Matthew M. Harkenrider

Cervical cancer: A global health crisis

Cervical cancer is the fourth most common malignancy diagnosed in women worldwide. Nearly all cases of cervical cancer result from infection with the human papillomavirus, and the prevention of cervical cancer includes screening and vaccination. Primary treatment options for patients with cervical cancer may include surgery or a concurrent chemoradiotherapy regimen consisting of cisplatin‐based chemotherapy with external beam radiotherapy and brachytherapy. Cervical cancer causes more than one quarter of a million deaths per year as a result of grossly deficient treatments in many developing countries. This warrants a concerted global effort to counter the shocking loss of life and suffering that largely goes unreported. This article provides a review of the biology, prevention, and treatment of cervical cancer, and discusses the global cervical cancer crisis and efforts to improve the prevention and treatment of the disease in underdeveloped countries. Cancer 2017;123:2404–12.

Image Guided Cervical Brachytherapy: 2014 Survey of the American Brachytherapy Society

PURPOSE To provide an update of the 2007 American brachytherapy survey on image-based brachytherapy, which showed that in the setting of treatment planning for gynecologic brachytherapy, although computed tomography (CT) was often used for treatment planning, most brachytherapists used point A for dose specification. METHODS AND MATERIALS A 45-question electronic survey on cervical cancer brachytherapy practice patterns was sent to all American Brachytherapy Society members and additional radiation oncologists and physicists based in the United States between January and September 2014. Responses from the 2007 survey and the present survey were compared using the χ(2) test. RESULTS There were 370 respondents. Of those, only respondents, not in training, who treat more than 1 cervical cancer patient per year and practice in the United States, were included in the analysis (219). For dose specification to the target (cervix and tumor), 95% always use CT, and 34% always use MRI. However, 46% use point A only for dose specification to the target. There was a lot of variation in parameters used for dose evaluation of target volume and normal tissues. Compared with the 2007 survey, use of MRI has increased from 2% to 34% (P<.0001) for dose specification to the target. Use of volume-based dose delineation to the target has increased from 14% to 52% (P<.0001). CONCLUSION Although use of image-based brachytherapy has increased in the United States since the 2007 survey, there is room for further growth, particularly with the use of MRI. This increase may be in part due to educational initiatives. However, there is still significant heterogeneity in brachytherapy practice in the United States, and future efforts should be geared toward standardizing treatment.

Image-Based Brachytherapy for the Treatment of Cervical Cancer

Cervical cancer is a disease that requires considerable multidisciplinary coordination of care and labor in order to maximize tumor control and survival while minimizing treatment-related toxicity. As with external beam radiation therapy, the use of advanced imaging and 3-dimensional treatment planning has generated a paradigm shift in the delivery of brachytherapy for the treatment of cervical cancer. The use of image-based brachytherapy, most commonly with magnetic resonance imaging (MRI), requires additional attention and effort by the treating physician to prescribe dose to the proper volume and account for adjacent organs at risk. This represents a dramatic change from the classic Manchester approach of orthogonal radiographic images and prescribing dose to point A. We reviewed the history and currently evolving data and recommendations for the clinical use of image-based brachytherapy with an emphasis on MRI-based brachytherapy.

Multi-institutional experience of stereotactic body radiotherapy for large (≥5 centimeters) non-small cell lung tumors.

Stereotactic body radiotherapy (SBRT) is the standard of care for patients with nonoperative, early‐stage non–small cell lung cancer (NSCLC) measuring < 5 cm, but its use among patients with tumors measuring ≥5 cm is considerably less defined, with the existing literature limited to small, single‐institution reports. The current multi‐institutional study reported outcomes evaluating the largest such population reported to date.

Markerless motion tracking of lung tumors using dual‐energy fluoroscopy

PURPOSE To evaluate the efficacy of dual-energy (DE) vs single-energy (SE) fluoroscopic imaging of lung tumors using a markerless template-based tracking algorithm. METHODS Ten representative patient breathing patterns were programmed into a Quasar™ motion phantom. The phantom was modified by affixing pork ribs to the surface, and a cedar insert with a small spherical volume was used to simulate lung and tumor, respectively. Sequential 60 kVp (6 mA) and 120 kVp (1.5 mA) fluoroscopic sequences were acquired. Frame-by-frame weighted logarithmic subtraction was performed resulting in a DE fluoroscopic sequence. A template-based algorithm was then used to track tumor motion throughout the DE and SE fluoroscopy sequences. Tracking coordinates were evaluated against ground-truth tumor locations. Fluoroscopic images were also acquired for two lung cancer patients, neither of which had implanted fiducials. RESULTS For phantom imaging, a total of 1925 frames were analyzed. The algorithm successfully tracked the target on 99.9% (1923/1925) of DE frames vs 90.7% (1745/1925) SE images (p < 0.01). The displacement between tracking coordinates and ground truth for the phantom was 1.4 mm ± 1.1 mm for DE vs 2.0 mm ± 1.3 mm for SE (p < 0.01). Images from two patients, one with a larger tumor and one with a smaller tumor, were also analyzed. For the patient with the larger tumor, the average displacement from physician defined ground truth was 1.2 mm ± 0.6 mm for DE vs 1.4 mm ± 0.7 mm for SE (p = 0.016). For the patient that presented with a smaller tumor, the average displacement from physician defined ground truth was 2.2 mm ± 1.0 mm for DE vs 3.2 mm ± 1.4 mm for SE (p < 0.01). Importantly, for this single patient with the smaller tumor, 15.6% of the SE frames had >5 mm displacements from the ground truth vs 0% for DE fluoroscopy. CONCLUSIONS This work indicates the potential for markerless tumor tracking utilizing DE fluoroscopy. With DE imaging, the algorithm showed improved detectability vs SE fluoroscopy and was able to accurately track the tumor in nearly all cases.

