Sequential magnetic resonance imaging of cervical cancer: the predictive value of absolute tumor volume and regression ratio measured before, during, and after radiation therapy.

BACKGROUND: The objectives of this study were to investigate outcome prediction by measuring absolute tumor volume and regression ratios using serial magnetic resonance imaging (MRI) during radiation therapy (RT) for cervical cancer and to develop algorithms capable of identifying patients at risk of a poor therapeutic outcome. METHODS: Eighty patients with stage IB2 through IVA cervical cancer underwent 4 MRI scans: before RT (MRI1), during RT at 2 to 2.5 weeks (MRI2) at 4 to 5 weeks (MRI3), and 1 to 2 months after RT (MRI4). The median follow-up was 6.2 years (range, 0.2-9.4 years). Tumor volumes at MRI1, MRI2, MRI3, and MRI4 (V1, V2, V3, and V4, respectively) and tumor regression ratios (V2/V1, V3/V1, and V4/V1) were measured by 3-dimensional volumetry. Predictive metrics based on tumor volume/regression parameters were correlated with ultimate clinical outcomes, including tumor local recurrence (LR) and dying of disease (DOD). Predictive power was evaluated using the Mann-Whitney test, sensitivity/specificity analyses, and Kaplan-Meier analyses. RESULTS: Both tumor volume and regression ratio were strongly correlated with LR (P=.06, P = 5×10(-4), P=1×10(-6), and P=2×10(-8) for V1, V2, V3, and V4, respectively; and P=7×10(-5), P=1×10(-6), and P=1×10(-8) for V2/V1, V3/V1, and V4/V1, respectively) and DOD (P=.015, P=.004, P=.001, and P=3×10(-4) for V1, V2, V3, and V4, respectively; and P=.03, P=.009, and P=3×10(-4) for V2/V1, V3/V1, and V4/V1, respectively). Algorithms that combined tumor volumes and regression ratios improved predictive power (sensitivity, 61%-89%; specificity, 79%-100%). The strongest predictor, pre-RT volume and regression ratio at MRI3 (V1>40 cm3 and V3/V1>20%, respectively), achieved 89% sensitivity, 87% specificity, and 88% accuracy for LR and achieved 54% sensitivity, 83% specificity, and 73% accuracy for DOD. CONCLUSIONS: The current results suggested that tumor volume/regression parameters obtained during primary therapy are useful in predicting LR and DOD. Both tumor volume and regression ratio provided important information as early outcome predictors that may guide early intervention for patients with cervical cancer who are at high risk of treatment failure.

Ultra-early predictive assay for treatment failure using functional magnetic resonance imaging and clinical prognostic parameters in cervical cancer.

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.

Predicting outcomes in cervical cancer: a kinetic model of tumor regression during radiation therapy.

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 S(2) < 0.70 vs. S(2) > or = 0.70) as a predictor (P = 0.001) and 89% vs. 57% using dead-cell resolving time (T(1/2) < 22 days versus T(1/2) > or = 22 days, P < 0.001). The 6-year disease-specific survival was 73% versus 41% with S(2) < 0.70 versus S(2) > or = 0.70 (P = 0.025), and 87% vs. 52% with T(1/2) < 22 days versus T(1/2) > or = 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.

Translating response during therapy into ultimate treatment outcome: a personalized 4-dimensional MRI tumor volumetric regression approach in cervical cancer.

PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS: Residual tumor volume, slope, and area under the regression curve correlated significantly with local control and survival. Residual volumes >or=20% at 40-50 Gy were independently associated with inferior 5-year local control (53% vs. 97%, p <0.001) and disease-specific survival rates (50% vs. 72%, p = 0.009) than smaller volumes. Patients with post-RT residual volumes >or=10% had 0% local control and 17% disease-specific survival, compared with 91% and 72% for <10% volume (p <0.001). CONCLUSION: 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 with >or=20% residual volume at 40-50 Gy and >or=10% post-RT, the risk for local failure and death are so high that aggressive intervention may be warranted.

Predicting control of primary tumor and survival by DCE MRI during early therapy in cervical cancer.

