Skip Navigation


Annals of Oncology Advance Access originally published online on February 13, 2007
Annals of Oncology 2007 18(5):881-885; doi:10.1093/annonc/mdl500
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
18/5/881    most recent
mdl500v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Riedinger, J.
Right arrow Articles by Pichon, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Riedinger, J.
Right arrow Articles by Pichon, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2007 European Society for Medical Oncology

gynecologic tumors

Change in CA 125 levels after the first cycle of induction chemotherapy is an independent predictor of epithelial ovarian tumour outcome

JM Riedinger1,*, F Bonnetain2, JP Basuyau3, N Eche4, H Larbre5, I Dalifard6, J Wafflart7, G Ricolleau8 and MF Pichon9

1 Laboratoire de Biologie Médicale, Centre Georges François Leclerc, Dijon
2 Unité de biostatistiques et d'épidémiologie, Centre Georges François Leclerc, Dijon
3 Laboratoire de Biologie, Centre Henri Becquerel, Rouen
4 Laboratoire de Biologie, Institut Claudius Regaud, Toulouse
5 Laboratoire de Biologie Clinique, Institut Jean Godinot, Reims
6 Laboratoire de Radioanalyse, Centre Paul Papin, Angers
7 Laboratoire de Radioanalyse, Institut Bergonié, Bordeaux
8 Laboratoire d' Oncobiologie, Centre René Gauducheau, Nantes
9 Laboratoire d'Oncobiologie, Centre René Huguenin, Saint-Cloud, France

* Correspondence to: Dr J. M. Riedinger, Laboratoire de Biologie Médicale, Centre GF Leclerc, 1 rue du Pr Marion, 21034 Dijon cedex, France. Tel: +33-3-80-73-75-10; Fax: +33-3-80-73-75-26; E-mail: jriedinger{at}dijon.fnclcc.fr


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 conclusion
 References
 
Background: CA 125 assays enable treatment response monitoring in ovarian cancer.

Patients and methods: This multicentric study was carried out to assess the prognostic value of the CA 125 change after the first and the second courses of induction chemotherapy (CT). Of the 494 stage IIc–IV patients, 194 had a surgical second look, 397 (80.4%) relapsed and 382 (77.3%) died from cancer. Median (range) follow-up time was 34 months (3–215 months).

Results: In Cox models, CA 125 change after the first course (P < 0.0001), residual tumour (P = 0.003), CA 125 before the second course (P = 0.025) and patients' age (P = 0.048) were independent prognostic factors for overall survival (OS). A normal CA 125 before each of the two first CT courses or a CA 125 decrease >50% after the first course with a normal CA 125 before the second course identify patients with good prognosis. Both criteria retained a significant value in predicting second-look findings by univariate and multivariate analysis (P < 0.0001).

Conclusion: Among well-established prognostic factors in ovarian cancers, the CA 125 change after first course of CT was independent prognostic factors for both achievement of pathological complete response and OS.

Key words: CA 125, chemotherapy, ovarian cancer, prognosis, second look, survival


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 conclusion
 References
 
The prognosis of advanced ovarian cancers remains very poor, due to tumour extent at the time of diagnosis and to the limited efficacy of treatment of advanced stages [1]. It would be extremely valuable for optimising therapeutic management to identify early indicators of the response to chemotherapy (CT). As CA 125 levels are easy to determine and elevated in ~90% of cases, we studied their value at different time points during the first courses of induction CT as a surrogate marker for patient responsiveness. We recently showed that the rate of CA 125 levels decreases during CT and its initial half-life can be extremely helpful to clinicians [2]. This approach, however, requires a dedicated software, so we sought for other criteria, easier to determine and directly usable by the clinician in routine clinical practice. In this retrospective multicentric study of stage IIc–IV patients, we evaluated the prognostic value of changes in CA 125 levels after one or two CT cycles for overall survival (OS). In addition, we evaluated the predictive value of these CA 125 variations with regard to pathological complete response (pCR) at second-look laparotomy (SLL) in patients showing clinical complete response (cCR) after treatment completion.


