Randomized Clinical Trial Paradigm
The mindset of cancer medicine is to think it's great science to identify the best treatment to give to the average patient is through prospective, randomized trials. We have produced an entire generation of investigators in clinical oncology who believe that the only valid form of clinical research is to perfrom well-designed, prospective randomized trials in which patients are randomized to receive one empiric drug combination versus another empiric drug combination. Do cancer cells like Coke or Pepsi?
All the rigorous clinical trials identified are the best treatments for the average patient. But cancer is not an average disease. Cancer is far more heterogeneous in response to various individual drugs than are bacterial infections. The tumors of different patients have different responses to chemotherapyterm. It requires individualized treatment based on testing the individual properties of each patient's cancer.
There are hundreds of different therapeutic drug regimens which any one or in combination can help cancer patients, with hundreds more drugs in the pipeline. The system is overloaded with drugs and underloaded with wisdom and expertise for using them. We are getting an expanding list of treatments which are partially effective in a minority of patients, ineffective in a majority, remarkably effective in a few, while being enormously expensive. The fastest way to improve things is to match treatment to the patient.
One of the main problems in providing effective chemotherapy is the situation that every patient is unique. Tumors grow and spread in different ways and their response to treatment depends on these characteristics. The amount of chemotherapy that each patient can tolerate varies considerably from patient to patient. Therapeutic protocols currently in use are limited in their effectiveness because they are based on the results of clinical trials conducted on a general patient population, yet no two patients are alike.
Clinical trials test the efficacy, not the accuracy of a drug. Efficacy means producing a desired effect, like tumor shrinkage. Single arm clinical trials provide the tumor response evidence that is the basis for approving new cancer drugs. Metastasistermterm is an organism-wide phenomenon that may involve dozens of processes. It's hard to do replicable experiements when there are so many variables. So, instead, researchers opt for more straightforward experiments that generate plenty of reproducible results (like tumor shrinkage). This gives the illusion that researchers have done something meaningful.
Tumor shrinkage should not be the criteria for approving cancer drugs. A patient responds to therapy when their tumor shrinks, but apparently this has nothing to do with survival. A tumor responds, that is, shrinks a little, then quickly grows and spreads. The cancer comes back with a vengeance and the cancer patient is given a death sentence.
There are tens of thousands of scientists pushing a goal of finding the tiniest improvements in treatment rather than genuine breakthroughs, that fosters redundant problems and rewards academic achievement and publication above all else. The randomized, controlled clinical trial may likely remain the standard for evidence of clinical decision-making in cancer medicine, however, observational methods and systems biology are clearly useful. Even with the importance of clinical trials, it is crucial to work on reducing their inherent limitations, including uncertain generalizations, and to expand the use of the randomized clinical trial paradigm to areas beyond proving biological activity, like diagnostic testing.
Recognizing the reliability of the evidence upon which clinical practice has increasingly come to depend, the time has come for physicians to reassess the value of direct observation, and to trust more readily both the empirical and intuitive discoveries they make each day in their personal experience, even if those discoveries are contradicted by the best available evidence.
As the number of possible treatment options supported by completed randomized clinical trials increases, the scientific literature becomes increasingly vague for guiding physicians. Almost any combination therapy is acceptable in the treatment of cancer these days. Physicians are confronted on nearly a daily basis by decisions that have not been addressed by randomized clinical trial evaluation. Their decisions are made according to experience, new basic science insights, bias or personal preference, philosophical beliefs, etc.
Whatever clinical response that has resulted to the average number of patients in a randomized trial is no indication of what will happen to an individual at any particular time. They are trying to identify the "best guess" treatment for the "average" patient. There is no accuracy, nor any proof that what works for the "average" patient population will work for the "individual."
Until the controlled, randomized trialist approach has delivered curative results with a high success rate, the choice of physicians to integrate promising insights and methods like chemoresponse assays, remains an essential component of this kind of treatment technology.