Chemotherapy Overdose II

It is reported in the 21 April edition of the Pharmceutical Journal that a misinterpretation of a myeloma chemotherapy protocol consisting of idarubicin and dexamethasone (Z-DEX treatment) has resulted in the deaths of two patients. The wording “40 mg/m2 in divided doses over four days” has led to 40 mg/m2 per day rather than 10 mg/m2 per day for four consecutive days.

A further letter in the 5 May edition calls our attention to the Systemic Anti-Cancer Therapy Study currently underway and run by the National Confidential Enquiry into Patient Outcome and Death (NCEPOD).

NCEPOD, a registered charity, aims to “review medical clinical practice and to make recommendations to improve the quality of the delivery of care. We do this by undertaking confidential surveys covering many different aspects of medical care and making recommendations for clinicians and management to implement.”

The aim of the study is to examine the care of adults with tumours, acute leukaemias or aggressive lymphomas who receive chemotherapy, monoclonal antibodies or cytokines and who die within 30 days of receiving treatment.

The protocol is here.

Chemotherapy Overdose

Oh dear ... something else to worry about.

Two men being treated for cancer and leukaemia at Birmingham's Heartlands Hospital died after receiving five times the correct dosage of a medication on 20 July. Apparently the drug (I wonder what) is to alleviate the side-effects of cancer treatment. A doctor and two nurses involved are apparently away from work but have not been suspended, An enquiry is taking place by both the hospital and the coroner. Press report here.

The risk is real. The UKALL 2003 protocol warns "All medical staff involved in the care of patients with leukaemia MUST be aware that the inadvertent administration of vincristine by the intrathecal route is invariably FATAL. Vincristine should NOT BE AVAILABLE when an intrathecal needle is in situ. This protocol has been written to provide separation of intrathecal methotrexate administration from intravenous vincristine administration in time. An additional precaution is that the two drugs should not be administered in the same place ...The single most crucial element in avoiding errors is the appropriate education and training of all personnel involved in the administration of chemotherapy".

Research

I promised to discuss the new research project for which Nanda had to sign a consent form and hand in yesterday.

First of all, it does not involve new or extra bone marrow or blood samples. It just involves existing bone marrow samples taken during her first four weeks of treatment.

I haven´t seen the whole consent letter but my brother summarised for me “the scientific part”. To quote:

“The aim of the study is to measure the levels of angiogenesis, MDR-1, MRP and indicators of hypoxia in the bone marrow samples taken routinely at diagnosis. These measures would then be related to the speed and extent (the level if any of minimal residual disease) of your child's response to the first four weeks of treatment. This is to help further understanding of the variations in the speed and extent to which the leukemia cells disappear from the bone marrow during the first four weeks of treatment. In many adult cancers the numbers of new blood cells (angiogenesis) and a low level of oxygen within the cancer (hypoxia) are recognised as making the tumours less responsive to treatment. It is not yet known whether the numbers of new blood vessels or low oxygen levels are important for making the treatment of childhood ALL more difficult. Also some cancers contain resistance proteins (MDR-1 and MRP) that may reduce the effectiveness of drugs such as vincristine.”

As I haven´t seen the whole consent document, I am not sure of the rest of its contents.

I am sure this consent letter has not been translated into the principal minority languages of England – Urdu, Punjabi etc – the principle ethnic minority languages of he hospital´s catchment area - let alone Nanda´s native language, an official language of the European Union. I am afraid that ethnic minorities, or many others with little literacy (whether UK or non-UK readers, writers, listeners or speakers of English) and those who don´t have a first idea about the science, are left in the dark.

UKALL 2003 - Delayed Intensification II contd

Kezia had Vincristine and her last PegAsparaginase today and they are home already.

Lots of small milestones the last few weeks - the last of this drug, the last of that drug, Next week sees the first Big Milestone - the last dose of this phase (Vincristine) and then we're into the much less intensive maintenance phases! Looking forward to it! Vinvcristine once a month through the maintenance phases.

France vs England

It is tempting to think the BBC read my post on access to cancer drugs yesterday given that they posted this 30 minutes ago and someone from the Beeb visited me early this morning.

