Localized kidney cancer is ideally managed with surgical extirpation. Historically renal cell carcinoma has been treated with radical nephrectomy, but partial nephrectomy has become increasingly used because of a growing body of evidence demonstrating equivalent oncologic control and a potential benefit in overall survival. In this article, the authors demonstrate that partial nephrectomy carries excellent oncologic efficacy. They additionally review the growing indications for partial nephrectomy and factors influencing candidate selection. The authors also compare the relative outcomes of open and minimally invasive techniques. Several factors influence outcome, and surgeon experience should dictate the choice of technique.
Partial nephrectomy (PN) has historically been used in urology for the treatment of benign processes of the kidney such as stone disease, nonfunction within a duplicated moiety, trauma, and infection. In the past 20 years, the major application of PN has been the treatment of localized renal tumors as an alternative to RN. Initially, indications were absolute, including patients with solitary kidney and bilateral tumors. With time, indications broadened based upon risk factors for kidney disease, and eventually elective PN was performed for tumors less than 4 cm in patients with normal kidney function and contralateral kidney. The safety of this approach has been proven through long-term follow-up, thereby allowing broadened indications for tumors larger than 4 cm. Today most renal cortical lesions are detected incidentally due to widespread use of medical imaging. Despite the long history and proven efficacy of radical nephrectomy (RN) in treating kidney cancer, the downward stage migration of renal cell carcinoma (RCC) and recent data demonstrating an increased risk of chronic kidney disease (CKD) with RN has called into question the use of RN as the treatment of choice in patients with newly diagnosed kidney tumors.
Outcomes: oncologic, complications, renal function
Oncologic Outcomes of PN
PN for renal tumor balances complete resection of the tumor-bearing portion of the kidney while preserving as much normal renal parenchyma as possible. Advantages of PN are the preservation of renal function, a reduced risk of future CKD, and avoidance of overtreatment of benign renal masses by nephrectomy. Despite studies demonstrating the importance of renal preservation in regard to renal function, local cancer control is still the primary goal of any cancer surgery, and acceptable oncologic efficacy must be demonstrated before PN can be accepted as a viable alternative to RN in an elective setting.
Long-term retrospective studies have demonstrated durable oncologic control with PN, but, in the case of early reported series, these have been generally limited by selection bias. Fergany and colleagues reported early results of patients treated with nephron-sparing surgery (NSS) with mean follow up of 104 plus or minus 57 months. The 10-year cancer-specific survival (CSS) survival rate was 73%; however, the cohort was distinct from current series in that 90% of patients underwent PN for absolute indications, and greater than one-third of patients had pT3 disease. In the subset of patients who underwent elective PN for unilateral disease and tumors less than 4 cm, the CSS and disease-free survival (DFS) rate was 100% at 10 years. Another study evaluating the survival of 70 patients undergoing PN demonstrated 10-year DFS and overall survival (OS) rates of 97% and 93%, respectively. Lau and colleagues also retrospectively reviewed long-term survival in a matched cohort of 164 patients with T1 tumors undergoing elective RN or PN and found no difference in 10-year OS (73% vs 74%) and CSS (98% vs 96%).
Most reported outcomes for PN have been from retrospectively evaluated series, which have the inherent potential for selection bias when comparing outcomes with RN. One randomized prospective phase 3 trial was conducted comparing open RN and PN in 541 patients with clinical tumors no more than 5 cm and a normal contralateral kidney. At a median follow up of 9.3 years, the total of number of deaths was 117, and the total number of cancer-related deaths was 12. The intention-to-treat (ITT) analysis demonstrated that the 10-year OS for patients who underwent RN was significantly better than for those undergoing PN (81.1% vs 75.7%, respectively; P = .03) The authors performed a secondary analysis in which they excluded patients with pathologic multifocality and upstaging. In this analysis, there was no difference in OS observed in either group. Oncologic equivalence with regard to CSS and progression could not be definitively demonstrated due to the limited number of cancer-related deaths as well as the small sample size. The authors did demonstrate similar 10-year progression rates of 4.1% and 3.3% ( P = .48) with PN and RN, respectively. Major limitations of the study included its early termination because of poor accrual (such that the required sample size of 1300 patients was not reached) and the high rate of crossover following randomization.
