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Prognostic significance of peritoneal cytology in low-intermediate risk endometrial cancer
YGYNO-976678; No. of pages: 7; 4C: Gynecologic Oncology xxx (2017) xxx–xxx
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Prognostic significance of peritoneal cytology in low-intermediate risk endometrial cancer S.A. Scott a,⁎, C. van der Zanden b, E. Cai c, C.E. McGahan c,d, J.S. Kwon e,f a
Dalhousie University, Canada Radboud University, Netherlands Cancer Surveillance & Outcomes, BC Cancer Agency, Canada d Surgical Oncology Network, BC Cancer Agency, Canada e BC Cancer Agency, Canada f University of British Columbia, Canada b c
H I G H L I G H T S • A retrospective population-based cohort study of endometrial cancer patients was carried out. • Grade, depth of myometrial invasion, LVSI, age and adjuvant therapy were controlled for. • Cytology was not an independent prognostic factor in low or intermediate risk endometrial cancer.
a r t i c l e
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Article history: Received 21 December 2016 Received in revised form 11 March 2017 Accepted 15 March 2017 Available online xxxx Keywords: Peritoneal cytology Endometrial cancer Low and intermediate risk Adjuvant treatment Prognostic factors
a b s t r a c t Objectives. There is uncertainty surrounding the prognostic value and clinical utility of peritoneal cytology in endometrial cancer. Our primary objective was to determine if positive cytology is associated with disease-free and overall survival in women treated surgically for endometrial cancer, specifically those with low or intermediate risk disease. Methods. This was a retrospective population-based cohort study of British Columbia Cancer Registry patients who underwent surgery with peritoneal washings for endometrioid-type endometrial cancer from 2003 to 2009. Low risk was defined as Stage IA grade 1 or 2, and intermediate risk defined as Stage IA grade 3, or Stage IB grade 1 or 2 tumours. Five-year overall and disease free-survival were assessed using Kaplan-Meier estimation. Potential covariates including peritoneal cytology, grade, depth of myometrial invasion, LVSI, age, and adjuvant therapy were evaluated in a multivariable Cox proportional hazards model. Results. There were 849 patients, of whom 370 (43.6%) and 298 (35.1%) had low- and intermediate-risk disease, respectively. Overall, forty-nine (5.8%) patients had positive cytology, including 6 and 9 with low- and intermediate-risk respectively (2.2% within low and intermediate risk combined). Positive peritoneal cytology was not significantly associated with disease-free (HR 3.17, 95% CI 0.91–11.03) or overall survival (HR 1.33, 95% CI 0.47–3.76) in low and intermediate risk patients. Only age and extensive LVSI were associated with lower overall survival (HR 1.10, 95% CI 1.08–1.13, and HR 2.39, 95% CI 1.02–5.61, respectively). Conclusions. Positive peritoneal cytology was not associated with disease-free and overall survival in women with low and intermediate risk endometrial cancer. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Prior to 2009 positive peritoneal cytology was utilized in endometrial cancer staging and influenced adjuvant treatment decisions ⁎ Corresponding author at: 5820 University Avenue, Room 5007, 5th floor Dickson Building, Halifax, Nova Scotia, Canada. E-mail address: [email protected] (S.A. Scott).
[1]. However, there was limited evidence demonstrating an independent association between positive cytology and adverse outcome in endometrial cancer. Although positive cytology is correlated with established adverse prognostic factors in endometrial cancer, the prognostic significance of positive cytology in isolation continues to be debated [1–10]. Although not an invasive or time-consuming intervention the cost associated with this practice is not insignificant [12].
http://dx.doi.org/10.1016/j.ygyno.2017.03.011 0090-8258/© 2017 Elsevier Inc. All rights reserved.
Please cite this article as: S.A. Scott, et al., Prognostic significance of peritoneal cytology in low-intermediate risk endometrial cancer, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.011
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S.A. Scott et al. / Gynecologic Oncology xxx (2017) xxx–xxx
In 2013, Garg et al. reported a superior disease-free survival in women with Stage I and II endometrial cancer with negative cytology [8]. The authors concluded that positive peritoneal cytology is an independent risk factor for patients with early stage endometrial cancer. Notably absent from the multivariate analysis within the aforementioned study were depth of myometrial invasion, LVSI, and adjuvant chemotherapy, all recognized to influence outcomes in endometrial cancer [13–15]. The primary objective of this study was to determine if positive cytology is independently associated with disease-free and overall survival in women treated surgically for endometrial cancer within a population, and specifically among those with low or intermediate risk disease. The secondary objective was to estimate what proportion of patients would have their treatment plan altered as a result of peritoneal cytology. 2. Methods We carried out a population-based retrospective cohort study of British Columbia Cancer Registry patients who had surgery for endometrioidtype endometrial cancer between January 1, 2003 and December 31, 2009. Although peritoneal cytology was excluded from the new FIGO staging classification for endometrial cancer in 2009, the procedure of obtaining washings for cytologic analysis (peritoneal cytology) was routinely done through most of 2009, and consistently for the preceding 5 years. Approval for this study was granted by the Research Ethics Board of the University of British Columbia/BC Cancer Agency. Data was extracted from patient records through the Cancer Agency Information System (CAIS) at the BC Cancer Agency, including age at diagnosis, surgical procedure, surgical stage, peritoneal cytology, tumour grade, histotype, depth of myometrial invasion, cervical stromal invasion, presence or absence of extrauterine disease including adnexal and/or serosal involvement, nodal metastases, distant metastases, LVSI, type of adjuvant therapy, date and status at last follow-up, date and site(s) of recurrence, and date of death if applicable. Patients were excluded if they had