TU-E-BRB-03: Biological Dose Optimization for SBRT of Lung Cancer: One Size Does Not Fit All.

PURPOSE: Given the differences in tumor size and location, encountered in lung SBRT, we hypothesize that 'one dose fractionation regimen does not fit all', i.e. that there is a role for patient-specific dose prescription based on optimization of biological models. METHODS: Sixty one NSCLC patients (tumor volume 46.5+/-47.3 cc) treated with stereotactic body radiotherapy (48 Gy in 4fx) were retrospectively studied. Clinically treated plans were generated using Brainlab's Pencil Beam (PB-BL), and then recalculated with fixed MUs using Anisotropic Analytic Algorithm (AAA), Pencil Beam (PB-EC), Monte Carlo (MC) and Collapsed-Cone-Convolution (CCC). DVHs were exported to calculate TCP (Poisson) and NTCP (Lyman-Kutcher-Burman). TCP/NTCP model parameters were utilized from published data. For each dose distribution two dose response curves were generated by scaling the prescription dose and assuming a linear relationship between the prescription dose and entire 3D dose distribution. In addition, associations were assessed between changes in each algorithm's TCP relative to PB-BL, target diameter, and local density (density of the 70% isodose covering the PTV). RESULTS: For PB-BL, mean TCP was 99.6%±0.9%, whereas for same MUs, mean TCP for PB-EC, AAA, CC and MC plans were 96.5±14.3%, 74.6±31.6%, 74.4±32.4% and 76.8±32.0%, respectively. With the same prescription dose for all plans, TCP values changed to 98.1±8.7%, 96.5±15.3%, 77.5±28.6%, 85.4±25.8% and 92.9±20.1% for PB-BL, PB-EC, AAA, and CCC, MC, respectively, indicating that AAA and CCC dose distributions are likely less homogeneous relative to MC. The TCP improvement was 12.3%, 8.9% and 4.4% for AAA, CCC and MC-based plans when the average NTCP before optimization was set as the upper limit for lung toxicity. CONCLUSIONS: This work supports patient-specific dose prescription strategies, based on biological optimization, for lung SBRT. However, further investigation is warranted. Acknowledgement: supported in part by a grant from Varian Medical Systems.

TU-E-BRB-10: Dosimetric Consequences of Setup Errors Using CBCT for SBRT Localization.

PURPOSE: Steep dose gradients and high dose per fraction in stereotactic ablative radiation therapy (SABR or SBRT) necessitate highly accurate tumor localization. This study evaluates inter-fraction shifts, as defined by couch correction analysis, and investigates the effect of tumor location and internal target volume (ITV) on these shifts. In addition, residual errors associated with post-CBCT correction and their dosimetric consequences were quantified. METHODS: Daily free-breathing (FB) CBCT images used for daily localization of 78 patients with non-small cell lung cancer were retrospectively evaluated. Among the population, 39 patients also received pre-treatment kV images after CBCT alignment. ITV inter-fraction displacement was evaluated by matching the CBCT and the FB helical CT images, and setup errors were quantified using orthogonal kV images. Associations between ITV location and inter-fraction motion were studied by categorizing tumors into the following locations: chest-wall seated (CWS) and island, peripheral, central, or upper, middle and lower. Dosimetric consequences for the patient with the largest setup error were explored. RESULTS: ITV inter-fraction motion included the mean of the systematic error, ?inter=(-1.4, 2.0, 1.6) mm, standard deviation (SD) of the systematic error, Σinter=(2.1, 4.2, 2.9) mm, and SD of random errors, sinter=(2.2, 3.2, 3.6) mm. No significant associations were observed between inter-fraction shifts and tumor location or volume. Using CBCT for image guidance reduced the observed errors to µsetup=(-0.3, 0.1, 0.0) mm, Σsetup=(0.6, 0.6, 0.4) mm and ssetup=(1.2, 0.7, 0.7) mm. Dosimetric consequences for the patient with the largest setup error were explored. It was shown that a 3.0 mm setup margin was sufficient to provide greater than 95% dose coverage to the ITV. CONCLUSION: CBCT image guidance reduced setup errors significantly such that 2-3 mm, population-based, setup margins provided proper dose coverage to the ITV. Further investigation of inter-and intrafraction error classification by tumor location is warranted.

SU-E-T-487: Spatial Assessment of Dose Distributions for Patients with Lung Cancer Treated with Stereotactic Ablative Radiotherapy (SABR).

