Radiation Oncology/Testis/Seminoma

Seminoma

Epidemiology

• Does not develop before puberty
• Stage distribution: Stage I 85%, Stage II 11%, Stage III 4%
• Risk factors: DES, cryptorchidism, Klinefelter's syndrome, microlithiasis, immunosuppression (3rd most common AIDS malignancy after Kaposis and NHL)
  • Cryptorchidism: Degree of maldescent related to risk with 1:20 risk for intraabdominal vs 1:80 if located in inguinal canal.
• Environmental factors play a role due to significant geographic variation in incidence (highest in Scandinavia, lowest in Asia)

Pathology

• Intratubular germ cell neoplasia (IGCN) is the putative precursor (also called testicular intraepithelial neoplasia, TIN, Tis)
  • Abnormal germ cells in seminal tubules
  • Found adjacent to germ cell tumors in >95% cases
  • Found in all clinical groups at high risk for testicular cancer (cryptorchidism, infertility, ambiguous genitalia, contralateral testes of patients with testicular CA)
  • Stain strongly for placental alkaline phosphatase (normal germ cells are negative)
  • Estimated risk of invasive germ cell tumors is 50% at 5-years, and 70% at 7 years
• Seminomas are not differentiated (unlike NSGCTs, which have some parthenogenesis), and retain some aspects of spermatogenesis
• Classic type seminoma
  • "Fried egg" appearance
  • >90% positive for placental alkaline phosphatase
  • hCG elevated in 15-30%, related to presence of syncytiotrophoblastic cells
  • AFP not elevated
  • Anaplastic seminoma no longer a separate category, since mitotic count is not prognostic
  • Younger patients (20-40)
• Spermatocytic Seminoma
  • Probably not a seminoma, but precursor unknown
  • Older patients (mean 54 years)
  • Different natural history and management (cured by orchidectomy alone)

• Radiation sensitivity
  • Type A spermatogonia: presumed stem cells of spermatogenesis, considered relatively radioresistant. Possibly due to long cell cycle
  • Type B spermatogonia: relatively radiosensitive

Link to University of Virginia Department of Pathology for slides and more detailed info

Lymphatic drainage

• 4-8 lymphatic trunks drain hilum of the testis, and run along spermatic cord up to the internal inguinal ring
• Drain into retroperitoneal LNs between T11-L4, with majority between L1-L3
• Then upward via thoracic duct through mediastinum and to supraclavicular fossae, and occasionally to axillary LNs
• Right testis tumor:
  • Landing zone: Inter-aorto-caval LNs immediately below renal vessels
  • Ipsilateral distribution: para-caval, pre-aortic, right common iliac
  • Para-aortic LNs are considered contra-lateral
• Left testis tumor:
  • Landing zone: Para-aortic LNs below left renal vessel
  • Ipsilateral distribution: para-aortic, pre-aortic, left common iliac
  • Para-caval LNs are considered contra-lateral
• Prior inguinal surgery may disrupt drainage, and redirect to iliac LNs

Staging

T-stage:

• T1 - limited to testis and epididymis without vascular/lymphatic invasion; may invade into the tunica albuginea but not the tunica vaginalis
• T2 - limited to testis and epididymis with vascular/lymphatic invasion; or tumor involving the tunica vaginalis
• T3 - invades the spermatic cord
• T4 - invades the scrotum

N-stage:
Clinical:

• N1 - lymph node mass 2 cm or less in greatest dimension; or multiple lymph nodes, none more than 2 cm in greatest dimension
• N2 - lymph node mass 2 - 5 cm; or multiple lymph nodes, any one mass 2 - 5 cm
• N3 - lymph node mass > 5 cm

Pathologic:

• N1 - lymph node mass 2 cm or less in greatest dimension, and <= 5 nodes positive, none more than 2 cm in greatest dimension
• N2 - lymph node mass 2 - 5 cm; or more than 5 nodes positive, none more than 5 cm; or evidence of extranodal extension
• N3 - lymph node mass > 5 cm

M-stage:

• M1a - non-regional nodal or pulmonary mets
• M1b - other distant mets

Serum tumor markers (S):

