Terapia sistémica de cáncer de testículo

Systemic therapy in testicular cancer

Mauricio Lema Medina MD

Clínica de Oncología Astorga, Clínica SOMA, Medellín

Simposio ACHO GU, Septiembre 23-24 de 2016, Bogotá

Mauricio Lema <mauriciolema@yahoo.com>Togarciaj4@ccf.org

Today at 7:36 AM

Hola Jorge, espero que estés bien. Te escribo para pedirte permiso para usar tu conferencia de cáncer de testículo de 2012 que diste en Medellín, que creo es la mejor conferencia que he escuchado sobre GCTs. Tengo que hablar del tema, y voy a tomarla como base.

Te agradezco que me autorices su uso (con crédito, por supuesto).

Un abrazo,

Mauricio Lema Medina MD

Garcia, M.D. Jorge A <GARCIAJ4@ccf.org>ToMauricio Lema

Today at 8:30 AM

Claro Mauricio

Si necesitas algunas otras slides me avisas

Un abrazo

Case 1

Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion

Not all Testis Cancers are the same

Seminoma- No AFP- Spurious elevations of HCG- Path must have 100% + seminoma cells- Radiotherapy or chemotherapy (recently)

Courtesy of Jorge A. García

Not all Testis Cancers are the same

Non-Seminoma- Any serum marker- Path could be mixed- Observation of RPLND

Non-Seminoma- % Embryonal component- Lymphovascular invasion- Paratesticular involvement

Seminoma- Tumor size (> 4cm)- Retetestis invasion

Pathological Features & Relapse

Stage I Stage IIa

- Miscroscopic- LNs < 2cm

Stage IIb- LNs 2-5cm

Stage IIc (LNs > 5cm) = Advanced disease

Early Testis Cancer Staging

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

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

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)

Radiation 4630 3.8%13 – 26 mo

(1 – 102)99.7%

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)

Carbo(1 cycle)

573 29 97.7% (96.0-98.6)

94.8%(92.5 – 96.4)

RT Oliver, Lancet, 2005;366:293Courtesy of Jorge A. García

EORTC/MRC Trial: 1 cycle Carboplatin v. Radiation: Relapse-Free Survival

Carboplatin: one or two cycles?

Toxicity from Single Agent Carboplatin

AUC = 7 x 2 cycles

400 mg/m2 x 2 cycles

Disability and toxicity during treatment: Radiation vs. Carboplatin RCT

Radiation- More missed work- More moderate to severe

lethargy- More dyspepsia

Carboplatin- More thrombocytopenia

Radiotherapy Carboplatin

Germ-CellTumors 10 2

New Primary Cancers: EORTC/MRC RCT

Sperm count in Swedish clinical stage I testicular cancer patients following modern adjuvant treatment.

Weibring K, Proc ASCO 2016, 4542

182 pts Stage I GCT

Surveillance: 28 ptsSingle-dose carboplatin: 22 ptsBEP x1: 62 ptsRT: 70 ptsSperm Count over time

What’s wrong with radiation? Burden of treatment Secondary Cancers Cardiovascular Dz Deaths from digestive

diseases

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

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: 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 have

been reported following RT but NOT followingcarboplatin.

The latest relapse after 2 cycles carbo was at 28 months

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.

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

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

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

Stage II Seminoma

RT CTBEP x3EP x4

NCCN Guidelines Version 2.2016

Metastatic Low-Risk Seminoma

Carboplatin AUC 10

PET-CT day 17-22

CMR No CMR

Carboplatin AUC 10 x3* (total) Carboplatin AUC 10 x4* (total)

*Cycles when plt>75, and rising

CarPET: Carboplatin AUC 10 in metastatic seminoma – early PET scanning can reduce the amount of treatment whilst maintaining outcome – A Phase

II Trial

Shamash J, Proc ASCO 2016, Abstract 4545

Metastatic Low-Risk Seminoma

Carboplatin AUC 10

PET-CT day 17-22

CMR No CMR

Carboplatin AUC 10 x3* (total) Carboplatin AUC 10 x4* (total)

*Cycles when plt>75, and rising

CarPET: Carboplatin AUC 10 in metastatic seminoma – early PET scanning can reduce the amount of treatment whilst maintaining outcome – A Phase

II Trial

n=21 n=26

Median follow-up of 25.8 mo: OS 100%

PFS: 97.1%Shamash J, Proc ASCO 2016, Abstract 4545

Observation/surveillance- 30% risk of occult RPL metastases

Cisplatin-based chemotherapy- BEP x1-2

Treatment Options for Stage I NSGCT

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

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 monthsPVB 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.

