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.

Outcomes research in cancer clinical trial cooperative groups: the RTOG model.

BACKGROUND: The Radiation Therapy Oncology Group (RTOG), a National Cancer Institute sponsored cancer clinical trials research cooperative, has recently formed an Outcomes Committee to assess a comprehensive array of clinical trial endpoints and factors impacting the net effect of therapy. METHODS: To study outcomes in a consistent, comprehensive and coordinated manner, the RTOG Outcomes Committee developed a model to assess clinical, humanistic, and economic outcomes important in clinical trials. RESULTS: This paper reviews how the RTOG incorporates outcomes research into cancer clinical trials, and demonstrates utilization of the RTOG Outcomes Model to test hypotheses related to non-small-cell lung cancer (NSCLC). In this example, the clinical component of the model indicates that the addition of chemotherapy to radiotherapy (RT) improves survival but increases the risk of toxicity. The humanistic component indicates that esophagitis is the symptom impacting quality of life the greatest and may outweigh the benefits in elderly (> or =70 years) patients. The economic component of the model indicates that accounting for quality-adjusted survival, concurrent chemoRT for the treatment of NSCLC is within the range of economically acceptable recommendations. CONCLUSION: The RTOG Outcomes Model guides a comprehensive program of research that systematically measures a triad of endpoints considered important to clinical trials research.

Prevalence and patterns of self-initiated nutritional supplementation in men at high risk of prostate cancer.

OBJECTIVE: To define the prevalence and patterns of self-initiated herbal and vitamin supplementation among men at high risk of developing prostate cancer, as there is increasing public awareness of prostate cancer screening, risk-factor assessment and prevention, leading to increasing interest in the use and systematic study of nutritional therapies for prostate cancer prevention. SUBJECTS AND METHODS: Since 1996 our institution has prospectively maintained a prostate cancer-risk registry through its Prostate Cancer Risk Assessment Program (PRAP). Eligibility includes African-American men, any man with at least one first-degree relative or two or more second-degree relatives with prostate cancer, or men who tested positively for the BRCA1 gene mutation. A 420-item self-administered questionnaire was completed and included the use of nutritional supplements and complementary therapies. We divided men into groups who used supplements to lessen their cancer risk and those who did not. The prevalence and patterns of use were evaluated and the two groups then compared for differences in demographic, socio-economic and risk-perception variables. RESULTS: In all, 345 high-risk men were enrolled in the PRAP over a 5-year period. Data on the use of dietary or herbal supplements were available on 333 men (97%), of whom over half (170) reported taking one or more supplements to prevent prostate cancer. Supplement use was divided into eight categories, including vitamins, minerals, extracts from fruits/seeds, organic compounds, flowers/bulbs, leaves/bark, roots, or animal products. Most commonly used for self-initiated chemoprevention were vitamins (95%), minerals (28%), and fruit/seed extracts (18%). More than a quarter of men (27%) took three or more agents. Men taking proactive preventative measures were statistically more likely to be Caucasian and aged > 60 years (P < 0.05). African-Americans were less likely to self-initiate preventative steps. Men taking supplements tended to return more often for follow-up and participate in PRAP longer, while those not taking supplements tended to earn less and report less self-perceived risk. CONCLUSIONS: A significant proportion of men at risk of developing prostate cancer initiate measures they perceive to reduce their risk. Although the chemopreventative efficacy of many of these supplements remains unsubstantiated, they are widely perceived by the public to reduce the risk of developing prostate cancer. These data provide an insight into patient perceptions and misconceptions of chemopreventative strategies, and may help to refine recruitment efforts in multi-institutional prostate cancer prevention trials.

Stereotactic IMRT for prostate cancer: dosimetric impact of multileaf collimator leaf width in the treatment of prostate cancer with IMRT.

