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Stage IIE-IV Follicular NHL


Stage IIE-IV follicular NHL is an advanced disease in which the cancer has invaded lymph node regions near the diaphragm (the breathing muscle separating the abdomen from the chest) and may have spread to organs outside the lymph system. The majority of patients diagnosed with follicular lymphoma have grade III-IV disease.

While follicular lymphoma is a slow growing cancer, most patients with advanced disease are considered to be incurable with currently available treatment techniques. Lymphoma is difficult to cure because traditional cancer treatments—such as chemotherapy—work by destroying rapidly growing cells, and are not as active against slow-growing cells. Nonetheless, treatment has been shown to improve survival, and some patients may survive a long time with their disease.

In fact, patients with advanced follicular lymphoma appear to be living longer. Researchers have reported that between 1972 and 2002, the proportion of patients with stage IV follicular lymphoma who survived at lease five years has increased from 64% to 95%. Also, many patients are surviving without a recurrence or progression of their disease. During the same period, the proportion of patients who survived for five years or more without relapse or disease progression increased from 29% to 60%.

The researchers concluded that the longer survival of patients with advanced follicular lymphoma can be attributed to newer approaches to treatment, including the use of the targeted therapy Rituxan® (rituximab).1

A wide range of treatment options does exist for advanced follicular lymphomas; however, these options make planning treatment confusing. Each treatment option is associated with unique side effects. When choosing a treatment, it may be most appropriate for older patients—who typically have more health concerns—to select the therapy with the least side effects. Younger patients may be able to tolerate more aggressive treatments, which offer a greater chance for long-term, cancer-free survival.

About this Treatment Information

The following is a general overview of treatment for stage IIE-IV follicular lymphoma. Cancer treatment may consist of chemotherapy, targeted therapy, or a combination of these treatment techniques. Combining two or more of these treatment techniques has become an important approach for increasing a patient’s chance of cure and prolonging survival.

In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. Treatments that may be available through clinical trials are discussed in the section titled Strategies to Improve Treatment .

Circumstances unique to each patient’s situation influence which treatment or treatments are utilized. The potential benefits of combination treatment, 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.

Types of Follicular Lymphoma

Follicular lymphomas are classified according to two systems, the Revised European American Lymphoma (REAL) system and the International Working Formulation (IWF). The following are types of follicular non-Hodgkin lymphoma (NHL); they are treated similarly (see table 1).

Table 1: Types of Follicular NHL according to two classification systems, REAL and IWF

REAL classification IWF classification
Follicle center cell (grade 1) Follicular small cleaved cell
Follicle center cell (grade 2) Follicular mixed small and large cell


Chemotherapy for Advanced Follicular Lymphoma

Single-agent chemotherapy: Clinical trials have shown that Fludara® (fludarabine) appears to be an effective single drug for the treatment of progressive or relapsed follicular lymphoma. Other chemotherapy drugs that may be used to treat follicular lymphoma include:

  • Cladribine® (2-chlorodeoxyadenosine),
  • Cyclophosphamide,
  • Chlorambucil,
  • doxorubicin (Adriamycin®), and
  • mitoxantrone (Novantrone®).

Combinations of chemotherapy: Several multidrug chemotherapy regimens can produce anticancer responses in patients with relapsed follicular lymphoma. Some of the combinations commonly used include the following:

  • CHOP: cyclophosphamide, doxorubicin, Oncovin®, and prednisone
  • CVP: cyclophosphamide, Oncovin®, and prednisone
  • C(M)OPP: cyclophosphamide, Oncovin®, procarbazine, and prednisone
  • FN: Fludara® and Novantrone®, with or without dexamethasone

Chemotherapy is commonly combined with the targeted therapy Rituxan®.

Targeted Therapy for Advanced Follicular Lymphoma

A targeted therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. The addition of targeted therapy to conventional chemotherapy may offer the advantage 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 of treating the cancer, which results in side effects. Chemotherapy damages rapidly dividing cells, a hallmark trait of cancer cells. In the process, 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® (rituximab)

Rituxan is a type of targeted therapy called a monoclonal antibody that binds to proteins on the surface of B-lymphocytes, which are the cells that are cancerous in follicular lymphoma. This binding stimulates the immune system to attack and kill the cancer cells. A benefit of Rituxan therapy is that healthy cells are not targeted, limiting side effects.

