Astrid A.C. de Leeuw

Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group: considerations and pitfalls in commissioning and applicator reconstruction in 3D image-based treatment planning of cervix cancer brachytherapy.

Image-guided brachytherapy in cervical cancer is increasingly replacing X-ray based dose planning. In image-guided brachytherapy the geometry of the applicator is extracted from the patient 3D images and introduced into the treatment planning system; a process referred to as applicator reconstruction. Due to the steep brachytherapy dose gradients, reconstruction errors can lead to major dose deviations in target and organs at risk. Appropriate applicator commissioning and reconstruction methods must be implemented in order to minimise uncertainties and to avoid accidental errors. Applicator commissioning verifies the location of source positions in relation to the applicator by using auto-radiography and imaging. Sectional imaging can be utilised in the process, with CT imaging being the optimal modality. The results from the commissioning process can be stored as library applicators. The importance of proper commissioning is underlined by the fact that errors in library files result in systematic errors for clinical treatment plans. While the source channel is well visualised in CT images, applicator reconstruction is more challenging when using MR images. Availability of commercial dummy sources for MRI is limited, and image artifacts may occur with titanium applicators. The choice of MR sequence is essential for optimal visualisation of the applicator. Para-transverse imaging (oriented according to the applicator) with small slice thickness (< or =5 mm) is recommended or alternatively 3D MR sequences with isotropic voxel sizes. Preferably, contouring and reconstruction should be performed in the same image series in order to avoid fusion uncertainties. Clear and correct strategies for the applicator reconstruction will ensure that reconstruction uncertainties have limited impact on the delivered dose. Under well-controlled circumstances the reconstruction uncertainties are in general smaller than other brachytherapy uncertainties such as contouring and organ movement.

Clinical outcome and dosimetric parameters of chemo-radiation including MRI guided adaptive brachytherapy with tandem-ovoid applicators for cervical cancer patients: A single institution experience

PURPOSE To evaluate dosimetric parameters and clinical outcome for cervical cancer patients treated with chemo-radiation and MR-image guided adaptive brachytherapy (MR-IGABT) using tandem-ovoid applicators for intracavitary or combined intracavitary/interstitial approaches. METHOD This retrospective analysis includes 46 patients treated between 2006 and 2008. Dose-volume parameters D90 HR-CTV (high-risk clinical target volume) and D(2cc) OARs (organs at risk) were determined and converted into biologically equivalent doses in 2 Gy fractions (EQD2). Clinical outcome parameters (local control (LC), progression free survival (PFS) and overall survival (OS)) were analysed actuarially and late morbidity crude rates were scored using CTCAEv3.0. RESULTS Mean D90 HR-CTV was 84 (SD9) Gy EQD2 for HR-CTV volumes of mean 57 (SD37) cm(3) at time of first brachytherapy (BT). Median follow-up was 41 (range, 4-67) months. Three year LC, PFS, and OS rates were 93, 71, and 65%, respectively. Node negative patients had significantly higher 3-year survival rates compared to node positive ones (PFS 85 versus 53% (p=0.013), OS 77 versus 50% (p=0.032), respectively) with an even larger difference for patients with FIGO stages IB-IIB (PFS 87 versus 42% (p=0.002), OS 83 versus 46% (p=0.007), respectively). Late grade 3-4 mainly gastrointestinal or vaginal morbidity was observed in 4 patients (9.5%). No correlations were seen between morbidity and D(2cc) OAR values. CONCLUSION (Chemo-) radiation and MR-IGABT with tandem-ovoid applicators result in high LC and promising survival rates with reasonable morbidity.

