A Prospective Study of Proton Beam Reirradiation for Esophageal Cancer.

PURPOSE: Reirradiation to the esophagus carries a significant risk of complications. Proton therapy may offer an advantage in the reirradiation setting due to the lack of exit dose and potential sparing of previously radiated normal tissues. METHODS AND MATERIALS: Between June 2010 and February 2014, 14 patients with a history of thoracic radiation and newly diagnosed or locally recurrent esophageal cancer began proton beam reirradiation on a prospective trial. Primary endpoints were feasibility and acute toxicity. Toxicity was graded according Common Toxicity Criteria version 4.0. RESULTS: The median follow-up was 10 months (2-25 months) from the start of reirradiation. Eleven patients received concurrent chemotherapy. The median interval between radiation courses was 32 months (10-307 months). The median reirradiation prescription dose was 54.0 Gy (relative biological effectiveness [RBE]) (50.4-61.2 Gy[RBE]), and the median cumulative prescription dose was 109.8 Gy (76-129.4 Gy). Of the 10 patients who presented with symptomatic disease, 4 patients had complete resolution of symptoms, and 4 had diminished or stable symptoms. Two patients had progressive symptoms. The median time to symptom recurrence was 10 months. Maximum acute nonhematologic toxicity attributable to radiation was grade 2 (64%, N=9), 3 (29%, N=4), 4 (0%), and 5 (7%, N=1). The acute grade 5 toxicity was an esophagopleural fistula more likely related to tumor progression than radiation. Grade 3 nonhematologic acute toxicities included dysphagia, dehydration, and pneumonia. There was 1 late grade 5 esophageal ulcer more likely related to tumor progression than radiation. There were 4 late grade 3 toxicities: heart failure, esophageal stenosis requiring dilation, esophageal ulceration from tumor, and percutaneous endoscopic gastrostomy tube dependence. The median time to local failure was 10 months, and the median overall survival was 14 months. CONCLUSIONS: Our data demonstrate that proton reirradiation is feasible, with an encouraging symptom control rate, modest radiation-related toxicity, and favorable survival in this high-risk population.

Comparative assessment of liver tumor motion using cine-magnetic resonance imaging versus 4-dimensional computed tomography.

PURPOSE: To compare the extent of tumor motion between 4-dimensional CT (4DCT) and cine-MRI in patients with hepatic tumors treated with radiation therapy. METHODS AND MATERIALS: Patients with liver tumors who underwent 4DCT and 2-dimensional biplanar cine-MRI scans during simulation were retrospectively reviewed to determine the extent of target motion in the superior-inferior, anterior-posterior, and lateral directions. Cine-MRI was performed over 5 minutes. Tumor motion from MRI was determined by tracking the centroid of the gross tumor volume using deformable image registration. Motion estimates from 4DCT were performed by evaluation of the fiducial, residual contrast (or liver contour) positions in each CT phase. RESULTS: Sixteen patients with hepatocellular carcinoma (n=11), cholangiocarcinoma (n=3), and liver metastasis (n=2) were reviewed. Cine-MRI motion was larger than 4DCT for the superior-inferior direction in 50% of patients by a median of 3.0 mm (range, 1.5-7 mm), the anterior-posterior direction in 44% of patients by a median of 2.5 mm (range, 1-5.5 mm), and laterally in 63% of patients by a median of 1.1 mm (range, 0.2-4.5 mm). CONCLUSIONS: Cine-MRI frequently detects larger differences in hepatic intrafraction tumor motion when compared with 4DCT most notably in the superior-inferior direction, and may be useful when assessing the need for or treating without respiratory management, particularly in patients with unreliable 4DCT imaging. Margins wider than the internal target volume as defined by 4DCT were required to encompass nearly all the motion detected by cine-MRI for some of the patients in this study.

Definitive dose thoracic radiation therapy in oligometastatic non-small cell lung cancer: A hypothesis-generating study.

