Extended-field bone marrow sparing radiotherapy for primary chemoradiotherapy in cervical cancer patients with para-aortic lymphadenopathy: Volumetric-modulated arc therapy versus helical tomotherapy

Abstract

BACKGROUND:

Extended-field (EF) bone marrow-sparing (BMS) radiotherapy is attracting interest for cervical cancer patients with para-aortic lymphadenopathy.

OBJECTIVE:

To compare dosimetric quality of volumetric-modulated arc therapy (VMAT) vs. helical tomotherapy (HT) during EF BMS radiotherapy.

METHODS:

HT dose-volume histogram parameters including (1) coverage, homogeneity, and conformity of target volumes, (2) sparing of organs-at-risk, (3) monitor units, and (4) estimated treatment time were compared with those of VMAT in 20 cervical cancer patients who underwent EF BMS radiotherapy. The pelvic and para-aortic regions received 45-Gy dose (25 fractions), with simultaneous integrated boost of 55 Gy (25 fractions) for pelvic and para-aortic lymphadenopathy, followed by a parametrial boost of 9 Gy (5 fractions).

RESULTS:

The HT-based and VMAT techniques achieved adequate and similar target volume coverage with good dose homogeneity and conformity, while sparing all organs-at-risk, including the rectum, bladder, bowel, bone marrow, femoral head, kidney, and spinal cord. The HT treatment plan had significantly higher monitor units (p < 0.001) and longer estimated treatment times (p < 0.001).

CONCLUSIONS:

VMAT and HT plans are suitable for EF BMS radiotherapy, which can achieve adequate target volume coverage while sufficiently sparing normal tissue. In addition, VMAT, compared to HT planning, yielded shorter estimated treatment times.

Keywords

Cervical cancer extended-field bone marrow sparing volumetric-modulated arc therapy helical tomotherapy

Abbreviations

CTV

Clinical target volume

EF BMS

Extended-field bone marrow-sparing

Helical tomotherapy

Lymph node

OAR

Organs at risk

PTV

Planning target volume

SIB

Simultaneously integrated boost

VMAT

Volumetric-modulated arc therapy

1 Introduction

Cervical cancer is the fifth most common cause of cancer-related deaths in women worldwide [22]. Although concomitant cisplatin-based radiotherapy is the current standard of treatment for locally advanced cervical cancer, this regimen is associated with considerable acute and late toxicities [11, 12]. Extended-field (EF) radiation therapy for the treatment of para-aortic lymphadenopathy in patients with cervical cancer delivers large irradiation volumes to the pelvis and abdomen and is thus associated with an even higher incidence of gastrointestinal and hematologic toxicities [5, 23]. Acute high-grade hematologic toxicities occur in approximately half of all patients who undergo EF radiotherapy and can lead to missed cycles of chemotherapy, potential delays in treatment and, consequently, worse clinical outcomes [26].

Currently, bone marrow-sparing (BMS) techniques are attracting clinical interest; researchers are currently investigating the hypothesis that lowering the radiation dose to the bone marrow reduces hematologic toxicity and permits more optimal chemotherapy delivery to patients undergoing chemoradiotherapy [15 , 20]. For cervical cancer, external beam radiotherapy is conventionally delivered using multiple conformal fields by three-dimensional conformal radiation therapy, and novel intensity-modulated volumetric techniques such as intensity-modulated radiation therapy (IMRT), volumetric-modulated arc therapy (VMAT), and helical tomotherapy (HT) have been introduced to reduce treatment toxicity and are becoming more widely available [21]. In EF BMS radiotherapy, novel radiation techniques may achieve adequate bone marrow-sparing and reduce hematological toxicity without increasing the radiation dose to the bladder, rectum, or bowels. This can be done without compromising target volume dose coverage.

Arc-based IMRT is designed to improve dose distribution through intensity modulation. Recently developed HT and VMAT are two arc-based approaches for IMRT delivery. HT technique combines inverse intensity modulation planning with a full 360-degree radiation beam to yield better dosage conformity, a higher probability of tumor control, and a lower probability of normal tissue complications [8, 25]. In cervical cancer patients, HT can reduce the mean dose to the bowels and provide better homogeneity and conformity when compared to IMRT [24]. However, HT requires a greater number of monitor units and a longer treatment time.

Volumetric-modulated arc therapy (VMAT) conducts dynamic modulation radiation therapy via a linear accelerator [4]. VMAT is administered by adjusting the gantry rotation speed, dose rate, and shape of a multi-leaf collimator to generate clinically useful patterns of intensity modulation that increase the benefit to the patient [1, 28]. Both HT and VMAT can achieve dose differentiation between tumorous and normal tissues and can enable dose escalation by simultaneous integrated boost. The difference between HT and VMAT can be explained by the delivery method; HT delivers the beam in a helical fashion in smaller slice volumes, whereas VMAT delivers radiotherapy using several larger volumes. Ultimately, these advantages yield better tumor coverage.

