Towards real-time topical detection and characterization of FDG dose infiltration prior to PET imaging.

PURPOSE: To dynamically detect and characterize 18F-fluorodeoxyglucose (FDG) dose infiltrations and evaluate their effects on positron emission tomography (PET) standardized uptake values (SUV) at the injection site and in control tissue. METHODS: Investigational gamma scintillation sensors were topically applied to patients with locally advanced breast cancer scheduled to undergo limited whole-body FDG-PET as part of an ongoing clinical study. Relative to the affected breast, sensors were placed on the contralateral injection arm and ipsilateral control arm during the resting uptake phase prior to each patient's PET scan. Time-activity curves (TACs) from the sensors were integrated at varying intervals (0-10, 0-20, 0-30, 0-40, and 30-40 min) post-FDG and the resulting areas under the curve (AUCs) were compared to SUVs obtained from PET. RESULTS: In cases of infiltration, observed in three sensor recordings (30 %), the injection arm TAC shape varied depending on the extent and severity of infiltration. In two of these cases, TAC characteristics suggested the infiltration was partially resolving prior to image acquisition, although it was still apparent on subsequent PET. Areas under the TAC 0-10 and 0-20 min post-FDG were significantly different in infiltrated versus non-infiltrated cases (Mann-Whitney, p < 0.05). When normalized to control, all TAC integration intervals from the injection arm were significantly correlated with SUVpeak and SUVmax measured over the infiltration site (Spearman ρ ≥ 0.77, p < 0.05). Receiver operating characteristic (ROC) analyses, testing the ability of the first 10 min of post-FDG sensor data to predict infiltration visibility on the ensuing PET, yielded an area under the ROC curve of 0.92. CONCLUSIONS: Topical sensors applied near the injection site provide dynamic information from the time of FDG administration through the uptake period and may be useful in detecting infiltrations regardless of PET image field of view. This dynamic information may also complement the static PET image to better characterize the true extent of infiltrations.

Validation of a Predictive Model for Survival in Patients With Advanced Cancer: Secondary Analysis of RTOG 9714.

Background: The objective of this study was to validate a simple predictive model for survival of patients with advanced cancer. Methods: Previous studies with training and validation datasets developed a model predicting survival of patients referred for palliative radiotherapy using three readily available factors: primary cancer site, site of metastases and Karnofsky performance score (KPS). This predictive model was used in the current study, where each factor was assigned a value proportional to its prognostic weight and the sum of the weighted scores for each patient was survival prediction score (SPS). Patients were also classified according to their number of risk factors (NRF). Three risk groups were established. The Radiation Therapy and Oncology Group (RTOG) 9714 data was used to provide an additional external validation set comprised of patients treated among multiple institutions with appropriate statistical tests. Results: The RTOG external validation set comprised of 908 patients treated at 66 different radiation facilities from 1998 to 2002. The SPS method classified all patients into the low-risk group. Based on the NRF, two distinct risk groups with significantly different survival estimates were identified. The ability to predict survival was similar to that of the training and previous validation datasets for both the SPS and NRF methods. Conclusions: The three variable NRF model is preferred because of its relative simplicity.

The Dose Verification System (DVS) for cancer patients receiving radiation therapy.

The Dose Verification System (DVS) is the first implantable radiation dosimeter designed for in situ measurement of dose delivered to the tissue being irradiated. The success of radiation therapy is predicated on maximizing tumor cell death and minimizing normal tissue toxicity. Tumor control increases with the delivery of appropriate radiation doses to the target area. These doses have been determined from in vitro and animal studies, which generated specific dose-response data. However, there has not been a practical system available to ensure that the appropriate dose was being delivered in situ to monitor the daily patient dose during radiation therapy. Studies have shown that dose variations can occur. Recently completed pivotal clinical studies using the DVS found a greater than 7% (positive or negative) change in cumulative dose in seven out of 36 (19%) breast cancer patients; and six out of 29 (21%) and eight out of 19 (42%) patients during large-field and boost irradiation of the prostate. The device is an important step to enable physicians to expand the concept of individualization of therapy.

