Technology in Cancer Research and Treatment ISSN 1533-0346 2014 April 1 Epub ahead of print.
Pelvic Lymph Node Irradiation Including Pararectal Sentinel Nodes for Prostate Cancer Patients: Treatment Optimization Comparing Intensity Modulated X-rays, Volumetric Modulated Arc Therapy, and Intensity Modulated Proton Therapy
Hansjörg Vees, M.D.1* Giovanna Dipasquale, M.Sc.1 Philippe Nouet, M.Sc.1 Thomas Zilli, M.D.1 Luca Cozzi, Ph.D.2 Raymond Miralbell, M.D.1
www.tcrt.org DOI: 10.7785/tcrt.2012.500405
Service of Radiation Oncology,
1
We aimed to assess the dosimetric impact of advanced delivery radiotherapy techniques using either intensity modulated x-ray beams (IMXT), volumetric modulated arc therapy (VMAT), or intensity modulated proton therapy (IMPT), for high-risk prostate cancer patients with sentinel nodes in the pararectal region. Twenty high-risk prostate cancer patients were included in a prospective trial evaluating sentinel nodes on pelvic SPECT acquisition. To be eligible for the dosimetric study, patients had to present with pararectal sentinel nodes usually not included in the clinical target volume encompassing the pelvic lymph nodes. Radiotherapy-plans including the prostate, the seminal vesicles, and the pelvic lymph nodes with the pararectal sentinel nodes were optimized for 6 eligible patients. IMXT and IMPT were delivered with 7 and 3 beams respectively and VMAT with 2 arcs. Results were assessed with Dose-Volume Histograms and predictive normal tissue complication probabilities (NTCPs) models between the three competing treatment modalities aiming to deliver a total dose of 50.4 Gy in 1.8 Gy daily fractions. Target coverage was optimized with IMPT when compared to IMXT and VMAT. Coverage of the sentinel node was slightly better with IMXT (D98% 5 57.3 5.1 Gy) when compared with VMAT (D98% 5 56.2 4.1 Gy). The irradiation of rectal, bladder, small bowel, and femoral heads volumes was significantly reduced with IMPT when compared to IMXT and VMAT. NTCPs rates for rectal and bladder grade-3 late toxicity were better with IMPT (0.4 0.0% and 0.0 0.0%) compared with IMXT (4.6 3.3% and 1.4 1.1%), and VMAT (4.5 4.0% and 1.6 1.6%), respectively. Acceptable dose-volume distributions and low rectal and urinary NTCPs were estimated to geometrically complex pelvic volumes such as the ones proposed in this study using IMXT, VMAT and IMPT. IMPT succeeded, however, to propose the best physical and biological treatment plans compared to both X-ray derived plans.
University Hospital of Geneva, Geneva, Switzerland Oncology Institute of Southern
2
Switzerland, Medical Physics Unit, Bellinzona, Switzerland
Key words: IMXT; IMPT; Prostate cancer; Sentinel node; SPECT; VMAT.
Introduction External beam radiotherapy (EBRT) is a treatment option for locally advanced prostate cancer. For high-risk patients radiotherapy (RT) is often delivered to the Abbreviations: 3D-CRT: 3-Dimensional Conformal RT Techniques; CTV: Clinical Target Volume; DVH: Dose-volume Histogram; EBRT: External Beam Radiotherapy; HI: Homogeneity Index; IMXT: Intensity Modulated X-ray Beams; IMPT: Intensity Modulated Proton Therapy; LN: Lymph Nodes; MLC: Multi Leaf Collimator; NTCPs: Normal Tissue Complication Probabilities; PTV: Planning Target Volume; RBE: Relative Biological Effectiveness; RT: Radiotherapy; SN: Sentinel Nodes; VMAT: Volumetric Modulated Arc Therapy.
*Corresponding author: Hansjörg Vees, M.D. Phone: 141 22 38 27 090 E-mail: [email protected]
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Vees et al.
prostate, the seminal vesicles, and the pelvic lymph nodes (LN) (1). Treatment techniques have evolved rapidly over the last decade with the introduction of Intensity-Modulated RT (IMXT) and its ability to optimize the target coverage while sparing organs at risk when compared to 3-dimensional conformal RT techniques (3D-CRT), thus reducing toxicity without the risk of reducing the chances of tumor control (2-4). In addition to IMXT, volumetric modulated arc therapy (VMAT) and intensity modulation proton therapy (IMPT) have also been recommended to optimize the curative treatment of prostate cancer with RT. Both X-ray and proton treatment techniques have shown to be effective with well-defined toxicity profiles also in the treatment of pelvic LN. This has been evaluated in different comparative planning exercises where VMAT, IMPT, and Tomotherapy have been compared to IMXT showing a dose distribution profile with VMAT and IMPT (5-8). Holl et al., have reported a 3% risk of lymph node metastases from prostate cancer in the pararectal region (9). This LN region is usually excluded from the pelvic treatment volume of high-risk prostate cancer patients as the inclusion of the whole pararectal region would increase the risk to unacceptable levels of acute and late rectal toxicities (10). Lymphoscintigraphy of the prostate with 99mTc-Nanocoll enables the detection of sentinel nodes (SNs) with a very high sensitivity (93-98%), and opens the question of their inclusion in the pelvic clinical target volume (CTV) (11). The next challenge is to assess the feasibility and safety of treating such CTV with the above mentioned highly conformal treatment techniques. The present study was undertaken to assess a treatment planning inter-comparison between IMXT, VMAT, and IMPT using a combination of dosimetric and biological endpoints for patients with pararectal SNs for whom an elective RT of the pelvic LN is foreseen.
slices by 2 experienced radiation oncologists and were defined according to the consensus guidelines of the Radiation Therapy Oncology Group (RTOG) (10). CTV1 included the prostate and seminal vesicles, while CTV2 included the pelvic LN plus CTV1. The pelvic organs at risk (OARs) were as well delineated using the RTOG guidelines, and included the rectum, the bladder, the small bowel, and the femoral heads (13). SPECT study was registered with the corresponding CT images. SNs were identified and contoured together with the lymph nodes of the CTV2 producing a CTV3. The planning target volume (PTV) 1 was derived by a 10-mm expansion around the CTV1 except in the posterior direction, where a 6 mm expansion was used. The PTV2 included the CTV3 plus an isotropic margin of 7 mm. The pelvic nodes, in addition to the prostate and seminal vesicles (PTV1 and PTV2) were planned treated to 50.4 Gy (in 1.8 Gy per fraction), followed by a volume reduction to the prostate and seminal vesicles (PTV1) with 28.0 Gy (in 2.0 Gy per fraction). The total prescribed dose was 78.4 Gy. The following planning objectives were determined for the PTVs and the OARs, when both phases were combined. Regarding the PTVs, treatment plans aimed to achieve 98% of the PTV covered by 95% of the prescribed dose and D1% 102% of the prescribed dose (Dx% is the dose received by at least x% of the volume). All plans were normalized to the mean dose of the PTV. For the rectum and the bladder the Dmean was 39 Gy and 47 Gy, respectively; while the D2% was 77 Gy and 75 Gy, respectively. For the small bowel the maximum dose (D1%) was constrained to 55 Gy and V45 Gy to 195cc. For the femoral heads the V45 Gy was 5%. In all cases, planning objectives were transferred into numerical dose-volume constraints used in the optimization phase and tailored to the specific patient’s characteristics. Priorities were adjusted during optimization to achieve the best results for each patient.
