TJ

ISSN 0300-8916
Tumori 2017; 00(00): 000-000
DOI: 10.5301/tj.5000702

ORIGINAL RESEARCH ARTICLE

Neoadjuvant volumetric modulated arc therapy in rectal

cancer and the correlation of pathological response
with diffusion-weighted MRI and apoptotic markers
Necla Gurdal1, Merdan Fayda2, Nijat Alishev3, BarisBakir3, Didem Tastekin4, Faruk Aykan4, Ugur Gezer5, Emre Balik6,
Esra Kaytan Saglam1, Ethem Nezih Oral1, Mine Gulluoglu7, Ahmet Kizir1
1
Department of Radiation Oncology, Institute of Oncology, Istanbul University, Istanbul - Turkey
2
Department of Radiation Oncology, Istinye University, Faculty of Medicine, Istanbul - Turkey
3
Department of Radiology, Istanbul University, Istanbul Faculty of Medicine, Istanbul - Turkey
4
Department of Medical Oncology, Institute of Oncology, Istanbul University, Istanbul - Turkey
5
Department of Basic Oncology, Institute of Oncology, Istanbul University, Istanbul - Turkey
6
Department of General Surgery, Istanbul University, Istanbul Faculty of Medicine, Istanbul - Turkey
7
Deparment of Pathology, Istanbul University, Istanbul Faculty of Medicine, Istanbul - Turkey

ABSTRACT
Purpose: In this prospective observational study, we aimed to report the applicability and tolerability of neoad-
juvant volumetric modulated arc therapy with simultaneous integrated boost (SIB-VMAT) and concurrent che-
motherapy in patients with locally advanced rectal cancer (LARC), and to evaluate the correlation of pathological
response with apparent diffusion coefficient (ADC) measurements on diffusion-weighted magnetic resonance
imaging (DW-MRI) and apoptotic markers.
Methods: The study enrolled 30 patients with T3 to T4 and/or N+ rectal cancer who preoperatively received SIB-
VMAT and concurrent chemotherapy. Before and after the neoadjuvant treatment, apoptotic markers including the
nucleosomes and cell-free DNA fragments in the serum samples were examined; DNA integrity was assessed by
amplifying the ACTB gene; and the ADC measurements on the DW-MRI were analyzed.
Results: No patients had acute or chronic grade III-IV toxicity. Pathologic complete response (pCR) was achieved
in 8 patients (27%), while in 10 patients (33%) near-complete pathological response was obtained. Posttreatment
ADC was significantly higher in patients with pCR compared with the others (1.28 vs. 1.10, p = 0.017). ROC curve
analysis showed that posttreatment ADC values had a sensitivity of 75% and a specificity of 77.3% for distinguish-
ing the patients with pCR from other responders. On the other hand, posttreatment DNA integrity values were
revealed lower than the pretreatment values (p = 0.36). Also, the results revealed an insignificant increase in the
posttreatment serum level of nucleosomes (p = 0.72).
Conclusions: Neoadjuvant SIB-VMAT with concurrent chemotherapy was proved to be a feasible treatment regi-
men in LARC with tolerable side effects, and improved local control rate and pCR rate.
Keywords: Apoptotic markers, Diffusion-weighted MRI, Nucleosomes, Pathologic complete response, Rectal
carcinoma, Volumetric modulated arc therapy-simultaneous integrated boost (SIB-VMAT)

Introductıon researchers to explore new strategies to increase the rate of

pathological response (1-7). Because of the easy determi-
Pathological response rate and stage regression has be- nation of serum samples, the significance of several serum
come one of the most important prognostic factors and led apoptotic markers (SAMs) in diagnosis, prognosis, and re-
lapse has been researched via ongoing studies (8-10).
In contrast, through diffusion-weighted magnetic reso-
Accepted: July 12, 2017 nance imaging (DW-MRI) created by measuring the molecu-
Published online: December 6, 2017 lar movements of water in the tissue, the cell density of the
lesion can be examined, so the actual tumor can be distin-
Corresponding author: guish from edema, infection, and ischemia. In addition, the
Necla Gurdal response to treatment can be analyzed with the apparent
Department of Radiation Oncology
Institute of Oncology,
diffusion coefficient (ADC) map, which is created by calculat-
Istanbul University ing the molecular water mobility in tissue. The most recent
34390 Capa, Istanbul, Turkey publications in the literature state that the response to treat-
gurdalnecla@hotmail.com ment can be analyzed with the changes of values in the ADC

