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1.  Stereotactic Ablative Radiosurgery for Locally Advanced or Recurrent Skull Base Malignancies with Prior External Beam Radiation Therapy 
Purpose: Stereotactic ablative radiotherapy (SABR) is an attractive modality to treat malignancies invading the skull base as it can deliver a highly conformal dose with minimal toxicity. However, variation exists in the prescribed dose and fractionation. The purpose of our study is to examine the local control, survival, and toxicities in SABR for the treatment of previously irradiated malignant skull base tumors.
Materials and methods: A total of 31 patients and 40 locally advanced or recurrent head and neck malignancies involving the skull base treated with a common SABR regimen, which delivers a radiation dose of 44 Gy in 5 fractions from January 1st, 2004 to December 31st, 2013, were retrospectively reviewed. The local control rate (LC), progression-free survival rate, overall survival (OS) rate, and toxicities were reported.
Results: The median follow-up time of all patients was 11.4 months (range: 0.6–67.2 months). The median tumor volume was 27 cm3 (range: 2.4–205 cm3). All patients received prior external beam radiation therapy with a median radiation dose of 64 Gy (range: 24–75.6 Gy) delivered in 12–42 fractions. Twenty patients had surgeries prior to SABR. Nineteen patients received chemotherapy. Specifically, eight patients received concurrent cetuximab (Erbitux™) with SABR. The median time-to-progression (TTP) was 3.3 months (range: 0–16.9 months). For the 29 patients (93.5%) who died, the median time from the end of first SABR to death was 10.3 months (range: 0.5–41.4 months). The estimated 1-year OS rate was 35%. The estimated 2-year OS rate was 12%. Treatment was well-tolerated without grade 4 or 5 treatment-related toxicities.
Conclusion: Stereotactic ablative radiotherapy has been shown to achieve low toxicities in locally advanced or recurrent, previously irradiated head and neck malignancies invading the skull base.
PMCID: PMC4362305  PMID: 25853093
SABR; low toxicities; re-irradiation; skull base malignancies; high-dose
2.  Tumor Bed Radiosurgery Following Resection and Prior Stereotactic Radiosurgery for Locally Persistent Brain Metastasis 
Despite advances in multimodality management of brain metastases, local progression following stereotactic radiosurgery (SRS) can occur. Often, surgical resection is favored, as it frequently provides immediate symptom relief as well as pathological characterization of any residual tumor. Should the pathological specimen contain viable tumor cells, further radiation therapy is an option to sterilize the tumor bed. We evaluated the use of repeat SRS (rSRS) in lieu of whole-brain radiation therapy (WBRT) as a means of improving local control (LC) while minimizing potential toxicity and dose to the normal brain.
A retrospective review was performed to identify patients with brain metastases who underwent SRS and then surgical resection for locally recurrent or persistent disease. From 2004 to 2014, 13 consecutive patients or 15 lesions were treated with rSRS after resection, either post-operatively to the tumor bed (n = 10, 66.6%) or after a second local recurrence (n = 5, 33.3%). LC, distant brain failure (DBF), and radiation toxicity were determined using patient records, RECIST criteria v1.1, and CTCAE v4.03.
At a median follow-up interval of 9.0 months (range 1.8–54.9 months) from time of rSRS, five patients remain alive. Following rSRS, 13 of the 15 (86.6%) lesions were locally controlled with an estimated 100% LC at 6 months and 75% LC at 1 year. However, 11 of the 15 (73.3%) treated lesions developed DBF after rSRS with 3 of 13 patients proceeding to WBRT. Two of 15 (13.3%) resulted in either grade 2 radionecrosis with grade 3 seizures or grade 3 radionecrosis.
Repeat SRS represents a potential salvage therapy for patients with locally recurrent brain metastases, providing additional tumor control with acceptable toxicity, even in the setting of prior SRS and surgical resection. rSRS may be reasonable to use as an alternative to WBRT in this setting.
PMCID: PMC4389371  PMID: 25905042
radiosurgery; brain metastases; re-irradiation; recurrence; cyberknife
3.  Salvage Stereotactic Body Radiotherapy for Locally Recurrent Non-Small Cell Lung Cancer after Sublobar Resection and I125 Vicryl Mesh Brachytherapy 
Frontiers in Oncology  2015;5:109.
Locally recurrent non-small cell lung cancer (LR-NSCLC) remains challenging to treat, particularly in patients having received prior radiotherapy. Heterogeneous populations and varied treatment intent in existing literature result in significant limitations in evaluating efficacy of lung re-irradiation. In order to better establish the impact of re-irradiation in patients with LR-NSCLC following high-dose radiotherapy, we report outcomes for patients treated with prior sublobar resection and brachytherapy that subsequently underwent stereotactic body radiotherapy (SBRT).
A retrospective review of patients initially treated with sublobar resection and I125 vicryl mesh brachytherapy, who later developed LR-NSCLC along the suture line, was performed. Patients received salvage SBRT with curative intent. Dose and fractionation were based on tumor location and size, with a median prescription dose of 48 Gy in 4 fractions (range 20–60 Gy in 1–4 fractions).
Thirteen consecutive patients were identified with median follow-up of 2.1 years (range 0.7–5.6 years). Two in-field local failures occurred at 7.5 and 11.1 months, resulting in 2-year local control of 83.9% (95% CI, 63.5–100.0%). Two-year disease-free survival and overall survival estimates were 38.5% (95% CI, 0.0–65.0%) and 65.8% (95% CI, 38.2–93.4%). Four patients (31%) remained disease-free at last follow-up. All but one patient who experienced disease recurrence developed isolated or synchronous distant metastases. Only one patient (7.7%) developed grade ≥3 toxicity, consisting of grade 3 esophageal stricture following a centrally located recurrence previously treated with radiofrequency ablation.
Despite high-local radiation doses delivered to lung parenchyma previously with I125 brachytherapy, re-irradiation with SBRT for LR-NSCLC results in excellent local control with limited morbidity, allowing for potential disease cure in a subset of patients.
