Posttreatment follow-up for testicular germ cell tumors

INTRODUCTION — Testicular germ cell tumor (GCT) is a highly curable cancer, with five-year survival rates of over 95 percent. As such, it is essential for survivors of testicular cancer to be monitored for disease recurrence.

The follow-up and surveillance for recurrence in patients with testicular cancer who have completed initial definitive therapy is presented here. The initial management of testicular germ cell tumors is discussed separately.

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

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

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

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

●(See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

ONCOLOGIC FOLLOW-UP — At the conclusion of treatment, surveillance is appropriate for:

●Patients with stage I testicular GCTs treated with orchiectomy alone. (See "Treatment of stage I seminoma", section on 'Surveillance' and "Management of stage I nonseminomatous germ cell tumors", section on 'Treatment approach'.)

●Patients with a complete response, defined as normal posttreatment serum tumor markers (alpha fetoprotein [AFP], beta-human chorionic gonadotropin [beta-hCG], and/or lactate dehydrogenase [LDH]) and no evidence of disease on imaging studies.

●Patients with a partial response, defined as stable or declining tumor markers (without normalization). This may be associated with evidence of persistent disease on imaging.

Routine follow-up care for patients who have successfully completed therapy for testicular cancer consists of periodic history and physical examinations (including testicular examination), assessment of serum tumor markers (beta-hCG, AFP, and LDH), and radiographic studies.

Factors that influence the nature and intensity of follow-up after completion of initial definitive therapy include histology (seminoma versus nonseminomatous germ cell tumors [NSGCTs]), risk of recurrence, and treatment.

Patients who have rising tumor markers and/or radiographically documented progressive disease following treatment should be evaluated for recurrent disease. (See 'Detection of recurrent disease' below.)

Duration of follow-up after treatment — The intensity of follow-up is guided in part by the probability of relapse over time.

●For patients with seminoma, the median time to relapse is 14 months. In addition, most relapses (over 90 percent) occur in the first three years after orchiectomy [1].

●For patients with NSGCT, most relapses (over 95 percent) occur within the first two years after orchiectomy [1].

Although the vast majority of relapses occur within the first five years for both seminoma and NSGCT, late recurrences can occur [2-4]. In one study that evaluated 1949 patients, 10 of 1123 patients with seminoma (0.8 percent) and 15 of 826 patients with NSGCT (1.8 percent) recurred more than five years after the original diagnosis [2]. Other series have reported a higher incidence of late recurrences [5,6], but these may be subject to referral bias.

Therefore, follow-up is most intensive during the first one to two years after treatment and then gradually decreases. However, most groups now recommend that follow-up continue for at least 10 years following initial treatment because of the risk of late relapse. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors", section on 'Timing of relapsed disease'.)

Monitoring approaches — The basic approaches used to monitor a patient following definitive therapy for a testicular GCT include:

●History and physical examination (see 'History and physical examination' below)

●Serum tumor markers (see 'Serum tumor markers' below)

●Imaging of the chest, abdomen, and pelvis (see 'Radiographic studies' below)

There are no prospective randomized trials that have defined the optimal follow-up strategy for patients who have completed their initial treatment. (See 'Guidelines for follow-up' below.)

History and physical examination — Posttreatment history and physical examination should be performed on the same schedule as measurement of tumor markers. Close attention should be paid to cervical and supraclavicular nodal regions, the abdominal exam (for the presence of masses or hepatomegaly), and the presence of neurologic signs or symptoms. (See 'Guidelines for follow-up' below.)

Testicular examination should be performed at each visit because of the higher incidence of contralateral testis cancer in patients with unilateral GCTs and of testis cancers in patients with primary extragonadal GCTs. Testicular ultrasound should be obtained for an equivocal exam. (See "Epidemiology and risk factors for testicular cancer" and "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum" and "Approach to the care of long-term testicular cancer survivors", section on 'Contralateral testicular cancer'.)

Serum tumor markers — For patients who have completed definitive therapy, tumor markers (beta-hCG, AFP, and LDH) should be measured at the same frequency as the history and physical exam.

