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Accepted: 5 July 2023
Pediatric Blood & Cancer
SOCIÉTÉ INTERNATIONALE D’ONCOLOGIE PÉDIATRIQUE SKOP INTERNATIONAL SOCIETY OF PAEDIATRIC ONCOLOGY
aspho The American Society of Pediatric Hematology/Oncology
Children’s Oncology Group’s 2023 blueprint for research: Rare tumors
Kris Ann P. Schultz1 İD Murali Chintagumpala2 Jin Piao3 Kenneth S. Chen4 İD
Robyn Gartrell5 İD Emily Christison-Lagay6 ☒ Jesse L. Berry7 İD
Rachana Shah 8
ID
Theodore W. Laetsch9 İD the Children’s Oncology Group Rare Tumor Committee1
1Cancer and Blood Disorders, Children’s Minnesota, Minneapolis, Minnesota, USA
2 Division of Hematology-Oncology, Department of Pediatrics, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, Texas, USA
3University of Southern California Keck School of Medicine, Los Angeles, California, USA
4 Department of Pediatrics, UT Southwestern Medical Center, Dallas, Texas, USA
5 Division of Pediatric Hematology/Oncology, Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, USA
6 Division of Pediatric Surgery, Yale School of Medicine, Yale New-Haven Children’s Hospital, New Haven, Connecticut, USA
7 The Vision Center, Children’s Hospital Los Angeles, The Saban Research Institute, Children’s Hospital Los Angeles, USC Roski Eye Institute, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
8 Division of Hematology-Oncology, Department of Pediatrics, Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
9 Division of Oncology, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Correspondence
Kris Ann P. Schultz, MD, Cancer and Blood Disorders, Children’s Minnesota, 2530 Chicago Avenue South, Minneapolis, MN 55404, USA.
Email: KrisAnn.Schultz@childrensmn.org
Funding information
National Institutes of Health/National Cancer Institute, Grant/Award Numbers: U10CA180886, U10CA180899, U24CA196173, R01/R37CA244940, K08CA232344; U.S. Department of Defense, Grant/Award Number: W81XWH2210654
Abstract
The Children’s Oncology Group (COG) Rare Tumor Committee includes the Infrequent Tumor and Retinoblastoma subcommittees, encompassing a wide range of extracranial solid tumors that do not fall within another COG disease committee. Current therapeu- tic trial development focuses on nasopharyngeal carcinoma, adrenocortical carcinoma, pleuropulmonary blastoma, colorectal carcinoma, melanoma, and thyroid carcinoma. Given the rarity of these tumors, novel strategies and international collaborative efforts are necessary to advance research and improve outcomes.
KEYWORDS
Adrenocortical carcinoma, Children’s Oncology Group, colorectal carcinoma, nasopharyngeal carcinoma, pleuropulmonary blastoma, rare cancer, rare tumor, retinoblastoma, thyroid cancer
Abbreviations: 5-FU, 5-fluorouracil; ABCDE, Asymmetry, irregular Borders, Color variation, Diameter > 6 mm, lesion Evolution; ACC, adrenocortical carcinoma; AH, aqueous humor; AJCC, American Joint Committee on Cancer; CCDI, Childhood Cancer Data Initiative; CDDP, cisplatin; COG, Children’s Oncology Group; CRC, colorectal carcinoma; CT, computed tomography; D4CG, Data for the Common Good; EBV, Epstein-Barr virus; EFS, event-free survival; ES, secondary enucleation; FAP, familial adenomatous polyposis; FNA, fine-needle aspirate; FOLFOX, folinic acid, fluorouracil, and oxaliplatin; GEM, gemcitabine; GPOH, Gesellschaft für Pädiatrische Onkologie und Hämatologie; ICI, immune-checkpoint inhibitor; IFV, integrative genomics viewer; IIRC, International Intraocular Retinoblastoma Classification; MCI, Molecular Characterization Initiative; NCI, National Cancer Institute; NIS, sodium iodine symporter; NPC, nasopharyngeal carcinoma; OS, overall survival; PCDC, Pediatric Cancer Data Commons; PD1, programmed death 1; PPB, pleuropulmonary Blastoma; PTC, papillary thyroid cancer; RAI, radioactive iodine; RPLND, retroperitoneal lymph node dissection; SCNAs, somatic copy-number alterations; TFx, tumor fraction; TKI, tyrosine kinase inhibitor.
K.A.P. Schultz and M. Chintagumpala contributed equally to this work.
1 INTRODUCTION
All childhood cancers are rare; however, there are some subtypes of pediatric cancer that are particularly rare and/or understudied within pediatric oncology. Some of these tumors are exceptionally rare, primarily occurring in young children (e.g., pancreatoblastoma and retinoblastoma), whereas others are common adult cancers that rarely occur in children and have limited pediatric management data available (e.g., colorectal carcinoma, non-small cell lung cancer, and melanoma). The Children’s Oncology Group (COG) Rare Tumor Committee con- sists of the infrequent tumor and retinoblastoma subcommittees. Infrequent tumors included under the heading of infrequent/rare tumors include adrenocortical carcinoma, nasopharyngeal carcinoma and other carcinomas, retinoblastoma, pleuropulmonary blastoma, melanoma, thyroid cancer, and colon cancer; a representative list is provided in Table 1.
