Objective The use of chemoradiation in patients with stage IVB cancer of the cervix was evaluated to determine if definitive treatment offers benefit.
Methods A database of 546 patients with cancer of the cervix treated between January 2005 and May 2021 at a tertiary academic medical center was reviewed retrospectively to identify patients with stage IVB disease. Log rank test, regression analysis, and the Kaplan–Meier method were used to identify and compare variables and estimate progression free survival and overall survival.
Results Thirty-three patients with stage IVB cervical cancer were identified. Median age was 53 years (range 28–78). Pathology subtypes were squamous cell (n=22, 67%), adenocarcinoma (n=8, 24%), and clear cell (n=3, 9%). Metastases were classified as lymphatic (n=14, 42%) or hematogenous (n=19, 58%). Following treatment to all sites with chemoradiotherapy and selected use of surgery (n=23), six patients (26%, lymphatic n=4, hematogenous n=2) remained disease free for a median duration of 4 years (range 3–17 years). Recurrences in the remaining patients were distant (n=13) or local (n=4). All patients in the chemotherapy group (n=10, 100%) progressed. Kaplan–Meier analysis showed that median progression free survival was longer for patients treated at all disease sites than for patients treated with chemotherapy alone (19 vs 11 months, p=0.01). However, this was not the case for overall survival (49 vs 33 months, p=0.15). Patients with metastases limited to lymph nodes also had longer median progression free survival (22 vs 11 months, p=0.04) but not overall survival (p=0.68).
Conclusions Patients with stage IVB cancer of the cervix may benefit from treatment to all sites of disease, if feasible and safe, as demonstrated by improved progression free survival.
- cervical cancer
- neoplasm metastasis
Data availability statement
Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, an indication of whether changes were made, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Clinical presentation of patients with stage IVB cancer of the cervix is heterogenous and includes patients with sites of disease limited to an isolated inguinal or supradiaphragmatic lymph node to widespread hematogenous dissemination.
Treatment guidelines suggest the use of systemic chemotherapy and an individualized approach to use of radiation and surgery but provide little specification for which patients may benefit from comprehensive treatment.
This retrospective review was done to better identify patients with stage IVB disease who may benefit from definitive therapy.
WHAT THIS STUDY ADDS
This retrospective analysis suggests that for patients with lymphatic or oligometastatic disease, treatment of all disease sites with definitive chemoradiotherapy or surgery to the pelvis and selected use of radiotherapy or surgery for metastases improves progression free survival compared with patients treated with palliative chemotherapy alone.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Our study warrants further investigation to evaluate current staging systems.
Guidelines should be reviewed to better identify patients with stage IVB cervical cancer who may benefit from definitive rather than palliative therapy.
The prognosis of patients with stage IVB cancer of the cervix varies depending on the extent and pattern of disease dissemination. Providing local control in the pelvis is an important palliative goal despite the risks of treatment toxicity because of significant morbidity from uncontrolled tumor. Some patients may derive a survival benefit from definitive treatment to the pelvis and metastatic sites.1 Management guidelines from the National Comprehensive Cancer Network2 and the European Society of Medical Oncology3 recommend use of radiation therapy based on individualized considerations, such as pattern and extent of disease spread or performance status, without providing guidance for selecting patients for definitive therapy.3 4
Since criteria for offering definitive therapy are undefined, investigations to identify who may benefit from local treatment are warranted. We compared outcomes in patients treated with palliative intent using chemotherapy alone or with definitive intent using chemoradiotherapy to the pelvis and radiotherapy or surgery to metastatic sites. Study endpoints included treatment toxicity, progression free survival, overall survival and local control.
A retrospective observational study was conducted using a cervical cancer database of patients treated consecutively at Sheba Cancer Center between January 2005 and May 2021. Eligible participants were aged ≥18 years and had biopsy confirmed stage IVB cervical cancer according to the International Federation of Gynecology and Obstetrics (FIGO) criteria (2018).5 Exclusion criteria were small cell histology and follow-up <90 days. Table 1 shows the clinical and pathological variables collected from medical records. Programmed death ligand 1 was considered positive if the combined positive score was ≥1. The European Society of Therapeutic Radiation Oncology (ESTRO) and the American Society of Therapeutic Radiation Oncology (ASTRO) consensus definitions of oligometastatic disease (≤5 lesions) and polymetastatic disease (>5 lesions) were used.6 Patients with both lymphatic and hematogenous spread were considered in the hematogenous group.
