Nuclear Oncology, 1 Ed.

CHAPTER 13

RENAL CARCINOMA

Antonija Balenovic • Jasna Mihailovic • Katherine Zukotynski

INTRODUCTION

Renal cell carcinoma (RCC) accounts for approximately 3% of all adult cancers1 although the incidence has been slightly increasing in recent years.2,3 It is estimated that over 50% of RCC cases are found incidentally on diagnostic imaging studies performed for other reasons. The average age at diagnosis is 60 years and men are more commonly affected than women, with a ratio of 1.5:1. A number of environmental, occupational, hormonal, cellular, and genetic factors have been associated with the development of RCC.4 The most frequent symptom associated with RCC is hematuria, which can be either microscopic or gross in advanced disease. Other signs and symptoms include flank pain, a palpable abdominal mass, systemic paraneoplastic syndromes, or symptoms from metastatic disease. Primary RCC is highly angioinvasive and is associated with hematogenous and lymphatic metastases. Malignant spread of disease can occur via local infiltration through the renal capsule, by growth along the venous channels to the renal vein or vena cava or by drainage along lymphatic vessels. The right kidney drains predominantly into the paracaval and interaortocaval lymph nodes whereas the left kidney drains to the para-aortic lymph nodes.5 Lymph node metastases occur with an incidence of 9% to 27% and most often involve renal hilar, para-aortic, and paracaval lymph nodes.6 The most common sites of RCC metastatic disease are the lungs (75%), soft tissue (36%), bone (20%), liver (18%), skin (8%), and the central nervous system (8%).7 The most lethal of all urologic malignancies, it is estimated that 25% to 30% of patients with RCC present with metastatic disease.3 The prognosis following a diagnosis of metastatic RCC is extremely poor, regardless of the site of disease.6,8,9 Moreover, it is thought that 20% to 40% of patients develop metastases following nephrectomy.7,10

PATHOLOGIC CLASSIFICATION

There are several histopathologic subtypes of RCC. The most common subtype is clear cell carcinoma, accounting for approximately 70% to 75% of cases.10 Other less common subtypes include papillary RCC (10% to 15%) and chromophobe RCC (5%). The sarcomatoid variant of RCC (1% to 6%) is associated with a significantly poorer prognosis.8 Malignant tumors arising in the upper urinary tract (renal pelvis and ureter) account for approximately 1% to 7% of all renal neoplasms. Since the mucosal surfaces of the renal pelvis, the ureter, and the bladder have the same embryologic origin, many of the etiologic factors as well as the natural history and general management of these tumors also apply to tumors of the urinary bladder. Therefore, these tumors will be described together in the chapter on cancer of the urinary bladder.

GENERAL MANAGEMENT OF RENAL CELL CARCINOMA PATIENTS

The standard therapy for nonmetastatic RCC has long been radical nephrectomy in which the malignant tumor is removed along with the kidney, the adrenal gland, and the perinephric fat enclosed within Gerota’s fascia. Regional lymph node dissection is performed routinely. More recently, less aggressive interventions including partial nephrectomy have emerged as an alternative to radical nephrectomy, particularly in patients with early stage tumors, poor renal reserve, or the absence of a normal functioning contralateral kidney.6,11 Of note, prospective randomized studies have not shown a benefit for patients receiving radiation therapy before or after surgery if RCC is confined to the kidney and/or renal vein.4,12

For patients with metastatic RCC, palliative nephrectomy can relieve pain, hemorrhage, hypertension, or hypercalcemia. Palliative radiation therapy is effective in relieving symptoms in patients with metastatic disease, especially those with bone and brain metastases.4,13 Chemotherapy has not produced significant results in advanced stage RCC. Conventional cytotoxic therapies as well as hormonal and immunotherapies have had low response rates. In the past, cytokine therapies such as interferon alpha (IFN-α) and interleukin (IL-2) were the main systematic treatments available for advanced RCC.14,15 However, recent advances have led to the development of agents that target specific biologic pathways. Tyrosine kinase inhibitors (multiple TKIs) that target the vascular endothelial growth factor receptors (VEGFRs) such as sunitinib, sorafenib, and pazopanib and inhibitors of the mammalian target of rapamycin (mTOR) such as temsirolimus and everolimus, are now available and have revolutionized the treatment of RCC.16,17 These new developments have made it necessary to find novel biomarkers to predict prognosis and to identify patients in such a way that optimal targeted therapy can be administered.13,1820 One such approach involves development of novel radiotracers for positron emission tomography (PET)/computed tomography (CT).20