In other personal news Kezia resumed treatment today with a dose of intrathecal methotrexate. Last four doses of cytarabine in the coming days.

Cancer Drug Access

Access to cancer drugs stayed in the news this weekend with the BBC reporting the results of its survey of 180 UK cancer specialists on their views. They are anxious about access to new treatments on the NHS and they are anxious about NHS patients having to pay for NHS-administration of non-NICE approved treatments.

Mens Sana also posted about access to Tarceva, Docetaxel and Pemetrexel.

My weekend reading was the Karolinska Institute report on EU access to cancer drugs we cited here.

Research at Columbia University in the USA, cited in the report, has shown that access to more cancer drugs is directly correlated to increased one and five year survival rates. It is in the interests of cancer patients to have access to new drugs as quickly as possible.

On the situation in the UK, where the authors reported access to new drugs was one of the worst in the European Union, it made disturbing reading. I will cite come examples …

Drug regulatory and approval regimes differ widely. For EU members the first step is for the drug to be approved by Committee for Human Medical Products (CHMP). Although this approval process is not meant to take more than 180 days, the reality is a median of 418 days. The approval process then passes to national authorities, clearly leading to further delays in patient access.

In the UK these national approvals are considered by three authorities – for Wales, the All Wales Medicine Strategy Group (AWMSG), for Scotland, the Scottish Medicines Consortium (SMC) and in England, the National Institute for Health and Clinical Excellence (NICE).

The report states that referral time to NICE “can be up to 18 months and this is prior to the beginning of any review”. The report does not cite referral times to the SMC but in my calculations below I will use the same..

Budgetary allocations for new treatments are not planned during England NICE evaluations so it is only after NICE has granted approval that budgetary planning for the next financial year (April to March in the UK) can take place. Knowing a little bit about the bean counters, I can I imagine that a drug approved in March 2007 (probably earlier), will not be approved for April 2007 but will only be approved for April 2008. Let us make budgetary planning six months/180 days.

The NICE review/approval time averages is 62 weeks, SMC is 12 weeks.

England:

EU CHMP 418 days + referral to the national authority 72 days + NICE review 434 days + budgetary planning 180 days = 1104 days = 3.02 years

Scotland:

EU CHMP 418 days + referral to the national authority 72 days + SMC review 90 days + budgetary planning 180 days = 760 days = 2.08 years

One year in the life of a cancer patient is a long time.

Move to Scotland. Is Scotland negligent? Methinks not. Is Switzerland, not a member of the EU, and with excellent cancer drug uptake and treatment rates negligent? Methinks not.

Dr. Crippen has reported on a cancer patient moving from England to Scotland for treatment. Potentilla – I´m happy you´re there!

Let us move on …

Cancer research

In the US public (and I´m taking that to mean state) funding of cancer research is seven times that of the EU. Fair enough. In the EU cancer research funding is 50/50 split between state and charities. The UK, within the EU, is the highest investor in cancer research, with the charities contributing more than the average 50%.

“Yet this report illustrates that the UK lags behind other EU countries in terms of the ability of cancer patients to access new drugs.”

Political factors

And this perhaps is the most horrific of all …

In the UK, in-patient care is taken into consideration for the funding of hospitals.The more in-patients the better for a hospital´s budget request. So although there is an oral form of 5-fluorocil, used in the treatment of colorectal and breast cancers, this is not advantageous to hospital budgets, so the IV form continues to be used even though it is disadvantageous to the patient – and I will go on to say disadvantageous to the economy as a whole as the patient’s labour hours are withdrawn, s/he occupies a bed, eats on the hospital etc.

UKALL 2003 - Delayed Intensification II (again!)

Kezia's counts were good enough today to start the reconsolidation phase of DI2. Four more weeks and counting!

UKALL 2003 - Delayed Intensification II contd

Treatment day again. Doxorubicin (her last ever - a milestone albeit a minor one!) and Vincristine. Kezia will be restarting Dexamethasone for a week. Jaime started his school holidays yesterday so went along as well. They are back from hospital as I write and Jaime got another present. At my suggestion that I will be able to look after Jaime during the next appointment, Nanda said he won't want to as he likes getting presents from the hospital!