PURPOSE: To assess the early predictive power of MRI perfusion and volume parameters, during early treatment of cervical cancer, for primary tumor control and disease-free-survival. MATERIALS AND METHODS: Three MRI examinations were obtained in 101 patients before and during therapy (at 2-2.5 and 4-5 weeks) for serial dynamic contrast enhanced (DCE) perfusion MRI and 3-dimensional tumor volume measurement. Plateau Signal Intensity (SI) of the DCE curves for each tumor pixel of all 3 MRI examinations was generated, and pixel-SI distribution histograms were established to characterize the heterogeneous tumor. The degree and quantity of the poorly-perfused tumor subregions, which were represented by low-DCE pixels, was analyzed by using various lower percentiles of SI (SI%) from the pixel histogram. SI% ranged from SI2.5% to SI20% with increments of 2.5%. SI%, mean SI, and 3-dimensional volume of the tumor were correlated with primary tumor control and disease-free-survival, using Student t test, Kaplan-Meier analysis, and log-rank test. The mean post-therapy follow-up time for outcome assessment was 6.8 years (range: 0.2-9.4 years). RESULTS: Tumor volume, mean SI, and SI% showed significant prediction of the long-term clinical outcome, and this prediction was provided as early as 2 to 2.5 weeks into treatment. An SI5% of <2.05 and residual tumor volume of > or =30 cm(3) in the MRI obtained at 2 to 2.5 weeks of therapy provided the best prediction of unfavorable 8-year primary tumor control (73% vs. 100%, P = 0.006) and disease-free-survival rate (47% vs. 79%, P = 0.001), respectively. CONCLUSIONS: Our results show that MRI parameters quantifying perfusion status and residual tumor volume provide very early prediction of primary tumor control and disease-free-survival. This functional imaging based outcome predictor can be obtained in the very early phase of cytotoxic therapy within 2 to 2.5 weeks of therapy start. The predictive capacity of these MRI parameters, indirectly reflecting the heterogeneous delivery pattern of cytotoxic agents, tumor oxygenation, and the bulk of residual presumably therapy-resistant tumor, requires future study.

Synergistic effects of hemoglobin and tumor perfusion on tumor control and survival in cervical cancer.

PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS: Local recurrence predominated in the group with both a low mean Hgb (<11.2 g/dL) and low perfusion (lowest 10th percentile of signal intensity <2.0 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. CONCLUSION: 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 germinomas: what is the best treatment strategy?

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.

Hypofractionation regimens for stereotactic radiotherapy for large brain tumors.

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 alpha/beta 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 alpha/beta 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.

What is the best adjuvant treatment for very young patients with medulloblastoma?

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.

Serial therapy-induced changes in tumor shape in cervical cancer and their impact on assessing tumor volume and treatment response.

OBJECTIVE: 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. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Brachytherapy management of the retroverted uterus using ultrasound-guided implant applicator placement.

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 137Cs. 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.

Interobserver variation in cervical cancer tumor delineation for image-based radiotherapy planning among and within different specialties.

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 < 0.01) among all observers based on a repeated measures ANOVA, which produced an F(5,95) = 3.55. The median difference between the maximum delineated volume and minimum delineated volume was 33.5 cm3 (which can be approximated by a sphere of 4.0 cm diameter) across all 20 patients. Challenges noted for tumor delineation included the following: (1) partial voluming by parametrial fat at the periphery of the uterus; (2) extension of the tumor into parametrial space; (3) similar signal intensity of structures proximal to the tumor such as ovaries, muscles, bladder wall, bowel loops, and pubic symphysis; (4) postradiation changes such as heterogeneity and necrosis; (5) susceptibility artifacts from bowels and vaginal tampons; (6) presence of other pathologies such as atypical myoma; (7) factors that affect pelvic anatomy, including the degree of bladder distension, bowel interposition, uterine malposition, retroversion, and descensus. Our limited study indicates significant interobserver variation in tumor delineation. Despite rapid progress in technology, which has improved the resolution and precision of image acquisition and the delivery of radiotherapy to the millimeter level, such "human" variations (at the centimeter level) may overshadow the gain from technical advancement and impact treatment planning. Strategies of standardization and training in tumor delineation need to be developed.

Does prone positioning reduce small bowel dose in pelvic radiation with intensity-modulated radiotherapy for gynecologic cancer?

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 degrees arc length) and (2) the extended arc technique (340 degrees 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 > or =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 > or =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 > or =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.

Pitfalls of radiation survey after brachytherapy implant removal preceding Tl-201 study.

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.