INTRODUCTION — Testicular germ cell tumors (GCTs) have become one of the most curable solid neoplasms due to remarkable treatment advances that began in the late 1970s. These include a better understanding of the natural history of testicular tumors, improved staging and surgical techniques, the availability of serum tumor markers, and the use of effective platinum-based combination chemotherapy [1]. Prior to that time, testicular cancer accounted for 11 percent of all cancer deaths in males between the ages of 25 and 34, and the five-year survival rate was 64 percent [2]. With modern treatment, the five-year survival rate for patients with testicular GCTs is over 95 percent [3].
Following orchiectomy, males with clinical stage I testicular GCTs (table 1A-B) can be managed with active surveillance or a short course of adjuvant chemotherapy. For males with seminoma, radiation therapy is also an option; for those with nonseminomatous GCTs, retroperitoneal lymph node dissection (RPLND) is an alternative. There have been no randomized trials comparing active surveillance with adjuvant therapy or RPLND.
Regardless of treatment strategy, the long-term cancer-specific survival for clinical stage I testicular GCTs approaches 100 percent [4]. The approach to treatment in an individual patient is based on a detailed consideration of patient-specific factors and the short-term and long-term toxicities associated with each approach.
This topic will review the role of active surveillance following orchiectomy in appropriately selected patients. Related topics include the following:
●(See "Overview of the treatment of testicular germ cell tumors".)
●(See "Retroperitoneal lymph node dissection for early-stage testicular germ cell tumors".)
●(See "Management of stage I nonseminomatous germ cell tumors".)
●(See "Treatment of stage I seminoma".)
GENERAL PRINCIPLES — For males 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 males 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 [5].
The presence of occult micrometastases is evidenced by a retroperitoneal relapse rate of approximately 20 to 25 percent in males with clinical stage I nonseminomatous GCTs who did not undergo retroperitoneal lymph node dissection (RPLND) [6,7].
For males with early stage nonseminomatous GCTs, the only reliable method to identify small nodal involvement is RPLND. However, approximately 70 percent of males 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 active surveillance or adjuvant chemotherapy following orchiectomy. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors".)
PATIENT SELECTION — Males with stage I testicular cancer and no risk factors for relapse are candidates for active surveillance. However, active surveillance must be considered a form of treatment that requires males who are motivated to rigidly adhere to a surveillance protocol. Appropriate candidates for surveillance include:
●Males with clinical stage I seminoma (pT1, pT2, and selected patients with pT3 disease) (table 1A-B).
●Males with clinical stage I nonseminomatous GCTs (NSGCTs; pT1-3N0M0) with normal serum tumor markers postorchiectomy (table 1A-B), provided no high-risk factors are present [8-11]. High-risk factors include the following:
•Vascular or lymphatic invasion.
•Embryonal carcinoma component greater than 40 percent of total tumor volume.
•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 males with clinical stage I NSGCTs [11].
The risk of relapse increases if any of these factors are present. In a series of 259 males 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 [12]. The relapse rates for males 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".)
ACTIVE SURVEILLANCE PROTOCOLS — Active surveillance should be considered a form of treatment with mandatory follow-up. Males undergoing surveillance must fully understand the risks of disease recurrence and should be willing to comply with the follow-up schedule. For males 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) [13]. (See "Posttreatment follow-up for men with testicular germ cell tumors".)
For patients with either nonseminomatous GCTs or seminoma, 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. Because of the amount of radiation from computed tomography (CT) scans and chest radiographs in otherwise young patients, methods to reduce radiation, such as low-radiation dose protocols or magnetic resonance imaging (MRI) studies, are being evaluated. (See "Radiation-related risks of imaging" and 'Radiation exposure' below and "Posttreatment follow-up for men with testicular germ cell tumors", section on 'Duration of follow-up after treatment'.)
Nonseminomatous GCTs — A history, physical examination, and serum tumor markers (alpha-fetoprotein [AFP], beta-human chorionic gonadotropin [hCG], and lactate dehydrogenase [LDH]) should be obtained every two months for the first year, every three months during the second year, every four to six months in year 3, and then decreased to annually beginning year 5. CT of the abdomen and pelvis should be obtained every four to six months in year 1, gradually decreasing to annually in year 3 or 4. Chest radiograph monitoring is indicated at 4 and 12 months for patients with clinical stage IA disease and then annually thereafter. For those with stage IB disease, chest radiograph should be monitored every two months during the first year and then gradually decreased to annually beginning year 5.
