Objective
The International Federation of Gynecology and Obstetrics (FIGO) staging for cervical cancer is based on clinical examination. Previous studies have demonstrated significant upstaging with surgical staging. However, no randomized trial has ever shown a survival benefit when radiation combined with chemoradiation (RCTX) is modified according to surgical staging. The objective of the study was to evaluate the feasibility and outcomes of surgical staging prior to radical RCTX treatment among patients with locally advanced cervical cancer in the setting of a larger, prospective, randomized study (the Uterus-11 study of the German Gynecologic Oncology Group).
Study Design
Between 2009 and 2013, 255 patients with advanced cervical cancer (FIGO IIB-IVA) were randomized to surgical staging and RCTX (arm A) or RCTX (arm B). RCTX in both arms included pelvic external beam radiotherapy with weekly cisplatin at 40 mg/m 2 and brachytherapy. Extended-field radiation was performed in cases of confirmed paraaortic metastases.
Results
One hundred thirty patients were randomized to surgical staging; 121 were eligible for this analysis. The mean patient age was 47.2 years, and the mean body mass index was 26.2 kg/m 2 ; the FIGO stages were IIB, IIIA, IIIB, and IVA in 85 (70.2%), 4 (3.3%), 29 (24%), and 3 (2.5%) patients, respectively. Arm A and arm B were similar with respect to Karnofsky performance status, histology, comorbidities, and lymphovascular space involvement. The surgical approach was transperitoneal laparoscopy in nearly all patients (93.4%), with no operative mortality. One patient (0.8%) had a conversion to laparotomy; 2 patients had more than 500 mL blood loss; the early postoperative complication rate was 7.3%. A mean of 19 pelvic and 17 paraaortic nodes were removed, with means of 2.4 and 1.3 positive nodes, respectively. RCTX began between 7 and 21 days after surgery. Operative staging led to upstaging in 40 of 121 (33%).
Conclusion
Surgical staging in patients with locally advanced cervical cancer is safe and does not delay primary RCTX in a randomized study.
Primary radiation combined with chemotherapy (RCTX) has become the standard treatment for patients with locally advanced cervical cancer. Patients with cervical tumors greater than 4 cm in diameter have an increased risk of lymph node metastases at the time of presentation, which have a significant prognostic impact. However, the most recent International Federation of Gynecology and Obstetrics (FIGO) statement reinforced the exclusive use of clinical staging in patients with cervical cancer. Although their sensitivity and specificity are rather disappointing, computed tomography (CT) and magnetic resonance imaging (MRI) are often performed as part of clinical staging. Furthermore, positron emission tomography (PET)-CT has failed to meet prior expectations because of its relatively high false-negative rates.
An alternative to clinical staging is surgical staging, which can evaluate the most important prognostic and therapeutic factors, including lymph node status, adjacent organ involvement, and intraabdominal tumor dissemination. The preferred approaches for surgical staging are laparoscopic or robotic transperitoneal or extraperitoneal techniques to minimize the duration of hospitalization and avoid delaying primary RCTX.
Several retrospective studies have demonstrated a significant rate of upstaging, mainly determined by nodal or peritoneal spread, as a confirmation of more extensive disease, in a nontrivial number of patients when comparing the results of clinical standard staging with histological features after surgery. However, controversy remains regarding whether adjusting the primary treatment according to the findings of surgical staging is associated with a survival benefit. One randomized trial failed to demonstrate an oncological benefit for surgical staging in patients with locally advanced cervical cancer. The main limitations of that study were its small sample size, its premature termination because of morbidity, and significant problems regarding the radiation technique.
The aim of this study was to evaluate the feasibility and outcomes of surgical staging prior to radical RCTX treatment among patients with locally advanced cervical cancer in the setting of a larger prospective randomized study (the Uterus-11 study of the German Gynecologic Oncology Group [ ClinicalTrials.gov , identifier NCT01049100 ]). The operative data from the surgical arm of this prospective randomized international multicenter study are reported in this first analysis.
Materials and Methods
Both informed consent and ethics committee approval for studies on patients, patient records, or volunteers were obtained before the study started (institutional review board approval EA4/148/05, June 28, 2008). Between 2009 and 2013, 255 patients were included. Histological reports confirmed the presence of squamous cell carcinoma, adenocarcinoma, or adenosquamous cervical cancer. The FIGO stage ranged from IIB to IVA. All of the patients underwent a general clinical and gynecological examination. Pretreatment imaging included a whole abdominal CT and/or an abdominal MRI and/or PET-CT as well as chest imaging.
