Dr. med. Dirk Manski

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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.

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:

Overview of treatment options for testicular germ cell tumors depending on clinical stage. For prognosis grouping of patients with advanced germ cell tumor see table UICC tumor stages of germ cell tumors.
Stage Seminoma Nonseminoma
Stage IA
Stage IB
Active surveillance or
1–2 cycles carboplatin (high risk) or
radiation therapy (20 Gy)
Active surveillance or
1 cycle PEB (high risk) or
nerve-sparing RLA
Stage IS radiation therapy (30 Gy)
or 1–3 cycles PEB
1–3 cycles PEB
Stage IIA radiation therapy (30 Gy)
or 3 cycles PEB
Positive tumor markers: 3 cycles PEB

Negative tumor markers: nerve-sparing RLA or restaging (CT) in six weeks (see text).
(good prognosis)
3 cycles PEB 3 cycles PEB
(intermediate prognosis)
4 cycles PEB 4 cycles PEB
(poor prognosis)
- 4 cycles PEB or
High-dose chemotherapy within trials
Residual tumor after chemotherapy RLA for PET active masses larger than 3 cm RLA for residual tumor > 1–2 cm

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:

High-risk Nonseminoma stage I:

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.

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.

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

Intermediate prognosis

Poor prognosis

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).

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.

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.

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.

Seminom or Nonseminoma Stage III After Chemotherapy And Good Prognosis:

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

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.

Index: 1–9 A B C D E F G H I J K L M N O P Q R S T U V W X Y Z


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