- Email: [email protected]
Space-Making Particle Therapy with Surgical Spacer Placement in Patients with Sacral Chordoma
Journal Pre-proof Space-Making Particle Therapy with Surgical Spacer Placement in Patients with Sacral Chordoma Daisuke Tsugawa, MD, PhD, Shohei Komatsu, MD, PhD, Yusuke Demizu, MD, PhD, Nor Shazrina Sulaiman, MD, PhD, Masaki Suga, MS, Masahiro Kido, MD, PhD, Hirochika Toyama, MD, PhD, Tomoaki Okimoto, MD, PhD, Ryohei Sasaki, MD, PhD, Takumi Fukumoto, MD, PhD PII:
S1072-7515(19)32220-3
DOI:
https://doi.org/10.1016/j.jamcollsurg.2019.11.007
Reference:
ACS 9682
To appear in:
Journal of the American College of Surgeons
Received Date: 11 September 2019 Revised Date:
15 October 2019
Accepted Date: 4 November 2019
Please cite this article as: Tsugawa D, Komatsu S, Demizu Y, Sulaiman NS, Suga M, Kido M, Toyama H, Okimoto T, Sasaki R, Fukumoto T, Space-Making Particle Therapy with Surgical Spacer Placement in Patients with Sacral Chordoma, Journal of the American College of Surgeons (2019), doi: https:// doi.org/10.1016/j.jamcollsurg.2019.11.007. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the American College of Surgeons.
1 Space-Making Particle Therapy with Surgical Spacer Placement in Patients with Sacral Chordoma Daisuke Tsugawa, MD, PhD,a Shohei Komatsu, MD, PhD,a Yusuke Demizu, MD, PhD,b,c Nor Shazrina Sulaiman, MD, PhD,c Masaki Suga, MS,d Masahiro Kido, MD, PhD,a Hirochika Toyama, MD, PhD,a Tomoaki Okimoto, MD, PhD,c Ryohei Sasaki, MD, PhD,e Takumi Fukumoto, MD, PhDa aDepartment of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Japan. b
Department of Radiation Oncology, Hyogo Ion Beam Medical Center Kobe Proton Center, Japan. c Department of Radiology, Hyogo Ion Beam Medical Center, Japan. d Department of Radiation Physics, Hyogo Ion Beam Medical Center, Japan. e
Division of Radiation Oncology, Kobe University Graduate School of Medicine, Japan.
Disclosure Information: Nothing to disclose. Disclosures outside the scope of this work: Dr Fukumoto is a paid consultant to, receives payment for development of educational presentations from, and holds a contract for cooperative research with Alfresa Pharma Corp, and holds stock options from Dream Fastener, Inc and PJHP Medical, Inc. Support: Dr Fukumoto is supported by Japan Agency for Medical Research and Development Grants-in-Aid for Scientific Research (JP12913592, JP16ck0106034, JP18ck0106301). Correspondence and address requests for reprints to: Daisuke Tsugawa, MD, PhD Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Japan. 7-5-2 Kusunokicho, chuoku, Kobe, Japan Phone number: +81-78-382-6302; Fax number: +81-78-382-6307 Email address: [email protected]
Brief title: Particle Therapy for Sacral Chordoma
2 Abstract Background: Sacral chordomas are rare malignant bone tumors and are often very large for complete resection. Particle therapy for these tumors, which are adjacent to the gastrointestinal tract, is restricted because the tolerance dose of the intestine is low. This study aimed to demonstrate the technical aspects and treatment results of space-making particle therapy (SMPT) with surgical spacer placement for sacral chordoma. We aimed to investigate the dosimetric change in the particle therapy before and after spacer placement and the safety, efficiency, and long-term outcomes of SMPT. Study design: Twenty-one patients with sacral chordomas who were excluded from typical particle therapy were enrolled between 2007 and 2015. Gore-Tex® sheets were folded and placed between the sacral and rectum. Particle therapy with 70.4 Gy (RBE) was then performed. Results: The mean V95% (volume that allows 95% of the treatment plan dose) of the gross tumor volume (GTV) and clinical tumor volume after spacer placement was improved to 97.7% and 96.4% from preoperative values of 91.0% and 89.5%, respectively. The recurrence rate within the GTV was only 4.8%. The 4-year local progression-free survival rate was 68.4%. The 5-year overall survival rate was 100%, and the adverse events were acceptable. Conclusions: Considering improvements in the dose-volume histogram after spacer placement, low recurrence rates within the GTV, good survival rates, and low incidences of side effects, treatment of sacral chordoma with SMPT shows promise.
3 Keywords: sacral chordoma, particle therapy, tumors Abbreviations CT: computed tomography CTV: clinical target volume Dmax: maximum dose DVH: dose–volume histogram GTV: gross tumor volume LC: local control MRI: magnetic resonance imaging MST: median survival time PFS: progression-free survival PTV: planning target volume SMPT: space-making particle therapy
4
Introduction Chordoma is a slow-growing and locally aggressive malignant tumor. It arises from notochord rests and shows fewer metastases than other bone and soft tissue tumors.1-3 Approximately 50% of chordomas originate in the sacrum, 35% at the base of the skull, and 15% in the true vertebrae.2 Furthermore, chordoma is the most common primary malignant tumor found in the sacrum. Resection is generally considered the treatment of choice for sacral chordoma because chordoma responds poorly to conventional radiotherapy and chemotherapy.4-6 Complete and radical resection contributes to a high local control (LC) rate and prolongation of disease-free survival.6-9 However, in many cases of sacral chordoma, complete resection is difficult due to the tumor size and location (close to the pelvic viscera and spinal cord). In addition, extended resection of the sacral bone often results in urination and defecation disorders. Particle therapy using protons and carbon ions is a promising new modality that has an inherent anti- tumor effect against many types of malignancies.10-13 However, the application of particle therapy for tumors adjacent to the intestinal tract, such as sacral chordoma, is sometimes restricted because the tolerance dose of the intestine is low. To overcome this situation, we developed a two-step treatment consisting of surgical spacer placement and particle therapy, named space-making particle therapy (SMPT), and used it to treat unresectable malignancies in the abdominal and retroperitoneal cavities, including sacral chordoma.10, 12, 14, 15 This study aimed to demonstrate the technical aspects of
5 surgical spacer placement and the dosimetric change in the particle beam before and after spacer placement in patients with sacral chordomas. In addition, we aimed to investigate the safety, efficiency, and long-term outcomes of SMPT for this type of refractory retroperitoneal malignancy. Methods Patients Eligibility criteria were as follows: (1) histologically confirmed primary sacral chordoma without metastases, (2) no previous radiotherapy, (3) Eastern Cooperative Oncology Group performance status (ECOG PS) ≤3, (4) adequate organ function (heart, lung, liver, and kidney function sufficient for general anesthesia and radiotherapy), (5) no active concomitant malignancy, (6) inability to deliver a radical dose of particle therapy due to the proximity of the gastrointestinal tract, (7) potential to place the surgical spacer in the pelvis, and (8) provision of written informed consent. Patients who met the following conditions were ineligible for SMPT: (1) those with tumors larger than 15 cm in diameter (upper limit of the irradiation field), (2) those with serious complications, and (3) those with refractory ascites with little therapeutic efficacy. All patients underwent surgical spacer placement at Kobe University Hospital and particle therapy at Hyogo Ion Beam Medical Center. This study was conducted in accordance with the ethical standards of the Declaration of Helsinki and approved by the ethics committee of Kobe University. All patients provided written informed consent before the initiation of treatment after an extensive discussion of the nature of the illness, therapeutic goals, alternative therapeutic options, and potential adverse effects of SMPT. Treatment
