Does Vascular Collapse Occur After Treatment of Hepatocellular Cancer With Stereotactic Body Radiation Therapy?

There is debate about why stereotactic body radiation therapy (SBRT) produces superior control of hepatocellular cancer (HCC) compared to fractionated treatment. Both preclinical and clinical evidence has been presented to support a "classic" biological explanation: the greater BED of SBRT produces more DNA damage and tumor cell kill. More recently, preclinical evidence has supported the concept of a "new biology", particularly radiation-induced vascular collapse, which increases hypoxia and free radical activation. This is hypothesized to cause much greater tumor cell death than was produced by the initial radiation-induced DNA damage to the tumor. We decided to investigate if vascular collapse occurs after standard SBRT for patients with HCC. Eight patients with 10 lesions underwent dynamic contrast enhanced MRI at the time of simulation and either 48 or 96 hours after the first fraction. Only three of 10 tumors showed a decrease in blood flow. These findings suggest that vascular collapse does not typically occur after SBRT for HCC.

Prostate Radiotherapy With Adjuvant Androgen Deprivation Therapy (ADT) Improves Metastasis-Free Survival Compared to Neoadjuvant ADT: An Individual Patient Meta-Analysis.

PURPOSE: There remains a lack of clarity regarding the influence of sequencing of androgen deprivation therapy (ADT) and radiotherapy (RT) on outcomes in prostate cancer (PCa). Herein, we evaluate the optimal sequencing of ADT with prostate-directed RT in localized PCa. METHODS: MEDLINE (1966-2018), Embase (1982-2018), ClinicalTrials.gov, and conference proceedings (1990-2018) were searched to identify randomized trials evaluating the sequencing, but not duration, of ADT with RT. Two randomized phase III trials were identified, and individual patient data were obtained: Ottawa 0101 and NRG Oncology's Radiation Therapy Oncology Group 9413. Ottawa 0101 randomly assigned patients to neoadjuvant or concurrent versus concurrent or adjuvant short-term ADT. Radiation Therapy Oncology Group 9413, a 2 × 2 factorial trial, included a random assignment of neoadjuvant or concurrent versus adjuvant short-term ADT. The neoadjuvant or concurrent ADT arms of both trials were combined into the neoadjuvant group, and the arms receiving adjuvant ADT were combined into the adjuvant group. The primary end point of this meta-analysis was progression-free survival (PFS). RESULTS: The median follow-up was 14.9 years. Overall, 1,065 patients were included (531 neoadjuvant and 534 adjuvant). PFS was significantly improved in the adjuvant group (15-year PFS, 29% v 36%, hazard ratio [HR], 1.25 [95% CI, 1.07 to 1.47], P = .01). Biochemical failure (subdistribution HR [sHR], 1.37 [95% CI, 1.12 to 1.68], P = .002), distant metastasis (sHR, 1.40 [95% CI, 1.00 to 1.95], P = .04), and metastasis-free survival (HR, 1.17 [95% CI, 1.00 to 1.37], P = .050) were all significantly improved in the adjuvant group. There were no differences in late grade ≥ 3 gastrointestinal (2% v 3%, P = .33) or genitourinary toxicity (5% v 5%, P = .76) between groups. CONCLUSION: The sequencing of ADT with prostate-directed RT has significant association with long-term PFS and MFS in localized PCa. Our findings favor use of an adjuvant over a neoadjuvant approach, without any increase in long-term toxicity.

Aspiration pneumonia after chemo-intensity-modulated radiation therapy of oropharyngeal carcinoma and its clinical and dysphagia-related predictors.

BACKGROUND: The purpose of this study was to assess aspiration pneumonia (AsPn) rates and predictors after chemo-irradiation for head and neck cancer. METHODS: The was a prospective study of 72 patients with stage III to IV oropharyngeal cancer treated definitively with intensity-modulated radiotherapy (IMRT) concurrent with weekly carboplatin and paclitaxel. AsPn was recorded prospectively and dysphagia was evaluated longitudinally through 2 years posttherapy by observer-rated (Common Toxicity Criteria version [CTCAE]) scores, patient-reported scores, and videofluoroscopy. RESULTS: Sixteen patients (20%) developed AsPn. Predictive factors included T classification (p = .01), aspiration detected on videofluoroscopy (videofluoroscopy-asp; p = .0007), and patient-reported dysphagia (p = .02-.0003), but not observer-rated dysphagia (p = .4). Combining T classification, patient reported dysphagia, and videofluoroscopy-asp, provided the best predictive model. CONCLUSION: AsPn continues to be an under-reported consequence of chemo-irradiation for head and neck cancer. These data support using patient-reported dysphagia to identify high-risk patients requiring videofluoroscopy evaluation for preventive measures. Reducing videofluoroscopy-asp rates, by reducing swallowing structures radiation doses and by trials reducing treatment intensity in patients predicted to do well, are likely to reduce AsPn rates.

