Pediatric Oncology is a great example of a field of medicine where clinical trials are routinely leading to improved therapies.
The first response when I tell someone that I am a pediatric oncologist is “how sad”. If I respond that “more children are cured than are not cured of their cancer (depending on the cancer type)”, the answer is typically “kids are resilient”. I admit that kids are typically free of other health issues (the medical term for this is “comorbidities”), and this is helpful for tolerating intense treatment with chemotherapy. If I have this conversation with someone knowledgeable about cancer biology, they will remind me that the biology of pediatric cancers is different. This is true, but I think there is another major reason for the better results that children have from cancer treatment compared with adults. This is the role of clinical trials.
We treat the majority of pediatric patients for their cancer by enrolling them in clinical treatment trials (>60%), whereas only a very small minority (<5%) of adults will be treated in a clinical trial. In the last 40+ years since Nixon declared a “war on cancer”, there has been a marked improvement in pediatric cancer results. Sadly, adult cancers have had only seen a slight improvement (mostly in the last two decades) as a result of new therapies. Pediatric cancer treatments have been progressively improving with an overall survival rate of childhood cancers from under 20% fifty years ago to better than 70% today, despite the fact that newer agents are less available in pediatrics.
How can this be? Because of clinical trials the treatment of childhood cancers is standardized. This means a child in New York, Texas, and even Paris who is diagnosed with acute lymphoid leukemia (ALL) will be treated exactly the same or very similarly. Clinical trials also mean that each patient is a data point for adjusting and improving future therapies. In adult oncology, the treatment offered can differ from oncologist to oncologist. Because most adult cancer patients are not treated in clinical trials, most cases are not providing information that will be beneficial for the greater patient population. More importantly to our own care, this means that we may get a variety of different recommendations that can be difficult for us to evaluate. The old proverb “two heads are better then one” is a simple way of thinking about the benefits of standardizing therapy. Having oncologists around the country and the world working together to determine the standard treatment is better then one oncologist evaluating the literature to determine the best treatment. Almost all pediatric oncologists in the USA are united through their membership in the Children’s Oncology Group (COG), which sponsors a vast majority of the pediatric oncology trials. There are exceptions to the generalizations above. There are rare and/or relapsed pediatric tumors that may have a specialized clinical trial open in only a couple of locations. This is especially true of phase 1 and 2 trials (will be discussed in part 2) which are mostly conducted at specialized centers for early-phase clinical trials. There are also very common adult tumors where one approach is used commonly known to be the standard treatment and is followed by the majority of oncologists.
Uncertainty is inherently part of cancer treatment which can lead to the mis-perception that we are guinea pigs.
The biggest misconception that I hear about clinical trials from my fellow cancer patients is “I will be experimented on”. As I have discussed in many of my past posts, with most cancer treatments there is an inherent uncertainty that differentiates it from other areas of medicine, due partly to the complexity of cancer biology. When we get an antibiotic for something like an ear infection, we can expect in most cases that that ear infection will go away. Bacteria cells are more simple then human cells. Antibiotics kill the infection and can easily distinguish the bacteria from human cells hosting the infection. Cancers come from our own cells and are complex. Therapy must distinguish the cancer cells from other non-cancerous cells in the body, and this can be difficult.
The biology of cancers is human biology. Just as we have some commonalities with all humans, we also have parts that make us individuals. Cancers also have unique properties, some that can be tested for and others that cannot. Sometimes this biological “uniqueness” of our cancer cells is clinically significant, meaning that it will influence whether a particular treatment will work , and sometimes it is not. Sometimes we understand the significance and sometimes we do not. All of these factors add to the uncertainty of how individual cancers and hosts will react to cancer drugs. An example is acute lymphoid leukemia (ALL) in which some patients express a gene product made from a gene rearrangement called the Philadelphia chromosome. We can test for this knowing that patients that test positive for this gene will require more intense chemotherapy. We also know that we can use medications that target this gene in this population. Other times the only test that we have to determine if a particular therapy will be effective is by trying it and monitoring the response of the tumor. So when our oncologist says we are going to “try” a therapy, it does not mean experimenting on us, but reflects the inherent uncertainty in cancer therapy. Therefore, even outside the setting of a clinical trial, we can mistakenly believe that we are being experimented on, despite the fact that uncertainty is associated with any cancer treatment. Clinical trials (also called studies) can increase this perception. But in these cases the doctors are just clearly defining a question about what aspect of a specific treatment and or cancer is uncertain and designing the study to answer that question.
