ACR Appropriateness Criteria Post-treatment Follow-up of Renal Cell Carcinoma EVIDENCE TABLE

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1 1. 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 Am 00; 0(): 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(): Ljungberg B, Alamdari FI, Rasmuson T, Roos G. Follow-up guidelines for nonmetastatic renal cell carcinoma based on the occurrence of metastases after radical nephrectomy. BJU Int 1999; 8(): Saidi JA, Newhouse JH, Sawczuk IS. Radiologic follow-up of patients with T1- a,b,c or TN+M0 renal cell carcinoma after radical nephrectomy. Urology 1998; 5(6): Sandock DS, Seftel AD, Resnick MI. A new protocol for the follow-up of renal cell carcinoma based on pathological stage. J Urol 1995; 15(1): patient cases Review of surveillance protocols in literature and at UCLA. To design radiologic follow-up protocol for patients after treatment for RCC. 187 patients To define guidelines for the follow-up management of nonmetastatic RCC, by assessing tumor recurrences and the clinical course in patients who had undergone radical nephrectomy. 5 patients To determine the pattern of disease recurrence after radical nephrectomy in patients with node-positive RCC in order to design a schedule for subsequent radiologic evaluation. 158 patients To design radiologic follow-up protocol for patients after treatment for RCC. Results UCLA integrated staging system (UISS) stratifies patients into risk groups based upon tumor stage, Fuhrman grade, and Eastern Cooperative Oncology Group performance status. 59/9 recurrences asymptomatic with on CXR and 1 with abnormal labs. Six patients ( T, T tumors) with isolated intraabdominal metastases all after months. The risk of metastatic RCC is stage dependent. Therefore, surveillance protocols should be based on the pathological stage of the primary tumor. An annual CXR, and serum liver function and alkaline phosphatase level tests for patients with pt1 disease are recommended. /0 lung metastases symptomatic. 15/15 bone and / brain metastases symptomatic. 5/5 liver and / intra-abdominal metastases symptomatic, and 9/9 in patients with T tumors. Mean follow-up of patients without progression was 9 months. Abdominal CT with CXR detects recurrence in all patients with T1-a, b, or c or TN+M0 RCC whose disease progresses and more than 90% of recurrences occur within the first years after surgery. Abdominal CT and CXR are recommended every 6 months for at least years and yearly thereafter in this high-risk group of patients. Disease recurred in 0%, 1.6% and 5.8% (50%,.% and 75%) of the patients, respectively. The average interval to recurrence was 9.5 months (range.5 to 88.8) for patients with stage T Page 1

2 6. Stephenson AJ, Chetner MP, Rourke K, et al. Guidelines for the surveillance of localized renal cell carcinoma based on the patterns of relapse after nephrectomy. J Urol 00; 17(1): Itano NB, Blute ML, Spotts B, Zincke H. Outcome of isolated renal cell carcinoma fossa recurrence after nephrectomy. J Urol 000; 16(): patients To analyze the pattern of disease relapse after nephrectomy to develop effective surveillance guidelines. 1,77 cases; 0 patients with ipsilateral renal fossa recurrence of RCC To determine incidence of isolated renal fossa recurrence after nephrectomy and outcome in those observed, treated surgically, or treated medically. Results Median follow-up was months. Risk of abdominal recurrence 1% for TA-B tumors vs 1.8% for T1- tumors. 7/0 T1- recurrences symptomatic. 11/15 TA-B recurrences symptomatic. For the surveillance of recurrent disease after nephrectomy it is recommended to have an annual clinical assessment and CXR in pt1- cases. Patients with pta-b should be followed every 6 months for the first years with clinical assessment and CXR, and annual follow-up thereafter. The higher risk of abdominal relapse in patients with pta-b indicates that they should receive surveillance abdominal imaging. It is recommended to have abdominal computerized tomography 6, 1, and 6 months postoperatively. 0 patients were identified with an ipsilateral renal fossa recurrence of renal cell carcinoma after complete nephrectomy in the absence of disseminated disease. Mean follow-up was. years (range to 1.8) and no patient was lost to follow-up. The T stage of the primary tumor was T1/T in 1 cases, Ta in, Tb in 1, and Tc in 1, and all were node negative. Mean time to metastasis was 1. 6 years (range to 7.) in the 19 patients who had documented interval metastatic disease after local recurrence. There were 6 deaths, of which 5 were disease specific. Estimated overall crude and cause specific survival at 1 and 5 years was 66% and 8%, respectively. Calculating survival among symptomatic and asymptomatic patients revealed no discernible difference in outcome (p = 0.9). The 5-year survival rate with surgical resection was 51% (SE 18) compared to 18% (1) treated with adjuvant medical therapy and only 1% (1) with observation alone. The differences in cause specific survival were significant (p </=0.0). Page

3 8. Graham SD, Jr. Immunotherapy of renal cell carcinoma. Semin Urol 1989; 7(): Zisman A, Pantuck AJ, Wieder J, et al. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol 00; 0(): Garcia JA, Rini BI. Recent progress in the management of advanced renal cell carcinoma. CA Cancer J Clin 007; 57(): NCCN Clinical Practice Guidelines in Oncology. Kidney Cancer. Version.01. Available at: an_gls/pdf/kidney.pdf. Accessed 7 September patients; (6 M1 or N1/NM0, 68 N0M0) To review the effectiveness of immunotherapy for metastatic RCC. To create an algorithm that can predict postoperative RCC patient outcomes and response to therapy. To summarize the current management and to discuss potential future directions in the management of metastatic RCC. To provide NCCN practice guidelines on kidney cancer. Results Aside from suppressor cells, investigators are beginning to realize that there are circulating proteins probably generated either by the tumor or in response to the tumor that are immunosuppressive (eg, circulating IL- receptors). Inhibition of these proteins by pheresis or other methods may provide increased immunoreactivity to the tumors, as has already been shown in a small series. Monoclonal antibodies offer the promise of the most specificity; however, the technology is still far from making this therapy imminently available. Only through additional laboratory and clinical investigation, will significant advances be made. NM-LR patients had 91% disease-specific survival at 5 years, lower recurrence rate, and better disease-free survival compared with NM-IR and HR patients. Disease progressed in 50% of NM-HR patients. Disease-specific survival of NM-HR patients who received immunotherapy (IMT) for recurrent disease was similar to that of M-LR patients treated with cytoreductive nephrectomy and adjuvant IMT. Time from recurrence to death for NM- HR patients was inferior to that for M-LR patients. After IMT, approximately 5% of M-LR and 1% of M-IR patients had longterm progression-free survival. M-HR patients did poorly despite IMT. In the treatment of advanced RCC patients, no single therapy should be considered as standard of care. Patients should instead be advised about the features of their disease and the impact on prognosis and outcome. 1 Page

