Transcript New Treatment Paradigms in Locally Advanced Non
ASCO 2006 Update:
Genitourinary Cancer
Selected Abstracts
Primo N. Lara, Jr., MD
Professor of Medicine University of California Davis Cancer Center
The Star of the Show: Kidney Cancer Targeted therapies hit their mark
–
Angiogenesis inhibitors
•
Sunitinib, Sorafenib
–
mTOR inhibitors
•
Temsirolimus, Everolimus
–
EGFR/ERB2 inhibitor
•
Lapatinib
Iressa
The Von-Hippel Lindau Gene
• • •
Located in the short arm of chromosome 3 Tumor suppressor function Found in up to 80% of sporadic (non hereditary) renal cell cancers
Inactivation of VHL: An Early Step in Kidney Carcinogenesis
Loss of remaining VHL allele Mutation/s at non VHL loci VHL (+/-) VHL (-/-): Cysts VHL (-/-): Tumor
Sporadic Renal Cell Cancer: VHL Two-Hit Hypothesis
At birth First Hit Second Hit: Cancer
Consequences of VHL Gene Mutation
Elongin B/C Cul2 Rbx1 pVHL-E pVHL-A X X HIF Accumulation HIFHIF HIFHIF HIFHIF Ubiquitin Ligase Complex Disrupted VEGF, PDGF
Glut-1, Erythropoietin TGF-
, CXCR4
Angiogenesis Increased Metabolism Autocrine Growth Metastasis
Horizontal vs. Vertical “Targeted” Strategies
pVHL HIF
VEGF KDR PDGF PDGFR TGF EGFR
Abstract # LBA3
Phase 3 Randomized Trial of Sunitinib malate (SU11248) versus Interferon-alfa as First-line Systemic Therapy for Patients with Metastatic Renal Cell Carcinoma
RJ Motzer, TE Hutson, P Tomczak, MD Michaelson, RM Bukowski, O Rixe, S Oudard, ST Kim, CM Baum, RA Figlin and the SU11248 Study Group
Supported by Pfizer Inc
Sunitinib Mechanism of Action in RCC
Loss of VHL Protein Function VEGFR ↑ VEGF VEGF Vascular Endothelial Cell ↑ PDGF PDGF PDGFR Pericyte/Fibroblast/ Vascular Smooth Muscle Vascular permeability Sunitinib Cell survival, proliferation, migration Vascular formation, maturation Inhibition of RCC pathogenesis and progression
Randomization Scheme
N=750
Stratification Factors
●
LDH
1.5 vs >1.5xULN
●
ECOG PS 0 vs 1
●
Presence vs Absence of Nephrectomy
A T I O N R A N D O M I Z Sunitinib (N=375) IFN-
(N=375)
Study Treatment
Arm A: Sunitinib 50 mg po daily on (4 weeks on/2 weeks off) Arm B: IFN-
3 MU TIW 1 st week
6 MU TIW 2 nd 9 MU TIW 3 rd week
week
thereafter; SC Injection
•
Repeated 6-week cycles
•
Response and safety assessments
•
Dose reduction for toxicity
•
Treatment continued unless progression or intolerance
Progression-Free Survival
(Independent Central Review) 1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0 0 Hazard Ratio = 0.415
(95% CI: 0.320
–0.539) P <0.000001
1 2 3 4
No. at Risk Sunitinib: No. at Risk IFN-
:
235 152 Sunitinib Median: 11 months (95% CI: 10 IFN-
Median: 5 months (95% CI: 4 5 6 7 8 Time (Months) 90 42 9 32 18 10 11 –12) –6) 12 13 14 2 0
Hazard Ratios Showing Treatment Effect for Progression-free Survival Adjusted By MSKCC Risk Features* (Independent Central Review) Sunitinib benefit IFN-
benefit Sunitinib vs. IFN-
treatment effect without adjusting for risk factors Prior nephrectomy (yes vs no) ECOG score (0 vs 1) LDH (≤1.5 vs >1.5 x ULN) Time since diagnosis (≥1 yr vs <1 yr) Hemoglobin (≥LLN vs
0.50
0.75
1.00
1.25
