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Applications of mathematical modeling can improve outcome predictions of cancer therapy. Here we present a kinetic model incorporating effects of radiosensitivity, tumor repopulation, and dead-cell resolving on the analysis of tumor volume regression data of 80 cervical cancer patients (stages 1B2-IVA) who underwent radiation therapy. Regression rates and derived model parameters correlated significantly with clinical outcome (P < 0.001; median follow-up: 6.2 years). The 6-year local tumor control rate was 87% versus 54% using radiosensitivity (2-Gy surviving fraction S2 < 0.70 vs. S2 ≥ 0.70) as a predictor (P = 0.001) and 89% vs. 57% using dead-cell resolving time (T1/2 < 22 days versus T1/2 ≥ 22 days, P < 0.001). The 6-year disease-specific survival was 73% versus 41% with S2 < 0.70 versus S2 ≥ 0.70 (P = 0.025), and 87% vs. 52% with T1/2 < 22 days versus T1/2 ≥ 22 days (P = 0.002). Our approach illustrates the promise of volume-based tumor response modeling to improve early outcome predictions that can be used to enable personalized adaptive therapy. Cancer Res; 70(2); 463–70

Free Article from Predicting Outcomes in Cervical Cancer: A Kinetic Model of Tumor Regression during Radiation Therapy

Background To investigate outcome prediction by measuring tumor absolute volume and regression ratio using serial magnetic resonance imaging (MRI) during radiation therapy (RT) of cervical cancer and to develop algorithms identifying patients at risk of poor therapeutic outcome.

To assess individual volumetric tumor regression pattern in cervical cancer during therapy using serial four-dimensional MRI and to define the regression parameters' prognostic value validated with local control and survival correlation.One hundred and fifteen patients with Stage IB(2)-IVA cervical cancer treated with radiation therapy (RT) underwent serial MRI before (MRI 1) and during RT, at 2-2.5 weeks (MRI 2, at 20-25 Gy), and at 4-5 weeks (MRI 3, at 40-50 Gy). Eighty patients had a fourth MRI 1-2 months post-RT. Mean follow-up was 5.3 years. Tumor volume was measured by MRI-based three-dimensional volumetry, and plotted as dose(time)/volume regression curves. Volume regression parameters were correlated with local control, disease-specific, and overall survival.Residual tumor volume, slope, and area under the regression curve correlated significantly with local control and survival. Residual volumesor=20% at 40-50 Gy were independently associated with inferior 5-year local control (53% vs. 97%, p0.001) and disease-specific survival rates (50% vs. 72%, p = 0.009) than smaller volumes. Patients with post-RT residual volumesor=10% had 0% local control and 17% disease-specific survival, compared with 91% and 72% for10% volume (p0.001).Using more accurate four-dimensional volumetric regression analysis, tumor response can now be directly translated into individual patients' outcome for clinical application. Our results define two temporal thresholds critically influencing local control and survival. In patients withor=20% residual volume at 40-50 Gy andor=10% post-RT, the risk for local failure and death are so high that aggressive intervention may be warranted.

BACKGROUND: The authors prospectively evaluated magnetic resonance imaging (MRI) parameters quantifying heterogeneous perfusion pattern and residual tumor volume early during treatment in cervical cancer, and compared their predictive power for primary tumor recurrence and cancer death with the standard clinical prognostic factors. A novel approach of augmenting the predictive power of clinical prognostic factors with MRI parameters was assessed. METHODS: Sixty-two cervical cancer patients underwent dynamic contrast-enhanced (DCE) MRI before and during early radiation/chemotherapy (2-2.5 weeks into treatment). Heterogeneous tumor perfusion was analyzed by signal intensity (SI) of each tumor voxel. Poorly perfused tumor regions were quantified as lower 10th percentile of SI (SI[10%]). DCE-MRI and 3-dimensional (3D) tumor volumetry MRI parameters were assessed as predictors of recurrence and cancer death (median follow-up, 4.1 years). Their discriminating capacity was compared with clinical prognostic factors (stage, lymph node status, histology) using sensitivity/specificity and Cox regression analysis. RESULTS: SI(10%) and 3D volume 2-2.5 weeks into therapy independently predicted disease recurrence (hazard ratio [HR], 2.6; 95% confidence interval [95% CI], 1.0-6.5 [P = .04] and HR, 1.9; 95% CI, 1.1-3.5 [P = .03], respectively) and death (HR, 1.9; 95% CI, 1.0-3.5 [P = .03] and HR, 1.9; 95% CI, 1.2-2.9 [P = .01], respectively), and were superior to clinical prognostic factors. The addition of MRI parameters to clinical prognostic factors increased sensitivity and specificity of clinical prognostic factors from 71% and 51%, respectively, to 100% and 71%, respectively, for predicting recurrence, and from 79% and 54%, respectively, to 93% and 60%, respectively, for predicting death. CONCLUSIONS: MRI parameters reflecting heterogeneous tumor perfusion and subtle tumor volume change early during radiation/chemotherapy are independent and better predictors of tumor recurrence and death than clinical prognostic factors. The combination of clinical prognostic factors and MRI parameters further improves early prediction of treatment failure and may enable a window of opportunity to alter treatment strategy. Cancer 2010. © 2010 American Cancer Society.

Applications of mathematical modeling can improve outcome predictions of cancer therapy. Here we present a kinetic model incorporating effects of radiosensitivity, tumor repopulation, and dead-cell resolving on the analysis of tumor volume regression data of 80 cervical cancer patients (stages 1B2-IVA) who underwent radiation therapy. Regression rates and derived model parameters correlated significantly with clinical outcome (P < 0.001; median follow-up: 6.2 years). The 6-year local tumor control rate was 87% versus 54% using radiosensitivity (2-Gy surviving fraction S2 < 0.70 vs. S2 ≥ 0.70) as a predictor (P = 0.001) and 89% vs. 57% using dead-cell resolving time (T1/2 < 22 days versus T1/2 ≥ 22 days, P < 0.001). The 6-year disease-specific survival was 73% versus 41% with S2 < 0.70 versus S2 ≥ 0.70 (P = 0.025), and 87% vs. 52% with T1/2 < 22 days versus T1/2 ≥ 22 days (P = 0.002). Our approach illustrates the promise of volume-based tumor response modeling to improve early outcome predictions that can be used to enable personalized adaptive therapy. Cancer Res; 70(2); 463–70

