Testis carcinoma- management- nsgct

MANAGEMENT OF NSGCTs
Dept of Urology
Govt Royapettah Hospital and Kilpauk Medical College
Chennai
1

Moderators:
Professors:
• Prof. Dr. G. Sivasankar, M.S., M.Ch.,
• Prof. Dr. A. Senthilvel, M.S., M.Ch.,
Asst Professors:
• Dr. J. Sivabalan, M.S., M.Ch.,
• Dr. R. Bhargavi, M.S., M.Ch.,
• Dr. S. Raju, M.S., M.Ch.,
• Dr. K. Muthurathinam, M.S., M.Ch.,
• Dr. D. Tamilselvan, M.S., M.Ch.,
• Dr. K. Senthilkumar, M.S., M.Ch.
Dept of Urology, GRH and KMC, Chennai. 2

Tumors of the testis
Tumorigenic hypothesis:
Normal spermatocyte
Totipotential germ cell
Embryonal carcinoma
(totipotential tumor cell)
Seminoma
Choriocarcimoma Yolk sac tumor Teratoma
?
Extra embryonic
differentiation
Trophoblastic
pathways
Yolk sac
pathways
Intra embryonic
differentiation
3
Dept of Urology, GRH and KMC, Chennai.

Pathological classification of testicular cancers
Teratoma Non-seminomatous germ cell
tumour
Teratoma Differentiated (TD) Mature teratoma
Malignant teratoma intermediate
(MTI)
Embryonal carcinoma with teratoma
(teratocarcinoma)
Malignant teratoma
undifferentiated (MTU)
Yolk sac tumour, embryonal carcinoma
Malignant teratoma trophoblastic
(MTT)
Yolk sac tumour; choriocarcinoma
4

INTRODUCTION
• Cancers with high cure rates especially in early
stages
• High orchidectomy should be followed by
Multimodality management which includes
chemotherapy and surgery
• Radiation unlike seminoma not an option
• Toxicities of chemotherapy and adverse
effects of RPLND should be kept in mind
5

40% GCT
6

TERMS
• PCS
• PSCS
• LVI
• EC
• BEP
7

NSGCT vs SGCT
SGCT  NSGCT

Tumour marker by histological type
hCG (%) AFP (%)
Seminoma 7 0
Teratoma 25 38
Teratocarcinoma 57 64
Embryonal 60 70
Choriocarcinoma 100 0

Clinical staging
• CS I is defined as disease clinically confined to the
testis,
• CS II indicates the presence of regional
(retroperitoneal) lymph node metastasis,
(A,B,C)
• CS III represents non regional lymph node and/or
visceral metastasis.
• The AJCC and UICC staging systems were updated
in 2002 and the new systems consider the
presence of LVI in the primary tumor as pT2 in an
otherwise organ-confined tumor.
10

On orchidectomy
• Organ-sparing surgery
– In suspicion of a benign-lesion
– In synchronous, bilateral testicular tumours
– In metachronous, contralateral tumours
– In a tumour in a solitary testis
The tumour should be less than 30% of the
testicular volume.
< 2cm sized tumors
11

HIGH INGUINAL
RADICAL
ORCHIECTOMY
12

13

14

GOOD 56%
15

INTERMEDIATE 28%
16

POOR - 16%
17

Stage I
• Observation
• Retroperitoneal lymph node dissection
• Chemotherapy
18

Indications for observation
• T1 (IA) primary tumor
• Normal radiographs and
physical examination
• Normal serum tumor
markers
• Compliant patients
Surveillance during the
first year should
include:
• physical examination
CXR, serum tumor
markers every 1-2
months
• Quarterly CT scan
Frequency of visits
gradually decreased
afterwards
19

Indications for surgery
• IB patients (T2,T3,T4)N0M0S0
• T1 patients who are non-compliant with
abnormal radiographs tumor markers
20

