R. Dinniwell

Phase I Study of Individualized Stereotactic Body Radiotherapy of Liver Metastases

PURPOSE To report on the outcomes of a phase I study of stereotactic body radiotherapy (SBRT) for treatment of liver metastases. PATIENTS AND METHODS Patients with liver metastases that were inoperable or medically unsuitable for resection, and who were not candidates for standard therapies, were eligible for this phase I study of individualized SBRT. Individualized radiation doses were chosen to maintain the same nominal risk of radiation-induced liver disease (RILD) for three estimated risk levels (5%, 10%, and 20%). Additional patients were treated at the maximal study dose (MSD) in an expanded cohort. Median SBRT dose was 41.8 Gy (range, 27.7 to 60 Gy) in six fractions over 2 weeks. RESULTS Sixty-eight patients with inoperable colorectal (n = 40), breast (n = 12), or other (n = 16) liver metastases were treated. Median tumor volume was 75.2 mL (range, 1.19 to 3,090 mL). The highest RILD risk level investigated was safe, with no dose-limiting toxicity. Two grade 3 liver enzyme changes occurred, but no RILD or other grade 3 to 5 liver toxicity was seen, for a low estimated risk of serious liver toxicity (95% CI, 0 to 5.3%). Six (9%) acute grade 3 toxicities (two gastritis, two nausea, lethargy, and thrombocytopenia) and one (1%) grade 4 toxicity (thrombocytopenia) were seen. The 1-year local control rate was 71% (95 CI, 58% to 85%). The median overall survival was 17.6 months (95% CI, 10.4 to 38.1 months). CONCLUSION Individualized six-fraction liver metastases SBRT is safe, with sustained local control observed in the majority of patients.

Inter- and Intrafractional Tumor and Organ Movement in Patients With Cervical Cancer Undergoing Radiotherapy: A Cinematic-MRI Point-of-Interest Study

PURPOSE Internal tumor and organ movement is important when considering intensity-modulated radiotherapy for patients with cancer of the cervix because of the tight margins and steep dose gradients. In this study, the internal movement of the tumor, cervix, and uterus were examined using serial cinematic magnetic resonance imaging scans and point-of-interest analysis. METHODS AND MATERIALS Twenty patients with Stage IB-IVA cervical cancer underwent pelvic magnetic resonance imaging before treatment and then weekly during external beam radiotherapy. In each 30-min session, sequential T(2)-sagittal magnetic resonance imaging scans were obtained. The points of interest (cervical os, uterine canal, and uterine fundus) were traced on each image frame, allowing the craniocaudal and anteroposterior displacements to be measured. The mean displacements and trends were analyzed using mixed linear models. Prediction intervals were calculated to determine the internal target margins. RESULTS Large interscan motion was found for all three points of interest that was only partially explained by the variations in bladder and rectal filling. The intrascan motion was much smaller. Both inter- and intrascan motion was greatest at the fundus of the uterus, less along the canal, and least at the cervical os. The isotropic internal target margins required to encompass 90% of the interscan motion were 4 cm at the fundus and 1.5 cm at the os. In contrast, smaller margins of 1 cm and 0.45 cm, respectively, were adequate to encompass the intrascan motion alone. CONCLUSION Daily soft-tissue imaging with correction for interfractional motion or adaptive replanning will be important if the benefits of intensity-modulated radiotherapy are to be maximized in women with cervical cancer.

Interfraction and Intrafraction Changes in Amplitude of Breathing Motion in Stereotactic Liver Radiotherapy

PURPOSE Interfraction and intrafraction changes in amplitude of liver motion were assessed in patients with liver cancer treated with kV cone beam computed tomography (CBCT)-guided stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS A total of 314 CBCTs obtained with the patient in the treatment position immediately before and after each fraction, and 29 planning 4DCTs were evaluated in 29 patients undergoing six-fraction SBRT for unresectable liver cancer, with (n = 15) and without (n = 14) abdominal compression. Offline, the CBCTs were sorted into 10 bins, based on phase of respiration. Liver motion amplitude was measured using liver-to-liver alignment from the end-exhale and end-inhale CBCT and four-dimensional CT reconstructions. Inter- and intrafraction amplitude changes were measured from the difference between the pre-SBRT CBCTs relative to the planning four-dimensional CT, and from the pre-SBRT and post-SBRT CBCTs, respectively. RESULTS Mean liver motion amplitude for all patients (range) was 1.8 (0.1-7.0), 8.0 (0.1-18.8), and 4.3 (0.1-12.1) mm in the mediolateral (ML), craniocaudal (CC), and anteroposterior (AP) directions, respectively. Mean absolute inter- and intrafraction liver motion amplitude changes were 1.0 (ML), 1.7 (CC), and 1.6 (AP) mm and 1.3 (ML), 1.6 (CC), and 1.9 (AP) mm, respectively. No significant correlations were found between intrafraction amplitude change and intrafraction time (range, 4:56-25:37 min:sec), and between inter- and intrafraction amplitude changes and liver motion amplitude. Intraobserver reproducibility (sigma, n = 29 fractions) was 1.3 (ML), 1.4 (CC), and 1.4 (AP) mm. CONCLUSIONS For the majority of liver SBRT patients, the change in liver motion amplitude was minimal over the treatment course and showed no apparent relationships with the magnitude of liver motion and intrafraction time.

