Current Management of Testicular Cancer

Testicular cancer represents 1% to 1.5% of male neoplasia and 5% of urologic tumors in general, with 3 to 6 new cases occurring per 100,000 males per year in Western society [1]. Also, a clear trend has been seen toward an increased testicular cancer incidence in the past 30 years in most industrialized countries [2]. The peak incidence is in the third decade of life for nonseminoma and in the fourth decade for pure seminoma. Familial clustering has been observed, particularly among siblings [3]. The epidemiologic risk factors for the development of testicular cancer are a history of cryptorchidism or undescended testis, Klinefelter syndrome, a familial history of testicular cancer among first-degree relatives (father or brothers), the presence of a contralateral tumor or testicular intraepithelial neoplasia, and infertility [4-6]. Testicular cancer has excellent cure rates. The main factors contributing to this are careful staging at diagnosis; adequate early treatment using chemotherapeutic combinations, with or without radiotherapy (RT) and surgery; and very strict follow-up and salvage therapy. The aim of this review was to summarize the current trends in the management of germ cell tumors (GCTs).

The staging system recommended is the 2009 tumor-node-metastasis (TNM) staging of the International Union Against Cancer [17]. Staging includes determination of the anatomic disease extent; assessment of the STMs, including the nadir values of hCG, AFP, and LDH after orchiectomy; a clear definition of the regional nodes; and N category modifications related to the nodal size. According to the 2009 TNM classification, stage I testicular cancer includes the following substages: stage IA, pT1N0M0S0; stage IB, pT2-T4N0M0S0; and stage IS, any pT/TxN0M0S1-S3. Patients with stage IA disease have primary tumors limited to the testis and epididymis, with no evidence of microscopic vascular or lymphatic invasion by tumor cells on microscopy, no sign of metastases on clinical examination or imaging, and postorchiectomy STM levels within normal limits. Patients with stage IB have a more locally invasive primary tumor, but no sign of metastatic disease. Patients with stage IS have persistently elevated STM levels after orchiectomy, which is evidence of subclinical metastatic disease. If the STM levels are declining according to the expected half-time decay after orchiectomy, the patient is usually followed up until normalization. In large, population-based patient series, 75% to 80% of patients with seminoma and about 55% of patients with NSGCT have stage I disease at diagnosis [18, 19]. True stage IS is found in about 5% of patients with nonseminoma. If staging retroperitoneal lymph node dissection were performed in patients with stage IS disease, nearly all patients would be found to have pathologic stage II disease [18]. In 1997, the IGCCCG defined a prognostic factor-based staging system for metastatic testis tumors by using the identification of some clinical, independent adverse factors. This staging system has been incorporated into the TNM classification and uses histologic type, primary tumor location, metastasis location, and prechemotherapy serum marker levels as prognostic factors to categorize patients according to a good, intermediate, or poor prognosis (Table 1) [20].

TABLE 1
International germ cell cancer collaborative group risk classification for advanced germ cell tumors (GCTs)

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For treatment purposes, the distinction between seminoma and NSGCT holds great importance. Compared with NSGCT, seminoma has a relatively favorable natural history. In general, seminoma tends to be less aggressive, to be diagnosed at an earlier stage, and to spread predictably along lymphatic channels to the retroperitoneum before spreading hematogenously to the lung or other organs. Seminoma is also associated with a lower incidence of occult metastasis and a lower risk of systemic relapse after treatment of the retroperitoneum, which has important implications for the use of chemotherapy. Compared with NSGCT, seminoma is exquisitely sensitive to radiation therapy and platinum-based chemotherapy [21]. RT is a standard treatment option for stage I and IIA-B seminoma, but has no role in the treatment of NSGCTs. NSGCTs are usually mixed tumors and teratoma often exists at metastatic sites with other GCT elements; cure often requires chemotherapy to kill the chemosensitive components and surgery to remove the teratomatous components [22, 23].

