Treatment of Testicular Tumours

Fig. 22.1

Algorithm of the management of testicular tumor

There is an excellent survival rate of GCTs owing to careful staging at diagnosis, efficacy of early adequate treatment based on chemotherapeutic combinations, with or without radiotherapy or surgery and the possibility of salvage therapies on subsequent follow-up. The 5-year overall survival of GCTs is estimated to be approximately 96–97 % in Germany and the United States, with spermatocytic seminoma having the best outcome (near 100 % 5-year survival rate) and choriocarcinoma portraying the worst relative survival rate (around 80 %) [20].

As already stated, testicular histopathology, tumour markers and radiological imaging form an essential clinical tripod in establishing the risk categories and deciding further treatment.

For localized diseases, the modality of treatment will depend on the prognostic risk factors for relapse.

(a)

Seminoma: Two options are possible for stage I seminoma and include surveillance and adjuvant chemotherapy with carboplatin [21]. Up to few years back adjuvant RT using 20 Gy was an option but is no more recommended due to the efficacy of carboplatin with less side effects as stated in a recent prospective randomized trial [22]. Active treatment with chemotherapy is considered in patients with testicular tumours greater than 4–cm diameter or when the rete testis is involved. Surveillance in this situation is associated with high relapse rate compared to active treatment. Surveillance is recommended in compliant patients with tumours of less than 4–cm diameter as they are associated with a low recurrence rate of 15–20 % which is manageable by an effective salvage therapy when it occurs. Therefore, unnecessary treatment is avoided in as much as 80 % of patients with low risk [23].

(b)

NSGCT: Three options are possible: Surveillance, chemotherapy with 2 cycles of PEB or RPLND [21] for patients with normalized serum markers. Patients with persistently high markers should receive 3 cycles of PEB: combination of cisplatin, etoposide and bleomycin (see the following section).

A prospective study found a 73 % relapse-free rate during surveillance of teratoma after radical orchidectomy alone [24] and identified a high-risk group for disease relapse (lymphovascular invasion and/or presence of embryonal element and absence of a yolk sac component) for which chemotherapy is advocated. There is an interest in performing a diagnostic and eventually therapeutic primary RPLND in clinical stage I NSGCTs as the only reliable staging method. Around 28 % of patients clinically labelled stage I or N0 disease were found to have retroperitoneal LN metastases [25].

A strict follow-up after chemotherapy and/or RPLND is mandatory to decide for further treatment depending on tumour marker response and residual tumours.

Metastatic disease [17, 21]: In advanced disease, risk categories will determine the type and duration of chemotherapy, in addition to the prognosis and survival (Table 21.3).

(a)

Seminoma: For low volume disease (LN <3 cm): RT with 30 Gy for stage IIA and 36 Gy for IIB. Technically, the radiation should be unilateral and cover the hockey-stick field including the para-aortic area and the ipsilateral iliac region. Alternatively, chemotherapy (3 PEB or 4 EP) for stage IIB. Above stage IIB: chemotherapy with 3 cycles of PEB for the good prognostic group and 4 cycles for the intermediate risk group.

(b)

NSGCTs: Despite a study having shown that primary RPLND should better be restricted to clinical stages I and IIA patients with normal tumour markers after orchiectomy and stable retroperitoneal disease [26], the European expert panel extend that option to IIB disease patients with normal tumour markers and unwilling to undergo primary chemotherapy [21] which is mandatory for all higher stages. Practically, the following protocol is recommended: Good prognosis: 3 PEB cycles. Intermediate and bad prognosis: 4 PEB cycles. Surveillance is also an option for IIA-B patients.

Drugs Used in Chemotherapy for GCTs

Presently the most commonly used drugs are cisplatin, etoposide and bleomycin (PEB). Secondarily, ifosfamide (Holoxan) and carboplatin are also used whenever one of the BEP components is contraindicated. New proposed drugs are epirubicin, taxanes (paclitaxel), oxaliplatin, gemcitabine (Gemzar), etc.

