Cost-Effectiveness Analysis of 68Ga-DOTATATE PET/MRI in Radiotherapy Planning in Patients with Intermediate-Risk Meningioma.

BACKGROUND AND PURPOSE: While contrast-enhanced MR imaging is the criterion standard in meningioma diagnosis and treatment response assessment, gallium 68Ga-DOTATATE PET/MR imaging has increasingly demonstrated utility in meningioma diagnosis and management. Integrating 68Ga-DOTATATE PET/MR imaging in postsurgical radiation planning reduces the planning target volume and organ-at-risk dose. However, 68Ga-DOTATATE PET/MR imaging is not widely implemented in clinical practice due to higher perceived costs. Our study analyzes the cost-effectiveness of 68Ga-DOTATATE PET/MR imaging for postresection radiation therapy planning in patients with intermediate-risk meningioma. MATERIALS AND METHODS: We developed a decision-analytical model based on both recommended guidelines on meningioma management and our institutional experience. Markov models were implemented to estimate quality-adjusted life-years (QALY). Cost-effectiveness analyses with willingness-to-pay thresholds of $50,000/QALY and $100,000/QALY were performed from a societal perspective. Sensitivity analyses were conducted to validate the results. Model input values were based on published literature. RESULTS: The cost-effectiveness results demonstrated that 68Ga-DOTATATE PET/MR imaging yields higher QALY (5.47 versus 5.05) at a higher cost ($404,260 versus $395,535) compared with MR imaging alone. The incremental cost-effectiveness ratio analysis determined that 68Ga-DOTATATE PET/MR imaging is cost-effective at a willingness to pay of $50,000/QALY and $100,000/QALY. Furthermore, sensitivity analyses showed that 68Ga-DOTATATE PET/MR imaging is cost-effective at $50,000/QALY ($100,000/QALY) for specificity and sensitivity values above 76% (58%) and 53% (44%), respectively. CONCLUSIONS: 68Ga-DOTATATE PET/MR imaging as an adjunct imaging technique is cost-effective in postoperative treatment planning in patients with meningiomas. Most important, the model results show that the sensitivity and specificity cost-effective thresholds of 68Ga-DOTATATE PET/MR imaging could be attained in clinical practice.

Medically inoperable peripheral lung cancer treated with stereotactic body radiation therapy.

BACKGROUND: Lung cancer is the most frequent cause of cancer-related death in North America. There is wide variation between patients who are medically inoperable and those managed surgically. The use of stereotactic body radiotherapy (SBRT) has narrowed the gap in survival rates between operative and non-operative management for those with early stage disease. This retrospective study reports outcomes for the treatment of peripheral non-small cell lung carcinoma (NSCLC) with SBRT from a single community practice. METHODS: Sixty-seven consecutive patients (pts) with inoperable, untreated peripheral lung tumors were treated from 2010 through 2012 and included in this study. Stereotactic targeting was facilitated by either spine or lung-based image guidance, either with or without fiducial marker tracking with a frameless robotic radiosurgery system. Peripheral tumors received a median biological effective dose (BED) of 105.6 Gy10 or in terms of a median physical dose, 48 Gy delivered over 4 daily fractions. Survival was measured using the Kaplan-Meier method to determine rates of local control, progression of disease and overall survival. The Cox proportional hazards regression model was used to study the effects of tumor size, stage, histology, patient age, tumor location (lobe), tracking method, and BED on the survival distributions. RESULTS: The median follow-up for this cohort was 24.5 months (range: 2.4-50.3) with an overall (OS) 3-year survival of 62.4 % (95 % CI: 74.3-47.3). The median progression-free survival was 28.5 months (95 % CI: 15.8 months to not reached). Local control (LC), defined as a lack of FDG uptake on PET/CT or the absence of tumor growth was achieved in 60 patients (90.9 %) at the time of first follow-up (median 3 months, range: 1-6). Local control at one year for the entire cohort was 81.8 % (95 % CI, 67.3-90.3). The one-year OS probability among those who achieved local control at first follow-up was 86.2 % (95 % CI, 74.3-92.9) but no patients who did not achieve LC at first follow-up survived one year. Of the 60 pts that achieved initial LC, 16 have died. The rates of local control, progression-free survival and overall survival were not statistically different for patients treated using a fiducial target tracking system versus non-invasive guidance. (p = 0.44, p = 0.97 and p = 0.66, respectively). No National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE-4) grade 3 or greater toxicity was observed. CONCLUSION: SBRT is an effective treatment for medically inoperable NSCLC patients with peripherally located tumors. This therapy appears to be well tolerated with low toxicity, and patient outcomes when using non-invasive tumor tracking systems are not inferior to traditional fiducial-based techniques.

