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The Oncologist, Vol. 9, No. 4, 417–421, July 2004
© 2004 AlphaMed Press

Serum CA125: A Tumor Marker for Monitoring Response to Treatment and Follow-up in Patients with Non-Hodgkin’s Lymphoma

Jamal Zidana,d, Osamah Husseinb, Walid Bashera, Shmuel Zoharc

a Oncology Unit, b Department of Internal Medicine, and c Otolaryngology Unit, Sieff Government Hospital, Safed, Israel; d Faculty of Medicine, Technion, Haifa, Israel

Correspondence: Jamal Zidan, M.D., Oncology Unit, Sieff Government Hospital, POB 1008, Safed, Israel. Telephone: 972-4-682-8951; Fax: 972-4-682-8621; e-mail: zidan.j{at}ziv.health.gov.il


   ABSTRACT
Top
 Abstract
Introduction
 Patients and Methods
 Statistical Analysis
 Results
 Discussion
 References
 
Purpose. Serum CA125 is an important prognostic factor in patients with non-Hodgkin’s lymphoma (NHL). Elevation of CA125 level correlates with advanced disease, poor response to treatment, and poor survival rates. The aim of the current study is to evaluate CA125 levels in patients with NHL and to investigate the correlations between high CA125 level and other presenting features.

Materials and Methods. Thirty-eight patients (14 with low-grade and 24 with aggressive histologically proven NHL) were studied prospectively. Serum CA125 assessment was done at diagnosis, during treatment, and at follow-up. The associations between CA125 levels and other presenting features were examined.

Results. CA125 levels were elevated in 43% of patients with low-grade NHL and in 46% of patients with aggressive NHL (i.e., 45% of all patients). A higher CA125 level was associated with advanced disease, bone marrow involvement, extranodal involvement, poor performance status, the presence of B symptoms, and high serum lactate dehydrogenase level. Complete responses occurred in 86% of patients with normal CA125 levels and in 59% of patients with elevated CA125 levels. In both low-grade and aggressive NHL, the estimated 5-year overall survival rate was higher in patients with normal CA125 levels than in patients with elevated CA125 levels (88% versus 50% and 70% versus 27%, respectively).

Conclusion. High serum CA125 is an important prognostic factor in NHL and correlates with more advanced disease, low response rates, and worse survival. CA125 measurements may be used for staging, monitoring response to treatment, and follow-up of patients with NHL.

Key Words. Non-Hodgkin’s lymphoma • CA125 • Prognostic factor • Response • Survival


   INTRODUCTION
Top
 Abstract
 Introduction
Patients and Methods
 Statistical Analysis
 Results
 Discussion
 References
 
The CA125 antigen is a glycoprotein expressed by epithelial ovarian cancer [1]. It is recognized by monoclonal antibody CA125. CA125 serum levels are used to monitor response to therapy and for follow-up of patients with ovarian cancer. Serum levels may be elevated in many other malignant and nonmalignant diseases [2, 3].

Non-Hodgkin’s lymphomas (NHLs) are more common than Hodgkin’s disease. They are also more heterogeneous tumors with different patterns of clinical behavior and response to chemotherapy [4]. Many prognostic factors have been described in aggressive NHL: B symptoms (fever, night sweats, weight loss), performance status, age, serum lactate dehydrogenase (LDH) level, serum ß2 microglobulin, tumor bulk, and number of nodal and extranodal sites of disease [5, 6]. The International Non-Hodgkin’s Lymphoma Prognostic Index (IPI) is a widely accepted prognostic tool [6].

Elevated serum CA125 levels have also been reported in patients with NHL, especially those with advanced disease [7]. CA125 was reported by Lazzarino et al. to be a reliable biologic marker for the staging and restaging of patients with NHL [8]. Serial measurements are useful, in conjunction with other markers, for monitoring response to treatment. In this prospective study we evaluated serum CA125 levels in patients with NHL at diagnosis and during and after treatment, aiming to investigate the relationships between an abnormal CA125 level and presenting features of the disease, response to treatment, and follow-up.


   PATIENTS AND METHODS
Top
 Abstract
 Introduction
 Patients and Methods
Statistical Analysis
 Results
 Discussion
 References
 