PURPOSE: We hypothesize that PTV margin dose is an important factor for local tumor control. We evaluated dose distributions for patients originally treated with pencil-beam (PB)-based plans and retrospectively calculated with Monte Carlo (MC) method, with emphasis on the spatial region between the ITV and PTV (PTV-margin), where the largest dose differences were expected. METHODS: Forty-six stage I-II lung cancer patients with 51 lesions treated with SABR were retrospectively analyzed (23 central and 28 peripheral tumors). All patients received 4DCT imaging, and an ITV was generated from the maximum intensity projection and subsequent review of four 4DCT phases. An isotropic 3mm ITV-to-PTV margin was used. The iPlan TPS was used to generate the original treatment plans using PB-based heterogeneity correction. MC doses were recalculated using the same MUs as in the PB plan. Dose distributions for the ITV, PTV-margin, and PTV were analyzed using generalized equivalent uniform dose (gEUD) with a = - 20. Student's paired t-test elucidated differences between PB and MC-based gEUD and the two different tumor locations. RESULTS: Mean ITV and PTV volumes were 24.2 cc (range: 2.2 to 99.3 cc) and 50.4 cc (range: 6.4 to 229.7 cc), respectively. The mean gEUDs of ITV, PTV-margin and PTV, normalized to PB-based 100% isodose were 1.02+/-0.04, 1.01+/-0.04 and 1.01+/-0.04 for PB-based plans, compared to 0.94+/-0.06, 0.88+/-0.08 and 0.90+/-0.08 (all p<0.05) for MC-based plans. The maximum overestimations with the PB algorithm in the PTV-margin average dose were 10.4% and 19.6% (p < 0.05) for peripheral tumor cases and central tumor cases, respectively. CONCLUSIONS: PB-based dose distributions showed the highest dose overestimation (relative to MC) in the PTV-margin spatial region. Analysis of spatial dose differences is an important precursor toward assessment of patterns-of-local failure, to be investigated in future work to explore possible association between dose and regions of failure. Acknowledgement: supported in part by grants from NIH R01 CA106770 and from Varian Medical Systems.

SU-E-T-197: A Comprehensive Variance Reporting System and an Analysis of Variances Reported at Our Institution.

PURPOSE: It is essential for radiation oncology departments to have comprehensive patient safety and quality programs. Two years ago we undertook a systematic review of our safety/QA program. Existing policies were updated and new policies created where necessary. One crucial component of any safety/QA program is continually updating it based on current information, the 'check' and 'act' portions of the Deming Cycle. We accomplished this with a transparent variance reporting system and a safety/QA committee reviewing and acting on reported variances. METHODS: With 5 radiation oncology centers in our institution, we needed to devise a system that would allow anyone to report a variance and provide our QA committee the ability to review variances system-wide. We developed the system using web-based tools. The system allows individuals to report variances, anonymously or named, specify the nature of the variance and indicate the tools used to identify the variance. RESULTS: In 2011, 285 variances were reported, 102 were reported by physicists, 86 anonymously, 71 by therapists and 26 by dosimetrists. We realized the need to develop clear classifications for variances. We added a high priority category, defined as variances which resulted in or had the potential to result in harm to a patient or when a policy is purposely overridden. Of the 285 variances reported, 5 were high priority. We created a process variance category, defined as variances where a specific clinical process is not followed. Of the 285 reported variances 155 were process variances. CONCLUSIONS: Reporting of variances through a centralized database is central toward developing a robust patient safety/quality assurance program. Anonymous reporting fosters a non-punitive environment, and promotes the 'safety culture'. The goal of such a system is to review trends in clinical processes and ultimately to improve safety/quality by reducing variances associated with these processes.

Extracranial radiosurgery: immobilizing liver motion in dogs using high-frequency jet ventilation and total intravenous anesthesia.

