• Albers P, Albrecht W, Algaba F, Bokemeyer C, Cohn-Cedermark G, Horwich A, Laguna MP. Guidelines on testicular cancer. Arnhem, The Netherlands: European Association of Urology (EAU); 2008 Mar. 54 p. [35 references]

This is the current release of the guideline.

Testicular cancers, including:

• Germ cell tumors
• Sex cord/gonadal stromal tumors
• Miscellaneous non-specific stromal tumors

Diagnosis
Management
Risk Assessment
Treatment

Oncology
Surgery
Urology

Physicians

• To help urologists assess the evidence-based management of testicular cancer
• To help urologists incorporate the guideline recommendations into their clinical practice

Men with germ cell or non germ cell testicular cancer

Screening/Diagnosis/Assessment

1. Imaging studies: ultrasound, magnetic resonance imaging (not recommended for diagnosis), computed tomography (CT), chest x-ray, fluorodeoxyglucose positron-emission tomography (FDG-PET) (not recommended for staging)
2. Serum tumour marker assessment
   • Germ cell tumours: alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), lactate dehydrogenase (LDH), placental alkaline phosphatase (PLAP; optional)
   • Stromal cell tumours: oestrogen, oestradiol, testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), progesterone, cortisol, PLAP
3. Inguinal exploration and orchidectomy
4. Organ sparing surgery
5. Pathologic assessment
6. Staging: tumor, node, metastasis (TNM) system; prognostic-based system
7. Post-orchidectomy tumour markers assessment
8. Retroperitoneal, mediastinal, and supraclavicular lymph nodes and visceral assessment
9. Screening self-examination

Treatment/Management

1. Surgery and second surgery
2. Cisplatin- or carboplatin-based chemotherapy
3. External beam radiotherapy
4. Retroperitoneal lymph node dissection (RPLND) (not recommended for primary treatment of stage 1 seminoma)
5. Timing of chemotherapy (adjuvant therapy, primary treatment, second-line and third-line treatment [consolidation therapy])
6. Risk-adapted chemotherapy
7. Salvage chemotherapy and/or surgery
8. Treatment of brain metastases
9. Frequency and duration of chemotherapy or radiotherapy treatments
10. Restaging after chemotherapy
11. Frequency and type of follow-up

• Sensitivity and specificity of diagnostic tests
• Recurrence rate
• Site and time of relapse
• Disease-free survival
• Morbidity and mortality

Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases

General Search Strategy

Up until 2007, the main strategy was to rely on the guidelines group members' knowledge and expertise on the current literature assuming that all, or almost all, relevant information would be captured.

In updates produced from 2008 onwards, a structured literature search will be performed for all guidelines but this search will be limited to randomized controlled trials and meta-analyses, covering at least the past three years, or up until the date of the latest text update if this exceeds the three-year period. Other excellent sources to include are other high-level evidence, Cochrane review and available high-quality guidelines produced by other expert groups or organizations. If there are no high-level data available, the only option is to include lower-level data. The choice of literature will be guided by the expertise and knowledge of the Guidelines Working Group.

Specific Strategy for this Guideline

A non-structured review of the literature through October 2007 concerning both the germ cell tumour and the non-germ cell part was conducted. Also data from meta-analysis studies, Cochrane evidence and the recommendations of the European Germ Cell Cancer Collaborative Group Meeting in Amsterdam November 2006, as well as other available guidelines, have been included.

A separate literature search for Leydig cell tumours (synonym: interstitial cell tumour) and Sertoli cell tumours (synonym: androblastoma) was performed.

The literature research for clinical data on Leydig cell tumours resulted in 193 publications dealing with more than 480 tumours in adults, including three publications reporting larger series on a total of 90 patients.

The literature research for clinical data on Sertoli cell tumours resulted in 93 publications dealing with more than 260 tumours in adults, including three publications (from the same group) reporting on a total of 80 patients.