The observed variance between predicted and measured radiation dose in breast and prostate patients utilizing an in vivo dosimeter.

PURPOSE: Report the results of using a permanently implantable dosimeter in radiation therapy: determine specific adverse events, degree of migration, and acquire dose measurements during treatment to determine difference between expected and measured dose. METHODS AND MATERIALS: The Dose Verification System is a wireless, permanently implantable metal-oxide semiconductor field-effect transistor dosimeter using a bidirectional antenna for power and data transfer. The study cohort includes 36 breast (33 patients received two devices) and 29 prostate (21 patients received two devices) cancer patients. A total of 1,783 and 1,749 daily dose measurements were obtained on breast and prostate patients, respectively. The measurements were compared with the planned expected dose. Biweekly computed tomography scans were obtained to evaluate migration and the National Cancer Institute's Common Toxicity Criteria, version 3, was used to evaluate adverse events. RESULTS: Only Grade I/II adverse events of pain and bleeding were noted. There were only four instances of dosimeter migration of >5 mm from known factors. A deviation of > or =7% in cumulative dose was noted in 7 of 36 (19%) for breast cancer patients. In prostate cancer patients, a > or =7% deviation was noted in 6 of 29 (21%) and 8 of 19 (42%) during initial and boost irradiation, respectively. The two patterns of dose deviation were random and systematic. Some causes for these differences could involve organ movement, patient movement, or treatment plan considerations. CONCLUSIONS: The Dose Verification System was not associated with significant adverse events or migration. The dosimeter can measure dose in situ on a daily basis. The accuracy and utility of the dose verification system complements current image-guided radiation therapy and intensity-modulated radiation therapy techniques.

Technical evaluation of radiation dose delivered in prostate cancer patients as measured by an implantable MOSFET dosimeter.

PURPOSE: To perform a comparison of the daily measured dose at depth in tissue with the predicted dose values from treatment plans for 29 prostate cancer patients involved in a clinical trial. METHODS AND MATERIALS: Patients from three clinical sites were implanted with one or two dosimeters in or near the prostatic capsule. The implantable device, known as the DVS, is based on a metal-oxide-semiconductor field effect transistor (MOSFET) detector. A portable telemetric readout system couples to the dosimeter antenna (visible on kilovoltage, computed tomography, and ultrasonography) for data transfer. The predicted dose values were determined by the location of the MOSFET on the treatment planning computed tomography scan. Serial computed tomography images were taken every 2 weeks to evaluate any migration of the device. The clinical protocol did not permit alteration of the treatment parameters using the dosimeter readings. For some patients, one of several image-guided radiotherapy (RT) modalities was used for target localization. RESULTS: The evaluation of dose discrepancy showed that in many patients the standard deviation exceeded the previous values obtained for the dosimeter in a phantom. In some patients, the cumulative dose disagreed with the planned dose by > or =5%. The data presented suggest that an implantable dosimeter can help identify dose discrepancies (random or systematic) for patients treated with external beam RT and could be used as a daily treatment verification tool for image-guided RT and adaptive RT. CONCLUSION: The results of our study have shown that knowledge of the dose delivered per fraction can potentially prevent over- or under-dosage to the treatment area and increase the accuracy of RT. The implantable dosimeter could also be used as a localizer for image-guided RT.

The impact of concurrent granulocyte macrophage-colony stimulating factor on radiation-induced mucositis in head and neck cancer patients: a double-blind placebo-controlled prospective phase III study by Radiation Therapy Oncology Group 9901.