PURPOSE: A subset of patients with minimal extrathoracic disease may benefit from aggressive primary tumor treatment. We report comparative outcomes in oligometastatic non-small cell lung cancer (NSCLC) treated with and without definitive, conventionally fractionated thoracic radiation therapy. METHODS AND MATERIALS: We identified consecutive patients with stage IV NSCLC who had an Eastern Cooperative Oncology Group performance status ≤2 and ≤4 total sites of metastatic disease and who had been prescribed ≥50 Gy of thoracic radiation. RESULTS: Twenty-nine patients with oligometastatic NSCLC were identified between January 2004 and August 2010. Median survival was 22 months from diagnosis. Four patients (14%) experienced pneumonitis greater than or equal to grade 3; 6 (21%) had esophagitis greater than or equal to grade 3. Local control was associated with improved survival (P = .02). In matched subset analysis, median survival was 9 months (P < .01) in patients who received chemotherapy alone. Median time to local failure was 18 versus 6 months (P = .01). On multivariable analysis, radiation (P < .01; odds ratio [OR], 0.33), fewer metastases (P < .01; OR, 2.14), and female sex (P < .01; OR, 0.41) were associated with improved survival. CONCLUSIONS: Definitive dose radiation therapy may improve survival in a select subset of patients with minimal extrathoracic disease in whom local progression is of primary concern. Prospective trials are needed to further evaluate the role of local control in oligometastatic NSCLC.

Clinical utility of integrated positron emission tomography/computed tomography imaging in the clinical management and radiation treatment planning of locally advanced rectal cancer.

PURPOSE: The role of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) in the staging and radiation treatment planning of locally advanced rectal cancer is ill defined. We studied the role of integrated PET/CT in the staging, radiation treatment planning, and use as an imaging biomarker in rectal cancer patients undergoing multimodality treatment. METHODS AND MATERIALS: Thirty-four consecutive patients with T3-4N0-2M0-1 rectal adenocarcinoma underwent FDG-PET/CT scanning for staging and radiation treatment planning. Planned clinical management was compared before and after the addition of PET/CT information. Three radiation oncologists independently delineated CT-based gross tumor volumes (GTVCT) using clinical information and CT imaging data, as well as gradient autosegmented PET/CT-based GTVs (GTVPETCT). The mean GTV, interobserver concordance index (CCI), and proximal and distal margins were compared. The maximal standardized uptake value (SUVmax), metabolic tumor volume (MTV), and dual-time point PET parameters were correlated with clinicopathologic endpoints. RESULTS: Clinical management was altered by PET/CT in 18% (n = 6) of patients with clinical upstaging in 6 patients and radiation treatment planning altered in 5 patients. Of the 30 evaluable preoperative patients, the mean GTVPETCT was significantly smaller than the mean GTVCT volumes: 88.1 versus 102.8 cc (P = .03). PET/CT significantly increased interobserver CCI in contouring GTV compared with CT only-based contouring: 0.56 versus 0.38 (P < .001). The proximal and distal margins were altered by a mean of 0.4 ± 0.24 cm and -0.25 ± 0.18 cm, respectively. MTV was inversely associated with 2-year progression-free survival (PFS) and overall survival (OS): smaller MTVs (<33 cc) had superior 2-year PFS (86% vs 60%, P = .04) and OS (100% vs 45%, P < .01) compared with larger MTVs (>33 cc). SUVmax and dual-time point PET parameters did not correlate with any endpoints. CONCLUSIONS: FDG-PET/CT imaging impacts overall clinical management and is useful in the radiation treatment planning of rectal cancer patients by decreasing interobserver variability in contouring target boost volumes. Pretreatment MTV may provide useful prognostic information and requires further study.

A systematic review of radiotherapy capacity in low- and middle-income countries.

