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Testicular Cancer: Treatment of Nonseminoma

General Treatment Options of Testicular Cancer

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 Nonseminoma Stage I A/B

Vascular invasion in the orchiectomy specimen is a critical risk factor for progression and defines the following risk groups: 14–22% progression without vascular invasion (low-risk nonseminoma stage I) vs. 48% progression with vascular invasion (high-risk nonseminoma stage I). All presented therapy options allow a cure rate of 99%.

Low-risk Nonseminoma stage I:

• Active surveillance: is the standard recommendation; the low risk of progression allows no therapy with side effects. Follow-up care includes multiple CT scans; see section follow-up care of germ cell tumor. Disadvantages include the psychological stress of initial nontreatment; approximately 20% of patients will require three cycles of PEB at progression.
• Adjuvant chemotherapy: non-therapy and necessary close monitoring are not a good option in patients with tumor anxiety, a high desire for therapy, or poor compliance. In this situation, adjuvant chemotherapy with one cycle of PEB is an option (Beyer et al., 2013).
• Nerve-sparing retroperitoneal lymphadenectomy: in experienced hands, nerve-sparing retroperitoneal lymphadenectomy is a treatment option if surveillance or adjuvant chemotherapy is not desired. However, in direct comparison with one cycle of PEB, oncologic advantages exist for adjuvant chemotherapy (1.1% vs. 7.5% recurrence). Another disadvantage of RLA is the surgical morbidity of 9%.

High-risk Nonseminoma stage I:

• Adjuvant chemotherapy with one cycle of PEB offers the best cost-benefit ratio, the former dosage of two cycles is no longer recommended in current guidelines. The risk of recurrence is reduced to 3%, and the cure rate is 99% (Tandstad et al., 2013). A disadvantage is the overtreatment of about half of the patients. The long-term consequences of PEB chemotherapy for a young person are uncertain concerning the induction of second malignancies.
• Alternatively, active surveillance or nerve-sparing RLA may be performed (see above).

Stage I teratomas with malignant somatic transformation:

Teratomas with malignant somatic transformation respond poorly to chemotherapy and have a poor prognosis. In stage I, RLA should be performed; it offers the chance of cure. The five-year survival rate is between 80–90% (Giannatempo et al., 2016).

Treatment of Nonseminoma Stage IS

Stage IS includes elevated or rising tumor markers after orchiectomy in patients with inconspicuous staging and normal contralateral testis. In case of rising specific tumor markers (HCG or AFP), chemotherapy comparable to stage IB–IIA is indicated. There are no exact recommendations regarding the dosage of chemotherapy (1–3 cycles); the individual decision depends on the level of tumor markers. As an alternative to immediate therapy (especially with elevated nonspecific markers such as LDH), waiting and regular imaging is an option until metastases are seen.

Treatment of Nonseminoma Stage IIA/IIB

Guideline-conform treatment leads to a cure rate of 95–98%. The treatment algorithm distinguishes between marker-positive nonseminoma (AFP, HCG, or LDH elevated after orchiectomy) or marker-negative nonseminoma (tumor markers in the normal range after orchiectomy).

Treatment of Marker-positive Nonseminoma stage IIA and all stage IIB:

Standard therapy is 3–4 cycles of PEB, depending on prognosis (see table \ref{IGCCCG}). Marker-negative residual tumors after chemotherapy greater than 1 cm in diameter are removed with RLA (see below). Many patients achieve complete remission and do not require RLA (83–91% in stage IIA, 61–87% in stage IIB). The risk of recurrence is 4–9% in stage IIA, and 11–15% in IIB.

Treatment of Marker-negative Nonseminoma stage IIA:

Causes of rare marker-negative lymph node enlargement are mainly teratoma, metastases, or benign lymph node enlargement. Two options exist: immediate RLA or restaging after six weeks.

• Nerve sparing RLA: no further therapy is necessary in case of benign histology or teratoma. If lymph node metastases are detected (frozen section diagnosis), contralateral dissection is performed, and close follow-up regarding pulmonary metastases (25%) is necessary. Alternatively (no frozen section necessary), 1–2 cycles of PEB chemotherapy are given to treat occult metastases in the lung and contralateral lymph nodes.
• Restaging after six weeks: abdominal CT to re-evaluate the enlarged lymph nodes. Possible findings are regredient lymph nodes, enlarged lymph nodes without tumor markers, and rising tumor markers with enlarged lymph nodes.
  • Patients with regredient lymph nodes need no treatment and regular follow-up (see below) follows.
  • Persistent or growing lymph nodes without rising tumor marker require nerve-sparing RLA (see above).
  • Patients with rising tumor markers and enlarged lymph nodes receive three cycles of PEB chemotherapy.

Treatment of Growing Teratoma Syndrome:

Growing teratoma syndrome includes increasing retroperitoneal lymph nodes under PEB chemotherapy despite adequate tumor marker normalization, caused by teratoma tissue not responding to chemotherapy. A prerequisite for the diagnosis is the presence of teratoma in the germ cell tumor. After completion of chemotherapy, an RLA with complete residual tumor resection is necessary. The complex operation often requires the resection of larger vessels, such as aorta or vena cava, and should be planned with vascular surgeons.

Treatment of Testicular Cancer 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 Testicular Carcinoma

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 Testicular Cancer

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 Testicular Cancer

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 Testicular Cancer

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 Testicular Cancer 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.

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