INTRODUCTION — Testicular cancer is the most common solid malignancy affecting males aged 15 to 35 years. Germ cell tumors (GCTs), which account for 95 percent of testicular cancers, are one of the most curable solid neoplasms due to treatment advances that began in the late 1970s.
GCTs can consist of one histologic pattern or a mix of multiple histologic types. Testicular GCTs are divided into two groups:
●Pure seminoma (ie, no nonseminomatous elements), which constitutes approximately 60 percent of GCTs [1,2].
●Nonseminomatous germ cell tumors (NSGCTs), which may include elements of seminoma along with one or more other histologic types.
Clinical stage II seminoma is defined by the presence of pure seminoma in the orchiectomy specimen and imaging studies of the abdomen and pelvis that show positive regional lymph nodes (table 1A-B). Positive nodes are those that measure at least 10 mm on the short axis of cross-sectional imaging. Other potential sites of metastasis, such as the chest, are free of disease. Approximately 15 percent of patients with seminoma have stage II disease at presentation [3].
Approximately 85 percent of men with stage I seminoma (ie, no lymph node involvement) who are managed with orchiectomy followed by active surveillance will remain disease-free. Most of those who relapse during surveillance have disease limited to the retroperitoneum, and these men are treated like those who initially present with stage II disease. (See "Treatment of stage I seminoma".)
The management of patients who present with stage II seminoma and of those with stage I disease who relapse in regional lymph nodes will be reviewed here. An overview of the approach to testicular GCTs is presented separately. (See "Overview of the treatment of testicular germ cell tumors" and "Treatment protocols for germ cell tumors".)
OVERVIEW OF TREATMENT — Seminomas are highly sensitive to both radiation therapy (RT) and chemotherapy. Successful control of seminoma can be achieved in almost all patients using contemporary treatment techniques. Thus, the focus has shifted to minimize treatment-related morbidity.
The optimal treatment for men with stage II seminoma depends upon the extent of nodal involvement (algorithm 1). Patients with stage II seminoma are managed according to the maximum diameter of involved lymph nodes (table 1A-B):
●Stage IIA: ≤2 cm – Treatment following staging in these patients generally consists of RT.
●Stage IIB: >2 and ≤5 cm – Treatment following staging in these patients generally consists of chemotherapy, although RT is occasionally used in nonbulky stage IIB cases (nodes <3 cm).
●Stage IIC: >5 cm – Treatment following staging in these patients always consists of chemotherapy.
These approaches are consistent with consensus guidelines from the National Comprehensive Cancer Network (NCCN), the European Society for Medical Oncology (ESMO), and the Canadian Germ Cell Cancer conference [4-6].
TREATMENT APPROACH
Stage IIA disease — Treatment for stage IIA seminoma generally consists of radiation therapy (RT), with chemotherapy reserved for salvage of patients who subsequently relapse. Contemporary studies in patients with stage IIA and nonbulky stage IIB seminoma have yielded five-year disease-free survival rates of 90 percent or higher [5,7,8].
The efficacy of treatment in men with nonbulky abdominal disease is illustrated by a prospective Swedish and Norwegian Testicular Cancer Group (SWENOTECA) study of 1384 men with pure testicular seminoma diagnosed and treated in Sweden and Norway from 2000 to 2006 with follow-up through 2010 [9]. This series included 102 patients with clinical stage IIA or IIB disease. The five-year overall and cancer-specific survival rates were 100 percent. There were three relapses in the 29 patients treated with RT, all of whom were salvaged with chemotherapy. These relapses may have been due to the somewhat lower than standard dose of radiation (27 Gy) used.
Radiation therapy — Standard RT following orchiectomy for patients with nonbulky stage II disease consists of low-dose treatment to the paraaortic lymph nodes and superior ipsilateral pelvis followed by a small, optional boost to the involved nodal areas [10]. The total radiation dose to areas of gross adenopathy is 30 to 36 Gy. The scrotum, inguinal and lower pelvic lymph nodes, and mediastinum are not routinely treated [11]. (See "Treatment of stage I seminoma", section on 'Adjuvant radiation therapy'.)
The adverse effects of RT for stage II seminoma are similar to those described following treatment of stage I disease. (See "Treatment of stage I seminoma", section on 'Adjuvant radiation therapy'.)
Chemotherapy — Concerns about the long-term toxicity of RT prompted consideration of chemotherapy as a less toxic alternative to RT for patients with stage II seminoma. However, increasing evidence suggests that chemotherapy is associated with more toxicity than previously appreciated [12]. (See "Treatment-related toxicity in men with testicular germ cell tumors".)
Relapse rates for patients with bulky disease may be higher following RT compared with chemotherapy, and thus, chemotherapy is now the preferred approach for all but nonbulky stage II cases. Although single-agent carboplatin is successfully used as an adjuvant for men with stage I seminoma who are not candidates for active surveillance, this approach has not been as effective for those with stage II disease [13,14]. (See "Treatment-related toxicity in men with testicular germ cell tumors" and "Treatment of stage I seminoma", section on 'Adjuvant chemotherapy'.)
The German Testicular Cancer Study Group (GTCSG) studied three to four cycles of single-agent carboplatin (dosed at an area under the concentration x time curve [AUC] of 7) in patients with stage IIA/IIB seminoma [15]. A complete response was achieved in 88 of 108 cases (81 percent). In five of the cases that did not achieve a complete response, viable tumor was identified in the surgical resection specimen of residual disease. Furthermore, 14 patients (13 percent) who initially achieved a complete response relapsed and required salvage therapy.