Material and Methods Twenty consecutive prostate cancer patients were prospectively entered into a protocol assessing the value of SN SPECT/CT in RT treatment planning. All patients were at high-risk for LN involvement. This study was approved by the Institutional Ethical Committee and the firsts results concerning target volume definition have been recently published by our group (12). Six patients with pararectal SNs not included in the pelvic CTV as defined by the RTOG guidelines (10) were selected for the purpose of this study. One of these patients presented with bilateral and the other 5 patients with only unilateral pararectal SNs. All 6 patients were planned in the supine position using a knee immobilization device. CTVs were drawn on CT
Three sets of plans were performed for all patients with IMXT, VMAT, and IMPT, respectively. All plans were designed on the Varian Eclipse treatment planning system (version 8.6.10). IMXT and VMAT treatment plans were calculated with 6-MV X-rays Clinac 2100 (Varian, Palo Alto, CA) and the Anisotropic Analytical Algorithm photon dose calculation algorithm was used. The dose calculation grid was set to 2.5 mm. Plans for VMAT were optimized selecting a maximum dose rate (DR) of 600 MU/min and a fixed DR of 600 MU/min was selected for IMXT. The Millennium multi leaf collimator (MLC) (with a spatial resolution of 5mm in the inner 20 cm section) was used for the study.
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Sentinel Nodes for Prostate Cancer Patients using IMXT, VMAT and IMPT IMXT: Plans were designed according to the dynamic sliding window method (14) with seven fixed gantry beams. One single isocentre was located at the center of the target volume. All beams were coplanar with collimator angle set to 0º. VMAT: This technique uses continuous variation of the instantaneous DR, MLC positions and gantry rotational speed to optimize the dose distribution. Details about VMAT optimization process have been published elsewhere (15). To minimize the contribution of tongue and groove effect during the arc rotation and to benefit from leaves trajectories noncoplanar with respect to patient’s axis, the collimator rotation in VMAT remains fixed to a value different from zero. In the present study collimator was rotated to 30º depending on the patient and 2 arcs were used. IMPT: Proton plans have been optimized and computed on the Eclipse treatment planning system (v.11, Varian, Palo Alto, CA). A proton beam line generated by the Varian ProBeam system was simulated. The high level description of the IMPT planning process (described in more detail in (16)) is characterized by the inverse optimization of dose distributions generated by a number of pencil beam spots scanned in the patient. Intensity modulation is realized by tuning of the spot energy and weights simultaneously. The basic workflow was as follows: calculation of the beam line settings, optimization of the spot weights for all field simultaneously inside a cloud describing OARs and target, post-processing of the spot list (where a deliverable spot scanning sequence was generated), and final dose calculation via summing all the scanning layers accounting for differences in tissue properties within the patient. The Bragg peak distribution in depth was achieved by using various pencil beam energies (nominal range: 70-245MeV), and the weights of individual beams were optimized simultaneously for irradiation fields. Energy layers were determined to cover proximally and distally the target (17, 18). Spot spacing was set to 3mm. To improve plan quality, additional, spots were created in the pre-optimisation phase out of the target volume (PTV) edges within a geometrical region defined as follows: laterally inside a circular ring of 5 mm radius; proximally and distally within 5 and 2 mm respectively. A smaller radius was chosen for the extra spots located distally to the target to compensate the trade-off between improved target coverage and undue involvement of abutting organs at risk (mainly bladder and rectum). For each patient, three beams were used to optimize the plans. Gantry angles were individually chosen to identify the best geometrical setting for an individual patients’ anatomy and tumor configuration. In general two oblique anterior fields were used supported by one posterior fields. Gantry angles
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were selected to avoid as much as possible direct entrance through OARs or to minimize the areas of the fields directly abutting against them at the distal edge. For optimization and dose calculation, the Proton Convolution Superposition algorithm was used. A constant relative biological effectiveness (RBE) of 1.1 was applied. Accuracy of the calculation is discussed for example in (19-21) pointing to a difference between calculated and measured point dose for prostate treatment of 0.0 0.7% and a g-index of 96.2 2.6%. Quantitative evaluation of plans was performed by means of standard Dose-Volume Histogram (DVH). For CTV and PTV, the values of D98% and D2% (dose received by at least 98% and 2% of the volume) were defined as metrics for minimum and maximum doses and thereafter reported. To complement the appraisal of minimum and maximum dose, V95% and V107% (the volume receiving at least 95% or at most 107% of the prescribed dose) were reported. The homogeneity of the treatment was expressed in terms of the standard deviation (SD) and of the Homogeneity Index (HI 5 (D5%-D95%)/Dmean). For OARs, the analysis included the mean dose, the maximum dose expressed as D1% and a set of appropriate volume (VX) and dose (DY) metrics. An additional analysis of the DeltaPTV was performed. The DeltaPTV is the difference between PTV1 and PTV2 (obtained with a Boolean operator in the treatment planning). In this case, since the boost PTV is fully included in the large PTV, DeltaPTV represent the part of the large PTV supposed to receive only the low dose level. To visualize the global difference between techniques, average cumulative DVH for CTV and PTV and OARs, were built from the individual DVHs. These DVHs were obtained by averaging the corresponding volumes over the whole patient’s cohort for each dose bin of 0.05 Gy. For the rectum, the bladder, the small bowel, and the femoral heads, the normal tissue complication probability (NTCP) model of Källman et al., was used (22) to ascertain the expected incidence of grade-3 complications. Parameters for various endpoints were derived from literature and reported in Table I. In the relative seriality model, “s” represents the degree of seriality of the organ (1 is for an organ ideally serial), “g” is the dose-response steepness index and D50 is the dose delivered to the whole organ to induce NTCP 5 50%. Statistical analyses and curve fitting were performed using SPSS® (version 15.0, SPSS Inc., Chicago, IL, USA). The paired, two-tails Student’s t-test was applied for comparison of the techniques. The level of statistical significance adopted was p 0.05.
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Vees et al. Table I Parameters used to compute NTCP with the relative seriality model.
Organ Rectum
Endpoint
Grade 3 Bleeding Bladder Contracture and volume loss Small bowel Obstruction perforation Femoral heads Necrosis
D50 (Gy) 83.1
g
s
1.69 0.49
Refs. (31)
80
3
0.18
(30) and (32)
53.6
2.3
1.5
(30)
65
2.7
1
(33)
Abbreviation: NTCP 5 Normal tissue complication probabilities.
Results Figure 1 displays the dose distribution for IMXT, VMAT, and IMPT treatment plans for one patient presenting with two pararectal SNs. In this patient the SN coverage was satisfying with all techniques though VMAT was moderately and IMPT significantly better than IMXT regarding bladder and rectum sparing. Similar results were obtained for the other five patients with one pararectal SN, though significant differences were only found for D1 Gy and the maximum point dose (Table II).
Figure 1: Color wash dose distributions for the planning target volume (PTV). Axial view for one patient with two pararectal sentinel nodes planned with IMXT, VMAT, and IMPT.
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Sentinel Nodes for Prostate Cancer Patients using IMXT, VMAT and IMPT Table II Dosimetric results for target volumes. Parameters
IMXT
VMAT
Table III Dosimetric results for organs at risk.