The tumor oxygenation status is likely influenced by two major factors: local tumor blood supply (tumor perfusion) and its systemic oxygen carrier, hemoglobin (Hgb). Each has been independently shown to affect the radiotherapy (RT) outcome in cervical cancer. This study assessed the effect of local tumor perfusion, systemic Hgb levels, and their combination on the treatment outcome in cervical cancer.A total of 88 patients with cervical cancer, Stage IB2-IVA, who were treated with RT/chemotherapy, underwent serial dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) before RT, at 20-22 Gy, and at 45-50 Gy. The DCE-MRI perfusion parameters, mean and lowest 10th percentile of the signal intensity distribution in the tumor pixels, and the Hgb levels, including pre-RT, nadir, and mean Hgb (average of weekly Hgb during RT), were correlated with local control and disease-specific survival. The median follow-up was 4.6 years.Local recurrence predominated in the group with both a low mean Hgb (11.2 g/dL) and low perfusion (lowest 10th percentile of signal intensity2.0 at 20-22 Gy), with a 5-year local control rate of 60% vs. 90% for all other groups (p = .001) and a disease-specific survival rate of 41% vs. 72% (p = .008), respectively. In the group with both high mean Hgb and high perfusion, the 5-year local control rate and disease-specific survival rate was 100% and 78%, respectively.These results suggest that the compounded effects of Hgb level and tumor perfusion during RT influence the radioresponsiveness and survival in cervical cancer patients. The outcome was worst when both were impaired. The management of Hgb may be particularly important in patients with low tumor perfusion.

CNS germ cell tumors are rare primary brain malignancies. Germinomas comprise approximately two-thirds of CNS germ cell tumors. Owing to their radiosensitivity, radiotherapy has been used to treat patients with CNS germinomas, with favorable treatment outcomes. Historically, craniospinal irradiation has been used. Given the concerns over long-term toxicities associated with craniospinal irradiation, reduced volume radiotherapy with or without chemotherapy has been employed. Data on the use of different strategies in the treatment of CNS germinomas are emerging but a standard strategy has not been established. This article reviews the different strategies used in the management of CNS germinomas.

The standard treatment for medulloblastoma is surgery followed by adjuvant chemotherapy and external beam radiotherapy to the craniospinal axis and posterior fossa. However, in very young children, craniospinal irradiation has a more significant detrimental effect in terms of neurocognitive function and growth. This article reviews the different strategies used for very young patients with medulloblastoma.

Many factors influence response in low-dose-rate (LDR) brachytherapy of prostate cancer. Among them, edema, relative biological effectiveness (RBE), and dose heterogeneity have not been fully modeled previously. In this work, the generalized linear-quadratic (LQ) model, extended to account for the effects of edema, RBE, and dose heterogeneity, was used to assess these factors and their combination effect. Published clinical data have shown that prostate edema after seed implant has a magnitude (ratio of post- to preimplant volume) of 1.3-2.0 and resolves exponentially with a half-life of 4-25 days over the duration of the implant dose delivery. Based on these parameters and a representative dose-volume histogram (DVH), we investigated the influence of edema on the implant dose distribution. The LQ parameters ({alpha}=0.15 Gy{sup -1} and {alpha}/{beta}=3.1 Gy) determined in earlier studies were used to calculate the equivalent uniform dose in 2 Gy fractions (EUD{sub 2}) with respect to three effects: edema, RBE, and dose heterogeneity for {sup 125}I and {sup 103}Pd implants. The EUD{sub 2} analysis shows a negative effect of edema and dose heterogeneity on tumor cell killing because the prostate edema degrades the dose coverage to tumor target. For the representative DVH, the V{sub 100} (volume covered by 100%more » of prescription dose) decreases from 93% to 91% and 86%, and the D{sub 90} (dose covering 90% of target volume) decrease from 107% to 102% and 94% of prescription dose for {sup 125}I and {sup 103}Pd implants, respectively. Conversely, the RBE effect of LDR brachytherapy [versus external-beam radiotherapy (EBRT) and high-dose-rate (HDR) brachytherapy] enhances dose effect on tumor cell kill. In order to balance the negative effects of edema and dose heterogeneity, the RBE of prostate brachytherapy was determined to be approximately 1.2-1.4 for {sup 125}I and 1.3-1.6 for {sup 103}Pd implants. These RBE values are consistent with the RBE data published in the literature. These results may explain why in earlier modeling studies, when the effects of edema, dose heterogeneity, and RBE were all ignored simultaneously, prostate LDR brachytherapy was reported to show an overall similar dose effect as EBRT and HDR brachytherapy, which are independent of edema and RBE effects and have a better dose coverage.« less

Radiation therapy for cervical cancer involves a team of specialists, including diagnostic radiologists (DRs), radiation oncologists (ROs), and medical physicists (MPs), to optimize imaging‐based radiation therapy planning. The purpose of the study was to investigate the interobserver variations in tumor delineation on MR images of cervical cancer within the same and among different specialties. Twenty MRI cervical cancer studies were independently reviewed by two DRs, two ROs, and two MPs. For every study, each specialist contoured the tumor regions of interest (ROIs) on T2‐weighted Turbo Spin Echo sagittal images on all slices containing tumor, and the total tumor volume was computed for statistical analysis. Analysis of variance (ANOVA) was used to compare the differences in tumor volume delineation among the observers. A graph of all tumor‐delineated volumes was generated, and differences between the maximum and minimum volumes over all the readers for each patient dataset were computed. Challenges during the evaluation process for tumor delineation were recorded for each specialist. Interobserver variations of delineated tumor volumes were significant (p