PURPOSE: Extracranial radiosurgery requires control of organ motion. The purpose of this study is to quantitatively determine the extent of liver motion in anesthetized dogs with continuous i.v. propofol infusion with or without muscle relaxants and high-frequency jet ventilation. METHODS AND MATERIALS: Five dogs were used in the experiment. Each dog was restrained while anesthetized in the supine position using an alpha cradle. Surgical metal clips were implanted around the liver periphery so that its motion could be visualized using a fluoroscopic imaging device in a conventional simulator. Initially, two orthogonal simulation films were taken to correlate locations of implanted clips. Two orthogonal views of fluoroscopic images for each anesthetized dog were recorded on a magnetic tape and analyzed from the post-imaging data. Liver motion was documented under the following three conditions: 1) ventilated with a conventional mechanical ventilator, 2) ventilated with a high-frequency jet ventilator, and 3) ventilated with a high-frequency jet ventilator and total muscle paralysis (with vecuronium injection). The maximum liver motion for each dog was analyzed in three orthogonal directions: the inferior-to-superior direction, the anterior-to-posterior direction, and the right-to-left direction. RESULTS: When the anesthetized dogs were ventilated with a conventional mechanical ventilator, the average liver motions were 1.2 cm in the inferior-to-superior direction, 0.4 cm in the anterior-to-posterior direction, and 0.2 cm in the right-to-left direction, respectively. After the introduction of high-frequency jet ventilation, the average liver motions were reduced to 0.2 cm in the inferior-to-superior direction, 0.2 cm in the anterior-to-posterior direction, and 0.1 cm in the right-to-left direction. The maximum liver motion was dependent on ventilator settings. There was no additional measurable motion reduction with the addition of the muscle relaxant. CONCLUSION: The liver motion in each anesthetized dog was controlled under 3.0 mm in all directions with the use of high-frequency jet ventilation. No detectable advantage was identified by the injection of muscle relaxant in terms of further reducing the liver motion. The preclinical animal study indicated that the use of high-frequency jet ventilation (HFJV) would be able to limit the liver motion to an extent acceptable for the application of extracranial radiosurgery in humans. Radiosurgery for localized liver tumors warrants further investigation.

The role of radiation therapy in the adjuvant treatment of rectal cancer.

There have been several advances in the treatment of rectal cancer in the past 20 years. The recognition that surgical therapy alone leads to a local failure rate of 15 to 50% in stages II and III has led to the use of adjuvant radiation therapy. Multiple prospective, randomized trials conducted by multi-institutional cooperative groups have resulted in the use of adjuvant combined modality therapy using radiation therapy and 5-fluorouracil chemotherapy. Some of the trials fine-tuned the sequencing and dose of radiation and chemotherapy to maximize efficacy and minimize toxicity. The advent of accurate endorectal ultrasound and MRI staging has allowed the use of preoperative therapy without the unnecessary treatment of patients with early stage. This has resulted in greater sphincter preservation and fewer complications. The optimal sequencing of adjuvant therapy has yet to be found.

Staging laparoscopy promotes increased utilization of postoperative therapy for unresectable intra-abdominal malignancies.

Staging laparoscopy avoids unnecessary laparotomies in patients with unresectable intra-abdominal malignancies. However, the postoperative oncologic treatment of these patients has not been documented. This study compares rates and timing of postoperative chemotherapy (ChT) and/or radiation therapy (XRT) in patients with unresectable intra-abdominal malignancies initially evaluated by staging laparoscopy (SL) or exploratory laparotomy (EL). The records of patients surgically evaluated for esophageal, gastric, hepatobiliary, and pancreatic cancers or abdominal lymphoma were retrospectively reviewed. Data gathered included type of exploration (SL or EL), resectability, whether postoperative cancer treatment was given (ChT, XRT, or both), and the time from surgery to the beginning of such treatment. This study includes only patients with unresectable malignancies. Twenty-one patients underwent SL and 58 EL. Sixteen of the SL patients (76%) and 25 of the EL patients (43%) received postoperative cancer treatment (P = 0.009). The median number of days from surgery to postoperative cancer treatment was 13 days (range 5 to 41 days) for the SL group and 35 days (range 16 to 89 days) for the EL group (P = 0.0004). We conclude that patients with unresectable intra-abdominal malignancies discovered by SL are more likely to receive postoperative ChT and/or XRT than patients surgically evaluated by EL. Further studies to determine whether this better utilization of postoperative treatment results in better outcomes in these patients are needed.

Adenocarcinoma of the head of the pancreas: effects of surgical and nonsurgical therapy on survival--a ten-year experience.

