SEOM clinical guidelines for the management of germ cell testicular cancer (2016)

To develop updated, accurate clinical guidelines , the Spanish Society of Medical Oncology (SEOM) and the Spanish Germ Cell Cancer Group (SGCCG) invited ten experts based on major scientific contribution in the field of germ-cell testicular cancer (GCTC). The purpose of this paper was to define current ‘‘state-of-the-art’’ in the treatment of this malignancy using the methodology of evidence-based medicine. The available medical literature was reviewed according to main topics of disease management, and classified by scientific levels of evidence and grades of clinical recommendation according to the Infectious Diseases Society of America grading system [1]. The resulting text was reviewed, discussed, and approved by all authors.

In 2012, around 55,000 new cases of germ cell testicular cancer were diagnosed worldwide. This represents about 1.5% of all cancer diagnosis globally [2]. Despite this overall low occurrence, GCTC is the most frequent malignancy in males aged 15–34 years and, therefore, represents a substantial medical challenge. Incidence has increased over the last decades [3] due to non-completely understood reasons and differs considerably across world regions. Age-standardized incidence rates (ASR) range from 1–2/10⁵ in Africa and most Asia to 9–12/10⁵ in Scandinavia. Spain is considered an intermediate ASR country with 3.5 cases per 10⁵ making a total of around 800 new GCTC patients diagnosed every year [2]. Initiation of pathogenesis is believed to occur in most cases intrauterine where primordial germ cells would escape normal differentiation to become germ cell neoplasia in situ (GCNIS) that during puberty would gain invasive capacity [4]. The exact aetiology of GCTC is not clear. The most solid epidemiological risk factors are cryptorchidism, with 2–18 fold increased risk and a previous history of GCTC, with around 5% of patients developing a second tumor in the remaining testicle.

Based on the most recent histological taxonomy of GCTC according to the World Health Organization classification (2016 version), testicular germ cell tumors are now divided into two different groups: those derived from GCNIS and those unrelated to GCNIS [5]. The former comprises a number of histological variants that have similar epidemiologic links and happen in a background of disturbed testicular development with typical morphologic features and amplification of genetic material through an isochromosome 12p. These tumors represent progression from GCNIS and consist of pure forms of seminomas and non-seminomas along with mixed forms. The germ cell cancers unrelated to GCNIS include the spermatocytic tumor (previously named spermatocytic seminoma) and some pre-puberal histological variants (Table 1).

In patients with a testicular mass, bilateral testicular ultrasound serves to confirm its presence and to explore the contralateral testis. The minimum mandatory tests are (recommendation grade A): physical examination, complete blood count, serum creatinine, electrolytes and liver enzymes, pre- and post-orchiectomy serum tumor markers [alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (BHCG) and lactate dehydrogenase (LDH)], chest (mandatory in non-seminoma), abdomen, and pelvic CT scan. A discussion with the patient about sperm banking is recommended.

Other tests: bone scan or spinal MRI is recommended in case of symptoms, brain imaging (CT scan or MRI) in the event of neurologic manifestations, and for patients with extensive metastatic disease and/or very high BHCG values. There is no evidence to support the use of fluorodeoxyglucose-PET (FDG-PET) in the staging of testis cancer.

Inguinal orchiectomy is both diagnostic (histology and staging) and therapeutic. Rarely, when a patient presents with rapidly increasing BHCG, symptoms related to disseminated disease and a testicular mass, chemotherapy can be initiated immediately without waiting for a histological diagnosis.

The TNM staging system is based on post-orchiectomy findings according to the American Joint Committee on Cancer (AJCC), and AFP, BHCG, and LDH values [6] (Table 2). Serum tumor markers post-orchiectomy and before the start of chemotherapy are important to classify the patient according to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification [7] (Table 3).

Approximately 75–80% of patients with seminoma present with stage I disease, with a survival rate of 99% that is independent of the chosen strategy. The most accepted treatment options are active surveillance and adjuvant chemotherapy with one course of single-agent carboplatin (AUC 7) [8, 9]. Carboplatin has demonstrated to be equally effective in reducing relapses compared with radiotherapy and is associated with less protracted toxicities [8] (I, A). The low incidence of relapses (15–20%, most in the retroperitoneum and within the first 14 months) and their high curability make surveillance a preferable option for patients compliant with follow-up.

Tumor size (either over 4 cm or as a continuous variable) and rete testis invasion are the most widely used (but not universally accepted) predictive factors for relapse on surveillance. The Spanish Germ Cell Cancer Group and the Swedish and Norwegian Testicular Cancer Group studies have validated them and support their utility to guide a risk-adapted, adjuvant chemotherapy approach [10, 11].

Relapses on surveillance or after adjuvant carboplatin can successfully be salvaged using the standard cisplatin-based chemotherapy adequate for their stage.