Local recurrence rates, defined as any disease presence in the treated kidney or associated renal fossa after treatment, are comparable between RN and PN regardless of surgical technique. Local recurrence-free survival for open RN is 98.1%, and for open PN (OPN), it is 98.0% at median follow-up 58.3 and 46.9 months, respectively. When comparing laparoscopic technique, local recurrence-free survival for RN is 99.2%, and for PN, it is 98.4% at a median follow up of 17.7 months and 15 months, respectively. It is important to note that in these studies, the median tumor size was larger in patients undergoing RN.
Impact of Surgical Margins on Oncologic Outcomes
In performing a PN for tumor, the fundamental tenet of the operation has classically been complete excision with a clear margin of normal parenchyma surrounding the tissue. The significance of a positive surgical margin (PSM) has been evaluated by a number of authors.
Yossepowitch and colleagues evaluated patients who underwent PN at 2 tertiary care centers with median follow-up of 3.4 years. Of the 1390 patients, 77 had PSMs. When stratified by surgical margin status, at 5 years the freedom of local recurrence was 98% and not statistically different from patients with negative surgical margins. Another multi-institutional retrospective study evaluated the natural history and the impact of PSMs on survival. Of 111 patients with PSMs with mean follow up of 37 months, 93 were monitored, while 18 patients underwent immediate reoperation with either PN or RN based upon surgeon preference. Only 40% of patients who underwent reoperation demonstrated residual tumor. Of the patients who underwent surveillance, there was no difference in CSS and OS at a mean follow-up of 37 months. On multivariate analysis, PSMs did not impact occurrence of recurrence. Given the slow growth rates described in the literature, the authors suggested that the impact of PSMs may require more years to become apparent and that median follow up of 3 years may be inadequate.
The excision of the tumor with a substantial margin of normal parenchyma is considered the standard technique to reduce risk of local recurrence; however, the minimal thickness of tumor-free surgical margin has not been specified. Simple enucleation consists of incision of the renal parenchyma within a few millimeters of the tumor and blunt dissection of a plane between the capsule of the tumor and healthy renal tissue without the inclusion in the removed tissue of any visible normal renal parenchyma. One study compared oncologic outcomes of 982 patients who underwent PN with 537 patients who had simple enucleation for renal tumors with mean follow-up of 51 and 54.4 months, respectively. There was no difference in local recurrence and oncologic control, with similar CSS at 5 and 10 years. It is important to note that most patients in the enucleation group were found to have a negative margin.
Despite the literature supporting the idea that no intervention is necessary for patients with a positive margin at PN, margin control remains, in the authors’ opinion, a critical component of the operation. One should not conclude from this literature that the margin is not an important goal of the operation, as pathologic positive margins may in many cases be artifactual due to tissue distortion or parenchymal retraction. This concept is supported by the observation that only 40% of patients are found to have residual tumor upon completion RN. Grossly positive margins, in which the surgeon violates the tumor capsule, or cuts into the tumor, would likely carry a much higher risk of local recurrence. As such, the authors continue to strive for achieving a 1 cm negative margin thickness at the time of PN to avoid inadvertently positive surgical margins.
Surgical Outcomes of Partial Nephrectomy: Complications
Although the oncologic equivalence of PN to RN for localized renal tumors has been demonstrated in the literature, patients undergoing PN are at potential increased risk for postoperative complications. The risks and benefits of PN should be addressed when counseling patients about NSS. Complications of PN include bleeding, urine leak, renal dysfunction, vascular fistula or malformation, positive margin, renal infarct, and renal loss.
