Abstract

You have accessJournal of UrologyAUA Guideline1 Aug 2013Follow-up for Clinically Localized Renal Neoplasms: AUA Guidelineis companion ofBalancing Process and Risk: Standardizing Posttreatment Surveillance for Renal Cell Carcinoma Sherri M. Donat, Mireya Diaz, Jay Todd Bishoff, Jonathan A. Coleman, Philipp Dahm, Ithaar H. Derweesh, S. Duke Herrell, Susan Hilton, Eric Jonasch, Daniel W. Lin, Victor E. Reuter, and Sam S. Chang Sherri M. DonatSherri M. Donat , Mireya DiazMireya Diaz , Jay Todd BishoffJay Todd Bishoff , Jonathan A. ColemanJonathan A. Coleman , Philipp DahmPhilipp Dahm , Ithaar H. DerweeshIthaar H. Derweesh , S. Duke HerrellS. Duke Herrell , Susan HiltonSusan Hilton , Eric JonaschEric Jonasch , Daniel W. LinDaniel W. Lin , Victor E. ReuterVictor E. Reuter , and Sam S. ChangSam S. Chang View All Author Informationhttps://doi.org/10.1016/j.juro.2013.04.121AboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Abstract Purpose: The purpose of this guideline is to provide a clinical framework for follow-up of clinically localized renal neoplasms undergoing active surveillance, or following definitive therapy. Materials and Methods: A systematic literature review identified published articles in the English literature between January 1999 and 2011 relevant to key questions specified by the Panel related to kidney neoplasms and their follow-up (imaging, renal function, markers, biopsy, prognosis). Study designs consisting of clinical trials (randomized or not), observational studies (cohort, case-control, case series) and systematic reviews were included. Results: Guideline statements provided guidance for ongoing evaluation of renal function, usefulness of renal biopsy, timing/type of radiographic imaging and formulation of future research initiatives. A lack of studies precluded risk stratification beyond tumor staging; therefore, for the purposes of postoperative surveillance guidelines, patients with localized renal cancers were grouped into strata of low- and moderate- to high-risk for disease recurrence based on pathological tumor stage. Conclusions: Evaluation for patients on active surveillance and following definitive therapy for renal neoplasms should include physical examination, renal function, serum studies and imaging and should be tailored according to recurrence risk, comorbidities and monitoring for treatment sequelae. Expert opinion determined a judicious course of monitoring/surveillance that may change in intensity as surgical/ablative therapies evolve, renal biopsy accuracy improves and more long-term follow-up data are collected. The beneficial impact of careful follow-up will also need critical evaluation as further study is completed. Introduction The purpose of this guideline is to provide a clinical framework for the follow-up for clinically localized renal neoplasms undergoing active surveillance or following definitive surgical or ablative therapy. Hereditary and pediatric kidney cancers were not addressed, although the proportion of adult patients who may harbor a yet unrecognized hereditary form of renal cell carcinoma was considered. Methodology Using a systematic English literature review, 252 articles published between January 1999 and 2011 relevant to key questions specified by the Panel related to kidney neoplasms and their follow-up (imaging, renal function, markers, biopsy, prognosis) were identified. Study designs consisting of clinical trials (randomized or not), observational studies (cohort, case-control, case series) and systematic reviews were included. The guideline statements and accompanying follow-up charts (Appendix 1) were formed based on the literature review. The guideline was distributed to 67 peer reviewers; 39 responded with comments, which were discussed by the Panel and, when deemed appropriate, incorporated into the final draft. The AUA nomenclature system explicitly links statement type to body of evidence strength and the Panel's judgment regarding the balance between benefits and risks/burdens.1 A complete discussion of the methodology and evidence grading is available in the unabridged guideline at www.AUAnet.org/education/guidelines/renal-cancer-follow-up.cfm. Background Followup for adult cancer survivors has traditionally focused on the early detection of a cancer recurrence based on the presumption that treatment of a lower tumor burden would result in better patient outcomes. Essential elements of adult cancer survivorship care now include not only monitoring for cancer recurrence, secondary cancers and treatment effects, but also the prevention of recurrences or new tumors, medical interventions for the consequences of