John Einck

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.

FAST NEUTRON RADIOTHERAPY FOR SOFT TISSUE AND CARTILAGINOUS SARCOMAS AT HIGH RISK FOR LOCAL RECURRENCE

PURPOSE The practice policy at the University of Washington has been to employ fast neutron radiotherapy for soft tissue sarcoma lesions with prognostic features predictive for poor local control. These include gross residual disease/inoperable disease, recurrent disease, and contaminated surgical margins. Cartilaginous sarcomas have also been included in this high-risk group. This report updates and expands our previously described experience with this approach. METHODS AND MATERIALS Eighty-nine soft tissue sarcoma lesions in 72 patients were treated with neutron radiotherapy in our department between 1984 and 1996. Six patients, each with solitary lesions, were excluded from analysis due to lack of follow-up. Seventy-three percent were treated with fast neutron radiation alone, the rest with a combination of neutrons and photons. Median neutron dose was 18.3 nGy (range 4.8-22). Forty-two patients with solitary lesions were treated with curative intent. Thirty-one patients (including 7 previously treated with neutrons) with 41 lesions were treated with the goal of local palliation. Tumors were predominantly located in the extremity and torso. Thirty of 35 (85%) of curative group patients treated postoperatively had close or positive surgical margins. Thirty-four (82%) lesions treated for palliation were unresectable. Thirty-five patients (53%) were treated at the time of recurrence. Median tumor size at initial presentation was 8.0 cm (range 0.6-29), median treated gross disease size was 5.0 cm (range 1-22), and 46/69 evaluable lesions (67%) were judged to be of intermediate to high histologic grade. Fourteen patients (21%) had chondrosarcomas. RESULTS Median follow-up was 6 months (range 2-47) and 38 months (range 2-175) for the palliative and curative groups, respectively. Kaplan-Meier estimates were obtained for probability of local relapse-free survival (68%), distant disease-free survival (59%), cause-specific survival (68%), and overall survival (66%) at 4 years for the curatively treated group. For the palliatively treated group, estimated local relapse-free survival at 1 year was 62%. Log-rank analysis of the curative group revealed recurrent disease to be the only risk factor predictive for significantly worse local and distant disease-free survival. Intermediate-/high-grade histology was predictive for inferior overall survival. Effective clinical response was documented for 21/27 (78%) lesions treated palliatively. Ten patients (15%) experienced serious chronic radiation-related complications. All of these patients had clinical situations requiring delivery of high neutron doses and/or large radiotherapy fields. CONCLUSION Fast neutron radiotherapy is locally effective for soft tissue and cartilaginous sarcomas having well-recognized high-risk features. Results in the palliative setting appear to be particularly encouraging, with neutrons frequently providing significant symptomatic response for gross disease, with minimal serious chronic sequelae. Fast neutron radiotherapy should be considered in patients at high risk for local recurrence in both the curative and palliative settings.

Role of Postmastectomy Radiation After Neoadjuvant Chemotherapy in Stage II-III Breast Cancer

PURPOSE To identify a cohort of women treated with neoadjuvant chemotherapy and mastectomy for whom postmastectomy radiation therapy (PMRT) may be omitted according to the projected risk of local-regional failure (LRF). METHODS AND MATERIALS Seven breast cancer physicians from the University of California cancer centers created 14 hypothetical clinical case scenarios, identified, reviewed, and abstracted the available literature (MEDLINE and Cochrane databases), and formulated evidence tables with endpoints of LRF, disease-free survival, and overall survival. Using the American College of Radiology appropriateness criteria methodology, appropriateness ratings for postmastectomy radiation were assigned for each scenario. Finally, an overall summary risk assessment table was developed. RESULTS Of 24 sources identified, 23 were retrospective studies from single institutions. Consensus on the appropriateness rating, defined as 80% agreement in a category, was achieved for 86% of the cases. Distinct LRF risk categories emerged. Clinical stage II (T1-2N0-1) patients, aged >40 years, estrogen receptor-positive subtype, with pathologic complete response or 0-3 positive nodes without lymphovascular invasion or extracapsular extension, were identified as having ≤ 10% risk of LRF without radiation. Limited data support stage IIIA patients with pathologic complete response as being low risk. CONCLUSIONS In the absence of randomized trial results, existing data can be used to guide the use of PMRT in the neoadjuvant chemotherapy setting. Using available studies to inform appropriateness ratings for clinical scenarios, we found a high concordance of treatment recommendations for PMRT and were able to identify a cohort of women with a low risk of LRF without radiation. These low-risk patients will form the basis for future planned studies within the University of California Athena Breast Health Network.

