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Ahmed ZeeneldinAssociate professor of Medical Oncology , NCI                    2013
¡   AdenoCA:    §   Clear    §   Papillary    §   Chromophobe    §   Unclassified    §   Sarcomatoid¡   TCC of renal pelvi...
TNM stagingT1: limited to kidney <= 7cm     T1a: <=4cm     T1b: >4-7 cmT2: limited to kidney > 7cm     T2a: 7-10 cm     T2...
¡   H&P:    § PS >1    § Time from Dx to start of systemic therapy <1y¡   Lab:    §   CBC: HB <1N, ANC >1N& Plts>1N    §  ...
§ Local Tx  ▪ Surgery  ▪ Thermal ablation, RFA  ▪ RT: limited role§ Systemic Tx:  ▪ Chemotherapy not in clear cell type  ▪...
Stage            TNM                 Surgery                           RTx                    CTx              Cytokine an...
¡   Surgery    § Thermal ablation    § Surveillance¡   No role for adjuvant RTx or systemic Tx
T1a (<4cm)                         RN             PNNo                                >5000         <2000Death due to RCC ...
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...
T1-3              T4¡   Types of surgery:           M0                PN/RN              CRS    § 1ry : RN or CRS         ...
¡   Resectable Stage IV RCC¡   RR of death decreased by    30%¡   Independent of    § patient performance status,    § the...
OS BENEFIT WAS MOREWITH PS>80%                                   VEGFTx alone   CSR+VEGFTx                      MOS p<0.01...
¡ Indications  § Metastatic (M1)  § Irresectable (T4)  § Recurrent¡ Risk stratification
¡   Memorial Sloan Kettering cancer center (MSKCC):    § for Advanced stages treated with immunotherapy      ▪ INF treated...
INF ERA                                ANTI-VEGF ERA             MSKCC MODEL                              IMRDC (HENG) MOD...
¡ 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  ...
Drug         Route          Dose                  DurationIL-2        IV 15min 600,000 -720,000         q2w X2à q3m X3*(Pr...
IL2                            INFA¡   Hypotension                   ¡   Less than IL-2¡   Cardiac arrhythmia¡   Metabolic...
¡   VEGF pathway    § VEGF Receptor-TKI    § Anti-VEGF mcAb¡   mTOR inhibitors
TKI                  Route Dose           Duration   ToxicitySunitinb (sutent)    PO    50mg qd x 4w   Continuous         ...
PFS: 11 VS 5 M (P <0.001)                OS : 26 M VS 22 M (P0.051)¡   90% had nephrectomy                 Motzer et al, N...
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   ...
Pazopanib   SunitinbNo    557         553PFS   8.4m        9.5m       NSOS    28.4m       29.3m      nsRR    31%         2...
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 a...
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     ...
¡   Hypertension: 25%¡   Renal impairment RR1.36¡   Arterial thromboembolism: 1.4%¡   Thyroid dysfunction¡   Cutaneous tox...
¡   In 25% of patients receiving Sunitinib or    sorafenib¡   Severe in 25% of the 25% i.e. 6%¡   May predict good respons...
Drug                             Route        Dose        Duration      ToxicityTemsorilimus (Torisel)         IV         ...
OS
PFS
PFS: 5VS 2 M (P <0.001)                           OS: 14.8 VS 14.4 M (P = 0.18)Independent prognostic factors for shorter ...
¡   Common: asthenia, rash, anemia, nausea,    and anorexia¡   Hypersensitivity¡   pneumonitis
Regimen         Setting            Therapy                       Options           MSKCC risk:        Sunitinib           ...
¡   Bevacizumab (+erlotinib) x 8 w    §     PFS = 11m    §     OS = 25 m    §     Most was SD¡   Sunitinb 2-3 cycles    § ...
¡   Temsorilimus: No 1¡   TKIs: sorafenib and sunitinb¡   Erlotinib¡   Chemotherapy: Dox-Gem with sarcomatoid    varaints¡...
Stage    TNM      Surgery            RTx         CTx      Cytokine and                                                    ...
Workup     Stage I-III                           Stage IV(T1-3 & N-0r N+, M0)                      (T4 or M1)  Surgery    ...
Systemic Treatment of kidney cancers 1 2013_3
Systemic Treatment of kidney cancers 1 2013_3
Systemic Treatment of kidney cancers 1 2013_3
Systemic Treatment of kidney cancers 1 2013_3
Systemic Treatment of kidney cancers 1 2013_3
Systemic Treatment of kidney cancers 1 2013_3
Systemic Treatment of kidney cancers 1 2013_3
Systemic Treatment of kidney cancers 1 2013_3
Systemic Treatment of kidney cancers 1 2013_3
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

