Patient selection and indications for postchemotherapy retroperitoneal lymph node dissection

The current indications for surgery after initial systemic chemotherapy depend on several factors, including (1) histology of primary tumor, (2) the presence and size of residual radiographic masses, and (3) the known distributions and natural history of the various post-chemotherapy mass histologies. Others have used predictive models to calculate the likelihood of viable GCT, using these models to guide therapeutic decision-making [26-29].

Histology of primary tumor

The approach to residual masses after chemotherapy in the setting of pure seminoma differs substantially from the residual masses in the setting of nonseminomatous GCT (NSGCT) for several reasons. First, the post-chemotherapy seminoma masses tend to be more desmoplastic in nature and consequently are more intimately associated with the great vessels. The result of this desmoplastic response to chemotherapy is an obliteration of tissue planes, more difficult resection, and resulting increased morbidity. second, teratoma is rare in a pure seminoma mass after chemotherapy. The aforementioned dangerous biologic potential of teratoma is thus avoided.

Lastly, there is evidence that some post-chemotherapy seminoma masses do not require resection. In a study of 55 patients who had advanced seminoma treated with chemotherapy, Herr and colleagues [30] showed that residual retroperitoneal masses greater than 3 cm harbored viable seminoma in 30%, but all masses less than 3 cm were found to have necrosis/fibrosis only. Others have found viable tumor in 13% to 22% of residual masses larger than 3 cm but none in masses smaller than 3 cm [31,32].

The remainder of this article focuses on post-chemotherapy surgery in the setting of NsGCT. in NsGCT, the finding of teratoma in the primary tumor has been associated with teratoma in the post-chemotherapy mass, and also has been incorporated into the multiple predictive models discussed later in this chapter. in general, the finding of teratoma in the primary tumor as a single variable correlates poorly with teratoma in the post-chemotherapy mass, and the authors support removal of all post-chemotherapy residual masses in NsGCT.

Persistent residual radiographic masses

Patients who have good-risk advanced disease experience disappearance of all radiographic tumor in 70% of cases but persistence of radiographic lesions in 30% [33]. The presence of persistent radiographic masses in the setting of normalized STM still poses the risk for residual teratoma or germ cell tumor as previously discussed, and surgery to remove these masses is recommended. Two clinical situations remain controversial, however: (1) the radiologic criteria of abnormal lesions, and (2) the need for surgery in radiologic complete responses to chemotherapy. With regard to radiologic criteria, the cutoff for a significant radiographic lesion varies with different institutions and different definitions of normality are used for CT scans. in some centers, lesions less than 20 mm are considered normal, whereas others classify lesions only less than 15 mm or 10 mm as normal [34-36]. Several investigators have found up to 35% and 44% false-negative rates when the cutoff for normal CT scans was 20 mm and 30 mm, respectively [34,37,38]. Toner and colleagues [39] reviewed their data in 39 patients who had residual masses less than 15 mm and found that 3 patients (8%) had remnant germ cell tumor and 5 (13%) had teratoma. Oldenberg and colleagues [40] confirmed this observation in 87 patients from Norway and found that 33% of lesions less than 20 mm contained ter-atoma or germ cell tumor. This finding was supported by data from Steyerberg and colleagues [41] who found teratoma or viable germ cell tumor in 29% of lesions between 0 to 10 mm and 44% of lesions between 11 to 20 mm. In this study, even lesions less than 10 mm, clearly within the definition of normal at most institutions, still harbored unfavorable histology in almost one third of cases. Size of the residual mass alone in patients who have minimal radiographic lesions after chemotherapy is therefore a poor predictor of histology, and the authors recommend the removal of all detectable masses.