Not stated

Weighting According to a Rating Scheme (Scheme Given)

Levels of Evidence

1a Evidence obtained from meta-analysis of randomized trials

1b Evidence obtained from at least one randomized trial

2a Evidence obtained from one well-designed controlled study without randomization

2b Evidence obtained from at least one other type of well-designed quasi-experimental study

3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports

4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities

Review of Published Meta-Analyses
Systematic Review

Not stated

Expert Consensus

• The first step in the European Association of Urology (EAU) guidelines procedure is to define the main topic.
• The second step is to establish a working group. The working groups comprise about 4 to 8 members, from several countries. Most of the working group members are academic urologists with a special interest in the topic. Specialists from other medical fields (radiotherapy, oncology, gynaecology, anaesthesiology, etc.) are included as full members of the working groups as needed. In general, general practitioners or patient representatives are not part of the working groups. Each member is appointed for a four-year period, renewable once. A chairman leads each group.*
• The third step is to collect and evaluate the underlying evidence from the published literature.
• The fourth step is to structure and present the information. All main recommendations are summarized in boxes and the strength of the recommendation is clearly marked in three grades (A-C), depending on the evidence source upon which the recommendation is based. Every possible effort is made to make the linkage between the level of evidence and grade of recommendation as transparent as possible.

*A multidisciplinary team of urologists, medical oncologists, radiotherapists and a pathologist were involved in producing the present text.

Grades of Recommendation

1. Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomized trial
2. Based on well-conducted clinical studies, but without randomized clinical trials
3. Made despite the absence of directly applicable clinical studies of good quality

Published cost analyses were reviewed.

• Magnetic resonance imaging (MRI) of the scrotum offers a sensitivity of 100% and a specificity of 95% to 100%, but its high cost does not justify its use for diagnosis.
• Cost analyses of surveillance compared with radiotherapy for stage I germ cell tumours indicate that it is more expensive, but estimates vary depending basically on the follow-up schedules.
• The results of cost analyses comparing surveillance, retroperitoneal lymph node dissection (RPLND) and primary chemotherapy for stage 1 non-seminomatous germ cell tumours show different results among the reported studies, possibly because of differences in intensity and costs related to follow-up procedures. With a low frequency of follow-up computed tomography (CT) (for instance, as has been proven effective for the surveillance strategy in non-seminoma clinical stage I), the costs of follow-up can considerably be reduced.
• The follow-up after RPLND is much simpler and less costly than that carried out during post-orchidectomy surveillance due to the reduced need for abdominal CT scans.

Internal Peer Review

Definitions for the grades of recommendation (A-B) are provided at the end of the "Major Recommendations" field.

Diagnosis and Staging of Testicular Cancer

Table: Recommended Tests for Staging at Diagnosis

hCG = human chorionic gonadotrophin; LDH = lactate dehydrogenase; CT = computed tomography; NSGCT = non-seminomatous germ cell tumour; MRI = magnetic resonance imaging; PET = positron emission tomography; FSH = follicle stimulating hormone

^a If negative, abdominopelvic computed tomography (CT) scan.

^b There is currently no indication for PET scan at diagnosis.

Guidelines on Diagnosis and Staging of Testicular Cancer

1. Testicular ultrasound is mandatory. (Grade of recommendation: B).
2. Orchidectomy and pathological examination of the testis is necessary to confirm the diagnosis and to define the local extension (pathologic tumour [pT] category) (Grade B recommendation). In a life-threatening situation due to extensive metastasis chemotherapy has to be started before orchidectomy.
3. Serum determination of tumour markers (alpha-fetoprotein [AFP], human chorionic gonadotropin [hCG], and lactate dehydrogenase [LDH] in metastatic disease) must be performed before and after orchidectomy for staging and prognostic reasons (Grade of recommendation: B).
4. Retroperitoneal, mediastinal and supraclavicular nodes and visceral state have to be assessed in testicular cancer. In seminoma, a chest computed tomography (CT) scan is not necessary if abdominal nodes are negative (Grade of recommendation: B).

Treatment of Seminoma Stage I

1. Surveillance (if available facilities and patient compliance) (Grade of recommendation: B).
2. Carboplatin based chemotherapy (one course at area under the curve [AUC] 7) can be recommended as an alternative to radiotherapy and surveillance (Grade of recommendation: A).
3. Adjuvant radiotherapy to a para-aortic or a hockey stick field, to a total dose of 20 Gy (Grade of recommendation: A).