1.1 Nasopharyngeal carcinoma (NPC)
NPC is very rare in children < 19 years of age, representing about 1% of all pediatric malignancies.1,2 In the United States, NPC appears to be more prevalent in the southern states and among African American children.3 In children, virtually all cases of NPC are type III histology and present with locoregionally advanced bulky disease.4
COG study ARAR0331 (NCT00274937-D2) treated NPC in pedi- atric patients with induction chemotherapy using cisplatin (CDDP) and fluorouracil (5FU) followed by chemoradiotherapy with an event- free survival (EFS) of 84.3% and overall survival (OS) of 89.2%. Most patients enrolled on ARAR0331 were adolescents (median age, 15 years), there were more Black patients (n = 52, 47%) than White patients (n = 43, 39%), and over 95% of patients had Epstein-Barr virus (EBV)-positive disease.5 Unfortunately, the regimen outlined in ARAR0331 is associated with significant morbidity with nearly all patients experiencing grade 3-4 acute and long-term toxicities.5-8 Therefore, the next strategic approach in pediatric NPC treatment is dose-deescalated radiation and alternate chemotherapy backbones to improve morbidity while preserving the excellent outcomes achieved on ARAR0331.
Studies in adults with NPC have found that compared with CDDP + 5FU, a combination of gemcitabine (GEM) + CDDP both improves survival and decreases toxicity.9 Additionally, studies have found that combining GEM + CDDP with an anti-PD1 immune-checkpoint inhibitor (ICI) results in robust activity with an excellent objec- tive response.9-11 The next COG study, ARAR2221, combines an ICI, nivolumab, with a CDDP + GEM chemotherapy backbone, and response-adapted, dose-reduced radiation in combination in an effort to preserve outcomes while limiting toxicity through radiation dose reduction.
1.2 Adrenocortical carcinoma (ACC)
ACC has an estimated incidence of 0.2-0.3 per million in children and adolescents.12 Most pediatric patients are diagnosed before the age of 5 years, are female, and present with virilization. Approxi- mately 50% of cases are associated with Li-Fraumeni syndrome, and rare cases have been associated with other cancer predisposition syn- dromes, including Beckwith-Wiedemann syndrome.13,14 ARAR0332 was a nonrandomized COG study that assessed outcomes following risk-adapted therapy.15 Patients with stage 1 disease (small, com- pletely resected tumors) had excellent outcomes with surgery alone. Patients with stage 2 disease (larger completely resected tumors) were assigned to undergo retroperitoneal lymph node dissection (RPLND) without systemic therapy; however, the 5-year EFS and OS for this cohort were only 53.3% and 78.8%, respectively, suggesting that such therapy was inadequate for at least a subset of these patients. Patients with stage 3 disease (residual disease or regional lymph node involvement) had excellent survival with RPLND followed by 8 cycles of cisplatin, etoposide, and doxorubicin chemotherapy and 8 months of mitotane, although this therapy was associated with significant toxicity. The outcome for patients with stage 4 disease (distant metastasis) was dismal despite this intense therapy. Notably, patients with stage 4 disease were older (median age, 13 years) on ARAR0332.
Current efforts for patients with ACC are focused on (1) improv- ing risk stratification for patients with stage 2 and 3 disease and (2) identifying novel therapies for patients with stage 4 disease. Histo- logic grading, ATRX mutation, and methylation profiling have been shown to predict outcomes in patients with ACC.16,17 Currently, these methylation studies are being validated with samples from the COG biospecimen repository. If confirmed, we plan to design a study using these markers to risk-stratify patients. Given the rarity of pediatric ACC, we have partnered with the Alliance for Clinical Trials in Oncology to propose an adolescent and adult trial concept testing the combi- nation of ICI and a multityrosine kinase inhibitor (TKI) for patients with stage 4 or recurrent disease, both of which have shown some clinical activity in adults with ACC.18-21 Other novel agents including steroidogenic factor-1 (SF-1) inhibitors remain of keen interest for this population.
1.3 Thyroid carcinoma
A majority of pediatric thyroid cancers occur in the second decade of life, andthyroid carcinoma accounts for more than 6% of all pediatric cancers.22,23 Papillary thyroid cancer (PTC) is the most common vari- ant, comprising 90%.24,25 Its incidence has been increasing over the past 4 decades,26 and there is a 5:1 female to male predominance.27-29 Despite being the most common histology within the COG Rare Tumor Committee, there have been no prospective therapeutic COG trials for
TABLE 1 List of tumors that are included in the Children’s Oncology Group Rare Tumor Committee.
Eligible rare tumor diagnoses:
Thyroid carcinoma Colorectal carcinoma
Gastrointestinal stromal tumors Adrenocortical carcinoma Nasopharyngeal carcinoma
Retinoblastoma
Melanoma
Desmoplastic small round cell tumors
Pancreatoblastoma Neuroendocrine tumors Pleuropulmonary blastoma Gonadal stromal tumors Any other carcinomas
patients with thyroid cancer, in part because these patients are more commonly treated by endocrinologists and head and neck or endocrine surgeons rather than pediatric oncologists, groups underrepresented in COG, and many adolescents are treated by adult providers at non- COG sites. The majority of children are treated per expert consensus as described in the American Thyroid Association pediatric guide- lines with near-total thyroidectomy, lymph node dissection, and in some cases radioactive iodine (RAI) therapy based on the extent of disease.30 The disease-specific mortality for pediatric patients with PTC is extremely low. However, several recent studies have found that RAI therapy results in complete remission in < 20% of children with pulmonary metastases visible on computed tomography (CT).31-34 This frequently leads to repeated RAI treatments with consequent increased risks of second malignancy and pulmonary fibrosis.31,32
Notably, targetable oncogenic drivers are common in pediatric PTC, particularly among metastatic tumors. Most tumors harbor an onco- genic fusion of RET (rearranged during transfection), NTRK, or less commonly other kinases or BRAFV600E mutation.23,35,36 The inclu- sion of patients with thyroid cancer on basket trials of RET and TRK inhibitors has demonstrated high levels of activity of these agents and resulted in FDA approval of multiple oncogene-specific targeted ther- apies for patients with RAI-refractory disease.37-39 In addition, both laboratory studies and case reports have highlighted the potential for targeted therapy to induce differentiation of PTC, increasing expres- sion of the sodium iodine symporter (NIS) and radioiodine uptake.40-47 Building on these findings, we have established a task force including endocrinologists and surgeons to consider the feasibility of conduct- ing a study to evaluate neoadjuvant targeted therapy to decrease surgical morbidity and/or increase sensitivity to RAI therapy and hope to leverage the COG/National Cancer Institute (NCI) Molecular Characterization Initiative (MCI) to profile tumors.
