ORIGINAL STUDY
Prognostic Relevance of Celiac Lymph Node Involvement in Ovarian Cancer Alejandra Martı´nez, MD,* Cristophe Pomel, PhD,Þ Thomas Filleron, PhD,þ Marjolein De Cuypere, MD,* Eliane Mery, MD,§ Denis Querleu, PhD,* Laurance Gladieff, MD,|| Mathieu Poilblanc, MD,* and Gwe´nae¨l Ferron, MD*
Objective: The aim of the study was to report on the oncologic outcome of the disease spread to celiac lymph nodes (CLNs) in advanced-stage ovarian cancer patients. Methods: All patients who had CLN resection as part of their cytoreductive surgery for epithelial ovarian, fallopian, or primary peritoneal cancer were identified. Patient demographic data with particular emphasis on operative records to detail the extent and distribution of the disease spread, lymphadenectomy procedures, pathologic data, and follow-up data were included. Results: The median follow-up was 26.3 months. The median overall survival values in the group with positive CLNs and in the group with negative CLNs were 26.9 months and 40.04 months, respectively. The median progression-free survival values in the group with metastatic CLNs and in the group with negative CLNs were 8.8 months and 20.24 months, respectively (P = 0.053). Positive CLNs were associated with progression during or within 6 months after the completion of chemotherapy (P = 0.0044). Tumor burden and extensive disease distribution were significantly associated with poor progression-free survival, shortterm progression, and overall survival. In multivariate analysis, only the CLN status was independently associated with short-term progression. Conclusions: Disease in the CLN is a marker of disease severity, which is associated to a high-risk group of patients with presumed adverse tumor biology, increased risk of lymph node progression, and worst oncologic outcome. Key Words: Ovarian cancer, Celiac lymph node, Cytoreductive surgery, Survival Received May 30, 2013. Accepted for publication October 17, 2013. (Int J Gynecol Cancer 2014;24: 48Y53)
*Department of Surgical Oncology, Claudius Regaud Comprehensive Cancer Center; †Department of Surgical Oncology, Jean Perrin Comprehensive Cancer Center, Clermont-Ferrand, France; Departments of ‡Biostatistics, §Pathology, and ||Medical Oncology, Claudius Regaud Comprehensive Cancer Center, Toulouse, France. Address correspondence and reprint requests to Alejandra Martı´nez, MD, Department of Surgical Oncology, Claudius Regaud Comprehensive Cancer Center, 20-24, Rue Pont-Saint-Pierre, 31052 Toulouse, France. E-mail: [email protected]. The authors declare no conflicts of interest. Copyright * 2014 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000041
48
of upper abdominal diseases increases the T heratetreatment of optimal cytoreduction from 50% to 76% in ovarian
cancer patients.1 Celiac lymph node (CLN) metastases and porta hepatis disease, usually due to retroperitoneal spread from upper abdominal disease, are one of the most frequent locations precluding complete cytoreduction.2 In an attempt to improve optimal cytoreduction rates, we expanded the surgical strategy to resection of metastatic involvement of the porta hepatis, suspected CLNs in patients with epithelial ovarian, fallopian, and primary peritoneal cancer, and demonstrated the feasibility of the procedure with acceptable morbidity.3 Some reports have also shown that the completeness of cytoreduction has a more significant influence on survival than on the extent of metastatic disease before
International Journal of Gynecological Cancer
& Volume 24, Number 1, January 2014
Copyright © 2013 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 24, Number 1, January 2014
CLN Involvement in Ovarian Cancer
review board from our institutions. Medical records were examined, and patient demographic data with particular emphasis on operative records to detail the extent and distribution of the disease spread, lymphadenectomy procedures, pathologic data, and follow-up data were included. Adjuvant chemotherapy was administered within 2 months of surgery, when feasible, at the discretion of the treating oncologist.
Statistical Methodology
FIGURE 1. Overall survival, OS curves according to CLN status. surgery.4 However, metastases to the CLNs could associate to worse survival when compared with patients with similar disease extension without CLN involvement. Main aim of the study was to report on oncologic outcome of disease spread to this location in advanced ovarian cancer patients.
MATERIALS AND METHODS A computer-generated search of the institutional patient database was performed to retrospectively identify all patients who had disease at the porta hepatis or CLN resection as part of the cytoreductive surgery for epithelial ovarian, fallopian, or primary peritoneal cancer between January 2009 and December 2011, at the Claudius Regaud Comprehensive Cancer Center (Toulouse, France) and at the Jean Perrin Comprehensive Cancer Center (Clermont-Ferrand, France). In all cases, the preoperative image study evaluation included a computed tomography of the chest, abdomen, and pelvis, and in selected cases, a positron emission tomography. All surgical procedures were performed by the same senior surgical oncologists as previously described.3 The extent and the distribution of the disease throughout the 13 abdominopelvic regions and surgical outcome were evaluated with the peritoneal cancer index (PCI) and the completeness of cytoreduction score.5 The indication for hepatic and/or CLN resection was based on the intraoperative findings of suspected lymph nodes (LNs), which included those measuring more than 1 cm and/or indurated at palpation. In our institutions, the indication for neoadjuvant chemotherapy was based on the sum of the procedures required to achieve complete cytoreduction, on medical comorbidities, and on the potential to tolerate an extensive procedure. Patients with deep infiltration of the small bowel mesentery, diffuse carcinomatosis involving large parts of the small bowel, stomach, infiltration of the duodenum or pancreas (not limited to the pancreatic tail), or more than 2 bowel resections required to eradicate the disease were considered for neoadjuvant chemotherapy. The study was approved by the institutional
The data were summarized by frequency and percentage for categorical variables and by median and range for continuous variables. All survival times were calculated from the date of diagnosis. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier methods, and a univariate analysis was performed using the log-rank test for categorical variable or the Cox model for continuous variable (Figs 1, 2). The association of all parameters with progression during or before 6 months after the end of chemotherapy was tested for statistical significance using the Pearson W2 test or the Fisher exact test for categorical variables and the Wilcoxon test for continuous variables. Multivariate analysis was performed using the logistic regression modeling. Only the variables statically significant in univariate analysis were taken into account in the multivariate analysis. All reported P values are 2-sided. For all the statistical tests, differences were considered significant at the 5% level. Statistical analyses were performed using the STATA 12.0 software.