Treatment parameters collected were use of systemic treatments, radiotherapy, and surgery. Treatment decisions were based on multidisciplinary tumor board review. Patients unfit for chemoradiotherapy were offered chemotherapy alone. Bevacizumab was added according to the Moore criteria.7 Immunotherapy was offered starting in 2019. Radiotherapy and high dose rate brachytherapy were given according to EMBRACE II (Image Guided Intensity Modulated External Beam Radiochemotherapy and MRI Based Adaptive BRAchytherapy in Locally Advanced CErvical Cancer) contouring recommendations8 and ESTRO guidelines.9 Metastatic sites were treated concurrently with pelvic radiotherapy by modifying or adding additional radiotherapy fields. Radiotherapy doses were converted to biological equivalent dose using an alpha/beta ratio of 10.10 In selected cases, the primary tumor or metastatic lesions were resected.
Follow-Up and Clinical Outcome
Follow-up examinations and imaging studies with computed tomography (CT) or fluorodeoxyglucose positron emission tomography were done at 3–6 month intervals during the initial 2 years post-treatment or as indicated. First recurrence was recorded as local, regional, or distant. Toxicity was assessed according to Common Terminology Criteria for Adverse Events V.5.11
Patients were divided into two groups for comparison of outcomes: chemotherapy group that received palliative chemotherapy alone and chemoradiotherapy group that received definitive treatment to all disease sites. Descriptive statistics, including proportions, means, medians, and standard deviations, were used to assess patient and treatment parameters. Duration of progression free survival and overall survival were calculated from date of diagnosis until progression, death, or were censured at the last evaluation. Time to event data were analyzed using the Kaplan–Meier method. The log rank test was used to compare outcomes between treatment groups. A significance threshold for p values was set at 0.05. Cox univariate and multivariate analyses were used to predict the hazard ratio (HR) for patient, disease, and treatment variables associated with progression free survival and overall survival. Multivariate analysis models included variables with a p value <0.2 in the univariate analysis. Variables correlating (p≤0.05) with progression free survival or overall survival were excluded from the multivariate analysis. Computed values reported include 1 year, 2 year, and median progression free survival and overall survival, HRs, 95% confidence intervals (CI) and p values. All analyses were performed using IBM SPSS 25.0 software (SPSS, Chicago, Illinois, USA).
Review of the cervical cancer database (n=546) identified 35 patients with stage IVB disease (online supplemental Figure 2). Patients were excluded due to small cell histology (n=1) and follow-up <90 days (n=1). Patient characteristics are shown in Table 1. Performance status in most patients was 0 when beginning treatment (70%). Comorbidities were present in almost half of patients (48%). Post-coital or post-menopausal bleeding (73%) was the most common symptom at diagnosis. Most patients had oligometastatic disease (n=25). The number of lesions per patient were: one (n=8), two (n=8), three (n=7), four (n=1), five (n=1), and >5 (n=8). Oligometastatic disease was more common in the chemoradiotherapy group (n=22/23) than in the chemotherapy group (n=3/10, p<0.001). Sites of lymph node metastases (n=14) were inguinal (n=5) or supradiaphragmatic (n=9), which included supraclavicular (n=3), axillary (n=3), and mediastinal (n=3) locations. Sites of hematogenic metastases (n=19) included bone (n=5), ovary (n=3), visceral organs (n=6), brain (n=4), and peritoneum (n=7).
Patients available for analysis (n=33) were treated with either chemotherapy (n=10, 30%) or chemoradiotherapy (n=23, 70%).
Chemotherapy regimens used are summarized in online supplemental Table 1. All patients received singlet or doublet platinum based chemotherapy. Some patients in the chemoradiotherapy group received neoadjuvant chemotherapy (n=6) for three cycles (range 2–6) with or without bevacizumab (n=3) or adjuvant chemotherapy (n=5) for two cycles. One of eight patients with polymetastatic disease had a good response to chemotherapy and then received chemoradiotherapy. One patient received pembrolizumab in a first line setting and 14 patients (chemotherapy=7, chemoradiotherapy=7) received immunotherapy in second and advanced line settings.