The effect of delayed postoperative irradiation on local control of soft tissue sarcomas of the extremity and torso

PURPOSE The impact of delayed adjuvant radiotherapy in patients treated by surgical resection for peripheral or torso soft tissue sarcoma has not been well characterized. We retrospectively examined this issue in an institutional patient cohort. METHODS AND MATERIALS One hundred two adult patients were treated at the University of Washington Medical Center between 1981 and 1998 with postoperative radiotherapy for cure of a newly diagnosed soft tissue sarcoma. Of this group, 58 patients had primary intermediate- or high-grade disease of the extremity or torso (50 extremity/8 torso). Tumor histology was predominantly malignant fibrohistiocytoma, synovial cell sarcoma, and leiomyosarcoma. The group was dichotomized according to time interval from definitive resection to the start of adjuvant radiation. Twenty-six patients had a short delay, defined as <4 months, and 32 patients had a long delay of >or=4 months. Both groups were balanced with regard to site, size, margin status, and tumor depth; however, the long-delay group had a larger proportion of high histologic grade lesions and was treated more frequently with chemotherapy (31/32 [97%] for long-delay patients vs. 14/26 [54%] for short-delay patients). Median follow-up was 49.5 months (range: 7-113 months). Median follow-up for patients still alive was 54 months (range: 9-113 months). Survival outcomes were estimated by the Kaplan-Meier method. RESULTS Overall local relapse-free survival at 5 years from the time of definitive resection was 74%. On univariate analysis, estimated 5-year local relapse-free survival was significantly improved in the short-delay group (88% vs. 62% for the long-delay group, p = 0.048 by log rank). Overall distant relapse-free survival, disease-free survival, and overall survival at 5 years were 77%, 68%, and 86%, respectively. These survival outcomes were statistically equivalent in both radiation delay groups. There was no evidence to suggest that delaying adjuvant systemic therapy for postoperative radiation negatively impacted distant relapse-free survival, disease-free survival, or overall survival. Patterns of failure analysis revealed that 11/12 disease failures in the long-delay group had a local component, with five patients presenting with solitary local recurrences. Severe chronic radiation-related soft tissue or peripheral nerve morbidity was infrequent (5/58 or 8.6%) and similar in both groups. CONCLUSIONS Postoperative radiation delays of 4 months or greater were associated with inferior local disease control for intermediate- and high-grade soft tissue sarcomas of the extremity and torso. Our results suggest that timing postoperative radiation before postoperative chemotherapy may optimize local therapy for such patients without adversely affecting distant disease control, long-term morbidity, or overall survival. Prospective testing of this hypothesis is warranted.