Initial Diagnostic Workup and Staging of Renal Cell Carcinoma

Renal lesions are common findings on anatomic imaging. Although the majority are benign (e.g., renal cysts and angiomyolipomas [AMLs]), if a malignant neoplasm is suspected, ultrasonography (USG), contrast-enhanced computed tomography (CECT) or magnetic resonance imaging (MRI) can be helpful for further evaluation. USG and CECT remain the initial imaging modalities of choice for the accurate assessment of renal lesions.13 Though MRI is usually not the initial imaging modality of choice, it has a higher sensitivity compared to CT for the evaluation of complicated cysts. Also, MRI provides additional diagnostic value in the evaluation of lesions with minimal amounts of fat or with intracellular fat.21

In most cases once the diagnosis of RCC is made, a staging evaluation should be undertaken, which includes a clinical history, physical examination, blood work, urinalysis, and imaging such as a chest x-ray and CT or MRI of the abdomen and pelvis.13 Patients with symptoms suggestive of bone metastases can be further evaluated with skeletal scintigraphy and CT or MRI of the brain can be performed if the physical examination suggests brain metastases. Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) PET/CT, although routinely used in the assessment of malignant disease,2224 is not a standard tool for the diagnosis or follow-up of patients with RCC, according to the National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines.13,25 The use of FDG PET/CT is limited in the evaluation of genitourinary lesions by significant physiologic FDG activity in the kidneys, collecting system, and urinary bladder26 and often low activity at sites of pathology. Therefore, close attention must be paid to both the PET and CT portions of the study to effectively characterize renal lesions.27 Despite these concerns, the role of FDG PET/CT in patients with suspected RCC has increased over the last few years.28 FDG PET/CT can be used to characterize indeterminate cysts, detect both primary and metastatic disease and may be useful for preoperative disease characterization/staging RCC and for postoperative surveillance of advanced RCC27,28 (Fig. 13.1). In addition, recent advances have led to the use of PET radiopharmaceuticals other than FDG in the evaluation of RCC patients, although this remains to a large extent still in the realm of research.2931

FIGURE 13.1. A 71-year-old male post left nephrectomy for renal cell carcinoma. A: PET/CT performed 3 months after radiotherapy of a left iliac bone metastasis (and prior to planned cardiosurgery), shows a large heterogenous FDG-avid lytic expansile mass in the left iliac bone. FDG activity is seen throughout the mass, most intense in the medial part of the lesion (SUVmax range 3.5 to 8.6). B: Follow-up PET/CT performed 8 months later shows progression of the FDG-avid left iliac bone mass (SUVmax 11.7). No additional sites of metastatic disease were seen (FDG activity in the sternal region was related to cardiac surgery).

FDG PET/CT in the Initial Evaluation and Staging of Renal Cell Carcinoma Patients

The most widely used PET radiotracer in genitourinary oncology is FDG, although it is well known that because of its urinary elimination, FDG is not an ideal radiotracer for this purpose32 (Table 13.1). To minimize this limitation, FDG PET/CT studies in renal and bladder cancer patients are occasionally modified by using diuretics and performing bladder catheterization. Otherwise, patient preparation and study acquisition is the same as in other cancer patients. In general, patients are asked to avoid strenuous exercise for 24 hours and to fast for 4 to 6 hours prior to radiotracer administration. It is also recommended that the level of glucose in the blood at the time of radiotracer administration should not exceed 10 mmol/L (ideally 8 mmol/L). In adults, an empiric dose of FDG is injected intravenously, typically ranging from 185 to 555 MBq (5 to 15 mCi). Imaging is performed after an uptake period of 60 ± 10 minutes. First a scout CT is performed, followed by a low-dose CT for PET attenuation correction and anatomical correlation. PET data acquisition follows, usually with the whole body scanning from the skull base to the thighs, requiring a total of 7 to 10 bed positions at 1 to 4 minutes per bed position, depending on the scanner type and the desired image quality. CECT may be performed either in conjunction with the PET/CT, as a separate study or not at all, depending on the clinical indication and pre-existing contraindications, if present.24

The timing of the PET/CT study should be coordinated with other procedures which could alter FDG uptake in the affected region such as surgery, radiotherapy, or chemotherapy. For example, increased FDG uptake can be seen in tissue after radiation therapy and it is therefore recommended to wait at least 8 weeks after external beam radiation before evaluating (or re-evaluating) the irradiated area for residual disease. For patients on chemotherapy, the timing of follow-up FDG PET/CT is variable. It has been suggested that at least 4 weeks be allowed to elapse between the last dose of chemotherapy and the follow-up FDG PET/CT however, data in genitourinary malignancy is limited.

