The Role Of RPLND In The Management Of Testis Cancer

Dr Manish I. Patel Urological Cancer Surgeon Westmead Hospital University of Sydney

The Role of RPLND

• Is there a role for primary RPLND?

• Indications for Post-chemo RPLND for NSGCT • Post-salvage chemo RPLND • Desperation RPLND • RPLND for post-chemo seminoma • Templates for RPLND • Nerve sparing RPLND

The Role Of Primary RPLND for NSGCT

• 30% Stage I NSGCT will have occult +RPLN • High risk Stage I will have >50% +RPLN • +RPLN- some will require adjuvant chemo BEPX2 – >5 nodes, >2cm, extranodal extension.(43%) • Despite RPLND some will relapse distantly- 11-34% – Chemotherapy • 1% die • Side effects – Anejaculation: With templates and nerve dissection=1-5% – Small bowel obstruction -1-3%

Role of Primary RPLND-NSGCT Adjuvant Chemo for Stage I NSGCT

• European and Australian Practice: • High risk Stage I NSGCT : >50% risk of relapse • Treat with BEPX2 adjuvant therapy • 2% relapse.

• 1% die • Side effects: – Lung, neuropathy, late malignancy – Late recurrence??

Primary RPLND vs Adjuvant Chemo?

Primary RPLND Adjuvant Chemo Surgery 100% Chemo-2-3 cycles 39% More cycles Death Double therapy 2% 1% 39% 1% 100% 2% 1% 1% Quality of life ?

?

Who should have primary RPLND?

• Can’t have chemo • Fertility is very important

The management of patients with minimal or no residual mass after chemotherapy for NSGCT is controversial.

What is a residual mass after chemo?

Pre-chemotherapy Post-chemotherapy

Post-Chemo NSGCT Resection of tumor is important.

• Teratoma: – Chemo-resistant (Baniel et al. JCO 1995) – Resection is curative.

– Unpredictable malignant potential- TMT.

– Late relapse.

• Median relapse time is 5-7 years.-flawed by short FU studies.

Post-Chemo NSGCT Resection of Viable Cancer is Important.

Predicitive Factors of Outcome In patients with viable cancer on Multivariate analysis.

•Complete resection •Proportion of viable cancer cells •Good risk IGCCC criteria • Complete resection for viable GCT – May be curative – Prognostic

Surgery for necrosis is not beneficial.

• Need to accurately predict those with necrosis.

• Minimise morbidity of surgery.

Instit.

Indiana

Accurately predicting the histology of PC residual masses has been difficult.

Steyerberg Netherlands MSKCC (old) NRH ReHit Study Group 716 PC RPLND Histology from 6 centers.

>90% residual masses >5mm

Histology of mass not resected by various policies

Policy N Necrosis Teratoma Resect None <10mm or >70%red+ 1 0 T. -ve 716 237 Mass <10mm Prediction model >70% necrosis Steyerberg JCO 1998 16(1): 269-274 Mass < 10mm and 1 0 T. -ve 204 181 114 <10mm + prechemo <=30mm <20mm+ 1 0 T. –ve+ prechemo markers normal 113 52 45% 72% 70% 81% 76% 65% 88% 42% 23% 25% 13% 17% 30% 4% Cancer 13% 5% 5% 7% 7% 5% 8%

PC-RPLND Good Risk (IGCCCG) Patients Histology of Residual Retroperitoneal Mass Size

Residual RP Mass Size No Mass <2cm > 2cm and <5cm >5cm and <10cm >10cm and <20cm Total 41 101 41 17 5 205 Total Cancer Teratoma Malignant Transformation Necrosis 0 7 (7%) 3 (7%) 3 (18%) 0 13 (6%) 15 (37%) 26 (26%) 21 (51%) 10 (59%) 3 (60%) 75 (37%) 0 2 (2%) 0 0 1 (20%) 3 (2%) 26 (63%) 66 (65%) 17 (42%) 4 (24%) 1(20%) 114 (56%)

PC-RPLND Good Risk (IGCCCG) Patients Histology of Residual Retroperitoneal Mass Residual Mass Less Than 2cm

Residual Retroperitoneal Mass Size Total Cancer Teratoma Malignant Transformation Necrosis No Mass >0cm and <0.5cm

>0.5cm and <1.0cm

>1.0cm and <1.5cm

>1.5cm and >2.0cm

Total 41 12 24 15 18 111 0 0 0 2 (13%) 2 (11%) 15 (37%) 3 (25%) 6 (25%) 4 (27%) 5 (28%) 4 (4%) 33 (30%) 0 0 0 1 (7%) 1 (6%) 2 (2%) 26 (63%) 9 (75%) 18 (75%) 8 (53%) 10 (56%) 71 (64%)

PC-RPLND Good Risk (IGCCCG) Patients Presence of Teratoma in the Residual RP Mass Residual Mass <2cm and Histology of Primary Tumor

