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Reply to G. Daugaard et al, K. Lu, and L.C. Pagliaro et al.

The optimal management of clinical stage I (CS 1) nonseminomatous germ cell tumors (NSGCT) remains controversial. Either early definitive treatment, or watchful waiting and chemotherapy at the time of disease recurrence, cures nearly 100% of patients. The total burden of treatment required to achieve cure, though, is not identical, and recent data show that this burden of treatment has become an essential component of the equation. Daugaard et al recently reported long-term disease-specific survival of 99.1% in 1,226 patients with CS 1 nonseminoma on surveillance. The authors concluded that surveillance is a safe approach with an excellent cure rate and an overall low treatment burden despite a high relapse rate in patients with adverse prognostic features. A noticeable observation in their study, though, was that of the relapsing patients; after full-dose (three to four cycles) chemotherapy, 26% still required postchemotherapy surgery. The postchemotherapy surgery, in most cases retroperitoneal lymph node surgery (RPLND), was done for solid reasons as there was an 8% incidence of residual viable cancer and as high as 50% of patients had mature teratoma (MT) in the resected specimens. In the accompanying editorial, I therefore tended to disagree with the conclusions and recommendations by Daugaard et al. Even though one to two cycles of adjuvant bleomycin, etoposide, and cisplatin (BEP), with recent data indicating that one cycle is sufficient, may represent overtreatment in 50% of high-risk patients with CS1 nonseminoma, the burden associated with full-dose chemotherapy plus the considerable risk of requiring additional surgery in the remaining 50% relapsing patients is substantial. After two decades of watchful waiting as my preferred option, the equation one cycle in all—versus proceeding with three to four cycles, plus a sizable risk for needing postchemotherapy surgery in the 50% of relapsing patients—has shifted my recommendation toward the use of one cycle of BEP in high-risk patients with CS 1 nonseminoma. Daugaard et al wrote a comment on my editorial. The authors dispute my conclusion that relapsing patients needed additional surgery, which could have been avoided by using early definitive (adjuvant) chemotherapy. They state that the finding of MT in 50% of patients indicates that these patients would have required surgery anyway, that is, also after adjuvant chemotherapy, as MT is not chemotherapy sensitive. This, however, is a misconception of germ cell cancer biology. Data on the high frequency of MT in postchemotherapy RPLND for low-volume disease are well known from several large data sets. In the largest series, comprising 300 patients with stage IIA/B disease, MT was found in 70% of the RPLND residuals, whereas 76% of these patients had no MT in the primary tumor. These and similar previous clinical and preclinical findings support the view that that MT may result either from clonal selection from pluripotent cells in metastatic lesions after chemotherapy, or by conversion into MT as a result of chemotherapy. The high frequency of postchemotherapy MT in stage IIA/B disease (stages that reflect the majority of CS 1 relapsing patients) thus evokes concern regarding a policy of surveillance in patients with high risk for recurrence. Early definitive chemotherapy may have spared these patients both relapsing viable cancer, as well as the development of postchemotherapy MT at the site of the metastatic disease that may not have occurred if the metastases had been avoided by the early definitive use of chemotherapy. What renders the findings from the Danish database particularly relevant for clinical practice is that the relapses with the associated frequent need for additional surgery occurred despite applying optimal surveillance consisting of monthly (first year), quarterly (second year), and semiannual visits (third to fifth year) and five to six computed tomography (CT) scans. This schedule is standard and is recommended in current guidelines. In my editorial I merely aimed to discourage a reduction in the number of CT scans as was recently advocated, with the evidence coming from a UK study that compared five CT scans with a mere two CT scans at 3 and 12 months, which was not sufficiently powered to allow any noninferiority conclusions. The comment by Lu on the report by Daugaard et al is helpful in this matter, as he emphasizes that the median time relapses were detected in the Daugaard et al study was 5 months. Hence, the 6-month CT scan in surveillance is essential. Any concerns with adherence to a strict surveillance protocol, as well as anxiety by patients for disease recurrence with each surveillance visit as Lu points out, are valid additional reasons to prefer early definitive treatment. The comments by Pagliaro et al are in line with the above considerations. The authors allude to the total burden of treatment associated with relapse as compared with a single cycle of BEP, and both Lu and Pagliaro et al correctly re-emphasize that few patients need RPLND at any point of time after adjuvant chemotherapy as compared with the frequent requirement to resect postchemotherapy MT following relapsed disease. The equation truly seems to be one BEP cycle in all patients, which will be definitive in over 95% of patients, versus the considerable burden of full-dose chemotherapy plus the sizable risk for additional RPLND in the 50% relapsing patients. These are data that physicians and patients need to consider.