Single-Fraction Stereotactic Ablative Body Radiotherapy to the Lung - The Knockout Punch.

This overview summarises the current evidence on efficacy and safety of single-fraction stereotactic ablative body radiotherapy (SABR) for primary lung cancers and lung metastases, in comparison with the more widely adapted multi-fraction SABR regimens. A literature search using the Medline database through PubMed was carried out using the following key words: ('stereotactic' or 'sabr' or 'sbrt'), ('radiotherapy' or 'radiation therapy'), ('lung' or 'thorax' or 'thoracic' or 'chest'), ('cancer' or 'metasta-' or 'oligometasta-'), alongside: (i) ('single-fraction' or 'single-dose') to identify trials and cohort studies with single-fraction SABR to lung malignant tumours and (ii) ('fraction' or 'schedule') limiting the search to 'clinical trial' and 'randomized controlled trial' to ensure thorough capture of lung SABR trials comparing different fractionations. The review discusses the radiobiological, technical and organ at risk considerations of single-fraction SABR to the lung.

Gefitinib in definitive management of esophageal or gastroesophageal junction cancer: a retrospective analysis of two clinical trials.

The role of epidermal growth factor receptor inhibition in resectable esophageal/gastroesophageal junction (E/GEJ) cancer is uncertain. Results from two Cleveland Clinic trials of concurrent chemoradiotherapy (CCRT) and surgery are updated and retrospectively compared, the second study differing only by the addition of gefitinib (G) to the treatment regimen. Eligibility required a diagnosis of E/GEJ squamous cell or adenocarcinoma, with an endoscopic ultrasound stage of at least T3, N1, or M1a (American Joint Committee on Cancer 6th). Patients in both trials received 5-fluorouracil (1000 mg/m(2) /day) and cisplatin (20 mg/m(2) /day) as continuous infusions over days 1-4 along with 30 Gy radiation at 1.5 Gy bid. Surgery followed in 4-6 weeks; identical CCRT was given 6-10 weeks later. The second trial added G, 250 mg/day, on day 1 for 4 weeks, and again with postoperative CCRT for 2 years. Preliminary results and comparisons have been previously published. Clinical characteristics were similar between the 80 patients on the G trial (2003-2006) and the 93 patients on the no-G trial (1999-2003). Minimum follow-up for all patients was 5 years. Multivariable analyses comparing the G versus no-G patients and adjusting for statistically significant covariates demonstrated improved overall survival (hazard ratio [HR] 0.64, 95% confidence interval [CI] = 0.45-0.91, P = 0.012), recurrence-free survival (HR 0.61, 95% CI = 0.43-0.86, P = 0.006), and distant recurrence (HR 0.68, 95% CI = 0.45-1.00, P = 0.05), but not locoregional recurrence. Although this retrospective comparison can only be considered exploratory, it suggests that G may improve clinical outcomes when combined with CCRT and surgery in the definitive treatment of E/GEJ cancer.

Clinicopathologic features and treatment outcomes of patients with human epidermal growth factor receptor 2-positive adenocarcinoma of the esophagus and gastroesophageal junction.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 21% of gastric and 33% of gastroesophageal junction (GEJ) adenocarcinomas. Trastuzumab has been approved for metastatic HER2-positive gastric/GEJ cancer in combination with chemotherapy. This retrospective analysis was undertaken to better define the clinicopathologic features, treatment outcomes, and prognosis in patients with HER2-positive adenocarcinoma of the esophagus/GEJ. Pathologic specimens from 156 patients with adenocarcinoma of the esophagus/GEJ treated on clinical trials with chemoradiation and surgery were tested for HER2. Seventy-six patients also received 2 years of gefitinib. Baseline characteristics and treatment outcomes of the HER2-positive and negative patients were compared both in aggregate and separately for each of the two trials. Of 156 patients, 135 had sufficient pathologic material available for HER2 assessment. HER2 positivity was found in 23%; 28% with GEJ primaries and 15% with esophageal primaries (P= 0.10). There was no statistical difference in clinicopathologic features between HER2-positive and negative patients except HER2-negative tumors were more likely to be poorly differentiated (P < 0.001). Locoregional recurrence, distant metastatic recurrence, any recurrence, and overall survival were also statistically similar between the HER2-positive and the HER2-negative groups, in both the entire cohort and in the gefitinib-treated subset. Except for tumor differentiation, HER2-positive and negative patients with adenocarcinoma of the esophagus and GEJ do not differ in clinicopathologic characteristics and treatment outcomes. Given the demonstrated benefit of trastuzumab in HER2-positive gastric cancer and the similar incidence of HER2 overexpression in esophageal/GEJ adenocarcinoma, further evaluation of HER2-directed therapy in this disease seems indicated.