LLN = lower limit of normal ULN = upper limit of normal
Hazard Ratio
* Cox proportional hazards analysis; Motzer et al. JCO 1999;17:2530-40; Motzer et al. JCO 2002;20:289-296
Overall Survival
0.4
0.3
0.2
0.1
0 1.0
0.9
0.8
0.7
0.6
0.5
Hazard Ratio = 0.65
(95% CI: 0.449
P = 0.0219* –0.942) Sunitinib (n=375) Median not reached IFN-
(N=375) Median not reached 0 1
No. at Risk Sunitinib: No. at Risk IFN-
:
2 3 341 296 4 5 6 190 162 7 8 9 Time (Months) 10 84 66 11 12 15 10 13 14 15 1 0 16
*The observed p-value did not meet the pre-specified level of significance for this interim analysis
Outcome Summary
Sunitinib Median Progression-free Survival*, mos (95% CI) Independent Review Investigator Objective response*, % (95% CI) Independent Review Investigator Safety Patient-reported Outcomes
11 (10-12) 11 (8-14) 31 (26-36) 37 (32-42) Acceptable Superior
*Sunitinib vs IFN-
: P <0.000001
IFN-
5 (4-6) 4 (4-5) 6 (4-9) 9 (6-12) — —
Abstract # 4524
Randomized Phase III Trial of Sorafenib in Advanced Renal Cell Carcinoma (RCC): Impact of Crossover on Survival
Eisen T, Bukowski RM, Staehler M, Szczylik C, Oudard S, Stadler WM, Schwartz B, Simantov R, Shan M, Escudier B For the Sorafenib TARGETs Clinical Trial Group
Eisen T
et al.
Oral presentation, ASCO 2006
Sorafenib (Nexavar
®
)
A Novel, Orally-Active Multi-Kinase Inhibitor
• • • •
Approved in the US in Dec 2005 for advanced RCC In vitro inhibitor of C-Raf, wild-type B-Raf, b-raf V600E, VEGFR-2/-3, PDGFR-
, c-Kit, and Flt-3 1 Broad-spectrum anti-tumor activity and inhibition of angiogenesis in several tumor xenografts 1 Sorafenib prevented tumor growth in RCC VHL –/– xenografts, via inhibition of angiogenesis 2
1. Wilhelm S, Chien DS.
Curr Pharm Des
2002;8:2255 –2257 2. Chang YS, et al.
Clin Cancer Res
2005;11:9011S
Phase III TARGETs
Treatment Approaches in Renal Cancer Global Evaluation Trial
Study Design
• • • • • • • •
Eligibility criteria
Confirmed, advanced disease Clear-cell histology Measurable disease Failed one prior systemic therapy in last 8 months Low/intermediate risk MSKCC groups included ECOG PS 0 or 1 Good organ function No brain metastasis
(1:1) Randomization n= 903
Sorafenib 400 mg bid
n=451 Stratification
• MSKCC criteria • Country
Placebo
n=452
• •
Primary endpoints
Survival (alpha=0.04) PFS (alpha=0.01)
TARGETs
Single, Planned Progression-Free Survival* Analysis 1.00
0.75
Median PFS**
Sorafenib = 24 weeks Placebo = 12 weeks Hazard ratio = 0.44
p
-value <0.000001
0.50
0.25
Sorafenib Placebo Censored observation 0 0 6 12 18 24 36 48 Time from randomization (weeks) 54
*Independently assessed **PFS analysis performed March, 2005 (data cut-off Jan 28, 2005)
60 66
Escudier B
et al.
Oral presentation, ASCO, 2005
1.00
TARGETs
Overall Survival at Time of Crossover*
Sorafenib Placebo Censored observation 0.75
0.50
0.25
Median OS
Sorafenib = Not reached Placebo = 14.7 months Hazard ratio = 0.72
p
-value = 0.018**
0 0 2 4 6 8 10 12 14 Time from randomization (months) 16 18 20
*At 220 events, May 31, 2005 **O’Brien-Fleming stopping boundary for significance was
p
<0.0005
Escudier B
et al.