Rationale of RPLND
(1) the retroperitoneum is the most common site of occult metastatic
disease and the risk of associated systemic disease is low;
(2) 15% to 25% incidence of retroperitoneal teratoma (which is
resistant to chemotherapy) in those with occult metastasis;
(3) low risk of abdominopelvic recurrence after full, bilateral template
RPLND thereby obviating the need for routine surveillance CT;
(4) high cure rates after RPLND alone for patients with low-volume
(pN1) retroperitoneal malignancy and teratoma (pN1-3);
(5) avoidance of chemotherapy in more than 75% or more of patients
if adjuvant chemotherapy is restricted to those with extensive
retroperitoneal malignancy (pN2-3);
(6) high salvage rate of relapses with good-risk, induction
chemotherapy; and
(7) low short- and long- term morbidity when a nerve-sparing RPLND is
performed by experienced surgeons
21

Retroperitoneal lymph node dissection
• Nerve-sparing RPLND must be performed
• Can be nerve dissection bilateral RPLND or
modified RPLND templates
• Avoids the retrograde ejaculation associated
with standard bilateral RPLND
• Because of long term toxicities, chemotherapy
is not standard
22

Chemotherapy
• Treatment of choice in stage IS
• RPLND is required if new disease is
demonstrated post chemotherapy
• Usually two cycles of BEP
23

• Primary chemotherapy offers patients the greatest
chance of being relapse free with any single treatment
modality
• The disadvantages of primary chemotherapy are
(1) it does not treat retroperitoneal teratoma and thus
exposes patients to the potential for chemoresistant
and/or late relapse
(2) long-term surveillance CT of the retroperitoneum is
required, and
(3) all patients are exposed to chemotherapy and the
potential risk of late toxicity (cardiovascular disease and
secondary malignant neoplasms among others).
24

CS II A-B
• ?
• RPLND
• CHEMOTHERAPY
25

RPLND
(1) 13% to 35% of patients have pathologically negative lymph
nodes and thus avoid chemotherapy;
(2) approximately 30% have retroperitoneal teratoma that is
resistant to chemotherapy;
(3) long-term cancer-specific survival is 98% to 100% with RPLND
± adjuvant chemotherapy;
(4) 10% to 52% avoid any chemotherapy and
(5) ejaculatory function is preserved in 70% to 90% of patients
The disadvantages of RPLND are
(1) additional therapy is required in 48% or more of patients;
(2) 13% to 15% have persistence of disease after RPLND and
require a full induction chemotherapy regimen, and
(3) high-quality RPLND may not be deliverable at all institutions 26

CT
The arguments in favor of induction chemotherapy are
(1) 60% to 78% of patients achieve a complete response
and avoid PCS;
(2) treatment can be delivered at community-based
institutions, and
(3) cancer-specific survival is 96% to 100%.
The disadvantages of chemotherapy are
(1) all patients are exposed to the risk of long-term
toxicity of chemotherapy and
(2) those who do not undergo postchemotherapy
RPNLD are at risk of relapse with chemorefractory GCT. 27

stage II (low tumor burden)
• Nerve sparing bilateral RPLND is the
treatment of choice
• Less than 3 cm nodes
• Not multifocal
• No suprahilar, retrocrural or contralateral nodes
• No history of back pain
• Normal or declining markers post orchidectomy
• For cases not satisfying the above criteria,
initial chemotherapy is the treatment of
choice
28

stage II (low tumor burden)
post RPLND
• Surveillance:
• Compliant patients
• Less than six involved nodes
• None greater than 2 cm (pN1)
• Adjuvant chemotherapy:
• pN2/N3
• Extra nodal extension
• Non-compliantpatients
• Usually two cycles of BEP
• Standard treatment at relapse : 3-4 cycles of BEP
29

Stage II (high tumor burden) and stage III
• Usually cisplatin - based chemotherapy followed by
nerve-sparing RPLND is the treatment of choice
• Surgery often essential to achieve a disease free
state
• Management based on an international consensus
for germ cell tumor risk stratification
– Site of primary
– Tumor markers
– Visceral metastasis
30

