Matthew M. Ladra

Preliminary Results of a Phase II Trial of Proton Radiotherapy for Pediatric Rhabdomyosarcoma

PURPOSE 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). PATIENTS AND METHODS 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 Childrens Oncology Group or European Pediatric Sarcoma Study Group protocols was allowed. All pathology and imaging were reviewed at the treating institution. RESULTS 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. CONCLUSION 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.

A dosimetric comparison of proton and intensity modulated radiation therapy in pediatric rhabdomyosarcoma patients enrolled on a prospective phase II proton study

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.

Proton therapy for pediatric and adolescent esthesioneuroblastoma

Esthesioneuroblastoma (EN) of the paranasal sinus comprises less than 3% of tumors of in pediatric and adolescent patients [1]. The collective adult literature indicates a critical role for radiotherapy in attaining cure [2], yet pediatric outcome data is limited. Radiation in pediatric patients with EN can cause significant morbidity due to the proximity of critical structures. Proton radiotherapy offers a potential dosimetric benefit that may improve long‐term survival and toxicity outcomes in the pediatric population [3].

Local Failure in Parameningeal Rhabdomyosarcoma Correlates With Poor Response to Induction Chemotherapy

BACKGROUND Local control remains a challenge in pediatric parameningeal rhabdomyosarcoma (PM-RMS), and survival after local failure (LF) is poor. Identifying patients with a high risk of LF is of great interest to clinicians. In this study, we examined whether tumor response to induction chemotherapy (CT) could predict LF in embryonal PM-RMS. METHODS We identified 24 patients with embryonal PM-RMS, age 2 to 18 years, with complete magnetic resonance imaging and gross residual disease after surgical resection. All patients received proton radiation therapy (RT), median dose 50.4 GyRBE (50.4-55.8 GyRBE). Tumor size was measured before initial CT and before RT. RESULTS With a median follow-up time of 4.1 years for survivors, LF was seen in 9 patients (37.5%). The median time from the initiation of CT to the start of RT was 4.8 weeks. Patients with LF had a similar initial (pre-CT) tumor volume compared with patients with local controlled (LC) (54 cm(3) vs 43 cm(3), P=.9) but a greater median volume before RT (pre-RT) (40 cm(3) vs 7 cm(3), P=.009) and a smaller median relative percent volume reduction (RPVR) in tumor size (0.4% vs 78%, P<.001). Older age (P=.05), larger pre-RT tumor volume (P=.03), and smaller RPVR (P=.003) were significantly associated with actuarial LF on univariate Cox analysis. CONCLUSIONS Poor response to induction CT appears to be associated with an increased risk of LF in pediatric embryonal PM-RMS.

Proton radiotherapy for pediatric sarcoma.

Pediatric sarcomas represent a distinct group of pathologies, with approximately 900 new cases per year in the United States alone. Radiotherapy plays an integral role in the local control of these tumors, which often arise adjacent to critical structures and growing organs. The physical properties of proton beam radiotherapy provide a distinct advantage over standard photon radiation by eliminating excess dose deposited beyond the target volume, thereby reducing both the dose of radiation delivered to non-target structures as well as the total radiation dose delivered to a patient. Dosimetric studies comparing proton plans to IMRT and 3D conformal radiation have demonstrated the superiority of protons in numerous pediatric malignancies and data on long-term clinical outcomes and toxicity is emerging. In this article, we review the existing clinical and dosimetric data regarding the use of proton beam radiation in malignant bone and soft tissue sarcomas.

Practice patterns of palliative radiation therapy in pediatric oncology patients in an international pediatric research consortium

The practice of palliative radiation therapy (RT) is based on extrapolation from adult literature. We evaluated patterns of pediatric palliative RT to describe regimens used to identify opportunity for future pediatric‐specific clinical trials.