Oral presentation, ECCO 13, 2005
TARGETs
Overall Survival Analysis 6 months post-crossover*
216 out of 452 placebo patients had crossed over to sorafenib
Placebo Sorafenib
Median OS
Placebo = 15.9 months Sorafenib = 19.3 months Hazard ratio = 0.77
p
-value = 0.015** Of 367 events, a total of 122 deaths were reported in the low-risk and 245 in the intermediate-risk groups *At 367 events, Nov. 30, 2005 **O’Brien-Fleming stopping boundary for significance was
p
<0.0094
TARGETs
Secondary Overall Survival Analysis with Censored Placebo Patients*
Sorafenib Placebo (censored at Jun 30, 2005)
Median OS
Placebo* = 14.3 months Sorafenib** = 19.3 months Hazard ratio = 0.74
p
-value = 0.01
*Results from a planned OS analysis in which placebo data were censored at June 30, 2005 **Results on sorafenib arm are not censored
Sorafenib + Interferon
Patients (#) SWOG 0412 (Ryan, #4525) 67 Duke phase II (Gollob, #4538) 39 RECIST RR Stable disease Median PFS Dose reductions 28% 38% 6.5 months 64% 38% 48% Not reported 63% * Interferon toxicity predominates
Abstract # LBA4
Global ARCC Trial
A Phase 3, Randomized, 3-Arm Study of Temsirolimus (TEMSR) or Interferon-Alpha (IFN) or the Combination of TEMSR + IFN in the Treatment of First-Line, Poor-Risk Patients With Advanced Renal Cell Carcinoma G Hudes, M Carducci, P Tomczak, J Dutcher, R Figlin, A Kapoor, E Staroslawska, T O’Toole, S Kong, and L Moore
Global ARCC Trial
Phase 3 Study of TEMSR and IFN in Advanced RCC
626 patients with advanced metastatic RCC with poor-risk features
209 sites (26 countries) Stratification by: Geographic Regions:
•
WEU + AU + CA (22%)
• •
US (30%) EEU + Other (48%) Nephrectomy:
• •
Yes (67%) No (33%) R A N D O M I Z E IFN: escalating to 18 MU SC TIW n = 207 TEMSR: 25 mg IV QW n = 209 TEMSR: 15 mg IV QW + IFN: 6 MU TIW n = 210
Global ARCC Trial Poor-Risk Features for Eligibility
Minimum of 3 poor-risk features required: 1. LDH > 1.5 X upper limit of normal 2. Hemoglobin < lower limit of normal 3. Corrected calcium > 10 mg/dL 4. Time from diagnosis to first treatment < 1 yr 5. Karnofsky Performance Status 60-70 6. Multiple organ sites of metastasis
Global ARCC Trial
Percent (%) of Patients with Any Grade 3-4 Adverse Event Any Grade 3-4 IFN n=203 85 TEMSR n=209 TEMSR + IFN n=209 69* 87 *p < 0.001 vs. IFN and vs. TEMSR + IFN Dose Reductions and Delays Modification Dose Reduction % of Patients Requiring Modification IFN TEMSR TEMSR + IFN 40 23 52 > 2 Dose Delays 42 24 76
Overall Survival by Treatment Arm Parameter n Comparisons Stratified Log-Rank p IFN Arm 1 207 TEMSR Arm 2 209 Arm 2 :Arm 1 0.0069
TEMSR + IFN Arm 3 210 Arm 3 :Arm 1 0.6912
Arm 2: Temsirolimus Arm 1: IFN Arm 3: IFN + Temsirolimus Time from Randomization, Months
Global ARCC Trial
Overall Survival by Treatment Arm Deaths, n Median Survival, months (95% CI) IFN Arm 1 n=207 149 7.3
(6.1 - 8.9) TEMSR Arm 2 n=209 141 10.9
(8.6 - 12.7) Arm 2: Arm 1 TEMSR + IFN Arm 3 n=210 152 8.4