6
Surgical spacer placement All procedures were performed under general anesthesia and conducted via open laparotomy. The treatment strategy was designed to keep the intestine away from the irradiation field with spacer placement and to perform particle therapy with a curative intent. In this treatment, each side of the peritoneum of the pelvic colon was freed in a downward direction from the region of the sigmoid. Where necessary, mobilization of the descending colon and/or sigmoid colon was performed. The peritoneum was divided anterior to the rectum at the level of the bladder or cervix. The rectum was freed posteriorly down to the hollow of the sacrum until the edge of the tumor. Gore-Tex® sheets (W. L. Gore and Associates, Flagstaff, AZ, USA), measuring 20 cm × 15 cm × 2 mm and folded four times were superimposed into the hollow of the sacrum between the tumor and rectum. Wrinkled four folded Gore-Tex sheets got gaps and made nearly 10 mm thickness. We modified the Gore-Tex® sheets with scissors and suturing to fit the expected space between the tumor and intestine (Fig. 1). The covering of the cranial space of the tumor is important because the small intestine might drop to the pelvic floor. The spacer was fixed to the tissue anterior to the sacrum to avoid migration of the spacer. The pelvic floor was reconstructed by repairing the peritoneum to avoid direct contact between the spacer and intestine. We conducted these procedures in a hybrid operation room and checked the relative position of the spacer, intestine, and tumor using intraoperative computed tomography (CT) images before fixing
7
the spacer. During spacer placement surgery, no part of the tumor was resected as this was the first step to facilitate particle therapy. We paid close attention to protect the intestine against damage from the Gore-Tex® sheets used in this procedure. Any complications requiring medication or an interventional procedure were considered to indicate postoperative morbidity. They were classified according to Common Terminology Criteria for Adverse Events (CTCAE) ver. 5.0. Particle therapy Particle therapy plans were developed using CT-based three-dimensional treatment planning systems, the FOCUS-M (Computerized Medical Systems Inc. (CMS), St Louis, MO, USA, and Mitsubishi Electric Corporation, Tokyo, Japan) until April 2008 and the Xio-M (CMS and Mitsubishi Electric Corporation) from May 2008. Each patient was immobilized in the prone position with a custom-made thermoplastic cast, and CT (2 mm slice thickness) and magnetic resonance imaging (MRI; 2-5 mm slice thickness) were performed. The gross tumor volume (GTV) was defined as the primary tumor volume determined by CT-MRI fusion images. The clinical target volume (CTV) comprised the addition of a 5-mm basic margin to the GTV. The planning target volume (PTV) was defined as the CTV plus a set-up margin (5 mm) and an internal margin (1 mm) under the respiratory gating system for all patients. We obtained CT images at inhalation and exhalation phases for every patient and
8
found that the amount of respiratory motion was 1 mm in all directions. However, we added a respiratory gating margin (internal margin) of 1 mm to all patients for safety. During the early treatment era, we used a protocol of 70.4 Gy (relative biological effectiveness [RBE]) in 16 fractions (4.4 Gy [RBE] per fraction) imported from an experienced institution, the National Institute of Radiological Sciences (Chiba, Japan). In the later treatment era, we employed a protocol of 70.4 Gy (RBE) in 32 fractions (2.2 Gy [RBE] per fraction), which is less toxic to normal tissues, although 70.4 Gy (RBE) in 16 fractions was also used for cases meeting the dose constraints for organs at risk, as described below. The dose constraints for the small bowel, large bowel, rectum, and spinal cord (cauda equina was not included) were maximum dose (Dmax) ≤43 Gy (RBE), Dmax ≤47 Gy (RBE), V65 (volume receiving ≥35 Gy (RBE) ≤semiperimeter), and Dmax ≤42 Gy (RBE), respectively, for the 16-fraction protocol. They were Dmax ≤52 Gy (RBE), Dmax ≤57 Gy (RBE), V65 (volume receiving ≥65 Gy [RBE] ≤7% and V40 ≤35%), and Dmax ≤48 Gy (RBE), respectively, for the 32-fraction protocol. For the skin dose, insufficient data from the early treatment era were available, although Dmax ≤56 Gy (RBE) was set for the 16-fraction protocol during the later treatment era, with no specific constraints for the 32-fraction protocol. The beam settings were chosen to facilitate the maximum possible irradiation to the GTV, CTV, and PTV, while keeping the maximum dose at no more than 0.5 ml of the organ volume to the gastrointestinal tract and limited to 48 Gy (RBE), and the maximum dose for
9 the spinal cord was 45 Gy (RBE).16, 17 Selection of proton or carbon ion beams was based on the dose distribution. We used the same dose constraints for organs at risk in both proton and carbon ion radiotherapy. Therefore, the beam type that achieved better target coverage was selected for each patient following discussion among several radiation oncologists.13, 18, 19 A representative case was described in the previous report14 (Figure 2). The patients were treated with carbon ion or proton beams. A respiratory gating system was used to irradiate the beam during the exhalation phase. The patient set-up was performed daily by subtracting the two sets of orthogonal digital radiographs before irradiation. The translation and rotation of the patient detected by the positioning system were compensated for by adjusting the treatment couch. The set-up was continued until the bony landmarks on the digitally reconstructed radiographs corresponded to within 1 mm. Surveillance After particle therapy, the patients were observed at 3-month intervals in the first, second, and third years and at 6-month intervals in the fourth year and thereafter. Regular follow-up studies included physical examination, diagnostic imaging (CT and/or MRI), and blood tests. Local recurrence was defined as radiographical enlargement of the primary tumor. Toxicities were evaluated using CTCAE ver. 5.0. Statistical analysis
10
The follow-up time was calculated from the day of surgery. Continuous variables are presented as medians and ranges, and categorical variables are presented as frequencies and proportions. The overall survival and progression-free survival (PFS) curves were estimated using the Kaplan–Meier method and were compared using the log-rank test. All p-values were two-sided, and p ≤0.05 was considered statistically significant. Statistical analyses were performed using SPSS® Statistics 24 (IBM Corporation, Armonk, NY, USA). Efficacy of the spacer To evaluate the efficacy of the surgical spacer, we analyzed each treatment plan using a dose-volume histogram (DVH) and compared V95% (volume that allows 95% of the treatment plan dose), D50% (dose intensity covering 50% of the target volume), and D95% (dose intensity covering 95% of the target volume). RESULTS Patient characteristics A total of 67 patients with sacral chordoma underwent particle therapy between February 2007 and September 2015, and 21 of these patients were enrolled in this study. Patient characteristics are summarized in Table 1. Surgical outcomes Surgical outcomes are summarized in Table 2. The average operative time was 158 (range, 78–243) minutes, mean blood loss was 100 ml (range, 0–350) ml, and mean
11
postoperative hospital stay was 10.1 (range, 7–19) days. No post-surgical adverse events occurred in the early and late phases. DVH parameter change before and after surgical spacer placement