Purpose Intensity-modulated radiotherapy (IMRT) has been shown to reduce the radiation dose to small bowel in pelvic RT in gynecology patients. Prone positioning has also been used to decrease small bowel dose by displacement of small bowel from the RT field in these patients. The purpose of this study was to determine whether the combination of both IMRT and prone positioning on a belly board can reduce small bowel dose further in gynecologic cancer patients undergoing pelvic RT. Methods and materials IMRT plans for pelvic RT were computed in 16 patients with gynecologic cancer who had undergone planning CT scans in both the supine and the prone positions on a belly board. For the gross tumor volume, the uterus, cervix, and tumor (or postoperative region) were traced. The clinical target volume was defined as the vessels and lymph nodes from the obturator level to the aortic bifurcation, presacral region, and upper 4 cm of the vagina, in addition to gross tumor volume. The planning target volume was defined as a 2-cm margin in addition to the gross tumor volume and upper 4 cm of the vagina, and 1.5 cm for lymph nodes and vessels. Normal tissue regions of interest included small bowel, large bowel, and bladder. IMRT plans using ( 1 ) the limited arc technique (180° arc length) and ( 2 ) the extended arc technique (340° arc length) were computed. Dose–volume histograms for normal tissue structures and target were compared between the supine and prone IMRT plans using the paired t test. Results Prone positioning on a belly board decreased the small bowel dose in gynecologic pelvic IMRT, and the magnitude of improvement depended on the specific IMRT technique used. With the limited arc technique, prone positioning significantly decreased the irradiated small bowel volume at the 25–50-Gy dose levels compared with supine positioning. Small bowel volumes receiving ≥45 Gy decreased from 19% to 12.5% ( p = 0.005) with prone positioning. With the extended arc technique, the decrease in irradiated small bowel volume was less marked, but remained detectable in the 35–45-Gy dose levels. Small bowel volumes receiving ≥45 Gy decreased from 13.6% to 10.1% ( p = 0.03) with prone positioning. The effect of prone positioning on large bowel and bladder was variable. Large bowel volumes receiving ≥45 Gy increased with prone positioning from 16.5% to 20.6% ( p = 0.02) in the limited arc technique and was unaffected in the extended arc technique. Conclusion These preliminary data suggest that prone positioning on a belly board can reduce the small bowel dose further in gynecology patients treated with pelvic RT, and that the dose reduction depends on the IMRT technique used.

An unexpected elevated postimplant radiation survey is described in an elderly patient with an interstitial low-dose-rate iridium-192 (Ir-192) needle implant for endometrial cancer. The elevated activity was related to prolonged clearance of Tl-201 from a cardiac study that had been performed 7 days earlier. The Tl-201 accumulated in the soft tissue, particularly the colon, resulting in increased survey readings over the abdomen and raising concern that an Ir-192 source remained within the patient. This case shows that delayed excretion of a diagnostic radionuclide agent can cause elevated activity high enough to confound postradiotherapy implant survey readings. The estimated surface exposure from a single iridium source left in the pelvis was determined using a phantom study. Possible factors causing decreased excretion of Tl-201 in a patient with heart disease, arteriosclerotic vascular disease, previous pelvic radiation therapy, and a brachytherapy procedure are discussed. A preloading radiation survey is recommended in patients who have had previous nuclear medicine studies involving radionuclides with long half-lives.

Intense p53 immunostaining may predict for a poor prognosis in central nervous system primitive neuroectodermal tumor of childhood. Background: Medulloblastoma is a common childhood primary brain tumor. Potential prognostic indicators for patients with local disease are age, extent of resection, and gender. However, none of these are well established. Immunohistologic staining is a potentially useful means to identify high-risk patients. The purpose of this clinical pathologic study was to investigate the prognostic significance of GFAP, synaptophysin, Ki-67, and p53 immunostaining in medulloblastoma/central nervous system primitive neuroectodermal tumors (CNS PNETs.) Materials and methods: The records of 40 patients with CNS PNETs were reviewed. Their surgical specimens were immunostained for p53, glial fibrillary acidic protein (GFAP), synaptophysin, and Ki-67. The p53 specimens were scored blindly for the intensity of staining of nuclei (intense vs weak) and the quantity of cells stained. The Ki-67, GFAP, and synaptophysin specimens were analyzed for quantity of cells stained. Results: Ten patients' specimens stained intensely for the p53 protein. Eleven had weakly staining nuclei. Nineteen specimens had no staining. The patients with specimens that stained intensely had a statistically significant decreased disease free survival (P = 0.03). Mere presence or quantity of p53 nuclear staining did not correlate with disease free survival. Immunohistochemical staining for Ki-67, GFAP, and synaptophysin did not correlate with disease free survival. Clinical parameters of age, gender, and extent of resection also did not approach statistical break significance for disease free survival. Conclusion: Intense nuclear staining for p53 was the only variable in this clinical pathologic study that reached statistical significance for disease free survival. This suggests that intense staining for p53 may be the most important prognostic indicator for non-metastatic CNS PNETs. p53 Immunostaining with antibodies against p53 in CNS PNETs should be studied in a multi-institutional setting with larger numbers of patients.

Symptomatic local failure following thoracic irradiation for bronchogenic carcinoma presents a clinical challenge to the Radiation Oncologist. We retrospectively evaluated the efficiency of reirradiation with external beam radiation of 30 patients. The median dose of initial irradiation was 6,000 cGy in 6 weeks. The median time following initial irradiation to recurrence was 12 months. The median dose of retreatment was 3,030 cGy in 3 weeks. Of the symptomatic patients, 88% and 70% subjectively responded to initial irradiation and to reirradiation, respectively. Retreatment toxicity included radiation esophagitis (6 patients), dry desquamation (4 patients), and symptomatic radiation pneumonitis (1 patient). Based on this study, doses of external beam radiation in the range of 2,000-3,000 cGy in 2 to 3 weeks appear safe and effective in reirradiating recurrent bronchogenic carcinoma.

