Salvage interstitial brachytherapy based on computed tomography for recurrent cervical cancer after radical hysterectomy and adjuvant radiation therapy: case presentations and introduction of the technique

Purpose

Patients with recurrent cervical cancers represent a therapeutic challenge. Choosing an optimal treatment approach for recurrent patients who have undergone radical hysterectomy, adjuvant radiation therapy, and possibly, concurrent chemotherapy is a difficult task. Surgical resection with pelvic exenteration is considered the treatment of choice, but this is associated with a severe treatment-related morbidity [1,2,3]. Moreover, some patients with recurrence of cancer on their pelvic walls are considered inoperable. Re-irradiation by using external beam radiotherapy (EBRT) alone may be difficult for treatment of pelvic recurrences, due to the high risk of complications [4,5].
Another treatment option for patients with recurrent tumors is brachytherapy (BT). Traditional intracavitary BT, using vaginal cylinder and ovoid pairs, may be sufficient for small and superficial tumors [6,7]. However, recurrent cervical cancers with bulky tumors, anatomical distortion, or pelvic wall involvement are difficult to cure by this technique, due to inadequate target coverage during intracavitary BT [8,9]. Interstitial BT, which has the ability to tailor the dose to the target, and allow for wider tumor coverage, is more advantageous than conventional intracavitary BT [10,11,12,13]. In this study, we introduce real-time interstitial BT guided by three-dimensional (3D) computed tomography (CT) as a treatment approach for recurrent cervical cancer after radical hysterectomy and adjuvant radiation therapy. This new technique may provide a simple and effective clinical treatment modality.

Material and methods

Patients and treatment

We analyzed consecutive patients who experienced isolated pelvic recurrences of cervical carcinoma, and had previously received initial radical surgery and adjuvant EBRT in our department, between December 2014 and May 2016. These patients underwent a systematic examination, including a pelvic MRI (magnetic resonance imaging) (1.5 T; 5 mm sections), a whole-body CT or positron emission tomography – computed tomography (PET-CT), and a gynecological examination. In all cases, either the recurrent tumors were inoperable or the patients refused surgical resection due to the possibility of serious complications. We performed re-irradiation on all these patients by using interstitial BT. A total of six high-dose-rate (HDR) interstitial BT procedures, using 192Ir and implantation with metal needles, were carried out for 4-5 days per fraction. This study and the treatment procedure used for patients was approved by the ethics committee of our hospital. All patients signed informed written consents before undergoing BT.

Needles implantation under real-time 3D-CT guidance

Each needle implantation procedure was performed with the patient under subarachnoid anesthesia in the lithotomy position. Interstitial metal needles (length = 16 cm, diameter = 1.3 mm, Elekta company, Elekta AB, Stockholm, Sweden) were inserted into the recurrent tumor at a depth of approximately 10 mm as a preliminary implantation, according to T2-weighted MRI and clinical gynecological examination before administration of BT. Specifically, metal needles were placed parallel to the vagina into the central tumor, and some tilted needles at different angles to the vagina were placed into the parametrial or lateral pelvic sidewall extensions, transvaginally. In case of a central tumor with anterior or posterior vaginal wall involvement, the needles were placed into the central tumor parallel to the vagina, but the inserted needles were close to the vaginal wall for optimal coverage of vaginal wall involvement. Vaginal packing was done by using gauze to push aside the rectum and the bladder, and to stabilize the metal needles.
After the initial implantation of needles, the bladder was filled with 50 ml of diluted urografin (dilution, 1 : 20) through a urinary catheter. Next, the process of final needles-implantation guided by real-time 3D-CT was performed. The direction and the depth of the metal needles were adjusted after every CT scan (Philips Healthcare, Eindhoven, The Netherlands, 4 mm slice intervals). Adjustment of needles was performed repeatedly through multiple CT scans until satisfactory distribution was achieved, including accurate needle-insertion in the recurrent tumor, and symmetrical needle-distribution in the tumor at a 1 cm distance from the central axis (Figure 1). Eligible dose-volume histogram (DVH) parameters for the target volume and the organs at risk (OAR) could be acquired with satisfactory distribution of needles in subsequent treatment planning.

Contouring and treatment planning

Using CT images, the high-risk clinical target volume (HR-CTV) that encompassed the volume occupied by the recurrent tumors, and OAR, including the bladder, rectum, and sigmoid, were contoured. Additionally, the T2-weighted MRI images and clinical gynecological examinations were also used as reference for tumor delineation.
The dose for the target volume during BT and the cumulative dose of OAR, obtained by combining previous EBRT and present BT, were all converted to the equivalent dose in 2 Gy (EQD2) by applying the linear quadratic model using an / = 10 for target coverage, and / = 3 for normal tissue. The final dose objective was HR-CTV D₉₀ (the minimum dose delivered to 90% of the target volume) ≥ 50 Gy EQD2 for BT; the cumulative D2cc (the minimal dose for the most irradiated 2 cm3) for the bladder ≤ 90 Gy EQD2; the cumulative D2cc for the rectum and sigmoid ≤ 75 Gy EQD2. For BT planning, needle applicators were initially reconstructed and registered to CT images (Oncentra Brachytherapy Treatment Planning System, Elekta). Subsequently, an inverse-planning simulated annealing (IPSA) was used with a 6 Gy prescription dose for the HR-CTV. Dwell positions and dwell weights of the radioactive source were manually adjusted until the dose distribution was optimally matched to our dose requirement when the first treatment plan based on IPSA did not meet the dose requirement (Figure 2).

