This randomized trial compared the rates of delayed xerostomia between two-dimensional radiation therapy (2DRT) and intensity-modulated radiation therapy (IMRT) in the treatment of early-stage ...nasopharyngeal carcinoma (NPC).
Between November 2001 and December 2003, 60 patients with T1-2bN0-1M0 NPC were randomly assigned to receive either IMRT or 2DRT. Primary end point was incidence of observer-rated severe xerostomia at 1 year after treatment based on Radiotherapy Oncology Group /European Organisation for the Research and Treatment of Cancer late radiation morbidity scoring criteria. Parallel assessment with patient-reported outcome, stimulated parotid flow rate (SPFR), and stimulated whole saliva flow rate (SWSFR) were also made.
At 1 year after treatment, patients in IMRT arm had lower incidence of observer-rated severe xerostomia than patients in the 2DRT arm (39.3% v 82.1%; P = .001), parallel with a higher fractional SPFR (0.90 v 0.05; P < .0001), and higher fractional SWSFR (0.41 v 0.20; P = .001). As for patient's subjective feeling, although a trend of improvement in patient-reported outcome was observed after IMRT, recovery was incomplete and there was no significant difference in patient-reported outcome between the two arms.
IMRT is superior to 2DRT in preserving parotid function and results in less severe delayed xerostomia in the treatment of early-stage NPC. Incomplete improvement in patient's subjective xerostomia with parotid-sparing IMRT reflects the need to enhance protection of other salivary glands.
This phase III randomized study compared concurrent cisplatin–radiotherapy (CRT) versus radiotherapy (RT) alone in patients with locoregionally advanced nasopharyngeal carcinoma. A total of 350 ...patients were randomly assigned to receive external RT alone or concurrently with cisplatin at a dosage of 40 mg/m2 weekly. The primary endpoint was overall survival, and the median follow-up was 5.5 years. The 5-year overall survival was 58.6% (95% confidence interval CI = 50.9% to 66.2%) for the RT arm and 70.3% (95% CI = 63.4% to 77.3%) for the CRT arm. In Cox regression analysis adjusted for T stage, age, and overall stage, the difference in overall survival was statistically significantly in favor of concurrent CRT (P = .049, hazard ratio HR = 0.71 95% CI = 0.5 to 1.0). Subgroup analysis demonstrated that there was no difference between overall survival in the arms for T1/T2 stage (P = .74, HR = 0.93 95% CI = 0.59 to 1.4), whereas there was a difference between the arms for T3/T4 stage (P = .013, HR = 0.51 95% CI = 0.3 to 0.88), favoring the CRT arm. The regimen of weekly concurrent CRT is a promising standard treatment strategy for locoregionally advanced nasopharyngeal carcinoma patients.
To compare intensity-modulated radiotherapy (IMRT) with two-dimensional RT (2D-RT) and three-dimensional conformal radiotherapy (3D-CRT) treatment plans in different stages of nasopharyngeal ...carcinoma and to explore the feasibility of dose escalation in locally advanced disease.
Three patients with different stages (T1N0M0, T2bN2M0 with retrostyloid extension, and T4N2M0) were selected, and 2D-RT, 3D-CRT, and IMRT treatment plans (66 Gy) were made for each of them and compared with respect to target coverage, normal tissue sparing, and tumor control probability/normal tissue complication probability values. In the Stage T2b and T4 patients, the IMRT 66-Gy plan was combined with a 3D-CRT 14-Gy boost plan using a 3-mm micromultileaf collimator, and the dose–volume histograms of the summed plans were compared with their corresponding 66-Gy 2D-RT plans.
In the dosimetric comparison of 2D-RT, 3D-CRT, and IMRT treatment plans, the T1N0M0 patient had better sparing of the parotid glands and temporomandibular joints with IMRT (dose to 50% parotid volume, 57 Gy, 50 Gy, and 31 Gy, respectively). In the T2bN2M0 patient, the dose to 95% volume of the planning target volume improved from 57.5 Gy in 2D-RT to 64.8 Gy in 3D-CRT and 68 Gy in IMRT. In the T4N2M0 patient, improvement in both target coverage and brainstem/temporal lobe sparing was seen with IMRT planning. In the dose-escalation study for locally advanced disease, IMRT 66 Gy plus 14 Gy 3D-CRT boost achieved an improvement in the therapeutic ratio by delivering a higher dose to the target while keeping the normal organs below the maximal tolerance dose.
IMRT is useful in treating all stages of nonmetastatic nasopharyngeal carcinoma because of its dosimetric advantages. In early-stage disease, it provides better parotid gland sparing. In locally advanced disease, IMRT offers better tumor coverage and normal organ sparing and allows room for dose escalation.
