- Email: [email protected]
Thrombocytosis at secondary cytoreduction for recurrent ovarian cancer predicts suboptimal resection and poor survival
Gynecologic Oncology 132 (2014) 556–559
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Thrombocytosis at secondary cytoreduction for recurrent ovarian cancer predicts suboptimal resection and poor survival Joshua G. Cohen, Arthur-Quan Tran, B.J. Rimel, Ilana Cass, Christine S. Walsh, Beth Y. Karlan, Andrew J. Li ⁎ Division of Gynecologic Oncology, Women's Cancer Program, Cedars-Sinai Medical Center, 8635 West 3rd Street, Suite 280W, Los Angeles, CA 90048, USA
H I G H L I G H T S • Epithelial ovarian cancer (EOC) patients who undergo secondary tumor debulking with a preoperative thrombocytosis have a shortened overall survival. • Preoperative thrombocytosis is associated with failure to achieve microscopic residual disease at time of secondary tumor debulking. • Preoperative thrombocytosis is an independent prognostic factor for patients with recurrent EOC who undergo secondary cytoreduction.
a r t i c l e
i n f o
Article history: Received 14 November 2013 Accepted 4 January 2014 Available online 11 January 2014 Keywords: Secondary debulking Thrombocytosis Ovarian carcinoma Peritoneal carcinoma
a b s t r a c t Objectives. A growing body of evidence supports a role for thrombocytosis in the promotion of epithelial ovarian cancer biology. However, studies have only linked preoperative platelet count at time of initial cytoreductive surgery to clinical outcome. Here, we sought to determine the impact of elevated platelet count at time of secondary cytoreductive surgery (SCS) for recurrent disease. Methods. Under an IRB-approved protocol, we identified 107 women with invasive epithelial ovarian cancer who underwent SCS between January 1997 and June 2012. We reviewed clinical, laboratory, and pathologic records from this retrospective cohort. The data was analyzed using the chi-squared, Fisher's exact, Cox proportional hazards, and Kaplan–Meier tests. We defined thrombocytosis as a platelet count ≥ 350 × 109/L and optimal resection at SCS as microscopic residual disease. Results. Thirteen of 107 women (12%) with recurrent ovarian cancer had thrombocytosis prior to SCS. Preoperative thrombocytosis at SCS was associated with failure to undergo optimal resection (p = 0.0001). Women with preoperative thrombocytosis at time of SCS demonstrated shorter overall survival (33 months) compared to those with normal platelet counts (46 months, p = 0.004). On multivariate analysis, only preoperative platelet count retained significance as an independent prognostic factor (p = 0.025) after controlling for age at SCS (p = 0.90), disease free interval from primary treatment (0.06), and initial stage of disease (0.66). Conclusions. Elevated platelet count at time of SCS is associated with suboptimal resection and shortened overall survival. These data provide further evidence supporting a plausible role for thrombocytosis in aggressive ovarian tumor biology. © 2014 Elsevier Inc. All rights reserved.
Introduction Epithelial ovarian cancer is an aggressive malignancy with various histologic subtypes. This year alone there will be 14,030 deaths due to ovarian cancer in the United States largely due to advanced stage of disease at presentation in 70% of women with five-year overall survival of approximately 30% [1,2]. Despite a high rate of remission following primary treatment of advanced stage disease with both surgery and chemotherapy, recurrence is common with more than 60% of advanced ⁎ Corresponding author at: Cedars-Sinai Medical Center, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, 8635 West 3rd Street, Suite 280W, Los Angeles, CA 90048, USA. Fax: +1 3104230155. E-mail address: [email protected] (A.J. Li). 0090-8258/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ygyno.2014.01.003
stage patients developing recurrent disease [3]. In counseling patients with recurrent tumor, secondary tumor debulking is a potential treatment option depending on various factors including disease free interval, platinum sensitivity, tumor burden, and performance status. Those patients who undergo complete cytoreduction at the time of secondary tumor debulking will benefit the most [3–8]. Good performance status and absence of ascites are predictors of complete surgical cytoreduction in recurrent platinum sensitive epithelial ovarian cancer [9]. At this time, there is still controversy as to which patients with recurrent epithelial ovarian cancer are the best candidates for secondary tumor debulking. A growing body of evidence supports a role for thrombocytosis in the promotion of cancer biology. Platelets are associated with metastasis, angiogenesis, and tumor cell proliferation [10,11]. In ovarian cancer
J.G. Cohen et al. / Gynecologic Oncology 132 (2014) 556–559
models, evidence indicates the existence of a paracrine circuit in which tumor growth is fostered by a paraneoplastic thrombocytosis driven by thrombopoeitic cytokines [12]. Thrombocytosis has been shown to be an unfavorable prognostic factor in a number of solid tumors including colorectal, breast, pancreatic, and lung cancer [13–17]. In advanced stage ovarian cancer, thrombocytosis at the time of initial staging surgery has been linked to worse prognosis including decreased disease free interval, shorter overall survival, and a greater likelihood of suboptimal resection [18,19]. In addition, thrombocytosis in early stage epithelial ovarian cancer has been linked to an eight-fold increase risk of recurrence [20]. Despite the available literature regarding thrombocytosis at the time of primary surgical debulking, it is unclear if thrombocytosis at the time of recurrence has clinical significance. If a patient is a candidate for secondary debulking at the time of recurrence, thrombocytosis may provide important prognostic information. We hypothesize that thrombocytosis negatively influences tumor biology throughout the disease course. In this study, we evaluate the association between preoperative thrombocytosis, survival, and other clinic-pathologic factors in women with epithelial ovarian cancer undergoing secondary cytoreductive surgery (SCS). Methods Under an IRB-approved protocol, we identified 107 women with invasive epithelial ovarian cancer who underwent SCS between January 1997 and June 2012. Patients with a history of invasive epithelial or primary peritoneal carcinoma who underwent secondary tumor debulking at Cedars-Sinai Medical Center in Los Angeles, CA were included in this study. Patients with a tumor of low malignant potential were excluded from this study. In general, patients were considered candidates for secondary tumor debulking if they had a disease free interval greater than six months, Gynecologic Oncology Group performance status less than two, and three sites or less of suspected disease recurrence. All patients underwent secondary tumor debulking by a gynecologic oncologist with the intent of optimal tumor cytoreduction. Patients undergoing palliative surgical procedures were excluded from this study. Following first line chemotherapy, no patient underwent chemotherapy prior to SCS. After secondary debulking all patients underwent treatment with chemotherapy, receiving either a platinum couplet or single agent platinum. A preoperative automated complete blood count within sixty days of surgery was available for all patients. Thrombocytosis was considered as a platelet count ≥ 350 × 109/L consistent with published criteria [14–16]. Optimal resection at SCS was considered microscopic residual disease. Suboptimal resection was based on residual tumor burden. The following data was abstracted: stage of disease, age at time of SCS, platelet level at time of initial staging surgery, disease free interval from time of initial treatment, platelet level at time of SCS, residual tumor at time of SCS, and overall survival. Differences in clinical and histopathologic factors between patients with and without thrombocytosis were examined with chi-squared and Fisher's exact test. The Cox proportional hazards model was used to assess the significance of potential prognostic factors as predictive parameters for patient survival. Survival probabilities were analyzed with Kaplan–Meier curves. A p-value of 0.05 was considered to be statistically significant.
352–527). Three of these 13 (23%) patients also had thrombocytosis at their initial staging surgery. Of 55 women with available preoperative platelet counts at initial staging surgery, 18 (33%) had thrombocytosis at that time and subsequently had normal platelet counts prior to SCS. Women without thrombocytosis at SCS had a median platelet count of 243 × 109/L (range 84–338). Of the 13 patients with a preoperative thrombocytosis at the time of SCS, 11 (85%) were stage III or IV, while 78 (83%) of patients without preoperative thrombocytosis had advanced stage disease. Median disease free interval following primary surgery for those with thrombocytosis at the time of SCS was 21 months (range 8–171) while women who had a normal platelet count prior to SCS had a median disease free interval of 34 months (6–311) after their initial surgery (Table 1). Of those patients with thrombocytosis at time of SCS, 4 patients (31%) underwent resection to less than 1 cm residual tumor while 9 patients (69%) underwent suboptimal tumor debulking. In contrast, 62 patients (66%) with a normal preoperative platelet count had microscopic residual disease, 25 patients (27%) underwent debulking to less than 1 cm residual disease, and only 7 patients (7%) had suboptimal tumor debulking. Preoperative thrombocytosis at SCS was strongly associated with failure to undergo optimal resection (p = 0.0001) (Fig. 1). Women with preoperative thrombocytosis at time of SCS had a shorter overall survival (median 33 months) compared to those with a normal platelet count (median 46 months) (p = 0.004). Overall survival was defined as time from SCS to death (Fig. 2). When examining platelet count as a continuous variable, univariate analysis identified a significant correlation with survival with a relative risk of 1.004 (1.0005–1.0069, p = 0.02). On multivariate analysis, only preoperative platelet count retained significance as an independent prognostic factor (p = 0.025) after controlling for age at SCS, disease free interval from primary treatment, and initial stage of disease (Table 2). Discussion To our knowledge this is the first study to evaluate the significance of thrombocytosis at the time of recurrence of ovarian carcinoma. Prior studies have demonstrated an association between thrombocytosis and poor clinical outcome at the time of initial treatment. With a high likelihood of recurrent disease in advanced stage ovarian cancer, understanding the significance of thrombocytosis in this setting may assist clinicians in counseling patients regarding treatment options. Elevated platelet count at time of SCS is associated with suboptimal resection and shortened overall survival. This data provides further evidence supporting a plausible role for thrombocytosis in aggressive ovarian tumor biology. Interestingly, eighteen of twenty-one patients with thrombocytosis at initial staging surgery did not have thrombocytosis at the time of SCS. In comparison, only three of thirteen patients with thrombocytosis at SCS had thrombocytosis at the time of initial staging. This may be for various reasons. Firstly, bone marrow may be negatively impacted by
Table 1 Patient characteristics by group.
Results Of the 107 women with recurrent epithelial or primary peritoneal ovarian cancer who underwent SCS, 13 (12%) had preoperative thrombocytosis (a platelet count ≥ 350 × 109/L) at the time of SCS. The median age for women with a preoperative thrombocytosis was 65 years old (range 51–83) while those without elevated platelets had a median age of 53 years old (range 36–75). Women with thrombocytosis had a median platelet count of 416 × 109/L (range
557
Age at SCSb, median DFIc after primary surgery, median in months Platelets, median Stage I/II Stage III/IV a b c
Thrombocytosisa (n = 13)
Normal platelets (n = 94)
65 (range 51–83) 21 (range 8–171)
53 (range 36–75) 34 (range 6–311)
416 (range 352–527) 2 11
243 (range 84–338) 16 78
Thrombocytosis defined as preoperative platelet count ≥ 350 × 109/L. Secondary cytoreductive surgery (SCS). Disease free interval (DFI).
