Thyroid-optimized and thyroid-sparing radiotherapy in oral cavity and oropharyngeal carcinoma: A dosimetric study.

BACKGROUND: Radiation-induced hypothyroidism is a common toxicity of head and neck radiation. Our re-planning study aimed to reduce thyroid dose while maintaining target coverage with IMRT. METHODS: We retrospectively identified patients with oral-cavity (n = 5) and oropharyngeal cancer (n = 5). Treatment plans were re-optimized with 45 Gy thyroid mean dose constraint, then we cropped the thyroid out of PTVs and further reduced thyroid dose. Target coverage was delivering 100% dose to ≥ 93% of PTV and 95% of dose to > 99% of PTV. RESULTS: Originally, average mean dose to thyroid was 5580 cGy. In model I, this dropped to 4325 cGy (p < 0.0001). In model II, average mean dose was reduced to 3154 cGy (p < 0.0001). For PTV low and PTV int, all had acceptable target coverage. CONCLUSION: In patients with oral-cavity and oropharyngeal cancers, mean dose could be significantly reduced using a thyroid-optimized or thyroid-sparing IMRT technique with adequate coverage.

Primary vs nodal site PET/CT response as a prognostic marker in oropharyngeal squamous cell carcinoma treated with intensity-modulated radiation therapy.

BACKGROUND: Positron emission tomography/computed tomography (PET/CT) in staging of advanced oropharyngeal squamous cell carcinoma (OPSCC) and at 3 months posttreatment (PETpost) is often utilized to assess response. The significance of lymph node vs primary site treatment response is incompletely understood. METHODS: We reviewed 230 patients treated with radiation therapy. PETpost response was graded at primary and nodal sites and correlated with survival. RESULTS: Median age was 58, and 83% were p16-positive. Median follow-up was 24.3 months. Nodal response at PETpost predicted improved 2-year local recurrence-free survival (LRFS) (93% vs 72%, P =.004), 2-year disease-free survival (DFS) (80% vs 61.3%, P =.021), and 2-year overall survival (OS) (89% vs 83%, P =.051), while primary response only predicted improved 2-year LRFS (91% vs 76% P = .035). CONCLUSION: In OPSCC patients, both nodal and primary response at 3 months on PET/CT predicted for improved LRFS, but only nodal response predicted DFS and OS.

Platinum-based regimens versus cetuximab in definitive chemoradiation for human papillomavirus-unrelated head and neck cancer.

For patients ineligible for cisplatin with definitive radiotherapy (CP-CRT) for locally advanced head and neck squamous cell carcinoma (LA-HNSCC), concurrent cetuximab (C225-RT) is a popular substitute. Carboplatin-based chemoradiation (CB-CRT) is another option; however, relative efficacies of CP-CRT, CB-CRT and C225-RT are unclear, particularly in the human papillomavirus (HPV)-unrelated population. We identified 316 patients with stage III-IVB cancers of the oropharynx (24.7%), larynx (58.2%) and hypopharynx (17.1%) undergoing definitive C225-RT (N = 61), CB-CRT (N = 74) or CP-CRT (N = 181). Kaplan-Meier and cumulative incidence functions were generated to estimate overall survival (OS), locoregional failure (LRF) and distant metastasis (DM). Cox proportional hazards were used to determine the association of survival endpoints with clinical characteristics. Respectively, 3-year cumulative incidences for CP-CRT, CB-CRT and C225-RT were: LRF (0.19, 0.18 and 0.48, p ≤ 0.001), DM (0.17, 0.12 and 0.25, p = 0.32). Kaplan-Meier estimates for 3 year OS were: CP-CRT: 71%; CB-CRT: 59% and C225-RT: 54%; p = 0.0094. CP-CRT (hazard ratio [HR] 0.336; 95% confidence interval [CI] 0.203-0.557, p < 0.01) and CB-CRT (HR 0.279; 95% CI 0.141-0.551, p < 0.01) were associated with reduced hazard for LRF on multivariable analysis. CP-CRT (HR 0.548; 95% CI 0.355-0.845, p < 0.01) and CB-CRT (HR 0.549; 95% CI 0.334-0.904, p = 0.02) were associated with a reduced hazard for death on multivariable analysis. Propensity matching confirmed reduced hazards with a combined CP/CB-CRT group compared to C225-RT for LRF: HR 0.384 (p = 0.018) and OS: HR 0.557 (p = 0.045) and CB-CRT group compared to C225-RT for LRF: HR 0.427 (p = 0.023). In conclusion, CB-CRT is an effective alternative to CP-CRT in HPV-unrelated LA-HNSCC with superior locoregional control and OS compared to C225-RT.

