Nelarabine is effective in inducing remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia (T-ALL) but has not been fully evaluated in those with newly diagnosed ...disease.
From 2007 to 2014, Children's Oncology Group trial AALL0434 (ClinicalTrials.gov identifier: NCT00408005) enrolled 1,562 evaluable patients with T-ALL age 1-31 years who received the augmented Berlin-Frankfurt-Muenster (ABFM) regimen with a 2 × 2 pseudo-factorial randomization to receive escalating-dose methotrexate (MTX) without leucovorin rescue plus pegaspargase (C-MTX) or high-dose MTX (HDMTX) with leucovorin rescue. Intermediate- and high-risk patients were also randomly assigned after induction to receive or not receive six 5-day courses of nelarabine that was incorporated into ABFM. Patients who experienced induction failure were nonrandomly assigned to HDMTX plus nelarabine. Patients with overt CNS disease (CNS3; ≥ 5 WBCs/μL with blasts) received HDMTX and were randomly assigned to receive or not receive nelarabine. All patients, except those with low-risk disease, received cranial irradiation.
The 5-year event-free and overall survival rates were 83.7% ± 1.1% and 89.5% ± 0.9%, respectively. The 5-year disease-free survival (DFS) rates for patients with T-ALL randomly assigned to nelarabine (n = 323) and no nelarabine (n = 336) were 88.2% ± 2.4% and 82.1% ± 2.7%, respectively (
= .029). Differences between DFS in a four-arm comparison were significant (
= .01), with no interactions between the MTX and nelarabine randomizations (
= .41). Patients treated with the best-performing arm, C-MTX plus nelarabine, had a 5-year DFS of 91% (n = 147). Patients who received nelarabine had significantly fewer isolated and combined CNS relapses compared with patients who did not receive nelarabine (1.3% ± 0.63%
6.9% ± 1.4%, respectively;
= .0001). Toxicities, including neurotoxicity, were acceptable and similar between all four arms.
The addition of nelarabine to ABFM therapy improved DFS for children and young adults with newly diagnosed T-ALL without increased toxicity.
Early intensification with methotrexate (MTX) is a key component of acute lymphoblastic leukemia (ALL) therapy. Two different approaches to MTX intensification exist but had not been compared in ...T-cell ALL (T-ALL): the Children's Oncology Group (COG) escalating dose intravenous MTX without leucovorin rescue plus pegaspargase escalating dose, Capizzi-style, intravenous MTX (C-MTX) regimen and the Berlin-Frankfurt-Muenster (BFM) high-dose intravenous MTX (HDMTX) plus leucovorin rescue regimen.
COG AALL0434 included a 2 × 2 randomization that compared the COG-augmented BFM (ABFM) regimen with either C-MTX or HDMTX during the 8-week interim maintenance phase. All patients with T-ALL, except for those with low-risk features, received prophylactic (12 Gy) or therapeutic (18 Gy for CNS3) cranial irradiation during either the consolidation (C-MTX; second month of therapy) or delayed intensification (HDMTX; seventh month of therapy) phase.
AALL0434 accrued 1,895 patients from 2007 to 2014. The 5-year event-free survival and overall survival rates for all eligible, evaluable patients with T-ALL were 83.8% (95% CI, 81.2% to 86.4%) and 89.5% (95% CI, 87.4% to 91.7%), respectively. The 1,031 patients with T-ALL but without CNS3 disease or testicular leukemia were randomly assigned to receive ABFM with C-MTX (n = 519) or HDMTX (n = 512). The estimated 5-year disease-free survival ( P = .005) and overall survival ( P = .04) rates were 91.5% (95% CI, 88.1% to 94.8%) and 93.7% (95% CI, 90.8% to 96.6%) for C-MTX and 85.3% (95% CI, 81.0%-89.5%) and 89.4% (95% CI, 85.7%-93.2%) for HDMTX. Patients assigned to C-MTX had 32 relapses, six with CNS involvement, whereas those assigned to HDMTX had 59 relapses, 23 with CNS involvement.
