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MRI-Guided 3D Optimization Significantly Improves DVH Parameters of Pulsed-Dose-Rate Brachytherapy in Locally Advanced Cervical Cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 71, No. 3, pp. 756–764, 2008 Copyright Ó 2008 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/08/$–see front matter
doi:10.1016/j.ijrobp.2007.10.032
CLINICAL INVESTIGATION
Cervix
MRI-GUIDED 3D OPTIMIZATION SIGNIFICANTLY IMPROVES DVH PARAMETERS OF PULSED-DOSE-RATE BRACHYTHERAPY IN LOCALLY ADVANCED CERVICAL CANCER JACOB C. LINDEGAARD, D.M.SC.,* KARI TANDERUP, M.SC.,y SØREN KYNDE NIELSEN, PH.D.,y SØREN HAACK, M.SC.,z AND JOHN GELINECK, M.D.x Departments of *Oncology; yMedical Physics; zBiomedical Engineering; and xRadiology, Aarhus University Hospital, Aarhus, Denmark Purpose: To compare dose–volume histogram parameters of standard Point A and magnetic resonance imagingbased three-dimensional optimized dose plans in 21 consecutive patients who underwent pulsed-dose-rate brachytherapy (PDR-BT) for locally advanced cervical cancer. Methods and Materials: All patients received external beam radiotherapy (elective target dose, 45 Gy in 25–30 fractions; tumor target dose, 50–60 Gy in 25–30 fractions). PDR-BT was applied with a tandem-ring applicator. Additional ring-guided titanium needles were used in 4 patients and a multichannel vaginal cylinder in 2 patients. Dose planning was done using 1.5 Tesla T1-weighted and T2-weighted paratransversal magnetic resonance imaging scans. T1-weighted visible oil-containing tubes were used for applicator reconstruction. The prescribed standard dose for PDR-BT was 10 Gy (1 Gy/pulse, 1 pulse/h) for two to three fractions to reach a physical dose of 80 Gy to Point A. The total dose (external beam radiotherapy plus brachytherapy) was normalized to an equivalent dose in 2-Gy fractions using a/b = 10 Gy for tumor, a/b = 3 Gy for normal tissue, and a repair half-time of 1.5 h. The goal of optimization was dose received by 90% of the target volume (D90) of $85 Gya/b10 in the high-risk clinical target volume (cervix and remaining tumor at brachytherapy), but keeping the minimal dose to 2 cm3 of the bladder and rectum/sigmoid at <90 and <75 Gya/b3, respectively. Results: Using three-dimensional optimization, all dose–volume histogram constraints were met in 16 of 21 patients compared with 3 of 21 patients with two-dimensional library plans (p < 0.001). Optimization increased the minimal target dose (D100) of the high-risk clinical target volume (p < 0.007) and decreased the minimal dose to 2 cm3 for the sigmoid significantly (p = 0.03). For the high-risk clinical target volume, D90 was 91 ± 8 Gya/b10 and D100 was 76 ± 5 Gya/b10. The minimal dose to 2 cm3 for the bladder, rectum, and sigmoid was 73 ± 6, 67 ± 6, and 69 ± 6 Gya/b3, respectively. Conclusion: The results of our study have shown that magnetic resonance imaging-guided optimization of PDR-BT for locally advanced cervical cancer significantly improved the dose–volume histogram parameters. Ó 2008 Elsevier Inc. Pulsed-dose-rate brachytherapy, Cervical cancer, Image guided, Treatment planning, Magnetic resonance imaging, MRI.
Recently, both European (1, 2) and American (3) guidelines for three-dimensional (3D) intracavitary brachytherapy (BT) for cervical cancer have been published. To date, only the European guidelines (Groupe Europe´en de Curiethe´rapie– European Society for Therapeutic Radiology and Oncology [GEC-ESTRO]) are supported by clinical data from studies in which systematic use of magnetic resonance imaging (MRI)-based planning was used (4–7). The primary advantage of this technique is the possibility to conform the dose
given by BT to the anatomy of each patient, taking into account both the tumor regression obtained by external beam radiotherapy (EBRT) and the position of nearby organs at risk (OARs). According to current experience, this technique has the potential to at least halve both the local failure rate and the rate of moderate to severe morbidity (4, 7). A response-adapted treatment strategy such as this requires that both a gynecologic examination and MRI with the BT applicator in situ be performed at BT (2). Visualization of the tumor is difficult with computed tomography (CT), necessitating MRI (8). Because significant changes in localization
Reprint requests to: Jacob Christian Lindegaard, D.M.Sc., Department of Oncology, Aarhus University Hospital, Bldg. 5, No¨rrebrogade 44, Aarhus DK-8000 Denmark. Tel: (+45) 8949-2577; Fax: (+45) 8949-2530; E-mail: [email protected] Supported by the Danish Cancer Society and the Aarhus County Research Initiative.
Presented at Canadian Association of Radiation Oncology-Canadian Organization of Medical Physicists 2007 Meeting, Toronto, ON, Canada, October 10, 2007. Conflict of interest: none. Received Aug 8, 2007, and in revised form Oct 7, 2007. Accepted for publication Oct 12, 2007.
INTRODUCTION
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of the target and OARs in relation to the position of the applicator can occur, each implant should ideally be determined using on a new MRI study (9, 10). Thus, for each implant, contouring of the clinical target volume (CTV) and OARs should be done using a 3D dose planning system. Subsequently, the applicator should be carefully reconstructed and the conventional standard loading pattern matching the prescribed dose to Point A applied. From this starting point, dose optimization can be performed with the goal of increasing the dose to the high-risk CTV (HR-CTV) to the dose level previously prescribed to Point A without exceeding the dose– volume constraints for the surrounding normal tissues (11). To date, the reporting of dose–volume histogram (DVH) parameters from MRI-based BT has been limited to the Viennese high-dose-rate (HDR) BT experience (4, 7, 11, 12). However, since December 2005, we have used MRI-guided 3D pulsed-dose-rate BT (PDR-BT) for locally advanced cervical cancer. The aim of the present study was to present the implementation of this method with PDR-BT, quantify the effect of MRI-guided 3D optimization on the DVH parameters, and compare our PDR data with the HDR data from Vienna. METHODS AND MATERIALS Staging, EBRT, and concomitant chemotherapy For all patients, staging involved gynecologic examination and cystoscopy with the patient under general anesthesia. In addition, diagnostic, whole-body fluorodeoxyglucose-positron emission tomography-CT and MRI of the pelvic region was performed. The tumor target (CTV-T) for EBRT included the gross tumor volume, whole cervix, and uterus. The elective target (CTV-E) was contoured according to the recommendations of Taylor et al. (13). The CTV-E included the CTV-T, lymph nodes in the parametria, and along the external iliac, internal iliac, common iliac/aorta to the L4–L5 interspace, and $2 cm of the vagina below the CTVT. The para-aortic region to the level of L1-L2 was included in CTV-E in patients with pathologic common iliac or para-aortic lymph nodes. The inguinal nodes were included for Stage IIIA disease. For patients with pathologic nodes, we used the fluorodeoxyglucose-positron emission tomography-CT information to define a specific nodal target (CTV-nodes [CTV-N]). Dose planning was done using conformal box techniques or intensity-modulated RT with a simultaneous integrated boost (SIB) to obtain differential dose levels for the CTV-T, CTV-E, and CTV–N. For tumors expected to be well covered by BT, the prescribed dose of EBRT to the CTV-T was 50 Gy in 25 fractions. For large tumors, the prescribed dose for the CTV-T was 60 Gy in 30 fractions. The CTV-E was treated with 45 Gy in 25 fractions, except for cases with an extended volume, for which the fractionation was 45 Gy in 30 fractions. The CTV–N, when present, was always treated with 60 Gy in 30 fractions. EBRT was given in 15–18 MV by a linear accelerator (Siemens Medical Systems, Malvern, PA and Varian Medical Systems, Palo Alto, CA), all equipped with a multileaf collimator. Concomitant chemotherapy (weekly cisplatin, 40 mg/m2) for a maximum of six courses was given to all patients with sufficient kidney and bone marrow function.
PDR-BT application Pulse-dose-rate BT was initiated during the last 1–2 weeks of EBRT, with two to three fractions given with a 1-week interval,
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aiming for a total treatment time for EBRT+BT of <7 weeks. Clinical assessment of the tumor volume and topography was repeated at each BT fraction, and a clinical drawing was made using standardized cartoons (2). A Foley catheter with 7-mL of X-ray diluted contrast was placed in the bladder. Dilation of the uterine canal and placement of the applicator was performed under ultrasound guidance. Vaginal packing with gauze soaked in diluted gadolinium (Magnevist 469 mg/mL, 7.5 mL in 100 mL NaCl) was used. A 20-cm drainage tube was inserted 15 cm into the rectum to allow for the introduction of rectal diodes for in vivo dosimetry (14). The applicator was an MRI-compatible plastic tandem-ring applicator (GammaMed, Varian) with a ring diameter of 26, 30, and 35 mm; the length of the tandem was 30–80 mm. A custom-made multichannel vaginal cylinder (15) attached to the tandem/ring applicator was used in 2 patients in whom the vaginal tumor extension was beyond the reach from the ring (Fig. 1). Also, a cap with steering holes for a combined intracavitary-interstitial (IC/IS) approach (7, 12) was used in 4 patients, in whom three to five blunt-ended titanium needles (Acrostack, Wintherthur, Switzerland) were implanted in the parametria (Fig. 1).
