Fundamentals of Pediatric Cancer: How Pediatric Pathology and Infrastructure of Clinical Trials Impact Contemporary Interventional Oncology in Children

Abstract

Pediatric cancer, though rare compared with adult malignancy, remains a significant cause of morbidity and mortality, with approximately 15,000 new diagnoses and over 1,500 deaths annually in the United States. Advances in multimodal therapy and cooperative group clinical trials have improved overall survival rates to over 80% in developed nations. Pediatric interventional oncology, a subset of pediatric interventional radiology (IR), has expanded beyond its role in biopsy and vascular access to include tumor-targeted and supportive care interventions. However, challenges in the field remain, including less pediatric-specific data and limited access to pediatric-trained interventional radiologists. Multidisciplinary collaboration is important for the integration of pediatric interventional oncology as a key component of pediatric cancer treatment.

Pediatric cancer is a rare entity in comparison to adult cancer. However, it is estimated that nearly 15,000 children and adolescents ages 0 to 19 will be diagnosed with a malignancy, and over 1,500 of these patients will die from their cancer annually in the United States. ¹ Leukemias, lymphomas, and malignant central nervous system (CNS) neoplasms are the most commonly diagnosed cancers in patients less than 20 years of age, with the incidence of specific cancer types varying across the age spectrum. For example, leukemias are more often diagnosed in children ages one through four, while lymphomas become more prominent in the older pediatric and adolescent population. ^{1 2} Similarly, non-CNS solid tumors such as neuroblastoma, hepatoblastoma, retinoblastoma, and Wilms tumor are more common in younger children, while older children and adolescents are more likely to develop bone tumors, soft tissue tumors, epithelial neoplasms, and melanoma. ^{1 2} In contrast, CNS malignancies and some soft tissue sarcomas are diagnosed with relative stability in numbers across the age spectrum. ^{1 2}

The field of pediatric oncology has changed dramatically in the past 50 years. The successive incorporation of multimodal systemic and local therapies has led to an increase in expected overall survival from approximately 50% in the 1970s to greater than 80% in developed countries today. ³ The main driver of this success has been the utilization of clinical trials focused on improving long-term survival as well as decreasing long term side effects of cancer treatments, performed within the context of large national and international cooperative groups including, but not limited to, the Children's Oncology Group (COG) and the International Society of Pediatric Oncology (SIOP).

COG, as the world's largest organization exclusively devoted to childhood and adolescent cancer research, includes over 12,000 experts in the field of Pediatric Oncology affiliated with over 220 member institutions in the United States, Canada, Australia, New Zealand, and Saudi Arabia. At any given time, the COG has more than 100 active clinical trials, and approximately 12,000 patients participate in a COG trial each year. Not only do these trials encompass front-line therapy for many types of pediatric cancers, but they also involve research into the underlying biology of the diseases, evaluation of new and emerging therapies for patients with relapsed/refractory disease, supportive care opportunities, and cancer survivorship.

SIOP, a similar global multidisciplinary society also entirely focused on pediatric and adolescent cancer, includes over 3,500 members worldwide representing pediatric oncology physicians, nurses, other healthcare professionals, scientists, and researchers. Specific SIOP “continental branches” provide an opportunity to improve therapy for and disseminate knowledge surrounding childhood malignancies in Africa, Oceania, Asia, and Europe. COG and SIOP are often considered complementary organizations.

Like pediatric oncology, interventional radiology (IR) has also evolved over recent decades, with a cancer-focused branch termed interventional oncology emerging and expanding. From what was initially a focus on biopsy and vascular access options, the field has grown to include additional, wide-ranging curative treatments, palliative measures, and supportive care. Many have considered interventional oncology as a fourth pillar of cancer therapy alongside systemic chemotherapy, radiation, and surgery, offering a variety of percutaneous and endovascular management strategies. ⁴

In this study, we aim to evaluate how pediatric cancer pathologies, clinical trial design for these rare cancers, and cooperative group clinical trial infrastructure influence the use and development of IR techniques for pediatric and adolescent oncology patients.