Recruitment constraints on Singapore's dwindling fluted giant clam, Tridacna squamosa, population were studied by modelling fertilisation, larval transport, and settlement using real-time ...hydrodynamic forcing combined with knowledge of spawning characteristics, larval development, behaviour, and settlement cues. Larval transport was simulated using a finite-volume advection-diffusion model coupled to a three-dimensional hydrodynamic model. Three recruitment constraint hypotheses were tested: 1) there is limited connectivity between Singapore's reefs and other reefs in the region, 2) there is limited exchange within Singapore's Southern Islands, and 3) there exist low-density constraints to fertilisation efficacy (component Allee effects). Results showed that connectivity among giant clam populations was primarily determined by residual hydrodynamic flows and spawning time, with greatest chances of successful settlement occurring when spawning and subsequent larval dispersal coincided with the period of lowest residual flow. Simulations suggested poor larval transport from reefs located along the Peninsular Malaysia to Singapore, probably due to strong surface currents between the Andaman Sea and South China Sea combined with a major land barrier disrupting larval movement among reefs. The model, however, predicted offshore coral reefs to the southeast of Singapore (Bintan and Batam) may represent a significant source of larvae. Larval exchange within Singapore's Southern Islands varied substantially depending on the locations of source and sink reefs as well as spawning time; but all simulations resulted in low settler densities (2.1-68.6 settled individuals per 10,000 m(2)). Poor fertilisation rates predicted by the model indicate that the low density and scattered distribution of the remaining T. squamosa in Singapore are likely to significantly inhibit any natural recovery of local stocks.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To evaluate the efficacy of using intensity-modulated radiotherapy (IMRT) in the primary treatment of nasopharyngeal carcinoma (NPC), including the role of dose escalation above 66 Gy level.
Between ...July 2000 and September 2002, 63 newly diagnosed NPC patients were treated with IMRT. The disease was Stage I in 9 (14%), Stage II in 18 (29%), Stage III in 22 (35%), and Stage IV in 14 (22%). The prescribed dose was 66 Gy to the gross tumor volume (GTV) and positive neck nodes, 60 Gy to the planning target volume (PTV), and 54–60 Gy to the clinically negative neck. All 20 (100%) patients with T1-2a tumors received intracavitary brachytherapy (ICB) boost, and 15/42 (36%) patients with T2b-T4 tumors received conformal boost (8 Gy/4 fractions). Nineteen patients with advanced stage disease also received either neoadjuvant or concurrent chemotherapy. Acute and late normal tissue effects were graded according to the Radiation Therapy Oncology Group (RTOG) radiation morbidity scoring criteria. Local relapse-free survival (LRFS), nodal relapse-free survival (NRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were estimated using the Kaplan-Meier method.
With a median follow-up of 29 months (range 8–45 months), 4 patients developed local in-field failure, 1 patient developed regional relapse, and 13 patients developed distant metastases. All 4 patients with local failure had either T3 or T4 disease before primary treatment and did not have ICB or conformal boost. The 3-year actuarial LRFS, NRFS, DMFS, and OS were 92%, 98%, 79%, and 90%, respectively. Multivariate analysis showed that dose escalation above 66 Gy was significantly associated with better PFS and DMFS, whereas GTV size was a significant adverse factor for OS. The worst acute mucositis was Grade 1 or 2 in 36 (59%), and Grade 3 in 25 (41%) patients. Acute dysphagia requiring tube feeding occurred in 5 (8%) patients. The proportion of patients with Grade 2-3 xerostomia was 57% at 3 months, and 23% at 2 years after IMRT. Within the subset of patients with a mean parotid dose of <31 Gy, the proportions with Grade 2-3 xerostomia were 30% and 17% at 3 months and 2 years, respectively.
Our experience of using IMRT in the primary treatment of NPC showed a very high rate of locoregional control and favorable toxicity profile. Furthermore, we found that dose escalation above 66 Gy of IMRT-based therapy was a significant determinant of progression-free survival and distant metastasis-free survival for advanced T-stage tumors. Distant metastases represent the predominant mode of treatment failure.
Organ-confined muscle-invasive bladder cancer is treated with cystectomy or bladder preservation techniques, including radiation therapy. There are currently no biomarkers to inform management ...decisions and aid patient choice. Previously we showed high levels of MRE11 protein, assessed by immunohistochemistry (IHC), predicted outcome after radiation therapy, but not cystectomy. Therefore, we sought to develop the MRE11 IHC assay for clinical use and define its relationship to clinical outcome in samples from 2 major clinical trials.
Samples from the BCON and BC2001 randomized controlled trials and a cystectomy cohort were stained using automated IHC methods and scored for MRE11 in 3 centers in the United Kingdom.
Despite step-wise creation of scoring cards and standard operating procedures for staining and interpretation, there was poor intercenter scoring agreement (kappa, 0.32; 95% confidence interval, 0.17-0.47). No significant associations between MRE11 scores and cause-specific survival were identified in BCON (n = 132) and BC2001 (n = 221) samples. Reoptimized staining improved agreement between scores from BCON tissue microarrays (n = 116), but MRE11 expression was not prognostic for cause-specific survival.
Manual IHC scoring of MRE11 was not validated as a reproducible biomarker of radiation-based bladder preservation success. There is a need for automated quantitative methods or a reassessment of how DNA-damage response relates to clinical outcomes.