Changes in tumor volume and DVH parameters from before surgery to after surgery are shown in Table 3. As for GTV, CTV, and PTV, significant improvements were seen for V95% (p=0.045, p=0.039, and p=0.023, respectively) with surgical spacer placement while a safe dose to the intestinal tract was maintained. Local control and survival outcomes with SMPT The median follow-up period was 50 (range, 7–114) months for all patients. The overall 5-year survival rate was 100%. The 4-year PFS rate was 54.1%, and the median survival time (MST) was 54.8 months (Fig. 3a). The 4-year local PFS rate was 68.4%, and the MST was 60.9 months (Fig. 3b). Of the 21 patients studied, 6 (29%) presented with local recurrence. One patient experienced recurrence within the GTV (48 months after particle therapy), and one experienced recurrence within the CTV margin (54 months after particle therapy). Three patients experienced recurrence within the PTV margin (15, 47, and 47 months after particle therapy) outside of the CTV, and one developed marginal (just outside of the PTV) recurrence (61 months after particle therapy). Six patients (29%) experienced distant metastasis. Among them, tumor dissemination occurred in two patients, bone metastasis in
12
one patient, lung metastasis in two patients, and lymph node metastasis in one patient (Table 4). Statistical analysis using the log-rank test revealed that no significant differences were seen for these factors (age, sex, ECOG PS, tumor volume, and number of Gore-Tex® sheets) in PFS (Table 5). Adverse events With regard to greater acute reactions that were Grade 3 or greater, Grade 3 dermatitis was observed in four patients (19%). However, all patients completed their planned radiotherapy and recovered from these reactions. Considering late toxicities, events that were Grade 3 or greater were observed in one patient (5%, Grade 4 dermatitis). No complications with surgical spacer placement were recorded. Discussion SMPT is a technique that combines surgery and radiation. This type of approach using a surgical spacer and conventional photon radiotherapy has been previously employed in other malignancies such as rectal cancer.20, 21 However, the low irradiation accuracy of photon radiotherapy requires an unreasonable spacer volume to facilitate SMPT. As a result, this technique has not been popular, and to date, no detailed reports including dosimetric evaluation of DVH have been published. Owing to the sharp dose distribution of particle therapy, a 10-mm distance between the tumor and adjacent gastrointestinal tract is sufficient
13 for the safe irradiation of the particle beam.12, 15 We believe that the introduction of particle therapy makes this approach feasible. To the best our knowledge, this is the first report to assess this type of approach and to include dosimetric evaluation of sacral chordoma. This study demonstrated the effectiveness of SMPT with respect to DVH parameters. As shown in Table 3, changes in DVH parameters significantly improved with spacer placement. V95% within the GTV after spacer placement reached up to 97%, and the recurrence rate within the GTV was only 4.8%. This result indicates that high V95%, which enables full-dose particle beam irradiation to nearly the entire tumor, is essential to reduce the risk of local recurrence. Considering improvements in DVH parameters after spacer placement, the low recurrence rate within the GTV, and the low incidence of side effects demonstrated in this study, treatment of sacral chordoma with SMPT is promising. If particle therapy was performed without a surgical spacer for patients in this study, the number of patients with local recurrence may have been higher due to an insufficient dose in the marginal area of the tumor. When recurrence rates with typical particle therapy for sacral chordoma in our study were compared with those of previous studies, the recurrence rate in this study was comparable to those of previous reports showing local control rates of 72%-90%.22-25 Caution must be exercised when interpreting these results, because there was substantial heterogeneity among the studies in terms of tumor progression. Our patients did not meet the inclusion
14
criteria of typical particle therapy because of the proximity of the sacral chordoma to the gastrointestinal tract. In this study, we applied Gore-Tex® sheets as surgical spacers because of their good biological compatibility and commercial availability. However, Gore-Tex® sheets were originally designed to be used for soft tissue repairs for abdominal incisional hernia; therefore, they have some weaknesses as spacers for SMPT. In particular, they have too much air content, resulting in low radiation shielding capacity. Surgical placement of Gore-Tex® sheets can protect the intestines from radiation fields but cannot stop the radiation beam from reaching the organs behind it. Unlike photon radiotherapy, the use of particle beams can compensate for this weakness because particle beams have the Bragg peak formation, which is the unique depth–dose characteristic of the radiation beam. Nevertheless, this weakness of Gore-Tex® sheets as a spacer has a negative effect on radiation treatment planning. V95% of the PTV improved after spacer placement, but it was still only 90%. This low V95% might account for the high recurrence rate of 23.8% within the PTV. Another weakness is the possibility of infection. Gore-Tex® sheets are made of an artificial unabsorbable material that remains in the body permanently after implantation. In this study, no patients developed spacer infection during the observation period. The incidence of infection following hernia repair using artificial materials has been reported very rare. However, the possibility of long-term spacer infection remains, and it would lead
15
discontinuation of particle therapy. In fact, some patients with other malignancies including retroperitoneal sarcoma performed spacer operations in our institute developed spacer infection. To overcome the weaknesses of Gore-Tex® sheets, the development of a novel spacer that has sufficient radiation shielding capacity and is made from absorbable material is required. Since 2010, we have developed a novel spacer made from absorbable material.26 This new spacer received pharmaceutical approval in Japan at the end of 2018 and will be ready for clinical use in the near future. This product may be the solution for increasing the efficacy and feasibility of SMPT.27 With regard to the technical aspects of spacer operation, spacer placement for sacral chordoma is not difficult because the procedure is similar to low anterior resection of the rectum. Differences between the two procedures are the dissection layer and surgical view. A dissection layer close to the sacrum must be selected to maintain the mesorectum and keep the intestinal blood flow. Direct view of the coccyx is sometimes disturbed by the overhanging tumor in front of the sacrum. In few cases, the area of the pelvic inlet is almost completely occupied by the tumor, and there is no room for the spacer. SMPT is not indicated in such cases. Despite the novelty of our findings, the generalization of our results is limited by the small number of patients and limited follow-up period. Recruitment of more patients and a
16
longer follow-up period are warranted, and further studies are needed to clarify our conclusions. Conclusion SMPT showed improvements in DVH parameters after spacer placement, low recurrence rate within the GTV, good survival rate, and low incidence of side effects. Considering these results, treatment of sacral chordoma with SMPT is promising. Acknowledgement The authors thank Daiki Takahashi, DDS, PhD, SungChul Park, MD, Yoshiro Matsuo, MD, PhD, Dongha Lee, MD, Kentaro Tai, MD, Kazuki Terashima, MD, PhD and Sunao Tokumaru, MD, PhD for their assistance with data acquisition and review of the manuscript.
