Chemotherapy

 

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Chemotherapy

  1. What are the most common chemo regimens?
  2. Is there a list of what drugs are in each regimen?
  3. How often is chemotherapy administered?
  4. What are the different "types" of drugs and how do they work?
  5. What is all this stuff about being "cell cycle specific"?
  6. What is this lifetime limit I hear about?
  7. What are the side effects of each of the drugs in my chemotherapy?
  8. Is there a checklist to help me prepare for my first chemotherapy session?

There are many different chemotherapy regimens used to treat non-Hodgkin's lymphoma. The choice of therapy will depend which type of NHL the patient has, their overall health, the extent of the disease and other factors. If you want to know what drugs are in your regimen click on Question #2 above. Below are the most common ones used, but there are many others. Under each regimen listed below is a list of the drugs in it, and a brief summary of what it is like. Click on the regimen name to get more detailed information. 

You can also visit our Side Effects page to get information about the side effects and how to manage them. Many, perhaps most drugs are dosed according to your body surface area or BSA. The BSA is a calculation that uses your height and weight to calculate just how much of "you" there is. Neither height nor weight alone is sufficient to get the correct amount of drugs into you.

Click here to go to a Body Surface Area Calculator

 

What are some of the more common chemotherapy regimens?

 There are many different chemotherapy regimens used for lymphoma. Some of the more common ones are shown below. Please note that you should not try to make any sense of the letters used for each drug in the acronyms below. Sometimes it is the drug name, sometimes the brand name, and sometimes...well just don't try to make sense of it. 

 

CHOP

C = Cyclophosphamide

H = Doxorubicin (Doxorubicin Hydrochloride) 

O = Vincristine 

P = Prednisone

CHOP is the most common of them all. It has been a highly effective regimen for decades and continues to be the treatment of choice for most of the aggressive lymphomas. It is also frequently used for the indolent lymphomas, but generally only after 2-3 other milder therapies have been tried first. While CHOP is extremely effective and results in a complete cure for many aggressive lymphomas, it is considered a medium strength chemotherapy. It has potent cancer killing ability but is generally well tolerated by most patients, although the side effects do vary greatly from patient to patient.

 

CVP

CVP is the same as CHOP but without the Doxorubicin. Doxorubicin can be toxic to the heart therefore CVP is often used in patients who have existing heart problems, who are at high risk for heart problems, or who have already had their lifetime maximum dose of Doxorubicin or other cardiotoxic drugs. 

 

BR

Bendaumstine and Rituxan: Commonly used for indolent lymphomas.

 

DHAP

D = Dexamethasone

HA = High dose Ara-C

P = Cisplatin

DHAP is a rather more toxic treatment than CHOP and usually involves 3-4 days as an inpatient at your hospital/cancer centre. The side effects are more difficult to tolerate, but the cancer killing ability of DHAP can be more potent than CHOP.  DHAP is often used as part of the preparatory regimen for a Stem Cell Transplant.

 

ESHAP

E = Etoposide

S = Methylprednisolone (SOL)

HA = High dose Ara-C

P = Cisplatin

Very similar to DHAP but with Etoposide added. It is just a bit more aggressive than DHAP.  Another regimen that is often used in conjunction with a Stem Cell Transplant.

 

ICE

I = Ifosfamide

C = Carboplatin

E = Etoposide

A common regimen that is used when initial chemotherapy has failed.

 

RICE

ICE with Rituxan added

 

Fludarabine

Fludarabine is a single agent drug which is very effective for many low grade types of lymphoma. Originally targeted at CLL (a type of leukaemia), it proved highly effective for lymphoma as well. The one major drawback to Fludarabine is that it suppresses the bone marrow and stem cell production to a major extent. In fact some doctors believe that the suppression to stem cell production is so severe that it may eliminate the possibility of an autologous stem cell transplant in the future. Other doctors believe that this problem can be overcome. In either case any patient considering therapy with Fludarabine should discuss this issue with their doctor.

 

FND

F = Fludarabine

N = Mitoxantrone (Novantrone)

D = Dexamethasone This combination is more recent but it has been showing a great deal of activity and is becoming more popular for relapsed indolent patients.  FND+R FND plus Rituxan Another combination to include Rituxan. Once again the addition of Rituxan seems to have a synergistic effect with the combination working better than either one alone.

