Objective The objective of this systematic review was to assess the oncologic outcomes of patients with International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IVB cervical cancer receiving definitive pelvic radiotherapy compared with systemic chemotherapy (with or without palliative pelvic radiotherapy).
Methods This study was registered in PROSPERO (registration number CRD42022333433). A systematic literature review was conducted following the MOOSE checklist. MEDLINE (through Ovid), Embase, and Cochrane Central Register of Controlled Trials were searched from inception until August 2022. The inclusion criteria were patients with metastatic FIGO 2018 stage IVB cervical cancer, a histologic subtype of squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma that received definitive pelvic radiotherapy (≥45 Gy) as part of management compared with systemic chemotherapy with or without palliative (30 Gy) pelvic radiotherapy. Randomized controlled trials and observational studies with two arms of comparison were considered.
Results The search identified 4653 articles; 26 studies were considered potentially eligible after removing duplicates, and 8 met the selection criteria. In total, 2424 patients were included. There were 1357 and 1067 patients in the definitive radiotherapy and chemotherapy groups, respectively. All included studies were retrospective cohort studies, and two were database population studies. The median overall survival reported in seven studies for the definitive radiotherapy arm versus systemic chemotherapy groups were 63.7 months versus 18.4 months (p<0.01), 14 months versus 16 months (p value not reported), 17.6 months versus 10.6 months (p<0.01), 32 months versus 24 months (p<0.01), 17.3 months versus 10 months (p<0.01), and 41.6 months versus 17.6 months (p<0.01), and not reached versus 19 months (p=0.13) respectively, favoring the groups that received definitive pelvic radiotherapy. The high clinical heterogeneity precluded the performance of meta-analysis, and all studies were at serious risk of bias.
Conclusions Definitive pelvic radiotherapy as part of treatment in patients with stage IVB cervical cancer may improve oncologic outcomes compared with systemic chemotherapy (with or without palliative radiotherapy); however, this is based on low-quality data. Prospective evaluation would be ideal before the adoption of this intervention in standard clinical practice.
- Cervical Cancer
Data availability statement
Data are available upon reasonable request.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
According to guidelines, patients with stage IVB cervical cancer, particularly those with oligometastatic disease, may receive pelvic locoregional therapy (surgery or pelvic radiotherapy). However, in such patients most evidence on the benefit of definitive (or therapeutic) radiotherapy is limited to single-arm retrospective studies.
WHAT THIS STUDY ADDS
Based on eight retrospective studies, including more than 2000 patients, the use of pelvic radiotherapy with definitive (≥45 Gy) doses may positively impact the oncologic outcomes of patients with stage IVB cervical cancer.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Given that evidence to support use of definitive pelvic radiotherapy in patients with stage IVB cervical cancer is at serious risk of bias, even when it is an option in clinical practice guidelines, this intervention should be assessed in randomized controlled trials before its general implementation.
Cervical cancer is the fourth most common malignancy in women worldwide. According to GLOBOCAN 2020, 604 127 new cases and 341 831 deaths were estimated that year.1 Patients with International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IVB represent a heterogenous group of patients (distant metastasis including but not limited to peritoneal spread or involvement of the supraclavicular, mediastinal, inguinal, or distant lymph nodes; lung; liver; or bone) that receive similar treatments.2 The approach for patients diagnosed with stage IVB cervical cancer is based on palliative systemic chemotherapy, with or without tailored local treatment (including external beam radiotherapy and, in some instances, surgery).3 4 Radiotherapy is a fundamental part of treatment for non-metastatic locally advanced cervical cancer and is associated with a high rate of local and regional control.5 6 In the context of stage IVB disease, the addition of definitive pelvic radiotherapy, considering its effectiveness for local control of the disease and the use of systemic therapy, could improve oncologic outcomes.