RESULTS Demographic and perioperative data from the 41 patients who underwent some kind of CLN resection or resection of metastatic involvement of the porta hepatis are described in Table 1. Seven (17.1%) patients presented with recurrent disease, 6 with primary recurrence, and the other one with a second recurrence 8 months after the completion of chemotherapy. Complete cytoreduction to (CC0) was achieved
FIGURE 2. Progression-free survival, PFS curves according to CLN status.
* 2014 IGCS and ESGO
Copyright © 2013 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
49
International Journal of Gynecological Cancer
Martı´nez et al
& Volume 24, Number 1, January 2014
TABLE 1. Patient characteristics
Age median (range)
All Patients
Negative CLNs
Positive CLNs
61 (22Y77)
59 (22Y72) n (%)
62 (39Y77) n (%)
n Operation Primary Recurrent Neoadjuvant chemotherapy Stage III IV Histologic subtype Serous ovarian cancer Clear cell ovarian cancer Endometrioid ovarian cancer Mixed tumors Primary fallopian tube cancer Primary peritoneum cancer Surgical Data PCI No. anatomic regions Ascites, mL
%
34 7 25
82.9 17.1 61
15 (83.3) 3 (16.7) 12 (66.7)
19 (82.6) 6 (26.1) 13 (56.5)
32 9
78 22
15 (83.3) 3 (16.7)
17 (73.9) 6 (26.1)
30 1 1 2 2 5 Median 18 9 1150
73.2 2.4 2.4 4.9 4.9 12.2 Range 0Y34 0Y13* 30Y10,000
13 (72.2) 0 1 (5.6) 1 (5.6) 1 (5.6) 2 (11.1) Median (Range) 15 (0Y34) 8 (0Y13)* 350 (30Y4300)*
17 (73.9) 1 (4.3) 0 1 (4.3) 1 (4.3) 3 (13) Median (Range) 20 (0Y31) 0 (0Y13) 2400 (200Y100,000)*
*Patient with PCI 0 had only retroperitoneal involvement.
in all, except in 1 patient who was cytoreduced to millimetric residue (CC1).3 A total of 413 patients underwent surgical approach for ovarian cancer in both institutions during the study period. The decision on whether to proceed with surgical approach or neoadjuvant chemotherapy and the decision whether or not the disease was resectable were performed outside our institutions. All patients except 2 were considered for interval debulking based on the extended abdominal tumor burden, requiring complex and extended procedures subjecting patients to important morbidity. One patient was considered for neoadjuvant chemotherapy based on her poor clinical status and the other one based on extended nodal disease above the renal vein. Abnormal mediastinal LNs were found in the computed tomography scans of 4 patients. Mediastinal abnormal nodes corresponded to cardiophrenic nodes in 3 patients and to an inferior anterior mediastinal node in the fourth patient. Abnormal subclavian LNs were found in 1 patient. All these patients underwent neoadjuvant chemotherapy. Two patients had complete radiologic response, and the LNs were not removed during the surgery. Two patients had a stable right cardiophrenic node removed during surgery; one of them had metastatic LN involvement at pathologic examination. This patient progressed after the second cycle of adjuvant chemotherapy in the mediastinal and subclavian LN area. A patient with suspected subclavian nodes had a cervical lymphadenectomy with complete histologic response.
50
There was 1 patient with suspected CLN before neoadjuvant chemotherapy with complete radiologic and histologic response. Metastatic involvement of CLNs was identified in 23 patients. There were no significant differences between the clinical and perioperative data of patients with positive and negative CLNs (Table 1). There was a trend toward more extensive disease in the group of patients with positive CLNs, with a higher median PCI (P = 0.06) and higher ascites volume (P = 0.2). The median follow-up was 26.3 months (95% confidence interval [CI], 16.13Y31.5 months). In univariate analysis, no correlation was found between age, histologic diagnosis, stage, primary or recurrent disease, or ascites volume. The median OS and PFS for all patients were 27.9 months (95% CI, 15Y40 months) and 11 months (95% CI, 6.99Y17.18 months), respectively. The median OS for patients with celiac involvement who underwent primary treatment was 23.9 months (95% CI, 7.75Y41.42 months). The median PFS values for patients with negative and positive CLN involvement were 17.18 months (95% CI, 8.15 monthsnot reached) and 8.8 months (95% CI, 5.30Y15.6 months), respectively. The median OS values in the group with positive and in the group with negative CLNs were 26.9 months (95% CI, 9.43Y39.79 months) and 40.04 months (95% CI, 18.9 months-not reached), respectively. The median PFS values in the group with metastatic and in the group with negative * 2014 IGCS and ESGO
Copyright © 2013 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 24, Number 1, January 2014
CLNs were 8.8 months (95% CI, 4.5Y17.6 months) and 20.24 months (95% CI, 8.14Y28.51 months), respectively (P = 0.053). A total of 14 (60.9%) patients with positive CLNs progressed during or developed recurrent disease within 6 months of completion of chemotherapy, compared with to 3 (16.7%) patients in the negative CLNs group (P = 0.0044). Excluding patients who presented with recurrent disease, 11 (57.9%) versus 2 (13.3%) patients, progressed during or with 6 months after the completion of chemotherapy (P = 0.0079). Tumor burden was significantly associated with poor PFS (P = 0.002), progression during or recurrence within 6 months after the completion of chemotherapy (P G 0.001), and OS (P = 0.005). The disease distribution measured by the number of anatomic regions was also significantly associated with poor oncologic outcome, decreasing PFS (P = 0.004), OS (P = 0.029), and short-term recurrence (P = 0.001). In multivariate analysis, only the CLN status was independently associated with the short-term progression (odds ratio, 23.3; P = 0.016). Lymph node progression to different locations was significantly associated to CLN disease (P = 0.0032). A total of 14 (70%) patients with positive CLNs presented with disease progression to LNs compared with 4 (22.2%) patients in the negative group.
