Impact of sea-level rise and coral mortality on the wave dynamics and wave forces on barrier reefs.

A one-dimensional wave model was used to investigate the reef top wave dynamics across a large suite of idealized reef-lagoon profiles, representing barrier coral reef systems under different sea-level rise (SLR) scenarios. The modeling shows that the impacts of SLR vary spatially and are strongly influenced by the bathymetry of the reef and coral type. A complex response occurs for the wave orbital velocity and forces on corals, such that the changes in the wave dynamics vary reef by reef. Different wave loading regimes on massive and branching corals also leads to contrasting impacts from SLR. For many reef bathymetries, wave orbital velocities increase with SLR and cyclonic wave forces are reduced for certain coral species. These changes may be beneficial to coral health and colony resilience and imply that predicting SLR impacts on coral reefs requires careful consideration of the reef bathymetry and the mix of coral species.

Phase Ib trial of radiotherapy in combination with combretastatin-A4-phosphate in patients with non-small-cell lung cancer, prostate adenocarcinoma, and squamous cell carcinoma of the head and neck.

BACKGROUND: The vascular disrupting agent combretastatin-A4-phosphate (CA4P) demonstrated antitumour activity in preclinical studies when combined with radiation. METHODS: Patients with non-small-cell lung cancer (NSCLC), prostate adenocarcinoma, and squamous cell carcinoma of the head and neck (SCCHN) received 27 Gy in 6 fractions treating twice weekly over 3 weeks, 55 Gy in 20 fractions over 4 weeks, and 66 Gy in 33 fractions over 6 weeks respectively. CA4P was escalated from 50 mg/m2 to 63 mg/m2. CA4P exposure was further increased from one to three to six doses. Patients with SCCHN received cetuximab in addition. RESULTS: Thirty-nine patients received 121 doses of CA4P. Dose-limiting toxic effects (DLTs) of reversible ataxia and oculomotor nerve palsy occurred in two patients with prostate cancer receiving weekly CA4P at 63 mg/m2. DLT of cardiac ischaemia occurred in two patients with SCCHN at a weekly dose of 50 mg/m2 in combination with cetuximab. Three patients developed grade 3 hypertension. Responses were seen in 7 of 18 patients with NSCLC. At 3 years, 3 of 18 patients with prostate cancer had prostate-specific antigen relapse. CONCLUSIONS: Radiotherapy with CA4P appears well tolerated in most patients. The combination of CA4P, cetuximab, and radiotherapy needs further scrutiny before it can be recommended for clinical studies.

Adaptive 18fluoro-2-deoxyglucose positron emission tomography/computed tomography-based target volume delineation in radiotherapy planning of head and neck cancer.

AIMS: This study investigated an adaptive threshold-based method to delineate the target volume using (18)fluoro-2-deoxyglucose ((18)FDG) positron emission tomography/computed tomography (PET/CT) before and during a course of radical radiotherapy or chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck. MATERIALS AND METHODS: Ten patients were enrolled between March 2006 and May 2008. (18)FDG PET/CT scans were carried out 72h before the start of radiotherapy and then at three time points during radiotherapy (8-18, 36-50 and 66Gy). Functional volumes were delineated using an adaptive iterative algorithm weighted according to the mean standard uptake value (SUV(mean)) within the region of interest. The background (18)FDG uptake, maximum standard uptake value (SUV(max)) and SUV(mean) within the volumes were assessed. RESULTS: There was no significant reduction in the primary target volumes defined by the adaptive threshold during radiotherapy. However, the SUV(max) significantly reduced within the primary (P=0.003-0.011) and lymph node (P<0.0001) target volume at 36-50 and 36-66Gy compared with 0Gy. The SUV(mean) was negatively correlated to radiation dose (P<0.0001-0.014). The ratio between the background uptake of (18)FDG and the SUV(mean) significantly reduced for both the lymph node target volume at 36-50Gy and the primary volume at 66Gy. The lack of significant correlation between the defined volume and radiation dose was because the SUV(mean) within the region of interest used to define the edge of the volume was equal to or less than the background (18)FDG uptake and the software was unable to effectively differentiate between tumour and background uptake. CONCLUSIONS: The adaptive threshold method may be of benefit when used to define the target volume before the start of radiotherapy. This method was not beneficial during radiotherapy because the software is not sensitive enough to distinguish tumour from background and define a volume. (18)FDG PET/CT-guided volumes delineated by automatic adaptive thresholding methods should only be used for dose escalation with the pretreatment imaging.

Carbogen breathing increases prostate cancer oxygenation: a translational MRI study in murine xenografts and humans.