 

HyperCVAD

C = twice daily Cyclophosphamide

V = Vincristine

A = Doxorubicin (brand name is Adriamycin)

D = Dexamethasone

This is alternated with high dose Methotrexate, and Ara-C. HyperCVAD has been showing much more activity in Mantle cell lymphoma than any other regimen, and in particular CHOP.  Its use is often followed by a Stem Cell Transplant.

 

BEAM

B = Carmustine (BCNU)

E = Etoposide

A = Ara-C

M = Melphalan

Another regimen commonly used in preparation for a Stem Cell Transplant

 

MINE

M = MESNA

I = Ifosphamide

N = Mitoxantrone

E = Etoposide

Another regimen commonly used in preparation for a Stem Cell Transplant

 

PROMACE CYTABOM

PROMACE Arm

CYCLOPHOSPHAMIDE

DOXORUBICIN

ETOPOSIDE P

REDNISONE

METHOTREXATE 

 

CYTABOM Arm

CYTARABINE

BLEOMYCIN

VINCRISTINE 

METHOTREXATE

LEUCOVORIN possibly added as a prophylactic

PROMACE-CYTABOM is an aggressive treatment for relapsed aggressive NHL.

 

Interferon alfa (Intron A)

Interferon's are proteins that are manufactured naturally by your body in small quantities. They are often called biologic response modifiers, because they help stimulate the immune system against foreign invaders such as bacteria, viruses and cancer. The role of Interferon therapy is controversial. It is most often used for follicular lymphomas and rarely for any of the aggressive types.  Many studies show that it significantly prolongs remission and overall survival, while other studies show no benefits. The side effects of Interferon can be overwhelming in some cases. Depression, fatigue and flu like symptoms make it difficult to tolerate for some people. To read more about Interferon visit the official  Intron A web site here

 

How often is chemotherapy given?

There are many questions, and misconceptions regarding how often chemotherapy is given. There is no single answer as to how often it is given because there are so many different regimens and the frequency depends in a large part upon how well the patient is able to tolerate the treatment and how quickly their blood counts recover. Many of the common multi-drug regimens are given on a three or four week schedule. That is, you have chemotherapy as an outpatient one day every three weeks or every four weeks. But there is nothing magic about the "3"  or "4" week schedule. While both are very common, they are based on the fact that years of experience have taught experts that this the length of time it takes the "average" patients blood counts to recover enough to tolerate another round of chemo. It could be given every two weeks, and in fact there are studies looking into giving lower doses every one or two weeks instead. 

It is not at all uncommon for a patient to have a treatment delayed by one or two weeks because their blood counts have not recovered sufficiently from the previous treatment. While it is important to remain on schedule, a delay of one or two weeks generally will not reduce the efficacy of the treatment.  Many other chemo regimens are given over several days, often as an inpatient at your local hospital. Others yet are given in pill form over many days.  Patients are sometimes under the misconception that the chemotherapy schedule is based upon the fact that many of the drugs are cell cycle specific, and that the chemo cycle is timed to match the cell cycle. That is simply not true. There are just too many billions of cancer cells, all in different stages of their cell cycle to ever invent a chemotherapy that specific.  Furthermore, each type of cell has a totally different life cycle and lifespan so it is not possible to coordinate the chemo with this wide variety. For example Neutrophils only live about 10 hours or less, plasma cells, (a type of B lymphocyte that manufactures antibodies) live several days, and memory cells (another type of lymphocyte) live for months or years.   Instead, the chemotherapy schedule is designed to give the maximum amount of drug with the minimum amount of side effects. No matter when you give the chemotherapy, there will always be some cancer cells in the optimum cell cycle, and some that are not. Luckily there are many drugs such as the alkylating agents that do not rely upon the specific cell cycle. 

 

Mechanism of Action

Each drug used is classified according to its "mechanism of action". In other words what does it do to the cancer cells. There are a variety of different ways to kill a cancer cell so many chemotherapy regimens combine various drugs that each have a different mechanism of action, in order to obtain the best results. The primary types of drugs used are:

 

Alkylating agents

Alkylating agents form new bonds within the double twisted DNA strand that resemble the ladder rungs we are all familiar with in a DNA helix. By forming new bonds it disrupts many normal functions of DNA including its ability to divide. It is able to do this at any time, even when the DNA is not uncoiled and separated. This makes alkylating agents non cell cycle specific. In other words they work at any time, and not just at a particular phase of the cells life cycle. This may be why they are so effective against so many cancers. One example of an Alkylating agent is Cyclophosphamide.