A multi-institutional retrospective study by Stephenson and colleagues reviewed complications associated with OPN and RN. Although patients undergoing PN did not experience more complications than those who underwent RN (19% vs 16%, P = .3), they did experience more grade 3 (4% vs 1.6%, P = .04) and procedure-related complications, defined as urinary leak, acute renal failure (ARF), retroperitoneal hemorrhage, organ injury (9% vs 3%, P = .0001). In the cohort of PN patients, the rate of postoperative hemorrhage requiring transfusion was 0.8%, and the rate of urinary leak was 6.6%, with a median time to fistula closure of 46 days. On multivariate analysis, patient age, operative time, and pathologic stage were associated with postoperative complications.
As experience and comfort level increased with PN, the complication rates have decreased. Thompson and colleagues reviewed their contemporary experience (1996–2001) with historical controls (1985–1995). In the contemporary cohort, there were significant decreases in the duration of hospitalization, intraoperative blood loss, and early complications (13.4% vs 6.9%, P = .002). Rates of urinary leakage also decreased in the contemporary group compared with the historic controls (0.6% vs 2.6%).
With the introduction of minimally invasive techniques, such as laparoscopy and robotics, patients benefit with decreased postoperative pain, shorter hospital stay, and improved cosmesis. However, the principles of PN in the open approach should be adhered to such that ischemia time and postoperative complications are minimal. A multi-institutional comparison of 1800 laparoscopic nephrectomy and OPN for solitary renal tumors evaluated the intraoperative and postoperative outcomes of these 2 techniques. The baseline characteristics were different between the groups, with more patients undergoing OPN for solitary kidneys, bilateral renal tumors, and larger renal tumors. Intraoperatively, patients who underwent laparoscopic partial nephrectomy (LPN) had 1.69 times longer warm ischemia times, more postoperative complications (18.6% vs 13.7%), including increased risk of postoperative hemorrhage (4.2% vs 1.6%), and increased risk of requiring a secondary procedure, compared with OPN. It is important to note that, as in the case of OPN, complication rates with LPN are likely to have decreased with operator experience.
Theoretical advantages of the robotic technique compared with pure laparoscopy include ease of suturing during reconstruction, resulting in reduced ischemia time. A single institutional study retrospectively evaluated outcomes for minimally invasive PN (laparoscopic and robotic) with OPN for pT1b tumors. There was no difference in tumor stage, margin status, complications, or postoperative use of narcotics; however, there was statistically significant difference in ischemia time and estimated blood loss in the OPN group, with more patients requiring transfusion. These differences can be explained by more patients undergoing OPN with hypothermia at the time of renal artery clamping (allowing more prolonged ischemic interval) as well as a subset undergoing OPN without renal artery clamping. Despite the noted differences, there was no difference in renal function 6 months after surgery.
None of the existing literature can account for surgeon experience and case selection when comparing PN technique with regard to risk of complications. Certain types of complication do appear to be greater within each technique, but overall complication rates have substantially declined in the contemporary era. In selecting an operative approach, one must gauge operator experience and focus upon avoidance of complications unique to the technique (ie, vascular complications with robot assisted laparoscopic partial nephrectomy (RALPN), pulmonary complications with OPN).
Renal Function Outcomes After PN
Treatment of RCC extends beyond cancer control and requires a thorough understanding of the risks of competing causes of mortality. There is growing concern regarding the management of localized renal tumors and the development of postoperative renal insufficiency, because it has been demonstrated that CKD is associated with an increased risk of cardiovascular morbidity, hospitalization, and death. The relation of CKD and overall mortality is imperative when counseling patients concerning treatment options. Surgeons managing these patients should be aware of factors impacting postoperative renal function, including: preoperative renal function, ischemia time, amount of normal parenchymal excision, and comorbid conditions (ie, diabetes, atherosclerotic disease, hypertension).