• S0 - serum markers within normal limits
• S1 - LDH < 1.5 * upper limit of normal, AND hCG < 5000 mIu/mL, AND AFP < 1000 ng/mL
• S2 - LDH 1.5 - 10 * normal range, OR hCG 5000-50,000, OR AFP 1000-10,000
• S3 - LDH > 10 * normal range, OR hCG >50,000, OR AFP > 10,000

Overall stage:

• IA - T1 N0 M0 S0
• IB - T2-4 N0 M0 S0
• IS - Any T N0 M0 S1-3
• IIA - Any T N1 M0 S0-1
• IIB - Any T N2 M0 S0-1
• IIC - Any T N3 M0 S0-1
• IIIA - Any T Any N M1a S0-1
• IIIB - S2 and either N1-3 or M1a
• IIIC - S3 and either N1-3 or M1a; or M1b
• There is no stage IV

Survival

• Perez, 4th edition

Data from 1985-1991

Stage	Distribution	Survival
I	85%	98%
II	11%	91%
III	4%	75%

Prognostic Factors

Stage I orchiectomy + surveillance

• Multi-national, 2002 PMID 12431967, 2002 — "Prognostic Factors for Relapse in Stage I Seminoma Managed by Surveillance: A Pooled Analysis. Warde P et al. J Clin Oncol. 2002 Nov 15;20(22):4448-52.
  • Pooled data from 4 large registries (Princess Margaret Hospital, Danish Testicular Cancer Study Group, Royal Marsden Hospital, and Royal London Hospital). 638 Stage I patients managed with surveillance after orchiectomy. Median follow-up of 7 years.
  • Multivariate predictors for relapse: 1) tumor size > 4 cm and 2) invasion of rete testis
    • If tumor < 4 cm then age less than 30 independent risk factor
  • 5-year actuarial relapse free survival (RFS) = 82%. Risk of relapse - no risk factors: 12%; one risk factor: 16%; both risk factors: 31%
    • If tumor < 4 cm, risk relapse if > 30 yo: 11%; if age < 30 yo: 20%
  • Comment: not validated by independent data set

Metastatic

• Multi-national, 1997 PMID 9053482, 1997 — "International germ cell consensus classification: a prognostic factor­-based staging system for metastatic germ cell cancers." J Clin Oncol 1997;15(2):594-603.
  • Pooled data from 10 countries. 5202 patients with non-seminoma and 660 with seminoma. Metastatic GCT treated with cisplatin-containing chemo. Median F/U 5 years
  • Good risk: Any primary site AND No nonpulmonary visceral metastases AND normal AFP (LDH and B-HCG can have any value)
  • Intermediate risk: Any primary site AND presence of nonpulmonary visceral metastases AND normal AFP
  • Poor risk: none

Surgery

• Inguinal orchiectomy
  • Inguinal incision
  • High ligation of spermatic cord
• Trans-scrotal orchiectomy contra-indicated
  • Development of alternative lymphatic drainage to inguinal and pelvic LNs
  • Leaves behind intact spermatic cord above scrotum

Stage 0 (TIN) Treatment

• TIN is a precursor for invasive CA, with 70% chance at 7 years. It may be found in ~5% of the contralateral testis of patients with germ cell CA
• A contralateral testicular biopsy is recommended in patients with testicular germ cell tumors. Due to false positives, it is common to do double biopsy
• TIN is effectively treated by 20/10 RT only (no surgery), but this dose damages Leydig cells in ~25%, leading to androgen dependency
• Chemotherapy is not particularly successful
• Results from de-escalation trials show that 16 Gy in standard fractionation is insufficient; testosterone production remains impaired even at 14 Gy
• Lowest effective dose/fractionation is yet to be determined

