cisplatin, and human chorionic gonadotropin (HCG) levels greater than 1,000 U/L before HDCT as independent adverse prognostic variables for FFS after HDCT. These variables were used to identify patients with good, intermediate, and poor prognoses. In the good-risk category, the predicted FFS rate at 2 years was 51%, compared with 27% and 5% in the intermediate-risk and poor-risk categories (P < .001). The increased risk for treatment failure was due to both a significantly lower rate of favorable responses and a significantly higher rate of relapses. Within the prognostic categories, the particular HDCT regimen or higher dosages of carboplatin or etoposide did not have a significant influence on treatment outcome. CONCLUSION Prognostic variables for treatment response after HDCT can be identified. The proposed prognostic model might help to optimize the use of HDCT in germ cell tumors and warrants validation in future trials.

Secondary leukemia following high cumulative doses of etoposide in patients treated for advanced germ cell tumors.

1998 ◽  
Vol 16 (10) ◽  
pp. 3386-3391 ◽  
Author(s):  
C Kollmannsberger ◽  
J Beyer ◽  
J P Droz ◽  
A Harstrick ◽  
J T Hartmann ◽  
...  
Keyword(s):  
General Population ◽  
Germ Cell ◽  
Germ Cell Tumors ◽  
High Dose Chemotherapy ◽  
Elevated Risk ◽  
High Dose ◽  
Secondary Acute Myeloid Leukemia ◽  
Low Incidence ◽  
Cell Support

PURPOSE High cumulative epipodophyllotoxin dosages are reported to be associated with an elevated risk for secondary acute myeloid leukemia (s-AML). This study examined the risk of s-AML following cumulative etoposide doses greater than 2 g/m2 in patients with metastatic germ cell tumors (GCT). PATIENTS AND METHODS The incidence of s-AML was retrospectively assessed in patients treated within clinical trials between January 1986 and February 1996 at four university centers. All patients received high-dose chemotherapy (HDCT) plus autologous stem-cell support for metastatic GCT, including high cumulative etoposide doses (> 2 g/m2). Minimum patient follow-up was 12 months. Standardized morbidity ratio (SMR) was calculated to estimate the risk associated with high cumulative etoposide doses, as compared with the general population. RESULTS A total of 302 patients with a median age of 29 years (range, 15 to 55) received a median cumulative etoposide dose of 5 g/m2 (range, 2.4 to 14 g/m2). Four cases of s-AML were observed, which resulted in a cumulative incidence of 1.3% (95% confidence interval [CI], 0.38% to 3.59%) at 52 months of median follow-up (range, 12 to 198). Two cases of secondary myelodysplasia (s-MDS) developed in patients with primary mediastinal GCT. Based on the observed four cases of AML, which are most likely etoposide-related, the risk for developing s-AML (SMR, 160 [95% CI, 43.7 to 411.2]) is significantly increased in comparison to the age-matched general population. CONCLUSION Due to the low incidence of AML in the general population, the significantly elevated risk for developing s-AML affects only 1.3% of all patients who receive etoposide doses greater than 2 g/m2. HDCT, including etoposide doses greater than 2 g/m2, is associated with an acceptably low incidence of s-AML in patients with advanced GCT.

Olaparib as salvage treatment for advanced germ cell tumors after chemotherapy failure: Results of the open-label, single-arm, IGG-02 phase II trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5058-5058
Author(s):  
Ugo De Giorgi ◽  
Giuseppe Schepisi ◽  
Giorgia Gurioli ◽  
Carmela Pisano ◽  
Umberto Basso ◽  
...  
Keyword(s):  
Dna Repair ◽  
Germ Cell ◽  
Phase Ii ◽  
Survival Probability ◽  
Phase Ii Trial ◽  
Cell Cancer ◽  
Germ Cell Tumors ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Open Label