1.4 Pleuropulmonary blastoma (PPB)
PPB is the most common malignant lung tumor in children with more than 90% of type I, II, and III PPB diagnosed in children younger than
7 years of age. PPB may progress from type I (purely cystic) to type II (mixed cystic and solid) to type III (solid) PPB. A fourth type of PPB, type Ir PPB, is a benign cystic lesion that may represent regressed or nonprogressed type I PPB.
PPB is associated with DICER1 pathogenic variants, generally fol- lowing a “loss of function plus hotspot” pattern with a loss-of-function variant, often but not always germline, accompanied by one of a spe- cific set of variants in the RNase IlIb (or rarely Illa) “hotspot” domain. DICER1 pathogenic/likely pathogenic variants are associated with a wide spectrum of other neoplasms including renal tumors, thyroid nod- ules, thyroid cancer, and gynecologic tumors, including Sertoli-Leydig cell tumor, gynandroblastoma, and genitourinary sarcomas. Type II and III PPB often have somatic p53 alterations, which may confer more aggressive clinical behavior.
Clinical outcomes in children with type I, Ir, II, and III PPB have recently been described.48,49 A newly proposed PPB trial, ARAR2331, aims to test the addition of camptothecins and mainte- nance chemotherapy to the treatment of types II and III PPB with the goal of optimizing tumor shrinkage and reducing the risk for local and CNS recurrence and metastatic disease while standardizing the approach to types I and Ir PPB.
1.5 Colorectal carcinoma (CRC)
While accounting for almost 10% of annually diagnosed malignan- cies in adults (approximately 150-160,000 cases in the United States per year), CRC remains infrequent in the pediatric population, with an annual incidence of 5 cases per 1 million individuals in the United States under age 20 (approximately 400 cases), the major- ity of which occur in older adolescents.50 Children and adolescents with CRC have a greater tendency toward unfavorable histologic diagnoses (including signet ring, mucinous, and undifferentiated his- tology) and stage 3 and 4 disease.51 Nearly 40% of cases may be associated with cancer predisposition syndromes (Lynch, Li Fraumeni, Cowden, familial adenomatous polyposis [FAP], and Peutz-Jegher syndrome, among others). Factors associated with poor prognosis include younger age at diagnosis, signet ring histology, development of colon cancer in the absence of a syndrome, and advanced stage at diagnosis.52 Widescale pediatric-specific molecular profiling, treat- ment, and outcome data are lacking, and the majority of pediatric patients are treated using adult protocols.51 Several smaller studies have suggested that younger patients with sporadic (noninherited) tumors lack KRAS mutations frequently seen in adults, but may be more likely to harbor mutations in DNA mismatch and repair pathways.52,53
Recently, the COG Rare Tumor Committee collaborated with the Alliance for Clinical Trials in Oncology in a randomized trial of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) alone or combined with atezolizumab, a PD-L1 inhibitor, for patients with stage III colon can- cer and deficient DNA mismatch repair or microsatellite instability (NCT02912559). This partnership enabled enrollment to be expanded to include children 12-17 years of age and exemplifies the benefits of
cooperative science for populations with rare tumors. The results of this trial are not yet published.
1.6 Melanoma
Although over 100,000 cases of melanoma are diagnosed in North America annually, fewer than 0.5% of these (approximately 400) are diagnosed in individuals less than 21 years old.54 Pediatric melanoma can present with atypical clinical features that fail to meet con- ventional ABCDE (Asymmetry, irregular Borders, Color variation, Diameter > 6 mm, lesion Evolution) detection criteria, leading to diagnostic delays. The genetic landscape and biological drivers of childhood melanomas differ by age and are also distinct from adult- onset melanomas.55,56 Melanomas in young children (< 10 years) are often characterized by Spitzoid histology with TERT promoter alterations, characterized by low metastatic potential and excellent outcomes, or arise in association with giant congenital nevi which har- bor activating mutations in NRAS and are characterized by aggressive behavior. Melanomas in older adolescents more frequently behave like conventional adult melanomas (with BRAF being the predominant driver). Additionally, individuals with known defects in DNA-repair mechanisms (xeroderma pigmentosa, Werner’s syndrome) or melanin production (MC1R mutations) also comprise distinct subgroups of pediatric melanomas.57
Significant advances have been made in the care of melanoma in adults over the past decade; however, pediatric-specific treat- ment and outcome data remain lacking. For older adolescent patients presenting with cutaneous melanoma with features akin to adult conventional melanoma, current best practice follows adult guide- lines with depth-dependent wide local excision.58 Immunotherapy and/or molecularly targeted therapy is offered for patients with stage 3 (lymph node involvement) or stage 4 (distant metastatic) disease.59
There is less consensus on the diagnosis and treatment of Spit- zoid tumors in children. The histopathologic and molecular features necessary to confirm the diagnosis of an atypical Spitz tumor or Spit- zoid melanoma have not been standardized. Distant metastasis or death is generally rare, but it remains a challenge to predict the malig- nant potential of atypical Spitz tumors, and surgical and systemic treatment approaches are widely variable. A COG Rare Tumor Com- mittee Melanoma Taskforce is actively considering a study designed to optimize and systematize an approach to these patients.