PURPOSE: Based on early clinical evidence of potential mucosal protection by granulocyte-macrophage colony stimulating factor (GM-CSF), the Radiation Therapy Oncology Group conducted a double-blind, placebo-controlled, randomized study to test the efficacy and safety of GM-CSF in reducing the severity and duration of mucosal injury and pain (mucositis) associated with curative radiotherapy (RT) in head-and-neck cancer patients. METHODS AND MATERIALS: Eligible patients included those with head-and-neck cancer with radiation ports encompassing >50% of oral cavity and/or oropharynx. Standard RT ports were used to cover the primary tumor and regional lymphatics at risk in standard fractionation to 60-70 Gy. Concurrent cisplatin chemotherapy was allowed. Patients were randomized to receive subcutaneous injection of GM-CSF 250 microg/m2 or placebo 3 times a week. Mucosal reaction was assessed during the course of RT using the National Cancer Institute Common Toxicity Criteria and the protocol-specific scoring system. RESULTS: Between October 2000 and September 2002, 130 patients from 36 institutions were accrued. Nine patients (7%) were excluded from the analysis, 3 as a result of drug unavailability. More than 80% of the patients participated in the quality-of-life endpoint of this study. The GM-CSF did not cause any increase in toxicity compared with placebo. There was no statistically significant difference in the average mean mucositis score in the GM-CSF and placebo arms by a t test (p = 0.4006). CONCLUSION: This placebo-controlled, randomized study demonstrated no significant effect of GM-CSF given concurrently compared with placebo in reducing the severity or duration of RT-induced mucositis in patients undergoing definitive RT for head-and-neck cancer.

An analysis of an implantable dosimeter system for external beam therapy.

BACKGROUND AND PURPOSE: To review the data from an implantable radiation dosimetry system used in a clinical setting and to examine correlations between dosimeter readings and potential causative error sources. MATERIALS AND METHODS: MOSFET (metal oxide semiconductor field effect transistor) based encapsulated dosimeters were evaluated in a phantom (in vitro) and in a study with 18 patients. The dosimeters were placed in the gross tumor volume or in collateral normal tissue. Predicted dose values were established by imaging the dosimeters in the planning CTs. RESULTS: The in vitro study confirmed that bounding cumulative errors due to setup, planning, and machine output within a +/-5% level is achievable. In patients, it was found that deviations from the targeted dose often exceeded the 5% level. CONCLUSIONS: The use of an implantable dosimeter system could provide an effective empiric check on the dose delivered at depth. Such a tool may have value for institutional quality assurance, as well as for therapy delivered to individual patients.

Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases.

BACKGROUND: Radiation therapy is effective in palliating pain from bone metastases. We investigated whether 8 Gy delivered in a single treatment fraction provides pain and narcotic relief that is equivalent to that of the standard treatment course of 30 Gy delivered in 10 treatment fractions over 2 weeks. METHODS: A prospective, phase III randomized study of palliative radiation therapy was conducted for patients with breast or prostate cancer who had one to three sites of painful bone metastases and moderate to severe pain. Patients were randomly assigned to 8 Gy in one treatment fraction (8-Gy arm) or to 30 Gy in 10 treatment fractions (30-Gy arm). Pain relief at 3 months after randomization was evaluated with the Brief Pain Inventory. The Wilcoxon-Mann-Whitney test was used to compare response to treatment in terms of pain and narcotic relief between the two arms and for each stratification variable. All statistical comparisons were two-sided. RESULTS: There were 455 patients in the 8-Gy arm and 443 in the 30-Gy arm; pretreatment characteristics were equally balanced between arms. Grade 2-4 acute toxicity was more frequent in the 30-Gy arm (17%) than in the 8-Gy arm (10%) (difference = 7%, 95% CI = 3% to 12%; P = .002). Late toxicity was rare (4%) in both arms. The overall response rate was 66%. Complete and partial response rates were 15% and 50%, respectively, in the 8-Gy arm compared with 18% and 48% in the 30-Gy arm (P = .6). At 3 months, 33% of all patients no longer required narcotic medications. The incidence of subsequent pathologic fracture was 5% for the 8-Gy arm and 4% for the 30-Gy arm. The retreatment rate was statistically significantly higher in the 8-Gy arm (18%) than in the 30-Gy arm (9%) (P < .001). CONCLUSIONS: Both regimens were equivalent in terms of pain and narcotic relief at 3 months and were well tolerated with few adverse effects. The 8-Gy arm had a higher rate of re-treatment but had less acute toxicity than the 30-Gy arm.

