Screening techniques for use in the general population have long been available for cervical cancer and are being actively developed for ovarian cancers.
This article is part II of a series. View part I:Evolving Paradigms in Gynecologic Cancer: Introduction > >Screening techniques for use in the general population have long been available for cervical cancer and are being actively developed for ovarian cancers. Early and accurate detection of these cancers is key to reducing mortality and increasing survival time in patients. However, the benefits of screening must be weighed against the potential harm of initiating unnecessary medical treatments due to false positives or detection of transient neoplasias. This task is both helped and hindered by the link between HPV infection and some gynecologic cancers, because these infections often spontaneously clear and do not progress to malignant pathology. The latest science and published guidelines for gynecologic cancer screening are reviewed in subsequent sections of this supplement.
Early-stage cervical cancer is often asymptomatic or characterized by symptoms that are not discerned by the patient, including watery vaginal discharge or intermittent spotting. Regular screening is therefore crucial for detecting patients with cervical cancer as early as possible.
The Papanicolaou cytological test (Pap smear) has long been used to identify preinvasive cervical lesions and early-stage cancer. This test can be conducted in 2 formats of equivalent efficacy: conventional cytology, in which cells are spread on a glass slide, or liquid-based cytology, in which the collected cells are suspended in a vial of preserving fluid.14The other primary method of cervical cancer screening is DNA testing for the presence of HPV infection, although this test should only be conducted on patients over the age of 30 years, because the high rate of infection in younger women may lead to overtreatment.15
Conventional Pap or liquid cytology test every 3 years
HPV test and Pap smear cotest every 5 years
Pap smear alone every 3 years
Stop screening if prior negative result and not at high risk
No screening if cervix removed and no prior high-grade precancer or cervical cancer
Post HPV vaccination
Same screening as nonimmunized women
Positive cytological screening tests should indicate a diagnostic follow-up by colposcopy, endocervical curettage, or biopsy.16Current guidelines issued by the American Cancer Society, the American Society of Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology are shown inTable 2.17
The early detection of EOC can significantly impact prognosis, as the 5-year survival rate for patients who receive treatment for stage 1 disease is >90%, but this figure plunges to less than 40% for those with advanced-stage disease.18Due to the heterogeneity of ovarian cancer, however, effective screening strategies have yet to be developed, and the majority of patients are diagnosed with malignancies in advanced stages.
Several prospective trials have been conducted to investigate potential screening strategies using combinations of physical examination, ultrasound imaging, and detection of cancer antigen 125 (CA-125). The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial used a protocol that combined testing of serum levels of CA-125 with transvaginal ultrasound imaging and reported no reduction in ovarian cancer mortality and increased risk of complications from false-positive results.19 These results led the US Preventive Services Task Force to recommend against screening for ovarian cancer in low-risk populations.20 A similar trial in a larger cohort, the United Kingdom Collaborative Trial of Ovarian Cancer Screening is ongoing, with mortality data expected in 2015.21At present, screening is not recommended by any professional body, although some clinicians use CA-125 levels and transvaginal ultrasound to monitor patients at high risk (eg, family history, BRCA mutations).22
There is no routine screening method available for uterine cancer. Unlike ovarian cancer, however, early-stage endometrial cancer is symptomatic, causing irregular vaginal bleeding in a patient population that is primarily postmenopausal, and patients therefore frequently seek care and are diagnosed at a treatable stage.6 The fact that most patients are diagnosed at an early stage and with localized disease contributes to a relatively high survival rate for this cancer, although the mortality rate has increased more quickly than the incidence rate in recent years.23
Early-stage vaginal cancer often does not have symptoms that cause a patient to seek medical care, and is therefore usually diagnosed at an advanced stage. A Pap test is capable of identifying early-stage disease because cells of the vaginal lining are sometimes inadvertently included in the sample when cervical samples are collected, and precancerous and early-stage abnormalities in these vaginal cells may then be observed. Because cervical cancer is so much more common than vaginal cancer, however, intentional collection of cells from the vaginal wall is not a routine practice.11
