Definitive Chemoradiation in Locally Advanced Squamous Cell Carcinoma of the Hypopharynx: Long-term Outcomes and Toxicity.

BACKGROUND/AIM: Definitive chemoradiation (CRT) is a common approach for locally advanced hypopharyngeal squamous cell carcinoma (SCC) with the goal of organ preservation. Reports on long-term oncologic and functional outcomes have been limited. This study reports on outcomes utilizing this approach at a single institution over 30 years. MATERIALS AND METHODS: Medical records for patients with stage III-IVB SCC of the hypopharynx were retrospectively reviewed. Patient and disease-related factors were identified and analyzed for impact on overall survival (OS), cancer-specific survival (CSS), disease-free survival, distant failure, and locoregional failure. RESULTS: A total of 54 patients were identified who were treated with definitive CRT to a mean dose of 72 Gy. With a median follow-up period of 49.8 months, 5- and 10-year OS was 62% and 43% respectively. Five and 10-year CSS were 74% and 72% respectively. Ten-year local control was 78%. Of the 37 patients with no treatment failure, 29% experienced a grade 3 or higher late toxicity, with the majority resolving during continued long-term follow-up. CONCLUSION: This study demonstrates good outcomes with long-term follow-up with acceptable rates of late toxicities. The findings here represent the longest published median follow-up in this population and validate the strategy of organ preservation.

p16 status, pathologic and clinical characteristics, biomolecular signature, and long-term outcomes in head and neck squamous cell carcinomas of unknown primary.

BACKGROUND: The purpose of this study was to report associations between p16 status, clinicopathologic characteristics, and outcomes for head and neck squamous cell carcinoma of unknown primary (CUP). METHODS: Specimens of squamous cell CUP were reanalyzed. Human papillomavirus (HPV) status was determined by p16 stain. A tissue microarray (TMA) was constructed to evaluate biomarkers potentially prognostic in head and neck squamous cell carcinoma (HNSCC). RESULTS: A majority of the population (n = 26; 74%) was p16 positive (+). Prognostic factors benefiting survival were p16+ status (p < .0001), absence of macroscopic extracapsular extension (ECE; p = .004), younger age (p = .01), and higher grade (p = 0.007). The prognostic implication of worse overall survival (OS) with macroscopic ECE (p = .009) remained significant when limited to patients who were p16+ (p = .002). Exploratory TMA between unknown primary and controls suggested a biomolecular difference between squamous cell CUP and known-primary cancer. CONCLUSION: The majority of patients with squamous cell CUP were p16+, indicative of HPV association. P16 staining and ECE seem to be the most prognostic features in squamous cell CUP.

Effect of Bra Use during Radiotherapy for Large-Breasted Women: Acute Toxicity and Treated Heart and Lung Volumes.

PURPOSE: Large breast size presents special problems during radiation simulation, planning and patient treatment, including increased skin toxicity, in women undergoing breast-conserving surgery and radiotherapy (BCT). We report our experience using a bra during radiation in large-breasted women and its effect on acute toxicity and heart and lung dosimetry. MATERIALS AND METHODS: From 2001 to 2006, 246 consecutive large-breasted women (bra size ≥ 38 and/or ≥ D cup) were treated with BCT using either 3D conformal (3D-CRT) or Intensity Modulated Radiation (IMRT). In 58 cases, at the physicians' discretion, a custom-fit bra was used during simulation and treatment. Endpoints were acute radiation dermatitis, and dosimetric comparison of heart and lung volumes in a subgroup of 12 left-sided breast cancer patients planned with and without a bra. RESULTS: The majority of acute skin toxicities were grade 2 and were experienced by 90% of patients in a bra compared to 70% of patients not in a bra (p=0.003). On multivariate analysis significant predictors of grade 2/3 skin toxicity included 3D-CRT instead of IMRT (OR=3.9, 95% CI:1.8-8.5) and the use of a bra (OR=5.5, 95% CI:1.6-18.8). For left-sided patients, use of a bra was associated with a volume of heart in the treatment fields decreased by 63.4% (p=0.002), a volume of left lung decreased by 18.5% (p=0.25), and chest wall separation decreased by a mean of 1 cm (p=0.03). CONCLUSIONS: The use of a bra to augment breast shape and position in large-breasted women is an alternative to prone positioning and associated with reduced chest wall separation and reduced heart volume within the treatment field.