Results

Initial and recurrence tumor characteristics

Sixteen patients with recurrent cervical cancer were enrolled into this study. All patients had undergone radical hysterectomy with pelvic lymph node dissection, and post-hysterectomy adjuvant EBRT with a total dose of 45 Gy administered as 1.8 Gy in 25 fractions, using either the four-field or intensity-modulated radiation-therapy- based 3D-CT. Twelve patients received 5 cycles of weekly cisplatin chemotherapy (dose, 40 mg/m2) and none of the patients were treated with initial vaginal BT. A summary of tumor characteristics at initial treatment and at the time of recurrence is presented in Table 1.

Dose-volume histogram parameters

Individual recurrent tumor characteristics and DVH parameters are shown in Table 2. Dose-volume histogram parameters related to HR-CTV D₉₀ showed that our interstitial technique resulted in a D₉₀ of ≥ 50 Gy in 93.4% patients. The target volume dose was unsatisfactory only for one patient who had central and pelvic wall extensions. High-risk clinical target volume D₉₀ for this patient was 45.1 Gy, which could be mainly attributed to dose constraint for the sigmoid (D2cc for sigmoid was 78.9 Gy for this patient). The results of DVH analysis for OAR showed that two patients had a D2cc of > 90 Gy for the bladder, and one patient had a D2cc of > 75 Gy for the rectum, due to involvement of bladder and rectum, respectively.
Table 3 shows the mean DVH parameters derived for all patients and for the patients with different sites of recurrence, respectively. A double-sided t test for two independent samples was used to compare the mean values of DVH parameters between patients with central recurrence and patients with central and pelvic wall involvement. A significant decrease in the mean D₉₀ value for HR-CTV was seen from the cases of central recurrence to those with central and pelvic wall involvement (p = 0.04). However, no statistically significant differences in the mean D100 value for HR-CTV, as well as the average D2cc value for the OAR were noted between the two.

Characteristics of free metal needles

In all, 588 free needles were used for 96 independent interstitial BT procedures, and 95.9% of all implanted needles were useful for treatment. The mean number of free needles was 6.1 ± 1.5 for each application, the mean implantation depth of the needles was 3.5 ± 0.9 cm, and the mean implanted length of the needles beyond the tumor was 0.4 ± 0.3 cm.
Mean time from preliminary insertion of needles to completion of CT scans for each interstitial implantation was 30.9 ± 8.6 minutes, and the mean number of CT scans was 2.3 ± 1.2 for every placement of metal needles.

Complications and tumor response

During real-time 3D-CT guided interstitial needle implantation, one patient with bladder involvement had a bladder perforation, and two patients had slight perforation of the intestine. These patients did not require any additional treatment because no clinical effects were observed. However, the radioactive source could not be placed in the perforated area during subsequent treatment planning. Minimal post-procedure edema occurred in one patient. No case of obvious infection or severe bleeding with requirement for transfusion was founded during or immediately after implantation. At the 3 months’ follow-up, one patient had bloody stools, which was resolved by treatment with clyster with styptic, hormones, and antibiotics. No serious complication was observed in the vaginal mucosa.
Initial response, defined as complete remission (CR) and partial remission (PR), was found in 13 (81.3%) patients, according to pelvic MRI findings and clinical gynecological examination at 3 months after interstitial BT. Of all the patients with initial responses, 6 (37.5%) exhibited CR, and 7 (43.8%) PR. The remaining three (18.7%) patients showed stable disease (SD) at 3 months after interstitial BT. No patient experienced progressive disease (PD).