The focus of this work is the dosimetric impact of multileaf collimator (MLC) leaf width on the treatment of prostate cancer with intensity-modulated radiation therapy (IMRT). Ten patients with prostate cancer were planned for IMRT delivery using two different MLC leaf widths--4mm and 10mm--representing the Radionics micro-multileaf collimator (mMLC) and Siemens MLC, respectively. Treatment planning was performed on the XKnifeRT2 treatment-planning system (Radionics, Burlington, MA). All beams and optimization parameters were identical for the mMLC and MLC plans. All the plans were normalized to ensure that 95% of the planning target volume (PTV) received 100% of the prescribed dose. The differences in dose distribution between the two different plans were assessed by dose-volume histogram (DVH) analysis of the target and critical organs. We specifically compared the volume of rectum receiving 40 Gy (V40), 50 Gy (V50), 60 Gy (V60), the dose received by 17% and 35% of rectum (D17 and D35), and the maximum dose to 1 cm3 of the rectum for a prescription dose of 74 Gy. For the urinary bladder, the dose received by 25% of bladder (D25), V40, and the maximum dose to 1 cm3 of the organ were recorded. For PTV we compared the maximum dose to the "hottest" 1 cm3 (Dmax1 cm3) and the dose to 99% of the PTV (D99). The dose inhomogeneity in the target, defined as the ratio of the difference in Dmax1 cm3 and D99 to the prescribed dose, was also compared between the two plans. In all cases studied, significant reductions in the volume of rectum receiving doses less than 65 Gy were seen using the mMLC. The average decrease in the volume of the rectum receiving 40 Gy, 50 Gy, and 60 Gy using the mMLC plans was 40.2%, 33.4%, and 17.7%, respectively, with p < 0.0001 for V40 and V50 and p < 0.012 for V60. The mean dose reductions for D17 and D35 for the rectum using the mMLC were 20.4% (p < 0.0001) and 18.3% (p < 0.0002), respectively. There were consistent reductions in all dose indices studied for the bladder. The target dose inhomogeneity was improved in the mMLC plans by an average of 29%. In the high-dose range, there was no significant difference in the dose deposited in the "hottest" 1 cm3 of the rectum between the two plans for all cases (p > 0.78). In conclusion, the use of the mMLC for IMRT of the prostate resulted in significant improvement in the DVH parameters of the prostate and critical organs, which may improve the therapeutic ratio.

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-utility analysis of a malignant glioma protocol.

PURPOSE: To perform a cost-utility analysis utilizing a cooperative group protocol and constrasting the results with the published quality adjusted survival. METHODS AND MATERIALS: A cost-utility analysis was performed on Radiation Therapy Oncology Group (RTOG) protocol 83-02. The quality-adjusted survival has been published previously. Pretreatment tests and chemotherapy costs are not considered, as these were similar across all treatment arms. Payor costs are calculated from Federal Register data for Medicare Region IV. Global charges are used to calculate the professional and technical charges. Costs are measured in relative value units (RVUs) and are tabulated assuming equal treatment complexity for all treatment arms. RESULTS: The number of RVUs calculated for each arm were 48 Gy--166.65; 54.4 Gy--182.17; 64.8 Gy--232.53; 72.0 Gy--272.19; 76.8 Gy--287.11; and 81.6 Gy--302.63. The RVU/QALY for the <50-year-old group were 48 Gy--119.03; 54.4 Gy--100.65; 64.8 Gy--104.78; 72.0 Gy--90.73; 76.8 Gy--193.99; and 81.6 Gy--165.37. The RVU/QALY for the >50-year-old group were 48 Gy--198.39; 54.4 Gy--276.85; 64.8 Gy--426.57; 72.0 Gy--423.71; 76.8 Gy--703.70; and 81.6 Gy--519.10. Sensitivity analysis of one treatment plan, simulation, and set of blocks for the 48 Gy and 54.4 Gy arms decreased the RVU/QALY to 105.34 and 90.05, respectively. DISCUSSION: Our analyses shows the experimental arm with the lowest RVU/QALY is also the arm with the longest quality-adjusted survival. This arm had the most efficient use of resources in this protocol. Prospective collection of all pertinent cost data is required for comparison of one treatment against another. All cooperative group protocols should have prospective quality of life and economic endpoints to allow for comparison of the most cost efficient treatment method.

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.

Prognostic characteristics of surgical stage I endometrial adenocarcinoma.

PURPOSE: To evaluate and correlate the expression of pathologic characteristics, flow cytometric DNA content analysis, and estrogen and progesterone receptor levels with survival in patients with surgical Stage I endometrial carcinoma. METHODS AND MATERIALS: Hospital tumor registry records were surveyed, and this identified 232 patients diagnosed with endometrial adenocarcinoma between July 1, 1989, and December 30, 1993. DNA content analysis was performed on either paraffin-embedded or fresh tissue samples. Survival was calculated from the date of diagnosis by the Kaplan-Meier method. Postoperative irradiation (whole pelvis external beam therapy and low dose rate vaginal cuff brachytherapy) was delivered to patients felt to be at high risk for failure. RESULTS: One hundred seventy-one patients had Stage I tumors and were available for analysis. Patients with Stage 1C tumors had a statistically significant lower survival rate compared to patients with Stages IA or IB (p = 0.03 and p < 0.01, respectively). Patients with DNA content diploid tumors had a slightly increased (but nonsignificantly so) survival compared to patients with non-DNA content diploid tumors (p = 0.12). Logistic regression analysis failed to identify an independent prognostic factor that could predict for disease specific survival in patients with Stage I cancers. CONCLUSION: Logistic regression analysis did not identify a single independent prognostic factor in patients with Stage I tumors. Pathologic characteristics reported to predict survival advantage correlated with pathologic stage. Additional translational research is needed to identify molecular characteristics of tumors that may indicate more aggressive treatment for patients at high risk for recurrence.

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.

Pelvic fractures following irradiation for endometrial carcinoma.

