Comparing survival outcomes between surgical and radiographic lymph node assessment in locally advanced cervical cancer: A propensity score-matched analysis

YGYNO-977753; No. of pages: 8; 4C: Gynecologic Oncology xxx (xxxx) xxx

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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno

Comparing survival outcomes between surgical and radiographic lymph node assessment in locally advanced cervical cancer: A propensity scorematched analysis Jie Yang a,d, Ritchie Delara a, Javier Magrina a, Paul Magtibay a, Johnny Yi a, Carrie Langstraat b, Matthew Robertson c, Tri Dinh c, Kristina Butler a,⁎ a

Department of Medical and Surgical Gynecology, Mayo Clinic, Phoenix, AZ, USA Department of Obstetrics and Gynecology, Division of Gynecologic Surgery, Mayo Clinic, Rochester, MN, USA c Department of Medical and Surgical Gynecology, Mayo Clinic, Jacksonville, FL, USA d Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing, China b

H I G H L I G H T S • Clinical and surgical staging for cervical cancer had comparable PFS and OS. • The sensitivity of combined imaging methods to detect PALN metastases was 62.5%. • The FIGO 2018 stage IIIC1 had heterogeneous survival outcomes.

a r t i c l e

i n f o

Article history: Received 29 October 2019 Received in revised form 6 December 2019 Accepted 7 December 2019 Available online xxxx

a b s t r a c t Objective. To investigate progression-free survival (PFS) and overall survival (OS) between women who underwent surgical versus radiographic assessment of pelvic lymph nodes (PLN) and para-aortic lymph nodes (PALN) prior to chemoradiation therapy for cervical cancer. Methods. In this retrospective cohort analysis, patients with stage IB2 - IIIB squamous cell, adenocarcinoma and adenosquamous carcinoma of the cervix who completed concurrent chemoradiation therapy (CCRT) between 2000 and 2017 from the Mayo Clinic Cancer Registry were identified. A 1:2 propensity score matching between surgical and imaging groups was performed and PFS and OS were compared between groups. Results. 148 patients were identified and after propensity score matching, 35 from the surgical group and 70 from the imaging group were included in the analysis. There were no statistical differences in baseline characteristics between the 2 groups. The median follow-up time was 41 months (range 7–218) for the surgical group and 51.5 months (range 7–198) for the imaging group. Five-year PFS was 62.6% for the surgical group and 72.4% in imaging group (HR 1.11, 95% CI 0.54–2.30, p = 0.77). Five-year OS was 70.2% for the surgical group and 70.5% for the imaging group (HR 1.02, 95% CI 0.46–2.29, p = 0.96). FIGO stage, PALN metastasis, and parametrial involvement were found to be poor prognosticators for PFS and OS in univariate analysis. Only PALN metastasis significantly predicted unfavorable PFS (HR 2.76, 95% CI 1.23–6.18, p = 0.01) and OS (HR 3.46, 95% CI 1.40–8.55, p = 0.01) in multivariate analysis. There were no differences in locoregional recurrence and distant metastasis between the two groups (p = 0.33 and 0.59 respectively). Conclusion. Patients with cervical cancer who underwent radiographic assessment of PLN and PALN had comparable survival outcomes to surgical assessment. © 2019 Published by Elsevier Inc.

1. Introduction

⁎ Corresponding author at: Department of Gynecologic Surgery, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA. E-mail address: [email protected] (K. Butler).

Cervical cancer is the fourth most frequently diagnosed cancer and the fourth most common cause of cancer death in women worldwide [1]. Concurrent chemoradiotherapy (CCRT) is considered standard treatment in patients with locally advanced cervical cancer, namely stage IB2 to IVA, and the decision for CCRT is dependent on clinical

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Please cite this article as: J. Yang, R. Delara, J. Magrina, et al., Comparing survival outcomes between surgical and radiographic lymph node assessment in locally advan..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.009