non-endometrioid histology, if they did not have peritoneal cytology performed as part of their initial surgery, or if they had neoadjuvant therapy (chemotherapy and/or radiotherapy). Kaplan-Meier method was used to estimate the survival probabilities of patients until death from any cause (overall survival) or recurrence (disease-free survival). Kaplan-Meier plots were generated while stratifying by peritoneal cytology results, and log-rank tests were used to assess the difference in survival according to peritoneal cytology status. Cox proportional hazards regression was used to model the hazard of death or recurrence. This analysis was performed on the entire cohort as well as on only those patients with low or intermediate risk Stage I disease. Patients with Stage I disease were categorized as low, intermediate and high risk, based on ESMO (European Society of Medical Oncology) criteria, according to the number of high-risk uterine factors present within the hysterectomy specimen [16]. Low risk was defined as grade 1 or 2 endometrioid cancers confined to the endometrium or b 50% myometrial invasion. Intermediate risk patients included those who had Stage 1A grade 3 or Stage 1B grade 1 or 2 disease. High-risk was defined as those with Stage IB grade 3 disease, Stage II, III, or IV disease. In British Columbia, women with low-risk disease endometrial cancer do not require adjuvant therapy, and those with intermediate risk are offered vault brachytherapy [17]. The only exception is the presence of LVSI, in which case they are offered pelvic radiotherapy. Women with high-risk disease (Stage IB grade 3 endometrioid carcinomas, and all non-endometrioid types) are generally offered adjuvant chemotherapy and involved field radiotherapy [17]. Because positive peritoneal cytology implies the possibility of intraperitoneal spread and may be associated with a worse outcome (higher risk of recurrence and mortality), positive peritoneal cytology could arguably justify adjuvant chemotherapy, which has been shown to improve survival in both early and advanced stage disease [13,18,19]. This would be particularly relevant to the low- and intermediate-risk group patients, whose adjuvant treatment recommendations would change as a result of peritoneal cytology
results. For this reason, we combined the low- and intermediate risk group patients and estimated the number of patients requiring washings for peritoneal cytology in order to alter one adjuvant treatment decision (number needed to treat, or NNT), assuming that positive cytology would justify adjuvant chemotherapy. Based on this NNT and assuming a survival benefit from chemotherapy, we estimated the potential survival benefit from washings in low-intermediate risk patients. 3. Results We identified 849 patients who had primary surgery for endometrioid-type endometrial cancer including washings for peritoneal cytology between 2003 and 2009 in British Columbia. The median follow-up was 40 months (1–143 months). Within this cohort, there were 370 women with low-risk, 298 with intermediate-risk, 56 with high-risk Stage I, 66 with Stage II and 59 with Stage III or IV disease. An additional 12 patients were found to have synchronous primaries of the endometrium and ovary, who were excluded from the remainder of the analysis. Within the entire population the rate of positive cytology was 5.8% (49/849). Of the combined 668 patients with low or intermediate risk disease (comprising 78.7% of the entire cohort), we found a positive cytology rate of 2.2% (15/668) (Table 1). Within the combined low/intermediate risk group, patients with positive cytology had inferior diseasefree and overall survival rates compared to those with negative cytology (Fig. 1). However, after controlling for grade, myometrial invasion, cervical stromal invasion, stage, LVSI, age at surgery and adjuvant treatment in the multivariable Cox model, positive cytology was no longer associated with disease-free or overall survival (Table 2). Only age,
Table 1 Peritoneal cytology and other covariates in low-intermediate risk endometrial cancer Peritoneal Cytology Test Result
All Patients Stage 1 - Low 1 - Intermediate Lymphovascular Space Involvement Focal Extensive None Depth of Myometrial Invasion b 50% N 50% Negative Nodes Not Sampled Negative Depth of Cervical Invasion Mucosal None Tumour Grade 1 2 3 External Beam Radiation Therapy Yes No Vaginal Vault Brachytherapy Yes No Chemotherapy (Adjuvant) Yes No
Positive
Negative
All
N
%
N
%
N
%
15 6
100.0 40.0
653 364
100.0 55.7
668 370
100.0 55.4
0.2635
9 6
60.0 40.0
289 117
44.3 17.9
298 123
44.6 18.4
0.0089
2 7 6
13.3 46.7 40.0
22 514 296
3.4 78.7 45.3
24 521 302
3.6 78.0 45.2
0.3559
8 1 14
53.3 6.7 93.3
223 134 436
34.2 20.5 66.8
231 135 450
34.6 20.2 67.4
0.0703
1 2
6.7 13.3
217 45
33.2 6.9
218 47
32.6 7.0
1.0000
13 5
86.7 33.3
608 311
93.1 47.6
621 316
93.0 47.3
0.3733
9 1 9
60.0 6.7 60.0
276 66 128
42.3 10.1 19.6
285 67 137
42.7 10.0 20.5
0.00096
6 11
40.0 73.3
525 201
80.4 30.8
531 212
79.5 31.7
0.00073
4 8
26.7 53.3
452 19
69.2 2.9
456 27
68.3 4.0
b 0.0001
7
46.7
634
97.1
641
96.0
P-value
Please cite this article as: S.A. Scott, et al., Prognostic significance of peritoneal cytology in low-intermediate risk endometrial cancer, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.011
S.A. Scott et al. / Gynecologic Oncology xxx (2017) xxx–xxx
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Fig. 1. Disease-free and overall survival in low-intermediate risk patients.
extensive LVSI, and chemotherapy were associated with an inferior overall survival, although these numbers are small. Adjuvant treatment and recurrence patterns for low and intermediate risk women are illustrated in Figs. 2 and 3, respectively. In the low risk group, only 6 had positive cytology, 3 of whom received chemotherapy. None of these patients recurred. Of the remaining 3 women who did not receive chemotherapy, one recurred at the vaginal vault (Fig. 2). Of the 9 patients with intermediate risk disease and positive cytology, only 2 recurrences were noted, which were both abdominal, including 1 of 4 who had received adjuvant chemotherapy, and 1 of 3 who had received adjuvant external beam pelvic radiotherapy (Fig. 3). We estimated the number of patients who could have benefitted from the addition of chemotherapy as a result of positive peritoneal
Table 2 Multivariable model for low-intermediate risk patients.
