Use of CA-125 in Clinical Trial Evaluation of New Therapeutic Drugs for Ovarian Cancer

Ovarian cancer is the fourth leading cause of death from cancer in women and accounts for the highest mortality rate of all of the gynecological cancers (1). Despite aggressive treatment via radical surgery, radiotherapy, or chemotherapy, the mortality rate remains >50% for diagnosed patients. Although approximately 90% of stage IA (growth limited to the ovary) and 70% of stage IIA (metastases to the uterus or Fallopian tubes) tumors are curable if detected, 70% of women who are diagnosed with stage III and IV tumors have widespread intra-abdominal disease or distant metastases at diagnosis. For these patients, the cure rate plummets to <30%. Recent data from the National Cancer Institute indicate a rise in the median 5-year survival rate (2), although the overall cure rate for ovarian cancer has remained relatively constant during the last 20 years. Ovarian cancer has an overall cure rate of approximately 45%, a relatively discouraging prognosis.Furthermore, the quality of life for many patients with ovarian cancer is compromised severely because only 20% of patients with advanced disease are long-term disease-free survivors. The remaining 80% will relapse, and many of these relapsing patients will receive second-, third-, fourth-, fifth-, or tenth-line therapies. New therapies are tested in relapsed patients, and better ways are needed to determine which of these patients should be selected for clinical trials.The standard first-line treatment for patients with ovarian cancer is a combination of carboplatin and paclitaxel (3). This regimen reflects collected wisdom from over 30 years of randomized, controlled clinical trials with various agents. Chemotherapy for ovarian cancer was first administered in the 1960s, following the synthesis of alkylating agents such as chlorambucil and melphalan. These compounds continued to be prescribed as single agents through the 1970s, although introduction of the platinum-based agent cisplatin in 1973 initiated a shift in treatment paradigms.Although no hard evidence for an overall survival advantage with platinum-based compounds was demonstrated until the 1990s (4, 5), early studies revealed that cisplatin significantly improved disease-free survival and response rates when compared with then-standard treatments. Cisplatin was effective as a single agent and in combination regimens, resulting in the relatively popular first-line combination of cisplatin with cyclophosphamide.The next major shift in therapy occurred in the early 1980s, with the development of carboplatin. Carboplatin proved equally efficacious (in single and combination therapy) but significantly less toxic than cisplatin (5). At standard doses, carboplatin has fewer adverse effects on kidneys, the nervous system, or the auditory system, and patients who receive carboplatin report reductions in nausea and vomiting relative to levels experienced with cisplatin. Because carboplatin-based regimens were significantly better tolerated than cisplatin-based therapies, single-agent carboplatin had effectively replaced cisplatin as the standard of care by the late 1980s (6).The treatment paradigm shifted again in the 1990s with the introduction of paclitaxel (Taxol). An alkaloid ester derived from the bark of the Pacific yew tree (Taxus brevifolia), paclitaxel arrests the cell cycle by disrupting microtubule formation during mitosis (7). Several Phase II trials showed that paclitaxel was active in cases of relapsed ovarian cancer, including patients who were unresponsive to or concomitantly receiving platinum-based treatments (8, 9, 10, 11, 12, 13). These pivotal studies led to the administration of paclitaxel as a first-line therapy in combination with cisplatin (14, 15).The acceptance of paclitaxel-cisplatin as the standard of care for ovarian cancer was established in two pivotal, large-scale trials that compared paclitaxel-cisplatin with cyclophosphamide-cisplatin regimens in patients with stage III–IV disease (14, 15). These studies proved the superiority of paclitaxel by demonstrating statistically significant differences in response rates, progression-free survival times, and median overall survival times. Subsequent trials demonstrated that carboplatin could be substituted for cisplatin to provide an equally efficacious but less toxic and better tolerated regimen (16, 17, 18). The failure of the very large ICON3 trial to demonstrate any superiority of paclitaxel plus carboplatin over carboplatin alone has led to many women in Europe being offered single-agent carboplatin (19).The combination of paclitaxel with carboplatin remains the standard first-line treatment of ovarian cancer in many centers. However, evidence from recent Phase II trials suggests that docetaxel, a semisynthetic derivative of Taxol, confers equal benefit with less neurotoxicity than paclitaxel (20, 21, 22). Thus, docetaxel may prove to be a more viable agent for first-line treatment regimens in the near future.Recent breakthroughs in our understanding of the molecular mechanisms of carcinogenesis and proliferation have resulted in the development of numerous molecularly targeted agents that inhibit signal transduction, angiogenesis, and other pathways. This increased understanding has led to the development of novel agents such as trastuzumab (Herceptin), a recombinant monoclonal antibody that has revolutionized treatment regimens for certain metastatic breast cancers (23, 24, 25, 26), and the rationally designed tyrosine kinase inhibitor imatinib mesylate (Gleevec), which has transformed protocols for chronic myeloid leukemia (27, 28). These successes and the numerous drugs under development that target molecular lesions characterized in ovarian cancers provide a great opportunity to continue