All patients were treated with definitive intent. Median time from diagnosis to starting radiotherapy was 1 month (range 1–4.25 months). The pelvis (n=27) and, when involved, the para-aortic lymph nodes (n=13) were treated with 45 Gy (biological equivalent dose=53.1 Gy). Enlarged or metabolically active pelvic lymph nodes (n=20) and para-aortic lymph nodes (n=13) were boosted to 55 Gy (biological equivalent dose=67.1 Gy) using a simultaneous integrated boost. The parametrium was given a supplementary dose to bring the pelvic sidewall dose to 50.4–54 Gy (biological equivalent dose=61.5–66 Gy). High dose rate brachytherapy was given twice weekly. Dose to the high risk clinical tumor volume was 27.5 Gy (biological equivalent dose=42.6 Gy). The median number of brachytherapy fractions was 5 (range 3–5). Brachytherapy was deferred (n=3) in patients who underwent surgery following neoadjuvant chemotherapy.
Six patients underwent radical hysterectomy (n=4) or pelvic exenteration (n=2) before chemoradiotherapy (n=3) or after chemoradiotherapy (n=3).
Treatment of Metastatic Sites
Most patients with lymph node metastases (n=14) were treated with definitive (n=10) rather than palliative intent (n=4). Inguinal lymph nodes (n=5) were treated with chemoradiotherapy to 55 Gy (biological equivalent dose=67.1 Gy) with two patients (40%) remaining disease free at 37 and 57 months post-treatment. Supraclavicular lymph nodes (n=3) were treated with chemoradiotherapy (n=2) to 45 Gy (biological equivalent dose=58.5 Gy) and 54 Gy (biological equivalent dose=63.7 Gy), respectively, or with lymphadenectomy (n=1). Both patients treated with radiotherapy recurred (20 months and 42 months). The patient who underwent lymphadenectomy remains disease free 17 years post-treatment.
Mediastinal lymph nodes (n=3) were treated with chemoradiotherapy (n=1, 60 Gy, biological equivalent dose=72 Gy) or chemotherapy (n=2). Although progression free survival was longer (21 months vs 7.5 months) in the patient treated with chemoradiotherapy, overall survival was shorter (24 months vs 30 months) because this patient died soon after recurrence, while the other two patients received immunotherapy within a clinical trial. Axillary lymph nodes (n=3) were treated surgically with axillary lymph node dissection (n=1) or chemotherapy only (n=2). The patient who underwent axillary lymph node dissection remains disease free 6 years post-treatment.
Patients with hematogenous metastases (n=19) were treated using palliative chemotherapy (n=6) or with chemoradiotherapy to the pelvis (n=13) plus stereotactic body radiation therapy (n=5), hypofractionated radiotherapy (n=5), or surgical resection (n=3) to the metastases. Single site oligometastatic disease (n=6) was treated with oophorectomy (n=2), pulmonary segmentectomy (n=1), or radiotherapy to the peritoneum (57.5 Gy, biological equivalent dose=70.7 Gy), the abdominal wall (52.5 Gy, biological equivalent dose=63.5 Gy), or a pelvic bone (stereotactic body radiation therapy, 30 Gy, biological equivalent dose=48 Gy). Two patients remain disease free >3 years post-treatment.
Response to Therapy
Following chemotherapy, responses were: complete response (n=2, 20%), partial response (n=6, 60%), or progressive disease (n=2, 20%). Following chemoradiotherapy, responses were: complete response (n=12, 52%), partial response (n=3, 13%), or progressive disease (n=8, 35%).
Median duration of follow-up was 45 months (range 32–not reached). Following treatment, six patients remain alive and disease free for a median duration of 4 years (range 3–17). Four patients had lymph node metastases (inguinal n=2, supraclavicular n=1, and axillary n=1) and two had hematogenous metastases (peritoneum and abdominal wall). All patients in the palliative chemotherapy group recurred. Deaths were more common in the chemoradiotherapy group (8/10) than in the chemoradiotherapy group (11/23). Recurrences following chemoradiotherapy were distant (n=13) or within the radiation field (n=4). Univariate analysis showed that the use of neoadjuvant (n=6) or adjuvant chemotherapy (n=5) had no effect on duration of progression free survival or overall survival (Table 2).
