Diagnosis and treatment of relapsed and refractory testicular germ cell tumors

INTRODUCTION — Testicular germ cell tumors (GCTs) are one of the most curable solid neoplasms, with five-year survival rates in the United States of over 95 percent with contemporary treatment regimens [1,2]. However, patients who relapse after first-line therapy have a substantial decrease in cure rate, with a five-year survival rate of 50 percent or lower [2].

Patients with good-risk advanced testicular GCTs who are treated with first-line chemotherapy are generally cured, with relapse-free survival rates of approximately 90 percent. In contrast, half of patients with poor-risk disease and about a quarter of patients with intermediate-risk disease require additional therapy for relapsed disease following first-line chemotherapy (table 1) [3-8]. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Definition of risk'.)

The management of relapsed or refractory testicular GCTs is complex, and patients should be referred to a cancer center with multidisciplinary expertise, and offered enrollment in clinical trials, where available.

The management of patients with relapsed or refractory GCTs will be presented here. The initial management of patients with advanced testicular germ cell tumors and extragonadal germ cell tumors is discussed separately.

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

●(See "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum".)

DIAGNOSIS — The diagnosis of relapsed or refractory GCTs is typically made based on an increase in serum tumor markers (alpha fetoprotein [AFP] or beta-human chorionic gonadotropin [beta-hCG]) and/or evidence of progressive disease on imaging studies. Relapsed disease sometimes presents with clinical symptoms or abnormalities on physical examination. Biopsy confirmation is not usually necessary but can be obtained in select situations where the diagnosis is unclear.

Most cases of relapsed testicular GCTs following chemotherapy are discovered during regular posttreatment surveillance. Such surveillance consists of periodic history and physical examinations, serum tumor marker assessments, and radiographic imaging studies. (See "Posttreatment follow-up for testicular germ cell tumors" and "Surveillance for stage I testicular germ cell tumors following orchiectomy".)

Location of relapsed disease — The locations of relapsed disease for most patients diagnosed with relapsed testicular GCTs are very predictable:

●Patients with clinical stage I disease generally relapse in the retroperitoneum. Thoracic metastases in the absence of retroperitoneal disease are unusual, particularly for pure seminomas. Biopsy may be indicated when serum tumor markers are normal and the pattern or location of an apparent relapse does not fit with the natural history of testicular GCTs. (See 'Role of biopsy' below.)

Relapsing patients previously diagnosed with metastatic disease whose prior treatment included chemotherapy often present with more disseminated disease. In such patients, common areas of relapse include the retroperitoneum (60 percent), lungs (40 to 50 percent), mediastinal nodes (26 to 32 percent) involvement, liver metastases (10 to 20 percent), and bones (2 to 11 percent) [9-11].

Serum tumor markers — The use of serum tumor markers to diagnose relapsed disease varies by tumor histology:

●Nonseminomatous germ cell tumors – An elevation of serum tumor markers represents the first evidence of disease in over one-half of patients with nonseminomatous GCTs (NSGCTs) who relapse, including some whose marker values were normal at the time of their initial presentation [9,12]. Serum beta-hCG and AFP are the most sensitive means of detecting relapsed disease for NSGCTs. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'Serum tumor markers'.)

●Seminomas – Approximately 60 percent of patients with seminomas (typically those with prior stage II or III disease) who relapse following chemotherapy present with elevated levels of serum beta-hCG and/or lactate dehydrogenase (LDH) [13-15]. By definition, AFP is never elevated in patients with pure seminomas either at initial diagnosis or relapse [16]. However, patients who are diagnosed with a pure seminoma but who actually have a mixed GCT may present with elevated AFP at the time of relapse disease. (See "Serum tumor markers in testicular germ cell tumors", section on 'Monitoring response to therapy' and "Posttreatment follow-up for testicular germ cell tumors", section on 'Serum tumor markers'.)

Of note, an isolated elevation in serum LDH should not be used to diagnose or monitor for relapsed disease. Numerous diverse medical conditions can cause an elevation in LDH, which inevitably results in many false-positive results [17].

Timing of relapsed disease — Most patients with relapsed disease present within two years after completing therapy, regardless of stage and prior therapy. Patients who relapse after more than two years are considered to have late relapses. Patients who relapse more than five years after completing treatment are considered to have very late relapses; data suggest that patients with very late relapses comprise more than one-half of all patients with late relapses [18-24].

Patients with late relapses have the following clinical presentation:

●Prior therapy – Among patients with clinical stage I disease, the risk of late relapse is significantly higher among those undergoing surveillance than those receiving adjuvant therapy (4 versus 1 percent) [24-26]. In general, late relapses in patients who previously received chemotherapy are biologically different from late relapses in chemotherapy-naïve patients [21]. Chemotherapy-resistant yolk sac tumors and teratoma with or without malignant transformation are more common after treatment with chemotherapy. The clinical outcomes of late relapses in patients with clinical stage I testicular GCTs on active surveillance are discussed separately. (See "Surveillance for stage I testicular germ cell tumors following orchiectomy", section on 'Surveillance outcomes'.)

●Nonseminomatous germ cell tumors – The frequency of late relapse for patients initially diagnosed with an NSGCT is approximately 3 percent [25]. Late relapses from NSGCT occur most commonly in the retroperitoneum (50 percent), lungs (17 percent), mediastinum (9 percent), neck and supraclavicular region (7 percent), pelvis (4 percent), and other locations such as the liver or bones (12 percent).

●Seminomas – The frequency of late relapse for patients initially diagnosed with a seminoma is less than 2 percent [25]. Late relapses from seminomas tend to occur in the lymph nodes, involving the retroperitoneum (55 percent), mediastinum (27 percent), and neck and supraclavicular region (15 percent). The lungs and pelvis were rarely involved (3 and 2 percent, respectively). In addition, approximately 5 percent of late seminoma relapses occurred in other locations.

