Department of Radiation Oncology Faculty Papers

Early results of prostate cancer radiation therapy: an analysis with emphasis on research strategies to improve treatment delivery and outcomes.

Kosj Yamoah et al. — Mon, 28 Jan 2013 07:59:46 PST

ABSTRACT: BACKGROUND: There is scant data regarding disease presentation and treatment response among black men living in Africa. In this study we evaluate disease presentation and early clinical outcomes among Ghanaian men with prostate cancer treated with external beam radiotherapy (EBRT). METHODS: A total of 379 men with prostate cancer were referred to the National Center for Radiotherapy, Ghana from 2003 to 2009. Data were collected regarding patient-and tumor-related factors such as age, prostate specific antigen (PSA), Gleason score (GS), clinical stage (T), and use of androgen deprivation therapy (ADT). For patients who received EBRT, freedom from biochemical failure (FFbF) was evaluated using the Kaplan-Meier method. RESULTS: Of 379 patients referred for treatment 69.6% had initial PSA (iPSA) >20 ng/ml, and median iPSA was 39.0 ng/ml. A total of 128 men, representing 33.8% of the overall cohort, were diagnosed with metastatic disease at time of referral. Among patients with at least 2 years of follow-up after EBRT treatment (n=52; median follow-up time: 38.9 months), 3- and 5-year actuarial FFbF was 73.8% and 65.1% respectively. There was significant association between higher iPSA and GS (8--10 vs.

Larynx-sparing techniques using intensity-modulated radiation therapy for oropharyngeal cancer.

Voichita Bar-Ad et al. — Mon, 26 Nov 2012 07:10:53 PST

The purpose of the current study was to explore whether the laryngeal dose can be reduced by using 2 intensity-modulated radiation therapy (IMRT) techniques: whole-neck field IMRT technique (WF-IMRT) vs. junctioned IMRT (J-IMRT). The effect on planning target volumes (PTVs) coverage and laryngeal sparing was evaluated. WF-IMRT technique consisted of a single IMRT plan, including the primary tumor and the superior and inferior neck to the level of the clavicular heads. The larynx was defined as an organ at risk extending superiorly to cover the arytenoid cartilages and inferiorly to include the cricoid cartilage. The J-IMRT technique consisted of an IMRT plan for the primary tumor and the superior neck, matched to conventional antero-posterior opposing lower neck fields at the level of the thyroid notch. A central block was used for the anterior lower neck field at the level of the larynx to restrict the dose to the larynx. Ten oropharyngeal cancer cases were analyzed. Both the primary site and bilateral regional lymphatics were included in the radiotherapy targets. The averaged V95 for the PTV57.6 was 99.2% for the WF-IMRT technique compared with 97.4% (p = 0.02) for J-IMRT. The averaged V95 for the PTV64 was 99.9% for the WF-IMRT technique compared with 98.9% (p = 0.02) for J-IMRT and the averaged V95 for the PT70 was 100.0% for WF-IMRT technique compared with 99.5% (p = 0.04) for J-IMRT. The averaged mean laryngeal dose was 18 Gy with both techniques. The averaged mean doses within the matchline volumes were 69.3 Gy for WF-MRT and 66.2 Gy for J-IMRT (p = 0.03). The WF-IMRT technique appears to offer an optimal coverage of the target volumes and a mean dose to the larynx similar with J-IMRT and should be further evaluated in clinical trials.

Radiation Oncology at Thomas Jefferson University: A Specialty Emerges as a Department Evolves

Eric Gressen MD et al. — Fri, 01 Jun 2012 06:57:48 PDT

Jefferson Radiation Oncology has maintained over fifty years of excellence led by only four chairmen. Dr Kramer after receiving his medical training inLondonled the department into the modern megavoltage era while creating the first independent academic radiation oncology department in the country. He was well-respected nationally as a leader and advocate for the specialty and he mastered the execution of progressive ideas that have raised the standard for the profession. The creation of the Radiation Therapy Oncology Group (RTOG) was critical in developing trials to expand the management and treatment of malignancy. The Patterns of Care Study (PCS) educated the masses on providing optimal care to patients by comparing strategies for the management and treatment of carcinoma through surveys across theUnited States. Dr Mansfield expanded his mentor’s vision and together they developed the Bodine Centre for Cancer Treatment, a new state-of-the-art building for cancer treatment. He helped to dispel common misconceptions, thus raising the social consciousness for managing and treating the underserved community. Dr Curran grew the RTOG to new levels in trial development, funding, and respect both domestically and internationally. He helped develop new technology in the department and markedly expanded the Jefferson Cancer Network. Finally, Dr Dicker set a new course for the department with biologically-driven radiation therapy keepingJeffersonat the forefront of new technology for the diagnosis and treatment of malignancy.

