Treatment of Stage IIE-IV Aggressive Lymphoma
Medically reviewed by Dr. C.H. Weaver M.D. (08/2018)
Patients classified as having stage IIE–IV disease are considered to have advanced stage Non-Hodgkin lymphoma.
Aggressive lymphomas are classified according to two systems: the Revised European American Lymphoma (REAL) system and the International Working Formulation (IWF). The following types of Non-Hodgkin lymphoma are all considered to be intermediate or aggressive in nature and are treated similarly (see table 1).
Table 1 Intermediate or aggressive NHL, as defined by IWF or REAL
For more than a decade, the conventional treatment for aggressive NHL has been CHOP chemotherapy. Two factors have been shown to improve outcomes over standard CHOP treatment: the addition of the targeted therapy Rituxan® (rituximab) to CHOP, and assuring that the full, planned dose of chemotherapy is delivered on time.
The following is a general overview of treatment for advanced stage, aggressive NHL. Multi-modality treatment, which utilizes two or more treatment techniques, is increasingly recognized as an important approach for improving a patient’s chance of cure or prolonging survival. In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. Circumstances unique to each patient’s situation may influence how these general treatment principles are applied. The potential benefits of multi-modality care, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.
Standard Treatment for Aggressive NHL: Chemotherapy Plus Targeted Therapy
CHOP chemotherapy plus the targeted therapy has recently become the standard treatment for aggressive NHL. Chemotherapy is any treatment involving the use of drugs to kill cancer cells. CHOP is a combination of four chemotherapy drugs: cyclophosphamide, doxorubicin, Oncovin®, and prednisone. Treatment with CHOP chemotherapy alone has been shown to produce remissions in 40-50% of patients with intermediate or high-grade NHL , and approximately 40% of patients are cured. More recently, the addition of the targeted therapy, Rituxan® (rituximab) , to CHOP has been shown to improve survival when compared to treatment with CHOP alone.
Targeted therapy: A targeted therapy is designed to treat only the cancer cells and minimize damage to normal, healthy cells. The addition of targeted therapy to conventional therapy offers the advantage of increasing the amount of treatment delivered to the cancer without increasing treatment-related side effects.
Conventional cancer treatments, such as chemotherapy and radiation therapy, cannot distinguish between cancer cells and healthy cells. Consequently, healthy cells are commonly damaged in the process, as described below:
- Chemotherapy damages rapidly dividing cells, a hallmark trait of cancer cells. Thus, healthy cells that are also rapidly dividing (such as blood cells and the cells lining the mouth and GI tract) are also damaged.
- Radiation therapy kills some healthy cells that are in the path of the radiation or near the cancer being treated. Newer radiation therapy techniques can reduce, but not eliminate this damage.
Treatment-related damage to healthy cells leads to complications of treatment, or side effects. These side effects may be severe, reducing a patient’s quality of life, compromising their ability to receive their full, prescribed treatment, and sometimes, limiting their chance for an optimal outcome from treatment.
Rituxan is a targeted therapy that can locate cancer cells and kill them directly. Because Rituxan is associated with minimal side effects, it can also be administered in combination with chemotherapy to provide patients with the advantage of both treatment approaches. Research indicates that patients treated with Rituxan plus CHOP (R-CHOP) chemotherapy live longer and are cancer-free longer than patients treated with CHOP alone. 
Researchers in Canada have found that patients with aggressive NHL, who were treated after a policy recommending the addition of Rituxan to CHOP was implemented, experienced significantly better outcomes than patients treated before the Rituxan was routinely added to therapy. 
Table 2 Outcomes for patients treated with R-CHOP vs. CHOP
Researchers from France have reported that 58% of elderly patients (age 60-80) treated with R-CHOP survived five years or more compared to 45% of patients treated with conventional CHOP. 
Managing Side Effects of Treatment
The standard treatment for NHL, chemotherapy, not only destroys cancer cells but also normal cells that grow rapidly such as blood cells, cells in the hair follicles, or cells in the mouth and intestines. Damage to blood cells can result in neutropenia, a condition characterized by abnormally low blood levels of infection-fighting white blood cells. Neutropenia increases the risk of contracting bacterial and fungal infections. Managing neutropenia is important because, in some cases, this side effect can be severe enough that chemotherapy treatment may need to be delayed or the dose reduced, which decreases some patients’ chance for cure .
Chemotherapy-induced neutropenia can be prevented in most patients with the administration of blood cell growth factors, which are substances produced by the body to stimulate blood cell production. There are two white blood cell growth factors that have been developed in a laboratory and approved by the Food and Drug Administration for the prevention of chemotherapy-induced neutropenia: Neupogen® (filgrastim) and Neulasta® (pegfilgrastim). Clinical trials have shown that Neulasta and Neupogen reduce the severity and duration of neutropenia associated with chemotherapy for the treatment of NHL. Neulasta is as effective as Neupogen and is administered only once every chemotherapy cycle, whereas Neupogen is administered daily. , 
For more in depth information, go to Neutropenia in the Managing Side Effects section.
Treatment of Elderly Patients
A large percentage of patients with NHL are 65 years or older. Because elderly patients commonly have concurrent illnesses or other medical difficulties that may exacerbate the side effects of chemotherapy, they are often treated with reduced doses of chemotherapy. Clinical studies have shown, however, that elderly patients get the same benefit from chemotherapy treatment as younger patients. While a dose reduction or delay may sometimes be necessary, it may also compromise the optimal treatment of some patients. All patients over 65 should consider measures to prevent side effects (such as neutropenia) in order to receive the full dose of chemotherapy. They should also be closely monitored for toxic side effects, especially after they receive their initial course of chemotherapy treatment.