4 1. Stenzl A, dekernion JB. The natural history of renal cell carcinoma. Semin Urol 1989; 7(): Hafez KS, Novick AC, Campbell SC. Patterns of tumor recurrence and guidelines for follow-up after nephron sparing surgery for sporadic renal cell carcinoma. J Urol 1997; 157(6): To review factors determining the likelihood of metastatic disease. 7 patients To delineate patterns of tumor recurrence and develop guidelines for follow-up after nephron sparing surgery for sporadic RCC. Results Size, stage, and grade are important in prognosis. RCC remains one of the most therapy resistant malignancies in human beings. Much additional information about cellular, biochemical, and immunologic mechanisms will be needed to understand its clinical behavior, and to enhance the ability to predict its clinical course. Renal cell carcinoma recurred after nephron sparing surgery in 8 patients (11.6%), including 1 (.0%) who had local tumor recurrence with (7) or without (6) metastatic disease and 5 (7.6%) who had metastatic disease without local tumor recurrence. Recurrent renal cell carcinoma was detected by associated symptoms in 5 patients and by a follow-up chest x-ray or abdominal computerized tomography (CT) in 1. The respective incidences of postoperative local tumor recurrence and metastatic disease according to initial pathological tumor stage were 0 and.% for stage T1,.0 and 5.% for stage T, 8. and 11.5% for stage Ta, and 10.6 and 1.9% for stage Tb disease. The peak postoperative intervals until local tumor recurrence were 6 to months (7 of 10 patients with stage T renal cell carcinoma) and longer than 8 months (all with stage T disease). Patients with isolated local tumor recurrence had better survival compared to those with local tumor recurrence and metastatic disease or metastases only. Page

5 1. Lau WK, Blute ML, Weaver AL, Torres VE, Zincke H. Matched comparison of radical nephrectomy vs nephron-sparing surgery in patients with unilateral renal cell carcinoma and a normal contralateral kidney. Mayo Clin Proc 000; 75(1): Bradford TJ, Montie JE, Hafez KS. The role of imaging in the surveillance of urologic malignancies. Urol Clin North Am 006; (): ,9 and 189 patients (16 in each cohort) To report the long-term follow-up of a matched comparison of radical nephrectomy (RN) and nephron-sparing surgery (NSS) in patients with single unilateral renal cell carcinoma (RCC) and a normal contralateral kidney. To review the role of imaging in surveillance of urologic cancers, including RCC. Results At last follow-up, 16 RN patients (77%) and 10 NSS patients (79%) were alive with no evidence of disease. There was no significant difference observed between patients who had RN and those who had NSS with respect to overall survival (risk ratio, 0.96; 95% confidence interval [CI], ; P =.88) or cancer-specific survival (risk ratio, 1.; 95% CI, ; P =.71). At 10 years, similar rates of contralateral recurrence (0.9% for RN vs 1% for NSS) and metastasis (.9% for RN vs.% for NSS) were seen in each group, whereas the rate of ipsilateral local recurrence for patients who underwent RN and NSS was 0.8% and 5.%, respectively (P =.18). There was no significant difference in the early complications between the RN and NSS groups. However, patients who underwent RN had a significantly higher risk for proteinuria as defined by a protein/osmolality ratio of 0.1 or higher (55.% vs.5%; P =.01). At 10 years, the cumulative incidence of chronic renal insufficiency (creatinine >.0 mg/dl at least 0 days after surgery) was.% and 11.6%, respectively, for the RN and NSS groups (risk ratio,.7; 95% CI, ; P =.01). Review of literature and authors recommendation for longer and more intense surveillance for higher T stage of disease. Example: lifelong surveillance for patients with T or T disease and reasonable life expectancy. Page 5

6 16. Chae EJ, Kim JK, Kim SH, Bae SJ, Cho KS. Renal cell carcinoma: analysis of postoperative recurrence patterns. Radiology 005; (1): Kradjian RM, Bennington JL. Renal Carcinoma Recurrent 1 Years after Nephrectomy. Arch Surg 1965; 90: Chin AI, Lam JS, Figlin RA, Belldegrun AS. Surveillance strategies for renal cell carcinoma patients following nephrectomy. Rev Urol 006; 8(1): total patients To retrospectively analyze the recurrence patterns of RCC and the factors affecting tumor recurrence. 1 patient To report the recurrence of metastatic renal cell 1 years after treatment. Review of surveillance protocols in literature and at UCLA. This is an update since reference one above. UISS stratifies patients into risk groups (low, intermediate, and high) based upon tumor stage, Fuhrman grade, and Eastern Cooperative Oncology Group performance status. Results Mean follow-up period was 5 months. 1 patients (1%) with recurrence; /1 (8%) of recurrences within years of surgery. Sites of recurrence in order of frequency: lung (n=9), bone (1), surgical site (7), brain (6), liver (5), mediastinal nodes (5), contralateral kidney (). Risk factors for recurrence: greatest tumor diameter, T stage, stage group, nuclear grade. RCC usually recurs within years after surgery, with the lung being the most vulnerable site; greatest tumor diameter, T stage, stage group, and nuclear grade are important factors for recurrence. Renal carcinoma recurred deep in the surgical site 1 years after nephrectomy. Since extension to the surgical scar is believed to be rare in renal carcinoma, it is suggested that such spread may occur more frequently after nephrectomy than is realized; and/or that long remission is favored by confinement of malignant cells to the scar, a site unfavorable for growth. Recommended guidelines based on UISS stratification, natural history of RCC, and available treatment modalities: Low risk: yearly chest CT for 5 years, abdominal CT at and years; Intermediate risk: chest CT every 6 months for years then yearly until 10 years, abdominal CT yearly for years then every years until 10 years; High risk: chest CT every 6 months for years then yearly until 10 years, abdominal CT every 6 months for years then yearly until 5 years then every years until 10 years. Page 6

