Attention Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder of childhood that is characterized by symptoms of inattention, impulsivity/hyperactivity, or a combination of both. Intrinsic brain dysfunction in ADHD can be examined through various methods including resting state functional Magnetic Resonance Imaging (rs-fMRI), which investigates patients’ functional brain connections in the absence of an explicit task. To date, studies of group differences in resting brain connectivity between patients with ADHD and typically developing controls (TDCs) have revealed reduced connectivity within the Default Mode Network (DMN), a resting state network implicated in introspection, mind-wandering, and day-dreaming. However, few studies have addressed the use of resting state connectivity measures as a diagnostic aide for ADHD on the individual patient level. In the current work, we attempted first to characterize the differences in resting state networks, including the DMN and three attention networks (the salience network, the left executive network, and the right executive network), between a group of youth with ADHD and a group of TDCs matched for age, IQ, gender, and handedness. Significant over- and under-connections were found in the ADHD group in all of these networks compared with TDCs. We then attempted to use a support vector machine (SVM) based on the information extracted from resting state network connectivity to classify participants as “ADHD” or “TDC.” The IFGmiddle temporal network (66.8% accuracy), the parietal association network (86.6% specificity and 48.5% PPV), and a physiological noise component (sensitivity 39.7% and NPV 69.6%) performed the best classifications. Finally, we attempted to combine and utilize information from all the resting state networks that we identified to improve classification accuracy. Contrary to our hypothesis, classification accuracy decreased to 54-55% when this information was combined. Overall, the work presented here supports the theory that the ADHD brain is differently connected at rest than that of TDCs, and that this information may be useful for developing a diagnostic aid. However, because ADHD is such a heterogeneous disorder, each ADHD patient’s underlying brain deficits may be unique making it difficult to determine what connectivity information is diagnostically useful.
Identification and Characteristics of Factors Regulating Hepatocellular Carcinoma Progression and Metastasis: A Dissertation
Hepatocellular carcinoma (HCC) is a common malignancy of the liver that is one of the most frequent causes of cancer-related death in the world. Surgical resection and liver transplantation are the only curative options for HCC, and tumor invasion and metastasis render many patients ineligible for these treatments. Identification of the mechanisms that contribute to invasive and metastatic disease may enlighten therapeutic strategies for those not eligible for surgical treatments. In this dissertation, I describe two sets of experiments to elucidate mechanisms underlying HCC dissemination, involving the activities of Krüppel-like factor 6 and a particular p53 point mutation, R172H.
Gene expression profiling of migratory HCC subpopulations demonstrated reduced expression of Krüppel-like factor 6 (KLF6) in invasive HCC cells. Knockdown of KLF6 in HCC cells increased cell transformation and migration. Single-copy deletion of Klf6 in a HCC mouse model results in increased tumor formation, increased metastasis to the lungs, and decreased survival, indicating that KLF6 suppresses both tumor formation and metastasis in HCC.
To elucidate the mechanism of KLF6-mediated tumor and metastasis suppression, we performed gene expression profiling and ChIP-sequencing to identify direct transcriptional targets of KLF6 in HCC cells. This analysis revealed novel transcriptional targets of KLF6 in HCC including CDC42EP3 and VAV3, both of which are positive regulators of Rho family GTPases. Concordantly, KLF6 knockdown cells demonstrate increased activity of the Rho family GTPases RAC1 and CDC42, and RAC1 is required for migration induced following KLF6 knockdown. Moreover, VAV3 and CDC42EP3 are also required for enhanced cell migration in HCC cells with KLF6 knockdown. Together, this work describes a novel signaling axis through which KLF6-mediated repression of VAV3 and CDC42EP3 inhibits RAC1Gmediated HCC cell migration in culture, and potentially HCC metastasis in vivo.