cancer and its treatment effects and the coordination between specialists and primary care physicians to meet survivors' needs.2 Due to the increasing rate of detection and subsequent treatment of small renal masses of uncertain biological potential, the widening spectrum of treatment options with varied treatment related effects and the advent of a new generation of targeted systematic therapy holding the promise of prolonged survival for patients identified with metastatic disease, the Panel took into consideration the various treatment options and their associated survivorship issues in formulating the guideline (Appendix 2). Radiographic Imaging Imaging modalities that play an important role in detecting disease regression, progression, recurrence or metastasis include computerized tomography, magnetic resonance imaging, diagnostic ultrasound, bone scan and plain film chest x-ray. Positron emission tomography scanning with labeled antibody3 is under evaluation for imaging of RCC and may play a role in the future, but it is currently not a standard or recommended diagnostic measure. Due to superior diagnostic accuracy, CT and MRI are used both for detection and characterization of neoplasms suspicious for RCC. The recent attention to radiation dose in CT scanning has stimulated the development of protocols that limit radiation dose without compromising diagnostic image quality; education initiatives on radiation safety/dosing for patients, physicians and radiological technologists;4–7 and led to a more prudent use of CT to clinical indications where the benefit outweighs the risk. Renal Function Assessment Preexisting renal dysfunction has been identified in over 25% of surgically managed patients with small renal masses,8 while the prevalence of chronic kidney disease in the general population has been estimated between 10% and 15%, suggesting that patients with renal tumors may have risk factors contributing to functional renal loss.9 Though the true impact of surgical or ablative therapies on renal function is still being elucidated, the timely identification of post-treatment progressive renal deterioration provides an opportunity for medical intervention aimed at preventing or delaying the progression of CKD.8,10,11 Renal Biopsy Considerations The accuracy of percutaneous biopsy has improved substantially in the last several years due to further refinements in CT and MRI-guided techniques.12 When non-diagnostic biopsies are discarded from analyses, sensitivity for core biopsy compared to fine needle aspiration is 99.5% v. 96.5% and specificity is 99.9% v. 98.9%, respectively.13–25 Given the heterogeneity seen in any given tumor, grading a tumor on an aspirate or core biopsy has not been shown to be reliable. Furthermore, interpretation of biopsies following ablative therapy is difficult due to the often small number of tumor cells present and the post-procedural distortion of the growth pattern and renal architecture. It is, therefore, important for the biopsy to be taken from an enhancing area of the neoplasm avoiding the center of the mass, which is commonly fibrotic. Evaluation of specimen adequacy at the time of biopsy is essential, assuring that sufficient diagnostic material remains for subsequent tumor characterization as it may be more important to perform ancillary studies, such as immunohistochemistry or fluorescent in situ hybridization, to arrive at the correct diagnosis. Comparison of post-treatment biopsy pathology to biopsy material performed prior to the initial ablation may be helpful. The incidence of symptomatic complications is relatively low, with only a very small percentage requiring any form of intervention. Needle-tract seeding, once a common fear of renal biopsy, also appears to be exceedingly rare, with the overall estimated risk of needle tract seeding of less than 0.01%.12,26 Ablation Considerations Thermal ablative techniques are associated with an increased risk of local recurrence compared to extirpative surgery in the current meta-analysis of available literature.27 In addition, the risk assessment for a local recurrent RCC and/or the development of metastatic disease and death from clinical stage T1 RCC after ablative procedures is difficult to ascertain with certainty from the current literature due to the evolving ablative techniques and criteria for ablation, the lack of pretreatment biopsy confirmation of tumor, the lack of long-term follow up, the difficulty in assessing recurrent/residual tumor on biopsy or radiographic imaging, poor quality of reporting and the lack of a uniform definition of a local recurrence. Guideline Statements 1. Patients undergoing follow-up for treated or observed renal masses should undergo a history and physical examination directed at detecting signs and symptoms of metastatic spread or local recurrence. (Clinical Principle) Interval patient history and physical examination are integral parts of medical care and may yield critical information regarding the presence of disease recurrence or adverse events related to treatment effects. Weight loss, night sweats, shortness of breath, dermatologic involvement, adenopathy, musculoskeletal pain or weakness may herald disease progression or developing complication and serve as an indication for further investigation. 