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Ovarian Cancer

Stage III Ovarian Cancer

Patients diagnosed with stage III ovarian cancer have cancer that has spread from the ovaries and pelvic organs into the upper abdomen or lymph nodes. Currently, the standard treatment for stage III ovarian cancer consists of both surgery and chemotherapy. Unfortunately, less than 40% of patients experience long-term survival following standard treatment. This is because stage III ovarian cancer is often difficult to remove completely with surgery and currently available chemotherapy is unable to eradiate all of the remaining cancer.

Cytoreductive Surgery

During cytoreductive surgery (also called debulking), physicians attempt to remove as much of the ovarian cancer as possible. Cytoreductive surgery is beneficial because it reduces the number of cancer cells that ultimately need to be destroyed by systemic therapy and therefore, decreases the likelihood of the cancer becoming resistant. Initial cytoreductive surgery in ovarian cancer is currently considered the standard of care because clinical studies have shown that patients who have had optimal cytoreductive surgery live longer and have a more prolonged time to cancer recurrence than patients who have had suboptimal cytoreductive surgery.

Following cytoreductive surgery, all patients with stage III ovarian cancer are offered additional systemic treatment. This is because approximately 60-80% of patients with stage III cancer will experience a recurrence of their cancer, even after complete surgical removal of cancer. Nearly all patients with stage III disease have small amounts of undetectable cancer that have spread outside the ovary and were not removed by surgery. Other patients cannot achieve optimal cytoreduction with initial surgery. An effective treatment is needed to eliminate the remaining cancer in order to improve the cure rate achieved with surgical removal of the cancer.

The combination of cytoreductive surgery and systemic chemotherapy treatment is the standard of care for treatment of stage III ovarian cancer. Researchers have also looked at initiating treatment with neoadjuvant chemotherapy, in order to decrease the tumor burden, then performing cytoreductive surgery, followed by several more cycles of adjuvant chemotherapy. This format has been compared with the more traditional sequence of surgery followed by adjuvant chemotherapy. Most research has not shown a benefit to the chemo-surgery-chemo format, although some work is looking at whether this format might be applicable to patients who are suspected of having potentially unresectable disease. In this case, current guidelines recommend chemotherapy for three cycles, followed by an interval cytoreductive surgery, and then the final three cycles of chemotherapy. Researchers are also continuing to evaluate the use of a second or interval cytoreductive surgery to be performed after the chemotherapy has had a chance to further decrease the amount of cancer.1

Adjuvant Systemic Therapy

The delivery of cancer treatment following local treatment with surgery is referred to as “adjuvant” therapy and may include chemotherapy, precision cancer medicines, radiation therapy and/or immunotherapy.

Adjuvant chemotherapy is administered to decrease the risk of cancer recurrence following recovery from surgery because treatment with combination chemotherapy prolongs the duration of survival and prevents more recurrences of cancer compared to treatment with alone.1

Current adjuvant therapy typically consists of a taxane and platinum chemotherapy regimen, however several other chemotherapy and precision cancer medicine drugs are available and others are being developed in clinical trials.

Unfortunately, many patients still experience recurrence of their cancer following standard adjuvant therapy, patients and their doctors should discuss participation in clinical trials evaluating new treatment approaches as their initial option.

Intraperitoneal Chemotherapy

Intraperitoneal (IP) chemotherapy delivers chemotherapy directly into the abdominal cavity, where there is the greatest number of cancer cells. The chemotherapy is administered through a large catheter that is placed into the abdomen during the surgery to remove the cancer. This treatment appears to be most effective if surgery or other therapy has already reduced the size of any remaining cancer deposits to less than 1 cm, or about half an inch (this is sometimes referred to as “optimally debulked”).

Among women with optimally debulked Stage III ovarian cancer, a phase III clinical trial compared treatment with intravenous (IV) chemotherapy alone to treatment with both IV and IP chemotherapy. Women who received both IV and IP chemotherapy survived more than a year longer than women who received only IV chemotherapy, but also experienced more severe side effects such as fatigue, pain, and low blood counts.2

According to a statement by the American College of Obstetricians and Gynecologists, “the decision to use IP chemotherapy must be individualized.”2 The combination of IV and IP chemotherapy appears to improve survival among women with optimally debulked Stage III ovarian cancer, but at the cost of increased side effects. Researchers continue to search for ways to reduce side effects and catheter problems among women treated with IP chemotherapy.

