Late Toxicity and Long-Term Local Control in Patients With Ultra-Central Lung Tumours Treated by Intensity-Modulated Radiotherapy-Based Stereotactic Ablative Body Radiotherapy With Homogenous Dose Prescription.

AIMS: To report late toxicity and long-term outcomes of intensity-modulated radiotherapy (IMRT)-based stereotactic ablative body radiotherapy (SABR) in patients with ultra-central lung tumours. MATERIALS AND METHODS: This is a single-institution retrospective analysis of patients treated with SABR for ultra-central tumours between May 2008 and April 2016. Ultra-central location was defined as tumour (GTV) abutting or involving trachea, main or lobar bronchi. Respiratory motion management and static-field dynamic-IMRT were used, with dose prescribed homogeneously (maximum <120%). Descriptive analysis, Kaplan-Meier method, log-rank test and Cox regression were used to assess outcomes. RESULTS: Sixty-five per cent of patients had inoperable primary non-small cell lung cancer and 35% had lung oligometastases. The median age was 72 (range 34-85) years. The median gross tumour volume and planning target volume (PTV) were 19.6 (range 1.7-203.3) cm3 and 57.4 (range 7.7-426.6) cm3, respectively. The most commonly used dose fractionation was 60 Gy in eight fractions (n = 51, 87.8%). Median BED10 for D98%PTV and D2%PTV were 102.6 Gy and 115.06 Gy, respectively. With a median follow-up of 26.5 (range 3.2-100.5) months, fatal haemoptysis occurred in five patients (8.7%), of which two were directly attributable to SABR. A statistically significant difference was identified between median BED3 for 4 cm3 of airway, for patients who developed haemoptysis versus those who did not (147.4 versus 47.2 Gy, P = 0.005). At the last known follow-up, 50 patients (87.7%) were without local recurrence. Freedom from local progression at 2 and 4 years was 92 and 79.8%, respectively. The median overall survival was 34.3 (95% confidence interval 6.1-61.6) months. Overall survival at 2 and 4 years was 55.1 and 41.2%, respectively. CONCLUSION: In patients with high-risk ultra-central lung tumours, IMRT-based SABR with homogenous dose prescription achieves high local control, similar to that reported for peripheral tumours. Although fatal haemoptysis occurred in 8.7% of patients, a direct causality with SABR was evident in only 3%. Larger studies are warranted to ascertain factors associated with outcomes, especially toxicity, and identify patients who would probably benefit from this treatment.

Long-term survival among Hodgkin's lymphoma patients with gastrointestinal cancer: a population-based study.

BACKGROUND: The increased risk of gastrointestinal (GI) cancers after Hodgkin's lymphoma (HL) is well established. However, no large population-based study has described the actuarial survival after subsequent GI cancers in HL survivors (HL-GI). PATIENTS AND METHODS: For 209 patients with HL-GI cancers (105 colon, 35 stomach, 30 pancreas, 21 rectum, and 18 esophagus) and 484 165 patients with first primary GI cancers (GI-1), actuarial survival was compared, accounting for age, gender, race, GI cancer stage, radiation for HL, and other variables. RESULTS: Though survival of HL patients who developed localized stage colon cancer was similar to that of the GI-1 group, overall survival (OS) of HL patients with regional or distant stage colon cancer was reduced [hazard ratio, (HR)=1.46, P=0.01]. The HL survivors with regional or distant stage colon cancer in the transverse segment had an especially high risk of mortality (HR: 2.7, P=0.001 for OS). For localized stomach cancer, OS was inferior among HL survivors (HR=3.46, P=0.006). CONCLUSIONS: The HL patients who develop GI cancer experience significantly reduced survival compared with patients with a first primary GI cancer. Further research is needed to explain the inferior survival of HL patients and to define selection criteria for cancer screening in HL survivors.

gamma-H2AX as a therapeutic target for improving the efficacy of radiation therapy.

Exposure to ionizing radiation (IR) results in the formation of DNA double strand breaks, resulting in the activation of phosphatidylinositol 3'-kinase-like kinases ATM, ATR and DNK-PKcs. A physiologically important downstream target is the minor histone H2A variant, H2AX, which is rapidly phosphorylated on Ser 139 of the carboxyl tail after IR. Recent work suggests that phosphorylated H2AX (gamma-H2AX) plays an important role in the recruitment and/or retention of DNA repair and checkpoint proteins such as BRCA1, MRE11/RAD50/NBS1 complex, MDC1 and 53BP1. H2AX-/- mouse embryonic fibroblasts are radiation sensitive and demonstrate deficits in repairing DNA damage compared to their wildtype counterparts. Cells treated with peptide inhibitors of gamma-H2AX demonstrate increased radiosensitivity following radiation compared with untreated irradiated cells. Analysis of the kinetics of gamma-H2AX clearance after IR or other DNA damaging agents reveals a correlation between increased gamma-H2AX persistence and unrepaired DNA damage and cell death. These data highlight the potential of post-translational modifications of chromatin as a therapeutic target for enhancing the efficacy of radiotherapy. Therapies that either block gamma-H2AX foci formation by inhibiting upstream kinase activity or that directly inhibit H2AX function may interfere with DNA damage repair processes and warrant further investigation as potential radiosensitizing agents. Agents that increase persistence of gamma-H2AX after IR are likely to increase unrepaired DNA damage.

