Objective The standard of care for early cervical cancer is radical hysterectomy; however, consideration of pre-operative brachytherapy has been explored. We report our experience using pre-operative brachytherapy plus Wertheim-type hysterectomy to treat early stage cervical cancer.
Methods This single-center study evaluated consecutive patients with histologically proven node-negative early stage cervical cancer (International Federation of Gynecology and Obstetrics 2009 stage IB1–IIB) that was treated using pre-operative brachytherapy and hysterectomy. Pre-brachytherapy staging was performed using magnetic resonance imaging (MRI) and pelvic lymph node assessment was performed using lymphadenectomy. The tumor and cervical tissues were treated using brachytherapy (total dose 60 Gy) followed by Wertheim-type hysterectomy. The study included patients from January 2000 to December 2013.
Results A total of 80 patients completed a median follow-up of 6.7 years (range 5.4–8.5). The surgical specimens revealed a pathological complete response for 61 patients (76%). Patients with incomplete responses generally had less than 1 cm residual tumor at the cervix, and only one patient had lymphovascular space involvement. The estimated 5-year rates were 88% for overall survival (95% CI 78% to 94%) and 82% for disease-free survival (95% CI 71% to 89%). Toxicities were generally mild-to-moderate, including 26 cases (33%) of grade 2 late toxicity and 10 cases (13%) of grade 3 late toxicity. Univariate analyses revealed that poor disease-free survival was associated with overweight status (≥25 kg/m2, HR 3.05, 95% CI 1.20 to 7.76, p=0.019) and MRI tumor size >3 cm (HR 3.05, 95% CI 1.23 to 7.51, p=0.016).
Conclusions Pre-operative brachytherapy followed by Wertheim-type hysterectomy may be safe and effective for early stage cervical cancer, although poorer outcomes were associated with overweight status and MRI tumor size >3 cm.
- early cervical cancer
- preoperative brachytherapy
- image-guided brachytherapy
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The pathological complete response rate after pre-operative brachytherapy was 76% of patients, with mild-to-moderate toxicities.
Poorer disease-free survival was associated with overweight status (>25 kg/m2) and MRI tumor size >3 cm.
Querleu B type hysterectomy is feasible after pre-operative brachytherapy.
Cervical cancer is the fourth leading cause of cancer among women.1 Surgical treatment is standard for smaller tumors with no lymph node involvement, while radiotherapy plus chemotherapy and image-guided brachytherapy is recommended for more advanced tumors.2–4 However, there remains controversy regarding the management of some early stage cases.2–5 The European guidelines suggest that pre-operative brachytherapy followed by hysterectomy is useful for patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB1 tumors (>2 cm), which could reduce local recurrence and the use of adjuvant radiation therapy and/or help tailor the surgical technique.2 However, the National Comprehensive Cancer Network guidelines only recommend primary surgery followed by radiotherapy, depending on the prognostic factors detected in the surgical specimen.4 Nevertheless, image-guided brachytherapy is effective for delivering high radiation doses to cervical cancer tumors while limiting the dose delivered to organs at risk, and available retrospective data suggest that pre-operative brachytherapy is a safe and effective treatment.6–11 Therefore, this study aimed to describe the experience at our academic center, where early stage cervical cancer is treated using pre-operative brachytherapy followed by Wertheim-type hysterectomy, and to determine which patients might benefit from this strategy.
This study complied with all applicable French laws and the Jardé law regarding bioethical research (18 November 2016). The study was approved by the institutional review board. All patients provided informed consent for data collection and analysis during the follow-up survey.
We reviewed consecutive patients treated using preoperative brachytherapy and radical hysterectomy for histologically proven early stage cervical cancer. Patients were included if they were >18 years old and had FIGO 2009 stage IB1–IIB tumors (<4 cm) and no nodal involvement. Staging was based on careful clinical examinations, pelvic magnetic resonance imaging (MRI), and positron emission tomography coupled with computed tomography (CT). The tumor size was defined as the maximal diameter from the MRI or clinical examinations, and the size of the surgical specimen was considered in cases with previous conization. Patients with no nodal involvement based on the imaging findings underwent pelvic lymphadenectomy for confirmation. The exclusion criteria were previous pelvic radiotherapy, pre-operative chemoradiotherapy, lymph node involvement or metastases discovered at the initial imaging assessment, lymph node involvement detected during the primary lymphadenectomy, no hysterectomy, or follow-up of <3 months after the hysterectomy. Eighty eligible patients were identified between January 2000 and December 2013.