Standardized Uptake Value in Renal Cell Carcinoma

The maximum SUV (SUVmax) represents the highest radioactivity concentration in one voxel within the region of interest (ROI) and is often used as a semiquantitative measure of FDG uptake or glucose utilization in an ROI. The SUVmax can serve as a biomarker, providing prognostic information or quantifying therapy response between baseline and follow-up FDG PET/CT studies.

There is no specific (or “cut-off ”) SUVmax that suggests a diagnosis of RCC. According to published reports, the SUVmax of biopsy-proven RCC, either primary or metastatic, demonstrates a broad range.33,34 Further, there is no definite correlation between SUVmax and RCC histopathologic subtype,34 although a correlation has been seen between SUVmax and lesion size, with lesions larger than 5 cm demonstrating increased FDG activity.35 There are mixed results regarding the analysis of glucose transporter GLUT-1 expression and RCC FDG avidity. For example, a study by Miyakita et al. suggested there was no correlation of GLUT-1 immunoreactivity and FDG-PET positivity;35 however, positive GLUT-1 expression was seen in larger tumors. Lidgren et al.36 showed that RCC was associated with high GLUT-1 expression and that there was a significant difference among different histologic subtypes of RCC. Specifically, in 187 patients GLUT-1 expression was significantly higher in clear cell RCC compared with papillary RCC or chromophobe RCC. However, in clear cell RCC, GLUT-1 expression had no correlation with clinicopathologic tumor stage. In the subgroup with low GLUT-1, there was a trend, although it was not significant, to improved survival in patients with either the clear cell or the papillary RCC subtypes.36 Several studies have explored the prognostic significance of an SUVmax index. In general, patients with RCC and a high SUVmax index have poor prognosis.20,33

FDG is sensitive for the detection of RCC metastases and it is estimated that FDG activity is seen in over 95% of metastases diagnosed by CT.20,37 There is no definite relationship between the SUVmax of the primary tumor and the SUVmax of metastatic disease or between different sites of metastatic disease in the same patient. Although the lungs are the most frequent site of metastases, certain anatomic sites which are rarely affected by RCC metastatic disease (uterus, pancreas, muscle metastasis) can present with the most intense FDG accumulation.20

TABLE 13.1

PET RADIOTRACERS IN RENAL CARCINOMAS

FIGURE 13.2. A 62-year-old male with an FDG-avid renal cell carcinoma. PET/CT shows multi-focal radiotracer activity in both kidneys related to physiologic urinary excretion. Axial nonenhanced CT shows a small left renal cortical nodule (green arrow), which was hypervascular on contrast enhanced images (red arrow) and intensely FDG-avid on PET (green arrow).

FDG PET/CT in Characterization of Renal Lesions

Detection and characterization of incidental renal lesions on PET/CT can be challenging because of the presence of physiologic FDG activity in urine and limited FDG activity at sites of disease. The importance of viewing both the PET and CT components of a PET/CT study to characterize renal lesions as benign or malignant cannot be overemphasized (Fig. 13.2). RCC typically shows FDG uptake comparable to normal renal parenchyma; however, FDG uptake can be heterogeneous depending on the subtype and the size of the tumor. Although RCC can be incidentally detected on FDG PET/CT, many incidentally detected renal lesions are benign and it is important to be aware of the imaging features that suggest specific pathology. Several causes of focal FDG accumulation in the kidney on PET/CT are summarized in Table 13.2.

TABLE 13.2

FDG PET/CT IN RENAL PATHOLOGY

FIGURE 13.3. A 50-year-old male post right nephrectomy for renal cell carcinoma. A: Nonenhanced CT shows a left renal cyst which is photopenic on PET (cursor ). B: Nonenhanced CT shows small retroperitoneal lymph nodes that are not significantly FDG-avid on PET (cursor ).