Effect of bra use during radiation therapy for large-breasted women: Acute toxicity and treated heart and lung volumes.

PURPOSE: Large breast size presents special problems during radiation simulation, planning, and patient treatment, including increased skin toxicity, in women undergoing breast-conserving surgery and radiation therapy (BCT). We report our experience using a bra during radiation in large-breasted women and its effect on acute toxicity and heart and lung dosimetry. METHODS AND MATERIALS: From 2001 to 2006, 246 consecutive large-breasted women (bra size ≥38 or ≥D cup) were treated with BCT using either 3-dimensional conformal radiation therapy (3DCRT) or intensity modulated radiation therapy (IMRT). In 58 cases, at the physicians' discretion, a custom-fit bra was used during simulation and treatment. Endpoints were acute radiation dermatitis and dosimetric comparison of heart and lung volumes in a subgroup of 12 left-sided breast cancer patients planned with and without a bra. RESULTS: The majority of acute skin toxicities were grade 2 and were experienced by 90% of patients in a bra compared with 70% of patients not in a bra (P = .003). On multivariate analysis significant predictors of grade 2 or 3 skin toxicity included the use of 3DCRT instead of IMRT (odds ratio, 3.9; 95% confidence interval, 1.8-8.5) and the use of a bra (odds ratio, 5.5; 95% confidence interval, 1.6-18.8). For left-sided patients, the use of a bra was associated with a volume of heart in the treatment fields decreased by 63.4% (P = .002), a volume of left lung decreased by 18.5% (P = .25), and chest wall separation decreased by a mean of 1 cm (P = .03). CONCLUSIONS: The use of a bra to augment breast shape and position in large-breasted women is an alternative to prone positioning and associated with reduced chest wall separation and reduced heart volume within the treatment field.

Five-year results of whole breast intensity modulated radiation therapy for the treatment of early stage breast cancer: the Fox Chase Cancer Center experience.

PURPOSE: To report the 5-year outcomes using whole-breast intensity-modulated radiation therapy (IMRT) for the treatment of early-stage-breast cancer at the Fox Chase Cancer Center. METHODS AND MATERIALS: A total of 946 women with early-stage breast cancer (stage 0, I, or II) were treated with IMRT after surgery with or without systemic therapy from 2003-2010. Whole-breast radiation was delivered via an IMRT technique with a median whole-breast radiation dose of 46 Gy and median tumor bed boost of 14 Gy. Endpoints included local-regional recurrence, cosmesis, and late complications. RESULTS: With a median follow-up of 31 months (range, 1-97 months), there were 12 ipsilateral breast tumor recurrences (IBTR) and one locoregional recurrence. The 5-year actuarial IBTR and locoregional recurrence rates were 2.0% and 2.4%. Physician-reported cosmestic outcomes were available for 645 patients: 63% were considered "excellent", 33% "good", and <1.5% "fair/poor". For physician-reported cosmesis, boost doses≥16 Gy, breast size>900 cc, or boost volumes>34 cc were significantly associated with a "fair/poor" cosmetic outcome. Fibrosis, edema, erythema, and telangectasia were also associated with "fair/poor" physician-reported cosmesis; erythema and telangectasia remained significant on multivariate analysis. Patient-reported cosmesis was available for 548 patients, and 33%, 50%, and 17% of patients reported "excellent", "good", and "fair/poor" cosmesis, respectively. The use of a boost and increased boost volume: breast volume ratio were significantly associated with "fair/poor" outcomes. No parameter for patient-reported cosmesis was significant on multivariate analysis. The chances of experiencing a treatment related effect was significantly associated with a boost dose≥16 Gy, receipt of chemotherapy and endocrine therapy, large breast size, and electron boost energy. CONCLUSIONS: Whole-breast IMRT is associated with very low rates of local recurrence at 5 years, 83%-98% "good/excellent" cosmetic outcomes, and minimal chronic toxicity, including late fibrosis.

Stamp test delivers message on erectile dysfunction after high-dose intensity-modulated radiotherapy for prostate cancer.