Strategies to Improve Treatment

The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Because of the poor prognosis with current treatment, all patients with stage III ovarian cancer should consider participation in a clinical trial. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Active investigation aimed at improving the treatment of ovarian cancer includes the following:

Improvement of Adjuvant Chemotherapy:  Clinical trials are currently ongoing to develop and compare adjuvant chemotherapy treatment regimens in women with Stage II ovarian cancer to improve outcomes.

Development of Precision Cancer Medicines:  Research is ongoing to develop new medications that specifically target cancer cells in clinical trials.  These trials typically require a sample of the cancer or liquid biopsy to be available in order to evaluate for biomarkers. Patients should learn about options to participate in these trials prior to surgery in order to ensure that cancer tissue is obtained correctly. Learn more about development of precision cancer medicines for treatment of ovarian cancer.

PARP Inhibitors: The poly ADP-ribose polymerase (PARP) enzyme plays a role in DNA repair, including the repair of DNA damage from chemotherapy. A new class of 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. The best way to incorporate PARP inhibitors into the overall management of ovarian cancer is being determined however they already have been shown to improve outcomes when used as maintenance therapy following completion of chemotherapy.3,4,5

Avastin® (bevacizumab: A targeted therapy that is showing promise in the treatment of ovarian cancer is Avastin®.6 Avastin slows or prevents the growth of new blood vessels by inhibiting a protein known as VEGF; this deprives the cancer of oxygen and nutrients. Avastin may also improve the delivery of chemotherapy to cancer cells by normalizing blood supply.

Intraperitoneal (IP) Chemotherapy: This treatment approach delivers chemotherapy directly into the abdominal cavity, where there is the greatest number of cancer cells. The chemotherapy is administered through a large catheter that is placed into the abdomen during the surgery to remove the cancer. This treatment appears to be most effective if surgery or other therapy has already reduced the size of any remaining cancer deposits to less than 1 cm, or about half an inch (this is often referred to as “optimally debulked”).

Among women with optimally debulked Stage III ovarian cancer, a phase III clinical trial compared treatment with intravenous (IV) chemotherapy alone to treatment with both IV and IP chemotherapy. Women who received both IV and IP chemotherapy survived more than a year longer than women who received only IV chemotherapy, but also experienced more severe side effects.78

Maintenance Therapy: Consolidation therapy, also called maintenance therapy, refers to extra systemic therapy that is given after completion of standard adjuvant chemotherapy.  Maintenance therapy with Taxol or the PARP inhibitor Zejula (Niraparib) have both been demonstrated to improve outcomes in select patients.3,9

Neoadjuvant Chemotherapy: Neoadjuvant chemotherapy refers to chemotherapy that is given prior to surgery. When surgery is performed after chemotherapy treatment, it is referred to as interval cytoreduction. Some doctors believe that neoadjuvant chemotherapy can reduce the size of the cancer, thereby allowing easier surgical removal and more effective results from the subsequent chemotherapy. Although ongoing work is being done to explore the neoadjuvant chemotherapy-surgery-adjuvant chemotherapy format, current results do not suggest that this format shows an advantage over the more conventional format of surgery followed by adjuvant chemotherapy. There are current clinical trials attempting to further define the answer to this question.

References


1 Armstrong DK, Bundy B, Lenzel L et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. New England Journal of Medicine. 2006;354:34-43.

2 ACOG Committee on Gynecologic Practice. Intraperitoneal chemotherapy for ovarian cancer. Obstetrics and Gynecology. 2008;111:249-251.

3 http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm427554.htm

4 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).

5 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.

6 Genetech. (2016.) FDA Approves Genetech’s Avastin® (Bevacizumab) Plus Chemotherapy for a Specific Type of Advanced Ovarian Cancer. [Press release.] Can be retrieved from https://www.gene.com/media/press-releases/14647/2016-12-06/fda-approves-genentechs-avastin-bevacizu

7 Armstrong DK, Bundy B, Lenzel L et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. New England Journal of Medicine. 2006;354:34-43.

8 ACOG Committee on Gynecologic Practice. Intraperitoneal chemotherapy for ovarian cancer. Obstetrics and Gynecology. 2008;111:249-251.

9 Markman M, Liu PY, Wilczynski S et al. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: A Southwest Oncology Group and Gynecologic Oncology Group trial. Journal of Clinical Oncology. 2003;

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