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Grapefruit juice and St John's Wortare just the tip of the icebergHow can we prevent damaging interactions in this era of long-term oral cancer therapies? Anna Wagstaff
Certain foods, prescription drugs and complementary remedies interact with cancer therapies, altering the effective dose and putting patients at risk. Yet there is scant clinical evidence on which interactions are dangerous, and many doctors are unaware of what their patients may be taking.
Calls are now growing for a strategy to get to grips with this hidden problem.
twice before casually reaching for a new ticular problems for cancer patients – health supplement from their local super- problems that are likely to get worse as new One of the biggest hurdles in bringing a new cancer drug tomarket is turning a promising market, or embarking on a course of an agents come onto the market, and as man- molecule into something that actually additional prescription medicine that agement of the disease moves towards works therapeutically in the human body.
could radically alter the way their body long-term control with oral therapies.
The active compound has to be absorbed deals with their cancer drugs.
Because of the toxic nature of many by the body and reach the parts that mat- If doctors, nurses and pharmacists cancer drugs, interactions that increase ter so that it acts before it is flushed from were more alert to the possibilities, they the amount of the active drug circulating the system or broken down in a way that might make more effort to ask what other in the body can have fatal consequences.
deprives it of its cancer fighting properties.
substances their cancer patients might be Even where the consequences are less The drug has to be effective at strengths taking that could interact with their ther- dramatic, if they are not properly explored, that don't put a patient's life and long-term apy, and be quicker to explore interaction they can lead to patients being taken off health at risk from heart failure, stroke, or as a possible factor if patients fail to a beneficial drug on the grounds that attacks on the liver or other organs. Tol- respond to a drug or experience unex- they are ‘intolerant'.
erability is also important, particularly for Interactions that lower the level of long-term therapies – no patient wants a It has long been known that medi- active drug in the body, on the other hand, life blighted by diarrhoea, vomiting or a cines can interact with other prescription render the therapy less effective. Again, facial acneiform rash.
drugs, with complementary/alternative without proper investigation, it can be If cancer patients were more aware of medicines (CAM), or even with certain easy to assume the patient is just one of the delicate balance, they might think items of food or drink. But this poses par- the unlucky ones whose disease is resist- 24 ■ CANCER WORLD JULY/AUGUST 2010
longer than intended – effectively anoverdose that could lead to very seriousside-effects.
CYP3A4 levels seem to be affected by a wide spectrum of substances. TheUnited States National Library of Medi-cine lists 38 prescription drugs – including antifungals, antibiotics and antidepres- sants – that inhibit CYP3A4 (making the cancer drug more toxic). It listsa further 20 drugs that induce CYP3A4 (reducing the efficacy of the cancer drug).Added to this are many CAM products and common foods known or suspected to inter- act with the enzyme – including grapefruit, starfruit, St John's Wort, kava-kava, cat's claw, valerian root, milk thistle, goldenseal, black cohosh, many herbal teas, ginseng, and genistein (found in soy products).
The potential for problems is clear.
Some of these interactions pose a very serious threat (see table overleaf). Theantifungal drug ketoconazole, for instance, can lead to a five-fold increase in serum concentrations of dasatinib, and a three-fold increase with nilotinib and lapatinib. While serum con- centrations of many of the TKIs are reduced by more than 80% in the presence of the bactericidal antibiotic rifampin. St John's Wort, known as the ‘sunshine herb', and com- K monly used in many countries as a natural .UO ant to the therapy. The problem is partic- tinib (Tasigna), sorafenib (Nexavar) and remedy to treat insomnia, sadness and TRA ularly acute with adjuvant treatments, sunitinib (Sutent), and indeed some non- depression, is known to reduce serum ISNA where evidence of response or resistance TKI anti-cancer drugs such as docetaxel, concentrations of imatinib by 30%, and is GR may not become apparent for many years.
irinotecan, taxol, vincristine, etoposide, likely to have a similar effect in other TKIs. OW ifosfamide and tamoxifen.
Interactions that are flagged up as WW, HOW SERIOUS IS THIS PROBLEM? If a patient's CYP3A4 levels increase potentially dangerous by preclinical phar- NEL The behaviour of cytochrome P450 3A4 above the range considered normal, these macological data do not always play out in EED (CYP3A4) offers a useful starting point for drugs are likely to be broken down into the clinic, however, as can be seen from NAV exploring the significance of the interac- inactive compounds and flushed from the clinical data on sorafenib (see table), DER tion problem. This enzyme plays a greater the system too quickly, giving them less where ketoconazole shows no effect on F:N or lesser role in metabolising the tyrosine chance to do their anti-cancer work – serum concentration levels. It is there- IOT kinase inhibitors (TKIs) dasatinib (Spry- effectively an underdose. If levels of the fore difficult to tell which of the sub- ARTS cel), erlotinib (Tarceva), gefitinib (Iressa), same enzyme are too low, however, more stances featured on lists of inhibitors or UL imatinib (Glivec), lapatinib (Tyverb), nilo- of the drug remains active in the body for inducers actually do pose a danger for IL CANCER WORLD JULY/AUGUST 2010 ■ 25
which cancer drugs, as only a minority that cancer patients take of their own tified, and by their very nature it is difficult have been studied in a clinical setting.
volition and that have never been sub- to know how widely this is happening.
