Abstract
Background: The aim of this study was to report the clinical results of salvage high-dose-rate interstitial brachytherapy (HDR-ISBT) for patients with cervical cancer with pelvic recurrence after hysterectomy. Patients and Methods: When there was no indication for total pelvic extenteration (TPE) and the tumor depth was more than 5 mm of invasion in the paracolpium, salvage HDR-ISBT was applied. Results: A total of 26 patients were included in this study. The median number of fractions and dose per fraction of HDR-ISBT were 5 (range=3-20 fractions) and 6 Gy (range=2.5-6 Gy), respectively. Three-year local control, progression-free survival, and overall survival were 51.1%, 34.4% and 57.1%, respectively. Combination of external-beam radiation therapy, clinical target volume D90 greater than 65 Gy, and dose per fraction greater than 5 Gy were associated with favorable local control. Conclusion: For patients with recurrent cervical cancer post hysterectomy who are not candidates for TPE, salvage HDR-ISBT is a possible curative treatment modality.
- Salvage interstitial brachytherapy
- high-dose-rate interstitial brachytherapy
- uterine cervical cancer
- post hysterectomy relapse
Radical hysterectomy is a standard treatment for patients with early-stage uterine cervical cancer. Treatment strategy for postoperative patients with cervical cancer with pelvic recurrence without distant metastasis depends largely upon whether patients had past history of pelvic irradiation or not, their age, and performance status (1). If patients did not have prior history of pelvic irradiation, salvage external-beam radiation therapy (EBRT) with or without brachytherapy is reported to be an appropriate treatment strategy, with a 5-year survival rate ranging from 33% to 74% (2-5). Among patients with pelvic recurrence, those with recurrent disease confined to the vaginal wall or tumor size smaller than 3 cm achieved favorable local control following salvage radiotherapy (2-4).
On the other hand, when patients have prior history of pelvic irradiation, generally re-irradiation is not applied because the possibility of severe sequelae is very high. Under these circumstances, anterior, posterior, or total pelvic extenteration (TPE) can be a possible curative treatment option for highly selected patients with disease confined to the vagina, with reported 5-year survival rates ranging from 48 to 60% (6-11). TPE is a radical and highly invasive surgical treatment through which the urinary bladder, urethra, rectum, genital tract, and anus are all removed. Although TPE is considered a potentially curative salvage treatment for central recurrence of gynecological malignancy, the postoperative mortality and morbidity rate is not low and it will likely worsen a patient's quality of life (6).
Although TPE is a recommended salvage treatment for pelvic recurrent patients with prior history of pelvic irradiation, due to its strict inclusion criteria and its probability of morbidity and mortality, re-irradiation is offered to such patients because otherwise there is no curative salvage treatment modality. Because EBRT often cannot deliver an adequate dose to eradicate recurrent disease due to the high risk of severe late toxicities, especially in such cases with previous history of pelvic radiation therapy, interstitial brachytherapy (ISBT) is preferred because of its intrinsic physical characteristic of having a steep dose gradient. Recently published data reported the safety and efficacy of ISBT for patients with prior history of pelvic radiation therapy (12-16).
Salvage outcomes including TPE and radiation therapy for post-hysterectomy recurrent cervical cancer patients in our hospital were reported in 2005 (17). Since 2009, image-based high-dose-rate (HDR) ISBT has been introduced for post-hysterectomy pelvic recurrent cervical cancer with or without past history of pelvic irradiation. The aim of this study was to report the clinical results of pelvic recurrence after hysterectomy for early-stage uterine cervical cancer treated by salvage HDR-ISBT.
Patients and Methods
At our hospital, postoperative radiation therapy (PORT) is offered for patients with high-risk histopathological features: i) pelvic lymph-node metastasis; ii) parametrial invasion; iii) positive surgical margins. Although the standard therapy for patients with postoperative high-risk early-stage cervical cancer is concurrent chemoradiation therapy (cCRT) (18), because of concern for late sequelae of ileus development, PORT alone had been offered for such patients. Until August 2010, a conventional four-field box technique was used; in August 2010, intensity-modulated radiation therapy (IMRT) was introduced. Owing to reduced incidence of acute and late bowel toxicities after the introduction of IMRT, cCRT using IMRT and weekly cisplatin (40 mg/m2) started in June 2014 at our hospital. Reduced bowel toxicities by IMRT will be reported in a different article.
Various treatment strategies are carried out outside our hospital. Since some of the gynecological oncologists are concerned about late bowel toxicities following PORT and favorable results of adjuvant chemotherapy alone for patients with intermediate- and high-risk post-hysterectomy cervical cancer were reported (19), some of the institutions in Japan do not utilize PORT for high-risk early-stage cervical cancer but apply adjuvant chemotherapy alone, which is not in line with the evidence.
