Impact of treatment time and dose escalation on local control in locally advanced cervical cancer treated by chemoradiation and image-guided pulsed-dose rate adaptive brachytherapy

doi:10.1016/j.radonc.2014.11.045

Radiotherapy and Oncology

Volume 114, Issue 2, February 2015, Pages 257-263

https://doi.org/10.1016/j.radonc.2014.11.045 Get rights and content

Abstract

Purpose

To report the prognostic factors for local control in patients treated for locally advanced cervical cancer with image guided pulsed-dose rate brachytherapy.

Materials/methods

Patients treated with curative intent by a combination of external beam radiotherapy and pulsed-dose rate brachytherapy were selected. Local failure was defined as any relapse in the cervix, vagina, parametria, or uterus during follow-up. Prognostic factors were selected based on log rank tests and then analyzed with a Cox model. Dose/effect correlations were performed using the probit model.

Results

Two hundred and twenty-five patients treated from 2006 to 2011 were included. According to the FIGO classification, 29% were stage IB, 58% stage II, 10% stage III, and 3% stage IVA; 95% received concomitant chemotherapy. Thirty patients were considered having incomplete response or local failure. Among the selected parameters, D90 for HR-CTV, D90 for IR-CTV, the overall treatment time, the TRAK, and the HR-CTV volume appeared significantly correlated with local control in univariate analysis. In multivariate analysis, overall treatment time >55 days and HR-CTV volume >30 cm³ appeared as independent. The probit analysis showed significant correlations between the D90 for both CTVs, and the probability of achieving local control (p = 0.008 and 0.024). The thresholds to reach to warrant a probability of 90% of local control were 85 Gy to the D90 of the HR-CTV and 75 Gy to 90% of the IR-CTV (in 2 Gy equivalent, α/β = 10). To warrant the same local control rate, the D90 HR-CTV should be significantly increased in stage III–IV tumors, in case of HR-CTV >30 cm³, excessive treatment time, or tumor width at diagnosis >5 cm (97, 92, 105, and 92 Gy respectively).

Conclusions

Overall treatment time and HR-CTV volume were independent prognostic factors for local control. The D90 for HR and IR CTV were significantly correlated with local control, and D90 HR-CTV should be adapted to clinical criteria.

Section snippets

Patient selection

Clinical and dosimetric data of patients with locally advanced cervical cancer defined as FIGO (Fédération International de Gynécologie Obstétrique) stage 1B1 with positive pelvic nodes ± paraaortic nodes, 1B2-IVA, were retrospectively reviewed. Patients were selected from the department database. Those treated with definitive radiotherapy and curative intent were included. The patients who were referred only for BT and never followed after the completion of their treatment were excluded (n = 9).

Treatment

Population

Two hundred and twenty-five patients fulfilled the inclusion criteria. The median follow-up was 39.0 months. Population characteristics are depicted in Table 1. The majority of the tumors were stage II according to the FIGO classification (52.4%, 118/225). Twenty-eight percent were stage IB (62/225), whereas 12.4% were stage III (28/225) and the remaining 3.1% stage IVA (7/225). Forty-three percent of the patients had lymph node involvement (97/225). Eighty-four of the patients had a PET-CT in

Discussion

Several studies have reported the detrimental effect of treatment duration on local control before the advent of chemoradiation and IGABT. Fyles et al. were the first to report a consistent loss of local control, approximately 1% per day of treatment prolongation beyond 30 days [11]. In this series, the majority of the patients received hypofractionated EBRT (45 Gy in 20 fractions) followed by a single BT fraction. Those results were later on confirmed by Girinsky et al., with a threshold of 52

Conclusions

Treatment intensification does not overcome the negative effect of overall treatment time, which remains an independent prognosis factor in the era of image-guided adaptive BT following concomitant chemoradiation, alongside the HR-CTV volume. D90 to both IR and HR-CTV are also predominant in the probability of local control. Dose–effect relationships suggest that the prescribed D90 HR-CTV should be increased to overcome adverse prognosis factors, or conversely could be safely decreased in good

Conflict of interest

None.