Impact of preoperative renal function on postoperative renal function
It has long been accepted that patients with substantial CKD are poor candidates for RN. Individuals with severe renal dysfunction, in whom RN may result in the need for dialysis, have generally been considered to have relative, or even absolute, indications for PN. It has recently, however, been demonstrated that individuals typically considered to have an elective indication for PN may have some CKD when renal function is measured by more accurate methods than serum creatinine alone. Among all individuals presenting for resection of an early stage renal tumor, those undergoing RN have a statistically significant greater risk for CKD after surgery (hazard ratio [HR] 3.8, P <.0001). A multi-institutional retrospective study demonstrated that approximately one-third of patients with an eGFR greater than 60 mL/minute/1.73 m2 will develop CKD stage 3 or greater after PN. The risk of developing CKD was independent of coexisting medical conditions such as coronary artery disease, diabetes mellitus, or hypertension. Despite the lack of relationship up to 25% of patients considered to have elective indications for PN with a small kidney tumor have been found to have pre-existing CKD. As such, even those with elective indications may often harbor underlying renal disease that will increase the risk of worsening renal function after PN.
The significance of long-term renal function is related to its overall risk to health. CKD and cardiovascular disease appear to act as strong independent risk factors for mortality. In a study using the Surveillance, Epidemiology and End Results (SEER) cancer registry linked to Medicare claims, RN was associated with an increased number of cardiovascular events and worsened OS compared with PN in patients with pT1a tumors. These findings have been supported by other studies as well. In a series from the Mayo Clinic, younger patients (<65 years) treated with RN instead of PN for pT1a tumors had a worsened overall survival. (relative risk [RR] 2.34, 95% confidence interval [CI], 1.17–4.69, P = .016). In a population-based cohort of patients from the SEER cancer registry matched for age, tumor size, and year of surgery, RN was associated with a 1.23-fold increase in overall mortality than PN ( P = .001). In a competing risk analysis, RN was associated with a higher rate of noncancer-related mortality.
Given the collective risk of renal dysfunction in all patients undergoing surgery, careful assessment of baseline renal function will allow better patient selection and operative planning. Better tools for assessment of renal function and relative risk of renal dysfunction are needed.
Modifiable factors: ischemia time and amount of parenchyma excised
The greatest modifiable risk factors for prevention of CKD in patients undergoing PN are the amount of parenchyma removed and the extent of ischemic injury experienced by the renal remnant. Acceptable threshold ischemia times and impact on postoperative complications and long-term renal function have been demonstrated in patients undergoing PN with solitary kidneys. Because measurement of individual renal moiety functional change remains a challenge, the most meaningful data regarding renal ischemia and its relationship with long-term renal function are typically derived from solitary kidney data.
Among the most important factors affecting immediate and long-term renal function in patients with a solitary kidney undergoing PN are ischemia time and type. A retrospective multi-institutional study evaluated the impact of ischemia time during NSS in 537 patients with solitary kidneys. All patients had OPN and were performed under warm ischemia, cold ischemia, or no ischemia. Patients with warm and cold ischemia had statistically larger tumors than patients not requiring ischemia. However, after adjusting for tumor size, patients requiring warm or cold ischemia were significantly more likely to have complications (ARF, urine leak, temporary dialysis). The odds ratio of developing ARF was 3.75 and 7.11, respectively. Although there was a significant difference in developing chronic renal insufficiency (CRI) postoperatively, there was no difference in the incidence of permanent dialysis among the 3 groups. When evaluating the subset of patients treated with warm ischemia, the authors concluded that more than 20 minutes of warm ischemia were associated with an increased risk of acute and chronic renal failure and the need for permanent dialysis. Additionally, cold ischemia of greater than 35 minutes was associated with an increased risk of ARF and urine leak, but no difference in CRI or dialysis.
La Rochelle and colleagues found similar threshold times for warm and cold ischemia and also observed that most patients with tumors in a solitary kidney present with evidence of CKD. With median follow-up 40 months (range 0.2–148 months), no variables, including type of ischemia or absence of ischemia, were associated with degree of decrease in late GFR values. The authors suggested that the greatest risk of developing end-stage renal disease (ESRD) was local recurrence (LR) requiring nephrectomy.
