For the 2021 Testicular Cancer Guidelines, new references have been added throughout the document. Key changes in this publication include:

The chapter on stromal tumours has been re-structured and revised under a new heading: “Rare adult testicular tumours”;
The chapter on epidemiology, aetiology and pathology has been revised;
Summaries of evidence have been added throughout the text;
Old citations have been refreshed and replaced with newer references;
A number of articles identified after the scope search cut-off date have been included as they contain important information pertaining to guidelines recommendations;
Supporting text and recommendations across the guideline have been rephrased and revised;
The recent re-validation of the 1997 International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic risk-factor based system for metastatic testicular Germ cell tumours in patients treated with cisplatin-etoposide as first-line chemotherapy has been included in the text replacing the old version;
New recommendations and supporting text regarding VTE prophylaxis in males with metastatic germ cell tumours (GCTs) receiving chemotherapy have been added.

New and updated summaries of evidence and recommendations include the following:

5.8 Guidelines for the diagnosis and staging of Testicular Cancer

Summary of evidence	LE
Poor sperm quality is frequently found in TC patients, before and after treatment. Semen preservation is the most cost-effective strategy for fertility preservation.	2b
Serum tumour markers (AFP, β-hCG and LDH) should be determined before and after orchidectomy and throughout follow-up. They are used for accurate staging, risk stratification, to monitor treatment and to detect relapse.	2b
For abdominal staging, CECT has a median sensitivity, specificity, PPV, NPV and accuracy of 67%, 95%, 87%, 73% and 83%, respectively. Sensitivity decreases and specificity increases with increasing lymph node size.	2a
For chest staging, CECT has a median sensitivity, specificity, PPV, NPV and accuracy of 100%, 93%, 68%, 100% and 93%, respectively.	2a
Contrast enhanced computerised tomography and MRI are key image modalities for the detection of brain metastasis. Magnetic resonance imaging is far more sensitive than CECT, though it does require expertise.	2b
Fluorodeoxyglucose-positron emission tomography has a limited diagnostic accuracy for staging before chemotherapy.	2b
There are no high-level evidence studies supporting screening programs.	2b
In testicular sparing surgery, FSE has shown to be reliable and highly concordant with final histopathology.	1b
There is no evidence supporting any size criteria for a testicular lesion to be safely followed-up.	2b
In patients without risk factors, there is low incidence of contralateral GCNIS and of metachronous GCTC.	2b

Recommendations	Strength rating
Encourage patients with TC to perform self-examination and to inform first-degree male relatives of the need for self-examination.	Weak
Discuss biopsy of the contralateral testis to patients with TC and who are at high-risk for contralateral germ cell neoplasia ‘in situ’ (GCNIS).	Weak

7.1.2.5 Guidelines for the treatment of stage I seminoma testis tumours

Summary of evidence	LE
Primary testicular tumour size and rete testis invasion correlate with the risk of relapse in clinical stage I seminoma testis patients. However, the evidence to guide adjuvant treatment decisions is too limited to justify the routine use in clinical practice.	2a
Active surveillance is a feasible approach in CS I seminoma testis patients. Conditional relapse risk in unselected series is between 12% and 20%.	2a
In patients without risk factors the five-year relapse rate under surveillance is 4% to 6%, whereas in the presence of one or two risk-factors, five-year relapse rate in contemporary surveillance series is 15% to 20%.	2b
In non-randomised prospective series five-year relapse rates with adjuvant carboplatin are 2% in patients without risk factors and 9% in patients with one or two risk factors.	2b
Adjuvant chemotherapy with one course carboplatin AUC 7 is not inferior to adjuvant radiotherapy when pathological risk-factors are taken into account. Relapse rates with both adjuvant treatments are around 5%.	1b
Adjuvant radiotherapy is associated with an increased risk of developing secondary non-germ cell malignancies.	2b

Recommendations

Strength rating

Do not routinely perform adjuvant radiotherapy.

Strong

Adjuvant radiotherapy should be reserved only for highly selected patients not suitable for

surveillance and with contraindication for chemotherapy.

Strong

7.1.3.6 Guidelines for the treatment of clinical stage I non-seminoma testis tumour

Summary of evidence	LE
Lymphovascular invasion increases the risk of relapse in CS I non-seminoma testis.	2a
The relapse rate in patients under active surveillance is up to 50%, depending on LVI status.	2a
The relapse rate in patients who receive adjuvant chemotherapy with BEP (x 1 cycle) is less than 3%.	2a
Adjuvant chemotherapy with BEP is superior to adjuvant RPLND in terms of the risk of relapse.	1b
A risk-adapted approach, based on LVI, is feasible. Risk of relapse with one cycle adjuvant BEP is about 2% to 3%.	2b
The acute toxicity of one cycle adjuvant BEP is rather low.	1b

