Understanding Testicular Cancer: A MUST for the Medical Oncologist
description
Transcript of Understanding Testicular Cancer: A MUST for the Medical Oncologist
![Page 1: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/1.jpg)
Understanding Testicular Cancer:A MUST for the Medical Oncologist
Jorge A. Garcia, MD., FACP.
Associate Professor Medicine
Director, Advanced Prostate Cancer Program
Cleveland Clinic Taussig Cancer Institute
Glickman Urological & Kidney Institute
Medellin, Colombia November 2012
![Page 2: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/2.jpg)
Case presentation (1)
• 23 y.o. man presented with right testicular swelling x 3 months; u/s revealed heterogenous mass; serum tumor markers: B-HCG nl, LDH nl, AFP 13.2.
• What do you do now?
![Page 3: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/3.jpg)
Case presentation (2)
• Pt. taken immediately to right radical inguinal orchiectomy
• Path = non-seminomatous GCT with 20% embryonal, no LV invasion, confined to testicle (T1)
• Serum tumor markers post-surgery nl with appropriate AFP decline.
• What is the next step in his management?
![Page 4: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/4.jpg)
Case presentation (3)
• CT scan a/p negative for lymphadenopathy; CXR negative
• Pt. present for opinion about further therapy.
• What is your recommendation now??
![Page 5: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/5.jpg)
Not all Testis Cancers are the same
• Early Seminoma–No AFP–Spurious elevations of HCG–Path must have 100% + seminoma cells–Radiotherapy or chemotherapy (recently)
![Page 6: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/6.jpg)
Not all Testis Cancers are the same
• Non-Seminoma–Any serum marker–Path could be mixed–Observation of RPLND
![Page 7: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/7.jpg)
• Non-Seminoma–% Embryonal component
–Lymphovascular invasion
–Paratesticular involvement
• Seminoma–Tumor size (> 4cm)
–Retetestis invasion
Pathological Features & Relapse:
![Page 8: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/8.jpg)
• Stage I
• Stage IIa– Miscroscopic
– LNs < 2cm
• Stage IIb– LNs 2-5cm
• Stage IIc (LNs > 5cm) = Advanced disease
Early Testis Cancer Staging
![Page 9: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/9.jpg)
• Observation/surveillance–30% risk of occult RPL metastases
• RPLND
• Cisplatin-based chemotherapy
Treatment Options for Stage I NSGCT
![Page 10: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/10.jpg)
Clinical trials of adjuvant chemotherapy in ‘high-risk’ clinical stage I NSGCT (1)
Author / year # of pts. Treatment Relapse (median f/u)
• Oliver, 1992 22 BEP x 2 5% (1 pt) at 43 months; 1 relapse at 6m w/ chemo
response, then relapse/death
• Abratt, 1994 20 BEP x 2 0% at 31 months
• Cullen, 1996 114 BEP x 2 1.7% (2 pts) at 4 years; 1 PD/death; 1 w/o GCT on retrosp. review
![Page 11: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/11.jpg)
Clinical Trials of adjuvant chemotherapy in ‘high-risk’ clinical stage I NSGC T (2)
Author / year # of pts. Treatment Relapse (median f/u)
• Pont ‘96 29 BEP x 2 6.9% (2 pts) at 79 months - 1 mature
teratoma s/p sg-> NED; 1 embryonal w/chemo response, then relapse/death
• Chevreau ‘97 38 BEP x 2 (33 pts.) 0% at 36 months
PVB x 2 (5 pts.)
• Studer, 2000 59 BEP x 2 (39pts.) 3.3% (2 pts) at 93 PVB x 2 (20 pts.) months; 1 mature
teratoma resected at 22m; 1 stage II seminoma at 7.5yrs.
