A leading US oncologist has cried “enough” on our drug-led approach to cancer treatment. Much better, says Azra Raza, is monitoring the human body like a machine.
Slash-poison-burn: that is how she refers to the combination of surgery, chemotherapy and radiation that over a 43-year career, with minor variations, has remained her most useful weapon against cancer. In a new book, The First Cell, Raza calls this “an embarrassment”, arguing that we should be doing better.
“We are living in a sophisticated era of technology and yet we are still using Paleolithic treatments,” she points out. “When I started, in 1977, as a fresh graduate of medical school, I had two drugs to offer, what we call the 7 + 3 [seven days of a drug called Cytarabine and three of Daunorubicin]. Today, in 2020, I am still using the same approach. And we still don’t know how those drugs work; we are just killing all kinds of cells. Why do some people respond while others don’t? We can’t tell you.
“I feel fraudulent, embarrassed and extremely depressed that I can’t offer anything different, that I just keep repeating the same conversation.”
Based in New York, Pakistan-born Raza is a professor of medicine at Columbia University, where she specialises in a bone marrow preleukaemic condition, myelodysplastic syndrome (MDS), and acute myeloid leukaemia, which develops in a third of MDS patients. She is a clinician who treats 30 to 40 people a week; the co-editor of a website, 3 Quarks Daily; the co-author of a book on celebrated Urdu poet Mirza Ghalib; and the kind of person who, when asked how it feels to face a new patient knowing the inadequacy of what she can offer, quotes Emily Dickinson: “I felt a cleaving in my mind, as if my brain had split.”
The First Cell is Raza’s latest attempt to get her message heard. She has made podcasts, delivered a TED Talk, appeared on radio and television, given interviews and, each time, said much the same thing – that we aren’t winning the war on cancer, and that we won’t unless we change our approach.
It is a view that hasn’t always won her friends. There has been hate mail and push back. But Raza stands firm. She maintains that too many new drugs treat too narrow a band of patients, offer marginal benefits, buy them too little time and come at too high a cost, both physical and financial.
She quotes US research that 42% of cancer patients spend their entire life savings within two years of diagnosis.
Raza isn’t the only leading cancer expert saying that sort of thing. In New Zealand last year for the “Cancer Care at a Crossroads” Conference, Richard Sullivan, professor of cancer and global health at King’s College London, spoke out about new cancer drugs with huge price tags and uncertainty about what they deliver to patients, saying, “There’s no doubt there are certain drugs being authorised for the market that really don’t do what they say on the tin.”
There is research to back this up, including a study published in the BMJ that found the majority of cancer drugs approved in Europe between 2009 and 2013 entered the market without clear evidence that they improved survival or quality of life for patients.
Of mice and humans
Raza is tired of hearing about the latest advance in our understanding of cancer cells, or reading about the newest breakthroughs in research, and not seeing them result in significant improvements for cancer patients.
One of her more unpopular opinions is that the system for developing drugs is broken, partly because of the reliance on animal models for testing them. She points out that we have cured a lot of mice of cancer using treatments that turn out not to work effectively for humans. Mice don’t mimic humans well; they have a shorter lifespan and a faster metabolism for a start. To take a healthy mouse, destroy its immune system so it will accept transplanted human cancer cells, grow a tumour and then test a therapy is a waste of research resources, says Raza, particularly for such a complex and fast-evolving disease as cancer.
“Wave after wave of researchers keep trying to develop drugs using these artificial systems and it ends in disaster – 95% fail outright, the other 5% should have failed because they don’t do very much, no one is cured,” she says.
There have been some successes, she concedes, such as Herceptin for HER2 breast cancer, Imatinib for chronic myeloid leukaemia and CAR-T therapy, which treats a type of leukaemia in children and young adults.
“But these are rare,” she says. “By and large, for the common cancers – prostate, gastrointestinal, lung, ovarian and so on – advances are painfully slow.”
When her husband, oncologist and cancer researcher Harvey Preisler, was diagnosed with lymphoma in 1998, it had already spread widely throughout his body. Both he and Raza knew exactly what lay ahead for him – the symptoms, the suffering, the toxic treatments and then, given the advanced stage of his disease, almost inevitable death.
She details some of this and how it affected his family – their daughter Sheherzad was only five. Disfiguring facial oedema, drenching sweats, swelling joints, respiratory problems, even shingles.
“I had been treating cancer for two decades, but until I shared a bed with a cancer patient, I had no idea how unbearably painful a disease it could be.”
