This article will not outline which treatment is best for you, as such information changes continually with treatment, research, and time. Nor will this article discuss rare treatments used outside the U.S. and Canada or treatments classified as alternative. Rather, we list generally accepted standards of care for broad classes of NHL at the time the book this article is exerted from was written. These descriptions are provided to give you an overview of treatments and a starting point to find out more about the treatments your doctors recommend for you.

The information in this article is drawn from the National Cancer Institute's non-Hodgkin's lymphoma state-of-the-art treatment statements for physicians, and is supplemented from various sources, such as the second edition of Magrath's The Non-Hodgkin's Lymphomas, as well as current research papers.

Knowing your classification, grade, and staging information gives you a way to compare your diagnosis and recommended treatment to reports in the literature or descriptions of clinical trials. It also gives you the vocabulary you need to speak with medical professionals who might not already be familiar with your case.

Many attempts have been made to categorize the NHLs in a way that is meaningful to the treatment chosen and the best outcome. Nonetheless, owing to the variety of ways NHL can manifest, a unified system has yet to be agreed upon.

You should ask your oncologist about your classification and grading information, about which classification system was used--Kiel, Working Formulation, the REAL system, or some amalgam of these--and obtain a copy of your pathology reports.

Because there is such disparity about classifying the NHLs, you should not become alarmed if a treatment described in this article as appropriate for another classification is recommended for yours.

This article includes the following sections:

• Treatment of low-grade disease
• General treatment of aggressive NHLs
• Lymphoblastic lymphoma
• Small noncleaved cell lymphomas
• Large-cell lymphomas
• Adult T-cell lymphoma/leukemia (ATLL)
• MALT lymphomas
• Cutaneous T-cell lymphoma
• Primary extranodal sites

Treatment of low-grade disease

Most low-grade NHLs, also called indolent NHLs, if found in the earliest stages--many are not found until quite advanced--are small-cell and follicular, that is, occurring only within the follicles of lymph nodes. Exceptions include the low-grade MALT lymphomas that occur outside lymph nodes in other lymphoid tissue such as the stomach and salivary glands.

Low-grade disease usually progresses slowly at first. As time passes, it may convert to a more aggressive disease with larger cell appearance and diffuse involvement of the entire lymph node instead of just the follicle. This is called diffuse disease within the node, but please note that the term "diffuse" may also be used to describe a wider spread of disease throughout the body, or may be used to describe certain types of bone marrow involvement.

It's possible for low-grade and higher-grade disease to coexist in the same patient or even within the same node, and when this is seen, it may be assumed by some practitioners to be a transition to a higher grade and is treated as a higher-grade disease.

It is much more common to find low-grade disease in adults than in children.

The National Cancer Institute recommends that all patients with low-grade disease should consider enrolling in a clinical trial. Many treatments in use today for low-grade disease result in remission, even in long remission, but usually these are not lasting remissions. By examining clinical trials, you may gain access to newer, better treatments years before they are made available to the general public. You and your oncologist should discuss the advantages and disadvantages of this option.

Low-grade disease may be treated with one of the monoclonal antibodies that sense particular cell surface proteins, such as Rituxan, which was approved by the FDA in November 1997, and is specific for the CD20 cell surface antigen.

A watch-and-wait approach may be suggested by your oncologist. This consists of watching for certain blood values to change, for nodes to enlarge, for other organs to become involved, or for the cell type to shift to a more aggressive grade. Visits for examination and testing, including blood tests, CT scans, and perhaps marrow biopsies, may be scheduled every three to six months, or oftener, depending on your individual circumstances. This posture is adopted because studies of those treated with chemotherapy in early stages of low-grade NHL have not shown an overall increase in survival over those who wait until disease is more symptomatic to start treatment. As many people with low-grade NHL can live for twelve years or more, five-year survival statistics following treatment must be interpreted very carefully. Ten- or fifteen-year survival statistics are more meaningful.

Low-grade disease may or may not exhibit symptoms initially. If symptoms are present and serious, immediate treatment may be called for.

One survivor describes why some NHL survivors of low-grade disease call "watchful waiting" by another name, "watch and worry":

I can tell you it is unnerving at best not knowing when, where, or how "the beast" will strike. I wake up every day and think, "Is today the day?" When it's time for a doctor visit or a CT scan, I think, "Have the nodes grown? Is this the visit when my doctor will tell me it's time for treatment?"

