Updates in the Management of Gynecologic Cancers
The 39th Annual Meeting of the Society of Gynecologic Oncologists (SGO) was held in Tampa, Florida, from March 9 to 12, 2008, and was attended by more than 1,000 oncologists and other healthcare professionals.
Established to “promote and ensure the highest quality of comprehensive clinical care through excellence in education and research in gynecologic cancers,” the SGO Annual Meeting this year included numerous presentations on gynecologic cancers and novel therapies.
Endometrial cancer is the most common gynecologic cancer diagnosed in the United States. It originates in the inner lining of the uterus called the endometrium. Many endometrial cancers occur in obese women and result from estrogen exposure. There is currently no screening test for this disease; however, an early symptom of postmenopausal bleeding often allows for this cancer to be detected in the early stages. In 2008 there are expected to be 40,100 new cases of cancer of the uterus1, with the vast majority of these being endometrial cancers. It is estimated that 7,470 women will die of uterine cancer this year.
Because endometrial cancer is detected early in most cases, patients are often treated surgically with a total hysterectomy and removal of the fallopian tubes, ovaries, and lymph nodes. In some patients, radiation treatments or chemotherapy may be recommended based on findings made at surgery. However, when the cancer is found to have spread during surgery-with visible evidence of tumor deposits in different parts of the abdomen and pelvis-the correct treatment is not very well defined.
Clinical Trial of the Gynecologic Oncology Group
A randomized Phase III clinical trial of surgery, radiation therapy, and chemotherapy in women with advanced endometrial cancer was recently conducted to determine if the addition of paclitaxel to a standard two-drug chemotherapy regimen (cisplatin plus doxorubicin) after surgery and radiation treatment improved survival in women with advanced endometrial cancer. Results were presented at the SGO meeting.
All patients underwent an aggressive surgical debulking procedure in which cancer metastases throughout the abdomen and pelvis, along with the uterus, ovaries, and fallopian tubes plus/minus lymph nodes, were removed, followed by radiation therapy. Of the 659 patients enrolled onto this trial from July 2000 to September 2004, 552 women were then eligible to receive either six cycles of the two-drug regimen (cisplatin plus doxorubicin) or six cycles of the three-drug regimen (cisplatin plus doxorubicin and paclitaxel).
As expected, patients treated with three drugs experienced more frequent and more severe side effects, including bone marrow suppression and numbness, related to paclitaxel. The proportion of patients alive and free of relapsing cancer at three years of follow-up was 62 percent for the two-drug regimen, and 64 percent for the three-drug regimen. The investigators concluded that the addition of paclitaxel to cisplatin plus doxorubicin in women who had undergone maximal surgical debulking and radiation therapy for advanced endometrial cancer was not associated with a significant improvement in survival.
To improve survival in advanced endometrial cancer, further studies involving newer chemotherapy agents and possibly novel biologic drugs need to be conducted.
Gestational Trophoblastic Disease
Molar pregnancies result in an abnormally developed placenta without a normal fetus. As a result, molar pregnancies are suctioned from the uterus through the vagina and in 20 percent of cases, will also require chemotherapy after surgery. In the “low risk” version of this situation-referred to as gestational trophoblastic neoplasia (GTN)-cure rates approach 100 percent when drugs such as methotrexate or dactinomycin are administered.
Methotrexate and dactinomycin have different side effects and different dosing schedules. Often when one of these drugs fails to cure a case of gestational trophoblastic neoplasia, the disease is then cured with the other drug. It is not known, however, which is the best drug to start treatment with or if it makes a difference.
Clinical Trial of the Gynecologic Oncology Group
A recent randomized Phase III trial of weekly intramuscular injections of methotrexate versus intravenous injections of dactinomycin every two weeks compared the two drugs as first-line therapies.
Of the 240 patients who were enrolled on this study from June 1999 to February 2007, 215 were eligible for analysis. Mild nausea, vomiting, and hair loss were reported by more patients treated with dactinomycin when compared with those receiving methotrexate. In addition, severe side effects related to bone marrow suppression occurred in two patients receiving dactinomycin. Sixty-nine percent of patients treated with dactinomycin were successfully placed into remission as compared with 53 percent who received methotrexate.