PMCID: PMC4426786  PMID: 26029665
SBRT; radiosurgery; re-irradiation; lung cancer; brachytherapy; non-small cell lung cancer; recurrent
4.  Extent of perilesional edema differentiates radionecrosis from tumor recurrence following stereotactic radiosurgery for brain metastases 
Neuro-Oncology  2013;15(12):1732-1738.
Differentiation of tumor recurrence from radionecrosis is a critical step in the follow-up management of patients treated with stereotactic radiosurgery (SRS) for brain metastases. A method that can reliably differentiate tumor recurrence from radiation necrosis using standard MR sequences would be of significant value.
We analyzed the records of 49 patients with 52 brain metastases treated with SRS who subsequently underwent surgical resection of the same lesion. Forty-seven of the lesions had preoperative MRI available for review (90%), including T1 postcontrast, T2, and fluid attenuated inversion recovery sequences. Pre-SRS and preoperative lesion and edema volumes were manually contoured and measured in a blinded fashion using radiation treatment planning software. A neuropathologist analyzed samples for the presence of tumor and/or radiation necrosis.
Longer time between SRS and resection (P < .001) and a larger edema/lesion volume ratio (high T2/T1c, P = .002) were found to be predictive of radionecrosis as opposed to tumor recurrence. Using a cutoff value of 10 for the edema/lesion volume ratio, we were able to predict the presence of tumor with a positive predictive value of 92%, which increased to 100% when looking only at patients who underwent resection <18 months following SRS.
On follow-up imaging, lesions with a high edema/lesion volume ratio and lesions that progress later after SRS are more likely to contain radionecrosis. These indices may help guide clinical decision making in the context of evolving lesions after SRS for brain metastases and thereby avoid unnecessary interventions.
PMCID: PMC3829597  PMID: 24243914
brain metastases; magnetic resonance imaging; radionecrosis; stereotactic radiosurgery
5.  Stereotactic Body Radiotherapy as Primary Treatment for Elderly Patients with Medically Inoperable Head and Neck Cancer 
Frontiers in Oncology  2014;4:214.
Purpose: With a growing elderly population, elderly patients with head and neck cancers represent an increasing challenge with limited prospective data to guide management. The complex interplay between advanced age, associated co-morbidities, and conventional local therapies, such as surgery and external beam radiotherapy ± chemotherapy, can significantly impact elderly patients’ quality of life (QoL). Stereotactic body radiotherapy (SBRT) is a well-established curative strategy for medical-inoperable early-stage lung cancers even in elderly populations; however, there is limited data examining SBRT as primary therapy in head and neck cancer.
Material/methods: Twelve patients with medically inoperable head and neck cancer treated with SBRT ± cetuximab from 2002 to 2013 were retrospectively reviewed. SBRT consisted of primarily 44 Gy in five fractions delivered on alternating days over 1–2 weeks. Concurrent cetuximab was administered at a dose of 400 mg/m2 on day −7 followed by 250 mg/m2 on day 0 and +7 in n = 3 (25%). Patient-reported quality of life (PRQoL) was prospectively recorded using the previously validated University of Washington quality of life revised (UW-QoL-R).
Results: Median clinical follow-up was 6 months (range: 0.5–29 months). The 1-year actuarial local progression-free survival, distant progression-free survival, progression-free survival, and overall survival for definitively treated patients were 69, 100, 69, and 64%, respectively. One patient (8%) experienced acute grade 3 dysphagia and one patient (8%) experienced late grade 3 mucositis; there were no grade 4–5 toxicities. Prospective collection of PRQoL as assessed by UW-QoL-R was preserved across domains.
Conclusion: Stereotactic body radiotherapy shows encouraging survival and relatively low toxicity in elderly patients with unresectable head and neck cancer, which may provide an aggressive potentially curative local therapy while maintaining QoL.
PMCID: PMC4128217  PMID: 25157336
SBRT; cetuximab; elderly; head and neck cancer; radiosurgery
6.  The Impact of Tumor Volume and Radiotherapy Dose on Outcome in Previously Irradiated Recurrent Squamous Cell Carcinoma of the Head and Neck Treated With Stereotactic Body Radiation Therapy 
To assess the effect of stereotactic body radiotherapy (SBRT) dose and tumor volume on outcomes in patients with recurrent, previously irradiated squamous cell carcinoma of the head and neck.
Materials and Methods
A total of 96 patients with recurrent, previously irradiated squamous cell carcinoma of the head and neck were treated with SBRT using Cyberknife and Trilogy-intensity-modulated radiosurgery. Kaplan-Meier survival analyses were used to estimate locoregional control (LRC) and overall survival rates. Response was evaluated using positron emission tomography/computed tomography or computed tomography and detailed physical examination.
The median follow-up for all patients was 14 months (2–39 months). The median dose of prior radiation was 68.4 Gy (32–170 Gy). Patients were divided into 4 SBRT dose groups: I (15–28 Gy/n = 29), II (30–36 Gy/n = 22), III (40 Gy/n = 18), and IV (44–50 Gy/n = 27). The median gross tumor volume (GTV) was 24.3 cm3 (2.5–162 cm3). For GTV ≤25 cm3 (n = 50), complete response rates were 27.8%/30%/45.5%/45.5%, and for GTV >25 cm3 (n = 46), complete response rates were 20%/25%/42.8%/50% for SBRT groups I–IV, respectively. The 1-/2-/3-year LRC rates for doses 40 to 50 Gy were 69.4%/57.8%/41.1%, respectively, whereas for 15 to 36 Gy, they were 51.9%/31.7%/15.9%, respectively (P = 0.02). The overall 1- and 2-year overall survival rates were 58.9% and 28.4%, respectively. Treatment was well tolerated with no grade 4/5 toxicities.
Dose escalation up to 50 Gy in 5 fractions is feasible with SBRT for recurrent head and neck squamous cell carcinoma. Higher SBRT doses were associated with significantly higher LRC rates. Large tumor volume required higher SBRT doses to achieve optimal response rates compared with smaller tumor volume.
