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Clinical implementation of coverage probability planning for nodal boosting in locally advanced cervical cancer
Radiotherapy and Oncology xxx (2017) xxx–xxx
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Original article
Clinical implementation of coverage probability planning for nodal boosting in locally advanced cervical cancer Anne Ramlov a,⇑, Marianne S. Assenholt a, Maria F. Jensen a, Caroline Grønborg a, Remi Nout b, Markus Alber a,c, Lars Fokdal a, Kari Tanderup a, Jacob Chr. Lindegaard a a Department of Oncology, Aarhus University Hospital, Denmark; b Department of Radiation Oncology, Leiden University Medical Center, The Netherlands; and Medical Physics, Aarhus University Hospital, Denmark and Heidelberg, Institute for Radiation Oncology (HIRO), Germany
a r t i c l e
i n f o
Article history: Received 2 December 2016 Received in revised form 25 January 2017 Accepted 25 January 2017 Available online xxxx Keywords: Radiotherapy Coverage probability Nodal boosting Cervical cancer
c
Department of
a b s t r a c t Purpose: To implement coverage probability (CovP) for dose planning of simultaneous integrated boost (SIB) of pathologic lymph nodes in locally advanced cervical cancer (LACC). Material and methods: CovP constraints for SIB of the pathological nodal target (PTV-N) with a central dose peak and a relaxed coverage at the perimeter were generated for use with the treatment planning system Eclipse: PTV-N D98 >90%, CTV-N D98 >100% and CTV-N D50 >101.5% of prescribed dose. Dose of EBRT was 45 Gy/25 fx with a SIB of 55–57.5 Gy depending on expected dose from brachytherapy (BT). Twenty-five previously treated patients with 47 boosted nodes were analysed. Nodes were contoured on cone beam CT (CBCT) and the accumulated dose in GTV-NCBCT and volume of body, pelvic bones and bowel receiving >50 Gy (V50) were determined. Results: Nearly all nodes (89%) were visible on CBCT and showed considerable concentric regression during EBRT. Total EBRT and BT D98 was >57 GyEQD2 in 98% of the visible nodes. Compared to treatment plans aiming for full PTV-N coverage, CovP significantly reduced V50 of body, bones and bowel (p < 0.001) Conclusion: CovP is clinically feasible for SIB of pathological nodes and significantly decreases collateral SIB dose to nearby OAR. Ó 2017 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2017) xxx–xxx
Definitive radiotherapy in locally advanced cervical cancer (LACC) often involves boosting of multiple pathological nodes, as approximately 50% of the patients have metastases to regional lymph nodes in the pelvic or para-aortic region [1]. The simultaneous integrated boost (SIB) technique delivered by intensity modulated radiotherapy (IMRT) or volumetric arc therapy (VMAT) is increasingly being used as recent studies have shown excellent nodal control with a boost of 55–60 Gy [2,3]. However, nodal boosting on top of elective whole pelvic radiotherapy at 45–50 Gy invariably causes collateral higher dose to especially bowel and pelvic bones, as metastatic nodes are most often situated in the retroperitoneal lymphatic space close to bowel loops and the pelvic wall [4]. This dilemma may be even worse in situations where metastatic para-aortic nodes are encountered and require irradiation. In addition significant nodal regression may occur during treatment leading to irradiation of the surrounding tissue to a higher dose than initially planned [5].
⇑ Corresponding author at: Department of Oncology, Aarhus University, Hospital, Noerrebrogade 44, 8000 Aarhus C, Denmark. E-mail address: [email protected] (A. Ramlov).
At present no consensus exists on the required margin for nodal boosting, but margins of 5–10 mm from the nodal gross tumour volume (GTV-N) to the planning target volume (PTV-N) have been reported in centres using SIB [2,3]. A study based on weekly MRI performed during radiotherapy showed that a 4–9 mm margin was needed around GTV-N to generate an internal target volume (ITV-N) covering 95% of all nodal excursions [6]. Since the diameter of pathological nodes in LACC most often is about 10–20 mm, SIB dose planning using a classical PTV concept of a dose plateau with full PTV-N coverage [7] will entail a relatively large volume being treated to high doses compared to the actual GTV-N volume. As multiple nodes often are in play the total volume being treated to >50 Gy may rapidly be clinically significant. Coverage probability treatment planning (CovP) has previously been shown to provide robust dose escalation for IMRT of prostate cancer with overlapping PTV and rectum planning volume as well as superior patient specific small bowel planning volume allowing for tighter OAR margins with for instance para-aortic radiotherapy [8–10]. CovP supplements probability information about geometric uncertainties to the classic PTV concept to allow for a relaxed planning aim at the edge of PTV-N. CovP is based on the probability of finding the CTV at a specific point in the PTV assuming a certain
http://dx.doi.org/10.1016/j.radonc.2017.01.015 0167-8140/Ó 2017 Elsevier B.V. All rights reserved.
Please cite this article in press as: Ramlov A et al. Clinical implementation of coverage probability planning for nodal boosting in locally advanced cervical cancer. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.01.015
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Coverage probability for nodal boosting in cervix cancer
Table 1 Median nodal D98, D50 and D2 and V50 of body, bones and bowel for full coverage with PTV-N10mm (plan 1), full coverage with PTV-N5mm (plan 2) and coverage probability with PTV-N5mm (plan 3). Plan No.
Plan-1
Plan-2
Plan-3
Target concept PTV margin Treatment planning Planning aims PTV volume (cm3) GTV-NCT planned D98 (%) GTV-NCBCT D98 (%) GTV-NCT planned D50 (%) GTV-NCBCT D50 (%) GTV-NCT planned D2 (%) GTV-NCBCT D2 (%) CTV-N planned D98 (%) CTV-N planned D50 (%) PTV-N planned D98 (%) V50 Body (cm3) V50 Pelvic bone (cm3) V50 Bowel (cm3)
CT based: GTV-NCT 10 mm Full coverage PTV-N D98: 95–107% 19.9 (9.2–8.5) 100.5 (98.4–101.7) 100.4 (98.2–101.8) 101.4 (99.6–102.5) 101.3 (100.2–102.5) 102.0 (101.0–103.5) 101.8 (100.9–103.5) 100.5 (95.1–101.7) 100.4 (96.8–102.5) 97.1 (95.4–99.9) 74.6 (32.3–314.9) 6.9 (0–50.4) 3.5 (0–106.3)
CT and MR based: CTV-N = GTV-NCT + GTV-NMRI 5 mm Full coverage PTV-N D98: 95–107% 8.4 (2.9–62.7) 100.5 (99.4–101.5) 100.2 (98.6–101.7) 101.5 (100.1–102.4) 101.3 (100.4–103.1) 102.5 (100.8–103.3) 102.2 (100.7–103.2) 100.4 (99.3–101.3) 101.4 (100.5–102.3) 97.7 (96.3–101.5) 48.9 (15.8–209.0) 2.2 (0–24.6) 1.9 (0–67.8)
CT and MR based: CTV-N = GTV-NCT + GTV-NMRI 5 mm CovP PTV-N D98 > 90% CTV-N D98 > 100% CTV-N D50 > 101.5% 8.4 (2.9–62.7) 100.4 (99.6–102.1) 99.4 (93.1–101.4) 102.4 (100.8–103.6) 102.1 (97.8–103.3) 103.9 (101.3–105.9) 103.6 (100.8–106.0) 100.0 (99.7–101.2) 101.9 (100.6–103.0) 91.8 (90.7–94.8) 27.5 (11.6–122.2) 0.9 (0–7.9) 0.7 (0–34.6)
distribution of systematic and random position errors. During dose optimization, this information can be employed to permit a lower than prescribed dose at the edge of the PTV. However, CovP has until now only been used with experimental software and not in clinical routine [8–10]. The dosimetric consequences of nodal movements during treatment with a SIB are unknown. Since the SIB is being embedded in the 45–50 Gy irradiation of the whole pelvis the dosimetric penalty may be less than expected based on the geometrical study [6]. This could open a window for considering CovP to safely reduce the SIB dose at the perimeter of the PTV-N with overlapping OAR. The aim of our study was to develop planning aims for clinical use of CovP treatment planning of nodal SIB in LACC and to investigate the cumulative CovP dose to individual nodes by use of repetitive cone beam CT. Methods and materials Patient selection Between January 2012 and January 2015, 64 patients with LACC were included from Aarhus in the Embrace study [11] and treated with external beam radiotherapy (EBRT), concomitant Cisplatin and MRI guided adaptive brachytherapy as previously described [12]. Twenty-five node positive patients were selected based on the following criteria: 1–4 metastatic lymph nodes, daily CBCT data available and at least one node within the CBCT field. Thirty-nine patients were not included: 22 were node negative, 10 had > 4 nodes and 7 had poor quality CBCT or the metastatic node(s) were outside the field of view on CBCT. The total number of CBCT contours in patients with >4 nodes were too large to be analysed within the frame of this study.
