R-EPOCH Therapy for Lymphoma

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R-EPOCH, also referred to as EPOCH-R, is a combination chemotherapy regimen used to treat certain malignancies, especially certain types of aggressive non-Hodgkin lymphoma.

The drug regimen consists of the following agents:

  • R = Rituximab
  • E = Etoposide phosphate
  • P = Prednisone
  • O = Vincristine sulfate (Oncovin)
  • C = Cyclophosphamide
  • H = Doxorubicin hydrochloride (Hydroxydaunorubicin)

R-EPOCH vs. R-CHOP

If you are already familiar with the acronym R-CHOP, a regimen commonly used for non-Hodgkin lymphoma, then you can think of R-EPOCH as a “scrambled” version of R-CHOP with a few important differences.

R-EPOCH differs from R-CHOP not only in the addition of etoposide, but also in the scheduled delivery of the chemotherapy agents and their doses to the body.

In R-EPOCH, the chemotherapies are infused at variable concentrations over a longer period of time—four days. This is in contrast to traditional R-CHOP, whereby for each cycle, the CHOP is delivered all at once, in a so-called bolus-type administration.

What Is DA-R-EPOCH?

DA-R-EPOCH, also referred to as DA-EPOCH-R, describes a regimen with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (and rituximab). In this variant of the regimen, doses of the chemotherapies are adjusted to try to maximize efficacy.

The DA-EPOCH regimen was developed at the National Cancer Institute (NCI) based on the hypothesis that optimization of drug selection, drug schedule, and drug exposure of the cancer cells would produce better outcomes than the CHOP regimen in patients with aggressive non-Hodgkin lymphoma.

A 96-hour continuous infusion regimen was developed, whereby DA-EPOCH is administered every 21 days. Dose adjustments to doxorubicin, etoposide, and cyclophosphamide are made based on the lowest count (absolute neutrophil count nadir) in the previous cycle.

Research on R-EPOCH for DLBCL Subsets

Lymphomas are generally grouped into two main categories: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell NHL, representing 30 to 35 percent of cases and affecting patients of all ages.

The World Health Organization (WHO) classifies DLBCL into four major categories. The largest category—DLBCL not otherwise specified—can be further subdivided into three subtypes based on the cell of origin, including germinal center B-cell–like (GCB), activated B-cell (ABC), and primary mediastinal B-cell lymphoma (PMBL).

In other words, when looking at the molecular level, DLBCL is a diverse group of lymphomas and different types of DLBCL may have different prognoses with treatment. In addition, a related type of aggressive lymphoma is called "double hit" lymphoma. DHL has specific genetic abnormalities that may affect outcomes. The use of all of this information about DLBCL can potentially alter treatment, but this is currently somewhat of an unsettled area and the topic of ongoing research.

At one time, there was hope that results with dose adjusted R-EPOCH would be superior to R-CHOP generally for patients with DLBCL. While this still may be true in selected subsets, it seems not to be the case generally, at least based on existing evidence.

A study of 524 participants compared the efficacy of R-CHOP and DA-R-EPOCH regimens in treating DLBCL patients, specifically in GCB and ABC subtypes. Participants were assigned to receive either R-CHOP or DA-EPOCH-R, and at a median follow up of about five years, survival outcomes were similar between the groups. DA-EPOCH showed increased toxicity, but this was expected based on the higher dose intensity.

Still, researchers were quick to point out that more analyses are required to determine the effect of various regimens on specific subsets of patients with DLBCL.

DLBCL With High Ki-67 Expression

Ki-67 is a marker that has been used in various cancers as a proliferation index—that is, a marker of cell growth in regard to cell division. Tumors with high proliferation are expected to have high expression of Ki-67.

The EPOCH regimen was developed in part based on the concept that the extension of drug exposure may yield better antitumor efficacy than a bolus regimen, such as CHOP.

In a previous study, it was determined that DLBCL patients with high Ki-67 expression received limited survival benefits from R-CHOP therapy. Hence, the study by Huang and colleagues aimed to investigate whether R-EPOCH is superior to R-CHOP in untreated DLBCL patients with high Ki-67 expression.

Huang and colleagues administered R-EPOCH as a first-line regimen in DLBCL patients with high Ki-67 expression and compared the treatment efficacy of R-EPOCH and R-CHOP therapy in this subgroup using matched-pair controls. Their results suggested that patients treated with the R-EPOCH regimen exhibited better survival than those administered the R-CHOP regimen, and they called for further prospective studies to confirm the findings and to identify possible prognostic biomarkers for use in association with R-EPOCH therapy.

Double Hit Lymphoma

Double hit lymphomas, or DHLs, account for five to 10 percent of DLBCL cases, and the majority can be profiled as the germinal center type and express the genes BCL-2 (BCL-2+/MYC+). A small subset of DHLs express BCL-6 (BCL-6+/MYC+) or express both BCL-2 and BCL-6 and are called triple-hit lymphomas (BCL-2+/BCL-6+/MYC+).

