Pharmacogenetic study in gastric cancer patients treated with adjuvant fluorouracil/leucovorin or epirubicin/cisplatin/fluorouracil before and after chemoradiation on CALGB 80101 (Alliance).

There is a lack of pharmacogenetic predictors of outcome in gastric cancer patients. The aim of this study was to assess previously identified candidate genes associated with 5-fluorouracil (5-FU), cisplatin, or epirubicin toxicity or response in a cohort of resected gastric cancer patients treated on CALGB (Alliance) 80101. Gastric or gastroesophageal cancer patients randomized to adjuvant 5-FU/leucovorin or epirubicin/cisplatin/5-FU before and after 5-FU chemoradiation were genotyped for single nucleotide polymorphisms (SNPs) in GSTP1 (rs1695), ERCC1 (rs11615 and rs3212986), XRCC1 (rs25487), UGT2B7 (rs7439366) and the 28 base-pair tandem repeats in TYMS (rs34743033). Logistic regression and log rank tests were used to assess the association between each SNP and incidence of grade 3/4 neutropenia and leukopenia, overall (OS) and progression-free survival (PFS), respectively. Toxicity endpoint analyses were adjusted for the treatment arm, while OS and PFS were also adjusted for performance status, sex, age, lymph node involvement, and primary tumor site and size. Of 281 subjects with successful genotyping results and available clinical (toxicity and efficacy) data, 166 self-reported non-Hispanic White patients were included in the final analysis. There was a lack of evidence of an association among any SNPs tested with grade 3/4 neutropenia and leukopenia or OS and PFS. Age, lymph node involvement, and primary tumor size were significantly associated with OS and PFS. This study failed to confirm results of previous gastric cancer pharmacogenetic studies.

Outcome results of the 1996-1999 patterns of care survey of the national practice for patients receiving radiation therapy for carcinoma of the esophagus.

PURPOSE: A Patterns of Care Study of patients treated from 1996 to 1999 evaluated the national practice for patients receiving radiation therapy for carcinoma of the esophagus in the United States. METHODS: A national survey was conducted at 59 institutions in a stratified random sample selected from a master list of radiation therapy facilities throughout the United States. Patient, tumor, and treatment characteristics were evaluated. Multivariate comparisons of survival times were made using the Cox proportional hazards model. RESULTS: Adenocarcinoma was diagnosed in 51% of patients and squamous cell carcinoma in 49% of patients. Sixteen percent of patients were clinical stage (CS) I (using the 1983 American Joint Committee on Cancer system), 39% were CS II, and 33% were CS III. Significant variables in the multivariate analysis of survival times included clinical stage, treatment approach, and facility size. Patients with CS III disease had a higher hazard risk of death as compared with CS I patients (hazard ratio [HR], 2.01; P = .001), whereas those treated with chemoradiotherapy followed by surgery (HR, 0.32; P < .0001) had a decreased risk of death compared with chemoradiotherapy-only patients. Patients at small centers had a higher risk of death (HR, 1.32; P = .03) compared with patients treated at larger facilities. CONCLUSION: Concurrent chemoradiotherapy continued to be the most commonly utilized treatment approach during the time period studied. The observation that patients undergoing surgical resection following chemoradiation have a decreased HR or chance of death compared with other treatment schemes supports the need for a randomized trial comparing these strategies.

Four-dimensional image-based treatment planning: Target volume segmentation and dose calculation in the presence of respiratory motion.

PURPOSE: To describe approaches to four-dimensional (4D) treatment planning, including acquisition of 4D-CT scans, target delineation of spatio-temporal image data sets, 4D dose calculations, and their analysis. METHODS AND MATERIALS: The study included patients with thoracic and hepatocellular tumors. Specialized tools were developed to facilitate visualization, segmentation, and analysis of 4D-CT data: maximum intensity volume to define the extent of lung tumor motion, a 4D browser to examine and dynamically assess the 4D data sets, dose calculations, including respiratory motion, and deformable registration to combine the dose distributions at different points. RESULTS: Four-dimensional CT was used to visualize and quantitatively assess respiratory target motion. The gross target volume contours derived from light breathing scans showed significant differences compared with those extracted from 4D-CT. Evaluation of deformable registration using difference images of original and deformed anatomic maps suggested the algorithm is functionally useful. Thus, calculation of effective dose distributions, including respiratory motion, was implemented. CONCLUSION: Tools and methods to use 4D-CT data for treatment planning in the presence of respiratory motion have been developed and applied to several case studies. The process of 4D-CT-based treatment planning has been implemented, and technical barriers for its routine use have been identified.

Moving targets: detection and tracking of internal organ motion for treatment planning and patient set-up.

BACKGROUND AND PURPOSE: Clinical target volumes of the thorax and abdomen are typically expanded to account for inter- and intrafractional organ motion. Usually, such expansions are based on clinical experience and planar observations of target motion during simulation. More precise, 4-dimensional motion margins for a specific patient may improve dose coverage of mobile targets and yet limit unnecessarily large field expansions. We are studying approaches to targeting moving tumors throughout the entire treatment process, from treatment planning to beam delivery. MATERIAL AND METHODS: Radio-opaque markers were implanted under CT guidance in the liver at the gross tumor periphery. Organ motion during light respiration was volumetrically imaged by 4D Computed Tomography. Marker motion was also acquired by fluoroscopy and compared with 4DCT data. During treatment, daily diagnostic x-ray images were captured at end-exhale and -inhale for patient setup and target localization. RESULTS: Based on the time-resolved CT data, target volumes can be designed to account for respiratory motion during treatment. Motion of the tumor as derived from 4DCT was consistent with fluoroscopic motion analysis. Radiographs acquired in the treatment room enabled millimeter-level patient set-up and assessment of target position relative to bony anatomy. Daily positional variations between bony anatomy and implanted markers were observed. CONCLUSIONS: Image guided therapy, based on 4DCT imaging, fluoroscopic imaging studies, and daily gated diagonstic energy set-up radiographs is being developed to improve beam delivery precision. Monitoring internal target motion throughout the entire treatment process will ensure adequate dose coverage of the target while sparing the maximum healthy tissue.

Intraoperative radiation therapy in the management of gynecologic and genitourinary malignancies.

Women with locally advanced primary or recurrent gynecologic malignancies have a poor prognosis. The doses of external radiation necessary to treat gross or microscopic recurrent disease in patients previously irradiated exceed the doses tolerated by normal tissue [1,3-5]. IORT has been added to the treatment armamentarium in this group of patients to maximize local control and minimize the radiation exposure to dose-limiting surrounding structures. In addition, IORT may improve the long-term local control and the overall survival rates in women with pelvic sidewall or para-aortic nodal recurrence [1,4,5]. The most encouraging results are seen in cases of microscopic residual disease following surgical debulking [4,6]. In gynecologic malignancies, IORT has served to reiterate the importance of optimal surgical resection. Higher 5-year disease-free and overall survival rates have been documented in women who have microscopic residual disease, compared with those who have gross residual disease [1,3-6]. IORT in the management of GU malignancies has not been used extensively. In RCC, where surgery alone often results in suboptimal treatment results, IORT seems to be well tolerated and controls local disease [2,27,29,30]. Because of the chemoresistant nature of RCC, IORT may play an important role in the future in the management of locally advanced and recurrent RCC. In bladder cancer, IORT had been used in combination with chemotherapy and EBRT, as part of bladder-sparing protocols. The data suggest that IORT in this patient population is also well tolerated, and may become more widely used as less radical surgical procedures gain clinical importance. IORT in the treatment of prostate and testicular cancers has not been used frequently, given the highly efficacious treatment modalities currently available to treat these malignancies. A review of institutional experiences with IORT may allow the establishment of guidelines for patient selection. These criteria, in turn, may be useful in the design of clinical trials. The construction, execution, and evaluation of clinical trials are mandatory to adequately assess the role of IORT in the treatment of patients with gynecologic and GU malignancies.