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Renal Tumors Part II Scott Wilkinson, DO, MS. Treatment Pearls.

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

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

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

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

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

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

9 RN Surveillance StageH/E/labsCXRCTa/p T1NOMO yearly T1NOMO yearly T2NOMO yearly yearly q 2 yrs T2NOMO yearly yearly q 2 yrs T3a-cNOMOq 6m x 3 yr - yr same 1yr then q 2 yr T3a-cNOMOq 6m x 3 yr - yr same 1yr then q 2 yr Bone scans, plain xr, and head CT if clinically indicated Bone scans, plain xr, and head CT if clinically indicated

10 Nephron-Sparing Surgery Czerny 1890 Czerny 1890 Vermooten 1950 – NSS Vermooten 1950 – NSS Indications include situations where pt would be anephric or high risk of needing HD Indications include situations where pt would be anephric or high risk of needing HD Solitary kidney RCC Solitary kidney RCC Bilateral RCC Bilateral RCC Contralateral dz (RAS, Hydro, chronic pyelo, reflux, stones, DM, nephrosclerosis) Contralateral dz (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 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) 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 Prevention: Protein restriction & ACEI

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

13 NSS Surveillance StageH/E/labsCXRCTa/p T1NOMO yearly T1NOMO yearly T2NOMO yearly yearly q 2 yrs T2NOMO yearly yearly q 2 yrs T3NOMOq 6m x 3 yr - yr same q6m x3y –q2yr T3NOMOq 6m x 3 yr - yr same q6m x3y –q2yr

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

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

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

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

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

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

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

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

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

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

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

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

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

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

29 Radiation Therapy Considered as the primary therapy for palliation Considered as the primary therapy for palliation Dose of 4500 centigray (cGy) is delivered, with consideration of a boost up to 5500 cGy Dose of 4500 centigray (cGy) is delivered, with consideration of a boost up to 5500 cGy Preoperative radiation therapy yields no survival advantage Preoperative radiation therapy yields no survival advantage Palliative radiation therapy often is used for local or symptomatic metastatic disease 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 Interferon alfa – protein with antiviral, immunomodulatory and antiproliferative activity IL-2 – stimulates cell mediated immunity (cytotoxic T cells) IL-2 – stimulates cell mediated immunity (cytotoxic T cells) Single agent ORR – 13-15% Single agent ORR – 13-15% Combination > 20%, no change OS Combination > 20%, no change OS Most effective regimen for IL-2 = high dose Most effective regimen for IL-2 = high dose SE – vascular leak (HypoTN, oliguria, organ failure = tx IVF) SE – vascular leak (HypoTN, oliguria, organ failure = tx IVF) *Improved OS with combo (vin, 5-FU, IL-2) *Improved OS with combo (vin, 5-FU, IL-2)

31 Treatment Multi-kinase inhibitors (VEGF and PDGF) Sorafenib (Nexavar) – OS 3 months Sorafenib (Nexavar) – OS 3 months Dec 2005 FDA patients randomized Dec 2005 FDA patients randomized median PFS was 6 mo sorafenib vs. 3 mo placebo median PFS was 6 mo sorafenib vs. 3 mo placebo 7 (2%) sorafenib patients and 0 (0%) placebo patients had confirmed partial responses. 7 (2%) sorafenib patients and 0 (0%) placebo patients had confirmed partial responses. Sunitinib (Sutent) Sunitinib (Sutent) FDA in January 2006 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 (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 Bevacizumab (IgG1 monoclonal ab Time to progression 4.8 mo vs placebo 2.5 mo Time to progression 4.8 mo vs placebo 2.5 mo Combo with erlotinib – ORR 26% with PFS 11 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) Synchronous mets = RN then systemic therapy (IL-2, I-a, kinase inhibitors) Most = RN first Most = RN first Alternative – delayed RN and only patients showing regression or stability of mets get surgery Alternative – delayed RN and only patients showing regression or stability of mets get surgery Solitary mets = metatectomy (pulm have more favorable prognosis, > 12mo) Solitary mets = metatectomy (pulm have more favorable prognosis, > 12mo)

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

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

35 Leiomyosarcoma – most common 50-60% 50-60% Origin – smooth muscle Origin – smooth muscle Female / 4 th to 6 th decade Female / 4 th to 6 th decade Liposarcoma – confused with AML +/- response to rad/cisplatin +/- response to rad/cisplatin Osteogenic sarcoma –Calcium /rock hard 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 Found in autopsy of 34% pts with L or L Renal involvement more common with Non-Hodgins Renal involvement more common with Non-Hodgins B symptoms – fever, wt loss, fatigue B symptoms – fever, wt loss, fatigue Heme dissem – 90% Heme dissem – 90% Suspect with mass RPLA, splenomegaly, LA elsewhere Suspect with mass RPLA, splenomegaly, LA elsewhere Renal leukemia more common in children (ALL > AML) Renal leukemia more common in children (ALL > AML) Perc bx, chemo +/- rad (CHOP) Perc bx, chemo +/- rad (CHOP)

37 Metastatic tumors Most common malignant tumor of the kidney Most common malignant tumor of the kidney Sources – lung, breast, GI, malignant melanoma Sources – lung, breast, GI, malignant melanoma Suspect with – multiple renal lesions and widespread mets or a h/o nonrenal primary ca = Bx 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 Carcinoid (neuroedocrine cells) – rare Correlation with horseshoe kidney Correlation with horseshoe kidney Check urine or plasma serotonin Check urine or plasma serotonin Minority – carcinoid syndrome (episodic flushing, wheezing, diarrhea) Minority – carcinoid syndrome (episodic flushing, wheezing, diarrhea) Surgical exision is mainstay of tx Surgical exision is mainstay of tx NSS preferred NSS preferred Colon/EGD r/o multifocal Colon/EGD r/o multifocal

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

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

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

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

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

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

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

46 Questions


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