Week in Review

Off-label and untapped – are old drugs new cancer treatments?

From the Bay of Islands to Brussels there’s a call to take a fresh look at old drugs to see if they could treat cancer for a fraction of the cost of new medicines. As New Zealand’s baby boomers develop age-related cancer, research investment now could help reduce future cost and improve lives.

What if treatments for cancer have been under our noses for decades, cost a few cents and have already been extensively tested for safety?

It’s an area of cancer treatment research which has been gaining steam. Scientists reviewing retrospective patient data have noticed people on medication for diabetes, acne, allergies and cholesterol are less likely to have cancer, or recover from cancer better than those not taking the medications.

Standing in the way of widespread adoption of repurposing drugs is a lack of clinical trials to take the clues seen in data and replicate them in a purpose-built study.

Clinical trials are expensive and time-consuming. Most of the patents on these drugs have long since expired. Putting it bluntly, there’s little economic incentive for drug companies to fund research into something they’re unlikely to profit from.

A Bay of Islands GP of 40 years, Dr David Jennings, thinks it’s time a conversation was had on the topic. He said he’s seen first-hand the positive effects some of these drugs can have.

Jennings believes if GPs place patients on some of these medicines "off-label" as soon as cancer is suspected its progress can be slowed or stopped, and he’s prepared to put “his head above the parapet” on the topic.

“I want this out there. I’m 72 years of bloody age, I really don’t want all this shit – I know I will get it – thrown at me. But I can’t sit by and see all these people, there must be up to a thousand people, dying every year who don’t need to die.”

Jennings is not suggesting conventional treatments be abandoned, he thinks repurposed drugs could be used in addition to conventional treatments.

The tipping point for Jennings came when a personal friend, Barry Downs, was diagnosed with a form of gall bladder cancer. By the time it was diagnosed the cancer had metastasised and spread to his lungs and beyond. It wasn’t something which could be cured.

The prognosis he was given was two or three weeks, with an outside chance of three months.

Barry’s wife, Adrianne, said Jennings visited them at home when he heard of the diagnosis. She said by this point her husband was in terrible pain.

“I said Davey, I think I’ve got a dead man walking. He’s really, really bad. We’ve got an appointment for an MRI on Thursday and I don’t think we’re going to get there.”

Jennings talked with the family about the potential of using repurposed drugs, and after doing some research the family decided to give them a go.

They felt they had little to lose. An appointment to talk to an oncologist about chemotherapy options was about six weeks away. Barry’s prognosis and the likely first appointment dates ran the risk of not matching up.

“We immediately feel this is worth a shot. There’s nothing else on the table. Nobody was offering anything else,” said Adrianne.

Jennings and Adrianne believe the repurposed drugs, which among others, included Metformin, Atorvastatin, Mebendazole, Loratadine and Cimetidine, impacted the cancer. These are drugs normally used to treat diabetes, cholesterol, parasitic worms, allergies and stomach ulcers.

Barry regained weight and some tumours shrank, umbilical leakage stopped. Pain levels which are usually excruciating for the type of cancer he had reduced. His morphine intake dropped from 60 milligrams twice a day to 10 milligrams twice daily.

Barry also completed rounds of chemotherapy. Jennings and Adrianne believe the repurposed drug regime he was on helped his body cope with the side-effects of chemotherapy and improved his quality of life.

He outlasted the bleakest prognosis of two to three weeks and the optimistic prognosis of three months. He died five and a half months after he was diagnosed.

The extra time meant the world to Adrianne.

“Every single minute was precious.”

Unexpectedly good side effects

Metformin has been prescribed since 1957 as a drug to treat type two diabetes.

In the early 2000s something unusual was noticed. Diabetics taking metformin had cancer rates less than half that of those who weren’t using the drug.

Metformin reduces the amount of sugar the body produces and absorbs. One theory is the effect on insulin might slow the proliferation of certain types of cancer cells which rely on insulin.

An association with metformin and its effects on liver, pancreatic, breast, colorectal, prostate, lung, thyroid, endometrial, cervical, renal cell, and melanoma has been noted in scientific literature.

In medical language “association” means attributes occur together more than they would by chance. It’s a more of a “hmm, that’s interesting” moment than a “eureka” one and is a sign-post that there may be something worth investigating.

There is precedent for drugs being used successfully for purposes different to those for which they were developed.

Some failed drugs turned into successes. The little blue pill, Viagra, is a rejected angina medicine. Thalidomide, once used disastrously to treat morning sickness, is now used to treat myeloma and a complication of leprosy.

In the case of cancers, repurposed medicines could reduce the cost of treatment. Treating a patient with newly developed drugs which are still under patent to a pharmaceutical company can cost over $170,000 per year.

Thanks to the lapsed patents of older drugs this could be reduced to between $17 and $1700 per year.

Charities funding clinical trials

Gauthier Bouche is the Anticancer Fund’s clinical research director. The Brussels-based non-profit supports clinical trials the pharmaceutical industry won’t fund. Delving in to the potential of existing drugs to be repurposed for use in cancer is one of the main functions of the organisation.

Bouche said the Anticancer Fund has identified 292 different drugs which have at least one scientific paper suggesting the drug might be of use against cancer.

