Annals of Oncology Advance Access originally published online on December 6, 2007
Annals of Oncology 2008 19(2):327-331; doi:10.1093/annonc/mdm495
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
gynecologic tumors |
Nadir CA-125 concentration in the normal range as an independent prognostic factor for optimally treated advanced epithelial ovarian cancer
1 Department of Medical Oncology
2 Department of Gynecologic Oncology
3 Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain
* Correspondence to: Dr A. Prat, Department of Medical Oncology, Vall d'Hebron University Hospital, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain. Tel: +34-93-489-30-00; Fax:+34-93-274-60-59; E-mail: alprat{at}vhebron.net
 |
Abstract |
|---|
 Top Abstract introductionpatients and methodsresultsdiscussionReferences |
|---|
Background: The amount of residual disease after surgery is considered the most important factor influencing the survival of patients with advanced epithelial ovarian cancer (adEOC). In optimally treated patients with adEOC, there are no well-established prognostic factors [excluding International Federation of Gynecology and Obstetrics (FIGO) stage]. The aim of this retrospective study is to analyze the prognostic value of the CA-125 nadir after the completion of an optimal primary treatment.
Patients and methods: Patients treated for adEOC were identified from January 1998 to December 2006. Inclusion criteria: elevated CA-125 at time of diagnosis (>35 kU/l); FIGO stage III–IV treated with optimal primary treatment (residual tumor <1 cm and carboplatin/taxane-based combination chemotherapy); and complete response to optimal primary treatment with normalization of CA-125.
Results: Patients, n = 96: 44 group A (
10 kU/l); 52 group B (11–35 kU/l). Median progression-free survival (PFS) was 42 and 20 months for groups A and B, respectively (P = 0.0087). Median overall survival (OS) was 84 and 43 months for groups A and B, respectively (P < 0.0001). The Cox model showed a highly significant impact on PFS and OS in relation to CA-125 nadir levels.
Conclusions: The CA-125 nadir value is a strong independent prognostic factor for optimally treated adEOC after achieving a complete response.
Key words: CA-125 nadir, carboplatin, ovarian cancer, paclitaxel, prognostic factor
|
introduction |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
In Western countries, epithelial ovarian cancer (EOC) is the leading cause of death for gynecologic malignancies [1]. Primary treatment for women with advanced EOC (adEOC) consists of cytoreductive surgery and postoperative platinum and taxane-based combination chemotherapy administered either i.v. and/or intraperitoneal [2–6]. The survival of these patients is largely related to the amount of residual disease after surgery [7], and residual tumor <1 cm in maximal diameter has been defined as an optimal cytoreductive procedure by the Gynecologic Oncology Group (GOG). However, despite an optimal primary treatment, the disease will ultimately recur in the majority of cases and the expected 5-year survival rate will not exceed 30%–50% [3, 8]. Therefore, it would be tremendously valuable for optimizing therapeutic management to identify early indicators of relapse and survival for this patient population.
In the last decade, the CA-125 serum concentration has been established as a tool of great importance in the diagnosis of the disease, prognosis and monitoring of treatment [9]. Several reports have recently indicated that it may be possible to define the risk of relapse and death by dividing patients that have achieved a complete biochemical (35 kU/l) and radiological response after primary treatment into arbitrary groups based on the CA-125 nadir [10–13]. Indeed, values 10–12 kU/l have been associated with an increase in progression-free survival (PFS) [10–13] and overall survival (OS)[13].
However, in these previous studies, different treatment strategies, disease progression definitions, and population heterogeneity may have had a potential effect in outcome. Thus, the aim of our retrospective study is to analyze the prognostic value of the CA-125 nadir in a homogenous group of adEOC treated in a single institution with optimal cytoreductive surgery and perioperative platinum/taxane-based chemotherapy followed by observation.
|
patients and methods |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
patient populations
From 1 January 1998 to 31 December 2006, all patients treated for EOC at Vall d'Hebron University Hospital were identified from the tumor registry database and screened retrospectively for their initial serum CA-125 level, age at diagnosis, tumor histology and grade, stage of disease based on the International Federation of Gynecology and Obstetrics (FIGO) staging system, the availability of serial serum CA-125 level determinations, and timing of recurrence and/or disease status at last follow-up. All patients received chemotherapy combination with carboplatin (area under the curve of 5) and paclitaxel (175 mg/m2 by 3-hour infusion) every 3 weeks for a total of 6–8 cycles. Patients with epithelial tumors of borderline malignancy were excluded from this investigation.
