As a practitioner in adult oncology, it is only on rare occasions that I see pediatric patients managed in our clinic. Generally speaking, such patients seen in this setting are mid-adolescents with diagnoses of Hodgkin lymphoma who are being treated with a standard adult regimen. These patients are presented with the option of being treated at the local children’s hospital or our cancer center, and those who choose the latter usually do so because they more closely identify with our adult patient population than with the young children they see at the facility down the street. However, a conscious choice to receive cancer therapy among adults does not an adult patient make for these adolescents who are younger than 20 years of age. Because of the age and the stage of maturation and physical development, there are issues that must be addressed in this patient population that are generally irrelevant for the majority of our adult patients with cancer. These situations frequently require that we “think outside of the box” of our standard protocols to address issues such as fertility preservation, hair loss, and issues related to drug dosing, supportive care, and therapeutic monitoring, which may vary greatly from the persons 50 years of age and older who constitute the majority of patients treated in our setting each day.
Certain themes that are gaining traction in the management of older adults diagnosed with cancer are often important for younger patients as well. These similarities are the starting point for identifying the common ground that provides us some element of assurance in knowing that we are providing the best possible care for our patients even while we are admittedly out of our comfort zone. Two of these areas in particular involve the concepts of identifying genetic polymorphisms related to individual drug metabolism and the use of pharmacogenomic screening to identify likely driver mutations that may be specifically targeted with certain drugs.
Advances in managing childhood cancers are one of the great success stories in our collective history of oncology care. We now see an overall cure rate of nearly 80% for the most common pediatric malignancies.1 This pattern is both a reflection of the use of more aggressive cytotoxic chemotherapy regimens (compared with adult regimens) and also of the natural resilience of children. Although success rates are one of the best measures of how far we have come in treating childhood cancers, patient tolerance should also be closely monitored, just as it is in adult patients. One intersection of drug tolerance and science was identified when it was recognized that certain pediatric patients with acute lymphoblastic leukemia (ALL) were more susceptible to specific adverse events, including a significantly higher incidence of febrile neutropenia associated with exposure to some purine analogs. The role of thiopurine S-methyltransferase gene polymorphisms was discovered to affect the serum concentration of active drug via inhibition of drug metabolism. The increased area under the curve that results from this low enzymatic activity has been clearly demonstrated to affect the incidence of adverse events, drug tolerance, and quality of life.2 Similar outcomes have been observed with individualizing doses of other commonly utilized drugs as well, based on the patient’s ability to clear the drug.3 Although these older pharmacogenetic approaches that focus on single-gene polymorphisms and their associated genotypic and phenotypic expression have been highly successful, the future more likely lies in the use of wholesale pharmacogenomic screening to identify actionable driver mutations in individual patients.
Much has been written in the past decade on the concept of driver versus passenger mutations and their relative contributions in human cancers. Daniel A. Haber, MD, PhD, Director of the Massachusetts General Hospital Cancer Center, has written extensively on this topic and defines driver mutations as exerting “selective pressure during tumorigenesis” versus passenger mutations, which he defines as incidental genetic abnormalities.4 The next-generation approach of Foundation Medicine in Cambridge, MA, builds upon this pioneering work in cancer biology to create a genomic profile from the tumor’s DNA. It is important to recognize that rather than screening for specific genetic polymorphisms, as described for children with ALL treated with specific drug therapy as discussed above, Foundation Medicine seeks to understand the role that known genetic abnormalities may play in cancer types where they are not commonly expected or found. Because many pediatric cancers do not share the number of available treatment options found in adult oncology, utilization of the Foundation Medicine approach for the youngest of cancer patients makes sense.
Hawryluk and colleagues from Foundation Medicine presented data at the 2014 annual meeting of the American Society of Clinical Oncology, which revealed that of 326 pediatric patients with cancer, 241 patients were found to have at least 1 mutation that could be targeted with existing or investigational drugs.5 When we consider that many of these patients may not have had other US Food and Drug Administration–approved drugs available for their disease states, this type of approach to patients may increase access to high-quality cancer care. Given the paradigm shift that is gradually occurring toward targeted therapies, it is safe to assume that this and other strategies involving pharmacogenomics will become commonplace.
These are but 2 of the trends that have experienced tremendous growth in the recent past. Although we could continue to discuss the role of clinical trials in evaluating novel combination therapies or the trickle-down effect of adult drugs being studied in pediatric populations, it is more interesting for me to consider the recent interest in understanding the molecular mechanisms of pediatric cancers and responding with appropriate drug therapy. This is a service that the pharmacist can provide to the oncology team and one that should not be overlooked as an opportunity to improve multidisciplinary cancer care delivery.
- Cantrell MA, Ruble K. Multidisciplinary care in pediatric oncology. J Multidiscip Healthc. 2011;4:171-181.
- Stocco G, Cheok MH, Crews KR, et al. Genetic polymorphism of inosine triphosphate pyrophosphatase is a determinant of mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia. Clin Pharmacol Ther. 2009;85:164-172.
- Evans WE, Relling MV, Rodman JH, et al. Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med. 1998;338:499-505.
- Haber DA, Settleman J. Drivers and passengers. Nature. 2007;446:145-146.
- Hawryluk MJ, Wang K, Chmielecki J, et al. Clinical application of comprehensive next-generation sequencing-based genomic profiling for identification of actionable genomic alterations in pediatric solid tumors and hematolymphoid malignancies: the Foundation Medicine pediatric experience. J Clin Oncol. 2014;32(15 suppl):Abstract 10035.