MRI technique, applicator reconstruction, and contouring Magnetic resonance imaging was performed on 1.5 Tesla scanner (Siemens Magnetom Symphony) using array coils. Thin plastic tubes filled with peanut oil and then sealed were inserted in the applicator channels to serve as ‘‘dummy wires’’ for the T1-weighted sequences. All MRI sequences were oriented according to the axis of the applicator (i.e., the paratransversal, parasagittal, and paracoronal planes) (2, 16). The MRI protocol involved a T1-weighted (Turbo Spin Echo) paratransversal scan with a 3-mm slice thickness and no gap was used to guide the applicator reconstruction. Then, T2-weighted (Turbo Spin Echo) sequences in all three planes: paratransversal, parasagittal, and paracoronal were produced with a slice thickness of 5 mm and a 1-mm gap. Applicator reconstruction was performed directly in BrachyVision, version 6.5 (Varian) on the paratransversal T2-weighted sequence by introducing library applicators with predefined geometry. The tandem and ring were positioned by measuring the distance from the ring surface to the ring channel and from the tip of the tandem to the first stopping position in the tandem. The T1-weighted images were fused with the T2-weighted images to aid in the reconstruction by visualization of the ‘‘dummy wires’’ in the paracoronal and parasagittal plane. The rotation of the ring in the paratransversal plane was determined from the T1-weighted sequence by measuring the angle of the guide tubes, which was clearly visible in the gauze-filled vagina. Contouring was performed on the T2-weighted paratransversal sequence supported by the clinical drawings and the MRI studies from diagnosis and at BT. The HR-CTV (GTV at BT plus the whole cervix), as well as the outer wall of the bladder, rectum, and sigmoid were contoured. The Point A and International Commission on Radiation Units and Measurements (ICRU) bladder and rectal points were positioned directly in the 3D study.
BT treatment planning and DVH analysis Each BT fraction was planned individually and was always initiated using a standard library plan (Fig. 2). For the ring, a standard plan contained three lateral stopping positions spaced by 5 mm in each side of the ring. For the tandem, the stopping positions were placed at a 5-mm distance from the tip to the level of the ring. For a standard plan, equal dwell times were used in all stopping positions in both the ring and the tandem. The prescribed standard dose for each fraction of PDR-BT was 10 Gy to Point A divided
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Fig. 1. Custom-made ‘‘add ons’’ for Varian standard tandem ring applicator in form of multichannel vaginal cylinder (Left) and ring cap for guidance of interstitial titanium needles (Right).
into 10 pulses of 1 Gy, with a pulse interval of 1 h. Optimization was performed by manually adding or removing stopping positions and adjusting the dwell times. The intention was to reach D90 $85 Gya/ b10 in the HR-CTV, but keeping D2 cc of bladder and rectum/sigmoid at below 90 and 75 Gya/b3, respectively. In this process, we were particularly focused on the high-dose volumes (i.e., 20 and 40 Gy isodose lines) and very heterogeneous dwell times in neighboring stopping positions. Also, we avoided extending the 10-Gy isodose curve to >25 mm from the center of the tandem at the level of Point A (11). For patients receiving combined IC/IS BT, we restricted loading of the parametrial needles to a maximum of 10– 20% of the dwell time for a standard stopping position (12). After inspecting the isodoses at all image levels, we obtained the cumulative DVH parameters from BrachyVision, version 6.5. The resulting dose was recalculated into the equivalent dose in 2-Gy fractions (EQD2) using the mono-exponential repair half time model with a/b = 10 for tumor, a/b = 3 for OARs, and a repair half time of 1.5 h (2). The EQD2 of EBRT and BT was then added to evaluate the optimized plan with regard to the DVH constraints. A worst-case approach was used in these calculations, assuming that the 2 cm3 of the OARs in question had received the full EBRT dose prescribed to the primary tumor (CTV-T) and that it was the same 2 cm3 of the organ that received the maximal BT dose at each BT fraction (11). In 10 BT fractions, radiobiological optimization was performed by increasing the number of pulses from 10 in the standard plan to 14–20 in the optimized plan. However, the pulse interval was always kept at 1 h. Finally a dose-point reflecting the expected maximal dose in the rectal diodes was inserted. In addition to the EQD2 calculations, we compared two-dimensional (2D) vs. 3D plans in terms of the sparing factor, calculated as the ratio of the cumulative physical doses of BT to OAR (2 cc) and HR-CTV (D90): SF = S D2 cc/S D90. Statistical comparisons between the DVH parameters of the standard vs. optimized plans were performed using a paired sample
t test. Fisher’s exact test was used to analyze the effect of optimization with regard to fulfillment of the DVH constraints. Comparisons between the Aarhus and Vienna parameters were performed using a standard t test. A two-tailed test was always performed using a significance level of 0.05.
RESULTS This study included 21 consecutive cases of biopsy-proven cervical cancer treated with curative intent December 2005 and March 2007 at the Department of Oncology, Aarhus University Hospital. Of the 21 patients, 2 had Stage IB2, 14 had Stage IIB, 3 had Stage IIIB, and 2 had Stage IIIA. The treatment characteristics are given in Table 1. The EBRT for most patients was 45 Gy given with a conformal four-field box to the CTV-E and a SIB, bringing the dose to the CTV-T to 50 Gy. In 7 patients with a large tumor volume, the CTV-T dose was increased to 60 Gy, and in 5 patients, pathologic lymph nodes were treated to 60 Gy using a SIB. Elective para-aortic RT was given to 3 patients. Concomitant chemotherapy was omitted in 4 patients because of age and comorbidity. Three fractions of PDR-BT were used in 14 patients in whom the EBRT dose to the CTV-T was 50 Gy. Two fractions of PDR-BT were used in 7 patients in whom the EBRT dose to the CTV-T was 60 Gy (Table 1). Thus, 56 fractions of PDR-BT were administered. Of these, 55 had been determined using the individual MRI studies with the applicator in situ. MRI was not possible for one of the PDR-BT fractions, which therefore had to be given using a standard loading pattern. The DVH parameters for this fraction were assessed by applying the loading pattern to the MRI study used for the subsequent PDR-BT fractions.
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Fig. 2. (Upper) Dwell times for standard (Left) and optimized (Right) dose plans. Standard plan (30-mm ring, 60-mm tandem) held 12 stopping positions in tandem and 3 stopping positions at each lateral side of ring. Dwell times indicated by length of bars. (Lower) Isodoses corresponding to prescribed dose (green) for standard (Left) and optimized (Right) loading patterns. High-risk clinical target volume indicated in red.
The relation between the BT dose to the tumor and OARs obtained using standard library plans and assessed with either the GEC-ESTRO (3D) or ICRU (2D) recommendations are shown in Fig. 3. For the tumor target, this 3D/2D relationship was evaluated by dividing the cumulative D90 of the HRCTV with the cumulative average Point A dose for each patient. For the OARs, the BT dose to 2 cm3 was divided
by the BT dose to the ICRU reference point for the relevant organ (bladder or rectum). Poor agreement was found for the tumor target, with the 3D/2D relative dose varying from 50% to 150%. In about 75% of the patients, the D90 was larger than the Point A dose. For the bladder, the variation was even larger, with the 3D/2D relative dose varying from 75% to 300%, again with the ICRU reference point underestimating the dose to the bladder in 75% of the patients. For the rectum, the variation was much less, but the ICRU reference point overestimated the dose in 75% of the patients.
Table 1. Physical doses and fractionation of EBRT and BT by standard plan BT
EBRT
EBRT+BT
Patients CTV-T CTV-E CTV-N Point A Point A Point A (n) (Gy/fx) (Gy/fx) (Gy/fx) (Gy/fx) (Gy) (EQD2, Gy) 12 2 4 3
Fig. 3. Box plot (10th, 25th, 50th, 75th, and 90th percentile) showing relative brachytherapy dose to tumor (minimal dose received by 90% of high-risk clinical target volume vs. Point A) and organs at risk (2 cm3 bladder and rectum vs. ICRU points) obtained by standard plans and assessed with GEC-ESTRO guidelines (three-dimensional) and ICRU (two-dimensional) recommendations.
50/25 50/30 60/30 60/30
45/25 45/30 45/25 45/30
— 60/30 — 60/30
30/3 30/3 20/2 20/2
80 80 80 80
83.7 82.3 82.4 82.4
Abbreviations: EBRT = external beam radiotherapy; BT = brachytherapy; CTV-T = tumor clinical target volume; fx = number of fractions; CTV-E = elective CTV; CTV-N = lymph node CTV; EQD2 = equivalent dose in 2-Gy fractions. Total dose of EBRT and BT was physical dose to Point A; cumulative equivalent dose of EBRT and BT in 2-Gy fractions (EQD2) at Point A calculated according to linear-quadratic model (a/b = 10, repair half time, 1.5 h) also shown.
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Fig. 4. Dose–volume histogram (DVH) parameters of standard (Left) vs. optimized (Right) plans for 2 cm3 of bladder, rectum, and sigmoid plotted against minimal dose received by 90% of target volume (D90) of high-risk clinical target volume (HR-CTV). DVH constraints indicated by horizontal dotted line (bladder = 90 Gy, rectum = 75 Gy, sigmoid = 75 Gy). Vertical dotted lines indicate desired D90 to HR-CTV (i.e., 85 Gy). Symbols within box fulfilled DVH constraints with respect both to organs at risk (OARs) and tumor.
