Germ Cell Tumors Flashcards
What are the risk factors for Germ Cell Tumors?
1) Prior Hx of GCT
2) FHx of GCT
3) Cryptorchidism
4) Testicular dysgenisis
5) Klinefelter syndrome (47XXY)
Which is more sensitive to RT? Seminioma or NSGCT?
Seminoma
What is the ratio of the composition of residual mass in GCT?
40% Fibrous tissue
40% Teratoma
20% Disease
Why do we need to resect a Teratoma?
1) Resistant to chemo and RT regimens for testicular GCTs
2) Recurrence can occur if viable GCT present in the residual mass
3) Malignant transformation can occur
- sarcomas/ adenoCas can arise from Teratoma. These can be resistant to chemo used for testicular GCTs and are a/w poor prognosis
4) Organ function may be compromised
Tell me about the S staging in the staging of GCT
Sx:N.A. /not performed
S0: Normal
S1:
LDH 10 X NI or
hCG >50 000 mIu/mL or
AFP >10 000 ng/L
What is the M staging for GCT?
M0 no distant mets
M1 distant mets
- M1a: non regional nodal or pulmonary mets
- M1b: distant mets
Tell me about the pathologic nodal staging
pN1 =
- Mets with a LN mass 2cm or less in greatest dimension, and
- less than or equal to 5 LN+, none >2cm
pN2 =
- LN mass >2cm, but not more than 5 cm; OR
- > 5LN positive, but none >5cm; OR
- evidence of Extranodal extension of tumor
pN3 =
- Mets with a LN mass >5cm
Tell me about the T staging for GCT
pT0 =
No evidence of primary tumor (eg histological scar)
pTis =
Intratubula Germ cell neoplasia (Carcinoma-in-situ)
pT1 =
- Tumor limited to testis and epididymis without vascular/lymphatic invasion;
- Tumor may invade into the tunica albuginea but NOT the tunica vaginalis
pT2 =
- Tumor limited to the testis and epididymis with vascular/lymphatic invasion, OR
- Tumor extending through the tunica albuginea with involvement of the tunica vaginalis
pT3 =
- Tumor invades the spermatic cord with or without vascular/lymphatic invasion
pT4 =
- Tumor invades the scrotum with or without vascular/lymphatic invasion
M1a + S0 = what stage?
Stage IIIA
M1a + S1 = what stage?
Stage IIIA
M1b = what stage?
Stage IIIC
Nodal involvement = what stage?
Stage II
N1 = Stage IIA at least
N2 = Stage IIB at least
N3 = Stage IIC at least
What is stage IS?
pTx N0 M0 S1-3
What is the approximate half life of AFP and hCG ?
AFP = 5-7 days hCG = 1.5 to 3 days
What is the risk of Contralateral CIS?
5-10%
When do we consider Contralateral testicular biopsy?
Controversial
Only if nudes ended testes/atrophy
Name me the types of GCT.
1) Seminoma
- Seminoma with syncytiotrophoblastic cells
2) Nonseminomatous GCT
- Teratoma (Dermoid cyst, mono dermal Teratoma, Teratoma with somatic type malignancy)
- Trophoblastic tumors (Choriocarcinoma)
- Yolk Sac tumor (endodermal sinus tumor)
- Mixed GCT
- Embryonic carcinoma
3) Spermatocytic Seminoma
- Spermatocytic Seminoma with sarcoma
Name me the sex cord-stromal tumors
1) Sertoli Cell
2) Leydig Cell
3) Granulosa cell
4) Mixed types
5) Unclassified
What are the main morbidities with RPLND?
1) Retrograde ejaculation resulting in infertility
2) Bowel dysfunction
3) Lymphoedema
4) Chylous ascites
What are the possible toxicities from adjuvant chemotherapy for GCT?