Imaging, target concept and organs at risk Imaging for treatment planning consisted of whole body FDG PET/CT and pelvic T2 weighted 1.5 T MRI. Patients were scanned in the supine position with a supporting knee cushion. A bladder filling protocol aiming for full bladder was used both at imaging and during treatment. CBCT was performed prior to each fraction of EBRT and couch correction was performed based on bony anatomy. All CBCT scans were matched with rigid registration to the planning PET/CT for delineation. A tumour-related CTV-T and an elective nodal CTV-E was delineated as previously described [12]. An individualized internal target volume (ITV-T) was constructed from CTV-T by considering
target and OAR anatomy on both CT and MR scans acquired for treatment planning. A 5 mm margin was added to the ITV-T and CTV-E to arrive at the total PTV. The GTV-N and CTV-N were always fully included in the CTV-E. Two margin strategies were used for SIB (Table 1 and Fig. 1, panel A). For the conventional strategy, GTV-N was contoured on the planning PET/CT. For the tight margin strategy, a more advanced target definition approach was applied by contouring GTV-N on both planning PET/CT and MRI and fusing the contours to form CTV-N. For the conventional margin strategy, a 10 mm concentric margin was added around the GTV-NCT to form PTV-N10mm. For the tight margin strategy, a 5 mm concentric margin was added around the CTV-N to create PTV-N5mm in accordance with the Embrace-II study [13]. Normal tissue was delineated on the planning PET/CT. The following normal tissue was delineated: bladder, rectum, sigmoid, bowel bag (containing small and large bowels), pelvic bones and the femoral heads. In case of para-aortic irradiation the kidneys and medulla were included. The PTV was not subtracted from the normal tissue delineations.
Coverage probability planning Planning aims for clinical use of CovP were developed in the research dose planning software Hyperion (version 2.4.4). Coverage probabilities and their estimation in Hyperion have previously been described [8]. In short, probability assumptions regarding the position of GTV-N over time was used by the optimizer to create a dose gradient around the CTV-N, which was allowed to lie partially inside the PTV-N. As input parameter for the geometrical error we used 4 mm, which is in line with the study by Schippers et al. [6]. Based on a number of CovP dummy runs performed in parallel in Hyperion and Eclipse (version 11.0.31, AAA, Aria Varian Eclipse) a set of dose constraints were selected for clinical use: PTV-N D98 >90%, CTV-N D98 >100% and a soft constraint of CTV-N D50 >101.5% of the prescribed dose. By comparison with Hyperion we found that these constraints, when used with Eclipse, produced almost completely overlapping dose gradients around CTV-N and were able to capture the nature of the CovP dose distributions for this particular setting of CTV-N size, SIB dose and assumed statistical distribution of systematic and random errors.
Treatment planning The planning aim for SIB was 55 Gy in 25 fractions for nodes located below the common iliac vessels (CI) and 57.5 Gy in 25 fractions to nodes located at CI or higher. The planning aim for PTV-T
Please cite this article in press as: Ramlov A et al. Clinical implementation of coverage probability planning for nodal boosting in locally advanced cervical cancer. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.01.015
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close as possible to D98 = 100%. In plans containing different dose prescriptions for CTV-Ns, normalization was to the CTV-N with the highest prescribed dose. The intrusion of the 90% nodal boost isodose into normal tissue and into CTV-E was minimized. PTV-E dose was between 95% and 107% of 45 Gy in all regions clear of the SIB. All treatment plans were made by two physicists, who applied the same strategy for fulfiling hard constraints on target coverage and reduce organ doses as much as possible. Table 1 summarizes the planning aims of the three SIB strategies and the obtained planned doses. Typical dose profiles and the resulting DVH curves are shown in Fig. 1 (panel B and C). An example of dose distributions for the three planning strategies is shown in colour wash in Fig. 2 (panel A-C). Dose and volume determination Contouring of the individual boosted node was done on every second or third CBCT aiming for delineation of 10 CBCTs for each patient. An example of nodal contours delineated from CBCT is shown in Fig. 2 (panel D). The geometric margin required to cover all excursions was calculated by the isotropic margin needed to cover the GTV-NCBCT including all CBCT delineations of each node. The CBCT lymph node delineations were propagated via rigid bony registration performed at treatment to the planning CT. The dose to 98% (D98%), 50% (D50%) and 2% (D2%) of each GTV-NCBCT was assessed according to the planning CT dose distribution. It was assumed that the dose delivered in fractions without a CBCT contour could be represented by the previous fractions with contour (Fig. 3). With this assumption the accumulated D98%, D50% and D2% was calculated as the mean of each DVH parameter across all CBCT contours in a given patient. Dose contribution from BT was determined for each node by estimating D98% with a near minimum point dose. Total dose of EBRT and BT was calculated in EQD2 using an a/b value of 10 and a T1/2 of 1.5 h [5]. Volume of bones, bowel and outer contour of body receiving >50 Gy (V50) was determined from the normal tissue delineation on the planning PET/CT. Statistical analyses Data were analysed using Stata statistical software, version 13.0. A paired t-test was used for comparison of nodal doses. Comparison of V50 was performed using Wilcoxon’s signed rank test. A two tailed p-value > 0.05 was considered significant. Fig. 1. A: Example of dose profiles for a simultaneous integrated nodal boost using full coverage (FC) with PTV-N10mm (plan 1), full coverage with PTV-N5mm (plan 2) and coverage probability with PTV-N5mm (plan 3). B: DVH curves for GTV-N and PTV-N for plan 1–3. C: Absolute volume of irradiated body as a function of dose level for plan 1–3.
and PTV-E was 45 Gy in 25 fractions. All dose plans were performed with Eclipse. Treatment plans were made as either IMRT or VMAT plans. Three different SIB plans were generated: Plan-1: Full Coverage (FC) with PTV-N10mm, Plan-2: FC with PTV-N5mm, and Plan-3: CovP with PTV-N5mm. For both FC plans PTV-N had to be covered with 95–107% of prescribed dose and were optimized so Dmean PTVN = prescribed dose. CovP plans were optimized to fulfil D98 >100% for CTV-N. In order to fulfil CovP constraints for PTV-N and achieve a dose gradient around CTV-N, an optimization volume (oPTV) containing the PTV-N with the CTV-N subtracted was used. The planning aim for oPTV was, that the dose should be 90% on the outer edge of PTV-N and a Dmax 100% of prescribed CTV-N dose. For plans with more than one CTV-N, the dose plan was normalized to fulfil D98 = 100% for the CTV-N with the lowest obtained dose after optimization and the other CTV-N as
Results Forty-seven nodes were boosted. Median number of lymph nodes per patient was 2 (range 1–4). The majority of nodes (87%) were located below the CI vessels (Table 2). Six nodes were at CI or in the para-aortic region. Three nodes were not visible on any CBCTs, two were outside the CBCT field and three nodes were not visible on some CBCT scan due to artefacts caused by bowel air. The number of CBCT delineations per node was median 10 (range 5–10). In total 417 nodal CBCT contours were evaluated. Based on measurements of the individual nodes at diagnosis, the median GTV-NCT, CTV-N, PTV-N5mm and PTV10mm volumes were 1 cm3 (range 0.1–25.5 cm3), 1.5 cm3 (range 0.2–28.6 cm3), 8.4 cm3 (range 2.9–62.7 cm3) and 19.9 cm3 (range 9.2–98.5 cm3), respectively. Dose constraints could be fulfiled for all nodes with the FC plan 1 and FC plan 2, where the PTV-N D98% was between 95% and 107%. For CovP (plan 3) CTV-N D98% was >99.7% for all nodes and CTV-N D50% >100.6%. Only seven nodes had a CTV-N D50% below 101.5%. Nodal volume diminished during treatment in 40/42 nodes and in the last week of EBRT, five nodes had regressed completely.
