Guy Soete

Duration of androgen suppression in the treatment of prostate cancer

BACKGROUND The combination of radiotherapy plus long-term medical suppression of androgens (> or = 2 years) improves overall survival in patients with locally advanced prostate cancer. We compared the use of radiotherapy plus short-term androgen suppression with the use of radiotherapy plus long-term androgen suppression in the treatment of locally advanced prostate cancer. METHODS We randomly assigned patients with locally advanced prostate cancer who had received external-beam radiotherapy plus 6 months of androgen suppression to two groups, one to receive no further treatment (short-term suppression) and the other to receive 2.5 years of further treatment with a luteinizing hormone-releasing hormone agonist (long-term suppression). An outcome of noninferiority of short-term androgen suppression as compared with long-term suppression required a hazard ratio of more than 1.35 for overall survival, with a one-sided alpha level of 0.05. An interim analysis showed futility, and the results are presented with an adjusted one-sided alpha level of 0.0429. RESULTS A total of 1113 men were registered, of whom 970 were randomly assigned, 483 to short-term suppression and 487 to long-term suppression. After a median follow-up of 6.4 years, 132 patients in the short-term group and 98 in the long-term group had died; the number of deaths due to prostate cancer was 47 in the short-term group and 29 in the long-term group. The 5-year overall mortality for short-term and long-term suppression was 19.0% and 15.2%, respectively; the observed hazard ratio was 1.42 (upper 95.71% confidence limit, 1.79; P=0.65 for noninferiority). Adverse events in both groups included fatigue, diminished sexual function, and hot flushes. CONCLUSIONS The combination of radiotherapy plus 6 months of androgen suppression provides inferior survival as compared with radiotherapy plus 3 years of androgen suppression in the treatment of locally advanced prostate cancer. (ClinicalTrials.gov number, NCT00003026.)

Innovations in image-guided radiotherapy

The limited ability to control for the location of a tumour compromises the accuracy with which radiation can be delivered to tumour-bearing tissue. The resultant requirement for larger treatment volumes to accommodate target uncertainty restricts the radiation dose because more surrounding normal tissue is exposed. With image-guided radiotherapy (IGRT) these volumes can be optimized and tumoricidal doses can be delivered, achieving maximal tumour control with minimal complications. Moreover, with the ability of high-precision dose delivery and real-time knowledge of the target volume location, IGRT has initiated the exploration of new indications for radiotherapy, some of which were previously considered infeasible.

Quality assurance of a system for improved target localization and patient set-up that combines real-time infrared tracking and stereoscopic X-ray imaging

BACKGROUND AND PURPOSE The aim of this study is to investigate the positional accuracy of a prototype X-ray imaging tool in combination with a real-time infrared tracking device allowing automated patient set-up in three dimensions. MATERIAL AND METHODS A prototype X-ray imaging tool has been integrated with a commercially released real-time infrared tracking device. The system, consisting of two X-ray tubes mounted to the ceiling and a centrally located amorphous silicon detector has been developed for automated patient positioning from outside the treatment room prior to treatment. Two major functions are supported: (a) automated fusion of the actual treatment images with digitally reconstructed radiographs (DRRs) representing the desired position; (b) matching of implanted radio opaque markers. Measurements of known translational (up to 30.0mm) and rotational (up to 4.0 degrees ) set-up errors in three dimensions as well as hidden target tests have been performed on anthropomorphic phantoms. RESULTS The systems accuracy can be represented with the mean three-dimensional displacement vector, which yielded 0.6mm (with an overall SD of 0.9mm) for the fusion of DRRs and X-ray images. Average deviations between known translational errors and calculations varied from -0.3 to 0.6mm with a standard deviation in the range of 0.6-1.2mm. The marker matching algorithm yielded a three-dimensional uncertainty of 0.3mm (overall SD: 0.4mm), with averages ranging from 0.0 to 0.3mm and a standard deviation in the range between 0.3 and 0.4mm. CONCLUSIONS The stereoscopic X-ray imaging device integrated with the real-time infrared tracking device represents a positioning tool allowing for the geometrical accuracy that is required for conformal radiation therapy of abdominal and pelvic lesions, within an acceptable time-frame.

Conformal Arc Radiotherapy for Prostate Cancer: Increased Biochemical Failure in Patients With Distended Rectum on the Planning Computed Tomogram Despite Image Guidance by Implanted Markers