558
J.G. Cohen et al. / Gynecologic Oncology 132 (2014) 556–559 Table 2 Multivariate analysis of possible prognostic factors in overall survival.
Thrombocytosisa DFIb after primary surgery Age at SCSc Initial stage of disease a b c
Fig. 1. Thrombocytosis is associated with suboptimal resection. Patients with a preoperative thrombocytosis were less likely to undergo optimal tumor debulking with no patients reaching microscopic residual disease.
adjuvant chemotherapy and radiation. Patients may be less likely to generate a thrombocytosis in the setting of recurrence as a result. Secondly, recurrent disease may represent chemoresistant or altered cancer cells that have become more aggressive compared to the primary tumor. Given thrombocytosis is likely linked to more aggressive solid tumors, this may explain why a thrombocytosis would be present at recurrence but not at the time of initial diagnosis. Thirdly, alternative causes such as active infection, splenectomy, myeloproliferative disorders, or acute inflammatory processes may result in a thrombocytosis. Elevated platelets are a poor prognostic factor, and our findings are consistent with prior studies evaluating the significance of thrombocytosis in ovarian cancer at the time of initial treatment [12,18–20]. Allensworth et al. found thrombocytosis to be associated with shortened disease free survival and overall survival in stage I/II patients, while in stage III/IV patients only disease free survival was negatively impacted. When performing a multivariate analysis with this cohort of patients using the same statistical model by Stone et al., Allensworth et al. did find thrombocytosis to negatively impact overall survival in ovarian cancer patients at all stages [12,20]. The variation in these results may stem from differences in patient cohorts and mathematical modeling, but the conclusion is similar: there is a relationship between thrombocytosis and worse prognosis in the setting of malignancy. Our study is a retrospective chart review and has various limitations including a small patient cohort. 97% of preoperative platelet levels were within thirty days of surgery, with the remainder of patients'
Hazard ratio
CI
p-Value
1.004 0.991 1.002 1.104
1.001–1.007 0.981–1.000 0.975–1.029 0.706–1.725
0.025 0.06 0.90 0.66
Thrombocytosis defined as preoperative platelet count ≥ 350 × 109/L. Disease free interval. Secondary cytoreductive surgery.
values obtained more than thirty days and less than sixty days prior to surgery. This leaves a small window in which the preoperative platelet count could have fluctuated prior to secondary tumor debulking. In this cohort of patients, thrombocytosis was considered to be a platelet count ≥ 350 × 109/L. While this is consistent with published criteria, there is variation in this number cutoff throughout the literature. A consideration in this patient population is the negative effect prior toxic agents have had on bone marrow reserve, potentially lowering baseline platelet counts. Lastly, we do not address a mechanistic relationship between thrombocytosis and aggressive tumor biology, however this area warrants further investigation. The relationship between elevated platelets and malignancy represents a potential treatment paradigm for patients with thrombocytosis in the recurrent setting. Radizon et al. demonstrated the significance of cancer–platelet interactions through which platelets increased the survival of ovarian adenocarcinoma cells treated with 5-fluorouracil and paclitaxel [21]. Chemoresistance is a common occurrence in recurrent epithelial ovarian cancer and platelets may contribute to this. Further evaluation of platelet secretory factors must be performed on a molecular level to better understand variations in tumor aggressiveness and potential treatment targets [22]. Tumor growth and elevated platelet levels appear to have a positive feedback mechanism. Tumorderived interleukin-6 increases platelet counts and promotes tumor growth in ovarian cancer models [12]. Targeting interleukin-6 in ovarian cancer patients with thrombocytosis has shown promise based on preliminary results and may represent a viable therapeutic target [12,23,24]. The majority of patients with advanced stage disease ovarian cancer will develop recurrence. As we move towards individualized cancer care based on patient specific genome analysis, patient centered outcomes will rise in importance. Secondary tumor debulking has its largest benefit in those patients who undergo complete cytoreduction. Predictors of successful surgery are more important now than ever, and preoperative thrombocytosis may assist with the ability to predict success of surgical resection in the recurrent setting. Preoperative thrombocytosis may also help identify those patients who will benefit from targeted treatment of platelet-tumor cell interactions. Prospective trials evaluating these treatments are warranted. Conflict of interest statement The authors declare that there are no conflicts of interest.
References
Fig. 2. Thrombocytosis correlates with shorter overall survival. Patients with a preoperative thrombocytosis at the time of SCS had a statistically shorter overall survival compared to those patients who did not have an elevated platelet count (median 33 vs 46 months respectively).