PMCID: PMC3177149  PMID: 20859194
head and neck cancer; outcome; radiation dose; reirradiation; stereotactic body radiotherapy; tumor volume
7.  Clinicopathologic features are stronger prognostic factors than histology or grade in risk stratification of primary parotid malignancies 
Head & neck  2011;33(2):225-231.
To determine the relative contribution of clinicopathologic risk factors versus low- and high-risk grade histologic groups to assist management of primary parotid cancers.
Study design
Retrospective chart review.
168 primary parotid malignancies were treated surgically at a tertiary care center from 1982 to 2005. Of these, 115 patients with complete follow up information were further analyzed. Pathologic updating and re-classification in 28% of cases enabled comparison of tumor histology or grade with current consensus criteria. Clinical outcomes of high- and low-risk histology and grade were compared with the influence of traditional clinicopathologic risk factors.
Of 115 cases, the male: female ratio was equal and the median age was 63 years (range, 15 to 89 years). Mucoepidermoid carcinoma (n=28) was the most common histology. The median follow-up was 44 months (range, 0 to 278 months). 40% of low-risk histology patients who underwent neck dissection had pN+ disease. The median time to recurrence was not reached for low-risk tumors as compared to 29 months for high-risk tumors (p = .0001). Interestingly, extracapsular spread (ECS) and margin status were independent prognostic factors and conferred significantly greater prognostic value than histologic grade risk group. Disease free survival (DFS) and overall survival (OS) at 5-years for the entire cohort was 51% and 57%, respectively. Risk group was a strong independent predictor of OS but not DFS.
Risk group defined by histology and grade was associated with disease-free survival. ECS and margin status were independent predictors of disease-free survival. Inclusion of ECS and margin status substantially improved the prediction of disease recurrence, supporting elective neck dissection and post-operative radiotherapy for high-grade tumors or low risk histologies with positive margins or ECS.
PMCID: PMC4164959  PMID: 21298822
Malignant parotid tumors; prognostic factors; neck dissection; neck metastasis
8.  “Prognostic factors in patients with high-risk locally advanced salivary gland cancers treated with surgery and postoperative radiotherapy” 
Head & neck  2011;33(3):318-323.
We sought to study the outcome of patients with locally advanced salivary gland cancers treated with surgery and postoperative radiotherapy.
Patients and methods:
We conducted a retrospective review of patients with salivary gland cancers registered in University of Pittsburgh databases from 1990-2006.
74 patients were analyzed. Histologic types included salivary duct carcinoma, 24%; adenoid cystic carcinoma, 23%; adenocarcinoma, 19%; mucoepidermoid carcinoma, 14%; N2, 39%; N0-1, 58%; major salivary gland origin, 80%. With a median follow-up of 4.1 years, the 5-year recurrence-free survival (RFS) was 49%, and the 5-year overall survival (OS) 55%. The 5-year local RFS was 76% and the 5-year distant RFS 60%. Using Cox-regression analysis, advanced nodal stage (N2) was the only significant predictor of both RFS and OS.
The long-term outcome of patients with high-risk, locally advanced salivary gland cancers is unsatisfactory. Nodal stage is a strong predictor of recurrence and overall survival.
PMCID: PMC4135528  PMID: 21284048
9.  Pretreatment SUVmax predicts progression-free survival in early-stage non-small cell lung cancer treated with stereotactic body radiation therapy 
This retrospective study aims to assess the usefulness of SUVmax from FDG-PET imaging as a prognosticator for primary biopsy-proven stage I NSCLC treated with SBRT.
This study includes 95 patients of median age 77 years, with primary, biopsy-confirmed peripheral stage IA/IB NSCLC. All patients were treated with 60Gy in 3 fractions with a median treatment time of six days. Local, regional, and distant failures were evaluated independently according to the terms of RTOG1021. Local, regional, and distant control, overall- and progression-free survival were estimated by the Kaplan-Meier method. Cox proportional hazards regression was performed to determine whether SUVmax, age, KPS, gender, tumor size/T stage, or smoking history influenced outcomes. SUVmax was evaluated as both a continuous and as a dichotomous variable using a cutoff of <5 and ≥5.
Median follow-up for the cohort was 16 months. Median OS and PFS were 25.3 and 40.3 months, respectively. SUV with a cutoff value of 5 predicted for OS and PFS (p = .024 for each) but did not achieve significance for LC (p = .256). On Cox univariate regression analysis, SUV as a dichotomous variable predicted for both OS and PFS (p = .027 and p = .030, respectively). Defined as a continuous variable, SUVmax continued to predict for OS and PFS (p = .032 and p = .003), but also predicted LC (p = .045) and trended toward significance for DC (p = .059).
SUVmax did not predict for OS as a dichotomous or continuous variable. It did, however, predict for PFS as a continuous variable (p = .008), neared significance for local control (p = .057) and trended towards, significance for distant control (p = .092).
SUVmax appears to be a statistically and clinically significant independent prognostic marker for progression-free survival in patients with stage I NSCLC treated with SBRT. Prospective studies to more accurately define the role of tumor FDG uptake in the prognosis of NSCLC are warranted.
PMCID: PMC3922961  PMID: 24479954
10.  National Cancer Institute’s Cancer Disparities Research Partnership Program: Experience and Lessons Learned 
Frontiers in Oncology  2014;4:303.
Purpose: To increase access of underserved/health disparities communities to National Cancer Institute (NCI) clinical trials, the Radiation Research Program piloted a unique model – the Cancer Disparities Research Partnership (CDRP) program. CDRP targeted community hospitals with a limited past NCI funding history and provided funding to establish the infrastructure for their clinical research program.
Methods: Initially, 5-year planning phase funding was awarded to six CDRP institutions through a cooperative agreement (U56). Five were subsequently eligible to compete for 5-year implementation phase (U54) funding and three received a second award. Additionally, the NCI Center to Reduce Cancer Health Disparities supported their U56 patient navigation programs.