Renal Cysts

The prevalence of several benign renal lesions, such as cysts, increases with age, male gender, renal dysfunction, and hypertension.38 The typical appearance of a simple cyst on PET/CT is a well-defined, thin-walled, low attenuation (0 to 20 Hounsfield units (HU)), photopenic lesion.39 Simple cysts do not require further follow-up (Fig. 13.3). Complex cysts often have suspicious features such as wall thickening, nodularity, or irregular peripheral calcifications and may be multilocular with multiple enhancing septa or nodularity. PET/CT may provide additional characterization and precise localization of complex cysts. For example, in autosomal dominant polycystic disease a benign appearing FDG PET/CT study in conjunction with a negative cyst aspiration can be helpful and avoid additional imaging/intervention.39 Even though USG, CT, or MRI with or without tissue sampling is preferred for the characterization of cystic renal lesions with solid components,40 FDG PET/CT can help prevent unnecessary intervention and optimal management of suspicious lesions in certain cases.41,42

Renal Angiomyolipoma

The renal AML is the most common benign tumor of the kidney. Most AMLs are found incidentally on imaging studies performed to investigate hematuria and contain variable amounts of blood vessels, adipose tissue, smooth muscle, and rarely calcification. The presence of macroscopic fat on imaging suggests the diagnosis.43 Usually asymptomatic, AMLs can be associated with life-threatening hemorrhage and therefore may require surgical resection. Since RCC frequently contains calcification and may infrequently contain a small amount of adipose tissue as well, the presence of calcium and fat suggests the diagnosis of RCC rather than AML. There is controversial and limited data on the role of FDG PET/CT in the diagnosis of AML, since AML lesions demonstrate variable FDG uptake.27

Renal Oncocytoma

The renal oncocytoma is typically an asymptomatic solid benign renal tumor that presents as an incidental finding at the time of imaging. On CT, oncocytomas are often isodense or hypodense compared to normal renal parenchyma with homogeneous enhancement. On FDG PET/CT oncocytomas often have low-level activity comparable to adjacent normal renal parenchyma; however, intense FDG uptake has also been reported.27,44,45 Renal oncocytomas are indistinguishable from RCC on imaging. Also, although oncocytomas are considered benign lesions, there are reported cases of local recurrence and metastases following resection.44 It has been postulated that oncocytomas could reflect a form of malignant chromophobe cell tumor, such as RCC. Tissue sampling is needed for a definitive diagnosis.

Renal Lymphoma

Primary renal lymphoma is rare and commonly associated with disseminated non-Hodgkin lymphoma. Typical radiologic patterns of disease are seen in renal lymphoma, including multiple renal masses, perirenal disease, renal invasion from contiguous retroperitoneal disease, and diffuse renal infiltration. On CECT, renal disease is typically of low attenuation compared with normal renal parenchyma. Large retroperitoneal masses can invade and displace the renal hilum. FDG PET/CT can detect metabolically active renal lymphoma although careful attention must be paid in order to distinguish FDG-avid renal lymphoma from physiologic activity in the collecting system.4648Primary renal leukemia is rare and there is little published data on the imaging features of leukemic involvement of renal parenchyma.48,49

Renal Metastases

Renal metastases are rare and are often clinically occult. These can present with a solitary renal mass or with multicentric disease involving one or both kidneys. Typically intensely FDG-avid on FDG PET/CT, the most common primary malignancies associated with renal metastases are lung, breast, and colon.48,50

ROLE OF PET/CT IN POSTOPERATIVE SURVEILLANCE OF ADVANCED RENAL CELL CARCINOMA

According to the ESMO Recommendations and the NCCN Guidelines,13,25 imaging examinations following surgery for advanced RCC should be symptom driven and dependent on the specific clinical situation. Accordingly, there are no definite recommendations on the use of FDG PET/CT in the surveillance of patients with RCC. Recent results in the literature suggest that imaging surveillance can detect early disease recurrence so that optimal salvage therapy can be administered. This is particularly important in RCC, where surgical resection might be the patient’s best option for cure. It is thought that RCC recurs locally in approximately 5% of patients after radical nephrectomy and that if diagnosed early, these recurrences are treatable.51 FDG PET/CT and CECT may be complementary in the diagnosis of recurrent disease, either locally or distant. In a study by Park et al.,37 63 RCC patients were evaluated after surgical treatment for an average of 24.3 months of follow-up; 51% of these patients developed a local recurrence or distant metastases. Among 12 patients with local recurrence, 5 had isolated local recurrence and 7 had distant metastases as well. All were diagnosed by abdominal CT; FDG PET/CT was falsely negative in one. However, FDG PET/CT correctly diagnosed a false-positive CT for local relapse in one patient and identified all bony metastases, whereas skeletal scintigraphy had two false negatives. Conventional imaging methods had higher sensitivity and lower specificity compared to FDG PET/CT (94.7% versus 89.5% and 80% versus 83.3%, respectively), but the overall accuracy of both methods was the same (85.7%).