Treatment of Non-Seminomatous Germ Cell Tumor (NSGCT) Stage I

Clinical Stage (CS) 1

Risk-adapted treatments based on vascular invasion or surveillance are recommended treatment options (Grade of recommendation: B)

CS1A (pT1, No Vascular Invasion): Low Risk

1. If the patient is willing and able to comply with a surveillance policy and long-term (at least 5 years) close follow-up should be recommended (Grade of recommendation: B).
2. Adjuvant chemotherapy or nerve-sparing retroperitoneal lymph node dissection (RPLND) in low-risk patients remain options for those not willing to undergo surveillance. If RPLND reveals PN+ (nodal involvement) disease, chemotherapy with two courses of cisplatin/etoposide/bleomycin (PEB) should be considered (Grade of recommendation: A).

CS1B (pT2-pT4); High Risk

1. Primary chemotherapy with two courses of PEB should be recommended (Grade of recommendation: B).

Surveillance or nerve-sparing RPLND in high-risk patients remain options for those not willing to undergo adjuvant chemotherapy. If pathological stage II is revealed at RPLND, further chemotherapy should be considered (Grade of recommendation: A).

Treatment of Metastatic Germ Cell Tumours

1. Low volume NSGCT stage IIA/B with elevated markers should be treated like 'good or intermediate prognosis' advanced NSGCT with 3 or 4 cycles of PEB. Stage II A/B without marker elevation can be treated either by RPLND or close surveillance.
2. In metastatic NSGCT (stage IIA [with positive markers]) with a good prognosis, three courses of PEB is the primary treatment of choice (Grade of recommendation: A).
3. In metastatic NSGCT with an intermediate or poor prognosis, the primary treatment of choice is four courses of standard PEB (Grade of recommendation: A).
4. Surgical resection of residual masses after chemotherapy in NSGCT is indicated in the case of visible residual masses and when serum levels of tumour markers are normal or normalizing (Grade of recommendation: B).
5. Clinical stage (CS) IIA/B can initially be treated with radiotherapy. When necessary, chemotherapy can be used as a salvage treatment with the same schedule as for the corresponding prognostic groups of NSGCT (Grade of recommendation: A). In stage IIB chemotherapy with three cycles of standard-dose bleomycin, etoposide, and cisplatin (BEP), or four cycles of etoposide (EP), represents a treatment alternative to radiotherapy, but may be associated with a higher risk of acute toxicity as compared to radiotherapy.
6. Seminoma, stage IIC and higher should be treated with primary chemotherapy according to the same principles used for NSGCT (Grade of recommendation: A).

Follow-up after Curative Therapy

General Considerations

The selection of the test to be performed in follow-up should adhere to the following principles:

• The interval between examinations and duration of testing should be consistent with the time of maximal risk of recurrence and the natural history of the tumour.
• The tests should be directed at the most likely sites of recurrence and should have a high predictive value, both positive and negative.
• Therapy should be available that will result in cure of the recurrence, significant prolongation of life or palliation of symptoms. The initiation of earlier therapy should improve the outcome compared with therapy given when the patient becomes symptomatic from the tumour recurrence.
• The increased risk of second malignancy, both in the primary site and in other tissues that may have been exposed to the same carcinogens, or in which there is epidemiological evidence of increased risk, should also guide the ordering tests. Malignant and non-malignant complications of therapy must also be considered. Such testing should also be performed with a frequency and duration consistent with the nature of the risk and include only tests with high positive- and negative-predictive values.

The following considerations apply in a general manner for the selection of an appropriate schedule and testing in the follow-up of all stages of testis tumour:

• Most recurrences after curative therapy will occur in the first 2 years; consequently surveillance should be most frequent and intensive during this time.
• Late relapses can occur beyond 5 years and therefore yearly follow-up for life may be advocated.
• After RPLND, relapse in the retroperitoneum is rare; the most likely site of recurrence being the chest.
• The value of chest X-ray has been recently questioned in the follow-up of patients with disseminated disease after complete remission.
• CT of the chest has a higher predictive value than chest X-ray.
• The results of therapy are dependent on the bulk of disease; thus an intensive strategy to detect asymptomatic disease may be justifiable.
• After chemotherapy or radiotherapy, a long-term risk for secondary malignancies development exists.

