Long-term Overall Survival after External Beam Radiotherapy for Localised Prostate Cancer.

AIMS: Knowledge on survival probabilities is essential for determining optimal treatment strategies. We studied overall survival and associated prognostic factors in Dutch patients with localised prostate cancer (PCa) selected for external beam radiotherapy. MATERIALS AND METHODS: For this single-centre retrospective cohort study, we identified all T1-T3 PCa patients (aged 55-80 years) in the radiotherapy planning database with a start date between January 2006 and December 2013, treated with 72-78 Gy in 2 Gy fractions to the prostate ± seminal vesicles (n = 1536). Long-term androgen deprivation therapy (ADT) was predominantly prescribed in the case of extracapsular disease (>T3). Overall survival was estimated using the Kaplan-Meier method. Prognostic factors were evaluated in Cox regression models for the intermediate-risk and high-risk groups. RESULTS: The median follow-up was 12 years for patients who were alive. Ten-year survival rates were 79.0% for low-risk (n = 120), 59.9% for intermediate-risk (n = 430) and 56.8% for high-risk patients (n = 986). A higher age, higher comorbidity score, active smoking and Gleason score ≥8 had a statistically significant negative impact on overall survival at multivariable analysis. ADT was associated with superior overall survival in the high-risk group translating into overall survival rates similar to the intermediate-risk group. CONCLUSIONS: Although PCa patients selected for external beam radiotherapy are typically in good health, their comorbidity score and smoking habits appeared to be dominant predictors for overall survival. Overall survival rates within the high-risk group varied, showing improved overall survival with ADT prescription and worse overall survival in the case of Gleason score ≥8.

Impact of Advanced External Beam Radiotherapy on Second Haematological Cancer Risk in Prostate Cancer Survivors.

AIMS: External beam radiotherapy (EBRT) for prostate cancer (PCa) has rapidly advanced over the years. Advanced techniques with altered dose distributions may have an impact on second haematological cancer (SHC) risks. We assessed SHC risk after EBRT for PCa and explored whether this risk has changed over the years. MATERIALS AND METHODS: Patients diagnosed with a T1-T3 PCa between 1990 and 2015 were selected from the Netherlands Cancer Registry. Patients treated with EBRT were assigned to EBRT eras based on the date of diagnosis. These eras represented two-dimensional radiotherapy (2D-RT; 1991-1996), three-dimensional conformal radiotherapy (3D-CRT; 1998-2005) or advanced EBRT (2008-2015). Standardised incidence ratios (SIR) and absolute excess risks (AER) were calculated overall and by EBRT era. Sub-hazard ratios (sHRs) were calculated for the comparison of EBRT versus radical prostatectomy and active surveillance. RESULTS: PCa patients with EBRT as the primary treatment (n = 37 762) had an increased risk of developing a SHC (SIR = 1.20; 95% confidence interval 1.13-1.28) compared with the Dutch male general population. Estimated risks were highest for the 2D-RT era (SIR = 1.32; 95% confidence interval 1.14-1.67) compared with the 3D-CRT era (SIR = 1.16; 95% confidence interval 1.05-1.27) and the advanced EBRT era (SIR = 1.21; 95% confidence interval 1.07-1.36). AER were limited, with about five to six extra cases per 10 000 person-years. Relative risk analysis (EBRT versus radical prostatectomy/active surveillance) showed significant elevation with EBRT versus active surveillance (sHR = 1.17; 95% confidence interval 1.03-1.33; P = 0.017), but not for EBRT versus radical prostatectomy (sHR = 1.08; 95% confidence interval 0.94-1.23; P = 0.281). CONCLUSION: Increased SHC risks after EBRT for PCa cancer were observed for all EBRT eras compared with the general Dutch male population. Excess risks for EBRT versus other PCa treatment groups were found for only EBRT versus active surveillance.

SU-E-T-617: Towards Fully Automated Multi-Criterial Plan Generation: A Prospective Clinical Study.

