AJR Not a Member? Click to Join ARRS!
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow CME
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Griffin, N.
Right arrow Articles by Sohaib, S. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Griffin, N.
Right arrow Articles by Sohaib, S. A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?
DOI:10.2214/AJR.07.2077
AJR 2007; 189:360-370
© American Roentgen Ray Society

Review

Imaging in Metastatic Renal Cell Carcinoma

Nyree Griffin1, Martin E. Gore2 and S. Aslam Sohaib1

1 Department of Diagnostic Imaging, Royal Marsden Hospital, 203 Fulham Rd., London SW3 6JJ, United Kingdom.
2 Department of Medical Oncology, Royal Marsden Hospital, London, United Kingdom.

Received December 30, 2006; accepted after revision March 26, 2007.

 
Address correspondence to S. A. Sohaib (aslam.sohaib{at}rmh.nhs.uk).

M. E. Gore participates in clinical trials and is on the advisory boards of Pfizer and Bayer, which make tyrosine kinase inhibitors for the treatment of metastatic renal cancer.

CME

This article is available for CME credit. See www.arrs.org for more information.

FOR YOUR INFORMATION

This article is available for CME credit. See www.arrs.org for more information.


Abstract
Top
 Abstract
Introduction
 Behavior of Renal Cancer...
 Distribution and Appearance of...
 Assessing Response to Therapy
 Summary
 References
 
OBJECTIVE. Metastatic disease occurs in a significant percentage of patients with renal cell carcinoma. Recent advances in systemic therapies for metastatic renal cell carcinoma are likely to have a significant effect on the way patients with advanced disease are imaged. These new therapies have shown a significant increase in progression-free survival.

CONCLUSION. Imaging is likely to play an increasing role in the management, diagnosis, and monitoring of response to treatment of metastatic renal cell carcinoma.

Keywords: CT • kidney • renal cell carcinoma


Introduction
Top
 Abstract
 Introduction
Behavior of Renal Cancer...
 Distribution and Appearance of...
 Assessing Response to Therapy
 Summary
 References
 
Recent advances in systemic therapies for metastatic renal cell carcinoma (RCC) are likely to have a significant effect on the way patients with advanced disease are imaged. Previously, the mainstay of therapy was immunotherapy with interferon or interleukin-2 with response rates of 10-20%, but this treatment was only appropriate for the 20% of patients with good prognostic features [1]. New agents such as the tyrosine kinase inhibitors have shown partial response rates of 4-40% but with more than 75% of patients obtaining minor responses or stabilization of disease [2]. Furthermore, randomized trials have consistently shown improvements in progression-free survival that are statistically significant [3, 4]. Treatment with these agents has already become the standard of care for many patients.

Randomized trials have also shown a survival advantage for cytoreductive nephrectomy before immunotherapy in metastatic RCC [5]. In addition, surgical excision of a solitary metastasis may confer a survival benefit [6], especially for lung and bone metastases [7].

Imaging is thus likely to play a greater role in the selection of patients with metastatic RCC for treatment and in monitoring response to treatment. In this article we review the role of imaging in metastatic RCC.


Behavior of Renal Cancer Metastases and Prognostic Factors
Top
 Abstract
 Introduction
 Behavior of Renal Cancer...
Distribution and Appearance of...
 Assessing Response to Therapy
 Summary
 References
 
At presentation, 25-30% of patients with RCC have metastases, giving an annual incidence in the United States of approximately 11,500 cases [8]. Locally advanced disease is present in approximately 20% of patients presenting with RCC [9]. After nephrectomy for earlier stages of RCC, up to 50% of patients develop recurrent or metastatic disease [10]. Eighty-five percent of these recurrences occur within 3 years after initial resection but have been reported up to several decades later [11]. The median time to diagnosis of recurrence ranges from 15 to 32 months for pT2 and pT3 tumors [11]. Spontaneous regression is rare (< 1%) and most frequently occurs in the lungs [12]. However, few such cases have been biopsy-proven, and studies have failed to show an improved survival in these patients [13].

One important risk factor for distant metastases after nephrectomy is the stage of the primary tumor [11]. Risk of relapse is stage-dependent, with a higher rate of relapse and shorter time to relapse in patients with pT3 and pT4 renal tumors compared with lower stages [11, 14-16] (Table 1). Staging is thus the single most important factor in determining prognosis. The presence of metastases has been shown to give a median survival of 6-9 months if untreated, with a 2-year survival rate of only 10-20% [17]. Metachronous metastases have a better prognosis than synchronous metastases [18]. Tumor recurrence occurring after a longer disease-free interval is associated with a better prognosis [15].


View this table:
[in this window]
[in a new window]

  		TABLE 1 : Studies Showing Percentage of Patients Developing Recurrent Disease and Time to Relapse According to Pathologic Stage After Surgery for Localized Renal Cell Carcinoma

 

Tumor nuclear grading of RCC (as developed by Fuhrman et al. [19]) is also a predictor of survival in clear cell RCC [19]. Higher tumor grades are more likely to develop metastases; one study showed 5-year survival rates of 89%, 65%, and 46% for grades 1, 2, and 3-4, respectively, independent of T stage [20].

The site of metastases and overall disease volume also influence prognosis [21]. For example, patients with lung-only metastases have a better survival rate than patients with other sites of metastases [22]. In particular, liver metastases are associated with a poor prognosis, whereas bone metastases appear to have an intermediate prognosis [22]. Regional lymph node involvement is associated with a higher incidence of metastatic disease and poorer response rates to immunotherapy [23].

