High-dose chemotherapy should be considered an integral component of the overall treatment strategy of all intermediate grade/aggressive non-Hodgkin's lymphomas in patients up to the age of 70. Consideration of its role in the treatment of a specific patient should be planned at initial diagnosis because high-dose chemotherapy cures more patients than conventional-dose chemotherapy in many situations.
All intermediate grade/aggressive lymphomas classified according the IWF or REAL system are listed below. The information presented in this section is applicable to all lymphomas in the table.
|International Working Formulation|
|Intermediate Grade:||Diffuse Large Cell|
|Follicular Large Cell|
|Diffuse Small Cleaved Cell|
|Diffuse Mixed Small and Large Cell|
|Revised European American Lymphoma Classification:|
|Diffuse Large B-Cell||Peripheral T-Cell|
|Anaplastic Large Cell||Follicle Center Lymphoma (grade 3)|
High-dose chemotherapy and autologous stem cell transplantation has been demonstrated to improve a patient's chance of cure when incorporated into the initial treatment or delivered to patients in complete remission after standard chemotherapy.
An Italian clinical study published in the New England Journal of Medicine performed a direct comparison of a high-dose chemotherapy treatment strategy to a standard conventional chemotherapy strategy. The comparison was made in patients with aggressive non-Hodgkin's lymphoma who had disease characteristics suggesting a high chance of their disease recurring following conventional treatment. There was no significant difference in the fatality associated with either treatment. Eighty-four percent of the patients receiving the high-dose chemotherapy and autologous stem cell transplant had no evidence of their disease progressing and 76% were alive with no evidence of disease, compared to only 49% of patients receiving the conventional chemotherapy. This trial demonstrates that certain high-risk patients are more likely to be cured of their non-Hodgkin's lymphoma if they receive high-dose chemotherapy as part of their initial treatment strategy.
Patients with aggressive non-Hodgkin’s lymphoma whose disease is in complete remission after initial chemotherapy treatment have been evaluated in clinical trials to determine whether additional treatment with high-dose chemotherapy and autologous stem cell transplantation or conventional chemotherapy treatment can improve the chance of cure.
In a large clinical trial, equal numbers of patients with non-Hodgkin's lymphoma in complete remission were treated with additional conventional chemotherapy or high-dose chemotherapy and autologous stem cell transplantation. Both treatments were well tolerated and no patient treated with either approach experienced fatal complications of treatment. An evaluation performed at 5 years from initial treatment in patients at high risk of relapse revealed that 59% of patients receiving high-dose chemotherapy and autologous stem cell transplantation were alive with no evidence of disease recurrence compared to only 39% of patients receiving conventional chemotherapy.
These clinical trials demonstrate that certain high-risk patients with non-Hodgkin's lymphoma are more likely to be cured if they receive high-dose chemotherapy as part of their initial treatment strategy. Patients at low risk of relapse however may not benefit from transplantation as initial therapy.
Patients who fail to achieve an initial complete remission or disappearance of their cancer following their first complete course of chemotherapy treatment are referred to as "induction failures". This is a broad group since it includes patients whose cancer actually grew or progressed during chemotherapy and those with an almost complete disappearance of cancer. Historically, all of these patients were treated with additional chemotherapy using drugs to which the patient had not been previously exposed and/or radiation therapy. Treatment of induction failures with several cycles of "salvage" chemotherapy can induce a remission of cancer and 25-50% survive without an additional cancer relapse.
In the 1980's, many clinical centers around the world began routinely utilizing high-dose chemotherapy and autologous stem cell transplantation as initial treatment of induction failures. High-dose chemotherapy and autologous stem cell transplantation appeared to cure up to 75% of these patients, which was a marked improvement over traditional conventional chemotherapies. High-dose chemotherapy has become the standard initial treatment for the majority of patients with lymphoma failing to achieve an initial remission.
Because of promising results from clinical trials, high-dose chemotherapy and autologous stem cell transplantation is now considered the standard of care for patients who fail initial treatment of their non-Hodgkin’s lymphoma because it cures five times as many patients.
Historically, patients with relapsed non-Hodgkin's lymphoma were treated with additional chemotherapy using drugs to which the patient had not been previously exposed and/or radiation therapy. Treatment of relapsed patients with several cycles of "salvage" chemotherapy is associated with a 1-5% risk of dying from treatment and produces a complete disappearance or remission of cancer in 30%-40% of patients. As many as 10-20% of patients with relapsed non-Hodgkin’s lymphoma appear cured with conventional-dose salvage chemotherapy.
In the 1980's, many clinical centers around the world began routinely utilizing high-dose chemotherapy and autologous stem cell transplantation as initial treatment for patients with relapsed non-Hodgkin's lymphoma. High-dose chemotherapy and autologous stem cell transplantation appeared to cure 40-50% of patients, which was a marked improvement over traditional salvage chemotherapy, which cured only 0-20% of patients.
In order to confirm that high-dose chemotherapy was superior to conventional-dose salvage chemotherapy, a clinical trial was designed that randomly treated equal numbers of patients under the age of 60 with intermediate or high-grade non-Hodgkin’s lymphomas that were still responsive to chemotherapy. Almost 50% of patients treated with high-dose chemotherapy and autologous stem cell transplantation survived without recurrence of lymphoma, compared to only 10% of patients treated with lower or conventional-dose chemotherapy. This direct comparison of high-dose chemotherapy and autologous stem cell transplantation to conventional-dose chemotherapy unequivocally demonstrated that high-dose chemotherapy and autologous stem cell transplantation is the standard of care for patients who fail initial treatment of their non-Hodgkin’s lymphoma because it cures 5 times as many patients.
