Treatment & Management of Ovarian Cancer

Understand the role of surgery, chemotherapy, and precision cancer medicines in the treatment of Ovarian Cancer.

Treatment & Management of Ovarian Cancer

Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor 10/2018

The optimal treatment of ovarian cancer requires a combination of surgery, systemic treatment with precision cancer medicines or chemotherapy, and occasionally radiation therapy. Specific treatment can depend on both the stage and the genomic profile of the cancer.

Individuals should seek care from a gynecologic oncologist, these are the doctors specifically trained to diagnose and treat patients with ovarian cancer. The single most important thing a patient can do may be to seek care at a “high volume” cancer center where providers have experience treating ovarian cancer. “High-volume” centers have more extensive experience in treating ovarian cancer and this is associated with improved survival rates.[1]

Surgery for Ovarian Cancer

All patients with ovarian cancer will have surgery as part of their overall evaluation and treatment for ovarian cancer. Initially this is to obtain a biopsy specimen of the cancer to confirm the diagnosis, determine the stage of the cancer, and to provide local treatment of the cancer in the pelvis and abdomen. The biopsy sample is also evaluated for prognostic information and genomic testing to determine whether any precision cancer medicines can be used as part of the treatment plan.

Radiation Therapy for Ovarian Cancer

Radiation therapy or radiotherapy uses high-energy rays to damage or kill cancer cells by preventing them from growing and dividing. Similar to surgery, radiation therapy is a local treatment and is not useful in eradicating cancer cells that have already spread to other parts of the body. Radiation therapy may be externally or internally delivered. External radiation delivers high-energy rays directly to the tumor site from a machine outside the body. Internal radiation, or brachytherapy, involves the implantation of a small amount of radioactive material in or near the cancer.

Systemic Therapy: Precision Cancer Medicine, Chemotherapy, and Immunotherapy

Systemic therapy is any treatment directed at destroying cancer cells throughout the body. Many patients with ovarian cancer already have small amounts of cancer that were not removed with surgery. These patients require systemic treatment to decrease the chance of cancer recurrence. More advanced cancers that cannot be treated with surgery can only be treated with systemic therapy. Systemic therapies commonly used in the treatment of ovarian cancer include:

Chemotherapy

Chemotherapy is any treatment involving the use of drugs to kill cancer cells. Cancer chemotherapy may consist of single drugs or combinations of drugs, and can be administered through a vein, injected into a body cavity, or delivered orally in the form of a pill. Chemotherapy is different from surgery or radiation therapy in that the cancer-fighting drugs circulate in the blood to parts of the body where the cancer may have spread and can kill or eliminate cancers cells at sites great distances from the original cancer. The drugs are usually given in cycles so that a recovery period follows every treatment period.

Initial chemotherapy treatment of ovarian cancer typically consists of a combination of platinum and taxane chemotherapy. These and other chemotherapy drugs are used for recurrent or resistant cancer.

  • Carboplatin, Platinol (cisplatin), Eloxatin (oxaliplatin)
  • Taxol (paclitaxel), Taxotere (docetaxel)
  • Abraxane (paclitaxel liposome injection)
  • Alimta (pemetrexed)
  • Doxil (doxorubicin liposome injection)
  • Camptosar (ironotecan)
  • Gemzar (gemcitabine)
  • Hexalin (altretamine)
  • Hycamtin (topotecan)
  • Xeloda (capecitabine)

Precision Cancer Medicines

The purpose of precision cancer medicine is to define the genomic alterations in the cancers DNA that are driving that specific cancer. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Checkpoint and PARP inhibitors are examples of two newer precision cancer medicine engineered to directly attack ovarian cancer cells. Patients should ask their doctor about whether testing is appropriate.

Intraperitoneal Chemotherapy

Intraperitoneal chemotherapy (IP) is a type of regional chemotherapy that is used to treat some stage III ovarian cancers. During IP chemotherapy the anticancer drugs are infused directly into the peritoneal cavity (the space that contains the abdominal organs) through a thin tube.

Ovarian Cancer Stages

Following surgical removal and staging of ovarian cancer, a final stage will be given. A Roman numeral from I to IV describes the stage and a letter from “A” to “C” describes a sub-stage. All new treatment information concerning ovarian cancer is categorized and discussed by the stage.

Stage I: Cancer is found only in one or both of the ovaries. Cancer cells may also be found in abdominal fluid, or ascites.

Stage II: Cancer is found in the ovaries and has spread to the uterus (womb), the fallopian tubes, or other areas within the pelvis. Cancer cells may also be found in abdominal fluid, or ascites.