Automated planning of tangential breast intensity-modulated radiotherapy using heuristic optimization.

PURPOSE To present an automated technique for two-field tangential breast intensity-modulated radiotherapy (IMRT) treatment planning. METHOD AND MATERIALS A total of 158 planned patients with Stage 0, I, and II breast cancer treated using whole-breast IMRT were retrospectively replanned using automated treatment planning tools. The tools developed are integrated into the existing clinical treatment planning system (Pinnacle(3)) and are designed to perform the manual volume delineation, beam placement, and IMRT treatment planning steps carried out by the treatment planning radiation therapist. The automated algorithm, using only the radio-opaque markers placed at CT simulation as inputs, optimizes the tangential beam parameters to geometrically minimize the amount of lung and heart treated while covering the whole-breast volume. The IMRT parameters are optimized according to the automatically delineated whole-breast volume. RESULTS The mean time to generate a complete treatment plan was 6 min, 50 s ± 1 min 12 s. For the automated plans, 157 of 158 plans (99%) were deemed clinically acceptable, and 138 of 158 plans (87%) were deemed clinically improved or equal to the corresponding clinical plan when reviewed in a randomized, double-blinded study by one experienced breast radiation oncologist. In addition, overall the automated plans were dosimetrically equivalent to the clinical plans when scored for target coverage and lung and heart doses. CONCLUSION We have developed robust and efficient automated tools for fully inversed planned tangential breast IMRT planning that can be readily integrated into clinical practice. The tools produce clinically acceptable plans using only the common anatomic landmarks from the CT simulation process as an input. We anticipate the tools will improve patient access to high-quality IMRT treatment by simplifying the planning process and will reduce the effort and cost of incorporating more advanced planning into clinical practice.

Local control with conventional and hypofractionated adjuvant radiotherapy after breast-conserving surgery for ductal carcinoma in-situ

PURPOSE Adjuvant whole breast radiotherapy (WBRT) for ductal carcinoma in situ (DCIS) improves local control, however an optimal dose fractionation remains undefined. WBRT following breast-conserving surgery for invasive breast cancer demonstrates equivalent efficacy and morbidity for conventional and hypofractionated treatment. Our group policy allowed for the use of both schedules, therefore we compared local control in women with DCIS following breast-conserving surgery. PATIENTS AND METHODS Two hundred and sixty-six patients treated between January 1999 and December 2004 with conventional (50Gy in 25 fractions) or hypofractionated (42.4Gy in 16 fractions or 40Gy/16+12.5Gy boost) WBRT after breast-conserving surgery for DCIS were retrospectively reviewed. Median follow-up was 3.76years (range 0.1-8.9 years). RESULTS One hundred and four patients (39%) were treated with conventional and 162 (61%) with hypofractionated WBRT. The median age was 56.7 years (range 32.2-83.8 years), and prognostic features were well matched in both groups, apart from a small increase in tumour size in the conventional arm (1.75 vs. 2.12 cm, p=0.05). Actuarial risk of recurrence at 4 years was 7% with hypofractionated WBRT and 6% with the conventional schedule (p=0.9). Univariate analysis showed an increased risk of recurrence with high nuclear grade tumours (11% at 4 years for grade 3 vs. 4% for grade 1/2, p=0.029). CONCLUSIONS Hypofractionated adjuvant WBRT following breast-conserving surgery for DCIS has comparable local control to a conventional radiation schedule. Hypofractionated WBRT is more convenient for patients, has equivalent morbidity and should be considered in this patient group.

Pelvic lymph node topography for radiotherapy treatment planning from ferumoxtran-10 contrast-enhanced magnetic resonance imaging.

