- Email: [email protected]
Point A vs. HR-CTV D90 in MRI-based cervical brachytherapy of small and large lesions
Brachytherapy
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(2016)
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Point A vs. HR-CTV D90 in MRI-based cervical brachytherapy of small and large lesions Grant Harmon1, Abbie Diak1, Steven M. Shea2, Joseph H. Yacoub2, William Small Jr.1, Matthew M. Harkenrider1,* 1
Department of Radiation Oncology, Loyola University, Chicago, IL 2 Department of Radiology, Loyola University, Chicago, IL
ABSTRACT
PURPOSE: To evaluate the dosimetric benefits of MRI-based brachytherapy in small and large high-risk clinical target volume (HR-CTV) in cervical cancer. METHODS AND MATERIALS: Twenty-eight fractions obtained from sixteen cervical cancer patients treated with MRI-based high-dose-rate brachytherapy with standard tandem and ovoid applicators were used; original fractions were optimized to HR-CTV D90. Fractions were separated based on the median volume into small and large (HR-CTV !25 cm3 or O25 cm3) lesion groups. Retrospective plans prescribed to Point A were created for each fraction. D0.1 cc, D2 cc, and International Commission of Radiation Unit and Measurements (ICRU) points were used to compare Point A vs. HR-CTV D90 plans for bladder, rectum, and sigmoid. RESULTS: In the small lesion group, Point A plans vs. HR-CTV D90 plans had significantly higher D0.1 cc, D2 cc, and ICRU points for bladder, rectum, and sigmoid ( p ! 0.05). In the large lesion group, there was no significant difference between Point A and HR-CTV D90 plans for D0.1 cc, D2 cc, and ICRU points to the organs at risk (OARs). CONCLUSIONS: The dosimetric advantages to OARs offered by MRI-based brachytherapy with prescription to HR-CTV D90 compared to Point A is most distinct for patients with smaller HR-CTV (!25 cm3). This study demonstrates sufficient tumor coverage with lower doses to OARs in HR-CTV D90 vs. Point A plans in the small lesion group. These improvements were not seen in the large lesion group, indicating a lesser dosimetric advantage of HR-CTV D90 compared to Point A planning when the cervical lesion is O25 cm3. Incorporation of interstitial needles for patients with larger HR-CTV is likely the best method to decrease dose to OARs and improve tumor coverage. Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
MRI-based brachytherapy; Cervical cancer; Point A; HR-CTV D90; Tumor size
Introduction A combination of concurrent chemotherapy and external beam radiation therapy (EBRT) with brachytherapy is standard of care in the treatment of advanced stages of cervical cancer (1e4). Brachytherapy represents an essential component of definitive radiation therapy for cervical cancer that has been shown to improve overall survival (5). In the past several years, cervical brachytherapy has evolved to integrate three dimensionalebased treatment
Received 22 June 2016; received in revised form 13 August 2016; accepted 25 August 2016. * Corresponding author. Loyola University Chicago, 2160 South 1st Avenue, Maywood, IL 60153. Tel.: (708)216-2575; fax: (708)216-6076. E-mail address: [email protected] (M.M. Harkenrider).
planning with improved local control and decreased toxicity compared to two-dimensional planning (6). CT scans have frequently been used for treatment planning due to their cost-effectiveness, ease of access, and ability to differentiate organs at risk (OARs). However, CT images are limited by poor soft tissue contrast and reduced ability to differentiate neoplastic tissue from normal soft tissue. This limits the ability to individualize dose distribution to patient tumor volume. Incorporating MRI into the radiotherapy planning process provides improved soft tissue contrast relative to CT imaging data, allowing for higher confidence in delineation of target volumes and OARs (7). Multiple studies have shown the imaging and dosimetric advantages of using MRI guidance in brachytherapy planning (8e12). MRI-based brachytherapy for gynecologic cancers has
1538-4721/$ - see front matter Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2016.08.010
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shifted the paradigm of radiation prescription planning from a more traditional point-based approach to one based on optimization of dose delivered to a target volume (7). Recommendations from the Groupe Europeen de Curietherapie and the European Society for Radiotherapy & Oncology (GEC-ESTRO) working group introduced new target volumes to receive prescribed doses, such as high-risk clinical target volume (HR-CTV), intermediaterisk clinical target volume, and gross tumor volume (13). Studies have shown that shifting from a point-based to a volume-based radiation prescription in MRI-based brachytherapy allows for dose reduction to OARs while maintaining therapeutic dose delivered to target volume (14). These efforts are being applied as an American Brachytherapy Society survey showed that MRI-based cervical brachytherapy and volume-based prescriptions are increasing in the United States (15). In this study, we investigate differences in MRI-based brachytherapy treatment planning for small and large HR-CTV when optimized to D90 (the minimum dose covering 90% of the volume) vs. Point A. Small HR-CTV may be overcovered and large HR-CTV may be undercovered if prescribing to Point A compared to HRCTV D90. We aim to quantify these differences to OARs for small and large HR-CTV. We compare tumor coverage and OAR dosage parameters in plans prescribed to Point A vs. plans optimized to HR-CTV D90 for patients with either small or large tumors at time of MRI-based brachytherapy.