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2024, Strategies for Overcoming Chemotherapy Resistance in Cervical Cancer: From Molecular Insights to Precision Solutions
Chemoradiotherapy is the mainstay of treatment for locally advanced cervical cancer. The response to chemoradiotherapy is based on disease stage. Numerous therapeutic strategies have led to improvement in locoregional control rates. These include the addition of concurrent chemotherapy to external beam radiotherapy and the use of image-guided brachytherapy. The latter has improved local control rates even in advanced stage disease. The use of intensity modulated radiotherapy, image-guided brachytherapy, and extended field para-aortic radiotherapy has further improved control rates. Nonetheless, systemic relapses remain an ongoing challenge. Various factors have been known to impact on radiotherapy response aside from access to effective care. Prolonged treatment time and low mean hemoglobin are well-known outcome response predictors. Adenocarcinoma appears to be genotypically different and behaves differently from the more frequent squamous cell cancer variant. The latter may relate to tumor hypoxia and its effect on radiotherapy response. Pretreatment imaging including 18-FDG PET imaging standardized uptake value may predict for tumor response. Human papilloma virus (HPV) viral load and HPV viral integration status have also been found to correlate with outcomes. HPV negative tumors have a poor outcome while those with a pretreatment high viral load appear to fare better. While tumor hypoxia is addressed through radiobiological principles of fractionation and maintenance of optimal hemoglobin levels, it is evident that pathways medicated through hypoxia-inducible factors mediated upstream through PI3K and RAS pathways also play a role in treatment response. Recent prospectively designed studies have identified molecular biomarkers that are predictive of disease response. These have included genomic and proteomic analysis, which has demonstrated several mutations, associated with poor responses. These include mutations in the PIK3CA as well as mutations in tumor suppressor genes and genes mediating response to immunotherapy. Proteomic analysis likewise has identified clusters that correlate with disease-related outcomes.
Retrospective analysis of local recurrence pattern by computed tomography image-guided intracavitary and interstitial brachytherapy for locally advanced cervical cancer in a single Japanese institution
2023, Brachytherapy
The purpose of this study was to investigate the treatment results with focus on local control (LC) by computed tomography (CT)-guided intracavity brachytherapy and interstitial brachytherapy (ICBT/ISBT) for locally advanced cervical cancer (LACC).
Patients with LACC undergoing ICBT/ISBT at least once in our institution between January 2017 and June 2019 were analyzed retrospectively. The primary endpoint was local control (LC), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and late toxicities. Differences between patient subgroups for prognostic factors in LC, PFS, and OS were analyzed using the log-rank test. The recurrence patterns of LC were also investigated.
Forty-four patients were included in the present study. The median high-risk clinical target volume (HR-CTV) at the initial brachytherapy was 48.2 cc. The median total dose of HR-CTV D90 (EQD2) was 70.7 Gy. The median followup period was 39.4 months. The 3-year LC, PFS and OS rates in all patients were 88.2%, 56.6%, and 65.4% (95% CI 50.3–78.0%), respectively. Corpus invasion and large HR-CTV (70 cc or more) were significant prognostic factors in LC, PFS, and OS. Marginal recurrences at the fundus of the uterus were detected in 3 of 5 patients in whom local recurrence was observed. Late toxicities of Grade 3 or higher were detected in 3 patients (6.8%).
Favorable LC was achieved by performing CT-guided ICBT/ISBT for LACC. The brachytherapy strategy for patients with corpus invasion or large HR-CTV may need to be reconsidered.
Clinical transfer of AGuIX®-based radiation treatments for locally advanced cervical cancer: MR quantification and in vitro insights in the NANOCOL clinical trial framework
2023, Nanomedicine: Nanotechnology, Biology, and Medicine