Histologic subtype of the primary RCC also predicts the development of metastatic disease and thus prognosis. The Heidelberg classification [24] identifies five distinct malignant histologic subtypes: conventional (clear cell) (75%), papillary (15%), chromophobe (5%), collecting duct (2%), and RCC unclassified. Clear cell RCCs have a variable clinical course. Sarcomatoid renal cell variants, which can occur with any of the subtypes, are highly aggressive and less responsive to conventional therapies. One study [25] showed that twice as many patients with the clear cell histology developed metastases as with the papillary and chromophobe cell types of RCC after a median follow-up of more than 33 months, giving an improved disease-free survival for papillary and chromophobe subtypes of RCC. This finding has been supported by other large studies [26]. However, the same study [25] found that for tumors of similar stage and size, only chromophobe RCC had a significantly improved nonprogression rate. The median time from nephrectomy to metastasis (32.4 months) and the time from metastasis to death (33.2 months) were twice as long for chromophobe RCC compared with the other two subtypes, suggesting a more indolent course. The authors [25] showed that lung (62%, 44%, 50%) and retroperitoneal lymph nodes (23%, 22%, 33%) were the commonest sites of recurrence for all three histologic subtypes (clear cell, papillary, and chromophobe subtypes, respectively), with bone metastases occurring in 7-11% in all subtypes. However, other studies have shown a greater propensity for clear cell RCC to metastasize to the lung, for chromophobe RCC to metastasize to the liver, and for papillary RCC to show locoregional invasion [27].

A prognostic model has been developed by Motzer et al. [28] at the Memorial Sloan-Kettering Cancer Center that is now commonly used to stratify patients entering clinical trials. Patients were categorized into favorable, intermediate, or poor prognostic groups based on five risk factors: Karnofsky performance status, elevated lactate dehydrogenase (> 1.5 times the upper limit of normal), low hemoglobin (less than normal), high "corrected" calcium, and absence of prior nephrectomy. Patients with no risk factors (favorable risk) had a median survival of 20 months; with one to two risk factors (intermediate risk), 10 months; and with three or more risk factors (poor risk), 4 months.

Isolated local recurrence in the renal bed after nephrectomy is uncommon (2-3%), and some studies have shown a better prognosis if local recurrence is treated aggressively with surgery [29]. Again, as with distant metastases, local recurrence is more likely if the original tumor is large, higher grade, and higher tumor stage [30]. The incidence of local recurrence is slightly higher in patients who have had a partial nephrectomy than in those who have had a radical nephrectomy [15]. Recurrence is also associated with incomplete resection of the primary tumor, positive surgical margins, and regional lymph node metastases [31].


Distribution and Appearance of Metastases
Top
 Abstract
 Introduction
 Behavior of Renal Cancer...
 Distribution and Appearance of...
Assessing Response to Therapy
 Summary
 References
 
The following sites may show metastases, in order of decreasing frequency: lung (50-60%) [32]; bone (30-40%) [33]; liver (30-40%) [34]; and adrenal gland, contralateral kidney, retroperitoneum, and brain (5% each) [34]. Studies describing the site and distribution of metastases after original surgery [14, 30, 35-40] are shown in Table 2. Practically any organ may be affected [41].


View this table:
[in this window]
[in a new window]

  		TABLE 2: Site and Distribution of Recurrent Disease in Seven Studies

 

Pulmonary and Mediastinal Metastases
Pulmonary metastases usually appear as well-defined round or ovoid nodules on both chest radiography and CT (Fig. 1). They can be solitary or multiple and typically range in size from 0.5 to 2 cm in diameter (Fig. 2A, 2B, 2C, 2D, 2E, 2F). They are one of the well-known causes of "cannonball" metastases. Pulmonary metastases are usually asymptomatic. Mediastinal lymph node involvement (Fig. 3A, 3B) is also a frequent finding and tends to involve the hilar, subcarinal, and paratracheal regions. Both large parenchymal lung and mediastinal lesions may show central necrosis.


Figure 1
View larger version (134K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 1 —76-year-old man with typical lung metastases from renal cancer on CT.

 

Figure 2
View larger version (80K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 2A —55-year-old woman with metastatic renal cell cancer undergoing treatment with sunitinib (tyrosine kinase inhibitor). Contrast-enhanced CT scans before treatment show rib metastasis (arrow, A), metastasis in intercostal muscle (arrow, B), and multiple small pulmonary metastases (arrows, C).

 

Figure 3
View larger version (82K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 2B —55-year-old woman with metastatic renal cell cancer undergoing treatment with sunitinib (tyrosine kinase inhibitor). Contrast-enhanced CT scans before treatment show rib metastasis (arrow, A), metastasis in intercostal muscle (arrow, B), and multiple small pulmonary metastases (arrows, C).

 

Figure 4
View larger version (113K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 2C —55-year-old woman with metastatic renal cell cancer undergoing treatment with sunitinib (tyrosine kinase inhibitor). Contrast-enhanced CT scans before treatment show rib metastasis (arrow, A), metastasis in intercostal muscle (arrow, B), and multiple small pulmonary metastases (arrows, C).

 

Figure 5
View larger version (77K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 2D —55-year-old woman with metastatic renal cell cancer undergoing treatment with sunitinib (tyrosine kinase inhibitor). After treatment CT scans show bone metastasis has reduced in size (arrow, D), soft-tissue metastases in intercostal space have resolved (E), and pulmonary metastases have resolved (F).