Cisplatin or cis-diamminedichloroplatinum(II) or CDDDP (Platinol^®) is nephrotoxic (reversible dose-dependant tubular necrosis), hematotoxic, ototoxic and neurotoxic. It may also induce azoospermia and gastrointestinal upset. A randomized trial has shown that adjunction of the cytoprotective agent amifostine (Ethyol) alleviated the nephrotoxicity of a platinum-based chemotherapy [27]. The usual dose is 20 mg/m²/day IV over 20–60 min for 5 days; repeated q21d for 3–4 cycles. The drug is contraindicated in documented hypersensitivity, pre-existing renal insufficiency (creatinine clearance <60 mL/min), myelosuppression or hearing impairment.
Etoposide or VP-16 (Toposar^®, VePesid^®, Etopophos^®) is haematotoxic (pancytopenia, possibility of late leukaemia). It also induces hypotension which may be severe, mucositis and gastrointestinal upset. More toxicity was found in patients with serum creatinine >130 umol/L, serum albumin <35 g/L, age >65 years and elevated liver enzymes. It appears to be caused by an increased concentration of free plasmatic etoposide found in these conditions [28]. The usual dose is 100 mg/m²/day IV for 5 days; repeated q21d for 3–4 cycles and adjusted in hepatic or renal function impairment. Documented hypersensitivity to the drug is an absolute contraindication.
Bleomycin (Blenoxane^®) is a glycopeptide antibiotic produced by the bacterium Streptomyces verticillus. It has a high toxicity rate causing hyperthermia, interstitial pneumonitis followed by lung fibrosis and Raynaud’s syndrome. The rate of pneumonitis varies with publications from 0 to 46 % of the patients depending on the definition criteria used [29]. Mortality rate also varies with publication and was shown to reach 14 % of the patients developing bleomycin pulmonary toxicity [30]. Pulmonary fibrosis characteristically appears after a cumulative dose >300,000 IU¹ (equivalent of 300 USP units² or 300 mg), mostly after radiation therapy. It affects mostly older patients (>40 years) as well as subjects with GFR <80 ml/min or stage IV disease at presentation. Patients respond poorly to steroids and are worse after oxygenation [30]. Lung toxicity occurs after a median time of 4.2 months from the start of bleomycin, but longer periods have been reported including an exceptional occurrence 10 years after cessation of the treatment [31]. Optionally a test dose can be given 1–2 mg IV/IM before starting the standard dose of 30 mg IV bolus every week on days 2, 9 and 16; repeated every 21 days (q21d) for 3–4 cycles. Documented hypersensitivity, significant renal function impairment and pre-existing compromised pulmonary function are absolute contraindications for this drug.

Due to the high toxicity of these drugs, supportive care is necessary with erythropoietin, G-CSF (Neupogen, Eprex.), anti-emetic and anti-allergic drugs, steroids, neuroleptic (chlorpromazine), etc. However, beware of a reported synergistic effect between bleomycin and G-CSF in promoting pulmonary toxicity [32]. Nowadays, the protocol PEB has become the international standard therapy since 1987 when Williams et al. demonstrated that it is less toxic and provides a better survival rate than the former PVB combination (cisplatin, vinblastine, bleomycin) [33]. This combination is credited with a higher than 85 % overall cure rate and the treatment duration has now been reduced to 3–4 months. It was shown that a 3–day cycle and a total of 3 PEB cycles carried less toxicity while maintaining same efficacy as a 5-day cycle and a total of 4 cycles for GCTs with a good prognosis [34].

Other protocols are EP (without bleomycine) and VIP: Etoposide, ifosfamide (Ifex), cisplatine.

Salvage protocols: VIP, VeIP (vinblastine, ifosfamide, and cisplatin), CARBOPEC (carboplatin, etoposide, cyclophosphamide).

Note: A transient elevation of βHCG and AFP can occur after the initiation of chemotherapy. AFP surge, as opposed to βHCG elevation, appears to be an adverse prognostic factor [35, 36].

22.3 Management of Residual Metastatic Masses After Chemotherapy (Fig. 22.1)

Seminomas: If para-aortic lymphadenopathy <3 cm is present after normalization of tumour markers, the patient can be put under careful surveillance and followed-up with repeat CT scan and/or PET scan [17, 21]. The rationale is the known slow regression of this tumour which may take months or even years to be completed [37]. However, if the masses are >3 cm, a PET scan is indicated to detect active tissue which is an indication for a RPLND.
NSGCTs: RPLND applies to any supracentimetric residual mass after normalization of serum markers [17, 21]. In case of persistently high serum markers after chemotherapy, a salvage second chemotherapy can be given. If the latter fails, a ‘desperation surgery’ can be attempted aiming at removing all resectable tumours [21]. When >10 % viable tumour is seen in the resected LN, this may be an indication for a postsurgical repeat chemotherapy with the same regimen used in the induction, that is, PEB protocol, but beware of the cumulative bleomycin dose. This so-called ‘consolidation chemotherapy’ is performed with 2 PEB cycles and is mostly justified when there is an incomplete resection of NSGCTs other than teratoma [21]. However, it was shown that the benefit of this post-surgical redo-chemotherapy is found only in patients with IGCCC intermediate prognostic group [38]. The completeness of the resection which is better performed by experienced surgeons is of paramount importance as it has been shown to be the strongest predictor of both progression-free survival and overall-survival [39]. Other predictors are <10 % viable malignant cells and favourable IGCCC group.