IMPT
p-value
Parameter
PTV1 Volume (cm3) 183.28 53.37 (110.50-263.10) Mean (Gy) 78.04 0.2 77.81 0.5 75.91 0.9
a, c
D50% (Gy)
SD (Gy)
1.98 0.6
2.10 1.22
8.53 1.5
a, c
D1% (Gy)
HI
0.08 0.02
0.08 0.04
0.27 0.10
a, c
V45 Gy (Gy)
D2% (Gy)
81.97 1.3
80.40 0.3
79.89 1.6
a
D98% (Gy)
72.71 2.1
71.63 5.7
74.3 1.1
a, c
V95% (%)
95.15 3.2
95.67 3.8
97.70 0.81
a, c
V107% (%)
0.10 0.2
0.24 0.5
0.00 0.0
PTV2 Volume (cm ) 999.07 225.2 (774.30-1340.20) Mean (Gy) 59.60 1.5 59.30 1.6 57.74 1.4
a, c
SD (Gy)
b, c
HI
0.48 0.02
10.64 0.5 0.49 0.02
11.36 0.9 0.50 0.01
D2% (Gy)
80.23 0.5
79.19 0.2
79.68 0.7
D98% (Gy)
49.29 0.9
49.17 0.9
48.50 1.1
a
V90% (%)
24.40 4.0
22.56 4.3
21.21 3.7
a, b, c
V95% (%)
20.57 3.6
19.13 3.3
19.39 4.0
a
V107% (%)
0.04 0.1
0.03 0.1
0.13 0.3
DeltaPTV Volume (cm3) 792. 177. (605-1043) Mean (Gy) 55.42 1.2 55.14 1.4 53.74 0.9
a, c
SD (Gy)
7.31 0.8
6.53 0.8
6.90 1.1
a, b
HI
0.41 0.04
0.37 0.03
0.39 0.05
D2% (Gy)
76.11 17
74.10 1.6
76.68 1.1
D98% (Gy)
49.41 0.5
49.31 0.6
49.64 0.4
V95% (%)
3.59 1.7
2.02 0.9
3.51 1.1
V107% (%)
0.03 0.06
0.00 0.0
0.16 0.36
Mean (Gy)
3.36 1.9
3.31 2.5
3.02 2.7
D1% (Gy)
70.08 5.0
67.91 7.5
64.62 11.2
D5% (Gy)
68.70 6.4
66.97 7.5
63.69 10.9
D98% (Gy)
57.30 5.1
56.22 4.1
53.84 4.8
V90% (%)
13.70 20.4
V95% (%)
2.88 7.0
Max point (Gy)
b, c
SN Volume (cm3) 2.03 1.9 (0.3-4.8) 62.47 7.0 61.19 6.0 58.10 8.2
SD (Gy)
V107% (%)
b, c
b
9.34 15.7 10.68 19.8 2.47 6.0
4.90 11.8
0.00 0.0
0.00 0.0
0.00 0.0
71.20 5.2
68.77 7.3
65.37 11.3
b
Abbreviations: Statistically significant p-values: a 5 IMXT vs. IMPT; b 5 IMXT vs. VMAT; c 5 IMPT vs. VMAT; SD 5 Standard deviation; HI 5 (D5-D95)/Dmean; SN 5 Sentinel node; Dx%: Dose received by at least x% of the volume; Vx%: Volume receiving at least x% of the prescribed dose; DeltaPTV: The difference between PTV1 and PTV2 (obtained with a Boolean operator in the treatment planning).
The average cumulative DVHs for PTV1, PTV2, SN and OARs are presented in Figure 2. Tables II and III summarizes the DVH findings. Data are presented as average values standard deviations (SD). None of the techniques achieved the goal of delivering the minimum and maximum
IMXT
VMAT
IMPT
LT Femur. Volume (cm3) 52.03 5.8 (46.6-62.1) 36.55 2.2 33.52 2.5 5.73 5.8
p-value
a, b, c
51.89 3.4
50.70 4.1
20.92 7.2
a, b
9.98 6.3
8.41 6.9
0.00 0.0
a, c
Right Femur. Volume (cm3) 50.50 4.2 (42.9-55.4) 37.53 2.5 35.31 1.9 4.38 3.9 D50% (Gy)
a, c
D1% (Gy)
50.69 3.6
49.56 3.9
18.16 7.7
a, c
V45 Gy (%)
8.91 7.5
7.57 6.2
0.00 0.0
a, c
Bladder. Volume (cm3) 71.60 23.4 (34.9-96.6) 51.4 4.71 50.4 7.7 22.3 5.4
a, c
3
11.02 0.5
5
Dmean (Gy) D50% (Gy)
49.83 7.7
48.13 11.7
12.60 6.7
a, c
D1% (Gy)
79.60 0.5
78.31 1.8
74.43 2.2
a, c
V35 Gy (%)
72.19 14.1
69.18 19.0
27.63 8.6
a, c
V50 Gy (%)
51.18 11.9
49.9 18.7
17.46 6.4
a, c
Rectum. Volume (cm3) 43.83 17.1 (24.5-74.8) 47.3 4.7 46.2 6.3 22.4 4.6
a, c
Dmean (Gy) D50% (Gy)
45.01 8.1
44.09 9.6
15.45 7.0
D1% (Gy)
78.06 1.1
77.29 2.0
72.67 1.8
a, c a
V35 Gy (%)
68.69 8.7
66.10 14.2
24.67 8.9
a, c
V45 Gy (%)
48.83 15.8
47.30 18.6
16.98 6.8
a, c
Small bowel. Volume (cm3) 221.28 140.7 (175.5-537.0) 60.4 9.7 60.9 12.3 60.5 11.7 D1% (Gy) D50% (Gy)
30.5 6.9
30.39 9.2
9.32 5.4
a, c
D25% (Gy)
41.17 4.9
40.24 8.3
24.87 13.7
a, c
V35 Gy (%) V45 Gy (%)
40.87 10.9 16.07 12.8
38.63 19.9 19.45 15.7
17.88 10.4 10.71 6.8
a, c a, c
Abbreviations: Statistically significant p-values: a 5 IMXT vs. IMPT; b 5 IMXT vs. VMAT; c 5 IMPT vs. VMAT; Dx%: Dose received by at least x% of the volume; Vx%: Volume receiving at least x% of the prescribed dose.
dose to the PTVs. IMXT and VMAT showed a target coverage comparable to IMPT although with some statistically significant difference of possibly minor clinical relevance. Dose homogeneity (SD and HI) for PTV1 was better with VMAT and IMXT compared to IMPT. The dose to the bladder and rectal walls, as well as to the small bowel was significantly decreased with IMPT compared to IMXT and VMAT (Figure 2). For the intermediate dose level, this technique reduced to less than a half the percent volume of OAR receiving 35 and 45 Gy (Table III). Only IMPT was able to comply with all dose constraints. IMXT and VMAT were almost identical. IMXT and VMAT were unable to comply with the dose constraints established for the femoral heads (Table III, Figure 2).
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Figure 2: Mean DVHs for PTVs and organs at risk.
Table IV NTCP Results organs at risk. NTCP
IMXT
VMAT
IMPT
Mean Max Min
0.3 0.0 0.6 0.0
Left Femur 0.2 0.0 0.7 0.0
0.0 0.0 0.0 0.0
Mean Max Min
0.2 0.0 0.5 0.0
Right Femur 0.2 0.0 0.6 0.0
0.0 0.0 0.0 0.0
Mean Max Min
1.4 1.1 3.6 0.6
Bladder 1.6 1.6 3.9 0.0
0.0 0.0 0.0 0.0
a
Mean Max Min
4.6 3.3 10.0 1.6
Rectum 4.5 4.0 10.0 1.3
0.4 0.0 0.8 0.1
a, c
Mean Max Min
14.3 9.2 27.4 3.9
Small Bowel 15.9 10.4 26.3 4.1
12.0 7.5 22.1 3.9
p-value
Table IV shows the estimated NTCP values with the different treatment techniques for the bladder, the rectum, the small bowel, and the femoral heads. The NTCP evaluation using the relative seriality model showed lower NTCP values with IMPT compared with the other two treatment techniques. A significant improvement was estimated for vesical and rectal (grade-3) late effects with IMPT (mean SD, 0.0 0.0 and 0.4 0.0) when compared with IMXT (1.4 1.1 and 4.6 3.3) and VMAT (0.4 0.0 and 4.5 4.0), respectively. NTCP values for femoral head necrosis were similarly low with all techniques. Regarding NTCP values for the small bowel there was no difference among treatment plans. Discussion and Conclusion
Abbreviations: Statistically significant p-values: a 5 IMXT vs. IMPT; b 5 IMXT vs. VMAT; c 5 IMPT vs. VMAT.
VMAT (D50G% 5 33.5 2.5 Gy) looked better than IMXT (D50% 5 36.6 2.2 Gy) for the left femoral head (Figure 2). The D50 Gy to the left and right femoral heads with IMPT was 5.7 5.8 Gy and 4.4 3.9 Gy respectively.
