Ovarian Cancer

Age, race, and ethnicity all appear to influence ovarian cancer incidence and survival. Women age 65 and older have a higher incidence and poorer survival. The disease occurs most frequently in white women, followed by Hispanic and black women. Three major factors influence survival: the type of cells involved (germ cell or stromal cell ovarian cancers have an excellent outcome, even in late-stage disease); the accuracy of the staging; and the extent of tumor resection, preferably to a reduction of less than 2 cm per nodule—i.e., optimum debulking. Combined carboplatin-paclitaxel (Taxol) is now the standard of care. “I don't know any medical oncologist who does not accept this,” said Robert F. Ozols, MD, PhD, Senior Vice President of the Division of Medical Science at Fox Chase Cancer Center.Figure: Robert Ozols, MD, PhD: “You could make a case that carboplatin may not be quite as good as cisplatin, but the latter is a more difficult and complicated treatment, and carboplatin is far less toxic….The take-home message is that we need to use chemotherapy along with biologics like Gleevec, Avastin, and Iressa. Targeted therapy is the future.”“And every single ovarian cancer trial now going on uses carboplatin-paclitaxel as the control. This is the hallmark of standard treatment.” Dr. Ozols added that carboplatin is the active drug in the equation. “Taxol may add something, but it isn't much.” Edward L. Trimble, MD, Associate Chief (Surgery) of the NCI's Clinical Investigations Branch, agreed: “Single-agent carboplatin is pretty much equivalent to paclitaxel plus a platinum. Adding paclitaxel increases bone marrow toxicity, neurotoxicity, and hair loss. We may not use it at all when there is significant comorbidity and the patient can't tolerate the adverse events.” Dr. Ozols was principal investigator of the Gynecologic Oncology Group (GOG) study that established carboplatin-paclitaxel as the standard, published in the Journal of Clinical Oncology in September 2003 (2003;21:3194–3200) (and online that July). Prior to this pivotal trial, studies of treatment for epithelial ovarian cancer were often not done in comparable patients, making the results less than definitive. Some patients had had surgery before entering a trial, and some had no treatment at all. Several trials in advanced disease showed that cisplatin-paclitaxel was superior to cisplatin plus cyclophosphamide, which had been widely used until then. As a result, cyclophosphamide fell by the wayside. Patterns of Care Study A study last year from NCI's Surveillance, Epidemiology, and End Results (SEER) program published in the Journal of Clinical Oncology (2003;21:3488–3494) examined patterns of care in 566 ovarian cancer patients diagnosed in 1991. Between 1991 and 1996, practice patterns changed dramatically, said Dr. Trimble, one of the authors of the study. The percentage of women who had what he termed “appropriate surgery” (that which included lymph node dissection) increased: In 1996, 59% of patients with early-stage ovarian cancer had lymph node biopsy, up from 38% in 1991. However, even now a significant number of women still do not receive precise staging because their physicians fail to assess lymph nodes or assign a tumor grade, Dr. Trimble said. “Physicians and surgeons who are not gynecologic oncologists do not have training in the operative management of ovarian cancer. A specialist will perform more aggressive surgery than a general surgeon.” He described what is appropriate as removal of the ovaries, fallopian tubes, omentum, uterus, all gross tumor, and a sampling of periaortic and pelvic nodes. If the disease has invaded the large or small bowel, which are common metastatic sites, then the affected sections of those organs also are excised. “The goal of surgery is to remove as much disease as possible,” he said. More than 65% of the patients in the SEER study were given cyclophosphamide in 1991, but only 14% received that drug in 1996. Similarly, paclitaxel use increased from 1% to 62% during that time.Figure: Edward L. Trimble, MD, MPH, said that even now a significant number of women with ovarian cancer do not receive precise staging because their physicians fail to assess lymph nodes or assign a tumor grade.Women with early-stage disease were significantly more often given NIH Consensus Development Conference guideline therapy in 1996 than in 1991, but for women with Stage III and IV disease, the use of guideline therapy did not increase much. (Other treatment guidelines have since been published.) Women with Stage III and IV disease and minorities received less guideline therapy, and the lack of private health insurance was an impediment for Hispanic and black women. Married women were more likely to receive guideline therapy than unmarried ones. Utah Study A larger SEER study conducted in just Utah compared the outcomes of patients with epithelial ovarian cancer who had and had not been seen by a gynecologic oncologist. It used the statewide Utah Cancer Registry of 848 patients diagnosed between 1992 and 1998. Thirty-nine percent of patients were seen by a gynecologic oncologist at some time during diagnosis and treatment, but there was significant variation by age: 36% of these women were under 40, 55% were between 40 and 59, 43% were 60 to 69, and 24% were age 70 or over. The percentage of women seen by a gynecologic oncologist increased from 