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© 2002 American Society for Clinical Oncology Increased Cyclooxygenase-2 Expression Is Associated With Chemotherapy Resistance and Poor Survival in Cervical Cancer PatientsByFrom the Departments of Obstetrics and Gynecology, Pathology, and Histology, Catholic University of the Sacred Heart, Rome, Italy. Address reprint requests to Franco O. Ranelletti, Department of Histology, Catholic University, L. go F. Vito, 1, 00168 Rome, Italy; email: ranelletti{at}rm.unicatt.it
PURPOSE: To investigate the expression of cyclooxygenase (COX-2) and its association with clinicopathologic parameters and clinical outcome in patients with cervical cancer. PATIENTS AND METHODS: The study included 84 patients with stage IB to IVA cervical cancer. Patients with early-stage cases (n = 21) underwent radical surgery, whereas patients with locally advanced cervical cancer (LACC) (n = 63) were first administered neoadjuvant cisplatin-based treatment and subjected to surgery in case of response. Immunohistochemical analysis was performed on paraffin-embedded sections with rabbit antiserum against COX-2. RESULTS: COX-2–integrated density values in the overall population ranged from 1.2 to 82.3, with mean ± SE values of 27.4 ± 2.4. According to the chosen cutoff value, 36 (42.9%) of 84 patients were scored as COX-2 positive. COX-2 levels were shown to be highly associated with tumor susceptibility to neoadjuvant treatment. COX-2 showed a progressive increase from mean ± SE values of 19.9 ± 8.0 in complete responders through 31.5 ± 3.5 in partial responses to 44.8 ± 3.9 in patients who were not responsive (P = .0054). When logistic regression was applied, only advanced stage and COX-2 positivity retained independent roles in predicting a poor chance of response to treatment. COX-2–positive patients had a shorter overall survival (OS) rate than COX-2–negative patients. In patients with LACC, the 2-year OS rate was 38% in COX-2–positive versus 85% in COX-2–negative patients (P = .0001). In the multivariate analysis, only advanced stage and COX-2 positivity retained independent negative prognostic roles for OS. CONCLUSION: The assessment of COX-2 status could provide additional information to identify patients with cervical cancer with a poor chance of response to neoadjuvant treatment and unfavorable prognosis.
SURGERY REPRESENTS THE mainstay of treatment for patients with early-stage cervical cancer, whereas multimodal treatment strategies, including radiotherapy combined with cisplatin-based chemotherapy or neoadjuvant chemotherapy or chemoradiation followed by radical surgery, have been reported to significantly improve disease-free as well as overall survival (OS) in patients with locally advanced cervical cancer (LACC).1-3 Several clinicopathologic parameters have been reported to be of prognostic significance in patients with early-stage cervical cancer and patients with LACC, including clinical stage, tumor volume, lymph node involvement, and lymphocytic infiltration.2,4,5 Moreover, chemotherapy resistance and disease recurrences could reliably be predicted by assessing biochemical factors strictly related to tumor cell biology and tumor aggressiveness, such as serum levels of squamous cell carcinoma antigen, microvessel density, oncogenes, and tumor suppressor genes.6-9 Recently, much attention has focused on the involvement of cyclooxygenase (COX), the key enzyme in the conversion of arachidonic acid to prostaglandins, in critical steps of tumor onset and progression. Epidemiologic studies in people continuously taking nonsteroidal anti-inflammatory drugs, well-known COX inhibitors, showed a 40% to 50% lower risk of colorectal cancer10 and, to a lesser extent, a lower risk of prostate and breast cancers,11,12 stimulating much effort in understanding the biology of COX. Two COX isoforms have been characterized. COX-1 is constitutively expressed in most tissues, where it serves homeostatic functions. COX-2 is highly inducible by growth factors, prostaglandins, and tumor promoters and is mainly associated with the inflammatory response.13 More recently, several in vitro and preclinical studies have shown that COX-2 overexpression is associated in colorectal cancer cells with bcl2 overexpression, apoptosis inhibition, increased adhesion to extracellular matrix, and increased metastatic potential and neoangiogenesis.14-16 Moreover, it has also been hypothesized that overexpression of COX-2 could impair host immune responses, as suggested by the ability of COX-2 inhibitors or COX-2 antisense constructs to revert tumor-induced immunosuppression.17 COX-2 has been found to be overexpressed in most colorectal cancer tumors as well as in other solid tumors and has been associated with clinicopathologic parameters of aggressiveness and unfavorable prognosis.18-22 Recent studies have also shown that the expression of COX-2 increases through more severe grade of cervical dysplasias to invasive cervical cancer.23,24 Moreover, high COX-2 expression has been associated with lymph-node metastasis or parametrial invasion in stage IB cervical tumor25 and correlated with worse prognosis in patients with cervical cancer treated with radiotherapy.26 To our knowledge, few studies have been reported until now26,27 on the possible role of COX-2 expression as a prognostic parameter in cervical cancer. The aim of the present study was to investigate by immunohistochemistry the expression of COX-2 and its association with clinicopathologic parameters and clinical outcome in terms of OS in a large single institutional series of patients with early-stage cervical cancer and LACC. The possible role of COX-2 status as predictor of response to neoadjuvant treatment in patients with LACC has also been analyzed.
