The standard treatment approach in almost all patients with ovarian cancer is maximal surgical resection, followed by combination chemotherapy.
Optimal resection is considered less than 1 cm of tumor remaining in the pelvic cavity after surgery. This has been shown to be an independent predictor of survival. For chemotherapy, the platinum agents are the cornerstone of ovarian cancer treatment, and whether the disease is platinum-sensitive or platinum-resistant is also an important determinant of long-term survival.
The initial goal of treatment for stages I, II, and III is cure, although many of these patients will have recurrent disease with currently available therapies. Stage IV ovarian cancer is not curable, therefore, improved survival and symptom management are the goals of therapy.
Common Treatment Options
Surgery is recommended for ALL stages of ovarian cancer. With many types of cancer, stage IV disease (distant spread) does not benefit from surgical resection of the primary tumor. With ovarian cancer, however, maximal reduction of the amount of tumor in the pelvis is key to long-term survival, even when complete cure is not possible.
As mentioned, optimally, less than 1 cm of tumor should remain in the pelvis after surgery. For patients with stage IA and IB disease, only surgery is required. All other patients have at least a 30% risk of recurrence after surgery and are referred for combination chemotherapy as described below.
In addition to removal of the ovaries, usually a total abdominal hysterectomy, including removal of the fallopian tubes, is done at the time of surgery. This allows examination of these organs for tumor. In addition, biopsies are taken from all peritoneal surfaces and pelvic lymph nodes and are sent for pathologic examination.
If any of these organs are positive for ovarian cancer, the patientís stage changes. Bowel resections and/or removal of the spleen may be done in some cases. In all cases, it is recommended that a gynecologic oncologist (rather than a general surgeon) perform the surgery. Recent clinical trials have shown that this alone leads to improved survival.
If the patient has stage I disease, is young, and still desires to have children, then removal only of the affected ovary can be done. Close monitoring after surgery for cancer relapse is critical. In these select patients, less invasive laparoscopic surgery may be performed.
In addition to the above surgical therapies, which are designed to prolong survival and potentially cure patients, there are a number of palliative surgical options in ovarian cancer. These are directed at relieving symptoms from large amounts of tumor in the abdominal and pelvic cavities.
Palliative procecures are often done after patients have ovarian cancer recurrence and are refractory to chemotherapy. Examples include: removal of fluid in the abdomen (with or without a drain implanted), stents in the ureters to improve renal function, surgery to relieve a small bowel obstruction, and PEG tubes to aid in nutrition.
Chemotherapy following surgery is recommended for all patients with stage IC, II, III, and IV ovarian cancer. It is also recommended for some patients with stage IA or IB/grade II or III tumors. Three to six cycles are given for stages I and II; six to eight cycles for stages III and IV.
Maintenance chemotherapy with single-agent paclitaxel for an additional 12 months is recommended in high-risk patients who achieve a complete response after six cycles of combination chemotherapy. Patients who are not initially surgical candidates due to the bulk or location of the tumor may receive so-called neoadjuvant chemotherapy for several cycles before surgery, to try and increase the likelihood of maximal surgical resection.
There are many drugs with significant activity in ovarian cancer. They include the following:
- Platinum Agents: Cisplatin, Carboplatin, Oxaliplatin
- Other Alkylating Agents: Cyclophosphamide, Ifosfamide, Melphalan
- Taxanes: Paclitaxel, Docetaxel
- Liposomal Doxorubicin
- Topotecan and Irinotecan
- Oral Capecitabine, Etoposide, and Altretamine
Chemotherapy may be administered as a single agent. However, the more usual approach for first-line treatment is to give combinations of agents. The most common combination chemotherapy regimens for ovarian cancer are listed below. These are all repeated in cycles every three to four weeks:
- Carboplatin + paclitaxel
- Carboplatin + docetaxel
- Carboplatin + gemcitabine
- Cisplatin + paclitaxel
- Cisplatin + gemcitabine
- Cisplatin + cyclophosphamide
- Oxaliplatin + docetaxel
Although cisplatin + cyclophosphamide was the gold standard for many years, it can cause a tremendous amount of nausea/vomiting, kidney failure, periperhal neuropathies (tingling in the hands and feet), and impaired hearing.
Carboplatin plus paclitaxel is currently considered the standard first-line regimen for the majority of patients due to diminished toxicity and superior efficacy. Other regimens may be chosen based upon expected side effects in individual patients.
The average time of remission following chemotherapy is over a year. If and when patients have ovarian cancer recurrence, they will often be able to tolerate additional chemotherapy.