This study compares three advanced delivery RT techniques IMXT, VMAT, and IMPT for high-risk prostate cancer patients with pararectal SNs included in the pelvic treatment volume (CTV3). As expected, IMPT presented a significantly better sparing of non target tissues though without a substantial improvement on target coverage compared to IMXT or VMAT. A dosimetric study by Chera et al., demonstrated that protontherapy was able to reduce the OAR volume receiving low- to medium-dose irradiation compared to IMXT in prostate cancer patients treated to the pelvic LN (8). In our study we observed a similar finding and were able to show that even with the addition of the pararectal SNs in the pelvic target the IMPT technique
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Sentinel Nodes for Prostate Cancer Patients using IMXT, VMAT and IMPT
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substantially decreased the dose in the intermediate range level to the bladder, the rectum, and the small bowel when compared to IMXT and VMAT.
patients with positive pararectal SNs and the magnitude of the clinical benefit of these latter techniques remains however to be demonstrated.
Previous studies have demonstrated that VMAT is able to provide similar conformality compared to 7 field IMXT for prostate cancer patients (5, 6, 23, 24). Davidson et al. and Myrehaug et al., have shown that IMXT and VMAT to the pelvic LN region produce similar dose distribution arrangements plans in the treatment of high-risk prostate cancer patients with pelvic lymph node irradiation (5, 25). The major advantage of VMAT over IMXT is the faster treatment delivery. Indeed, we also observed dosimetric equivalent estimations with both IMXT and VMAT in our cohort of patients including the pararectal SN in the target volume. IMXT plans showed higher dose heterogeneity and hot spots in the PTV compared to VMAT or IMPT. Cozzi et al. have shown, however, a better dose distribution to the OAR with VMAT compared to 5 field IMXT in a treatment planning study for cervix cancer (15).
In summary, Acceptable dose-volume distributions and low rectal and urinary NTCPs were estimated to geometrically complex pelvic volumes such as the ones proposed in this study using IMXT, VMAT and IMPT. IMPT succeeded, however, to propose the best physical and biological treatment plans compared to both X-ray derived plans.
As in our study, Ganswindt et al., observed in 32% of their patients’ positive pararectal SNs (11). They showed that IMXT for prostate cancer patients with the inclusion of SNs is feasible with acceptable acute gastrointestinal and genitourinary toxicity. They compared IMXT (5-7 fields) with 3D-CRT and estimated the largest benefit for the rectum for doses 56 Gy. Indeed, the median V56 Gy was 34.2% with IMXT compared to 73.3% with 3D-CRT. In our study the corresponding V56 Gy for the rectum was similar for both IMXT and VMAT but significantly lower for IMPT (Figure 2).
Acknowledgements
Another objective of this study was to evaluate the capability of the different radiation techniques to manage opposite planning objectives such as SN coverage vs. rectum sparing. Only IMPT was able to achieve this paradoxal dose-constraint in these challenging patients, while IMXT and VMAT failed (Tables II and III; Figure 2). The low NTCP values for the femoral heads indicate a negligible long-term risk regardless of planning technique described in this work for the treatment of high-risk prostate cancer patients including pararectal SNs. Different studies have shown a dose-volume relationship for rectal toxicity in treatment of the prostate cancer. In these studies the high and mid dose region are most predictive for rectal toxicity (2628). Concerning urinary toxicity and bladder Cheung et al. showed that “hot-spots” are related to GU toxicity (29). In our study IMPT showed reduced NTCP scores, especially for bladder contraction and volume loss as well as for rectal bleeding. A limitation of our study is the small sample size that limits the applicability of our conclusions to all prostate cancer
Conflict of Interest All authors certify that his manuscript has not been published in whole or in part nor is it being considered for publication elsewhere. Dr. L. Cozzi acts as Scientific Advisor to Varian Medical Systems and is Head of Research and Technological Development to Oncology Institute of Southern Switzerland, IOSI, Bellinzona. Other authors have no conflict of interest.
This study was possible thanks to the support of Fundació Privada CELLEX. References 1. Aizer, A. A., Yu, J. B., McKeon, A. M., Decker, R. H., Colberg, J. W., Peschel, R. E. Whole pelvic radiotherapy versus prostate only radiotherapy in the management of locally advanced or aggressive prostate adenocarcinoma. Int J Radiat Oncol Biol Phys 75, 1344-1349 (2009). DOI: 10.1016/j.ijrobp.2008.12.082 2. Bauman, G., Rumble, R. B., Chen, J., Loblaw, A., Warde, P. Members of the IMRT indications expert panel. Intensity-modulated radiotherapy in the treatment of prostate cancer. Clin Oncol (R Coll Radiol) 24, 461-73 (2012). DOI: 10.1016/j.clon.2012.05.002 3. Yang, B., Zhu, L., Cheng, H., Li, Q., Zhang, Y., Zhao, Y. Dosimetric comparison of intensity modulated radiotherapy and three-dimensional conformal radiotherapy in patients with gynecologic malignancies: a systematic review and meta-analysis. Radiat Oncol 2012, 7:197. DOI: 10.1186/1748-717X-7-197 4. Guckenberger, M., Baier, K., Richter, A., Vordermark, D., Flentje, M. Dose Intensity Modulated Radiation Therapy (IMRT) prevent additional toxicity of treating the pelvic lymph nodes compared to treatment of the prostate only? Radiat Oncol 3, 3 (2008). DOI: 10.1186/1748-717X-7-197 5. Davidson, M. T., Blake, S. J., Batchelar, D. L., Cheung, P., Mah, K. Assessing the role of volumetric modulated arc therapy (VMAT) relative to IMRT and helical tomotherapy in the management of localized, locally advanced, and post-operative prostate cancer. Int J Radiat Oncol Biol Phy 80, 1550-1558 (2011). DOI: 10.1016/ j.ijrobp.2010.10.024 6. Fontenot, J. D., King, M. L., Johnson, S. A., Wood, C. G., Price, M. J., Lo, K. K. Single-arc volumetric-modulated arc therapy can provide dose distributions equivalent to fixed-beam intensity- modulated radiation therapy for prostatic irradiation with seminal vesicle and/or lymph node involvement. Br J Radiol 85, 231-236 (2012). DOI: 10.1259/bjr/94843998