OBJECTIVES: The cancer burden in low- and middle-income countries (LMIC) is substantial. The purpose of this study was to identify and describe country and region-specific patterns of radiotherapy (RT) facilities in LMIC. METHODS: A systematic review of the literature was undertaken. A search strategy was developed to include articles on radiation capacity in LMIC from the following databases: PubMed, Embase, CINAHL Plus, Global Health, and the Latin American and Caribbean System on Health Sciences Information. Searches included all literature up to April 2013. RESULTS: A total of 49 articles were included in the review. Studies reviewed were divided into one of four regions: Africa, Asia, Eastern Europe, and South America. The African continent has the least amount of resources for RT. Furthermore, a wide disparity exists, as 60% of all machines on the continent are concentrated in Egypt and South Africa while 29 countries in Africa are still lacking any RT resource. A significant heterogeneity also exists across Southeast Asia despite a threefold increase in megavoltage teletherapy machines from 1976 to 1999, which corresponds with a rise in economic status. In LMIC of the Americas, only Uruguay met the International Atomic Energy Agency recommendations of 4 MV/million population, whereas Bolivia and Venezuela had the most radiation oncologists (>1 per 1000 new cancer cases). The main concern with the review of RT resources in Eastern Europe was the lack of data. CONCLUSION: There is a dearth of publications on RT therapy infrastructure in LMIC. However, based on limited published data, availability of RT resources reflects the countries' economic status. The challenges to delivering radiation in the discussed regions are multidimensional and include lack of physical resources, lack of human personnel, and lack of data. Furthermore, access to existing RT and affordability of care remains a large problem.

Impact of PET staging in limited-stage small-cell lung cancer.

INTRODUCTION: Although positron emission tomography computed tomography (PET-CT) has been widely used for small-cell lung cancer (SCLC) staging, no study has examined the clinical impact of PET staging in limited-stage (LS) SCLC. METHODS: We identified patients with LS-SCLC treated definitively with concurrent chemoradiation. Outcomes were assessed using the Kaplan-Meier approach, Cox regression, and competing risks method. RESULTS: We treated 54 consecutive LS-SCLC patients with concurrent chemoradiation from January 2002 to August 2010. Forty underwent PET, 14 did not, and all underwent thoracoabdominopelvic CT and magnetic resonance imaging neuroimaging. Most patient characteristics were balanced between the comparison groups, including age, race, sex, bone scanning, median dosage, and performance status. More number of PET-staged patients presented with nodal metastases (p = 0.05). Median follow-up was similar for PET-staged and non-PET-staged patients (p = 0.59). Median overall survival from diagnosis in PET-staged patients was 32 versus 17 months in patients staged without PET (p = 0.03), and 3-year survival was 47% versus 19%. Median time-to-distant failure was 29 versus 12 months (p = 0.04); median time-to-local failure was not reached versus 16 months (p = 0.04). On multivariable analysis, PET staging (odds ratio [OR] = 0.24; p = 0.04), performance status (OR = 1.89; p = 0.05), and N-stage (OR = 4.94; p < 0.01) were associated with survival. CONCLUSION: LS-SCLC patients staged with PET exhibited improved disease control and survival when compared with non-PET-staged LS-SCLC patients. Improved staging accuracy and better identification of intrathoracic disease may explain these findings, underscoring the value of PET-CT in these patients.

Brachial plexopathy in apical non-small cell lung cancer treated with definitive radiation: dosimetric analysis and clinical implications.

PURPOSE: Data are limited on the clinical significance of brachial plexopathy in patients with apical non-small cell lung cancers (NSCLC) treated with definitive radiation therapy. We report the rates of radiation-induced brachial plexopathy (RIBP) and tumor-related brachial plexopathy (TRBP) and associated dosimetric parameters in apical NSCLC patients. METHODS AND MATERIALS: Charts of NSCLC patients with primary upper lobe or superiorly located nodal disease who received ≥50 Gy of definitive conventionally fractionated radiation or chemoradiation were retrospectively reviewed for evidence of brachial plexopathy and categorized as RIBP, TRBP, or trauma-related. Dosimetric data were gathered on ipsilateral brachial plexuses (IBP) contoured according to Radiation Therapy Oncology Group atlas guidelines. RESULTS: Eighty patients were identified with a median follow-up and survival time of 17.2 and 17.7 months, respectively. The median prescribed dose was 66.6 Gy (range, 50.4-84.0), and 71% of patients received concurrent chemotherapy. RIBP occurred in 5 patients with an estimated 3-year rate of 12% when accounting for competing risk of death. Seven patients developed TRBP (estimated 3-year rate of 13%), comprising 24% of patients who developed locoregional failures. Grade 3 brachial plexopathy was more common in patients who experienced TRBP than RIBP (57% vs 20%). No patient who received ≤78 Gy to the IBP developed RIBP. On multivariable competing risk analysis, IBP V76 receiving ≥1 cc, and primary tumor failure had the highest hazard ratios for developing RIBP and TRBP, respectively. CONCLUSIONS: RIBP is a relatively uncommon complication in patients with apical NSCLC tumors receiving definitive doses of radiation, while patients who develop primary tumor failures are at high risk for developing morbid TRBP. These findings suggest that the importance of primary tumor control with adequate doses of radiation outweigh the risk of RIBP in this population of patients.