Purpose: To study the temporal changes of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion patterns during the radiation therapy (RT) course and their influence on local control and survival in cervical cancer. Methods and Materials: DCE-MRI was performed in 98 patients with Stage IB{sub 2}-IVA cervical cancer before RT (pre-RT) and during early RT (20-25 Gy) and mid-RT (45-50 Gy). Signal intensity (SI) from the DCE-MRI time-SI curve was derived for each tumor voxel. The poorly perfused low-DCE tumor subregions were quantified as lower 10th percentiles of SI (SI10). Local control, disease-specific survival, and overall survival were correlated with DCE parameters at pre-RT, early RT, and mid-RT. Median follow-up was 4.9 (range, 0.2-9.0) years. Results: Patients (16/98) with initial pre-RT high DCE (SI10 >=2.1) had 100% 5-year local control, 81% disease-specific survival, and 81% overall survival, compared with only 79%, 61%, and 55%, respectively, in patients with pre-RT low DCE. Conversion from pre-RT low DCE to high DCE in early RT (28/82 patients) was associated with higher local control, disease-specific survival, and overall survival (93%, 74%, and 67%, respectively). In comparison with all other groups, outcome was worst in patients with persistently low DCE from pre-RT throughout the mid-RT phasemore » (66%, 44%, and 43%; p = 0.003, 0.003, and 0.020; respectively). Conclusion: Longitudinal tumor perfusion changes during RT correlate with treatment outcome. Persistently low perfusion in pre-RT, early RT, and mid-RT indicates a high risk of treatment failure, whereas outcome is favorable in patients with initially high perfusion or subsequent improvements of initially low perfusion. These findings likely reflect reoxygenation and may have potential for noninvasive monitoring of intra-treatment radio-responsiveness and for guiding adaptive therapy.« less

Purpose To investigate equivalent regimens for hypofractionated stereotactic radiotherapy (HSRT) for brain tumor treatment and to provide dose-escalation guidance to maximize the tumor control within the normal brain tolerance. Methods and Materials The linear-quadratic model, including the effect of nonuniform dose distributions, was used to evaluate the HSRT regimens. The α/β ratio was estimated using the Gammaknife stereotactic radiosurgery (GKSRS) and whole-brain radiotherapy experience for large brain tumors. The HSRT regimens were derived using two methods: (1) an equivalent tumor control approach , which matches the whole-brain radiotherapy experience for many fractions and merges it with the GKSRS data for few fractions; and (2) a normal-tissue tolerance approach , which takes advantages of the dose conformity and fractionation of HSRT to approach the maximal dose tolerance of the normal brain. Results A plausible α/β ratio of 12 Gy for brain tumor and a volume parameter n of 0.23 for normal brain were derived from the GKSRS and whole-brain radiotherapy data. The HSRT prescription regimens for the isoeffect of tumor irradiation were calculated. The normal-brain equivalent uniform dose decreased as the number of fractions increased, because of the advantage of fractionation. The regimens for potential dose escalation of HSRT within the limits of normal-brain tolerance were derived. Conclusions The designed hypofractionated regimens could be used as a preliminary guide for HSRT dose prescription for large brain tumors to mimic the GKSRS experience and for dose escalation trials. Clinical studies are necessary to further tune the model parameters and validate these regimens.

Purpose: To evaluate the potential therapeutic advantage of external beam grid therapy in treating cervical cancers in comparison of conventional open field radiotherapy.

Purpose To evaluate the conventionally fractionated and hypofractionated grid therapy in debulking cervical cancers using the linear quadratic (LQ) model. Methods and Materials A Monte Carlo technique was used to calculate the dose distribution of a commercially available grid in a 6-MV photon beam. The LQ model was used to evaluate the therapeutic outcome of both the conventionally fractionated (2 Gy/fraction) and hypofractionated (15 Gy/fraction) grid therapy regimens to debulk cervical cancers with different LQ parameters. The equivalent open-field dose (EOD) to the cancer cells and therapeutic ratio (TR) were defined by comparing grid therapy with the open debulking field. The clinical outcomes from 114 patients were used to verify our theoretical model. Results The cervical cancer and normal tissue cell survival statistics for grid therapy in two regimens were calculated. The EODs and TRs were derived. The EOD was only a fraction of the prescribed dose. The TR was dependent on the prescribed dose and the LQ parameters of both the tumor and normal tissue cells. The grid therapy favors the acutely responding tumors inside radiosensitive normal tissues. Theoretical model predictions were consistent with the clinical outcomes. Conclusions Grid therapy provided a pronounced therapeutic advantage in both the hypofractionated and conventionally fractionated regimens compared with that seen with single fraction, open debulking field regimens, but the true therapeutic advantage exists only in the hypofractionated grid therapy. The clinical outcomes and our study indicated that a course of open-field radiotherapy is necessary to control tumor growth fully after a grid therapy.

The purpose of this study was to evaluate the patterns and distribution of tumor shape and its temporal change during radiation therapy (RT) in cervical cancer and the effect of tumor configuration changes on the correlation between region of interest (ROI)-based and diameter-based MRI tumor measurement.Serial MRI examinations (T1-weighted and T2-weighted images) were performed in 60 patients (age range, 29-75 years; mean, 53.3 years) with advanced cervical cancer (stages IB2-IVB/recurrent) who were treated with RT at four time points: start of RT, during RT (at 2-2.5 and at 4-5 weeks of RT), and post-RT. Tumor configuration was classified qualitatively into oval, lobulated, and complex based on MR film review. Two methods of tumor volume measurement were compared: ellipsoid computation of three orthogonal diameters (diameter based) and ROI volumetry by delineating the entire tumor volume on the MR workstation (ROI based). Temporal changes of tumor shape and the respective tumor volumes measured by the two methods were analyzed using linear regression analysis.Most tumors (70%) had a non-oval (lobulated and complex) shape before RT and became increasingly irregular during and after RT: 84% at 2-2.5 weeks of RT (p = 0.037), 86% (p = 0.025) at 4-5 weeks, and 96% post-RT (p = 0.010), compared with 70% pre-RT. Diameter-based and ROI-based measurement correlated well before RT (r = 0.89) but not during RT (r = 0.68 at 2-2.5 weeks, r = 0.67 at 4-5 weeks of RT).Most cervical cancers are not oval in shape pretherapy, and they become increasingly irregular during and after therapy because of nonconcentric tumor shrinkage. ROI-based volumetry, which can optimally measure irregular volumes, may provide better response assessment during treatment than diameter-based measurement.

Previous treatment of cerebrospinal fluid (CSF) malignancies by intrathecal administration of (131)I-radiolabelled monoclonal antibodies has led to the assumption that more healthy tissue will be spared when a pure beta-emitter such as (90)Y replaces (131)I. The purpose of this study is to compare and quantitatively evaluate the dose distribution from (90)Y to the CSF space and its surrounding spinal structures to (131)I. A 3D digital phantom of a section of the T-spine was constructed from the visible human project series of images which included the spinal cord, central canal, subarachnoid space, pia mater, arachnoid, dura mater, vertebral bone marrow and intervertebral disc. Monte Carlo N-particle (MCNP4C) was used to model the (90)Y and (131)I radiation distribution. Images of the CSF compartment were convolved with the radiation distribution to determine the dose within the subarachnoid space and surrounding tissues. (90)Y appears to be a suitable radionuclide in the treatment of central nervous system (CNS) malignancies when attached to mAb's and the dose distribution would be confined largely within the vertebral foramen. This choice may offer favourable dose improvement to the subarachnoid and surface of spinal cord over (131)I in such an application.

