Brent S. Rose

Population-Based Study of Competing Mortality in Head and Neck Cancer

PURPOSE Patients with head and neck cancer (HNC) are at high risk of death resulting from noncancer causes and second malignancies (ie, competing mortality). Variation in competing mortality risk complicates individual treatment choices and design and interpretation of clinical studies. METHODS Using the Surveillance, Epidemiology, and End Results registry, we identified 34,568 patients with nonmetastatic squamous cell carcinoma of the head and neck diagnosed between 1994 and 2003. We developed a multivariable competing-risk regression model to stratify patients according to competing mortality risk and evaluate the impact of this risk on power loss in clinical studies. RESULTS The 5-year cumulative incidences of all-cause mortality, HNC-specific mortality, and competing mortality were 51.3% (95% CI, 50.8% to 51.9%), 23.8% (95% CI, 23.3% to 24.2%), and 27.6% (95% CI, 26.8% to 28.3%), respectively. Factors associated with increased competing mortality were increasing age, male sex, black race, unmarried status, localized disease, higher socioeconomic status, nonsurgical treatment, and hypopharyngeal, nasopharyngeal, and oral cavity subsites. The 5-year cumulative incidences of competing mortality for patients in low-, medium-, and high-risk score tertiles were 20.0% (95% CI, 18.8% to 21.3%), 27.7% (95% CI, 26.3% to 29.1%), and 33.7% (95% CI, 32.2% to 35.2%), respectively. Compared with patients with low competing mortality risk, relative sample sizes required to show benefit of a treatment regarding all-cause mortality were 12% and 42% higher in the medium- and high-risk groups, respectively. CONCLUSION Multiple factors affect risk of competing mortality among patients with HNC. Risk stratification would be useful to identify patients most likely to benefit from treatment intensification.

Clinical Outcomes of Intensity-Modulated Pelvic Radiation Therapy for Carcinoma of the Cervix

PURPOSE To evaluate disease outcomes and toxicity in cervical cancer patients treated with pelvic intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS We included all patients with Stage I-IVA cervical carcinoma treated with IMRT at three different institutions from 2000-2007. Patients treated with extended field or conventional techniques were excluded. Intensity-modulated radiation therapy plans were designed to deliver 45 Gy in 1.8-Gy daily fractions to the planning target volume while minimizing dose to the bowel, bladder, and rectum. Toxicity was graded according to the Radiation Therapy Oncology Group system. Overall survival and disease-free survival were estimated by use of the Kaplan-Meier method. Pelvic failure, distant failure, and late toxicity were estimated by use of cumulative incidence functions. RESULTS The study included 111 patients. Of these, 22 were treated with postoperative IMRT, 8 with IMRT followed by intracavitary brachytherapy and adjuvant hysterectomy, and 81 with IMRT followed by planned intracavitary brachytherapy. Of the patients, 63 had Stage I-IIA disease and 48 had Stage IIB-IVA disease. The median follow-up time was 27 months. The 3-year overall survival rate and the disease-free survival rate were 78% (95% confidence interval [CI], 68-88%) and 69% (95% CI, 59-81%), respectively. The 3-year pelvic failure rate and the distant failure rate were 14% (95% CI, 6-22%) and 17% (95% CI, 8-25%), respectively. Estimates of acute and late Grade 3 toxicity or higher were 2% (95% CI, 0-7%) and 7% (95% CI, 2-13%), respectively. CONCLUSIONS Intensity-modulated radiation therapy is associated with low toxicity and favorable outcomes, supporting its safety and efficacy for cervical cancer. Prospective clinical trials are needed to evaluate the comparative efficacy of IMRT vs. conventional techniques.