Results: Community-based hospitals with little or no clinical trials experience required at least a year to develop the infrastructure and establish community outreach/education and patient navigation programs before accrual to clinical trials could begin. Once established, CDRP sites increased their yearly patient accrual mainly to NCI-sponsored cooperative group trials (~60%) and Principal Investigator/mentor-initiated trials (~30%). The total number of patients accrued on all types of trials was 2,371, while 5,147 patients received navigation services.
Conclusion: Despite a historical gap in participation in clinical cancer research, underserved communities are willing/eager to participate. Since a limited number of cooperative group trials address locally advanced diseases seen in health disparities populations; this shortcoming needs to be rectified. Sustainability for these programs remains a challenge. Addressing these gaps through research and public health mechanisms may have an important impact on their health, scientific progress, and efforts to increase diversity in NCI clinical trials.
PMCID: PMC4217306  PMID: 25405101
cancer disparities; underserved populations; patient accrual; access to clinical trials; clinical research
11.  Pathologic response with neoadjuvant chemotherapy and stereotactic body radiotherapy for borderline resectable and locally-advanced pancreatic cancer 
Neoadjuvant stereotactic body radiotherapy (SBRT) has potential applicability in the management of borderline resectable and locally-advanced pancreatic adenocarcinoma. In this series, we report the pathologic outcomes in the subset of patients who underwent surgery after neoadjuvant SBRT.
Patients with borderline resectable or locally-advanced pancreatic adenocarcinoma who were treated with SBRT followed by resection were included. Chemotherapy was to the discretion of the medical oncologist and preceded SBRT for most patients.
Twelve patients met inclusion criteria. Most (92%) received neoadjuvant chemotherapy, and gemcitabine/capecitabine was most frequently utilized (n = 7). Most were treated with fractionated SBRT to 36 Gy/3 fractions (n = 7) and the remainder with single fraction to 24 Gy (n = 5). No grade 3+ acute toxicities attributable to SBRT were found. Two patients developed post-surgical vascular complications and one died secondary to this. The mean time to surgery after SBRT was 3.3 months. An R0 resection was performed in 92% of patients (n = 11/12). In 25% (n = 3/12) of patients, a complete pathologic response was achieved, and an additional 16.7% (n = 2/12) demonstrated <10% viable tumor cells. Kaplan-Meier estimated median progression free survival is 27.4 months. Overall survival is 92%, 64% and 51% at 1-, 2-, and 3-years.
This study reports the pathologic response in patients treated with neoadjuvant chemotherapy and SBRT for borderline resectable and locally-advanced pancreatic cancer. In our experience, 92% achieved an R0 resection and 41.7% of patients demonstrated either complete or extensive pathologic response to treatment. The results of a phase II study of this novel approach will be forthcoming.
PMCID: PMC4228466  PMID: 24175982
Pancreatic cancer; Stereotactic body radiotherapy; SBRT; Neoadjuvant; Pathologic response
12.  Stereotactic body radiotherapy in the treatment of Pancreatic Adenocarcinoma in elderly patients 
Treatment of pancreatic adenocarcinoma in the elderly is often complicated by comorbidities that preclude surgery, chemotherapy and/or conventional external beam radiation therapy (EBRT). Stereotactic body radiotherapy (SBRT) has thus garnered interest in this setting.
A retrospective review of 26 patients of age ≥ 80 with pancreatic adenocarcinoma treated with definitive SBRT+/-chemotherapy from 2007–2011 was performed. Twenty-seven percent of patients were stage I, 38% were stage II, 27% were stage III and 8% were stage IV. Patients most commonly received 24 Gy/1 fraction or 30-36 Gy/3 fractions. Kaplan-Meier was used to estimate overall survival (OS), local control (LC), cause specific survival (CSS) and freedom-from-metastatic disease (FFMD).
The median age was 86 (range 80–91), and median follow-up was 11.6 months (3.5-24.6). The median planning target volume was 21.48 cm3 (6.1-85.09). Median OS was 7.6 months with 6/12 month OS rates of 65.4%/34.6%, respectively. Median LC was 11.5 months, 6-month and 12-month actuarial LC rates were 60.1% and 41.2%, respectively. There were no independent predictors for LC, but there was a trend for improved LC with prescription dose greater than 20 Gy (p = 0.063). Median CSS was 6.3 months, and 6-month and 12-month actuarial CSS were 53.8% and 23.1%, respectively. Median FFMD was 8.4 months, and 6-month and 12-month actuarial rates were 62.0% and 41.4%, respectively. Nine patients (47%) had local failures, 11 (58%) had distant metastasis, and 7 (37%) had both. There were no acute or late grade 3+ toxicities.
Definitive SBRT is feasible, safe and effective in elderly patients who have unresectable disease, have comorbidities precluding surgery or decline surgery.
PMCID: PMC4015447  PMID: 24131503
13.  Thirty and Ninety Day Outcomes after Sublobar Resection with and without brachytherapy for Non-small cell lung cancer: Results from a Multicenter Phase III study 
Sublobar resection (SR) is commonly used for patients considered high-risk for lobectomy. Non-operative therapies are increasingly being reported for similar risk patients because of perceived lower morbidity. We report 30 and 90 day adverse events (AEs) from ACOSOG Z4032; a multicenter phase III study for high-risk stage I non-small cell lung cancer (NSCLC) patients.