[1] Siegel R, Naishadham D, Jemal A. Cancer Stat 2013;63(1):11–30 [Ca]. [2] Lu KH, Skates S, Hernandez MA, Bedi D, Bevers T, Leeds L, et al. A 2-stage ovarian cancer screening strategy using the Risk of Ovarian Cancer Algorithm (ROCA) identifies early-stage incident cancers and demonstrates high positive predictive value. Cancer 2013;119(19):3454–61. [3] Salani R, Santillan A, Zahurak ML, Giuntoli II RL, Gardner GJ, Armstrong DK, et al. Secondary cytoreductive surgery for localized, recurrent epithelial ovarian cancer: analysis of prognostic factors and survival outcome. Cancer 2007;109(4):685–91. [4] Chi DS, McCaughty K, Diaz JP, Huh J, Schwabenbauer S, Hummer A, et al. Guidelines and selection criteria for secondary cytoreductive surgery in patients with recurrent, platinum-sensitive epithelial ovarian carcinoma. Cancer 2006;106(9):1933–9. [5] Tian W, Chi DS, Sehoulii J, Tropé CG, Jiang R, Ayhan A, et al. A risk model for secondary cytoreductive surgery in recurrent ovarian cancer: an evidence-based proposal for patient selection. Ann Surg Oncol 2012;19(2):597–604.
J.G. Cohen et al. / Gynecologic Oncology 132 (2014) 556–559 [6] Al Rawahi T, Lopes AD, Bristow RE, Bryant A, Elattar A, Chattopadhyay S, et al. Surgical cytoreduction for recurrent epithelial ovarian cancer. Cochrane Database Syst Rev 2013;2:CD008765. [7] Chuang C, Chou Y, Yen M, Chao K, Twu N, Wu H, et al. The role of secondary cytoreductive surgery in patients with recurrent epithelial ovarian, tubal, and peritoneal cancers: a comparative effectiveness analysis. Oncologist 2012;17(6):847–55. [8] Bristow RE, Puri I, Chi DS. Cytoreductive surgery for recurrent ovarian cancer: a meta-analysis. Gynecol Oncol 2009;112(1):265–74. [9] Harter P, Sehouli J, Reuss A, Hasenberg A, Scambia G, Cibula D, et al. Prospective validation study of a predictive score for operability of recurrent ovarian cancer: the Multicenter Intergroup Study DESKTOP II. A project of the AGO Kommission OVAR, AGO Study Group, NOGGO, AGO-Austria, and MITO. Int J Gynecol Cancer 2011;21(2):289–95. [10] Cho MS, Bottsford Miller J, Vasquez HG, Stone R, Zand B, Kroll MH, et al. Platelets increase the proliferation of ovarian cancer cells. Blood 2012;120(24):4869–72. [11] Holmes CE, Levis JE, Ornstein DL. Activated platelets enhance ovarian cancer cell invasion in a cellular model of metastasis. Clin Exp Metastasis 2009;26(7):653–61. [12] Stone RL, Nick AM, McNeish IA, Balkwill F, Han HD, Bottsford Miller J, et al. Paraneoplastic thrombocytosis in ovarian cancer. N Engl J Med 2012;366(7):610–8. [13] Ishizuka M, Nagata H, Takagi K, Iwasaki Y, Kubota K . Preoperative thrombocytosis is associated with survival after surgery for colorectal cancer. J Surg Oncol 2012;1 06(7):887–91. [14] Sasaki K, Kawai K, Tsuno NH, Sunami E, Kitawama J. Impact of preoperative thrombocytosis on the survival of patients with primary colorectal cancer. World J Surg 2012;36(1):192–200.
559
[15] Stravodimou A, Voutsadakis IA. Pretreatment thrombocytosis as a prognostic factor in metastatic breast cancer. Int J Breast Cancer 2013;2013:289563. [16] Hwang SG, Kim KM, Cheong JH, Kim HI, An JY, Hyung WJ, et al. Impact of pretreatment thrombocytosis on blood-borne metastasis and prognosis of gastric cancer. Eur J Surg Oncol 2012;38(7):562–7. [17] Maráz A, Furák J, Varga Z, Káhan Z, Tiszlavicz L, Hideghéty K. Thrombocytosis has a negative prognostic value in lung cancer. Anticancer Res 2013;33(4):1725–9. [18] Li AJ, Madden AC, Cass I, Leuchter RS, Lagasse LD, Karlan BY. The prognostic significance of thrombocytosis in epithelial ovarian carcinoma. Gynecol Oncol 2004;92(1):211–4. [19] Crasta JA, Premlatha TS, Krishnan SM, Vallikad E, Rameshkumar K. Significance of preoperative thrombocytosis in epithelial ovarian cancer. Indian J Pathol Microbiol 2010;53(1):54–6. [20] Allensworth SK, Langstraat CL, Martin JR, Lemens MA, McGree ME, Weaver AL, et al. Evaluating the prognostic significance of preoperative thrombocytosis in epithelial ovarian cancer. Gynecol Oncol 2013;130(3):499–504. [21] Radziwon Balicka A, Medina C, O'Driscoll L, Treumann A, Bazou D, Inkielewicz-Stepniak I, et al. Platelets increase survival of adenocarcinoma cells challenged with anticancer drugs: mechanisms and implications for chemoresistance. Br J Pharmacol 2012; 167(4):787–804. [22] Gungor T, Kanat Pektas M, Sucak A, Sucak A, Mollamahmutoglu L, et al. The role of thrombocytosis in prognostic evaluation of epithelial ovarian tumors. Arch Gynecol Obstet 2009;279(1):53–6. [23] Banerjee S, Kaye SB. New strategies in the treatment of ovarian cancer: current clinical perspectives and future potential. Clin Cancer Res 2013;19(5):961–8. [24] Rao AK, Rao DA. Platelets signal and tumors take off. Blood 2012;120(24):4667–8.