UKALL 2003 - Delayed Intensification II contd

Second doses of doxorubicin and vincristine are scheduled for today. Peg Asparaginase Saturday last - Jaime went with them to the hospital and received, as Nanda described it, a "big" present. Didn't quite ascertain what ((don't think he's suffering from lack of attention, Rob!). Almost a week's worth of dexamethasone and it has kicked in. Moody. Not sure if she's got leg pains yet as happened in Delayed Intensification I.

Her Hickman Line is playing up. It is allowing medication in, but not blood out. This is probably due to a tiny bloodclot acting as a one-way gate valve. Such micro-clots are pretty common even in healthy people. J., our consultant, does not want to change the line again if not really necessary - especially as we are so near the maintenance phases and the removal of the line.

In other events ... I had quite a good weekend. Friday to Saturday we had an enormous storm. After several weeks without rain, I was grateful to have our cisterns replenished and it rained again today (Monday). However, it brought down our "izaquenteira" (Treculia africana - cannot find an English name) - this is a tree of about 10 metres height that bears medicine ball-size fruit with numerous seeds that are locally prepared into traditional dishes, one sweet, vaguely reminiscent of Indian kulfi, and one savoury with palm oil and smoked fish. The latter I adore, not having a "sweet tooth" for the former. Fortunately, it did not fall on the house but did smash into our wiremesh fencing. Probably repairable. I heard this morning that some poor guy in the city had both his cars smashed by a falling tree!

On Saturday afternoon, seven friends came round loaded with fresh bonito, saltfish, plantains and breadfruit. They cooked, I provided the beer and wine and did a pizza. Good time had by all.

Back Home

Kezia and Nanda got home Sunday afternoon. Phew!

Jaime had a good time with M. They went swimming on Saturday and he went to Sunday school at M.'s church. They then picked up Nanda and Kezia in the afternoon. He got a prize at school on Friday for progress in learning English - M. tells me he is now producing short sentences. (So maybe he can translate for Nanda and save the NHS some money!). Thanks again M.

Kezia received vincristine on Friday but her counts were too low to receive IV methotrexate - so we've now finished Escalating Capizzi II. Next up Delayed Intensification II - which Lucia assures me is the shittiest of the lot! Apparently, H. has just started it and is feeling dreadful.

Side Effects

I said I should do a drug side effects post at the end of the Asparaginase post and Jessica left a comment that yes, I really should. So this weekend's offering ...

There are many resources out there dealing with side-effects of specific drugs so I won't try and reinvent the wheel but will talk in a more general way.

First off, most of these drugs are cytotoxins i.e. they are toxic, poisonous – to both bad and good cells. As well as killing the bad cells, they'll kill the good cells. Often they produce useless by-products that can do damage as well.

Many of the side-effects are common to several drugs. Both this and that and that may produce this or that or that side-effect. But there's no guarantee that you/your child will suffer any particular effect. What causes one person's hair to fall out, won't for another person.

So let's start with the common effects that everyone will suffer at some time or another (in no particular order):

Hair loss: everyone's hair falls out. Then it will start to grow back, and then you repeat the drug that caused it to fall out in the first place, and yes, you've got it, it falls out again. Kezia isn't bothered about it, (hey punk!), but for teenage girls it's a bit depressing. In the UK the NHS provides wigs. Lucia (a teenager) has some advice for teenagers on her Teenage Cancer site

Mucosis: sore and/or infected mouth. The degree to which this happens will vary from person to person. Kezia has suffered just a bit – soft foods and antiseptic mouthwash have been enough. H.'s mouth went green and she couldn't eat or drink. If it gets this far, they'll suspend the treatment that has caused it, put you on antibiotics and hydration.

Both of these occur because hair and mouth cells naturally reproduce and die very quickly compared to other cells so if you're killing them off even quicker, their reproduction cannot keep up with their loss.