Covariate
Disease-free survival HR (95% CI)
Overall survival HR (95% CI)
Cytology positive Grade 3 N50% Myoinvasion Extensive LVSI Age EBRT Vault BT Chemotherapy
3.17 (0.91–11.03) 1.81 (0.78–4.19) 1.00 (0.42–2.39) 2.21 (0.72–6.77) 1.00 (0.98–1.03) 0.80 (0.32–1.87) 0.59 (0.28–1.25) 1.73 (0.62–4.85)
1.32 (0.47–3.76) 1.52 (0.78–2.98) 0.84 (0.43–1.64) 2.39 (1.02–5.61) 1.10 (1.08–1.13) 0.57 (0.30–1.08) 1.55 (0.92–2.63) 6.14 (2.57–14.64)
LVSI = lymphovascular space invasion; EBRT = external beam radiotherapy; BT = brachytherapy.
Please cite this article as: S.A. Scott, et al., Prognostic significance of peritoneal cytology in low-intermediate risk endometrial cancer, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.011
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S.A. Scott et al. / Gynecologic Oncology xxx (2017) xxx–xxx
Fig. 2. Treatment and outcomes in low risk patients. LVSI = lymphovascular space invasion; EBRT = external beam radiotherapy; BT = brachytherapy.
cytology, who would otherwise not receive this adjuvant therapy. Only those with low- and intermediate risk disease might have benefitted from this procedure, as all high-risk patients would have been offered chemotherapy according to provincial treatment policy [17], regardless of peritoneal cytology results. The majority of women in our study had low-intermediate risk disease (668/849, 78.7%), but only 15 of this subgroup (2.2%) had positive cytology. Therefore adjuvant treatment decisions could be influenced in 15 women with positive cytology out of 849 having washings for peritoneal cytology, which translates into a number needed to treat (to obtain washings for cytology) of 57, in order to change treatment for one patient. However, as discussed above, among those with low-intermediate risk disease and positive peritoneal cytology, there was no difference in outcomes between those who did and did not receive adjuvant chemotherapy (Figs. 2 & 3). 4. Discussion In this population-based study, our rates of peritoneal washings with positive cytology were low and consistent with those reported in other studies. We found inferior disease-free and overall survival rates among those with positive cytology compared to negative cytology
with low-intermediate risk endometrial cancer. However, after controlling for other risk factors, there was no longer a significant association between cytology and outcome. The utility and clinical significance of malignant cells in peritoneal washings in endometrial cancer has long been debated and the gynecologic oncology community remains divided [10]. In a survey of gynecologic oncologists, 66% felt that cytology should remain in the current staging system, however recommendations regarding adjuvant therapy were variable in the setting of isolated positive peritoneal cytology. For grades 1 and 2 endometrioid histology, 46% and 62% of surveyed gynecologic oncologists, respectively, would recommend adjuvant treatment based on positive cytology alone [10]. Numerous authors have reported on the association between positive peritoneal cytology and adverse outcomes in patients with endometrial cancer [1,5–8]. Positive cytology has been correlated with other known adverse prognostic factors in endometrial cancer such as grade, stage, myometrial invasion, and LVSI [3]. Many of the aforementioned studies did not control for uterine factors that may confound the prognostic significance of positive peritoneal cytology [8]. Garg et al. published a large study from the SEER database on 14,704 patients with Stage I and II endometrial cancer, for whom the incidence
Fig. 3. Treatment and outcomes in intermediate risk patients. LVSI = lymphovascular space invasion; EBRT = external beam radiotherapy; BT = brachytherapy.