Table 2 shows that progression free survival on univariate analysis was associated with programmed death ligand 1 status <1% (p=0.0018), pattern of metastasis (p=0.049), treatment to all sites (p=0.019), and tumor response (partial response, p=0.0006 and complete response, p=0.003). Overall survival on univariate analysis was associated with tumor response (partial response, p=0.034 and complete response, p=0.0001). Kaplan–Meier estimates of median progression free survival and overall survival for the cohort (n=33) were 17 months (95% CI 11 to 24) and 45 months (95% CI 32 to not reached), respectively. Figure 1A shows that median progression free survival was longer for patients treated with chemoradiotherapy than chemotherapy (19 months, 95% CI 14 to not reached vs 11.5 months, 95% CI 6 to not reached, p=0.016). Figure 1B shows that median progression free survival was longer in patients with lymphatic versus hematogenous spread (22 months, 95% CI 19 to not reached vs 11 months, 95% CI 10 to 22, p=0.044). Figure 2A shows that there was no difference in median overall survival in patients treated with chemoradiotherapy or chemotherapy (49 months, 95% CI 40 to not reached, vs 33 months, 95% CI 20 to not reached, p=0.15). Figure 2B shows that the difference in median overall survival for lymphatic versus hematogenous spread was not significant (51 months, 95% CI 29 to not reached vs 45 months, 95% CI 20 to not reached, p=0.68).
Table 3 lists the toxicities associated with chemoradiotherapy and chemotherapy. Two patients developed fistulae (vesicovaginal and vesicorectovaginal) treated with bilateral nephrostomies (n=2) and diverting colostomy (n=1). The fistulae in both patients were attributed to progression of pelvic disease rather than chemoradiotherapy, although chemoradiotherapy could not be excluded as a cause. Other grade 3 late toxicities were fatigue and pelvic pain (n=3) and gastrointestinal (n=3), genitourinary (n=1), or gynecological symptoms (n=1).
Summary of Main Results
This retrospective analysis suggests that some patients treated with definitive intent using chemoradiotherapy or surgery to the pelvis and selected use of radiotherapy and surgery for metastatic lesions may remain disease free for extended periods and even achieve long term survival compared with patients treated with palliative chemotherapy alone. In this series, long term survivors were treated with definitive intent and had either lymphatic only metastases or hematogenous spread with an oligometastatic lesion involving a single site.
Results in the Context of Published Literature
Our findings are consistent with other studies comparing outcomes for patients with stage IVB disease treated with chemoradiotherapy with chemotherapy alone (online supplemental Table 2). Kim et al and Perkins et al showed that the use of chemoradiotherapy versus chemotherapy alone was associated with longer progression free survival (40.5 vs 7.8 months, p<0.01) and overall survival (63.7 vs 18.4 months, p<0.01),12 and progression free survival (13 vs 5.9 months, p=0.0006) and overall survival (41.6 vs 17.6 months, p=0.0005),13 respectively. Two sequential reports using the National Cancer Database showed that treatment with chemoradiotherapy or surgery was associated with longer median overall survival than treatment with chemotherapy only (19.2 vs 10.1 months, p<0.001,14 and 14.4 vs 10.6 months, p<0.001,15 respectively). Several other single institution studies as well as two recent SEER (Surveillance, Epidemiology, and End Results) database studies also showed a survival benefit with the addition of pelvic radiotherapy to chemotherapy.13 16–18
Our results are consistent with reports showing that patients with lymphatic metastases alone have better outcomes than patients with hematogenous dissemination.19–21 Inguinal lymph node involvement was treated with curative intent to 55 Gy (biological equivalent dose=67.1 Gy), with 2/5 patients (40%) remaining disease free for 37 and 56 months, consistent with other reports describing long term survival.19 22 23 In contrast, only 2/9 patients (22%) with supradiaphragmatic lymph nodes achieved long term survival. While these results are consistent with the 5 year overall survival rate of 16.5% for patients with supraclavicular lymph node metastasis reported by Qiu et al,24 other investigators reported better outcomes with higher radiotherapy doses. Kim et al reported a median overall survival of 32 months25 in patients receiving a mean dose of 59.4 Gy to the para-aortic lymph nodes and supraclavicular lymph nodes compared with 7.5 months when 50% of patients received chemotherapy alone.26 Lee et al reported 5 year overall survival and progression free survival of 55.6% and 44.4%, respectively, in patients who received a median radiotherapy dose of 66.6 Gy (range 60–75.6)27 to supraclavicular lymph nodes. The unfavorable outcomes for patients with supradiaphragmatic lymphatic involvement in our cohort may be due to a less aggressive treatment approach using palliative chemotherapy alone or low radiotherapy doses. We adjusted treatment protocols to deliver >60 Gy to supradiaphragmatic lymph node metastasis.