2. Patients undergoing follow-up for treated or observed renal masses should undergo basic laboratory testing to include blood urea nitrogen/creatinine, urinalysis and estimated glomerular filtration rate. Other laboratory evaluations, including complete blood count, lactate dehydrogenase, liver function tests, alkaline phosphatase and calcium level, may be used at the discretion of the clinician. (Expert Opinion) LDH has shown prognostic value for patients with advanced disease and is included in several nomograms;28 however, there are no data demonstrating benefit of interval LDH measurements in clinically localized disease to improve detection of metastasis. While elevated pre-operative ALP is a potential prognostic marker for metastatic RCC,29 retrospective reviews do not demonstrate utility of ALP or bone scan in the initial evaluation or follow-up of asymptomatic patients.30 Despite the lack of evidence for the use of these laboratory tests for follow-up of clinically localized RCC, a common sense approach dictates that measures of general organ function are part of routine follow-up for patients with cancer. 3. Patients with progressive renal insufficiency on follow-up laboratory evaluation should be referred to nephrology. (Expert Opinion) The long-term impact of CKD increases risks of osteoporosis, anemia, metabolic and cardiovascular disease, hospitalization and death. Effective treatment strategies are available to slow the progression of CKD and reduce cardiovascular risks and, therefore, timely identification of progressive renal dysfunction can provide opportunity for medical intervention. 4. The Panel recommends a bone scan in patients with an elevated ALP, clinical symptoms such as bone pain, and/or if radiographic findings are suggestive of a bony neoplasm. (Recommendation; Evidence Strength: Grade C) Studies indicate the presence of an elevated ALP or clinical symptoms such as bone pain, raise the probability of metastatic spread to greater than 5% to 10%. Assuming a sensitivity of 94% and a specificity of 86%31 with a pre-test probability of 5%, a negative bone scan would drop the post-test probability below 1%, whereas a positive test would raise the post-test probability to 26%, likely necessitating further diagnostic evaluation; therefore, the benefit to risk/burden ratio favors the performance of a bone scan. 5. The Panel recommends against the performance of a bone scan in the absence of an elevated ALP or clinical symptoms, such as bone pain, or radiographic findings suggestive of a bone neoplasm. (Recommendation; Evidence Strength: Grade C) Studies indicate that in the absence of an elevated ALP or clinical symptoms, such as bone pain, the prevalence of bony metastases is very low (less than 1%); therefore, routine imaging of asymptomatic patients would result in a high rate of false-positive findings necessitating further burdensome, potentially invasive and resource-intensive studies. 6. Patients with a history of a renal neoplasm presenting with acute neurological signs or symptoms must undergo prompt neurological cross-sectional CT or MRI scanning of the head or spine based on localization of symptomatology. (Standard; Evidence Strength: Grade A) This recommendation is based a high diagnostic accuracy of neurological cross-sectional (CT or MRI) imaging to rule in or rule out metastases to the brain and/or spine, in addition to a high prevalence of underlying management-altering pathology in patients with these symptoms. MRI may be more sensitive than CT scan for the detection of small CNS neoplasms.32 7. The Panel recommends against the routine use of molecular markers, such as Ki-67, p-53 and VEGF, as benefits remain unproven at this time. (Recommendation; Evidence Strength: Grade C) None of the current molecular pathological markers, such as Ki-67, p-53 and VEGF, has been prospectively validated in large series of patients; therefore, their utility in routine follow-up of patients is unknown. Surgery: Low-Risk Patients (pT1, N0, Nx) 8. Patients should undergo a baseline abdominal scan (CT or MRI) for nephron-sparing surgery and abdominal imaging (US, CT or MRI) for radical nephrectomy within three to twelve months following renal surgery. (Expert Opinion) Baseline abdominal scanning (CT or MRI) rather than US after nephron-sparing surgery serves as a comparison for future evaluations and may be clinically indicated to monitor for postoperative complications and recurrent disease in both kidneys. Post-radical nephrectomy for low-risk cT1 tumors, a baseline postoperative US may suffice. 