Brain metastases are a common sequelae of breast cancer. Survival varies widely based on diagnosis-specific prognostic factors (PF). We previously published a prognostic index (Graded Prognostic ...Assessment GPA) for patients with breast cancer with brain metastases (BCBM), based on cohort A (1985-2007, n = 642), then updated it, reporting the effect of tumor subtype in cohort B (1993-2010, n = 400). The purpose of this study is to update the Breast GPA with a larger contemporary cohort (C) and compare treatment and survival across the 3 cohorts.
A multi-institutional (19), multinational (3), retrospective database of 2473 patients with breast cancer with newly diagnosed brain metastases (BCBM) diagnosed from January 1, 2006, to December 31, 2017, was created and compared with prior cohorts. Associations of PF and treatment with survival were analyzed. Kaplan-Meier survival estimates were compared with log-rank tests. PF were weighted and the Breast GPA was updated such that a GPA of 0 and 4.0 correlate with the worst and best prognoses, respectively.
Median survival (MS) for cohorts A, B, and C improved over time (from 11, to 14 to 16 months, respectively; P < .01), despite the subtype distribution becoming less favorable. PF significant for survival were tumor subtype, Karnofsky Performance Status, age, number of BCBMs, and extracranial metastases (all P < .01). MS for GPA 0 to 1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0 was 6, 13, 24, and 36 months, respectively. Between cohorts B and C, the proportion of human epidermal receptor 2 + subtype decreased from 31% to 18% (P < .01) and MS in this subtype increased from 18 to 25 months (P < .01).
MS has improved modestly but varies widely by diagnosis-specific PF. New PF are identified and incorporated into an updated Breast GPA (free online calculator available at brainmetgpa.com). The Breast GPA facilitates clinical decision-making and will be useful for stratification of future clinical trials. Furthermore, these data suggest human epidermal receptor 2-targeted therapies improve clinical outcomes in some patients with BCBM.
Theranostics, a combination of therapy and diagnostics, is a field of personalized medicine involving the use of the same or similar radiopharmaceutical agents for the diagnosis and treatment of ...patients. Prostate-specific membrane antigen (PSMA) is a promising theranostic target for the treatment of prostate cancers. Diagnostic PSMA radiopharmaceuticals are currently used for staging and diagnosis of prostate cancers, and imaging can predict response to therapeutic PSMA radiopharmaceuticals. While mainly used in the setting of metastatic, castrate-resistant disease, clinical trials are investigating the use of PSMA-based therapy at earlier stages, including in hormone-sensitive or hormone-naïve prostate cancers, and in oligometastatic prostate cancers. This review explores the use of PSMA as a theranostic target and investigates the potential use of PSMA in earlier stage disease, including hormone-sensitive metastatic prostate cancer, and oligometastatic prostate cancer.
18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is now a standard diagnostic imaging test performed in patients with head and neck cancer for staging, re-staging, radiotherapy ...planning, and outcome assessment. Currently, quantitative analysis of FDG PET scans is limited to simple metrics like maximum standardized uptake value, metabolic tumor volume, or total lesion glycolysis, which have limited predictive value. The goal of this work was to assess the predictive potential of new (i.e., nonstandard) quantitative imaging features on head and neck cancer outcome.
This retrospective study analyzed fifty-eight pre- and post-treatment FDG PET scans of patients with head and neck squamous cell cancer to calculate five standard and seventeen new features at baseline and post-treatment. Cox survival regression was used to assess the predictive potential of each quantitative imaging feature on disease-free survival.
Analysis showed that the post-treatment change of the average tracer uptake in the rim background region immediately adjacent to the tumor normalized by uptake in the liver represents a novel PET feature that is associated with disease-free survival (HR 1.95; 95% CI 1.27, 2.99) and has good discriminative performance (c index 0.791).
The reported findings define a promising new direction for quantitative imaging biomarker research in head and neck squamous cell cancer and highlight the potential role of new radiomics features in oncology decision making as part of precision medicine.