1.7 Retinoblastoma
Approximately 300 cases of retinoblastoma are diagnosed in the United States annually.60 Racial and gender predilections are unknown, although children with Hispanic ethnicity or lower socioe- conomic status are more likely to present with advanced disease.61 Retinoblastoma may affect one or both eyes. Biopsy is contraindicated due to risk of extraocular spread; examination under anesthesia by an
ocular oncologist is diagnostic. Baseline magnetic resonance imaging of the brain/orbits is recommended. The American Joint Committee on Cancer (AJCC) staging is utilized for intra- and extraocular disease.62
Treatment aims to preserve life, eye, and vision. Survival exceeds 95% in children with intraocular retinoblastoma; ocular survival is less. Survival is ~70% for extraocular disease but remains dismal with CNS involvement.63 Survivorship is impacted by second malig- nancies largely due to either cancer predisposition syndromes and/or treatment, vision loss, and ototoxicity.
Biallelic loss of the RB1 tumor suppressor gene is the initiating event in > 98% of cases; this loss may be germline (40%) or somatic (60%). All patients with bilateral retinoblastoma and 15% with unilateral retinoblastoma have germline disease. A rare, aggressive, nonheritable form of retinoblastoma is characterized by MYCN amplification with- out RB1 alteration. Patients with germline disease have an ~20% risk of second primary cancers.64 Genetic testing informs risk-adapted coun- seling and surveillance.64,65 In addition, copy-number alterations of 1q, 2p, 6p, 13q, and loss of 13q, and 16q are common.66 Recent advances in aqueous humor liquid biopsy (Figure 1) have facilitated the detection of molecular biomarkers in vivo, and there is a growing understanding of their prognostic implications and inter-eye heterogeneity.67,68 Gain of chromosome 6p is associated with the risk of intraocular relapse69 and extraocular disease.70 Circulating blood RB1-mutant DNA may be associated with extraocular disease.71 Aberrant methylation portends aggressive tumor behavior.72
The unique ocular physiology presents challenges and opportuni- ties. Adjuvant systemic intravenous chemotherapy is recommended for high-risk histopathology73 and in individuals with extraocular disease.63 Systemic intravenous chemotherapy and intra-arterial and intravitreal chemotherapy are effective frontline therapies for intraoc- ular disease.74,75
Several COG clinical trials have been completed which demon- strate:
A. Outcomes with systemic chemotherapy are suboptimal com- pared with single institutional studies of intra-arterial chemother- apy/intravitreal chemotherapy for group B, C, and D disease.74-76
B. Adjuvant chemotherapy for high-risk histopathologic features (massive choroid and post-laminar optic nerve invasion) results in excellent outcomes and observation without systemic therapy is acceptable for patients without high-risk histopathologic features following enucleation.73
C. Intensive systemic chemotherapy and risk-adapted radiotherapy for non-CNS extraocular disease show improved survival.63
An ongoing trial, ARET2121, is evaluating the role of intravitreal melphalan with systemic chemotherapy in improving the outcome of group D disease (NCT05504291).
Key priorities for future retinoblastoma trials include (a) validation of molecular biomarker(s) to prognosticate ocular salvage, personalize treatment, and facilitate early detection of relapse; (b) identifica- tion of effective treatments for extraocular retinoblastoma with CNS metastases; and (c) discovery of novel agents for relapsed/refractory
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retinoblastoma. Trans-scleral diffusion using an episcleral depot has encouraging initial results (NCT04156347 and NCT04428879).
1.8 Molecular characterization initiative
The rare tumor cohort of the MCI was activated in September 2022. The MCI, offered as a part of Project EveryChild (APEC14B1) enroll- ment, is a collaborative effort of COG and the NCI’s Childhood Cancer Data Initiative (CCDI), which provides clinical tumor DNA sequenc- ing and an RNA fusion panel as well as limited germline analysis. Results are returned to patients and treating physicians at no cost to the patient or hospital. For rare tumors, whole-exome and methy- lation data are also being generated on a research basis. Accrual to the rare tumor cohort has been limited by specimen availability (e.g., biopsies not performed for intraocular retinoblastoma, limited fine- needle aspirate [FNA] samples for thyroid carcinoma, limited sample size for melanoma), but enrollment and tissue submission is gradu- ally increasing. Efforts are underway to reach a multidisciplinary group of treating teams not traditionally a focus of COG, such as gynecolo- gists caring for girls and young women with gonadal stromal tumors, dermatologists caring for individuals with melanoma, and endocrinol- ogists caring for children, adolescents, and young adults with thyroid carcinoma.
2 KEY PRIORITIES AND STRATEGIES TO ADVANCE RESEARCH FOR RARE TUMORS
Given the rarity and clinical heterogeneity of these tumors, specific strategies are needed to increase accrual and advance outcomes. Our focus in the coming years falls into several aims:
2.1 Elucidate the molecular basis of rare cancers in children, adolescents, and adults
To advance novel therapy efforts, understanding the underlying biol- ogy of pediatric rare tumors is needed. For tumors that are more common in adults than in children, it is also necessary to understand how the biology of these tumors may differ for younger compared with older patients and how such differences may contribute to therapeu- tic efficacy or resistance. Understanding the biology of these tumors will also require expansion of current biology study eligibility criteria to include a subset of premalignant/borderline tumors currently excluded from Project EveryChild, to identify genetic factors associated with malignant behavior.