to improve the treatment of this disease.Evaluation of new drugs for ovarian cancer has been hampered by difficulties in measuring i.p. disease; the tumor deposits associated with ovarian cancer are usually very difficult to clearly delineate by noninvasive techniques. This has significance for diagnosing early-stage disease, as well as measuring response to therapy. As stated, ovarian cancer is chemosensitive, and chemotherapy has impacted the curability for a fraction of patients. This result could be much improved with better methods to determine whether a tumor is responding to therapy in the early stages of treatment. Because aggressive chemotherapy is accompanied by drug toxicity, which lowers the quality of life for the patient, and because it is difficult to monitor the response of ovarian carcinoma to therapy, a serum biomarker such as CA-125 has great potential for optimizing both therapeutic regimens and clinical trials in which they are tested.End points currently used in clinical trials for ovarian cancer include survival, progression-free survival, and objective tumor response associated with the administration of anticancer agents. However, each of these end points presents unique difficulties when applied to clinical trials for ovarian cancer. Current clinical trial designs do not allow optimal dosing, scheduling, and duration of drug therapy because of difficulties in making timely measurement of disease response to therapy by noninvasive methods. The development of better measures of tumor response would not only aid clinical trial design and conduct but would also provide guidance for individualized therapy with approved drugs because, when treating individual patients, difficulties in measuring response can lead to overtreatment of nonresponding disease with toxic therapy and reduced quality of life for the patient. In this section, we present some of the issues that hamper current clinical trial design.Defining the end point is one of the most crucial, yet most difficult, issues in trial design for ovarian cancer therapy. Although survival is the ultimate end point of all clinical trials for ovarian cancer, it may require a lengthy time to obtain and may be affected by therapeutic interventions other than the therapy under investigation. Progression-free survival from start of treatment to clinical progression has therefore become an increasingly important end point when evaluating drug combinations because it may be obtained earlier and is unaffected by therapies subsequent to the trial therapy. However, if the therapies under comparison are of different duration, progression-free survival becomes a less robust end point and can create uncertainty about results, particularly if used to discontinue a trial prematurely (29). In one major trial, the use of progression as an end point was compromised by the introduction of second-line therapy, in many cases because of a rise in CA-125 before the date of clinical progression had been reached (30). Without clinical evidence of progression, the date of progression becomes difficult to determine, thus leading to a diverse and inconsistent set of methods to classify such patients.In addition to using survival parameters as end points, researchers have attempted to measure objective response of a tumor to therapy for more than 40 years (31, 32). In 1979, the WHO published classifications and criteria of tumor response designed to standardize measurements for solid cancers (33, 34). Although these criteria have been widely used, shortcomings have resulted in a number of modifications and clarifications to the WHO definitions by such organizations as the Eastern Cooperative Oncology Group (35) and the Gynecologic Oncology Group (36). To address these issues, the Response Evaluation Criteria in Solid Tumors (RECIST) Group recently proposed guidelines to evaluate the response to treatment in solid tumors (37). Whereas the RECIST criteria address many shortcomings of previous attempts to codify tumor response, they have limited utility in the evaluation of ovarian cancer. The RECIST criteria define progression on the basis of evaluation of measurable disease, and therefore response rate, as defined by RECIST, applies only to patients who present with measurable disease, which precludes its use in almost 50% of ovarian cancer patients.Because it varies as a function of prognostic factors as well as drug efficacy, to use response rate as an end point in a clinical trial, the patient group must be defined (e.g., those who relapse <6 months, 6–12 months, and >12 months after platinum therapy). To maximize the benefits of therapeutic regimens being tested in future clinical trials for ovarian cancer, an objective, reliable, and meaningful measure is required to assess end points.Characterized in 1981, the CA-125 antigen (38) remains the only serum tumor marker routinely used to test for epithelial cancer of the ovary (39). CA-125 is a membrane glycoprotein expressed by epithelial cells of different origins and thus is present in the serum of patients who have a variety of tumors. Different sites of glycosylation on CA-125 produce a heterogeneous mixture of varying molecular mass (mostly >1000 kDa) glycoproteins (40).The first method developed to measure CA-125 was a radioimmunometric assay that used the murine monoclonal antibody OC 125 as both capture and indicator antibodies (39). OC 125 was obtained after immunization with the OVCA 433 cell line, which was derived from the ascites fluid of a patient with papillary cystadenocarcinoma of the ovary (38). OC 125 recognizes the CA-125 epitope on a high molecular weight glycoprotein designated MUC 16. Monoclonal antibodies raised against other epitopes expressed by this molecule have led to the development of the CA-125-II assay, a variant of the original