The impact of extent and location of mediastinal lymph node involvement on survival in Stage III non-small cell lung cancer patients treated with definitive radiotherapy.

PURPOSE: Several surgical series have identified subcarinal, contralateral, and multilevel nodal involvement as predictors of poor overall survival in patients with Stage III non-small-cell lung cancer (NSCLC) treated with definitive resection. This retrospective study evaluates the impact of extent and location of mediastinal lymph node (LN) involvement on survival in patients with Stage III NSCLC treated with definitive radiotherapy. METHODS AND MATERIALS: We analyzed 106 consecutive patients with T1-4 N2-3 Stage III NSCLC treated with definitive radiotherapy at the University of Pennsylvania between January 2003 and February 2009. For this analysis, mediastinal LN stations were divided into four mutually exclusive groups: supraclavicular, ipsilateral mediastinum, contralateral mediastinum, and subcarinal. Patients' conditions were then analyzed according to the extent of involvement and location of mediastinal LN stations. RESULTS: The majority (88%) of patients received sequential or concurrent chemotherapy. The median follow-up time for survivors was 32.6 months. By multivariable Cox modeling, chemotherapy use (hazard ratio [HR]: 0.21 [95% confidence interval (CI): 0.07-0.63]) was associated with improved overall survival. Increasing primary tumor [18F]-fluoro-2-deoxy-glucose avidity (HR: 1.11 [CI: 1.06-1.19]), and subcarinal involvement (HR: 2.29 [CI: 1.11-4.73]) were significant negative predictors of overall survival. On univariate analysis, contralateral nodal involvement (HR: 0.70 [CI: 0.33-1.47]), supraclavicular nodal involvement (HR: 0.78 [CI: 0.38-1.67]), multilevel nodal involvement (HR: 0.97 [CI: 0.58-1.61]), and tumor size (HR: 1.04 [CI: 0.94-1.14]) did not predict for overall survival. Patients with subcarinal involvement also had lower rates of 2-year nodal control (51.2% vs. 74.9%, p = 0.047) and 2-year distant control (28.4% vs. 61.2%, p = 0.043). CONCLUSIONS: These data suggest that the factors that determine oncologic outcome in Stage III NSCLC patients treated with definitive radiotherapy are distinct from those observed in patients who undergo surgical resection. The ultimate efficacy of radiation in locally advanced NSCLC is dependent on the intrinsic biology of the tumor.

Photodynamic therapy and the evolution of a lung-sparing surgical treatment for mesothelioma.

BACKGROUND: Photodynamic therapy (PDT) is a light-based cancer treatment that acts to a depth of several millimeters into tissue. This study reviewed the results of patients who underwent a macroscopic complete resection, by two different surgical techniques, and intraoperative PDT as a treatment for malignant pleural mesothelioma. METHODS: From 2004 to 2008, 28 patients with malignant pleural mesothelioma underwent macroscopic complete resection, 14 by modified extrapleural pneumonectomy (MEPP) and 14 by radical pleurectomy (RP) and intraoperative PDT. The surgical technique evolved over this period such that 13 of the last 16 patients underwent lung-sparing procedures, even in the setting of large-bulk tumors. RESULTS: Demographics in the MEPP and RP cohorts were similar in age, sex, stage, nodal status, histology, and adjuvant treatments. Stage III/IV disease was present in 12 of 14 patients (86%), with 50% or more with +N2 disease. The median overall survival for the MEPP group was 8.4 months, but has not yet been reached for the RP group at a median follow-up of 2.1 years. CONCLUSIONS: In addition to the inherent advantages of sparing the lung, RP plus PDT yielded a superior overall survival than MEPP plus PDT in this series. The overall survival for the RP plus PDT group was, for unclear reasons, superior to results reported in many surgical series, especially for a cohort with such advanced disease. Given these results, we believe RP plus PDT is a reasonable option for appropriate patients pursuing a surgical treatment for malignant pleural mesothelioma and that this procedure can serve as the backbone of surgically based multimodal treatments.