Multiple courses of stereotactic re-irradiation in recurrent oligodendroglioma: a case report.

Shannon Fogh et al. — Thu, 23 Feb 2012 10:49:25 PST

INTRODUCTION: High grade gliomas are an insidious disease associated with an extremely poor prognosis. The role of re-irradiation for recurrent gliomas is unclear but several retrospective studies have indicated mild toxicity and modest outcomes with this regimen. With subsequent progression, it is unclear what options remain and more radiotherapy is rarely offered for fear of surpassing normal central nervous system tissue tolerance and causing significant side effects without significant benefit.

CASE PRESENTATION: In this report, we describe a 37-year-old Caucasian male initially diagnosed with a grade IV oligodendroglioma, who received multiple courses of re-irradiation and experienced a survival of 10 years with minimal cognitive or neurologic deficits.

CONCLUSION: Significant toxicity with multiple courses of radiation does not always occur. Re-irradiation should be considered in a salvage setting.

Distinguishing post-treatment changes from recurrent disease in cholangiocarcinoma: a case report.

Timothy N Showalter et al. — Fri, 17 Feb 2012 13:16:10 PST

INTRODUCTION: Three-dimensional techniques for radiotherapy have expanded possibilities for partial volume liver radiotherapy. Characteristic, transient radiographic changes can occur in the absence of clinical radiation-induced liver disease after hepatic radiotherapy and must be distinguished from local recurrence. CASE PRESENTATION: In this report, we describe computed tomography changes after chemoradiotherapy for cholangiocarcinoma as an example of collaboration to determine the clinical significance of the radiographic finding. CONCLUSION: Because of improved three-dimensional, conformal radiotherapy techniques, consultation across disciplines may be necessary to interpret post-treatment imaging findings.

Department of Radiation Oncology and Kimmel Cancer Center, Thomas jefferson University, The intronic G13964C variant in p53 is not a high-risk mutation in familial breast cancer in Australia.

Anna Marsh et al. — Fri, 17 Feb 2012 13:16:09 PST

BACKGROUND: Mutations in BRCA1 and BRCA2 account for approximately 50% of breast cancer families with more than four affected cases, whereas exonic mutations in p53, PTEN, CHK2 and ATM may account for a very small proportion. It was recently reported that an intronic variant of p53--G13964C--occurred in three out of 42 (7.1%) 'hereditary' breast cancer patients, but not in any of 171 'sporadic' breast cancer control individuals (P = 0.0003). If this relatively frequent occurrence of G13964C in familial breast cancer and absence in control individuals were confirmed, then this would suggest that the G13964C variant plays a role in breast cancer susceptibility. METHOD: We genotyped 71 familial breast cancer patients and 143 control individuals for the G13964C variant using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analysis. RESULTS: Three (4.2%; 95% confidence interval [CI] 0-8.9%) G13964C heterozygotes were identified. The variant was also identified in 5 out of 143 (3.5%; 95% CI 0.6-6.4%) control individuals without breast cancer or a family history of breast cancer, however, which is no different to the proportion found in familial cases (P = 0.9). CONCLUSION: The present study would have had 80% power to detect an odds ratio of 4.4, and we therefore conclude that the G13946C polymorphism is not a 'high-risk' mutation for familial breast cancer.

Phase i study of 'dose-dense' pemetrexed plus carboplatin/radiotherapy for locally advanced non-small cell lung carcinoma.

Xinglei Shen et al. — Fri, 17 Feb 2012 13:16:07 PST

BACKGROUND: This phase I study investigates the feasibility of carboplatin plus dose-dense (q2-week) pemetrexed given concurrently with radiotherapy (XRT) for locally advanced and oligometastatic non-small cell lung cancer (NSCLC).

