Surveillance for stage I testicular germ cell tumors following orchiectomy

INTRODUCTION — Testicular germ cell tumor (GCT) is a highly curable cancer, with five-year survival rates of over 95 percent. For most patients with stage I GCTs (table 1A-B) who are treated with orchiectomy, surveillance is the preferred approach given low relapse rates, excellent long-term overall survival, and avoidance of unnecessary toxicity [1].

Patients with clinical stage I testicular seminoma who undergo orchiectomy are preferably managed with active surveillance; other options include adjuvant chemotherapy or adjuvant radiation therapy (algorithm 1). Patients with clinical stage I nonseminomatous germ cell tumor (NSGCT) who undergo orchiectomy are preferably managed with surveillance; other options include adjuvant chemotherapy or retroperitoneal lymph node dissection (RPLND). Active surveillance has not been directly compared with these other treatment strategies in randomized trials.

The role of surveillance in stage I testicular GCTs (both seminoma and NSGCT) treated with orchiectomy is presented here. Other treatment strategies for stage I testicular seminoma and NSGCTs are discussed separately.

●(See "Treatment of stage I seminoma".)

●(See "Management of stage I nonseminomatous germ cell tumors".)

GENERAL PRINCIPLES — For patients with testicular cancer, the detection of involvement of the retroperitoneal nodes and treatment with curative intent are important.

If imaging of the retroperitoneum were sufficiently accurate to identify patients whose testicular cancer was totally confined to the testis (T1-3N0M0 disease (table 1A-B)), orchiectomy alone would yield disease-free survival results that are equal to those of strategies that incorporate treatment of the retroperitoneal lymph nodes. However, the interpretation of computed tomography (CT) and magnetic resonance imaging (MRI) findings is limited by the need to use size criteria (>1 cm diameter in the short axis) rather than physiologic measures. Therefore, false-negative findings are frequent [2].

The presence of occult micrometastases is evidenced by a retroperitoneal relapse rate of approximately 20 to 25 percent in patients with clinical stage I nonseminomatous germ cell tumors (NSGCTs) who did not undergo retroperitoneal lymph node dissection (RPLND) [3,4].

For patients with early stage NSGCTs, the only reliable method to identify small nodal involvement is RPLND. However, approximately 70 percent of patients who undergo RPLND are pathologically node negative. Thus, the majority of those who undergo RPLND do not benefit from surgery. These observations have led to the use of surveillance or adjuvant chemotherapy following orchiectomy. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors".)

PATIENT SELECTION — Patients with stage I testicular cancer and no risk factors for relapse are candidates for surveillance. However, surveillance requires that patients strictly adhere to an outlined surveillance protocol. (See 'Surveillance protocols' below.)

Appropriate candidates for surveillance include:

●Patients with clinical stage I seminoma (pT1, pT2, and selected patients with pT3 disease) (table 1A-B).

●Patients with clinical stage I nonseminomatous germ cell tumors (NSGCTs; pT1-3N0M0) with normal serum tumor markers postorchiectomy (table 1A-B), preferably when no high-risk clinical factors are present [5-8].

For clinical stage I NSGCT, clinical factors that indicate an increased risk of relapse include the following:

•Lymphatic or vascular invasion.

•Embryonal carcinoma component greater than 40 percent of total tumor volume.

•Invasion of the spermatic cord or the scrotum.

•Absence of yolk sac elements.

•Elevated serum tumor markers prior to orchiectomy that do not decrease within the expected half-life (one day for human chorionic gonadotropin [hCG], five to seven days for alpha-fetoprotein [AFP]).

In Europe, vascular invasion is the sole criterion used to define high-risk disease among patients with clinical stage I NSGCTs [9].

The risk of relapse increases if any of these high-risk factors are present. In a series of 259 patients with stage I NSGCTs, four features were independently predictive of relapse: invasion of blood vessels or testicular lymphatics, absence of yolk sac elements, and presence of embryonal cell carcinoma [10]. The relapse rates for patients with none, one, two, or three to four risk factors were 0, 10, 24, and 58 percent, respectively. (See "Management of stage I nonseminomatous germ cell tumors".)

SURVEILLANCE PROTOCOLS — Surveillance is a form of management with mandatory follow-up. Patients undergoing surveillance must fully understand the risks of disease recurrence and should be willing to comply with the follow-up schedule. For patients who will be followed without further treatment after inguinal orchiectomy, our approach is generally consistent with the surveillance recommendations from the National Comprehensive Cancer Network (NCCN) [11]. (See "Posttreatment follow-up for testicular germ cell tumors".)

For patients with either seminoma or nonseminomatous germ cell tumors (NSGCTs), surveillance is necessary for a minimum of five years and possibly 10 years following orchiectomy. Relapses more than 15 years after orchiectomy have been reported, although late relapses are rare. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'Duration of follow-up after treatment'.)

Nonseminomatous GCTs — For patients with stage I NSGCT treated with orchiectomy alone who select surveillance, follow-up protocols include history, physical exam, serum tumor markers, and imaging studies. Specific details, including frequency of surveillance, are discussed separately. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'Stage I NSGCT (surveillance)'.)

Seminoma — For patients with stage I seminoma treated with orchiectomy alone who select surveillance, follow-up protocols include history, physical exam, serum tumor markers, and imaging studies. Specific details, including frequency of surveillance, are discussed separately. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'Stage I seminoma'.)

