Management of stage I nonseminomatous germ cell tumors

INTRODUCTION — Testicular cancers, the majority of which are germ cell tumors (GCTs), are one of the most curable solid neoplasms, with a five-year survival rate of over 95 percent. Testicular GCTs are more sensitive to systemic chemotherapy than most adult solid tumors. As a result, chemotherapy is the standard treatment for men with advanced seminoma or nonseminomatous germ cell tumors (NSGCTs) and for those with persistently elevated serum tumor markers following orchiectomy. The success of chemotherapy in advanced disease has led to its use in selected men with stage I and II disease.

The management of men with stage I NSGCT following orchiectomy, including the choice between adjuvant chemotherapy, retroperitoneal lymph node dissection (RPLND), and active surveillance, will be reviewed here. The management of men with stage II NSGCT is presented separately. (See "Management of stage II nonseminomatous germ cell tumors".)

GENERAL PRINCIPLES — With only rare exceptions (eg, men who present with widely disseminated disease requiring emergent treatment), men with testicular cancer undergo a radical inguinal orchiectomy for diagnosis and initial treatment. If radiographic imaging studies show no evidence of regional or distant metastases and serum tumor markers are normal after orchiectomy, patients are defined as having clinical stage I nonseminomatous germ cell tumor (NSGCT) (table 1 and table 2). (See "Radical inguinal orchiectomy for testicular germ cell tumors", section on 'Surgical treatment of the testis' and "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors", section on 'CT scan'.)

The majority (75 percent) of clinical stage I NSGCTs are cured with orchiectomy alone and do not require further treatment. However, it is difficult to identify which patients with stage I NSGCT are at highest risk for recurrence and thus have the most to gain from adjuvant treatment. While treatment immediately following orchiectomy can reduce the risk of relapse, it represents overtreatment for most patients and can result in both short- and long-term complications. In addition, although the risk of recurrence is approximately 25 percent for men undergoing surveillance, treatment at the time of recurrence is almost always curative [1-3]. Long-term disease-specific survival exceeds 99 percent regardless of whether patients undergo surveillance, chemotherapy, or retroperitoneal lymph node dissection. (See "Approach to the care of long-term testicular cancer survivors".)

Men with persistently elevated postorchiectomy serum tumor markers and normal imaging studies are defined as having clinical stage IS disease. Persistently elevated markers generally indicate the presence of metastatic disease [4]. Therefore, these patients should be treated with chemotherapy similarly to men with stage III disease. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

RISK STRATIFICATION — Numerous attempts have been made to identify men with clinical stage I nonseminomatous germ cell tumors (NSGCTs) at high risk for relapse and thus most likely to benefit from adjuvant treatment following orchiectomy. The most widely used risk factors for recurrence in men undergoing surveillance following orchiectomy for clinical stage I disease include the following [5-10]:

●Lymphovascular invasion (LVI).

●Predominance of an embryonal carcinoma (EC) component in the primary tumor – Predominance is histologically defined when EC comprises a greater proportion of the tumor than any other individual germ cell tumor component.

●Pathologic tumor stage T3 or T4 (table 1).

These risk factors can stratify men with testicular NSGCT by risk of relapse:

●Low risk – Tumors with none of these risk factors are associated with relapse rates ranging from 10 to 14 percent [1,2,11].

●High risk – Tumors with one or more of these risk factors have a higher risk of relapse.

•Tumors with a predominance of EC alone (no LVI) are associated with relapse rates between 20 and 40 percent, although the data on this are mixed [1,2,12,13]. For tumors demonstrating LVI alone (no EC), relapse rates range between 40 and 55 percent [1,2,11]. Tumors with both a predominance of EC and LVI are associated with relapse rates of over 50 percent [1,14-16].

•There are limited data for relapse rates in patients with T3 or T4 disease due to the rarity of these tumors and their exclusion from most surveillance series [17,18].