• German Testicular Study, 2003 (1998-2001) PMID 12644817 - "Radiotherapy with 16 Gy may fail to eradicate testicular intraepithelial neoplasia: preliminary communication of a dose-reduction trial of the German Testicular Cancer Study Group." (Classen J, Br J Cancer. 2003 Mar 24;88(6):828-31.)
  • Prospective. Step-wise dose reduction starting at 18/9 Gy in 2 Gy steps. Results verified by biopsies
  • Dose level 14 Gy aborted after a similar Danish trial (below) experienced a failure at 14 Gy. Cohort 16 Gy was expanded for more statistical power
  • Interim resuls show that 16 Gy is not sufficient to control TIN (there were also viable spermatogonia present). Recommend considering different fractionation schedules. Endocrinology data not yet mature

• Copenhagen, 2002 (Denmark) PMID 11896102 -- "Effect of graded testicular doses of radiotherapy in patients treated for carcinoma-in-situ in the testis." (Petersen PM, J Clin Oncol. 2002 Mar 15;20(6):1537-43.)
  • Prospective. Dose reduction starting at 20/10 in 2 Gy steps. Results verified by biopsies
  • Remission in all patients at 20, 18, and 16 Gy. One relapse at 14 Gy after 20 months
  • Toxicity: Leydig cell function - testosterone decrease for >5 years after RT. Need for androgen substitution similar at all RT dose levels
  • Conclusion: 20/10 safe, 14/7 might result in relapse. Hormone production impaired even at 14 Gy

Stage I Treatment

Treatment Overview

• Historically, seminoma was treated with orchiectomy + inguinal/para-aortic RT, and sometimes also mediastinal RT
• Prophylactic mediastinal RT resulted in significantly increased cardiac mortality, and was ultimately abandoned in the 1960's and 1970's
• Para-aortic fields plus ipsilateral iliac LNs ("dog leg") at 30/15 became standard
• British MRC trial TE10 published in 1999 showed that para-aortic fields only are comparable to classical "dog-leg" extended fields, with lower acute toxicity and improved sperm counts. Para-aortic irradiation became accepted as the new standard, recognizing that there is a small but higher risk of pelvic relapse
• British MRC trial TE18 published in 2005 demonstrated dose equivalence between 30/15 and 20/10, with lower toxicity and faster return to work in the 20/10 cohort
• For patients who had prior inguinal surgery, ipsilateral LNs ("dog leg" field) should still be used
• Meanwhile, since chemotherapy is very effective in more advanced disease, efforts are being made to use chemotherapy in Stage I. British MRC trial TE19 published in 2005 showed comparable outcomes with single dose of carboplatin (AUCx7) to RT (both 20 and 30 Gy). The follow-up is still somewhat short, so no conclusion can yet be drawn
• Some institutions are also experimenting with surveillance only in selected patients. Early outcomes appear good (20% relapse at 15 years), with very high rates of salvage. A risk-adapted management as demonstrated by the Spanish Germ Cell Group may be a reasonable treatment paradigm

Surveillance Only

• Toronto, 2005 (1985-1996) PMID 15708251 -- "Long-term outcome of postorchiectomy surveillance for Stage I testicular seminoma." (Choo R, Int J Radiat Oncol Biol Phys. 2005 Mar 1;61(3):736-40.)
  • Prospective, single-arm. 88 patients with Stage I (normal post-op AFP and hCG) managed with radical inguinal orchiectomy alone, followed by surveillance. 20% rete testis invasion, 45% >4cm. Median F/U 12.1 years, 3 lost to follow-up
  • Relapse-free rate: 5-years 83%, 10-years 80%, 15-years 80%
  • Relapse site: 88% (15/17) below diaphragm. Predictor for relapse: invasion of rete testis (HR 3.5)
  • Salvage: 14/17 treated with RT, 3/17 chemo-RT. 1 had second relapse, and was further salvaged by chemotherapy. All 17 remained disease free after salvage
  • Conclusion: Surveillance is a safe alternative