With regard to the need for surgery in patients who initially present with retroperitoneal disease and experience a complete response to chemotherapy, multiple investigators have addressed the outcome of surgery in this setting. Fossa and colleagues [42] examined the retroperitoneal histology in men who had previously metastatic NSGCT with normal post-chemotherapy CT scans. In this series 67% of men had necrosis in the retroperitoneal dissection specimen, 30% had teratoma, and 3% had viable germ cell tumor. In a recent Memorial Sloan-Kettering Cancer Center study, 23% of men who had normal post-chemotherapy CT scans had teratoma in the RPLND specimen [43]. The need for surgery in chemotherapy complete responders thus remains controversial. This uncertainty has led many to attempt to develop instruments to predict retroperitoneal histology and thus theoretically avoid or tailor their surgery.

Predictors of retroperitoneal histology

Models to predict retroperitoneal histology have been developed by several investigators [26-29]. The goal of most models is to avoid surgery in patients who harbor necrosis or fibrosis, thus in those for whom surgery is associated with no therapeutic benefit and may cause unnecessary morbidity. Others have constructed models to predict teratoma in the post-chemotherapy residual mass [43]. These models use various parameters, including primary tumor histology, pre-chemotherapy STM status, post-chemotherapy mass size, and mass size change during chemotherapy. An examination of the sensitivity, specificity, and accuracy of these models is central to their usefulness in the management of residual masses following chemotherapy.

Proponents of predictive models for the probability of necrosis or fibrosis posit such factors as the lack of teratomatous elements in the primary tumor, more than 90% decrease in size of mass, low pre-chemotherapy STM, and serologic complete response as the determinants of whether or not to proceed with surgical removal of the residual mass following induction chemotherapy. For example, Donohue and colleagues [44] studied the change in volume and computerized tomographic density of retroperitoneal disease before and after chemotherapy, the presence of teratoma in the primary testis tumor, and the histologic findings at retroperito-neal lymphadenectomy in 80 patients who had stage B3 or B2/C germ cell tumors. Of the patients who had no teratomatous elements in the original tumor and a greater than 90% decrease in the volume of retroperitoneal masses, no teratoma or viable germ cell tumor was found in the surgical specimen. In contrast, 7 of 9 patients (78%) who had teratomatous elements in the original specimen had either teratoma or carcinoma in the retroperi-toneal lymphadenectomy specimens despite having a greater than 90% decrease in tumor volume (P < .05). These data suggest that patients who have no teratomatous elements in the original specimen and a greater than 90% decrease in the volume of retro-peritoneal masses in response to chemotherapy may be closely observed and thus avoid surgery. This series was updated by Debono and colleagues [35] who examined 295 patients placed into five groups based on response to primary chemotherapy and the presence or absence of teratoma in the primary tumor: group A (complete remission [CR]), group B (unresectable), group C (serologic CR, teratoma-positive primary tumor, resectable partial remission [PR]), group D (serologic CR, teratoma-negative primary tumor, < 90% radiographic PR), and group E (serologic CR, teratoma-negative primary tumor, >90% radiographic PR). Group A, B, and E patients were routinely observed after chemotherapy, whereas group C and D patients were routinely taken to surgery after chemotherapy. The investigators found that patients had no evidence of disease in 92% of group A, 40% of group B, 87% of group C, 86% of group D, and 74% of group E. They concluded that patients who have NSGCT who achieve a serologic and radiographic CR with primary chemotherapy (group A) can be safely observed without surgical intervention, regardless of initial tumor bulk. Patients who had a teratoma-negative primary tumor who achieve a serologic CR and 90% or greater radiographic remission were still found to be of significantly greater risk for relapse on surveillance, and the study concluded that these patients could be either observed or undergo RPLND.