1) 5dB hearing loss
2) 5% reduction in lung function
3) 10% decline in GFR
4) 20% long-term peripheral neuropathy
5) 30% impaired spermatogenesis at 3 years
6) Increased risk of CVS toxicities
7) risk of 2nd malignancies
- 2x increase in solid tumors 10 years after treated GCT
- 0.5% risk of developing leukemia, related to total dose of Etoposide
RPLND vs 1# BEP in Stage I disease. Which is better and why?
AUO trial JCO 2008 by Albers et al.
N=400
Randomized into 2 arms after orchidectomy:
60% of patients are pT1 tumors
- RPLND performed according to community standards
- 1# BEP
F/u 5 years, RESULTS:
- 2y RFS: 99.5% (Chemo) vs 92%
Tell me about the SWENOTECA management program for Clinical Stage I NSGCT
Torgrim Tandstad JCO 2009
Aim: reduce risk of relapse and thereby reducing need for salvage chemo, but maintain a high cure rate.
N=750 Treatment strategy depended on presence or absence of vascular tumor invasion. 2 big groups: 1) Vascular invasion present - BEP 1 or 2 # (patient's Choice) 2) Vascular invasion not present. This is then divided into 2 further groups according to pt's choice : (A) Surveillance (B) BEP 1 cycle
RESULTS:
F/u 5 years:
Recurrence rate: 42%(VASC+) s 13% (VASC -)
After 1 course of BEP, 3% of VASC+ and 1% of VASC- patients relapsed
CONCLUSION:
- 1# BEP reduced the risk of relapse by ~90% in both VASC+ and VASC- CS1 NSGCT
What are the treatment options for CS IA/IB pure Seminoma?
1) Surveillance
- for pT1 or pT2 tumors
2) Single agent Carboplatin AUC 7 X 1 cycle or 2 cycles
3) RT
Tell me about the MRC TE19/EORTC 30982 Study.
Oliver et al. First in Lancet 2005, updated JCO 2011
Aim: Compare RT with chemotherapy in Seminoma treatment
N=1500
2 arms:
1) RT (para-aortic strip or dog-leg field)
2) 1# Caroboplatin AUC 7
RESULTS:
2y RFS 97% vs 98% (Chemo)
3y RFS 96% vs 95% (Chemo)
5y RFS 96% vs 95% (Chemo)
Patients given Carboplatin less lethargic and less likely to take time off work than those given RT
2nd primary testicular GCT reported in 2% (RT) vs 0.5% (Chemo)
- at 6.5y, clear reduction I the rate of Contralateral GCT. HR 0.2
Between Carboplatin and CDDP, which would you choose and why?
CDDP
Bajorin et al JCO 1993
N=270 with good-risk GCTs, were randomized to:
1) 4# EP Q21days
- Etoposide 100mg/m2 D1-5
- CDDP (20) D1-5
2) 4# EC Q28days
- Etoposide 100mg/m2 D1-5
- Carboplatin (500) D1
RESULTS:
CR: 90% (EP) v 88% (EC)
Median f/u of 2 years, EFS and RFS inferior for pts treated with EC
No difference in OS evidence
Tell me about the 2nd Spanish GC cancer Cooperative study
Jorge Aparicio JCO 2005
Aim: To assess the efficacy of a risk-adapted treatment policy for stage I Seminoma.
N=300
CS I Seminoma after orchidectomy
2 arms:
1) Surveillance
- No risk factors
- 30% of patients
2) 2# Adjuvant Carboplatin
- >4cm tumors (40% of patients)
- Rete testis involvement (10.5%)
- both risk factors (16%)
RESULTS:
- chemo well-tolerated. 8% p/w G3/4 toxicity
- Relapses in 3% (chemo) an 6% (surveillance)
- 5y DFS 93% (Surveillance) and 96% (Chemo)
- Overall 5y survival 100%
Conclusion: Adjuvant Carboplatin is effective in reducing the relapse rate in those with Stage I Seminoma with risk factors
- risk-adapted strategy is safe and feasible.
