From 2011–2015, 31 patients were included after a positive votum of the Ethical Committee and the Agency for Radiation Protection. All patients were aware of the experimental character of the treatment and gave their informed consent. Patient characteristics are summarized in Table
1. Indications for CyberKnife® boost treatment were uterus bi-collis and bi-cornis (
n = 1), refusal of Smit sleeve insertion (
n = 3), refusal of brachytherapy (
n = 7) and inability to find the cervical os and implant the Smit sleeve or loss of Smit sleeve and refusal of reinsertion (
n = 22).
Table 1
Patient characteristics
1 | 32 | 51 | IB | Yes, pN1 (1/32) | No | No progression |
2 | 35 | 66 | IB | Yes, pN1 (4/32) | No | No progression |
3 | 30 | 44 | IIA | Yes, pN1 (4/25) | No | Multiple |
4 | 71 | 12 | IIA | Yes, radiologic | No | Local |
5 | 55 | 84 | IIB | No, radiologic | No | No progression |
6 | 61 | 79 | IIB | No, radiologic | No | No progression |
7 | 47 | 32 | IIB | No, pN0 (0/39) | No | Unknown |
8 | 47 | 63 | IIB | No, radiologic | No | No progression |
9 | 33 | 8 | IIB | Yes, pN1 (9/20; ece+) | No | Unknown |
10 | 62 | 49 | IIB | No, radiologic | No | No progression |
11 | 46 | 73 | IIB | Yes, pN1 (1/19) | No | No progression |
12 | 63 | 30 | IIB | No, radiologic | No | Unknown |
13 | 46 | 8 | IIB | Yes, pN1 (17/23) | No | Unknown |
14 | 73 | 49 | IIB | No, radiologic | No | Unknown |
15 | 48 | 39 | IIB | Yes, pN1 (4/32) | No | No progression |
16 | 39 | 45 | IIB | No, radiologic | No | No progression |
17 | 32 | 50 | IIB | No, radiologic | No | No progression |
18 | 44 | 36 | IIB | No, radiologic | No | No progression |
19 | 53 | 13 | IIB | No, pN0 (0/32) | No | No progression |
20 | 57 | 21 | IIB | No, radiologic | No | Local |
21 | 65 | 49 | IIB | No, pN0 (0/31) | No | No progression |
22 | 58 | 64 | IIB | Yes, radiologic | No | No progression |
23 | 77 | 11 | IIIB | No, radiologic | No | Multiple |
24 | 67 | 66 | IIIB | No, radiologic | No | No progression |
25 | 74 | 35 | IIIB | No, radiologic | No | Multiple |
26 | 65 | 12 | IIIB | No, radiologic | No | Liver |
27 | 32 | 58 | IVA | Yes, pN1 | Yes, pM1 (LYM) | No progression |
28 | 51 | 76 | IVA | Yes, pN1 (9/40) | Yes, pM1 (LYM) | No progression |
29 | 57 | 30 | IVA | Yes, radiologic | Yes | Lung |
30 | 57 | 14 | IVA | Yes, pN1 (24/35) | Yes, pM1 (20/21) (LYM) | Unknown |
31 | 49 | 12 | IVA | Yes, radiologic | No | Lymph nodes |
Mean | 52 (30–77) | 41 (8–84) | – | – | – | – |
The oncologic outcome was analyzed using the endpoints overall survival (OS), progression-free survival (PFS), and local control (LC).
The institutional standard consists of chemoradiation with intracervical brachytherapy. The patients usually receive a Smit sleeve implantation in the third or fourth week of treatment. We perform another MRI (magnetic resonance imaging) with the sleeve in place. Brachytherapy equipment consists of a 2-channel pin/ring applicator (Varian). For brachytherapy, patients are placed on a gynecological chair with an empty rectum, the applicator is inserted and the vagina is stuffed with gauze bandages and a rectal probe is inserted. A CT (computed tomography) scan then is performed and fused with the current and pretherapeutic MRI. The planning target volume (PTV) consists of the cervix and the residual tumor from the T2-weighted MRI sequence. The image information from the pretherapeutic MRI is always cointerpreted and it is up to the treating radio-oncologist to adjust the target volumes accordingly.
Treatment planning and delivery
CT-planning for external beam radiation (EBRT) was done in supine position with emptied rectum and filled bladder with kneefix and footfix on a big bore TOSHIBA CT. Primary EBRT chemoradiation was performed. It included) with 6/15 MV photons using volumetric arc techniques (VMAT) on a linear accelerator (DHX, Varian) or TomoTherapy (Accuray Inc.). Five weekly single doses of 1.8 Gy to the primary tumor including the uterus, pelvic, and in case of histologically confirmed para-aortic lymph nodes including the para-aortic node up to the renal vessels to a total dose of 50.4 Gy in 28 fractions were given. A simultaneous boost was given with five weekly single doses of 2.12 Gy to both parametric regions to a total dose of 59.36 Gy in 28 fractions to all patients. Cisplatin 40 mg/m2 body surface area was administered once weekly for five applications.
In the 3rd or 4th week of EBRT, a second gynecologic examination was performed and three to four fiducials were implanted to the right and left anterior and posterior tumor border.