The DVH parameters related to Point A and the HR-CTV for the standard and optimized plans are given in Table 2. The total reference air kerma was significantly lower for the optimized plans (p = 0.04), whereas, the volume receiving the
prescribed and double the prescribed dose did not change significantly. Also, the average Point A dose was the same for the standard vs. optimized plans. However, the individualization of the PDR-BT was reflected in the significantly
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Table 2. Dose–volume histogram parameters related to primary tumor target Aarhus
Vienna
Parameter
Standard
Optimized
IC; Kirisits et al. (11)
IC/IS; Kirisits et al. (12)
Patients (n) BT fractions (n) Prescribed dose (Gyab10) TRAK VPD (cm3) V2PD (cm3) Point A, all patients (Gyab10) Average left and right Difference Point A, IC patients only* (Gyab10) Average left and right Difference HR-CTV Volume (cm3) D100 (Gyab10) D90 (Gyab10) V100 (%)
— — 83 1 1.6 0.3 86 4 30 1
21 56 83 1 1.5 0.4 80 17 29 9
22 76 85 4 1.7 0.3 85 19 25 8
22 44 85 2 1.9 0.2 101 18 33 7
84 1 0.2 0.9
82 6 4.5 8
— —
— —
84 1 0.2 0.8
81 5 2.8 2
82 9 —
— —
— 73 7 89 10 92 9
34 12 76 5 91 8 96 7
34 17 66 7 87 10 89 8
44 27 70 6 96 12 93 9
Abbreviations: IC = intracavitary; IC/IS = combined intracavitary-interstitial; TRAK = total reference air kerma; VPD = volume encompassed by prescribed dose; V2PD = volume encompassed by twice prescribed dose; HR-CTV = high-risk clinical target volume; D100 = minimal target dose; D90 = dose received by 90% of target volume; V100 = percentage of target treated with at least prescribed dose; HDR = high dose rate; other abbreviations as in Table 1. Data presented as mean standard deviation. Doses calculated as cumulative equivalent dose in 2-Gy fractions of EBRT and BT using linear-quadratic model (a/b = 10 Gy, repair half time = 1.5 h); for comparison, DVH parameters reported by Kirisits et al. (11, 12) for HDR shown. * Values do not include 4 patients treated with IC/IS.
increased asymmetry between the doses to Point A on each side, increasing from a difference of 0.2 Gy to one of 4.5 Gy (p = 0.03). The maximal Point A dose was 118 Gy, recorded in 1 patient treated with IC/IS BT. However, the asymmetry between the dose to Point A on the left and right remained significant when only the patients treated with IC BT were analyzed (p <0.001). The mean D90 was the same for the standard and optimized plans, but optimization significantly increased both the minimal target dose (D100) and the percentage of target treated with at least the prescribed dose (V100) of the HR-CTV (p <0.007). Table 2 also includes a comparison, in terms of the EQD2, of the HDR DVH parameters from Vienna for pure IC and combined IC/IS BT. Compared with the IC Vienna study (11), the Aarhus values for D100 and V100 were significantly greater (p = 0.005), a difference that disappeared when comparing the Aarhus data with the combined IC/IS Vienna data (12). The DVH parameters related to the OARs for the standard and optimized plans are given in Table 3. When comparing the standard and optimized plans, only the dose and dose rate for 2 cm3 of the sigmoid were significantly reduced (p <0.03). However, for the bladder, a reduction also occurred in the standard deviation for all DVH parameters. When considering the effect of optimization in terms of the sparing factor for the cumulative physical dose of BT, significant reductions were found for both the bladder and the sigmoid (p <0.02). When comparing our data with the Vienna (IC and IC/IS) data, the doses to 0.1, 1, and 2 cm3 of the bladder were significantly lower in the Aarhus data (p<0.004), but the
dose to 1 and 2 cm3 of the sigmoid were larger in the Aarhus data than in IC Vienna series (p <0.04). When comparing the Aarhus series with the IC/IS Vienna series, no difference was found in the DVH parameters for the sigmoid. Also, the DVH parameters for the rectum were not significantly different between the Aarhus and either the Vienna IC or IC/IS series. Because the average DVH values given in Tables 2 and 3 do not show the interplay between the gain and loss in terms of the dose to the HR-CTV vs. the OARs, we also compared the number of patients with fulfilled DVH constraints for the standard and optimized dose plans. Using 3D optimization, all DVH constraints (HR-CTV, bladder, rectum, and sigmoid) were met in 16 of 21 of our patients compared with 3 of 21 patients using the 2D library plans (p <0.001). In Fig. 4, the D90 for the HR-CTV is plotted against the 2-cm3 dose (EQD2) for the bladder, rectum, and sigmoid. For the HR-CTV in relation to the bladder and rectum, the requirement for the D90 and dose to 2 cm3 was met in 18 of 21 patients in the optimized plan vs. 13 of 21 patients in the standard plans (p = 0.16). For the HR-CTV in relation to the sigmoid, optimization significantly changed the distribution from 5 to 16 of 21 patients meeting the DVH constraint for both D90 and the dose to 2 cm3 (p = 0.002). DISCUSSION Depending primarily on tumor size, International Federation of Gynecology and Obstetrics stage, and overall treatment time, pelvic control rates of 50–90% are usually
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Table 3. Dose–volume histogram parameters related to organs at risk Aarhus Parameter Bladder Sparing factor ICRU point (Gyab3) D0.1 (Gyab3) D1 (Gyab3) D2 (Gyab3) Dose rate D2 (Gyab3) Rectum Sparing factor ICRU point (Gyab3) Rectal diode (Gyab3) D0.1 (Gyab3) D1 (Gyab3) D2 (Gyab3) Dose rate D2 (Gyab3) Sigmoid Sparing factor D0.1 (Gyab3) D1 (Gyab3) D2 (Gyab3) Dose rate D2 (Gyab3)
Vienna
Standard
Optimized
IC; Kirisits et al. (11)
IC/IS; Kirisits et al. (12)
0.72 0.32 75 31 99 45 83 22 78 16 0.93 0.56
0.61 0.20 67 8 86 12 77 8 73 6 0.69 0.20
— 75 16 121 25 92 11 83 9 HDR
— 73 19 113 30 90 16 83 14 HDR
0.50 0.25 70 5 63 6 74 10 69 7 67 6 0.52 0.21
0.47 0.22 71 7 63 5 74 9 69 6 67 6 0.48 0.18
— 69 13 60 8 77 10 66 7 64 6 HDR
— 71 13 63 9 77 9 69 6 66 6 HDR
0.59 0.20 82 13 74 10 72 9 0.72 0.32
0.51 0.13 79 10 72 7 69 6 0.58 0.21
— 79 12 67 8 63 7 HDR
— 85 14 71 8 67 7 HDR
Abbreviations: ICRU = International Commission on Radiation Units and Measurements; D0.1, D1, D2 = minimal dose to most irradiated 0.1, 1, and 2 cm3 of organ at risk; HDR = high dose rate; other abbreviations as in Tables 1 and 2. Radiation doses calculated as cumulative equivalent dose in 2-Gy fractions of EBRT and BT using linear-quadratic model (a/b = 3 Gy, repair half time = 1.5 h), assuming that most irradiated 0.1, 1, and 2 cm3 volume of organ at risk was same for each BT fraction and received full dose of EBRT prescribed to primary tumor. For comparison, DVH parameters reported by Kirisits et al. (11, 12) for HDR shown.
obtained with 2D BT (17). However, in retrospect, it has been difficult to demonstrate a formal dose–response curve (18), with the Point A dose being superseded by stronger prognostic parameters (19). This indicates that Point A dose is a weak surrogate marker for the actual dose to the 3D BT target as estimated by DVH analysis (11). In our experience (Fig. 3), this difference can vary by as much as 50–150%, which could explain the limitation of Point A in this context. It is anticipated that the D90 for the HR-CTV will be a much strong prognostic factor than the Point A dose, with an expected local control rate of 90–95% even in large tumors, provided that a D90 of $85–90 GyEQD2 is obtained in the HR-CTV (4, 7, 20). With comparable D90 values for HR-CTV reached in most of our patients, we expect to observe similar rates of long-term local control. For the OARs, a relationship between the dose to the ICRU rectal point and rectal complications has been established (21). At a median dose of 84 GyEQD2, the risk of severe complications was around 10%, increasing steeply for greater doses. A comparison of the 2D and 3D volumetric CT-based calculations has shown that the ICRU rectal point is a reasonable surrogate for the minimal dose to the most irradiated 2 cm3 of the rectal wall (22, 23). The 2-cm3 volume in the greatest dose region has been found to be a clinically relevant parameter correlating with complications (24). Our MRIbased volumetric data also showed that the ICRU rectal point is performing reasonable. A specific uncertainty with 2D BT
is the dose to the upper rectum and sigmoid, which is very difficult to estimate and where significant morbidity can arise (25). Essentially, the dose contribution to these parts of the gastrointestinal tract can only be assessed by 3D DVH analysis. For the rectum and sigmoid, it has been shown that a limit of a minimal dose of 70–75 GyEQD2 to the most exposed 2 cm3 is a good cutoff point (4, 26). Thus, recent studies with MRI-based HDR BT and concomitant cisplatin have shown a complete absence of Grade 3-4 rectal and sigmoid complications if these DVH constraints were fulfilled (6, 7). Regarding the bladder, the ICRU bladder point is known to be an uncertain predictor of the minimal dose the most irradiated 2 cm3 of the bladder, as shown in both the present study and previous studies (22, 23). Uncertainty exists as to the true dose–volume constraint to apply for the bladder. Severe toxicity has been reported in 2 patients with 2-cm3 doses >100 GyEQD2. Currently, 90 GyEQD2 to 2 cm3 is being advocated as an appropriate dose–volume constraint for the bladder (4, 26). The follow-up in the present study was too short to report on late toxicity, but, as in the experience reported from Vienna (7), we have not seen treatment prohibitive acute toxicity or consequential late damage, even using the IC/IS technique. With the 3D technique, we have for the first time evaluated the doses to the sigmoid and, as have others, we found that dose to the sigmoid often seems greater than that to the rectum (10, 26). However, by optimization, we
MRI-based PDR brachytherapy for cervical cancer d J. C. LINDEGAARD et al.
