Except for the single-agent carboplatin, most chemotherapy regimens used to treat testicular cancer are combinations of 2 or more chemotherapy agents. For this review, we will focus on the 3 most commonly used regimens: bleomycin, etoposide, and cisplatin (BEP), etoposide and cisplatin (EP), and etoposide, ifosfamide, and cisplatin (VIP).
The core principles of testicular cancer chemotherapy are:
- Minimize dose interruptions, delays, or reductions, as these adversely affect outcomes without clearly improving side effect profile;
- Do not substitute carboplatin for cisplatin in combination regimens because carboplatin-containing combination regimens have been shown to result in significantly poorer outcomes in multiple trials of adults with germ cell tumors;24-27 and
- Give myeloid growth factor support, if necessary.
The standard BEP regimen comprises a 21-day cycle with bleomycin 30 units on days 1, 8, and 15; etoposide 100 mg/m2 on days 1 to 5; and cisplatin 20 mg/m2 on days 1 to 5. Number of cycles varies based on histology and stage (Table 3). A strong justification to maintain treatment intensity comes from the Australian and New Zealand Germ Cell Trial Group trial. In this study, 166 men were randomly assigned to treatment using 3 cycles of standard BEP or 4 cycles of a modified BEP regimen (bleomycin 30 units day 1; etoposide 120 mg/m2 days 1 to 3; cisplatin 100 mg/m2 day 1) every 21 days. This trial was stopped at interim analyses because the modified BEP arm was inferior to the standard BEP arm. With a median follow-up of 8.5 years, 8-year overall survival was 92% with standard BEP and 83% with modified BEP (P = 0.037).28
Bleomycin used in the BEP regimen has been associated with uncommon but potentially fatal pulmonary toxicity that tends to present as interstitial pneumonitis, which may ultimately progress to fibrosis or bronchiolitis obliterans with organizing pneumonia.29 This has led to evaluation of EP as an alternative to BEP.
The standard EP regimen consists of a 21-day cycle with etoposide 100 mg/m2 on days 1 to 5, and cisplatin 20 mg/m2 on days 1 to 5. Due to conflicting data from multiple randomized trials, there is considerable debate in the field regarding whether 4 cycles of EP are equivalent to 3 cycles of BEP.30,31 The benefit of the EP regimen is that it avoids the higher rates of pulmonary, cutaneous, and neurologic toxicities associated bleomycin, but it does result in the patient receiving an up to 33% higher cumulative dose of cisplatin and etoposide due to the extra cycle of treatment. This has important implications in terms of tolerability and side effects, including delayed toxicities such as second malignancies, which increase with a higher cumulative dose of these agents (etoposide in particular).
The standard VIP regimen consists of a 21-day cycle with etoposide 75 mg/m2 on days 1 to 5; cisplatin 20 mg/m2 on days 1 to 5; ifosfamide 1200 mg/m2 on days 1 to 5; and mesna 120 mg/m2 IV push on day 1 followed by 1200 mg/m2 on days 1 to 5. For patients with intermediate- or poor-risk disease, 4 cycles of VIP has demonstrated comparable efficacy but higher rates of hematologic toxicities compared with 4 cycles of BEP.32-34 It remains an option for upfront treatment of patients who are not good candidates for a bleomycin-based regimen, and for patients who need salvage chemotherapy.
Adverse Effects of Chemotherapy
Acute and late chemotherapy toxicities vary significantly between regimens depending on the chemotherapy drugs used. Bleomycin-induced pneumonitis may masquerade as a “pneumonia,” which can lead to a delay in diagnosis or institution of treatment, as well as institution of an incorrect treatment (for example, there is a concern that bleomycin toxicity can be precipitated or worsened by a high fraction of inspired oxygen). Chemotherapy-associated neutropenia tends to occur a few days (7–10 days) after initiation of chemotherapy, and neutrophil counts recover without intervention in most patients after an additional 7 to 10 days. Myeloid growth factor support (eg, filgrastim, pegfilgrastim) can be given to patients either prophylactically (if they had an episode of febrile or prolonged neutropenia with the preceding cycle) or secondarily if they present with neutropenia (an absolute neutrophil count ≤ 500 cells/µL) with fever or active infection. Such interventions tend to shorten the duration of neutropenia but does not affect overall survival. Patients with asymptomatic neutropenia do not benefit from growth factor use.35