Please cite this article in press as: Ramlov A et al. Clinical implementation of coverage probability planning for nodal boosting in locally advanced cervical cancer. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.01.015
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Coverage probability for nodal boosting in cervix cancer
Fig. 2. Treatment plans in colour wash (95–107% of prescribed dose): A) Full coverage with PTV-N10mm (plan 1), B) full coverage with PTV-N5mm (plan 2) and C) coverage probability with PTV-N5mm (plan 3). Panel D is showing an example of delineations of a node (red) on CBCT during external beam radiotherapy. A 5 mm CTV-N to PTV-N margin is indicated by the blue contour. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3. Dose per fraction (D98%) for GTV-NCBCT during external beam radiotherapy in the worst (black) and the best (white) case of a simultaneous integrated boost planned by use of coverage probability (plan 3). Dose per fraction was determined on every second or third cone-beam scan (large symbol).
However, the cystic compartment of two large nodes (7.8 and 25.0 cm3) increased during treatment by 18% and 47%. Including all 42 CBCT visible nodes, the median volume of GTV-NCBCT was
reduced from 1.0 cm3 to 0.2 cm3 on the last CBCT delineation. The mean reduction in nodal size during five weeks of EBRT was 71% (Fig. 4). No significant difference in delivered D98%, D50% or D2% to GTVNCBCT was seen when comparing FC plan 1 and FC plan 2 (Table 1). D98% was >98% for all boosted nodes. One node had a D98% of 93% with CovP (plan 3). The volume of this node was 1 cm3 and the node was located close to the bladder, which with varying bladder filling during EBRT was displaced for some fractions. The remaining nodes all had D98% >95%. Median D98% was significantly lower by 0.7 Gy (p < 0.001) for CovP (plan 3) compared with the FC plan 2. No difference in D50% was found between CovP (plan 3) compared with the FC plan 2 (p = 0.33). D2% was significantly higher by 1.4 Gy (p < 0.001) for CovP (plan 3) compared with the FC plan 2. The median margin required to cover all positional shifts of GTV-NCBCT during EBRT was 5 mm (range 3–12 mm). Fourteen nodes required a margin >5 mm. The node with a D98% of 93% with CovP (plan 3) required a margin of 9 mm to counter all internal motion. D98% for that specific node was 99% with FC plan 2 and 100% with FC plan 1. The remaining nodes with excursions >5 mm all had a coverage with D98% >98% for the two FC plans and >96% with CovP (plan 3). The cumulative dose (EQD2) to GTV-N delivered by CovP planned SIB and BT as a function of GTV-NCBCT volume is shown in Table 2. Neither nodal volume nor anatomical location had an apparent impact on the EQD2. In total, 41/42 of the CBCT visible nodes received a cumulative D98% EBRT and BT >57 GyEQD2.
Please cite this article in press as: Ramlov A et al. Clinical implementation of coverage probability planning for nodal boosting in locally advanced cervical cancer. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.01.015
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Table 2 Nodal location and cumulative equivalent dose in 2 Gy fractions (EQD2) for nodes visible on CBCT. All nodes were treated with a simultaneous integrated boost planned by use of coverage probability planning (plan 3). Nodal location
Boosted nodes
Boosted nodes visible on CBCT
Median EBRT D98, EQD2 (Gy)
Median BT Point dose, EQD2 (Gy)
Total D98 + BT EQD2 (Gy)
Para-aortic Common iliac Presacral Iliaca interna Iliaca externa Obturator Total
4 3 3 7 15 15 47
2 3 2 6 14 15 42
58.5 57.4 54.9 54.6 55.3 55.6 55.6
0 1.2 3.7 4.7 4.5 3.6 3.8
58.5 58.5 58.5 60.0 59.8 59.5 59.5
(58.3–58.5) (55.7–59.6) (54.9–54.9) (51.4–56.0) (53.6–56.9) (54.3–57.0) (51.4–59.6)
(0–2.8) (2.4–4.9) (2.3–9.6) (1.8–6.4) (1.6–5.6) (0–9.6)
(58.3–58.5) (57.4–60.8) (57.3–59.8) (55.5–62.9) (57.3–62.5) (58.0–61.2) (55.5–62.9)
Fig. 4. Relative reduction of nodal volume during external beam radiotherapy in 25 patients with a total number of 42 nodes (Median + 95% CI). An example of nodal volume at planning CT (O) and the subsequent nodal regression observed during treatment (week 1–5) on CBCT is shown below the x-axis.
V50 was significantly reduced for body, bones and bowel comparing FC plan 1 and FC plan 2 with a factor of 1.5, 3.5 and 2 respectively (p < 0.01). With CovP (plan 3), a further decrease in V50 was obtained for all three OARs by a factor of 1.7, 2 and 2 (p < 0.001), respectively compared to the FC plan 2 (Table 1). Not all patients had nodes in the vicinity of bones or bowel, but for some a large gain was achieved. Two patients with several nodes located adjacent to pelvic bones had a decrease from 50 cm3 with FC plan 1– 25 cm3 with FC plan 2 and a further reduction to 6 and 8 cm3 respectively with CovP (plan 3). For the patient with the highest bowel V50, a reduction was seen from 106 cm3 to 68 cm3 from FC plan 1 to FC plan 2 and to 35 cm3 with CovP (plan 3).
