Wednesday, February 6, 2013
Grapefruit has been waging it out now for a year or so, it seems.
“Drinking grapefruit juice can dramatically boost the effectiveness of cancer drugs,” the Daily Express today reported.This headline is based on an early clinical trial investigating the effect of grapefruit juice on the ability to treat terminally ill cancer patients successfully with a drug called sirolimus.
Sirolimus is widely used in transplant patients in order to prevent their immune system from rejecting transplanted organs. It is also believed to have the potential to treat certain types of cancers. A drawback is that if it is given in doses high enough to be useful in treating cancer, it can cause unpleasant side effects.
Grapefruit juice is known to make certain drugs break down more slowly within the body. Researchers hoped that if grapefruit juice was given alongside sirolimus, it would be possible to maintain higher levels of the drug circulating in the body with fewer side effects.
The findings of the research do suggest that combining sirolimus with grapefruit juice may achieve a successful “trade-off” between effectiveness and reduced side effects. However, the researchers are clear that further research must be done to develop these preliminary findings.
Therefore, headlines claiming that grapefruit juice "boosts cancer drugs" are both misleading and irresponsible. This was a carefully controlled trial, looking at a single medication, that employed rigorous safety protocols.
Encouraging people to mix grapefruit juice with both prescription and non-prescription drugs could lead to overdoses, which could be dangerous. Cancer patients should not alter their current medication dosages or start drinking grapefruit juice based on this research.
Where did the story come from?
The study was carried out by researchers from the University of Chicago and University of Texas Medical School. It was funded by the US National Institutes of Health and the William F. O’Connor Foundation.
The study was published in the peer-reviewed medical journal Clinical Cancer Research.
The media reports failed to give clear warnings about the potential dangers of anyone drinking grapefruit juice while taking certain medications, due to its ability to strengthen the drug’s dose.
The Express’s headline was particularly misleading as it implied that all cancer drugs would benefit from being combined with grapefruit juice. In fact, the researchers were only looking at a single drug, and even then, this medication is not widely used to treat cancer.
The reports may lead some cancer patients to think that reaching for the juice is a good or at least harmless idea. However, drinking grapefruit juice while taking medication is potentially dangerous. NHS Choices specifically states that if you are taking immunosuppressant medications such as sirolimus, you should never drink grapefruit juice without consulting your doctor.
What kind of research was this?
This research was a phase I clinical trial, a dose-finding study testing the effect of pharmacokinetic modulators, including grapefruit juice, on the action of the drug sirolimus in patients with advanced cancer.
Sirolimus is currently used to suppress the immune system to aid acceptance of a donor organ during organ transplantation, but its potential for use as cancer drug was explored in this research.
Currently, oral sirolimus is not an approved cancer treatment, but a similar drug, temsirolimus, is licensed to be given intravenously for some rare types of cancer.
The aim of the study was to ﬁnd out what the dose was of oral sirolimus alone (taken weekly), or in combination with either ketoconazole or grapefruit juice, that achieved similar blood concentrations to temsirolimus.
What did the research involve?
Adult patients with incurable cancer were given one of three treatments:
weekly sirolimus alone
weekly sirolimus plus ketoconazole
weekly sirolimus plus grapefruit juice
Sirolimus was administered once a week at 1mg/ml oral solution when given alone or with grapefruit juice. It was given weekly as a 1mg tablet when used with ketoconazole. Participants in the grapefruit group received 240ml of juice, once a day.
The dose of sirolimus was then periodically increased in each patient with the aim of achieving the same drug exposure as that achieved by giving the intravenous drug temsirolimus at its recommended dosage. Drug exposure was measured by taking blood samples from the patients to analyse circulating levels of the drug.
This type of approach is known as an “adaptive escalation design” and is often used to find the acceptable dose of new drugs in development. Drug exposure was measured by taking blood samples from the patients to analyse circulating levels of the drug.
Once blood levels of sirolimus were equivalent to the standard treatment (temsirolimus), the oral dose of sirolimus was not escalated further. The researchers then assessed whether the use of ketoconazole or grapefruit juice meant that patients who took a lower oral dose of sirolimus still had high enough levels of the drug in their blood (total drug circulation) for it to still be clinically effective.
