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Pediatric Blood & Cancer
SOCIÉTÉ INTERNATIONALE D’ONCOLOGIE PÉDIATRIQUE
aspho The American Society of Pediatric Hematology/Oncology
INTERNATIONAL SOCIETY OF PAEDIATRIC ONCOLOGY
WILEY
Rare tumors: Retinoblastoma, nasopharyngeal cancer, and adrenocorticoid tumors
Samir Patel1 İD
Jennifer Vogel2 Kristin Bradley3 Paul J. Chuba4
Jeffrey Buchsbaum5
Matthew J. Krasin6
1Divisions of Radiation Oncology and Pediatric Hematology, Oncology and Palliative Care, University of Alberta, Stollery Children’s Hospital, Edmonton, Canada
2 Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, Tennessee
3Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
4 Department of Radiation Oncology, St. John Providence Health Systems Webber Cancer Center, Warren, Michigan
5 Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland
6 Department of Radiation Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee
Correspondence
Samir Patel, Division of Radiation Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada. Email: samir.patel2@albertahealthservices.ca
Abstract
The role of surgery, chemotherapy, and radiation therapy for retinoblastoma has evolved con- siderably over the years with the efficacy of intraarterial chemotherapy and the high inci- dence of secondary malignant neoplasms following radiation therapy. The use of spot scanning intensity-modulated proton therapy may reduce the risk of secondary malignancies. For pediatric nasopharyngeal carcinoma, the current standard of care is induction chemotherapy followed by chemoradiation therapy. For adrenocortical carcinoma, the mainstay of treatment is surgery and chemotherapy. The role of radiation therapy remains to be defined.
KEYWORDS
adrenocorticoid tumors, chemotherapy, nasopharyngeal carcinoma, radiation therapy, retinoblas- toma, surgery
1 RETINOBLASTOMA
Retinoblastoma arises from the biallelic mutation of the retinoblas- toma gene (RB1) within a single primitive retinal cell, likely a cone photoreceptor precursor.1 It is the most common primary intraocular malignancy of childhood and accounts for 11% of cancer diagnoses in the first year of life.2 Unilateral cases have a mean age of diagnosis of 24 months3 and rarely are followed by the development of a new metachronous lesion in the contralateral eye > 30 days after diagnosis in 1.5% to 3% of cases.4,5 One third of children have bilateral disease, with an earlier mean age of diagnosis of 15 months.3 About 40% of chil- dren with retinoblastoma carry a germline mutation of RB1 including almost all bilateral cases and 15% to 18% of unilateral cases.6 These children have 28% risk at 40 years for secondary cancers7,8 and are
associated with primary intracranial tumors having partial photorecep- tor and neuronal differentiation, termed trilateral retinoblastoma.9
The survival rate is >95% with early detection and modern therapy in the United States and Europe.6 Although retinoblastoma is highly curable, the most common cause of mortality in five-year survivors of bilateral disease is secondary cancers, particularly sarcomas and leukemias.10-13 Given that external beam radiation therapy (EBRT) increases the risk of secondary cancers, especially in early child- hood when most cases present,14 it has been largely replaced by chemotherapy and focal therapies in current management. More recently, secondary leukemias after chemotherapy have also been reported in heritable retinoblastomas.10,15,16
1.1 General treatment approach
Staging has evolved considerably in recent decades. The Reese- Ellsworth grouping system was developed in the 1960s to predict vision preservation after EBRT, the most common treatment in that era. In 2004, the International Classification of Retinoblastoma was
Abbreviations: ACC, adrenocortical carcinoma; COG, Children’s Oncology Group; EBRT, external beam radiation therapy; EBV, Epstein-Barr virus; IAC, intraarterial chemotherapy; IPATR, International Pediatric Adrenocortical Tumor Registry; IVC, intravenous chemotherapy; MEN, multiple endocrine neoplasia; NPC, nasopharyngeal cancer; PD-L1, programmed death-ligand 1; RB1, retinoblastoma gene.
