A recent article in The New York Times, New Drugs Stir Debate on Rules of Clinical Trials, discusses the highly controversial matter of a new drug, PLX4032, which has demonstrated new promise for patients with melanoma in early clinical trials. The drug, which targets a specific genetic mutation known as B-RAF, has resulted in symptomatic relief and shrinkage of tumors, mainly for patients with metastatic melanoma who express the targeted mutation. The overall prognosis for metastatic melanoma is poor and death usually occurs less than a year after diagnosis – at best. This new drug offers hope to patients – if not for survival, then at least for improvement of symptoms.
The article comes at an opportune time, as I am reading The Immortal Life of Henrietta Lacks. Henrietta Lacks is the African-American woman from whom the famous HeLa cells originated. This novel tells the story of her and her family. Although Henrietta was never aware that her cells were being used for experimentation, they now weigh more than 50 million metric tons – the equivalent of a hundred Empire State Buildings – and can wrap around the Earth three times. They helped researchers develop drugs to fight herpes, leukemia, influenza, hemophilia, and Parkinson’s disease.
Henrietta Lacks, circa 1945.
Although Henrietta died from cervical cancer over 60 years ago, her cells are immortal and have spanned the entire globe. The story is a remarkable one – but it brings to the surface the troubling questions of medical ethics. Henrietta was never asked permission for her cervical cells. Nor was her family notified of their significance until many years later.
Within the woven tapestry of history, there are several stories of physicians and researchers breaching ethical boundaries. The first recorded autopsies were performed by doctors in Alexandria around 300 BC. Da Vinci and Michelangelo performed autopsies to better understand human anatomy for the purpose of art. These autopsies were performed in secret and were generally frowned upon by the community. And there are countless stories of the abuse of live human subjects – the Tuskegee syphilis study, during which 400 men died after researchers had discovered that penicillin could cure them. The list goes on. James Marion Sims performed pelvic surgeries without anesthesia in the mid-1800s. Wendell Johnson spearheaded the infamous “Monster Study” which involved placing children under intense psychological pressure in an attempt to cause stuttering.
The controversy over PLX4032 is yet another in a long list of medical ethics issues. The current clinical trial assigns patients randomly to receive dacarbazine or PLX4032. Unlike other clinical trials, however, patients and physicians known which drug patients are receiving because dacarbazine is administered intravenously while PLX4032 is administered orally. Dacarbazine is a cytotoxic drug, with a plethora of adverse effects, which has demonstrated minimal effectiveness for tumor shrinkage (15 to 20%) but has not demonstrated any effect on prolonging overall survival for patients with metastatic melanoma.
Some physicians and researchers argue that PLX4032 should go through a full phase III clinical trial in order to answer the most important question: Does PLX4032 prolong survival in melanoma patients? The trial will also provide good data for comparing it against other targeted drugs for melanoma which will be emerging soon.
But I think the drug should be administered to patients who request it. First, the clinical trial is limited by the fact that it cannot be double-blinded. Patients’ and physicians’ knowledge of the treatment they are receiving inevitably skews the results. When a patient knows he is receiving dacarbazine – a drug with minimal effectiveness for his cancer – the effect is worse than placebo. He does not even have hope that he may be receiving the newer drug.
Secondly, the new drug works by an entirely different mechanism than dacarbazine. PLX4032 targets a specific mutation in tumor cells. Dacarbazine is an alkylating agent which inserts itself between the DNA strands in both normal and tumor cells. Because of its broad effects, it is used for treatment of several cancers, including Hodgkin’s lymphoma, sarcoma, and pancreatic cancer. If comparison is the primary goal, it would be much more beneficial to compare drugs with similar mechanisms – take another drug that targets a mutation in melanoma cells and compare PLX4032 to that.
Thirdly, even if patients are assigned to the dacarbazine group, they should be given the option to switch to the PLX4032 group if they are not tolerating side effects of dacarbazine or if they are not responding to treatment. With this method, we would be able to gather preliminary data to compare the effectiveness of the two drugs. Another possibility is combination therapy – compare dacarbazine plus PLX4032 to PLX4032 alone. This would provide important information to clinicians – and it may provide enough evidence to minimize the use of a toxic drug.
Fourth, regardless of effectiveness of PLX4032 at prolonging survival, it alleviates symptoms. It may do so even better than our traditional pain medications such as morphine, because it targets the source of the pain rather than simply masking it. For this purpose alone, as long as the drug has passed various safety trials, it should be administered to patients who are in pain due to melanoma. Dacarbazine is certainly not a competitor in this area – and in patients with a median survival of 6 to 12 months, shouldn’t comfort be a primary concern?
Fifth, dacarbazine is a drug of the past and PLX4032 is a drug of the future. As we become more adept at understanding the mechanisms behind certain tumor cells – specific both to the type of cancer and to the individual – we will become better at developing targeted therapies. Just as bloodletting through leeches is now largely a therapy of the past (and a therapy which was the standard of care for almost every disease through the early 1800s), the current chemotherapy regimens will someday be outdated. Their replacement? Gene targeting drug therapy.
Lastly, sometimes we need to acknowledge that the public knows best, and sometimes we need to sacrifice theoretical science for humanity. People need hope. As physicians and researchers, we need to work better to establish trust – and hope – between the research world and the patient world. After all, we make no progress in medical science without patients – courageous patients like Henrietta Lacks, who have sacrificed themselves, whether they knew it or not, for the greater good. As clinicians, we need to honor this and we, too, sometimes must be willing to sacrifice ourselves – and pristine research – for the benefit of humanity.