Parotid glands dose-effect relationships based on their actually delivered doses: implications for adaptive replanning in radiation therapy of head-and-neck cancer.

PURPOSE: Doses actually delivered to the parotid glands during radiation therapy often exceed planned doses. We hypothesized that the delivered doses correlate better with parotid salivary output than the planned doses, used in all previous studies, and that determining these correlations will help make decisions regarding adaptive radiation therapy (ART) aimed at reducing the delivered doses. METHODS AND MATERIALS: In this prospective study, oropharyngeal cancer patients treated definitively with chemoirradiation underwent daily cone-beam computed tomography (CBCT) with clinical setup alignment based on the C2 posterior edge. Parotid glands in the CBCTs were aligned by deformable registration to calculate cumulative delivered doses. Stimulated salivary flow rates were measured separately from each parotid gland pretherapy and periodically posttherapy. RESULTS: Thirty-six parotid glands of 18 patients were analyzed. Average mean planned doses was 32 Gy, and differences from planned to delivered mean gland doses were -4.9 to +8.4 Gy, median difference +2.2 Gy in glands in which delivered doses increased relative to planned. Both planned and delivered mean doses were significantly correlated with posttreatment salivary outputs at almost all posttherapy time points, without statistically significant differences in the correlations. Large dispersions (on average, SD 3.6 Gy) characterized the dose-effect relationships for both. The differences between the cumulative delivered doses and planned doses were evident at first fraction (r=.92, P<.0001) because of complex setup deviations (eg, rotations and neck articulations), uncorrected by the translational clinical alignments. CONCLUSIONS: After daily translational setup corrections, differences between planned and delivered doses in most glands were small relative to the SDs of the dose-saliva data, suggesting that ART is not likely to gain measurable salivary output improvement in most cases. These differences were observed at first treatment, indicating potential benefit for more complex setup corrections or adaptive interventions in the minority of patients with large deviations detected early by CBCT.

A phase I/II trial of intensity modulated radiation (IMRT) dose escalation with concurrent fixed-dose rate gemcitabine (FDR-G) in patients with unresectable pancreatic cancer.

PURPOSE: Local failure in unresectable pancreatic cancer may contribute to death. We hypothesized that intensification of local therapy would improve local control and survival. The objectives were to determine the maximum tolerated radiation dose delivered by intensity modulated radiation with fixed-dose rate gemcitabine (FDR-G), freedom from local progression (FFLP), and overall survival (OS). METHODS AND MATERIALS: Eligibility included pathologic confirmation of adenocarcinoma, radiographically unresectable, performance status of 0-2, absolute neutrophil count of ≥ 1,500/mm(3), platelets ≥ 100,000/mm(3), creatinine <2 mg/dL, bilirubin <3 mg/dL, and alanine aminotransferase/aspartate aminotransferase ≤ 2.5 × upper limit of normal. FDR-G (1000 mg/m(2)/100 min intravenously) was given on days -22 and -15, 1, 8, 22, and 29. Intensity modulated radiation started on day 1. Dose levels were escalated from 50-60 Gy in 25 fractions. Dose-limiting toxicity was defined as gastrointestinal toxicity grade (G) ≥ 3, neutropenic fever, or deterioration in performance status to ≥ 3 between day 1 and 126. Dose level was assigned using TITE-CRM (Time-to-Event Continual Reassessment Method) with the target dose-limiting toxicity (DLT) rate set to 0.25. RESULTS: Fifty patients were accrued. DLTs were observed in 11 patients: G3/4 anorexia, nausea, vomiting, and/or dehydration (7); duodenal bleed (3); duodenal perforation (1). The recommended dose is 55 Gy, producing a probability of DLT of 0.24. The 2-year FFLP is 59% (95% confidence interval [CI]: 32-79). Median and 2-year overall survival are 14.8 months (95% CI: 12.6-22.2) and 30% (95% CI 17-45). Twelve patients underwent resection (10 R0, 2 R1) and survived a median of 32 months. CONCLUSIONS: High-dose radiation therapy with concurrent FDR-G can be delivered safely. The encouraging efficacy data suggest that outcome may be improved in unresectable patients through intensification of local therapy.