were able to significantly reduce the dose to this organ in terms of both the cumulative EQD2 of EBRT and BT and the physical dose delivered by BT (sparing factor). We also observed a significant improvement of the sparing factor for the bladder, especially for 2 patients in whom a very high dose to the bladder would have been the result if 2D BT had been used and they were most likely saved from severe bladder toxicity by 3D optimization (6). Probably because of the vaginal packing, the rectum was already sufficiently spared using the library plans and no further sparing was obtained. We found that 3D MRI-guided BT is a challenging technique to master. For the implementation of this technique in our department, we therefore used both internal and external assessment of the DVH parameters. Our internal comparison was primarily done to ensure that the new 3D BT procedure really was a reallocation of radioactivity according to the individual case, rather than a hidden general dose escalation. We therefore systematically compared the DVH parameters from our optimized plans with our 2D standard library plans. It was reassuring to observe that the total reference air kerma was reduced by a minor amount, yet the coverage and minimal dose to the HR-CTV were significantly increased. One reason was that the 3D technique allowed us to take advantage of the versatility of the tandem-ring applicator and to use ‘‘add-ons’’ in the form of a custom-made multichannel vaginal cylinder and modified Vienna applicator for combined IC/IS BT. This would have been difficult to perform using 2D orthogonal X-rays or even CT-based 3D BT. The external comparison between the DVH data of Aarhus and Vienna was more difficult because it involved radiobiological assumptions, not only on the 3D summation of the dose from EBRT and BT, but also on the effect of the dose rate. For the 3D summation of EBRT and BT, the same ‘‘worst case scenario,’’ as used by Kirisits et al. (11, 12), was used. That is, we supposed that the OARs had received the same EBRT dose as the primary tumor target (CTV-T) despite the use of a SIB technique for treating this target to a 5–10-Gy greater dose than the elective volume (CTV-E). As did Kirisits et al. (11, 12), we assumed that no organ movement occurred between BT fractions (i.e., we assumed that it was the same 2 cm3 of the OARs that received the greatest dose at each BT fraction. For the biologic equivalence calculations, the GEC-ESTRO guidelines have recommended a/b = 10 for tumor, a/b = 3 for OARs, and a mono-exponential repair model with a repair half time of 1.5 h to account for dose rate effects (2). Concerning the radiobiologic assumptions, the repair capacity in the form of a/b values of 10 for tumor and 3 for OARs are generally accepted (18, 27); however, larger uncertainty exists for the repair kinetics (28–30). Even with these limitations, we found it a useful method for comparing the DVH parameters from Aarhus and Vienna. In view of the different treatment approaches used in the Aarhus and Vienna series in imaging (high vs. low tesla MRI), dose rate (PDR vs. HDR), and the relative contribution
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of BT to total dose to the HR-CTV, the most striking features of Tables 2 and 3 are the similarities in all the important DVH parameters. Apart from a greater D100 and V100 in the Aarhus series compared with the IC Vienna data (11), all the tumorrelated parameters were comparable. For the D100 and V100, these parameters are known to be sensitive to small contouring inconsistencies (11). However, the use of combined IC/IS in selected cases in the Aarhus series is also important in explaining this difference. For the OARs, the most important difference was the greater bladder doses in Vienna and a tendency for greater sigmoid doses in Aarhus, at least for the 2-cm3 dose (Table 3). This difference can be explained by the different packing approaches. We, in line with our lowdose-rate tradition, might have a policy for tighter vaginal packing, which could push the applicator more proximally and clear of the bladder but closer to the sigmoid. Also, the difference in bladder filling (open catheter in Aarhus vs. 50–100-mL filling in Vienna) could have contributed to the observed difference. Our different starting positions with regard to the standard loading pattern, with more weight to the ring in the Vienna vs. the Aarhus standard plan, could also have contributed, although we did not see any differences for the rectum. Also, the dose falloff in the OARs from 0.1 cm3 to 2 cm3 was steeper in the Vienna series than in the Aarhus series. This was most probably caused by the lesser contribution of BT to the total dose of the HR-CTV, with only 30–40% of the dose delivered by BT in the Aarhus series compared with the BT dose in the Vienna series, in which it was almost 50%. However, the dose rate effect also works in this direction when calculating the EQD2 levels for PDR and HDR. CONCLUSION Magnetic resonance imaging-guided 3D optimization significantly improved PDR-BT for locally advanced cervical cancer. The possibility of adapting the BT dose specifically to the tumor target at BT represents an important development for gynecologic BT compared with the level described in ICRU report 38. Also, the possibility of using individualized applicator adaptation, such as additional interstitial needles, considerably increased the possibility of increasing the tumor coverage. The present results have demonstrated that it is possible, not only to transfer this technique from one department to another, but also to use the GEC-ESTRO guidelines for BT in cervical cancer as a meaningful tool for reporting and comparing doses to the target and OARs between different departments (1, 2). The first clinical outcome data have been encouraging (4, 6, 7), and the technique holds promise for additional research and progress using, for example, functional imaging and deformable registration to better understand and characterize the medical aspects and uncertainties of the underlying dose–volume relations. To sustain these data, a European study on MRI guided brachytherapy in locally advanced cervical cancer (EMBRACE) is currently being planned within the Gynaecological GEC-ESTRO network.
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REFERENCES 1. Haie-Meder C, Po¨tter R, van Limbergen E, et al. Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (I): Concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV. Radiother Oncol 2005;74: 235–245. 2. Po¨tter R, Haie-Meder C, Limbergen EV, et al. Recommendations from Gynaecological (GYN) GEC ESTRO Working Group (II): Concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy—3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol 2006;78:67–77. 3. Nag S, Cardenes H, Chang S, et al. Proposed guidelines for image-based intracavitary brachytherapy for cervical carcinoma: Report from Image-Guided Brachytherapy Working Group. Int J Radiat Oncol Biol Phys 2004;60:1160–1172. 4. Po¨tter R, Dimopoulos J, Georg P, et al. Clinical impact of MRI assisted dose volume adaptation and dose escalation in brachytherapy of locally advanced cervix cancer. Radiother Oncol 2007;83:148–155. 5. Muschitz S, Petrow P, Briot E, et al. Correlation between the treated volume, the GTV and the CTV at the time of brachytherapy and the histopathologic findings in 33 patients with operable cervix carcinoma. Radiother Oncol 2004;73:187–194. 6. Po¨tter R, Dimopoulos J, Bachtiary B, et al. 3D conformal HDRbrachy- and external beam therapy plus simultaneous cisplatin for high-risk cervical cancer: Clinical experience with 3 year follow-up. Radiother Oncol 2006;79:80–86. 7. Dimopoulos JC, Kirisits C, Petric P, et al. The Vienna applicator for combined intracavitary and interstitial brachytherapy of cervical cancer: Clinical feasibility and preliminary results. Int J Radiat Oncol Biol Phys 2006;66:83–90. 8. Krempien RC, Daeuber S, Hensley FW, et al. Image fusion of CT and MRI data enables improved target volume definition in 3D-brachytherapy treatment planning. Brachytherapy 2003; 2:164–171. 9. Kirisits C, Lang S, Dimopoulos J, et al. Uncertainties when using only one MRI-based treatment plan for subsequent high-dose-rate tandem and ring applications in brachytherapy of cervix cancer. Radiother Oncol 2006;81:269–275. 10. Al-Booz H, Boiangiu I, Appleby H, et al. Sigmoid colon an unexpected organ at risk in brachytherapy for cervix cancer. Egypt Natl Cancer Inst 2006;18:156–160. 11. Kirisits C, Po¨tter R, Lang S, et al. Dose and volume parameters for MRI-based treatment planning in intracavitary brachytherapy for cervical cancer. Int J Radiat Oncol Biol Phys 2005; 62:901–911. 12. Kirisits C, Lang S, Dimopoulos J, et al. The Vienna applicator for combined intracavitary and interstitial brachytherapy of cervical cancer: Design, application, treatment planning, and dosimetric results. Int J Radiat Oncol Biol Phys 2006;65:624–630. 13. Taylor A, Rockall AG, Reznek RH, et al. Mapping pelvic lymph nodes: Guidelines for delineation in intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2005;63:1604–1612. 14. Tanderup K, Christensen JJ, Granfeldt J, et al. Geometric stability of intracavitary pulsed dose rate brachytherapy monitored by in vivo rectal dosimetry. Radiother Oncol 2006;79:87–93. 15. Tanderup K, Lindegaard JC. Multi-channel intracavitary vaginal brachytherapy using three-dimensional optimization of source geometry. Radiother Oncol 2004;70:81–85. 16. Dimopoulos JC, Schard G, Berger D, et al. Systematic evaluation of MRI findings in different stages of treatment of cervical