Initial clinical results of an in vivo dosimeter during external beam radiation therapy.

PURPOSE: An implantable radiation dosimeter has been developed to monitor dose delivered at depth in patients undergoing external beam therapy. A clinical pilot study was conducted to test the safety, efficacy, and utility of the device. METHODS AND MATERIALS: Ten patients, all with unresectable malignant disease, were enrolled to assess implantation risk and movement of the device in the body and to compare the in vivo measured dose to the value predicted by the treatment planning system software. RESULTS: Migration of the sensor away from the point of original placement was noted in only 1 patient (due to unconsolidated host tissue) and no adverse events were recorded during the implantation procedure or thereafter. Daily dose measurements were recorded successfully for all sensors in all patients. Variance between measured and predicted dose values was reported as a frequency of error at the > or =5% and > or =8% levels. The error frequency at the > or =8% level was as high as 47%, 29%, and 21% for lung, prostate, and rectal tumors, respectively. CONCLUSIONS: The implantable dosimeter was found to be safe and effective in measuring dose at depth. There are many factors that can influence delivered dose, and the implantable dosimeter measures the net effect of these factors. The daily sensor readings provide a new tool for rigorous treatment quality assurance.

An implantable radiation dosimeter for use in external beam radiation therapy.

An implantable radiation dosimeter for use with external beam therapy has been developed and tested both in vitro and in canines. The device uses a MOSFET dosimeter and is polled telemetrically every day during the course of therapy. The device is designed for permanent implantation and also acts as a radiographic fiducial marker. Ten dogs (companion animals) that presented with spontaneous, malignant tumors were enrolled in the study and received an implant in the tumor CTV. Three dogs received an additional implant in collateral normal tissue. Radiation therapy plans were created for the animals and they were treated with roughly 300 cGy daily fractions until completion of the prescribed cumulative dose. The primary endpoints of the study were to record any adverse events due to sensor placement and to monitor any movement away from the point of placement. No adverse events were recorded. Unacceptable device migration was experienced in two subjects and a retention mechanism was developed to prevent movement in the future. Daily dose readings were successfully acquired in all subjects. A rigorous in vitro calibration methodology has been developed to ensure that the implanted devices maintain an accuracy of +/-3.5% relative to an ionization chamber standard. The authors believe that an implantable radiation dosimeter is a practical and powerful tool that fosters individualized patient QA on a daily basis.

Phase III quality-of-life study results: impact on patients' quality of life to reducing xerostomia after radiotherapy for head-and-neck cancer--RTOG 97-09.

PURPOSE: To determine whether prevention of hyposalivation after curative radiotherapy (RT) to the head and neck improves patients' quality of life (QOL). METHODS AND MATERIALS: Patients were to receive at least 50 Gy to 50% of the volume of the major salivary glands, provide unstimulated and stimulated saliva samples, and complete the University of Washington head-and-neck QOL tool before RT and 3 and 6 months after RT. Patients were randomized to receive pilocarpine 5 mg or placebo q.i.d. RESULTS: A total of 249 patients was randomized between March 1998 and January 2000. Of these, 214 were eligible for QOL analysis. Patients were evenly distributed between arms by race, gender, tobacco use, tumor site, T stage (50% T2-T3), and salivary function. A Karnofsky performance status of 90% was more common in the pilocarpine arm. Twenty percent of the patients on the pilocarpine arm and 29% of the patients on the placebo arm were taking nutritional supplements. The placebo arm patients had greater mouth pain and chewing difficulties. Compliance for the QOL tool at 3 and 6 months was 65% and 50%, respectively. Despite statistically significant (p = 0.047 and p = 0.049, respectively) preservation of salivary function in the pilocarpine arm, patients on the pilocarpine arm reported difficulties with swallowing (75%), activity (80%), hyposalivation (64%), and taste (81%). No difference was noted between arms at 3 months in mucositis scores, with both arms demonstrating increased requirement for oral nutrients. CONCLUSION: Objective prevention of hyposalivation did not affect patients' assessment of salivary function or QOL because of the greater impact mucositis plays in QOL after RT.