Residual Retroperitoneal Mass Size No Mass >0cm and <0.5cm

>0.5cm and <1.0cm

>1.0cm and <1.5cm

>1.5cm and >2.0cm

Total

Teratoma in Primary

+ + + + + + -

Total 18 23 6 6 8 16 8 7 6 12 46 64 Teratoma in Retroperitoneum 10 (56%) 5 (22%) 1 (17%) 2 (33%) 2 (25%) 4 (25%) 3 (38%) 1 (14%) 5 (83%) 0 21 (46%) 12 (19%)

Variable

PC-RPLND Good Risk (IGCCCG) Patients Variables Predicting Necrosis in the Retroperitoneum

Univariate P value Multivariate Odds Ratio (95%CI) P value Absence of teratoma in the primary <0.001

2.8 (1.1-7.2) 0.03

Normal pre-chemotherapy AFP Size of residual RP mass Normal pre-chemotherapy HCG Pre-chemotherapy RP mass size Initial Stage Age Normal pre-chemotherapy LDH 0.003

0.001

0.107

0.233

0.422

0.461

0.647

2.8 (1.1-7.3) 0.03

0.07

• 87 patients with PC masses <=20mm.

• 23 patients mass<=5mm • All had RPLND • Increasing incidence of teratoma with size of mass.

• No significant pre or post PC factor predicted necrosis.

Decision analysis model predicts increased survival with resection of minimal residual masses.

• Decision analysis model for estimating survival achieved by resection or observation of minimal residual masses.

According to the model: Survival=+2 years with resection of masses 10-20mm.

Survival=+1 year with resection of masses 0-10mm.

What To Do With Post-Chemo Residual Masses?

• Overall incidence of tumor is 44%; teratoma (36%); TMT (2%); viable cancer (6%).

• Incidence of tumor in residual masses <2cm is 35%; teratoma (29%); TMT (1%); viable cancer (5%).

– In a multivariate analysis, absence of teratoma in the primary and normal pre-chemotherapy AFP are predictive of necrosis in the RP.

• Observation of minimal/ no residual masses results in 5% RP recurrence in 4 years. How much later? • What is an acceptable risk of tumour in the RP to necessitate surgery?

Complete Resection after Salvage Chemotherapy is Paramount!

• 580 PC-RPLND at Indiana University.

– 417 after induction chemo.(markers normal) • 10% viable cancer rate.

– 163 after salvage chemotherapy (markers normal) • 55% (90) viable cancer rate.

– 53/90 were able to be completely resected.

» 25 had adjuvant chemotherapy: only 9 (36%) cNED » 28 had no adj. Chemotherapy: 23 (82%) cNED – All incompletely resected patients died.

• Imperative to resect all post-salvage chemo masses.

• Must attempt complete resection as post-op Chemo does not appear effective.

Fox et.al. JCO 1993; 11(7): 1294

Desperation Surgery Has A Place.

• When all chemotherapy options have been exhausted, surgical resection is an option.

– Solitary RP masses have a much better outcome.

• 2 studies Murphy and Wood.

– 63 patients underwent desperation surgery.

– 50/63 had a complete resection.

• 23/50 (46%) are cNED Murphy et.al.J Clin Oncol,

11:

324, 1993 Wood et al. Cancer,

70:

2354, 1992

Management of Post-Chemo Seminoma Mass.-MSKCC

104 PC seminomas Residual mass <3cm N=74 Surgery n=28 Observation n=46 Residual mass =>3cm N=30 Observation n=3 Surgery n=27 Necrosis=28 Relapsed in RP N=2 No relapse Seminoma=6 Teratoma=2 Herr et.al. JUrol 1997 157(3): 860 Puc et.al JCO 1996 14(2): 454

Complete Resection is Important.

All who relapse DOD, All incomplete resections DOD

Management of Post-Chemo Seminomatous Mass.-Indiana University

21 PC seminoma residual mass Residual mass <3cm N=12 NED n=11 relapse n=1 Residual mass =>3cm N=9 NED n=8 Relapse n=1 Approx 50% of non-resected masses completely resolved a median of 12 months form chemotherapy Schultz et.al. JCO 1990 8(4): 756

Prospective studies show a low relapse rate for residual masses =>3cm.

DeSantis. JCO 2004; 22:1034-1039

FDG-PET is useful in masses >3cm.

• FDG PET studies in 51 patients with metastatic pure seminoma who had radiographically defined postchemotherapy residual masses, were correlated with either the histology of the resected lesion or the clinical outcome • Supported by other studies in post induction chemotherapy patients.

DeSantis. JCO 2004; 22:1034-1039

Suggested management of PC-Seminoma

• PC seminoma residual masses <3cm should be observed.

• PC seminoma residual masses => 3cm should be imaged with FDG-PET.

• Complete resection is very important for outcome.

Antegrade Ejaculation Can Be Preserved After Lumbar Sympathetic Nerve Sparing During Post Chemotherapy Retroperitoneal Lymph Node Dissection For Testicular Cancer

Manish Patel & Howard Gurney Department of Urology and Medical Oncology Westmead Hospital

What type of surgery is required?

• With

extensive

prechemo disease in the RP, a full bilateral dissection is required.

– The incidence of tumor away from the primary landing zone or main mass is common

.