METHODS: Eligible patients had Stage III or IV (oligometastatic) NSCLC. Patients received XRT to 63 Gy in standard fractionation. Patients received concurrent carboplatin (AUC = 6) during weeks 1 and 5 of XRT, and pemetrexed during weeks 1, 3, 5, and 7 of XRT. The starting dose level (level 1) of pemetrexed was 300 mg/m2. Following the finding of dose limiting toxicity (DLT) in dose level 1, an amended dose level (level 1A) continued pemetrexed at 300 mg/m2, but with involved field radiation instead of extended nodal irradiation. Consolidation consisted of carboplatin (AUC = 6) and pemetrexed (500 mg/m2) q3 weeks × 2 -3 cycles.

RESULTS: Eighteen patients were enrolled. Fourteen patients are evaluable for toxicity analysis. Of the initial 6 patients treated on dose level 1, two experienced DLTs (one grade 4 sepsis, one prolonged grade 3 esophagitis). There was one DLT (grade 5 pneumonitis) in the 8 patients treated on dose level 1A. In 16 patients evaluable for response (4 with oligometastatic stage IV disease and 12 with stage III disease), the median follow-up time is 17.8 months. Thirteen of 16 patients had in field local regional response. The actuarial median survival time was 28.6 months in all patients and 34.7 months (estimated) in stage III patients.

CONCLUSIONS: Concurrent carboplatin with dose-dense (q2week) pemetrexed at 300 mg/m2 with involved field XRT is feasible and encouraging in patients with locally advanced and oligometastatic NSCLC.

Differential regulation of p53 function by the N-terminal ΔNp53 and Δ113p53 isoforms in zebrafish embryos.

William R Davidson et al. — Tue, 14 Feb 2012 11:18:56 PST

BACKGROUND: The p53 protein family coordinates stress responses of cells and organisms. Alternative promoter usage and/or splicing of p53 mRNA gives rise to at least nine mammalian p53 proteins with distinct N- and C-termini which are differentially expressed in normal and malignant cells. The human N-terminal p53 variants contain either the full-length (FL), or a truncated (ΔN/Δ40) or no transactivation domain (Δ133) altogether. The functional consequences of coexpression of the different p53 isoforms are poorly defined. Here we investigated functional aspects of the zebrafish ΔNp53 ortholog in the context of FLp53 and the zebrafish Δ133p53 ortholog (Δ113p53) coexpressed in the developing embryo.

RESULTS: We cloned the zebrafish ΔNp53 isoform and determined that ionizing radiation increased expression of steady-state ΔNp53 and Δ113p53 mRNA levels in zebrafish embryos. Ectopic ΔNp53 expression by mRNA injection caused hypoplasia and malformation of the head, eyes and somites, yet partially counteracted lethal effects caused by concomitant expression of FLp53. FLp53 expression was required for developmental aberrations caused by ΔNp53 and for ΔNp53-dependent expression of the cyclin-dependent kinase inhibitor 1A (CDKN1A, p21, Cip1, WAF1). Knockdown of p21 expression markedly reduced the severity of developmental malformations associated with ΔNp53 overexpression. By contrast, forced Δ113p53 expression had little effect on ΔNp53-dependent embryonal phenotypes. These functional attributes were shared between zebrafish and human ΔNp53 orthologs ectopically expressed in zebrafish embryos. All 3 zebrafish isoforms could be coimmunoprecipitated with each other after transfection into Saos2 cells.

CONCLUSIONS: Both alternative N-terminal p53 isoforms were expressed in developing zebrafish in response to cell stress and antagonized lethal effects of FLp53 to different degrees. However, in contrast to Δ113p53, forced ΔNp53 expression itself led to developmental defects which depended, in part, on p21 transactivation. In contrast to FLp53, the developmental abnormalities caused by ΔNp53 were not counteracted by concomitant expression of Δ113p53.

From survival to survivorship: late side effects become an issue in high-grade glioma.

Yaacov R Lawrence et al. — Thu, 04 Nov 2010 07:05:13 PDT

“For many patients, controlling neurological symptoms, preventing cognitive dysfunction and maintaining functional independence are just as important as prolonging survival.”

Splenic infarction: an update on William Osler's observations.