![Page 12: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/12.jpg)
Acute and Long-term AEs in Adjuvant Chemo Trials
• Hematologic: G3 leukopenia (3.5%, 18%, 24%); no other significant toxicity
• GI: G3 emesis (27%, 13%); G2 Alopecia and G1Tinitus
--------------------------------------------------------------------------------------
• Fertility: no change in pre- vs. post-sperm density/motility in two studies; 2 others with 1-2 pts. with azoospermia (not different than controls in one study)
• Lung function: no change in PFTs in 2 studies
• Audiometry: high-tone hearing loss (12%, 5%)
• No 11q23 (etoposide-induced) AML reported
![Page 13: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/13.jpg)
• Observation/surveillance–15% risk of occult disease
• Radiotherapy
• Chemotherapy with Carboplatin (only scenario where this agent is accepted in testis cancer)
Treatment Options for Stage I Seminoma
![Page 14: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/14.jpg)
The Argument for Carboplatin for Stage I Seminoma
• Carboplatin is the most effective way to prevent relapse
• Carboplatin is associated with minimal acute toxicity
• Radiation therapy is associated with unacceptable late toxicity
• The risk of late complications from single agent carboplatin is hypothetical whereas the risk of late complications from radiation therapy is well documented
• Carboplatin appears to reduce the risk of second primary germ cell tumors
![Page 15: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/15.jpg)
Stage I Seminomas: Outcomes in published reports
ManagementNumber of Patients Relapse
Median Time To Relapse
(range) 5-year DSS
Surveillance 1032 18.4% 99.6%
Carboplatin(2 cycles)
660 2.0%9 – 15 mo
(4 – 28)100%
Radiation 4630 3.8%13 – 26 mo
(1 – 102)99.7%
![Page 16: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/16.jpg)
EORTC/MRC Randomized Controlled Trial: Single Dose of Carboplatin vs. Radiation
Arm 3-yr Relapse Rate
RT 4.1% (2.9 – 5.6)
Carbo (1 cycle) 5.2% (3.6 – 7.5)
Arm N Relapses 2 year RFS
3 year RFS
Seminoma Deaths
RT 904 36 96.7%(95.3 – 97.7)
95.9%(94.4 – 97.1)
1
Carbo(1 cycle)
573 29 97.7% (96.0-98.6)
94.8%(92.5 – 96.4)
0
RT Oliver, Lancet, 2005;366:293
![Page 17: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/17.jpg)
EORTC/MRC Trial: 1 cycle Carboplatin v. Radiation: Relapse-Free Survival
RT Oliver, Lancet, 2005;366:293
![Page 18: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/18.jpg)
Carboplatin: one or two cycles?
RT Oliver, Lancet, 2005;366:293
![Page 19: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/19.jpg)
Toxicity from Single Agent Carboplatin
AUC = 7 x 2 cycles
400 mg/m2 x 2 cycles
![Page 20: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/20.jpg)
Disability and toxicity during treatment: Radiation vs. Carboplatin RCT
• Radiation
–More missed work
–More moderate to severe lethargy
–More dyspepsia
• Carboplatin
–More thrombocytopenia
RT Oliver, Lancet, 2005;366:293
![Page 21: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/21.jpg)
Radiotherapy Carboplatin
Other
TOTAL
Germ-CellTumors
10 2
4 3
14 5
New Primary Cancers: EORTC/MRC RCT
RT Oliver, Lancet, 2005;366:293
![Page 22: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/22.jpg)
What’s wrong with radiation? Burden of treatment Secondary Cancers Cardiovascular Dz Deaths from digestive
diseases
![Page 23: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/23.jpg)
Do the math• 100 men with stage I seminoma
– 80-82 cured with orchiectomy
– 18-20 destined to relapse on surveillance
– 3-5 relapse after radiation
– 13-17 relapses prevented by radiation
– 6-13 cancers result from radiation
![Page 24: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/24.jpg)
Do the math• 100 men with stage I seminoma
– 80-82 cured with orchiectomy
– 18-20 destined to relapse on surveillance
– 3-5 relapse after radiation
– 13-17 relapses prevented by radiation
– 6-13 cancers result from radiation
![Page 25: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/25.jpg)
False Arguments Against Carboplatin
• Claim: Relapses after radiation are above the diaphragm so surveillance CT scans are not needed
• Fact: In the RT vs. Carbo trial, 41% of relapses in the RT arm were below the diaphragm
In the two large RCTs of radiation for seminoma, two thirds of relapses presented with disease below the diaphragm
![Page 26: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/26.jpg)
False Arguments Against Carboplatin
• Claim: Relapses after radiation are above the diaphragm so surveillance CT scans are not needed
• Fact: In the RT vs. Carbo trial, 41% of relapses in the RT arm were below the diaphragm
In the two large RCTs of radiation for seminoma, two thirds of relapses presented with disease below the diaphragm
• Claim: Late relapses are a risk after carboplatin
• Fact: Relapses more than five years after treatment havebeen reported following RT but NOT followingcarboplatin.