And just try to explain to outsiders that you have cancer, but are receiving no treatment. Outsiders are sometimes confused--sometimes they believe you're "too far gone" for treatment. You can see a look of doom come over their faces. This can be frightening or funny, depending on who's doing it, when, and so on.

For those on watch-and-wait before treatment, there's an eerie aspect concerning our denial. There are moments when we can pretend not to be sick, and we do such a good job of denying our illness that when a node suddenly grows, or when the doctor says it's time for treatment, we feel foolish and betrayed.

Many research centers are studying the effect of bone marrow or stem cell transplantation on low-grade disease.

Stage I or contiguous stage II low-grade disease

This stage, usually symptomless, can be treated, and might possibly be cured, with local radiation or surgery.

Additional treatments that might be recommended:

• Single chemotherapeutic agent such as fludarabine or chlorambucil.

• Interferon.

• Monoclonal antibodies.

Stage II noncontiguous or stages III/IV low-grade disease

• Single-agent chemotherapeutic agents such as 2-CDA, cyclophosphamide, chlorambucil, or fludarabine.

• Combination chemotherapy, such as CVP or CHOP.

• Surgery to remove the spleen (splenectomy) if the spleen is affected.

• Radiotherapy to selected locations.

• Monoclonal antibodies.

• Bone marrow transplantation.

Recurrent low-grade disease

If low-grade disease relapses to a higher grade, treatment is geared to its grade. For relapses that remain low-grade, one of the treatments described in the preceding sections usually is used.

General treatment of aggressive NHLs

The aggressive NHLs include a large group categorized as intermediate- or high-grade disease: low-grade disease converting to a higher grade, lymphoblastic lymphoma, angiocentric lymphoma, angioblastic lymphoma, immunoblastic lymphoma, Burkitt's or the Burkitt-like small noncleaved lymphomas, true histiocytic lymphoma, viral-associated adult T-cell lymphoma/leukemia, and others.

Not surprisingly, the most important determinant in treating the aggressive NHLs is the subtype being treated, some of which have quite specific therapies. An accurate diagnosis is mandatory for selecting the right treatment.

In addition to this general information, see separate discussions later in this article for lymphoblastic, small noncleaved (Burkitt's and Burkitt-like), large-cell, MALT, cutaneous T-cell, and extranodal lymphomas.

Stage I or contiguous stage II aggressive disease

According to the National Cancer Institute's PDQ State-of-the-Art Treatment Statement for Adult NHL, studies have shown that long-term survival or cure is achieved more often if both chemotherapy and radiation therapy are used for this stage of disease, in spite of its relatively limited spread. Usually CHOP or a related regimen is used, but important differences in treatment exist for many aggressive lymphomas such as the large-cell, lymphoblastic, and small noncleaved cell lymphomas, which are discussed separately later in this article.

Your doctor may determine that chemotherapy alone, or radiotherapy alone, is more appropriate for your circumstances than combined chemotherapy and radiotherapy.

Stage II noncontiguous or stages III / IV aggressive disease

Because at these stages disease usually is more widely distributed through the body, combination chemotherapy alone usually is recommended, without radiation, as radiotherapy doses to multiple sites for widespread disease would be too toxic. There may be instances, however, when local radiotherapy is needed to reduce tumor size in one location.

Usually CHOP or a related regimen is used, but important differences in treatment exist for many aggressive lymphomas such as the large-cell, lymphoblastic, and small noncleaved cell lymphomas, which are discussed separately later in this article.

Patients at high risk of relapse might be advised to consider autologous or allogeneic bone marrow transplantation.

Other chemotherapeutic regimens used

Some studies have shown that, for many of the aggressive NHLs that respond to anthracycline-based therapies like CHOP, other chemotherapeutic regimens have not emerged as clearly superior to CHOP, but more than forty such similar regimens in addition to CHOP are recorded in the medical literature. Often, alternate regimens containing some of the same drugs used in CHOP are used for a variety of reasons tailored to the specific patient.

