The following is a collection of excerpts from New York Time’s bestselling book Tripping Over The Truth by Travis Christofferson. I highly recommend this book to anyone seeking to better understand the history behind traditional medicine’s most recognized form of cancer treatment. ~ Michelle Hamburger
Tripping over the Truth, by Travis Christofferson
“Fittingly, and maybe ironically,
chemotherapy was born out of one of the atrocities of World War II…
[in] December, 1943 the Germans had bombed the port of Bari, in southern Italy, an important hub for the Allied forces.
The initial attack killed a thousand Allied servicemen. Hundreds of sailors jumped into the water to escape the sinking ships. When they emerged, covered in an oily amalgam from the destroyed and leaking ships, many noticed a garlicky odor. Strange symptoms began to afflict them. Many complained of a burning sensation, but didn’t associate it with the oily mixture saturating their uniforms and clinging to their skin.
The medical staff noticed that blisters began to form, and even worse symptoms developed throughout the night. In addition to the burning skin, hundreds of soldiers went blind.
Recognizing the symptoms, it had to be mustard gas.
Doctors soon got to work analyzing the tissue samples from the affected victims. One consistent feature stood out: the samples all displayed a striking depletion of white blood cells within the lymph nodes and bone marrow, precisely the tissues that become packed with the feverishly dividing cells of lymphoma patients.
Two Yale pharmacologists, Louis Goodman & Alfred Gilman, entertained the possibility that nitrogen mustard possessed a dual nature that could exist both on the battlefield and within a physician’s clinic.
An experiment was devised to test the bizarre idea that the war gas might function as a long-awaited chemotherapeutic agent. Their series of experiments confirmed that the mustard compound significantly decreased the size of lymphoid tumors in mice.
The pharmacologists asked a thoracic surgeon to administer nitrogen mustard to a lymphoma patient. The first patient treated had a severe case of non-Hodgkin’s lymphoma and all other options had been exhausted. To everyone’s amazement, the patient’s tumors regressed. The drug was then injected into other patients with the same result. When the research was finally published in 1946, it inspired a wave of excitement.
The uncomfortable fact was that cancer treatment had been stagnant for centuries and consisted of only two principles: remove as much as possible with surgery and treat what was left with radiation.
The idea that drugs could diffuse through the body, bringing the fight to cancer wherever it hid, had been a long-standing dream. Drugs were the only conceivable solution to “liquid” cancers such as leukemia and lymphoma that were impossible to cut out or irradiate. Maybe drugs could be developed to treat – or even cure – cancer.
Nitrogen mustard works by attacking DNA itself, preventing cell division.
Of course, nitrogen mustard is unable to distinguish a normal cell from a cancerous one, so it travels through the body indiscriminately locking the DNA of every cell it encounters.
Sadly, after the drug was widely distributed, the remission induced by nitrogen mustard turned out to be for only a matter of weeks. The cancer then sprang back to life, packing lymph nodes full of solid malignancy. In the weeks that follow, the numbers of red & white blood cells and platelets drop precipitously. Bruises appear, anemia induces fatigue, the chance of infection increases, hair cannot grow, rapidly dividing cells of the gut lining are killed resulting in uncontrolled diarrhea, black and tarry episodes result from intestinal bleeding, patients become sterile, mouth sores appear, and the veins used to carry the drug to the rest of the body begin to darken.
As WWII came to its conclusion, the pessimism surrounding chemotherapy and the disappointment of nitrogen mustard lifted enough to allow reconsideration.
In 1947, the compound methotrexate was found by Harvard pathologist Sydney Farber to be capable of invoking remissions in children with leukemia, again sparking hope. Methotrexate is a synthetic form of folate, a vitamin required for DNA to replicate. Methotrexate looked just enough like folic acid to trick the body into thinking it was the real thing. But although it looked like folate, it didn’t act like folate.
Rather, it acted like a broken key in a lock, gumming up and halting the biological process, thereby actually inhibiting the replication of DNA.