Purpose Patients with a retroverted uterus present a dilemma for brachytherapy in gynecologic malignancies because of the challenges of the procedure and the risk of uterine perforation. The purpose of this study was to evaluate the efficacy and outcome of ultrasound-guided brachytherapy applicator placement and intraoperative uterine anteversion in patients with gynecologic malignancies, who have a retroverted uterus. Methods and materials Thirty-three brachytherapy insertions were performed in 18 patients with retroverted uterus (cervical cancer, 17; vaginal cancer, 1). The endocervical canal was dilated, the intrauterine Fletcher tandem was inserted in retroverted fashion and then anteverted along with the uterus under continuous ultrasound guidance. The anteverted tandem position was secured with vaginal packing and use of a second and/or third flange on the tandem stem. Treatment was delivered with low-dose-rate brachytherapy using afterloading with 137 Cs. Brachytherapy was combined with external beam radiation in all patients. Median post-therapy follow-up was 2.17 years (range, 0.75–9.25 years). Results Procedure. Ultrasound-guided dilation of the cervix was achieved in all procedures. Sounding of the retroverted uterus up to the fundus was accomplished successfully in all but one procedure (because severe retroflexion of the uterus and fixation of the fundus to the sacrum). Ultrasound-guided anteversion of the inserted tandem and uterus was achieved in all procedures. No ultrasonographic evidence of perforation was seen in any of the procedures. Intraoperative radiographs showed satisfactory position of the applicators in 31 of the 33 procedures; 2 cases were re-packed resulting in acceptable final applicator position. No backward rotation of the tandem was observed over the duration of the low-dose-rate brachytherapy application. The mean ratio between the dose to the rectum and Point A was 73%; the ratio between the dose to the bladder and Point A was 76%. Outcome. In the 17 patients with cervical cancer, 2-year pelvic tumor control rate was 100%, and 2-year actuarial disease-free survival was 73%. The patient with vaginal cancer has no evidence of disease 5 months post-therapy. There was one complication (1/18 patients, 5.5%): a rectal stricture in a patient with stage IVA cervical cancer requiring colostomy. Conclusions The use of ultrasound-guided uterine anteversion for brachytherapy applicator placement is feasible and results in acceptable outcome and complication rates in a population otherwise difficult to manage and at high risk for uterine perforation. Based on these results, this method is likely preferable to brachytherapy with a retroverted tandem, or to the omission of brachytherapy.

Purpose: To investigate the outcome predictive power of tumor volume measured by serial MR imaging(MRI) of cervical cancer, including the sensitivity and specificity to identify patients at risk of local failure. Method and Materials: Seventy‐nine patients with cervical cancer stages IB2‐IVA, treated with radiation/chemotherapy (RT/CT), underwent serial MRI:MRI 1(pre‐RT), MRI 2(at 20–25 Gy/2 weeks), MRI 3(at 40–50 Gy/4 weeks), and MRI 4(at 1–2 months post‐RT). Mean follow up was 6.2 (0.2–9.4) years. Tumor volumes (V1,V2,V3,V4) and regression ratios (V2/V1,V3/V1,V4/V1) were measured by MRI 3D volumetry, and correlated with local tumor‐control and disease‐free survival using Mann‐Whitney rank‐sum test. Results: The volume data collected in this study were analyzed and the predictive power in terms of p‐value to discriminate local tumor‐control and disease‐free survival was computed. The absolute tumor volumes (V2,V3,V4) and the regression ratios (V2/V1,V3/V1,V4/V1) strongly correlated with local tumor‐control (p 20% and V4/V1 >10%), which have a sensitivity of 89% and a specificity of 100%. Local failure can also be predicted as early as 2–3 weeks (MRI 2), the method of V1 >40 cc and V2/V1 >75% shows a sensitivity of 61% and a specificity of 93%. Conclusion: MRI‐based volumetric tumor measurement provides important predictive information about tumor response to the ongoing RT/CT. The methods developed in this study demonstrate a high specificity (87%–100%) for patients at risk of local failure based on long‐term follow‐up. These methods may classify patients who require more aggressive therapeutic intervention.

Children with pulmonary sarcomas who have diffuse contamination of the pleural cavity present a difficult management problem for the radiation oncologist. Doses required to control even microscopic disease exceed lung tolerance. We report on the use of intracavity colloid P-32 in an attempt to treat the pleural surface and spare normal lung parenchyma and tissues of the chest wall. Three children--18 months, 12 years, and 3 years of age--had spillage of pulmonary sarcomas into the chest cavity. All children were treated with systemic chemotherapy. Initially, 0.5 mCi of technetium sulfur colloid (99mTc-sulfur colloid) was instilled into the pleural space to ascertain even distribution of isotope. This was then followed by installation of 5.0 mCi of colloidal P-32. Uniform distribution was then confirmed by bremsstrahlung scanning. All three patients are in complete remission 3.5 years, 3 years, and 1 year after treatment, respectively. The major toxicity was asymptomatic pleural thickening, which could be confused with disease. This was confirmed histologically to be fibrous in the first patient. The process diminished or stabilized with time in all 3 patients over the period of observation. In this small series, intrapleural colloidal P-32 appeared to be safe and well tolerated and would be expected to be less toxic than wide-field external beam in the treatment of spilled pulmonary sarcomas.

