• Introduction
  
• A word of caution
  
• Theories of treatment
  
  • DNA and cancer
    
  • How NHL chemotherapies work
    
  • How radiotherapy works
    
  • How phototherapy works
    
  • How biological therapies work
    
  • How surgery is used
    
  • How marrow or stem cell transplantation works
    
• Treatment of special groups (children, the elderly, and the immune-compromised)

The non-Hodgkin's lymphomas are a collection of diseases. How they are treated depends on what type of NHL is found; the location of the tumor or tumors; the number of tumors; how rapidly the tumors are progressing; the health of the patient, including HIV status; and her willingness to undergo certain therapies, including promising experimental therapies in clinical trials.

In this article, we will discuss the theories behind chemotherapy, radiation therapy, marrow transplantation, and biological treatments. Typical treatments used today against many of the various types of NHL will be outlined. However, full details of all treatments for all subtypes of NHL cannot be covered in an article of this length.

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.

A word of caution

Most medical writers approach an article such as this one with great caution, and so should the reader. The reason is this: no single publication of this type can possibly reflect current progress in cancer research.

Few formal vehicles of communication, printed or otherwise, can reflect the continually evolving judgment of the finest researchers in the field. None is permitted to publish very early results from promising clinical trials until the results are vetted by peer review. The best any medium can hope to capture is a snapshot of theories and findings as understood at the moment.

For your needs in battling NHL, that's not good enough.

No matter how recent the copyright date is in the opening pages of any medical book, you will always get the latest information on the best way to treat your disease from the medical doctors and researchers in the trenches. Your oncologist, who knows how to tailor your treatment and schedule to suit your circumstances, may recommend treatment options that are different from those you'll read here or elsewhere. You should always verify treatment information with your doctor, and you should attempt to find the very latest information on treatment using reliable sources such as peer-reviewed medical journals.

Please note that cell histology (cell appearance), which is currently heavily used to distinguish subtypes of NHL, may be eclipsed by the evolving discipline of immunogenetics for the identification and treatment of the non-Hodgkin's lymphomas. The design and function of monoclonal antibodies, for example, are based on genetic characteristics of cancer cells and their resulting physical characteristics and immunologic behavior. This means that current attempts to describe treatments based on terms such as "indolent," "aggressive," or "diffuse" may become outdated and misleading if treatments are designed that work equally well on both indolent and aggressive subtypes of NHL.

Currently, there are about forty multi-drug chemotherapy regimens used to treat the NHLs. New combinations and agents arise almost daily, so don't be concerned if you don't see your regimen mentioned. Instead, ask your doctor for a breakdown of the drugs used in your regimen, and for an explanation of its superiority over other approaches and its appropriateness for your case.

Theories of treatment

Chemotherapy and radiotherapy regimens currently used against NHL work by interfering with a cancer cell's ability to sustain and reproduce itself.

Surgery, with a few exceptions, generally is a means to remove a badly diseased organ or to supply biopsy material rather than a method to achieve a cure.

Biological therapies work in a variety of ways, usually by mimicking or emphasizing a natural body process.

Marrow or stem cell transplantation or rescue allow very high, marrow-killing doses of chemotherapy and radiation therapy to be used.

In order to understand how each of these cancer treatments work, we first need to understand a bit about cell division and genetics.

DNA and cancer

Chemotherapy and radiation are often described as effective at killing rapidly dividing cells. This section describes the events that take place as cells divide, and describes some of the points in a cancer cell's division when it is most vulnerable to cancer therapies.

Human DNA is stored on forty-six paired chromosomes. With a couple of exceptions, each cell in our body has one copy of all forty-six chromosomes, coiled tightly in a ball, stored in the cell nucleus.

Each chromosome is composed of two long strings of genes held together like a ladder, with rungs consisting of electrochemical bonds. Because the rungs and sides of the ladder are not symmetrical, the ladder twists along its length. Owing to this configuration, a strand of DNA often is referred to as a double helix.

When a cell begins dividing, DNA relaxes out of its balled shape. On each strand of DNA (chromosome), the ladder rungs break, giving two separate strings of genes. These gene strings are processed by polymerase enzymes that are present in the nucleus for creating and lengthening DNA strings. When this process is complete, an exact replica of each chromosome exists, the cell has ninety-two chromosomes--double its usual number--and can commence dividing in two.

In a normal cell, the process of replication and division is a scheduled, orderly process. In a cancer cell, it's a continual, dictatorial annexing of bodily resources, nutrition, and space.