Modern Radiation Therapy and Cardiac Outcomes in Breast Cancer

PURPOSE Adjuvant radiation therapy, which has proven benefit against breast cancer, has historically been associated with an increased incidence of ischemic heart disease. Modern techniques have reduced this risk, but a detailed evaluation has not recently been conducted. The present study evaluated the effect of current radiation practices on ischemia-related cardiac events and procedures in a population-based study of older women with nonmetastatic breast cancer. METHODS AND MATERIALS A total of 29,102 patients diagnosed from 2000 to 2009 were identified from the Surveillance, Epidemiology, and End Results-Medicare database. Medicare claims were used to identify the radiation therapy and cardiac outcomes. Competing risk models were used to assess the effect of radiation on these outcomes. RESULTS Patients with left-sided breast cancer had a small increase in their risk of percutaneous coronary intervention (PCI) after radiation therapy-the 10-year cumulative incidence for these patients was 5.5% (95% confidence interval [CI] 4.9%-6.2%) and 4.5% (95% CI 4.0%-5.0%) for right-sided patients. This risk was limited to women with previous cardiac disease. For patients who underwent PCI, those with left-sided breast cancer had a significantly increased risk of cardiac mortality with a subdistribution hazard ratio of 2.02 (95% CI 1.23-3.34). No other outcome, including cardiac mortality for the entire cohort, showed a significant relationship with tumor laterality. CONCLUSIONS For women with a history of cardiac disease, those with left-sided breast cancer who underwent radiation therapy had increased rates of PCI and a survival decrement if treated with PCI. The results of the present study could help cardiologists and radiation oncologists better stratify patients who need more aggressive cardioprotective techniques.

Implementation of a high-dose-rate brachytherapy program for carcinoma of the cervix in Senegal: a pragmatic model for the developing world.

West Africa has one of the highest incidence rates of carcinoma of the cervix in the world. The vast majority of women do not have access to screening or disease treatment, leading to presentation at advanced stages and to high mortality rates. Compounding this problem is the lack of radiation treatment facilities in Senegal and many other parts of the African continent. Senegal, a country of 13 million people, had a single (60)Co teletherapy unit before our involvement and no brachytherapy capabilities. Radiating Hope, a nonprofit organization whose mission is to provide radiation therapy equipment to countries in the developing world, provided a high-dose-rate afterloading unit to the cancer center for curative cervical cancer treatment. Here we describe the implementation of high-dose-rate brachytherapy in Senegal requiring a nonstandard fractionation schedule and a novel treatment planning approach as a possible blueprint to providing this technology to other developing countries.

Clinical Outcomes of Computed Tomography-Based Volumetric Brachytherapy Planning for Cervical Cancer

PURPOSE/OBJECTIVES A report of clinical outcomes of a computed tomography (CT)-based image guided brachytherapy (IGBT) technique for treatment of cervical cancer. METHODS AND MATERIALS Seventy-six women with International Federation of Gynecology and Obstetrics stage IB to IVA cervical carcinoma diagnosed between 2007 and 2014 were treated with definitive external beam radiation therapy (EBRT) with or without concurrent chemotherapy followed by high-dose-rate (HDR) IGBT. All patients underwent planning CT simulation at each implantation. A high-risk clinical target volume (HRCTV) encompassing any visible tumor and the entire cervix was contoured on the simulation CT. When available, magnetic resonance imaging (MRI) was performed at implantation to assist with tumor delineation. The prescription dose was prescribed to the HRCTV. RESULTS The median follow-up time was 17 months. Thirteen patients (17%) had an MRI done before brachytherapy, and 16 patients (21%) were treated without MRI guidance. The mean EBRT/IGBT sum 2-Gy equivalent dose (EQD2) delivered to the 90% volume of the HRCTV was 86.3 Gy. The mean maximum EQD2s delivered to 2 cm(3) of the rectum, sigmoid, and bladder were 67.5 Gy, 66.2 Gy, and 75.3 Gy, respectively. The 2-year cumulative incidences of local, locoregional, and distant failure were 5.8% (95% confidence interval [CI]: 1.4%-14.8%), 15.1% (95% CI: 5.4%-29.4%), and 24.3% (95% CI: 12.1%-38.9%), respectively. The 2-year overall and disease-free survival rates were 75% (95% CI, 61%-91%) and 73% (95% CI, 60%-90%), respectively. Twenty-nine patients (38%) experienced grade ≥ 2 acute toxicity, with 5 cases of acute grade 3 toxicity and no grade ≥ 4 toxicities. One patient experienced grade 3 gastrointestinal toxicity. No other late grade ≥ 3 events were observed. CONCLUSIONS This is the largest report to date of CT/MRI-based IGBT for the treatment of cervical cancer. The results are promising, with excellent local control and acceptable toxicity. Further investigation is needed to assess the long-term safety and efficacy of this treatment.

