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Germ Cell Tumor of the Testis: Treatment of Seminoma

General Treatment Options of Seminoma Germ Cell Tumors

Radical orchiectomy:

Radical orchiectomy includes inguinal incision, exposure of the spermatic cord, delivery of the testicle into the surgical field, and ligation and transection of the spermatic cord at the inner inguinal ring. For technique and complications, see section inguinal radical orchiectomy. If desired (and the costs are covered), a testicular prosthesis can be inserted during the same procedure. Radical orchiectomy is always the first therapeutic step, except in cases of life-threatening metastases, which require chemotherapy first.

Organ preservation:

Tumor enucleation (after an inguinal approach) is an option to prevent orchiectomy in patients with a small tumor with unclear dignity on ultrasound imaging or MRI. The lesion is examined by a frozen section. Benign tumors need no safety margin, and orchiectomy is unnecessary. If a malignant germ cell tumor is detected by frozen section, radical orchiectomy is the standard procedure. Organ-sparing surgery may be considered for small malignant lesions after complete resection of the tumor, especially in cases of bilateral manifestation or patients with a single testis. Since there is a high risk of concomitant GCNIS, adjuvant local radiotherapy of the testis with 16–20 Gy should be performed.

Contralateral testicular biopsy:

The risk of contralateral GCNIS is between 5–10%. Risk factors for contralateral GCNIS are a testicular volume of less than 12 ml, a history of cryptorchidism, and an age under 30 years, increasing the risk to ≥34%. Consider contralateral testicular biopsy for risk patients.

If cisplatin-based chemotherapy is already foreseeable at the time of orchiectomy, a contralateral testicular biopsy should not be performed. Chemotherapy cures GCNIS in more than 60% of cases. If risk factors for GCNIS are present, contralateral testicular biopsy should be performed two years after completion of therapy for the primary tumor, if necessary.

General Principles of Chemotherapy for Testicular Carcinoma

Many advanced germ cell tumor stages require chemotherapy. The most commonly used regimen is PEB chemotherapy with cisplatin, etoposide, and bleomycin. The PE regimen is used if contraindications to bleomycin are present. The PEI regimen is also an alternative in contraindications to bleomycin, especially in intermediate and poor prognosis. Options for prophylactic chemotherapy in stage I germ cell tumors are carboplatin and PEB.

• PEB chemotherapy: combination chemotherapy with cisplatin, etoposide and bleomycin, one cycle of PEB lasts 21 days. One cycle of (prophylactic) PEB chemotherapy is indicated for stage I nonseminomas with a high risk of metastasis. Indications for three cycles of PEB chemotherapy are advanced seminomas from stage IIB, nonseminomas with proven metastasis (from stage II), and tumor recurrence after radiotherapy or after lymphadenectomy. At least four cycles of PEB are given for large tumor burden (intermediate or poor prognosis according to IGCCCG).
  • Cisplatin (20 mg/m²): days 1, 2, 3, 4, 5 as an intravenous infusion over one hour.
  • Etoposide (100 mg/m²): days 1, 2, 3, 4, 5 as an intravenous infusion over one hour.
  • Bleomycin (30 mg): days 1, 8, 15 as an i.v. bolus.
• PE chemotherapy: combination chemotherapy with cisplatin and etoposide. PE is an option for patients with a good prognosis and contraindications to bleomycin. One cycle of PE lasts 21 days; the dosage of cisplatin and etoposide is the same as for PEB. Four cycles of PE are given for patients with good prognosis; these are as effective as three cycles of PEB.
• PEI chemotherapy: with cisplatin, etoposide, and ifosfamide. Indications are contraindications for bleomycin in intermediate and poor prognosis, reaching the maximum dose for bleomycin or second-line therapy for progression after PEB chemotherapy. One cycle lasts 21 days:
  • Cisplatin (20 mg/m²): days 1, 2, 3, 4, 5 i.v. infusion over 30 min.
  • Etoposide (75 mg/m²): days 1, 2, 3, 4, 5 i.v. infusion over one hour.
  • Ifosfamide (1200 mg/m²): days 1, 2, 3, 4, 5 i.v. infusion over four hours.