Risk-Adapted Management

• 2nd Spanish Germ Cell CCG (1999-2003) PMID 16260698 -- "Risk-adapted management for patients with clinical stage I seminoma: the Second Spanish Germ Cell Cancer Cooperative Group study." (Aparicio J, J Clin Oncol. 2005 Dec 1;23(34):8717-23.)
  • Prospective. 314 patients. 100 with no risk factors treated with surveillance. 214 patients with risk factors (tumor >4 cm, rete testis involvement) had carboplatin x2. Median F/U 34 months
  • 5-year DFS: surveillance 94%, chemo 96%. Relapses: surveillance 6%, chemo 3% (1% if tumor >4cm, 9% if rete testis, 6% if both). All but one in retroperitoneum. Median time to relapse 9 months (4-28 months)
  • Conclusion: risk-adapted strategy safe and feasible

• 3rd Spanish Germ Cell CCG (2004-8) PMID 22042940 -- "Risk-Adapted Treatment in Clinical Stage I Testicular Seminoma: The Third Spanish Germ Cell Cancer Group Study." (Aparicio J, J Clin Oncol. 2011 Oct 31. [Epub ahead of print])
  • Prospective. 227 pts. 84 pts (37%) with no risk factors treated with surveillance. 44 pts (19%) had tumor > 4 cm, 25 (11%) with rete testis, 74 (33%) had both. Only the latter group (both risk factors) received treatment w/ carboplatin x 2. All others received surveillance only.
  • Median f/u 34 mo. 16 relapses (7%) for pts on surveillance; 1 relapse (1.4%) for pts on surveillance. 3 yr DFS 88% (surveillance group), 98% (adjuvant carboplatin group). OS 100%.
  • All relapses in retroperitoneal LNs except 1 pt w/ pelvic nodes. Median time to recurrence 14 mos; median node size 2.5 cm. All pts w/ relapse were made NED with chemotherapy.
  • Conclusion: risk-adapted strategy is effective for stage I seminoma. For 2 risk factors: carboplatin. For 0-1 risk factors: observation.

RT Field size

Superior edge of para-aortic field

• Hannover; 2005 (1992-1999) PMID 15788293 -- "Adjuvant radiotherapy in stage I seminoma: is there a role for further reduction of treatment volume?" (Bruns F, Acta Oncol. 2005;44(2):142-8.)
  • Retrospective. 80/163 patients, Stage I seminoma. Treated with PA field extending from T11/T12 (vs historical T10/T11) to L4/L5. Median dose 20 Gy. Median F/U 7.1 years
  • Outcome: 5-year RFS 95%; no relapse above T12
  • Dosimetry: Median reduction of treated volume 16% (13-21%)
  • Conclusion: This approach is recommended to minimize risk of radiation-related late effects

Dog-Leg vs. Para-aortic

• MRC Trial TE 10 (1989-1993)
  • 1999 PMID 10561173 -- "Optimal planning target volume for stage I testicular seminoma: A Medical Research Council randomized trial. Medical Research Council Testicular Tumor Working Group." (Fossa SD, J Clin Oncol. 1999 Apr;17(4):1146.)
  • Randomized. 478 men with Stage I to PA or Dog-Leg. RT 30 Gy. Median F/U 4.5 years
  • Fields: PA (sup T10/T11, inf L5/S1, lat inclusion of ipsilateral renal hilum); Dog-Leg (sup T10/T11; inf mid-obturator foramen; ipsilateral inclusion of renal hilum vertically down to L5/S1, then diagonal to lateral edge of acetabulum, then vertically down to mid-obturator foramen; contralateral transverse process vertically to L5/S1, then diagonal parallel with ipsilateral and vertically down to mid-obturator foramen)
  • Relapse: 9 in each group (NS), but pelvic recurrences 0 DL vs. 4 PA
  • Toxicity: Acute toxicity less frequent and less pronounced in PA arm; sperm counts significantly higher in PA arm (median time to recovery 13 months vs. 20 months if normal, 24 vs. 37 months if abnormal pre-RT)
  • Conclusion: No difference, decreased morbidity in PA-only arm. Recommended PA as standard