MRI-guided treatment-planning optimisation in intracavitary or combined intracavitary/interstitial PDR brachytherapy using tandem ovoid applicators in locally advanced cervical cancer

PURPOSE To study the impact of MRI-guided treatment planning on dose/volume parameters in pulsed dose rate (PDR) brachytherapy (BT) for cervical cancer. Additionally, we investigated the potential benefit of an intracavitary/interstitial (IC/IS) modification of the classical tandem ovoid applicator. MATERIAL AND METHODS For 24 patients we compared Standard PDR BT plans, Scaled Standard plans and MRI-guided Optimised plans. The total EBRT/BT prescribed dose to Manchester point A or to 90% of the HR-CTV (D90 HR-CTV) expressed in EQD(2) was 80 Gy(alphabeta10) in 17 patients (Period I) and 84 Gy(alphabeta10) in 7 patients (Period II). The constraints to 2 cm(3) of the OAR were 90 Gy(alphabeta3) for bladder and 75 Gy(alphabeta3) for rectum, sigmoid and bowel. Most cases were treated with a traditional intracavitary tandem ovoid applicator. In 6 patients we used a newly designed combined IC/IS modification for the second PDR fraction and investigated the benefit of the interstitial part. RESULTS The average gain of MRI-guided optimisation expressed in D90 HR-CTV was 4+/-9 Gy(alphabeta10) (p<0.001) and 10+/-7 Gy(alphabeta10) (p=0.003) in the two periods. The dose to 2 cm(3) of the OAR met the constraints. In the group that was treated with the combined IC/IS approach, we could increase the D90 HR-CTV for the second PDR fraction with 5.4+/-4.2 Gy(alphabeta10) (p=0.005) and the D100 with 4.8+/-3.1 Gy(alphabeta10) (p=0.07). CONCLUSIONS Three-dimensional MRI-guided treatment planning and optimisation improves the DVH parameters compared to conventional planning strategies. Additional improvement can be achieved by using a combined IC/IS approach.

A multicentre comparison of the dosimetric impact of inter- and intra-fractional anatomical variations in fractionated cervix cancer brachytherapy

Background and purpose To compare the dosimetric impact of organ and target variations relative to the applicator for intracavitary brachytherapy by a multicentre analysis with different application techniques and fractionation schemes. Material and methods DVH data from 363 image/contour sets (120 patients, 6 institutions) were included for 1–6 fractions per patient, with imaging intervals ranging from several hours to ∼20 days. Variations between images acquired within one (intra-application) or between consecutive applicator insertions (inter-application) were evaluated. Dose plans based on a reference MR or CT image series were superimposed onto subsequent image sets and D2cm3 for the bladder, rectum and sigmoid and D90 for HR CTV were recorded. Results For the whole sample, the systematic dosimetric variations for all organs at risk, i.e. mean variations of D2cm3, were found to be minor (<5%), while random variations, i.e. standard deviations were found to be high due to large variations in individual cases. The D2cm3 variations (mean ± 1SD) were 0.6 ± 19.5%, 4.1 ± 21.7% and 1.6 ± 26.8%, for the bladder, rectum and sigmoid. For HR CTV, the variations of D90 were found to be −1.1 ± 13.1% for the whole sample. Grouping of the results by intra- and inter-application variations showed that random uncertainties for bladder and sigmoid were 3–7% larger when re-implanting the applicator for individual fractions. No statistically significant differences between the two groups were detected in dosimetric variations for the HR CTV. Using 20% uncertainty of physical dose for OAR and 10% for HR CTV, the effects on total treatment dose for a 4 fraction HDR schedule at clinically relevant dose levels were found to be 4–8 Gy EQD2 for OAR and 3 Gy EQD2 for HR CTV. Conclusions Substantial variations occur in fractionated cervix cancer BT with higher impact close to clinical threshold levels. The treatment approach has to balance uncertainties for individual cases against the use of repetitive imaging, adaptive planning and dose delivery.