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staging [2]. Pelvic lymph node (PLN) and para-aortic lymph node (PALN) status dictates need for extended field radiotherapy (EFRT) and boost radiotherapy [2]. The International Federation of Gynecology and Obstetrics (FIGO) revised the staging of cervical cancer in 2018 [3]. In the FIGO 2018 staging system, patients with positive PLN and PALN metastases are identified as stage IIIC, reflecting the role of lymph node (LN) metastases as a prognostic factor for cervical cancer [4]. Current literature describes different methods to determine LN metastases [3]. FIGO allows for assessment of retroperitoneal LN metastases through use of imaging with or without pathologic diagnosis to designate cancer stage [3]. Pathologic assessment of LN involvement is considered gold standard and provides precise information on LN status [5]. Some data suggest a therapeutic effect of lymphadenectomy in improving survival outcomes for patients with advanced-stage cancer [6]. However surgery can increase the risk for perioperative complications, which can potentially delay start of CCRT [7]. In addition, there are discrepancies on extent of LN dissection [6]. Most studies describe only PALN dissection, however bulky PLN (≥2 cm) is a risk factor for radiation failure and recurrence, suggesting need for PLN excision [8]. Complete resection of bulky PLN had comparable survival to patients with micrometastases [9]. Currently, there is no consensus on whether complete PLN dissection or resection of bulky LN should be considered in pretreatment surgical staging. The advancement of radiographic modalities, such as Positron Emission Tomography (PET), has allowed practitioners to evaluate disease extent and determine cancer staging. Magnetic Resonance Imaging (MRI) and Computerized Tomography (CT) are comparable in diagnostic accuracy with reported false negative rates of 20–50% in assessment of macroscopic LN metastasis [10]. PET-CT has a sensitivity for detection of PLN metastasis of 0.83, and for PALN metastasis, a sensitivity of 0.50 [11]. Other non-invasive radiological modalities for detection of PALN involvement remain unsatisfactory [11]. There is no consensus on which method of LN assessment, surgical or radiographic, is superior. One randomized trial failed to prove any benefit of pretreatment surgical staging in cervical cancer and was closed early [12]. Retrospective studies also demonstrate controversial results on progression-free survival (PFS) and overall survival (OS) by different LN assessment methods [6,13]. The primary aim of this study was to assess survival outcomes of different staging methods before CCRT in patients with locally advanced cervical cancer. 2. Methods The Mayo Clinic Institutional Review Board (IRB #19-007429) approved this multi-site retrospective cohort study. We queried the Mayo Clinic Cancer Registry for patients with carcinoma of the cervix treated with CCRT from 2000 to 2017 at 3 Mayo Clinic sites, Minnesota, Arizona, and Florida. Patients with FIGO 2009 stage IB2 to IIIB pathologically-confirmed squamous cell, adenocarcinoma or adenosquamous carcinoma of the cervix were included. Patients with stage IVA were excluded from this study due to variable treatment protocols in this staging group. Patient characteristics including age at time of cancer diagnosis, race, and CCRT treatment time were collected. Tumor characteristics including FIGO 2009 stage, histology, tumor grade and size (on imaging), depth of invasion, parametrial involvement and lymphovascular space invasion (LVSI) were also obtained.

LN on imaging were recorded. In this study, all patients were also restaged using the revised FIGO 2018 system to account for prognostic differences, and PFS and OS were compared between the FIGO 2009 and FIGO 2018 staging. The decision to proceed with surgical assessment of LN was made by a multidisciplinary team that included a gynecologic oncologist, radiation oncologist, and medical oncologist. If suspicious PLN involvement was identified on imaging, excision of enlarged PLN and PALN was performed. Surgical staging was also performed if occult LN metastasis was identified intraoperatively at time of planned radical hysterectomy. In this case, if positive LN was identified at time of surgery via frozen section, the radical hysterectomy was aborted, and the patient received definitive radiation therapy. There were also patients without evidence of LN metastasis on imaging who underwent surgical staging because of their participation in a research trial by the American College of Radiology Imaging Network (ACRIN) which used PET-CT for assessment of LN metastasis in cervical cancer (Fig. 1). Surgical LN assessment was performed via laparotomy or laparoscopy using either a transperitoneal or retroperitoneal approach. The cranial border of the PALN dissection was identified either at the level 3 of the inferior mesenteric artery (IMA) or the level 4 of the left renal vein. Perioperative complications were classified using the ClavienDindo grading system with grades I-II identified as minor and grades IIIA-IV identified as major complications. Major complications related to surgical and chemoradiotherapy were documented and analyzed in this study. 2.2. Chemoradiotherapy All patients received CCRT and brachytherapy and completed radiation therapy within 10 weeks. External beam radiation therapy (EBRT) to the pelvis delivered at a dose of 45 Gy in 25 fractions and weekly cisplatin (40 mg/m2) were administered for 5 weeks in node negative patients. Patients with PLN metastasis received boost radiotherapy up to 62.5 Gy in the area of metastasis. Patients with PALN metastasis received EFRT to the T12 level. Brachytherapy with a total dose of 28–30 Gy in 4–6 fractions was delivered after completion of EBRT. If any LN metastases or advanced-stage disease, some patients were offered dual-agent CCRT with gemcitabine and cisplatin with consolidation adjuvant chemotherapy with gemcitabine and cisplatin (Table 2) [16]. Dual-agent CCRT and 2 cycles of consolidation adjuvant chemotherapy were optional after CCRT based on shared-decision making between the physician and the patient as well as insurance coverage. 2.3. Follow-up After treatment completion, patients were followed every 3–6 months for the first 2 years, 6–12 months for 3–5 years, then annually thereafter. Patients were actively followed by the Mayo Clinic Cancer Registry with a minimum follow-up rate of 80%. Site of recurrence was documented as central (cervical or vaginal), locoregional (PLN or PALN), distant and multiple. Distant recurrences were identified as metastases beyond the PALN, intraperitoneal tumor dissemination, or metastases to abdominal viscera. PFS was defined as the time (months) from diagnosis to disease recurrence. OS was defined as the time (months) from initial diagnosis to death from all causes. Data on patients with no evidence of disease recurrence or death were censored at the date of last follow-up.