From January 1993 to December 1999, 38 patients with NHL were treated in the Oncology Unit of Sieff Hospital (Safed, Israel). All 38 underwent serum CA125 measurements at diagnosis, during treatment, and at follow-up. Serum CA125 was measured by radioimmunoassay (CIS bio international; Yvette, France). Normal values were considered to be below 30 u/ml. Patients with NHL evaluated at diagnosis were classified according to the international working formulation [9]. The fourteen patients with low-grade lymphoma included four with mantle-cell lymphoma. Aggressive lymphoma was diagnosed in 24 patients, 18 of whom had diffuse large-cell lymphoma. The evaluation of patients for clinical staging included a history, a physical examination, a performance status assessment using the World Health Organization (WHO) classification system, a differential blood cell count, renal and liver function tests, an assessment of HIV status, measurements of CA125 and LDH levels, iliac crest bone marrow biopsies, chest x-rays, and a gallium scan and computed tomography scan of the neck, chest, abdomen, and pelvis. Patients with low-grade NHL were treated either with single-agent alkylating therapy (n = 6), chemotherapy regimens without anthracyclines (n = 3), or combination chemotherapy including anthracyclines (n = 5). All patients with aggressive NHL received doxorubicin-based chemotherapy. Three patients also received intrathecal treatment with methotrexate. Complete response (CR) was defined as the disappearance of all clinical and radiographic evidence of disease, with normalization of elevated laboratory values. Partial response (PR) was defined as a 50% or greater reduction in the sum of the products of the perpendicular diameters of all measurable sites of tumor. Nonresponse (NR) was defined as a <50% decrease in the tumor mass or tumor growth during therapy.


   STATISTICAL ANALYSIS
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 Abstract
 Introduction
 Patients and Methods
 Statistical Analysis
Results
 Discussion
 References
 
The associations between CA125 level and patient characteristics were assessed using either a chi-squared test or a Fisher’s exact test, as appropriate. Odds ratios were computed as well. Two-tailed p values of 0.05 or less were considered significant.


   RESULTS
Top
 Abstract
 Introduction
 Patients and Methods
 Statistical Analysis
 Results
Discussion
 References
 
The median age of the 38 patients at diagnosis was 56 years (range 17–84). Twenty-five patients were male and 13 were female (Table 1Go). Histologically, 14 patients were considered to have low-grade NHL and 24 had aggressive NHL. Of the 14 patients with low-grade lymphomas, five were stage I-II and nine were stage III-IV (Ann Arbor staging). Among patients with aggressive NHL, 10 were stage I-II and 14 were stage III-IV. Sixty-one percent of all patients were stage III or IV (n = 23, six stage III and 17 stage IV). Bone marrow involvement was diagnosed in 13 patients with stage IV disease. Five patients had pericardial, pleural, or peritoneal effusion, and one patient had lung metastases. B symptoms were present in 32% (n = 12) of patients at diagnosis. Sixty-eight percent (n = 26) of patients had performance statuses of 0–1.


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  		Table 1. Characteristics of the 38 patients with NHL according to histologic type
 
Serum CA125 levels were high in 17 (45%) patients, with a median value of 86 u/ml (range 41–1,070 u/ml), and the mean value was 218 u/ml. CA125 levels were elevated in 43% of patients with low-grade NHL and in 46% of patients with aggressive NHL. Table 2Go shows the frequency of elevated CA125 levels associated with each presenting feature for 38 patients. A high serum level of CA125 correlated with advanced stage (p = 0.07), bone marrow involvement (p = 0.028), high performance status (p = 0.02), the presence of B symptoms (p = 0.05), extranodal involvement (p = 0.004), and a high serum LDH level (p = 0.01). Four of five patients with effusion at diagnosis had high CA125 levels; CA125 levels ranged from 520–1,070 u/ml in three of those patients.


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  		Table 2. Incidences of elevated serum CA125 level according to presenting features in 38 patients with NHL
 
After initial treatment of all patients (low- and high-grade NHL), the CR rate was 74%, the PR rate was 16%, and 10% of patients had stable disease or progression. The CR rate was lower in patients with elevated CA125 levels than in those with normal CA125 levels (58% versus 86%, respectively; p = 0.06) (Fig. 1Go). In the group of 17 patients presenting with elevated CA125 levels, serial CA125 measurements showed that all those who achieved CRs (10 of 17) had normalizations of their serum CA125 levels by the end of treatment (Fig. 2Go). On the other hand, none of the patients with PRs or no response had a return of their serum CA125 levels to normal. Three patients with aggressive NHL and normal LDH levels but high CA125 levels achieved CRs. The remaining patients with CRs and with elevated levels of both LDH and CA125 had normalizations of both markers by the end of treatment.



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  		Figure 1. Difference in CR rates between patients with normal CA125 levels after treatment and those with high CA125 levels after treatment among patients with previously high levels.

 


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  		Figure 2. Difference in serum CA125 levels after treatment among patients with CRs compared to patients with non-CRs in 17 patients with previously high levels.

 
With a median follow-up of 49 months (range 26–96 months), the 5-year overall survival rate in the low-grade NHL group with high CA125 levels was 50%, versus 88% (p < 0.05) in patients with normal CA125 levels. In the aggressive NHL group, the 5-year overall survival rate was 27% in patients with high CA125 levels and 70% in patients with normal CA125 levels (p = 0.01). The overall 5-year survival rate of all patients with high CA125 levels was 35% (6 of 17 patients), and the overall 5-year survival rate for those with normal CA125 levels was 76% (16 of 21 patients) (Fig. 3Go). Relapse of NHL occurred in 6 of 10 patients with CRs and elevated CA125 levels at diagnosis. In all those patients, CA125 values were elevated at relapse.