Methods and materials In July 2014, we began an MRI-based brachytherapy program for cervical cancer at Loyola University Medical Center and enrolled patients on a prospective IRB approved study. This study reports on the first 16 histologically confirmed cervical cancer patients treated with MRI-based brachytherapy and volume-based prescriptions. Patients had varying stages of cervical cancer, ranging from Stage IB2 to IVB. All patients received EBRT to the whole pelvis paraaortic lymph node chain with a prescription dose of 45e50.4 Gy in 25e28 fractions. Our usual brachytherapy regimen is to perform two implants with two fractions delivered per implant (total four fractions) and MRI with the applicator in place at each implant. Brachytherapy planning process starts at 7 Gy per fraction to point A, and then, dose is optimized to maximize coverage of the HR-CTV and minimize dose to OARs according to the GEC-ESTRO guidelines (13). Our treatment goal was to deliver an HR-CTV D90 EQD2 (equivalent dose at 2 Gy per fraction) of $ 87 Gy (16). Brachytherapy doses for larger lesions tended to be lower than for smaller lesions to limit dose to OARs. Most patients received concurrent weekly cisplatin chemotherapy in combination with radiation.
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Treatment plans consisted of two implants with two fractions administered per implant per patient for 12 patients. Four patients had one implantation with all fractions delivered. In total, there were 28 implants for use in this project. Treatments for all patients employed an MRI-conditional tandem and ovoid applicator without interstitial needles. With the applicator in place, T2-weighted sequences were obtained in the paratransverse, parasagittal, and paracoronal planes with a 1.5 T MRI. We retrospectively created alternate plans to deliver the same prescribed dose to Point A by rescaling the plan and adjusting ovoid weighting (max vaginal surface dose) to match the initial plan. Contours of OARs were delineated according to Radiation Therapy Oncology Group atlas recommendations (17). The outer wall of the bladder, rectum, and sigmoid was contoured to include each organ lumen. In addition to organ delineation, both bladder and rectal International Commission of Radiation Unit and Measurements (ICRU) points were inserted (18). A medical physicist (AD) created each alternate plan, and an attending radiation oncologist (MMH) reviewed each plan to evaluate dose distribution, target volume and OAR delineation, and ICRU point identification. To determine how size of the HR-CTV affects dose distribution, patients were split into two equally sized groups dividing at the median volume: small volume (!25 cm3, N 5 14) and large volume (O25 cm3, N 5 14) of the HR-CTV. Dosimetric parameters were obtained using dose-volume histograms generated by the treatment planning software. The dosimetric parameters used to compare groups were HR-CTV D90, D100, and doses to OARs. OAR D0.1 cc and D2 cc (minimum dose to maximally irradiated 0.1 cc and 2 cc, respectively) were compared between Point A and HR-CTV plans for both small and large HR-CTV groups. To determine degree of tumor coverage in the Point A plans, the ratio of the HR-CTV D90 to the dose delivered to Point A in small vs. large HR-CTV plans was obtained. For statistical analysis, a Wilcoxon signed rank test was chosen to directly compare differences between HR-CTV D90 and Point A dosage parameters in both the small and large HR-CTV groups. For the target coverage ratio between small and large groups, an unpaired t test was used. A value of p ! 0.05 was set for statistical significance.
Results The characteristics of the patient population can be found in Table 1. A diagram of the distribution of treatment groups can be found in Fig. 1. The median HR-CTV volume for the entire cohort was 24.6 cm3. The median HR-CTV volumes were 14.8 cm3 for the small lesion group and 37.4 cm3 for the large lesion group.
G. Harmon et al. / Brachytherapy Table 1 Patient population characteristics Characteristic Patients Age (years) Histologic type Squamous cell carcinoma Adenocarcinoma FIGO stage IB2 IIAeIIB IIIAeIIIB IVAeIVB Chemotherapy Cisplatin Carboplatin No chemotherapy Chemotherapy cycles completed Tumor size at diagnosis (cm) HR-CTV (cm3) EBRT dose (Gy) HR-CTV D90 (Gy) EQD2 (Gy)
Median
Range
Total (n) 16
61
41e72 15 1 6 4 4 2 13 2 1
5 6.5 25 45 27 88.6
0e6 3.0e10.0 7.7e78.2 45e50.4 24.2e31.2 80.0e97.1
FIGO 5 Federation Internationale de Gynecologie et d’Obstetrique; HR-CTV 5 high-risk clinical target volume; EBRT 5 external beam radiation therapy; EQD2 5 equivalent total dose in 2-Gy fractions of EBRT þ BT dose to original HR-CTV D90 plansa/b510Gy.
The results of the dosage parameters for the small and large lesion groups can be found in Tables 2 and 3, respectively. For the small HR-CTV group, the plans prescribed to Point A had significantly higher doses to bladder, rectum, and sigmoid compared to HR-CTV D90
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plans in all parameters tested ( p ! 0.05). In addition, there was significantly higher dose to the HR-CTV D90 and D100 parameters ( p ! 0.05). In the large lesion group, there was no significant difference between Point A and HR-CTV D90 plans seen in dosage parameters to the bladder, rectum, or sigmoid (Table 3). There was also no significant difference in tumor coverage between Point A and HR-CTV D90 plans in the large lesion group. The mean ratio of the HR-CTV D90 dose to Point A dose was significantly larger in the small group (1.30) compared to the large group (0.96, p ! 0.01).