Quantitative CT of lung nodules: dependence of calibration on patient body size, anatomic region, and calibration nodule size for single- and dual-energy techniques.

Calcium concentration may be a useful feature for distinguishing benign from malignant lung nodules in computer-aided diagnosis. The calcium concentration can be estimated from the measured CT number of the nodule and a CT number vs calcium concentration calibration line that is derived from CT scans of two or more calcium reference standards. To account for CT number nonuniformity in the reconstruction field, such calibration lines may be obtained at multiple locations within lung regions in an anthropomorphic phantom. The authors performed a study to investigate the effects of patient body size, anatomic region, and calibration nodule size on the derived calibration lines at ten lung region positions using both single energy (SE) and dual energy (DE) CT techniques. Simulated spherical lung nodules of two concentrations (50 and 100 mg/cc CaCO3) were employed. Nodules of three different diameters (4.8, 9.5, and 16 mm) were scanned in a simulated thorax section representing the middle of the chest with large lung regions. The 4.8 and 9.5 mm nodules were also scanned in a section representing the upper chest with smaller lung regions. Fat rings were added to the peripheries of the phantoms to simulate larger patients. Scans were acquired on a GE-VCT scanner at 80, 120, and 140 kVp and were repeated three times for each condition. The average absolute CT number separations between the calibration lines were computed. In addition, under- or overestimates were determined when the calibration lines for one condition (e.g., small patient) were used to estimate the CaCO3 concentrations of nodules for a different condition (e.g., large patient). The authors demonstrated that, in general, DE is a more accurate method for estimating the calcium contents of lung nodules. The DE calibration lines within the lung field were less affected by patient body size, calibration nodule size, and nodule position than the SE calibration lines. Under- or overestimates in CaCO3 concentrations of nodules were also in general smaller in quantity with DE than with SE. However, because the slopes of the calibration lines for DE were about one-half the slopes for SE, the relative improvement in the concentration estimates for DE as compared to SE was about one-half the relative improvement in the separation between the calibration lines. Results in the middle of the chest thorax section with large lungs were nearly completely consistent with the above generalization. On the other hand, results in the upper-chest thorax section with smaller lungs and greater amounts of muscle and bone were mixed. A repeat of the entire study in the upper thorax section yielded similar mixed results. Most of the inconsistencies occurred for the 4.8 mm nodules and may be attributed to errors caused by beam hardening, volume averaging, and insufficient sampling. Targeted, higher resolution reconstructions of the smaller nodules, application of high atomic number filters to the high energy x-ray beam for improved spectral separation, and other future developments in DECT may alleviate these problems and further substantiate the superior accuracy of DECT in quantifying the calcium concentrations of lung nodules.

Grading xerostomia by physicians or by patients after intensity-modulated radiotherapy of head-and-neck cancer.

PURPOSE: To assess observer-based vs. patient self-reported scoring of xerostomia after intensity-modulated radiotherapy (IMRT) of head-and-neck (HN) cancer. METHODS: A total of 38 patients who had received IMRT for HN cancer underwent xerostomia evaluations 6 to 24 months after completion of therapy using three methods each time: (1) Grading by 3 observers according to the Radiotherapy Oncology Group/European Organization for Research and Therapy of Cancer (RTOG/EORTC) system; (2) patient self-reported validated xerostomia questionnaire (XQ); and (3) major salivary gland flow measurements. RESULTS: The interobserver agreement regarding the RTOG/EORTC grades was moderate: kappa-coefficient 0.54 (95% CI=0.31-0.76). The correlations between the average RTOG/EORTC grades and the salivary flow rates were not statistically significant. A trend for significant correlation was observed between these grades and the percent (relative to the pretherapy) nonstimulated salivary flow rates (p=0.07), but not with the percent stimulated flow rates. Better correlations were found between grading made more than the median time (15 min) after the last liquid sipping and the nonstimulated (but not the stimulated) flows compared with grading made shortly after sipping. In contrast, significant correlations were found between the XQ scores and the nonstimulated (p<0.005) and the stimulated (p<0.005) salivary flow rates, as well as with the percentages of the corresponding pretherapy values (p=0.002 and 0.038, respectively). No significant correlation was found between the RTOG/EORTC grades and the XQ scores. The observer-based grades underestimated the severity of xerostomia compared with the patient self-reported scores. CONCLUSIONS: Patient self-reported, rather than physician-assessed scores, should be the main end points in evaluating xerostomia.