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Proof of principle: Applicator-guided stereotactic IMRT boost in combination with 3D MRI-based brachytherapy in locally advanced cervical cancer Marianne S. Assenholt1,*, Anne Vestergaard1, Jesper F. Kallehauge1, Sandy Mohamed2, Søren K. Nielsen1, Jørgen B. Petersen1, Lars Fokdal2, Jacob C. Lindegaard2, Kari Tanderup1,2,3 1
Department of Medical Physics, Aarhus University Hospital, Aarhus, Denmark 2 Department of Oncology, Aarhus University Hospital, Aarhus, Denmark 3 Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
ABSTRACT
PURPOSE: To describe a new technique involving high-precision stereotactic intensity-modulated radiation therapy (IMRT) boost in combination with intracavitary-interstitial (IC-IS) brachytherapy (BT) in cervical tumors that cannot be sufficiently covered by IC-IS-BT due to extensive residual disease and/or difficult topography at the time of BT. METHODS AND MATERIALS: Three patients with stage IIIB-IVA cervical cancer had significant residual disease at the time of BT. MRI-guided IC-IS-BT (pulsed-dose rate) was combined with a stereotactic IMRT boost guided according to the BT applicator in situ, using cone beam CT. The planning aim dose (total external beam radiotherapy and BT) for the high-risk clinical target volume (HR-CTV) was D90 O70e85 Gy, whereas constraints for organs at risk were D2cm3 !70 Gy for rectum, sigmoid, and bowel and !90 Gy for bladder in terms of equivalent total dose in 2 Gy fractions. An IMRT boost adapted to the BT dose distribution was optimized to target the regions poorly covered by BT. RESULTS: HR-CTV doses of D90 O81 Gy were obtained in the central HR-CTV and D90 O69 Gy in the distal regions of HR-CTV. Image-guided set up of the IMRT boost with the applicator in situ was feasible. The dose plans were robust to intra-fraction uncertainties of 3 mm. Local control with acceptable morbidity was obtained at a followup of 3, 2.5, and 1 year, respectively. CONCLUSIONS: The combination of MRI-guided BT with an applicator-guided stereotactic IMRT boost is feasible. This technique seems to be useful in the few cases where HR-CTV coverage cannot be obtained even with IS-IC-BT. Ó 2014 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Brachytherapy; MRI-guidance; Cervical cancer; IMRT boost; Applicator-guidance
Introduction Radiotherapy for cervical cancer typically combines external beam radiotherapy (EBRT) with a boost of intracavitary (IC) brachytherapy (BT). Major breakthroughs in Received 25 November 2013; received in revised form 27 January 2014; accepted 12 February 2014. Conflict of interest: The authors report no conflicts of interest. Dr. MSA reports grants from Danish Cancer Society, Danish Council for Strategic Research, CIRROdthe Lundbeck Foundation, FP7 ICT-2011.5.2, during the conduct of the study; grants from Varian, Nucletron, outside the submitted work. * Corresponding author. Aarhus University Hospital, Department of Medical Physics, Nørrebrogade 44, bygn. 5, 2. DK-8000 Aarhus C. Tel.: þ45-7846-4448; fax: þ45-7846-4522. E-mail address: [email protected] (M.S. Assenholt).
radiotherapy have recently been made with 3D imagee guided adaptive radiotherapy in locally advanced cervical cancer with application of CT and MRI at the time of BT (1, 2). Image guidance enables the delivery of high doses of radiation tailored selectively to the cancer target in both space and time domains (3e5). MRI offers excellent softtissue contrast, and MRI with the BT applicator in situ is advocated for 3D planning of BT (6). Excellent clinical results have been demonstrated with MRI-guided BT (7e11). However, tumors with significant residual disease and/or unfavorable topography after EBRT may still represent a therapeutic challenge. In these cases, it can be difficult to reach sufficient dose by IC-BT to the high-risk clinical target volume (HR-CTV) (12, 13). This problem is currently mainly addressed in two different
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ways: parametrial boost (PMB) or addition of an interstitial (IS) component to the basic IC applicator. Substantial additional morbidity has been reported with the use of PMB (14), and HR-CTV dose may still be compromised in large tumors despite application of PMB (15, 16). An alternative to PMB is to combine IC-BT with IS-BT (17e19). This technique offers the possibility to adapt the applicator to HR-CTV and thereby obtain a high dose to the tumor with no significant additional dose imposed on OAR. However, even with IS-IC-BT, the HRCTV dose may be insufficient for some tumors with large residual tumor/or challenging topography. A previous dose planning study (20) compared IC-BT, intracavitary-interstitial brachytherapy (IC-IS-BT), IC-IS-BT þ intensity-modulated radiation therapy (IMRT), and IMRT boost and found that in certain cases combined IC-IS-BT with a stereotactic IMRT boost may significantly improve the dose to tumor. The purpose of this study was to demonstrate, as proof of principle, that image-guided BT can be combined with a stereotactic IMRT boost in a robust way and improve target coverage of tumors with significant residual disease at the time of BT. Three patients have been treated with IC-IS-BT combined with an applicator-guided stereotactic IMRT boost. Methods and materials Three patients with locally advanced cervical cancer were selected in the period May 2009 until March 2012 for stereotactic IMRT boost treatment based on the clinical presentation at diagnosis and response to EBRT. Patient A had FIGO (International Federation of Obstetrics and Gynecology) Stage IVA disease with a tumor extending around and invading the entire circumference of the rectum. Patient B and C had FIGO Stage IIIB disease with massive parametrial infiltration and tumor extension to the pelvic wall as well as vaginal involvement. All tumors were squamous cell carcinomas. The ages of the patients were 71, 48, and 38 years, respectively, at the time of treatment. The overall treatment schedule is shown in Fig. 1. The patients received elective whole pelvis IMRT of 50 Gy in 30 fractions with a concomitant simultaneous integrated boost of 60 Gy to areas with pathologic enlarged lymph nodes. In Patients B and C a total of five cycles of concomitant weekly cisplatinum were prescribed. Patient A was treated with two cycles of neoadjuvant chemotherapy (cisplatinum, 5-Flouracile, and Ifosfamide). Due to impaired renal function, no further chemotherapy was prescribed during radiotherapy. At the time of BT, all patients had some tumor regression but HR-CTV was still large in Patient A (115 cm3) and C (77 cm3). In Patient B, HR-CTV was 36 cm3 but with a very unfavorable topography with lateral extension toward the pelvic wall. In Week 5, preplanning of BT and IMRT boost was performed (BT-IMRT0) involving a gynecologic examination