●Risk factors – Risk factors for late relapse include poor-prognosis disease at initial diagnosis, bulky retroperitoneal disease, lack of prior retroperitoneal lymph node dissection, and prior early relapse [27].

●Malignant disease versus teratoma – All relapses in seminomas are malignant. In NSGCT, most late relapses are malignant while approximately 10 to 20 percent are teratomas. (See 'Metastatic teratoma' below.)

●Tumor markers at diagnosis of late relapse – Between 30 and 50 percent of late relapses are associated with normal serum tumor markers. In a pooled analysis of observational studies evaluating late relapsed GCTs, approximately 50 percent of patients with NSGCTs had elevated AFP, and approximately 25 percent of patients with either seminoma or NSGCT histology had elevated beta-hCG at the time of late relapse [25].

Imaging studies — Although serum tumor markers often provide the first clinical evidence of relapse, a substantial minority of patients will have normal serum tumor markers at the time of relapse. In this situation, radiographic imaging, particularly CT scans of the abdomen and pelvis, generally provides the first evidence of relapse.

Recurrence of seminoma can be identified based on imaging findings, especially relapses in the retroperitoneum. However, patients previously diagnosed with stage II or III disease may present with elevated serum tumor markers. (See 'Serum tumor markers' above.)

In contrast, for patients with NSGCT who have undergone a retroperitoneal lymph node dissection or patients with seminoma who have undergone paraaortic radiation therapy (RT), relapse in the retroperitoneum is rare. In such patients, relapse is typically detected either by elevated serum tumor markers and/or evidence of metastatic disease on thoracic imaging with a chest radiograph or CT scan.

Role of biopsy — Biopsy confirmation of relapsed disease is not usually necessary, but it can be obtained when the initial diagnostic work-up is inconclusive or when the clinical pattern of relapse is atypical. General indications for a biopsy include late relapses and relapses in atypical locations (eg, absence of retroperitoneal lymphadenopathy or when a nodule or mass appears outside the expected pattern of spread) with normal serum tumor markers such as AFP and beta-hCG. Clinical judgment is required to balance the potential benefit of additional information from a biopsy versus the risks associated with invasive procedures and with delaying treatment.

As an example, a biopsy may be obtained to exclude other diagnoses (such as sarcoidosis) in patients with pure seminomas, normal beta-hCG, and no prior treatment with paraaortic RT whose imaging suggest relapsed disease isolated to the mediastinal and hilar nodes. Sarcoidosis is significantly more common among males with GCTs than the general population. However, case reports have demonstrated the simultaneous presentation of noncaseating granulomas and relapsed testis cancer [28-32].

Conversely, when the pattern of recurrence (eg, enlarged retroperitoneal lymph nodes on imaging, or rising serum beta-hCG or alpha fetoprotein) and the timing of recurrence (eg, first two years after initial treatment) are consistent with relapsed GCT, then salvage treatment should be initiated without delay because the likelihood of biopsy contributing to the management of disease is very low.

MANAGEMENT — The optimal treatment for patients with relapsed or refractory GCTs depends upon the initial treatment and response to prior therapy, the location and timing of the relapse (early versus late relapsed disease), and tumor histology.

Cisplatin-naïve disease — Patients with relapsed, cisplatin-naïve disease are defined as:

●Those who originally presented with stage I GCT and received surveillance or radiation therapy (RT).

●Those who originally presented with stage I seminoma and received single-agent carboplatin.

●Those with stage I or II nonseminomatous GCT (NSGCT) treated with retroperitoneal lymph node dissection (RPLND) only.

Patients with an initial diagnosis of stage I NSGCT who were treated with a single cycle of BEP chemotherapy are also considered to be cisplatin naïve even though they have received one cycle of cisplatin-based chemotherapy. The approach to these patients is discussed below. (See 'Clinical stage I NSGCT treated with BEP' below.)

Most patients with relapsed cisplatin-naïve disease are typically treated with cisplatin-based chemotherapy. However, RPLND may be an option for select patients with NSGCT, depending on the presence of tumor markers and the extent of disease at relapse. Multidisciplinary input from surgical oncology and medical oncology is necessary.

For patients with relapsed, cisplatin-naïve disease, our approach is as follows:

●Seminomas, elevated tumor markers or extensive disease – We suggest cisplatin-based chemotherapy for patients with a seminoma, elevated serum tumor markers (see 'Serum tumor markers' above), involved retroperitoneal lymph nodes greater than 2 cm in greatest dimension, or disease outside the retroperitoneum.

For such patients with relapsed cisplatin-naïve disease, the chemotherapy regimen depends on tumor risk category (table 1), using a similar approach to those with newly diagnosed disease. Patients with good-risk disease should receive three cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy or four cycles of etoposide plus cisplatin (EP), whereas patients with intermediate- and poor-risk disease should receive four cycles of BEP or four cycles of etoposide, ifosfamide, and cisplatin [VIP]. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

●NSGCT, normal tumor markers and limited retroperitoneal disease – We suggest RPLND rather than chemotherapy for select patients with NSGCT, normal serum tumor markers, and disease limited to the retroperitoneum lymph nodes that are less than or equal to 2 cm in greatest dimension. Select cases with lymph nodes between 2 to 3 cm in greatest dimension may also be evaluated for RPLND. RPLND must be performed by a surgical oncologist with extensive expertise in this procedure. (See "Approach to surgery following chemotherapy for advanced testicular germ cell tumors", section on 'Normalized tumor markers with abnormal imaging findings'.)

