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Cancere urogenitale non-prostata
Cristina Cebotaru
Update and Controversies in Advanced GCT
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Learning Objectives
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Background: Advanced GCT
Presented By Darren Feldman at 2014 ASCO Annual Meeting
International Germ Cell Cancer Collaborative Group (IGCCCG) Risk Classification1
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Randomized Trials in Intermediate/Poor Risk
Presented By Darren Feldman at 2014 ASCO Annual Meeting
EORTC 30983 Plan
Presented By Darren Feldman at 2014 ASCO Annual Meeting
EORTC 30983 Actual Enrollment
Presented By Darren Feldman at 2014 ASCO Annual Meeting
EORTC 30983
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Summary of EORTC 30983
Presented By Darren Feldman at 2014 ASCO Annual Meeting
GETUG 13: Phase III Schema
Presented By Darren Feldman at 2014 ASCO Annual Meeting
GETUG 13: Phase III Schema
Presented By Darren Feldman at 2014 ASCO Annual Meeting
GETUG 13: PFS in Randomized Pts
Presented By Darren Feldman at 2014 ASCO Annual Meeting
GETUG 13: OS in Randomized Pts
Presented By Darren Feldman at 2014 ASCO Annual Meeting
GETUG 13: Toxicities and Salvage Rx
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Breaking Down GETUG-13
Presented By Darren Feldman at 2014 ASCO Annual Meeting
GETUG 13: Conclusions & Questions
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Phase II Trial of TIP in Int/Poor-Risk GCT
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Ongoing and Planned Trials
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Novel Trial Development (n=470)
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Summary: Intermediate and Poor-risk GCT
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Salvage Treatment of GCT
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Slide 22
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Slide 23
Presented By Darren Feldman at 2014 ASCO Annual Meeting
CDCT for Initial Salvage: VIP/VeIP
Presented By Darren Feldman at 2014 ASCO Annual Meeting
TIP Results at MSKCC
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Slide 26
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Prognostic Factors From HDCT Series
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Slide 28
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Slide 29
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Difficulties in Interpreting IT-94
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Variance in Practices Around the World
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Alliance 031102 / EORTC 1407 (TIGER)
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Conclusions
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Thank you for your attention!
Presented By Darren Feldman at 2014 ASCO Annual Meeting
Improving Outcomes in Metastatic Renal Cell Carcinoma by Sequencing Therapy
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Outcomes with Targeted Agents in 2006 and 2014
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Despite Approval of Many Agents, Long-Term Survival Remains Rare
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Improving Outcomes by Wise Sequencing Strategies?
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Guidelines for 2nd-Line Treatment After Failure of VEGF-Inhibitors (Clear Cell)
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
No Agent is Powerful Enough to Change Entirely the Course of Disease….
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
…Either Much Better Agents or<br />Much Better Strategies with Existing Agents
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Improving <br />Outcomes <br />with Existing Strategies?
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Improving <br />Outcomes <br />with Existing Strategies?
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Timing of 1st-Line Treatment Important?
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Prospective Data: Rini BI <br />ASCO 2014, abstract 4520
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Improving <br />Outcomes <br />with Existing Strategies?
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Maximizing Outcomes by Dosing?
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Patient EA: no response, no hypertension with sunitinib 50 mg dose escalation to 75 mg
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Magnitude of Tumour Shrinkage May Predict Overall Survival
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Improving <br />Outcomes <br />with Existing Strategies?
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Treatment Interruption To Extend 1st-line Duration and OS?
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Improving <br />Outcomes <br />with Existing Strategies?
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Case 1: Inappropriate Exposure May Feign Resistance
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Staging December 2010
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Dose-Reescalation: PRCR<br />Ongoing, Confirmed May 2014
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Case 2: Dose Escalation at Occurrence of Progression
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Sunitinib Dose Escalation: <br />Evidence from Xenografts and Patients
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Improving <br />Outcomes <br />with Existing Strategies?
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Trials with Second-Line or Sequencing Results
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Different Agents, Different Population, Different Study Endpoints….
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
A Discussion Between a Proponent of „Changing MoA“ and a Proponent of „Maintaining“ MoA in 2nd-Line)
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Slide 28
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Slide 29
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Because axitinib and everolimus haven‘t been compared in a pure sunitinib-refractory patient population, it remains unclear which agent is better in this setting
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Role of Prognostic and Predictive Factors
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Because Predictive and Prognostic Factors Mostly Apply to Both Treatment Arms, they May NOT Help to Facilitate 2nd-Line Treatment Choices Either!
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Proposed Mechanisms of Evasive Resistance1
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Epithelial to Mesenchymal Transition in Metastases of a Sunitinib Resistant Patient
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Reversible Epithelial to Mesenchymal Transition
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Slide 36
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Other Observations and Possible Assumptions…..
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Biological Considerations May Increase the Understanding Why One Agent May Work Better than Another, at Occurrence of Resistance<br />
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Improving <br />Outcomes <br />with Existing Strategies?
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Beyond Second-Line?
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Patient SD
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Treatment Summary Patient SD
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
March 2013: Sixth-Line sunitinib 50 mg 2/1(second re-challenge)
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Treatment Summary Patient SD
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Improving <br />Outcomes <br />with Existing Strategies?
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Metastasectomy as Integral Part of Sequencing Strategies?