TP53 gene mutations are commonly found in HCC and are associated with poor prognosis. Prior studies have suggested that p53 mutants can display gain-of- function properties in other tumor types. Therefore, I sought to determine if a particular hotspot p53 mutation, p53R172H, provided enhanced, gain-of-function properties compared to p53 loss in HCC. In vitro, soft agar colony formation and cell migration is reduced upon knockdown of p53R172H, indicating that this mutation is required for transformation-associated phenotypes in these cells. However, p53R172H-expressing mice did not have enhanced tumor formation or metastasis compared to p53-null mice. These data suggest that p53R172H and p53 deletion are functionally equivalent in vivo, and that p53R172H is not a gain-of-function mutant in HCC. Inhibition of the related transcription factors p63 and p73 has been suggested as a potential mechanism by which mutant p53 exerts its gain-of-function effects. Analysis of p63 and p73 target genes demonstrated that they are similarly suppressed in p53-null and p53R172H-expressing HCC cell lines, suggesting a potential explanation for the phenotypes I observed in vivo and in vitro.
Together, the studies described in this dissertation increase our understanding of the mechanisms underlying HCC progression and metastasis. Specifically, we find and characterize KLF6 as a novel suppressor of HCC metastasis, and determine the contribution of a common p53 point mutation in HCC. This work contributes to ongoing efforts to improve treatment options for HCC patients.
Optimal equations for describing the relationship between prostate volume, number of sources, and total activity in permanent prostate brachytherapy
OBJECTIVES: To determine whether there is an optimal type of mathematical equation for predicting seed and activity requirements for permanent prostate brachytherapy.
METHODS: Four institutions with extensive brachytherapy experience each submitted details of more than 40 implants. The data was used to generate power and linear equations to reflect the relationship between preimplant volume and the number of seeds implanted, and preimplant volume and the total implant activity. We compared the R and standard error of the generated equations to determine which type of equation better fit the data.
RESULTS: For the limited range of prostate volumes commonly implanted (20-60 mL), power and linear equations predict seed and activity requirements comparably well.
CONCLUSIONS: Linear and power equations are equally suitable for generating institution-specific nomograms.
PURPOSE: Variability in computed tomography/magnetic resonance imaging (CT/MR) cranial image registration was assessed using a benchmark case developed by the Quality Assurance Review Center to credential institutions for participation in Children's Oncology Group Protocol ACNS0221 for treatment of pediatric low-grade glioma.
METHODS AND MATERIALS: Two DICOM image sets, an MR and a CT of the same patient, were provided to each institution. A small target in the posterior occipital lobe was readily visible on two slices of the MR scan and not visible on the CT scan. Each institution registered the two scans using whatever software system and method it ordinarily uses for such a case. The target volume was then contoured on the two MR slices, and the coordinates of the center of the corresponding target in the CT coordinate system were reported. The average of all submissions was used to determine the true center of the target.
RESULTS: Results are reported from 51 submissions representing 45 institutions and 11 software systems. The average error in the position of the center of the target was 1.8 mm (1 standard deviation = 2.2 mm). The least variation in position was in the lateral direction. Manual registration gave significantly better results than did automatic registration (p = 0.02).
CONCLUSION: When MR and CT scans of the head are registered with currently available software, there is inherent uncertainty of approximately 2 mm (1 standard deviation), which should be considered when defining planning target volumes and PRVs for organs at risk on registered image sets.
PURPOSE: Exploration of Howard Atwood Kelly's contributions to gynecologic brachytherapy.
METHODS AND MATERIALS: Review of contemporary journals, texts, newspaper accounts, and the memoirs of Kelly's associates. Information from unpublished material, including Kelly's handwritten notes and diaries, was culled from the Alan Mason Chesney Archives of the Johns Hopkins Medical Institutions.
