Personalized Therapeutic Drug Monitoring in the Treatment of Colorectal Cancer

8/14/2019 Personalized Therapeutic Drug Monitoring in the Treatment of Colorectal Cancer

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Personalized Therapeutic Drug Monitoring in the Treatment of Colorectal

Cancer: Pharmacokinetic-Guided Dosing of 5 Fluorouracil

Ernest C. Borden, MD, FACP, FAAAS (Moderator)

Edward Chu, MD

Dr Ernest Borden: Welcome to this CME program entitled Personalized

Therapeutic Drug Monitoring in the Treatment of Colorectal Carcinoma,

Pharmacokinetic-Guided Dosing of 5 Fluorouracil. This activity is

supported by an educational grant from Myriad Genetics and is jointly

sponsored by The Postgraduate Institute for Medicine and Miller Medical

Communications, LLC. My name is Dr Ernest Borden and I will be your

moderator for this program. I am the Associate Editor of Seminars in

Oncology and I am with the Taussig Cancer Institute at the Cleveland

Clinic. I am a Program Leader for Developmental Therapeutics at theCase Comprehensive Cancer Center and Professor of Molecular Medicine

at the Cleveland Clinic Lerner College of Medicine of Case Western

Reserve in Cleveland. I am also a practicing medical oncologist. I would

like to welcome Dr Edward Chu, Chief of the Division of Hematology and

Oncology at the University of Pittsburgh School of Medicine. He is

Professor of Medicine, Professor of Pharmacology and Chemical Biology,

and Deputy Director of the University of Pittsburgh Cancer Institute in

Pittsburgh, Pennsylvania.

I will now turn the program over to Dr Chu for the start of this educationalprogram.

Dr Edward Chu: Dr Borden, thank you for the introduction and thank you for

moderating this program. As I think everyone knows, in the field of

oncology the big buzz word these days is individualized, personalized

medicine, and the whole concept of this approach is to move from the

empiric delivery of chemotherapy, which we have done for the last 30 to

40 years, and to begin to change the paradigm to a more individually

tailored treatment. The whole concept of this approach is to treat with the

right drug to the right patient at the right dose, although in truth, I think

really where we focused our efforts is on trying to identify the right patient

to be treated with the right drug. Obviously, this more individualized

approach can lead to a more optimal clinical benefit, avoid unnecessary

side effects and toxicity, and I think also, especially as were now more


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concerned about the pharmacoeconomic aspects of treatment, offers

significant financial cost savings.

Now with respect to this whole concept of therapeutic drug monitoring, as

you see here in this slide, there are a whole host of non-cancer associated

medications where we actually measure drug levels on an everyday

clinical basis. And so there are a number of antibiotics, a number of anti-

epileptic agents, drugs that we use to treat asthma, COPD, cardiac

indications, HIV, immunosuppressant agents, psychotics, and of course

everyone knows that we have to very carefully follow the coagulation

parameters to see if were treating a particular patient with the right dose

of the oral anticoagulant Coumadin.

However, if you look in the field of oncology, there are actually still only a

very small handful of drugs for which actually therapeutic drug monitoringis used on an everyday clinical basis. In fact, probably the only drug

where this is really being used presently in the United States is looking at

busulfan levels, which can help us to determine whether or not a patient

actually is receiving an appropriate dose of busulfan and actually whether

or not the patient will then benefit from busulfan therapy in the setting of

stem cell transplantation. We all know that we get methotrexate levels,

but we dont get methotrexate levels to guide what dose of methotrexate

should be used on subsequent cycles; we use that dose to determine

what we should treat patients with in terms of leucovorin rescue. In

carboplatin we dont actually follow drug levels, but we use an AUC target

level of carboplatin to figure out what dose of carboplatin should be used.

The focus of todays discussion will be on what has been presently done

with respect to the therapeutic drug monitoring of the fluoropyrimidine 5-

fluorouracil. There is actually now emerging data that for docetaxel and

paclataxel that measuring taxane drug levels actually is correlated with

clinical efficacy. and there is also some retrospective data which is really, I

think, quite intriguing to suggest that higher levels of the small molecule

inhibitor imatinib, aka Gleevec, actually is associated with higher rates of

molecular complete response.

