TARGIT-R (Retrospective): 5-Year Follow-Up Evaluation of Intraoperative Radiation Therapy (IORT) for Breast Cancer Performed in North America.

BACKGROUND: Intraoperative radiation therapy (IORT) has been investigated for patients with low-risk, early-stage breast cancer. The The North American experience was evaluated by TARGIT-R (retrospective) to provide outcomes for patients treated in "real-world" clinical practice with breast IORT. This analysis presents a 5-year follow-up assessment. METHODS: TARGIT-R is a multi-institutional retrospective registry of patients who underwent lumpectomy and IORT between the years 2007 and 2013. The primary outcome of the evaluation was ipsilateral breast tumor recurrence (IBTR). RESULTS: The evaluation included 667 patients with a median follow-up period of 5.1 years. Primary IORT (IORT at the time of lumpectomy) was performed for 72%, delayed IORT (after lumpectomy) for 3%, intended boost for 8%, and unintended boost (primary IORT followed by whole-breast radiation) for 17% of the patients. At 5 years, IBTR was 6.6% for all the patients, with 8% for the primary IORT cohort and 1.7% for the unintended-boost cohort. No recurrences were identified in the delayed IORT or intended-boost cohorts. Noncompliance with endocrine therapy (ET) was associated with higher IBTR risk (hazard ratio [HR], 3.67). Patients treated with primary IORT who were complaint with ET had a 5-year IBTR rate of 3.9%. CONCLUSION: The local recurrence rates in this series differ slightly from recent results of randomized IORT trials and are notably higher than in previous published studies using whole-breast radiotherapy for similar patients with early-stage breast cancer. Understanding differences in this retrospective series and the prospective trials will be critical to optimizing patient selection and outcomes going forward.

TARGIT-R (Retrospective): North American Experience with Intraoperative Radiation Using Low-Kilovoltage X-Rays for Breast Cancer.

BACKGROUND: Single-dose intraoperative radiotherapy (IORT) is an emerging treatment for women with early stage breast cancer. The objective of this study was to define the frequency of IORT use, patient selection, and outcomes of patients treated in North America. METHODS: A multi-institutional retrospective registry was created, and 19 institutions using low-kilovoltage IORT for the treatment of breast cancer entered data on patients treated at their institution before July 31, 2013. Patient selection, IORT treatment details, complications, and recurrences were analyzed. RESULTS: From 2007 to July 31, 2013, a total of 935 women were identified and treated with lumpectomy and IORT. A total of 822 patients had at least 6 months' follow-up documented and were included in the analysis. The number of IORT cases performed increased significantly over time (p < 0.001). The median patient age was 66.8 years. Most patients had disease that was <2 cm in size (90 %) and was estrogen positive (91 %); most patients had invasive ductal cancer (68 %). Of those who had a sentinel lymph node procedure performed, 89 % had negative sentinel lymph nodes. The types of IORT performed were primary IORT in 79 %, secondary IORT in 7 %, or planned boost in 14 %. Complications were low. At a median follow-up of 23.3 months, crude in-breast recurrence was 2.3 % for all patients treated. CONCLUSIONS: IORT use for the treatment of breast cancer is significantly increasing in North America, and physicians are selecting low-risk patients for this treatment option. Low complication and local recurrence rates support IORT as a treatment option for selected women with early stage breast cancer.

The Role of Radiotherapy Among Patients With Prostate Ductal Adenocarcinoma.

INTRODUCTION: The aim of this study was to perform a Surveillance, Epidemiology, and End Results (SEER) analysis on the effect of radiotherapy (RT) on survival among patients with prostate ductal adenocarcinoma (DA), a rare variant of prostate cancer. PATIENTS AND METHODS: Cases of T1 to 4 N0 M0 prostate DA diagnosed between 2004 and 2013 were extracted from SEER. The association between categorical variables and radiation therapy was assessed for statistical significance using the χ2 test or Fisher exact test. Difference in continuous variables across the RT groups was assessed for statistical significance using the 2-sample t test or non-parametric test. The distribution of overall survival (OS) and disease-specific survival (DSS) between the RT groups was assessed using the Kaplan-Meier method and the log rank test and after propensity matching. The association between hazards of death (HR) and covariates was examined using Cox proportional hazards model. A 2-sided P-value of .05 was used to determine statistical significance. RESULTS: A total of 205 patients met inclusion criteria. On univariate analysis, RT was associated with significant improvement in OS and DSS. On multivariate Cox regression, RT significantly decreased risk of death for both OS and DSS (HR, 0.516; 95% confidence interval [CI], 0.273-0.978 and HR, 0.232; 95% CI, 0.082-0.658, respectively). After propensity score matching, RT demonstrated a persistent improvement in both OS and DSS. CONCLUSIONS: RT decreased risk of death for both OS and DSS in patients with node-negative, nonmetastatic prostate DA on multivariable analysis. RT was also associated with improved OS and DSS after propensity matching.