RESULTS: Despite European reports of radium's efficacy, gynecologists on both sides of the Atlantic resisted its adoption. The endorsement of radium therapy by America's foremost gynecologist, Howard Kelly, was instrumental in its acceptance. His consummate skill as clinician, investigator, publicist, and entrepreneur established brachytherapy as the primary treatment modality for carcinoma of the cervix and vagina. The technique he pioneered in the second decade of the 20th century, a combination of brachytherapy and megavoltage-equivalent teletherapy, presaged modern practice.
CONCLUSION: Principles for the management of female genital neoplasia, outlined by Howard Kelly nine decades ago, remain relevant today.
Impact of high-dose chemotherapy on the ability to deliver subsequent local-regional radiotherapy for breast cancer: analysis of Cancer and Leukemia Group B Protocol 9082
PURPOSE: To report, from Cancer and Leukemia Group B Protocol 9082, the impact of high-dose cyclophosphamide, cisplatin, and BCNU (HD-CPB) vs. intermediate-dose CPB (ID-CPB) on the ability to start and complete the planned course of local-regional radiotherapy (RT) for women with breast cancer involving >or=10 axillary nodes.
METHODS AND MATERIALS: From 1991 to 1998, 785 patients were randomized. The HD-CPB and ID-CPB arms were balanced regarding patient characteristics. The HD-CPB and ID-CPB arms were compared on the probability of RT initiation, interruption, modification, or incompleteness. The impact of clinical variables and interactions between variables were also assessed.
RESULTS: Radiotherapy was initiated in 82% (325 of 394) of HD-CPB vs. 92% (360 of 391) of ID-CPB patients (p = 0.001). On multivariate analyses, RT was less likely given to patients who were randomized to HD treatment (odds ratio [OR] = 0 .38, p < 0.001), older (p = 0.005), African American (p = 0.003), postmastectomy (p = 0.02), or estrogen receptor positive (p = 0.03). High-dose treatment had a higher rate of RT interruption (21% vs. 12%, p = 0.001, OR = 2.05), modification (29% vs. 14%, p = 0.001, OR = 2.46), and early termination of RT (9% vs. 2%, p = 0.0001, OR = 5.35), compared with ID.
CONCLUSION: Treatment arm significantly related to initiation, interruption, modification, and early termination of RT. Patients randomized to HD-CPB were less likely to initiate RT, and of those who did, they were more likely to have RT interrupted, modified, and terminated earlier than those randomized to ID-CPB. The observed lower incidence of RT usage in African Americans vs. non-African Americans warrants further study.
PURPOSE: Initial experience with delivering frameless stereotactic radiotherapy (SRT) using volumetric intensity-modulated radiation therapy (IMRT) delivered with RapidArc is presented.
METHODS AND MATERIALS: Treatment details for 12 patients (14 targets) with a mean clinical target volume (CTV) of 12.8 +/- 4.0 cm(3) were examined. Dosimetric indices for conformality, homogeneity, and dose gradient were calculated and compared with published results for other frameless, intracranial SRT techniques, including CyberKnife, TomoTherapy, and static-beam IMRT. Statistics on setup and treatment times and per patient dose validations were examined.
RESULTS: Dose indices compared favorably with other techniques. Mean conformality, gradient, and homogeneity index values were 1.10 +/- 0.11, 64.9 +/- 14.1, 1.083 +/- 0.026, respectively. Median treatment times were 4.8 +/- 1.7 min.
CONCLUSION: SRT using volumetric IMRT is a viable alternative to other techniques and enables short treatment times. This is anticipated to have a positive impact on radiobiological effect and for facilitating wider use of SRT.
Quality of radiotherapy reporting in randomized controlled trials of Hodgkin's lymphoma and non-Hodgkin's lymphoma: in regard to Bekelman and Yahalom (Int J Radiat Oncol Biol Phys 2009;73:492-498)
Comment on Quality of radiotherapy reporting in randomized controlled trials of Hodgkin's lymphoma and non-Hodgkin's lymphoma: a systematic review. [Int J Radiat Oncol Biol Phys. 2009]
PURPOSE: The practice of brachytherapy was in steep decline in the mid-20th century, largely because of safety issues. This article explores the innovations that revitalized brachytherapy with special attention to the introduction of low-energy seeds for permanent implantation.