EF BMS radiotherapy treatment presents a great challenge due to complex tumor geometries, large target volumes that require high radiation doses (especially in the superior-inferior direction), numerous critical structures surrounding these targets, and dose escalation to para-aortic lymphadenopathy, pelvic lymphadenopathy, and the parametrium [19, 30]. To date, no study has comprehensively compared the above-mentioned EF BMS radiotherapy techniques. Here, we aimed to determine and compare the dosimetric qualities of VMAT and HT for the delivery of EF BMS radiotherapy in cervical cancer patients with para-aortic lymphadenopathy.

2 Material and methods

2.1 Patients

Twenty cervical cancer patients with para-aortic lymphadenopathy who underwent extended-field BMS radiotherapy from 2017 to 2018 were investigated. The patients were staged according to the American Joint Committee on Cancer TNM classification, 7th edition [17]. The patients’ characteristics are shown in Table 1.

Table 1
Patient characteristics and treatment parameters (n = 20)

Age by median (range), years 57.4 (37.0– 66.4)

Performance status (ECOG 0/1/2) 5/14/1

Histology (SCC/Adenocarcinoma) 16/4

T (T2a2/T2b/T3b/T4) 3/10/4/3

Tumor size by median (range), cm^a 5.9 (4.3– 7.0)

Number of pelvic LN metastasis by median (range) 4 (0– 6)

Number of para-aortic LN metastasis by median (range) 2 (1– 3)

Age by median (range), years	57.4 (37.0– 66.4)
Performance status (ECOG 0/1/2)	5/14/1
Histology (SCC/Adenocarcinoma)	16/4
T (T2a2/T2b/T3b/T4)	3/10/4/3
Tumor size by median (range), cm^a	5.9 (4.3– 7.0)
Number of pelvic LN metastasis by median (range)	4 (0– 6)
Number of para-aortic LN metastasis by median (range)	2 (1– 3)

Abbreviations: ECOG = Eastern Cooperative Oncology Group; SCC = squamous cell carcinoma; LN = lymph node. ^aTumor size was classified according to the American Joint Committee on Cancer 7th edition TNM classification, measuring the greatest diameter in two or three dimensions.

2.2 Contouring

All women underwent planning computed tomography (CT) using a Brilliance Big Bore instrument (Philips Healthcare, Foster City, CA, USA) at a slice thickness of 3 mm from the diaphragm to the trochanter minor. A custom vacuum bag was created to immobilize the abdomen, pelvis, and proximal legs of all women in the supine position with both arms above the head. Two series of treatment planning CT scans were obtained for each patient: one with a full urinary bladder and one after voiding; patient get off and on the tables between two CT scans. No instructions were provided for rectal filling.

For consistency, all contours were delineated by a single radiation oncologist with expertise in gynecologic oncology and 10 years of experience [12, 13]. The Pinnacle planning system was used for contouring (Pinnacle planning software, version 9.0; Philips Healthcare). The targets and critical structures were contoured on CT slice with full bladder according to the updated delineation consensus for gynecologic malignancy [1 , 16]. The organs-at-risk (OAR), including the bladder, rectum, bowel, kidneys, bone marrow, femoral heads, and spinal cord, were delineated. The bowel included all bowel structures, including the small, large, and sigmoid bowel but excluded the rectum, up to 2 cm above the planning target volume (PTV) but not beyond. The pelvic bone and lumbar spine were contoured as a surrogate for the bone marrow, and the external contour of bone marrow was delineated, rather than the low-density regions within the bones, to ensure reproducibility and minimize dependence of the contours on CT windowing and leveling [31]; the bone marrow contour also included the femoral heads, but not the femoral necks.

The target volumes were defined using the full-bladder CT scan. Pretreatment magnetic resonance studies were co-registered rigidly with the CT scan of the full bladder to guide the delineation of the gross tumor, parametrium, and lymph nodes. Clinical target volume (CTV)-A includes the cervix tumor, uterus, upper vagina, parametrium, and pelvic and para-aortic lymphatics, CTV-B includes the bilateral parametria, and CTV-LN includes para-aortic and pelvic lymphadenopathy. The pelvic lymphatics were defined as the external, internal, and common iliac vessels with a 7-mm margin plus the pre-sacral lymphatics, while the para-aortic lymphatics encompassed the aorta and inferior vena cava with a 7-mm margin. The superior CTV-A border was placed 1 cm below the level of the T12– L1 interspace, while the inferior border was 1 cm above the bottom of the obturator foramen. When required, the superior aspect of the CTV-A was modified laterally and anteriorly to spare the kidney and bowel, respectively. The internal target volume-A integrated the internal motions of the uterus, cervix, and upper vagina as delineated on both the empty- and full-bladder CT. The internal target volume-A, CTV-LN, and CTV-B borders were uniformly expanded by 5 mm to create planning target volumes (PTV)-A, PTV-LN, and PTV-B, respectively.