proposed to predict success of chemotherapy plus focal therapies to avoid EBRT or enucleation for intraocular tumors,17 and later updated (see Table 1).18 For patients having enucleation or extraocular disease, the international retinoblastoma staging system was proposed (see Table 2).19 This system predicts disease-free survival at higher stages20 and is used by the Children’s Oncology Group (COG).21 A recently pro- posed staging system for vitreous seeding helps predict response to intravitreal chemotherapy.22
Therapy aims for cure while preserving vision and preventing late effects, particularly secondary cancers, and depends on group or
| A. Very low risk | Small tumors ≤ 3 mm in basal diameter or thickness | |
|---|---|---|
| B. Low risk | Larger tumors > 3 mm in basal diameter or thickness, or | |
| Macular location (≤ 3 mm to fovea) Juxtapapillary location (≤ 1.5 mm to disk) | ||
| Clear subretinal fluid ≤ 3 mm from margin | ||
| C. Moderate risk | C1 | Subretinal seeds ≤ 3 mm away |
| C2 | Vitreous seeds ≤ 3 mm away | |
| C3 | Both subretinal and vitreous seeds ≤ 3 mm away | |
| D. High risk | D1 | Subretinal seeds > 3 mm away |
| D2 | Vitreous seeds > 3 mm away | |
| D3 | Both subretinal and vitreous | |
| seeds > 3 mm away | ||
| E. Very high risk | E | Extensive disease occupying > 50% of globe or neovascular glaucoma; opaque media from hemorrhage in anterior chamber, vitreous, or subretinal space; or invasion of post-laminar optic nerve, choroid (> 2 mm), sclera, orbit, anterior chamber |
| Stage 0 | Treated conservatively |
| Stage I | Eye enucleated, completely resected histologically |
| Stage II | Eye enucleated, microscopic residual tumor |
| Stage III | Regional extension |
| a. Overt orbital disease | |
| b. Preauricular or cervical lymph node extension | |
| Stage IV | Metastatic disease |
| a. Hematogenous metastases (without CNS involvement) 1. Single lesion 2. Multiple lesions | |
| b. CNS extension (± other sites of regional or metastatic disease) | |
| 1. Prechiasmatic lesion | |
| 2. CNS mass | |
| 3. Leptomeningeal and CSF disease |
stage, status of the other eye, and access to care.6,23 For unilateral intraocular disease, focal therapies such as laser ablation, cryotherapy, or plaque brachytherapy can be used for group A and small, peripheral group B tumors. Large group B, C, and D tumors are most often treated with intraarterial chemotherapy (IAC) or intravenous chemotherapy (IVC) with or without intravitreal chemotherapy instead of EBRT due to risks of late effects. Enucleation is reserved for tumors having risk for extraocular extension, including most group E and some group D eyes, or after failure of other treatments. The modern approach for bilateral disease is tandem IAC to both eyes in a single session or IVC, with or without intravitreal chemotherapy and focal therapy.
Trilateral retinoblastoma refers to presentation with or later devel- opment of a primary intracranial primitive neuroectodermal tumor, usually in the pineal region.24 Some (25%) have suprasellar tumors, or both pineal and suprasellar tumors (quadrilateral retinoblas- toma). Intensive chemotherapy with autologous stem cell rescue has improved five-year survival to 44% for pineal and to 57% for nonpineal tumors in a meta-analysis, compared with virtually no survivors prior to institution of this therapy.25
Long-term follow-up for late effects and secondary cancers is essen- tial. The most common secondary cancers are bone and soft-tissue sar- comas (median age, 13 years), melanomas (median age, 27 years), or bladder, lung, and breast carcinomas (median age, 29 years).26 Life- long ophthalmologic follow-up is needed to screen for cataracts, optic neuropathy, and retinopathy.