The latest relapse after 2 cycles carbo was at 28 months
![Page 27: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/27.jpg)
False Arguments Against Carboplatin
• Claim: Carboplatin isn’t good enough for GCTs – cisplatin is needed
• Fact: Disease specific survival is between 99.9% and 100%.Two cycles of carboplatin results in a relapse rate of
2%
![Page 28: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/28.jpg)
False Arguments Against Carboplatin
• Claim: Carboplatin isn’t good enough for GCTs – cisplatin is needed
• Fact: Disease specific survival is between 99.9% and 100%.Two cycles of carboplatin results in a relapse rate of
2%
• Claim: Carboplatin causes secondary malignancies.
• Fact: Carboplatin has been associated with secondary leukemias in women treated for ovarian cancer but not at the doses used for seminoma.
![Page 29: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/29.jpg)
False Arguments Against Carboplatin
• Claim: Carboplatin isn’t good enough for GCTs – cisplatin is needed
• Fact: Disease specific survival is between 99.9% and 100%.Two cycles of carboplatin results in a relapse rate of 2%
• Claim: Carboplatin causes secondary malignancies.
• Fact: Carboplatin has been associated with secondary leukemiasin women treated for ovarian cancer but not at the doses used for seminoma.
• Claim: Modern radiation is safe
• Fact: We have no long-term follow-up data on modern radiation
![Page 30: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/30.jpg)
Summary: Radiation Therapy
• Radiation therapy has been proven to result in substantial late morbidity and mortality
• The long-term safety of current radiation therapy which uses lower doses and smaller fields remains unproven
• The switch to lower doses and small radiation fields has resulted in more infra-diaphragmatic relapses after radiation
![Page 31: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/31.jpg)
Summary: Carboplatin
• Single-Agent Carboplatin is very well tolerated
• Two cycles of single-agent carboplatin has resulted in the lowest published relapse rates for stage I seminoma
• One cycle of carboplatin results in equivalent relapse rates to radiation therapy
• With over 1200 patients treated with carboplatin in published reports, only one unsalvageable relapse has been reported
• Whether or not single-agent carboplatin causes any significant late morbidity or mortality remains unknown
![Page 32: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/32.jpg)
Advanced Germ Cell Tumors
• Defined as Stage IIC or higher
- Any pT/Tx N3 (>5cm) M0
• Overall CR’s 70-80%
• Poor outcome 20-30%
• Identification by risk groups
- International Germ Cell Cancer Collaborative Group (IGCCCG)
![Page 33: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/33.jpg)
Risk Assessment of Advanced Disease (IGCCCG) NSGCT - Good Prognosis
• Testis or RP primary, AND
• No nonpulmonary visceral metastases, AND
• Good Markers including all the following:– AFP < 1,000 ng/ml
– HCG < 5,000 IU/L (1,000 ng/ml)
– LDH < 1.5 x upper limit of normal
• 56% of nonseminomas
• 5-year PFS 89%
• 5-year OS 92%
![Page 34: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/34.jpg)
Risk Assessment of Advanced Disease (IGCCCG) NSGCT - Intermediate Prognosis
• Testis or RP primary, AND
• No nonpulmonary visceral metastases, And
• Intermediate Markers including any the following:– AFP >= 1,000 ng/ml and <= 10,000 ng/ml
– HCG >= 5,000 IU/L and <= 50,000 IU/L
– LDH >= 1.5 x Nl and <= 10 x Nl
• 28% of nonseminomas
• 5-year PFS 75%
• 5-year OS 80%
![Page 35: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/35.jpg)
Risk Assessment of Advanced Disease (IGCCCG) NSGCT - Poor Prognosis
• Mediastinal primary, OR
• Nonpulmonary visceral metastases, OR
• Poor Markers including any the following:– AFP >= 10,000 ng/ml
– HCG >= 50,000 IU/L (10,000 ng/ml)
– LDH >= 10 x upper limit of normal
• 16% of nonseminomas
• 5-year PFS 41%
• 5-year OS 48%
![Page 36: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/36.jpg)
Risk Assessment of Advanced Disease (IGCCCG) Seminoma
Good Prognosis
• Any primary site, AND
• No nonpulmonary visceral metastases, AND
• Normal Markers– 90% of seminomas, 5-year PFS 82%, 5-year OS 86%
Intermediate Prognosis
• Any primary site, AND
• Nonpulmonary visceral metastases, AND
• Normal Markers– 10% of seminomas, 5-year PFS 67%, 5-year OS 72%
![Page 37: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/37.jpg)
Treatment for Good-Risk Advanced Germ Cell Tumors
• Cisplatin, Etoposide and Bleomycin (PEB) x 4–Standard of Therapy since the late 80’s
• PVB x 4 v PEB x 4 (E = Etoposide or VP-16)–Randomized Phase III study of 244 patients
–CR 74% v 83% with or without surgery (P not significant)
–High-Tumor Volume (n=157) - CR 61% v 77% (P < 0.05)
–5-year OS greater with PEB (P < 0.048)
–Less toxicities with PEB– Paresthesias (p= 0.02)
– Abdominal Cramps (p= 0.0008)– Myalgias (p= 0.00002)
Williams SD, et al. NEJM 316, 1987
![Page 38: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/38.jpg)
Clinical Trials for Good-Risk Advanced Germ Cell Tumors
Goal is to decrease toxicity
• Are 4 cycles of PEB better than 3 ??