Treatment Options for Seminoma and Nonseminoma Depending on Clinical Stage

An overview of stage-dependent treatment options for germ cell tumors is shown in the following table:

Treatment of Germ Cell Neoplasia In-Situ

The first-line treatment for germ cell neoplasia in situ (GCNIS) is irradiation of the testis with 16–20 Gy (8–10×2 Gy over two weeks) with a very high cure rate. The disadvantage is the permanent destruction of spermatogenesis; testosterone production is partly preserved. However, long-term controls of testosterone concentration are necessary; hypogonadism will develop in 30–57%. For patients with an atrophic testis and pre-existing hypogonadism, orchiectomy is the more reasonable option.

Treatment of GCNIS in the contralateral testis may be postponed under close control if the patient desires to conceive children due to the latency between GCNIS and testicular tumor of five years.

Chemotherapy cures GCNIS in 50–80% of cases (depending on the dose), and radiation of the testis should not be added. Two years after chemotherapy, a testicular biopsy may be offered for follow-up.

Treatment of Seminoma Stage IA/IB

After radical orchiectomy, the risk of progression for stage I seminoma is 6–30% if staging has been performed with morn imaging techniques. The following options exist for adjuvant therapy:

Active surveillance for Seminoma Stage I:

Risk factors for progression include a primary tumor size greater than 4 cm and tumor invasion into the rete testis. The risk of progression without risk factors is only 6%, with both risk factors 20–30%. The prognosis for the patient is excellent (cure rate of 99% independent of recurrence risk), if guideline-compliant surveillance and immediate therapy of recurrence is ensured. Active surveillance is the best therapeutic option for reliable patients.

Adjuvant Chemotherapy for Seminoma Stage I:

One cycle of carboplatin at the AUC (area under the curve) dosage of 7 reduces the risk of recurrence to 3–4% and is thus similarly effective to adjuvant radiotherapy (Oliver et al., 2011). See also dose calculation and pharmacology of carboplatin. Compared with radiotherapy, the following advantages exist: the brevity and simplicity of adjuvant therapy and the reduction in the risk of contralateral testicular tumors (2 of 573 vs. 15 of 904 compared with radiotherapy). On the downside, the short follow-up of the MRC/EORTC trial radiotherapy vs carboplatin prohibits a statement regarding the tumor induction risk. Further studies showed higher recurrence rates of up to 9% (Tandstad et al., 2016a) with one cycle of carboplatin, raising doubts about the low dose. All previous studies with two cycles of carboplatin were able to keep the recurrence rate below 2%.

In summary, adjuvant chemotherapy is a treatment option for stage I seminoma with a high risk of progression (1–2 risk factors). Two cycles of carboplatin should be recommended according to current data.

Adjuvant Radiotherapy for Stage I Seminoma:

Prophylactic irradiation of the retroperitoneal lymph nodes (dose 20 Gy) reduces the risk of recurrence to 3–4%. Field borders: top of T11–12 to lower edge L5 vertebral body, lateral borders are ipsilateral renal hilus and contralateral transverse processes. The initial side effects of radiotherapy are rare and mild overall. Induction of second malignancies is problematic, with up to a 20% increase in prevalence in the long-term (Lewinshtein et al., 2012). Studies using modern field techniques and low doses of 20 Gy have not confirmed this high rate of second malignancies. However, the frequency of retroperitoneal radiotherapy has decreased significantly, considering the excellent data for active surveillance in low-risk seminoma and the benefits of chemotherapy in high-risk seminoma.

Therapy of Seminoma Stage IS

Stage IS includes elevated or rising tumor markers after orchiectomy in patients with inconspicuous staging and normal contralateral testis. Radiotherapy comparable to stage IB–IIA is recommended. Chemotherapy with PEB is an alternative to radiotherapy. There are no exact recommendations regarding the dosage of chemotherapy (1–3 cycles); the decision should be individualized and depend on the level of tumor markers.

As an alternative to immediate therapy, detection and localization of metastases can also be awaited with regular imaging controls. Retroperitoneal lymph node metastases are treated with radiotherapy (dose 30 Gy), and lung metastases require three cycles of PEB chemotherapy.

Treatment of Seminoma Stage IIA

Lymph node enlargement up to 2 cm may have malignant or benign causes. If tumor markers are elevated, lymph node metastases are likely, and therapy can start immediately. The treatment decision is more difficult in marker-negative patients because benign lymph node enlargement must also be considered. Lymph node metastasis should be confirmed by biopsy, restaging after six weeks, or tumor marker elevation should be awaited.

