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Renal cell carcinoma

Renal cell carcinoma. Joby thomas 2002 batch. Epidemiology. RESPONSIBLE FOR 80-85% OF PRIMARY RENAL NEOPLASMS TCC next most common (8%) Incidence increased gradually over past 20 Yrs, probably due to advances in Radiology. Risk factors. Risk factors SMOKING (2 FOLD )

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Renal cell carcinoma

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  1. Renal cell carcinoma Joby thomas 2002 batch

  2. Epidemiology • RESPONSIBLE FOR 80-85% OF PRIMARY RENAL NEOPLASMS • TCC next most common (8%) • Incidence increased gradually over past 20 Yrs, probably due to advances in Radiology

  3. Risk factors • Risk factors • SMOKING (2 FOLD) • POSSIBLY ASBESTOS, CADMIUM OR GASOLINE EXPOSURE (1.4–2 fold) • HTN ? • ACQUIRED CYSTIC DISEASE OF THE KIDNEY (30 fold) • ACKD occurs in 35-50% of chronic dialysis (usually after 8-10 yrs of dialysis)

  4. OTHER RISK FACTORS - GENETIC • VON HIPPEL-LINDAU DISEASE (1/3 get RCC) • Autosomal dominant • Abnormality is in chromosome 3p • HEREDITARY PAPILLARY RCC • Mutated c-met oncogene in chromosome 7p) • TUBEROUS SCLEROSIS (<5%) • Autosomal dominant • 2 loci have been identified • chromosome 9 • chromosome 16p near the gene for the most common form of autosomal dominant polycystic kidney disease (PKD1)

  5. Renal cell carcinoma

  6. Pathology • Five subtypes • CLEAR CELL (75-85%) • Proximal tubule origin • Abnormalities in chromosome 3p • CHROMOPHILIC (15%) • 85% of these are Dx as stage I tumors • Also prox tubule in origin, but 3p is normal • Trisomy 12, 16, 20 can be seen • CHROMOPHOBIC (5%) • ONCOCYTIC (UNCOMMON) – usually not aggressive • Collecting duct origin • 11q13 rearrangements in some cases • COLLECTING DUCT (BELLINI’S DUCT) TUMORS – VERY RARE • Unclassifiable (<3%) – probably has worst prognosis

  7. Pathology – molecular markers • None are routinely used • However proliferation markers (Ki-67, PCNA) and somatic mutations in VHL gene are being explored

  8. Pathogenesis • Role of VHL locus (3p) • VHL is mutated in 57% of sporadic cases • VHL expressed at high levels in kidney and brain • Codes for elongation in B and C • facilitate rate of transcriptional elongation • May also serve to suppress TGF- and TGF- • Transfection of normal VHL into RCC cell lines leads to decrease tumor in mice but no decrease in growth in vitro

  9. Pathogenesis • Absence of VHL  accumulation of hypoxia-induced proteins like VEGF  vascular proliferation  tumorigenesis • P53 mutations are seen (rarely)

  10. Clinical features CLASSIC TRIAD • FLANK PAIN, • HEMATURIA, • PALPABLE ABDOMINAL RENAL MASS, (UNCOMMON) (If present, strongly suggests metastatic disease) • 25% Metastatic At Diagnosis

  11. HEMATURIA(40%) Often with clots ABDOMINAL OR FLANK MASS (more with lower pole tumors) SCROTAL VARICOCELE (mostly L sided) – 11% Obstruction of gonadal vein where it enters the renal vein VENA CAVAL / ATRIAL INVOLVEMENT (5-10%) can produce ascites, hepatic dysfunction, Local extension (liver, pancreas, colon) signs and symptoms….

  12. SITES OF METASTATIC DISEASE • LUNG, • LYMPH NODES, • BONE, • LIVER • BRAIN, • IPSILATERAL ADRENAL, • CONTRALATERAL KIDNEY

  13. Atriocaval involvement

  14. Systemic or paraneoplastic symptoms

  15. Endocrine abnormalities • Erythrocytosis (1-5%) • Mutate VHL protein • Excess erythropoietin production • Excess parathyroid hormone related protein (PTHrP) • Hypercalcemia (15%) • PTHrP, lytic bone lesions, or excess production of IL-6 can all contribute

  16. Pre-surgical evaluation • Diagnosis most often occurs now due to abdominal CT or ultrasound performed for another reason • Ultrasound: can differentiate simple cysts from other lesions with >95% accuracy. If not clearly a cyst  CT. D/Dx mainly RCC, hamartoma, xanthogran pyelo • CT scan: 91% accurate for staging (as compared to stage after surgery) • 98% sens, 96% spec for renal vein invasion • 83% sens, 88% spec for metastatic/ LAD • 46% sens, 98% spec for perinephric invasion • 100% spec for adjacent organ invasion