Combination chemotherapy is more effective, but it is associated with increased toxicity. Treatment with four cycles of cisplatin and etoposide or three cycles of cisplatin, etoposide, and bleomycin was evaluated in 72 patients with stage IIA or IIB seminoma in a trial from the Spanish Germ Cell Cancer Group [16]. There were no relapses in the 18 patients with IIA disease, and there were six (11 percent) in those with IIB disease. The overall survival rate at five years was 95 percent, with only one death secondary to progressive seminoma.
The side effects associated with combination chemotherapy are discussed separately. (See "Treatment-related toxicity in men with testicular germ cell tumors".)
Stage IIB and IIC seminoma — Patients with stage IIB or IIC seminoma are generally managed with a cisplatin-based chemotherapy regimen. Although RT can successfully treat the majority of patients with stage II disease, the incidence of relapse and the associated need for salvage chemotherapy have made chemotherapy the preferred treatment option. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Good risk'.)
Seminoma is highly sensitive to chemotherapy, and even men with advanced seminoma are classified as having good-risk disease by the International Germ Cell Cancer Collaborative Group (IGCCG) [17]. Multiple clinical trials have documented the favorable outcome in this population, with 90 percent of patients achieving long-term relapse-free survival. Typical regimens include three cycles of bleomycin, etoposide, and cisplatin or four cycles of etoposide plus cisplatin. The clinical trials supporting these regimens are discussed elsewhere. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)
The efficacy of combination chemotherapy in men with stage IIC seminoma treated with chemotherapy is illustrated by a series of 42 men who were treated with four cycles of etoposide plus cisplatin between 2000 and 2006 as part of the SWENOTECA study [9]. The five-year cancer-specific and overall survival rates were 97.6 and 95.1 percent, respectively; there were six relapses and three deaths due to progressive cancer. (See 'Stage IIA disease' above.)
The long-term results after chemotherapy appear to be better for patients with bulky disease who have had limited infradiaphragmatic-only RT as compared with those who were irradiated more extensively [18,19].
SPECIAL CONSIDERATIONS
Posttherapy residual masses — Many patients with stage II seminoma have residual masses detected by imaging following treatment, including up to 80 percent of those managed with chemotherapy for bulky disease [20,21]. Many of these masses do not contain viable tumor, and approximately one-half of these will disappear during surveillance [22]. The presence of such masses can pose a difficult problem in assessing the adequacy of initial treatment since these do not necessarily require resection.
Early studies reported that there was a higher incidence of viable seminoma or local disease progression in cases where the residual mass was ≥3 cm on computed tomography (CT) scan [22,23]. However, this criterion does not detect all cases with viable tumor in smaller nodes, and many cases with larger residual masses are comprised exclusively of necrotic tissue.
Imaging with positron emission tomography (PET) scanning appears to be a better indicator of the presence of viable residual tumor tissue [24-26]. The most extensive data on the use of PET come from the multicenter SEMPET study [25]. In that study, 56 PET scans were performed in 51 patients with CT-documented residual masses 1 to 11 cm after chemotherapy for bulky seminoma.
●The overall sensitivity of PET was superior to that with CT using a size criterion of 3 cm (80 versus 70 percent), as was the specificity (100 versus 74 percent).
●In the 19 patients with a residual lesion >3 cm, PET detected all 7 cases that either had tumor documented at resection or subsequently relapsed, while accurately predicting the absence of tumor in the remaining 12 cases.
●In the 37 patients with a residual lesion ≤3 cm, PET detected one of three cases that contained tumor and accurately predicted the absence of tumor in 34 of 36 cases without disease. There were no false positives in any of the cases where tumor was not documented.
Elective irradiation in patients with a residual mass and normal serum tumor markers does not appear to improve outcome. In a nonrandomized series of 174 men with seminoma who had residual masses following chemotherapy, one-half received elective postchemotherapy radiation [27]. The use of elective radiation therapy was not associated with improved progression-free survival. (See "Serum tumor markers in testicular germ cell tumors".)
METASTATIC SEMINOMA — The majority of men with advanced or recurrent seminoma are treated with cisplatin-based combination chemotherapy. This topic is discussed in detail separately. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Good risk'.)
Radiation therapy (RT) may have a role in the management of men with metastases of seminoma beyond the retroperitoneum. For patients with limited sites of metastatic disease outside of the retroperitoneum, the exquisite sensitivity of seminoma to RT has permitted successful salvage with radiation alone [28-31].
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 — Stage II seminoma, either at presentation or at relapse following treatment for stage I disease, is a highly curable malignancy (table 1A-B). Patients are managed with radiation therapy (RT) or cisplatin-based combination chemotherapy depending upon the extent of retroperitoneal involvement (algorithm 1).
●For men with stage IIA seminoma, we suggest low-dose RT to the paraaortic lymph nodes and superior ipsilateral pelvis followed by a small boost to the involved nodal areas rather than chemotherapy (Grade 2B). Cisplatin-based combination chemotherapy is a reasonable alternative for patients in whom RT is not feasible. (See 'Stage IIA disease' above.)
●For men with stage IIB or IIC seminoma, we recommend combination chemotherapy with a cisplatin-based regimen, rather than RT (Grade 1B). Widely used regimens in this setting include three cycles of cisplatin, etoposide, and bleomycin (table 2) or four cycles of etoposide and cisplatin. (See 'Stage IIB and IIC seminoma' above and "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Treatment options'.)
●For men with residual retroperitoneal masses and normal tumor markers following chemotherapy, we suggest that treatment decisions (observation versus treatment) be based upon the results of positron emission tomography (PET) scan rather than the size of the residual mass (Grade 2B). (See 'Posttherapy residual masses' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Clair J Beard, MD, who contributed to an earlier version of this topic review.
