Indications, evolving technique, and early outcomes with... : Current Opinion in Urology

Last updated: 03-24-2019

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Indications, evolving technique, and early outcomes with... : Current Opinion in Urology

Recent findings Open RPLND has been the longstanding standard of care for both primary and post chemotherapy RPLND. Recently, robotic RPLND has been an attractive option with the intent of reducing the morbidity associated with open surgery while providing identical oncologic efficacy. Naysayers of robotic RPLND suggest it is often inappropriately used as a staging procedure and consequently can compromise oncologic efficacy.

Summary Robotic RPLND is being evaluated as a therapeutic equivalent to open RPLND. On the basis of limited published data with modest follow-up from experienced centers, robotic RPLND appears to provide effective staging and therapeutic data mirroring that of open surgery.

Testicular cancer is the most common malignancy in men between the ages of 20 and 40 years where 15–40% of patients harbor micrometastatic disease despite no evidence of metastasis on imaging . It is unique among cancers, as patients with limited nodal metastases can often be cured with a retroperitoneal lymph node dissection (RPLND) alone and patients with more extensive disease burden can be cured with platinum-based chemotherapy combined with consolidative surgery. RPLND has classically been performed via an open technique with excellent results. However, open RPLND requires a large incision and can be associated with significant morbidity.

In stage I nonseminomatous germ cell tumor (NSGCT), where ∼20–25% harbor radiographically and serologically undetectable metastatic disease, many men elect surveillance or primary chemotherapy over primary RPLND. However, chemotherapy in young men is associated with an elevated long-term risk of cardiac disease, pulmonary disease, and secondary malignancies Although surveillance can avoid chemotherapy in 70–80% of men, 20–30% will recur and require full induction chemotherapy . Intending to decrease the morbidity associated with open RPLND, robotic-assisted laparoscopic RPLND has been implemented at high-volume centers with favorable preliminary results in both the primary and postchemotherapy setting. The purpose of this review is to examine the indications, technical considerations, and early outcomes of robotic RPLND in testicular cancer.

Surveillance, adjuvant chemotherapy [bleomycin etoposide cisplatin (BEP) x 1–2], and RPLND are all reasonable options for clinical stage I nonseminoma, all associated with a 99% cancer-specific survival. There are variable risks and benefits, both short and long-term for all options. Primary RPLND is an option for selected, well-counseled patients, particularly those with higher risk features for microscopic metastases such as lymphovascular invasion (lymphovascular invasion-stage IB) or predominant embryonal carcinoma in the orchiectomy specimen or patients who are at risk of noncompliance The overall relapse rate following primary RPLND is 5–10%, nearly all should occur outside the retroperitoneum, and salvage rates with chemotherapy are very high . If primary RPLND is performed for stage IA/IB disease, modified templates can be used to reduce the morbidity associated with the operation and maximize the benefit by limiting dissection to the most likely landing zone of metastatic spread. However, patients who undergo modified templates potentially have a higher risk of retroperitoneal relapse .

The treatment options for clinical stage IIA NSGCT are primary RPLND or induction chemotherapy with three cycles of BEP or four cycles of etoposide cisplatin. Survival remains excellent in this patient population (>95%) regardless of which option they choose . RPLND with pathologic N1 (five or fewer nodes, all < 2 cm, no extranodal extension) is associated with ∼85% likelihood of cure without additional therapy

Conventional treatment for stage II seminoma has been radiotherapy or induction chemotherapy with BEP. RPLND is a standard and well-studied treatment in patients with NSGCT but currently does not have a role in early-stage seminoma. There have been four retrospective studies evaluating primary RPLND as a treatment option for patients who present with low-volume retroperitoneal seminoma with promising results. Hu et al. reviewed these four retrospective studies and reported a retroperitoneal recurrence rate of 14% (14/92) for patients with stage I–IIC seminoma following RPLND where patients with IIC disease had the highest risk of relapse. Currently, there are two prospective clinical trials evaluating the efficacy of primary RPLND in the management of low-volume stage II seminoma.