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Thrombocytosis at secondary cytoreduction for recurrent ovarian cancer predicts suboptimal resection and poor survival Joshua G. Cohen, Arthur-Quan Tran, B.J. Rimel, Ilana Cass, Christine S. Walsh, Beth Y. Karlan, Andrew J. Li ⁎ Division of Gynecologic Oncology, Women's Cancer Program, Cedars-Sinai Medical Center, 8635 West 3rd Street, Suite 280W, Los Angeles, CA 90048, USA
H I G H L I G H T S • Epithelial ovarian cancer (EOC) patients who undergo secondary tumor debulking with a preoperative thrombocytosis have a shortened overall survival. • Preoperative thrombocytosis is associated with failure to achieve microscopic residual disease at time of secondary tumor debulking. • Preoperative thrombocytosis is an independent prognostic factor for patients with recurrent EOC who undergo secondary cytoreduction.
a r t i c l e
i n f o
Article history: Received 14 November 2013 Accepted 4 January 2014 Available online 11 January 2014 Keywords: Secondary debulking Thrombocytosis Ovarian carcinoma Peritoneal carcinoma
a b s t r a c t Objectives. A growing body of evidence supports a role for thrombocytosis in the promotion of epithelial ovarian cancer biology. However, studies have only linked preoperative platelet count at time of initial cytoreductive surgery to clinical outcome. Here, we sought to determine the impact of elevated platelet count at time of secondary cytoreductive surgery (SCS) for recurrent disease. Methods. Under an IRB-approved protocol, we identified 107 women with invasive epithelial ovarian cancer who underwent SCS between January 1997 and June 2012. We reviewed clinical, laboratory, and pathologic records from this retrospective cohort. The data was analyzed using the chi-squared, Fisher's exact, Cox proportional hazards, and Kaplan–Meier tests. We defined thrombocytosis as a platelet count ≥ 350 × 109/L and optimal resection at SCS as microscopic residual disease. Results. Thirteen of 107 women (12%) with recurrent ovarian cancer had thrombocytosis prior to SCS. Preoperative thrombocytosis at SCS was associated with failure to undergo optimal resection (p = 0.0001). Women with preoperative thrombocytosis at time of SCS demonstrated shorter overall survival (33 months) compared to those with normal platelet counts (46 months, p = 0.004). On multivariate analysis, only preoperative platelet count retained significance as an independent prognostic factor (p = 0.025) after controlling for age at SCS (p = 0.90), disease free interval from primary treatment (0.06), and initial stage of disease (0.66). Conclusions. Elevated platelet count at time of SCS is associated with suboptimal resection and shortened overall survival. These data provide further evidence supporting a plausible role for thrombocytosis in aggressive ovarian tumor biology. © 2014 Elsevier Inc. All rights reserved.
Introduction Epithelial ovarian cancer is an aggressive malignancy with various histologic subtypes. This year alone there will be 14,030 deaths due to ovarian cancer in the United States largely due to advanced stage of disease at presentation in 70% of women with five-year overall survival of approximately 30% [1,2]. Despite a high rate of remission following primary treatment of advanced stage disease with both surgery and chemotherapy, recurrence is common with more than 60% of advanced ⁎ Corresponding author at: Cedars-Sinai Medical Center, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, 8635 West 3rd Street, Suite 280W, Los Angeles, CA 90048, USA. Fax: +1 3104230155. E-mail address: [email protected] (A.J. Li). 0090-8258/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ygyno.2014.01.003
stage patients developing recurrent disease [3]. In counseling patients with recurrent tumor, secondary tumor debulking is a potential treatment option depending on various factors including disease free interval, platinum sensitivity, tumor burden, and performance status. Those patients who undergo complete cytoreduction at the time of secondary tumor debulking will benefit the most [3–8]. Good performance status and absence of ascites are predictors of complete surgical cytoreduction in recurrent platinum sensitive epithelial ovarian cancer [9]. At this time, there is still controversy as to which patients with recurrent epithelial ovarian cancer are the best candidates for secondary tumor debulking. A growing body of evidence supports a role for thrombocytosis in the promotion of cancer biology. Platelets are associated with metastasis, angiogenesis, and tumor cell proliferation [10,11]. In ovarian cancer
J.G. Cohen et al. / Gynecologic Oncology 132 (2014) 556–559
models, evidence indicates the existence of a paracrine circuit in which tumor growth is fostered by a paraneoplastic thrombocytosis driven by thrombopoeitic cytokines [12]. Thrombocytosis has been shown to be an unfavorable prognostic factor in a number of solid tumors including colorectal, breast, pancreatic, and lung cancer [13–17]. In advanced stage ovarian cancer, thrombocytosis at the time of initial staging surgery has been linked to worse prognosis including decreased disease free interval, shorter overall survival, and a greater likelihood of suboptimal resection [18,19]. In addition, thrombocytosis in early stage epithelial ovarian cancer has been linked to an eight-fold increase risk of recurrence [20]. Despite the available literature regarding thrombocytosis at the time of primary surgical debulking, it is unclear if thrombocytosis at the time of recurrence has clinical significance. If a patient is a candidate for secondary debulking at the time of recurrence, thrombocytosis may provide important prognostic information. We hypothesize that thrombocytosis negatively influences tumor biology throughout the disease course. In this study, we evaluate the association between preoperative thrombocytosis, survival, and other clinic-pathologic factors in women with epithelial ovarian cancer undergoing secondary cytoreductive surgery (SCS). Methods Under an IRB-approved protocol, we identified 107 women with invasive epithelial