Metastatic Renal Cell Carcinoma by yaoyufang

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									The Ever-Changing Landscape

  Daniel Heng MD MPH FRCPC
           University of Calgary
Outline
 Staging
 Genetics behind RCC
 Treatment of metastatic disease
     Case
     Prognostic Factors
     Mechanisms of Resistance
   Cytoreductive nephrectomy
Staging




          Cohen et al NEJM 2004
Von Hippel Lindau
      VHL               HIF1a




                    Ub
                     Ub
                       Ub
                        Ub




      Proteosome
      Degradation
         Of HIF1a




                         Courtesy sppider.cchmc.org & www.bme.jhu.edu
Von Hippel Lindau
      VHL           HIF1a




                        Transcription of Genes
                        Associated with
                        Angiogenesis and
                        Proliferation
Angiogenesis and Proliferation
 VEGF                  TGFa/B/                PDGF

 VEGFR                 EGFR                   PDGFR

        Angiogenesis     Cell Proliferation   Endothelial Stabilization




                                                              Cohen et al NEJM 2005
Von Hippel Lindau
   75-80% of sporadic clear cell RCCs
    have VHL defect:
     Frameshift / truncation mutation
     Deletion
     Promoter methylation


                           CH3



                          Promoter        Von Hippel Lindau Gene
                                     Transcription


                                                      Cohen et al NEJM 2005
Targeted Therapies:
The Revolution




                      Courtesy AZ
Targeted Therapy in mRCC
   VEGF inhibitors      mTOR inhibitors
     Sunitinib            Temsirolimus
     Sorafenib            Everolimus
     Bevacizumab
     Pazopanib
     Axitinib
Targets and Inhibitors




                         Rini et al JCO 2005, 2009
            Treatment of mRCC: 2011
  Setting          Patients            Therapy         Other Options
                                  (level 1 evidence) (>level 1 evidence)

Untreated     Good or             Sunitinib          HD IL-2
              intermediate risk   Bevacizumab+IFN    Sorafenib
                                  Pazopanib          Clinical Trial
                                                     Observation
              Poor risk           Temsirolimus       Sunitinib
                                                     Clinical Trial
Second-line   Cytokine            Axitinib           Sunitinib
              refractory          Sorafenib          Bevacizumab+IFN

              Prior VEGF          Axitinib           Targeted therapy
                                  Everolimus         not previously used
                                  Clinical Trial
Case I: JN
•   60F otherwise healthy
•   Had abdominal discomfort so abdominal
    ultrasound was ordered
•   7x5 cm central mass in right kidney
    incidentally detected
•   pT3a N0 M0 clear cell renal cell carcinoma
    resected by laparoscopic right radical
    nephrectomy
•   Staging CT scans revealed no other
    metastases
Case I: JN
   Standard of care would be CT scans of
    the abdomen and pelvis with chest x-ray
     every 6 months for first 2 years
     yearly thereafter
   Because of 50% chance of recurrence,
    was offered adjuvant clinical trial
     REC2 clinical trial
      ○ One year of sunitinib, sorafenib, or placebo
Case I: JN
   Consented to ASSURE clinical trial
     Had no side effects whatsoever … was she
      on placebo?
     6 month CT scan clear
     12 month CT scan
     ○ Multiple pulmonary metastases bilaterally max
       2 cm
     ○ Liver metastases
Case I: JN
Case I: JN
 She now has metastatic disease
 Her calcium, LDH, neutrophils, platelets
  are within normal range, ECOG 0
 Her hemoglobin is low at 100

What is her Prognostic Category?

1) Favorable risk – median OS 44 months
2) Intermediate risk – median OS 21 months
3) Poor risk – median OS 8 months
  Intl mRCC Database Consortium:
  Independent Predictors of Poor OS
                      KPS < 80
                 Dx to Tx Interval <1yr
                       Anemia
                       Hypercalcemia
                        Neutrophilia
                      Thrombocytosis
Heng et al JCO 2009
Prognostic Factors
If patient has 0 factors:
Favorable Prognosis

If patient has 1-2 factors:
Intermediate Prognosis

If patient has 3-6 factors:
Poor Prognosis
Overall Survival in the New Era



                              Favorable: 0 factors
                                   (mOS 44 mos)

                          Intermediate: 1-2 factors
                                    (mOS 21 mos)


                                 Poor: 3-6 factors
             p<0.0001               (mOS 8 mos)



Heng et al
ASCO 2011
Case I: JN
    She has intermediate risk criteria due to
     anemia

     What first line targeted therapy would you
                       choose?