DISCUSSION The prognostic value of complete cytoreductive surgery has been addressed in several reports.6,7 The surgical approach to advanced ovarian cancer involving the upper abdomen has changed in the last decades, and upper abdominal surgical procedures have been incorporated to increase the rate of optimal cytoreduction.1 The addition of these procedures is both feasible and associated with acceptable morbidity in selected patients. The outcome of surgery also depends on the patient’s ability to tolerate extensive surgical approach. Resection of metastatic involvement of suspected CLNs has been reported and considered feasible and safe.3,8 Disease to this location is associated with extensive intraperitoneal disease leading to the question of the prognostic relevance of this finding.
Therapeutic Effect of Systematic Lymphadenectomy Ovarian cancer dissemination pattern most commonly occurs through the intraperitoneal route, followed by lymphatic invasion. The incidence of retroperitoneal LN metastases in advanced ovarian cancer ranges from 62% to 75% in reported studies, being para-aortic involvement as the most frequent.9Y11 Literature evidence shows that lymphatic metastasis adversely affects the outcome in patients with advanced-stage disease, suggesting that surgical removal of the involved nodes would be associated with improved survival.12 Survival benefit is most likely conferred to patients with complete intraperitoneal debulking.13 Available data regarding the performance of systematic aortic and pelvic lymphadenectomy are controversial. SEER database showed the beneficial therapeutic effect of pelvic and para-aortic lymphadenectomy in epithelial ovarian cancer, regardless of the stage of the disease. The number of
CLN Involvement in Ovarian Cancer
resected LNs was also a significant prognostic factor.14 The single randomized trial evaluating the systematic lymphadenectomy in optimally debulked advanced ovarian cancer patients demonstrated an increase in disease-free survival but not in OS.15 However, only 37% underwent complete cytoreduction. The therapeutic effect of systematic lymphadenectomy in completely cytoreduced patients is currently being evaluated by the French trial CARACO and by the German AGO group as part of the LION trial. Important LN disease may lead to lymphangiosis and intraperitoneal persistence in poor chemoresponsiveness and worse intrinsic tumor biology.16 Based on this rationale, resection of suspected LNs at the celiac axis participates to complete resection of the retroperitoneal disease. Metastatic CLNs were found in more than 80% of patients with diffuse upper abdominal disease and/or more than 4 metastatic aortic LNs in our series. However, real incidence of CLN diseases in patients with diffuse metastatic LNs to the aortic region or with an upper abdominal spread draining to the CLNs is unknown. This could be a possible explanation for residual disease decreasing survival impact of systematic lymphadenectomy in advanced-stage patients in previous reports.
Extent of Peritoneal Carcinomatosis and Survival in Completely Cytoreduced Patients No residual tumor is the most important prognostic factor for long-term survival6 based on the removal of chemoresistant clones and of poorly vascularized tumor, a higher growth fraction in better perfused small residual tumors increasing chemosensitivity, and the improvement of host immunocompetence by resection of the bulky tumor.17 The extent of disease as a marker of biological aggressiveness remains a controversial question. Hamilton et al18 have recently addressed this question by evaluating 417 advanced ovarian cancer patients with no residual tumor after cytoreductive surgery. Patients with upper abdominal diseases and no residual tumor after surgery had a poorer prognosis than similarly staged patients whose initial disease burden did not involve the upper abdomen.18 The GOG 52 of Hoskins et al19 found similar results and concluded that initial extrapelvic disease remained a significant predictor of decreased survival. MSKCC also found that the benefit of optimal cytoreduction on PFS and OS decreased with increasing initial tumor volume, probably because of more aggressive ovarian cancer phenotypes or patients with disease for a longer period.20 Eisenkop et al4 demonstrated that complete surgical cytoreduction had a more significant independent influence on survival than with the total extent of intra-abdominal tumor burden. Other series also support equivalent survival in patients with extensive upper abdominal disease requiring radical cytoreductive procedures when compared with that in patients optimally cytoreduced with less aggressive surgery.21Y23 In this series, extensive abdominal disease and positive CLNs defined a less favorable patient subgroup that was associated with poor oncologic outcome and resistance to platinum-based chemotherapy. The degree to which CLNs correlate with other survival variables such as volume and
* 2014 IGCS and ESGO
Copyright © 2013 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
51
International Journal of Gynecological Cancer
Martı´nez et al
distribution of tumor burden, and outcome is uncertain. However, in multivariate analysis, CLN status remained the only significant prognostic factor associated with platinumbased chemotherapy resistance. Our findings indicate that CLN involvement is a high-risk marker to select patients who will not benefit from maximal cytoreductive effort. All patients with peritoneal metastasis above 2 cm beyond the pelvis and those with LN involvement are classified as stage IIIC of the FIGO. This means that most ovarian cancer patients are stage IIIC with very distinct prognostic outcomes. The CLN involvement in most cases is due to extensive supra-abdominal carcinomatosis and/or disseminated retroperitoneal involvement. In this series, this subgroup of stage IIIC patients had poor outcome even after complete cytoreduction. We believe that FIGO stage IIIC patients should be subdivided, by at least separating IIIC with isolated infrarenal LN involvement with a distinctly better outcome and those with large-volume upper abdominal involvement. Criteria to define this last subgroup and its specific outcome on cytoreductive surgery have to be determined. Celiac lymph nodes could be used in patients with extensive carcinomatosis to define a IIIC stage subgroup with poor outcome. The weaknesses of the study, which limit conclusions, are the retrospective design, the inclusion of both primary and recurrent cases, the limited follow-up, and the small number of patients enrolled. More studies are needed to define whether positive CLNs influence survival significantly enough to preclude benefit from maximal cytoreductive effort or whether positive CLN patients obtain enough oncologic benefit to subject associated morbidity, short-term mortality, and impact on quality of life associated to surgical procedure.