Radiation oncology in Africa: improving access to cancer care on the African continent.

Radiation Oncology in Africa: Improving Access to Cancer Care on the African Continent Brandon J. Fisher, DO,* Larry C. Daugherty, MD,y John P. Einck, MD,{ Gita Suneja, MD,x Mira M. Shah, MD,k Luqman K. Dad, MD,{ Robert W. Mutter, MD, J. BenWilkinson, MD,** and Arno J. Mundt, MDz *Gamma West Cancer Services, Salt Lake City, Utah; yMayo Clinic, Jacksonville, Florida; zMoores Cancer Center, University of California San Diego, San Diego, California; xAbramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; kHenry Ford Health System, Detroit, Michigan; {Anne Arundel Medical Center, Annapolis, Maryland; Mayo Clinic, Rochester, Minnesota; and **Willis-Knighton Health System/LSU Health Science Center, Shreveport, Louisiana

The Unique Issues With Brachytherapy in Low- and Middle-Income Countries ☆

Gynecologic carcinomas, including cervical cancer, present a significant burden on low- and middle-income countries (LMICs). Brachytherapy plays an integral role in the treatment of gynecologic carcinomas, as it is essential for both curative and palliative treatment. However, there are numerous geographic and economic barriers to providing brachytherapy to cancer patients in LMICs. This article examines the role and delivery of brachytherapy in gynecological cancer treatment; brachytherapy capacity in LMICs, including infrastructure, equipment, and human resources considerations; commissioning, training, and clinical implementation of brachytherapy in LMICs; other challenges, and strategies for improvement in brachytherapy delivery in LMICs, including innovation and current and upcoming international initiatives.

The Impact of Radiation Oncologists on the Early Adoption of Hypofractionated Radiation Therapy for Early-Stage Breast Cancer

PURPOSE Despite multiple randomized trials showing the efficacy of hypofractionated radiation therapy in early-stage breast cancer, the United States has been slow to adopt this treatment. The goal of this study was to evaluate the impact of individual radiation oncologists on the early adoption of hypofractionated radiation therapy for early-stage breast cancer. METHODS We identified 22,233 Medicare beneficiaries with localized breast cancer that was diagnosed from 2004 to 2011 who underwent breast-conserving surgery with adjuvant radiation. Multilevel, multivariable logistic models clustered by radiation oncologist and geographic practice area were used to determine the impact of the provider and geographic region on the likelihood of receiving hypofractionated compared with standard fractionated radiation therapy while controlling for a patients clinical and demographic covariates. Odds ratios (OR) describe the impact of demographic or clinical covariates, and the median OR (MOR) describes the relative impact of the individual radiation oncologist and geographic region on the likelihood of undergoing hypofractionated radiation therapy. RESULTS Among the entire cohort, 2333 women (10.4%) were treated with hypofractionated radiation therapy, with unadjusted rates ranging from 0.0% in the bottom quintile of radiation oncologists to 30.4% in the top quintile. Multivariable analysis found that the individual radiation oncologist (MOR 3.08) had a greater impact on the use of hypofractionation than did geographic region (MOR 2.10) or clinical and demographic variables. The impact of the provider increased from the year 2004 to 2005 (MOR 2.82) to the year 2010 to 2011 (MOR 3.16) despite the publication of long-term randomized trial results in early 2010. Male physician and radiation oncologists treating the highest volume of breast cancer patients were less likely to perform hypofractionation (P<.05). CONCLUSIONS The individual radiation oncologist strongly influenced the likelihood of a patients receiving hypofractionated radiation therapy, and this trend increased despite the publication of long-term data showing equivalence to standard fractionation. Future research should focus on physician-related factors that influence this decision.