What about the Third Spanish Germ Cell Cancer Study Group paper?
Jorge Aparicio JCO 2011
Aim: To confirm the efficacy of a risk-adapted treatment strategy for those with clinical stage I Seminoma.
- to reduce risk of relapse
- reduce proportion of patients receiving chemo
- maintaining a high cure rate.
200 patients, s/p orchidectomy
20% with tumors >4cm
10% with Rete testis involvement
30% with both criteria
2 arms:
1) Surveillance
2) 2# Adjuvant Carboplatin
- only those with Tumors >4cm AND Rete testes involvement. = 30% of patients
RESULTS:
- Relapse rate at 3y = 7% (surveillance) and 1.5% (Chemo)
- 3yDFS = 88% (surveillance) and 98% (Chemo)
- 3y OS 100%
What is the Rete testis?
A communicating network of seminal channels traversing the mediastinum (or helium) of the testis
For disseminated good-risk GCT, how many courses of BEP would you give and why?
3# BEP
1) de Wit JCO 2001
2) Einhorn JCO 1989
1) de Wit JCO 2001
2 aims:
- test equivalence of 3# and 4#
- test equivalence of 3-day course vs 5-day course
2x2 factorial design.
N=800
RESULTS:
- 2y PFS 90%~ For 3 and 4#
- 2y PFS 89% vs 90%, for 5-versus 3-day regimen
- Frequencies of hematologic and non-hematologic toxicities similar.
- QoL better with 3#, no diff between 3- and 5-day regimens.
2) Einhorn JCO 1989 N=180 1y DFS 98% (3#) vs 97%(4#) Results: - 3# reduces toxicity, cost, inconvenience
What is the evidence for using 4# EP in metastatic Good-risk GCT?
Kondagunta JCO 2005
N=300
4# EP
- Etoposide 100mg/m2, CDDP 20mg/m2 D1-5 Q21 days
RESULTS:
- 98% received CR
- 93% responded to chemo alone, 5% responded to chemo + surgery to remove viable disease
30% with NSGCT had findings of Teratoma/viable GCT at post chemo surgery.
How does BEP 3# and EP 4# compare?
GETUG study by Culine Annals of Oncology 2007
N=250
2 arms:
- 3# BEP
- 4# EP
RESULTS:
Med f/u 4.5 years
4y EFS 91% vs 86% (EP)
4y OS ~
Conclusions: Both resulted in similar results
What are the risk factors for Bleomycin toxicity?
Heavy smoker
Age > 40 yo a/w 2x increased risk
Poor renal function
- >80% of drug is rapidly eliminated by kidney
Dose > 400 U cumulative of Bleomycin
High O2 exposure
Previous RT
- whether prior to or simultaneously with Bleomycin
GCSF usage
Severity of underlying malignancy at presentation
Chemotherapeutic agents - high cumulative doses of CDDP
BEP > PVB (CDDP, Vinblastine, Bleomycin).
What is the evidence?
Williams NEJM 1987
Aim: to compare efficacy and toxicity of BEP and PVB
N=250 DFS 70% (Vinblastine) vs 80% (Etoposide) - with or without subsequent surgery - p not significant Those with high tumor volume, DFS: - 60% (Vinblastine) - 75% (Etoposide) Survival higher in those who had Etoposide. P=0.048 Regimens similar in terms of myelosuppression and pulmonary toxicity. Etoposide caused fewer: - parasthesias - abdominal cramps - myalgia
BEP and VIP. Which is better?
BEP > VIP.
Nichols JCO 1998
ECOG/SWOG/CALGB study
Aim: Compare BEP vs VIP (Etoposide, Ifosfamide, CDDP) as primary treatment for advanced disseminated GCT
N=300
2 arms:
1) 4# BEP
2) 4# VIP
RESULTS: Overall CR Rate 37% (VIP) vs BEP 31% Favorable response rate 60%~ Failure-free survival at 2 years ~60% 2yOS ~70% G3 or worse toxicity (ESP hematologic, genitourinary) more common in VIP
What are the long-term concerns with RT?