Following initial eligibility screening, the following inclusion criteria were applied to determine the final study population: (i) an elevated CA-125 at time of diagnosis (>35 kU/l); (ii) stages of disease III (A, B and C) and IV treated with either optimal cytoreductive surgery and postoperative chemotherapy, or neoadjuvant chemotherapy followed by optimal interval cytoreductive surgery; (iii) stage IV patients were eligible if the only evidence of stage IV disease was malignant cells in pleural effusion; (iv) complete clinical and radiographic response (CR) to initial treatment with normalization of serum CA-125 (35 kU/l); (v) at least two serial serum CA-125 level determinations (at intervals ranging from 1 to 4 months following CR) that remained within the normal range (35 kU/l); (vi) clinical and/or radiographic determination of disease status at the time of last follow-up or recurrence; (vii) time elapsed between surgery and chemotherapy or vice versa <28 days. Abdominopelvic surgery was defined as a procedure including at least total hysterectomy, bilateral adnexectomy and omentectomy and peritoneal debulking. Cytoreductive surgery was considered to be optimal if, following review of the surgery and pathology report, <1 cm of residual disease was present (following the recommendations of the GOG [14]). Primary and interval surgery were carried out in all cases by a gynecologic oncologist. This retrospective study was approved by the ethics committee of our institution.
statistical methodology
The primary study goal was to determine whether CA-125 serum level at the completion of primary treatment is a predictor of survival. The nadir value of CA-125 was categorized into two arbitrary groups: group A, 10 kU/l; and group B, 11–35 KU/l. Disease progression/recurrence was defined on imaging-based criteria: appearance of new lesions by computed tomography or by positron emission tomography scan imaging. PFS was defined as the interval between the date of primary surgery or the date of initiation of neoadjuvant chemotherapy and the date of progression/recurrence or death, whichever came first. OS was calculated from the date of primary surgery or the date of initiation of neoadjuvant chemotherapy until the last date of follow-up or date of death.
Standard Kaplan–Meier methods were used to plot the survival of members of each of the nadir groups. Comparison between the survival curves was analyzed using the log-rank test. A multivariate Cox proportional hazards model for PFS and OS was employed to assess differences in outcome on the basis of the CA-125 nadir after primary treatment, including other variables such as age (>65 versus 65), stage (IV versus III) and timing of cytoreductive surgery (primary versus interval). Step-wise regression techniques were used to build multivariate models using a significance level of 0.10 to remain in the model. SPSS statistical software (SPSS Inc, Chicago, IL) was used for all statistical analyses. All P values presented are two-sided, and associations are considered significant if the P value < 0.05.
|
results |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
After screening 275 patients from our records, a total of 96 patients satisfied the study inclusion criteria. Characteristics of the patient population included in this analysis are outlined in Table 1. The majority of patients had FIGO stage III (91%), and serous tumor histology (58%) at initial diagnosis. The median age at diagnosis was 59 years. Nine patients had FIGO stage IV (pleural effusion), and six (12%) were included in group B and three (7%) in group A. Twenty-six (27%) patients were treated with interval cytoreductive surgery, 10 (23%) and 16 (31%) patients in group A and B, respectively.
|
Median follow-up for all the 96 patients was 38 months (range, 1–96 months). The PFS of the two groups can be seen in Figure 1. Median PFS was 42 and 20 months (P = 0.0087, log-rank test) in patients with baseline CA-125 values of
10 kU/l (group A) and 11–35 kU/l (group B), respectively. Median OS was 84 and 43 months (P < 0.0001, log-rank test) in patients with baseline CA-125 values of 10 kU/l (group A) and 11–35 kU/l (group B), respectively (Figure 2). Thus, 
5-year survival rates were 80% for group A and 47.5% for group B.