Bill's story

Bill is a survivor of high-grade NHL who was treated with both chemotherapy and radiation therapy. He describes his treatment and the side effects, and offers encouragement that the discomfort is temporary:

I was diagnosed April 1, 1996. I had a swollen neck gland and the back of my tongue had a huge hump on it. The ear, nose, and throat (ENT) doctor took a piece off the back of my tongue, sent me over for x-rays and a CT scan (both negative, by the way). I went back to the ENT doctor in two days and he gave me the news: large B-cell NHL, diffuse. I then went to an oncologist friend who I had known for twenty-five years, though not professionally. He did bone marrow studies, a spinal fluid analysis, more CT scans, all kinds of blood work, and put me to sleep for a gastroenterology look-see ... all negative, so he staged it IIA, high grade.

The tumors completely disappeared with the first CHOP (plus VP-16) treatment, which was administered three days running, every third week.

I do recall several times just feeling so bad during treatment. Not nausea or digestive sickness, but just sick. Just about the sickest I've ever been. But it did pass in a few days.

After the third of these treatments, I suffered a heart attack, but ended up with minimal to no damage. I had two stents implanted in my right coronary artery. I did nicely with that.

After seven CHOP treatments, I had radiation to the neck area every day for four weeks. I was left with very painful yet numb feet, and tingling in my left arm, which is still there. The neurologist has not found an answer to that. He says numbness results from vincristine, but it ought not to hurt.

Rest assured that I was so sick several times that death would have been a relief (not really, but it felt like it).

One last thing: I did not taper off the prednisone dose, and I have since felt that the precipitous drop in dosage may have been responsible for the sickness. But, while taking it for those five days, I was king of the world, fit to be tied, a bundle of energy--though that got to be less and less with each session.

Take it easy. Easier said than done, I know, but just recognize the fact that you will not feel well some of the time.

Lymphoblastic lymphoma

This form of lymphoma, usually found in children and young adults, is rapid and aggressive, and often resembles acute lymphoblastic leukemia.

Treatment is begun as soon as possible. If disease has already spread as indicated by staging at levels III or IV, the same highly successful approach that is used for acute lymphoblastic leukemia (ALL) may be used, involving two to three years of treatment, and precautionary treatment of the central nervous system. This treatment is divided into three phases: induction of remission, consolidation of remission, and maintenance. Each phase uses different drugs and timing to eradicate all disease. In adults, areas of bulky tumor involvement may be irradiated to reduce tumor mass.

It is possible for this form of NHL to lodge in the central nervous system. Treatment to kill all cells that may be lingering there might be recommended, consisting of either cranial and spinal irradiation or methotrexate injected into cerebrospinal fluid.

Postremission therapy, called maintenance, which improves the survival odds in this form of NHL, may include short-term intense chemotherapy, longer, less intense chemotherapy, or bone marrow transplantation.

Stage I / II

Several treatment regimens produce good results against early stage lymphoblastic lymphoma. Treatments that might be recommended include:

• Vincristine, doxorubicin, cyclophosphamide, prednisone, mercaptopurine, methotrexate.

• CHOP alternating with infusional methotrexate.

• COMP.

• LMT 81: LSA2L2 plus methotrexate.

• For adults, CHOP plus methotrexate, 6-MP, and l-asparaginase are sometimes used.

Stage III

The National Cancer Institute recommends that patients with a large anterior mediastinal (chest) tumor should consider clinical trials, because of the risks associated with superior vena cava syndrome and with treating such a large tumor in this location.

If the tumor is pressing on the superior vena cava, low-dose radiation may be used to shrink the tumor.

Treatment that might be recommended:

• LSA2L2, a multi-phase treatment consisting of induction, consolidation, and maintenance.

• LSA2L2 plus high-dose methotrexate.

• CHOP, alternating with methotrexate.

• ACOP+.

• BFM, a multi-phase treatment consisting of induction, consolidation, and maintenance.

• LMT 81: LSA2L2 plus methotrexate.

• Addition of VM-26 (teniposide) and ARA-C (cytarabine) to multi-phase therapies such as LSA2L2.

• For adults, CHOP plus methotrexate, 6-MP, and l-asparaginase are sometimes used.

Stage IV

Although there are several FDA-approved treatment options available for this stage of disease, the National Cancer Institute recommends that all patients at this stage should consider entering a clinical trial to take advantage of the foremost improvements in treatment.

If you have disseminated lymphoblastic lymphoma, treatment for possible spread to the central nervous system should be considered.

Compression of the superior vena cava may be treated with low-dose radiation.

Treatment that might be recommended:

• LSA2L2, a multi-phase treatment consisting of induction, consolidation, and maintenance.