ovarian cancer who underwent SCS between January 1997 and June 2012. Patients with a history of invasive epithelial or primary peritoneal carcinoma who underwent secondary tumor debulking at Cedars-Sinai Medical Center in Los Angeles, CA were included in this study. Patients with a tumor of low malignant potential were excluded from this study. In general, patients were considered candidates for secondary tumor debulking if they had a disease free interval greater than six months, Gynecologic Oncology Group performance status less than two, and three sites or less of suspected disease recurrence. All patients underwent secondary tumor debulking by a gynecologic oncologist with the intent of optimal tumor cytoreduction. Patients undergoing palliative surgical procedures were excluded from this study. Following first line chemotherapy, no patient underwent chemotherapy prior to SCS. After secondary debulking all patients underwent treatment with chemotherapy, receiving either a platinum couplet or single agent platinum. A preoperative automated complete blood count within sixty days of surgery was available for all patients. Thrombocytosis was considered as a platelet count ≥ 350 × 109/L consistent with published criteria [14–16]. Optimal resection at SCS was considered microscopic residual disease. Suboptimal resection was based on residual tumor burden. The following data was abstracted: stage of disease, age at time of SCS, platelet level at time of initial staging surgery, disease free interval from time of initial treatment, platelet level at time of SCS, residual tumor at time of SCS, and overall survival. Differences in clinical and histopathologic factors between patients with and without thrombocytosis were examined with chi-squared and Fisher's exact test. The Cox proportional hazards model was used to assess the significance of potential prognostic factors as predictive parameters for patient survival. Survival probabilities were analyzed with Kaplan–Meier curves. A p-value of 0.05 was considered to be statistically significant.
352–527). Three of these 13 (23%) patients also had thrombocytosis at their initial staging surgery. Of 55 women with available preoperative platelet counts at initial staging surgery, 18 (33%) had thrombocytosis at that time and subsequently had normal platelet counts prior to SCS. Women without thrombocytosis at SCS had a median platelet count of 243 × 109/L (range 84–338). Of the 13 patients with a preoperative thrombocytosis at the time of SCS, 11 (85%) were stage III or IV, while 78 (83%) of patients without preoperative thrombocytosis had advanced stage disease. Median disease free interval following primary surgery for those with thrombocytosis at the time of SCS was 21 months (range 8–171) while women who had a normal platelet count prior to SCS had a median disease free interval of 34 months (6–311) after their initial surgery (Table 1). Of those patients with thrombocytosis at time of SCS, 4 patients (31%) underwent resection to less than 1 cm residual tumor while 9 patients (69%) underwent suboptimal tumor debulking. In contrast, 62 patients (66%) with a normal preoperative platelet count had microscopic residual disease, 25 patients (27%) underwent debulking to less than 1 cm residual disease, and only 7 patients (7%) had suboptimal tumor debulking. Preoperative thrombocytosis at SCS was strongly associated with failure to undergo optimal resection (p = 0.0001) (Fig. 1). Women with preoperative thrombocytosis at time of SCS had a shorter overall survival (median 33 months) compared to those with a normal platelet count (median 46 months) (p = 0.004). Overall survival was defined as time from SCS to death (Fig. 2). When examining platelet count as a continuous variable, univariate analysis identified a significant correlation with survival with a relative risk of 1.004 (1.0005–1.0069, p = 0.02). On multivariate analysis, only preoperative platelet count retained significance as an independent prognostic factor (p = 0.025) after controlling for age at SCS, disease free interval from primary treatment, and initial stage of disease (Table 2). Discussion To our knowledge this is the first study to evaluate the significance of thrombocytosis at the time of recurrence of ovarian carcinoma. Prior studies have demonstrated an association between thrombocytosis and poor clinical outcome at the time of initial treatment. With a high likelihood of recurrent disease in advanced stage ovarian cancer, understanding the significance of thrombocytosis in this setting may assist clinicians in counseling patients regarding treatment options. Elevated platelet count at time of SCS is associated with suboptimal resection and shortened overall survival. This data provides further evidence supporting a plausible role for thrombocytosis in aggressive ovarian tumor biology. Interestingly, eighteen of twenty-one patients with thrombocytosis at initial staging surgery did not have thrombocytosis at the time of SCS. In comparison, only three of thirteen patients with thrombocytosis at SCS had thrombocytosis at the time of initial staging. This may be for various reasons. Firstly, bone marrow may be negatively impacted by
Table 1 Patient characteristics by group.
Results Of the 107 women with recurrent epithelial or primary peritoneal ovarian cancer who underwent SCS, 13 (12%) had preoperative thrombocytosis (a platelet count ≥ 350 × 109/L) at the time of SCS. The median age for women with a preoperative thrombocytosis was 65 years old (range 51–83) while those without elevated platelets had a median age of 53 years old (range 36–75). Women with thrombocytosis had a median platelet count of 416 × 109/L (range
557
Age at SCSb, median DFIc after primary surgery, median in months Platelets, median Stage I/II Stage III/IV a b c
Thrombocytosisa (n = 13)
Normal platelets (n = 94)
65 (range 51–83) 21 (range 8–171)
53 (range 36–75) 34 (range 6–311)
416 (range 352–527) 2 11
243 (range 84–338) 16 78
Thrombocytosis defined as preoperative platelet count ≥ 350 × 109/L. Secondary cytoreductive surgery (SCS). Disease free interval (DFI).
