Over the past 2 decades, we have seen major progress in the management of women with ovarian cancer, with improvements in both overall survival and quality of life. To truly appreciate this progress, it is important to understand the state of affairs regarding the treatment of ovarian cancer in the early 1980s. This paper will discuss that historical background, describe the increasingly favorable impact of evolving treatment paradigms in ovarian cancer, and note future directions for clinical research in this complex disease process.
Dr. Markman carefully reviews many of the important advances in the management of ovarian cancer that have taken place since the 1980s. Although there is no question that there has been an improvement in both survival and quality of life, ovarian cancer remains the fifth leading cause of cancer death in women.
A subset of patients with ovarian cancer not reviewed by Dr. Markman are young women with germ cell tumors of the ovary, for whom there truly have been dramatic improvements in survival and quality of life. Prior to the development of platinum-based chemotherapy, young women with germ cell tumors frequently died of their disease despite aggressive surgery and extended chemotherapy. Now, not only is death in this setting infrequent, but most young women with germ cell tumors of the ovary are treated with conservative surgery, maintaining their ability to subsequently have a normal pregnancy.
In contrast, women with advanced ovarian cancer who undergo aggressive cytoreductive surgery but have residual tumor nodules greater than 1 cm (suboptimally debulked) have less than a 10% long-term survival, and only 20% to 25% of those women who undergo optimal cytoreductive surgery will be alive at 10 years. While germ cell tumors of the ovary and the more common epithelial ovarian cancer (which occurs in elderly women) are clearly different biologic and clinical entities, the goals of therapy remain the same: to improve survival and to maintain quality of life. What then are the challenges that need to be met before we can achieve the same results that we have been able to accomplish in younger women with germ cell tumors of the ovary?
A major problem of ovarian cancer continues to be that the majority of women (75%) are diagnosed with advanced-stage disease. Although in the last 20 years it appears that we have been making progress in diagnosing some epithelial tumors at earlier stages, there are still no effective screening techniques for ovarian cancer, and most patients are diagnosed with intraperitoneal carcinomatosis. Screening with either serum CA-125 levels or transvaginal sonography lacks the requisite sensitivity and specificity. Whether the identification of novel tumor markers and proteomic assays will lead to earlier diagnosis remains uncertain. Part of the problem is the relatively low incidence of ovarian cancer, which mandates a very high screening specificity in order to avoid unnecessary laparotomies for false-positive tests.
A major accomplishment in the past 2 decades has been the identification of the role of BRCA1/2 mutations in characterizing women at high risk for breast and ovarian cancers. Even in this group of women, screening is not relied upon and women undergo prophylactic oophorectomies after childbearing. Future studies may identify the mechanisms by which mutations in these genes increase the risk for ovarian cancer. This, in turn, may facilitate the development of chemopreventive strategies to obviate the need for prophylactic surgery.
Surgery in Ovarian Cancer
Few would argue with the accepted dogma that cytoreductive surgery benefits patients with ovarian cancer. As Dr. Markman points out, however, the optimal manner in which chemotherapy and surgery are utilized in the management of patients with advanced ovarian cancer remains unknown. Ovarian cancer is a highly chemosensitive disease, and neoadjuvant chemotherapy has the potential for chemically debulking patients, making subsequent surgery perhaps less morbid and even more effective by increasing the number of patients who are left with minimal or no disease after surgery. Unfortunately-in contrast to other solid tumors in which neoadjuvant chemotherapy has been explored in prospective randomized trials-only one ongoing trial in Europe is addressing this clinically important issue in ovarian cancer.
In the past 25 years, a series of clinical trials have been performed in patients with early- and advanced-stage ovarian cancer, both to identify which patients may benefit from treatment and to develop more effective systemic treatments. It is now clear that women with FIGO stage IA and IB and well-differentiated tumors do not require adjuvant chemotherapy, as their relapse rate is less than 5%. Randomized trials have demonstrated that women with early-stage high-risk disease (stage IC as well as select stage IA and IB patients with poorly differentiated tumors) have improved survival from immediate chemotherapy, compared to observation followed by treatment at relapse.
However, a subset analysis has led to controversy as to exactly which patients may benefit from chemotherapy. Molecular prognostic factors such as gene-expression profiles are needed to better identify women who do and do not need adjuvant therapy, as well as those in whom standard therapy is unlikely to be beneficial and who then can be recommended for trials of novel agents.
For patients with advanced ovarian cancer, there have been numerous prospective randomized trials evaluating different chemotherapeutic agents and combinations. There is little doubt that carboplatin, when administered using area-under-the-curve (AUC) dosing (as developed by Calvert), is the most effective agent in this disease. Some would argue about how much added benefit there is to combining paclitaxel with carboplatin. Nevertheless, a recent consensus conference of investigators from major clinical trial groups throughout the world concluded that carboplatin/paclitaxel is the standard of care against which all new chemotherapeutic regimens should be evaluated.
That said, it is clear that more effective treatments are needed. Even in patients with optimal stage III disease, the median progression-free survival is less than 2 years, and median overall survival is approximately 5 years.