|
Of all the baseline characteristics that were included in the Cox model, baseline CA-125 was the most important predictor of PFS and OS (Table 2 and 3). Patients that achieved a CA-125 nadir
10 kU/l (group A) had an 84% reduction in death hazard ratio (HR) compared with patients with CA-125 values between 11 and 35 kU/l (HR = 0.1616, P = 0.0002). The timing of surgery was also predictive of OS. Patients who received neoadjuvant chemotherapy and interval cytoreductive surgery had inferior median PFS and OS than patients who had primary surgery followed by postoperative chemotherapy (20 versus 32 months; P = 0.2072, log-rank test) and (45 versus 84 months; P = 0.0038, log-rank test), respectively. In the multivariable analysis, timing of surgery was an independent predictor of a poor OS (primary versus interval, HR = 0.3088, P = 0.0236).
|
|
In an exploratory analysis, the CA-125 levels of 11–35 kU/l group was further divided into those with values 11–20 kU/l (group B1, n = 36) versus those with values 21–35 kU/l (group B2, n = 16). There were statistically significant differences in OS between the two groups with greater survival in those patients with CA-125 nadir values of 11–20 kU/l (65 versus 22 months, P = 0.0013, log-rank test). Differences in PFS did not reach statistical significance (24 months for group B1 versus 18 months for group B2, P = 0.1465, log-rank test).
Finally, when we used a dichotomous variable that grouped patients using the median CA-125 nadir level of 11.04 kU/l, results were unchanged.
|
discussion |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
The concept of optimal cytoreduction has evolved over time and now generally applies to residual lesions no larger than 1 cm in diameter [14]. This surgical goal is achieved in only 50%–60% of women presenting with advanced EOC, and despite an optimal cytoreduction, the majority of patients recur and ultimately succumb to their disease. In the current retrospective study, using two arbitrary serum CA-125 groups based on the results of previous reports [10, 12], we have shown that the baseline serum marker level obtained after primary treatment in women with advanced EOC optimally treated and who have achieved a biochemical and clinically defined complete response to primary treatment, is a significant prognostic factor for subsequent disease relapse and OS. To our knowledge, this is the first report to evaluate the prognostic role of this serum marker in a homogenous group of advanced EOC optimally treated in a single institution.
Almost all surgically demonstrated advanced EOC have serum-elevated levels of antigen CA-125 [15]. This serum marker has a definitive value in the diagnosis of EOC, surveillance for recurrent disease, and monitoring the response to treatment. The prognostic role of the CA-125 nadir in the normal range (0–35 kU/l) after primary treatment has been recently evaluated. Crawford et al. [10] examined 79 patients with EOC stage IC–IV treated with cytoreductive surgery followed by chemotherapy. A variety of treatments were used, and only 38% of patients received a taxane. In this study, CA-125 nadir after primary treatment was predictive of biochemical PFS. Furthermore, OS of patients in the group with values of CA-125 inferior to 10 kU/l was highly significantly greater than the other group of patients. In a subsequent data analysis from the Scottish Randomised Trial in Ovarian Cancer trial and the Scottish Gynaecological Cancer Trials Group study G44, Crawford confirmed that the CA-125 nadir following chemotherapy for EOC stage IC–IV was a reproducible predictor of PFS [11]. Based on these findings and due to the increasing interest in evaluating consolidation therapies in the treatment of advanced EOC, Markman et al. [12] observed that the amount of residual tumor at the beginning of primary chemotherapy and the baseline CA-125 level after primary treatment and before initiation of maintenance chemotherapy strongly predicted the risk of subsequent relapse in advanced EOC. Patients with premaintenance baseline CA-125 values 10 kU/l had a superior PFS compared with higher levels in the normal CA-125 range. With a similar objective, Juretzka et al. [13] found that the CA-125 level in the normal range at the end of primary therapy for EOC stage I–IV was also predictive of OS before to the initiation of intraperitoneal consolidation therapy either as a continuous variable or when stratified into two categories divided at a cut-off value of 12 kU/l.
What can be implied from the results of our study? First, we have identified a subgroup of patients with a higher probability of being cured from their advanced disease. The median PFS and OS generally reported in this optimally treated patient population is 20–30 and 50–60 months, respectively [4–6, 16]. This outcome is in concordance to the survival of our group of patients with CA-125 nadir values between 11–35 kU/l (PFS and OS of 20 and 43 months, respectively). Patients with CA-125 nadir values 10 kU/l have a better prognosis achieving longer statistically significant PFS and OS of 42 and 84 months, respectively. Although surprising, median OS of 100 months have previously been reported in this optimally treated patient population [17, 18].
