Dose escalation of Stereotactic Body Radiotherapy (SBRT) for locally advanced unresectable pancreatic cancer patients with CyberKnife: protocol of a phase I study
Qing et al. Radiation Oncology
Dose escalation of Stereotactic Body Radiotherapy (SBRT) for locally advanced unresectable pancreatic cancer patients with CyberKnife: protocol of a phase I study
Shui-Wang Qing 0
Xiao-Ping Ju 0
Yang-Sen Cao 0
Huo-Jun Zhang 0
0 Department of Radiation Oncology, Changhai Hospital , No.168 Changhai road, Shanghai , China
Background: Dose escalation of SBRT for locally advanced pancreatic cancer patients had been reported in several studies in one or three fractions, and phase I protocol was developed to investigate the maximum tolerated dose with CyberKnife for locally advanced unresectable pancreatic cancer patients in five fractions. Methods: The study is designed as a mono-center phase I study. The primary endpoint is to determine the maximum tolerated dose by frequency of III/IV GI (gastrointestinal) toxicity. Adverse events (AE) according to Common Toxicity Criteria (CTC) version 4. Doses of 7 Gy, 7.5 Gy, 8 Gy, 8.5 Gy, 9 Gy, 9.5Gy x 5 respectively would be delivered while meeting with normal tissue constraints. A minimum of three patients will be included for each dosage level. And an interval is 4 weeks from the first patient treatment to the next patient treatment at each dose level. The maximal tolerated dose will be defined as the dose for which at least two patients in three, or at least three patients in nine, will present with a limiting toxicity. Discussion: Since the dose and fractions of SBRT treatment for locally advanced pancreatic cancer patients are still unknown, we propose to conduct a Phase I study determining the maximum tolerated dose of CyberKnife SBRT for the treatment of locally advanced pancreatic tumor based on a 5 fractions treatment regimen. This trial protocol has been approved by the Ethics committee of Changhai hospital. The ethics number is 2016-030-01. Trial registration: Clinical trials number: NCT02716207. Date of registration: 20 March 2016.
Locally advanced pancreatic cancer; SBRT study protocol
Pancreatic cancer is the fourth-leading cause of
cancerrelated death in the world. It is characterized by
metastatic spread and local failure and seldom detected in its
earlier stages. For locally advanced stage pancreatic
cancer, the complete surgical removal is hard to achieve.
Stereotactic body radiotherapy (SBRT) with CyberKnife
for locally advanced unresectable pancreatic cancer is a
relatively new treatment option made available because of
significant improvements in diagnostic imaging and
radiation delivery techniques. Different from the conventional
radiotherapy, radiation dose is delivered in fewer fractions
and higher fractional doses in SBRT. Gurka  reported
that 14 patients received SBRT with prescription dose of
25 Gy in five fractions with BED (biologically equivalent
doses) of α/β = 10 in correspondence to 37.5Gy. Grade 1
to 2 gastrointestinal toxicity (no grade 3 or 4
radiationrelated toxicities) was observed 2 weeks after treatment.
Two patients had a partial response, and 12 patients were
with stable diseases. In the previous dose escalation study,
a single fraction upto15 Gy, 20 Gy, 25 Gywhich is an
equivalent BED10 to 37.5Gy,60Gy,87.5Gy respectively is
recommended by Koong AC  and his team. Even
though the local control rate is 100%, the follow up is
short and the sample size of 15 patients is relatively small.
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Moreover, the late toxicity is not investigated. And with
single fraction scheme, higher late GI toxicities were
reported [2–4]. In the meanwhile, investigators [5, 6] from
South Korea examined that a Dmax of 35Gy and 38Gy in
3 fractions (BED10 to75.8Gy and 86.1Gy) of SBRT
correlated with a 5 and 10% rate of grade 3 of gastroduodenal
toxicity for abdominal malignant tumor, respectively.
Chuong  used 5 fractions to potentially decrease the
risk of late normal tissue injury compared with 1 to 3
fractions commonly used in other institutions. Assuming
α/β = 3, the EQD2 = nd*(d + α/β/2 + α/β) delivered to
normal tissue in this study (using a mean 36.4 Gy in 5
fractions to the high dose PTV) was 75Gy, which is
lower than the mean EQD2 from other series, the
corresponding values from Boston and Stanford were 92.2Gy
(mean, 32.96 Gy in 3 fractions) and 140Gy (mean, 25Gy
in 1 fraction), respectively [8, 9]. And a relatively lower
incidence of grade ≥3 late adverse effects (5.3% VS 9%)
To determine the maximum tolerated dose.