1)Sunitinib
2)Temsirolimus
3)Everolimus
4)Interferon
5)High dose IL-2
Sunitinib PFS




                Motzer et al NEJM 2007
 Pazopanib PFS




Sternberg et al..J Clin Oncol 2010; 28: 1061-1068.
Bevacizumab+IFN
    AVOREN Phase III Trial

                                           IFN-α2b SC

        Met clear cell
        RCC
        Treatment naive
                                           IFN-α2b SC +
                                           Bevacizumab IV



Progression free survival benefit (10.2 vs. 5.4 months p<0.0001)
No OS benefit due to crossover
Temsirolimus
               Overall Survival Benefit
               TEMSR vs IFN log rank p=0.0069
               PFS 3.7 vs. 1.9 months
               mOS 10.9 vs. 7.3 months




                                       Hudes et al NEJM 2007
Sorafenib PFS
      Progression-free Survival
                                                         Improved with Sorafenib
                                              1.00
      Probability of Being Progression-free




                                                                              Sorafenib (n = 451) = 5.5 months
                                              0.75                            Placebo (n = 452) = 2.8 months
                                                                              Hazard ratio = 0.51; P < 0.001

                                              0.50




                                              0.25




                                              0.00
                                                     0   2   4    6     8    10   12     14     16    18       20
                                                             Time from Randomization (Months)
 * Based on investigator assessment

 Escudier B, Eisen T, Stadler WM, et al. N Engl J Med. 2007;356:125-134.                                               47

                                                                                                     Escudier et al NEJM 2007
              Treatment of mRCC: 2011
  Setting          Patients            Therapy         Other Options
                                  (level 1 evidence) (>level 1 evidence)

Untreated     Good or             Sunitinib          HD IL-2
              intermediate risk   Bevacizumab+IFN    Sorafenib
                                  Pazopanib          Clinical Trial
                                                     Observation
              Poor risk           Temsirolimus       Sunitinib
                                                     Clinical Trial
Second-line   Cytokine            Axitinib           Sunitinib
              refractory          Sorafenib          Bevacizumab+IFN

              Prior VEGF          Axitinib           Targeted therapy
                                  Everolimus         not previously used
                                  Clinical Trial
Case I: JN
• She chooses to be on sunitinib
• She is dosed at the standard 50 mg 4
  weeks on and 2 weeks off
• Her baseline assessments included
    – CT scan of the chest, abdomen, pelvis
    – Bone scan (normal)
    – CBC, liver function tests, creatinine, baseline
      TSH
    – MUGA/echo only in patients with prior history of
      cardiac disease or significant risk factors
Case I: JN
•   She is followed with CT scans every 3
    months (every 2 cycles)
    – 3 month CT: 19% tumor reduction
    – 6 month CT: stable disease from previous
    – 9 month CT: stable disease from previous
•   At 11 months:
    –   She develops significant anemia (Hb 88)
    –   She is tired, symptomatic of anemia
    –   Had syncopal episode
    –   She requires a transfusion of 2 units PRBC
Case I: JN
• Sunitinib was held for 4 weeks but counts
  did not recover, required blood transfusions
  every 3 days
• Became neutropenic despite not being on
  any drug
• Considered bone marrow infiltration of
  RCC
    – Bone marrow biopsy could not confirm this
      (sampling error)
    – Decided that this was progressive disease and
      needed new line of therapy
Mechanisms of Resistance
Mechanisms of Resistance
1)   Angiogenic redundancy
     –   PDGF, FGF, PIGF


2)   Intratumoral hypoxia induces redundancy
     factors




                                Grepin R et al J Oncology 2010
Mechanisms of Resistance
3) Natural selection of more invasive tumor
  cells




                               Grepin R et al J Oncology 2010
Mechanisms of Resistance
4) Recruitment of bone marrow derived
   proangiogenic and inflammatory cells
  – IL-6, GCSF recruitment


5) Targeted endothelial cells can recruit
  pericytes to protect them and release
  PDGF

6) Vessel cooption: smaller, new tumors
  develop around normal blood vessels

                                  Grepin R et al J Oncology 2010
     Everolimus: Progression-Free Survival
     Central Radiology Review
                        100



                         80                                                         Hazard ratio = 0.30
                                                                                    95% CI [0.22, 0.40]

                                                                                    Median PFS
                         60
                                                                                    Everolimus: 4.0 mo
       Probability, %




                                                                                    Placebo: 1.9 mo
                         40                                                         Log rank P value <0.001
                                                                                           RAD001 (n=272)
                                                                                           Placebo (n=138)

                         20



                          0

                              0               2                   4       6     8                10           12
                                                                       Months
Patients at Risk
 Everolimus                   272             132                 47       8    2                     0            0
 Placebo                      138             32                   4       1    0                     0            0



      Motzer R, Escudier B, Oudard S et al. LBA 5026 ASCO 2008.
       Axitinib Progression-free Survival
       (IRC Assessment)
        Progression-Free Survival (probability)
                                                                                                       mPFS, mo        95% CI
                                                  1.0
                                                                                              Axitinib      6.7       6.3–8.6
                                                  0.9                                         Sorafenib     4.7       4.6–5.6
                                                  0.8
                                                                                                       P<0.0001 (log-rank)
                                                  0.7                                                  Stratified HR 0.665
                                                  0.6                                                  (95% CI 0.544–0.812)
                                                  0.5
                                                  0.4
                                                  0.3
                                                  0.2
                                                  0.1
                                                  0.0
                                                        0   2     4     6     8    10   12        14       16     18      20
                                                                              Time (months)
Subjects at risk, n
          Axitinib 361                                      256   202   145   96   64    38       20       10     1        0
        Sorafenib 362                                       224   157   100   51   28    12        6        3     1        0