SU-E-T-486: Volume and Location Dependence on the Difference Between Monte Carlo and Pencil Beam Dose Calculations for Lung Stereotactic Body Radiation Therapy.

PURPOSE: Stereotactic body radiotherapy has been an efficacious treatment modality for early stage non-small cell lung cancer. The accuracy of dose calculations is in question due to the presence of inhomogeneity. It was required in several clinical trials to calculate dose without heterogeneity correction. However, to better correlate the outcomes with the planned dose, accurate dose calculation with heterogeneity correction is highly desirable. METHODS: We compared the recalculated dose with Monte Carlo (MC) algorithm to the original Pencil Beam (PB) calculations for clinical lung SBRT plans. Thirty-one clinical plans that followed protocol guidelines were retrospectively investigated. Dosimetric parameters D1, D95 and D99 for the PTV and D1 for organs at risk were compared. Correlations of mean lung dose and V20 of lungs between two calculations were investigated. RESULTS: Compared to the PB calculations without heterogeneity correction in clinical plans, we found that in terms of D95 of PTV, (1) the two calculations resulted in similar D95 for edge tumors with volumes greater than 25.1cc; (2) an average overestimation of 5% in PB calculations for edge tumors with volumes less than 25.1cc; and (3) an average overestimation of 9% or underestimation of 3% in PB calculations for island tumors with volumes smaller or greater than 22.6 cc, respectively. With heterogeneity correction, the PB calculation resulted in an average reduction of 23.8% and 15.3% in D95 for island and edge lesions respectively compared to the MC calculation. For organs at risks, no clinical meaningful differences were found among all the comparisons. Excellent correlations for mean dose and V20 of lungs were observed between the two calculations. CONCLUSIONS: Using a single scaling factor to account for the differences in using heterogeneity correction may not be sufficient. To understand dose-response relation in Lung SBRT, accurate dose calculation such as the Monte Carlo algorithms is highly recommended.

SU-E-J-10: Accuracy of Image Guidance Using Cone-Beam CT with Multiple Breath Hold Using Active Breathing Coordination.

PURPOSE: To complete a CBCT for a treatment using ABC, multiple breath hold (BH) (>3) were used due to the slow gantry rotation and the short BH period. Inter-BH tumor position variability may introduce distortion in the reconstructed images. This study aims to determine a threshold of the inter-BH scan displacement so that the inconsistency can be identified from the CBCT images. METHODS: A numerical phantom was constructed to represent the thorax region of a human body. To simulate the inter-BH displacements, known magnitudes of motion (s = 0, 1, 3, 5 mm) along the longitudinal direction were introduced for the 'tumor' and 'diaphragm' in the phantom. Two different irregular motion patterns (s1=s3=/=s2 and s1=/=s2=/=s3) during CBCT scans were tested. Furthermore, a physical phantom with a movable insert was scanned using a commercial CBCT system. The insert of the phantom was programmed to move in the longitudinal direction according to the same motion patterns as designed in the numerical simulations. Subsequently, nine CBCT's in 'half-fan' mode for the physical phantom were acquired with the insert in various positions. These CBCT images were then fused to the reference CT by aligning to either the body of the phantom or the 'tumor' inside the insert. RESULTS: Based on numerical simulation, position variation >1mm can be observed from the reconstructed CBCT images. Based on acquired CBCTs of the physical phantom, position variations of >3mm or 5mm were observed, depending on the motion pattern during the data acquisition. Because of the use of half-fan mode, we observed the order of position displacements of the tumor during CBCT acquisition drastically affected the outcome of imaging registration. CONCLUSIONS: Using ABC device, the inter-BH variability during a CBCT acquisition affects accuracy of tumor localization. A patient individualized planning margin might be necessary to account for this effect.

Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01).

BACKGROUND: We recently published the results of the PCI99 randomised trial comparing the effect of a prophylactic cranial irradiation (PCI) at 25 or 36 Gy on the incidence of brain metastases (BM) in 720 patients with limited small-cell lung cancer (SCLC). As concerns about neurotoxicity were a major issue surrounding PCI, we report here midterm and long-term repeated evaluation of neurocognitive functions and quality of life (QoL). PATIENTS AND METHODS: At predetermined intervals, the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and brain module were used for self-reported patient data, whereas the EORTC-Radiation Therapy Oncology Group Late Effects Normal Tissue-Subjective, Objective, Management, Analytic scale was used for clinicians' assessment. For each scale, the unfavourable status was analysed with a logistic model including age, grade at baseline, time and PCI dose. RESULTS: Over the 3 years studied, there was no significant difference between the two groups in any of the 17 selected items assessing QoL and neurological and cognitive functions. We observed in both groups a mild deterioration across time of communication deficit, weakness of legs, intellectual deficit and memory (all P < 0.005). CONCLUSION: Patients should be informed of these potential adverse effects, as well as the benefit of PCI on survival and BM. PCI with a total dose of 25 Gy remains the standard of care in limited-stage SCLC.