Heterogeneity in Outcomes of Pathologic T1-2N1 Breast Cancer After Mastectomy: Looking Beyond Locoregional Failure Rates.

PURPOSE: A meta-analysis of 22 randomized trials accrued from 1964 to 1986 demonstrated significantly higher rates of locoregional failure (LRF) and breast-cancer mortality in women with 1-3 positive nodes without postmastectomy radiotherapy (PMRT) after mastectomy (mast.). Recent data demonstrate that PMRT reduces distant metastases (DM) in women with pN1 disease. The challenge today is whether all patients with pathologic T1-2pN1 disease have similar substantial LRF/DM risk that routinely warrants PMRT. METHODS: We reviewed patients with pT1-2N1 breast cancer treated with mast. ± adjuvant systemic therapy without PMRT from 2000 to 2013. The endpoints were LRF and DM rates, estimated by cumulative incidence method. RESULTS: We identified 468 patients with median follow-up of 6.3 years. Most (71%) were estrogen receptor/progesterone receptor + human epidermal growth factor receptor 2 (HER2). There were 269 patients with 1+ node, 140 patients with 2+ nodes, and 59 patients with 3+ nodes. The 6-year LRF/DM rates were 4.1%/8.4%. Patients with 1+, 2+, and 3+ nodes had 6-year LRF of 2.3, 5.1 and 8.9%, respectively (p = 0.13). The 6-year DM rate was higher in patients with 3+ nodes versus 1-2+ nodes: 15.7% versus 7.4% (p = 0.02). Several subgroups had low 6-year LRF and DM rates, including T1/1+ node (0.8%/4.1% LRF/DM) and micrometastases (0%/5.8% LRF/DM). CONCLUSIONS: Patients with pT1-2pN1 represent a heterogeneous group with a wide range of LRF/DM rates. In particular, patients with pT1 tumors and 1 + LN, and patients with micrometastases, had low event rates. These groups would derive small absolute reductions in LRF and DM with addition of PMRT, underscoring the importance of patient selection for PMRT in pT1-2pN1 breast cancer.

Mutational landscape of radiation-associated angiosarcoma of the breast.

PURPOSE: Radiation-associated breast angiosarcomas are a rare complication of radiation therapy for breast carcinoma. With relatively little is known about the genetic abnormalities present in these secondary tumors, we examined genomic variation in biospecimens from radiation-associated breast angiosarcomas. EXPERIMENTAL DESIGN: Patients were identified that had a previous breast cancer diagnosis, received radiation therapy, and developed angiosarcoma in the ipsilateral breast as the earlier cancer. Tumor regions were isolated from archival blocks using subsequent laser capture microdissection. Next generation sequencing was performed using a targeted panel of 160 cancer-related genes. Genomic variants were identified for mutation and trinucleotide-based mutational signature analysis. RESULTS: 44 variants in 34 genes were found in more than two thirds of the cases; this included 12 variants identified as potentially deleterious. Of particular note, the BRCA1 DNA damage response pathway was highly enriched with genetic variation. In a comparison to local recurrences, 14 variants in 11 genes were present in both the primary and recurrent lesions including variants in genes associated with the DNA damage response machinery. Furthermore, the mutational signature analysis shows that a previously defined IR signature is present in almost all of the current samples characterized by predominantly C→T substitutions. CONCLUSIONS: While radiation-associated breast angiosarcomas are relatively uncommon, their prognosis is very poor. These data demonstrate a mutational pattern associated with genes involved in DNA repair. While important in revealing the biology behind these tumors, it may also suggest new treatment strategies that will prove successful.

