Testicular CancerGerm Cell Tumors

Marc WygodaDepartment of Oncology

Testicular Cancer

Germ Cell Tumors

• Most common Solid Tumor in men 20-35– 1% of cancers in males– Great impact on “years of life” saved

• 95% arise in testis• 5% are “extra-gonadal”: mediastinum,

retroperitoneum, pineal body

• Model of a Curable Cancer even in advanced stage• Model of a Cancer with Tumor Markers playing a

crucial role in management

Risk Factors

• Age

• Family history

• Personal history

• Cryptorchidism (undescended testicle)• Association with Infertility (mild)

• Klinefelter’s syndrome

Age at presentation

Symptoms

• Painless lump or swelling of testicle• Pain or discomfort in a testicle or the scrotum

• Breast tenderness or growth

• Symptoms of advanced cancer– lower back pain, – abdominal pain, – shortness of breath, – chest pain

How is Testicular Cancer Diagnosed?

• Physical examination

• Ultrasound of Testis

• Blood tests / tumor markers

• Diagnosis is confirmed by surgically removing the testicle

• Needle biopsy not used (except in very specific situations)

• CTS of Chest, Abdomen and Pelvis– No role for MRI. – Mild role of PET (only in Seminoma)

DICTUM FOR ANY SOLID SCROTAL SWELLINGS

All patients with a solid testicular mass should be regarded as malignant, unless proven

otherwise

Radical inguinal orchiectomy

• Most men are still able to have children after the removal of one testicle

• No effect on sexual function (men with sexual problems after surgery should have their testosterone level checked)

• Some men may choose to have an artificial testicle implanted

Histologic Subtypes of GCT

SEMINOMA (40%)

• Classical (32%)• Anaplastic (4%)• Spermatocytic (4%)

NON SEMINOMA (60%)

• Embryonal Ca (25%)• Teratoma (25%)• Yolk sac Tumor• Choriocarcinoma

Mixed GCT: 40%

Staging

• Serum tumor markers (S): AFP, β-HCG, LDH

Tumor Markers• AFP

– Half-life: 5-7 days– Produced by several Non Seminoma subtypes (embryonal, teratocarcinoma,

yolk sac, mixed tumors)– Never produced by Seminoma or pure choriocarcinoma– Falsely elevated in liver dysfunction, viral hepatitis and ETOH

• β-HCG– Half-life: 24-36 hours– Produced by syncytiotrophoblastic tissue– All choriocarcinomas, 40-60% embryonal, 5-10% seminoma– Falsely elevated in hypogonadism and marijuana use

• LDH– Most useful in advanced seminoma & when other markers are not ↑– Many false positives

How is Testicular Cancer Treated?

• Depends on stage of cancer and type of tumor

• More than one treatment may be used– Surgery– Active surveillance– Radiation therapy– Chemotherapy

• Patients should talk with their doctor about whether treatment plan could affect sexual function and fertility before treatment begins

Seminoma

• Tend to remain localized or spread only to LN

• The disease spreads in an orderly fashion: retroperitoneal LN – (SII). Mediastinal/supraclavicular LN (SIII). Lung and then non pulmonary (brain/bone/liver)

• If LN <1cm repeat in 6w if normal → follow marker decline to distinguish between stage 1 and disseminated disease.

• Tumor marker analysis should be performed before surgery and, if elevated, 7 days after surgery to determine the half-life kinetics. Tumor markers should be monitored until normalization.

Seminoma: stage at diagnosis

• stage I: 70-80% • Stage II (Retroperitoneal Nodes): 15-20%

• Stage III (Other metastases): 5%

Lymph Nodal spreadFor Right & Left Sided Testicular Tumors

Testis cancer: seminoma stage IManagement options

• Surveillance only

• Adjuvant Radiotherapy

• Adjuvant Chemotherapy

Surveillancestage 1 seminoma

• Relapse rate in surveillance studies:

Year ref N FU Relapse (%) Late (>4y) DOD

1993von der Maase, Eur J Cancer 14:1931, 1993

261 4y 19% 1%

1997Warde, J Urol 157:1705, 1997

225 5y 15% 1/3 0.50%

1992Horwich, Br J Cancer 65:775, 1992

103 5y 18% 0%

Testicular Lymphatic Drainage

Stage I Seminoma adjuvant Radiotherapy

Classical “Hockey Stick” Field

Adjuvant radiotherapystage I seminoma

• 22.5-25 Gy ( ~3 weeks of treatment)

• Target: Paraaortic + Ipsilateral Pelvic Nodes

• Relapse rate: 0-2%

Hadassah experience in stage I

adjuvant Radiotherapy

• 36 patients with stage I seminoma

• Post orchiectomy “hockey stick “ irradiation

• 22.5-24 Gy in 1.5 Gy fractions

• Testicular shell was always used

• Semen preservation was recommended to all patients

Outcome

• Median follow-up 98 mo

• No recurrences!

