Clinical practice in chemotherapy for colorectal cancers: A note on current practice and research

Hello Again

I am really glad that you are looking into this and I appreciate what you are saying but can I ask some simple questions that might not have a simple answer and are not covered in your summary above? 

The usual 5-FU regime for example is 2 days of 5-FU in combination with other drugs, followed by 12 days without. I assume therefore that on the first few days the dose is at it's highest and that it then falls until it is at it's lowest level and the fall will vary according to the patient, their weight, metabolism, the efficiency of their liver and kidneys etc and how far they are into the regime as side effects may be cumulative.

In order to determine the blood levels I assume that you want the patient to have regular blood tests during this time to ensure that the highest level is below the toxic level and the lowest is above the ineffective level. Are the dose adjustment algorithms able to function accurately on just one blood test a month given the patient specific variables, or do you envisage the patient needing to attend the cancer centre regularly for blood tests through the two weeks and is this practical given the huge push on resources?

Are oncologists just trying to ensure a therapeutic dose on some of these days and then giving the body a rest before administering the next dose or should the patient be within the therapeutic dose every day and might this mean for example having lower dose infusions more frequently?

Therefore:

• What is the TDM regime you are proposing? How many additional blood tests per patient and on a nationwide basis?
• Does a standard hospital lab have access to High Performance Liquid Chromatography (HPLC) assay equipment or might they have to be bought in and staff trained to use it?
• What might the cost implications be on a per patient basis?

I am just trying to understand what it is that I am asking for and how practical this is, as we all want the chemotherapy to be effective. If we are going to make this happen then we need to know what we are asking NICE/the NHS to fund? Are any of my bullet points known or are you asking NICE to just investigate the practicality of implementing TDM?

Thanks

Nicky

I was told the standard regime for rectal cancer is 30 weekly doses of 5FU (only), which is what I am doing.  So how would this be implemented  under TDM?

Hi Gemmary - thank you for engaging in this topic. To be able to answer your question properly, I would need to know over how long you receive your dose?

Regards

Hello Nicky - I can see my summary has got you thinking, which is excellent news. The more people that start thinking and asking about this, the better!

Okay, so you're right, the answers are not simple!

With the normal regimen, 5-FU is given over a 46 hour period, usually in a take home pump.

5-FU has a half life of 13 minutes so you reach a steady state of the amount in your system fairly quickly and then it leaves your system equally quickly once the infusion is finished (every 13 minutes, there is only half as much of it in your system than there was 13 minutes ago and so on - half becomes a quarter becomes an eighth, becomes a sixteenth every 13 minutes etc), leaving you with negligible levels of 5-FU in your system for most of the days between doses (giving your body a rest).

Only one blood test is required per cycle, not several over each fortnight. It needs to be taken when the amount of 5-FU in your system is at a maximum steady state (commonly known as Area Under the Curve, or AUC), which can be any time after the first few hours of an infusion beginning through to a few hours before the end of the infusion. Generally though, a blood sample should be taken around six hours before the end of an infusion to ensure you are well into the steady state condition (timing can be fairly flexible though because you spend most of the 46 hours at steady state conditions). Your first cycle of 5-FU would be based on the initial BSA calculated dose, because there is nowhere else to start from and then the result from the blood test taken during your first cycle would be used to check if you were getting the right dose for you as an individual and so on for each cycle. It seems to take around three cycles to get people into the right therapeutic range for them (as you say, enough to be effective and not so much as to be toxic).

The algorithms are well established. They are used to interpret each result coming out of the assay machine and yes, they work for each sample taken.

There are logistical issues raised by the use of TDM, I agree, but they are not insurmountable. We overcame them to get a sample taken from my wife privately, so I know it can be done. Here's some examples of how that extra blood sample per cycle could be taken - Day 1 5-FU infusion starts. Day 3 - TDM blood draw is taken, either by the patient returning to the cancer centre or taken at a GP surgery, or at a community health centre (open all weekend) or by a district nurse. The sample is then separated and the resulting plasma is stabilised and sent to a lab for assay, which doesn't take long. The results of that test are then available for your oncologist to use to adjust your next dose, if necessary. For the patient, I would suggest the inconvenience of this additional blood draw, is a minor one, considering it is an improvement in your outcome that you're playing for here.