Discussion This study demonstrates that CovP based planning of pelvic lymph node SIB in LACC is highly robust when IMRT/VMAT is combined with daily image guidance based on bony fusion. We also demonstrate that most pathological nodes are visible on CBCT and can be monitored for both response and location. The nodal excursions found in our study are in accordance with results of Schippers et al. using repetitive MRI [6]. The 5 mm SIB margin produced ‘‘geographical misses” in 33% of nodal boosts. Still, all nodes received >95% of prescribed dose. By use of CovP we were able to further reduce collateral irradiation of normal tissue and increase the central GTV dose. CovP resulted in D98% >93%
of boosted nodes, and combined EBRT and BT D98% >55.5 Gy for all nodes. Accordingly, we have shown that a heterogeneous dose administration can spare normal tissue and reach a higher dose to the central GTV. This is superior to a classical approach, which aims for a homogeneous dose. In fact, the slight variation in delivered EBRT SIB dose with CovP was smaller than the variation induced by the BT dose to the nodes. There is limited consensus with regard to dose prescription to pathologic lymph nodes. Beadle et al. [14] pointed to the importance of boosting grossly involved nodes. However, a recent study did not find an additional advantage of a cumulative dose including BT >60 GyEQD2 [15]. Thus, the dose–response relationship for pathological nodes seems to be flat already at 55–60 Gy, and small dosimetric variations in delivered dose are not expected to have clinical impact. In accordance with this observation, the recurrence rates of SIB boosted pathological nodes to >55–60 Gy have been shown to be 1–3% [3,15]. The major clinical challenge with regard to nodal control is therefore not control of ‘‘in-field” nodes, but rather nodal recurrences mainly cranially of the EBRT target [14,15]. Irradiation induced morbidity is a significant burden for cervix cancer patients, and relevant reductions of dose and irradiated volume has potential to improve quality of life. Simpson et al. demonstrated a significant relation between bowel V45 and acute bowel toxicity. An increase of 100 ml bowel receiving >45 Gy resulted in a 2-fold increased risk for acute toxicity [16]. A study by Oh et al. found a significant relation between a sacral dose >50.4 Gy and
Please cite this article in press as: Ramlov A et al. Clinical implementation of coverage probability planning for nodal boosting in locally advanced cervical cancer. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.01.015
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Coverage probability for nodal boosting in cervix cancer
the risk of developing pelvic insufficiency fractures [17]. Waldenström et al. demonstrated a correlation between pain and mean absorbed dose of sacral and pubic bones [18,19]. With the proposed CovP planning aims for nodal boosting by SIB, we demonstrated that V50 for bowel and pelvic bones on average could be significantly reduced. As our study is dominated by patients with 1–2 nodes in the true pelvis it is likely that the OAR sparing will be even larger for patients with multiple nodes especially if located at the common iliac vessels or higher. Also on the individual level we noted that the sparing was much greater in certain patients with unfavourable anatomy. Recently the switch to image guided adaptive brachytherapy has led to a significant decrease in G3– G4 bladder, rectum and vaginal toxicity by minimizing the overlapping high dose volume of similar magnitude into OAR in patients with unfavourable anatomy in the central pelvis [12,20– 23]. We may therefore expect that the normal tissue sparing obtained by CovP planned SIB in cases with unfavourable anatomy at the pelvic wall will also be of clinical importance. With CovP a new tool is available in the clinic for nodal SIB in LACC. CovP allows controlled underdosage at the edge of the PTV. Notice also, that geographic misses have only mild dosimetric consequences in a SIB situation, which in turn weakens the justification of a conventional PTV concept. The results presented here for LACC are potentially applicable to other pelvic sites such as anal, vulva, bladder, penile and prostate cancer. As our study is mainly based on pelvic nodes along the major vessels it is still unclear how CovP will perform when using SIB for nodes in the para-aortic region or in the groins. Nodes in the vicinity of organs which may be displaced e.g. by the bladder or rectum, may also need monitoring in terms of delivered dose and eventually plan adaptation during EBRT. Since modern external beam radiotherapy and image guided brachytherapy in LACC now are providing excellent pelvic disease control [12,20–23] a logical priority for further development will be normal tissue sparing for instance through application of highly focal lymph node boosts, and improved selection of patients for para-aortic irradiation. The presented dosimetric results validate the CovP concept for pelvic nodes and quantify the substantial normal tissue sparing in exchange for a minute loss in nodal CTV coverage. This is predominantly the consequence of two factors: the shallow dose gradients around the nodes in the SIB situation, and their volume shrinkage during therapy. Furthermore, as it is feasible to treat pathological nodes with tight margins, it is also expected that the elective nodal target can be treated safely with limited margins (5 mm) when daily IGRT is applied. The current work has been included in the recently initiated EMBRACE II study where reduced PTV margins (5 mm), daily IGRT, IMRT/VMAT CovP planning for SIB and risk adapted use of para-aortic irradiation will be implemented. With an estimated accrual of 800 patients, and 50% of these having node positive disease, a comprehensive study regarding follow-up after CovP based nodal boosting can be expected. Conclusion CovP for nodal SIB in LACC provided sufficient target coverage and a significant reduction in dose to adjacent organs at risk. An increased central dose could be obtained for most nodes. CovP based SIB is now standard in our institution for nodal boosting and is implemented in the Embrace II study. Conflict of interest Anne Ramlov received research grants from the Danish Cancer Society, Denmark and Varian Medical Systems, USA.
Acknowledgements EMBRACE was supported by Varian Medical Systems. Furthermore, this study was supported by research grants to Aarhus University Hospital from Varian Medical Systems and the Danish Cancer Society. References [1] Kidd EA, Siegel BA, Dehdashti F, et al. Lymph node staging by positron emission tomography in cervical cancer: relationship to prognosis. J Clin Oncol 2010;28:2108–13. [2] Cihoric N, Tapia C, Kruger K, Aebersold DM, Klaeser B, Lossl K. IMRT with 18 FDG-PET\CT based simultaneous integrated boost for treatment of nodal positive cervical cancer. Radiat Oncol 2014;9. 83-717X-9-83. [3] Vargo JA, Kim H, Choi S, et al. Extended field intensity modulated radiation therapy with concomitant boost for lymph node-positive cervical cancer: analysis of regional control and recurrence patterns in the positron emission tomography/computed tomography era. Int J Radiat Oncol Biol Phys 2014;90:1091–8. [4] Taylor A, Rockall AG, Reznek RH, Powell ME. Mapping pelvic lymph nodes: guidelines for delineation in intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2005;63:1604–12. [5] Pötter R, Haie-Meder C, Van Limbergen E, et al. Recommendations from gynaecological (GYN) GEC ESTRO working group (II): concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol 2006;78:67–77. [6] Schippers MG, Bol GH, de Leeuw AA, et al. Position shifts and volume changes of pelvic and para-aortic nodes during IMRT for patients with cervical cancer. Radiother Oncol 2014;111:442–5. [7] International Commission on Radiation Units and Measurements. ICRU report 62. Prescribing, recording, and reporting photon beam therapy (Supplement to ICRU report 50). Bethesda, MD: ICRU; 1999. [8] Baum C, Alber M, Birkner M, Nusslin F. Robust treatment planning for intensity modulated radiotherapy of prostate cancer based on coverage probabilities. Radiother Oncol 2006;78:27–35. [9] Hysing LB, Sohn M, Muren LP, Alber M. A coverage probability based method to estimate patient-specific small bowel planning volumes for use in radiotherapy. Radiother Oncol 2011;100:407–11. [10] Stroom JC, de Boer HC, Huizenga H, Visser AG. Inclusion of geometrical uncertainties in radiotherapy treatment planning by means of coverage probability. Int J Radiat Oncol Biol Phys 1999;43:905–19. [11] Embrace study protocol 2008 www.embracestudy.dk. [12] Lindegaard JC, Fokdal LU, Nielsen SK, Juul-Christensen J, Tanderup K. MRIguided adaptive radiotherapy in locally advanced cervical cancer from a Nordic perspective. Acta Oncol 2013;52:1510–9. [13] EMBRACE-II study protocol. 2016 www.embracestudy.dk. [14] Beadle BM, Jhingran A, Yom SS, Ramirez PT, Eifel PJ. Patterns of regional recurrence after definitive radiotherapy for cervical cancer. Int J Radiat Oncol Biol Phys 2010;76:1396–403. [15] Ramlov A, Kroon PS, Jurgenliemk-Schulz IM, et al. Impact of radiation dose and standardized uptake value of (18)FDG PET on nodal control in locally advanced cervical cancer. Acta Oncol 2015;54:1567–73. [16] Simpson DR, Song WY, Moiseenko V, et al. Normal tissue complication probability analysis of acute gastrointestinal toxicity in cervical cancer patients undergoing intensity modulated radiation therapy and concurrent cisplatin. Int J Radiat Oncol Biol Phys 2012;83:e81–6. [17] Oh D, Huh SJ, Nam H, et al. Pelvic insufficiency fracture after pelvic radiotherapy for cervical cancer: analysis of risk factors. Int J Radiat Oncol Biol Phys 2008;70:1183–8. [18] Waldenström AC, Olsson C, Wilderang U, et al. Pain and mean absorbed dose to the pubic bone after radiotherapy among gynecological cancer survivors. Int J Radiat Oncol Biol Phys 2011;80:1171–80. [19] Waldenström AC, Olsson C, Wilderang U, et al. Relative importance of hip and sacral pain among long-term gynecological: cancer survivors treated with pelvic radiotherapy and their relationships to mean absorbed doses. Int J Radiat Oncol Biol Phys 2012;84:428–36. [20] Pötter 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;100:116–23. [21] Nomden CN, de Leeuw AA, 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;107:69–74. [22] Rijkmans EC, Nout RA, Rutten IH, et al. Improved survival of patients with cervical cancer treated with image-guided brachytherapy compared with conventional brachytherapy. Gynecol Oncol 2014;135:231–8. [23] Sturdza A, Potter R, Fokdal LU, et al. Image guided brachytherapy in locally advanced cervical cancer: Improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study. Radiother Oncol 2016;120: 428–33.