Generally, there is a wide disparity reported in the overall accuracy of FDG PET/CT for RCC. Reports of sensitivity range from 31%35 to 95%.20 Data from published reports are summarized in Table 13.3.

In a study by Safaei et al.,52 36 patients with advanced RCC referred for restaging had FDG PET and the sensitivity and specificity of lesions detected with FDG PET later biopsied were 88% and 75%, respectively. In a series of 53 patients who had FDG PET, 35 patients for characterization and staging of a suspicious renal mass and 18 patients for restaging after surgery, PET produced a high rate of false-negative results (sensitivity, specificity, and accuracy were 47%, 80%, and 51%, respectively). However, PET detected all sites of metastatic disease identified by CT and an additional 8 sites, leading to an accuracy for metastatic disease of 94% versus 89% for CT.53 In a series of 66 patients who had FDG PET for suspected or known RCC, FDG PET had a sensitivity of 60% (compared to 91.7% for CT) and was less sensitive in detecting primary tumors, retroperitoneal lymph node metastases, and distant metastases.54 The discrepancy in the reported FDG PET sensitivity may be partly caused by the increasing knowledge gained over the years resulting in better image interpretation and significant improvement in equipment.

The strength of whole-body PET/CT in postoperative surveillance for RCC is the ability to image the entire body for sites of metastatic disease (Fig. 13.4). This is important since a solitary metastasis, if treated aggressively, might result in alleviation of symptoms and prolonged survival. Ramdave et al.56 reported that in eight patients referred for evaluation of local recurrence and/or metastatic disease, FDG PET changed management in four patients (50%), namely the disease was up-staged in three and recurrence was excluded in one. In addition, in six patients (35%) who would have had a radical nephrectomy after initial conventional imaging, FDG PET altered the proposed treatment; in three cases, surgery was avoided because of the interpretation of benign pathology or detection of unsuspected metastatic disease. Another issue, also affecting treatment decisions in RCC patients, is the detection of incidental second primary cancers. Overall, 5% to 10% of patients on whom FDG PET/CT is performed are found to have a second primary tumor. FDG is a highly sensitive method in this regard with a reported sensitivity of over 90% and positive predictive value (PPV) of 69%.57

TABLE 13.3

FDG—PUBLISHED STUDIES ON POSITRON EMISSION TOMOGRAPHY IN RENAL CELL CARCINOMAS

FIGURE 13.4. A 56-year-old male post left nephrectomy for renal cell carcinoma. A: PET/CT performed 1 month after the nephrectomy shows an intensely FDG-avid retroperitoneal lymph node (size 1 cm, SUVmax 6.2). B:Because of postoperative complications (thrombosis), systemic therapy was postponed and a repeat PET/CT performed 4 months later shows multiple intensely FDG-avid and enlarged lymph nodes (SUVmax 9.3). A single site of focal FDG uptake in the left supraclavicular region corresponds to a small lymph node on CT (SUVmax 3.8). C: Follow-up PET/CT performed 9 months after sunitinib and sorafenib therapy shows FDG-avid metastatic disease involving lymph nodes above and below the diaphragm, the lungs, and liver consistent with disease progression.

PET/CT ASSESSMENT OF TREATMENT RESPONSE

For decades, treatment options for patients with metastatic RCC have been limited. Increasing knowledge of the underlying biology of RCC, however, has identified pathways for targeted therapy, implying an increasing need for surrogate markers to assess early tumor response.58 There are several criteria that can be used to categorize disease response such as Response Evaluation Criteria in Solid Tumors (RECIST),59 RECIST 1.1, the Choi criteria, the modified Choi criteria, and the Size and Attenuation CT (SACT) criteria. However, these criteria are anatomically based and several new drugs (sunitinib, sorafenib, temsirolimus, etc.) result in disease stabilization, rather than substantial tumor regression. Therefore, treatment with those drugs is associated with a low response rate, according to the anatomic-based criteria, but with improvement of overall survival (OS).58 Therefore, in early evaluation of patients, anatomic-based criteria such as RECIST does not discriminate patients with stable disease (SD) from patients who have progressive disease (PD) or partial response (PR). In addition, treatment-induced changes in tumor density, which may be the result of response to therapy could be incorrectly interpreted as disease progression.60,61 These limitations have led to the introduction of new criteria based on functional imaging such as dynamic contrast-enhanced MRI (DCE-MRI), dynamic contrast-enhanced USG (DCE-USG), FDG PET/CT. Data analyses of DCE-MRI and DCE-USG are promising but complex. These imaging modalities are dependent on acquisition protocols and the individual interpretation of results; consensus has not yet been reached. Also, DCE imaging has risks associated with contrast media, which can jeopardize patients with renal insufficiency.58