3.
4.
5. 6.
7.
8.
9.
10.
11.
CONCLUSIONS Disease in the CLN is a marker of disease severity, which is associated to a high-risk group of patients with presumed adverse tumor biology, increased risk of LN progression, and worst oncologic outcome. These results improve data on identification of ‘‘preoperative biologic factors’’ to define the subgroup patients who do not seem to benefit from an upfront aggressive surgical approach. Oncologic outcome of complete cytoreductive surgery on patients with positive CLN and large-volume disease needs to be carefully assessed in larger studies with longer follow-up. A prospective multicentric cohort study to assess the impact of CLN involvement on oncologic outcome will be opened in France.
REFERENCES 1. Chi DS, Franklin CC, Levine DA, et al. Improved optimal cytoreduction rates for stages IIIC and IV epithelial ovarian, fallopian tube, and primary peritoneal cancer: a change in surgical approach. Gynecol Oncol. 2004;94:650Y654. 2. Eisenkop SM, Spirtos NM. What are the current surgical objectives, strategies, and technical capabilities of gynecologic
52
12.
13.
14.
15.
16.
17. 18.
& Volume 24, Number 1, January 2014
oncologists treating advanced epithelial ovarian cancer? Gynecol Oncol. 2001;82:489Y497. Martinez A, Pomel C, Mery E, et al. Celiac lymph node resection and porta hepatis disease resection in advanced or recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer. Gynecol Oncol. 2011;121:258Y263. Eisenkop SM, Spirtos NM, Friedman RL, et al. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol. 2003;90:390Y396. Sugarbaker PH. Peritoneal Carcinomatosis. Principles of Management. Kluwer, Boston. 1996. Bristow RE, Tomacruz RS, Armstrong DK, et al. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol. 2002;20:1248Y1259. du Bois A, Reuss A, Pujade-Lauraine E, et al. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d’Investigateurs Nationaux Pour les Etudes des Cancers de l’Ovaire (GINECO). Cancer. 2009;115:1234Y1244. Raspagliesi F, Ditto A, Martinelli F, et al. Advanced ovarian cancer: omental bursa, lesser omentum, celiac, portal and triad nodes spread as cause of inaccurate evaluation of residual tumor. Gynecol Oncol. 2013;129:92Y96. Benedetti-Panici P, Greggi S, Maneschi F, et al. Anatomical and pathological study of retroperitoneal nodes in epithelial ovarian cancer. Gynecol Oncol. 1993;51:150Y154. Morice P, Joulie F, Camatte S, et al. Lymph node involvement in epithelial ovarian cancer: analysis of 276 pelvic and paraaortic lymphadenectomies and surgical implications. J Am Coll Surg. 2003;197:198Y205. Onda T, Yoshikawa H, Yokota H, et al. Assessment of metastases to aortic and pelvic lymph nodes in epithelial ovarian carcinoma. A proposal for essential sites for lymph node biopsy. Cancer. 1996;78:803Y808. Aletti GD, Dowdy S, Podratz KC, et al. Role of lymphadenectomy in the management of grossly apparent advanced stage epithelial ovarian cancer. Am J Obstet Gynecol. 2006;195:1862Y1868. du Bois A, Reuss A, Harter P, et al. Potential role of lymphadenectomy in advanced ovarian cancer: a combined exploratory analysis of three prospectively randomized phase III multicenter trials. J Clin Oncol. 2010;28:1733Y1739. Rouzier R, Bergzoll C, Brun JL, et al. The role of lymph node resection in ovarian cancer: analysis of the surveillance, epidemiology, and end results (SEER) database. BJOG. 2010;117:1451Y1458. Panici PB, Maggioni A, Hacker N, et al. Systematic aortic and pelvic lymphadenectomy versus resection of bulky nodes only in optimally debulked advanced ovarian cancer: a randomized clinical trial. J Natl Cancer Inst. 2005;97:560Y566. Ayhan A, Gultekin M, Dursun P, et al. Metastatic lymph node number in epithelial ovarian carcinoma: does it have any clinical significance? Gynecol Oncol. 2008;108:428Y432. Covens AL. A critique of surgical cytoreduction in advanced ovarian cancer. Gynecol Oncol. 2000;78:269Y274. Hamilton CA, Miller A, Miller C, et al. The impact of disease distribution on survival in patients with stage III epithelial * 2014 IGCS and ESGO
Copyright © 2013 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 24, Number 1, January 2014
ovarian cancer cytoreduced to microscopic residual: a Gynecologic Oncology Group study. Gynecol Oncol. 2011;122:521Y526. 19. Hoskins WJ, Bundy BN, Thigpen JT, et al. The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol. 1992;47:159Y166. 20. Zivanovic O, Sima CS, Iasonos A, et al. The effect of primary cytoreduction on outcomes of patients with FIGO stage IIIC ovarian cancer stratified by the initial tumor burden in the upper abdomen cephalad to the greater omentum. Gynecol Oncol. 2010;116:351Y357.
CLN Involvement in Ovarian Cancer
21. Aletti GD, Dowdy SC, Gostout BS, et al. Aggressive surgical effort and improved survival in advanced-stage ovarian cancer. Obstet Gynecol. 2006;107:77Y85. 22. Eisenhauer EL, Abu-Rustum NR, Sonoda Y, et al. The addition of extensive upper abdominal surgery to achieve optimal cytoreduction improves survival in patients with stages IIIC-IV epithelial ovarian cancer. Gynecol Oncol. 2006;103:1083Y1090. 23. Luyckx M, Leblanc E, Filleron T, et al. Maximal cytoreduction in patients with FIGO stage IIIC to stage IV ovarian, fallopian, and peritoneal cancer in day-to-day practice: a retrospective French multicentric study. Int J Gynecol Cancer. 2012;22:1337Y1343.