Yaacov R Lawrence, MA MBBS MRCP et al. — Thu, 04 Nov 2010 06:54:42 PDT

BACKGROUND: Osler taught that splenic infarction presents with left upper abdominal quadrant pain, tenderness and swelling accompanied by a peritoneal friction rub. Splenic infarction is classically associated with bacterial endocarditis and sickle cell disease.

OBJECTIVES: To describe the contemporary experience of splenic infarction.

METHODS: We conducted a chart review of inpatients diagnosed with splenic infarction in a Jerusalem hospital between 1990 and 2003.

RESULTS: We identified 26 cases with a mean age of 52 years. Common causes were hematologic malignancy (six cases) and intracardiac thrombus (five cases). Only three cases were associated with bacterial endocarditis. In 21 cases the splenic infarction brought a previously undiagnosed underlying disease to attention. Only half the subjects complained of localized left-sided abdominal pain, 36% had left-sided abdominal tenderness; 31% had no signs or symptoms localized to the splenic area, 36% had fever, 56% had leukocytosis and 71% had elevated lactate dehydrogenase levels. One splenectomy was performed and all patients survived to discharge. A post hoc analysis demonstrated that single infarcts were more likely to be associated with fever (20% vs. 63%, p < 0.05) and leukocytosis (75% vs. 33%, P = 0.06)

CONCLUSIONS: The clinical presentation of splenic infarction in the modern era differs greatly from the classical teaching, regarding etiology, signs and symptoms. In patients with unexplained splenic infarction, investigation frequently uncovers a new underlying diagnosis.

Chart Rounds in the Digital Age: A Survey of North American Institutions

M. A. Whiton et al. — Thu, 04 Nov 2010 06:31:56 PDT

Purpose:

Recent reports of medical errors in radiaKon treatment delivery have emphasized the importance of quality assurance (QA) pracKces. Strict guidelines exist for medical physics QA, but not for QA procedures as applied to clinicians. We sought to document how clinical quality assurance (QA) meeKngs or “chart rounds” are performed across academic North American RadiaKon Oncology departments.

IMRT commissioning: multiple institution planning and dosimetry comparisons, a report from AAPM Task Group 119.

Gary A Ezzell et al. — Wed, 06 Jan 2010 07:11:25 PST

AAPM Task Group 119 has produced quantitative confidence limits as baseline expectation values for IMRT commissioning. A set of test cases was developed to assess the overall accuracy of planning and delivery of IMRT treatments. Each test uses contours of targets and avoidance structures drawn within rectangular phantoms. These tests were planned, delivered, measured, and analyzed by nine facilities using a variety of IMRT planning and delivery systems. Each facility had passed the Radiological Physics Center credentialing tests for IMRT. The agreement between the planned and measured doses was determined using ion chamber dosimetry in high and low dose regions, film dosimetry on coronal planes in the phantom with all fields delivered, and planar dosimetry for each field measured perpendicular to the central axis. The planar dose distributions were assessed using gamma criteria of 3%/3 mm. The mean values and standard deviations were used to develop confidence limits for the test results using the concept confidence limit = /mean/ + 1.96sigma. Other facilities can use the test protocol and results as a basis for comparison to this group. Locally derived confidence limits that substantially exceed these baseline values may indicate the need for improved IMRT commissioning.

Initial Tumor Metabolic Parameters (Maximum SUV and Metabolic Volume) Predict Death From Lung Cancer and Rapid SUV Decline is Associated with Local Control

Maria Werner-Wasik et al. — Wed, 16 Dec 2009 10:15:59 PST

Factors associated with local failure and death from lung cancer were evaluated based on post-treatment FDG-PET imaging in patients (pts) with non-small cell lung cancer (NSCLC).

PET-CT scans were obtained 6-8 weeks after thoracic RT and approximately every 3 months thereafter.

Combination of vandetanib, radiotherapy, and irinotecan in the LoVo human colorectal cancer xenograft model.