Because it affects an external bodily structure, visual changes associated with the development of vulvar cancer are often identified at a relatively early stage by patients, who then seek medical care. The other primary means of early detection of vulvar cancer is a routine pelvic examination during a gynecologic exam.12Infections by HPV do not normally cause serious pathology in women and are most often spontaneously cleared. However, some cases result in persistent infection lasting many years and eventually lead to transformation and the development of cervical cancer and, to a lesser extent, vaginal and vulvar cancer. Therefore, HPV vaccines have been developed both as prophylactic measures to prevent initial infection and as therapeutic tools to promote clearance of persistent infections.24
Several years after the initiation of HPV vaccination programs in Australia and Denmark, investigators observed a significant reduction in the number of precancerous cervical abnormalities,25,26 indicating that this strategy will prove effective in reducing the incidence of cervical cancer in the general population. As of 2013, use of HPV vaccinations in the United States is low, with 57% of girls and 35% of boys having received at least one dose of the vaccine, and completion rates being lower than that.27
There are currently 2 HPV vaccines approved by the US Food and Drug Administration (FDA): a quadrivalent vaccine (Gardasil) that protects against HPV types 6, 11, 16, and 18, and a bivalent vaccine (Cervarix) that targets HPV types 16 and 18. Guidelines published in 2014 by the Advisory Committee for Immunization Practices recommend that girls 11 to 12 years old should be routinely vaccinated using either the bivalent or quadrivalent vaccine. Older girls and women (13 to 26 years old) who have not received or completed the vaccine series should also be vaccinated.27
Therapeutic vaccines to promote the clearance of ongoing persistent HPV infections are currently under development. One such effort used a DNA vaccine to induce T-cell immunity directed against the HPV E6 and E7 antigens in 9 out of 9 patients in the study.28Importantly, this immune activation resulted in viral clearance and regression of neoplastic lesions in 7 of these patients, demonstrating the feasibility of such a treatment strategy in the future.Several different treatment options are available for gynecologic cancers depending on the stage and the specific type of cancer concerned. In 2014, the treatment of advanced, recurrent cervical and ovarian cancers experienced a significant change due to the FDA approval of the antiangiogenic drug bevacizumab. The August approval for late-stage cervical cancer was the first since the combination of topotecan with cisplatin received approval in 2006, while bevacizumab became the first new drug approved for recurrent ovarian cancer in more than 15 years. These approvals also represented firsts for targeted therapy for gynecologic cancers and a brand new avenue for treatment of these diseases.
Broadly, approved treatments for gynecologic cancer include surgery, chemotherapy, radiotherapy, and antiangiogenic therapy. Recommendations for the treatment of several types of gynecologic cancer have been published in guidelines developed by the NCCN.5,6,8
Surgical resection of the affected tissue is recommended for patients with early-stage disease (in situ or stage 1A), including conization or trachelectomy in patients wishing to preserve fertility or hysterectomy for older patients and those unconcerned with sparing fertility.16Lymphadenectomy may also be appropriate if pelvic lymph nodes are involved. Internal radiation therapy is an option for patients who are not candidates for surgery. Concomitant radiotherapy and cisplatin-based chemotherapy or neoadjuvant chemotherapy is recommended in the NCCN practice guidelines for patients with more advanced disease.
In August 2014, the FDA approved the antiangiogenesis drug bevacizumab, an antibody targeting the angiogenic signaling molecule vascular endothelial growth factor A (VEGF-A), for use in combination with chemotherapy for the treatment of persistent, recurrent, and metastatic cervical cancer. This approval was based on data from the phase III GOG 240 trial that demonstrated that adding bevacizumab to either cisplatin-paclitaxel or topotecan-paclitaxel chemotherapy significantly increased OS and response rates in patients with recurrent, persistent, or metastatic cervical cancer.29
For treatment of early-stage ovarian epithelial cancer (stage 1), surgical resection alone is often appropriate and should include hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. Unilateral salpingo-oophorectomy, a fertility sparing procedure, has been reported to be comparable in outcome to radical resection in patients who are ≤40 years old, undergo comprehensive surgical staging, and have one disease-free ovary.30
Though rare in comparison to EOC, ovarian cancer also occurs as malignant germ cell tumors, including dysgerminomas, immature teratomas, embryonal tumors, and endodermal sinus (yolk sac) tumors. These cancers are primarily diagnosed at an early stage in relatively young women (≤35 years); therefore, the 5-year survival rates are >95% for patients with stage 1 tumors and >70% for those with advanced disease.31The primary treatment for malignant germ cell tumors is surgical resection. In patients with stage 2 to 4 disease, additional postoperative chemotherapy with bleomycin/etoposide/platinum is recommended.
