Laparoscopic Cytoreductive Nephrectomy: A Three-Center Retrospective Analysis

Introduction

M ore than 6600 people are found to have renal cancer each year in the United Kingdom and there are around 3600 deaths. ¹ Renal cell carcinoma (RCC) accounts for ∼3% of adult malignancies and the incidence is steadily increasing at a rate of 2.5% per year across population groups. ² RCC is the most lethal of the urological malignancies with more than a 40% subsequent mortality. ³ Approximately 20% to 30% of patients present with metastatic disease and 20% to 40% of patients undergoing nephrectomy for clinically localized RCC will develop metastases. ⁴ Patients with metastatic RCC (MRCC) face a poor prognosis, with a historical median survival of 6 to 10 months and a 2-year survival of 10% to 20%. ⁵ Despite adjuvant systemic chemotherapy, hormonal or cytokine therapies, used alone or in combination, overall response rates rarely exceed 20% and complete responses are rare. ⁶ Outlook for patients with advanced and MRCC has improved since the 1990s, and this is related to the introduction of immunotherapeutic approaches and a better understanding of the role and timing of surgery. Nephrectomy for MRCC has traditionally been performed to provide palliation via pain control, treating intractable hematuria, managing uncontrolled hypertension, and persistent hypercalcaemia. ⁷ Surgical intervention in patients with MRCC can be either to render a patient clinically free of metastases or to involve resection of the primary tumor before initiation of systemic therapy (cytoreductive nephrectomy [CRN]). ^6,8,9 The exact mechanisms that underlie the survival benefit of CRN are still not clearly understood, but various theories have been put forward.

Removal of a symptomatic local tumor may improve performance status and therefore prognosis in addition to removing a source of future metastases. ¹⁰

Spontaneous regression rates of between 0.8% and 7% have been reported ^{11 –13} and nearly all foci of spontaneous metastatic regression occur in the lung possibly as a result of the rich macrophage, immunoglobulin, and lymphocyte supply. Spontaneous regression may occur if the primary tumor is absorbing circulating antibodies and lymphocytes away from distant metastases. The primary lesion in MRCC rarely responds to systemic immunotherapy even when there is significant regression of distant metastases. ¹⁴ This lack of response of the primary tumor to immunotherapy is additional evidence that the primary tumor causes immune dysfunction and implies a benefit to preimmunotherapy CRN. Finally, it is postulated that cytokines and growth factors released by the primary tumor (e.g., vascular endothelial growth factor) may promote growth of metastases. If this is true, removal of this cytokine release by CRN might benefit the patient and allow for an improved therapeutic response to growth factor inhibitors. Multiple retrospective reports of immunotherapy for RCC have shown prior nephrectomy to be a positive prognostic factor independent of other well-recognized factors such as performance status and site or burden of disease. ^{6,15 –17}

The concerns surrounding CRN are related to surgical mortality, morbidity, and the possible failure to complete immunotherapy as a result of postoperative complications. Surgical mortality has been reported as 2% to 11% for patients with large primary renal tumors and metastatic disease. ^{6,18 –20} Patients may not recover sufficiently after radical nephrectomy to receive systemic immunotherapy as reported in a series of 195 patients with MRCC treated at the National Cancer Institute. In this series, 38% of patients who underwent nephrectomy did not receive immunotherapy, because of either complications of nephrectomy or rapid deterioration caused by disease progression. ¹⁶

Despite the apparent survival benefit conferred by CRN, referral patterns, surgical judgment, and patient selection have an impact on the frequency with which it is performed. Concerns remained with the effects on quality of life (QoL) and recovery time in patients undergoing open CRN, and so laparoscopic cytoreductive nephrectomy (LCRN) aims to reduce both these parameters.