Towards patient specific thermal modelling of the prostate

The application of thermal modelling for hyperthermia and thermal ablation is severely hampered by lack of information about perfusion and vasculature. However, recently, with the advent of sophisticated angiography and dynamic contrast enhanced (DCE) imaging techniques, it has become possible to image small vessels and blood perfusion bringing the ultimate goal of patient specific thermal modelling closer within reach. In this study dynamic contrast enhanced multi-slice CT imaging techniques are employed to investigate the feasibility of this concept for regional hyperthermia treatment of the prostate. The results are retrospectively compared with clinical thermometry data of a patient group from an earlier trial. Furthermore, the role of the prostate vasculature in the establishment of the prostate temperature distribution is studied. Quantitative 3D perfusion maps of the prostate were constructed for five patients using a distributed-parameter tracer kinetics model to analyse dynamic CT data. CT angiography was applied to construct a discrete vessel model of the pelvis. Additionally, a discrete vessel model of the prostate vasculature was constructed of a prostate taken from a human corpse. Three thermal modelling schemes with increasing inclusion of the patient specific physiological information were used to simulate the temperature distribution of the prostate during regional hyperthermia. Prostate perfusion was found to be heterogeneous and T3 prostate carcinomas are often characterized by a strongly elevated tumour perfusion (up to 70-80 ml 100 g(-1) min(-1)). This elevated tumour perfusion leads to 1-2 degrees C lower tumour temperatures than thermal simulations based on a homogeneous prostate perfusion. Furthermore, the comparison has shown that the simulations with the measured perfusion maps result in consistently lower prostate temperatures than clinically achieved. The simulations with the discrete vessel model indicate that significant pre-heating takes place in the prostate capsule vasculature which forms a possible explanation for the discrepancy. Pre-heating in the larger pelvic vessels is very moderate, approximately 0.1-0.3 degrees C. In conclusion, perfusion imaging provides important input for thermal modelling and can be used to obtain a lower limit on the prostate and tumour temperature in regional hyperthermia. However, it is not sufficient to calculate in detail the prostate temperature distribution in individual patients. The prostate vasculature plays such a crucial role that a patient specific discrete vessel model of the prostate vasculature is required.

Prostate Perfusion In Patients With Locally Advanced Prostate Carcinoma Treated With Different Hyperthermia Techniques

PURPOSE We determined prostate perfusion in 18 patients with locally advanced prostate carcinoma treated with a combination of external beam irradiation and regional (10) or interstitial (8) hyperthermia. MATERIALS AND METHODS Perfusion values were calculated from temperature elevations due to constant applied power and from transient temperature measurements after a change in applied power. Students t test was used for comparing perfusion values with time and in the 2 groups. RESULTS At the start of regional hyperthermia treatment mean estimated perfusion plus or minus standard deviation was 10 +/- 8 ml./100 gm. per minute. At the end of treatment mean perfusion was increased to 14 +/- 2 ml./100 gm. per minute (p <0.01). Achieved thermal parameters were a mean temperature of at least 40.3C +/- 0.6C in 90% of the prostate, 40.9C +/- 0.6C in 50% and a mean maximum temperature of 41.6C +/- 0.6C. At the end of interstitial hyperthermia treatment estimated mean perfusion was 47 +/- 5 ml./100 gm. per minute, which was significantly different compared with the end of regional hyperthermia (p < 0(-7) ). Mean temperature was at least 39.4C +/- 0.9C in 90% of the prostate and 41.8C +/- 1.6C in 50%, while mean maximum temperature was 53.1C +/- 6.3C. Systemic temperature increased during regional hyperthermia up to 38.6C, whereas during interstitial hyperthermia body temperature was not elevated. CONCLUSIONS During interstitial hyperthermia perfusion values are higher than during regional hyperthermia. Hyperthermia causes increased prostate perfusion.

Experimental validation of hyperthermia SAR treatment planning using MR B1+ imaging