PURPOSE: To prospectively compare plans generated with iCycle, an in-house developed algorithm for fully automated multi-criterial IMRT beam profile and beam orientation optimization (Breedveld, Med. Phys. 2012), and plans manually generated by dosimetrists with the clinical treatment planning system. METHODS: For 20 randomly selected head-and-neck cancer patients with various tumour locations (of whom 13 received sequential boost treatments) we offered the treating physician the choice between an automatically generated iCycle plan and a manually optimized plan following standard clinical procedures. While iCycle used a fixed'wish-list' with hard constraints and prioritised objectives, the dosimetrists manually selected the beam configuration and fine-tuned the constraints and objectives for each IMRT plan. Dosimetrists and treating physicians were not informed in advance whether a competing iCycle plan was made or not. The two plans were simultaneously presented to the physician who then selected the plan to be used for treatment. For the patient group, we quantified differences in PTV coverage and sparing of critical tissues. RESULTS: In 32/33 plan comparisons the physician selected the iCycle plan for treatment. This highly consistent preference for automatically generated plans was mainly caused by improved sparing for the large majority of critical structures. With iCycle, the NTCPs for parotid and submandibular glands were reduced by 2.4% ± 4.9% (maximum: 18.5%, p=0.001) and 6.5% ± 8.3% (maximum: 27%, p=0.005), respectively. The reduction in mean oral cavity dose was 2.8 Gy ± 2.8 Gy (maximum: 8.1 Gy, p=0.005). For swallowing muscles, esophagus and larynx, the mean dose reduction was 3.3 Gy ± 1.1Gy (maximum: 9.2 Gy, p<0.001). Moreover, for 15 patients, the target coverage was improved as well. CONCLUSIONS: In 97% of cases, the automatically generated plan was selected for treatment because of superior quality. Apart from improved plan quality, automatic plan generation is economically attractive because of reduced workload.

Improvement of radiotherapy treatment delivery accuracy using an electronic portal imaging device.

Reliable application of advanced external beam techniques for the treatment of patients with cancer, such as intensity modulated radiotherapy, requires an adequate quality assurance programme for the verification of the dose delivery. Accurate patient positioning is mandatory because of the steep dose gradients outside the tumour volume. Owing to the increased complexity of the treatment planning and delivery techniques, verification of the dose delivery before and during the actual patient treatment is equally important. For this purpose, a quality assurance programme has been established in our clinic that is primarily based on measurements with electronic portal imaging devices. To minimise systematic set-up errors, the patient positioning is measured in the first few treatment fractions and a set-up correction is applied in the subsequent ones. Before the first treatment fraction, portal dose measurements are performed for each treatment field with the electronic portal imaging device to verify that the planned fluence distribution is correctly delivered at the treatment unit. Dosimetric measurements are also performed during patient treatment to derive the actually delivered fluence maps. By combining this information with knowledge on the patient set-up, the delivered 3-D dose distribution to both the tumour and sensitive organs may be assessed. However, for the highest accuracy, exact knowledge on the (internal) patient geometry during treatment, e.g. using a cone-beam CT, is required.

Dosimetric verification of x-ray fields with steep dose gradients using an electronic portal imaging device.

Regions with steep dose gradients are often encountered in clinical x-ray beams, especially with the growing use of intensity modulated radiotherapy (IMRT). Such regions are present both at field edges and, for IMRT, in the vicinity of the projection of sensitive anatomical structures in the treatment field. Dose measurements in these regions are often difficult and labour intensive, while dose prediction may be inaccurate. A dedicated algorithm developed in our institution for conversion of pixel values, measured with a charged coupled device camera based fluoroscopic electronic portal imaging device (EPID), into absolute absorbed doses at the EPID plane has an accuracy of 1-2% for flat and smoothly modulated fields. However, in the current algorithm there is no mechanism to correct for the (short-range) differences in lateral electron transport between water and the metal plate with the fluorescent layer in the EPID. Moreover, lateral optical photon transport in the fluorescent layer is not taken into account. This results in large deviations (>10%) in the penumbra region of these fields. We have investigated the differences between dose profiles measured in water and with the EPID for small heavily peaked fields. A convolution kernel has been developed to empirically describe these differences. After applying the derived kernel to raw EPID images, a general agreement within 2% was obtained with the water measurements in the central region of the fields, and within 0.03 cm in the penumbra region. These results indicate that the EPID is well suited for accurate dosimetric verification of steep gradient x-ray fields.