(Donohue 1982 JUrol 127)

• The dissection may be limited when the prechemo disease is minimal and limited to the primary landing zone.

– Advantage: limited morbidity – Disadvantage: RP recurrence – Currently performed at Indiana, not MSKCC.

Only a small number of non-palapable tumors will be located outside the modified dissection template.

Herr et.al. J Urol. 1992;148(6):1812-5 • Studied 113 patients.PC RPLND for initial bulky disease. – Tumor was located outside the boundaries of a modified retroperitoneal lymph node dissection in 14/ 60 with residual disease.

– But tumor was present within a palpable mass in 6/14 patients. – If the residual mass was removed and a modified retroperitoneal lymph node dissection was performed only 8% would have tumor left in the retroperitoneum. Rabbani et.al. BJU. 1998; 81(2): 295-300 • 50 patients undergoing PC-RPLND – 39=BRPLND. 1 patient had tumor outside modified template.

– 9= modified RPLND. No recurrence with 55month FU.

– 2= lumpectomy. 1 pt had recurrence.

Lumber Sympathetic Nerves Control Ejaculation

Sympathetic chain Lumber Sympathetic Nerves Hypogastric plexus

Nerve sparing: Dissection of individual sympathetic nerves

Left Sympathetic nerves Aorta IVC Right Sympathetic nerves

R L R Full bilateral Dissection Prima ry Site of Mass L PA Size of Mass (mm) 155 # Nerve preser ved 0 AGE?

N IAC 60 PA/IA C IAC/P C 50 70 0 2 1 N Y Y

Modified Bilateral Dissection

l r r l l l R r l r Cancer side PA 30 IAC 25 25 35 15 45 35 25 20 25 Nerves preserved AGE 4 Y 5 Y 4 Y 3 Y 5 Y 3 Y 3 Y 4 Y 3 Y 4 Y

Unilateral template with nerve sparing

Prima ry Site of Mass Size of Mass (mm) # Nerve preser ved AGE?

L R R L PA IAC IAC 10 20 15 3+2 3+3 3+1 Y Y Y PA 15 3+2 Y

Nerve-sparing PC-RPLND is safe.

Lumber nerve roots spared

All Right 3 right 2 right 1 right All Left 3 Left 2 Left Bilateral All

Antegrade Ejaculation

80% 92% 67% 0% 70% 67% 75% 80%

Total Patients

• Ejaculatory status of 81 patients after nerve sparing PC-RPLND.

30 12 6 1 • 35 months FU – 6 recurrences – 0 in RP.

• This data confirmed by SD Fossa’s data BJC 1999 80(1/2): 249-255 20 3 4 5 Coogan CL.JUrol. 1996; 156(5) :1656-1658.

75%-89% incidence of necrosis in lung if necrosis in RP.

Brenner et.al. JCO 1996 14(6): 1765 24 patients with simultaneous PC-RP and chest + neck resection.

6 (25%) patients had discordent pathology.

Toginini et.al. JUrol 1998 159(6): 1833 143 patients with simultaneous PC-RP and chest resection.

77.5% had the same pathological condition in the chest.

7/40 patients showing RP necrosis has viable cancer in their chest.

Steyerberg et.al.JUrol 1997 158(2): 474 159 patients undergoing PC-RP and thoracotomy.

Neither size nor degree of shrinkage was predicitive of chest pathology.

Necrosis in RP correlated with necrosis in chest 89%.

Steyerberg et.al. Cancer 1997 79(2).

215 patients, 6 centers (ReHit study).- Predictors of necrosis.

no teratoma in primary, normal prechemo markers and single unilateral mass.

RP histology is not sufficiently accurate to eliminate the need to resect chest masses.

Conclusion • It is possible to spare ejaculation with post chemo-RPLND • A minimum of 1 nerve needs preservation along with the hypogastric plexus to maintain ejaculation.

• Templates can be modified based on PC mapping studies by Herr et.al. and Rabbani et.al.

• Groups from Denmark, Indiana and MSKCC have shown that modified dissections are safe.

RP Pathology RP:Tumor RP: Necrosis Total

Histology at Other Sites

Concordance 54% 80% Cancer 4 2 6 Pathology: Other Sites Malignant Transformation 2 Teratoma 7 0 2 1 8 Necrosis 11 12 23 Univariate analysis of predictors of Necrosis at Other Sites Factor Necrosis in RP Histology Normal pre-chemotherapy AFP Absence of teratoma in primary Normal pre-chemotherapy LDH Clinical stage Normal pre-chemotherapy HCG P value 0.035

0.057

0.126

0.212

0.368

0.571

PC-RPLND Good Risk (IGCCCG) Patients Post-operative Complications

Complication All patients Residual Mass <2cm Number Major Small Bowel Obstruction Chylous Ascites Other Minor Atelectasis Lymphocele Prolonged Ileus Blood transfusion Wound Infection Other 205 (%) 5 (2) 2 (1) 2 (1) 3 (1) 13 (6) 6 (3) 7 (3.4) 11 (5) 13 (6) 142 (%) 4 (3) 1(1) 0 2 (1) 7 (5) 7 (5) 1 (1) 8 (6) 7 (5)