A Case of Metastatic Head and Neck Squamous Cell Carcinoma with Multiple Treatments Including Stereotactic Ablative Body Radiotherapy Alone for Oligometastases to the Parotid Gland.

Head and neck squamous cell carcinoma (HNSCC) has a reported average of around 15% metastases at presentation with chemotherapy being the mainstay of treatment for widely metastatic disease. However, in select patients with oligometastatic disease, local ablative therapy (commonly including surgery or radiotherapy) can be utilized with the possibility of improving survival, decreasing morbidity from the metastases, and obviating the need for systemic therapy with its possible side effects. However, most research has been of ablative therapy has been performed for pulmonary and hepatic oligometastatic lesions.  In this case, we present a patient who initially presented with a metastatic base of tongue malignancy with left axilla metastases who was treated palliatively with systemic therapy with an initial complete response. She subsequently progressed on maintenance therapy with a locoregional recurrence that was treated with definitive chemoradiation with complete response. There was a subsequent recurrence again in the left axilla that was treated as well with chemoradiation with complete response. Next, there was a recurrence in the right occipital lobe and left parotid gland with treatment with surgical resection, plus stereotactic radiotherapy boost and stereotactic ablative body radiotherapy (SABR), respectively. This all occurred over a 30-month time frame from initial therapy to her last treatment, with an additional 42 months at the present time with no recurrence.  This case highlights the future of care of oligometastatic disease of HNSCC with potential long-term survival in appropriately selected patients treated with stereotactic ablative body radiotherapy. Furthermore, this is one of the first reported cases in the literature of SABR for an oligometastatic lesion of the parotid gland, especially from squamous cell carcinoma (SCC) of the oral cavity, with no recurrence of disease over 40 months removed from treatment.

Thermal assembly of a biomimetic mineral/collagen composite.

A strategy is described for exploiting temperature driven self-assembly of collagen and thermally triggered liposome mineralization to form a mineralized collagen composite from an injectable precursor fluid. Optical density and rheological experiments demonstrated the formation of a collagen gel when acid-soluble type I collagen solutions (1-7 mg/ml) were heated to 24-30 degrees C. Scanning calorimetry experiments demonstrated that mixtures of calcium- and phosphate-loaded liposomes composed of dipalmitoylphosphatidylcholine (90 mol%) and dimyristoylphosphatidylcholine (10 mol%) were stable at room temperature but formed calcium phosphate mineral when heated above 35 degrees C, a consequence of the release of entrapped salts at the lipid chain melting transition. The formation of calcium phosphate mineral induced by triggered release of calcium and phosphate was detected as an endothermic transition (deltaH=6.2+/-1.1 kcal/mol lipid) near the lipid chain melting transition (Tm=37 degrees C). Combining an acid-soluble collagen solution with calcium- and phosphate-loaded liposomes resulted in a liposome/collagen precursor fluid, which when heated from room temperature to 37 degrees C formed a mineralized collagen gel. The dynamic storage modulus of the collagen scaffold increased upon mineralization, and direct nucleation of mineral from the collagen scaffold was detected by electron microscopy.

In vivo dosimetry with optically stimulated dosimeters and RTQA2 radiochromic film for intraoperative radiotherapy of the breast.