Non-small-cell lung cancer (NSCLC) represents approximately 80-85% of lung cancer diagnoses and is the leading cause of cancer-related death worldwide. Recent studies indicate that image-based ...radiomics features from positron emission tomography/computed tomography (PET/CT) images have predictive power for NSCLC outcomes. To this end, easily calculated functional features such as the maximum and the mean of standard uptake value (SUV) and total lesion glycolysis (TLG) are most commonly used for NSCLC prognostication, but their prognostic value remains controversial. Meanwhile, convolutional neural networks (CNN) are rapidly emerging as a new method for cancer image analysis, with significantly enhanced predictive power compared to hand-crafted radiomics features. Here we show that CNNs trained to perform the tumor segmentation task, with no other information than physician contours, identify a rich set of survival-related image features with remarkable prognostic value. In a retrospective study on pre-treatment PET-CT images of 96 NSCLC patients before stereotactic-body radiotherapy (SBRT), we found that the CNN segmentation algorithm (U-Net) trained for tumor segmentation in PET and CT images, contained features having strong correlation with 2- and 5-year overall and disease-specific survivals. The U-Net algorithm has not seen any other clinical information (e.g. survival, age, smoking history, etc.) than the images and the corresponding tumor contours provided by physicians. In addition, we observed the same trend by validating the U-Net features against an extramural data set provided by Stanford Cancer Institute. Furthermore, through visualization of the U-Net, we also found convincing evidence that the regions of metastasis and recurrence appear to match with the regions where the U-Net features identified patterns that predicted higher likelihoods of death. We anticipate our findings will be a starting point for more sophisticated non-intrusive patient specific cancer prognosis determination. For example, the deep learned PET/CT features can not only predict survival but also visualize high-risk regions within or adjacent to the primary tumor and hence potentially impact therapeutic outcomes by optimal selection of therapeutic strategy or first-line therapy adjustment.
Conventional wisdom has rendered patients with brain metastases ineligible for clinical trials for fear that poor survival could mask the benefit of otherwise promising treatments. Our group ...previously published the diagnosis-specific Graded Prognostic Assessment (GPA). Updates with larger contemporary cohorts using molecular markers and newly identified prognostic factors have been published. The purposes of this work are to present all the updated indices in a single report to guide treatment choice, stratify research, and define an eligibility quotient to expand eligibility.
A multi-institutional database of 6,984 patients with newly diagnosed brain metastases underwent multivariable analyses of prognostic factors and treatments associated with survival for each primary site. Significant factors were used to define the updated GPA. GPAs of 4.0 and 0.0 correlate with the best and worst prognoses, respectively.
Significant prognostic factors varied by diagnosis and new prognostic factors were identified. Those factors were incorporated into the updated GPA with robust separation (
< .01) between subgroups. Survival has improved, but varies widely by GPA for patients with non-small-cell lung, breast, melanoma, GI, and renal cancer with brain metastases from 7-47 months, 3-36 months, 5-34 months, 3-17 months, and 4-35 months, respectively.
Median survival varies widely and our ability to estimate survival for patients with brain metastases has improved. The updated GPA (available free at brainmetgpa.com) provides an accurate tool with which to estimate survival, individualize treatment, and stratify clinical trials. Instead of excluding patients with brain metastases, enrollment should be encouraged and those trials should be stratified by the GPA to ensure those trials make appropriate comparisons. Furthermore, we recommend the expansion of eligibility to allow for the enrollment of patients with previously treated brain metastases who have a 50% or greater probability of an additional year of survival (eligibility quotient > 0.50).
Ketogenic diets are high in fat and low in carbohydrates as well as protein which forces cells to rely on lipid oxidation and mitochondrial respiration rather than glycolysis for energy metabolism. ...Cancer cells (relative to normal cells) are believed to exist in a state of chronic oxidative stress mediated by mitochondrial metabolism. The current study tests the hypothesis that ketogenic diets enhance radio-chemo-therapy responses in lung cancer xenografts by enhancing oxidative stress.
Mice bearing NCI-H292 and A549 lung cancer xenografts were fed a ketogenic diet (KetoCal 4:1 fats: proteins+carbohydrates) and treated with either conventionally fractionated (1.8-2 Gy) or hypofractionated (6 Gy) radiation as well as conventionally fractionated radiation combined with carboplatin. Mice weights and tumor size were monitored. Tumors were assessed for immunoreactive 4-hydroxy-2-nonenal-(4HNE)-modified proteins as a marker of oxidative stress as well as proliferating cell nuclear antigen (PCNA) and γH2AX as indices of proliferation and DNA damage, respectively.
The ketogenic diets combined with radiation resulted in slower tumor growth in both NCI-H292 and A549 xenografts (P < 0.05), relative to radiation alone. The ketogenic diet also slowed tumor growth when combined with carboplatin and radiation, relative to control. Tumors from animals fed a ketogenic diet in combination with radiation showed increases in oxidative damage mediated by lipid peroxidation as determined by 4HNE-modified proteins as well as decreased proliferation as assessed by decreased immunoreactive PCNA.
These results show that a ketogenic diet enhances radio-chemo-therapy responses in lung cancer xenografts by a mechanism that may involve increased oxidative stress.