AALL0434 established that ABFM with C-MTX was superior to ABFM plus HDMTX for T-ALL in approximately 90% of patients who received CRT, with later timing for those receiving HDMTX.
We examined correlates of low engagement in the healthcare system, experiences with survivorship care, barriers to follow-up care, and potential resources for promoting follow-up care among young ...adult survivors of childhood cancers. We conducted a mixed-method study involving surveys of 106 survivors of childhood cancer aged 18–34 recruited from a university-affiliated children’s hospital and an NCI-designated cancer center in the Southeastern USA. Phone-based semistructured interviews were then conducted in a subset of 26. Assessments included health factors, psychosocial factors, healthcare system interaction, and interest in resources to promote engagement in healthcare. Survey participants were on average 22.14 (SD = 3.16) years old, 50.0 % female, and 77.4 % White. Overall, 46.0 % had attended survivorship clinic, 47.2 % reported receiving a treatment summary, 68.9 % had a primary care provider, and 17.0 % reported no interaction with healthcare in the past 2 years. Correlates of less than annual healthcare provider visits included being older (
p
= 0.003), being male (
p
< 0.001), lack of insurance (
p
= 0.002), and having had chemotherapy (
p
= 0.05). Participants reported varied experiences in terms of how health and treatment information was presented, from none or too little to overwhelming or anxiety-provoking amounts. Barriers to engaging in survivorship care included no/limited insurance, time, or transportation; major life changes; anxiety; and difficulty transitioning from pediatrics to adult care. Participants highlighted the need for educational and psychosocial resources, particularly technology-based resources. Multilevel interventions are needed to increase engagement in survivorship care among young adult cancer survivors. Technology-based resources addressing social support and mental well-being are intervention possibilities.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Learning Objectives
After completing this course, the reader will be able to:
Appreciate the evolution of methods of managing anal carcinomas and appropriate selection of modalities to employ in ...various situations at the present time.
Understand methods of integrating chemotherapy and radiation to achieve desirable outcomes.
Understand considerations in choice of chemotherapy agents and radiation doses.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
The management of anal cancer underwent an interesting transformation over the last two decades. Prior to this period, the standard definitive treatment for carcinoma of the anal canal was abdominal‐perineal resection, which necessitated a permanent colostomy. The organ preservation concept appeared following the discovery of a high complete response rate from preoperative combined chemoradiation prior to abdominal‐perineal resection.
The organ preservation method of treatment rapidly gained popularity and ultimately saved a large number of patients from undergoing abdominal‐perineal resection and colostomy. Chemoradiation treatment itself subsequently went through an evolutionary process. Several studies have sought to define the optimal chemotherapeutic regimen as well as radiation treatment dose and fractionation. Ongoing studies attempt to define an optimal treatment regimen that yields a higher cure rate while minimizing toxicity. We review the etiology, epidemiology, and treatment regimens for anal cancer.
A PENTEC (Pediatric Normal Tissue Effects in the Clinic) review was performed to estimate the dose-volume effects of radiation therapy on spine deformities and growth impairment for patients who ...underwent radiation therapy as children.
A systematic literature search was performed to identify published data for spine deformities and growth stunting. Data were extracted from 12 reports of children irradiated to the spine (N = 603 patients). The extracted data were analyzed to find associations between complication risks and the radiation dose (conventional fractionation throughout) as impacted by exposed volumes and age using the mixed-effects logistic regression model. When appropriate, corrections were made for radiation modality, namely orthovoltage beams.