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

Case 2: 23 year-old patient undergoing BEP cycle #2 for early-stage GCT

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)

International Germ Cell Cancer Collaborative Group (IGCCCG)

I – triple C – entre Gs

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%

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

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

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%

Outcomes by IGCCCG risk categories in GCTs

Clinical scenario 5-yr PFS 5-yr OSSeminoma Good-Prognosis 82% 86%Seminoma Intermediate-Prognosis 67% 72%Non-Seminoma Good-Prognosis 89% 92%Non-Seminoma Intermediate-Prognosis 75% 80%Non-Seminoma Poor-Prognosis 41% 48%

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

Clinical Trials for Good-Risk Advanced Germ Cell Tumors

Goal is to decrease toxicityAre 4 cycles of PEB better than 3 ??Administration over 5 days vs. 3 days ??Bleomycin or not ??Carboplatin vs. Cisplatin ??

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% RelapseSECSG 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)

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

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

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)

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)

IGCCCG Good-Risk GCT

EPx4 BEPx3

NCCN Guidelines Version 2.2016

Case 3

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

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.Courtesy of Jorge A. García

Eligibility/Stratification

• Modified IGCCCG* - Poor vs. Intermediate

• Center (CALGB-MSKCC-SWOG and ECOG)

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

Outcome: Response RateBEP (%)(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.

Event-Free Survival and Overall Survival

B E P alone (110 P ts , 60 Failures )

B E P + HD T (107 P ts , 55 Failures )

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

MO NTHS0 12 24 36 48 60 72 84 96 108 120

p=0.94

Overall SurvivalEvent-Free Survival

Long-Term Outcomes According to Initial Marker Decline Status

S at D ec line (96 P ts , 78 Alive)

Uns at D ec line (69 P ts , 46 Alive)PR

MO NTHS0 12 24 36 48 60 72 84 96 108 120

Sat D ec line (95 P ts , 38 Failures )

Uns at D ec line (67 P ts , 37 Failures )

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%

Marker Decline Status and Event-free Survival

Satisfactory Marker Decline

Unsatisfactory Marker Decline

P=.50 P=.03

BE P alone (62 P ts , 23 Failures )

BE P + HD T (33 P ts , 15 Failures )

MO NTHS0 12 24 36 48 60 72 84 96 108 120

BE P alone (29 P ts , 20 Failures )

BE P + HD T (38 P ts , 17 Failures )

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%

Marker Decline Status and Overall Survival

Satisfactory Marker Decline Unsatisfactory Marker Decline

2-yr survival 78% vs 85% 2-yr survival 78% vs 55%

BE P alone (31 P ts , 18 Alive)

BE P + HD T (38 P ts , 28 Alive)PR

MO NTHS0 12 24 36 48 60 72 84 96 108 120

BEP alone (63 P ts , 53 Alive)

BEP + HD T (33 P ts , 25 Alive)PR

MO NTHS0 12 24 36 48 60 72 84 96 108 120

P=.34 P=.10

Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors

Fizazi K, Proc ASCO 2016, Abstract 4504

High-dose Chemotherapy and Autologous Peripheral-Blood Stem Cell Transplant for Relapsed Metastatic

Germ-Cell Tumors: The Indiana University Experience.

Adra N, Proc ASCO 2016, Abstract 4505

Case 4

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

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

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 PIncomplete 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% CIFavorable 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%

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

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)

Terapia sistémica de cáncer de testículo

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