The Surgery in Early Metastastatic Seminoma (SEMS) trial is enrolling patients with primary testicular seminoma with retroperitoneal nodal size ranging from 1 to 3 cm but no more than two enlarged lymph nodes. Patients with a history of radiation, chemotherapy, or secondary malignancy are excluded. The primary endpoint is 2-year recurrence-free survival .

The second trial PRIMETEST (Trial to Evaluate Progression Free Survival with Primary Retroperitoneal Lymph-Node Dissection Only in Patients with Seminomatous Testicular Germ Cell Tumors with Clinical Stage IIA/B) is a German trial. This trial is different in that it allows patients with up to a 5 cm retroperitoneal node, but only unilateral disease. Patients who have received a single dose of carboplatin are also included. Their primary outcome is 3-year progression-free-survival .

These trials will serve to evaluate if primary RPLND for low-volume clinical stage IIA/IIB seminoma can achieve similar cancer-specific outcomes compared to the current historical standard of care while potentially reducing long-term morbidity.

RPLND is indicated in all patients who have NSGCT with a postchemotherapy retroperitoneal mass more than 1 cm on axial imaging with negative tumor markers and can be considered following a PET-avid mass more than 3 cm in seminoma . Typically patients undergo a full bilateral RPLND, although modified templates have been described. Different management strategies for postchemotherapy masses in seminoma and NSGCT are because of the higher rate of viable tumor and teratoma in NSGCT .

For early-stage testicular cancer, the primary goal is to minimize treatment-related morbidity because of excellent survival outcomes overall. In this young patient population, there are long-term toxicity concerns for the use of cisplatin-based chemotherapy . Primary RPLND for selected patients with early-stage NSGCT is one strategy that can limit unnecessary exposure to chemotherapy but can be associated with unnecessary overtreatment. Although surgery is associated with some potential perioperative morbidity and a rare incidence of late postoperative complications such as bowel obstruction (∼1%), the long-term risks associated with chemotherapy are more frequent and more meaningful, an increased risk of cardiovascular, neurologic, renal and pulmonary dysfunction, hypogonadism, infertility, and secondary malignancies . Platinum can be detected in the urine and circulating in plasma up to 20 years after the treatment . Concern for the toxicity of adjuvant chemotherapy must be tempered by the data showing long-term toxicity after chemotherapy is following three or four cycles of a cisplatin-based induction regimen in contrast to one or two cycles for adjuvant treatment of NSGCT or a single cycle of carboplatin for seminoma.

The first report of cardiovascular toxicity included 62 patients treated prior to 1987 with cisplatin containing chemotherapy . They had a seven-fold increased risk of coronary artery disease compared to the general population and a high prevalence of hyperlipidemia (80%), hypertension (40%), and Raynaud phenomenon (25%) (please triple check the seven-fold increased risk as most modern JNCI studies by Travis suggest 2–3 fold). Numerous large, multicenter, and population-based studies from the United States and Europe have since confirmed the association between cisplatin and cardiovascular morbidity including hypertension, hyperlipidemia, coronary artery disease, myocardial infarction, and cardiovascular mortality .

Bleomycin-induced pulmonary fibrosis is well described; however, cisplatin treatment also appears to cause pulmonary toxicity. Haugnes et al. observed that cisplatin was independently associated with increased risk of restrictive lung disease [odds ratio (OR) 3.1, 95% confidence interval (CI) 1.3–7.3)] compared to surgery alone in a cohort of 1049 germ cell tumor (GCT) survivors in Norway. Another large study including patient data from 14 cancer registries across North America and Europe demonstrated increased mortality from respiratory disease in men treated with chemotherapy .

Secondary malignancies represent a significant concern for GCT survivors exposed to previous chemotherapy or radiation, particularly considering these patients’ young age at diagnosis and long period of survivorship. Multiple population-based tumor registries have reported an increased incidence and mortality from secondary malignancies among GCT survivors. Receipt of cisplatin-based chemotherapy was found to be an independent risk factor (OR 1.8, 95% CI 1.3–2.5) for the development of solid malignancies in a study of over 40,000 GCT survivors . Cisplatin treatment also increases the risk of developing secondary leukemia in a dose-dependent manner .