In the regression analysis, the association between vertebral dose and scoliosis rate was highly significant (P < .001). Additionally, young age at time of radiation was highly predictive of adverse outcomes. Clinically significant scoliosis can occur with doses ≥15 Gy to vertebrae during infancy (<2 years of age). For children irradiated at 2 to 6 years of age, overall scoliosis rates of any grade were >30% with doses >20 Gy; grade 2 or higher scoliosis was correlated with doses ≥30 Gy. Children >6 years of age remain at risk for scoliosis with doses >30 Gy; however, most cases will be mild. There are limited data regarding the effect of dose gradients across the spine on degree of scoliosis. The risk of clinically meaningful height loss was minimal when irradiating small volumes of the spine up to 20 Gy (eg, flank irradiation), except in infants who are more vulnerable to lower doses. Growth stunting was more frequent when larger segments of the spine (eg, the entire spine or craniospinal irradiation) were irradiated before puberty to doses >20 Gy. The effect was modest when patients were irradiated after puberty to doses >20 Gy.
To reduce the risk of kyphoscoliosis and growth impairment, the dose to the spine should be kept to <20 Gy for children <6 years of age and to <10 to 15 Gy in infants. The number of vertebral bodies irradiated and dose gradients across the spine should also be limited when possible.
The primary objective of the Children's Oncology Group study ANBL0531 (ClinicalTrials.gov identifier: NCT00499616) was to reduce therapy for subsets of patients with intermediate-risk neuroblastoma ...using a biology- and response-based algorithm to assign treatment duration while maintaining a 3-year overall survival (OS) of 95% or more for the entire cohort.
Children younger than age 12 years with intermediate-risk stage 2A/2B or stage 3 tumors with favorable histology; infants younger than age 365 days with stage 3, 4 or 4S disease; and toddlers from 365 to younger than 547 days with favorable histology, hyperdiploid stage 4, or unfavorable histology stage 3 tumors were eligible. Patients with
-amplified tumors were excluded. Patients were assigned to initially receive two (group 2), four (group 3), or eight (group 4) cycles of chemotherapy with or without surgery on the basis of prognostic markers, including allelic status of chromosomes 1p and 11q; ultimate duration of therapy was determined by overall response.
Between 2007 and 2011, 404 evaluable patients were enrolled. Compared with legacy Children's Oncology Group studies, subsets of patients had a reduction in treatment. The 3-year event-free survival and OS rates were 83.2% (95% CI, 79.4% to 87.0%) and 94.9% (95% CI, 92.7% to 97.2%), respectively. Infants with stage 4 tumors with favorable biology (n = 61) had superior 3-year event-free survival compared with patients with one or more unfavorable biologic features (n = 47; 86.9% 95% CI, 78.3% to 95.4%
66.8% 95% CI, 53.1% to 80.6%;
= .02), with a trend toward OS advantage (95.0% 95% CI, 89.5% to 100%
86.7% 95% CI, 76.6% to 96.7%, respectively;
= .08). OS for patients with localized disease was 100%.
Excellent survival was achieved with this treatment algorithm, with reduction of therapy for subsets of patients. More-effective treatment strategies still are needed for infants with unfavorable biology stage 4 disease.
Abstract
BACKGROUND: Therapy for pediatric craniopharyngioma, a rare suprasellar tumor, includes surgical resection with consideration for intracranial radiation. Radiation is associated with ...increased risk of secondary malignancies. Between 2000 and 2021, 81 pediatric patients with craniopharyngioma were treated at our institution; 3 of 54 (5.6%) who received radiation therapy(RT) developed secondary malignancy within the treatment field. CASE DESCRIPTIONS: In all 3 cases, initial imaging demonstrated cystic/solid suprasellar mass and underwent resection; pathology revealed calcifications and wet keratin consistent with craniopharyngioma. None had known cancer predispositions. The first patient (male), presented at 4-years-old with headaches. He underwent subtotal resection (STR) with cyst fenestration(w/CF) and received 55.8Gy photon 3D-Conformal RT. Six-years later, the tumor progressed (edge of RT field). Patient underwent a second STRw/CF and fractionated RT(50.4Gy). Both pathologies were consistent with(c/w) papillary craniopharyngioma. Eight-years from first RT, progression occurred again within the RTfield; pathology revealed an (adeno)squamous carcinoma. The second patient, a 5-year-old female, presented with vision loss, underwent partial resection and received 54Gy focal proton therapy for adamantinonatous craniopharyngioma. Almost 5-years later, an unresectable right basal ganglia/globus pallidus mass was noted in the 30-54Gy field. Pathology was c/w anaplastic astrocytoma(AA). The third, a 9-year-old female was treated with 54Gy photon radiation and 7 years later had evidence of increasing mass. Pathology revealed high-grade-diffuse-glioma(HGDG). Molecular analysis of AA/HGDG both revealed PDGFRA amplification and CDKN2A/B homozygous loss. DISCUSSION/CONCLUSION: Malignant CNS tumors are reported following radiotherapy for a variety of primary CNS lesions. While radiation is a valuable therapy in achieving long-term disease control of pediatric craniopharyngiomas, it is important to understand the risk of developing secondary malignant neoplasms. Our report adds to the body of literature describing secondary malignancies post radiation therapy for the treatment of pediatric craniopharyngioma.