Purpose/Objective(s): With the development of molecular imaging technique, it is possible to define early stage tumors while their volume is very small. Therefore, there is an increasing need to understand the effectiveness of current Stereotactic Radiosurgery equipments in treating very small targets. In this study, we compared and evaluated treatment options for the highest physical resolution Stereotactic Radiosurgery equipments from 2.5mm Moduleaf Linac based IMRT (Moduleaf), Nomos MIMiC ARC tomotherapy with 4mm beak (Nomos) and Leksell Gamma Knife C Model with 4mm helmet size (GK). Materials/Methods: An isolated target with the size less than 50mm was identified and treatment plans were developed for Moduleaf, Nomos and GK respectively. First, the target was identified in the GK Treatment Planning System (TPS) and transferred to Nomos Covus 8.1 TPS and X-Knife RT TPS. Prescription was 50% isodose line covering the target in GK TPS, and the plugging pattern web engine was employed to generate a more conformal plan. The 2.5mm Moduleaf plan was computed using Xknife RT TPS with a twelve-field setup. For Nomos TPS, the arc length was set to 340 degrees. Comparisons of all 3 treatment plans was carried out using dose-volume histogram (DVH), target-volume ratio (TVR), which is defined as the ratio of volume that receives a dose higher than or equal to the minimum tumor dose and the tumor volume, maximum dose to the prescription dose ratio (MDPD), ratio PITV (PIV/TV), radiation conformity index (TVPIV/TV), and a combined conformity index (TVPIV /(TV×PIV)), where PIV is the prescription isodose surface volume, TV is target volume, and TVPIV is the intersection of TV and the PIV. Results: With normal treatment planning efforts, plan evaluation parameters from GK TPS, Nomos TPS and XKnife RT TPS are 1.0, 1.5, 2.0 for TVR, 2.0, 1.05, 1.05 for MPPD, 2.3, 1.5, 2.0 for PITV, 1.0, 1.0, 1.0 for TVPIV/TV, and 0.43, 0.67 and 0.5 for (TVPIV /(TV×PIV)), which is the inverse of the TVR for both plans from Nomos Covus 8.1 TPS and XKnife RT TPS because the prescription dose surface covered the target volume. Conclusions: For targets smaller than 50mm, the Gamma Knife treatment plan gave the best target volume ratio. Both Nomos arc Tomotherapy and X-Knife LINAC based IMRT gave better dose homogeneity. In addition to improvements in localization accuracy, smaller sizes of Nomos MLC and better IMRT planning algorithms for 2.5mm Moduleaf are needed to improve the plan comformality for very small targets.

Purpose: A kinetic model on describing tumor response to radiation therapy (RT) was developed to analyze the tumor regression data and predict the RT outcome for cervical cancer.Methods and Materials: Eighty patients of cervical cancer (stages IB2‐IVA) completed four sequential magnetic resonance imaging(MRI) scans before, during and after RT. The median follow‐up time is 5.5 years (range 0.2–9.4 years). A kinetic model incorporating three major effects: radiation cell killing, dead‐cell resolving, and tumor repopulation, was developed to fit the volumetric regression data measured by serial MRI scans. The derived radiobiological parameters were correlated with long‐term clinical outcome. Results: The tumor regression kinetics was significantly different for the two outcome groups: local control vs. local failure. The tumor regression rate and model parameters correlated significantly with the treatment outcome (p

Purpose: In conventional craniospinal irradiation (CSI), hot/cold dose spots are commonly seen with two adjacent fields that cover the spinal cord due to different beam divergences. The purpose of this study was to develop new techniques to reduce or eliminate the hot/cold spots, and achieve a more uniform dose coverage of the spinal cord. Materials and Methods: Two approaches to reduce the effect of beam divergence were investigated. Tilted beams were used with the table in the 90° position and patient in prone position. In the first method, we used four beams in two pairs to reduce the divergence. Wedges were used to improve the dose uniformity. In the second method, two IMRT fields with beam‐divergence match were employed to compensate the dose inhomogeneity due to different SSD. Based on a phantom torso, plans were created for each new method and compared with the conventional CSI technique. Results: Both new techniques improved the dose homogeneity of spinal cord. When normalizing the mean dose to 180 cGy, the minimum dose is approximately 168 cGy for all three plans; however, the maximal cord doses are different: 237, 204 and 201 cGy for the conventional, 4‐field and IMRT plans, respectively. The maximal body dose is 269, 214 and 216 cGy, and the volumes receiving a dose >200 cGy are 128, 78 and 42 cm3, respectively. Conclusion: Two new techniques with matching beam‐divergence have been developed for CSI to effectively reduce hot/cold spots and improve the dose uniformity in the spinal cord. The two‐field IMRT technique showed the best improvement in dose homogeneity, and is feasible to be implemented clinically. The 4‐field technique can be used in IMRT‐incapable facilities. The observed improvements in dose coverage and homogeneity with the beam‐divergence matching techniques warrant further studies with more patient data.

Purpose: To assess the impact of circulating white blood cell (WBC) counts during the treatment course for local tumorcontrol in patients treated with radiation therapy (RT) for cervical cancer.Method and Materials: Forty‐two advanced cervical cancer patients (FIGO stage IB2‐IVA) were studied as a part of IRB‐approved protocol. The standard RT for cervical cancer included ∼5 weeks of external beam RT, followed by brachytherapy within 3 weeks. Blood tests, including white blood cell counts, were collected approximately once per week longitudinally during the two month RT course. For each patient, the mean (mWBC) and median of white blood cell counts were evaluated across the RT course. The outcome endpoints, local (pelvic) tumor recurrence (LR) and death of disease (DOD), were determined by long term patients follow‐up 3.9 ∼9 years (median 7.5 years). Cox proportional hazards model was applied to correlate of WBC parameters with RT outcome. Survival analysis was carried out with Kaplan‐Meier method. Results: The parameter mWBC correlated with RT outcome including LR (p= 0.004) and DOD (p= 0.032). The median of mWBC in patient subgroup with LR (13 patients, median= 6.2×109/ l) was higher than that in the subgroup with local tumorcontrol (29 patients, median= 5.5×109/ l). Kaplan‐Meier analysis confirmed higher LR rate of 47% for mWBC >5.4×109/ l versus LR rate of 7% for mWBC < 5.4×109/ l (p= 0.017). The sensitivity, specificity, and accuracy of high mWBC to predict LR were 85%, 48%, and 60%, respectively. Correlation of high mWBC with higher DOD rate was marginally (p= 0.059). Conclusions: Our preliminary results suggest that higher white blood cell counts during the course of radiation therapy correlate with higher local tumor recurrence rate. The etiology is unknown, however, may be related to inflammatory changes and tumor necrosis, and requires further investigation e.g. imaging assessment.