17
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10.
Komatsu S, Iwasaki T, Demizu Y, et al. Two-stage treatment with hepatectomy and
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Iwata H, Murakami M, Demizu Y, et al. High-dose proton therapy and carbon-ion
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Fukumoto T, Komatsu S, Hori Y, et al. Particle beam radiotherapy with a surgical
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Mima M, Demizu Y, Jin D, et al. Particle therapy using carbon ions or protons as a
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Komatsu S, Hori Y, Fukumoto T, et al. Surgical spacer placement and proton
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Kavanagh BD, Pan CC, Dawson LA, et al. Radiation dose-volume effects in the
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21
Figure Legends Figure 1. Due to the specific location of sacral chordoma, the organs at risk for particle therapy are rectum, sigmoid colon and small intestine. (A) Mobilization of the sigmoid colon and explosion of the ventral space of the tumor. (B) Placement of modified Gore-Tex sheets as the spacer. (Reprinted courtesy of the artist, Yoshihiko Tsuda.) Figure 2. A 35-year-old woman was diagnosed with sacral chordoma. (A) Abdominal MRI before the operation for spacer placement. (B) Abdominal CT image after the operation for spacer placement. The spacer maintained sufficient open space between the tumor and intestine. Figure 3. (A) Progression-free survival determined using the Kaplan-Meier method for all patients. (B) Local progression-free survival for all patients. LPFS, local progression-free survival; MST, median survival time; PFS, progression-free survival
22 Table 1. Patient Characteristics Characteristic
Data (N=21)
Age, y, (range)
63.5 (35-80)
Sex, n (%) Male
10 (48)
Female
11 (52)
Eastern Cooperative Oncology Group performance status, n (%) 0
3 (14)
1
17 (81)
2
1 (5)
Dose fraction, n (%) 70.4GyE/16Fr
5 (24)
70.4GyE/32Fr
14 (67)
79.2GyE/18Fr
1 (5)
80.0GyE/40Fr
1 (5)
Planning target volume, mL, mean (range)
496.6 (178-944)
Ion type, n (%) Carbon ion
6 (32)
Proton
15 (68)
23 Table 2. Surgical Outcomes Outcome
Data (N=21)
Number of Gore-Tex seats, n (%) 1
3 (14)
2
15 (71)
3
3 (14)
Operative time, min, mean (range)
158 (78-243)
Blood loss, mL, mean (range)
100 (0-350)
Adverse events of surgery, n
0
Postoperative hospital length of stay, d, mean (range)
10.1 (7-19)
Days between surgery and initiation of particle therapy, d, mean (range)
29.7 (16-56)
24 Table 3. Changes of Dose Volume Histogram Parameters Before and After the Spacer Operation Variable, parameter
Preoperative mean value
Postoperative mean value
T-test
Volume, mL
220.1
226.3
0.043
V95%, %
91.0
97.7
0.045
D50%, GyE
71.1
71.2
0.458
D95%, GyE
64.2
68.8
0.086
Dmean, GyE
70.2
71.0
0.065
Dmin, GyE
54.5
55.9
0.748
V95% (%)
89.5
96.4
0.039
D50%, GyE
71.1
71.2
0.298
D95%, GyE
63.0
67.7
0.090
Dmean, GyE
70.0
71.0
0.067
Dmin, GyE
50.2
47.6
0.593
V95%, %
81.1
90.6
0.023
D50%, GyE
70.8
71.1
0.115
D95%, GyE
57.3
62.4
0.144
Dmean, GyE
68.7
70.0
0.079
Dmin, GyE
35.3
32.5
0.637
Dmax, GyE
52.4
50.8
0.468
V30GyE, cc
28.9
1.2
0.032
V40GyE, cc
23.3
0.3
0.036
Dmax, GyE
51.7
47.6
0.262
V30GyE, cc
14.6
7.3
0.150
V40GyE, cc
9.9
3.4
0.078
Dmax, GyE
59.9
62.0
0.168
V40%, %
32.6
34.8
0.444
V65%, %
5.9
8.8
0.223
GTV
CTV
PTV
Small bowel
Large bowel
Rectum
25
CTV, clinical target volume; GTV, gross tumor volume; PTV, planning target volume; GyE, gray equivalent; V95%, the volume that 95% of the treatment planning dose is irradiated; D50%, a dose intensity covering 50% of the target volume; D95%, a dose intensity covering 95% of the target volume; Dmean, the average dose of the target volume; Dmin, the minimum dose of the target volume; D max, the maximum dose of the target volume; V30GyE, the volume of more than 30 GyE was irradiated; V40GyE, the volume of more than 40 GyE was irradiated; V40% V65%
26
Table 4: Outcomes of Space-Making Particle Therapy with Surgical Spacer Placement Variable
Data (N=21) n
%
6
29
Within GTV
1
5
Within CTV
1
5
Within PTV
3
14
Marginal recurrence
1
5
6
29
Peritoneal dissemination
2
10
Bone metastasis
1
5
Lung metastasis
2
10
Lymph node metastasis
1
5
Recurrence pattern Local recurrence
Distant metastasis
CTV, clinical target volume; GTV, gross tumor volume; PTV, planning target volume
27
Table 5: Log-Rank Test for Progression-Free Survival Variable
n
Age
p Value 0.798
<60 y
6
>60 y
15
Sex
0.13
Male
10
Female
11
Eastern Cooperative Oncology Group performance status
0.599
0
3
1
17
2
1
Tumor volume
0.174
<500 mL
13
>500 mL
8
Number of Gore-Tex
0.749
1
3
2
15
3
3
28 Precis We developed space-making particle therapy with surgical spacer placement and treated sacral chordoma using Gore-Tex sheets as the spacer. Space-making particle therapy showed improvement in the dose-volume histogram after spacer placement, low recurrence rate, good survival rate, and low incidence of side effects.