 

Figure 6
View larger version (89K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 2E —55-year-old woman with metastatic renal cell cancer undergoing treatment with sunitinib (tyrosine kinase inhibitor). After treatment CT scans show bone metastasis has reduced in size (arrow, D), soft-tissue metastases in intercostal space have resolved (E), and pulmonary metastases have resolved (F).

 

Figure 7
View larger version (110K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 2F —55-year-old woman with metastatic renal cell cancer undergoing treatment with sunitinib (tyrosine kinase inhibitor). After treatment CT scans show bone metastasis has reduced in size (arrow, D), soft-tissue metastases in intercostal space have resolved (E), and pulmonary metastases have resolved (F).

 

Figure 8
View larger version (92K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 3A —61-year-old woman with metastatic renal cell cancer. Contrast-enhanced CT scans show enlarged pretracheal lymph node (arrow, A) and pancreatic metastases (arrows, B).

 

Figure 9
View larger version (152K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 3B —61-year-old woman with metastatic renal cell cancer. Contrast-enhanced CT scans show enlarged pretracheal lymph node (arrow, A) and pancreatic metastases (arrows, B).

 
Both chest radiography and CT can be used for follow-up [11, 16] in the detection of pulmonary metastases. A study by Lim and Carter [42] showed a significant correlation between chest radiography and CT in the preoperative staging of pulmonary metastases in patients with RCC. Those authors suggested that in patients with a relatively small tumor (T1), a normal chest radiograph would suffice for pulmonary staging in the asymptomatic patient. Additional CT should be reserved for patients with a solitary nodule on chest radiography, respiratory symptoms, or extensive regional disease. However, CT is more likely to detect pulmonary metastases at an earlier stage, which is helpful in identifying the solitary lesion that may be amenable to surgical resection. CT can also show mediastinal and hilar lymph node involvement and bone and subcutaneous lesions more clearly than chest radiography.

It has been suggested that for solitary pulmonary lesions that are indeterminate on chest radiography and CT, 18F-FDG PET may be a useful adjunct [43]. However, FDG PET is not a sensitive imaging technique in the evaluation of metastatic RCC [43-47] (Table 3). In a series of 24 patients with metastatic RCC [45], 19 patients had pulmonary metastases. Sensitivity for FDG PET was 63% (12/19) and false-negatives were seen in both the lung (in 7/19 sites) and in the mediastinum (in 2/10 sites). Sensitivity was improved for larger lesions, with a mean lesion size of 2 cm associated with true-positive FDG PET compared with 0.8 cm in patients with false-negative FDG PET. A negative result did not exclude the possibility of a metastasis in RCC.


View this table:
[in this window]
[in a new window]

  		TABLE 3: Studies of 18F-FDG PET in Metastatic Renal Cell Carcinoma with Final Diagnosis Confirmed on Histology or Follow-Up

 

Abdominal Metastases
CT is the mainstay of imaging in the detection of intraabdominal metastases. On CT, liver metastases can appear as ill-defined low-attenuation lesions that may show peripheral enhancement or appear as hypervascular masses with or without central necrosis (Fig. 4A, 4B, 4C, 4D). To optimize detection of visceral metastases, the abdomen and pelvis should be scanned first in the arterial phase, followed by imaging of the chest from the lung apices through the liver and remaining kidney. Contrast-enhanced CT is sensitive in detecting metastases in the abdomen (Figs. 4A, 4B, 4C, 4D, 5A, 5B, 6A, 6B, 7A, 7B), showing not only lesions in the liver, renal bed, adrenal gland, and retroperitoneum, but also in more unusual sites such as the pancreas, peritoneum, and bowel [48, 49]. Some authors advocate the routine use of CT [15, 16], whereas others advocate using CT when patients become symptomatic [11].


Figure 10
View larger version (124K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 4A —63-year-old man with metastatic renal cell cancer undergoing treatment with sunitinib (tyrosine kinase inhibitor). Contrast-enhanced CT scans before treatment show large enhancing liver metastasis (arrow, A) and disease in right renal bed (arrow, B).

 

Figure 11
View larger version (142K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 4B —63-year-old man with metastatic renal cell cancer undergoing treatment with sunitinib (tyrosine kinase inhibitor). Contrast-enhanced CT scans before treatment show large enhancing liver metastasis (arrow, A) and disease in right renal bed (arrow, B).

 

Figure 12
View larger version (111K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 4C —63-year-old man with metastatic renal cell cancer undergoing treatment with sunitinib (tyrosine kinase inhibitor). After treatment, CT scans show reduction in density and size of liver metastasis (arrow, C) and decrease in size of mass (arrow, D) in renal bed.

 

Figure 13
View larger version (149K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 4D —63-year-old man with metastatic renal cell cancer undergoing treatment with sunitinib (tyrosine kinase inhibitor). After treatment, CT scans show reduction in density and size of liver metastasis (arrow, C) and decrease in size of mass (arrow, D) in renal bed.

 

Figure 14
View larger version (145K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 5A —60-year-old man with retroperitoneal lymphadenopathy (arrow). Contrast-enhanced CT scan before treatment with sunitinib (tyrosine kinase inhibitor) shows metastasis (arrow).

 

Figure 15
View larger version (152K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 5B —60-year-old man with retroperitoneal lymphadenopathy (arrow). After two cycles of therapy, scan shows decrease in attenuation of lymph node but little change in size of lesion (arrow).

 

Figure 16
View larger version (127K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 6A —59-year-old man with metastatic renal cell cancer. Contrast-enhanced CT scans show metastasis (arrows, A) to spleen, which is enlarged, and metastasis (arrow, B) to umbilicus.