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 conclusion
 References
 
patient selection
Four hundred and ninety-four patients with epithelial ovarian cancer diagnosed and treated in eight French Cancer Centres were retrospectively studied. Their primary treatment was carried out from 1988 to 1996 and the study end point was May 2005 [2]. Diagnostic and treatment procedures, identical in each Centre, followed standard methods described in the Standards Options et Recommendations of the French Fédération des Centres de Lutte Contre le Cancer [1]. Patient characteristics are summarised in Table 1. All patients underwent a primary laparotomy and received a first line of CT with platinum salts and cyclophosphamide. To ensure treatment homogeneity, patients treated by taxanes were excluded from our study.


View this table:
[in this window]
[in a new window]

  		Table 1. Clinical and pathological characteristics of patients (n = 494)

 
Tumour stage and histological diagnosis were determined according to the criteria of the International Federation of Gynaecology and Obstetrics (FIGO) and the histological typing system of the World Health Organisation, respectively. Tumour grading was not included in the analyses due to insufficient reproducibility [1].

Induction CT started 2–4 weeks after surgery and patients received six courses of CT. Treatment evaluation was on the basis of biological and clinical data recorded at each cycle and on medical imaging. During and after CT, chest X-rays, abdominopelvic scans, magnetic resonance imaging or ultrasonography were carried out according to identified targets. Three to five weeks after the end of CT, a SLL was carried out in 194 stage III patients with cCR. A pCR was defined as the disappearance of all tumour deposits with negative peritoneal washing and negative multiple random biopsies.

CA 125 determination
All patients had a CA 125 determination before each cycle of CT (on average each 3 weeks). Depending on the Centre, three different assay formats were used for CA 125 determination [2]. All the assays were on the basis of the use of Centocor/Fujirebio® antibodies. IRMA-mat CA 125 II technique (DiaSorin, Antony, France) was used in the Bordeaux Centre for 77 patients, CPE CA 125 II kit (CIS Bio International, Gif-sur-Yvette, France) was used for 130 patients from the Dijon and Toulouse Centres and ELSA CA 125 II technique (CIS Bio International, Gif-sur-Yvette, France) was used for 223 patients monitored in the Nantes, Rouen, Reims, Saint-Cloud and Angers Centres. Each Centre consistently used the same technique during patient monitoring. All determinations were carried out in duplicate and the threshold for CA 125 elevation was 35 kU/l for all methods, as indicated by the manufacturer.

analysis of early changes in CA 125 levels
Different biological variables derived from CA 125 kinetics during the first two CT courses were examined: (i) the relative change in CA 125 levels from baseline CA 125 (before the first CT course) to CA 125 before the second CT course (denoted C1.2-CA 125); (ii) the relative change in CA 125 levels from baseline CA 125 to CA 125 before the third CT cycle (denoted C1.3-CA 125); (iii) the relative change in CA 125 concentration before the second to the third CT cycles (denoted C2.3-CA 125) and (iv) CA 125 measured before the third CT cycle. All changes in CA 125 levels were expressed as a percentage of its baseline value. To ensure unbiased calculations of CA 125 changes, only variations relying on a baseline CA 125 concentration >35 kU/l were calculated (the cases with initial CA 125 ≤35 kU/l were considered as nonassessable). Since treatment was given in 21-day cycles, the time points before the second and third cycles are equivalent to 3- and 6-weeks post-CT initiation.

Changes in CA 125 levels (C1.2-CA 125, C1.3-CA 125 or C2.3-CA 125) were classified in six groups: group 1 = baseline CA 125 ≤35 kU/l, group 2 = elevated baseline CA 125 increasing during following courses, group 3 = elevated baseline CA 125 and further CA 125 decreasing by ≥75% during treatment, group 4 = elevated baseline CA 125 and CA 125 decreasing by 50%–74% during treatment, group 5 = elevated baseline CA 125 and further CA 125 decrease by 25%–49% and group 6 = elevated baseline CA 125 and CA 125 decrease of <25% (Table 2). For CA 125 before the third CT course, patient population was divided in two groups: CA 125 ≤35 kU/l versus CA 125 >35 kU/l.