Retroperitoneal lymph node metastases up to 2 cm diameter are irradiated with 30 Gy (2 Gy/d, 5 irradiations per week). The irradiation field is extended to the ipsilateral iliac/inguinal region compared to stage I. There is an 8% recurrence after radiation therapy; the localization of the recurrence is usually outside the irradiation field (e.g., lung). Tumor recurrence is treated with three cycles of PEB. The overall cure rate is 99%.

Chemotherapy with three cycles of PEB is a possible alternative to radiotherapy. Advantages are a low risk of recurrence after completion of therapy and a low risk of second malignancies in the long-term course. However, the side effects (early toxicity) of chemotherapy are significantly higher than with radiotherapy.

An alternative to reduce the toxicity is to combine radiotherapy and chemotherapy with reduced doses: dose and field reduction of radiotherapy with restriction to the enlarged lymph nodes and administration of 1–2 cycles of carboplatin as chemotherapy (Horwich et al., 2013), but controlled trials are unavailable.

Treatment of Seminoma Stage IIB

In stage IIB, chemotherapy with three cycles of PEB is the treatment of first choice. Radiotherapy of the retroperitoneal lymph nodes with 36 Gy is an alternative possibility. After therapeutic radiation, recurrence is to be expected in 10%, which must be treated with three cycles of PEB. The overall cure rate is 99%.

An alternative to reduce the toxicity is to combine radiotherapy and chemotherapy with reduced doses: dose and field reduction of radiotherapy with restriction to the enlarged lymph nodes and administration of 1–2 cycles of carboplatin as chemotherapy (Horwich et al., 2013), but controlled trials are unavailable.

Treatment of Germ Cell Tumors Stage IIC and III

Chemotherapy is chosen depending on the prognosis of the patient, see section prognosis groups of metastatic germ cell tumor.

• Good prognosis: chemotherapy with three cycles of PEB. In case of contraindication to bleomycin, four cycles of PE (cisplatin and etoposide) are possible.
• Intermediate prognosis: chemotherapy with four cycles of PEB. In case of contraindication to bleomycin, four cycles of PEI (cisplatin, etoposide and ifosfamide) are a possible alternative.
• Poor prognosis: chemotherapy with four cycles of PEB. In case of contraindication to bleomycin, four cycles of PEI (cisplatin, etoposide, and ifosfamide) are a possible alternative. The following risk factors support intensification of therapy (high-dose chemotherapy): poor tumor marker response after 1–2 cycles, brain metastases, bone metastases, and primary mediastinal disease. However, the exact indications and further subgroups that benefit from dose escalation are unclear. Not only for this reason, treatment of patients with poor prognosis should be performed in specialized centers within trials.
• Principles of chemotherapy: see section PEB and PEI chemotherapy.
• Brain metastases: therapy consists of a combination of chemotherapy and radiotherapy, cure is possible in 30%. Brain metastases that manifest as recurrence have a very poor prognosis with a five-year survival rate of 2–5%.
• Bone metastases: are associated with an unfavorable prognosis with long-term cure rates of 35–45%. Following chemotherapy, subsequent local therapy of the bone metastases should be considered (surgery or radiotherapy). High-dose chemotherapy should be considered on an individual basis.
• RLA after chemotherapy: surgical removal of residual tumor tissue after chemotherapy (retroperitoneal lymphadenectomy, RLA) is a difficult operation with high morbidity. Fibrotic changes after chemotherapy, which firmly connect vital pathways (vena cava, aorta, and ureters) to the residual tumor, make dissection partially impossible. Appropriate resections and vascular replacements must be anticipated to ensure an excellent oncological outcome. Furthermore, patients have limited (pulmonary) reserves after several cycles of chemotherapy. Indications for post-chemotherapy RLA differ between seminoma and nonseminoma. Imaging regarding residual tumors should not be performed until eight weeks after the end of chemotherapy.
  • Retroperitoneal residual tumor after nonseminoma therapy: RLA is indicated for residual tumors over 1 cm and negative tumor markers. Progressive tumor markers are a contraindication to RLA, and salvage chemotherapy is necessary (see below). Additional imaging with PET is not helpful. The goal is to remove chemoresistant portions of the tumor (teratoma) and to determine the need for further chemotherapy. The limits of lymphadenectomy are based on the extent of metastasis before chemotherapy; the minimum extent of dissection is shown in section RLA. The probability of a vital malignant residual tumor is approximately 15%, teratoma is detected in 35%, and necrosis in 50%.
  • Retroperitoneal residual tumor after seminoma therapy: often, a fibrotic residual tumor remains after chemotherapy, which wraps around the great vessels like Ormond's disease. Residual seminoma tumors after chemotherapy are controlled using tumor markers and imaging. PET scan is indicated for residual tumors over 3 cm diameter. If a growing metabolic active lesion is detected (repeat imaging may be necessary), surgical resection (if possible) should be considered, other treatment options are salvage chemotherapy or radiotherapy.
  • Pulmonary residual tumor: resection of residual tumors larger than 1 cm should be considered. In the case of bilateral residual tumors, individual treatment decisions should be made based on the histology of the first resection specimen.