Hypoxia has been associated with poor local tumour control and relapse in many cancer sites, including carcinoma of the prostate. This translational study tests whether breathing carbogen gas improves the oxygenation of human prostate carcinoma xenografts in mice and in human patients with prostate cancer. A total of 23 DU145 tumour-bearing mice, 17 PC3 tumour-bearing mice and 17 human patients with prostate cancer were investigated. Intrinsic susceptibility-weighted MRI was performed before and during a period of carbogen gas breathing. Quantitative R(2)* pixel maps were produced for each tumour and at each time point and changes in R(2)* induced by carbogen were determined. There was a mean reduction in R(2)* of 6.4% (P=0.003) for DU145 xenografts and 5.8% (P=0.007) for PC3 xenografts. In all, 14 human subjects were evaluable; 64% had reductions in tumour R(2)* during carbogen inhalation with a mean reduction of 21.6% (P=0.0005). Decreases in prostate tumour R(2)* in both animal models and human patients as a result of carbogen inhalation suggests the presence of significant hypoxia. The finding that carbogen gas breathing improves prostate tumour oxygenation provides a rationale for testing the radiosensitising effects of combining carbogen gas breathing with radiotherapy in prostate cancer patients.

Positron emission tomography in oncology: a review.

Positron emission tomography is an evolving imaging tool that is becoming increasingly available for use in clinical practice. This overview will look at the current evidence for the use of positron emission tomography in imaging different tumour types and the different radiotracers that are either available or being evaluated in an investigational setting.

Pre-treatment haemoglobin concentration in accelerated and conventional radiotherapy for non-small cell lung carcinoma.

Serum haemoglobin has been shown to be an independent prognostic factor for a number of cancers including head and neck, bladder, cervix and anal cancers. This study has investigated the prognostic significance of pre-treatment haemoglobin in 164 consecutive patients receiving radical radiotherapy for non-small cell lung cancer. Forty-six received conventional fractionation to 60 Gy in 30 fractions and the remainder received accelerated fractionation, either CHART, 54 Gy in 36 fractions over 12 days (27 patients) or CHARTWEL, 60 Gy in 40 fractions over 18 days (76 patients). Patients were divided into three equal groups by haemoglobin concentration. The median overall survival in each of the three groups from lowest to highest haemoglobin was 17.5 months (95% CI 7.9 25), 18.4 months (95% CI 15.0 25.9) and 16.3 months (95% CI 13.0-19.6). No significant effect of pre-treatment haemoglobin concentration was seen in predicting overall, local disease free or metastases free survival.

A phase I/II study of CHARTWEL with concurrent chemotherapy in locally advanced, inoperable carcinoma of the oesophagus.

AIM: To evaluate the feasibility, efficacy and toxicity of concurrent chemotherapy and continuous, hyperfractionated, accelerated radiotherapy weekend less (CHARTWEL) in the treatment of locally advanced, inoperable oesophageal cancer. METHODS: A prospective study of 19 patients with histologically confirmed, locally advanced, inoperable carcinoma of the oesophagus. CHARTWEL was prescribed from day 1 to doses of 40.5 Gy (three patients), 42 Gy (five patients), 45 Gy (four patients), 46.5 Gy (three patients) and 49.5 Gy (four patients). Cisplatin 75 mg/m2 was administered on day 1 of radiotherapy, followed by 5-fluorouracil (5-FU) 1000 mg daily for 4 days. RESULTS: All patients completed radiotherapy, with two requiring modification of their chemotherapy dose. Acute toxicity was acceptable, with no interruptions to treatment. The median dysphagia free time was 9.6 months with 38% of patients being dysphagia free at 42 months. The median time to locoregional relapse was 13.2 months with 50% being free at 1 year and 35% at 3.5 years. There was a trend towards greater control when the higher doses (45-49.5 Gy) were compared with the lower doses (40.5-42 Gy), P = 0.07. The median survival time was 10.7 months with 1- and 2-year survival rates of 50 and 26%, respectively. Strictures developed in seven out of 18 patients (38%), but five were found on biopsy to be due to recurrent disease. There was no other long-term toxicity and no treatment-related death occurred. CONCLUSIONS: CHARTWEL with concomitant cisplatin/5-FU chemotherapy is a feasible treatment option in these patients. It is well tolerated, achieves a high rate of local control and effectively palliates the symptoms of dysphagia, all with relatively rapid resolution of treatment-related toxicity. The results warrant continued dose escalation to 51 Gy.