1. To assess the pain intensity by NRS scores.
2. To assess acute and late toxicities following CyberKnife SBRT.
3. Response rate by RECIST criteria.
4. Relapse-free survival (RFS) and overall survival (OS).
Creatinine < 2.0 mg/dL
INR < 2 (0.9–1.1)
AST < 2.5 × ULN (Upper Limit of Normal) (0–64U/L)
ALT < 2.5 × ULN (0–64U/L).
Both men and women and members of all races and
ethnic groups are eligible for this study.
Ability of the research subject or authorized legal
representative to understand and the willingness to sign a
written informed consent document.
Tumor markers and lab test should be done less than
1 week before recruitment.
Prior surgery, chemotherapy or radiation for pancreatic
Prior radiotherapy of the upper abdomen, evidence of
metastatic disease such as nodal or distant metastases by
abdomen CT and chest CT.
Contraindication to receiving radiotherapy.
Distance between GTV (lesion) and luminal structures
(including liver, stomach, duodenum, small or large bowel)
is less than 5 mm.
Women who are pregnant or participation in another
clinical treatment trial while on study.
Patients in whom fiducial implantation were not possible.
Radiation treatment planning
SBRT will be delivered on CyberKnife with Synchrony
Respiratory Tracking system. The tumor will be tracked
with implanted fiducial markers by Fiducial Tracking
System. Treatment will be delivered in 5 fractions within
1 to 2 weeks at the discretion of the investigator.
A body fixation (vacuum-bag) will be used in
immobilizing the body, the arms (both arms are along the body)
and the legs.
Dose will be administered according to the following
recommended schedule: Doses of 7 Gy, 7.5 Gy, 8 Gy,
8.5 Gy, 9 Gy, 9.5Gy x 5 with BED10 in correspondence
to 59.5 Gy, 65.6 Gy, 72 Gy, 78.6 Gy, 85.5 Gy, 92.6 Gy
respectively would be delivered while meeting with normal
tissue constraints (Table 1). A minimum of three
patients will be included for each dosage level. And an
interval is 4 weeks from the first patient treatment to
the next patient treatment at each dose level. In case
Table 1 Diagram of dose escalation
patient presents III/IV GI toxicity, three additional
patients will be included at the same dose level.
The maximal tolerated dose will be defined as the dose
for which at least patients in 3, or at least three patients
in 9, will present with a limiting toxicity.
Margins: The Gross Tumor Volume (GTV) is defined
as the visible tumor based on contrast enhanced CT
acquired on portal-venous phase. The clinical target
volume (CTV) equals the GTV. The planning target
volume (PTV) was usually defined as the region of 2–
5 mm outside of CTV. When tumor is adjacent to
critical organs especially duodenum, we choose to avoid
expanding PTV outside of CTV in this direction.
An individualized treatment plan will be developed
based on tumor geometry and location. At least 90%
volume of PTV should be covered by the prescription dose.
The prescription isodose line was limited to 70–75%
which will restrict tumor Dmax. e. If dose level violates
the constraint of SBRT, the patient will be considered as
ineligible for this trial (Table 2).
Fiducial (Soft tissue gold markers, 0.9 × 3 mm, CIVCO,
Orange City, lowa 51041 USA) implantation will be
done under endoscopic ultrasonography (EUS) guidance.
The recommended number of implanted fiducials is 3
(at least 1) which is preferable to be close to, but not in
the tumor. A time-period of 4–7 days between
implantation and treatment planning CT-scan is recommended.
Intervention and mode of delivery
The planning CT scan and enhanced pancreatic
parenchymal phase CT should be acquired under breath hold
(preferably end-expiratory). The scan range includes the
whole pancreas, at least 10 cm above and below the
tumor. The spiral thin-slice CT was with 1.5 mm slice
collimation and images were reconstructed in slices of
1.5 mm at the most. Co-registration of planning CT to
contrast enhanced CT is based on fiducial and
Table 2 Critical structures and constraints
Dose limits (5 fractions)
anatomical (spinal) fusion. With fiducials >3, 3D data
could be tracked whereas it is hard to implant three
fiducials in clinical practice. If fiducials <3, method of 1
fiducial plus X-sight spine and Synchrony Tracking
technique will be applied. Before the treatment, DRR
images on spine will be applied to detect the 6-D error and
correction will be done thereafter for the X-sight spine
tracking on patients’ positioning. During treatment,
fiducial tracking will be applied.