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cancer: Potential of MRI on delineation of target, pathoanatomic structures, and organs at risk. Int J Radiat Oncol Biol Phys 2006;64:1380–1388. Perez CA, Grigsby PW, Chao KS, et al. Tumor size, irradiation dose, and long-term outcome of carcinoma of uterine cervix. Int J Radiat Oncol Biol Phys 1998;41:307–317. Petereit DG, Pearcey R. Literature analysis of high dose rate brachytherapy fractionation schedules in the treatment of cervical cancer: Is there an optimal fractionation schedule? Int J Radiat Oncol Biol Phys 1999;43:359–366. Fyles AW, Pintilie M, Kirkbride P, et al. Prognostic factors in patients with cervix cancer treated by radiation therapy: Results of a multiple regression analysis. Radiother Oncol 1995;35: 107–117. Dimopoulos J, Georg P, Kirisits C, et al. The predictive value of dose volume parameters on local tumor control in MRI assisted brachytherapy of cervix cancer [Abstract]. Radiother Oncol 2006;81:S39. Leborgne F, Fowler JF, Leborgne JH, et al. Biologically effective doses in medium dose rate brachytherapy of cancer of the cervix. Radiat Oncol Invest 1997;5:289–299. Wachter-Gerstner N, Wachter S, Reinstadler E, et al. Bladder and rectum dose defined from MRI based treatment planning for cervix cancer brachytherapy: Comparison of dose-volume histograms for organ contours and organ wall—Comparison with ICRU rectum and bladder reference point. Radiother Oncol 2003;68:269–276. Pelloski CE, Palmer M, Chronowski GM, et al. Comparison between CT-based volumetric calculations and ICRU reference-point estimates of radiation doses delivered to bladder and rectum during intracavitary radiotherapy for cervical cancer. Int J Radiat Oncol Biol Phys 2005;62:131–137. van den Bergh F, Meertens H, Moonen L, et al. The use of a transverse CT image for the estimation of the dose given to the rectum in intracavitary brachytherapy for carcinoma of the cervix. Radiother Oncol 1998;47:85–90. Cheng JC, Peng LC, Chen YH, et al. Unique role of proximal rectal dose in late rectal complications for patients with cervical cancer undergoing high-dose-rate intracavitary brachytherapy. Int J Radiat Oncol Biol Phys 2003;57:1010–1018. Georg P, Dimopoulos J, Kirisits C, et al. Dose volume parameters in cervical cancer patients treated with MRI based brachytherapy and their predictive value for late adverse side effects in rectum, sigmoid and bladder [Abstract]. Radiother Oncol 2006; 81:S38–S39. Stuschke M, Thames HD. Fractionation sensitivities and dosecontrol relations of head and neck carcinomas: analysis of the randomized hyperfractionation trials. Radiother Oncol 1999; 51:113–121. Bentzen SM, Ruifrok ACC, Thames HD. Repair capacity and kinetics for human mucosa and epithelial tumors in the head and neck: Clinical data on the effect of changing the time-interval between multiple fractions per day in radiotherapy. Radiother Oncol 1996;38:89–101. Millar WT, Hopewell JW. Effects of very low dose-rate (90)Sr/ (90)Y exposure on the acute moist desquamation response of pig skin. Radiother Oncol 2007;83:187–193. Roberts SA, Hendry JH, Swindell R, et al. Compensation for changes in dose-rate in radical low-dose-rate brachytherapy: A radiobiological analysis of a randomised clinical trial. Radiother Oncol 2004;70:63–74.
doi:10.1016/j.ijrobp.2007.10.032
CLINICAL INVESTIGATION
Cervix
MRI-GUIDED 3D OPTIMIZATION SIGNIFICANTLY IMPROVES DVH PARAMETERS OF PULSED-DOSE-RATE BRACHYTHERAPY IN LOCALLY ADVANCED CERVICAL CANCER JACOB C. LINDEGAARD, D.M.SC.,* KARI TANDERUP, M.SC.,y SØREN KYNDE NIELSEN, PH.D.,y SØREN HAACK, M.SC.,z AND JOHN GELINECK, M.D.x Departments of *Oncology; yMedical Physics; zBiomedical Engineering; and xRadiology, Aarhus University Hospital, Aarhus, Denmark Purpose: To compare dose–volume histogram parameters of standard Point A and magnetic resonance imagingbased three-dimensional optimized dose plans in 21 consecutive patients who underwent pulsed-dose-rate brachytherapy (PDR-BT) for locally advanced cervical cancer. Methods and Materials: All patients received external beam radiotherapy (elective target dose, 45 Gy in 25–30 fractions; tumor target dose, 50–60 Gy in 25–30 fractions). PDR-BT was applied with a tandem-ring applicator. Additional ring-guided titanium needles were used in 4 patients and a multichannel vaginal cylinder in 2 patients. Dose planning was done using 1.5 Tesla T1-weighted and T2-weighted paratransversal magnetic resonance imaging scans. T1-weighted visible oil-containing tubes were used for applicator reconstruction. The prescribed standard dose for PDR-BT was 10 Gy (1 Gy/pulse, 1 pulse/h) for two to three fractions to reach a physical dose of 80 Gy to Point A. The total dose (external beam radiotherapy plus brachytherapy) was normalized to an equivalent dose in 2-Gy fractions using a/b = 10 Gy for tumor, a/b = 3 Gy for normal tissue, and a repair half-time of 1.5 h. The goal of optimization was dose received by 90% of the target volume (D90) of $85 Gya/b10 in the high-risk clinical target volume (cervix and remaining tumor at brachytherapy), but keeping the minimal dose to 2 cm3 of the bladder and rectum/sigmoid at <90 and <75 Gya/b3, respectively. Results: Using three-dimensional optimization, all dose–volume histogram constraints were met in 16 of 21 patients compared with 3 of 21 patients with two-dimensional library plans (p < 0.001). Optimization increased the minimal target dose (D100) of the high-risk clinical target volume (p < 0.007) and decreased the minimal dose to 2 cm3 for the sigmoid significantly (p = 0.03). For the high-risk clinical target volume, D90 was 91 ± 8 Gya/b10 and D100 was 76 ± 5 Gya/b10. The minimal dose to 2 cm3 for the bladder, rectum, and sigmoid was 73 ± 6, 67 ± 6, and 69 ± 6 Gya/b3, respectively. Conclusion: The results of our study have shown that magnetic resonance imaging-guided optimization of PDR-BT for locally advanced cervical cancer significantly improved the dose–volume histogram parameters. Ó 2008 Elsevier Inc. Pulsed-dose-rate brachytherapy, Cervical cancer, Image guided, Treatment planning, Magnetic resonance imaging, MRI.
Recently, both European (1, 2) and American (3) guidelines for three-dimensional (3D) intracavitary brachytherapy (BT) for cervical cancer have been published. To date, only the European guidelines (Groupe Europe´en de Curiethe´rapie– European Society for Therapeutic Radiology and Oncology [GEC-ESTRO]) are supported by clinical data from studies in which systematic use of magnetic resonance imaging (MRI)-based planning was used (4–7). The primary advantage of this technique is the possibility to conform the dose
given by BT to the anatomy of each patient, taking into account both the tumor regression obtained by external beam radiotherapy (EBRT) and the position of nearby organs at risk (OARs). According to current experience, this technique has the potential to at least halve both the local failure rate and the rate of moderate to severe morbidity (4, 7). A response-adapted treatment strategy such as this requires that both a gynecologic examination and MRI with the BT applicator in situ be performed at BT (2). Visualization of the tumor is difficult with computed tomography (CT), necessitating MRI (8). Because significant changes in localization
Reprint requests to: Jacob Christian Lindegaard, D.M.Sc., Department of Oncology, Aarhus University Hospital, Bldg. 5, No¨rrebrogade 44, Aarhus DK-8000 Denmark. Tel: (+45) 8949-2577; Fax: (+45) 8949-2530; E-mail: [email protected] Supported by the Danish Cancer Society and the Aarhus County Research Initiative.
Presented at Canadian Association of Radiation Oncology-Canadian Organization of Medical Physicists 2007 Meeting, Toronto, ON, Canada, October 10, 2007. Conflict of interest: none. Received Aug 8, 2007, and in revised form Oct 7, 2007. Accepted for publication Oct 12, 2007.