A retrospective analysis of all patients treated for adenocarcinoma of the head of the pancreas from 1989 to 1998 was performed. Excluded were cancers in the body and tail, cystic neoplasms, ampullary tumors, and cancers of the duodenum and bile ducts. One hundred forty-five patients were reviewed, and 43 patients underwent pancreaticoduodenectomy. Data collected included the stage, lymph node status, surgical margins, adjuvant therapies, and survival. Statistical analysis was performed with Cox's Proportional Hazards Analysis and Log-Rank Life Table Analysis. The surgical population had a 21 per cent 3-year survival rate and a 7 per cent operative mortality rate. Median survival was: 1) the resection group versus no resection was 13.5 versus 3.1 months; 2) adjuvant therapy versus no therapy after resection was 16.1 versus 5.1 months; and 3) chemoradiation therapy versus no therapy for unresectable disease was 5.3 versus 1.8 months. The presence of positive surgical margins was found in 33 per cent of the surgical specimens and carried an increased mortality hazard ratio of 3.1. Patients with negative lymph nodes had a 15 per cent 5-year survival, versus 0 per cent with positive nodes. Seventy-three per cent of those resected had a T2 lesion, and 46 per cent of patients presented with metastatic disease. Surgical resection and adjuvant therapy significantly improves survival in patients with adenocarcinoma of the head of the pancreas. All patients who underwent resection as part of their therapy showed extended survival compared with chemoradiation therapy alone. Adjuvant chemoradiation improved survival when compared with surgery alone. Multimodality treatment in carcinoma of the head of the pancreas provides the best treatment option. However, better adjuvant therapies are needed.

Radiation-induced Proctitis.

The incidence of chronic, radiation-induced proctitis is between 2% and 5 %. There is not a direct relationship between the incidence of acute radiation proctitis and the subsequent development of chronic proctitis. The treatment for this condition should proceed in a step-wise fashion from conservative therapy such as antidiarrhea medication, topical steroids, sucralfate enemas, and iron replacement to more aggressive treatment in those who do not respond. In the case of persistent rectal bleeding, laser therapy and formalin instillation should be tried prior to surgical intervention. If surgery is necessary, a transverse or descending colostomy should be tried. Aggressive surgery such as rectal resection and colo-anal anastomosis is associated with significant morbidity and mortality and should be reserved as a last resort measure.

Accelerated-interrupted radiation therapy given concurrently with chemotherapy for locally advanced non-small cell lung cancer.

PURPOSE: To evaluate the efficacy of multidrug chemotherapy combined with accelerated radiation therapy in the treatment of localized but unresectable non-small cell lung cancer. PATIENTS AND METHODS: Between September 1990 and February 1993, 35 patients with Stage III (15 IIIA & 20 IIIB) non-small cell lung cancer were entered on a protocol using combined accelerated radiation therapy and chemotherapy. Radiation therapy consisted of 55.6 Gy in 30 fractions (1.8 Gy bid for 5 consecutive days given in 3 weeks [total of 15 days], every other week). Chemotherapy consisted of cisplatin (10 mg/m2), vinblastine (4 mg/m2), 6-thioguanine (40 mg bid), and 5-fluorouracil (400 mg/m2 as continuous infusion) given concomitantly with radiation therapy. Approximately 3 weeks following completion of radiation therapy, two cycles of consolidation chemotherapy were given, consisting of two doses of cisplatin (120 mg/m2) 4 weeks apart and six doses of vinblastine (4 mg/m2) given on two consecutive days every other week for 3 weeks. RESULTS: Six patients were still alive at last follow-up; for them the median follow-up time is 47 months (range, 39-55.8). The median survival time is 17.5 months. The 1-, 2-, 3- and 4.5-year survival rates are 69%, 37%, 20% and 17%, respectively. Overall response rate is 63%, with 51.5% partial response and 11.5% complete response rates. Esophagitis occurred as follows: Grade 4 = 0, Grade 3 = 1, Grade 2 = 6, and Grade 1 = 13. No patient developed Grade 3 or 4 acute respiratory toxicity. Significant hematologic toxicity occurred as follows: 37% Grade 3 and 31% Grade 4 leukopenia. Radiation pneumonitis occurred in two patients. DISCUSSION: The regimen tested in this protocol appears to be very well tolerated with minimal pulmonary or esophageal toxicity. This, coupled with the shortened course of radiation therapy and the ability to deliver the combined radiation and chemotherapy portion of the treatment on an outpatient basis most of the time, has made multi-modality treatment for this malignancy much easier and more convenient for patients. In addition, the favorable survival in this group of patients with locally advanced disease is very encouraging and warrants further study.

Results of abdominoperineal resections for failures after combination chemotherapy and radiation therapy for anal canal cancers.

