Originally published as JCO Early Release 10.1200/JCO.2005.05.027 on August 8 2005

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by McGuire, W. P. Search for Related Content PubMed PubMed Citation Articles by McGuire, W. P. Related Articles Related Article Social Bookmarking                            What's this?

CA-125 and Early Ovarian Cancer: Does This Help the Clinician or Further Muddy the Water?

Harry and Jeanette Weinberg Cancer Institute, Franklin Square Hospital Center; University of Maryland School of Medicine, Baltimore, MD

Some 25% to 30% of patients with epithelial ovarian cancer present with localized disease (International Federation of Gynecology and Obstetrics [FIGO] stage I and II) and there remains no real consensus on how best to treat these patient after laparotomy. The real quandary is limited to patients with ovary-confined disease (stage I) since the risk of recurrence following surgery for patients with pelvic-confined disease (stage II) is so high that most agree that adjuvant chemotherapy is required. This fact has led the Gynecologic Oncology Group (GOG) recently to include most stage II patients in studies of advanced ovarian cancer. However, many studies over the last two decades have left us with a lack of consensus on what if any therapy is required, due to many factors including (1) studies that are underpowered to detect small differences in outcome in a disease where events are rather uncommon, (2) inclusion of many borderline tumors with inherently good biology may make outcomes appear better than they really are, and (3) lack of adequate staging, which may lead to inclusion of understaged stage III patients, making outcomes appear worse than they really are. Thus, in the stage I patient the questions that remain are as follows: (1) Was staging adequate to verify stage I disease? If not, should the patient have additional surgery to more definitively stage the patient or should adjuvant therapy be given without further staging? (2) In the properly staged patient, are there data that help to separate those patients who are unlikely to benefit from adjuvant therapy and those who are likely to benefit? (3) What adjuvant therapy is preferable in those selected to receive it? In the United States, those patients with low- or moderate-grade tumors, without extension of tumor through the ovarian capsule and without ascites, are typically not considered candidates for adjuvant therapy. Further, patients with borderline histology are typically not treated with chemotherapy.

Studies performed many years ago tested pelvic radiation, intraperitoneal ³²P-chromic phosphate, and various classic alkylating agents and were unable to show any benefit of adjuvant therapy compared with no adjuvant therapy.^1,2 Further, there was a better therapeutic index without adjuvant therapy due to chronic toxicities of a serious nature in the treated patients (acute leukemia and myelodysplastic syndromes with classic alkylating agents and small bowel toxicity with intraperitoneal ³²P). Nonetheless, in the United States randomized trials in early ovarian cancer since the early 1970s have not included a control arm, so that treatment decisions were based on therapeutic index; that is, which therapy was less toxic, rather than efficacy of therapy compared with no therapy. No obvious winner was detected from these early trials and the current accepted practice is 3 to 6 cycles of carboplatin plus paclitaxel. The major toxicity of this regimen is peripheral neuropathy, which is persistent in some 5% to 10% of patients.

One trial³ that compared no therapy to cisplatin monotherapy in stage I disease demonstrated a trend favoring cisplatin in disease-free survival, but not overall survival, and the trial was underpowered to make any other observation (n = 83). Most recently, the data from two trials—International Collaborative Ovarian Neoplasm (ICON1) and Adjuvant Chemotherapy in Ovarian Neoplasm (ACTION)—that were run simultaneously were combined and reported.⁴ In both trials, no therapy was compared with platinum-based therapy in patients with stages I and IIA disease. Each trial analyzed alone showed trends in favor of adjuvant therapy, but when the two were combined there was an 11% absolute improvement in recurrence-free survival (76% v 65%) and an 8% improvement in overall survival (82% v 74%) associated with adjuvant chemotherapy. These data would seem to definitively answer whether platinum-based adjuvant therapy is beneficial in early ovarian cancer. Unfortunately, that is not the case, since in one of these studies (the ICON1 trial) the entry criteria were loose and staging was not rigorously defined. Thus, there remain the problems of understaged stage III patients or patients with borderline tumors. One could simply accept the combined analysis as "real world" and treat all stage I patients with adjuvant chemotherapy, understanding that one is over treating many patients who were cured by the initial surgery. In the ACTION trial, 35% of patients had complete surgical staging and there was no apparent benefit from adjuvant therapy. We are not clear about the specific characteristics of these patients who did not benefit, but know that some had characteristics which many in the United States still advocate treating with adjuvant therapy, such as patients with grade 3 tumors or patients with adherence of the ovary to adnexal structures. Armed with these data, then, one could simply agree to treat all apparent stage I but suboptimally staged patients with adjuvant chemotherapy; but in this "real world" example 65% of the patients were inadequately staged and subjected to adjuvant therapy that might have been avoided with more stringent staging.

Other factors have been identified that have prognostic value in early ovarian cancer including grade (often poorly reproducible), ploidy,⁵ degree of adherence of the adnexae to pelvic peritoneum, and, most recently, proteomic or genomic patterns.⁶ But none of these alone or in combination has been evaluated prospectively as predictive of outcome to dictate the need for adjuvant therapy. What is really needed is some method to determine which patients can have adjuvant therapy withheld after adequate staging for stage I disease.

