Retroperitoneal lymph node dissection

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In the united States and parts of Europe, the conventional approach to patients who have CS I NSGCT has been bilateral infrahilar RPLND. The main factors in favor of RPLND are that the retroperitoneum is the initial site of metastatic spread in 70% to 80% of patients who have occult metastasis, retroperitoneal lymph nodes often harbor chemotherapy-resistant teratomas, and there is a low rate of relapse following RPLND [12]. The argument for RPLND is thus that the therapeutic focus for CS I patients should be control of the retroperitoneum, and RPLND is the most effective way to achieve this goal.

The four largest series that have described the outcome of CS I patients managed by primary RPLND at centers of excellence are listed in Table 3. The rate of pathologic stage II in these series ranges from 19% to 28%. Of the patients who have pathologic stage II, an estimated 66% to 81% were cured after RPLND alone, demonstrating the therapeutic efficacy of RPLND. Improvements in clinical staging and patient selection have had a favorable impact on the extent of retro-peritoneal metastasis among patients who have low-stage NSGCT. In the Memorial Sloan-Ketter-ing series, approximately two thirds of patients who had pathologic stage II disease had low-volume (pN1) retroperitoneal disease (five or fewer involved nodes, none greater than 2 cm, no extra-nodal extension), and an estimated 90% were cured after RPLND alone [12]. Most RPLND series have reported retroperitoneal recurrences in less than 2% of patients, demonstrating its efficacy for control of regional metastasis. Patients undergoing this operation should be referred to a surgeon who has extensive RPLND experience to achieve comparable results.

The route of metastatic spread for NSGCT is primarily by way of lymphatics to the retroper-itoneum. Hematogenous dissemination that bypasses the retroperitoneum is uncommon in germ cell testicular cancer (GCT) and is usually heralded by elevated serum tumor markers. The rate of occult systemic disease in CS I NSGCT is low. Of the 70% to 81% of patients who have pathologically negative retroperitoneal lymph nodes (pathologic stage I) at RPLND, relapses are reported in 6% to 12%. Among patients who have pathologic stage II, an estimated 20% to 35% have occult systemic disease [12].

The retroperitoneum is the most frequent site of chemoresistant GCT elements and failure to control the retroperitoneum surgically during the initial treatment phase may compromise patient curability. In autopsy studies of patients who died of NSGCT, visceral metastases were late events in the course of the disease and most patients had concomitant (and usually bulky) uncontrolled retroperitoneal disease. Approximately 20% to 30% of CS I patients who have pathologic stage II disease have retroperitoneal teratoma, which is relatively resistant to chemotherapy [12,22,23]. The absence of teratoma in the primary tumor does not reliably predict for its absence in the retroperitoneum among patients who have pathologic stage II [23]. Although histologically benign, the biologic potential of teratoma is unpredictable and it may grow and become unresectable, undergo malignant transformation, or result in late relapse. All of these events may have lethal consequences. The retroperitoneum is also the most frequent site of chemoresistant malignant GCT elements (most commonly yolk sac or EC). In post-chemotherapy RPLND series, 10% to 20% of patients who have metastatic NSGCT have viable malignancy in the retroperitoneum following induction chemotherapy for metastatic

Table 3

Summary of published series of retroperitoneal lymph node dissection for clinical stage I nonseminomatous germ cell testicular cancer

Table 3

Summary of published series of retroperitoneal lymph node dissection for clinical stage I nonseminomatous germ cell testicular cancer

PS

Retroperitoneal

Relapse

Relapse

Adjuvant

Dead of testis

Study

Patients

II (%)

teratoma (%)

PS I (%)

PS II (%)

chemotherapy (%)

cancer (%)

Donohue et al [26]

378

113 (30)

15

12

34

13

3 (0.8)

Hermans et al [8]

292

67 (23)

NR

10

22

12

1 (0.3)

Nicolai et al [9]

322

61 (19)

NR

NR

27

NR

4(1.2)

Stephenson et al [12]

297

83 (28)

15

6

19

15

0

disease [24,25]. For patients who have clinical stage IIA and IIB NSGCT, the incidence of chemoresistant malignancy is estimated to be as high as 8% [12]. RPLND may thus be the best way to ensure long-term cancer control in patients who have metastatic NSGCT.

