Clinical trialPhase 3Testicular cancer

Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council

J Clin Oncol · 2001812 patients (681 in the 5-day vs 3-day comparison)

de Wit R, Roberts JT, Wilkinson PM, de Mulder PH, Mead GM, Fosså SD, et al. J Clin Oncol. 2001. 19:1629-1640

Study type: Clinical trial
Phase: Phase 3
Design: Randomised 2 × 2 factorial equivalence trial (3 vs 4 cycles, and 5-day vs 3-day schedule)
Sample size: 812 patients (681 in the 5-day vs 3-day comparison)
Source: J Clin Oncol · 2001

In plain words

In this large study, men with testicular cancer that had spread but with a good prognosis received 3 or 4 courses of BEP chemotherapy. Treatment results were almost the same in both groups, and quality of life was better with 3 courses. Giving the drugs over 3 days instead of 5 days did not reduce the effect of treatment either.

Key results

90.4% vs 89.4%

Projected 2-year PFS: 3 vs 4 cycles

Difference minus 1.0%; 80% confidence limits minus 3.8% to plus 1.8%; equivalence claimed

88.8% vs 89.7%

Projected 2-year PFS: 5-day vs 3-day

Difference minus 0.9%; 80% confidence limits minus 4.1% to plus 2.2%; equivalence claimed

Essentially similar

Haematological and non-haematological toxicity

Better preserved with 3 cycles

Quality of life

No difference between the 3-day and 5-day schedules

Drugs in this study:Cisplatin (Platinol)Etoposide

Dose and schedule cards

One cycle of adjuvant BEP (stage I non-seminoma)

Clinical stage I non-seminoma with lymphovascular invasion (the EAU’s preferred adjuvant option), or without it in patients who do not want or cannot undergo surveillanceCycle length: One 21-day cycleOn the page “Testicular cancer” · Adjuvant treatment of stage I after orchidectomy

Clinical stage I non-seminoma with lymphovascular invasion (the EAU’s preferred adjuvant option), or without it in patients who do not want or cannot undergo surveillance

Drug	Dose	Route	Schedule
Bleomycin	30 units (30 mg)	IV (or IM)	Days 1, 8 and 15
Etoposide	100 mg/m²	IV	Days 1 to 5
Cisplatin	20 mg/m²	IV	Days 1 to 5

Cycle length: One 21-day cycle
Duration: 1 cycle

The doses of each cycle are those of standard 5-day BEP; SWENOTECA used one cycle of BEP. In the 111 trial, one cycle of 3-day BE500P was given: bleomycin 30,000 IU on days 1, 8 and 15, etoposide 165 mg/m² on days 1 to 3 and cisplatin 50 mg/m² on days 1 and 2, with antibacterial and G-CSF prophylaxis. EAU recommendation. Stage I with persistently raised markers after orchidectomy (IS) is treated as metastatic disease.

On the page “Testicular cancer” · Adjuvant treatment of stage I after orchidectomy

BEP, 3 cycles (good prognosis)

Metastatic seminoma or non-seminoma with IGCCCG good prognosis; also stage IIA/IIB seminoma (the EAU’s preferred option) and stage IIA/IIB non-seminoma with raised markersCycle length: Every 21 daysOn the page “Testicular cancer” · First-line chemotherapy for metastatic disease (by IGCCCG group)

Metastatic seminoma or non-seminoma with IGCCCG good prognosis; also stage IIA/IIB seminoma (the EAU’s preferred option) and stage IIA/IIB non-seminoma with raised markers

Drug	Dose	Route	Schedule
Bleomycin	30 units (30 mg)	IV (or IM)	Days 1, 8 and 15
Etoposide	100 mg/m²	IV	Days 1 to 5
Cisplatin	20 mg/m²	IV	Days 1 to 5

Cycle length: Every 21 days
Duration: 3 cycles (9 doses of bleomycin)

Doses as in the EORTC/MRC trial and the Indiana regimen in the ANZ trial; cisplatin and etoposide doses are within the FDA label ranges. EAU: 5-day schedule at 21-day intervals without delay or dose reduction. A 3-day schedule (etoposide 165 mg/m² on days 1 to 3 and cisplatin 50 mg/m² on days 1 and 2) was equivalent in efficacy in the EORTC/MRC trial. Full regimen page: BEP regimen.