Data from 222 evaluable patients randomized to SR (n=114) or SR with brachytherapy (SRB) (n=108) are reported. AEs were recorded using the Common Terminology Criteria for Adverse Events, Version 3.0 at 30 and 90 days post surgery. Risk factors (age, baseline DLCO%, and FEV1%, upper lobe versus lower lobe resections, performance status, surgery approach; VATS versus open and extent ; wedge versus segmentectomy) were analyzed using a multivariable logistic model for their impact on the incidence of Grade 3 (G3+) and higher AEs. Respiratory AEs were also specifically analyzed
Median age, FEV1% and DLCO% were similar for the two treatment groups. There was no difference in the location of resection (upper versus lower lobe) or in the use of segmental or wedge resections. There were no differences between the groups with respect to “respiratory” G3+ (30 days: 14.9% vs. 19.4%; p=0.35; 0–90 days: 19.3% vs. 25%; p=0.31) and “any” G3+AEs (30 days: 25.4% vs. 30.6%; p=0.37; 0–90 days: 29.8% vs. 37%; p=0.25). Further analysis combined the two groups. Mortality occurred in 3 (1.4%) patients by 30 days and in 6 (2.7%) patients by 90 days. Four of the six deaths were felt to be attributable to surgery. When considered as continuous variables, FEV1% was associated with “any” grade 3 + AE at days 0–30 (p=0.03; OR=0.98), and days 0–90 (p=0.05; OR=0.98) respectively; and DLCO% was associated with “respiratory” grade 3+AE at days 0–30 (p=0.03; OR=0.97), and days 0–90 (p=0.05; OR=0.98) respectively. Segmental resection was associated with a higher incidence of any G3+ AE compared to wedge at days 0–30(40.3% versus 22.7%; OR=2.56; p<0.01) and days 0–90 (41.5% versus 29.7%; OR=1.96; p=0.04). The median FEV1% was 50% and the median DLCO% was 46%. Using these median values as potential cutpoints, only a DLCO% of less than 46% was significantly associated with an increased risk of “respiratory” and “any” grade 3+ AE for days 0–30, and 0–90.
In a multicenter setting, SRB was not associated with increased morbidity compared to SR alone. SR/SRB can be performed safely in high-risk patients with NSCLC with low 30 and 90 day mortality and acceptable morbidity. Segmental resection was associated with increased “any” G3+ AE, and DLCO% less than 46% was associated with “any” G3+AE as well as “respiratory” G3+ AE at both 30 and 90 days.
PMCID: PMC3199353  PMID: 21872277
14.  Prescription dose and fractionation predict improved survival after stereotactic radiotherapy for brainstem metastases 
Brainstem metastases represent an uncommon clinical presentation that is associated with a poor prognosis. Treatment options are limited given the unacceptable risks associated with surgical resection in this location. However, without local control, symptoms including progressive cranial nerve dysfunction are frequently observed. The objective of this study was to determine the outcomes associated with linear accelerator-based stereotactic radiotherapy or radiosurgery (SRT/SRS) of brainstem metastases.
We retrospectively reviewed 38 tumors in 36 patients treated with SRT/SRS between February 2003 and December 2011. Treatment was delivered with the Cyberknife™ or Trilogy™ radiosurgical systems. The median age of patients was 62 (range: 28–89). Primary pathologies included 14 lung, 7 breast, 4 colon and 11 others. Sixteen patients (44%) had received whole brain radiation therapy (WBRT) prior to SRT/SRS; ten had received prior SRT/SRS at a different site (28%). The median tumor volume was 0.94 cm3 (range: 0.01-4.2) with a median prescription dose of 17 Gy (range: 12–24) delivered in 1–5 fractions.
Median follow-up for the cohort was 3.2 months (range: 0.4-20.6). Nineteen patients (52%) had an MRI follow-up available for review. Of these, one patient experienced local failure corresponding to an actuarial 6-month local control of 93%. Fifteen of the patients with available follow-up imaging (79%) experienced intracranial failure outside of the treatment volume. The median time to distant intracranial failure was 2.1 months. Six of the 15 patients with distant intracranial failure (40%) had received previous WBRT. The actuarial overall survival rates at 6- and 12-months were 27% and 8%, respectively. Predictors of survival included Graded Prognostic Assessment (GPA) score, greater number of treatment fractions, and higher prescription dose. Three patients experienced acute treatment-related toxicity consisting of nausea (n = 1) and headaches (n = 2) that resolved with a short-course of dexamethasone.
SRT/SRS for brainstem metastases is safe and achieves a high rate of local control. We found higher GPA as well as greater number of treatment fractions and higher prescription dose to be correlated with improved overall survival. Despite this approach, prognosis remains poor and distant intracranial control remains an issue, even in patients previously treated with WBRT.
PMCID: PMC3487996  PMID: 22784482
Stereotactic radiosurgery; Brain metastases; Brainstem; Fractionation
15.  A retrospective, deformable registration analysis of the impact of PET-CT planning on patterns of failure in stereotactic body radiation therapy for recurrent head and neck cancer 
Head & Neck Oncology  2012;4:12.
Stereotactic body radiation therapy (SBRT) has seen increasing use as a salvage strategy for selected patients with recurrent, previously-irradiated squamous cell carcinoma of the head and neck (rSCCHN). PET-CT may be advantageous for tumor delineation and evaluation of treatment failures in SBRT. We analyzed the patterns of failure following SBRT for rSCCHN and assessed the impact of PET-CT treatment planning on these patterns of failure.
We retrospectively reviewed 96 patients with rSCCHN treated with SBRT. Seven patients (7%) were treated after surgical resection of rSCCHN and 89 patients (93%) were treated definitively. PET-CT treatment planning was used for 45 patients whereas non-PET-CT planning was used for 51 patients. Categories of failure were assigned by comparing recurrences on post-treatment scans to the planning target volume (PTV) from planning scans using the deformable registration function of VelocityAI™. Failures were defined: In-field (>75% inside PTV), Overlap (20-75% inside PTV), Marginal (<20% inside PTV but closest edge within 1cm of PTV), or Regional/Distant (more than 1cm from PTV).
Median follow-up was 7.4 months (range, 2.6–52 months). Of 96 patients, 47 (49%) developed post-SBRT failure. Failure distribution was: In-field–12.3%, Overlap–24.6%, Marginal–36.8%, Regional/Distant–26.3%. There was a significant improvement in overall failure-free survival (log rank p = 0.037) and combined Overlap/Marginal failure-free survival (log rank p = 0.037) for those receiving PET-CT planning vs. non-PET-CT planning in the overall cohort (n = 96). Analysis of the definitive SBRT subgroup (n = 89) increased the significance of these findings (overall failure: p = 0.008, Overlap/Marginal failure: p = 0.009). There were no significant differences in age, gender, time from prior radiation, dose, use of cetuximab with SBRT, tumor differentiation, and tumor volume between the PET-CT and non-PET-CT groups.