Stage III: Cancer is found in the ovaries and has spread to other body locations within the abdomen, such as the surface of the liver, intestine or lymph nodes.

Stage IV: Cancer is found in the ovaries and has spread outside the abdomen or inside of the liver.

Recurrent or Refractory: Recurrent disease means that the cancer has returned (recurred) after it has been treated. Refractory disease means the cancer is no longer responding to treatment.

Surgery for Ovarian Cancer

The successful treatment of ovarian cancer requires the involvement and coordination of several different treatment approaches, including surgery, systemic therapy, and, in rare cases, radiation therapy. Nearly all women with ovarian cancer will undergo surgery and systemic treatment. The role of surgery in the initial management of ovarian cancer is to obtain a biopsy specimen of the cancer to confirm the diagnosis, determine the stage of cancer and to provide local treatment of the cancer in the pelvis and abdomen. The tissue sample is also evaluated for prognostic information and may be sent for genomic testing to determine whether any precision cancer medicines can be used.

Despite surgical removal of the cancer, many patients with ovarian cancer will already have microscopic cancer cells, called micrometastases that have spread away from the ovary to other locations in the abdomen and distant parts of the body. Additional systemic treatment using chemotherapy or precision cancer medicines are required to treat micrometastatic cancer. Most patients with ovarian cancer will require systemic treatment as part of the overall treatment plan.

Patients with ovarian cancer are often initially treated with surgery aimed at debulking (decreasing the size of) the cancer. This type of surgery, in which the goal is to remove the greatest volume of cancer cells possible, is also called “cytoreductive” surgery. After completion of this initial surgery, most patients are placed on a systemic treatment regimen.

Over the past several years, there has been increasing interest in administering chemotherapy both before and after surgery. Chemotherapy given before surgery is referred to as neoadjuvant chemotherapy, and the surgery that follows is referred to as “interval” cytoreductive surgery. By administering chemotherapy first, micrometastatic cancer cells may be more easily destroyed and chemotherapy may reduce the amount of cancer, thereby allowing for more complete surgical removal of the cancer. The use of neoadjuvant therapy may be considered for selected patients with advanced disease who do not appear to be candidates for initial surgery.(1)

Laparotomy (Initial Cytoreductive Surgery)

For patients diagnosed with ovarian cancer during surgery, the first phase of treatment is surgical laparotomy or exploration of the abdomen. During a laparotomy, the surgeon makes an incision down the middle of the abdomen and attempts to remove as much of the cancer within the abdomen and pelvis as possible. The goal of laparotomy is to accurately diagnose and stage the cancer and gain prognostic information that can determine the most appropriate additional therapy.

Typical debulking during the laparotomy includes:

  • A total hysterectomy (removal of the uterus)
  • Bilateral salpingo-oophorectomy (removal of the ovaries and fallopian tubes)
  • Omentectomy (removal of a flap of fatty tissue covering the bowel in the abdomen).
  • Removal of any visible cancer within the abdomen.
  • If the cancer appears to be limited to the ovaries or the pelvis, the surgeon will also cut small pieces of tissue (biopsy) from the upper abdomen.
  • Peritoneal washings -collection of abdominal fluid samples and removal of lymph nodes so that they can be examined under a microscope to determine whether they contain cancer.

These extensive and time-consuming surgeries are best performed by a gynecologic oncologist, who is a surgeon specialized in the treatment of female pelvic cancers.

For patients with metastatic ovarian cancer (cancer detected outside the abdomen), surgery may be beneficial for relief of symptoms and to improve duration of survival. Surgery to remove cancer in the abdomen may help relieve pain, prevent obstruction or blockage of the bowel, and improve a patient’s nutritional status.

The typical surgery for ovarian cancer prevents women from future childbearing because the reproductive organs (ovaries and uterus) are removed. Occasionally, ovarian cancer will occur in a younger woman who wishes to maintain fertility. If the cancer involves only one ovary and the surgery shows no cancer beyond a single ovary, a unilateral salpingo-oophorectomy (removal of one ovary and fallopian tube) can be performed. This allows the patient to bear children and still provides adequate treatment for the cancer. After childbearing is complete, the remaining ovary and the uterus are often removed in an effort to prevent a recurrence.

Despite surgical removal of the cancer, the majority of patients with stage II-IV ovarian cancer will experience a recurrence if no additional systemic treatment is given. This is because patients have undetectable microscopic cancer cells that have spread from the original site of cancer to distant locations in the body and were not removed by surgery. In other cases, patients have visible spread of cancer cells outside the ovary into the abdomen, pelvis, or lymph nodes that cannot be completely removed by surgery.