●NSGCT – For patients with NSGCTs, serum concentrations of beta-hCG and/or AFP are elevated in 85 percent of patients at diagnosis. Following treatment, periodic measurements of serum beta-hCG and AFP represent the most sensitive means of detecting early relapse. (See 'NSGCT' below.)

●Seminoma – For patients with seminoma, we generally monitor serum tumor markers, although relapse is usually detected on radiographic imaging [7,8]. Beta-hCG is increased in 15 to 20 percent of patients with advanced disease. AFP, by definition, is never elevated in patients with pure seminoma [9]. Although LDH is a less sensitive and less specific tumor marker than either beta-hCG or AFP, it may be the only elevated marker in some patients with seminoma. (See 'Seminoma' below and "Serum tumor markers in testicular germ cell tumors", section on 'Human chorionic gonadotropin' and "Serum tumor markers in testicular germ cell tumors", section on 'Alpha-fetoprotein'.)

Radiographic studies

●CT or MRI abdomen and pelvis – Imaging of the abdomen and pelvis using either contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans should be used to monitor for disease recurrence.

The utility of periodic CT scans of the abdomen and pelvis was evaluated in a series of 170 patients undergoing surveillance following orchiectomy for stage I NSGCTs [10]. History and physical examination, serum tumor markers, CT of the abdomen and pelvis, and chest radiography provided the initial evidence of progression in 38, 71, 71, and 8 percent of patients, respectively. Removal of routine chest radiography from the surveillance protocol would not have altered the detection of progressive disease.

There is concern about the risk of second malignancies due to the radiation from CT scans. Efforts to reduce the amount of radiation by using different techniques, such as MRI, or changing the number and/or frequency of CT scans remain an area of active investigation. (See "Radiation-related risks of imaging".)

●Chest radiographs – Chest radiographs (CXR) can be performed as a component of the posttreatment surveillance schedule to monitor for recurrences in the lungs, although there are no firm data supporting the benefit of chest imaging. (See 'Guidelines for follow-up' below.)

In one series, 290 patients with disseminated testicular cancer were followed on a posttreatment surveillance protocol that included serum tumor markers, physical examination, and CXR after attaining a complete remission from chemotherapy [11]. Tumor relapse was documented in 33 (11.4 percent). Relapse was detected by rising tumor markers only in 27 (82 percent) and by rising tumors markers plus abnormal physical examination in four patients. A total of 10,160 routine CXR were performed during surveillance, and none played a role in detecting tumor relapse. Prior to the initiation of treatment for relapsed disease, all patients but one had elevated serum tumor markers.

Guidelines for follow-up — Various urologic and oncologic groups have published guidelines or recommendations based upon histology (NSGCTs versus seminomas) and stage of disease using data from observational studies [9,12-19]. There are no prospective randomized trials that define the optimal follow-up strategy for patients who have completed their initial treatment. Although there are some differences in guidelines between these groups, all rely upon interval history and physical examination, assessment of serum tumor markers, CXR, and contrast-enhanced CT or MRI of the abdomen and pelvis.

NSGCT — For patients with NSGCT, our approach to follow-up after completion of definitive therapy is as follows, which is consistent with guidelines from the National Comprehensive Cancer Network (NCCN) [19].

Stage I NSGCT (surveillance) — For patients with stage I NSGCT treated with orchiectomy alone who select surveillance, follow-up includes:

●History, exam, tumor markers – History, physical examination, and serum tumor markers (AFP, beta-hCG, and LDH) every two months in year 1, every three months in year 2, every four to six months in year 3, every six months in year 4, then annually in year 5.

●No risk factors for recurrence – For patients without risk factors for recurrence (lymphovascular invasion; invasion of the spermatic cord or scrotum; or presence of embryonal carcinoma), follow-up includes:

•Abdominopelvic imaging – Contrast-enhanced CT of the abdomen and pelvis every four to six months in year 1, every six months in year 2, annually in year 3, then as clinically indicated. Contrast-enhanced MRI of the abdomen and pelvis is a reasonable alternative to CT.