Other groups have performed similar analyses, confirming the Indiana findings. In a small study of 48 patients, Stomper and colleagues [38] found no significant correlation between the combined features of absence of teratoma in a histologic specimen of the primary testicular tumor and CT findings (residual mass size, attenuation, and greater than 90% shrinkage of masses during chemotherapy) and the absence of malignancy or ter-atoma in residual masses. The German Testicular Cancer Study Group [45] also studied percentage shrinkage during chemotherapy in 193 patients who had nonseminomatous germ cell tumor but found that a-fetoprotein (AFP) values before chemotherapy less than 20 ng/mL and a high percentage of shrinkage during chemotherapy reliably predicted only 19% of cases of necrosis with a test accuracy of 75%, a sensitivity to predict necrosis of 52%, and a specificity of 87%. Furthermore, with regard to the issue of teratoma in the orchiectomy specimen as a primary determinant of teratoma in the retroperitoneum, several series have shown that even in the absence of teratoma in the orchiectomy specimen, teratoma is present in 28% to 41% of the post-chemotherapy retro-peritoneal masses [35,43]. Even in the setting of post-chemotherapy masses of less than 1 cm and no teratoma in orchiectomy specimen, teratoma was still found in 19% of the retroperitoneal lymph nodes [43].

Finally, multiple logistic regression analyses incorporating all variables with more sophisticated modeling have been performed by others.

Steyerberg and associates [46] incorporated several patient characteristics in a statistical model, including the presence of teratomatous elements in the primary testis tumor, pre-chemotherapy STM levels, size of residual mass, and reduction in size after chemotherapy. These investigators validated the model in a study of 172 patients and found that this model could predict the probability of necrosis in more than 90% of cases (goodness-of-fit tests, P > .20); however, cancer could not be reliably discriminated from mature teratoma. In an external validation study using this model, Ver-gouwe and colleagues [27] compared the observed histology with the predicted probability in 105 patients who had good-prognosis germ cell cancer who underwent RPLND between 1995 and 1998, finding that nearly all predicted probabilities (n = 101) were less than 70%, and that 35% of patients currently under surveillance (84 out of 241) had predicted probabilities less than 70%, thus concluding that use of the model would change the policy from RPLND to surveillance in relatively few patients.

In summary, extensive modeling has sought to define appropriate post-chemotherapy surgical candidates based on various clinical and pathologic parameters. These investigations have certainly provided insight into predictive factors for necrosis/fibrosis and teratoma in the retroperito-neal specimen. In large single- and multi-institutional series, the combination of factors seemed to more accurately predict histology than the known histologic distributions. Controversy remains about not only whether these models can predict histology with acceptable accuracy and thus stratify patients by need for surgery but also whether these models will ultimately affect disease-specific survival.

Role of imaging

Multiple groups have examined the role of positron emission tomography (PET) in postchemotherapy testis cancer masses. In NSGCT, the usefulness of PET has been hampered by the limited accuracy for predicting viable germ cell tumor as opposed to teratoma, because teratoma can also be 2-18fluoro-deoxy-D-glucose avid, and thus PET positive. Furthermore, inflammation in necrotic masses may mimic viable GCT on PET scans, and timing of PET in relation to chemotherapy is a crucial issue. Most recently, the largest series of PET in post-chemotherapy NSGCT

examined 140 patients who had post-chemotherapy masses following various chemotherapy regimens. The test sensitivity and specificity of PET were 73% and 44%, respectively, with an accuracy of 56%. As in other studies, these authors concluded that FDG-PET for germ cell tumor following chemotherapy has a higher accuracy than CT, but the sensitivity is still too low to avoid subsequent resections in patients who have NSGCT [47-51].