Implant volume as a prognostic variable in brachytherapy decision-making for malignant gliomas stratified by the RTOG recursive partitioning analysis.

PURPOSE: When an initial retrospective review of malignant glioma patients (MG) undergoing brachytherapy was carried out using the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) criteria, it revealed that glioblastoma multiforme (GBM) cases benefit the most from implant. In the present study, we focused exclusively on these GBM patients stratified by RPA survival class and looked at the relationship between survival and implanted target volume, to distinguish the prognostic value of volume in general and for a given GBM class. METHODS AND MATERIALS: Between 1991 and 1998, 75 MG patients were treated with surgery, external beam radiation, and stereotactic iodine-125 (I-125) implant. Of these, 53 patients (70.7%) had GBMs, with 52 (98%) having target volume (TV) data for analysis. Stratification by RPA criteria showed 12, 26, 13, and 1 patients in classes III to VI, respectively. For analysis purposes, classes V and VI were merged. There were 27 (51.9%) male and 25 (48.1%) female patients. Mean age was 57.5 years (range 14-79). Median Karnofsky performance status (KPS) was 90 (range 50-100). Median follow-up time was 11 months (range 2-79). RESULTS: At analysis, 18 GBM patients (34.6%) were alive and 34 (65.4%) were dead. Two-year and 5-year survivals were 42% and 17.5%, respectively, with a median survival time (MST) of 16 months. Two-year survivals and MSTs for the implanted GBM patients compared to the RTOG database were as follows: 74% vs. 35% and 28 months vs. 17.9 months for class III; 32% vs. 15% and 16 months vs. 11.1 months for class IV; 29% vs. 6% and 11 months vs. 8.9 months for class V/VI. Mean implanted TV was 15.5 cc (range 0.8-78), which corresponds to a spherical implant diameter of 3.1 cm. Plotting survival as a function of 5-cc TV increments suggested a trend toward poorer survival as the implanted volume increases. The impact of incremental changes in TV on survival within a given RPA class of GBMs was compared to the RTOG database. Looking at absolute differences in MSTs: for classes III and IV, there was little effect of different TVs on survival; for class V/VI, a survival benefit to implantation was still seen at the target volume cutoff (TV > 25 cc). Within a given RPA class, no significant differences were found within class III; for class IV, the most significant difference was at 10 cc (p = 0.05); and for class V/VI, at 20 cc (p = 0.06). CONCLUSION: For all GBM patients, an inverse relationship between implanted TV size and median survival is suggested by this study. However, when GBM patients are stratified using the RTOG's RPA criteria, the prognostic effect of implant volume disappears within each RPA survival class. At the critical volume of 25 cc, which approximates an implant of 5-cm diameter (upper implantation limit of many CNS brachytherapy protocols), the "poorest" prognosis GBM patients stratified by RPA still demonstrate a survival benefit with implant. We suggest that any GBM patient meeting brachytherapy recognized size criteria be considered for I-125 implant.

Using treatment interruptions to palliate the toxicity from concurrent chemoradiation for limited small cell lung cancer decreases survival and disease control.