An important consideration regarding RPLND is that patients who relapse are ''chemo-therapy-nai've" and can be cured with ''good-risk'' cisplatin-based chemotherapy regimens and resection of any residual masses in virtually all cases. In the cisplatin era, the cancer-specific survival after primary RPLND for CS I in the Memorial Sloan-Kettering and Indiana University experience is 100% (297 patients) and 99.4% (666 of 670 patients), respectively [8,26]. In addition, the risk for retroperitoneal relapse after RPLND is less than 2%. By clearing the retroper-itoneum of all GCT elements, the risk for late relapse after RPLND is substantially reduced. Over a median follow-up of almost 5 years, the late relapse rate among 297 CS I patients treated by RPLND at Memorial Sloan-Kettering was 0.3%.

The debate over RPLND is most contentious with regard to patients who have high-risk CS I NSGCT. Relapse rates between 23% and 37% after RPLND have been reported for patients who have CS I with EC predominance or LVI in the primary tumor and pathologic stage I disease [8,9]. Proponents of BEPx2 for CS I have questioned the appropriateness of performing such a major operation in patients who would be left with such a high postoperative risk for relapse [27]. In a review of 267 patients who had CS I and IIA NSGCT with EC predominance or LVI treated by RPLND, 42% had pathologic stage II disease, of whom 54% had pN1 disease and 16% had retroperitoneal teratoma [12]. The 5-year relapse-free probability after RPLND alone for pathologic stage I and pN1 was 90% and 86%, respectively. An estimated 28% of patients required chemotherapy as adjuvant therapy for pathologic stage II or for treatment of relapse. In contrast to the earlier reports, this study thus found that the risk for occult systemic disease in patients who had CS I with EC predominance and LVI is low and, similar to the CS I population overall, the most frequent site of metastatic disease is the retroperitoneum. In this series, RPLND in high-risk patients provided an excellent likelihood of cure without the need for additional therapy in many patients. Nonetheless, nearly one third of high-risk patients receive systemic chemotherapy at some time after RPLND and patients should be so advised when choosing their treatment.

Adjuvant chemotherapy for pathologic stage II

The role of adjuvant chemotherapy after RPLND for patients who have pathologic stage II disease is controversial. A randomized trial of adjuvant chemotherapy versus observation for pathologic stage II NSGCT showed a significant reduction in the rate of relapse (6% versus 49%), but no overall survival difference was demonstrated [28]. Most studies have found that the risk for relapse is related to the size or number of involved lymph nodes [29,30]. As a result, adjuvant chemotherapy is generally recommended for patients who have pN2-3 disease or patients who have pN1 disease who are anticipated to be noncompliant with surveillance testing. Responsible patients who have pN1 disease are safely managed with surveillance given the low (10%-20%) risk for relapse. The administration of two cycles of chemotherapy using either etoposide-cisplatin (EP) or BEP has been associated with 99% relapse-free survival [31,32]. Only patients who are completely resected and are clinically free of disease after RPLND are candidates for adjuvant chemotherapy. Patients who have incompletely resected disease or elevated serum tumor markers postoperatively should receive a full induction chemotherapy regimen.

By pathologically staging the retroperitoneum, RPLND provides more accurate information to gauge patient prognosis and thus the need for subsequent adjuvant therapy is more clearly defined. Some 70% to 80% of CS I patients are pathologic stage (PS) I and up to two thirds of PS II patients have low-volume (pN1) retroperitoneal disease. With RPLND and selective use of adjuvant chemotherapy for PS II disease, overall freedom from relapse rates after RPLND is reported in 85% to 92% of patients and adjuvant chemotherapy is administered to only 12% to 15% of CS I patients overall (40%-50% of patients who have PS II) [8,9,12,26]. If adjuvant chemotherapy is restricted to patients who have PN2-3 disease, up to 84% of patients avoid chemotherapy after RPLND as adjuvant therapy or for treatment of relapse. Many patients who have PN1 disease elect to undergo adjuvant chemotherapy, however, to reduce their relapse risk from more than 10% down to 1% [12].