PURPOSE: Measurements were taken with optically stimulated luminescence dosimeters (OSLDs) and with RTQA2 radiochromic film to evaluate the use of each for in vivo dosimetry with intraoperative radiotherapy of the breast. METHODS: Nonlinear calibration curves were established for OSLDs and RTQA2 radiochromic film using the Intrabeam 50 kVp source. Measurements were taken in a water phantom and compared to absolute dose measurements taken with an ionization chamber to investigate the characteristics of both types of dosimeters, including energy response and radiative absorption. In vivo readings were taken on the skin and in the tumor cavity using OSLDs and RTQA2 radiochromic film for 10 patients and 20 patients respectively. A prescription of 20 Gy to the surface of the applicator was used for all in vivo measurements in this study. RESULTS: OSLDs were found to have an approximate uncertainty of ± 7% for readings near the surface of the applicator and ± 17% for readings at distances typical to the skin. The radiative absorption by OSLD was negative, indicating that this type of dosimeter absorbs less radiation than water in the targeted intraoperative radiotherapy energy range. RTQA2 film exhibited no energy dependence and all film readings were within ± 8% of the delivered dose. The maximum radiative absorption in film was 8.5%. Radiochromic film measurements were found to be on average 18.2 ± 3.3 Gy for the tumor cavity and 2.1 ± 0.8 Gy for positions on the skin superior and inferior to the Intrabeam applicator. Average cavity measurements taken with OSLDs were 15.9 ± 3.9 Gy and average skin doses were 1.4 ± 0.8 Gy. CONCLUSIONS: OSLDs produce results with an uncertainty comparable to other dosimeters near the surface of the applicator but the uncertainty increases to an unacceptably high level with distance from the applicator. RTQA2 radiochromic film is shown to be accurate both at the surface of the applicator and at distances of 1-2 cm.

Late toxicity after intensity-modulated radiation therapy for localized prostate cancer: an exploration of dose-volume histogram parameters to limit genitourinary and gastrointestinal toxicity.

PURPOSE: To characterize the late genitourinary (GU) and gastrointestinal (GI) toxicity for prostate cancer patients treated with intensity-modulated radiation therapy (IMRT) and propose dose-volume histogram (DVH) guidelines to limit late treatment-related toxicity. METHODS AND MATERIALS: In this study 296 consecutive men were treated with IMRT for adenocarcinoma of the prostate. Most patients received treatment to the prostate with or without proximal seminal vesicles (90%), to a median dose of 76 Gy. Concurrent androgen deprivation therapy was given to 150 men (51%) for a median of 4 months. Late toxicity was defined by Common Toxicity Criteria version 3.0 as greater than 3 months after radiation therapy completion. Four groupings of DVH parameters were defined, based on the percentage of rectal or bladder tissue receiving 70 Gy (V(70)), 65 Gy (V(65)), and 40 Gy (V(40)). These DVH groupings, as well as clinical and treatment characteristics, were correlated to maximal Grade 2+ GU and GI toxicity. RESULTS: With a median follow-up of 41 months, the 4-year freedom from maximal Grade 2+ late toxicity was 81% and 91% for GU and GI systems, respectively, and by last follow-up, the rates of Grade 2+ GU and GI toxicity were 9% and 5%, respectively. On multivariate analysis, whole-pelvic IMRT was associated with Grade 2+ GU toxicity and age was associated with Grade 2+ GI toxicity. Freedom from Grade 2+ GI toxicity at 4 years was 100% for men with rectal V(70) ≤ 10%, V(65) ≤ 20%, and V(40) ≤ 40%; 92% for men with rectal V(70) ≤ 20%, V(65) ≤ 40%, and V(40) ≤ 80%; and 85% for men exceeding these criteria (p = 0.13). These criteria were more highly associated with GI toxicity in men aged ≥70 years (p = 0.07). No bladder dose-volume relationships were associated with the risk of GU toxicity. CONCLUSIONS: IMRT is associated with low rates of severe GU or GI toxicity after treatment for prostate cancer. Rectal dose constraints may help limit late GI morbidity.

Concurrent chemotherapy and intensity-modulated radiotherapy for organ preservation of locoregionally advanced oral cavity cancer.

OBJECTIVES: To report outcomes of oral cavity cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy (chemoIMRT). METHODS: Between 2001 and 2004, 21 patients with oral cavity squamous cell carcinoma underwent definitive chemoIMRT. Sites included were oral tongue (n = 9), floor of mouth (n = 6), buccal mucosa (n = 3), retromolar trigone (n = 2), and hard palate (n = 1). Most had stage III-IV disease (n = 20). The most common regimen was 5 days infusional 5-fluorouracil (600 mg/m(2)/d × 5 days), hydroxyurea (500 mg, PO BID), and 1.5 Gy twice-daily irradiation to 72 to 75 Gy. RESULTS: The median follow-up for surviving patients was 60 months. Treatment failure occurred as follows: local-1, regional-1, and distant metastases-2. The 2- and 5-year estimates of locoregional progression-free survival, disease-free survival, and overall survival were 90% and 90%, 71% and 71%, and 76% and 76%, respectively. Late complications included osteoradionecrosis (3 patients, 14%). CONCLUSIONS: Concurrent chemoIMRT results in promising locoregional control for oral cavity squamous cell carcinomas with acceptable toxicity.