Some retrospective studies7 8 have shown a high locoregional disease control in patients treated with definitive doses of pelvic radiotherapy as part of management in this population. However, direct comparisons are scarce, and evidence regarding indications, doses, and follow-up is limited. The objective of this systematic review was to assess the oncologic outcomes (progression-free survival and overall survival) of definitive pelvic radiotherapy as part of treatment in patients with stage IVB cervical cancer compared with systemic chemotherapy (with or without palliative doses of pelvic radiotherapy).
A systematic literature review was conducted following the MOOSE checklist. This study was registered in PROSPERO (CRD42022333433). MEDLINE (through Ovid), Embase, and Cochrane Central Register of Controlled Trials databases were searched from inception until August 2022. The overall search strategy is included in Online supplemental file 1. We included articles published in the English language reporting randomized controlled trials and observational studies with two arms of intervention comparing the use of definitive doses of pelvic radiotherapy (≥45 Gy) in conjunction with systemic therapy versus systemic chemotherapy (with or without palliative doses of pelvic radiotherapy). Here on forward in the article, the latter group is referred to as the ‘chemotherapy group’. Single-arm studies, case reports, abstracts, unpublished studies, and commentaries were excluded.
Studies including patients with confirmed metastatic cervical cancer FIGO 2018 stage IVB were considered. Histologic subtypes of squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma (at least 90% of included patients in each trial) were allowed. Criteria for excluding studies for this review were patients under 18 years of age, pregnancy, previous pelvic radiotherapy or chemoradiotherapy, and previous surgical management for cervical or synchronous cancer. Only the most complete article was included in the review if two or more articles were published by the same author/institution or using the same primary data source. The measured outcomes were overall survival (as defined by trial authors), progression-free survival (as defined by trial authors), and toxicity (as reported by trial authors).
Two authors (SV-S, DV-C) independently assessed all titles and abstracts of records retrieved from the search strategy for inclusion. The final selection of trials for inclusion was undertaken independently by three authors (RP, N-MS, DV-C), and any disagreement was resolved through discussion. We designed a form to extract data, which was pilot tested. Two authors (SV-S, DV-C) extracted the data independently using the form for eligible studies. Any disagreement about extracted data was resolved through discussion until a consensus was reached. As all included studies were observational studies, the risk of bias was assessed using the ROBINS-I tool according to our protocol. Seven domains were evaluated with this tool. Bias due to confounding, bias due to selection of participants, bias in classification of interventions, bias due to deviations from intended interventions, bias due to missing data, bias in measurement of outcomes, and bias in selection of the reported result. Judgements for each bias domain, and for overall risk of bias, could be ‘Low’, ‘Moderate’, ‘Serious’, or ‘Critical’ risk of bias.9
The information was presented in the median or mean (according to its normal distribution) and percentages with absolute counts, if it was a quantitative or qualitative variable, respectively. The descriptive statistics were performed in SPSS 20. According to local regulations, no institutional review board agreement was required for this study. Ethical approval was not required as only data from previously published studies were retrieved and analyzed. No new data are presented. In accordance with the Journal’s guidelines, we will provide our data for independent analysis by a team selected by the Editorial Team for the purposes of additional data analysis or for the reproducibility of this study in other centers if such is requested.
The search identified 4653 articles; after duplicates were removed, 3315 articles were evaluated, and the title and abstract screening of these references identified 26 studies as potentially eligible for this review. The full-text screening excluded 18 studies. Nine studies were excluded because they were single-arm studies,7 8 10–16 five because they did not include the comparison of interest, three because they included the same database population from another included study, one because it did not include the correct study population, and eight studies finally met the selection criteria (Figure 1 and Online supplemental file 2).
In total, 2424 patients were included in the eight studies. In the definitive radiotherapy group there were 1357 patients, and in the chemotherapy group there were 1067 patients. All were retrospective cohort studies, and two were database population studies.17 18 All included studies were at serious risk of bias according to ROBINS-I evaluation (Online supplemental file 3). Recruitment periods ranged from 1994 to 2017. All included studies had a group of patients that received definitive doses of pelvic radiotherapy for locoregional control compared with a group of patients that received systemic chemotherapy with or without palliative doses of pelvic radiotherapy. Most studies17 19–23 reported the median age for each group of patients, and this ranged from 44.8 years and up to 55 years. Details of included studies are provided in Table 1.