Normal Tissue Complication Probability Modeling of Acute Hematologic Toxicity in Cervical Cancer Patients Treated With Chemoradiotherapy

PURPOSE To test the hypothesis that increased pelvic bone marrow (BM) irradiation is associated with increased hematologic toxicity (HT) in cervical cancer patients undergoing chemoradiotherapy and to develop a normal tissue complication probability (NTCP) model for HT. METHODS AND MATERIALS We tested associations between hematologic nadirs during chemoradiotherapy and the volume of BM receiving≥10 and 20 Gy (V10 and V20) using a previously developed linear regression model. The validation cohort consisted of 44 cervical cancer patients treated with concurrent cisplatin and pelvic radiotherapy. Subsequently, these data were pooled with data from 37 identically treated patients from a previous study, forming a cohort of 81 patients for normal tissue complication probability analysis. Generalized linear modeling was used to test associations between hematologic nadirs and dosimetric parameters, adjusting for body mass index. Receiver operating characteristic curves were used to derive optimal dosimetric planning constraints. RESULTS In the validation cohort, significant negative correlations were observed between white blood cell count nadir and V10 (regression coefficient (β)=-0.060, p=0.009) and V20 (β=-0.044, p=0.010). In the combined cohort, the (adjusted) β estimates for log (white blood cell) vs. V10 and V20 were as follows: -0.022 (p=0.025) and -0.021 (p=0.002), respectively. Patients with V10≥95% were more likely to experience Grade≥3 leukopenia (68.8% vs. 24.6%, p<0.001) than were patients with V20>76% (57.7% vs. 21.8%, p=0.001). CONCLUSIONS These findings support the hypothesis that HT increases with increasing pelvic BM volume irradiated. Efforts to maintain V10<95% and V20<76% may reduce HT.

A survey of image‐guided radiation therapy use in the United States

Image‐guided radiation therapy (IGRT) is a novel array of in‐room imaging modalities that are used for tumor localization and patient setup in radiation oncology. The prevalence of IGRT use among US radiation oncologists is unknown.

Prospective Study of Functional Bone Marrow-Sparing Intensity Modulated Radiation Therapy With Concurrent Chemotherapy for Pelvic Malignancies

PURPOSE To test the hypothesis that intensity modulated radiation therapy (IMRT) can reduce radiation dose to functional bone marrow (BM) in patients with pelvic malignancies (phase IA) and estimate the clinical feasibility and acute toxicity associated with this technique (phase IB). METHODS AND MATERIALS We enrolled 31 subjects (19 with gynecologic cancer and 12 with anal cancer) in an institutional review board-approved prospective trial (6 in the pilot study, 10 in phase IA, and 15 in phase IB). The mean age was 52 years; 8 of 31 patients (26%) were men. Twenty-one subjects completed (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) simulation and magnetic resonance imaging by use of quantitative IDEAL (IDEAL IQ; GE Healthcare, Waukesha, WI). The PET/CT and IDEAL IQ were registered, and BM subvolumes were segmented above the mean standardized uptake value and below the mean fat fraction within the pelvis and lumbar spine; their intersection was designated as functional BM for IMRT planning. Functional BM-sparing vs total BM-sparing IMRT plans were compared in 12 subjects; 10 were treated with functional BM-sparing pelvic IMRT per protocol. RESULTS In gynecologic cancer patients, the mean functional BM V(10) (volume receiving ≥10 Gy) and V(20) (volume receiving ≥20 Gy) were 85% vs 94% (P<.0001) and 70% vs 82% (P<.0001), respectively, for functional BM-sparing IMRT vs total BM-sparing IMRT. In anal cancer patients, the corresponding values were 75% vs 77% (P=.06) and 62% vs 67% (P=.002), respectively. Of 10 subjects treated with functional BM-sparing pelvic IMRT, 3 (30%) had acute grade 3 hematologic toxicity or greater. CONCLUSIONS IMRT can reduce dose to BM subregions identified by (18)F-fluorodeoxyglucose-PET/CT and IDEAL IQ. The efficacy of BM-sparing IMRT is being tested in a phase II trial.