Please cite this article as: S.A. Scott, et al., Prognostic significance of peritoneal cytology in low-intermediate risk endometrial cancer, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.011
S.A. Scott et al. / Gynecologic Oncology xxx (2017) xxx–xxx
of positive cytology was 3%. The 5-year disease specific survival was worse among patients with endometrioid carcinoma and positive peritoneal cytology compared to negative cytology (80.8% versus 95.1%). These observations are consistent with our population-based study. The authors' conclusion was that positive peritoneal cytology is an independent risk factor in patients with early Stage (I and II) endometrial cancer and that cytology should still be considered for accurate risk stratification. They acknowledge several limitations to their study, including the inability to evaluate the association of LVSI or depth of myometrial invasion, two well-known prognostic factors in endometrial cancer, in their multivariate analysis [8]. There was also no information about chemotherapy, and therefore ongoing uncertainty about whether positive cytology should influence adjuvant treatment decisions. Others have failed to demonstrate the prognostic significance of positive peritoneal cytology in isolation [3,4,9]. Takeshima et al., in 2001 reported on 534 patients stratified into low, moderate and high risk groups. Among the 250 low-risk patients, there was no difference in 5-year disease-free survival between positive and negative cytology (98.1 vs. 100%, respectively) [3]. Similarly, Kasamatsu et al. demonstrated no significant difference in outcomes between women with positive and negative peritoneal cytology in their study of 280 women with Stage I endometrial cancer (3-year DFS 90% vs. 94%, log-rank p = 0.52, and 5-year OS 91% vs. 95%, log-rank p = 0.42, respectively). None of these patients received adjuvant therapy [4]. There is uncertainty about the role of adjuvant therapy among women with low-intermediate risk disease and positive peritoneal cytology, as no studies have shown clear evidence of benefit to individual patients in this setting. Slomovitz et al. reported no difference in outcomes between treated and untreated patients in the setting of isolated positive peritoneal cytology [11]. It may be that the available studies, including ours, do not have sufficient numbers of patients to demonstrate a benefit from adjuvant therapy. The rate of positive cytology among early stage patients is low (2–4%), and these women appear to do well in the absence of adjuvant therapy. Takeshima et al. reported a 1.8% recurrence rate among cytology-positive low-risk patients who did not receive adjuvant therapy (3). Pooled data estimate that the overall risk of recurrence in low-risk early stage endometrioid carcinoma with positive cytology (former Stage IIIA1) is 4.1%, irrespective of treatment [2]. In our study, adjuvant therapy was variable for those with low-intermediate risk disease and positive cytology, ranging from none to chemotherapy, with or without radiotherapy. Although chemotherapy was associated with an inferior overall survival, there were only 27 patients with low-intermediate risk disease who received chemotherapy, and there may have been other unrecognized risk factors that influenced the decision to offer such treatment. The numbers are likely too small to determine if treatment improves outcome, as the positive cytology rate and the event rates (recurrence or death) are so low. We determined that the number needed to treat (to obtain washings for peritoneal cytology) to identify women with low or intermediate risk disease and positive cytology was 57. However, in the absence of evidence for a benefit of adjuvant therapy, the utility of this information remains unknown. Assuming that chemotherapy is the logical treatment choice because of the theoretical risk of intraperitoneal metastases, the absolute benefit of chemotherapy is unlikely to be that high, if it exists at all. We did not find a survival benefit from chemotherapy among low-intermediate risk patients in our study, although the numbers were low. Preliminary results from GOG 249 did not reveal a survival benefit associated with chemotherapy in high-intermediate risk endometrial cancer [20], which means that a significant survival benefit in low-intermediate risk disease is even less likely. In contrast, the absolute survival benefit in high-risk early stage patients from the pooled NSGO/EORTC/MaNGO ILIADE-III trials was 10% (improvement from 74% to 84%) [19]. Even if the absolute survival benefit from chemotherapy in the low-intermediate risk group was as high as 10%, this treatment could only be justified to those with positive cytology,
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representing just over 2% of all low-intermediate risk patients. This means that a maximum of 10% (improvement in survival) among 2.2% (low-intermediate risk patients with positive peritoneal cytology), among 79% (of all endometrioid endometrial cancer patients), could benefit from having washings for peritoneal cytology, which translates into 0.17% of the entire cohort (1.5 in 849, or 1 in 588). This estimation of survival benefit is illustrated in Fig. 4. Furthermore, although obtaining peritoneal cytology is a low-risk procedure it is not cost-neutral [12]. In their 1999 study Sharifi et al. reported a cost of $60–76 USD for processing and analyzing peritoneal cytology [12]. Seventeen years later in Canada this value approaches $150 when collection equipment, fixative and interpretation are taken into account [21]. Given the estimated 1 in 588 unselected endometrial cancer patients whose survival might be improved as a result of peritoneal washings for cytology and subsequent chemotherapy, this yields a cost of at least $88,000 in processing peritoneal washings (not including costs of chemotherapy) to potentially improve the survival of one patient. This is almost certainly an underestimate of the true cost to improve survival for one patient, as the survival benefit of 10% is likely an overestimate. The major strengths of this study are our large sample size, population-based data, and details on uterine risk factors and adjuvant treatment, both well-recognized confounding factors, which must be taken into account when evaluating the effect of positive peritoneal cytology. This study specifically evaluated the association of peritoneal cytology in low and intermediate risk patients, whose adjuvant treatment may change as a result of this information. Limitations of our study include the small number of patients in the low and intermediate risk group with a low positive cytology rate and event rate. There may not have been enough patients with positive cytology to find a difference in outcome according to cytology status. We did not evaluate the association between cytology and outcome specifically in the high-risk subgroup of patients (Stage IB grade 3, and Stages II, III, and IV), because the identification of positive cytology in the high-risk group would not influence adjuvant treatment, as these women are eligible for chemotherapy and radiotherapy according to provincial treatment policy [17]. We also did not evaluate the effect of peritoneal cytology in non-endometrioid cancers. The metastatic potential of these cancers is much different than endometrioid cancers, and it is possible that peritoneal cytology may influence outcome, specifically among those with disease confined to the endometrium, who would not be offered adjuvant therapy after comprehensive surgical staging in our province [17].
5. Conclusion It is important to recognize that women with low or intermediate risk disease generally do very well, irrespective of adjuvant therapy and peritoneal cytology status. The majority of these women will be cured by surgery alone. Although we are no longer routinely evaluating washings for peritoneal cytology in our population, we acknowledge that this remains a controversial topic and that it is still done in many jurisdictions. Given the low rate of positive cytology and the estimated small absolute benefit associated with chemotherapy in the low-intermediate risk subgroup, and the costs associated with these interventions, further evidence is needed to justify the practice of routine washings for peritoneal cytology during surgery for women with endometrioid-type endometrial cancer. Conflict of interest statement The authors declare that there are no conflicts of interest associated with this manuscript.
Funding The authors acknowledge support from the British Columbia Surgical Oncology Network.
Please cite this article as: S.A. Scott, et al., Prognostic significance of peritoneal cytology in low-intermediate risk endometrial cancer, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.011
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S.A. Scott et al. / Gynecologic Oncology xxx (2017) xxx–xxx
Fig. 4. Estimation of the effect of washings on treatment and survival.