Please cite this article in press as: Ramlov A et al. Clinical implementation of coverage probability planning for nodal boosting in locally advanced cervical cancer. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.01.015
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Original article
Clinical implementation of coverage probability planning for nodal boosting in locally advanced cervical cancer Anne Ramlov a,⇑, Marianne S. Assenholt a, Maria F. Jensen a, Caroline Grønborg a, Remi Nout b, Markus Alber a,c, Lars Fokdal a, Kari Tanderup a, Jacob Chr. Lindegaard a a Department of Oncology, Aarhus University Hospital, Denmark; b Department of Radiation Oncology, Leiden University Medical Center, The Netherlands; and Medical Physics, Aarhus University Hospital, Denmark and Heidelberg, Institute for Radiation Oncology (HIRO), Germany
a r t i c l e
i n f o
Article history: Received 2 December 2016 Received in revised form 25 January 2017 Accepted 25 January 2017 Available online xxxx Keywords: Radiotherapy Coverage probability Nodal boosting Cervical cancer
c
Department of
a b s t r a c t Purpose: To implement coverage probability (CovP) for dose planning of simultaneous integrated boost (SIB) of pathologic lymph nodes in locally advanced cervical cancer (LACC). Material and methods: CovP constraints for SIB of the pathological nodal target (PTV-N) with a central dose peak and a relaxed coverage at the perimeter were generated for use with the treatment planning system Eclipse: PTV-N D98 >90%, CTV-N D98 >100% and CTV-N D50 >101.5% of prescribed dose. Dose of EBRT was 45 Gy/25 fx with a SIB of 55–57.5 Gy depending on expected dose from brachytherapy (BT). Twenty-five previously treated patients with 47 boosted nodes were analysed. Nodes were contoured on cone beam CT (CBCT) and the accumulated dose in GTV-NCBCT and volume of body, pelvic bones and bowel receiving >50 Gy (V50) were determined. Results: Nearly all nodes (89%) were visible on CBCT and showed considerable concentric regression during EBRT. Total EBRT and BT D98 was >57 GyEQD2 in 98% of the visible nodes. Compared to treatment plans aiming for full PTV-N coverage, CovP significantly reduced V50 of body, bones and bowel (p < 0.001) Conclusion: CovP is clinically feasible for SIB of pathological nodes and significantly decreases collateral SIB dose to nearby OAR. Ó 2017 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2017) xxx–xxx
Definitive radiotherapy in locally advanced cervical cancer (LACC) often involves boosting of multiple pathological nodes, as approximately 50% of the patients have metastases to regional lymph nodes in the pelvic or para-aortic region [1]. The simultaneous integrated boost (SIB) technique delivered by intensity modulated radiotherapy (IMRT) or volumetric arc therapy (VMAT) is increasingly being used as recent studies have shown excellent nodal control with a boost of 55–60 Gy [2,3]. However, nodal boosting on top of elective whole pelvic radiotherapy at 45–50 Gy invariably causes collateral higher dose to especially bowel and pelvic bones, as metastatic nodes are most often situated in the retroperitoneal lymphatic space close to bowel loops and the pelvic wall [4]. This dilemma may be even worse in situations where metastatic para-aortic nodes are encountered and require irradiation. In addition significant nodal regression may occur during treatment leading to irradiation of the surrounding tissue to a higher dose than initially planned [5].
⇑ Corresponding author at: Department of Oncology, Aarhus University, Hospital, Noerrebrogade 44, 8000 Aarhus C, Denmark. E-mail address: [email protected] (A. Ramlov).
At present no consensus exists on the required margin for nodal boosting, but margins of 5–10 mm from the nodal gross tumour volume (GTV-N) to the planning target volume (PTV-N) have been reported in centres using SIB [2,3]. A study based on weekly MRI performed during radiotherapy showed that a 4–9 mm margin was needed around GTV-N to generate an internal target volume (ITV-N) covering 95% of all nodal excursions [6]. Since the diameter of pathological nodes in LACC most often is about 10–20 mm, SIB dose planning using a classical PTV concept of a dose plateau with full PTV-N coverage [7] will entail a relatively large volume being treated to high doses compared to the actual GTV-N volume. As multiple nodes often are in play the total volume being treated to >50 Gy may rapidly be clinically significant. Coverage probability treatment planning (CovP) has previously been shown to provide robust dose escalation for IMRT of prostate cancer with overlapping PTV and rectum planning volume as well as superior patient specific small bowel planning volume allowing for tighter OAR margins with for instance para-aortic radiotherapy [8–10]. CovP supplements probability information about geometric uncertainties to the classic PTV concept to allow for a relaxed planning aim at the edge of PTV-N. CovP is based on the probability of finding the CTV at a specific point in the PTV assuming a certain
http://dx.doi.org/10.1016/j.radonc.2017.01.015 0167-8140/Ó 2017 Elsevier B.V. All rights reserved.
Please cite this article in press as: Ramlov A et al. Clinical implementation of coverage probability planning for nodal boosting in locally advanced cervical cancer. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.01.015
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Coverage probability for nodal boosting in cervix cancer
Table 1 Median nodal D98, D50 and D2 and V50 of body, bones and bowel for full coverage with PTV-N10mm (plan 1), full coverage with PTV-N5mm (plan 2) and coverage probability with PTV-N5mm (plan 3). Plan No.
Plan-1
Plan-2
Plan-3
Target concept PTV margin Treatment planning Planning aims PTV volume (cm3) GTV-NCT planned D98 (%) GTV-NCBCT D98 (%) GTV-NCT planned D50 (%) GTV-NCBCT D50 (%) GTV-NCT planned D2 (%) GTV-NCBCT D2 (%) CTV-N planned D98 (%) CTV-N planned D50 (%) PTV-N planned D98 (%) V50 Body (cm3) V50 Pelvic bone (cm3) V50 Bowel (cm3)
CT based: GTV-NCT 10 mm Full coverage PTV-N D98: 95–107% 19.9 (9.2–8.5) 100.5 (98.4–101.7) 100.4 (98.2–101.8) 101.4 (99.6–102.5) 101.3 (100.2–102.5) 102.0 (101.0–103.5) 101.8 (100.9–103.5) 100.5 (95.1–101.7) 100.4 (96.8–102.5) 97.1 (95.4–99.9) 74.6 (32.3–314.9) 6.9 (0–50.4) 3.5 (0–106.3)
CT and MR based: CTV-N = GTV-NCT + GTV-NMRI 5 mm Full coverage PTV-N D98: 95–107% 8.4 (2.9–62.7) 100.5 (99.4–101.5) 100.2 (98.6–101.7) 101.5 (100.1–102.4) 101.3 (100.4–103.1) 102.5 (100.8–103.3) 102.2 (100.7–103.2) 100.4 (99.3–101.3) 101.4 (100.5–102.3) 97.7 (96.3–101.5) 48.9 (15.8–209.0) 2.2 (0–24.6) 1.9 (0–67.8)
CT and MR based: CTV-N = GTV-NCT + GTV-NMRI 5 mm CovP PTV-N D98 > 90% CTV-N D98 > 100% CTV-N D50 > 101.5% 8.4 (2.9–62.7) 100.4 (99.6–102.1) 99.4 (93.1–101.4) 102.4 (100.8–103.6) 102.1 (97.8–103.3) 103.9 (101.3–105.9) 103.6 (100.8–106.0) 100.0 (99.7–101.2) 101.9 (100.6–103.0) 91.8 (90.7–94.8) 27.5 (11.6–122.2) 0.9 (0–7.9) 0.7 (0–34.6)
distribution of systematic and random position errors. During dose optimization, this information can be employed to permit a lower than prescribed dose at the edge of the PTV. However, CovP has until now only been used with experimental software and not in clinical routine [8–10]. The dosimetric consequences of nodal movements during treatment with a SIB are unknown. Since the SIB is being embedded in the 45–50 Gy irradiation of the whole pelvis the dosimetric penalty may be less than expected based on the geometrical study [6]. This could open a window for considering CovP to safely reduce the SIB dose at the perimeter of the PTV-N with overlapping OAR. The aim of our study was to develop planning aims for clinical use of CovP treatment planning of nodal SIB in LACC and to investigate the cumulative CovP dose to individual nodes by use of repetitive cone beam CT. Methods and materials Patient selection Between January 2012 and January 2015, 64 patients with LACC were included from Aarhus in the Embrace study [11] and treated with external beam radiotherapy (EBRT), concomitant Cisplatin and MRI guided adaptive brachytherapy as previously described [12]. Twenty-five node positive patients were selected based on the following criteria: 1–4 metastatic lymph nodes, daily CBCT data available and at least one node within the CBCT field. Thirty-nine patients were not included: 22 were node negative, 10 had > 4 nodes and 7 had poor quality CBCT or the metastatic node(s) were outside the field of view on CBCT. The total number of CBCT contours in patients with >4 nodes were too large to be analysed within the frame of this study.
