**3. Survival of renal cancer patients treated with renal artery embolization**

Up to 30% of patients diagnosed with RC have metastatic disease at presentation [27]. De‐ spite its sometimes favourable course, patients with metastatic RC generally die within 2 years of diagnosis. DeKernion et al [20] found that cumulative survival in 86 patients with metastatic RCC was 53% at 6 months, 43% at 1 year, 26% at 2 years and 13% at 5 years. The treatment of patients with metastatic RC has not improved over the years and continues to pose a problem for clinicians. Surgery is not curative in this group; however, recent advan‐ ces in immunotherapy have rekindled interest in cytoreductive nephrectomy. A combined analysis [21] of two prospective randomized trials, [15, 16], found a small survival advant‐ age (5.8 months) in patients who underwent nephrectomy followed by interferon-alpha based immunotherapy compared with immunotherapy alone. This survival benefit relates to patients with a good performance status whose primary tumour has been assessed to be surgically operable and who are good candidates for subsequent immunotherapy. Unfortu‐ nately, many elderly patients with disseminated RC do not fit these criteria and have signifi‐ cant comorbidity. Radical nephrectomy may cause significant morbidity post-surgery, particularly in elderly patients, and in some cases precludes the use of systemic therapy. It is in this situation that renal artery embolisation appears to have a role.

ized patients with RC was selected. This group was matched for sex, age, stage, tumor size, and tumor grade, with the embolized patients (p < 0.01). All important prognostic factors were studied as to their influence on survival by the treatment group. The overall 5- and 10-year sur‐ vival was 62% and 47%, respectively (Figure 2). The 5- and 10-year survival rates were signifi‐ cantly better (p < 0.01) for patients with pT2 than for those with pT3 tumors (79% vs. 50% and 59% vs. 35%, respectively) (Figure 2). Involvement of regional lymph nodes (N+) was an impor‐ tant prognostic factor for survival in patients with pT3 tumors. The 5-year survival for pT3 N+ was 39%, compared with 66% in those with pT3N0 (p < 0.01). Preoperative embolization was

Renal Artery Embolization in Treatment of Renal Cancer with Emphasis on Response of Immune System

http://dx.doi.org/10.5772/54116

101

**Figure 2.** Estimated probability of survival from all causes of death by pathologic stage, pT2 vs. pT3. Open circles rep‐

**Figure 3.** Estimated probability of survival in the 118 patients treated with preoperative embolization as compared to

resent death of a patient. Tick marks represent a patient who was alive at last follow-up.

the 116 patients in radical nephrectomy alone group (matched patients).

also an important factor influencing survival (Figure 3).

Previous studies had reported that delayed nephrectomy following embolisation of RC may be of clinical benefit to high risk patients with reduction in the size and vascularity of the primary tumour prior to surgery [9]. Subsequent studies have, however, found no survival benefit for patients with metastatic disease undergoing embolisation and nephrectomy [23]. The survey also indicated that a significant proportion of respondents (35%) still believed that the technique had a role in palliation of haematuria or pain in unfit or inoperable cases, or as the sole treatment modality in patients with metastatic disease.

Park et al [19] investigated the effectiveness of RAE with a mixture of ethanol and lipiodol in 27 patients with unresectable RC. 10 of the patients had stage III disease with 15 of the 27 patients having stage IV disease. Overall the median survival of the 27 patients was 8.5 months. The median survival was 23 months in the 10 patients with stage III disease and 7 months in 15 patients with stage IV disease. A similar study by Onishi et al [24] compared two groups of patients with unresectable RC with stage IV disease. 24 patients underwent renal embolisation with ethanol while 30 patients did not have any intervention. The me‐ dian survival for the renal embolisation group was 229 days and for the control group 116 days. Those undergoing renal embolisation had a significantly better prognosis than those who did not (*p*=0.019). Other authors [18, 25, 26] have reported median survival times for patients treated with renal embolisation ranging from 4 months to 8.4 months. This equates to a 1 year survival rate of 36.8% and a 2 year survival rate of 15.8%. Ridley et al. [28] sup‐ port the view that embolisation is not a curative treatment and probably only minimally al‐ ters the natural course of the disease, but it gives palliation of local symptoms related to advanced renal malignancy and is a safe alternative to radical nephrectomy, with low mor‐ bidity and complication rate and shorter hospital stay.

