Pediatric Oncologist A Firm Believer in the Potential of Next Generation Sequencing

Rajen Mody, MBBS, is a pediatric oncologist at the University of Michigan Health System. Dr Mody, who has been a part of several drug development trials for pediatric cancer conducted by the Children’s Oncology Group, is currently investigating the application of precision medicine through the use of next generation sequencing (NGS). He recently co-authored a paper in JAMA,¹ evaluating the use of integrative clinical sequencing and genetic counseling when treating pediatric and young adult (YA) patients with cancer.

Evidence-Based Oncology spoke with Dr Mody about his experiences when treating this patient population, the survivorship program offered by the University of Michigan to help with care transition, and his belief in NGS as the path to improved patient outcomes.

What are some of the challenges faced by healthcare providers when treating pediatric and YA patients who have cancer?

Our biggest challenge is the small numbers of these patients—there are only about 13,000 to 14,000 new cancer diagnoses in North America, which, in a way, is a good problem to have. But with respect to clinical trials and advancing cancer care, there is need for a certain number of patients; fewer patients, especially with hard-to-treat cancers, can be an impediment in terms of pharmaceutical interest [in developing specific drugs].

Also, among young patients being treated for cancer, the associated toxicity is heart-wrenching. Pediatric and YA patients are quite resilient to harsh medical treatment, considering that most pediatric chemotherapy regimens that we use are much greater in intensity than the adult regimens because most pediatric cancers are very aggressive. Younger patients actually tolerate the regimens really well and that has led to nearly 75% to 80% of patients in long-term remission, nearly 70% of whom are cured.

We have, however, become a victim of our own success, with the myth that pediatric cancers are very treatable. The problem is the 30% of patients who end up with a recurrence; the curves have not shifted for those patients in the last 15 years…the improvements have plateaued. The absolute number of 70% needs to improve, and that’s where some of the research that our group is involved in—where we are sequencing every tumor that has relapsed or has metastatic disease—will help.

The hard-to-treat population—that is, patients who have relapsed following frontline treatment—are the ones we included in our recently published study¹ for which we conducted whole-exome sequencing on patient tumor samples and gathered information that helped modify treatment regimens in nearly 50% of the patients analyzed. Even with the 70% of patients who are cured, we would like to sequence their tumors and gain information that would allow for less toxic treatment, avoid radiation treatment, or even change diagnosis in some cases.

How long are survivors followed? Do you work with the child’s pediatrician post diagnosis and during cancer treatment?

Most programs, including ours at the University of Michigan Health System, follow the patient until they are 21 years of age or 10 years from diagnosis, whichever is later; some programs follow these patients until they are 25 years of age. There are a few YA survivor groups that follow them for an even longer duration.

The biggest challenge is the transition of care, and the biggest resistance we face is sometimes from parents. However, we, as pediatric oncologists, want to mainstream the patient and so we do try to explain to the parents the important role played by the child’s pediatrician or primary care physician in care continuum.

Our strategy is to co-manage the patient a few years prior to transition. The patients continue to see their pediatrician while they are in our care, but about 2-years before transition, we help them transition out of our care. Our team also assists with identifying a good physician and establishing care if the patient will be transitioning to a new geographic location. We also share the Passport for Care² with the survivor and the future provider. And while we do attempt to work with the transition, many times we are not able to identify good pediatric and family practice doctors comfortable with complex patients like these.

[At the University of Michigan,] we have a long-term survivorship program that is staffed by physicians, nurse practitioners, social workers, a school teacher within the hospital, a dietician, and several administrative staff members who help with the entire process. It is clearly a team effort.

How important is integrating psychosocial aspects into the care plan?

We have a combined team of pediatric and adult oncologists that takes care of the YA population at our hospital, based on whether they have an adult or pediatric type of disease. In addition to the physicians, we have special clinics that cater to the educational needs of the YA patients and offer early or really late appointments or weekend infusions etc.