INTRODUCTION
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of the target and OARs in relation to the position of the applicator can occur, each implant should ideally be determined using on a new MRI study (9, 10). Thus, for each implant, contouring of the clinical target volume (CTV) and OARs should be done using a 3D dose planning system. Subsequently, the applicator should be carefully reconstructed and the conventional standard loading pattern matching the prescribed dose to Point A applied. From this starting point, dose optimization can be performed with the goal of increasing the dose to the high-risk CTV (HR-CTV) to the dose level previously prescribed to Point A without exceeding the dose– volume constraints for the surrounding normal tissues (11). To date, the reporting of dose–volume histogram (DVH) parameters from MRI-based BT has been limited to the Viennese high-dose-rate (HDR) BT experience (4, 7, 11, 12). However, since December 2005, we have used MRI-guided 3D pulsed-dose-rate BT (PDR-BT) for locally advanced cervical cancer. The aim of the present study was to present the implementation of this method with PDR-BT, quantify the effect of MRI-guided 3D optimization on the DVH parameters, and compare our PDR data with the HDR data from Vienna. METHODS AND MATERIALS Staging, EBRT, and concomitant chemotherapy For all patients, staging involved gynecologic examination and cystoscopy with the patient under general anesthesia. In addition, diagnostic, whole-body fluorodeoxyglucose-positron emission tomography-CT and MRI of the pelvic region was performed. The tumor target (CTV-T) for EBRT included the gross tumor volume, whole cervix, and uterus. The elective target (CTV-E) was contoured according to the recommendations of Taylor et al. (13). The CTV-E included the CTV-T, lymph nodes in the parametria, and along the external iliac, internal iliac, common iliac/aorta to the L4–L5 interspace, and $2 cm of the vagina below the CTVT. The para-aortic region to the level of L1-L2 was included in CTV-E in patients with pathologic common iliac or para-aortic lymph nodes. The inguinal nodes were included for Stage IIIA disease. For patients with pathologic nodes, we used the fluorodeoxyglucose-positron emission tomography-CT information to define a specific nodal target (CTV-nodes [CTV-N]). Dose planning was done using conformal box techniques or intensity-modulated RT with a simultaneous integrated boost (SIB) to obtain differential dose levels for the CTV-T, CTV-E, and CTV–N. For tumors expected to be well covered by BT, the prescribed dose of EBRT to the CTV-T was 50 Gy in 25 fractions. For large tumors, the prescribed dose for the CTV-T was 60 Gy in 30 fractions. The CTV-E was treated with 45 Gy in 25 fractions, except for cases with an extended volume, for which the fractionation was 45 Gy in 30 fractions. The CTV–N, when present, was always treated with 60 Gy in 30 fractions. EBRT was given in 15–18 MV by a linear accelerator (Siemens Medical Systems, Malvern, PA and Varian Medical Systems, Palo Alto, CA), all equipped with a multileaf collimator. Concomitant chemotherapy (weekly cisplatin, 40 mg/m2) for a maximum of six courses was given to all patients with sufficient kidney and bone marrow function.
PDR-BT application Pulse-dose-rate BT was initiated during the last 1–2 weeks of EBRT, with two to three fractions given with a 1-week interval,
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aiming for a total treatment time for EBRT+BT of <7 weeks. Clinical assessment of the tumor volume and topography was repeated at each BT fraction, and a clinical drawing was made using standardized cartoons (2). A Foley catheter with 7-mL of X-ray diluted contrast was placed in the bladder. Dilation of the uterine canal and placement of the applicator was performed under ultrasound guidance. Vaginal packing with gauze soaked in diluted gadolinium (Magnevist 469 mg/mL, 7.5 mL in 100 mL NaCl) was used. A 20-cm drainage tube was inserted 15 cm into the rectum to allow for the introduction of rectal diodes for in vivo dosimetry (14). The applicator was an MRI-compatible plastic tandem-ring applicator (GammaMed, Varian) with a ring diameter of 26, 30, and 35 mm; the length of the tandem was 30–80 mm. A custom-made multichannel vaginal cylinder (15) attached to the tandem/ring applicator was used in 2 patients in whom the vaginal tumor extension was beyond the reach from the ring (Fig. 1). Also, a cap with steering holes for a combined intracavitary-interstitial (IC/IS) approach (7, 12) was used in 4 patients, in whom three to five blunt-ended titanium needles (Acrostack, Wintherthur, Switzerland) were implanted in the parametria (Fig. 1).
MRI technique, applicator reconstruction, and contouring Magnetic resonance imaging was performed on 1.5 Tesla scanner (Siemens Magnetom Symphony) using array coils. Thin plastic tubes filled with peanut oil and then sealed were inserted in the applicator channels to serve as ‘‘dummy wires’’ for the T1-weighted sequences. All MRI sequences were oriented according to the axis of the applicator (i.e., the paratransversal, parasagittal, and paracoronal planes) (2, 16). The MRI protocol involved a T1-weighted (Turbo Spin Echo) paratransversal scan with a 3-mm slice thickness and no gap was used to guide the applicator reconstruction. Then, T2-weighted (Turbo Spin Echo) sequences in all three planes: paratransversal, parasagittal, and paracoronal were produced with a slice thickness of 5 mm and a 1-mm gap. Applicator reconstruction was performed directly in BrachyVision, version 6.5 (Varian) on the paratransversal T2-weighted sequence by introducing library applicators with predefined geometry. The tandem and ring were positioned by measuring the distance from the ring surface to the ring channel and from the tip of the tandem to the first stopping position in the tandem. The T1-weighted images were fused with the T2-weighted images to aid in the reconstruction by visualization of the ‘‘dummy wires’’ in the paracoronal and parasagittal plane. The rotation of the ring in the paratransversal plane was determined from the T1-weighted sequence by measuring the angle of the guide tubes, which was clearly visible in the gauze-filled vagina. Contouring was performed on the T2-weighted paratransversal sequence supported by the clinical drawings and the MRI studies from diagnosis and at BT. The HR-CTV (GTV at BT plus the whole cervix), as well as the outer wall of the bladder, rectum, and sigmoid were contoured. The Point A and International Commission on Radiation Units and Measurements (ICRU) bladder and rectal points were positioned directly in the 3D study.
BT treatment planning and DVH analysis Each BT fraction was planned individually and was always initiated using a standard library plan (Fig. 2). For the ring, a standard plan contained three lateral stopping positions spaced by 5 mm in each side of the ring. For the tandem, the stopping positions were placed at a 5-mm distance from the tip to the level of the ring. For a standard plan, equal dwell times were used in all stopping positions in both the ring and the tandem. The prescribed standard dose for each fraction of PDR-BT was 10 Gy to Point A divided
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Fig. 1. Custom-made ‘‘add ons’’ for Varian standard tandem ring applicator in form of multichannel vaginal cylinder (Left) and ring cap for guidance of interstitial titanium needles (Right).
into 10 pulses of 1 Gy, with a pulse interval of 1 h. Optimization was performed by manually adding or removing stopping positions and adjusting the dwell times. The intention was to reach D90 $85 Gya/ b10 in the HR-CTV, but keeping D2 cc of bladder and rectum/sigmoid at below 90 and 75 Gya/b3, respectively. In this process, we were particularly focused on the high-dose volumes (i.e., 20 and 40 Gy isodose lines) and very heterogeneous dwell times in neighboring stopping positions. Also, we avoided extending the 10-Gy isodose curve to >25 mm from the center of the tandem at the level of Point A (11). For patients receiving combined IC/IS BT, we restricted loading of the parametrial needles to a maximum of 10– 20% of the dwell time for a standard stopping position (12). After inspecting the isodoses at all image levels, we obtained the cumulative DVH parameters from BrachyVision, version 6.5. The resulting dose was recalculated into the equivalent dose in 2-Gy fractions (EQD2) using the mono-exponential repair half time model with a/b = 10 for tumor, a/b = 3 for OARs, and a repair half time of 1.5 h (2). The EQD2 of EBRT and BT was then added to evaluate the optimized plan with regard to the DVH constraints. A worst-case approach was used in these calculations, assuming that the 2 cm3 of the OARs in question had received the full EBRT dose prescribed to the primary tumor (CTV-T) and that it was the same 2 cm3 of the organ that received the maximal BT dose at each BT fraction (11). In 10 BT fractions, radiobiological optimization was performed by increasing the number of pulses from 10 in the standard plan to 14–20 in the optimized plan. However, the pulse interval was always kept at 1 h. Finally a dose-point reflecting the expected maximal dose in the rectal diodes was inserted. In addition to the EQD2 calculations, we compared two-dimensional (2D) vs. 3D plans in terms of the sparing factor, calculated as the ratio of the cumulative physical doses of BT to OAR (2 cc) and HR-CTV (D90): SF = S D2 cc/S D90. Statistical comparisons between the DVH parameters of the standard vs. optimized plans were performed using a paired sample
t test. Fisher’s exact test was used to analyze the effect of optimization with regard to fulfillment of the DVH constraints. Comparisons between the Aarhus and Vienna parameters were performed using a standard t test. A two-tailed test was always performed using a significance level of 0.05.
RESULTS This study included 21 consecutive cases of biopsy-proven cervical cancer treated with curative intent December 2005 and March 2007 at the Department of Oncology, Aarhus University Hospital. Of the 21 patients, 2 had Stage IB2, 14 had Stage IIB, 3 had Stage IIIB, and 2 had Stage IIIA. The treatment characteristics are given in Table 1. The EBRT for most patients was 45 Gy given with a conformal four-field box to the CTV-E and a SIB, bringing the dose to the CTV-T to 50 Gy. In 7 patients with a large tumor volume, the CTV-T dose was increased to 60 Gy, and in 5 patients, pathologic lymph nodes were treated to 60 Gy using a SIB. Elective para-aortic RT was given to 3 patients. Concomitant chemotherapy was omitted in 4 patients because of age and comorbidity. Three fractions of PDR-BT were used in 14 patients in whom the EBRT dose to the CTV-T was 50 Gy. Two fractions of PDR-BT were used in 7 patients in whom the EBRT dose to the CTV-T was 60 Gy (Table 1). Thus, 56 fractions of PDR-BT were administered. Of these, 55 had been determined using the individual MRI studies with the applicator in situ. MRI was not possible for one of the PDR-BT fractions, which therefore had to be given using a standard loading pattern. The DVH parameters for this fraction were assessed by applying the loading pattern to the MRI study used for the subsequent PDR-BT fractions.