View this table:
[in this window]
[in a new window]

  		Table 2. Distribution of relative changes in CA 125 concentrations after the first (C1.2-CA 125), the second (C2.3-CA 125) and the two first (C1.3-CA 125) chemotherapy courses (494 patients, 1482 carcinologic events)

 
statistical methods
Analyses were carried out with STATA version 8. As the biological variables were not normally distributed, we used nonparametric tests (Mann–Whitney and Kruskall–Wallis tests) and signed quantitative variables were described by median and range (minimum–maximum). Signed rank test was carried out for pairwise comparisons of relative CA 125 change during the first three cycles. Frequencies were compared by using {chi}2 or Fisher's exact tests. OS was calculated from the date of the first CT cycle to the date of cancer-related death and patients still alive were censored at study end point. We used univariate and multivariate logistic regression analyses to identify predictive factors of complete remission in stage III patients who underwent a SLL. Univariate OS curves were estimated using the Kaplan–Meier method with log-rank tests. Univariate and multivariate Cox proportional hazards models were used to determine the relative importance of prognostic factors. P values <0.05 were considered significant in all tests.


   results
Top
 Abstract
 introduction
 patients and methods
 results
discussion
 conclusion
 References
 
evaluation of the therapeutic procedures
After initial laparotomy, 142 patients (28.7%) had no residual disease, 123 (24.9%) had a residual disease of ≤1 cm in the largest diameter and 229 (46.4%) had a residual disease >1 cm. Patients received 6.0 ± 1.7 (mean ± standard deviation) cycles of CT. SLL was carried out in 194 stage III patients in cCR after CT completion; 111 of them (57.2%) showed a pCR while 83 (42.8%) showed incomplete response.

distribution of biological variables
Table 2 shows CA 125 variations during the first three CT cycles. Median C1.2-CA 125 was a 65% decrease (range 82% increase to 99% decrease). Median C2.3-CA 125 was a 61% decrease (133% increase to 98% decrease) and median C1.3-CA 125 was a 86% decrease (115% increase to 100% decrease). Pairwise comparisons showed nonsignificant differences between C1.2-CA 125 and C2.3-CA 125 (Wilcoxon signed rank test; P = 0.3348). Significant differences were recorded between C1.3-CA 125 and C1.2-CA 125 and between C1.3-CA 125 and C2.3-CA 125 (Wilcoxon signed rank test; P < 0.0001 for both). CA 125 before the third CT course was in the normal range in 270 cases and elevated in 223 cases.

prognostic value of CA 125 changes
The prognostic impact of the various relative changes in CA 125 concentration on survival is shown in Table 3. Noteworthy, the CA 125 concentration measured before the third CT course was found to bear a prognostic value for OS: median OS was 1.9 years (1.6–2.1 years) for patients with a CA 125 >35 kU/l and 4.9 years (4.0–5.4 years) for patients with a CA 125 ≤35 kU/l [hazard ratio (HR) = 2.7 (2.2–3.3); log-rank test P < 0.0001].


View this table:
[in this window]
[in a new window]

  		Table 3. Median (95% confidence interval) survival (years) on the basis of percent change in CA 125 concentration after the first (C1.2-CA 125), the second (C2.3-CA 125) and the two first (C1.3-CA 125) chemotherapy courses (n = 494)

 
Univariate survival analyses revealed that change in CA 125 levels during the first, second and the two first CT courses, CA 125 before third CT cycle, age, FIGO stage and residual tumour mass all had a strong prognostic value for OS (all with P < 0.0001) (Table 4).


View this table:
[in this window]
[in a new window]

  		Table 4. Univariate and multivariate (Cox model) analyses of prognostic factors for overall survival

 
In multivariate analyses including all these factors, change in CA 125 level during the first CT course (P < 0.0001), residual tumour mass (P = 0.003), CA 125 before second CT course (P = 0.037) were found to be independent prognostic variables for OS (Table 4).

delimiting groups with favourable or poor prognosis
CA 125 kinetics during first CT cycle allowed the identification of two groups with different prognoses. The first group, with a favourable prognosis, included 132 patients: 64 patients with normal CA 125 before each of the two first CT courses and 68 patients with an elevated baseline CA 125 which decreased by >50% during the first CT course and was normalized before the second CT course. The second group had a much poorer prognosis and included 362 patients who did not satisfy all of these criteria. Median OS of patients with favourable prognosis was 6.4 years (4.7–11.2 years). The patients with a poor prognosis had a significantly lower OS [median 2.3 years (1.9–2.6 years)] [HR 2.61 (2.07–3.31); log-rank test P < 0.0001] (Figure 1).