Cisplatin-based chemotherapy is an appropriate alternative if such surgical expertise is not available. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

Data for using RPLND come from an observational study of 580 males with clinical stage I NSGCT who were initially managed with surveillance [33]. In this study, 162 patients relapsed while on surveillance. Of the 122 patients who relapsed with the equivalent of de novo stage II disease, 61 received chemotherapy, and 60 were treated with RPLND. At median follow-up of 7.6 years, among those treated with chemotherapy at relapse, overall survival was 96.9 percent. There were five deaths in the chemotherapy arm (one death from bleomycin toxicity and four deaths from testicular cancer despite receiving standard chemotherapy). Among those treated with RPLND at relapse, overall survival was 100 percent (no deaths), possibly due to the more favorable disease characteristics of this group. More patients treated with RPLND had lower disease stage (75 percent had stage IIA disease) than those treated with chemotherapy (58 percent had stage IIB/IIC disease).

RPLND is also preferred in patients with normal tumor markers at relapse because they are less likely to need additional therapy. In this study, among patients treated with RPLND who had normal serum AFP or beta-hCG at the time of relapse, 82 percent required no further treatment after RPLND. In contrast, 9 of 17 patients with elevated tumor markers (53 percent) required additional treatment. Among patients treated with chemotherapy, 61 percent required no further treatment.

Clinical stage I NSGCT treated with BEP — The optimal treatment is unclear for patients with clinical stage I nonseminomatous GCT (NSGCT) who relapse after one or two cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy. Since relapses are rare and data are limited in this population, the outlined treatment approach is based upon the clinical experience of the UpToDate experts. Selection of therapy depends upon the number of BEP cycles previously received and risk category at relapse. (See "Management of stage I nonseminomatous germ cell tumors".)

●One prior cycle of BEP with good-risk disease at relapse – For patients with Stage I NSGCT who previously received one cycle of BEP and present with good-risk disease at relapse (table 1), we offer either three cycles of BEP or four cycles of EP chemotherapy (table 2), using a similar approach to those with treatment-naïve, good-risk disease. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Good risk'.)

●Two prior cycles of BEP with good-risk disease at relapse – For patients with stage I NSGCT who previously received two cycles of BEP and present with good risk disease at relapse, we suggest four cycles of etoposide and cisplatin (EP) rather than additional cycles of BEP. Although there are limited data comparing additional cycles of BEP over EP in this population, this approach limits the cumulative dose of bleomycin [34].

●One or two prior cycles of BEP with intermediate- or poor-risk disease at relapse – For patients with stage I NSGCT who previously received either one or two cycles of BEP and present with intermediate- or poor-risk disease at relapse (table 1), we suggest ifosfamide-based chemotherapy rather than EP or additional cycles of BEP. Options include four cycles of either VIP (table 3) or paclitaxel, ifosfamide, and cisplatin (TIP (table 4)). We prefer this approach due to concerns of potential chemotherapy resistance to the original regimen (BEP) and to limit the cumulative dose of bleomycin.

●Indications for RPLND – RPLND is a reasonable alternative to chemotherapy in patients whose relapsed disease is limited to the retroperitoneum and who have normal serum tumor markers. Further details are discussed separately. (See "Approach to surgery following chemotherapy for advanced testicular germ cell tumors", section on 'Normalized tumor markers with abnormal imaging findings'.)

Studies have reported successful outcomes in patients with stage I NSGCT who relapse after one or two cycles of BEP and are treated with either additional cycles of BEP or with regimens that include ifosfamide such as VIP and TIP [34-36].

Various cisplatin and ifosfamide-based treatment regimens were investigated in an observational study of 51 patients with clinical stage I NSGCT who experienced relapse after either one or two cycles of adjuvant BEP [34]. The median time to relapse was 13 months (range 2 months to 25 years). Approximately one-third of patients had late relapse (see 'Timing of relapsed disease' above). Most patients presented with stage IIB (38 percent) or III (33 percent) disease at relapse; a majority (84 percent) had good-prognosis disease, and the remainder had intermediate- (12 percent) or poor-prognosis (4 percent) disease. A variety of chemotherapy regimens were used including BEP, VIP, and TIP; only two patients received the EP regimen. At median follow-up of 96 months, the five-year overall survival was 81 percent.

Treatment after three or four cycles of cisplatin-based chemotherapy — Patients who relapse after three or four cycles of initial cisplatin-based chemotherapy are usually diagnosed within the first two years after receiving such therapy. For these patients, we suggest either standard-dose ifosfamide and cisplatin-based chemotherapy or high-dose chemotherapy with autologous hematopoietic cell transplantation (HCT) rather than surgery, radiation, or other systemic therapies. Either approach is reasonable, as both treatments have demonstrated similar survival outcomes in randomized trials. The choice of therapy is based upon patient performance status and comorbidities, treatment preferences, and institutional experience.

Standard-dose chemotherapy — Patients who relapse after three or four cycles of cisplatin-based chemotherapy can be treated with standard-dose chemotherapy regimens that combine three drugs and include both ifosfamide and cisplatin:

●TIP – Paclitaxel 175 to 250 mg/m² infused over 24 hours on day 1 followed by ifosfamide 1500 mg/m² daily for four days (days 2, 3, 4, and 5) and cisplatin 25 mg/m² daily for four days (days 2, 3, 4, and 5) (table 4) [10].

●VeIP – Vinblastine 0.11 mg/kg per day for two days, ifosfamide 1200 mg/m² daily for five days, and cisplatin 20 mg/m² daily for five days [37].

For the rare patient whose initial chemotherapy did not include etoposide, we offer the VIP regimen:

●VIP – Etoposide 75 mg/m², ifosfamide 1.2 g/m², and cisplatin 20 mg/m² daily for five days every three weeks (table 3) [38].

For select patients who previously were treated with VIP as first-line chemotherapy, the optimal second-line chemotherapy is not defined. We prefer high-dose chemotherapy with etoposide plus carboplatin followed by HCT. For patients who are ineligible for or decline high-dose chemotherapy followed by HCT, options include cisplatin, vinblastine, and bleomycin (PVB) for those without a contraindication to bleomycin [39], or the combination of gemcitabine, paclitaxel, and either cisplatin or oxaliplatin [40-44]. We do not offer TIP or VeIP, since both regimens include two drugs the patient has already received (ifosfamide and cisplatin).

