This prospective phase II study was designed to assess disease control and to describe acute and late adverse effects of treatment with proton radiotherapy in children with rhabdomyosarcoma (RMS).
...Fifty-seven patients with localized RMS (age 21 years or younger) or metastatic embryonal RMS (age 2 to 10 years) were enrolled between February 2005 and August 2012. All patients were treated with chemotherapy based on either vincristine, actinomycin, and cyclophosphamide or vincristine, actinomycin, and ifosfamide-based chemotherapy and proton radiation. Surgical resection was based on tumor site and accessibility. Common Terminology Criteria for Adverse Events, Version 3.0, was used to assess and grade adverse effects of treatment. Concurrent enrollment onto Children's Oncology Group or European Pediatric Sarcoma Study Group protocols was allowed. All pathology and imaging were reviewed at the treating institution.
Median follow-up was 47 months (range, 14 to 102 months) for survivors. Five-year event-free survival (EFS), overall survival (OS), and local control (LC) were 69%, 78%, and 81%, respectively, for the entire cohort. The 5-year LC by risk group was 93% for low-risk and 77% for intermediate-risk disease. There were 13 patients with grade 3 acute toxicity and three patients with grade 3 late toxicity. There were no acute or late toxicities higher than grade 3.
Five-year LC, EFS, and OS rates were similar to those observed in comparable trials that used photon radiation. Acute and late toxicity rates were favorable. Proton radiation appears to represent a safe and effective radiation modality for pediatric RMS.
Cardiac toxicity due to conventional breast radiation therapy (RT) has been extensively reported, and it affects both the life expectancy and quality of life of affected women. Given the favorable ...oncologic outcomes in most women irradiated for breast cancer, it is increasingly paramount to minimize treatment side effects and improve survivorship for these patients. Proton RT offers promise in limiting heart dose, but the modality is costly and access is limited. Using cost-effectiveness analysis, we provide a decision-making tool to help determine which breast cancer patients may benefit from proton RT referral.
A Markov cohort model was constructed to compare the cost-effectiveness of proton versus photon RT for breast cancer management. The model was analyzed for different strata of women based on age (40 years, 50 years, and 60 years) and the presence or lack of cardiac risk factors (CRFs). Model entrants could have 1 of 3 health states: healthy, alive with coronary heart disease (CHD), or dead. Base-case analysis assumed CHD was managed medically. No difference in tumor control was assumed between arms. Probabilistic sensitivity analysis was performed to test model robustness and the influence of including catheterization as a downstream possibility within the health state of CHD.
Proton RT was not cost-effective in women without CRFs or a mean heart dose (MHD) <5 Gy. Base-case analysis noted cost-effectiveness for proton RT in women with ≥1 CRF at an approximate minimum MHD of 6 Gy with a willingness-to-pay threshold of $100,000/quality-adjusted life-year. For women with ≥1 CRF, probabilistic sensitivity analysis noted the preference of proton RT for an MHD ≥5 Gy with a similar willingness-to-pay threshold.
Despite the cost of treatment, scenarios do exist whereby proton therapy is cost-effective. Referral for proton therapy may be cost-effective for patients with ≥1 CRF in cases for which photon plans are unable to achieve an MHD <5 Gy.
To report, from a longitudinal study, cognitive outcome in pediatric patients treated with proton radiation therapy (PRT) for central nervous system (CNS) tumors.
Sixty patients receiving PRT for ...medulloblastoma (38.3%), gliomas (18.3%), craniopharyngioma (15.0%), ependymoma (11.7%), and other CNS tumors (16.7%) were administered age-appropriate measures of cognitive abilities at or near PRT initiation (baseline) and afterward (follow-up). Patients were aged ≥ 6 years at baseline to ensure consistency in neurocognitive measures.
Mean age was 12.3 years at baseline; mean follow-up interval was 2.5 years. Treatment included prior surgical resection (76.7%) and chemotherapy (61.7%). Proton radiation therapy included craniospinal irradiation (46.7%) and partial brain radiation (53.3%). At baseline, mean Wechsler Full Scale IQ was 104.6; means of all 4 Index scores were also in the average range. At follow-up, no significant change was observed in mean Wechsler Full Scale IQ, Verbal Comprehension, Perceptual Reasoning/Organization, or Working Memory. However, Processing Speed scores declined significantly (mean 5.2 points), with a significantly greater decline for subjects aged <12 years at baseline and those with the highest baseline scores. Cognitive outcome was not significantly related to gender, extent of radiation, radiation dose, tumor location, histology, socioeconomic status, chemotherapy, or history of surgical resection.
Early cognitive outcomes after PRT for pediatric CNS tumors are encouraging, compared with published outcomes from photon radiation therapy.
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► Kaolinite is a good adsorbent for ciprofloxacin (Cip) in aqueous solution. ► Cation exchange is the dominant mechanism for Cip adsorption. ► Cip adsorption is on the external ...surfaces of kaolinite. ► Solution pH had strong influence on Cip adsorption.
