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Renal Tumors

Renal Tumors. Part II Scott Wilkinson, DO, MS. Treatme nt Pearls. Obstacles Towards Treatment. RCC is historically resistant to many types of treatment Chemotherapy (MDR-1) Radiation Very aggressive in nature (TGF alpha and EGFR) Highly vascular (VEGF secondary to loss of vHL)

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Renal Tumors

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  1. Renal Tumors Part II Scott Wilkinson, DO, MS

  2. Treatment Pearls

  3. Obstacles Towards Treatment • RCC is historically resistant to many types of treatment • Chemotherapy (MDR-1) • Radiation • Very aggressive in nature (TGF alpha and EGFR) • Highly vascular (VEGF secondary to loss of vHL) • Expresses tumor-associated antigens (PRAME, RAGE-1, gp75, and MN-9) which contributes to its immunogenicity

  4. Tx of Localized RCC • Radical nephrectomy • Nephron-sparing surgery (NSS) • NSS with normal opposite kidney • NSS with vHL disease • Thermal ablative therapies • Observation

  5. Radical nephrectomy • Robson and colleagues “gold standard” 1969 • Prototype – A then B, Gerota’s intact, ipsi adrenal, LND (crus to aortic bifurcation) • Now – no adrenal if: no rad evidence unless extensive renal involvement, locally advanced, located upper pole, immediately adjacent to adrenal

  6. Today – LND = controversial • Heme & Lymph spread • Lymphatic drainage variable • <2-3% benefit • However, more accurate staging • Risk factors indicating LND • High tumor grade • Sarcomatoid component • Histologic tumor necrosis • Large size (> 10 cm) • pT3 or pT4 • *incidence 10% with 2 or >, 0.6% if <

  7. Surgical approach determined by size, location of tumor and body habitus • Transperitoneal • Subcostal • thoracoabdominal • Extraperitoneal • Flank • Laparoscopic (trans, retro, hand-assist)

  8. Laparoscopic • Cancer specific survival comparable to open • Usually < 8-10cm; localized with no local invasion, renal vein involvement, or lymphadenopathy

  9. RN Surveillance Stage H/E/labs CXR CTa/p • T1NOMO yearly ---- ---- • T2NOMO yearly yearly q 2 yrs • T3a-cNOMO q 6m x 3 yr - yr same 1yr then q 2 yr • Bone scans, plain xr, and head CT if clinically indicated

  10. Nephron-Sparing Surgery • Czerny 1890 • Vermooten 1950 – NSS • Indications include situations where pt would be anephric or high risk of needing HD • Solitary kidney RCC • Bilateral RCC • Contralateraldz (RAS, Hydro, chronic pyelo, reflux, stones, DM, nephrosclerosis)

  11. A functional remnant of at least 20% of one normal kidney is necessary to avoid end-stage renal failure • IF solitary kidney, > 50% reduction in renal mass = incr risk of hyperfiltration renal injury (proteinuria, focal segmental glomerulosclerosis, progressive renal failure) • Prevention: Protein restriction & ACEI

  12. Preoperative testing • r/o local extension, mets, vascular/collecting system relationship • Renal angio, veno, 3DCT or MRI • Cancer-specific survival rates 78-100% • Recurrence – undetected dz in remnant • Complications – majority hemorrhagic

  13. NSS Surveillance Stage H/E/labs CXR CTa/p • T1NOMO yearly ---- ---- • T2NOMO yearly yearly q 2 yrs • T3NOMO q 6m x 3 yr - yr same q6m x3y –q2yr

  14. NSS with normal opposite kidney • CSS 5yr 100% with small unilat T1-2 • Licht et al 1994 (< 4 cm) • CSS 5 yr central vs peripheral (100 vs 97%), tumor recurrance (5.7 vs 4.5%), renal fxn equivocal • Hafez et al 1999 • Adv: 17-28% excised = benign (MSK)

  15. NSS in vHL disease • Differs via – young age @ dx, usually multiple bilateral tumors • Solid and cystic (lining of hyperplastic clear cells) • Intraop US may help to get all • Options – B/l RN, PN & RN, B/l PN • High incidence of recurrence in remnant 27.4% • Duffey and colleuges 2004 – 3 cm threshold

  16. Thermal ablative • Both perc or lap approach • Lack of histo/path staging • ? High recurrence rate • Ideal – advanced age, comorbidities, local recurrance, hereditary renal cancer • Cryosurgery • Repetition of freeze-thaw cycle (-20C) • Immediate cellular cryodestruction and delayed microcirculatory failure. • Radiofrequency ablation • 45C irreversible cell damage • 55-60C immediate cell death