Data supporting the use of TIP are as follows:

●In one study, 46 patients with relapsed testicular GCTs were treated with the TIP regimen, with granulocyte colony-stimulating factor support [10]. Eligibility in this trial was limited to patients with highly favorable prognostic factors, including:

•No prior history of an extragonadal primary tumor

•No more than six cycles of cisplatin-based chemotherapy prior to enrollment

•History of either a complete response or a partial radiographic response plus normalization of serum tumor markers for more than six months

In this highly selected patient population, at a median follow-up of 69 months, chemotherapy alone resulted in a complete and durable response in 29 patients for an overall response rate (ORR) of 63 percent. Among those who also underwent subsequent resection of residual masses, 32 patients (70 percent) achieved a durable response. At a mean duration of follow-up of 69 months, only 3 of the 32 complete responders relapsed. The two-year progression-free survival rate was 65 percent.

●In another phase II trial of 51 patients with poor- and good-risk disease who received a modified TIP regimen, complete and partial responses were seen in 8 and 18 patients, respectively (ORR 60 percent) [45]. Unlike the prior series, the failure-free survival rate at one year was only 36 percent. When the analysis was limited to good-risk patients, one-year failure-free survival was 43 percent. Of note, this study used lower doses of paclitaxel (175 mg/m² versus 250 mg/m²) and ifosfamide (5 g/m² versus 6 g/m²) compared with other studies [10].

High-dose chemotherapy and autologous HCT — High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) is another treatment option for patients who relapse after three or more cycles of cisplatin-based chemotherapy. In such patients, treatment-related mortality is less than 10 percent, and long-term disease-free survival is between 40 and 70 percent [46-52].

For patients who select this approach, we suggest high-dose chemotherapy with etoposide and carboplatin (EC) followed by HCT rather than other high-dose chemotherapy regimens. We administer at least two cycles of high-dose chemotherapy because a single-cycle of high-dose chemotherapy followed by HCT did not confer survival benefit over standard dose-chemotherapy alone in a randomized trial [9]. Intensifying the high-dose EC regimen by adding additional agents (such as cyclophosphamide [CEC]) and increasing the doses of carboplatin and etoposide did not improve survival outcomes and was associated with more treatment-related toxicity in one randomized trial [53]. The optimal approach to high-dose chemotherapy, including the ideal regimen and number of cycles of chemotherapy, is not established, and further randomized studies are necessary. (See 'Investigational approaches' below.)

Studies are mixed for the efficacy of high-dose chemotherapy followed by HCT as subsequent-line therapy. Observational studies report favorable results for high dose chemotherapy followed by HCT over standard-dose chemotherapy [47]. In contrast, randomized trials suggest a similar survival benefit for both approaches [9,47,53]. Interpretation of these data is further complicated by heterogeneous patient populations and the use of different high-dose and standard-dose chemotherapy regimens. Studies are also needed to compare TIP (table 4) with high-dose chemotherapy followed by HCT in this setting.

Data are as follows:

●In a phase III trial (IT-94), 280 patients who relapsed after first-line chemotherapy were randomly assigned to either four cycles of VIP/VeIP (chemotherapy alone), or three cycles of VIP/VeIP followed by one cycle of high-dose chemotherapy (carboplatin, etoposide, cyclophosphamide; CEC) followed by autologous HCT [9]. Compared with standard-dose chemotherapy alone, high-dose chemotherapy followed by HCT had a similar three-year event-free survival (EFS) rate (42 versus 35 percent) and resulted in a higher toxic death rate (7 versus 3 percent).

●In contrast, one observational study suggested superior outcomes for high dose chemotherapy followed by HCT. In this study, 1594 patients with GCTs who relapsed after treatment at least three cycles of cisplatin-based chemotherapy were treated with either standard-dose chemotherapy or high-dose carboplatin-based chemotherapy followed by autologous HCT [47]. There was marked heterogeneity in the type and frequency of high-dose chemotherapy regimens used. Patients were classified into five prognostic categories, based upon histology, primary tumor site, response to first-line chemotherapy, progression-free interval, serum tumor markers, and sites of metastatic involvement. At a median follow-up of five years, compared with standard-dose chemotherapy, high-dose chemotherapy plus HCT was associated with a higher two-year progression-free survival (50 versus 28 percent, hazard ratio [HR] 0.44, 95% CI 0.39-0.51) and higher five-year overall survival rate (53 versus 41 percent, HR 0.65, 95% CI 0.56-0.75). Analyses of progression-free survival and overall survival rates based upon prognostic classification found similar results in all groups, except for the low-risk group for whom there was no difference in overall survival between the two approaches.

Platinum-refractory disease — Platinum refractory disease is defined as GCTs that relapse after second-line chemotherapy; or progress during or within a month of completing their initial cisplatin-based chemotherapy [54]. Clinical trial enrollment is encouraged for these patients, where available. (See 'Investigational approaches' below.)

For patients with platinum-refractory disease who decline or are ineligible for clinical trials, high-dose chemotherapy (if not previously received) with autologous HCT is one option, as limited data show durable complete responses with this approach [55]. We also prefer high dose chemotherapy and autologous HCT for patients relapse after two prior cisplatin-based regimens (such as BEP and TIP).

For patients with platinum-refractory disease who have not received high-dose chemotherapy and have no previous exposure to paclitaxel or ifosfamide, another option is standard-dose TIP chemotherapy (table 4). In these patients, TIP has resulted in durable complete responses based on the clinical experience of UpToDate contributors.