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Cancer Center, Proton Therapy Center, Houston. Med Phys 37, 154163 (2010). PMID: 20175477 20. Arjomandy, B., Sahoo, N., Ciangaru, G., Zhu, R., Song, X., Gillin, M. Verification of patient-specific dose distributions in proton therapy using a commercial two-dimensional ion chamber array. Med Phys 37, 5831-5837 (2010). PMID: 21158295 21. Zhu, X. R., Poenisch, F., Song, X., Johnson, J. L., Ciangaru, G., Taylor, M. B., Lii, M., Martin, C., Arjomandy, B., Lee, A. K., Choi, S., Nguyen, Q. N., Gillin, M. T., Sahoo, N. Patient-specific quality assurance for prostate cancer patients receiving spot scanning proton therapy using single-field uniform dose. Int J Radiat Oncol Biol Phys 81, 552-559 (2011). DOI: 10.1016/j.ijrobp.2010.11.071 22. Källman, P., Agren, A., Brahme, A. Tumour and normal tissue responses to fractionated non-uniform dose delivery. Int J Radiat Biol 62, 249-262 (1992). PMID: 1355519 23. Palma, D., Vollans, E., James, K., Nakano, S., Moiseenko, V., Shaffer, R., McKenzie, M., Morris, J., Otto, K. Volumetric modulated arc therapy for delivery of prostate radiotherapy: Comparison with intensity-modulated radiotherapy and three dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 72, 996-1001 (2008). DOI: 10.1016/j.ijrobp.2008.02.047 24. Wolff, D., Stieler, F., Welzel, G., Lorenz, F., Abo-Madyan, Y., Mai, S., Herskind, C., Polednik, M., Steil, V., Wenz, F., Lohr, F. Volumetric modulated arc therapy (VMAT) vs. serial tomotherapy, step-and-shoot IMRT and 3D conformal RT for treatment of prostate cancer. Radiother Oncol 93, 226-233 (2009). DOI: 10.1016/ j.radonc.2009.08.011 25. Myrehaug, S., Chan, G., Craig, T., Weinberg, V., Cheng, C., Roach, M. 3rd, Cheung, P., Sahgal, A. A treatment planning and acute toxicity comparison of two pelvic nodal volume delineation techniques and delivery comparison of intensity-modulated radiotherapy versus volumetric modulated arc therapy for hypofractionated high-risk prostate cancer radiotherapy. Int J Radiat Oncol Biol Phys 82, 657662 (2012). DOI: 10.1016/j.ijrobp.2011.09.006 26. Ballare, A., Di Salvo, M., Loi, G., Ferrari, G., Beldi, D., Krengli, M. Conformal radiotherapy of clinically localized prostate cancer: analysis of rectal and urinary toxicity and correlation with dose-volume parameters. Tumori 95, 160-168 (2009). PMID: 19579861 27. Skwarchuk, M. W., Jackson, A., Zelefsky, M. J., Venkatraman, E. S., Cowen, D. M., Levegrün, S., Burman, C. M., Fuks, Z., Leibel, S. A., Ling, C. C. Late rectal toxicity after conformal radiotherapy of prostate cancer (I): multivariate analysis and dose-response. Int J Radiat Oncol Biol Phys 47, 103-113 (2000). PMID: 10758311 28. Koper, P. C., Heemsbergen, W. D., Hoogeman, M. S., Jansen, P. P., Hart, G. A., Wijnmaalen, A. J., van Os, M., Boersma, L. J., Lebesque, J. V., Levendag, P. Impact of volume and location of irradiated rectum wall on rectal blood loss after radiotherapy of prostate cancer. Int J Radiat Oncol Biol Phys 58, 1072-1082 (2004). PMID:15001247 29. Cheung, M. R., Tucker, S. L., Dong, L., de Crevoisier, R., Lee, A. K., Frank, S., Kudchadker, R. J., Thames, H., Mohan, R., Kuban, D. Investigation of bladder dose and volume factors influencing late urinary toxicity after external beam radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 67, 1059-1065 (2007). PMID: 17241755 30. Muren, L. P., Wasbø, E., Helle, S. I., Hysing, L. B., Karlsdottir, A., Odland, O. H., Valen, H., Ekerold, R., Johannessen, D. C. Intensity- modulated radiotherapy of pelvic lymph nodes in locally advanced prostate cancer: planning procedures and early experiences. Int J Radiat Oncol Biol Phys 71, 1034-1041 (2008). DOI: 10.1016/j. ijrobp.2007.11.060 31. Rancati, T., Fiorino, C., Gagliardi, G., Cattaneo, G. M., Sanguineti, G., Borca, V. C., Cozzarini, C., Fellin, G., Foppiano, F., Girelli, G., Menegotti, L., Piazzolla, A., Vavassori, V., Valdagni, R. Fitting late
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Sentinel Nodes for Prostate Cancer Patients using IMXT, VMAT and IMPT rectal bleeding data using different NTCP models: results from an Italian multi-centric study (AIROPROS0101). Radiother Oncol 73, 21-32 (2004). PMID: 15465142 32. Å´gren-Cronqvist, A. K. Quantification of the Response of Heterogeneous Tumours and Organized Normal Tissues to Fractionated
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Radiotherapy. PhD Thesis, Stockholm University, Department of Medical Radiation Physics Stockholm (1995). 33. Burman, C., Kutcher, G. J., Emami, B., Goitein, M. Fitting of normal tissue tolerance data to an analytic function. Int J Radiat Oncol Biol Phys 21, 123-135 (1991). PMID: 2032883 Received: September 26, 2013; Revised: November 4, 2013; Accepted: November 9, 2013
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Pelvic Lymph Node Irradiation Including Pararectal Sentinel Nodes for Prostate Cancer Patients: Treatment Optimization Comparing Intensity Modulated X-rays, Volumetric Modulated Arc Therapy, and Intensity Modulated Proton Therapy
Hansjörg Vees, M.D.1* Giovanna Dipasquale, M.Sc.1 Philippe Nouet, M.Sc.1 Thomas Zilli, M.D.1 Luca Cozzi, Ph.D.2 Raymond Miralbell, M.D.1
www.tcrt.org DOI: 10.7785/tcrt.2012.500405
Service of Radiation Oncology,
1
We aimed to assess the dosimetric impact of advanced delivery radiotherapy techniques using either intensity modulated x-ray beams (IMXT), volumetric modulated arc therapy (VMAT), or intensity modulated proton therapy (IMPT), for high-risk prostate cancer patients with sentinel nodes in the pararectal region. Twenty high-risk prostate cancer patients were included in a prospective trial evaluating sentinel nodes on pelvic SPECT acquisition. To be eligible for the dosimetric study, patients had to present with pararectal sentinel nodes usually not included in the clinical target volume encompassing the pelvic lymph nodes. Radiotherapy-plans including the prostate, the seminal vesicles, and the pelvic lymph nodes with the pararectal sentinel nodes were optimized for 6 eligible patients. IMXT and IMPT were delivered with 7 and 3 beams respectively and VMAT with 2 arcs. Results were assessed with Dose-Volume Histograms and predictive normal tissue complication probabilities (NTCPs) models between the three competing treatment modalities aiming to deliver a total dose of 50.4 Gy in 1.8 Gy daily fractions. Target coverage was optimized with IMPT when compared to IMXT and VMAT. Coverage of the sentinel node was slightly better with IMXT (D98% 5 57.3 5.1 Gy) when compared with VMAT (D98% 5 56.2 4.1 Gy). The irradiation of rectal, bladder, small bowel, and femoral heads volumes was significantly reduced with IMPT when compared to IMXT and VMAT. NTCPs rates for rectal and bladder grade-3 late toxicity were better with IMPT (0.4 0.0% and 0.0 0.0%) compared with IMXT (4.6 3.3% and 1.4 1.1%), and VMAT (4.5 4.0% and 1.6 1.6%), respectively. Acceptable dose-volume distributions and low rectal and urinary NTCPs were estimated to geometrically complex pelvic volumes such as the ones proposed in this study using IMXT, VMAT and IMPT. IMPT succeeded, however, to propose the best physical and biological treatment plans compared to both X-ray derived plans.
University Hospital of Geneva, Geneva, Switzerland Oncology Institute of Southern
2
Switzerland, Medical Physics Unit, Bellinzona, Switzerland
Key words: IMXT; IMPT; Prostate cancer; Sentinel node; SPECT; VMAT.
Introduction External beam radiotherapy (EBRT) is a treatment option for locally advanced prostate cancer. For high-risk patients radiotherapy (RT) is often delivered to the Abbreviations: 3D-CRT: 3-Dimensional Conformal RT Techniques; CTV: Clinical Target Volume; DVH: Dose-volume Histogram; EBRT: External Beam Radiotherapy; HI: Homogeneity Index; IMXT: Intensity Modulated X-ray Beams; IMPT: Intensity Modulated Proton Therapy; LN: Lymph Nodes; MLC: Multi Leaf Collimator; NTCPs: Normal Tissue Complication Probabilities; PTV: Planning Target Volume; RBE: Relative Biological Effectiveness; RT: Radiotherapy; SN: Sentinel Nodes; VMAT: Volumetric Modulated Arc Therapy.