About two-thirds of patients with non-seminomatous testicular tumors are diagnosed with stage I disease. Orchiectomy alone cures approximately 75% of these patients. The rest of them will relapse, usually within the first 2 years after surgery, and the majority as good-risk advanced disease. The presence of lymphovascular invasion in the primary tumor defines a subgroup with high risk of relapse, approaching 50% in several series (in contrast to a 15% in the rest of patients) [9]. Five-year disease-specific survival of stage I non-seminoma patients is close to 100%, irrespective of the therapeutic alternative performed.

Two different approaches are available. Active surveillance for all patients provides an excellent cure rate and avoids unnecessary therapy and potential long-term toxicity in many patients [9, 12]. Alternatively, a risk-adapted approach, i.e., the administration of adjuvant chemotherapy for high-risk patients, allows a less intense follow-up, reduces the stress and life disruption associated with relapse, and decreases the need of postchemotherapy retroperitoneal lymphadenectomy. Two cycles of adjuvant BEP chemotherapy (Table 4) have been administered in the majority of studies [13]. However, some recent series suggest that a single cycle could be enough [14]. Retroperitoneal lymphadenectomy is being progressively abandoned as alternative for high-risk patients, because it appears to be less effective than adjuvant chemotherapy and constitutes overtreatment in many patients [15].

Stage II-A (retroperitoneal lymph nodes 1–2 cm).

The classical treatment for patients with stage II-A seminoma has been radiotherapy. Despite the good disease control achieved with this approach, the risk of long-term, radio-induced neoplasms, and the excellent results of chemotherapy in this setting make this second option currently preferred for many clinicians.

Recommendation We recommend three cycles of BEP chemotherapy as the standard treatment if the patient does not have an increased risk of bleomycin-induced lung toxicity. Where this risk exists, four cycles of EP chemotherapy may be a good option [16‐19] (III, B).

However, radiotherapy could also be an alternative in selected cases with risk of chemotherapy toxicity or patient preference. In these patients, radiotherapy to para-aortic and ipsilateral iliac lymph nodes with 30 Gy in 2 Gy fractions is recommended [20] (III, B).

Stage II-B, II-C, and III (IGCCCG low risk).

Recommendation Even though radiotherapy was the classic treatment for stage II-B patients, three cycles of BEP chemotherapy is today the recommended approach to prevent relapses, especially outside the radiation therapy field [16, 17] (II, B). For stages II-C and III considered as low risk as per the IGCCCG classification, three cycles of BEP chemotherapy are also the standard treatment [18] (I, A). Four cycles of EP chemotherapy are a reasonable option in cases with risk of bleomycin lung toxicity [19] (II, B).

Stage III (IGCCCG intermediate risk)

Recommendation Patients with intermediate risk (i.e., extrapulmonary visceral metastasis), stage III should be treated with four cycles of standard BEP chemotherapy. If there is any concern about an increased probability of bleomycin lung toxicity, this drug might be replaced by ifosfamide (i.e., four courses of VIP) [21] (I, A).

Treatment recommendations for these patients are mainly based on the IGCCCG prognostic classification. As a general rule for all these patients, dose reductions should be avoided as treatment efficacy could be compromised; the routine use of prophylactic G-CSF from the first cycle is not clearly indicated, but it should be prescribed if severe neutropenia appears afterwards. It is also important to monitor weekly the decline in serum tumor markers after the first cycle, until they return to normal levels. It is recommended to perform serial diffusing capacity of the lung for carbon monoxide (DLCO) tests in patients who are planned to receive bleomycin. A DLCO drop over 30% and/or the onset of respiratory symptoms should prompt to omit this drug.

For patients with good-risk germ cell tumors, three cycles of BEP are considered standard therapy. In special situations, four cycles of EP can be an alternative option if patient comorbidities preclude the use of bleomycin [18, 19]. With these therapies, 5-year PFS and OS rates approach 90%.

For intermediate-risk patients, four cycles of BEP remain the standard choice, with a 5-year OS rate about 80%. If bleomycin cannot be used, VIP × 4 cycles could be an alternative option [21].

For poor-risk patients, four cycles of BEP are also the standard therapy, although the outcomes in this subgroup are poorer, with 5-year OS rates of 50%. In patients presenting with poor performance status, high tumor burden, or very extensive pulmonary or liver metastases, a first cycle of reduced-dose therapy (usually EP × 3 days) may decrease acute mortality without compromising long-term outcome. For poor-risk patients with slow marker decline, the role of intensification therapy remains controversial; the results of the GETUG-13 trial may indicate a benefit in PFS for patients with non-satisfactory marker decline after BEP first cycle with intensification, but it cannot be considered as a standard strategy [22]. It is strongly advised that patients with poor prognosis tumors should be referred to centers with experience managing these patients, and enrolled in clinical trials if available.

For intermediate- and poor-risk patients, BEP × 4 is considered as standard therapy (I, A).

Approximately 30% of metastatic GCTC will present residual masses (RM) after the first-line chemotherapy and their management is one of the most important keynotes for achieving high curability of these neoplasms [23].