The choice of high-dose chemotherapy prior to HCT varies among institutions. In the United States and some European centers, high-dose EC is the most commonly used regimen [4,55-58]. High-dose regimens that incorporate paclitaxel, cisplatin, cyclophosphamide, and thiotepa have also been used [57,59-63]. There are no randomized trials that compare these more complex regimens with EC.

In one study from Indiana University, 364 patients (122 with platinum-refractory disease) were treated with two cycles of high-dose EC chemotherapy followed by HCT [55]. At median follow-up of 3.3 years, for patients with platinum-refractory disease, the two-year progression-free survival was 33 percent, and the two-year overall survival was 37 percent.

The management of patients who relapse after high-dose chemotherapy and HCT is discussed below. (See 'Treatment after progression on high-dose chemotherapy and HCT' below.)

Residual masses — We offer surgical resection to patients with NSGCTs who have residual masses after subsequent-line standard chemotherapy or high-dose chemotherapy followed by HCT. Further details on the approach to surgery following systemic therapy in seminomas and NSGCTs are discussed separately. (See "Approach to surgery following chemotherapy for advanced testicular germ cell tumors".)

Treatment after progression on high-dose chemotherapy and HCT — For patients who progress after high-dose chemotherapy and hematopoietic cell transplantation (HCT), treatment options include gemcitabine plus paclitaxel [42,44]; gemcitabine plus oxaliplatin [43,64]; paclitaxel, gemcitabine, and cisplatin [40]; paclitaxel, gemcitabine, and oxaliplatin [41,65]; epirubicin plus cisplatin [66]; and oral etoposide [39,67]. Long-term disease control with these regimens is uncommon but may occasionally be seen. Clinical trial enrollment is also encouraged, where available. (See 'Investigational approaches' below.)

SPECIAL CONSIDERATIONS

Late relapse — Late-relapsed GCTs are defined as relapses that occur more than two years after completion of initial therapy. The clinical presentation of these patients is discussed above. (See 'Timing of relapsed disease' above.)

Our treatment approach to patients with late-relapsing disease are as follows:

●Late-relapsing seminomas – Patients with late-relapsing seminomas should be treated in the same manner as those with early-relapsing seminomas. (See 'Management' above.)

●Late-relapsing NGCTs – For patients with a late-relapsing nonseminomatous GCT (NSGCT) and resectable disease isolated to a single site (eg, retroperitoneum) and regardless of the presence or absence of tumor marker elevation, we suggest surgical resection rather than systemic therapy.

For those with multifocal or unresectable late-relapsing NSGCT, we suggest standard-dose chemotherapy followed by surgical resection, if feasible, rather than chemotherapy alone. Options for standard-dose chemotherapy are discussed above. (See 'Standard-dose chemotherapy' above and "Approach to surgery following chemotherapy for advanced testicular germ cell tumors".)

Most patients with late relapses are typically treated with a combination of standard-dose chemotherapy regimens followed by surgery. Surgical resection is crucial to achieve long-term survival and some patients may achieve durable treatment responses. High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) is associated with poor outcomes in late-relapsed disease and should only be offered in the context of a clinical trial [68]. Multidisciplinary input from surgical oncology and medical oncology are necessary.

Data to support this approach are as follows:

●In one observational series of 122 patients with late relapses after initial therapy included 72 patients with NSGCTs and 50 patients with seminomas [69]. For those patients with NSGCTs, the highest cure rate (50 percent) was achieved among those who underwent surgery as a component of their treatment. For patients with seminomas, chemotherapy alone was effective in over one-half of cases. Similar results have been seen in other studies [19].

●In another observational series of 75 patients with late relapsed disease (70 of whom had NSGCTs), the five-year cancer-specific survival (CSS) was 60 percent [70]. Survival outcome was better in those who underwent complete surgical resection than those without complete resection at the time of late relapse (five-year CSS 79 versus 36 percent). Patients who had not been treated previously with chemotherapy also had better survival outcomes (five-year CSS 93 versus 49 percent). In a multivariable analysis, unifocal disease and the absence of symptoms were associated with longer CSS.

Lifetime follow-up is necessary for patients who achieve disease-free status after a late relapse because of the high frequency of subsequent relapses [27,71]. (See "Posttreatment follow-up for testicular germ cell tumors".)

Metastatic teratoma — For patients with a diagnosis of an NSGCT, the possibility of metastatic teratoma complicates management. Good clinical judgment and experience are essential to determine the appropriate treatment.

The possibility of a growing teratoma must be evaluated in patients with a history of NSGCT who have an enlarging mass and normal serum tumor markers [72]. Because there is no way to know what histopathological elements are present within a mass prior to resection, growing masses are typically treated with chemotherapy to eradicate non-teratoma components, with the exception of late relapses with a single and resectable site of disease, in which case we favor resection. When the initial treatment is chemotherapy, it should be followed by resection of any residual disease [72]. A growing teratoma should be suspected in late relapses and when a mass grows during chemotherapy, especially if serum tumor markers are declining [73]. (See 'Late relapse' above.)

Teratomas are usually managed with resection because they are relatively insensitive to chemotherapy. For patients with unresectable teratomas, response to systemic therapy is very low and we offer such patients clinical trials, when feasible. Responses to treatment with cyclin dependent kinase 4/6 inhibitors have been reported [74,75]. (See "Approach to surgery following chemotherapy for advanced testicular germ cell tumors", section on 'Rationale for resection of residual masses in patients with NSGCT'.)

In contrast, residual masses in patients with pure seminoma are usually observed and only treated if they enlarge. For residual masses 3 cm or larger in diameter, fluorodeoxyglucose (FDG) positron emission tomography CT (PET-CT) scans are sometimes performed. If there is FDG avidity in the residual masses, then open biopsy is typically performed. We recommend obtaining a biopsy to determine whether a residual viable malignancy is present when FDG-avid masses are present, due to the false-positive rate for PET scans in this setting, which has been reported to be as high as 73 percent [76]. If the biopsy is positive, then the patient is typically treated with additional chemotherapy. (See "Treatment of stage II seminoma", section on 'Posttherapy residual masses' and "Approach to surgery following chemotherapy for advanced testicular germ cell tumors", section on 'Seminoma'.)

