Radiotherapy and Oncology

Published by Elsevier
Print ISSN: 0167-8140
Residual damage in haemopoietic progenitor cell populations, spleen and granulocyte-macrophage colony-forming cells (CFU-S and GM-CFC) was detected in mice after 15 daily fractions where the dose per fraction was as low as 0.1 Gy. The injury was dose-dependent and after higher total fractionated doses of 7.5-10 Gy the CFU-S population recovered to about 50% of control between 2 and 12 months after irradiation. Residual damage was also detected in the stroma, in the form of reduced numbers of fibroblastoid colony-forming cells and of CFU-S in ossicles under the kidney capsule. The response to a second course of 15 fractions, given 3 weeks after the end of the first course, was similar and additive to the response to the first course in the short term. However, in the long term, recovery levels were similar after either one or two courses.
To evaluate the impact of two different methods of geometric distortion correction of MR images from a Siemens Magnetom Open Viva 0.2T resistive MR unit on the process of external beam radiotherapy treatment planning for prostate cancer. A method for correction of system related and object induced distortions and one for correction of purely system related distortions have been evaluated. The latter used information extracted from MR images of a 3D phantom specifically designed for geometric distortion evaluation. An active shim procedure was performed prior to all phantom and patient scans. For each of five patients five standard treatment plans were compared using uncorrected and corrected MR images alone (density=water) and CT images alone. Finally internal anatomical landmarks were used for image registration between MR images (corrected and uncorrected) and CT images to evaluate the impact of distortion correction on the image registration process. Maximum distortions of 28 mm (mean 2.2 mm) were found within the FOV in frequency encode direction. Maximum distortions could be reduced by a factor of two (mean factor four) by our phantom measurement based technique. Distortion patterns were found to be stable and reproducible over several weeks with this MR unit. For 4/5 patients, relative doses at the normalization point as calculated on the distortion corrected MR images only (all tissues taken water equivalent) were all within 1% of the corresponding value from the standard CT-based plan (actual Hounsfield units). The largest differences in isocentric dose found in one case were 3.1% MR uncorrected vs. CT and 2.6% MR corrected vs. CT. Typical sites of internal anatomical landmarks chosen for image registration show distortions up to 3 mm. Object induced distortions are negligible at such low field strengths compared to system related distortions. Treatment plans for prostate cancer do not seem to differ significantly from "standard" plans calculated on CT images when calculated on distortion corrected MR images, even if all tissues are assigned the electron density of water. Distortion correction of MR images can theoretically improve the starting point for image registration of MR and CT images.
Magnetic resonance (MR) imaging is widely recognised as the modality of choice for imaging soft tissue such as the target volume and critical structures relevant to high dose rate (HDR) brachytherapy of the cervix. This work sets out to assess some of the issues faced when introducing this technique clinically compared to the more widely used computed tomography (CT). MR can be used either as the sole imaging modality, or in conjunction with CT. Distortion of the images produced by the MR scanner was assessed with a geometrical phantom. Distortion local to the titanium applicators, introduced by the susceptibility of the applicators themselves, was also measured. The technique used to reconstruct applicators is briefly described. An inter-operator study was performed to assess the variability of applicator reconstruction between operators when MR images are used alone to reconstruct the applicators. A 14-cm cube within which distortion was less than 2mm at all points was identified. The inter-operator study showed some variability in applicator reconstruction with both MR and CT (median MR/CT 1.3mm/0.9 mm, range 0-3.6mm/0-3.3mm). Inter-operator variation in planning target volume (PTV) V 100% and PTV D 90% for MR/CT was 6.1%/3.0% and 7.4%/6.3%, respectively, and D(2cc) OAR doses varied by up to 1.0 Gy between operators for both MR and CT. In this study distortion was minimal within a defined volume and inter-observer errors were comparable on MR and CT when used to define applicators and when applied to dose-volume histograms (DVHs). However this does not assure the technique is appropriate with other scanners and applicator sets without further commissioning.
Comorbidity is common in head and neck squamous cell carcinoma (HNSCC) patients due to the etiology of the disease being primarily smoking. The aim of this study was to investigate the impact of comorbidity on survival in a national population-based cohort study on 9388 HNSCC-patients treated with radiotherapy (RT), to re-evaluate the prognostic impact of individual diseases within the Charlson Comorbidity Index (CCI), and to develop a revised head and neck comorbidity index (HN-CCI). A national cohort of 9388 HNSCC-patients treated with curative intended RT diagnosed from 1992 to 2008 was identified from the DAHANCA-database. Data on comorbidity prior to HNSCC-diagnosis was obtained from the National Patient Registry and adapted to the CCI. By dividing the patients into two groups, we tested and validated which type of comorbidities within the CCI affected overall survival (OS) and cancer specific death (CSD). In total, 36% of patients had comorbidity. Six comorbid conditions within the CCI significantly reduced five-year OS probability: congestive heart failure, cerebrovascular disease, chronic pulmonary disease, peptic ulcer disease, liver disease, and diabetes, and based on these conditions the new head and neck specific comorbidity index was developed, the HN-CCI. Comorbidity according to HN-CCI had a highly significant impact on OS, whereas it was not associated with CSD. Chronological age was not associated with increased risk of CSD after controlling for comorbidity. Comorbidity is frequent in HNSCC patients and negatively impacts OS. Therefore assessment of comorbidity will be of great importance, both in order to treat/optimize patient's health before radiotherapy, but also in order to be able to stratify/control for comorbidity in randomized trials to avoid bias. Re-evaluation of the CCI revealed that only six conditions had an impact on survival, and a new modified index to assess comorbidity for HNSCC-patients was developed. The performance of HN-CCI to stratify patients on survival was good and HN-CCI is highly recommended for future assessment of comorbidity and prognostic staging of radiotherapy-treated HNSCC-patients.
The applicability of various detectors for small field dosimetry and whether there are differences in the detector response when irradiated with FF- and FFF-beams was investigated. Output factors of 6 and 10MV FF- and FFF-beams were measured with 14 different online detectors using field sizes between 10×10 and 0.6×0.6cm(2) at a depth of 5cm of water in isocentric conditions. Alanine pellets with a diameter of 5 and 2.5mm were used as reference dosimeters for field sizes down to 1.2×1.2 and 0.6×0.6cm(2), respectively. The ratio of the relative output measured with the online detectors to the relative output measured with alanine was evaluated (referred to as dose response ratio). The dose response ratios of two different shielded diodes measured with 10MV FF-beams deviated substantially by 2-3% compared to FFF-beams at a field size of 0.6×0.6cm(2). This difference was less pronounced for 6MV FF- and FFF-beams. For all other detectors the dose response ratios of FF- and FFF-beams showed no significant difference. The dose response ratios of the majority of the detectors agreed within the measurement uncertainty when irradiated with FF- and FFF-beams. Of all investigated detectors, the microDiamond and the unshielded diodes would require only small corrections which make them suitable candidates for small field dosimetry in FF- and FFF-beams.
Measured OR f clin det data plotted as a function of the nominal (left) and effective (right) field sizes. Shown in the Supplementary Materials are the effective field sizes and measured output ratios presented in a table form. SCC-0,-1,-2 and QUT-1,-2 are labels for the five Varian iX linacs used in this study (See Supplementary Materials for details). It should be noted that the output ratio and measured field widths for linac SCC-0 are from Cranmer-Sargison et al. [8] and therefore do not include the full characterization in field width uncertainty. 
DOSXYZnrc simulation data showing the relationship between the dosimetric field widths plotted as a function of the geometric field width for the upper (left) and lower (right) jaws, incident electron energy (top) and FWHM (bottom). 
DOSRZnrc simulated OR f clin det data (solid line) plotted as a function of the nominal field size (left) and effective field size (right) calculated for the incident electron FWHM shown in Fig. 2. In all cases experimental data are given as a function of the effective field size. The solid line connecting the MC data points is included as a guide only and does not represent a functional fit. 
Corrected relative output data plotted as a function of the measured effective field size. The dashed lines connect the data points and do not represent a functional fit. 