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under general anesthesia, insertion of a tandem ring applicator, and an MRI scan with the BT applicator in situ (17). The first application of pulsed-dose rate (PDR) BT with an IMRT boost was delivered in Week 6 (BT-IMRT1) and the second fraction in Week 7 (BT-IMRT2). CT and MR imaging, contouring, and dose planning was performed for both BT-IMRT1 and BT-IMRT2 to adapt the treatment to the patient anatomy and applicator position for each boost session. This is according to the common approach in image-guided adaptive BT, where imaging and adaptation is performed for each BT fraction to eliminate uncertainties related to application of the same treatment plan to different anatomies (21). Combined IC-IS-BT technique using 3e7 needles inserted through the ring cap in parallel to the tandem were used in all three patients for both BT implants used for treatment. For Patient B, a vaginal cylinder was also attached to the ring to facilitate vaginal irradiation. Vaginal gauze packing was performed in the patients without vaginal cylinder. An MRI scan (MRBT) was performed with the combined IC-IS ring applicator in situ (6). Directly after MRI, a CT scan (CTBT) was also obtained for EBRT dose calculation purposes. Following contouring and treatment planning (see below), PDR-BT was delivered in 15e17 hourly pulses. After a treatment gap of 4e6 h after the last pulse of BT, the patient was transferred to the accelerator (Varian Clinac [Varian Medical Systems, Inc., Palo Alto, CA] Patients A and B, and Varian TrueBeam Patient C) with the BT applicator still in situ and the stereotactic IMRT boost tailored to the BT dose distribution was delivered. The BT applicator was removed immediately after the IMRT boost. This procedure was repeated 1 week later at the second BT þ IMRT boost fraction (BT-IMRT2). The boost target for BT-IMRT was HR-CTV including the residual GTV, the whole cervix, and the presumed extra-cervical tumor extension at the time of BT (22). HR-CTV was defined based on MRI and clinical examination. OARs taken into account were rectum, sigmoid, bladder, and bowel. MRBT and CTBT were fused to transfer contours from MRI to CT. Applicator reconstruction was performed according to GEC ESTRO recommendations (23). Total EBRT and BT doses were evaluated in terms of equivalent dose in 2 Gy fractions (EQD2) by use of the monoexponential repair half-time model with a/b 5 10 Gy for tumor, a/b 5 3 Gy for normal tissue, and a repair half-time of 1.5 h. The tumor dose planning aim was individualized according to the disease burden and the proximity of OARs. HR-CTV was divided into two parts: 1) HR-CTVcentral, which was the central part of the target covered by the BT dose and 2) HR-CTVdistal extending into the BT low dose region. The planning aim (total EBRT þ BT) for HR-CTVcentral was D90 O 85 Gy EQD210 (EQD2 with a/b 5 10 Gy) for all patients. A lower dose was prescribed to HR-CTVdistal due to close proximity of the rectum, sigmoid, and bowel, respectively. For Patient
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Fig. 1. EBRT, BT, and IMRT boost schedule. EBRT 5 external beam radiotherapy; BT 5 brachytherapy; IMRT 5 intensity-modulated radiation therapy.
A, a dose of 70 Gy EQD210 was planned for D90 HRCTVdistal, which fully surrounded the rectum, which was then considered as both a target and OAR. For Patients B and C, a planning aim of 70e75 Gy EQD210 was applied to D90 HR-CTVdistal, which was extending to the pelvic wall. Planning aims for OAR D2cm3 were !90 Gy EQD23 for bladder and !70 Gy EQD23 for rectum, sigmoid, and bowel. It was assumed that the most exposed parts of OARs were exposed to the full whole pelvis EBRT dose of 50 Gy/30fx or 60 Gy/30fx in regions where this was relevant. No setup margins were added to HR-CTVcentral for BT treatment planning (24). For the IMRT boost, a 3 mm radial setup margin was used for HR-CTVdistal. The first step was to plan the BT boost. Manual dwell time optimization was performed with the aim to cover HR-CTVcentral while keeping dose OARs well below constraints to leave space for additional dose contribution from the IMRT boost. The individual dwell times in the needles were aimed to be less than 10%e20% of the tandem dwell times to maintain the major dose contribution from the intracavitary applicator. After BT planning, the volume that needed the additional boosting from the IMRT plan was identified. Due to BT dose gradients, the dose contribution from the IMRT boost varied significantly across the target to match the BT dose gradient. The biologic effect of a given total BT þ IMRT physical dose depended on the specific contribution of BT and IMRT because iso-effective dose depends on both fraction size and dose rate, which varies throughout the entire target volume, for example, a physical dose of 7 Gy from IMRT boost was equivalent to an EQD210 dose of 10 Gy, whereas a physical dose of 7 Gy from PDR BT was equivalent to an EQD210 of 7 Gy when delivered over 15 pulses. To take this into account, the target was divided into sectors (‘‘shells’’) according to BT dose contribution (Fig. 2). Four BT isodose curves were converted into contours and from Boolean operations four shells were
generated and represented regions with different IMRT dose planning aims. In the dose planning system (8.6.15, AAA calculation, Eclipse 8.2.23, Varian Medical Systems, Inc., Palo Alto, CA), each shell was optimized to a certain dose by inverse dose optimization. For evaluation of the dose plans, the software CERR (A Computational Environment for Radiotherapy Research, J.O. Deasy, St. Louis) and Matlab (The MathWorks, Inc., Natick, MA) was used to convert the physical 3D dose matrix for BT and IMRT into an EQD2 3D dose matrix. a/b Values of 10 Gy were assigned to voxels within the target volumes, and a/b values of 3 Gy were assigned in voxels outside target volumes. Three-dimension (3D) summations of EQD2 doses were then performed to obtain a total EQD2 3D dose matrix. Doseevolume histogram parameters were obtained from the EQD2 sum plan. The IMRT boost was guided by the BT applicator position by on board cone beam CT (cone beam computertomografi [CBCT]). CBCT was matched with CTBT according to the applicator position. Because the BT dose distribution is defined by the position of the applicator, this procedure ensured that the IMRT dose gradients were aligned with the BT dose gradients. Couch translation and rotation (yaw) was used to position the isocenter. There was no specific device used to control the angulation of the applicator except that the patient was positioned and rotated according to skin marks. However, residual rotations (roll and pitch) leading to deviations of O1e2 mm of the applicator position in CBCT as compared with the planning CT were not accepted. In this case, the patient was re-positioned, and a new CBCT was acquired. The bladder filling was controlled with a bladder catheter, so that the bladder was empty during PDR and during IMRT delivery. Rectum, sigmoid, and bowel movement was assessed visually on CBCT as far as possible according to CBCT image quality. The stability of the combined BT and IMRT boost toward geometric uncertainties was evaluated, to investigate whether
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Fig. 2. Transversal (a) and sagittal (b) MRI at the time of BT1 for Patient A. HR-CTVcentral and HR-CTVdistal are indicated in yellow and red, respectively. The isodose curves for BT1 divide the HR-CTVdistal into four shells indicated by the shaded areas. The blue line is PTV for HR-CTVdistal. HR-CTV 5 high-risk clinical target volume; BT 5 brachytherapy. (For interpretation of references to color in this figure legend, the reader is referred to the web version of this article.)
