242243 Controversies in the Management of Testicular Cancer
While many aspects of the care of testicular cancer patients and survivors are established, there are a number of areas in which controversy continues to exist. A few of these areas are described next.
Case 1: A 33-year-old man was treated with bleomycin, etoposide, and cisplatin (BEP) for a clinical stage IIA nonseminomatous germ cell tumor (NSGCT). A restaging CT scan showed residual retroperitoneal lymph nodes measuring up to 0.9 cm.
Question 1: Is postchemotherapy retroperitoneal lymph node dissection (RPLND) for patients with sub-centimeter residual masses indicated?
Standards defining the size of “normal” retroperitoneal lymph nodes differ depending on the institution; thus, the indication for RPLND following chemotherapy is controversial (1). Ehrlich et al reported on 141 patients who underwent chemotherapy for metastatic NSGCTs with radiographic complete response (defined as residual mass <1 cm) and subsequent management with surveillance (2). After a median follow-up of 15.5 years, only 12 experienced relapse, and of these only four died. Interestingly, five patients relapsed after more than 2 years (range 3–13 years), emphasizing the need for long-term surveillance in testicular cancer patients. The authors concluded that relapses are rare and potentially curable with treatment on relapse. However, other investigators have identified viable germ cell tumor (GCT) or teratoma in patients with subcentimeter retroperitoneal 244adenopathy. Steyerberg et al evaluated small retroperitoneal masses and found teratoma or viable GCT in 45% of lesions measuring 1.1 mm to 2.0 cm and in 28% of lesions measuring up to 1.0 cm on CT imaging (3). These numbers are concerning since unresected GCTs are likely to relapse and more likely to be resistant to chemotherapy. Growing teratomas may be more difficult to resect than immediately after chemotherapy, and a risk of malignant transformation has been reported. As a result of this information, some institutions advocate postchemotherapy RPLND in select patients with radiographically detectable retroperitoneal masses after chemotherapy.
Question 2: This patient is now considering RPLND, but he is extremely concerned about the risk of retrograde ejaculation after the operation. What are the advantages and concerns of contemporary retroperitoneal lymph node dissection techniques?
The role of RPLND is well established in the management of GCT; however, the extent of resection remains an area of controversy. Before effective chemotherapy was available, extensive resection and removal of all lymph nodes in the retroperitoneum was emphasized. Later studies demonstrated that resection of nodes above the renal hilum provided no additional benefit, but did increase morbidity in patients with low-stage disease. More recently, the focus on preservation of sympathetic innervation to prevent retrograde ejaculation and infertility, which led to the development of nerve-sparing bilateral template RPLND. In high-volume centers, this approach has resulted in antegrade ejaculation in more than 95% of patients undergoing primary RPLND. Anatomic mapping studies led to the development of modified unilateral RPLND, whose goal is to minimize resection while maintaining cancer control (4). The major concern for this approach is the danger of unresected disease outside the resection template, and the primary criticism of these mapping studies was their retrospective nature. Two studies from the Memorial Sloan-Kettering group evaluated the incidence of disease outside the resection template in patients undergoing both primary and postchemotherapy RPLND (5,6). Depending on the setting, up to 32% of patients had either viable GCT or teratoma outside the resection template. These studies challenge 245the equivalence of bilateral and unilateral modified template RPLND, and thus the role of modified unilateral RPLND remains controversial.
Case 2: A 46-year-old man with a history of heavy smoking who was recently diagnosed with stage IIB NSGCT is in your office to discuss options for chemotherapy.
Question 3: Is BEP equivalent to etoposide/cisplatin (EP)?