Discussion This study aimed to compare target volume coverage and OAR dose in high-dose-rate cervical brachytherapy in point-based plans vs. HR-CTV D90 plans for small and large cervical HR-CTV volumes. Though it reasons that prescribing dose to Point A for small and large tumors results in overcoverage and undercoverage, respectively, this has not been previously quantified. As the results demonstrate, the superiority of MRI-based brachytherapy prescribing to HR-CTV D90 is most pronounced in small lesions (!25 cm3). In the small lesion group, the HR-CTV D90 plans had significantly lower doses to all OARs, while still delivering the desired dose to the target volume (Table 2). A visual example of the differences in dose distribution in a Point A prescription plan is
Fig. 1. Distribution of patient population. Sixteen total patients, with a total of 28 fractions divided into small HR-CTV group (N 5 14) and large HR-CTV group (N 5 14). Both small and large HR-CTV groups had original plans optimized to HR-CTV D90 and retrospective plans created and prescribed to Point A. HR-CTV 5 high-risk clinical target volume.
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Table 2 Coverage and dosage parameters of plans prescribed to Point A vs. plans optimized to HR-CTV D90 in small HR-CTV group (HR-CTV ! 25 cm3)
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Table 3 Coverage and dosage parameters of plans prescribed to Point A vs. plans optimized to HR-CTV D90 in large HR-CTV group (HR-CTV O 25 cm3)
Small HR-CTV (!25 cm3) Dose volume histogram parameter HR-CTV D90 D100 Point A Bladder D2 cc D0.1 cc ICRU Rectum D2 cc D0.1 cc ICRU Sigmoid D2 cc D0.1 cc Max vaginal surface dose
Optimized to HR-CTV D90 (Gy) 7.6 0.5a 5.1 0.6 5.8 0.9
Prescription to Point A (Gy) 9.9 1.5 6.4 1.4 7.6 0.6a
Large HR-CTV (O25 cm3) p-Value 0.001 0.002 0.001
5.7 1.1 7.8 2.2 4.8 1.4
7.4 1.4 10.3 2.5 6.0 2.0
0.001 0.001 0.001
3.8 0.8 5.0 1.0 3.9 0.8
4.3 1.3 5.9 1.8 4.3 0.9
0.01 0.002 0.001
3.8 1.3 5.4 1.9 8.3 1.0
4.9 1.5 7.0 2.1 8.3 1.0
0.001 0.001 1.00
Dose volume histogram parameter HR-CTV D90 D100 Point A Bladder D2 cc D0.1 cc ICRU Rectum D2 cc D0.1 cc ICRU Sigmoid D2 cc D0.1 cc Max vaginal surface dose
Optimized to HR-CTV D90 (Gy)
Prescription to Point A (Gy)
p-Value
6.9 0.5a 4.2 0.9 7.4 1.3
6.7 1.7 4.1 1.5 6.9 0.6a
0.65 0.76 0.38
6.3 1.4 8.7 2.6 5.6 2.0
6.3 2.0 8.7 3.8 5.7 2.6
0.78 0.92 0.78
3.9 0.7 5.2 1.1 3.8 0.9
3.9 0.9 5.4 1.6 3.7 1.3
0.76 0.61 0.65
3.9 1.1 5.1 1.5 8.9 1.1
3.7 1.3 5.0 1.7 8.9 1.1
0.7 0.62 1.00
HR-CTV 5 high-risk clinical target volume; ICRU 5 International Commission of Radiation Unit and Measurements. Values depicted are group mean SD. Statistical significance determined by Wilcoxon signed rank test, with significance set at p-value ! 0.05. a Plan prescription dose.
HR-CTV 5 high-risk clinical target volume; ICRU 5 International Commission of Radiation Unit and Measurements. Values depicted are group mean SD. Statistical significance determined by Wilcoxon signed rank test, with significance set at p-Value ! 0.05. a Plan prescription dose.
depicted in Fig. 2. The Point A plans also had significantly higher dose values to HR-CTV D90dmuch higher doses than the desired prescribed dose. This is evident by the mean ratio of HR-CTV D90:Point A dose of 1.30 in the Point A plans, indicating overcoverage of 30%. In the large lesion group, the comparison of Point A vs. HR-CTV D90 prescribed plans was less definitive. No statistically significant differences in dosage to OARs were seen in Point A vs. HR-CTV D90 plans. A visual representation of the differences in dose distribution is depicted in Fig. 3. The mean ratio of HR-CTV D90:Point A was 0.96 in the Point A plans, indicating that the dose to Point A and the dose to HR-CTV D90 did not differ. It is this group of patients where a combined intracavitaryinterstitial applicator has its greatest benefit (19e22). Brabandere et al. performed a study that had similar results for the advantages of MRI vs. conventional point-based brachytherapy of the cervix though, conversely to our study, they prescribed to Point A with pulsed-doserate brachytherapy and retrospectively created plans optimized to HR-CTV D90. They found lower doses to the bladder, rectum, and sigmoid while increasing HR-CTV D90. Results showed an average increase of 3 Gy to HR-CTV D90 in all MRI plans, with an average D2 cc reduction in bladder and sigmoid doses by 7 Gy and 7 Gy, respectively (23). A similar study by Zwhalen et al. examined 20 patients who underwent conventional, Point A-prescribed pulseddose-rate brachytherapy to the cervix and developed