• One contralateral second primary GCT

• No effect of Radiotherapy on fertility

Stage II Seminoma - Treatment

• Cancer has spread to lymph nodes in the retroperitoneum, but not lymph nodes in other parts of the body

– Stage IIA: ≤ 2 cm: Radiotherapy

– Stage IIB: 2-5cm: Radiotherapy or Chemotherapy

– Stage IIC: >5cm: Chemotherapy

• Prognosis: > 95% Cure

Stage III-IV Seminoma - Treatment

• Chemotherapy

Stage I Non Seminoma Management

• Surveillance

• Adjuvant Chemotherapy

• Surgery: RPLND (Retro Peritoneal Lymph Node Dissection)

Surveillance for Markers negative stage I Non seminomas

• Appropriate for “low risk” patients:– Compliant patient– No vascular/lymphatic invasion– No dominant presence of Embryonal Carcinoma

• Regular physical examination, CT scans, chest x-rays, and blood tests (Markers), performed every few months for the first 2 years and less often thereafter

• Risk of Relapse is then ~25%• At relapse excellent chances of cure with chemo

Adjuvant Chemotherapyfor High Risk stage I NSGCT

• Definition of High Risk Stage I NSGCT:– Lympho-vascular invasion, or– Embryonal Carcinoma Predominance (≥ 45%)

• Natural History: ~ 50% recurrence rate

Moul et al: Cancer Res 54:1, 1994

MRC Prospective Surveillance Study 1984 - 1987

Relapse-free Rate by vascular invasion

Months from orchidectomy

168144120967248240

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1.0

.9

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No VI (n=199)

VI (n=192)

• 23 publications (1979-2001; 2587 cases) repeatedly confirm overwhelming importance of VI

• RR is 45-50% in VI positive tumorsVergouwe et al JCO 2003

Hadassah Adjuvant Chemotherapy PEB x2 Protocol

• Entry: Feb. 1993 → June 2011• Eligibility:

– High Risk Stage I NSGCT– Normal Chest-Abdomen-Pelvis CTS– AFP and ΒHCG normal, or return to normal

according to ½ lives after Orchiectomy

• Number of pts: 31 • Age: 15-53 ( median 25 )

• Sperm Banking recommended to all pts

Results

• Median Follow-Up: 9.4yrs (range: 0.5-19 yrs)

• # of Relapses: 1 (3%) (Retroperitoneal mass 3months after PEB Completion in a pt with pure EC without LVI → RPLND: Growing Mature Teratoma)

• DFS: 97%• OS: 100%

• 3/31 Controlateral Testicular Cancer:– Stage I Embryonal Ca after 3 yrs → NED– Stage IIB Seminoma after 7yrs → XRT → NED– Stage I Mixed GCT (Teratoma + Seminoma) after 19m → NED

• No other Secondary Malignancy seen

Fertility

• 11/31 pts have not attempted to father children

• 16/20 pts known to have desired it, were able to impregnate their wives, and to father 34 healthy children (1-4), without need to use their banked sperm.

• Overall Fertility Ratio: 80% (85%?)

Retroperitoneal Lymph node dissection

• Major morbidity is ejaculatory dysfunction• Modified nerve sparing RPLND preserves function in >

90%– Identify the sympathetic nerves– Dissection is limited to below the level of the IMA on the ipsilateral

side only

STAGE I NSGCT382 pts

RPLND Adjuvant PEB x 1

Pathologic stage 1Follow up

Pathologic stage 2PEB x 2

Follow up

German Randomized Trialin all stage I NSGCTRisk Grouping by T Stage

German Randomized Trialin all stage I NSGCTRecurrence Free Survival

Stage II to IV Non Seminoma

• Chemotherapy

• Important role for Surgery to resect post chemo residual mass

Advanced Testicular Cancer: Risk Group Classification

• Based on tumor location, tumor spread, and serum marker levels

• 3 groups for both seminoma and non-seminoma– Good risk– Intermediate risk– Poor risk

• Patients with poor-risk cancer still have about a 50% chance of successful treatment

PFS and OS according to risk

5y PFS (%) 5y OS (%)

prognosis seminoma Non seminoma

seminoma Non seminoma

good 82 89 90 92-94

intermediate

67 75 72 80-83

poor 41 71

Cancer Treatment: Chemotherapy

• Classical Protocol: PEB– Platinum (Cisplatinum)

– Etoposide (VP-16)

– Bleomycin

• Common Side effects may include fatigue, infection, nausea and vomiting, alopecia.

• Rare side effects: hearing loss, skin marks, numbness and tingling, lung damage, kidney damage, cardiovascular disease, and secondary cancers

Nowadays very little severe long term side effects

Highly Curable Cancereven in Advanced Stage

Before chemo After chemo

Lung mets before and after Chemo

Metastatic SeminomaChemotherapy PEB x 3

Post Chemo RPLNDPathological findings

– 40-45% teratoma– 40-45% Necrosis– 10-20% viable Tumor

PROGNOSIS

Seminoma Nonseminoma

Stage I99% 95% to 99%

Stage II 95% 90%

Stage III 80% to 85% 70% to 80%

Post treatment Follow up

• Regular physical examinations and/or medical tests may be required to monitor for the following long-term effects– Effect of bleomycin on lungs– Effect of chemotherapy on kidneys, blood vessels and

lipids profile– Effect of cisplatin on nerves, hearing, and the brain– Secondary cancers– Fertility problems– Testosterone levels

• Fear of recurrence is common: psychological support

Relapse of Testicular Cancer

• Still Curable

– 2nd line Chemotherapy

– High Dose Chemo with Stem Cell Rescue

– Post chemo Surgery

Conclusions

Imperial Surgery Turkey/Persia 15th century

Bibliotheque Nationale, Paris

Testicular Germ Cell tumors

• Model of highly curable cancel

• Stage I pts have a long term cure rate close to 100%

• Low to intermediate burden metastatic pts cure rate: ~90%

• Very advanced pts are infrequent: cure rate ~50-60%

• Pts can still be cured after relapse

Progress Against Testicular Cancer

Five-Year Survival

80

82

84

86

88

90

92

94

96

98

100

1975

1977

1979

1981

1983

1985

1987

1989

1991

1993

1995

1997

1999

2001

2003

2005

2007

2009

Year of Diagnosis

% o

f Pa

tien

ts S

urv

ivin

g F

ive

Ye

ars

Source: National Cancer Institute

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