Information regarding histologic subtypes for each intervention group was available for five studies,17 21–24 and a total of 1052 patients. This information was not available for one of the database studies,18 and in two studies it was presented for the whole cohort and not individually for each intervention group.19 20 In the 815 patients of the radiotherapy group, 641 patients had a squamous cell carcinoma (78.7%), 139 an adenocarcinoma (17.1%), 33 adenosquamous carcinoma (4%), and two patients had another unspecified type of tumor. Of the 239 patients in the chemotherapy group, 182 patients had a squamous cell carcinoma (76.1%), 35 an adenocarcinoma (14.6%), 13 adenosquamous carcinoma (5.4%), and nine patients had another unspecified type of tumor (3.8%).
Information about radiotherapy techniques was limited for all reports. Five studies,18 19 21 23 24 including 1361 patients, provided information about the radiotherapy doses that were administered. All studies used external beam radiotherapy with definitive doses (≥45 Gy), and in at least four studies18 19 21 24 some patients received additional brachytherapy. One study22 reported the comparison of whole pelvic radiotherapy and chemotherapy, and we included that population as part of the definitive radiotherapy group, and the systemic chemotherapy with or without palliative radiotherapy population as part of the systemic chemotherapy group. One study20 reported the use of external beam radiotherapy and brachytherapy, and a high radiotherapy dose (≥45 Gy) was assumed for the radiotherapy population.
Chemotherapy regimens varied among studies, and details were available for only six studies,19–24 including 329 patients. All patients received platinum-based regimens (including cisplatin, carboplatin, oxaliplatin, and nedaplatin), although doses and schemas varied for all studies. Some patients received combinations with taxanes, but some patients received platinum-alone schemas. Three studies20 22 23 reported the use of bevacizumab in combination with platinum-based chemotherapy. Four studies20 21 23 24 reported the number of chemotherapy cycles; however, they were not consistent with a range from 1 to 23 cycles. Follow-up time and schemas varied for all studies. Six studies18 19 21 22 24 reported the median follow-up time, which ranged from 9 to 20.3 months. Details regarding treatment and follow-up of studies included in the systematic review are provided in Online supplemental file 4.
The progression-free survival was reported in five studies.20–24 All studies described the median progression-free survival, but not all provided the IQR. The reported median progression-free survival for the definitive radiotherapy groups versus systemic chemotherapy groups were 40.5 versus 7.8 months (p<0.01),24 24 versus 12 months (p<0.01),20 9.4 versus 4.1 months (p=0.015),21 13 versus 5.9 months (p<0.01),22 and 12 versus 5.2 months (p=0.62),23 respectively, favoring the groups that received definitive radiotherapy. Details are provided in Table 2.
The overall survival was reported in all but one study.17 As for progression-free survival, all studies reported the median overall survival, but not all provided an IQR. The reported median overall survival for the definitive radiotherapy groups compared with the systemic chemotherapy groups were 63.7 versus 18.4 months (p<0.01),24 14 versus 16 months (p value not reported),19 17.6 versus 10.6 months (p<0.01),18 32 months versus 24 months (p<0.01),20 17.3 versus 10 months (p<0.01),21 and 41.6 versus 17.6 months (p<0.01),22 not reached versus 19 months (p=0.13),23 respectively, favoring the groups that received definitive radiotherapy. One study17 reported cause-specific survival. The 3-year cause-specific survival rate was 32.4% in the definitive pelvic radiotherapy group and 14.4% in the chemotherapy group (p<0.001) (Table 2).
Given the high clinical heterogeneity, including relevant differences in the recruitment periods, radiotherapy techniques (external beam radiotherapy technique and inclusion of brachytherapy), radiotherapy doses, chemotherapy regimens (including schemas, doses, and use of anti-angiogenic agents), follow-up schemas, recurrence diagnosis, and reported oncologic outcomes it was considered that carrying out a meta-analysis was not methodologically correct.