Thirty patients treated with combination chemotherapy (CT) and radiation therapy (RT) for anal canal carcinoma were reviewed retrospectively to analyze the results of abdominoperineal resection (APR) for treatment failures. Mean follow-up was 34.9 months. Twenty-four patients had squamous carcinomas, and six had cloacogenic carcinomas. Twenty-five had negative inguinal lymph nodes, and five had positive inguinal lymph nodes. The group received 5-fluorouracil, mitomycin C, and 30 to 50 Gy of RT. Biopsy was obtained at six weeks posttherapy. Seventeen of 22 patients (77 percent) with primary tumors of less than 5 cm and negative nodes were disease free at 37 months post-CT-RT. None of the seven patients with primary tumors of greater than 5 cm or positive nodes were free of disease. APR was done for positive biopsy in eight patients and for local recurrence (disease detected after six months of treatment) in one patient. Eight of nine patients who had APR died of disease (mean, 20 months), and one of nine died of other causes. A review of published series, including our data, reveals 24 cases of APR post-CT-RT for positive biopsy, with 17 of 24 (71 percent) dead of disease within three years. APR for CT-RT failures has a poor prognosis. Future protocols may determine whether further CT-RT will improve survival. APR for palliation should always remain an option.

Concomitant radiation therapy and constant infusion FUdR for unresectable hepatic metastases.

Ten patients with unresectable liver metastases from intraabdominal primary malignancies were treated with combined hepatic irradiation and hepatic artery infusion with FUdR using an Infusaid pump. The median survival for the entire group was 10 months. Four (40%) demonstrated an objective response to treatment: Three patients had a decrease in tumor mass on computed tomography (CT) scan, and one patient had a reduction in liver size as measured by palpation. The survival of two of the three patients whose tumor size was observed to be reduced on CT scan was significantly longer than that of the rest of the group (23, 37, and 12 months). Treatment was generally well tolerated with only mild side effects. Morbidity from chemotherapy did not appear to be enhanced by combination with hepatic irradiation. This form of treatment, although it has not demonstrated improved survival compared with other treatments in this setting, may be considered for adjuvant therapy in patients with hepatic metastases.

Role of brachytherapy in the management of pulmonary and mediastinal malignancies.

Brachytherapy, the permanent or temporary implantation of radioactive sources, has been performed in limited numbers of patients with lung cancer over the last 50 years. Because of renewed interest in this modality, we reviewed our experience with 103 patients treated over a 7-year period. The mean age of this group was 55.5 years (range, 1 to 84 years). Primary lung cancer accounted for 82 patients (79.6%); metastatic lesions to the lung, 13 (12.6%); and mediastinal malignancies, 8 (7.8%). Indications for brachytherapy included mediastinal and chest wall invasion in 42 patients (40.8%), unresectable tumors and mediastinal adenopathy in 30 (29.1%), medical contraindications to extensive pulmonary resection in 20 (19.4%), and irradiation of excised lymph node beds in 11 (10.7%). Seeds labeled with radioactive iodine 125 alone were used in 65 patients (63.1%), afterloading catheters containing iridium 192 sources in 25 (24.3%), and both in 13 (12.6%). There were no operative deaths. With a mean follow-up of 18.6 months, the mean and median survivals for the entire group were 17.3 and 14.0 months, respectively. The 1-year, 2-year, and 3-year survivals for the entire group were 67.9%, 38.7%, and 27.8%, respectively. In summary, brachytherapy offers a useful surgical approach in patients in whom unresectable pulmonary or mediastinal malignancies are found at the time of thoracotomy or in patients previously treated with other modalities for whom limited therapeutic alternatives exist.

Review of recent experience in the treatment of carcinoma of the anal canal.

A retrospective study was conducted for evaluation for the therapeutic efficacy of the various modalities for treatment of carcinoma of the anal canal. Thirty-seven patients were reviewed. Patients commonly presented in their sixth decade of life and a four-fold predominance of women was noted. Tumor histopathology was of little relevance in determining prognosis. Surgery alone was performed on 15 patients, consisting of either abdominoperineal resection or wide excision. Multidisciplinary therapy as described by Nigro et al., 10-12 which included preoperative chemotherapy and radiation followed by surgery within a period of 4-6 weeks, was used to treat 13 patients. Radiation alone or in combination with surgery was used to treat six patients. One patient refused further treatment following radiation and chemotherapy, and the remaining two patients refused treatment from the onset. There was no difference in survival in Stages O and I patients when treated by surgery alone or with the Nigro protocol. However, Stages II and III patients had a more favorable outcome when treated by the Nigro protocol than by any other regimen. Thirteen of 21 patients treated by surgery and/or radiation therapy developed recurrence, resulting in seven deaths. Three out of 13 patients treated by the Nigro protocol developed recurrence, all of whom are alive and well following salvage treatment. Despite its infrequent use, a favorable trend is noted as a result of utilizing the multimodality protocol, particularly in patients with invasive disease.