Recommendations	Strength rating
Offer surveillance or risk-adapted treatment based on lymphovascular invasion in patients with stage I NSGCT (see below).	Strong
Discuss one course of cisplatin, etoposide, bleomycin as an adjuvant treatment alternative if patients are not willing to undergo or comply with surveillance.	Strong

7.1.3.7 Risk-adapted treatment for clinical stage I non-seminomatous germ cell tumour based on vascular invasion

Recommendations	Strength rating
*Stage IA (pT1, no vascular invasion): low risk*
Offer adjuvant chemotherapy with one course of cisplatin, etoposide, bleomycin (BEP) in low-risk patients not willing (or unsuitable) to undergo surveillance.	Strong
*Stage IB (pT2-pT4): high risk*
Primary RPLND should be advised in men with post-pubertal teratoma with somatic-malignant component.	Weak

7.2.3.1.6 Prevention of thromboembolism events during chemotherapy

Summary of evidence

LE

Thromboembolic events occur more frequently in male patients with GCTs receiving chemotherapy than in young males under chemotherapy for other cancers.

2b

Retrospective studies have identified multiple risk factors for the development of thromboembolic

events including: increasing stage, size of retroperitoneal lymph nodes at different cut-offs, Khorana score ≥ 3 and indwelling vascular access device (only modifiable risk factor).

2b

Recommendations	Strength rating
Balance the individual patients’ potential benefits and risks of thromboprophylaxis during first-line chemotherapy in men with metastatic germ cell tumours.	Weak
Avoid use of central venous-access devices during first-line chemotherapy whenever possible.	Weak

7.3.6.1 Guidelines for the treatment of metastatic testicular germ cell tumours

Summary of evidence	LE
In the NSGCT good-prognosis-risk group (IGCCG), BEP x 3 is superior to other chemotherapy regimens. Toxicity is lower when treatment is delivered in five-day regimes rather than three-day regimes.	1b
In NSGCT intermediate-prognosis-risk groups (IGCCCG) BEP x 4 is the standard treatment of choice with a five-year survival of 89% in contemporary series.	1b
In pathological stage II NSGCT disease, RPLND performed in specialised centres without adjuvant chemotherapy results in 73% to 81% of long-lasting remissions.	2b
In patients with a poor-prognosis metastatic NSGCT (defined by IGCCCG), treatment with BEP x 4 with five-year PFS, results in a five-year PFS of 67%. There is no advantage in OS for high-dose chemotherapy.	1b
Patients with a poor-prognosis metastatic NSGCT and early unfavourable tumour marker decline may benefit from intensification of treatment with dose-dense chemotherapy, with improvement of PFS in spite of no benefit being observed for OS.	1b
Following first-line BEP chemotherapy, 6% to 10% of NSGCT residual masses contain active cancer, 50% have post-pubertal teratoma, and 40% comprise of necrotic-fibrotic tissue only. Figures regarding persistence of residual active are slightly lower in post chemotherapy residual masses < 1 cm. Currently there is no accurate prognostication method of histology.	2b
In CS IIA/B seminoma radiotherapy and chemotherapy treatment show similar effectiveness, with a non-significant trend towards greater efficacy of chemotherapy in CS IIB. However, risk of second malignancies and cardiovascular events is higher after radiotherapy.	2a
In metastatic seminoma stage ≥ IIC, primary chemotherapy with BEP, tailored to the IGCCCG risk group, has proven superior to Carboplatin based chemotherapy.	1b
Fluorodeoxyglucose-positron emission tomography has a high NPV in patients with post-chemotherapy seminoma residual masses (> 3 cm) when performed > two months after chemotherapy.	2b

Recommendations	Strength rating
Nerve-sparing RPLND when performed by an experienced surgeon in a specialised centre is the recommended initial treatment in clinical stage (CS) IIA NSGCT disease without elevated tumour markers.	Weak
Repeat staging after six weeks before making a final decision on further management should be considered in patients with small volume (CS IIA < 2 cm) marker negative NSGCT.	Weak
Treat metastatic NSGCT (stage ≥ IIC) with an intermediate-prognosis with four cycles of standard BEP.	Strong
In metastatic NSGCT with a poor-prognosis, treat with one cycle of BEP, (or cisplatin, etoposide and ifosfamide [PEI], in cases with pulmonary dysfunction), followed by tumour marker assessment after three weeks. Continue the same schedule up to a total of four cycles with favourable marker decline. With unfavourable decline, initiate chemotherapy intensification.	Weak
Perform surgical resection of visible (> 1 cm) residual masses after chemotherapy for NSGCT when serum levels of tumour markers are normal or normalising.	Strong
Initially offer cisplatin-based chemotherapy according to IGCCCG prognosis groups, or alternatively radiotherapy to seminoma patients with stage II A/B and, inform the patient of potential long-term side effects of both treatment options.	Weak
Treat seminoma stage IIC and higher, with primary chemotherapy according to IGCCCG classification (BEP x 3 in good-prognosis and BEP x 4 in intermediate prognosis).	Strong