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Fig. 2. (Upper) Dwell times for standard (Left) and optimized (Right) dose plans. Standard plan (30-mm ring, 60-mm tandem) held 12 stopping positions in tandem and 3 stopping positions at each lateral side of ring. Dwell times indicated by length of bars. (Lower) Isodoses corresponding to prescribed dose (green) for standard (Left) and optimized (Right) loading patterns. High-risk clinical target volume indicated in red.
The relation between the BT dose to the tumor and OARs obtained using standard library plans and assessed with either the GEC-ESTRO (3D) or ICRU (2D) recommendations are shown in Fig. 3. For the tumor target, this 3D/2D relationship was evaluated by dividing the cumulative D90 of the HRCTV with the cumulative average Point A dose for each patient. For the OARs, the BT dose to 2 cm3 was divided
by the BT dose to the ICRU reference point for the relevant organ (bladder or rectum). Poor agreement was found for the tumor target, with the 3D/2D relative dose varying from 50% to 150%. In about 75% of the patients, the D90 was larger than the Point A dose. For the bladder, the variation was even larger, with the 3D/2D relative dose varying from 75% to 300%, again with the ICRU reference point underestimating the dose to the bladder in 75% of the patients. For the rectum, the variation was much less, but the ICRU reference point overestimated the dose in 75% of the patients.
Table 1. Physical doses and fractionation of EBRT and BT by standard plan BT
EBRT
EBRT+BT
Patients CTV-T CTV-E CTV-N Point A Point A Point A (n) (Gy/fx) (Gy/fx) (Gy/fx) (Gy/fx) (Gy) (EQD2, Gy) 12 2 4 3
Fig. 3. Box plot (10th, 25th, 50th, 75th, and 90th percentile) showing relative brachytherapy dose to tumor (minimal dose received by 90% of high-risk clinical target volume vs. Point A) and organs at risk (2 cm3 bladder and rectum vs. ICRU points) obtained by standard plans and assessed with GEC-ESTRO guidelines (three-dimensional) and ICRU (two-dimensional) recommendations.
50/25 50/30 60/30 60/30
45/25 45/30 45/25 45/30
— 60/30 — 60/30
30/3 30/3 20/2 20/2
80 80 80 80
83.7 82.3 82.4 82.4
Abbreviations: EBRT = external beam radiotherapy; BT = brachytherapy; CTV-T = tumor clinical target volume; fx = number of fractions; CTV-E = elective CTV; CTV-N = lymph node CTV; EQD2 = equivalent dose in 2-Gy fractions. Total dose of EBRT and BT was physical dose to Point A; cumulative equivalent dose of EBRT and BT in 2-Gy fractions (EQD2) at Point A calculated according to linear-quadratic model (a/b = 10, repair half time, 1.5 h) also shown.
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Fig. 4. Dose–volume histogram (DVH) parameters of standard (Left) vs. optimized (Right) plans for 2 cm3 of bladder, rectum, and sigmoid plotted against minimal dose received by 90% of target volume (D90) of high-risk clinical target volume (HR-CTV). DVH constraints indicated by horizontal dotted line (bladder = 90 Gy, rectum = 75 Gy, sigmoid = 75 Gy). Vertical dotted lines indicate desired D90 to HR-CTV (i.e., 85 Gy). Symbols within box fulfilled DVH constraints with respect both to organs at risk (OARs) and tumor.
The DVH parameters related to Point A and the HR-CTV for the standard and optimized plans are given in Table 2. The total reference air kerma was significantly lower for the optimized plans (p = 0.04), whereas, the volume receiving the
prescribed and double the prescribed dose did not change significantly. Also, the average Point A dose was the same for the standard vs. optimized plans. However, the individualization of the PDR-BT was reflected in the significantly
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Table 2. Dose–volume histogram parameters related to primary tumor target Aarhus
Vienna
Parameter
Standard
Optimized
IC; Kirisits et al. (11)
IC/IS; Kirisits et al. (12)
Patients (n) BT fractions (n) Prescribed dose (Gyab10) TRAK VPD (cm3) V2PD (cm3) Point A, all patients (Gyab10) Average left and right Difference Point A, IC patients only* (Gyab10) Average left and right Difference HR-CTV Volume (cm3) D100 (Gyab10) D90 (Gyab10) V100 (%)
— — 83 1 1.6 0.3 86 4 30 1
21 56 83 1 1.5 0.4 80 17 29 9
22 76 85 4 1.7 0.3 85 19 25 8
22 44 85 2 1.9 0.2 101 18 33 7
84 1 0.2 0.9
82 6 4.5 8
— —
— —
84 1 0.2 0.8
81 5 2.8 2
82 9 —
— —
— 73 7 89 10 92 9
34 12 76 5 91 8 96 7
34 17 66 7 87 10 89 8
44 27 70 6 96 12 93 9
Abbreviations: IC = intracavitary; IC/IS = combined intracavitary-interstitial; TRAK = total reference air kerma; VPD = volume encompassed by prescribed dose; V2PD = volume encompassed by twice prescribed dose; HR-CTV = high-risk clinical target volume; D100 = minimal target dose; D90 = dose received by 90% of target volume; V100 = percentage of target treated with at least prescribed dose; HDR = high dose rate; other abbreviations as in Table 1. Data presented as mean standard deviation. Doses calculated as cumulative equivalent dose in 2-Gy fractions of EBRT and BT using linear-quadratic model (a/b = 10 Gy, repair half time = 1.5 h); for comparison, DVH parameters reported by Kirisits et al. (11, 12) for HDR shown. * Values do not include 4 patients treated with IC/IS.
increased asymmetry between the doses to Point A on each side, increasing from a difference of 0.2 Gy to one of 4.5 Gy (p = 0.03). The maximal Point A dose was 118 Gy, recorded in 1 patient treated with IC/IS BT. However, the asymmetry between the dose to Point A on the left and right remained significant when only the patients treated with IC BT were analyzed (p <0.001). The mean D90 was the same for the standard and optimized plans, but optimization significantly increased both the minimal target dose (D100) and the percentage of target treated with at least the prescribed dose (V100) of the HR-CTV (p <0.007). Table 2 also includes a comparison, in terms of the EQD2, of the HDR DVH parameters from Vienna for pure IC and combined IC/IS BT. Compared with the IC Vienna study (11), the Aarhus values for D100 and V100 were significantly greater (p = 0.005), a difference that disappeared when comparing the Aarhus data with the combined IC/IS Vienna data (12). The DVH parameters related to the OARs for the standard and optimized plans are given in Table 3. When comparing the standard and optimized plans, only the dose and dose rate for 2 cm3 of the sigmoid were significantly reduced (p <0.03). However, for the bladder, a reduction also occurred in the standard deviation for all DVH parameters. When considering the effect of optimization in terms of the sparing factor for the cumulative physical dose of BT, significant reductions were found for both the bladder and the sigmoid (p <0.02). When comparing our data with the Vienna (IC and IC/IS) data, the doses to 0.1, 1, and 2 cm3 of the bladder were significantly lower in the Aarhus data (p<0.004), but the
dose to 1 and 2 cm3 of the sigmoid were larger in the Aarhus data than in IC Vienna series (p <0.04). When comparing the Aarhus series with the IC/IS Vienna series, no difference was found in the DVH parameters for the sigmoid. Also, the DVH parameters for the rectum were not significantly different between the Aarhus and either the Vienna IC or IC/IS series. Because the average DVH values given in Tables 2 and 3 do not show the interplay between the gain and loss in terms of the dose to the HR-CTV vs. the OARs, we also compared the number of patients with fulfilled DVH constraints for the standard and optimized dose plans. Using 3D optimization, all DVH constraints (HR-CTV, bladder, rectum, and sigmoid) were met in 16 of 21 of our patients compared with 3 of 21 patients using the 2D library plans (p <0.001). In Fig. 4, the D90 for the HR-CTV is plotted against the 2-cm3 dose (EQD2) for the bladder, rectum, and sigmoid. For the HR-CTV in relation to the bladder and rectum, the requirement for the D90 and dose to 2 cm3 was met in 18 of 21 patients in the optimized plan vs. 13 of 21 patients in the standard plans (p = 0.16). For the HR-CTV in relation to the sigmoid, optimization significantly changed the distribution from 5 to 16 of 21 patients meeting the DVH constraint for both D90 and the dose to 2 cm3 (p = 0.002). DISCUSSION Depending primarily on tumor size, International Federation of Gynecology and Obstetrics stage, and overall treatment time, pelvic control rates of 50–90% are usually
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Table 3. Dose–volume histogram parameters related to organs at risk Aarhus Parameter Bladder Sparing factor ICRU point (Gyab3) D0.1 (Gyab3) D1 (Gyab3) D2 (Gyab3) Dose rate D2 (Gyab3) Rectum Sparing factor ICRU point (Gyab3) Rectal diode (Gyab3) D0.1 (Gyab3) D1 (Gyab3) D2 (Gyab3) Dose rate D2 (Gyab3) Sigmoid Sparing factor D0.1 (Gyab3) D1 (Gyab3) D2 (Gyab3) Dose rate D2 (Gyab3)
Vienna
Standard
Optimized
IC; Kirisits et al. (11)
IC/IS; Kirisits et al. (12)
0.72 0.32 75 31 99 45 83 22 78 16 0.93 0.56
0.61 0.20 67 8 86 12 77 8 73 6 0.69 0.20
— 75 16 121 25 92 11 83 9 HDR
— 73 19 113 30 90 16 83 14 HDR
0.50 0.25 70 5 63 6 74 10 69 7 67 6 0.52 0.21
0.47 0.22 71 7 63 5 74 9 69 6 67 6 0.48 0.18
— 69 13 60 8 77 10 66 7 64 6 HDR
— 71 13 63 9 77 9 69 6 66 6 HDR
0.59 0.20 82 13 74 10 72 9 0.72 0.32
0.51 0.13 79 10 72 7 69 6 0.58 0.21
— 79 12 67 8 63 7 HDR
— 85 14 71 8 67 7 HDR
Abbreviations: ICRU = International Commission on Radiation Units and Measurements; D0.1, D1, D2 = minimal dose to most irradiated 0.1, 1, and 2 cm3 of organ at risk; HDR = high dose rate; other abbreviations as in Tables 1 and 2. Radiation doses calculated as cumulative equivalent dose in 2-Gy fractions of EBRT and BT using linear-quadratic model (a/b = 3 Gy, repair half time = 1.5 h), assuming that most irradiated 0.1, 1, and 2 cm3 volume of organ at risk was same for each BT fraction and received full dose of EBRT prescribed to primary tumor. For comparison, DVH parameters reported by Kirisits et al. (11, 12) for HDR shown.