Imaging, target concept and organs at risk Imaging for treatment planning consisted of whole body FDG PET/CT and pelvic T2 weighted 1.5 T MRI. Patients were scanned in the supine position with a supporting knee cushion. A bladder filling protocol aiming for full bladder was used both at imaging and during treatment. CBCT was performed prior to each fraction of EBRT and couch correction was performed based on bony anatomy. All CBCT scans were matched with rigid registration to the planning PET/CT for delineation. A tumour-related CTV-T and an elective nodal CTV-E was delineated as previously described [12]. An individualized internal target volume (ITV-T) was constructed from CTV-T by considering
target and OAR anatomy on both CT and MR scans acquired for treatment planning. A 5 mm margin was added to the ITV-T and CTV-E to arrive at the total PTV. The GTV-N and CTV-N were always fully included in the CTV-E. Two margin strategies were used for SIB (Table 1 and Fig. 1, panel A). For the conventional strategy, GTV-N was contoured on the planning PET/CT. For the tight margin strategy, a more advanced target definition approach was applied by contouring GTV-N on both planning PET/CT and MRI and fusing the contours to form CTV-N. For the conventional margin strategy, a 10 mm concentric margin was added around the GTV-NCT to form PTV-N10mm. For the tight margin strategy, a 5 mm concentric margin was added around the CTV-N to create PTV-N5mm in accordance with the Embrace-II study [13]. Normal tissue was delineated on the planning PET/CT. The following normal tissue was delineated: bladder, rectum, sigmoid, bowel bag (containing small and large bowels), pelvic bones and the femoral heads. In case of para-aortic irradiation the kidneys and medulla were included. The PTV was not subtracted from the normal tissue delineations.
Coverage probability planning Planning aims for clinical use of CovP were developed in the research dose planning software Hyperion (version 2.4.4). Coverage probabilities and their estimation in Hyperion have previously been described [8]. In short, probability assumptions regarding the position of GTV-N over time was used by the optimizer to create a dose gradient around the CTV-N, which was allowed to lie partially inside the PTV-N. As input parameter for the geometrical error we used 4 mm, which is in line with the study by Schippers et al. [6]. Based on a number of CovP dummy runs performed in parallel in Hyperion and Eclipse (version 11.0.31, AAA, Aria Varian Eclipse) a set of dose constraints were selected for clinical use: PTV-N D98 >90%, CTV-N D98 >100% and a soft constraint of CTV-N D50 >101.5% of the prescribed dose. By comparison with Hyperion we found that these constraints, when used with Eclipse, produced almost completely overlapping dose gradients around CTV-N and were able to capture the nature of the CovP dose distributions for this particular setting of CTV-N size, SIB dose and assumed statistical distribution of systematic and random errors.
Treatment planning The planning aim for SIB was 55 Gy in 25 fractions for nodes located below the common iliac vessels (CI) and 57.5 Gy in 25 fractions to nodes located at CI or higher. The planning aim for PTV-T
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close as possible to D98 = 100%. In plans containing different dose prescriptions for CTV-Ns, normalization was to the CTV-N with the highest prescribed dose. The intrusion of the 90% nodal boost isodose into normal tissue and into CTV-E was minimized. PTV-E dose was between 95% and 107% of 45 Gy in all regions clear of the SIB. All treatment plans were made by two physicists, who applied the same strategy for fulfiling hard constraints on target coverage and reduce organ doses as much as possible. Table 1 summarizes the planning aims of the three SIB strategies and the obtained planned doses. Typical dose profiles and the resulting DVH curves are shown in Fig. 1 (panel B and C). An example of dose distributions for the three planning strategies is shown in colour wash in Fig. 2 (panel A-C). Dose and volume determination Contouring of the individual boosted node was done on every second or third CBCT aiming for delineation of 10 CBCTs for each patient. An example of nodal contours delineated from CBCT is shown in Fig. 2 (panel D). The geometric margin required to cover all excursions was calculated by the isotropic margin needed to cover the GTV-NCBCT including all CBCT delineations of each node. The CBCT lymph node delineations were propagated via rigid bony registration performed at treatment to the planning CT. The dose to 98% (D98%), 50% (D50%) and 2% (D2%) of each GTV-NCBCT was assessed according to the planning CT dose distribution. It was assumed that the dose delivered in fractions without a CBCT contour could be represented by the previous fractions with contour (Fig. 3). With this assumption the accumulated D98%, D50% and D2% was calculated as the mean of each DVH parameter across all CBCT contours in a given patient. Dose contribution from BT was determined for each node by estimating D98% with a near minimum point dose. Total dose of EBRT and BT was calculated in EQD2 using an a/b value of 10 and a T1/2 of 1.5 h [5]. Volume of bones, bowel and outer contour of body receiving >50 Gy (V50) was determined from the normal tissue delineation on the planning PET/CT. Statistical analyses Data were analysed using Stata statistical software, version 13.0. A paired t-test was used for comparison of nodal doses. Comparison of V50 was performed using Wilcoxon’s signed rank test. A two tailed p-value > 0.05 was considered significant. Fig. 1. A: Example of dose profiles for a simultaneous integrated nodal boost using full coverage (FC) with PTV-N10mm (plan 1), full coverage with PTV-N5mm (plan 2) and coverage probability with PTV-N5mm (plan 3). B: DVH curves for GTV-N and PTV-N for plan 1–3. C: Absolute volume of irradiated body as a function of dose level for plan 1–3.
and PTV-E was 45 Gy in 25 fractions. All dose plans were performed with Eclipse. Treatment plans were made as either IMRT or VMAT plans. Three different SIB plans were generated: Plan-1: Full Coverage (FC) with PTV-N10mm, Plan-2: FC with PTV-N5mm, and Plan-3: CovP with PTV-N5mm. For both FC plans PTV-N had to be covered with 95–107% of prescribed dose and were optimized so Dmean PTVN = prescribed dose. CovP plans were optimized to fulfil D98 >100% for CTV-N. In order to fulfil CovP constraints for PTV-N and achieve a dose gradient around CTV-N, an optimization volume (oPTV) containing the PTV-N with the CTV-N subtracted was used. The planning aim for oPTV was, that the dose should be 90% on the outer edge of PTV-N and a Dmax 100% of prescribed CTV-N dose. For plans with more than one CTV-N, the dose plan was normalized to fulfil D98 = 100% for the CTV-N with the lowest obtained dose after optimization and the other CTV-N as
Results Forty-seven nodes were boosted. Median number of lymph nodes per patient was 2 (range 1–4). The majority of nodes (87%) were located below the CI vessels (Table 2). Six nodes were at CI or in the para-aortic region. Three nodes were not visible on any CBCTs, two were outside the CBCT field and three nodes were not visible on some CBCT scan due to artefacts caused by bowel air. The number of CBCT delineations per node was median 10 (range 5–10). In total 417 nodal CBCT contours were evaluated. Based on measurements of the individual nodes at diagnosis, the median GTV-NCT, CTV-N, PTV-N5mm and PTV10mm volumes were 1 cm3 (range 0.1–25.5 cm3), 1.5 cm3 (range 0.2–28.6 cm3), 8.4 cm3 (range 2.9–62.7 cm3) and 19.9 cm3 (range 9.2–98.5 cm3), respectively. Dose constraints could be fulfiled for all nodes with the FC plan 1 and FC plan 2, where the PTV-N D98% was between 95% and 107%. For CovP (plan 3) CTV-N D98% was >99.7% for all nodes and CTV-N D50% >100.6%. Only seven nodes had a CTV-N D50% below 101.5%. Nodal volume diminished during treatment in 40/42 nodes and in the last week of EBRT, five nodes had regressed completely.