  • When the cancer is removed with surgery so that no remaining cancer is larger than 1 cm (about three-quarters of an inch), the cancer is referred to as “optimally debulked” or “optimally cytoreduced.”
  • When cancer larger than 1 cm remains after the surgery, the cancer is referred to as “suboptimally debulked” or “suboptimally cytoreduced.”

Patients with optimally cytoreduced cancer are more likely to survive longer and less likely to experience cancer recurrence following systemic therapy than patients who are suboptimally cytoreduced.

Patients who undergo laparotomy for ovarian cancer may experience lower abdominal pain after the operation. Complications related to surgery may include bleeding, infection, a slow recovery of bowel function, temporary difficulty emptying the bladder or other less common conditions. Your surgeon should explain the risk of side effects associated with treatment.

Second-Look Laparotomy

After completion of systemic therapy, patients undergo a physical examination, a CA-125 blood test and radiologic studies to evaluate the effectiveness of treatment. When all of these tests are negative for cancer, a patient is said to be in a complete clinical remission. Many patients in complete remission still have microscopic cancer that was not detected with the available tests. Some doctors recommend an additional surgical evaluation after completion of systemic therapy in order to further evaluate the response to treatment. This operation is called a “second-look laparotomy.” A second-look laparotomy is the most accurate method of detecting persistent cancer cells when CA-125 levels are normal.

Second-look laparotomy will detect evidence of cancer in at least half of patients thought to be in clinical remission. Even when the second-look laparotomy does not detect any cancer cells, cancer still recurs in approximately 30-50% of patients.

Routine second-look laparotomy is no longer recommended as standard treatment. Many doctors recommend that it only be used as part of a clinical trial. This is because a second-look laparotomy only has value to a patient if the information gained during the laparotomy can change a patient’s outcome or subsequent treatment options. This is important for patients to understand because undergoing a second or unnecessary surgery is associated with additional risks and emotional discomfort. These risks include bowel obstruction, adhesions and pain.

Precision Cancer Medicine for Ovarian Cancer

There is no longer a “one-size-fits-all” approach to cancer treatment. Even among patients with the same type of cancer, the behavior of the cancer and its response to treatment can vary widely. By exploring the reasons for this variation, researchers have begun to pave the way for more personalized cancer treatment. It is becoming increasingly clear that specific characteristics of cancer cells and cancer patients can have a profound impact on prognosis and treatment outcome. Although factoring these characteristics into treatment decisions makes cancer care more complex, it also offers the promise of improved outcomes.

Not all cancer cells are alike

Cancer cells may differ from one another based on what genes have mutations. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. This “genomic testing” is performed on a biopsy sample of the cancer and increasingly in the blood using a “liquid biopsy”

Once a genetic abnormality is identified, a specific precision cancer medicine or targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells.

Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.

Precision cancer medicines can be used both instead of and in addition to chemotherapy to improve treatment outcomes.

By testing an individual’s ovarian cancer for specific unique biomarkers doctors continue to develop new precision medicines. Individuals not previously tested undergo genomic testing to determine whether newer precision cancer medicines are a treatment option.

PARP Inhibitors for Ovarian Cancer

The poly ADP-ribose polymerase (PARP) enzyme plays a role in DNA repair, including the repair of DNA damage from chemotherapy. Precision cancer medicines that target and inhibit this enzyme may contribute to cancer cell death and increased sensitivity to chemotherapy and are called PARP inhibitors. By blocking this enzyme, DNA inside the cancerous cells is less likely to be repaired, leading to cell death and possibly a slow-down or stoppage of tumor growth.

PARP inhibitors have the greatest effect in women with mutations of the BRCA genes but may benefit additional patients with different genetic profiles as well. BRCA genes are involved with repairing damaged DNA and normally work to prevent tumor development. However, mutations of these genes may lead to certain cancers, including ovarian cancers.

The BRCA genes are involved with repairing damaged DNA and normally work to suppress tumor growth. Women with mutations resulting in defective BRCA genes are more likely to get ovarian cancer, and it is estimated that 10 to 15 percent of all ovarian cancer is associated with these hereditary BRCA mutations.[2],[3],[4]

Lynparza™ (olaparib); constitutes the first PARP inhibitor approved for treating ovarian cancer. Lynparza was approved for patients with specific abnormalities in the BRCA gene.[2]The FDA approved Lynparza with a genetic test called BRACAnalysis CDx, a companion diagnostic that will detect the presence of mutations in the BRCA genes (gBRCAm) in blood samples from patients with ovarian cancer.