Personalized vaginal molds were created to reflect the anatomy of the patients12 and brachytherapy was performed to deliver a dose of 60 Gy in 120 pulses (0.5 Gy/pulse) using a 192-iridium remote afterloading brachytherapy system (Nucletron, Elekta Company, Elekta AB, Stockholm, Sweden). The target volume was defined on the basis of the treatment technique. For two-dimensional treatments, the aim was to deliver 60 Gy at an isodose volume encompassing point A.13 For three-dimensional treatments, the CT and MRI findings were used to define the target volume as the gross tumor volume plus the whole cervical tissue and adequate margins.14 The dose prescription aimed to deliver at least 60 Gy to 90% of this volume. Dose constraints to organs at risk were defined as a <85 Gy dose delivered to 2 cm3 of the bladder and a <75 Gy dose delivered to 2 cm3 of the rectum and sigmoid colon.
Surgery was performed 6–8 weeks after the brachytherapy based on radical hysterectomy, which removes the uterus and the surrounding parametrial tissue, as well as bilateral salpingo-oophorectomy.
Patients were followed with clinical examinations every 4–6 months for 5 years in our institution, then annually by their gynecologist. MRI and/or pelvic tomodensitometry were performed at 5 years or in cases with suspected recurrence.
Data were retrospectively collected from the patients’ medical records. Only the first recurrence was considered for calculating the time from the hysterectomy to recurrence. Toxicities were assessed using the Common Terminology Criteria for Adverse Events (Version 4). Patients with no follow-up in the last 1 year were surveyed using a standardized telephone questionnaire to collect information regarding any recent event (see online supplementary information 1).
Categorical variables were expressed as number and percentage, while continuous variables were expressed as median (range) or mean (SD). Disease-free survival and overall survival were assessed using the Kaplan–Meier method. Outcomes were analyzed using the Cox model or the Fine and Gray model in case of competing events. Results were reported as hazard ratios with 95% CIs, and differences were considered statistically significant at p values <0.05. All statistical analyses were performed using Stata software (version 15).
Eighty patients were included in the study. Median age at diagnosis was 45 years (range 25–75). Twenty-eight patients (53%) were overweight or obese (body mass index ≥25 kg/m2). The majority of patients had a squamous cell carcinoma (64/80 patients, 80%) and a FIGO IB1 stage disease (72/80 patients, 90%). The patients’ characteristics are detailed in Table 1.
The pre-operative brachytherapy was delivered using two-dimensional planning (33 patients, 41%) or three-dimensional planning (47 patients, 59%). All patients underwent radical hysterectomy initially using the laparoscopic approach, although four patients (5%) required a laparotomy conversion. The median delay between the pre-operative brachytherapy and hysterectomy was 57 days (range 34–154). Two patients had a delay of >100 days, which was related to initial refusal in the first case. In the second case, the hysterectomy was deemed technically impossible at another center because the patient was still morbidly obese 6 weeks after the brachytherapy. No adjuvant radiotherapy or chemoradiotherapy was performed for the patients.
Histological response and outcomes
The surgical specimens revealed that 61 patients (76%) had a pathological complete response. Residual tumors (median size 0.5 cm, range 0.1–3.5) were generally located at the uterine cervix, with no invasion of the parametrial or vaginal tissues. During a median follow-up of 6.7 years (range 5.4–8.5), 16 patients (20%) had a recurrence (see online supplementary table 1), with the first recurrence sites being the pelvis (11 cases, 13.8%), metastatic recurrence (9 cases, 11.3%), or vaginal cuff (2 cases, 2.5%) (Figure 1). The cumulative incidence of local recurrence at 5 years was 1% (95% CI 0.1% to 6%), with a 5-year disease-free survival rate of 82% (95% CI 71% to 89%) and a 5-year overall survival rate of 88% (95% CI 78% to 94%) (Figure 2). The final follow-up revealed that 14 patients (17.5%) had died, which was related to metastatic disease (10 cases, 12.5%), lung cancer (1 case, 1.25%), acute leukemia (1 case, 1.25%), and unknown reasons (2 cases, 2.5%) (see online supplementary table 2 for survival outcomes).
Acute toxicities were generally mild-to-moderate. Three patients experienced urinary disorders after pre-operative brachytherapy (grade 1 or 2) and five patients experienced digestive toxicities (grade 2 or 3). Late toxicities were more frequent, including 10 cases (13%) of grade 3 toxicities and no grade 4 or 5 toxicities. The most frequent disorder was lymphedema (grade 1 or 2). The gynecological toxicities were generally grade 1 or 2, although three grade 3 cases were identified (3.8%, 2 cases of evisceration and 1 fistula needing surgical intervention). Urinary disorders occurred in 26 patients (33%), which were also generally grade 1 or 2. Digestive toxicities occurred in 23 patients (29%), which included four grade 3 cases (5%, 1 case of proctitis, 2 cases of rectal bleeding, and 1 case of stenosis).
