Surgical Management of Kidney Cancer. Adam R. Metwalli, M.D. Urologic Oncology Branch National Cancer Institute

Transcription

1 Surgical Management of Kidney Cancer Adam R. Metwalli, M.D. Urologic Oncology Branch National Cancer Institute

2 Background Cancer of the Kidney 95% of cases refers to Renal Cell Carcinoma (RCC) 5% refers to Transitional Cell Cancer U.S. Burden of Renal Cell Carcinoma 60,000 U.S. cases / year 13,000 U.S. Deaths/year 271,000 are diagnosed worldwide annually 116,000 deaths worldwide annually There are over 200,000 alive with kidney cancer in the U.S. Ca Cancer J Clin 62:2012 Int J Cancer 127:2010

3 Age-Adjusted Incidence Trends by Race and Sex: to Rate per 100,000 Person-Years 10 Renal Cell Carcinoma Black Male White Male Black Female White Female Year of Diagnosis Chow, et al. JAMA 281:1999

4 Outbreak of Kidney Cancer in the US? Incidence is increasing each year Mortality fairly stable Welch HG, Black WC: Overdiagnosis in cancer. J Natl Cancer Inst :605-13

5 Outbreak of Cross-Sectional Imaging Practitioners ordered unnecessary imaging studies Increase cost Excess radiation exposure incidentally detected cancers Welch HG, Black WC: Overdiagnosis in cancer. J Natl Cancer Inst 102:605-13

6 Changing Pattern of Detection Prior to 1980 s called the internist s tumor Classic Triad- flank pain, abdominal mass, hematuria Other signs and symptoms- fevers, cough, high calcium, high blood count, elevated liver tests, peripheral edema 1980 onwards- major increase in the incidentally detected tumors

7 Changing Pattern of Presentation >7 cm 4-7 cm 2-4 cm <2 cm Hollingsworth JM, Miller DC, Daignault S, et al: Rising incidence of small renal masses: a need to reassess treatment effect. J Natl Cancer Inst 98:1331-4, 2006.

8 Risk Factors Male Sex Obesity Hypertension Smoking Dialysis NSAIDs Hereditary Risk factors*

9 Hereditary Risk Factors Initially thought to only account for 1-2% Characterized kidney cancer syndromes Characterized by multiple tumor types VHL (brain, spine, adrenal, pancreas, kidney) BHD (lung, skin, kidney) HLRCC (skin, uterus, kidney) HPRCC (kidney, skin) Generational Family Study- likely 60% of cases have hereditary component or predisposition

10 Local Treatments Surgery- mainstay of therapy Localized tumors curative in majority of cases radical nephrectomy entailed removal of whole kidney and adrenal gland Can be done traditionally open vs laparoscopic

11 Anatomy Radical Nephrectomy tumor

12 How Much to Remove? Surgical fields have moved towards removal of less normal tissue Partial nephrectomy increasingly utilized Once reserve for bilateral tumors, hereditary conditions, poor renal function Long-term studies show similar outcomes regardless of radical vs partial nephrectomy

13 Anatomy Partial Nephrectomy tumor

14 Partial Nephrectomy Open partial nephrectomy Laparoscopic Partial Nephrectomy Robotic/Laparoscopic Partial Nephrectomy

15 Staging and Prognosis Based on tumor characteristics Size, Invasiveness into surrounding tissues Based on extent of spread Regional spread to nodes Distant spread to other organs (lung, bone, liver, distant nodes)

16 Not All Kidney Tumors are Created Equal

17 Tumor Stage vs Location: Not all tumors are created equal (T1 tumors)

18 Tumor stage: Not all tumors are created equal (T1 vs T2 or greater) 2 cm Mass 30 cm Mass

19 Not all Tumors are created equal: Impact of Histology RCC is a heterogeneous disease Clear cell RCC Papillary RCC (Type 1 and Type 2) Chromophobe RCC Sarcomatoid RCC Collecting Duct Medullary Unclassified

20 Not all Tumors are created equal: Impact of Histology

21 Clear Cell RCC Most common histologic variant (70-80%) Often associated with VHL mutation (90%) Hereditary ccrcc with VHL mutation has shown it is safe to wait until 3cm before operating Grade of tumor also important in prognosis 3 Radiology 174: 1990 J Urol: 153:1995 J Urol 165:2001 J Urol 165:2001 J Urol 172:2004 J Urol

22 VHL: Renal Cell Carcinoma CT Scan: Bilateral, Multifocal RCC VHL Kidney: Multifocal RCC

23 Robotic Assisted Partial Nephrectomy

24 Papillary Renal Carcinoma Type 1 Type 2

25 Papillary RCC Hereditary Leiyomyoma and Renal Cell Cancer (HLRCC) is characterized by papillary RCC type 2 and it is not safe to observe this tumor Metastasis seen with tumors as small as 0.5cc Hereditary Papillary Renal Cancer (HPRC) is characterized by papillary RCC type 1 and is safe to observe to 3cm