: Chemoradiation therapy is the mainstay for treatment of locally advanced, borderline resectable pancreatic cancer. Pharmacologic ascorbate (P-AscH
, i.e., intravenous infusions of ascorbic acid, ...vitamin C), but not oral ascorbate, produces high plasma concentrations capable of selective cytotoxicity to tumor cells. In doses achievable in humans, P-AscH
decreases the viability and proliferative capacity of pancreatic cancer via a hydrogen peroxide (H
O
)-mediated mechanism. In this study, we demonstrate that P-AscH
radiosensitizes pancreatic cancer cells but inhibits radiation-induced damage to normal cells. Specifically, radiation-induced decreases in clonogenic survival and double-stranded DNA breaks in tumor cells, but not in normal cells, were enhanced by P-AscH
, while radiation-induced intestinal damage, collagen deposition, and oxidative stress were also reduced with P-AscH
in normal tissue. We also report on our first-in-human phase I trial that infused P-AscH
during the radiotherapy "beam on." Specifically, treatment with P-AscH
increased median overall survival compared with our institutional average (21.7 vs. 12.7 months,
= 0.08) and the E4201 trial (21.7 vs. 11.1 months). Progression-free survival in P-AscH
-treated subjects was also greater than our institutional average (13.7 vs. 4.6 months,
< 0.05) and the E4201 trial (6.0 months). Results indicated that P-AscH
in combination with gemcitabine and radiotherapy for locally advanced pancreatic adenocarcinoma is safe and well tolerated with suggestions of efficacy. Because of the potential effect size and minimal toxicity, our findings suggest that investigation of P-AscH
efficacy is warranted in a phase II clinical trial. SIGNIFICANCE: These findings demonstrate that pharmacologic ascorbate enhances pancreatic tumor cell radiation cytotoxicity in addition to offering potential protection from radiation damage in normal surrounding tissue, making it an optimal agent for improving treatment of locally advanced pancreatic adenocarcinoma.
Ionizing radiation is a common and effective therapeutic option for the treatment of glioblastoma (GBM). Unfortunately, some GBMs are relatively radioresistant and patients have worse outcomes after ...radiation treatment. The mechanisms underlying intrinsic radioresistance in GBM has been rigorously investigated over the past several years, but the complex interaction of the cellular molecules and signaling pathways involved in radioresistance remains incompletely defined. A clinically effective radiosensitizer that overcomes radioresistance has yet to be identified. In this review, we discuss the current status of radiation treatment in GBM, including advances in imaging techniques that have facilitated more accurate diagnosis, and the identified mechanisms of GBM radioresistance. In addition, we provide a summary of the candidate GBM radiosensitizers being investigated, including an update of subjects enrolled in clinical trials. Overall, this review highlights the importance of understanding the mechanisms of GBM radioresistance to facilitate the development of effective radiosensitizers.
Segmentation of multiple surfaces in medical images is a challenging problem, further complicated by the frequent presence of weak boundary evidence, large object deformations, and mutual influence ...between adjacent objects. This paper reports a novel approach to multi-object segmentation that incorporates both shape and context prior knowledge in a 3-D graph-theoretic framework to help overcome the stated challenges. We employ an arc-based graph representation to incorporate a wide spectrum of prior information through pair-wise energy terms. In particular, a shape-prior term is used to penalize local shape changes and a context-prior term is used to penalize local surface-distance changes from a model of the expected shape and surface distances, respectively. The globally optimal solution for multiple surfaces is obtained by computing a maximum flow in a low-order polynomial time. The proposed method was validated on intraretinal layer segmentation of optical coherence tomography images and demonstrated statistically significant improvement of segmentation accuracy compared to our earlier graph-search method that was not utilizing shape and context priors. The mean unsigned surface positioning errors obtained by the conventional graph-search approach (6.30 ±1.58 μ m) was improved to 5.14±0.99 μ m when employing our new method with shape and context priors.
Determine the degree of interfraction prostate motion and its components measured by using daily megavoltage (MV) cone beam computed tomography (CBCT) imaging.
A total of 984 daily MV CBCT images ...from 24 patients undergoing definitive intensity-modulated radiotherapy for localized prostate cancer were analyzed retrospectively. Pretreatment couch shifts, based on physician registration of MV CBCT to planning CT data sets, were used as a measure of daily interfraction motion. Off-line bony registration was performed to separate bony misalignment from internal organ motion. Interobserver and intraobserver variation studies were performed on 20 MV CBCT images.
Mean interfraction prostate motion was 6.7 mm, with the greatest single-axis deviation in the anterior-posterior (AP) direction. The largest positional inaccuracy was accounted for by systematic deviations in bony misalignment, whereas random deviations occurred from bony misalignment and internal prostate motion. In the aggregate, AP motion did not correlate with days elapsed since beginning therapy or on average with rectal size at treatment planning. Interobserver variation was greatest in the AP direction, decreased in experienced observers, and further decreased in intraobserver studies. Mean interfraction motion during the first 6 days of therapy, when used as a subsequent offset, reduced acceptable AP planning target volume margins by 50%.
The MV CBCT is a practical direct method of daily localization that shows significant interfraction motion with respect to conventional three-dimensional conformal and intensity-modulated radiotherapy margins, similar to that measured in other modalities.
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