2.1. Lymph node assessment 2.4. Data analysis All patients underwent pre-procedure imaging with at least one of the following modalities: contrast CT, MRI, or PET-CT for clinical assessment. LNs with short axis over 10 mm were considered positive on CT and MRI [14]. LNs with increased radiotracer uptake on PET were deemed positive for metastatic spread even if they were smaller than 1 cm in short-axis diameter [15]. Data on the site and size of metastatic

Because of the nonrandomized nature of the study design and potential allocation biases arising from the retrospective comparison between groups, propensity score matching was utilized. A propensity score was developed through a multivariable logistic regression model. The following variables were included in the model: FIGO 2009

Please cite this article as: J. Yang, R. Delara, J. Magrina, et al., Comparing survival outcomes between surgical and radiographic lymph node assessment in locally advan..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.009

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Fig. 1. LN status at time of surgical staging after preoperative radiographic LN assessment.

stage, histology, and PALN metastasis. Patients from the surgical group were matched 1:2 to patients from the imaging group using a caliper width ≤0.02 standard deviations of the logit odds of the estimated propensity score. Data were documented as numbers or percentages unless otherwise specified. Mann-Whitney U test was used to analyze continuous variables as appropriate. Frequency distributions were compared using Chi-square and Fisher's exact test for categorical variables. Survival outcomes (PFS and OS) were estimated using the Kaplan-Meier method and log rank test. Predictors for recurrence (age, surgical staging, histology, tumor grade, LVSI, cervical stromal invasion, parametrial involvement) were assessed using univariate analyses. Univariate and multivariate Cox proportional hazard ratio (HR) analyses were performed to identify independent prognostic factors. Multivariate Cox models included factors associated with a statistically significant increased risk for death or recurrence in the univariate analysis. In all cases, a p value b0.05 was considered statistically significant. SPSS ver. 23.0 (IBM, Armonk, NY, USA) and Prism 6.0c software (GraphPad, San Diego, CA, USA) were used for statistical analyses. 3. Results 3.1. Patient and treatment characteristics Of the 148 patients who met criteria for inclusion into this study, 35 underwent surgical LN assessment and 113 underwent clinical staging. Table 1 summarizes patient demographics and tumor characteristics before and after propensity score matching. Prior to propensity score matching, statistically significant differences were noted between both groups with respect to stage, pelvic LN metastasis, LVSI and parametrial involvement. After matching, 35 patients in surgical group and 70 patients in imaging group were included in the analysis. All patients underwent preoperative imaging with enhanced CT (n = 21, 20%), MRI (n = 16, 15.2%), PET-CT (n = 15, 14.3%), or a combination of CT, MRI, and PET imaging modalities (n = 53, 50.5%). All the patients with radiologic PALN metastasis also had positive pelvic nodes. Baseline

characteristics between the two groups were well balanced without significant differences. Treatment characteristics are summarized in Table 2. The time from diagnosis to start of radiation therapy was longer in the surgical group with a median of 47 days (range 14–119) as compared to 28 days (range 3–90) in the imaging group (p b 0.01). More patients received full fractions of brachytherapy in the imaging group than the surgical group with a rate of 95.7% vs. 80% respectively (p = 0.01). The rate of consolidation adjuvant chemotherapy after CCRT was 20% in the surgical group, which is significantly higher than 4.3% in the imaging group (p = 0.02). There were no significant differences with respect of EBRT dosage, rate of EFRT, duration of radiation treatment, concurrent chemotherapy, remission rate or recurrence pattern between groups.