Most failures after SBRT treatment for rSCCHN were near misses, i.e. Overlap/Marginal failures (61.4%), suggesting an opportunity to improve outcomes with more sensitive imaging. PET-CT treatment planning showed the lowest rate of overall and near miss failures and is beneficial for SBRT treatment planning.
PMCID: PMC3414786  PMID: 22515371
Stereotactic body radiotherapy; Recurrent head & neck cancer; Salvage; PET-CT; Patterns of failure
16.  Induction Docetaxel, Cisplatin, and Cetuximab Followed by Concurrent Radiotherapy, Cisplatin, and Cetuximab and Maintenance Cetuximab in Patients With Locally Advanced Head and Neck Cancer 
Journal of Clinical Oncology  2010;28(36):5294-5300.
We incorporated cetuximab, a chimeric monoclonal antibody against the epidermal growth factor receptor (EGFR), into the induction therapy and subsequent chemoradiotherapy of head and neck cancer (HNC).
Patients and Methods
Patients with locally advanced HNC, including squamous and undifferentiated histologies, were treated with docetaxel 75 mg/m2 day 1, cisplatin 75 mg/m2 day 1, and cetuximab 250 mg/m2 days 1, 8, and 15 (after an initial loading dose of 400 mg/m2), termed TPE, repeated every 21 days for three cycles, followed by radiotherapy with concurrent cisplatin 30 mg/m2 and cetuximab weekly (XPE), and maintenance cetuximab for 6 months. Quality of life (QOL) was assessed using Functional Assessment of Cancer Therapy–Head and Neck. In situ hybridization (ISH) for human papillomavirus (HPV), immunohistochemistry for p16, and fluorescence ISH for EGFR gene copy number were performed on tissue microarrays.
Of 39 enrolled patients, 36 had stage IV disease and 23 an oropharyngeal primary. Acute toxicities during TPE included neutropenic fever (10%) and during XPE, grade 3 or 4 oral mucositis (54%) and hypomagnesemia (39%). With a median follow-up of 36 months, 3-year progression-free survival and overall survival were 70% and 74%, respectively. Eight patients progressed in locoregional sites, three in distant, and one in both. HPV positivity was not associated with treatment efficacy. No progression-free patient remained G-tube dependent. The H&N subscale QOL scores showed a significant decrement at 3 months after XPE, which normalized at 1 year.
This cetuximab-containing regimen resulted in excellent long-term survival and safety, and warrants further evaluation in both HPV-positive and -negative HNC.
PMCID: PMC3018361  PMID: 21079141
17.  Radiotherapy and temozolomide for newly diagnosed glioblastoma and anaplastic astrocytoma: validation of Radiation Therapy Oncology Group-Recursive Partitioning Analysis in the IMRT and temozolomide era 
Journal of Neuro-Oncology  2010;104(1):339-349.
Since the development of the Radiation Therapy Oncology Group-Recursive Partitioning Analysis (RTOG-RPA) risk classes for high-grade glioma, radiation therapy in combination with temozolomide (TMZ) has become standard care. While this combination has improved survival, the prognosis remains poor in the majority of patients. Therefore, strong interest in high-grade gliomas from basic research to clinical trials persists. We sought to evaluate whether the current RTOG-RPA retains prognostic significance in the TMZ era or alternatively, if modifications better prognosticate the optimal selection of patients with similar baseline prognosis for future clinical protocols. The records of 159 patients with newly-diagnosed glioblastoma (GBM, WHO grade IV) or anaplastic astrocytoma (AA, WHO grade III) were reviewed. Patients were treated with intensity-modulated radiation therapy (IMRT) and concurrent followed by adjuvant TMZ (n = 154) or adjuvant TMZ only (n = 5). The primary endpoint was overall survival. Three separate analyses were performed: (1) application of RTOG-RPA to the study cohort and calculation of subsequent survival curves, (2) fit a new tree model with the same predictors in RTOG-RPA, and (3) fit a new tree model with an expanded predictor set. All analyses used a regression tree analysis with a survival outcome fit to formulate new risk classes. Overall median survival was 14.9 months. Using the RTOG-RPA, the six classes retained their relative prognostic significance and overall ordering, with the corresponding survival distributions significantly different from each other (P < 0.01, χ2 statistic = 70). New recursive partitioning limited to the predictors in RTOG-RPA defined four risk groups based on Karnofsky Performance Status (KPS), histology, age, length of neurologic symptoms, and mental status. Analysis across the expanded predictors defined six risk classes, including the same five variables plus tumor location, tobacco use, and hospitalization during radiation therapy. Patients with excellent functional status, AA, and frontal lobe tumors had the best prognosis. For patients with newly-diagnosed high-grade gliomas, RTOG-RPA classes retained prognostic significance in patients treated with TMZ and IMRT. In contrast to RTOG-RPA, in our modified RPA model, KPS rather than age represented the initial split. New recursive partitioning identified potential modifications to RTOG-RPA that should be further explored with a larger data set.
PMCID: PMC3151374  PMID: 21181233
Glioblastoma; Anaplastic Astrocytoma; RTOG-RPA; Validation; Temozolomide; IMRT
18.  A multi-institutional mobility model for regional deployment of Telesynergy telemedicine systems 
The Telesynergy workstation is a remote medical consultation system that provides medical staff with the means to collaborate with one another on cancer research and treatment. There are about 25 systems in use around the world. In order to share the equipment with five community hospital partners in Western Pennsylvania, we designed and implemented a transport system for the workstation. Small groups can be accommodated within the trailer and larger groups can participate inside a building when the system is offloaded at a suitable site. We designed special transport cases for the main components and chose a trailer suitable to move them by road. The transport cases were secured by inexpensive, ratchet style tiedown devices made of woven nylon webbing with steel end hooks. Calculations suggest that these restraints are sufficient to protect the equipment in a 48 km/h vehicle collision. During the first 12 months, we moved the trailer more than 700 km without system damage. Mobile videoconferencing seems to be successful on both environmental and cost grounds.
