CREATE Childhood Cancer Rehabilitation Program development: Increase access through interprofessional collaboration.

BACKGROUND: Cancer and its treatment can lead to functional limitations affecting ongoing development in children and adolescents. We developed a pediatric cancer rehabilitation program that integrates evidence-based rehabilitative care into cancer treatment. The program utilizes the CREATE (collaboration, rehabilitation/research, education, assessment, treatment, evaluation) Childhood Cancer Rehabilitation model. We aim to describe the structural and process components of our rehabilitation program and provide an access and utilization analysis. PROCEDURES: To evaluate the rehabilitation program, we identified new patients with oncologic diagnoses from 2002 to 2019 using our database. To evaluate rehabilitative care, descriptive data, including the timing and type of rehabilitation services utilized within 5 years of a child's diagnosis, were collected and reviewed. Statistical analysis focused on change over time. RESULTS: Among 1974 children assessed, 1580 (80.0%) received care from at least one rehabilitation service. Between 2002 and 2018, the percentage of children receiving rehabilitation services grew significantly throughout all disciplines, except for outpatient speech-language pathology. Utilization differed by age and diagnosis. Integrating therapists in the clinic improved patient access, reduced the time to access outpatient services, and increased the number of attended visits. Additional factors supporting program growth included: identifying leaders, using a prospective surveillance model, education, and program evaluation. CONCLUSION: A multimodal interprofessional approach, such as the CREATE model, improves access to and the efficiency of evidence-based rehabilitation services promoting recovery, ongoing development, and quality of life.

Maintenance DFMO Increases Survival in High Risk Neuroblastoma.

High risk neuroblastoma (HRNB) accounts for 15% of all pediatric cancer deaths. Despite aggressive therapy approximately half of patients will relapse, typically with only transient responses to second-line therapy. This study evaluated the ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) as maintenance therapy to prevent relapse following completion of standard therapy (Stratum 1) or after salvage therapy for relapsed/refractory disease (Stratum 2). This Phase II single agent, single arm multicenter study enrolled from June 2012 to February 2016. Subjects received 2 years of oral DFMO (750 ± 250 mg/m2 twice daily). Event free survival (EFS) and overall survival (OS) were determined on an intention-to-treat (ITT) basis. 101 subjects enrolled on Stratum 1 and 100 were eligible for ITT analysis; two-year EFS was 84% (±4%) and OS 97% (±2%). 39 subjects enrolled on Stratum 2, with a two-year EFS of 54% (±8%) and OS 84% (±6%). DFMO was well tolerated. The median survival time is not yet defined for either stratum. DFMO maintenance therapy for HRNB in remission is safe and associated with high EFS and OS. Targeting ODC represents a novel therapeutic mechanism that may provide a new strategy for preventing relapse in children with HRNB.

The Stoplight Program: A Proactive Physical Therapy Intervention for Children With Acute Lymphoblastic Leukemia.

Chemotherapy may cause neuromuscular impairments that can have life-long effects. The Stoplight Program (SLP) was developed as a proactive physical therapy (PT) intervention directed at impairments in children with acute lymphoblastic leukemia (ALL). In this program evaluation, we assessed the feasibility of the SLP delivered as part of standard care and identified body function and activity patterns in patients who received the intervention. Children ages 1 to 22 years, diagnosed with ALL, received an assessment by a physical therapist as part of usual care. The SLP intervention used 3 levels to categorize the impairment levels and intensity of PT. Of the children (n = 135) screened, 46% completed 5 intervention visits and 32% completed the program and met discharge criteria. At initial assessment, 46% of children ages 1 to 5 years and 67% of children ages 6 to 22 years had abnormal motor function. Those completing the program tested within the healthy norms. Research is needed on variables that influence adherence to a PT program and the range of functional impairment and activity limitations in this population.

Ovarian tumors related to intronic mutations in DICER1: a report from the international ovarian and testicular stromal tumor registry.