We analyzed outcomes of pediatric rhabdomyosarcoma (RMS) of the female genitourinary (GU) tract using the Surveillance Epidemiology and End Result database.
Females (0 to 19 years of age) diagnosed ...with RMS of GU sites between 1973 and 2006 were included in the analysis as 2 groups, 0 to 9 and 10 to 19-year-olds. They were compared for primary site distribution, stage, histology, and therapy. Kaplan-Meier method was used for survival analysis by histology, stage, and primary sites.
Sixty-seven cases were identified. Twenty-six cases (38.8%) had localized disease, 11 (16.2%) had regional disease, 15 (28.4%) had distant spread, and 15 (28.4%) were unstaged. The majority (85%) had embryonal RMS. Twenty-eight tumors originated in the vagina, 26 in the cervix/uterus, and 13 in other sites including vulva, labia, ovaries. Age groups did not differ with respect to race, cancer stage, histologic type, percent of cases treated surgically, and the proportion receiving radiotherapy. Vaginal RMS was predominant in the younger age group (68.4%). In the older age group, 65.5% had RMS of the cervix or uterus. This age-related prevalence of tumor sites was statistically significant (P<0.001). Survival of patients with embryonal and early-stage tumor was superior. There was no significant difference in survival by age or primary tumor site.
This population-based study confirmed the significance of tumor histology and stage for female GU RMS patients. Tumor sites are strongly associated with age at diagnosis.
Endocrine dysfunction is a common sequela of craniospinal irradiation (CSI). Dosimetric data suggest that proton radiotherapy (PRT) may reduce radiation-associated endocrine dysfunction but clinical ...data are limited.
Seventy-seven children were treated with chemotherapy and proton (n = 40) or photon (n = 37) radiation between 2000 and 2009 with ≥3 years of endocrine screening. The incidence of multiple endocrinopathies among the proton and photon cohorts is compared. Multivariable analysis and propensity score adjusted analysis are performed to estimate the effect of radiotherapy type while adjusting for other variables.
The median age at diagnosis was 6.2 and 8.3 years for the proton and photon cohorts, respectively (P = .010). Cohorts were similar with respect to gender, histology, CSI dose, and total radiotherapy dose and whether the radiotherapy boost was delivered to the posterior fossa or tumor bed. The median follow-up time was 5.8 years for proton patients and 7.0 years for photon patients (P = .010). PRT was associated with a reduced risk of hypothyroidism (23% vs 69%, P < .001), sex hormone deficiency (3% vs 19%, P = .025), requirement for any endocrine replacement therapy (55% vs 78%, P = .030), and a greater height standard deviation score (mean (± SD) -1.19 (± 1.22) vs -2 (± 1.35), P = .020) on both univariate and multivariate and propensity score adjusted analysis. There was no significant difference in the incidence of growth hormone deficiency (53% vs 57%), adrenal insufficiency (5% vs 8%), or precocious puberty (18% vs 16%).
Proton radiotherapy may reduce the risk of some, but not all, radiation-associated late endocrine abnormalities.
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