METHODS AND MATERIALS: Literature review; interviews; and the memos, records, and correspondence of Donald C. Lawrence.
RESULTS: Paul Harper first proposed the use of radionuclides that decay by k-capture in the 1950s. But it was the vision and tenacity of health physicist Donald Lawrence that led to the successful implementation of I-125 (in the 1960s) and Cs-131 (40 years later).
Critical impact of radiotherapy protocol compliance and quality in the treatment of advanced head and neck cancer: results from TROG 02.02
PURPOSE: To report the impact of radiotherapy quality on outcome in a large international phase III trial evaluating radiotherapy with concurrent cisplatin plus tirapazamine for advanced head and neck cancer.
PATIENTS AND METHODS: The protocol required interventional review of radiotherapy plans by the Quality Assurance Review Center (QARC). All plans and radiotherapy documentation underwent post-treatment review by the Trial Management Committee (TMC) for protocol compliance. Secondary review of noncompliant plans for predicted impact on tumor control was performed. Factors associated with poor protocol compliance were studied, and outcome data were analyzed in relation to protocol compliance and radiotherapy quality.
RESULTS: At TMC review, 25.4% of the patients had noncompliant plans but none in which QARC-recommended changes had been made. At secondary review, 47% of noncompliant plans (12% overall) had deficiencies with a predicted major adverse impact on tumor control. Major deficiencies were unrelated to tumor subsite or to T or N stage (if N+), but were highly correlated with number of patients enrolled at the treatment center (< five patients, 29.8%; > or = 20 patients, 5.4%; P < .001). In patients who received at least 60 Gy, those with major deficiencies in their treatment plans (n = 87) had a markedly inferior outcome compared with those whose treatment was initially protocol compliant (n = 502): -2 years overall survival, 50% v 70%; hazard ratio (HR), 1.99; P < .001; and 2 years freedom from locoregional failure, 54% v 78%; HR, 2.37; P < .001, respectively.
CONCLUSION: These results demonstrate the critical importance of radiotherapy quality on outcome of chemoradiotherapy in head and neck cancer. Centers treating only a few patients are the major source of quality problems.
Treatment results for patients with localized, completely resected (Group I) alveolar rhabdomyosarcoma on Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols III and IV, 1984-1997: a report from the Children's Oncology Group
PURPOSE: To assess local control, event-free survival (EFS), and overall survival (OS) rates in 71 patients with localized, completely resected (Group I) alveolar rhabdomyosarcoma (ALV RMS) and their relation to radiation therapy (RT) on IRSG Protocols III and IV, 1984-1997. METHODS: Chart review and standard statistical procedures.
PATIENTS AND TUMORS: Patients were 1-18 years at diagnosis (median, 6 years). Primary tumor sites were extremity/trunk (N = 54), head/neck (N = 9), genitourinary tract (N = 7), and perineum (N = 1). Thirty patients received VA +/- C with RT; 41 received VA +/- C alone. RT was assigned, not randomized.
RESULTS: Fifty-four patients had Stage 1 (favorable site, any size) or Stage 2 (unfavorable site, < or = 5 cm) tumors. Eight-year EFS was 90%, with 100% local control for 17 patients given RT. Eight-year EFS was 88%, with 92% local control for 37 patients without RT; P = 0.52 for EFS comparisons, 0.3 for local control comparisons. In 17 Stage 3 patients (unfavorable site, tumors >5 cm, N0), 8-year EFS was 84% with 100% local control in 13 patients given RT; 8-year EFS was only 25% and local control 50% in 4 patients without RT. Local recurrence was the most common site of first failure in non-irradiated patients.