(6.6 - 10.2) Arm 3: Arm 1 Increase in Median Survival Hazard Ratio (95% CI) Stratified Log-Rank p 49% 0.73
(0.57 - 0.92) 0.0069* 15% 0.95
(0.76 - 1.2) 0.6912
*O’Brien-Fleming boundary for significance = 0.0155
Global ARCC Trial
Conclusions
Temsirolimus significantly improved OS and PFS of poor-risk RCC patients as compared with IFN:
3.6 month (49%) improvement in median OS
1.8 month (95%) improvement in median PFS
Temsirolimus was better tolerated than IFN
mTOR is an important therapeutic target in RCC
Everolimus (RAD001): an orally bioavailable mTOR inhibitor
RAD001 for Renal Cell Carcinoma
Phase 2 Study
Amato,et al. Abstract # 4530 Design Single-arm, IRB-approved trial Primary endpoint of time to progression Secondary endpoint of overall response rate 2-stage design, target accrual of 40 patients Eligibility Metastatic RCC No more than 1 prior therapy Adequate PS, hematology, and chemistry studies Normal cardiac function
RAD001 for Renal Cell Carcinoma
Phase 2 Study
• Treatment regimen: 10 mg of daily oral therapy • Dose reduced to 5 mg for grade 3 /4 toxicity • Monitoring of CBC, chemistry, lipid profile, and pulmonary function • Response assessed by RECIST • Treatment continued unless progression or intolerability
RAD001 for Renal Cell Carcinoma
Independent radiology review of serial CT scans -20 -30 -40 -50 -60 -70 30 20 10 0 -10
Max % decrease tumor size
Ra
70 % of patients have tumor shrinkage, 50% show 10% shrinkage or greater RECIST PR rate = 36%; Median TTP = 6+ months
Advanced or metastatic renal cell cancer (no prior systemic therapy)
R A N D O M I Z E
Proposed Phase III Trial of RAD001 plus Sunitinib or Sorafenib
Sunitinib Sunitinib + RAD001 At progression R A N D O M I Z E Sorafenib Sorafenib + RAD001
Phase III Trial of the Dual EGFR/HER-2 inhibitor Lapatinib in RCC (Ravaud, et al. # 4502) N = 417 Time to progression* Overall survival* EGFR 3+ (N=241) Lapatinib (n=209) Hormones** (n=207) 15.3 15.4
Hazard ratio 0.94 (p=0.60) 46.9
43.1
0.88 (p=0.29) Time to progression* Overall survival* 15.1
46 10.9
37.9
0.76 (p=0.06) 0.69 (p=0.02) * Median time to progression (TTP) and overall survival (OS) in weeks ** Tamoxifen or Megestrol acetate
Non Metastatic Kidney Cancer Disease Stage: II III IV
Intergroup Adjuvant Phase III Trial (ASSURE)
N E P H R E C T O M Y
Stratify
UISS: II III IV V
Histologic Subtype
Clear cell Non-clear cell R A N D O M I Z E Sorafenib 1 Cycle = 400mg po BID X 42 days Total = 9 cycles * Sunitinib 1 Cycle= 50 mg po q am and placebo q pm X 28 days, then placebo BID x 2 weeks Total= 9 cycles* Placebo 1 cycle = 2 pills BID X 42 days for 9 cycles*
Advanced Renal Cell Cancer: Post-ASCO 2006 Menu
• • •
Previously untreated, frontline
–
High dose interleukin-2 (select patients)
– –
Sunitinib Temsirolimus (poor risk patients) Second line and beyond
–
Sorafenib (also approved for frontline)
– –
Bevacizumab Interferon (select patients) Emerging contenders
– –
Everolimus (RAD001) Lapatinib? (subset of EGFR over-expressors?)