residual uncertainties in patient setup or intra-fraction movement could result in significant hot spots or cold spots in the junction zone between the BT and IMRT boost. The dosimetric impact of displacing the IMRT boost plan by 3 mm toward or away from the high-dose area in the BT boost plan was evaluated. The isocenter displacement was performed in the direction of the steepest dose gradients. The addition of the BT EQD2 dose and the shifted IMRT boost EQD2 dose was performed with the software described previously. The dose profiles across the intersection of the BT and the IMRT were evaluated as well as the doseevolume histogram for the HR-CTV and the OARs. After radiotherapy, patients were followed in the outpatient clinic with regular followup visits every third month the first year. Subsequently, they were seen every 6 months. At 3 months, MRI and positron emissions tomography CT were performed. MRI was routinely repeated at 12 months after the completion of treatment. The CTCSAE V.3.0 system was used to score the side effects. Results Dose planning and dose delivery were feasible for all three patients. The treatment was delivered in the planned time schedule for all treatments, and the patients were able to cooperate. The workload for each boost was approximately 8 h for a physicist for dose planning and delivering the IMRT boost, although there was a considerable learning curve and the treatment planning of the first patient was more time consuming. Adding to this, a radiation oncologist spent 2e3 h of additional work as compared with a normal BT. The minimum HR-CTV dose from IC-IS-BT was 2e3 Gy for each BT application in all patients. This would have corresponded to a total EBRT þ BT dose of 52e53 Gy EQD2 in the most distal region of HR-CTV if the stereotactic IMRT boost had not been applied. IMRT
doses up of 6e7 Gy per fraction were applied in HRCTVdistal. An example of a dose plan is shown in Fig. 3. Volumes and doses are listed in Table 1. HR-CTV doses were according to planning aims for Patients B and C, whereas Patient A received less HR-CTV dose due to the OAR priorities (rectum dose). Dose constraints for OARs were respected in all organs and patients, except for the rectal dose in Patient A. Table 2 shows the impact of 3 mm setup uncertainties or intra-fractional movements for the IMRT boost plan. Moving the IMRT boost plan 3 mm away from the tandem decreased the HR-CTVdistal dose with a maximum of 2.4 Gy (total EQD2). The highest increase in OAR dose was seen in the sigmoid and was 1.2 Gy (EQD2). Assessment of tumor control and morbidity was available at 3, 2.5, and 1 year, in Patients A, B, and C, respectively. In Patient A, the tumor was extending around the rectum resulting in a stenosis at the time of diagnosis. Before radiotherapy, a tumor stent was inserted into the rectum, and after termination of treatment the patient had a planned stoma. At 3-year followup, the patient had no evidence of recurrence. She still had the stoma, but apart from this, no other late effects that could be attributed to radiotherapy. In Patient B, no evidence of disease was found at 2.5 years of followup. Apart from vaginal stenosis Grade 1, no other late effects had been diagnosed. In Patient C, no evidence of disease was found at 1 year. This patient had Grade 1 rectal and bladder bleeding as well as diarrhea. Moreover Grade 2 cystitis and Grade 3 pelvic pain were diagnosed. The etiology of the pelvic pain was not known, but might be attributed to soft-tissue fibrosis. Discussion This study demonstrated that it was technically possible to combine a BT-boost with a high-precision IMRT boost.
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Fig. 3. MRI at the time of second BT for Patient B. (a) BT dose distribution (physical doses) for the combined IC-IS tandem/ring applicator in situ, minimum dose in colored area is 3 Gy. (b) Dose distribution (physical doses) for IMRT boost plan, minimum dose in colored area is 4 Gy. (c) The accumulated EQD2 dose for second boost. Minimum dose in colored area is 7 Gy EQD2. The dose heterogeneity seen at the distal border of HR-CTV is due to use of different a/b values in tumor and normal tissue. (d) EQD2 dose contribution from one fraction of BT and IMRT boosting and the accumulated dose. (For interpretation of references to color in this figure legend, the reader is referred to the web version of this article.)
It was feasible to use the LQ model (EQD2) to calculate the planning aim and the delivered dose for the combined BT and IMRT boost, and it was possible to deliver the treatment with a good clinical result. This boost combination improved the dose to the HR-CTV significantly without compromising the constraints for OARs. The dose distribution of the combined boost plan was stable within uncertainties of 3 mm, and the risk of significant cold and hot spots in the target and OARs were limited even if the patient would move 3 mm during the treatment. The minimum requirement for an institute to implement this technique is to have expertise in image-guided BT, IMRT dose planning, and CBCT image guidance. Boosting the parametria has traditionally been performed by EBRT PMB, often with the application of midline blocked fields (25). Fenkel et al. (15) has assessed this modality of midline blocked PMB with regard to
dosimetric performance and concluded that the midline blocked fields contribute substantial dose to the bladder, rectum, and sigmoid. Furthermore, the midline blocked PMB did not result in significant and predictable dose to HR-CTV. During the last decade, significant improvements in the treatment of locally advanced cervical cancer have been achieved with the introduction of 3D-image guidance (26). In particular, for large tumors, mono-institutional data indicate that it is possible to improve local control by using MR imageeguided BT (7, 9e11). MRI-guided BT involves individualization of the dose distribution with optimization of the dwell times in the intracavitary applicator as well as adaptation of the application itself with the addition of interstitial needles positioned through to the tandem/ring intracavitary applicator. From a geometric point of view, needle placement through the ring in
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Table 1 Volumes and total equivalent dose in 2 Gy fractions (EQD2) (whole pelvis external beam radiotherapy, brachytherapy and intensity-modulated radiation therapy boost), doseevolume histogram parameters for targets and organs at risk Volumes Volumes (cm3) HR-CTV (total) at BT1 HR-CTVcentral at BT1 HR-CTVdistal at BT1 Total doses, EQD2 (Gy) HR-CTVcentral D98 HR-CTVcentral D90 HR-CTVdistal D98 HR-CTVdistal D90 Bladder D2cm3 Rectum D2cm3 Sigmoid D2cm3
Patient A
Patient B
Patient C
115 55 60
36 23 13
77 68 9
82.2 86.8 70.1 71.2 73.0 68.9 70.2
78.7 88.0 70.7 71.2 81.2 67.0 67.4
74.1 80.7 69.3 69.7 75.6 78.3 70.7
HR-CTV 5 high-risk clinical target volume; BT 5 brachytherapy; EQD2 5 equivalent total dose in 2 Gy fractions.