*Corresponding author: Hansjörg Vees, M.D. Phone: 141 22 38 27 090 E-mail: [email protected]
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prostate, the seminal vesicles, and the pelvic lymph nodes (LN) (1). Treatment techniques have evolved rapidly over the last decade with the introduction of Intensity-Modulated RT (IMXT) and its ability to optimize the target coverage while sparing organs at risk when compared to 3-dimensional conformal RT techniques (3D-CRT), thus reducing toxicity without the risk of reducing the chances of tumor control (2-4). In addition to IMXT, volumetric modulated arc therapy (VMAT) and intensity modulation proton therapy (IMPT) have also been recommended to optimize the curative treatment of prostate cancer with RT. Both X-ray and proton treatment techniques have shown to be effective with well-defined toxicity profiles also in the treatment of pelvic LN. This has been evaluated in different comparative planning exercises where VMAT, IMPT, and Tomotherapy have been compared to IMXT showing a dose distribution profile with VMAT and IMPT (5-8). Holl et al., have reported a 3% risk of lymph node metastases from prostate cancer in the pararectal region (9). This LN region is usually excluded from the pelvic treatment volume of high-risk prostate cancer patients as the inclusion of the whole pararectal region would increase the risk to unacceptable levels of acute and late rectal toxicities (10). Lymphoscintigraphy of the prostate with 99mTc-Nanocoll enables the detection of sentinel nodes (SNs) with a very high sensitivity (93-98%), and opens the question of their inclusion in the pelvic clinical target volume (CTV) (11). The next challenge is to assess the feasibility and safety of treating such CTV with the above mentioned highly conformal treatment techniques. The present study was undertaken to assess a treatment planning inter-comparison between IMXT, VMAT, and IMPT using a combination of dosimetric and biological endpoints for patients with pararectal SNs for whom an elective RT of the pelvic LN is foreseen.
slices by 2 experienced radiation oncologists and were defined according to the consensus guidelines of the Radiation Therapy Oncology Group (RTOG) (10). CTV1 included the prostate and seminal vesicles, while CTV2 included the pelvic LN plus CTV1. The pelvic organs at risk (OARs) were as well delineated using the RTOG guidelines, and included the rectum, the bladder, the small bowel, and the femoral heads (13). SPECT study was registered with the corresponding CT images. SNs were identified and contoured together with the lymph nodes of the CTV2 producing a CTV3. The planning target volume (PTV) 1 was derived by a 10-mm expansion around the CTV1 except in the posterior direction, where a 6 mm expansion was used. The PTV2 included the CTV3 plus an isotropic margin of 7 mm. The pelvic nodes, in addition to the prostate and seminal vesicles (PTV1 and PTV2) were planned treated to 50.4 Gy (in 1.8 Gy per fraction), followed by a volume reduction to the prostate and seminal vesicles (PTV1) with 28.0 Gy (in 2.0 Gy per fraction). The total prescribed dose was 78.4 Gy. The following planning objectives were determined for the PTVs and the OARs, when both phases were combined. Regarding the PTVs, treatment plans aimed to achieve 98% of the PTV covered by 95% of the prescribed dose and D1% 102% of the prescribed dose (Dx% is the dose received by at least x% of the volume). All plans were normalized to the mean dose of the PTV. For the rectum and the bladder the Dmean was 39 Gy and 47 Gy, respectively; while the D2% was 77 Gy and 75 Gy, respectively. For the small bowel the maximum dose (D1%) was constrained to 55 Gy and V45 Gy to 195cc. For the femoral heads the V45 Gy was 5%. In all cases, planning objectives were transferred into numerical dose-volume constraints used in the optimization phase and tailored to the specific patient’s characteristics. Priorities were adjusted during optimization to achieve the best results for each patient.
Material and Methods Twenty consecutive prostate cancer patients were prospectively entered into a protocol assessing the value of SN SPECT/CT in RT treatment planning. All patients were at high-risk for LN involvement. This study was approved by the Institutional Ethical Committee and the firsts results concerning target volume definition have been recently published by our group (12). Six patients with pararectal SNs not included in the pelvic CTV as defined by the RTOG guidelines (10) were selected for the purpose of this study. One of these patients presented with bilateral and the other 5 patients with only unilateral pararectal SNs. All 6 patients were planned in the supine position using a knee immobilization device. CTVs were drawn on CT
Three sets of plans were performed for all patients with IMXT, VMAT, and IMPT, respectively. All plans were designed on the Varian Eclipse treatment planning system (version 8.6.10). IMXT and VMAT treatment plans were calculated with 6-MV X-rays Clinac 2100 (Varian, Palo Alto, CA) and the Anisotropic Analytical Algorithm photon dose calculation algorithm was used. The dose calculation grid was set to 2.5 mm. Plans for VMAT were optimized selecting a maximum dose rate (DR) of 600 MU/min and a fixed DR of 600 MU/min was selected for IMXT. The Millennium multi leaf collimator (MLC) (with a spatial resolution of 5mm in the inner 20 cm section) was used for the study.
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Sentinel Nodes for Prostate Cancer Patients using IMXT, VMAT and IMPT IMXT: Plans were designed according to the dynamic sliding window method (14) with seven fixed gantry beams. One single isocentre was located at the center of the target volume. All beams were coplanar with collimator angle set to 0º. VMAT: This technique uses continuous variation of the instantaneous DR, MLC positions and gantry rotational speed to optimize the dose distribution. Details about VMAT optimization process have been published elsewhere (15). To minimize the contribution of tongue and groove effect during the arc rotation and to benefit from leaves trajectories noncoplanar with respect to patient’s axis, the collimator rotation in VMAT remains fixed to a value different from zero. In the present study collimator was rotated to 30º depending on the patient and 2 arcs were used. IMPT: Proton plans have been optimized and computed on the Eclipse treatment planning system (v.11, Varian, Palo Alto, CA). A proton beam line generated by the Varian ProBeam system was simulated. The high level description of the IMPT planning process (described in more detail in (16)) is characterized by the inverse optimization of dose distributions generated by a number of pencil beam spots scanned in the patient. Intensity modulation is realized by tuning of the spot energy and weights simultaneously. The basic workflow was as follows: calculation of the beam line settings, optimization of the spot weights for all field simultaneously inside a cloud describing OARs and target, post-processing of the spot list (where a deliverable spot scanning sequence was generated), and final dose calculation via summing all the scanning layers accounting for differences in tissue properties within the patient. The Bragg peak distribution in depth was achieved by using various pencil beam energies (nominal range: 70-245MeV), and the weights of individual beams were optimized simultaneously for irradiation fields. Energy layers were determined to cover proximally and distally the target (17, 18). Spot spacing was set to 3mm. To improve plan quality, additional, spots were created in the pre-optimisation phase out of the target volume (PTV) edges within a geometrical region defined as follows: laterally inside a circular ring of 5 mm radius; proximally and distally within 5 and 2 mm respectively. A smaller radius was chosen for the extra spots located distally to the target to compensate the trade-off between improved target coverage and undue involvement of abutting organs at risk (mainly bladder and rectum). For each patient, three beams were used to optimize the plans. Gantry angles were individually chosen to identify the best geometrical setting for an individual patients’ anatomy and tumor configuration. In general two oblique anterior fields were used supported by one posterior fields. Gantry angles
3
were selected to avoid as much as possible direct entrance through OARs or to minimize the areas of the fields directly abutting against them at the distal edge. For optimization and dose calculation, the Proton Convolution Superposition algorithm was used. A constant relative biological effectiveness (RBE) of 1.1 was applied. Accuracy of the calculation is discussed for example in (19-21) pointing to a difference between calculated and measured point dose for prostate treatment of 0.0 0.7% and a g-index of 96.2 2.6%. Quantitative evaluation of plans was performed by means of standard Dose-Volume Histogram (DVH). For CTV and PTV, the values of D98% and D2% (dose received by at least 98% and 2% of the volume) were defined as metrics for minimum and maximum doses and thereafter reported. To complement the appraisal of minimum and maximum dose, V95% and V107% (the volume receiving at least 95% or at most 107% of the prescribed dose) were reported. The homogeneity of the treatment was expressed in terms of the standard deviation (SD) and of the Homogeneity Index (HI 5 (D5%-D95%)/Dmean). For OARs, the analysis included the mean dose, the maximum dose expressed as D1% and a set of appropriate volume (VX) and dose (DY) metrics. An additional analysis of the DeltaPTV was performed. The DeltaPTV is the difference between PTV1 and PTV2 (obtained with a Boolean operator in the treatment planning). In this case, since the boost PTV is fully included in the large PTV, DeltaPTV represent the part of the large PTV supposed to receive only the low dose level. To visualize the global difference between techniques, average cumulative DVH for CTV and PTV and OARs, were built from the individual DVHs. These DVHs were obtained by averaging the corresponding volumes over the whole patient’s cohort for each dose bin of 0.05 Gy. For the rectum, the bladder, the small bowel, and the femoral heads, the normal tissue complication probability (NTCP) model of Källman et al., was used (22) to ascertain the expected incidence of grade-3 complications. Parameters for various endpoints were derived from literature and reported in Table I. In the relative seriality model, “s” represents the degree of seriality of the organ (1 is for an organ ideally serial), “g” is the dose-response steepness index and D50 is the dose delivered to the whole organ to induce NTCP 5 50%. Statistical analyses and curve fitting were performed using SPSS® (version 15.0, SPSS Inc., Chicago, IL, USA). The paired, two-tails Student’s t-test was applied for comparison of the techniques. The level of statistical significance adopted was p 0.05.