OBJECTIVE: To evaluate erectile function after high-dose radiotherapy for prostate cancer using the International Index of Erectile Function, Expanded Prostate Cancer Index Composite, and stamp test. METHODS: Men with favorable and intermediate-risk prostate cancer were assigned to receive prostate intensity-modulated radiotherapy (IMRT) versus an erectile tissue-sparing IMRT technique in a Phase III randomized, prospective study. The stamp test and International Index of Erectile Function and Expanded Prostate Cancer Index Composite questionnaires were completed at baseline and 6 months, 1 year, and 2 years after IMRT. The Sexual Health Inventory for Men scores were abstracted from the International Index of Erectile Function questionnaire. A partner questionnaire, designated IIEF-P, modeled after the International Index of Erectile Function questionnaire but from the perspective of the partner, was also collected. RESULTS: The data from 94 men who were enrolled in the trial and who had completed ≥1 questionnaire or 1 stamp test were analyzed. The median age of the patient population was 62.5 years. The median radiation dose was 76 Gy (range 74-80). At 6 months and 1 year after high-dose IMRT, a positive stamp result correlated significantly with the median Expanded Prostate Cancer Index Composite sexual summary, sexual function, and bother subscale scores. Additionally, 6 months after IMRT, the stamp test correlated with the median International Index of Erectile Function, International Index of Erectile Function sexual function domain, and Sexual Health Inventory for Men scores. Robust concordance for the International Index of Erectile Function and Sexual Health Inventory for Men scores was appreciated between responding patient and partner pairs. CONCLUSION: Nocturnal tumescence, as indicated by a positive stamp test, correlated well with established quality of life questionnaires after IMRT. The stamp test should strongly be considered as an objective measure of erectile function in future studies of erectile dysfunction in patients with prostate cancer.

The role of qualitative and quantitative analysis of F18-FDG positron emission tomography in predicting pathologic response following chemoradiotherapy in patients with esophageal carcinoma.

OBJECTIVE: The aim of this study was to determine if a qualitative and quantitative assessment of pre- and post-chemoradiotherapy (CRT) F18-FDG PET scans of esophageal cancer patients could predict for residual disease in esophagectomy specimens. METHODS: We retrospectively reviewed the records of esophageal cancer patients who had undergone CRT at a single institution. Analysis was limited to esophagectomy patients with both pre- and post-CRT F18-FDG PET scans. The maximum standardized uptake value (SUV), location, and measured length of esophagus with increased F18-FDG uptake were obtained from the PET scan before and 3-4 weeks following CRT (preoperatively). The pattern of F18-FDG uptake was qualitatively assigned a category of diffuse, focal, or diffuse with focal component. RESULTS: Fifty-seven patients with localized esophageal carcinoma underwent F18-FDG PET/CT scans as part of their initial staging and post-CRT restaging workup, followed by esophagectomy. The pathologic complete response (pCR) rate was 25%. The presence of a focal component on post-CRT PET predicted residual disease on univariate analysis (86% vs. 64%), and achieved significance when controlling for SUV and presence of diabetes on MVA (OR = 5.59, p = 0.028). There was no significant relationship between pre- or post-CRT SUV, tumor histology, or length of increased F18-FDG uptake and presence of residual disease. SUV and focality did not interact significantly to predict residual disease. CONCLUSIONS: Qualitative but not quantitative PET imaging can help predict increased likelihood of residual tumor in esophageal cancer patients following CRT; however, it is not sensitive enough to solely rule out the presence of residual disease. Additional investigation with a larger cohort of patients is warranted.

Prostate bed motion during intensity-modulated radiotherapy treatment.