alternate plans optimized using MRI. Analysis of the plans revealed that the MRI optimized plans had a higher mean percentage tumor volume treated to $ 100% of prescribed dose when compared to conventional plans. In addition, the study showed that MRI-based plans maintained tumor coverage while reducing dose to the bladder, rectum, and sigmoid, with a reduction of 12e32% compared to conventional two-dimensional brachytherapy planning. This relationship was most significant in smaller tumors (smaller than median HR-CTV size of 16 cm3)(24). This difference between target volume size at diagnosis and/or at brachytherapy has been investigated clinically by other groups. Mazeron et al. (25) described that patients with larger HR-CTV (O30 cm3) at diagnosis had increased rate of local failure, though this could be overcome by escalation of the HR-CTV and intermediate-risk clinical target volume D90. Dimopoulos et al. studied initial maximum dimension of the gross tumor volume and HR-CTV compared to maximum dimension at the time of brachytherapy. They found that favorable response to EBRT and greater D90 and D100 for large lesions predicted for improved local control (22). In a recent analysis from the retro EMBRACE study, Fokdal et al. compared intracavitary vs. intracavitary/interstitial hybrid approach in patients with locally advanced cervical cancer. They found intracavitary/interstitial applicators increased the mean HR-CTV D90 from 83 Gy to 92 Gy, with no difference in doses to OARs. Local control was 10% higher in patients with a large HR-CTV (O30 cm3), with no
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Fig. 2. Treatment plan images from a patient from small HR-CTV group (HR-CTV 5 8.2 cm3). (a) Sagittal image with dose optimized to HR-CTV D90. (b) Sagittal image with dose prescribed to Point A. (c) Axial image with dose optimized to HR-CTV D90. (d) Axial image with dose prescribed to Point A. Structure 1 5 HR-CTV. Structure 2 5 bladder. Structure 3 5 rectum. Structure 4 5 sigmoid. Isodose lines 5 150%, 100%, and 70% of prescribed dose. HR-CTV 5 high-risk clinical target volume.
significant differences in late toxicities (26). Potter et al. (27) reported outcomes of patients treated with or without MRI-guided adaptive brachytherapy and showed that MRI-guided adaptive brachytherapy patients had a relative reduction in pelvic recurrence and reduced rates of severe morbidity. Other groups with limited access to MRI perform the MRI before first implant or at first implant only as a way to use the benefits of MRI-based treatment planning (28, 29). Our results demonstrate that dosimetric advantages to normal surrounding tissue, when using MRI to optimize dose to HR-CTV D90, are more pronounced for smaller target volumes. However, there are some inherent limitations of this study. The patient numbers are relatively low because the MRI-based brachytherapy program has been in place for only 2 years. The need to retrospectively generate plans to Point A is an unavoidable limitation because the patients on this study were all optimized to HR-CTV D90, and Point A has less clinical relevance with MRI-based treatment planning. All patients included on this study did not have interstitial needles incorporated into their implants. Incorporation of needles is an important way to escalate dose to the target and/or decrease dose to OAR for larger HR-CTV volumes by reducing weighting of the tandem and ovoids.
This study is one of the first to quantify the doses to OAR with MRI-based brachytherapy when dose is optimized to HR-CTV D90 compared to Point A. Based on the dosimetric results of this study, the advantages are greatest when the HR-CTV is smaller. Prescribing to the HR-CTV D90 rather than Point A in this situation prevents overdosing and reduces unnecessary irradiation to the OAR. For the large tumor group, the lack of significant differences in dosage parameters in Point A vs. HR-CTV D90 groups indicates that dosimetric advantages of MRI planning are less pronounced in larger target volumes though a difference may be realized when needles are incorporated into the implant. Using this data and those from other groups as described, our institutional standard is to use intracavitary only implants for smaller HR-CTV and incorporate interstitial needles using a hybrid applicator for patients with large HR-CTV, parametrial or pelvic sidewall extension, initial bulky disease, and/or poor response to EBRT.
Conclusions The results obtained in this study indicate that MRIbased brachytherapy with dose optimized to HR-CTV D90
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Fig. 3. Treatment plan images from a patient from large HR-CTV group (HR-CTV 5 77.3 cm3). (a) Sagittal image with dose optimized to HR-CTV D90. (b) Sagittal image with dose prescribed to Point A. (c) Axial image with dose optimized to HR-CTV D90. (d) Axial image with dose prescribed to Point A. Structure 1 5 HR-CTV. Structure 2 5 bladder. Structure 3 5 rectum. Structure 4 5 sigmoid. Isodose lines 5 150%, 100%, and 70% of prescribed dose. HR-CTV 5 high-risk clinical target volume.
offers dosimetric benefits to OARs and ensures accuracy of dose to the target volume in smaller HR-CTV compared to treatment plans to Point A. To obtain similar benefits to OAR and target volume coverage for patients with larger HR-CTV likely requires incorporation of interstitial needles.
