Neoadjuvant Therapy for Locally Advanced Renal Cell Carcinoma with Sorafenib in a Reference Center in Mexico

doi:10.4236/ss.2011.26077

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Surgical Science, 2011, 2, 356-359

doi:10.4236/ss.2011.26077 Published Online August 2011 (http://www.SciRP.org/journal/ss)

Neoadjuvant Therapy for L ocally Advanced Renal

Cell Carcinoma with Sorafenib in a Reference

Center in Mexico

Axel Costilla-Montero1, Benjamín Guadarrama-Benítez1, Marco A. Aragón-Castro1,

Omar Morales-Ordaz1, Rubén Gutiérrez-Rosales1, Claudia Carrillo-Ponce2,

Marcela Janka-Zires2, Luis Gabriel Vázquez-Lavista1*

1Departament of Ur ology, Centro Médico ISSEMYM Toluca, Tol uca, México

2Departament of Pathology, Centro Médico ISSEMYM Toluca, Toluca , México

3Department of Internal Medicine Fundacion, Centro Médi co IS SEMYM Toluca, Toluca, México

*E-mail: [email protected]

Received May 5, 2011; revised June 24, 2011; accepted July 7, 2011

Abstract

Background: neo-adjuvant therapy is usually indicated in locally advanced tumors, the aim is to decrease

the tumoral burden and enhance overall survival. Renal cell carcinoma is a chemo and radio resistant neo-

plasm and this type of approach is not as effective as in other solid tumors. On the other hand immunother-

apy is indicated in metastatic disease, demonstrating a better overall survival. Sorafenib is an antiangiogenic

drug approved for locally advanced or metastatic RCC. We postulated that it can be used in a neoadjuvant

way to decrease the vascularization of selected tumors. Report of the Case: 57 years old male referred to

our service with a right renal mass and metastatic disease to lumbar spine and suprarenal gland. He was

treated with three months of sorafenib previous to the surgery. Results: the patient went into surgery three

months after initiating the antiangiogenic drug, during the surgery we found less neo-formance vessels; the

dissection was subjectively easier, due to peri-renal edema. The pathologic analysis of the specimen was re-

nal cell carcinoma. Interestingly, 40% of central ischemic (coagulative) necrosis was found. Conclusion:

there are no neoadjuvant drugs accepted for the treatment of renal cell carcinoma; using an antiagiogenic

drug to decrease the vascular burden characteristic of this type of tumors could be a viable option in selected

cases. We used a lower dose of the drug with an acceptable safety profile.

Keywords: Renal Cell Carcinoma, Antiagiogenic Drugs, Neoadyvant Therapy, Sorafenib

1. Introduction

Kidney cancer is the seventh leading malignant co ndition

among m en and the twelfth a mong women, a ccounting for

2.6% of all cancers in the United States [1] and is the tenth

cause in México [2]. The most frequent histology is renal

clear cell carcinoma (RCCC). When RCCC in an organ

confined stage, it is surgically treated with good overall

survival rate, whoe ver, 30% of the cases are detected in an

advanced stage, in the world and in México, with a high

mortality rate [3,4]. RCCC shows poor response to che-

motherapy due to multiple mechanisms [5]. Currently

FDA approved treatment strategies for metastatic stages

are immunotherapy with cytokines [interferon alpha and

interleukine-2] and the use of antibodies against specific

proteins (vascular endothelial growth factor, platelet de-

rived growth factor, and tumor growth factor alpha) such

as sunitinib [6], sorafenib [7] or bevacizumab [8].

Neo-adjuvant therapy is usually indicated in locally

advanced tumors, and the aim is to decrease the tumoral

burden and enhance overall survival . As m entioned a bove,

due to the chemo-resitance of RCCC, neoadjuvant studies

are scarce. On the other hand, the response to immuno-

therapy is limited and tox icicity is h igh. Th ere are stud ies

using immunotherapy as an adjuvant therapy along with

cito-reducti ve nefrectom y wi th a better overal l survival o f

the patients; [6-8] the aim of this study is to report our

experience in one case treated with sorafenib as a neoad-

juvant drug.

Scientific evidence suggests that the concept of

A. COSTILLA-MONTERO ET AL.357

neoadjuvant therapy for RCCC should be revisited [9],

especially in selected patients according to the NCCN

guidelines [10].

2. Case Report

Fifty seven year old male referred to our service with a

right renal mass and metastatic disease to lumbar spine

and suprarenal gland.