The role of vaginal cuff brachytherapy in endometrial cancer

OBJECTIVE The purpose of this article is to review the data, rationale, and recommendations of vaginal brachytherapy (VBT) in the post-operative treatment of endometrial cancer patients. METHODS The authors performed a thorough review of the medical literature regarding the use of adjuvant VBT in the treatment of endometrial cancer. Relevant data are presented in this review. Additionally, personal and institutional practices from the authors are incorporated where relevant. RESULTS VBT for the adjuvant treatment of early stage endometrial cancer patients results in a low rate of recurrence (0-3.1%) with very low rates of toxicity. PORTEC-2 supports the use of adjuvant VBT versus external beam radiotherapy specifically for high-intermediate risk endometrial cancer patients. VBT has low rates of acute and chronic gastrointestinal and genitourinary toxicity and very low rates of second primary malignancy. The primary toxicity of VBT is vaginal atrophy and stenosis with controversy regarding the use of vaginal dilators for prevention. Data support that patients prefer to be involved in the decision making process for their adjuvant therapy, and patients have a lower minimal desired benefit of adjuvant VBT than do physicians. Guidelines exist from the American Brachytherapy Society and American Society of Radiation Oncology with support from the Society for Gynecologic Oncologists regarding the use of adjuvant VBT. CONCLUSIONS VBT decreases the risk of recurrence with minimal toxicity in the adjuvant treatment of endometrial cancer. Adjuvant therapy should be discussed in a multi-disciplinary setting with detailed counseling of the risks and benefits with the patient so that she ultimately makes an informed decision regarding her adjuvant therapy.

Consensus recommendations for radiation therapy contouring and treatment of vulvar carcinoma

PURPOSE The purpose of this study was to develop a radiation therapy (RT) contouring atlas and recommendations for women with postoperative and locally advanced vulvar carcinoma. METHODS AND MATERIALS An international committee of 35 expert gynecologic radiation oncologists completed a survey of the treatment of vulvar carcinoma. An initial set of recommendations for contouring was discussed and generated by consensus. Two cases, 1 locally advanced and 1 postoperative, were contoured by 14 physicians. Contours were compared and analyzed using an expectation-maximization algorithm for simultaneous truth and performance level estimation (STAPLE), and a 95% confidence interval contour was developed. The level of agreement among contours was assessed using a kappa statistic. STAPLE contours underwent full committee editing to generate the final atlas consensus contours. RESULTS Analysis of the 14 contours showed substantial agreement, with kappa statistics of 0.69 and 0.64 for cases 1 and 2, respectively. There was high specificity for both cases (≥99%) and only moderate sensitivity of 71.3% and 64.9% for cases 1 and 2, respectively. Expert review and discussion generated consensus recommendations for contouring target volumes and treatment for postoperative and locally advanced vulvar cancer. CONCLUSIONS These consensus recommendations for contouring and treatment of vulvar cancer identified areas of complexity and controversy. Given the lack of clinical research evidence in vulvar cancer radiation therapy, the committee advocates a conservative and consistent approach using standardized recommendations.

Tumor volume change with stereotactic body radiotherapy (SBRT) for early-stage lung cancer: evaluating the potential for adaptive SBRT.