Eligible patients were randomly assigned to either the experimental arm, which incorporated surgical staging (arm A), or to traditional clinical staging (arm B). Patients in arm A underwent surgical staging with a transperitoneal laparoscopic, extraperitoneal laparoscopic, or open transperitoneal approach, followed by primary RCTX. For patients in arm B with suspicious paraaortic lymph nodes, a CT-guided biopsy was performed prior to primary RCTX ( Figure 1 ).
Primary RCTX in both arms consisted of the following 3 steps: (1) external beam radiotherapy to the pelvis; (2) brachytherapy; and (3) concurrent chemotherapy with cisplatin 40 mg/m 2 weekly for 5 cycles. Carboplatinum was substituted for cisplatin in patients with contraindications to the use of cisplatin.
Surgical staging always started with a careful inspection of the abdominal cavity. Biopsies were taken from any suspicious areas and sent for frozen section. If peritoneal spread or a positive supraclavicular lymph node was confirmed, the retroperitoneal lymph node dissection was abandoned, and the patient was referred for palliative chemotherapy.
In patients without peritoneal carcinomatosis, paraaortic and bilateral pelvic lymphadenectomy was performed ( Figure 2 ). The proximal limit of the paraaortic lymphadenectomy was the left renal vein. The pelvic lymphadenectomy included the external iliac, internal iliac, and obturator lymph nodes. If enlarged/bulky paraaortic and/or pelvic lymph nodes were identified, their removal was recommended to reduce the volume of disease for subsequent RCTX. Clip placement to mark the upper margin of the lymphadenectomy was optional.
In young patients (younger than 40 years), ovarian transposition was offered and, if desired, performed during the paraaortic node dissection. Drainage was performed at the surgeon’s discretion. Postoperatively, all of the patients were referred for radiation oncology evaluation with the goal of starting radiation treatment as soon as possible. When histologically confirmed paraaortic lymph node metastases were identified, the radiation field was extended to encompass the paraaortic region (extended field RCTX [EFRT]).
The primary analysis was an intention-to-treat analysis. However, safety was analyzed according to the treatment performed. The statistical analysis was primarily descriptive and included means or medians as well as ranges for continuous variables and absolute and percentage frequencies for categorical variables. P values (χ 2 and Mann-Whitney tests between the study arms) are not confirmatory but describe the success of randomization.
For the main results (complications and upstaging), exact 2-sided 95% confidence limits based on a binomial distribution are presented. Calculations were performed using the software programs Statistical Package for Social Science (SPSS), release 21 (SPSS; IBM, Armonk, NY), and R, release 3.0.1 (R Foundation for Statistical Computing, Vienna, Austria, 2014, http://www.R-project.org ).
Results
A total of 130 patients were randomized to arm A, including 1 patient who was included in the intention-to-treat analysis, 120 patients who were treated according to the protocol, and 9 who were not eligible for the analysis ( Table 1 ). The mean age in the operative group was 47.2 years (range, 20–69 years), and the mean body mass index (BMI) was 26.2 kg/m 2 (range, 16.4–48.1 kg/m 2 ). The distribution of FIGO stages at the time of the randomization to arm A was 85 stage IIB (70.2%), 4 stage IIIA (3.3%), 29 stage IIIB (24%), and 3 stage IVA (2.5%) patients.