The goal of this work was to set out a methodology for measuring and reporting small field relative output and to assess the application of published correction factors across a population of linear accelerators. Measurements were made at 6MV on five Varian iX accelerators using two PTW T60017 unshielded diodes. Relative output readings and profile measurements were made for nominal square field sizes of side 0.5 to 1.0cm. The actual in-plane (A) and cross-plane (B) field widths were taken to be the FWHM at the 50% isodose level. An effective field size, defined as FSeff=A·B, was calculated and is presented as a field size metric. FSeff was used to linearly interpolate between published Monte Carlo (MC) calculated [Formula: see text] values to correct for the diode over-response in small fields. The relative output data reported as a function of the nominal field size were different across the accelerator population by up to nearly 10%. However, using the effective field size for reporting showed that the actual output ratios were consistent across the accelerator population to within the experimental uncertainty of ±1.0%. Correcting the measured relative output using [Formula: see text] at both the nominal and effective field sizes produce output factors that were not identical but differ by much less than the reported experimental and/or MC statistical uncertainties. In general, the proposed methodology removes much of the ambiguity in reporting and interpreting small field dosimetric quantities and facilitates a clear dosimetric comparison across a population of linacs.
Prior to randomization of patients into the UK Medical Research Council multicentre randomized trial (RT-01) of conformal radiotherapy (CFRT) in prostate cancer, clinicians at participating centres were required to complete a quality assurance (QA) clinical planning exercise to enable an investigation of inter-observer variability in gross target volume (GTV) and normal structure outlining. Thirteen participating centres and two investigators completed the clinical planning exercise of three practice planning cases. Clinicians were asked to draw outlines of the GTV, rectum and bladder on hard-copy computerized tomography (CT) films of the pelvis, which were transferred onto the Cadplan computer planning system by a single investigator. Centre, inferior and superior CT levels of GTV, rectum and bladder were noted, and volume calculations performed. Planning target volumes (PTV) were generated using automatic volume expansion of GTVs by a 1 cm margin. Anterior, right and left lateral beam eye views (BEV) of the PTVs were generated. Using a common central point, the BEV PTVs were superimposed for each beam direction of each case. Radial PTV variation was investigated by measurement of a novel parameter, termed the radial line measurement variation (RLMV). GTV central slice and length were defined with reasonable consistency. The RLMV analysis showed that the main part of the prostate gland, bladder and inferior rectum were outlined with good consistency among clinicians. However, the outlining of the prostatic apex, superior aspect of the prostate projecting into the bladder, seminal vesicles, the base of seminal vesicles and superior rectum were more variable. This exercise has demonstrated adequate consistency of GTV definition. The RLMV method of analysis indicates particular regions of clinician uncertainty. Appropriate feedback has been given to all participating clinicians, and the final RT-01 trial protocol has been modified to accommodate these findings.
Randomised trial ICORG 97-01 (1997–2001). Four month neo-adjuvant hormone therapy (arm 1) versus 8months (arm 2) prior to radiation. N0 M0. Participant flow.
Survival of erectile function grades 1–2 (sufficient for penetration) for patients randomly assigned to 4months neo-adjuvant hormone therapy (4; n=62) versus 8months (8; n=79), prior to radiation (median duration of follow-up: 87months).
Erectile dysfunction is a common consequence of external beam radiotherapy (EBRT) for prostate cancer. The addition of neo-adjuvant androgen deprivation (NAD) has an indeterminate additive effect. We examined the long-term effect on erectile function (EF) of two durations (4 months: arm 1 and 8 months: arm 2) of NAD prior to radiation (RT) for patients with localised prostate cancer from the Irish Clinical Oncology Research Group (ICORG 97-01) 4- versus 8-month trial. In this study we aimed to (1) analyse the overall effect on EF of NAD in an EBRT population, (2) compare the probability of retained EF over time in an EBRT population treated with either 4 or 8 months of NAD and (3) identify any variables such as risk group and age which may have an additive detrimental effect. This analysis provides unique long term follow up data. From 1997 to 2001, 276 patients with adenocarcinoma of the prostate were randomised to 4 or 8 months of NAD before RT. EF data were recorded at baseline and at each follow-up visit by physician directed questions, using a 4-point grading system. Two hundred and thirty patients were included in the analysis of EF and were followed for a median of 80 months. One hundred and forty-one patients had EF at baseline. Neo-adjuvant androgen deprivation in addition to radiation therapy caused a significant reduction in EF. The most significant reduction in EF happens within the first year. The median time to grade 3-4 EF toxicity was 14.6 months, 17.6 months in arm 1 and 13.7 in arm 2. Freedom from late EF toxicity did not differ significantly between arms, overall or at 5 years (n=141). The cumulative probability of EF preservation at 5 years was 28% (22-34) in arm 1 and 24% (19-30) in arm 2. Age was a significant predictor of post-treatment EF. The first year post ADT and EBRT poses the greatest risk to sexual function and a continued decline may be expected. However, 26% of men can expect to retain sexual function at 5 years.
To investigate the effects of starting gantry angle and number of equiangular-spaced beams for prostate cancer radiotherapy on the Radiation Therapy Oncology Group (RTOG) 0126 protocol using intensity-modulated radiation therapy (IMRT). Ten localized prostate cancer patients were prescribed to 79.2Gy in 44 fractions. Static IMRT plans using five and seven equiangular-spaced beams were generated. The starting gantry angles were incremented by 5 degrees resulting in 15 (5 beams) and 11 (7 beams) plans per patient. Constant target coverage was ensured for all plans in order to isolate the variation in the rectal and bladder metrics as a function of starting gantry angle. The variation with starting gantry angle in rectal metrics using 5 beams was statistically significant (p<0.001) with dosimetric importance. The 5-beam rectal V 75Gy and V 70Gy demonstrated a class solution with a characteristic 'W' pattern and two optimal starting gantry angles near 20 degrees and 50 degrees . Statistically insignificant differences were observed for the bladder metrics using 5 beams. There was little dosimetric variation in the rectal and bladder metrics with 7 beams. Nearly equivalent rectal V 75Gy was achieved between 5 optimal equiangular-spaced beams starting at 20 degrees (class solution) and 7 equiangular-spaced beams starting at 0 degrees for most patients. The use of an optimal starting gantry angle for 5 equiangular-spaced beams, as indicated by a class solution in this study, will facilitate rectal sparing and can produce plans that are equivalent to those employing 7 equiangular-spaced beams.
Randomised trials testing 15- or 16-fraction regimens of adjuvant radiotherapy in women with early breast cancer have reported favourable outcomes compared with standard fractionation. To evaluate hypofractionation further, two 5-fraction schedules delivering 1 fraction per week have been tested against a 25-fraction regimen. Women aged ⩾50years with node negative early breast cancer were randomly assigned after microscopic complete tumour resection to 50Gy in 25 fractions versus 28.5 or 30Gy in 5 once-weekly fractions of 5.7 or 6.0Gy, respectively, to the whole breast. The primary endpoint was 2-year change in photographic breast appearance. Nine hundred and fifteen women were recruited from 2004 to 2007. Seven hundred and twenty-nine patients had 2-year photographic assessments. Risk ratios for mild/marked change were 1.70 (95% CI 1.26-2.29, p<0.001) for 30Gy and 1.15 (0.82-1.60, p=0.489) for 28.5Gy versus 50Gy. Three-year rates of physician-assessed moderate/marked adverse effects in the breast were 17.3% (13.3-22.3%, p<0.001) for 30Gy and 11.1% (7.9-15.6%, p=0.18) for 28.5Gy compared with 9.5% (6.5-13.7%) after 50Gy. With a median follow-up in survivors of 37.3months, 2 local tumour relapses and 23 deaths have occurred. At 3years median follow-up, 28.5Gy in 5 fractions is comparable to 50Gy in 25 fractions, and significantly milder than 30Gy in 5 fractions, in terms of adverse effects in the breast.