Germline DICER1 mutations have been described in individuals with pleuropulmonary blastoma (PPB), ovarian Sertoli-Leydig cell tumor (SLCT), sarcomas, multinodular goiter, thyroid carcinoma, cystic nephroma and other neoplastic conditions. Early results from the International Ovarian and Testicular Stromal Tumor Registry show germline DICER1 mutations in 48 % of girls and women with SLCT. In this report, a young woman presented with ovarian undifferentiated sarcoma. Four years later, she presented with SLCT. She was successfully treated for both malignancies. Sequence results showed a germline intronic mutation in DICER1. This mutation results in an exact duplication of the six bases at the splice site at the intron 23 and exon 24 junction. Predicted improper splicing leads to inclusion of 10 bases of intronic sequence, frameshift and premature truncation of the protein disrupting the RNase IIIb domain. A second individual with SLCT was found to have an identical germline mutation. In each of the ovarian tumors, an additional somatic mutation in the RNase IIIb domain of DICER1 was found. In rare patients, germline intronic mutations in DICER1 that are predicted to cause incorrect splicing can also contribute to the pathogenesis of SLCT.

Improved quality of life at end of life related to home-based palliative care in children with cancer.

BACKGROUND: Nearly 2000 children die due to a malignancy in the United States annually. Emerging data suggest that home is the desired location of care for children with cancer at end of life. However, one obstacle to enrollment in a pediatric palliative care (PPC) home care program may be fear that distressing symptoms at end of life cannot be adequately managed outside the hospital. OBJECTIVE: To compare the symptom distress and quality-of-life experience for children who received concurrent end-of-life care from a PPC home care program (PPC/Oncology) with that of those who died without exposure to the PPC program (Oncology). METHODS: We conducted a retrospective survey study of a cohort of bereaved parents of children who died of cancer between 2002 and 2008 at a U.S. tertiary pediatric institution. RESULTS: Sixty bereaved parents were surveyed (50% PPC/Oncology). Prevalence of constipation and high distress from fatigue were more common in the PPC/Oncology group; other distressing symptoms were similar between groups, showing room for improvement. Children who received PPC/Oncology were significantly more likely to have fun (70% versus 45%), to experience events that added meaning to life (89% versus 63%), and to die at home (93% versus 20%). CONCLUSIONS: This is the first North American study to assess outcomes among children with cancer who received concurrent oncology and palliative home care compared with those who received oncology care alone. Symptom distress experiences were similar in groups. However, children enrolled in a PPC home care program appear to have improved quality of life and are more likely to die at home.

Surgery for pediatric invasive fungal sinonasal disease.

OBJECTIVES/HYPOTHESIS: To evaluate the management and outcomes of children with invasive fungal sinonasal disease treated with radical surgery. STUDY DESIGN: Retrospective case series. METHODS: From 1994 to 2007, 11 pediatric patients were identified with invasive fungal sinonasal disease treated surgically by the same pediatric otolaryngologist. Collected data included demographics, oncologic diagnoses, absolute neutrophil counts, symptoms, computed tomography scan findings, biopsy and culture results, surgical procedures, concurrent medical therapies, complications, and survival. RESULTS: The studied patient population consisted of four males and seven females with an average age of 10 years (range, 2-14 years). Six patients were diagnosed with acute lymphoblastic leukemia and five with acute myeloid leukemia, which included 10 cases of relapsed disease. The average number of severely neutropenic days prior to diagnosis of an invasive fungal infection was 18 (range, 8-41 days). Culture results demonstrated Alternaria in seven patients and Aspergillus in four. Nine patients underwent an external medial maxillectomy, five of which were bilateral, and six underwent septectomy. All 11 patients (100%) were cured of their invasive fungal sinonasal disease without relapse. Three patients eventually died from unrelated causes. CONCLUSIONS: Invasive fungal sinonasal disease is a life-threatening problem in immunocompromised children, especially with relapsed leukemia. Successful treatment depends on timely and aggressive surgical, antifungal, and supportive therapies. To our knowledge, this study represents the largest series of pediatric patients with invasive fungal sinonasal disease managed via an aggressive surgical approach with the best outcomes to date. LEVEL OF EVIDENCE: 4.

CAM and Pediatric Oncology: Where Are All the Best Cases?