Rituxan plus CHOP (R-CHOP) may be the optimal treatment for elderly patients with NHL. Research indicates that patients between 60 and 80 years of age who were treated with R-CHOP lived longer and were cancer-free longer than patients treated with CHOP alone. 
Determining Risk of Cancer Recurrence
Doctors can predict whether NHL is likely to recur after conventional treatment based on characteristics of the patient and the disease. Five risk factors have been identified as important predictors of cancer recurrence in NHL (see table 3). 
Table 3 Risk factors that are associated with cancer recurrence (International Prognostic Index)
A diagnosis of T-cell lymphoma is also associated with a greater chance of cancer progression than other types of NHL. 
Patients with more risk factors have a greater risk of cancer recurrence:
Low-risk: 0-1 risk factor
- Low-intermediate risk: 2 risk factors
- High-intermediate risk: 3 risk factors
- High-risk: =4 risk factors
Determining risk of recurrence helps doctors prescribe treatment. Patients with a higher risk of cancer recurrence are more likely to experience disease progression following conventional treatment. Patients with a greater risk of disease progression should make sure they understand their chance of cure with conventional treatment and discuss the risks and benefits of more aggressive or investigational treatments that may be available in clinical trials.
Strategies to Improve Treatment
The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in the treatment of advanced stage, aggressive NHL will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Areas of active investigation aimed at improving the treatment of early stage, aggressive NHL include the following:
- High-dose Chemotherapy with Stem Cell Transplantation
- Improving Chemotherapy
- Adding etoposide to CHOP and shortening the treatment interval
- New Targeted Therapy
High-Dose Chemotherapy with Stem Cell Transplantation
More chemotherapy has been shown to kill more cancer cells in the treatment of patients with NHL. Since conventional doses of chemotherapy appear to cure some patients with NHL, some doctors believe that more intensive regimens that deliver chemotherapy more frequently and/or at higher doses may cure even more patients. However, high-dose chemotherapy kills critical red and white blood cells; therefore, to combat this side effect, high-dose treatment is coupled with the administration of the patient’s own stem cells to grow new blood cells, a procedure called stem cell transplantation.
Timing of high-dose therapy and stem cell transplantation: Typically, stem cell transplantation is utilized in the treatment of patients with NHL only after their cancer has progressed with conventional treatment. However, up-front treatment with high-dose chemotherapy and stem cell transplant rather than conventional CHOP may improve survival in the treatment of some patients with very aggressive NHL. A clinical trial has shown that approximately 75% of patients with intermediate-high-risk disease treated with high-dose chemotherapy and autologous stem cell transplant lived five years or more after treatment compared to 45% of the patients treated with conventional dose CHOP. 
Planning for stem cell transplantation: Approximately 50% of patients treated with R-CHOP ultimately experience a cancer recurrence that may be treated with high-dose chemotherapy and stem cell transplantation. Due to this likelihood, some patients and physicians choose to prepare for this treatment. Planning for a potential stem cell transplant involves collecting stem cells early in the treatment plan and having them stored for future use. Even conventional-dose chemotherapy can damage the bone marrow where stem cells are produced; therefore, it is important the stem cells be collected before the patient undergoes any treatment. Waiting until the cancer recurs to collect stem cells is problematic because the procedure is difficult to perform on short notice. As well, the resulting collection sample may be contaminated with cancer cells.
For in depth information, go to Autologous Stem Cell Transplantation for Non-Hodgkin Lymphoma.
Adding etoposide to CHOP and shortening the treatment interval: Chemotherapy is administered in cycles, which is a period of treatment followed by several days to weeks of rest. Since chemotherapy damages some normal cells in addition to the cancer cells, this rest period allows the normal cells an opportunity to recover. Unfortunately, the cancer cells may also recover during this period. CHOP is typically administered every 21 days. Doctors have evaluated administering chemotherapy more frequently, with a shorter recovery period between treatments, to determine whether this approach may kill more cancer cells and improve outcomes.
Researchers have reported that patients lived longer when treated with chemotherapy administered every 14 days instead of the standard 21 days. Also, adding the drug etoposide to the CHOP regimen (CHOPE) appears to increase complete remissions. In this clinical trial comparing four treatment regimens (CHOP 21, CHOEP21, CHOP14, CHOEP 14), the only treatment that produced inferior results was the conventional CHOP every 21 days (see table). 
Table 4 Rates of survival and complete remission for CHOP21, CHOPE21, CHOP14, and CHOEP14 regimens
EPOCH (etoposide, Oncovin, doxorubicin, cyclophosphamide, prednisone): Treatment with the regimen called EPOCH may produce longer survival in the treatment of advanced NHL than conventionally administered CHOP. Among 50 patients between the ages of 20 and 88 treated with EPOCH, 73% survived approximately five years or more and 70% were free from cancer progression. An important step in this trial was adjustment of the chemotherapy dose at each cycle to maintain neutrophils below a predetermined level. 
New Targeted Therapy
Vaccines: Cancer vaccines are a type of targeted therapy. They are typically made from a patient’s own cancer cells and work by stimulating the body to recognize and attack cancer cells. Cancer cells often display certain small proteins and/or carbohydrates (antigens) on their surface that are not displayed by healthy cells. Vaccines are often comprised of these specific antigens. When the vaccine is injected into the patient, the immune system recognizes the antigens as “foreign” and will attack the cancer cells that display the antigens on their surface. Vaccines are currently being tested in patients with low-grade lymphomas, but progress in this area may be applicable to more aggressive forms of NHL.
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