© 2017 Wichtig Publishing

2 Neoadjuvant SIB-VMAT in rectal cancer

map (11). Therefore, the main goal in the present study is to regression scoring system created by Dworak et al (16) was
evaluate applicability and tolerability of 4-week radiotherapy used to evaluate response to the treatment.
with SIB-VMAT, and to determine the correlation of patho-
logic response with the SAMs and DW-MRI findings, prospec- Detection of serum apoptosis marker
tively (12-15).
Before and after the NACRT, the serum samples were ob-
Methods tained from all the patients, and the circulating nucleosomes
and circulating cell-free DNA fragments were examined as
Patient selection apoptotic markers by the ELISA Cell Detection kit. At first,
DNA was isolated from 200 µL of serum by the phenol/chlo-
Thirty patients with the locally advanced rectal cancer roform extraction method to analyze serum DNA integrity.
(LARC) who were admitted to the Istanbul University Institute Two overlapping fragments from ACTB gene sequences in
of Oncology between January 2013 and August 2013 were in- 106 and 384 base pairs length were amplified by quantitative
cluded in the study. Pretreatment evaluation included a com- polymerase chain reaction from the isolated DNA samples. A
plete medical history of patients and physical examination, 384/106 ratio was accepted as the serum DNA integrity in-
colonoscopy and biopsy, laboratory tests, pelvic MRI (with dex. Values were between 0 and 1 while a value closer to zero
T1-T2 and diffusion weighted), positron emission tomography meant more pieced DNA (DNA derived from apoptotic cells).
with fluorodeoxyglucose, and computed tomography (PET- A total of 25 µL of serum was used for nucleosome ELISA.
FDG-CT) and, in selected patients, endorectal ultrasound. After color change following incubation, the absorbance val-
ues ​were read in the ELISA reader at 405 nm, and values were
Simulation, volume definition, and radiotherapy technique taken as relative apoptosis quantities.

All patients underwent CT simulation with a Philips Bril- Diffusion MRI-ADC measurement
liance (Philips) scanner in the supine position with a slice
thickness of 5 mm. These simulation CT imagings were fused Diffusion-weighted MRIs were obtained from all patients
with DW + T2-weighted MRI scans taken for diagnostic pur- before and after NACRT in order to confirm staging and pro-
poses, and delineation was carried out using Varian Eclipse vide detailed preoperative evaluation. ADC values were mea-
TPS station Version 8.9 (Varian Medical Systems). sured and compared on these images. ADC measurements
A radiologist determined the gross target volume (GTV) of the images taken with 1.5T MR scanner (Achieva; Philips
and clinical target volume corresponding to the boost volume Medical Systems) were obtained with Philips MR Workspace
(CTV 46), which were generated with DW-MRI fusion. GTV software by subtracting the mean ADC value from the diffu-
was defined as a primary tumor and involved lymph nodes. sion-weighted images with a b-value of 1,000. The protocol
CTV 46 included the GTV and the related mesorectal field. of MRI scans consisted of standard axial, sagittal, and coronal
A 1 cm margin in all directions was added to the CTV 46 to T2-W fast spin echo sequences, and axial diffusion weighted
define the planning target volume (PTV 46) which constituted imaging (DWI) single-shot echo planar sequence acquired
the simultaneous integrated boost volume. The whole me- with b-values of 0, 500, and 1000 s/mm2. The ROI (region of
sorectum, including GTV and the remainder pelvic structures interest) was drawn manually in the tumoral tissue on axial
including all the pararectal, presacral, internal iliac, obturator, images that were planned perpendicularly to the tumor axis.
mesenteric lymph node regions (up to L5–S1 interspace), was The method of ROI drawing was the “single slice” method;
defined as CTV 40. PTV 40 volume was created with a 1 cm drawing along the tumour margins on a single slice with larg-
margin in all directions to the CTV 40. est tumour area. In patients with good response to the treat-
The bladder, rectum, small intestine, and femoral heads ment, the ROI was drawn in the area corresponding to the
were delineated as the organs at risk (OAR). Dose constraints hypointense fibrotic area in T2-weighted images.
for the OAR are shown in Table I. Plans were created with the
volumetric arc technique (single arc) according to the healthy Statistical methods
tissue tolerance dose limits.​Treatment was delivered on a Rap-
idarc–Trilogy linear accelerator, and the daily treatment time The follow-up time of the patients was measured from
was approximately 5-8 minutes. Port images of all patients the date of application. Actuarial local control (LC), disease-
were taken prior to the initiation of the therapy, and subse- free survival (DFS) and overall survival (OS) were estimated by
quent port checks were made on a weekly basis. The prescribed Kaplan Meier analysis. The quantity of serum nucleosomes,
doses were 46 Gy to PTV 46, and 40 Gy to PTV 40, which were and ADC measurements in DW-MRI before and after treatment
delivered simultaneously over 20 daily fractions. Therefore, were evaluated using the Wilcoxon test. Paired samples t-test
the entire course of SIB-VMAT was given over 4 weeks. was used to evaluate the changes of serum DNA integrity val-
ues before and after treatment. The correlation between the
Chemotherapy and surgery differences in nucleosomes quantities before and after treat-
ment, and the response to treatment were evaluated using the
All patients received concurrent infusional 5-FU with a Mann-Whitney U-test. This test was used again to reveal the
daily dose of 200-225 mg/m2. Total mesorectal excision was differences between Dworak 4-pCR group and all other groups
performed in all patients after 8-10 weeks following the in terms of ADC values. Sensitivity, specificity, and area under
completion of neoadjuvant chemoradiation (NACRT). The curve (AUC) for posttreatment ADC values were determined