Conversely, the role of PET in seminoma is more encouraging. This clinical promise is largely due to the aforementioned rare teratomatous differentiation of seminoma during chemotherapy. Consequently, the binary outcome of viable tumor versus necrosis/fibrosis increases the accuracy of PET. In the largest prospective trial, involving 51 patients who had pure seminoma, De Santis and colleagues [52] reported that a positive 2-18fluoro-deoxy-D-glucose positron emission tomography (FDG PET) scan reliably predicts the presence of viable residual tumor in post-chemotherapy seminoma residual masses. The specificity, sensitivity, positive predictive value, and negative predictive value of FDG PET were 100% (95% CI, 92%-100%), 80% (95% CI, 44%-95%), 100%, and 96%, respectively, versus 74% (95% CI, 58%-85%), 70% (95% CI, 34%-90%), 37%, and 92%, respectively, for CT discrimination of the residual tumor by size. The efficacy of FDG PET is further supported by the findings of Putra and colleagues [53] in a group of Australian men. In a smaller study by Ganjoo and colleagues [54], however, FDG PET was less efficacious in detecting viable residual seminoma in the post-chemotherapy setting. Although these studies were limited by incomplete pathologic confirmation (ie, some patients did not undergo surgical resection), the improvements in PET accuracy and relative accuracy to CT supports the use of PET in post-chemotherapy seminoma masses. Still, until larger prospective trials are completed, the general 3 cm cutoff rule previously discussed has largely remained standard of care.

Increasing serum tumor markers after chemotherapy

Persistently elevated STMs after chemotherapy present a unique and difficult clinical scenario. Traditionally, elevated tumor markers after primary induction chemotherapy mandates second-line chemotherapy, and persistence of elevated tumor markers following second-line therapy portends a poor prognosis. There is, however, a subset of patients who have elevated STMs after primary chemotherapy who are curable with surgery, particularly those who have normalization of markers following salvage or second-line chemotherapy. Most notable in these situations is the histologic distribution in the retroperitoneal masses, a distribution distinctly different from the more common situation of normalization of tumor markers after induction chemotherapy. For example, Beck and colleagues [55] reviewed 114 patients who had elevated STMs after first-line (50 patients) or second-line chemotherapy (64 patients) who underwent salvage or desperation RPLND between 1977 and 2000 with a minimum follow-up of 2 years. The 5-year overall survival was 53.9%. Sixty-one patients (53.5%) are alive with a median follow-up of 72 months. Fifty-three patients died of disease, with a median time to death of 8.0 months. Histopathology revealed germ cell cancer in 53.5% of patients, teratoma in 34.2% of patients, and fibrosis in 12.2% of patients, with 5-year survival rates of 31.4%, 77.5%, and 85.7%, respectively (P!.0001). The prognostic factors predictive of outcome in this analysis include an increasing b-HCG, serum AFP level, redo RPLND, and germ cell cancer in the resected specimen. Albers and colleagues [56] evaluated 30 patients who had persistent marker elevation after chemotherapy for meta-static germ cell tumors who underwent salvage RPLND with a mean follow-up of 120.3 months (range 1 to 228). Overall persistent viable cancer and teratomatous elements were identified in 64% and 11% of cases, respectively. Seventeen patients (57%) had no evidence of disease after salvage surgery. Those who had worse outcome included poor-risk patients according to International Germ Cell Cancer Collaborative Group (IGCCCG) guidelines [57], viable residual germ cell tumor with predominant embryonal histology, multiple site involvement, and incomplete resection.

Not all patients who had elevated serum markers post-chemotherapy may require second-line chemotherapy. Beck and colleagues [58] reported 11 cases of primary testicular teratoma with post-chemotherapy cystic masses. Fluid from these lesions contained elevated levels of HCG and AFP, and the authors postulated that they may have slow leak of fluid into the serum, resulting in elevated serum markers. Two of the patients who subsequently underwent RPLND had marker normalization postoperatively.

In summary, patients who undergo induction chemotherapy, have increasing STMs, and undergo second-line salvage chemotherapy or highdose chemotherapy with bone marrow support with subsequent normalization of STMs are offered surgery to remove significant residual masses (salvage RPLND). Patients who have clinically localized retroperitoneal disease with increasing STMs despite second-line combination chemotherapy may be offered surgical resection (desperation RPLND), and patients who had previous RPLND with in-field recurrence may be offered a redo RPLND. Their outcomes are described in Table 2 [59-62] and discussed later in this article.

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