Pencil‐beam scanning for pediatric rhabdomyosarcoma: Promise and precautions

Despite the proliferation of proton therapy centers worldwide, questions regarding the true benefit and safety of the modality remain. At present, a multitude of dosimetric studies clearly demonstrate that proton therapy has the ability to reduce dose to critical structures in the head and neck and other rhabdomyosarcoma (RMS) sites,1–3 but useful clinical data demonstrating a meaningful benefit in light of this dosimetric advantage are sparse. This is in part due to the scarcity of large proton cohorts with long-term follow-up, as well as the absence of comparable photon toxicity data from recent cooperative group trials and single-institution studies utilizingmodern photon techniques. In this issue of Pediatric Blood & Cancer, Weber et al. present the results of 39 pediatric parameningeal (PM) RMS patients treated with pencil-beam scanning (PBS) at the Paul Scherrer Institute (PSI) over the last 16 years.4 With a median follow-up of 47 months for survivors, their study represents the largest published series of PM-RMS treatedwithproton therapy.Clinical outcomes for this cohortofmainly embryonal (97%) PM-RMS patients were reasonable, with a 5-year progression-free survival of 72% and a local failure (LF) rate of 23% despite a relatively unfavorable patient population (72%, ≥5 cm; 74% with intracranial extension; 13% with M1 disease). In a joint prospective trial of pediatric RMS treated with protons at Massachusetts General Hospital (MGH) and MD Anderson Cancer Center (MDACC), the LF was also 23% for 27 patients with PM-RMS.1 Results from these two proton cohorts are in line with recent multi-institutional trials in which LF for PM-RMS was 19% in Intergroup Rhabdomyosarcoma Study-IV (IRS-IV) and D9803 (though up to 28% for those with CNS extension).5 Interestingly, multiple single-institution retrospective studies including PM-RMS treated with intensity-modulated radiation therapy (IMRT) have found LF rates ranging from 0% to 14%, though only one had follow-up of 5 years (Yang et al., LF= 14%).6,7 MGH also published a retrospective subset analysis of 24 embryonal PM-RMS patients treatedwith passive scatter protons, looking at the correlation between LF and response to induction chemotherapy.8 In this study, the LF rate for the entire cohort was 37%, raising concerns about the potential for an increased risk of local or marginal failures with protons, due to the rapid dose fall off and high sensitivity to anatomy changes. Close examination of the study patients found that all local recurrences were within the high radiation dose region without marginal failures, and no differences in target coverage were observed between local control (LC) and LF patients. The authors did find a strong correlation between response to induction chemotherapy and LF, with 100% LC in patients achieving a complete or partial response prior to radiation versus 46%LC in thosewith no response or progressive disease. In the MGH study, the objective response rate to induction chemotherapy (tumor reduction of >50%) was 42%, significantly lower than the 81%and85% seen in theCOG IRS-IV andD9803 studies, and the authors felt that the higher rate of LF seen was likely attributable to this poorer chemotherapeutic response.9,10 Ultimately, the current study by Weber et al. suggests that LF rates utilizing PBS for PM-RMS are acceptable. The potential benefit of proton therapy rests in the expected reduction in late toxicity. Weber et al. reported four occurrences of grade 3 late toxicities in three patients (8%), including three cataracts and one instance of hearing loss. There were no grade 4 or 5 late toxicities. The total incidence of grade 1 or 2 toxicitieswas 18% for endocrinopathies, 20% for facial hypoplasia, and 8% for visual complications. Similarly, in the prospective proton study fromMGH andMDACC, there were two occurrences of grade3 late toxicity (chronic otitis and retinopathy) and no grade 4 or 5 late toxicity in 21 evaluable patients with PM-RMS.11 The rates of grade 1 or 2 toxicity for endocrinopathies (14%), facial hypoplasia (10%), hearing (10%), and vision (5%) were also quite low. Direct comparison of these results to modern photon cohorts using IMRT is difficult, as most published photon series are small, retrospective in nature, and generally have included orbital patients in the toxicity rates.6,7,12 Similarly, in the PSI study, the data were retrospectively retrieved and as the authors state, toxicities may have been underreported. At present, it is still unclear that proton therapy actually results in lower rates of late toxicity for the PM-RMS population compared to well-planned and delivered IMRT, although results from PSI and MGH/MDACC are encouraging. As a final consideration, the apparent efficacy and safety of PBS used in this study adds an important piece to the growing literature in its support. Nearly all of the existing clinical data for protons in pediatric malignancies are derived from centers where passive scatter

Children's Oncology Group L991 final study report: Establishing an important benchmark for assessing late effects of trimodality care of pediatric patients treated for high grade gliomas

As advances are made in children’s cancer care, there will be growing numbers of adult survivors of pediatric cancer. In the United States, the number of adult survivors of pediatric cancers is approaching 300,000 (1). According to the National Cancer Institute’s Surveillance Epidemiology and End Result’s Cancer Statistics Review 1975-2008, the 5 year overall survival rate for children with brain tumors has risen from 58.8 % in 1975-1977 to 75% from 2001-2007 (2). With improved survivorship from childhood cancers, researchers have generated an abundance of literature pertaining to quality of life. A PubMed literature search with the terms “childhood cancer survivors quality of life” yields 420 citations. Studies focus on late effects in nearly every organ system, secondary malignancies, fertility, productivity, socioeconomic impact, and numerous other effects.

Proton therapy for central nervous system tumors in children

Proton therapy is a form of particle therapy with physical properties that provide a superior dose distribution compared to photons. The ability to spare healthy, developing tissues from low dose radiation with proton therapy is well known. The capability to decrease radiation exposure for children has been lauded as an important advance in pediatric cancer care, particularly for central nervous system (CNS) tumors. Favorable clinical outcomes have been reported and justify the increased cost and burden of this therapy. In this review, we summarize the current literature for proton therapy for pediatric CNS malignancies, with a focus on clinical outcomes to date.

Principles of Radiation Oncology

Radiation therapy plays an important role in the management of pediatric brain tumors. Despite advances in the fields of pediatric and medical oncology and neurosurgery, radiation is still a necessary treatment for local control and cure for most central nervous system (CNS) malignancies. Brain tumors, a heterogeneous group of diseases, together represent the most common disease site encountered by radiation oncologists. The eloquent areas from which these tumors arise makes the balance between the risks of life-altering side effects of radiation and the likelihood of local control and/or cure a difficult one to strike. While often we consider the main goal of our treatment to be cure, we must keep in mind the additional goal of allowing these children to grow and continue to live meaningful lives without a significant burden of major medical complications resulting from treatment. Technical and biological advances have enabled radiation oncologists to decrease the amount of healthy, uninvolved brain tissue and nearby organs that receive radiation. Trials that combine radiation with chemotherapy have allowed for a decrease in the dose and/or volume of radiation for some pediatric brain tumors. Neurosurgical advances have allowed for avoidance of radiation for selected tumors. In addition, advances in neuroradiology have led to better visualization of tumors and CNS structures. Advances in treatment planning software and the development of new radiation modalities have allowed for improvements in dose delivery.