Rituxan has become standard treatment for patients with follicular lymphoma. However, research is still being conducted to determine the optimal timing of treatment with Rituxan.

Rituxan alone: As initial treatment for follicular lymphoma, Rituxan alone has been shown to produce anticancer responses in approximately three-quarters (73%) of patients with follicular lymphoma. Clinical trial results also indicate that an anticancer response may last for up to one year, which increases the likelihood of long-term, progression-free survival in some patients.2

Chemotherapy plus Rituxan

The addition of Rituxan to chemotherapy improves response rates, but may also increase side effects.

CHOP plus Rituxan: Several clinical trials have demonstrated that CHOP chemotherapy plus Rituxan improves outcomes compared to CHOP alone in the treatment of patients with follicular lymphoma.

In a large clinical trial that directly compared CHOP plus Rituxan and CHOP alone, patients treated with the combination had a reduced risk of cancer progression and experienced a longer time before their cancer progressed. Overall, 96% of patients treated with R-CHOP responded to treatment compared to 90% of patients treated with CHOP alone.3

CVP plus Rituxan: The addition of Rituxan to CVP chemotherapy (cyclophosphamide, vincristine, prednisone) has been shown to produce more anticancer responses and prolong disease progression compared to CVP alone, but does not appear to significantly improve survival (see table 2).4,5

Table 2: The addition of Rituxan to chemotherapy produces more anticancer responses

CVP plus Rituxan CVP alone
Complete or partial disappearance of lymphoma 81% 57%
Time to cancer progression 34 months 15 months
Survival after three years 89% 81%


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 IIE-IV follicular lymphoma will result from the continued evaluation of new treatments in clinical trials.

Patients may gain access to better treatments by participating in a clinical trial. Participation in a clinical trial also contributes to the cancer community’s understanding of optimal cancer care and may lead to better standard treatments. 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 stage IIE-IV follicular lymphoma include the following:

Targeted Therapy

Rituxan maintenance therapy: For patients who respond to treatment with Rituxan, continuing treatment with Rituxan may be a more effective strategy than stopping treatment and resuming once the cancer recurs. Research indicates that patients who received repeated Rituxan treatments every six months for a total of four courses—called maintenance therapy—were more likely to experience progression-free survival, continuous remission, or complete remission compared to patients who ceased Rituxan after the initial four-week period and were retreated upon progression (see table 1)6.

Table 3: Maintenance Rituxan vs. Rituxan retreatment

Maintenance Rituxan Rituxan retreatment
Median progression-free survival (months) 31 8
Patients in continuous remission 45% 24%
Patients in complete remission 23% 2%
Anticancer response 52% 35%
Complete anticancer response 27% 4%

CVP plus Rituxan maintenance: Rituxan maintenance therapy after CVP chemotherapy appears to improve survival of patients with advanced follicular lymphoma. In a clinical trial, 237 patients with stage III or IV disease were treated with six to eight cycles of chemotherapy. Approximately half then received Rituxan for three years, and the other half received no further treatment. Nearly two-thirds (62%) of patients treated with Rituxan survived three years or more without worsening of their lymphoma, compared to approximately one-third (38%) of patients who did not receive Rituxan. Overall, 91% of the patients treated with Rituxan survived three years or more, compared to 75% of patients who did not receive additional treatment.7

Zevalin (90Yttrium-2b8 ibritumomab tiuxetan): Zevalin is comprised of the targeted therapy Rituxan with a radioactive material (Yttrium 90) attached. This combination takes advantage of the anticancer effect of Rituxan while the radioactive material emits radiation that can directly destroy the cancer cells. Zevalin has been proven effective for the treatment of relapsed follicular lymphoma.8Research is ongoing to determine if it may also provide some benefit as initial therapy.

Bexxar (tositumomab and iodine 131): Bexxar is similar to Zevalin in that it is comprised of a monoclonal antibody (tositumomab) that is attached to a radioactive material (iodine 131). Bexxar is FDA-approved for the treatment of patients with relapsed disease, but is being evaluated to determine if it may provide benefit as an initial treatment for follicular lymphoma.

Initial finidings suggest that Bexxar can be moved to up-front treatment without adding significantly to side effects. However, the difference between administering Bexxar up-front versus after disease progression has not been evaluated. Unless future clinical trials reveal that Bexxar produces some “cures” rather than just palliation, there may be no real benefit to early administration.