Nausea and vomiting: they can give you an anti-emetic (anti-nausea) medication for this.

Stomach cramps, diarrohea etc: speaks for itself.

Odd eating habits: increased appetite, decreased appetite, manias for certain foods – at the end of Kezia's induction nothing but chips and roast chicken crisps! The glucocortisoids, dexamethasone and prednisone, are particularly good at increasing appetite leading to weight-gain and puffy faces.

Neural effects: tingling or pins-and-needles in limbs etc. At the moment Kezia has sensitive feet and doesn't want to walk.

Mood swings: depression and euphoria, temper tantrums, unco-operativeness, Irritable Bastard Syndrome, highs and lows. This is especially difficult with young children who cannot verbalise it and cannot rationalise it. As a parent carer you've got to be especially sensitive – what is normal childhood pain-in-the-neck, what is drug-induced, what is both, and then how do you draw the lines?

As an absent father, I don't have to deal with this very much. But Nanda does.

Infections: your white blood counts are low so you don't have the normal protection against infections. At the slightest sign of an infection, a temperature or whatever, into hospital, normal chemotherapy suspended and onto the antibiotics.

You will be warned that THIS WILL HAPPEN right at the beginning. It's normal. It's happened to Kezia now on two occasions.

You may need a blood and/or platelet transfusions. Even if you don't have an infection, if your blood counts are really low, then you'll get a transfusion.

With kids you really have to look out for chicken-pox – if someone at school, comes down with it, then you keep your child at home.

Photophobia: sensitivity to light in the eyes. Kezia has this right now due to the IV methotrexate she's receiving in Escalating Capizzi II (obviously she had it in Escalating Capizzi I as well).

Contracting tendons: we were taught foot exercises to help prevent this. H. got it so bad that even physiotherapy didn't help and they had to put her ankles in plaster to resolve it.

Feeling Shit: ...

So those are (some of) the common side-effects! You think that's bad?

Less common effects ... (this isn't a full list – just a sampler!)

Vincristine: convulsions, optical atrophy with blindness

6-Mercapturine: abnormal liver functions

Dexamethasone: diabetes (Lucia and H.), inhibits growth, intestinal ulcers.

Cytarabine: liver injury

Methotrexate: liver, lung, kidney damage, stoke, seizure, neurotoxicity leading to learning difficulties.

etc etc

P.S. Lucia in the comments to this post describes severe bone pains as a result of dexamethasone. This is so bad for her that it was reported as a Severe Adverse Event (severe reactions are reported) to the UKALL 2003 trial, necessitates morphine when she comes off steroids and changing from dexamethasone to prednisone.

UKALL 2003 - Asparaginase

Asparagine is an amino-acid produced by normal cells. It was the first amino-acid to be discovered back in 1806 in asparagus – hence its name. One of the twenty most common amino-acids. Because human cells produce their own it is not considered essential in your diet.

It is required for protein synthesis and thence the synthesis of RNA and DNA. Most lymphoblasts, however, cannot produce asparagine and depend on freely circulating (or exogenous) asparagine produced by healthy cells.

If we can wipe up all this freely circulating asparagine, then the lymphoblasts cannot reproduce and cell death (apoptosis) results.

L-Asparaginase breaks asparagine down into aspartic acid and ammonia. It was first discovered in guinea pig serum about 30 years ago and found to suppress the growth of lymphosarcomas in mice. But, as the UKALL 2003 points out, “Clearly it was not a viable option to source this agent from guinea pig serum ...”. However, it is widely found in nature and ideal sources were discovered in the bacteria Escherichia coli and Erwinia crysanthemi.

It has quite a fantastic chemical formula C₁₃₇₇H₂₂₀₈N₃₈₂O₄₄₂S₁₇. With that number of atoms in a molecule, you're unlikely to find a diagram of it!

Early experiments found that the half life E. coli and E. crysanthemi asparaginase was about 10-12 hours which necessitated frequent injections and higher risks of side-effects. However, when attached to polyethylene glycol (pegylated), E. coli asparaginase has a half life of 5.73 days thus necessitating less frequent injections.