• Administration over 5 days vs. 3 days ??
• Bleomycin or not ??
• Carboplatin vs. Cisplatin ??
![Page 39: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/39.jpg)
Are 4 cycles of PEB better than 3 ??
Adapted from Einhorn LH, et al. JCO 7:387-391.1989. de Wit R, et al. JCO 19:1629-1640. 2001.
Institution n Regimen Response Relapses Toxicities
PEB x 4 6% Relapse
SECSG 184 v 98%
PEB x 3 92% NED
74.9% v 73% (p= 0.41) 2-year PFS
PEB x 4 2-year OS (90.4% v 89.4%)
EORTC 812 v (97% v 97.1%) HR 0.93
PEB x 3 HR 1.02 (80%CI 0.71-1.24)
(80%CI 0.61-1.73)
![Page 40: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/40.jpg)
Administration Schedule: Is it 5 days better than 3 days ?
RANDOMIZATION
PEB x 3 for 3 days(CDDP 50mg/m2 D1-2, VP-16 165mg/m2 D1-3Bleomycin 30mg D1, D8, D15 for 3 cycles)
PEB x 3 for 5 days(CDDP 20mg/m2 D1-5, VP-16 100mg/m2 D1-5 Bleomycin 30mg D1, D8, D15 for 3 cycles)
PEB x 3 + PE x 1 for 3 days(CDDP 50mg/m2 D1-2, VP-16 165mg/m2 D1-3Bleomycin 30mg D1, D8, D15 for 3 cycles)
PEB x 3 + PE x 1 for 5 days(CDDP 50mg/m2 D1-2, VP-16 165mg/m2 D1-3Bleomycin 30mg D1, D8, D15 for 3 cycles)
n = 812
de Wit R, et al. JCO 19:1629-1640. 2001
![Page 41: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/41.jpg)
Administration Schedule: Is it 5 days better than 3 days ?
3days (n = 333) 5 days (n = 329) _____________________ _______________________
Variable No. % No. % p
Complete Response 247 74.1% 240 72.9% 0.718(Chemo + Surgery)
2 year PFS 89.7% 88.8%
HR 1.05 (80% CI 0.78-1.41)
96.4% 97.5% 2 year OS
HR 0.80 (80% CI 0.4-1.42)
Adapted from de Wit R, et al. JCO 19:1629-1640. 2001
![Page 42: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/42.jpg)
What is the Role of Bleomycin ?
• ECOG (Loehrer PJ, et al. JCO 13:470-476, 1995)– Randomized 178 pts to PEB x 3 v PE x 3 (American regimen)
–Complete Response 94% v 88% (p= not significant)
–Greater Treatment Failures in PE arm (post-chemo masses and relapses from CR) (p= 0.004)
–Overall Survival 95% v 86% (p= 0.01)
• EORTC (de Wit R, et al. JCO 15:1837-1843,1997) – Randomized 395 pts to PEB x 4 v PE x 4 (European regimen)
–Complete Response 95% v 87% (p= 0.0075)
–TTP (p= 0.136) and Overall Survival (p= 0.262)
–Neurotoxicity and Pulmonary Toxicity greater with PEB (p< 0.001)
![Page 43: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/43.jpg)
Carboplatin instead of CDDP ?