[6]
[7]
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brachytherapy treatment in locally advanced cervical cancer. Int J Radiat Oncol Biol Phys 2012;82:1424e1430. Dimopoulos JC, P€otter 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. Brabandere M, Mousa A, Nulens A, et al. Potential of dose optimization in MRI-based PDR brachytherapy of cervix carcinoma. Radiother Oncol 2008;88:217e226. Zwahlen D, Jezioranski J, Chan P, et al. Magnetic resonance imaging-guided intracavitary brachytherapy for cancer of the cervix. Int J Radiat Oncol Biol Phys 2009;74:1157e1164. Mazeron R, Castelnau-Marchand P, Dumas I, et al. Impact of treatment time and dose escalation on local control in locally advanced cervical cancer treated by chemoradiation and image-guided pulsed-dose rate adaptive brachytherapy. Radiother Oncol 2015;114:257e263. Fokdal L, Sturdza A, Mazeron R, et al. Image guided adaptive brachytherapy with combined intracavitary and interstitial technique improves the therapeutic ratio in locally advanced cervical cancer: Analysis from the retroEMBRACE study. Radiother Oncol 2016;0: 305e313. 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. Choong ES, Bownes P, Musunuru HB, et al. Hybrid (CT/MRI based) vs. MRI only based image-guided brachytherapy in cervical cancer: Dosimetry comparisons and clinical outcome. Brachytherapy 2016; 15:40e48. Trifiletti D, Libby B, Feuerlein S, et al. Implementing MRI-based target delineation for cervical cancer treatment within a rapid workflow environment for image-guided brachytherapy: A practical approach for centers without in-room MRI. Brachytherapy 2015; 14:905e909.
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Point A vs. HR-CTV D90 in MRI-based cervical brachytherapy of small and large lesions Grant Harmon1, Abbie Diak1, Steven M. Shea2, Joseph H. Yacoub2, William Small Jr.1, Matthew M. Harkenrider1,* 1
Department of Radiation Oncology, Loyola University, Chicago, IL 2 Department of Radiology, Loyola University, Chicago, IL
ABSTRACT
PURPOSE: To evaluate the dosimetric benefits of MRI-based brachytherapy in small and large high-risk clinical target volume (HR-CTV) in cervical cancer. METHODS AND MATERIALS: Twenty-eight fractions obtained from sixteen cervical cancer patients treated with MRI-based high-dose-rate brachytherapy with standard tandem and ovoid applicators were used; original fractions were optimized to HR-CTV D90. Fractions were separated based on the median volume into small and large (HR-CTV !25 cm3 or O25 cm3) lesion groups. Retrospective plans prescribed to Point A were created for each fraction. D0.1 cc, D2 cc, and International Commission of Radiation Unit and Measurements (ICRU) points were used to compare Point A vs. HR-CTV D90 plans for bladder, rectum, and sigmoid. RESULTS: In the small lesion group, Point A plans vs. HR-CTV D90 plans had significantly higher D0.1 cc, D2 cc, and ICRU points for bladder, rectum, and sigmoid ( p ! 0.05). In the large lesion group, there was no significant difference between Point A and HR-CTV D90 plans for D0.1 cc, D2 cc, and ICRU points to the organs at risk (OARs). CONCLUSIONS: The dosimetric advantages to OARs offered by MRI-based brachytherapy with prescription to HR-CTV D90 compared to Point A is most distinct for patients with smaller HR-CTV (!25 cm3). This study demonstrates sufficient tumor coverage with lower doses to OARs in HR-CTV D90 vs. Point A plans in the small lesion group. These improvements were not seen in the large lesion group, indicating a lesser dosimetric advantage of HR-CTV D90 compared to Point A planning when the cervical lesion is O25 cm3. Incorporation of interstitial needles for patients with larger HR-CTV is likely the best method to decrease dose to OARs and improve tumor coverage. Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
MRI-based brachytherapy; Cervical cancer; Point A; HR-CTV D90; Tumor size
Introduction A combination of concurrent chemotherapy and external beam radiation therapy (EBRT) with brachytherapy is standard of care in the treatment of advanced stages of cervical cancer (1e4). Brachytherapy represents an essential component of definitive radiation therapy for cervical cancer that has been shown to improve overall survival (5). In the past several years, cervical brachytherapy has evolved to integrate three dimensionalebased treatment
Received 22 June 2016; received in revised form 13 August 2016; accepted 25 August 2016. * Corresponding author. Loyola University Chicago, 2160 South 1st Avenue, Maywood, IL 60153. Tel.: (708)216-2575; fax: (708)216-6076. E-mail address: [email protected] (M.M. Harkenrider).
planning with improved local control and decreased toxicity compared to two-dimensional planning (6). CT scans have frequently been used for treatment planning due to their cost-effectiveness, ease of access, and ability to differentiate organs at risk (OARs). However, CT images are limited by poor soft tissue contrast and reduced ability to differentiate neoplastic tissue from normal soft tissue. This limits the ability to individualize dose distribution to patient tumor volume. Incorporating MRI into the radiotherapy planning process provides improved soft tissue contrast relative to CT imaging data, allowing for higher confidence in delineation of target volumes and OARs (7). Multiple studies have shown the imaging and dosimetric advantages of using MRI guidance in brachytherapy planning (8e12). MRI-based brachytherapy for gynecologic cancers has
1538-4721/$ - see front matter Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2016.08.010
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shifted the paradigm of radiation prescription planning from a more traditional point-based approach to one based on optimization of dose delivered to a target volume (7). Recommendations from the Groupe Europeen de Curietherapie and the European Society for Radiotherapy & Oncology (GEC-ESTRO) working group introduced new target volumes to receive prescribed doses, such as high-risk clinical target volume (HR-CTV), intermediaterisk clinical target volume, and gross tumor volume (13). Studies have shown that shifting from a point-based to a volume-based radiation prescription in MRI-based brachytherapy allows for dose reduction to OARs while maintaining therapeutic dose delivered to target volume (14). These efforts are being applied as an American Brachytherapy Society survey showed that MRI-based cervical brachytherapy and volume-based prescriptions are increasing in the United States (15). In this study, we investigate differences in MRI-based brachytherapy treatment planning for small and large HR-CTV when optimized to D90 (the minimum dose covering 90% of the volume) vs. Point A. Small HR-CTV may be overcovered and large HR-CTV may be undercovered if prescribing to Point A compared to HRCTV D90. We aim to quantify these differences to OARs for small and large HR-CTV. We compare tumor coverage and OAR dosage parameters in plans prescribed to Point A vs. plans optimized to HR-CTV D90 for patients with either small or large tumors at time of MRI-based brachytherapy.
