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Chemo’s early victims

About the author: 
Bryan Hubbard

Around 8 per cent of cancer patients are dying within 15 days of starting treatment, a startling new study has discovered

With the smart money switching to immunotherapy as the new drug hope for treating cancer, the truth about the lethal effects of chemotherapy is suddenly surfacing. Three times as many patients are dying from chemo drugs within the first 30 days of starting treatment than was previously believed, and some hospitals in the UK are reporting that up to half of all patients are dying in the first month, with many within the first two weeks.

The mortality rate is higher among older patients and varies from region to region across the UK, but the figures are nonetheless shocking. Overall, 3 per cent of patients are dying within the first month—which suggests it’s the chemotherapy and not the cancer that’s killing them—whereas earlier research had concluded that the 30-day mortality rate was just 0.8 per cent. The rate is highest for lung-cancer patients, with 8 per cent dying in the first 30 days, while the average for breast cancer is 2 per cent.

But some hospitals are reporting that half of all their treated cancer patients are dying inside of the first 30 days, say leading oncologists, including representatives of Public Health England and others associated with the charity Cancer Research UK.1

Most of the deaths are happening between just 11 to 15 days of starting treatment, and the most common cause of death is neutropenic sepsis, or infections that arise after a sudden drop in the numbers of white blood cells, which are essential for the healthy functioning of the immune system. If the side-effects of chemotherapy are also added to the overall picture, then using those drugs for palliative reasons—to ease symptoms rather than attempt a cure—are probably doing more harm than good, the researchers say.

They tracked the progress of more than 23,000 breast-cancer patients and more than 9,600 people with lung cancer, who were aged 24 years or older (average age: 54), all of whom had started chemotherapy in a UK hospital in 2014. The 30-day mortality rate was highest among the older patients and in those given chemotherapy to reverse the
cancer, suggesting they were given stronger doses.

The rate of deaths was also much higher in patients who had never received chemotherapy before, suggesting a fatal reaction to the treatment (whether curative or palliative). This suggests that oncologists need to pay special attention to first-time patients, as they are more susceptible and should be monitored carefully, especially during the first 30 days of starting chemo.

Results also varied from one hospital to another. One in Milton Keynes reported that around half of its cancer patients were dying within 30 days of starting chemotherapy, although this was based on a small number of patients, while the Lancashire Teaching Hospitals revealed a mortality rate of 28 per cent with low-dose palliative chemotherapy. Not far behind were the Cambridge University Hospitals, which had a 30-day mortality rate of 20 per cent.

Not recorded

The truth about the lethal effects of chemotherapy is often hidden, the researchers say. The cause of death in nearly all the cases they had monitored was recorded as cancer, and not the chemotherapy, making assessment of
the toxic effects of the drugs difficult.

It would also explain why some researchers have suggested far lower 30-day mortality rates.

Researchers at the Royal Marsden Hospital, a major cancer centre in London, didn’t have to rely on death certificates, but instead had direct access to patient records—yet they came up with similar 30-day mortality rates. Chemotherapy was the cause of 7.5 per cent of deaths in the first month, and the cause of death in these cases was also the same—neutropenic sepsis, or infection that followed a precipitous drop in white blood cells.2

This team of researchers had looked at the records of nearly 2,000 cancer patients given chemotherapy between April and September in 2005. Within the first 30 days of starting treatment, 161 patients died, and the researchers think that more than three-fourths of those deaths were the result of cancer progression. But while they’re not sure about the cause of death in the remaining 25 patients who died, they are confident that 12 of the 161 deaths were the direct result of the chemo. Most of the deaths happened within the first two weeks of starting treatment.

But what happens to the cancer patient who survives the first 30 days? Researchers from the Princess Royal Hospital in Hull, UK, analyzed 14 previously published studies and five abstracts that had monitored the progress of more than 6,212 pancreatic cancer patients over the first three months of treatment.

In that time, 1,447 patients—23.3 per cent—died, and yet cancer progression was reported as the cause of death in only 21 cases. In fact, a cause of death was cited in just 40 cases, so the assumption must have been that the cancer was responsible for the vast majority of deaths.3

Early-death burden

But while pancreatic cancer was most likely responsible for most of these deaths, it cannot fully explain the “phenomenon of 3-month early death burden”, say the researchers. When they examined the autopsy reports, they discovered that many of the deaths had the hallmarks of the chemotherapy agent itself, including infections and kidney failure, with a surprising number that were the result of vascular thromboembolism (myocardial infarction and blood clots in the lungs).

