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
Patients’ characteristicsAge Median 57 years Range 32–90 years Squamous cell carcinoma 67 80.7% Adenocarcinoma 14 16.9% Adenosquamous carcinoma 2 2.4% G1 8 9.6% G2 24 28.9% G3 35 42.2% GX 16 19.3% I 2 2.4% II 4O 48.2% III 15 18.1% IV 26 31.3% T1 3 3.6% T2 46 55.4% T3 25 30.1% T4 9 10.8% N0 28 33.7% N1 55 66.3% M0 64 77.1% M1a 12 14.5% M1c 7 8.4%
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.
RT was conducted as EBRT (69.9% IMRT, 30.1% 3D-conformal RT), with or without sequential boost / SIB to parametria and involved pelvic / paraaortic lymph nodes (43.4% no boost, 37.3% sequential boost, 19.3% SIB), and high-dose-rate (HDR) ICBT boost (tandem and ring applicator). Median EBRT EQD210 to the whole pelvic (and paraaortic) planning target volume (PTV) was 44 Gy (range 35–51 Gy) and median parametrial EQD210 was 53 Gy (range 38–67 Gy). Including ICBT boost, as prescribed to point A, with a median EQD210 of 40 Gy (range 10–50 Gy), the median prescribed primary tumour EQD210 was 84 Gy (range 54–95 Gy). Seventy-one patients (85.5%) received concomitant ChT with 4–6 cycles of cisplatin 40 mg/m2 weekly (Table 2).
Treatment and toxicity EBRT = external beam radiotherapy; ECs = erythrocyte concentrates; EQD2 = equivalent doses in 2-Gy fractions; GI = gastrointestinal; GU = genitourinary; Hb = haemoglobin; HDR-BT = high-dose-rate brachytherapy; IMRT = intensity-modulated radiotherapy; SIB = simultaneous integrated boostRadiotherapy dose in EQD2 (α/β = 10) Median EBRT 44 Gy Range EBRT 35–51 Gy Median parametria 53 Gy Range parametria 38–67 Gy Median HDR-BT 40 Gy Range HDR-BT 10–50 Gy IMRT 58 69.9% 3D-conformal 25 30.1% No boost 36 43.4% Sequential 31 37.3% SIB 16 19.3% ≤ 53 Gy 56 67.5% > 53 Gy 27 32.5% Cisplatin 40 mg/m2 71 85.5% None 12 14.5% < 6 weeks 9 10.8% 6-8 weeks 52 62.7% ≥ 9 weeks 22 26.5% min. Hb < 10 g/dl 38 45.8% min. Hb ≥ 10 g/dl 45 54.2% ≤ 2 ECs 69 83.1% > 2 ECs 14 16.9% Grade 0 33 39.8% Grade I 15 18.1% Grade II 20 24.1% Grade III 12 14.5% Grade IV 3 3.6% Grade 0 15 18.1% Grade I 34 41.0% Grade II 28 33.7% Grade III 6 7.2%
Mean bladder D0.1cc, D1cc and D2cc were 130.2 Gy (± SD 31.7 Gy), 105.6 Gy (± SD 14.2 Gy) and 97.1 Gy (± SD 9.9 Gy), respectively. Mean sigmoid D0.1cc, D1cc and D2cc were 71.9 Gy (± SD 10.6 Gy), 64.1 Gy (± SD 7.9 Gy) and 61.1 Gy (± SD 6.9 Gy), respectively. Mean rectum D0.1cc, D1cc and D2cc were 89.8 Gy (± SD 23.1 Gy), 74.3 Gy (± SD 12.8 Gy) and 68.8 Gy (± SD 9.4 Gy), respectively.
Thirty-six patients (43.4%) died, 18 (21.7%) had a local progression and 24 (28.9%) developed new distant metastases during follow-up. Calculated 3- / 5-year LPFS, DPFS and OS were 80.5% / 73.2%, 76.7% / 65.3% and 66.5% / 53.2%, respectively.
In univariate analysis (Table 3), Fédération Internationale de Gynécologie et ďObstétrique (FIGO) stage (I/II
Prognostic factors for survival DPFS = Distant progression-free survival; ECs = erythrocyte concentrates; EQD2 = equivalent doses in 2-Gy fractions; FIGO = Fédération Internationale de Gynécologie et d’Obstétrique; Hb = haemoglobin; LPFS = Local progression-free survival OS = overall survivalOS Univariate analysis (log-rank test) Mean (months) p-value FIGO I/II 72.6 FIGO III/IV 50.8 T1/2 69.2 T3/4 50.4 G1/2 72.4 0.053 G3 50.5 yes 69.9 no 51.2 ≤ 50 Gy 50.7 > 50 Gy 71.5 ≤ 53 Gy 59.5 0.194 > 53 Gy 64.1 yes 67.4 no 32.1 6–8 weeks 71.6 ≥ 9 weeks 44.7 min. Hb < 10 g/dl 52.1 min. Hb ≥ 10 g/dl 70.3 ≤ 2 ECs 67.6 > 2 ECs 41.6 FIGO I/II 85.9 0.072 FIGO III/IV 66.7 T1/2 85.7 T3/4 64.1 yes 84.1 0.095 no 56.1 N0 85.6 N1 61.0 M0/M1a 75.2 M1c 37.1 G1/2 84.6 G3 59.8 yes 0.417 0.192-0.900 no Reference yes 0.382 0.152-0.961 no Reference T1/2 Reference T3/4 2.668 1.032-6.896 0.043 N0 Reference N1 4.383 1.003-19.154 M0/M1a Reference M1c 4.646 1.466-14.719
In multivariate analysis (Table 3), parametrial boost (yes
We found the values of the functioning and symptoms scores in our cohort to be significantly worse comparison those from the normative population (Table 4). Generally, age must be considered when looking at quality of life and we used age as a covariate for our analyses, however age only correlated with menopausal symptoms (p = 0.003) in our analysis and did not affect global health status or any of the other functioning or symptom items scores from the QLQ-C30 or QLQ-CX24 questionnaires in our cohort.