Indeed, many potential interactions would jected to pharmacological scrutiny.
Research by Molassiotis et al. (Ann be unlikely to occur in practice – perhaps Oncol 16:655-663) showed that around because the interacting drug is taken at a 35% of Europe's cancer patients use some different time of day, or prescribed for too form of CAM, with rates in some countries short a time, or the dose is too low to have Drug interactions cannot always be as high as 73%. Not every CAM is biolog- a serious impact.
avoided, but so long as they are identified, ically active, but a lot are, and very little is More of a worry, perhaps, are the they can at least be managed. The danger known about how these products may hundreds of non-prescription products lies in interactions that are not being iden- interact with cancer medication. Molassi-otis found that herbal medicine was the SOME INTERACTIONS CAN HAVE A MAJOR IMPACT
most used CAM in the majority of coun-tries and was in the top five CAM types Object Drug Inhibitor
used in every country bar one. Megavita- mins/vitamins/minerals, homeopathy, andmedicinal teas were also all in the top five in at least half of the countries surveyed.
Studies confirm what is already well known among patient advocacy groups – that doctors are often unaware of what Smokers have 65% lower additional substances their patients are AUC than nonsmokers taking. They seldom ask and patients canbe reluctant to reveal the information, per- haps for fear of being ridiculed or told to stop, or simply because they don't per-ceive ‘natural' remedies as relevant.
There is less excuse for such commu- nication failures with prescription medi- cines. General practitioners wanting to prescribe an antibiotic will usually ask their patients if they are taking any other pre- scription medicines and in most cases they know if their patient is being treated for can- cer. Community pharmacists who provide the antibiotics should be aware of what other prescription drugs that patient is tak- 3-fold↑AUC of pazopanib ing. However, they may not, if those drugs are delivered by the hospital, which is usu- ally the case with chemotherapy and, inmany countries, with oral cancer therapies.
In the absence of computerised med- ical records and automatic interactionalerts, the system relies on professional vigilance, and there are many opportunities AUC – area under the curve (effective concentration of the drug) for potential problems to be overlooked.
Source: J Horn and Philip Hansten, Pharmacy Times April 2010 A study of the literature on the fre- quency of drug–drug interactions (DDIs)in cancer published in the Annals of Oncol-ogy last year (vol 20, pp1907–1912), found 26 ■ CANCER WORLD JULY/AUGUST 2010
at the scale of the interaction problems Use of CAM in cancer across Europe among cancer patients. She is convinced, Around 35% of Europe's however, that it is steadily growing. "The cancer patients are thought problem with TKIs and drugs like that is to use some type of CAM – they are for the long term. Chemotherapy much of it biologically lasts for about three months, and in most active. Herbal medicine was cases it is only the day of therapy itself that in the top five most popular is the really sensitive period. TKIs, or types of CAM in every even oral chemotherapy, is something country surveyed bar one.
patients take at home, so the possibility of interactions is much greater." minerals, homeopathy, and She points to the steady rise in the medicinal teas were in the number of CAM substances now avail- top five in at least half of able on the Internet, including a lot of tra- ditional Chinese andAyurvedic medicines Source: Molassiotis et al.
which are often biologically highly active, (2005) Ann Oncol but in ways that have never been phar- macologically investigated. Compoundingthe effects of this rise in supply is a parallel only eight publications, six of which ifen. Excess mortality was reduced to rise in demand, with the trend for patients reported on potential interactions, with 24% increased risk if the overlap was only to want to know more and take more only two trying to estimate the frequency for 25% of their time on tamoxifen (Kelly personal responsibility for their own of actual interactions. It concluded that et al. 2010, BMJ 340:c693).