Hypogonadism is diagnosed in ∼15% of testicular cancer survivors and fertility concerns remain significant. Eighty percentage of patients recover spermatogenesis within 5 years of treatment with cisplatin; however, a subset of patients exhibit persistent abnormalities on semen analysis including reduced sperm count and concentration . Survivors treated with cisplatin have a decreased paternity rate compared to those treated with surgery alone (75% vs. 88%, P = 0.03).

In 1992, the first laparoscopic RPLND (L-RPLND) was performed on a patient with stage 1 NSGCT . Since then, other small series have been published touting improved blood loss, shorter length of stay, and faster recovery when compared to an open approach . However, the major critiques were low lymph node yield, lack of dissection posterior to the great vessels, and liberal use of adjuvant chemotherapy. However, L-RPLND continued to evolve as learning curves improved. Hyams et al. reported 3-year follow up on patients treated at a single institution and demonstrated the procedure can be performed reliably and safely. However, 14 of 21 pN1 patients received adjuvant chemotherapy. Another group reported post chemotherapy L-RPLND results in 67 patients with median follow up of 21 months. In this series, all patients received modified template dissections where anterograde ejaculation was preserved in 98% of patients with a minimal complication profile. All patients remained disease free at date of last follow up . Table 1 summarizes comparisons between laparoscopic RPLND vs. open RPLND for stage I disease from high-volume institutions. A recent meta-analysis evaluated the oncologic efficacy of L-RPLND vs. open RPLND in stage I NSGCT at high-volume centers and found there was no difference in retroperitoneal relapse, in-field recurrences, or disease-specific survival .

L-RPLND is a safe and efficacious procedure based on published literature from high-volume centers for well-selected patients with low-volume, unilateral disease. However, there is concern for an increased rate of recurrences among patients receiving template-based dissections and the learning curve for L-RPLND remains steep . The use of the Da-Vinci robotic system has allowed laparoscopic surgery to mimic an open bilateral approach without repositioning the patient. The robot also facilities more facile and complicated dissections that may allow more advanced postchemotherapy masses to be resected and more complete dissection behind the great vessels.

Oncologic outcome data for robotic RPLND are limited to retrospective case series from single-center and multicenter collaborations and summarized in Table 2 . Unfortunately, there are no comparative studies appraising robotic RPLND relative to open RPLND. Oncologic evaluation of robotic RPLND for primary treatment of patients with stage I and select IIA NSGCT has been hampered by short follow-up and high rates of adjuvant chemotherapy for pN1 disease. The largest series describing results of robotic primary RPLND for early-stage NSGCT was a multicenter collaboration that included 47 patients with stage I and II NSGCT . Eight patients had viable GCT on RPLND disease and five (63%) were treated with adjuvant chemotherapy. Despite these significant limitations (low rate of retroperitoneal metastases and relatively short follow-up), early oncologic outcomes for robotic primary RPLND are acceptable with recurrence-free survival approaching 100% . More importantly, from a surgical quality perspective, there have been no published reports of in-field or retroperitoneal recurrences following robotic primary RPLND. Concerns regarding a potential publication bias do exist.

Application of robotic RPLND in the postchemotherapy setting has been shown to be feasible and safe with excellent recurrence-free survival rates and no in-field recurrences . Pathologic findings at the time of postchemotherapy RPLND, with viable GCT or teratoma, are consistent with historic benchmarks established by open RPLND. Follow-up in the postchemotherapy setting is longer compared to the primary setting, with four of six series reporting follow-up of 22 months or greater . Taken together, robotic RPLND in the postchemotherapy setting is a reasonable option for experienced minimally invasive surgeons and further prospective study is needed.

In the absence of long-term oncologic outcomes, lymph node yield is often used as a surrogate for surgical quality. Incomplete dissection could lead to retroperitoneal recurrences, increased therapeutic burden, and decreased cure rates. The average lymph node yield across all series was 20.1 (SD 7.6) (Table 2). Higher yields were achieved in the primary setting (range 17–30) compared to the postchemotherapy setting (range 7–20). These results are slightly lower compared to contemporary open series which report mean lymph node counts ranging from 28 to 38 . It must be noted that most open series utilize a full, bilateral dissection where higher lymph node counts are expected compared to a modified template dissection. Furthermore, lymph node yields are notoriously subjective and dependent on the surgeon, specimen labeling, central processing, and the pathologist analyzing the specimen . The development of the supine approach to robotic RPLND allows surgeons to better mimic open techniques and perform a full, bilateral dissection. Future studies assessing robotic RPLND must account for dissection template and other factors known to influence lymph node yield if this is to be used as a proxy for surgical quality.