The use of polarographic needle electrodes for measurement of oxygen tension (pO2) in tumours requires documentation of the validity of the method. In the present work the pO2 values measured polarographically with the Eppendorf pO2 histograph in human tumours were compared with the histological appearance of the tumour tissue, i.e. vascular density, fraction of necrosis and fraction of hypoxic tissue, to investigate whether the measurements reflected the expected pO2. The pO2 was measured in cervix tumours in patients and in human melanoma xenografted tumours in athymic mice. Vascular density was determined in the cervix tumours by histological analysis of biopsies from the pO2 measurement tracks. Fraction of necrosis and fraction of hypoxic tissue, i.e. tissue binding the hypoxia marker pimonidazole, were determined in the melanomas by analysis of histological sections from the tumour planes in which the pO2 measurements were performed. The pO2 distributions showed large intratumour heterogeneity. In cervix tumours, tumour regions with vascular density (vascular length per unit tissue volume) in the range of 47-77 mm/mm3 showed higher pO2 than tumour regions with vascular density in the range of 20-47 mm/mm3, which in turn showed higher pO2 than tumour regions with vascular density in the range of 0-20 mm/mm3. In melanomas, tumour regions in which necrosis and hypoxia constituted more than 50% of the tissue showed lower pO2 than other tumour regions. The pO2 measured in the tumours was consistent with the histological appearance of the tissue in which the measurements were performed, suggesting that reliable pO2 distributions of tumours can be obtained with polarographic needle electrodes.
Purpose: After publication of EORTC-22863 trial, prolonged androgen deprivation therapy (ADT) combined with radiation therapy (RT) became standard policy for high-risk prostate cancer patients in British Columbia (BC) in 1997. We evaluated whether population-based survival improved after this policy change. Patients and methods: Two cohorts comprising all patients with T3-T4 prostate cancer treated with curative-intent RT in BC were reviewed. The Early cohort (n=730) was all patients treated between 1993 and 1995, and the Late cohort (n=584) was all patients treated between 1999 and 2001. The BC Cancer Registry, which collects data on survival, was linked to RT and pharmacy databases. Duration of ADT, age, stage, grade, presenting PSA, and Charlson comorbidity index (CCI; none=0, minor=1, major=2+), were abstracted from charts. Results: Usage of ≥6 months and ≥18 months of neoadjuvant and adjuvant ADT increased from 14% and 1% to 97% and 59% (p<0.0001). Baseline characteristics were similar, except for lower Gleason score (G2-6: 45% vs. 20%, G7: 35% vs. 48%, G8-10: 19% vs. 32%; p<0.0001), higher T-stage (T4: 9% vs. 5%, p=0.004) and higher comorbidity (CCI 0: 62% vs. 71%, CCI 1: 26% vs. 20%, CCI 2+: 11% vs. 9%, p=0.002) in the Early cohort. Disease-specific survival adjusted for competing risks from other causes mortality was improved (90% vs. 86%, p=0.042). On multivariate analysis, the Late cohort was independently associated with improved 8-year overall survival (76% vs. 64%, p=0.0002). Conclusions: This population-based study demonstrated improved overall survival following a policy change to use of prolonged ADT with curative RT for patients with T3-T4 prostate cancer.
The aim of this study was to evaluate the efficacy and safety of a two-week schedule of radiotherapy with oral capecitabine in locally advanced rectal cancer. Eighty patients with rectal cancer located in the mid to low rectum, staged cT3-4N0-2M0, were prospectively enrolled. They underwent preoperative chemoradiotherapy and delayed surgery 6-8weeks after the completion of radiation therapy. A radiation dose of 33Gy in 10 fractions was delivered to the pelvis for 2weeks. One cycle of oral capecitabine was administered at a dose of 1650mg/m(2)/day during radiotherapy. Tumor response and toxicity were the study endpoints. This study was registered at (number, NCT01431599). All included patients underwent total mesorectal excisions including 12 cases of robot assisted surgery and 50 cases of laparoscopic surgery. Of the 80 patients, 27 (33.8%) achieved downstaging (ypT0-2N0) of a rectal tumor and 11 (13.8%) had a pathologically complete response (ypCR). Downstaging rates were 45% for T classification and 65% for N classification. Sphincter saving was achieved in 73 (91.3%) of the 80 patients. Of the 80 patients, 3 (3.8%) experienced grade 3 hematologic toxicity, and 2 (2.5%) had grade 3 postoperative complications such as ileus and wound dehiscence. There was no grade 4 toxicity. A two-week schedule of radiotherapy with oral capecitabine in locally advanced rectal cancer patients showed low toxicity profiles and promising results in terms of tumor response.
Acute toxicities
RTOG 95-02 assessed patient tolerance to hypoxic cell radiosensitizer, etanidazole (SR-2508), combined with radiosurgery. Patients had primary or metastatic brain tumors and previously localized or whole brain irradiation. The toxicity is reported in three groups of patients according to the tumor size. Etanidazole doses of 12g/m2 combined with radiosurgery were well tolerated.
To prospectively investigate the effect of radiotherapy fraction size on clinical outcomes in early glottic carcinoma METHODS AND MATERIALS: Patients with T1-2 glottic carcinoma were eligible for the protocol. Although 282 patients were required, the study was closed prematurely due to poor accrual with only 156 patients. Of these, 82 were allocated to conventional fractionation (CONV) arm (66Gy/33 fractions/6.5weeks), with 74 to hypofractionation (HYPO) arm (63Gy/28 fractions/5.5weeks). The primary objective was local progression-free survival (LPFS). With a median follow-up of 67months (range, 2-122months), the 5-year LPFS was 77.8% for CONV arm and 88.5% for HYPO arm (HR 1.55, p=0.213). No significant difference was observed in the toxicity profile between the two arms. In a subgroup exploratory analysis for T1a disease, the 5-year LPFS trended positively in HYPO arm (76.7% vs. 93.0%, HR 3.65, p=0.056). Given that HYPO is at least not inferior to CONV with a similar toxicity profile, the hypofractionation scheme used in this study can be offered to patients with T1-2 glottic carcinoma with potential advantages in terms of local control and a shortened overall treatment time.
Irradiation of the supraclavicular lymph nodes has historically increased the risk of brachial plexopathy. We report long-term symptoms after modern radiotherapy (based on 3D dose planning) in breast cancer patients with or without irradiation of the supraclavicular lymph nodes. We collected information from 814 women consecutively treated with adjuvant radiotherapy for breast cancer. The women had breast surgery with axillary dissection (AD) or sentinel node biopsy (SNB). The breast area was treated to 50 Gy in 2.0 Gy fractions. Women with >three lymph node metastases had regional radiotherapy (RRT) to the supraclavicular lymph nodes. Three to eight years after radiotherapy, they received a questionnaire asking about paraesthesia, oedema, pain, and strength in the upper limb. Paraesthesia was reported by 38/192 (20%) after AD with RRT compared to 68/505 (13%) after AD without RRT (relative risk [RR] 1.47; 95% confidence interval [CI] 1.02-2.11) and by 9/112 (8%) after SNB without RRT (RR 2.46; 95% CI 1.24-4.90). Corresponding risks adjusted for oedema (RR 1.28; 95% CI 0.93-1.76) and (RR 1.75; 95% CI 0.90-3.39). In women ≤ 49years with AD and RRT, 27% reported paraesthesia. No significant pain or decreased strength was reported after RRT. Radiotherapy to the supraclavicular lymph nodes after axillary dissection increases the occurrence of paraesthesia, mainly among younger women. When adjusted for oedema the contribution from radiotherapy is no longer formally statistically significant indicating that there is also an indirect effect mediated by the oedema.
This randomized phase III trial investigated the potential benefit of concurrent re-irradiation, fluorouracil and hydroxyurea versus methotrexate for patients treated with palliative intent for recurrent or second primary head and neck squamous cell carcinoma (HNSCC) in previously irradiated area. Patients with recurrent HNSCC or a second primary not amenable to curative-intent treatment were randomized to the R-RT arm (concurrent re-irradiation, fluorouracil and hydroxyurea) or to the Ch-T arm (methotrexate). The primary endpoint was overall survival (OS). Due to a very slow accrual, the trial was closed after inclusion of 57 patients. Fifty-seven patients were included. All patients died in the two arms with a maximal follow-up of 5years. Although four complete responses were achieved in R-RT arm, (none in Ch-T arm) re-irradiation did not improve OS compared with methotrexate (23% versus 22% at 1year, NS). Sixteen patients experienced clinical grade ⩾3 late toxicities (>6months), 11 in R-RT arm and five in Ch-T arm. Premature discontinuation of the trial did not allow us to draw firm conclusions. However, there was no suggestion that concurrent re-irradiation, fluorouracil and hydroxyurea improved OS compared to methotrexate alone in patients treated with palliative intent for a recurrent or second primary HNSCC.