2.2 Novel therapies
For cancers that are rare in children and adults, additional efforts are required to develop new treatment strategies. There is an urgent need
for novel therapies, many of which may be based on targetable alter- ations (e.g., Akt inhibition for juvenile granulosa cell tumors) and/or our understanding of the biology of these rare tumors. As our understand- ing of pathophysiology evolves, we must find ways to translate this into clinical improvements through advancing clinical trials.
2.3 Strategies to optimize accrual
In rare/low-prevalence tumors, timely accrual presents a substantial challenge. Future advances in rare cancer research will require the expansion of potential cohorts to expedite accrual and allow evaluation of both histologically and molecularly defined cohorts and subcohorts of children and adolescents with cancer.
Given resource limitations both within the cooperative groups and individual sites, it can be challenging to open each rare tumor trial at individual sites, especially smaller sites that may have no or only a few eligible patients during a particular trial time period. Thus, for rare tumors, we encourage study designs such as NCT02912559, an Alliance trial on which COG collaborated to include patients 12 years and older with stage III mismatch-repair-deficient colon cancer. This trial allowed chemotherapy initiation followed by just-in-time acti- vation prior to cycle 2 of therapy when an eligible patient presents for care. One limitation of this approach is that studies utilizing an upfront window therapy approach may not be amenable to just-in-time activation.
Consideration of statistical strategies relatively unique to rare tumors may also be needed for specific tumor types. These approaches may include comparison with historical cohorts and novel statistical methods for analysis.
In addition to study design focused on rare tumors (just-in-time acti- vation, comparison with high-quality historical cohorts), we must also foster international collaboration and concrete mechanisms to over- come the multitude of barriers to expeditious international clinical trials. COG currently includes more than 200 institutions in the United States, Canada, Australia, New Zealand, and Saudi Arabia. Significant barriers to further collaborations include legal and financial hurdles. Streamlining the process of further international collaborations with Europe, Asia, and Africa remains a key clinical priority. Importantly, this should include a bilateral approach with consideration of ways to allow these sites to participate in COG trials but also ways to foster COG participation in external clinical trials.
Although future broad-scale internationally collaborative efforts are necessary to improve outcomes, current opportunities include parallel trials and retrospective and prospective data sharing and anal- ysis. In NPC, for example, the ARAR2221 study endpoints have been determined in collaboration with Die Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH), allowing future comparison anal- ysis with a parallel GPOH trial (EudraCT 2021-006477-32). Current efforts also include the standardization of an NPC-shared data dic- tionary across cooperative groups using the Pediatric Cancer Data Commons (PCDC)/Data for the Common Good (D4CG) platform, a time-intensive but high-yield investment.
We must also, as a pediatric oncology community and as a rare tumor committee specifically, address diversity, equity, and inclusion. Some rare tumors are known to disproportionately affect specific demographic subgroups. For instance, NPC is particularly common among African American children, and gonadal stromal tumors primar- ily affect girls and young women. One objective of offering molecular characterization through APEC14B1 is to provide state-of-the-art molecular testing for patients regardless of socioeconomic status and independent of the size of the institution at which they are treated. As we develop new therapeutic trials for children with rare tumors, we must remain cognizant of these barriers and ensure that advances in clinical care and biological insight are applied equitably.
Although substantial challenges exist, the rare tumor committee is poised to make key advancements in rare cancer research in a specific and expanding set of rare cancers impacting children, adolescents, and young adults.
CONFLICTS OF INTEREST STATEMENT
Jesse Berry receives funding from Children’s Oncology Group/ St. Baldrick’s Foundation for a prospective study looking at liquid biopsy biomarkers for retinoblastoma. Theodore Laetsch has consulted for Advanced Microbubbles, AI Therapeutics, Bayer, GentiBio, Jazz Phar- maceuticals, MassiveBio, Menarini, Novartis, Pyramid Biosciences, and Treeline Bio. The remaining authors have no conflicts of interest to disclose.
FUNDING INFORMATION
This work was funded by Children’s Oncology Group NCTN Oper- ations Center, Grant Number: U10CA180886, NCTN Statistics and Data Center, Grant Number: U10CA180899, and Biospecimen Bank, Grant Number: U24CA196173. Jesse Berry receives funding from the National Institutes of Health/National Cancer Institute grant K08CA232344, The Wright Foundation, Children’s Oncol- ogy Group, and St. Baldrick’s Foundation. Robyn Gartrell receives funding from Swim Across America. Kris Ann Schultz receives fund- ing from National Institutes of Health/National Cancer Institute grant R01/R37CA244940, Children’s Minnesota Foundation, Pine Tree Apple Classic Fund, and Rein in Sarcoma. Theodore Laetsch receives funding from the US Department of Defense Grant Number W81XWH2210654.
DISCLAIMER
The views expressed in this presentation are those of the authors and do not reflect the official policy of the Department of Defense or the U.S. Government including the National Institutes of Health
ORCID
Kris Ann P. Schultz ID https://orcid.org/0000-0002-1788-5832 Kenneth S. Chen D https://orcid.org/0000-0003-2304-4631 Robyn Gartrell D https://orcid.org/0000-0003-3287-4223 Jesse L. Berry (D https://orcid.org/0000-0002-8907-9100 Rachana Shah D https://orcid.org/0000-0002-8445-2172 Theodore W. Laetsch D https://orcid.org/0000-0002-8497-3138
REFERENCES
1. Ayan I, Altun M. Nasopharyngeal carcinoma in children: retrospective review of 50 patients. Int J Radiat Oncol Biol Phys. 1996;35(3):485-492.