PURPOSE: To investigate the incidence and etiologic factors of pelvic fractures following radiation therapy for endometrial carcinoma. METHODS AND MATERIALS: Tumor registry and radiation oncology records of patients treated for endometrial carcinoma at The Toledo Hospital between April 1989, and December 1992, were reviewed. Patients identified as having pelvic fractures without the presence of metastatic disease underwent total body mineral density measurement with dual x-ray densitometry. RESULTS: Two of 75 patients (2.7%) were found to have pelvic fractures an average of 29 months from the completion of postoperative irradiation. One patient, who received preoperative irradiation, was also identified as having developed a fracture of the pelvis and was included in the analysis. All patients were treated prone with 10-15 MV photons in four fields daily. All three fracture patients received 45 Gy external beam radiation therapy. The two postoperative patients each received a single vaginal brachytherapy application delivering 20 Gy to 0.5 cm deep to the vaginal mucosa with a vaginal cylinder containing 30 mgRaeq 137Cs. The preoperative patient received a single brachytherapy application with tandem and colpostats delivering 20 Gy to point A. Only one of the three fracture patients had the entire pubis included in the field of external beam treatment. One patient was taking nonsteroidal anti-inflammatory medication, one patient thyroid hormone replacement, and one patient was taking both types of medication. CONCLUSION: The etiology of pelvic fractures after irradiation is multifactorial. A complete medication history should be obtained, and care should be exercised in positioning the radiation fields to avoid inclusion of the entire pubis prior to the initiation of the radiation treatment.

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.

Flow cytometric DNA content analysis of paraffin-embedded tissue derived from cervical carcinoma.

PURPOSE: Flow cytometric deoxyribonucleic acid (DNA) content analysis has been shown to be of prognostic importance in some cancers. There have been recent reports of a prognostic importance for DNA content analysis in cervical carcinoma. METHODS AND MATERIALS: We retrospectively reviewed the hospital and radiation oncology records of cervical carcinoma patients who presented between 1984-1990. RESULTS: A total of 101 archival paraffin-embedded blocks were processed, of which 77 were of technical quality for analysis. Thirty-five percent were found to be DNA content aneuploid (DNA-A) and 65% DNA content diploid (DNA-D). No statistical difference was found between the two groups in age at diagnosis, % S-phase, coefficient of variation (CV), or proliferative index (PI). A statistical difference was noted in the G2M phase between the two groups (p = 0.004). The median % S-phase was 8.4% in the DNA-D group. A statistical difference (p = 0.017) in survival was noted between the low and high % S-phase DNA-D groups. In patients who received radiation alone, high-PI patients had improved survival compared to low-PI patients. No statistical difference in survival was noted in the high % S-phase DNA-D group and DNA-A group (p = 0.28). Proportional Hazard (Cox) Regression found clinical stage the only independent prognostic indicator for survival. CONCLUSION: Flow cytometric DNA content analysis is being used more frequently in the management of different malignant tumors. Our study shows that DNA content analysis is useful in determining the prognosis and survival outcomes in cervical carcinomas and may aid in predicting outcome to certain types of treatment regimens.

The use of intraoperative electron beam radiation therapy in the treatment of para-aortic metastases from gynecologic tumors: a pilot study.

The abdomens of 16 patients with para-aortic nodal metastases were explored in the Clement O. Miniger Radiation Oncology Center's (COMROC) intraoperative radiation therapy suite. At the time of initial diagnosis 8 patients were found to have para-aortic metastases, and 8 developed para-aortic disease after completion of primary treatment. The median age of patients in the "initial group" was 37.5 years: 7 of these 8 patients had radiation only, and 1 patient had radiation and chemotherapy as initial treatment. Bulk disease in the para-aortic region was noted in 2 patients, microscopic disease in 5 patients, and prophylactic radiation was given to the para-aortic area in 1 patient. Ten para-aortic fields in 8 patients were treated with a median dose of 20 (range 10-25) Gy with 6-18 MeV electrons. Median survival from time of diagnosis was 31 (range 9-59) months and 27 (range 8-56) months from the date of IOEBRT. The median time to recurrence after IOEBRT was 8 (range 4-32) months. One patient is alive without disease 59 months and 1 is alive with disease 44 months from IOEBRT, with neither patient failing in the treated area. Eight patients were treated for recurrent disease in the para-aortic area: 5 cervical primaries, 2 endometrial adenocarcinoma primaries, and 1 uterine sarcoma. The median age was 60.5 (range 45-70) years. Median time to recurrence from initial diagnosis was 20 (range 7-37) months. In seven fields 6 of 8 patients received IOEBRT, median dose 20 (range 10-25) Gy. After IOEBRT, 4 of 6 patients received 45 Gy external beam irradiation. Median survival from IOEBRT was 9 (range 3-23) months, 37.5 (range 11-56) months from diagnosis. One patient is alive without disease at 11 months and one is alive with disease 19 months after IOEBRT. Toxicity of the IOEBRT is discussed.

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.