Now, why actually measure 5-FU drug levels? Well, over the past 30 or

40 years where 5-FU has been used in clinical practice, it is clear that

there is significant inter-individual as well as intra-individual variability in

the levels of 5-FU when dosing is based purely on body surface area

(BSA). With 5-FU, as well as with pretty much all of the other anticancer


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agents that we use to treat our patients, there is a relatively narrow

therapeutic window and obviously once were above a certain

concentration, that leads to dose-limiting toxicity. As I will show you in the

next slide, really going back to the late 1970s, there has been a very well-

defined relationship between 5-FU drug levels and biological effect, either

in the form of toxicity and/or efficacy.

Again, the rationale for trying to more precisely manage the dose of 5-FU

but really this holds for pretty much any anticancer drugis we want to

get into this so-called optimal therapeutic range, the so-called sweet spot,

because obviously if were above that sweet spot concentration, that will

lead to toxicity; if were below that optimal therapeutic drug level, that can

actually reduce the potential clinical efficacy of 5-FU and/or any other

drug.

This slide reviews with you the correlation of 5-FU AUC drug levels, and it

is interesting that AUC, which stands for area under the concentration

curve, seems to be the pharmacokinetic parameter that most closely

associates with both efficacy as well as toxicity. Again, going back to the

late 1970s up until recently, there actually has been a very strong

correlation between AUC drug levels of 5-FU and either clinical efficacy

and/or toxicity.

This slide shows that if the AUC drug levels are greater than 25 mg per

hour per liter, that actually is associated with a higher incidence of toxicity

in the form of myelosuppresion, mucositis, stomatitis, GI toxicity in the

form of diarrhea, and the dermatologic skin toxicity, the hand-foot

syndrome. And also, it doesnt really matter how the 5-FU is given,

whether it be given bolus or intravenous infusion.

Now a very interesting study was conducted by Eric Gamelin and his

colleagues in France and I think it is fair to say that Dr Gamelin really has

been the true pioneer in trying to understand 5-FU drug levels as it relates

to eventual clinical outcome. And so the French group actually conducteda randomized phase 3 study, the goal was to assess the value of PK-

guided 5-FU dose adjustment in controlling toxicity and improving efficacy

in patients with metastatic colorectal cancer. This was a prospective

randomized multicenter study done in France: 104 patients were

randomized into each arm and this was in the front-line setting of patients

with metastatic disease. In the control arm, patients were randomized to


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receive 5-FU based on conventional BSA dosing, whereas in the second

arm patients received 5-FU in the first cycle using traditional BSA dosing;

but all subsequent cycles were individualized based on 5-FU drug levels.

What Dr Gamelin did was, he used a target AUC of 20 to 24 mg per hour

per liter based on the data that I had shown you a couple of slides ago.

What was interesting is, in those patients who were randomized to the PK-

guided dosing arm, as you can see here, there is a wide spread of 5-FU

doses that were ultimately given. Initially patients received a dose of 1500

mg per meter squared of 5-FU on a weekly basis. But as you see here on

the PK-guided dosing, you have a number of patients who received doses

below 1500 and a significant number of patients who ultimately had to

receive higher doses than the 1500 mg per meter squared.

This shows that in patients who were randomized to the control arm, whoreceived the conventional dose of 5-FU based on BSA dosing, obviously

the majority of patients received the 1500 mg per meter squared dose and

then some patients had to have dose reduction, presumably because of

toxicity. What was striking about this study was that 68% of patients were

underdosed, 17% of patients were overdosed, and only 14% of patients

received an optimal dose of 5-FU, which means that 85% of all patients

did not receive an optimal dose of 5-FU.

What was nice about this study was that ultimately with PK-guided dose

adjustment, the 5-FU AUC drug levels, that sweet spot of 20 to 24, was

ultimately achieved in almost 100% of patients; on average it took about 3

to 4 cycles, and in this regimen 3 to 4 weeks were required to achieve that

target concentration, and adjustments to dose were based on the

measured 5-FU AUC drug levels and also clinically assessing the patients.

And another important point was that patients were continued to be

following with ongoing monitoring to maintain that target concentration

drug level.