Simultaneously integrated boost (SIB) was administered [17]. Our strategy included administering a 45-Gy dose (25 fractions) to the pelvic and para-aortic regions with a SIB to 55 Gy (25 fractions) for pelvic and para-aortic lymphadenopathy, followed by a parametrial boost of 9 Gy (5 fractions). The basic plan was generated for PTV-A and PTV-LN, while the parametrial boost plan was generated for PTV-B. PTV-A received 45 Gy at 1.8 Gy/fraction, whereas PTV-LN received a SIB to 55 Gy at 2.2 Gy/fraction. Afterward, PTV-B received a boost dose of 1.8 Gy/fraction for a total dose of 54 Gy. For patients with pelvic lymphadenopathy within the parametrium boost volumes (PTV-B), a total of 64 Gy in 30 fractions to the pelvic lymphadenopathy, combining the basic plan SIB (55 Gy in 25 fractions) and the parametrial boost plan (9 Gy in 5 fractions), was acceptable.

2.3 Treatment planning

For consistency, all treatment planning procedures were developed by the same radiation physicist. For a fair comparison between each technique, 6-MV photon beams were used for both the HT and VMAT plans. Neither plan used non-coplanar fields. In the optimization process, all plans were generated adopting an identical set of PTV and OAR dose-volume constraints to keep the results comparable. During the optimization process, the PTV was given the highest priority. For PTV-A, PTV-LN, and PTV-B, the lower constraint was 95% of the prescribed dose in 95% of the target volume; however, the upper dose constraint of 110% was only reasonable for PTV-B. The priority was set higher for the rectum, bowel, bone marrow, and spinal cord, relative to the femoral heads, bladder, kidney, or liver, accounting for the importance. The OAR volumes were used directly instead of the ring volumes. The dose constraints and relative priority for OAR are shown in Table 2, according mainly to the NRG Oncology-RTOG 1203 protocol [1] and published results on bone marrow effects [15].

Table 2
Dosimetric constraints for target volumes and organs-at-risk

Structures Constraints^a Relative Priority

PTVs >95% of volumes receiving 95% of the prescribed dose 150

Maximal dose, <110% of the prescribed dose

Rectum^b <80% of volumes receiving≥40 Gy 80

Bowel <30% of volumes receiving≥40 Gy 80

Maximal dose, <55 Gy

Bone marrow <90% of volumes receiving≥10 Gy 80

<80% of volumes receiving≥20 Gy

<37% of volumes receiving≥40 Gy

Spinal cord Maximal dose, <45 Gy 80

Bladder <35% of volumes receiving≥45 Gy 50

Kidneys <20% of volumes receiving≥20 Gy 50

Femoral heads <15% of volumes receiving≥30 Gy 50

Liver Mean dose, <15 Gy 50

Structures	Constraints^a	Relative Priority
PTVs	>95% of volumes receiving 95% of the prescribed dose	150
	Maximal dose, <110% of the prescribed dose
Rectum^b	<80% of volumes receiving≥40 Gy	80
Bowel	<30% of volumes receiving≥40 Gy	80
	Maximal dose, <55 Gy
Bone marrow	<90% of volumes receiving≥10 Gy	80
	<80% of volumes receiving≥20 Gy
	<37% of volumes receiving≥40 Gy
Spinal cord	Maximal dose, <45 Gy	80
Bladder	<35% of volumes receiving≥45 Gy	50
Kidneys	<20% of volumes receiving≥20 Gy	50
Femoral heads	<15% of volumes receiving≥30 Gy	50
Liver	Mean dose, <15 Gy	50

Abbreviations: PTV = planning target colume. ^aThe constraints for organs-at-risk were according to the NRG Oncology-RTOG 1203 protocol and published results on bone marrow effects [15]. ^bFor the rectum, the variation of “more than 80% but less than 100% receives 40 Gy” was acceptable.