  17. Thermal Ablative Pearls • In general, enhancement within the tumor bed on extended follow-up has been considered diagnostic of local recurrence, and the clinical experience thus far has supported this

  18. Observation • Median growth rate 0.36 cm/yr • Alternative for asymptomatic elderly and poor surgical risk, consider with solid/small/enhancing/well-marginated/homogeneous • Serial imaging 6mo or 1yr intervals • Not appropriate: >3cm, poor margins, nonhomogeneous, young healthy with abn imaging

  19. Tx of Locally Advanced RCC • IVC involvement • Locally invasive RCC • Local recurrence after RN or NSS • Adjuvant therapy for RCC

  20. IVC Involvement • Unique feature of RCC • 45-70% of RCC with IVC thrombus cured • Local extension/invasion much higher risk of recurrence • Occurs 4-10% of patients • Suspect with : LE edema, R varicocele, distended abd veins, proteinuria, PE, R atrial mass, nonfxn kidney

  21. IVC Thrombus staging • I – adjacent to ostium of renal vein • II – extends up to liver • III – intrahepatic portion of IVC below diaphragm • IV – above the diaphragm • Imaging • ? CT & AUS • Occasional TEE and TA doppler • Contrast inferior venacavography – if prob with MRI • MRI – study of choice • ? Renal arteriography

  22. Locally Invasive RCC • Present with pain from invasion of posterior abd wall, nerve roots or paraspinous muscles • Duodenal & pancreas uncommon • En bloc may be beneficial • Partial / debulking – only 12% alive in 1 yr • Preoperative rad – not beneficial (van derWerf-Messing 1973) • Residual tumor, rad may retard growth (Kao et al 1994)

  23. Local Recurrence after RN or NSS • LR in RN – 2-4% • Risk factors – T stage, local adv, node + disease • LR in NSS – 1.4-10% • Risk factors – T stage • Most LR occur distant to tumor bed • *pts with isolated recurrence after PN can ? Repeat PN

  24. Adjuvant Therapy for RCC • Include hormonal manipulation, radiotherapy, vaccines, cytokines, etc… • Most studies to date – not significant • Vaccine – irradiated tumor cells/BCG, heat shock proteins (HSPPC) = no proven benefit • Interferon alfa – modest survival benefit • IL-2 – no benefit

  25. Tx of Metastatic RCC • Nephrectomy • Hormonal therapy • Chemotherapy • Radiation therapy • Cytokines and Immunologic therapy • Multimodal therapy

  26. Nephrectomy • 1/3rd of RCC have mets • 40-50% will develop mets after initial dx • Regression of mets after RN – 1-2% (lung) • Benefit for synchronous mets with interferon alfa after RN • Individuals with: adv dz (PS > 2), mets (CNS, SC compression), MOD, significant comorbidities – not candidate

  27. Hormone Therapy • Minimal value • Progesterone – inhibit growth of DES-induced renal tumors in Syrian hamsters • No correlation with human RCC • Progestational agents = useful for symptom palliation

  28. Chemotherapy • 1980s – chemo-resistant tumor • Variety of agents RR 6% • Yagoda and assoc 1995 • In past, fluoropyrimidines & vinblastine – RR 2.5% (better with Vin and I-alfa) • Uniformly discouraging • MDR-1 (P-glycoprotein) = efflux pump reducing intracellular [] of agents • ? Role of Ca channel blockers, cyclosporine • Metastatic Non-clear cell or sarcomatoid diff – (doxorubicin & gemcitabine) RR 39% • Anecdotal responses with collecting duct cancers with cisplatin & gemcitabine

  29. Radiation Therapy • Considered as the primary therapy for palliation • Dose of 4500 centigray (cGy) is delivered, with consideration of a boost up to 5500 cGy • Preoperative radiation therapy yields no survival advantage • Palliative radiation therapy often is used for local or symptomatic metastatic disease

  30. Cytokines and Immunologic Therapy • Interferon alfa – protein with antiviral, immunomodulatory and antiproliferative activity • IL-2 – stimulates cell mediated immunity (cytotoxic T cells) • Single agent ORR – 13-15% • Combination > 20%, no change OS • Most effective regimen for IL-2 = high dose • SE – vascular leak (HypoTN, oliguria, organ failure = tx IVF) • *Improved OS with combo (vin, 5-FU, IL-2)