Salvage Chemotherapy of Recurrent Germ Cell Tumor

Indications for salvage chemotherapy are recurrent or persistent germ cell tumors after first-line chemotherapy. The following combinations are used: PEI, VeIP (vinblastine, ifosfamide, and cisplatin), or TIP (paclitaxel, ifosfamide, and cisplatin).

RLA after salvage chemotherapy:

RLA for marker-positive residual tumors after salvage chemotherapy may be an option for patients with localized disease in the retroperitoneum and moderately elevated tumor markers without rapid progression. Durable response rates are low (about 25% are possible, "desperation surgery").

Therapy of late recurrence:

Late recurrence is defined as tumor recurrence more than two years after successful first-line therapy. Patients with late recurrence have a very poor prognosis. If possible, resection of the tumor recurrence should be performed; alternatively, salvage chemotherapy is planned after a biopsy of the recurrence.

Prognosis of Germ Cell Tumors

Non-metastatic testicular tumors have a very good prognosis (cure rate close to 100%). 50% of patients have a metastatic tumor stage at diagnosis. Pure seminomas present with metastases in 15–35%, nonseminomas with 60–70% at diagnosis. For the prognosis of metastatic testicular tumors, see next section.

Prognostic Risk Groups of Metastatic Germ Cell Tumors

The prognostic risk groups of metastatic GCT are classified according to the guidelines of the International Germ Cell Cancer Collaborative Group (IGCCCG) [see below]. The grouping determines the prognosis and the number of recommended chemotherapy cycles for treatment. The lowest value (nadir) of the tumor markers after orchiectomy is used for grouping (Kier et ak., 2017).

Good prognosis

• 90% of seminomas have a good prognosis with a five-year progression-free survival (PFS) of 82–87% and a five-year survival rate (5-YSR) of 86–93%: any tumor marker and no non-pulmonary visceral metastases and any tumor location.
• 56% of nonseminomas have a good prognosis with a five-year progression-free survival (PFS) of 89–90% and a five-year survival rate (5-YSR) of 92–95%: Tumor marker stage S0–S1 and No non-pulmonary visceral metastases primary tumor in testicular or retroperitoneal location.

Intermediate prognosis

• 10% of seminomas have an intermediate prognosis with a five-year progression-free survival (PFS) of 67% and a five-year survival rate (5-YSR) of 72%: any tumor marker and non-pulmonary visceral metastases and any tumor location.
• 28% of nonseminomas have an intermediate prognosis with a five-year progression-free survival (PFS) of 75% and a five-year survival rate (5-YSR) of 80–85%: Tumor marker stage S2 and No non-pulmonary visceral metastases primary tumor in testicular or retroperitoneal location.

Poor prognosis

• The poor prognosis does not apply to seminomas.
• 16% of nonseminomas have a poor prognosis with a five-year progression-free survival (PFS) of 41–55% and a five-year survival rate (5-YSR) of 48–64%: Tumor marker stage S3 or non-pulmonary visceral metastases or primary tumor in mediastinal location.