Diagnostic Considerations in Pediatric Interventional Oncology

The utility of an IR-facilitated biopsy is well-recognized, with benefits including image-guidance, minimally invasive approaches, reduced recovery times, and lower risk of complications. ⁵ Non-CNS solid tumors are primary candidate diagnoses amenable to this type of biopsy due to their heterogeneous location of origin and greater dependence on molecular diagnosis rather than architectural histology, as is necessary in lymphomas. ⁶

There are unique pathological considerations in the pediatric oncology patient, as tumor types, molecular characteristics, and pathogenesis differ from those in adults. Malignancies in adults are mostly of epithelial origin, often caused by long-term exposure to carcinogens, resulting in the accumulation and selection of unrepaired gene mutations over time. ⁷ In contrast, tumors in childhood are often derived from the mesoderm or neuroectoderm and are more likely to originate from a single genetic driver event. ^{8 9 10 11} With the exception of an underlying hereditary cancer predisposition, occurring in approximately 10% of patients, the etiology of pediatric malignancies is largely unknown. ¹²

One of the biggest differences between adult and pediatric tumor biopsy practice may be the size of the tumor sample required. Pediatric tumor diagnosis and molecular testing for risk stratification often requires much larger tissue samples, considering large-scale molecular profiling of these malignancies is becoming standard of care. ¹³ Additionally, review by expert pediatric pathologists well-versed in the unique features of pediatric cancer is essential to proper diagnosis and treatment. For this reason, it is not uncommon for biopsy samples, especially in the setting of more rare tumors, to be sent for a second or even third expert opinion. Whereas a diagnostic biopsy, obtaining two to four cores, may be routine practice in adult patients, pediatric tumor diagnosis often requires more tissue, typically on the order of ten to fifteen core biopsy samples. ^{14 15} Notably, this requires significant technical expertise, as while the sample volume required is larger, the patient is often drastically smaller than adult counterparts.

The specific modality used for image guidance in pediatric biopsies has been a topic of importance, with ultrasound often preferred over computed tomography (CT) due to the ability to image in real time, ultrasound portability, and absence of ionizing radiation. The latter point, reducing radiation exposure to the patient, is a unique consideration in children, given their increased sensitivity to radiation compared with adults and their longer life expectancy, which lengthens the window of opportunity to experience the long-term effects of radiation exposure. Children may receive a higher radiation dose than necessary if CT settings are not adjusted for a smaller body size. ^{16 17}

A key consideration in the potential use of IR for tissue sampling is the tumor location. For example, nearly any pediatric renal tumor is a candidate for upfront surgical resection via radical nephrectomy, with specific exceptions including occurrence in a patient with an underlying predisposition syndrome and bilateral kidney involvement. Prenephrectomy tumor biopsies are contraindicated, as studies have shown a higher risk of recurrence in patients with tumor spill or rupture. ^{18 19} Needle, core, or open biopsies “upstage” the tumor and subsequently result in a recommendation for more intensive treatment. Additionally, needle biopsies cannot distinguish between a tumor and a nephrogenic rest, a benign precursor lesion, nor can they reliably diagnose diffuse anaplasia, a crucial pathologic distinction with significant therapy and prognostic indications. ²⁰

In contrast to renal tumors, many other pediatric malignancies are amenable to image-guided core needle biopsy techniques. For example, currently-enrolling COG clinical trials for both pleuropulmonary blastoma and neuroblastoma provide specific guidance on the use of core needle biopsy, including recommendations for needle size, number of passes to generate sufficient tissue samples, and ideal length of the tissue core specimens. Of note, fine-needle aspiration cytology is rarely indicated in the diagnosis of pediatric cancer. ^{21 22}

Other Considerations in Pediatric Interventional Oncology

Vascular access: There is consensus that chemotherapy medications should be delivered through an adequate central venous access with a goal of reducing infusion-related injuries. Additionally, intensive, multimodal treatments commonplace in the field of pediatric oncology are accompanied by a need for frequent blood draws, blood component transfusions, apheresis, prolonged parenteral nutrition, intravenous continuous drip pain medications, and other interventions. Long-term central catheters are crucial devices for the management of these patients, and pediatric interventional radiologists are well-positioned to place all types of catheters. However, central vascular access procedures for pediatric patients necessitate a widely variable skillset, adjustable for vastly different body sizes from neonate to adult, different catheter sizes, and changes in physiology related to general anesthesia during the procedure, all following the common tenet in the care of young children, “kids are not just little adults.” ²³