The aim of this study was to prospectively assess the quality of life (QOL) of patients treated by concomitant chemo radiation for locally advanced anal canal carcinoma. We report on a subgroup of 119 patients enrolled in a 306-patient therapeutic intensification prospective trial (ACCORD 03). This trial evaluated the impact on colostomy-free survival of induction chemotherapy and/or high dose radiotherapy (factorial design 2 *2 treatment arms). QOL was assessed both before and 2 months after treatment using the EORTC QLQ-C30 questionnaire as well as a questionnaire relating to anal sphincter conservative treatment (AS-CT). Compared to pre-treatment scores, patients reported significant improvement in their emotional function (+8.4 points p=0.002), global health status (+5.9 points p=0.0007), as well as a decrease in insomnia (-13.8 points p<0.0001), constipation (-12.0 points p<0.0001), appetite loss (-10.3 points p<0.0001) and pain (-9.6 points p=0.0002). The AS-CT degree of satisfaction with intestinal functions score was increased (+11.2 points p<0.0001). This is the first prospective study comparing QOL of patients with advanced anal canal carcinoma, before and 2 months after conservative treatment. Two months after treatment, QOL was improved. Induction chemotherapy and/or high dose radiotherapy did not provide a negative impact on QOL.
The hypoxic cell sensitizer Ro 03-8799 has been given with radiotherapy to achieve complete and sustained regression in 5 of 7 cases of recurrent malignant melanoma treated with the object of cure and in 1 of 3 treated palliatively. Particularly high tumour concentrations of this radiosensitizing drug have been found in 3 of 6 cases studied.
In 2003, the French Authority for Health (HAS) recommended the use of intensity modulated radiotherapy (IMRT) in prospective trial before its routine use. The Oncology and Radiotherapy Group for Head and Neck Cancer (GORTEC) proposed to evaluate prospectively acute and late toxicities, locoregional control and overall survival for patients treated for head and neck cancer (HNC) with IMRT and bilateral neck irradiation. Between 2002 and 2008, 208 patients with HNC were treated with IMRT in 8 centres. There were 38 nasopharynx, 117 oropharynx, 25 pharyngo-larynx, 24 oral cavity and 4 unknown primary (28.5% stage I-II and 71% Stage III-IV). Ninety-three patients (46%) had postoperative IMRT and 78 patients (37.5%) received concurrent chemotherapy. The doses were 70 Gy to the gross tumour, 66 Gy to the high-risk postoperative sites and 50 Gy to the subclinical disease. Toxicities were graded according to the RTOG-EORTC scales. The median follow-up was 25.3 months (range: 0.4-72 months). There were 29 local-regional failures: 24 were in-field, three were marginal and one was out-field. The two-year loco-regional control and overall survival were 86% and 86.7%, respectively. At 18 months, grade ≥ 2 xerostomia was 16.1%. A mean dose to the spared parotid below 28 Gy led to significantly less grade ≥ 2 xerostomia (8.5% vs 24%) with a relative risk of 1.2 [95% CI: 1.02-1.41, p = 0.03]. Grade ≥ 2 xerostomia increased by approximately 3% per Gy of mean parotid dose up to 28, Gy then 7% per Gy above 33 Gy. IMRT for HN cancer seems to reduce late toxicities without jeopardising local control and overall survival.
Background: The RADAR trial determines whether adjuvant androgen suppression, bisphosphonates and radiation dose escalation for localised prostate cancer (PC) may improve oncologic outcomes. This study examines whether these measures increase rectal and urinary dysfunction and are secondary trial endpoints. Methods: Using a 2×2 factorial trial design men with locally advanced PC were randomly allocated 6 months i.m. leuprorelin prior to radiotherapy either alone or followed by 12 months i.m. leuprorelin. These two groups received 18 months i.v. zoledronic acid (Z) commencing at randomisation or no further treatment. Radiotherapy dose was escalated in a regulated way using external beam techniques (EBRT) or by a high dose rate brachytherapy (HDRB) boost. Prevalence rates of rectal and urinary dysfunctional symptoms were compared at baseline, the end of RT, 18 and 36 months according to treatment arm, dose and technique using multiple regression models. Results: Between 2003 and 2007, 1071 men were randomly allocated and eligible for inclusion in this study. No persistent differences in rectal or urinary dysfunction were attributable to treatment arm or to increasing EBRT dose. However following HDRB statistical increases (p<0.001) in urinary dysfunction were measured using the EORTC PR25 instrument at 18 and 36 months. Conclusion: Adjuvant androgen suppression, bisphosphonates and increasing EBRT dose did not increase rectal or urinary dysfunction in this trial. However dose escalation using HDRB increased urinary dysfunction.
A multi-centre clinical trial for prostate cancer patients provided an opportunity to introduce conformal radiotherapy with dose escalation. To verify adequate treatment accuracy prior to patient recruitment, centres submitted details of a set-up accuracy study (SUAS). We report the results of the SUAS, the variation in clinical practice and the strategies used to help centres improve treatment accuracy. The SUAS required each of the 24 participating centres to collect data on at least 10 pelvic patients imaged on a minimum of 20 occasions. Software was provided for data collection and analysis. Support to centres was provided through educational lectures, the trial quality assurance team and an information booklet. Only two centres had recently carried out a SUAS prior to the trial opening. Systematic errors were generally smaller than those previously reported in the literature. The questionnaire identified many differences in patient set-up protocols. As a result of participating in this QA activity more than 65% of centres improved their treatment delivery accuracy. Conducting a pre-trial SUAS has led to improvement in treatment delivery accuracy in many centres. Treatment techniques and set-up accuracy varied greatly, demonstrating a need to ensure an on-going awareness for such studies in future trials and with the introduction of dose escalation or new technologies.
Summary of patient's characteristics.
Sites of loco-regional recurrence (LRR).
LRR after sub-classification of patients based on molecular profiling.
Five-year overall survival rates within the low (L), intermediate (I) and high (H) risk group.
The loco-regional recurrence rates within the low (L), intermediate (I) and high (H) risk group.
Post mastectomy radiotherapy (PMRT) reduces loco-regional recurrence (LRR) and has been associated with survival benefit. It is recommended for patients with T3/T4 tumours and/or ⩾4 positive lymph nodes (LN). The role of PMRT in 1-3 positive LN and LN negative patients is contentious. The C-PMRT index has been designed for selecting PMRT patients, using independent prognostic factors for LRR. This study reports a 10year experience using this index. The C-PMRT index was constructed using the following prognostic factors (a) number of positive LN/lymphovascular invasion, (b) tumour size (c) margin status and (d) tumour grade. Patients were categorised as high (H) risk, intermediate (I) risk and low (L) risk. PMRT was recommended for H and I risk patients. The LRR, distant metastasis and overall survival (OS) rates were measured from the day of mastectomy. From 1999 to 2009, 898 invasive breast cancers in 883 patients were treated by mastectomy (H: 323, I: 231 and L: 344). At a median follow up of 5.2years, 4.7% (42/898) developed LRR. The 5-year actuarial LRR rates were 6%, 2% and 2% for the H, I and L risk groups, respectively. 1.6% (14/898) developed isolated LRR (H risk n=4, I risk group n=0 and L risk n=10). The 5-year actuarial overall survival rates were 67%, 77% and 90% for H, I and L risk groups, respectively. Based on published literature, one would have expected a higher LRR rate in the I risk group without adjuvant RT. We hypothesise that the I risk group LRR rates have been reduced to that of the L risk group by the addition of RT. Apart from LN status and tumour size, other prognostic factors should also be considered in selecting patients for PMRT. This pragmatic tool requires further validation.