A comprehensive review of MR imaging changes following radiosurgery to 500 brain metastases.

BACKGROUND AND PURPOSE: Stereotactic radiosurgery is known to control 85%-95% of intracranial metastatic lesions during a median survival of 6-8 months. However, with the advent of newer systemic cancer therapies, survival is improving; this change mandates a longitudinal quantitative analysis of the radiographic response of brain metastases to radiosurgery. MATERIALS AND METHODS: MR imaging of 516 metastases in 120 patients treated with GK-SRS from June 2006 to December 2009 was retrospectively reviewed. Lesion volume at initial treatment and each follow-up was calculated by using the following formula: length × width × height / 2. Volume changes were correlated with patient demographics, histopathology, and radiation treatment variables. RESULTS: Thirty-two percent of lesions increased in volume following radiosurgery. Clinically, this translated into 54% of patients having ≥1 of their lesions increase in size. This increase begins at 6 weeks and can last beyond 15 months' post-SRS. Male sex (P = .002), mean voxel dose <37 Gy (P = .009), and initial treatment volume >500 mm(3) (P < .001) are associated with posttreatment increases in tumor size. Median survival following radiosurgery was 9.5 months for patients with all lesions exhibiting stable/decreased volumes, >18.4 months for patients with all lesions exhibiting increased volumes, and 16.4 months for patients with mixed lesional responses. CONCLUSIONS: Most metastatic lesions are stable or smaller in size during the first 36 months post-SRS. However, a transient increase in volume is seen in approximately one-third of lesions. Sex, treatment dose, initial lesion size, and histopathology all correlate with variations in lesion volume post-SRS. The longer the patient survives, the more likely an increase in lesion size will be seen on follow-up imaging.

Constrained non-rigid registration for use in image-guided adaptive radiotherapy.

A constrained non-rigid registration (CNRR) algorithm for use in prostate image-guided adaptive radiotherapy is presented in a coherent mathematical framework. The registration algorithm is based on a global rigid transformation combined with a series of local injective non-rigid multi-resolution cubic B-spline Free Form Deformation (FFD) transformations. The control points of the FFD are used to non-rigidly constrain the transformation to the prostate, rectum, and bladder. As well, the control points are used to rigidly constrain the transformation to the estimated position of the pelvis, left femur, and right femur. The algorithm was tested with both 3D conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) dose plan data sets. The 3DCRT dose plan set consisted of 10 fan-beam CT (FBCT) treatment-day images acquired from four different patients. The IMRT dose plan set consisted of 32 cone-beam CT (CBCT) treatment-day images acquired from 4 different patients. The CNRR was tested with different combinations of anatomical constraints and each test significantly outperformed both rigid and non-rigid registration at aligning constrained bones and critical organs. The CNRR results were used to adapt the dose plans to account for patient positioning errors as well as inter-day bone motion and intrinsic organ deformation. Each adapted dose plan improved performance by lowering radiation distribution to the rectum and bladder while increasing or maintaining radiation distribution to the prostate.

A constrained non-rigid registration algorithm for use in prostate image-guided radiotherapy.

A constrained non-rigid registration (CNRR) algorithm for use in updating prostate external beam image-guided radiotherapy treatment plans is presented in this paper. The developed algorithm is based on a multi-resolution cubic B-spline FFD transformation and has been tested and verified using 3D CT images from 10 sets of real patient data acquired from 4 different patients on different treatment days. The registration can be constrained to any combination of the prostate, rectum, bladder, pelvis, left femur, and right femur. The CNRR was tested with 5 different combinations of constraints and each test significantly outperformed both rigid and non-rigid registration at aligning constrained bones and critical organs. The CNRR was then used to update the treatment plans to account for articulated, rigid bone motion and non-rigid organ deformation. Each updated treatment plan outperformed the original treatment plan by increasing radiation dosage to the prostate and lowering radiation dosage to the rectum and bladder.

TRACKING ORGAN OVERLAP FOR A CONSTRAINED NON-RIGID REGISTRATION ALGORITHM.