9. Additional abdominal imaging (US, CT or MRI) may be performed in patients with low-risk (pT1, N0, Nx) disease following a radical nephrectomy if the initial postoperative baseline image is negative. (Option; Evidence Strength: Grade C) Abdominal imaging (US, CT or MRI) beyond the baseline postoperative evaluation is optional, as the risk of local recurrence (in the renal remnant or the renal fossa) and visceral or nodal metastatic progression is low. 10. Abdominal imaging (US, CT or MRI) may be performed yearly for three years in patients with low-risk (pT1, N0, Nx) disease following a partial nephrectomy based on individual risk factors if the initial postoperative scan is negative. (Option; Evidence Strength: Grade C) Local recurrence rates following nephron-sparing surgery for smaller renal neoplasms is reported in the range of 1.4% to 2%;33,34 however, the risk increases to 10% following nephron-sparing surgery for imperative indications and for larger renal masses.35 Additionally, multicentricity is noted in 10% to 20% of RCC cases, with higher prevalence in papillary and familial RCC for which more frequent monitoring may be considered.36 Therefore, careful attention is needed in patients with higher risk for recurrence (imperative surgical indications, clinical T1b and above, positive margins, higher tumor grade or aberrant histology) or in patients who have perioperative adverse events, which warrant further imaging until resolved. 11. The Panel recommends that patients with a history of low-risk (pT1, N0, Nx) RCC undergo yearly CXR to assess for pulmonary metastases for three years and only as clinically indicated beyond that time period. (Recommendation; Evidence Strength: Grade C) Pulmonary metastases are the most common site of recurrence and are associated with more favorable outcome when the sole site of recurrence and with appropriate treatment. CXR may be preferable to chest CT, given the increased risk of false-positive radiographic findings (intrapulmonary lymph nodes/granulomas) with CT that lead to further testing. Surgery: Moderate- to High-Risk Patients (pT2-4N0 Nx or any stage N+) 12. The Panel recommends that moderate- to high-risk patients undergo baseline chest and abdominal scan (CT or MRI) within three to six months following surgery with continued imaging (US, CXR, CT or MRI) every six months for at least three years and annually thereafter to year five. (Recommendation; Evidence Strength: Grade C) Moderate- to high-risk tumors have a substantially higher risk of both local and metastatic recurrence (approximately 30% to 70%); therefore, for candidates for further therapy to treat a local or metastatic disease recurrence, an increased frequency of examinations is recommended. 13. The Panel recommends site specific imaging as warranted by clinical symptoms suggestive of recurrence or metastatic spread. (Recommendation; Evidence Strength: Grade C) With symptoms attributable to disease recurrence or metastasis, site specific imaging should be obtained and the modality of imaging (CT, MRI, US, bone scan, plain films) tailored accordingly. 14. Imaging (US, CXR, CT or MRI) beyond five years may be performed at the discretion of the clinician for moderate to high-risk patients. (Option; Evidence Strength: Grade C) The type of abdominal imaging utilized should be based on clinical factors and physician discretion, keeping in mind the limitations of US vs MRI or CT in visualizing a recurrence, radiation exposure and the limitations based on contrast allergies or renal function. Most studies show disease relapse is most common within the first three years with a decreasing frequency thereafter. Studies support continued imaging up to five years from surgery;37 however, there is a paucity of data to direct the frequency of imaging (US, CT or MRI) beyond five years. Studies provide recurrence rates for 10 years,38–41 mainly for cancer specific survival, based on stage or risk groups from the available tools in a non-overlapping manner, so overall estimates as those obtained for five years cannot be calculated. Overall, studies enumerating the occurrence of metastases following surgery in terms of location and timing show that (1) metastases to the lung, solitary or in combination with other sites, are the most common and occur at any time between 10 to 20 years,42 (2) the contralateral kidney, bones and brain are other common metastatic sites between 10 and 15 years, (3) even individuals with pT1a disease can experience distant metastases beyond five years42,43 and (4) metastases have been reported beyond 30 to 40 years,44 indicating a possible benefit for some in continued monitoring beyond five years following surgery. 