So, in short, it's one additional blood test per patient per cycle. HPLC and other assay machines are standard pieces of lab equipment and have been for years (any self-respecting hospital will already have several of them; they just use them for other things), they don't cost a huge amount of money and have high throughput (example - Olympus AU 400, can do 400 samples an hour and it's big brother, can do 800), so cost per unit blood sample is low (for example, our private sample analysis, cost us £32 on a one off basis). NICE have already looked at one assay test and equipment and have determined it to be cost effective in terms of their QUALYs. It will be the same for any chosen test method and equipment. It's all well established. Any lab technician can use these machines, you don't have to be a specialist and the test consumables are just bought-in items that are plugged into the machines.

I hope that answers your questions! If not, don't be shy in asking some more or use the link to my blog, where you will find much more information and answers to your questions.

I agree, we all want chemotherapy to be as effective as possible; that's why I am passionate about getting TDM adopted in the UK, as it is in at least France and the Netherlands.

I will not achieve revolution (although, I believe that is what is required!), it is evolution that I seek from NICE and the NIHR, because that's a more realistic thing to ask for.

If you are concerned you are getting the right dose though, ask your oncologist as to how they know you are getting the right dose for you as an individual and see what they say and how awkward it makes them when you let them know that you know about these issues. You could always take a copy of my spreadsheet from my blog and show it to them.

If you are then still concerned, there is a way of getting your own sample taken - it's not the easiest thing to do on your own, but we have done it once, so if you wanted to, I could help you with some advice as to how to do it. You would only need the one sample to show whether you were getting the right dose at that time, which would be enough to take back and show your oncologist. Please read my blog and you will see what we had to do to get that sample and how my wife's oncologist reacted to that result.

Regards

Hi, I started weekly 5FU with folinic acid, on 1 May, and should have had week 12 on Wed 17 July but they stopped it due to side effects. Seeing oncologist on Monday and assume they will restart on Wed . They will then continue upto the 30 weekly doses -I assume! Bloods were taken weekly, now monthly.

If you mean time as in how long to inject, once they sort cannula etc it only takes 20min or so.

Hope that answers your query.

I have now read some of your blog (can't seem to access some of it) and just thought I would add the following.

After week 5 I felt crap, lots of side effects, so week 6 they reduced the dose from 700 to 600. I don't know the units. Side effects eased up, but are obviously restarting to cause problems with either hand/foot syndrome or peripheral neuropathy I don't know which at the moment. I somehow need to know whether it is worth continuing as my hands are my life and job. Am accumulating questions to ask on Monday!!

Okay, so that suggests you get a bolus of 5-FU, which means it's quickly in and out of your system (half life of 5-FU is only 13 minutes) that means you could easily get a blood draw to determine the steady state (or perhaps in your case, peak) concentration of 5-FU in your blood plasma before you left the hospital, if TDM was offered and that would tell you if the dose you are getting is too little to be effective, just the right amount, or too much, which is toxic. But oncologists don't do that sadly and that's what I'm campaigning about.

Regards

Hmm - that's strange - if you click on read more at the bottom of the page, it should take you all the way back to Part 1, but if you tell me which posts you can see, I'll send you a link to the ones you can't see if you like.

I can't really advise you whether to stop taking your chemo. If your hands are your life and your job, then you might want to consider stopping now. But on the other hand, if you stop taking the chemo, your life might be rather shorter had you continued with the chemo, which substantially decreases the chances of the cancer ever coming back. It's a tough one. That discussion with your oncologist, weighing up the risks and benefits of doing either, will help you decide though.

Good luck and let me know how you go on.

Regards

bump

Had a meeting with a professor at The Christie about this on Monday. He completely agrees with my findings. They cannot do anything without funding though. Nevertheless, it’s good to know I’m not some sort of crank; I’m right!

Have now written to every single party about it, below the level of the Chief Medical Officer and await their responses. If they are all negative, then the CMO will get a letter.

It’s time for change.

Everyone whose chemo dose is calculated on Body Surface Area, should be asking about why Therapeutic Drug Monitoring is not used.