Prostate Cancer: ASCO 2006
• • • •
Intermittent vs. continuous androgen blockade (# 4513) Absolute PSA nadir as predictor of survival (# 4517) Nomogram for salvage radiation after prostatectomy (# 4514) Intermittent chemotherapy for HRPC (#4518)
Da Silva, Abstract #4513
Intermittent vs. Continuous Maximal Androgen Blockade (MAB)
N=766 Prostate Cancer T3/T4 M0 or M1 MAB: Cyproterone acetate + LHRH agonist X 14 weeks N=626 PSA
80% or < 4 R A N D O M I Z E Continuous MAB (n=312) Intermittent MAB (n=314) Treatment resumed on the intermittent arm if PSA > 20 or PSA > 10 with symptoms
Intermittent vs. Continuous Maximal Androgen Blockade (MAB)
• • • •
Most were M0 (68%) Mean age = 73 years At randomization:
–
Median PSA = 1.2
–
PSA > 4 in 22% Progression defined as:
–
Rising PSA x 2
– –
Increasing pain Performance status decline by 2 levels
Relevant Outcomes
• • •
Patients on the intermittent arm enjoyed substantial “drug-free holiday” periods
– –
50% > 1 year 29% > 3 years Patients with PSA declines < 2 ng/mL enjoyed even longer holidays
–
Median time off therapy = 1.5 years The majority of patients who resumed MAB responded
Survival Outcomes
Median Follow-up = 51 months Deaths 5-year survival Intermittent N=314 162 Continuous N=312 159 HR (p-value) 1.03 (p=0.8) 54% 51% Progression (to HRPC) Sexual function Hot flashes 113 Better Better 111 Worse Worse 1.09 (p=0.5) P<0.01
P<0.01
Intermittent vs. Continuous MAB: Issues and Insights
• • • •
MAB vs. single agent LHRH agonist: still controversial
–
Patient-based meta-analyses (8000 patients in 27 trials) showed no significant benefit to MAB
–
Cyproterone acetate is not the ideal anti androgen: trend to worse survival analyses in meta Intermittent therapy better tolerated associated with worse outcome and not Intermittent therapy is a reasonable option patients requiring androgen deprivation for We need to complete SWOG 9346 !!!
Prostate Cancer Trialists Collaborative Group; Lancet, 2000
S9346 Study Schema
Men with newly diagnosed stage D2 prostate cancer and PSA > 5 ng/ml Late Induction Registration Started AD < 6 months prior to registration S9346 Induction Registrations Early Induction Registration (to start AD after registration) AD* = Goserelin + Bicalutamide x 7 months Men treated with AD for 7 months who achieve a PSA < 4 ng/ml If PSA > 4 ng/ml, off protocol Randomization Continuous AD
* = Androgen Deprivation
Intermittent AD
S9346: Study Status
Hussain,et al. Abstract #4517
• • •
Accrual goal 1,512 eligible & randomized.
As of 5/23/06:
–
Induction Registrations: n=2423
–
Randomized: n=1316
PSA assessments were pre-specified by the study at scheduled intervals: and 7 of the induction period months 1, 4, 6
100% 80% 60%
Survival by PSA Normalization Status at End of Induction PSA ≤ 0.2
0.2 < PSA ≤ 4.0
PSA > 4.0
At Risk 602 360 383 Deaths 199 166 322 P < .0001
Median in Months 75 44 13
40% 20% 0% 0 24 48 72 Months After End of Induction 96
At Risk PSA ≤ 0.2 ng/ml 453 210 63 0.2 < PSA ≤ 4.0 219 77 20 PSA > 4.0 92 17 7
120
Multivariate Proportional Hazards Model: Testing Effect of PSA < 4 ng/ml or < 0.2 at Months 6,7 on Subsequent Risk of Death (Estimates and p-values
adjusted for other variables in the model)
Predictor Hazard Ratio (95% CI) Performance Status 2 vs 0,1 1.86 (1.34, 2.60) 1.50 (1.25, 1.80) Bone Pain Present Gleason sum ≥8 Prestudy PSA in 50 unit increments 1.35 (1.13, 1.62) 0.99 (0.99, 1.00) P-value <0.001
<0.0001
0.001
0.005
0.30
# (0.24, 0.38) <0.0001
0.2 < PSA < 4 ng/ml at Months 6 & 7 PSA ≤ 0.2 ng/ml at Months 6&7 0.17
# (0.13, 0.21) <0.0001
#
comparison of these two estimates with a Wald chi-square, p <0.0001.
