Testicular cancer is 1%–2% of all tumors in men between the ages of 15 and 35 (1). In 2015, there were an estimated 8,430 new testicular cancer cases in the United States, accounting for 380 deaths from testicular cancer (2). Testicular cancer classically presents with a painless testicular mass, which should be evaluated urgently. The standard work up of testicular cancer includes a routine complete blood count with differential, complete metabolic panel, and testicular ultrasound. The first step of treatment in testicular cancer is orchiectomy. Inguinal orchiectomy is the standard of care, and transscrotal orchiectomy should never be performed when malignancy is suspected. Beta-human chorionic gonadotropin (B-HCG), alpha-fetoprotein (AFP), and lactate dehydrogenase (LDH) are the serum tumor markers (STMs) in testicular cancer, useful in diagnosis, prognosis, and staging. However, none of the STMs are specific for testicular cancer. STMs should be checked prior to orchiectomy and repeated following orchiectomy.
Germ cell tumors (GCTs) comprise 95% of all primary testicular cancers. GCTs are divided into seminomas and nonseminomas. Sixty percent of all GCTs of the testis are seminomas (1). A diagnosis of pure seminoma requires both histologic evidence of seminoma and a normal AFP level, as pure seminomas do not 216produce AFP. Patients with elevated AFP despite apparently pure seminoma histology should be evaluated carefully for the presence of a nonseminomatous component of the tumor. They should be treated as nonseminomas unless a nontumor related cause is found for the increased AFP.
SERUM TUMOR MARKERS
STMs are an essential part of the tumor, node, metastasis (TNM) staging of testicular cancer. The half-lives of AFP and beta HCG are 7 and 3 days, respectively. Proper staging of testicular cancer is done after radical orchiectomy. STMs are expected to decline according to their half-lives once the tumor has been surgically removed.
There are three stages of testicular cancer. In stage I testicular cancer, the tumor is confined to the testis or spermatic cord with normal STMs. In stage II testicular cancer, retroperitoneal (RP) lymph nodes are involved and the size of the RP lymph nodes with normal or mildly elevated STMs define stage II A, B, or C (RP lymph node <2 cm defines stage IIA, 2 to 5 cm defines stage IIB, and >5 cm defines stage IIC). Stage III testicular cancer is characterized by the presence of distant organ metastasis, pelvic lymph node involvement, or RP lymph node involvement with moderately/highly elevated STMs (Table 29.1) (3).
For stage I or II, tumor markers cannot be highly elevated. Very high tumor markers are consistent with stage III seminoma. The persistence of STMs after treatment of stage I seminoma implies the presence of micrometastatic disease and is treated as stage III. Based on STMs and primary and metastatic tumor site, the International Germ Cell Cancer Collaborative Group (IGCCCG) system categorized metastatic GCTs into good risk, intermediate risk, and poor risk groups, with 5-year survival rates of 91%, 79%, and 48%, respectively (4). There is no high risk seminoma, only good risk or intermediate risk seminoma. Metastatic disease to organs other than lungs is considered intermediate risk seminoma, and the rest of seminomas are good risk disease.
218219EARLY STAGE SEMINOMA
Stage I Seminoma
Patients present with stage I disease in 80% of cases. There are three standard treatment options in stage I seminoma following radical inguinal orchiectomy: Active surveillance, adjuvant radiotherapy, or adjuvant chemotherapy with one or two cycles of carboplatin. Any of these three strategies results in an almost 100% disease free survival in stage I seminoma (1, 5). Active surveillance is the preferred approach per National Comprehensive Cancer Network (NCCN) guidelines, and the pros and cons of each treatment option should be discussed with the patient (6). The reported relapse rates ranged between 1.8 and 8.6 after one or two cycles of carboplatin (7). The updated results of a randomized trial of one cycle of carboplatin versus radiotherapy in 1,477 patients with stage I seminoma reported a 5-year relapse rate of 5.3% for the carboplatin arm and 4% for the radiotherapy arm (8). The relapse rate is between 13% and 19% for active surveillance (1, 5). An increased risk of secondary malignancies and cardiovascular diseases should be noted as long-term risks of radiation therapy in the management of early stage seminoma (1). Sperm banking should be discussed with the patients prior to chemotherapy due to an increased risk of infertility.
CT abdomen/pelvis is the recommended imaging modality for surveillance of early stage seminomas. Time intervals depend on whether adjuvant chemotherapy or radiotherapy was given following radical orchiectomy. Chest x-ray is utilized as clinically indicated. STMs have low utility in active surveillance for stage I seminoma, and the American Society of Clinical Oncology recommended against the use of STMs in surveillance of stage I seminoma (9).