2. Marks JE, Phillips JL, Menck HR, The National Cancer Data Base report on the relationship of race and national origin to the histology of nasopharyngeal carcinoma. Cancer. 1998;83(3):582-588.
3. Greene MH, Fraumeni JF, Hoover R. Nasopharyngeal cancer among young people in the United States: racial variations by cell type. J Natl Cancer Inst. 1977;58(5):1267-1270.
4. Ayan I, Kaytan E, Ayan N. Childhood nasopharyngeal carcinoma: from biology to treatment. Lancet Oncol. 2003;4(1):13-21.
5. Rodriguez-Galindo C, Krailo MD, Krasin MJ, et al. Treatment of child- hood nasopharyngeal carcinoma with induction chemotherapy and concurrent chemoradiotherapy: results of the Children’s Oncology Group ARAR0331 Study. J Clin Oncol. 2019;37(35):3369-3376.
6. Hu S, Xu X, Xu J, Xu Q, Liu S. Prognostic factors and long-term outcomes of nasopharyngeal carcinoma in children and adolescents. Pediatr Blood Cancer. 2013;60(7):1122-1127.
7. Louis CU, Paulino AC, Gottschalk S, et al. A single institution expe- rience with pediatric nasopharyngeal carcinoma: high incidence of toxicity associated with platinum-based chemotherapy plus IMRT. J Pediatr Hematol Oncol. 2007;29(7):500-505.
8. Ozyar E, Selek U, Laskar S, et al. Treatment results of 165 pedi- atric patients with non-metastatic nasopharyngeal carcinoma: a Rare Cancer Network study. Radiother Oncol. 2006;81(1):39-46.
9. Zhang L, Huang Y, Hong S, et al. Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial. Lancet. 2016;388(10054):1883-1892.
10. Fang W, Yang Y, Ma Y, et al. Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials. Lancet Oncol. 2018;19(10):1338-1350.
11. Lv JW, Li JY, Luo LN, Wang ZX, Chen YP. Comparative safety and efficacy of anti-PD-1 monotherapy, chemotherapy alone, and their combination therapy in advanced nasopharyngeal carcinoma: find- ings from recent advances in landmark trials. J Immunother Cancer. 2019;7(1):159.
12. Siegel DA, King J, Tai E, Buchanan N, Ajani UA, Li J. Cancer incidence rates and trends among children and adolescents in the United States, 2001-2009. Pediatrics. 2014;134(4):e945-e955.
13. Wasserman JD, Novokmet A, Eichler-Jonsson C, et al. Prevalence and functional consequence of TP53 mutations in pediatric adreno- cortical carcinoma: a children’s oncology group study. J Clin Oncol. 2015;33(6):602-609.
14. Else T. Association of adrenocortical carcinoma with familial cancer susceptibility syndromes. Mol Cell Endocrinol. 2012;351(1):66-70.
15. Rodriguez-Galindo C, Krailo MD, Pinto EM, et al. Treatment of pedi- atric adrenocortical carcinoma with surgery, retroperitoneal lymph node dissection, and chemotherapy: the Children’s Oncology Group ARAR0332 protocol. J Clin Oncol. 2016;0(0):JCO2002871.
16. Clay MR, Pinto EM, Cline C, et al. DNA methylation profiling reveals prognostically significant groups in pediatric adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Reg- istry. JCO Precis Oncol. 2019;3:1-21.
17. Pinto EM, Rodriguez-Galindo C, Pounds SB, et al. Identification of clin- ical and biologic correlates associated with outcome in children with adrenocortical tumors without germline TP53 mutations: a St Jude Adrenocortical Tumor Registry and Children’s Oncology Group Study. J Clin Oncol. 2017;35(35):3956-3963.
18. Raj N, Zheng Y, Kelly V, et al. PD-1 blockade in advanced adrenocorti- cal carcinoma. J Clin Oncol. 2020;38(1):71-80.
19. Miller KC, Chintakuntlawar AV, Hilger C, et al. Salvage therapy with multikinase inhibitors and immunotherapy in advanced adrenal cortical carcinoma. J Endocr Soc. 2020;4(7):bvaa069-bvaa069.
WILEY
20. Habra MA, Stephen B, Campbell M, et al. Phase II clinical trial of pem- brolizumab efficacy and safety in advanced adrenocortical carcinoma. J Immunother Cancer. 2019;7(1):253.
21. Kroiss M, Megerle F, Kurlbaum M, et al. Objective response and pro- longed disease control of advanced adrenocortical carcinoma with cabozantinib. J Clin Endocrinol Metab. 2020;105(5):1461-1468.
22. Noone AM, Cronin KA, Altekruse SF, et al. Cancer incidence and sur- vival trends by subtype using data from the Surveillance Epidemiology and End Results Program, 1992-2013. Cancer Epidemiol Biomarkers Prev. 2017;26(4):632-641.
23. Paulson VA, Rudzinski ER, Hawkins DS. Thyroid cancer in the pediatric population. Genes (Basel). 2019;10(9):723.
24. Gupta A, Ly S, Castroneves LA, et al. A standardized assessment of thyroid nodules in children confirms higher cancer prevalence than in adults. J Clin Endocrinol Metab. 2013;98(8):3238-3245.