Studies that have evaluated the risk for relapse associated with EC and/or LVI include the following:

●In one observational series of 223 men, the relapse rate was about 20 percent in those whose tumor had a predominance of EC without LVI, 40 percent in those with LVI but no EC predominance, and 55 percent in those with both risk factors compared with 10 percent in those with neither risk factor [1].

●By contrast, another series reported that men with pure EC (ie, tumor that is comprised entirely of EC) with or without LVI had a relapse rate of 45 percent [2].

●Several studies reported that men with LVI and no EC at all had relapse rates of 20 percent or less [14,19,20].

●Other research indicates that the risk of micrometastatic disease increases as the proportion of EC increases [15,16].

Interpreting studies of the prognostic significance of EC is complicated by the fact that different studies have used different measures to pathologically characterize EC, including whether EC is present or absent, whether it is predominant (variously defined as more than 40 percent, more than 50 percent, or representing a greater proportion of the tumor than any other individual germ cell tumor type), or whether it is pure [13]. These issues have made it more challenging to clarify its significance as an independent prognostic risk factor. At least three studies suggest that the mere presence of EC is a significant risk factor for relapse, and a meta-analysis suggests that both the presence and predominance of EC are significant prognostic risk factors [13,14,19-21]. Regardless, EC is a weaker predictor of relapse than LVI [13].

As an example, one systematic review and meta-analysis of 24 studies evaluating LVI and EC as risk factors for relapse in men with clinical stage I NSGCT demonstrated that LVI was a strong risk factor and that both the presence and predominance of EC had prognostic value for occult metastatic disease [13]. This study defined occult metastatic disease as either lymph node metastases discovered during primary retroperitoneal lymph node dissection or relapse during surveillance. In the pooled analysis, the presence of LVI was associated with a higher rate of occult metastases versus the absence of LVI (48 versus 17 percent, odds ratio [OR] 4.33, 95% CI 3.55-5.3). Both presence and predominance of EC were also associated with higher rates of occult metastases (33 versus 16 percent, OR 2.49, 95% CI 1.64-3.77 for presence versus absence of EC; 40 versus 20 percent, OR 2.62, 95% CI 1.93-3.56 for tumors with EC involvement greater than 50 percent versus less than 50 percent).

TREATMENT APPROACH — Surveillance, adjuvant chemotherapy, and retroperitoneal lymph node dissection (RPLND) are therapeutic options for men with clinical stage I nonseminomatous germ cell tumors (NSGCTs) (algorithm 1). Each approach is associated with a 99 percent rate of long-term disease-specific survival. Importantly, for men who are interested in fertility preservation, sperm banking should be performed prior to treatment with RPLND or chemotherapy.

The approach to management depends upon various factors, including:

●The likelihood of relapse (based on the presence of low- versus high-risk disease characteristics)

●The relative importance of the risk of relapse and of the different toxicities for an individual patient

●The ability of a patient to adhere to posttreatment surveillance

The importance of a multidisciplinary approach was illustrated in a Dutch study that included almost 1300 men with clinical stage I NSGCT [14]:

●The relapse rate for the entire cohort at five years was 30.6 percent; the median time to relapse was five months. Despite this, the mortality rate was <0.5 percent; only six men died of testicular cancer.

●Of 356 patients treated with chemotherapy at the time of relapse, 98 underwent postchemotherapy resection of residual masses, indicating that 8 percent of the nearly 1300 men undergoing surveillance ended up receiving multimodality treatment (ie, chemotherapy followed by surgery).

Low-risk disease — For men with low-risk disease, reasonable options include surveillance or adjuvant chemotherapy. These men have an excellent prognosis, and surveillance avoids the complications and toxicity of chemotherapy [1,2,9]. Although surveillance is appropriate for most patients with low-risk disease, not all men will be comfortable with surveillance, even if their risk of relapse is "only" approximately 10 to 15 percent. For men who express a preference for treatment at the time of initial diagnosis, adjuvant chemotherapy is also reasonable [22]. For men who have access to a urological surgeon with extensive experience performing RPLNDs, surgery is also a reasonable option and reduces the need for surveillance computed tomography (CT) scans; however, most urologists do not have such experience. In our view, men whose disease is comprised predominantly of teratoma are ideal candidates for RPLND. For men with teratoma with somatic malignant transformation, RPLND is the preferred treatment option, and we do not offer surveillance or primary chemotherapy for such patients. (See 'Risk stratification' above and "Surveillance for stage I testicular germ cell tumors following orchiectomy".)