For late retroperitoneal relapses that occur either after two years of observation or after primary chemotherapy for clinical stage I NSGCT, there is an increased possibility of teratoma. Retroperitoneal lymph node dissection (RPLND), which is both diagnostic and therapeutic, is a reasonable alternative to chemotherapy as the initial intervention. (See 'Late relapse' above and "Approach to surgery following chemotherapy for advanced testicular germ cell tumors".)

Brain metastases — Central nervous system (CNS), or brain, metastases can occur in up to 4 percent of patients with relapsed disease [77-80]. Brain metastases almost always occur in the setting of concurrent or prior disseminated disease and are associated with a poor prognosis [81]. Brain metastases are common with choriocarcinoma, and these metastases tend to bleed both spontaneously and during treatment with chemotherapy. (See "Epidemiology, clinical manifestations, and diagnosis of brain metastases".)

Classification — For prognostic purposes, patients with brain metastases can be divided into three groups [82,83]:

●Group 1 – Those who have brain metastases detected prior to first-line chemotherapy.

●Group 2 – Those who relapse only in the brain after achieving a complete response to chemotherapy and, if indicated, subsequent surgery.

●Group 3 – Those who develop brain metastases after failing to achieve a complete response to chemotherapy and surgery or who develop both brain and extracranial metastases during or after chemotherapy.

Various studies have evaluated clinical outcomes for patients with CNS metastases [81-88]. As an example, one retrospective study evaluated the clinical outcomes of 523 patients with brain metastases from a GCT [81]. Among the 228 patients who had brain metastases present at the time of their initial diagnosis, the three-year overall survival rate was 48 percent. Among the 295 patients who had brain metastases at the time of relapse, the three-year overall survival rate was only 27 percent. Adverse prognostic factors included the presence of liver or bone metastases, a serum beta-human chorionic gonadotropin (beta-hCG) ≥5000 international units/L, or an alpha fetoprotein (AFP) ≥100 ng/mL.

Treatment — Patients with CNS metastases from GCTs should be treated in a tertiary care center with access to neurosurgery, radiation oncology, and medical oncology expertise in treating this disease. The use of chemotherapy for initial management is associated with the risk of CNS hemorrhage due to the highly vascular nature of choriocarcinomas and the high sensitivity and rapid necrotic response of GCTs to chemotherapy.

The optimal treatment approach for patients with brain metastases is uncertain, and there are no prospective data that adequately address this issue. Treatment options include systemic chemotherapy, radiation therapy (RT), and/or surgical excision.

●Brain metastases prior to initial chemotherapy – It is uncommon for patients with early stage testicular GCTs who are naïve to systemic therapy to present with relapsed CNS metastases. For such rare patients who do relapse with CNS metastases, standard-dose systemic chemotherapy (bleomycin, etoposide, and cisplatin [BEP] (table 5), or etoposide, ifosfamide, and cisplatin [VIP] (table 3)) is used initially prior to resection or radiation therapy. We use these regimens to both control systemic disease, which is an important priority for most patients who have brain metastases, and because cisplatin and etoposide can penetrate the blood-brain barrier to treat CNS metastases.

If repeat contrast-enhanced imaging of the brain with MRI following chemotherapy documents a complete response, we generally prefer careful observation without further treatment. If there is a limited amount of residual tumor following chemotherapy, surgical excision (preferred) and/or RT with stereotactic radiosurgery (SRS) is used to eradicate the residual disease. Patients with numerous brain metastases whose metastases do not resolve with chemotherapy and whose tumors are not amenable to resection or stereotactic radiosurgery should be evaluated for whole-brain radiation therapy.

●Brain metastases at relapse after initial chemotherapy – For patients with brain metastases at time of relapse after first-line chemotherapy, the standard approach is either standard-dose chemotherapy or high-dose chemotherapy plus HCT followed by resection of residual masses. Patients with residual masses that cannot be resected should be evaluated for either SRS or whole-brain RT.

For patients with a resectable solitary brain metastasis as the only site of relapse, surgical resection followed by SRS and/or two cycles of adjuvant chemotherapy are reasonable options. Alternatively, solitary brain relapses can also be treated with standard-dose or high-dose chemotherapy followed by either surgical resection of any residual mass, or SRS if the residual mass is unresectable.

When possible, whole-brain RT is avoided because of concerns about the late complications of cranial irradiation. Whole-brain RT may be indicated for patients with more extensive residual disease or those with brain metastases that do not respond to systemic chemotherapy. Although whole-brain RT has been combined with concurrent chemotherapy [83,89], this approach may increase the risk of severe, symptomatic white matter changes [84]. (See "Delayed complications of cranial irradiation", section on 'Neurocognitive effects'.)

Disease with high tumor mutational burden — Some relapsed and refractory GCTs harbor a high tumor mutational burden of high levels of microsatellite instability (MSI-H), which may predict benefit from immune checkpoint inhibitor immunotherapy [90]. Several immune checkpoint inhibitors are approved for the treatment of a variety of advanced solid tumors, regardless of tumor type, that are MSI-H or have deficient mismatch repair (dMMR), that progressed following prior treatment, and for which there are no satisfactory alternative treatment options. Treatment options for these tumors are discussed separately. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)

The presence of a MSI-H or dMMR tumor may indicate a diagnosis of Lynch syndrome, an inherited condition that predisposes to several cancers, particularly colorectal cancer. Given that Lynch syndrome is more prevalent than previously thought, all patients with an MSI-H/dMMR solid tumor should be referred for germline genetic assessment for Lynch syndrome, regardless of family history [91]. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Microsatellite instability testing'.)