During the process of replication, when DNA is uncoiled and separated, it is vulnerable to damage. A large proportion of each cell's time and energy is devoted to making sure our DNA is repaired, intact, functional, and correctly copied.

In most tumors, and especially in high-grade NHLs, cancer cells divide rapidly, so their DNA is untwisted and separated--naked--more often than that of a healthy cell. Naked DNA is more vulnerable to damage induced by many substances, including chemotherapy and radiation. When the DNA of a cancer cell is damaged, it may die, or, at the very least, cease being able to replicate. This immobilization deprives it of the essence of cancer: continuous, uncontrolled cell division and growth.

Most cancer treatments used today exploit the vulnerability of a cancer cell's naked DNA, and the fact that cancer cells divide more rapidly than most normal cells.

How NHL chemotherapies work

There are five categories of chemotherapy drugs used for NHL: topoisomerase inhibitors, tubulin binding agents, alkylating agents, antimetabolites, and immune suppressants. In addition, there are several drugs used against NHL that don't fit well into any of these five categories, and several that are used to offset the dangerous effects of chemotherapy.

Topoisomerase inhibitors

Topoisomerases are enzymes our cells use to break DNA bonds before copying and repair the breaks after copying. Topoisomerase inhibitors interfere with DNA repair, causing the cancer cell to die, because damaged DNA cannot be translated into proteins, such as transport and digestive proteins, that each cell needs to breathe or eat. Some topoisomerase inhibitors currently used against NHL are doxorubicin, idarubicin, mitoxantrone, daunorubicin, etoposide, and camptothecin. Camptothecin, although chemically a plant-derived alkaloid, does not behave as do the tubulin-binding vinca alkaloids vincristine, vinblastine, and vindesine. It acts instead as a topoisomerase I inhibitor. Doxorubicin, idarubicin, and daunorubicin are unique as topoisomerase inhibitors because they are both antibiotics and cardiotoxic.

Tubulin binding agents

When a cell has made a copy of all of its chromosomes and is ready to divide, spindles made of tubulin form to pull the two copies of each chromosome apart into two identical clusters of forty-six chromosomes apiece. Tubulin binding agents stop spindles from forming, thus stopping the cell from dividing. Some tubulin binding agents currently used against NHL are vincristine, vinblastine, vindesine, and paclitaxel.

Alkylating agents

Alkylating agents form new bonds within the double twisted DNA strand that resemble the ladder rungs. This disrupts many normal functions of DNA, including its ability to divide. Alkylating agents are able to affect a cancer cell's DNA even when the DNA is not uncoiled and separated--in other words, they are not cell-cycle specific-- which may explain their relatively high activity against many cancers. Some alkylating agents currently used against NHL are mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, procarbazine, dacarbazine, and CCNU.

As the word "antimetabolite" implies, these substances in some way impede the cell's metabolism--its building up and breaking down of cell parts. Each of the antimetabolites used for NHL works a bit differently from the others.

• L-asparaginase destroys asparagine, which the cell needs for DNA and RNA synthesis.
• Cytosine arabinoside (Cytarabine, ARA-C) is a close copy of deoxycytidine, a natural bodily substance that lengthens a DNA strand as it's being copied. ARA-C substitutes in deoxycytidine's place, and, because ARA-C differs from deoxycytidine in critical ways, the DNA is not able to be copied.
• Fludarabine, pentostatin, and 2-CDA, although their exact mechanisms of action are unknown, appear to interfere with certain enzymes that aid in copying, lengthening, or repairing DNA and perhaps RNA.
• 5-fluorouracil is incorporated into RNA and DNA in place of uracil, causing malfunction of protein synthesis.
• Hydroxyurea blocks ribonucleotide reductase, without which DNA synthesis is impaired.
• Methotrexate is a folate antagonist. Folate or folic acid, a B vitamin found in many green vegetables, is needed to make the building blocks of DNA, purines and pyrimidines. If these are absent, new copies of DNA cannot be made. Methotrexate blocks the action of an enzyme called dihydrofolate reductase, which is necessary for the metabolism of folate.
• Mercaptopurine can be substituted in DNA in place of adenine, leading to a misreading of the DNA message. It also can be converted to a substance called a nucleotide that inhibits manufacture of a group of building blocks called purines that are needed for RNA and DNA synthesis.
• Mitoguazone disrupts polyamine manufacture (biosynthesis), thus disrupting formation of DNA.
• Thioguanine can be substituted into DNA in place of guanine, causing misreading of the DNA message, or it can be processed and converted to a DNA building block that inhibits an enzyme essential for RNA and DNA synthesis.