•Chest imaging – CXR at 4 and 12 months, annually in years 2, 3, and 4, then as clinically indicated. A contrast-enhanced CT of the chest is preferred in patients with pulmonary symptoms.

●Risk factors for recurrence – For patients with risk factors for recurrence, follow-up includes:

•Abdominopelvic imaging – Contrast-enhanced CT of the abdomen and pelvis every four months in year 1, every four to six months in year 2, every six months in year 3, annually in year 4, then as clinically indicated. Contrast-enhanced MRI of the abdomen and pelvis is a reasonable alternative to CT.

•Chest imaging – CXR every four months in year 1, every four to six months in year 2, every six months in year 3, annually in year 4, then as clinically indicated. A contrast-enhanced CT of the chest is preferred in patients with pulmonary symptoms.

Stage I NSGCT treated with adjuvant chemotherapy or RPLND — For patients with clinical stage IA or IB NSGCT treated with adjuvant chemotherapy or primary retroperitoneal lymph node dissection (RPLND), follow-up includes:

●History, exam, tumor markers – History, physical examination, and tumor markers every three months in years 1 and 2, every six months in years 3 and 4, and then annually.

●Abdominopelvic imaging – Contrast-enhanced CT of the abdomen and pelvis annually in years 1 and 2. Contrast-enhanced MRI of the abdomen and pelvis is a reasonable alternative to CT. For those treated with RPLND, imaging in year 2 is not necessary.

●Chest imaging – CXR every 6 to 12 months in year 1 and annually in year 2. A contrast-enhanced CT of the chest is preferred in patients with pulmonary symptoms.

Stage II to III NSGCT

●Follow-up for pathologic stage IIA or IIB treated with RPLND without adjuvant chemotherapy

•History, exam, tumor markers – History, physical examination, and tumor markers every two to three months in years 1 and 2, every four months in year 3, every six months in year 4, and then annually in year 5.

•Abdominopelvic imaging – Contrast-enhanced CT of the abdomen and pelvis at three to four months in year 1, annually in year 2, then as clinically indicated thereafter. Contrast-enhanced MRI of the abdomen and pelvis is a reasonable alternative to CT.

•Chest imaging – CXR every 2 to 4 months in year 1, every 3 to 6 months in year 2, and annually in years 3, 4, and 5. A contrast-enhanced CT of the chest is preferred in patients with pulmonary symptoms.

●Follow-up for pathologic stage IIA or IIB treated with RPLND and adjuvant chemotherapy

•History, exam, tumor markers – History, physical examination, and tumor markers every six months in years 1 and 2, and annually in years 3, 4, and 5.

•Abdominopelvic imaging – CT of the abdomen and pelvis four months after RPLND and as clinically indicated thereafter. MRI of the abdomen and pelvis is a reasonable alternative to CT.

•Chest imaging – CXR every six months in year 1, and annually in years 2, 3, 4, and 5. A contrast-enhanced CT of the chest is preferred in patients with pulmonary symptoms.

●Follow-up for clinical stage II/III treated with chemotherapy with or without subsequent RPLND

•History, exam, tumor markers – History, physical examination, and tumor markers every two months in year 1, every three months in year 2, and every six months in years 3, 4, and 5.

•Abdominopelvic imaging – CT of the abdomen and pelvis every six months in year 1, every 6 to 12 months in year 2, annually in year 3, and then as clinically indicated. MRI of the abdomen and pelvis is a reasonable alternative to CT.

•Chest imaging – CXR every six months in years 1 and 2. Annual imaging in years 3 and 4 is optional. A contrast-enhanced CT of the chest is preferred in patients with pulmonary symptoms.

Seminoma — For patients with seminoma, our approach to follow-up after completion of definitive therapy (algorithm 1) is as follows, which is consistent with guidelines from the NCCN [19].

