High-Dose Methotrexate In The Treatment Of Primary Testicular Lymphoma
Authors: Reinius Marika , Ahmad Saif S , Crawley Charles , Williams Michael V , Wimperis Jennie , Follows George A 
Published: October 2019

Abstract

Background
Primary testicular lymphoma (PTL) presents in most cases, histologically, as a diffuse large B-cell lymphoma. PTL has a propensity for metastases to the central nervous system (CNS) cited as 20% at 5 years. Bilateral testicular involvement is seen in 35% of cases. Treatment commonly consists of orchidectomy followed by Rituximab- cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP), intrathecal methotrexate (IT-MTX) and prophylactic radiotherapy to the contralateral testis. Administration of systemic high-dose MTX (HD-MTX), at 3 g/m2, has been proposed as an approach to improve CNS parenchymal penetration and may prevent the need for scrotal irradiation. From 2005 within the Anglia Cancer Network, HD-MTX was incorporated into standard treatment for patients with PTL, who were fit enough to receive high dose therapy. Here we report outcomes from the 2 largest lymphoma centres within the network.

Method
A retrospective review was carried out using medical records of patients with PTL treated with HD-MTX at Cambridge University Hospitals (CUH) and Norfolk and Norwich University Hospital (NNUH), UK, from 2005 onwards. Histological diagnoses were made via orchidectomy or testicular biopsy. Factors reviewed included: age, stage, ECOG performance status, presence of B symptoms and IPI score at diagnosis, treatment regimen, grade 3/4 toxicity and clinical outcome. Stage IV disease was excluded as it cannot be distinguished from a non-testicular primary.

Results
10 patients were identified who met the search criteria. 6 were treated at CUH and 4 at NNUH. Median age at diagnosis was 61.5 (49-71). All patients presented with scrotal swelling and 30% had bilateral tumours. ECOG PS was 0 (90%) and 1 (10%). 80% had stage IE disease and 20% stage IIE (paraaortic). Median IPI was 1.
Patients were planned to receive 6 cycles of R-CHOP21 with 3-6 cycles IT-MTX with 3 cycles HD-MTX (3 g/m2) administered between or after R-CHOP21. Patients at NNUH only also received radiotherapy at 30 Gy in 15 fractions to the contralateral testis +/- PA nodes if stage IIE disease. One NNUH patient did not receive IT-MTX and one CUH patient only received 2 cycles HD-MTX for logistical reasons. No grade 3 or 4 toxicities were noted.
At time of submission with a median follow-up of 4.27 years, only 1 patient has relapsed within the bone marrow. He died of systemic disease but was not shown to have CNS relapse. One patient died of a non-PTL related cause. 8 patients remain in ongoing first remission. No cases of CNS or testicular relapse have been noted in our 10 patients including the 6 patients who did not receive scrotal irradiation.
One patient at CUH with bilateral disease was diagnosed on biopsies alone. He underwent unilateral orchidectomy after completing systemic treatment demonstrating a complete response, despite no radiotherapy. He declined a second orchidectomy and remains relapse free at 5.91 years follow-up.

Conclusion
Treating PTL with HD-MTX, IT-MTX and R-CHOP has shown encouraging clinical outcomes in terms of treatment tolerability and disease-free survival at a median follow-up of 4.27 years. Accepting the small numbers, the absence of CNS relapse with this follow-up suggests prophylactic efficacy of HD-MTX. The finding that disease was eliminated in an in situ testis following treatment is also significant, given the standard practice of contralateral testicular irradiation. These results highlight the need for further prospective research to determine the role of HD-MTX in the management of PTL.

Disclosures:
No relevant conflicts of interest to declare.