Pieter Hofman

Clinical feasibility study for the use of implanted gold seeds in the prostate as reliable positioning markers during megavoltage irradiation

BACKGROUND AND PURPOSE The aim of this study was to assess the feasibility of using gold seed implants in the prostate for position verification, using an a-Si flat panel imager as a detector during megavoltage irradiation of prostate carcinoma. This is a study to guarantee positioning accuracy in intensity-modulated radiotherapy. METHODS AND MATERIALS Ten patients with localized prostate carcinoma (T2-3) received between one and three fiducial gold markers in the prostate. All patients were treated with 3-D conformal radiotherapy with an anterior-posterior (AP) and two lateral wedge fields. The acute gastrointestinal (GI) and genitourinary (GU) toxicities were scored using common toxicity criteria scales (CTC). Using three consecutive CT scans and portal images obtained during the treatment we have studied the occurrence of any change in prostate shape (deformation), seed migration and the magnitude of translations and rotations of the prostate. RESULTS We observed no acute major complications for prostate irradiation regarding the seed implantation. The maximum acute GU toxicity grade 2 (dysuria and frequency) was observed in seven patients during the treatment. The maximum grade 2 (diarrhoea) was scored in two patients regarding the acute GI toxicities. No significant prostate deformation could be detected in the consecutive CT scans. It appeared that the distances between the markers only slightly changed during treatment (S.D. 0.5 mm). Random prostate translations were (1 S.D.) 2.1, 3.2 and 2.2 mm in the lateral (LR), AP and cranial-caudal (CC) directions, respectively, whereas systematic translations were 3.3, 4.8 and 3.5 mm in the LR, AP and CC directions, respectively. Random prostate rotations were (1 S.D.) 3.6, 1.7 and 1.9 degrees around the LR, AP and CC axis, respectively, whereas systematic rotations were 4.7, 2.0 and 2.7 degrees around the LR, AP and CC axis, respectively. CONCLUSIONS We found that the fiducial gold seeds are a safe and appropriate device to verify and correct the position of prostate during megavoltage irradiation. The amount of seed migration and prostate deformation is far below our present tumour delineation accuracy.

Measurements and clinical consequences of prostate motion during a radiotherapy fraction.

PURPOSE Here we study the magnitude of prostate motion during the delivery of a radiotherapy fraction. These motions have clinical consequences for on-line position verification and the choice of margins around the target volume. METHODS AND MATERIALS We studied the motion of the prostate for 10 patients during 251 radiotherapy treatment fractions by assessing the position of implanted gold markers. Gold markers of 1 mm diameter and 5 mm length were implanted in the prostate before the start of the radiotherapy. We obtained movies during each fraction using an a-Si flat-panel imager. The markers could be detected in separate frames using a marker extraction kernel. RESULTS Marker displacements as large as 9.5 mm were detected in one fraction. The motion of the prostate is greatest in the caudal-cranial and the anterior-posterior directions. Within a time window of 2 to 3 min, deviations from the initial marker position, averaged over all patients, are 0.3 +/- 0.5 mm and -0.4 +/- 0.7 mm in the anterior-posterior and caudal-cranial directions, respectively. CONCLUSIONS It appeared that on average, the intrafraction prostate motions did not result in margins larger than 1 mm, provided that the position verification is performed at time intervals of 2 to 3 min. Only for some patients performing more frequent position verification or adding extra margins of 2 to 3 mm is required to account for intrafraction prostate motions.

Second primary tumors in hereditary retinoblastoma: a register-based study, 1945-1997: is there an age effect on radiation-related risk?

OBJECTIVE The aim of this study is to evaluate the influence of age at external beam irradiation (EBRT) on the occurrence of second primary tumors (SPTs) inside and outside the irradiation field in hereditary retinoblastoma patients. DESIGN Cross-sectional study. PARTICIPANTS The study included 263 hereditary retinoblastoma patients born in The Netherlands between 1945 and 1997. METHODS A national register-based follow-up cohort study was performed on hereditary retinoblastoma patients. Information on therapy, age at irradiation, and location of SPT was obtained from the register. The Kaplan-Meier method calculated cumulative incidences of SPT in three subgroups: irradiation before (early EBRT) and after 12 months of age (late EBRT), and no irradiation. The Mantel-Cox method determined the statistical significance of differences between the cumulative incidence curves. MAIN OUTCOME MEASURES Development of SPT inside and outside a precisely defined irradiation field in relation to age at irradiation. Our definition excluded pineoblastoma as SPT, because they constitute part of a trilateral retinoblastoma; in addition, they lie outside the field of irradiation. RESULTS The cumulative incidence of SPT at the age of 25 years was 22% (95% confidence intervals 13%-34%) in the early EBRT group, 3% (0%-14%) in the late EBRT group, and 5% (1%-16%) in the nonirradiated group (Mantel-Cox overall: P = 0.001; between early and late EBRT, P = 0.04). However, in early irradiated patients, the incidence of SPTs inside and outside the irradiation field was similar (11%), and the difference between early and late EBRT in incidence of SPT inside the field of irradiation was less prominent than overall (11% vs. 3%: P = 0.37). Sensitivity analysis showed the results depended on the way SPT, irradiation field, and, especially, pineoblastomas are defined. CONCLUSIONS Hereditary retinoblastoma confers an increased risk for the development of SPT, especially in patients treated with EBRT before the age of 12 months. However, the presence of similar numbers of SPTs inside and outside the irradiation field suggests that irradiation is not the cause. In other words, this study does not show an age effect on radiation-related risk. Rather, early EBRT is probably a marker for other risk factors of SPT.