Immune suppressants

Glucocorticoids such as dexamethasone, prednisone, and methylprednisolone are manmade copies of the human corticosteroid hydrocortisone normally produced by the adrenal glands. They're used against hematologic cancers--lymphomas and leukemias, cancers of the white blood cells--to suppress the rampant growth of cancerous white blood cells.

Rescue drugs are used to offset certain dangerous effects of chemotherapy:

• Leucovorin is folinic acid, one of the B vitamins. It's used several days after methotrexate to offset the toxicity of this folate antagonist and allow the building of DNA to resume in healthy cells.
• Allopurinol is used to protect kidneys from urate nephropathy, a possible aspect of tumor lysis syndrome. Urate nephropathy can arise spontaneously in patients with a high tumor mass.
• Mesna protects the bladder by offsetting the negative effects of cyclophosphamide metabolites called acroleins, which are excreted in urine and can cause a severe form of hemorrhagic cystitis.

Drugs that don't fit well into other categories

Idiosyncratic agents include:

• Cisplatin. Similar to the alkylating agents, platinum-based cisplatin forms rung-like cross-links on the DNA ladder that disrupts DNA function, including replication. Like the alkylating agents, cisplatin is able to affect a cancer cell's DNA even when the DNA is not uncoiled and separated.
• Bleomycin. Made from parts of the fungus Streptomyces vesticillis, bleomycin joins with one form of iron to create breaks in the DNA strands. When DNA strands are broken, many cell processes, including replication, cannot proceed.

How radiotherapy works

Radiation therapy interferes with the growth and replication of cancer cells by changing the structure of molecules that make up the cell's DNA.

A beam of radiation, which is a stream of energy, can knock the electrons from the atoms that make up the molecules of DNA. Removing electrons changes the structure of critical molecules, after which the DNA strand can no longer be copied, lengthened, paired, and twined.

Similar damage is possible in healthy cells that happen to be in the path of the radiation beam, especially if they are in the process of dividing, but cancerous cells are more likely to be disturbed by radiation because their DNA is more often uncoiled and separated.

Sometimes only local or involved-field radiation is used. This targets only the tumor and not the surrounding or extended fields. Irradiating extended fields has proven to be unhelpful against many NHLs, which do not often spread in an orderly, adjacent way.

Occasionally an area called the mantle field, involving portions of the chest, is irradiated if the tumor is in this area (the mediastinum) or is causing superior vena cava syndrome (SVCS). SVCS is a collection of symptoms including swelling of the trunk, neck, face, or arms, or their veins; difficulty breathing; cough; hoarseness; eye swelling, redness, or vision changes; chest pain; upper back pain or numbness; dizziness, headache, nosebleed; or changed cognitive abilities or mood. SVCS arises when the superior vena cava--a large vein that drains blood from the head, upper trunk, and arms--is blocked by a tumor, blood clot, or, most often, by compression owing to a nearby chest tumor or enlarged lymph node. The increased pressure in this system of veins causes fluid leakage and swelling in areas that are drained by branches of the SVC.

Total body irradiation (TBI) may be used to prepare NHL patients for a bone marrow transplant.

When radiotherapy is used for children, very undesirable side effects may occur many years after treatment. To avoid these serious effects, radiotherapy is avoided as treatment for children with NHL, except to control symptoms that are not responding to any other treatment.

How phototherapy works

Phototherapy, or light therapy, can be used for types of NHL that emerge primarily in the skin, and can be used either as single-agent treatment or as an adjunct to other treatment.

Researchers have long noted that ultraviolet A sunlight and manmade versions of it have an immunosuppressive effect on the white blood cells in our skin. Because lymphomas are cancers of the white blood cells, immunosuppressant therapies, such as prednisone and phototherapy, can slow or halt their growth. Although natural and manmade UVA light has immunosuppressive effects that are effective against benign diseases such as psoriasis and rheumatoid arthritis, when used alone they are not strong enough to combat the T-cell cutaneous lymphomas.

The immunosuppressive effects of UVA light can be boosted, however, by treating tissue first with photosensitizing compounds that make the effect of light more pronounced. Psoralen, for instance, embeds in DNA and makes it more sensitive to breakage from both natural light and from manmade UVA irradiation.

There are a number of biological therapies, and each works differently, but in general, they are manmade copies of natural body substances and enhance the action of these substances. Some biological therapies are also biological response modifiers.

Monoclonal antibodies

Monoclonal antibodies are manmade copies of proteins--antibodies--that our white blood cells secrete. Because a particular cell surface protein, or antigen, attracts a particular antibody, natural antibodies are responsible for attaching to foreign substances in the body, and for initiating an attack against invaders such as viruses and bacteria.