IRC = Independent Review Committee
                                                                                                          Rini et al ASCO 2011
              Treatment of mRCC: 2011
  Setting          Patients            Therapy         Other Options
                                  (level 1 evidence) (>level 1 evidence)

Untreated     Good or             Sunitinib          HD IL-2
              intermediate risk   Bevacizumab+IFN    Sorafenib
                                  Pazopanib          Clinical Trial
                                                     Observation
              Poor risk           Temsirolimus       Sunitinib
                                                     Clinical Trial
Second-line   Cytokine            Axitinib           Sunitinib
              refractory          Sorafenib          Bevacizumab+IFN

              Prior VEGF          Axitinib           Targeted therapy
                                  Everolimus         not previously used
                                  Clinical Trial
Case I: JN
•   Began Everolimus 10mg/kg
    – No longer required transfusions
    – Feeling much better
    – Minimal side effects
    – Monitored with CT scans and Hb every 3 months
      • 3 month CT: stable disease, Hb 135
    – 6 months: symptomatic anemia again, Hb 88
      • Did not recover with everolimus cessation
      • Required transfusions every 3 days
      • Deemed to have progressive disease
Case I: JN
   What third-line targeted therapy would you
                     choose?
1)Sunitinib
2)Temsirolimus
3)Everolimus
4)Interferon
5)High dose IL-2
6)Pazopanib
7)Bevacizumab+IFN
8)Clinical Trial
Case I: JN
•   Patient chooses pazopanib as she had
    third party insurance
•   Monitored patient with CT scans every 3
    months
    – 3 months: 18% decrease
    – 6 months: slowly progressive liver disease,
      lungs stable (15% increase)
    – 9 months: progressive disease in liver (20%
      increase)
Case I: JN
 Screening for clinical trial of BMS PD-1
  inhibitor
 Still slightly anemic
Lessons Learned
   Targeted therapy extended her life
    significantly
     “Thank you, this time last year I thought I
     wouldn’t be here anymore”
 Progression can come in different ways
  and not just on CT scans
 Third line therapy is therapy that you
  haven’t used before, if available
Background
   Two prospective randomized trials1,2 with metastatic
    RCC showed that the addition of cytoreductive
    nephrectomy (CN) improves overall survival (OS) as
    compared to interferon-alpha (IFN-a) alone (13.6
    months vs. 7.8 months; Hazard ratio=0.69, p=0.001)

   IFN-a is a historic standard of care.

   Patients were enrolled between 1991-1998.

   The role of debulking nephrectomy in the era of novel
    VEGF-targeted agents remains poorly defined.

                                      1. Flanigan RC et al. N Eng J Med. 2001;345:1655.
                                              2. Mickisch GH et al. Lancet. 2001;358:966
    RCC Consortium Database
   Consecutive 645 patients with median follow up 25
    months.
   Metastatic RCC, any histology.
   Treated with anti-VEGF agents:
      ○ Sunitinib
      ○ Sorafenib
      ○ Bevacizumab

   No prior VEGF-targeted agents.
   Data collected using uniform data collection software and
    standardized definitions.
   Excluded N=331 (s/p nephrectomy, but not cytoreductive).
Overall Survival on Univariable Analysis

                  mOS: 19.8 vs. 9.4 months
             Hazard Ratio:0.44 (95% CI: 0.32-0.59)
                           p<0.001
 Cytoreductive Nephrectomy
    Cytoreductive nephrectomy in era of
     targeted therapy may produce superior
     OS when adjusted for known prognostic
     factors

Adjusted Hazard Ratio 0.68 (95% CI: 0.46, 0.99)




                                    Choueiri et al J Urol 2011
The impact of cytoreductive nephrectomy
by risk groups1
   Favorable risk group (N=23):
     22/23 underwent CN


   Intermediate risk group (N=143):
     HR: 0.46 (95% CI: 0.27-0.78, p=0.004)


   Poor risk group (N=117):
     HR: 0.67 (95% CI: 0.44-1.01, p=0.056)




                                    1. Heng et al. JCO 2009; 27: 5794-9
Cytoreductive Nephrectomy by KPS

        -KPS>80: 23.9 vs. 14.5 months, p=0.003
           -KPS<80: 10.1 vs. 6 months, p=0.077
Cytoreductive Nephrectomy
 Cytoreductive Nephrectomy (CN) is
  independently associated with an improved
  overall survival in metastatic RCC patients
  treated with VEGF-targeted agents
 Cytoreductive nephrectomy in era of
  targeted therapy may produce superior OS
  when adjusted for known prognostic factors
 The benefit seems to be marginal in
  patients in the poor-risk group/poor KPS
 Prospective clinical trials in progress




                                      Choueiri et al J Urol 2011
Conclusions
   mRCC Treatment Revolution
     VEGF inhibitors
     mTOR inhibitors
     Clinical trials are important to find new drugs
 Cytoreductive nephrectomy may be
  helpful in certain patients
 Our patients are living much longer than
  they used to … progress!!

								
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