With active surveillance, more than 90% of relapses occur in the first 3 years. After adjuvant therapy, 99% of relapses occur within the first 3 years. For patients who relapse during surveillance, treatment is still given with curative intent. Para-aortic lymph nodes are the most common sites of relapse. Radiation therapy can cure nonbulky (<5 cm) relapse in more than 90% of 220patients (1). Three cycles of bleomycin, etoposide, and cisplatin (BEP) or four cycles of etoposide and cisplatin (EP) are typically used for large, bulky relapses (10). Relapses may occur in a supradiaphragmatic site after adjuvant radiotherapy, and cisplatin-based chemotherapy is used in this setting. Relapses occurring in RP lymph nodes after adjuvant chemotherapy can be treated with salvage radiation therapy or cisplatin-based salvage chemotherapy.
Stage II Seminoma
Clinical or pathological abdominal and/or pelvic lymph involvement indicates stage II seminoma. At initial presentation, 15% to 20% of cases are stage II (11). The size of the lymph node involvement determines stages IIA, B, and C. Treatment modalities include adjuvant chemotherapy or radiotherapy. The optimal treatment modality depends on the extent of lymph node involvement. Essentially, stage IIA disease can be treated with radiation therapy or chemotherapy, and stage IIB and stage IIC are treated with chemotherapy only. Radiation therapy to para-aortic and ipsilateral iliac lymph nodes with 30 Gy is the preferred dose for stage IIA seminoma per NCCN guidelines, and 36 Gy can be considered for nonbulky stage IIB disease (6). Single agent carboplatin is not adequate treatment for stage IIA and B disease, as the phase II clinical trial conducted by the German Testicular Cancer Study Group revealed only an 81% (88/108 patients) complete response rate in patients with stage IIA and B seminoma after three or four cycles of carboplatin AUC 7, respectively (12). Cisplatin-based combination chemotherapy is recommended for stage IIA disease, especially in the setting of multiple lymph node involvement, and is the preferred approach for stages IIB and IIC disease. Three cycles of BEP or four cycles of EP are typical chemotherapy combinations. The disease specific survival rate exceeds 95% in stage II seminoma, regardless of the initial treatment modality (11).
A residual mass following the primary treatment with combination chemotherapy or radiotherapy is one of the challenges in the management of stage II seminoma. The majority 221of these masses include necrotic or fibrotic tissue, but a few contain tumor. Although the size of the residual mass may be helpful to determine the next step of action, PET scan can be instrumental in guiding clinical decisions. Surveillance or PET scan can be considered if the size of the residual mass is less than 3 cm versus greater than 3 cm, respectively. If the PET scan is negative, surveillance can be considered. If it is positive, retroperitoneal lymph node dissection (RPLND) or second line chemotherapy are options. Surveillance strategy includes periodic history and physical examinations, CT abdomen/pelvis, and chest x-ray. The time intervals of the imaging studies depend on the bulkiness of disease and staging as outlined in NCCN guidelines (6).
LATE STAGE SEMINOMA
Stage III Seminoma
Nonregional lymph node or distant organ metastasis indicates stage III seminoma. As mentioned earlier, metastasis to distant organs other than lungs is considered intermediate risk disease; all other seminomas are considered good risk disease. Chemotherapy is the treatment of choice in late stage seminoma, and the risk group determines the number of chemotherapy cycles. Standard chemotherapy options are three cycles of BEP or four cycles of EP for good risk disease, whereas four cycles of BEP is recommended for intermediate risk disease. VIP (etoposide, ifosfamide, and cisplatin) can be used in patients who cannot receive bleomycin. Seminomas are highly chemosensitive, and cure rates exceed 80% in disseminated good risk seminomas in the first-line chemotherapy setting (13).
The majority of relapses occur in the first 2 years of treatment. Late relapse for seminomas is rare. Most trials evaluating salvage chemotherapy regimens in relapsed or disseminated GCT included more nonseminomatous GCTs than pure seminomas. However, chemotherapy regimens are similar for seminomas and nonseminomatous GCTs in the second line setting. Second line chemotherapy options are VeIP (vinblastine, ifosfamide, and cisplatin), TIP (paclitaxel, ifosfamide, and cisplatin), 222and high dose chemotherapy (HDC) followed by autologous stem cell transplant. Sustained complete response rates are between 24% and 25% for VeIP, 38% to 63% for TIP, and 40% to 50% for HDC (13). Palliative chemotherapy options for refractory patients include gemcitabine, oxaliplatin, paclitaxel, or irinotecan as a single agent or in combination, as well as single agent oral etoposide (6, 14).