Intensity-modulated radiation therapy in the treatment of gastric cancer: early clinical outcome and dosimetric comparison with conventional techniques.

The purpose of this study was to assess the efficacy and toxicity of intensity-modulated radiation therapy (IMRT) in the treatment of gastric cancer. Seven patients with gastric cancer were treated with IMRT. Six patients (all Stage III) received post-operative chemoradiotherapy with concurrent 5-fluorouracil and leucovorin. One received planned pre-operative radiation, though did not proceed to surgery. All patients were planned to receive 50.4 Gy in 1.8 Gy fractions. IMRT planning was compared with opposed anterior-posterior: posterior-anterior (AP/PA) and 3-field conventional three-dimensional plans. When compared with either AP/PA or 3-field plans, IMRT significantly reduced the volume exceeding the threshold dose of the liver and at least one kidney. Target coverage with IMRT was excellent, with 98+/-1% of the target receiving >or=100% of the dose. Compared with AP/PA and 3-field plans, IMRT plans had a greater percentage of target receiving the prescribed dose, but also a greater volume receiving >110% of the dose. IMRT was well tolerated; no patients developed acute gastrointestinal toxicity greater than grade 2. All seven experienced grade 2 nausea, three had grade 2 diarrhoea and two had grade 2 oesophagitis. Weight loss ranged from 0-12% (mean 6.1% and median 5.8%). IMRT in the treatment of gastric malignancies reduces the mean and above threshold doses to critical normal tissues. In an initial cohort of seven patients, 50.4 Gy delivered by IMRT is well tolerated and safe.

The influence of packing on free radical yields in solid-state DNA: film compared to lyophilized frozen solution.

Radiation-induced free radical damage in solid-state DNA arises from direct-type damage mechanisms. In the present study, free radical yields in film and lyophilized Na DNA model systems are compared. The free radical yields in lyophilized samples are significantly greater than those in films. Since DNA conformation cannot account for the differences in free radical yields between different DNA preparations, it is proposed that the intermolecular spacing of DNA is a critical variable. The differences in the hydration dependence of free radical yields between the film and lyophilized DNA model systems are consistent with this thesis. The relatively large free radical yields observed in lyophilized DNA emphasize the fact that DNA is an extremely effective electron and hole scavenger, more so than previously thought.

The effect of packing and conformation on free radical yields in films of variably hydrated DNA.

This work investigates the direct-type action of radiation (involving electron addition and electron abstraction) on DNA. Specifically, the effects of DNA hydration, conformation and packing on free radical yields are examined. The fact that these variables are interdependent complicates the analysis of how each variable affects free radical yields. The hydration dependence of free radical yields in films of both Li and Na DNA was examined. At low levels of DNA hydration (less than 25 waters per nucleotide), the relatively high free radical yields and the lack of water-derived radicals are evidence that damage transfer from the DNA solvation shell to the DNA molecule occurs. The scatter of measured free radical yields is significant (50-70%) in Li DNA, while in Na DNA it is much less (<25%). Our conclusions hinge upon two known differences between Li DNA and Na DNA: (1) At low DNA hydrations, the conformation of Na DNA undergoes several changes with increasing hydration, while the conformation of Li DNA is relatively constant over the same range. (2) Compared to Na DNA, Li DNA is more prone to self-associate, giving rise to macroscopic and microscopic crystalline domains in Li DNA films. The greater scatter of free radical yields in Li DNA films is therefore attributed to variability in packing. By virtue of the greater reproducibility of free radical yields in Na DNA films, the effects of DNA packing, conformation and hydration can be ascertained. In Na DNA, hydration-dependent changes in free radical yields are attributed primarily to changes in DNA packing.

Migration of electrons and holes in crystalline d(CGATCG)-anthracycline complexes X-irradiated at 4 K.

Electrons and holes generated in irradiated DNA migrate to stable trapping sites. Protonation and deprotonation reactions at these sites promote the trapping of electrons and holes, thereby inhibiting further migration. The extent of migration determines the final distribution of damage in irradiated DNA. In this study, electron and hole migration is investigated in a crystalline DNA hexamer intercalated with an anthracycline drug. The intercalator is no further than 2 base pairs away from any DNA base. From EPR measurements, there is no evidence of DNA-centered radicals in the irradiated DNA hexamer. The aromatic region of the anthracycline intercalator evidently sequesters most or all of the electrons and most of the holes. Further hole trapping and radical stabilization appear to occur on the anthracycline's amino sugar group, which is nestled in the minor groove of the hexamer. The relatively large yield of this proposed amino sugar radical suggests that holes generated in the DNA solvation shell migrate to the amino sugar, where they become trapped. This would be the first observation of a radical formed by the direct effect of low-dose, low-LET radiation that is trapped within the DNA helix, yet lies outside of the stacked bases. With respect to holes generated in the DNA bases at 4 K, we conclude that most, if not all, are capable of migrating to an intercalator < or = 2 base pairs away. With respect to dry electrons, we conclude that anthracycline competes effectively for electron trapping over a region of at least 2 base pairs; our experiments cannot distinguish between electron attachment to the bases followed by transfer to the intercalator and direct attachment to the intercalator.