558
J.G. Cohen et al. / Gynecologic Oncology 132 (2014) 556–559 Table 2 Multivariate analysis of possible prognostic factors in overall survival.
Thrombocytosisa DFIb after primary surgery Age at SCSc Initial stage of disease a b c
Fig. 1. Thrombocytosis is associated with suboptimal resection. Patients with a preoperative thrombocytosis were less likely to undergo optimal tumor debulking with no patients reaching microscopic residual disease.
adjuvant chemotherapy and radiation. Patients may be less likely to generate a thrombocytosis in the setting of recurrence as a result. Secondly, recurrent disease may represent chemoresistant or altered cancer cells that have become more aggressive compared to the primary tumor. Given thrombocytosis is likely linked to more aggressive solid tumors, this may explain why a thrombocytosis would be present at recurrence but not at the time of initial diagnosis. Thirdly, alternative causes such as active infection, splenectomy, myeloproliferative disorders, or acute inflammatory processes may result in a thrombocytosis. Elevated platelets are a poor prognostic factor, and our findings are consistent with prior studies evaluating the significance of thrombocytosis in ovarian cancer at the time of initial treatment [12,18–20]. Allensworth et al. found thrombocytosis to be associated with shortened disease free survival and overall survival in stage I/II patients, while in stage III/IV patients only disease free survival was negatively impacted. When performing a multivariate analysis with this cohort of patients using the same statistical model by Stone et al., Allensworth et al. did find thrombocytosis to negatively impact overall survival in ovarian cancer patients at all stages [12,20]. The variation in these results may stem from differences in patient cohorts and mathematical modeling, but the conclusion is similar: there is a relationship between thrombocytosis and worse prognosis in the setting of malignancy. Our study is a retrospective chart review and has various limitations including a small patient cohort. 97% of preoperative platelet levels were within thirty days of surgery, with the remainder of patients'
Hazard ratio
CI
p-Value
1.004 0.991 1.002 1.104
1.001–1.007 0.981–1.000 0.975–1.029 0.706–1.725
0.025 0.06 0.90 0.66
Thrombocytosis defined as preoperative platelet count ≥ 350 × 109/L. Disease free interval. Secondary cytoreductive surgery.
values obtained more than thirty days and less than sixty days prior to surgery. This leaves a small window in which the preoperative platelet count could have fluctuated prior to secondary tumor debulking. In this cohort of patients, thrombocytosis was considered to be a platelet count ≥ 350 × 109/L. While this is consistent with published criteria, there is variation in this number cutoff throughout the literature. A consideration in this patient population is the negative effect prior toxic agents have had on bone marrow reserve, potentially lowering baseline platelet counts. Lastly, we do not address a mechanistic relationship between thrombocytosis and aggressive tumor biology, however this area warrants further investigation. The relationship between elevated platelets and malignancy represents a potential treatment paradigm for patients with thrombocytosis in the recurrent setting. Radizon et al. demonstrated the significance of cancer–platelet interactions through which platelets increased the survival of ovarian adenocarcinoma cells treated with 5-fluorouracil and paclitaxel [21]. Chemoresistance is a common occurrence in recurrent epithelial ovarian cancer and platelets may contribute to this. Further evaluation of platelet secretory factors must be performed on a molecular level to better understand variations in tumor aggressiveness and potential treatment targets [22]. Tumor growth and elevated platelet levels appear to have a positive feedback mechanism. Tumorderived interleukin-6 increases platelet counts and promotes tumor growth in ovarian cancer models [12]. Targeting interleukin-6 in ovarian cancer patients with thrombocytosis has shown promise based on preliminary results and may represent a viable therapeutic target [12,23,24]. The majority of patients with advanced stage disease ovarian cancer will develop recurrence. As we move towards individualized cancer care based on patient specific genome analysis, patient centered outcomes will rise in importance. Secondary tumor debulking has its largest benefit in those patients who undergo complete cytoreduction. Predictors of successful surgery are more important now than ever, and preoperative thrombocytosis may assist with the ability to predict success of surgical resection in the recurrent setting. Preoperative thrombocytosis may also help identify those patients who will benefit from targeted treatment of platelet-tumor cell interactions. Prospective trials evaluating these treatments are warranted. Conflict of interest statement The authors declare that there are no conflicts of interest.
References
Fig. 2. Thrombocytosis correlates with shorter overall survival. Patients with a preoperative thrombocytosis at the time of SCS had a statistically shorter overall survival compared to those patients who did not have an elevated platelet count (median 33 vs 46 months respectively).