Complications of therapy:

Especially radiotherapy but also chemotherapy harbor the risk of long-term complications, which can occur dose-dependent years to decades after "successful" therapy. Unfortunately, there are no long-term studies comparing the side effects of (adjuvant) chemotherapy and radiotherapy (Travis et al., 2010).

• Tumor induction: the exact frequencies of second cancers after chemotherapy or radiotherapy are unclear. Second cancers after radiotherapy occur mainly near the radiation field (colon, pancreas, stomach, urinary tract) with an increased relative risk of 2–3. Chemotherapy increases the risk of solid tumors and leukemia.
• Cardiovascular complications: chemotherapy increases cardiovascular risk through endothelial damage and by nearly doubling the incidence of metabolic syndrome. The risk of pulmonary embolism is significantly increased during chemotherapy.
• Nephrotoxicity: cisplatin-containing chemotherapy leads to a long-term reduction in GFR of up to 30%; this could also be a mechanism for the increased cardiovascular risk.
• Hypogonadism: without chemotherapy, the risk for hypogonadism is low despite orchiectomy. After chemotherapy, 10–30% will develop testosterone deficiency, which is also a risk factor for metabolic syndrome.
• Infertility: chemotherapy causes a dose-dependent long-term deterioration of sperm count to azoospermia. When a maximum of three cycles of PEB are administered, sperm count parameters recover within two years in 80% of patients (Suzuki et al., 2013c).
• Other long-term complications: ototoxicity with high-frequency hearing loss and tinnitus, neurotoxicity with peripheral polyneuropathy, and chronic fatigue syndrome.

Follow-up after Treatment of Germ Cell Tumors

General examination:

Follow-up is performed every three months in the first two years, every six months in years 3–5, and then annually. For patients after radiation or chemotherapy, basic follow-up does not end. For patients with active surveillance (stage I), follow-up is terminated after ten years.

• Physical examination: testes, abdomen, lymph node regions, blood pressure, and body weight.
• Tumor markers: AFP, HCG, and LDH, even if initially in the normal range.
• Ultrasound imaging of the contralateral testis: annual examination.
• Further laboratory tests: annual blood lipids, testosterone, LH, and FSH to detect hypogonadism or metabolic syndrome.

The imaging intervals of the abdomen and chest depend on the tumor stage and treatment performed; considerable differences in international guidelines exist. Recurrence occurs mainly in the first two years after therapy, but late relapses after more than two years after successful primary treatment are possible in 1–3% (Oldenburg et al., 2009). The following recommendations are based on German and European guidelines:

Follow-up of Seminoma and Nonseminoma Stage I Without Chemotherapy:

The risk of recurrence is 12–48%, depending on histology.

• Abdominal CT or MRI: 6, 12, 18, and 24 months after orchiectomy. The EAU recommends additional imaging at 36 and 60 months instead of abdominal ultrasound.
• Abdominal ultrasound imaging: at 30, 36, 48, and 60 months.
• Chest X-ray: at 6, 12, 18, 24, 30, 36, 48, and 60 months.

Follow-up of Seminoma and Nonseminoma Stage I-IIC After Chemotherapy or Radiation Therapy And Good Prognosis:

The risk of recurrence is 3–18%, depending on tumor stage and histology.

• Abdominal CT or MRI: 6, 12, 18, and 24 months after primary therapy. The EAU recommends additional imaging at 36 and 60 months instead of abdominal ultrasound.
• Abdominal ultrasound imaging: at 30, 36, 48, and 60 months.
• Chest X-ray: at 6, 12, 18, 24, 30, 36, 48, and 60 months.

Seminom or Nonseminoma Stage III After Chemotherapy And Good Prognosis:

The risk of recurrence is 3–18%, depending on tumor stage and histology.

• Abdominal CT or MRI: 6, 12, and 24 months after primary therapy. The EAU recommends additional imaging at 36 and 60 months instead of abdominal ultrasound.
• Abdominal ultrasound imaging: at 18, 36, 48, and 60 months.
• Chest CT: at 6, 12, 24, and 60 months.

Follow-up of Metastatic Germ Cell Tumors With Intermediate or Poor Prognosis:

Tailor the follow-up individually depending on response and progression; as a minimum, see the recommendation for stage III follow-up.

References

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  Deutsche Version: Therapie des Hodenkarzinoms: Seminome und Therapie des Hodenkarzinoms: Nonseminome