tratamiento adyuvante y neoadyuvante del cáncer renal en 2017€¦ · del cáncer renal en 2017...
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Tratamiento adyuvante yneoadyuvante
del cáncer renal en 2017
Tratamiento adyuvante yneoadyuvante
del cáncer renal en 2017
Xavier Garcia del Muro SolansInstitut Català d’Oncologia Hospitalet. Barcelona
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Pronóstico del CR mediante un sistema integradoen 468 pts CR localizado (N0M0):
UCLA Integrated Staging System (UISS)
Zisman A. JCO 2002
5-year OS: 83% 72% 44%
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Tumor Stage, Size, Grade and Necrosis: the SSIGN score forpatients with clear cell renal cell carcinoma
Frank I. J Urol 2002Leibovich BC. Cancer 2003
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Randomized phase III trials of adjuvant therapyafter nephrectomy for high-risk RCC
TreatmentTreatment OutcomeOutcome
RT vs.RT vs. observationobservation SurvivalSurvival (NS)(NS)MPA vs.MPA vs. observationobservation RelapseRelapse raterate (NS)(NS)TmTm cellscells + BCG vs.+ BCG vs. observationobservation DFS (NS)DFS (NS)INF vs.INF vs. observationobservation SurvivalSurvival (NS)(NS)HDHD--IL 2 vs.IL 2 vs. observationobservation DFSDFS (NS)(NS)INF + ILINF + IL--2 + 5FU vs2 + 5FU vs observationobservation OS (p=.02)OS (p=.02)TmTm cellcell vaccinevaccine vs.vs. observationobservation 5y PFS (p=.02)5y PFS (p=.02)HSPPCHSPPC--9696 VaccineVaccine vsvs observobserv.. RFS (NS)RFS (NS)ThalidomideThalidomide 3y RFS (p=.02)3y RFS (p=.02)G250 vsG250 vs observationobservation DFS (NS)DFS (NS)
TreatmentTreatment OutcomeOutcome
RT vs.RT vs. observationobservation SurvivalSurvival (NS)(NS)MPA vs.MPA vs. observationobservation RelapseRelapse raterate (NS)(NS)TmTm cellscells + BCG vs.+ BCG vs. observationobservation DFS (NS)DFS (NS)INF vs.INF vs. observationobservation SurvivalSurvival (NS)(NS)HDHD--IL 2 vs.IL 2 vs. observationobservation DFSDFS (NS)(NS)INF + ILINF + IL--2 + 5FU vs2 + 5FU vs observationobservation OS (p=.02)OS (p=.02)TmTm cellcell vaccinevaccine vs.vs. observationobservation 5y PFS (p=.02)5y PFS (p=.02)HSPPCHSPPC--9696 VaccineVaccine vsvs observobserv.. RFS (NS)RFS (NS)ThalidomideThalidomide 3y RFS (p=.02)3y RFS (p=.02)G250 vsG250 vs observationobservation DFS (NS)DFS (NS)
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Adjuvant targeted therapy trials in RCC
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Phase III Adjuvant sunitinibor sorafenib for high-risk,non-metastatic renal-cellcarcinoma (ECOG-ACRIN)
Haas NB. Lancet 2016
34Confidential. Internal Use Only.
ASSURE Compared Effect of Sunitinib orSorafenib Versus Placebo on DFS
Haas NB et al. Lancet. 2016;387:2008-2016.
34
Arm CPlacebo
Daily for 1 year
Arm ASunitinib
50 mg QD 4/2 for 1 year
Enrollment Criteria:Nonmetastatic RCCthat meets radiologiccriteria to be clinically³ T1b N any (resectable)M0 disease
NEPHRECTOMY
Arm BSorafenib
400 mg BID for 1 year
Stratification• UISS risk
– Intermediate highrisk
– Very high risk• Histologic subtype
– Clear cell– Nonclear cell
• Performance status• Surgery
– Type of approach
Primary Endpoint Disease-free survival (investigator assessed)
Secondary Endpoints Overall survival, disease-free survival for clear cell RCC, and safety
RAND
OMIZE
N=1943
1:1:1
Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma
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Phase III trial of sunitinib versus placebo as adjuvant treatmentfor high-risk renal cell carcinoma after nephrectomy (S-TRAC)
Patient Disposition and Treatment
* Duration of treatment was defined as the period between first and last doses of the drugand included interruptions, cycle delays, and the scheduled 2-week off treatment.† Investigators had to select only one reason.