(Prophylactic) Mediastinal Irradiation

• MD Anderson, 2004 (1951-1999) PMID 14726503 -- "Mortality after cure of testicular seminoma." (Zagars GK, J Clin Oncol. 2004 Feb 15;22(4):640-7.)
  • Retrospective. 477 patients Stage I or II seminoma treated, 453 (95%) never relapsed and were evaluated. 71 treated with PMI. Median F/U 13.3 years
  • All-cause specific mortality ratio: no difference first 15 years of follow-up (SMR 1.3, NS), but increased thereafter (SMR 1.9, SS). Cardiac SMR 1.61 (SS)
  • Prophylactic mediastinal irradiation (PMI): more cancer deaths (SMR 2.0, SS), and more cardiac deaths (SMR 2.4, SS), but significant only >15 years out

• US National Survey, 1992 (1973-1974) PMID 1447034 -- "Seminoma of the testis: long-term beneficial and deleterious results of radiation." (Hanks GE, Int J Radiat Oncol Biol Phys. 1992;24(5):913-9.)
  • Retrospective. 387 patients followed for >15 years
  • Freedom from recurrence: Stage I 93%, Stage II 96%. Second malignancy 8% (SS)
  • Non-cancer deaths: cardiac 10 (8 received mediastinal RT), SMR 2.3 (SS); pulmonary fibrosis 2
  • Conclusion: Eliminate mediastinal RT in Stage IIA, treat Stage IIB with chemotherapy. Dose shouldn't exceed 30 Gy for Stage I and 35 Gy for Stage II

• Princess Margaret, 1982 (1958-1976) PMID 7085374 -- "Seminoma of the testis: results of treatment and patterns of failure after radiation therapy." (Thomas GM, Int J Radiat Oncol Biol Phys. 1982 Feb;8(2):165-74.)
  • Retrospective. 444 patients with seminoma Stage I-III (using Walter Reed staging)
  • No PMI used for Stage I (testicle, capsule or cord): only 6/329 relapsed in mediastinum; 4 were ultimately not salvaged (1.2%)
  • Stage II (intra-abdominal tumor spread): nonpalpable disease 0/40 relapsed in mediastinum; palpable disease 10/46 relapsed in mediastinum (7/10 salvaged with mediastinal RT)
  • Conclusion: PMI unnecessary in Stage I and II patients

RT Dose

• MRC Trial TE 18 (1995-98)
  • 2005 PMID 15718317 -- "Randomized trial of 30 versus 20 Gy in the adjuvant treatment of stage I Testicular Seminoma: a report on Medical Research Council Trial TE18, European Organisation for the Research and Treatment of Cancer Trial 30942 (ISRCTN18525328)". (Jones WG et al.J Clin Oncol. 2005 Feb 20;23(6):1200-8.)
  • Randomized. 625 pts. Paraaortic radiation (dogleg for patients with prior inguinal surgery). 20Gy/10 vs 30Gy/15 after orchiectomy
  • Relapse: 30 Gy 10 relapses vs. 20 Gy 11 relapses (NS), 2-year relapse rate of 3-4%. 1 death (allocated to 20 Gy)
  • Toxicity: At 4 weeks, 20 Gy significantly better (moderate/severe lethargy 5% vs. 20%); at 12 weeks no difference
  • Conclusion: 20 Gy/10 sufficient, with faster return to work

• German Testicular Study PMID 12644817 - Classen J et al. "Radiotherapy with 16 Gy may fail to eradicate testicular intraepithelial neoplasia: preliminary communication of a dose-reduction trial of the German Testicular Cancer Study Group." Br J Cancer. 2003 Mar 24;88(6):828-31.
  • Please see above, but 16 Gy considered insufficient to eliminate TIN/Tis