S1072-7515(19)32220-3
DOI:
https://doi.org/10.1016/j.jamcollsurg.2019.11.007
Reference:
ACS 9682
To appear in:
Journal of the American College of Surgeons
Received Date: 11 September 2019 Revised Date:
15 October 2019
Accepted Date: 4 November 2019
Please cite this article as: Tsugawa D, Komatsu S, Demizu Y, Sulaiman NS, Suga M, Kido M, Toyama H, Okimoto T, Sasaki R, Fukumoto T, Space-Making Particle Therapy with Surgical Spacer Placement in Patients with Sacral Chordoma, Journal of the American College of Surgeons (2019), doi: https:// doi.org/10.1016/j.jamcollsurg.2019.11.007. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the American College of Surgeons.
1 Space-Making Particle Therapy with Surgical Spacer Placement in Patients with Sacral Chordoma Daisuke Tsugawa, MD, PhD,a Shohei Komatsu, MD, PhD,a Yusuke Demizu, MD, PhD,b,c Nor Shazrina Sulaiman, MD, PhD,c Masaki Suga, MS,d Masahiro Kido, MD, PhD,a Hirochika Toyama, MD, PhD,a Tomoaki Okimoto, MD, PhD,c Ryohei Sasaki, MD, PhD,e Takumi Fukumoto, MD, PhDa aDepartment of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Japan. b
Department of Radiation Oncology, Hyogo Ion Beam Medical Center Kobe Proton Center, Japan. c Department of Radiology, Hyogo Ion Beam Medical Center, Japan. d Department of Radiation Physics, Hyogo Ion Beam Medical Center, Japan. e
Division of Radiation Oncology, Kobe University Graduate School of Medicine, Japan.
Disclosure Information: Nothing to disclose. Disclosures outside the scope of this work: Dr Fukumoto is a paid consultant to, receives payment for development of educational presentations from, and holds a contract for cooperative research with Alfresa Pharma Corp, and holds stock options from Dream Fastener, Inc and PJHP Medical, Inc. Support: Dr Fukumoto is supported by Japan Agency for Medical Research and Development Grants-in-Aid for Scientific Research (JP12913592, JP16ck0106034, JP18ck0106301). Correspondence and address requests for reprints to: Daisuke Tsugawa, MD, PhD Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Japan. 7-5-2 Kusunokicho, chuoku, Kobe, Japan Phone number: +81-78-382-6302; Fax number: +81-78-382-6307 Email address: [email protected]
Brief title: Particle Therapy for Sacral Chordoma
2 Abstract Background: Sacral chordomas are rare malignant bone tumors and are often very large for complete resection. Particle therapy for these tumors, which are adjacent to the gastrointestinal tract, is restricted because the tolerance dose of the intestine is low. This study aimed to demonstrate the technical aspects and treatment results of space-making particle therapy (SMPT) with surgical spacer placement for sacral chordoma. We aimed to investigate the dosimetric change in the particle therapy before and after spacer placement and the safety, efficiency, and long-term outcomes of SMPT. Study design: Twenty-one patients with sacral chordomas who were excluded from typical particle therapy were enrolled between 2007 and 2015. Gore-Tex® sheets were folded and placed between the sacral and rectum. Particle therapy with 70.4 Gy (RBE) was then performed. Results: The mean V95% (volume that allows 95% of the treatment plan dose) of the gross tumor volume (GTV) and clinical tumor volume after spacer placement was improved to 97.7% and 96.4% from preoperative values of 91.0% and 89.5%, respectively. The recurrence rate within the GTV was only 4.8%. The 4-year local progression-free survival rate was 68.4%. The 5-year overall survival rate was 100%, and the adverse events were acceptable. Conclusions: Considering improvements in the dose-volume histogram after spacer placement, low recurrence rates within the GTV, good survival rates, and low incidences of side effects, treatment of sacral chordoma with SMPT shows promise.
3 Keywords: sacral chordoma, particle therapy, tumors Abbreviations CT: computed tomography CTV: clinical target volume Dmax: maximum dose DVH: dose–volume histogram GTV: gross tumor volume LC: local control MRI: magnetic resonance imaging MST: median survival time PFS: progression-free survival PTV: planning target volume SMPT: space-making particle therapy
4
Introduction Chordoma is a slow-growing and locally aggressive malignant tumor. It arises from notochord rests and shows fewer metastases than other bone and soft tissue tumors.1-3 Approximately 50% of chordomas originate in the sacrum, 35% at the base of the skull, and 15% in the true vertebrae.2 Furthermore, chordoma is the most common primary malignant tumor found in the sacrum. Resection is generally considered the treatment of choice for sacral chordoma because chordoma responds poorly to conventional radiotherapy and chemotherapy.4-6 Complete and radical resection contributes to a high local control (LC) rate and prolongation of disease-free survival.6-9 However, in many cases of sacral chordoma, complete resection is difficult due to the tumor size and location (close to the pelvic viscera and spinal cord). In addition, extended resection of the sacral bone often results in urination and defecation disorders. Particle therapy using protons and carbon ions is a promising new modality that has an inherent anti- tumor effect against many types of malignancies.10-13 However, the application of particle therapy for tumors adjacent to the intestinal tract, such as sacral chordoma, is sometimes restricted because the tolerance dose of the intestine is low. To overcome this situation, we developed a two-step treatment consisting of surgical spacer placement and particle therapy, named space-making particle therapy (SMPT), and used it to treat unresectable malignancies in the abdominal and retroperitoneal cavities, including sacral chordoma.10, 12, 14, 15 This study aimed to demonstrate the technical aspects of
5 surgical spacer placement and the dosimetric change in the particle beam before and after spacer placement in patients with sacral chordomas. In addition, we aimed to investigate the safety, efficiency, and long-term outcomes of SMPT for this type of refractory retroperitoneal malignancy. Methods Patients Eligibility criteria were as follows: (1) histologically confirmed primary sacral chordoma without metastases, (2) no previous radiotherapy, (3) Eastern Cooperative Oncology Group performance status (ECOG PS) ≤3, (4) adequate organ function (heart, lung, liver, and kidney function sufficient for general anesthesia and radiotherapy), (5) no active concomitant malignancy, (6) inability to deliver a radical dose of particle therapy due to the proximity of the gastrointestinal tract, (7) potential to place the surgical spacer in the pelvis, and (8) provision of written informed consent. Patients who met the following conditions were ineligible for SMPT: (1) those with tumors larger than 15 cm in diameter (upper limit of the irradiation field), (2) those with serious complications, and (3) those with refractory ascites with little therapeutic efficacy. All patients underwent surgical spacer placement at Kobe University Hospital and particle therapy at Hyogo Ion Beam Medical Center. This study was conducted in accordance with the ethical standards of the Declaration of Helsinki and approved by the ethics committee of Kobe University. All patients provided written informed consent before the initiation of treatment after an extensive discussion of the nature of the illness, therapeutic goals, alternative therapeutic options, and potential adverse effects of SMPT. Treatment
6
