CA-125 and Early Ovarian Cancer: Does This Help the Clinician or Further Muddy the Water?
Authors: William P. McGuire
Journal: Journal of Clinical Oncology (2005)

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 pelvicconfined 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 lowor 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 P-chromic phosphate, and various classic alkylating agents and were unable to show any benefit of adjuvant therapy compared with no adjuvant therapy. 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 P). 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 trial 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. 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 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 25 SEPTEMBER 1 2005