7 19. Skolarikos A, Alivizatos G, Laguna P, de la Rosette J. A review on follow-up strategies for renal cell carcinoma after nephrectomy. Eur Urol 007; 51(6): ; discussion Crispen PL, Boorjian SA, Lohse CM, Leibovich BC, Kwon ED. Predicting disease progression after nephrectomy for localized renal cell carcinoma: the utility of prognostic models and molecular biomarkers. Cancer 008; 11(): To provide a comprehensive review of the evidence supporting the necessity for followup after nephrectomy for RCC. To review the usefulness of prognostic models and molecular biomarkers for predicting disease progression after nephrectomy for localized RCC. Results Suggested algorithm, based on most frequently proposed surveillance protocols in the literature yet without being a result of high-level evidence-based urology : pt1: clinical assessment and CXR twice a year for three years, then annually. Abdominal CT not recommended. pt: clinical assessment and CXR twice a year for years, then annually. Abdominal CT not recommended or every years. pt: clinical assessment and CXR twice a year for years, then annually. Abdominal CT every 6 months for - years, then every - years. IMP-, CXCR, p5, Surviving, ciap1, B7- H1, and B7-H have all been associated with disease progression after nephrectomy. The incorporation of one or more of these biomarkers may increase the accuracy of currently available prognostic models and help facilitate the appropriate use of adjuvant therapies aimed at preventing future disease progression. Page 7

8 1. Kroeger N, Rampersaud EN, Patard JJ, et al. Prognostic value of microvascular invasion in predicting the cancer specific survival and risk of metastatic disease in renal cell carcinoma: a multicenter investigation. J Urol 01; 187():18-.. Kumar R, Shandal V, Shamim SA, Jeph S, Singh H, Malhotra A. Role of FDG PET-CT in recurrent renal cell carcinoma. Nucl Med Commun 010; 1(10):8-850.,596 patients (75 with microvascula r invasion &,11 without microvascula r invasion) To evaluate the prognostic value of microvascular invasion in the occurrence of metastases and cancer specific survival in a large multicenter study. 6 patients To determine the efficacy of FDG-PET/CT in diagnosing the recurrence of RCC in patients treated earlier with partial or radical nephrectomy. Results Patients with microvascular invasion presented with higher age (p = 0.001) and a worse Eastern Cooperative Oncology Group performance status (p <0.0001). Microvascular invasion was associated with larger tumor diameter (p <0.0001), higher Fuhrman grade (p <0.0001), more advanced pt stage (p <0.0001), and the presence of lymph node and distant metastases (p <0.0001). In nonmetastatic cases worse survival was associated with microvascular invasion (p <0.0001, HR.8). Univariate analysis demonstrated a strong correlation between microvascular invasion and cancer specific survival (p <0.0001). However, after controlling for gender, Eastern Cooperative Oncology Group performance status, Fuhrman grade and TNM stage statistical significance was lost. Of interest, low stage tumors with microvascular invasion were strongly correlated with the occurrence of metastases (p <0.0001). A total of 10 PET/CT studies were done in these 6 patients, of which 6 studies were true positive, 0 studies were true negative, 7 studies were false negative and remaining studies were false positive. In 6 true-positive scans, PET/CT showed 109 lesions. Of these, 8 lesions were in the lungs, 1 lesions were at a locoregional site, 1 were in the bones, 1 in the retroperitoneal lymph nodes and 7 at other sites. The sensitivity, specificity and accuracy of PET/CT were 90%, 91% and 90%, respectively. Page 8

9 . Park JW, Jo MK, Lee HM. Significance of 18F-fluorodeoxyglucose positronemission tomography/computed tomography for the postoperative surveillance of advanced renal cell carcinoma. BJU Int 009; 10(5): Davis SD. CT evaluation for pulmonary metastases in patients with extrathoracic malignancy. Radiology 1991; 180(1): Kutty K, Varkey B. Incidence and distribution of intrathoracic metastases from renal cell carcinoma. Arch Intern Med 198; 1(): Lim DJ, Carter MF. Computerized tomography in the preoperative staging for pulmonary metastases in patients with renal cell carcinoma. J Urol 199; 150(): patients To evaluate the role of FDG-PET/CT for the surveillance of patients with RCC who have a high risk of local recurrence or distant metastasis, by comparing the results with those of conventional imaging methods. To evaluate CT with linear tomography for chest metastases. 6 patients To review CXR findings in patients treated for RCC. 10 patients To evaluate the role of CT in examining the chest for staging of RCC. Results The FDG-PET/CT accurately classified the presence of a recurrence or metastasis in 56 (89%) patients. FDG-PET/CT had 89.5% sensitivity, 8.% specificity, 77.% PPV, 9.6% NPV, and 85.7% accuracy in detecting recurrence or metastasis, which was not significantly different from the results with conventional methods. Moreover, the accuracy of the FDG-PET/CT by nuclear grade and histological subtypes was not significantly different. CT is more sensitive and useful in the evaluation of an apparent solitary pulmonary nodule or an equivocal radiographic finding. Future large prospective studies evaluating individual malignancies are needed to assess the impact on long-term survival of early detection of pulmonary metastases with CT. 5 had metastases, 8 of which appeared after therapy. Metastases may appear in nodes only. Mediastinal lymph node metastasis from RCC occurs more frequently than previously reported and may be the only chest roentgenographic manifestation of the disease. In patients with a relatively small tumor (stage T1) a normal CXR suffices for pulmonary staging. The indications for additional chest CT would include solitary nodule on CXR before salvage resection of metastasis, chest symptoms suggestive of endobronchial metastasis or extensive regional disease. Page 9