PURPOSE: Conformal radiation therapy in the postprostatectomy setting requires accurate setup and localization of the prostatic fossa. In this series, we report prostate bed localization and motion characteristics, using data collected from implanted radiofrequency transponders. METHODS AND MATERIALS: The Calypso four-dimensional localization system uses three implanted radiofrequency transponders for daily target localization and real-time tracking throughout a course of radiation therapy. We reviewed the localization and tracking reports for 20 patients who received ultrasonography-guided placement of Calypso transponders within the prostate bed prior to a course of intensity-modulated radiation therapy at Fox Chase Cancer Center. RESULTS: At localization, prostate bed displacement relative to bony anatomy exceeded 5 mm in 9% of fractions in the anterior-posterior (A-P) direction and 21% of fractions in the superior-inferior (S-I) direction. The three-dimensional vector length from skin marks to Calypso alignment exceeded 1 cm in 24% of all 652 fractions with available setup data. During treatment, the target exceeded the 5-mm tracking limit for at least 30 sec in 11% of all fractions, generally in the A-P or S-I direction. In the A-P direction, target motion was twice as likely to move posteriorly, toward the rectum, than anteriorly. Fifteen percent of all treatments were interrupted for repositioning, and 70% of patients were repositioned at least once during their treatment course. CONCLUSION: Set-up errors and motion of the prostatic fossa during radiotherapy are nontrivial, leading to potential undertreatment of target and excess normal tissue toxicity if not taken into account during treatment planning. Localization and real-time tracking of the prostate bed via implanted Calypso transponders can be used to improve the accuracy of plan delivery.

Pre-Clinical Assessment of Lu-Labeled Trastuzumab Targeting HER2 for Treatment and Management of Cancer Patients with Disseminated Intraperitoneal Disease.

Studies from this laboratory have demonstrated the potential of targeting HER2 for therapeutic and imaging applications with medically relevant radionuclides. To expand the repertoire of trastuzumab as a radioimmunoconjugate (RIC) vector, use of (177)Lu was investigated. The combination of a 6.7 d half-life, lower energy ß(-)-emissions (500 keV max; 130 keV ave), and an imagable γ-emission make (177)Lu an attractive candidate for radioimmunotherapy (RIT) regimens for treatment of larger tumor burdens not possible with α-zparticle radiation. Radiolabeling trastuzumab-CHX-A"-DTPA with (177)Lu was efficient with a specific binding of 60.8 ± 6.8% with HER2 positive SKOV-3 cells. Direct quantitation of tumor targeting and normal tissue uptake was performed with athymic mice bearing subcutaneous and intraperitoneal LS-174T xenografts; a peak tumor %ID/g of 24.70 ± 10.29 (96 h) and 31.70 ± 16.20 (72 h), respectively, was obtained. Normal tissue uptake of the RIC was minimal. Tumor targeting was also demonstrated by γ-scintigraphy. A therapy study administering escalating doses of (177)Lu-trastuzumab to mice bearing three day LS-174T i.p. xenografts established the effective therapeutic dose of i.p. administered (177)Lu-trastuzumab at 375 µCi with a median survival of 124.5 d while a median survival of 10 d was noted for the control (untreated) group. In conclusion, trastuzumab radiolabeled with (177)Lu has potential for treatment of disseminated, HER2 positive, peritoneal disease.

Oxidation of A2E results in the formation of highly reactive aldehydes and ketones.

It has been reported that the photo-oxidation of A2E, a component of human retinal lipofuscin, leads to products that are toxic to cells via dark reactions. Because these compounds have been implicated in the development of various maculopathies such as age-related macular degeneration (AMD), it is important to determine the structures of those deleterious compounds. Both the photo-oxidation and auto-oxidation of A2E lead to the same complex mixture of products, some of which have lower molecular weights than the staring material. Because A2E is homologous to beta-carotene, it was hypothesized that its oxidation would lead to products analogous to those found in oxidized beta-carotene, namely, a series of cleavage products along the acyclic chain with the concomitant formation of aldehydes. This was found to be the case based upon 1) the formation of all of the aldehydes predicted from the oxidation of beta-carotene, 2) the loss of 28 amu (carbonyl moiety) from the molecular ion, 3) the facile reaction of the aldehydes with nitrophenylhydrazines to form nitrophenylhydrazones and 4) the subsequent MS/MS cleavage of those derivatives at the N-N bond. If formed in vivo, these aldehydes would have toxic effects on any cell. Finally, the similarity in product mixtures from both the photo-oxidation and auto-oxidation strongly suggests that the intermolecular photo-oxidation of A2E results primarily from a radical process without the involvement of singlet oxygen. Any formation of singlet oxygen most likely arises from sensitization by the aldehyde oxidation products, as this process is well known for aldehydes, in general, and retinal, specifically.