Purpose: Tumor hypoxia is known to be associated with resistance to chemotherapy, radiotherapy, and poorer survival. Recently, it
is shown that hypoxia induces the expression of hypoxia-inducible ...factor-1α and 2α (HIF-1α and HIF-2α), which then up-regulates
the expression of downstream genes such as carbonic anhydrase IX (CA IX) and vascular endothelial growth factor (VEGF).
Experimental Design: We examined the expression of HIF-1α, HIF-2α, CA IX, and VEGF by immunohistochemistry in nasopharyngeal carcinoma (NPC) biopsies
from 90 consecutive patients recruited between 1994 and 1997 in a randomized controlled trial of chemoradiation in locally
advanced NPC and investigated their relationship with survival.
Results: HIF-1α was expressed in 52 of 90 (58%), HIF-2α in 6 of 89 (7%), CA IX in 51 of 90 (57%), and VEGF in 54 of 90 (60%) of tumors.
Tumor HIF-1α expression correlated significantly with that of CA IX ( P = 0.008) and VEGF ( P = 0.003). High tumor HIF-1α expression was associated with a trend for poor overall survival ( P = 0.06). Tumors with a positive hypoxic profile (defined as high expression of both HIF-1α and CA9) were associated with
worse progression-free survival ( P = 0.04). Tumors with both hypoxic and angiogenic profile (defined as high VEGF expression) were associated with a worse progression-free
survival ( P = 0.0095).
Conclusion: Overexpression of HIF-1α, CA IX, and VEGF is common in NPC, which is probably related to hypoxia up-regulated expression
involving a HIF-dependent pathway, and is associated with poor prognosis. Targeting the hypoxia pathway may be useful in the
treatment of NPC.
Purpose:
To study the factors affecting the risk of symptomatic temporal lobe necrosis after different fractionation schedules.
Methods and Materials:
One thousand thirty-two patients with T1-2 ...nasopharyngeal carcinoma treated with radical radiotherapy in Hong Kong during 1990–1995 were studied. They were treated at four different centers with similar techniques but different fractionation schedules: 984 patients were given 1 fraction daily throughout (q.d.), and 48 patients were irradiated twice daily (b.i.d.) for part of the course. The median total dose was 62.5 Gy (range 50.4–71.2), dose per fraction was 2.5 Gy (range 1.6–4.2), and overall treatment time (OTT) was 44 days (range 29–70). In addition, 500 patients received supplementary doses for parapharyngeal extension, 113 received booster doses by brachytherapy, and 114 received sequential chemotherapy using cisplatin-based regimes.
Results:
Altogether, 24 patients developed symptomatic temporal lobe necrosis: 18 from the q.d. group and 6 from the b.i.d. group. The 5-year actuarial incidence ranged from 0% (after 66 Gy in 33 fractions within 44 days) to 14% (after 71.2 Gy in 40 fractions within 35 days). Multivariate analyses showed that the risk was significantly affected by the fractional effect of the product of total dose and dose per fraction (hazard ratio HR = 1.04, 95% confidence interval CI 1.02–1.05), OTT (HR 0.88, 95% CI 0.80–0.97), and b.i.d. scheduling (HR 13, 95% CI 3–54). Repeating the analyses for patients treated with the q.d. schedules confirmed the independent significance of OTT in addition to the product of total dose and dose per fraction.
Conclusion:
The tentative results suggest that in addition to fractional dose, the OTT also had significant impact on the risk of temporal lobe necrosis, and b.i.d. scheduling increased the hazard further.
Adaptive radiotherapy (ART) has recently been introduced to restore the planned dose distribution by accounting for the anatomic changes during treatment. By quantifying the anatomic changes in ...nasopharyngeal carcinoma (NPC) patients, this study aimed to establish an ART strategy for NPC cases. A total of 30 NPC patients treated with helical tomotherapy were recruited. In the pretreatment megavoltage CT images, the anatomic changes of the posterolateral wall of nasopharynx (P-NP), neck region and parotid glands were measured and assessed. One-way repeated measure ANOVA was employed to define threshold(s) at any time-point. The presence of a threshold(s) would indicate significant anatomical change(s) such that replanning should be suggested. A pragmatic schedule for ART was established by evaluating the threshold for each parameter. Results showed the P-NP, parotid gland and neck volumes demonstrated significant regressions over time. Respectively, the mean loss rates were 0.99, 1.35, and 0.39 %/day, and the mean volume losses were 35.70, 47.54 and 11.91% (all P < 0.001). The parotid gland shifted medially and superiorly over time by a mean of 0.34 and 0.24 cm, respectively (all P < 0.001). The neck region showed non-rigid posterior displacement, which increased from upper to lower neck. According to the threshold occurrences, three replans at 9th, 19th and 29th fractions were proposed. This ART strategy was able to accommodate the dosimetric consequences due to anatomic deviation over the treatment course. It is clinically feasible and would be recommended for centers where an adaptive planning system was not yet available.
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