Ovarian cancer
Ovarian cancer is a cancer that forms in an ovary. It results in abnormal cells that have the ability to invade or spread to other parts of the body. When this process begins, there may be no or only vague symptoms. Symptoms become more noticeable as the cancer progresses. These symptoms may include bloating, pelvic pain, abdominal swelling, and loss of appetite, among others. Common areas to which the cancer may spread include the lining of the abdomen, lining of the bowel and bladder, lymph nodes, lungs, and liver.
The risk of ovarian cancer increases in women who have ovulated more over their lifetime. This includes those who have never had children, those who begin ovulation at a younger age or reach menopause at an older age. Other risk factors include hormone therapy after menopause, fertility medication, and obesity. Factors that decrease risk include hormonal birth control, tubal ligation, and breast feeding. About 10% of cases are related to inherited genetic risk; women with mutations in the genes BRCA1 or BRCA2 have about a 50% chance of developing the disease. The most common type of ovarian cancer, comprising more than 95% of cases, is ovarian carcinoma. There are five main subtypes of ovarian carcinoma, of which high-grade serous carcinoma is the most common. These tumors are believed to start in the cells covering the ovaries, though some may form at the Fallopian tubes. Less common types of ovarian cancer include germ cell tumors and sex cord stromal tumors. A diagnosis of ovarian cancer is confirmed through a biopsy of tissue, usually removed during surgery.
Screening is not recommended in women who are at average risk, as evidence does not support a reduction in death and the high rate of false positive tests may lead to unneeded surgery, which is accompanied by its own risks. Those at very high risk may have their ovaries removed as a preventive measure. If caught and treated in an early stage, ovarian cancer may be curable. Treatment usually includes some combination of surgery, radiation therapy, and chemotherapy. Outcomes depend on the extent of the disease and the subtype of the cancer present. The overall five-year survival rate in the United States is 45%. Outcomes are worse in the developing world.
In 2012, ovarian cancer occurred in 239,000 women and resulted in 152,000 deaths worldwide. This makes it, among women, the seventh-most common cancer and the eighth-most common cause of death from cancer. The typical age of diagnosis is 63. Death from ovarian cancer is more common in North America and Europe than in Africa and Asia.
Signs and symptoms
Signs and symptoms of ovarian cancer are frequently absent in early stages; even when they do exist, they may be subtle. In most cases, symptoms exist for several months before being recognized and diagnosed, or they may initially be misdiagnosed as a condition such as irritable bowel syndrome. The early stages of ovarian cancer tend to be painless unless the growing mass causes ovarian torsion. Early symptoms can include bloating, abdominopelvic pain, and pain in the side. The most typical symptoms of ovarian cancer include bloating, abdominal or pelvic pain or discomfort, back pain, irregular menstruation or postmenopausal vaginal bleeding, pain or bleeding after or during sexual intercourse, difficulty eating, loss of appetite, fatigue, diarrhea, indigestion, heartburn, constipation, nausea, early satiety, and possibly urinary symptoms (including frequent urination and urgent urination); typically these symptoms are caused by a mass pressing on the other abdominopelvic organs or from metastases. If these symptoms start to occur more often or more severely than usual, especially after no significant history of such symptoms, ovarian cancer should be considered. Metastases may cause a Sister Mary Joseph nodule.
In adolescents or children with ovarian tumors, the presenting symptoms can include severe abdominal pain, irritation of the peritoneum, or bleeding. As the cancer becomes more advanced, it can cause an accumulation of fluid in the abdomen. If the malignancy has not been diagnosed by the time it causes ascites, it is typically diagnosed shortly thereafter. Advanced cancers can also cause abdominal masses, lymph node masses, or pleural effusion.
Ovarian cancer symptoms can vary based on the subtype. Low malignant potential (LMP) tumors, also known as borderline tumors, do not cause an increase in CA125 levels and are not identifiable with an ultrasound. The typical symptoms of an LMP tumor can include abdominal distension or pelvic pain. Particularly large masses tend to be benign or borderline. Rarely, teratomas can cause growing teratoma syndrome or peritoneal gliomatosis. The symptoms of sex cord-stromal tumors belie their ability to produce hormones. In prepubertal children, early puberty is the main symptom; abdominal pain and distension are also common. Rather than early puberty, adolescents with sex cord-stromal tumors may experience amenorrhea. Adults instead experience menometrorrhagia and abnormal vaginal bleeding after menopause in most cases. Other common symptoms include hirsutism, abdominal pain, virilization, and an adnexal mass.
Management
Treatment usually involves chemotherapy and surgery, and sometimes radiotherapy, regardless of the subtype of ovarian cancer. Surgical treatment may be sufficient for well-differentiated malignant tumors and confined to the ovary. Addition of chemotherapy may be required for more aggressive tumors confined to the ovary. For patients with advanced disease, a combination of surgical reduction with a combination chemotherapy regimen is standard. Borderline tumors, even following spread outside of the ovary, are managed well with surgery, and chemotherapy is not seen as useful. Second-look surgery and maintenance chemotherapy have not been shown to provide benefit.