• LSA2L2 plus high-dose methotrexate.

• BFM, a multi-phase treatment consisting of induction, consolidation, and maintenance.

• LMT 81: LSA2L2 plus methotrexate.

• Addition of VM-26 (teniposide) and ARA-C (cytarabine) to multi-phase therapies such as LSA2L2.

• For adults, CHOP plus methotrexate, 6-MP, and l-asparaginase are sometimes used.

Relapsed disease

How relapse is treated depends on what treatments were used in the past, and where the disease has recurred. Clinical trials, intensive regimens, other regimens containing drugs not previously used, and bone marrow transplantation are possible choices you should discuss with your doctor.

Small noncleaved cell lymphomas

This category includes Burkitt's as well as the Burkitt-like lymphomas.

Treatment for adults and children is similar, and may include brief, intensive combination chemotherapy, with or without radiation.

Surgical removal of disease in the abdomen may be advantageous if the tumor can be completely removed.

Stage I / II

Treatment that might be recommended:

• COMP.

• CHOP.

• CHOP plus methotrexate.

• BFM 86.

• High-intensity, brief-duration treatment: cyclophosphamide, etoposide, vincristine, bleomycin, methotrexate, doxorubicin, allopurinol, and prednisone.

• ARA-C, high-dose methotrexate, ifosfamide, and etoposide also may be used if bone marrow or central nervous system involvement is found.

Stage III / IV

Although there are several FDA-approved treatment options available for this stage of disease, the National Cancer Institute recommends that all patients at this stage should consider entering a clinical trial to take advantage of the foremost improvements in treatment.

Treatment that might be recommended:

• French LMB-89.

• Total B (St. Jude's).

• BFM 86.

• ARA-C, high-dose methotrexate, ifosfamide, and etoposide also may be used if bone marrow or central nervous system involvement is found.

• High-intensity, brief-duration treatment: cyclophosphamide, etoposide, vincristine, bleomycin, methotrexate, doxorubicin, allopurinol, and prednisone.

• For stage IV, modified "total B": cyclophosphamide, doxorubicin, vincristine, methotrexate, cytarabine.

Recurrent disease

How relapse is treated depends on what treatments were used in the past and where the disease has recurred. Clinical trials, aggressive or intensive regimens, other regimens containing drugs not previously used, and bone marrow transplantation are possible choices you should discuss with your doctor.

Large-cell lymphomas

Several types of large-cell lymphomas are found in both adults and children. These include Ki-1 anaplastic large-cell lymphoma (ALCL), and centroblastic and immunoblastic lymphomas.

Stage I / II

Treatment that might be recommended, depending on subtype:

• COMP.

• CHOP.

• MACOP-B may be recommended for mediastinal disease.

Stage III / IV

Treatment that might be recommended, depending on subtype:

• APO.

• ACOP or ACOP+.

• COMP.

• CHOP.

• MACOP-B may be recommended for mediastinal disease.

• The Milan protocol.

• NHL-BFM 86/90.

• POG 8106.

• LSA2L2, as used for acute lymphoblastic leukemia/lymphoma.

Recurrent disease

How relapse is treated depends on what treatments were used in the past, and where the disease has recurred. Clinical trials, aggressive or intensive regimens, other regimens containing drugs not previously used, treatment using regimens tested under stage III or IV small noncleaved cell lymphoma, and bone marrow transplantation are possible choices you should discuss with your doctor.

Adult T-cell lymphoma/leukemia (ATLL)

This form of NHL arises in about 3 percent of those who test positive for the virus known as HTLV-I, human T-Cell lymphotropic virus. It's found among IV drug users in many parts of the world, and among those living in parts of Japan and parts of the Caribbean. A smaller number of infected population also is found in the southeastern U.S.

Treatments that might be recommended are:

• Pentostatin (deoxycoformycin) plus interferon-beta or IFN-gamma.

• Monoclonal antibodies that target CD25-positive B-cells.

• Antivirals such as zidovudine plus interferon-alfa.

MALT lymphomas

MALT lymphomas arise in the mucosa-associated lymphoid tissues, such as the stomach, tonsils, thyroid, or parts of the small intestine. MALT lymphomas may be low-grade or aggressive, but are usually low-grade.

The gastric MALT lymphomas, which comprise the bulk of the MALT lymphomas, usually are associated with infection by the bacteria Helicobacter pylori and may respond to treatment with antibiotics. If they do not, generally single-agent chemotherapeutic drugs are attempted.