BACKGROUND AND PURPOSE: We analyzed the impact on survival outcomes of treatment interruptions due to toxicity arising during the concurrent phase of chemotherapy/radiotherapy (ChT/RT) for our limited-stage small-cell cancer (LSCLC) population over the past 10 years. MATERIALS AND METHODS: From 1989 to 1999, 215 patients received treatment for LSCLC, consisting of six cycles of alternating cyclophosphamide/doxorubicin or epirubicin/vincristine (CAV; CEV) and etoposide/cisplatin (EP). Thoracic RT was started with EP at either the second or third cycle (85% of patients). RT dose was either 40 Gy in 15 fractions over 3 weeks or 50 Gy in 25 fractions over 5 weeks, delivered to a target volume encompassing gross disease and suspected microscopic disease with a 2 cm margin. Treatment breaks arising during concurrent ChT+RT were used to manage severe symptomatic or hematologic toxicities. We used the interruptions in thoracic RT as the 'marker' for any concurrent break and measured 'break duration' by the total length of time (in days) RT was interrupted, since that also signaled that ChT could be re-initiated. Patient results were analyzed for the impact of interruptions/treatment prolongation on overall and disease-free survival. RESULTS: For all patients, 2-year and 5-year overall and disease-specific survivals were 22.7 and 7.2, 27.6 and 9.3%, respectively; overall and disease-specific median survivals were 14.7 months each. A total of 56 patients (26%) had treatment breaks due to toxicity. Hematologic depression caused the majority of breaks (88%). The median duration of breaks was 5 days (range 1-18). Patients with and without interruptions were compared for a range of prognostic factors and were not found to have any significant differences. Comparing interrupted/uninterrupted courses, median survivals were 13.8 versus 15.6 months, respectively, and 5-year overall survivals were 4.2 versus 8.3%, respectively. There was a statistical difference between overall survival curves which favored the uninterrupted group (P=0.01). When comparing a series of prognostic variables, multivariable analysis found that the most significant factor influencing survival in the present study was the presence of treatment breaks (P=0.006). There was a trend for development of any recurrence in the patients with breaks (P=0.08). When controlling for the use of prophylactic cranial irradiation (PCI) in the two groups, the rate of failure in the chest was higher in the patients with RT breaks (58 vs. 33%). The rate of failure in the brain was dependent on the use of PCI only. CONCLUSIONS: Interruptions in treatment to palliate the toxicity from concurrent chemoradiation result in poorer local control and decreased survival.

HIV complicates the management of oncological emergencies: a case involving the superior vena cava syndrome.

An association exists between human immunodeficiency virus (HIV) and an increased incidence of lung cancer. Superior vena cava syndrome (SVCS) is an oncological emergency seen in the presence of chest tumours. We report on an otherwise well HIV-positive male who presented with SVCS due to lung cancer. He was commenced on dexamethasone and radiotherapy with curative intent. Treatment was complicated by accelerated steroid- and radiation-induced morbidity. The patient died of disseminated aspergillosis after receiving 27 of 35 planned radiotherapy fractions. The management of SVCS in those with HIV is challenging and requires the judicious use of steroids, antifungal prophylaxis and palliative radiotherapy doses.

Use of the RTOG recursive partitioning analysis to validate the benefit of iodine-125 implants in the primary treatment of malignant gliomas.

PURPOSE: To date, numerous retrospective studies have suggested that the addition of brachytherapy to the conventional treatment of malignant gliomas (MG) (surgical resection followed by radiotherapy +/- chemotherapy) leads to improvements in survival. Two randomized trials have suggested either a positive or no survival benefit with implants. Critics of retrospective reports have suggested that the improvement in patient survival is due to selection bias. A recursive analysis by the RTOG of MG trials has stratified MG patients into 6 prognostically significant classes. We used the RTOG criteria to analyze the implant data at Wayne State University to determine the impact of selection bias. METHODS AND MATERIALS: Between July 1991 and January 1998, 75 patients were treated with a combination of surgery, radiotherapy, and stereotactic I-125 implant as primary MG management. Forty-one (54.7%) were male; 34 (45.3%) female. Median age was 52 years (range 4-79). Twenty-two (29.3%) had anaplastic astrocytoma (AA); 53 (70.7%), glioblastoma multiforme (GBM). Seventy-two patients had data making them eligible for stratification into the 6 RTOG prognostic classes (I-VI). Median Karnofsky performance status (KPS) was 90 (range 50-100). There were 14, 0, 14, 31, 12, and 1 patients in Classes I to VI, respectively. Median follow-up time for AA, GBM, and any surviving patient was 29, 12.5, and 35 months, respectively. RESULTS: At analysis, 29 (40.3%) patients were alive; 43 (59.7%), dead. For AA and GBM patients, 2-year and median survivals were: 58% and 40%; 38 and 17 months, respectively. For analysis purposes, Classes I and II, V and VI were merged. By class, the 2-year survival for implanted patients compared to the RTOG data base was: III--68% vs. I--76%; III--74% vs. 35%; IV--34% vs. 15%; V/VI--29% vs. V--6%. For implant patients, median survival by class was (in months): I/II--37; III--31; IV--16; V/VI--11. CONCLUSION: When applied to MG patients receiving permanent I-125 implant, the criteria of the RTOG recursive partitioning analysis are a valid tool to define prognostically distinct survival groups. As reflected in the RTOG study, a downward survival trend for the implant patients is seen from "best to worse" class patients. Compared to the RTOG database, median survival achieved by the addition of implant is improved most demonstrably for the poorer prognostic classes. This would suggest that selection bias alone does not account for the survival benefit seen with I-125 implant and would contradict the notion that the patients most eligible for implant are those gaining the most benefit from the treatment. In light of the contradictory results from two randomized studies and given the present results, further randomized studies with effective stratification are required since the evidence for a survival benefit with brachytherapy (as seen in retrospective studies) is substantial.