Seminoma — A history, physical examination, and tumor markers (AFP, beta-hCG, and LDH) should be obtained every three to six months for the first year, then every 6 to 12 months in years 2 and 3, then annually. CT of the abdomen and pelvis should be obtained at 3, 6, and 12 months, every 6 to 12 months in years 2 and 3, and then every 12 to 24 months in years 4 and 5. A chest radiograph is performed only if clinically indicated.
OUTCOME OF ACTIVE SURVEILLANCE — Long-term survival is excellent for males with low-risk, low-stage testicular GCTs who are treated with active surveillance, adjuvant chemotherapy, or primary retroperitoneal lymph node dissection (RPLND). (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)
The frequency and timing of relapses, as well as clinical outcomes following treatment, are illustrated by a series of 3366 patients from the Danish Testicular Cancer database [14]. All patients had clinical stage I testicular GCTs managed with active surveillance without any adjuvant therapy.
●Seminoma – In the 2000 males 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.
●Nonseminomatous GCT – In the 1366 males with nonseminomatous GCTs, 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 active surveillance [15]. 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. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors", section on 'Late relapse'.)
ISSUES REGARDING ACTIVE SURVEILLANCE
Compliance — Patient compliance with the surveillance protocol is a valid concern for testicular GCTs. However, whether compliance impacts overall survival is not clear [16,17].
This was demonstrated in a study involving 197 patients with stage I nonseminomatous GCTs followed at one of seven cancer centers with a minimum of two years of follow-up [16]. 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 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'.)
●Nonseminomatous GCTs – An increase in serum tumor markers outside of the normal range represents the first evidence of disease in over one-half of males with nonseminomatous GCTs who relapse, including some whose marker values were normal at the time of their initial presentation [18,19].
●Seminoma – Recurrence of seminoma is typically identified based on imaging findings, especially of the retroperitoneum. Elevated serum tumor markers are unusual among males with chemotherapy-naïve pure seminomas [20-22]. (See "Serum tumor markers in testicular germ cell tumors", section on 'Monitoring response to therapy'.)
For males who present with evidence of disease progression and have normal serum tumor markers, biopsy should be performed, particularly in the absence of retroperitoneal lymphadenopathy. The treatment approach for males who relapse following surveillance is covered separately. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)
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
●For males with stage I testicular germ cell tumors (GCTs), standard options include active surveillance, retroperitoneal lymph node dissection (RPLND), and adjuvant chemotherapy, depending on risk factors. Regardless of treatment strategy, the long-term cancer-specific survival approaches 100 percent.
●For males with stage I testicular seminoma, we recommend active surveillance rather than adjuvant treatment (Grade 1B). Adjuvant chemotherapy or radiation therapy is an alternative for patients for whom active surveillance is not appropriate. (See "Treatment of stage I seminoma".)
●For males with low-risk, clinical stage I nonseminomatous GCTs (NSGCTs), we recommend surveillance rather than adjuvant therapy (Grade 1B). For males with low-risk disease who decline active surveillance or are not good candidates for active surveillance, adjuvant chemotherapy with one or two cycles of platinum-based chemotherapy or RPLND is an appropriate alternative. (See "Management of stage I nonseminomatous germ cell tumors".)
●Active surveillance protocols vary based on whether patients have seminoma or an NSGCT and include a combination of history, physical examination, serum tumor markers, and imaging. In general, a more intensive approach of surveillance is used for males with NSGCTs. Surveillance is necessary for a minimum of five years and, for some patients, up to 10 years following orchiectomy. (See 'Active surveillance protocols' above.)
●An increase in serum tumor markers represents the first evidence of disease recurrence in over one-half of males with NSGCTs, including some whose marker values were normal at the time of their initial presentation. Abnormalities identified by imaging are the usual initial evidence of relapse in patients with chemotherapy-naïve pure seminomas; elevated serum tumor markers are unusual. (See "Serum tumor markers in testicular germ cell tumors", section on 'Monitoring response to therapy'.)
●For males with normal serum tumor markers who present with evidence of disease progression on imaging, biopsy should be performed, particularly in the absence of retroperitoneal lymphadenopathy. (See 'Diagnosis of relapse' above.)
