Localized Renal Cell Carcinoma Management : An Update

Objective: To review the current modalities of treatment for localized renal cell carcinoma. Materials and Methods: A literature search for keywords: renal cell carcinoma, radical nephrectomy, nephron sparing surgery, minimally invasive surgery, and cryoablation was performed for the years 2000 through 2008. The most relevant publications were examined. Results: New epidemiologic data and current treatment of renal cancer were covered. Concerning the treatment of clinically localized disease, the literature supports the standardization of partial nephrectomy and laparoscopic approaches as therapeutic options with better functional results and oncologic success comparable to standard radical resection. Promising initial results are now available for minimally invasive therapies, such as cryotherapy and radiofrequency ablation. Active surveillance has been reported with acceptable results, including for those who are poor surgical candidates. Conclusions: This review covers current advances in radical and conservative treatments of localized kidney cancer. The current status of nephron-sparing surgery, ablative therapies, and active surveillance based on natural history has resulted in great progress in the management of localized renal cell carcinoma.


INTRODUCTION
Renal cell carcinoma (RCC) is the third most frequent urologic cancer and represents 2-3% of all adult malignancies.Adenocarcinoma is the most prevalent histologic subtype, responsible for approximately 85% of renal tumors (1).Historically, RCC was known as the tumor of multiple presentations due to the several signs and symptoms that could be present at the time of diagnosis.Currently, up to 40% of kidney neoplasms are detected incidentally because of the widespread use of imaging technologies (2).This has led to an apparent increase in the incidence of RCC (3).
For decades, radical nephrectomy was considered the gold standard treatment for localized RCC, representing the only curative option.Several open or Review Article Review Article laparoscopic approaches are now available.However, despite a small improvement in overall survival and good oncologic outcomes, radical surgery has a relapse rate that can reach 30% (4).Likewise, renal function outcomes can be poor, even in patients with a normal contralateral kidney.More recently, renal parenchyma preservation and nephron-sparing procedures are beginning to demonstrate satisfactory results, pointing toward a possible role of new minimally invasive energy-based ablation techniques in renal tumor therapy.

EPIDEMIOLOGY
World statistics show 208,000 new renal cell carcinoma cases/year and 102.000 deaths/year (1).
There is a geographical prevalence variation.The smallest incidence rates have been observed in Africa, some countries, such as Denmark and Sweden the incidence has been decreasing for the last 20 years (5).
observed in Uruguay and in the south of Brazil (Porto Alegre 10.2 per 100.000men) (6), contrasting with low rates in the north of Brazil and in the middle-west area, Goiania for instance (7,8).
According to the American Cancer Society, more than 54,390 new cases and 13,010 deaths are expected in 2008 in the United States.Since 1950, the annual incidence has grown by 130%, at a rate of 3.7% (9).
Data from the U.S. Surveillance, Epidemiology and End-Results (SEER) study shows that 54% are locally advanced and 25% of the patients already have disseminated disease.Approximately 50% of these patients will develop metastases.The 2-year survival rate for patients with untreated metastases at 5 and 10 years are 65% and 56%, respectively.

TREATMENT The Trial Search Strategy
The computerized database of the US National Library of Medicine of the search engine PubMed (http://www.pubmed.gov),and the Latin American and Caribbean Health Sciences were primarily searched for articles on localized to identify the records, the search descriptors: "renal cell carcinoma", "kidney neoplasm", were combined with the following terms: "radical nephrectomy", "nephron sparing surgery", "minimally invasive surgery", "radio frequency", "active surveillance" and "cryoablation".The databases search was conducted from March to April 2008.These terms were crossed, resulting in vast number of papers.Among the basis of their clinical relevance with respect to the aim of the review.
The introduction of radical nephrectomy as the standard of care, together with earlier diagnosis provided by an increased frequency of radiological imaging, has made some progress in RCC managebetter global survival (7).(Figure -1)