Clinical trials incorporating metallic nanoparticles (NPs) have recently begun. Radiotherapy planning does not take into account NPs concentrations observed in the patients' target volumes. In the framework of the NANOCOL clinical trial including patients treated for locally advanced cervical cancers, this study proposes a complete method to evaluate the radiation-induced biological effects of NPs. For this, calibration phantom was developed and MRI sequences with variable flip angles were acquired. This process allowed the quantification of NPs in the tumor of 4 patients, which was compared to the results of mass spectrometry obtained from 3 patient biopsies. The concentration of the NPs was reproduced in 3D cell models. Based on clonogenic assays, the radio-enhancement effects were quantified for radiotherapy and brachytherapy, and the impact in terms of local control was evaluated. T₁ signal change in GTVs revealed NPs accumulation ∼12.4 μmol/L, in agreement with mass spectrometry. Radio-enhancement effects of about 15 % at 2 Gy were found for both modalities, with a positive impact on local tumor control. Even if further follow-up of patients in this and subsequent clinical trials will be necessary to assess the reliability of this proof of concept, this study opens the way to the integration of a dose modulation factor to better take into account the impact of NPs in radiotherapy treatment.
ESGO/ESTRO quality indicators for radiation therapy of cervical cancer
2023, Radiotherapy and Oncology
The European Society of Gynaecological Oncology (ESGO) has previously defined and established a list of quality indicators for the surgical treatment of cervical cancer. As a continuation of this effort to improve overall quality of care for cervical cancer patients across all aspects, ESGO and the European SocieTy for Radiotherapy and Oncology (ESTRO) initiated the development of quality indicators for radiation therapy of cervical cancer.
To develop a list of quality indicators for radiation therapy of cervical cancer that can be used to audit and improve clinical practice by giving to practitioners and administrators a quantitative basis to improve care and organizational processes, notably for recognition of the increased complexity of modern external radiotherapy and brachytherapy techniques.
Quality indicators were based on scientific evidence and/or expert consensus. The development process included a systematic literature search for identification of potential quality indicators and documentation of scientific evidence, consensus meetings of a group of international experts, an internal validation process, and external review by a large international panel of clinicians (n = 99).
Using a structured format, each quality indicator has a description specifying what the indicator is measuring. Measurability specifications are detailed to define how the quality indicators will be measured in practice. Targets were also defined for specifying the level which each unit or center should be aiming to achieve. Nineteen structural, process, and outcome indicators were defined. Quality indicators 1–6 are general requirements related to pretreatment workup, time to treatment, upfront radiation therapy, and overall management, including active participation in clinical research and the decision making process within a structured multidisciplinary team. Quality indicators 7–17 are related to treatment indicators. Quality indicators 18 and 19 are related to patient outcomes.
This set of quality indicators is a major instrument to standardize the quality of radiation therapy in cervical cancer. A scoring system combining surgical and radiotherapeutic quality indicators will be developed within an envisaged future ESGO accreditation process for the overall management of cervical cancer, in an effort to support institutional and governmental quality assurance programs.
Early outcomes of abbreviated multi-fractionated brachytherapy schedule for cervix cancer during COVID-19 pandemic
2023, Brachytherapy
Brachytherapy (BT) for cervix cancer was listed as a level I priority and reduced number of implants and multiple fractions were recommended during COVID-19 pandemic. We present early clinical outcome of this approach.
Patients treated with (chemo)radiotherapy and BT with single implant and multiple fractions BT were included. Treatment protocol included 3−5 fractions of 5−8.5 Gy with an aim to achieve point A dose of 70 Gy EQD2_10Gy (or HRCTV dose of >80 Gy EQD2_10Gy) in those undergoing intracavitary (IC) and HRCTV dose >85 Gy EQD2 10Gy in patients undergoing Intracavitary-Interstitial (IC/IS) whereas maintaining bladder (B2cc), rectum (R2cc), sigmoid (S 2cc) doses of 90, 75, and 75 Gy EQD2_3Gy. Time to event analysis was used to report oncological endpoints. Toxicity was reported using crude proportions.