Although the latter are usually seen after a heart attack or stroke, other researchers have discovered that blood clots are also a common reaction to chemotherapy. In a review of 198 cancer patients given different chemotherapy agents or combinations of agents, researchers from the Memorial Sloan Kettering Cancer Center in New York found that the rates of VTEs (vascular thromboembolic events) varied from 15 per cent to 26 per cent in patients receiving platinum-based chemotherapy drugs. Their average risk of a blood clot after chemotherapy was 20 per cent, the researchers found, a figure considerably higher than expected.4

But what happens beyond the three-month mark? In fact, the standard measure of chemotherapy safety—such as it is—doesn’t usually extend beyond the first three months, presumably because the lines between the effects of cancer progression and the treatment become blurred.

Yet, what is clear is that chemotherapy is far more lethal than even its sternest critics may have imagined. The gallows-humour joke that the treatment was a success, but the patient died, is beginning to sound less like a quip and more like a prognosis.

Chemo’s time line

1907 - The term ‘chemotherapy’ is coined by German scientist Paul Ehrlich to describe any therapy that uses chemicals to treat disease. Only later did it come to refer specifically to cancer

1917 - Mustard gas (sulphur mustard) is used by the German army at the Battle of Ypres

1919 - Scientists discover that mustard gas suppresses haematopoiesis (the process of making new white blood cells)

1925 - Mustard gas is banned by the Geneva Protocol as a chemical agent in warfare

1940 - Yale University researchers are commissioned to explore potential antidotes to the toxicity of mustard gas. As part of this task, they discover its usefulness as a potential treatment for Hodgkin’s lymphoma and leukaemia

1942 - A more stable form of mustard gas, nitrogen mustard, is used for the first time on a cancer patient with non-Hodgkin’s lymphoma

1943 - An air raid on the port of Bari in Italy strikes a ship that was secretly transporting mustard gas. Autopsy reports of the victims reveal suppression of their bone marrow and white blood cell production, leading scientists to speculate that, as mustard gas stops cells with quick turnover times, it might also slow the progress of cancer cells, which share those qualities

1946 - The first clinical trial of mustine, an injectable agent based on nitrogen mustard, is published

1948 - Children with acute lymphoblastic leukaemia are injected with the chemotherapy agent aminopterin, later replaced with amethopterin (or methotrexate today), which block the folate enzymes that feed cancer cells

1951 - Methotrexate is tested on breast cancer, the first solid-tumour cancer to be treated by chemotherapy

1955 - The US Congress creates the Cancer Chemotherapy National Service Center to research chemotherapy agents to treat cancer

1965 - Researchers hypothesize that chemotherapy drugs could be used in combinations

1969 - The MOPP protocol—mustine, Oncovin (vincristine), procarbazine, prednisone—is developed to treat Hodgkin’s and non-Hodgkin’s lymphoma

1971 - US President Richard Nixon declares a ‘war on cancer’, with chemotherapy agents as the vanguard

1971 - to today—drug companies begin researching and developing their own chemotherapy agents, eventually producing the most profitable drugs in the world

2003 - Andrew von Eschenbach, then director of the US National Cancer Institute, announces that its goal is to eliminate cancer by 2015

2004 - Australian researchers discover that only 2.3 per cent of cancer sufferers, and 2.1 per cent in the US, are still alive after five years of chemotherapy

2012 - A secret meeting of the world’s leading cancer experts concludes that, despite the development of hundreds of chemotherapy agents, cancer cures are ‘rare’

Immunotherapy: the great new hope

Immunotherapy is medicine’s great new hope for treating cancer. Described as a ‘game changer’, it harnesses the body’s immune system to target only cancer cells—unlike chemotherapy, which damages the immune system by suppressing production of its white blood cells.

Immunotherapy drugs are being fast-tracked for approval, and the share prices of the biotech companies developing them are skyrocketing, as early trials discovered that immunotherapy is helping cancer patients live longer, sometimes doubling the time achieved by chemotherapy.

But, right now, it’s more hype than genuine hope. A study of 361 people with head and neck cancers revealed that 36 per cent of those given immunotherapy were still alive a year later—so 64 per cent of them weren’t—compared with 17 per cent of those in the chemotherapy group.1

Early deaths are commonly seen with immunotherapy. Juno Therapeutics revealed that five of their 20 leukaemia patients died while on the therapy, prompting the US drugs regulator, the Food and Drug Administration (FDA), to put a temporary halt on the research.

Cancer patients with autoimmune conditions like rheumatoid arthritis, psoriasis and polymyalgia have also been warned not to undergo immunotherapy, as it could trigger fatal allergic reactions.


Bugs in the system

Back in action

References

References

1

BMJ, 2015; 350: h2435

Immunotherapy: the great new hope

References

1

N Engl J Med, 2016; 375: 1856–67

Main

References

1

Lancet Oncol, 2016; 17: 1203–16

2

Br J Cancer, 2006; 95: 1632–6

3

Acta Oncol, 2008; 47: 337–46

4

Cancer, 2016; 122: 712–21

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