As one of the most important soil components, kaolinite plays a vital role in transport and retention of ionizable contaminants in soils of warm and wet climate. Ciprofloxacin (Cip) is a second generation fluoroquinolone (FQ) antibiotic of high use. It has high aqueous solubility under high and low pH conditions and higher stability in soil system. In this study, the interactions between Cip and kaolinite in aqueous solution were investigated by batch experiments, XRD and FTIR analyses. Quantitative correlation between the exchangeable cations desorbed and Cip adsorbed confirmed experimentally that cation exchange was the dominant mechanism of Cip adsorption on kaolinite. Fitting of experimental data to the cation exchange model resulted in a selectivity coefficient of 27, suggesting a strong affinity of Cip on negatively charged kaolinite surfaces. At the adsorption maximum 190–200
Å
2 was available per Cip molecule, much larger than the Cip molecule area, confirming charge-limited instead of surface-limited Cip adsorption. The invariable d-spacing after uptake of different amounts of Cip suggested that the adsorption of Cip was on the external surfaces of kaolinite. As solution pH increased beyond 8, the amount of Cip adsorption decreased significantly and reached close to zero at pH 11. The high adsorption rate constant due to surface adsorption instead of intercalation and the wide distribution of kaolinite in different soils suggest that the fate and transport of Cip may be governed by the transport of colloidal sized clays.
Abstract Background Pediatric rhabdomyosarcoma (RMS) is highly curable, however, cure may come with significant radiation related toxicity in developing tissues. Proton therapy (PT) can spare excess ...dose to normal structures, potentially reducing the incidence of adverse effects. Methods Between 2005 and 2012, 54 patients were enrolled on a prospective multi-institutional phase II trial using PT in pediatric RMS. As part of the protocol, intensity modulated radiation therapy (IMRT) plans were generated for comparison with clinical PT plans. Results Target coverage was comparable between PT and IMRT plans with a mean CTV V95 of 100% for both modalities ( p = 0.82). However, mean integral dose was 1.8 times higher for IMRT (range 1.0–4.9). By site, mean integral dose for IMRT was 1.8 times higher for H&N ( p < 0.01) and GU ( p = 0.02), 2.0 times higher for trunk/extremity ( p < 0.01), and 3.5 times higher for orbit ( p < 0.01) compared to PT. Significant sparing was seen with PT in 26 of 30 critical structures assessed for orbital, head and neck, pelvic, and trunk/extremity patients. Conclusions Proton radiation lowers integral dose and improves normal tissue sparing when compared to IMRT for pediatric RMS. Correlation with clinical outcomes is necessary once mature long-term toxicity data are available.
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.
Ependymoma is treated with maximal surgical resection and localized radiotherapy. Minimizing unnecessary exposure to radiation is of paramount importance for young children. Proton radiotherapy (PRT) ...spares healthy tissues outside the target region, but reports of clinical outcomes are scarce. We report outcomes for 70 patients treated with PRT for intracranial ependymoma.
Seventy patients with localized ependymoma treated with involved-field PRT at the Massachusetts General Hospital between October 2000 and February 2011 were included.
Median age at diagnosis was 38 months (range, 3 mo-20 y). Nineteen (27%) patients had supratentorial ependymoma and 51(73%) had infratentorial ependymoma. Forty-six (66%) had gross total resection (GTR), and 24 (34%) had subtotal resection (STR). At a median follow-up of 46 months, 3-year local control, progression-free survival, and overall survival were 83%, 76%, and 95%, respectively. STR was significantly associated with worse progression-free survival (54% vs 88%, P = .001) and overall survival (90% vs 97% for GTR, P = .001). In a subset of patients (n = 14), mean intelligence was 108.5 at baseline and 111.3 after mean 2.05 years of follow-up. In a larger group of patients (n = 28), overall adaptive skills were 100.1 at baseline and 100.8 after 2.21 years of follow-up. Few patients developed evidence of growth hormone deficiency, hypothyroidism, or hearing loss.
Outcomes for children treated with PRT compare favorably with the literature. STR correlated with inferior outcome. The young age at diagnosis and the proximity of critical structures in patients with ependymoma make PRT an ideal radiation modality.
To report the clinical outcome and late side effect profile of proton radiotherapy in the treatment of children with parameningeal rhabdomyosarcoma (PM-RMS).
Seventeen consecutive children with ...PM-RMS were treated with proton radiotherapy at Massachusetts General Hospital between 1996 and 2005. We reviewed the medical records of all patients and asked referring physicians to report specific side effects of interest.
Median patient age at diagnosis was 3.4 years (range, 0.4-17.6). Embryonal (n = 11), alveolar (n = 4), and undifferentiated (n = 2) histologies were represented. Ten patients (59%) had intracranial extension. Median prescribed dose was 50.4 cobalt gray equivalents (GyRBE) (range, 50.4-56.0 GyRBE) delivered in 1.8-2.0-GyRBE daily fractions. Median follow-up was 5.0 years for survivors. The 5-year failure-free survival estimate was 59% (95% confidence interval, 33-79%), and overall survival estimate was 64% (95% confidence interval, 37-82%). Among the 7 patients who failed, sites of first recurrence were local only (n = 2), regional only (n = 2), distant only (n = 2), and local and distant (n = 1). Late effects related to proton radiotherapy in the 10 recurrence-free patients (median follow-up, 5 years) include failure to maintain height velocity (n = 3), endocrinopathies (n = 2), mild facial hypoplasia (n = 7), failure of permanent tooth eruption (n = 3), dental caries (n = 5), and chronic nasal/sinus congestion (n = 2).
Proton radiotherapy for patients with PM-RMS yields tumor control and survival comparable to that in historical controls with similar poor prognostic factors. Furthermore, rates of late effects from proton radiotherapy compare favorably to published reports of photon-treated cohorts.
The unique physical and biological characteristics of proton and carbon ions allow for improved sparing of normal tissues, decreased integral dose to the body, and increased biological effect through ...high linear energy transfer. These properties are particularly useful for sarcomas given their histology, wide array of locations, and age of diagnosis. This review summarizes the literature and describes the clinical situations in which these heavy particles have advantages for treating sarcomas.
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