Like nitrogen mustard, methotrexate was far from specific. It indiscriminately prevented both cancerous and normal cells from dividing, but because cancer cells divided more often, it killed them with a slight preference. Also like nitrogen mustard, methotrexate was able to eke out only brief remissions, but it was enough.
Farber’s discovery urged the US Congress to initiate a national program dedicated to the discovery of more chemo drugs, and in 1955 the Senate Appropriations Committee allocated $5 million for the development of the Cancer Chemotherapy National Service Center.
Drugs of the same ilk followed. In 1951 synthetic chemist Gertrude Elion designed a molecule to look like one of the four bases of DNA. She followed the logic that if the molecule could trick the cell into thinking it was a nucleotide, then it could throw a wrench in the DNA replication process.
Elion’s drug, 6-MP, threw the cancer into remission and, like the other drugs, the respite was measured only in weeks. But even if individual drugs disappointed, slowly an arsenal was being built. While alone each compound may have been weak, doctors reasoned that, similarly to antibiotics, when administered together, they might be strong. There was no hiding the fact that they were blunt, indiscriminate poisons.
To use them in combination might improve the outcome, but it might also double or triple the toxicity, potentially killing patients before they could get better.
During the winter of 1957, doctors Emil Frei and Emil Freireich were given permission to treat children with leukemia with a combination of two drugs: Farber’s Methotrexate and Elion’s 6-MP. The study was designed with one goal: to determine whether chemotherapy drugs were more powerful when used in combination, to reduce the amount of cancer. When the results were tallied, the difference was striking.
Given alone, the drugs produced response rates between 15 and 20%. Combined, the response rates were much better. Although the combination of drugs was extremely toxic, it boosted response rates by more than 45%. These results set the stage for moving forward, but the path was not without friction.
The leukemia ward at the hospital contained ashen-faced kids huddled over buckets – anemic zombies of sorts.
As the fledgling field of chemotherapy was taking shape, it galvanized doctors into opposing camps.
One camp wanted to push forward, reasoning that the children had no other options. They had a disease that sentenced them to death. The other camp felt that it came at too high a price. Most practitioners declared it “inhumane” to drip poison into the veins of patients. Even though patients faced an invariably fatal disease, some felt that to put them through hell for what time they had left was morally reprehensible.
Emil Freireich reasoned that if the drugs that killed cancer cells by different mechanisms were used together, the toxicity would be diluted instead of being additive.
Months of intense discussion culminated in a bold strategic regimen that combined four drugs: vincristine, amethopterin (aka methotrexate), mercaptopurine, and prednisone, a regimen given the acronym VAMP.
When the trial was launched in 1961, it was far from clear whether the poisonous cocktail would be too much for the sick children, killing more than helping. The four-drug combination devastated the children’s cell counts, debilitating to the point where they were left hanging by a thread. Platelet tansfusions were given to prevent bleeding, combinations of new & old antibiotics were given to prevent infection. For three anxious weeks, everyone watched with bated breath. When they finally arrived at the finish line, one thing was different. The grossly distorted leukemia cells were conspicuously absent. Yet as striking as the remissions were, they would have to prove durable. The question was whether the regimen eradicated allleukemia cells, or whether there were cells yet in hiding, buying time.
Buoyed by the initial remissions from the VAMP trial, cardiologist Vincent DeVita set out to prove the viability of the new multidrug approach. To do this he would need to tackle another cancer, Hodgkin’s disease, an invariably fatal but rare form of lymphoma.
DeVita chose a regimen mirroring that of VAMP, a four-drug combination titled MOPP consisting of nitrogen mustard, Oncovin (the brand name for vincristine), procarbazine, and prednisone. In 1964 victims of advanced Hodgkin’s began to sign up to receive DeVita’s new protocol. In all, 43 patients received the cocktail.
As expected, MOPP drove patients into a haze of debilitating nausea, their immune systems destroyed. In addition to common side effects like hair loss and vomiting, unanticipated ones – like sterility in both men and women – were seen. Like VAMP, however, once the limits of tolerability and morality were stretched to the snapping point, the payoff phase eclipsed the ugliness. The swollen nodes disappeared, the patients slowly recovered, their hair grew back, they could keep food down and health was restored.