Figure 3 shows the disease-free survival curves according to MRI tumor size and body mass index status. Relative to patients with a normal weight, overweight patients (≥25 kg/m2) had poorer 5-year disease-free survival (HR 3.05, 95% CI 1.20 to 7.76; p=0.019) relative to patients with smaller tumors; patients with a MRI tumor size of >3 cm also had poorer disease-free survival (HR 3.05, 95% CI 1.23 to 7.51, p=0.016). Poor disease-free survival was only marginally associated with a clinical tumor size of >3 cm (HR 2.65, 95% CI 0.99 to 7.08, p=0.052), and was not associated with initial lymphovascular space invasion status, stage II disease, pathological complete response status, or the use of CT or MRI for brachytherapy planning (Table 2). Poor disease-free survival was also not associated with late toxicities and clinical or dosimetric factors (see online supplementary table 3).
Surgical improvements have reduced the operative morbidity after cervical cancer treatment,15 although achieving local control remains a major concern for patients with early stage cervical cancer. There is no consensus regarding the use of brachytherapy before hysterectomy in this setting, as the American guidelines recommend upfront surgery and the European guidelines consider the possibility of pre-operative brachytherapy.2 4 Moreover, although surgery remains the cornerstone of treatment for early stage cervical cancer, radiation therapy is also effective. For example, a randomized prospective trial which compared surgery with radiotherapy alone for FIGO stage IB–IIA cervical cancer found no significant difference in the 5-year overall survival rates (83% vs 74%), and radiotherapy was associated with a lower rate of toxicity (12% vs 28% grade 2–3 toxicities).16 Thus, when surgery is not feasible, the guidelines recommend definitive radiation therapy followed by brachytherapy, and adjuvant radiotherapy or chemoradiation should be proposed.2–5
Pre-operative brachytherapy aims to avoid the combination of surgery and external beam radiotherapy, and our findings suggest that pre-operative brachytherapy is useful for tumor downstaging (pathological complete response of 76% and minimal residual disease in other cases). Moreover, none of our patients underwent post-operative radiotherapy or chemoradiation, which might help preserve their quality of life. Atlan et al analyzed the outcomes of 246 patients who underwent preoperative brachytherapy followed by hysterectomy and reported that post-operative radiotherapy was associated with a significantly higher 10-year rate of grade 3–4 late toxicities (22% vs 7%, p=0.0002).6 Landoni et al also reported that combining radiotherapy with surgery for early cervical cancer in patients with pathological risk factors for local recurrence increased the rate of late grade 2–3 morbidity from 16% in the radiotherapy arm to 29% in the surgery plus radiotherapy arm.16
In cases of FIGO stage I cervical cancer, open surgery is superior to minimally invasive surgery.17 Pre-operative brachytherapy might help to reduce surgical morbidity by allowing a more limited hysterectomy in select cases. Current practice involves type B hysterectomy based on Querleu and Morrow’s classification, which includes part of the parametrial tissue in the surgical specimen, where cervical cancer dissemination is frequently detected. However, performing more extensive hysterectomy can be a source of complications, especially urinary complications, because of the dissection of the ureters.18 Two randomized prospective trials have assessed the use of a less radical hysterectomy for early stage cervical cancer.19 20 The first trial compared Piver type I and III hysterectomy for FIGO stage IB1–IIA cervical cancer, and the second trial compared Piver type II and III hysterectomy for FIGO stage IB–IIA cervical cancer, which revealed roughly equivalent oncological outcomes (local recurrence, overall survival, and progression-free survival) with proportional or inferior late morbidity.
Only preliminary data are available for one randomized trial (185 patients with early stage cervical cancer who underwent high-dose rate pre-operative brachytherapy (2×8 Gy) followed by radical hysterectomy or surgery alone) which examined the role of preoperative brachytherapy in managing early cervical cancer.7 The preliminary results indicate a pathological complete response rate of 25.7% after pre-operative brachytherapy, with no residual disease in 11.2% of the patients who were treated using hysterectomy alone after previous conization (p=0.03). Furthermore, positive surgical margins were less common after pre-operative brachytherapy relative to cases without pre-operative brachytherapy (1.5% vs 11.4%, p=0.02), with no significant differences in local control or survival after 29 months. However, additional follow-up will be needed to elucidate the effects of pathological complete response on local control and overall survival. Moreover, the brachytherapy technique was unusual for pre-operative treatment, as high-dose brachytherapy is usually administered as a definitive treatment for patients with locally advanced cervical cancer following chemoradiation and there are no consistent data regarding its use for early stage cervical cancer.