CONCLUSION: Patients with Stage 1-2 ALV RMS had slightly but statistically insignificantly improved local control, EFS, and OS rates when local RT was given. The need for local RT in Stage 1-2 patients deserves evaluation in a randomized study. Local control, EFS, and OS rates were significantly improved in Stage 3 patients receiving local RT.
Impact of tumor viability at second-look procedures performed before completing treatment on the Intergroup Rhabdomyosarcoma Study Group protocol IRS-IV, 1991-1997: a report from the children's oncology group
PURPOSES: The aims of the study were to compare results of clinical/radiographic studies before second-look procedures (SLP) with SLP specimens from patients with gross residual sarcoma at diagnosis and to relate tumor viability to outcome.
PATIENTS: Seventy-three patients underwent SLP before completing chemotherapy, with (n = 59) or without (n = 14) radiotherapy. Tumor sites were bladder/prostate (n = 27), head/orbit/parameningeal (n = 22), extremity/trunk (n = 14), and retroperitoneum/pelvis (n = 10).
RESULTS: Of 14 patients, 1 (7%) with clinical/radiographic complete response (CR) had viable tumor. Of 59 patients, 35 (59%) without CR had viable tumor. Five-year failure-free survival (FFS) rates were 81% in 37 patients without viable tumor and 53% in 36 patients with viable tumor (Cox proportional hazards adjusted P = .05). Five-year FFS rates were 67% in 15 patients with clear margins and 43% in 21 patients with tumor-involved margins (n = 18) or viable gross tumor (n = 3) (Cox proportional hazards adjusted P = .04). Five-year survival was 78% to 79% among 73 patients with and 333 patients without SLP during treatment.
CONCLUSIONS: Second-look procedures can show whether viable tumor is present and may be beneficial in selected patients with rhabdomyosarcoma. Disappearance of tumor (CR) usually correlated with no viable tumor at SLP. However, 41% of patients without CR had no viable tumor. Those without viable tumor had increased FFS but not survival compared to those with viable tumor.
Results of the Intergroup Rhabdomyosarcoma Study Group D9602 protocol, using vincristine and dactinomycin with or without cyclophosphamide and radiation therapy, for newly diagnosed patients with low-risk embryonal rhabdomyosarcoma: a report from the Soft
PURPOSE: Patients with localized, grossly resected, or gross residual (orbital only) embryonal rhabdomyosarcoma (ERMS) had 5-year failure-free survival (FFS) rates of 83% and overall survival rates of 95% on Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols III/IV. IRSG D9602 protocol (1997 to 2004) objectives were to decrease toxicity in similar patients by reducing radiotherapy (RT) doses and eliminating cyclophosphamide for the lowest-risk patients.
PATIENTS AND METHODS: Subgroup A patients (lowest risk, with ERMS, stage 1 group I/IIA, stage 1 group III orbit, stage 2 group I) received vincristine plus dactinomycin (VA). Subgroup B patients (ERMS, stage 1 group IIB/C, stage I group III nonorbit, stage 2 group II, stage 3 group I/II) received VA plus cyclophosphamide. Patients in group II/III received RT. Compared with IRS-IV, doses were reduced from 41.4 to 36 Gy for stage 1 group IIA patients and from 50 or 59 to 45 Gy for group III orbit patients.
RESULTS: Estimated 5-year FFS rates were 89% (95% CI, 84% to 92%) for subgroup A patients (n = 264) and 85% (95% CI, 74%, 91%) for subgroup B patients (n = 78); median follow-up: 5.1 years. Estimated 5-year FFS rates were 81% (95% CI, 68% to 90%) for patients with stage 1 group IIA tumors (n = 62) and 86% (95% CI, 76% to 92%) for patients with group III orbit tumors (n = 77).
CONCLUSION: Five-year FFS and OS rates were similar to those observed in comparable IRS-III patients, including patients receiving reduced RT doses, but were lower than in comparable IRS-IV patients receiving VA plus cyclophosphamide. Five-year FFS rates were similar among subgroups A and B patients.