parallel to the tandem provides about 10 mm additional coverage in the lateral part of the tumor, which corresponds to the inner two-thirds of the parametrium (27). To cover residual tumor in the distal parametria at the time of BT, it is necessary to use oblique or free needles that can be inserted in directions and angles that are not parallel to the tandem/ring applicator (17). In our current clinical experience, IS-BT is now a days added to IC-BT in ~50% of patients and more often in extensive disease where ~70% of patients with Stage IIIB, IVA, IVB disease receive IC-IS-BT (17). In a few patients with large tumors and unfavorable topography, it was not possible to cover HR-CTV with IC-IS-BT. In these patients, it was decided to provide an IMRT boost. In our experience, the administration of IC-IS-BT combined with an IMRT boost was performed in 3 patients out of 137 consecutive patients (2%) treated in our institution during the period 2009e2012. This was for a stage distribution of Stage IB-IIA 14%, IIB 56%, III-IV 30% (7). An alternative technique would be template-based BT with perineal interstitial needle implantation. However, for tumors reaching the pelvic wall, the long needle path and diverging needles may result in sub-optimal tumor Table 2 Mean over all patients and range of dose differences (equivalent dose in 2 Gy fractions), when moving the intensity-modulated radiation therapy boost plan 3 mm toward and away from tandem, respectively Volume
3 mm Toward tandem
3 mm Away from tandem
HR-CTVcentral D98 (Gy) HR-CTVcentral D90 (Gy) HR-CTVdistal D98 (Gy) HR-CTVdistal D90 (Gy) Rectum (Gy) Sigmoid (Gy) Bladder (Gy)
0.8 0.6 0.8 0.9 0.3 0.9 0.2
0.6 0.5 1.9 1.8 0.2 0.8 0.1
(0.4; 1) (0.4; 0.9) (0.4; 1.2) (0.6; 1.4) (0.8; 0.0) (1.7; 0.1) (0.3; 0.1)
(0.8; 0.4) (1.2; 0.0) (2.4; 1.2) (2.3; 1.4) (0.2; 0.8) (0.2; 1.2) (0.0; 0.2)
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coverage. Furthermore, it is assumed to be an advantage to apply as much dose as possible from an intracavitary component because the uterine cavity is known to be radioresistant. Radiobiological uncertainties may be significant when applying the linear quadratic model, in particular, in case of large doses per fraction. However, it is of importance to notice that the doses applied in the junction region between the BT and IMRT boosts were in the range of 2e10 Gy (PDR BT) and 2e7 Gy (IMRT), respectively. There is considerable clinical experience with similar dose levels from image-guided adaptive BT, where the same radiobiological assumptions have been used as in this study to estimate EQD2 doses. We did not apply fractional doses beyond levels normally applied in current clinical practice. It is likely of more importance that the patient treatments in this study involved an escalation of the volume irradiated to significant doses (O65e70 Gy). While the clinical effect of irradiation of small volumes to high doses is well known from cervix cancer brachytherapy, the clinical effect of volume escalation is less well known. Pelvic pain (frozen pelvis) has been described as a side effect following radiotherapy and may be related to large volumes irradiated to high or intermediate doses. Prompted by EBRT technological developments during the last decades, it has been speculated whether BT of the primary cervix tumor could be replaced by, for example, IMRT, stereotactic boost, or proton boost (28, 29). However, most of the published treatment planning studies have been based on non-optimized BT and have neglected that EBRT boosting volumes must be larger than BT volumes due to the need for application of appropriate PTV margins in EBRT (24, 30). Furthermore, these studies have not taken into account that the BT dose distribution in the target region is fundamentally different from a homogeneous IMRT dose distribution. In BT, 50% of the target is typically irradiated to more than 150% of prescribed dose, and this seems to be of utmost importance for local control. Recent planning studies comparing advanced BT with IMRT and proton irradiation conclude that BT is superior both of these modalities with regard to tumor and OAR dose (20, 30). In this context, it is of great concern that recent data show that the use of BT in cervix cancer seems to have declined in the United States during the last 25 years (31, 32). Lack of BT was correlated with a significant decrease in overall survival by O10%. Along these lines, it is important to note that the majority of the boost dose in our study is still delivered through the BT component, whereas the IMRT boost only adds dose in regions where BT dose would be compromised in the periphery. Conclusion This study has demonstrated that it is feasible to create robust dose plans that combine an image-guided IC-IS-BT
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boost with an applicator-guided IMRT boost in patients with extensive residual disease at BT. With this technique, it was possible to deliver a high dose to the HR-CTV while respecting the OAR dose constraints. The clinical consequence of this dosimetric achievement was local control in all patients and some but at least acceptable morbidity.
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Acknowledgments Aarhus University Hospital was supported by research Grants from the Danish Cancer Society, Danish Council for Strategic Research, CIRRO-the Lundbeck Foundation Centre for Interventional Research in Radiation Oncology. Funding from the European Programme (FP7/2013-2016) under grant agreement no [ICT-2011.5.2] (DrTherapat) was received. References [1] P€ otter R, Kirisits C, Fidarova EF, et al. Present status and future of high-precision image guided adaptive brachytherapy for cervix carcinoma. Acta Oncol 2008;47:1325e1336. [2] Tanderup K, Georg D, Potter R, et al. Adaptive management of cervical cancer radiotherapy. Semin Radiat Oncol 2010;20:121e129. [3] Tanderup K, Nielsen SK, Nyvang GB, et al. From point A to the sculpted pear: MR image guidance significantly improves tumour dose and sparing of organs at risk in brachytherapy of cervical cancer. Radiother Oncol 2010;94:173e180. [4] Kirisits C, P€ otter 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;62:901e911. [5] Dimopoulos JC, Schard G, Berger D, et al. Systematic evaluation of MRI findings in different stages of treatment of cervical cancer: Potential of MRI on delineation of target, pathoanatomic structures, and organs at risk. Int J Radiat Oncol Biol Phys 2006;64:1380e1388. [6] Dimopoulos JC, Petrow P, Tanderup K, et al. Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (IV): Basic principles and parameters for MR imaging within the frame of image based adaptive cervix cancer brachytherapy. Radiother Oncol 2012; 103:113e122. [7] Lindegaard JC, Fokdal LU, Nielsen SK, et al. MRI-guided adaptive radiotherapy in locally advanced cervical cancer from a Nordic perspective. Acta Oncol 2013;52:1510e1519. [8] Nomden CN, de Leeuw AAC, Roesink JM, et al. 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. Radiother Oncol 2013;107:69e74. [9] P€ otter 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;83:148e155. [10] P€ otter R, Georg P, Dimopoulos JC, et al. Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer. Radiother Oncol 2011;100: 116e123. [11] Mazeron R, Gilmore J, Dumas I, et al. Adaptive 3D image-guided brachytherapy: A strong argument in the debate on systematic radical hysterectomy for locally advanced cervical cancer. Oncologist 2013; 18:415e422. [12] Dimopoulos JC, Lang S, Kirisits C, et al. Dose-volume histogram parameters and local tumor control in magnetic resonance image-guided