Radical Nephrectomy
Open Radical Nephrectomy nephrectomy.However, high sepsis and mortality Robson et al., published one of the most recognized and cited articles concerning the standardization of radical nephrectomy (11).
The choice of surgical access for radical nephrectomy is determined by the size and location of the tumor, patients' anatomy, and the surgeon's preferences.Whatever the choice of incision, the radical treatment should follow accepted oncologic principles.Contemporary series of open radical nephrectomies (ORN) report acceptable complication rates between 2-7%.The most common immediate complication is secondary hemorrhage (12).
Radical nephrectomy remains the most generclinical stage T3b tumors, radical nephrectomy with thrombectomy offers curative potential particularly in patients not exhibiting evidence of metastatic disease (13).Radical nephrectomies have been performed by laparoscopic approaches, emulating the open tech-nique-with "en bloc" resection both feasible and desirable.Although it is possible to remove the specimen by morcellation, it impairs pathologic analysis and risks perforating the extractor bag.However, port site recurrences have been only rarely reported.Morcellation has been found to be a safe procedure, although contraindicated in patients with ascites (17).
LRN is an established standardized procedure for treatment of T1, T2 and some T3aN0 tumors.Nevertheless, despite some success of laparoscopy for more locally advanced tumors such as T3, open radical nephrectomy remains the gold-standard for these lesions (20).Today nephron sparing surgery is emerging as the new standard of care for small renal lesions (T1a and probably some T1b) (Table-1).

Adrenalectomy
Although ipsilateral adrenalectomy is feasible during radical nephrectomy, the real risk of adrenal invasion is low.Moreover, adrenal involvement can be detected preoperatively by computerized tomography or magnetic resonance image with a high sensitivity (21).However, false negative adrenal metastasis rate can be meaningful, particularly in upper pole masses and in the context of large renal masses.Direct tumor extension or metastatic involvement of the ipsilateral adrenal gland occurs in only 1.2-10% of surgical specifound in 3.1% of 866 radical specimens (21).There are no reported prospective randomized studies examining the role of adrenalectomy in kidney cancer surgery.The low incidence of adrenal involvement and current imaging technology makes such a study unlikely.

Lymphadenectomy
Based on numerous published reports, such as: the UCLA experience and the EORTC 30881 randomized study, lymph node dissection is desirable only if preoperative imaging demonstrates enlarged lymph nodes.Lymph node involvement is associated with a poor prognosis although resection can increase survival when these patients are selected for adjuvant prospective oncologic outcomes, lymphadenectomy is considered unnecessary in unsuspected lymph node metastases as assessed by pre-operative imaging.

Open Partial Nephrectomy (Nephron-Sparing Surgery -NSS)
in 1870, by Simon, in a patient with hydronephrosis.
plished by Vizenz Czerny, successor of Simon in Heidelberg.
Today there is a debate about the accepted tumor size for partial nephrectomy.Patients with tumors of 4-7 cm with favorable anatomical characteristics are now treated conservatively (24).The complete removal of the tumor should be extended to have a negative margin.As regards the size of the normal parenchyma rim, some authors have reported that a macroscopic surgical margin of 0.5 cm is desirnegative margin irrespective of size is adequate and safe (25).The survival data are excellent and 5-year analysis demonstrated a local recurrence rate of 7.5% (0-12%) (27).The partial nephrectomy is criticized for its higher complication rate, chance of local recurrence due to incomplete resection, and because some of these tumors can be multifocal.However, recent series report low rates of local recurrence, even in patients with positive surgical margins (27).
mors, inadequate renal function or Von Hippel-Lindau disease (VHL), partial nephrectomy has mandatory indications to avoid dialysis and possible renal transmultifocal tumors and multiple premalignant cysts.
with the intention of delaying the onset of renal insufreaches a determined size (28).radical nephrectomy is a risk factor for development GFR < 60 mL/min for 1.73m 2 ) when compared to patients undergoing partial nephrectomy (29).Studying a cohort of 662 patients, 171 had some degree of preoperative renal dysfunction, 50/287 and 142/204 patients developed CRD after partial and radical nephrectomy, respectively.The probability of not having chronic renal disease in 3 and 5 years was 80% and 67% in nephron-sparing surgery, respectively; and 35% and 23% in the radical surgery group (p < 0.0001).This functional result questions the role of radical nephrectomy, as the previous gold standard, in terms of best preserving long-term renal function for small cortical tumors (29,30).
There are no prospective clinical trials that demonstrate the long-term oncological results of nephron-sparing surgery.However, the first ran-Genito-urinary Group of the European Organization for Research and Treatment of Cancer (EORTC) in collaboration with groups in North America (EORTC 30904).Van Poppel et al., randomized 541 patients with tumors less than 5 cm and a normal contralateral kidney (partial nephrectomy PN = 268 and Radical nephrectomy RN = 273).They concluded that the complication rate with partial surgery is slightly greater than in the radical procedure.The oncological results are not yet available (31) Therefore, based on functional long-term outcomes and similar retrospective oncologic endpoints compared to radical procedure, elective NSS an Tumor < 4 cm, if it is not a candidate for partial nephrectomy T1, T2-3a N0 and < 10-12 cm acceptable option for treat small RCC regardless of a higher complication rate.Nevertheless, the choice of invasiveness of the (laparoscopic or open) approach should not be considered the most important issue to select patients to radical or NSS procedures.

