Dr. Grossbard pointed out that, in Europe, rituximab(Drug information on rituximab) (Rituxan) has been tested in large numbers of patients with aggressive non-Hodgkins lymphoma, patients who would ordinarily have been treated with chemotherapy, and some who relapsed after chemotherapyand there was marked shrinkage of their tumors.
Though the results do not make rituximab an established therapy in aggressive disease, Dr. Grossbard said, it gives us a very good clue to its activity in that class of disease. There are now a number of ongoing clinical trials of rituximab for the treatment of aggressive lymphomas in the United States, he said.
Though antibodies are targeted they are not without side effects, he added; they can cause fever, chills, and occasionally serious allergic reactions, but generally are well tolerated even in patients who have had extensive prior treatment of their lymphoma.
Antibodies that carry chemotherapy or radiation directly to the tumor cells are also being tested. Bexxariodine I-131 tositumomabis a radioactive iodine(Drug information on iodine) conjugate of the same type of antibody used in rituximab and also targets B-lymphoma cells. Trials using Bexxar, which had mostly been tested in patients with low-grade lymphoma, are now being expanded to include patients with aggressive lymphomas. Results so far are good and show relatively long lasting responses, Dr. Grossbard said.
These antibodies have the advantage of not only targeting the tumor cell to which they bind, but also irradiating the cells surrounding the tumor cell. However, people with extensive marrow disease are not good candidates for this treatment and may have significant toxicity with this agent, Dr. Grossbard pointed out.
LYM1 (Oncolym) is another antibody conjugate and is attached to iodine. It is being widely tested in patients with aggressive non-Hodgkins lymphoma. Significant numbers of patients have shown good responses, he said.
So in terms of the antibody area, we really are beginning to see a lot of these therapies taken out of the laboratory and brought to fruition, Dr. Grossbard said. Were beginning to see very good activity in patients. What were still learning is how to properly dose these drugs, how to sequence them with chemotherapy, and how to give them at the best timeshould they be given early in the course of disease or later?
The study of potential lymphoma vaccines has been more limited, he said. They have been studied mostly in patients with low-grade lymphomas and used to immunize patients who have already achieved remission after therapy. A portion of the tumor is taken out and prepared ahead of time to make the vaccine.
There have been intriguing responses that suggest that tumor recurrences can be delayed in some patients with adequate use of these vaccines, Dr. Grossbard said, but this is still highly investigational. We dont know how beneficial this will be down the road, but it gets us pointing away from the usual standard doses of chemotherapy and more toward harnessing the immune system to treat these cancers. I think in the next several years we will learn how to use these treatments optimally, how to sequence them for our patients, how to get better and more lasting responses&ldots;
Dr. Chabner took up the question of chemotherapy. The most important innovation there, he said, has been the use of etoposide(Drug information on etoposide), which can either be added to the standard combination, CHOP (cyclophosphamide, doxorubicin(Drug information on doxorubicin) HCl, Oncovin, and prednisone(Drug information on prednisone)), or used in an infusional regimen.
The reason for the infusional regimen is that theres some evidence that by prolonging drug exposure one can overcome drug resistance. There have been some very interesting trials done at the National Cancer Institute showing that, in patients who relapse after remission with CHOP, infusional chemotherapy can produce a reasonably high rate of responses and some long-term survivors, said Dr. Chabner. New agents such as topotecan(Drug information on topotecan) (Hycamtin) are also being used in conjunction with bone marrow transplantation, he said.
Bone marrow transplantation much earlier in the disease course is also being studied, he said, and is being used as up-front treatment in patients with intermediate and high-grade lymphomas who have bad prognostic factors when they present with their disease, Dr. Chabner said. It is being compared to conventional CHOP chemotherapy to see if the cure rate might be higher using transplantation with high-dose chemotherapy from the start.
One of the more interesting new observations in regard to the use of antibodies for lymphoma is that, when used with chemotherapy, the antibodies enhance the response to chemotherapy. Theres a lot of precedent for this from other studies, such as in breast cancer using the antibody Herceptin with chemotherapy, Dr. Chabner said. There is the potential to do the same with lymphoma patients. The logical next step is to combine rituximab with chemotherapy, and in fact several protocols are now testing this approach. Weve participated in one such study here at Masachusetts General Hospital and there was a very high up front response rate to the combination. However, the study is still ongoing and preliminary, so were not sure if its really better than CHOP alone. The regimen needs to be confirmed in a larger trial, he added.
Currently, we are conducting a trial of rituximab with infusional chemotherapy, a regimen that has been piloted at the National Cancer Institute and has shown good activity in relapsed patients, Dr. Chabner said. So there is some hope that the combination of rituximab with chemotherapy will be advantageous.