In own studies [1] a series of 474 patients with RC, who had radical nephrectomy during a peri‐ od of 15 years, was studied to assess the prognostic significance of various pathologic parame‐ ters (tumor stage [pT], lymph node status, metastasis, tumor grade, venous involvement) and value of preoperative RAE. There were: 20 (4%) pT1, 204 (43%) pT2, 245 (52%) pT3, and 5 (1%) pT4 patients. All 474 patients underwent nephrectomy including a group of 118 (25%) patients (24 pT2, 90 pT3, and 4 pT4) who underwent preoperative embolization of the renal artery. To compare treatment outcomes in embolized patients with RC, a group of 116 (24%) nonembol‐ ized patients with RC was selected. This group was matched for sex, age, stage, tumor size, and tumor grade, with the embolized patients (p < 0.01). All important prognostic factors were studied as to their influence on survival by the treatment group. The overall 5- and 10-year sur‐ vival was 62% and 47%, respectively (Figure 2). The 5- and 10-year survival rates were signifi‐ cantly better (p < 0.01) for patients with pT2 than for those with pT3 tumors (79% vs. 50% and 59% vs. 35%, respectively) (Figure 2). Involvement of regional lymph nodes (N+) was an impor‐ tant prognostic factor for survival in patients with pT3 tumors. The 5-year survival for pT3 N+ was 39%, compared with 66% in those with pT3N0 (p < 0.01). Preoperative embolization was also an important factor influencing survival (Figure 3).

treatment of patients with metastatic RC has not improved over the years and continues to pose a problem for clinicians. Surgery is not curative in this group; however, recent advan‐ ces in immunotherapy have rekindled interest in cytoreductive nephrectomy. A combined analysis [21] of two prospective randomized trials, [15, 16], found a small survival advant‐ age (5.8 months) in patients who underwent nephrectomy followed by interferon-alpha based immunotherapy compared with immunotherapy alone. This survival benefit relates to patients with a good performance status whose primary tumour has been assessed to be surgically operable and who are good candidates for subsequent immunotherapy. Unfortu‐ nately, many elderly patients with disseminated RC do not fit these criteria and have signifi‐ cant comorbidity. Radical nephrectomy may cause significant morbidity post-surgery, particularly in elderly patients, and in some cases precludes the use of systemic therapy. It is

Previous studies had reported that delayed nephrectomy following embolisation of RC may be of clinical benefit to high risk patients with reduction in the size and vascularity of the primary tumour prior to surgery [9]. Subsequent studies have, however, found no survival benefit for patients with metastatic disease undergoing embolisation and nephrectomy [23]. The survey also indicated that a significant proportion of respondents (35%) still believed that the technique had a role in palliation of haematuria or pain in unfit or inoperable cases,

Park et al [19] investigated the effectiveness of RAE with a mixture of ethanol and lipiodol in 27 patients with unresectable RC. 10 of the patients had stage III disease with 15 of the 27 patients having stage IV disease. Overall the median survival of the 27 patients was 8.5 months. The median survival was 23 months in the 10 patients with stage III disease and 7 months in 15 patients with stage IV disease. A similar study by Onishi et al [24] compared two groups of patients with unresectable RC with stage IV disease. 24 patients underwent renal embolisation with ethanol while 30 patients did not have any intervention. The me‐ dian survival for the renal embolisation group was 229 days and for the control group 116 days. Those undergoing renal embolisation had a significantly better prognosis than those who did not (*p*=0.019). Other authors [18, 25, 26] have reported median survival times for patients treated with renal embolisation ranging from 4 months to 8.4 months. This equates to a 1 year survival rate of 36.8% and a 2 year survival rate of 15.8%. Ridley et al. [28] sup‐ port the view that embolisation is not a curative treatment and probably only minimally al‐ ters the natural course of the disease, but it gives palliation of local symptoms related to advanced renal malignancy and is a safe alternative to radical nephrectomy, with low mor‐

In own studies [1] a series of 474 patients with RC, who had radical nephrectomy during a peri‐ od of 15 years, was studied to assess the prognostic significance of various pathologic parame‐ ters (tumor stage [pT], lymph node status, metastasis, tumor grade, venous involvement) and value of preoperative RAE. There were: 20 (4%) pT1, 204 (43%) pT2, 245 (52%) pT3, and 5 (1%) pT4 patients. All 474 patients underwent nephrectomy including a group of 118 (25%) patients (24 pT2, 90 pT3, and 4 pT4) who underwent preoperative embolization of the renal artery. To compare treatment outcomes in embolized patients with RC, a group of 116 (24%) nonembol‐

in this situation that renal artery embolisation appears to have a role.

