Management of Testicular Cancer

Hassan G. TAANUrology Resident

AUBMC Moderator: Prof. Rami Nasr

• Testicular cancer :1% male neoplasms , 5% urological tumours, incidence 3-10 /100,000 per year in West

• Risk factors : cryptorchidism, Klinefelter’s syndrome, family history, contralateral tumor, and infertility

• Germ cell tumors constitutes 95% of testicular tumors

• Testicular tumours show excellent cure rates. – proper staging– chemotherapeutic combinations– early treatment-based radiotherapy and surgery– strict follow-up & salvage therapies

STAGING Of TESTICULAR CANCER

Staging – AJCC (American Joint Comittee on Cancer)

• Stage 0 – CIS

• Stage I – T1-4/N0/M0– IA – T1– IB – T2-4– IS – ANY T, S1-3

• Stage II – T1-4/N1-3/M0– IIA – N1– IIB – N2– IIC – N3

• Stage III – T1-4/N1-3/M1

Tumour Markers• Alpha-fetoprotein– Trophoblasts– Major serum binding protein produced by foetal yolk sac, liver, GIT– Negligible amounts after 1 year of age– T1/2 :4-6 days

• Beta-human chorionic gonadotrophin– Syncytiotrophoblasts– Secreted by placenta for maintanence of corpus luteum– T1/2:24 hours

• LDH– tumour burden

GERM CELL TUMORS• Seminoma :

– Typical/Classic (82 – 85 % of seminomas)

– Spermatocytic (2 – 12 % of seminomas)—extremely low metastatic potential. Men>50years

– Anaplastic previously classified as separate entity that was believed to be more aggressive/lethal due to greater mitotic activity. However, mitotic index is not associated with worse prognosis, so term no longer used

• Nonseminomatous Germ Cell Tumors Embryonal cell carcinoma Yolk sac tumor Teratoma Choriocarcinoma • Mixed Tumors • Intratubular germ cell neoplasia (CIS)

• Frequency of Histologic causes:

GCT constitute 90 – 95% of all primary testicular malignancies

Seminoma: 30 – 60% Embryonal carcinoma: 3- 4 % in pure form (present in 40% of NSGCTs)

Teratoma: 5 – 10% Pure choriocarcinoma: 1% Mixed GCTs: 60%

PATTERNS OF SPREAD OF GCTs

• Right testis : - Interaortocaval nodes at level of 2nd vertebral body • Left testis : Left paraaortic and preaortic nodes (bounded by left ureter, left renal

vein, aorta and origin of IMA)

• Cross-over: Right to left (but NOT left to right)

• Epididymis: external iliac chain

• Inguinal node mets may occur if: Scrotal involvement of primary tumor Prior inguinal or scrotal surgery Retrograde lymphatic spread from massive retroperitoneal LN deposits

STAGE I SEMINOMA

• The overall CSS rate under surveillance : 97-100% for seminoma stage I .

• The drawback of surveillance :intensive follow-up, repeated imaging of the retroperitoneal lymph nodes, for at least 5 years after orchidectomy

• There was no significant difference between one cycle of carboplatin compared to adjuvant radiotherapy, with regard to recurrence rate, time to recurrence, and survival after a median follow-up of 4 years

• Adjuvant radiotherapy to a para-aortic field or to a hockeystick field , with moderate doses (total 20-24 Gy), will reduce the relapse rate to 1-3%

SURVEILLANCE FOR STAGE I SEMINOMA

• H& PE ,serum tumor markers (bhCG, LDH, AFP) every 3-4 months the first year, every 6 months the second year, then annually thereafter

• Imaging: Chest radiography each visit; CT scan of the pelvis annually for 3 years if status post para-aortic radiotherapy

STAGE IIA-B SEMINOMA

• 15 to 20 percent of seminoma patients have CS II disease, 70% of whom have CS IIA-B. Dog-leg radiotherapy using 25 to 30 Gy is employed at most centers

• Long-term disease-free survival rates are 92% to 100% for CS IIA and 87% to 90% for CS IIB , with in-field recurrences reported in 0% to 2% and 0% to 7% of cases, respectively

• Relapses are cured in virtually all cases with first-line chemotherapy, and disease-specific survival approaches 100%

• Induction chemotherapy using first-line regimens (BEP×3 or EP×4) is an accepted alternative to dog-leg radiotherapy for patients with bulky (>3 cm) and/or multiple retroperitoneal masses because the risk of relapse is lower than with dog-leg radiotherapy (15% and 30% of CS IIA and IIB patients in one center)

Surveillance for stage IIa/b seminoma

• H& PE and serum tumor markers every 3-4 months in years 1-3, every 6 months in year 4, and then annually thereafter

• Imaging: Radiography each visit; CT scan of the abdomen and pelvis during month 4 of the first year

STAGE IIC AND III

• Patients with CS IIC and III seminoma are treated with induction chemotherapy

• Ninety percent of patients with advanced seminoma are classified as good risk and should receive either BEP×3 or EP×4 chemotherapy

• Complete radiographic responses are reported in 70% to 90% of patients, and the 5-year overall survival is 91%