Clinical outcomes and prognostic factors in cisplatin versus cetuximab chemoradiation for locally advanced p16 positive oropharyngeal carcinoma.

OBJECTIVES: Randomized trials evaluating cisplatin versus cetuximab chemoradiation (CRT) for p16+ oropharyngeal cancer (OPC) have yet to report preliminary data. Meanwhile, as a preemptive step toward morbidity reduction, the off-trial use of cetuximab in p16+ patients is increasing, even in those who could potentially tolerate cisplatin. The purpose of this study was to compare the efficacy of cisplatin versus cetuximab CRT in the treatment of p16+ OPC and to identify prognostic factors and predictors of tumor response. MATERIALS AND METHODS: Cases of p16+ OPC treated with cisplatin or cetuximab CRT at our institution from 2010 to 2014 were identified. Recursive partitioning analysis (RPA) classification was used to determine low-risk (LR-RPA) and intermediate-risk (IR-RPA) groups. Log-rank/Kaplan-Meier and Cox Regression methods were used to compare groups. RESULTS: We identified 205 patients who received cisplatin (n = 137) or cetuximab (n = 68) CRT in the definitive (n = 178) or postoperative (n = 27) setting. Median follow-up was 3 years. Cisplatin improved 3-year locoregional control (LRC) [92.7 vs 65.4%], distant metastasis-free survival (DMFS) [88.3 vs 71.2%], recurrence-free survival (RFS) [86.6 vs 50.6%], and overall survival (OS) [92.6 vs 72.2%] compared to cetuximab [all p < .001]. Concurrent cisplatin improved 3-year OS for LR-RPA (97.1 vs 80.3%, p < .001) and IR-RPA (97.1 vs 80.3%, p < .001) groupings. CONCLUSION: When treating p16+ OPC with CRT, the threshold for substitution of cisplatin with cetuximab should be maintained appropriately high in order to prolong survival times and optimize locoregional and distant tumor control. When cetuximab is used in cisplatin-ineligible patients, altered fractionation RT should be considered in an effort to improve LRC.

Sinonasal adenoid cystic carcinoma: Treatment outcomes and association with human papillomavirus.

BACKGROUND: The purpose of this study was to review long-term outcomes of sinonasal adenoid cystic carcinoma (ACC) and to clarify its association with human papillomavirus (HPV). METHODS: The medical records of 23 patients with sinonasal ACC treated with primary surgical resection between 1998 and 2013 were reviewed. Tissue specimens were available for 17 patients. The p16 testing was performed using immunohistochemistry (IHC), and HPV infection was determined using quantitative polymerase chain reaction (PCR) with primers targeting the E6/E7 region. RESULTS: Two of the 17 samples showed strong and diffuse p16 staining, whereas the remaining 15 cases showed p16-positivity isolated to the luminal cells. Only one of the p16-positive cases was positive for HPV. The 5-year local failure, disease-free survival (DFS), and overall survival (OS) were 51%, 52%, and 62%, respectively. CONCLUSION: Local failures are common with advanced sinonasal ACC, and the association of HPV with true sinonasal ACC is low.

Multivariate Preoperative and Intraoperative Predictors of Postmastectomy Radiation Therapy in Patients for Whom Immediate Breast Reconstruction Is Planned.