Phyllis Wachsberger et al. — Tue, 08 Dec 2009 10:14:18 PST

PURPOSE: The tumor growth kinetics of the human LoVo colorectal xenograft model was assessed in response to vandetanib, an orally available receptor tyrosine kinase inhibitor, radiotherapy (RT), or irinotecan (CPT-11), as single therapies and in combination. METHODS AND MATERIALS: LoVo cells were injected subcutaneously into the right hind limb (5 x 10(6) cells in 100 microL phosphate-buffered saline) of athymic NCR NUM mice and tumors were grown to a volume of 200-300 mm(3) before treatment. Vandetanib was administered at 50 mg/kg daily orally for 14 days starting on Day 1. RT was given as three fractions (3 x 3 Gy) on Days 1, 2, and 3. CPT-11 was given at 15 mg/kg intraperitoneally on Days 1 and 3. Tumor volumes were measured on a daily basis and calculated by measuring tumor diameters with digital calipers in two orthogonal dimensions. RESULTS: All three single treatments (vandetanib, CPT-11, and radiation) significantly slowed LoVo colorectal tumor growth. Vandetanib significantly increased the antitumor effects of CPT-11 and radiation when given in combination with either of these treatments. These treatment combinations resulted in a slow tumor growth rate during the 2 weeks of vandetanib administration. The triple combination of vandetanib, CPT-11, and radiation produced the most marked improvement in response as observed by measurable shrinkage of tumors during the first week of treatment. CONCLUSIONS: The tumor growth delay kinetics observed in this study of the LoVo colorectal model suggest concurrent and sustained post-sequencing of vandetanib with cytotoxic therapy may be beneficial in tumors of this type.

Recent trends in soft-tissue infection imaging.

Nicholas Petruzzi, MD et al. — Thu, 01 Oct 2009 08:36:35 PDT

This article discusses the current techniques and future directions of infection imaging with particular attention to respiratory, central nervous system, abdominal, and postoperative infections. The agents currently in use localize to areas of infection and inflammation. An infection-specific imaging agent would greatly improve the utility of scintigraphy in imaging occult infections. The superior spatial resolution of (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) and its lack of reliance on a functional immune system, gives this agent certain advantages over the other radiopharmaceuticals. In respiratory tract infection imaging, an important advancement would be the ability to quantitatively delineate lung inflammation, allowing one to monitor the therapeutic response in a variety of conditions. Current studies suggest PET should be considered the most accurate quantitative method. Scintigraphy has much to offer in localizing abdominal infection as well as inflammation. We may begin to see a gradual increase in the usage of (18)F-FDG-PET in detecting occult abdominal infections. Commonly used modalities for imaging inflammatory bowel disease are scintigraphy with (111)In-oxine/(99m)Tc-HMPAO labeled autologous white blood cells. The literature on central nervous system infection imaging is relatively scarce. Few clinical studies have been performed and numerous new agents have been developed for this use with varying results. Further studies are needed to more clearly delineate the future direction of this field. In evaluating the postoperative spine, (99m)Tc-ciprofloxacin single-photon emission computed tomography (SPECT) was reported to be >80% sensitive in patients more than 6 months after surgery. FDG-PET has also been suggested for this purpose and may play a larger role than originally thought. It appears PET/computed tomography (CT) is gaining support, especially in imaging those with fever of unknown origin or nonfunctional immune systems. Although an infection-specific agent is lacking, the development of one would greatly advance our ability to detect, localize, and quantify infections. Overall, imaging such an agent via SPECT/CT or PET/CT will pave the way for greater clinical reliability in the localization of infection.

Genomic biomarkers for molecular imaging: predicting the future.

Mathew L. Thakur — Wed, 30 Sep 2009 13:04:01 PDT

Over the past few decades, great strides have been made in anatomical imaging of disease that has led to their diagnosis with minimal invasion. Despite these advances, diseases such as cancer continue to take one human life every minute in the United States. Complimentary approaches that pertain directly to the genesis of the disease might contribute to its early diagnosis and subsequent management. In cancer, an array of molecular abnormalities leading to the modulations in expression of key proteins important in the cellular signaling pathways and cell proliferation has been identified. These specific disease fingerprints, biomarkers, are overexpressed on malignant cell surfaces or within the cytoplasm, and they provide unique targets that are promising for improving cancer diagnosis and therapy. We and others have designed, synthesized, and evaluated some novel probes specific for those oncogenes and oncogene product biomarkers for PET and SPECT molecular imaging of certain types of cancers. This article briefly describes this approach and gives specific examples that depict the ability of molecular imaging to detect occult lesions not detectable by current scintigraphic approaches. The article also outlines a few examples predicting other possible applications of targeting such specific probes not yet used.