Not all patients have access to high-dose chemotherapy and autologous stem cell transplantation. Patients with sensitive disease who are unable to receive high-dose chemotherapy and autologous stem cell transplantation have approximately a 10% chance of cure with conventional or low-dose chemotherapy strategies.
It is useful to think of high-dose chemotherapy as a sequence of events. Improving the cure rates associated with high-dose chemotherapy may result from intervening in one or more points in this sequence. The typical sequence of delivering high-dose chemotherapy starts with reinduction conventional-dose chemotherapy followed by collection of stem cells. The next step is treatment with the high-dose chemotherapy regimen, followed by infusion of the previously collected stem cells and then the post-transplant recovery period.
Progress in the treatment of lymphoma with high-dose chemotherapy and autologous stem cell transplantation will result from continued participation in appropriate clinical trials. Currently, there are several areas of active exploration aimed at improving high-dose chemotherapy treatment of lymphoma.
Pre-High-Dose Chemotherapy Cytoreduction: Current chemotherapy reinduction regimens utilizing conventional doses are used to reduce the amount of cancer prior to high-dose chemotherapy and induce complete remissions in a minority of patients. Most patients are not in complete remission at the time of high-dose chemotherapy and autologous stem cell transplantation. Intensive pre-transplant treatment with reinduction chemotherapy, however, also increases the toxicity of delivering high-dose chemotherapy and reduces the number of stem cells that can be collected to support high-dose chemotherapy. Clinical trials are ongoing to evaluate whether increased pre-transplant treatment can improve outcomes or whether it merely increases the toxicity of high-dose chemotherapy treatment. Patients treated with reinduction may also want to have their stem cells harvested before starting treatment since up to 25% will be unable to have stem cells collected after reinduction.
Cell Processing: When stem cells are collected from a patient for infusion after high-dose chemotherapy, cancer cells may be present in the stem cell collection. Although the majority of cancer relapses after high-dose chemotherapy and autologous stem cell transplantation occur because the high-dose chemotherapy did not kill all of the cancer cells, it is possible that some patients may also relapse from infusion of the cancer cells "contaminating" the collected stem cells. Many techniques are being evaluated that effectively remove cancer cells from the stem cell collection. It is currently unknown whether enough cancer cells can be removed to decrease relapse rates. To learn more about techniques for removing cancer cells from the stem cell collection, select Autologous Stem Cell Collection and Processing.
Increased Dose Intensity of the High-Dose Chemotherapy Regimen: Since more treatment kills more cancer cells, increasing the intensity of treatment delivered can be accomplished by utilizing high doses of anti-cancer therapies or by delivering more than 1 cycle of high-dose treatment supported by stem cells. While increasing the intensity of treatment may kill more cancer cells, this approach may also damage normal cells and increase the toxicity or side effects.
Monoclonal Antibodies: Another approach is to deliver additional treatment directed specifically to the lymphoma cells and avoid harming the normal cells. Monoclonal antibodies are a treatment that can locate cancer cells and kill them directly or stimulate the immune system to attack them. Rituxan® is the first monoclonal antibody approved for the treatment of B-cell lymphomas. It can be administered during or after high-dose chemotherapy and is being evaluated to determine whether the combination can improve cure rates. Monoclonal antibodies can also be linked to other anti-cancer toxins or radiation to deliver additional anti-cancer treatment. These strategies are being tested in patients with lymphoma.
Minimal Residual Disease: More patients achieve a complete remission following treatment with high-dose chemotherapy than treatment with conventional doses. Unfortunately, many patients who achieve a remission still experience a relapse of their cancer. This is because not all of the cancer cells were destroyed by treatment and may not have been detected. Doctors refer to this as a state of "minimal residual disease". Many doctors believe that applying additional cancer treatments during the post-transplant recovery period when only a few cancer cells remain represents the best opportunity to prevent the cancer from returning.
Maintenance Chemotherapy: The administration of relatively low doses of chemotherapeutic drugs after an autologous transplant could delay time to cancer progression or prevent relapses. New drugs are constantly being evaluated in the conventional treatment of patients with lymphoma and could be used after high-dose chemotherapy with autologous stem cell support.
Vaccines: Vaccines are being actively investigated, but this therapy currently is limited by the fact that a unique vaccine has to be developed for each specific patient.
Biological Modifier Therapy: Biologic response modifiers are naturally occurring or synthesized substances that direct, facilitate or enhance the body's normal immune defenses. Biologic response modifiers include interferons, interleukins and monoclonal antibodies. In an attempt to improve survival rates, these and other agents are being evaluated in the post-transplant period.
Early Aggressive Treatment: Early use of high-dose chemotherapy treatment for patients at high risk of treatment failure is an important strategy to improve cure of patients with lymphoma. Patients treated with high-dose chemotherapy and autologous stem cell transplantation as part of initial therapy have fewer side effects compared to patients who receive high-dose chemotherapy as a "treatment of last resort". Significant toxicity of high-dose chemotherapy is no greater than conventional chemotherapy when used early.