Toxicity was reported only in three studies.22–24 In one study,24 including 24 patients, the reported grade 3 or 4 leukopenia was more common in patients treated with concomitant chemoradiotherapy compared with systemic chemotherapy (24.4% vs 9.1%, p=0.03), whereas grade 3 or 4 neutropenia was more frequent in those treated with systemic chemotherapy compared with concomitant chemoradiotherapy (28.4% vs 11.1%, p=0.03). One patient (10%) who underwent brachytherapy and previous external beam radiotherapy developed grade 3 proctitis, and no vesicovaginal fistula was reported in that study population. Another study22 showed that the most common morbidity was vaginal or rectal bleeding requiring hospitalization or transfusion, but it was not statistically different between groups (66.7% in the radiation group vs 58.0% in the chemotherapy group, p=0.43). Pelvic pain requiring hospitalization occurred in 45.2% of the chemoradiotherapy group compared with 30.4% of the chemotherapy alone group; however, this difference was not significant (p=0.19). The third study23 showed that the rate of toxicities was not statistically different between groups.
Summary of Main Results
Based on low-quality evidence, the use of definitive pelvic radiotherapy in patients with stage IVB cervical cancer was associated with better oncologic outcomes such as progression-free survival, cause-specific survival, and overall survival. High clinical heterogeneity precluded performing a meta-analysis, and all studies were at serious risk of bias.
Results in the Context of Published Literature
Patients with metastatic or advanced cervical cancer have a wide variety of therapeutic options, including systemic chemotherapy (with or without anti-angiogenic treatments), radiotherapy, immunotherapy, and even surgery according to local tumor volume and the characteristics of metastatic disease.4 However, most patients receive treatment with palliative intention. The main treatment modality for patients with stage IVB disease is systemic chemotherapy, but it has low durable response even when systemic treatment could influence systemic and also local control of the disease.25 26 With the addition of bevacizumab or immunotherapy there are only modest improvements and most patients will die due to disease with median overall survival shorter than 24 months.2 Evidence for anti-angiogenic therapy, immune therapy, and chemotherapy schemas are based on previously published randomized controlled trials,27–29 but the use of radiotherapy in definitive doses has not been assessed in randomized controlled trials, and the evidence is based on retrospective studies.
Radiotherapy is associated with an improvement in locoregional control in adjuvant treatment for intermediate-risk30 and high-risk31 disease. In patients with locally advanced disease, concomitant chemoradiotherapy is associated with high cure and locoregional control rates,6 32 and its use in metastatic disease could be associated with better locoregional control of disease and improved oncologic outcomes.
In a survey conducted by the EMBRACE research network,33 including 22 centers for patients presenting with de novo oligometastatic disease, 100% of the respondents considered the use of pelvic radiation in addition to systemic therapy, and more than half of respondents (54.5%) stated that they would consider chemoradiation in patients who responded to systemic chemotherapy and would also consider using brachytherapy. Also, 22.7% considered the use of upfront chemoradiation followed by brachytherapy with subsequent systemic chemotherapy as the ideal primary treatment.
Several studies have previously reported the association of pelvic radiotherapy with high local disease control with definitive doses (≥45 Gy). In a retrospective cohort study including 50 patients11 with stage IVB cervical cancer including distant lymph nodal or visceral organ metastasis, the 5-year pelvic control rate was 85.8%, and this was higher in the group of patients with lymph node disease (87.4%) compared with visceral disease (74.7%) although not statistically significant. Unfortunately, with the available information in the studies of this systematic review, an analysis according to the disease location was not possible, and the differences among the characteristics of metastatic disease for each patient showing a wide range of progression-free survival and overall survival made comparisons difficult.