100 Renal Tumor

or as the sole treatment modality in patients with metastatic disease.

bidity and complication rate and shorter hospital stay.

**Figure 2.** Estimated probability of survival from all causes of death by pathologic stage, pT2 vs. pT3. Open circles rep‐ resent death of a patient. Tick marks represent a patient who was alive at last follow-up.

**Figure 3.** Estimated probability of survival in the 118 patients treated with preoperative embolization as compared to the 116 patients in radical nephrectomy alone group (matched patients).

The overall 5- and 10-year survival for 118 patients embolized before nephrectomy was 62% and 47%, respectively, and it was 35% and 23%, respectively, for the matched group of 116 pa‐ tients treated with surgery alone (p = 0.01). The most important finding of this study was an ap‐ parent importance of preoperative embolization in improving patients' survival. This finding needs to be interpreted with caution and confirmed in a prospective randomized trial.

of which appear to have an immunosuppressive effect. The main task of the immune system is to maintain homeostasis. The basic unit, often defined as "immune orchestra conductor" is thymus-dependent T lymphocyte, which, based on the phenomenon of re‐ striction major histocompatibility complex I and II expresses the phenomenon of violence against its own unnormal or changed antigens, and the phenomenon of tolerance to its own antigens [32, 33]. Embolization may lead to stimulation of the immune system in the following mechanism: close off blood supply to the tumor leads to necrosis which gives a chance to enhance antigenicity of cancer cells and evoke the potential amplifica‐ tion of the immune system [14]. This leads in turn to destruction of tumor tissue by infil‐

Renal Artery Embolization in Treatment of Renal Cancer with Emphasis on Response of Immune System

http://dx.doi.org/10.5772/54116

103

Recent studies in patients with metastatic RC have shown a small survival advantage in pa‐ tients undergoing radical nephrectomy followed by immunotherapy; however, these studies are biased towards patients with good performance status aqccording to ECOG (Eastern Co‐ operative Oncology Group) scale status 0 or status 1. This small survival benefit should also be viewed in light of the morbidity and mortality associated with a large surgical procedure. The increased morbidity associated with radical nephrectomy may preclude or delay the ad‐ ministration of systemic immunotherapy, which has demonstrated reproducible response

In two randomized trials with identical design, patients who underwent nephrectomy fol‐ lowed by interferon alpha (IFN-α) therapy had improved survival (median 13.6 months) compared with those treated with IFN-α alone (median 7.8 months) [15, 16]. The antivascu‐ lar endothelial growth factor (VEGF) antibody; the multityrosine kinase inhibitors, sorafe‐ nib, sunitinib, and pazopanib; and the mammalian target of rapamycin (mTOR) inhibitors, temsirolimus and everolimus, have become the mainstay of therapy for the vast majority of patients with metastatic renal cell carcinoma (mRCC). Large randomized controlled clinical trials have shown improved progression-free survival with these agents and improved sur‐ vival in selected populations, but the majority of these study patients had prior nephrecto‐

In own studies [14] we examined functional status of immunocompetent cells isolated from peripheral blood of patients with advanced RC treated with RAE. Blood samples were collected by vein puncture and peripheral blood mononuclear cells (PBMC) were isolated on Ficol-Paque gradient, and after determination of cell viability (usually no less than 80% viable cells), the microcultures were set up in triplicates (105 cells/0.2 ml RPMI + 15% autologous inactivated serum) in Nuncoln microplates. Respective triplicates were left without stimulation or stimulated with phytohemagglutinin (PHA, HA16, Murex Bio‐ tech Ltd Dartford U.K., 0.4 μg/cult.) or with concanavalin A (Con A, Sigma, 8 μg/cult.). The plates were placed inside the anechoic chamber in the ASSAB incubator at 37o C and 5% CO2. An identical plate of control cultures was also set up and placed in the AS‐ SAB incubator beyond the chamber. At 24h of incubation, rearrangements of the cultures

tration with cytolytic immunocompetent cells.

my and good performance status [16, 17, 20, 21].

were performed as described elsewhere [32,33].

rates of 10–20% [15].

In conclusion, the available data suggest that RAE is a convenient, relatively tolerable man‐ agement option in patients with unresectable renal tumours and in patients unfit or unwill‐ ing to undergo surgery as a means of palliation of local symptoms and improving clinical status. We believe there is also a role for this procedure in asymptomatic patients who have potentially resectable disease who are unfit or unwilling to undergo surgery, and in asymp‐ tomatic patients with inoperable metastatic disease.
