Stephanie A. Terezakis

Role of External Beam Radiotherapy in Patients With Advanced or Recurrent Nonanaplastic Thyroid Cancer: Memorial Sloan-Kettering Cancer Center Experience

PURPOSE External beam radiotherapy (EBRT) plays a controversial role in the management of nonanaplastic thyroid cancer. We reviewed our institutions outcomes in patients treated with EBRT for advanced or recurrent nonanaplastic thyroid cancer. METHODS AND MATERIALS Between April 1989 and April 2006, 76 patients with nonanaplastic thyroid cancer were treated with EBRT. The median follow-up for the surviving patients was 35.3 months (range, 4.2-178.4). The lesions were primarily advanced and included Stage T2 in 5 (7%), T3 in 5 (7%), and T4 in 64 (84%) patients. Stage N1 disease was present in 60 patients (79%). Distant metastases before EBRT were identified in 27 patients (36%). The median total EBRT dose delivered was 6,300 cGy. The histologic features examined included medullary in 12 patients (16%) and nonmedullary in 64 (84%). Of the 76 patients, 71 (93%) had undergone surgery before RT, and radioactive iodine treatment was used in 56 patients (74%). RESULTS The 2- and 4-year overall locoregional control rate for all histologic types was 86% and 72%, respectively, and the 2- and 4-year overall survival rate for all patients was 74% and 55%, respectively. No significant differences were found in locoregional control, overall survival, or distant metastases-free survival for patients with complete resection, microscopic residual disease, or gross residual disease. Grade 3 acute mucositis and dysphagia occurred in 14 (18%) and 24 (32%) patients, respectively. Late adverse toxicity was notable for percutaneous endoscopic gastrostomy tube use in 4 patients (5%). CONCLUSION The results of our study have shown that EBRT is effective for locoregional control of selected locally advanced or recurrent nonanaplastic thyroid malignancies, with acceptable acute toxicity.

Association between radiation dose to neuronal progenitor cell niches and temporal lobes and performance on neuropsychological testing in children: a prospective study

BACKGROUND Neurocognitive toxicity from radiation therapy (RT) for brain tumors may be related to damage to neural progenitor cells that reside in the subventricular zone and hippocampus. This prospective study examines the relationship between RT dose to neural progenitor cell niches, temporal lobes, and cerebrum and neurocognitive dysfunction following cranial irradiation. METHODS Standardized assessments of motor speed/dexterity, verbal memory, visual perception, vocabulary, and visuospatial working memory were conducted in 19 pediatric patients receiving cranial RT and 55 controls at baseline and 6, 15, and 27 months following completion of RT. Prescription doses ranged from 12 Gy to 59.4 Gy. Linear mixed effects regression model analyses were used to examine the relationships among neuropsychological performance, age, and radiation dose to the subventricular zone, hippocampus, temporal lobes, and cerebrum. RESULTS Performance on all neuropsychological tests, except vocabulary, was significantly reduced in patients relative to controls, particularly among younger children. Performance on motor speed/dexterity decreased with increasing dose to hippocampus (P < .05) and temporal lobes (P < .035). There was also a significant relationship between (i) reduced performance on verbal learning and increasing dose to the cerebrum (P = .022) and (ii) reduced performance on visual perception and increasing dose to the left temporal lobe (P = .038). There was no association between radiation dose to evaluated structures and performance on vocabulary or visuospatial working memory. CONCLUSIONS These prospective data demonstrate a significant association between increasing RT dose to hippocampus and temporal lobes and decline in neurocognitive skills following cranial irradiation. These findings have important implications for trials, including RTOG 0933 (hippocampal-sparing whole brain radiation therapy for brain metastases).

How Safe Is Safe? Risk in Radiotherapy

Receiving radiotherapy could be compared to taking an airplane flight. It can be an uncomfortable and scary process for some people, but it is often necessary to get from point A to point B. In the vast majority of cases, everything goes well. The recent front-page article in the New York Times (‘‘Radiation Offers New Cures, and Ways to Do Harm,’’ Sunday, January 24, 2010) highlights what can happen when the technologically advanced processes do not go well and leads us to ask the question: How safe are our patients? Although radiation oncology does not have the equivalent of the National Transportation Safety Board to provide data on the frequency of accidents, a back-of-the-envelope estimate can be made. The investigation by the New York Times suggests that there were 621 misadministrationsin New York State over an 8-year period from 2001 to 2009. This is likely a substantial underestimation of the problem, as noted by the reporters, because it is based largely on incidents serious enough to be reported to the New York State Department of Health. Nevertheless, if this error rate is representative of the nation as a whole, then, scaling to the U.S. population (308.6 million in the United States vs. 19.5 million in New York State), we calculate that there may be some 1,225 mistreatments per year. Although 1,225 is a large number, considering the large number of radiation treatments that are delivered each year, it is a small fraction of the total number of patients treated. To quantify how small, we estimate that there are currently approximately 740,000 patients in the United States receiving radiation each year. This is based on the fact that approximately 1.5 million people were diagnosed with cancer in 2009 (1), and approximately 50% of cancer patients receive radiation at some point according to statistics from the National Cancer Institute. The estimated rate of misadministrations for each patient is then approximately 0.2% (1 in 600). The question then is, how bad is 0.2%, given that the goal is zero?

