Systemic Treatment of kidney cancers 1 2013_3
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Systemic Treatment of kidney cancers 1 2013_3

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Comprehensive overview of systemic treatment of kidney cancers: staging, diagnosis, risk stratification and treatment

Comprehensive overview of systemic treatment of kidney cancers: staging, diagnosis, risk stratification and treatment

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Systemic Treatment of kidney cancers 1 2013_3 Systemic Treatment of kidney cancers 1 2013_3 Presentation Transcript

  • Ahmed ZeeneldinAssociate professor of Medical Oncology , NCI 2013
  • ¡ AdenoCA: § Clear § Papillary § Chromophobe § Unclassified § Sarcomatoid¡ TCC of renal pelvis¡ Rare tumors¡ Metastatic: lung, ovary, colon, breast
  • TNM stagingT1: limited to kidney <= 7cm T1a: <=4cm T1b: >4-7 cmT2: limited to kidney > 7cm T2a: 7-10 cm T2b: >10 cmT3: outside capsule but limited to Gerota’s fascia T3a perinephric fat and limited to Gerota’s fascia, OR RV T3b: infradiaph IVC T3c: supradiaph IVC or IVC wallT4: beyond Gerota’s fascia or into adrenalN1: one + LNM1: mets T1 T2 T3 T4 M1N0 I (95%) II (80%) III (65%) IV (25%) IVN1 III III III IV IV
  • ¡ H&P: § PS >1 § Time from Dx to start of systemic therapy <1y¡ Lab: § CBC: HB <1N, ANC >1N& Plts>1N § KFT & urine § LFT § Others: calcium>10, LDH>1.5N, coagulation profile¡ Imaging: § CT with contrast: CAP § MRI if we cannot use CT e contrast : CAP or to detect IVC invasion § Others if indicated: MRI/CT brain, Bone scan § PET alone : is not standard due to high false positive and negative¡ Needle biopsy: diagnostic and guide surveillance
  • § Local Tx ▪ Surgery ▪ Thermal ablation, RFA ▪ RT: limited role§ Systemic Tx: ▪ Chemotherapy not in clear cell type ▪ Cytokines ▪ Targeted therapy: ▪ VGEF pathway: TKIs, anti-VEGF mcAb ▪ mTORi§ Surveillance ▪ Limited life expectancy ▪ Severe Comorbidities
  • Stage TNM Surgery RTx CTx Cytokine and Targeted therapyI T1: PN*/RN No No No adjuvant <4 cm <7omII T2 RN No No No adjuvant <10 cm >10 cmIII T3 RN No No No adjuvant N1IV T4 RN/CRS/ No** Yes M1 Metastatectomy Bone/brain met * in T1 tumors (up to 7cm) Surveillance may be used in selected cases and thermal ablation if surgically unfit **May be given in non-clear cell histology PN: Partial nephrectomy, RN: radical nephrectomy, CRS: cytoreductive surgery
  • ¡ Surgery § Thermal ablation § Surveillance¡ No role for adjuvant RTx or systemic Tx
  • T1a (<4cm) RN PNNo >5000 <2000Death due to RCC 2% 4%RR of death 1 0.54 (0.34-0.85) Tan et al. JAMA. 2012;307(15):1629-35. T1b-T3 (>4cm) RN PN No 75 35 Overall mortality 11% 11% RCC specific mortality 3% 3% Recurrence 3% 6% (NS) Simmons et al., Urology. 2009;73(5):1077-82
  • OS: HR 1.07 (0.89, 1.28) Scherr et al. BMC CANCER; MAR 31, 2011; 11
  • DFS: HR 1.03 (0.87, 1.21)
  • ¡ Stage IV categories: § Locally advanced: T4 § Distant: M1¡ Options: § Surgery: § RTx: Bone or Brain mets § Systemic therapy:
  • T1-3 T4¡ Types of surgery: M0 PN/RN CRS § 1ry : RN or CRS M1 multiple RN CRS § 2ry: Metastatectomy M1 single* RN + CRS+ metastatectmoy metastatectmoy ▪ Solitary mets: lungs, bone and brain¡ Beneficial for patients treated with: § Cytokines: INF, IL § Targeted therapy¡ More benefit in: § Lung only mets § Good prognostic features (0 score) § Good PS
  • ¡ Resectable Stage IV RCC¡ RR of death decreased by 30%¡ Independent of § patient performance status, § the site of metastases and § the presence of measurable disease. INF INF + alone Surgery MOS (P<0.002) 7.8 m 13.6 m Flanigan et al, N Engl J Med. 2001;345(23):1655-9.