  31. Treatment Multi-kinase inhibitors (VEGF and PDGF) • Sorafenib (Nexavar) – OS 3 months • Dec 2005 FDA - 769 patients randomized • median PFS was 6 mo sorafenib vs. 3 mo placebo • 7 (2%) sorafenib patients and 0 (0%) placebo patients had confirmed partial responses. • Sunitinib (Sutent) • FDA in January 2006 • (40% partial responses) and a median time to progression of 8.7 months and an overall survival of 16.4 months • Bevacizumab (IgG1 monoclonal ab • Time to progression 4.8 mo vs placebo 2.5 mo • Combo with erlotinib – ORR 26% with PFS 11 mo

  32. Multimodal Therapy • Synchronous mets = RN then systemic therapy (IL-2, I-a, kinase inhibitors) • Most = RN first • Alternative – delayed RN and only patients showing regression or stability of mets get surgery • Solitary mets = metatectomy (pulm have more favorable prognosis, > 12mo)

  33. Other Malignant Renal Tumors • Sarcomas of the kidney • Renal lymphoma and leukemia • Metastatic tumors • Other malignant tumors of the kidney

  34. Sarcomas of the kidney • 1-2% of adult malignant tumors • 5th decade • Rapid growth +/- lymphadenopathy • Derived mesenchymal components (free of barriers) • Pseudocapsule • Tx RN with enbloc • Chemo (doxycycline and ifosfamide) have shown some activity • Combo rad / chemo – not well defined for renal

  35. Leiomyosarcoma – most common • 50-60% • Origin – smooth muscle • Female / 4th to 6th decade Liposarcoma – confused with AML • +/- response to rad/cisplatin • Osteogenic sarcoma –Calcium /rock hard *Less common – rhadomyosarcoma, fibrosarcoma, carcinosarcoma, angiosarcoma, malignant hemangiopericytoma (very vascular)

  36. Renal Lymphoma and Leukemia • Found in autopsy of 34% pts with L or L • Renal involvement more common with Non-Hodgins • B symptoms – fever, wt loss, fatigue • Hemedissem – 90% • Suspect with mass RPLA, splenomegaly, LA elsewhere • Renal leukemia more common in children (ALL > AML) • Percbx, chemo +/- rad (CHOP)

  37. Metastatic tumors • Most common malignant tumor of the kidney • Sources – lung, breast, GI, malignant melanoma • Suspect with – multiple renal lesions and widespread mets or a h/o nonrenal primary ca = Bx

  38. Other Malignant Tumors of the Kidney • Carcinoid (neuroedocrine cells) – rare • Correlation with horseshoe kidney • Check urine or plasma serotonin • Minority – carcinoid syndrome (episodic flushing, wheezing, diarrhea) • Surgical exision is mainstay of tx • NSS preferred • Colon/EGD r/o multifocal

  39. Wilm’s • 3% seen in adults • Triphasic • Staging and tx same as for children • Multimodal therapy (surg, chemo, +/- rad) • Prognosis worse in adults

  40. PNET (primitive neuroectodermal tumor) • Related to Ewing’s sarcoma • Derived from neural crest cells • Hist – small round cells (Homer Wright rosettes) • Difficult to differentiate from RCC • Multimodal tx (RN or debulk, chemo, rad)

  41. Small cell carcinoma • Locally advanced or metastatic at presentation • Multimodal tx (RN or debulk with platinum based chemo)

  42. Paraneoplastic Syndromes • Up to 30% of RCC patients • Reversible with tumor resection • If persist after resection, r/o mets • Syndromes • Elevated ESR • Wt loss, cachexia • Fever • Anemia • HTN (increased renin) • Hypercalcemia (PTH like substance • Stauffer’s syndrome • Elevated Alkphos • Polycythemia (incr erythropoietin)

  43. Management of Para-neoplastic Problems • Hypercalcemia • Pamidronate or zolendronate • These may also alter the bone microenvironment in a way that interrupts tumor growth • Inhibits osteoclastic activity • Hydration • Diuretics • Steroids • Calcitonin • Resolve with nephrectomy

  44. Palliative / supportive care • Pain, bleeding • Analgesic medications • XRT to sites of painful mets (esp bone mets) • XRT for cord compression • Arterial embolization • No survival benefit but can relieve Sx • “Clot colic” • Ureteral stents • hydration

  45. References • Wein, Alan J.; et al; Campbell-Walsh Urology, Saunders publishing, 9th edition, chapter 47, pages 1608-37. • Hanno, Philip M.; et al; Clinical Manual of Urology, McGraw-Hill Publishing, 3rd edition, pages 487-502. • Wieder, Jeff A.; Pocket Guide To Urology, Griffith Publishing, 3rd edition, pages 1-20.

  46. Questions

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