PMCID: PMC2843398  PMID: 19948703
19.  Novel Method for Benchmarking Recruitment of African American Cancer Patients to Clinical Therapeutic Trials 
Journal of Clinical Oncology  2008;26(31):5074-5077.
The National Cancer Institute (NCI) has historically evaluated the participation of underserved minorities within University of Pittsburgh Cancer Institute (UPCI) clinical trials in relation to the proportion of African Americans in the general population of the UPCI primary service area of Allegheny County (12%). This standard seemed to be unrealistically high as a result of a younger age distribution of African Americans within the county.
The proportions of African Americans within the following four separate county populations were compared using data from 2000 to 2004: general population; invasive cancer patients; invasive cancer patients diagnosed or treated at UPCI-affiliated facilities; and patients enrolled onto UPCI's clinical therapeutic trials.
Although the proportion of African Americans within the general population was approximately 13%, only 9.8% of patients diagnosed with invasive cancers were African American. Approximately 9.5% of all cancer patients diagnosed or treated at UPCI facilities were African American, which is comparable to the county-wide percentage of African American cancer patients. Recruitment rate of African Americans to oncology clinical trials from within the UPCI patient population was 7.6%. The NCI benchmark did not reflect the actual invasive cancer incidence rate in African American patients. By comparing the percentage of African Americans contributing to cancer incidence with the percentage of African American cancer patients treated at research-affiliated institutions, a more appropriate benchmark was derived.
The method developed by UPCI is recommended as a useful mechanism for benchmarking recruitment of African American cancer patients to clinical therapeutic trials at other cancer centers.
PMCID: PMC2737051  PMID: 18809610
20.  Comparison of knowledge and attitudes toward cancer among African Americans 
Infectious Agents and Cancer  2009;4(Suppl 1):S15.
It has been noted that the African American population in the U.S. bears disproportionately higher cancer morbidity and mortality rates than any racial and ethnic group for most major cancers. Many studies also document that decreased longevity is associated with low educational attainment and other markers of low socioeconomic status (SES), both of which are prevalent in African American communities across the nation. Evidence suggests that this phenomenon may be due to attitudes that reflect a lack of knowledge surrounding facts about cancer awareness and prevention. This study was designed to yield data concerning the general population's attitudes toward cancer, taking into consideration racial and/or socioeconomic differences in the population studied.
Two hundred and fifteen subjects participated in the survey, of which 74% (159/215) defined themselves as African-American, 20% were White, and 6% were of other races. While only 38% of the study population was able to identify at least 5 risk factors associated with cancer, a lower proportion of African Americans identified at least 5 risk factors than whites (34% vs. 53%, p = 0.03). In addition, a slightly higher percentage of African Americans (10%) were not aware of the definition of a clinical trial when compared to whites (8%, p > 0.1). Of those aware of the definition of a clinical trial, African Americans were more reluctant to participate in clinical trials, with 53% answering no to participation compared to 15% of whites (p = 0.002).
When comparing results to a similar study conducted in 1981, a slight increase in cancer knowledge in the African American population was observed. Our results suggest that while knowledge of cancer facts has increased over the years amongst the general population, African Americans and lower income populations are still behind. This may affect their risk profile and cancer early detection.
PMCID: PMC2638460  PMID: 19208206
21.  Knowledge about human papillomavirus and the HPV vaccine – a survey of the general population 
Infectious Agents and Cancer  2009;4(Suppl 1):S10.
The United States (US) Food & Drug Administration (FDA) recently approved a human papillomavirus (HPV) vaccine with the purpose of reducing the risk of cervical cancers caused by HPV 16 and HPV 18. It is important that the general population be educated about HPV and the HPV vaccine in order to make the appropriate decision whether or not to vaccinate against this virus. Participants from the adult US general population of Pittsburgh, Pennsylvania, USA and Hampton, Virginia, USA (18+ years old) were surveyed to determine their knowledge about HPV and the HPV vaccine, and to evaluate their perception of the vaccine efficacy and safety.
We report herein preliminary data for 202 participants. Fifty-five percent (55%) of the study population was White, 45% Black, and 1% was from other ethnic groups or did not disclose their ethnicity. A large proportion of participants had heard of the human papillomavirus (overall population: 93.6%; Pittsburgh: 95%; Hampton: 90%). Participants of African descent were slightly less aware of HPV than Whites (Black 89% vs. Whites 97%, p > 0.1). Although the majority of participants knew that HPV caused cervical cancer (84%), Whites were more informed than Black participants (91% vs. 73%, p = 0.044). Eighty-seven percent (87%) of participants had heard of the HPV vaccine (Pittsburgh: 92% and Hampton: 74%, p = 0.029); a higher proportion of Whites were aware of the vaccine when compared with Blacks (93% vs. 76%, p = 0.031). However, only 18% of the population knew that the current FDA-approved vaccine protected against genital warts and most cervical cancer (20% of Blacks and 16% of Whites, p > 0.1).
These data suggest that although the general population might be aware of HPV and the HPV vaccine, knowledge of the benefits of the HPV vaccination may not be apparent. Knowledge of HPV and the HPV vaccine could result in a likely choice of HPV vaccination and would subsequently reduce the incidence of cervical cancer.
PMCID: PMC2638455  PMID: 19208201
22.  High-dose rate brachytherapy (HDRB) for primary or recurrent cancer in the vagina 
The purpose of this study was to evaluate the efficacy of HDR brachytherapy for primary or recurrent vaginal cancer.