  • OS BENEFIT WAS MOREWITH PS>80% VEGFTx alone CSR+VEGFTx MOS p<0.01 9m 20m
  • ¡ Indications § Metastatic (M1) § Irresectable (T4) § Recurrent¡ Risk stratification
  • ¡ Memorial Sloan Kettering cancer center (MSKCC): § for Advanced stages treated with immunotherapy ▪ INF treated¡ International mRCC Database Consortium (IMRDC) prognostic model or Heng’s model: § For patients treated with anti-VEGF therapy ▪ sunitinib, sorafenib, or bevacizumab plus interferon
  • INF ERA ANTI-VEGF ERA MSKCC MODEL IMRDC (HENG) MODEL1. Clinical 1. Clinical 1. Interval from original 1. Interval from original diagnosis to the start of diagnosis to the start of cytokine therapy < 1 year anti-VEGF therapy < 1year 2. KPS < 80 (ECOG >1) 2. KPS < 80 (ECOG >1)2. Lab: 2. Lab: 1. Calcium (corrected S) > 10 1. Calcium (corrected S) > 10 mg/dl (2.5 mmol/liter) mg/dl (2.5 mmol/liter) 2. HB <1 LLN 2. HB <1 LLN ------ 3. ANC >1x ULN --- 4. Plts > 1x ULN 3. LDH >1.5 ULN --------------------------
  • ¡ Chemotherapy not in clear cell type¡ Cytokines¡ Targeted therapy:
  • ¡ Agents: § IL-2 (not other ILs same results as combinations with LAK) § INF a (not INFγ)¡ Mechanism of action § Poorly understood § Induction of antitumor immunity through direct killing of tumor cells by activated T cells (LAK) and natural killer (NK) cells § INFa also may have antiangiogenic effects¡ May be used in § Goof PS 0-1 § Good organ function § Clear RCC + alveolar features § Better after nephrectomy
  • Drug Route Dose DurationIL-2 IV 15min 600,000 -720,000 q2w X2à q3m X3*(Proleukin) IU/kg q 8h, D1-5 IV or SC 0.1 dose ? X2 q2w à X3 q3m*INFa SC 9 MU 3times q w Continuous(roferon a)IL2 + INFa SC Both: 5MU/sqm ?ContinuousDrug Toxicity RR% CR% RD m PFS m OS mIL-2 +++++ 20 10 19m ~17m ++ 13 Lower ~15mINFa ++ 15 3 <12m 5m ~13m (+4m)IL2 + INFa ++ 10 15m 13m
  • IL2 INFA¡ Hypotension ¡ Less than IL-2¡ Cardiac arrhythmia¡ Metabolic acidosis ¡ Fatigue¡ Fevers/chills ¡ Fever, chills¡ Nausea/vomiting ¡ myalgia¡ Dyspnea ¡ Flu-like¡ Peripheral edema¡ Oliguria, rising creatinine ¡ Nausea¡ Transminase elevations ¡ rash¡ Neurotoxicity¡ Skin rash, pruritus INFa is recommended to be the control arm in future studies
  • ¡ VEGF pathway § VEGF Receptor-TKI § Anti-VEGF mcAb¡ mTOR inhibitors
  • TKI Route Dose Duration ToxicitySunitinb (sutent) PO 50mg qd x 4w Continuous and 2w offPazopanib (Votrient) PO 800 mg qd Continuous LiverAxitinb (Inlyta) PO 5mg BID ContinuousTivozanib (AV 951 ) PO 1.5 mg qd 3w Continuous and 1w offSorafinib (Nexavar) PO 400mg BID ContinuousmcAb Route Dose Duration ToxicityBevacizumab (avastin) + IV 10 mg/kg q2w ContinuousINF
  • PFS: 11 VS 5 M (P <0.001) OS : 26 M VS 22 M (P0.051)¡ 90% had nephrectomy Motzer et al, N Engl J Med 2007;356:115-124.¡ 90% were low or intermediate risk
  • No improvement in PFS in poor risk patinets
  • ¡ Mainly retrospective data¡ Effectiveness following cytokine therapy¡ effective after soreafenib and vice versa
  • - Most patients were low or intermediate risk- OS still immature- PFS all p <0.001 all patinets: 9m vs 4m Tx naieve: 11m vs 3m prior cytokine: 7m vs 4m Cora et al, JCO 2010;28:1061-1068.