BACKGROUND: Postmastectomy radiation therapy often impacts decision-making and outcomes of breast reconstruction. However, plastic surgeons typically have limited information regarding the likelihood of radiation therapy when decisions about immediate breast reconstruction are made. The study objective was to examine whether commonly available information can be used to predict the probability of radiation therapy. METHODS: A retrospective review was performed of patients undergoing mastectomy and sentinel lymph node biopsy. Multivariate logistic regression analysis of variables available in greater than 95 percent of patients was performed in relation to predicting radiation therapy. RESULTS: A total of 322 patients were reviewed, of whom 55 (17.1 percent) received radiation therapy, which was indicated for patients having four or more positive axillary lymph nodes in all cases. Multivariate logistic regression identified the intraoperative sentinel lymph node frozen section results (OR, 27.3), tumor size (OR, 1.7), and age (OR, 0.96) as significant predictors. The sentinel lymph node frozen section exhibited negative and positive predictive values for radiation therapy of 95.4 percent and 54.3 percent, respectively. When sentinel lymph node frozen section was combined with tumor size greater than or equal to 2.0 cm, the positive predictive value increased to 80.5 percent. CONCLUSION: Immediate breast reconstruction patients who have negative intraoperative sentinel lymph node frozen section results have a less than 5 percent chance of radiation therapy, whereas patients with positive intraoperative sentinel lymph node frozen section results and tumor size greater than or equal to 2.0 cm have a greater than 80 percent chance of radiation therapy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Seven-Year Outcomes Following Accelerated Partial Breast Irradiation Stratified by ASTRO Consensus Groupings.

OBJECTIVES: Limited long-term data exist regarding outcomes for patients treated with accelerated partial breast irradiation (APBI), particularly, when stratified by American Society for Radiation Oncology (ASTRO) Consensus Statement (CS) risk groups. The purpose of this analysis is to present 5- and 7-year outcomes following APBI based on CS groupings. MATERIALS AND METHODS: A total of 690 patients with early-stage breast cancer underwent APBI from 1993 to 2012, receiving interstitial brachytherapy (n=195), balloon-based brachytherapy (n=290), or 3-dimensional conformal radiotherapy (n=205) at a single institution. Patients were stratified into suitable, cautionary, and unsuitable groups with 5-year outcomes analyzed. Seven-year outcomes were analyzed for a subset with follow-up of ≥2 years (n=625). RESULTS: Median follow-up was 6.7 years (range, 0.1 to 20.1 y). Patients assigned to cautionary and unsuitable categories were more likely to have high-grade tumors (21% to 25% vs. 9%, P=0.001), receive chemotherapy (15% to 38% vs. 6%, P<0.001), and have close/positive margins (9% to 11% vs. 0%, P<0.001). There was no difference in ipsilateral breast tumor recurrence at 5 or 7 years: 2.2%, 1.2%, 2.8% at 5 years (P=0.57), and 2.2%, 1.9%, 4.6% at 7 years (P=0.58) in the suitable, cautionary, and unsuitable groups, respectively. As compared with the suitable group, increased rates of distant metastases were noted for the unsuitable and cautionary groups at 5 years (P=0.04). CONCLUSIONS: No differences in rates of ipsilateral breast tumor recurrence were seen at 5 or 7 years when stratified by ASTRO CS groupings. Modest increases in distant recurrence were noted in the cautionary and unsuitable groups. These findings suggest that the ASTRO CS groupings stratify more for systemic recurrence and may not appropriately select patients for whole versus partial breast irradiation.

Adjuvant Radiotherapy in Early-Stage Breast Cancer: Evidence-Based Options.

BACKGROUND: Patients with a diagnosis of early-stage breast cancer are offered the option of either mastectomy or breast-conserving therapy (BCT) secondary to multiple randomized trials demonstrating equivalent long-term outcomes. Traditionally, BCT has used standard whole-breast irradiation (SWBI) after breast-conserving surgery, although several alternatives have emerged during the past few decades. METHODS: This report reviews key studies supporting each radiation technique and its respective eligibility criteria to assist clinicians in deciding which adjuvant radiotherapy options are appropriate for their patients. RESULTS: In the past, completion of SWBI required 5-7 weeks of daily treatments. During the past two decades, alternatives to SWBI have emerged including hypofractionated whole-breast irradiation (3-4 weeks), accelerated partial-breast irradiation (1-3 weeks), and endocrine therapy alone. Multiple randomized trials have established the equivalence of these alternative strategies to SWBI for appropriately selected patients. Additionally, the current guidelines for patient selection demonstrate a large amount of overlap in the selection criteria for each technique. CONCLUSION: Clinicians must evaluate patient and pathologic criteria and engage in informed discussions with patients when determining which adjuvant radiation techniques are appropriate. Future strategies being explored include using tumor genetics to identify low-risk patients and switching from paradigms that omit radiotherapy to those that omit endocrine therapy.