Comparison of megavoltage position verification for prostate irradiation based on bony anatomy and implanted fiducials.

PURPOSE The patient position during radiotherapy treatment of prostate cancer can be verified with the help of portal images acquired during treatment. In this study we quantify the clinical consequences of the use of image-based verification based on the bony anatomy and the prostate target itself. PATIENTS AND METHODS We analysed 2025 portal images and 23 computed tomography (CT) scans from 23 patients with prostate cancer. In all patients gold markers were implanted prior to CT scanning. Statistical data for both random and systematic errors were calculated for displacements of bones and markers and we investigated the effectiveness of an off-line correction protocol. RESULTS Standard deviations for systematic marker displacement are 2.4 mm in the lateral (LR) direction, 4.4 mm in the anterior-posterior (AP) direction and 3.7 mm in the caudal-cranial direction (CC). Application of off-line position verification based on the marker positions results in a shrinkage of the systematic error to well below 1 mm. Position verification based on the bony anatomy reduces the systematic target uncertainty to 50% in the AP direction and in the LR direction. No reduction was observed in the CC direction. For six out of 23 patients we found an increase of the systematic error after application of bony anatomy-based position verification. CONCLUSIONS We show that even if correction based on the bony anatomy is applied, considerable margins have to be set to account for organ motion. Our study highlights that for individual patients the systematic error can increase after application of bony anatomy-based position verification, whereas the population standard deviation will decrease. Off-line target-based position verification effectively reduces the systematic error to well below 1 mm, thus enabling significant margin reduction.

An improved breast irradiation technique using three-dimensional geometrical information and intensity modulation

BACKGROUND AND PURPOSE In spite of the complex geometry of the breast, treatment planning for tangential breast irradiation is conventionally performed using two-dimensional patient anatomy information. The purpose of this work was to develop a new technique which takes the three-dimensional (3D) patient geometry into account. MATERIALS AND METHODS An intensity-modulated radiotherapy (IMRT) technique was developed based on the division of the tangential fields in four multi-leaf collimator (MLC) shaped segments. The shape of these segments was obtained from an equivalent path length map of the irradiated volume. Approximately 88% of the dose was delivered by two open fields covering the whole treated volume. Dose calculations for the IMRT technique and the conventional technique were performed for five patients, using computer tomography (CT) data and a 3D calculation algorithm. A planning target volume (PTV) and ipsilateral lung volume were delineated in these CT data. RESULTS All patients showed similar equivalent path length patterns. Analysis of the dose distribution showed an improved dose distribution using the IMRT technique. The dose inhomogeneity in the PTV was 9.0% (range 6.4-11.4%) for the conventional and 7.6% (range 6.5-10.3%) for the IMRT technique. The mean lung dose was reduced for the IMRT technique by approximately 10% compared with the conventional technique. CONCLUSION A new breast irradiation technique has been developed which improves the dose homogeneity within the planning target volume and reduces the dose to the lung. Furthermore, the IMRT technique creates the possibility to improve the field matching in case of multiple field irradiations of the breast and lymph nodes.