As a general rule, RM greater than 1 cm should be resected from all locations. The presence of fibrosis in a retroperitoneal residual mass does not exclude the presence of teratoma in thoracic metastases (up to 20% of cases). Only patients with necrosis in both retroperitoneum and in one side of the lung can avoid contralateral lung resections [29].

Patients that relapse or progress after the first-line chemotherapy comprise a heterogeneous group of patients with varied outcomes, and a 2 year survival rate that ranges from 6 to 75% according to the International Prognostic Factor Study Group (IPFSG) risk classification (Table 5) [30].

Salvage treatment is based on chemotherapy and salvage surgery. When possible, it is recommended to refer these patients to experienced high-volume centers. Conventional-dose chemotherapy (CDCT) includes regimens that contain cisplatin and ifosfamide plus either etoposide (VIP), vinblastine (VeIP), or paclitaxel (TIP) are effective mainly in patients with good-risk features as those with primary gonadal tumors and good response to the previous first-line chemotherapy [31]. However, more than a half of these patients will progress from CDCT.

High-dose chemotherapy (HDCT) has demonstrated to cure a significant proportion of patients who relapse after CDCT and should be considered as a reasonable option for patients fit enough for this treatment. Phase III clinical trials including HDCT as the first-line salvage therapy are scarce and inconclusive. A large international retrospective pooled-data analysis [32] has suggested a benefit for HDCT over CDCT as the first-line salvage therapy, with a 35% reduction in the risk of death. This encouraging study prompted the development of an intergroup prospective randomized trial comparing HDCT to CDCT in the first salvage treatment (the TIGER study). This kind of trial is the best option for GCTC patients that fail first-line chemotherapy. When a clinical trial is not available, treatment should be based on the patient characteristics and medical experience [33]. Surgery is mandatory after salvage chemotherapy if there is any RM according to the previously described criteria and should be performed as soon as the patient is fit for the intervention.

GCTC is one of the few tumors in which more than 90% of metastatic patients are cured. Therefore, understanding the long-term effects of therapy and developing research studies and guidelines in this field are important to optimize the care in this population. Fertility, cardiovascular toxicity, specific sequela from chemotherapy, incidence of second neoplasms, and other chronic health-related issues are the main long-term toxicities to be discussed.

Approximately 2–5% of germ cell tumors are of extragonadal origin. The most common sites are in the midline: mediastinum (PM-EGCT) and retroperitoneum, followed by the central nervous system (CNS) [40, 41]. They are classified with the same IGCCCG criteria [7]. The prognosis of extragonadal seminomas is favorable regardless of its location, whereas that of non-seminomatous tumors (NS-EGCT) is indisputably unfavorable [40‐42]. PM-EGCT appears to represent a clinically and biologically distinct disease entity, associated with lower complete response rates, high rates of relapse, and frequent failure to salvage chemotherapy. Presence of visceral disease (liver, lung, or CNS metastases), a primary mediastinal location site, and elevation of BHCG are independent prognostic factors for survival in NS-EGCT [42]. LDH and AFP are less predictive for survival. The main prognostic factor related to refractoriness to therapy is non-seminomatous histology. The management of primary CNS germ cell cancer is complex, requires the integration of neurosurgeons, radiation oncologist, and medical oncologists, and should be performed in experienced institutions.

Late relapse of GCTC is uncommon: 1.4% in seminomas and 3.2% in non-seminomas. It is defined as recurrence occurring >2 years after the completion of the primary treatment for metastatic testicular cancer (with at least three cycles of chemotherapy). This definition excludes patients who relapse after adjuvant treatment or during surveillance who are usually cured by chemotherapy alone [23]. Patients with late relapse represent a subgroup with an adverse prognosis, do not tend to respond favorably to new chemotherapy, are usually AFP-positive, and often contain mature teratoma and/or non-GCTC elements [28, 43]. If technically feasible, all lesions should be removed by radical surgery at experienced centers. Further chemotherapy must be individualized according to histology and serum tumor markers. If salvage chemotherapy is the first treatment option for a late relapse (particularly for patients with rapidly raising BHCG), surgery should be conducted whenever possible.

Brain metastases (BM) can be present at the initial diagnosis or at relapse [44, 45]. Their prognosis is poor. Adverse risk factors for both groups are: (1) the multiplicity of BM; and (2) the presence of liver or bone metastases. For patients with synchronous BM, chemotherapy is the standard of care with BEP × 4. These patients have better prognosis. Radiotherapy and/or neurosurgery should be offered to patients with adverse risk factors (i.e., primary mediastinal non-seminoma). For patients with metachronous BM, chemotherapy has worse results, suggesting that chemotherapy resistance is critically related to outcome. The use of HDCT and multimodality treatment (radiotherapy/neurosurgery) are associated with a better outcome, especially in patients with poor prognostic factors (AFP > 100 ng/ml or BHCG > 5000 U/L) [45]. If clinically indicated and feasible, surgical resection of the metastasis should also be performed.

The early detection and treatment of relapse represent the primary objective of follow-up visits during the first 5 years. Follow-up schedules are empirical and have never been validated. Table 6 summarizes current recommendations from the SGCCG in our country.