33% in 1992 to 47.5% in 1998, and as one might guess, more women who lived in the Salt Lake City area (43%) saw a gynecologic oncologist than did those who lived in rural parts of the state (27%). In women with local or regional disease, there was no significant difference in survival between those treated or not treated by a specialist, but women with advanced disease had a major survival advantage when they saw a gynecologic oncologist (26 vs 15 months). Reasons for the Differences Both SEER studies concluded that significant numbers of women with epithelial ovarian cancer were not being given appropriate care for a number of reasons: ▪ The public is poorly informed about gynecologic oncologists; thus, women do not know enough to ask for a referral. Too many women are strongly attached to their gynecologists and want to stay with them, or they perceive that the physician will be insulted if they go elsewhere for treatment. ▪ Many gynecologists hesitate to refer patients to an oncology specialist. Some don't want to lose the income, and some labor under inappropriate and unwarranted confidence that they can treat cancer appropriately.Figure: Michael Bookman, MD: “It has been difficult to find new combinations to use with carboplatin that don't increase bone marrow toxicity. A major goal is to get newer drugs into front-line treatment.”▪ Young women (under age 40) are particularly at risk for being treated by non-gynecologic oncologists, perhaps because there are no reliable screening tools for ovarian cancer. Thus, non-specialists encounter ovarian malignancies in a general oncology practice. ▪ Physicians may have the mistaken perception that ovarian cancer is always rapidly fatal and thus do not offer aggressive treatment to women over age 65. ▪ Many women, especially poor and unmarried ones, do not have a strong support system and don't know where to turn for appropriate referrals. ▪ Lack of private health insurance almost guarantees that a gynecologic oncologist will not treat a woman. With private insurance, the standard of care increases significantly. The lead author of the national SEER study, Linda C. Harlan, PhD, Senior Scientist in the NCI Division of Cancer Control and Population Sciences, noted, “You don't see this dichotomy between the insured and uninsured in breast cancer, perhaps because the surgery is not as complex. Many physicians can operate on breast cancer, but few are trained in ovarian cancer surgery.” Even public insurance like Medicare is inadequate to reimburse for optimum care, unless the woman also has private Medigap coverage. ▪ Practitioners are notoriously resistant to change, and many of them are not aware that there is standard treatment. Dr. Trimble said that this happens far more with nonspecialists than with gynecologic oncologists. ▪ Comorbidity complicates treatment, and some oncologists are reluctant to use aggressive treatment when the patient is ill with other conditions. Also, some patients don't want to undergo difficult and uncomfortable therapy. ▪ When white women were treated in an institution that has an approved residency-training program in gynecologic oncology, the use of guideline therapy increased. The SEER researchers suggested that the residency program may have served as a proxy for the presence of an oncologist and thus improved management of the disease. Next Steps for Better Treatment Dr. Ozols bemoaned the fact that once a woman relapses after response to first-line treatment, cure is usually no longer an option. The goals then are focused on preventing complications, maintaining quality of life, and extending survival. The largest of the many ongoing trials, sponsored by GOG, is taking place in about 200 centers in the US, UK, Italy, Australia, and New Zealand. It is a five-arm randomized (but not blinded) trial of more than 4,000 patients with Stage III and IV epithelial ovarian cancer. The trial has finished accruing patients and was closed on September 1, reported the Chairman of the GOG's Developmental Therapeutics Committee, Michael A. Bookman, MD, Director of Medical Gynecologic Oncology at Fox Chase Cancer Center. The trial is the largest ever in ovarian cancer and will compare the standard treatment of carboplatin-paclitaxel (Arm 1) to: ▪ Eight cycles of carboplatin-paclitaxel plus gemcitabine (Arm 2) ▪ Eight cycles of carboplatin-paclitaxel plus pegylated liposomal doxorubicin (Arm 3) ▪ Four cycles of carboplatin and topotecan followed by four cycles of carboplatin-paclitaxel (Arm 4) ▪ Four cycles of carboplatin and gemcitabine followed by four cycles of carboplatin-paclitaxel (Arm 5). Dr. Bookman agreed with Dr. Ozols about the significant risk of recurrence and the frustration of having nothing curative to offer: “The major purpose of this trial is to add newer drugs with known clinical benefit to standard treatment to prevent or decrease the risk of recurrence,” he said. “However, it has been difficult to find new combinations to use with carboplatin that don't increase bone marrow toxicity. A major goal is to get newer drugs into front-line treatment.” All patients have had surgery prior to entering the study, but about 20% still have visible residual disease. Dr. Bookman explained that if a patient wants to have further cytoreductive surgery, she could elect to have it after the fourth cycle of chemotherapy. Approximately one third of that 20% will do so. The primary