19668 Background: Rapid and cost-effective palliation is of great importance in patients with complications from lung cancer progression. To offer immediate treatment for a tumor-related obstructed bronchus or SVC, we have implemented the SMART technique which has been shown to be effective and safe in the primary and re-treatment of malignant bronchial/SVC obstructions. The purpose of this study was to determine if the dose coverage to the obstructed bronchus/SVC and normal tissue sparing achieved by SMART compare favorably to the lengthier and more expensive IMRT technique. Methods: Treatment planning CT’s from 9 patients with a bronchial obstruction and 1 with SVC were studied. The planning target volume (PTV) consisted of the clinical target volume (CTV = obstructed bronchus or SVC) plus a 1 cm margin. For SMART, a dose of 10 Gy in a single treatment to the target was computed using 18 MV photons with 5 to 8 non-coplanar arcs with field sizes ranging from 4 cm2 to 8 cm2. For a dosimetric comparison using the same planning CT, an IMRT plan with 5 to 9 fields using 6 MV photons with 95% CTV coverage was computed to deliver the same dose. Dose volume histograms (DVH), treatment delivery time based on monitor units (MUs), and mean doses to the CTV, PTV, heart, lungs, spinal cord, and total body dose were compared using Student’s t-test. Results: Pooled DVH analysis of SMART and IMRT showed that SMART provided slightly better, but not statistically significant, coverage of the CTV (97±1.1 vs. 92±5%) and PTV (94±2 vs. 89±5%). There was no difference in normal tissue sparing between SMART and IMRT with respect to the mean lung dose (9±7 vs. 9±7%), heart dose (7±10 vs. 3±5%), cord dose (37±13 vs.30±13%), and total body dose (8±4 vs.7±4 Joules). However, SMART delivery was faster requiring significantly less MUs compared to IMRT (1,284±65 vs.1984±90, p No significant financial relationships to disclose.

Purpose: Hemoglobin (Hgb) has been considered as an important factor on radiation therapy for cervical cancer. However, recent studies reported that anemia is only a secondary symptom associated with disease stage and tumor volume, but not an independent predictor for outcome. Our study is to investigate whether low Hgb actively influences the effectiveness of radiation therapy or is merely a symptom of tumor burden. Materials/Methods: The study was based on 67 cervical cancer patients (stage IB2‐IVA). Serial Hgb measurements were performed before and during therapy. Tumor volume was obtained from 3D MRI volumetry. Median follow‐up was 2.9 years (range 0.09∼6.4 years). Treatment outcome was evaluated with local tumor‐control and disease‐free survival. Correlations between Hgb parameters and clinical variables were evaluated with Spearman‐rank method. Outcome prediction was based on univariate and multivariate analyses with Cox regression model. Survival analysis was assessed using Kaplan‐Meier method. Results: Hgb levels were not correlated with tumor stage (correlation coefficient −0.1∼ −0.2) and weakly correlated with tumor volume (correlation coefficient −0.4∼ −0.5). In univariate analysis, local tumor‐control was predicted by mean Hgb (p=0.009) and nadir Hgb (p=0.004); disease‐free survival was only predicted by nadir Hgb (p=0.031). In multivariate analysis, Hgb parameters were the best predictors of outcome: local tumor‐control was predicted by mean Hgb (p=0.013) and nadir Hgb (p=0.007); disease‐free survival was only marginally predicted by nadir Hgb (p=0.053). Kaplan‐Meier analysis demonstrated that Hgb (>12g/dl vs

Purpose: To evaluate the hypo‐fractionated and conventionally fractionated grid therapy in treating cervical cancers.Material and methods: A Monte Carlo technique was employed to calculate dose distribution of a commercially available grid. Based on the previously validated Monte Carlo technique, our new study has considered the divergence of all holes and thus improved the accuracy of grid geometry description in the simulations. The linear‐quadratic (LQ) model is used to evaluate the therapeutic outcome of both the hypo‐fractionated (fewer fractions and higher dose/fraction, herein 15 Gy/fraction) and conventionally fractionated (2Gy/fraction) regimens using grid therapy to treat cervical tumors that were represented by different radio‐biological responses. Results: The dose profiles and 2D dose distributions at dmax (d=1.5 cm) and 5 cm depths in water were obtained. An excellent agreement of dose profiles between calculated and measured was confirmed. The tumor cell and normal tissue survival statistics of grid therapy for two types of treatment regimens were calculated using the 2‐D dose distributions at the depth of 5 cm, and the therapeutic ratios and equivalent open field doses were obtained. Conclusions: The consideration of the divergence of grid holes has improved the Monte Carlo simulation results. In both the hypo‐fractionated and conventionally fractionated regimens, the therapeutic ratio depends not only on the single α/β value, but also on the individual α and β values. There is a significant therapeutic advantage of grid therapy for treating the studied cervical cancer cells because of their large α/β values, and the normal tissue sparing effect for the hypo‐fractionation regimen with few fractions is comparable to the conventional fractionation regimen with many fractions. For the radiosensitive normal tissues, both regimens give almost the same results, but for the radio‐resistant normal tissue the conventional fractionation regimen is preferred to spare them.

Purpose: Repair of sublethal damage plays an important role in radiation therapy. Conventional radiobiology concepts are based on the assumption that the repair rate remains constant during the entire radiation course. However, increasing evidence from animal experiments report that the repair process may slow down with time and the data does not fit an exponential pattern. To address this dilemma, we developed a new closed form of Linear‐Quadratic (LQ) model based on the repair pattern with a reciprocal time. The new formulas were tested with published experimental data. Methods and Materials: The LQ model has been widely used in radiation therapy, S = exp (−αD − βGD 2 ) . The parameter G represents the repair process of sublethal damage with Tr as the repair half‐time: G(t) = 2 D 2 ∫ 0 t dwI(w) ∫ 0 w dvI(v) 1 1 + (w − v)/T r in the reciprocal pattern. A closed form of G was derived analytically for arbitrary radiation schemes: dose rate I(t)=I i , t i−1 i , I=1,…,N . A set of published animal data was adopted to test the reciprocal formulas, in which rat foot skin was irradiated in split‐doses with increasing time intervals (0–22h). The complication data of moist desquamation were analyzed using the generalized LQ model. Results: A closed form of the LQ model to describe the repair process in a reciprocal pattern was obtained: G= 2T r 2 D 2 ∑ i=1 N I i { I i [Y(t i −t i−1 )+1]+ ∑ j=1 i−1 I j [Y(t i −t j−1 )−Y(t i −t j )+Y(t i−1 −t j )−Y(t i−1 −t j−1 )] } , where function Y(t) = ( 1 + t T r ) [ ln ( 1 + t T r ) − 1 ] . Formulas for special cases were derived from this general form. The reciprocal model showed a better fit to the animal data than the exponential model, especially for the ED50 data (reduced χ min 2 of 2.0 vs. 4.3, p=0.11 vs. 0.006), with the following LQ parameters: α/β = 2.6–4.8Gy, Tr = 3.2–3.9h. Conclusions: The repair process following a reciprocal‐time has been investigated in this study and a closed form of the generalized LQ model was presented and validated. These formulas can be used to analyze the experimental and clinical data, where a slowing‐down repair process appears during the radiation course.