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Systemic Treatment of kidney cancers 1 2013_3

  1. 1. Ahmed ZeeneldinAssociate professor of Medical Oncology , NCI 2013
  2. 2. ¡ AdenoCA: § Clear § Papillary § Chromophobe § Unclassified § Sarcomatoid¡ TCC of renal pelvis¡ Rare tumors¡ Metastatic: lung, ovary, colon, breast
  3. 3. 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
  4. 4. ¡ 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
  5. 5. § 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
  6. 6. 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
  7. 7. ¡ Surgery § Thermal ablation § Surveillance¡ No role for adjuvant RTx or systemic Tx
  8. 8. 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
  9. 9. OS: HR 1.07 (0.89, 1.28) Scherr et al. BMC CANCER; MAR 31, 2011; 11
  10. 10. DFS: HR 1.03 (0.87, 1.21)
  11. 11. ¡ Stage IV categories: § Locally advanced: T4 § Distant: M1¡ Options: § Surgery: § RTx: Bone or Brain mets § Systemic therapy:
  12. 12. 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
  13. 13. ¡ 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.
  14. 14. OS BENEFIT WAS MOREWITH PS>80% VEGFTx alone CSR+VEGFTx MOS p<0.01 9m 20m
  15. 15. ¡ Indications § Metastatic (M1) § Irresectable (T4) § Recurrent¡ Risk stratification
  16. 16. ¡ 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
  17. 17. 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 --------------------------
  18. 18. ¡ Chemotherapy not in clear cell type¡ Cytokines¡ Targeted therapy:
  19. 19. ¡ 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
  20. 20. 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
  21. 21. 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
  22. 22. ¡ VEGF pathway § VEGF Receptor-TKI § Anti-VEGF mcAb¡ mTOR inhibitors
  23. 23. 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
  24. 24. 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
  25. 25. No improvement in PFS in poor risk patinets
  26. 26. ¡ Mainly retrospective data¡ Effectiveness following cytokine therapy¡ effective after soreafenib and vice versa
  27. 27. - 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.
  28. 28. Pazopanib SunitinbNo 557 553PFS 8.4m 9.5m NSOS 28.4m 29.3m nsRR 31% 25% 0.03
  29. 29. No improvement in PFSCross over of INF patients and dose escalation of sorafenib
  30. 30. 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
  31. 31. improvement in PFS (7m vs 5m)Cytokine pretreated: PFS 12m vs 7m Sunitinb pretreated: PFS 5vs 3m
  32. 32. ¡ PFS: ++ (5à8.5 m) OS not mature CALGB trial Brian et al, Clin Oncol 2008; 26:5422-5428
  33. 33. ¡ PFS: ++ (5à10 m, S) OS (21 vs 23m , NS) AVERON trial Brian et al, Clin Oncol 2008; 26:5422-5428
  34. 34. ¡ Subgroup analysis: not poor MSKCC risk AVERON trial Brian et al, Clin Oncol 2008; 26:5422-5428
  35. 35. ¡ TKIs may be used after Avastin¡ Sorafenib after sunitinb: 10%RR¡ Axitinib after sorafenib: 23% RR
  36. 36. 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
  37. 37. ¡ Hypertension: 25%¡ Renal impairment RR1.36¡ Arterial thromboembolism: 1.4%¡ Thyroid dysfunction¡ Cutaneous toxicity : hand foot syndrome¡ Glucose metabolism: hypoglyemia¡ Hepatotoxicity¡ Muscle wasting
  38. 38. ¡ 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
  39. 39. 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
  40. 40. OS
  41. 41. PFS
  42. 42. 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).
  43. 43. ¡ Common: asthenia, rash, anemia, nausea, and anorexia¡ Hypersensitivity¡ pneumonitis
  44. 44. 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
  45. 45. ¡ 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%
  46. 46. ¡ Temsorilimus: No 1¡ TKIs: sorafenib and sunitinb¡ Erlotinib¡ Chemotherapy: Dox-Gem with sarcomatoid varaints¡ Collecting duct: Gem-cis/carbo
  47. 47. 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
  48. 48. 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

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