Stage I seminoma

●Approach to chest imaging for all patients – For any patient with treated stage I seminoma (regardless of whether surveillance or adjuvant therapy was selected), a CXR should be performed only if clinically indicated. A contrast-enhanced CT of the chest is preferred in patients with symptoms concerning for disease recurrence.

●Surveillance after orchiectomy – For patients with stage I seminoma treated with orchiectomy alone who select surveillance (algorithm 1), follow-up includes:

•History, exam, and tumor markers – History, physical exam, and tumor markers (AFP, beta-hCG, and LDH) every three to six months in year 1, every six months in year 2, every 6 to 12 months in year 3, and then annually in years 4 and 5.

•Abdominopelvic imaging – Contrast-enhanced CT or MRI of the abdomen and pelvis at four to six months, and 12 months in year 1, every six months in year 2, every 6 to 12 months in year 3, and every 12 to 24 months in years 4 and 5.

Further details on surveillance for stage I seminoma treated with orchiectomy alone are discussed separately. (See "Surveillance for stage I testicular germ cell tumors following orchiectomy".)

●Follow-up after adjuvant therapy (chemotherapy or radiation therapy) (algorithm 1)

•History, exam, and tumor markers – History and physical exam every 6 to 12 months for years 1 and 2, then annually in years 3, 4, and 5. Serum tumor markers (AFP, beta-hCG, and LDH) are optional.

•Abdominopelvic imaging – Contrast-enhanced CT or MRI of the abdomen and pelvis annually for years 1 to 3.

Stage II to III seminoma

●Follow-up for clinical stage IIA and non-bulky stage IIB seminoma after radiation therapy or chemotherapy – Definitions for stage II seminoma (algorithm 2) are discussed separately. (See "Treatment of stage II seminoma", section on 'Definition of stage II seminoma'.)

•History and exam – History and physical exam every three months in year 1, then every six months for years 1 through 5. Serum tumor markers are optional.

•Abdominopelvic imaging – Contrast-enhanced CT of the abdomen and pelvis at three months, then at 9 or 12 months during year 1, annually in years 2 and 3, and subsequently as clinically indicated. Contrast-enhanced MRI of the abdomen and pelvis is a reasonable alternative to CT.

•Chest imaging – CXR every six months for years 1 and 2. A contrast-enhanced CT of the chest is preferred in patients with symptoms concerning for disease recurrence.

●Follow-up for bulky clinical stage IIB, IIC, and III seminoma after chemotherapy

•All patients – History, physical exam, and tumor markers (AFP, beta-hCG, and LDH) every two months in year 1, every three months in year 2, every six months in years 3 and 4, then annually in year 5.

•Abdominopelvic imaging – Contrast-enhanced CT of the abdomen and pelvis every four months in year 1, every six months in year 2, annually in years 3 and 4, then as clinically indicated in year 5. Contrast-enhanced MRI of the abdomen and pelvis is a reasonable alternative to CT. MRI of the abdomen and pelvis is a reasonable alternative to CT.

Patients with residual abdominal or pelvic masses after completing chemotherapy may have a different approach to surveillance imaging, including the use of fluorodeoxyglucose positron emission tomography-CT. Further details are discussed separately. (See "Approach to surgery following chemotherapy for advanced testicular germ cell tumors", section on 'Seminoma'.)

•Chest imaging – CXR every two months in year 1, every three months in year 2, and annually in years 3, 4, and 5. A contrast-enhanced CT of the chest is preferred for patients with supradiaphragmatic masses at diagnosis and for those with symptoms concerning for disease recurrence.

Detection of recurrent disease — Rising tumor markers and/or the presence of radiographically documented progressive disease are usually an indication of disease recurrence or progression. Patients who exhibit either of these during surveillance are candidates for further treatment. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors".)

Interpreting serum tumor markers — Serum tumor markers alone are infrequently a sign of recurrence among patients with seminoma [7,8]. False-positive values may be due to a number of other causes. (See "Serum tumor markers in testicular germ cell tumors".)