Initially, during robotic RPLND, patients would be placed in a lateral decubitus position to facilitate modified template dissection. For left-sided primary tumors, patients are placed in right lateral decubitus position with a camera port, three robotic ports, and a single assistant port. The robot is docked over the patient's back . Right-sided tumors are approached by positioning the patient in left lateral decubitous position with similar port placement and a 5 mm subxiphoid liver retraction port . This approach allows modified template-based dissection as previously published and is sufficient for early-stage disease, but may require repositioning if a full bilateral dissection is attempted.

Bilateral dissections without repositioning require a different approach. Patients are placed in the supine position with the arms padded and tucked at the sides . When the DaVinci Si is used, the 12 mm camera port is placed 4 cm beneath the umbilicus. Two 8-mm robotic trocars are placed in the left lower quadrant, and an 8 mm robotic trocar and 12 mm assistant port are placed in the right lower quadrant (Fig. 1). The patient is then placed in steep Trendelenburg position to allow the bowel to fall into the diaphragm area. The robot is docked over the patient's left shoulder. The disadvantage of using this approach is that redocking is required in order to complete the spermatic cord excision.

Use of the DaVinci Xi system has allows wider dissection and eliminates the need to redock . Patient positioning is similar to the DaVinci Si approach with a few differences. The 12 mm, 30-degree down camera is placed a few centimeters caudad to the umbilicus and just lateral to the right median umbilical ligament. Three robotic 8 mm ports are placed in a straight line across the abdomen with approximately 7 cm between ports and a single 12 mm assistant port is placed in the patient's right lower quadrant. The Xi robot is side docked over the patient's right side (Fig. 2) .

The robotic supine approach mimics the open operative approach by opening the posterior peritoneum just below the cecum and continuing this incision along the root of the small bowel mesentery. It is important to not take the right lateral incision cranial to the cecum along the ascending colon as this aids in retraction. Exposure of the posterior peritoneum is continued until the left renal vein is visualized. To maximize exposure, the right peritoneal edge can be sutured to the anterior abdomen wall. This helps create a ‘hammock’ for the small bowel to be retracted superiorly . The left medial edge of the peritoneum along the inferior mesenteric vein can then be sutured to the anterior abdomen wall. This maneuver lifts the small bowel up and cephelad out of the operative field. The fourth arm is then free to be used for deeper retraction, if needed. This exposure technique is especially useful when performing large postchemotherapy retroperitoneal dissections.

Patients undergoing R-RPLND typically have an average stage of 1 day compared to a 4–5 day hospital course with open RPLND . Although complication rates between open and R-RPLND are comparable, the rate of chylous ascites is reportedly higher in L-RPLND and R-RPLND series at around 4 vs. < 1%, respectively . Meticulous use of surgical clips around the left renal vein and lymphatic channels may minimize the risk of chylous ascites. In addition, our practice is to obtain a nutrition consult during their hospitalization and send patients home on a low-fat diet. Although this is thought to be useful in the treatment of chylous ascities, taking a proactive approach may help prevent this complication. Loss of anterograde ejaculation is another often cited complication associated with RPLND. In R-RPLND, at least in the primary setting with modified templates, 100% of patients retained ejaculatory function .

Robotic surgery continues to evolve and attempts to strike a balance by offering low morbidity associated with minimally invasive surgery while striving to maintain the principles of contemporary open surgery. Clearly, further studies are needed to compare the cancer-specific and complication-related outcomes between open and robotic RPLND, particularly in the postchemotherapy setting. For optimal outcomes, these operations should continue to be performed by high-volume surgeons, regardless of operative technique.

There are no conflicts of interest.

Papers of particular interest, published within the annual period of review, have been highlighted as:

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