Infertility
GI manifestations
Secondary malignancies
What is standard 20Gy radiation. What does it encompass?
Delivered to infradiaphragmatic area, including para-aortic LN.
With or without ipsilateral ileoinguinal LN
What does a “dog leg” field of RT encompass?
Bilateral para-aortic and pelvic LN
What is the benefit of PA-strip radiation ?
Incidence of azoospermia was significantly decreased
What is the supporting evidence for using 20Gy of RT for Stage I Testicular Seminoma (as opposed to 30Gy)
TE18/EORTC study Jones JCO 2005 N=600 2 arms: - 20Gy/10#/2 weeks - 30Gy/15#/3 weeks
RESULTS:
Absolute difference in 2y Relapse rate 0.7%
Treatment with 20Gy of RT is unlikely to produce relapse rates of more than 3% higher than that for 30Gy RT.
What are the poor prognostic factors for relapsed GCT?
1) Response to treatment (CR vs PR vs PD)
2) Duration of remission
- PD during or within 4/52 of completion of chemo
3) Duration of remission
- If PD after 2 years = late relapse
4) High tumor burden
5) Extra-testicular primary
What are the standard-dose first-line salvage regimens?
1) VeIP
- Vinblastine + Ifosfamide + CDDP
2) TIP
- Pacliatxel + Ifosfamide + CDDP
3) VIP
- Etoposide + Ifosfamide + Cisplatin
- If did not receive Etoposide in 1st line chemotherapy
If a patient received VIP as first-line chemo, what is the optimal 2nd line chemotherapy?
Not well-defined Alternatives include: - High Dose chemotherapy - PVB (CDDP, Vinblastine, Bleomycin) - GEMOX
What do you know about High dose chemotherapy + ASCT For met GCT?
Does it work?
Yes.
Einhorn NEJM 2007
Retrospective review of 184 consecutive patients where HDC+ASCT was given as 1st or 2nd salvage treatment.
N=180
170 patients were given 2 consecutive courses of HDC, with each followed by an infusion of autologous peripheral-blood hematopoietic stem cells
- HDC = Carboplatin 700mg/m2 + Etoposide 750mg/m2 D1-3
In 110 patients, cytoreduction with 1 or 2 # of Vinblastine was given before HDC
RESULTS:
- 116/184 had CR without relapse during the median f/u of 4 years (60%)
- As 2nd line = 135 patients =70%
» 94 were DFS during f/u = 50% of whole cohort, 70% of all 2nd-line patients
- As 3rd line or later = 49 patients = 18.5%
» 22/49 were DFS
CONCLUSION = Testicular tumors are potentially curable by means of HDC + ASCT
What constitutes a mini-transplant?
Non-myeloablative or reduced-intensity transplant
This is a type of allogenic transplant
Uses lower, less toxic doses of chemo +/- RT
Cells from both donor and patient may exist in the patient
Cause the GVT effect and work to destroy the cancer cells
What is a tandem transplant?
Autologous transplant
S/p 2 sequential courses of HDC with stem cell transplant
The 2 courses are given several weeks to several months apart.
What is Bleomycin-induced lung injury?
Life-threatening interstitial pulmonary fibrosis
Organizing pneumonia
Hypersensitivity pneumonitis
How do patients with Bleomycin injury present?
Sub acutely between 1-6 months after Bleomycin
But may also occur during therapy or after 6 months
Nonproductive cough, dyspnoea, pleuritic or substernal chest pain Fever Tachypnoea Auscultatory crackles Lung restriction Hypoxemia
What do you find on lung function testing in one with Bleomycin injury?
Decreased FVC and decreased TLC
Which is more sensitive to RT? Seminoma or NSGCT
Seminoma
What is the treatment for Stage IS for Seminoma and for NSGCT?