Accelerated partial breast irradiation: An update on published Level I evidence.

Multiple adjuvant radiation therapy options currently exist for women following breast-conserving surgery including standard fractionated whole breast irradiation (WBI), accelerated whole breast irradiation (AWBI), and accelerated partial breast irradiation (APBI). The recent publication of several randomized trials comparing APBI to standard WBI provides Level I evidence supporting APBI. The purpose of this review is to summarize the Level I data supporting APBI in an effort to provide guidance when to offer this treatment approach vs. standard WBI, AWBI, or excision alone and to address questions related to its application. Four contemporary trials with over 2000 patients comparing APBI and WBI have been published and demonstrate no differences in the rates of local/regional recurrence or survival though long-term followup is limited to one study. In addition, reductions in the rates of acute and chronic toxicity and improvements in cosmetic outcome were noted in two of these trials (the University of Florence and the Hungarian Phase III trials, respectively). When contrasting other treatment approaches to APBI, patients treated in studies using AWBI have many comparable clinical and pathologic characteristics, whereas studies investigating endocrine therapy alone (surgery with no adjuvant radiation therapy) have much "lower risk" patients based on clinical, pathologic, and treatment-related criteria. Although significant Level I evidence now exists supporting the use of APBI as an alternative to WBI in selected patients undergoing breast-conserving therapy, additional data are needed to (1) help further refine patient selection criteria, (2) better clarify the optimal partial breast irradiation target and technique for each clinical setting, (3) determine when AWBI, standard WBI, or excision alone may be more appropriate, and (4) investigate if further reductions in fractionation schedules are possible.

Management of Ductal Carcinoma In Situ of the Breast: A Review.

IMPORTANCE: Ductal carcinoma in situ (DCIS) of the breast represents a disease process that continues to increase in incidence with treatment paradigms that continue to evolve. Greater access to long-term data from large observational studies addressing the natural history of the disease has contributed to changes in treatment paradigms and put into question traditional management strategies. OBSERVATIONS: While recent analyses have suggested that a more conservative approach to the management of DCIS without surgical intervention or radiation therapy may be advisable based on breast cancer mortality data, there is a lack of level 1 or prospective evidence to support the widespread adoption of these approaches. Currently, surgery remains the standard of care for the initial treatment of DCIS. Adjuvant radiation therapy (RT) has consistently demonstrated a reduction in the risk of local recurrence following breast-conserving surgery (BCS), even in "low-risk" populations of patients. Invasive recurrences following BCS are associated with increases in breast cancer mortality. Questions that remain to be answered include (1) what constitutes an acceptable risk of local recurrence, (2) what are the costs associated with managing local recurrences compared with RT given initially after BCS (particularly in light of data supporting shorter courses of RT), and (3) what are the benefits of endocrine therapy on local recurrence, and do they justify the additional toxic effects and potential noncompliance with their long-term administration? CONCLUSIONS AND RELEVANCE: Surgery and RT remain standard of care treatment options in the management of DCIS. Future studies are required to identify cohorts of patients in which RT can be safely omitted as well as to evaluate whether short-course RT alone may represent a better option than endocrine therapy with respect to compliance, toxic effects, cost and local control following BCS.

Role of Internal Mammary Node Radiation as a Part of Modern Breast Cancer Radiation Therapy: A Systematic Review.