Figure 1
View larger version (13K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1. Kaplan–Meier analysis of overall survival according to CA 125-based prognostic groups (log-rank test: P ≤ 0.0001). Favourable prognosis: patients with an initial CA 125 concentration <35 kU/l or with a decrease of >50% after the first cycle of chemotherapy and a concentration of CA 125 <35 kU/l before the second cycle.

 
Among the 194 stage III patients who underwent a SLL, the frequency of pCR was 77.2% (61 of 79) in the subgroup with favourable prognosis and was only 43.5% (50 of 115) for patients with poor prognosis. This difference was highly significant ({chi}2 test: P ≤ 0.0001). Univariate logistic regression analysis identified early changes in CA 125 concentration, residual tumour mass, tumour histology and age as important predictive factors of pCR (P < 0.0001). The multivariate analyses revealed that early change in CA 125 concentration was the most powerful independent predictive factor (P = 0.001) to obtain a pCR at the end of induction CT (Table 5).


View this table:
[in this window]
[in a new window]

  		Table 5. Identification of early predictive criteria for the absence of complete histological remission after initial treatment in 194 patients with stage III tumours who underwent second-look surgery (univariate and multivariate logistic regression)

 

   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
conclusion
 References
 
In the present work, the study population was homogeneous, a particularly important feature for this type of disease, with a long inclusion and follow-up period. Our main result is that CA 125 normalisation induced by the first CT course was an independent prognostic factor both for the probability of achieving a pCR after CT and for OS. The group of good prognosis comprised patients with normal CA 125 before first and second CT courses and patients with elevated baseline CA 125 decreasing by >50% during the first CT course and falling in normal range before the second CT course. Our results indicate that CA 125 variations before the second CT course enable to differentiate responder and nonresponder patients. Furthermore, analysis of the initial changes in CA 125 concentration is not hampered by paradoxical CA 125 increase during the first 14 days after initiation of CT, since it is rarely encountered [3].

The results presented were not affected by the use of three different techniques for CA 125 determination (all were on the basis of the same antibody) [2].

Two biases might interfere in the interpretation of our data. First, the CA 125 fall can be partially influenced by a durable effect of surgical debulking. Our CA 125-based criteria, however, remained highly significant in multivariate survival analysis which included residual disease as a marker for the effect of surgical tumour reduction. Secondly, in spite of a good response, patients with an initial low CA 125 will have a low CA 125 fall and might be classified in the same group as patients with an elevated baseline CA 125 and a low response. Aware of this situation, we overcame this problem by a separate analysis of patients with high or low baseline CA 125. A similar prognosis was found for patients with a low baseline CA 125 and for those with elevated baseline CA 125 which decreased by >50% during the first CT course. We hypothesise that a good initial response to CT might compensate the deleterious effects on prognosis of a large residual tumour load after surgery, responsible for an elevated CA 125 concentration. This observation, associated with the known heterogeneity of CA 125 production by individual tumours, might partially explain the weak prognostic value of post-surgical CA 125 concentration when considered as single variable [4–12].

While it is commonly accepted that changes in serum CA 125 during early CT are strong predictors of patient clinical outcome [4, 10], the prognostic value of absolute CA 125 concentration is still debated. In our study, CA 125 level after one course of CT was found to bear an independent prognostic value, in agreement with the findings of Fisken et al. [10] in multivariate analysis. However, in contrast to a majority of studies [5, 7–9, 11–14], we found that CA 125 after two CT courses had no independent prognostic value for OS.


   conclusion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 conclusion
References
 
To conclude, our data showed that early CA 125 change induced by the first CT courses was strongly correlated both with the probability of achieving a pCR after CT and with survival duration. Analysis of CA 125 changes before second CT course enables the detection of a subset of patients with poor prognosis for whom an alternative ‘non-cross resistant’ CT strategy can be tried.

Received for publication November 10, 2006. Revision received December 12, 2006. Accepted for publication December 15, 2006.


   References
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 conclusion
 References
 
1. Standards, Options et Recommandations. Tumeurs épithéliales malignes de l'ovaire. (1998) Paris, France: John Libbey Eurotext.