Raza believes that rather than chasing the last cancer cell with treatments that can only extend life, not cure the disease, we need to focus on eliminating the very first cell. Better still, prevent its appearance by finding its earliest footprints.
“It’s very clear to me that the war on cancer won’t be won by finding new treatments,” she says. “We have to prevent it with early detection. And forget about annual screening using ancient methods, I’m talking about a shift towards continuous monitoring of the human body as a machine. It is happening, it isn’t far away, it’s not pie in the sky.”
Already, there are researchers looking at identifying early biomarkers of malignancy in body fluids using a variety of genetic, sonic and imaging techniques. Japanese company Toshiba recently announced it has developed a low-cost and effective way to detect the markers of 13 common cancers in a single drop of blood. At the Johns Hopkins University School of Medicine, Bert Vogelstein and his team are developing blood tests to identify patients with inherited dispositions to colorectal cancer, as well as early-detection tests using technology that can pick out a single mutant gene from tens of thousands of normal copies.
Raza is working with biomedical engineers at Columbia to develop an implantable chip that will sit under the skin and search for the appearance of the first cancer cell.
She is optimistic that this is only the beginning. In her book, she outlines her dream scenario for the future of cancer care: machines that can scan your entire body while you are taking your morning shower; smart bras that are an early warning system for breast cancer (a Mexican teenager has already produced a prototype that is being tested); devices that will detect early cancers from our breath, saliva or tears.
No one is arguing that early detection isn’t important. Find a cancer in its initial stages and the treatment has more chance of success and is far less costly. The major push back that Raza has experienced is against her optimism that, once detected at its earliest stage, a cancer could be snuffed out effectively by targeting the few abnormal cells with laser-like precision.
Her response is that things will likely co-evolve. “Earlier detection will lead to novel ways of treatment,” she says. “Also, many of the targeted therapies and immune therapies producing only temporary benefit now may be sufficient to eliminate cancer in its early stages. Basically, if we don’t try it, we will never find out. The old strategies have been milked to the maximum. More resources in that area will produce only very small and incremental advances.”
Bone marrow bank
Does Raza have a personal agenda? Well, yes. Since 1984, she has been amassing what is now the largest tissue repository in the US, about 60,000 samples from her patients, including bone marrow donated using painful procedures. She wants to use this resource to contribute to the advancement of medical science to the point where doctors can identify who is most likely to develop an aggressive cancer, and how best to monitor and cure them.
Raza sees the potential for a wealth of information to be extracted from studying the samples of large numbers of patients, using every technology available, to understand why certain people are at risk of preleukaemia and why the disease progresses to its acute form in some and not others, by searching for biomarkers in patients whose serial bone marrows she has stored over the decades.
This is going to be expensive; Raza estimates that it will cost about US$100 million. “It costs US$1 million a year just to maintain the lab and pay for the people I employ,” she says. “I raise that through fundraisers or patients that give me money.”
She has written begging letters to billionaires that have mostly gone unanswered. She has been turned down for funding because she isn’t planning to use mice models in her research. Progress has been frustratingly slow.
In the meantime, she continues to treat patients and agonise over the cruelty of the choices she can offer. Is it less painful to let cancer kill someone when experience suggests the chance of recovery will be nil, or should she make aggressive attempts at producing remission? Is it right to offer potentially toxic experimental drugs that may win them only a few extra weeks? How can she best give patients a sense of control over their treatment? Raza doesn’t have all the answers, she carries on imperfectly, hopeful that the oncologists of the future won’t face the same dilemmas.
“It is going to happen to all of healthcare – prevention rather than treatment, wellness rather than illness, catching it early so that we can live to our maximum lifespan, whatever that is, in a way that is healthy and free of disease instead of being crippled by these diseases and put through these treatments.”
Accepting the inevitable
When Auckland author, columnist and broadcaster Gordon McLauchlan was diagnosed with aggressive lymphoma last year, aged 88, he was offered treatment but advised by both his GP and haematologists that, at his age, chemotherapy and radiotherapy would be painful and win him only a small amount of time alive, but not well. In a letter he circulated to friends and relatives following the diagnosis, McLauchlan was very much at peace with his decision to opt for palliative care, describing himself as “someone coming towards the end of his life, as everyone must, in a stable and untroubled way”.
Many of those whose stories are shared in The First Cell – even the older ones – aren’t so accepting. They demand therapies, refuse to give up and ask Raza to do anything possible to keep them alive. She writes of the toll it takes on both her and these patients, of the human cost of pursuing cancer to the last, even when all hope of a cure is long gone.