PURPOSE To define a population-based pelvic lymph node clinical target volume (CTV) for radiotherapy treatment planning using magnetic resonance (MR) imaging and the ultrasmall superparamagnetic iron oxide lymph node contrast agent ferumoxtran-10. METHODS AND MATERIALS A total of 55 eligible patients with endometrial, cervical, prostate, or bladder cancer underwent MR imaging sessions before and after contrast administration on 2 consecutive days. Ferumoxtran-10 was administered immediately after the first scan. The three-dimensional spatial distribution of the pelvic lymph nodes was determined in relation to adjacent vessels and other musculoskeletal landmarks, from which guidelines for determining a nodal CTV in individual patients were developed. RESULTS On average, 30 lymph nodes (range, five to 62 nodes) were identified in each patient. The distribution of nodal distances to the closest artery or vein was observed to vary in different anatomic regions. Symmetrical three-dimensional margins of expansion around the distal para-aortic (12 mm), common iliac (10 mm), external iliac (9 mm), and internal iliac (10 mm) vessels, drawn in continuity with a 12-mm expansion anterior to the sacrum and a 22-mm expansion medial to the pelvic sidewall, were shown to encompass the majority of detectable lymph nodes in most patients. CONCLUSION Use of MR lymphography with ferumoxtran-10 provides an objective description of lymph node locations for radiotherapy planning. Use of this nodal CTV model in clinical practice could ensure a high probability of encompassing the regions at risk of harboring metastatic disease while minimizing the dose to adjacent normal tissues.

Phase II Trial of Palliative Radiotherapy for Hepatocellular Carcinoma and Liver Metastases

PURPOSE To evaluate the feasibility and response of liver radiotherapy (RT) in improving symptoms and quality of life in patients with hepatocellular carcinoma (HCC) or liver metastases (LM). PATIENTS AND METHODS Eligible patients had HCC or LM, unsuitable for or refractory to standard therapies, with an index symptom of pain, abdominal discomfort, nausea, or fatigue. The Brief Pain Inventory (BPI), Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep), and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) were completed by patients at baseline and each follow-up. The primary outcome was the percentage of patients with a clinically significant change at 1 month in the BPI subscale of symptom on average in the past 24 hours. Secondary outcomes were improvement in other BPI subscales and at other time points, FACT-Hep and EORTC QLQ-C30 at each follow-up, and toxicity at 1 week. RESULTS Forty-one patients (30 men and 11 women) with HCC (n = 21) or LM (n = 20) were accrued. At 1 month, 48% had an improvement in symptom on average in the past 24 hours. Fifty-two percent of patients had improvement in symptom at its worst, 37% at its least, and 33% now. Improvements in the FACT-G and hepatobiliary subscale were seen in 23% and 29% of patients, respectively, at 1 month. There were also improvements in EORTC QLQ-C30 functional (range, 11% to 21%) and symptom (range, 11% to 50%) domains. One patient developed grade 3 nausea at 1 week. CONCLUSION Improvements in symptoms were observed at 1 month in a substantial proportion of patients. A phase III study of palliative liver RT is planned. [Corrected]

Prospective Evaluation of Acute Toxicity and Quality of Life After IMRT and Concurrent Chemotherapy for Anal Canal and Perianal Cancer

PURPOSE A prospective cohort study was conducted to evaluate toxicity, quality of life (QOL), and clinical outcomes in patients treated with intensity modulated radiation therapy (IMRT) and concurrent chemotherapy for anal and perianal cancer. METHODS AND MATERIALS From June 2008 to November 2010, patients with anal or perianal cancer treated with IMRT were eligible. Radiation dose was 27 Gy in 15 fractions to 36 Gy in 20 fractions for elective targets and 45 Gy in 25 fractions to 63 Gy in 35 fractions for gross targets using standardized, institutional guidelines, with no planned treatment breaks. The chemotherapy regimen was 5-fluorouracil and mitomycin C. Toxicity was graded with the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. QOL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and CR29 questionnaires. Correlations between dosimetric parameters and both physician-graded toxicities and patient-reported outcomes were evaluated by polyserial correlation. RESULTS Fifty-eight patients were enrolled. The median follow-up time was 34 months; the median age was 56 years; 52% of patients were female; and 19% were human immunodeficiency virus-positive. Stage I, II, III, and IV disease was found in 9%, 57%, 26%, and 9% of patients, respectively. Twenty-six patients (45%) required a treatment break because of acute toxicity, mainly dermatitis (23/26). Acute grade 3 + toxicities included skin 46%, hematologic 38%, gastrointestinal 9%, and genitourinary 0. The 2-year overall survival (OS), disease-free survival (DFS), colostomy-free survival (CFS), and cumulative locoregional failure (LRF) rates were 90%, 77%, 84%, and 16%, respectively. The global QOL/health status, skin, defecation, and pain scores were significantly worse at the end of treatment than at baseline, but they returned to baseline 3 months after treatment. Social functioning and appetite scores were significantly better at 12 months than at baseline. Multiple dose-volume parameters correlated moderately with diarrhea, skin, and hematologic toxicity scores. CONCLUSION IMRT reduces acute grade 3 + hematologic and gastrointestinal toxicities compared with reports from non-IMRT series, without compromising locoregional control. The reported QOL scores most relevant to acute toxicities returned to baseline by 3 months after treatment.

