High-Risk Clinical Stage I NSGCT: The Case for...

High-Risk Clinical Stage I NSGCT:The Case for RPLND

Andrew J. Stephenson, MD, FRCSC, FACSDirector, Urologic Oncology

Associate Professor of SurgeryGlickman Urological and Kidney Institute

Cleveland Clinic

Treatment Options for CS I NSGCT

1. Surveillance 2. RPLND3. BEP x 2 chemotherapy

• Survival approaches 100% for all

• 70-80% cured by orchiectomy overall

Guidelines for Clinical Stage I NSGCT• USA: National Comprehensive Cancer Network

– Low-risk: surveillance, RPLND– High-risk: RPLND, BEP x 2 chemotherapy, surveillance

Motzer et al. J Natl Comp Canc Netw 2006

• Europe: European Germ Cell Cancer Consensus Group, European Society of Medical Oncology– Low-risk: surveillance, BEP x 2 chemotherapy– High-risk: surveillance, BEP x 2 chemotherapy

“For very restricted cases, only if surveillance or adjuvant chemotherapy is declined by the patient due to very specific or personal reasons, a nerve-sparing RPLND may be considered. This treatment has the highest treatment burden with the lowest efficacyand should be performed by specialized surgeons only.”

Schmoll et al. Ann Oncol 2009; Krege et al. Eur Urol 2008

Société Internationale d’Urologie-ICUD Guidelines: CS I NSGCTClinical Stage I NSGCT

Rising post-orchiectomy AFP or HCGYES

BEPx3 or EPx4 chemotherapy

False-positive STM elevations should be

considered in patients with slightly elevated

and stable AFP or HCG levels

NO

High-risk of occult metastasis based on histopathological and CT parametersNO

SurveillanceBEPx2 may be

considered in regions without expertise in

diagnosis and treatment of GCT

YES

Surveillance*BEPx 2* NS-RPLND*+/- Adjuvant

BEPx2 or EPx2 for PS II

* Treatment based on patient preference and physician-hospital expertise

Stephenson et al. Urology 2011

CS I NSGCT: Treatment Selection

• Risk of occult retroperitoneal and systemic disease

• Treatment-related morbidity

• Patient factors (compliance, preference)

• Unique institutional expertise

• “Double-therapy”

MSKCC (LVI+, EC predom): 1989-1993 48%; 1999-2006 33% PS II, relapse

SWENOTECA: LVI+ 40% relapse on surveillance

German TCSG (42% LVI+) 18% pathologic stage II

Risk-Adapted Therapy: Accurate Today?

High Risk Relapse Low Risk Relapse

1981-1992 60 53% 81 17%

1993-2004 44 39% 120 12%

Princess Margaret Hospital

Duran et al. ASCO 2007; Stephenson et al. J Clin Oncol 2005;

Tanstad et al. J Clin Oncol 2009; Albers et al. J Clin Oncol 2008

Normal CT?

Leibovitch et al. J Urol 1995; Hilton et al. AJR 1997

Normal CT?

Leibovitch et al. J Urol 1995; Hilton et al. AJR 1997

Any node > 5-6 mm in

primary landing zone is suspicious

for mets

Active Treatment for Clinical Stage I NSGCT

• Favorable morbidity profile• Avoids chemotherapy in > 75% of

pts with LVI+ or EC predom• Retroperitoneum is the most

common site for mets in CS I• RPLND is therapeutic in 90% of

men with low-volume mets• RPLND is most effective means for

clearing the retroperitoneum• Survival (not recurrence) is

objective• 33-60% of pts with mets have pN2-

3 disease is 1-2 cycles sufficient?