 

Figure 17
View larger version (131K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 6B —59-year-old man with metastatic renal cell cancer. Contrast-enhanced CT scans show metastasis (arrows, A) to spleen, which is enlarged, and metastasis (arrow, B) to umbilicus.

 

Figure 18
View larger version (129K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 7A —18-year-old woman with metastatic renal cell cancer. Contrast-enhanced CT scans show peritoneal metastasis (arrow, A) and bone metastasis (arrow, B) in right ileum.

 

Figure 19
View larger version (122K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 7B —18-year-old woman with metastatic renal cell cancer. Contrast-enhanced CT scans show peritoneal metastasis (arrow, A) and bone metastasis (arrow, B) in right ileum.

 
Pancreatic lesions (Fig. 3A, 3B) may be multifocal and can appear well defined and hypervascular on CT. They may mimic islet cell tumors. Central necrosis may be shown in larger lesions. Peritoneal lesions occur in 1% of cases and can appear as extensive ascites, omental infiltration, or peritoneal implants [49] (Fig. 7A, 7B). Small-bowel metastases are rare and can be one cause of intussusception [50].

Local recurrence at the nephrectomy site can be shown on CT as solid enhancing masses with central necrosis (Fig. 4A, 4B, 4C, 4D). The masses may involve the underlying quadratus lumborum or psoas muscle. The incidence of local recurrence ranges from 1.8% to 27% [51]. Bowel loops and tail of the pancreas prolapsing into the renal bed may be mistaken for recurrence on CT. CT or MRI with oral contrast material may be helpful in distinguishing them. One study assessing local recurrence on FDG PET [52] showed that in the eight patients referred for this condition, PET was able to clearly differentiate tumor recurrence (Fig. 8A, 8B) from fibrosis or necrosis and thus alter subsequent management.


Figure 20
View larger version (137K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 8A —Fluorine-18-FDG PET CT in 61-year-old man with recurrent renal cancer. CT image shows soft-tissue disease in left posterior abdominal wall (arrow).

 

Figure 21
View larger version (102K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 8B —Fluorine-18-FDG PET CT in 61-year-old man with recurrent renal cancer. Fused PET/CT image shows increased activity in left posterior abdominal wall (arrow) corresponding to soft-tissue disease.

 

After nephrectomy, adrenal metastases can develop in up to 10% of patients [40]. Visualization of a normal adrenal gland on CT in patients with RCC has 100% negative predictive value for tumor spread, confirmed on subsequent histology [53].

Retroperitoneal adenopathy can occur in metastatic RCC (Fig. 5A, 5B). Metastatic nodes are more likely to enhance than reactive lymph nodes [54]. On both CT and MRI, the diagnosis of lymph node involvement is based on size criteria. CT and MRI cannot identify metastases in normal-sized lymph nodes, and both are unable to distinguish reactive enlarged nodes from enlargement due to metastases. However, metastatic tumor is invariably present in nodes larger than 2 cm. Microscopic lymph node invasion is uncommon, occurring in fewer than 5% of patients. Overall lymph node staging accuracy on CT and MRI has been reported to be 83-88%. MR lymphography with lymph node-specific contrast media (ultrasmall superparamagnetic iron oxide particles [USPIO]) [55] may improve the diagnostic sensitivity and accuracy in assessing lymph node metastases; however, there have been no studies in patients with renal cancer. PET has also shown accuracy in detecting lymph node metastases in RCC [56]. Kang et al. [44] showed that for retroperitoneal lymph node metastases or renal bed recurrence, FDG PET was 75% sensitive and 100% specific. Other studies have shown a sensitivity of 100% for lymph node metastases compared with a sensitivity of 83-89% for CT [57].

Bone Metastases
Bone metastases classically appear as large expansile lytic lesions on plain radiography, most commonly in the axial skeleton. Contrast-enhanced CT shows bone destruction with or without the presence of an enhancing soft-tissue mass (Figs. 2A, 2B, 2C, 2D, 2E, 2F and 7A, 7B).

Bone metastases show variable uptake on bone scintigraphy. Most bone metastases are symptomatic, so most authors have advocated the selected use of bone scintigraphy when patients develop symptoms with or without a raised level of alkaline phosphatase [11, 15, 16]. Routine imaging in asymptomatic patients with RCC has been shown to give a low yield of skeletal metastatic involvement [58]. Correlation with plain radiography is helpful. Staudenherz et al. [59] showed that the sensitivity of bone scintigraphy in RCC varied from 10% to 60%, even among preselected patients with a high probability of skeletal involvement, and bone scintigraphy underestimated the extent of metastatic involvement in all cases.

MRI can also detect bone metastases [60]. Using T1-weighted and STIR sequences, MRI has been shown to be more sensitive and specific than bone scintigraphy [61]. Whole-body MRI is facilitated on modern systems with rapid imaging sequences, moving table-top techniques, and, in some systems, the use of coil technology. On T1-weighted images, focal or diffuse areas of hypointensity are shown; on STIR images, lesions appear hyperintense. In vertebrae, other features indicative of malignancy are signal intensity changes that extend into the pedicle and extraosseous involvement.

FDG PET may offer improved specificity over bone scintigraphy in the detection of bone metastases. Wu et al. [62] showed that FDG PET had both a sensitivity and accuracy of 100% compared with 77.5% and 59.6%, respectively, for bone scintigraphy. However, false-negative results of up to 30% have been reported both with bone scintigraphy and with FDG PET [46, 63].

