The optimal chemotherapy regimen for primary mediastinal B-cell lymphoma: we may never know

Abstract

Rituximab plus dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin administered over 96 hours by intravenous infusion (DA-REPOCH) is an effective therapy for primary mediastinal B-cell lymphoma (PMBL), and it is unlikely that any other chemotherapy regimen will be proven to be better. In multiple series, roughly 90% of PMBL patients were cured by DA-R-EPOCH without the need for mediastinal radiation [1–3]. But R-EPOCH has its drawbacks. It’s a drag for patients, who either must be admitted or need to return to the clinic daily for 5 days. Neutropenic fever is about two times more likely than with rituximab plus single-day dosing of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), and peripheral neuropathy is common [4]. Etoposide comes with a risk of secondary myeloid cancers, and the total dose of doxorubicin received can significantly exceed the dose administered with other regimens, a potential concern in younger patients who may experience increased cardiovascular morbidity decades later. Additionally, DA-R-EPOCH requires a central line, which is frequently associated with venous thrombosis in patients with bulky mediastinal tumors; almost 30% of patients with PMBL treated with DA-R-EPOCH experienced a thrombotic complication in one recent series [2]. R-CHOP is also effective in PMBL, with cure rates in the 85–90% range in retrospective series [3] and in the 80% range in a subgroup analysis of a prospective UK NCRI phase III trial [5]. The bulk of data supporting its use comes from centers that commonly used consolidative mediastinal radiation. Over the past couple decades, rightly or wrongly but probably rightly, there has been a push to eliminate radiation from all sorts of lymphoma therapies, and there is a strong case to be made in PMBL: Who would advocate radiation of the heart, breasts, and lungs of an otherwise healthy 30-year-old woman? What a dilemma! Do we choose the toxic, laborious DA-R-EPOCH regimen or the more palatable R-CHOP followed by the demon radiation? But what if we don’t have to choose between two undesirable options? In this edition of Leukemia & Lymphoma, Mesmer et al. [6] describe the outcomes of a retrospective cohort of patients with PMBL treated with R-CHOP and no radiation who had a 93% freedom from progression or death at three years. Indeed, multiple other cohorts had subsets of patients that also did not receive radiation following R-CHOP [3]. Even in the prospective UK R-CHOP trial, 42% of PMBL did not undergo radiation raising the question of whether there really is a dilemma after all. Maybe the real question is not “Which chemotherapy regimen is best?”, but rather “Which patients really need radiation?” Fortunately, this question may be clarified by the ongoing IELSG-37 trial (NCT01599559), although we may be waiting several years to get that answer. Future prospective trials (at least one is in development through the US cooperative group network) are more likely to address the addition of novel agents, such as immune checkpoint inhibitors, to standard chemotherapy regimens rather than the regimens themselves. So, which regimen do we choose in the meantime? I don’t know the answer; I don’t think anyone knows. Lately, I have been thinking about it this way. Every morning I finely grind 15 g of medium-roasted Nicaraguan coffee beans and put them in my upright Aeropress coffee maker. Then I pour in 200mL of water heated to 88 C, stir for a couple seconds, insert the plunger to make a seal, wait for 90 seconds, and then press down on the plunger to filter the coffee, to which I add another small amount of hot water. I like my coffee. When I try other coffees, usually served in a paper cup with a plastic lid, I am occasionally impressed, and I sort of wonder which coffee I prefer: