Phase I study of capecitabine combined with radioembolization using yttrium-90 resin microspheres (SIR-Spheres) in patients with advanced cancer.

BACKGROUND: This was a prospective single-centre, phase I study to document the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and the recommended phase II dose for future study of capecitabine in combination with radioembolization. METHODS: Patients with advanced unresectable liver-dominant cancer were enrolled in a 3+3 design with escalating doses of capecitabine (375-1000 mg/m(2) b.i.d.) for 14 days every 21 days. Radioembolization with (90)Y-resin microspheres was administered using a sequential lobar approach with two cycles of capecitabine. RESULTS: Twenty-four patients (17 colorectal) were enrolled. The MTD was not reached. Haematologic events were generally mild. Common grade 1/2 non-haematologic toxicities included transient transaminitis/alkaline phosphatase elevation (9 (37.5%) patients), nausea (9 (37.5%)), abdominal pain (7 (29.0%)), fatigue (7 (29.0%)), and hand-foot syndrome or rash/desquamation (7 (29.0%)). One patient experienced a partial gastric antral perforation with a capecitabine dose of 750 mg/m(2). The best response was partial response in four (16.7%) patients, stable disease in 17 (70.8%) and progression in three (12.5%). Median time to progression and overall survival of the metastatic colorectal cancer cohort was 6.4 and 8.1 months, respectively. CONCLUSIONS: This combined modality treatment was generally well tolerated with encouraging clinical activity. Capecitabine 1000 mg/m(2) b.i.d. is recommended for phase II study with sequential lobar radioembolization.

Esophageal motion during radiotherapy: quantification and margin implications.

The purpose was to evaluate interfraction and intrafraction esophageal motion in the right-left (RL) and anterior-posterior (AP) directions using computed tomography (CT) in esophageal cancer patients. Eight patients underwent CT simulation and CT-on-rails imaging before and after radiotherapy. Interfraction displacement was defined as differences between pretreatment and simulation images. Intrafraction displacement was defined as differences between pretreatment and posttreatment images. Images were fused using bone registries, adjusted to the carina. The mean, average of the absolute, and range of esophageal motion were calculated in the RL and AP directions, above and below the carina. Thirty-one CT image sets were obtained. The incidence of esophageal interfraction motion > or =5 mm was 24% and > or =10 mm was 3%; intrafraction motion > or =5 mm was 13% and > or =10 mm was 4%. The average RL motion was 1.8 +/- 5.1 mm, favoring leftward movement, and the average AP motion was 0.6 +/- 4.8 mm, favoring posterior movement. Average absolute motion was 4.2 mm or less in the RL and AP directions. Motion was greatest in the RL direction above the carina. Coverage of 95% of esophageal mobility requires 12 mm left, 8 mm right, 10 mm posterior, and 9 mm anterior margins. In all directions, the average of the absolute interfraction and intrafraction displacement was 4.2 mm or less. These results support a 12 mm left, 8 mm right, 10 mm posterior, and 9 mm anterior margin for internal target volume (ITV) and can guide margins for future intensity modulated radiation therapy (IMRT) trials to account for organ motion and set up error in three-dimensional planning.

Can costs be measured and predicted by modeling within a cooperative clinical trials group? Economic methodologic pilot studies of the radiation therapy oncology group (RTOG) studies 90-03 and 91-04.

PURPOSE: To (1) measure radiation therapy costs for patients in randomized controlled clinical trials, (2) compare measured costs to modeling predictions, (3) examine cost distributions, and (4) assess feasibility of collecting economic data within a cooperative group. METHODS: The Radiation Therapy Oncology Group conducted economic pilot studies for two Phase III studies that compared fractionation patterns. Expected quantities of Current Procedural Terminology (CPT) codes and relative value units (RVU) were modeled. Institutions retrospectively provided procedure codes, quantities, and components, which were converted to RVUs used for Medicare payments. Cases were included if the radiation therapy quality control review judged them to have been treated per protocol or with minor variation. Cases were excluded if economic quality review found incomplete economic data. RESULTS: The median and mean RVUs were within the range predicted by the model for all arms of one study and above the predicted range for the other study. CONCLUSION: The model predicted resource use well for patients who completed treatment per protocol. Actual economic data can be collected for critical cost items. Some institutions experienced difficulty collecting retrospective data, and prospective collection of data is likely to allow wider participation in future Radiation Therapy Oncology Group economic studies.

Cost minimization analysis of various treatment options for surgical stage I endometrial carcinoma.

PURPOSE: This study compares the payors' cost of treatment for surgical Stage I endometrial carcinoma with results of published clinical studies to determine which treatment most efficiently uses available resources. METHODS AND MATERIALS: Six options for treatment of surgical Stage I endometrial carcinoma were selected for comparison. The treatment options were observation only, low-dose-rate brachytherapy (LDRB) (nonremote afterloading), LDRB and external beam radiation (EBRT), EBRT only, high-dose-rate brachytherapy (HDRB) only (three applications), and EBRT and HDRB (three applications). The literature was reviewed to obtain disease-free survival (DFS) rates corresponding to the treatment options chosen in surgical Stages IA, IB, and IC. Metaanalysis and sensitivity testing were performed on the collected clinical data. A typical midsized city in Medicare region IV was used as our representative payor cost basis. RESULTS: Thirteen retrospective articles contained sufficient clinical information for analysis. Comparison of DFS between the observation, LDRB, and EBRT treatment groups was made for Stage IA; LDRB and EBRT for Stage IB; and LDRB, EBRT, LDRB +/- EBRT, LDRB + EBRT, and HDRB + EBRT for Stage IC. Meta-analysis failed to reveal statistically significant DFS between the respective treatment options within Stages IA, IB, or IC. The RVUs for each treatment option were LDRB, 21.7; EBRT, 117.1; EBRT + LDRB, 130.7; HDRB, 155.5; and EBRT + HDRB, 264.4. The DRG payment for LDRB is $2714.92. The calculated payor's cost for each treatment option was: LDRB, $3466.62; EBRT, $4053.03; EBRT + LDRB, $7238.55; HDRB, $5381.19; and EBRT + HDRB, $9153.14. CONCLUSION: Our analysis reveals no statistically significant differences in DFS among the treatment options considered within each surgical stage. Observation appears to result in acceptable DFS with minimal cost in Stage IA. Low-dose-rate brachytherapy was the most cost-effective treatment in Stage IB, with no statistically significant difference in DFS between LDRB and EBRT. Although LDRB had inferior DFS compared to other treatment options in surgical Stage IC, this difference failed to reach statistical significance. Our analysis implies, excluding observation, that LDRB may be a more cost-efficient treatment than the other treatment options considered. Further studies stratifying for surgical stage and grade are needed to determine the optimal cost-effective treatment for this common malignancy.

Physician involvement and assessment in the development of hospital oncology programs.

Hospitals and other healthcare facilities are focusing resources on the care of the cancer patient. Physicians should become involved in all aspects of the development of oncology programs. Physicians need to be involved from the initial program development, through the strategic planning to the formulation of the business plan. Strong physician leadership is needed to coordinate care provided by physicians and ancillary staff. Educational programs for patients, their families, and physicians need to be developed by the medical director, physicians, and ancillary staff. Continuing evaluation and assessment of the entire cancer program is essential to monitor the achievement of goals and objectives set forth in the strategic plan.

Clinicopathologic correlation of DNA flow cytometric content analysis (DFCA), surgical staging, and estrogen/progesterone receptor status in endometrial adenocarcinoma.

DNA flow cytometric content analysis (DFCA) and estrogen (ER) and progesterone (PR) receptor levels are reported to be prognostic with regard to the malignant potential of endometrial adenocarcinoma. We retrospectively reviewed the records of 50 patients presenting with endometrial adenocarcinoma between July 1990 and December 1992, to determine the extent of any pathologic features reported at the time of hysterectomy. Patients whose tumors were nondiploid (aneuploid) by flow cytometry generally presented with a higher pathologic stage, higher grade, and more frequent lymph node involvement. In addition, the majority of clear cell and uterine papillary serous (UPS) adenocarcinoma were also nondiploid. Fourteen of 21 ER-positive tumors aneuploid, as were 18 of 37 PR-positive tumors. We also found DNA-A (DNA content aneuploid) patterns frequently associated with tumor characteristics implicated by other authors as related to aggressiveness. Further studies comparing the molecular biology of tumors to their clinicopathologic features and behavior are needed to fully understand the ultimate malignant potential.

Radiation therapy and 5-fluorouracil modulated by leucovorin for adenocarcinoma of the pancreas. A phase I study.

This Phase I study was designed to build on the Gastrointestinal Tumor Study Group's experience with combined modality therapy in patients with pancreatic cancer. Thirteen patients with adenocarcinoma of the pancreas received weekly 5-fluorouracil by rapid intravenous infusion midway through a 2-h infusion of high dose leucovorin during external beam radiation therapy. Twelve patients received 100% of planned external beam radiation; treatment delays occurred in only three. Four patients received 100% of planned chemotherapy doses. Leukopenia and thrombocytopenia caused reduction of the number of chemotherapy doses given during radiation in six patients; diarrhea, severe nausea and vomiting, and wound abscess caused reduction in three patients. Ten patients were evaluable for response; two had complete responses, one had a partial response, and two had minor responses. In this small series baseline and post-treatment CA 19-9 levels predicted and correlated with response. We conclude that radiation and 5-FU modulated by leucovorin is a tolerable treatment regimen for carcinoma of the pancreas, with preliminary suggestion of activity, that warrants further Phase II testing.

Prevention of heterotopic ossification with irradiation after total hip arthroplasty. Radiation therapy with a single dose of eight hundred centigray administered to a limited field.

Sixty-two hips in fifty-five patients who were considered to be at risk for postoperative heterotopic ossification were randomly divided into two groups: one received a single 800-centigray dose of limited-field radiation and the other, 1000 centigray of limited-field radiation in divided doses. The risk for heterotopic-bone formation was identified on the basis of previously described criteria, which included previous heterotopic ossification after an operation about the hip, hypertrophic osteoarthritis or post-traumatic osteoarthrosis characterized by formation of extensive osteophytes, radiographic evidence of diffuse idiopathic skeletal hyperostosis, ankylosing spondylitis, and male sex. The treatment portals excluded prosthetic surfaces that were intended for biological fixation by ingrowth of bone. At a minimum six-month follow-up, progression of heterotopic ossification had occurred in seven (21 per cent) of thirty-four hips in the first group and in six (21 per cent) of twenty-eight hips in the second group. The ossification had advanced more than one grade in only one hip. Extra-field ossification occurred in fifteen (43 per cent) of thirty-five hips that had not had previous heterotopic ossification. Since the time of the study, the treatment portal has been modified to include the lateral aspect of the greater trochanter, so that the risk of bursitis associated with ossification in this area is minimized. Single-dose limited-field radiation is effective for the prevention of heterotopic ossification, without compromise of early fixation of an uncemented implant.

Flow cytometric DNA content analysis of paraffin block embedded endometrial carcinomas.

Flow cytometry is being used as an aid in planning the treatment of patients with various malignancies. We report our experience with DNA content analysis on paraffin-embedded carcinomas. Hospital, radiation therapy, clinic, and pathology records were reviewed in 139 cases of endometrial carcinoma diagnosed between December 1980 and December 1986. Patients having Stage IV tumors, endometrial sarcomas, dual primary tumors, or incomplete records were eliminated from the analysis, which left 98 evaluable patients. This report outlines our experience with the first 20 patients. Five of 20 (25%) specimens demonstrated DNA content consistent with aneuploidy, median coefficient of variance of 5.3%. The median survival time of these five patients is 55 months, with three dying of cancer and one patient dying of other causes but with metastatic disease. The median %S phase was 3.7% in the 15 patients comprising the DNA content diploid population, median coefficient of variance 5.4%. No patient whose tumor showed S-phase cells below 3.7% died of endometrial cancer. Four of 7 patients developed recurrent cancer with 3 of the 4 patients dying of disease in the high %S phase group. The median patients survival time in the DNA content diploid population was 73 (range: 17-98) months. Patients with 3.7% or below S-phase cells had a median survival time of 75 (range: 40-98) months whereas the median survival time was 48 (range: 17-89) months for patients having a %S phase fraction above 3.7%. Although the number of patients studied is small, it appears that DNA content aneuploid tumors are frequently "upstaged" at surgery. These patients may not benefit from preoperative irradiation. Accurate determination of the %S phase fraction in DNA content diploid tumors may possibly identify patients with a poorer prognosis who may benefit from adjuvant therapy.

Intraoperative radiation therapy for pancreatic, biliary and gastric carcinoma: the US experience.

The experience with pancreatic, biliary and gastric cancer in the US has demonstrated that IORT is technically a feasible and therapeutically relatively safe modality. However, much research remains to be done. The toxicity in humans of single large dose radiation to normal tissue has not been firmly established. Clinical studies must be able to demonstrate the efficacy of IORT as well as a therapeutic advantage for this approach. IORT is potentially a very effective adjuvant therapy in treating tumors which are technically difficult to treat surgically or which have a high rate of recurrence following radical surgery. The combination of surgery and IORT may improve local control of the tumor by removing gross disease and identifying areas of potential risk for recurrence. Regional and distant failure, however, remains a problem. Because of this, future investigations are underway to combine chemotherapy with IORT, surgery and EBRT. The effectiveness of IORT needs to be established with prospective randomized trials. The appeal of this procedure is demonstrated by its rapidly growing popularity, and this very appeal requires that the value of the procedure be determined.

Intraoperative electron beam radiation therapy (IOEBRT) for carcinoma of the exocrine pancreas.

The abdominal cavities of 50 patients were explored in a specially constructed intraoperative radiotherapy operating amphitheater at the Medical College of Ohio. Twenty-six patients were treated with intraoperative and postoperative precision high dose external beam therapy, 12 with intraoperative irradiation but no external beam therapy, and 12 with palliative surgery alone. All but two patients completed the postoperative external beam radiation therapy as initially prescribed. The median survival time for patients treated with palliative surgery alone was 4 months, and that for patients treated with intraoperative radiotherapy without external beam therapy was 3.5 months. Patients undergoing intraoperative irradiation and external beam radiation therapy had a median survival time of 10.5 months. Four patients died within 30 days of surgery and two patients died of gastrointestinal hemorrhage 5 months posttreatment.

A pilot study investigating intraoperative electron beam irradiation in the treatment of ovarian malignancies.

Intraoperative electron beam radiation therapy (IOEBRT) in the treatment of ovarian malignancies was investigated at the Clement O. Miniger Radiation Oncology Center (COMROC). Nine patients were operated in the COMROC IOEBRT operating amphitheater and five were found to have disease sufficiently limited to allow for IOEBRT. The patients' ages ranged from 13 to 80 (median 53) years. Five patients had serous cystadenocarcinoma, one papillary adenocarcinoma, one mixed germ cell tumor, one squamous cell carcinoma, and one granular cell tumor of the ovary. The median survival of the non-IOEBRT group was 13 (range 12-29) months, while the IOEBRT group's median survival was 14 (range 18-46) months. All of the patients tolerated IOEBRT well without addition to the surgical morbidity.

2'5'-adenylate inhibition of erythropoietin-dependent colony formation.

The tetramer core of 2'5'-adenylate was tested in vitro for its effect on erythroid colony-forming units (CFU-E) from bone marrow of adult rats. Inhibition of CFU-E was 2'5'-adenylate dose dependent, when tested with concentrations of 0.05- 1.0 mM. Also, 2'5'-adenylate was inhibitory when incubated with 2, 6 or 10 X 10(4) cells/0.1 ml plasma clot. At 0.1 mM concentration of 2'5'-adenylate there was a 30-50% reduction of erythroid colonies for each of these three cell concentrations. There was an early decrease in 3H-thymidine incorporation when 2'5'-adenylate was added to erythropoietin-stimulated bone marrow cell suspensions prior to plating. It is suggested that in situ production of 2'5'-adenylate may represent a regulatory mechanisms in red cell maturation.