Our management of local recurrence of postoperative cervical cancer was described in our previous report (17). The general treatment strategy was as follows: i) patients with recurrent disease arising in the previously irradiated pelvis received chemotherapy or palliative care, except for patients with central recurrence after a disease-free period of longer than 1 year who are candidate for TPE; ii) radiotherapy was used to treat recurrent disease in patients who had no prior history of receiving radiotherapy. If the recurrent tumor was confined to the vaginal surface within 5 mm of depth, intracavitary vaginal brachytherapy was applied. If the tumor had a depth of more than 5 mm or invaded the paracolpium, HDR-ISBT was applied. When patients already had a prior history of radiotherapy but there was no indication for TPE or patients refused TPE, and patients did not wish to proceed to palliative care, salvage HDR-ISBT was proposed. After providing patients with information regarding the high possibility of severe late toxicities following re-irradiation such as vesicovaginal and rectovaginal fistula and when informed consent was obtained, salvage HDR-ISBT was also applied for these patients.
EBRT was omitted in the following two circumstances: i) for patients with prior pelvic irradiation because HDR-ISBT focuses the dose to the recurrent tumor more sharply than EBRT, ii) for patients whose disease-free interval was longer than 2 to 3 years after initial therapy where the possibility of microscopic disease dissemination to the regional lymphatic region was considered to be lower compared to those whose recurrence was shortly after the initial treatment.
The detailed procedure of HDR-ISBT for patients with cervical cancer was described in our previous studies (20, 21). In brief, transperineal needle applicators were inserted under either general or local anesthesia with the patients in lithotomy position and guided by transrectal ultrasound (TRUS). Simulation computed tomography (CT) was carried out by large-bore CT (Aquilion® LG, Toshiba, Tokyo, Japan) which could take images with patients lying in the lithotomy position with applicators in place without moving patients and image-guided brachytherapy planning was performed based on those CT images with slice interval of 2 mm. Treatment planning was done with brachytherapy planning system (Oncentra® Nucletron, Veenendaal, the Netherlands). For advanced large tumors with extensive paracolpial extension in which multiple applicators were needed, the Syed-Neblett perineal template (Best Medical International, Inc., Springfield, VA, USA) was used because it has the advantage of ensuring parallelism and stability of applicator needles throughout the treatment period. For localized small tumors with or without limited paracolpial extent, freehand needle insertion was applied under local anesthesia. A few titanium seed markers were inserted into the target and these markers were used as a reference for daily correction of needle deviation. The clinical target volume (CTV) was defined based on the CT image taken after needle insertion with patients in the lithotomy position, with information derived from gynecological examination performed immediately before needle insertion, intra-operative TRUS images, and the most recent magnetic resonance imaging (MRI) if available was also taken into consideration. Reference points were set on the surface of the CTV and the prescribed dose was delivered to those points. Dose calculation was performed by geometrical optimization or dose point volume optimization followed by manual graphical modification to cover the CTV with the prescription dose while keeping the dose to organs at risk (OAR) to a minimum.
Regular prescription dose of HBR-ISBT at our Department is 6 Gy. However, if patients had already received prior radiation therapy either in the form of external beam or brachytherapy, besides regular 6 Gy fractionation, reduced prescription dose with increased fractions was also delivered in some cases. There was no set fractionation for such circumstances, therefore, several different fractionations were tried such as 50 Gy in 20 fractions, 47.5 Gy in 19 fractions, 36 Gy in nine fractions or 45 Gy in nine fractions. In such cases where more than 10 fractions were used, needle insertion was performed twice and needles were removed every Friday. HDR-ISBT was performed twice daily at 6-hour interval. Needle displacement was checked and corrected by CT taken before every morning session and if needle displacement greater than 5 mm was found, the needles were repositioned and CT was taken also before evening session.
When calculating the combined dose of EBRT and HDR-ISBT, the equivalent dose in 2 Gy fractions (EQD2) was utilized according to the linear-quadratic dose-effect model (22-24). The minimum dose covering 90% of the CTV (CTV D90) in EQD2 was used as the representative dose of HDR-ISBT because several different dose schedules were used in this study. Since in our previous report the relationship between late complications and dose for OAR, especially the vaginal tolerance, was investigated in detail (21), we focused on tumor control in the current study. Therefore, the radiation dose delivered prior to salvage HDR-ISBT was ignored.
