Percutaneous parametrial dose escalation in women with advanced cervical cancer: feasibility and efficacy in relation to long-term quality of life

Primary radiochemotherapy (RChT) with external beam radiotherapy (EBRT), intracavitary brachytherapy (ICBT), and concomitant chemotherapy (ChT) remains a frequently used treatment for advanced cervical cancer (ACC). However, local tumour control requires comparatively large doses, which in turn may lead to relevant treatment-related morbidity.1,2 In recent years, image guided adaptive brachytherapy (IGABT), based on magnetic resonance imaging (MRI) and combined interstitial / intracavitary brachytherapy (IBT/ICBT), has been successfully implemented as the new standard of care for local dose escalation and substantial reduction of therapy-related morbidity.3,4,5

However, access to IGABT is limited at many brachytherapy facilities. Therefore, despite evidence of the inferiority of percutaneous boosting in terms of organ sparing and target coverage, another approach has been to combine ICBT with modern radiotherapy (RT) techniques, such as intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) to the parametria, for percutaneous local dose escalation.6,7 There is a low incidence of acute toxicities after SIB, but clinical outcome and QoL of these patients have not been investigated so far.7 Due to limited access to IGABT at many brachytherapy facilities and the unknown effects of SIB in terms of chronic morbidity, IMRT with sequential boost remains a widely used method for parametrial dose escalation. Given the comparatively young age of patients with cervical cancer and improving prognosis, long-term quality of life (QoL) and extent of chronic morbidity become increasingly important issues.

Therefore, we conducted this study to analyze feasibility and efficacy of a percutaneous parametrial boost in relation to long-term QoL as well as to assess tumour- and treatment-related prognostic factors for long-term QoL and outcome in women with ACC.

Between 2008 and 2014, eighty-three women with ACC underwent primary treatment at our department. Patients’ data were acquired from the institutional electronic patient charts and the institutional follow-up database. Median age at first diagnosis was 57 years (range 32–90 years; Table 1). Due to the substantially differing fractionation schedules, all reported doses were recalculated as equivalent doses in 2-Gy fractions with α/β = 10 (EQD2₁₀) for the tumour and α/β = 3 (EQD2₃) for the organs at risk (OARs). OAR doses were documented for volumes of 0.1 cm³ (D0.1cc), 1 cm³ (D1cc) and 2 cm³ (D2cc). They were calculated as the sum of the individual doses received from all brachytherapy fractions and the EBRT plan.8

Table 1

Patients’ characteristics

Survival was plotted according to Kaplan and Meier. Overall survival (OS) was defined as the time between first diagnosis and death. Local progression-free survival (LPFS) was defined as the time between first diagnosis and occurrence of any local progression. Since patients with distant metastases (cM1a and cM1c) at first diagnosis were included in this study, distant progression-free survival (DPFS) was defined as the interval between first diagnosis of cervical cancer and occurrence of new distant metastases. Prognostic factors for survival were analyzed with the log-rank test (univariate analysis) and a Cox proportional hazards model (multivariate analysis).

Three years (median; range 2–8 years) after treatment, patients were approached during clinical follow-up examinations and asked to fill-in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Patients 30 (QLQ-C30) and the Cervical Cancer Module (QLQ-CX24). Thirty-one women agreed to participate. The difference between patients’ QoL items scores and published German reference values was analyzed with the t-test (9). Possible prognostic factors for QoL (age, stage, tumour size, lymph node status, distant metastases status, histological grading, histology, RT techniques, applied RT doses, OAR doses, ChT, treatment duration, observed acute toxicities, anemia during RChT, number of transfusions during RChT) were investigated with an analysis of variances and the t-test. Age was used as a covariate. A p-value ≤ 0.05 was considered statistically significant. All statistical analyses were performed with IBM SPSS version 24.0.

This study was conducted in accordance with the declaration of Helsinki and was approved by the responsible independent ethics committee on 22 October 2012 (#S-513/2012). The requirement of informed consent was waived by the ethics committee, due to the retrospective nature of the study.