1.2 Role of focal therapy
Focal therapy is typically reserved for small lesions < 6 mm in diameter and < 3 mm thick and may be used in combination with chemotherapy.2 Response is normally seen within six weeks.27 Cryotherapy involves one to two monthly sessions of three freeze-thaw cycles. Diode laser photocoagulation takes one to three sessions and may cause focal scarring of the retina. Thermotherapy using ultrasound, microwave, or infrared radiation to heat lesions to 42℃ to 60℃ frequently is combined with chemotherapy based on preclinical data showing synergism.28,29
Plaque brachytherapy, most often with iodine-125 or ruthenium- 106, can treat tumors that are 3 to 15 mm wide with thickness of less than 8-12 mm.2,30-33 Self-collimating plaques with sources inside wells decrease scatter, and notched plaques can be employed to treat tumors around the optic nerve.2,31,32 Control rates are 85% to 90% and highest for small group A and B tumors.32 The American Brachyther- apy Society guidelines recommend brachytherapy for tumors anterior to the equator in unilateral disease34 but outcomes in bilateral disease are also excellent.35 There is no evidence that plaque brachytherapy substantially increases risk of secondary cancers.
Repeat focal therapy, IAC, intravitreal chemotherapy, or chemore- duction plus focal therapy can be used to treat recurrences depending on severity. Repeated lines of therapy to avoid enucleation, however, have lower success rates, increased risk for metastasis and morality, and cause families stress and financial burden.36
1.3 Role of chemotherapy
IAC involves microcatheterization of the ostium of the ophthalmic artery or, occasionally, the orbital branch of the middle meningeal artery, under general anesthesia.37 Melphalan, carboplatin, and/or topotecan chemotherapy is then infused in pulses. Bridge therapy such as intravenous carboplatin is normally used until young infants grow to 6 to 10 kg due to procedural risks in small infants,38 but recent series have safely treated infants less than three months old.39,40
IAC has been widely adopted based on single-institution data sup- porting superior outcomes and lower systemic toxicity compared with IVC. At Memorial Sloan Kettering Cancer Center (MSKCC), > 90% of patients have primary IAC, leading to a significantly improved four- year ocular salvage rate from 68% in the late 2000s to 93% between 2010 and 2014.41 In a meta-analysis of 12 case series of 655 patients, ocular salvage was 86% in group A, B, and C eyes and 57% in group D and E eyes, and higher with primary IAC (74%) compared with sec- ondary IAC after IVC or EBRT (67%).42 However, no prospective trials comparing IAC to other treatment modalities exist.
The avascular nature of the vitreous limits drug bioavailability from IAC and IVC for vitreous seeding. 43 Intravitreal injection through the pars plana achieves the higher drug bioavailability in the vitreous.44 Melphalan and topotecan are commonly injected. Risk of needle tract seeding can be addressed by ultrasound biomicroscopy-assisted injec- tion, injecting small volumes, cryotherapy of the injection site, irriga- tion of the ocular surface, and subconjunctival chemotherapy.45 In a 2013 systematic review of 14 studies of > 1300 intravitreal injections, only one case of extraocular tumor spread was seen.46 Intravitreal chemotherapy has been widely adopted for refractory or recurrent vit- real seeding after IAC or IVC45 and provides nearly 100% two-year control in this setting. 44,47
IVC frequently was used with focal therapies to avoid EBRT and enucleation in the 1990s until the development of IAC in the 2000s. The combination of vincristine, etoposide, and carboplatin is commonly used. IVC is useful in shrinking large tumors and those near the fovea to permit use and improve success of focal therapy (chemoreduction),48-52 as bridge therapy for young infants until IAC can be used,45 adjuvant therapy after enucleation of tumors with high-risk pathological features, or metastatic or trilateral disease.53 Chemoreduction can be successful in avoiding EBRT and enucleation for 100% of group A, 93% of group B, 90% of group C, and 47% of group D eyes.18
1.4 Role of surgery