Raza lost her husband to lymphoma on a bright spring day in 2002. By then, the treatments he had received had destroyed his immune system and he was suffering from frequent infections. Before he became ill, Preisler was focused on what he called “bench-to-bedside” investigations, looking for ways to diagnose cancer earlier and finding less-toxic treatments that could be rapidly delivered to patients.
“Cancer researchers keep congratulating themselves that they are developing insights into the biology of the disease,” Raza says. “But Harvey’s point was that whatever we do in cancer should have only one aim – to improve the outcome.
“What good is it that I understand all this if it isn’t going to help the patient?”
She is waiting for a paradigm shift in cancer, the equivalent of the co-operation between scientists around the world in the human-genome project. She is convinced things can change dramatically in the near future, and that we already have much of the technology required to make it happen.
“We have patients who have cancer now and we need to help them but, going forward with future patients – and we’re all at risk of getting cancer – maybe we can design a better solution, a compassionate, humane approach.”
‘I threw everything at it’
A mother of three pushed for a radical response to her repeat-cancer diagnosis.
It was 2017, and Robinson had found a lump in her breast that turned out to be lobular carcinoma. Screening for this type of cancer can be challenging because it has a spider web-like growth pattern that is difficult to detect by mammogram and ultrasound, particularly in younger, denser breasts. Even an MRI didn’t show just how large it had become – 7cm.
By then, the cancer had spread to her lymph nodes, but body scans suggested it hadn’t travelled further. What followed was the classic slash-poison-burn approach, with Robinson undergoing surgery, chemotherapy, radiation therapy and then hormone treatment. She also investigated complementary therapies that might help.
“I had vitamin C infusions, was careful with my diet and, since I believe in mind/body links, did a lot of meditation and visualised [being] healthy, trying to really believe in the outcomes I was seeking,” she says.
Her breast cancer treatment was successful but, unfortunately, Robinson’s cancer story doesn’t end there. Two years later, she spotted something unusual on the skin of her reconstructed breast.
“I had developed a spot, like an itchy bite, and then another joined it,” she recalls. “It turned out to be a completely different type of cancer.”
Robinson had radiation-associated angiosarcoma, one of the potential side effects she remembers being warned about. It is rare and aggressive and, in the few who are affected, usually doesn’t show up until much longer after the original therapy. “That meant when I was deciding on treatment, there weren’t a lot of studies to reference,” she says. “It is such a grey area and there was no right or wrong path to take. Angiosarcoma is so complex, there were differing views among the medical specialists involved in my case. Obviously, I had to remove the cancer; the issue was how big an approach we were going to take.”
“Each decision has to be weighed so carefully,” she says. “But I felt that a radical response was required to give me any chance of success. I literally mapped it all out on a decision tree [a flowchart-like tool], wrote it down and went through it with my doctors.”
And so the reconstructed breast was removed, and when more cells were found some distance from the original spot, Robinson opted for the removal of all the skin that had been radiated, a large area along her left side from beneath her rib cage up to her neck and beneath her armpit. It was a tricky procedure that involved a graft using skin from her thigh, and she spent two weeks in Auckland’s Middlemore Hospital burns unit.
“Once I recovered from that, I advocated for chemotherapy,” says Robinson. “It is hardly used for prevention in sarcoma, almost always employed in palliative care. But I thought that if there was something microscopic still circulating, it could put it to bed. One oncologist was reluctant. He believed it was irresponsible because he couldn’t say there would be a benefit, only harm.”
Another oncologist agreed to the treatment. However, three-quarters of the way through, she had to take the decision to stop because she was experiencing severe and harmful side effects with the potential to affect her permanently.
Robinson is grateful for all the options she has had available to her – even the radiation that may well have saved her life even if it went on to threaten it again. “I don’t regret it at all; I would lose an arm to live.”
She is aware of how tough it must have been for her doctors, too, as they tried to settle on a treatment plan that offered a higher chance of doing her good rather than harm.
“They’re overworked, they’ve got patients’ lives in their hands, people whose expectations are pretty high, and not really a great toolkit, so there is tremendous pressure.
“If I’m talking to someone who has been newly diagnosed, I’ll say to take ownership of the situation, be know-ledgeable about where you’re at and, whatever the situation, choose the path with which you are most comfortable.”
Today, Robinson is focusing on living healthily. Knowing she has done everything possible to ensure a recovery, she tries not to dwell on the possibility of getting sick again.
“The cancer may come back, or it may not, that’s the reality of it.”
This article was first published in the February 15, 2020 issue of the New Zealand Listener.