Correlation Between Radiation Dose to 18F-FDG-PET Defined Active Bone Marrow Subregions and Acute Hematologic Toxicity in Cervical Cancer Patients Treated With Chemoradiotherapy

PURPOSE To test the hypothesis that radiation dose to (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET)-defined active bone marrow (BM(ACT)) subregions is correlated with hematologic toxicity in cervical cancer patients treated with chemoradiotherapy. METHODS AND MATERIALS The conditions of 26 women with cervical cancer who underwent (18)F-FDG-PET before treatment with concurrent cisplatin and intensity-modulated radiation therapy were analyzed. BM(ACT) was defined as the subregion of total bone marrow (BM(TOT)) with a standardized uptake value (SUV) equal to or above the mean for that individual. Inactive bone marrow (BM(INACT)) was defined as BM(TOT) - BM(ACT). Generalized linear modeling was used to test the correlation between BM(ACT) and BM(INACT) dose-volume metrics and hematologic nadirs, particularly white blood cell count (WBC) and absolute neutrophil count (ANC). RESULTS Increased BM(ACT) mean dose was significantly associated with decreased log(WBC) nadir (β = -0.04; 95% CI, -0.07 to -0.01; p = 0.009), decreased log(ANC) nadir (β = -0.05; 95% CI, -0.08 to -0.02; p = 0.006), decreased hemoglobin nadir (β = -0.16; 95% CI, -0.27 to -0.05; p = 0.010), and decreased platelet nadir (β = -6.16; 95% CI, -9.37 to -2.96; p < 0.001). By contrast, there was no association between BM(INACT) mean dose and log(WBC) nadir (β = -0.01; 95% CI, -0.06 to 0.05; p = 0.84), log(ANC) nadir (β = -0.03; 95% CI, -0.10 to 0.04; p = 0.40), hemoglobin nadir (β = -0.09; 95% CI, -0.31 to 0.14; p = 0.452), or platelet nadir (β = -3.47; 95% CI, -10.44 to 3.50; p = 0.339). CONCLUSIONS Irradiation of BM subregions with higher (18)F-FDG-PET activity was associated with hematologic toxicity, supporting the hypothesis that reducing dose to BM(ACT) subregions could mitigate hematologic toxicity. Future investigation should seek to confirm these findings and to identify optimal SUV thresholds to define BM(ACT).

Toxicity analysis of postoperative image-guided intensity-modulated radiotherapy for prostate cancer.

PURPOSE To report on the acute and late gastrointestinal (GI) and genitourinary (GU) toxicity associated with a unique technique of image-guided radiotherapy (IGRT) in patients undergoing postprostatectomy irradiation. METHODS AND MATERIALS Fifty patients were treated with intensity-modulated radiation therapy (IMRT) after radical prostatectomy. Daily image guidance was performed to localize the prostate bed using kilovoltage imaging or cone-beam computed tomography. The median prescription dose was 68 Gy (range, 62-68 Gy). Toxicity was graded every 3 to 6 months according to the Common Terminology Criteria for Adverse Events version 3.0. RESULTS The median follow-up was 24 months (range, 13-38 months). Grade 2 acute GI and GU events occurred in 4 patients (8%) and 7 patients (14%), respectively. No Grade 3 or higher acute GI or GU toxicities were observed. Late Grade 2 GI and GU events occurred in 1 patient (2%) and 8 patients (16%), respectively. Only a single (2%) Grade 3 or higher late toxicity was observed. CONCLUSIONS Image-guided IMRT in the postprostatectomy setting is associated with a low frequency of acute and late GI/GU toxicity. These results compare more favorably to radiotherapy techniques that do not use in-room image-guidance, suggesting that daily prostate bed localization may reduce the incidence of adverse events in patients undergoing postprostatectomy irradiation.