Purpose: To evaluate the potential therapeutic advantage of external beam grid therapy in treating cervical cancer in comparison of conventional open field radiotherapy.Method and Materials: A Monte Carlo technique was employed to calculate 2‐dimensinal dose distribution of a commercially available grid, and the linear‐quadratic (LQ) model was applied to study the therapeutic advantage of using grid therapy for treating cervical cancers. A list of cervical cancer cell lines with known LQ parameters were used to calculate the radiotherapy response. Acutely responding normal muscle with α/β value of 3.1 Gy was used to evaluate the outcomes of between the open and grid field irradiations. The normal muscle tissue with three different sensitivities was assumed according to their response to a 2Gy open field. The therapeutic ratio based on sparing normal cells has been defined and calculated. The treatment regimens with 2Gy per fraction and 5 to 20 fractions were used in the calculations. Results: The survival fractions of normal tissues as well as tumor cells in the open and grid field are calculated. An appreciable therapeutic advantage has been demonstrated. Therapeutic ratio up to 9.5 for radio‐sensitive normal muscles was found. However, the radio‐resistant muscle does not show apparent advantage benefiting from the grid therapy. The results of data analysis showed that the therapeutic outcome depends not only on the single value α/β, but also on the individual α and β values of both the tumor and normal tissue cells. Conclusion:Monte Carlo technique was proven to be able to provide the dosimetric characteristics for grid therapy. The grid therapy in this study was found to be advantageous for treating the acutely responding cervical tumors (α/β>6), but not for slow responding ones (α/β⩽6). The acutely responding tumors and radio‐sensitive normal tissues are more suitable for using the grid therapy.

5025 Background: The ability to predict efficacy prior to or early during the course of a therapeutic modality can lead to improved outcome by avoiding ineffectual therapies. The purpose of this study was to test if in-vivo functional MR imaging can, by reflecting microcirculatory response of tumor to cytotoxic therapy, predict failure early during the course of treatment in cervical cancer. Methods: One-hundred and one patients with cervical cancer stages IB2-IV treated with radiation/chemotherapy (RT/CT) underwent Dynamic Contrast Enhanced (DCE) MRI before (1st MRI) and during RT at 2 weeks (2nd MRI) and 4 weeks of RT (3rdMRI). Mean follow up was 4.9 years (1.5–8.0 years). Pelvic tumor control and disease-free survival were correlated with imaging parameters derived from the time/signal-intensity curve of the DCE-MRI of each tumor pixel. These included the signal intensity (SI) of the plateau phase (SIp), the lowest 2.5th and 5.0th percentiles of the entire tumor pixels (SI 2.5 and SI 5.0), the slope of...

5095 Background: Pixel-by-pixel analysis of signal intensity (SI) using dynamic contrast enhanced MRI (DCE- MRI) in cervical cancer has been reported to predict treatment outcome. Low enhancement correlates with treatment failure presumably due to poor blood supply/hypoxia. However, within a heterogeneous tumor, the relative volume and degree of low-enhancement regions that correlate with failure is uncertain. This project analyzed the threshold of low-enhancement pixels within the tumor to optimize the predictive power for treatment outcome. Methods: 101 patients with advanced cervical cancer underwent DCE-MRI early during radiation/chemotherapy (2 weeks after therapy start). The SI of each pixel was calculated from the time-intensity curve of the DCE-MRI at the plateau phase. The SI of all pixels within the tumor was plotted as a pixel SI spectrum. The lowest 2.0th through 40th percentiles of the pixel spectrum were used to define the low-enhancement volume, and each percentile category was correlated w...

The cases of 76 patients with chronic radiation dermatitis resulting from low-dose ionizing radiation for benign disease were reviewed retrospectively for risk factors leading to the development of neoplasia. The patients were studied with respect to original hair color, eye color, sun reactive skin type, benign disease treated, area treated, age at treatment, and age at development of first skin cancer. Analysis of data showed 37% of patients had sun-reactive skin type I, 27% had type II, and 36% had type III. Types IV through VI were not represented. There appeared to be an overrepresentation of types I and II. Increased melanin pigmentation may therefore be either directly or indirectly protective against the development of skin cancers in patients who have received low-dose superficial ionizing radiation for benign disease. The sun-reactive skin type of patients with chronic radiation dermatitis may be used as a predictor of skin cancer risk when the total dose of ionizing radiation is not known.

Radiation is an effective modality for palliation of osseous metastases. In patients with a limited number of lesions, local external beam irradiation is the most expedient method of delivering radiation therapy. Complete or partial relief of pain will occur in 80-90% of patients. When metastases are widespread or when new sites continue to appear, localized external irradiation becomes logistically difficult. In such cases, hemibody irradiation has been effective with an overall response rate of 85%. However, nausea, vomiting, diarrhea, and bone marrow and pulmonary toxicity may complicate therapy. In these cases, an effective alternative is systemic phosphorus-32 (32P) or strontium-89 (89Sr). Relief of pain in the range of 60-90% has been reported. Toxicity of 32P is largely that of bone marrow suppression, while 89Sr appears to be relatively marrow-sparing. In this review, we consider systemic 32P or 89Sr as viable options to external beam or hemibody irradiation in the presence of numerous bone metastases.