Laparoscopic Nephron-Sparing Nephrectomy
partial nephrectomy (LPN) is the standard technique for small cortical tumors (< 4 cm).Concerning the surgical technique, the vascular anatomy is very important (32).The polar nephrectomy is indicated in polar tumors as the wedge resection is indicated for central tumors (33).With this approach, the artery and the vein can be clamped when convenient even without cooling the kidney.Maintaining the kidney in warm ischemia enables a resection of up to 30 minutes (34).When complicated resections are anticipated, the hilum clamping is advised in conjunction with previous mannitol (12.5g) 20% administration and furosemide (10 mg) 5 to 10 minutes before clamping.Cooling the kidney with ice (for about 25 minutes lowering the temperature to 5-19º C) (35,36), helps prevent irreversible ischemic damage, thus making it possible longer resections up to 3 hours (37).
The most common complications of partial nethe majority of cases, such complications can be managed conservatively, through endoluminal vascular or endourological techniques.The use of intraoperative ultrasound is a useful tool to evaluate depth and the presence of other tumors.Except in few centers, warm ischemia time is longer than in open surgery.

Permpongkosol et al. demonstrated that LPN has 5-year oncologic outcomes similar to open partial nephrectomy (40) (Table-3).
Even in modern series, there are heterogeneous populations between LPN and OPN, suggesting different indications.T1b tumors are more common in OPN than in LPN cohorts (41).Few studies report good initial results with hand-assisted technique and tele-robotic surgery (42).

Minimally Invasive Techniques
The minimally invasive techniques give new perspectives to the treatment of localized RCC, offering alternatives to conventional surgery.Currently,

Elective Indication
Tumor with a normal contra-lateral kidney

Controversial Indication
Large (T2), central, multifocal and non-familial tumors great interest exists in renal ablations by radio-frequency and cryotherapy.Frequently, those therapies are reserved for patients with serious co-morbidities.However, their low morbidity and ability to preserve renal parenchyma make them promising techniques.

Cryoablation
Hypothermic ablation therapy (-40° C) is performed through the introduction of a probe, whose

Radio Frequency Ablation
Hyperthermic ablation therapy by radio frequency elevates the temperature of the tissues above 100 o tion of a probe, causing coagulation necrosis.
Short and intermediate-term results have demonstrated the safety and effectiveness of this method in small renal tumors.Follow-up of 27 months 92.3% and 98.5% respectively were observed (50).
Stern et al., published their results in 37 ASA 1-2 patients.Only one patient had a local recurrence in a period over 2 years and he was treated by radical nephrectomy without recurrence after 1 year followup (51).The same author compared intermediate-term results of partial nephrectomy and radiofrequency ablation and concluded that 3-year oncological outcomes were similar (52).
Gervais and colleagues published a series of 85 patients with the treatment of 100 tumors percutaneously.One local recurrence was seen and there were deed, 100% of the tumors smaller than 3 cm achieved complete ablation while only 25% of tumors greater paper of the same group, a cohort of 16 patients was reported with the longest term follow-up available (4.6 years).Five patients died of unrelated causes and the Zagoria et al., obtained complete ablation (absence of contrast enhancement in the tumors on residual tumors were observed in 30% of those larger than 3.7 cm in a follow-up of 13.8 months (55).
Centrally located tumors and those greater than 3 cm have been implicated as negative predictive factors for success.The observed complications are usually ureteral stenosis and urinomas.Residual tumors have been observed in nephrectomy specimens previously treated with radio-frequency ablation.There are concerns about viable tumor cells remaining after thermal ablation.However, such histological analyses were made in specimens previously treated with radiofrequency ablation just before the excision, therefore before complete coagulation necrosis had a chance to occur (56).
There are no systematic follow-up strategies after ablations of renal tumors.Usually, local recurrences or development of metastasis are assessed by has been the absence of contrast enhancement in the nition of radiographic success has been inadequate for determining complete ablation since positive biopsies have been reported in un-enhancing tumor beds (48).Therefore, current imaging techniques are quite limited to monitor and precise recurrences and repeated biopsies can be necessary to these follow-up should be established, based on radio-in future, molecular markers will also be considered as well as reporting of outcomes, technique and make possible comparisons of these ablative series with surgery.