Patients with DHLs often have poor prognostic features, high IPI score, and involvement of the bone marrow or the central nervous system. The optimal regimen for DHLs is not known; however, patients who received R-CHOP–like regimens have a poor prognosis, with a median overall survival of fewer than 12 months.

In a retrospective review, the overall progression-free survival improved with more intensive regimens, including DA-EPOCH-R, compared with R-CHOP. The DA-EPOCH-R regimen resulted in significantly higher rates of complete remission than the other intensive regimens.

Primary Mediastinal Lymphoma (PMBL)

PMBL is another subtype of DLBCL that represents 10 percent of DLBCL cases. It is clinically and biologically related to nodular sclerosing Hodgkin lymphoma, which also arises from thymic B-cells.

PMBL is aggressive and develops into a mediastinal mass. Most patients have mutations in the BCL-6 gene. Standard immunochemotherapy is not effective, and most patients require mediastinal radiation, which may lead to late adverse effects. This is a relatively rare lymphoma with not a lot of clinical study data; however, data looking back at past cases (retrospective studies) suggest that more intensive chemotherapy regimens appear to be more effective than R-CHOP.

In a retrospective analysis, the failure rate for R-CHOP was 21 percent, suggesting the need for treatment alternatives.

DA-EPOCH-R uses infusion strategies in which doses of the drugs etoposide, doxorubicin, and cyclophosphamide are adjusted for greatest efficacy. Results of a single arm trial with DA-EPOCH-R, conducted by researchers at the NCI, which followed 51 patients for a period of up to 14 years, were published in the April 11, 2013, issue of the New England Journal of Medicine.

Fifty-one patients with untreated primary mediastinal B-cell lymphoma were included in this study. All but two patients achieved a complete remission with DA-EPOCH-R therapy, and none of the patients with a complete remission have developed a recurrent lymphoma. The two patients who did not achieve a complete remission received radiation and have also not had their tumors recur. There was no evidence of other diseases developing later on or cardiac toxic effects.

A multi-institutional analysis of adults with PMBL compared overall survival in patients treated with these regimens (132 patients identified from 11 contributing centers; 56 R-CHOP and 76 DA-R-EPOCH). While complete remission rates were higher with DA-R-EPOCH (84 percent vs. 70 percent), these patients were more likely to experience treatment-related toxicities. At two years, 89 percent of R-CHOP patients and 91 percent of DA-R-EPOCH patients were alive.

R-EPOCH for Burkitt Lymphoma in Patients With/Without HIV

Burkitt lymphoma is more common in equatorial Africa than in Western countries. Burkitt is a disease that occurs frequently in immune-suppressed AIDS patients. Cure rates for Burkitt lymphoma in Western countries approach 90 percent in children, whereas only 30 percent to 50 percent of children in Africa are cured due to an inability to safely administer high-dose treatment.

A trial was conducted by Wilson and colleagues at the National Cancer Institute (NCI) and appeared in the New England Journal of Medicine. The trial involved two variants of EPOCH-R, involving longer exposures to lower concentrations of drugs instead of briefer exposures to higher concentrations of drugs.

Thirty patients with previously untreated Burkitt lymphoma were included in the trial. The patients received one of the two EPOCH-R variants, depending on their HIV status. Nineteen HIV-negative patients received dose-adjusted (DA)-EPOCH-R, whereas 11 HIV-positive patients received SC-EPOCH-RR, which is a short-course (SC) variant of EPOCH-R that includes two doses of rituximab per treatment cycle and has a lower treatment intensity than DA-EPOCH-R.

Adjustment of dose levels is done to try to provide the optimum amount of drug based on a person’s tolerance of chemotherapy. The main toxicities seen in the trial were fever and neutropenia (low white blood cell counts); no treatment-related deaths occurred. With median follow-up times of 86 and 73 months, the overall survival rates were 100 percent and 90 percent, respectively, with DA-EPOCH-R and SC-EPOCH-RR.

Based on these results, trials to confirm the efficacy of EPOCH-R therapy in adult and pediatric Burkitt lymphoma patients were initiated.

A Word From Verywell 

The dose-adjusted-EPOCH regimen was developed at the National Cancer Institute, based on the hypothesis that optimizing drug selection, delivery and exposure incurred by cancer cells would produce better outcomes than the CHOP regimen in patients with aggressive non-Hodgkin lymphoma.

While there was initial hope that R-EPOCH would achieve better outcomes than R-CHOP generally in patients with DLBCL, the focus now is on the possibility that this regimen might improve outcomes for various select subsets of patients with DLBCL and other malignancies. If you fall into these subsets, discuss the option with your doctor.

 

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Article Sources
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  • Dunleavy K, Pittaluga S, Shovlin M, et al. Low-intensity therapy in adult Burkitt lymphoma. N Engl J Med. 2013 ;369(20):1915-25.
  • Wilson H.W. et al. Phase III randomized study of R-CHOP versus DA-EPOCH-R and molecular analysis of untreated Diffuse Large B-Cell Lymphoma: CALGB/ Alliance 50303. 2016 December 4; Oral Abstract #469: ASH 58th Annual Meeting and Exposition, San Diego, CA.