When mass-produced in the laboratory, antibodies can be made all of one type (monoclonal) to target only a certain kind of invader. Because cancer cells are different in some ways from healthy cells, such as in the proteins that extend from their surface, manmade monoclonal antibodies (abbreviated as moabs or mabs) can be made to aim only for cancer cells by sensing these surface proteins. A monoclonal antibody may be naked, or it may be coupled or conjugated with another substance called a payload--a toxic substance such as ricin, or a radioactive substance (radioisotope) such as iodine-131 or yttrium-90. When the conjugated monoclonal antibody attaches to the cancer cell's surface protein, the proximity of the toxic substance damages or kills the cancer cell.

Each monoclonal antibody is a bit different from the next, because each cell surface protein to which it binds plays a slightly different role in the cell's life. For instance, Rituxan, a naked antibody, couples with the surface antigen CD20 on the cancer cell and causes the cell to burst. Rituxan has also been shown to re-sensitize drug-resistant B-cell lymphomas to chemotherapy. Monoclonal antibodies that target the CD22 cell surface antigen, on the other hand, can take advantage of this antigen's tendency to cause whatever attaches to it to be carried inside the cell.

Cytokines

Cytokines are substances that the body uses to trigger other immunologic events.

• Interferons. Interferon-alfa-2B, the interferon most often used in NHL therapy, halts growth, forces cells to maturity, and interrupts cell motility. It stabilizes NHL, and in some cases, kills it.
• Interleukins. There are several interleukins; the one best studied for use against cancer is interleukin-2. IL-2 stimulates growth and maturation of white blood cells (lymphocytes), and can direct lymphocytes to attack tumors.
• TNF. Tumor necrosis factor appears to have a role in killing both healthy and cancerous cells.

Colony stimulating factors

Colony stimulating factors are substances that cause growth of new cells.

• G-CSF. Granulocyte colony stimulating factor is a manmade copy of a protein that causes bone marrow to grow new white blood cells called neutrophils.
• GM-CSF. Granulocyte-macrophage colony stimulating factor, like G-CSF, is a manmade copy of a protein that causes bone marrow to grow both new white blood cells called neutrophils and new monocytes. Macrophages, which develop from monocytes, are cells that surround and eat foreign material and microorganisms in the body.
• EPO. Erythropoietin, like the colony stimulating factors, is a manmade copy of a substance made by the kidneys (and in lesser quantities by other organs, such as the liver and adrenal glands) that causes bone marrow to produce new red blood cells.
• TPO. Thrombopoietin, like G-CSF and EPO, is a manmade copy of a body product that causes bone marrow to grow new platelets. Currently, manmade TPO still is awaiting FDA approval.

Tumor vaccines

For reasons still unknown, at some point the body stops attacking cancer cells, even though evidence suggests that it does mount an immune attack against cancer cells when they are still small and few in number. Tumor vaccines are an attempt to re-educate the body to attack tumor cells.

How surgery is used

Surgery is rarely used as a means to cure NHL. Rather, surgery may be used in the following ways:

• Surgery may be the best means of obtaining tissue for diagnosis.
• Surgical removal of certain organs heavily affected by NHL, such as the spleen or thyroid, may be recommended to control symptoms. Such instances of extranodal disease usually relapse elsewhere; therefore, chemotherapy usually is used in these cases, whether surgery is used or not.
• Surgery may be used to reduce tumor volume before other treatments, but it is more common to use radiation therapy for this purpose, except in specific cases such as intestinal involvement of aggressive lymphomas.

If your spleen is removed, you should discuss with your doctor the need to be revaccinated every few years with pneumococcal, Haemophilus influenzae type b, and meningococcal vaccines. The risk of being overwhelmed by agents capable of producing encapsulated infections is higher in those lacking a spleen.

How marrow or stem cell transplantation works

Transplantation may be recommended as first-line treatment if the patient has several bad-risk features, or if the lymphoma is particularly aggressive.

Reintroducing marrow or stem cells to the body after high-dose treatment permits very high doses of chemotherapy or radiotherapy to be used--high enough to destroy bone marrow. Moreover, if donor marrow is used, the attack of incoming alien white blood cells against your tissues, called a graft-versus-host reaction, also confers a graft-versus-lymphoma effect that may overcome any residual cancer cells.