Table: Recommended Minimum Follow-Up Schedule in a Surveillance Policy: Stage I Non-Seminoma

Table: Recommended Minimum Follow-Up Schedule after Retroperitoneal Lymphadenectomy or Adjuvant Chemotherapy: Stage I Non-Seminoma

Table: Recommended Minimum Follow-Up Schedule for Post-Orchidectomy Surveillance, Radiotherapy or Chemotherapy: Stage I Seminoma

Table: Recommended Minimum Follow-Up Schedule in Advanced NSGCT and Seminoma

^a Abdominal CT scanning has to be performed at least annually if teratoma is found in the retroperitoneum.

^b If the post-chemotherapy evaluation shows any mass >3 cm, the appropriate CT scan should be repeated 2 and 4 months later to ensure that the mass is continuing to regress. If available, fluorodeoxyglucose-positron-emission tomography (FDG-PET) scanning can be performed.

^c A chest CT is indicated if abnormality is detected on chest X-ray and after pulmonary resection.

^d In patients with headaches, focal neurological findings or any central nervous system symptom.

Testicular Stromal Tumours

Leydig Cell Tumours

Diagnosis

Diagnostic work-up must include markers, hormones (at least testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH); if not conclusive, additionally, oestrogen, oestradiol, progesterone and cortisol), ultrasound of both testes and CT scan of chest and abdomen. On ultrasound, it may be possible to observe well-defined, small, hypoechoic lesions with hypervascularization, but the appearance is variable and is indistinguishable from germ cell tumours.

Treatment

Asymptomatic testicular tumours of small volume are often misinterpreted as germ cell tumours and inguinal orchidectomy is performed. It is highly recommended to perform an organ-sparing procedure in every small intraparenchymal lesion to gain the histological diagnosis. Especially in patients with symptoms of gynaecomastia or hormonal disorders, a non germ-cell tumour should be considered and immediate orchidectomy should be avoided. In cases of germ cell tumour in either frozen section or paraffin histology, orchidectomy is recommended as long as a contralateral normal testicle is present.

In stromal tumours with histological signs of malignancy, especially in patients of older age, orchidectomy and retroperitoneal lymphadenectomy is recommended to prevent metastases. Without histological signs of malignancy, an individualized surveillance strategy after orchidectomy is recommended (CT follow-up may be most appropriate since specific tumour markers are not available).

Tumours that have metastasized to lymph nodes, lung, liver or bone respond poorly to chemotherapy or radiation and survival is poor.

Follow-up

Recommendations for appropriate follow-up cannot be given because of the lack of follow-up data in most reported cases and the lethal outcome of metastatic tumours, irrespective of the therapy chosen.

Sertoli Cell Tumour

Diagnosis

Diagnostic work-up has to include tumour markers, hormones (at least testosterone, LH and FSH; if not conclusive, additionally, oestrogen, oestradiol, progesterone and cortisol), ultrasound of both testes and CT scan of chest and abdomen.

Treatment

Testicular tumours of small volume, otherwise asymptomatic, are often misinterpreted as germ cell tumours and inguinal orchidectomy is performed. It is highly recommended to proceed with an organ-sparing approach in small intraparenchymal testicular lesions until final histology is available. Especially, in patients with symptoms of gynaecomastia or hormonal disorders or typical imaging on ultrasound (calcifications, small circumscribed tumours), organ-sparing surgery should be considered. Secondary orchidectomy can be performed if final pathology reveals a non-stromal (e.g., germ cell) tumour. Organ-sparing surgical approaches are justified as long as the remaining testicular parenchyma is sufficient for endocrine (and in stromal tumours also exocrine) function.