From April 2020 to March, 2021, 64 patients with stage IB2-IV received single implant and multi-fraction BT after external radiation of 45 Gy/25 fractions/5 weeks. Only 76.7% (n = 49) received concurrent chemotherapy. Median overall treatment time (OTT) was 56 days (38−131 days). Overall, 62.5% (n = 40) patients received IC and 37.5% (n = 24) received IC+IS. The median HRCTV was 34.7 cc (IQR 25−41). Median (IQR) point A dose, HRCTV D90, B2cc, R2cc, and S2cc for those undergoing IC was 74 Gy (71−78), 80 Gy (73−84), 86 Gy (82−89), 70 Gy (65−74), 65 Gy (59−73) respectively. For the IC+IS cohort, HRCTV D90, B2cc, R2cc, and S2cc was 84 Gy (78−89 Gy), 89 Gy (86−92), 70 Gy (67−74), 68 Gy (59−76). At a median follow-up of 16 months (5−27) the 2-year local control, pelvic control, cause specific and overall survival was 88%, 85.3%, 92.2%, and 81.3% respectively. Late gastrointestinal and genitourinary grade ≥III toxicities were 14% and 1.5% each.
Abbreviated BT outcomes are encouraging for oncological outcomes despite delays in overall treatment time and omission of chemotherapy. Further mature follow up is needed.
Image-guided adaptive brachytherapy for advanced cervical cancer spreading to the bladder and/or rectum: Clinical outcome and prognostic factors
2023, Gynecologic Oncology
Refinements of brachytherapy techniques have led to better local control of locally advanced cervical cancer (LACC), especially with the development of image-guided adaptive brachytherapy (IGABT). Data on the efficacy of brachytherapy in cervical cancer spreading to adjacent organs are scarce. We report the experience of our institution in the treatment of these advanced tumors with IGABT.
Medical records of patients treated for a LACC spreading to the bladder and/or rectum between 2006 and 2020 at Gustave Roussy Institute were analyzed. Dosimetric parameters were collected and converted into 2 Gy per fraction equivalent doses, including the minimal dose received by 90% of the high-risk target volume (D₉₀ CTV_HR) and intermediate-risk target volume (D₉₀ CTV_IR), as well as the dose received by the most exposed 2 cm³ of the organs at risk. A Cox regression model was used to study the potential associations between clinical and dosimetric factors with survival endpoints and fistula formation.
A total of 81 patients were identified. All patients received pelvic+/− para-aortic radiotherapy, 45 Gy in 25 fractions +/− boost to gross lymph nodes. Concomitant platinum-based chemotherapy was administered in 93.8% of cases. The median D₉₀ CTV_HR dose was 75.5 Gy_EQD2 (SD: 10.39 Gy_EQD2) and median CTV_HR volume was 47.6 cm³ (SD: 27.9 cm³). Median bladder and rectal D2_cm3 dose were 75.04 Gy_EQD2 (SD: 8.72 Gy_EQD2) and 64.07 Gy_EQD2 (SD: 6.68 Gy_EQD2). After a median follow-up of 27.62 ± 25.10 months, recurrence was found in 34/81 patients (42%). Metastatic failure was the most common pattern of relapse (n = 25). Use of a combined interstitial/intracavitary technique and D₉₀ CTV_HR ≥ 75.1 Gy_EQD2 were prognostic factors for OS in univariate analysis (HR = 0.24, 95%IC: 0.057–1, p = 0.023; HR = 0.2, 95%IC: 0.059–0.68, p = 0.0025, respectively). In multivariate analysis, a D₉₀ CTV_HR ≥ 75.1 Gy_EQD2 was significant for OS (HR = 0.23; 95%IC: 0.07, 0.78, p = 0.018). The occurrence of vesicovaginal fistula (VVF) was the most frequent pattern of local recurrence (HR = 4.6, 95%CI: 1.5–14, p = 0.01).
Advances in brachytherapy modalities improved local control and survival while reducing toxicities. Enhancing local control through dose escalation and combined intracavitary/interstitial brachytherapy techniques is a major factor in patients cure probability, together with systemic intensification to better control distant events.

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Cervical cancer brachytherapyImpact of treatment time and dose escalation on local control in locally advanced cervical cancer treated by chemoradiation and image-guided pulsed-dose rate adaptive brachytherapy

Abstract

Purpose

Materials/methods

Results

Conclusions

Section snippets

Patient selection

Treatment

Population

Discussion

Conclusions

Conflict of interest

Int J Radiat Oncol Biol Phys

Radiother Oncol

Radiother Oncol

Radiother Oncol

Radiother Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Cervical cancer brachytherapy
Impact of treatment time and dose escalation on local control in locally advanced cervical cancer treated by chemoradiation and image-guided pulsed-dose rate adaptive brachytherapy