26 Hereditary Papillary Renal Carcinoma Type 1 papillary renal carcinoma MET is the HPRC Gene Nature Genetics 16:1997

27 Hereditary Leiomyomatosis Renal Cell Carcinoma: HLRCC Cutaneous leiomyomas Uterine leiomyomas (fibroids) Renal cell carcinoma Fumarate Hydratase Gene Mutation

28 HLRCC: Cutaneous Manifestations

29 HLRCC: Uterine leiomyomas Am J Hum Genet 71:2003

30 HLRCC Kidney Cancer 18 y.o. Female Germline FH Mutation: c.240dupa, NT 110, p.ile81aspfsx14, AA# 38, Exon 1, Frameshift

31 HLRCC Kidney Cancer 21 Year Old Male J Urol:

32 HLRCC Patient 2/22/02 J Urol:

33 HLRCC Kidney Cancer: Papillary Type 2 20X 20X Am J Surg Path 31:2007

34 Surgical Management of HLRCC-Associated Renal Carcinoma 3 33 cm rule Delay surgery until diameter of largest renal tumor = 3 cm Surgical management should NOT be delayed Wide Surgical Margins Mostly Open Procedures Can be bilateral and multifocal Nature CPU 3:2007 J Urol 177:2007

35 HLRCC Tumors In Vivo are Readily Detected by [18]Fluoro-deoxyglucose-based PET Scan

36 HLRCC Retroperitonal Tumor: PET Scan

37 Other Variant Histologies Birt-Hogg-Dube (BHD) is characterized by chromophobe RCC, ccrcc, hybrid tumors and oncocytoma and have proven safe to observe using the 3cm rule Unclassified ccrcc familial syndromes have largely proven safe to observe to 3cm Medullary and Collecting Duct RCC are almost uniformly fatal and observation is not appropriate although surgery is largely futile

38 Birt Hogg Dubé

39 Kidney Tumors in Birt Hogg Dubé

40 Birt Hogg Dubé Renal Tumors Chromophobe RCC Hybrid RCC Clear Cell RCC Oncocytoma

41 Folliculin-FNIP1/2-AMPK Interactions PNAS 103:2006 Gene 415:2008

42 If Histology is So Important: why not biopsy everyone? Renal mass biopsy once verboten now increasing in use Technically difficult procedure Tumor size and location Skill of the physician performing the biopsy Histologic accuracy is good but needs to be better Tumor heterogeneity is a problem Grading of tumors is not reliably accurate

43 Renal Mass Biopsy Only 6% of patients have RMB within 6mos of nephrectomy 5% false positive rate 25% false negative rate More recent data suggests 4.4% false negative rate and 1.2% false positive rate Technical failures not counted as a false negative in this analysis Sensitivity of 80-92%; Specificity of % Dechet et al did ex vivo RMB on surgical specimens with 11-17% non-diagnostic rate Interpretation of biopsy is pathologist dependent 5% minor complication rate; < 1% major complication and <0.1% mortality risk with RMB AVF occurs in 1.5% of cases

44 Summary of Staging

45 AJCC 2010 TNM Staging for RCC Primary tumor (T): TX: Primary tumor cannot be assessed T0: No evidence of primary tumor T1: Tumor 7 cm or less, limited to kidney T1a: Tumor 4cm limited to kidney T1b: Tumor >4cm but <7cm, limited to kidney T2: Tumor greater than 7 cm, limited to kidney T2a: Tumor >7cm but < 10cm confined to kidney T2b: Tumor 10cm, limited to kidney T3: Tumor extends into major veins/adrenal/ perinephric tissue; not beyond Gerota's fascia T3a: Tumor invades adrenal/perinephric fat T3b: Tumor extends into renal vein(s) or vena cava below diaphragm T3c: Tumor extends into vena cava above diaphragm T4: Tumor invades beyond Gerota's fascia (including contiguous extension into the ipsilateral adrenal gland) N - Regional lymph nodes NX: Regional nodes cannot be assessed N0: No regional lymph node metastasis N1: Metastasis in a regional lymph node(s) M - Distant metastasis MX: Distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis AJCC: Kidney. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp

46 All patients should get: T1 Renal Masses Cross sectional imaging w/ & w/o contrast (in presence of adequate renal function) to assess: Tumor size Invasiveness Enhancement Exclude AML Identify relevant anatomy Assess status of contralateral kidney AUA Best Practice Statement Small Renal Masses 2009

47 T1 Renal Masses All patients should also get: Discussion of natural history of these tumors Potential for benign lesions (~20%) Potential for aggressive variant at this size range low Potential role of active surveillance (AS) All pts w/ concern for metastatic disease, lymphoma, abcess, or those undergoing thermal therapy should get percutaneous biopsy Standard of care is consideration of partial Nx in most cases AUA Best Practice Statement Small Renal Masses 2009

48 AUA Best Practice Statement

49 T1 Renal Masses Standard of care is consideration of partial Nx in most cases Is there a predictor for feasibility of partial Nx?