This paper tracks organ (prostate, rectum, bladder) overlap in a constrained non-rigid registration (NRR) algorithm to register computed tomographic (CT) images used in external beam prostate radiotherapy. The local motion of the organs is described by a hierarchical multi-resolution FFD based on cubic B-splines. Registration is achieved by minimizing a cost function which is a combination of three functions representing the overlap of the critical organs, image similarity and smoothness of the transformation. The constrained NRR algorithm generated better registration results when compared to an unconstrained NRR algorithm.

A CONSTRAINED NON-RIGID REGISTRATION ALGORITHM FOR APPLICATION IN PROSTATE RADIOTHERAPY.

This paper presents a novel free-form deformation registration algorithm with non-rigid constraints to capture the transformation between the planning day and treatment day CT images used for external beam radiotherapy for prostate cancer. The algorithm is constrained to the predetermined motion of a segmented organ, which is described by an injective free-form deformation (FFD) based on B-splines. The end goal is for the injective transformation to be used to update the radiotherapy plan to take into account bone and soft tissue deformation. The results of the algorithm have been compared to those achieved using rigid and fully non-rigid registration. The results clearly indicate that the constrained non-rigid registration algorithm presented in this paper performed much better at capturing the motion of the constrained organ, the bladder in this case, than the rigid or fully non-rigid registration algorithms.

Phase II evaluation of preoperative chemoradiation and postoperative adjuvant chemotherapy for squamous cell and adenocarcinoma of the esophagus.

PURPOSE: This phase II trial evaluated continuous-infusion cisplatin and fluorouracil (5-FU) with radiotherapy followed by esophagectomy. The objectives of this trial were to determine the complete pathologic response rate, survival rate, toxicity, pattern of failure, and feasibility of administering adjuvant chemotherapy in patients with resectable cancer of the esophagus treated with preoperative chemoradiation. PATIENTS AND METHODS: Patients were staged using computed tomography, endoscopic ultrasound, and laparoscopy. The preoperative treatment plan consisted of continuous intravenous infusion of cisplatin and 5-FU and a total dose of 44 Gy of radiation. Esophagogastrectomy was planned for approximately 4 weeks after the completion of chemoradiotherapy. Paclitaxel and cisplatin were administered as postoperative adjuvant therapy. RESULTS: Forty-two patients were enrolled onto the trial. Of the 39 patients who proceeded to surgery, 29 responded to preoperative treatment: 11 achieved pathologic complete response (CR) and 18 achieved a lower posttreatment stage. Five patients had no change in stage, whereas eight had progressive disease (four with distant metastases and four with increases in the T and N stages). At a median follow-up of 30.2 months, the median survival time has not been reached and the 2-year survival rate is 62%. The median survival of pathologic complete responders has not been reached, whereas the 2-year survival rate of this group is 91% compared with 51% in patients with complete tumor resection with residual tumor (P =.03). CONCLUSION: An excellent survival rate, comparable to that of our prior preoperative trial, was achieved with lower doses of preoperative cisplatin and 5-FU concurrent with radiotherapy.

Image registration and calculation of a biologically effective dose for multisession radiosurgical treatments. Technical note.

The purpose of this study was to develop techniques for registering image sets associated with staged or multifraction radiosurgical treatments of large targets with the Leksell gamma knife to transform shot coordinates between treatment sessions and produce cumulative dose distributions and to investigate the theoretical biological effects of such protracted treatments by means of such concepts as the linear-quadratic model and biologically effective dose. An image registration technique based on normalized mutual information was adapted to produce one fused-image study from an imaging series acquired during distinct treatment sessions. A spreadsheet computer program was developed to determine coordinate transformations between the associated stereotactic coordinate systems based on digitized coordinates of fiducial markers appearing on the fused images. Coordinates of shots used during one treatment session could then be transformed to the stereotactic space of another session, and cumulative dose distributions could be computed. The procedure was applied to the two-stage treatment of a giant arteriovenous malformation (AVM). Overall uncertainty in each transformed shot position is approximately 0.7 mm. An effective single-fraction dose (D(eff)) was defined and computed for the two-stage AVM treatment. The simple summed dose distribution was compared with the D(eff) distribution. Because dose values differ significantly in overlap regions between the individual distributions, the clinical usefulness of the simple cumulative distribution is dubious. It may be useful for a future update of the GammaPlan treatment planning software to generate effective single-session dose distributions for such cases.