endpoint is survival, with secondary endpoints of progression-free survival, objective response rate, toxicity, and tolerability. All patients will have eight cycles of therapy, so the first analysis of survival is scheduled for about January 2006. Regarding quality of life, Dr. Bookman said it was not specified as part of the protocol, but it can be inferred by the amount and type of toxicity patients are experiencing. Next Step: Targeted Therapies Dr. Ozols thinks that the next step in ovarian cancer treatment lies in targeted therapies. “A trial of carboplatin and paclitaxel compared with that combination plus Avastin [bevacizumab] is under discussion now,” he said. Avastin has been approved for colorectal cancer, so it stands to reason that it might work in ovarian cancer. “The take-home message here is that we need to use chemotherapy along with biologics like Gleevec [imatinib], Avastin, and Iressa [gefitinib]). Targeted therapy is the future.” Before & After Paclitaxel Before paclitaxel was found to have a clinically beneficial effect, however small, the major research issues in epithelial ovarian cancer were the relative advantages of platinum over non-platinum agents for first-line treatment, the advantages of anthracycline-containing regimens, single-agent chemtherapy compared with combination therapy, and cisplatin vs carboplatin. A number of randomized studies were done, but most were too small to detect significant treatment differences. However, several meta-analyses produced the following conclusions. ▪ Platinum-containing combinations are better than regimens without platinum. ▪ Combination chemotherapy is generally more advantageous than a single-agent. ▪ Cisplatin and carboplatin were about equally effective. ▪ Combination treatment with cyclophosphamide, doxorubicin, and cisplatin (CAP) is significantly superior to cyclophosphamide and cisplatin (CP). In the late 1980s, studies showed that paclitaxel produced objective results in 16% to 37% of women with relapsed epithelial ovarian cancer. Platinum-paclitaxel combinations were developed and compared with a non-paclitaxel arm in a series of randomized trials conducted by the Gynecology Oncology Group, the European Organization for Research and Treatment of Cancer, and groups in Canada, Scotland, and Norway. These studies confirmed the survival advantage of paclitaxel-cisplatin over cyclophosphamide-cisplatin. Paclitaxel was given over three hours, a convenient dosing schedule, and it produced less myelosuppression in most patients but more neurologic toxicity in some. At the same time, two other types of studies were going on: comparing single-agent platinum to paclitaxel plus platinum, as well as paclitaxel-cisplatin compared with paclitaxel-carboplatin. Paclitaxel was almost equally effective with both platinum drugs. “You could make a case that carboplatin may not be quite as good as cisplatin, but the latter is a more difficult and complicated treatment, and carboplatin is far less toxic,” said Robert Ozols, MD, PhD. He also said that there has been some controversy about neoadjuvant chemotherapy, but unless the patient is so debilitated that she cannot tolerate surgery, it is preferable to remove the tumor and surrounding tissues first and then start chemo. If surgery is not possible at all, a woman can be treated with chemotherapy alone. “Ovarian cancer is very chemosensitive and many of these patients do well,” he said. Definitive Study All these studies were the basis for the large non-inferiority trial conducted by GOG with Dr. Ozols as primary investigator pitting cisplatin and paclitaxel against carboplatin and paclitaxel. The 792 patients selected had advanced disease (Stage III or IV). “But they had good surgery—no residual mass greater than 1 cm postoperatively,” Dr. Ozols explained. They were randomized to two arms: Arm 1 received cisplatin at 75 mg/m2 plus a 24-hour infusion of paclitaxel at 135 mg/m2. Arm 2 received carboplatin at an area under the curve of 7.5 intravenously plus paclitaxel at 175 mg/m2 over three hours. Overall survival and progression-free survival were 19.4 and 48.7 months, respectively, for Arm 1 compared with 20.7 and 57.4 months, respectively, for Arm 2. Gastrointestinal, renal, and metabolic toxicity, as well as Grade IV leukopenia, were significantly more frequent in Arm 1. Grade II or higher thrombocytopenia was higher in Arm 2. Neurologic toxicity was similar in both groups. It thus appeared that in patients with advanced ovarian cancer, carboplatin plus paclitaxel is not inferior to cisplatin-paclitaxel. In addition, it is less toxic and easier to administer. The GOG investigators concluded that carboplatin-paclitaxel should be the treatment of choice for ovarian cancer patients with small-volume Stage III disease. The downside, though, is that about 75% of patients have disease recurrence, with a median time to progression of less than two years. Survival after progression is also less than two years, and overall survival—from time of diagnosis—is four to five years. Nevertheless, the outlook is positive. “Out of every 100 women with Stage III or IV disease who are treated with appropriate surgery and carboplatin plus paclitaxel, 75 will go into complete remission,” Dr. Ozols said. “The problem is that once a woman relapses, there's not much more we can do for her.” —MJF

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.