SWENOTECA — Evidence supporting the role of active surveillance comes from the Swedish and Norwegian Testicular Cancer Project (SWENOTECA) Management Program [9]. Between 1998 and 2005, 745 men in Sweden and Norway were treated prospectively for clinical stage I NSGCTs. Active surveillance was recommended for men without lymphovascular invasion (LVI; n = 491), although they were allowed to choose adjuvant chemotherapy. At a median follow-up of 4.7 years:

●The relapse rate was higher among men who underwent surveillance rather than BEP (bleomycin, etoposide, and cisplatin (table 3)) chemotherapy (12 versus 1.3 percent with one cycle of BEP or 0 percent with two cycles of BEP).

●The overall mortality rate was only 1 percent, and none of these deaths was due to progressive testicular cancer.

The SWENOTECA results for men with high-risk disease are discussed below. (See 'Active surveillance' below.)

British Columbia Cancer Agency and the Oregon Testis Cancer Program — Similar results were reported from the British Columbia Cancer Agency and the Oregon Testis Cancer Program [1]. Among those with low-risk disease (n = 77), the relapse rate during surveillance was 10 percent. No deaths from testicular cancer were reported.

Other data — An international pooled analysis of 1139 men with clinical stage I testicular NSGCTs reported that among the 935 with low-risk disease, 132 (14 percent) relapsed [11]:

●Among the men who relapsed, 88, 10, and 2 percent were classified as having good-risk disease, intermediate-risk disease, and poor-risk disease, respectively. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors", section on 'Management'.)

●Among low-risk patients (ie, no evidence of LVI), the median time to relapse was eight months. Most relapses (89 percent) occurred within two years.

●Of the 812 men who were disease-free at three years, only eight (1 percent) subsequently relapsed. Late relapse was not associated with adverse outcome.

●Five men in the entire cohort (0.5 percent) died of their cancer or from treatment, and one was alive with disease at the time of the report. The disease-specific survival exceeded 99 percent.

High-risk disease — For men with high-risk disease, adjuvant chemotherapy, active surveillance, and RPLND, if an appropriately experienced urological surgeon is available, are reasonable options. Because all three options are associated with a greater than 99 percent disease-specific survival, there is no single best option for all patients [23]. For those rare men with teratoma with somatic malignant transformation, RPLND is the preferred treatment option and we do not recommend either surveillance or primary chemotherapy for such patients.

One factor that must be taken into account if placing high-risk patients on surveillance is the psychological stress of worrying about relapse and the potential psychological trauma to the patient if relapse occurs and his life must be put on hold on short notice and at an unpredictable time. One appeal of adjuvant chemotherapy after orchiectomy is the near certainty it provides that the disease has been cured, particularly in this high-risk group.

Therefore, the decision of which modality to use should be based on patient preference:

●For men with high-risk NSGCTs, active surveillance is a highly effective strategy with regard to long-term survival, although it leaves the patient with a substantial risk of recurrence (which would require treatment) at some point in the subsequent two to three years. (See "Surveillance for stage I testicular germ cell tumors following orchiectomy", section on 'Surveillance protocols'.)

Roughly half of men with high-risk disease will relapse, and approximately one-fourth of those (ie, one-eighth of high-risk men undergoing surveillance) will require additional treatment (eg, RPLND in addition to three or four cycles of chemotherapy). In light of these statistics, some men may reasonably choose to proceed with chemotherapy after orchiectomy in order to nearly eliminate the risk of needing such aggressive treatment in the future. (See 'Adjuvant chemotherapy' below.)