In this paper the concept of using B1+ imaging as a means to validate SAR models for radiofrequency hyperthermia is presented. As in radiofrequency hyperthermia, in common clinical MR imaging which applies RF frequencies between 64 and 128 MHz, the RF field distribution inside a patient is largely determined by the dielectric distribution of the anatomy. Modern MR imaging techniques allow measurement of the RF magnetic field component B1+ making it possible to measure at high resolution the dielectric interaction of the RF field with the patient. Given these considerations, we propose to use MR imaging to verify the validity of our dielectric patient model used for SAR models of radiofrequency hyperthermia. The aim of this study was to investigate the feasibility of this concept by performing B1+ measurements and simulations on cylindrical split phantoms consisting of materials with dielectric properties similar to human tissue types. Important topics of investigation were the accuracy and sensitivity of B1+ measurements and the validity of the electric model of the MR body coil. The measurements were performed on a clinical 1.5 T MR scanner with its quadrature body coil operating at 64 MHz. It was shown that even small B1+ variations of 2 to 5% could be measured reliably in the phantom experiments. An electrical model of the transmit coil was implemented on our FDTD-based hyperthermia treatment planning platform and the RF field distributions were calculated assuming an idealized quadrature current distribution in the coil. A quantitatively good correlation between measurements and simulations was found for phantoms consisting of water and oil, while highly conductive phantoms show considerable deviations. However, assuming linear excitation for these conductive phantoms resulted in good correspondence. As an explanation it is suggested that the coil is being detuned due to the inductive nature of the conductive phantoms, breaking up the phase difference of pi/2 between the two quadrature modes. It is concluded that B1+ imaging is an accurate and sensitive method for obtaining quantitative information about the RF field in phantoms. The electrical model of the body coil is inadequate for highly conductive phantoms. It is expected that for experiments on human bodies the inductive coupling is also significant, demonstrating the need for a full resonant FDTD model of the transmit coil. This will be pursued in the near future.

The use of MR B+1 imaging for validation of FDTD electromagnetic simulations of human anatomies

In this study, MR B(+)(1) imaging is employed to experimentally verify the validity of FDTD simulations of electromagnetic field patterns in human anatomies. Measurements and FDTD simulations of the B(+)(1) field induced by a 3 T MR body coil in a human corpse were performed. It was found that MR B(+)(1) imaging is a sensitive method to measure the radiofrequency (RF) magnetic field inside a human anatomy with a precision of approximately 3.5%. A good correlation was found between the B(+)(1) measurements and FDTD simulations. The measured B(+)(1) pattern for a human pelvis consisted of a global, diagonal modulation pattern plus local B(+)(1) heterogeneties. It is believed that these local B(+)(1) field variations are the result of peaks in the induced electric currents, which could not be resolved by the FDTD simulations on a 5 mm(3) simulation grid. The findings from this study demonstrate that B(+)(1) imaging is a valuable experimental technique to gain more knowledge about the dielectric interaction of RF fields with the human anatomy.

Intra-fraction uncertainties of MRI guided brachytherapy in patients with cervical cancer

Dosimetric intra-fraction uncertainties in MRI-guided brachytherapy were analysed for HR-CTV and OARs. While dose differences were generally small, individual outliers occurred. In contrast to HDR, patients treated with PDR show increased mean rectal dose over time. Re-imaging prior to dose delivery helps to detect unfavorable anatomical changes, and allows for intervention.

The effect of alternative biological modelling parameters (α/β and half time of repair T1/2) on reported EQD2 values in the treatment of advanced cervical cancer

PURPOSE To evaluate the effect of different α/β and half-time of repair T(½) on the assessment of clinical treatment plans for patients with cervical cancer. MATERIALS AND METHODS We used EBRT and BT treatment plans of five patients, planned with MRI guided BT. We computed 3D EQD2 dose distributions of combined EBRT and BT treatments and calculated D90 of high-risk clinical target volume (HR-CTV) and D(2cc) for bladder and rectum, and the ratio D(2cc)(bladder)/D90(HR-CTV). BT was modelled as PDR (two applications of 32×60cGy) and HDR (two applications of 2×7Gy). We assumed a low, standard and high value for the biological parameters: HR-CTV α/β=5/10/15Gy and T(½)=0.5/1.5/2.5h; OAR α/β=2/3/4Gy; T(½)=0.5/1.5/4.5h. RESULTS The chosen variation in modelling parameters had a much larger effect on PDR treatments than on HDR treatments, especially for OAR, thus creating larger uncertainties. The relative mean range of the ratio D(2cc)(bladder)/D90(HR-CTV) is 72% for PDR and 25% for HDR. Out of the 125 modelled combinations 48 PDR plans and 23 HDR plans comply with clinical objectives. CONCLUSION For HDR brachytherapy, only α/β has a significant impact on reported EQD2 values, whereas for PDR both α/β and T(½) are important. Generally, the ratio D(2cc)(bladder)/D90(HR-CTV) is more favourable for PDR, even considering the larger uncertainties in EQD2.