© 2017 Wichtig Publishing

Gurdal et al 3

using ROC analysis. Pearson correlation analysis was carried changes did not demonstrate any statistical significance. Simi-
out to observe the correlation between each Dworak group larly, a significant association could not be observed between
and pathologic response. Frequency, tables and statistics were pre- and posttreatment quantities of nucleosomes and treat-
performed using SPSS 16.0 (SPSS Inc.) statistical software. The ment response. An increase in the quantities of posttreatment
statistically significant threshold was accepted as p = 0.05. serum nucleosomes was recorded in our study group, but this
increase did not reach statistical significance (Tab. III).
Ethical standards A statistically significant difference in the measured ADC
values ​was observed in DW-MRI of the patients taken before
The study protocol was approved by the Local Ethics and after NACRT (Tab. III). Considering the subgroups, mea-
Committee of Istanbul University, Istanbul Faculty of Medi- sured ADC values ​after NACRT were statistically significantly
cine, and written informed consent was obtained from each higher in the pCR (Dworak-4) group compared with all other
patient. The study was performed in accordance with the response groups (1.28 vs. 1.10, p = 0.017). In addition, the
­Declaration of Helsinki (5th revision, October 2000) of the ROC curve analysis results showed that at the optimal cut-off
World Medical Association and was approved by the National (1.2585), posttreatment ADC values had a sensitivity of 75%
Medical Ethics Committee of the Republic of Turkey. and a specificity of 77.3% for distinguishing the patients with
pCR from other responders with an AUC of 0.761 (p = 0.031;
Results
The results were evaluated in August 2014 and revised in TABLE I - Dose constraints used for organs at risk (OAR)
February 2017. Of the patients, 21 (70%) were males and 9
(30%) were female. The median age was 60.5 (34–79 years). Small intestine Femoral heads Bladder
The median follow-up time was 42 months (20-49 months). V15 <150 cc V20 <50% V25 <50%
The initial median distance from the anal verge measured
was 5.5 cm (0–10 cm). The tumor location was in the distal V45 <80 cc V30 <20% V45 <20%
rectum in 15 (50%) patients and the middle rectum in 15 V50 <20 cc Dmax <40-45 Gy - -
(50%) patients. According to the tumor, node, and metastasis
classification, tumor depth was determined as T3 in 29 (97%)
patients and T4 in 1 (3%) patient clinically. Clinical node posi- TABLE II - The characteristics of surgical procedures and pathologic
tivity was seen in 28 patients (93%). An NACRT schedule was results of the patients
administered to all patients. No treatment interruption was
needed due to radiation therapy (RT) toxicity. Variables N
Surgery
Surgery Sphincter-sparing 23 (77%)
All patients underwent surgery after NACRT. The median Abdominoperineal resection 7 (23%)
surgery period was 9.5 weeks (8-16 weeks). No correlation was Total mesorectal excision
observed between the pathological response rate and time to Complete 24 (80%)
surgery. The sphincter-sparing rate in those with tumors locat- Incomplete 6 (20%)
ed ≤5 cm from the anal verge was 53%. Surgical margins were
determined to be negative in all patients. Of 30 patients, 25 Time to surgery
(83%) received adjuvant chemotherapy treatment for 4 months 8 weeks 0 (0%)
following the first month postoperatively. Two patients received 8-10 weeks 18 (60%)
XELOX while the remaining patients followed the FOLFOX regi- ≥11 weeks 12 (40%)
men. Postoperative findings are presented in Table II. Pathological T stage
ypT0 8 (26.7%)
Pathological results
ypT1 2 (6.7%)
According to Dworak regression, grade IV regression pCR ypT2 6 (20%)
was obtained in 8 (27%) of the 30 patients who underwent ypT3 14 (46.7%)
surgery. Grade III regression (near complete response) was Pathological nodal stage
­obtained in 10 patients (33%) in 9 of whom (30%) pathology ypN0 24 (80%)
reports showed complete near total regression (NTR) since only
ypN1 3 (10%)
alive tumor cells were observed. The distribution of patients
according to the tumor regression score is shown in Table II. ypN2 3
Pathologic responses
Evaluation of treatment response with serum apoptosis Dworak 1 4 (13%)
marker levels and diffusion MRI Dworak 2 8 (27%)
Dworak 3 10 (33%)
The analysis revealed that posttreatment serum DNA
integrity decreased compared with pretreatment, but these Dworak 4 8 (27%)