Good – prognosis NSGCTs
• EP4 or BEP3 is the standard
• Complete response rate ranges form 88-95%
• Various trials have proved the efficacy and
toxicity of various regimens
• Cumulative dose per cycle of treatment is
cisplatin 100mg/m2 and etoposide 500mg/m2
31

Intermediate and poor – risk NSGCTs
• BEP4 is the treatment of choice
• Also various other regimens used
• VIP with hematopoietic growth factor
• High-dose carboplatin based chemotherapy
• A slow serum marker decline after two cycles
is associated with shorter progression-free
and overall survival rates
32

Management of residual disease
• Aim: resection of all residual disease and
normalization of tumor markers
• Done by standard or nerve sparing RPLND
• Template RPLND not useful
• Stage III disease without retroperitoneal
involvement – RPLND not needed
33

Histology of residual disease post chemotherapy:
• Necrosis-45%
• Teratoma-40%
• Viable GCT-15%
• PET scans not useful post chemotherapy-high
false negative rate
34

Limitations of FDG PET
- ≤ 2 weeks after chemotherapy, tumor- and treatment
specific
- Limited resolution in lesions <5mm
(possible positivity of extremely active lesions 5-
10mm)
- Mature teratoma,
negative result expected
 False negative
35

FDG PET and the
„teratoma dilemma“
Residual tumors Resection PET
Fibrosis/
necrosis 40% No Negative
Mature teratoma 40% Yes Negative*
Viable tumor 20% Yes Positive
*Differences in the kinetic rate constants of FDG uptake between mature
teratoma and necrosis/fibrosis, based on kinetic modeling (n=6).
Sugawara Y et al , Radiology 1999;211:249-56

[18F]-FDG-PET in Germ Cell Tumors following Chemotherapy:
Results of the German Multicenter Trial
n= 141
NPV
Negative
predictive value
PPV
Positive
predictive value
ACC
Accuracy
CT
95% CI
0% 51%
43; 60%
51%
43; 60%
PET
95% CI
59%
44; 72%
57%
46; 67%
57%
49; 66%
M. De Wit, ASCO 2006, abstract # 4521
Statistical plan: estimate of >70% accuracy for PET
37

PET in postchemotherapy
non-seminoma residuals
• False positives due to inflammation
• False negatives due to teratoma or small lesions
• High PPV in poor prognosis or relapsed patients after
high dose-chemotherapy
• Strict timing of PET after chemotherapy is key
38

39

PET in postchemotherapy
non-seminoma residuals
Conclusion
• Resection of postchemotherapy NSGCT residuals
continues to be mandatory.
• In poor prognosis and relapse-patients after
HD-chemotherapy, PET might be helpful for decision
making.
– Further prospective trials are needed to explore this
indication of PET.
40

Surveillance :
• Good-risk patients
• Residual disease <1cm
• Infrequent or rare
relapses
RPLND:
• Residual disease >1 cm
• Poor risk patients
• High frequency of
teratoma and viable
GCT
• Templates leave behind
disease in 7-32%
41

Relapse and refractory disease
• 20-30% - relapse or refractory to standard
treatment
• Salvage chemotherapy is the treatment of
choice
• Response to salvage chemotherapy is better
with
• Testis primary
• Initial CR to BEP
• 35-40 % 3-year survival rate
42

Salvage therapy
• Conventional dose salvage therapy
• VeIP Regimen
• TIP Regimen
• High dose salvage therapy
• Carboplatin and etoposide with or without cyclophosphamide
• Europe : high dose chemotherapy not first salvage
• USA: used as first salvage
• High dose chemotherapy (TI-CE) is the treatment of
choice after failure of first salvage (second salvage)
and for late relapses
43

44

Role for surgery after salvage
chemotherapy
• If viable NSGCT persists after salvage
chemotherapy, additional standard
chemotherapy offers no survival benefit
• most of them are not surgical candidates
• Some are given better results with
“desperation” surgeries – DESPERATE RPLND
45