Dosing InformationSunitinib
n=306Placebon=304
Treatment duration*, median (range), months 12.39 (0.13–14.9) 12.42 (0.03–13.7)
Treatment completion, % 55.6 69.4Treatment discontinuation, % 44.4 30.6Reasons for discontinuation†, %
Adverse events 27.5 5.3Disease progression/relapse 7.2 19.4Other 9.8 5.6
Dose reductions, n (%) 45.8 4.9Dose interruptions, n (%) 54.2 27.6Relative dose intensity, median (range) 88.4 (15–106.2) 99.7 (10–105.7)
9
Ravaud A. NEJM 2016
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Disease-Free Survival By BlindedIndependent Central Review
* Two-sided P value from log-rank test stratified by UISS high-risk group.
5-yearDFS rate:59.3%
51.3%
3-yearDFS rate:64.9%
59.5%
Prop
ortio
nD
isea
se-F
ree
Disease-Free Survival (years)
10
P=0.030*
Ravaud A. NEJM 2016
Disease-Free Survival By BlindedIndependent Central Review
* Two-sided P value from log-rank test stratified by UISS high-risk group.
5-yearDFS rate:59.3%
51.3%
3-yearDFS rate:64.9%
59.5%
Prop
ortio
nD
isea
se-F
ree
Disease-Free Survival (years)
10
P=0.030*
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ASSURE and S-TRAC in perspective
Variable ASSURE S-TRACStudy Conduct Central Scans Review No Yes (eligibility and efficacy)
PatientCharacteristics
ccRCC 79.1% 99.0%
ECOG PS 0 81.8% 73.8%
RCC Stage I-II 33.4% 0%
Doseadministered
Starting Dose levels 2(50 mg and 37.5 mg)
1(50 mg)
50mg 4/2 as starting dose 69.6% 100%
Minimum Dose Reduction 25 mg 37.5 mg
Relative Dose intensityFull Dose: 40.2%
Reduced Dose 44.5%(first 3 cycles)
88.4%
ASSURE and S-TRAC in perspective
Variable ASSURE S-TRACStudy Conduct Central Scans Review No Yes (eligibility and efficacy)
PatientCharacteristics
ccRCC 79.1% 99.0%
ECOG PS 0 81.8% 73.8%
RCC Stage I-II 33.4% 0%
Doseadministered
Starting Dose levels 2(50 mg and 37.5 mg)
1(50 mg)
50mg 4/2 as starting dose 69.6% 100%
Minimum Dose Reduction 25 mg 37.5 mg
Relative Dose intensityFull Dose: 40.2%
Reduced Dose 44.5%(first 3 cycles)
88.4%
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• DFS and OS for 1069high-risk patients who hadccRCC histology and pT3,pT4, or N+ disease ofASSURE randomized trial.
• Outcome analyses bydose quartiles of thesepatients receiving sunitinibor sorafenib were alsoperformed
• CONCLUSIONS: Neitherprognostic category of thetumor nor dose intensity oftherapy altered the lack ofdifference in DFS or OS inthis population of patientswith high-risk ccRCC
• DFS and OS for 1069high-risk patients who hadccRCC histology and pT3,pT4, or N+ disease ofASSURE randomized trial.