Brain Metastases
Brain metastases (Fig. 9) appear as enhancing nodules up to 4 cm in size, with associated vasogenic edema on both CT and MRI. For the detection of cerebral metastases, MRI is the preferred technique because it is more sensitive for the detection of smaller lesions than CT [64]. Identification of a solitary lesion on MRI is important because the lesion may be suitable for surgery. Some authors advocate screening for occult metastases because the seizure threshold is decreased with interleukin-2 (IL-2) therapy [65].


Figure 22
View larger version (114K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 9 —41-year-old woman with brain metastases. Coronal T1-weighted image after IV contrast enhancement with gadolinium shows multiple enhancing lesions (arrows).

 


Assessing Response to Therapy
Top
 Abstract
 Introduction
 Behavior of Renal Cancer...
 Distribution and Appearance of...
 Assessing Response to Therapy
Summary
 References
 
Tumor response in metastatic RCC is usually assessed on CT (Figs. 2A, 2B, 2C, 2D, 2E, 2F, 4A, 4B, 4C, 4D, 5A, 5B, and 10A, 10B). The standard criteria for assessing response are based on change in size. The World Health Organization (WHO) [66] or the RECIST (Response Evaluation Criteria in Solid Tumors) criteria [67] are used for response evaluation. RECIST, introduced in 2000, is based on the change in maximum diameter of the tumor. This replaced the previous WHO criteria from 1981, based on bidimensional tumor measurements. The differences between these two systems are well documented [68, 69]. Studies on metastatic RCC comparing outcomes according to RECIST and WHO criteria have correlated well [70]. The advantage of using a size change as response criteria is that it is simple, easily quantifiable, and an objective end point. It requires little training, is well established, and correlates with outcome for many chemotherapeutic agents.


Figure 23
View larger version (126K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 10A —62-year-old man with thyroid metastases (arrow). Contrast-enhanced CT scan before treatment with sunitinib (tyrosine kinase inhibitor) shows metastasis (arrow).

 

Figure 24
View larger version (124K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Fig. 10B —62-year-old man with thyroid metastases (arrow). Scan after drug therapy shows thyroid metastases are smaller and of lower density (arrow).

 

However, using size change in response criteria has limitations. There are issues of reproducibility in irregular lesions, in lesions that show diffuse infiltration, and in widely disseminated disease. Many of these features are a factor in assessing response in metastatic RCC. In patients with primary renal tumors in situ, a significant discrepancy often exists between the size of the renal mass and the size of its metastases. Because many primary RCC lesions are large relative to their metastatic disease, inclusion of the primary tumor in the sum of measurements may greatly (and disproportionately) affect therapy response assessment. In addition, the primary RCC tumor frequently does not change substantially in size compared with metastatic disease at follow-up. Schwartz et al. [71] have suggested using the average percentage of change in size of all the lesions to allow this.

The size criteria end point for assessing tumor response is based on the assumption that tumor size is proportional to the number of tumor cells. The size criteria method works well for assessing response to cytotoxic agents. However, size criteria may not be applicable to new agents such as the tyrosine kinase inhibitors, which show clinical benefit without tumor regression. These drugs act as cytostatic agents and inhibit growth rather than induce tumor regression. In the drug trial setting, efficacy of these agents can be assessed in terms of progression-free survival or overall survival. In the clinic, assessment of response is necessary to determine whether to continue these drugs.

As a result, considerable interest exists in developing additional response criteria to overcome these limitations. Reports from the functional imaging literature suggest that metabolic and physiologic changes precede size change—for example, FDG PET in lymphoma [72]. As the new agents for the treatment of metastatic RCC inhibit angiogenesis, imaging tumor vascularity may allow assessment of treatment response. Dynamic contrast-enhanced MRI provides information relating to tumor perfusion, capillary permeability, and leakage space. Limited data exist on the use of dynamic contrast-enhanced MRI in RCC with tyrosine kinase inhibitors. A small series showed that tumors that responded clinically to sorafenib had higher dynamic contrast-enhanced MRI indexes of vascularity [73]. Tumor vascularity can also be assessed with contrast-enhanced sonography. Lamuraglia et al. [74] performed a pilot study using dynamic contrast-enhanced Doppler sonography in 30 patients with metastatic RCC who were randomized to either sorafenib or a placebo. They found that patients who showed a good response on sonography (defined as a decrease in contrast media uptake > 10% and stability or decrease in tumor volume) at 3 or 6 weeks into treatment showed significantly better progression-free survival than poor responders.

The limitations of functional imaging include lack of availability and increased complexity. An alternative approach is to modify the existing RECIST criteria. Choi et al. [75] have suggested defining tumor response as a 10% decrease in tumor size or 15% decrease in tumor density on contrast-enhanced CT. This concept was initially introduced because of the limitation of using RECIST in evaluating gastrointestinal stromal tumors. The tyrosine kinase inhibitor imatinib has been shown to prolong survival even when partial response is not reached by RECIST criteria. After treatments with imatinib, these tumors have been noted to show rapid transit from heterogeneous hyperattenuating masses to homogeneous hypoattenuating lesions, reflecting myxoid degeneration, hemorrhage, or necrosis. Paradoxically, tumors may enlarge during treatment because of this, despite a response.

Our experience using the new tyrosine kinase inhibitors in metastatic RCC is that some lesions show a response in terms of size (Figs. 2A, 2B, 2C, 2D, 2E, 2F, 4A, 4B, 4C, 4D, 5A, 5B, and 10A, 10B). Most show stabilization on RECIST criteria, but there is a decrease in the attenuation of the lesions. CT offers the simplest way to assess metastatic RCC.