CHOP plus Bexxar: CHOP chemotherapy followed by Bexxar appears to be a promising initial treatment for patients with newly diagnosed follicular lymphoma. Results from a clinical trial have shown that nearly three quarters of the patients (72%) experienced a complete disappearance of their cancer with chemotherapy followed by Bexxar and 81% of the patients survived two years or more without cancer progression.9

Fludara® plus Bexxar: A short course of Fludara chemotherapy (three cycles) followed six to eight weeks later with Bexxar may be a promising initial treatment for patients with follicular lymphoma. A clinical trial that evaluated this treatment in 35 patients showed that approximately nine out of 10 patients had an anticancer response to treatment. On average, the patients survived four years after treatment.10

Single-dose Bexxar: Results from a clinical trial have shown that a single dose of Bexxar without any other therapies produced complete remissions in patients with previously untreated follicular lymphoma. More than half of the patients (59%) were still in remission five years after treatment. Nearly nine out of every 10 patients (89%) treated with this technique survived five years or more.11Since this study included predominantly younger patients with follicular lymphoma, which does not represent the majority of lymphoma patients, further research will be necessary to determine how the typically older lymphoma patients may respond.

New Developments in Chemotherapy

Doctors continue to develop multidrug chemotherapy treatments that incorporate new or additional anticancer therapies. Combining Fludara with other chemotherapy regimens is one approach that is under investigation.

Velcade® (bortezomib) is a chemotherapy drug that is FDA-approved for the treatment of patients with multiple myeloma. Velcade appears to produce anticancer responses in the treatment of patients with some types of NHL.12Research with this drug continues, and future clinical trials may evaluate Velcade in the treatment of patients with follicular lymphoma.


Immunotherapies are substances that stimulate the body’s immune system to destroy foreign substances, such as infection and cancer. Interleukins are substances that are produced by the body’s immune system and stimulate the immune system to attack cancer cells.

Interferon: An evaluation of 10 phase III studies involving almost 2,000 patients with newly diagnosed follicular lymphoma has revealed that the addition of Intron® A (interferon) to initial chemotherapy may improve survival when administered at relatively high doses and combined with intensive chemotherapy.13 The role of interferon in improving response rates or maintaining remissions has been controversial, but this evaluation appears to point to a benefit when administered with intensive combination treatment.

Rituxan plus interleukin-12 (IL-12): Researchers at the Mayo Clinic have reported that the combination of Rituxan and IL-12 appears to produce promising results in the treatment of patients with relapsed follicular lymphoma.14,15 Research evaluating the addition of IL-12 to treatment for follicular lymphoma is ongoing; future clinical trials may be conducted in patients with newly diagnosed disease.

High-Dose Chemotherapy with Stem Cell Transplantation

High-doses of chemotherapy are more effective at killing cancer cells than lower doses. However, high-dose therapy destroys many other cells in the body. A dangerous side effect of administering high-dose therapy is damage to the cells in the bone marrow that develop into mature blood cells, called stem cells. Without functioning stem cells in the bone marrow, the body cannot produce red blood cells, white blood cells or platelets, which leaves patients vulnerable to infection and bleeding, and unable to supply adequate oxygen to their tissues.

However, bone marrow function can be restored after high-dose therapy by replacing the damaged stem cells with healthy ones. This is a procedure known as a stem cell transplant.

There are two possible sources of stem cells for transplantation; they may be collected from the patient prior to undergoing high-dose therapy or they may be collected from a donor. A stem cell transplant that utilizes the patient’s own cells is called an autologous stem cell transplant. When the stem cells are from a donor the procedure is called an allogeneic stem cell transplant.

High-dose therapy with ASCT is reserved for patients with relapsed disease. Research shows that these patients survive longer with high-dose chemotherapy and ASCT compared to conventional chemotherapy.16

Research has shown that high-dose chemotherapy followed by ASCT can produce long remissions in the treatment of younger patients with newly diagnosed advanced follicular lymphoma.17

Unfortunately, the risk of secondary cancers that comes with high-dose therapy has been shown to outweigh the benefit of longer survival that may be achieved with high-dose therapy and ASCT.18 The use of newer chemotherapy drugs that are less toxic or delivery of reduced intensity treatment prior to ASCT may reduce the risk of second cancers and move this therapy forward in the future.