The study of Peg Asparaginase is one of the objectives of the UKALL 2003 trial. More specifically, the study aims

To test whether with current dosing/scheduling/product used we achieve:-

a) Adequate Asparaginase levels for the appropriate duration
b) Whether these levels deplete asparagines?
c) What is the rate of anti-asparaginase antibodies?
d) How many of the reactions to pegaspase are inhibitory?

To test the feasibility of routine Asparaginase monitoring.

Various measures on blood samples are performed – levels of asparaginase, levels of asparagine and levels of antibodies to the asparaginase. These will then be correlated to early leukaemic cell kill as measured by peripheral blood blast clearance, Day 8/15 and Day 29 marrow clearance plus the minimal residual disease estimates that form other objectives of the UKALL 2003 trial.

The Peg Asparaginase is administered as an intramuscular injection in this trial as it is thought that this route results in decreased hypersensitivity, although it may be administered intravenously in other protocols. The brand name is Oncaspar.

Numerous possible side-effects. Maybe I'll have to do an entire post on side-effects of all these drugs!

UKALL 2003 - 6-Mercaptopurine

Also more commonly known simply as 6-MP, this is given orally at various stages of the first year of treatment and then daily throughout the maintenance phases.

Again I am indebted to Patty Feist (link on right) for her explanation of its mode of action. It appears to have three modes of action. In the liver 6-MP is converted to a corresponding ribonucleotide (i.e. links to a ribose sugar – see the post on cytarabine). This inhibits the conversion of a compound called inosinic acid to adenylic acid which is needed to make the DNA base adenine.

In its second mode of action it also inhibits the conversion of inosinic acid to xanthylic acid that is necessary for the synthesis of guanylic acid necessary for the synthesis of the DNA base guanine.

Finally, it also works by being incorporated into nucleic acids as thioguanosine deoxyribose, rendering the resulting nucleic acids (DNA, RNA) unable to direct proper protein synthesis. Thus in this case we're changing the base rather than the sugar as is the case with cytarabine. (See this abstract)

Some people have different levels of TPMT (thiopurine methyltranserase - the enzyme that metabolizes 6-MP) activity that controls the first two modes of action (but not the third). This is controlled genetically (good explanation of this here). In fact, 1 in 300 individuals cannot break down 6-MP at all. In the UKALL 2003 protocol this is tested at diagnosis and later on, if found necessary due to adverse reactions.

In an earlier clinical trial UKALL 1997 the related drug 6-Thioguanine (6-TG) was found to increase remission death rates in comparison with 6-MP and so is no longer used. However, it would seem to be still used in other protocols (e.g the CCG 1961 protocol that Patty Feist's son was on).

It will be taken at night (see this paper on chronotherapy), at least one hour after a meal and with no recent intake of milk (see this abstract) as a compound in milk converts the 6-MP into useless by-products

See this link on Gertrude Elion, the discoverer of 6-MP and 6-TG.

UKALL 2003 - Vincristine

Another drug derived from a natural source – the Madagascan Periwinkle Caranthus roseus. The plant has been in use in traditional medicine for centuries treating anything from diabetes to wasp stings to eye infections. When scientists began looking at it in the 1950s, they discovered over 70 alkaloids among which was vincristine.

Microtubules form part of the structural network, or cytoskeleton, of a cell's cytoplasm. They are made of a protein called tubulin. They form various structures and have various functions. One of these is the formation of a structure called a mitotic spindle (mitosis = cell division). This segregates chromosomes correctly during cell division so that each daughter cell receives the correct number of chromosomes. In the picture below the mitotic spindle is green and the chromosomes are blue.

Vincristine binds to tubulin and prevents the formation of microtubules and, in particular, the mitotic spindle. Thus the cell dies without being able to divide.

Unlike our other chemotherapy agents so far, this is not working directly on the cell nucleus and DNA but within the cell's cytoplasm surrounding the nucleus.

It has, like all our drugs, many side-effects. Particularly, noticeable are neurological effects – Kezia developed tingling feet making her unwilling to walk. Others report similar effects.