3.2. Surgical staging characteristics Of the 35 patients who underwent surgical staging, 4 patients had negative LN metastasis identified on preoperative imaging (Fig. 1). Two of the 4 patients had positive LN metastasis confirmed on pathology after planned radical hysterectomy. The other 2 patients were enrolled in the ACRIN trial and underwent surgical staging but had negative LN metastasis confirmed on pathology. Six patients (17%) underwent laparotomy, and 29 patients (83%) underwent minimally invasive surgery. Of the minimally invasive procedures, 13 (45%) were performed laparoscopic and 16 (55%) robotic. There were no conversions from minimally invasive surgery to laparotomy. Transperitoneal lymphadenectomy was performed in 26 patients (74%) while laparoscopic retroperitoneal lymphadenectomy was performed in 9 patients (26%). Eight patients (23%) had PALN dissection alone (Fig. 1). Three patients (8.5%) had PLN dissection alone due to negative common iliac LN on frozen section. Both PLN and PALN dissection were performed in 24 patients (68.5%). Among the 32 patients who underwent PALN dissection, 11 (34%) had a level 3 dissection and 21 (66%) had a level 4 dissection. Median LN yield was 18 (range 4–58).

Please cite this article as: J. Yang, R. Delara, J. Magrina, et al., Comparing survival outcomes between surgical and radiographic lymph node assessment in locally advan..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.009

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Table 1 Patient demographics and tumor characteristics.

Age (years) ± SD Race – no. (%) White Black Asian Others Period – no. (%) 2000–2005 2006–2011 2012–2017 Histology – no. (%) Squamous Adenocarcinoma Adenosquamous Stagea – no. (%) IB IIA IIB IIIA IIIB LN metastasisb – no. (%) Pelvic Both pelvic & para-aortic Bulky pelvic LN Tumor size – no. (%) ≤4 cm 4–8 cm N8 cm Depth of invasion – no. (%) b½ ≥½ LVSI – no. (%) No Yes Parametrium – no. (%) No Yes a b

Surgical group (n = 35)

Imaging group (n = 113)

47.8 ± 13.3

52.6 ± 12.4

28 (80) 3 (8.5) 0 4 (11.4)

88 (77.9) 6 (5.3) 3 (2.6) 16 (14.2)

6 (17.1) 12 (34.3) 17 (48.6)

10 (8.8) 36 (31.9) 67 (59.3)

23 (65.7) 9 (25.7) 3 (8.6)

86 (76.1) 20 (17.7) 7 (6.2)

16 (45.7) 3 (8.6) 10 (28.6) 2 (5.7) 4 (11.4)

26 (23.0) 13 (11.5) 41 (36.3) 1 (0.9) 32 (28.3)

31 (88.6) 7 (20) 5 (14.3)

65 (57.5) 20 (17.7) 20 (17.7)

15 (42.8) 19 (54.3) 1 (2.9)

32 (28.3) 73 (64.6) 8 (7.1)

10 (19.6) 25 (71.4)

19 (16.8) 94 (83.2)

27 (77.1) 8 (22.9)

107 (94.7) 6 (5.3)

21 (60.0) 14 (40.0)

36 (31.9) 77 (68.1)

0.17 0.67

Matched imaging group (n = 70)

p value

54.4 ± 12.9

0.33 0.72

56 (80) 3 (4.3) 2 (2.9) 9 (12.8) 0.32

0.45 10 (14.3) 33 (47.1) 27 (38.6)

0.47

0.95 48 (68.6) 16 (22.8) 6 (8.6)

0.03

0.66 26 (37.1) 8 (11.4) 24 (34.3) 0 12 (17.1)

b0.01 0.80 0.86 0.13

43 (61.4) 12 (17.1) 8 (11.1)

0.08 0.59 0.68 0.91

29 (41.4) 39 (55.7) 2 (2.9) 0.15

0.82 18 (25.7) 52 (74.3)

b0.01

0.07 64 (91.4) 6 (8.6)

b0.01

0.22 32 (45.7) 38 (54.3)

FIGO 2009 staging. Positive LN on clinical evaluation.

The mean estimated blood loss was significantly higher in patients who underwent laparotomy compared to patients who underwent minimally invasive surgery, 208.3 ml vs. 91.5 ml respectively (p = 0.01). Perioperative complications occurred in 3 patients who underwent minimally invasive PALN dissection: One with trocar site

Table 2 Chemotherapy and radiotherapy treatment characteristics.