Hyperbaric oxygen corrects sacral plexopathy due to osteoradionecrosis appearing 15 years after pelvic irradiation.

In 1982, a 55-year-old woman was treated by total cystectomy and adjuvant radiotherapy/chemotherapy for a leiomyosarcoma of the bladder. Fifteen years later she presented with symptoms and signs of sacral plexopathy. Investigations revealed osteoradionecrosis of the sacrum. Hyperbaric oxygen therapy (HBO2) was instituted and progressive resolution of the neurological complaints followed. HBO2 should be considered when managing late-onset sequelae in previously irradiated patients.

Preoperative radiation with concurrent 5-fluorouracil continuous infusion for locally advanced unresectable rectal cancer.

BACKGROUND AND PURPOSE: To determine the percentage of complete responders and the resectability rate for patients with locally advanced carcinoma of the rectum treated by 5-fluorouracil (5-FU) infusional chemotherapy and pelvic radiation. MATERIALS AND METHODS: Between October 1992 and June 1996, 29 patients with a diagnosis of locally advanced unresectable rectal cancer received preoperative 5 FU by continuous intravenous infusion at a dose of 225 mg/m2/day concurrent with pelvic radiation (median 54 Gy/28 fractions). All patients were clinical stage T4 on the bases of organ invasion or tumor fixation. Median time for surgical resection was 6 weeks. RESULTS: Median follow-up for the group was 28 months (range 5-57 months). Six patients were felt to be persistently unresectable or developed distant metastases and did not undergo surgical resection. Of the 29 patients, 23 proceeded to surgery, 18 were resectable for cure, 13 by abdominoperineal resection, 3 by anterior resection and 2 by local excision. Of the 29 patients, 4 (13%) had a complete response, and 90% were clinically downstaged. Of the 18 resected patients, 1 has died of his disease, 17 are alive, and 15 disease-free. The regimen was well tolerated; there was only one treatment-related complication, a wound dehiscence. CONCLUSION: The combination of 5 FU infusion and pelvic radiation in the management of locally advanced rectal cancer is well tolerated and provides a baseline for comparison purposes with future combinations of newer systemic agents and radiation.

Hypercalcemia and carcinoma of the penis.

Hypercalcemia is the most common metabolic disorder associated with malignancies. Squamous cell carcinoma of the penis is a tumor for which this abnormality has rarely been described. This report presents a case of hypercalcemia seen in a patient with advanced penile cancer. A chemotherapy regimen of intravenous cisplatin and fluorouracil caused regression of the primary tumor and normalization of the serum calcium. A literature review supported an association between squamous cell carcinoma of the penis and hypercalcemia.

A case of melanoma concurrent with progressive systemic sclerosis.

The association between progressive systemic sclerosis (PSS; scleroderma) and malignancy has been a controversial issue in the literature. The present report describes a rare case of concurrent malignant melanoma and PSS. A literature review suggests a possible connection between these two conditions.

Sensitivity of BB rat beta cells as determined by dose-responses to the cytotoxic effects of streptozotocin and alloxan.

BB rats of diabetes-prone lines develop a spontaneous Type 1 diabetic syndrome, with many immunological concomitants. No data are available as to the integrity of their islet beta cells prior to onset of the insulitis which proceeds to their selective destruction. We tested the effects of the beta-cytotoxins streptozotocin and alloxan on such rats, compared to Wistar and to non diabetes-prone BB control rats studied prior to usual age of diabetes onset. A dose-response of a single injection of the agents with respect to pancreatic insulin content 48 hr post-injection as well as to circulating insulin and glucose, weight, and lymphocyte counts was established. Clear dose-responses were found for pancreatic insulin content. Though less sensitive, plasma insulin and glucose values showed responses. Whereas some litters of diabetes-prone rats showed greater reductions of pancreatic insulin than controls after some doses of streptozotocin, overall results in 8-26 recipients of each dose showed no significant differences when compared with either BB or Wistar controls. With smaller numbers of diabetes-prone rats, the same was obtained for alloxan, though with fewer doses tested. The latter required the construction of an alloxan dose-response in normal Wistar rats. Thus, this study has not demonstrated a nonspecific increase in "fragility" of BB rat beta cells in response to these classical diabetogenic agents. This would be consistent with other data suggesting that the primary abnormality in the syndrome does not necessarily reside within the beta cell.