Summary
Top
 Abstract
 Introduction
 Behavior of Renal Cancer...
 Distribution and Appearance of...
 Assessing Response to Therapy
 Summary
References
 
With the advent of new therapies for metastatic RCC, imaging is likely to play a more important role in assessing the extent of metastatic disease and evaluating response to treatment. CT, bone scintigraphy, and MRI have established roles in staging and assessing the presence of visceral, bone, vertebral, and brain metastases. The use of FDG PET remains to be defined. CT has traditionally been used to assess response to treatment using size change criteria. However, these assessment criteria may have limitations in the assessment of response to antiangiogenesis agents that may show clinical benefit without a reduction in size of metastatic lesions. Modification to the RECIST criteria or their use in combination with other clinical or imaging markers of response may be needed.


References
Top
 Abstract
 Introduction
 Behavior of Renal Cancer...
 Distribution and Appearance of...
 Assessing Response to Therapy
 Summary
 References
 

  1. Coppin C, Porzsolt F, Awa A, Kumpf J, Coldman A, Wilt T. Immunotherapy for advanced renal cell cancer. Available at: http://www.cochrane.org/reviews/en/ab001425.html. Accesssed May 24, 2007
  2. Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA2006; 295:2516 -2524[Abstract/Free Full Text]
  3. Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24 : 2505-2512[Abstract/Free Full Text]
  4. Gore ME, Escudier B. Emerging efficacy endpoints for targeted therapies in advanced renal cell carcinoma. Oncology (Williston Park) 2006; 20[6 suppl 5]: 19-24[Medline]
  5. Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 2001; 358:966 -970[CrossRef][Medline]
  6. Sandhu SS, Symes A, A'Hern R, et al. Surgical excision of isolated renal-bed recurrence after radical nephrectomy for renal cell carcinoma. BJU Int 2005; 95:522 -525[CrossRef][Medline]
  7. Thyavihally YB, Mahantshetty U, Chamarajanagar RS, Raibhattanavar SG, Tongaonkar HB. Management of renal cell carcinoma with solitary metastasis. World J Surg Oncol 2005;3 : 48[CrossRef][Medline]
  8. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin 2006;56 : 106-130[Abstract/Free Full Text]
  9. Sivaramakrishna B, Gupta NP, Wadhwa P, et al. Pattern of metastases in renal cell carcinoma: a single institution study. Indian J Cancer 2005; 42:173 -177[Medline]
  10. Janzen NK, Kim HL, Figlin RA, Belldegrun AS. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am2003; 30:843 -852[CrossRef][Medline]
  11. Sandock DS, Seftel AD, Resnick MI. A new protocol for the followup of renal cell carcinoma based on pathological stage. J Urol 1995; 154:28 -31[CrossRef][Medline]
  12. Snow RM, Schellhammer PF. Spontaneous regression of metastatic renal cell carcinoma. Urology 1982;20 : 177-181[CrossRef][Medline]
  13. Davis SD, Koizumi JH, Pitts WR. Spontaneous regression of pulmonary metastases from renal cell carcinoma. Urology1989; 33:141 -144[CrossRef][Medline]
  14. Masatoshi M, Masatsugu I, Jun-ichiro I, Shiro B. An optimal follow-up protocol for renal cell carcinoma based on the occurrence of recurrences after surgery [in Japanese]. Nippon Hinyokika Gakkai Zasshi 2000; 91:700 -707[Medline]
  15. Hafez KS, Novick AC, Campbell SC. Patterns of tumor recurrence and guidelines for followup after nephron sparing surgery for sporadic renal cell carcinoma. J Urol 1997;157 : 2067-2070[CrossRef][Medline]
  16. Levy DA, Slaton JW, Swanson DA, Dinney CP. Stage-specific guidelines for surveillance after radical nephrectomy for local renal cell carcinoma. J Urol 1998;159 : 1163-1167[CrossRef][Medline]
  17. Flanigan RC, Campbell SC, Clark JI, Picken MM. Metastatic renal cell carcinoma. Curr Treat Options Oncol2003; 4:385 -390[Medline]
  18. O'Dea MJ, Zincke H, Utz DC, Bernatz PE. The treatment of renal cell carcinoma with solitary metastasis. J Urol1978; 120:540 -542[Medline]
  19. Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982; 6:655 -663[Medline]
  20. Tsui KH, Shvarts O, Smith RB, Figlin RA, de-Kernion JB, Belldegrun A. Prognostic indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the revised 1997 TNM staging criteria. J Urol 2000; 163:1090 -1095; quiz 1295[CrossRef][Medline]
  21. Han KR, Pantuck AJ, Bui MH, et al. Number of metastatic sites rather than location dictates overall survival of patients with node-negative metastatic renal cell carcinoma. Urology2003; 61:314 -319[CrossRef][Medline]
  22. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001;345 : 1655-1659[Abstract/Free Full Text]
  23. Pantuck AJ, Zisman A, Dorey F, et al. Renal cell carcinoma with retroperitoneal lymph nodes: impact on survival and benefits of immunotherapy. Cancer 2003; 97:2995 -3002[CrossRef][Medline]
  24. Kovacs G, Akhtar M, Beckwith BJ, et al. The Heidelberg classification of renal cell tumours. J Pathol1997; 183:131 -133[CrossRef][Medline]