Please cite this article in press as: Ramlov A et al. Clinical implementation of coverage probability planning for nodal boosting in locally advanced cervical cancer. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.01.015
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Coverage probability for nodal boosting in cervix cancer
Fig. 2. Treatment plans in colour wash (95–107% of prescribed dose): A) Full coverage with PTV-N10mm (plan 1), B) full coverage with PTV-N5mm (plan 2) and C) coverage probability with PTV-N5mm (plan 3). Panel D is showing an example of delineations of a node (red) on CBCT during external beam radiotherapy. A 5 mm CTV-N to PTV-N margin is indicated by the blue contour. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3. Dose per fraction (D98%) for GTV-NCBCT during external beam radiotherapy in the worst (black) and the best (white) case of a simultaneous integrated boost planned by use of coverage probability (plan 3). Dose per fraction was determined on every second or third cone-beam scan (large symbol).
However, the cystic compartment of two large nodes (7.8 and 25.0 cm3) increased during treatment by 18% and 47%. Including all 42 CBCT visible nodes, the median volume of GTV-NCBCT was
reduced from 1.0 cm3 to 0.2 cm3 on the last CBCT delineation. The mean reduction in nodal size during five weeks of EBRT was 71% (Fig. 4). No significant difference in delivered D98%, D50% or D2% to GTVNCBCT was seen when comparing FC plan 1 and FC plan 2 (Table 1). D98% was >98% for all boosted nodes. One node had a D98% of 93% with CovP (plan 3). The volume of this node was 1 cm3 and the node was located close to the bladder, which with varying bladder filling during EBRT was displaced for some fractions. The remaining nodes all had D98% >95%. Median D98% was significantly lower by 0.7 Gy (p < 0.001) for CovP (plan 3) compared with the FC plan 2. No difference in D50% was found between CovP (plan 3) compared with the FC plan 2 (p = 0.33). D2% was significantly higher by 1.4 Gy (p < 0.001) for CovP (plan 3) compared with the FC plan 2. The median margin required to cover all positional shifts of GTV-NCBCT during EBRT was 5 mm (range 3–12 mm). Fourteen nodes required a margin >5 mm. The node with a D98% of 93% with CovP (plan 3) required a margin of 9 mm to counter all internal motion. D98% for that specific node was 99% with FC plan 2 and 100% with FC plan 1. The remaining nodes with excursions >5 mm all had a coverage with D98% >98% for the two FC plans and >96% with CovP (plan 3). The cumulative dose (EQD2) to GTV-N delivered by CovP planned SIB and BT as a function of GTV-NCBCT volume is shown in Table 2. Neither nodal volume nor anatomical location had an apparent impact on the EQD2. In total, 41/42 of the CBCT visible nodes received a cumulative D98% EBRT and BT >57 GyEQD2.
Please cite this article in press as: Ramlov A et al. Clinical implementation of coverage probability planning for nodal boosting in locally advanced cervical cancer. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.01.015
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Table 2 Nodal location and cumulative equivalent dose in 2 Gy fractions (EQD2) for nodes visible on CBCT. All nodes were treated with a simultaneous integrated boost planned by use of coverage probability planning (plan 3). Nodal location
Boosted nodes
Boosted nodes visible on CBCT
Median EBRT D98, EQD2 (Gy)
Median BT Point dose, EQD2 (Gy)
Total D98 + BT EQD2 (Gy)
Para-aortic Common iliac Presacral Iliaca interna Iliaca externa Obturator Total
4 3 3 7 15 15 47
2 3 2 6 14 15 42
58.5 57.4 54.9 54.6 55.3 55.6 55.6
0 1.2 3.7 4.7 4.5 3.6 3.8
58.5 58.5 58.5 60.0 59.8 59.5 59.5
(58.3–58.5) (55.7–59.6) (54.9–54.9) (51.4–56.0) (53.6–56.9) (54.3–57.0) (51.4–59.6)
(0–2.8) (2.4–4.9) (2.3–9.6) (1.8–6.4) (1.6–5.6) (0–9.6)
(58.3–58.5) (57.4–60.8) (57.3–59.8) (55.5–62.9) (57.3–62.5) (58.0–61.2) (55.5–62.9)
Fig. 4. Relative reduction of nodal volume during external beam radiotherapy in 25 patients with a total number of 42 nodes (Median + 95% CI). An example of nodal volume at planning CT (O) and the subsequent nodal regression observed during treatment (week 1–5) on CBCT is shown below the x-axis.
V50 was significantly reduced for body, bones and bowel comparing FC plan 1 and FC plan 2 with a factor of 1.5, 3.5 and 2 respectively (p < 0.01). With CovP (plan 3), a further decrease in V50 was obtained for all three OARs by a factor of 1.7, 2 and 2 (p < 0.001), respectively compared to the FC plan 2 (Table 1). Not all patients had nodes in the vicinity of bones or bowel, but for some a large gain was achieved. Two patients with several nodes located adjacent to pelvic bones had a decrease from 50 cm3 with FC plan 1– 25 cm3 with FC plan 2 and a further reduction to 6 and 8 cm3 respectively with CovP (plan 3). For the patient with the highest bowel V50, a reduction was seen from 106 cm3 to 68 cm3 from FC plan 1 to FC plan 2 and to 35 cm3 with CovP (plan 3).