Significant (p<0.05) univariate predictors with < 15% missing included in model
Conclusions
•
In hormone naive D2 prostate cancer patients treated with AD:
–
Absolute PSA value after 7 months of ADT is the most powerful prognostic predictor of Risk of Death.
–
The observed variability in survival is striking; overall survivals ranging from 13 to 75 months. This variability is a clear reflection of the biologic heterogeneity of this disease.
–
These findings should be considered in the design of future trials .
Predicting the outcome of salvage radiotherapy (RT) for recurrent prostate cancer after prostatectomy
Stephenson et al, Abstract #4514
• • •
Objective : Develop a nomogram for salvage RT outcomes from a database of 1,540 patients with post-prostatectomy biochemical (PSA) recurrence Method : Cox proportional hazards regression analysis Primary endpoint : Disease progression after salvage RT
–
PSA > 0.2 followed by another increase
– –
Initiation of systemic therapy Clinical recurrence
Progression-Free Probability after Salvage Radiotherapy
• • •
Disease Progression: patients (56%) 866 6-Yr PFP: 32%
(CI, 28-35)
10-Yr PFP: 19%
(CI, 15-23)
Outcome Stratified by Pre-Radiotherapy PSA PSA < 0.5
PSA 0.5-1.0
PSA 0.21-0.50
PSA 0.51-1.00
PSA 1.01-1.50
PSA > 1.50
6-Yr PFP 48% 40% 28% 18% Adjusted HR 1.0
1.2 (0.9-1.6) 2.0 (1.5-2.7) 2.3 (1.8-3.0) PSA 1.0-1.5
PSA > 1.5
328 178 96 32 11 414 231 134 51 24 243 122 65 26 12 513 279 97 37 11
Early intervention when the PSA is lowest is associated with improved outcome
Nomogram Predicting 6-Year Progression-Free Probability after Salvage Radiotherapy Concordance Index = 0.69
Salvage RT Nomogram: Take Home Points
• • •
Earlier intervention (when PSA is < 0.5) associated with best outcomes (cure rate of ~ 50%) Results still need to be prospectively validated in a randomized trial Salvage RT can be offered to highly selected patients but likelihood of cure is low
Intermittent chemotherapy in HRPC:
Beer et al, Abstract #4518 ASCENT Trial Docetaxel/DN101 vs. Docetaxel/Placebo
• • •
Eligibility for Intermittent Chemotherapy PSA response (50% reduction confirmed 4 weeks apart) AND Serum PSA <= 4 ng/ml No other evidence of disease progression
• • •
Intermittent Chemotherapy Protocol Serum PSA and clinical examination every 4 weeks Measurable disease assessment every 8 weeks in patient with measurable disease Chemotherapy resumed after a confirmed PSA increase of 50% when the PSA was >= 2 ng/ml or for any other evidence of disease progression.
Intermittent chemotherapy in HRPC: Results from ASCENT
• • •
18% of patients entered intermittent chemotherapy The median duration of the first chemotherapy holiday was 17 weeks (range 4 – 74+ weeks) Response to re-treatment after the first treatment holiday (n=34)
–
56% of patients responded with a ≥ 50% reduction in serum PSA from their post-holiday baseline
–
21% met criteria for stable PSA weeks for at least 12
–
24% progressed on therapy
45% 40% 35% 30% 25% 20% 15% 10% 5% 0% 2% < 4
Duration of first chemotherapy holiday
9% 4 to 8 20% 16% 11% 8 to 12 12 to 16
Weeks
16 to 20 42% >= 20
Testis Cancer: ASCO 2006
• • •
Stage I NSGCT
–
Surveillance: 5 vs. 2 CT scans (Mead, #4519)
–
PET scanning (Huddart, #4520) Metastatic GCT
–
Conventional vs. high dose chemo (Bajorin, #4510)
–
Salvage high dose chemo (Einhorn, #4549) Survivorship issues (Fossa, #4508; Raghavan, #4509)
BEP vs BEP + High-dose Chemotherapy
Bajorin, et al. Abstract #4510
Stratify: Risk Poor vs Intermediate Center MSKCC, ECOG, SWOG, CALGB
R a n d o m i z e BEP x 4 cycles BEP x 2 cycles & HD-CEC x 2 cycles Trial Considerations Use International Risk Criteria for eligibility; BEP as standard arm Randomize all patients; insufficient patients to randomize by marker decline status. Target accrual was 218 pts to detect an improvement of 20% in CR at 1 year (alpha=0.05 and 80% power).