[1] Siegel R, Naishadham D, Jemal A. Cancer Stat 2013;63(1):11–30 [Ca]. [2] Lu KH, Skates S, Hernandez MA, Bedi D, Bevers T, Leeds L, et al. A 2-stage ovarian cancer screening strategy using the Risk of Ovarian Cancer Algorithm (ROCA) identifies early-stage incident cancers and demonstrates high positive predictive value. Cancer 2013;119(19):3454–61. [3] Salani R, Santillan A, Zahurak ML, Giuntoli II RL, Gardner GJ, Armstrong DK, et al. Secondary cytoreductive surgery for localized, recurrent epithelial ovarian cancer: analysis of prognostic factors and survival outcome. Cancer 2007;109(4):685–91. [4] Chi DS, McCaughty K, Diaz JP, Huh J, Schwabenbauer S, Hummer A, et al. Guidelines and selection criteria for secondary cytoreductive surgery in patients with recurrent, platinum-sensitive epithelial ovarian carcinoma. Cancer 2006;106(9):1933–9. [5] Tian W, Chi DS, Sehoulii J, Tropé CG, Jiang R, Ayhan A, et al. A risk model for secondary cytoreductive surgery in recurrent ovarian cancer: an evidence-based proposal for patient selection. Ann Surg Oncol 2012;19(2):597–604.
J.G. Cohen et al. / Gynecologic Oncology 132 (2014) 556–559 [6] Al Rawahi T, Lopes AD, Bristow RE, Bryant A, Elattar A, Chattopadhyay S, et al. Surgical cytoreduction for recurrent epithelial ovarian cancer. Cochrane Database Syst Rev 2013;2:CD008765. [7] Chuang C, Chou Y, Yen M, Chao K, Twu N, Wu H, et al. The role of secondary cytoreductive surgery in patients with recurrent epithelial ovarian, tubal, and peritoneal cancers: a comparative effectiveness analysis. Oncologist 2012;17(6):847–55. [8] Bristow RE, Puri I, Chi DS. Cytoreductive surgery for recurrent ovarian cancer: a meta-analysis. Gynecol Oncol 2009;112(1):265–74. [9] Harter P, Sehouli J, Reuss A, Hasenberg A, Scambia G, Cibula D, et al. Prospective validation study of a predictive score for operability of recurrent ovarian cancer: the Multicenter Intergroup Study DESKTOP II. A project of the AGO Kommission OVAR, AGO Study Group, NOGGO, AGO-Austria, and MITO. Int J Gynecol Cancer 2011;21(2):289–95. [10] Cho MS, Bottsford Miller J, Vasquez HG, Stone R, Zand B, Kroll MH, et al. Platelets increase the proliferation of ovarian cancer cells. Blood 2012;120(24):4869–72. [11] Holmes CE, Levis JE, Ornstein DL. Activated platelets enhance ovarian cancer cell invasion in a cellular model of metastasis. Clin Exp Metastasis 2009;26(7):653–61. [12] Stone RL, Nick AM, McNeish IA, Balkwill F, Han HD, Bottsford Miller J, et al. Paraneoplastic thrombocytosis in ovarian cancer. N Engl J Med 2012;366(7):610–8. [13] Ishizuka M, Nagata H, Takagi K, Iwasaki Y, Kubota K . Preoperative thrombocytosis is associated with survival after surgery for colorectal cancer. J Surg Oncol 2012;1 06(7):887–91. [14] Sasaki K, Kawai K, Tsuno NH, Sunami E, Kitawama J. Impact of preoperative thrombocytosis on the survival of patients with primary colorectal cancer. World J Surg 2012;36(1):192–200.
559
[15] Stravodimou A, Voutsadakis IA. Pretreatment thrombocytosis as a prognostic factor in metastatic breast cancer. Int J Breast Cancer 2013;2013:289563. [16] Hwang SG, Kim KM, Cheong JH, Kim HI, An JY, Hyung WJ, et al. Impact of pretreatment thrombocytosis on blood-borne metastasis and prognosis of gastric cancer. Eur J Surg Oncol 2012;38(7):562–7. [17] Maráz A, Furák J, Varga Z, Káhan Z, Tiszlavicz L, Hideghéty K. Thrombocytosis has a negative prognostic value in lung cancer. Anticancer Res 2013;33(4):1725–9. [18] Li AJ, Madden AC, Cass I, Leuchter RS, Lagasse LD, Karlan BY. The prognostic significance of thrombocytosis in epithelial ovarian carcinoma. Gynecol Oncol 2004;92(1):211–4. [19] Crasta JA, Premlatha TS, Krishnan SM, Vallikad E, Rameshkumar K. Significance of preoperative thrombocytosis in epithelial ovarian cancer. Indian J Pathol Microbiol 2010;53(1):54–6. [20] Allensworth SK, Langstraat CL, Martin JR, Lemens MA, McGree ME, Weaver AL, et al. Evaluating the prognostic significance of preoperative thrombocytosis in epithelial ovarian cancer. Gynecol Oncol 2013;130(3):499–504. [21] Radziwon Balicka A, Medina C, O'Driscoll L, Treumann A, Bazou D, Inkielewicz-Stepniak I, et al. Platelets increase survival of adenocarcinoma cells challenged with anticancer drugs: mechanisms and implications for chemoresistance. Br J Pharmacol 2012; 167(4):787–804. [22] Gungor T, Kanat Pektas M, Sucak A, Sucak A, Mollamahmutoglu L, et al. The role of thrombocytosis in prognostic evaluation of epithelial ovarian tumors. Arch Gynecol Obstet 2009;279(1):53–6. [23] Banerjee S, Kaye SB. New strategies in the treatment of ovarian cancer: current clinical perspectives and future potential. Clin Cancer Res 2013;19(5):961–8. [24] Rao AK, Rao DA. Platelets signal and tumors take off. Blood 2012;120(24):4667–8.