obtained with 2D BT (17). However, in retrospect, it has been difficult to demonstrate a formal dose–response curve (18), with the Point A dose being superseded by stronger prognostic parameters (19). This indicates that Point A dose is a weak surrogate marker for the actual dose to the 3D BT target as estimated by DVH analysis (11). In our experience (Fig. 3), this difference can vary by as much as 50–150%, which could explain the limitation of Point A in this context. It is anticipated that the D90 for the HR-CTV will be a much strong prognostic factor than the Point A dose, with an expected local control rate of 90–95% even in large tumors, provided that a D90 of $85–90 GyEQD2 is obtained in the HR-CTV (4, 7, 20). With comparable D90 values for HR-CTV reached in most of our patients, we expect to observe similar rates of long-term local control. For the OARs, a relationship between the dose to the ICRU rectal point and rectal complications has been established (21). At a median dose of 84 GyEQD2, the risk of severe complications was around 10%, increasing steeply for greater doses. A comparison of the 2D and 3D volumetric CT-based calculations has shown that the ICRU rectal point is a reasonable surrogate for the minimal dose to the most irradiated 2 cm3 of the rectal wall (22, 23). The 2-cm3 volume in the greatest dose region has been found to be a clinically relevant parameter correlating with complications (24). Our MRIbased volumetric data also showed that the ICRU rectal point is performing reasonable. A specific uncertainty with 2D BT
is the dose to the upper rectum and sigmoid, which is very difficult to estimate and where significant morbidity can arise (25). Essentially, the dose contribution to these parts of the gastrointestinal tract can only be assessed by 3D DVH analysis. For the rectum and sigmoid, it has been shown that a limit of a minimal dose of 70–75 GyEQD2 to the most exposed 2 cm3 is a good cutoff point (4, 26). Thus, recent studies with MRI-based HDR BT and concomitant cisplatin have shown a complete absence of Grade 3-4 rectal and sigmoid complications if these DVH constraints were fulfilled (6, 7). Regarding the bladder, the ICRU bladder point is known to be an uncertain predictor of the minimal dose the most irradiated 2 cm3 of the bladder, as shown in both the present study and previous studies (22, 23). Uncertainty exists as to the true dose–volume constraint to apply for the bladder. Severe toxicity has been reported in 2 patients with 2-cm3 doses >100 GyEQD2. Currently, 90 GyEQD2 to 2 cm3 is being advocated as an appropriate dose–volume constraint for the bladder (4, 26). The follow-up in the present study was too short to report on late toxicity, but, as in the experience reported from Vienna (7), we have not seen treatment prohibitive acute toxicity or consequential late damage, even using the IC/IS technique. With the 3D technique, we have for the first time evaluated the doses to the sigmoid and, as have others, we found that dose to the sigmoid often seems greater than that to the rectum (10, 26). However, by optimization, we
MRI-based PDR brachytherapy for cervical cancer d J. C. LINDEGAARD et al.
were able to significantly reduce the dose to this organ in terms of both the cumulative EQD2 of EBRT and BT and the physical dose delivered by BT (sparing factor). We also observed a significant improvement of the sparing factor for the bladder, especially for 2 patients in whom a very high dose to the bladder would have been the result if 2D BT had been used and they were most likely saved from severe bladder toxicity by 3D optimization (6). Probably because of the vaginal packing, the rectum was already sufficiently spared using the library plans and no further sparing was obtained. We found that 3D MRI-guided BT is a challenging technique to master. For the implementation of this technique in our department, we therefore used both internal and external assessment of the DVH parameters. Our internal comparison was primarily done to ensure that the new 3D BT procedure really was a reallocation of radioactivity according to the individual case, rather than a hidden general dose escalation. We therefore systematically compared the DVH parameters from our optimized plans with our 2D standard library plans. It was reassuring to observe that the total reference air kerma was reduced by a minor amount, yet the coverage and minimal dose to the HR-CTV were significantly increased. One reason was that the 3D technique allowed us to take advantage of the versatility of the tandem-ring applicator and to use ‘‘add-ons’’ in the form of a custom-made multichannel vaginal cylinder and modified Vienna applicator for combined IC/IS BT. This would have been difficult to perform using 2D orthogonal X-rays or even CT-based 3D BT. The external comparison between the DVH data of Aarhus and Vienna was more difficult because it involved radiobiological assumptions, not only on the 3D summation of the dose from EBRT and BT, but also on the effect of the dose rate. For the 3D summation of EBRT and BT, the same ‘‘worst case scenario,’’ as used by Kirisits et al. (11, 12), was used. That is, we supposed that the OARs had received the same EBRT dose as the primary tumor target (CTV-T) despite the use of a SIB technique for treating this target to a 5–10-Gy greater dose than the elective volume (CTV-E). As did Kirisits et al. (11, 12), we assumed that no organ movement occurred between BT fractions (i.e., we assumed that it was the same 2 cm3 of the OARs that received the greatest dose at each BT fraction. For the biologic equivalence calculations, the GEC-ESTRO guidelines have recommended a/b = 10 for tumor, a/b = 3 for OARs, and a mono-exponential repair model with a repair half time of 1.5 h to account for dose rate effects (2). Concerning the radiobiologic assumptions, the repair capacity in the form of a/b values of 10 for tumor and 3 for OARs are generally accepted (18, 27); however, larger uncertainty exists for the repair kinetics (28–30). Even with these limitations, we found it a useful method for comparing the DVH parameters from Aarhus and Vienna. In view of the different treatment approaches used in the Aarhus and Vienna series in imaging (high vs. low tesla MRI), dose rate (PDR vs. HDR), and the relative contribution
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of BT to total dose to the HR-CTV, the most striking features of Tables 2 and 3 are the similarities in all the important DVH parameters. Apart from a greater D100 and V100 in the Aarhus series compared with the IC Vienna data (11), all the tumorrelated parameters were comparable. For the D100 and V100, these parameters are known to be sensitive to small contouring inconsistencies (11). However, the use of combined IC/IS in selected cases in the Aarhus series is also important in explaining this difference. For the OARs, the most important difference was the greater bladder doses in Vienna and a tendency for greater sigmoid doses in Aarhus, at least for the 2-cm3 dose (Table 3). This difference can be explained by the different packing approaches. We, in line with our lowdose-rate tradition, might have a policy for tighter vaginal packing, which could push the applicator more proximally and clear of the bladder but closer to the sigmoid. Also, the difference in bladder filling (open catheter in Aarhus vs. 50–100-mL filling in Vienna) could have contributed to the observed difference. Our different starting positions with regard to the standard loading pattern, with more weight to the ring in the Vienna vs. the Aarhus standard plan, could also have contributed, although we did not see any differences for the rectum. Also, the dose falloff in the OARs from 0.1 cm3 to 2 cm3 was steeper in the Vienna series than in the Aarhus series. This was most probably caused by the lesser contribution of BT to the total dose of the HR-CTV, with only 30–40% of the dose delivered by BT in the Aarhus series compared with the BT dose in the Vienna series, in which it was almost 50%. However, the dose rate effect also works in this direction when calculating the EQD2 levels for PDR and HDR. CONCLUSION Magnetic resonance imaging-guided 3D optimization significantly improved PDR-BT for locally advanced cervical cancer. The possibility of adapting the BT dose specifically to the tumor target at BT represents an important development for gynecologic BT compared with the level described in ICRU report 38. Also, the possibility of using individualized applicator adaptation, such as additional interstitial needles, considerably increased the possibility of increasing the tumor coverage. The present results have demonstrated that it is possible, not only to transfer this technique from one department to another, but also to use the GEC-ESTRO guidelines for BT in cervical cancer as a meaningful tool for reporting and comparing doses to the target and OARs between different departments (1, 2). The first clinical outcome data have been encouraging (4, 6, 7), and the technique holds promise for additional research and progress using, for example, functional imaging and deformable registration to better understand and characterize the medical aspects and uncertainties of the underlying dose–volume relations. To sustain these data, a European study on MRI guided brachytherapy in locally advanced cervical cancer (EMBRACE) is currently being planned within the Gynaecological GEC-ESTRO network.
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