Quality of life of patients compared to reference populations (EORTC QLQ-C30) EORTC = European Organization for Research and Treatment of Cancer; QLQ-C30 = quality of life questionnaire for cancer patients 30n mean SD p-value Reference 1309 74.5 15.5 0.001 Patients 30 60.3 21.7 Reference 1309 91.5 15.5 < 0.001 Patients 30 73.6 19.6 Reference 1309 89.9 20.6 < 0.001 Patients 31 58.1 33.0 Reference 1309 83.2 19.3 0.001 Patients 31 65.1 26.7 Reference 1309 93.4 14.6 < 0.001 Patients 31 73.2 28.4 Reference 1309 93.3 17.1 < 0.001 Patients 31 69.9 29.0 Reference 1309 16.4 21.4 < 0.001 Patients 31 51.6 28.0 Reference 1309 2.4 9.6 0.030 Patients 31 11.3 21.7 Reference 1309 17.0 24.2 0.025 Patients 31 26.9 24.2 Reference 1309 7.2 18.7 0.020 Patients 30 18.9 25.8 Reference 1309 13.0 23.6 < 0.001 Patients 31 40.9 36.2 Reference 1309 4.2 13.9 0.002 Patients 31 21.5 27.7 Reference 1309 3.1 12.1 < 0.001 Patients 31 22.6 27.7 Reference 1309 2.9 12.7 < 0.001 Patients 31 29.0 30.7 Reference 1309 4.8 16.3 < 0.001 Patients 31 29.0 29.5
The doses to bladder, sigmoid and rectum did not correlate with any of the QoL item scores. However, we found a statistically significant correlation between the degree of observed acute gastrointestinal (GI) and genitourinary (GU) toxicities with chronic symptom experience (p = 0.038 and p = 0.041), which can be considered an indicator for the known dose-volume dependence of chronic morbidity. Patients with higher degree of observed acute GI toxicity also complained more about chronic diarrhea (p = 0.053). Since most of our patients underwent IMRT and all of them received HDR ICBT, we found no difference in QoL between RT techniques. Importantly, we could show, that a parametrial EQD210 > 53 Gy statistically significantly correlated with reduced sexual/vaginal functioning (p = 0.009) and increased sexual worry (p = 0.009). Additionally, these patients also suffered more from chronic constipation (p = 0.057). Whether parametrial dose escalation was achieved by sequential boost or SIB did not affect QoL. Sexual/vaginal functioning was statistically significantly worse in patients with T3/4 tumours compared to those with T1/2 tumours (p = 0.012). Details are shown in Table 5.
Prognostic factors for patients’ long-term quality of life (EORTC QLQ-C30, QLQ-CX24) expressed as equivalent dose in 2-Gy fractions (EQD2) with α/β = 10 expressed as equivalent dose in 2-Gy fractions (EQD2) with α/β = 10 expressed as equivalent dose in 2-Gy fractions (EQD2) with α/β = 10 expressed as equivalent dose in 2-Gy fractions (EQD2) with α/β = 10 expressed as equivalent dose in 2-Gy fractions (EQD2) with α/β = 10 expressed as equivalent dose in 2-Gy fractions (EQD2) with α/β = 10 EORTC = European Organization for Research and Treatment of Cancer; GI = gastrointestinal; GU = genitourinary; QLQ-C30 = quality of life questionnaire for cancer patients 30; QLQ-CX24 = quality of life questionnaire cervical cancer modulen mean SD p-value Acute GI 0 11 12.1 16.8 0.053 Acute GI I/II 15 35.6 32.0 Acute GI III/IV 5 46.7 38.0 Parametria ≤ 53 Gy 19 14.0 23.1 0.057 Parametria > 53 Gy 11 33.3 29.8 Acute GI toxicity 0 11 9.4 8.6 Acute GI toxicity I/II 14 20.6 15.9 Acute GI toxicity III/IV 5 30.3 22.7 Acute GU toxicity 0 5 14.3 12.9 Acute GU toxicity I/II 22 22.4 9.7 Acute GU toxicity III/IV 3 38.4 33.5 ≤ 49 years 7 57.1 25.2 50–59 years 12 36.1 36.1 60–69 years 7 14.3 26.2 ≥ 70 years 4 8.3 16.7 T1/2 9 93.5 11.6 T3/4 3 41.7 52.0 Parametria ≤ 53 Gy 8 96.9 6.2 Parametria > 53 Gy 4 47.9 44.2 Parametria ≤ 53 Gy 17 15.7 26.6 Parametria > 53 Gy 9 51.8 37.7
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
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%
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.