  25. Beck SD, Patel MI, Snyder ME, et al. Effect of papillary and chromophobe cell type on disease-free survival after nephrectomy for renal cell carcinoma. Ann Surg Oncol 2004;11 : 71-77[Abstract/Free Full Text]
  26. Amin MB, Tamboli P, Javidan J, et al. Prognostic impact of histologic subtyping of adult renal epithelial neoplasms: an experience of 405 cases. Am J Surg Pathol 2002;26 : 281-291[CrossRef][Medline]
  27. Renshaw AA, Richie JP. Subtypes of renal cell carcinoma: different onset and sites of metastatic disease. Am J Clin Pathol 1999; 111:539 -543[Medline]
  28. Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999;17 : 2530-2540[Abstract/Free Full Text]
  29. Bruno JJ 2nd, Snyder ME, Motzer RJ, Russo P. Renal cell carcinoma local recurrences: impact of surgical treatment and concomitant metastasis on survival. BJU Int 2006;97 : 933-938[CrossRef][Medline]
  30. Saidi JA, Newhouse JH, Sawczuk IS. Radiologic follow-up of patients with T1-3a,b,c or T4N+M0 renal cell carcinoma after radical nephrectomy. Urology 1998; 52:1000 -1003[CrossRef][Medline]
  31. Rabinovitch RA, Zelefsky MJ, Gaynor JJ, Fuks Z. Patterns of failure following surgical resection of renal cell carcinoma: implications for adjuvant local and systemic therapy. J Clin Oncol1994; 12:206 -212[Abstract]
  32. Cozzoli A, Milano S, Cancarini G, Zanotelli T, Cosciani Cunico S. Surgery of lung metastases in renal cell carcinoma. Br J Urol 1995; 75:445 -447[Medline]
  33. Kollender Y, Bickels J, Price WM, et al. Metastatic renal cell carcinoma of bone: indications and technique of surgical intervention. J Urol 2000; 164:1505 -1508[CrossRef][Medline]
  34. Ritchie AW, Chisholm GD. The natural history of renal carcinoma. Semin Oncol 1983;10 : 390-400[Medline]
  35. Kuczyk MA, Bokemeyer C, Kohn G, et al. Prognostic relevance of intracaval neoplastic extension for patients with renal cell cancer. Br J Urol 1997;80 : 18-24[Medline]
  36. Stenzl A, deKernion JB. The natural history of renal cell carcinoma. Semin Urol 1989;7 : 144-148[Medline]
  37. Beisland C, Medby PC, Beisland HO. Presumed radically treated renal cell carcinoma: recurrence of the disease and prognostic factors for subsequent survival. Scand J Urol Nephrol2004; 38:299 -305[CrossRef][Medline]
  38. Eggener SE, Yossepowitch O, Pettus JA, Snyder ME, Motzer RJ, Russo P. Renal cell carcinoma recurrence after nephrectomy for localized disease: predicting survival from time of recurrence. J Clin Oncol 2006; 24:3101 -3106[Abstract/Free Full Text]
  39. Chae EJ, Kim JK, Kim SH, Bae SJ, Cho KS. Renal cell carcinoma: analysis of postoperative recurrence patterns. Radiology 2005;234 : 189-196[Abstract/Free Full Text]
  40. Dinney CP, Awad SA, Gajewski JB, et al. Analysis of imaging modalities, staging systems, and prognostic indicators for renal cell carcinoma. Urology 1992;39 : 122-129[CrossRef][Medline]
  41. Park YW, Hlivko TJ. Parotid gland metastasis from renal cell carcinoma. Laryngoscope 2002;112 : 453-456[CrossRef][Medline]
  42. Lim DJ, Carter MF. Computerized tomography in the preoperative staging for pulmonary metastases in patients with renal cell carcinoma. J Urol 1993; 150:1112 -1114[Medline]
  43. Chang CH, Shiau YC, Shen YY, Kao A, Lin CC, Lee CC. Differentiating solitary pulmonary metastases in patients with renal cell carcinomas by 18F-fluoro-2-deoxyglucose positron emission tomography: a preliminary report. Urol Int 2003;71 : 306-309[CrossRef][Medline]
  44. Kang DE, White RL Jr, Zuger JH, Sasser HC, Teigland CM. Clinical use of fluorodeoxyglucose F-18 positron emission tomography for detection of renal cell carcinoma. J Urol 2004;171 : 1806-1809[CrossRef][Medline]
  45. 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[Abstract/Free Full Text]
  46. Jadvar H, Kherbache HM, Pinski JK, Conti PS. Diagnostic role of [F-18]-FDG positron emission tomography in restaging renal cell carcinoma. Clin Nephrol 2003;60 : 395-400[Medline]
  47. Safaei A, Figlin R, Hoh CK, et al. The usefulness of F-18 deoxyglucose whole-body positron emission tomography (PET) for restaging of renal cell cancer. Clin Nephrol 2002;57 : 56-62[Medline]
  48. Alter AJ, Uehling DT, Zwiebel WJ. Computed tomography of the retroperitoneum following nephrectomy. Radiology1979; 133:663 -668[Abstract]
  49. Tartar VM, Heiken JP, McClennan BL. Renal cell carcinoma presenting with diffuse peritoneal metastases: CT findings. J Comput Assist Tomogr 1991; 15:450 -453[Medline]
  50. Roviello F, Caruso S, Moscovita Falzarano S, et al. Small bowel metastases from renal cell carcinoma: a rare cause of intestinal intussusception. J Nephrol 2006;19 : 234-238[Medline]
  51. Itano NB, Blute ML, Spotts B, Zincke H. Outcome of isolated renal cell carcinoma fossa recurrence after nephrectomy. J Urol 2000; 164:322 -325[CrossRef][Medline]
  52. 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[CrossRef][Medline]