* 2014 IGCS and ESGO
Copyright © 2013 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
53
Prognostic Relevance of Celiac Lymph Node Involvement in Ovarian Cancer Alejandra Martı´nez, MD,* Cristophe Pomel, PhD,Þ Thomas Filleron, PhD,þ Marjolein De Cuypere, MD,* Eliane Mery, MD,§ Denis Querleu, PhD,* Laurance Gladieff, MD,|| Mathieu Poilblanc, MD,* and Gwe´nae¨l Ferron, MD*
Objective: The aim of the study was to report on the oncologic outcome of the disease spread to celiac lymph nodes (CLNs) in advanced-stage ovarian cancer patients. Methods: All patients who had CLN resection as part of their cytoreductive surgery for epithelial ovarian, fallopian, or primary peritoneal cancer were identified. Patient demographic data with particular emphasis on operative records to detail the extent and distribution of the disease spread, lymphadenectomy procedures, pathologic data, and follow-up data were included. Results: The median follow-up was 26.3 months. The median overall survival values in the group with positive CLNs and in the group with negative CLNs were 26.9 months and 40.04 months, respectively. The median progression-free survival values in the group with metastatic CLNs and in the group with negative CLNs were 8.8 months and 20.24 months, respectively (P = 0.053). Positive CLNs were associated with progression during or within 6 months after the completion of chemotherapy (P = 0.0044). Tumor burden and extensive disease distribution were significantly associated with poor progression-free survival, shortterm progression, and overall survival. In multivariate analysis, only the CLN status was independently associated with short-term progression. Conclusions: Disease in the CLN is a marker of disease severity, which is associated to a high-risk group of patients with presumed adverse tumor biology, increased risk of lymph node progression, and worst oncologic outcome. Key Words: Ovarian cancer, Celiac lymph node, Cytoreductive surgery, Survival Received May 30, 2013. Accepted for publication October 17, 2013. (Int J Gynecol Cancer 2014;24: 48Y53)
*Department of Surgical Oncology, Claudius Regaud Comprehensive Cancer Center; †Department of Surgical Oncology, Jean Perrin Comprehensive Cancer Center, Clermont-Ferrand, France; Departments of ‡Biostatistics, §Pathology, and ||Medical Oncology, Claudius Regaud Comprehensive Cancer Center, Toulouse, France. Address correspondence and reprint requests to Alejandra Martı´nez, MD, Department of Surgical Oncology, Claudius Regaud Comprehensive Cancer Center, 20-24, Rue Pont-Saint-Pierre, 31052 Toulouse, France. E-mail: [email protected]. The authors declare no conflicts of interest. Copyright * 2014 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000041
48
of upper abdominal diseases increases the T heratetreatment of optimal cytoreduction from 50% to 76% in ovarian
cancer patients.1 Celiac lymph node (CLN) metastases and porta hepatis disease, usually due to retroperitoneal spread from upper abdominal disease, are one of the most frequent locations precluding complete cytoreduction.2 In an attempt to improve optimal cytoreduction rates, we expanded the surgical strategy to resection of metastatic involvement of the porta hepatis, suspected CLNs in patients with epithelial ovarian, fallopian, and primary peritoneal cancer, and demonstrated the feasibility of the procedure with acceptable morbidity.3 Some reports have also shown that the completeness of cytoreduction has a more significant influence on survival than on the extent of metastatic disease before
International Journal of Gynecological Cancer
& Volume 24, Number 1, January 2014
Copyright © 2013 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 24, Number 1, January 2014
CLN Involvement in Ovarian Cancer
review board from our institutions. Medical records were examined, and patient demographic data with particular emphasis on operative records to detail the extent and distribution of the disease spread, lymphadenectomy procedures, pathologic data, and follow-up data were included. Adjuvant chemotherapy was administered within 2 months of surgery, when feasible, at the discretion of the treating oncologist.
Statistical Methodology
FIGURE 1. Overall survival, OS curves according to CLN status. surgery.4 However, metastases to the CLNs could associate to worse survival when compared with patients with similar disease extension without CLN involvement. Main aim of the study was to report on oncologic outcome of disease spread to this location in advanced ovarian cancer patients.
MATERIALS AND METHODS A computer-generated search of the institutional patient database was performed to retrospectively identify all patients who had disease at the porta hepatis or CLN resection as part of the cytoreductive surgery for epithelial ovarian, fallopian, or primary peritoneal cancer between January 2009 and December 2011, at the Claudius Regaud Comprehensive Cancer Center (Toulouse, France) and at the Jean Perrin Comprehensive Cancer Center (Clermont-Ferrand, France). In all cases, the preoperative image study evaluation included a computed tomography of the chest, abdomen, and pelvis, and in selected cases, a positron emission tomography. All surgical procedures were performed by the same senior surgical oncologists as previously described.3 The extent and the distribution of the disease throughout the 13 abdominopelvic regions and surgical outcome were evaluated with the peritoneal cancer index (PCI) and the completeness of cytoreduction score.5 The indication for hepatic and/or CLN resection was based on the intraoperative findings of suspected lymph nodes (LNs), which included those measuring more than 1 cm and/or indurated at palpation. In our institutions, the indication for neoadjuvant chemotherapy was based on the sum of the procedures required to achieve complete cytoreduction, on medical comorbidities, and on the potential to tolerate an extensive procedure. Patients with deep infiltration of the small bowel mesentery, diffuse carcinomatosis involving large parts of the small bowel, stomach, infiltration of the duodenum or pancreas (not limited to the pancreatic tail), or more than 2 bowel resections required to eradicate the disease were considered for neoadjuvant chemotherapy. The study was approved by the institutional
The data were summarized by frequency and percentage for categorical variables and by median and range for continuous variables. All survival times were calculated from the date of diagnosis. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier methods, and a univariate analysis was performed using the log-rank test for categorical variable or the Cox model for continuous variable (Figs 1, 2). The association of all parameters with progression during or before 6 months after the end of chemotherapy was tested for statistical significance using the Pearson W2 test or the Fisher exact test for categorical variables and the Wilcoxon test for continuous variables. Multivariate analysis was performed using the logistic regression modeling. Only the variables statically significant in univariate analysis were taken into account in the multivariate analysis. All reported P values are 2-sided. For all the statistical tests, differences were considered significant at the 5% level. Statistical analyses were performed using the STATA 12.0 software.
