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 10 mg/dL) 0 0.25

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