Objectives:To quantify gross tumor volume (GTV) change during stereotactic body radiotherapy (SBRT) and on first follow-up, as well as to evaluate for any predictive prognostic risk factors related to GTV decrease. An attempt was also made to identify the potential timing for adaptive SBRT. Methods:Twenty-five tumors in 24 consecutive patients were treated with SBRT to total dose of 50 Gy in 5 fractions. Median age was 72.5 years. Tumor stage was T1, 68%; T2, 20%; and other, 12%. The GTVs of on the 5 cone-beam computed tomographies (CBCT1-5) obtained before each fraction and the first follow-up CT (CTPOST) were analyzed. Results:Median time from diagnosis to initiation of radiotherapy was 64 days. GTV on CBCT1 was the baseline for comparison. GTV decreased by a mean of 7% on CBCT2 (P=0.148), 11% on CBCT3 (P=0.364), 19% on CBCT4 (P=0.0021), and 32% on CBCT5 (P=0.0004). Univariate analyses of GTV shrinkage was significantly associated with “time from CBCT5 to CTPOST” (P=0.027) and “T-stage” (P=0.002). In multivariate analyses, “T-stage” remained significant with T1 tumors showing greater GTV shrinkage than T2 tumors. Conclusions:Significant decrease in GTV volume based on daily CBCT was demonstrated during SBRT treatment. Adaptive SBRT has the potential to minimize integral dose to the surrounding normal tissues without compromising GTV coverage.

Prospective Evaluation of Dual-Energy Imaging in Patients Undergoing Image Guided Radiation Therapy for Lung Cancer: Initial Clinical Results

PURPOSE A prospective feasibility study was conducted to investigate the utility of dual-energy (DE) imaging compared to conventional x-ray imaging for patients undergoing kV-based image guided radiation therapy (IGRT) for lung cancer. METHODS AND MATERIALS An institutional review board-approved feasibility study enrolled patients with lung cancer undergoing IGRT and was initiated in September 2011. During daily setup, 2 sequential respiration-gated x-ray images were obtained using an on-board imager. Imaging was composed of 1 standard x-ray image at 120 kVp (1 mAs) and a second image obtained at 60 kVp (4 mAs). Weighted logarithmic subtraction of the 2 images was performed offline to create a soft tissue-selective DE image. Conventional and DE images were evaluated by measuring relative contrast and contrast-to-noise ratios (CNR) and also by comparing spatial localization, using both approaches. Imaging dose was assessed using a calibrated ion chamber. RESULTS To date, 10 patients with stage IA to IIIA lung cancer were enrolled and 57 DE images were analyzed. DE subtraction resulted in complete suppression of overlying bone in all 57 DE images, with an average improvement in relative contrast of 4.7 ± 3.3 over that of 120 kVp x-ray images (P<.0002). The improvement in relative contrast with DE imaging was seen for both smaller (gross tumor volume [GTV] ≤5 cc) and larger tumors (GTV >5 cc), with average relative contrast improvement ratios of 3.4 ± 4.1 and 5.4 ± 3.6, respectively. Moreover, the GTV was reliably localized in 95% of the DE images versus 74% of the single energy (SE images, (P=.004). Mean skin dose per DE image set was 0.44 ± 0.03 mGy versus 0.43 ± 0.03 mGy, using conventional kV imaging parameters. CONCLUSIONS Initial results of this feasibility study suggest that DE thoracic imaging may enhance tumor localization in lung cancer patients receiving kV-based IGRT without increasing imaging dose.

Reirradiation as a Component of the Multidisciplinary Management of Locally Recurrent Breast Cancer

BACKGROUND AND PURPOSE Our intent was to review a modern multidisciplinary institutional experience involving reirradiation of the breast, chest wall, and lymphatics for locoregional recurrences of breast cancer and report toxicity and clinical outcomes. MATERIALS AND METHODS Between 1995 and 2009, 12 locoregional recurrences were reirradiated in 8 patients. The mean dose of initial radiotherapy was 57.1 Gy (range, 50.4-60.6 Gy), and the mean dose of reirradiation was 46.7 Gy (range, 30-62.1 Gy). The second course of radiotherapy was delivered using daily radiotherapy to 5 recurrences, twice-daily radiotherapy to 5 recurrences (1 with mold brachytherapy boost), and a combination of once- and twice-daily radiotherapy to 2 recurrences. RESULTS The median follow-up from time of completion of reirradiation was 30 months (range, 1.5-67 months). Local control was achieved in 7 of 8 patients and 11 of 12 recurrences. Regional control was achieved in 5 of 8 patients and 6 of 12 recurrences. Distant control was achieved in 5 of 8 patients. At time of analysis, 5 of 8 patients were alive. Median survival since reirradiation completion was 36 months (range, 4.5-47 months). Acute toxicity included grade 2 dermatitis in 4 patients, ipsilateral shoulder pain in 1 patient, and ipsilateral pleurisy in 1 patient. Late skin and soft tissue toxicity manifested as fibrosis in 4 patients, hyperpigmentation in 3 patients, and telangiectasia in 3 patients. Three patients reported lymphedema, 1 patient reporting chest wall pain and 1 patient with an ipsilateral rib fracture. CONCLUSIONS Multidisciplinary management of locoregional recurrence of breast cancer using reirradiation is well tolerated as salvage treatment and provides durable locoregional control.