Chemotherapy was a new form of healing that was designed to tear the body down and then allow it to heal. The hope was that the distorted cancer cells, wherever they came from, would be unable to make the journey back.
It was a bit like burning down a house to rid it of rats, hoping, in the end, that it could still be rebuilt.
Whatever invisible event conspired to spark Hodgkin’s genesis didn’t matter. For the moment, the cancer was gone.
However, in the fall of 1963, the striking remissions achieved from the VAMP trial proved not to be as enduring as hoped. Once by one, Frei & Freireich’s children returned to the clinic with a cadre of neurological complaints: seizures, tingling sensations and persistent headaches. Cerebrospinal fluid was extracted for analysis, and what they found crushed any remaining hope. Inside the murky fluid lurked leukemia cells. VAMP had rid the bone marrow & lymph nodes of leukemia, but the cancer had taken asylum in the one place it couldn’t be followed. All it took was a few cells to squeeze through the blood-brain barrier and begin new rounds of growth. Frei and Freireich had to watch helplessly as the children spiraled to their deaths as the cancer exploded within the safe-haven of the brain. In the winter of 1963, Frei left the National Cancer Institute, and Freireich soon followed.
As VAMP disappeared into oblivion, Donald Pinkel, a Navy doctor, showed up to pick up the pieces, reorganize them, and try again. In 1962 he opened St. Jude Children’s Research Hospital in Memphis and turned his focus to acute lymphoblastic leukemia (ALL). Because of the lessons of the VAMP trial, he knew where the cancer cells were hiding, just beyond the fragile blood-brain-barrier in the cerebrospinal fluid.
He injected drugs directly into the safe-haven, removing the reason for VAMP’s failure. He dosed the brain with radiation too, just to make absolutely sure to extinguish the possibility that even a single cancer cell survived. Pinkel proposed combinations of combinations, scrambling up to eight different drugs, attacking the cancer from every conceivable direction. And to further prevent any possibility of a single surviving cell, he stretched the duration of the treatment from months into years. He called the approach “Total Therapy”.
Even though on paper the protocol was long and exhaustively precise, the logic of Total Therapy was simple.
Without a clear understanding of the disease, and with only certain weapons available, if they didn’t beat the cancer the first time, then pushing harder was the only option.
When the survival data was tallied, Pinkel and DeVita were transformed into heroes. Eighty percent of Pinkel’s kids were estimated to be cured. DeVita was able to cure 60 percent of his patients with Hodgkin’s disease.
As the accomplishments were celebrated on television and in newspapers & magazines everywhere, young doctors were learning by example. Too much caution could thwart real advances in medicine. It was a fine line, but there were rewards for being the one brave enough to push boundaries.
Two days before Christmas in 1971, President Richard Nixon declared the war against cancer. It was widely believed that it would only be a matter of years before a general cure for cancer was discovered. It was simply a matter of getting the right combination and dose of drugs. With targeted therapy still in its infancy, this meant continuing the same toxic, indiscriminate, and blunt war. MOPP, VAMP, and Pinkel’s Total Therapy established the foundation of chemotherapeutic logic: combine drugs, up the dose, hit first, and hit hard. The medical slang for cancer treatment, “slash and burn” now had a third component: “slash, burn and poison”.
The National Cancer Institute turned into a chemotherapy factory. Its Developmental Therapeutics Program budget swelled to $68 million and transformed into a drug-screening juggernaut, churning through 3 million mice and screening forty thousand drugs annually. Once it was proven that the drugs could be prescribed and a profit could be realized, the process spun off an entire industry of oncological pharmaceuticals. By 1980, the budget available for a single branch of clinical trials swelled to $199 million.
A seemingly unending supply of new patients provided a constant fresh canvas for experimentation with new drugs, combinations of existing drugs, or combinations of old with new. The doctors tormented patients, sending them to the brink of death, bringing them back, and bombarding them again. As the colorful chemicals dripped into the patients, a spectrum of side effects left no organ or cell unscathed.