PURPOSE: Despite data from multiple randomized trials, the role of internal mammary lymph node irradiation as a part of regional nodal irradiation (IMLN RT-RNI) remains unanswered. Recent noteworthy data and modern RT techniques might identify a subset of patients who will benefit from IMLN RT-RNI, lending insight into the balance between improved outcomes and acceptable toxicity. We evaluated the current role of IMLN RT-RNI by analyzing randomized, prospective, and retrospective data. METHODS AND MATERIALS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a review of the published data was performed using PubMed to evaluate published studies from 1994 to 2015. The information evaluated included the number of patients, follow-up period, technical aspects of RT, and outcomes (clinical outcomes, complications/toxicity). RESULTS: We included 16 studies (4 randomized, 4 nonrandomized, 7 retrospective, and 1 meta-analysis). Although older randomized trials failed to show differences in clinical outcomes or toxicity with IMLN RT-RNI, recent randomized data suggest the potential for improved outcomes, including overall survival, with IMLN RT-RNI. Furthermore, nonrandomized data have suggested a potential benefit for central tumors with IMLN RT-RNI. Although recent data have suggested a potential increase in pulmonary complications with IMLN RT-RNI with the use of advanced radiation techniques, toxicity rates remain low with limited cardiac toxicity data available. CONCLUSIONS: Increasing data from recent randomized trials support the use of IMLN RT-RNI. IMLN RT can be considered based on the inclusion of IMLN RT as a part of RNI in recent trials and the inclusion criteria from IMLN RT-RNI trials and for patients with central or medial tumors and axillary disease.

Accelerated partial breast irradiation utilizing brachytherapy: patient selection and workflow.

Accelerated partial breast irradiation (APBI) represents an evolving technique that is a standard of care option in appropriately selected woman following breast conserving surgery. While multiple techniques now exist to deliver APBI, interstitial brachytherapy represents the technique used in several randomized trials (National Institute of Oncology, GEC-ESTRO). More recently, many centers have adopted applicator-based brachytherapy to deliver APBI due to the technical complexities of interstitial brachytherapy. The purpose of this article is to review methods to evaluate and select patients for APBI, as well as to define potential workflow mechanisms that allow for the safe and effective delivery of APBI. Multiple consensus statements have been developed to guide clinicians on determining appropriate candidates for APBI. However, recent studies have demonstrated that these guidelines fail to stratify patients according to the risk of local recurrence, and updated guidelines are expected in the years to come. Critical elements of workflow to ensure safe and effective delivery of APBI include a multidisciplinary approach and evaluation, optimization of target coverage and adherence to normal tissue guideline constraints, and proper quality assurance methods.

Brachytherapy-based Accelerated Partial Breast Irradiation Provides Equivalent 10-Year Outcomes to Whole Breast Irradiation: A Matched-Pair Analysis.

INTRODUCTION: Although whole breast irradiation (WBI) represents the standard radiotherapy technique in breast conserving therapy, accelerated partial breast irradiation (APBI) has emerged as an option to reduce treatment duration with comparable clinical outcomes. The purpose of this analysis is to present long-term clinical outcomes between WBI and APBI. METHODS: A total of 3009 patients were treated with breast conserving therapy at a single institution between 1980 and 2012. Among them, 2528 patients received WBI and 481 received APBI (interstitial or balloon based). A matched-pair analysis was performed with patients matched by age (±3 years), stage (T-stage vs. T1 vs. T2), and estrogen receptor status (+/-). All patients had a minimum of 12 months follow-up. A total of 274 matches (ratio 1:1) were made. RESULTS: No differences between groups were noted with respect to clinicopathologic features; WBI patients demonstrated a trend for slightly larger tumors (1.3 vs. 1.1 cm, P=0.06). At 10 years, no differences were noted with respect to rates of ipsilateral breast tumor recurrence (4% vs. 4%, P=0.11), regional recurrence (1% vs. 1%, P=0.20), contralateral breast failure (9% vs. 3%, P=0.06), or distant metastases (3% vs. 6%, P=0.47) for WBI and APBI, respectively. In addition, 10-year disease-free survival (93% vs. 91%, P=0.10) and overall survival (83% vs. 75%, P=0.34) were similar. Long-term cosmesis was good to excellent in 94% of WBI patients versus 95% of APBI patients (P=0.78). CONCLUSIONS: At 10 years, no differences in recurrence or survival were found between patients undergoing WBI or brachytherapy-based APBI.

