Elsevier

European Journal of Cancer

Volume 115, July 2019, Pages 27-36
European Journal of Cancer

Original Research
Intravenous but not intrathecal central nervous system–directed chemotherapy improves survival in patients with testicular diffuse large B-cell lymphoma

https://doi.org/10.1016/j.ejca.2019.04.004Get rights and content

Highlights

  • Intravenous central nervous system (CNS)–directed chemotherapy translates to superior survival in testicular lymphoma.

  • Phophylactic treatment of contralateral testis is associated with improved survival.

  • Intrathecal CNS-directed chemotherapy does not have impact on survival.

  • The benefit of rituximab is seen only among the patients with high International Prognostic Index.

Abstract

Background

Testicular lymphoma is a rare malignancy affecting mainly elderly men, the majority representing diffuse large B-cell lymphoma (DLBCL). Its relapse rate is higher than that of nodal DLBCL, often affecting the central nervous system (CNS) with dismal prognosis.

Patients and methods

We searched for patients with testicular DLBCL (T-DLBCL) involvement from the pathology databases of Southern Finland University Hospitals and the Danish Lymphoma Registry. Clinical information was collected, and outcomes between treatment modalities were evaluated. Progression-free survival (PFS), disease-specific survival (DSS) and overall survival (OS) were assessed using Kaplan–Meier and Cox proportional hazards methods.

Results

We identified 235 patients; of whom, 192 were treated with curative anthracycline-based chemotherapy. Full survival data were available for 189 patients. In univariate analysis, intravenous CNS-directed chemotherapy, and irradiation or orchiectomy of the contralateral testis translated into favourable PFS, DSS and OS, particularly among the elderly patients (each p ≤ 0.023). Intrathecal chemotherapy had no impact outcome. In multivariate analyses, the advantage of intravenous CNS-directed chemotherapy (hazard ration [HR] for OS, 0.419; 95% confidence interval [CI], 0.256–0.686; p = 0.001) and prophylactic treatment of contralateral testis (HR for OS, 0.514; 95% CI, 0.338–0.782; p = 0.002) was maintained. Rituximab improved survival only among high-risk patients (International Prognostic Index≥3, p = 0.019). The cumulative risk of CNS progression was 8.4% and did not differ between treatment modalities.

Conclusion

The results support the use of CNS-directed chemotherapy and prophylactic treatment of the contralateral testis in patients with T-DLBCL involvement. Survival benefit appears resulting from better control of systemic disease rather than prevention of CNS progression.

Introduction

Primary testicular lymphoma is a rare malignancy with an estimated yearly incidence of less than 0.3/100,000 [1]. Testicular involvement is seen in 1–2% of patients with lymphoma. The median age of patients with testicular lymphoma is on the later 7th decade of life, and lymphoma is the most common testicular malignancy in men older than 50 years of age. Most lymphomas with testicular involvement represent diffuse large B-cell lymphoma (DLBCL) [1], [2], [3], [4].

Common prognostic factors of DLBCL, such as International Prognostic Index (IPI) and high tumour burden, have been shown to correlate with survival also in testicular DLBCL (T-DLBCL). However, even after aggressive chemotherapy relapse rate of T-DLBCL is higher and overall prognosis of T-DLBCL is worse than those of nodal DLBCL, relapses often occur in the central nervous system (CNS), and the prognosis for patients with CNS involvement is dismal [5], [6].

T-DLBCLs represent most commonly non–germinal centre B-cell (non-GCB) subtype [2]. BCL2 positivity is also common, whereas expression of BCL6 and MYC is infrequent [7]. Prognostic role of these three proteins remains to be shown. Molecular studies in T-DLBCL are still based on small series. Nevertheless, as recently elegantly summarised by Twa et al [8], T-DLBCL is likely to represent a biologically distinct lymphoma entity. In addition to the molecular features of the lymphoma cells, elements of the microenvironment have been shown to have prognostic impact [9], [10] and therapeutic potential [11].

T-DLBCL is considered a curable disease with modern treatment comprising anthracycline-based immunochemotherapy, CHOP (cyclophosphamide, Adriamycin, vincristine, prednisolone) with CD20 antibody rituximab (R--CHOP). However, the optimal therapy is unclear. As for many DLBCL subtypes, no randomised trials specifically in T-DLBCL have been conducted, and treatment guidelines are based on phase II trials [12], [13]. In addition to R--CHOP, eligible patients commonly receive CNS prophylaxis with either intravenous (i.v.) or intrathecal (i.t.) methotrexate (MTX) or cytarabine (AraC) [14]. Thus far, however, no prospective randomised studies on the benefit of this approach have been published. In a retrospective series of 373 patients from the prerituximab era, i.t. chemotherapy resulted in improved progression-free survival (PFS) without benefit in overall survival (OS) or disease-specific survival (DSS) rates [3]. Furthermore, the contralateral testis also serves as a sanctuary to lymphoma cells, leading to risk of testicular relapse after immunochemotherapy. Therefore, contralateral orchiectomy or irradiation is recommended for eligible patients [12], [15]. Owing to these recommendations, T-DLBCL is underrepresented in prospective clinical trials not allowing the use of CNS prophylaxis or irradiation, which may be the reason the testes were not recognised as a risk factor for CNS recurrence in the CNS-IPI model [16].

In the Nordic countries, the most applied current therapy for T-DLBCL consists of R--CHOP–/CHOP-like regimen in combination with systemic CNS prophylaxis (high-dose(HD)-MTX or HD-cytarabine) and prophylactic contralateral orchiectomy or irradiation. However, the efficacy of this approach has never been evaluated. In the present Nordic collaborative study looking at population-based cohorts from Denmark and Finland, we investigated the impact of different treatment eras on survival and risk of CNS progression in patients with T-DLBCL.

Section snippets

Patients

We searched for patients with T-DLBCL from the pathology databases of three Southern Finland University Hospitals and the Danish Lymphoma Registry. Only the patients with testicular involvement at primary diagnosis were included, and those with primary CNS lymphoma involvement were excluded. For the Finnish cohort, the clinical data were collected from patient records, and a tissue microarray (TMA) from the diagnostic tumour samples was assembled. The TMA was subjected to standard diagnostic

Baseline and treatment characteristics

Clinical data were available from 235 patients diagnosed with T-DLBCL between 1987 and 2013. The median age at diagnosis was 71 years (range, 37–93 years). Two hundred thirty-three patients (98%) underwent orchiectomy. The disease was limited to the testis in 95 (41%) patients and regarded as primary testicular (PT)–DLBCL (stage I-II) in 146 (63%) patients according to standard staging criteria. In eight patients (11%) of the Finnish cases (N = 75), both testes were affected, which was

Discussion

This is to our knowledge the largest cohort of patients with testicular DLBCL involvement reported so far covering both prerituximab and rituximab eras and characterised by a long-term follow-up and comprehensive clinical data. In our cohort, i.v. CNS-directed chemotherapy and prophylactic treatment of the contralateral testis were associated with favourable survival independently of classical risk factors. In the lack of prospective clinical trials, this type of real-life data may support

Acknowledgement

The authors thank Anne Aarnio and Marika Tuukkanen for technical assistance. This work was supported by grants from the Academy of Finland (to S.L.), Finnish Cancer Foundation (to S.L.), Sigrid Juselius Foundation (to S.L.), University of Helsinki (to S.L. and P.V.), Helsinki University Hospital (to S.L. and S.M) and Finnish Oncology Association (to M.P. and P.V.).

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