2. Riedinger JM, Wafflart J, Ricolleau G, et al. CA 125 half-life and CA 125 nadir during induction chemotherapy are independent predictors of epithelial ovarian cancer outcome. Results of a French multicentric study. Ann Oncol (2006) 17(8):1234–1238.[Abstract/Free Full Text]

3. Sogaard CH, Lindegaard JC, Havsteen H, et al. Chemotherapy-induced changes of CA 125 in patients with epithelial ovarian cancer. Gynecol Oncol (2005) 97(2):410–412.[CrossRef][Web of Science][Medline]

4. Markman M, Federico M, Liu PY, et al. Significance of early changes in the serum CA-125 antigen level on overall survival in advanced ovarian cancer. Gynecol Oncol (2006) 103(1):195–198.[CrossRef][Web of Science][Medline]

5. Rustin GJ, Gennings JN, Nelstrop AE, et al. Use of CA-125 to predict survival of patients with ovarian carcinoma. North Thames Cooperative Group. J Clin Oncol (1989) 7(11):1667–1671.[Abstract]

6. Van der Burg ME, Lammes FB, van Putten WL, Stoter G. Ovarian cancer: the prognostic value of the serum half-life of CA 125 during induction chemotherapy. Gynecol Oncol (1988) 30(3):307–312.[CrossRef][Web of Science][Medline]

7. Sevelda P, Schemper M, Spona J. CA 125 as an independent prognostic factor for survival in patients with epithelial ovarian cancer. Am J Obstet Gynecol (1989) 161(5):1213–1216.[Web of Science][Medline]

8. Mogensen O, Mogensen B, Jakobsen A. Tumor-associated trypsin inhibitor and cancer antigen 125 in pelvic masses. Gynecol Oncol (1990) 38(2):170–174.[CrossRef][Web of Science][Medline]

9. Mogensen O. Prognostic value of CA 125 in advanced ovarian cancer. Gynecol Oncol (1992) 44(3):207–212.[CrossRef][Web of Science][Medline]

10. Fisken J, Leonard RC, Stewart M, et al. The prognostic value of early CA 125 serum assay in epithelial ovarian carcinoma. Br J Cancer (1993) 68(1):140–145.[Web of Science][Medline]

11. Gadducci A, Zola P, Landoni F, et al. Serum half-life of CA 125 during early chemotherapy as an independent prognostic variable for patients with advanced epithelial ovarian cancer: results of a multicentric Italian study. Gynecol Oncol (1995) 58(1):42–47.[CrossRef][Web of Science][Medline]

12. Colakovic S, Lukic V, Mitrovic L, et al. Prognostic value of CA 125 kinetics and half-life in advanced ovarian cancer. Int J Biol Markers (2000) 15(2):147–152.[Web of Science][Medline]

13. Ron IG, Inbar M, Gelernter I, et al. Use of CA-125 response to predict survival parameters of patients with advanced ovarian carcinoma. Acta Obstet Gynecol Scand (1994) 73(8):658–662.[Web of Science][Medline]

14. Redman CW, Blackledge GR, Kelly R, et al. Early serum CA 125 response and outcome in epithelial ovarian cancer. Eur J Cancer (1990) 26(5):593–596.[Web of Science][Medline]


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Ann OncolHome page
A. Prat, M. Parera, B. Adamo, S. Peralta, M. A. Perez-Benavente, A. Garcia, A. Gil-Moreno, J. M. Martinez-Palones, J. Baselga, and J. M. del Campo
Risk of recurrence during follow-up for optimally treated advanced epithelial ovarian cancer (EOC) with a low-level increase of serum CA-125 levels
Ann. Onc., February 1, 2009; 20(2): 294 - 297.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
K. A. Lowe, C. Shah, E. Wallace, G. Anderson, P. Paley, M. McIntosh, M. R. Andersen, N. Scholler, L. Bergan, J. Thorpe, et al.
Effects of Personal Characteristics on Serum CA125, Mesothelin, and HE4 Levels in Healthy Postmenopausal Women at High-Risk for Ovarian Cancer
Cancer Epidemiol. Biomarkers Prev., September 1, 2008; 17(9): 2480 - 2487.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
18/5/881    most recent
mdl500v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Riedinger, J.
Right arrow Articles by Pichon, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Riedinger, J.
Right arrow Articles by Pichon, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?