Antonija Balenovic • Jasna Mihailovic • Katherine Zukotynski
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
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.13,18–20 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,22–24 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.29–31
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
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.
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 ).
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
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
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.
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.46–48Primary renal leukemia is rare and there is little published data on the imaging features of leukemic involvement of renal parenchyma.48,49
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
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.
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.67–70 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 (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).
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.79–81 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
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.79–81 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.
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.
1. Siegel R, Naishadham D, Jemal A. Cancer Statistics, 2012. CA Cancer J Clin. 2012;62:10–29.
2. Chow WH, Devesa SS, Warren JL, et al. Rising incidence of renal cell carcinoma in the United States. JAMA. 1999;281:1628–1631.
3. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin. 2007; 57:43–66.
4. Michalski JM. Kidney, renal pelvis, and ureter. In: Perez CA, Brady LW, eds. Principles and Practice of Radiation Oncology. 3rd ed. Philadelphia, PA: Lippincott-Raven Publishers; 1997:1525–1541.
5. Marshall FF, Powell KC. Lymphadenectomy for renal cell carcinoma: Anatomical and therapeutic considerations. J Urol. 1982;128:677–681.
6. Blom JH, van Poppel H, Maréchal JM, et al. Radical nephrectomy with and without lymph-node dissection: Final results of European Organization for Research and Treatment of Cancer (EORTC) randomized phase 3 trial 30881. Eur Urol. 2009;55:28–34.
7. Gupta K, Miller JD, Li JZ, et al. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): A literature review. Cancer Treat Rev. 2008;34:193–205.
8. Nanus DM, Garino A, Milowsky MI, et al. Active chemotherapy for sarcomatoid and rapidly progressing renal cell carcinoma. Cancer. 2004;101:1545–1551.
9. Naito S, Yamamoto N, Takayama T, et al. Prognosis of Japanese metastatic renal cell carcinoma patients in the cytokine era: A cooperative group report of 1463 patients. Eur Urol. 2009;57:317–325.
10. Shinagare AB, Krajewski KM, Jagannathan JP, et al. Genitourinary imaging: Part 2, role of imaging in medical management of advanced renal cell carcinoma. AJR Am J Roentgenol. 2012;199:W554–W564.
11. Blute ML, Leibovich BC, Cheville JC, et al. A protocol for performing extended lymph node dissection using primary tumor pathological features for patients treated with radical nephrectomy for clear cell renal cell carcinoma. J Urol. 2004; 172:465–469.
12. Kjaer M, Frederiksen PL, Engelholm SA. Postoperative radiotherapy in stage II and III renal adenocarcinoma. A randomized trial by the Copenhagen Renal Cancer Study Group. Int J Radiat Oncol Biol Phys. 1987;13:665–672.
13. National Comprehensive Cancer Network: NCCN Clinical Practice Guideline in Oncology: Kidney Cancer V.2. 2012. February 16, 2012. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed August 21, 2012.
14. McDermott DF, Regan MM, Clark JI, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005;23:133–141.
15. Negrier S, Perol D, Ravaud A, et al. For the French Immunotherapy Intergroup. Medroxyprogesterone, interferon alfa-2a, interleukin 2, or combination of both cytokines in patients with metastatic renal carcinoma of intermediate prognosis: Results of randomized controlled trial. Cancer. 2007;110:2468–2477.
16. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal cell carcinoma. N Engl J Med. 2007;356:115–124.
17. Escudier B, Eisen T, Stadler WM, et al. TARGET Study Group. Sorafenib in advanced clear cell renal cell carcinoma. N Engl J Med. 2007;356:125–134.
18. Motzer RJ. New perspectives on the treatment of metastatic renal cell carcinoma: An introduction and historical overview. Oncologist. 2011;16:1–3.
19. Smith AD, Shah SN, Rini BI, et al. Morphology, attenuation, size, and structure (MASS) criteria: Assessing response and predicting clinical outcome in metastatic renall cell carcinoma on antiangiogenic targeted therapy. Am J Roentgenol. 2010;194:1470–1478.
20. Namura K, Minamimoto R, Yao M, et al. Impact of maximum standardized uptake value (SUVmax) evaluated by 18-Fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG-PET/CT) on survival for patients with advanced renal cell carcinoma: A preliminary report. BMC Cancer. 2010;10:667.