Local tumor control: Curative intent of treatment in pediatric oncology patients is very often the standard, utilizing aggressive systemic chemo- and immunotherapies. Surgical resection and/or radiation therapy have long been viewed as the primary local tumor control modalities for children and adolescents. However, with greater experience in the use of transarterial antitumor therapies, including transarterial chemoembolization or transarterial radioembolization (Y-90) as well as percutaneous ablations for adult oncology patients, these techniques have been translated to similar clinical scenarios in pediatric oncology. ^{14 24} Adjusting these techniques for use in pediatric patients can be technically challenging due to small patient size and, therefore, small vessel diameter, as well as adapting doses to pediatric patients in whom chemotherapeutic agents are standardly dosed based on weight or body surface area. ^{14 24}

Enteric access: Placement of fluoroscopic-guided gastrostomy or gastrojejunostomy tubes is a necessary supportive care measure for many types of pediatric cancer treatments. Most commonly, pediatric patients with brain tumors and head and neck malignancies undergo insertion of these tubes to ensure adequate nutrition and hydration during periods of planned high-dose radiation or due to risk for aspiration secondary to neurologic impairment. These interventions are even more critical in babies and very young children who have limited fluid reserves and a high metabolic rate, leading to increased vulnerability to dehydration and malnutrition.

Challenges in the Utilization of Pediatric Interventional Oncology

There are several barriers to the more widespread utilization of pediatric interventional oncology. The lack of large-scale prospective data limits broader use and wider inclusion in cooperative group clinical trials. ²⁵ Available literature describes IR-guided procedures as mainly rescue procedures for unresectable and recurrent tumors as opposed to first-line therapeutics. ²⁶ Additionally, as in any evolving field, there is a need for broad consensus guidelines and standardized protocols specific to pediatric patients, not just an adaptation of guidelines used in adults. ²⁵

IR interventions have historically not been included in pediatric oncology-focused clinical trials for several reasons. Resource constraints of the cooperative groups and the rarity of pediatric cancer limit the number of questions that can be asked within a given study and impact the length of time it takes to complete a trial. In addition, the lack of pediatric-trained interventional radiologists at all cooperative group member sites presents an obstacle to including an IR intervention in a group-wide study. Finally, many cooperative group clinical trials are iterative, with the next trial building upon the results of the prior. With low available patient numbers due to the rarity of each disease, comparison to historical controls is often necessary. As a result, significant changes to standard local control modalities (surgery and radiation) are difficult.

Apart from hurdles in the systematic study of interventional oncology procedures in pediatric patients, even off-study utilization poses challenges. The lack of available data in pediatric patients or pediatric-specific cancers creates logistical concerns due to a lack of robust or detailed protocols. It also creates uncertainty amongst pediatric oncologists whether IR approaches will work as effectively as standard local control measures. There is higher scrutiny around innovative or off-label procedures in children, with related ethical concerns when consenting patients and/or families for these procedures. Additionally, although most pediatric oncology care is provided at large tertiary care facilities, the availability of pediatric interventional radiologists at smaller or more rural centers poses a potential disparity in available services. Procedural volumes necessary to maintain niche expertise are also lower. ²⁷

Conclusion

Pediatric interventional oncology is a promising, yet often underutilized, clinical tool. As childhood cancers differ significantly from adult malignancies in biology, presentation, and, frequently, with regard to long-term treatment goals, IR approaches must be adapted to meet the specific diagnostic, therapeutic, and supportive needs of the patient population. Despite the technical expertise of and innovative care provided by pediatric IR clinicians, broader application remains hindered by challenges in pediatric clinical trial inclusion, limited pediatric-specific data, resource disparities, and ethical considerations. To advance the field of pediatric interventional oncology, it is essential to promote collaborative research through prospective multi-site clinical trials as well as within established cooperative groups, develop consensus guidelines tailored to children, and ensure equitable access to skilled pediatric IR services across care settings. Multidisciplinary collaboration with a focus on patient-centered care and shared decision-making will be critical to the future of IR as a more fully integrated component of pediatric cancer treatment.

Funding Statement

Funding None.