Diagnosis to radiation time (days) – median (range) EBRT dose (Gy) ± SD Brachytherapy – no. (%) b4 fractions 4–6 fractions Extended field radiation – no. (%) Duration of radiation ≤8 weeks N8 weeks Chemotherapya – no. (%) None Weekly cisplatin Dual agent Consolidationa – no. (%) Remission – no. (%) Recurrence pattern – no. (%) Central failure Locoreginal failure Distant failure a

p value

Adjuvant chemotherapy.

Surgical group (n = 35)

Imaging group (n = 70)

p value

47 (14–119)

28 (3–90)

b0.01

51.1 ± 5.2

51.8 ± 5.5

0.53 0.01

7 (20) 28 (80) 8 (22.9)

3 (4.3) 67 (95.7) 12 (17.1)

33 (94.3) 2 (5.7)

63 (90.0) 7 (10.0)

0 33 (94.3) 2 (5.7) 7 (20.0) 33 (94.3)

1 (1.4) 64 (91.4) 5 (7.1) 3 (4.3) 57 (81.4)

0.02 0.13

1 (2.9) 4 (11.4) 8 (22.9)

0 9 (12.9) 12 (17.1)

0.33 0.83 0.48

0.42 0.71

herniation surgically corrected, and two with lymphedema managed with physical therapy. Preoperative imaging of LN metastases was compared to the final pathology report. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of imaging modalities in detection of PLN metastases were 88.9%, 22.2%, 69.6% and 50% respectively; and 62.5%, 92%, 71.4% and 88.5% respectively in PALN metastases. The median time from surgery to start of radiation was 14 days (range 6–112 days) for surgical groups. Eleven patients (31.4%) had a modification in their treatment plan based on the pathologic findings from surgical LN assessment: 3 received EFRT, 3 received boost radiotherapy to the PLN, and 5 did not receive boost radiotherapy due to negative LN metastasis. Toxicities during radiation and long term complications were similar between the two groups. In the surgical group, there was 1 small bowel obstruction, 1 radiation enteritis, 1 rectovaginal fistula, 1 vesicovaginal fistula, 1 cystitis, and 1 deep vein thrombosis. In the imaging group, there was 1 small bowel obstruction, 1 vesicovaginal fistula, 1 rectovaginal fistula, 1 deep vein thrombosis, and 1 cardiac arrhythmia.

0.74

3.3. Survival outcomes Median follow-up time was 41 months (range 7–218) for the surgical group and 51.5 months (range 7–198) for the imaging group. Fiveyear PFS was 62.6% for the surgical group and 72.4% for the imaging group (HR 1.11, 95% CI 0.54–2.30, p = 0.77). Five-year OS was 70.2% for the surgical group and 70.5% for the imaging group (HR 1.02, 95% CI 0.46–2.29, p = 0.96). (Fig. 2) There were no differences in

Please cite this article as: J. Yang, R. Delara, J. Magrina, et al., Comparing survival outcomes between surgical and radiographic lymph node assessment in locally advan..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.009

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Fig. 2. Kaplan-Meier curves comparing PFS and OS in patients who underwent surgical versus radiographic staging.

Table 3 Univariate and multivariate analysis of potential prognostic risk factors in patients with locally advanced cervical cancer. Variable

5-Year PFS

5-Year OS

Univariate % 2009 stage I II III 2018 stage I II III Histology Squamous Adenocarcinoma Adenosquamous Grade Low Moderate High Undifferentiated PLNa No Yes b2 cm ≥2 cm PALNa No Yes Parametrium No Yes Tumor size ≤4 cm 4–8 cm N8 cm Depth of invasion b½ ≥½ LVSI No Yes Duration of CCRT ≤8 weeks N8 weeks Brachytherapy ≤3 fractions ≥4 fractions Dual agentb No Yes Consolidationb No Yes a b

