A Rose is a Rose or a Thorn is a Thorn
Chemotherapy for Sarcomas
What is chemotherapy? Why does the word chemotherapy almost always evoke negative thoughts?
History tells us that the first use of chemotherapy was when Jesuit priests in Peru discovered that the bark of the cinchona tree is useful to reduce the fever of malaria. Chemotherapy came to mean using a natural product (something from nature) to treat human disease. The bark of the cinchona tree contains quinine. The priests didn’t know what quinine was or begin to understand the chemical structure. Perhaps, they didn’t care. However, using this product, they were able to improve the quality of life of the Peruvians who had contracted malaria.
Centuries later Paul Ehrlich, a German physician scientist coined the term "chemotherapy." Ehrlich was the first to systematically search a chemical inventory to find a useful drug against a major disease of his day, syphilis.
In modern drug discovery, researchers often gather a large number of chemicals of similar structure or function. They then try to determine which specific chemical has the most efficacy or minimizes a side effect. That chemical is then chosen as the drug for further development. It is said that Ehrlich had to evaluate 603 arsenical compounds before discovering that the 604th compound had the desired effect. Ehrlich started this methodical process. He demonstrated the 4 essential characteristics of a successful drug developer: perseverance; worthy ideas, sufficient resources and luck.
Ehrlich's life is depicted in the movie "The Magic Bullet." He was awarded the 1908 Nobel Prize in Medicine.
Indeed, Ehrlich was successful, and found a derivative of arsenic that was useful in his animal model system.
Researchers have known for many years that efficient clinical research depends upon having effective animal models. It would be vastly too expensive, too slow, and unethical to do all experiments about human disease in people. Mice and rats are the most common animals used to serve as models of human cancer. These small mammals are injected or fed substances that induce a cancer and then various treatments area applied to determine safety and effect. Large breed dogs very often develop osteosarcoma and are now being used as a "natural" model. Ehrlich used a parasitic infection in rabbits to evaluate his arsenical compounds.
Thus, 18 months of painful injections became the first successful treatment reducing the mortality of syphilis. Of course, in the mid 20th century Alexander Fleming discovered the new chemotherapy of the day, penicillin. Now, the new curative chemotherapy for syphilis required a single intramuscular injection and the cure rate was successful beyond anyone’s expectations. Ironically, in this century another derivative of arsenic was proven helpful in treating leukemia.
In the middle of the 20th century, chemotherapy came to mean the first successful treatment for tuberculosis (TB). TB was almost always a lethal infection and our best supportive care involved admitting patients to sanitariums. With the advent of combination chemotherapy, TB became a curable infection. Infected patients returned to a normal life and the sanitariums were no longer necessary. Infectious disease specialists thought to combine drugs that individually had a modest effect but when used in combination became curable. They chose drugs that had different mechanisms of action and drugs that did not have overlapping toxicities.
But, now, of course, when we say chemotherapy we mean the treatment of cancer. Some experts will point out that the successful treatment of AIDS is a consequence of effective chemotherapy. The first broad success in the treatment of cancer was a combination chemotherapy approach to treat patients with Hodgkin’s disease. The major pathology textbook used in the mid 1960’s stated that "Hodgkin’s disease is an often fatal cancer." In 1968, Vincent Devita from the National Cancer Institute reported that "MOPP" chemotherapy cured 50% of patients with the most advanced stage IV disease. MOPP was in many ways a mimic of the chemotherapy used to treat TB. Devita chose cancer chemotherapy drugs that worked on different targets of the cancer cell and had minimal overlap in toxicity.
The "MOPP" study, which referred to the first initials of the four drugs used in the study — Nitrogen Mustard, Vincristin (Oncovin®), Prednisone and Procarbazine — was initially reported in DeVita V T, Serpick A A & Carbone P P. Combination chemotherapy in the treatment of advanced Hodgkin’s disease. Ann. Intern. Med. 73: 881-95, 1970.
Today chemotherapy still means to most in our society the treatment of cancer with a drug or drugs. Many people believe that chemotherapy only means the use of cytotoxic drugs given intravenously. Patients are often surprised to learn that some cytotoxic drugs have been available as pills for many years. Giving a medicine as a pill or capsule is certainly more convenient but not necessarily with less side effects or potency. Other drugs, that are used to treat cancer and often called "targeted agents" such as imatinib are really chemotherapy in every sense of the word — a systemic medication used to eradicate or control a life threatening disease.
So, now the second question, "Why does the word chemotherapy almost always evoke a negative response?" Part of the answer is easy. Most of the cytotoxic chemotherapies are associated with (ob) noxious side effects: profound nausea and vomiting; loss of hair; significant weakness; marked increase in susceptibility to infection, etc.
Even still, did Lance Armstrong think the chemotherapy was not worth it? Mr. Armstrong is a celebrity who had widespread testicular cancer with metastasis to his lungs and brain. But his cancer was eradicated; he recovered from the devastating side effects; and went on to an extraordinary career as an athlete. More than 90% of men diagnosed with testicular cancer are cured; but, not 100%. If Mr. Armstrong had died of cancer or as a consequence of the treatment would he be a celebrity or a victim?
The fact is most patients and especially those with a sarcoma who are treated with chemotherapy experience these same awful side effects. The fact is when I finished my fellowship training in medical oncology in 1972 only 20% of patients diagnosed with osteosarcoma survived and NO patient diagnosed with Ewing’s sarcoma survived. Today, approximately 60-70% of patients diagnosed with osteosarcoma or Ewing’s sarcoma are cured. We learned 25 years ago from several important clinical trials that if we used chemotherapy, more patients would be cured. We have gotten a little better managing the side effects of chemotherapy but no new drug has been discovered to improve the clinical outcome in these past 25 years.
Chemotherapy significantly improves the prognosis of a newly diagnosed patient with osteosarcoma or Ewing’s sarcoma. But the success is not as great as the success in treating tuberculosis or syphilis. More progress is clearly needed. So, if I were the parent of a child who died of one of these sarcomas, I may think the problem is chemotherapy. It didn’t help my child! Sometimes we need demons to blame for ill fortune. But what we really need is progress. To make progress we must first define the problem. Chemotherapy is not the problem….it's cancer.