Between the years 2000 to 2006, 18 patients with primary or recurrent vaginal cancer were treated with brachytherapy (HDRB). Six patients had primary vaginal cancer (stage II to IVA) while 12 were treated for isolated vaginal recurrence (primary cervix = 4, vulva = 1 and endometrium = 7). Five patients had previous pelvic radiation therapy. All except one patient received external beam radiation therapy to a median dose of 45 Gy (range 31.2–55.8 Gy). The HDRB was intracavitary using a vaginal cylinder in 5 patients and interstitial using a modified Syed-Nesblett template in 13 patients. The dose of interstitial brachytherapy was 18.75 Gy in 5 fractions delivered twice daily. The median follow-up was 18 months (range 6–66 months).
Complete response (CR) was achieved in all but one patient (94%). Of these 17 patients achieving a CR, 1 had local recurrence and 3 had systemic recurrence at a median time of 6 months (range 6–22 months). The 2-year actuarial local control and cause-specific survival for the entire group were 88% and 82.5%, respectively. In subset analysis, the crude local control was 100% for primary vaginal cancer, 100% for the group with recurrence without any prior radiation and 67% for group with recurrence and prior radiation therapy. Two patients had late grade 3 or higher morbidity (rectovaginal fistula in one patient and chronic vaginal ulcer resulting in bleeding in one patient). Both these patients had prior radiation therapy.
Our small series suggests that HDRB is efficacious for primary or recurrent vaginal cancer. Patients treated with primary disease and those with recurrent disease without prior irradiation have the greatest benefit from HDRB in this setting. The salvage rate for patients with prior radiation therapy is lower with a higher risk of significant complications. Additional patients and follow-up are ongoing to determine the long-term efficacy of this approach.
PMCID: PMC2270281  PMID: 18271958
23.  Breast cancer risk assessment in socioeconomically disadvantaged urban communities. 
During 2005, a risk assessment tool based on the Gail model was used to calculate the five-year risk of developing breast cancer for 445 women who live in socioeconomically disadvantaged urban communities in western Pennsylvania and who attended health fairs and other community-sponsored activities. This tool allowed us to evaluate each woman and advise her of her risks in a process lasting 15-20 minutes. Of the 445 women, 71.7% were black and 21.6% had a higher than average risk. The proportion of white women at high risk was significantly greater than the proportion of black women at high risk (33.3% vs. 16.9%; P < 0.01). The Gail model assessment tool for use in low-income and minority populations holds promise because it is noninvasive, is easy to use and provides immediate data about risk. This risk communication may help encourage minority and low-income women to receive screening mammography. It has the potential to improve breast cancer screening rates.
PMCID: PMC2574352  PMID: 17668640
24.  Radiation medicine innovations for the new millenium. 
PURPOSE OF THE STUDY: To review technological advances in the field of radiation oncology in the management of benign and malignant diseases. BASIC PROCEDURES: We reviewed major advances in the field of radiation oncology in the past decade with special emphasis on reduction of treatment related toxicities, and technological improvements in planning and delivery of radiation. Modalities reviewed include computerized three-dimensional conformal treatment planning, stereotactic radiosurgery, intensity-modulated radiation therapy, ultrasound-guided transperineal permanent brachytherapy of the prostate, and high-dose rate brachytherapy. MAIN FINDINGS: There have been major technological advances as evidenced by a decrease in treatment-related toxicities and better target definition resulting in higher local control rates. PRINCIPAL CONCLUSIONS: Significant improvements in technique and equipment have firmly positioned radiotherapy as major artillery in the fight against both benign and malignant diseases.
PMCID: PMC2594374  PMID: 12656450
25.  Multi‐institutional, randomized, double‐blind, placebo‐controlled trial to assess the efficacy of a mucoadhesive hydrogel (MuGard) in mitigating oral mucositis symptoms in patients being treated with chemoradiation therapy for cancers of the head and neck 
Cancer  2014;120(9):1433-1440.
The objective of this trial was to determine how a mucoadhesive hydrogel (MuGard), a marketed medical device, would fare when tested with the strictness of a conventional multi‐institutional, double‐blind, randomized, placebo‐controlled study format.
A total of 120 subjects planned to receive chemoradiation therapy (CRT) for treatment of head and neck cancers were randomized to receive either MuGard or sham control rinse (SC) during CRT. Subjects completed the validated Oral Mucositis Daily Questionnaire. Weight, opiate use, and World Health Organization (WHO) oral mucositis (OM) scores were recorded. Subjects who dosed at least once daily during the first 2.5 weeks of CRT were included in the efficacy analysis.
Of 120 subjects enrolled, 78 (SC, N = 41; MuGard, N = 37) were eligible for efficacy analysis. Both cohorts were similar in demographics, baseline characteristics, primary tumor type, and planned CRT regimen. MuGard effectively mitigated OM symptoms as reflected by area under the curve of daily patient‐reported oral soreness (P = .034) and WHO scores on the last day of radiation therapy (P = .038). MuGard was also associated with nonsignificant trends related to therapeutic benefit including opioid use duration, and OM scores (WHO criteria) at CRT week 4. Rinse compliance was identical between cohorts. No significant adverse events were reported, and the adverse event incidence was similar between cohorts.
Testing MuGard, a rinse marketed as a device, in a standard clinical trial format demonstrated its superiority to SC in mitigating OM symptoms, delaying OM progression, and its safety and tolerability. Cancer 2014;120:1433–1440. © 2014 Access Pharmaceuticals, Inc. Cancer published by Wiley Periodicals. Inc. on behalf of American Cancer Society.
In a randomized, double‐blind, placebo‐controlled trial, the mucoadhesive hydrogel MuGard proved to be superior to saline‐bicarbonate rinse in mitigating oral mucositis (OM) symptoms and delaying OM progression. MuGard was safe and well‐tolerated, and favorably affected the rate and incidence of ulcerative lesions, consistent with the patient‐reported outcomes.
PMCID: PMC4164024  PMID: 24877167
mucositis; mucoadhesive gel; head and neck cancer; chemoradiation

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