Surgery
Surgery is the preferred treatment and is frequently necessary to obtain a tissue specimen for differential diagnosis via its histology. The type of surgery depends upon how widespread the cancer is when diagnosed (the cancer stage), as well as the presumed type and grade of cancer. The surgeon, who is usually a specialized gynecologic oncology surgeon, may remove one (unilateral oophorectomy) or both ovaries (bilateral oophorectomy), the Fallopian tubes (salpingectomy), the uterus (hysterectomy), and the omentum (omentectomy). Typically, all of these are removed. For low-grade, unilateral stage-IA cancers, only the involved ovary (which must be unruptured) and Fallopian tube will be removed. This can be done especially in young people who wish to preserve their fertility. However, a risk of microscopic metastases exists and staging must be completed. If any metastases are found, a second surgery to remove the remaining ovary and uterus is needed. Tranexamic acid can be administered prior to surgery to reduce the need for blood transfusions due to blood loss during the surgery.
If a tumor in a premenopausal woman is determined to be a low malignant potential tumor during surgery, and it is clearly stage I cancer, only the affected ovary is removed. For postmenopausal women with low malignant potential tumors, hysterectomy with bilateral salpingo-oophorectomy is still the preferred option. During staging, the appendix should be examined or removed. This is particularly important with mucinous tumors. In children or adolescents with ovarian cancer, surgeons typically attempt to preserve one ovary to allow for the completion of puberty, but if the cancer has spread, this is not always possible. Dysgerminomas in particular tend to affect both ovaries: 8–15% of dysgerminomas are present in both ovaries. People with low-grade (well-differentiated) tumors are typically treated only with surgery, which is often curative. In general, germ cell tumors can be treated with unilateral surgery unless the cancer is widespread or fertility is not a factor.
In advanced cancers, where complete removal is not an option, as much tumor as possible is removed in a procedure called debulking surgery. This surgery is not always successful, and is less likely to be successful in women with extensive metastases in the peritoneum, stage- IV disease, cancer in the transverse fissure of the liver, mesentery, or diaphragm, and large areas of ascites. Debulking surgery is usually only done once. More complete debulking is associated with better outcomes: women with no macroscopic evidence of disease after debulking have a median survival of 39 months, as opposed to 17 months with less complete surgery. By removing metastases, many cells that are resistant to chemotherapy are removed, and any clumps of cells that have died are also removed. This allows chemotherapy to better reach the remaining cancer cells, which are more likely to be fast-growing and therefore chemosensitive.
Interval debulking surgery is another protocol used, where neoadjuvant chemotherapy is given, debulking surgery is performed, and chemotherapy is finished after debulking. Though no definitive studies have been completed, it is shown to be approximately equivalent to primary debulking surgery in terms of survival, and shows slightly lower morbidity.
There are several different surgical procedures that can be employed to treat ovarian cancer. For stage I and II cancer, laparascopic (keyhole) surgery can be used, but metastases may not be found. For advanced cancer, laparoscopy is not used, since debulking metastases requires access to the entire peritoneal cavity. Depending on the extent of the cancer, procedures may include a bilateral salpingo-oophorectomy, biopsies throughout the peritoneum and abdominal lymphatic system, omentectomy, splenectomy, bowel resection, diaphragm stripping or resection, appendectomy, or even a posterior pelvic exenteration.
To fully stage ovarian cancer, lymphadenectomy should be included in the surgery, but a significant survival benefit to this practice may not happen. This is particularly important in germ cell tumors because they frequently metastasize to nearby lymph nodes.
If ovarian cancer recurs, secondary surgery is sometimes a treatment option. This depends on how easily the tumor can be removed, how much fluid has accumulated in the abdomen, and overall health. It can be helpful in people who had their first surgery done by a generalist and in epithelial ovarian cancer. Secondary surgery can be effective in dysgerminomas and immature teratomas.
The major side effect of an oophorectomy in younger women is early menopause, which can cause osteoporosis. After surgery, hormone replacement therapy can be considered, especially in younger women. This therapy can consist of a combination of estrogen and progesterone, or estrogen alone. Estrogen alone is safe after hysterectomy; when the uterus is still present, unopposed estrogen dramatically raises the risk of endometrial cancer. Estrogen therapy after surgery does not change survival rates. People having ovarian cancer surgery are typically hospitalized afterwards for 3–4 days and spend around a month recovering at home. Surgery outcomes are best at hospitals that do a large number of ovarian cancer surgeries.