To investigate scanned-beam proton dose distribution reproducibility in the lung under high frequency jet ventilation (HFJV). For 11 patients (12 lesions), treated with single-fraction photon stereotactic radiosurgery under HFJV, scanned-beam proton plans were prepared with the TRiP98 treatment planning system using 2, 3-4 and 5-7 beams. The planning objective was to deliver at least 95% of the prescription of 33Gy (RBE) to 98% of the PTV. Plans were subsequently recomputed on localization CT scans. Additionally, for selected cases, the effects of range uncertainties were investigated. Median GTV V98% was 98.7% in the original 2-field plans and 93.7% in their recomputation (p=0.039). The respective values were 99.0% and 98.0% (p=0.039) for the 3-4-field plans and 100.0% and 99.6% (p=0.125) for the 5-7-field plans. CT calibration uncertainties of ±3.5% led to a GTV V98% reduction below 1.5 percentual points in most cases and reaching 3 percentual points for 2-field plans with beam undershoot. Through jet ventilation, reproducible tumor fixation for proton radiotherapy of lung lesions is achievable, ensuring excellent target coverage in most cases. In few cases, non-optimal patient setup reproducibility induced density changes across beam entrance channels, leading to dosimetric deterioration between planning and delivery.
Contact radiotherapy uses small field sizes and very short SSDs to deliver low-energy X-rays very close to the position of a tumour. We present a Monte Carlo simulation of the Papillon contact radiotherapy machine, and in particular the backscatter factor, to investigate whether the factors given in current Codes of practice for kV dosimetry remain valid under these conditions.
Many head and neck cancer (HNC) survivors experience diminished quality of life due to radiation-induced dysphagia. The aim of this study was to investigate frequency, intensity and dose-volume dependency for late dysphagia in HNC patients treated with curative IMRT. Candidates for the study were 294 patients treated with primary IMRT from 2006 to 2010; a total of 259 patients accepted to participate by answering the EORTC QLQ-C30 and H&N35 questionnaires. A total of 65 patients were further examined with modified barium swallow (MBS) and saliva collection. Data on patient, tumor and treatment characteristics were prospectively recorded in the DAHANCA database. Dose-volume histograms (DVH) of swallowing-related structures were retrospectively analyzed. QoL data showed low degree of dysphagia (QoL subscales scores of 17 and below) compared to objective measures. The most frequent swallowing dysfunction was retention; penetration and aspiration was less common. In general, objective measurements and observer-assessed late dysphagia correlated with dose to pharyngeal constrictor muscles (PCM), whereas QoL endpoints correlated with DVH parameters in the glottis/supraglottic larynx. Both xerostomia and dysphagia has been reduced after introduction of IMRT. Radiation-induced dysphagia is still important, with a high degree of retention and penetration. Introduction of parotid-sparing IMRT has reduced the severity of dysphagia, primarily through a major reduction in xerostomia. Dose-response relationships were found for specific dysphagia endpoints.
Survivors of Hodgkin's lymphoma (HL) are at risk of secondary tumors. We investigated the risk of secondary skin cancers after radiotherapy compared to treatment without radiation and to an age-matched population. We conducted a retrospective cohort study of 889 HL patients treated between 1965 and 2005. Data on secondary skin cancers and treatment fields were retrieved. Incidence rates were compared to observed rates in the Dutch population. 318 skin cancers were diagnosed in 86 patients, showing significantly higher risks of skin cancers, the majority being BCC. The standardized incidence ratio (SIR) of BCC in HL survivors was significantly increased (SIR 5.2, 95% CI 4.0-6.6), especially in those aged <35years at diagnosis (SIR 8.0, 95% CI 5.8-10.7). SIR increased with longer follow-up to 15.9 (95% CI 9.1-25.9) after 35years, with 626 excess cases per 10,000 patients per year. Most (57%) skin cancers developed within the radiation fields, with significantly increased risk in patients treated with radiotherapy compared to chemotherapy alone (p=0·047, HR 2·75, 95% CI 1·01-7.45). Radiotherapy for HL is associated with a strongly increased long-term risk of secondary skin cancers, both compared to the general population and to treatment with chemotherapy alone.
Background and purpose: When treated by radiotherapy, patients with squamous cell carcinomas of the head and neck (HNSCC) positive for HPV and p16(INK4a) possess a clearly favorable prognosis as compared to those with HPV-negative HNSCC. The aim of this work was to study whether the better outcomes might be caused by an enhanced cellular radiosensitivity. Materials and methods: The radiation response of five HPV/p16(INK4a)-positive and five HPV-negative cell lines was characterized with regard to cellular radiosensitivity by colony formation assay. Furthermore G1- and G2-arrest, apoptosis and residual DNA double-strand breaks (DSB) were analyzed by the colcemid-based G1-efflux assay, propidium iodide staining, the detection of PARP cleavage, the fluorescence-based detection of caspase activity and the immunofluorescence staining of γH2AX and 53BP1 foci. Results: On average, the cellular radiosensitivity of the HNSCC cell lines positive for HPV and p16(INK4a) was higher as compared to the sensitivity of a panel of five HPV-negative HNSCC cell lines (SF3=0.2827 vs. 0.4455). The higher sensitivity does not result from increased apoptosis or the execution of a permanent G1-arrest, but is rather associated with both, elevated levels of residual DSBs and extensive G2-arrest. Conclusions: Increased cellular radiosensitivity due to compromised DNA repair capacity is likely to contribute to the improved outcome of patients with HPV/p16(INK4a)-positive tumors when treated by radiotherapy.
Despite the wide use of permanent prostate implants for the treatment of early stage prostate cancer, there is no consensus for optimal pre-implant planning guidelines that results in maximal post-implant target coverage. The purpose of this study was to compare post-implant target volume coverage and dosimetry between patients treated before and after Radiation Therapy Oncology Group (RTOG) 98-05 guidelines were adopted using several dosimetric endpoints. Ten consecutively treated patients before the adoption of the RTOG 98-05 planning guidelines were compared with ten consecutively treated patients after implementation of the guidelines. Pre-implant planning for patients treated pre-RTOG was based on the clinical target volume (CTV) defined by the pre-implant TRUS definition of the prostate. The CTV was expanded in each dimension according to RTOG 98-05 and defined as the planning target volume. The evaluation target volume was defined as the post-implant computed tomography definition of the prostate based on RTOG 98-05 protocol recommendations. Implant quality indicators included V(100), V(90), V(100), and Coverage Index (CI). The pre-RTOG median V(100), V(90), D(90), and CI values were 82.8, 88.9%, 126.5 Gy, and 17.1, respectively. The median post-RTOG V(100), V(90), D(90), and CI values were 96.0, 97.8%, 169.2 Gy, and 4.0, respectively. These differences were all statistically significant. Implementation of the RTOG 98-05 implant planning guidelines has increased coverage of the prostate by the prescription isodose lines compared with our previous technique, as indicated by post-implant dosimetry indices such as V(100), V(90), D(90). The CI was also improved significantly with the protocol guidelines. Our data confirms the validity of the RTOG 98-05 implant guidelines for pre-implant planning as it relates to enlargement of the CTV to ensure adequate margin between the CTV and the prescription isodose lines.
A dose-escalation study of docetaxel combined with cisplatin, 5-fluorouracil, and concurrent radiotherapy (DCF-R) was performed to determine the optimal dose in patients with advanced esophageal carcinoma. A total of 19 patients who had previously untreated thoracic esophageal carcinoma with T4 tumors and/or M1 lymph-node metastasis were studied. The Patients received an infusion of docetaxel (levels 1, 2, 3, 2.5: 20, 30, 40, 35 mg/m(2)) and an infusion of cisplatin (40 mg/m(2)) on days 1, 15, 29, and 43 plus a continuous infusion of 5-fluorouracil (400mg/m(2)/day) on days 1-5, 15-19, 29-33, and 43-47. And patients received 61.2 Gy/34 fractions/7 weeks of concurrent radiotherapy. Dose-limiting toxicities (DLTs) were febrile neutropenia and grade 4 leukopenia lasting 3 days. DLT occurred in 2 of 6 patients at level 2, 3 of 4 patients at level 3, and 2 of 6 patients at level 2.5. The main toxicities were myelotoxicity and esophagitis. The overall response rate was 89.5%, including a complete response rate of 42.1%. The maximum-tolerated dose was level 3, because 50% or more of the patients had DLTs. Therefore, level 2.5 was recommended for phase II studies. This regimen was tolerable and highly active.