In this issue of the Journal is the report of another factor appearing to have some prognostic significance from a retrospective review of a large series of stage I cases from eleven centers in Australia. The investigators found in 518 patients that preoperative CA 125 levels correlated with survival in the 346 adequately staged patients (69%). Five-year survival was 95% compared with 82% for patients with CA-125 30 or > 30, respectively (P = .028). Of the properly staged patients, 110 (32%) had CA-125 levels 30 and 236 (68%) had elevated values preoperatively. Curiously, for the 172 patients (31%) who had suboptimal staging, CA-125 did not have prognostic value (78% v 70% for normal or elevated CA-125). Thus, if one follows the conclusions in this study and the combined analysis of the ICON1/ACTION trials, one would err on the side of treatment for the 172 patients who were inadequately staged as well as the 236 patient with proper staging but elevated CA-125 levels. Adjuvant treatment would then be delivered to 408 (79%) of 518 patients with stage I disease, recognizing that unnecessary therapy is being given to at least 70% of this cohort (0.7 x 408 = 286 patients) who were cured by the primary surgery. The authors conclude that "... CA-125 levels are independent prognostic factors and should be included in the decision making for chemotherapy." They forget, however, to tell the reader just how exactly this information should be used to select therapy and what form of therapy should be used. The CA-125 appears to be prognostic but these data to not speak at all to the predictive value of the assay, which will help to determine whether treating patients with elevated CA-125 alters the natural history of the disease.

To take some lessons from our colleagues who treat breast cancer, there are markers that are both prognostic and predictive. Expression of hormone receptors confers a better prognosis while also conferring benefit with use of adjuvant hormonal therapy. Similarly, overexpression of HER2neu has negative prognostic implications but also is predictive of a benefit when trastuzumab is used as an adjuvant. Most recently there has been another prognostic tool added to the treatment paradigm in breast cancer, a 21-gene panel that appears to have prognostic value for those patients with node-negative breast cancer.⁷ This assay appears to shift a significant number of patients who would currently be classified as being at intermediate risk for recurrence to a low-risk group based on a retrospective evaluation of patients on the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 study. Similar studies were performed to evaluate this gene pool as discriminating the need for adjuvant chemotherapy in the NSABP B-20 trial. Again, the assay appeared to move a significant number of patients from an intermediate- to a low-risk group (approximately 50%). In both groups of patients, the recurrence score was more predictive of outcome than current NCCN guidelines. This assay is currently only of prognostic import since it has not yet been prospectively evaluated to demonstrate its ability to identify patients who can be left untreated after appropriate local therapy. One would need to prospectively randomly assign patients identified as low risk by the multigene assay to hormonal therapy compared to no hormonal therapy or chemotherapy compared to no chemotherapy. Such studies are under development.

Unfortunately, the playing field in ovarian cancer is much muddier. If one follows the ICON1 paradigm then all stage I patients would receive adjuvant chemotherapy, as would the 65% of inadequately staged patients in the ACTION trial. Many patients in both of these trials would not be considered for adjuvant therapy in the United States due to intrinsic good biology. Using the data from the retrospective Australian analysis only 21% of 518 patients who were both properly staged and had low preoperative CA-125 would escape adjuvant therapy. These "good prognosis" patients are not described separately in the manuscript, so one cannot know that these patients would not have been excluded from a trial of adjuvant therapy (38% grade 1 and 64% stage IA) in the United States due to known good prognosis. Although CA-125 remains prognostic in the multivariate model, it is the weakest of the three, which includes grade, adequate surgical staging, and CA-125. Perhaps we need to follow the lead of our colleagues who treat breast cancer and find better discriminators of risk such as genes or proteins that are reproducible, prognostic, and able to classify at least 50% of early ovarian cancer into a low risk category. The final step, then, would be mount a large, hopefully international, trial to determine if adjuvant therapy is even necessary in a large segment of this patient population.

Author's Disclosures of Potential Conflicts of Interest

The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other William P. McGuire Unither (B); GlaxoSmithKline (A) GlaxoSmithKline (B) GlaxoSmithKline (B)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

REFERENCES

1. Young RC, Decker DG, Wharton JT, et al: Adjuvant therapy in stage I and stage II epithelial ovarian cancer: Results of two prospective randomized trials. N Engl J Med 322:1021-1027, 1990[Abstract]

2. Vergote IB, Vergote-de vos LN, Abeler VM, et al: Randomized trial comparing cisplatin with radioactive phosphorous or whole abdomen irradiation as adjuvant treatment of ovarian cancer. Cancer 69:741-749, 1992[CrossRef][Medline]

3. Bolis G, Colombo N, Pecorelli S, et al: Adjuvant treatment for early epithelial ovarian cancer: Results of two randomized clinical trials comparing cisplatin to no further treatment or chromic phosphate. Ann Oncol 9:887-893, 1995

4. Trimbos JB, Parmar M, Guthrie D, et al: International collaborative ovarian neoplasm trial 1 and adjuvant chemotherapy in ovarian neoplasm trial: Two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian cancinoma. J Natl Cancer Inst 95:105-112, 2003[Abstract/Free Full Text]

5. Trope C, Kaern J, Hogberg T, et al: Randomized study on adjuvant chemotherapy in stage I high-risk ovarian cancer with evaluation of DNA-ploidy as prognostic instrument. Ann Oncol 11:281-288, 2000[Abstract/Free Full Text]

6. Petricoin EF, Ardekani AM, Hitt BA, et al: L. Use of proteomic patterns in serum to identify ovarian cancer. Lancet 359:272-277, 2002

7. Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817-2826, 2004[Abstract/Free Full Text]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Article

• Prognostic Importance of Preoperative CA-125 in International Federation of Gynecology and Obstetrics Stage I Epithelial Ovarian Cancer: An Australian Multicenter Study
  Sellva Paramasivam, Lee Tripcony, Alex Crandon, Micheal Quinn, Ian Hammond, Donald Marsden, Anthony Proietto, Margaret Davy, Jonathan Carter, James Nicklin, Lewis Perrin, and Andreas Obermair
  JCO 2005 23: 5938-5942 [Abstract] [Full Text]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by McGuire, W. P. Search for Related Content PubMed PubMed Citation Articles by McGuire, W. P. Related Articles Related Article Social Bookmarking                            What's this?