Research Article: Adjuvant Therapy for Stage IB Germ Cell Tumors: One versus Two Cycles of BEP

Date Published: April 2, 2018

Publisher: Hindawi

Author(s): Robert A. Huddart, Alison M. Reid.

http://doi.org/10.1155/2018/8781698

Abstract

Testicular germ cell tumours are the commonest tumours of young men and are broadly managed either as pure seminomas or as ‘nonseminomas’. The management of Stage 1 nonseminomatous germ cell tumours (NSGCTs), beyond surgical removal of the primary tumour at orchidectomy, is somewhat controversial. Cancer-specific survival rates in these patients are in the order of 99% regardless of whether surveillance, retroperitoneal lymph node dissection, or adjuvant chemotherapy is employed. However, the toxicities of these treatment modalities differ. Undertreating those destined to relapse exposes them to the potentially significant toxicities of 3-4 cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy. Conversely, giving adjuvant chemotherapy to all patients following orchidectomy results in overtreatment of a significant proportion. Therefore, the challenge lies in delineating the patient population who require adjuvant chemotherapy and in determining how much chemotherapy to give to adequately reduce relapse risk. This chapter reviews the factors to be considered when adopting a risk-adapted strategy for giving adjuvant chemotherapy in Stage 1B NSGCT sand discusses the data regarding the number of BEP cycles to administer.

Partial Text

Testicular germ cell tumours (TGCTs) are the commonest tumours of young men aged between 20 and 35 years. They are divided into those of pure seminoma subtype (that histologically resemble primordial germ cells) and those with elements that resemble extra embryonic tissue (with or without seminoma components), generally termed “nonseminomas.” Nonseminomatous germ cell tumours (NSGCT) make up roughly 50% of cases and are common in a younger age group than seminomas (median age around 25 years). A characteristic of TGCT is their sensitivity to cisplatin-based chemotherapy which means that, in contrast to most solid tumours, patients with metastasis are usually cured. The most commonly used schedule is “BEP,” consisting of bleomycin, etoposide, and cisplatin. This is highly successful chemotherapy and will cure around 85–90% of patients with metastatic disease and over 95% of those with good prognostic features (i.e., absence of visceral metastasis and low tumour markers) [1]. The cost of this is the risk of significant toxicity, both acute and late (e.g., renal damage, peripheral neuropathy, hearing damage, increased risk of cardiovascular disease, and second cancer; summarised in Table 1). Management of these patients is supported by monitoring tumour markers such as alpha fetoprotein (AFP) and human chorionic gonadotrophin (HCG), which are elevated in patients with metastatic NSGCT in around two-thirds of cases [2].

An alternative approach to surveillance is to use adjuvant chemotherapy following treatment. This was first explored in the early 1990s after the success of using BEP chemotherapy in metastatic disease. It was argued that using more limited chemotherapy in those at high risk would restrict exposure to chemotherapy and prevent relapse. The key study of this approach was the MRC TE05 study. 114 patients were recruited with a predicted recurrence risk based on MRC risk factors of >50% [9]. Two patients recurred but one patient on histology review was proven to have a non-germ cell cancer, so in the 108 patients with centrally reviewed NSGCT, 1 relapsed and the 95% CI excluded a risk of relapse of 5%. This study was supported by similar smaller studies from Bern and Vienna [10, 11]. These data have been replicated in a number of reported studies totalling almost 1000 patients and a combined risk of relapse of <2% (summarised in Table 2). Most of the studies have used BEP for adjuvant treatment though a few studies have used variants of BEP. MD Anderson reported on substituting carboplatin for cisplatin [12], and the MRC replaced etoposide with vincristine [13], both achieving results similar to that achieved by BEP. The lower efficacy of carboplatin in metastatic disease and concerns regarding neurotoxicity, respectively, has meant that these approaches have not been adopted. At the Royal Marsden, we initially investigated a single cycle of BEP in patients with intermediate risk of recurrence. In 22 patients with approximately 20% risk of recurrence (i.e., 4-5 patients expected to recur), no active recurrences were noted though 1 patient required resection for teratoma differentiated [20]. In a similar higher risk group (defined as presence of vascular invasion or predominant embryonal carcinoma) in 42 patients, Westermann and colleagues reported a single active relapse compared to an expected rate of around 15 patients [21] (updated in [22]). It is our opinion that the data discussed are now robust enough to conclude that 1 cycle of BEP can successfully reduce the risk of recurrence to less than 5%. The additional benefit of adding a second cycle in terms of risk reduction of relapse is small and, in our judgement, is not sufficient to justify the additional toxicity. Using a single cycle of BEP would reduce the overall use of chemotherapy in the “high-risk” vascular invasion population. Using the model described above, treating 100 patients with single-cycle adjuvant BEP would give 100 cycles to this population compared to 150 cycles if it is assumed that 50% relapse on surveillance. In addition to amount of chemotherapy, the balance of who receives is very different either spread across the whole population or concentrating, with greater exposure, in those with proven disease. There is no evidence in any of the studies of adjuvant chemotherapy or surveillance that use of either approach affects overall survival. This has prompted a vigorous debate between supporters [26–28] of adjuvant chemotherapy and surveillance as to the optimal approach, both in seminoma and nonseminoma. To our mind, to exclusively offer either approach, given lack of survival difference, is inappropriate. We attempt to present a balanced argument of the pros and cons of the two approaches stressing the impact on relapse and discussing what is known regarding immediate- and long-term toxicity (including risk of cardiovascular disease and second malignancy). The idea of adjuvant toxicity seems intrinsically attractive to many, with the wish to get treatment over with and avoid future uncertainty of relapse as common levers for deciding on adjuvant chemotherapy. Single-cycle BEP is effective at reducing the risk of recurrence of stage 1 NSGCT to less than 5% and should be the preferred over two cycles of BEP if adjuvant therapy is chosen rather than surveillance. However, surveillance approaches can legitimately still be offered to all patients.   Source: http://doi.org/10.1155/2018/8781698

 

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