Many dose-limiting normal tissues in radiotherapy (RT) display considerable internal motion between fractions over a course of treatment, potentially reducing the appropriateness of using planned dose distributions to predict morbidity. Accounting explicitly for rectal motion could improve the predictive power of modelling rectal morbidity. To test this, we simulated the effect of motion in two cohorts. The included patients (232 and 159 cases) received RT for prostate cancer to 70 and 74Gy. Motion-inclusive dose distributions were introduced as simulations of random or systematic motion to the planned dose distributions. Six rectal morbidity endpoints were analysed. A probit model using the QUANTEC recommended parameters was also applied to the cohorts. The differences in associations using the planned over the motion-inclusive dose distributions were modest. Statistically significant associations were obtained with four of the endpoints, mainly at high doses (55-70Gy), using both the planned and the motion-inclusive dose distributions, primarily when simulating random motion. The strongest associations were observed for GI toxicity and rectal bleeding (Rs=0.12-0.21; Rs=0.11-0.20). Applying the probit model, significant associations were found for tenesmus and rectal bleeding (Rs=0.13, p=0.02). Equally strong associations with rectal morbidity were observed at high doses (>55Gy), for the planned and the simulated dose distributions including in particular random rectal motion. Future studies should explore patient-specific descriptions of rectal motion to achieve improved predictive power.
Documenting the distribution of radiotherapy departments and the availability of radiotherapy equipment in the European countries is an important part of HERO - the ESTRO Health Economics in Radiation Oncology project. HERO has the overall aim to develop a knowledge base of the provision of radiotherapy in Europe and build a model for health economic evaluation of radiation treatments at the European level. The aim of the current report is to describe the distribution of radiotherapy equipment in European countries.
For toxicities occurring during the course of radiotherapy, it is conceptually inaccurate to perform normal-tissue complication probability analyses using the complete dose-volume histogram. The goal of this study was to analyze acute rectal toxicity using a novel approach in which the fit of the Lyman-Kutcher-Burman (LKB) model is based on the fractional rectal dose-volume histogram (DVH). Grade ≥2 acute rectal toxicity was analyzed in 509 patients treated on Radiation Therapy Oncology Group (RTOG) protocol 94-06. These patients had no field reductions or treatment-plan revisions during therapy, allowing the fractional rectal DVH to be estimated from the complete rectal DVH based on the total number of dose fractions delivered. The majority of patients experiencing Grade ≥2 acute rectal toxicity did so before completion of radiotherapy (70/80=88%). Acute rectal toxicity depends on fractional mean rectal dose, with no significant improvement in the LKB model fit when the volume parameter differs from n=1. The incidence of toxicity was significantly lower for patients who received hormone therapy (P=0.024). Variations in fractional mean dose explain the differences in incidence of acute rectal toxicity, with no detectable effect seen here for differences in numbers of dose fractions delivered.
To compare the coronary angiographic findings between patients who had previous left sided versus right sided breast cancer radiotherapy (RT). Between 1995 and 2009, 12,696 patients who underwent curative RT for breast cancer at Princess Margaret Hospital were screened to assess if they had been investigated with a post-RT coronary angiogram. Two cardiologists, blinded to the laterality of radiation treatment, assessed all angiograms and measured the percentage of stenotic lesions, the mean diameters of each segment of the left anterior descending artery (LAD) and the right coronary artery (RCA) using quantitative coronary angiography (QCA). Ninety-one patients were included, 49 patients with left sided RT and 42 with right sided RT. The median time from RT to coronary angiogram was 4.2 years (range: 22 days-16.9 years). Seventeen patients (35%) in the left sided RT group and 17 (40%) in the right sided RT group needed coronary revascularization (percutaneous coronary intervention or by-pass surgery). The LAD territory was revascularized in 12 (24%) and 11 (26%) patients, respectively. The proportion of clinically significant stenoses, degree of stenoses and mean vessel diameter were not significantly different between the two groups. In 33 patients who had coronary angiograms >5 years after breast RT (17 left-sided and 16 right-sided), the only statistically significant finding was marginally narrower mid RCA segments among those who had right sided RT: 2.52 mm versus 2.92 mm (P=0.039). In our patients, left sided breast cancer RT did not increase the risk of coronary artery disease within the first few years, when compared to right sided RT. However, with the limitation of short duration between radiotherapy and coronary angiogram, late development of coronary artery stenoses 10-15 years after left sided RT could not be excluded.
In 1994 a prospective study of the 'Arbeitsgemeinschaft Radiologische Onkologie' of the German Cancer Society was initiated to examine the results of a standardized radiation therapy for choroidal metastases with 40 Gy. Recommendations in the literature vary from 21 to 50 Gy of total dose and from 2 to 5 Gy per single fraction. To date, no larger series treated with both a standardized technique and dose has been reported. Between 1994 and 1998, 56 patients were enrolled and 50 patients with 65 involved eyes were available for analysis. Thirty-five patients (70%) had unilateral and 15 patients (30%) had bilateral choroidal metastases. Fifty eyes (77%) were symptomatic and 15 eyes (23%) were asymptomatic. Thirty-one patients (62%) had breast cancer and 13 patients (26%) lung cancer as the primary tumor. Patients were treated with 40 Gy in 20 fractions with bilateral asymmetric fields for bilateral or a unilateral field for unilateral choroidal metastasis. Seventeen patients had additional chemotherapy after radiotherapy for general tumor progression. With a median follow-up of 5.8 months (1-44 months) 41 out of 50 patients were dead. The median survival of all patients was 7 months and for patients with breast cancer 10 months. Of the 50 symptomatic eyes visual acuity increased for two or more lines in 36% (18/50), was stabilized in 50% (25/50 eyes), and decreased in 14% (7/50). No patient with asymptomatic metastasis (n = 15 eyes) developed ocular symptoms during follow-up. No patient with unilateral tumor and unilateral irradiation developed contralateral metastasis. Severe side effects, possibly related to tumor progression, occurred in three eyes (5%). Radiation therapy with 40 Gy is an effective and safe palliative treatment for symptomatic and asymptomatic choroidal metastases to preserve vision in the majority of the patients. A unilateral field for unilateral metastasis seems to be sufficient to prevent contralateral disease. Side effects of radiotherapy are acceptable: 50% of patients developed a mild skin erythema and conjunctivitis (RTOG I). Late side effects were seen in three eyes (5%).
Randomised controlled trials (RCTs) can be hampered by poor patient accrual and retention. Decision aids (DAs) containing simple, evidence-based information, may assist patients with decision-making regarding trial participation. The current DA was of use for 95% of participants. Further evaluation of the DA in a RCT is currently underway.
RTOG 0933 is a phase II clinical trial of hippocampal avoidance during whole-brain radiotherapy (HA-WBRT) to prevent radiation-induced neurocognitive decline. By quantifying baseline incidence of perihippocampal or hippocampal metastasis, we sought to estimate the risk of developing metastases in the hippocampal avoidance region (the hippocampus plus 5mm margin). Patients with < or = 10 brain metastases treated at two separate institutions were reviewed. Axial images from pre-treatment, post-contrast MRIs were used to contour each metastasis and hippocampus according to a published protocol. Clinical and radiographic variables were correlated with perihippocampal metastasis using a binary logistical regression analysis, with two-sided p<0.05 for statistical significance. 1133 metastases were identified in 371 patients. Metastases within 5mm of the hippocampus were observed in 8.6% of patients (95% CI 5.7-11.5%) and 3.0% of brain metastases. None of the metastases lay within the hippocampus. A 1-cm(3) increase in the aggregate volume of intra-cranial metastatic disease was associated with an odds ratio of 1.02 (95% CI 1.006-1.034, p=0.003) for the presence of perihippocampal metastasis. With an estimated perihippocampal metastasis risk of 8.6%, we deem HA-WBRT safe for clinical testing in patients with brain metastases as part of RTOG 0933.