Comparison of chronic toxicities between brachytherapy-based accelerated partial breast irradiation and whole breast irradiation using intensity modulated radiotherapy.

PURPOSE: Brachytherapy-based APBI (bAPBI) shortens treatment duration and limits dose to normal tissue. While studies have demonstrated similar local control when comparing bAPBI and whole breast irradiation using intensity modulated radiotherapy (WBI-IMRT), comparison of late side effects is limited. Here, we report chronic toxicity profiles associated with these two treatment modalities. METHODS: 1034 patients with early stage breast cancer were treated at a single institution; 489 received standard-fractionation WBI-IMRT between 2000 and 2013 and 545 received bAPBI (interstitial 40%, applicator-based 60%) between 1993 and 2013. Chronic toxicity was evaluated ≥6 months utilizing CTCAE version 3.0; cosmesis was evaluated using the Harvard scale. RESULTS: Median follow-up was 4.6 years (range 0.1-13.4) for WBI-IMRT versus 6.7 years (range 0.1-20.1) for bAPBI (p < 0.001). Compared to WBI-IMRT, bAPBI was associated with higher rates of ≥grade 2 seroma formation (14.4% vs 2.9%, p < 0.001), telangiectasia (12.3% vs 2.1%, p = 0.002) and symptomatic fat necrosis (10.2% vs 3.6%, p < 0.001). Lower rates of hyperpigmentation were observed (5.8% vs 14.5%; p = 0.001). Infection rates were similar (3.3% vs 1.3%, p = 0.07). There was no difference between rates of fair (6.1% vs. 4.1%, p = 0.30) or poor (0.2% vs. 0.5%, p = NS) cosmesis. Mastectomy rates for local recurrence (3.1% for WBI-IMRT and 1.2% for bAPBI, p = 0.06), or for other reasons (0.8% and 0.6%, p = 0.60) were similar between groups. CONCLUSION: With 5-year follow-up, WBI-IMRT and bAPBI are associated with similar, acceptable rates of toxicity. These data further support the utilization of bAPBI as a modality to deliver adjuvant radiation in a safe and efficacious manner.

The association of (18)F-FDG PET and glucose metabolism biomarkers GLUT1 and HK2 in p16 positive and negative head and neck squamous cell carcinomas.

OBJECTIVES: To investigate the relationship between FDG-PET maximum standard uptake value (SUVmax), p16, EGFR, GLUT1 and HK2 expression in head and neck squamous cell carcinomas (HNSCC). MATERIALS AND METHODS: Immunohistochemical staining of p16, EGFR, GLUT1 and HK2 was performed on primary tumor tissue from 97 locally advanced HNSCC patients treated with definitive chemoradiation. SUVmax along with p16, EGFR, GLUT1 and HK2 expression were analyzed for associations including local control, locoregional control and disease free survival. RESULTS: Pretreatment SUVmax in primary tumors did not differ when stratified by p16, EGFR or GLUT1 expression but SUVmax was significantly higher in HK2 expressing tumors (p=0.021) and in tumors with higher T-stage (p=0.022). GLUT1 expression was significantly higher in p16 negative (p<0.001) and EGFR positive tumors (p<0.01). HK2 expressing tumors were associated with EGFR positive tumors (p=0.022) but not with p16 or GLUT1 expression. EGFR positive, p16 negative and high GLUT1 expressing tumors were associated with worse local control and disease free survival on univariate analyses. After adjusting for patient and treatment characteristics p16 status was the only factor that predicted for outcome on multivariate analysis. CONCLUSIONS: High GLUT1 expression was associated with EGFR positive and p16 negative HNSCC tumors. GLUT1 maybe an important biomarker in HNSCC but its expression appears dependent on p16 status.