Background. Use of complementary and alternative medicine (CAM) by children with cancer is high; however, pediatric best cases are rare. Objectives. To investigate whether best cases exist in pediatric oncology using a three-phase approach and to compare our methods with other such programs. Methods. In phase I, Children's Oncology Group (COG) oncologists were approached via email and asked to recall patients who were (i) under 18 when diagnosed with cancer, (ii) diagnosed between 1990 and 2006, (iii) had unexpectedly positive clinical outcome, and (iv) reported using CAM during or after cancer treatment. Phase II involved partnering with CAM research networks; patients who were self-identified as best cases were asked to submit reports completed in conjunction with their oncologists. Phase III extended this partnership to 200 CAM associations and training organizations. Results. In phase I, ten cases from three COG sites were submitted, and most involved use of traditional Chinese medicine to improve quality of life. Phases II and III did not yield further cases. Conclusion. Identification of best cases has been suggested as an important step in guiding CAM research. The CARE Best Case Series Program had limited success in identifying pediatric cases despite the three approaches we used.

Complementary and alternative medicine use in children with cancer and general and specialty pediatrics.

The objective of this survey is to determine the frequency, reasons, and factors influencing use of complementary and alternative medicine (CAM) in general and specialty pediatrics within the same geographic area. Of the 281 surveys completed, CAM use was higher in children with epilepsy (61.9%), cancer (59%), asthma (50.7%), and sickle cell disease (47.4%) than in general pediatrics (36%). Children most often used prayer (60.5%), massage (27.9%), specialty vitamins (27.2%), chiropractic care (25.9%), and dietary supplements (21.8%). Parents who used CAM for themselves (68.7%) were more likely to access CAM for their child. Most parents (62.6%) disclosed some or all of their child's use of CAM to providers. This study confirms that within the same geographic region, children with chronic and life-threatening illness use more CAM therapies than children seen in primary care clinics. Children with cancer use CAM for different reasons than children with non-life-threatening illnesses.

Massage therapy for children with cancer.

This pilot study aimed to determine the feasibility of providing massage to children with cancer to reduce symptoms in children and anxiety in parents. Twenty-three children/parent dyads were enrolled; 17 completed all data points. Children with cancer, ages 1 to 18 years, received at least 2 identical cycles of chemotherapy, and one parent, participated in the 2-period crossover design in which 4 weekly massage sessions alternated with 4 weekly quiet-time control sessions. Changes in relaxation (heart and respiratory rates, blood pressure, and salivary cortisol level) and symptoms (pain, nausea, anxiety, and fatigue) were assessed in children; anxiety and fatigue were measured in parents. Massage was more effective than quiet time at reducing heart rate in children, anxiety in children less than age 14 years, and parent anxiety. There were no significant changes in blood pressure, cortisol, pain, nausea, or fatigue. Children reported that massage helped them feel better, lessened their anxiety and worries, and had longer lasting effects than quiet time. Massage in children with cancer is feasible and appears to decrease anxiety in parents and younger children.

Comparison of results of a pilot study of alternating vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide with IRS-IV in intermediate risk rhabdomyosarcoma: a report from the Children's Oncology Group.

BACKGROUND: Over 50% of patients with rhabdomyosarcoma (RMS) have intermediate risk disease, with a 3-year failure-free survival (FFS) of 50%-70% depending on histology. Doxorubicin is active against RMS, but its role in improving outcome remains controversial. Ifosfamide is as active as cyclophosphamide in RMS, with the Fourth Intergroup RMS Study (IRS-IV) showing equivalent outcomes for patients treated with ifosfamide for the first 28 weeks compared to cyclophosphamide. Treatment with alternating cycles of non-cross-resistant chemotherapy has been used in a number of diseases with good results. PROCEDURE: The results of a pilot study utilizing alternating courses of vincristine, doxorubicin, cyclophosphamide, and etoposide/ifosfamide (VDC/IE) were compared for outcome and patient characteristics to a group of similar matched patients treated on IRS-IV. RESULTS: The 5-year FFS for patients with parameningeal (PM) primaries on IRS-IV and the VDC/IE study were 72% and 82%, respectively (P = 0.26); for patients with non-PM primaries, the estimated risk of failure for VDC/IE study versus IRS-IV was 0.54. Combining all disease sites and performing analysis for relative risk of failure for 46 VDC/IE patients and 342 IRS-IV patients, the relative risk of failure for the VDC/IE study compared to the IRS-IV study is 0.5 (P = 0.06). CONCLUSIONS: VDC/IE is as effective therapy for intermediate risk RMS as IRS-IV therapy. It is being explored along with irinotecan in relapsed patients and newly diagnosed high-risk patients.

