What is Chemotherapy?

Chemotherapy is the use of cytotoxic (chemotherapeutic) drugs in the treatment of cancer. Tumour cells are more sensitive than normal cells to chemotherapeutic drugs because they are rapidly dividing cells.

Chemotherapy disrupts the cell cycle in an attempt to cause enough changes in the cellular makeup so that the cell cannot divide, or damages the cellular makeup enough to cause the cell to die. Some chemotherapeutic agents are cell cycle specific while others can be given at any time in a cells life and cause these terminal changes.

People who work in the cancer field often refer to the cell cycle. The cell cycle is a diagram of the process of cell division.

The Cell Cycle

The cell cycle is a sequence of events that occur during the growth and division of cells in the human body. The cell cycle is made up of 5 phases. There are three potential cell groups:

• Those that are actively dividing. These cells are the most sensitive to chemotherapy and radiotherapy.
• Those that leave the cell cycle after a certain point and are destined to die.
• Those that remain in a dormant state until they re enter into the cycle again. (ie a resting phase) Those cells that are in a resting phase are less likely to sustain damage from anti-cancer treatment.

It is important to remember that whether the tissue is normal or abnormal this cycle of the cell will occur.

The cell cycle time of cancer cells is generally not much different to that of normal cells. It is believed that only a fraction of the cells in a tumour are dividing at any one time. However, the fraction of cells dividing causes a total increase in the cell numbers. Therefore in contrast to the normal balance maintained in normal tissues in cancerous tissue the number of new cells is far greater than the number of cells dying through natural cell death or injury. It is believed that the abnormal growth in cancer cells is due to the lack of appropriate control responses to the signals that normally cause the cell to stop going through the cell cycle and as a result stop growing. This ultimately results in the development of a tumour mass.

For those people with an interest in biology, the following technical paper may be of interest.

Figure 1 : Cell Cycle
The cell cycle is an ordered set of events, culminating in cell growth and division into two daughter cells. Non-dividing cells are not considered to be in the cell cycle are represented by the G0 stage. This is a cell "resting" phase where little cellular activity occurs. The G1 stage stands for "GAP 1". The S stage stands for "Synthesis". This is the stage when DNA replication occurs. The G2 stage stands for "GAP 2". The M stage stands for "mitosis", and is when nuclear (chromosomes separate) and cytoplasmic (cytokinesis) division occur.

Regulation of the cell cycle
Cell division (and thus tissue growth) is controlled is very complex. Cancer is a disease where regulation of the cell cycle goes awry and normal cell growth and behaviour is lost.

G1
G1 is the normal growth and metabolic state of a cell. Duplication of organelles may occur in the lead up to the synthesis phase

Synthesis
During synthesis DNA reallocation and chromosomal duplication occur.

G2
Cells grow rapidly and continue to produce mRNA and other intracellular proteins in preparation for Mitosis.

Mitosis
Mitosis is nuclear division and cytokinesis that produces two identical daughter cells. The process involves several stages prophase, prometaphase, metaphase, anaphase, and telophase. Interphase is often included in discussions of mitosis, but interphase is technically not part of mitosis, but rather encompasses stages G1, S, and G2 of the cell cycle.

Interphase & mitosis
The cell is engaged in metabolic activity and performing its prepare for mitosis (the next four phases that lead up to and include nuclear division). Chromosomes are not clearly discerned in the nucleus, although a dark spot called the nucleolus may be visible. The cell may contain a pair of centrioles (or microtubule organizing centres in plants) both of which are organizational sites for microtubules.

Prophase
Chromatin in the nucleus begins to condense and becomes visible in the light microscope as chromosomes. The nucleolus disappears. Centrioles begin moving to opposite ends of the cell and fibres extend from the centromeres. Some fibres cross the cell to form the mitotic spindle.

Prometaphase
The nuclear membrane dissolves, marking the beginning of prometaphase. Proteins attach to the centromeres creating the kinetochores. Microtubules attach at the kinetochores and the chromosomes begin moving.

Metaphase
Spindle fibres align the chromosomes along the middle of the cell nucleus. This line is referred to as the metaphase plate. This organization helps to ensure that in the next phase, when the chromosomes are separated, each new nucleus will receive one copy of each chromosome.

Anaphase
The paired chromosomes separate at the kinetochores and move to opposite sides of the cell. Motion results from a combination of kinetochore movement along the spindle microtubules and through the physical interaction of polar microtubules.

Telophase
Chromatids arrive at opposite poles of cell, and new membranes form around the daughter nuclei. The chromosomes disperse and are no longer visible under the light microscope. The spindle fibres disperse, and cytokinesis or the partitioning of the cell may also begin during this stage.

Cytokinesis
In animal cells, cytokinesis results when a fibre ring composed of a protein called actin around the centre of the cell contracts pinching the cell into two daughter cells, each with one nucleus.

The above diagram and biology should help you when you read any technical papers about chemotherapy.