21. Nikken JJ, Krestin GP. MRI of the kidney – state of the art. Eur Radiol. 2007;17: 2780–2793.
22. Powles T, Murray I, Brock C, et al. Molecular positron emission tomography and PET/CT imaging in urological malignancies. Eur Urol. 2007;51:1511– 1520.
23. Bouchelouche K, Oehr P. Recent developments in urologic oncology: Positron emission tomography molecular imaging. Curr Opin Oncol. 2008;20:321– 326.
24. Avril N, Dambha F, Murray I, et al. The clinical advances of fluorine-2-D-deoxyglucose - positron emission tomography/computed tomography in urological cancers. Int J Urol. 2010;17:501–511.
25. Escudier B, Kataja V. ESMO Guidelines Working Group. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21:v137–v139.
26. Majhail NS, Urbain JL, Albani JM, et al. F-18 fluorodeoxyglucose positron emission tomography in the evaluation of distant metastases from renal cell carcinoma. J Clin Oncol. 2003;21:3995–4000.
27. Kochhar R, Brown RK, Wong CO, et al. Role of PET/CT in imaging of renal lesions. J Med Imaging Radiat Oncol. 2010;54:347–357.
28. Rioja J, Rodriguez-Fraile M, Lima-Favaretto R, et al. Role of positron emission tomography in urological oncology. BJU Int. 2010;106:1578–1593.
29. Hugonnet F, Fournier L, Medioni J, et al. Metastatic renal cell carcinoma: Relationship between initial metastasis hypoxia, change after 1 month’s sunitinib, and therapeutic response: An 18F-fluoromisonidazole PET/CT study. J Nucl Med. 2011;52:1048–1055.
30. Liu G, Jeraj R, Vanderhoek M, et al. Pharmacodynamic study using FLT PET/CT in patients with renal cell cancer and other solid malignancies treated with sunitinib malate. Clin Cancer Res. 2011;17:7634–7644.
31. Bahnson EE, Murrey DA, Mojzisik CM, et al. PET/CT imaging of clear cell renal cell carcinoma with 124I labeled chimeric antibody. Ther Adv Urol. 2009;1: 67–70.
32. Podoloff DA, Ball DW, Ben-Josef E, et al. NCCN Task Force: Clinical utility of PET in variety of tumor types. J Natl Compr Canc Netw. 2009;7:S1–S26.
33. Revheim ME, Winge-Main AK, Hagen G, et al. Combined positron emission tomography/computed tomography in sunitinib therapy assessment of patients with metastatic renal cell carcinoma. Clin Oncol. 2011;23:339–343.
34. Ueno D, Yao M, Tateishi U, et al. Early assessment by FDG-PET/CT of patients with advanced renal cell carcinoma treated with tyrosine kinase inhibitors is predictive of disease course. BMC Cancer. 2012;12:162.
35. Miyakita H, Tokunaga M, Onda H, et al. Significance of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) for detection of renal cell carcinoma and immunohistochemical glucose transporter 1 (GLUT-1) expression in the cancer. Int J Urol. 2002;9:15–18.
36. Lidgren A, Bergh A, Grankvist K, et al. Glucose transporter-1 expression in renal cell carcinoma and its correlation with hypoxia inducible factor-1 alpha. BJU Int. 2008;101:480–484.
37. Park JW, Jo MK, Lee HM. Significance of 18F-fluorodeoxyglucose positron-emission tomography/computed tomography for the postoperative surveillance of advanced renal cell carcinoma, BJU Int. 2009;103:615–619.
38. Terada N, Arai Y, Kinukawa N, et al. Risk factors for renal cysts. BJU Int. 2004; 93:1300-1302.
39. Goldberg MA, Mayo-Smith WW, Papanicolaou N, et al. FDG PET characterization of renal masses: Preliminary experience. Clin Radiol. 1997;52:510–515.
40. Shannon BA, Cohen RJ, de Bruto H, et al. The value of preoperative needle core biopsy for diagnosing benign lesions among small, incidentally detected renal masses. J Urol. 2008;180:1257–1261.
41. Krajewski KM, Giardino AA, Zukotynski K, et al. Imaging in renal cell carcinoma. Hematol Oncol Clin North Am. 2011;25:687–715.
42. Zukotynski K, Lewis A, O’Regan K, et al. PET/CT and renal pathology: A blind spot for radiologists? Part 1, primary pathology. AJR Am J Roentgenol. 2012;199: W163–W167.