The role of FDG PET/CT in evaluating response to targeted therapy in RCC is expanding. Several prospective studies have suggested FDG PET/CT could serve as a biomarker of response to sunitinib or sorafenib.29,30,33,34,55,62 A significant decrease of FDG uptake has been seen in treated patients after only one treatment cycle with sorafenib or sunitinib. The most interesting finding is that patients with decreases in SUV can, simultaneously, have an increase in tumor size. Since patients with decreases in tumor SUV have had a long progression-free survival (PFS), the change in tumor size is explained as probably caused by necrosis.63 In a study by Ueno et al.,34 the effect of sunitinib or sorafenib therapy on long-term outcome was assessed with FDG PET. Patients presenting with a high baseline SUVmax had shorter PFS and OS, where baseline SUVmax ranged from 2.3 to 16.6 (mean 9). Patient whose SUVmax decreases less than 20% after therapy (cut-off for response in this study) had a worse prognosis, where SUVmax after therapy ranged from 3.7 to 5.5 (median 7.1).34 In another study, patients who had a response to therapy, 20% reduction in SUV after 16 weeks, had better OS, whereas SUV reduction observed after only 4 weeks was not prognostically significant.62 Discrepancy between FDG PET and CT in the evaluation of treatment response after two courses of sunitinib was observed in a study by Revheim et al.33 FDG PET showed PD in 3 of 12 patients whereas CT detected progression in only one; PR was observed in 6 patients (no responders on CT), whereas SD was observed in 4 (compared to all 12 on CT). These results suggest that evaluating metabolic tumor response with FDG PET may provide additional important information (Fig. 13.5).

New PET tracers such as F-18-labeled sunitinib and Zr-89-labeled bevacizumab provide a unique opportunity for personalized treatment planning64,65 and might give insight into drug uptake during treatment as well as information on the development of tumor resistance. At the present time, PET is not incorporated in commonly used response evaluation criteria; however, it is accepted as an adjunct study in the evaluation of the progression of disease.59

OTHER PET RADIOTRACERS USED IN RENAL CELL CARCINOMA

Radionuclides used in PET typically have short half-lives and are incorporated to form radiopharmaceuticals that can be divided into two groups: Tracers that follow a particular metabolic pathway or tracers that target a specific receptor. The most widely used radiopharmaceutical is 18F-FDG, a radioactive glucose analog. Other radiotracers, that follow metabolic pathways and are not excreted in the urine, are currently being investigated in RCC patients. Radiotracers that target specific receptors such as 18F-labeled sunitinib and 89Zr-labeled bevacizumab are also being investigated.

Fluorine-18-Fluoromisonidazole PET/CT

An important mechanism of RCC growth involves overexpression of a hypoxia-inducible factor and increased secretion of vascular endothelial growth factor (VEGF) leading to angiogenesis, neoangiogenesis, tumor proliferation, and metastatic spread.66 These newly formed tortuous immature vessels have increased permeability resulting in elevated interstitial pressure, impaired oxygen diffusion, and tumor hypoxia. Tumor hypoxia can be imaged with fluorine-18-fluoromisonidazole (FMISO) PET/CT.29 FMISO diffuses across cell membranes. When the tissue oxygen partial pressure is less than 10 mm Hg and the cells are viable, FMISO is reduced by nitroreductase at which point it is trapped in the cell and accumulates. Intracellular retention of FMISO observed 1 hour after radiotracer administration is thought to be specific for cellular hypoxia. The identification of hypoxia in RCC and its impact on tumor biology and prognosis is an area of ongoing research.6770 A study by Hugonnet et al.29 evaluated initial tumor hypoxia in metastatic RCC, the change in hypoxia following sunitinib treatment, and the possible prognostic value of these parameters. Fifty-three antiangiogenic naïve patients with metastatic RCC were prospectively enrolled; metastatic targets were defined by CT before initiation of therapy and assessed at 1 and 6 months after the initiation of therapy, using RECIST. Pretreatment target uptake of FMISO was compared with uptake at 1 month. The relationship between baseline and follow-up tumor hypoxia, with OS and PFS were assessed. There was an association between baseline tumor and PFS with increased hypoxia suggesting shorter PFS. After 1 month of sunitinib therapy, FMISO uptake significantly decreased in target metastases that were initially hypoxic, but did not significantly decrease in baseline nonhypoxic metastases. OS was not significantly different between hypoxic and nonhypoxic disease at baseline and reduction in tumor hypoxia following therapy did not correlate with either OS or PFS. Interestingly, tumor hypoxia as assessed by FMISO uptake in metastatic RCC was less frequent and less pronounced than initially suspected. Further studies with prolonged follow-up are needed to evaluate the prognostic significance of tumor hypoxia on PFS and OS.29,71