Two to three days after fiducial implantation, CT and MRI were performed in the treatment position. Patients emptied rectum prior to scanning. All patients were placed in the supine position on a 2-inch foam mat to enhance patient comfort. A knee rest and foot rest were added to stabilize the pelvic region. CT images were acquired with 1‑mm slice thickness including the pelvic region as well as the lumbar vertebra 4 (L4) and lumbar vertebra 5 (L5) vertebrae, which is necessary for later digitally reconstructed radiograph (DRR) generation and spinal alignment. The MRI of the pelvis was conducted (T1 + gadolinium contrast, T2) with the patient in the same position as in the CT scan. Contouring for the boost techniques was performed on CT and MRI images, which were fused using bony structures and fiducial clips. The PTV was defined as the cervix including the residual tumor as identified on T2-weighted MRI, the parametric region, and/or the corpus uteri. In analogy to brachytherapy (BT), no margin was added.
The CyberKnife® boost was performed in the 4th to 6th week of treatment. An “Xsight Spine Setup Plan” was created to optimize the initial treatment alignment, defining the lower part of the lumbar spine as the tracking target. With this setup plan, the patient can be positioned according to the bony structures of the spine. By moving the treatment couch, the patient is aligned so that the translational and rotational positional deviations are corrected. This step facilitates the finding of the cervical target. After spinal alignment, the current treatment plan was loaded and the patient was brought into the actual treatment position. With the help of translatory table movements, which were previously calculated from the location of the treatment center in the planning software, the patient was brought into the treatment position without rotation changes occurring. The dose was prescribed to the 70% isodose to allow higher doses within the target volume like conventional brachytherapy. Small subvolumes with up to 200% of the prescribed dose were allowed.
Five fractions to a total dose of 25–30 Gy were prescribed comparable to the institutional brachytherapy concept. The institution changed the brachytherapy concept between 2011 and 2015 from 5 × 6 Gy to 5 × 5 Gy, which is why some patients received 30 Gy and others 25 Gy boost dose. Two or three weekly robotic radiosurgery fractions were given (every other day) overlapping with external beam radiation. This procedure has already been described in earlier work as safe and reliable and with favorable dose–volume histogram (DVH) parameters [
16,
17].
Treatment planning was carried out using Multiplan® 4.5 (Accuray Inc.) planning workstations. Inverse planning was performed to obtain the optimal dose distribution.
The rectal wall, bladder wall, and sigmoid wall were contoured as the outer wall of the organs minus 2 mm for the inner wall so that a ring structure was created. The small intestine was defined as the entire abdominal cavity without other organs at risk (OARs), musculature or the planning target volume (PTV) up to the fourth lumbar vertebra. Biologically effective doses of EBRT and CyberKnife were calculated with α/β = 3 for normal tissue.
For the CyberKnife boost, organ walls were generated from rectum, sigma and bladder like for EBRT. The EQD2 (α/β = 3) on 0.1, 2 and 5 ccm of rectal wall, bladder wall and sigma wall were calculated from DVHs of EBRT + CyberKnife according to Georg et al. [
1]. For the EBRT (IMRT, Helical Tomotherapy or Rapid Arc) the following dose constraints were used for the whole organ: small intestine: V45 <20%, V20 <40%, Dmean <30 Gy; rectum: V40 <70%, V50 <50%; bladder: V30 <60%, V50 <30%; femoral heads: Dmean <40 Gy.
For the organs at risk, EQD2 was calculated to 0.1, 2, 5 cc of the rectal, sigmoid and bladder wall, respectively for robotic radiosurgery and EBRT (Tables
2 and
3). For the target volume, V100, V90, D100, D90, D
max, D
mean, Conformity Number (CN) and Conformity Gradient Index (CGI) were analyzed (Table
4).
Table 2
EQD2 for CyberKnife® deposed to subvolumes of the critical organs at risk (OAR) (rectum, sigmoid, bladder)
Rectal wall |
D 0.1cc | 26.9 ± 4 |
D 2.0cc | 13.8 ± 2.6 |
D 5.0cc | 6.2 ± 2.2 |
Sigmoid wall |
D 0.1cc | 22.8 ± 5 |
D 2.0cc | 11.4 ± 3.6 |
D 5.0cc | 6.2 ± 1.9 |
Bladder wall |
D 0.1cc | 36.2 ± 5.5 |
D 2.0cc | 25.7 ± 4.3 |
D 5.0cc | 15.4 ± 2.4 |
Table 3
Organ doses for external beam radiation (EBRT)
Small bowel | 30.29 ± 4.50 | 57.20 ± 4.28 | 4.82 ± 2.22 |
Rectum | 46.29 ± 3.91 | 57.81 ± 4.12 | 17.70 ± 10.40 |
Sigma | 48.15 ± 4.60 | 56.29 ± 4.36 | 38.25 ± 8.74 |
Bladder | 47.77 ± 4.65 | 59.28 ± 3.94 | 31.52 ± 8.77 |
Table 4
Planning target volume (PTV) parameters obtained from the dose–volume histogram (DVH) analysis
V100 (%) | 96.97 ± 2.05 |
V90 (%) | 99.49 ± 0.73 |
D100 (Gy) | 20.75 ± 4.16 |
D90 (Gy) | 28.75 ± 4.51 |
Dmax (Gy) | 39.69 ± 7.71 |
Dmean (Gy) | 32.53 ± 5.41 |
CN | 0.79 ± 0.07 |
CGI | 36.88 ± 16.0 |