Although the prognosis for patients with hematogenous metastasis is poor, with a 5.3-fold higher risk of death than lymphatic metastasis,28 when disease involves only a single site, we found that long term survival may be possible. Our results are consistent with other series showing long term disease free survival in patients with oligometastatic disease treated at metastatic sites using stereotactic body radiation therapy or surgery.29 30 An international effort (ESTRO-ASTRO consensus) is in progress to better define oligometastatic disease that may benefit from an intensified treatment approach.6
The late effects of chemoradiotherapy include incidence of rectovaginal or vesicovaginal fistulae in 1–2% as well as gastrointestinal, urological, female genital, skeletal, and vascular toxicities, secondary malignancies, and quality of life issues31 In our study, a higher fistula formation rate was found (2/33, 6%), probably due to the small sample size and advanced pelvic disease at diagnosis. The addition of bevacizumab to pelvic radiotherapy in patients with cervical cancer has been associated with an increased risk of fistula formation.32 In our study, fistula formation was not associated with bevacizumab treatment.
Strengths and Weaknesses
We collected and reviewed comprehensive clinical and pathological information, detailed treatment plans, and long term outcomes in patients treated with modern radiotherapy techniques. In comparison, large database studies, such as SEER or the National Cancer database, often provide insufficient information for analysis of treatment details that may influence outcomes. For example, detailed review of dosimetric data enabled us to identify a subgroup of patients (lymphatic spread to the thorax) that had a higher than expected rate of failure, possibly due to omission of radiotherapy or treatment with a sub-therapeutic radiotherapy dose.
The small cohort size limits the statistical power of the results. For example, conclusions on how treatment with bevacizumab or immunotherapy affected progression free survival or overall survival could not be reached due to the small numbers. Selection biases, inherent to retrospective studies, may result in patients with good performance status or favorable prognostic variables receiving more aggressive treatments. This was apparent in our study where patients with more advanced and perhaps more biologically aggressive disease were predominantly in the chemotherapy group rather than in the chemoradiotherapy group. In consideration of the multiple analyses performed in this limited cohort, caution must be undertaken when interpreting results specifically considering selection bias for patients with favorable clinical parameters who received chemoradiotherapy rather than chemotherapy. Information bias from incomplete record entries may have led to underestimation of treatment toxicities.
Implications for Practice and Future Research
Patients with stage IVB cervical cancer treated with chemoradiotherapy and selected use of surgery had longer progression free survival and trended towards longer overall survival compared with patients treated with chemotherapy alone.
Patients with stage IVB cancer of the cervix who receive treatment to all sites of disease may have improved progression free survival compared with patients treated with palliative chemotherapy alone. Patients presenting with lymph node metastasis or oligometastatic disease and treated with definitive intent may have an opportunity for long term survival with a limited risk of toxicity.
Data availability statement
Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.
Patient consent for publication
The institutional ethics committee approved the study (identifier SMC-5899–19).
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Contributors SPH analyzed the data and drafted and revised the paper. JG monitored the data collection for the whole trial, analyzed the data, and drafted and revised the paper. AS designed the data collection tools, monitored data collection for the whole trial, wrote the statistical analysis plan, cleaned and analysed the data, and drafted and revised the paper. AS accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish. All other authors revised the draft paper.
Funding SPH received financial support from the Parasol Foundation.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.