CT scan was performed with the evidence of a renal

mass. He was treated with three months of sorafenib pre-

vious to the surgery. He received 200 mgs PO every 12

hrs for a month, the subsequent month no drug was ad-

ministered, and the cycle was repeated for a third month.

Figure 1 shows two slides of the CT scan demonstrating

densities changes in the center of the mass before and

after the neoadjuvant treatment.

3. Results

The patient went into surgery three months after initiating

the antiangiogenic drug, during the surgery we found less

neo-formance vessels; the dissection was subjectively

easier, due to peri-renal e dema. The pathologic analysis of

the specimen was T4 renal cell carcinoma Fuhrman III in

95% of the kidney. I nteresti ngl y, 40% o f central ischem i c

(coagulative) necrosis was found. The suprarenal gland

was found with metastatic disease Figure 2.

4. Discussion

Controlled fase III studies have demonstrated superiority

in those patients treated with INF and targeted therapies.

Sorafenib is a multi kinase inhibitor including VEGFr,

PDGFr and RAF. Using it as a unique drug the results

are promising, showing a better overall and progression

free survival in metastatic disease [7]. One of the first

case reports is bi Di Silverio et al. where they describe A

71-year-old man with advanced left renal cell carcinoma

(lymph node involvement and vena cava thrombus) was

submitted to 6 months of neoadjuvant treatment with

sorafenib before open radical nephrectomy. After soraf-

enib treatment and before surgery a new CT scan con-

firmed the presence of a 9.0 cm in diameter solid mass in

the left kidney but a reduction in thrombus extension,

limited to the left renal v ein. At histological examination

after radical nephrectomy, over 90% of the renal mass

was substituted by necrotic tissue [11].

Our patient showed 50% necrosis in the pre surgery

CT scans and this was corroborated in the final patho-

logical specimen with 40% of central ischemic (coagula-

tive) necrosis. It is worth to mention that the neoplastic

necrosis is usually a liquefactive one, and it is character-

ized by digestion of the dead cells resulting in transfor-

mation of the tissues into a liquid viscous mass. In this

case the architecture of the dead tissue was preserved and

the affected tissue exhibited a firm texture so it was sec-

ondary to ischemia. Subjectively during the dissection we

found a peri renal edema that made easier the surgery. It

is also worth mentioning th at the therapeutic dose used in

this patient was lower than that used in a palliative scen-

ery, and only a few adverse effects were reported, no

important co morbidity was found during the follow up.

The biggest case control series with tyrosine kinase

inhibition is with 14 patients who underwent cytoreduc-

tive nephrectomy for advanced renal cell carcinoma with

prior treatment with sorafenib or sunitinib, and were

compared with 73 patients without neoadjuvant therapy,

Figure 1. Pre- and post-neo-adjuvant treatment with sorafenib CT scan of the renal mass.

A. COSTILLA-MONTERO ET AL.

358

Figure 2. Pahtological specimen of right kidney with central

necrosis and metastatic disease to suprarrenal gland.

the parameters studied were: the incidence of periopera-

tive complications and outcomes after surgical procedures

between the two cohorts. The median preoperative renal

mass size was 11 cm (6.7 - 4.2 cm). Primary tumor

shrinkage was seen in 57%; median shrinkage was 18%

(8% - 25%). The median treatment period was 17 weeks,

and the median time from TKI discontinuation was 2

weeks. Compared with a control group and after adjust-

ing for confounding covariates, presurgical TKI use was

not associated with a significant increase in perioperative

complications (50% vs 40%, P = 0.25) or perioperative

bleeding (36% vs 34%, P = 0.97) but was associated

with increased incidence and grade of intraoperative ad-

hesions (86% vs 58%, P = 0.001; grade 3 vs 1, P =

0.002). They concluded that they found less hemorrhagic

and wound healing issues but a significant increase in

incidence and severity of intraoperative adhesions, which

can present a formidable technical challenge. The pre-

surgical TKI therapy can permit effective surgical cy-

toreduction with a safety and complication profile

equivalent to that of non-TKI-nephrectomy; however

safety data continue to evolve, and preoperative TKI use

requires further prospective investigation [12].

5. Conclusions

Sorafenib is a drug that inhibits specific proteins in neo-

plastic cells, it modulates transduction signal and has

shown to create intratumoral ischemic necrosis. The

NCCN [9] and the EUA [13] guidelines have suggested

that this drug can be used as a first line of treatment and

the neoadjuvant setting should be investigated thor-

oughly.

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