Multivariate

Univariate

p

HR

95% CI

p

b0.01

1.41

0.76–2.62

0.28

85.2 63.1 38.9

%

HR

95% CI

p

b0.01

1.52

0.77–2.98

0.23

0.03

1.73

0.65–4.57

0.27

0.79

0.23–2.71

0.71

0.00

3.46

1.40–8.55

0.01

0.03

1.29

0.50–3.33

0.59

0.02

1.42

0.71–2.81

0.32

82.4 74.4 37.5 0.02

1.77

0.73–4.26

0.20

88.4 83.3 57.2

85.2 85.9 62.2 0.29

0.31

70.2 68.0 41.7

72.7 74.0 42.9 0.17

0.27

66.7 81.1 62.9 44.4

73.8 78.4 67.6 50.8 0.08

78.3 61.8 69.4 53.6

Multivariate p

0.90

0.30–2.71

0.85

0.03 0.00

0.11 78.2 66.8 77.7 57.9

2.76

1.23–6.18

0.01

74.4 32.4

0.02

76.3 36.1 0.01

1.39

0.58–3.36

0.46

80.2 55.2

78.9 62.1 0.16

65.5 70.7 40.0

1.07

0.57–1.98

0.84 68.5 74.5 30.0

0.12 80.9 62.7

0.22 81.4 67.2

0.36 69.0 55.6

0.81 71.1 61.1

0.62 66.3 76.2

0.76 70.3 72.9

0.60 60.0 68.0

0.91 59.3 71.7

0.48 60.8 75.0

0.77 63.4 75.0

0.36 64.1 50.0

0.18 66 50

Positive metastases on preoperative imaging. Adjuvant chemotherapy.

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locoregional recurrence and distant metastasis between the two groups (p = 0.33 and 0.59 respectively). On univariate analysis, FIGO 2009 and 2018 stage, radiologic PALN metastasis, parametrial involvement were found to be poor prognosticators for PFS and OS (Table 3). Increasing tumor size was associated with unfavorable OS (p = 0.02). PLN metastasis had no prognostic effect on PFS or OS (p = 0.08 and 0.11 respectively). Significant variables from univariate analysis were included in multivariate analysis. On multivariate analysis, only PALN metastasis had statistical significance in predicting unfavorable PFS (HR 2.76, 95% CI 1.23–6.18) and OS (HR 3.46, 95% CI 1.40–8.55, p = 0.01) (Table 2). There were no differences in recurrence patterns between the two groups but with a higher but not significant distant failure rate in surgical group (22.9% vs. 17.1%, p = 0.48). Twenty-six patients in the surgical group and 36 in the imaging group had positive LN and were re-staged using the FIGO 2018 system as stage IIIC (Table 4). Within the stage IIIC subgroups, 46 (74.2%) had positive PLN (IIIC1), 16 (25.8%) had positive PALN. The 5-year PFS for FIGO 2018 stage IIIB, IIIC1, IIIC2 were 60.0, 63.4, 36.5% respectively with a 5-year OS of 60.0, 72, 32.1% respectively. 4. Discussion Patients with locally advanced cervical cancer who underwent radiographic LN assessment had comparable PFS and OS outcomes as compared to patients who underwent surgical LN assessment. More than 30% of patients had a modification in her therapeutic plan based on pathologic findings. Although surgical assessment of LN status potentially informs the need for additional chemotherapy or radiotherapy without the addition of undue perioperative complications, our data shows a lack of survival benefit with surgical staging in patients with cervical cancer stage IB2-IIIB. Literature on clinical versus surgical LN assessment is conflicting. To our knowledge, there are only two randomized controlled trails (RCT) that compared radiologic to surgical LN assessment in primary cervical cancer [12,17]. Both studies included patients with stage IB2-IVA cervical cancer who received definitive radiotherapy. Lai CH et al. evaluated PFS and OS in 61 patients with cervical cancer. However the study terminated prematurely after an interim analysis showed the surgicallystaged patients had worse PFS (HR 3.13, p = 0.005) [12]. One of the limitations of this study was the presence of poor prognosticators and fewer recipients of CCRT in the patients who were surgically staged, potentially predisposing this cohort to worse survival outcomes. A multicenter RCT from Germany, Uterus-11, evaluated perioperative morbidity and survival outcomes in 255 patients with locally advanced cervical cancer who underwent surgical LN assessment [17]. Uterus-11 study showed that surgical staging had acceptable morbidity and did not delay initiation of radiotherapy. However, surgical LN assessment led to a nearly 2-fold increase in the number of patients receiving EFRT [18]. Final analysis on survival outcomes are pending. The Lymphadenectomy in Locally Advanced Cervical Cancer Study (LiLACS), an international, prospective, multicenter, and randomized phase 3 clinical trial (ClinicalTrials.gov identifier NCT02848716), evaluated survival outcomes in patients with locally advanced cervical cancer who received pretherapeutic surgical staging in comparison to

