The following excerpt is taken from Chapter 6 of
Non-Hodgkin's Lymphomas: Making Sense of Diagnosis, Treatment, and
Options by Lorraine Johnston, copyright 1999 by O'Reilly & Associates,
Inc. For book orders/information, call 1-800-998-9938. Permission is
granted to print and distribute this excerpt for noncommercial use as
long as the above source is included. The information in this article is
meant to educate and should not be used as an alternative for
professional medical care.
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
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
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
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
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
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.
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,
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
- 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
- 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.
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
- 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
- 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
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
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
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.
How biological therapies work
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
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 are substances that the body uses to trigger other
- 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
- 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
- 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
- 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
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
- 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
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
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
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
Treatment of special groups
Some individuals require special consideration when facing
treatment owing to vulnerabilities associated with age or other health
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
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
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
- 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
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:
- 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.