●For some men, the potential life disruption associated with recurrent disease and the psychological trauma of relapse (with the subsequent need to undergo 9 to 12 weeks of chemotherapy) are unacceptable. In such cases, chemotherapy at the time of initial presentation is a reasonable option.

●For other men who wish to lower their risk of relapse and who decline chemotherapy, we proceed with RPLND, provided the technical expertise is available. In our view, men whose disease is predominantly comprised of teratoma are ideal candidates for this approach. (See "Retroperitoneal lymph node dissection for early-stage testicular germ cell tumors".)

Active surveillance — For men with high-risk disease, several studies have shown that although active surveillance is associated with a higher rate of relapse, overall survival is excellent [1,2,11,24].

British Columbia Cancer Agency and the Oregon Testis Cancer Program — The safety of surveillance was reported from the British Columbia Cancer Agency and the Oregon Testis Cancer Program, which included 209 men with high-risk clinical stage I NSGCT (60 with LVI, 109 with embryonal carcinoma [EC]-predominant tumors, and 40 with both) [1]. After a median follow-up of over four years:

●Disease-specific survival was 100 percent, and only one patient had evidence of cancer at the time of the report.

●The relapse rate was 50 percent among men with LVI (30 of 60 relapsed) and 55 percent for men with LVI and EC-predominant tumors. In contrast, it was <20 percent for men with EC-predominant tumors but no evidence of LVI.

Despite the high rate of relapse, all but one patient had good-risk disease at relapse, and only 17 (8 percent) required postchemotherapy resection of residual masses. No patients required second-line chemotherapy.

Princess Margaret Hospital — A separate study from Princess Margaret Hospital in Toronto reported similar outcomes among 125 men with high-risk clinical stage I NSGCT [2].

●Among men with clinical stage I NSGCT with LVI (n = 92), the relapse rate was 54 percent.

●Among men with tumors that were pure EC without LVI (n = 33), the relapse rate was 45 percent.

Survival data were not reported separately for high-risk and low-risk patients. In the total study of 371 men, 104 men relapsed, three of whom died and two of whom were alive with evidence of disease, including one who refused treatment for relapse. While the five-year disease-specific survival was 99 percent for the entire cohort, the mortality rate was 3 percent following relapse, and 2 percent were alive with disease.

Other data — An international pooled analysis of 183 men with high-risk stage I NSGCT due to LVI reported a relapse rate of 44 percent [11]. At the time of the report, none had died from his cancer. One patient died of other causes, and one was alive with disease.

Adjuvant chemotherapy — For men with high-risk stage I NSGCT who select adjuvant chemotherapy, we administer BEP for one cycle (table 3). Special circumstances for which two cycles of BEP may be offered are discussed below. (See 'One versus two cycles of BEP' below.)

The data to support the use of BEP are discussed below.

German Testicular Cancer Study Group — The use of adjuvant chemotherapy was evaluated by the German Testicular Cancer Study Group (GTCSG), which randomly assigned 382 men with clinical stage I NSGCT to treatment with either one cycle of BEP or RPLND [25]. With a median follow-up of 4.7 years, there were two relapses and no cancer-related deaths among the 191 men treated with BEP. Four developed febrile neutropenia. The study reported:

●A significantly lower rate of recurrence with BEP compared with RPLND (2 versus 15 events)

●An improvement in the two-year recurrence-free survival rate with BEP (99 versus 92 percent, hazard ratio [HR] 7.9, 95% CI 1.8-34.5)

●Cancer-specific survival was 100 percent in both arms

SWENOTECA — The data that adjuvant chemotherapy may be preferable to active surveillance come from the SWENOTECA Management Program. Men with LVI present (n = 227) were recommended to proceed with one cycle of BEP (although they could choose active surveillance or two cycles of BEP) (table 3) [9].