Commissioning of a commercially available system for intensity-modulated radiotherapy dose delivery with dynamic multileaf collimation.

PURPOSE: To commission commercially available equipment for intensity-modulated radiotherapy (IMRT) using dynamic multileaf collimation (DMLC). MATERIALS AND METHODS: First, the stability in leaf positioning and in realized IMRT profiles on a Varian 2300 C/D machine were determined as a function of time and gantry angle, and as a result of treatment interrupts. Second, dose distributions calculated with the CadPlan (Varian) treatment planning system, using leaf trajectories calculated with the leaf motion calculator (LMC) algorithm, were compared with distributions realized at the 2300 C/D unit. RESULTS: Day-to-day and gantry angle variations in leaf positioning and dose delivery were very small (less than 0.1-0.2 mm and 2%). The effect of treatment interrupts on measured dose distributions was less than 2%. The agreement between the final dose distribution calculated by CadPlan and the measured dose was generally within 2%, or 2 mm at steep dose gradients, using a leaf transmission value of 1.8% and a leaf separation value of 2 mm in LMC. For narrow peaks, deviations of up to 6% were observed. LMC does not synchronize adjacent leaf trajectories resulting in tongue-and-groove underdosages of up to 29% for extreme cases. CONCLUSIONS: The 2300 C/D machine is suitable for accurate and reproducible DMLC treatments. The agreement between dose predictions with LMC and CadPlan, and realized doses at this unit is clinically acceptable for most cases. However, differences between calculated and actual dose values may exist in peaked fluences or due to tongue-and-groove effects. Therefore, pretreatment dosimetric verification for each patient is recommended.

An evaluation of two techniques for beam intensity modulation in patients irradiated for stage III non-small cell lung cancer.

In locally advanced lung cancer, the use of high dose radiotherapy (RT) and/or concurrent chemo-RT is associated with significant pulmonary and esophageal toxicity. Despite a 3D conformal RT technique and the omission of elective mediastinal fields, three (of ten) patients with inoperable stage 3 NSCLC who were treated with induction chemotherapy (carboplatin-paclitaxel) followed by RT to 70 Gy, developed symptomatic radiation pneumonitis. In this planning study, the actual treatment plans of all ten patients were compared to plans derived using two beam intensity-modulated (BIM) techniques, for which similar geometrical beam setup parameters were used. In the first technique (BF-BIM), cranial and caudal boost fields were applied in order to allow field length reduction. The second technique (C-BIM) utilised 3-D missing-tissue compensators for all radiation beams. Both BIM techniques resulted in a significant sparing of critical normal tissues and the C-BIM technique was superior in all cases. When compared to the actual RT technique used for treatment, a reduction of 8.1+/-4.7% (1 S.D.) was observed in the mean lung dose for the BF-BIM plan, vs. 20.3+/-5.8% (1 S.D.) for the C-BIM plan. Similar reductions were observed in the percentage of the total lung volume exceeding 20 Gy (V(20)) for these techniques. BIM techniques appear to be a promising tool for enabling radiation dose-escalation and/or intensive concurrent chemo-RT in inoperable lung cancer.

Beam intensity modulation for penumbra enhancement and field length reduction in lung cancer treatments: a dosimetric study.