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Please cite this article as: S.A. Scott, et al., Prognostic significance of peritoneal cytology in low-intermediate risk endometrial cancer, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.011
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Prognostic significance of peritoneal cytology in low-intermediate risk endometrial cancer S.A. Scott a,⁎, C. van der Zanden b, E. Cai c, C.E. McGahan c,d, J.S. Kwon e,f a
Dalhousie University, Canada Radboud University, Netherlands Cancer Surveillance & Outcomes, BC Cancer Agency, Canada d Surgical Oncology Network, BC Cancer Agency, Canada e BC Cancer Agency, Canada f University of British Columbia, Canada b c
H I G H L I G H T S • A retrospective population-based cohort study of endometrial cancer patients was carried out. • Grade, depth of myometrial invasion, LVSI, age and adjuvant therapy were controlled for. • Cytology was not an independent prognostic factor in low or intermediate risk endometrial cancer.
a r t i c l e
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Article history: Received 21 December 2016 Received in revised form 11 March 2017 Accepted 15 March 2017 Available online xxxx Keywords: Peritoneal cytology Endometrial cancer Low and intermediate risk Adjuvant treatment Prognostic factors
a b s t r a c t Objectives. There is uncertainty surrounding the prognostic value and clinical utility of peritoneal cytology in endometrial cancer. Our primary objective was to determine if positive cytology is associated with disease-free and overall survival in women treated surgically for endometrial cancer, specifically those with low or intermediate risk disease. Methods. This was a retrospective population-based cohort study of British Columbia Cancer Registry patients who underwent surgery with peritoneal washings for endometrioid-type endometrial cancer from 2003 to 2009. Low risk was defined as Stage IA grade 1 or 2, and intermediate risk defined as Stage IA grade 3, or Stage IB grade 1 or 2 tumours. Five-year overall and disease free-survival were assessed using Kaplan-Meier estimation. Potential covariates including peritoneal cytology, grade, depth of myometrial invasion, LVSI, age, and adjuvant therapy were evaluated in a multivariable Cox proportional hazards model. Results. There were 849 patients, of whom 370 (43.6%) and 298 (35.1%) had low- and intermediate-risk disease, respectively. Overall, forty-nine (5.8%) patients had positive cytology, including 6 and 9 with low- and intermediate-risk respectively (2.2% within low and intermediate risk combined). Positive peritoneal cytology was not significantly associated with disease-free (HR 3.17, 95% CI 0.91–11.03) or overall survival (HR 1.33, 95% CI 0.47–3.76) in low and intermediate risk patients. Only age and extensive LVSI were associated with lower overall survival (HR 1.10, 95% CI 1.08–1.13, and HR 2.39, 95% CI 1.02–5.61, respectively). Conclusions. Positive peritoneal cytology was not associated with disease-free and overall survival in women with low and intermediate risk endometrial cancer. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Prior to 2009 positive peritoneal cytology was utilized in endometrial cancer staging and influenced adjuvant treatment decisions ⁎ Corresponding author at: 5820 University Avenue, Room 5007, 5th floor Dickson Building, Halifax, Nova Scotia, Canada. E-mail address: [email protected] (S.A. Scott).
[1]. However, there was limited evidence demonstrating an independent association between positive cytology and adverse outcome in endometrial cancer. Although positive cytology is correlated with established adverse prognostic factors in endometrial cancer, the prognostic significance of positive cytology in isolation continues to be debated [1–10]. Although not an invasive or time-consuming intervention the cost associated with this practice is not insignificant [12].
http://dx.doi.org/10.1016/j.ygyno.2017.03.011 0090-8258/© 2017 Elsevier Inc. All rights reserved.
Please cite this article as: S.A. Scott, et al., Prognostic significance of peritoneal cytology in low-intermediate risk endometrial cancer, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.011
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S.A. Scott et al. / Gynecologic Oncology xxx (2017) xxx–xxx
In 2013, Garg et al. reported a superior disease-free survival in women with Stage I and II endometrial cancer with negative cytology [8]. The authors concluded that positive peritoneal cytology is an independent risk factor for patients with early stage endometrial cancer. Notably absent from the multivariate analysis within the aforementioned study were depth of myometrial invasion, LVSI, and adjuvant chemotherapy, all recognized to influence outcomes in endometrial cancer [13–15]. The primary objective of this study was to determine if positive cytology is independently associated with disease-free and overall survival in women treated surgically for endometrial cancer within a population, and specifically among those with low or intermediate risk disease. The secondary objective was to estimate what proportion of patients would have their treatment plan altered as a result of peritoneal cytology. 2. Methods We carried out a population-based retrospective cohort study of British Columbia Cancer Registry patients who had surgery for endometrioidtype endometrial cancer between January 1, 2003 and December 31, 2009. Although peritoneal cytology was excluded from the new FIGO staging classification for endometrial cancer in 2009, the procedure of obtaining washings for cytologic analysis (peritoneal cytology) was routinely done through most of 2009, and consistently for the preceding 5 years. Approval for this study was granted by the Research Ethics Board of the University of British Columbia/BC Cancer Agency. Data was extracted from patient records through the Cancer Agency Information System (CAIS) at the BC Cancer Agency, including age at diagnosis, surgical procedure, surgical stage, peritoneal cytology, tumour grade, histotype, depth of myometrial invasion, cervical stromal invasion, presence or absence of extrauterine disease including adnexal and/or serosal involvement, nodal metastases, distant metastases, LVSI, type of adjuvant therapy, date and status at last follow-up, date and site(s) of recurrence, and date of death if applicable. Patients were excluded