The VMAT plans were optimized using the Philips Pinnacle Planning System 9.0 (Philips Healthcare) and the SmartArc module with the collapsed-cone convolution algorithm. To optimize the treatment planning calculation time and accuracy, the spacing unit was set at 4°. The system was set to create two full arcs of 181°– 179° and 179°– 181° for the PTV-A with SIB for the PTV-LN (total: 182 control points), followed by six partial arcs of 181°– 240°, 300°– 60°, 120°– 179°, 179°– 120°, 60°– 300°, and 240°– 181° to boost the parametrium (PTV-B) while avoiding doses to the rectum and bladder.

The HT plans were generated using the TomoTherapy Planning Station (Hi-Art Version 5.1.4; TomoTherapy Inc., Madison, WI, USA) with the following major parameter settings: field width, 2.5 cm; pitch, 0.287; and modulation factor, 2.5, with fixed jaw mode. A fine dose calculation grid (256×256 pixels) with a superposition/convolution algorithm was used for the dose calculation.

The doses from all plans were summed up for evaluation. The dose-volume histogram parameters for HT were compared to those of VMAT, and analyses were applied to both the PTVs and the OARs. Monitor units are used to measure the output of a radiotherapy machine to deliver the accurate dose, which is unique and calibrated by each radiotherapy machine. Estimated treatment time is ordinarily evaluated using the MU values, the dose rate (MU per minutes), and the gantry rotation time estimated by the radiotherapy machine. The number of monitor units (MU) and the estimated treatment times of the VMAT and HT plans were recorded.

2.4 Treatment delivery

Our National Health Insurance policy reimburses linear accelerator-based radiotherapy (not tomotherapy) as it is the treatment for all patients with gynecologic cancers in our institution. Therefore, all patients received VMAT radiation therapy delivered using the Elekta Synergy accelerator (Elekta, Stockholm, Sweden) [14]. Cone beam computed tomography (CBCT) scanners on-board were used for daily image guidance before treatment. The CBCT images were acquired with scan parameters of 125 kV and 80 mA in the half-fan mode using a half bowtie filter. An automatic rigid registration process of the CBCT to the planning CT was performed in three translational directions, including left – right, superior – inferior, and anterior – posterior, evaluating by the automatic bony match to acquire satisfactory treatment positioning. When deviations exceeded 5 mm, repositioning the patient was considered and CBCT was performed again with repeating the aforementioned matching process. The first CBCT procedure was verified by the radiation oncologist online while subsequent procedures were verified via the offline review. All patients underwent Ir-192 high-dose-rate intracavitary brachytherapy with a total dose of≥24 Gy (four fractions at≥6 Gy per fraction) delivered to the macroscopic tumor as defined via magnetic resonance imaging (Gammamed Brachyvision, Varian Medical Systems, Palo Alto, CA, USA) once or twice weekly [12]. The brachytherapy dose was not included in the dosimetric analysis. Concomitant with radiation therapy, all 20 patients received simultaneous cisplatin (40 mg/m²) chemotherapy weekly.

2.5 Follow-up assessment

Follow-up analyses were conducted implementing a comprehensive protocol using the relevant data available as of October 1, 2019. Acute and late toxicities were rated according to the Common Terminology Criteria for Adverse Events version 4.0. All patients were followed for at least 3 months for the first 2 years, and every 4– 6 months thereafter until recurrence or death [12, 13]. Locoregional recurrence was defined as failure in the primary tumor, new pelvic tumors, or pelvic or para-aortic lymph nodes below the T12– L1 interspace. Distant metastasis was defined as disease relapse outside the treated area as detected pathologically, cytologically, or radiologically. Progression-free survival was defined as the time (in months) from the date of treatment completion to that of progression or censoring, while overall survival was defined as the time in months from the date of treatment completion to that of death, last follow-up, or censoring.

2.6 Statistical analyses

Statistical analyses were performed using the Statistical Package for Social Sciences for Windows, version 17.0 (SPSS Inc., Chicago, IL, USA). The target volumes were evaluated by V_95 % (percent volume receiving at least 95% of the prescribed dose), conformity index, and homogeneity index. The conformity index was calculated as the ratio of the volume receiving 95% of the prescribed dose (V95%) and the corresponding PTV; an index approaching 1 indicated better dose conformity [25]. The homogeneity index was defined as the ratio of the dose received by 95% (D95%) of the PTV to the minimum dose received by the “hottest” 5% (D5%) of the PTV; an index approaching 1 indicated better homogeneity. The OAR data were evaluated by the mean dose (Dmean), the volumes receiving 10 (V10), 20 (V20), 30 (V30), 40 (V40), (V45), and 50 (V50) Gy, and the maximum dose (Dmax). The monitor units and estimated treatment times for all plans were recorded. All the above data were organized into paired samples (HT vs. VMAT) for comparison using two-sided Student’s paired t-tests. The survival rates were estimated using Kaplan-Meier life table analyses. P-values≤0.05 were considered statistically significant.