Morbidity of retroperitoneal lymph node dissection

Primary RPLND is associated with negligible mortality and minimal morbidity rates when performed by experienced surgeons [33,34]. In the Indiana University experience there were no perioperative deaths, no permanent disability from complications, and 2.3% of patients required reoperation [33]. The most common long-term complications of primary RPLND are a 1% to 2% incidence of small bowel obstruction, a 0.4% incidence of lymphocele or chylous ascites, and a midline abdominal surgical scar.

The most consistent long-term sequela of RPLND is the loss of ejaculation, which in turn can compromise fertility. The postganglionic sympathetic fibers from T12-L3 mediate the neuro-muscular events that are responsible for antegrade ejaculation. These fibers form the hypogastric plexus near the takeoff of the inferior mesenteric artery (IMA) just above the aortic bifurcation. Based on the improved understanding of the neuroanatomy of ejaculation, the pattern and distribution of retroperitoneal lymph node metastases for right- and left-sided tumors, and surgical mapping studies, modified RPLND templates were developed initially to minimize intraoperative injury to these structures and ejaculatory rates of 51% to 88% are reported [25,35]. In general, these modified templates attempted to minimize contralateral dissection, particularly below the level of the IMA. More recently, nerve-sparing techniques have been developed whereby the sympathetic chains, the postganglionic sympathetic fibers, and the hypogastric plexus are prospectively identified, meticulously dissected, and preserved [36]. Antegrade ejaculation rates greater than 95% have been reported with these techniques [25]. The completeness of resection should never be compromised to maintain ejaculatory function.

Modified templates of dissection

Modified RPLND remains an appropriate option for low-stage NSGCT but urologists must be diligent to extend the limits of dissection to the appropriate anatomic boundaries. Modified templates minimize contralateral dissection below the IMA. For right-sided tumors, contralateral spread to the para-aortic and left hilar regions is observed in up to 20% of patients who have low-stage NSGCT. Dissection above the IMA should thus extend to the left ureter for right-sided tumors. For left-sided tumors, contralateral spread is uncommon in low-stage disease and contralateral dissection above the IMA can safely extend to the lateral border of the IVC. Retro-aortic and retrocaval dissection should never be omitted within the boundaries of a modified template. Omitting these critical areas exposes patients to the risks of retroperitoneal recurrences, which are associated with diminished survival. Alternatively, the use of nerve-sparing techniques enables a full bilateral infrahilar dissection without compromising ejaculatory dysfunction and this has replaced modified templates at several institutions.

Laparoscopic retroperitoneal lymph node dissection

To reduce the morbidity of RPLND, several investigators have evaluated the role of minimally invasive techniques [37-39]. The therapeutic efficacy of laparoscopic RPLND is largely unknown because virtually all patients who have pathologic stage II disease receive adjuvant chemotherapy regardless of the extent of retroperitoneal disease [37-40]. The routine administration of adjuvant chemotherapy to all patients who have pathologic stage II disease after laparoscopic RPLND leads to an increase in morbidity compared with standard RPLND. Moreover, the templates reported in laparoscopic series are inadequate for complete retroperitoneal clearance. Because of the technical challenge of controlling lumbar vessels, retroa-ortic and retrocaval tissue was not routinely removed in several of the laparoscopic series [38,39]. Some authors do not remove interaorto-caval lymph nodes for left-sided tumors [38,39], nor the preaortic and para-aortic lymph nodes for right-sided tumors [38]. The risk for late relapse with an uncontrolled retroperitoneum in these patients is concerning. Laparoscopic RPLND should be considered an investigational and diagnostic procedure rather than a therapeutic operation for CS I NSGCT.

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