If given intrathecally (in the spine), it is fatal. For this reason the UKALL 2003 protocol gives the following warning:

“All medical staff involved in the care of patients with leukaemia MUST be aware that the inadvertent administration of vincristine by the intrathecal route is invariably FATAL. Vincristine should NOT BE AVAILABLE when an intrathecal needle is in situ. This protocol has been written to provide separation of intrathecal methotrexate administration from intravenous vincristine administration in time. An additional precaution is that the two drugs should not be administered in the same place.”

UKALL 2003 - Cytarabine (Ara C)

Cytarabine, more commonly known as Ara C, is administered over four consecutive days in four blocks during Augmented BFM Consolidation, and two blocks each in Delayed Intensification I and II (in Regime C of UKALL 2003). It is administered through the Hickman Line and is generally done at home as four consecutive days visiting the hospital is a bit much for both patients and carers. You'll be given a choice of learning to do it yourself or have a community nurse visit. However, the latter is a bit infeasible if a dose falls on a weekend so I would really recommend learning to do it yourself. The hospital will train you and check you are proficient as well as providing written instructions to take home.

It's really best to have two people present when administering it so the second can both check the first is doing it right, and comfort the child. We have a two-person safety rule at work for any electrical or mechanical maintenance – the second person can catch any potentially dangerous slip-ups and assist if there are difficulties – the same is true here.

The process consists of cleaning the line with saline, injecting the drug, injecting Hepsal (Heparin Sodium – an anti-clotting agent to stop the line getting blocked) and finally saline again.

The story of the development of Cytarabine is fascinating – I will try and summarise here but go to Patty Feist's page for a more in-depth account A Tale from the Sea to Ara C. Thanks also to Patty for the graphics here.

The story starts in 1945 when a young scientist, Werner Bergmann, was collecting sea sponges (Cryptotethia crypta) on the coast of Florida. He boiled them up in acetone and instead of finding a steroid as expected, discovered a new substance similar to the DNA building-block, the nucleoside thymidine. Bergmann named the new compound Spongothymidine.

The two diagrams below demonstrate the very slight difference between the two molecules. The blue portion is known as the base, and the red part is a sugar. The base of each is the same, thymine, whilst the sugars differ slightly. In thymidine the sugar is known as deoxyribose and in spongothymidine it is arabinose.

Deoxyribose sugars (plus base) form the backbone of DNA, and ribose sugars (plus base) form the backbone of RNA. So arabinose is unlike either of them.

Early research in chemotherapy concentrated on changing the base but with the discovery of spongothymidine the focus moved to changing the sugar. John Evans and Seymour Cohen bound the sugar arabinose to another of the four DNA-bases, cytosine, making Cytosine arabinoside or Ara C, and tested its anti-cancer properties with positive results.

Here's how it works (another Patty page here).

In a cell Cytosine riboside (an RNA molecule) is converted to Cytosine deoxyribose (a DNA molecule) with the help of an enzyme. The enzyme needs to bind to the riboside and strip off an oxygen atom from the OH group (on the bottom right of the sugars in the diagrams below) to make the deoxyribose. However, if cytosine arabinoside is present, the enzyme binds to it through mistaken identity but as that OH group is on the top-right of the sugar instead, it cannot find it and cannot convert it to deoxyribose. Without the cytosine deoxyribose, new DNA cannot be made and the cell will die.

Other anti-cancer drugs are now being developed from marine organisms. Patty discusses Ara G and Clofarabine in the treatment of childhood leukaemia. Other anti-cancer drugs derived from marine organisms and currently under trial include Yondelis and Apledin derived from marine tunicates and Kalahide derived from a nudibranch (a sea slug).

This just goes to show how important biodiversity conservation is – new substances, of great scientific use, are still being found in plants and animals around the world. If we lose these, before discovering what they have to offer us, we have lost an incredible resource.

UKALL 2003 - Escalating Capizzi II

Finally Kezia started Escalating Capizzi II today with a dose of intrathecal methotrexate. So I guess her neutrophil and platelet counts were good. Tomorrow intravenous methotrexate and vincristine. The IV methotrexate is particularly nasty with its side effects but I'm pleased we've started - only 16 weeks give or take until we start the alot less intensive maintenance phases.