It is unclear if laparoscopy or laparotomy is better or worse for FIGO stage I ovarian cancer. There is also no apparent difference between total abdominal hysterectomy and supracervical hysterectomy for advanced cancers. Approximately 2.8% of people having a first surgery for advanced ovarian cancer die within two weeks of the surgery (2.8% perioperative mortality rate). More aggressive surgeries are associated with better outcomes in advanced (stage III or IV) ovarian cancer.
Chemotherapy
Chemotherapy has been a general standard of care for ovarian cancer for decades, although with variable protocols. Chemotherapy is used after surgery to treat any residual disease, if appropriate. In some cases, there may be reason to perform chemotherapy first, followed by surgery. This is called "neoadjuvant chemotherapy", and is common when a tumor cannot be completely removed or optimally debulked via surgery. Though it has not been shown to increase survival, it can reduce the risk of complications after surgery. If a unilateral salpingo-oophorectomy or other surgery is performed, additional chemotherapy, called "adjuvant chemotherapy", can be given. Adjuvant chemotherapy is used in stage 1 cancer typically if the tumor is of a high histologic grade (grade 3) or the highest substage (stage 1c), provided the cancer has been optimally staged during surgery. Bevacizumab may be used as an adjuvant chemotherapy if the tumor is not completely removed during surgery or if the cancer is stage IV; it can extend progression-free survival but has not been shown to extend overall survival. Chemotherapy is curative in approximately 20% of advanced ovarian cancers; it is more often curative with malignant germ cell tumors than epithelial tumors.
Chemotherapy in ovarian cancer typically consists of platins, a group of platinum-based drugs, combined with non-platins. Common therapies can include paclitaxel, cisplatin, topotecan, doxorubicin, epirubicin, and gemcitabine. Carboplatin is typically given in combination with either paclitaxel or docetaxel; the typical combination is carboplatin with paclitaxel. Carboplatin is superior to cisplatin in that it is less toxic and has fewer side effects, generally allowing for an improved quality of life in comparison, though both are similarly effective. Three-drug regimens have not been found to be more effective, and platins alone or nonplatins alone are less effective than platins and nonplatins in combination. Chemotherapy can be given intravenously or in the peritoneal cavity. Though intraperitoneal chemotherapy is associated with longer progression-free survival and overall survival, it also causes more adverse side effects than intravenous chemotherapy. It is mainly used when the cancer has been optimally debulked. Intraperitoneal chemotherapy can be highly effective because ovarian cancer mainly spreads inside the peritoneal cavity, and higher doses of the drugs can reach the tumors this way.
Chemotherapy can cause anemia; intravenous iron has been found to be more effective than oral iron supplements in reducing the need for blood transfusions. Typical cycles of treatment involve one treatment every 3 weeks, repeated for 6 weeks or more. Fewer than 6 weeks (cycles) of treatment is less effective than 6 weeks or more. Germ-cell malignancies are treated differently than other ovarian cancers — a regimen of bleomycin, etoposide, and cisplatin (BEP) is used with 5 days of chemotherapy administered every 3 weeks for 3 to 4 cycles. Chemotherapy for germ cell tumors has not been shown to cause amenorrhea, infertility, birth defects, or miscarriage. Maintenance chemotherapy has not been shown to be effective.
In people with BRCA mutations, platinum chemotherapy is more effective. Germ-cell tumors and malignant sex-cord/stromal tumors are treated with chemotherapy, though dysgerminomas and sex-cord tumors are not typically very responsive.
Platinum-sensitive or platinum-resistant
If ovarian cancer recurs, it is considered partially platinum-sensitive or platinum-resistant, based on the time since the last recurrence treated with platins: partially platinum-sensitive cancers recurred 6–12 months after last treatment, and platinum-resistant cancers have an interval of less than 6 months. Second-line chemotherapy should be given only after the cancer becomes symptomatic, because no difference in survival is seen between treating asymptomatic (elevated CA-125) and symptomatic recurrences.
For platinum-sensitive tumors, platins are the drugs of choice for second-line chemotherapy, in combination with other cytotoxic agents. Regimens include carboplatin combined with pegylated liposomal doxorubicin, gemcitabine, or paclitaxel. Carboplatin-doublet therapy can be combined with paclitaxel for increased efficacy in some cases. Another potential adjuvant therapy for platinum-sensitive recurrences is olaparib, which may improve progression-free survival but has not been shown to improve overall survival. (Olaparib, a PARP inhibitor, was approved by the US FDA for use in BRCA-associated ovarian cancer that had previously been treated with chemotherapy.) For recurrent germ cell tumors, an additional 4 cycles of BEP chemotherapy is the first-line treatment for those tho have been treated with surgery or platins.
If the tumor is determined to be platinum-resistant, vincristine, dactinomycin, and cyclophosphamide (VAC) or some combination of paclitaxel, gemcitabine, and oxaliplatin may be used as a second-line therapy.