  17. PRE-SURGICAL EVALUATION (CONT.) • CXR – if no LAD on abdominal CT, otherwise, get chest CT • MRI useful if IVC/ATRIAL involvement suspected and to identify extent of IVC involvement • Bone scan – esp. if >T3a or if nodes • PET scan may be more sensitive for bony mets • Renal arteriography – if nephron sparing approach planned

  18. Staging..

  19. Prognostic factors • INVASION INTO CAVAL WALL • TUMOR THROMBUS EXTENDING ABOVE DIAPHRAGM • FOR PTS WITH ADVANCED DISEASE, OVERALL SURVIVAL IS POOR, BUT CERTAIN FEATURES ARE RELATIVELY FAVORABLE • LONG INTERVAL FROM SURGERY AND METS • SINGLE SITE OF MET DISEASE (ESP IF LUNG) • HIGH LDH, CA >10, ANEMIA, PRIOR CHEMO - ADVERSE

  20. Obtaining tissue • If synchronous lesions – Biopsy of metastatic lesion is preferred • Isolated solid renal mass  resection • Do Partial or complete nephrectomy • Never take needle biopsy from kidney and testis

  21. MANAGEMENT

  22. SURGICAL MANAGEMENT

  23. STAGE I (<7CM) OR STAGE II (>7CM BUT LIMITED TO KIDNEY, NO NODES OR METS) •  Partial or radical nephrectomy • PARTIAL IF • BILATERAL TUMORS • PT WITH SOLITARY KIDNEY • SMALL (4CM) OR TUMOR AT POLE • Laproscopic nephrectomy possible if mass <10cm • Less operative morbidity and shorter hosp stays

  24. Stage III • INVASION INTO ADRENAL OR PERINEPHRIC REGION • NOT BEYOND GEROTA’S FASCIA • ENLARGED NODES IN ABDOMEN (OFTEN INFLAMMATORY AND NOT MALIGNANT) • RENAL VEIN OR IVC INVASION Radical nephrectomy • If IVC involvement above hepatic veins, technically difficult surgery (often requires C-P bypass)

  25. STAGE IV DISEASE • EXTENSION BEYOND GEROTA’S FASCIA • MORE THAN ONE REGIONAL NODE GROUP • FRANK METS NEPHRECTOMY DONE ONLY FOR PALLIATIVE PURPOSES OR AS PART OF AN IMMUNORX TREATMENT PROGRAM (“DEBULKING NEPHRECTOMY”) • Dissection of regional nodes can provide important prognositc information • If microscopic node involvement, 50% 5yr OS

  26. Debulking nephrectomy • Criteria • >75% debulking possible • No CNS, extensive liver or bone mets • Adequate pulmonary and cardiac function • Clear cell histology (if histology is known) • Otherwise, many pts won’t end up getting immunotherapy and benefit of DN will be lost.

  27. METASTATIC DISEASE.. • If single or a few met lesions (esp if lung, bone or ipsi adrenal)  resection can be curative • Resection of residual disease after response to IL-2 appears effective with a 37% 2 yr survival • Path often shows lymphocytic infiltrate around residual tumor, or no residual tumor cells STEREOTACTIC RADIOSURGERY FOR SMALL (<3CM) BRAIN METS • One study looked at pts with avg of 6 lesions • Local control rate of 99% CRYO-ABLATION Possible alternative to surgery Under investigation for small tumors

  28. Medical management • 50% of pts have locally advanced or metastaticdisease at presentation • IN THAT CASE SURGERY ALONE IS NOT CONSIDERED CURATIVE

  29. Medical management • Hormonal Rx • PROGESTINS : • ANDROGENS, ANTIESTROGENS • MEDROXYPROGESTERONE • Prob no benefit except stimulation of appetite

  30. Systemic chemotherapy

  31. Single agent • VINBLASTINE • FLOXURIDINE • Mostly limited responses, rare to see increased survival

  32. COMBINATION CHEMOTHERAPY • GEMCITABINE / 5FU UNCLEAR IF SUPERIOR TO SINGLE AGENT RX • OVERALL, RCC IS CONSIDERED CHEMOTHERAPY RESISTANT, AND NO REGIMEN CAN BE CONSIDERED STANDARD OF CARE AT THIS TIME.