Enucleation entails removal of the entire globe, intact to avoid seed- ing, and 10 to 20 mm of the optic nerve for staging.2 A deep orbital implant is placed at the time of surgery, and fitted with a realistic pros- thesis by an ocularist about six weeks later.54 Provision of a temporary prosthesis after surgery helps families cope.55,56 In 1674 consecutive patients receiving enucleation, orbital recurrence was 4.2%, and recur- rences occurred within 24 months with 75% mortality from metastatic disease.57
55.0 Gy
50.4 Gy
45.0 Gy
25.0 Gy
10.0 Gy
1
Primary enucleation is recommended for most group E and some group D tumors. Secondary enucleation is used for intraocular tumors refractory to other therapies, refractory subretinal and vit- reous seeding, vitreous hemorrhage, secondary glaucoma, and psy- chological fatigue to repeated salvage therapies.6 Adjuvant EBRT and chemotherapy are recommended for positive optic nerve mar- gin or scleral invasion, and adjuvant chemotherapy for other high- risk features for metastasis, including tumor extension up to the lamina cribrosa, choroidal invasion, or sometimes massive choroidal involvement.58,59
1.5 Role of radiation therapy
Retinoblastoma is highly radiosensitive. The first patient treated with a linear accelerator in the United States in 1957 had retinoblastoma.60 In the modern era, EBRT is reserved for salvage of an only remaining eye after failure of other therapies6 or advanced disease (stage II, III, and IV).2 To minimize integral dose and consequent risk of secondary cancers, proton therapy is recommended with ocular immobilization and lens sparing, where available (see Figure 1).30,61,62 Spot scanning intensity-modulated proton therapy allows avoidance of the lens, con- current proximal and distal blocking for lid and lacrimal glad sparing, and partial-retina treatment.2 In a report of 49 patients (60 eyes; 84% bilateral disease) treated with proton therapy, no patients had devel- oped an in-field secondary cancer with a median follow-up of eight years.63 In a comparison of photon and proton therapy, cumulative inci- dence of in-field secondary cancer at ten years was significantly lower with proton therapy (0% vs 14%, P = 0.015).64
Extraocular disease is treated with EBRT with craniospinal irradi- ation for CSF positive and trilateral disease. Metastatic disease usu- ally develops within 12 months of diagnosis and carries poor progno- sis. The COG ARET0321 study allowed randomization to no EBRT for stage IV disease with complete response to transplant with intensive chemotherapy.21
1.6 Future research directions
Ongoing studies aim to further improve ocular salvage rates and reduce late effects (see Table 3). The ongoing COG ARET12P1 study
| Number | Lead site | Abbreviated title | Phase | n | Start date | Completion date |
|---|---|---|---|---|---|---|
| NCT03016156 | St. Jude | Smartphone application to detect retinoblastoma | N/A | 290 | Mar 2018 | Mar 2021 |
| NCT03475121 | Hospital JP Garrahan | Treatment for nonmetastatic unilateral Rb | 3 | 200 | Jan 2018 | Dec 2025 |
| NCT03284268 | Fundació Sant Joan de Déu | Oncolytic adenovirus VCN-01 for refractory Rb | 1 | 13 | Sep 2017 | Nov 2019 |
| NCT03026998 | Institut Curie | MRI screening of second primary cancer after RT | N/A | 190 | Mar 2017 | Jan 2032 |
| NCT02792036 | St. Jude | Intravitreal carboplatin for recurrent or refractory intraocular Rb | 1 | 18 | Nov 2016 | Dec 2024 |
| NCT02116959 | UCSF | Alternating systemic chemotherapy and intra-arterial melphalan for intraocular Rb | 1 | 6 | Apr 2014 | May 2019 |
| NCT01783535 | St. Jude | Treatment of intraocular Rb | 2 | 125 | Jun 2013 | Jun 2022 |
| NCT01906814 | Sun Yat-sen University | Adjuvant chemotherapy for high-risk Rb after enucleation | 3 | 156 | Jan 2013 | Dec 2023 |
| NCT02866136 | Institut Curie | Conservative treatments of Rb | 2 | 133 | Feb 2012 | Feb 2027 |
| NCT02870907 | Institut Curie | Adjuvant treatment in extensive unilateral Rb primary enucleated | 2 | 125 | Mar 2010 | Sep 2026 |
| NCT00554788 | COG | Combination chemotherapy, autologous transplant, and/or RT for extraocular Rb (ARET0321) | 3 | 60 | Feb 2008 | Jun 2018ª |
| NCT00186888 | St. Jude | Treatment for Rb | 3 | 107 | Apr 2005 | Sep 2021 |
| NCT00110110 | Sick Kids | Combination chemotherapy and cyclosporin for bilateral Rb | 2 | 71 | Jun 2004 | Dec 2019 |
| NCT02097134 | COG | Intraarterial melphalan for unilateral Rb (ARET12P1) | N/A | 14 | Apr 2014 | Jun 2017 |
Abbreviations: COG, Children’s Oncology Group; Rb, retinoblastoma; RT, radiation therapy. aPrimary completion date.