• MSKCC (Bajorin DF, et al. JCO 11:598-606, 1993)– Multicenter Phase III - Randomized 270 pts to EP x 4 v EC x 4
–Complete Response 90% v 88% (p= 0.32)
–Event-Free Survival inferior for EC arm (p= 0.02)
–Relapse-Free Survival inferior for EC arm (p= 0.005)
–No difference in Overall Survival (p= 0.52)
• MRC/EORTC (Horwich A, et al. JCO 15:1844-1852, 1997)– Multicenter Phase III - Randomized 598 pts to PEB x 4 v CEB x 4
–Complete Response 94.4% v 87.3% (p= 0.009)
–1-year failure-free rates 91% (95% CI, 88%-94%) and 77% (95% CI, 72%-82%) p < 0.001
–Overall Survival 97% v 90% (p= 0.003)
![Page 44: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/44.jpg)
Clinical Trials for Intermediate and Poor-Risk Advanced Germ Cell Tumors
Goal is to Increase Efficacy
• Exploiting agents used in the salvage setting
• Evaluation of the role of dose escalation
• Alternating non-cross resistant Chemotherapy
• Evaluation of HDC-PSCT as in the salvage setting
![Page 45: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/45.jpg)
Poor Risk – Advanced NSGCT’s
• Suboptimal outcome of poor-risk patients – 5-year PFS 41% and 5-year OS 48%
• Goal is to increase efficacy– Alternating non-cross-resistant chemotherapy– Dose escalation– Exploiting agents used in the salvage setting including
HDCT-ASCT
• Single Institutional Trials (MSKCC)*– VAB-6 and VAB-6 + EP (CR’s = 45% and 46%)– VAB-6 + HDCT(EC)-ASCT (CR = 56%)– VIP X4 vs.VIPX2 > HDCT (EC)-ASCT (CR = 53%)
*Motzer et al. J Clin Oncol 1997;15:2546-2552.
![Page 46: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/46.jpg)
Eligibility/Stratification
• Modified IGCCCG*
- Poor vs. Intermediate
• Center (CALGB-MSKCC-SWOG and ECOG)
Ran
do
miz
atio
n (
N=
218)
Cisplatin 20 mg/m2 daily x 5 days Etoposide 100 mg/m2 daily x 5 daysBleomycin 30 mg days 1, 8, and 15G-CSF days 5 mcg/kg days 7-16 excluding bleomycin days
Carboplatin 600 mg/m2 daily x 3 days Etoposide 600 mg/m2 daily x 3 daysCyclophosphamide 50 mg/kg x 3 daysAutologous stem cells day 5Growth factor support
BEP X2 – HDCT (CEC) X2
BEP X4
Target accrual was 218 pts to detect an improvement of 20% in CR at 1 yearwith an alpha=0.05 and 80% power
*Motzer et al. J Clin Oncol 1997;15:2546-2552.Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006.
Intergroup Study of Poor-risk GCT
![Page 47: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/47.jpg)
Outcome: Response Rate
BEP (%)(n=111)
BEP + HD (%)(n=108)
Complete response (CR) 55 56
CR to chemotherapy 46 48
CR to chemotherapy + Surgery 9 8
Incomplete response 44 43
PR – negative markers 5 10
1-year durable CR rate 48 52
Completion of C1-2 BEP 99 100
Completion of C3-4 BEP or HD-CEC 88 77
Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006.
![Page 48: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/48.jpg)
Event-Free Survival and Overall Survival
Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006.
B E P alone (110 P ts , 60 Failures )
B E P + HD T (107 P ts , 55 Failures )
PR
OP
OR
TIO
N E
VE
NT
-FR
EE
0 .0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MO NTHS0 12 24 36 48 60 72 84 96 108 120
p=0.40
B E P alone (111 P ts , 77 Alive)
B E P + HD T (108 P ts , 73 Alive)P
RO
PO
RT
ION
SU
RV
IVIN
G
0 .0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MO NTHS0 12 24 36 48 60 72 84 96 108 120
p=0.94
Overall SurvivalEvent-Free Survival
![Page 49: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/49.jpg)
Long-Term Outcomes According to Initial Marker Decline Status
Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006.
S at D ec line (96 P ts , 78 Alive)
Uns at D ec line (69 P ts , 46 Alive)PR
OP
OR
TIO
N S
UR
VIV
ING
0 .0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MO NTHS0 12 24 36 48 60 72 84 96 108 120
S at D ec line (95 P ts , 38 Failures )
Uns at D ec line (67 P ts , 37 Failures )
PR
OP
OR
TIO
N E
VE
NT
-FR
EE
0 .0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MO NTHS0 12 24 36 48 60 72 84 96 108 120
Overall SurvivalEvent-Free Survival
p=.02p=0.03
1-yr Durable CR 63% vs 45% 2-yr survival 83% vs 68%
![Page 50: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/50.jpg)
Marker Decline Status and Event-free Survival
Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006.