1 Liu Q, Fayad L, Cabanillas F et al. Improvement of Overall and Failure-Free Survival in Stage IV Follicular Lymphoma: 25 Years of Treatment Experience at the University of Texas M.D. Anderson Cancer Center. Journal of Clinical Oncology. 2006;24:1582-1589.

2 Colombat P, Salles G, Brousse N, et al. Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. Blood. 2001;97:101-106.

3 Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2005;106(12):3725-32.

4 Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005;105:1417-1423.

5 Solal-Celigny P, Imrie K, Belch A, et al.  Mabthera (Rituximab) Plus CVP Chemotherapy for First-Line Treatment of Stage III/IV Follicular Non-Hodgkin Lymphoma (NHL): Confirmed Efficacy with Longer Follow-Up. Blood. 2005;106:106a, Abstract #350.

6 Hainsworth JD, Litchy S, Shaffer DW, et al. Maximizing therapeutic benefit of rituximab: maintenance therapy versus retreatment at progression in patients with indolent non-Hodgkin lymphoma—a randomized trial of the Minnie Pearl cancer research network. Journal of Clinical Oncology. 2005;23:1088-1095.

7 Hochster HS, Weller E, Gascoyne RD, et al. Maintenance Rituximab after CVP Results in Superior Clinical Outcome in Advanced Follicular Lymphoma (FL): Results of the E1496 Phase III Trial from the Eastern Cooperative Oncology Group and the Cancer and Leukemia Group B. Blood. 2005;106:106a, Abstract #349.

8 Witzig TE, Flinn IW, Gordon LI, et al. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin lymphoma. Journal of Clinical Oncology. 2002;20:3262-3269

9 Press OW, Unger JM, Braziel RM, et al. A Phase II Trial of CHOP Chemotherapy Followed by iodine I 131 Tositumomab for Previously Untreated Follicular Non-Hodgkin Lymphoma: Southwest Oncology Group Protocol S9911. Blood. 2003;102:1606-1612.

10 Leonard JP, Coleman M, Kostakoglu L, et al. Abbreviated chemotherapy with fludarabine followed by tositumomab and iodine I 131 tositumomab for untreated follicular lymphoma. Journal of Clinical Oncology. 2005;23(24):5695-704.

11 Kaminski MS, Tuck M, Estes J, et al. 131I-Tositumomab Therapy as Initial Treatment for Follicular Lymphoma. New EnglandJournal of Medicine. 2005;352:441-449

12 Goy A, Younes A, McLaughlin P, et al. Phase II Study of Proteasome Inhibitor Bortezomib in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma. Journal of Clinical Oncology. 2005; 23: 667-675.

13 Rohatiner AZ , Bregory WM, Peterson B, et al. Meta-analysis to evaluate the role of interferon in follicular lymphoma. Journal of Clinical Oncology. 2005;23(10):2215-23.

14 Ansell SM, Witzig TE, Kurtin PJ, et al. Phase 1 study of interleukin-12 in combination with rituximab in patients with B-cell non-Hodgkin lymphoma. Blood. 2002;99:67-74.

15 Friedberg JW, Neuberg D, Gribben JD et al. Combination immunotherapy with rituximab and interleukin 2 in patients with relapsed or refractory follicular non-Hodgkin lymphoma. British Journal of Haematology. 2002;117: 828-834.

16 Schouten HC, Quan W, Kvalay S, et al. High-Dose Therapy Improves Progression-Free Survival and Survival in Relapsed Follicular Non-Hodgkin Lymphoma: Results From the Randomized European CUP Trial. Journal of Clinical Oncology. 2003;21:3918-3927.

17 Long-Term Follow-Up of Indolent Lymphoma Patients Treated with High-Dose Sequential Chemotherapy and Autografting: Evidence That Durable Molecular and Clinical Remission Frequently Can be Attained Only in Follicular Subtypes. Journal of Clinical Oncology. 2004;22;1460-1468.

18 Deconinck E, Foussard D, Milpied N, et al. High Dose Therapy followed by autologous purged stem cell transplantation and doxorubicin based hemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by the GOELAMS. Blood. 2005;105(10):3817-23.

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