is evaluating IAC for primary therapy of group D eyes with focus on safety.37 Increased risk of metastasis and secondary cancers have been raised as concerns of IAC by clinicians who continue to use IVC.42,65 Future studies of extraocular disease will likely use lower doses of EBRT (36 Gy).2 Results of proton therapy are encouraging, and studies with longer follow-up are needed to confirm its low rate of secondary cancers.62 Two percent of unilateral cases show amplifi- cation of the MYCN oncogene without RB1 mutation.66 These tumors have chromosomal variations (17q gain, 11q loss) and histology similar to neuroblastoma,67 and further study regarding optimal therapy is needed.
2 NASOPHARYNGEAL CANCER
Nasopharyngeal cancer (NPC) has a bimodal age distribution in North America and northwestern Europe, with an early peak inci- dence between 15 and 24 years and a second peak between 65 and 79 years.68,69 It is rare in adolescents and children, accounting for < 1% of childhood cancers.70-72 Endemic regions in China and southeast Asia, the Mediterranean, and northern Africa have 10- to 20-fold higher incidence and unimodal distribution without an early childhood peak.69,73-75 In the United States, childhood NPC is most
prevalent in African Americans.76 Despite presenting more often with locoregionally advanced disease, prognosis in children is better than in adults (five-year overall survival of > 85%71,77).
About 90% of childhood NPCs have WHO type III undifferentiated carcinoma,78,79 previously called lymphoepithelioma or Schminke tumor,71 with latent Epstein-Barr virus (EBV) infection in tumor cells80,81 and B-lymphocytes.82 Elevated serum EBV DNA levels are associated with advanced stage and worsened survival,80 and rapid declines following EBRT predict for better relapse-free and overall survival in adults.83 Genetics84,85 and dietary patterns, includ- ing consumption of nitrosamines such as in salted fish, especially in children,86,87 and Chinese herbal plants,88 may contribute to pathogenesis.
