Is Chemo Toxic?

[beach sunrise]

Moss Report
Considering Toxicity
Let us consider the question of toxicity, which we discussed in articles on specific trials of so-called “Precision Medicine’ for cancer. When targeted therapy was first proposed, it was assumed that the treatment would be virtually non-toxic. The word “targeted” was meant to contrast these new drugs with the indiscriminate poisoning of normal cells through toxic chemotherapy. Textbooks of the time spoke of “relatively non-toxic targeted therapies.” They claimed that “the driving force to discover” these new drugs was that “these compounds may be able to suppress human tumor development in a non-toxic way.”

Avastin
When the first reports of phase I trials appeared on Avastin (bevacizumab) it was said that the drug was “well tolerated” with “no attributable grade 3 or 4 toxicity.” This fed the idea that a new era of non-toxic or less-toxic treatment was indeed at hand. But as a Dutch professor wrote, in a textbook co-edited by Judah Folkman, MD of Harvard Medical School,

“The true frequency and spectrum of bevacizumab toxicities became apparent in subsequent larger trials and when bevacizumab was combined with other agents.”
In fact, according to the same textbook, this one drug causes bleeding episodes in up to 53% of patients who receive it; protein in the urine in up to 38%; high blood pressure in up to 32%; gastrointestinal perforation in up to 11.4%; poor wound healing in up to 10%; and arterial thrombosis (blood clots in an artery) in 3.8% of cases.

A meta-analysis of trials of Avastin showed that, overall, the rate of GI perforation was just 0.9% of patients. Others put the number at 2.1%. However, that may be because the patients in question were “cherry-picked” to have better-than-average health, at least for cancer patients.

But in the ORBIT clinical trial, where ovarian cancer patients who had previously received (and failed) intensive chemotherapy, 5 of the first 44 patients (11.4%) developed GI perforations, which led to the early termination of the study.

Gastrointestinal Perforation
“Gastrointestinal perforation” was and is a dreaded side effect of this drug. Another name for this condition is a ruptured bowel, which is a hole in the wall of part of the gastrointestinal tract. Symptoms include severe abdominal pain and tenderness. The pain is typically constant. The treatment is major surgery. Avastin can also cause holes in other parts of the body, such as the septum that divides one’s two nostrils in the nose.

Since 2003 there have been at least 128 articles on GI perforation and Avastin. According to a 2009 review article:

“The addition of [Avastin] to cancer therapy significantly increased the risk of gastrointestinal perforation compared with controls. The risk may vary with bevacizumab dose and tumor type.”
The death rate from this condition averages 21.7%. However, in other studies “the mortality rate for patients with [Avastin]-induced bowel perforation has been reported as high as 50%.”

The current version of the NCI website states quite accurately:

“Scientists had expected that targeted cancer therapies would be less toxic than traditional chemotherapy drugs because cancer cells are more dependent on the targets than are normal cells. However, targeted cancer therapies can have substantial side effects.”
Different Side Effects
There is no doubt that the side effects of targeted therapies are different from those of toxic chemotherapy. But often they are no less serious, and may in fact be more so. “Gastrointestinal perforation” for example, was rarely seen before the introduction of Avastin in February 2004.

According to the NCI, other typical side effects of targeted therapy may include:

Diarrhea
Hepatitis with elevated liver enzymes.
Skin problems (acneiform rash, dry skin, nail changes, hair depigmentation)
Problems with blood clotting and wound healing
High blood pressure
Gastrointestinal perforation
ALEX Trial
For example, in the ALEX trial, Xalkori (crizotinib) alone caused grade 3 to 5 (serious to severe) side effects in 50% of the patients. “Grade 5” is code for a fatal drug reaction, and in fact, one in 20 patients died from the treatment itself.

In the 2018 clinical trial of another single targeted drug (part of the NCI-MATCH trial), common side effects included fatigue, anorexia, dry mouth, nausea/vomiting, diarrhea, constipation, oral mucositis [i.e., painful inflammation and ulceration of the mucous membranes of the GI tract], anemia and liver function abnormalities.

Many patients barely got through the trial of this one drug alive. So how could doctors give five, ten, or more drugs in a super cocktail of toxic agents? The question answers itself. They can’t.