Patients with histologically proven cervical squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma who initially underwent hysterectomy followed by pelvic recurrence without distant metastasis and who underwent salvage HDR-ISBT with a minimum follow-up period of 12 months were included in this study. Patients with pelvic lymph-node metastasis who received salvage EBRT or with vaginal recurrence within the surface of the vagina which was treatable by ICBT were excluded from this study, because the aim of this study was to investigate the clinical result of salvage HDR-ISBT for patients with post hysterectomy pelvic recurrence of cervical cancer. Therefore, relatively advanced cases were included in this study.
Demographic, disease-specific, treatment details, and outcome data were collected. Survival time was calculated from the start of salvage radiation therapy until the last follow-up attendance or death from any cause. The local control rate (LC) was calculated from the start of the salvage radiation therapy and histological or apparent radiological evidence of pelvic disease recurrence within the salvage radiation field was considered to be an event and was censored at the time of death, non-local relapse, or last follow-up visit. Progression-free survival (PFS) was calculated from the start of the salvage radiation therapy until the last follow-up attendance or the any disease recurrence. The cumulative overall survival (OS) and PFS after salvage radiation therapy were calculated by the Kaplan–Meier method. Univariate survival curve comparisons were performed by the log-rank test. The level of statistically significance was defined as p<0.05.
This retrospective study was approved by the Institutional Ethical Review Board of the National Cancer Center Hospital (approval number is 2015-359) and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Results
Thirty-four consecutive patients with postoperative pelvic recurrent cervical cancer without distant metastasis who were treated by salvage HDR-ISBT between April 2009 and September 2014 were identified. Eight patients were excluded from the study because of incomplete hysterectomy followed by salvage interstitial brachytherapy, all of whom were referred to our Department from other hospitals, therefore, 26 patients comprised the current study. Table I summarizes patient's characteristics. There were 11 patients with squamous cell carcinoma, 11 with adenocarcinoma, and four with adenosquamous carcinoma. Histology in more than half the cases was non-squamous cell carcinoma, suggesting that the patient group had unfavorable clinical features than the normal cervical cancer population. Seven out of 26 patients (26.9%) were positive for disease in regional pelvic lymph nodes or had parametrial invasion or positive surgical margins proven by postoperative histology, however, only three patients underwent PORT; all of the patients without PORT who underwent adjuvant chemotherapy alone were referred to our Department from other hospitals.
Table II summarizes clinical features of patients with pelvic recurrence. Nine patients had pelvic side-wall involvement, whereas 17 patients had their recurrent disease confined to the central pelvis. Nine patients had regional pelvic lymph-node metastasis at the time of disease relapse.
Baseline patient and tumor characteristics at presentation and initial treatment given (n=26).
Ten patients had prior history of pelvic irradiation before salvage HDR-ISBT; three had had adjuvant whole pelvic irradiation as initial treatment, three received EBRT for side-wall recurrence at other hospitals, and the others received ICBT with or without EBRT for central pelvic recurrence at a referral hospital.
Eleven patients had prior history of systemic chemotherapy; four patients had indication for PORT because of having adverse pathological features and should have been given PORT, but received only adjuvant combination of paclitaxel and carboplatin (TC) according to the treatment policy of previous institutions. Two patients received TC or combination of cisplatin, aclacinomycin A, and mitomycin C after development of pelvic recurrence, the others received TC, cisplatin, or combination of paclitaxel and cisplatin either concurrently or sequentially with radiation therapy after disease recurrence.
Salvage treatment details for pelvic recurrence are summarized in Table III. Twenty one patients received EBRT in combination with HDR-ISBT and median dose of EBRT was 30 Gy (range=0-50 Gy). The median number of fractions and dose per fraction of HDR-ISBT were 5 (range=3-20 fractions) and 6 Gy (range=2.5-6 Gy), respectively. Six patients were treated with smaller than 6 Gy per fraction because of prior pelvic irradiation. The median CTV D90 in EQD2, combining dose of EBRT if given, was 68.4 Gy (range=48.8-94.2 Gy). Five patients received concurrent chemotherapy; four received weekly cisplatin and one TC.
Clinical status of patients with pelvic recurrence after hysterectomy for cervical cancer, N=26.
Treatment details for pelvic recurrence after hysterectomy, N=26.
Clinical results. Sixteen patients experienced disease recurrence and 11 patients died of their disease after salvage HDR-ISBT. The median follow-up period of patients without disease recurrence was 31.3 months (range=12.1-62.1 months). Three-year LC, PFS, and OS were 51.1%, 34.4% and 57.1%, respectively (Figure 1). Patterns of first failure are summarized in Table IV. The most frequent type of relapse was local failure, followed by distant metastasis. Among 16 patients with disease recurrence, three underwent salvage TPE and one achieved a disease-free interval longer than 5 years after TPE. Except for this patient, no one was disease-free at the time of the analysis.