How did that impact on toxicity? And this slide shows us very nicely.Overall, there was a significantly reduced level of Grade III, Grade IV

toxicity in those patients randomized to the PK-guided dosing arm, and

this was reflected primarily by a significant reduction in the levels of Grade

III/Grade IV GI toxicity in the form of diarrhea; so very impressive results

with respect to reducing toxicity.


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And how about clinical efficacy? As you see here in this slide, the overall

response rate was doubled from 17% to 34% in those patients who were

randomized to the PK-guided dosing arm.

If one looks at median overall survival, overall survival increased from 16

to 22 months. So an increase of 6 months survival in those patients

receiving the PK-guided dosing of 5-FU. This did not reach statistical

significance as you see here in the upper right hand corner of the slide,

but I guess I would make 2 points, one is that this was still a relatively

small study, clearly not powered to look for survival differences. The other

thing is that in both arms patients could receive the same types of

effective salvage therapies, as well as perhaps undergo surgical resection,

so those secondary salvage therapies would certainly dilute the effect of

PK-guided dosing, as it certainly relates to survival.

There is a more recent study that was done by, again, Dr Gamelins group

in France; so that first study was just looking solely at 5-FU leucovorin, the

subsequent study, which was published in the journal Clinical Colorectal

Cancer earlier this year, was a phase 2 multicenter study looking at

FOLFOX4 chemotherapy. This was not a randomized study: there were

39 patients you kind of used as controls who were treated with 5-FU using

traditional BSA-guided dosing, and then 118 patients received 5-FU based

on this PK-guided dosing approach. So again, the first cycle they received

5-FU using BSA and then all subsequent cycles, their 5-FU dose was

tweaked depending upon the 5-FU drug levels. Importantly, 83% of the

patients required 5-FU dose adjustment of more than 10% to achieve that

target concentration of 20 to 24, which was, again, very similar, nearly

identical to the results seen in the previous study. Sixty-four percent of

the patients required an increase in 5-FU dose, about 20% required dose

reduction, and almost 40% of patients were under-dosed by at least 20%.

If one looks at the efficacy in terms of median progression-free survival for

the BSA-based dosing, the PFS was 10 months; in those who were

receiving PK-guided dosing of 5-FU, that increased to 16 months. And ifyou look at overall survival, it went from 22 to 28 months. So again, I

would just emphasize this was not a true randomized study, but again I

think if you look at PFS and overall survival, there really is a clear sense

that clinical outcome is improved in those patients who receive 5-FU using

a PK-guided dosing approach.


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If you look at toxicity, the instance of Grade III/Grade IV diarrhea was

significantly reduced, from 12% to nearly 2%. Neutropenia,

myelosuppression, reduced from 25% to 18%, and the instance of

mucositis was significantly reduced from 15% to less than 1%.

There also is a very interesting phase 2 retrospective evaluation of 5-FU-

based chemotherapy in the adjuvant setting in patients who had Stage 3

colon cancer. So 115 patients were studied; this was a study done by

Antonello Di Paolo in Italy, this was published in Clinical Cancer Research

about 4 years ago, and what is significant but actually very consistent with

what I have shown you thus far is that there was a significant improvement

in 10-year disease-free survival in patients who had 5-FU AUC drug levels

greater than 8.4 mg per hour per liter.

In terms of the US clinical experience, there is an experience of USmedical oncologists using a newly developed 5-FU immunoassay; this

clinical experience went from 2009 to 2010. This included patients who

were receiving 5-FU infusional therapy for both adjuvant as well as

metastatic disease. The main regimen was FOLFOX6, and patients could

receive the anti-VEGF antibody bevacizumab.

The bottom line was, with the first test only 21% of patients were within

that target range of 20 to 24. So again, this analysis here in the United

States pretty much confirms the experience from Eric Gamelin and his

group in France showing a wide exposure to 5-FU drug levels in the US

population.

This just shows it here, 51% of patients were underdosed, 28% of patients

were overdosed, and again, only 21% of patients were in that sweet spot.

And this slide just shows that now almost 80% of patients are outside the

target 5-FU AUC drug range with the first dose of 5-FU which was given

based on body surface area.

What can we conclude from all of this? Clearly there is significant

variability in patient 5-FU drug exposure across all 5-FU base regimens,

either infusional 5-FU monotherapy, FOLFOX regimen, and there also is

very consistent data with FOLFIRI regimens. PK-guided dose monitoring

allows the practicing oncologist to individualize and optimize the patients


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exposure to 5-FU treatment and in this setting can maximize efficacy,

minimize toxicity.