© 2017 Wichtig Publishing

4 Neoadjuvant SIB-VMAT in rectal cancer

TABLE III - Pre- and posttreatment mean serum DNA integrity, me-
dian serum nucleosome, and median DW-MRI ADC lev-
els of the patients

Variables Pretreatment Posttreatment p value

Mean serum DNA 0.83 0.79 0.72

integrity levels
Median serum 0.62 0.73 0.36
nucleosome levels
Median DW-MRI 0.79 1.14 <0.001
ADC levels
ADC = apparent diffusion coefficient; DW-MRI = diffusion-weighted magnetic
resonance imaging.

Fig. 2 - The relationship between tumor regression scores and

changes in ADC restrictions in DW-MRI (Pearson correlation anal-
ysis). ADC = apparent diffusion coefficient; DW-MRI = diffusion-
weighted magnetic resonance imaging.

metastatic disease. The sites of distant recurrence were liver,

lung, and bones. Three patients died from disease progres-
sion. After a median follow-up of 42 months, the LC, DFS, and
OS rates were 96%, 87%, and 89% respectively.

Discussion
Since the better prognosis of patients with pCR is shown,
RT techniques become a crucial issue (17-21). The pCR rate
provided by the combination of preoperative 5-FU and the
conventional RT technique (45-50 Gy/1.8-2 Gy) is 5% to 27%
(22). However, severe acute toxicity rate with the conven-
Fig. 1 - The ROC curve analysis of posttreatment ADC values. At the tional technique is observed as approximately 24% to 40%
optimal cut-off (1.2585), posttreatment ADC values had a sensitivity (23). Moreover, in the majority of phase II-III trials, the grade
of 75% and a specificity of 77.3% for distinguishing the patients with III-IV toxicity rate is as high as 12% to 30% in conformal RT
pCR from other responders with an area under the curve (AUC) of
0.761 (p = 0.031; 95% confidence interval, 0.557-0.965). ADC = ap- (45-50 Gy/1.8-2 Gy) with concomitant capesitabin and/or
parent diffusion coefficient; pCR = pathologic complete response. oxaliplatin, while pCR is around 15% (24). Concerning these
high rates of toxicity, it has become a substantial subject to
decrease side effects while increasing pCR rates. Higher gas-
95% confidence interval, 0.557-0.965) (Fig. 1). When response trointestinal system side effects, especially, led research-
groups were examined separately, the correlation of pre- and ers to investigate the efficacy and tolerability of different
posttreatment ADC value differences and pathological tumor chemotherapy combinations as well as RT techniques and
response could be shown as weak, since the number of patients fractionation schedules. Volumetric modulated arc therapy
distributed in each group was small (r = -0.39; p = 0.03) (Fig. 2). with simultaneous integrated boost (SIB-VMAT) enables the
delivery of higher doses to the tumor while sparing critical
Side effects normal tissues (14). Furthermore, the total treatment time
can be shortened by increasing doses per fraction; there-
Patients were examined weekly according to RTOG/EORTC fore, 5-6 weeks’ duration of treatment can be completed in
acute radiation criteria and it was found that side effects were a 26% shorter period of approximately 4 weeks with lower
observed mostly during the last 2 weeks of the NACRT. No monitor units and shorter beam-on time (25, 26).
grade III or IV acute toxicity was observed, and no interrup- The pCR rate was 27% in the present study and NTR was
tion in chemotherapy or RT was needed due to toxicity. The achieved in 30% of patients while 57% and 80% downstaging
incidences of acute side effects are detailed in Table IV. rates were observed in T and N stages, respectively. Li et al
(27) obtained a pCR rate of 31% in their study, which includ-
Local control and survival ed 58 patients with LARC (T3-T4/N+). The patients received
41.8 Gy/22 fr/1.9 Gy to the pelvic region and 50.6 Gy/22
After a median follow-up of 42 months (20-49 months), fr/2.3 Gy to the tumor with concurrent capesitabin. Similar to
1 patient developed local disease, and 3 patients developed our study, they achieved 56.9% and 79.2% improvements in