Factors potentially correlating with LC, PFS, or OS were analyzed and summarized in Table V. While regional lymph-node metastases present at the time of relapse did not correlate with PFS or OS, regional lymph node metastasis found at the initial hysterectomy did correlate with PFS and OS (p=0.010 and p=0.012, respectively; Figure 2a). A recurrence-free interval longer than 3 years also correlated with favorable PFS and OS (p=0.030 and p=0.020, respectively; Figure 2b). With regard to LC, the combination of EBRT, CTV D90 greater than 65 Gy, and dose per fraction greater than 5 Gy were associated with favorable LC.
Patterns of first failure after salvage high-dose-rate interstitial brachytherapy (N=26).
Potential predictors influencing local control (LC), progression-free (PFS) and overall survival (OS) at 3 years in patients with pelvic recurrence after hysterectomy who received salvage high-dose-rate interstitial brachytherapy.
Because local recurrence was the most frequent relapse and in many cases pelvic radiation was incorporated with initial or salvage management, factors which affected LC for patients with past history of radiation therapy was of great concern. Therefore, 10 patients with past history of radiation therapy were further investigated and it was found that a dose per fraction greater than 5 Gy and high-risk CTV D90 greater than 65 Gy (EQD2) were associated with favorable LC (Figure 3).
Toxicities. Patients with pelvic recurrence were excluded from analysis of late toxicities because it was difficult to attribute the event to HDR-ISBT or to recurrent disease itself. Among 14 patients without local relapse, one patient experienced both rectal ulcer and vesicovaginal fistula, which was conservatively managed by 80 sessions of hyperbaric oxygen therapy. This patient had a past history of 50 Gy of whole pelvic irradiation and 1440 mCih of radium intracavitary vaginal brachytherapy and salvaged by 36 Gy in 12 fractions of HDR-ISBT for central recurrence. Two patients experienced grade 1 rectal bleeding and one patient developed grade 2 urethral stenosis requiring catheter insertion.
Discussion
There have been several reports about ISBT, but most of them were clinical results for patients with various gynecological malignancies, such as cervical carcinoma, endometrial carcinoma, and ovarian carcinoma or mixture of postoperative and post-radiotherapy cases (12-16, 20). As far as we know, this is the first report which focused only on salvage HDR-ISBT after hysterectomy for uterine cervical cancer.
Kaplan–Meier survival curves for local control (LC), progression-free survival (PFS), and overall survival (OS) in patients with pelvic recurrence after hysterectomy who received salvage high-dose-rate interstitial brachytherapy.
Overall survival (OS) curves stratified by presence of metastatic regional lymph nodes found at initial hysterectomy (a) and disease-free interval before pelvic relapse (b).
Local control (LC) curves for patients with past history of pelvic irradiation (n=10) stratified by dose per fraction (a) and high-risk clinical target volume (HR-CTV) D90 (EQD2) (b).
Although PORT is a standard therapy after radical hysterectomy for intermediate- and high-risk early-stage cervical cancer (18, 25), due to the concern for possible late severe bowel toxicities related to the combination of laparotomy and pelvic radiation, and recent emerging positive results from adjuvant chemotherapy alone for intermediate- and high-risk post-hysterectomy cervical cancer (19), several Japanese hospitals stopped using PORT (26). As shown in Table I, most patients included in this study were referred from other hospitals and four of them theoretically had indications for PORT but did not receive it, which is contrary to evidence. A prospective clinical trial is under preparation in Japan to determine the feasibility and efficacy of postoperative cCRT using IMRT (27-30) which may possibly reduce late bowel toxicities, which gynecological oncologists are most concerned with, and this trial will hopefully contribute to promoting PORT in situations where it is required and encourage evidence-based practice.
Adenocarcinoma is a well-known adverse prognostic factor for cervical cancer (31, 32) and as shown in Table I, more than half of the patients were classified as having non-squamous carcinoma histology. This is one of the reasons for unfavorable clinical results after salvage HDR-ISBT in this study.
In this study, local failure was the most frequent type of relapse and LC by HDR-ISBT as a salvage treatment was not satisfactory. This is partly because detection of tumor spread, especially in postoperative recurrent cases, was difficult on plain CT image. Viswanathan et al. compared high-risk CVT determined by CT and MRI and reported that MRI was more accurate than CT in soft-tissue resolution (33). In HDR-ISBT, especially in cases not combined with EBRT, accurate target detection is critical and geometrical miss can directly influence LC. Recently, favorable clinical results were reported using MRI-assisted HDR-ISBT for primary uterine cervical cancer (34). In the current study, even if in many cases MRIs taken immediately before HDR-ISBT were used as a reference, no MRI was taken with applicators in place. Therefore, MRI-based image-guided ISBT should improve the tumor detection and LC rates in the future.