An Evaluation of Departmental Radiation Oncology Incident Reports: Anticipating a National Reporting System

PURPOSE Systems to ensure patient safety are of critical importance. The electronic incident reporting systems (IRS) of 2 large academic radiation oncology departments were evaluated for events that may be suitable for submission to a national reporting system (NRS). METHODS AND MATERIALS All events recorded in the combined IRS were evaluated from 2007 through 2010. Incidents were graded for potential severity using the validated French Nuclear Safety Authority (ASN) 5-point scale. These incidents were categorized into 7 groups: (1) human error, (2) software error, (3) hardware error, (4) error in communication between 2 humans, (5) error at the human-software interface, (6) error at the software-hardware interface, and (7) error at the human-hardware interface. RESULTS Between the 2 systems, 4407 incidents were reported. Of these events, 1507 (34%) were considered to have the potential for clinical consequences. Of these 1507 events, 149 (10%) were rated as having a potential severity of ≥2. Of these 149 events, the committee determined that 79 (53%) of these events would be submittable to a NRS of which the majority was related to human error or to the human-software interface. CONCLUSIONS A significant number of incidents were identified in this analysis. The majority of events in this study were related to human error and to the human-software interface, further supporting the need for a NRS to facilitate field-wide learning and system improvement.

Mechanism of Inhibition of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase by d4TTP: an Equivalent Incorporation Efficiency Relative to the Natural Substrate dTTP

ABSTRACT Among the clinically used nucleoside analogue inhibitors that target human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), there is little detailed mechanistic information on the interactions of 2′,3′-didehydro-2′,3′-dideoxythymidine-5′-triphosphate (d4TTP) with the enzyme · primer-template complex and how these interactions compare with those of the natural substrate, dTTP. Using a pre-steady-state kinetic analysis, we found that d4TTP was incorporated by HIV-1 RT just as efficiently as dTTP during both DNA- and RNA-dependent DNA synthesis. To our knowledge, these results represent the first observation of a 3′-modified nucleoside triphosphate analogue that has an incorporation efficiency comparable to that observed for the natural substrate during DNA synthesis by HIV-1 RT. This information provides a mechanistic basis for understanding the inhibition of HIV-1 RT by d4TTP as well as insight into the clinically observed lack of d4T resistance mutations in HIV-1 RT isolated from AIDS patients.

[18F]FDG-positron emission tomography coregistration with computed tomography scans for radiation treatment planning of lymphoma and hematologic malignancies

PURPOSE Positron emission-tomography (PET) using 2-[(18)F]fluoro-2-deoxyglucose (FDG-PET) increases sensitivity and specificity of disease detection in lymphoma and thus is standard in lymphoma management. This study examines the effects of coregistering FDG-PET and computed tomography (CT) (PET/CT) scans on treatment planning for lymphoma patients. METHODS AND MATERIALS Twenty-nine patients (30 positive PET scans) underwent PET/CT treatment planning from July 2004 to February 2007 and were retrospectively studied. For each patient, gross tumor volume was blindly contoured on the CT-only and PET/CT studies by a radiation oncologist. Treatment plans were generated for both the CT-only and PET/CT planning target volumes (PTVs) for all patients. Normal tissue doses and PTV coverage were evaluated using dose--volume histograms for all sites. RESULTS Thirty-two treatment sites were evaluated. Twenty-one patients had non-Hodgkin lymphoma, 5 patients had Hodgkin lymphoma, and 3 patients had plasma cell neoplasms. Previously undetected FDG-avid sites were identified in 3 patients during PET/CT simulation, resulting in one additional treatment field. Due to unexpected PET/CT simulation findings, 2 patients did not proceed with radiation treatment. The addition of PET changed the volume of 23 sites (72%). The PTV was increased in 15 sites (47%) by a median of 11% (range, 6-40%) and reduced in 8 sites (25%) by a median of 20% (range, 6%-75%). In six (19%) replanned sites, the CT-based treatment plan would not have adequately covered the PTV defined by PET/CT. CONCLUSIONS Incorporation of FDG-PET into CT-based treatment planning for lymphoma patients resulted in considerable changes in management, volume definition, and normal tissue dosimetry for a significant number of patients.