Although side effects were more common in patients treated with dactinomycin, this study demonstrated that biweekly administration of dactinomycin was statistically superior to weekly administration of methotrexate as initial management of low-risk GTN. Future studies will likely be needed to address whether alternating dactinomycin with methotrexate will place patients into remission sooner than dactinomycin alone.
Advanced Ovarian Cancer
Because there is no screening test for ovarian cancer and because early symptoms are often missed, the vast majority of patients are diagnosed with advanced disease, placing overall five-year survival rates at 20 to 30 percent. In 2008 it is estimated that there will be 21,650 new cases in the United States and 15,520 deaths from this disease.1 Standard therapy involves aggressive surgical debulking of the tumor (removing as much as possible) followed by intravenous (IV) chemotherapy.
Intrapeitoneal (IP) chemotherapy involves administering the chemotherapy drugs directly into the patient’s abdominal cavity, and this method has been shown to prolong survival in patients with optimally debulked ovarian cancer (where the amount of residual visible cancer left behind at the end of surgery is less than 1 cm). Unfortunately, many patients cannot enjoy the survival benefit associated with IP chemotherapy because they are not able to be optimally debulked at the time of surgery. In many centers, patients who are felt to be inoperable or for whom the likelihood of optimal debulking is felt to be very low, are given chemotherapy first in a strategy known as neoadjuvant chemotherapy, which is then followed by interval debulking.
Clinical Trial of the Southwest Oncology Group
A recent clinical trial that evaluated whether intraperitoneal (IP) chemotherapy could be incorporated into the treatment of women with advanced ovarian cancer who were rendered optimally debulked after first having been treated with neoadjvuant chemotherapy. Among the 62 patients registered between March 2001 and February 2006, 26 were rendered optimally debulked following neoadjuvant chemotherapy and were then eligible to receive a combination of IV and IP chemotherapy. Four of these patients experienced severe bone marrow suppression. The overall survival of these 26 patients was reported as being 34 months.
Because the survival results in this study are superior to those reported for patients who cannot be optimally debulked, it suggests that another viable indication for IP therapy would include patients who are able to be optimally debulked following neoadjvuant chemotherapy. To validate these results, a larger Phase III trial comparing the outcome of patients who are rendered optimally debulked following neoadjuvant chemotherapy is needed wherein patients are then randomized to either standard postoperative IV therapy or postoperative IV and IP therapy.
Early Ovarian Cancer
With the exception of very specialized tumors of the ovary (for example, borderline tumors and malignant germ cell tumors), ovarian cancer typically presents in the advanced stages. For those patients fortunate enough to be diagnosed with a Stage I ovarian cancer, cure rates following chemotherapy can be as high as 90 percent.
Among those patients with Stage I ovarian cancer for whom chemotherapy is recommended, it is not clear whether a limited number of cycles of chemotherapy (for example, three) is as effective as the six cycles used in the setting for patients who are diagnosed with advanced disease.
Exploratory Analysis of a Gynecologic Oncology Group Clinical Trial
A randomized Phase III clinical trial conducted by the Gynecologic Oncology Group (GOG) and published in 2006 compared three versus six cycles of chemotherapy in 427 patients with early Stage I-II ovarian cancer. This study revealed a trend toward an improved survival in those patients who received six cycles of chemotherapy. At the recent SGO meeting, another trial sought to build on the findings of that GOG study by identifying subsets of patients with early-stage ovarian cancer who may benefit from six cycles of chemotherapy.
Some of the factors that the investigators looked at included: age of the patients and their functional status (for example, whether they were active and healthy or less so), ethnicity, stage of disease (I versus II), the grade of the cancers (1, 2 or 3), presence of ascites fluid (abnormal buildup of fluid in the abdomen), and whether the ovarian tumor had ruptured.
The risk of relapse in those who received six versus three cycles of chemotherapy was not different based on age, race, functional status, stage, grade, or for presence of ascites or rupture. However, for women with serous ovarian cancers, the risk of relapse was significantly decreased after six compared with three cycles of chemotherapy; Five-year relapse-free survival rates were 83 percent versus 60 percent, respectively.