In cases with a past history of pelvic irradiation, a fractionated schedule with single dose lower than 6 Gy was tried to minimize the severe late toxicities. However, we found that lower than 5 Gy per fraction was associated with a worse LC rate (Table V). Patients with a past history of pelvic irradiation were further analyzed for LC, and higher than 5 Gy per fraction and high-risk CTV D90 greater than 65 Gy were associated with favorable LC (Figure 3). Having a subgroup of patients with an inadequate dose schedule appears to be another reason why LC of this study was unsatisfactory. Therefore, recently we began to apply 48 Gy in eight fractions for patients with a past history of pelvic irradiation. It is true that this schedule can potentially cause more frequent severe late toxicities, therefore, we will report its efficacy and toxicities in a subsequent study.
On the other hand, about one-third of patients developed relapse outside of radiation field (Table IV). Clinical results for patients with a disease-free interval shorter than 3 years were found to be worse than for those with intervals longer than 3 years. The reason for this finding was considered to be that the disease was not truly confined locally, but in fact some microscopic disease spread would have existed which could not be detected with conventional CT, MRI, or PET/CT. MRI with lymphotropic superparamagnetic nanoparticles (35) was reported to be able to detect lymph node metastasis smaller than 5 mm in diameter more accurately than MRI alone. This kind of report suggests that recurrent diseases diagnosed as localized by conventional modalities are not always localized diseases, but may have subclinical microscopic disease at a distant site. Such new modalities which can detect micrometastasis should enable selection of patients with truly locally confined diseases who are better candidates for salvage HDR-ISBT, and for patients with local relapse with microscopic metastasis, regional EBRT with/without systemic chemotherapy combined with HDR-ISBT would potentially benefit those patients, thereby the treatment results will be improved.
The existence of regional lymph node metastasis is a well-known prognostic factor for cervical cancer (30), and in this study, lymph-node metastasis found at hysterectomy also influenced prognosis after salvage treatment (Figure 2a, Table V).
One patient was successfully salvaged by TPE for disease recurrence after HDR-ISBT. This shows that in selected patients, TPE plays an important role even after salvage HDR-ISBT. However, because the patient's quality of life will be worsened after TPE and only selected patients are candidates for TPE, the role of salvage HDR-ISBT continues to be important.
Because there were many patients with disease recurrence after salvage HDR-ISBT in this study, analysis of the relationship between late toxicities and the dose to OAR was not performed. Toxicities after HDR-ISBT for gynecological malignancies, especially vaginal toxicities, was explored in detail in our previous report (21).
There were several limitations to our study. This study was a retrospective study from a single institution with a limited number of patients with heterogeneous pre-treatments, and the follow-up period was short. Another limitation was the method of comparison of different dose and time schedules. Brachytherapy can deliver a high dose compared with conventional EBRT, and it is easy to imagine that the biological effect of x Gy in y days will not be the same as that of x Gy in z days. There are several models for fractionation which incorporate a time factor (36, 37), however, because such models need many assumptions before calculation, we did not use them and simply used the linear-quadratic dose-effect model (22-24). Simple and more reliable models which take time factors into consideration would make it possible to compare the different dose schedules. Therefore, the results of this study should be interpreted with caution.
However, because in Japan the availability of HDR-ISBT is very limited due to the paucity of institutions which have enough human resources and capacity to perform this procedure, and curative treatment modalities are limited for patients with pelvic recurrence after hysterectomy, we considered it to be worth reporting our results in order to help promote the importance of salvage HDR-ISBT among other radiation oncologists. If the availability of HDR-ISBT is not improved, such patients who are possible candidates for salvage HDR-ISBT must proceed to systemic chemotherapy as best supportive care.
Conclusion
For post hysterectomy cervical cancer patients with pelvic recurrence who are not candidates for TPE, salvage HDR-ISBT is a possible curative treatment modality. However, because the treatment result was not satisfactory, further improvement of LC is warranted through incorporating MRI for more accurate target recognition or adjusting the dose fractionation schedule.
Acknowledgements
This study was partially supported by the Japan Agency for Medical Research and Development, AMED, the National Cancer Center Research and Development Fund (26-A-18 and 26-A-28), and JSPS KAKENHI Grant Number 15K19836.
- Received February 7, 2016.
- Revision received March 30, 2016.
- Accepted March 31, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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