The role of radiation therapy in malignant thymoma: a Surveillance, Epidemiology, and End Results database analysis.

INTRODUCTION: The potential benefits and long-term complications of radiotherapy treatment for malignant thymoma are unclear. This is a retrospective analysis of outcome in patients with malignant thymoma from the Surveillance, Epidemiology, and End Results database between 1973 and 2005. METHODS: Of the 1987 patients identified, 1334 were analyzed. Patients were categorized according to the Masaoka staging system as stage I to IIA, IIB or III to IV. The primary end points were overall survival, cardiac mortality, and the development of secondary malignancies. RESULTS: Patients received surgery and radiation (50%), surgery alone (26%), radiation alone (12%), or no treatment (12%). The median follow-up time for survivors was 65 months (range, 1-361 months). There was no significant increase in the 12-year cumulative incidence rate of death from heart disease (10.2% radiation versus 7.5% no radiation, p = 0.83) or incidence of secondary malignancies (11.7% versus 12.4%, p = 0.70) with radiation. Compared with surgery alone, adjuvant radiation significantly improved overall survival in patients with stage III to IV disease (p = 0.04) and demonstrated a nonsignificant trend in patients with stage IIB disease (p = 0.09). However, after excluding patients surviving less than 4 months to account for surgical mortality, the benefit with radiation was no longer significant (stage IIB: p = 0.45, stage III-IV: p = 0.44). CONCLUSIONS: Radiation does not seem to increase the risk of cardiac mortality or secondary malignancy in patients with malignant thymoma. Although the routine use of postoperative radiotherapy in malignant thymoma does not appear warranted, high-risk patients may benefit from adjuvant radiation. This study can help to design prospective trials to further establish the role of radiotherapy in malignant thymoma.

Elective nodal irradiation (ENI) vs. involved field radiotherapy (IFRT) for locally advanced non-small cell lung cancer (NSCLC): A comparative analysis of toxicities and clinical outcomes.

BACKGROUND: Elective nodal irradiation (ENI) and involved field radiotherapy (IFRT) are definitive radiotherapeutic approaches used to treat patients with locally advanced non-small cell lung cancer (NSCLC). ENI delivers prophylactic radiation to clinically uninvolved lymph nodes, while IFRT only targets identifiable gross nodal disease. Because clinically uninvolved nodal stations may harbor microscopic disease, IFRT raises concerns for increased nodal failures. This retrospective cohort analysis evaluates failure rates and treatment-related toxicities in patients treated at a single institution with ENI and IFRT. METHODS: We assessed all patients with stage III locally advanced or stage IV oligometastatic NSCLC treated with definitive radiotherapy from 2003 to 2008. Each physician consistently treated with either ENI or IFRT, based on their treatment philosophy. RESULTS: Of the 108 consecutive patients assessed (60 ENI vs. 48 IFRT), 10 patients had stage IV disease and 95 patients received chemotherapy. The median follow-up time for survivors was 18.9 months. On multivariable logistic regression analysis, patients treated with IFRT demonstrated a significantly lower risk of high grade esophagitis (Odds ratio: 0.31, p = 0.036). The differences in 2-year local control (39.2% vs. 59.6%), elective nodal control (84.3% vs. 84.3%), distant control (47.7% vs. 52.7%) and overall survival (40.1% vs. 43.7%) rates were not statistically significant between ENI vs. IFRT. CONCLUSIONS: Nodal failure rates in clinically uninvolved nodal stations were not increased with IFRT when compared to ENI. IFRT also resulted in significantly decreased esophageal toxicity, suggesting that IFRT may allow for integration of concurrent systemic chemotherapy in a greater proportion of patients.