This analysis identified a subgroup of early-stage ovarian cancer patients who are likely to benefit from six cycles of chemotherapy-specifically, those with serous ovarian cancers. This important observation supports and validates the trend that was seen in the original publication of this GOG trial. Because early-stage ovarian cancer is relatively uncommon, it is unlikely that any trial group will be able to run another large study on early-stage ovarian cancer, thus making this exploratory analysis of existing GOG data an invaluable contribution to the body of literature on this disease.
Cancer of the vulva accounts for 8 percent of gynecologic malignancies, and women are usually diagnosed later in life-many in their 70s and 80s. It is estimated that there will be 3,460 new cases and 870 deaths in the Unites States in 2008.1 The cancer usually spreads by local extension of the tumor or through the lymphatic pathways, first to the lymph nodes in the groin, followed by spread to the lymph nodes in the pelvis.
Treatment of vulvar cancer typically consists of radical vulvectomy (partial or complete removal of the vuvla), with dissection of one or both sides of the lymph nodes in the groin. Patients found to have disease in the groin lymph nodes are candidates for additional therapy. In a previous randomized study by the Gynecologic Oncology Group, investigators reported that the addition of pelvic and groin radiation therapy to women found to have cancerous groin lymph nodes was superior to surgical removal of the lymph nodes in the pelvis.
Updated Analysis of a Gynecologic Oncology Group Study
Long-term follow-up data on the original GOG trial recently revealed that among the 111 patients who had been enrolled onto this protocol from 1977 to 1984, the six-year cancer-related survival significantly favored the group of patients who had received postoperative pelvic and groin radiation therapy as compared with those patients who had been randomly assigned to undergo pelvic lymph node dissection on the side of the body where lymph node metastases to the groin had been found. This benefit was especially important in those patients with enlarged or fixed groin nodes and for those with two or more positive groin lymph nodes. When more than 20 percent of the groin nodes on the same side of the vulvar cancer were positive for metastases, cancer-related death and overall survival were significantly influenced. Interestingly, late toxic effects were similar among the two different treatments.
With prolonged follow-up, this study verified that the results obtained in the original GOG study published in the early 1990s were sustained: postoperative radiation to the groin and pelvis is superior to pelvic lymph node dissection when vulvar cancer metastases are found in the groin. Furthermore, this study identified important subsets of patients whose groin lymph nodes were involved with metastases (for example, those with 20 percent groin nodes positive, two or more positive nodes) who are at especially high risk of relapse and death for whom innovative new therapies (for example, chemotherapy) are needed.
Vaccination Against Cervical Cancer
Pap smears have decreased the incidence and death rate of cervical cancer among women in developed countries such as the United States. Cervical cancer is caused by the specific high-risk strains of the human papillomavirus (HPV), which can be detected by a special test called Hybrid Capture II (made by Digene).
Now that an HPV vaccine (Gardasil®, manufactured by Merck) has been approved by the U.S. FDA, further reductions in cervical cancer incidence and death may be anticipated. Gardasil is a quadrivalent vaccine because it confers protection against four subtypes of HPV (HPV 6 and HPV 11, which cause 90 percent of genital warts, and HPV 16 and HPV 18, which cause 70 percent of cervical cancers).
Despite the success of Pap smear programs and the ability to detect HPV, over 2 billion dollars in healthcare expenditure occurs annually as a result of abnormal Pap tests and their subsequent evaluation, which often requires cervical biopsies and other surgical procedures on the cervix. This is because, although Pap smears and HPV detection allow a pre-cancerous or dysplastic state of the cervix to be detected and treated before it can turn into cancer, neither of these two methods eliminate the original problem, which is infection with HPV.