 

Anthracyclines

A member of a family of chemotherapy drugs that are also antibiotics. (comes from the fungus Streptococcus peucetius)  They pose a risk of cardio toxicity (severe heart problems) and therefore, they are typically used in limited doses. Patients should also be closely monitored for any heart problems during treatment. The anthracyclines act to prevent cell division by disrupting the structure of the DNA and terminate its function. They do so in two ways: (1) they intercalate into the base pairs in the DNA minor grooves; and (2) they cause free radical damage of the ribose in the DNA. The anthracyclines are frequently used in leukemia and lymphoma therapy.

The anthracyclines include daunorubicin (Cerubidine), doxorubicin (Adriamycin, Rubex), epirubicin (Ellence, Pharmorubicin), and idarubicin (Idamycin). 

 

Topoisomerase inhibitors

Topoisomerases are enzymes our cells use to break the DNA bonds before copying and repair of 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. Topoisomerase inhibitors are cell cycle specific, that is, they only kill cells that are in a particular phase of cell division and generally do not have any effect on other cells. Examples of Topoisomerase inhibitors are Etoposide and Topotecan. 

 

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 46 chromosomes apiece. Tubulin binding agents stop spindles from forming, thus stopping the cell from dividing. Tubulin binding agents are cell cycle specific, that is, they only kill cells that are in a particular phase of cell division and generally do not have any effect on other cells. Vincristine is an example of a tubulin binding agent. 

 

Antimetabolites

The role of antimetabolites is to somehow impede the cell's metabolism just as the name suggests. That is, it impedes the cells building up and breaking down of cell parts. There are many antimetabolites, and they each work in different ways. Once example is Methotrexate, which is a folate antagonist. Folate (folic acid) is needed by the body to help make DNA. Methotrexate blocks the action of an enzyme called dihydrofolate reductase which is necessary for the metabolism of folate. 

 

Immune suppressants

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

 

Lifetime limit

Some drugs used in various chemotherapy regimens have a lifetime limit due to their cumulative toxic effects. It is important to understand that it is the individual drug, not the entire chemotherapy regimen that has a lifetime limit. With respect to lymphoma the biggest example of all is CHOP. Many people mistakenly believe that there is a lifetime limit of CHOP that you can have (often quoted as 8 cycles) This just is not true. What is true is that the Doxorubicin in CHOP (the H) does have a lifetime limit. If you eliminate the Doxorubicin from CHOP, what remains is (CVP) which has no lifetime limit.

The list of the most commonly used anthracyclines is: Doxorubicin Epirubicin Idarubicin Daunorubicin Mitoxantrone respinomycin (leukaemia) Annamycin (leukaemia) The definition of Anthracyclines is: Anthracycline: A member of a family of chemotherapy drugs that are also antibiotics. The anthracyclines act to prevent cell division by disrupting the structure of the DNA and terminate its function. They do so in two ways: (1) they intercalate into the base pairs in the DNA minor grooves; and (2) they cause free radical damage of the ribose in the DNA. The anthracyclines are frequently used in leukemia therapy. These drugs have a risk of cardiac toxicity. Primarily cardiomyopathy and congestive heart failure. When in doubt check the drug here:  Chemotherapy drug monographs Just to give a specific example, we will discuss Doxorubicin. Research has shown that the risk of heart damage is very small when the patient is given up to 450mg/m2 in their lifetime. (450 mg per square meter of body surface area) Between 450-550mg/m2 the risk increases very slightly and therefore 550mg/m2 is generally used as the lifetime limit. At doses higher than 550mg/m2 the risk of heart damage jumps up to 30% or more. Each of the anthracyclines adds to this cumulative dose so if you have already maxed out your dose of Doxorubicin at 550mg/m2 you cannot have any idarubicin, or daunorubicin etc.

 

What does that mean to the average patient? First you have to calculate your body surface area. For a typical average weight/height male it would be about 1.95 square meters. For the average female that would be about 1.60 square meters. Thus, the maximum lifetime dose of Doxorubicin for each would be 1073mg for the male, and 880mg for the female.   Eight cycles of CHOP is usually considered the maximum. Not because CHOP has a lifetime maximum, but just because if you don't get the results you are looking for after eight CHOP then more is certainly not going to do any better, and it is time to try something else. 

  

The usual dose of Doxorubicin for example, is 50mg/m^2. Using that dosage, a typical patient could have 9 cycles of CHOP before reaching their conservative lifetime limit, and as much as 11 doses before reaching the upper limit. In truth, most patients receive much less CHOP with 3 or 6 being the most common number of cycles.

References:

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