Utilization of Advanced Imaging Technologies for Target Delineation in Radiation Oncology

PURPOSE The aim of this study was to evaluate the utilization of advanced imaging technologies for target delineation among radiation oncologists in the United States. METHODS A random sample of 1,600 radiation oncologists was contacted by Internet, e-mail, and fax and questioned regarding the use of advanced imaging technologies, clinical applications, and future plans for use. Advanced imaging technologies were defined as any of the following that were directly incorporated into radiation therapy planning: MRI, PET, single-photon emission CT, 4-D CT, functional MRI, and MR spectroscopy. RESULTS Of 1,089 contactable physicians, 394 (36%) responded. Of respondents, 65% were in private practice and 35% were in academic practice. The proportion using any advanced imaging technology for target delineation was 95%. However, the majority reported only rare (in <25% of their patients; 46.6%) or infrequent (in 25%-50% of their patients; 26.0%) utilization. The most commonly used technologies were 2-[(18)F]fluoro-2-deoxyglucose PET (76%), MRI (72%), and 4-D CT (44%). The most common cancers treated using image-guided target delineation were those of the lung (83%), central nervous system (79%), and head and neck (79%). Among users of advanced imaging technologies, 66% planned to increase use; 30% of nonusers planned to adopt these technologies in the future. CONCLUSIONS Advanced imaging technologies are widely used by US radiation oncologists for target delineation. Although the majority of respondents used them in <50% of their patients, the frequency of utilization is expected to increase. Studies determining the optimal application of these technologies in radiation therapy planning are needed.

Complications of pelvic radiation in patients treated for gynecologic malignancies.

Radiation therapy is a critical treatment modality in the management of patients with gynecologic tumors. New highly conformal external‐beam and brachytherapy techniques have led to important reductions in recurrence and patient morbidity and mortality. However, patients who receive pelvic radiation for gynecologic malignancies may experience a unique constellation of toxicity because of the anatomic locations, combination with concurrent chemotherapy and/or surgery, as well as potential surgical interventions. Although side effects are often categorized into acute versus late toxicities, several late toxicities represent continuation and evolution of the same pathologic process. Comorbidities and radiation dose can significantly increase the risk of morbidity. Current understanding of the incidence of various morbidities in patients treated with current radiation techniques for gynecologic malignancies, the impact of chemotherapy and surgery, treatment options for those effects, and future areas of research are highlighted. Cancer 2014;120:3870–3883.

Clinical practice patterns of lung stereotactic body radiation therapy in the United States: a secondary analysis.

Objectives:Stereotactic body radiation therapy (SBRT) is a technique used to deliver high, ablative doses of radiation in a limited number of fractions to ≥1 extracranial target(s). Although recent studies have shown that SBRT provides effective local tumor control in medically inoperable early-stage lung cancer patients, its implementation in clinical practice is unknown. Methods:A random sample of 1600 American radiation oncologists was surveyed regarding lung SBRT usage, including year adopted, most common prescription, respiratory motion management, and target localization. A biological equivalent dose (BED) was calculated using the linear quadratic model with &agr;/&bgr;=10. Spearman rank correlation coefficients (rs) were calculated to identify factors associated with BED. Results:Of 1373 contactable physicians, 551 responses (40%) were received. Of 510 evaluable responses, 275 physicians (54%) reported using lung SBRT, over half of whom adopted it in 2008 or later. The most commonly reported prescriptions were 20 Gy×3 (22%), 18 Gy×3 (21%), and 12 Gy×4 (17%). Three fraction regimens were most common (48%), with nearly all (89%) prescribing ≥18 Gy/fraction. The median BED was 132 Gy, with 95% of reported prescriptions having BED≥100 Gy. Factors associated with increased BED included use of fiducial markers (rs=0.26, P<0.001), use of planar imaging (rs=0.18, P<0.01), and years of experience with lung SBRT (rs=0.13, P=0.04). Conclusions:Lung SBRT has rapidly become a widely adopted treatment approach in the United States with a range of varying implementations. Further research and additional prospective trials are necessary to optimize this novel approach.