• With BEP×4 chemotherapy, the 5-year overall and progression-free survival is 79% and 75%, respectively

Surveillance for stage IIc, III seminoma

• H& PE and serum tumor markers every 2 months the first year, every 3 months the second year, every 4 months the third year, every 6 months the fourth year, and then annually thereafter

• Imaging: Chest radiography each visit; CT scan of the abdomen and pelvis during month 4 of the first year status post surgery (otherwise, every 3 months until stable); PET scan as clinically indicated

Follow Up - Seminoma

Relapses

• Surveillance/Radiotherapy– BEP x 3

• Chemotherapy cohort– VIP x 4 (vinblastine, ifosfamide and cisplatin) or– TIP x 4 (paclitaxol, ifosfamide and cisplatin)

Prognostic factors for occult metastatic disease in testicular cancer

Impact on fertility and fertility-associated issues

• In patients in the reproductive age group, pre-treatment fertility assessment (testosterone, LH and FSH levels) should be performed, and

semen analysis and cryopreservation should be offered.

• If cryopreservation is desired, it should preferably be performed before orchidectomy, but in any case prior to chemotherapy treatment

• In cases of bilateral orchidectomy or low testosterone levels after treatment of TIN, life-long testosterone supplementation is necessary

• Patients with unilateral or bilateral orchidectomy should be offered a testicular prosthesis

Non Sminoma Germ Cell Tumors

• Approximately one third of NSGCT patients have CS I with normal postorchiectomy levels of serum tumor markers

• The optimal management of these patients continues to generate controversy because the long-term survival associated with surveillance, RPLND, and primary chemotherapy approaches 100%

• Up to 30% of NSGCT patients with clinical stage I (CS1) disease have subclinical metastases and will relapse if surveillance alone is applied after orchidectomy.

Surveillance In NSGCT CS1

• Close surveillance after orchidectomy in CS1 NSGCT patients showed a cumulative relapse rate of ~30%, with 80% of relapses occurring during the first

12 months of follow-up, 12% during the second year and 6% during the third year, decreasing to 1% during the fourth and fifth years

• 35% of relapsing patients have normal levels of serum tumour markers at relapse. 60% of relapses are in the retroperitoneum

• Despite very close follow-up, 11% of relapsing patients presented with large-volume recurrent disease.

• surveillance within an experienced surveillance programme may be offered to patients with non-risk stratified clinical stage I non-seminoma as long as they are compliant and informed about the expected recurrence rate as well as the salvage treatment

Follow Up – Surveillance Stage I NSGCT

Primary chemotherapy In NSGCT CS1

• Several studies involving two courses of chemotherapy with cisplatin, etoposide and bleomycin (PEB) as primary treatment for high-risk patients (having ~50% risk of relapse) have been reported .

• In these series, involving > 200 patients, some with a median follow-up of nearly 8 years , a relapse rate of only 2.7% was reported, with very little long-term toxicity

• Two cycles of cisplatin-based adjuvant chemotherapy do not seem to adversely affect fertility or sexual activity

• slow-growing retroperitoneal teratomas after primary chemotherapy

Retroperitoneal lymph node dissection

• If RPLND done, ~30% have lymph node involvement, pathological stage II (PS2) disease . RPLND -> -ve L.N (PS1), ~10% of the PS1 patients relapse at distant sites.

• The main predictor of relapse in CS1 NSGCT managed by surveillance, for having PS2 disease and for relapse in PS1 after RPLND- vascular invasion in the primary tumour .

• Patients without vascular invasion constitute ~50-70% of the CS1 population, and these patients have only a 15-20% risk of relapse on surveillance, VS 50% relapse rate in patients with vascular invasion

• The risk of relapse for PS1 patients is < 10% for those without vascular invasion and ~30% for those with vascular invasion

• If two (or more) courses of cisplatin-based chemotherapy are given adjuvant to RPLND in PS2 cases, the relapse rate is reduced to < 2%, including teratoma relapse .

• The risk of retroperitoneal relapse after a properly performed nerve-sparing RPLND is very low (< 2%), as is the risk of ejaculatory disturbance or other significant side-effects

• In a randomised comparison of RPLND with one course of PEB chemotherapy, adjuvant chemotherapy significantly increased the 2-year recurrence-free survival to 99.41% as opposed to surgery, which had a 2-year recurrence-free survival of 92.37%

• It was also found that one adjuvant PEB reduced the number of recurrences to 3.2% in the high-risk and to 1.4% in the low-risk patients

CS1S with (persistently) elevated serum tumour markers

• If the marker level increases after orchidectomy, the patient has residual disease. If RPLND is performed, up to 87% of these patients have pathological finding in the nodes .

• An U/S of the contralateral testicle must be performed, if this was not done initially.

• The treatment of true CS1S patients is still controversial. They may be treated with three courses of primary PEB chemotherapy and with follow-up as for CS1B patients (high risk) after primary chemotherapy, or by RPLND .

• The presence of vascular invasion may strengthen the indication for primary chemotherapy as most CS1S with vascular invasion will need chemotherapy

sooner or later

PS – pathologic stage,PD – progressive disease, NC – no change