CA-125 assay that utilizes the M 11 monoclonal antibody as the capture antibody (41, 42). Both assays have proved reliable for measuring CA-125 levels in a number of benign and cancerous conditions, most notably ovarian cancer.Several studies document the similarities of sensitivity and specificity obtained with the original CA-125 and newer CA-125-II assays (43, 44). In addition to the very high correlation to the original CA-125 assay, the CA-125-II assay exhibits significantly less day-to-day variation and has better measurement characteristics for low CA-125 values (45). For the purposes of monitoring response to therapy, higher CA-125 values are generally observed and (over time) can be measured more precisely with the CA-125 II assay.CA-125 concentration is elevated most consistently in epithelial ovarian cancer, and its value has been demonstrated as a marker for patient prognosis, disease progression, and response to chemotherapy. At diagnosis, approximately 50% of patients who have stage I ovarian cancer and 90% of those with advanced-stage disease have elevated concentrations of CA-125 in their sera (2, 41, 46). However, CA-125 is expressed by a number of different cell types, both cancerous and noncancerous. Some patients with cancers of the lung, breast, endometruim, and gastrointestinal tract present elevated levels of CA-125, and CA-125 levels are also elevated in endometriosis, benign diseases of the liver and gastrointestinal tract, inflammation, and benign tumors of the ovary and uterus (47). Normal physiological conditions may also modulate CA-125 levels because concentrations are elevated slightly during menstruation (48) and more prominently during the first trimester of pregnancy.In clinical practice, CA-125 has important CA-125 in patients with a mass the of ovarian cancer, thus the patient a gynecological for chemotherapy, a CA-125 and patient that the tumor is CA-125 during chemotherapy can indicate development of drug This to an earlier or of therapy than if clinical criteria alone were CA-125 that is elevated but at the end of the of chemotherapy disease, but it remains this should be women in the have CA-125 levels measured during relapse, on months before is clinical evidence of However, is no evidence to that early treatment on a of CA-125 in an patient confers survival or An trial is whether early of chemotherapy relapse has been by an elevated CA-125 that can be to assess response to and subsequent of treatment. use obtained at of to indicate response and to indicate potential of CA-125 as a prognostic marker has been well and the biomarker has some in clinical trials that large of all ovarian cancer, the of CA-125 is about and studies have demonstrated that those patients with a of have a The of CA-125 before therapy has also been to be of prognostic These factors could be used to patients clinical trials.The rate of of CA-125 long-term response to therapy. For the individual patient, a serum CA-125 of measured before the of chemotherapy has been to be the most of early relapse or death the serum of CA-125 during chemotherapy is an prognostic marker for survival, rate of progression, time to progression, and the for a of progression rate of to 20% the value of these measurements for of individual patients. This of would inhibit the therapy of an individual patient but could be used in a clinical For if a high of patients in one of a trial had a CA-125 or higher CA-125 levels after of therapy, this would indicate the of that of therapy earlier than any other currently used an could an to determine whether to discontinue this treatment at an early time thus to therapy is an to trials with to early of the effective will benefit patients and an should be used if any of the are to cause disease than response for addition to its potential as a prognostic CA-125 has been to be as a for measuring tumor response to chemotherapy more patients who are first-line treatment are to CA-125 than those by used to assess standard or response criteria measurement of CA-125 is less and more for patients than In defined criteria for evaluating 50% and response to CA-125 in and these a 50% response to CA-125 is defined as a 50% in serum CA-125 as through a of CA-125 with elevated the that a 50% and a at the response is established if has been a in serum CA-125 levels of over In both the 50% and response the must be at after the previous recent the of response rates obtained using 50% and response definitions in of drugs in Phase II trials for ovarian cancer, compared with response rates obtained by standard criteria were obtained from treatment Phase II clinical trials of different drugs for relapsed ovarian cancer. Response rates were in patients to standard criteria and in patients to For each trial, the observed response rates as evaluation of the two criteria would in a Phase II trial, a target drug rate of 20% and a of was no response rate obtained by standard criteria and that obtained by CA-125 and therefore was no in whether a Phase II drug is active and in clinical this data on CA-125, its use in a clinical trial as a marker of response rate will have significant on the evaluation of new of any Phase II trial is to determine whether the of a drug is to continued and CA-125 measurement of tumor response has for clinical trial For the to discontinue a clinical trial or a therapeutic regimen can be early if the tumor response rate to CA-125 to a a trial that a response rate to CA-125 should be to include patients to be using both CA-125 and RECIST of CA-125 response rate could also be used to the less effective treatment to determine which should be is our that CA-125 response rate, using an should be in the of all clinical trials that evaluate therapy for ovarian cancer. The of response on CA-125 has been developed from clinical and with