BACKGROUND AND PURPOSE: In a recent treatment planning study, a previously published technique for superior-inferior field length reduction for prostate cancer patients, based on penumbra enhancement using static beam intensity modulation (BIM) with a multileaf collimator, was investigated for lung cancer treatments. For the patient group studied, the field lengths could be reduced by 1.4 cm and an average dose escalation of 6 Gy (maximum 16 Gy) appeared to be possible without any increase in the calculated risk of radiation pneumonitis. However, this planning study was performed with a treatment planning system that does not correctly account for the increased lateral secondary electron transport in lung tissue, resulting in too steep beam penumbrae. Therefore, prior to clinical implementation, an extensive dosimetric study was performed to evaluate and optimize BIM for penumbra enhancement and superior-inferior field length reduction in lung cancer treatments. MATERIALS AND METHODS: Film dosimetry was performed in several phantoms consisting of water equivalent and lung equivalent materials, both for a 6 and a 10 MV photon beam. Measured dose distributions were used to (i) adapt the BIM technique to properly account for increased lateral secondary electron transport, (ii) compare BIM dose distributions in lung material with dose distributions of standard treatment fields, and (iii) investigate the use of our treatment planning system for the design of BIM plans for lung cancer patients. RESULTS: Compared with our treatment planning study the superior and inferior boost fields, used in the BIM technique for penumbra enhancement, had to be longer and of a higher weight to compensate for the increased lateral secondary electron transport in lung tissue. With these modifications in the BIM technique, field lengths could indeed be reduced by 1.4 cm compared with treatment with standard fields, without the appearance of underdosages in the most superior and inferior target areas, whilst better sparing the healthy lung tissue. Practical rules were derived to use our treatment planning system for the design of BIM treatment plans. CONCLUSIONS: In spite of the increased lateral secondary electron transport in lung tissue, static BIM with a multileaf collimator may effectively be used for penumbra enhancement and superior-inferior field length reduction in lung cancer treatments.

Testing of the stability of intensity modulated beams generated with dynamic multileaf collimation, applied to the MM50 racetrack microtron.

Recently, we have published a method for the calculation of required leaf trajectories to generate optimized intensity modulated x-ray beams by means of dynamic multileaf collimation [Phys. Med. Biol. 43, 1171-1184 (1998)]. For the MM50 Racetrack Microtron it has been demonstrated that the dosimetric accuracy of this method, in combination with the dose calculation algorithm of the Cadplan 3D treatment planning system, is adequate for a clinical application (within 2% or 0.2 cm). Prior to initiating patient treatment with dynamic multileaf collimation (DMLC), tests have been performed to investigate the stability of DMLC fields generated at the MM50, (i) in time, (ii) subject to gantry rotation and (iii) in case of treatment interrupts, e.g., caused by an error detected by the treatment machine. The stability of relative dose profiles, normalized to a reference point in a relatively flat part of the modulated beam profile, was assessed from measurements with an electronic portal imaging device (EPID), with a linear diode array attached to the collimator and with film. The dose in the reference point was monitored using an ionization chamber. Tests were performed for several intensity modulated fields using 10 and 25 MV photon beams. Based on film measurements for sweeping 0.1 cm leaf gaps it was concluded that in an 80 days period the variation in leaf positioning was within 0.05 cm, without requiring any recalibration. For a uniform 10x10 cm2 field, realized dynamically by a scanning 0.4x10 cm2 slit beam, a maximum variation in slit width of 0.01 cm was derived from ionization chamber measurements, both in time and for gantry rotation. For a clinical example, the dose in the reference point reproduced within 0.2% (1 SD) over a period of 100 days. Apart from regions with very large dose gradients, variations in the relative beam profiles measured with the EPID were generally less than 1% (1 SD). For different gantry angles the dose profiles also reproduced within 1%, showing that gravity has a negligible influence. No significant deviations between uninterrupted and interrupted treatments could be observed, indicating that the effects of acceleration and deceleration of the leaves are negligible and that a DMLC treatment can be finished correctly after a treatment interrupt. Our previous and present studies have demonstrated that the dosimetric accuracy and stability of intensity modulated beams, generated at the MM50 by means of dynamic multileaf collimation, are adequate for clinical use. Patient treatment using dynamic multileaf collimation has been started in our clinic.