There is now a dose optimization test, there is a 5-FU immunoassay that

allows us to more effectively and more rapidly measure 5-FU drug levels,

which can then allow us, the practicing oncologists, to individually manage

and optimize 5-FU-containing regimens in colorectal cancer. Up until the

development of this 5-FU immunoassay, 5-FU drug levels were measured

using much more sophisticated labor-intensive HPLC and LC mass spec

technologies. Now we just have a very simple test that can help us to

measure drug levels. My feeling is that this has significant potential

relevance for the treatment of other gastrointestinal cancers as well as

other solid tumors. The question is, can a similar kind of 5-FU dose

monitoring be extended to oral 5-FU agents, such as capecitabine, which

is the only oral 5-FU drug approved here in the United States, but UFTand S1, which is used in Europe and in countries throughout Asia.

With that I would like to stop, thank you for your attention, and I would

certainly be very happy to answer any questions.

Dr Ernest Borden: Thank you, Ed, for a very informative presentation on how to

potentially improve outcomes for patients with colorectal carcinoma and

potentially other gastrointestinal malignancies receiving 5-fluorouracil.

Perhaps I might start the questions by asking you to put this in the context

of utilization in colorectal cancer for individual stages of disease that we

manage, both the adjuvant setting and the metastatic disease setting.

Dr Edward Chu: It is a very good question. I think, based on the data that

was presented, I think the implications are even greater for our patients

with early-stage colon cancer who are receiving adjuvant chemotherapy,

because as you saw, so upwards of 60%, 65% of patients who were

treated with infusional 5-FU are actually being underdosed. That is really

an important issue, especially as were going for the cure in patients who

are receiving adjuvant chemotherapy. Obviously in the metastatic disease

setting, it is also important, but obviously I think it is critically more

important to get the right drug levels of 5-FU when were trying to cure

those patients and try to prevent the cancer from recurring locally and/or

systemically.


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Dr Ernest Borden: That is very helpful just in terms of utilization of this from a

clinical practice standpoint. One aspect that comes up from a clinical

practice standpoint is the element of what is the turnaround of this, utilize

it in Cycle 1; I take it from the presentation that that data would come back

in time for start of Cycle 2, but tell us something about the logistics.

Dr Edward Chu: I think the whole process has been revolutionized now with

the development of this 5-FU immunoassay, and so the methodology is

very simple, it is very reliable, it is consistent, and to the issue that you

raise, turnaround time, what is nice is that the turnaround time is within 5

to 7 days. That then gives the practicing physician time to be able to

figure out what dose of 5-FU needs to be administered on the subsequent

cycle.

In fact, it is interesting, these tests can be done on an Olympus analyzer,which all of the clinical laboratories have. Truthfully, the test can actually

be done within an hour. Actually, up to 300 or 400 samples could be

potentially run in an hour. But I think the way that Myriad Genetics has set

up the testand they're the only ones in this country who can perform this

immunoassay at least right nowI think they're committed to a turnaround

time of 5 days.

Dr Ernest Borden: Is this something that the practicing oncologist will send to

his clinical laboratories and coordinate with his clinical pathology

colleague, or is this a direct mail from your clinic to Myriad Genetics?

Dr Edward Chu: Right now as it stands, so all the testing, all the samples

have to be sent to Salt Lake City, Utah, to have the 5-FU drug levels run.

There may be a time down the road where it might be more readily

available to the local clinical laboratories, but right now and for the

immediate future, all the samples will go to Utah, but I can tell you there

are already many of our oncologists within our UPMC Cancer Center

network who are sending their samples to Salt Lake City, Utah, and the

whole process has really been very much facilitated.

Dr Ernest Borden: This requires 1 single tube?

Dr Edward Chu: It requires 1 single tube of blood, that is right. Traditionally,

the optimal timing to get the blood sample is any time after 18 hours of the

infusional therapy.


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Dr Ernest Borden: I was surprised, one of your slides referred to taking

approximately 4 cycles to get to that sweet spot. I am surprised that the

dose adjustment takes that long. Any tips there in terms of the practical

aspects of the dose adjustment?