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Gurdal et al 5

TABLE IV - The incidence of acute side effects observed in patients according to RTOG/EORTC acute radiation criteria

Grade I Grade II Grade III Grade IV Grade V

Gastrointestinal 17 (56%) 12 (40%) - - -

Genitourinary 10 (33%) 3 (10%) - - -
Skin toxicities 4 (13%) 3 (10%) - - -
Hematopoietic system toxicities
Neutropenia 2 (6,5%) - - - -
Leukopenia 3 (10%) - - - -
Anemia 4 (13%) 2 (6.5%) - - -
Thrombocytopenia 3 (10%) - - - -

T and N stages, respectively. We did not observe any grade ­ ifferent b-values and models to calculate ADC from ­DW-MRI.
d
III or IV toxicity, whereas grade III diarrhea, dermatitis, and In the present study, a significant increase in ADC value was
neutropenia in their study were reported to be 9.5%, 3%, observed after NACRT in all response groups (p<0.001). Con-
and 1.6%, respectively (27). On the other hand, Cotted et al sidering the subgroups, the measured ADC values after NAT
(28) reported that both local and distant recurrences were were found to be statistically significantly higher in the pCR
observed as 9.6% at 1 year, 39.5% during the first 5 years, and group (Dworak 4) compared with all other response groups
43.1% in 10 years in 1,222 patients with rectal cancer. The (Dworak 1, 2, 3) (p = 0.017). Similarly Jung et al (39) found
10-year recurrence rate in patients who received NACRT was that pretreatment ADC values were lower, and differences in
18.3%, whereas 3.8% of the patients who had no recurrence ADC values prepost NACRT were higher in patients with good
during the first 5 years developed local recurrence between response than those with poorer r­ esponse (39).
5 and 10 years. Since the follow-up time of our study is still We achieved pCR or NTR in 57% of patients with our
quite short, longer follow-up is required to find out the actual shorter treatment schedule, which consisted of concurrent
recurrence rates of our patients. infusional 5-FU and the SIB-VMAT technique with the toxici-
Obtaining better prognosis with the pCR has induced ties of normal tissue at risk, which were limited at the level
several biomolecular studies in these patients. Dead cells of grade II due to better sparing. However, studies with an
are eliminated by phagocytes under normal physiological extended number of patients are required to investigate the
processes; however, in the presence of malignancy, nucleo- use of SIB-VMAT, because there is a lack of clinical studies on
somes and free DNA fragments may pass to blood circulation SIB-VMAT in patients with locally advanced rectal adenocar-
due to excessive production. There is a correlation between cinoma, or the existing studies in this area only have a small
tumor stage and metastases in gastrointestinal cancer with number of patients. Although a statistically significant rela-
the quantity of nucleosomes (29). Al-Shuneigat et al (30) and tionship between treatment response, the quantity of serum
Hao et al (31) showed that serum nucleosome quantity and nucleosomes, and DNA integrity could not be determined,
free DNA fragments were significantly higher in patients with the statistically significant response predictability of the ADC
colorectal cancer compared with healthy controls, respec- changes demonstrated in this study is promising for more
tively. Furthermore, free DNAs were higher in metastatic/­ comprehensive research.
recurrent patients than in newly diagnosed or operated ones.
In addition, the level of free DNA decreased significantly Acknowledgments
during the postoperative period. In our study, the increased
We would like to thank Rümeysa Çiftçi,Uğur Akbaş, Dilek Şahin,
quantity of serum nucleosomes was recorded after the treat- Hakan Yanar, Metin Keskin, Mehmet İlhan, and Rabia Nergiz Dağoğlu
ment. Similarly, serum DNA integrity was decreased, com- for their selfless contribution.
pared to pretreatment levels; however, both changes did not
reach statistical ­significance. Disclosures
In several studies, the benefit of ADC differences for the
assessment of treatment response was determined in pa- Financial support: No grants or funding have been received for this
study.
tients with rectal cancer (32, 33). Conflict of interest: None of the authors has financial interest related
Some authors have reported correlations between low to this study to disclose.
pretreatment ADC values and/or the change of ADC values Meeting presentation: A part of this study was selected for pre-
through treatment and good histopathological response (34, sentation in the Poster Viewing Session at the ASTRO’s 57th Annual
35); while others have reported associations between low Meeting. October 2015, San Antonio, TX, USA.
pretreatment ADC values and more aggressive tumours (36,
37), or they could not find any association between ADC val-
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