if they had non-endometrioid histology, if they did not have peritoneal cytology performed as part of their initial surgery, or if they had neoadjuvant therapy (chemotherapy and/or radiotherapy). Kaplan-Meier method was used to estimate the survival probabilities of patients until death from any cause (overall survival) or recurrence (disease-free survival). Kaplan-Meier plots were generated while stratifying by peritoneal cytology results, and log-rank tests were used to assess the difference in survival according to peritoneal cytology status. Cox proportional hazards regression was used to model the hazard of death or recurrence. This analysis was performed on the entire cohort as well as on only those patients with low or intermediate risk Stage I disease. Patients with Stage I disease were categorized as low, intermediate and high risk, based on ESMO (European Society of Medical Oncology) criteria, according to the number of high-risk uterine factors present within the hysterectomy specimen [16]. Low risk was defined as grade 1 or 2 endometrioid cancers confined to the endometrium or b 50% myometrial invasion. Intermediate risk patients included those who had Stage 1A grade 3 or Stage 1B grade 1 or 2 disease. High-risk was defined as those with Stage IB grade 3 disease, Stage II, III, or IV disease. In British Columbia, women with low-risk disease endometrial cancer do not require adjuvant therapy, and those with intermediate risk are offered vault brachytherapy [17]. The only exception is the presence of LVSI, in which case they are offered pelvic radiotherapy. Women with high-risk disease (Stage IB grade 3 endometrioid carcinomas, and all non-endometrioid types) are generally offered adjuvant chemotherapy and involved field radiotherapy [17]. Because positive peritoneal cytology implies the possibility of intraperitoneal spread and may be associated with a worse outcome (higher risk of recurrence and mortality), positive peritoneal cytology could arguably justify adjuvant chemotherapy, which has been shown to improve survival in both early and advanced stage disease [13,18,19]. This would be particularly relevant to the low- and intermediate-risk group patients, whose adjuvant treatment recommendations would change as a result of peritoneal cytology
results. For this reason, we combined the low- and intermediate risk group patients and estimated the number of patients requiring washings for peritoneal cytology in order to alter one adjuvant treatment decision (number needed to treat, or NNT), assuming that positive cytology would justify adjuvant chemotherapy. Based on this NNT and assuming a survival benefit from chemotherapy, we estimated the potential survival benefit from washings in low-intermediate risk patients. 3. Results We identified 849 patients who had primary surgery for endometrioid-type endometrial cancer including washings for peritoneal cytology between 2003 and 2009 in British Columbia. The median follow-up was 40 months (1–143 months). Within this cohort, there were 370 women with low-risk, 298 with intermediate-risk, 56 with high-risk Stage I, 66 with Stage II and 59 with Stage III or IV disease. An additional 12 patients were found to have synchronous primaries of the endometrium and ovary, who were excluded from the remainder of the analysis. Within the entire population the rate of positive cytology was 5.8% (49/849). Of the combined 668 patients with low or intermediate risk disease (comprising 78.7% of the entire cohort), we found a positive cytology rate of 2.2% (15/668) (Table 1). Within the combined low/intermediate risk group, patients with positive cytology had inferior diseasefree and overall survival rates compared to those with negative cytology (Fig. 1). However, after controlling for grade, myometrial invasion, cervical stromal invasion, stage, LVSI, age at surgery and adjuvant treatment in the multivariable Cox model, positive cytology was no longer associated with disease-free or overall survival (Table 2). Only age,
Table 1 Peritoneal cytology and other covariates in low-intermediate risk endometrial cancer Peritoneal Cytology Test Result
All Patients Stage 1 - Low 1 - Intermediate Lymphovascular Space Involvement Focal Extensive None Depth of Myometrial Invasion b 50% N 50% Negative Nodes Not Sampled Negative Depth of Cervical Invasion Mucosal None Tumour Grade 1 2 3 External Beam Radiation Therapy Yes No Vaginal Vault Brachytherapy Yes No Chemotherapy (Adjuvant) Yes No
Positive
Negative
All
N
%
N
%
N
%
15 6
100.0 40.0
653 364
100.0 55.7
668 370
100.0 55.4
0.2635
9 6
60.0 40.0
289 117
44.3 17.9
298 123
44.6 18.4
0.0089
2 7 6
13.3 46.7 40.0
22 514 296
3.4 78.7 45.3
24 521 302
3.6 78.0 45.2
0.3559
8 1 14
53.3 6.7 93.3
223 134 436
34.2 20.5 66.8
231 135 450
34.6 20.2 67.4
0.0703
1 2
6.7 13.3
217 45
33.2 6.9
218 47
32.6 7.0
1.0000
13 5
86.7 33.3
608 311
93.1 47.6
621 316
93.0 47.3
0.3733
9 1 9
60.0 6.7 60.0
276 66 128
42.3 10.1 19.6
285 67 137
42.7 10.0 20.5
0.00096
6 11
40.0 73.3
525 201
80.4 30.8
531 212
79.5 31.7
0.00073
4 8
26.7 53.3
452 19
69.2 2.9
456 27
68.3 4.0
b 0.0001
7
46.7
634
97.1
641
96.0
P-value
Please cite this article as: S.A. Scott, et al., Prognostic significance of peritoneal cytology in low-intermediate risk endometrial cancer, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.011
S.A. Scott et al. / Gynecologic Oncology xxx (2017) xxx–xxx
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Fig. 1. Disease-free and overall survival in low-intermediate risk patients.
extensive LVSI, and chemotherapy were associated with an inferior overall survival, although these numbers are small. Adjuvant treatment and recurrence patterns for low and intermediate risk women are illustrated in Figs. 2 and 3, respectively. In the low risk group, only 6 had positive cytology, 3 of whom received chemotherapy. None of these patients recurred. Of the remaining 3 women who did not receive chemotherapy, one recurred at the vaginal vault (Fig. 2). Of the 9 patients with intermediate risk disease and positive cytology, only 2 recurrences were noted, which were both abdominal, including 1 of 4 who had received adjuvant chemotherapy, and 1 of 3 who had received adjuvant external beam pelvic radiotherapy (Fig. 3). We estimated the number of patients who could have benefitted from the addition of chemotherapy as a result of positive peritoneal
Table 2 Multivariable model for low-intermediate risk patients.