2.7 Ethical approval

This retrospective study was approved by our Institutional Review Board (approval number 201706041RINC) and was performed in accordance with the Declaration of Helsinki, including all relevant details.

3 Results

3.1 Patient characteristics

The median patient age was 57.4 years (range, 37.0– 66.4 years) (Table 1). All patients had para-aortic lymphadenopathy according to the American Joint Committee on Cancer TNM classification, 7th edition [17]. We intended to give 45-Gy dose (25 fractions) to the pelvic and para-aortic regions (PTV-A), with SIB to 55 Gy (25 fractions) for pelvic and para-aortic lymphadenopathy (PTV-LN), followed by a parametrial boost of 9 Gy (5 fractions) to PTV-B. The mean PTV-A and PTV-LN volumes were 1935.3±324.1 and 63.4±62.5 cm³, respectively, and the mean parametrial boost volume (PTV-B) was 436.9±141.8 cm³. The average length of PTV-A in the superior-inferior direction was 31.7±2.0 cm. The mean volumes of the bladder, rectum, bowel, bone marrow, kidneys, and femoral heads were 284.2±158.1, 75.2±37.2, 1657.6±425.1, 1461.7±163.9, 221.3±121.1, and 144.8±59.4 cm³, respectively.

3.2 Comparison of HT and VMAT

The isodose distributions for a representative cervical cancer patient with para-aortic lymphadenopathy who underwent planned curative radiotherapy using VMAT and HT are shown in Fig. 1. Both techniques yielded good conformity indices for PTVs, with values approaching 1 (Table 3). The two techniques differed little in terms of target dose distribution homogeneity, and both yielded good homogeneity indices for the PTVs.

Fig.1

The isodose distributions in a cervical cancer patient with para-aortic lymphadenopathy who underwent planned curative radiotherapy via helical tomotherapy (HT, left) and volumetric modulated arc therapy (VMAT, right). Shown are (a) the axial views at the pelvic level and (b) abdominal level, (c) the coronal view, and (d) the sagittal planes. A 45-Gy dose (25 fractions) was prescribed to the pelvis and para-aortic region (PTV-A) with a simultaneously integrated boost to 55 Gy (25 fractions) to the involved pelvic and para-aortic lymph nodes (PTV-LN), followed by a parametrial boost (PTV-B) of 9 Gy (5 fractions). The color-washed areas indicate the following: blue, planning target volume (PTV)-A (i.e., cervix tumor, uterus, upper vagina, parametrium, pelvis, and para-aortic lymphatics); red, the PTV-LN (gross pelvic and para-aortic lymph nodes); and green, the PTV-B (bilateral parametrium boost). The red, indigo, green, blue, pink, and yellow lines represent isodose curves of 64, 55, 54, 45, 40, and 30 Gy, respectively.

Table 3

Comparison of irradiation parameters to the target volumes

DVH parameter	HT (mean±SD)	VMAT (mean±SD)	p-value ^a
PTV-A
V_95 % (%)	98.6±1.2	99.1±0.7	0.146
HI	0.78±0.03	0.78±0.03	0.778
CI	0.99±0.01	0.99±0.01	0.146
PTV-B
V_95 % (%)	99.6±0.8	98.9±3.2	0.287
Dmax (%)	107.3±5.3	110.2±3.8	0.082
HI	0.91±0.06	0.88±0.04	0.099
CI	0.99±0.01	0.99±0.03	0.287

Abbreviations: DVH = dose-volume histogram; HT = helical tomotherapy; VMAT = volumetric modulated arc therapy; PTV = planning target volume; V_95 % = percent volume receiving at least 95% of the prescribed dose; HI = homogeneity index; CI = conformity index; Dmax = maximal dose. ^ap-values were calculated using Student’s paired-samples t-test.

Regarding the rectum, both techniques met the dose constraints (defined as “per protocol” and “acceptable variation”) as shown in Table 2, and no plan had an unacceptable variation. The rectum dose-volume histogram (Fig. 2a, Table 4) demonstrated corresponding V40 values of 92.3% ±6.1% and 83.4% ±10.2% for HT and VMAT, respectively (P = 0.062), corresponding V50 values of 48.1% ±18.6% and 26.9% ±16.9% for HT and VMAT, respectively (P = 0.051), and a mean rectal dose of 48.8±1.8 Gy and 46.3±2.5 Gy for HT and VMAT, respectively (P = 0.063).