10 7. Winter H, Meimarakis G, Angele MK, et al. Tumor infiltrated hilar and mediastinal lymph nodes are an independent prognostic factor for decreased survival after pulmonary metastasectomy in patients with renal cell carcinoma. J Urol 010; 18(5): Jadvar H, Kherbache HM, Pinski JK, Conti PS. Diagnostic role of [F-18]-FDG positron emission tomography in restaging renal cell carcinoma. Clin Nephrol 00; 60(6): 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 00; 1(1): patients To analyze the value of CT to predict mediastinal/hilar lymph node involvement as well as the impact of systematic lymphadenectomy on survival in patients with pulmonary RCC metastasis. 5 patients To retrospectively assess the diagnostic utility of FDG-PET in restaging RCC. patients To evaluate the role of FDG-PET in the detection of distant metastases from RCC. Results Lymph node metastasis was histologically proved in 5% of patients. Metastasis was not associated with initial tumor grade, lymph node status, the number of pulmonary metastases or recurrent pulmonary metastasis. CT had 8% sensitivity and 97% specificity to predict lymph node metastasis. Sensitivity was markedly better for detecting mediastinal than hilar lymph node metastasis (90% vs 69%). Patients with lymph node metastasis had significantly shorter median survival than patients without lymph node metastasis (19 vs 10 months, P<0.001). Multivariate analysis revealed that tumor infiltrated mediastinal lymph nodes were an independent prognostic factor for patient survival. Match paired analysis showed that after lymph node dissection patients showed a trend toward improved survival. FDG-PET performance in detecting local recurrence and metastases: 71% sensitivity, 75% specificity, 7% accuracy, % NPV and 9% PPV. False negatives: lung, 1 adrenal, bone, and mediastinum nodal metastases. FDG-PET performance in detecting pathologically-proven metastases in 1 patients: 6% sensitivity, 100% specificity, and 100% PPV. False negatives: 7 lung, 1 adrenal, 1 chest wall, 1 brain, and mediastinum nodal metastases. FDG-PET is not a sensitive imaging modality for the evaluation of metastatic RCC and may not adequately characterize small metastatic lesions. However, positive FDG-PET is predictive for the presence of RCC in lesions imaged, may complement anatomic radiologic imaging modalities, and may alleviate the need for a biopsy in selected situations. A negative FDG-PET, however does not rule out active malignancy. Page 10

11 0. 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 00; 171(5): Platzek I, Zastrow S, Deppe PE, et al. Whole-body MRI in follow-up of patients with renal cell carcinoma. Acta Radiol 010; 51(5): Fielding JR, Aliabadi N, Renshaw AA, Silverman SG. Staging of 119 patients with renal cell carcinoma: the yield and cost-effectiveness of pelvic CT. AJR 1999; 17(1): patients To retrospectively evaluate the role of FDG- PET in renal cancer; compared to CT and bone scan. 8 patients To compare the diagnostic accuracy of wholebody MRI and CT in follow-up of patients with RCC. 119 patients Computerized review of medical records to determine the yield and cost-effectiveness of pelvic CT in staging RCC. Results 15 primary tumors, 17 metastases. PET sensitivities: 60% of primary renal tumors, 75% of retroperitoneal nodal and renal bed metastases, 75% of lung metastases, 77% of bone metastases. PET may have complementary role in equivocal cases because of its high specificity, particularly for lung and bone metastases. MRI demonstrated a significantly better diagnostic accuracy regarding musculoskeletal metastases compared with CT (97.7% vs 8%, P<0.001). In contrast, CT was superior in the detection of pulmonary metastases (88.5% vs 71.9%, P<0.001). Both methods had similar diagnostic performance regarding lymph node metastases (CT, accuracy 8.%; MRI, accuracy 8.%, P=0.5). The concordance of both modalities regarding N and M stage was excellent (Cohen's kappa 1.00). In two patients cerebral metastases were revealed by MRI, which led to a change in therapy. Total estimated cost of the 119 CT examinations of the pelvis was $0,698 ($ each). No findings of probable malignancy were identified. In 7 patients, CT showed benign findings; these results did not cause planned surgery to be delayed. Three of these 7 patients underwent further radiologic tests at an estimated total cost of $. Page 11