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Vees et al. Table I Parameters used to compute NTCP with the relative seriality model.
Organ Rectum
Endpoint
Grade 3 Bleeding Bladder Contracture and volume loss Small bowel Obstruction perforation Femoral heads Necrosis
D50 (Gy) 83.1
g
s
1.69 0.49
Refs. (31)
80
3
0.18
(30) and (32)
53.6
2.3
1.5
(30)
65
2.7
1
(33)
Abbreviation: NTCP 5 Normal tissue complication probabilities.
Results Figure 1 displays the dose distribution for IMXT, VMAT, and IMPT treatment plans for one patient presenting with two pararectal SNs. In this patient the SN coverage was satisfying with all techniques though VMAT was moderately and IMPT significantly better than IMXT regarding bladder and rectum sparing. Similar results were obtained for the other five patients with one pararectal SN, though significant differences were only found for D1 Gy and the maximum point dose (Table II).
Figure 1: Color wash dose distributions for the planning target volume (PTV). Axial view for one patient with two pararectal sentinel nodes planned with IMXT, VMAT, and IMPT.
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Sentinel Nodes for Prostate Cancer Patients using IMXT, VMAT and IMPT Table II Dosimetric results for target volumes. Parameters
IMXT
VMAT
Table III Dosimetric results for organs at risk.
IMPT
p-value
Parameter
PTV1 Volume (cm3) 183.28 53.37 (110.50-263.10) Mean (Gy) 78.04 0.2 77.81 0.5 75.91 0.9
a, c
D50% (Gy)
SD (Gy)
1.98 0.6
2.10 1.22
8.53 1.5
a, c
D1% (Gy)
HI
0.08 0.02
0.08 0.04
0.27 0.10
a, c
V45 Gy (Gy)
D2% (Gy)
81.97 1.3
80.40 0.3
79.89 1.6
a
D98% (Gy)
72.71 2.1
71.63 5.7
74.3 1.1
a, c
V95% (%)
95.15 3.2
95.67 3.8
97.70 0.81
a, c
V107% (%)
0.10 0.2
0.24 0.5
0.00 0.0
PTV2 Volume (cm ) 999.07 225.2 (774.30-1340.20) Mean (Gy) 59.60 1.5 59.30 1.6 57.74 1.4
a, c
SD (Gy)
b, c
HI
0.48 0.02
10.64 0.5 0.49 0.02
11.36 0.9 0.50 0.01
D2% (Gy)
80.23 0.5
79.19 0.2
79.68 0.7
D98% (Gy)
49.29 0.9
49.17 0.9
48.50 1.1
a
V90% (%)
24.40 4.0
22.56 4.3
21.21 3.7
a, b, c
V95% (%)
20.57 3.6
19.13 3.3
19.39 4.0
a
V107% (%)
0.04 0.1
0.03 0.1
0.13 0.3
DeltaPTV Volume (cm3) 792. 177. (605-1043) Mean (Gy) 55.42 1.2 55.14 1.4 53.74 0.9
a, c
SD (Gy)
7.31 0.8
6.53 0.8
6.90 1.1
a, b
HI
0.41 0.04
0.37 0.03
0.39 0.05
D2% (Gy)
76.11 17
74.10 1.6
76.68 1.1
D98% (Gy)
49.41 0.5
49.31 0.6
49.64 0.4
V95% (%)
3.59 1.7
2.02 0.9
3.51 1.1
V107% (%)
0.03 0.06
0.00 0.0
0.16 0.36
Mean (Gy)
3.36 1.9
3.31 2.5
3.02 2.7
D1% (Gy)
70.08 5.0
67.91 7.5
64.62 11.2
D5% (Gy)
68.70 6.4
66.97 7.5
63.69 10.9
D98% (Gy)
57.30 5.1
56.22 4.1
53.84 4.8
V90% (%)
13.70 20.4
V95% (%)
2.88 7.0
Max point (Gy)
b, c
SN Volume (cm3) 2.03 1.9 (0.3-4.8) 62.47 7.0 61.19 6.0 58.10 8.2
SD (Gy)
V107% (%)
b, c
b
9.34 15.7 10.68 19.8 2.47 6.0
4.90 11.8
0.00 0.0
0.00 0.0
0.00 0.0
71.20 5.2
68.77 7.3
65.37 11.3
b
Abbreviations: Statistically significant p-values: a 5 IMXT vs. IMPT; b 5 IMXT vs. VMAT; c 5 IMPT vs. VMAT; SD 5 Standard deviation; HI 5 (D5-D95)/Dmean; SN 5 Sentinel node; Dx%: Dose received by at least x% of the volume; Vx%: Volume receiving at least x% of the prescribed dose; DeltaPTV: The difference between PTV1 and PTV2 (obtained with a Boolean operator in the treatment planning).
The average cumulative DVHs for PTV1, PTV2, SN and OARs are presented in Figure 2. Tables II and III summarizes the DVH findings. Data are presented as average values standard deviations (SD). None of the techniques achieved the goal of delivering the minimum and maximum
IMXT
VMAT
IMPT
LT Femur. Volume (cm3) 52.03 5.8 (46.6-62.1) 36.55 2.2 33.52 2.5 5.73 5.8
p-value
a, b, c
51.89 3.4
50.70 4.1
20.92 7.2
a, b
9.98 6.3
8.41 6.9
0.00 0.0
a, c
Right Femur. Volume (cm3) 50.50 4.2 (42.9-55.4) 37.53 2.5 35.31 1.9 4.38 3.9 D50% (Gy)
a, c
D1% (Gy)
50.69 3.6
49.56 3.9
18.16 7.7
a, c
V45 Gy (%)
8.91 7.5
7.57 6.2
0.00 0.0
a, c
Bladder. Volume (cm3) 71.60 23.4 (34.9-96.6) 51.4 4.71 50.4 7.7 22.3 5.4
a, c
3
11.02 0.5
5
Dmean (Gy) D50% (Gy)
49.83 7.7
48.13 11.7
12.60 6.7
a, c
D1% (Gy)
79.60 0.5
78.31 1.8
74.43 2.2
a, c
V35 Gy (%)
72.19 14.1
69.18 19.0
27.63 8.6
a, c
V50 Gy (%)
51.18 11.9
49.9 18.7
17.46 6.4
a, c
Rectum. Volume (cm3) 43.83 17.1 (24.5-74.8) 47.3 4.7 46.2 6.3 22.4 4.6
a, c
Dmean (Gy) D50% (Gy)
45.01 8.1
44.09 9.6
15.45 7.0
D1% (Gy)
78.06 1.1
77.29 2.0
72.67 1.8
a, c a
V35 Gy (%)
68.69 8.7
66.10 14.2
24.67 8.9
a, c
V45 Gy (%)
48.83 15.8
47.30 18.6
16.98 6.8
a, c
Small bowel. Volume (cm3) 221.28 140.7 (175.5-537.0) 60.4 9.7 60.9 12.3 60.5 11.7 D1% (Gy) D50% (Gy)
30.5 6.9
30.39 9.2
9.32 5.4
a, c
D25% (Gy)
41.17 4.9
40.24 8.3
24.87 13.7
a, c
V35 Gy (%) V45 Gy (%)
40.87 10.9 16.07 12.8
38.63 19.9 19.45 15.7
17.88 10.4 10.71 6.8
a, c a, c
Abbreviations: Statistically significant p-values: a 5 IMXT vs. IMPT; b 5 IMXT vs. VMAT; c 5 IMPT vs. VMAT; Dx%: Dose received by at least x% of the volume; Vx%: Volume receiving at least x% of the prescribed dose.