Satisfactory Marker Decline
Unsatisfactory Marker Decline
P=.50 P=.03
B E P alone (62 P ts , 23 Failures )
B E P + HD T (33 P ts , 15 Failures )
PR
OP
OR
TIO
N E
VE
NT
-FR
EE
0 .0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MO NTHS0 12 24 36 48 60 72 84 96 108 120
B E P alone (29 P ts , 20 Failures )
B E P + HD T (38 P ts , 17 Failures )
PR
OP
OR
TIO
N E
VE
NT
-FR
EE
0 .0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MO NTHS0 12 24 36 48 60 72 84 96 108 120
1-yr durable CR 58% vs 66% 1-yr durable CR 61% vs 34%
![Page 51: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/51.jpg)
Marker Decline Status and Overall Survival
Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006.
Satisfactory Marker Decline
Unsatisfactory Marker Decline
2-yr survival 78% vs 85% 2-yr survival 78% vs 55%
B E P alone (31 P ts , 18 Alive)
B E P + HD T (38 P ts , 28 Alive)PR
OP
OR
TIO
N S
UR
VIV
ING
0 .0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MO NTHS0 12 24 36 48 60 72 84 96 108 120
B E P alone (63 P ts , 53 Alive)
B E P + HD T (33 P ts , 25 Alive)PR
OP
OR
TIO
N S
UR
VIV
ING
0 .0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MO NTHS0 12 24 36 48 60 72 84 96 108 120
P=.34 P=.10
![Page 52: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/52.jpg)
Risk Assessment of Residual Masses after Chemotherapy for Seminoma
• Observed in 60-85%
• 20-25% with (+) masses have residual malignancy
• 42% of residual mass > 3cm will have viable malignant cells and should undergo surgery
• Masses < 3cm can be observed
• PET has been shown to be a predictor for malignancy:
(De Santis M, et al. JCO 19, 2001)
• Predicting: 96% of masses < 3cm / 100% of masses > 3cm
![Page 53: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/53.jpg)
Risk Assessment of Residual Masses after Chemotherapy for NSGCT
• Observed in 30-40%
• 15% with (+) masses have viable malignant cells
• Histology is a predicting factor for survival:
–Carcinoma 15% with CR 60-70%
–Teratoma 35% with CR 85%
–Necrosis/Fibrosis 50% with CR 85-90%
• Role of Surgery
• Role of Chemotherapy post-surgery
![Page 54: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/54.jpg)
Viable Cells After Chemotherapy for NSGCT International Study Group
Multivariate Analysis of SurvivalPFS OS
Unfavorable Prognostic Factors Risk Ratio 95 % CI P Risk Ratio 95% CI P
Incomplete surgery 2.75 1.51 – 4.98 <.001 3.82 1.94 – 7.52 <.001
Viable malignant cells > = 10 2.25 1.28 – 3.94 .005 3.31 1.62 – 6.78 .001
Poor or intermediate IGCCC 2.58 1.34 – 4.97 .005 3.22 1.32 – 7.82 .01
Prognostic Index5 – Year PFS 5 – Year OS
Risk GroupNo of Adverse
FactorsPatients
(%) % 95% CI % 95% CI
Favorable 0 22 90 79 - 100 100
Intermediate 1 40 76 65 – 87 83 73 - 93
Poor >= 2 38 41 28 - 54 51 37 - 65
Adapted from Fizazi K, et al. JCO 19, 2001
- 238 pts with viable malignant cells in their resected specimen
- 5 year PFS and OS = 64% and 73%
![Page 55: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/55.jpg)
Summary of Management for Advanced Germ Cell Tumors
• Stratification by IGCCCG
• Good-risk
–PEB x 3 (if Pulmonary toxicity) >PE x 4
• Intermediate-risk
–PEB x 4 v Clinical Trial
–VIP-TIP
• Poor-risk
–PEB x 4 v Clinical trial
–VIP-TIP
![Page 56: Understanding Testicular Cancer: A MUST for the Medical Oncologist](https://reader033.fdocuments.net/reader033/viewer/2022061421/5681593b550346895dc675e1/html5/thumbnails/56.jpg)
Summary of Management for Advanced Germ Cell Tumors
• Salvage Therapy –VIP - TIP - HDCT/PSCT
• Post-chemotherapy residual masses–Observation if <3cm (seminoma)
–Resection if >3cm (seminoma)
–Resection in NSGCT vs. Salvage chemotherapy (poor-risk)