Aaron W. Pederson

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.

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

BackgroundTo report the outcomes of patients with locoregionally advanced and high- risk salivary gland malignancies treated with surgery followed by adjuvant chemoradiotherapy.MethodsFrom 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.ResultsMedian 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).ConclusionsSurgical resection followed by adjuvant chemoradiotherapy results in promising locoregional control for high-risk salivary malignancy patients.

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.

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

Our aim was to report the outcomes of base of tongue cancers treated with chemoradiotherapy.

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/m2/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.

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.

Abstract 573: Ionizing radiation activates IFN signaling in tumor cells

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Ionizing radiation (IR) uses multiple pathways to mediate killing in tumor cells. We found that fractionated irradiation leads to the constitutive overexpression of Interferon Stimulated Genes (ISGs) which are controlled by Signal Transducer and Activator of Transcription 1 (Stat1). Stat1 mediated IFN signal transduction and at the same time was involved in the production of Type I and Type II IFNs. IR-induced ISGs represent the following groups: 1) mitochondrial-related genes with pro- and anti-apoptotic functions, 2) cell cycle control and regulators of transcription, 3) protein modification and degradation, 4) cytoplasmic sensors of nucleic acids, and 5) anti-viral defense. Fractionated or single-dose IR induced the IFN pathway mediated by activation of Stat1 in breast, colon, prostate and head and neck tumor xenografts. Depletion of tumor-derived IFNs led to the suppression of IR response indicating that IFN production/signaling is a component of anti-tumor IR action. Cell-autonomous experiments indicated that tumor cells up-regulate Stat1 and ISGs and produce IFNα in response to single dose IR (3Gy). Up-regulated Stat1 in irradiated tumor cells was not phosphorylated at Tyr701 position compared to Stat1 activation following interferon stimulation. In a syngeneic tumor model of B16F1, IR-induced activation of IFN signaling in tumors (assessed both by up-regulation of the Stat1-dependent pathway and induction of Type I and Type II IFNs) was dependent on TNFα signaling in the host and was impaired in TNFR1,2-/- mice. We therefore conclude that IR induces IFN signaling in tumor cells as a component of the cytotoxic response. This interferon induction depends on TNFα signaling in host cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 573. doi:10.1158/1538-7445.AM2011-573