Surgical spacer placement All procedures were performed under general anesthesia and conducted via open laparotomy. The treatment strategy was designed to keep the intestine away from the irradiation field with spacer placement and to perform particle therapy with a curative intent. In this treatment, each side of the peritoneum of the pelvic colon was freed in a downward direction from the region of the sigmoid. Where necessary, mobilization of the descending colon and/or sigmoid colon was performed. The peritoneum was divided anterior to the rectum at the level of the bladder or cervix. The rectum was freed posteriorly down to the hollow of the sacrum until the edge of the tumor. Gore-Tex® sheets (W. L. Gore and Associates, Flagstaff, AZ, USA), measuring 20 cm × 15 cm × 2 mm and folded four times were superimposed into the hollow of the sacrum between the tumor and rectum. Wrinkled four folded Gore-Tex sheets got gaps and made nearly 10 mm thickness. We modified the Gore-Tex® sheets with scissors and suturing to fit the expected space between the tumor and intestine (Fig. 1). The covering of the cranial space of the tumor is important because the small intestine might drop to the pelvic floor. The spacer was fixed to the tissue anterior to the sacrum to avoid migration of the spacer. The pelvic floor was reconstructed by repairing the peritoneum to avoid direct contact between the spacer and intestine. We conducted these procedures in a hybrid operation room and checked the relative position of the spacer, intestine, and tumor using intraoperative computed tomography (CT) images before fixing
7
the spacer. During spacer placement surgery, no part of the tumor was resected as this was the first step to facilitate particle therapy. We paid close attention to protect the intestine against damage from the Gore-Tex® sheets used in this procedure. Any complications requiring medication or an interventional procedure were considered to indicate postoperative morbidity. They were classified according to Common Terminology Criteria for Adverse Events (CTCAE) ver. 5.0. Particle therapy Particle therapy plans were developed using CT-based three-dimensional treatment planning systems, the FOCUS-M (Computerized Medical Systems Inc. (CMS), St Louis, MO, USA, and Mitsubishi Electric Corporation, Tokyo, Japan) until April 2008 and the Xio-M (CMS and Mitsubishi Electric Corporation) from May 2008. Each patient was immobilized in the prone position with a custom-made thermoplastic cast, and CT (2 mm slice thickness) and magnetic resonance imaging (MRI; 2-5 mm slice thickness) were performed. The gross tumor volume (GTV) was defined as the primary tumor volume determined by CT-MRI fusion images. The clinical target volume (CTV) comprised the addition of a 5-mm basic margin to the GTV. The planning target volume (PTV) was defined as the CTV plus a set-up margin (5 mm) and an internal margin (1 mm) under the respiratory gating system for all patients. We obtained CT images at inhalation and exhalation phases for every patient and
8
found that the amount of respiratory motion was 1 mm in all directions. However, we added a respiratory gating margin (internal margin) of 1 mm to all patients for safety. During the early treatment era, we used a protocol of 70.4 Gy (relative biological effectiveness [RBE]) in 16 fractions (4.4 Gy [RBE] per fraction) imported from an experienced institution, the National Institute of Radiological Sciences (Chiba, Japan). In the later treatment era, we employed a protocol of 70.4 Gy (RBE) in 32 fractions (2.2 Gy [RBE] per fraction), which is less toxic to normal tissues, although 70.4 Gy (RBE) in 16 fractions was also used for cases meeting the dose constraints for organs at risk, as described below. The dose constraints for the small bowel, large bowel, rectum, and spinal cord (cauda equina was not included) were maximum dose (Dmax) ≤43 Gy (RBE), Dmax ≤47 Gy (RBE), V65 (volume receiving ≥35 Gy (RBE) ≤semiperimeter), and Dmax ≤42 Gy (RBE), respectively, for the 16-fraction protocol. They were Dmax ≤52 Gy (RBE), Dmax ≤57 Gy (RBE), V65 (volume receiving ≥65 Gy [RBE] ≤7% and V40 ≤35%), and Dmax ≤48 Gy (RBE), respectively, for the 32-fraction protocol. For the skin dose, insufficient data from the early treatment era were available, although Dmax ≤56 Gy (RBE) was set for the 16-fraction protocol during the later treatment era, with no specific constraints for the 32-fraction protocol. The beam settings were chosen to facilitate the maximum possible irradiation to the GTV, CTV, and PTV, while keeping the maximum dose at no more than 0.5 ml of the organ volume to the gastrointestinal tract and limited to 48 Gy (RBE), and the maximum dose for
9 the spinal cord was 45 Gy (RBE).16, 17 Selection of proton or carbon ion beams was based on the dose distribution. We used the same dose constraints for organs at risk in both proton and carbon ion radiotherapy. Therefore, the beam type that achieved better target coverage was selected for each patient following discussion among several radiation oncologists.13, 18, 19 A representative case was described in the previous report14 (Figure 2). The patients were treated with carbon ion or proton beams. A respiratory gating system was used to irradiate the beam during the exhalation phase. The patient set-up was performed daily by subtracting the two sets of orthogonal digital radiographs before irradiation. The translation and rotation of the patient detected by the positioning system were compensated for by adjusting the treatment couch. The set-up was continued until the bony landmarks on the digitally reconstructed radiographs corresponded to within 1 mm. Surveillance After particle therapy, the patients were observed at 3-month intervals in the first, second, and third years and at 6-month intervals in the fourth year and thereafter. Regular follow-up studies included physical examination, diagnostic imaging (CT and/or MRI), and blood tests. Local recurrence was defined as radiographical enlargement of the primary tumor. Toxicities were evaluated using CTCAE ver. 5.0. Statistical analysis
10
The follow-up time was calculated from the day of surgery. Continuous variables are presented as medians and ranges, and categorical variables are presented as frequencies and proportions. The overall survival and progression-free survival (PFS) curves were estimated using the Kaplan–Meier method and were compared using the log-rank test. All p-values were two-sided, and p ≤0.05 was considered statistically significant. Statistical analyses were performed using SPSS® Statistics 24 (IBM Corporation, Armonk, NY, USA). Efficacy of the spacer To evaluate the efficacy of the surgical spacer, we analyzed each treatment plan using a dose-volume histogram (DVH) and compared V95% (volume that allows 95% of the treatment plan dose), D50% (dose intensity covering 50% of the target volume), and D95% (dose intensity covering 95% of the target volume). RESULTS Patient characteristics A total of 67 patients with sacral chordoma underwent particle therapy between February 2007 and September 2015, and 21 of these patients were enrolled in this study. Patient characteristics are summarized in Table 1. Surgical outcomes Surgical outcomes are summarized in Table 2. The average operative time was 158 (range, 78–243) minutes, mean blood loss was 100 ml (range, 0–350) ml, and mean
11
postoperative hospital stay was 10.1 (range, 7–19) days. No post-surgical adverse events occurred in the early and late phases. DVH parameter change before and after surgical spacer placement