a has been the of by the Gynecologic Cancer a if would an of response than that has been to be an marker to define relapse of ovarian cancer The of of and the National Cancer has recently defined the date of progression to CA-125 using progression criteria These criteria are compared with the RECIST criteria in that CA-125 measurement be the of all ovarian cancer trials to define a date of disease progression for each patient. In addition to the number of patients for a trial, measurement of disease progression by CA-125 measurement with standard or RECIST criteria will the number of in the clinical In many progression defined using CA-125 will be earlier than progression established using RECIST data indicate that the is as an indicator of disease progression as the RECIST when used in a variety of clinical trials for or relapsed ovarian cancer Because of the of disease in ovarian cancer, an that measurements of CA-125 and measurable disease will provide a more of the tumor In certain an in progression-free survival using RECIST or CA-125 criteria should be to clinical benefit and should be used to of new drugs for ovarian for CA-125 measurement in has been proposed by CA-125 should be at each months for the first months after of chemotherapy. This can be increased to months for months and from years after the diagnosis. CA-125 in an patient is cause for but not treatment by The to on a CA-125 should be on the of CA-125 from a value the of should be the drugs clinical trials are to produce disease than with an rise in CA-125 levels who as progression to CA-125 are a particularly group in to test these is important that use of an elevated CA-125 as an with the of progression to CA-125 by the The to evaluating a drug would be to patients a test therapy and or no treatment. data in such a of patients, is a to for in fewer are potential as to could be to The is to use the response criteria only disease is one could for of that are for a as in a trial of and patients are CA-125 measurements months during the time from last CA-125 the to a the of can be used to the time therapy. This value can be compared with the time after a new therapy. from the treatment of the for and of Cancer CA-125 will clearly demonstrate the of the CA-125 rise over time in patients. These data will the of the CA-125 rise and the potential of before and after introduction of a novel this use of CA-125 can indicate for drugs in a Phase II it could be used to those drugs evaluation in would be to the CA-125 at the start of the new trial therapy as the CA-125 from that would be The time before progression could be the to CA-125 such as disease would require would require in different trials and against standard a of CA-125 levels is used as an the CA-125 not continue to rise at the rate monitoring of CA-125 will be required to a point the rise in CA-125 is significantly In this to that used for early of ovarian cancer with CA-125 values must be developed such as monitoring is therefore when any new definitions on are a large number of Phase II and Phase III clinical trials evaluating new and regimens of approved as well as new and drugs for treatment of ovarian cancer. The is to a of these and some of these trials have the CA-125 response rate criteria as well as the criteria for of progression-free survival Whereas much is required to or trial in of a Phase II trial using these criteria the and value of these methods for making in development of drugs for treatment of ovarian is currently a of data to the acceptance of CA-125 as a marker in clinical trials for the evaluation of drugs for ovarian cancer is our that CA-125 has numerous in the design of clinical from to of CA-125 as a biomarker for ovarian cancer will the number of patients for clinical trials in ovarian cancer. CA-125 should be as a that is to standard criteria for disease CA-125 measurement with RECIST therapies can be more and therapies can be These will benefit both the patient and the data that demonstrate the utility of a drug on progression-free survival to CA-125 and RECIST criteria proposed by the should be used to of therapies. therefore the following with to CA-125 in clinical trials for ovarian CA-125 should be used routinely in Phase II clinical trials to for to determine response rates using both CA-125 criteria and RECIST criteria would be designed that if the CA-125 response rate is than a that has 90% to the rate, the trial would be continued that response can be measured with the by RECIST should be that in trials of chemotherapy early CA-125 response is to both and these values should not be as response to chemotherapy. Because the CA-125 is the CA-125 response to should no be a by the start of the of treatment. treatment of trials of therapy should the of patients with CA-125 levels the of at the start of their of chemotherapy from or CA-125 of should be for early of those with significantly defined by Progression-free survival the date of progression should be defined to the CA-125 and RECIST criteria proposed by the CA-125 should be in Phase I and II trials to the optimal and of therapies such as signal Several methods for and evaluating response criteria for these newer drugs are and their is and should be the of and new such as and should aid for both Phase II and pivotal trials and could be end points to CA-125 in evaluating new ovarian cancer therapies. may be to to therapeutic response for which assays could be These assays could new therapies, trial data that demonstrate CA-125 response defined and in previous and an in progression-free survival defined to the CA-125 and RECIST criteria proposed by the should be used to of therapies. These trials would be designed to allow of evaluation to survival or quality of life end points or to be in Phase IV trials using these standard end for of Cancer