25. Halac I, Zimmerman D. Thyroid nodules and cancers in children. Endocrinol Metab Clin North Am. 2005;34(3):725-744.
26. Vergamini LB, Frazier AL, Abrantes FL, Ribeiro KB, Rodriguez-Galindo C. Increase in the incidence of differentiated thyroid carcinoma in children, adolescents, and young adults: a population-based study. J Pediatr. 2014;164(6):1481-1485.
27. Hogan AR, Zhuge Y, Perez EA, Koniaris LG, Lew JI, Sola JE. Pediatric thyroid carcinoma: incidence and outcomes in 1753 patients. J Surg Res. 2009;156(1):167-172.
28. Wu XC, Chen VW, Steele B, et al. Cancer incidence in adolescents and young adults in the United States, 1992-1997. J Adolesc Health. 2003;32(6):405-415.
29. Francis GL, Waguespack SG, Bauer AJ, et al. Management guidelines for children with thyroid nodules and differentiated thyroid cancer. Thyroid. 2015;25(7):716-759.
30. Jeon MJ, Kim YN, Sung TY, et al. Practical initial risk stratifica- tion based on lymph node metastases in pediatric and adolescent differentiated thyroid cancer. Thyroid. 2018;28(2):193-200.
31. Pawelczak M, David R, Franklin B, Kessler M, Lam L, Shah B. Outcomes of children and adolescents with well-differentiated thyroid carcinoma and pulmonary metastases following (1)(3)(1)I treatment: a systematic review. Thyroid. 2010;20(10):1095-1101.
32. Alzahrani AS, Alswailem M, Moria Y, et al. Lung metastasis in pediatric thyroid cancer: radiological pattern, molecular genetics, response to therapy, and outcome. J Clin Endocrinol Metab. 2019;104(1):103-110.
33. Nies M, Vassilopoulou-Sellin R, Bassett RL, et al. Distant metas- tases from childhood differentiated thyroid carcinoma: clinical course and mutational landscape. J Clin Endocrinol Metab. 2020;106(4):1683- 1697.
34. Chesover AD, Vali R, Hemmati SH, Wasserman JD. Lung metastasis in children with differentiated thyroid cancer: factors associated with diagnosis and outcomes of therapy. Thyroid. 2020;31(1):50-60.
35. Bauer AJ. Molecular genetics of thyroid cancer in children and adoles- cents. Endocrinol Metab Clin North Am. 2017;46(2):389-403.
36. Pekova B, Sykorova V, Dvorakova S, et al. RET, NTRK, ALK, BRAF, and MET fusions in a large cohort of pediatric papillary thyroid carcinomas. Thyroid. 2020;30(12):1771-1780.
37. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET- altered thyroid cancers. N Engl J Med. 2020;383(9):825-835.
38. Food and Drug Administration. RETEVMO (selpercatinib) Prescribing information. 2020.
39. Hong DS, DuBois SG, Kummar S, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020;21(4):531-540.
40. Ullmann TM, Liang H, Moore MD, et al. Dual inhibition of BRAF and MEK increases expression of sodium iodide symporter in patient- derived papillary thyroid cancer cells in vitro. Surgery. 2020;167(1):56- 63.
41. Zhang H, Chen D. Synergistic inhibition of MEK/ERK and BRAF V600E with PD98059 and PLX4032 induces sodium/iodide symporter (NIS)
expression and radioiodine uptake in BRAF mutated papillary thyroid cancer cells. Thyroid Res. 2018;11:13.
42. Vadysirisack DD, Venkateswaran A, Zhang Z, Jhiang SM. MEK sig- naling modulates sodium iodide symporter at multiple levels and in a paradoxical manner. Endocr Relat Cancer. 2007;14(2):421-432.
43. Rothenberg SM, McFadden DG, Palmer EL, Daniels GH, Wirth LJ. Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib. Clin Cancer Res. 2015;21(5):1028-1035.
44. Jaber T, Waguespack SG, Cabanillas ME, et al. Targeted therapy in advanced thyroid cancer to resensitize tumors to radioactive iodine. J Clin Endocrinol Metab. 2018;103(10):3698-3705.
45. Lee YA, Lee H, Im S-W, et al. NTRK- and RET-fusion-directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake. J Clin Invest. 2021;131(18).
46. Waguespack SG, Tewari SO, Busaidy NL, Zafereo ME. Larotrectinib before initial radioactive iodine therapy in pediatric trk fusion- positive papillary thyroid carcinoma: time to reconsider the treat- ment paradigm for distantly metastatic disease? JCO Precis Oncol. 2022;6:e2100467.
47. Groussin L, Clerc J, Huillard O. Larotrectinib-enhanced radioac- tive iodine uptake in advanced thyroid cancer. N Engl J Med. 2020;383(17):1686-1687.
48. Nelson AT, Harris AK, Watson D, et al. Type I and Ir pleuropulmonary blastoma (PPB): a report from the International PPB/DICER1 Registry. Cancer. 2023;129(4):600-613.
49. Schultz KAP, Harris AK, Nelson AT, et al. Outcomes for children with type II and type III pleuropulmonary blastoma following chemother- apy: a report from the International PPB/DICER1 Registry. J Clin Oncol. 2023;41(4):778-789.
50. SEER. Cancer Stat Facts: Colorectal Cancer. 2023.
51. Poles GC, Clark DE, Mayo SW, et al. Colorectal carcinoma in pediatric patients: a comparison with adult tumors, treatment and outcomes from the National Cancer Database. J Pediatr Surg. 2016;51(7):1061- 1066.