RT vs. Chemo

• MRC TE19/EORTC 30982 (1996-2001)
  • Randomized multi-national. 14 countries. 1447 patients, Stage I. Arm 1) 1 cycle carboplatin (AUCx7) vs. Arm 2) radiation (PA or DL AND 20Gy/10 - 30Gy/15).
  • 4-years; 2005 PMID 16039331 - Oliver RT et al. Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial. Lancet. 2005 Jul 23-29;366(9482):293-300. Median F/U 4 years
    • 3-year relapse-free survival: RT 96% vs. carbo 95% (NS)
    • Toxicity: carbo less lethargy and less likely to cause time off work. One seminoma-related death after RT, none after carbo
    • Second testicular tumors: RT 10 vs. chemo 2 (SS)
    • Conclusion: 1 dose of carbo not inferior to RT, but follow-up only 4 years
  • 6.5-years; 2008 ASCO Abstract -- "Radiotherapy versus carboplatin for stage I seminoma: Updated analysis of the MRC/EORTC randomized trial (ISRCTN27163214)." (Oliver RT, J Clin Oncol 26: 2008 (May 20 suppl; abstr 1))
    • Outcome: RFS carbo 95% vs. RT 96% (NS); 1 death from seminoma in RT arm. Predictors: large tumors (>4 cm), carbo AUC <7
    • Second testicular tumors: carbo 2 vs. RT 15 (HR 0.2, SS)
    • Conclusion: Non-inferiority of single dose of carboplatin AUC7; reduced risk of 2nd GCT
  • 6.5-years; 2011 PMID 21282539 -- "Randomized Trial of Carboplatin Versus Radiotherapy for Stage I Seminoma: Mature Results on Relapse and Contralateral Testis Cancer Rates in MRC TE19/EORTC 30982 Study (ISRCTN27163214)." (Oliver RT, J Clin Oncol. 2011 Mar 10;29(6):957-962.) -- Median f/u 6.5 yrs
    • 5-yr RFS 94.7% (carbo) vs 96.0% (RT); HR 1.25. 1 death from seminoma in RT arm.
    • Pts receiving >= 99% of the AUC 7 dose had RFS of 96.1% vs 92.6% of those who had lower doses (p=0.08).
    • Reduction of contralateral GCTs with carbo (carbo n=2 vs RT n=15; HR 0.22).
    • Conclusion: confirmed non-inferiority of single dose carboplatin vs RT; reduced risk of 2nd GCT.
    • Editorial; 2011 PMID 21282532 -- "Carboplatin in Clinical Stage I Seminoma: Too Much and Too Little at the Same Time." (Bosl GL, J Clin Oncol. 2011 Mar 10;29(6):949-952.)

Stage II

Stage IIC (lymph nodes > 5 cm) is considered advanced seminoma and is classified as good risk.

Radiation

• Tubingen; 2003 (Germany)(1991-1994) PMID 12637477 -- "Radiotherapy for stages IIA/B testicular seminoma: final report of a prospective multicenter clinical trial." (Classen J, J Clin Oncol. 2003 Mar 15;21(6):1101-6.)
  • Prospective. 94 patients, seminoma Stage IIA (n=66) or IIB (n=21). RT to para-aortic and high ipsilateral iliac LNs. Dose Stage IIA 30 Gy and Stage IIB 36 Gy. Median F/U 5.8 years
  • Outcome: 6-year RLF Stage IIA 95%, Stage IIB 89%
  • Toxicity: Grade 3 nausea 8-10%; no late toxicity
  • Conclusion: RT for Stage IIA-B seminoma, with reduced portals, yields excellent tumor control and no late toxicity

Chemotherapy

• Spanish Germ Cell Cancer Group (1994-2003)
  • Prospective, non-randomized. 72 pts (18-Stage IIA, 54-Stage IIB). Treatment with 4 cycles of cisplatin + etoposide or 3 cycles of BEP (bleomycin, etoposide, cisplatin).
  • 2008: PMID 18936476 — "Chemotherapy As an Alternative to Radiotherapy in the Treatment of Stage IIA and IIB Testicular Seminoma: A Spanish Germ Cell Cancer Group Study." (Garcia-Del-Muro X, J Clin Oncol. 2008 Nov 20;26(33):5416-5421.)
  • Median f/u 71 m. 83% achieved CR, 17% PR. 5-yr PFS 100% and 87% for Stage IIA and IIB. 5-yr OS 95%
  • Conclusion: Chemotherapy is a highly effective and well-tolerated treatment for patients with stage IIA or IIB seminoma and represents an available alternative that could avoid some of the serious late effects associated with radiotherapy.

Stage III

Stage III is considered advanced seminoma. Patients are considered good risk unless they have non-pulmonary visceral metastases, which are considered intermediate risk.