C.W. Williamson

Fat Composition Changes in Bone Marrow During Chemotherapy and Radiation Therapy

PURPOSE To quantify changes in bone marrow fat fraction and determine associations with peripheral blood cell counts. METHODS AND MATERIALS In this prospective study, 19 patients received either highly myelotoxic treatment (radiation therapy plus cisplatin, 5-fluorouracil mitomycin C [FU/MMC], or cisplatin/5-FU/cetuximab) or less myelotoxic treatment (capecitabine-radiation therapy or no concurrent chemotherapy). Patients underwent MR imaging and venipuncture at baseline, midtreatment, and posttreatment visits. We performed mixed effects modeling of the mean proton density fat fraction (PDFF[%]) by linear time, treatment, and vertebral column region (lumbar [L]4-sacral [S]2 vs thoracic [T]10-L3 vs cervical[C]3-T9), while controlling for cumulative mean dose and other confounders. Spearman rank correlations were performed by white blood cell (WBC) counts versus the differences in PDFF(%) before and after treatment. RESULTS Cumulative mean dose was associated with a 0.43% per Gy (P=.004) increase in PDFF(%). In the highly myelotoxic group, we observed significant changes in PDFF(%) per visit within L4-S2 (10.1%, P<.001) and within T10-L3 (3.93%, P=.01), relative to the reference C3-T9. In the less myelotoxic group, we did not observe significant changes in PDFF(%) per visit according to region. Within L4-S2, we observed a significant difference between treatment groups in the change in PDFF(%) per visit (5.36%, P=.04). Rank correlations of the inverse log differences in WBC versus the differences in PDFF(%) overall and within T10-S2 ranged from 0.69 to 0.78 (P<.05). Rank correlations of the inverse log differences in absolute neutrophil counts versus the differences in PDFF(%) overall and within L4-S2 ranged from 0.79 to 0.81 (P<.05). CONCLUSIONS Magnetic resonance imaging fat quantification is sensitive to marrow composition changes that result from chemoradiation therapy. These changes are associated with peripheral blood cell counts. This study supports a rationale for bone marrow-sparing treatment planning to reduce the risk of hematologic toxicity.

Improved Method to Stratify Elderly Patients With Cancer at Risk for Competing Events

PURPOSE To compare a novel generalized competing event (GCE) model versus the standard Cox proportional hazards regression model for stratifying elderly patients with cancer who are at risk for competing events. METHODS We identified 84,319 patients with nonmetastatic prostate, head and neck, and breast cancers from the SEER-Medicare database. Using demographic, tumor, and clinical characteristics, we trained risk scores on the basis of GCE versus Cox models for cancer-specific mortality and all-cause mortality. In test sets, we examined the predictive ability of the risk scores on the different causes of death, including second cancer mortality, noncancer mortality, and cause-specific mortality, using Fine-Gray regression and area under the curve. We compared how well models stratified subpopulations according to the ratio of the cumulative cause-specific hazard for cancer mortality to the cumulative hazard for overall mortality (ω) using the Akaike Information Criterion. RESULTS In each sample, increasing GCE risk scores were associated with increased cancer-specific mortality and decreased competing mortality, whereas risk scores from Cox models were associated with both increased cancer-specific mortality and competing mortality. GCE models created greater separation in the area under the curve for cancer-specific mortality versus noncancer mortality (P < .001), indicating better discriminatory ability between these events. Comparing the GCE model to Cox models of cause-specific mortality or all-cause mortality, the respective Akaike Information Criterion scores were superior (lower) in each sample: prostate cancer, 28.6 versus 35.5 versus 39.4; head and neck cancer, 21.1 versus 29.4 versus 40.2; and breast cancer, 24.6 versus 32.3 versus 50.8. CONCLUSION Compared with standard modeling approaches, GCE models improve stratification of elderly patients with cancer according to their risk of dying from cancer relative to overall mortality.

Five Simultaneous Primary Tumors in a Single Patient: A Case Report and Review of the Literature.