Covariate
Disease-free survival HR (95% CI)
Overall survival HR (95% CI)
Cytology positive Grade 3 N50% Myoinvasion Extensive LVSI Age EBRT Vault BT Chemotherapy
3.17 (0.91–11.03) 1.81 (0.78–4.19) 1.00 (0.42–2.39) 2.21 (0.72–6.77) 1.00 (0.98–1.03) 0.80 (0.32–1.87) 0.59 (0.28–1.25) 1.73 (0.62–4.85)
1.32 (0.47–3.76) 1.52 (0.78–2.98) 0.84 (0.43–1.64) 2.39 (1.02–5.61) 1.10 (1.08–1.13) 0.57 (0.30–1.08) 1.55 (0.92–2.63) 6.14 (2.57–14.64)
LVSI = lymphovascular space invasion; EBRT = external beam radiotherapy; BT = brachytherapy.
Please cite this article as: S.A. Scott, et al., Prognostic significance of peritoneal cytology in low-intermediate risk endometrial cancer, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.011
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S.A. Scott et al. / Gynecologic Oncology xxx (2017) xxx–xxx
Fig. 2. Treatment and outcomes in low risk patients. LVSI = lymphovascular space invasion; EBRT = external beam radiotherapy; BT = brachytherapy.
cytology, who would otherwise not receive this adjuvant therapy. Only those with low- and intermediate risk disease might have benefitted from this procedure, as all high-risk patients would have been offered chemotherapy according to provincial treatment policy [17], regardless of peritoneal cytology results. The majority of women in our study had low-intermediate risk disease (668/849, 78.7%), but only 15 of this subgroup (2.2%) had positive cytology. Therefore adjuvant treatment decisions could be influenced in 15 women with positive cytology out of 849 having washings for peritoneal cytology, which translates into a number needed to treat (to obtain washings for cytology) of 57, in order to change treatment for one patient. However, as discussed above, among those with low-intermediate risk disease and positive peritoneal cytology, there was no difference in outcomes between those who did and did not receive adjuvant chemotherapy (Figs. 2 & 3). 4. Discussion In this population-based study, our rates of peritoneal washings with positive cytology were low and consistent with those reported in other studies. We found inferior disease-free and overall survival rates among those with positive cytology compared to negative cytology
with low-intermediate risk endometrial cancer. However, after controlling for other risk factors, there was no longer a significant association between cytology and outcome. The utility and clinical significance of malignant cells in peritoneal washings in endometrial cancer has long been debated and the gynecologic oncology community remains divided [10]. In a survey of gynecologic oncologists, 66% felt that cytology should remain in the current staging system, however recommendations regarding adjuvant therapy were variable in the setting of isolated positive peritoneal cytology. For grades 1 and 2 endometrioid histology, 46% and 62% of surveyed gynecologic oncologists, respectively, would recommend adjuvant treatment based on positive cytology alone [10]. Numerous authors have reported on the association between positive peritoneal cytology and adverse outcomes in patients with endometrial cancer [1,5–8]. Positive cytology has been correlated with other known adverse prognostic factors in endometrial cancer such as grade, stage, myometrial invasion, and LVSI [3]. Many of the aforementioned studies did not control for uterine factors that may confound the prognostic significance of positive peritoneal cytology [8]. Garg et al. published a large study from the SEER database on 14,704 patients with Stage I and II endometrial cancer, for whom the incidence
Fig. 3. Treatment and outcomes in intermediate risk patients. LVSI = lymphovascular space invasion; EBRT = external beam radiotherapy; BT = brachytherapy.
Please cite this article as: S.A. Scott, et al., Prognostic significance of peritoneal cytology in low-intermediate risk endometrial cancer, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.011
S.A. Scott et al. / Gynecologic Oncology xxx (2017) xxx–xxx
of positive cytology was 3%. The 5-year disease specific survival was worse among patients with endometrioid carcinoma and positive peritoneal cytology compared to negative cytology (80.8% versus 95.1%). These observations are consistent with our population-based study. The authors' conclusion was that positive peritoneal cytology is an independent risk factor in patients with early Stage (I and II) endometrial cancer and that cytology should still be considered for accurate risk stratification. They acknowledge several limitations to their study, including the inability to evaluate the association of LVSI or depth of myometrial invasion, two well-known prognostic factors in endometrial cancer, in their multivariate analysis [8]. There was also no information about chemotherapy, and therefore ongoing uncertainty about whether positive cytology should influence adjuvant treatment decisions. Others have failed to demonstrate the prognostic significance of positive peritoneal cytology in isolation [3,4,9]. Takeshima et al., in 2001 reported on 534 patients stratified into low, moderate and high risk groups. Among the 250 low-risk patients, there was no difference in 5-year disease-free survival between positive and negative cytology (98.1 vs. 100%, respectively) [3]. Similarly, Kasamatsu et al. demonstrated no significant difference in outcomes between women with positive and negative peritoneal cytology in their study of 280 women with Stage I endometrial cancer (3-year DFS 90% vs. 94%, log-rank p = 0.52, and 5-year OS 91% vs. 95%, log-rank p = 0.42, respectively). None of these patients received adjuvant therapy [4]. There is uncertainty about the role of adjuvant therapy among women with low-intermediate risk disease and positive peritoneal cytology, as no studies have shown clear evidence of benefit to individual patients in this setting. Slomovitz et al. reported no difference in outcomes between treated and untreated patients in the setting of isolated positive peritoneal cytology [11]. It may be that the available studies, including ours, do not have sufficient numbers of patients to demonstrate a benefit from adjuvant therapy. The rate of positive cytology among early stage patients is low (2–4%), and these women appear to do well in the absence of adjuvant therapy. Takeshima et al. reported a 1.8% recurrence rate among cytology-positive low-risk patients who did not receive adjuvant therapy (3). Pooled data estimate that the overall risk of recurrence in low-risk