2.1 General treatment approach
In 2017, the American Joint Committee on Cancer released the eighth edition of the staging system for NPC.89 All staging is described in terms of this recent edition, including for the discussed COG study. Unlike in adults, > 80% of children have stage IV disease at diagnosis with more extensive primary tumors and nodal involvement.71 Few (< 10%) have distant metastatic disease.90
The multimodal treatment approach in children has incorpo- rated induction chemotherapy, typically incorporating cisplatin-based chemotherapy followed by reduced-dose radiation with concurrent chemotherapy.91 Children, and even adolescents, are at higher risk than adults for significant acute and late effects, often secondary to high-dose EBRT, including severe late fibrosis of soft tissues, endocrinopathies, dental sequelae, and secondary cancers.91-93
The recently published COG ARAR0331 study is the largest prospective trial of childhood NPC to date and has defined a new standard of care for pediatric NPC, incorporating an imaging-based response paradigm allowing partial responders to be treated with reduced-dose chemoradiation in an effort to reduce late effects.77 Although the earliest stage patients (stage I) can be managed with reduced-dose EBRT alone, most cases (stages II-IV) now receive response-based EBRT with concurrent cisplatin following three cycles of induction chemotherapy with cisplatin and 5-fluorouracil. In par- tially responding patients (making up over three-quarters of the sub- jects on the recent COG trial), the total dose of radiation can success- fully be reduced to 61.2 Gy (from a more conventional adult dose of 70.2 Gy) with no loss in efficacy.77 Surgery is rarely used given the relative surgical inaccessibility of the nasopharynx. Endoscopic and robotic techniques may occasionally allow for resection of not only T1 but possibly higher stage primary tumors and recurrences at experi- enced centers.94 Neck dissection is reserved for refractory nodal dis- ease after primary chemoradiation. Most recurrences, however, are distant, usually in bone, occurring within two years and carrying worse prognosis compared with locoregional failures.2
2.2 Role of radiation therapy
Nasopharyngeal carcinoma is radiosensitive with moderate to high doses of radiation. On the ARAR0331 study,77 stage I tumors were planned for EBRT alone of 61.2 Gy if confined to the nasopharynx or 66.6 Gy if extending to the oropharynx or nasal fossa. Stage II-IV tumors were treated with induction chemotherapy and concurrent chemoradiation with reduced-dose EBRT of 61.2 Gy after complete or partial response to induction chemotherapy compared with 70.2 Gy for patients with stable disease. Response was classified as partial at the primary site if the volumetric reduction (the product of the perpendicular measurements) was at least 64% and at the nodal sites was at least a 50% reduction in the largest three lymph nodes. Five-year event-free and overall survival rates were 84.3% and 89.2%, respectively. The cumulative incidence of local, distant, and local plus distant recurrence was 3.7%, 8.7%, and 1.7%, respectively, demon- strating that radiation dose reduction is possible for responders to induction therapy.77
Modern intensity-modulated radiation therapy techniques can reduce risk of adverse events such as xerostomia, dysphagia, trismus, and chronic otitis media.95-98 Proton therapy has the additional benefit of minimizing integral dose and potential risk of secondary malignancies.99,100 These treatment techniques have become the standard of care for pediatric NPC over the past decade. Target vol- umes include the areas initially involved by gross disease with a small 5
to 10 mm margin that should receive the highest doses (61.2-70.2 Gy), with the areas of potential microscopic disease in the bilateral neck receiving 45 Gy. The cytoprotective agent amifostine was prescribed on the ARAR0331 study based on available evidence at the time of trial design. A systematic review, however, suggested that most studies failed to show that amifostine reduced the impact of EBRT on salivary flow rate,101 and amifostine is no longer recommended. Timely initiation of EBRT appears to be important as a prolonged interval > 30 days between EBRT initiation and induction chemother- apy has been associated with higher risk of distant metastases and death.102
2.3 Role of chemotherapy
Cisplatin-based chemotherapy has become the standard of care for stage II-IV NPC. Induction chemotherapy is used to facilitate dose reduction of EBRT in patients with complete103 or partial response77,104 to reduce the risk of late effects. The survival benefit of induction chemotherapy remains unclear, with several phase III trials in adults suggesting improved overall survival105,106 but not others. 107 In more recent years, induction chemotherapy has been combined with concurrent chemoradiation based on emerging evidence in adult patients.108-110 A meta-analysis of chemotherapy included individual patient data of 5144 adults in 20 trials with a median follow-up of 7.7 years.108 Concurrent chemotherapy with EBRT (without induc- tion or adjuvant chemotherapy) significantly improved overall survival and reduced locoregional and distant failure.109 Higher rate of hear- ing loss and cranial nerve palsy were observed in the long term fol- lowing chemoradiation. In subgroup analysis, the highest benefit was seen in adults receiving adjuvant chemotherapy following concurrent chemoradiation compared with EBRT alone,108 but three phase III trials of adjuvant chemotherapy have failed to show overall survival benefit.111-113
2.4 Future research directions
Excellent local control rates achieved in ARAR0331 enable further studies of EBRT dose and volume deescalation for pediatric NPC. Metabolic response on positron emission tomography may be useful in guiding risk-adapted therapy.114 Late effects of chemoradiation could potentially be reduced by intensity-modulated proton therapy, which may be especially useful in children due to its lower integral dose compared with photon radiation to reduce risk of secondary cancers.99,100,115
A number of systemic agents are under active investigation in adults that may be helpful for childhood NPC. Antiprogrammed death- ligand (PD-L1) antibodies, avelumab (NCT02875613), pembrolizumab (NCT03558191), and SHR-1210 (NCT03544099), may improve out- comes in patients with disease refractory to chemoradiation due to increased expression of PD-1 and PD-L1 in these patients. The safety and efficacy of VK-2019, an orally administered EBV nuclear antigen- 1 inhibitor, are being assessed (NCT03682055). Apatinib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, is
being studied for NPC refractory to platinum-based chemotherapy (NCT03213587).