Fluorine-18-3-Deoxy-3-Fluorothymidine PET/CT

Fluorine-18-3-deoxy-3-fluorothymidine (FLT) is a PET tracer used for imaging tumor proliferation.72,73 FLT is a thymidine analog that is trapped in the cytosol after being monophosphorylated. It enters the exogenous DNA pathway via the action of thymidine kinase 1 (TK1), where TK1 is an enzyme synthesized when proliferating cells enter the S-phase in the salvage pathway of DNA synthesis. The accumulation of FLT is tightly linked to TK1 enzyme activity, which is closely associated with cellular proliferation. The Ki-67 protein is required for cell proliferation through the synthesis of ribosome during the cell cycle and its expression phase in the cell cycle parallels that of TK1. Indeed, a direct correlation between FLT uptake and proliferation as assessed by Ki-67 labeling index (Ki-67 LI) has been observed.74 It has already been validated that tumor proliferation assessed by Ki-67 is an important prognostic factor in nonsmall cell lung cancer.75 Further, the intensity of tumor FLT activity (SUV) is significantly correlated with Ki-67.76 In RCC patients, FLT PET/CT has been used to characterize and quantify changes in tumor proliferation during sunitinib exposure and temporary sunitinib withdrawal.30 FLT PET/CT scans were obtained 60 minutes after the injection of FLT: At baseline, during sunitinib exposure and after sunitinib withdrawal. Plasma levels of VEGF and sunitinib were assessed at the same time points. Sixteen patients were evaluated and nearly all had some initial reduction in tumor proliferation as measured by FLT PET/CT after 4 weeks of sunitinib treatment. During the treatment break, patients with a relative increase in FLT uptake suggesting an increase in tumor proliferation (withdrawal flare) also had increased levels of plasma VEGF and comparatively worse outcome than those who did not have or had a more limited withdrawal flare.

FIGURE 13.5. A 66-year-old male post nephrectomy for renal cell carcinoma, surgery for metastatic disease to the right adrenal gland, and 2 years of sinitinib and sorafenib therapy. A: PET/CT shows increased FDG avidity in the right adrenal fossa (SUVmax 5.3). B: PET/CT performed 3 months later shows progressive disease in the right adrenal fossa (SUVmax 6.9) and multiple FDG-avid subcutaneous nodules (cursors) throughout the torso and in both lower extremities (SUVmax 3.6).

11C-Acetate PET/CT

Carbon-11-acetate is a PET radiotracer, which is not eliminated via the urinary tract and therefore may be of interest for evaluation of RCC patients. Although Shreve et al.77 reported that RCC accumulates more 11C-acetate than normal kidney parenchyma, this was not confirmed in a subsequent study by Kotzerke et al.78

Iodine-124 (124I)-cG250 PET/CT

Monoclonal antibody (MAb) G250 binds to carbonic anhydrase IX (CAIX), a transmembrane protein that is overexpressed in primary and metastatic clear cell renal cell carcinoma (ccRCC).31 Of note, G250 is thought to be absent in normal kidney parenchyma. A chimeric form of G250 (cG250) labeled with iodine-124 (124I) has recently been used for imaging RCC. Human clinical trials using 124I-cG250 have shown high sensitivity, specificity, positive predictive values, and negative predictive values in the detection of primary RCC and in metastatic disease.7981 In 26 patients with renal masses, Divgi et al. found that 124I-cG250 PET/CT accurately identified 15 of 16 ccRCC patients whereas all nonclear cell renal masses were negative for tracer uptake.81 Sensitivity, specificity, positive predictive values, and negative predictive values were 94%, 100%, 100% and 90%, respectively. In future, 124I-cG250 may prove to be a valuable tool in diagnosing metastases in patients with a G250 positive primary tumor and in the work up of unknown renal masses. Further, the favorable targeting properties of antibodies combined with radionuclides (124I-cG250) may also have therapeutic potential for targeted radionuclide therapy (TRT) of RCC.82