Zejula (Niraparib): when used as maintenance therapy following platinum-based chemotherapy appears to improve the time to cancer progression among patients with recurrent ovarian cancer. Patients with BRCA 1 and BRCA 2 germline mutations appear to derive the greatest benefit from Zejula.

Researchers reported the results of approximately 500 women who had responded to platinum-based chemotherapy for recurrent ovarian cancer who were then treated with Zejula.[3]

One group of patients in the trial had a BRCA1 or BRCA2 germline gene mutation, which predisposes individuals to a significantly increased risk of developing ovarian cancer within their lifetime; one group of patients had without germline BRCA1 or BRCA2 mutations; and one group of individuals had neither BRCA1 or BRCA2 germline mutations nor HRD.

  • Among patients with germline BRCA 1 or 2 mutations, median survival time without progression of cancer (progression-free survival, PFS) was 21 months among patients treated with Zejula, compared with only 5.5 months for those who received placebo.
  • Among patients without germline BRCA1 or 2 mutations who were homologous recombination deficiency (HRD) positive, the median PFS was 12.9 months for those treated with naraparib, compared with only 3.8 months for those who received placebo.
  • Among patients without germline BRCA1 or 2 mutations who had either HRD-positive or HRD-negative cancers, median PFS was 9.3 months for those treated with naraparib, compared with 3.9 months for who received placebo.

Rubraca™ (rucaparib): In patients with BRCA-positive ovarian cancer that had returned after previous treatment more than half of the patients treated with Rubraca responded to treatment for an overall response rate of 65%. Patients who had the longest time to cancer progression before the study had the highest response rates.[4]

Avastin® (Bevacizumab) is a precision cancer medicine that targets a protein known as VEGF. VEGF plays a key role in the development of new blood vessels necessary for cancer cell growth. By blocking VEGF, Avastin deprives the cancer of nutrients and oxygen and inhibits its growth. Clinical trials have shown a improvement in overall survival for women with platinum-sensitive recurrent ovarian cancer who were treated with Avastin plus chemotherapy compared to chemotherapy alone.

Checkpoint Inhibitors

Checkpoint inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight the lung cancer cells. A diagnostic test to measure the level of PD-L1 is available and checkpoint inhibitors are being evaluated in ovarian cancer.

Radiation Therapy for Ovarian Cancer

Radiation therapy or radiotherapy uses high-energy rays to damage or kill cancer cells by preventing them from growing and dividing. Radiation therapy, like surgery, is a local treatment used to eliminate or eradicate cancer that can be encompassed within a radiation field. Radiation therapy is not typically useful in eradicating cancer cells that have already spread to other parts of the body. Radiation therapy may be externally or internally delivered. External radiation delivers high-energy rays directly to the tumor site from a machine outside the body. Internal radiation, or brachytherapy, refers to the implantation of a small amount of radioactive material in or near the cancer.

Prior to the development of platinum-based chemotherapy, radiation therapy was frequently used in an effort to prevent ovarian cancer recurrences after surgery (adjuvant radiation therapy) or to treat recurrences. Currently, radiation therapy is sometimes used to treat a very localized recurrence, or as a treatment in women who cannot tolerate chemotherapy drugs. Radiation may also be used as palliative treatment (treatment of symptoms), when shrinking a tumor may provide symptom relief. In the vast majority of cases, however, the use of radiation therapy has been replaced by chemotherapy. Ongoing clinical trials are still trying to evaluate whether radiation therapy may have a place in the overall treatment of patients with advanced ovarian cancer.

References:

[1] Armstrong, D. Ovaries and fallopian tubes. In: Abeloff MD ed. Abeloff’s Clinical Oncology, 4th ed. Philadelphia: Churchill Livingstone, 2008: 1827-50.

[2 fda.gov/newsevents/newsroom/pressannouncements/ucm427554.htm

[3] Shapira-Frommer R, Oza AM, Domchek SM, et al. A phase II open-label, multicenter study of single-agent rucaparib in the treatment of patients with relapsed ovarian cancer and a deleterious BRCA mutation. Journal of Clinical Oncology. 33, 2015 (supplement; abstract 5513).

[4] Tesaro Inc., press release. Tesaro’s niraparib significantly improved progression-free survival for patients with ovarian cancer in both cohorts of the phase 3 NOVA trial. Available at: http://ir.tesarobio.com/releasedetail.cfm?ReleaseID=977524. Accessed July 6, 2016.

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