For platinum-resistant tumors, there are no high-efficacy chemotherapy options. Single-drug regimens (doxorubicin or topotecan) do not have high response rates, but single-drug regimens of topotecan, pegylated liposomal doxorubicin, or gemcitabine are used in some cases. Topotecan cannot be used in people with an intestinal blockage. Paclitaxel used alone is another possible regimen, or it may be combined with liposomal doxorubicin, gemcitabine, cisplatin, topotecan, etoposide, or cyclophosphamide. ( See also Palliative care below.)
Radiation therapy
Dysgerminomas are most effectively treated with radiation, though this can cause infertility and is being phased out in favor of chemotherapy. Radiation therapy does not improve survival in people with well-differentiated tumors.
In stage 1c and 2 cancers, radiation therapy is used after surgery if there is the possibility of residual disease in the pelvis but the abdomen is cancer-free. Radiotherapy can also be used in palliative care of advanced cancers. A typical course of radiotherapy for ovarian cancer is 5 days a week for 3–4 weeks. Common side effects of radiotherapy include diarrhea, constipation, and frequent urination.
Hormonal therapy
Despite the fact that 60% of ovarian tumors have estrogen receptors, ovarian cancer is only rarely responsive to hormonal treatments. Estrogen alone does not have an effect on the cancer, and tamoxifen and letrozole are rarely effective.
Immunotherapy
Immunotherapy is a topic of current research in ovarian cancer. In some cases, the antibody drug bevacizumab, though still a topic of active research, is used to treat advanced cancer along with chemotherapy. It has been approved for this use in the European Union.
Follow-up
Specific follow-up depends on, for example, the type and stage of ovarian cancer, the treatment, and the presence of any symptoms. Usually, a check-up appointment is made about every 2 to 3 months initially, followed by twice per year for up to 5 years. For epithelial ovarian cancers, the most common test upon follow-up is CA-125 level. However, treatment based only on elevated CA-125 levels and not any symptoms can increase side effects without any prolongation of life, so the implication of the outcome of a CA-125 test should be discussed before taking it. The recommendation as of 2014 is recurrent cancer may be present if the CA-125 level is twice normal. Treating a recurrence detected by CA-125 does not improve survival.
For women with germ-cell tumors, follow-up tests generally include alpha-fetoprotein (AFP) and/or human chorionic gonadotropin. For women with stromal cancers, tests for hormones like estrogen, testosterone, and inhibin are sometimes helpful. Inhibin can also be useful for monitoring the progress of sex-cord tumors, along with mullerian inhibiting substance. AFP can also be used to monitor Sertoli-Leydig tumors. In dysgerminomas, lactate dehydrogenase and its two isozymes (LDH-1 and LDH-2) are used to test for recurrence.
Women with ovarian cancer should not have routine surveillance imaging to monitor the cancer unless new symptoms appear or tumor markers begin rising. Imaging without these indications is discouraged because it is unlikely to detect a recurrence, improve survival, and because it has its own costs and side effects. However, CT imaging can be used if desired, though this is not common. If a tumor is easily imaged, imaging may be used to monitor the progress of treatment.
Palliative care
Palliative care focuses on relieving symptoms and increasing or maintaining quality of life. It has been recommended as part of the treatment plan for any person with advanced ovarian cancer or patients with significant symptoms. In platinum-refractory and platinum-resistant cases, palliative non-platin chemotherapy is the main treatment.
Palliative care can entail treatment of symptoms and complications of the cancer, including pain, nausea, constipation, ascites, bowel obstruction, edema, pleural effusion, and mucositis. Especially if the cancer advances and becomes incurable, treatment of symptoms becomes one of the main goals of therapy. Palliative care can also entail helping with decision-making such as if or when hospice care is appropriate, and the preferred place for the patient at end of life care.
Bowel obstruction can be treated with palliative surgery (colostomy, ileostomy, or internal bypass) or medicine, but surgery has been shown to increase survival time. Palliative surgery may result in short bowel syndrome, enterocutaneous fistula, or re-obstruction; or may not be possible due to the extent of obstruction. Other treatments of complications can include total parenteral nutrition, a low-residue diet, palliative gastrostomy, and adequate pain control. Bowel obstruction can also be treated with octreotide when palliative surgery is not an option. Cancer can also block the ureters, which can be relieved by a nephrostomy or a ureteric stent. Ascites can be relieved by repeated paracentesis or placement of a drain to increase comfort. Pleural effusions can be treated in a similar manner, with repeated thoracentesis, pleurodesis, or placement of a drain.
Radiation therapy can be used as part of the palliative care of advanced ovarian cancer, since it can help to shrink tumors that are causing symptoms. Palliative radiotherapy typically lasts for only a few treatments, a much shorter course of therapy than non-palliative radiotherapy. It is also used for palliation of chemotherapy-resistant germ cell tumors.