In tumours with histological signs of malignancy, especially in patients of older age, orchidectomy and retroperitoneal lymphadenectomy are recommended to prevent metastases. Without signs of malignancy, an individualized surveillance strategy after orchidectomy is recommended (CT scans may be most appropriate since specific tumour-markers are not available). Tumours metastasizing to lymph nodes, lung or bone respond poorly to chemotherapy or radiation and survival is poor.

Follow-up

Recommendations for appropriate follow-up cannot be given because of the lack of follow-up data in most reported cases and the lethal outcome of metastatic tumours, irrespective of the therapy chosen.

Definitions:

Grades of Recommendation

1. Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomized trial
2. Based on well-conducted clinical studies, but without randomized clinical trials
3. Made despite the absence of directly applicable clinical studies of good quality

None provided

The type of supporting evidence is identified and graded for selected recommendations (see "Major Recommendations").

Appropriate diagnosis and management of testicular cancer

• Infertility will result after radiotherapy and the risk of long-term Leydig cell insufficiency after radiotherapy of a solitary testis is increased.
• The rate of severe radiation-induced long-term toxicity is less than 2% when treating stage 1 seminoma. Moderate chronic gastrointestinal (GI) side-effects are seen in about 5% of patients and moderate acute GI toxicity in about 60%. The main concern surrounding adjuvant radiotherapy is the potentially increased risk of radiation-induced secondary non-germ-cell malignancies.
• The risk of retroperitoneal relapse after a properly performed nerve-sparing retroperitoneal lymph node dissection (RPLND) is very low (less than 2%), as is the risk of ejaculatory disturbance or other significant side effects.
• The risk of retrograde ejaculation after radical post-chemotherapy (PC) RPLND is 100%, with nerve-sparing 15%.

Computed tomography scanning is contraindicated in cases of allergy to contrast media.

• The purpose of this text is not to be proscriptive in the way a clinician should treat a patient but rather to provide access to the best contemporaneous consensus view on the most appropriate management currently available. European Association of Urology (EAU) guidelines are not meant to be legal documents but are produced with the ultimate aim to help urologists with their day-to-day practice.
• The EAU believe that producing validated best practice in the field of urology is a very powerful and efficient tool in improving patient care. It is, however, the expertise of the clinician which should determine the needs of their patients. Individual patients may require individualized approaches which take into account all circumstances and treatment decisions often have to be made on a case-by-case basis.

Getting Better
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• Albers P, Albrecht W, Algaba F, Bokemeyer C, Cohn-Cedermark G, Horwich A, Laguna MP. Guidelines on testicular cancer. Arnhem, The Netherlands: European Association of Urology (EAU); 2008 Mar. 54 p. [35 references]

Not applicable: The guideline was not adapted from another source.

2008 Mar

European Association of Urology - Medical Specialty Society

European Association of Urology

Testicular Cancer Guidelines Writing Panel

Panel Members: P. Albers (Chairman); W. Albrecht; F. Algaba; C. Bokemeyer; G. Cohn-Cedermark; A. Horwich; M.P. Laguna

All members of the Testicular Cancer guidelines writing panel have provided disclosure statements of all relationships which they have and which may be perceived as a potential source of conflict of interest. The information is kept on file in the European Association of Urology (EAU) Central Office database. This guidelines document was developed with the financial support of the EAU. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

This is the current release of the guideline.

The following are available:

• EAU guidelines office template. Arnhem, The Netherlands: European Association of Urology (EAU); 2007. 4 p.
• The European Association of Urology (EAU) guidelines methodology: a critical evaluation. Arnhem, The Netherlands: European Association of Urology (EAU); 18 p.

The following is also available:

• Guidelines on testicular cancer. 2008, Ultra short pocket guidelines. Arnhem, The Netherlands: European Association of Urology (EAU); 2008 Mar. 19 p.

Print copies: Available from the European Association of Urology, PO Box 30016, NL-6803, AA ARNHEM, The Netherlands.

None available

This NGC summary was completed by ECRI Institute on July 2, 2008. The information was verified by the guideline developer on August 29, 2008.

This summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.

Downloads are restricted to one download and print per user, no commercial usage or dissemination by third parties is allowed.