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Research
If you are not a physician, please click here for IPACTR information
| Background | Eligibility to Participate in the IPACTR |
| Inherited Constitutional Genetic Changes in Pediatric ACT | References |
| Aims and Objectives of the IPACTR |
Adrenocortical tumors (ACT) are very rare in children and teenagers,1 making up only about 0.2% of all new cases of cancer diagnosed each year in the United States and Europe in patients younger than 20 years.2,3 The international incidence of ACT is not well defined but appears to differ geographically; for example, a high incidence is observed in southern Brazil.4-8 The International Pediatric Adrenocortical Tumor Registry (IPACTR) was established to expedite studies of this rare pediatric tumor.
Because of the rarity of childhood ACT, its natural history is not known. ACT is clinically heterogeneous, comprising both heritable and sporadic subtypes.9 Studies at St. Jude and elsewhere10-12 have revealed that most children with ACT, particularly those younger than 4 years of age, carry constitutional P53 mutations, whereas these mutations are relatively infrequent in older pediatric patients with ACT and very rare in adults with ACT.
Some germline P53 mutations associated with ACT leave the function of the mutant p53 protein relatively intact. For example, the R337H mutation, which encodes an arginine-to-histidine substitution at codon 337 of P53, is associated with a relatively unremarkable history of cancer in carriers and their families.13-15 Other germline mutations that functionally impair the protein are associated with a pervasive history of familial cancer (Li-Fraumeni syndrome).16
The IPACTR has allowed studies of prognostic features, treatment modalities, and outcomes for children with this tumor.17-20 In a large series of registered patients,20 complete vs. incomplete tumor resection was the most important prognostic indicator. Residual disease after surgery was associated with a dismal outcome. Among children whose tumors had been completely resected, tumor size was the strongest prognostic indicator. Among children with large tumors (≥200 cm3), the probability of disease-free survival was about half that for children with smaller tumors. Young age (<3 years) and clinical syndrome (the presence vs. absence of virilization) were also independently associated with prognosis. However, this analysis did not allow further general conclusions about treatment because the patients were not managed uniformly.
The Children’s Oncology Group (COG) is currently conducting a prospective clinical trial in which children with ACT are uniformly treated. Treatment guidelines recently published by the United Kingdom’s pediatric rare tumor consortium should also provide information derived from uniform treatment.21 These data will allow analysis of the prognostic importance of different constitutional P53 mutations and of somatic genetic changes observed within the tumors22-24 in uniformly treated patients.
A specific rare tumor registry such as IPACTR allows the collection of multi-institutional and multinational information. Analysis of registry data will provide an overview of the clinical, epidemiological, and survival data and the current treatment standards for these patients and thus help to guide future research. It may also facilitate the development of treatment consensus among investigators who register their patients. Moreover, the combined COG and IPACTR studies are expected to provide meaningful insight into the biology of ACT, including clinical phenotype/genotype relationships, treatment outcome, and long-term follow-up data. Finally, the registry data will shed light on the long-term effect of exposure to tumor-secreted androgens (found in more than 80% of pediatric cases) on children's growth and development.
In addition to demographic, clinical, and epidemiological information, we plan to store ACT tissue and patient’s blood for molecular studies. The tumor samples will be kept and managed at St. Jude according to established procedures, and country-specific guidelines regarding the release of blood and tumor tissue to the St. Jude tumor bank will be followed. No patient identifiers will be associated with the tumor samples. The samples will be coded and only the referring physicians, the principal investigators, and study coordinators will know the names of the patients.
Because of the strong association between pediatric ACT and inherited P53 mutations, patients and one of the parents are likely to carry a P53 mutation. Most carriers have a life-long increased risk of various types of cancer, and the risk of cancer appears to be greatest when the function of the p53 protein is severely compromised. An available blood test (P53 sequencing) can reveal whether an individual carries a P53 mutation; a 3–5 mL blood sample is required.
Before testing is provided, we recommend that parents and patients (depending on the child’s age) meet with a health care provider trained in genetic counseling (genetic counselor) to receive further information about the implications of P53 testing.
Because carriers of P53 mutations have an increased incidence of diverse types of cancer, the patients’ family cancer history can be added to IPACTR. The relatives can also be contacted and asked whether they would agree to contribute to research by providing a blood sample and/or tumor tissue to IPACTR to determine the germline and somatic P53 status. The patients may also develop or have developed other types of cancer. To determine whether these tumors harbor a P53 mutation, IPACTR investigators would like to obtain tumor samples to determine tumor P53 status.
The primary goal of the IPACTR is to collect demographic and medical information about children and teenagers with adrenocortical tumors—including a detailed family cancer history—to learn more about the clinical and epidemiological aspects, treatment, and outcome of patients with this rare disease, worldwide. In addition, we would like to store adrenocortical tumor tissue (tumor banking) for molecular studies to clarify the role of the P53 gene and other genetic pathways in these tumors.
Participating patients must be ≤21 years of age at the time of diagnosis of ACT. Their parents and relatives who develop cancer can be registered at any age. Participants need not come to St. Jude Children’s Research Hospital; they can be registered via telephone conference.
Physicians who wish to register patients on IPACTR will contact one of PIs. The referring physician and the PI will determine whether the IPACTR study will be submitted to the local IRB (collaborating institution) or whether informed consent will be obtained by the St. Jude PI by telephone. In the latter case, informed consent will be obtained from the patients/parents/legal guardian via telephone dialogue according to St. Jude IRB guidelines.
Physicians at collaborating institutions who enroll a patient with ACT after obtaining approval from their local IRB should contact one of the PIs (Raul C Ribeiro, MD, E-mail: raul.ribeiro@stjude.org; Phone: 1-901-595-3694; Fax: 1-901-595-5319) and fax or mail a copy of the local IRB approval document and a copy of the IRB-approved consent form.
After the consent form is signed, the collaborating institutions should send the following items to St. Jude: the completed Patient Eligibility Checklist (leave the Patient ID blank), the signed consent form and completed Registration Form; and a tumor paraffin block or tumor slides with the pathology report for review of diagnosis at St. Jude.
For physicians at non-collaborating institutions, St. Jude will use the same process as that explained above to confirm patient eligibility. The referring physician is asked to send a tumor paraffin block or tumor slides to St. Jude with the pathology report for review of diagnosis. After the referring physician has provided general information to the patient/parent/legal guardian about the study, St. Jude will contact the patient/parent/legal guardian to request permission to send the IRB-approved consent forms.
The identities of patients/parents/legal guardians who agree to participation will be kept strictly confidential as required by policies and procedures of the institution. The informed consent process must include an interpreter who is fluent in the parent’s/patient’s language. Informed consent by phone will be conducted only by St. Jude PIs. Patients' follow-up information will be requested from the patients/parents/legal guardians once a year.
After patients/parents/legal guardians review the consent form, a St. Jude PI telephones them again with a witness to discuss the study and ask whether they wish to participate. Patients/parents/legal guardians then mail the signed consent form back to the St. Jude PI. St. Jude will request yearly follow-up information from collaborating and non-collaborating sites; a separate form will be completed at the time of each relapse or disease progression.
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