Management of EGGCT
• SURGICAL EXCISION – sacrococcygeal tumors,
mediastinal
• RADIOTHERAPY – pineal
• CHEMOTHERAPY-retroperitoneal, mediastinal
46

Newer agents
• Gemcitabine plus paclitaxel with or without
oxaliplatin
• Flavopiridol plus FOLFOX
• Inhibitor of cdk 4/6
• Oral etoposide – only palliative role
47

Retroperitoneal lymph
node resection
48

Retroperitoneal lymph node resection
• Critical staging information
• Performed with curative intent
• Bilateral RPLND is the standard
• Mortality <1%
• Dissection of precaval, retrocaval, paracaval,
interaortocaval, retroaortic, preaortic, Para -
aortic and common-iliac lymph nodes
49

50

Types of RPLND:
• Bilateral infrahilar
• Suprahilar
• Nerve –dissection
bilateral
• Modified RPLND
templates
51

RPLND types (Infra hilar dissection)
• Rationale:
– The incidence of supra hilar metastasis in low
stage NSGCT is very rare
– Infra hilar dissection diminishes morbidity and
reduces mortality below 1%
• Complications:
– loss of antegrade ejaculation
52

Bilateral infrahilar
• Standard against which
the therapeutic
alternatives are tested
• Ipsilateral gonadal vein
and surrounding fibro
adipose tissue from its
insertion to the deep
ring must be completely
excised
53

RPLND types (Supra hilar dissection)
• Initial method:
– Bilateral suprahilar dissections
– All the nodal tissue between both ureters down to the
bifurcation of the common iliac arteries are dissected
• Complications
– Pancreatic injury - infection
– Renovascular complications
• Current role of supra hilar dissection is reserved
for residual mass after cytoreductive chemo for
advanced NSGCT
54

Bilateral dissection - boundaries
• Ureters laterally
• Superiorly the inferior border of the superior
mesenteric artery extended bilaterally at a
level 1 to 2 cm above the renal arteries
• Inferiorly to the midpoint of the ipsilateral
external iliac artery and to the bifurcation of
the contralateral common iliac artery
including the aortic bifurcation
55

Suprahilar
• Supra-hilar metastasis
rare in low stage NSGCT
• Reserved for residual
hilar or suprahilar
masses following
chemotherapy
• Higher complication
rates
• Chylous ascites
56

Modified RPLND templates
• Limiting dissection in
areas thought to be at
reduced risk for
metastatic spread
• Based on surgical
mapping studies
• Do not identify specific
nerve fibers resection of
all interaortocaval and
ipsilateral nodes
57

• Reduces trauma to
hypo gastric plexus and
contralateral post
ganglionic sympathetic
fibers
• Emerging data:
underestimation of
disease (3-23%)
58

59

“Split & roll” technique
60

Nerve –dissection bilateral
• Prospectively identifies
and preserves both
sympathetic chains, post
ganglionic fibers and hypo
gastric plexus
• Anterograde ejaculation
preserved in over 95%
61

Nerve-Sparing Techniques - requisites
1) In depth understanding of retroperitoneal
anatomy
2) Ability to recognise variations in anatomy
3) Excellent exposure of the retroperitoneum
4) Meticulous application of “split and roll
“ technique
62

Prospective Nerve-Sparing Technique
• Appropriate candidates
– Clinical stage I & low-volume stage II NSGCT
– Selected subset of patients in post chemo RPLND
63

Prospective Nerve-Sparing Technique
• The emphasis is in identification and
preservation of relevant sympathetic nerves
– (1) The sympathetic chains bilaterally
– (2) The postganglionic sympathetic nerves arising
from the sympathetic chains
– (3) The hypogastric plexus (anastomosing network
of nerve fibers anterior to the lower aorta)
64

Complications
• Retrograde Ejaculation
• Infertility
• Prolonged ileus
• Hemorrhage
• Ureteral injury
• Injury to major viscera
• Lymphocele
• Wound infection
• Atelectasis
• Pulmonary embolism
• Bowel obstruction
• Wound dehiscence
65