Through sequential clinical trials we have changed incurable diseases to curable.
This paragraph includes some bold words which will be defined below.
There are all kinds of studies. One of the most common studies to which I consented when practicing pediatric oncology was a phase 3 (more on that soon) trial for newly diagnosed leukemia. The majority of the pediatric patients with this diagnosis will be cured, and this cure was established because of sequential clinical trials. Whereas less then 20% were cured in the 1960’s, through trials that sequentially built upon each other so that every couple of years they were tweaked and changed to answer a new question, we are at a point today where over 80% of patients with pediatric ALL will be cured. These studies are designed to ask very specific questions. All patients tend to get very similar treatments but are also broken into two or more groups through a process called randomization, where there are minor differences in treatment to target the question being asked. All patients typically get a very similar treatment. Many phase 3 trials will not include new or experimental medications but may be designed to answer the best way to give medicines already well established to be effective in the specific disease. Such trials may mean a different dosing schedule or using medications in new combinations. Other phase 3 trials will have newer drugs added into the treatment.
In all cases where there is randomization, it is not known which arm of the study (group) is superior. That is why there is a study to answer that question, although there is rationale for why the experimental arm (newer arm) might be thought to be better then the standard arm. No group goes untreated, and no one is intentionally given a less effective therapy. The data from the trial is also continuously processed, so that if we are being treated on a trial and suddenly it becomes clear that another arm is better, the study will be stopped and treatment will be changed to the best known treatment of the time. For pediatric patients treated in these large studies, I can reliably say that being treated in a study is a very effective way to get the best known therapy.
In our medical training we are often taught about the history of clinical trials. Some of this history is shameful. Although I rarely think this is the reason for patients’ hesitation about clinical trials, it is perhaps this unsavory past that has led to a common psyche that is distrustful of medical studies. But this history, especially the Tuskegee experiments, has led to the multiple layers of federal regulations that ensure patient consent and safety. This is why we have Institutional Review Boards (IRBs) and informed consents. For folks who have been disappointed with a doctor for not reviewing all possible side effects, this is another benefit of clinical trial because the physician must take you through a very long and detailed informed-consent process which means a long discussion about the medicines that will be used.
Definition of bold terms above
Randomization: Is the process of randomly assigning patients to different arms of a study. Often this means that a computer generates randomly which arm the doctor will treat the patient on. What is known is that the patient has the features that qualify for the study, but since it is unknown if one arm of the study is better this part is left to chance. The computer uses an algorithm so that enough patients are distributed on the different arms to answer the question. It requires that the two groups be the same, which may not be the case if doctors who have more knowledge about their patients were allowed to assign the groups. They may have some bias that distinguishes patients based on their own thought process and if this influenced their grouping, then the study could be falsely interpreted because the groups would not really be equal.
Experimental Arm: The arm of the study that includes a “new” agent or contains a new “method” of delivering a treatment. Often a study is done to test if this is an improvement from the standard arm.
Standard Arm: The arm of study where the treatment is the current “standard” therapy and the best known therapy at the time for the particular group of patients. Typically, in sequential clinical trials the standard arms was the arm established to be the superior arm in the last study.
Tuskegee experiments: A medical study of syphilis that was started in 1930’s. This was in an era before informed consent, and participants were often unaware that they had syphilis. Participants were also untreated even after penicillin was shown to be an effective therapy in the 1940’s. No such study could be done today, because of the strict regulations that were developed in response to this horrid past.
What will be included in the next posting:
A second part to this post will be posted within the next week and will include what we mean by phase 1,2,3, and 4 clinical trials and give some of the reasons why we should consider participating. I will also include information and resources for how to go about searching for clinical trials for your type of cancer in that post.