Adjuvant chemoradiotherapy for locoregionally advanced and high-risk salivary gland malignancies.

BACKGROUND: To report the outcomes of patients with locoregionally advanced and high- risk salivary gland malignancies treated with surgery followed by adjuvant chemoradiotherapy. METHODS: From 09/1991 - 06/2007, 24 high-risk salivary gland cancer patients were treated with surgery, followed by adjuvant chemoradiotherapy for high-risk pathologic features including, perineural involvement, nodal involvement, positive margins, or T3/T4 tumors. Chemoradiotherapy was delivered for 4-6 alternating week cycles: the most common regimen, TFHX, consisted of 5 days paclitaxel (100 mg/m² on d1), infusional 5-fluorouracil (600 mg/m²/d × 5d), hydroxyurea (500 mg PO BID), and 1.5 Gy twice daily irradiation followed by a 9-day break without treatment. RESULTS: Median follow-up was 42 months. The parotid gland was more frequently involved (n = 17) than minor (n = 4) or submandibular (n = 3) glands. The median radiation dose was 65 Gy (range 55-68 Gy). Acute treatment related toxicity included 46% grade 3 mucositis and 33% grade 3 hematologic toxicity. Six patients required feeding tubes during treatment. One patient progressed locally, 8 patients progressed distantly, and none progressed regionally. Five-year locoregional progression free survival was 96%. The 3 and 5 year overall survival was 79% and 59%, respectively. Long-term complications included persistent xerostomia (n = 5), esophageal stricture requiring dilatation (n = 1), and tempromandibular joint syndrome (n = 1). CONCLUSIONS: Surgical resection followed by adjuvant chemoradiotherapy results in promising locoregional control for high-risk salivary malignancy patients.

Chemoradiotherapy for locoregionally advanced squamous cell carcinoma of the base of tongue.

BACKGROUND: Our aim was to report the outcomes of base of tongue cancers treated with chemoradiotherapy. METHODS: Between 1990 and 2004, 127 patients with stage III or IV base of tongue cancer were treated with chemoradiotherapy on protocol. Indications included nodal involvement, T3/T4 tumors, positive margins, those patients refusing surgery, or were medically inoperable. The most common regimen was paclitaxel (100 mg/m2 on day 1), infusional 5-fluorouracil (600 mg/m2/day × 5 days), hydroxyurea (500 mg prescribed orally [PO] 2 × daily [BID]), and 1.5 Gy twice daily irradiation followed by a 9-day break without treatment. RESULTS: Median follow-up was 51 months. The median dose to gross tumor was 72.5 Gy (range, 40-75.5 Gy). Five-year locoregional progression-free survival, overall survival, and disease-free survival was 87.0%, 58.2%, and 46.0%, respectively. CONCLUSION: Concurrent chemoradiotherapy results in promising locoregional control for base of tongue cancer. As distant relapse was common, further investigation of systemic therapy with novel agents may be warranted.

Chemoreirradiation for recurrent salivary gland malignancies.

BACKGROUND AND PURPOSE: To report our experience in treating recurrent salivary gland malignancies using concurrent chemotherapy and reirradiation. MATERIALS AND METHODS: Between 1986 and 2007, 14 patients with locoregionally recurrent salivary gland cancer underwent maximal surgical resection followed by adjuvant 5-fluorouracil and hydroxyurea-based chemotherapy concurrently with 1.5Gy twice daily or 2Gy daily reirradiation. Each cycle consisted of chemoreirradiation for 5 consecutive days followed by a 9-day break. The median reirradiation dose was 66Gy (R 30-72Gy) after a mean radiation treatment interval of 48 months. RESULTS: The median follow-up for all patients was 18 months (R 2-125 months) and 41 months for survivors. The parotid gland (n=6) and minor salivary glands (n=6) were involved more commonly than the submandibular gland (n=2). Locoregional control at 1 and 3years was 72.2% and 51.6%, respectively. Actuarial overall survival at 3 and 5 years was 35.7% and 26.8%, respectively. Tracheostomies and feeding tubes were placed in 2 and 8 patients, respectively. Six patients had feeding tubes at last follow-up or death. CONCLUSIONS: Concurrent chemotherapy and reirradiation for recurrent salivary malignancies result in promising locoregional control for patients with recurrent salivary gland malignancies.