In Reply to Dr. Hurkmans et al.

Ying Xiao, PhD et al. — Mon, 21 Sep 2009 09:58:41 PDT

A real-time prostate cancer detection technique using needle insertion force and patient-specific criteria during percutaneous intervention

Kaiguo Yan et al. — Thu, 06 Aug 2009 06:34:10 PDT

In this article, the authors present a novel real-time cancer detection technique by using needle insertion forces in conjunction with patient-specific criteria during percutaneous interventions. Needle insertion experiments and pathological analysis were performed for developing a computer-aided detection (CAD) model. Backward stepwise regression method was performed to identify the statistically significant patient-specific factors. A baseline force model was then developed using these significant factors. The threshold force model that estimated the lower bound of the cancerous tissue forces was formulated by adding an adjustable classifier to the baseline force model. Trade-off between sensitivity and specificity was obtained by varying the threshold value of the classifier, from which the receiver-operating characteristic (ROC) curve was generated. Sequential quadratic programming was used to optimize the CAD model by maximizing the area under the ROC curve (AUC) using a set of model-training patient data. When the CAD model was evaluated using an independent set of model-validation patient data, an AUC of 0.90 was achieved. The feasibility of cancer detection in real time during percutaneous interventions was established.

Radioactive seed immobilization techniques for interstitial brachytherapy

K. Yan et al. — Tue, 23 Jun 2009 07:09:36 PDT

Purpose In prostate brachytherapy, seeds can detach from their deposited sites and move locally in the pelvis or migrate to distant sites including the pulmonary and cardiac regions. Undesirable consequences of seed migration include inadequate dose coverage of the prostate and tissue irradiation effects at the site of migration. Thus, it is clinically important to develop seed immobilization techniques.

Methods We first analyze the possible causes for seed movement, and propose three potential techniques for seed immobilization: (1) surgical glue, (2) laser coagulation and (3) diathermy coagulation. The feasibility of each method is explored. Experiments were carried out using fresh bovine livers to investigate the efficacy of seed immobilization using surgical glue.

Results Results have shown that the surgical glue can effectively immobilize the seeds. Evaluation of the radiation dose distribution revealed that the non-immobilized seed movement would change the planned isodose distribution considerably; while by using surgical glue method to immobilize the seeds, the changes were negligible.

Conclusions Prostate brachytherapy seed immobilization is necessary and three alternative mechanisms are promising for addressing this issue. Experiments for exploring the efficacy of the other two proposed methods are ongoing. Devices compatible with the brachytherapy procedure will be designed in future

Dosimetric evaluation of heterogeneity corrections for RTOG 0236: stereotactic body radiotherapy of inoperable stage I-II non-small-cell lung cancer.

Ying Xiao et al. — Mon, 06 Apr 2009 10:13:56 PDT

PURPOSE: Using a retrospective analysis of treatment plans submitted from multiple institutions accruing patients to the Radiation Therapy Oncology Group (RTOG) 0236 non-small-cell stereotactic body radiotherapy protocol, the present study determined the dose prescription and critical structure constraints for future stereotactic body radiotherapy lung protocols that mandate density-corrected dose calculations.

METHOD AND MATERIALS: A subset of 20 patients from four institutions participating in the RTOG 0236 protocol and using superposition/convolution algorithms were compared. The RTOG 0236 protocol required a prescription dose of 60 Gy delivered in three fractions to cover 95% of the planning target volume. Additional requirements were specified for target dose heterogeneity and the dose to normal tissue/structures. The protocol required each site to plan the patient's treatment using unit density, and another plan with the same monitor units and applying density corrections was also submitted. These plans were compared to determine the dose differences. Two-sided, paired Student's t tests were used to evaluate these differences.

RESULTS: With heterogeneity corrections applied, the planning target volume receiving >/=60 Gy decreased, on average, 10.1% (standard error, 2.7%) from 95% (p = .001). The maximal dose to any point >/=2 cm away from the planning target volume increased from 35.2 Gy (standard error, 1.7) to 38.5 Gy (standard error, 2.2). CONCLUSION: Statistically significant dose differences were found with the heterogeneity corrections. The information provided in the present study is being used to design future heterogeneity-corrected RTOG stereotactic body radiotherapy lung protocols to match the true dose delivered for RTOG 0236.