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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

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
slide5

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
slide6

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 <
slide7

Surgical approach determined by size, location of tumor and body habitus

  • Transperitoneal
    • Subcostal
    • thoracoabdominal
  • Extraperitoneal
    • Flank
  • Laparoscopic (trans, retro, hand-assist)
slide8

Laparoscopic

    • Cancer specific survival comparable to open
    • Usually < 8-10cm; localized with no local invasion, renal vein involvement, or lymphadenopathy
rn surveillance
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
slide10

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)
slide11

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
slide12

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
nss surveillance
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
slide14

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)
slide15

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
slide16

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
slide17

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
slide18

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
tx of locally advanced rcc
Tx of Locally Advanced RCC
  • IVC involvement
  • Locally invasive RCC
  • Local recurrence after RN or NSS
  • Adjuvant therapy for RCC
slide20

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
slide21

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
slide22

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)
slide23

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
slide24

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
tx of metastatic rcc
Tx of Metastatic RCC
  • Nephrectomy
  • Hormonal therapy
  • Chemotherapy
  • Radiation therapy
  • Cytokines and Immunologic therapy
  • Multimodal therapy
slide26

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
slide27

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
slide28

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
slide29

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
slide30

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)
treatment
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
slide32

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)
other malignant renal tumors
Other Malignant Renal Tumors
  • Sarcomas of the kidney
  • Renal lymphoma and leukemia
  • Metastatic tumors
  • Other malignant tumors of the kidney
slide34

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
slide35

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)

slide36

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)
slide37

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
slide38

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
slide39

Wilm’s

    • 3% seen in adults
    • Triphasic
    • Staging and tx same as for children
    • Multimodal therapy (surg, chemo, +/- rad)
    • Prognosis worse in adults
slide40

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)
slide41

Small cell carcinoma

  • Locally advanced or metastatic at presentation
  • Multimodal tx (RN or debulk with platinum based chemo)
paraneoplastic syndromes
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)
management of para neoplastic problems
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
palliative supportive care
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
references
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.
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