Changes in tumor volume and DVH parameters from before surgery to after surgery are shown in Table 3. As for GTV, CTV, and PTV, significant improvements were seen for V95% (p=0.045, p=0.039, and p=0.023, respectively) with surgical spacer placement while a safe dose to the intestinal tract was maintained. Local control and survival outcomes with SMPT The median follow-up period was 50 (range, 7–114) months for all patients. The overall 5-year survival rate was 100%. The 4-year PFS rate was 54.1%, and the median survival time (MST) was 54.8 months (Fig. 3a). The 4-year local PFS rate was 68.4%, and the MST was 60.9 months (Fig. 3b). Of the 21 patients studied, 6 (29%) presented with local recurrence. One patient experienced recurrence within the GTV (48 months after particle therapy), and one experienced recurrence within the CTV margin (54 months after particle therapy). Three patients experienced recurrence within the PTV margin (15, 47, and 47 months after particle therapy) outside of the CTV, and one developed marginal (just outside of the PTV) recurrence (61 months after particle therapy). Six patients (29%) experienced distant metastasis. Among them, tumor dissemination occurred in two patients, bone metastasis in
12
one patient, lung metastasis in two patients, and lymph node metastasis in one patient (Table 4). Statistical analysis using the log-rank test revealed that no significant differences were seen for these factors (age, sex, ECOG PS, tumor volume, and number of Gore-Tex® sheets) in PFS (Table 5). Adverse events With regard to greater acute reactions that were Grade 3 or greater, Grade 3 dermatitis was observed in four patients (19%). However, all patients completed their planned radiotherapy and recovered from these reactions. Considering late toxicities, events that were Grade 3 or greater were observed in one patient (5%, Grade 4 dermatitis). No complications with surgical spacer placement were recorded. Discussion SMPT is a technique that combines surgery and radiation. This type of approach using a surgical spacer and conventional photon radiotherapy has been previously employed in other malignancies such as rectal cancer.20, 21 However, the low irradiation accuracy of photon radiotherapy requires an unreasonable spacer volume to facilitate SMPT. As a result, this technique has not been popular, and to date, no detailed reports including dosimetric evaluation of DVH have been published. Owing to the sharp dose distribution of particle therapy, a 10-mm distance between the tumor and adjacent gastrointestinal tract is sufficient
13 for the safe irradiation of the particle beam.12, 15 We believe that the introduction of particle therapy makes this approach feasible. To the best our knowledge, this is the first report to assess this type of approach and to include dosimetric evaluation of sacral chordoma. This study demonstrated the effectiveness of SMPT with respect to DVH parameters. As shown in Table 3, changes in DVH parameters significantly improved with spacer placement. V95% within the GTV after spacer placement reached up to 97%, and the recurrence rate within the GTV was only 4.8%. This result indicates that high V95%, which enables full-dose particle beam irradiation to nearly the entire tumor, is essential to reduce the risk of local recurrence. Considering improvements in DVH parameters after spacer placement, the low recurrence rate within the GTV, and the low incidence of side effects demonstrated in this study, treatment of sacral chordoma with SMPT is promising. If particle therapy was performed without a surgical spacer for patients in this study, the number of patients with local recurrence may have been higher due to an insufficient dose in the marginal area of the tumor. When recurrence rates with typical particle therapy for sacral chordoma in our study were compared with those of previous studies, the recurrence rate in this study was comparable to those of previous reports showing local control rates of 72%-90%.22-25 Caution must be exercised when interpreting these results, because there was substantial heterogeneity among the studies in terms of tumor progression. Our patients did not meet the inclusion
14
criteria of typical particle therapy because of the proximity of the sacral chordoma to the gastrointestinal tract. In this study, we applied Gore-Tex® sheets as surgical spacers because of their good biological compatibility and commercial availability. However, Gore-Tex® sheets were originally designed to be used for soft tissue repairs for abdominal incisional hernia; therefore, they have some weaknesses as spacers for SMPT. In particular, they have too much air content, resulting in low radiation shielding capacity. Surgical placement of Gore-Tex® sheets can protect the intestines from radiation fields but cannot stop the radiation beam from reaching the organs behind it. Unlike photon radiotherapy, the use of particle beams can compensate for this weakness because particle beams have the Bragg peak formation, which is the unique depth–dose characteristic of the radiation beam. Nevertheless, this weakness of Gore-Tex® sheets as a spacer has a negative effect on radiation treatment planning. V95% of the PTV improved after spacer placement, but it was still only 90%. This low V95% might account for the high recurrence rate of 23.8% within the PTV. Another weakness is the possibility of infection. Gore-Tex® sheets are made of an artificial unabsorbable material that remains in the body permanently after implantation. In this study, no patients developed spacer infection during the observation period. The incidence of infection following hernia repair using artificial materials has been reported very rare. However, the possibility of long-term spacer infection remains, and it would lead
15
discontinuation of particle therapy. In fact, some patients with other malignancies including retroperitoneal sarcoma performed spacer operations in our institute developed spacer infection. To overcome the weaknesses of Gore-Tex® sheets, the development of a novel spacer that has sufficient radiation shielding capacity and is made from absorbable material is required. Since 2010, we have developed a novel spacer made from absorbable material.26 This new spacer received pharmaceutical approval in Japan at the end of 2018 and will be ready for clinical use in the near future. This product may be the solution for increasing the efficacy and feasibility of SMPT.27 With regard to the technical aspects of spacer operation, spacer placement for sacral chordoma is not difficult because the procedure is similar to low anterior resection of the rectum. Differences between the two procedures are the dissection layer and surgical view. A dissection layer close to the sacrum must be selected to maintain the mesorectum and keep the intestinal blood flow. Direct view of the coccyx is sometimes disturbed by the overhanging tumor in front of the sacrum. In few cases, the area of the pelvic inlet is almost completely occupied by the tumor, and there is no room for the spacer. SMPT is not indicated in such cases. Despite the novelty of our findings, the generalization of our results is limited by the small number of patients and limited follow-up period. Recruitment of more patients and a
16
longer follow-up period are warranted, and further studies are needed to clarify our conclusions. Conclusion SMPT showed improvements in DVH parameters after spacer placement, low recurrence rate within the GTV, good survival rate, and low incidence of side effects. Considering these results, treatment of sacral chordoma with SMPT is promising. Acknowledgement The authors thank Daiki Takahashi, DDS, PhD, SungChul Park, MD, Yoshiro Matsuo, MD, PhD, Dongha Lee, MD, Kentaro Tai, MD, Kazuki Terashima, MD, PhD and Sunao Tokumaru, MD, PhD for their assistance with data acquisition and review of the manuscript.
