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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

Renal Tumors

Part II

Scott Wilkinson, DO, MS


Treatme nt pearls

Treatment Pearls


Obstacles towards treatment
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


Tx of localized rcc
Tx of Localized RCC

  • Radical nephrectomy

  • Nephron-sparing surgery (NSS)

  • NSS with normal opposite kidney

  • NSS with vHL disease

  • Thermal ablative therapies

  • Observation


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


  • 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 <



  • Laparoscopic body

    • Cancer specific survival comparable to open

    • Usually < 8-10cm; localized with no local invasion, renal vein involvement, or lymphadenopathy


Rn surveillance
RN Surveillance body

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


Nephron body -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)


  • 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


  • Preoperative testing necessary to avoid end-stage renal failure

    • 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


Nss surveillance
NSS Surveillance necessary to avoid end-stage renal failure

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


NSS with normal opposite kidney necessary to avoid end-stage renal failure

  • 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)


NSS in necessary to avoid end-stage renal failurevHL 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


Thermal ablative necessary to avoid end-stage renal failure

  • 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


    • Thermal Ablative Pearls necessary to avoid end-stage renal failure

      • 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


    Observation necessary to avoid end-stage renal failure

    • 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


    Tx of locally advanced rcc
    Tx necessary to avoid end-stage renal failure of Locally Advanced RCC

    • IVC involvement

    • Locally invasive RCC

    • Local recurrence after RN or NSS

    • Adjuvant therapy for RCC


    IVC Involvement necessary to avoid end-stage renal failure

    • 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


    • IVC Thrombus staging necessary to avoid end-stage renal failure

      • 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


    • Locally Invasive RCC necessary to avoid end-stage renal failure

      • 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)


    Local Recurrence after RN or NSS necessary to avoid end-stage renal failure

    • 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


    Adjuvant Therapy for RCC necessary to avoid end-stage renal failure

    • 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


    Tx of metastatic rcc
    Tx necessary to avoid end-stage renal failure of Metastatic RCC

    • Nephrectomy

    • Hormonal therapy

    • Chemotherapy

    • Radiation therapy

    • Cytokines and Immunologic therapy

    • Multimodal therapy


    Nephrectomy necessary to avoid end-stage renal failure

    • 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


    Hormone Therapy necessary to avoid end-stage renal failure

    • Minimal value

      • Progesterone – inhibit growth of DES-induced renal tumors in Syrian hamsters

        • No correlation with human RCC

    • Progestational agents = useful for symptom palliation


    Chemotherapy necessary to avoid end-stage renal failure

    • 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


    Radiation Therapy necessary to avoid end-stage renal failure

    • 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


    Cytokines and Immunologic Therapy necessary to avoid end-stage renal failure

    • 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)


  • Treatment
    Treatment necessary to avoid end-stage renal failure

    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


    Multimodal Therapy necessary to avoid end-stage renal failure

    • 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)


    Other malignant renal tumors
    Other Malignant Renal Tumors necessary to avoid end-stage renal failure

    • Sarcomas of the kidney

    • Renal lymphoma and leukemia

    • Metastatic tumors

    • Other malignant tumors of the kidney


    Sarcomas of the kidney necessary to avoid end-stage renal failure

    • 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


    Leiomyosarcoma necessary to avoid end-stage renal failure – 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)


    Renal Lymphoma and Leukemia necessary to avoid end-stage renal failure

    • 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)


    Metastatic tumors necessary to avoid end-stage renal failure

    • 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


    Other Malignant Tumors of the Kidney necessary to avoid end-stage renal failure

    • 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


    • Wilm’s necessary to avoid end-stage renal failure

      • 3% seen in adults

      • Triphasic

      • Staging and tx same as for children

      • Multimodal therapy (surg, chemo, +/- rad)

      • Prognosis worse in adults


    PNET (primitive necessary to avoid end-stage renal failureneuroectodermal 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)


    Small cell carcinoma necessary to avoid end-stage renal failure

    • Locally advanced or metastatic at presentation

    • Multimodal tx (RN or debulk with platinum based chemo)


    Paraneoplastic syndromes
    Paraneoplastic necessary to avoid end-stage renal failure 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)


    Management of para neoplastic problems
    Management of Para- necessary to avoid end-stage renal failureneoplastic 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


    Palliative supportive care
    Palliative / supportive care necessary to avoid end-stage renal failure

    • 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


    References
    References necessary to avoid end-stage renal failure

    • 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.


    Questions

    Questions necessary to avoid end-stage renal failure


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