15. Routine FDG-PET scan is not indicated in the follow-up for renal cancer. (Expert Opinion) Currently, there are no data to support the routine use of PET scanning in the follow-up of patients with renal neoplasms due to the lack of data on the specificity and sensitivity, although ongoing studies with newer imaging agents, such as G-250, are under evaluation.3 Active Surveillance 16. Percutaneous biopsy may be considered in patients planning to undergo active surveillance. (Option; Evidence Strength: Grade C) The accuracy of percutaneous biopsy has improved substantially due to refinements in CT and MRI-guided techniques.12 Renal biopsy is not indicated for comorbid patients who may consider only conservative management options regardless of biopsy results or have higher risks of biopsy related complications. Difficult tumor location, cystic characteristics and hemorrhagic necrosis may diminish the contribution of renal biopsy. 17. The Panel recommends that patients undergo cross-sectional abdominal scanning (CT or MRI) within six months of active surveillance initiation to establish a growth rate. The Panel further recommends continued imaging (US, CT or MRI) at least annually thereafter. (Recommendation; Evidence Strength: Grade C) There are limited studies evaluating long-term growth patterns; however, they suggest a linear growth pattern rather than logarithmic growth;45 therefore, obtaining an abdominal scan (CT or MRI) as early as six months from initiation of surveillance will establish the expected growth pattern. Subsequent imaging (US, CT or MRI) can then be performed yearly unless the pace or characteristics of growth are concerning. Importantly, with respect to tumor size measurements, differences of <3.1 mm for inter-observer or <2.3 mm for intra-observer evaluations are within the variability of measurement and should not be attributed to tumor growth,27 unless there are persistent increases over two or more interval exams. Alternative methods for limiting the amount of radiation/contrast exposure include limiting CT use to yearly unless otherwise indicated, using a low-dose radiation CT protocol, using MRI and/or alternating the use of CT or MRI with US for surveillance. The lack of inferiority of ultrasonography in predicting tumor size affords opportunities for reducing ionizing radiation and intravenous contrast exposure, especially in those with CKD.46 These benefits should be weighed against the superiority of CT or MRI to evaluate perirenal or sinus fat invasion and lymph node involvement. The findings of renal biopsy and subsequent neoplasm growth rate should dictate follow-up. RCC, oncocytoma, oncocytic neoplasms and indeterminate histologies should be followed with the same imaging protocols for untreated, low-risk (cT1, N0, Nx) RCC for several reasons. First, oncocytomas, while benign, can exhibit substantial growth over time that may threaten the renal unit. Second, the differentiation between oncocytoma and oncocytic neoplasms (chromophobe RCC) on percutaneous biopsy can present a diagnostic dilemma. Third, chromophobe RCC, in general, has a more indolent natural history, allowing for a lower intensity surveillance protocol.38,47,48 18. The Panel recommends that patients on active surveillance with biopsy proven RCC or a tumor with oncocytic features undergo an annual CXR to assess for pulmonary metastases. (Recommendation; Evidence Strength: Grade C) Although studies indicate a low metastatic rate (1% to 2%) during the first few years of active surveillance, approximately 20% to 30% have potentially aggressive features.27,45 In addition there is a possible ascertainment bias introduced by lack of chest imaging in most surveillance and pT1 surgical series. For biopsy-proven high grade RCC and/or neoplasms displaying rapid interval growth patterns, chest imaging may be performed annually or more frequently based on clinical behavior. Conversely, chest imaging in biopsy-proven benign neoplasms49 may be omitted. Neoplasms with oncocytoma, oncocytic features or indeterminate findings on biopsy should be followed like a low-risk (clinical T1, N0, Nx) RCC. Ablation 19. A urologist should be involved in the clinical management of all patients undergoing renal ablative procedures including percutaneous ablation. (Expert Opinion) The Panel considers urologists to be the experts in the evaluation, management and follow-up of renal neoplasms, RCC and their treatment associated complications and, therefore, should actively partner with interventional radiologists and be involved in the care of the patient whether or not they perform the procedure. 