Fig.2

The average dose-volume histograms of the organs at risk in 20 patients during volumetric modulated arc therapy (VMAT, grey) and helical tomotherapy (HT, black). Shown are the (a) rectum, (b) bowel, (c) bone marrow, and (d) bladder. Points indicate mean values (n = 20) at 10 Gy, 20 Gy, 30 Gy, 40 Gy, 50 Gy, and 54 Gy; bars indicate standard deviations (n = 20) at 10 Gy, 20 Gy, 30 Gy, 40 Gy, 50 Gy, and 54 Gy. Dmean = mean dose. p-value for statistical comparisons was performed by two-sided Student’s paired t-tests.

Table 4

Comparison of irradiation parameters to the organs-at-risk

DVH parameter	HT (mean±SD)	VMAT (mean±SD)	p-value ^a
Rectum
Dmean (Gy)	48.8±1.8	46.3±2.5	0.063
V40 (%)	92.3±6.1	83.4±10.2	0.062
V50 (%)	48.1±18.6	26.9±16.9	0.051
Bowel
Dmean (Gy)	21.8±2.3	22.8±3.3	0.186
V20 (%)	41.5±6.4	47.6±12.5	0.051
V40 (%)	13.7±5.9	15.0±7.2	0.094
Bone marrow
Dmean (Gy)	28.2±2.9	29.7±2.8	0.162
V10 (%)	86.6±7.3	86.2±4.9	0.851
V20 (%)	63.3±9.1	71.3±9.7	0.069
V40 (%)	27.0±5.2	29.5±5.5	0.063
Bladder
Dmean (Gy)	45.8±4.5	44.2±4.2	0.163
V40 (%)	74.1±14.8	68.1±15.9	0.117
V50 (%)	45.2±14.4	41.7±11.3	0.139
Femoral head
Dmean (Gy)	18.7±4.3	16.4±4.0	0.115
V30 (%)	14.0±9.4	10.8±4.0	0.059
Kidney
Dmean (Gy)	15.0±3.1	15.1±4.6	0.647
V20 (%)	15.0±7.9	17.7±14.8	0.429
Liver
Dmean (Gy)	6.6±2.7	4.8±1.9	0.159
Spinal cord
Dmax (Gy)	28.7±10.1	29.3±6.5	0.808

Abbreviations: DVH = dose-volume histogram; HT = helical tomotherapy; VMAT = volumetric modulated arc therapy; PTV = planning target volume; V10, V20, V30, V40, V50 = percent volume receiving at least 10, 20, 30, 40, 50 Gy, respectively. Dmean = mean dose; Dmax = maximal dose. ^ap-values were calculated using Student’s paired-samples t-test.

Both techniques sufficiently spared the bowels (Fig. 2b, Table 4), as evident by the Dmean values of 21.8±2.3 Gy with HT and 22.8±3.3 Gy with VMAT (P = 0.186). Similarly, both techniques delivered an equivalent low-dose bath (V10) to the bowels (83.5% ±8.2% with HT and 84.9% ±7.7% with VMAT, P = 0.479). Regarding the absolute volumes, both techniques maintained acceptable levels of high-dose irradiation to the bowels; here, the volumes of bowels receiving > 50 Gy were 34.9±12.9 cm³ with HT and 49.2±31.2 cm³ with VMAT (P = 0.398).

Furthermore, both techniques sufficiently spared the bone marrow (Fig. 2c, Table 4) and yielded similar mean doses (28.2±2.9 Gy with HT and 29.7±2.8 Gy with VMAT, P = 0.162). The bone marrow volumes receiving > 10 Gy and > 20 Gy were not significantly different with both techniques (86.6% ±7.3% with HT and 86.2% ±4.9% with VMAT, P = 0.851; 63.3% ±9.1% with HT and 71.3% ±9.7% with VMAT, P = 0.069). Similarly, the bone marrow volumes receiving > 40 Gy were small with both techniques (27.0±5.2% with HT and 29.5±5.5% with VMAT; P = 0.063).

The mean dose to the bladder (45.8±4.5 Gy with HT and 44.2±4.2 Gy with VMAT, P = 0.163, Fig. 2d, Table 4) and femoral head (18.7±4.3 Gy with HT and 16.4±4.0 Gy with VMAT, P = 0.115) did not differ significantly. Although kidney and liver sparing are an expected challenge during extended-field planning, these organs were well-protected in all patients during both techniques, with a kidney V20 of 15.0% ±7.9% using HT and 17.7% ±14.8% using VMAT (P = 0.429) and a liver mean dose of 6.6±2.7 Gy using HT and 4.8±1.9 Gy using VMAT (P = 0.159).