Clinical trials have evaluated the role of maintenance therapy, new drug combinations, and intraperitoneal chemotherapy in an effort to improve overall survival. As yet, no maintenance strategy has been shown to improve survival in patients with advanced ovarian cancer, and the list of clearly ineffective approaches keeps getting longer, including topotecan (Hycamtin), intraperitoneal p32, whole-abdominal radiation therapy, high-dose chemotherapy, and interferon. Studies of antibodies against CA-125 and taxanes are still in progress, but truly effective maintenance therapy may require as yet undefined molecularly targeted agents.
Intraperitoneal (IP) therapy has been studied extensively in ovarian cancer for over 2 decades. A recent Gynecologic Oncology Group (GOG) study reported improvement in survival for patients treated with an IP regimen compared to intravenous (IV) cisplatin/paclitaxel. This prompted a National Cancer Institute (NCI) alert that, like Dr. Markman's review, recommended that IP chemotherapy be considered for patients with stage III disease that has been optimally debulked.
Some investigators have suggested that the GOG study and the NCI alert may overestimate the benefit of IP therapy, since the comparative arm was IV cisplatin/paclitaxel instead of IV carboplatin/paclitaxel, which in a previous GOG trial produced an 8-month improvement in median survival compared to IV cisplatin/paclitaxel. Furthermore, IP therapy is associated with formidable toxicity, and only 42% of patients were able to tolerate all six cycles of planned treatment. Many investigators continue to feel that until a prospective randomized trial of a tolerable IP regimen results in an improvement in survival compared to IV carboplatin/paclitaxel, the latter, much more convenient regimen should remain the standard of care for patients with optimal stage III disease.
A series of prospective randomized trials have been (or shortly will be) completed, in which carboplatin/paclitaxel has been compared with two-drug and three-drug combinations including agents such as gemcitabine (Gemzar), encapsulated doxorubicin (Doxil), topotecan, epirubicin (Ellence), and docetaxel. As with maintenance therapy, the list of drugs that have failed to improve survival over standard therapy continues to grow, raising questions about the futility of combining cytotoxic agents.
Management of Recurrent Disease
A major accomplishment in the management of patients with ovarian cancer in the past 2 decades has been in the number of patients who achieve a clinical complete remission following cytoreductive surgery and chemotherapy-approximately 75% of all patients will have no evidence of disease with a normal serum CA-125, negative computed tomography scan, and normal physical exam. However, disease will recur in the majority of these patients, and recurrent ovarian cancer remains an invariably fatal disease.
Dr. Markman carefully reviews the considerations involved in selecting chemotherapy for patients with recurrent ovarian cancer. The classification of patients into platinum-sensitive and platinum-resistant disease more than a decade ago by Dr. Markman and his colleagues has continued to guide clinicians in how these patients should be treated. Dr. Markman stresses that an underlying principle in the selection of therapy for patients with recurrent ovarian cancer is to maintain quality of life and to avoid exacerbating preexisting toxicities, such as neuropathy.
Future Directions in Ovarian Cancer
There is no doubt that the development of the carboplatin/paclitaxel regimen has led to an improvement in survival and quality of life for patients with advanced ovarian cancer. Unfortunately, the improvement in survival is modest, and it is obvious to patients and clinicians that better systemic therapy is desperately needed. New cytotoxic agents are under development, and some combinations may have the potential to reverse platinum resistance, but it is also possible that cytotoxic chemotherapy does not have significant potential to further improve survival compared to carboplatin/paclitaxel.
While cytotoxic chemotherapy may have peaked, biologic therapy is on the ascendancy. Molecular-targeted therapy with agents such as cetuximab (Erbitux), trastuzumab (Herceptin), and bevacizumab (Avastin) has already altered the landscape of common epithelial tumors, including breast cancer, colorectal cancer, and lung cancer. It is highly probable that novel targeted therapies will also affect the management of ovarian cancer. It has already been shown that bevacizumab produced a 17% response rate in patients with recurrent ovarian cancer. Based on this study, the GOG is currently evaluating bevacizumab in combination with paclitaxel/carboplatin in patients with advanced suboptimal ovarian cancer. Targeted therapies are likely to become more effective as we identify molecular markers that predict for response to a specific biologic treatment.
Although, in general terms, biologic and targeted therapies are less toxic than cytotoxic chemotherapy, they have their own distinct patterns of toxicity that can be serious and require intervention. For example, bevacizumab is associated with hypertension and the risk of bowel perforations. The molecular and clinical characteristics of patients at risk for these toxicities will be essential in maximizing the potential benefit of biologic therapy.
Instead of having to rely on surgery and chemotherapy alone, it seems probable that molecular-targeted therapy will become an important modality in the treatment of this disease. A sustained effort, primarily funded by the federal government, is essential to maintain the momentum toward unraveling the molecular characteristics of ovarian cancer. These findings can then be quickly translated into clinical trials evaluating new strategies, in both prevention and treatment.
-Robert F. Ozols, MD, PhD
Dr. Ozols is a consultant for Bristol-Myers Squibb, Eli Lilly, Genentech, Telik, and Unither.
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