A streamlined failure mode and effects analysis

PURPOSE Explore the feasibility and impact of a streamlined failure mode and effects analysis (FMEA) using a structured process that is designed to minimize staff effort. METHODS FMEA for the external beam process was conducted at an affiliate radiation oncology center that treats approximately 60 patients per day. A structured FMEA process was developed which included clearly defined roles and goals for each phase. A core group of seven people was identified and a facilitator was chosen to lead the effort. Failure modes were identified and scored according to the FMEA formalism. A risk priority number,RPN, was calculated and used to rank failure modes. Failure modes with RPN > 150 received safety improvement interventions. Staff effort was carefully tracked throughout the project. RESULTS Fifty-two failure modes were identified, 22 collected during meetings, and 30 from take-home worksheets. The four top-ranked failure modes were: delay in film check, missing pacemaker protocol/consent, critical structures not contoured, and pregnant patient simulated without the teams knowledge of the pregnancy. These four failure modes had RPN > 150 and received safety interventions. The FMEA was completed in one month in four 1-h meetings. A total of 55 staff hours were required and, additionally, 20 h by the facilitator. CONCLUSIONS Streamlined FMEA provides a means of accomplishing a relatively large-scale analysis with modest effort. One potential value of FMEA is that it potentially provides a means of measuring the impact of quality improvement efforts through a reduction in risk scores. Future study of this possibility is needed.

Intensity-modulated radiation therapy

Intensity‐modulated radiation therapy (IMRT) has found widespread use in the treatment of head and neck cancers. This technology allows for conformal dose distributions around a tumor target while a rapid dose fall‐off spares surrounding critical structures. The properties of IMRT are particularly suited for treating head and neck cancers due to the close proximity of dose‐limiting normal tissues allowing for potential dose escalation. Further studies are ongoing to investigate long‐term clinical outcomes and toxicity. J. Surg. Oncol. 2008;97:691–696.

Management of Pediatric Myxopapillary Ependymoma: The Role of Adjuvant Radiation

INTRODUCTION Myxopapillary ependymoma (MPE) is a rare tumor in children. The primary treatment is gross total resection (GTR), with no clearly defined role for adjuvant radiation therapy (RT). Published reports, however, suggest that children with MPE present with a more aggressive disease course. The goal of this study was to assess the role of adjuvant RT in pediatric patients with MPE. METHODS Sixteen patients with MPE seen at Johns Hopkins Hospital (JHH) between November 1984 and December 2010 were retrospectively reviewed. Fifteen of the patients were evaluable with a mean age of 16.8 years (range, 12-21 years). Kaplan-Meier curves and descriptive statistics were used for analysis. RESULTS All patients received surgery as the initial treatment modality. Surgery consisted of either a GTR or a subtotal resection (STR). The median dose of adjuvant RT was 50.4 Gy (range, 45-54 Gy). All patients receiving RT were treated at the involved site. After a median follow-up of 7.2 years (range, 0.75-26.4 years), all patients were alive with stable disease. Local control at 5 and 10 years was 62.5% and 30%, respectively, for surgery alone versus 100% at both time points for surgery and adjuvant RT. Fifty percent of the patients receiving surgery alone had local failure. All patients receiving STR alone had local failure compared to 33% of patients receiving GTR alone. One patient in the surgery and adjuvant RT group developed a distant site of recurrence 1 year from diagnosis. No late toxicity was reported at last follow-up, and neurologic symptoms either improved or remained stable following surgery with or without RT. CONCLUSIONS Adjuvant RT improved local control compared to surgery alone and should be considered after surgical resection in pediatric patients with MPE.

Radiotherapy for Rhabdomyosarcoma: Indications and Outcome

Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Improvements in the clinical outcomes of rhabdomyosarcoma have been secondary to the intensification and refinement of treatment investigated by the Intergroup Rhabdomyosarcoma Study Group. Advances in diagnostic imaging techniques have led to improvements in staging and contribute to precision in radiation field design. Radiation treatment has been integrated into the primary treatment of most patients with rhabdomyosarcoma. Each treatment site has special considerations with regards to prognosis, outcomes and potential morbidities that affect the choice of local therapy. Advanced radiotherapy techniques using conformal treatment with intensity-modulated radiotherapy and proton therapy are particularly advantageous for the treatment of sites close to critical structures, such as the head and neck and genitourinary system. Active investigation is underway to develop strategies to reduce the radiation dose and volume in an effort to minimise late toxicity and improve the therapeutic ratio.