The HT-based treatment plan required significantly higher monitor units (Table 5) in both the basic and parametrial boost plans. Furthermore, HT was associated with a significantly longer estimated treatment time for the basic plan (623.4±104.5 vs. 273.1±78.2 s with VMAT, P < 0.001). Both techniques yielded equivalent estimated treatment times for the parametrial boost plan (P = 0.704).

Table 5

Comparisons of energy, monitor units, and treatment time estimates

	HT (mean±SD)	VMAT (mean±SD)	p-value^a
Basic plan
Energy	6MV	6MV	–
Monitor units	9053.1±1544.2	730.6±116.9	<0.001^b
Treatment time estimates (sec)	623.4±104.5	273.1±78.2	<0.001^b
Parametrial boost plan
Energy	6MV	6MV	–
Monitor units	4419.4±922.9	559.7±206.7	<0.001^b
Estimated treatment time (sec)	309.7±265.9	231.5±121.0	0.704

Abbreviations: HT = helical tomotherapy; VMAT = volumetric modulated arc therapy; MV = megavoltage. ^ap-values were calculated using Student’s paired-samples t-test. ^bA p-value < 0.05 indicated statistical significance.

3.3 Clinical outcomes

All patients completed their planned EF BMS radiotherapy using VMAT, and 85.0% completed≥5 cycles of cisplatin. The median duration of chemoradiotherapy treatment was 55 days (range, 44– 63 days). The median low-dose rate-equivalent to point A was 8667 cGy (range, 8500– 9083 cGy). Regarding acute side effects, the incidence of grade≥3 neutropenia was 10.0%, and neither grade≥3 anemia nor thrombocytopenia occurred; fifty percent of patients had grade 2 diarrhea; however, none had acute grade 3 diarrhea or urinary symptoms.

The median follow-up was 27.6 months (range, 14.2– 33.0 months), during which one patient had locoregional recurrence at para-aortic lymphadenopathy. Six patients developed distant metastasis (2 had left supraclavicular lymphadenopathy, 2 had liver metastasis, 1 had lung metastasis, and 1 had bone metastasis). The 2-year progression-free survival and overall survival rates for all patients were 65.0% and 88.9%, respectively. Only two instances of grade≥3 late toxicity were observed in patients with grade 3 radiation proctitis at 11 and 17 months after chemoradiotherapy completion; these two patients were successfully treated by colonoscopy argon plasma coagulation. The 2-year cumulative incidences of locoregional failure, distant metastasis, and grade≥3 late toxicity in all patients were 6.2%, 30.7%, and 13.5%, respectively.

4 Discussion

To our knowledge, this is the first study to compare the dosimetric qualities of VMAT and HT planning for EF BMS chemoradiotherapy in cervical cancer patients with para-aortic lymphadenopathy. We demonstrated that both techniques achieved adequate planning target volume coverage while sufficiently sparing healthy organs and therefore were both suitable for EF BMS radiotherapy; however, VMAT planning yielded shorter estimated treatment times when compared to HT planning.

The complex tumor geometries needing SIB and numerous critical structures surrounding the targets pose challenges to intensity modulation in both VMAT and HT. Considering multileaf collimator movement constraints and multiple arc requirements, we expected extended treatment times for VMAT plans at first. Surprisingly, compared to HT, VMAT achieved equivalently high-quality treatment plans with shorter treatment times. All the PTVs were fewer than 40 cm (average±SD, 31.7±2.0 cm) in the superior-inferior direction; thus, there was no need to junction different arc fields in the VMAT plans.

According to our results, both techniques also sufficiently spared the bone marrow, as indicated by the low bone marrow volumes receiving > 20 Gy (63.3% with HT and 71.3% with VMAT) and > 40 Gy (27.0% with HT and 29.5 with VMAT). According to Albuquerque et al., risk of hematologic toxicity increased if more than 80% of the bone marrow volumes receiving > 20 Gy [15], and our study adhered to the criteria to lower the bone marrow volumes receiving > 20 Gy to less than 80%. Our findings are in line with an earlier study by Klopp et al., which demonstrated that IMRT techniques spared the bone marrow such that less than 30% of the volume received > 40 Gy [1]. According to Jodda et al., VMAT plans effectively reduced the dose to the BM without increasing the doses to the bladder, rectum, and bowels [2]. In agreement with the above-mentioned study, we found that VMAT and HT sufficiently spared the bone marrow while protecting the OARs.