12 . Khaitan A, Gupta NP, Hemal AK, Dogra PN, Seth A, Aron M. Is there a need for pelvic CT scan in cases of renal cell carcinoma? Int Urol Nephrol 00; (1): Marano I, Stagni V, Tovecci F, Covello M, Porta G. [Computed tomography in the follow-up of patients nephrectomized for adenocarcinoma]. Radiol Med 199; 85(1- ): McClennan BL, Deyoe LA. The imaging evaluation of renal cell carcinoma: diagnosis and staging. Radiol Clin North Am 199; (1): patients Retrospective study to determine the necessity of pelvic CT in patients of RCC. 6 patients; 159 exams To retrospectively follow patients post nephrectomy with CT. To review radiology for diagnosis, staging and follow-up of RCC. Results Of the 00 cases, 11 were stage I, 68 were stage II, 99 were stage III and 119 were stage IV. In all patients, tumor was identified in the kidney on preoperative CT scan. 1 patients (.5%) had an abnormality on pelvic CT. Five (1.5%) had category 1, three (0.75%) had category and six (1.5%) had category abnormality on pelvic CT. However, all these abnormalities in pelvis were detected prior to CT by other investigations (ultrasonograms or plain radiograph). Of the six cases with malignant findings, two had superficial bladder cancer, one had RCC in a pelvic kidney and three had bone metastases in the pelvis. Pelvic CT does not offer additional information in the vast majority of cases with RCC and should be performed selectively. Thus the cost of diagnostic imaging in RCC can be reduced. 0 had local recurrences, 15 had liver metastases. The study suggests the value of a methodical CT follow-up of asymptomatic post-nephrectomy patients. CT immediately after surgery is also recommended to serve as a baseline reference for subsequent examinations. CT was accurate in the early detection of both local recurrences and distant solitary metastases. Bone scans are not appropriate in asymptomatic patients; abdomen CT should be performed for years. Page 1

13 6. Jain Y, Liew S, Taylor MB, Bonington SC. Is dual-phase abdominal CT necessary for the optimal detection of metastases from renal cell carcinoma? Clin Radiol 011; 66(11): Brouwers AH, Dorr U, Lang O, et al. 11 I-cG50 monoclonal antibody immunoscintigraphy versus [18 F]FDG- PET imaging in patients with metastatic renal cell carcinoma: a comparative study. Nucl Med Commun 00; (): 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 001; 166(): 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 00; 57(1): patients To determine whether dual-phase abdominal CT detected more metastases than portalphase CT alone in patients with RCC. 0 patients To establish the percentage of metastatic RCC lesions detected by RIS with the chimeric monoclonal antibody I11-cG50 vs FDG- PET, and to evaluate the use of these radionuclide imaging modalities compared with routinely used imaging techniques. 8 patients To evaluate the accuracy of FDG-PET for staging and management of RCC. 6 patients To examine the diagnostic accuracy and clinical usefulness of whole-body PET imaging for re-staging of renal cell cancer. Results Metastases were identified in the liver in 7 patients, pancreas in 1, and contralateral kidney in patients. 9/7 (%) liver metastases, /1 (5%) pancreatic metastases, and / (9%) renal metastases were only detected in the arterial phase, whilst /7 (15%) liver metastases, /1 (5%) pancreatic metastases, and / (9%) renal metastases were only detected in the portal phase. Nine patients (9%) had metastases only visualized in the arterial phase, and 6 (6%) only in the portal phase. Detection of metastases only visible in the arterial phase led to a change of management in patients (%). FDG-PET superior to I11-cG50 for detection of metastases. CT and FDG-PET detected 70% and 69%, respectively, of 11 metastatic lesions. FDG-PET results influenced treatment decisions in /8 patients. In all 8 patients, PET accurately differentiated local tumor recurrence from post-operative, post RT changes. FDG-PET may have a role in the diagnostic evaluation of patients with RCC preoperatively and staging of metastatic disease. FDG-PET accurately classified /6 patients as being disease free or having recurrent/metastatic disease. False negatives: 1 bone, 1 nodal, and liver metastases. PET is useful in characterizing anatomic lesions of unknown significance in patients with renal cell cancer. Page 1

14 0. Blacher E, Johnson DE, Haynie TP. Value of routine radionuclide bone scans in renal cell carcinoma. Urology 1985; 6(5):-. 1. Chancellor MB, Konnak JW, Grossman HB. Diagnostic value of routine bone scintigraphy renal imaging in renal cell carcinoma. Urology 1989; (5):0-.. Rosen PR, Murphy KG. Bone scintigraphy in the initial staging of patients with renal-cell carcinoma: concise communication. J Nucl Med 198; 5(): Sohaib SA, Cook G, Allen SD, Hughes M, Eisen T, Gore M. Comparison of whole-body MRI and bone scintigraphy in the detection of bone metastases in renal cancer. Br J Radiol 009; 8(980): patients To evaluate routine bone scanning for staging for RCC. 9 patients To evaluate bone scintigraphy for metastases during follow-up. 0 consecutive patients To evaluate routine bone scanning for staging RCC. 7 patients To compare the sensitivity of whole-body MRI with bone scintigraphy in the detection of bone metastases in patients with renal cancer. Results Sensitivity 9%, specificity 86%. Although bone scanning was useful for confirming clinically or radiographically suspected metastatic disease, it did not influence the staging of the RCC in any patient. It is concluded that bone scans should be used to confirm the presence and to determine the extent of osseous metastases in patients with RCC but are unnecessary as a routine staging procedure. 1% positive. 9% of the patients had abnormal bone scan renal images (8% had focal decreased uptake, and 1% had focal increased uptake). 6% of the renal images were symmetrical bilaterally. When bone scans are employed in the postoperative follow-up of patients with renal cancer, they can be used to assess the status of the remaining kidney. Bone scintigrams were positive in /0 patients at the time of diagnosis. In view of the low yield of bone imaging, it appears that routine scintigraphy is unwarranted in the absence of skeletal symptoms before the diagnosis of renal lesions. The presence of a positive bone image did not alter the indication for nephrectomy. 15 patients (%) had bone metastases at different sites. Both scintigraphy and MRI were highly specific (9% and 97%, respectively), but the sensitivity of MRI (9%) was superior (P=0.007) to that of scintigraphy (6%). MRI identified more metastases in the spine and appendicular skeleton, whereas scintigraphy showed more lesions in the skull/facial and thoracic bones. MRI identified extra-osseous metastases in patients (70%), these were mainly lung and retroperitoneal in site. Page 1