health. "Our patients learn that they have "although it seems that one-third of cancer It is difficult to know how many of the to look for themselves in the system.And outpatients are at risk of DDI, the doctors who prescribe antidepressants, when you look for yourself, you find some proportion of them who actually suf- the pharmacists who administer them things that are good and some things that fer from DDIs remains unknown." and the breast cancer patients who are problematic. It is very hard for the They advise caution, in particular, in take them are aware of these dan- patients to know which way to go." prescribing warfarin, anticonvulsants gers. There is anecdotal evidence Hübner offers a couple of examples that awareness is not as high as it from her own recent experience to illus- Warnings have also been sounded should be even among psycho- trate how various and unpredictable are about the risk of interactions between oncologists.And while some breast cancer the potential problems. One patient on tamoxifen and antidepressants. Estimates advocacy organisations such as Mama- chemotherapy had come in after suffering (Horn and Hansten, Pharmacy Times, zone in Germany cover this issue in their very serious side-effects. It turned out March 2009) suggest that almost a third of national and regional education days and that she had been drinking her own urine, patients on tamoxifen are taking anti- provide information and advice on their having read that this could help fight the depressants. But many antidepressants – website, the UK advocacy organisation cancer.As her urine contained large quan- particularly fluoxetine (Prozac), paroxetine Breast Cancer Care makes no mention of tities of the metabolites of the chemother- (Paxil), bupropion (Wellbutrin) and dulox- it in their patient leaflet on tamoxifen, apy drug that had been flushed from etine (Cymbalta) – are known to signifi- and nor does the website of the her system, she was in effect giving cantly inhibit the enzyme CYP2D6, which Macmillan Cancer Support.
herself a second dose.
is needed to make tamoxifen do its job.
Another patient who had been A recent retrospective clinical study A GROWING CONCERN doing very well on chemotherapy did not find evidence that all these drugs Jutta Hübner, a medical oncologist recently turned up at clinic, also suf- reduced the effectiveness of tamoxifen in specialising in the use of CAM, fering very serious side-effects. This clinical practice, but it did find almost who heads the department of Pal- wasn't a problem with interaction. It double the risk of death (91% increase) liative, Supportive and Complementary was simply that since starting a ‘cancer among women taking paroxetine for at Therapy at the University Cancer Centre diet', she had lost so much weight that the least 75% of the time they were on tamox- in Frankfurt, is reluctant to hazard a guess chemotherapy dose she had started on CANCER WORLD JULY/AUGUST 2010 ■ 27
"Some things are good and some things are problematic – it is very hard for patients to know which way to go" was now too big for her reduced body pretty much the advice some patients are Hübner herself has been arguing for many mass, and the change had gone given. "I have seen some sheets years about the need for guidelines on unnoticed. Hübner says, "She for patients telling them what CAM, including simple and clinically could have had very, very serious they should not eat, and some- relevant information on interactions, to consequences, but fortunately times I'm asking, ‘For heavens sake replace the current reliance on lengthy they stopped the chemotherapy.
what do you eat if you have to be lists of hypothetical dangers. This would This is an example that shows we careful of all these things?'" be helpful for doctors and for pharmacists, really should be careful to ask our Hübner, who chairs the CAM she suggests, but also for patients, many patients what they are doing." .
working party of the German of whom are currently well aware of the Doctors are aware that interactions Cancer Society (Deutsche Krebsge- dangers of interactions, but hazy on can be a problem, she adds, but they don't sellschaft), wants to see a whole new details. "Nearly everyone seems to have really know what to look for. "Most of our approach to dealing with this issue, heard of St John's Wort and grapefruit," data about interactions are derived from she says, "but often they assume that if preclinical experiments in laboratories and regular communication with patients they stay away from these two products animal experiments, whereas most inter- a more open-minded approach to then everything else is OK." actions that really happen are not reported." CAM, based on seeking expert advice As so often happens, however, the clin- She worries that there is too much hype rather than always advising against, and ical studies needed to draw up these guide- around some of the pharmacological data a systematic effort to build up an evi- lines and develop knowledge and expertise on interactions, and cites the recent flurry dence base about which substances in this area are being held up by lack of of articles around green tea and borte- present significant interaction prob- funding. "We have many interesting proj- zomib (Velcade) as a case in point.
lems with which therapies in clinical ects, but no funding. We are waiting for a "There are pretty few data, and I've had response from the Deutsche Krebshilfe, so much discussion with patients: ‘Can we With her colleagues on the CAM working (German CancerAid) which gives support drink one cup of green tea a day or not?' party, she is recommending the use of a to research, and I am talking to many other I think we need to calm down. There is questionnaire that could be used in out- people who may give some money to some even a new paper saying green tea extract patient clinics and hospitals to regularly of our projects. This is a big difference to and Velcade go very well together." If you screen patients about what they are the US system where the cancer centres create too much hype over very uncertain doing. This would be backed up get public funding for their comple- data, you end up with a confused picture by an expert advice centre that mentary activities as well." that can make life very stressful for patients doctors could turn to for advice and very difficult for oncologists when on interactions, This would A ROLE FOR PHARMACISTS they are asked for advice.