• Outcome analyses bydose quartiles of thesepatients receiving sunitinibor sorafenib were alsoperformed
• CONCLUSIONS: Neitherprognostic category of thetumor nor dose intensity oftherapy altered the lack ofdifference in DFS or OS inthis population of patientswith high-risk ccRCC
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Randomized phase III trial of adjuvant pazopanib vs placebo afternephrectomy in patients with locally advanced RCC (PROTECT)
Motzer R. ASCO 2017
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Motzer R. ASCO 2017
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Sternberg C. ASCO 2017
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ONGOING ADJUVANT STUDIES IN RCC
• Targeted therapy trials:- SORCE: Sorafenib 1y. vs. 3y. vs. placebo. 592 pts
- ATLAS: Axitinib 3 y. vs. Placebo. 142 pts
- EVEREST: Everolimus vs placebo. 1218 pts
• Immune Checkponit Inhibitors trials:- PROSPER: Perioperative Nivolumab vs. surgery alone
- Immotion 10: Atezolizumab vs. placebo
- KEYNOTE 564: Pembrolizumab vs. placebo
• Targeted therapy trials:- SORCE: Sorafenib 1y. vs. 3y. vs. placebo. 592 pts
- ATLAS: Axitinib 3 y. vs. Placebo. 142 pts
- EVEREST: Everolimus vs placebo. 1218 pts
• Immune Checkponit Inhibitors trials:- PROSPER: Perioperative Nivolumab vs. surgery alone
- Immotion 10: Atezolizumab vs. placebo
- KEYNOTE 564: Pembrolizumab vs. placebo
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NEOADYUVANCIA EN CANCER DE RIÑÓN
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OUTCOMES AND POTENTIAL BENEFITSOF NEOADJUVANT THERAPY IN RCC
• Tumor downsizing
Aprox. 30% pts have RR. 75-85% stabilization o shrinkage
• Reducing tumor complexity (RENAL score)
55% reduction in nephrometry score
• Facilitate radical to partial nephectomyReduction of tumor volume and complexity. PN safe
• Regression of tumor thrombus level and facilitate surg.Aprox. 25% of reduction. Surgery safe
• Making unresectable tumors resectableIt makes resection possible in Tm considered unrectable
•
• Tumor downsizing
Aprox. 30% pts have RR. 75-85% stabilization o shrinkage
• Reducing tumor complexity (RENAL score)
55% reduction in nephrometry score
• Facilitate radical to partial nephectomyReduction of tumor volume and complexity. PN safe
• Regression of tumor thrombus level and facilitate surg.Aprox. 25% of reduction. Surgery safe
• Making unresectable tumors resectableIt makes resection possible in Tm considered unrectable
•
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• Prospective study of preoperative Sorafenib in 30 ptscandidates to nephrectomy, to assess toxicities, surgicalcomplications and tumor responses
• 17 pts had localized and 13 metastatic disease• 2 PR and 26 SD• All pts were able to proceed with nephrectomy and nocomplications related to sorafenib were observed
• Prospective study of preoperative Sorafenib in 30 ptscandidates to nephrectomy, to assess toxicities, surgicalcomplications and tumor responses
• 17 pts had localized and 13 metastatic disease• 2 PR and 26 SD• All pts were able to proceed with nephrectomy and nocomplications related to sorafenib were observed
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CONCLUSIONS
• Adjuvant therapy trials in RCC have conflicting results. However,some data suggest that appropriate selection of patients (high-risk,clear cell) and optimal doses might be relevant factors associatedwith benefit
• At present, available data do not justify the systematic use ofadjuvant therapy. However, adjuvant sunitinib for one year couldbe an option to consider in patients with very high-risk disease
• Neoadjuvant therapy before surgery for localized renal cell canceris feasible and might be especially useful in selected patients withlarge unresectable masses, high-level venous tumor thrombusinvolvement, and patients with large masses and indications fornephron sparing surgery. Nevertheless, this approach is stillinvestigational and should be carefully used in selected patients
CONCLUSIONS
• Adjuvant therapy trials in RCC have conflicting results. However,some data suggest that appropriate selection of patients (high-risk,clear cell) and optimal doses might be relevant factors associatedwith benefit
• At present, available data do not justify the systematic use ofadjuvant therapy. However, adjuvant sunitinib for one year couldbe an option to consider in patients with very high-risk disease
• Neoadjuvant therapy before surgery for localized renal cell canceris feasible and might be especially useful in selected patients withlarge unresectable masses, high-level venous tumor thrombusinvolvement, and patients with large masses and indications fornephron sparing surgery. Nevertheless, this approach is stillinvestigational and should be carefully used in selected patients