The study included a total of 84 stage IB to IVA patients with cervical cancer consecutively admitted to the Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Catholic University of Rome between October 1995 and December 2000. Staging was performed according to International Federation of Gynecology and Obstetrics (FIGO) staging system classification. Pretreatment evaluation consisted of a history and physical examination, biopsy and gynecologic examination under general anesthesia, abdominal-pelvic magnetic resonance imaging, pelvic ultrasonography, and chest x-ray. Cystoscopy and sigmoidoscopy were performed when indicated. Median age was 50 years (range, 24 to 76). Twenty-two patients had stage IB disease, nine patients had stage IIA, and 37 patients had stage IIB, whereas advanced stage of disease was observed in 16 patients. Most of the tumors (n = 70) were squamous cell carcinomas, although 11 cases were adenocarcinomas and three patients revealed an adenosquamous histotype. The other clinicopathologic characteristics are summarized in Table 1.
The flow chart of the overall patient population and clinical management is shown in Fig 1. Patients with early-stage disease (FIGO stage IB to IIA, major tumor diameter < 4 cm) were primarily submitted to radical surgery (n = 21), whereas locally advanced cancer cases (n = 63) were first administered neoadjuvant cisplatin–based treatment (cisplatin dose 100 mg/m2 every 3 weeks for two to three courses). In stage IV disease, concurrent radiotherapy was administered. In cases of clinical response, assessed by the procedures described above and recorded according to World Health Organization response evaluation criteria,27 patients with LACC were submitted to radical surgery. Patients clinically showing no change or progression during neoadjuvant treatment were subjected to exclusive radiotherapy, with the exception of one patient in whom surgery was attempted because of her very young age, despite there being no evidence of response to treatment. This patient underwent explorative laparotomy.
In patients submitted to radical surgery (n = 69), operative technique consisted of type II to IV radical hysterectomy and systematic pelvic lymphadenectomy. Patients with positive aortic lymph nodes at imaging, palpable aortic nodes, positive external iliac or obturator nodes at frozen sections, cervical adenocarcinoma, or poorly differentiated tumors were submitted to para-aortic lymphadenectomy up to the level of inferior mesenteric artery. An anterior exenteration was performed in two patients with persisting involvement of the bladder after neoadjuvant treatment. In cases of pathologically documented lymph node involvement, additional chemotherapy was administered.
Immunohistochemistry
Quantification of Immunohistochemical Staining
Statistical Analysis Disease-free survival was calculated from the date of surgery to the date of relapse or date last seen, whereas OS was calculated from the date of diagnosis to the date of death or date last seen. Medians and life tables were computed using the product limit estimate by the Kaplan-Meier method,31 and the log-rank test was used to assess the statistical significance. To reduce the possible bias related to the use of an arbitrary cutoff32 required in the Kaplan-Meier analysis, we also analyzed the prognostic role of COX-2 as a continuous variable by means of the Cox Mantel method.33 A Cox’s regression model with stepwise variable selection34 and multiple logistic analysis35 was used to analyze the role of clinicopathologic parameters and COX-2 staining as prognostic factors and predictors of response to neoadjuvant treatment. Statistical analysis was carried out using SOLO (BMDP Statistical Software, Los Angeles, CA).
Cox-2 Immunostaining A variability of expression in COX-2 immunostaining was observed both in cytoplasm and in nuclei of tumor cells. Figure 2 shows a representative tumor with intense COX-2 immunostaining (Fig 2A) compared with a tumor with a low percentage of COX-2–stained cells (Fig 2B). Stromal cells also show different intensities of COX-2 immunoreaction. COX-2–integrated density values in the overall population range from 1.2 to 82.3, with mean ± SE values of 27.4 ± 2.4. According to the chosen cutoff value, 36 (42.9%) of 84 tumors were scored as COX-2 positive.
Correlation With Clinicopathologic Parameters When the reciprocal correlations among all clinicopathologic parameters were analyzed, larger volume tumors were detected in more advanced stage disease (P = .0001). Moreover, a trend toward an association between older age and more advanced stage was found, although this was not statistically significant (P = .054). Finally, squamous cell tumors were poorly differentiated in a higher percentage with respect to adenocarcinomas (P = .07). Table 2 lists the distribution of COX-2–integrated density values, as well as COX-2 positivity, according to clinicopathologic characteristics. COX-2 values showed a trend to be higher in older patients (mean ± SE = 30.4 ± 3.1) than in younger ones (mean ± SE = 23.9 ± 3.8) (P = .09).