dose to the PTVs. IMXT and VMAT showed a target coverage comparable to IMPT although with some statistically significant difference of possibly minor clinical relevance. Dose homogeneity (SD and HI) for PTV1 was better with VMAT and IMXT compared to IMPT. The dose to the bladder and rectal walls, as well as to the small bowel was significantly decreased with IMPT compared to IMXT and VMAT (Figure 2). For the intermediate dose level, this technique reduced to less than a half the percent volume of OAR receiving 35 and 45 Gy (Table III). Only IMPT was able to comply with all dose constraints. IMXT and VMAT were almost identical. IMXT and VMAT were unable to comply with the dose constraints established for the femoral heads (Table III, Figure 2).
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Figure 2: Mean DVHs for PTVs and organs at risk.
Table IV NTCP Results organs at risk. NTCP
IMXT
VMAT
IMPT
Mean Max Min
0.3 0.0 0.6 0.0
Left Femur 0.2 0.0 0.7 0.0
0.0 0.0 0.0 0.0
Mean Max Min
0.2 0.0 0.5 0.0
Right Femur 0.2 0.0 0.6 0.0
0.0 0.0 0.0 0.0
Mean Max Min
1.4 1.1 3.6 0.6
Bladder 1.6 1.6 3.9 0.0
0.0 0.0 0.0 0.0
a
Mean Max Min
4.6 3.3 10.0 1.6
Rectum 4.5 4.0 10.0 1.3
0.4 0.0 0.8 0.1
a, c
Mean Max Min
14.3 9.2 27.4 3.9
Small Bowel 15.9 10.4 26.3 4.1
12.0 7.5 22.1 3.9
p-value
Table IV shows the estimated NTCP values with the different treatment techniques for the bladder, the rectum, the small bowel, and the femoral heads. The NTCP evaluation using the relative seriality model showed lower NTCP values with IMPT compared with the other two treatment techniques. A significant improvement was estimated for vesical and rectal (grade-3) late effects with IMPT (mean SD, 0.0 0.0 and 0.4 0.0) when compared with IMXT (1.4 1.1 and 4.6 3.3) and VMAT (0.4 0.0 and 4.5 4.0), respectively. NTCP values for femoral head necrosis were similarly low with all techniques. Regarding NTCP values for the small bowel there was no difference among treatment plans. Discussion and Conclusion
Abbreviations: Statistically significant p-values: a 5 IMXT vs. IMPT; b 5 IMXT vs. VMAT; c 5 IMPT vs. VMAT.
VMAT (D50G% 5 33.5 2.5 Gy) looked better than IMXT (D50% 5 36.6 2.2 Gy) for the left femoral head (Figure 2). The D50 Gy to the left and right femoral heads with IMPT was 5.7 5.8 Gy and 4.4 3.9 Gy respectively.
This study compares three advanced delivery RT techniques IMXT, VMAT, and IMPT for high-risk prostate cancer patients with pararectal SNs included in the pelvic treatment volume (CTV3). As expected, IMPT presented a significantly better sparing of non target tissues though without a substantial improvement on target coverage compared to IMXT or VMAT. A dosimetric study by Chera et al., demonstrated that protontherapy was able to reduce the OAR volume receiving low- to medium-dose irradiation compared to IMXT in prostate cancer patients treated to the pelvic LN (8). In our study we observed a similar finding and were able to show that even with the addition of the pararectal SNs in the pelvic target the IMPT technique
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substantially decreased the dose in the intermediate range level to the bladder, the rectum, and the small bowel when compared to IMXT and VMAT.
patients with positive pararectal SNs and the magnitude of the clinical benefit of these latter techniques remains however to be demonstrated.
Previous studies have demonstrated that VMAT is able to provide similar conformality compared to 7 field IMXT for prostate cancer patients (5, 6, 23, 24). Davidson et al. and Myrehaug et al., have shown that IMXT and VMAT to the pelvic LN region produce similar dose distribution arrangements plans in the treatment of high-risk prostate cancer patients with pelvic lymph node irradiation (5, 25). The major advantage of VMAT over IMXT is the faster treatment delivery. Indeed, we also observed dosimetric equivalent estimations with both IMXT and VMAT in our cohort of patients including the pararectal SN in the target volume. IMXT plans showed higher dose heterogeneity and hot spots in the PTV compared to VMAT or IMPT. Cozzi et al. have shown, however, a better dose distribution to the OAR with VMAT compared to 5 field IMXT in a treatment planning study for cervix cancer (15).
In summary, Acceptable dose-volume distributions and low rectal and urinary NTCPs were estimated to geometrically complex pelvic volumes such as the ones proposed in this study using IMXT, VMAT and IMPT. IMPT succeeded, however, to propose the best physical and biological treatment plans compared to both X-ray derived plans.
As in our study, Ganswindt et al., observed in 32% of their patients’ positive pararectal SNs (11). They showed that IMXT for prostate cancer patients with the inclusion of SNs is feasible with acceptable acute gastrointestinal and genitourinary toxicity. They compared IMXT (5-7 fields) with 3D-CRT and estimated the largest benefit for the rectum for doses 56 Gy. Indeed, the median V56 Gy was 34.2% with IMXT compared to 73.3% with 3D-CRT. In our study the corresponding V56 Gy for the rectum was similar for both IMXT and VMAT but significantly lower for IMPT (Figure 2).
Acknowledgements
Another objective of this study was to evaluate the capability of the different radiation techniques to manage opposite planning objectives such as SN coverage vs. rectum sparing. Only IMPT was able to achieve this paradoxal dose-constraint in these challenging patients, while IMXT and VMAT failed (Tables II and III; Figure 2). The low NTCP values for the femoral heads indicate a negligible long-term risk regardless of planning technique described in this work for the treatment of high-risk prostate cancer patients including pararectal SNs. Different studies have shown a dose-volume relationship for rectal toxicity in treatment of the prostate cancer. In these studies the high and mid dose region are most predictive for rectal toxicity (2628). Concerning urinary toxicity and bladder Cheung et al. showed that “hot-spots” are related to GU toxicity (29). In our study IMPT showed reduced NTCP scores, especially for bladder contraction and volume loss as well as for rectal bleeding. A limitation of our study is the small sample size that limits the applicability of our conclusions to all prostate cancer
Conflict of Interest All authors certify that his manuscript has not been published in whole or in part nor is it being considered for publication elsewhere. Dr. L. Cozzi acts as Scientific Advisor to Varian Medical Systems and is Head of Research and Technological Development to Oncology Institute of Southern Switzerland, IOSI, Bellinzona. Other authors have no conflict of interest.
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