Dose-escalation with CHARTWEL (continuous hyperfractionated accelerated radiotherapy week-end less) combined with neo-adjuvant chemotherapy in the treatment of locally advanced non-small cell lung cancer.

PURPOSE: a radiation-dose-escalation study was undertaken to assess the therapeutic benefit of combining accelerated hyperfractionated radiotherapy (RT) with neo-adjuvant chemotherapy (CT) in non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: One hundred and thirteen patients with locally advanced NSCLC were entered into a phase II trial of CHARTWEL (CHART Week-End-Less) 54 Gy or 60 Gy with or without three cycles of CT. Acute oesophageal reactions and analgesia were scored for up to 8 weeks after the start of RT. Pneumonitis, lung fibrosis, spinal cord and oesophageal strictures, were assessed using clinical and radiological criteria from 3 months onwards and throughout the study. Haematological and gastrointestinal toxicity was monitored in those patients undergoing CT. Endpoints for treatment outcome were overall survival, disease-free survival and loco-regional control. RESULTS: Chemotherapy enhanced the incidence and duration of acute dysphagia,but the increase was transient. Healing occurred in all cases and there has been no evidence of long-term oesophageal complications. Clinically, almost 25% of those receiving CT+RT had Grade 2 pneumonitis, higher than seen with RT alone. However, the 1 patient with severe Grade 3 pneumonitis was in the RT 60 Gy alone group. An incidence of 17% Grade 2 pulmonary fibrosis at 2 years was seen with CT, slightly lower than with RT alone. To date, there is no evidence of Grade 3 lung fibrosis. There was a higher scoring of lung damage with the radiological endpoint, which gave no indication that CT increased pulmonary toxicity over that of RT alone. Loco-regional control at 2 years was 37% and 55% for CHARTWEL 54 Gy and 60 Gy alone compared with 72% in those treated with 60 Gy and neo-adjuvant CT However, this did not translate into a survival advantage. CONCLUSIONS: This study of CHARTWEL combined with induction chemotherapy, has shown that the strategy is feasible and that a possible therapeutic benefit may be obtained by the addition of CT. Although neo-adjuvant treatment increased acute mucosal reactions and slight-to-moderate pneumonitis seen with CHARTWEL 60 Gy, the clinical management and quality of life of these patients is similar to those treated with radiotherapy alone.

From CHART to CHARTWEL in non-small cell lung cancer: clinical radiobiological modelling of the expected change in outcome.

CHART (Continuous Hyperfractionated Accelerated Radiotherapy) has been shown to improve the tumour control probability and survival relative to conventional radiotherapy in patients with inoperable non-small cell lung cancer (NSCLC). CHARTWEL (CHART Weekend-less) is a further development of this schedule escalating the physical dose to 60 Gy while maintaining the low dose per fraction of 1.5 Gy. In this schedule, three fractions, with a minimum interval of 6 h between fractions, are delivered 5 days per week. This extends overall treatment time from the 12 days of CHART to 18 days. Radiobiological modelling is used to estimate the expected tumour control and normal tissue morbidity after CHARTWEL relative to CHART. The estimations are based on the outcome of the CHART trial and published values for dose-fractionation and dose-response parameters for human tissues and tumours. Two new estimates of quantitative radiobiological parameters for early normal-tissue morbidity after chest irradiation are reported here. For radiation pneumonitis, the dose recovered per day is estimated at 0.44 Gy/day with 95% confidence limits 0.07 Gy/day and 0.80 Gy/day. For oesophagitis, the normalized dose-response gradient, gamma50, is estimated at 2.1 with 95% confidence limits 1.4 and 3.6. With regard to normal tissue effects, the increase in total dose when going from CHART to CHARTWEL is moderated by the slightly longer overall treatment time in case of early morbidity while the introduction of the weekend gaps may moderate the effect for late-responding normal tissues with a long repair halftime. Tumour control at 3 years is expected to increase by some 7-14 percentage points (from 19% to 26-33%) whereas the incidence of moderate and severe early oesophagitis and pneumonitis is expected to increase by about 2 percentage points. The incidence of late morbidity, lung fibrosis and oesophageal strictures, is expected to increase by 3-4 percentage points. The analyses conclude that CHARTWEL is likely to improve the therapeutic ratio relative to CHART.

Failure-specific prognostic factors after continuous hyperfractionated accelerated radiotherapy (CHART) or conventional radiotherapy in locally advanced non-small-cell lung cancer: a competing risks analysis.