We have a resident school teacher who helps the YAs with homework and even “teaches the teachers” to work with YAs who are undergoing chemotherapy infusions but are planning to take their SATs. Social workers on our team maintain special hours to accommodate this population of patients. Additionally, infusion rooms have separate pods for teenagers so they can get the privacy that they might crave, and nurses and teams familiar with YA care are specifically assigned for care management.

Does your cancer center offer fertility services?

Parents are quite aware and maybe more involved than the YA when it comes to fertility preservation. The teenagers themselves are sometimes not interested in discussing options, either due to embarrassment or the contradiction of speaking about their disease and then fertility in the same breath. Parents, however, want us to discuss the options with their teenager, maybe because they had never broached this topic at home prior to their child’s diagnosis.

Although most parents do want the option, sometimes it may not be practical, especially if treatment needs to be initiated immediately [depending on the diagnosis], because there are some technical challenges associated with this, particularly for girls. The process is much more involved for girls because they need to be medicated to induce ovulation to collect oocytes and there could even be a minor surgery involved. This can sometimes lead to care providers not opting to offer the option to patients. Sometimes, the aggressive nature of their disease may not leave the option of waiting to start treatment.

I do hope that the situation improves for YA girls receiving cancer care. In our survivorship clinic that I was a part of and ran for about 5 years before I moved into more translational genomic research, we learned that our inability to help YAs with fertility preservation actually has a much greater impact on women’s survivorship.

In your experience, does insurance access influence care decisions made by family members?

With our precision oncology approach in pediatric oncology, we have had a slightly easier time in getting off-label drugs than our colleagues who treat adult cancer patients. Most of the drugs used in pediatric oncology are off-label because [the pharmaceutical industry] will not develop drugs for a small patient population. We have been quite successful in gaining access to drugs based on the results of our genomic analyses, and we appreciate the cooperation we have received from payers to consider our request for treatment of our pediatric cancer patients, guided by precision oncology.

I expect there will be an increasing trend where patients will approach third-party payers with genomic evidence of a particular molecular aberration. The treatment would obviously need to be carried out under the umbrella of a clinical trial, but the fact remains that there just aren’t enough clinical trials being conducted for pediatric oncology patients.

There are great expectations from the NCI-MATCH trial. Do you think pediatric and YA patients could also benefit from a similar trial design?

I am actually a part of the pediatric version of the NCI-MATCH trial, which we are hoping to initiate sometime next year. We are currently finalizing the agents to include, and we will then set up discussions with the pharmaceutical industry to see whether they’d be willing to provide the necessary agents for the trial.

NGS of course can provide a tremendous amount of data. What are the advantages and some of the challenges of clinical implementation of this technology?

Genomic sequencing clearly identifies actionable mutations in only 50% of the population. Our recent results tell us that we need to temper down our enthusiasm around this technique, especially for parents who are always expecting an answer. While NGS provides us answers for 50% of patients, only 25% of those could actually be acted upon owing to logistical challenges. These challenges include the drug not being accessible, the available drug might be the wrong dose or formulation, long turnaround time for NGS results, and cost of the analysis.

I do think, however, that NGS analysis will soon be much cheaper and the turnaround time will reduce; however, the technology itself needs to evolve and the NGS panels should be developed to analyze epigenetic findings so they can truly impact patient care. The central message remains that we need more drugs developed specifically for pediatric cancer patients.

EBO

While we have made great strides over the last 4 decades in terms of care rendered and outcomes of pediatric cancer patients, a lot more efforts are necessary for the 25% to 30% of hard-to-treat patients who do not benefit from the current standard-of-care treatments. I believe precision oncology and immunotherapy will hopefully lead the way to provide improved outcomes for the hard-to-treat patients. Ultimately, though, care for young cancer patients does not culminate with their cancer treatment; efficient survivorship programs are as important for them to lead a healthy and meaningful life.

References

1. Mody RJ, Wu YM, Lonigro RJ, et al. Integrative clinical sequencing in the management of refractory or relapsed cancer in youth. JAMA. 2015;314(9):913-925.

2. Horowitz ME, Fordis M, Krause S, McKellar J, Poplack DG. Passport for care: implementing the survivorship care plan. J Oncol Pract. 2009;5(3):110-112.

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