  33. PROXIMAL TUBULE CELLS (SOURCE OF MOST RCC), HAVE HIGH EXPRESSION OF P-GLYCOPROTEIN (MDR) MRNA IN ONE STUDY 6/8 RCC’S AND 4/4 RCC CELL LINES OVEREXPRESSED MDR ATTEMPTS TO USE MDR MODIFIERS LIKE CSA OR PSC 833 HAVE SO FAR BEEN UNREWARDING Reasons for chemo resistance of RCC

  34. IMMUNOTHERAPY

  35. Immunotherapy • Interferon alpha • Often short-lived and/or partial responses Largest study to eval long-term outcome Retrospective review of 463 pts on 6 trials • Median OS 13 months • 14% 2yr PFS

  36. Immunotherapy • No clear benefit to IFN-alpha + vinblastine or 5-FU • IFN-alpha + cis-retinoic acid IFN-alpha at 3-9 MU/d SC +/- cis retinoic acid • 19% vs 10% 2 yr PFS in favor of combination (p=0.05) • IFN-gamma • some studies: no significant activity as monotherapy

  37. COMBINATIoNS IFN alpha + IFN gamma • Promising results in mice • 8-30% resp rates in phase I studies • 11% resp rate with 28% rate of grade IV tox IFN alpha + vinblastine • 16mo vs 9 mo medial survival in one study • 10% resp rate for both in another study • Overall prob no better than IFN alone IFN alpha + floxuridine 33% rate in one small study

  38. INTERLEUKIN-2 • High dose bolus IL-2 + LAK cells • In mid-1980s • Dramatic and durable responses in some pts • Later, IL-2 alone shown to be equivalent • High-dose IL-2 • 600,000 – 720,000 IU/kg q8h up to 14 doses. Repeat q 12 weeks, up to 3 cycles • IN Pts with excellent organ function. • May need ICU monitoring

  39. Immunotherapy – IL-2 • High-dose bolus IL-2 • 14% resp rate 23 months median duration of response • 4% toxic death • rare to relapse after 20 months.

  40. Immunotherapy – IL-2 • Cont infusion IL-2 • Slight decrease in resp rate • No improvement in toxicity • Inhalational Rx • Results confusing, as it was given with SC doses as well • Outpt SC admin • 6% PR rate in one study • 22% PR rate in another

  41. Immunotherapy – IL-2 • Lower dose IL-2 IV therapy • Only 4% resp rate c/w 16% for std dosing and 11% for SC dosing. • Low dose IL-2 and SC dosing had less toxicity • Repeat IL-2 treatement • For pts who respond and then relapse, only 2% will respond to the same IL-2 regimen

  42. MINIMIZING TOXICITY OF IL-2 IL-2 STIMULATES IL-1, TNF ALPHA, IFN GAMMA, NO CO-ADMIN OF L-NMMA (NO INHIBITOR) LED TO IMPROVEMENT IN HYPOTENSION IN ALL PATIENTS WITH IL-2 INDUCED HYPOTENSION

  43. Combinations of IL-2 and IFN gamma • Low dose IL-2 + IFN gamma • Intermediate dose IL-2 + IFN gamma • Low dose IL-2 + IFN gamma + CD8+ TILs • Some studies have shown benefit (often not reproducable) • Data not convincing enough to replace hi-dose bolus IL-2 as std of care

  44. Nonablative stem cell transplantation • Since RCC is very sensitive to immunomodulation, would expect graft versus tumor effect would be possible for RCC

  45. OTHER AGENTS • IL-12: rare responses in phase I trials • Angiogenesis inhibitors • Anti-VEGF Ab’s appear to have some acitivity • Thalidomide: low resp rate, but 56% without progression after 6 or more months • IL-4, IL-6 : minor responses • CCI-779 (mTOR inhibitor), anti-EGF Ab (ABX-EGF)

  46. ANTIGEN PULSED DENDRITIC CELLS vaccination with hybrid cells consisting of autologous tumor and allogeneic dendritic cells Next step is to test DC vaccines + IL-2 or IL-12 to drive the immune response generated ANTI-LYMPHOCYTE RX (EX-VIVO ACTIVATED MEMORY T CELLS) Increase in survival seen Immunotherapy – other

  47. Adjuvant therapy - INTERFERON • IFN alpha-2b, 6MU 3x/week x 6 months • No significant survival advantage

  48. Adjuvant Rx - RADIATION • 3 different studies of post-op XRT • No benefit in 2, some benefit in 1 • However unsophistocated techniques and XRT protocols used, with high (20%) mortality • Studies of pre-op XRT have also been done • No benefits seen, but again each had major flaws

  49. Management Of Paraneoplastic Problems • HYPERCALCEMIA • Pamidronate or zolendronate • These may also alter the bone microenvironment in a way that interrupts tumor growth

  50. Palliative / supportive care • PAIN, BLEEDING • ANALGESIC MEDICATIONS • Radiation to sites of painful mets (esp bone mets) • Angioinfarction (renal artery embolization) • No survival benefit but can relieve symptoms • radiation for cord compression • “CLOT COLIC” • Ureteral stents • Hydration • HYPERCA, FATIGUE, FEVER, DECR APPETITE • Nsaids, bisphosphonates, hydration, appetite stimulants

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