The aim of this study was to identify possible failure-specific prognostic factors in non-small-cell lung cancer. Clinical outcome was analysed in 549 patients participating in the randomized controlled trial of CHART vs conventional radiotherapy. Local failure and distant failure with or without concurrent local relapse were subjected to a competing risk analysis using an accelerated failure-time model with a log-logistic hazard function. Randomization to CHART (2 P = 0.005), increasing age (2 P = 0.036) and female sex (2 P = 0.09) was all associated with a prolonged interval to failure. Advanced clinical stage was associated with a decreased interval to failure (2 P = 0.004) and a significantly increased risk (2 P = 0.009) of failing in distant rather than in local position. From this model, prognostic indices for local and distant failure were estimated for each individual patient. Competing risk analysis allows identification of patients with different failure patterns, and may provide a means of stratifying patients for intensified local or systemic therapy.

BOLD MRI of human tumor oxygenation during carbogen breathing.

An MRI method is described for demonstrating improved oxygenation of human tumors and normal tissues during carbogen inhalation (95% O2, 5% CO2). T2*-weighted gradient-echo imaging was performed before, during, and after carbogen breathing in 47 tumor patients and 13 male volunteers. Analysis of artifacts and signal intensity was performed. Thirty-six successful tumor examinations were obtained. Twenty showed significant whole-tumor signal increases (mean 21.0%, range 6.5-82.4%), and one decreased (-26.5 +/- 8.0%). Patterns of signal change were heterogeneous in responding tumors. Five of 13 normal prostate glands (four volunteers and nine patients with nonprostatic tumors) showed significant enhancement (mean 11.4%, range 8.4-14.0%). An increase in brain signal was seen in 11 of 13 assessable patients (mean 8.0 +/- 3.7%, range 5.0-11.7%). T2*-weighted tumor MRI during carbogen breathing is possible in humans. High failure rates occurred due to respiratory distress. Significant enhancement was seen in 56%, suggesting improved tissue oxygenation and blood flow, which could identify these patients as more likely to benefit from carbogen radiosensitization.

Radiotherapy-related early morbidity in head and neck cancer: quantitative clinical radiobiology as deduced from the CHART trial.

BACKGROUND AND PURPOSE: Early reactions after radiotherapy for head and neck cancer may become the limiting factor in current attempts to intensify loco-regional therapy through altered fractionation or combination of radiotherapy with chemotherapy. The aim of the present study was to quantify the dependence of early reactions on the dose-fractionation used in radiotherapy and on patients' age and radiation field size. PATIENTS AND METHODS: The data analyzed are from the randomized controlled trial of CHART (continuous hyperfractionated accelerated radiotherapy) vs. conventional radiotherapy in head and neck cancer. The trial accrued 918 patients from March 1990 to April 1995. Several early morbidity items were evaluated weekly for the first 8 weeks after the start of treatment. Weekly evaluation was continued in patients with early reactions extending beyond 8 weeks. Linear regression was used to analyze the time with reactions in individual patients. Polychotomous ordinal response regression was used to analyze the peak grade of early reactions in individual patients. RESULTS: The main findings of this analysis were as follows. (1) The incidence and peak prevalence of confluent mucositis was higher after CHART than after conventional radiotherapy. Therefore, the average time spent with confluent mucositis per patient treated was significantly longer after CHART than after conventional fractionation. (2) In patients who actually developed confluent mucositis, the average duration of this grade of reaction was not significantly different after CHART compared with conventional radiotherapy. (3) Confluent mucositis developed earlier after the start of treatment (2.9 vs. 4.9 weeks) but also started to improve sooner (5.4 vs. 7.5 weeks after the start of treatment) after CHART than after conventional radiotherapy. (4) The dose recovered per 1-day protraction of overall treatment time, D(prolif), was estimated at 0.80 Gy with 95% confidence limits 0.7 and 1.1 Gy/day for human mucosa. (5) For human skin erythema, the estimate of D(prolif) was 0.12 Gy/day with 95% confidence limits -0.12 and 0.22 Gy/day. (6) Highly significant relationships were found between the grade of morphological mucositis on one hand and dysphagia, pain on swallowing and prescribed analgesics on the other. Patients with confluent mucositis had fewer functional problems if this was confined to the larynx as compared with other subsites in the head and neck. (7) Although the incidence of confluent mucositis was higher in the oral cavity and oropharynx than in the hypopharynx and larynx, the radiobiological properties of mucosal reactions did not show significant variation among the various subsites within the head and neck region. (8) For a given dose and overall treatment time, a highly significant increase in incidence and severity of both mucositis and erythema was seen with increasing field size. Thus, a significant dose-volume or dose-area effect exists for both of these tissues. (9) Patients' age had no significant influence on the incidence and severity of mucositis or erythema. CONCLUSIONS: This study provides quantitative estimates of the dose-time and dose-volume relationships for human skin and normal mucosa in the head and neck region based on an analysis of data from 918 patients entered into a randomized-controlled trial of altered dose fractionation in radiotherapy.

bcl-2 expression in head and neck cancer: an enigmatic prognostic marker.