The objective of this study was to analyze the feasibility and efficacy of a parametrial boost in relation to long-term QoL of patients with ACC. Secondly, we aimed to assess tumour- and treatment-related prognostic factors for long-term QoL and clinical outcome.

Currently, for the QLQ-CX24 items, there are only reference populations from 2 Korean studies available and possible social or cultural differences prevent these cohorts from being reference populations for European studies.10,11 Therefore, we were unable to compare the QLQ-CX24 items scores of our patients and we can only report on the comparison between our patients’ QLQ-C30 items scores and German normative data.9 Compared to the reference population, the patients in our cohort had significantly worse functioning and symptoms item scores. Similar results have been reported in a large population-based study from the United States. They found health-related QoL in survivors of cervical cancer to be worse than in the normal population as well.12 In women treated with IGABT within the “European and international study on MRI-guided brachytherapy in locally advanced cervical cancer” (EMBRACE), after a median follow-up of 21 months, functioning and general QoL returned to levels of the reference population, but several clearly treatment-related symptoms, e.g. diarrhea and sexual dysfunction, did develop or persist in those patients during follow-up as well.13

While we, probably due to the small cohort, were unable to show a significant correlation between the doses received by the OARs and any of the QoL item scores, others have found a significant dose-volume effect relationship for late rectal and urinary morbidity. Particularly, patients with bladder D2cc > 95 Gy and rectum D2cc ≥ 75 Gy are at risk for severe late toxicities.14,15 It has been shown that chronic bladder and rectal morbidity can be further reduced by IGABT.3 Therefore, in the ongoing EMBRACE-2 trial, the planning aims / limits for the prescribed EQD2₃ to rectum (D2cc < 65 / < 75 Gy) and bladder (D2cc < 80 / < 90 Gy) are substantially lower than the mean dose values achieved in our cohort.5 Consequently, the QLQ-CX24 symptom experience score was higher in our patients compared to those treated within the EMBRACE study (18.1 ± SD 16.4 vs. 12.1 ± SD 11.9; p = 0.063) after 36 months of follow-up.13 As a further indicator for the dose-volume dependence of chronic morbidity, we found the degree of RT-related acute GI und GU toxicities in patients with ACC to statistically significantly correlate with the extent of chronic symptoms and we have already shown this correlation in a previous study from our institution on women with endometrial cancer.16 In that study we also demonstrated an improved global health status and fewer chronic GI symptoms by reduction of acute toxicities with IMRT.16 Since most of the patients in our current analysis were treated with IMRT, we were unable to demonstrate such a benefit in terms of long-term QoL. Apart from the dose-volume-relationship found in both, acute and late toxicities, chronic toxicities may be consequential to acute damage, thus amelioration of the acute response to irradiation may be a useful approach to minimize late side effects.17

Our analysis showed a significant impairment of sexual/vaginal functioning, significantly increased sexual worry, and a trend towards more chronic constipation in patients exceeding an EQD2₁₀ of 53 Gy in the parametria. This was equally true for patients with SIB or sequential boost. The required dose to the parametria for adequate local tumour control has not been established and dose prescriptions vary greatly among radiation oncologists.2,18 In patients with traditional midline-shielding, parametrial boost resulted in a significantly higher incidence of radiation proctitis and enterocolitis when > 54 Gy were applied.19,20 and this technique has been described to substantially contribute to rectum, sigmoid and bladder doses.21 In the times of IMRT and SIB to the parametria, studies have shown, that local dose escalation can be achieved with a relevantly reduced incidence of acute toxicities.7,22 So far, no study has ever looked at percutaneous parametrial dose escalation regarding QoL and chronic morbidity. Particularly, chronic vaginal morbidity after EBRT boost has not been the focus of research so far. The Vienna group has provided important evidence, that IGABT delivers superior outcome.3,23 and can reduce vaginal morbidity significantly, but sexual dysfunction remained a problem in patients treated within the EMBRACE trial as well.13,24 It is assumed that vaginal toxicity may be further reduced with IGABT by decreasing dwell times in the ovoid/ring and increasing dwell times in tandem/needles.25,26 In this context it is important to state that the ongoing EMBRACE-2 trial limits percutaneous IMRT boost as SIB to involved lymph nodes and does not allow a parametrial IMRT boost.5 At our institution, MRI-guided IGABT with combined IBT/ICBT was recently implemented and we are currently planning a study with longitudinal QoL assessment in these patients. Certainly, it should be the ultimate goal to enable access to IGABT at all brachytherapy facilities. Nevertheless, at the moment, availability of IBT and MRI-guidance is low at most brachytherapy centers and EBRT boost remains a widely used method for parametrial dose escalation. This underlines the importance of our investigation.