PURPOSE To evaluate the effect of rectal distention on the planning computed tomogram on freedom from biochemical failure (FFBF) of prostate cancer patients treated with image-guided conformal arc radiotherapy. METHODS AND MATERIALS The outcomes of 238 patients with T1-T3N0M0 tumors were analyzed, with a median follow-up of 53 months (range, 24-93 months). In 213 patients, daily co-registration of X-rays and digitally reconstructed radiographs was used for positioning, whereas in 25 patients positioning was done using direct prostate visualization with implanted markers. The rectal average cross-sectional area was determined on the planning computed tomogram. RESULTS The 5-year freedom from Grade 3 to 4 late gastrointestinal and urinary side effect, according to the Radiation Therapy Oncology Group criteria, was 100% and 99.4% respectively. The 5-year FFBF was 88.4%. On multivariate analysis the following variables were significantly related to worse FFBF: risk group according to the National Comprehensive Cancer Network (high- to very high risk vs. intermediate- to low-risk), dose (70 vs. 78 Gy), average cross-sectional area (> or =16 vs. <16 cm(2)) and, unexpectedly, the use of implanted markers as opposed to bony structures for patient positioning. In retrospect, the margins around the clinical target volume appeared to be inadequate in the cases in which markers were used. CONCLUSION Overall, the outcome of patients treated with image-guided conformal arc radiotherapy is excellent. We were able to confirm the negative prognostic impact of a distended rectum on the planning computed tomogram described by others. The study illustrates the potential danger of image guidance techniques as to margin reduction around the clinical target volume.

Initial clinical experience with infrared-reflecting skin markers in the positioning of patients treated by conformal radiotherapy for prostate cancer

PURPOSE To evaluate an infrared (IR) marker-based positioning system in patients receiving conformal radiotherapy for prostate cancer. METHODS AND MATERIALS During 553 treatments, the ability of the IR system to automatically position the isocenter was recorded. Setup errors were measured by means of orthogonal verification films and compared to conventional positioning (using skin drawings and lasers) in 184 treatments. RESULTS The standard deviation of anteroposterior (AP) and lateral setup errors was significantly reduced with IR marker positioning compared to conventional: 2 vs. 4.8 mm AP (p < 0.01) and 1.6 vs. 3.5 mm laterally (p < 0.01). Longitudinally, the difference was not significant (3.5 vs. 3.0 mm). Systematic errors were on the average smaller AP and laterally for the IR method: 4.1 vs. 7.8 mm AP (p = 0.01) and 3.1 vs. 5.6 mm lateral (p = 0.07). Longitudinally, the IR system resulted in somewhat larger systematic errors: 5.0 vs. 3.4 mm for conventional positioning (p = 0.03). The use of an off-line correction protocol, based on the average deviation measured over the first four fractions, allowed virtual elimination of systematic errors. Inability of the IR system to correctly locate the markers, leading to an executional failure, occurred in 21% of 553 fractions. CONCLUSION IR marker-assisted patient positioning significantly improves setup accuracy along the AP and lateral axes. Executional failures need to be reduced.

Clinical use of stereoscopic X-ray positioning of patients treated with conformal radiotherapy for prostate cancer.

PURPOSE To evaluate accuracy and time requirements of a stereoscopic X-ray-based positioning system in patients receiving conformal radiotherapy to the prostate. METHODS AND MATERIALS Setup errors of the isocenter with regard to the bony pelvis were measured by means of orthogonal verification films and compared to conventional positioning (using skin drawings and lasers) and infrared marker (IR) based positioning in each of 261 treatments. In each direction, the random error represents the standard deviation and the systematic error the absolute value of the mean position. Time measurements were done in 75 treatments. RESULTS Random errors with the X-ray positioning system in the anteroposterior (AP), lateral, and longitudinal direction were (average +/- 1 standard deviation) 2 +/- 0.6 mm, 1.7 +/- 0.6 mm, and 2.4 +/- 0.7 mm. The corresponding values of conventional as well as IR positioning were significantly higher (p < 0.01). Systematic errors for X-ray positioning were 1.1 +/- 1.2 mm AP, 0.6 +/- 0.5 mm laterally, and 1.5 +/- 1.6 mm longitudinally. Conventional and IR marker-based positioning showed significantly larger systematic errors AP and laterally, but longitudinally, the difference was not significant. Depending on the axis looked at, errors of >or=5 mm occurred in 2%-14% of treatments after X-ray positioning, 13%-29% using IR markers, and 28%-53% with conventional positioning. Total linac time for one treatment session was 14 min 51 s +/- 4 min 18 s, half of which was used for the X-ray-assisted positioning procedure. CONCLUSION X-ray-assisted patient positioning significantly improves setup accuracy, at the cost of an increased treatment time.

Post-surgery radiation in early breast cancer: survival analysis of registry data

BACKGROUND AND PURPOSE Overviews of randomized trials have shown a small survival advantage with post-surgery radiation in early breast cancer. The present study attempts to extend this observation through a systematic analysis of population data. MATERIALS AND METHODS This retrospective cohort study used the Surveillance, Epidemiology, and End Results (SEER) data on 83,776 women with breast cancer diagnosed between 1988 and 1997, stage T1-T2, node negative or node positive. The analysis was performed using the proportional hazard models. RESULTS Radiation was associated with a reduced mortality after breast-conserving surgery in node negative patients (hazard ratio 0.757; 95% confidence interval 0.709-0.809; using total mastectomy without radiation as reference) and in node positive patients (hazard ratio 0.777; 0.717-0.842), and after total mastectomy in node positive patients (hazard ratio 0.885; 0.815-0.961). Radiation was associated with an increased hazard ratio of 1.271 (1.080-1.496) after total mastectomy in node negative patients. Without radiation, breast-conserving surgery in node negative patients was associated with an increased hazard ratio (1.167; 1.036-1.314); a similar increase was not observed in node positive patients (hazard ratio 1.011; 0.884-1.155). In all cases, the best survival rates were found with combined breast-conserving surgery and radiation. CONCLUSION The available data indicate that post-surgery radiation provides a survival advantage irrespective of the type of surgery in node positive patients. Likewise, survival advantage was observed with post-surgery radiation and breast-conserving procedure in node negative patients.