Since the early 1990s laparoscopic radical nephrectomy (LRN) for RCC has grown in popularity and acceptance. Evidence has consistently shown less postoperative pain and a shorter hospital stay and convalescence for patients undergoing LRN than open nephrectomy. ²¹ Tumors resected in the setting of cytoreduction are not considered ideal for laparoscopic surgery. They tend to be large and have extensive vascularity, nodal disease, renal vein, and inferior vena caval extension. The potential benefits of laparoscopic approaches such as reduced perioperative morbidity and quicker recovery may shorten the interval between surgery and systemic therapy. In one series, the median time to immunotherapy in 19 patients undergoing open nephrectomy was 67 days (range 50–151 days) compared with 60 days (range 47–63 days) in 5 patients who underwent hand-assisted laparoscopic nephrectomy and only 37 days (range 34–57 days) in 6 patients who underwent pure LRN. ^17,22 Although the role of laparoscopy is still being refined in CRN, it seems clear that this has a role in centers with adequate laparoscopic experience and for patients who are properly selected and counseled.

LCRN is associated with less blood loss, a lower transfusion rate, less pain, and shorter hospitalization than open CRN. ^16,17,22,23

At our institution, we believe that tumors confined to the kidney without evidence of local invasion, tumor thrombus, or significant lymphadenopathy that are 15 cm or less can be safely removed intact with a laparoscopic approach.

Patients and Methods

Between 2003 and 2007, 25 patients underwent LCRN in three centers under three consultant surgeons. All patients were considered eligible for postprocedure systemic therapy by the eligibility criteria listed below.

ECOG status 0 or 1 ²⁴

Patient demographics are listed in Table 1. Four male patients and 11 female patients were included (age range, 30–85 years; mean, 60 years; median, 63 years). Nine left and 16 right LCRNs were performed. Eleven patients underwent LCRN through an extraperitoneal approach and 14 through a transperitoneal approach. This was based purely upon surgeon preference. In addition to Hem-o-loK clips (Weck Closure Systems, Research Triangle Park, NC) hemostasis was enabled via Floseal (Fusion Medical Technologies, Mountain View, CA), + Surgicel + 0 Vicryl suture (Johnson and Johnson Medical, Inc., Arlington, TX) in 16 patients and harmonic (Ethicon Endosurgery, Cincinnati, OH) in 9. Patients were given Flow-Tron™ boots for 24 hours postoperation. They were also given low-dose Tinzaparin daily, including the evening before surgery and until discharge. All patients wore thrombo embolus deterrent (TED) stockings throughout their admission and were given antibiotics perioperatively.

Results

Twenty-five patients underwent LCRN; one procedure was abandoned as a result of advanced tumor extension. Two cases required conversion from laparoscopic to open nephrectomy. One of these was to assist in hemostatsis and the other to provide better access to divide adhesions. Operating times ranged from 89 to 310 minutes (median, 175 minutes). Blood loss ranged from minimal (<50 mL) to 2300 mL in the case already mentioned requiring open conversion. The median amount of blood loss was 150 mL, and hence the transfusion rate was low with only one patient requiring on-table transfusion and two patients requiring additional blood before discharge. Analgesia was given via patient controlled analgesia (PCA), the amount of postoperative opiates given was recorded, and this ranged between 8 and 150 mg with a median of 21 mg of morphine. Hospital stay ranged between 2.5 and 11 days, and median was 3 days (see Table 2).

As one would expect the operating time appears to increase slightly in proportion to the tumor size. The largest tumor measured 12 cm and operating time was 215 minutes compared to the smallest tumor measuring 3.4 cm with an operating time of 140 minutes.

The age of patients did not appear to influence the postoperative stay until the >80-year group, where the average stay was 7.75 days. There were, however, only two patients in this group, so no real conclusions can be drawn.

The duration of operation had little effect on postoperative stay except for the group with the shortest operation times (60–119 minutes) who on average stayed for 1 to 1.5 less nights postoperatively.

The complexity of the procedure was expected to increase as tumor size increased as a result of adhesions, loss of tissue planes, and angiogenesis. In our experience apart from tumors between 9 and 10.9 cm in diameter, there was little impact on operation duration.