Although RT was previously the standard for patients with clinical stage I seminoma, recognition has been growing since the early 1990s that adjuvant RT is associated with an increased risk of late side effects, including second non-germ cell malignancies and cardiovascular disease [24-29]. Concerns regarding the late toxicity of RT, the success of surveillance of stage I nonseminomatous GCTs, and improvements in diagnostic imaging have led to an assessment of close surveillance after orchiectomy for stage I seminoma with treatment reserved for those with relapse. In addition, adjuvant carboplatin chemotherapy has been shown to give results similar to RT. With any of these approaches including surveillance, RT, or carboplatin chemotherapy, 5-year disease-specific survival rates of above 99% can be expected [30].

At workup after orchiectomy, about 15% to 20% of patients have radiologically involved para-aortic lymph nodes. The number of patients with stage II disease has been too small to mount phase III studies of treatment, and treatment decisions must be determined from reports from single institutions where patients have been treated in a uniform fashion. The most important prognostic factor in stage II seminoma is the bulk of the retroperitoneal tumor. The lymph node size was the only factor that predicted recurrence in 95 patients with stage II seminoma treated with RT at the Princess Margaret Hospital from 1981 to 1999 [36]. The 5-year relapse-free rate in 79 patients with nodal disease of less than 5 cm (stage IIA-IIB) was 91% (7 of 79 patients) compared with 44% (9 of 16 patients) in patients with bulkier disease (stage IIC). Of these patients, 13 were treated with chemotherapy at relapse, and 9 were free of disease at the last follow-up visit. However, the high failure rate after RT in patients with bulky retroperitoneal disease, that not all patients with recurrence can be salvaged, and the apparently better outcome of similar patients who were treated with chemotherapy at diagnosis mandates primary chemotherapy, instead of RT, for this population. Staging should not be the only parameter used to decide the treatment of retroperitoneal disease in patients with stage II seminoma. The tumor bulk must also be considered. In patients with such bulky disease, chemotherapy, rather than RT, should be used [36]. The technique of RT for stage II seminoma is similar to that used for stage I disease. The treatment volume includes the gross tumor and the para-aortic and ipsilateral common and external iliac lymph nodes. The radiation dose is typically 25 Gy in 20 daily fractions, plus a boost of an additional 10 Gy to the gross lymphadenopathy [36]. The use of combination carboplatin and RT in stage IIA-IIB seminoma has been suggested by Gilbert et al. [37]. They described a series of 62 patients treated with 1 to 2 courses of carboplatin 4 to 6 weeks before RT. Since 1997, 29 patients have been treated with 1 course of carboplatin before RT to the para-aortic nodes alone, and no relapses were observed. This approach is attractive in that it offers the potential of reducing the treatment volume with RT, at the same time improving the results compared with RT alone. However, this approach cannot be accepted as routine practice without additional study, especially because the use of combined modality therapy has been shown to increase the risk of second non-GCT and cardiovascular disease in long-term survivors [38]. If chemotherapy is recommended as the primary treatment or for relapse after RT, 3 cycles of bleomycin, etoposide, and cisplatin (BEP) or 4 courses of etoposide and cisplatin (EP) should be considered as standard options.

After treatment, patients with stage II disease require follow-up imaging of the abdomen until complete disease regression has occurred. A stable, persistent mass often represents fibrosis or necrosis, and only a few such masses will contain active tumor. However, the possibility of a nonseminomatous component to explain the residual mass must be kept in mind, even in patients whose primary tumors show pure seminoma [39]. The Memorial Sloan-Kettering Cancer Center group published their data from 55 of 104 patients who had demonstrated residual masses after chemotherapy [40]. Of these 55 patients, 32 (58%) had undergone formal retroperitoneal lymph node dissection, and 23 (42%) had multiple intraoperative biopsies performed because the residual mass was deemed unresectable. Among patients with a mass of more than 3 cm (n = 27), 8 (30%) had a residual viable tumor. Of the 8 recurrences, 2 were teratoma and 6 were seminoma. Given this high proportion of persistent malignancy, the Memorial Sloan-Kettering Cancer Center investigators have recommended resection or biopsy of masses of 3 cm or larger. Numerous studies have demonstrated that, on average, patients with residual masses of 2 cm or smaller have a 30% and 6% incidence of teratoma and viable malignancy, respectively (Table 2). In patients with disseminated seminoma, postchemotherapy masses of smaller than 3 cm may be safely observed, whereas patients with masses of larger than 3 cm should be evaluated with positron emission tomography or CT 2 months after completion of chemotherapy, with very selective administration of postchemotherapy retroperitoneal lymph node dissection (PC-RPLND). Late relapse occurring more than 2 years after chemotherapy is rare, and surgery remains the mainstay of therapy in cases of resectable masses independent of tumor markers. Surgery should always be considered for resectable masses following salvage therapies or in chemoresistant disease to maximize the chance of cure.