3 ADRENOCORTICOID TUMORS
Adrenocortical carcinomas (ACC) represent 0.2% of all childhood malignancies diagnosed in the United States.116 The disease is asso- ciated with genetic syndromes including Li Fraumeni, Beckwith- Wiedemann, and multiple endocrine neoplasia type I (MEN I).117,118 The prevalence of TP53 mutations in patients registered on the Inter- national Pediatric Adrenocortical Tumor Registry (IPATR) was 50% and was reported up to 90% in southeastern Brazil.119-121 Genetic profiling has revealed additional driver mutations are likely to play important roles in tumorigenesis and prognosis. 122
3.1 General treatment approach
The only definitive criteria distinguishing ACC from adenoma are dis- tant metastasis or the presence of local invasion. Histopathologic crite- ria predicting tumor behavior in adults including mitoses, necrosis, and capsular invasion have been unreliable in children.123-125 Important clinical prognostic features in children include age, tumor weight, and tumor extension or spillage.119 A modified staging system adopted by the IPATR stratifies patients based on tumor size, lymph node involve- ment, and extent of resection.116,119 For locally confined disease, com- plete surgical resection is curative. Adjuvant therapy is individualized based on risk of recurrence. Patients with unresectable, metastatic, or recurrent disease are managed primarily with systemic therapy. Of patients with stage I disease, > 90% will be long-term survivors, com- pared with 10% of those with stage IV disease.119,126,127
3.2 Role of surgery
Complete surgical resection is the primary treatment, and resectabil- ity is therefore an important prognostic factor. Prior to resection, all patients should undergo complete hormonal assessment. ACC is often friable, resulting in tumor rupture with spillage in approximately 20% of cases. Tumors may be locally adherent with the need for extensive resection of adjacent organs. Therefore, open rather than laparo- scopic resection has been recommended in multiple series.128-130 Even after radical resection, patients with locoregionally advanced disease have a 60% to 80% risk of recurrence.119,127,131 Lymph node involvement has been reported in up to 40% of adult cases.132,133 Single-institution series in adult patients have demonstrated sig- nificantly reduced risk for tumor recurrence and disease-specific mortality following lymphadenectomy.134 However, in practice, nodal sampling is not routinely performed except for obvious nodal enlargement.