On the page “Testicular cancer” · First-line chemotherapy for metastatic disease (by IGCCCG group)

BEP, 4 cycles (intermediate or poor prognosis)

Seminoma with intermediate prognosis and non-seminoma with IGCCCG intermediate or poor prognosis; in poor prognosis, continue BEP if the marker decline after cycle 1 is favourableCycle length: Every 21 daysOn the page “Testicular cancer” · First-line chemotherapy for metastatic disease (by IGCCCG group)

Seminoma with intermediate prognosis and non-seminoma with IGCCCG intermediate or poor prognosis; in poor prognosis, continue BEP if the marker decline after cycle 1 is favourable

Drug	Dose	Route	Schedule
Bleomycin	30 units (30 mg)	IV (or IM)	Days 1, 8 and 15
Etoposide	100 mg/m²	IV	Days 1 to 5
Cisplatin	20 mg/m²	IV	Days 1 to 5

Cycle length: Every 21 days
Duration: 4 cycles (12 doses of bleomycin)

Doses of each cycle as for 3 cycles of BEP; in the 4-cycle BEP arm of the EORTC trial, bleomycin 30 mg was given weekly for 12 weeks. Place in therapy as in the EAU guideline. In poor prognosis, measure AFP and beta-hCG on days 18–21 of cycle 1; with an unfavourable decline, consider intensification (GETUG 13 regimen). With impaired lung function, VIP is the alternative.

On the page “Testicular cancer” · First-line chemotherapy for metastatic disease (by IGCCCG group)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

13 cycles of BEP

Each cycle: etoposide 500 mg/m² (100 mg/m² on days 1 to 5, or 165 mg/m² on days 1 to 3), cisplatin 100 mg/m² (20 mg/m² on days 1 to 5, or 50 mg/m² on days 1 and 2) and bleomycin 30 mg on days 1, 8 and 15.

24 cycles (bleomycin only in cycles 1 to 3)

The same etoposide and cisplatin doses for 4 cycles; bleomycin 30 mg on days 1, 8 and 15 was given only in cycles 1 to 3.

35-day vs 3-day schedule (second randomisation)

5-day schedule: etoposide 100 mg/m² and cisplatin 20 mg/m² on days 1 to 5. 3-day schedule: etoposide 165 mg/m² on days 1 to 3 and cisplatin 50 mg/m² on days 1 and 2.

Source of the regimen details: Abstract of the paper (PubMed 11250991)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with good-prognosis germ cell cancer, randomised from March 1995 to April 1998. Histology, markers and disease extent were balanced between arms. Detailed inclusion criteria are not given in the abstract.

Endpoints

Primary endpoint: 2-year progression-free survival (PFS); the aim was to rule out a 5% decrease in 2-year PFS. Quality of life was also assessed.

Safety and side effects

The frequencies of haematological and non-haematological toxicities were essentially similar between groups. Exact rates of grade 3 or higher adverse events are not reported in the abstract.

Clinical significance and place in guidelines

Together with the SECSG trial, this trial made 3 cycles of BEP the standard for good prognosis. For good prognosis, the EAU guideline recommends BEP×3 on a 5-day schedule at 21-day intervals without delay or dose reduction.

Limitations

This card is based on the abstract. Equivalence was defined with an 80% confidence limit and a 5% margin. The 4-cycle arm received no bleomycin in the fourth cycle. Good prognosis was defined at the time of design, before the IGCCCG classification was published, and its exact criteria are not given in the abstract.

Original article (DOI)PubMed

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.