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cervical cancer brachytherapy. Int J Radiat Oncol Biol Phys 2009;75: 56e63. Dimopoulos JC, Potter R, Lang S, et al. Dose-effect relationship for local control of cervical cancer by magnetic resonance image-guided brachytherapy. Radiother Oncol 2009;93:311e315. Huang EY, Lin H, Hsu HC, et al. High external parametrial dose can increase the probability of radiation proctitis in patients with uterine cervix cancer. Gynecol Oncol 2000;79:406e410. Fenkell L, Assenholt MS, Nielsen SK, et al. Parametrial boost using midline shielding results in an unpredictable dose to tumor and organs at risk in combined external beam radiotherapy and brachytherapy for locally advanced cervical cancer. Int J Radiat Oncol Biol Phys 2010;79:1572e1579. Lindegaard JC, Tanderup K, Nielsen SK, et al. MRI-guided 3D optimization significantly improves DVH parameters of pulsed-dose-rate brachytherapy in locally advanced cervical cancer. Int J Radiat Oncol Biol Phys 2008;71:756e764. Fokdal L, Tanderup K, Hokland SB, et al. Clinical feasibility of combined intracavitary/interstitial brachytherapy in locally advanced cervical cancer employing MRI with a tandem/ring applicator in situ and virtual preplanning of the interstitial component. Radiother Oncol 2013;107:63e68. 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;66:83e90. J€urgenliemk-Schulz IM, Tersteeg RJ, Roesink JM, et al. MRI-guided treatment-planning optimization in intracavitary or combined intracavitary/interstitial PDR brachytherapy using tandem ovoid applicators in locally advanced cervical cancer. Radiother Oncol 2009;93:322e330. Assenholt MS, Petersen JB, Nielsen SK, et al. A dose planning study on applicator guided stereotactic IMRT boost in combination with 3D MRI based brachytherapy in locally advanced cervical cancer. Acta Oncol 2008;47:1337e1343. Mohamed S, Nielsen SK, Fokdal LU, et al. Feasibility of applying a single treatment plan for both fractions in PDR image guided brachytherapy in cervix cancer. Radiother Oncol 2013;107:32e38. Haie-Meder C, P€otter 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;74:235e245. Hellebust TP, Kirisits C, Berger D, et al. 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. Radiother Oncol 2010;96:153e160. Tanderup K, Potter R, Lindegaard JC, et al. PTV margins should not be used to compensate for uncertainties in 3D image guided intracavitary brachytherapy. Radiother Oncol 2010;97:495e500. Wolfson AH, bdel-Wahab M, Markoe AM, et al. A quantitative assessment of standard vs. customized midline shield construction for invasive cervical carcinoma. Int J Radiat Oncol Biol Phys 1997;37:237e242. Charra-Brunaud C, Harter V, Delannes M, et al. Impact of 3D imagebased PDR brachytherapy on outcome of patients treated for cervix carcinoma in France: Results of the French STIC prospective study. Radiother Oncol 2012;103:305e313. 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;65:624e630. Jhingran A. Potential advantages of intensity-modulated radiation therapy in gynecologic malignancies. Semin Radiat Oncol 2006;16: 144e151. Wolfson AH. Magnetic resonance imaging and positron-emission tomography imaging in the 21st century as tools for the evaluation
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and management of patients with invasive cervical carcinoma. Semin Radiat Oncol 2006;16:186e191. [30] Georg D, Kirisits C, Hillbrand M, et al. Image-guided radiotherapy for cervix cancer: High-tech external beam therapy versus hightech brachytherapy. Int J Radiat Oncol Biol Phys 2008;71: 1272e1278.
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[31] Han K, Milosevic M, Fyles A, et al. Trends in the utilization of brachytherapy in cervical cancer in the United States. Int J Radiat Oncol Biol Phys 2013;87:111e119. [32] Tanderup K, Eifel PJ, Yashar CM, et al. Curative radiation therapy for locally advanced cervical cancer: Brachytherapy is NOT optional. Int J Radiat Oncol Biol Phys 2014;88:537e539.
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Proof of principle: Applicator-guided stereotactic IMRT boost in combination with 3D MRI-based brachytherapy in locally advanced cervical cancer Marianne S. Assenholt1,*, Anne Vestergaard1, Jesper F. Kallehauge1, Sandy Mohamed2, Søren K. Nielsen1, Jørgen B. Petersen1, Lars Fokdal2, Jacob C. Lindegaard2, Kari Tanderup1,2,3 1
Department of Medical Physics, Aarhus University Hospital, Aarhus, Denmark 2 Department of Oncology, Aarhus University Hospital, Aarhus, Denmark 3 Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
ABSTRACT
PURPOSE: To describe a new technique involving high-precision stereotactic intensity-modulated radiation therapy (IMRT) boost in combination with intracavitary-interstitial (IC-IS) brachytherapy (BT) in cervical tumors that cannot be sufficiently covered by IC-IS-BT due to extensive residual disease and/or difficult topography at the time of BT. METHODS AND MATERIALS: Three patients with stage IIIB-IVA cervical cancer had significant residual disease at the time of BT. MRI-guided IC-IS-BT (pulsed-dose rate) was combined with a stereotactic IMRT boost guided according to the BT applicator in situ, using cone beam CT. The planning aim dose (total external beam radiotherapy and BT) for the high-risk clinical target volume (HR-CTV) was D90 O70e85 Gy, whereas constraints for organs at risk were D2cm3 !70 Gy for rectum, sigmoid, and bowel and !90 Gy for bladder in terms of equivalent total dose in 2 Gy fractions. An IMRT boost adapted to the BT dose distribution was optimized to target the regions poorly covered by BT. RESULTS: HR-CTV doses of D90 O81 Gy were obtained in the central HR-CTV and D90 O69 Gy in the distal regions of HR-CTV. Image-guided set up of the IMRT boost with the applicator in situ was feasible. The dose plans were robust to intra-fraction uncertainties of 3 mm. Local control with acceptable morbidity was obtained at a followup of 3, 2.5, and 1 year, respectively. CONCLUSIONS: The combination of MRI-guided BT with an applicator-guided stereotactic IMRT boost is feasible. This technique seems to be useful in the few cases where HR-CTV coverage cannot be obtained even with IS-IC-BT. Ó 2014 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Brachytherapy; MRI-guidance; Cervical cancer; IMRT boost; Applicator-guidance
Introduction Radiotherapy for cervical cancer typically combines external beam radiotherapy (EBRT) with a boost of intracavitary (IC) brachytherapy (BT). Major breakthroughs in Received 25 November 2013; received in revised form 27 January 2014; accepted 12 February 2014. Conflict of interest: The authors report no conflicts of interest. Dr. MSA reports grants from Danish Cancer Society, Danish Council for Strategic Research, CIRROdthe Lundbeck Foundation, FP7 ICT-2011.5.2, during the conduct of the study; grants from Varian, Nucletron, outside the submitted work. * Corresponding author. Aarhus University Hospital, Department of Medical Physics, Nørrebrogade 44, bygn. 5, 2. DK-8000 Aarhus C. Tel.: þ45-7846-4448; fax: þ45-7846-4522. E-mail address: [email protected] (M.S. Assenholt).