INVESTIGATIONAL APPROACHES

TI-CE regimen — Various chemotherapy regimens are being investigated for relapsed and refractory GCTs. For example, one randomized phase III trial (TIGER) is comparing four cycles of paclitaxel, ifosfamide, and cisplatin (TIP) with two cycles of paclitaxel plus ifosfamide followed by three cycles of high-dose carboplatin and etoposide (TI-CE) [92].

Other agents

●Immune checkpoint inhibitors that have been investigated in relapsed and refractory GCTs include nivolumab [93] and pembrolizumab [93-95].

●Testicular cancers that are resistant to or relapse after standard chemotherapy may harbor genomic alterations that are potentially targetable, particularly in the clinical trial setting. Genomic profiling can guide clinical research and disclose therapeutic opportunities for these patients. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

PROGNOSIS — The prognosis of patients with relapsed disease is influenced by various clinical factors. These include response to initial chemotherapy, the site of the primary germ cell tumor, and histology, among others. The heterogeneity of patients within clinical studies based upon these and other factors makes it difficult to compare the relative efficacy of treatment for relapsed disease.

Response to initial therapy — Risk classification of the primary tumor, response to initial therapy (complete versus partial versus no response) and the duration of remission (primary refractory versus recurrence after a complete response) are important prognostic indicators.

●Treatment response – A majority of patients with a complete response to their initial treatment are usually cured and are less likely to be diagnosed with relapsed disease, compared with those who have a partial or no response to initial treatment [96].

●Cisplatin-refractory disease – Patients with cisplatin-refractory disease (progression of disease either during or within four weeks after completion of cisplatin-based chemotherapy) generally have a poor prognosis [46,50,97-99]. (See 'Platinum-refractory disease' above.)

●Late relapses – Patients with nonseminomatous GCTs (NSGCTs) who relapse more than two years after their initial chemotherapy were previously considered to have a poor prognosis, but cure rates of up to approximately 70 percent have been reported in contemporary series [18,69,70]. These patients are typically treated with surgical resection either as the primary treatment or following chemotherapy. (See 'Late relapse' above and "Approach to surgery following chemotherapy for advanced testicular germ cell tumors".)

In contrast, the prognosis of late-relapsing seminomas has not been shown to differ from early-relapsing seminomas [19,20,69].

Primary tumor site — Primary tumor sites include testicular versus extragonadal (retroperitoneal or mediastinal). Patients with a relapse of a testicular NSGCT generally have a better prognosis than those with a relapse of an extragonadal NSGCT, although this can be influenced by the type of treatment used for relapsed disease.

Patients with relapsed testicular NSGCTs have long-term disease-free survival of approximately 35 percent after subsequent treatment with standard-dose chemotherapy [9]. In contrast, among patients with relapsed primary mediastinal or retroperitoneal NSGCT who are treated with standard-dose chemotherapy, durable remission rates are approximately 10 and 30 percent, respectively [100-102].

Slightly better results have been reported with high-dose chemotherapy with HCT. Data suggest that approximately 40 percent of patients with retroperitoneal primary tumors achieve long-term disease free-survival, compared with 14 to 25 percent of patients with mediastinal NSGCT [14,55,103]. (See "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum".)

Histology — Patients with relapsed seminoma have better outcomes than those with NSGCTs [46,104]. Standard-dose regimens used for relapsed or refractory disease can result in long-term disease-free survival in approximately one-half of seminoma patients [13,14] compared with approximately 35 percent for NSGCTs [9,45]. This is also true for seminomas that relapse beyond two years. (See 'Late relapse' above.)

Among patients treated with high-dose chemotherapy and hematopoietic cell transplantation (HCT) for recurrent disease, one study conducted at Indiana University reported a two-year progression-free survival rate of 90 percent for seminoma and 52 percent for NSGCTs [55]. In another observational study at Memorial Sloan Kettering Cancer Center, 15 of 27 patients (56 percent) with relapsed seminomas achieved durable remissions with either standard-dose chemotherapy or high-dose chemotherapy with HCT [14].

Treatment-related toxicity — Patients who have relapsed after their initial therapy can often be salvaged and remain disease-free with second or subsequent lines of therapy. However, these long-term survivors are at risk for long-term treatment-related morbidity and mortality.

In patients with testicular cancer, both cisplatin-based chemotherapy and radiation therapy (RT) are associated with an increased risk of death from secondary malignancies and non-cancer-related causes [105,106]. In a retrospective study from the Danish Testicular Cancer database of 268 patients who relapsed after initial RT and/or chemotherapy, approximately one-half (132 patients) were salvaged with one or more chemotherapy regimens [105]. For these patients, the risks of death from a secondary malignancy or other causes (gastric ulcer, renal failure, and neurologic disease) were significantly increased compared with patients who were disease-free after initial treatment with one cycle of bleomycin, etoposide, and cisplatin (BEP (table 5)) therapy. Similar findings have been seen in other observational studies of patients with relapsed disease treated with chemotherapy, RT, or both modalities [106].

Patients who received a total of three or more cycles of chemotherapy are also at increased risk for non-testis-cancer related mortality. As an example, in a Norwegian study of over 5700 survivors of testicular GCT, non-testis cancer mortality increased by about 43 percent with three or four cycles of cisplatin-based chemotherapy and was doubled in patients who received more than four cycles [106].

Further details on long-term toxicities in survivors of testicular cancer are discussed separately. (See "Treatment-related toxicity in testicular germ cell tumors" and "Approach to the care of long-term testicular cancer survivors".)