While survival rates were generally adequate in our study and in line with previously published data from randomized controlled trials on RChT in patients with ACC, a comparison of our results to data on IGABT is quite challenging because our cohort consists of mostly advanced stage patients.27,28 The RetroEMBRACE study, a multicenter retrospective observational study, found substantially better 5-year pelvic control and overall survival rates (84% vs. 73.2% and 65% vs. 53.2%), but their cohort contained much more stage I and far less stage IV patients than our study (16.8% vs. 2.4% and 3.1% vs. 31.3%) (23). A Dutch retrospective analysis on 46 patients treated with IGABT found a 3-year regional control rate of 86% and a 3-year overall survival rate of 65%.29 Similarly, Pötter et al. found pelvic control and overall survival to be 91% and 68% after 3-years, respectively.3 The patient cohorts in these two studies were very similar to the collective of the RetroEMBRACE study. Therefore, our results, despite the large proportion of stage IV patients and the negligible amount of stage I patients, are not inferior in terms of overall survival and seem comparable with respect to local pelvic control. However, primary tumour control was remarkably high with 93% after 3 years in the Vienna series.3 Furthermore, an analysis from the RetroEMBRACE study comparing IGABT with IBT/ICBT to ICBT only showed the feasibility of local dose escalation without an increase in dose to organs at risk as well as a 10% higher 3-year local control rate with IBT.30 These results clearly demonstrate the advantage of MRI-based IGABT with combined IBT/ICBT for local dose escalation.

Nevertheless, our analysis showed a statistically significant overall survival benefit from a parametrial boost and this was equally true for patients with SIB or sequential boost. Alongside with simultaneous ChT, parametrial boost was as an independent prognostic factor for OS in the multivariate analysis. Local control was also improved in patients with parametrial boost, but, probably due to the comparatively few events, this did not reach statistical significance. However, the survival benefit was dependent on the applied dose. In particular, overall survival was statistically significantly prolonged in patients with a parametrial EQD2₁₀ > 50 Gy, but a dose escalation beyond an EQD2₁₀ of 53 Gy did not further improve survival. Thus, we believe IMRT with 25 × 1.8 Gy to the whole pelvic PTV including a SIB with 25 x 2.1 Gy to the parametria to be a feasible and overall efficient EBRT concept for centers without access to IGABT.

We acknowledge that our study is substantially limited by its retrospective nature, the comparatively small sample size and the conductance of multiple subgroup analyses, but we believe our results on parametrial dose and chronic morbidity to be of importance for all brachytherapy centers without access to MRI-guidance and IBT.

Primary RChT is an effective treatment for ACC, but long-term QoL of survivors is inferior compared to normative data. The degree of acute side effects of RChT correlates with the extent of chronic symptoms. For patients treated with EBRT boost and ICBT, we have shown a significant survival benefit from parametrial dose escalation as SIB or sequential boost, but exceeding an EQD2₁₀ of 53 Gy with this technique does not further improve survival and has a negative impact on QoL. Therefore, the conductance of a percutaneous parametrial boost has to be seen very critically with respect to local tumour control and long-term QoL. MRI-guided IGABT with combined IBT/ICBT certainly is the gold standard for local dose escalation in ACC.