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  		Figure 3. Difference in survival rates between patients with high CA125 levels and those with normal CA125 levels.

 

   DISCUSSION
Top
 Abstract
 Introduction
 Patients and Methods
 Statistical Analysis
 Results
 Discussion
References
 
A variety of pretreatment clinical characteristics have been identified to be associated with response to treatment and survival of patients with NHL [6]. CA125 is widely used as a tumor marker in the monitoring of epithelial ovarian cancer. Serum CA125 level has also been reported to be a significant prognostic factor for complete remission and survival in patients with NHL [10]. High serum CA125 levels in NHL patients correlated with advanced disease, mediastinal and/or abdominal involvement, bulky tumors, high tumor burden, effusions, extranodal extension, LDH activity, and elevated ß2 microglobulin [8, 10]. The peritoneal mesothelial cells stimulated by the lymphokines produced by lymphoma cells have been suggested to be responsible for the high serum levels of CA125 [11, 12].

In the present study, serum CA125 levels were elevated in 45% of patients with NHL. Elevation was observed in both low-grade and aggressive NHL. Benboubker et al. found higher CA125 levels in low-grade NHL than in aggressive NHL [10], while Lazzarino et al. reported higher CA125 levels in aggressive NHL than in low-grade NHL.

An analysis of the 38 patients in our study showed statistically significant associations between a high CA125 level at diagnosis and other clinical and pathologic features (Table 2Go). Among these were performance status, the presence of B symptoms, extranodal involvement, bone marrow involvement, and elevated serum LDH level. CA125 level was independently correlated with IPI score in the present study.

Serial measurements of serum CA125 during and at the end of treatment and during follow-up showed strong relationships between CA125 level and response to treatment and survival. All patients presenting with high CA125 levels had normalizations of this marker when they achieved CRs. On the other hand, CA125 levels remained high in patients with elevated levels at diagnosis who did not respond completely. Elevated levels at relapse were only seen in patients with abnormal values at baseline.

Serum CA125 level is an indicator of response and survival in NHL patients [10]. The present study showed higher response and survival rates in patients with normal CA125 levels than in those with high CA125 levels, similar to findings in other publications.

In conclusion, our data indicate that serum CA125 is a useful tumor marker in patients with NHL. A high CA125 level at diagnosis correlates with advanced disease and poor outcome. Repeated CA125 measurements are useful in monitoring response to treatment and in the follow-up for early detection of recurrence in NHL patients.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Statistical Analysis
 Results
 Discussion
 References
 

  1. Canney PA, Moore M, Wilkinson PM et al. Ovarian cancer antigen CA125: a prospective clinical assessment of its role as tumour marker. Br J Cancer 1984;50:765–769.[Medline]
  2. Imai A, Itoh T, Niwa K et al. Elevated CA125 serum levels in a patient with tuberculosis peritonitis. Arch Gynecol Obstet 1991;248:157–159.[CrossRef][Medline]
  3. Halila H, Stenman UH, Seppala M. Ovarian cancer antigen CA 125 levels in pelvic inflammatory disease and pregnancy. Cancer 1986;57:1327–1329.[CrossRef][Medline]
  4. Armitage JO. Treatment of non-Hodgkin’s lymphoma. N Engl J Med 1993;328:1023–1030.[Free Full Text]
  5. Shipp MA. Prognostic factors in aggressive non-Hodgkin’s lymphoma: who has "high-risk" disease? Blood 1994;83:1165–1173.[Abstract/Free Full Text]
  6. A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 1993;329:987–994.[Abstract/Free Full Text]
  7. Zacharos ID, Efstathiou SP, Petreli E et al. The prognostic significance of CA 125 in patients with non-Hodgkin’s lymphoma. Eur J Haematol 2002;69:221–226.[CrossRef][Medline]
  8. Lazzarino M, Orlandi E, Klersy C et al. Serum CA 125 is of clinical value in the staging and follow-up of patients with non-Hodgkin’s lymphoma: correlation with tumor parameters and disease activity. Cancer 1998;82:576–582.[CrossRef][Medline]
  9. National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin’s lymphoma Pathologic Classification Project. Cancer 1982;49:2112–2135.[CrossRef][Medline]
  10. Benboubker L, Valat C, Linassier C et al. A new serologic index for low-grade non-Hodgkin’s lymphoma based on initial CA125 and LDH serum levels. Ann Oncol 2000;11:1485–1491.[Abstract/Free Full Text]
  11. Apel RL, Fernandes BJ. Malignant lymphoma presenting with an elevated serum CA-125 level. Arch Pathol Lab Med 1995;119:373–376.[Medline]
  12. Pabst T, Ludwig C. CA-125: a tumor marker in non-Hodgkin’s lymphomas? J Clin Oncol 1995;13:1827–1828.[Free Full Text]
Received November 20, 2003; accepted for publication February 11, 2004.




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