SURVEILLANCE OUTCOMES — Long-term survival is excellent for patients with low-risk, low-stage testicular germ cell tumors (GCTs) who are treated with surveillance. (See "Treatment of stage I seminoma", section on 'Approach to surveillance and rationale'.)

As an example, in one observational series from the Danis Testicular Cancer Database, 3366 patients with clinical stage I testicular GCT were managed with surveillance and without adjuvant therapy [12]. During surveillance, the frequency and timing of relapses as well as overall survival outcomes were as follows:

●Seminoma – In the 2000 patients with seminoma, 388 (19.4 percent) relapsed. Of these, 288 patients (14.4 percent) relapsed in the first two years, and 100 patients had a late (two to five years) or very late (greater than five years) relapse. The conditional risk of relapse for those disease free after two years was 5 percent, and the risk of relapse for those disease free after five years was 1 percent. Among those who relapsed, there were 12 deaths (3.1 percent, 0.6 percent of the entire cohort) from testicular cancer or treatment-related complications.

●NSGCT – In the 1366 patients with NSGCTs, 424 (31 percent) relapsed. This included 400 (29 percent) who relapsed in the first two years and 24 (1.8 percent) who relapsed after two years. The conditional risk of relapse for those disease free after two years was 2.1 percent, and the risk of relapse for those disease free after five years was 1 percent. In those who relapsed, there were 15 patients (3.9 percent, 1.1 percent of the entire cohort) who died of progressive disease or treatment-related complications.

Similar results were reported in a Canadian study of 1239 patients with clinical stage I testicular GCTs managed with surveillance [13]. For patients without relapse within the first two years of follow-up, the risk of relapse in the five years after being relapse free for two years ranged from 0 to 5.6 percent based on histology and risk stratification.

One-half of relapses are retroperitoneal, and of these, one-third are not accompanied by significant elevations in serum tumor markers. An additional one-third of all relapses are in the lungs or mediastinum, while approximately 11 percent are manifested only by elevated serum tumor markers.

The diagnosis of late relapses in patients with testicular GCTs treated with systemic therapy is discussed separately. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors", section on 'Timing of relapsed disease'.)

ISSUES REGARDING SURVEILLANCE

Compliance — Patient compliance with the surveillance protocol is a valid concern for testicular germ cell tumors (GCTs). However, whether compliance impacts overall survival is not clear [14,15].

This was demonstrated in a study involving 197 patients with stage I nonseminomatous germ cell tumors (NSGCTs) followed at one of seven cancer centers with a minimum of two years of follow-up [14]. The main outcomes were as follows:

●The mean compliance rate (defined as missing no more than two assessments per year) was 78 percent. Compliance with computed tomography (CT) scanning was 64 percent.

●The relapse rate at five years was 29 percent, but overall survival at five years was 100 percent.

●The only factor predictive of relapse was the presence of lymphovascular invasion in the primary tumor.

●Despite differences in the frequency of visits at each center, there were no significant differences in either the rates of relapse or survival.

Radiation exposure — Clinicians should consider the potential risks of second malignancies induced by radiation exposure when planning the frequency of imaging (particularly by CT), particularly in younger patients. (See "Radiation-related risks of imaging".)

Attempts to lower the radiation exposure associated with CT scans may be appropriate to diminish this risk by using lower radiation dose CT scans or substituting magnetic resonance imaging (MRI). However, long-term data about the efficacy of these alternate approaches are not available.

DIAGNOSIS OF RELAPSE — Most cases of relapsed testicular germ cell tumors (GCTs) are discovered during routine follow-up care based on either imaging findings or assessment of serum tumor markers. Fluctuation of serum tumor markers within the normal range is not considered clinically significant. (See "Serum tumor markers in testicular germ cell tumors", section on 'Monitoring response to therapy'.)

The diagnosis of patients with relapsed testicular GCTs, including indications for biopsy, is discussed separately. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors", section on 'Diagnosis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Testicular cancer".)

SUMMARY AND RECOMMENDATIONS

●General principles – For most patients with stage I testicular germ cell tumors (GCTs) who are treated with orchiectomy, surveillance is the preferred treatment strategy given low relapse rates, excellent long-term overall survival (>95 percent), and avoidance of unnecessary toxicity with this approach. (See 'Introduction' above and 'Surveillance outcomes' above.)

●Surveillance protocols following orchiectomy – Following orchiectomy, surveillance protocols vary based on the type of tumor (seminoma versus nonseminomatous germ cell tumor [NSGCT]) and include a combination of history, physical examination, serum tumor markers, and imaging studies. Surveillance is necessary for a minimum of five years and, for some patients, up to ten years. (See 'Surveillance protocols' above.)

•Surveillance for stage I seminoma – For patients with clinical stage I germ cell tumors treated with orchiectomy who undergo surveillance, we offer the following protocol, as discussed separately. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'Stage I seminoma'.)

Adjuvant treatment options to minimize the chances of relapse are discussed separately (algorithm 1). (See "Treatment of stage I seminoma".)

•Surveillance for stage I NSGCTs – For patients with low-risk clinical stage I NSGCTs (see 'Patient selection' above) treated with orchiectomy who undergo surveillance, we offer the following protocol, as discussed separately. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'Stage I NSGCT (surveillance)'.)

Adjuvant treatment options to minimize the chances of relapse are discussed separately. (See "Management of stage I nonseminomatous germ cell tumors".)

●Diagnosis of relapse – Patients who present with evidence of disease progression on imaging or serum tumor markers should be evaluated for relapsed disease. (See 'Diagnosis of relapse' above and "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors", section on 'Diagnosis'.)