• Ante grade ejaculation requires:
– Closure of bladder neck
– Seminal emission
– Ejaculation
• Sympathetic fibers : T12-L3
• Parasympathetic fibers : S2,3,4
66

When Primary RPLND ?
• EAU
• Alternative to Chemotherapy or Surveillance in –
markers
• Not willing to undergo primary Chemotherapy
• NCCN
• In CS IIa/b choice of treatment depends on marker
levels,
• And extension of abnormal radiographic findings in CS
IIb (landing zone)
• IGCCCG
• In – markers and lymph nodes 1 -2 cm (CS IIa) as
alternative to Surveillance
67

Primary NS-RPLND
• Advantages RPLND
– True pathological stage
• Imaging 25% suprastaging /10% underestimation
– If PS I : Follow-up (spare Chemotherapy)
– If PS II: Follow-up or reduced Chemotherapy ( 2 vs 3 cycle )
– If Teratoma in the primary (?)
• Disadvantages
– Morbidity (perioperative / retrograde ejaculation)
– Loco-regional treatment
68

Goals Primary NS- RPLND
• As a Staging procedure
– Very low morbidity !!
• As a Curative procedure
– No adjuvant chemotherapy
– Less cycles than primary chemotherapy
• As a Loco-regional procedure
– Systemic relapse
– Relapse outside landing zone
69

A standard established in 1987…
• Phase III trial: 4 BEP vs 4 PVB (n=261)
• BEP > PVB:
– Poor prognosis NSGCT: DFS: 77% vs 61%
(p<0.05) and OS (p<0.05)
– Better tolerance (neurotoxicity)
4 BEP= standard 70

4 BEP are not 5, 6, or 7…
• Giving additional cycles:
– Did not demonstrate any improvement in outcome
– Increases the risk of:
• severe paresthesia,
• auditive toxicity,
• neutropenic fever,
• and fertility troubles
71

4 BEP vs 4 VIP
VIP: Etoposide,Ifosfamide,Cisplatin
Nichols,J Clin Oncol 1998, 16: 1287-93
Hinton,Cancer 2003, 97: 1869-75
n= 304
Intermediate/poorrisk
IGCCCG Poor prognosis (n=181)
OS: 57% vs 62%
72

73

74

75

Toxicities of chemotherapy
• Nausea & vomiting
• Nephrotoxicity
• Myelosuppression
• Peripheral neuropathy
• Auditory toxicity
• Pulmonary toxicity
• Sarcoidosis
76

Vascular toxicity and metabolic syndrome
• The most significant delayed toxicity of BEP
chemotherapy
• Risk of cardiac events 2-7 fold
• Reynaud's phenomenon
• Altered lipoprotein
• Hypercholestrolemia
• Weight gain
• Hypertension
• Erectile dysfunction
• Acute vascular events
77

Hypogonadism & infertility
• Can be due to RT or chemotherapy
• Chemotherapy affects germinal epithelium
directly
• Paternity – 62% at 15 years of surveillance
• Cis-platin main offender
• Cryopreservation of semen should offered to
all patients (RT or chemotherapy or RPLND)
78

Second malignancies
• Second primary GCT in contralateral testis –
2%
• Etoposide - secondary leukemia
– 6% patients receiving cumulative doses of
3000mg/m2
– 2-4 years latency
• Solid tumors with RT and radiation exposure
due to CT and PET scans (cum dose of 100
mSv)
79

Follow-up
• Aim is to:
– find out early and late relapses
– Identify and manage treatment related side effects
– Identify second malignancies
• Frequency varies between institutions
• Yearly visits after 5 years
• Investigation during follow-up visit includes :
80

81

Summary
• Chemotherapy and RPLND cornerstones for
the management of NSGCTs
• Very high cure rates possible in these patients
who are very young in the productive period
• Follow up is essential not only to identify
relapses but also for complications arising out
of therapy in these long term survivors
• Sperm banking is a very good option prior to
treatment
82

83

84

Testis carcinoma- management- nsgct

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