17
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Mima M, Demizu Y, Jin D, et al. Particle therapy using carbon ions or protons as a
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21
Figure Legends Figure 1. Due to the specific location of sacral chordoma, the organs at risk for particle therapy are rectum, sigmoid colon and small intestine. (A) Mobilization of the sigmoid colon and explosion of the ventral space of the tumor. (B) Placement of modified Gore-Tex sheets as the spacer. (Reprinted courtesy of the artist, Yoshihiko Tsuda.) Figure 2. A 35-year-old woman was diagnosed with sacral chordoma. (A) Abdominal MRI before the operation for spacer placement. (B) Abdominal CT image after the operation for spacer placement. The spacer maintained sufficient open space between the tumor and intestine. Figure 3. (A) Progression-free survival determined using the Kaplan-Meier method for all patients. (B) Local progression-free survival for all patients. LPFS, local progression-free survival; MST, median survival time; PFS, progression-free survival
22 Table 1. Patient Characteristics Characteristic
Data (N=21)
Age, y, (range)
63.5 (35-80)
Sex, n (%) Male
10 (48)
Female
11 (52)
Eastern Cooperative Oncology Group performance status, n (%) 0
3 (14)
1
17 (81)
2
1 (5)
Dose fraction, n (%) 70.4GyE/16Fr
5 (24)
70.4GyE/32Fr
14 (67)
79.2GyE/18Fr
1 (5)
80.0GyE/40Fr
1 (5)
Planning target volume, mL, mean (range)
496.6 (178-944)
Ion type, n (%) Carbon ion
6 (32)
Proton
15 (68)
23 Table 2. Surgical Outcomes Outcome
Data (N=21)
Number of Gore-Tex seats, n (%) 1
3 (14)
2
15 (71)
3
3 (14)
Operative time, min, mean (range)
158 (78-243)
Blood loss, mL, mean (range)
100 (0-350)
Adverse events of surgery, n
0
Postoperative hospital length of stay, d, mean (range)
10.1 (7-19)
Days between surgery and initiation of particle therapy, d, mean (range)
29.7 (16-56)
24 Table 3. Changes of Dose Volume Histogram Parameters Before and After the Spacer Operation Variable, parameter
Preoperative mean value
Postoperative mean value
T-test
Volume, mL
220.1
226.3
0.043
V95%, %
91.0
97.7
0.045
D50%, GyE
71.1
71.2
0.458
D95%, GyE
64.2
68.8
0.086
Dmean, GyE
70.2
71.0
0.065
Dmin, GyE
54.5
55.9
0.748
V95% (%)
89.5
96.4
0.039
D50%, GyE
71.1
71.2
0.298
D95%, GyE
63.0
67.7
0.090
Dmean, GyE
70.0
71.0
0.067
Dmin, GyE
50.2
47.6
0.593
V95%, %
81.1
90.6
0.023
D50%, GyE
70.8
71.1
0.115
D95%, GyE
57.3
62.4
0.144
Dmean, GyE
68.7
70.0
0.079
Dmin, GyE
35.3
32.5
0.637
Dmax, GyE
52.4
50.8
0.468
V30GyE, cc
28.9
1.2
0.032
V40GyE, cc
23.3
0.3
0.036
Dmax, GyE
51.7
47.6
0.262
V30GyE, cc
14.6
7.3
0.150
V40GyE, cc
9.9
3.4
0.078
Dmax, GyE
59.9
62.0
0.168
V40%, %
32.6
34.8
0.444
V65%, %
5.9
8.8
0.223
GTV
CTV
PTV
Small bowel
Large bowel
Rectum
25
CTV, clinical target volume; GTV, gross tumor volume; PTV, planning target volume; GyE, gray equivalent; V95%, the volume that 95% of the treatment planning dose is irradiated; D50%, a dose intensity covering 50% of the target volume; D95%, a dose intensity covering 95% of the target volume; Dmean, the average dose of the target volume; Dmin, the minimum dose of the target volume; D max, the maximum dose of the target volume; V30GyE, the volume of more than 30 GyE was irradiated; V40GyE, the volume of more than 40 GyE was irradiated; V40% V65%
26
Table 4: Outcomes of Space-Making Particle Therapy with Surgical Spacer Placement Variable
Data (N=21) n
%
6
29
Within GTV
1
5
Within CTV
1
5
Within PTV
3
14
Marginal recurrence
1
5
6
29
Peritoneal dissemination
2
10
Bone metastasis
1
5
Lung metastasis
2
10
Lymph node metastasis
1
5
Recurrence pattern Local recurrence
Distant metastasis
CTV, clinical target volume; GTV, gross tumor volume; PTV, planning target volume
27
Table 5: Log-Rank Test for Progression-Free Survival Variable
n
Age
p Value 0.798
<60 y
6
>60 y
15
Sex
0.13
Male
10
Female
11
Eastern Cooperative Oncology Group performance status
0.599
0
3
1
17
2
1
Tumor volume
0.174
<500 mL
13
>500 mL
8
Number of Gore-Tex
0.749
1
3
2
15
3
3
28 Precis We developed space-making particle therapy with surgical spacer placement and treated sacral chordoma using Gore-Tex sheets as the spacer. Space-making particle therapy showed improvement in the dose-volume histogram after spacer placement, low recurrence rate, good survival rate, and low incidence of side effects.