A progressive increase in COX-2 values according to stage of disease was found (P = .054). Moreover, higher COX-2 values were detected in adenocarcinoma (mean ± SE = 49.6 ± 6.7) versus squamous cell (mean ± SE = 24.2 ± 2.5) tumors (P = .005). No significant association between COX-2 levels and grade of differentiation was found. Interestingly, a significant difference in COX-2 values according to cervical tumor size was found. In particular, higher COX-2 levels were found in tumors  4 cm (mean ± SE = 32.2 ± 3.0) than in smaller tumors (mean ± SE = 18.8 ± 3.8) (P = .0024). As expected, because of the strict association between high COX-2 values and stage as well as tumor size, COX-2 values were found to be associated with clinical parametrial involvement. Mean ± SE COX-2 values were 32.4 ± 3.1 in the case of positive parametrium versus 20.0 ± 3.6 in the case of uninvolved parametrium (P = .0053). No association between COX-2 values and lymph node involvement as assessed by magnetic resonance imaging was found. Similar results were obtained when COX-2–positive versus COX-2–negative status was considered according to the chosen cutoff value (Table 2). A higher percentage of COX-2 positivity in older (55.6%) versus younger (28.2%) patients was found (P = .021). A trend of COX-2 positivity to increase from stage I through stage II to stage III and IV was found, although this was not statistically significant. More interestingly, the percentage of COX-2 positivity was higher in cases with tumor volume of 4 cm or greater than in smaller tumors (51.8% v 26.7%) (P = .045). The percentage of COX-2 positivity was higher in cases with parametrial involvement (52%) than in cases with negative parametria (29.4%) (P = .06). COX-2 positivity was found not to be differently distributed according to grade of differentiation and clinical lymph node involvement. We also tested whether COX-2 could be related to histopathologic findings in patients undergoing radical hysterectomy. In 14 (20.3%) of 69 cases, metastatic lymph node involvement was found. The percentage of COX-2 tumor positivity was 28.6% in lymph node–positive cases compared with 35.7% in lymph node–negative cases (difference not significant). We failed to find any association between COX-2 and pathologic response or pathologic parametrial involvement (data not shown).
COX-2 Status and Response to Neoadjuvant Treatment Table 3 lists the univariate and multivariate analysis of clinicopathologic parameters and COX-2 status as predictors of response to neoadjuvant therapy (complete or partial v no response). When logistic regression was applied, only more advanced stage and COX-2 positivity retained independent roles in predicting a poor chance of response to treatment. Similar results were obtained when COX-2 was analyzed as a continuous variable (data not shown).
Survival Analysis Follow-up data were available for 84 patients. As of March 2001, the median follow-up was 20 months (range, 3 to 65). During the follow-up period, 18 (21.4%) of 84 patients died of disease. In patients with radical operations, recurrence of disease occurred in 12 (17.4%) of 69 cases. To minimize possible bias because of heterogeneity of patient population, we showed only the survival analysis relative to the group of patients with LACC, according to COX-2 status (Fig 3).
COX-2–positive patients had a shorter OS than COX-2–negative patients. In particular, the 2-year OS rate was 38% (95% confidence interval, 18% to 58%; median, 17 months) in COX-2–positive patients versus 85% (95% confidence interval, 70% to 100%; median not reached) (P = .0001) in COX-2–negative patients. The plot of the estimate of OS at 2 years as a function of COX-2–integrated density values is shown in Fig 4. COX-2–integrated density values were shown to be directly associated with risk of death (  2 = 10.68; P = .0011) as assessed by Cox univariate analysis using COX-2 values as continuous covariate. We obtained similar results when analyzing the OS relative to the whole population (data not shown).
In the multivariate analysis, only advanced stage and COX-2 positivity retained independent negative prognostic roles for OS (Table 4). Similar results were obtained in multivariate analysis considering COX-2 values as continuous variables (data not shown). COX-2–positive cases showed a trend to a shorter disease-free survival than COX-2–negative cases, although the difference was not statistically significant (data not shown).
