Cancere Urogenitale Non-prostata

Cancere urogenitale non-prostata

Cristina Cebotaru

Update and Controversies in Advanced GCT

Presented By Darren Feldman at 2014 ASCO Annual Meeting

Learning Objectives

Background: Advanced GCT

International Germ Cell Cancer Collaborative Group (IGCCCG) Risk Classification1

Randomized Trials in Intermediate/Poor Risk

EORTC 30983 Plan

EORTC 30983 Actual Enrollment

EORTC 30983

Summary of EORTC 30983

GETUG 13: Phase III Schema

GETUG 13: PFS in Randomized Pts

GETUG 13: OS in Randomized Pts

GETUG 13: Toxicities and Salvage Rx

Breaking Down GETUG-13

GETUG 13: Conclusions & Questions

Phase II Trial of TIP in Int/Poor-Risk GCT

Ongoing and Planned Trials

Novel Trial Development (n=470)

Summary: Intermediate and Poor-risk GCT

Salvage Treatment of GCT

CDCT for Initial Salvage: VIP/VeIP

TIP Results at MSKCC

Prognostic Factors From HDCT Series

Difficulties in Interpreting IT-94

Variance in Practices Around the World

Alliance 031102 / EORTC 1407 (TIGER)

Conclusions

Thank you for your attention!

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

Despite Approval of Many Agents, Long-Term Survival Remains Rare

Improving Outcomes by Wise Sequencing Strategies?

Guidelines for 2nd-Line Treatment After Failure of VEGF-Inhibitors (Clear Cell)

No Agent is Powerful Enough to Change Entirely the Course of Disease….

…Either Much Better Agents or Much Better Strategies with Existing Agents

Improving Outcomes with Existing Strategies?

Timing of 1st-Line Treatment Important?

Prospective Data: Rini BI ASCO 2014, abstract 4520

Maximizing Outcomes by Dosing?

Patient EA: no response, no hypertension with sunitinib 50 mg dose escalation to 75 mg

Magnitude of Tumour Shrinkage May Predict Overall Survival

Treatment Interruption To Extend 1st-line Duration and OS?

Case 1: Inappropriate Exposure May Feign Resistance

Staging December 2010

Dose-Reescalation: PRCR Ongoing, Confirmed May 2014

Case 2: Dose Escalation at Occurrence of Progression

Sunitinib Dose Escalation: Evidence from Xenografts and Patients

Trials with Second-Line or Sequencing Results

Different Agents, Different Population, Different Study Endpoints….

A Discussion Between a Proponent of „Changing MoA“ and a Proponent of „Maintaining“ MoA in 2nd-Line)

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

Role of Prognostic and Predictive Factors

Because Predictive and Prognostic Factors Mostly Apply to Both Treatment Arms, they May NOT Help to Facilitate 2nd-Line Treatment Choices Either!

Proposed Mechanisms of Evasive Resistance1

Epithelial to Mesenchymal Transition in Metastases of a Sunitinib Resistant Patient

Reversible Epithelial to Mesenchymal Transition

Other Observations and Possible Assumptions…..

Biological Considerations May Increase the Understanding Why One Agent May Work Better than Another, at Occurrence of Resistance

Beyond Second-Line?

Patient SD

Treatment Summary Patient SD

March 2013: Sixth-Line sunitinib 50 mg 2/1(second re-challenge)

Treatment Summary Patient SD

Metastasectomy as Integral Part of Sequencing Strategies?

Conclusions

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

Cancere Urogenitale Non-prostata

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