| Demographic | Arm A | Arm B | P value |
|---|---|---|---|
| Randomized patients | 130 | 125 | |
| Not eligible | 9 | 6 | |
| Intention to treat | 1 | 5 | |
| Per protocol | 120 | 114 | |
| Evaluable patients | 121 | 119 | |
| Mean age, y | 47.2 | 49.6 | .091 |
| Range | 20–69 | 24–71 | |
| Mean BMI, kg/m 2 | 26.2 | 26.2 | .830 |
| Range | 16.4–48.1 | 15.7–51.4 | |
| Karnofsky score, % | 90 (70–100) | 90 (70–100) | .450 |
| Comorbidity | |||
| Cardiovascular disease | 24/121 (19.8%) | 24/119 (20.2%) | .950 |
| Diabetes | 9/121 (7.4%) | 7/119 (5.9%) | .630 |
| Previous abdominal surgery | 56/121 (46.3%) | 46/119 (38.7%) | .230 |
| Tumor FIGO stage at randomization | |||
| IIB | 85 (70.2%) | 80 (67.2%) | |
| IIIA | 4 (3.3%) | 6 (5%) | |
| IIIB | 29 (24%) | 24 (20.2%) | |
| IVA | 3 (2.5%) | 9 (7.6%) | .440 |
| Tumor size | |||
| <4 cm | 31/121 (25.6%) | 22/119 (18.5%) | |
| >4 cm | 90/121 (74.4%) | 97/119 (81.5%) | .183 |
| Histology | |||
| Squamous cell carcinoma | 103/121 (85.1%) | 108/119 (90.8) | |
| Adenocarcinoma | 15/121 (12.4%) | 8/119 (6.7%) | |
| Adenosquamous carcinoma | 3/121 (2.5%) | 3/119 (2.5%) | .330 |
| Grading | |||
| G1 | 5/121 (4.1%) | 1/119 (0.8%) | |
| G2 | 85/121 (70.3%) | 76/119 (63.9%) | |
| G3 | 31/121 (25.6%) (rounding error) | 42/119 (35.3%) | .046 |
| Lymphatic space involvement | (n = 99) | (n = 93) | |
| Negative | 57/99 (57.5%) | 57/93 (61.3%) | |
| Positive | 17/99 (17.2%) | 11/93 (11.8%) | |
| Indeterminate | 25/99 (25.3%) | 25/93 (26.9%) | .58 |
| Vascular space involvement | (n = 98) | (n = 94) | |
| Negative | 61/98 (62.2%) | 65/94 (69.1%) | |
| Positive | 8/98 (8.2) | 3/94 (3.2%) | |
| Indeterminate | 29/98 (29.6%) | 26/94 (27.7%) | .29 |
Cardiovascular comorbidity was present in 24 patients (19.8%), whereas 9 patients had diabetes (7.4%), and 56 patients had undergone at least 1 previous abdominal surgery (46.3%). The primary histology was squamous cell carcinoma in 103 of 121 cases (85.1%), adenocarcinoma in 15 of 121 cases (12.4%), and adenosquamous carcinoma in 3 of 121 cases (2.5%). The largest tumor diameter was less than 4 cm in 31 of 121 patients (25.6%) and more than 4 cm in 90 of 121 patients (74.4%). The tumor grade was G1, G2, and G3 in 5 (4.1%), 85 (70.2%), and 31 (25.6%) women, respectively.
Tumor biopsies were evaluated for vascular and/or lymphatic space involvement (LSI) in 98 cases. LSI involvement was present in 17.2% of cases, absent in 60% of cases, and indeterminate in 25.3% of cases. Vascular space involvement was detected in 8.2% of cases, not detected in 62.2% of cases, and indeterminate in 29.6% of cases.
There were no significant differences between arm A and arm B with respect to age, BMI, Karnofsky performance status, histological type, comorbidity, LSI, or vascular space involvement. The distribution of the tumor grade was significantly different between arm A and arm B, with a larger number of G3 tumors in arm B.
The surgical approach for operative staging was laparoscopic transperitoneal, laparoscopic extraperitoneal, and open transperitoneal in 113 of 120 (93.4%), 4 of 120 (3.3%) and 3 of 120 (2.6%) patients, respectively ( Table 2 ). In 1 patient, an enlarged left-sided supraclavicular lymph node was identified under anesthesia. This node was removed and confirmed to be positive for carcinoma. In this patient, retroperitoneal lymphadenectomy was abandoned.
| Variable | Arm A |
|---|---|
| Surgical approach for staging | |
| Laparoscopic extraperitoneal | 4/120 (3.3%) |
| Laparoscopic transperitoneal | 113/120 (93.4%) |
| Open transperitoneal | 3/120 (2.6%) |
| Open retroperitoneal | 0 |
| Other | 1 a |
| Conversion of laparoscopy to laparotomy | 1/120 (0.8%) (because of obesity and severe adhesions) |
| Intraoperative complications b | 2/123 (1.6%) (vessel injuries, 1 × 600 mL, 1 × 1500 mL blood loss; arm A plus 3 patients who changed study arm) |
| Perioperative mortality b | 0 |
| Early postoperative complications b | 9/123 (7.3%) |
| Thrombosis | 1 |
| Wound infection | 0 |
| Ileus | 1 |
| Sepsis | 0 |
| Symptomatic lymphocele | 4 |
| Nerve irritation | 1 |
| Others | 2 c |
| Median number of harvested pelvic lymph nodes (range) | 19 (1–70) |
| Median number of harvested paraaortic lymph nodes (range) | 17 (3–74) |
| Mean number of involved pelvic lymph nodes (range) | 2.4 (0–24) |
| Mean number of involved paraaortic lymph nodes (range) | 1.3 (0–25) |
| Mean time interval (days) between surgery and start of chemoradiation (range) | 13 (7–21) |
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