Discussion This study demonstrates that CovP based planning of pelvic lymph node SIB in LACC is highly robust when IMRT/VMAT is combined with daily image guidance based on bony fusion. We also demonstrate that most pathological nodes are visible on CBCT and can be monitored for both response and location. The nodal excursions found in our study are in accordance with results of Schippers et al. using repetitive MRI [6]. The 5 mm SIB margin produced ‘‘geographical misses” in 33% of nodal boosts. Still, all nodes received >95% of prescribed dose. By use of CovP we were able to further reduce collateral irradiation of normal tissue and increase the central GTV dose. CovP resulted in D98% >93%
of boosted nodes, and combined EBRT and BT D98% >55.5 Gy for all nodes. Accordingly, we have shown that a heterogeneous dose administration can spare normal tissue and reach a higher dose to the central GTV. This is superior to a classical approach, which aims for a homogeneous dose. In fact, the slight variation in delivered EBRT SIB dose with CovP was smaller than the variation induced by the BT dose to the nodes. There is limited consensus with regard to dose prescription to pathologic lymph nodes. Beadle et al. [14] pointed to the importance of boosting grossly involved nodes. However, a recent study did not find an additional advantage of a cumulative dose including BT >60 GyEQD2 [15]. Thus, the dose–response relationship for pathological nodes seems to be flat already at 55–60 Gy, and small dosimetric variations in delivered dose are not expected to have clinical impact. In accordance with this observation, the recurrence rates of SIB boosted pathological nodes to >55–60 Gy have been shown to be 1–3% [3,15]. The major clinical challenge with regard to nodal control is therefore not control of ‘‘in-field” nodes, but rather nodal recurrences mainly cranially of the EBRT target [14,15]. Irradiation induced morbidity is a significant burden for cervix cancer patients, and relevant reductions of dose and irradiated volume has potential to improve quality of life. Simpson et al. demonstrated a significant relation between bowel V45 and acute bowel toxicity. An increase of 100 ml bowel receiving >45 Gy resulted in a 2-fold increased risk for acute toxicity [16]. A study by Oh et al. found a significant relation between a sacral dose >50.4 Gy and
Please cite this article in press as: Ramlov A et al. Clinical implementation of coverage probability planning for nodal boosting in locally advanced cervical cancer. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.01.015
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Coverage probability for nodal boosting in cervix cancer
the risk of developing pelvic insufficiency fractures [17]. Waldenström et al. demonstrated a correlation between pain and mean absorbed dose of sacral and pubic bones [18,19]. With the proposed CovP planning aims for nodal boosting by SIB, we demonstrated that V50 for bowel and pelvic bones on average could be significantly reduced. As our study is dominated by patients with 1–2 nodes in the true pelvis it is likely that the OAR sparing will be even larger for patients with multiple nodes especially if located at the common iliac vessels or higher. Also on the individual level we noted that the sparing was much greater in certain patients with unfavourable anatomy. Recently the switch to image guided adaptive brachytherapy has led to a significant decrease in G3– G4 bladder, rectum and vaginal toxicity by minimizing the overlapping high dose volume of similar magnitude into OAR in patients with unfavourable anatomy in the central pelvis [12,20– 23]. We may therefore expect that the normal tissue sparing obtained by CovP planned SIB in cases with unfavourable anatomy at the pelvic wall will also be of clinical importance. With CovP a new tool is available in the clinic for nodal SIB in LACC. CovP allows controlled underdosage at the edge of the PTV. Notice also, that geographic misses have only mild dosimetric consequences in a SIB situation, which in turn weakens the justification of a conventional PTV concept. The results presented here for LACC are potentially applicable to other pelvic sites such as anal, vulva, bladder, penile and prostate cancer. As our study is mainly based on pelvic nodes along the major vessels it is still unclear how CovP will perform when using SIB for nodes in the para-aortic region or in the groins. Nodes in the vicinity of organs which may be displaced e.g. by the bladder or rectum, may also need monitoring in terms of delivered dose and eventually plan adaptation during EBRT. Since modern external beam radiotherapy and image guided brachytherapy in LACC now are providing excellent pelvic disease control [12,20–23] a logical priority for further development will be normal tissue sparing for instance through application of highly focal lymph node boosts, and improved selection of patients for para-aortic irradiation. The presented dosimetric results validate the CovP concept for pelvic nodes and quantify the substantial normal tissue sparing in exchange for a minute loss in nodal CTV coverage. This is predominantly the consequence of two factors: the shallow dose gradients around the nodes in the SIB situation, and their volume shrinkage during therapy. Furthermore, as it is feasible to treat pathological nodes with tight margins, it is also expected that the elective nodal target can be treated safely with limited margins (5 mm) when daily IGRT is applied. The current work has been included in the recently initiated EMBRACE II study where reduced PTV margins (5 mm), daily IGRT, IMRT/VMAT CovP planning for SIB and risk adapted use of para-aortic irradiation will be implemented. With an estimated accrual of 800 patients, and 50% of these having node positive disease, a comprehensive study regarding follow-up after CovP based nodal boosting can be expected. Conclusion CovP for nodal SIB in LACC provided sufficient target coverage and a significant reduction in dose to adjacent organs at risk. An increased central dose could be obtained for most nodes. CovP based SIB is now standard in our institution for nodal boosting and is implemented in the Embrace II study. Conflict of interest Anne Ramlov received research grants from the Danish Cancer Society, Denmark and Varian Medical Systems, USA.
Acknowledgements EMBRACE was supported by Varian Medical Systems. Furthermore, this study was supported by research grants to Aarhus University Hospital from Varian Medical Systems and the Danish Cancer Society. References [1] Kidd EA, Siegel BA, Dehdashti F, et al. Lymph node staging by positron emission tomography in cervical cancer: relationship to prognosis. J Clin Oncol 2010;28:2108–13. [2] Cihoric N, Tapia C, Kruger K, Aebersold DM, Klaeser B, Lossl K. IMRT with 18 FDG-PET\CT based simultaneous integrated boost for treatment of nodal positive cervical cancer. Radiat Oncol 2014;9. 83-717X-9-83. [3] Vargo JA, Kim H, Choi S, et al. Extended field intensity modulated radiation therapy with concomitant boost for lymph node-positive cervical cancer: analysis of regional control and recurrence patterns in the positron emission tomography/computed tomography era. Int J Radiat Oncol Biol Phys 2014;90:1091–8. [4] Taylor A, Rockall AG, Reznek RH, Powell ME. Mapping pelvic lymph nodes: guidelines for delineation in intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2005;63:1604–12. [5] Pötter R, Haie-Meder C, Van Limbergen E, et al. Recommendations from gynaecological (GYN) GEC ESTRO working group (II): concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol 2006;78:67–77. [6] Schippers MG, Bol GH, de Leeuw AA, et al. Position shifts and volume changes of pelvic and para-aortic nodes during IMRT for patients with cervical cancer. Radiother Oncol 2014;111:442–5. [7] International Commission on Radiation Units and Measurements. ICRU report 62. Prescribing, recording, and reporting photon beam therapy (Supplement to ICRU report 50). Bethesda, MD: ICRU; 1999. [8] Baum C, Alber M, Birkner M, Nusslin F. Robust treatment planning for intensity modulated radiotherapy of prostate cancer based on coverage probabilities. Radiother Oncol 2006;78:27–35. [9] Hysing LB, Sohn M, Muren LP, Alber M. A coverage probability based method to estimate patient-specific small bowel planning volumes for use in radiotherapy. Radiother Oncol 2011;100:407–11. [10] Stroom JC, de Boer HC, Huizenga H, Visser AG. Inclusion of geometrical uncertainties in radiotherapy treatment planning by means of coverage probability. Int J Radiat Oncol Biol Phys 1999;43:905–19. [11] Embrace study protocol 2008 www.embracestudy.dk. [12] Lindegaard JC, Fokdal LU, Nielsen SK, Juul-Christensen J, Tanderup K. MRIguided adaptive radiotherapy in locally advanced cervical cancer from a Nordic perspective. Acta Oncol 2013;52:1510–9. [13] EMBRACE-II study protocol. 2016 www.embracestudy.dk. [14] Beadle BM, Jhingran A, Yom SS, Ramirez PT, Eifel PJ. Patterns of regional recurrence after definitive radiotherapy for cervical cancer. Int J Radiat Oncol Biol Phys 2010;76:1396–403. [15] Ramlov A, Kroon PS, Jurgenliemk-Schulz IM, et al. Impact of radiation dose and standardized uptake value of (18)FDG PET on nodal control in locally advanced cervical cancer. Acta Oncol 2015;54:1567–73. [16] Simpson DR, Song WY, Moiseenko V, et al. Normal tissue complication probability analysis of acute gastrointestinal toxicity in cervical cancer patients undergoing intensity modulated radiation therapy and concurrent cisplatin. Int J Radiat Oncol Biol Phys 2012;83:e81–6. [17] Oh D, Huh SJ, Nam H, et al. Pelvic insufficiency fracture after pelvic radiotherapy for cervical cancer: analysis of risk factors. Int J Radiat Oncol Biol Phys 2008;70:1183–8. [18] Waldenström AC, Olsson C, Wilderang U, et al. Pain and mean absorbed dose to the pubic bone after radiotherapy among gynecological cancer survivors. Int J Radiat Oncol Biol Phys 2011;80:1171–80. [19] Waldenström AC, Olsson C, Wilderang U, et al. Relative importance of hip and sacral pain among long-term gynecological: cancer survivors treated with pelvic radiotherapy and their relationships to mean absorbed doses. Int J Radiat Oncol Biol Phys 2012;84:428–36. [20] Pötter 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;100:116–23. [21] Nomden CN, de Leeuw AA, 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;107:69–74. [22] Rijkmans EC, Nout RA, Rutten IH, et al. Improved survival of patients with cervical cancer treated with image-guided brachytherapy compared with conventional brachytherapy. Gynecol Oncol 2014;135:231–8. [23] Sturdza A, Potter R, Fokdal LU, et al. Image guided brachytherapy in locally advanced cervical cancer: Improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study. Radiother Oncol 2016;120: 428–33.
Please cite this article in press as: Ramlov A et al. Clinical implementation of coverage probability planning for nodal boosting in locally advanced cervical cancer. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.01.015