radiotherapy have recently been made with 3D imagee guided adaptive radiotherapy in locally advanced cervical cancer with application of CT and MRI at the time of BT (1, 2). Image guidance enables the delivery of high doses of radiation tailored selectively to the cancer target in both space and time domains (3e5). MRI offers excellent softtissue contrast, and MRI with the BT applicator in situ is advocated for 3D planning of BT (6). Excellent clinical results have been demonstrated with MRI-guided BT (7e11). However, tumors with significant residual disease and/or unfavorable topography after EBRT may still represent a therapeutic challenge. In these cases, it can be difficult to reach sufficient dose by IC-BT to the high-risk clinical target volume (HR-CTV) (12, 13). This problem is currently mainly addressed in two different
1538-4721/$ - see front matter Ó 2014 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2014.02.003
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ways: parametrial boost (PMB) or addition of an interstitial (IS) component to the basic IC applicator. Substantial additional morbidity has been reported with the use of PMB (14), and HR-CTV dose may still be compromised in large tumors despite application of PMB (15, 16). An alternative to PMB is to combine IC-BT with IS-BT (17e19). This technique offers the possibility to adapt the applicator to HR-CTV and thereby obtain a high dose to the tumor with no significant additional dose imposed on OAR. However, even with IS-IC-BT, the HRCTV dose may be insufficient for some tumors with large residual tumor/or challenging topography. A previous dose planning study (20) compared IC-BT, intracavitary-interstitial brachytherapy (IC-IS-BT), IC-IS-BT þ intensity-modulated radiation therapy (IMRT), and IMRT boost and found that in certain cases combined IC-IS-BT with a stereotactic IMRT boost may significantly improve the dose to tumor. The purpose of this study was to demonstrate, as proof of principle, that image-guided BT can be combined with a stereotactic IMRT boost in a robust way and improve target coverage of tumors with significant residual disease at the time of BT. Three patients have been treated with IC-IS-BT combined with an applicator-guided stereotactic IMRT boost. Methods and materials Three patients with locally advanced cervical cancer were selected in the period May 2009 until March 2012 for stereotactic IMRT boost treatment based on the clinical presentation at diagnosis and response to EBRT. Patient A had FIGO (International Federation of Obstetrics and Gynecology) Stage IVA disease with a tumor extending around and invading the entire circumference of the rectum. Patient B and C had FIGO Stage IIIB disease with massive parametrial infiltration and tumor extension to the pelvic wall as well as vaginal involvement. All tumors were squamous cell carcinomas. The ages of the patients were 71, 48, and 38 years, respectively, at the time of treatment. The overall treatment schedule is shown in Fig. 1. The patients received elective whole pelvis IMRT of 50 Gy in 30 fractions with a concomitant simultaneous integrated boost of 60 Gy to areas with pathologic enlarged lymph nodes. In Patients B and C a total of five cycles of concomitant weekly cisplatinum were prescribed. Patient A was treated with two cycles of neoadjuvant chemotherapy (cisplatinum, 5-Flouracile, and Ifosfamide). Due to impaired renal function, no further chemotherapy was prescribed during radiotherapy. At the time of BT, all patients had some tumor regression but HR-CTV was still large in Patient A (115 cm3) and C (77 cm3). In Patient B, HR-CTV was 36 cm3 but with a very unfavorable topography with lateral extension toward the pelvic wall. In Week 5, preplanning of BT and IMRT boost was performed (BT-IMRT0) involving a gynecologic examination
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under general anesthesia, insertion of a tandem ring applicator, and an MRI scan with the BT applicator in situ (17). The first application of pulsed-dose rate (PDR) BT with an IMRT boost was delivered in Week 6 (BT-IMRT1) and the second fraction in Week 7 (BT-IMRT2). CT and MR imaging, contouring, and dose planning was performed for both BT-IMRT1 and BT-IMRT2 to adapt the treatment to the patient anatomy and applicator position for each boost session. This is according to the common approach in image-guided adaptive BT, where imaging and adaptation is performed for each BT fraction to eliminate uncertainties related to application of the same treatment plan to different anatomies (21). Combined IC-IS-BT technique using 3e7 needles inserted through the ring cap in parallel to the tandem were used in all three patients for both BT implants used for treatment. For Patient B, a vaginal cylinder was also attached to the ring to facilitate vaginal irradiation. Vaginal gauze packing was performed in the patients without vaginal cylinder. An MRI scan (MRBT) was performed with the combined IC-IS ring applicator in situ (6). Directly after MRI, a CT scan (CTBT) was also obtained for EBRT dose calculation purposes. Following contouring and treatment planning (see below), PDR-BT was delivered in 15e17 hourly pulses. After a treatment gap of 4e6 h after the last pulse of BT, the patient was transferred to the accelerator (Varian Clinac [Varian Medical Systems, Inc., Palo Alto, CA] Patients A and B, and Varian TrueBeam Patient C) with the BT applicator still in situ and the stereotactic IMRT boost tailored to the BT dose distribution was delivered. The BT applicator was removed immediately after the IMRT boost. This procedure was repeated 1 week later at the second BT þ IMRT boost fraction (BT-IMRT2). The boost target for BT-IMRT was HR-CTV including the residual GTV, the whole cervix, and the presumed extra-cervical tumor extension at the time of BT (22). HR-CTV was defined based on MRI and clinical examination. OARs taken into account were rectum, sigmoid, bladder, and bowel. MRBT and CTBT were fused to transfer contours from MRI to CT. Applicator reconstruction was performed according to GEC ESTRO recommendations (23). Total EBRT and BT doses were evaluated in terms of equivalent dose in 2 Gy fractions (EQD2) by use of the monoexponential repair half-time model with a/b 5 10 Gy for tumor, a/b 5 3 Gy for normal tissue, and a repair half-time of 1.5 h. The tumor dose planning aim was individualized according to the disease burden and the proximity of OARs. HR-CTV was divided into two parts: 1) HR-CTVcentral, which was the central part of the target covered by the BT dose and 2) HR-CTVdistal extending into the BT low dose region. The planning aim (total EBRT þ BT) for HR-CTVcentral was D90 O 85 Gy EQD210 (EQD2 with a/b 5 10 Gy) for all patients. A lower dose was prescribed to HR-CTVdistal due to close proximity of the rectum, sigmoid, and bowel, respectively. For Patient
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Fig. 1. EBRT, BT, and IMRT boost schedule. EBRT 5 external beam radiotherapy; BT 5 brachytherapy; IMRT 5 intensity-modulated radiation therapy.