Dosimetric verification of intensity modulated beams produced with dynamic multileaf collimation using an electronic portal imaging device.

Dose distributions can often be significantly improved by modulating the two-dimensional intensity profile of the individual x-ray beams. One technique for delivering intensity modulated beams is dynamic multileaf collimation (DMLC). However, DMLC is complex and requires extensive quality assurance. In this paper a new method is presented for a pretreatment dosimetric verification of these intensity modulated beams utilizing a charge-coupled device camera based fluoroscopic electronic portal imaging device (EPID). In the absence of the patient, EPID images are acquired for all beams produced with DMLC. These images are then converted into two-dimensional dose distributions and compared with the calculated dose distributions. The calculations are performed with a pencil beam algorithm as implemented in a commercially available treatment planning system using the same absolute beam fluence profiles as used for calculation of the patient dose distribution. The method allows an overall verification of (i) the leaf trajectory calculation (including the models to incorporate collimator scatter and leaf transmission), (ii) the correct transfer of the leaf sequencing file to the treatment machine, and (iii) the mechanical and dosimetrical performance of the treatment unit. The method was tested for intensity modulated 10 and 25 MV photon beams; both model cases and real clinical cases were studied. Dose profiles measured with the EPID were also compared with ionization chamber measurements. In all cases both predictions and EPID measurements and EPID and ionization chamber measurements agreed within 2% (1 sigma). The study has demonstrated that the proposed method allows fast and accurate pretreatment verification of DMLC.

Beam intensity modulation for penumbra enhancement in the treatment of lung cancer.

PURPOSE: A treatment planning study was performed for patients with lung cancer in order to investigate the extent to which doses to critical structures could be reduced by penumbra enhancement at the superior and inferior field edges, using beam intensity modulation (BIM) with a multileaf collimator. By applying two independent published models for the prediction of the incidence of normal tissue complications, the potential for dose escalation without increasing the incidence of pneumonitis was estimated. METHODS AND MATERIALS: For 12 patients, the standard treatment technique was compared with the BIM technique using the Cadplan 3D planning system (Varian-Dosetek). Dose distributions in the healthy lung tissue were evaluated by considering both lungs minus the tumor as one functional unit. The following parameters were compared: (i) the average normalized total dose (NTD), (ii) the lung volume receiving an NTD of more than 20 Gy, and (iii) the calculated normal tissue complication probability (NTCP). RESULTS: Due to the applied BIM technique, the field lengths could be reduced by 1.4 cm for all patients, while achieving a minimum dose at the superior and inferior parts of the target of 95% of the isocenter dose. Compared to the standard technique, BIM reduced the patient mean of the average NTD for the healthy lung tissue from 16.5 to 15.3 Gy. The volume of healthy lung tissue receiving an NTD of 20 Gy or more was reduced by 9.7% (range 2.2 to 23.1%). The calculated NTCP reduced from 10.7% to 7.6% on average. The length of the esophagus that received a dose of 60 Gy or more could be reduced for 5 of the 6 stage III patients in this study. Based on equal lung NTCPs for the standard technique and the BIM technique, a mean dose escalation of 5.7 Gy (range 1.1 to 16.0 Gy) was possible for the 12 patients in this study. Based on equal average NTDs for the two techniques, the patient mean of the allowed dose escalation was 6.5 Gy (range 1.1 to 18.2 Gy). All dose escalations would be possible without exceeding the spinal cord tolerance dose. CONCLUSIONS: The BIM technique reduced the dose delivery to critical tissues. Two published methods for estimating the incidence of pneumonitis both pointed to a potential for dose escalation of 6 to 7 Gy on average with the BIM technique, without increasing the incidence of pneumonitis. For 2 of the 12 patients in this study the estimated allowed dose escalation even exceeded 15 Gy.

Leaf trajectory calculation for dynamic multileaf collimation to realize optimized fluence profiles.