RADIOIMMUNOTHERAPY

Monoclonal antibodies targeting tumor-associated antigens have been developed for RCC and are being increasingly used for the treatment of metastatic RCC in investigational settings. In particular, the cG20 antibody that targets the CAIX antigen has been used for both diagnosis and therapy.7981 In a study by Divgi et al.,83 escalating doses of 131I-G250 were administered to patients with metastatic RCC. Fifty-two percent of patients showed stabilization of disease progression. However, all patients developed a HAMA reaction to the murine antibodies that were used. The excellent targeting and the SD population, however, suggested that repeat therapies of a nonimmunogenic G250 may have promise in metastatic ccRCC therapy. Therefore, chimeric form of G250 (cG250) has also been tested in clinical radioimmunotherapy (RIT) trials.84,85 RIT with cG250 was well tolerated and generally safe. Kinetics of a therapeutic administration of RIT could be predicted by a scout infusion. External imaging permitted assessment of tumor dosimetry, whereas serial measurements of blood radioactivity permitted quantification of whole body and marrow radiation absorbed dose. The maximum tolerated dose (MTD) of 131I-cG250 is thought to be 2220 MBq/m2,86 with hematologic toxicity being the dose-limiting factor. The use of dose fractionation and the effect of two sequential high doses of 131I -cG250 have been investigated. A fractionated schema was much less likely to be immunogenic than a schema where there was a 3-month or greater interval between treatments. It thus appeared that a shorter interval between administrations of xenogenetic protein was more likely to result in tolerance, whereas longer intervals resulted in an immune response. Although patients achieved stabilization of their disease lasting up to 12 months, there was no decrease in the burden of disease. 131I has a relatively “soft” β-minus emission, limiting radiation dose to contiguous normal tissue. Its gamma emissions, although relatively high energy, nonetheless permit external imaging and quantification. Attachment of radioiodine to protein is easily accomplished by established direct iodination methods. Iodinated antibodies, however, suffer from disadvantages, particularly when the antibody undergoes cellular internalization into lysosomes. This usually results in prompt dehalogenation of the radioiodinated antibody with rapid clearance of the (now unbound) radioactivity.

Studies have demonstrated that in internalizing systems, radiometal-labeled antibodies accumulate to a greater extent in tumor than do radioiodinated antibodies. Other radionuclides that can be combined with cG250 in order to optimize cG250 RIT include 177Lu and 90Y.87 Medium-energy β-emitters 131I and 177Lu are thought to be more effective for the treatment of small tumors, whereas in larger tumors 90Y may be a better option. The results of an in vivo study has suggested that, compared to the other conjugates, 177Lu- and 90Y-cG250 in combination may be the best option for RIT. Preliminary results have shown excellent tumor targeting of RCC lesions and stabilization of previously progressive metastatic RCC disease with 177Lu-cG250 therapy.88 It is becoming clear that solid tumor RIT will be most useful in small volume disease, with an inverse correlation between tumor mass and absorbed dose being observed. RIT will therefore be most promising as part of a multimodality therapeutic strategy.

CONCLUSIONS

As the quality of diagnostic imaging has improved, the presentation of RCC has changed from that of a large palpable symptomatic mass to that of an “incidentaloma.” Since small renal masses are often benign, urologists are faced with a new dilemma: Perform a nephrectomy on a potentially benign mass, or watch a potentially aggressive tumor progress. As such, the need for an accurate noninvasive method of characterizing renal lesions has become increasingly important. Also, since surgery is often the only treatment that is curative for RCC patients, accurate staging is very important. Although sensitive diagnostic imaging is necessary to avoid futile surgical intervention, a highly sensitive imaging modality could limit treatment options because of false-positive findings. FDG PET/CT is complementary to anatomic imaging for the characterization of indeterminate incidental renal lesions and for staging and follow-up in patients with RCC. However, accurate interpretation of FDG PET/CT findings depends on a detailed knowledge of the benign diseases that involve the kidney, RCC pathophysiology, and the effects of therapeutic intervention. Although prospective PET/CT studies in RCC patients have been the focus of scientific research for several years, many clinical questions remain unanswered, for example, why do patients eventually progress on antiangiogenic therapy or become resistant to therapy? Perhaps the use of different PET radiotracers to evaluate cell proliferation and tumor hypoxia, thought to be implicated with the development of resistance to chemotherapy and radiation, can help answer these questions. Further, it is likely that metabolic response criteria coupled with anatomic response criteria will be more helpful in the evaluation of therapy response than anatomic criteria alone. Developments of response criteria that include PET/CT findings are underway.

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