Discussion

We studied the dosimetric results for treatment of 16 patients with recurrent cervical cancer who had received previous radical surgery and adjuvant EBRT with a novel form of interstitial BT that used free-hand placement of metal needles under guidance of real-time 3D-CT. Cervical cancer with parametrial extensions after surgery often reoccurs [14]. Salvage interstitial BT is an effective treatment strategy [15], especially for inoperable pelvic recurrence. However, the prescribed dose needs to be strictly limited to avoid serious complications in OAR. A total dose of 40-50 Gy for BT alone might be effective and well tolerated [16]. Nag et al. reported the clinical outcomes of using interstitial BT for re-irradiation, with a median dose of 50 Gy for patients with recurrent gynecologic malignancies [17]. This study showed a 5-year local control of 54%. In the current study, a HR-CTV D₉₀ of ≥ 50 Gy produced excellent results in > 93% of patients. High-risk clinical target volume D₉₀ of the only one patient with central and pelvic wall extension was less than 50 Gy. This can be attributed mainly to dose constraint of the sigmoid. A compromise on the actual delivered HR-CTV dose in this patient had to be done in order to avoid potential radiation-related intestinal perforation. Dose constraints for OAR, with D2cc ≤ 90 Gy for the bladder, and D2cc ≤ 75 Gy for the rectum and sigmoid, were recommended by the American Brachytherapy Society (ABS) [18]. In this study, D2cc for OAR in all patients reached 43.2 Gy EQD2 because of prior pelvic irradiation. Resultantly, for the present protocol of interstitial BT, D2cc for the bladder of ≤ 46.8 Gy EQD2, and D2cc for the rectum and sigmoid of ≤ 31.8 Gy EQD2 were decided. It was important to consider the cumulative EQD2 of OAR D2cc, combining previous EBRT and present BT, because this was a setting for re-irradiation. Our results indicate that the cumulative EQD2 of OAR D2cc were generally eligible, except in two patients with bladder involvement, one patient with rectum involvement, and one patient with adherence of the sigmoid to the tumor. Although the mean HR-CTV D₉₀ of patients with central and pelvic wall involvement was poorer than that of the patients with central recurrence, it can be mainly attributed to the difficulty in distributing needles effectively in the distal tumor; the mean HR-CTV D₉₀ for these patients with central and pelvic wall involvement still reached 50 Gy. Our current clinical experience suggests that this technique has the potential to ensure relatively satisfactory dose-coverage to the HR-CTV, and reduce the irradiated dose of OAR in patients with recurrent cervical cancer.
Traditionally, interstitial BT for recurrent cervical cancer was performed using the classic transperineal interstitial applicators, including Syed-Neblett butterfly template [19,20] and Martinez Universal Perineal Interstitial Template (MUPIT) (Varian Medical Systems, Inc., Palo Alto, CA, USA) [9,21]. Limitations of both these techniques include the following: inaccuracy of needle positioning resulting from a long distance between the template and the tumor, leaving the applicators in place for a few days after implantation, and high risk of complications due to the need for multiple needles.
Free-hand placement of needles is conventionally used for recurrent tumors in many centers. However, accurate free-hand placement is difficult without guidance by real-time images. Guidance by real-time 3D-CT may overcome the shortcomings of traditional free needles. In the present study, real-time 3D-CT guided placement of the needles is performed, to ensure proper needle-positioning for effective target dose coverage. It is the most important procedure for adjusting the direction and depth of metal needles repeatedly, until satisfactory results are obtained through multiple CT scans. In our clinical experience, the metal needles parallel to the vagina as well as at different angles to the vagina were used, according to various case scenarios of recurrence. Typically, the needles did not need to be inserted into the vaginal wall involvement but close to it; greater angulation of vagina and depth of needles were required in case of severe lateral involvement. Two experienced gynecologic radiation oncologists performed the entire process of needle implantation. Real-time 3D-CT guidance of the free needles provides some advantages, including flexibility and accuracy in needle positioning.
In the present study, more than 95% of all inserted needles were used for BT treatment. This indicates great efficiency of needles in performing dose-coverage of the target volume. The mean number of needles needed for each BT was significantly fewer than that required in a previous study, in which a median of 14 (range, 8-22) interstitial needles had been implanted using MUPIT applicator [22]. Undoubtedly, risks for complications, such as bleeding, increase proportionally with the number of needles. Therefore, this real-time CT guided method of needle implantation may present lower risks for patients than the classic transperineal interstitial method. Mean time of metal needle implantation in this study were relatively short, indicating the high efficiency and procedural simplicity of this technique. In addition, the metal needle is reusable and is available in most centers; this suggests that our technique is low-cost, easy to spread, and especially helpful for departments with limited resources.
The risk of complications such as perforation, bleeding, and infection for interstitial BT, during or immediately after implantation, may be inevitable [23,24,25]. In this study, a clinically insignificant bladder perforation was found in one patient with bladder involvement. Moreover, intestine perforation without any clinical effect occurred in other two patients. Our technique shows a low rate of perforation during implantation, which could be attributed to the use of real-time CT guidance. In our clinical practice, needle implantation is always performed cautiously with an adjustment of less than 1 cm depth after every CT scan to reduce occurrence of perforation-related complications. Incidence rate of post-procedure edema was low, probably because the number of free needles was low for each BT, and needles were inserted transvaginally, not transperineally. Slight bleeding often occurred due to the insertion of metal needles. However, as the needles were very thin, gauze padding was sufficient to resolve the bleeding.
At the 3 months’ follow-up, we diagnosed treatment-related rectum morbidity, but during later follow-ups, the adverse effect had been resolved. The 3 month tumor-response rate was excellent; initial response was more than 80%. These results indicate that our technique was well tolerated by patients and exhibited an excellent initial curative effect.

Conclusions

Salvage interstitial BT with placement of free needles, under real-time 3D-CT guidance, is a particularly appealing treatment option for inoperable pelvic recurrence of cervical carcinoma after radical hysterectomy and pelvic irradiation. However, the long-term curative effect and late toxicities of the current technique need to be evaluated further in future studies.

Disclosure

Authors report no conflict of interest.

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