Bleomycin, Etoposide, Cisplatin (BEP) administered 3-weekly x 4 remains standard 1st line chemotherapy for intermediate- and poor-risk metastatic germ cell tumours (GCTs). Cure rates are over 90% for good-risk disease, 85% with intermediate-risk, and about 70% for poor-risk disease. Previous strategies to improve first-line chemotherapy have failed to improve cure rates and were more toxic than BEP. New strategies are needed for patients with intermediate and poor-risk disease. BEP is accelerated by cycling Cisplatin and etoposide 2-weekly instead of 3-weekly. The Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) is conducting a trial comparing accelerated BEP with standard BEP. The aim of this study is to determine if accelerated BEP is superior to standard BEP as first-line chemotherapy for intermediate and poor risk metastatic GCTs.
Inclusion Criteria:
1. Age ≥ 11 years and ≤ 45 years on the date of randomisation
2. Histologically or cytologically confirmed germ cell tumour (non-seminoma or seminoma);
or Exceptionally raised tumour markers (AFP ≥ 1000ng/mL and/or HCG ≥ 5000 IU/L)
without histologic or cytologic confirmation in the rare case where pattern of
metastases consistent with GCT, high tumour burden, and a need to start therapy
urgently
3. Primary arising in testis, ovary, retro-peritoneum, or mediastinum
4. Metastatic disease or non-testicular primary
5. Intermediate or poor prognosis as defined by IGCCC classification3 (modified with
different LDH criteria for intermediate risk non-seminoma, and inclusion of ovarian
primaries). (See protocol for more information).
6. Adequate bone marrow function with ANC ≥1.0 x 10^9/L, Platelet count ≥100 x 10^9/L
7. Adequate liver function where bilirubin must be ≤1.5 x ULN, except participants with
Gilbert's Syndrome where bilirubin must be ≤2.0 x ULN; ALT and AST must be ≤2.5 x ULN,
except if the elevations are due to hepatic metastases, in which case ALT and AST must
be ≤ 5 x ULN
8. Adequate renal function with estimated creatinine clearance of ≥60 ml/min according to
the Cockcroft-Gault formula, unless calculated to be < 60 ml/min or borderline in
which case GFR should be formally measured, eg. with EDTA scan
9. ECOG Performance Status of 0, 1, 2, or 3
10. Study treatment both planned and able to start within 14 days of randomisation.
11. Willing and able to comply with all study requirements, including treatment, timing
and nature of required assessments
12. Able to provide signed, written informed consent
Exclusion Criteria:
1. Other primary malignancy (EXCEPT adequately treated non-melanomatous carcinoma of the
skin, germ cell tumour, or other malignancy treated at least 5 years previously with
no evidence of recurrence)
2. Previous chemotherapy or radiotherapy, except if patient has pure seminoma relapsing
after adjuvant radiotherapy or adjuvant chemotherapy with 1-2 doses of single agent
carboplatin or if patient has non-seminoma and poor prognosis by IGCCC criteria in the
rare case where low-dose induction chemotherapy is given prior to registration because
patient is not fit enough to receive protocol chemotherapy (eg. organ failure, vena
cava obstruction, overwhelming burden of disease). In these instances acceptable
regimens include cisplatin 20 mg/m^2 days 1-2 and etoposide 100 mg/m^2 days 1-2;
carboplatin AUC 3 days 1-2 and etoposide 100 mg/m^2 days 1-2; or baby-BOP. Patients
must meet all other inclusion and exclusion criteria at the time of registration.
Additionally participants who need to start therapy urgently prior to completing
study-specific baseline investigations may commence study chemotherapy prior to
registration and randomisation. Such patients must be discussed with the coordinating
centre prior to registration, and must be registered within 10 days of commencing
study chemotherapy.
3. Significant cardiac disease resulting in inability to tolerate IV fluid hydration for
cisplatin
4. Significant co-morbid respiratory disease that contraindicates the use of bleomycin
5. Peripheral neuropathy ≥ grade 2 or clinically significant sensorineural hearing loss
or tinnitus
6. Concurrent illness, including severe infection that may jeopardize the ability of the
participant to undergo the procedures outlined in this protocol with reasonable safety
7. Inadequate contraception. Men must use 2 effective methods of contraception, including
use of a condom, during chemotherapy and for a year after completing chemotherapy.
8. Known allergy or hypersensitivity to any of the study drugs
9. Presence of any psychological, familial, sociological or geographical condition that
in the opinion of the investigator would hamper compliance with the study protocol and
follow-up schedule, including alcohol dependence or drug abuse
The above inclusion and exclusion criteria will apply to stage 1 (n=150) and stage 2 (n=500
including stage 1) of the study. All sites will participate in both stages of the study
with the exception of the Children's Oncology Group who will be participate in stage 1
only.
Other Female Genital
Other Male Genital
Ovary