For patients with advanced tumors that cannot be completely resected, the benefit of maximal debulking is controversial.128 Although debulking may improve control hormone hypersecretion and potentially increase the efficacy of other therapies, the decision for
resection should be individualized based on symptoms and anticipated prognosis.132,135,136
3.3 Role of radiation therapy
The role of radiation therapy in pediatric ACC has not been systemati- cally investigated. Retrospective series of adjuvant EBRT in adults have demonstrated improved local recurrence but no significant differences in recurrence-free or overall survival.137,138 Adjuvant radiation to the tumor bed is therefore generally reserved for those at highest risk of recurrence (large tumors with local invasion, intraoperative tumor rupture, or gross residual disease). Of concern in the pediatric popula- tion is the risk of secondary malignancy in the setting of germline TP53 mutations. Driver et al. reported that among five long-term survivors of pediatric ACC, three died due to secondary sarcoma arising within the radiation field.139 Adjuvant EBRT was delivered to only two of 196 patients in the report from the IPATR and was not included on the prospective GHOP-MET 97 or COG ARAR0332 protocols.119,140 Pal- liative treatment of metastatic or recurrent disease is recommended for bone, brain, and other metastases as well as symptomatic local recurrences in a consensus report for adults.128 Dose and fraction- ation vary widely, from 15 to 56 Gy.141 In a meta-analysis of adult patients treated palliatively, 57% had a benefit from EBRT.141
3.4 Role of chemotherapy
Systemic therapy is most commonly used for pediatric patients with locally advanced, unresectable, or metastatic disease. At low doses, mitotane suppresses steroid secretion and may provide symptomatic improvement in patients with functional tumors. At higher serum lev- els, it has a cytotoxic effect.142 Retrospective data have demonstrated improved outcomes with adjuvant mitotane monotherapy in adults, and an international consensus panel recommended that adjuvant mitotane was indicated for those with incomplete resection or a high proliferative rate.143-146 Indications for mitotane monotherapy in pediatric patients are less defined. Adjuvant mitotane was given to a small subset of early-stage patients in the report from the IPACTR but was not generally recommended in this setting nor was it adminis- tered as monotherapy on GHOP-MET 97 or ARAR0332.119,140 There have been reports of complete response with mitotane monother- apy in the locally advanced and metastatic settings, but this is rare.147-149
For patients with advanced disease, combination systemic therapy is often used. Response to cisplatin alone is approximately 25%, and in combination with doxorubicin, cyclophosphamide, or 5-florouracil, the response is 20% to 40%.150-152 Responses of up to 55% have been seen in patients using mitotane with cisplatin, etoposide, and doxorubicin.119,153,154 On GHOP-MET 97, systemic therapy consisted of vincristine, ifosfamide, adriamycin, carboplatin, etoposide, and mitotane. Systemic therapy was given for metastatic disease, in the neoadjuvant setting for unresectable tumors, or in the adjuvant setting for residual disease or lymph node involvement. Event-free survival was 43.9%, 25%, and 36% in stage III, III, and IV diseases,
respectively. Of 11 patients treated with neoadjuvant systemic therapy, five subsequently underwent complete surgical resection.140
3.5 Future research directions
Ongoing studies aim to further refine optimal surgical management and systemic therapies for pediatric patients with ACC in the upfront setting. The ARAR0332 protocol investigated three clinical questions: (1) resection alone for stage I disease; (2) the utility of retroperitoneal lymph node resection to reduce local recurrences in stage II disease; and (3) the efficacy of mitotane- and cisplatin-based chemotherapy for unresectable and metastatic disease. The study has completed accrual and results are pending. Numerous targeted agents for refractory or recurrent disease have been evaluated in adults with low response rates.154-158 In pediatric patients, the ongoing phase I ADVL0911 pro- tocol is investigating the use of a novel oncolytic RNA virus NTX-010. Patients will receive NTX-010 in addition to low-dose metronomic cyclophosphamide to evaluate tolerability and establish optimal dos- ing for a phase II study.
CONFLICTS OF INTEREST
The authors have no conflicts of interest to declare.
ORCID
Samir Patel iD https://orcid.org/0000-0001-6198-6430
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How to cite this article: Patel S, Vogel J, Bradley K, Chuba PJ, Buchsbaum J, Krasin MJ. Rare tumors: retinoblastoma, nasopharyngeal cancer, and adrenocorti- coid tumors. Pediatr Blood Cancer. 2021;68:(Suppl. 2):e28253. https://doi.org/10.1002/pbc.28253