15 . Seto E, Segall GM, Terris MK. Positron emission tomography detection of osseous metastases of renal cell carcinoma not identified on bone scan. Urology 000; 55(): Wu HC, Yen RF, Shen YY, Kao CH, Lin CC, Lee CC. Comparing whole body 18F- -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 00; 18(9): Atwell TD, Farrell MA, Callstrom MR, et al. Percutaneous cryoablation of 0 solid renal tumors with US guidance and CT monitoring: initial experience. Radiology 007; (1):76-8. Results 1case To evaluate the clinical utility of PET in RCC. FDG-PET shows asymptomatic bone metastases not detected on bone scan. This case illustrates the potential superiority of PET in evaluating skeletal metastases of RCC. 18 patients; 0 bone metastases; 1 benign bone lesions 0 total patients; 0 RCC, oncocytic neoplasms, 5 oncocytomas 11 without diagnosis To compare FDG-PET to Tc99m-MDP bone scan for RCC metastases. To retrospectively determine the safety and effectiveness of percutaneous cryoablation monitored with CT, for the treatment of solid renal masses. Sensitivity and accuracy: 100%, 100% for PET; 78%, 60% for bone scan. The data suggest that FDG-PET has a higher sensitivity and a better accuracy than that of bone scan to detect bone metastases in patients with RCC. 8/0 (95%) of the cryoablation procedures were technically successful (ablation produced a volume of tissue with no contrast enhancement in the area encompassing the original tumor). 9/8 (76%) in whom ablation was technically successful underwent follow-up imaging with CT or MRI (mean of 8 months with range of months). No local tumor recurrence was found. Complication rate of 8% with one being major (large perinephric hemorrhage with hypotension and requiring multiple transfusions) and two being minor (large perinephric hemorrhage not requiring transfusion nor intervention; hypertensive crisis). Surveillance protocol after ablation: precontrast and postcontrast CT immediately after cryoablation and at -6 months, 1, 18,, and 6 months after ablation. If contraindication to contrast enhanced CT, MRI was used with first contrast enhanced MRI within 8 hours after ablation. Page 15

16 7. Gill IS, Remer EM, Hasan WA, et al. Renal cryoablation: outcome at years. J Urol 005; 17(6): McDougal WS, Gervais DA, McGovern FJ, Mueller PR. Long-term follow-up of patients with renal cell carcinoma treated with radio frequency ablation with curative intent. J Urol 005; 17(1): patients 6 with RCC 0 with benign lesions 16 patients (0 tumors) To evaluate the success rate of cryoablation of renal lesions followed for a minimum of years. Evaluate cryolesion size reduction over time. To evaluate the success rate of RFA of RCC followed for a minimum of years. All tumors were biopsy proven RCC. Results Of the 6 patients with RCC cryoablated, two had abnormal enhancement on MRI that was biopsy proven to be recurrent RCC at 18 months and 0 months post-ablation. Both were disease free.5 and years, respectively, after radical nephrectomy. Renal function was not compromised by the cryoablation. Surveillance protocol after ablation: contrast-enhanced MRI at 1 day, months 1,, 6, 1, 18, and, and yearly thereafter for 5 years. CT guided needlebiopsy of the cryolesion was performed at 6 months postablation and repeated if MRI findings abnormal. For mean tumor size of. cm, mean intraoperative size of cryolesion on US was.6 cm. Mean cryolesion size on MRI was.7,.8,., 1.7, 1., and 0.9 cm at postoperative day 1, month, 6, 1,, and 6, representing a 6%, 9%, 56%, 69%, and 75% reduction at, 6, 1,, and 6 months, respectively. 5/16 patients died of unrelated causes before years of follow-up. All except one tumor was successfully treated. Surveillance protocol: postablation contrast-enhanced CT (or MRI if abnormal renal function) was performed within 1 month, at months and 6 months if no residual disease requiring treatment. At 6 months patients were imaged at 6 months to yearly intervals thereafter. RFA of exophytic RCC >5 cm in diameter is effective in eradicating the tumor and comparable to surgical extirpation at years. Page 16

17 9. Rukstalis DB, Khorsandi M, Garcia FU, Hoenig DM, Cohen JK. Clinical experience with open renal cryoablation. Urology 001; 57(1): Zagoria RJ, Hawkins AD, Clark PE, et al. Percutaneous CT-guided radiofrequency ablation of renal neoplasms: factors influencing success. AJR 00; 18(1): Zagoria RJ, Traver MA, Werle DM, Perini M, Hayasaka S, Clark PE. Oncologic efficacy of CT-guided percutaneous radiofrequency ablation of renal cell carcinomas. AJR 007; 189(): total patients; 17 with RCC confirmed on intraoperativ e biopsy patients tumors treated with 7 ablation sessions 10 total patients; 15 RCC To evaluate the safety and efficacy of open renal cryoablation of small solid renal masses, since the delivery of freezing temperatures has been shown to effectively ablate solid neoplasms of the liver, uterus, and prostate. To evaluate the success rate for RFA of renal tumors and to determine the risk of serious complications. To examine CT-guided percutaneous RFA of biopsy-proven RCC to determine the diseasefree survival and complication rate. Results Median follow-up of 16 months with range of 1 to months. Of the patients with biopsy proven RCC, 15/17 (88.%) had MRI demonstrate complete resolution of the mass. Surveillance protocol: contrast-enhanced MRI between and 0 days, and then at, 6, and 1 months postablation. Subsequently, patients were evaluated yearly. Open renal cryoablation appears to be a safe technique for the in situ destruction of solid or complex renal masses. However, inadequate freezing of RCC may result in local disease persistence. The expected slow growth rate of small renal cancers necessitates prolonged radiologic follow-up. Continued clinical research is required before renal cryoablation can be considered an acceptable curative treatment for renal cancer. Complete tumor ablation was achieved after a single treatment session in 8% of patients, and in 8% of patients after subsequent ablation sessions. Size was the major determinant for achieving tumor eradication with a single session of ablation, with all 11 tumors cm or smaller being completely ablated after one session. Tumor location, histology, and the presence of renal disease did not correlate with treatment success. Contrast-enhanced CT performed immediately after ablation is reliable to exclude residual viable tumor. CT-guided RFA of renal tumors is safe and has a high rate of success in the treatment of small renal tumors, with no evidence of recurrence at midterm follow-up of treated patients. CT-guided percutaneous RFA is a safe method to treat small RCC. shows that RFA can reliably eradicate carcinomas <.7 cm. Page 17