Methods and materials In July 2014, we began an MRI-based brachytherapy program for cervical cancer at Loyola University Medical Center and enrolled patients on a prospective IRB approved study. This study reports on the first 16 histologically confirmed cervical cancer patients treated with MRI-based brachytherapy and volume-based prescriptions. Patients had varying stages of cervical cancer, ranging from Stage IB2 to IVB. All patients received EBRT to the whole pelvis paraaortic lymph node chain with a prescription dose of 45e50.4 Gy in 25e28 fractions. Our usual brachytherapy regimen is to perform two implants with two fractions delivered per implant (total four fractions) and MRI with the applicator in place at each implant. Brachytherapy planning process starts at 7 Gy per fraction to point A, and then, dose is optimized to maximize coverage of the HR-CTV and minimize dose to OARs according to the GEC-ESTRO guidelines (13). Our treatment goal was to deliver an HR-CTV D90 EQD2 (equivalent dose at 2 Gy per fraction) of $ 87 Gy (16). Brachytherapy doses for larger lesions tended to be lower than for smaller lesions to limit dose to OARs. Most patients received concurrent weekly cisplatin chemotherapy in combination with radiation.
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Treatment plans consisted of two implants with two fractions administered per implant per patient for 12 patients. Four patients had one implantation with all fractions delivered. In total, there were 28 implants for use in this project. Treatments for all patients employed an MRI-conditional tandem and ovoid applicator without interstitial needles. With the applicator in place, T2-weighted sequences were obtained in the paratransverse, parasagittal, and paracoronal planes with a 1.5 T MRI. We retrospectively created alternate plans to deliver the same prescribed dose to Point A by rescaling the plan and adjusting ovoid weighting (max vaginal surface dose) to match the initial plan. Contours of OARs were delineated according to Radiation Therapy Oncology Group atlas recommendations (17). The outer wall of the bladder, rectum, and sigmoid was contoured to include each organ lumen. In addition to organ delineation, both bladder and rectal International Commission of Radiation Unit and Measurements (ICRU) points were inserted (18). A medical physicist (AD) created each alternate plan, and an attending radiation oncologist (MMH) reviewed each plan to evaluate dose distribution, target volume and OAR delineation, and ICRU point identification. To determine how size of the HR-CTV affects dose distribution, patients were split into two equally sized groups dividing at the median volume: small volume (!25 cm3, N 5 14) and large volume (O25 cm3, N 5 14) of the HR-CTV. Dosimetric parameters were obtained using dose-volume histograms generated by the treatment planning software. The dosimetric parameters used to compare groups were HR-CTV D90, D100, and doses to OARs. OAR D0.1 cc and D2 cc (minimum dose to maximally irradiated 0.1 cc and 2 cc, respectively) were compared between Point A and HR-CTV plans for both small and large HR-CTV groups. To determine degree of tumor coverage in the Point A plans, the ratio of the HR-CTV D90 to the dose delivered to Point A in small vs. large HR-CTV plans was obtained. For statistical analysis, a Wilcoxon signed rank test was chosen to directly compare differences between HR-CTV D90 and Point A dosage parameters in both the small and large HR-CTV groups. For the target coverage ratio between small and large groups, an unpaired t test was used. A value of p ! 0.05 was set for statistical significance.
Results The characteristics of the patient population can be found in Table 1. A diagram of the distribution of treatment groups can be found in Fig. 1. The median HR-CTV volume for the entire cohort was 24.6 cm3. The median HR-CTV volumes were 14.8 cm3 for the small lesion group and 37.4 cm3 for the large lesion group.
G. Harmon et al. / Brachytherapy Table 1 Patient population characteristics Characteristic Patients Age (years) Histologic type Squamous cell carcinoma Adenocarcinoma FIGO stage IB2 IIAeIIB IIIAeIIIB IVAeIVB Chemotherapy Cisplatin Carboplatin No chemotherapy Chemotherapy cycles completed Tumor size at diagnosis (cm) HR-CTV (cm3) EBRT dose (Gy) HR-CTV D90 (Gy) EQD2 (Gy)
Median
Range
Total (n) 16
61
41e72 15 1 6 4 4 2 13 2 1
5 6.5 25 45 27 88.6
0e6 3.0e10.0 7.7e78.2 45e50.4 24.2e31.2 80.0e97.1
FIGO 5 Federation Internationale de Gynecologie et d’Obstetrique; HR-CTV 5 high-risk clinical target volume; EBRT 5 external beam radiation therapy; EQD2 5 equivalent total dose in 2-Gy fractions of EBRT þ BT dose to original HR-CTV D90 plansa/b510Gy.