Seminoma = RT (subdiphragmatic area)
NSGCT = Chemo, as for good risk
How often is it for residual masses to occur in Seminoma?
> 80 of time
In a Seminoma, which tumor marker will be elevated?
AFP : Never elevated in pure Seminoma
Beta-hCg = 15-20% in advanced disease
LDH = 40-60% of patients
What other tumor types can cause a rise in hCG?
Neuroendocrine Bladder Kidney Head Neck Lung Kidney GI Cervix Uterus Vulva Lymphoma Leukemia
What are the different types of Teratoma tt you know of?
Dermoid cyst
Mono dermal Teratoma
Teratoma with somatic type malignancy
Which is more Chemosensitive? Seminomas or NSGCT?
Seminomas
What is the cure rate like for Germ Cell tumors?
~100% in Stage I disease and > 80% in metastatic disease
Where are extragonadal GCTs usually found?
How frequent are they?
~5% of of GCTs
Usually in body’s mid line
-eg retro peritoneum, mediastinum, cerebrum
What genetic aberration is common to both TGCT and EGGCT?
isochromosome 12p - pathognomonic
What are the risk factors for developing testicular intraepithelial neoplasia (TIN) in the Contralateral testis?
Testicular atrophy, ESP if volume
What is considered a late relapse?
Occurs in 2-3% of survivors.
New tumor growth > 2 years after at least 3# of preceding chemotherapy
These relapses do not respond so well to chemotherapy
- oftentimes they are yolk sac tumor (usu AFP+) or slow-growing Teratoma
Tell me about the prognostic score for patients with relapsing non-Seminoma or Seminoma
Lorch et al, 2010 ASCO
5 parameters: (P.P.P A.H)
1) Primary site: Gonadal (0) Extra-gonadal (1) Mediastinal (3)
2) Prior response: CR/PRm-(0), PRm+/SD (1), PD (2)
3) PFI: >3m (0) 3m or less (1)
4) AFP salvage: Normal (0), 1000 or less (1), >1000 (2)
5) hCG salvage: 1000 or less(0), >1000 (1)
*m- = marker negative* Score the total above then regroup into categories: (0) =0 (1 or 2) = 1 (3 or 4) = 2 (5 or more) = 3
Then add histology score points.
Pure Seminoma = -1
NSGCT or mixed = 0
Final prognostic score: -1 = very low risk 0 = low risk 1 = intermediate risk 2 = high risk 3 = very high risk
What are the possible late toxicity for pts with/had GCT?
1) Infertility (Testosterone levels)
- 10y post-treatment paternity rate significantly reduced, in part due to pre-existing fertility problems.
- 15y fatherhood rate ~70%
2) 2x risk of late post-chemo CVS disease
3) Early-onset metabolic syndrome
- usually 3-5 years after to
4) Pulmonary toxicity
5) Renal toxicity
6) Oto-toxicity
7) Neurotoxicity
8) Second solid non-germ cell tumor
- ESP GI tract and urinary tract
- risk is doubled after RT, with latency of 10 years or more
9) Cumulative risk of leukemia
- occurs usually
When do you check serum tumors markers for GCTs?
Seminoma: After treatment completes
NSGCTs: every cycle. If rises, considered as PD.
What is associated with a rise in AFP?
Malignant:
- GCT
- HCC
- Gastric
- Lung (rare), Colon (Rare), pancreatic (rare)
Non-malignant:
- Alcohol abuse
- hepatitis
- Cirrhosis
- Biliary tract obstruction
- Hereditary persistence (rare)
What is associated with a rise in hCG?
Malignant:
- NET
- Bladder, kidney
- H&N, Lung
- GI
- Cervix, uterus, vulva
- Lymphoma, leukemia (Rare)
Non-malignant:
- Marijuana
- Hypogonadism
What is the half-life of AFP?
5-7 days
What is the half-life of hCG?
1.5-3 days