The Effects of Pulsed Radiation Therapy on Tumor Oxygenation in 2 Murine Models of Head and Neck Squamous Cell Carcinoma.

PURPOSE: To evaluate the efficacy of low-dose pulsed radiation therapy (PRT) in 2 head and neck squamous cell carcinoma (HNSCC) xenografts and to investigate the mechanism of action of PRT compared with standard radiation therapy (SRT). METHODS AND MATERIALS: Subcutaneous radiosensitive UT-SCC-14 and radioresistant UT-SCC-15 xenografts were established in athymic NIH III HO female mice. Tumors were irradiated with 2 Gy/day by continuous standard delivery (SRT: 2 Gy) or discontinuous low-dose pulsed delivery (PRT: 0.2 Gy × 10 with 3-min pulse interval) to total doses of 20 Gy (UT14) or 40 Gy (UT15) using a clinical 5-day on/2-day off schedule. Treatment response was assessed by changes in tumor volume, (18)F-fluorodeoxyglucose (FDG) (tumor metabolism), and (18)F-fluoromisonidazole (FMISO) (hypoxia) positron emission tomography (PET) imaging before, at midpoint, and after treatment. Tumor hypoxia using pimonidazole staining and vascular density (CD34 staining) were assessed by quantitative histopathology. RESULTS: UT15 and UT14 tumors responded similarly in terms of growth delay to either SRT or PRT. When compared with UT14 tumors, UT15 tumors demonstrated significantly lower uptake of FDG at all time points after irradiation. UT14 tumors demonstrated higher levels of tumor hypoxia after SRT when compared with PRT as measured by (18)F-FMISO PET. By contrast, no differences were seen in (18)F-FMISO PET imaging between SRT and PRT for UT15 tumors. Histologic analysis of pimonidazole staining mimicked the (18)F-FMISO PET imaging data, showing an increase in hypoxia in SRT-treated UT14 tumors but not PRT-treated tumors. CONCLUSIONS: Differences in (18)F-FMISO uptake for UT14 tumors after radiation therapy between PRT and SRT were measurable despite the similar tumor growth delay responses. In UT15 tumors, both SRT and PRT were equally effective at reducing tumor hypoxia to a significant level as measured by (18)F-FMISO and pimonidazole.

Nomogram for predicting the risk of locoregional recurrence in patients treated with accelerated partial-breast irradiation.

PURPOSE: To develop a nomogram taking into account clinicopathologic features to predict locoregional recurrence (LRR) in patients treated with accelerated partial-breast irradiation (APBI) for early-stage breast cancer. METHODS AND MATERIALS: A total of 2000 breasts (1990 women) were treated with APBI at William Beaumont Hospital (n=551) or on the American Society of Breast Surgeons MammoSite Registry Trial (n=1449). Techniques included multiplanar interstitial catheters (n=98), balloon-based brachytherapy (n=1689), and 3-dimensional conformal radiation therapy (n=213). Clinicopathologic variables were gathered prospectively. A nomogram was formulated utilizing the Cox proportional hazards regression model to predict for LRR. This was validated by generating a bias-corrected index and cross-validated with a concordance index. RESULTS: Median follow-up was 5.5 years (range, 0.9-18.3 years). Of the 2000 cases, 435 were excluded because of missing data. Univariate analysis found that age <50 years, pre-/perimenopausal status, close/positive margins, estrogen receptor negativity, and high grade were associated with a higher frequency of LRR. These 5 independent covariates were used to create adjusted estimates, weighting each on a scale of 0-100. The total score is identified on a points scale to obtain the probability of an LRR over the study period. The model demonstrated good concordance for predicting LRR, with a concordance index of 0.641. CONCLUSIONS: The formulation of a practical, easy-to-use nomogram for calculating the risk of LRR in patients undergoing APBI will help guide the appropriate selection of patients for off-protocol utilization of APBI.