Perioperative complications were minimal with bleeding being the main concern. No patients had significant short-term postoperative complications, and hence the hospital stay was acceptable in all cases (Table 3). There was one superficial wound infection, two patients required a blood transfusion before discharge, and one patient required on-table conversion to an open procedure to achieve hemaostasis and blood transfusion. No patients died within 30 days of surgery. In total, 19/25 patients went on to have adjuvant therapy. Because of the introduction of tyrosine kinase inhibitors during the study, 16/25 patients received tyrosine kinase inhibitors and 3/25 patients received interferon therapy. The remaining six patients chose did not receive adjuvant treatment because their disease was considered stable (2/25) and in the remaining four patients the reason is unknown. There is no evidence from our study to suggest that after LCRN, patients did not recover satisfactorily enough to receive adjuvant therapy. Where available long-term survival was assessed. At a mean 48-month follow-up 52.6% of patients had died from disease progression; in those patients who died, the mean survival was 10.7 months from surgery.

Discussion

We have adopted LCRN as an integral part of the multimodal therapy for MRCC and report acceptable results with minimal peri- and postoperative complications. The size of tumor and presence of advanced disease did not adversely affect outcome and all patients were discharged within 11 days. Our results show comparable operative duration, blood loss, minor complication rate, analgesic requirement, and hospital stay to other series (Table 4).

In patients with MRCC subject to performance status there are four management options: (1) nephrectomy and/or metastasectomy only, (2) cytoreductive surgery followed by systemic therapy, (3) initial systemic therapy followed by adjuvant nephrectomy, and (4) systemic therapy alone.

In patients with metastatic disease, CRN before subsequent immunotherapy has been proven to provide a 5.8 months survival benefit. ⁶ Surgical mortality has been reported as 2% to 11% for patients with large primary renal tumors and metastatic disease. ¹⁷ Appropriately selected patients can, in addition, benefit from a laparoscopic approach, decreasing the period of recovery and hence expediting the administration of immunotherapy in a shorter period. ^{26 –28}

The rationale for CRN is based on two factors: preventing complications related to the primary tumor during systemic therapy and removing a large, potentially immunosuppressive tumor burden. Radical nephrectomy should not be performed solely with the aim of inducing spontaneous remission, as evidence suggests only 0.8% of patients treated with radical nephrectomy alone achieve this outcome. ¹¹

The selection criteria for these patients remain unclear; however, current evidence suggests that factors such as performance status and metabolic indicators of advanced disease, for example, calcium level, hemoglobin level, and renal function, should all be considered. ^13,14

Many previous studies attempted to identify the ideal population for CRN. Criteria such as site of metastases, preoperative performance status, age, surgical technique, histology, nodal metastases, and neo- or adjuvant treatments have been studied with limited benefit as predictive of favorable outcome after cytoreductive surgery. An important consideration is the postoperative QoL in patients with MRCC considering the high rates of morbidity reported in this disease and the short life expectancy. ²⁹

Flanigan ⁸ in the combination study of Southwestern Oncology Group (SWOG) and European Organisation for Research and Treatment of Cancer (EORTC) trials reported recovery from surgery occurring within 45 days with a median time of 19 days.

Therefore, in a disease with limited short-term survival, undergoing a procedure that might keep a patient hospitalized or restricted to bed, might not address the QoL of the patient.

CRN as an integral part of multimodal therapy in the management of MRCC has shown a survival benefit. A number of retrospective studies have reported on combined therapy with CRN followed by immunotherapy, with response rates that have ranged from 8% to 34%. We have yet to determine the role of CRN and tyrosine kinase inhibitors; however, on the basis of these results we conclude that LCRN as a procedure in its own right can be safe and effective and is an acceptable management strategy. As in all retrospective analyses, selection bias is inherent in the investigational design.

Conclusion

Metastatic renal cancer is an extremely challenging problem in need of additional therapies. Prognostic factors defined in systemic therapy clinical trials, including performance status, serum hemoglobin, serum calcium, prior nephrectomy, and serum lactate dehydrogenase, stratify patients with metastatic renal cancer into low-, intermediate-, and high-risk groups. LCRN has been shown in our experience to be a viable and safe treatment modality for patients with MRCC and should be considered in patients with suitable disease burden, performance status, and general health, preparatory to immunotherapy with interferon-a or interleukin-2, or other trial regimens as appropriate. Spontaneous regression should not be an indication for surgery in MRCC. Definitive recommendations on management cannot be established from the results of our retrospective study of a small number of patients. Patient selection is critical to minimizing the complications during and after surgery. Currently, we offer a laparoscopic approach to patients who are candidates for immunotherapy.