Optimal Management of Clinical Stage I Testis Cancer: One Size Does Not Fit All
Authors: Ronald de Wit, George J. Bosl
Journal: Journal of Clinical Oncology (2013)

The optimal management for clinical stage (CS) I testicular germ cell tumors (GCTs) is controversial. Simply put, the efficacy of cisplatin-based chemotherapy cures nearly 100% of both seminoma (SEM) and nonseminomatous germ cell tumors (NSGCTs) that relapse after either early definitive treatment or active surveillance. Since no trial data provide evidence for the superiority of one approach over another, personal belief, institutional preference, or national consensus guides the treatment choice. In the article that accompanies this editorial, Nichols et al aim to end the debate, arguing that active surveillance should be recommended to all patients with CS I testicular GCT. We do not believe that the evidence warrants this universal guideline. CS I NSGCTs. The management of CS I NSGCT generates the most debate. The risk of occult metastasis is less than 20% in CS IA NSGCT (lymphovascular invasion [LVI] absent in the primary tumor) and most investigators agree that active surveillance is preferable, although not mandatory. However, the risk of recurrence is 40% to 50% in CS IB NSGCT (LVI present), most commonly in the retroperitoneum. While Nichols et al recommend active surveillance, many prefer one to two cycles of adjuvant chemotherapy and a minority favors nerve-sparing retroperitoneal lymph node dissection (RPLND). A more nuanced approach was outlined in 2006 in a special Urologic Oncology issue in Journal of Clinical Oncology. The differences lie not in the cure rate but, rather, in the proportion of patients who receive chemotherapy to achieve cure and the potential for longterm toxicity that cannot be easily quantified. Does adjuvant chemotherapy have a role in the treatment of CS IB NSGCT? Many, including one of us (R.dW.), believe that it does. Nichols et al argue that adjuvant chemotherapy results in unnecessary treatment for approximately 50% of the patients. One obvious reason for their plea is the increasing awareness of the long-term increased risk for cardiovascular disease and second malignancies attributable to platinum-based chemotherapy. However, the data on late consequences are derived from testis cancer survivors who had mostly received four cycles of cisplatin plus bleomycin plus either vinblastine or etoposide (BEP). The degree to which excess risk exists after one to two cycles of BEP is unknown. The risk is unlikely to be zero, since old data show that even one cycle of cisplatin-based chemotherapy has a measurable effect on renal function. However, a lower risk is likely since a lower risk of acute leukemia was observed after one to two cycles of etoposide compared with four cycles. Therefore, the 50% of patients relapsing from active surveillance require three to four cycles of chemotherapy and face the full risk of late cardiovascular and second malignancy consequences. Therefore, with a systemic relapse rate of 1% to 3%, the reduced late toxicity risk after adjuvant chemotherapy seems reasonable to those who favor it. Does RPLND have a role in CS IB NSGCT? Some, including one of us (G.J.B.), favor RPLND. The relapse rate after RPLND is approximately 5% to 10% and the risk of retrograde ejaculation after a nerve-sparing RPLND is less than 5% in the hands of an expert surgeon. Because the operation is curative for the majority of patients with pathologic stage II disease, only 15% of patients receive chemotherapy after nerve-sparing bilateral RPLND, compared with 50% of patients who relapse during active surveillance, all of whom require three to four cycles of chemotherapy, and 100% of patients with CS IB disease, who receive one to two cycles of adjuvant chemotherapy. Hence, the chemotherapy risks are the least following RPLND. Informed decision-making by these patients is especially relevant since the threshold for preferring early definitive treatment over surveillance is precisely at the actual 50% risk cutoff for recurrence. Nichols et al express concern over the ability of pathologists to identify LVI and the availability of expert surgeons. We posit that neither of these reasons defines acceptable practice. First, LVI is an established component of pathologic staging in GCT and cannot be ignored simply because the pathologic error can be masked by successful chemotherapy. LVI is important in the management of many cancers, so pathologists should be familiar with this feature and be able to reproducibly identify it. Second, while access to expert surgeons might be sometimes limited, RPLND is the standard of care for NSGCT patients with residual retroperitoneal masses greater than 1 cm after chemotherapy. Is it acceptable to have these more difficult postchemotherapy operations performed by ill-trained surgeons, or not performed at all, simply because referral to an expert surgeon is needed? Since expert surgeons are necessary for the management of residual masses, then it follows that they are also available for patients with CS IB NSGCT. CS I SEM. For CS I SEM, we agree that standard management has shifted largely to active surveillance. In the Netherlands, active surveillance has been a standard option for more than a decade. Nonetheless, approximately 5% of relapses occur after 5 years, and a JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 28 OCTOBER 1 2013