An algorithm for the calculation of the required leaf trajectories to generate optimized intensity modulated beam profiles by means of dynamic multileaf collimation is presented. This algorithm iteratively accounts for leaf transmission and collimator scatter and fully avoids tongue-and-groove underdosage effects. Tests on a large number of intensity modulated fields show that only a limited number of iterations, generally less than 10, are necessary to minimize the differences between optimized and realized fluence profiles. To assess the accuracy of the algorithm in combination with the dose calculation algorithm of the Cadplan 3D treatment planning system, predicted absolute dose distributions for optimized fluence profiles were compared with dose distributions measured on the MM50 Racetrack Microtron and resulting from the calculated leaf trajectories. Both theoretical and clinical cases yield an agreement within 2%, or within 2 mm in regions with a high dose gradient, showing that the accuracy is adequate for clinical application.

Field margin reduction using intensity-modulated x-ray beams formed with a multileaf collimator.

PURPOSE: In axial, coplanar treatments with multiple fields, the superior and inferior ends of a planning target volume (PTV) are at risk to get underdosed due to the overlapping penumbras of all treatment fields. We have investigated a technique using intensity modulated x-ray beams that allows the use of small margins for definition of the superior and inferior field borders while still reaching a minimum PTV-dose of 95% of the isocenter dose. METHODS AND MATERIALS: The applied intensity modulated beams, generated with a multileaf collimator, include narrow (1.1-1.6 cm) boost fields to increase the dose in the superior and inferior ends of the PTV. The benefits of this technique have been assessed using 3D treatment plans for 10 prostate cancer patients. Treatment planning was performed with the Cadplan 3D planning system (Varian-Dosetek). Dose calculations for the narrow boost fields have been compared with measurements. The application of the boost fields has been tested on the MM50 Racetrack Microtron (Scanditronix Medical AB), which allows fully computer-controlled setup of all involved treatment fields. RESULTS: Compared to our standard technique, the superior-inferior field length can be reduced by 1.6 cm, generally yielding smaller volumes of rectum and bladder in the high dose region. For the narrow boost fields, calculated relative dose distributions agree within 2% or 0.2 cm with measured dose distributions. For accurate monitor unit calculations, the phantom scatter table used in the Cadplan system had to be modified using measured data for square fields smaller than 4 x 4 cm2. The extra time needed at the MM50 for the setup and delivery of the boost fields is usually about 1 min. CONCLUSION: The proposed use of intensity modulated beams yields improved conformal dose distributions for treatment of prostate cancer patients with a superior-inferior field size reduction of 1.6 cm. Treatments of other tumor sites can also benefit from the application of the boost fields.

Daily dosimetric quality control of the MM50 Racetrack Microtron using an electronic portal imaging device.

The MM50 Racetrack Microtron, suited for advanced three-dimensional conformal radiotherapy techniques, is a complex machine in various respects. Therefore, for a number of gantry angles, daily quality control of the absolute output and fluence profiles of the scanned beams are mandatory. For the applied photon beams, a fast method for these daily checks, based on dosimetric measurements with the Philips SRI-100 Electronic Portal Imaging Device (EPID), has been developed and tested. Open beams are checked for four different gantry angles; for gantry angle 0, a wedged field is checked as well. Performing and analyzing the measurements takes about 10 min. The applied EPID has favourable characteristics for dosimetric quality control measurements: absolute output measurements reproduce within 0.5% (1 SD) and the reproducibility of relative (2D) beam profile measurements is 0.2% (1 SD). The day-to-day sensitivity stability over a period of one month is 0.6% (1 SD). Measured grey scale values are within 0.2% linear with the applied dose. The 2D fluence profile of the 25 MV photon beam of the MM50 is very stable in time: during a period of 5 months a maximum fluctuation of 2.2% has been observed. Once, a deviation in the cGy/MU-value of 6% was detected. There is no interlock in the MM50-system that would have prevented patient treatment with this strongly deviating output. Based on the results of this study and on clinical requirements regarding acceptability of deviations of beam characteristics, a protocol has been developed including action levels for additional investigations and, if necessary, adjustment of the beam characteristics.