Patients classified as having stage I, IE, or IIA non-Hodgkin’s lymphoma (NHL) are considered to have localized disease. More than half of these patients can be cured with initial treatment.
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’s lymphoma are all considered to be intermediate or aggressive in nature and are treated similarly (see table 1).
Table 1 Types of intermediate or aggressive NHL, as defined by two classification systems
|REAL Classes of Aggressive NHL||IWF Classes of Aggressive NHL|
|Diffuse large B-cell||Intermediate grade|
|Anaplastic large cell||Diffuse large cell|
|Peripheral T-cell||Follicular large cell|
|Follicular center lymphoma||Diffuse small cleaved cell|
|Diffuse mixed small and large cell|
Patients have a greater risk of disease progression if their disease is:
- Stage II localized with bulky disease—cancer greater than 10 centimeters (about 4 inches) in diameter
- Extra-nodal “E” type disease
To learn more about managing NHL that displays these characteristics, go to Stage IIE–IV Non-Hodgkin’s Lymphoma.
The following is a general overview of treatment for stage I-II, aggressive NHL. Treatment may consist of chemotherapy with or without targeted therapy or radiation therapy. 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.
Determining a Patient’s 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 factors have been identified as important predictors of cancer recurrence in all grades of NHL (see table 2). 
Table 2 Risk factors that are associated with cancer recurrence
> 65 years
|Stage of disease||
III or IV
|Disease outside of lymph nodes||
|Performance status (a measure used by doctors to assess how the cancer affects the daily living abilities of the patient)||
|Level of serum lactate dehydrogenase (LDH)||
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 factor
- High-intermediate risk: 3 risk factor
- 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.
Treatment of Localized NHL
Chemotherapy is the standard treatment for NHL. Chemotherapy is any treatment involving the use of drugs to kill cancer cells. The combination of chemotherapy that is usually administered for initial treatment is called CHOP and includes four drugs: cyclophosphamide, doxorubicin, Oncovin®, and prednisone.
Approximately more than half of patients treated with CHOP experience a remission of their cancer and over half are cured. The addition of the targeted therapy Rituxan® (rituximab) or radiation therapy to CHOP chemotherapy further increases the chance of cure.
Chemotherapy plus radiation therapy: Two clinical trials have demonstrated that approximately 85-88% of patients treated with CHOP plus radiation live five years or more after treatment without evidence of cancer recurrence. , 
A targeted therapy is one that is designed to treat only cancer cells and minimize damage to normal, healthy cells. The addition of targeted therapy to conventional therapy may offer the advantages of increasing the intensity of treatment delivered to the cancer and improving outcomes 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.
Advances in science and technology have led to the development of several types of targeted therapies. Each of these new treatments targets cancer through different mechanisms:
Rituxan® (rituximab): 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 take maximal advantage of both treatment approaches. The combination of CHOP chemotherapy plus Rituxan has been shown to cure more patients than CHOP alone in the treatment of advanced stages of NHL. , 
Managing Side Effects of Treatment
Chemotherapy, the standard treatment for NHL, 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—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.
Second cancers: A second cancer is a new cancer that occurs as a result of previous treatment with radiation or chemotherapy. Secondary cancers may occur months or years after treatment and are a consequence or side effect of the initial cancer treatment.
Research indicates that individuals who undergo treatment for NHL are nearly 50% more likely to develop a second cancer compared to the expected rate for the general public. Researchers have evaluated the rate of second cancers among 109,451 patients diagnosed with NHL and determined that treatment for NHL may be linked to the development of the following second cancers: 
- Bladder cancer
- Hodgkin’s disease
- Lung cancer
- Myeloid leukemia
- Stomach cancer
Patients may wish to speak to their doctor about their risk of developing a second cancer and screening techniques that may help diagnose cancers when they are small and more treatable.
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. 6
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 stage I-II, 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: 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.
For more detailed information, go to Stem Cell Transplantation for Non-Hodgkin’s Lymphoma
New chemotherapy regimens: While CHOP is the standard chemotherapy treatment, doctors continue to evaluate new combinations of drugs and schedules for delivering chemotherapy.
Results of a clinical trial have shown that younger patients with localized NHL who were administered a combination of chemotherapy drugs with a more intensive dose and delivery schedule than the conventional CHOP regimen lived longer than patients treated with CHOP plus radiation therapy. Approximately half of the 647 patients in this trial were treated with the dose-intensive chemotherapy regimen twice per week, every two weeks. They received three cycles consisting of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVP), followed by sequential chemotherapy every two weeks. The other half of the patients received CHOP administered on a conventional schedule plus radiation. The patients were under 61 years of age and had the following types of localized NHL:
- Diffuse large B-cell
- Anaplastic large cell
- Non-anaplastic T-cell or NK-cell lymphoma
- Unclassified aggressive
Patients treated with the intensive chemotherapy had more anti-cancer responses, and a larger number lived five years or longer compared to patients treated with CHOP plus radiation therapy (see table 3). 
Table 3 Outcomes in NHL with ACVB compared to CHOP plus radiotherapy
|Intensive chemotherapy||CHOP plus radiotherapy|
|Complete response rate||93%||92%|
|5-year overall survival||90%||83%|
Researchers plan to evaluate the addition of Rituxan to this intensive chemotherapy regimen.
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 displaying 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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