Table 4 5-Year PFS and OS by stage for FIGO 2009 and FIGO 2018 staging. Staging

I II IIIA/B IIIC1 IIIC2

FIGO 2009

FIGO 2018

n

5-Year PFS, %

5-Year OS, %

n

5-Year PFS, %

5-Year OS, %

42 45 18

85.2 63.1 38.9

82.4 74.4 37.5

20 18 5 46 16

88.4 83.3 60.0 63.4 36.5

85.2 85.9 60.0 72.0 32.1

radiologic staging. LiLACS required enrollment of 600 patients with an estimated 8 years to study completion [19]. However, this trial is currently closed for enrollment due to poor accrual. Retrospective studies also present conflicting survival outcomes. Gold et al. reviewed data from GOG 85, 120 and 165 and reported significant differences between surgically- and radiographically-staged survival outcomes with respect to 5-year PFS (49 vs. 36% respectively, p = 0.055) and OS (50 vs. 40% respectively, p = 0.038) in favor of surgical LN assessment in patients with FIGO stage III and IV [13]. However, these 3 GOG studies demonstrated variability in their chemotherapy and radiotherapy protocols, which introduce patient selection bias. Pomel et al. compiled patients from 2 centers and found surgical staging more deleterious than clinical staging in terms of OS (HR 2.55, 95% CI 1.09–5.99) and PFS (HR 1.93, 95% CI 1.03–3.61) [6]. In this retrospective cohort, patients who underwent clinical staging had less PALN involvement on imaging, and less patients received completion surgery but more received brachytherapy. A recent study by Gonzalez-Benitez et al. showed lack of survival benefit of surgical staging despite its higher diagnostic accuracy and higher number of patient who received EFRT [20]. The patients in this study also underwent varying therapies with a higher rate of EFRT, higher total radiation dose, and higher rate of chemotherapy administration in surgically staged patients. In addition, 21 (48.8%) stage IVB patients were included in the imaging group despite study inclusion criterion of only FIGO stage IIA2-IVA patients. These studies were limited by their retrospective nature and inherent selection bias with patients of varying tumor and treatment characteristics. In our study, propensity score matching was utilized to balance treatment groups based on the most significant prognostic factors including stage, histology and PALN metastasis. Radiation therapy and CCRT were standardized among the majority of patients, and the median time from surgery to initiation of radiotherapy was only 14 days, in contrast to other studies that reported a median time of over 3 weeks from diagnosis to initiation of radiotherapy [21,22]. However, there was a significant delay in initiation of CCRT in surgical patients as compared to those who were clinically staged (47 vs. 28 days, p b 0.01). In addition, despite all the patients in this cohort having received brachytherapy, there were fewer patients in the surgical group that completed all the fractions compared to imaging group (80 vs. 95.7%, p = 0.01). The delay in initiation of CCRT and less number of fractions of brachytherapy could negatively impact survival, diminishing the potentially beneficial effect of surgical resection of positive nodes. Also, more patients in the surgical group received consolidation chemotherapy than those in the imaging group (20 vs 4%, p = 0.01). This may imply that patients in the surgical group were at higher risk thus the effect of LN dissection was reduced. Our study confirmed prior reports suggesting extraperitoneal LN dissection is safe and feasible [23]. Both the median estimated blood loss and the rate of surgical complications (8.6%) were low if performed by a minimally invasive approach. The rates of surgical complications in our series were comparable to the 0–19% reported in the literature [18]. There were no additional complications observed during or after CCRT in the surgical group compared to the imaging group. The role of lymphadenectomy in local control and distant metastasis for locally advanced cervical cancer is uncertain. There are reports about lymphadenectomy improving local control as well as possibly decreasing extra-pelvic failures in patients with metastatic LN [22,24]. In our study, there was a trend towards increased distant metastasis after LN dissection with no significant difference in OS. A total of 31.4% of patients in the surgical group received radiation field modifications after surgical staging. One could theorize that this change is clinically significant and should offer accurate EFRT planning and avoid unnecessary radiation doses. However, our results suggest that lymphadenectomy with EFRT has limited survival benefit. We hypothesize that the survival benefit for lymphadenectomy may be limited due to the natural history of cervical cancer and the treatment effect of radiation therapy. If there

Please cite this article as: J. Yang, R. Delara, J. Magrina, et al., Comparing survival outcomes between surgical and radiographic lymph node assessment in locally advan..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.009