  53. Gill IS, McClennan BL, Kerbl K, Carbone JM, Wick M, Clayman RV. Adrenal involvement from renal cell carcinoma: predictive value of computerized tomography. J Urol 1994;152 : 1082-1085[Medline]
  54. Sheth S, Scatarige JC, Horton KM, Corl FM, Fishman EK. Current concepts in the diagnosis and management of renal cell carcinoma: role of multidetector CT and three-dimensional CT. Radio-Graphics 2001;21 [spec no]:S237 -S254[Abstract/Free Full Text]
  55. Rockall AG, Sohaib SA, Harisinghani MG, et al. Diagnostic performance of nanoparticle-enhanced magnetic resonance imaging in the diagnosis of lymph node metastases in patients with endometrial and cervical cancer. J Clin Oncol 2005;23 : 2813-2821[Abstract/Free Full Text]
  56. Bachor R, Kotzerke J, Gottfried HW, Brandle E, Reske SN, Hautmann R. Positron emission tomography in diagnosis of renal cell carcinoma. Urologe A 1996;35 : 146-150[Medline]
  57. Levine E. Renal cell carcinoma: clinical aspects, imaging diagnosis, and staging. Semin Roentgenol1995; 30:128 -148[CrossRef][Medline]
  58. Henriksson C, Haraldsson G, Aldenborg F, Lindberg S, Pettersson S. Skeletal metastases in 102 patients evaluated before surgery for renal cell carcinoma. Scand J Urol Nephrol 1992;26 : 363-366[Medline]
  59. Staudenherz A, Steiner B, Puig S, Kainberger F, Leitha T. Is there a diagnostic role for bone scanning of patients with a high pretest probability for metastatic renal cell carcinoma? Cancer 1999; 85:153 -155[CrossRef][Medline]
  60. Hughes MJ, Sohaib SA, Eisen T, Gore M. Comparison of whole-body MR imaging and bone scintigraphy in the detection of bone metastases in renal carcinoma. AJR 2005;184 [American Roentgen Ray Society 105th Annual Meeting Abstract Book suppl]: 31[Abstract/Free Full Text]
  61. Eustace S, Tello R, DeCarvalho V, et al. A comparison of whole-body turboSTIR MR imaging and planar 99mTc-methylene diphosphonate scintigraphy in the examination of patients with suspected skeletal metastases. AJR 1997;169 : 1655-1661[Abstract/Free Full Text]
  62. Wu HC, Yen RF, Shen YY, Kao CH, Lin CC, Lee CC. Comparing whole-body 18F-2-deoxyglucose positron emission tomography and technetium-99m methylene diphosphate bone scan to detect bone metastases in patients with renal cell carcinomas: a preliminary report. J Cancer Res Clin Oncol 2002; 128:503 -506[CrossRef][Medline]
  63. Seto E, Segall GM, Terris MK. Positron emission tomography detection of osseous metastases of renal cell carcinoma not identified on bone scan. Urology 2000;55 : 286[Medline]
  64. Schellinger PD, Meinck HM, Thron A. Diagnostic accuracy of MRI compared with CCT in patients with brain metastases. J Neurooncol 1999; 44:275 -281[CrossRef][Medline]
  65. Lam JS, Leppert JT, Figlin RA, Belldegrun AS. Surveillance following radical or partial nephrectomy for renal cell carcinoma. Curr Urol Rep 2005;6 : 7-18[CrossRef][Medline]
  66. Miller AB. Reporting results of cancer treatment. Cancer 1981; 47:207 -214[CrossRef][Medline]
  67. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92:205 -216[Abstract/Free Full Text]
  68. Negrier S, Thiesse C, Vincent C, et al. Different measurement criteria give different tumour response classifications in patients with metastatic renal cell cancer (MRCC). (abstr 6013) Proc Am Soc Clin Oncol 2004 2004; 23:520
  69. Sohaib SA, Turner B, Hanson JA, Farquharson M, Oliver RT, Reznek RH. CT assessment of tumour response to treatment: comparison of linear, cross-sectional and volumetric measures of tumour size. Br J Radiol 2000; 73:1178 -1184[Abstract]
  70. Therasse P, Eisenhauer EA, Verweij J. RECIST revisited: a review of validation studies on tumour assessment. Eur J Cancer2006; 42:1031 -1039[CrossRef][Medline]
  71. Schwartz LH, Mazumdar M, Wang L, et al. Response assessment classification in patients with advanced renal cell carcinoma treated on clinical trials. Cancer 2003;98 : 1611-1619[CrossRef][Medline]
  72. Jerusalem G, Beguin Y, Fassotte MF, et al. Early detection of relapse by whole-body positron emission tomography in the follow-up of patients with Hodgkin's disease. Ann Oncol2003; 14:123 -130[Abstract/Free Full Text]
  73. Rosen M, Veronese M, Lee R, et al. Dynamic contrast-enhanced MRI (DCE-MRI) of primary and metastatic renal cell carcinoma in humans: measurement of tumor vascularity as a means of assessing anti-vascular effects of BAY-43-9006 in vivo. (abstr) Radiological Society of North America 90th scientific assembly and annual meeting program.2004 : 155
  74. Lamuraglia M, Escudier B, Chami L, et al. To predict progression-free survival and overall survival in metastatic renal cancer treated with sorafenib: pilot study using dynamic contrast-enhanced Doppler ultrasound. Eur J Cancer 2006;42 : 2472-2479[CrossRef][Medline]
  75. Choi H, Charnsangavej C, de Castro Faria S, et al. CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate treatment: a quantitative analysis correlated with FDG PET findings. AJR 2004; 183:1619 -1628[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us