Dr Edward Chu: Well, it is interesting. So it can take up to 3 to 4 cycles to get

ultimately to that sweet spot, although even with Cycle 2 and Cycle 3, you

know, one inches closer. There are some examples that we have had a

chance to review where even with the second cycle you already get to that

sweet spot. I think the key issue to remember is that when we look at

potential sources of pharmacokinetic variability, there just are a whole host

of what I call patient-specific factors and then a whole host of kind of drug-

related factors that need to be factored in. When we give a patient a

chemotherapy drug using BSA, so that is just only looking at height and

weight, but that is 2 of what probably are at least 10 to 12 other factors,other variables that go into determining drug metabolism, drug clearance,

and pharmacokinetic variability. There just are a lot of other issues that

one has to consider and so that is why actually, I guess, to me it probably

is not that surprising that it may take 3 to 4 cycles to get to that sweet

spot.

Dr Ernest Borden: Are there guidelines towards getting dose adjusting to get to

that sweet spot?

Dr Edward Chu: Myriad Genetics has actually put together a very nicealgorithm and, in fact, based on their clinical experience, I think they

found, actually, because there can be also intra-individual variability and

even kind of the test itself, there can be a certain amount of variability, so

rather than using what I think we consider to be a pretty tight sweet spot of

20 to 24, looking at all of the data, looking at the data that has been

generated from the US community clinical experience, the sweet spot has

kind of been broadened out, so it is now 20 to 30. Myriad has now put

together a very nice algorithm, so depending upon what 5-FU AUC drug

level one has, they can then recommend how much the dose should be

either increased or decreased.

Dr Ernest Borden: That is, I think, helpful in terms of managing the individual

patient toward improving outcomes and decreasing adverse events. Your

last slide made reference to the possible utilization with capecitabine, Im

sure, in the management of colorectal carcinoma patients, this is

something that is being actively considered. Any further experience there?


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Dr Edward Chu: No, I mean, it is a great question. I think in many ways I

think those of us who treat patients using capecitabine have found that

there can be significant variability, and again this is an oral agent so the

variability also starts from absorption and the metabolism, and then

potential drug-drug interactions and impact on food and patient

compliance. There is a whole host of other issues that one has to factor

into the use of Xeloda. It is interesting you asked the question, our group

has been very interested in this; we actually are hoping to actually start a

clinical study where we will actually be treating patients with different

doses of capecitabine and then kind of use 5-FU drug levels as a

surrogate, and then try to see if we can then make similar kinds of

correlations and identify a similar kind of 5-FU AUC drug range that would

best correlate with toxicity and efficacy to capecitabine. Obviously, the 5-

FU drug levels in the peripheral blood are going to be much, much lowerthan what we typically see with infusional 5-FU, but our hope is, probably,

if we were to have this discussion a year from now we actually might have

some data to present.

Dr Ernest Borden: From all of those factors that you mentioned earlier that can

influence drug levels, I imagine that the outcomes of your research study

may well find even greater variability towards getting towards that sweet

spot with an orally administered agent such as capecitabine in contrast to

the infusional 5-FU.

Dr Edward Chu: I think that is absolutely correct and especially as now were

using more and more oral agents in the treatment of cancer, I think that is

going to become a much more relevant issue.

Dr Ernest Borden: For other targeted agents, you have referred to the possible

PK variability being seen with imatinib or sunitinib or other targeted

agents, and importance and relevance there may prove over the long term

to be particularly valuable.

In closing, any other points that you would like to make?

Dr Edward Chu: I think this is a very interesting approach. Obviously it

changes the whole paradigm, but my feeling is the studies I presented for

5-FU I think are certainly relevant, but I think has even broader

implications and my feeling is this whole concept of PK-guided dose


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monitoring with subsequent dose adjustment, I think will find its way into

every day clinical oncology practice down the road.

Dr Ernest Borden: I think you have made a very excellent summary indicating

its importance in that regard.

For those of you, who are listening, please click through onto the CME

quiz to obtain credit for participating in this activity.

Thank you, Dr Chu. Thank you, those of you who are listening for both

your interest and attention. Good day.

Personalized Therapeutic Drug Monitoring in the Treatment of Colorectal Cancer

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