18 5. Best SL, Park SK, Yaacoub RF, et al. Long-term outcomes of renal tumor radio frequency ablation stratified by tumor diameter: size matters. J Urol 01; 187(): Pirasteh A, Snyder L, Boncher N, Passalacqua M, Rosenblum D, Prologo JD. Cryoablation vs. radiofrequency ablation for small renal masses. Acad Radiol 011; 18(1): tumors To analyze tumor size related outcomes for RFA, focusing on patients with long-term follow-up. 111 patients A retrospective review of the imaging and histologic outcomes during the transition from CT-guided percutaneous RFA to cryoablation. Results Median tumor size was. cm (range 0.9 to 5.) with a median follow-up of 5 months (range 1.5 to 10). Renal cell carcinoma was confirmed in 7% of the 150 tumors that had pre-ablation biopsy (9%). The and 5-year disease-free survival was comparable at 9% and 91% overall, and was dependent on tumor size, being 96% and 95% for tumors smaller than.0 cm and 79% and 79%, respectively, for tumors cm or larger (p=0.001). Most failures (1 of 18) were local, either incomplete ablations or local recurrences. This is an intent to treat analysis and, therefore, includes patients ultimately found to have benign tumors, although outcomes were comparable in patients with cancer. There were four cases of suspicious enhancement on follow-up computed tomography or magnetic resonance imaging in each group, with cumulative imaging recurrence rates of 11% and 7% for radiofrequency ablation and cryoablation, respectively. Log rank test analysis revealed no significant difference between rates of imaging recurrence between the two groups (P =.60). Page 18

19 5. Mues AC, Okhunov Z, Haramis G, D'Agostino H, Shingleton BW, Landman J. Comparison of percutaneous and laparoscopic renal cryoablation for small (<.0 cm) renal masses. J Endourol 010; (7): Young EE, Castle SM, Gorbatiy V, Leveillee RJ. Comparison of safety, renal function outcomes and efficacy of laparoscopic and percutaneous radio frequency ablation of renal masses. J Urol 01; 187(): PCA patients for 99 lesions; 81 LCA patients for 97 lesions 98 patients with 16 renal tumors To review laparoscopic cryoablation (LCA) and percutaneous cryoablation (PCA) in the management of small renal tumors and to compare clinical outcomes, short-term oncologic results, and patient complications. To compare the laparoscopic and percutaneous approach for the radio frequency ablation of renal tumors under the guidance of urological surgeons. Results The PCA group had two major complications (%), and the LCA group had three major complications (.7%) (P = 0.7). In the LCA group, estimated blood loss was associated with tumor location with hilar tumor demonstrating a significantly higher mean blood loss (191 ml) compared with endophytic, mesophytic, and exophytic tumors (70 ml, 71 ml, 7.5 ml), respectively (P = 0.05). Malignancies rated in the PCA and LCA groups were 50.5% and 60.0%, respectively (P < 0.05). In the PCA group, nine (9.1%) patients demonstrated treatment failure with a persistent enhancement in the ablation bed. All nine were treated with a subsequent PCA. One patient had subsequent tumor bed enhancement and underwent an open radical nephrectomy. Treatment failed in three (.1%) patients in the LCA cohort (incomplete ablation or recurrence). There were no statistically significant differences between the laparoscopic and computerized tomography guided radio frequency ablation groups with respect to patient demographics, complication rates and renal functional outcomes (p>0.05). The - year Kaplan-Meier estimation of radiographic recurrence-free probability was 95% for computerized tomography guided radio frequency ablation and 9% for laparoscopic radio frequency ablation (p=0.8). Subanalysis of the 1 (67%) renal cell carcinoma tumors showed a -year Kaplan- Meier estimation of oncologic recurrence-free probability (post-ablation biopsy proven viable tumor) of 9% for computerized tomography guided radio frequency ablation and 100% for laparoscopic radio frequency ablation (p=0.16). Median follow-up was 1 months for laparoscopic radio frequency ablation) and 19 months for computerized tomography guided radio frequency ablation. Page 19

20 56. Ferakis N, Bouropoulos C, Granitsas T, Mylona S, Poulias I. Long-term results after computed-tomography-guided percutaneous radiofrequency ablation for small renal tumors. J Endourol 010; (1): Tracy CR, Raman JD, Donnally C, Trimmer CK, Cadeddu JA. Durable oncologic outcomes after radiofrequency ablation: experience from treating small renal masses over 7.5 years. Cancer 010; 116(1): patients; 9 renal tumors 08 patients with SRMs To present the long-term results and to identify possible risk factors for recurrence after radiofrequency ablation (RFA) for renal tumors. To determine intermediate and long-term oncologic outcomes for patients with SRMs who underwent RFA over the past 7.5 years. Results Initial ablation success rate was 90% and with repeated treatment, a success rate of complete ablation reached 97%. Average follow-up was 61. months (range 6-8 mos). Recurrence was seen in four tumors. The risk factor associated with recurrence was tumor size exceeding cm (P < 0.01, relative risk [RR] =.1). Overall - and 5-year tumor control rate was 9% and 89%, respectively. Tumor size was also predictive for recurrence in the subgroup of 17 patients followed for more than 5 years (P = 0.0, RR =.15). Tumor control rate for this subgroup was 90%. Two hundred eight patients (with SRMs) who had no evidence of previous ipsilateral renal cancer treatment underwent RFA and had follow-up imaging studies available for review. Overall, tumor size averaged. cm, and follow-up ranged from 1.5 months to 90 months (mean, 7 months). Of the 7 tumors (9%) that underwent preablation biopsy, RCC was confirmed in 79%. The initial treatment success rate was 97%, and the overall 5-year recurrence-free survival rate was 9% (90% for 160 patients who had biopsy-proven RCC). During follow-up, patients developed metastatic disease, and 1 patient died of RCC, yielding 5-year actuarial metastasis-free and cancer-specific survival rates of 95% and 99%, respectively. Page 0