Discovered by accident, Cisplatin was one of the more exciting drugs put into trials. It operated with the same mechanism as its cousin, nitrogen mustard, locking strands of DNA together and rendering replication impossible. Cisplatin became so popular that it became known as the “penicillin” of cancer. With the yellow toxin came a severity of nausea not seen before – on average, patients taking cisplatin vomited once every hour they were awake.
In the background, as the basic science of cancer research trudged forward, others couldn’t help commenting on the apparently indiscriminate experimentation. Kidneys were put into failure, hearts were damaged, lungs & skin were scarred and burnt, hearing was lost, septic shock was induced and immune systems were devastated. Many patients even died outright from the trials.
Physician and author Eric Topol said,
“Chemotherapy is just medieval. It’s such a blunt instrument. We’re going to look back on it like we do the dark ages.”
The director of NCI encouraged doctors to expand the chemotherapeutic paradigm to include “solid” cancers, the ruthless forms that were responsible for 95% of all cancer deaths. The shift in target garnered some initial success treating testicular cancer, however testicular cancer proved to be the weakest of the lot. When doctors moved to other solid cancers, the drugs proved ineffectual. Even as they tried different combinations and upped the dose, they were able to beat the cancer back only for weeks or months at best. Without question, cytotoxic chemotherapy would one day be viewed by future physicians as a terribly primitive episode in medical history. For now, toxic chemotherapy was inextricably intertwined with cancer, shaping the way we viewed the disease, framing the restoration of health as a fight or a battle. Someone with cancer was “at war” with the disease.
As Stanford University Medical professor Abraham Verghese said, “In America, we have always taken it as an article of faith that we “battle” cancer; we attack it with knives, we poison it with chemotherapy or we blast it with radiation. If we are fortunate, we “beat” the cancer. If not, we are posthumously praised for having “succumbed after a long battle”.
Into the 1980’s statisticians did something many labeled outrageous: They looked closely at the numbers. Over a decade into the war against cancer, it was time to objectively assess the results. When Yale-educated biostatistician John Bailer and his colleagues released their findings in 1986 titled “Progress Against Cancer?”, they were instantly demonized. What the math revealed was that all efforts combined since the “war on cancer” began saved the lives of only 4 percent of those diagnosed with cancer.
As Bailer dug further, he focused on the only number that mattered: the raw death rate, the sheer body count. By counting the bodies left on the “battlefield”, every aspect of the war on cancer was included, from new cases to the number of people saved by all medical intervention.
In essence his analysis read like this: since 1950, death by cancer had increased by 9 percent. The influence of lifestyle, and how carcinogenic we have made our world, dwarfed every effort made to combat cancer. Looking at the only yard stick that really mattered, we were losing the war, or at the very least our focus had been dead wrong.
Prevention clearly mattered more than desperately trying to find cures.
Unable to argue with the math, many attacked Bailer personally. The president of the American Society of Clinical Oncology called Bailer, “the great naysayer of our time”.
Survival data revealed another surprise. Beyond the debilitating side effects, there was an additional price to pay for the massive doses of toxins injected into the sick children. Decades later, The New England Journal of Medicinepublished the follow-up data: “In addition to sharply increased risk of heart attack and stroke, the children who were successfully treated for Hodgkin’s disease are 18 times more likely later to develop secondary malignant tumors. Girls face a 35% chance of developing breast cancer by the time they are 40 – which is 75 times greater than the average. The risk of leukemia increased markedly 4 years after the ending of successful treatment, and reached a plateau after 14 years, but the risk of developing solid tumors remained high and approached 30% at 30 years.”
The 1960’s and 70’s were known for the unenlightened crusade against cancer using a handful of systemic toxins, but researchers believed they now had a road map. They could now begin to move away from the indiscriminate poisons of the past and approach cancer rationally. With understanding would come targeted therapies designed to specifically kill cancer cells non-toxically while sparing healthy cells. In 1983 MIT’s Robert Weinberg, one of the most highly esteemed cancer researchers, said, “The major details of carcinogenesis should be largely worked out by the end of this decade.”
We are now well into the 21st Century (over 30 years later) and the biggest question-of-all still remains: Are we winning the war on cancer?