Out of patent, these drugs are financial orphans. A pharmaceutical company could run a costly clinical trial which shows amazing results only to have competing companies piggyback off the results and sell the same drug, without incurring any research costs.

As a result, potential lies untapped, says Bouche.

“It’s a huge, huge list. It’s quite hard for us to prioritise ... the potential is really huge.”

At the moment the fund has 15 clinical trials underway into different drugs, or combinations of drugs.

Only one has been completed so far, and the result hasn't replicated the association seen in data . Ketoroloc, an anti-inflammatory drug, had been associated with better breast cancer outcomes in retrospective studies. The clinical trial did not show the same results and no difference in outcome was seen between participants who took the anti-inflammatory.

The Anticancer Fund is not the only group conducting research. Studies are underway all around the world, with most centred in Europe, North America, China and India.

The trials are usually funded by charities, philanthropic organisations or from government funding.

The Anticancer Fund’s executive director Lydie Meheus thinks the model needs to be fixed.

“We should try and set up collaborations between private philanthropy to go with governments' public money. We should really invest in this type of drug development.

“I think it’s very unrealistic to expect this type of development from the pharma companies and certainly not from the generic developers.”

She said despite there being no incentive for companies to invest in trials “governments always think that companies will solve their problems”.

New Zealand’s baby boomer cancer boom

Michael Jameson has skin in the game. He’s an academic oncologist based at Waikato District Health Board and is particularly interested in the role statins could play in cancer treatment.

Despite his vested interest he’s more cautious than enthusiastic. He thinks the biggest opportunity lies in using existed funded treatments better and getting people through the system faster.

“I think the systems issue is the one that needs the most attention to get the best bang for the buck out of the health dollar. The data 25 percent of women with metastatic breast cancer never get to see an oncologist is absolutely shocking.”

He can see a looming cancer boom as baby-boomers age. He expects a 30 percent increase in the number of people diagnosed with cancer over the next 15 years.

Currently around 24,000 New Zealanders are diagnosed with cancer each year.

“There is no health system in the world that can afford to keep doing what we do with a 30 to 50 percent increase over the next 20 years from demand, particularly not with rapidly increasing costs of new drugs.”

This is where he gets excited about repurposing “cheap, old” drugs.

“The absolute dollar cost - it’s trivial - but you need to fund the research up front.”

One trial underway is looking at whether taking simvastatin, a drug usually used for cholesterol and heart conditions, for three months during radiation or chemotherapy treatment for rectal cancer will reduce cancer recurrence.

Three months’ supply of simvastatin would cost $5 in New Zealand.

Jameson said there’s retrospective positive evidence for repurposed drugs in breast, bowel, pancreatic, stomach and lung cancer as well as others.

“If you go looking, there’s a lot of evidence retrospectively. The challenge is trying to confirm the effect in prospective randomised trials to show, yes, this is really the effect of the drug rather than just an association.”

There are many reasons why retrospective data could be skewed.

“One person said to me, ‘People who are healthy and have a better prognosis tend to be kept on other drugs like beta blockers, statins and aspirin for the heart compared to people who are doing poorly’.”

The only way to prove causation is a long-term clinical trial. In New Zealand these are hindered by funding rules.

“The frustration is that you've got this data, you try and do a prospective study and there's no money in this for anyone. All these drugs have long since been off patent. They're all generic, they're cheap as chips. But the clinical trials to do this... you're paying for everything.”

He said the Ministry of Health currently wouldn’t allow district health boards to spend money conducting research.

Funding can be applied for from the Health Research Council, but Jameson said this was capped at $1.2 million over three years.

“You do not have enough money to do a large enough randomised trial and follow people up for long enough to actually answer most of the questions you're looking at.”

Is association enough for off-label prescribing?

Until clinical trials are funded and completed, GPs and oncologists are in a no-man's land where there are plenty of hints repurposed drugs could treat cancer, but little concrete proof.

At the same time, these drugs have been tested for safety, with side effects well documented.

Royal New Zealand College of General Practitioners medical director Dr Richard Medlicott thinks currently most New Zealand GPs wouldn’t instigate a treatment regime of repurposed drugs, but would be open to it if a patient suggested it.

“You wouldn’t want to rain on their parade. You might have a conversation where you would might say something like ‘I’m not sure this is going to help, I’m happy to prescribe and let’s watch out for side effects and make sure you let your oncologists know you are taking these medications.’”

He said GPs should draw the line where there is a clear case where harm could occur, and databases exist where GPs can check for interactions between drugs.

Learning about new treatments is up to GPs and awareness of new treatments is sometimes driven by seeing oncologists prescribing medication.

Jennings, the Bay of Islands GP who lost his friend to cancer, is frustrated by the lack of awareness of repurposed drugs. In New Zealand GPs are allowed to prescribe drugs “off label” for uses they weren’t made for.

While the global health system lumbers on figuring out who’s going to foot the research bill he thinks thousands of New Zealanders could have better cancer outcomes.

For Adrianne Downs the extra time she thinks her husband had as a result of the repurposed drugs that Jennings suggested was priceless.

“He had a birthday, he had two grandchildren who had a birthday, I had a birthday. He had Easter. He had quite a few significant other occasions.

“He was able to write things; he was able to say things. We did things. You can’t put a value on that.”

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