The irradiation planning and radiation techniques
Collimator selection: there are 12 size options for
collimators selections from 5 to 60 mm, and it depends on
tumor size and the distance to organ at risk (OAR). To
improve the treatment efficiency, the collimator size for
each enrolled patient is fixed in our study.
MU limit is set up to avoid large MU for single beam.
And the total MU is 90,000 for 5 fractions. Maximum
MU/beam is limited to 500 and maximum MU/node is
limited to 1600.
PTV is taken as the source, and shells are expanded
isotropically to constrain high dose volume outside
target and increase conformity index of PTV.
OCO (optimize coverage) technique is applied to
optimize coverage and conformity.
Beam reduction technique is applied to increase
treatment efficiency by deleting beams with small MU.
High resolution is applied to the treatment planning to
further optimize and normalize the prescription dose.
Duration of intervention and evaluation
The duration of treatment will be 1 to 2 weeks. It is
delivered every day and 5 times a week. In case of machine
breakdown, it will be extended to 2 weeks. The
followup period will be for 1 year following completion of
therapy. The trial is planned to begin on September
2016. There cruitment period of the entire study (27
patients) will take approximately 1 year. Acute and late
toxicity according to CTCAE 4.0will be evaluated. Triple
phase enhanced abdomen CT scan (<4 weeks), physical
examination and lab test will be assessed at 1, 3, 6, 9,
12 months after completion of treatment.
Since the treatment modality and dose are still under
exploratory stage, we propose to conduct a Phase I study
determining the maximum tolerated dose of CyberKnife
SBRT for the treatment of locally advanced pancreatic
tumor based on a 5 fractions treatment regimen. A
prescription dose of 35–47.5 Gy in five fractions was
chosen, with an equivalent to the traditional dose of
2 Gy in 25–39 fractions of BED10. And this is assumed
to be the safe and effective dose for unresectable
pancreatic cancer patients.
Initial dose: No severe gastrointestinal toxicities were
reported when Dmax to the gastrointestinal organs was
within 30 Gy [10, 11]. Based on these results, Kavanagh
 suggested that Dmax of the intestine should be less
than 30 Gy in three fractions (BED10 to 60 Gy). The
initial dose in our study will be defined as 35 Gy in 5
fractions (BED10 to 59.5 Gy), which is an equivalent to the
traditional dose of 2 Gy in 25 fractions in BED10.
The classical “4R” radiobiological factors and
linearquadratic (LQ) model are useful for calculating iso-effect
doses in conventional 2Gy fractionated irradiation, which
is not enough for estimating hypo-fractionated SBRT .
The SBRT may prolong the time of repairing sub-lethal
radiation damage compared to conventional irradiation in
mamalian cells . Moreover many evidences show that
DNA double-strand breaks alone cannot explain the
highly effective SBRT [15, 16], which encompasses not
only direct but also indirect cell deaths  including
differential endothelial, overcoming hypoxic radio resistance
and activation of immunological pathways.
These biological properties may contribute to reduce
normal tissue toxicity and hypofractionation is more
effective than conventional radiation therapy.
4R: Reoxygenation, repair, repopulation, and redistribution; AAPM: American
association of physicists in medicine; BED: Biologically equivalent doses;
CT: Computer tomography; CTV: Clinical target volume; EUS: Endoscopic
ultrasonography; GI: Gastrointestinal; GTV: Gross tumor volume;
INR: International standard ratio; KPS: Karnofsky performance status;
LA: Locally advanced; LQ: Linear-quadratic; NRS: Numeric rating scales;
OAR: Organ at risk; OCO: Optimize coverage; PTV: Planning target volume;
SBRT: Stereotactic body radiotherapy
The authors acknowledge Dr. Jiuhong Chen and Dr. Fabienne
Hirogoyenberry for their valuable advice of revising the manuscript.
Availability of data and materials
Materials and Methods are available in the clinicaltrials.gov.
ZHJ is the principle investigator (PI) of this study and made contributions to the
protocol design. QSW is the study coordinator and drafted the manuscript. CYS,
JXP and ZXF participated in revising the manuscript in physical and clinical
protocols. All authors read and approved the final manuscript.
The authors declare that there is no competing interests.
Consent for publication
Ethics approval and consent to participate
This trial protocol has been approved by the Ethics committee of Changhai
hospital. The Ethics number is: 2016-030-01.
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