RESULTS Demographic and perioperative data from the 41 patients who underwent some kind of CLN resection or resection of metastatic involvement of the porta hepatis are described in Table 1. Seven (17.1%) patients presented with recurrent disease, 6 with primary recurrence, and the other one with a second recurrence 8 months after the completion of chemotherapy. Complete cytoreduction to (CC0) was achieved
FIGURE 2. Progression-free survival, PFS curves according to CLN status.
* 2014 IGCS and ESGO
Copyright © 2013 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
49
International Journal of Gynecological Cancer
Martı´nez et al
& Volume 24, Number 1, January 2014
TABLE 1. Patient characteristics
Age median (range)
All Patients
Negative CLNs
Positive CLNs
61 (22Y77)
59 (22Y72) n (%)
62 (39Y77) n (%)
n Operation Primary Recurrent Neoadjuvant chemotherapy Stage III IV Histologic subtype Serous ovarian cancer Clear cell ovarian cancer Endometrioid ovarian cancer Mixed tumors Primary fallopian tube cancer Primary peritoneum cancer Surgical Data PCI No. anatomic regions Ascites, mL
%
34 7 25
82.9 17.1 61
15 (83.3) 3 (16.7) 12 (66.7)
19 (82.6) 6 (26.1) 13 (56.5)
32 9
78 22
15 (83.3) 3 (16.7)
17 (73.9) 6 (26.1)
30 1 1 2 2 5 Median 18 9 1150
73.2 2.4 2.4 4.9 4.9 12.2 Range 0Y34 0Y13* 30Y10,000
13 (72.2) 0 1 (5.6) 1 (5.6) 1 (5.6) 2 (11.1) Median (Range) 15 (0Y34) 8 (0Y13)* 350 (30Y4300)*
17 (73.9) 1 (4.3) 0 1 (4.3) 1 (4.3) 3 (13) Median (Range) 20 (0Y31) 0 (0Y13) 2400 (200Y100,000)*
*Patient with PCI 0 had only retroperitoneal involvement.
in all, except in 1 patient who was cytoreduced to millimetric residue (CC1).3 A total of 413 patients underwent surgical approach for ovarian cancer in both institutions during the study period. The decision on whether to proceed with surgical approach or neoadjuvant chemotherapy and the decision whether or not the disease was resectable were performed outside our institutions. All patients except 2 were considered for interval debulking based on the extended abdominal tumor burden, requiring complex and extended procedures subjecting patients to important morbidity. One patient was considered for neoadjuvant chemotherapy based on her poor clinical status and the other one based on extended nodal disease above the renal vein. Abnormal mediastinal LNs were found in the computed tomography scans of 4 patients. Mediastinal abnormal nodes corresponded to cardiophrenic nodes in 3 patients and to an inferior anterior mediastinal node in the fourth patient. Abnormal subclavian LNs were found in 1 patient. All these patients underwent neoadjuvant chemotherapy. Two patients had complete radiologic response, and the LNs were not removed during the surgery. Two patients had a stable right cardiophrenic node removed during surgery; one of them had metastatic LN involvement at pathologic examination. This patient progressed after the second cycle of adjuvant chemotherapy in the mediastinal and subclavian LN area. A patient with suspected subclavian nodes had a cervical lymphadenectomy with complete histologic response.
50
There was 1 patient with suspected CLN before neoadjuvant chemotherapy with complete radiologic and histologic response. Metastatic involvement of CLNs was identified in 23 patients. There were no significant differences between the clinical and perioperative data of patients with positive and negative CLNs (Table 1). There was a trend toward more extensive disease in the group of patients with positive CLNs, with a higher median PCI (P = 0.06) and higher ascites volume (P = 0.2). The median follow-up was 26.3 months (95% confidence interval [CI], 16.13Y31.5 months). In univariate analysis, no correlation was found between age, histologic diagnosis, stage, primary or recurrent disease, or ascites volume. The median OS and PFS for all patients were 27.9 months (95% CI, 15Y40 months) and 11 months (95% CI, 6.99Y17.18 months), respectively. The median OS for patients with celiac involvement who underwent primary treatment was 23.9 months (95% CI, 7.75Y41.42 months). The median PFS values for patients with negative and positive CLN involvement were 17.18 months (95% CI, 8.15 monthsnot reached) and 8.8 months (95% CI, 5.30Y15.6 months), respectively. The median OS values in the group with positive and in the group with negative CLNs were 26.9 months (95% CI, 9.43Y39.79 months) and 40.04 months (95% CI, 18.9 months-not reached), respectively. The median PFS values in the group with metastatic and in the group with negative * 2014 IGCS and ESGO
Copyright © 2013 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 24, Number 1, January 2014
CLNs were 8.8 months (95% CI, 4.5Y17.6 months) and 20.24 months (95% CI, 8.14Y28.51 months), respectively (P = 0.053). A total of 14 (60.9%) patients with positive CLNs progressed during or developed recurrent disease within 6 months of completion of chemotherapy, compared with to 3 (16.7%) patients in the negative CLNs group (P = 0.0044). Excluding patients who presented with recurrent disease, 11 (57.9%) versus 2 (13.3%) patients, progressed during or with 6 months after the completion of chemotherapy (P = 0.0079). Tumor burden was significantly associated with poor PFS (P = 0.002), progression during or recurrence within 6 months after the completion of chemotherapy (P G 0.001), and OS (P = 0.005). The disease distribution measured by the number of anatomic regions was also significantly associated with poor oncologic outcome, decreasing PFS (P = 0.004), OS (P = 0.029), and short-term recurrence (P = 0.001). In multivariate analysis, only the CLN status was independently associated with the short-term progression (odds ratio, 23.3; P = 0.016). Lymph node progression to different locations was significantly associated to CLN disease (P = 0.0032). A total of 14 (70%) patients with positive CLNs presented with disease progression to LNs compared with 4 (22.2%) patients in the negative group.