• High-quality RPLND is not deliverable

• BEPx2 is well tolerated

• Systemic relapse may occur in up to 25% pathologic stage I

• RPLND is staging and not therapeutic

• Retroperitoneal teratoma is bengin and relapses may be cured with surgery

• Lowest risk of recurrence

Pro-RPLND Pro-BEP x 2

CS I NSGCT: Retroperitoneum is Therapeutic Focus

• Systemic relapse 1.2%

• Only 24% of CS I NSGCT require any form of chemotherapy

• RPLND alone curative in 90% with pN1

• Majority with PS II have pN1 disease, 22% have teratoma

1989-1998 1999-2002 P value

RPLND Patients 345 108Elevated STM 8% 0 < .001CS IIB 7% 0 .03Path Stage II 44% 33% .06PN1 40% 64% .01Teratoma 21% 22% .9

Stephenson et al. J Clin Oncol 2005

Teratoma• Benign

• Uncertain biology:–Growing teratoma syndrome–Malignant transformation–Late recurrence

• 20-30% in RPN in low-stage NSGCT

• Absence in testis Absence in retroperitoneum

• Resistant to chemotherapy

• Outcome = surgical complete resection

Morbidity of RPLND

• Small bowel obstruction: 1%

• Mid-line scar: 100%

• Ejaculatory dysfunction:–Centers of excellence < 5% with nerve-sparing–Other 30-40% with modified RPLND

Late Toxicity of Cisplatin-Based Chemo

• Cardiovascular disease: 1.4-7.1-fold riskMeinardi J Clin Oncol 2000; Huddart J Clin Oncol 2003; van den Belt-Dusebout J Clin Oncol 2007

• Secondary malignancy: 1.8-2.1 fold riskTravis J Natl Cancer Inst 2005; van den Belt-Dusebout J Clin Oncol 2007

• Risks of CVD + 2nd malignancy similar to smoking

• Other: Raynaud’s, neuropathy, ototoxicty

• Long-term data lacking for BEPx2

• No safe lower limit!

• Phase III, randomized trial of BEP x 1 vs. RPLND for CS I NSGCT

• Primary endpoint: Recurrence

• “BEP x 1 superior to RPLND”

Albers et al. J Clin Oncol 2008

• Phase III, randomized trial of BEP x 1 vs. RPLND for CS I NSGCT

• Primary endpoint: Recurrence

• “BEP x 1 superior to RPLND”

“The study puts an end to time-honored surgical approaches to management of CS I NSGCT”

C. Nichols, JClin Oncol 2009


CS I NSGCT

All Risk

N = 382

R

A

N

D

O

M

I

Z

E

Arm 2: Modified RPLND

BEP x 2 for PS II (pN1-3)

Arm 1: BEP x 1

Progression

Free

Survival


How Not to Treat Clinical Stage I NSGCT !

CS I NSGCT

All Risk

N = 382

R

A

N

D

O

M

I

Z

E



Arm 1: BEP x 1

Progression

Free

Survival



Patients treated at 64 centers across Germany

Rationale for BEP for all? only 18% pathologic stage II

CS I NSGCT

All Risk

N = 382

R

A

N

D

O

M

I

Z

E



Arm 1: BEP x 1

Progression

Free

Survival



Rationale for modified RPLND? 9 of 15 relapses were local

CS I NSGCT

All Risk

N = 382

R

A

N

D

O

M

I

Z

E



Arm 1: BEP x 1

Progression

Free

Survival



Rationale for BEP x 1? 22% pN2-3

CS I NSGCT

All Risk

N = 382

R

A

N

D

O

M

I

Z

E



Arm 1: BEP x 1

Progression

Free

Survival



No cancer-specific mortality in either arm

CS I NSGCT

All Risk

N = 382

R

A

N

D

O

M

I

Z

E



Arm 1: BEP x 1

Progression

Free

Survival



Nguygen et al. J Clin Oncol 2010

Treatment of CS I NSGCT My Thoughts…• Surveillance for low-risk

• RPLND or surveillance for high-risk

• BEPx2 for pts unfit for surveillance and without access to surgeons experienced in RPLND

• CS I NSGCT is most often a retroperitoneal only disease with risks of teratoma similar to high-stage → best managed by RPLND

• Favorable long-term morbidity profile of RPLND relative to BEPx2

High-Risk Clinical Stage I NSGCT: The Case for...

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