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is PLN involvement, radiation therapy with pelvic boost can be used to achieve local control. If there is PALN involvement, there may already be distant metastasis beyond the PALN, and neither EFRT nor consolidation chemotherapy will improve the already poor survival outcomes associated with more advanced stages. In our study, PALN metastasis was an independent risk factor for unfavorable prognosis in patients with locally advanced cervical cancer on both univariate and multivariate analysis. We were unable to determine survival benefit for PLN dissection as in this cohort pelvic lymphadenectomy was performed according to surgeon preference and often based on subjective assessment and inspection of LN intraoperatively. Patients with FIGO 2018 stage IIIC1 showed very heterogeneous survival outcomes. Survival rates for stage IIIC1 were superior to stage IIIA and IIIB, and more closely resembles survival rates of patients with FIGO 2009 stage II. Notably, patients with FIGO 2018 stage IIIC2 had more unfavorable outcomes. Our results are concordant to NCDB data reported by Wright et al. analyzing the performance of the FIGO 2018 staging system; the authors also suggested inconsistent prognosis with stage III tumors [25]. Radiography is an important tool used in the evaluation of tumor extent and metastasis. In our study, 50.5% patients underwent at least 2 imaging techniques for evaluation. After 2009, at our institution, patients from all 3 sites received PET imaging assessment of LN status and distant metastasis. The sensitivity in detection of PLN and PALN metastasis were 88.9% and 62.5%, respectively, at our institution, slightly higher than cited in the literature [26]. The largest prospective study is the ACRIN6671/GOG0233 trial, which reported a mean sensitivity of 50% and 83% in detection of PALN and PLN metastasis, respectively, using PET and diagnostic CT in advanced cervical cancer [11]. Notably, the specificity in assessment of PALN in our study was 92% as compared to 85% in the ACRIN trial. We hypnosis that combined imaging modalities may improve sensitivity and specificity of LN metastases and reduce need for treatment modifications thereby diminishing the potentially therapeutic effect of lymphadenectomy in most patients. This study suggests radiographic assessment of LN eliminates the requisite for surgery and thus risk for perioperative complications, expedites initiation of CCRT, and increases tolerability of more fractions of brachytherapy, while providing comparable PFS and OS. A sensitivity of 62.5% in detection of PALN is still not satisfactory, and change in the radiation plan after surgical LN assessment is as high as 31.4%. It may still justify surgical staging especially for those patients with high risk for PALN metastasis, such as bulky PLN or common iliac LN involvement, but with negative PALN on imaging. One of the strengths of our study includes our use of propensity score matching to balance patient and tumor characteristics between groups, reducing effect of potential confounders in our analysis. Other strengths are the inclusion of patients from 3 tertiary care referral centers with similar therapies. All patients received brachytherapy and completed radiation therapy within an acceptable time frame, and most patients received concurrent chemotherapy with the exception of 1 patient in the imaging group due to renal impairment. This study provided adequate long follow-up for evaluation of survival outcomes. We included patients over a 7-year time period and analyzed survival outcomes using both FIGO 2009 and the revised 2018 staging systems, providing valuable prognostic data for the new staging system. Our study had several limitations in addition to being a retrospective review with its inherent bias. The decision for surgical staging was at the discretion of individual surgeons. The surgical approach also varied between surgeons with a mix of laparotomy, laparoscopic and robotic surgery. In addition, we could not account for other potential confounding variables such as patient comorbidities, size of LN metastasis, adjuvant chemotherapy and response to treatment in the study. This inherent selection bias may have obscured the therapeutic effect of surgical LN assessment. Lastly, there was a small sample size included for propensity score matching, and thus not enough patients to reach the power needed to declare noninferiority. However adequate sample size was even difficult to achieve with an estimated patient enrollment of 600 for the LiLACS multi-center prospective randomized clinical trial. In conclusion, radiographic vs surgical PLN and PALN assessment in patients with cervical cancer stage IB2-IIIB had comparable PFS and OS. The authors have no potential financial disclosures. Author contribution

Conception and design of study Data collection Data analysis and interpretation Responsible surgeon or imager Statistical analysis Manuscript preparation Patient recruitment

J. Yang

R. Delara

x x

x x

x x

x

J. Magrina

P. Magtibay

x x

x x

x x

x x

J. Yi x x

x

C. Langstraat

M. Robertson

T. Dinh

K. Butler

x x

x x

x x

x x x x

x x

x

x x

x x

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Please cite this article as: J. Yang, R. Delara, J. Magrina, et al., Comparing survival outcomes between surgical and radiographic lymph node assessment in locally advan..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.009