Phase 1 Trial of Sorafenib and Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma

PURPOSE To determine the maximally tolerated dose of sorafenib delivered before, during, and after stereotactic body radiation therapy (SBRT) in hepatocellular carinoma (HCC). METHODS AND MATERIALS Eligible patients had locally advanced Child-Pugh class A HCC, showed Eastern Cooperative Oncology Group performance status 0-1, and were ineligible for standard local-regional therapies. Sorafenib was dose escalated in 2 strata: (1) low effective irradiated liver volume (veff) < 30% and (2) high veff 30%to 60%. Sorafenib (400 mg daily = dose level 1) was administered for 12 weeks, with 6 fractions SBRT delivered weeks 2 and 3, and escalation to full dose (400 mg twice daily) after 12 weeks as tolerated. Standard 3 + 3 cohorts with dose escalation of sorafenib were planned. RESULTS Sixteen patients (4 low veff, median dose 51 Gy; 12 high veff, median dose 33 Gy) were treated at 2 sorafenib dose levels. Of those patients 75% were had Barcelona Clinic Liver Cancer stage C, and 63% had main branch portal vein invasion. In the low veff stratum, no dose-limiting toxicities (DLTs) were observed in 4 patients treated with SBRT and sorafenib 400 mg. Inb the high veff stratum: 2 of 3 evaluable patients treated with sorafenib 400 mg experienced DLT (grade 3 large bowel bleed and grade 4 bowel obstruction 51 and 27 days, respectively, after SBRT). One of 6 evaluable patients at dose level -1 (200 mg once daily) experienced a grade 3 tumor rupture at week 5. Median overall survival and in-field local progression have not been reached. Worsening of Child-Pugh liver function class was seen in 6 of 12 patients in the high veff stratum. CONCLUSIONS Significant toxicity was observed in the high veff stratum, and concurrent SBRT with sorafenib is not recommended outside a clinical trial.

Automation and Intensity Modulated Radiation Therapy for Individualized High-Quality Tangent Breast Treatment Plans

PURPOSE To demonstrate the large-scale clinical implementation and performance of an automated treatment planning methodology for tangential breast intensity modulated radiation therapy (IMRT). METHODS AND MATERIALS Automated planning was used to prospectively plan tangential breast IMRT treatment for 1661 patients between June 2009 and November 2012. The automated planning method emulates the manual steps performed by the user during treatment planning, including anatomical segmentation, beam placement, optimization, dose calculation, and plan documentation. The user specifies clinical requirements of the plan to be generated through a user interface embedded in the planning system. The automated method uses heuristic algorithms to define and simplify the technical aspects of the treatment planning process. RESULTS Automated planning was used in 1661 of 1708 patients receiving tangential breast IMRT during the time interval studied. Therefore, automated planning was applicable in greater than 97% of cases. The time for treatment planning using the automated process is routinely 5 to 6 minutes on standard commercially available planning hardware. We have shown a consistent reduction in plan rejections from plan reviews through the standard quality control process or weekly quality review multidisciplinary breast rounds as we have automated the planning process for tangential breast IMRT. Clinical plan acceptance increased from 97.3% using our previous semiautomated inverse method to 98.9% using the fully automated method. CONCLUSIONS Automation has become the routine standard method for treatment planning of tangential breast IMRT at our institution and is clinically feasible on a large scale. The method has wide clinical applicability and can add tremendous efficiency, standardization, and quality to the current treatment planning process. The use of automated methods can allow centers to more rapidly adopt IMRT and enhance access to the documented improvements in care for breast cancer patients, using technologies that are widely available and already in clinical use.