Cells that are dividing rapidly are the most sensitive to anti cancer treatment. This is because the cell nucleus can be damaged during the division process by treatment and if it is damaged sufficiently, it will not divide properly and it will die.

Certain normal cells in the body have naturally high division rates, such as the hair follicles, the epithelium (lining) of the gut and mouth and the bone marrow. These normal cells are nearly as sensitive to some forms of chemotherapy as cancer cells and this is why some chemotherapy side effects occur:

• If the cells in the hair follicles are affected, hair loss will result
• If the cells lining the gut are affected, diarrhoea may result
• If the cells lining the mouth are affected, sore mouth may result

Fast Growing or Slow Growing?

It can sometimes be confusing about how fast tumours are growing and what this means with respect to treatment.

Aggressive tumours divide and grow rapidly. Tumour lumps can be seen to enlarge quickly. However, if a tumour is growing fast it means that most of the cells in the tumour are in the growth phase and are thus more susceptible to damage from anti-tumour treatment.

Slowly growing tumours have less cells at any one time in the growth phase and are also therefore less sensitive to the anti-tumour treatment.

Some aggressive lymphomas may be curable by chemotherapy as so many of the cells are growing while the chemotherapy treatment is being given. Slower, less aggressive (indolent) lymphomas may not be curable, but can be kept in remission for very long periods of time by courses of chemotherapy.

The degree of differentiation is an expression of the similarity of the cancer cells to the original normal cell tissue. The more well differentiated the tumour, in general the better the prognosis. Well differentiated prostate cancer, for instance, tends to respond very well to hormonal therapy and may be kept at bay for many years even when it has spread to bone.

The type of treatment that your treating doctor gives you will be designed with this in mind. Aggressive, rapidly growing tumours may be treated with short sharp treatments eg just one or two doses of radiotherapy may have excellent results in shrinking tumours. For slow growing tumours (eg some types of brain tumour) treatment may be given in very small doses over a prolonged period of time.

In some situations, the radiation will need to be given over a longer or shorter period of time depending on your own individual and unique set of circumstances. Your treating specialists will be able to advise you of the best approach for treatment for you.

Statistics Discussion

Sometime during treatment, discussions will often be had talking about statistics as relating to survival or chance of responding to treatment.

This area is fraught with difficulty and danger of misinterpretation.

As an example, if a person asks "How long have I got?" an answer might be given such as 6 months to 2 years. Some people walk away from that discussion shaking their head in horror saying he told me I have only got 6 months. Sometimes, people who take this view, then spend the next 6 months worrying and waiting for the day to arrive. If they are still alive at 7 months, they can sometimes feel that nobody knows anything about their disease and almost feel let down that people have given them incorrect information.

Another personality type may walk away from the conversation saying "He has given me 2 years!" and be very pleased about that. If they get very sick after just 12 months, they can feel very let down and feel the doctors have misinformed them.

The most important fact regarding these types of discussion is that nobody can tell you for sure exactly what time span you might have. It is often possible to make an educated guess such as months to years or weeks to months but it must be borne in mind that every single person is different. Because every single person is different, we each have different resilience in face of hazard and illness. As a general rule, younger people tend to be stronger than older folk and can be more resilient.

Another confusion thing is that sometimes a sudden event will happen. For example, if someone is expected to live for 2-3 years, the person might suffer from a disastrous complication of their illness such as tumour invading a vital organ or eroding a vital blood vessel. This can lead to a sudden life threatening complication which can dramatically alter the time scale in an unexpected manner. These sorts of events need to be understood for what they are - something completely unexpected which cannot be predicted.

Everyone's individual tumour grows at different rates and has different sensitivities to the same treatments. This is why you cannot compare your own treatment to somebody else's. The reasons why one person might live 3 months with one illness and another person might live 3 years is very poorly understood. It is likely to be related to an individuals genetic make-up and "the luck of the draw".

Yet another thing which tends to confuse the issue is that, for want of a better expression, miracles do sometimes happen. For a religious person this may represent an act of God. For somebody who has embarked upon a miracle new treatment, they may feel that the treatment has been entirely responsible for their miracle cure. What is known is that certain tumours may change as they grow until by changing so much, they actually die off. This is known to happen with kidney cancers, for instance, which may undergo that sort of change as often as 1 in a 100 times.

The good news is that new cancer treatments are being developed all the time. If someone has treatment today which makes them survive for another 2 years, then by the time that 2 years has come there may well be a host of new treatments against the illness.

What must be remembered is that progress is happening all the time and it is important to keep hope alive. It must also be stressed that hope can sometimes cause more anguish and problems if the hope is completely unrealistic. If someone has an extremely aggressive disease which fails to respond to every treatment, it can become very hard to accept the reality of the situation. Hope can lead people to try other treatments which are at best useless and sometimes frankly harmful. Beware of miracle cures which are guaranteed to work, because there is no such thing. Be especially wary if the miracle cure comes at a very high financial cost. People have been known to mortgage their homes to go for miracle cures in far off countries with very badly developed medical services and never to return. The family that survives not only has to cope with the loss of their loved one, but also the loss of all their life as they know it such as, car etc. Please bear this in mind.