A, a dose of 70 Gy EQD210 was planned for D90 HRCTVdistal, which fully surrounded the rectum, which was then considered as both a target and OAR. For Patients B and C, a planning aim of 70e75 Gy EQD210 was applied to D90 HR-CTVdistal, which was extending to the pelvic wall. Planning aims for OAR D2cm3 were !90 Gy EQD23 for bladder and !70 Gy EQD23 for rectum, sigmoid, and bowel. It was assumed that the most exposed parts of OARs were exposed to the full whole pelvis EBRT dose of 50 Gy/30fx or 60 Gy/30fx in regions where this was relevant. No setup margins were added to HR-CTVcentral for BT treatment planning (24). For the IMRT boost, a 3 mm radial setup margin was used for HR-CTVdistal. The first step was to plan the BT boost. Manual dwell time optimization was performed with the aim to cover HR-CTVcentral while keeping dose OARs well below constraints to leave space for additional dose contribution from the IMRT boost. The individual dwell times in the needles were aimed to be less than 10%e20% of the tandem dwell times to maintain the major dose contribution from the intracavitary applicator. After BT planning, the volume that needed the additional boosting from the IMRT plan was identified. Due to BT dose gradients, the dose contribution from the IMRT boost varied significantly across the target to match the BT dose gradient. The biologic effect of a given total BT þ IMRT physical dose depended on the specific contribution of BT and IMRT because iso-effective dose depends on both fraction size and dose rate, which varies throughout the entire target volume, for example, a physical dose of 7 Gy from IMRT boost was equivalent to an EQD210 dose of 10 Gy, whereas a physical dose of 7 Gy from PDR BT was equivalent to an EQD210 of 7 Gy when delivered over 15 pulses. To take this into account, the target was divided into sectors (‘‘shells’’) according to BT dose contribution (Fig. 2). Four BT isodose curves were converted into contours and from Boolean operations four shells were
generated and represented regions with different IMRT dose planning aims. In the dose planning system (8.6.15, AAA calculation, Eclipse 8.2.23, Varian Medical Systems, Inc., Palo Alto, CA), each shell was optimized to a certain dose by inverse dose optimization. For evaluation of the dose plans, the software CERR (A Computational Environment for Radiotherapy Research, J.O. Deasy, St. Louis) and Matlab (The MathWorks, Inc., Natick, MA) was used to convert the physical 3D dose matrix for BT and IMRT into an EQD2 3D dose matrix. a/b Values of 10 Gy were assigned to voxels within the target volumes, and a/b values of 3 Gy were assigned in voxels outside target volumes. Three-dimension (3D) summations of EQD2 doses were then performed to obtain a total EQD2 3D dose matrix. Doseevolume histogram parameters were obtained from the EQD2 sum plan. The IMRT boost was guided by the BT applicator position by on board cone beam CT (cone beam computertomografi [CBCT]). CBCT was matched with CTBT according to the applicator position. Because the BT dose distribution is defined by the position of the applicator, this procedure ensured that the IMRT dose gradients were aligned with the BT dose gradients. Couch translation and rotation (yaw) was used to position the isocenter. There was no specific device used to control the angulation of the applicator except that the patient was positioned and rotated according to skin marks. However, residual rotations (roll and pitch) leading to deviations of O1e2 mm of the applicator position in CBCT as compared with the planning CT were not accepted. In this case, the patient was re-positioned, and a new CBCT was acquired. The bladder filling was controlled with a bladder catheter, so that the bladder was empty during PDR and during IMRT delivery. Rectum, sigmoid, and bowel movement was assessed visually on CBCT as far as possible according to CBCT image quality. The stability of the combined BT and IMRT boost toward geometric uncertainties was evaluated, to investigate whether
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Fig. 2. Transversal (a) and sagittal (b) MRI at the time of BT1 for Patient A. HR-CTVcentral and HR-CTVdistal are indicated in yellow and red, respectively. The isodose curves for BT1 divide the HR-CTVdistal into four shells indicated by the shaded areas. The blue line is PTV for HR-CTVdistal. HR-CTV 5 high-risk clinical target volume; BT 5 brachytherapy. (For interpretation of references to color in this figure legend, the reader is referred to the web version of this article.)
residual uncertainties in patient setup or intra-fraction movement could result in significant hot spots or cold spots in the junction zone between the BT and IMRT boost. The dosimetric impact of displacing the IMRT boost plan by 3 mm toward or away from the high-dose area in the BT boost plan was evaluated. The isocenter displacement was performed in the direction of the steepest dose gradients. The addition of the BT EQD2 dose and the shifted IMRT boost EQD2 dose was performed with the software described previously. The dose profiles across the intersection of the BT and the IMRT were evaluated as well as the doseevolume histogram for the HR-CTV and the OARs. After radiotherapy, patients were followed in the outpatient clinic with regular followup visits every third month the first year. Subsequently, they were seen every 6 months. At 3 months, MRI and positron emissions tomography CT were performed. MRI was routinely repeated at 12 months after the completion of treatment. The CTCSAE V.3.0 system was used to score the side effects. Results Dose planning and dose delivery were feasible for all three patients. The treatment was delivered in the planned time schedule for all treatments, and the patients were able to cooperate. The workload for each boost was approximately 8 h for a physicist for dose planning and delivering the IMRT boost, although there was a considerable learning curve and the treatment planning of the first patient was more time consuming. Adding to this, a radiation oncologist spent 2e3 h of additional work as compared with a normal BT. The minimum HR-CTV dose from IC-IS-BT was 2e3 Gy for each BT application in all patients. This would have corresponded to a total EBRT þ BT dose of 52e53 Gy EQD2 in the most distal region of HR-CTV if the stereotactic IMRT boost had not been applied. IMRT
doses up of 6e7 Gy per fraction were applied in HRCTVdistal. An example of a dose plan is shown in Fig. 3. Volumes and doses are listed in Table 1. HR-CTV doses were according to planning aims for Patients B and C, whereas Patient A received less HR-CTV dose due to the OAR priorities (rectum dose). Dose constraints for OARs were respected in all organs and patients, except for the rectal dose in Patient A. Table 2 shows the impact of 3 mm setup uncertainties or intra-fractional movements for the IMRT boost plan. Moving the IMRT boost plan 3 mm away from the tandem decreased the HR-CTVdistal dose with a maximum of 2.4 Gy (total EQD2). The highest increase in OAR dose was seen in the sigmoid and was 1.2 Gy (EQD2). Assessment of tumor control and morbidity was available at 3, 2.5, and 1 year, in Patients A, B, and C, respectively. In Patient A, the tumor was extending around the rectum resulting in a stenosis at the time of diagnosis. Before radiotherapy, a tumor stent was inserted into the rectum, and after termination of treatment the patient had a planned stoma. At 3-year followup, the patient had no evidence of recurrence. She still had the stoma, but apart from this, no other late effects that could be attributed to radiotherapy. In Patient B, no evidence of disease was found at 2.5 years of followup. Apart from vaginal stenosis Grade 1, no other late effects had been diagnosed. In Patient C, no evidence of disease was found at 1 year. This patient had Grade 1 rectal and bladder bleeding as well as diarrhea. Moreover Grade 2 cystitis and Grade 3 pelvic pain were diagnosed. The etiology of the pelvic pain was not known, but might be attributed to soft-tissue fibrosis. Discussion This study demonstrated that it was technically possible to combine a BT-boost with a high-precision IMRT boost.
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Fig. 3. MRI at the time of second BT for Patient B. (a) BT dose distribution (physical doses) for the combined IC-IS tandem/ring applicator in situ, minimum dose in colored area is 3 Gy. (b) Dose distribution (physical doses) for IMRT boost plan, minimum dose in colored area is 4 Gy. (c) The accumulated EQD2 dose for second boost. Minimum dose in colored area is 7 Gy EQD2. The dose heterogeneity seen at the distal border of HR-CTV is due to use of different a/b values in tumor and normal tissue. (d) EQD2 dose contribution from one fraction of BT and IMRT boosting and the accumulated dose. (For interpretation of references to color in this figure legend, the reader is referred to the web version of this article.)