The approach to interpreting serum tumor markers depends on the scenario:

●For patients who experienced declining serum tumor markers during treatment but did not normalize by the end of treatment, we consider an increase in AFP or beta-hCG a sign of disease recurrence. However, no particular level of increase is pathognomonic of a tumor recurrence.

●For patients who normalized serum tumor markers, we do not consider values that fluctuate (or increase) but stay within the normal range a sign of relapse.

●For patients with a stable but elevated level of AFP (ie, AFP level 25 percent higher than the upper limit of normal), an increase in the AFP or beta-hCG is likely a sign of disease recurrence.

Pulmonary nodules — Patients who received bleomycin as part of their original treatment are at risk for pulmonary toxicity during follow-up. This may present on imaging (CXR or CT) as nodular lesions shortly after the completion of chemotherapy (table 1) [20]. Characteristically, these are subpleural in location, and serum tumor markers are normal. (See "Bleomycin-induced lung injury" and "Approach to the care of long-term testicular cancer survivors", section on 'Bleomycin-induced lung injury'.)

Growing teratoma syndrome — Benign teratomatous elements may enlarge during or after chemotherapy, mimicking progressive or relapsed disease [21]. In such patients, tumor markers may be normal. Complete surgical resection is indicated rather than additional chemotherapy. (See "Approach to surgery following chemotherapy for advanced testicular germ cell tumors", section on 'Rationale for resection of residual masses in patients with NSGCT'.)

False-positive elevation of serum beta-hCG — Because there is some cross reactivity with luteinizing hormone (LH), a false-positive elevation of serum beta-human chorionic gonadotropin (beta-hCG) may occur in patients with hypogonadism, which may occur following systemic chemotherapy. Administration of testosterone may resolve this issue. (See "Serum tumor markers in testicular germ cell tumors" and "Clinical features and diagnosis of male hypogonadism" and "Causes of secondary hypogonadism in males" and "Approach to the care of long-term testicular cancer survivors", section on 'Hypogonadism'.)

TREATMENT-RELATED COMPLICATIONS — Patients who have been treated for a testicular GCT are at risk for late complications of therapy, as well as for recurrence of cancer. The immediate and late complications of treatment in patients with testicular GCTs are discussed in detail separately. (See "Treatment-related toxicity in testicular germ cell tumors" and "Approach to the care of long-term testicular cancer survivors".)

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

●Timing of relapse – Most patients with testicular cancer who will relapse do so within the first two years after initial treatment. Late relapses (after five years) can occur but are rare. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors", section on 'Timing of relapsed disease'.)

●Factors that influence follow-up – Posttreatment follow-up is influenced by the histology of the original tumor (seminoma versus nonseminomatous germ cell tumor [NSGCT]), the stage and risk of recurrence at presentation, and initial therapy. (See 'Oncologic follow-up' above.)

●Posttreatment follow-up guidelines – Follow-up after initial therapy to monitor for disease recurrence includes history and physical examination, serum tumor markers (beta-human chorionic gonadotropin [beta-hCG], alpha-fetoprotein [AFP]), and imaging studies (contrast-enhanced computed tomography [CT] or magnetic resonance imaging [MRI] of abdomen and pelvis, chest radiograph [CXR]). (See 'Guidelines for follow-up' above.)

•Follow-up for NSGCT (see 'NSGCT' above)

•Follow-up for seminoma (see 'Seminoma' above)

●Clinical conditions that mimic relapse – Several clinical situations may mimic tumor relapse. These situations must be carefully distinguished from a true relapse to prevent overtreatment. Examples include pulmonary nodules secondary to bleomycin lung injury, the growing teratoma syndrome, and false-positive elevation of tumor markers (such as beta-hCG elevation due to hypogonadism). (See 'Detection of recurrent disease' above.)

●Surveillance for treatment-related toxicity – Patients who are treated for testicular germ cell tumors also require surveillance for therapy-related complications. (See "Treatment-related toxicity in testicular germ cell tumors" and "Approach to the care of long-term testicular cancer survivors".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William K Oh, MD, who contributed to earlier versions of this topic review.