Treatment Statistics

What happens if a doctor says this treatment has a 10% chance of working? The answer to this question is that it depends on the individual. The percentage likelihood of the particular treatment working is generally only useful to compare treatments. Ie, if treatment (a) has a 90% chance of working and treatment (b) has a 5% chance of working then the obvious choice would be treatment (a). This is the main purpose of percentage response rates.

Peoples reaction to the information given on response rates, depends upon their philosophy. Some people may refuse to have a treatment which is 90% likely to put them into a prolonged remission because it is not a 100% guarantee of cure. This choice would seem bazaar to other people who would accept a treatment which has a 10% chance of working because they may feel that "10% chance is better than no chance". Ultimately, the percentage figures are only useful as a general guide and to help your doctors to choose the right type of treatment and the treatment which has got the best chance of working for you. For instance, very early Hodgkin's disease, the knowledge that this is 95% curable is of no comfort to any of the 5% of people who are not cured from that disease. Likewise, if a person decides to undertake a treatment which has a 20% chance of working, who is to say that that person will not be one of the 20% in whom it works.

Ultimately it boils down to personal choice and if you feel that you would like to try a treatment, once you know what the percentage likelihood of it putting you into a remission is, then you must discuss this and make this plain to your treating doctors. Your treating doctors will generally try to discourage you from trying treatments which are frankly dangerous and sometimes their very firm advice not to try a particular treatment is because, given your particular set of circumstances, it may be that the treatment has more chance of causing you harm than helping you. Your treating doctor is the best person to give you this advice.

Also, there are some treatments which may have a less than 50% chance of working for you, but given your particular set of circumstances, your treating doctor may well believe that you will be in the 40% group of people who will respond well to that treatment. This is why all of the information contained within the web site must be discussed fully with your treating team.

What About Side Effects?

Unfortunately, there is no such thing as a drug without side effects. Even oxygen therapy can be harmful in some people with certain types of lung disease, even though we need it to stay alive.

It must be remembered that the Regulatory Bodies which have proved whether or not a drug can be used in a country, look very carefully at the evidence relating to the use of the drug in a particular disease or area. The Regulatory Bodies are very strict on only allowing treatments to be licensed if there is good evidence that the treatment may work and benefit at least a significant proportion of individuals. They also want to satisfy themselves that the treatment is as safe as possible. This means that acceptable side effects have to occur in a minority of individuals. The general principle is that the dud points of a particular treatment must far outweigh the potential bad points.

Having said all that, side effects can either be relatively common with certain medications (eg nausea with Morphine, which can incidentally treated with anti-nausea medication) or can be extremely rare (eg an epileptic shock with Penicillin). Generally speaking, your doctor will warn you of side effects which have got a reasonable possibility of occurring (eg hair loss is very likely to occur with a number of chemotherapy agents, but by no means the majority). By law, companies must disclose every single known side effect that may be attributable to the drug, and generally they have to be on the safe side. This means that sometimes potential side effects may be included on the list of side effects, even if it is not absolutely certain that the side effect can be attributed to the drug (ie be on the safe side). It should be stressed that the majority of people do not get these side effects although unfortunately it is something that everybody worries about, sometimes more than any other feature of treatment.

It must be stressed that the majority of side effects are 'fixable' - there are excellent anti-nausea drugs available for medications which are known to cause nauseous side effects, for instance. If you believe you are having a particular side effect from your treatment, you should discuss this with your treating team and they can point you in the right direction regarding how to sort out that problem.

It is a clinical experience of the Author, that more people feel anxiety about potential side effects than actually get side effects. The anxiety relating to the potential for side effects can be quite extreme, can make people feel very uncomfortable. I think good general advice is to acknowledge that side effects may occur to your medication, but if they do, it is often possible to achieve the same result by using a different medication, or have specific therapy to get around the problem of the side effect.

Cancer Terminology

Radical
Attempted cure - i.e. the treatment is being given with the intention of curing the cancer

Palliative
The goal of treatment is to prolong life, shrink the disease or improve symptoms. It usually means cure is not possible, but it should be remembered that sometimes people have much better responses than expected i.e. some people get prolonged remissions from what was originally palliative treatment

Adjuvant
Treatment given "as an extra" to improve the chances of cure or response. For example, adjuvant chemotherapy may be given after a bowel resection for colon cancer, if it is thought that the disease has a chance of coming back or it is considered a "high risk" tumour.

Neo-adjuvant
Treatment given prior to another more definitive treatment. For example, some cancers of the oesophagus are treated with radiotherapy and / or chemotherapy prior to being removed surgically. The aim of the treatment is to make the disease more easily resectable.