The results of the dosage parameters for the small and large lesion groups can be found in Tables 2 and 3, respectively. For the small HR-CTV group, the plans prescribed to Point A had significantly higher doses to bladder, rectum, and sigmoid compared to HR-CTV D90
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plans in all parameters tested ( p ! 0.05). In addition, there was significantly higher dose to the HR-CTV D90 and D100 parameters ( p ! 0.05). In the large lesion group, there was no significant difference between Point A and HR-CTV D90 plans seen in dosage parameters to the bladder, rectum, or sigmoid (Table 3). There was also no significant difference in tumor coverage between Point A and HR-CTV D90 plans in the large lesion group. The mean ratio of the HR-CTV D90 dose to Point A dose was significantly larger in the small group (1.30) compared to the large group (0.96, p ! 0.01).
Discussion This study aimed to compare target volume coverage and OAR dose in high-dose-rate cervical brachytherapy in point-based plans vs. HR-CTV D90 plans for small and large cervical HR-CTV volumes. Though it reasons that prescribing dose to Point A for small and large tumors results in overcoverage and undercoverage, respectively, this has not been previously quantified. As the results demonstrate, the superiority of MRI-based brachytherapy prescribing to HR-CTV D90 is most pronounced in small lesions (!25 cm3). In the small lesion group, the HR-CTV D90 plans had significantly lower doses to all OARs, while still delivering the desired dose to the target volume (Table 2). A visual example of the differences in dose distribution in a Point A prescription plan is
Fig. 1. Distribution of patient population. Sixteen total patients, with a total of 28 fractions divided into small HR-CTV group (N 5 14) and large HR-CTV group (N 5 14). Both small and large HR-CTV groups had original plans optimized to HR-CTV D90 and retrospective plans created and prescribed to Point A. HR-CTV 5 high-risk clinical target volume.
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Table 2 Coverage and dosage parameters of plans prescribed to Point A vs. plans optimized to HR-CTV D90 in small HR-CTV group (HR-CTV ! 25 cm3)
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Table 3 Coverage and dosage parameters of plans prescribed to Point A vs. plans optimized to HR-CTV D90 in large HR-CTV group (HR-CTV O 25 cm3)
Small HR-CTV (!25 cm3) Dose volume histogram parameter HR-CTV D90 D100 Point A Bladder D2 cc D0.1 cc ICRU Rectum D2 cc D0.1 cc ICRU Sigmoid D2 cc D0.1 cc Max vaginal surface dose
Optimized to HR-CTV D90 (Gy) 7.6 0.5a 5.1 0.6 5.8 0.9
Prescription to Point A (Gy) 9.9 1.5 6.4 1.4 7.6 0.6a
Large HR-CTV (O25 cm3) p-Value 0.001 0.002 0.001
5.7 1.1 7.8 2.2 4.8 1.4
7.4 1.4 10.3 2.5 6.0 2.0
0.001 0.001 0.001
3.8 0.8 5.0 1.0 3.9 0.8
4.3 1.3 5.9 1.8 4.3 0.9
0.01 0.002 0.001
3.8 1.3 5.4 1.9 8.3 1.0
4.9 1.5 7.0 2.1 8.3 1.0
0.001 0.001 1.00
Dose volume histogram parameter HR-CTV D90 D100 Point A Bladder D2 cc D0.1 cc ICRU Rectum D2 cc D0.1 cc ICRU Sigmoid D2 cc D0.1 cc Max vaginal surface dose
Optimized to HR-CTV D90 (Gy)
Prescription to Point A (Gy)
p-Value
6.9 0.5a 4.2 0.9 7.4 1.3
6.7 1.7 4.1 1.5 6.9 0.6a
0.65 0.76 0.38
6.3 1.4 8.7 2.6 5.6 2.0
6.3 2.0 8.7 3.8 5.7 2.6
0.78 0.92 0.78
3.9 0.7 5.2 1.1 3.8 0.9
3.9 0.9 5.4 1.6 3.7 1.3
0.76 0.61 0.65
3.9 1.1 5.1 1.5 8.9 1.1
3.7 1.3 5.0 1.7 8.9 1.1
0.7 0.62 1.00
HR-CTV 5 high-risk clinical target volume; ICRU 5 International Commission of Radiation Unit and Measurements. Values depicted are group mean SD. Statistical significance determined by Wilcoxon signed rank test, with significance set at p-value ! 0.05. a Plan prescription dose.
HR-CTV 5 high-risk clinical target volume; ICRU 5 International Commission of Radiation Unit and Measurements. Values depicted are group mean SD. Statistical significance determined by Wilcoxon signed rank test, with significance set at p-Value ! 0.05. a Plan prescription dose.