PURPOSE: To identify the earliest practitioners of prostate brachytherapy.
METHODS AND MATERIALS: Review of contemporary literature.
RESULTS: Radiotherapy has been used for benign prostatic ailments as early as 1902. Prostate cancer was first treated by teletherapy in 1904. Several urologists, in Paris and Vienna, applied intracavitary radium for prostate disease in 1908-1909. We present evidence that Henri Minet was the first to perform prostate brachytherapy, as early as 1908.
CONCLUSION: Brachytherapy has been used to treat prostate cancer for more than a century.
Influence of noncompliance with radiation therapy protocol guidelines and operative bed recurrences for children with rhabdomyosarcoma and microscopic residual disease: a report from the Children's Oncology Group
PURPOSE: Postoperative radiation therapy (RT) is recommended for patients with rhabdomyosarcoma having microscopic disease. Sometimes RT dose/volume is reduced or omitted in an attempt to avoid late effects, particularly in young children. We reviewed operative bed recurrences to determine if noncompliance with RT protocol guidelines influenced local-regional control.
METHODS AND MATERIALS: All operative bed recurrences among 695 Group II rhabdomyosarcoma patients in Intergroup Rhabdomyosarcoma Study Group (IRS) I through IV were reviewed for deviation from RT protocol. Major/minor dose deviation was defined as >10% or 6-10% of the prescribed dose (40-60 Gy), respectively. Major/minor volume deviation was defined as tumor excluded from the RT field or treatment volume not covered by the specified margin (preoperative tumor volume and 2- to 5-cm margin), respectively. No RT was a major deviation.
RESULTS: Forty-six of 83 (55%) patients with operative bed recurrences did not receive the intended RT (39 major and 7 minor deviations). RT omission was the most frequent RT protocol deviation (19/46, 41%), followed by dose (17/46, 37%), volume (9/46, 20%), and dose and volume deviation (1/46, 2%). Only 7 operative bed recurrences occurred in IRS IV (5% local-regional failure) with only 3 RT protocol deviations. Sixty-three (76%) patients with recurrence died of disease despite retrieval therapy, including 13 of 19 nonirradiated children.
CONCLUSION: Over half of the operative bed recurrences were associated with noncompliance; omission of RT was the most common protocol deviation. Three fourths of children die when local-regional disease is not controlled, emphasizing the importance of RT in Group II rhabdomyosarcoma.
PURPOSE: Examination of Geoffrey Keynes's contributions to brachytherapy and the management of breast cancer.
METHODS AND MATERIALS: Review of publications and texts of the era.
RESULTS: In an era when radical mastectomy was accepted as standard treatment for breast cancer, Keynes demonstrated that brachytherapy (with or without local excision) was equally effective, while sparing body form and function.
CONCLUSIONS: Keynes established that conservative surgery, combined with radiotherapy, was the preferable option for managing breast cancer.
Pulmonary toxicity in Stage III non-small cell lung cancer patients treated with high-dose (74 Gy) 3-dimensional conformal thoracic radiotherapy and concurrent chemotherapy following induction chemotherapy: a secondary analysis of Cancer and Leukemia Grou
PURPOSE: Cancer and Leukemia Group B (CALGB) 30105 tested two different concurrent chemoradiotherapy platforms with high-dose (74 Gy) three-dimensional conformal radiotherapy (3D-CRT) after two cycles of induction chemotherapy for Stage IIIA/IIIB non-small cell lung cancer (NSCLC) patients to determine if either could achieve a primary endpoint of >18-month median survival. Final results of 30105 demonstrated that induction carboplatin and gemcitabine and concurrent gemcitabine 3D-CRT was not feasible because of treatment-related toxicity. However, induction and concurrent carboplatin/paclitaxel with 74 Gy 3D-CRT had a median survival of 24 months, and is the basis for the experimental arm in CALGB 30610/RTOG 0617/N0628. We conducted a secondary analysis of all patients to determine predictors of treatment-related pulmonary toxicity.