43. Israel GM, Bosniak MA. How I do it: Evaluating renal masses. Radiology. 2005; 236:441–450.
44. Choyke PL, Glenn GM, Walther MM, et al. Hereditary renal cancers. Radiology. 2003;226:33–46.
45. Blake MA, McKernan M, Setty B, et al. Renal oncocytoma displaying intense activity n 18F-FDG PET. AJR Am J Roentgenol. 2006;186:269–270.
46. Ye XH, Chen LH, Wu HB, et al. 18F-FDG PET/CT evaluation of lymphoma with renal involvement: Comparison with renal carcinoma. South Med J. 2010;103:642–649.
47. Balenović A, Ostojić Kolonić S, Mihailović J. Positron emission tomography in lymphoma – fine tuning of International Harmonization Project. Arch Oncol. 2012;20:17–23.
48. Zukotynski K, Lewis A, O’Regan K, et al. PET/CT and renal pathology: A blind spot for radiologists? Part 2–lymphoma, leukemia, and metastatic disease. AJR Am J Roentgenol. 2012;199:W168–W174.
49. Hilmes MA, Dillman JR, Mody RJ, et al. Pediatric renal leukemia: Spectrum of CT imaging findings. Pediatr Radiol. 2008;38:424–430.
50. Kaneta T, Hakamatsuka T, Yamada T, et al. FDG PET in solitary metastatic/secondary tumor of the kidney: A report of three cases and a review of the relevant literature. Ann Nucl Med. 2006;20:79–82.
51. Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med. 1996; 335:865–875.
52. Safaei A, Figlin R, Hoh CK, et al. The usefulness of F-18 deoxyglucose wholebody positron emission tomography (PET) for re-staging of renal cell cancer. Clin Nephrol. 2002;57:56–62.
53. Aide N, Cappele O, Bottet P, et al. Efficiency of [(18)F]FDG PET in characterising renal cancer and detecting distant metastases: A comparison with CT. Eur J Nucl Med Mol Imaging. 2003;30:1236–1245.
54. Kang DE, White RL Jr, Zuger JH, et al. Clinical use of fluorodeoxyglucose F 18 positron emission tomography for detection of renal cell carcinoma. J Urol. 2004; 171:1806–1809.
55. Kayani I, Avril N, Bomanji J, et al. Sequential FDG-PET/CT as a biomarker of response to Sunitinib in metastatic clear cell renal cancer. Clin Cancer Res. 2011;17:6021–28.
56. Ramdave S, Thomas GW, Berlangieri SU, et al. Clinical role of F-18 fluorodeoxyglucose positron emission tomography for detection and management of renal cell carcinoma. J Urol. 2001;166:825–830.
57. Choi JY, Lee KS, Kwon OJ, et al. Improved detection of second primary cancer using integrated [18F] fluorodeoxyglucose positron emission tomography for initial tumor staging. J Clin Oncol. 2005;23:7654–7659.
58. van der Veldt AA, Meijerink MR, van den Eertwegh AJ, et al. Targeted therapies in renal cell cancer: Recent developments in imaging. Targ Oncol. 2010;5:95–112.
59. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45:228–247.
60. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–134.
61. Hudes G, Carducci M, Tomczak P, et al. The Global ARCC. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007; 356:2271–2281.
62. Lyrdal D, Boijsen M, Suurkula M, et al. Evaluation of sorafenib treatment in metastatic renal cell carcinoma with 2-fluoro-2-deoxyglucose positron emission tomography and computed tomography. Nucl Med Commun. 2009;30:519–524.
63. Vercellino L, Bousquet G, Baillet G, et al. 18F-FDG PET/CT imaging for an early assessment of response to sunitinib in metastatic renal carcinoma: Preliminary study. Cancer Biother Radiopharm. 2009;24:137–144.
64. Wang JQ, Miller KD, Sledge GW, et al. Synthesis of 18F-SU11248, a new potential PET tracer for imaging cancer tyrosine kinase. Bioorg Med Chem Lett. 2005;15:4380–4384.
65. Nagengast WB, De Korte MA, Oude Munnink TH, et al. 89Zr-bevacizumab PET of early antiangiogenic tumor response to treatment with HSP90 inhibitor NVP-AUY922. J Nucl Med. 2010;51:761–767.
66. Kim W, Kaelin WJ. The von Hippel-Lindau tumor suppressor protein: new insights into oxygen sensing and cancer. Curr Opin Genet Dev. 2003;13:55–60.