depicted in Fig. 2. The Point A plans also had significantly higher dose values to HR-CTV D90dmuch higher doses than the desired prescribed dose. This is evident by the mean ratio of HR-CTV D90:Point A dose of 1.30 in the Point A plans, indicating overcoverage of 30%. In the large lesion group, the comparison of Point A vs. HR-CTV D90 prescribed plans was less definitive. No statistically significant differences in dosage to OARs were seen in Point A vs. HR-CTV D90 plans. A visual representation of the differences in dose distribution is depicted in Fig. 3. The mean ratio of HR-CTV D90:Point A was 0.96 in the Point A plans, indicating that the dose to Point A and the dose to HR-CTV D90 did not differ. It is this group of patients where a combined intracavitaryinterstitial applicator has its greatest benefit (19e22). Brabandere et al. performed a study that had similar results for the advantages of MRI vs. conventional point-based brachytherapy of the cervix though, conversely to our study, they prescribed to Point A with pulsed-doserate brachytherapy and retrospectively created plans optimized to HR-CTV D90. They found lower doses to the bladder, rectum, and sigmoid while increasing HR-CTV D90. Results showed an average increase of 3 Gy to HR-CTV D90 in all MRI plans, with an average D2 cc reduction in bladder and sigmoid doses by 7 Gy and 7 Gy, respectively (23). A similar study by Zwhalen et al. examined 20 patients who underwent conventional, Point A-prescribed pulseddose-rate brachytherapy to the cervix and developed
alternate plans optimized using MRI. Analysis of the plans revealed that the MRI optimized plans had a higher mean percentage tumor volume treated to $ 100% of prescribed dose when compared to conventional plans. In addition, the study showed that MRI-based plans maintained tumor coverage while reducing dose to the bladder, rectum, and sigmoid, with a reduction of 12e32% compared to conventional two-dimensional brachytherapy planning. This relationship was most significant in smaller tumors (smaller than median HR-CTV size of 16 cm3)(24). This difference between target volume size at diagnosis and/or at brachytherapy has been investigated clinically by other groups. Mazeron et al. (25) described that patients with larger HR-CTV (O30 cm3) at diagnosis had increased rate of local failure, though this could be overcome by escalation of the HR-CTV and intermediate-risk clinical target volume D90. Dimopoulos et al. studied initial maximum dimension of the gross tumor volume and HR-CTV compared to maximum dimension at the time of brachytherapy. They found that favorable response to EBRT and greater D90 and D100 for large lesions predicted for improved local control (22). In a recent analysis from the retro EMBRACE study, Fokdal et al. compared intracavitary vs. intracavitary/interstitial hybrid approach in patients with locally advanced cervical cancer. They found intracavitary/interstitial applicators increased the mean HR-CTV D90 from 83 Gy to 92 Gy, with no difference in doses to OARs. Local control was 10% higher in patients with a large HR-CTV (O30 cm3), with no
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Fig. 2. Treatment plan images from a patient from small HR-CTV group (HR-CTV 5 8.2 cm3). (a) Sagittal image with dose optimized to HR-CTV D90. (b) Sagittal image with dose prescribed to Point A. (c) Axial image with dose optimized to HR-CTV D90. (d) Axial image with dose prescribed to Point A. Structure 1 5 HR-CTV. Structure 2 5 bladder. Structure 3 5 rectum. Structure 4 5 sigmoid. Isodose lines 5 150%, 100%, and 70% of prescribed dose. HR-CTV 5 high-risk clinical target volume.
significant differences in late toxicities (26). Potter et al. (27) reported outcomes of patients treated with or without MRI-guided adaptive brachytherapy and showed that MRI-guided adaptive brachytherapy patients had a relative reduction in pelvic recurrence and reduced rates of severe morbidity. Other groups with limited access to MRI perform the MRI before first implant or at first implant only as a way to use the benefits of MRI-based treatment planning (28, 29). Our results demonstrate that dosimetric advantages to normal surrounding tissue, when using MRI to optimize dose to HR-CTV D90, are more pronounced for smaller target volumes. However, there are some inherent limitations of this study. The patient numbers are relatively low because the MRI-based brachytherapy program has been in place for only 2 years. The need to retrospectively generate plans to Point A is an unavoidable limitation because the patients on this study were all optimized to HR-CTV D90, and Point A has less clinical relevance with MRI-based treatment planning. All patients included on this study did not have interstitial needles incorporated into their implants. Incorporation of needles is an important way to escalate dose to the target and/or decrease dose to OAR for larger HR-CTV volumes by reducing weighting of the tandem and ovoids.
This study is one of the first to quantify the doses to OAR with MRI-based brachytherapy when dose is optimized to HR-CTV D90 compared to Point A. Based on the dosimetric results of this study, the advantages are greatest when the HR-CTV is smaller. Prescribing to the HR-CTV D90 rather than Point A in this situation prevents overdosing and reduces unnecessary irradiation to the OAR. For the large tumor group, the lack of significant differences in dosage parameters in Point A vs. HR-CTV D90 groups indicates that dosimetric advantages of MRI planning are less pronounced in larger target volumes though a difference may be realized when needles are incorporated into the implant. Using this data and those from other groups as described, our institutional standard is to use intracavitary only implants for smaller HR-CTV and incorporate interstitial needles using a hybrid applicator for patients with large HR-CTV, parametrial or pelvic sidewall extension, initial bulky disease, and/or poor response to EBRT.
Conclusions The results obtained in this study indicate that MRIbased brachytherapy with dose optimized to HR-CTV D90
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Fig. 3. Treatment plan images from a patient from large HR-CTV group (HR-CTV 5 77.3 cm3). (a) Sagittal image with dose optimized to HR-CTV D90. (b) Sagittal image with dose prescribed to Point A. (c) Axial image with dose optimized to HR-CTV D90. (d) Axial image with dose prescribed to Point A. Structure 1 5 HR-CTV. Structure 2 5 bladder. Structure 3 5 rectum. Structure 4 5 sigmoid. Isodose lines 5 150%, 100%, and 70% of prescribed dose. HR-CTV 5 high-risk clinical target volume.
offers dosimetric benefits to OARs and ensures accuracy of dose to the target volume in smaller HR-CTV compared to treatment plans to Point A. To obtain similar benefits to OAR and target volume coverage for patients with larger HR-CTV likely requires incorporation of interstitial needles.
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