Neo Adjuvant Therapy for Localized Renal Cancer
The role of neoadjuvant cytokines was investigated in patients with renal cancer undergoing were allocated alternately to 2 groups: perioperative in the week before surgery and control (57).The two groups had similar characteristics.Median follow-up was 40 months.The results revealed a difference in 98% vs. 81% and 86% vs. 73% (p = 0.04) in treated vs. control groups.Despite this paper's non-randomized design, it signals a possible new approach in localized renal cell carcinoma.Future research in this as an option in selected patients with a high risk for recurrence.

Adjuvant Therapy for Localized RCC
Renal cell carcinoma expresses tumor antithese antigens promote an immune system response and eventually tumor destruction.These tumor antigens are available as potential targets for vaccination.Different mechanisms can make the tumor cells escape from immune surveillance.The cornerstone of response.
Adjuvant tumor vaccination was reported in a randomized trial.A total of 553 patients were enrolled, comparing an autologous cancer cell vaccine.
Randomized trials have shown no improvement in overall or disease-free survival with the adjuvant treatments radiotherapy, interferon, interleukin or BCG (58,59).The new targeted therapies are fast becoming the standard treatment for metastatic RCC.Nonetheless, it is not yet known whether adjuvant angiogenesis inhibitors are more effective than observation in treating locally advanced renal cell carcinoma.Several adjuvant trials for high risk localized RCC are recruiting patients to evaluate the role of adjuvant G250Ab, sunitinib and sorafenib versus observation after complete excision of unfavorable RCC (ASSURE, SORCE and S-TRAC trials) (60)(61)(62).Preliminary results concerning patient-reported outcomes and safety are not expected before 2010.

Active Surveillance
including a better understanding of tumor molecular biology, improved imaging, and minimally invasive procedures, approximately 30% of localized RCC will recur and progress.The current treatment framework considers that a better oncological outcome can be assured with early intervention.Hollingsworth et al., analyzing the SEER database that enrolled more than 34,500 tumors, concluded that the incidence of small tumors has increased (< 4 cm) and represents the largest increase in annual incidence of RCC.Similarly, surgical treatment has increased (63).Nevertheless, even with preclinical tumor detection and the treatment of incidental tumors, the overall mortality of RCC has not been impacted.Hence, current assumptions of treatment are being reviewed and new concepts of management have been created.Active surveillance is being proposed to treat some of these indolent tumors, but there are doubts regarding this indolence (64).
The tenets of surveillance propose that small renal masses (< 3.5 cm) with a slow annual growth rate (< 0.28 cm/year) can be observed and should not be promptly treated (63).Unfortunately, tumor stage and growth kinetics are not reliable factors to predict a tumor's natural history; in part because of the heterogeneous range of tumors considered here (65).that 46% of tumors less than 1 cm were benign (66).Also, Gill reported a cohort where the median tumor size was 3 cm and 32% of these lesions were benign, the great majority was cancerous (67).oncocytomas and RCC variants.Although rare, metastatic disease was observed in 3 patients (1%).Two of these patients became metastatic after the primary tumor reached 8 cm (54 and 111 months).Another patient had metastasis after a follow-up of 134 months.The pathological evaluation was provided in 131/286 (64).Although renal biopsy should not be performed in the majority of patients, more recent studies have reported less complications and better accuracy.
Active surveillance should be restricted to elderly patients with co-morbidities or patients that refuse surgery.Thus, histological factors and molecular markers of progression are needed to improve the selection of patients for active surveillance.
Regardless of the approach, surgery remains the preferred standard of care for treating localized RCC.Complication rates of partial nephrectomies are not insignificant and ablative technologies are assuming a more prominent role.Recently, a meta-analysis compared oncological outcomes of these three strategies.Kunkle et al. analyzed 6,471 small renal masses described in 99 studies: 5,037 tumors were treated with nephron sparing surgery, 496 with cryoablation, 607 with radio frequency ablation and 331 were observed.The authors concluded that different groups have been treated by these strategies.This selection bias is clear when analyzing differences in tumor size, patient age, follow-up, and pathologic results.Although local control with ablation techniques has been inferior to nephron sparing surgery (radio-frequency 18-fold were found concerning metastatic progression, even with surveillance (68).