Intrinsic radiosensitivity of human pancreatic tumour cells and the radiosensitising potency of the nitric oxide donor sodium nitroprusside

A panel of eight human pancreatic tumour cell lines displayed high intrinsic radioresistance, with mean inactivation doses between 2.4 and 6.5 Gy, similar to those reported for melanoma and glioblastoma. The radiosensitising potency of sodium nitroprusside, a bioreductive nitric oxide donor, was assessed in a model of metabolism-induced hypoxia in a cell micropellet. Sodium nitroprusside at 0.1 mM revealed a radiosensitising effect with an overall enhancement ratio of 1.9 compared with 2.5 for oxygen. Radiosensitising activity correlated with the enhancement of single-strand DNA breakage caused by radiation. In suspensions with cell densities of between 3% and 30% (v/v), the half-life of sodium nitroprusside decreased from 31 to 3.2 min, suggesting a value of around 1 min for micropellets. Despite this variation, the radiosensitising activity was similar in micropellets and in diluted cell suspensions. S-nitroso-L-glutathione was found to possess radiosensitising activity, consistent with a possible role of natural thiols in the storing of radiobiologically active nitric oxide adducts derived from sodium nitroprusside. As measured by a nitric oxide-specific microsensor, activation of sodium nitroprusside occurred by bioreduction, whereas S-nitroso-L-glutathione showed substantial spontaneous decomposition. Both agents appear to exert radiosensitising action through nitric oxide as its scavenging by carboxy phenyltetramethylimidazolineoxyl N-oxide (carboxy-PTI0) and oxyhaemoglobin resulted in attenuated radiosensitisation. Sodium nitroprusside was at least 10-fold more potent than etanidazole, a 2-nitroimidazole used as a reference. Our data suggest that sodium nitroprusside, a drug currently used for the treatment of hypertension, is a potential tumour radioresponse modifier.

Omission of radiotherapy after breast-conserving surgery: survival impact and time trends

PURPOSE To evaluate the survival impact of omission of radiotherapy after breast-conserving surgery and the changes with time. MATERIAL AND METHODS Women aged 40-69 with non-metastasized T1-T2 breast cancer, who underwent breast-conserving surgery with axillary node dissection, with or without post-surgery radiotherapy, selected from the SEER (Surveillance, Epidemiology, and End Results) database. The analysis uses proportional hazards models. RESULTS Omission of radiotherapy as compared to delivery of radiotherapy was associated with an overall increased mortality hazard ratio of 1.346 (95% confidence interval: 1.204-1.504). Test of constancy showed significant changes with time. The time profile suggested an exponential-like increase from a baseline mortality hazard ratio of 1.17, or 17% excess of relative mortality risk, to a projected hazard ratio of 2.26, or more than doubling of relative mortality risk, for omission of radiotherapy. CONCLUSION Omission of radiotherapy in breast-conserving surgery is found to be independently associated with an increase in mortality. The data do not give support to omitting radiation or give rationale to clinical trials that would omit radiation.

Considerations on treatment efficiency of different conformal radiation therapy techniques for prostate cancer

BACKGROUND AND PURPOSE To evaluate the treatment efficiency of different conformal radiation therapy techniques in prostate cancer. MATERIALS AND METHODS Three major classes of intensity-modulated radiation therapy (IMRT) delivery as well as a conformal rotation technique have been evaluated: sequential tomotherapy, dynamic multileaf collimation (DMLC) with conventional MLC, DMLC with miniMLC and dynamic field shaping arc. Treatment planning for the IMRT techniques has been performed with inverse planning. Forward planning was used for the dynamic arc technique. The four techniques have been compared to treat two different prostate cases with a conservative target dose of 70 Gy: a convex shaped target volume and one containing concavities formed by the bladder and rectum. Cumulative dose volume histograms, tumor control probability and normal tissue complication probability, conformity index and dose heterogeneity, and finally efficiency of treatment delivery have been evaluated. RESULTS For the convex shaped target, all treatment modalities met the desired treatment goals, although the conventional MLC delivered more dose to the bladder. Compared to the dynamic arc modality, both tomotherapy and the conventional MLC technique needed a tenfold higher number of monitor units per target dose, and the miniMLC a twofold higher number. The same trend has been observed for the concave target, yet the dynamic arc did not meet the desired dose reduction for the rectum. The miniMLC configuration represented the best compromise for both targets with respect to treatment goals and delivery efficiency. Sequential tomotherapy performed adequately with respect to conformity at the cost of efficiency. CONCLUSIONS Together with conformity and delivery efficiency the shape of the target should be considered as an important parameter in the selection of the treatment modality.