The radiosensitizing ability of two analogues of cisplatin have been tested in vitro. The analogues, CBDCA (JM8) and EDMP (JM40), are currently undergoing clinical tests in the search for an active but less toxic cancer chemotherapeutic agent than cisplatin. The compounds were cytotoxic to log phase RIF1 cells in culture, but at higher concentrations than the parent compound. Both analogues were radiosensitizers of oxic cells when given as 1 h exposures beginning either 3 h before, 1 h before or 2 h after irradiation, giving modest enhancements of approximately 1.2. Each drug caused an inhibition of the repair of sublethal damage which was greatest after CBDCA treatment. Although neither analogue was as good a radiosensitizer as cisplatin, CBDCA appears to show promise as a potential radioenhancing platinum compound.
Previously, we have reported that 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide (DCQ) is a radiosensitizer. Here, we investigate the mechanism of radiosensitization. EMT6 cells were treated with DCQ for 4h prior to ionizing radiation (IR). Flow cytometry, clonogenic assay, TUNEL, and Western blotting were performed to assess the effect of treatment on cells. Propidium iodide staining of EMT6 cells treated with IR+/-DCQ revealed high numbers of cells with decreased DNA, consistent with an apoptotic response. TUNEL assay revealed apoptosis was 4%, 38%, and 49% 24h after treatment with IR alone, DCQ alone, and DCQ+IR, respectively. Clonogenic assays revealed that the survival of irradiated EMT6 cells was significantly reduced by DCQ treatment. DCQ treatment abrogated the radiation-induced expression of p21 and p53. The increased apoptosis observed in DCQ+IR-treated cells was correlated to suppression of radiation-induced phosphorylation of Akt and the expression of Bcl-X(L). DCQ also caused the phosphorylation of mitogen-activated protein kinases Erk and Jnk. The radiosensitization effect of DCQ occurs through enhancement of radiation-induced apoptosis, which correlates to the inhibition of p-Akt kinase and Bcl-X(L) and the activation of Erk and Jnk kinases, but appears independent of p53 induction or modulation of Bax/Bcl-2 gene expression. These data suggest DCQ should be tested as a radiosensitizer in vivo and has potential in the treatment of human solid tumors.
Daily variations in bladder filling make conformal treatment of bladder cancer challenging. On-line adaptive radiotherapy with a choice of plans has been demonstrated to reduce small bowel irradiation in single institution trials. In order to support a multicentre feasibility clinical trial on adaptive radiotherapy for bladder cancer (TROG 10.01) a credentialing programme was developed for centres wishing to participate. The credentialing programme entails three components: a facility questionnaire; a planning exercise which tests the ability of centres to create three adaptive plans based on a planning and five cone beam CTs; and a site visit during which image quality, imaging dose and image guidance procedures are assessed. Image quality and decision making were tested using customised inserts for a Perspex phantom (Modus QUASAR) that mimic different bladder sizes. Dose was assessed in the same phantom using thermoluminescence dosimetry (TLD). All 12 centres participating in the full credentialing programme were able to generate appropriate target volumes in the planning exercise and identify the correct target volume and position the bladder phantom in the phantom within 3mm accuracy. None of the imaging doses exceeded the limit of 5 cGy with a CT on rails system having the lowest overall dose. A phantom mimicking the decision making process for adaptive radiotherapy was found to be well suited during site visits for credentialing of centres participating in a clinical trial of adaptive radiotherapy for bladder cancer. Combined with a planning exercise the site visit allowed testing the ability of centres to create adaptive treatment plans and make appropriate decisions based on the volumetric images acquired at treatment.
To assess whether online adaptive radiotherapy for bladder cancer is feasible across multiple Radiation Oncology departments using different imaging, delivery and recording technology. A multi-centre feasibility study of online adaptive radiotherapy, using a choice of three "plan of the day", was conducted at 12 departments. Patients with muscle-invasive bladder cancer were included. Departments were activated if part of the pilot study or after a site-credentialing visit. There was real time review of the first two cases from each department. 54 patients were recruited, with 50 proceeding to radiotherapy. There were 43 males and 7 females with a mean age of 78years. The tumour stages treated included T1 (1 patient), T2 (35), T3 (10) and T4 (4). One patient died of an unrelated cause during radiotherapy. The three adaptive plans were created before the 10th fraction in all cases. In 8 (16%) of the patients, a conventional plan using a 'standard' CTV to PTV margin of 1.5cm was used for one or more fractions where the pre-treatment bladder CTV was larger than any of the three adaptive plans. The bladder CTV extended beyond the PTV on post treatment imaging in 9 (18%) of the 49 patients. From a technical perspective an online adaptive radiotherapy technique can be instituted in a multi-centre setting. However, without further bladder filling control or imaging, a CTV to PTV margin of 7mm is insufficient.
Background and purpose: An e-Learning programme appeared useful for providing training and information regarding a multi-centre image guided radiotherapy trial. The aim of this study is to demonstrate the utility of this e-Learning programme. Materials and methods: Modules were created on relevant pelvic anatomy, Cone Beam CT soft tissue recognition and trial details. Radiation therapist participants' knowledge and confidence were evaluated before, at the end of, and after at least 6 weeks of e-Learning (long term). Results: One hundred and eighty-five participants were recruited from 12 centres, with 118 in the first, and 67 in the second cohort. One hundred and forty-six participants had two tests (pre and post e-Learning) and 39 of these had three tests (pre, post, and long term). There was an increase confidence after completion of modules (p<0.001). The first cohort pre scores increased from 67 ± 11 to 79 ± 8 (p<0.001) post. The long term same question score was 73 ± 14 (p=0.025, comparing to pre-test), and different questions' score was 77 ± 13 (p=0.014). In the second cohort, pre-test scores were 64 ± 10, post-test same question score 78 ± 9 (p<0.001) and different questions' score 81 ± 11 (p<0.001). Conclusions: e-Learning for a multi-centre clinical trial was feasible and improved confidence and knowledge.
CD133 is controversially discussed as putative (surrogate) marker for cancer stem/tumor-initiating cell populations (CSC/TIC) in epithelial tumors including colorectal carcinomas (CRCs). We studied CD133 expression in established CRC cell lines and examined in vitro behavior, radioresponse and in vivo tumor formation of CD133+/- subpopulations of one cell line of interest. Ten CRC cell lines were analyzed for CD133 expression using flow cytometry and Western blotting. CD133+ and CD133- HCT-116 subpopulations were separated by FACS and studied in 2-D and 3-D culture and colony formation assays after irradiation. Subcutaneous xenograft formation was monitored in NMRI (nu/nu) mice. CRC cell lines could be classified into three groups: (i) CD133-, (ii) CD133+ and (iii) those with two distinct CD133+ and CD133- subpopulations. Isolated CD133+/- HCT-116 subpopulations were studied relative to the original fraction. No difference was found in 2-D growth, spheroid formation or radioresponse in vitro. Also, tumor formation and growth rate did not differ for the sorted subpopulations. However, a subset of xenografts originated from CD133- HCT-116 showed a striking enrichment in the CD133+ fraction. Our data show that CD133 expression is not selective for sphere forming, tumor-initiating or radioresistant subpopulations in the HCT-116 CRC cell line. This implies that CD133 cannot be regarded as a CSC/TIC marker in all CRC cell lines and that functional measurements of tumor formation have to generally accompany CSC/TIC-directed mechanistic or therapeutic studies.