Quantification of orbital and mid-facial growth retardation after megavoltage external beam irradiation in children with retinoblastoma

PURPOSE The late side effects of external beam irradiation in patients with retinoblastoma such as orbital bony growth retardation, are a serious problem in adolescence. Therefore, a quantitative study was performed to investigate the late effects of irradiation on orbital growth in patients with retinoblastoma. METHODS The orbits of 68 patients with retinoblastoma, 52 bilateral and 16 unilateral, were divided into two treatment groups: radiotherapy alone, 77 orbits; and radiotherapy + enucleation, 43 orbits. Follow-up time was 12 to 240 months (mean, 95 months) in group 1 and 27 to 216 months (mean, 97 months) in group 2. These groups were subdivided further into age groups at which radiotherapy was given. The morphometric measurements of these groups were compared. RESULTS The authors showed that irradiation causes a significant growth retardation when compared with the growth of nonirradiated orbits (P<0.001). They also demonstrated that radiotherapy in children younger than 6 months of age is more damaging to the orbital growth than at an older age (P<0.01). Finally, the authors showed that secondary enucleation does not have an additive growth-retarding effect. CONCLUSION Orbital growth retardation in patients with retinoblastoma after radiotherapy is influenced mainly by the age at which irradiation is given and is defined at 6 months. Theoretically, it would be desirable to postpone irradiation in children until they are older than 6 months of age if possible. The irradiation effect on these orbits is not enhanced by enucleation.

DETECTION OF FIDUCIAL GOLD MARKERS FOR AUTOMATIC ON-LINE MEGAVOLTAGE POSITION VERIFICATION USING A MARKER EXTRACTION KERNEL (MEK)

PURPOSE In this study automatic detection of implanted gold markers in megavoltage portal images for on-line position verification was investigated. METHODS AND MATERIALS A detection method for fiducial gold markers, consisting of a marker extraction kernel (MEK), was developed. The detection success rate was determined for different markers using this MEK. The localization accuracy was investigated by measuring distances between markers, which were fixed on a perspex template. In order to generate images comparable to images of patients with implanted markers, this template was placed on the skin of patients before the start of the treatment. Portal images were taken of lateral prostate fields at 18 MV within 1-2 monitor units (MU). RESULTS The detection success rates for markers of 5 mm length and 1.2 and 1.4 mm diameter were 0.95 and 0.99 respectively when placed at the beam entry and 0.39 and 0.86 when placed at the beam exit. The localization accuracy appears to be better than 0.6 mm for all markers. CONCLUSION Automatic marker detection with an acceptable accuracy at the start of a radiotherapy fraction is feasible. Further minimization of marker diameters may be achieved with the help of an a-Si flat panel imager and may increase the clinical acceptance of this technique.

Feasibility of automatic marker detection with an a-Si flat-panel imager

Here we study automatic detection of implanted gold markers relative to the field boundary in portal images for on-line position verification. Portal images containing 1-2 MU were taken with an amorphous silicon flat-panel imager. The images were obtained with lateral field at 18 MV. Both the detection success rate and the localization accuracy of markers of 1.0 and 1.2 mm diameter were determined with the help of a marker detection method based on a marker extraction kernel. A method for determining a fiducial reference point related to the field boundary was developed. Detection success rates were 0.99, 0.90 and 0.95 for markers of 1.2 mm diameter and 5 mm length, 1.0 mm diameter and 5 mm length and 1.0 mm diameter and 10 mm length respectively. The localization accuracy appeared to be better than 0.3 mm. The reference point could be reproduced with an accuracy equal to 1 pixel (0.5 mm at isocentre) within one fraction. During the first few seconds of a treatment fraction the field edge was not stable, which appeared to be an effect of the motion of the radiation source. Thanks to the use an a-Si flat-panel imager, on-line position verification using implanted gold markers becomes clinically feasible. We can use a clinically acceptable marker diameter as small as 1.0 mm. These markers can be automatically detected in portal images obtained with 1-2 MU relative to a stable reference point related to the field boundary.

Radiotherapy and hyperthermia in the treatment of patients with locally advanced prostate cancer: preliminary results

To report an interim clinical evaluation of combined external beam irradiation (EBRT) and interstitial or regional hyperthermia in the treatment of locally advanced prostate cancer.

Perfusion analyses in advanced breast carcinoma during hyperthermia

Blood flow in tumours and healthy tissue determines the ability of obtaining satisfactory temperature distributions in clinical hyperthermia, as well as the success of hyperthermia and radiation treatment. During the hyperthermia treatment, diagnostic data related to tissue blood flow can be determined by analysing the relationship between the amount of power absorbed in the tissue and the resulting temperature rise. The interpretation of the perfusion data (PERF) is highly complicated by the lack of an adequate theory to describe the heat transport in vascularized tissues. In vascularized breast tissues about 10 times as much power is needed to maintain therapeutic temperatures as is necessary in a stationary breast phantom. This large difference in maintenance power levels indicates the extreme importance of blood flow in tissue heat transport. PERF has been determined in 23 patients with advanced breast tumours. In this series (a) perfusion typically did not change during the stationary part of the individual hyperthermic sessions, (b) minimum tumour PERF was not related to tumour volume, and (c) there was no relation between tumour PERF and the ability to heat tumours. PERF can both increase and decrease after successful hyperthermia.