Multiple primary malignancies (MPMs) are present when a patient is diagnosed with more than one primary malignancy and when each tumor is histologically unrelated to the others. MPMs are considered synchronous when they present within 6 months of one another. Here, we report the case of a 57-year-old woman with a past medical history significant for melanoma in 1988, who presented in 2014 with 5 distinct tumors within 4 months: malignant melanoma of the right popliteal fossa, invasive lobular breast carcinoma, diffuse large B cell lymphoma, nodular lymphocyte predominant Hodgkin lymphoma, and a giant cell tumor of tendon sheath/pigmented villonodular synovitis. We discuss her treatment and also present a brief review of the literature. The incidence of MPMs appears to be on the rise, which demands an interdisciplinary, multimodal, and personalized approach to care.

Prospective Validation of a High-Dimensional Shape Model for Organ Motion in Intact Cervical Cancer.

PURPOSE Validated models are needed to justify strategies to define planning target volumes (PTVs) for intact cervical cancer used in clinical practice. Our objective was to independently validate a previously published shape model, using data collected prospectively from clinical trials. METHODS AND MATERIALS We analyzed 42 patients with intact cervical cancer treated with daily fractionated pelvic intensity modulated radiation therapy and concurrent chemotherapy in one of 2 prospective clinical trials. We collected online cone beam computed tomography (CBCT) scans before each fraction. Clinical target volume (CTV) structures from the planning computed tomography scan were cast onto each CBCT scan after rigid registration and manually redrawn to account for organ motion and deformation. We applied the 95% isodose cloud from the planning computed tomography scan to each CBCT scan and computed any CTV outside the 95% isodose cloud. The primary aim was to determine the proportion of CTVs that were encompassed within the 95% isodose volume. A 1-sample t test was used to test the hypothesis that the probability of complete coverage was different from 95%. We used mixed-effects logistic regression to assess effects of time and patient variability. RESULTS The 95% isodose line completely encompassed 92.3% of all CTVs (95% confidence interval, 88.3%-96.4%), not significantly different from the 95% probability anticipated a priori (P=.19). The overall proportion of missed CTVs was small: the grand mean of covered CTVs was 99.9%, and 95.2% of misses were located in the anterior body of the uterus. Time did not affect coverage probability (P=.71). CONCLUSIONS With the clinical implementation of a previously proposed PTV definition strategy based on a shape model for intact cervical cancer, the probability of CTV coverage was high and the volume of CTV missed was low. This PTV expansion strategy is acceptable for clinical trials and practice; however, we recommend daily image guidance to avoid systematic large misses in select patients.

Feasibility of atlas-based active bone marrow sparing intensity modulated radiation therapy for cervical cancer

BACKGROUND To test the hypothesis that atlas-based active bone marrow (ABM)-sparing intensity modulated radiation therapy (IMRT) yields similar dosimetric results compared to custom ABM-sparing IMRT for cervical cancer patients. METHODS We sampled 62 cervical cancer patients with pre-treatment FDG-PET/CT in training (n=32) or test (n=30) sets. ABM was defined as the subvolume of the pelvic bone marrow (PBM) with standardized uptake value (SUV) above the mean on the average FDG-PET image (ABMAtlas) vs. the individuals PET (ABMCustom). Both were deformed to the planning CT. Overlap between the two subvolumes was measured using the Dice coefficient. Three IMRT plans designed to spare PBM, ABMAtlas, or ABMCustom were compared for 30 test patients. Dosimetric parameters were used to evaluate plan quality. RESULTS ABMAtlas and ABMCustom volumes were not significantly different (p=0.90), with a mean Dice coefficient of 0.75, indicating good agreement. Compared to IMRT plans designed to spare PBM and ABMCustom, ABMAtlas-sparing IMRT plans achieved excellent target coverage and normal tissue sparing, without reducing dose to ABMCustom (mean ABMCustom dose 29.4Gy vs. 27.1Gyvs. 26.9Gy, respectively; p=0.10); however, PTV coverage and bowel sparing were slightly reduced. CONCLUSIONS Atlas-based ABM sparing IMRT is clinically feasible and may obviate the need for customized ABM-sparing as a strategy to reduce hematologic toxicity.