67. Nordsmark M, Bentzen SM, Rudat V, et al. prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol. 2005;77:18–24.
68. Rischin D, Hicks R, Fisher R, et al. Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: A substudy of Trans-Tasman Radiation Oncology group Study 98.02. J Clin Oncol. 2006;24:2098–3004.
69. Lawrentschuk N, Poon AM, Foo SS, et al. Assessing regional hypoxia in human renal tumours using 18F-fluoromisonidazole positron emission tomography. BJU Int. 2005;96:540–546.
70. Motzer R, Hutson T, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–124.
71. Motzer R, Hutson T, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:3584–3590.
72. Rasey JS, Grierson JR, Wiens LW, et al. Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells. J Nucl Med. 2002;43: 1210–1217.
73. Barthel H, Cleij MC, Collongridge DR, et al. 3′-deoxy-3′-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Cancer Res. 2003;63:3791–3798.
74. Muzi M, Vesselle H, Grierson JR, et al. Kinetic analysis of 3′-deoxy-3′-fluorothymidine PET studies: Validation studies in patients with lung cancer. J Nucl Med. 2005;46:274–282.
75. Martin B, Paesmans M, Mascaux C, et al. Ki-67 expression and patients survival in lung cancer: Systematic review of the literature with meta-analysis. Br J Cancer. 2004;91:2018–2025.
76. Yang W, Zhang Y, Fu Z. Imaging proliferation of (18)F-FLT PET/CT correlated with the expression of microvessel density of tumour tissue in non-small-cell lung cancer. Eur J Nucl Med Mol Imaging. 2012;39:1289–1296.
77. Shreve P, Chiao PC, Humes HD, et al. Carbon-11-acetate PET imaging in renal disease. J Nucl Med. 1995;36:1595–1601.
78. Kotzerke J, Linne C, Meinhardt M, et al. [1-(11)C]acetate uptake is not increased in renal cell carcinoma. Eur J Nucl Med Mol Imaging. 2007;34:884–888.
79. Brouwers AH, Buijs WC, Oosterwijk E, et al. Targeting of metastatic renal cell carcinoma with the chimeric monoclonal antibody G250 labeled with (131)I or (111)In: An intrapatient comparison. Clin Cancer Res. 2003;9:3953S– 3960S.
80. Brouwers AH, Mulders PF, Oyen WJ. Carbonic anhydrase IX expression in clear cell renal cell carcinoma and normal tissues: Experiences from (radio) immunotherapy. J Clin Oncol. 2008;26:3808–3809.
81. Divgi CR, Pandit-Taskar N, Jungbluth AA, et al. Preoperative characterisation of clear-cell renal carcinoma using iodine-124-labelled antibody chimeric G250 (124I-cG250) and PET in patients with renal masses: A phase I trial. Lancet Oncol. 2007;8:304–310.
82. Bouchelouche K, Capala J. “Image and treat”: An individualized approach to urological tumors. Curr Opin Oncol. 2010;22:274–280.
83. Divgi CR, Bander NH, Scott AM, et al. Phase I/II radioimmunotherapy trial with iodine-131-labeled monoclonal antibody G250 in metastatic renal carcinoma. Clin Cancer Res. 1998;4:2729–2739.
84. Steffens MG, Boerman OC, Oosterwijk-Wakka JC, et al. Targeting of renal cell carcinoma with iodine 131-labeled chimeric monoclonal antibody G250. J Clin-Oncol. 1997;15:1529–1537.
85. Divgi CR, O’Donoghue JA, Welt S, et al. Phase I clinical trial with fractionated radioimmunotherapy using 131I-labeled chimeric G250 in metastatic renal cancer. J Nucl Med. 2004;45:1412–1421.
86. Steffens MG, Boerman OC, de Mulder PH, et al. Phase I radioimmunotherapy of metastatic renal cell carcinoma with iodine 131-labeled chimeric monoclonal antibody G250. Clin Cancer Res. 1999;5:3268s–3274s.
87. Brouwers AH, van Eerd JE, Frielink C, et al. Optimization of radioimmunotherapy of renal cell carcinoma: Labeling of monoclonal antibody cG250 with 131I, 90Y, 177Lu, or 186Re. J Nucl Med. 2004;45:327–337.
88. Stillebroer AB, Oosterwijk E, Mulders PF, et al. Radioimmunotherapy with lutetium-177 labeled monoclonal antibody cG250 in patients with advanced renal cell carcinoma. Cancer Biother Radiopharm. 2008;23:523–524.