PURPOSE: The role of bcl-2 overexpression in cancer presents a paradox. In some tumor types, it is associated with favorable outcome, whereas in others the reverse is true. The purpose of this study was to explore the influence of bcl-2 in a large series of head and neck cancer patients treated in the CHART randomized trial. METHODS AND MATERIALS: Histologic material was obtained from 400 patients; bcl-2 expression was assessed by immunohistochemistry as either positive or negative cytoplasmic staining. RESULTS: Positivity of bcl-2 was recorded in 12.8% (9.5-16.5%, 95% confidence limits) of tumors. There were significant differences in positive tumors within different sites with nasopharynx showing the highest incidence (46.2%). A multivariate logistic regression analysis showed that bcl-2 was strongly associated with histologic dedifferentiation, as well as increasing N stage and female gender. In univariate analyses, bcl-2 positive patients had a lower locoregional relapse rate (RR 0.57, p = 0.02) and improved survival (RR 0.49, p = 0.004) compared to bcl-2 negative patients; this became more significant in multivariate analysis. CONCLUSION: These data demonstrate that bcl-2 overexpression is a marker of what is considered to be more advanced and aggressive disease yet it is associated with a more favorable outcome irrespective of the treatment schedule.

Programming of radiotherapy in the treatment of non-small-cell lung cancer--a way to advance care.

Radical radiotherapy, the mainstay of treatment for early inoperable non-small-cell lung cancer, is most commonly given in daily fractions, Monday to Friday, to a total dose of 60-70 Gy over 6-8 weeks. Since the 1980s, novel fractionation schedules have been explored with the aim of improving local tumour control and survival without increasing late morbidity. There have been two main approaches. In hyperfractionated radiotherapy the dose per fraction is reduced and the total dose increased to give improved tumour control without increased late morbidity. Hyperfractionation schedules, with more than one fraction per day have been successfully evaluated, but so far significant benefit has not been achieved when compared with conventional radiotherapy plus chemotherapy. In accelerated radiotherapy the overall duration of radiotherapy is reduced to overcome repopulation of tumour cells during the course of treatment. In all the different regimens of accelerated radiotherapy a common feature is giving two or more fractions on some or all treatment days and, in some cases, a lower dose per fraction is also incorporated. CHART (continuous hyperfractionated accelerated radiotherapy) is the most novel and accelerated schedule tested, and a randomised controlled trial showed a significant survival advantage from CHART compared with conventional radiotherapy. Changes in the fractionation of radiotherapy must be combined with other approaches such as neoadjuvant and concomitant chemotherapy, hypoxic-cell modifiers, and conformal radiotherapy, so that care of patients with non-small-cell lung cancer can be further advanced.

Sweat gland function as a measure of radiation change.

BACKGROUND: Radiotherapy may result in dryness of the skin even when no other change can be detected. We describe a system for recording the electrical conductance of skin as a measure of sweat gland function. PATIENTS AND METHODS: In 22 normal volunteers close agreement was obtained between measurements obtained from comparable sites on both sides of the chest. Measurements were subsequently made in 38 patients treated by radiotherapy to one side of the chest for tumours of the breast or lung using one of five different fractionation schedules. Simultaneous readings were obtained from both sides of the chest with the non irradiated side acting as a control. RESULTS: A dose response relationship was demonstrated: five patients who received the equivalent total dose of 15 Gy in 2-Gy fractions showed no change in conductance. Sixteen out of 23 who received an equivalent total dose of 42-46 Gy in 2-Gy fractions had a greater than 22% reduction in mean skin conductance compared with that of the control areas despite the skin appearing normal in the large majority. Marked changes in skin conductance were seen after higher total doses. In a prospective study 18 women receiving breast irradiation underwent weekly readings during treatment. A mean reduction of 40% in skin conductance was noted by the end of the second week of treatment prior to any clinical evidence of radiation change. Skin conductance returned to normal in 44% of patients by 6 months. In the remainder, those patients who showed the greatest reduction in skin conductance during treatment demonstrated the least recovery. CONCLUSIONS: Changes in sweat gland function can be detected and quantified in skin which may otherwise appear normal. Differences may so be demonstrated between areas treated using different fractionation schedules and the method may be applied to the detection during radiotherapy of unusually sensitive patient.