METHODS AND MATERIALS: Patient, tumor, and treatment-related variables were analyzed to determine their relation with treatment-related pulmonary toxicity.
RESULTS: Older age, higher N stage, larger planning target volume (PTV)1, smaller total lung volume/PTV1 ratio, larger V20, and larger mean lung dose were associated with increasing pulmonary toxicity on univariate analysis. Multivariate analysis confirmed that V20 and nodal stage as well as treatment with concurrent gemcitabine were associated with treatment-related toxicity. A high-risk group comprising patients with N3 disease and V20 >38% was associated with 80% of Grades 3-5 pulmonary toxicity cases.
CONCLUSIONS: Elevated V20 and N3 disease status are important predictors of treatment related pulmonary toxicity in patients treated with high-dose 3D-CRT and concurrent chemotherapy. Further studies may use these metrics in considering patients for these treatments.
Recent selected developments of the molecular science of prostate cancer (PrCa) biology and radiation oncology are reviewed. We present potential targets for molecular integration treatment strategies with radiation therapy (RT), and highlight potential strategies for molecular treatment in combination with RT for patient care. We provide a synopsis of the information to date regarding molecular biology of PrCa, and potential integrated research strategy for improved treatment of PrCa. Many patients with early-stage disease at presentation can be treated effectively with androgen ablation treatment, surgery, or RT. However, a significant portion of men are diagnosed with advanced stage/high-risk disease and these patients progress despite curative therapeutic intervention. Unfortunately, management options for these patients are limited and are not always successful including treatment for hormone refractory disease. In this review, we focus on molecules of extracellular matrix component, apoptosis, androgen receptor, RUNX, and DNA methylation. Expanding our knowledge of the molecular biology of PrCa will permit the development of novel treatment strategies integrated with RT to improve patient outcome.
Effect of radiotherapy techniques (IMRT vs. 3D-CRT) on outcome in patients with intermediate-risk rhabdomyosarcoma enrolled in COG D9803--a report from the Children's Oncology Group
PURPOSE: To compare the dosimetric parameters of intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) in patients with intermediate-risk rhabdomyosarcoma and to analyze their effect on locoregional control and failure-free survival (FFS).
METHODS AND MATERIALS: The study population consisted of 375 patients enrolled in the Children's Oncology Group protocol D9803 study, receiving IMRT or 3D-CRT. Dosimetric data were collected from 179 patients with an available composite plan. The chi-square test or Fisher's exact test was used to compare the patient characteristics and radiotherapy parameters between the two groups. The interval-to-event outcomes were estimated using the Kaplan-Meier method and compared using log-rank tests. Cox proportional hazards regression analysis was used to examine the effect of the treatment technique on FFS after adjusting for primary site and risk group.
RESULTS: The median follow-up time was 5.7 and 4.2 years for patients receiving 3D-CRT and IMRT, respectively. No differences in the 5-year failure of locoregional control (18% vs. 15%) or FFS (72% vs. 76%) rates were noted between the two groups. Multivariate analysis revealed no association between the two techniques and FFS. Patients with primary tumors in parameningeal sites were more likely to receive IMRT than 3D-CRT. IMRT became more common during the later years of the study. Patients receiving IMRT were more likely to receive >50 Gy, photon energy of 5 radiation fields than those who received 3D-CRT. The coverage of the IMRT planning target volume by the prescription dose was improved compared with the coverage using 3D-CRT with similar target dose heterogeneity.
CONCLUSIONS: IMRT improved the target dose coverage compared with 3D-CRT, although an improvement in locoregional control or FFS could not be demonstrated in this population. Future studies comparing the integral dose to nontarget tissue and late radiation toxicity between the two groups are warranted.