  • Pazopanib SunitinbNo 557 553PFS 8.4m 9.5m NSOS 28.4m 29.3m nsRR 31% 25% 0.03
  • No improvement in PFSCross over of INF patients and dose escalation of sorafenib
  • improvement in PFS (6m vs 3m)Cross over of placebo patientsà OS (19 vs 16 m, NS) Can also be used after sunitinb or avastin
  • improvement in PFS (7m vs 5m)Cytokine pretreated: PFS 12m vs 7m Sunitinb pretreated: PFS 5vs 3m
  • ¡ PFS: ++ (5à8.5 m) OS not mature CALGB trial Brian et al, Clin Oncol 2008; 26:5422-5428
  • ¡ PFS: ++ (5à10 m, S) OS (21 vs 23m , NS) AVERON trial Brian et al, Clin Oncol 2008; 26:5422-5428
  • ¡ Subgroup analysis: not poor MSKCC risk AVERON trial Brian et al, Clin Oncol 2008; 26:5422-5428
  • ¡ TKIs may be used after Avastin¡ Sorafenib after sunitinb: 10%RR¡ Axitinib after sorafenib: 23% RR
  • TKI Vs. RR% CR% SD% PFS m OS mSunitinb (sutent) INF 31 vs.6 0 48 vs49 11 vs. 5m 26 vs. 22*Pazopanib (Votrient) Placebo 30 vs 3 9 vs 4 m 23 vs 22 mAxitinb (Inlyta) sorafenib 18 vs 9 27 vs 20 7 vs. 5m ??Tivozanib (AV 951 ) sorafenib 33 vs 23 12 vs 10 m ??Sorafinib (Nexavar) Placebo 5.5 vs. 2.5 m 18 vs 15mmcAb Vs. RR% CR% SD% PFS m OS mBevacizumab (avastin) + INF 31 vs. 13 10 vs 5.5 23 vs 21 mINF
  • ¡ Hypertension: 25%¡ Renal impairment RR1.36¡ Arterial thromboembolism: 1.4%¡ Thyroid dysfunction¡ Cutaneous toxicity : hand foot syndrome¡ Glucose metabolism: hypoglyemia¡ Hepatotoxicity¡ Muscle wasting
  • ¡ In 25% of patients receiving Sunitinib or sorafenib¡ Severe in 25% of the 25% i.e. 6%¡ May predict good response to TKI HT NO HT RR 55% (x5) 10% PFS 13m (X5) 3m OS 31m (x5) 7m
  • Drug Route Dose Duration ToxicityTemsorilimus (Torisel) IV 15mg q w ContinuousEverolimus (Afinitor) PO 10 mg qd ContinuousDrug Vs. RR% CR% SD% PFS m OS mTemsorilimus (Torrisel) INF 6m vs 3m 11 vs 7msEverolimus (Affinitor) placebo 1vs 0 63 vs 32 5m vs 2 m 15 vs 14.s m
  • OS
  • PFS
  • PFS: 5VS 2 M (P <0.001) OS: 14.8 VS 14.4 M (P = 0.18)Independent prognostic factors for shorter OS Cross overlow performance status, high corrected calcium,low hemoglobin, and prior sunitinib (P < .01).
  • ¡ Common: asthenia, rash, anemia, nausea, and anorexia¡ Hypersensitivity¡ pneumonitis
  • Regimen Setting Therapy Options MSKCC risk: Sunitinib High-dose IL-2 Good (0) or pazopanib1st line intermediate (1-2) bevacizumab + IFN-α MSKCC risk: Temsirolimus Sunitinib Poor (>2) Cytokine- Sorafenib Temsirolimus refractory Sunitinib bevacizumab pazopanib2nd line Sequential TKIs (Sorafenib, Sunitinib TKI Refractory Everolimus pazopanib) or Bevacizumab Temsirolimus mTOR inhibitors TKI Bevacizumab
  • ¡ Bevacizumab (+erlotinib) x 8 w § PFS = 11m § OS = 25 m § Most was SD¡ Sunitinb 2-3 cycles § PR: 6% § Tumor necrosis was common § PFS: 8m¡ Sorafenib 33 days § Shrinkage by 10%
  • ¡ Temsorilimus: No 1¡ TKIs: sorafenib and sunitinb¡ Erlotinib¡ Chemotherapy: Dox-Gem with sarcomatoid varaints¡ Collecting duct: Gem-cis/carbo
  • Stage TNM Surgery RTx CTx Cytokine and Targeted therapyI T1 PN*/RN No No No adjuvantII T2 RN No No No adjuvantIII T3 RN No No No adjuvant N1IV T4 RN/CRS/ No** Yes-à M1 Metastatectomy Bone/brain met risk stratification
  • Workup Stage I-III Stage IV(T1-3 & N-0r N+, M0) (T4 or M1) Surgery Surgery Systemic therapy (PN, RN) (RN, CRN, met’my (Cytokines, VGEF targeted, mTORi) Good risk Intermediate risk IL-2 Poor risk Sunitinib Sunitinib temsorilimus Pazopanib Pazopanib ?everolimus INF-bevaciz INF-bevaciz