TABLE 2
Histology of postchemotherapy residual masses less than 20 mm

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An estimated 20% to 30% of patients with clinical stage I NSGCTs have occult metastasis, with the retroperitoneum being the most common site. Thus, any treatment after orchiectomy represents overtreatment for most patients. The long-term, cancer-specific survival rate approaches 100% for all patients, regardless of the initial treatment strategy. Thus, efforts to reduce treatment-related toxicity are paramount in the treatment of these patients.

Patients with no clinical evidence of metastatic NSGCT after orchiectomy other than persistently elevated or increasing AFP or HCG levels should receive chemotherapy, just as for advanced disease, usually with either BEP×3 cycles or EP×4 cycles [57-59]. Studies of primary RPLND for clinical stage IS NSGCT have reported that 37% to 100% of patients subsequently required chemotherapy for retroperitoneal metastasis, persistently elevated STM, or relapse [57-59]. A general consensus has been reached that these patients should receive induction chemotherapy. An elevated STM level at a single point after orchiectomy does not necessarily indicate stage IS disease. In this situation, the marker might be decreasing according to its expected biological half-life, and the measurements should be repeated to clarify the situation.

Patients with elevated postorchiectomy AFP or HCG levels should receive induction chemotherapy. Induction chemotherapy and primary RPLND are acceptable treatment options for patients with clinical stage IIA with normal postorchiectomy AFP and HCG levels. Also, induction chemotherapy is the preferred treatment in patients with clinical stage IIB with normal postorchiectomy AFP and HCG levels [60, 61]. Patients should be informed of both treatments, including the potential short- and long-term treatment-related toxicity and the risk and nature of any additional treatments. The decision to proceed with induction chemotherapy or RPLND should be determined by patient preference and the specific expertise of the treating physician and institution.

Approximately one-third of patients who undergo chemotherapy for metastatic NSGCT have residual retroperitoneal disease. Patients who obtain a complete serologic remission and radiographic residual mass in the transverse axial CT of diameter <1 cm after chemotherapy have a 6% to 9% risk of relapse [55].These patients are considered by most experts to be at low risk of relapse. There is universal agreement that patients with residual radiographic masses >1 cm following initial chemotherapy require resection [55]. Patients with a completely resected teratoma in only the PC-RPLND specimen have a >90% chance of cure, whereas patients with viable GCT should be considered for additional therapy [62].

Patients with advanced GCT can achieve long-term, disease-free survival when chemotherapy is combined with expert and judicious resection of residual disease. Patients with advanced GCTs should choose a chemotherapy regimen on the basis of their IGCCCG risk classification (Table 1). BEP×3 cycles or BEP×4 cycles is the standard therapy for good-risk patients with advanced GCT. BEP×4 cycles is the standard therapy for poor- and intermediate-risk patients with GCT. Using these treatments, we can achieve durable remissions of approximately 90%, 75%, and 45% in patients with good, intermediate, and poor risk, respectively [62-68].

For the management of seminoma and NSGCTs, clear standards have been defined on the basis of the results of prospective clinical trials. Careful management according to these guidelines will give the patient the greatest chance for a high cure rate or at least an optimal outcome.