50 Lymph Node Dissection for T1 Tumors Predominant majority of pts T2 disease or less G2 disease or less

51 Lymph Node Dissection for T1 Tumors

52 Limitations Not a risk based protocol Most patients were low risk disease (low grade, low stage) All patients clinically node negative Therefore might not apply to patients w/ high risk disease & clinically positive nodes

53 T2 or Larger Renal Masses Standard of care is radical Nephrectomy, however Some non-randomized studies showing Partial Nx not inferior

54 T2 or Larger Renal Masses 46 Patients w/ tumors > 7cm underwent partial Nx 5 & 10 yr CSS was 94 & 70%

55 T3 RCC T3 tumors have venous invasion/involvement or extension into the peri-renal fat or sinus fat

56 Tumor Thrombus Excision Level I Level II Level IV Level III

57 Level I Tumor Thrombus Into renal vein Almost always can be milked back so that the vein can be taken with a stapler off of the IVC If needed a spoon clamp or satinsky can be used on the edge of the IVC to get around the tumor thrombus. Vein is transected & IVC is sown on free edge of satinsky w/ prolene IVC can be narrowed but minimize as much as possible.

58 Level II Tumor Thrombus Transesophageal Echo utilized to identify level of cephalad extension Adequate cross sectional imaging to determine if thrombus below or above hepatic veins Adequate support from vascular surgeon & hepatobiliary surgeon colleagues

59 Level II Tumor Thrombus Chevron incision most commonly Nephrectomy performed w/ renal artery transection leaving tumor attached by renal vein Adequate cephalad, caudad, & contralateral control. Lumbar veins isolated & transected if possible Cephalad IVC clamped, contralateral vein clamped, and caudal IVC clamped.

60 Level II Tumor Thrombus Anterior cavotomy made & tumor thrombus milked out Usually not attached to IVC wall, if so a patch may need to be performed Inferior IVC occlusion can be transiently removed to flush IVC of fragments or cephalad IVC can be unoccluded with positive pressure from anesthesia to flush backwards. Cavotomy repaired Inferior IVC release, Contralateral renal vein, then cephalad IVC released.

61 Level III & IV Evidence supports resection if patients w/o metastatic disease or extensive locoregional disease CPB or Venovenous bypass may be required

62 Lymph Node Dissection for High Risk Disease

63 Lymph Node Dissection for High Risk Disease Pts high risk if (2 +) Intra-op frozen section Grade 3 or 4 dz Sarcomatoid features Tumor necrosis 10cm or greater Stage T3 or higher

64 Lymph Node Dissection for High Risk Disease Of these high risk pts 38% had + nodes at dissection Also found No skip lesions, in other words no contralateral disease w/o ipsilateral or aortocaval disease Hilar dissection not adequate

65 Lymph Node Dissection for High Risk Disease

66 Limitations 66% of patients had clinically + nodes Therefore this paradigm might not extrapolate to pts w/ occult LN disease Requires intra-op frozen section

67 T4 RCC Invasion into adjacent organs Different from Stage 4 disease which is metastatic distantly Often deemed unresectable and treated with systemic therapy up front Very morbid surgery, many complications Survival is very poor

68 High Risk Patients After Surgery Adjuvant Therapy- aimed at decreasing risk of recurrence after removal of tumor To date no studies have demonstrated a benefit (chemotherapy and immunotherapy) Multiple trials open aimed at high risk patients within 3 months of surgery

69 Distant Disease Most Cancers- once spread outside of primary organ, no role of surgery Kidney cancer- debulking has been mainstay of therapy Cytoreductive Nephrectomy Removal of large primary tumor prior to systemic therapy Local symptom improvement (pain, bleeding) Improved outcome with immunotherapy Still important in this current treatment era

70 Targeting VHL/HIF in Clear Cell RCC VHL Bevacizumab (Antibody) HIF mtor Temsirolimus VEGF PDGF TGF-α Everolimus VEGFR PDGFR EGFR Pazopanib Axitinib Sunitinib Sorafenib

71 Distant Disease- Systemic Therapy New Treatment Era of Kidney Cancer Targeted Kidney Cancer Agents Aimed at Known Biology of Kidney Cancer 6 New Drugs approved in 12/2005 Sorafenib Sunitinib Torisel Avastin Affinitor Votrient -Improved Response Rates -NOT Curative -More Research Needed!!!!!

72 Take Home Messages For low stage RCC, surgery offers excellent 5 year survival rates Survival rates drop precipitously with advanced stage Histology matters and affects clinical decision making Improved staging modalities will enable physicians to better select who will benefit most from surgery Biopsy leaves much to be desired Improved imaging will improve staging

73 Take Home Messages Small renal masses are over-treated with surgery Active Surveillance (AS) is appropriate for many patients but patient selection is critical This is where pathway-based imaging may be key Accurate staging will allow physicians to recommend AS more confidently

74 Thank You

75 Acknowledgements Urologic Oncology Branch, National Cancer Institute, NIH W. Marston Linehan, M.D. Peter A. Pinto, M.D. Piyush K. Agarwal, M.D. Ramaprisad Srinivasan, M.D., Ph.D. Fellows, Residents and Staff

76 Family 166 I 1 2 II III Urologic Oncology Branch National Cancer Institute

77 NIH Clinical Center