DISCUSSION The prognostic value of complete cytoreductive surgery has been addressed in several reports.6,7 The surgical approach to advanced ovarian cancer involving the upper abdomen has changed in the last decades, and upper abdominal surgical procedures have been incorporated to increase the rate of optimal cytoreduction.1 The addition of these procedures is both feasible and associated with acceptable morbidity in selected patients. The outcome of surgery also depends on the patient’s ability to tolerate extensive surgical approach. Resection of metastatic involvement of suspected CLNs has been reported and considered feasible and safe.3,8 Disease to this location is associated with extensive intraperitoneal disease leading to the question of the prognostic relevance of this finding.
Therapeutic Effect of Systematic Lymphadenectomy Ovarian cancer dissemination pattern most commonly occurs through the intraperitoneal route, followed by lymphatic invasion. The incidence of retroperitoneal LN metastases in advanced ovarian cancer ranges from 62% to 75% in reported studies, being para-aortic involvement as the most frequent.9Y11 Literature evidence shows that lymphatic metastasis adversely affects the outcome in patients with advanced-stage disease, suggesting that surgical removal of the involved nodes would be associated with improved survival.12 Survival benefit is most likely conferred to patients with complete intraperitoneal debulking.13 Available data regarding the performance of systematic aortic and pelvic lymphadenectomy are controversial. SEER database showed the beneficial therapeutic effect of pelvic and para-aortic lymphadenectomy in epithelial ovarian cancer, regardless of the stage of the disease. The number of
CLN Involvement in Ovarian Cancer
resected LNs was also a significant prognostic factor.14 The single randomized trial evaluating the systematic lymphadenectomy in optimally debulked advanced ovarian cancer patients demonstrated an increase in disease-free survival but not in OS.15 However, only 37% underwent complete cytoreduction. The therapeutic effect of systematic lymphadenectomy in completely cytoreduced patients is currently being evaluated by the French trial CARACO and by the German AGO group as part of the LION trial. Important LN disease may lead to lymphangiosis and intraperitoneal persistence in poor chemoresponsiveness and worse intrinsic tumor biology.16 Based on this rationale, resection of suspected LNs at the celiac axis participates to complete resection of the retroperitoneal disease. Metastatic CLNs were found in more than 80% of patients with diffuse upper abdominal disease and/or more than 4 metastatic aortic LNs in our series. However, real incidence of CLN diseases in patients with diffuse metastatic LNs to the aortic region or with an upper abdominal spread draining to the CLNs is unknown. This could be a possible explanation for residual disease decreasing survival impact of systematic lymphadenectomy in advanced-stage patients in previous reports.
Extent of Peritoneal Carcinomatosis and Survival in Completely Cytoreduced Patients No residual tumor is the most important prognostic factor for long-term survival6 based on the removal of chemoresistant clones and of poorly vascularized tumor, a higher growth fraction in better perfused small residual tumors increasing chemosensitivity, and the improvement of host immunocompetence by resection of the bulky tumor.17 The extent of disease as a marker of biological aggressiveness remains a controversial question. Hamilton et al18 have recently addressed this question by evaluating 417 advanced ovarian cancer patients with no residual tumor after cytoreductive surgery. Patients with upper abdominal diseases and no residual tumor after surgery had a poorer prognosis than similarly staged patients whose initial disease burden did not involve the upper abdomen.18 The GOG 52 of Hoskins et al19 found similar results and concluded that initial extrapelvic disease remained a significant predictor of decreased survival. MSKCC also found that the benefit of optimal cytoreduction on PFS and OS decreased with increasing initial tumor volume, probably because of more aggressive ovarian cancer phenotypes or patients with disease for a longer period.20 Eisenkop et al4 demonstrated that complete surgical cytoreduction had a more significant independent influence on survival than with the total extent of intra-abdominal tumor burden. Other series also support equivalent survival in patients with extensive upper abdominal disease requiring radical cytoreductive procedures when compared with that in patients optimally cytoreduced with less aggressive surgery.21Y23 In this series, extensive abdominal disease and positive CLNs defined a less favorable patient subgroup that was associated with poor oncologic outcome and resistance to platinum-based chemotherapy. The degree to which CLNs correlate with other survival variables such as volume and
* 2014 IGCS and ESGO
Copyright © 2013 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
51
International Journal of Gynecological Cancer
Martı´nez et al
distribution of tumor burden, and outcome is uncertain. However, in multivariate analysis, CLN status remained the only significant prognostic factor associated with platinumbased chemotherapy resistance. Our findings indicate that CLN involvement is a high-risk marker to select patients who will not benefit from maximal cytoreductive effort. All patients with peritoneal metastasis above 2 cm beyond the pelvis and those with LN involvement are classified as stage IIIC of the FIGO. This means that most ovarian cancer patients are stage IIIC with very distinct prognostic outcomes. The CLN involvement in most cases is due to extensive supra-abdominal carcinomatosis and/or disseminated retroperitoneal involvement. In this series, this subgroup of stage IIIC patients had poor outcome even after complete cytoreduction. We believe that FIGO stage IIIC patients should be subdivided, by at least separating IIIC with isolated infrarenal LN involvement with a distinctly better outcome and those with large-volume upper abdominal involvement. Criteria to define this last subgroup and its specific outcome on cytoreductive surgery have to be determined. Celiac lymph nodes could be used in patients with extensive carcinomatosis to define a IIIC stage subgroup with poor outcome. The weaknesses of the study, which limit conclusions, are the retrospective design, the inclusion of both primary and recurrent cases, the limited follow-up, and the small number of patients enrolled. More studies are needed to define whether positive CLNs influence survival significantly enough to preclude benefit from maximal cytoreductive effort or whether positive CLN patients obtain enough oncologic benefit to subject associated morbidity, short-term mortality, and impact on quality of life associated to surgical procedure.