Data from large retrospective studies also provide further support for the concept of pre-operative brachytherapy. Escande et al10 recently reviewed 182 patients with 'high-risk' stage IB1–IIA1 tumors (tumor size >2 cm and/or lymphovascular space invasion) and only identified three cases (1.6%) with local recurrence and 14 cases (7.7%) with any recurrence during a median follow-up of 5.3 years. Furthermore, pelvic nodal metastases after brachytherapy and tumor size ≥3 cm were associated with poor disease-free survival. Uzan et al9 also reviewed 162 patients with stage IB1 cervical cancer who underwent preoperative brachytherapy and hysterectomy, and only identified nine patients who experienced recurrence during a median follow-up of 39 months (range 3–118). The 5-year overall survival rate was 95% (95% CI 88.2% to 97.9%), although they failed to detect significant prognostic factors. Nevertheless, none of the cases with recurrence had a tumor size <2 cm, and the very small sample size and short follow-up might explain the lack of an association between tumor size and outcomes. Grigsby et al retrospectively evaluated 177 patients with early stage cervical cancer who underwent preoperative irradiation and surgery (stage IB in 141 cases and stage IIA in 36 cases) and found a 5-year progression-free survival rate of 16% for the stage IB cases.21
The present study revealed a relationship between tumor size and outcomes, as patients with a MRI tumor size of >3 cm had relatively poor disease-free survival and a lower 5-year disease-free survival rate (66%, 95% CI 41% to 82%). Tumor size is also a well-known prognostic factor for all stages of cervical cancer,22–24 and the optimal cut-off value has been defined as 3 cm for patients treated using the radiosurgical approach. Other studies have failed to detect significant relationships between tumor size and outcomes among patients treated using external beam radiotherapy plus brachytherapy or brachytherapy plus hysterectomy, although the high delivered doses (>60 Gy) and the non-systematic use of MRI at the diagnosis might explain these results.25 26 The present study only found a marginally significant relationship between a clinical tumor size of >3 cm and poor disease-free survival, which confirms the superiority of using MRI to determine cervical tumor size.27
Our patients underwent pelvic lymphadenectomy for pre-brachytherapy staging to tailor the patient’s definitive treatment, as lymph node metastasis is a major prognostic factor in early cervical cancer.28 Furthermore, imaging-based staging using MRI, CT, and/or positron emission tomography coupled with CT remains inferior to surgical assessment of lymph node status.29 The pelvic lymphadenectomy revealed micrometastasis in eight patients (10%), although we did not perform adjuvant treatment targeting the pelvis after brachytherapy and hysterectomy because of its unclear effects on patient outcomes.30 31
The present study found that overweight status was associated with poor disease-free survival. In this context, obesity is a well-known risk factor for the development of all types of carcinoma.32 Furthermore, abnormal body mass index values are also considered a prognostic factor for cervical cancer, as underweight and overweight/obese patients have significantly poorer progression-free survival than patients with normal body mass index values (median 7.6 months vs 25.0 months, p=0.01; 20.3 months vs 25.0 months, p=0.03).33 Obesity may promote malignant transformation via several pathophysiological mechanisms, as well as radioresistance.34 35
This study has several limitations. First, the retrospective design and small sample size are associated with risks of bias. Second, differences in tumor stage, brachytherapy dose, brachytherapy technique, and hysterectomy technique were detected based on the prolonged study period (2000–2013). Third, we detected trends in the associations between survival outcomes and several clinical factors (clinical tumor size, lymphovascular space invasion, pathological complete response, and the delay between brachytherapy and hysterectomy), although significant associations were only detected for body mass index and MRI, which suggests that the study might have been underpowered.
Pre-operative image-guided brachytherapy followed by radical hysterectomy may be an effective and safe treatment for patients with early stage node-negative cervical cancer and a tumor size of 2–4 cm. However, patients with >3 cm tumors had poorer disease-free survival than patients with locally advanced cervical cancer, which suggests that more aggressive treatment might be useful in that setting. Overweight status also seems to be associated with poor disease-free survival outcomes. Nevertheless, further prospective studies are needed to better clarify which patients will benefit from the combination of brachytherapy and hysterectomy.
Contributors Conceptualization: BB, AC, EL, XM. Methodology: BB, AC, AE, EL, FN. Data acquisition: BB, AC. Data analysis: EB, AP. Writing the original draft: BB, AC, AE, LB. Revising and editing the manuscript: all authors. Supervision: AC, EL.
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.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
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