They also looked at whether the addition of ketoconazole and grapefruit juice improved the side effects known to be associated with sirolimus.
The study defined clear criteria for limiting the dose of sirolimus if it caused serious side effects likely to be due to the effect of the drug.
What were the basic results?
A total of 138 terminally ill cancer patients were enrolled in the study, of which 101 were included in the final analysis.
The results showed that both ketoconazole and grapefruit juice significantly increased the levels of circulating sirolimus in the blood. When given alone, an oral dose of 90mg of sirolimus a week was needed to achieve the same circulating level as achieved using the standard treatment. This dose was much lower when the drug was supplemented with ketoconazole (16mg) or grapefruit juice (25mg).
When sirolimus was given alone at 90mg a week there were significant gastrointestinal side effects (such as diarrhoea and loss of appetite) that meant the dose had to be split into two equal doses. This was not necessary for the ketoconazole and grapefruit juice groups, where the same circulating levels of the drug were achieved at much lower oral doses leading to fewer side effects.
Across all participants, the most commonly observed side effects occurring in their bloodstream were:
too much glucose, known as hyperglycemia (52%)
abnormally high concentration of fats, known as hyperlipidemia (43%)
too few white lymphocytes (a subset of white blood cells), known as lymphopenia (41%)
Stable disease (cancer that doesn’t get significantly worse) was observed in:
16 patients in the sirolimus alone group (40%)
16 patients in the sirolimus plus ketoconazole group (28%)
11 patients in the sirolimus plus grapefruit juice group (27%)
No participants were cured of their cancers, although one patient was categorised as having a partial response and remained on sirolimus with grapefruit juice for more than three years after their enrolment.
How did the researchers interpret the results?
The authors concluded that giving oral sirolimus is feasible for patients with cancer and that weekly sirolimus by mouth can achieve drug levels similar to that of the approved way of giving temsirolimus intravenously. They highlighted that the target drug levels were achieved at significantly lower sirolimus doses with the addition of ketoconazole or grapefruit juice than through giving sirolimus alone. Furthermore, they stated that “sirolimus represents a viable cancer drug whose development would offer several advantages […particularly] by combining the drug with agents that inhibit its metabolism,” such as grapefruit juice.
This early phase clinical trial showed that grapefruit juice can lower the dose of oral sirolimus necessary to achieve a target drug level equivalent to a currently approved treatment (temsirolimus) in adult patients with terminal cancer. The drug did not cure the cancer patients but appeared to halt progression of their disease in some cases. This finding suggests that it may be useful to carry out further studies to develop sirolimus as a cancer drug in combination with pharmacokinetic modulators such as grapefruit juice or ketoconazole.
It is important to note that this research only tested the effect of grapefruit juice on one drug (sirolimus) that was being tested for, but isn’t yet approved for, use in cancer treatment. Therefore, the effect grapefruit juice might have on other cancer drugs is not studied here. This would need to be investigated in future research.
The researchers also noted that grapefruit juice can range in potency depending on its source, so it would be necessary to ensure any patients were getting a standardised dose before grapefruit juice could be used safely in this way.
Grapefruit juice is known to inhibit enzymes that break down certain prescription and non-prescription drugs and this interaction can be dangerous. Most drugs that interact with grapefruit juice are found at higher concentrations when the juice is drunk and this leads to more side effects as effectively the person receives a higher-than-intended dose of the drug. Therefore it is alarming that the risks of consuming grapefruit juice while on medication were absent from the media reporting of this study.
NHS Choices specifically states that if you are taking immun suppressant medications such as sirolimus, you should not drink grapefruit juice without first consulting your doctor.
Similarly, the statement from the Express that “patients might be able to lower their dose of medication while still getting the same benefits as if from a higher one” is potentially hazardous. Patients should not be tempted to lower their medication and drink more juice based on this study. People on medications should not change their normal dose without consulting their doctor first.
Analysis by Bazian. Edited by NHS Choices.
Two reference articles:
‘Grapefruit juice gives cancer drugs a boost’. Daily Express, August 8 2012
‘Grapefruit juice can give cancer drugs dramatic boost’. Daily Mail, August 8 2012
or click here to link to the top article in NHS health choices