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Key Words

Non-Hodgkin’s lymphoma, large-B-cell lymphoma, CHOP, rituximab (Rituxan®), monoclonal antibody, targeted therapy. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary ³.)

Summary

Addition of the drug rituximab (Rituxan®, a monoclonal antibody) to a standard chemotherapy regimen for diffuse large-B-cell lymphoma significantly increased survival for patients with good-prognosis disease who were younger than 60.

Source

The Lancet Oncology, published online April 5, 2006; in print May 2006 (see the journal abstract)
(Lancet Oncol. 2006 May;7(5):379-91)

Background

B-cell lymphoma is a cancer of the B cells, a type of white blood cell. As part of the immune system, normal B cells make antibodies and help fight infections. B-cell lymphoma is the most common type of non-Hodgkin's lymphoma.

The chemotherapy regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone, known as CHOP, is currently the standard treatment for B-cell lymphoma. The addition of the drug etoposide to CHOP (CHOEP) improves survival, but is more toxic than CHOP alone and is not generally used in the United States.

Rituximab is a monoclonal antibody that binds to a specific protein (CD20) on the surface of many B cells, thus tagging those cells for destruction by the patient’s own immune system. Targeted therapies such as rituximab tend to be less toxic than other kinds of systemic treatments that affect a variety of normal tissues.

A previous study showed that the addition of rituximab to CHOP increased survival for elderly patients. The trial described here evaluated whether the addition of rituximab to CHOP, CHOEP, and related chemotherapy regimens in younger patients with good-prognosis disease provides a similar benefit.

The Study

Patients were enrolled in this phase III trial if they had untreated diffuse large-B-cell lymphoma that tested positive for CD20 (the rituximab target) and that fell into categories known to pose a low or intermediate risk of recurrence after treatment. The participants ranged in age from 16 to 60 years old.

Researchers with the trial randomly assigned participants to receive either six cycles of CHOP-like chemotherapy plus rituximab or six cycles of CHOP-like chemotherapy alone. Some participants in both groups also received radiation therapy as needed for bulky disease, following their country’s national standards.

The researchers measured the time before patients’ disease progressed (called event-free survival), as well as overall survival and toxicity of the therapy. Patients returned for follow-up every three months for the first two years and then every six months thereafter.

The trial was a cooperative effort of the MabThera International Trial (MInT) Group, with sites in Europe, Latin America, Australia, and Israel. The lead author is Michael Pfreundschuh, M.D. of the University Clinic of Saarland, in Homburg, Germany.

Results

From 2000 to 2003, investigators from 18 countries enrolled 824 patients. In November 2003, at the first planned analysis of the data before the end of the study, the difference in event-free survival between groups was significant enough for the researchers monitoring the trial to recommend that the trial be stopped early and rituximab be offered to all participants.

Five months after starting treatment, 86 percent of those patients receiving rituximab and any CHOP-like chemotherapy regimen had experienced complete remission of their cancer, compared to 68 percent of patients receiving CHOP-like chemotherapy alone.

Around the three-year mark, 79 percent of the rituximab patients were alive and had yet to see their disease progress, compared to 59 percent of the chemotherapy-only patients. Overall survival at three years was also significantly greater in patients receiving both rituximab and any CHOP-like chemotherapy (93 percent versus 84 percent).

Among patients receiving chemotherapy alone, use of the CHOEP regimen resulted in higher three-year event-free survival than use of CHOP. However, CHOEP’s advantage over CHOP disappeared with the addition of rituximab.

Finally, toxic effects were low and were about the same across all the groups, regardless of treatment.

Comments

“This is the result we would have anticipated from what we know about the biology of the disease,” says John Janik, M.D., co-director of the National Cancer Institute’s Clinical Trials Team. Clinicians now know for certain that “…rituximab works well in older patients and works equally well in younger patients.”

The MInT investigators wrote that “to our knowledge, these findings are the best reported for this group of patients to date in a randomised trial….[T]he proportion of young patients who need salvage treatment – usually high-dose chemotherapy with haemopoietic stem-cell transplantation – could be halved with the addition of rituximab.”

Janik also notes that a new chemotherapy regimen called EPOCH (etoposide, vincristine, and doxorubicin with bolus doses of cyclophosphamide and oral prednisone) plus rituximab is now being tested in clinical trials against CHOP plus rituximab. In preliminary studies, the EPOCH regimen “appears to have better impact than CHOP chemotherapy and generally eliminates the requirement for radiation in patients with bulky disease.”

Glossary Terms

A protein made by plasma cells (a type of white blood cell) in response to an antigen (a substance that causes the body to make a specific immune response). Each antibody can bind to only one specific antigen. The purpose of this binding is to help destroy the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen.

A type of protein made in the laboratory that can locate and bind to substances in the body, including tumor cells. There are many kinds of monoclonal antibodies. Each monoclonal antibody is made to find one substance. Monoclonal antibodies are being used to treat some types of cancer and are being studied in the treatment of other types. They can be used alone or to carry drugs, toxins, or radioactive materials directly to a tumor.

A study to compare the results of people taking a new treatment with the results of people taking the standard treatment (for example, which group has better survival rates or fewer side effects). In most cases, studies move into phase III only after a treatment seems to work in phases I and II. Phase III trials may include hundreds of people.

A molecule made up of amino acids that are needed for the body to function properly. Proteins are the basis of body structures such as skin and hair and of substances such as enzymes, cytokines, and antibodies.

A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial.

A monoclonal antibody used to treat certain types of B-cell non-Hodgkin lymphoma and symptoms of rheumatoid arthritis. Monoclonal antibodies are made in the laboratory and can bind to substances in the body, including cancer cells. Rituximab binds to the protein called CD20, which is found on B-cells, and may kill cancer cells. Also called Rituxan.

In medicine, treatment that experts agree is appropriate, accepted, and widely used. Health care providers are obligated to provide patients with standard therapy. Also called best practice and standard of care.

Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. Also called significant.

A method of replacing immature blood-forming cells that were destroyed by cancer treatment. The stem cells are given to the person after treatment to help the bone marrow recover and continue producing healthy blood cells.

A type of treatment that uses drugs or other substances, such as monoclonal antibodies, to identify and attack specific cancer cells. Targeted therapy may have fewer side effects than other types of cancer treatments.

A type of immune cell. Most white blood cells are made in the bone marrow and are found in the blood and lymph tissue. White blood cells help the body fight infections and other diseases. Granulocytes, monocytes, and lymphocytes are white blood cells. Also called leukocyte and WBC.