3.
4.
5. 6.
7.
8.
9.
10.
11.
CONCLUSIONS Disease in the CLN is a marker of disease severity, which is associated to a high-risk group of patients with presumed adverse tumor biology, increased risk of LN progression, and worst oncologic outcome. These results improve data on identification of ‘‘preoperative biologic factors’’ to define the subgroup patients who do not seem to benefit from an upfront aggressive surgical approach. Oncologic outcome of complete cytoreductive surgery on patients with positive CLN and large-volume disease needs to be carefully assessed in larger studies with longer follow-up. A prospective multicentric cohort study to assess the impact of CLN involvement on oncologic outcome will be opened in France.
REFERENCES 1. Chi DS, Franklin CC, Levine DA, et al. Improved optimal cytoreduction rates for stages IIIC and IV epithelial ovarian, fallopian tube, and primary peritoneal cancer: a change in surgical approach. Gynecol Oncol. 2004;94:650Y654. 2. Eisenkop SM, Spirtos NM. What are the current surgical objectives, strategies, and technical capabilities of gynecologic
52
12.
13.
14.
15.
16.
17. 18.
& Volume 24, Number 1, January 2014
oncologists treating advanced epithelial ovarian cancer? Gynecol Oncol. 2001;82:489Y497. Martinez A, Pomel C, Mery E, et al. Celiac lymph node resection and porta hepatis disease resection in advanced or recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer. Gynecol Oncol. 2011;121:258Y263. Eisenkop SM, Spirtos NM, Friedman RL, et al. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol. 2003;90:390Y396. Sugarbaker PH. Peritoneal Carcinomatosis. Principles of Management. Kluwer, Boston. 1996. Bristow RE, Tomacruz RS, Armstrong DK, et al. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol. 2002;20:1248Y1259. du Bois A, Reuss A, Pujade-Lauraine E, et al. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d’Investigateurs Nationaux Pour les Etudes des Cancers de l’Ovaire (GINECO). Cancer. 2009;115:1234Y1244. Raspagliesi F, Ditto A, Martinelli F, et al. Advanced ovarian cancer: omental bursa, lesser omentum, celiac, portal and triad nodes spread as cause of inaccurate evaluation of residual tumor. Gynecol Oncol. 2013;129:92Y96. Benedetti-Panici P, Greggi S, Maneschi F, et al. Anatomical and pathological study of retroperitoneal nodes in epithelial ovarian cancer. Gynecol Oncol. 1993;51:150Y154. Morice P, Joulie F, Camatte S, et al. Lymph node involvement in epithelial ovarian cancer: analysis of 276 pelvic and paraaortic lymphadenectomies and surgical implications. J Am Coll Surg. 2003;197:198Y205. Onda T, Yoshikawa H, Yokota H, et al. Assessment of metastases to aortic and pelvic lymph nodes in epithelial ovarian carcinoma. A proposal for essential sites for lymph node biopsy. Cancer. 1996;78:803Y808. Aletti GD, Dowdy S, Podratz KC, et al. Role of lymphadenectomy in the management of grossly apparent advanced stage epithelial ovarian cancer. Am J Obstet Gynecol. 2006;195:1862Y1868. du Bois A, Reuss A, Harter P, et al. Potential role of lymphadenectomy in advanced ovarian cancer: a combined exploratory analysis of three prospectively randomized phase III multicenter trials. J Clin Oncol. 2010;28:1733Y1739. Rouzier R, Bergzoll C, Brun JL, et al. The role of lymph node resection in ovarian cancer: analysis of the surveillance, epidemiology, and end results (SEER) database. BJOG. 2010;117:1451Y1458. Panici PB, Maggioni A, Hacker N, et al. Systematic aortic and pelvic lymphadenectomy versus resection of bulky nodes only in optimally debulked advanced ovarian cancer: a randomized clinical trial. J Natl Cancer Inst. 2005;97:560Y566. Ayhan A, Gultekin M, Dursun P, et al. Metastatic lymph node number in epithelial ovarian carcinoma: does it have any clinical significance? Gynecol Oncol. 2008;108:428Y432. Covens AL. A critique of surgical cytoreduction in advanced ovarian cancer. Gynecol Oncol. 2000;78:269Y274. Hamilton CA, Miller A, Miller C, et al. The impact of disease distribution on survival in patients with stage III epithelial * 2014 IGCS and ESGO
Copyright © 2013 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 24, Number 1, January 2014
ovarian cancer cytoreduced to microscopic residual: a Gynecologic Oncology Group study. Gynecol Oncol. 2011;122:521Y526. 19. Hoskins WJ, Bundy BN, Thigpen JT, et al. The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol. 1992;47:159Y166. 20. Zivanovic O, Sima CS, Iasonos A, et al. The effect of primary cytoreduction on outcomes of patients with FIGO stage IIIC ovarian cancer stratified by the initial tumor burden in the upper abdomen cephalad to the greater omentum. Gynecol Oncol. 2010;116:351Y357.
CLN Involvement in Ovarian Cancer
21. Aletti GD, Dowdy SC, Gostout BS, et al. Aggressive surgical effort and improved survival in advanced-stage ovarian cancer. Obstet Gynecol. 2006;107:77Y85. 22. Eisenhauer EL, Abu-Rustum NR, Sonoda Y, et al. The addition of extensive upper abdominal surgery to achieve optimal cytoreduction improves survival in patients with stages IIIC-IV epithelial ovarian cancer. Gynecol Oncol. 2006;103:1083Y1090. 23. Luyckx M, Leblanc E, Filleron T, et al. Maximal cytoreduction in patients with FIGO stage IIIC to stage IV ovarian, fallopian, and peritoneal cancer in day-to-day practice: a retrospective French multicentric study. Int J Gynecol Cancer. 2012;22:1337Y1343.
* 2014 IGCS and ESGO
Copyright © 2013 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
53