Researchers are currently investigating the hypothesis that lowering the radiation dose to the bone marrow reduces hematologic toxicity and permits more optimal chemotherapy delivery to patients undergoing chemoradiotherapy [15 , 30]. In our present study, we found that EF BMS protected the bone marrow and resulted in a lower incidence of grade≥3 neutropenia (10.0%); by comparison, studies of EF chemoradiotherapy without BMS reported grade≥3 neutropenia rates of 37.5– 77.5% [5, 23]. Importantly, our aim to achieve good BMS did not compromise the delivery of safe radiation doses to the bowels. In our present study, EF BMS did not increase the incidence of GI toxicities, as 50.0% of patients experienced grade 2 diarrhea while none experienced grade≥3 diarrhea; by contrast, the aforementioned studies on EF chemoradiotherapy without BMS reported grade≥3 GI toxicity rates of 12.5– 25.0% [5, 23]. These data demonstrated that the use of BMS during optimization of VMAT or HT plans effectively reduced the dose in BM without increasing the dose in the bladder, rectum and bowels.

We used on-board CBCT scanners for image guidance by the automatic bony match to acquire satisfactory treatment positioning. Although Yodda et al. suggested an image guidance protocol based on matching soft tissue for cervical cancer radiotherapy to help reduce the dose delivered to the rectum and bladder [3], our institution adapted the image guidance based on bony landmarks because all our patients had para-aortic and pelvic lymphadenopathy. The image guidance based on bony landmarks would give accurate positioning and robust radiation doses for lymphadenopathy, which might result in better locoregional control and longer disease-free survival.

In our study, the dose distributions for VMAT and HT were similar in regard to planning target volume coverage and OARs, but HT required a longer estimated treatment time when delivering the basic extended-field plan which comprised long cranio-caudal distance. According to published results, the estimated treatment time of HT depended on conditions of pitch, field width, and modulation factors [27, 29]. For long targets in the cranio-caudal direction, using larger field widths (e.g. 5 cm) and smaller modulation factors (e.g.<3.0) effectively reduced estimated treatment time without decreasing dose distribution. According to Kim et al., under the HT parameters of field width 5.04 cm, pitch 0.172, and modulation factor 2.0, the estimated treatment time of BMS abdominopelvic radiotherapy using HT technique was 12.7 minutes [29], which is not so different to our time of 10.4 minutes. Time needed for gantry rotation could be reduced by upgrading the system. With an upgrade from version 3.5 to version 4.0, the time for gantry rotations decreased from 15 sec to 12 sec [27]. In our HT plans, we used the updated system version 5.1 which reduced the time for gantry rotations to 10 sec, with HT parameters of field width 2.5 cm; pitch 0.287; and modulation factor 2.5, resulting in a fairly acceptable estimated treatment time of 10.4 minutes. In reported data, increasing field width from 2.5 cm to 5 cm width reduced the estimated treatment time by approximately 40% while slightly worsening OAR doses and plan quality [7]. For patients who need shorter than 10 minutes of estimated treatment time with HT, a bigger field width of 5 cm can be carried out, but plan quality and OAR doses should be confirmed sufficient for clinical use.

Although we have advances in treatment planning techniques including VMAT and HT, the dose delivered during radiotherapy should be as precise as planned. The actual distribution of radiation dose accumulated in targets and normal tissues over the complete course of radiation therapy is still hard to quantify. Differences in patient anatomy between daily treatments undermine the accuracy of the planned dose distribution. The needed accuracy can be achieved through proper image guidance protocols, tissue-mapping algorithms, uncertainty estimation, automated dose accumulation schemes, and the development of informatics tools to support subsequent analysis [9].

This study was limited by its retrospective design, single-institution setting, and small number of patients. Accordingly, prospective studies of EF BMS radiotherapy are warranted.

5 Conclusion

We conclude that the addition of BMS planning constraint to the HT or VMAT techniques provided adequate PTV coverage and did not compromise quality. Both techniques yielded a homogeneous dose with the inclusion of SIB for lymphadenopathy while protecting OARs. High-quality VMAT and HT plans are both suitable for EF BMS radiotherapy when aiming to achieve minimal acute toxicities. VMAT, when compared to HT, yielded shorter estimated treatment times.

Conflicts of interest

The authors indicate no potential conflicts of interest.

Funding information

This work was supported by the National Taiwan University Hospital (grant numbers NTUH 107-N4008, NTUH 108-N4353) and the Ministry of Science and Technology (MST, Taiwan, Contract No. MST 106-2314-B-002-052-MY2).

Footnotes

Acknowledgments

This study was presented in part at the Radiological Society of North America 104th Scientific Assembly and Annual Meeting (Chicago, USA, November 25– 30, 2018). We thank the doctors, nurses, healthcare providers, and other sources of health information who contributed to the study. We thank the staff of the Core Labs, Department of Medical Research, National Taiwan University Hospital, for their technical support.

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