Other factors — Other factors also have a significant impact on prognosis following treatment for relapsed disease. As an example, data from one study of 1594 patients were used to develop the International Prognostic Factors Study Group (IPFSG) prognostic model for patients who progressed following treatment with first-line platinum-based therapy [107]. This model took into account seven factors:

●Response to initial therapy – Complete response (CR), partial response (PR) with negative markers (PR-neg), PR with positive markers (PR-pos), stable disease (SD), or progressive disease (PD)

●Alpha fetoprotein (AFP) level – Normal, ≤1000 ng/mL, or >1000 ng/mL

●Beta-human chorionic gonadotropin (beta-hCG) level – ≤1000 mUI/mL or >1000 mUI/mL

●Presence of bone, liver, or brain metastases

●Duration of initial remission – ≤3 or >3 months

●Site of primary tumor – Gonadal, retroperitoneal, or mediastinal

●Histology – Pure seminoma versus NSGCT or mixed tumor

Using all of these factors, three-year overall survival ranged from 65 to 89 percent for the lowest-risk group as compared with 4 to 27 percent for the highest-risk group.

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Testicular cancer (The Basics)")

●Beyond the Basics topic (see "Patient education: Testicular cancer (Beyond the Basics)")

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

●Diagnosis – The diagnosis of relapsed or refractory germ cell tumors (GCTs) is typically made based on an increase in serum tumor markers and/or evidence of progressive disease on imaging studies. Biopsy confirmation of relapsed disease is not usually necessary. (See 'Diagnosis' above.)

●Cisplatin-naïve disease – For most patients with cisplatin-naïve relapsed disease who have a seminoma; elevated serum tumor markers (alpha fetoprotein [AFP] or beta-human chorionic gonadotropin [beta-hCG]); involved retroperitoneal lymph nodes >2 cm in greatest dimension; or disease outside the retroperitoneum, we suggest cisplatin-based chemotherapy (Grade 2B), as for newly diagnosed disease. (See 'Cisplatin-naïve disease' above and "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

However, for patients with cisplatin-naïve nonseminomatous GCT (NSGCT), normal serum AFP and beta-hCG, and disease limited to retroperitoneal lymph nodes that are ≤2 cm in greatest dimension, we suggest retroperitoneal lymph node dissection (RPLND) rather than chemotherapy (Grade 2C), provided that appropriate surgical expertise is available. Select cases with lymph nodes between 2 and 3 cm in greatest dimension may also be evaluated for RPLND. If appropriate surgical expertise is not available, cisplatin-based chemotherapy is an appropriate alternative. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

●Clinical stage I NSGCT treated with BEP – For those with stage I NSGCT, and:

•One prior cycle of BEP with good-risk (table 1) disease at relapse – We suggest either three cycles of bleomycin, etoposide, and cisplatin (BEP) or four cycles of cisplatin and etoposide (EP) chemotherapy (table 2) (Grade 2C).

•Two prior cycles of BEP with good-risk disease at relapse – We suggest four cycles of EP rather than additional cycles of BEP (Grade 2C), to limit the cumulative dose of bleomycin.

•One or two prior cycles of BEP with intermediate/poor-risk (table 1) disease at relapse – We suggest ifosfamide-based chemotherapy rather than EP or additional cycles of BEP. Options include four cycles of either etoposide, ifosfamide, and cisplatin (VIP) (table 3) or paclitaxel, ifosfamide, and cisplatin (TIP) (table 4).

•Indications for RPLND – RPLND is a reasonable alternative to chemotherapy in patients with NSGCT whose relapsed disease is limited to the retroperitoneum and who have normal serum tumor markers. (See "Approach to surgery following chemotherapy for advanced testicular germ cell tumors", section on 'Normalized tumor markers with abnormal imaging findings'.)

●Treatment after three or four cycles of initial cisplatin-based chemotherapy – For patients who relapse after three or four cycles of initial cisplatin-based chemotherapy, we suggest either standard-dose ifosfamide and cisplatin-based chemotherapy or high-dose chemotherapy with autologous hematopoietic cell transplantation (HCT) rather than surgery, radiation, or other systemic therapies (Grade 2C).

•Standard-dose chemotherapy – For patients who select standard dose chemotherapy, options include either TIP (table 4) or vinblastine, ifosfamide, plus cisplatin (VeIP). For patients who have not previously received etoposide, we offer VIP (table 3).

•High-dose chemotherapy with HCT – For patients who select high-dose chemotherapy with autologous HCT, we suggest initial high-dose chemotherapy with two cycles of high-dose carboplatin and etoposide (EC) rather than other high-dose chemotherapy regimens (Grade 2C). (See 'Treatment after three or four cycles of cisplatin-based chemotherapy' above.)

•Indications for RPLND – In patients with NSGCTs, residual masses should be resected following either standard-dose chemotherapy or high-dose chemotherapy with HCT. (See "Approach to surgery following chemotherapy for advanced testicular germ cell tumors", section on 'Normalized tumor markers with abnormal imaging findings'.)

●Platinum-refractory disease – Platinum-refractory disease is defined as GCTs that relapse after second-line therapy; or progress during or within a month of initial cisplatin-based chemotherapy (See 'Investigational approaches' above.)

For such patients, we encourage participation in a clinical trial. If not feasible, options include high-dose chemotherapy with autologous HCT or standard-dose chemotherapy with TIP (table 4). (See 'Platinum-refractory disease' above.)

●Late-relapsed disease – This is defined as relapse that occurs more than two years after completion of initial therapy. (See 'Late relapse' above.)

•Late-relapsing seminomas – Patients with late-relapsing seminomas should be treated in the same manner as those with early-relapsing seminomas.

•Late-relapsing NGCTs – For patients with a late-relapsing NSGCT and resectable disease isolated to a single site, we suggest surgical resection rather than systemic chemotherapy (Grade 2C).

For those with multifocal or unresectable late-relapsing NSGCT, we suggest standard-dose chemotherapy followed by surgical resection, if feasible, rather than chemotherapy alone (Grade 2C).

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Philip W Kantoff, MD, who contributed to earlier versions of this topic review.