The relapse rate was higher among men managed with surveillance compared with one or two cycles of BEP adjuvant chemotherapy (42 versus 3 and 0 percent, respectively). There were no relapses among the 70 patients who chose to receive two cycles of BEP [9]. Still, the mortality rate in the entire cohort was 1 percent (n = 8 deaths), none of which was from progressive disease. A follow-up publication on this study when it had accrued more patients reported that among 258 men with LVI who received a single cycle of BEP, the relapse rate remained 3.2 percent and five-year disease-specific survival was 100 percent [26].

United Kingdom 111 trial — In a multi-center single-arm trial, 236 men with clinical stage I NSGCT received a single cycle of BEP and were followed for a median of 49 months [18]. With a median follow-up of 49 months, four patients had a malignant recurrence (1.3 percent), and three had a benign recurrence (1.2 percent), for a combined malignant plus benign recurrence rate of approximately 3 percent. Following salvage treatment with a combination of chemotherapy and surgery, three of the four patients with malignant recurrence were alive and had no evidence of disease, while the fourth died of refractory cancer. The three patients with benign relapse (teratoma) were all rendered disease free with retroperitoneal lymph node dissection. Two-year relapse-free and overall survival rates were 97 and 99 percent, respectively.

Other data — The benefit of chemotherapy is also supported by a review of the data from available published nonrandomized studies performed by the authors of this topic [10,27-35]. Among 655 men who received adjuvant chemotherapy for clinical stage I disease, there were only 16 relapses (2.4 percent), which occurred at a median follow-up ranging from 31 to 113 months. In addition, there were only seven cancer-related deaths identified (1 percent).

One versus two cycles of BEP — All men who opt to proceed with chemotherapy should receive either one or two cycles of BEP (bleomycin, etoposide, and cisplatin) (table 3). We prefer a single cycle rather than two because disease-specific survival is over 99 percent with either approach, and BEP chemotherapy is associated with dose-dependent long-term toxicity. However, given that studies of two cycles report a slightly lower relapse rate than studies of one cycle, proceeding with two cycles of therapy in patients with stage IB disease is a reasonable alternative. For patients with T3 or T4 tumors, we prefer two cycles of BEP due to the limited data on outcomes for these rare cases.

Limiting treatment to up to two courses of platinum-based chemotherapy has reduced concerns of acute and delayed side effects of treatment (including a lowered risk of bleomycin-induced pulmonary toxicity), which are generally seen when four or more cycles are administered. There is also evidence that limiting the exposure to chemotherapy reduces the risk that men will become infertile [27,28,36]. (See "Treatment-related toxicity in testicular germ cell tumors" and "Approach to the care of long-term testicular cancer survivors" and 'Risk stratification' above.)

There are no data from randomized controlled trials to determine whether one or two cycles should be administered. Data suggest a lower rate of relapse with two cycles of BEP (up to 2.9 percent) versus those treated with a single cycle of BEP (up to 6.5 percent). However, this difference may have been due to chance. Moreover, it is not clear that the small absolute benefit, if real, justifies the potential late toxicities of an additional cycle of chemotherapy. Long-term overall survival in this population is excellent regardless of the number of cycles given. (See "Approach to the care of long-term testicular cancer survivors", section on 'Side effects of treatment'.)

The following studies illustrate the relapse rates seen with one and two cycles of BEP:

●The United Kingdom 111 study of over 230 patients with clinical stage IB disease treated with one cycle of BEP reported that two-year disease-free and overall survival rates were 97 and 99 percent, respectively.

●Similarly, the German Testicular Cancer Study Group trial reported a two-year disease-free survival rate of 99.5 percent with one cycle of BEP.

●Another study of primary chemotherapy for men with stage I NSGCT (considered to have an estimated relapse risk of at least 30 percent) reported a 6.5 percent relapse rate (3 of 46 patients) with a single cycle of BEP versus a rate of 2.9 percent (3 of 102 patients) with two cycles [30].

●The SWENOTECA group reported that among men with LVI, a single cycle of BEP was associated with a relapse rate of 3.2 percent (8 of 258 men) compared with a rate of 0 percent among 70 men treated with two cycles [9,26].