Lane and colleagues investigated the functional outcomes of patients who underwent PN or RN for clinical stage T1 renal cell carcinoma to determine whether RN is comparable to PN with extended ischemia. Preoperative renal function was similar in all groups (eGFR >80 mL/min/1.73 m 2 ) compared including patients with limited ischemia (<30 min), extended ischemia (>30 min), and RN. At last follow-up, there were significantly more patients with postoperative eGFR <45 mL/minute/1.73 m 2 who underwent RN compared with limited and extended ischemia (35%, 6.1%, and 14%, respectively, P <.001). They demonstrated that although outcomes in patients with extended ischemia may be poorer than in those with more limited duration ischemia, they are better than with RN.
Cold ischemia has traditionally been used during PN based on the beneficial effects observed during kidney transplantation and other renovascular surgery necessitating prolonged ischemic intervals. Lane and colleagues assessed the outcomes following PN in a solitary kidney with multivariate analysis of modifiable and nonmodifiable factors to evaluate the determinants of renal function after PN. Among 660 patients with solitary kidneys who underwent PN, patients in whom surgery was performed with cold ischemia were older and had poorer baseline renal function. There was no difference in development of postoperative acute kidney injury in the postoperative period ( P = .4) among those with cold ischemia as compared with those without. On multivariate analysis of early and late renal function, the strongest predictors were preoperative GFR and percentage of parenchyma preserved ( P <.00001), while ischemia time and type were not. This study was the first to evaluate percentage of parenchyma preserved and its effects on postoperative renal function, and it draws into question some of the conventional assumptions regarding the influence of ischemia.
While minimization of ischemia remains a critical goal of PN, it is clear that multiple factors, modifiable and nonmodifiable, influence long-term renal function. In planning PN, the strategy to reduce ischemia must be balanced with the desire to maximally preserve parenchyma. Given the decreased visualization during tumor excision without ischemia, for example, there may be a tendency to widen the margin, thereby removing more normal parenchyma. These relationships warrant further evaluation to determine if short ischemic intervals are preferable to no ischemia at all.
Candidate selection
Absolute indications for PN include tumor in a solitary kidney or bilateral tumors. Baseline azotemia whereby RN would likely result in the need for dialysis also confers an absolute indication. Relative indications for PN include pre-existing medical renal disease and medical conditions that predispose to renal disease such as diabetes, hypertension, and atherosclerotic vascular disease. Multifocal tumors associated with a genetic syndrome are also considered a relative indication for PN. The most difficult decision for the contemporary urologist is in the consideration of elective partial nephrectomy for T1a, T1b, and T2 or T3 tumors ( Table 1 ).
| Study | Study Design | Mean/Median Follow-up (mo) | N | Surgery Type | OS (%) | CSS (%) | LR (%) | ||
|---|---|---|---|---|---|---|---|---|---|
| 5 y | 10 y | 5 y | 10 y | ||||||
| pT1a | |||||||||
| Fergany et al , a | Retrospective | 104 | 117 a | Open | — | — | 97.6 a | 94.5 a | 0 a |
| Crepel et al | Retrospective (m) | 24 | 1564 | Open | — | — | 97.4 | — | — |
| Van Poppel et al , b | Prospective (r) | 111.6 | 268 | Open | — | 75.2% | — | — | 2.2% |
| pT1b | |||||||||
| Crepel et al | Retrospective (m) | 30 | 275 | Open | — | — | 91.4 | — | — |
| Weight et al | Retrospective | 49 | 212 | Open/lap | 94.5 | — | 97.8 | 86 | — |
| pT2/T3 | |||||||||
| Weight et al | Retrospective | 53 | 96 | Open | — | — | 82 | — | — |
| Breau et al | Retrospective (m) | 38.4 | 69 | Open | — | — | — | — | 6 |
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Histologic Variants of Renal Cell Carcinoma: Does Tumor Type Influence Outcome?
Current Practice Patterns in the Surgical Management of Renal Cancer in the United States
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