Cisplatin combination therapy cures even advanced GCTs, and several large studies have demonstrated that carboplatin is inferior to cisplatin for achieving cure (7). Standard chemotherapy treatments have not changed since BEP became a standard regimen for GCTs. The value of using bleomycin with its increased risk of pulmonary toxicity has been questioned in several studies. The Australasian Germ Cell Trial Group compared PVB (cisplatin/vinblastine/bleomycin) with PV (cisplatin/vinblastine) and concluded that there were an increased number of cancer deaths in the PV arm. Thirty-four percent of patients in the PVB arm experienced pulmonary toxicity, but the authors felt that the difference in survival far outweighed the lung issues. In a study conducted by the Genito-Urinary Group of the French Federation of Cancer Centers (GETUG), 270 patients with NSGCT were randomized to receive either three cycles of BEP or four cycles of EP. The 4-year event-free survival rates were 91% for the BEP group and 86% for the EP group (P = .135) (8). The 4-year overall survival rates were not significantly different (5 deaths vs. 12 deaths, respectively [P = .096]). Although outcome did not reach statistical significance, bleomycin has maintained its important role in curative treatment. Most oncologists reserve EP for those who have contraindication to the use of bleomycin. In making a choice between regimens, one must weigh the toxicities associated with the increased cumulative dose of cisplatin and etoposide in four cycles of EP against the risk of pulmonary toxicity from bleomycin in three cycles of BEP. The GETUG demonstrated more neurotoxicity, dermatitis, and Raynaud phenomenon in patients receiving BEP and more high-grade neutropenia in those receiving EP. There was no statistically significant difference in neutropenic fever and pulmonary toxicity between the two arms.
246Question 4: This patient successfully completed his chemotherapy with BEP with no evidence of disease, but has not been compliant with surveillance. He now developed shortness of breath 2 years after completion of chemotherapy and was found to have multiple lung masses bilaterally. The biopsy confirmed recurrent NSGCT. What are the options for second-line chemotherapy?
Overall, 20% to 30% of patients presenting with metastatic GCT are refractory to treatment or relapse after initial chemotherapy. Few prospective studies have addressed the issue of optimal treatment in this setting, and no studies gave compared salvage chemotherapy with high-dose chemotherapy with stem cell rescue. Since the advent of BEP as the optimal initial regimen for GCT, etoposide is generally not used in second-line therapy. Combinations of ifosfamide and cisplatin with either vinblastine (VeIP) or paclitaxel (TIP) are typically used in this setting. The largest single study of VeIP in the second line following EP or BEP in the first line demonstrated 49.6% disease-free status after four cycles of treatment and/or surgical resection of residual disease (9). Seven-year survival in the VeIP study was 32%. The largest study of TIP in the second line in patients who had received BEP was conducted by the British Medical Research Council. The complete response (CR) rate in the study was 31%, with a 1-year failure-free survival of 38% (10). Patients with primary mediastinal GCTs and late relapse were included in this study as they were in the large VeIP study. Comparison of VeIP and TIP in the second line was undertaken in a randomized phase 3 study, but the study was stopped due to poor accrual leaving the choice of regimen in this setting open.
There are also data examining high-dose chemotherapy (HDCT) with stem cell rescue in the second-line setting. The IT-94 study, a European multicenter study, randomized patients who failed first-line platinum containing regimens to either four cycles of VIP or VeIP versus three cycles of VeIP/VIP followed by HDCT with carboplatin, etoposide, and cyclophosphamide with stem cell rescue (11). CR rates were similar in both arms and there was no survival benefit to HDCT, although the study has been criticized for the fact that only one cycle of HDCT was given, and only 81% of patients in the HDCT arm proceeded to transplant. Retrospective data from nearly 2,000 patients treated with conventional chemotherapy and HDCT demonstrated 247superior progression free survival and overall survival in all risk categories (12). Patients with favorable prognostic features may achieve durable remissions without HDCT and its attendant risks. However, the criteria for optimal patient selection remain unclear, and many centers employ a risk stratification algorithm to assist in advising patients. The Alliance randomized phase 3 trial of initial salvage chemotherapy for patients with germ cell tumors (NCT02375204), which compares survival outcomes with TIP versus paclitaxel/ifosfamide/carboplatin/etoposide (TI-CE) for relapsed or refractory GCT patients, should resolve this controversy.