She was meant to start this phase last week but her counts weren't adequate. Not surprising really as she had been hospitalised with a temperature the previous Wednesday to Friday. Nothing really to be worried about but it did bring on a small family crisis over Jaime's childcare when they're in hospital. Anyway, with the great help of the social services, we have put in place some alternative childcare arrangements for the next time this happens.

UKALL 2003 - Dexamethasone 2

I've refrained from tackling this until now as I really didn't understand even a twinkling of the science behind Dexamethasone's anti-cancer properties. After much reading I discover that not even the scientists fully understand the mechanisms.

In my last post on Dexamethasone I attempted to explain its anti-emetic (nausea, vomiting) properties. However, talking to our consultant J. over the holidays, it seems the justification for its use in the treatment of leukaemia is its anti-cancer properties – the anti-emetic effects are a beneficial side-effect.

Right, I'll try and explain what is known about its anti-cancer properties. There appear to be several mechanisms at work:

• It appears to trigger programmed cell death (apoptosis). Both good and leukaemic cells.

• They inhibit the production of interleukins which are signalling chemicals which stimulate a variety of cell behaviours. The IL-2 interleukin (there are 33 of them) is produced by T-lymphocytes. The IL-2 then binds itself to the T-lymphocyte signalling it to grow and differentiate. (This self-signalling is termed autocrine). Clearly, inhibiting the production of leukaemic T-cells (or T-cell blastogenesis) is one of our goals.

• It can also (seemingly) increase the ability other chemotherapy drugs to destroy leukaemic cells

It can also prevent white blood cells from reaching sites of infection. Hence (as with most chemotherapy drugs) there is an increased risk of infection when taking it. Strangely, as the WBCs cannot reach the infection, the white blood count may be seen to go up.

I should also add that one of the lesser known and rarer side effects of the glucocortisoids is induced diabetes - this is what H. suffered from - she got over it but insulin injections in the stomach were no fun. I guess no more dexamethasone for her!

Next in the series is Cytarabine - this is kind of cool!

Update: in the comments Lucia also reports having suffered from diabetes so they have switched her to prednisone.

UKALL 2003 - Cyclophosphamide and Chemical Warfare

This is the one we really don't look forward to as it takes 4.5 hours at the hospital to administer. If the transport at either end is late, then we're talking a very very long day. Well, in fact it only takes about half an hour as an IV drip but they have to give you half an hour of saline beforehand and 3.5 hours afterwards to counteract one of its potential side-effects – more of that anon.

Cyclophosphamide is what is called a pro-drug – that is it doesn't act directly itself but gets changed into something else and this something else does the work.

In the case of Cyclophosphamide it is changed into aldophosphamide in the liver. Most of this is then oxidised by the enzyme aldehyde dehydrogenase (ALDH) into the pretty useless carboxyphosphamide. However, a small amount is converted into the good phosphamaride mustard and the harmful acrolein.

Now phosphamaride mustard is pretty cool stuff! It's one of a group of substances called nitrogen mustards and the first nitrogen mustard, mustine, is on Schedule 1 of the Chemical Weapons Convention!

At the end of the first world war mustard gas was quite widely used by both sides. Although there were only isolated incidents of its use in the second world war, both sides had large stockpiles. In 1943 a U.S. stockpile in Italy was bombed exposing thousands of people. It was noticed that one of its effects was to lower the white blood count – and this led to research into its use as an anti-cancer agent.

My dad was a Gas Identification Officer in the second world war. He worked in a factory producing paint for military aircraft – a protected occupation meaning he didn't get conscripted. After air raids he would have to go out and check that the bombs dropped were not gas bombs. He also went the rounds giving talks to air raid protection people – I remember when I was a child him showing us his sample kit which he would get people to sniff so they would be able to recognise chemical warfare agents. Blimey – if he was found with that stuff today they'd arrest him as a terrorist!