A retrospective cohort study13 of 23 patients with metastatic cervical cancer with an oligometastatic disease in the lungs reported that only 39.1% of patients completed pelvic radiotherapy without interruption, with a prescribed dose of 50.4 Gy, and the reported 1-year progression-free rate was 95.2%. Fourteen of the 23 patients received concomitant chemotherapy with weekly cisplatin (40 mg/m2) for a median of four cycles.
Of all included studies, only one19 reported similar overall survival for the chemoradiotherapy group and chemotherapy group. In this study, patients had variable metastatic lesions, including lung, bone, liver, vulva, and ovary, and received treatments according to the disease volume and patient characteristics. The median external beam radiotherapy dose was 50 Gy, and brachytherapy with a dose of 6–18 Gy in 1–3 fractions. Patients that received this schema did not receive combined systemic chemotherapy later, and some patients that received initial systemic chemotherapy also received pelvic radiotherapy with palliative (30 Gy) doses, which could impact the treatment effect. Progression-free survival was not reported, and the impact of pelvic radiotherapy in local disease control was not assessed in this population.
Strengths and Weaknesses
The main strength of our review is the rigorous methodology for data collection. We have a pre-registered protocol with a complete search strategy, specified selection criteria, and a rigorous predefined process for data analysis. Our review is limited for several reasons. The clinical heterogeneity of the studies must be highlighted as we included retrospective cohort studies and population database studies. Patients had different metastatic sites for stage IVB cervical cancer diagnosis (bone, lung, lymph node, liver, brain, among others). They received different treatments regarding the chemotherapy agents and the number of cycles, the use of anti-angiogenic agents, the techniques, and doses for radiotherapy (including the use of brachytherapy). The follow-up schemas and lengths differed among studies and could be considered relatively short, as some studies had fewer than 12 months of median follow-up. The retrospective nature of all studies, with potential selection and publication bias, must also be considered. We did not have complete information from most studies on adverse events and methods for disease progression or diagnosis of recurrence. There was no central imaging review or complete information about pre-treatment imaging studies. As we limited the search to published data in the English language, we could have missed some relevant references published in other languages; and as the studies were conducted over a long period, there could be performance bias.
Implications for Practice and Future Research
The use of definitive radiotherapy is an option in clinical practice guidelines in patients with cervical cancer stage IVB disease,4 but the quality of evidence is low as all studies had serious risk of bias. High-quality randomized controlled trials should be conducted before its general implementation in routine clinical practice for this patient population. There are still many gaps to be resolved regarding the use of pelvic radiotherapy in this context, and questions remain as to whether it is better to start with systemic chemotherapy or radiotherapy, or if it is better to receive concomitant chemotherapy with pelvic radiotherapy before the use of systemic chemotherapy. Similarly, when proceeding with this approach one needs to question what the minimum required dose is, the role of brachytherapy, and the impact of anti-angiogenic agents. In case of immunotherapy, there remain several aspects to be defined like the real interaction of radiotherapy and the immune system in this context, the identification of the best schemas to combine with immunotherapy, and how to improve the possible abscopal effect.
Definitive pelvic radiotherapy as a component of treatment in patients with stage IVB cervical cancer could be associated with an improvement in oncologic outcomes such as progression-free survival, cause-specific survival, and overall survival. There are many gaps regarding the best treatment schemas for patients with stage IVB cervical cancer. Prospective evaluation of definitive chemoradiotherapy along with systemic treatment is recommended before the clinical implementation of this intervention in this patient population.
Data availability statement
Data are available upon reasonable request.
Patient consent for publication
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Contributors DV-C: conceptualization, investigation, methodology, writing - original draft, writing - review and editing. Responsible for the overall content as the guarantor. SV-S: investigation, data curation, writing - review. CFG-A: methodology, formal analysis. JR: data curation, formal analysis, methodology, N-MS: writing - original draft, writing - review and editing. AJ: writing - review and editing. PTR: writing - review and editing, supervision. RP: conceptualization, methodology, formal analysis, writing - review and editing, supervision.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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