This study highlights the potential clinical role of COX-2 as a predictor of chemotherapy response and survival in a large series of patients with primary cervical cancer. As reported for other tissue types,19 COX-2 is overexpressed in tumor cells compared with normal counterparts. Although the mechanism of COX-2 upregulation is unknown, recent evidence suggests that it could result from dysregulation of key steps in epidermal growth factor receptor signaling pathways, particularly ras and mitogen-activated protein kinases.24,36 The involvement of COX-2 overexpression in cervical tumor onset and progression is plausible considering the progressive increase of COX-2 expression from normal cervical epithelium through increasing grades of severity in cervical dysplasias.23,24 Consistently, we found a strict correlation between high COX-2 expression and local tumor spread, as suggested by the association with advanced stage of disease and larger tumor size, confirming results seen in other tumors.37 No association was found between COX-2 levels and clinical as well as pathologic lymph node involvement. These findings differ from those reported by Ryu et al,25 who studied 36 stage IB cervical tumors and did not distinguish between lymph node versus parametrial involvement as parameters of tumor invasion. On the other hand, we failed to confirm the association between COX-2 and pathologic parametrial involvement. However, considering that surgery was performed only in the subgroup of chemosensitive patients, it is conceivable that the lack of association between COX-2 and pathologic parametrial involvement could be related to the effects of chemotherapy on tumor volume. Our data suggest, therefore, that in cervical cancer, COX-2 is more strictly related to local tumor spread than node metastasization, differing from other studies in colon and gastric cancer.38,39 However, this could reflect the particular natural history of cervical cancer, which mainly spreads locally, through a direct infiltration of the surrounding tissues. In this context, studies are in progress in our laboratory to assess local host factors, such as flogistic and lymphoid infiltrate, cytokines, and neovascularization as well as markers of extracellular matrix degradation, and their relationship with COX-2 expression, because this issue has been suggested to be of utmost importance in tumor and host interactions.40,41 The most interesting finding of our study was the strong correlation between COX-2 expression and clinical response to treatment. Almost all patient progressing during treatment showed positive COX-2 tumors. More importantly, the ability of COX-2 expression to predict cervical tumor susceptibility to therapy was retained in multivariate analysis, including stage of disease and tumor histotype. We did not find any association between COX-2 and pathologic response to chemotherapy in clinically responsive patients subjected to radical surgery. However, it should be taken into account that in the group of clinically responsive patients, a relatively homogenous population, the strength of the association between COX-2 expression and chemotherapy resistance could be reduced. The biochemical link between COX-2 overexpression and resistance to chemotherapy is unclear, although it is conceivable that COX-2 could be involved in the inhibition of apoptosis and induction of neoangiogenesis. In particular, COX-2 overexpression has been associated with the induction of the antiapoptotic protein bcl2.39 Moreover, COX-2 has been reported to mediate the growth factor–induced production of vascular endothelial growth factor mRNA and protein42 and to be associated with neoangiogenesis in tumor-bearing mice.43 Because apoptosis and neoangiogenesis processes are highly correlated44 and associated with resistance to chemotherapy and radiotherapy in cervical cancer patients,8,45 our findings strongly support the predictive role of COX-2 expression as a marker of chemoresistance in cervical cancer. In this context, it is noteworthy that cyclooxygenase inhibitors have been demonstrated to enhance the cytotoxicity in vitro of several chemotherapeutic agents46 and to potentiate tumor cell radiosensitivity in vivo,47 possibly through the suppression of vascular endothelial growth factor–regulated neoangiogenesis.48 Moreover, the possibility of investigating the role of COX-2 as predictor of sensitivity to radiation therapy is also of great clinical relevance, because evidence has shown that COX-2 may be involved in radioresistance. In particular, Kishi et al49 demonstrated that the use of selective inhibitor of COX-2 potentiates radiation efficacy in sarcoma-bearing mice. Moreover, Gaffney et al26 reported that COX-2 is associated with shorter survival in cervical cancer patients treated with radiotherapy. Finally, analysis of OS supported the correlation between COX-2 overexpression and unfavorable clinical outcome in cervical as well as in other tumors.18,21,26 Although the results of multivariate analysis always need to be interpreted with caution, our data, which demonstrated that COX-2 positivity retained the prognostic significance in multivariate analysis, suggest an independent role of COX-2 as a prognostic marker in this neoplasia. It is noteworthy that the use of an arbitrary cutoff value to distinguish COX-2–negative versus COX-2–positive cases probably did not introduce any bias, because a direct correlation with risk of death also in multivariate analysis using COX-2–integrated values as continuous variable was also observed. In conclusion, the present study showed that the assessment of COX-2 status could provide additional information to identify patients with cervical cancer with a poor chance of response to neoadjuvant therapy and unfavorable prognosis and, therefore, potential candidates for more individualized treatments. Moreover, these findings suggest that COX-2 may represent a new potential target not only for chemoprevention in cervical dysplasias23 but also for new therapeutic approaches, at least in certain subsets of patients with cervical cancer. In this context, the use of selective COX-2 inhibitors, characterized by low toxicity and good oral bioavailability and already approved for treatment of familial colorectal adenomatous polyposis, potentially could be exploited.
Supported by grants from Ministero dell’Università e della Ricerca Scientifica e Tecnologica.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