A couple of chemistry diagrams to demonstrate the relationship between cyclophosphamide and mustard gas.




At the top is a cyclophosphamide molecule, below mustard gas. Those two chlorine arms on each side of the nitrogen and sulphur atoms are what make them similar.

And lastly in this little digression – its called mustard because its smell is vaguely similar to edible mustard, not because edible mustard is otherwise faintly related.

The Acrolein is the reason behind all the hydration before and after. It is toxic to the surface of the bladder and can cause hemorraghic cystitis!

Phosphamaride mustard doesn't have much effect in the bone marrow (or liver) as the cells here have high levels of ALDH. Where it does have effect is on leukaemic blood cells where, and they're not quite sure how, it gets to work on the DNA causing cell death.

Usual range of side-effects: nausea, hair-loss, low WBC etc etc as well as the bladder problems mentioned above.

Today, neutrophils and platelets permitting, is Kezia's cyclophosphamide day.

P.S. I have added some dosing information to the post concerning Methotrexate.

UKALL 2003 - Dexamethasone 1

As previously mentioned the gluco-corticoid, (a steroid), Dexamethasone has two roles in ALL treatment. The first of these, to combat the side-effect of nausea caused by the anthracyclines. I'll discuss now, and leave its other role until a later date (when I understand it!).

Nausea and vomiting (known as emesis) are controlled in part of the brain known as ... the Vomiting Centre (not often that medical jargon is this straightforward!). The anthracyclines stimulate the production of a chemical called Serotonin (or more correctly 5-HT) in the gut. This Serotonin then binds to and stimulates the vagus nerve which in turn stimulates the spinal cord and the chemo-receptors. There are many types of these receptors sensitive to different chemical compounds and seven of them are sensitive to Serotonin. The one that stimulates the Vomit Centre is known as 5-HT₃.

So if we can successfully block, desensitise or turn off the 5-HT₃ receptor, then we can stop the nausea – and this is what Dexamethasone (as an anti-emetic) does.

Unfortunately, it has its own side-effects such as increased appetite (Kezia put on weight!), sleeplessness and mood swings.

Kezia definitely suffered from mood swings. I sometimes think it is easier for an older person to rationalise these – I'm grumpy (or as Cass of Cancergiggles calls it – Irritable Bastard Syndrome) but it's due to the medication. Kezia cannot do this and does not understand why she is upset, which must be distressing in itself.

However, there's a downside to the ability for rationalisation that comes with age. Kezia does not understand ALL, cannot imagine her own mortality or the battles still to come. She lives from day to day, oblivious to such feelings – if one day she is down, the next will be happy, not remembering yesterday. For this, we must be grateful.

UKALL 2003 - Daunorubicin and Doxorubicin

These drugs belong to a family of medications called anthracyclines which act directly on cell DNA and prevent the cell from replicating.

Daunorubicin: this is administered during the first Induction phase. It binds to the DNA and intercalates with it i.e. it inserts a molecule of itself in between the DNA molecules. This distorts the DNA, messing with the way it functions and preventing it from replicating.

In the picture above normal DNA is shown on the left and DNA intercalated at three locations (in red) is shown on the right.

Doxorubicin: this is given in the two Delayed Intensification phases (4 and 6). It binds to the DNA and inhibits the enzyme which unwinds the DNA double helix to be read for copying. It stops the enzyme from resealing the double helix thereby stopping replication.

Both drugs are administered by IV drip.

One of the side-effects of both these drugs is feeling sick (nausea) and vomiting. For this the gluco-corticoid (a steroid), Dexamethasone, is given. As well as combatting the side-effect of nausea, Dexamethasone is also used as a first-line treatment drug in later maintenance phases. For this reason, I'll leave its discussion until a later post (as I'm still trying to get my head around how it works!).

Another side-effect of the anthracyclines is hair-loss. In young adults, this can be a major psychological issue (Lucia discusses it in her blog – link on right). However, although it has happened to Kezia, she has not yet developed the self-consciousness for it to be a problem. I think Nanda and I have been more effected – Kezia's hair was so beautiful! However, it will grow back!