It was feasible to use the LQ model (EQD2) to calculate the planning aim and the delivered dose for the combined BT and IMRT boost, and it was possible to deliver the treatment with a good clinical result. This boost combination improved the dose to the HR-CTV significantly without compromising the constraints for OARs. The dose distribution of the combined boost plan was stable within uncertainties of 3 mm, and the risk of significant cold and hot spots in the target and OARs were limited even if the patient would move 3 mm during the treatment. The minimum requirement for an institute to implement this technique is to have expertise in image-guided BT, IMRT dose planning, and CBCT image guidance. Boosting the parametria has traditionally been performed by EBRT PMB, often with the application of midline blocked fields (25). Fenkel et al. (15) has assessed this modality of midline blocked PMB with regard to
dosimetric performance and concluded that the midline blocked fields contribute substantial dose to the bladder, rectum, and sigmoid. Furthermore, the midline blocked PMB did not result in significant and predictable dose to HR-CTV. During the last decade, significant improvements in the treatment of locally advanced cervical cancer have been achieved with the introduction of 3D-image guidance (26). In particular, for large tumors, mono-institutional data indicate that it is possible to improve local control by using MR imageeguided BT (7, 9e11). MRI-guided BT involves individualization of the dose distribution with optimization of the dwell times in the intracavitary applicator as well as adaptation of the application itself with the addition of interstitial needles positioned through to the tandem/ring intracavitary applicator. From a geometric point of view, needle placement through the ring in
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Table 1 Volumes and total equivalent dose in 2 Gy fractions (EQD2) (whole pelvis external beam radiotherapy, brachytherapy and intensity-modulated radiation therapy boost), doseevolume histogram parameters for targets and organs at risk Volumes Volumes (cm3) HR-CTV (total) at BT1 HR-CTVcentral at BT1 HR-CTVdistal at BT1 Total doses, EQD2 (Gy) HR-CTVcentral D98 HR-CTVcentral D90 HR-CTVdistal D98 HR-CTVdistal D90 Bladder D2cm3 Rectum D2cm3 Sigmoid D2cm3
Patient A
Patient B
Patient C
115 55 60
36 23 13
77 68 9
82.2 86.8 70.1 71.2 73.0 68.9 70.2
78.7 88.0 70.7 71.2 81.2 67.0 67.4
74.1 80.7 69.3 69.7 75.6 78.3 70.7
HR-CTV 5 high-risk clinical target volume; BT 5 brachytherapy; EQD2 5 equivalent total dose in 2 Gy fractions.
parallel to the tandem provides about 10 mm additional coverage in the lateral part of the tumor, which corresponds to the inner two-thirds of the parametrium (27). To cover residual tumor in the distal parametria at the time of BT, it is necessary to use oblique or free needles that can be inserted in directions and angles that are not parallel to the tandem/ring applicator (17). In our current clinical experience, IS-BT is now a days added to IC-BT in ~50% of patients and more often in extensive disease where ~70% of patients with Stage IIIB, IVA, IVB disease receive IC-IS-BT (17). In a few patients with large tumors and unfavorable topography, it was not possible to cover HR-CTV with IC-IS-BT. In these patients, it was decided to provide an IMRT boost. In our experience, the administration of IC-IS-BT combined with an IMRT boost was performed in 3 patients out of 137 consecutive patients (2%) treated in our institution during the period 2009e2012. This was for a stage distribution of Stage IB-IIA 14%, IIB 56%, III-IV 30% (7). An alternative technique would be template-based BT with perineal interstitial needle implantation. However, for tumors reaching the pelvic wall, the long needle path and diverging needles may result in sub-optimal tumor Table 2 Mean over all patients and range of dose differences (equivalent dose in 2 Gy fractions), when moving the intensity-modulated radiation therapy boost plan 3 mm toward and away from tandem, respectively Volume
3 mm Toward tandem
3 mm Away from tandem
HR-CTVcentral D98 (Gy) HR-CTVcentral D90 (Gy) HR-CTVdistal D98 (Gy) HR-CTVdistal D90 (Gy) Rectum (Gy) Sigmoid (Gy) Bladder (Gy)
0.8 0.6 0.8 0.9 0.3 0.9 0.2
0.6 0.5 1.9 1.8 0.2 0.8 0.1
(0.4; 1) (0.4; 0.9) (0.4; 1.2) (0.6; 1.4) (0.8; 0.0) (1.7; 0.1) (0.3; 0.1)
(0.8; 0.4) (1.2; 0.0) (2.4; 1.2) (2.3; 1.4) (0.2; 0.8) (0.2; 1.2) (0.0; 0.2)
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coverage. Furthermore, it is assumed to be an advantage to apply as much dose as possible from an intracavitary component because the uterine cavity is known to be radioresistant. Radiobiological uncertainties may be significant when applying the linear quadratic model, in particular, in case of large doses per fraction. However, it is of importance to notice that the doses applied in the junction region between the BT and IMRT boosts were in the range of 2e10 Gy (PDR BT) and 2e7 Gy (IMRT), respectively. There is considerable clinical experience with similar dose levels from image-guided adaptive BT, where the same radiobiological assumptions have been used as in this study to estimate EQD2 doses. We did not apply fractional doses beyond levels normally applied in current clinical practice. It is likely of more importance that the patient treatments in this study involved an escalation of the volume irradiated to significant doses (O65e70 Gy). While the clinical effect of irradiation of small volumes to high doses is well known from cervix cancer brachytherapy, the clinical effect of volume escalation is less well known. Pelvic pain (frozen pelvis) has been described as a side effect following radiotherapy and may be related to large volumes irradiated to high or intermediate doses. Prompted by EBRT technological developments during the last decades, it has been speculated whether BT of the primary cervix tumor could be replaced by, for example, IMRT, stereotactic boost, or proton boost (28, 29). However, most of the published treatment planning studies have been based on non-optimized BT and have neglected that EBRT boosting volumes must be larger than BT volumes due to the need for application of appropriate PTV margins in EBRT (24, 30). Furthermore, these studies have not taken into account that the BT dose distribution in the target region is fundamentally different from a homogeneous IMRT dose distribution. In BT, 50% of the target is typically irradiated to more than 150% of prescribed dose, and this seems to be of utmost importance for local control. Recent planning studies comparing advanced BT with IMRT and proton irradiation conclude that BT is superior both of these modalities with regard to tumor and OAR dose (20, 30). In this context, it is of great concern that recent data show that the use of BT in cervix cancer seems to have declined in the United States during the last 25 years (31, 32). Lack of BT was correlated with a significant decrease in overall survival by O10%. Along these lines, it is important to note that the majority of the boost dose in our study is still delivered through the BT component, whereas the IMRT boost only adds dose in regions where BT dose would be compromised in the periphery. Conclusion This study has demonstrated that it is feasible to create robust dose plans that combine an image-guided IC-IS-BT
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boost with an applicator-guided IMRT boost in patients with extensive residual disease at BT. With this technique, it was possible to deliver a high dose to the HR-CTV while respecting the OAR dose constraints. The clinical consequence of this dosimetric achievement was local control in all patients and some but at least acceptable morbidity.
[13]
[14]
[15]
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