If your doctor has recommended transplantation, ask her for help weighing the risks and benefits, particularly for an allogeneic (donor marrow) transplant. At the time of this writing, the mortality rate for an allogeneic transplant ranges from 15 to 25 percent associated with the procedure itself, that is, death associated with treatment, not from a relapse of disease. Offsetting this is preliminary evidence that allogeneic transplantation may offer the best hope for cure. Autologous (self) transplantation, while entailing a much lower treatment-related risk of about 3 percent, usually lacks the graft-versus-lymphoma effect that appears to be responsible for the higher number of relapse-free patients following allogeneic transplantation.

Treatment of special groups

Some individuals require special consideration when facing treatment owing to vulnerabilities associated with age or other health problems.

Treatment of children

The NHLs most commonly found in children are the small noncleaved cell (Burkitt's or Burkitt-like) lymphomas, large-cell lymphomas, and lymphoblastic lymphoma that melds into acute lymphoblastic leukemia, depending on a somewhat arbitrary definition that considers the amount of bone marrow involvement.

All parents of children with non-Hodgkin's lymphoma should consider enrolling their child in a clinical trial. The most current methodologies for dealing with what are usually aggressive cancers can be found in these settings. Seventy-five percent of children with cancer are treated in clinical trials, and your oncologist will almost certainly approach you about this. Call the National Cancer Institute on 1-800-4-CANCER for the pediatric oncology center closest to you.

Because NHL in children frequently is spread throughout the body by the time it is diagnosed, combined chemotherapy treatment using multiple drugs normally is recommended.

According to the National Cancer Institute's PDQ State-of-the-Art Treatment Statement for Childhood NHL, evidence is building that radiation therapy for children with NHL is not only of no benefit, but also poses long-term risks to healthy tissue, such as fibrosis and second cancers, that are too dangerous. Thus radiation therapy might best be avoided, except for unusual cases such as primary lymphoma of bone, a rare and distinct form of NHL that is not the same as bone marrow involvement.

Treatment of the elderly

Often, special precautions are taken for those over age sixty-five to avoid taxing healthy organs with toxic treatments. In general, older people have more difficulty metabolizing drugs than do younger people. The concern is heightened if the patient is dealing with any of the illnesses that may accompany aging, such as heart disease or diabetes.

To circumvent problems, a standard chemotherapy regimen may be adapted to the older patient by:

• Using only some fraction of the recommended dose.
• Using fewer doses than are given to younger patients.
• Substituting a gentler drug for a more toxic one, such as substituting pirarubicin for doxorubicin.
• Using longer infusion times to spread out the delivery of some drugs, perhaps by using an implanted pump.
• Using shorter infusion times for certain cycle-specific chemotherapies such as vincristine that are increasingly toxic with increased presence, as more cells entering various stages of cell division become exposed.

Treatment of the immune-compromised

Immune-compromised patients who may develop NHL as a result of their suppressed immune status are:

• Those who are deliberately immune-suppressed with drugs following organ transplant.
• Those with AIDS.
• Those with genetic diseases that cause the immune system to fail.

NHLs that appear in these patients, especially in AIDS patients, are unique in some respects. Often these NHLs appear first in the brain or other parts of the central nervous system, gastrointestinal tract, body cavity, head, neck, or nasal passages, but often they also are characterized by unusual presentations such as the pancreas, esophagus, anus, or rectum.

Frequently these tumors have not developed from a single (monoclonal) cell line as most other cancers do. In these cases, they often contain evidence of Epstein-Barr (EBV) or human herpes virus 8 (HHV-8) infections. Usually they are high-grade, aggressive tumors that are difficult to treat.

The threat to survival often is the patient's already lowered immune status, further exacerbated by cytotoxic cancer treatment that permits infection to gain a foothold. Some studies have found that immune-compromised patients do as well following anticancer therapy as the immune-competent do, if careful measures are taken to prevent, detect, and control infection.

For transplant survivors, lowering of immunosuppressive drugs may cause the NHL to recede, especially if the tumor cell line was found to be polyclonal.

For those with AIDS, boosting of CD4+ T-cell counts can cause tumors to regress, especially if the tumor cell line was found to be polyclonal, but the presence of other AIDS-related illness also may affect outcome.

For any immune-compromised patient, excellent nursing care and social support to prevent, detect, and combat infection is needed.

Treatments that might be recommended include:

• Interferon-alfa.
• Monoclonal antibodies that target CD21- or CD24-positive B-cells.
• Monoclonal antibodies conjugated with toxins such as CD19-ricin.
• Radiation therapy for single sites of disease.
• Central nervous system treatment with methotrexate or ARA-C.
• Antiviral or antiretroviral drugs such as AZT.
• Combined chemotherapy.