Complementary and alternative therapy use in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.

BACKGROUND: Little information is available on the use of complementary and alternative medicine (CAM) in long-term survivors of childhood and adolescent cancer. PROCEDURE: The Childhood Cancer Survivor Study (CCSS) is a resource evaluating the long-term effects of cancer and associated therapies in 5-year survivors of childhood and adolescent cancer diagnosed between 1970 and 1986 before the age of 21 years. A survey of CAM use during the previous year was distributed in 2000-2001 and completed by 9,984 survivors and 2,474 sibling controls. RESULTS: CAM use reporting was similar in cases (39.4%) and siblings (41.1%). Compared to female siblings, female survivors were more likely to use biofeedback (odds ratio (OR) = 3.3; 95% CI = 1.0-10.8) and hypnosis/guided imagery (OR = 3.2; 95% CI = 1.6-6.8); male survivors were more likely than male siblings to use herbal remedies (OR = 1.3; 95% CI = 1.1-1.6). Factors associated with CAM use in survivors included elevated scores on the brief symptom inventory (BSI)-18 (OR = 1.6; 95% CI = 1.3-1.9), prolonged pain (OR = 1.5; 95% CI = 1.3-1.7), and having seen a physician in the past 2 years (OR = 1.6; 95% CI = 1.4-1.8). Survivors reporting low alcohol intake and excellent or good general health reported lower levels of CAM use (OR = 0.7; 95% CI = 0.7-0.8 and OR = 0.8; 95% CI = 0.7-0.9, respectively). CONCLUSIONS: Survivors have a similar reported use of CAM compared to a sibling cohort. However, our data suggest that survivors turn to CAM for specific symptoms related to previous diagnosis and treatment. Future research is needed to determine whether CAM use reflects unmet health needs in this population.

Complementary and alternative therapies in pediatric oncology.

Evidence on the science of complementary and alternative medicine (CAM) in children with cancer is slowly evolving. Most parents of children with cancer want their children to receive state-of-the-art therapy, which generally includes chemotherapy, radiation, and surgery. Increasingly, they also want the concomitant use of CAM therapies to help effect a cure or to alleviate symptoms. The ideal model of integrative pediatric oncology offers safe and effective CAM therapies in a pediatric hospital or medical center setting which participates in the clinical trials network of a pediatric oncology cooperative group setting.

Complementary and alternative medicine in pediatric oncology: availability and institutional policies in Canada--a report from the Children's Oncology Group.

Complementary and alternative medicine (CAM) is used frequently by pediatric oncology patients. A survey exploring the institutional practices and policies surrounding CAM use in pediatric oncology patients was completed by 17 pediatric hematology/oncology centers in Canada. We found that CAM was offered in only 18% of the institutions, but 94% of the communities. Only 6% of oncology divisions made direct referrals to community CAM providers, and only 20% of the centers had policies regarding use of CAM therapies for their patients. Despite published widespread use of CAM therapies, our study demonstrates that institutional CAM resources and policies on CAM are present in much lower proportions.

Pediatric ovarian tumors: a review of 67 cases.

BACKGROUND: Ovarian tumors are uncommon but important childhood neoplasms. PROCEDURE: We reviewed records of 67 pediatric patients presenting to three pediatric referral centers from 1980 to 2003. RESULTS: Thirty patients had benign tumors. Thirty-seven patients had malignant tumors: 11 immature teratomas, seven malignant mixed germ cell tumors, seven juvenile granulosa cell tumors, five dysgerminomas, two endodermal sinus tumors, two serous papillary cystadenocarcinomas, one small cell carcinoma, one anaplastic sex-cord tumor, and one undifferentiated sarcoma. More than half presented with abdominal pain. Forty-six percent had an abdominal mass at the time of presentation. Other signs and symptoms included poor appetite (15%), urinary symptoms/urinary infection (9%), menstrual changes (9%), and weight loss (6%). Precocious puberty was noted in seven patients. Torsion was seen more often in patients with benign tumors (23 vs. 8%); two patients had both torsion and acute appendicitis. The neoplasm was an incidental finding in 12 patients. CONCLUSIONS: Fifty-five percent of the 67 ovarian tumors presenting to our centers were malignant. Pain was the most common symptom, although presence of an abdominal mass was frequent, and other symptoms non-specific. Almost all neoplasms presented as unilateral masses and rarely were metastatic at diagnosis. Ovarian tumors must be considered in the differential diagnosis of young girls with abdominal pain, mass, or other non-specific symptoms.

Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood.

The clinical, cytogenetic, and molecular findings of 2 Fanconi anemia (FA) subtype D1 kindreds, initially identified through a young child with a solid tumor (medullobastoma, Wilms tumor), are described. Each kindred subsequently had a second affected child; one developed Wilms tumor followed by a medulloblastoma, and the other developed T-lineage acute lymphoblastic leukemia. Cytogenetic studies revealed an unusually high spontaneous chromosome aberration rate, contrasting with other FA subtypes. Molecular analysis revealed biallelic BRCA2/FANCD1 mutations. The patients did not exhibit bone marrow failure. Our studies suggest that the D1 subtype represents a severe end of the cytogenetic spectrum within FA, consistent with a critical downstream role of BRCA2 in the FA pathway. Furthermore, this FA subgroup may be preferentially associated with an increased predisposition to solid tumors in early childhood. Recognition of this constellation of findings has significant implications for medical management and genetic counseling of FA families.

A pharmacoeconomic analysis of pegaspargase versus native Escherichia coli L-asparaginase for the treatment of children with standard-risk, acute lymphoblastic leukemia: the Children's Cancer Group study (CCG-1962).

PURPOSE: The purpose of this pharmacoeconomic analysis was to compare pegaspargase. a newer chemotherapeutic agent used for treating acute lymphoblastic leukemia, with native Escherichia coli L-asparaginase in induction, delayed intensification 1 and delayed intensification 2. MATERIALS AND METHODS: A subset of patients with newly diagnosed, standard-risk, acute lymphoblastic leukemia enrolled in the Children's Cancer Group (CCG) study CCG-1962 at seven participating institutions gave consent and was enrolled in our pharmacoeconomic analysis study. Societal (transportation, lodging, missed workdays, food, babysitter) and payer (frequency of encounters) cost data were collected from diaries (n = 27). Additional payer costs, such as drug costs, cost per clinic visit, and cost per inpatient day stay were collected from patients in CCG-1962 and participating institutions. We considered costs of therapy, including higher pegaspargase costs when comparing regimens of pegaspargase versus native E. coli L-asparaginase in induction, delayed intensification 1, and delayed intensification 2. RESULTS: Our results showed that the costs of the two therapies were similar from the payer perspective, with pegaspargase costing 1.8% more than E. coli L-asparaginase. The difference between groups also was small (<1%) from the societal perspective. Inpatient stay accounted for 88% of pegaspargase payer costs and 91% of the native E. coli L-asparaginase costs. CONCLUSION: We recommend that pegaspargase not be withheld from treatment protocols solely because of its higher pharmacy costs.

A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study.

For this study, 118 children with standard-risk acute lymphoblastic leukemia (ALL) were given randomized assignments to receive native or pegylated Escherichia coli asparaginase as part of induction and 2 delayed intensification phases. Patients treated with pegaspargase had more rapid clearance of lymphoblasts from day 7 and day 14 bone marrow aspirates and more prolonged asparaginase activity than those treated with native asparaginase. In the first delayed intensification phase, 26% of native asparaginase patients had high-titer antibodies, whereas 2% of pegaspargase patients had those levels. High-titer antibodies were associated with low asparaginase activity in the native arm, but not in the pegaspargase arm. Adverse events, infections, and hospitalization were similar between arms. Event-free survival at 3 years was 82%. A population pharmacodynamic model using the nonlinear mixed effects model (NONMEM) program was developed that closely fit the measured enzyme activity and asparagine concentrations. Half-lives of asparaginase were 5.5 days and 26 hours for pegaspargase and native asparaginase, respectively. There was correlation between asparaginase enzymatic activity and depletion of asparagine or glutamine in serum. In cerebrospinal fluid asparagine, depletion was similar with both enzyme preparations. Intensive pegaspargase for newly diagnosed ALL should be tested further in a larger population.