A few studies have shown a possible link between H. pylori and MALT lymphoma in the lung.

Other sites of disease, such as the thyroid, might be treated with surgery followed by chemotherapy.

Enteropathy-associated T-cell MALT lymphoma, which is linked to inherited celiac disease, dermatitis herpetiformis, and possibly to Epstein-Barr virus, might be treated with surgery.

Monocytoid B-cell MALT lymphoma might be treated with the COP, CHOP, ABVD, or m-BACOD regimens.

Other MALT lymphomas, such as those of the lung, pharynx, salivary gland, stomach, thyroid, or immunoproliferative small intestine disease (IPSID) may be approached with combination chemotherapies such as COP, CHOP, or CVD in addition to surgeries or antibiotic treatments.

Malignancies that arise in Waldeyer's Ring, consisting of the nasopharynx, tonsils, and the base of the tongue, are considered by some researchers to be nodal NHLs, but by others to be MALT NHLs, and will be treated according to the physician's beliefs. (Note that two tonsils remain after tonsillectomy, at the base of the tongue and at the back of the roof of the mouth.)

Cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma, also called mycosis fungoides, begins as low-grade disease and may entail a long survival time of twenty years or more. It may progress beyond skin involvement (Sezary syndrome) to a more serious and rapid disease. Cutaneous T-cell lymphoma is treated in different ways, depending on how much of the body is affected.

This form of lymphoma should not be confused with peripheral T-cell lymphoma, adult T-cell leukemia/lymphoma, or anaplastic large-cell lymphoma, which are higher-grade lymphomas that also may present in the skin and are treated with therapies suitable for high-grade disease.

Many treatments are geared to cutaneous lymphoma still found only in the skin:

• Radiotherapy.
  • Total skin electron beam therapy (TSEBT).
  • Local electron-beam irradiation.
  • Orthovoltage radiation therapy.
  • Carbon dioxide laser.

• Light therapy.
  • Psoralen/PUVA light therapy.
  • Extracorporeal photochemotherapy (photopheresis): blood circulated through a pheresis machine (ECPP).
  • Phototherapy with ultraviolet B in clinical trials.

• Topical medications.
  • Mechlorethamine (nitrogen mustard).
  • Carmustine (BCNU).
  • Retinoids (etretinate).
  • Phosphocholines (hexadecylphosphocholine).

Disease that has spread to other organs might be treated with multiple agents, combined with skin treatments above, perhaps including:

• Interferon alfa.

• Monoclonal antibodies.

• Systemic (whole-body oral or IV) chemotherapies such as fludarabine, 2-chlorodeoxyadenosine (2-CDA), pentostatin, chlorambucil and prednisone, cyclophosphamide, methotrexate, or combinations of these and other chemotherapeutic agents.

Relapses might be treated with recombinations of the treatments listed above, with bone marrow transplantation, or with novel approaches available through clinical trials.

Primary extranodal sites

Disease that has not spread from elsewhere, but instead has arisen outside a lymph node or lymphatic organ, requires a specialized approach depending on the location of the disease. This appearance of an NHL is called "primary disease in an extranodal site," and characterizes several of both the low-grade and aggressive lymphomas.

Owing to the great number of extranodal sites in which an NHL can arise, a detailed outline of standard treatments for each site cannot be given here. Magrath's The Non-Hodgkin's Lymphomas and current research papers and NCI treatment statements are your best sources for information about the rare primary extranodal NHLs.

The tissues comprising Waldeyer's Ring--the base of the tongue, the palatine, sublingual, and pharyngeal tonsils (the latter two are not removed during tonsillectomy), the nasopharynx, and the larynx--are considered by many researchers to be either nodal or MALT lymphomas rather than extranodal sites, as these tissues are lymphatic tissue. For these sites, see the descriptions of treatment for low-grade, aggressive, or MALT diseases earlier in this article.

Other extranodal NHLs, such as certain intestinal NHLs, also may be determined to be MALT lymphomas if they arise in the mucosa-associated lymphoid tissues.

Primary lymphoma of bone is distinct from lymphoma that has arisen elsewhere and traveled to bone marrow.

Each extranodal presentation is treated in a highly individualized way with chemotherapy, radiotherapy, or a combination of the two.