allow the patient to ‘own up' to Hübner and her colleagues can "The question always for a doctor is taking something without expect support for their efforts from what to tell the patients. We can't say, feeling they will be punished one key group of professionals, who 10 ‘Don't use all these things', because, using by their oncologist.
years ago joined together to form the the example of green tea and Velcade, the They also want to set up European Society of Oncology Phar- problem is not just green tea; any antioxi- a register where doctors can macy. ESOP believes oncology pharma- dant will do exactly the same. So if you report interactions or unexpected cists are perfectly positioned to play a want to say ‘no green tea', you also have to side-effects, in order to compile information key role in communicating with patients tell the patient: ‘Don't eat any fruit, don't and to allow doctors to swap notes with col- about interactions, side-effects and ad- drink any tea, drink water and eat bread leagues elsewhere whose patients are tak- herence, as the trend towards long-term and that's all.'" Which, as she points out, is ing similar compounds.
oral therapies reduces the contact 28 ■ CANCER WORLD JULY/AUGUST 2010
between patients and their cancer clinic.
DGOP has started consulting with wave of birth deformities when it At a European level they are still try- pharmaceutical companies and was first introduced in the 1960s, ing to identify the role currently played by others with a view to drawing up which was recently given approval ESOP members in their contact with patient-friendly leaflets for use for use in patients with multiple cancer patients in different countries, to in pharmacies.
myeloma. Should these proposals be which end they conducted a survey, pub- "If you tell patients 20 topics, they will accepted, both doctors and pharmacists lished last year in the European Journal of have forgotten 18 when they leave," says would be required to sign on the pre- Oncology Pharmacy (vol 3, p 25). This Meier. "We want to focus on just, for scription for any oral cancer medicine asked a number of general questions, but instance, the three main drugs and the that they have given key information to also looked specifically at how well three main non-prescription drugs with their patients and asked certain manda- equipped they are to advise patients with which it will not work. We will choose tory questions.
CML (chronic myeloid leukaemia) – a those that do the main harm, and those that "There's also the question of financial particularly relevant group because of the may not be quite so harmful, but are most support, if you ask pharmacists to have long-term nature of their treatment and more time and space in their pharmacy for the variety of oral therapies.
This would be supplemented by a private consultations," adds Meier – not At the same time, ESOP's German questionnaire. Part would be filled out by to mention the cost of the additional affiliate is forging ahead with pro- the patient at home, to record for training, which the DGOP has already posals designed to significantly instance when they take their started, with a series of courses running step up the contribution phar- drug and what side-effects they across Germany's 16 regions.
macies play in the long-term experience. The rest would be German pharmacies are under pres- management of cancer patients. If filled in at a monthly consultation sure in today's cost-conscious environ- successful, it could provide a tem- with the pharmacist, including a ment to justify the monopoly position plate that could be adjusted for question about what else the patient they hold, and this may be part of the use elsewhere.
is using to promote their health. Such motivation behind the DGOP's bid to These proposals seek to: a system would allow pharmacists to indi- step up the value-added they can offer for Ensure every patient on oral cancer vidualise their advice, says Meier. "We cancer patients. But it is hard to deny the therapies receives accurate, relevant want to know what really is going on with need for the sort of systematic, individu- and concise information the patient, and not just fill them up with alised and informed follow-up of patients Provide for regular consultations general stuff. What really is the problem?" on oral therapies that they are proposing, where the pharmacists get feedback If successful, such procedures should whether this is done in pharmacies, or in on side-effects, adherence and about not only help improve patient outcomes, out-patient clinics, as Hübner suggests, or what else the patient is doing that but could also provide a goldmine of by cancer nurses over the phone.
might affect their therapy, and can information on adherence, side-effects, Meier argues that you not only bene- what CAM patients are using, and symp- fit from a reduction in the likelihood of Klaus Meier, the president of ESOP, has tomatic interactions. But Meier knows potentially fatal interactions, but also been at the forefront of developing and that getting pharmacies to expand their maximise the value for money from very pushing forward these proposals on behalf role in this way will be neither cheap nor expensive cancer drugs. With some oral of its German affiliate, the Deutsche easy. As a means of enforcement, the therapies costing tens of thousands of Gesellschaft für Onkologische Pharmazie DGOP is actually proposing to extend to euros per patient per year, it would surely (DGOP). Like Hübner, he feels the cur- all oral cancer drugs the conditions be worth a little investment to ensure rently available interaction lists are of lit- demanded by the European regulatory that their effects are not largely wiped out tle use in advising patients, and together body, EMEA, for the administration of by a bottle of sunshine herb purchased at with the German Cancer Society, the thalidomide – the drug that caused a €12.95 from the local corner shop.
"We want to know what is really going on with the patient, not just fill them up with general stuff" CANCER WORLD JULY/AUGUST 2010 ■ 29

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