Therapy of primary central nervous system lymphoma with pre-irradiation methotrexate, cyclophosphamide, doxorubicin, vincristine, and dexamethasone (MCHOD)

Abstract

Prior studies have suggested that pre-irradiation methotrexate (MTX)-based chemotherapy improves duration of response and survival in primary central nervous system lymphoma (PCNSL). To circumvent the potential emergence of drug resistance, we combined high-dose MTX with agents highly active against systemic lymphoma. Patients received three week cycles of CHOD (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 [2 mg maximum] on day 1; dexamethasone 10 mg/m2 days 1-5), and MTX (3.5 gm/m2) with leucovorin rescue on day 8 (or on recovery from the CHOD nadir). Whole brain irradiation (WBRT) was planned after at least three cycles. Eighteen patients were treated. Complete responses were seen in eleven patients, and partial responses in three. Four progressed during therapy, three succumbing to progressive disease and one subsequently responding to WBRT. Response duration was 37.5 months in those responding to therapy. The time to progression for all eighteen patients was 19.5 months. Medial survival was 25.5 months. Disease-free survival was 50% at 38 months in MCHOD responders. Grade 3 or 4 myelotoxicity was seen in 19 of 50 cycles. There were three instances of neutropenic fever, three of azotemia, two of deep vein thrombosis, and one each of community-acquired pneumonia, intracranial hemorrhage, superior vena cava syndrome, and hepatotoxicity. Late radiation-related toxicities were seen in two patients. Pre-irradiation MCHOD has activity against PCNSL, but appears to be no better than MTX monotherapy and has greater toxicity.

Primary CNS Lymphoma in Immunocompetent Patients

“…These disappointing results have led to the use of chemotherapy in combination with WBRT. Since the 1990s, numerous convergent phase II studies have shown that the addition of high-dose methotrexate (MTX)-based chemotherapy to RT results in a substantially longer survival time than with RT alone (median survival time, 2-4 years; 5-year survival rate, 20%-40%) ( Table 1) [52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67]. In contrast, adding standard chemotherapy for systemic lymphoma, such as cyclophosphamide, doxorubicin, vincristine, and prednisone (the CHOP regimen), to RT did not appear to result in longer survival than with RT alone.…”

Complete Response to Temozolomide Treatment in an Elderly Patient With Recurrent Primary Central Nervous System Lymphoma-Case Report-

“…About half of immunocompetent patients with primary CNS lymphoma who achieve complete recovery after primary treatment suffer relapse, and the disease is refractory in 10-15%. 7,9) The prognosis for both recurrent and progressive primary CNS lymphoma is poor and most patients die within 2-4 months of neurological deterioration. 7,21) The present patient underwent further chemotherapy with rituximab and temozolomide.…”

Treatment approaches for primary CNS lymphomas

“…The addition of CHOP or other anthracycline-containing regimens to HD-MTX produces results similar to those of HD-MTX alone, with a CR ranging from 60 to 67% and a median OS of 20 --25 months. Meanwhile, an increased toxicity is reported with these regimens [17,18].…”

“…Even if only a minority of relapsed patients are routinely assessed for meningeal recurrence, the majority of meningeal relapses seems to occur in patients with positive CSF cytology at diagnosis [8,18,29]. This has led some authorities to suggest that, to minimize toxicity, intrathecal chemotherapy should be reserved for patients with positive CSF cytology [29,52].…”

“…CSF and meningeal relapses have not been reported in series treated with intrathecal chemotherapy, whereas they constituted 11% of all relapses in one of the series treated without this strategy [2]. Conversely, some prospective [18,29,55] and retrospective [8,56] studies suggest that intrathecal chemotherapy does not improve outcome in patients who receive HD-MTX-based chemotherapy. Moreover, preliminary data suggest that systemic HD-MTX is associated with eradication of neoplastic cells from CSF [28,57], which deserves to be confirmed in future trials.…”