20. The Panel recommends that all patients undergoing ablation procedures for a renal mass undergo a pretreatment diagnostic biopsy. (Recommendation; Evidence Strength: Grade C) A pretreatment diagnostic biopsy (whether benign or malignant) will help refine the post-ablative follow-up, allowing for risk stratification and counseling, reduce the intensity and risks of surveillance in patients with benign tumor histology and prevent empirically labeling a patient as having renal cancer. Conversely, patients without a biopsy or with indeterminate results should be followed as a RCC patient. 21. The standardized definition of "treatment failure or local recurrence" suggested in the Clinical T1 Guideline document should be adopted by clinicians. This should be further clarified to include a visually enlarging neoplasm or new nodularity in the same area of treatment whether determined by enhancement of the neoplasm on post-treatment contrast imaging, or failure of regression in size of the treated lesion over time, new satellite or port site soft tissue nodules or biopsy proven recurrence. (Clinical Principle) Utilization of a standardized definition of failure may reduce delivery of inappropriate follow-up care, help with future comparative outcomes studies and support new knowledge in the understanding of response to ablative treatments. 22. The Panel recommends that patients undergo cross-sectional scanning (CT or MRI) with and without IV contrast unless otherwise contraindicated at three and six months following ablative therapy to assess treatment success. This should be followed by annual abdominal scans (CT or MRI) thereafter for five years. (Recommendation; Evidence Strength: Grade C) Thermal ablative techniques are associated with an increased risk of local recurrence compared to extirpative surgery in current meta-analysis of the available literature.27 The recommendation is based on a 5% to 10% failure rate of ablative therapy, which may be underestimated given the lack of pretreatment histological confirmation in most studies, and the 10% to 30% incidence of benign histology in renal masses under 3 cm in surgical series.27 In addition, high value is placed on the early detection to direct potential re-treatment; therefore, close attention to the overall morphology of the treated neoplasm, with respect to growth/shrinkage, nodularity and contrast enhancement on serial follow-up scanning is advised. 23. Patients may undergo further scanning (CT or MRI) beyond five years based on individual patient risk factors. (Option; Evidence Strength: Grade C) A limitation of the current ablative literature is the dearth of long-term outcomes studies with confirmed histology, attributed to initial ablative series mostly focusing on comorbid elderly patients with poor surgical risks. However, with increasing utilization of ablative modalities in younger patients and the intensity of post-treatment radiographic imaging, longer term follow up will likely become a more significant issue since patients undergoing ablative therapy are monitored with the same clinical principles as RCC patients treated by extirpative modalities of similar size/histology. 24. Patients undergoing ablative procedures who have either biopsy proven low-risk RCC, oncocytoma, a tumor with oncocytic features, non-diagnostic biopsies or no prior biopsy, should undergo annual CXR to assess for pulmonary metastases for five years. Imaging beyond five years is optional based on individual patient risk factors and the determination of treatment success. (Expert Opinion) Although the potential burdens and risks of over-surveillance should be borne in mind, it was the panel's opinion that these patients should be followed with the assumption that the neoplasm is RCC, given the risk of metastatic progression even in clinical T1a renal masses and the yet unknown long-term (five years and beyond) oncological efficacy for ablative procedures. 25. The Panel recommends against further radiological scanning in patients who underwent an ablative procedure with pathological confirmation of benign histology at or before