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Conclusions
Presented By Manuela Schmidinger at 2014 ASCO Annual Meeting
Chemotherapy in Advanced and Metastatic Bladder Cancer
Extravesical Disease: T3/T4/N+
• Patients with clinical evidence of extravesical tumor have a 5-year OS as high as 30% to 40% after cystectomy
• As tumor recurrence is common in this population, perioperative systemic CT has been advocated
• Both, neoadjuvant and adjuvant CT offer advantages and disadvantages to the patient
Adjuvant therapy benefits
• Pathologic staging is the best prognostic indicator and will be known after surgical treatment
• Low-risk pts are spared unnecessary treatment and toxicity if their staging is favorable
• No delay in surgery exists• Chance of cure for pts with chemoresistant disease is
maximized• The lower toxicity of newer combinations CT is likely to
improve tolerance and compliance with postoperative therapy
Adjuvant Chemotherapy 1
• Four randomized studies have evaluated the benefit of CT after cystectomy
• Two of these trials did not show a benefit when adjuvant treatment was compared with observation
• The study by Studer has been criticized for using an inferior regimen, single-agent cisplatin, when a cisplatin-based multidrug regimen such as MVAC was known to be more efficacious
• The study by Freiha has been criticized for being underpowered
Ajuvant Chemotherapy 2
• In the Skinner study, pts with T3-T4 or N+ disease were randomized to obs vs 4 cy of adjuvant CISCA
• A significant delay in recurrence was observed in the adjuvant CT group vs cystectomy alone (70% vs 46% 3-year-DFS)
• A significant improvement in OS (4.3 vs 2.4 years) was also observed
• Criticized for: small nb pts, premature termination, flawed statistical methods, nonstandard CT, poor CT compliance
Adjuvant Chemotherapy 3
• In the study by Stockle, pts with pT3a-pT4a or N+ were rand to MVAC vs obs
• A significant reduction in the risk of recurrence was observed in the CT arm: 17% CT relapsed vs 82%
• This study faced poor CT compliance• Unfortunately, both the Skinner and the Stockle
trials ended prematurely based on interim analyses favoring adjuvant CT
Positive Adjuvant Trials
• Skinner: 91 pts, T3Nx, CISCA (p=0.099)– 3-yr DFS: 70% vs 46%: Benefit : yes– 3-yr OS: 66% vs 50%: Benefit: No
• Stockle: 49 pts, pT3, pT4, N+, MVAC/MVEC (p=0.0012)– DFS in 73% vs 18%: Benefit-yes
Negative Adjuvant Trials
• Struder: 77 pts, pT1-4 N0-2, Cisplatin (p=0.65)– 5-yr OS: 57% vs 54%: Benefit: No
• Freiha: 50 pts, pT3b, pT4 N0-1, CMV (p=0.32)– Median OS: 63 mo vs 36 mo: Benefit: No for OS
Adjuvant Chemotherapy Conclusions
• Despite criticism of adjuvant trials, there is a suggested survival benefit for patients with extravesical or nodal extension to neighboring viscera
Chemotherapy in Metastatic Bladder Cancer 1
• Cisplatin-containing combination CT with Gemcitabine (GC) or MVAC (methotrexate, vinblastine, adriamycin and cisplatin) is standard in pts fit enough to tolerate cisplatin [IA]
• High-dose intensity MVAC with G-CSF is an option in fit pts with limited advanced disease
• Median Sv is 14 months• Long-term disease-free Sv has been reported in 15%
pts, in 20.9% with lymph-node-only disease compared with only 6.8% with visceral metastases
Chemotherapy in M+ BC 2
• GC is less toxic than MVAC• MVAC is better tolerated with the use of G-CSF• So far, no improvement in Sv with newer triplets,
novel four-drug regimens or dose-dense sequential CT
• The addition of a third agent (paclitaxel) to GC has been demonstrated to be of some benefit in a subset of pts having the bladder as the primary origin of disease and should be considered investigational
Prognostic Factors in First-Line Advanced Disease
• Performance status (Karnofsky PS) < 80%• The presence of viscecral metastases• Risk factors:
– 0=KPS>80, no visceral mets: Sv 33.0 mo– 1=KPS<80 or visecral mets: Sv: 13.4 mo– 2=KPS<80 and visceral mets: 9.3 mo
Chemotherapy alternatives
• 50% of pts are unfit for cisplatin-containing CT due to poor PS, impaired renal function or comorbidity
• May be palliated with a carboplatin-based regimen or single-agent taxane or gemcitabine
• M-CAVI (MTX-CBDCA-VBL) and CG are active but without a statistically significant difference in OS and PFS
• Severe acute toxicity was > on M-CAVI, which makes CG the preferred regimen
Treatment of relapse• RR with mono-CT are lower than with combinations, but PFS has
been short with both options • Independent adverse prognostic factors for Sv (PS>0, Hb<10,
presence of liver mets) have been defined and validated: OS vs Risk– 0: 11.5 mo– 1: 7.3 mo– 2: 3.9 mo– 3: 2.4 mo
• The only valid randomized trial for pts progressing after platinum is with Vinflunine (novel 3rd generation vinca alkaloid) with only ORR 8.6%, a clinical benefit with favorable safety profile and a Sv benefit
Conclusion
• Chemotherapy in bladder cancer is effective and worth the race