21 58. Zagoria RJ, Pettus JA, Rogers M, Werle DM, Childs D, Leyendecker JR. Longterm outcomes after percutaneous radiofrequency ablation for renal cell carcinoma. Urology 011; 77(6): Beland MD, Wolf FJ, Grand DJ, Dupuy DE, Mayo-Smith WW. Incidence of multiple sporadic renal cell carcinomas in patients referred for renal radiofrequency ablation: implications for imaging followup. AJR 011; 197(): RCCs in 1 patients 16 patients (10 men and 58 women) To assess the long-term oncological efficacy of radiofrequency ablation (RFA) for treatment of renal cell carcinoma (RCC). To report the incidence of multiple sporadic primary RCCs in patients referred for RFA. Results Median size of RCC treated was.6 cm (range: cm). Of the 8 treated RCCs, 5 (1%) had recurrent tumor after a single ablation session. The median size of the index lesion in the cases with recurrence was 5. cm (interquartile range [IQR]: -5.) compared with. cm (IQR: , P =.001) without local recurrence. There were no recurrences when RCCs less than cm were treated. Seventeen (1%) patients with 18 treated RCCs died during the follow-up period at a median time of (IQR: 10-7) months. One patient (%) died of metastatic RCC, whereas 16 died of unrelated causes. Twenty-four patients with 0 RCCs treated with RFA survived. For the remaining 0 RCCs, median follow up was 61 months (IQR: 5-68). No patients in this group of survivors had metastatic RCC, 1 had recurrence diagnosed at 68 months. The long-term recurrence-free survival rate was 88% after RFA. 8 patients (17%) had multiple biopsy-proven RCCs. 18 patients (11%) had undergone prior nephrectomy for surgically proven RCC. The mean interval between prior nephrectomy and RFA referral was 1 months (range, 1-56 months). 7 patients (%) without a history of nephrectomy presented with biopsy-proven RCCs at RFA referral. patients (%) who had not undergone nephrectomy and had a solitary RCC at the time of RFA had developed a new biopsy-proven RCC separate from the original treatment site on follow-up imaging after RFA. The mean time to diagnosis from the initial RFA treatment was 5 months (range, 5-89 months). Page 1

22 60. Matin SF, Ahrar K, Cadeddu JA, et al. Residual and recurrent disease following renal energy ablative therapy: a multiinstitutional study. J Urol 006; 176(5): Aron M, Kamoi K, Remer E, Berger A, Desai M, Gill I. Laparoscopic renal cryoablation: 8-year, single surgeon outcomes. J Urol 010; 18(): Meloni MF, Bertolotto M, Alberzoni C, et al. Follow-up after percutaneous radiofrequency ablation of renal cell carcinoma: contrast-enhanced sonography versus contrast-enhanced CT or MRI. AJR 008; 191(): American College of Radiology. Manual on Contrast Media. Available at: 0D1FE0ECE5EAB6861BD179E5&a mp;_z=z. 616 total patients; 7 institutions To look at the incidence and pattern of residual and recurrent disease after RF and cryoablation of a renal mass to determine a reasonable surveillance imaging protocol. 80 patients To report oncological outcomes in patients at a minimum 5-year follow-up after laparoscopic renal cryoablation done by a single surgeon. 9 patients; 0 RCC To evaluate, using contrast-enhanced CT or MRI as the reference imaging technique, the diagnostic performance of low-mechanicalindex contrast-enhanced US in detecting local tumor progression after percutaneous RFA of renal tumors. Guidance document on contrast media to assist radiologists in recognizing and managing risks associated with the use of contrast media. Results At a mean follow-up of years patients with residual or recurrent disease had an overall survival rate of 8.5% and a -year metastasis-free survival rate of 97.% for those with localized, unilateral renal tumors. In most cases initial treatment failure was detected within the first months after treatment. Our findings support a minimum of to imaging studies in year one after ablative therapy, and at months 1,, 6 (optional) and 1. In the 80 patients with minimum 5-year follow-up mean age was 66 years, mean tumor size was. cm (range 0.9 to 5.0), median American Society of Anesthesiologists score was and mean body mass index was 8 kg/m. Five patients had local recurrence, had locoregional recurrence with metastasis and had distant metastasis without locoregional recurrence. Six patients died of cancer. In the 55 patients with biopsy proven renal cell cancer at a median follow-up of 9 months (range 60 to 1) 5-year overall, disease specific and disease-free survival rates were 8%, 9% and 81%, and 10-year rates were 51%, 8% and 78%, respectively. On multivariate analysis previous radical nephrectomy for RCC was the only significant predictor of disease-free and disease specific survival (p 0.0 and 0.00, respectively). Sensitivity, specificity, PPV, NPV, and overall accuracy of contrast-enhanced US were 96.6%, 100%, 100%, 95.8%, and 98.1%, respectively. Contrast-enhanced US is an effective alternative to CT and MRI in the follow-up of renal tumors managed with percutaneous RFA. Page