This study was designed to ascertain whether a prior reduction of tumor size by drugs could affect the final outcome of tumors treated with radiation. 142 patients with head and neck cancer (oropharynx, maxillary antrum and intra-oral) were randomized for the study. In 72 cases, irradiation was preceded by a continuous intra-arterial infusion of 3-5 mg/day methotrexate to a total dose of 90-120 mg; the other 70 patients were treated with radiotherapy alone. Chemotherapy, given prior to radiotherapy, caused a shift in the tumor stage (i.e. a reduction in tumor size) in more than one third of the cases. The overall 5-year survival was 43% in the combined treatment group and 25% in the group treated with radiation alone (statistical difference: p less than .05). However, when analysed separately the difference was statistically significant only in oral cavity tumors (5-year survival of 54% in the combined modality group vs. 27% in the control group), although local control rates after both single and combined modalities were not statistically different from those of oropharynx and maxillary antrum tumors. In these last lesions, however, the dissemination of disease was more frequent; therefore, the lack of improvement of cure rate with the combined modality in these cases seems to be related to both the higher tendency of these tumors to disseminate and the low effectiveness of intra-arterial chemotherapy in controlling distant metastases. Mild and transient local and systemic toxicities were observed during chemotherapy infusion, but no radiosensitising effect on normal skin and mucosa was seen during radiotherapy in patients who had received pre-irradiation chemotherapy.
Treatment of local and distant head and neck cancer recurrences after radiotherapy remains an unsolved problem. In order to identify potential targets for use in effective therapy of recurrent tumors, we have investigated protein patterns in radioresistant (FaDu-IRR and SCC25-IRR, "IRR cells") as compared to parental (FaDu and SCC25) head and neck carcinoma cells. Radiation resistant IRR cells were derived from parental cells after repeated exposure to ionizing radiation 10 times every two weeks at a single dose of 10 Gy, resulting in a total dose of 100 Gy. Protein profiling in parental and IRR cells was carried out using two-dimensional differential gel electrophoresis (2D-DIGE) followed by MALDI-TOF/TOF mass spectrometry. Cell viability, cell migration assays and Western blot analysis were used to confirm results obtained using the proteome approach. Forty-five proteins that were similarly modulated in FaDu-IRR and SCC25-IRR cells compared to parental cells were selected to analyze their common targets. It was found that these either up- or down-regulated proteins are closely related to the enhancement of cell migration which is regulated by Rac1 protein. Further investigations confirmed that Rac1 is up-regulated in IRR cells, and inhibiting its action reduces the migratory abilities of these cells. Additionally, the Rac1 inhibitor exerts cytostatic effects in HNSCC cells, mostly in migratory cells. Based on these results, we conclude that radioresistant HNSCC cells possess enhanced metastatic abilities that are regulated by a network of migration-related proteins. Rac1 protein may be considered as a putative biomarker of HNSCC radiation resistance, and as a potential therapeutic target for treating local and distant HNSCC recurrences.
To validate the predictive impact of a hypoxia gene expression classifier in identifying patients with head and neck squamous cell carcinoma (HNSCC) having benefit from hypoxic modification of radiotherapy. Gene expressions were quantified from formalin-fixed, paraffin-embedded tumour biopsies of 323 HNSCC patients randomized for placebo or nimorazole in conjunction with radiotherapy in the DAHANCA 5 study. Tumours were classified as either "more" or "less" hypoxic with a classifier constituting of 15 hypoxia responsive genes. The predictive impact was evaluated by analysing the response to nimorazole vs. placebo in terms of loco-regional tumour control (LRC) and disease-specific survival (DSS) in the two classified groups. Hundred and fourteen patients (35%) were classified as having "more" hypoxic tumours. These patients had a significant benefit of hypoxic modification with nimorazole compared with placebo in terms of LRC (5-year actuarial values 49% vs. 18%; p=0.001) and DSS (48% vs. 30%; p=0.04). "Less" hypoxic tumours had no significant effect of hypoxic modification (LRC: 50% vs. 44%; p=0.39, DSS: 57% vs. 51%; p=0.49) and generally an outcome, which was similar to "more" hypoxic tumours treated with nimorazole. In contrast to HPV-negative tumours, HPV-positive tumours had a substantially better outcome in response to radiotherapy, which was irrespective of hypoxic modification. A predictive 15-gene hypoxia classifier could identify patients associated with improved outcome after combining radiotherapy with hypoxic modification and underlines the relevance of such therapy. The impact of the classifier was limited to HPV-negative tumours.
The aim of this single-arm multicenter phase II clinical trial was to assess the feasibility and tolerability of preoperative radiotherapy and simultaneous capecitabine and bevacizumab. Secondary endpoints were downstaging-rate and induction of complete pathological response. Patients with cT3 rectal cancer were eligible. Capecitabine (825 mg/sqm twice daily on radiotherapy-days weeks 1-4) and bevacizumab (5 mg/kg on days 1, 15 and 29) were administered concurrently to pelvic radiotherapy (1.8 Gy daily up to 45 Gy in 5 weeks). Surgery followed 6-8 weeks later. A two-stage trial was designed with early termination at eight patients if more than three patients had experienced a common toxicity criteria ≥grade 3 according to the NCI CTC guidelines. In the first stage eight patients were enrolled. Median age was 70 years (range 55-76) and ECOG PS 0/1 (%) was 87.5/12.5. Major side effects were mostly intestinal bleeding (grade 3, 25%), diarrhea (grade 3, 25%), perianal and abdominal pain (grades 3 and 4, 25%) followed by anemia (grade 3, 12.5%). Tumor downstaging was observed in 37.5% of patients with complete pathological response in two patients (25%). After interim analysis of feasibility and tolerability, accrual was terminated according to protocol due to ≥grade 3 toxicities in 50% of patients. Complete pathological response was seen in 25% of patients but was accompanied by considerable toxicity. Further clinical trials are needed to clarify the role of bevacizumab in this setting.
A prospective observational multicentre trial was carried out to assess the incidence, pattern, and prognostic factors of radiation-induced emesis (RIE), and to evaluate the use of antiemetic drugs in patients treated with radiotherapy or concomitant radio-chemotherapy. The application in clinical practice of the Multinational Association of Supportive Care in Cancer guidelines was also studied. Forty-five Italian radiation oncology centres took part in this trial. The accrual lasted for 3 consecutive weeks and only patients starting radiotherapy or concomitant radio-chemotherapy in this period were enrolled. Evaluation was based on diary card filled in daily by patients during treatment and one week after stopping it. Diary card recorded the intensity of nausea/vomiting and prophylactic/symptomatic antiemetic drug prescriptions. A total of 1020 patients entered into the trial, and 1004 were evaluable. Vomiting and nausea occurred in 11.0% and 27.1% of patients, respectively, and 27.9% patients had both vomiting and nausea. In multifactorial analysis, the only statistically significant patient-related risk factors were concomitant chemotherapy and previous experience of vomiting induced by chemotherapy. Moreover, two radiotherapy-related factors were significant risk factors for RIE, the irradiated site (upper abdomen) and field size (>400 cm(2)). An antiemetic drug was given only to a minority (17%) of patients receiving RT, and the prescriptions were prophylactic in 12.4% and symptomatic in 4.6%. Different compounds and a wide range of doses and schedules were used. These data were similar to those registered in our previous observational trial, and the radiation oncologists' attitude in underestimating RIE and under prescribing antiemetics was confirmed.
From 1966 to 1985, 103 patients with a localized (stages I and II) follicular lymphoma (Kiel classification) were treated at the Fondation Bergonié. Clinical staging was performed using, after physical examination, chest X-rays (100%), bipedal lymphangiography (98%) and unilateral bone marrow biopsy (BMB) (51.5%). The patients were then treated by radiotherapy with or without chemotherapy. Overall survival (OS) at 5 and 10 years is 69 and 56.3%, respectively. Relapse-free survival (RFS) is 53.7 and 49%. Unifactorial analysis shows three prognostic parameters to be independently significant in terms of OS: age, stage and B symptoms. In terms of RFS, only 2 factors are significant: age and B symptoms. Multivariate analysis (Cox model) shows that age is a more important prognostic factor than stage.
Top-cited authors
Jens Overgaard
  • Aarhus University Hospital
Richard Pötter
  • Medical University of Vienna
Philippe Lambin
  • Maastricht University
Erik Van Limbergen
  • Universitair Ziekenhuis Leuven
Jean-Claude Horiot
  • Institut Multidisciplinaire d'Oncologie - Clinique de Genolier