52. de Voer RM, Diets IJ, van der Post RS, et al. Clinical, pathology, genetic, and molecular features of colorectal tumors in adolescents and adults 25 years or younger. Clin Gastroenterol Hepatol. 2021;19(8):1642- 1651.e8.
53. Tricoli JV, Boardman LA, Patidar R, et al. A mutational comparison of adult and adolescent and young adult (AYA) colon cancer. Cancer. 2018;124(5):1070-1082.
54. SEER. Cancer Stat Facts: Melanoma of the Skin. 2023; https://seer. cancer.gov/statfacts/html/melan.html
55. Lee S, Barnhill RL, Dummer R, et al. TERT promoter mutations are predictive of aggressive clinical behavior in patients with spitzoid melanocytic neoplasms. Sci Rep. 2015;5:11200.
56. Ferrari A, Lopez Almaraz R, Reguerre Y, et al. Cutaneous melanoma in children and adolescents: the EXPERT/PARTNER diagnostic and therapeutic recommendations. Pediatr Blood Cancer. 2021;68:e28992. Suppl 4.
57. Childhood melanoma treatment (PDQ(R)): health professional ver- sion. In: PDQ cancer information summaries. 2002.
58. Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599-609.
59. Margolin K. The promise of molecularly targeted and immunotherapy for advanced melanoma. Curr Treat Options Oncol. 2016;17(9):48.
60. Ries LAG SM, Gurney JG, Linet M, Tamra T, Young JL, Bunin GR, eds. Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995, National Cancer Institute, SEER Program. NIH Pub; 1999:99-4649.
61. Truong B, Green AL, Friedrich P, Ribeiro KB, Rodriguez-Galindo C. Ethnic, racial, and socioeconomic disparities in retinoblastoma. JAMA Pediatr. 2015;169(12):1096-1104.
WILEY
62. Mallipatna ACGB, Chévez-Barrios P, Lumbroso-Le Rouic L. In: Amin MB, Edge SB, Greene FL, eds. AJCC cancer staging manual. 8th ed. Springer; 2017.
63. Dunkel IJ, Piao J, Chantada GL, et al. Intensive multimodality ther- apy for extraocular retinoblastoma: a Children’s Oncology Group trial (ARET0321). J Clin Oncol. 2022;40(33):3839-3847.
64. Kamihara J, Bourdeaut F, Foulkes WD, et al. Retinoblastoma and neuroblastoma predisposition and surveillance. Clin Cancer Res. 2017;23(13):e98-e106.
65. Skalet AH, Gombos DS, Gallie BL, et al. Screening children at risk for retinoblastoma: consensus report from the American Associ- ation of Ophthalmic Oncologists and Pathologists. Ophthalmology. 2018;125(3):453-458.
66. Kooi IE, Mol BM, Massink MP, et al. Somatic genomic alterations in retinoblastoma beyond RB1 are rare and limited to copy-number changes. Sci Rep. 2016;6:25264.
67. Xu L, Kim ME, Polski A, et al. Establishing the clinical utility of ctDNA analysis for diagnosis, prognosis, and treatment monitoring of retinoblastoma: the aqueous humor liquid biopsy. Cancers (Basel). 2021;13(6):1282.
68. Wong EY, Xu L, Shen L, et al. Inter-eye genomic heterogeneity in bilat- eral retinoblastoma via aqueous humor liquid biopsy. NPJ Precis Oncol. 2021;5(1):73.
69. Xu L, Polski A, Prabakar RK, et al. Chromosome 6p amplification in aqueous humor cell-free DNA is a prognostic biomarker for retinoblastoma ocular survival. Mol Cancer Res. 2020;18(8):1166- 1175.
70. Stalhammar G, Yeung A, Mendoza P, Dubovy SR, William Harbour J, Grossniklaus HE. Gain of chromosome 6p correlates with severe anaplasia, cellular hyperchromasia, and extraocular spread of retinoblastoma. Ophthalmol Sci. 2022;2(1):100089.
71. Kothari P, Marass F, Yang JL, et al. Cell-free DNA profiling in retinoblastoma patients with advanced intraocular disease: an MSKCC experience. Cancer Med. 2020;9(17):6093-6101.
72. Li HT, Xu L, Weisenberger DJ, et al. Characterizing DNA methylation signatures of retinoblastoma using aqueous humor liquid biopsy. Nat Commun. 2022;13(1):5523.
73. Chevez-Barrios P, Eagle RC Jr, Krailo M, et al. Study of unilateral retinoblastoma with and without histopathologic high-risk features and the role of adjuvant chemotherapy: a Children’s Oncology Group study. J Clin Oncol. 2019;37(31):2883-2891.
74. Francis JH, Levin AM, Zabor EC, Gobin YP, Abramson DH. Ten-year experience with ophthalmic artery chemosurgery: ocular and recurrence-free survival. PLoS One. 2018;13(5): e0197081.
75. Dalvin LA, Kumari M, Essuman VA, et al. Primary intra-arterial chemotherapy for retinoblastoma in the intravitreal chemotherapy era: five years of experience. Ocul Oncol Pathol. 2019;5(2):139- 146.
76. Friedman DL, Krailo M, Villaluna D, et al. Systemic neoadjuvant chemotherapy for group B intraocular retinoblastoma (ARET0331): a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2017;64(7):e26394.
How to cite this article: Schultz KAP, Chintagumpala M, Piao J, et al. Children’s Oncology Group’s 2023 blueprint for research: Rare tumors. Pediatr Blood Cancer. 2023;70(Suppl. 6):e30574. https://doi.org/10.1002/pbc.30574