Selective inhibition of Ras, phosphoinositide 3 kinase, and Akt isoforms increases the radiosensitivity of human carcinoma cell lines.

Ras activation promotes the survival of tumor cells after DNA damage. To reverse this survival advantage, Ras signaling has been targeted for inhibition. Other contributors to Ras-mediated DNA damage survival have been identified using pharmacologic inhibition of signaling, but this approach is limited by the specificity of the inhibitors used and their toxicity. To better define components of Ras signaling that could be inhibited in a clinical setting, RNA interference was used to selectively block expression of specific isoforms of Ras, phosphoinositide 3 (PI3) kinase, and Akt. Inhibition of oncogenic Ras expression decreased both phospho-Akt and phospho-p42/44 mitogen-activated protein (MAP) kinase levels and reduced clonogenic survival. Because pharmacologic inhibition of PI3 kinases and Akt radiosensitized cell lines with active Ras signaling, whereas inhibition of the MAP/extracellular signal-regulated kinase (ERK) kinase/ERK pathway did not, we examined the contribution of PI3 kinases and Akts to radiation survival. Selective inhibition the PI3 kinase P110alpha + p85beta isoforms reduced Akt phosphorylation and radiation survival. Similarly, inhibition of Akt-1 reduced tumor cell radiation survival. Inhibition of Akt-2 or Akt-3 had less effect. Retroviral transduction and overexpression of mouse Akt-1 was shown to rescue cells from inhibition of endogenous human Akt-1 expression. This study shows that Ras signaling to the PI3 kinase-Akt pathway is an important contributor to survival, whether Ras activation results from mutation of ras or overexpression of epidermal growth factor receptor. This study further shows that selective inhibition of the PI3 kinase P110alpha + p85beta isoforms or Akt-1 could be a viable approach to sensitizing many tumor cells to cytotoxic therapies.

The influence of Ras pathway signaling on tumor radiosensitivity.

Radiotherapy is used to treat approximately 60% of solid tumors in the US. The relative radiosensitivity of these tumors can have a significant impact upon local control. One factor that has been shown to contribute to the increased survival of tumor cells is the activation of signaling pathways in which oncogene products play a central role. The Ras oncoprotein family, comprised of H-, K-, and N-Ras are frequently activated by mutation in certain tumors such as pancreatic and non-small cell lung cancers and are activated by receptor tyrosine kinase activity in an even wider range of tumor types. The role of ras mutation and more recently Ras signaling has been an area of intense study in both radiobiology and tumor biology in general. In this review, we focus on findings from our lab and others that led to the current hypotheses relating to the role of Ras signaling in tumor radiation survival and the strategies used to block Ras activation. We will also point out new means of studying the contribution of Ras and Ras pathway components that could contribute to defining new targets for inhibition in the context of radiation therapy.

Structural similarity between the bone marrow extracellular matrix protein and neurokinin 1 could be the limiting factor in the hematopoietic effects of substance P.

In the adult bone marrow (BM), immune cells are replenished through the process of definitive hematopoiesis, which is regulated by a complex process of cellular and humoral interactions. The latter include substance P (SP), a neurotransmitter that is produced by neural and nonneural cells. Neurokinin-1 (NK-1), the high-affinity SP receptor, shares structural similarity with fibronectin, a component of the BM extracellular matrix proteins. This study examines how such similarity could alter the effects of SP on the proliferation of the immature BM progenitors. In vitro studies show that 1 ng fibronectin/mL enhanced the stimulatory effect of SP on the proliferation of primitive BM progenitors. This finding was studied by computational studies: proteomics and three-dimensional molecular modeling. Use of surface-enhanced laser desorption/ionization ProteinChip technology showed that despite the induction of neutral endopeptidase, exogenous fibronectin hindered the degradation of SP to SP(1-4). These findings support a protective role for fibronectin in the digestion of SP. Since SP(1-4) is a negative regulator of hematopoiesis, this report indicates that the structural similarity between fibronectin and NK-1 could be important for maintaining hematopoietic stimulation. These studies could be extrapolated to hematological disorders that are associated with SP-fibronectin complexes.