CONCLUSIONS
Surgery has been mostly responsible for the improvement in survival in localized renal cell carcinoma.Unfortunately, surgery for advanced localized disease (T3 and T4) remains unsatisfactory with high recurrence rates (20 to 30%).With a better understanding of the molecular basis of RCC the natural history can be predicted with improved accuracy, helping to identify high-risk tumors and establish targeted Laparoscopic radical nephrectomy is the preferred treatment for localized renal masses (T1 and T2) deemed not amenable to partial nephrectomy (open or laparoscopic).The quality of life and preservation of renal function have now become important clinical issues.Therefore, attempts to achieve these goals have resulted in better clinical results and similar 10-year oncological outcomes for T1a lesions managed by partial nephrectomy, as well as T1b lesions (<7 cm) in favorable locations amenable to a partial nephrectomy..

EDITORIAL COMMENT
on the management of localized renal tumors.The authors have adequately depicted that the management of small renal masses is no longer a simplistic discussion with patients that "the kidney needs to be removed" but rather that a spectrum of treatment choices are currently available from minimally invasive treatment modalities such as percutaneous radiofrequency ablation or cryotherapy, to nephron sparing surgery (laparoscopic, robotic assisted, open partial nephrectomy), extirpative surgery (laparoscopic or open radical nephrectomy), and active surveillance (for well-selected patients committed to a rigorous surveillance strategy and accepting of the potential risk of local, regional, and systemic progression).that partial nephrectomy remains the "gold standard" approach for the management of localized renal masses deemed amenable to partial excision with nephrectomy are increasingly being shown in terms of long-term renal function.The surgical approach used in performing a partial nephrectomy (i.e.open, pure laparoscopic, or robotic assisted laparoscopic) surgeon skill, and available hospital resources.The issue that is clear is that patient and case selection is of primordial importance.
Non-surgical, minimally invasive approaches to renal masses i.e. percutaneous cryotherapy or radiofrequency ablation are appealing to patients not ideally suited for aggressive surgical management and presenting with small renal masses amenable to this modality.Patients considering such minimally invasive approaches must be informed and accepting that long-term data on the effectiveness of these approaches are currently lacking and furthermore, patients must be committed to frequent radiologic imaging studies following the ablative procedure par-Patients must also be informed that a residual enhancing renal mass post-ablation may require repeated therapy (with either the same modality or another form of therapy).
What is clearly illustrated in the present discussion is that it is no longer appropriate for urologists to offer radical nephrectomy alone as the sole form of treatment for a suspected localized renal mass.Patients must be educated and guided along this spectrum of currently available treatment armamentarium.With this knowledge at hand, patients are able to decide for themselves which modality is best suited for them.Furthermore, our knowledge is evolving and future discoveries and technological advances will impact our treatment options for a localized renal mass, our role will be to keep abreast of these advances and make them readily available to our patients.

Department of Interdisciplinary Oncology University of South Florida
Tampa, Florida, USA

Figure 1 -
Figure 1 -The observed 5-year relative survival rate of the kidney cancer patients and the historical facts responsible for a better rate of survival.Source: J Urol, 1969

Table 3 -
Published long-term outcomes for treatment of localized RCC regarding local recurrence, chronic renal disease