5058 Background: Therapeutic options for patients with advanced germ cell tumors (GCTs) after multiple relapses or resistant disease are limited. Olaparib is an inhibitor of poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. We aimed to evaluate olaparib activity in patients with refractory GCT. Methods: In this proof-of principle open-label, single-arm, phase II trial of olaparib 300 mg twice daily in patients with relapsed/refractory metastatic germ cell cancer IGG-02 study (NCT02533765), patient eligibility included failure after high-dose chemotherapy or after at least 2 different cisplatin-based regimens. Measurements of serum tumor markers and computed tomography were carried out at baseline and every 6 weeks of olaparib treatment. The study primary endpoint was the overall response rate, the study planned to recruit initially 18 patients and not continue further recruitment until one or more responses were observed. Results: Between September 2015 and February 2019, 18 patients, median age 39 years (range, 22-61) were enrolled. The number of prior chemotherapy regimens was: 2 for 3 patients (16.7%), 3 for 5 patients (27.8%), >3 for 10 patients (55.6%). Sixteen cases (89.9%) received prior high-dose chemotherapy with support of hematopoietic progenitor cells. Grade 3-4 adverse events were observed in 5 patients (27.7%). There were no partial responses, 5 cases (27.8%) with stable disease (SD) lasting 3, 4, 4, 7 and 7+ months and 13 (72.2%) progressive disease. The 12-week progression-free survival probability was 27.8% [95% confidence interval (CI): 10.1%-48.9%]. The 12-month overall survival probability was 27.8% (95% CI: 10.1%-48.9%). A germline DNA repair profile panel showed only a BRCA1 mutated case associated with a SD lasted 4 months. Conclusions: Olaparib as a single agent has marginal activity in heavily pretreated GCT patients, however, an anecdotic 4-month SD in the only BRCA mutated patient has been reported. Plans for future studies with olaparib are suggested in combination or following salvage chemotherapy in less pretreated and more selected GCT patients. The Study has been conducted with AstraZeneca contribution. Clinical trial information: NCT02533765 .

Randomized study of cisplatin dose intensity in poor-risk germ cell tumors: a Southeastern Cancer Study Group and Southwest Oncology Group protocol.

1991 ◽  
Vol 9 (7) ◽  
pp. 1163-1172 ◽  
Author(s):  
C R Nichols ◽  
S D Williams ◽  
P J Loehrer ◽  
F A Greco ◽  
E D Crawford ◽  
...  
Keyword(s):  
Germ Cell ◽  
Standard Dose ◽  
Cell Cancer ◽  
Single Agent ◽  
Prospective Trial ◽  
Germ Cell Tumors ◽  
Dose Intensity ◽  
Germ Cell Cancer ◽  
High Dose ◽  
Disease Free

Between 1984 and 1989, 159 patients presenting with advanced germ cell cancer were entered on a randomized clinical trial comparing the efficacy and toxicity of etoposide and bleomycin and either standard-dose cisplatin (20 mg/m2 daily for 5 days) or high-dose cisplatin (40 mg/m2 daily for 5 days). Of the 159 patients, 153 were assessable for toxicity and response. As expected, patients receiving the high-dose cisplatin regimen experienced significantly more neurotoxicity, ototoxicity, nausea and vomiting, and myelo-suppression. Four patients (3%) died related to therapy. Despite the toxicity encountered, dose intensity was maintained. Overall, 84% of patients in the high-dose arm received 80% or more of the projected dose of cisplatin, etoposide, and bleomycin; and 90% of patients on the standard-dose arm received 80% or more of the projected dose. Of the 76 eligible patients randomized to receive the high-dose cisplatin regimen, 52 (68%) became disease-free with chemotherapy alone or with subsequent resection of residual teratoma or cancer. Of the 77 patients randomized to the standard-dose arm, 56 (73%) became disease-free with chemotherapy alone or with surgery. Median follow-up is now 24 months. Eleven patients (three high-dose and eight standard-dose) relapsed from disease-free status. Overall, 74% of patients receiving the high-dose cisplatin regimen are alive, and 63% are continuously free of disease. Of the patients receiving the standard-dose cisplatin regimen, 74% are alive, and 61% are continuously free of disease. This randomized prospective trial in advanced germ cell cancer achieved dose intensity of the most active single agent in this disease. This dose intensity did not translate into an improved survival or cure. We conclude that dose escalation of cisplatin beyond standard doses results in excess toxicity with no accompanying therapeutic benefit.

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