Secondly, our results emphasize the need to look for novel treatment strategies focusing on the group of patients with CA-125 nadir values of 11–35 kU/l. Although the benefit of consolidation treatment has not been clearly established, several types of consolidation treatments have been conducted in order to improve survival. A recent study by Markman et al. [19] provides evidence favoring this approach with paclitaxel monotherapy. Although counterintuitive, patients with CA-125 nadir values 10 kU/l after primary treatment and before maintenance paclitaxel benefited the most [12]. A possible explanation indicated by the authors is that the extended paclitaxel treatment could be more effective in the subgroup of patients with the smallest volume of residual disease and/or the most chemo-sensitive tumors.
Thirdly, future trials of maintenance therapy or secondary cytoreductive surgery should consider CA-125 nadir value after primary treatment as an important prognostic factor to take into account, stratifying patients according to their risk of progression and survival following a complete response. A possible explanation of the strong prognostic value of the CA-125 nadir in the normal range is that it could be a surrogate marker of size of residual disease. A relationship between disease status at second-look operation and absolute levels of serum CA-125 35 kU/l after primary treatment has previously been demonstrated [20, 21]. In 95 patients with advanced-stage EOC treated with cytoreductive surgery and postoperative chemotherapy, 50% of patients with values <20 kU/l had residual disease compared with >90% of patients with values 20–35 kU/l [21]. Furthermore, the size of residual disease, even within the definition of optimal cytoreduction, is of prognostic value. In patients with advanced EOC treated with optimal cytoreductive surgery and i.v. chemotherapy, a relationship between size of disease at second-look surgery (none, microscopic and macroscopic <1 cm) and survival has been demonstrated by Barakat et al. [17]. The median PFS by residual disease reported was none, 42 months; microscopic, 26 months and <1 cm, 16 months. In our exploratory analysis, the difference in PFS observed matched with the results of Barakat study. In patients with CA-125 nadir values of 11–20 kU/l and 21–35 kU/l, PFS was 24 and 18 months, respectively. In addition, those patients with CA-125 nadir values 10 kU/l achieved median PFS that were similar to that obtained in the group of no residual disease in the Barakat et al. [17] study (42 months). However, although interval-debulking surgery may have a place in the future management of EOC, the value of second-look laparatomy is still controversial due to the lack of prospective data supporting its use. Therefore, the demonstration and the utility of CA-125 nadir as a surrogate marker of residual disease after primary treatment needs further confirmation in future clinical trials for this patient population.
Fourthly, despite achieving an optimal cytoreduction, patients in our study selected for neoadjuvant chemotherapy showed an intrinsically worse prognosis probably related to the disease extension at diagnosis. Eight of 26 patients treated with neoadjuvant chemotherapy debuted with stage IV and the other 18 patients were not considered surgical candidates due to the presence of unresectable bulky disease. Previous results indicate that when surgery is abandoned in favor of initial chemotherapy, the survival outcome approximates that of suboptimal primary surgery [22]. Nevertheless, other reports indicate that there is no negative impact on survival when neoadjuvant chemotherapy is substituted for primary surgery [2, 23]. Indeed, neoadjuvant chemotherapy for primary unresectable EOC may lead to the selection of a subset of patients sensitive to chemotherapy in whom optimal cytoreduction can be achieved after chemotherapy in a high proportion of cases [24]. New data from well-designed and conduced phase III randomized trials is needed to properly address this issue.
Finally, despite the limitations of analyzing retrospective data, our results indicate that the CA-125 nadir is a strong independent prognostic factor for optimally treated advanced EOC after achieving a complete response. Prospective studies of maintenance–consolidation therapies or different approaches in this patient population based on CA-125 nadir seem warranted.
|
Received for publication June 9, 2007. Revision received August 14, 2007. Accepted for publication September 14, 2007.
|
References |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
1. Brun J-L, Feyler A, Chene G, et al. Long-term results and prognostic factors in patients with epithelial ovarian cancer. Gynecol Oncol (2000) 78:21–27.[CrossRef][Web of Science][Medline]
2. Schwartz PE, Rutherford TJ, Chambers JT, et al. Neoadjuvant chemotherapy for advanced ovarian cancer: long-term survival. Gynecol Oncol (1999) 72:93–99.[CrossRef][Web of Science][Medline]
3. Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol (2003) 21:3194–3200.
4. Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med (1996) 335:1950–1955.
5. Markman M, Bundy BN, Alberts DS, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol (2001) 19:1001–1007.
6. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med (2006) 354:34–43.
7. 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) 20:1248–1259.
8. The ICON Group. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet (2002) 360:505–515.[CrossRef][Web of Science][Medline]
9. Meyer T, Rustin G. Role of tumour markers in monitoring epithelial ovarian cancer. Br J Cancer (2000) 82:1535–1538.[CrossRef][Web of Science][Medline]
10. Crawford SM, Peace J. Does the nadir CA125 concentration predict a long-term outcome after chemotherapy for carcinoma of the ovary? Ann Oncol (2005) 16:47–50.
11. Crawford SM, Paul J, Reed NS, et al. The prognostic significance of the CA125 nadir in patients that achieve a CA125 response. Proc Am Soc Clin Oncol (2004) 22:14s. (Abstr 5001).
12. Markman M, Liu PY, Rothenberg ML, et al. Pretreatment CA-125 and risk of relapse in advanced ovarian cancer. J Clin Oncol (2006) 24:1454–1458.
13. Juretzka MM, Barakat RR, Chi DS, et al. CA125 level as a predictor of progression-free survival and overall survival in ovarian cancer patients with surgically defined disease status prior to the initiation of intraperitoneal consolidation therapy. Gynecol Oncol (2007) 104:176–180.[CrossRef][Web of Science][Medline]
14. Omura GA, Brady MF, Homesley HD, et al. Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experience. J Clin Oncol (1991) 9:1138–1150.[Abstract]
15. Bast RC, Klug TL, St John E, et al. A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med (1983) 309:883–887.[Abstract]
16. 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) 97:560–566.
17. Barakat RR, Sabbatini P, Bhaskaran D, et al. Intraperitoneal chemotherapy for ovarian carcinoma: results of long-term follow-up. J Clin Oncol (2002) 20:694–698.
18. Chi DS, Eisenhauer EL, Lang J, et al. What is the optimal goal of primary cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC)? Gynecol Oncol (2006) 103:559–564.[CrossRef][Web of Science][Medline]
19. Markman M, Liu PY, Wilczynski S, et al. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group Trial. J Clin Oncol (2003) 21:2460–2465.
20. Bese T, Demirkiran F, Arvas M, et al. What should be the cut-off level of serum CA125 to evaluate the disease status before second-look laparotomy in epithelial ovarian carcinoma? Int J Gynecol Cancer (1997) 7:42–45.[CrossRef][Web of Science][Medline]
21. Gallion H, Hunter J, van Nagell J, et al. The prognostic implications of low serum CA 125 levels prior to the second-look operation for stage III and IV epithelial ovarian cancer. Gynecol Oncol (1992) 46:29–32.[CrossRef][Web of Science][Medline]
22. Bristow RE, Chi DS. Platinum-based neoadjuvant chemotherapy and interval surgical cytoreduction for advanced ovarian cancer: a meta-analysis. Gynecol Oncol (2006) 103:1070–1076.[CrossRef][Medline]
23. Kuhn W, Rutke S, Späthe K, et al. Neoadjuvant chemotherapy followed by tumor debulking prolongs survival for patients with poor prognosis in International Federation of Gynecology and Obstetrics Stage IIIC ovarian carcinoma. Cancer (2001) 92:2585–2591.[CrossRef][Medline]
24. Ansquer Y, Leblanc E, Clough K, et al. Neoadjuvant chemotherapy for unresectable ovarian carcinoma. Cancer (2001) 91:2329–2334.[CrossRef][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Prat, M. Parera, and J. M. Del Campo Prognostic Role of CA-125 Nadir in Stage IV Epithelial Ovarian Cancer J. Clin. Oncol., April 1, 2008; 26(10): 1771 - 1772. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||