Polarographic measurements of oxygen tension in human glioma and surrounding peritumoural brain tissue.

This study quantifies the spatial distribution of pO2 in glioma and in the surrounding brain tissue. Both glioma and peritumoural brain contain regions at oxygen tensions less than 2.5 mmHg. Modalities targeting hypoxia to improve the efficacy of therapy may have an important role in the management of this disease.

Effective treatment of stage I uterine papillary serous carcinoma with high dose-rate vaginal apex radiation (192Ir) and chemotherapy.

PURPOSE: Uterine papillary serous carcinoma (UPSC) is a morphologically distinct variant of endometrial carcinoma that is associated with a poor prognosis, high recurrence rate, frequent clinical understaging, and poor response to salvage treatment. We retrospectively analyzed local control, actuarial overall survival (OS), actuarial disease-free survival (DFS), salvage rate, and complications for patients with Federation International of Gynecology and Obstetrics (FIGO) (1988) Stage I UPSC. METHODS AND MATERIALS: This retrospective analysis describes 38 patients with FIGO Stage I UPSC who were treated with the combinations of radiation therapy, chemotherapy, total abdominal hysterectomy, and bilateral salpingo-oophorectomy (TAH/BSO), with or without a surgical staging procedure. Twenty of 38 patients were treated with a combination of low dose-rate (LDR) uterine/vaginal brachytherapy using 226Ra or 137Cs and conventional whole-abdomen radiation therapy (WART) or whole-pelvic radiation therapy (WPRT). Of 20 patients (10%) in this treatment group, 2 received cisplatin chemotherapy. Eighteen patients were treated with high dose-rate (HDR) vaginal apex brachytherapy using 192Ir with an afterloading device and cisplatin, doxorubicin, and cyclophosphamide (CAP) chemotherapy (5 of 18 patients). Only 6 of 20 UPSC patients treated with combination LDR uterine/vaginal brachytherapy and conventional external beam radiotherapy underwent complete surgical staging, consisting of TAH/BSO, pelvic/para-aortic lymph node sampling, omentectomy, and peritoneal fluid analysis, compared to 15 of 18 patients treated with HDR vaginal apex brachytherapy. RESULTS: The 5-year actuarial OS for patients with complete surgical staging and adjuvant radiation/chemotherapy treatment was 100% vs. 61% for patients without complete staging (p = 0.002). The 5-year actuarial OS for all Stage I UPSC patients treated with postoperative HDR vaginal apex brachytherapy and systemic chemotherapy was 94% (18 patients). The 5-year actuarial OS for Stage I UPSC patients treated with HDR vaginal apex brachytherapy and chemotherapy who underwent complete surgical staging was 100% (15 patients). The 5-year actuarial OS for the 20 Stage I UPSC patients treated with combinations of pre- and postoperative LDR brachytherapy and postop WART was 65%. None of the 6 surgically staged UPSC patients treated with LDR radiation and WART/WPRT developed recurrent disease. For patients with FIGO Stage IA, IB, and IC UPSC who underwent complete surgical staging, the 5-year actuarial DFS by depth of myometrial invasion was 100, 71, and 40%, respectively (p = 0.006). The overall salvage rate for local and distant recurrence was 0%. Complications following HDR vaginal apex brachytherapy included only Radiation Therapy Oncology Group (RTOG) grade 1 and 2 toxicity in 16% of patients. However, complications from patients treated with WART/WPRT, and/or LDR brachytherapy, included RTOG grade 3 and 4 toxicity in 15% of patients. CONCLUSION: Patients with UPSC should undergo complete surgical staging, and completely surgically staged FIGO Stage I UPSC patients can be effectively and safely treated with HDR vaginal apex brachytherapy and chemotherapy. Both OS and DFS of patients with UPSC are dependent on depth of myometrial invasion. The salvage rate for both local and distant UPSC recurrences is extremely poor. Complications from HDR vaginal apex brachytherapy were minimal.

Early vs. delayed radiotherapy in a small cohort of patients with supratentorial low grade glioma.

In a cohort of 25 patients with supratentorial low grade glioma, the timing of radiotherapy made no significance difference for 10 year survival. Patients who received early radiotherapy had a 55% 10 year survival and those receiving delayed radiotherapy had a 53% 10 year survival. Radiotherapy was delayed a median of 4.8 years in those receiving delayed radiotherapy.