Clinical Trial of the Quadrivalent HPV Vaccine Merck Study Group
Recently, the end-of-study data from three pivotal Phase II/III clinical trials of the quadrivalent HPV vaccine were reported at the SGO meeting.A total of 18,15016 to 26-year-old women were enrolled in one of three randomized, placebo-controlled trials. Vaccine or placebo was given at Day 1, Month 2, and Month 6. Subjects underwent Pap testing on Day 1 and every six to 12 months for up to 48 months. Patients with specific abnormalities on the Pap smear were referred for colposcopy and, depending on the findings, definitive treatment was carried out.
After an average follow-up period of four years, the investigators noted a reduction in Pap tests, colposcopy, cervical biopsy, and definitive treatment among patients who were uninfected with HPV at the time of vaccination. Interestingly, these reductions were seen irrespective of the specific type of HPV involved.
Vaccination with the quadrivalent vaccine appears to be able to decrease the number of Pap tests, colposcopies, cervical biopsies, and treatment women require. This occurs presumably because the vaccine protects against infection with HPV, which is the inciting event in the development of pre-cancerous cervical disease (which is not possible with Pap smears and HPV testing along). Long-term studies are required to determine the duration of protection that is achieved by the three-dose vaccination series.
Advanced and Recurrent Cervical Cancer
It is estimated that in 2008 there will be 11,070 new cases of cervical cancer in the United States and 3,870 deaths.1 This relatively low incidence of cervical cancer has been primarily brought about through the inclusion of Pap smears in screening programs. However, for women who do not have access to healthcare, important clinical tools, such as Pap smears, HPV testing, and the HPV vaccine, will remain unavailable.
Fortunately, many cervical cancers are diagnosed at an early stage when they may be cured through radical surgery. For those cancers that are locally advanced but have not metastasized, a combination of pelvic radiation plus chemotherapy has resulted in respectable cure rates, which approach nearly 80 percent in some groups. For metastatic cervical cancer and most cases in which relapse occurs, treatment is often futile, with most patients surviving less than one year despite chemotherapy. The armamentarium of chemotherapy drugs, either alone or in combination with one another, has been exhausted in a number of previous trials for this disease with mixed results.
Clinical Trial of the Gynecologic Oncology Group
A recent Phase II trial investigated the novel biologic agent bevacizumab in women with relapsing cervical cancer. Bevacizumab is considered an anti-vascular drug, which prevents the tumor from growing blood vessels to the patient, thus preventing ongoing nutrition of the cancer. The investigators reported on 46 patients who were treated with this unique drug after having received unsuccessful treatment with chemotherapy drugs for relapsing disease. For 38 patients, their cervical cancer had originally been treated with radiation therapy. Although several severe side effects associated with bevacizumab were observed, there were no treatment-related deaths. Importantly, five patients (11 percent of the study group) experienced cancer shrinkage and 11 patients (24 percent of the study group) had tumors that did not grow for at least six months.
Because the results of this study involving a biological agent compared favorably with those studies that have tested chemotherapy drugs for metastatic cervical cancer, serious consideration will be given by the GOG to conduct a randomized clinical trial comparing chemotherapy drugs with and without bevacizumab for this disease.
Coverage of the 39th Annual Meeting of the Society of Gynecologic Oncologists Provided by:Krishnansu S Tewari, MD, FACOG, FACS Associate Professor The Division of Gyncologic Oncology The Chao Family Comprehensive Cancer Center University Of California, Irvine
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 Tiersten A, Liu P, Smith H, Wilcynski S, Robinson W, Markman M, Alberts D. phase II evaluation of neoadjuvant chemotherapy and interval debulking followed by intraperitoneal chemotherapy in women with stage III and IV epithelial ovarian, fallopian tube, or primary peritoneal cancer: A Southwest Oncology Group study. 39th Annual Meeting of the Society of Gynecologic Oncologists, Tampa, FL, Plenary Session I, 9 March 2008, Abstract #3. Gynecologic Oncology. 2008;108:S3.
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 Huh WK. Impact of quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus-like particle vaccine on the incidence of abnormal pap tests and cervical procedures. 39th Annual Meeting of the Society of Gynecologic Oncologists, Tampa, FL, Plenary Session III, 10 March 2008, Abstract #20. Gynecologic Oncology. 2008;108:S10.
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