Patients with stage 2, 3, or 4 EOC at diagnosis can be treated with cytoreductive surgery and adjuvant chemotherapy with platinum-based regimens that may be combined with alkylating agents or paclitaxel depending on patient characteristics and optimal toxicity profile.22In cases of recurrent EOC that is resistant or refractory to platinum-based agents, recommended drugs include docetaxel, oral etoposide, gemcitabine, liposomal doxorubicin, weekly paclitaxel, and topotecan.
Bevacizumab has been frequently used off-label by clinicians to treat ovarian cancer in the past.32The interest in bevacizumab in treating ovarian cancer has been driven by the known importance of angiogenic pathways in EOC and the efficacy reported in other solid tumors.
Two phase III trials (GOG-0218 and ICON7) have investigated the efficacy of bevacizumab as an adjuvant to a carboplatin/paclitaxel chemotherapy regimen as first-line therapy in EOC,33 and the data demonstrated increased progression-free survival (PFS) in patients who received bevacizumab, although there was no evidence of increased OS or quality of life. Therefore, the NCCN guidelines include category 3 recommendations for the use of bevacizumab, according to the ICON7 and GOG-0281 regimens, as an adjuvant in first-line treatment of EOC and as maintenance therapy.
Two other phase III trials have examined the efficacy of bevacizumab in recurrent EOC that is both platinum-resistant (AURELIA)34and platinum-sensitive (OCEANS).35The results have demonstrated a benefit to PFS when bevacizumab is combined with either platinum-based or nonplatinum chemotherapies, and the NCCN recommends both of these protocols for recurrent ovarian cancer. Additionally, on November 14, 2014, the FDA approved the combination of bevacizumab with nonplatinum chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan) for use in recurrent, platinum-resistant disease on the basis of results from the AURELIA trial. In the trial, bevacizumab improved PFS in all chemotherapeutic regimens, and the greatest increase was observed in the cohort receiving weekly paclitaxel, although the inter-cohort results were not significant.34
On December 19, 2014, the FDA approved the poly ADP-ribose polymerase (PARP) inhibitor olaparib for treating advanced ovarian cancer. Drugs in this family target cells with deficiencies in DNA repair pathways, including mutations in the breast cancer 1, early-onset (BRCA1) and breast cancer 2, early-onset (BRCA2) genes that are observed in 10% to 15% of all patients with ovarian cancer. The FDA decision was based on trial data showing improved objective response rates in patients with BRCA mutations, and the approval applies to patients with such mutations who have already received at least 3 previous chemotherapy treatments.36,37
The most common type of uterine cancer, endometrial cancer (EC), can be treated surgically with hysterectomy and bilateral salpingo-oophorectomy if it is diagnosed at an early stage and is localized. Pelvic lymphadenectomy and postoperative radiation therapy may also be necessary. In highly selected patients with early-stage EC, treatment with progestins, such as megestrol acetate or medroxyprogesterone, is a fertility-sparing alternative to surgery.38
Adjuvant chemotherapy or radiation is recommended for patients with advanced or extrauterine disease. Surgery, chemotherapy, radiation, and hormone therapy with progestational agents are all recommended options for recurrent or metastatic EC.
Uterine serous adenocarcinomas, clear cell adenocarcinomas, and carcinosarcomas are all more aggressive variants of uterine cancer and are treated with surgical resection and highly individualized adjuvant therapy. Platinum-based and taxane-based therapy is recommended for patients with uterine serous adenocarcinoma and clear cell adenocarcinoma, and ifosfamide-paclitaxel chemotherapy is recommended for carcinosarcomas.
The primary treatment for vulvar carcinoma at all stages is surgical resection with radiation integrated into treatment for cases of stage 3 or stage 4 cancer.10Newer regimens have been developed using neoadjuvant or primary chemoradiation, though these approaches have not been standardized, nor have they been shown to be more effective or safe than primary surgery.39,40
The rarity of vaginal carcinoma has constrained the ability of investigators to conduct prospective studies and develop standard therapy protocols for this cancer. Surgical resection and radiation are often curative in early-stage disease, and radiotherapy is standard care at later stages, though survival rates are lower than those achieved in cervical cancer.41Concurrent chemotherapy, including cisplatin and 5-fluorouracil (5-FU), is sometimes administered on the basis of the treatment’s efficacy in cervical cancer, and there is evidence of potential benefits of this treatment in increased OS and disease-free survival (DFS).42Further investigation is required to verify these benefits, however.
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