early stage endometrioid carcinoma with positive cytology (former Stage IIIA1) is 4.1%, irrespective of treatment [2]. In our study, adjuvant therapy was variable for those with low-intermediate risk disease and positive cytology, ranging from none to chemotherapy, with or without radiotherapy. Although chemotherapy was associated with an inferior overall survival, there were only 27 patients with low-intermediate risk disease who received chemotherapy, and there may have been other unrecognized risk factors that influenced the decision to offer such treatment. The numbers are likely too small to determine if treatment improves outcome, as the positive cytology rate and the event rates (recurrence or death) are so low. We determined that the number needed to treat (to obtain washings for peritoneal cytology) to identify women with low or intermediate risk disease and positive cytology was 57. However, in the absence of evidence for a benefit of adjuvant therapy, the utility of this information remains unknown. Assuming that chemotherapy is the logical treatment choice because of the theoretical risk of intraperitoneal metastases, the absolute benefit of chemotherapy is unlikely to be that high, if it exists at all. We did not find a survival benefit from chemotherapy among low-intermediate risk patients in our study, although the numbers were low. Preliminary results from GOG 249 did not reveal a survival benefit associated with chemotherapy in high-intermediate risk endometrial cancer [20], which means that a significant survival benefit in low-intermediate risk disease is even less likely. In contrast, the absolute survival benefit in high-risk early stage patients from the pooled NSGO/EORTC/MaNGO ILIADE-III trials was 10% (improvement from 74% to 84%) [19]. Even if the absolute survival benefit from chemotherapy in the low-intermediate risk group was as high as 10%, this treatment could only be justified to those with positive cytology,
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representing just over 2% of all low-intermediate risk patients. This means that a maximum of 10% (improvement in survival) among 2.2% (low-intermediate risk patients with positive peritoneal cytology), among 79% (of all endometrioid endometrial cancer patients), could benefit from having washings for peritoneal cytology, which translates into 0.17% of the entire cohort (1.5 in 849, or 1 in 588). This estimation of survival benefit is illustrated in Fig. 4. Furthermore, although obtaining peritoneal cytology is a low-risk procedure it is not cost-neutral [12]. In their 1999 study Sharifi et al. reported a cost of $60–76 USD for processing and analyzing peritoneal cytology [12]. Seventeen years later in Canada this value approaches $150 when collection equipment, fixative and interpretation are taken into account [21]. Given the estimated 1 in 588 unselected endometrial cancer patients whose survival might be improved as a result of peritoneal washings for cytology and subsequent chemotherapy, this yields a cost of at least $88,000 in processing peritoneal washings (not including costs of chemotherapy) to potentially improve the survival of one patient. This is almost certainly an underestimate of the true cost to improve survival for one patient, as the survival benefit of 10% is likely an overestimate. The major strengths of this study are our large sample size, population-based data, and details on uterine risk factors and adjuvant treatment, both well-recognized confounding factors, which must be taken into account when evaluating the effect of positive peritoneal cytology. This study specifically evaluated the association of peritoneal cytology in low and intermediate risk patients, whose adjuvant treatment may change as a result of this information. Limitations of our study include the small number of patients in the low and intermediate risk group with a low positive cytology rate and event rate. There may not have been enough patients with positive cytology to find a difference in outcome according to cytology status. We did not evaluate the association between cytology and outcome specifically in the high-risk subgroup of patients (Stage IB grade 3, and Stages II, III, and IV), because the identification of positive cytology in the high-risk group would not influence adjuvant treatment, as these women are eligible for chemotherapy and radiotherapy according to provincial treatment policy [17]. We also did not evaluate the effect of peritoneal cytology in non-endometrioid cancers. The metastatic potential of these cancers is much different than endometrioid cancers, and it is possible that peritoneal cytology may influence outcome, specifically among those with disease confined to the endometrium, who would not be offered adjuvant therapy after comprehensive surgical staging in our province [17].
5. Conclusion It is important to recognize that women with low or intermediate risk disease generally do very well, irrespective of adjuvant therapy and peritoneal cytology status. The majority of these women will be cured by surgery alone. Although we are no longer routinely evaluating washings for peritoneal cytology in our population, we acknowledge that this remains a controversial topic and that it is still done in many jurisdictions. Given the low rate of positive cytology and the estimated small absolute benefit associated with chemotherapy in the low-intermediate risk subgroup, and the costs associated with these interventions, further evidence is needed to justify the practice of routine washings for peritoneal cytology during surgery for women with endometrioid-type endometrial cancer. Conflict of interest statement The authors declare that there are no conflicts of interest associated with this manuscript.
Funding The authors acknowledge support from the British Columbia Surgical Oncology Network.
Please cite this article as: S.A. Scott, et al., Prognostic significance of peritoneal cytology in low-intermediate risk endometrial cancer, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.011
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S.A. Scott et al. / Gynecologic Oncology xxx (2017) xxx–xxx
Fig. 4. Estimation of the effect of washings on treatment and survival.
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Please cite this article as: S.A. Scott, et al., Prognostic significance of peritoneal cytology in low-intermediate risk endometrial cancer, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.011