Patient Eligibility*
•
Poor-risk GCT
–
All mediastinal NSGCT
–
Gonadal NSGCT with AFP > 10,000, HCG > 50,000, LDH > 10 x ULN or nonpulmonary visceral metastases
•
Intermediate GCT
–
Seminoma with nonpulmonary visceral metastases
–
NSGCT with AFP 1,000-10,000, HCG 10,000 100,000, or LDH 3-10 x ULN
*Modified IGCCCG criteria from J Clin Oncol 15:594, 1997
BEP vs BEP + High-dose Chemotherapy Event-Free Survival Survival
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 1.0
0.9
0.8
0.7
0.6
P=.40
0.5
0.4
BEP alone (110 Pts, 60 Failures) BEP + HDT (107 Pts, 55 Failures) 0.3
0.2
0.1
12 24 36 48 60 72 84 96 108 120 MONTHS 0.0
0
P=.94
BEP alone (111 Pts, 77 Alive) BEP + HDT (108 Pts, 73 Alive) 12 24 36 48 60 72 84 96 108 120 MONTHS
Salvage therapy with high dose carboplatin + etoposide (HDCE) in GCT patients Einhorn, et al. Abstract # 4549
• • • •
Retrospective review of 184 patients treated with tandem transplant (HDCE + stem cell transplant) Cytoreduction with 0-2 courses of standard dose vinblastine + ifosfamide + cisplatin (VeIP) preceded tandem transplant VeIP not given if progression within 4 weeks of last platinum course (N = 30 platinum refractory) Carboplatin 700 mg/M 2 + Etoposide 750 mg/M 2 x 3 days Maintenance daily oral etoposide for 3 months given to most patients achieving serologic CR
• • • • •
HDCE as salvage therapy: Results
Median time to second HDCE = 28 days (range 20-42) Three early drug-related deaths –ARDS (1) and liver failure (2) Three patients developed AML (2 fatal), 1 GBM 11 of 184 (6%) received only 1 course HDCE due to progressive disease (6) or toxicity (5) 117 of 184 (64%) are continuously NED with median follow-up 42 months
– –
97 of 117 (83 %) greater than 2 year NED 6 additional patients currently NED with further therapy
HDCE as salvage therapy: Results
# of Pts.
# Continuously NED (%) Entire series Second-line therapy Third-line or later Platinum refractory hCG > 1,000* AFP > 1,000* + 184 133 51 30 20 7 117 (64%) 92 (69%) 25 (49%) 15 (50%) 12 (60%) 2 (29%) + progression within 4 weeks last platinum * at start of high dose chemotherapy
Survivorship Issues in Testis Cancer
Fossa et al, Abstract #4508 Raghavan, et al. Abstract #4509
• •
Abstract 4508
–
N = 39,657 survivors
–
Excess non-cancer deaths due to infections and digestive disease Abstract 4509
– –
Case (survivors) and control subjects (male friend) 951 surveys sent, 300 returned, 298 valid
– –
Only 67 control subjects replied Cases (vs. controls) had an excess of late toxicity: cardiovascular, neurological, hematologic, musculoskeletal, and neoplastic
Survivorship Issues in Testis Cancer
Fossa et al, Abstract #4508 Raghavan, et al. Abstract #4509 Issues: 1) What causes late toxicity? Treatment vs. Disease Variability in treatments - Type: chemo, RT - Dose-schedule - RT fields, etc. etc.
2) Duration of follow-up In GCT survivors: LIFELONG!!!
3) Management of late complications