●Among eight studies that included a total of 622 men with high-risk disease, the relapse rate following two cycles of BEP was 1.6 percent (n = 10) [9,17,28,30,32,37-39].

Retroperitoneal lymph node dissection — RPLND remains a reasonable alternative to chemotherapy, particularly for men with a teratoma-predominant tumor and for those patients who are not comfortable with active surveillance and decline chemotherapy for whatever reason. However, RPLND should only be performed if the technical expertise is available (ie, surgeons who perform at least 24 procedures annually, in our opinion) [5]. When performed by experienced surgeons, RPLND is safe, with essentially no mortality and an extremely low rate of ejaculatory dysfunction or other long-term morbidity. In addition, the use of RPLND substantially reduces the number of men who ultimately receive chemotherapy. (See "Retroperitoneal lymph node dissection for early-stage testicular germ cell tumors".)

Unfortunately, very few centers have specialized surgeons sufficiently trained and experienced to perform a high-quality RPLND, and the effectiveness and safety of RPLND in less experienced hands may be compromised [1]. In addition, men should be aware that chemotherapy may still be required after RPLND. Among patients managed with RPLND, 20 percent are likely to be upstaged at final pathology and will undergo adjuvant chemotherapy with two cycles of either BEP (table 3) or EP (etoposide and cisplatin). (See "Management of stage II nonseminomatous germ cell tumors", section on 'Pathologic stage II NSGCT'.)

In the German testicular cancer study discussed above, 7 of the 15 patients (47 percent) who underwent RPLND had recurrent retroperitoneal disease, which may reflect a lack of experience in performing an RPLND [25]. This high rate of relapse underscores the importance of the experience, knowledge, and skill of the surgeon. Referral to a center of excellence should be strongly considered for patients undergoing RPLND. (See "Retroperitoneal lymph node dissection for early-stage 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

●General principles – The effectiveness of systemic chemotherapy for advanced or metastatic testicular germ cell tumors (GCTs) has led to its integration into the management of patients with early stage disease. The goal of therapy is to reduce the likelihood of relapse and minimize overtreatment and treatment-related toxicity. (See 'General principles' above.)

●Risk stratification – The most widely evaluated histologic risk factors for recurrence in men undergoing surveillance following orchiectomy for clinical stage I disease include the presence of lymphovascular invasion (LVI), the predominance of embryonal carcinoma (EC), and tumor stage above T2. (See 'Risk stratification' above.)

•Men are at low risk if they have none of these risk factors.

•Men are at high risk if they have any of the following: LVI, a predominance of EC, or a T3 or T4 primary tumor. Men with both LVI and a predominance of EC are at highest risk of relapse.

●Low-risk disease – For men with low-risk disease, we recommend surveillance rather than adjuvant therapy (algorithm 1) (Grade 1B). However, not all men will be comfortable with active surveillance, despite their excellent prognosis. For men who express a preference for treatment at the time of initial diagnosis, we suggest adjuvant BEP (bleomycin, etoposide, and cisplatin (table 3)) for one cycle (Grade 2C). For men who have access to a urologist with extensive experience performing retroperitoneal lymph node dissections (RPLNDs), RPLND is also a good option, especially if the tumor is predominantly teratoma. (See 'Low-risk disease' above.)

●High-risk disease – For men with high-risk disease, options include adjuvant chemotherapy with BEP chemotherapy (table 3), active surveillance, or RPLND (algorithm 1). The specific choice should be based upon patient preference and should take into account the available expertise. (See 'High-risk disease' above.)

•In most patients, we prefer one cycle of BEP rather than two cycles, as disease-specific survival is high with either approach and BEP chemotherapy is associated with long-term toxicity. However, some experts may alternatively offer two cycles of BEP in patients with stage IB disease, given a slightly lower relapse rates with this approach. (See 'One versus two cycles of BEP' above.)

•For patients with T3 or T4 tumors, we prefer two cycles of BEP due to the limited data on outcomes for these rare cases.

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