Patients who relapse more than six months after initial treatment may be re-treated with a platinum-containing regimen. Patients who relapse less than six months after primary treatment are considered to be resistant to the platinum agents and paclitaxel and are most often treated with single agent liposomal doxorubicin or topotecan. No agent or regimen has shown superiority as second-line or salvage therapy. Patients who fail to respond to two different salvage regimens are unlikely to respond to any additional chemotherapy and should be considered for participation in a clinical trial or for palliative care.
Note that patients receiving chemotherapy for ovarian cancer relapse are at increased risk of bone marrow suppression. White blood cell colony-stimulating factors such as G-CSF may be considered to decrease the risk of infections. In addition, if patients receive multiple cycles of platinum agents, they are at risk of developing severe allergic reactions.
Although radiation therapy plays a crucial role in the management of many cancers, itís role as first line treatment of ovarian cancer is limited. If used, the usual approach is whole abdominal radiation, which can lead to significant toxicity to adjacent pelvic organs, such as the bladder and bowel. Patients with low-bulk, stage III disease may receive consolidation radiation after chemotherapy.
Radiation therapy does play an important part in the palliative management of ovarian cancer. Patients with advanced disease with bone or brain metastases often experience significant symptomatic relief with radiation to those areas. Toxicity from this type of limited field radiation therapy is minimal.
Intraperitoneal (IP) chemotherapy refers to the administration of chemotherapy into the peritoneal cavity through a surgically implanted catheter. The potential benefit in ovarian cancer is delivery of the chemotherapy directly to the site of action.
The most benefit has been seen in stage III patients who have less than 1 cm of tumor remaining after surgery. In these patients, survival may be increased by as much as 16 months over older regimens of intravenous chemotherapy. The cost unfortunately is more side effects, primarily abdominal pain, catheter complications such as infection, and nausea/vomiting/dehydration.
Most common regimen (repeated every 3 weeks for 6 cycles) is:
- Intravenous paclitaxel on day 1
- Intraperitoneal cisplatin in day 2
- Intraperitoneal paclitaxel on day 8
Note that in studies, only 42% of patients were able to tolerate all six cycles compared to over 80% who received intravenous chemotherapy only. In addition, there are currently no head-to-head trials with carboplatin plus paclitaxel, the favored first-line intravenous combination regimen.
Patients who should NOT receive IP therapy include those with stage IV disease, comorbidities which could be aggravated by chemotherapy (e.g., pre-existing peripheral neuropathy), or advanced age. To receive IP chemotherapy, patients must have normal renal function and adequate performance status.
BONE MARROW TRANSPLANT
Bone marrow transplant (BMT) is also called hematopoietic stem cell transplant. The most common procedure is autologous BMT, in which the patientís own blood stem cells are harvested, then re-infused following very-high-dose chemotherapy.
The rationale in ovarian cancer is that this is a very chemo-sensitive cancer and that drug resistance is common. High doses of chemotherapy, therefore, may be able to overcome resistance and cure more patients.
Initial trials done in stage III and IV patients appeared to show prolonged survival. However, large randomized trials comparing BMT to conventional salvage chemotherapy have not demonstrated a survival advantage.
Patients live longer if they have platinum-sensitive disease at the time of transplant. Currently, BMT is still considered an experimental treatment and should be considered only in the context of a clinical trial.
A drug therapy option for symptom management in patients who are refractory to chemotherapy or who cannot tolerate chemotherapy is hormonal therapy. Hormonal agents block the activity of or decrease the synthesis of endogenous estrogen, which is a growth factor for many ovarian cancers.
Hormonal agents lack the severe side effects associated with chemotherapy and are often administered orally, which is convenient for patients. Most of these drugs are more commonly known as treatments for breast cancer. Tamoxifen blocks the effects of estrogen on ovarian cancer cells. Anastrozole, letrozole, exemestane, and leuprolide all decrease the synthesis of estrogen in the body. The most common side effect of this class of drugs is hot flashes. These treatments are palliative not curative.
CLINICAL TRIALS AND NOVEL TREATMENTS
One of the most promising novel treatments for ovarian cancer is antiangiogenesis therapy. Drugs are given that inhibit blood vessel formation by the tumor, leading to cancer cell death and decreased spread of the tumor to distant organs. The most studied antiangiogenesis agent in ovarian cancer is bevacizumab.
This is a monoclonal antibody targeting vascular endothelial growth factor (or VEGF). Response rates are as high as 35% in patients who have failed multiple chemotherapy regimens. Toxicity may be significant, with a risk of hypertension, blood clots, hemorrhage, and GI perforation. Trials in combination with chemotherapy are ongoing.
Other antiangiogenesis agents being studied in ovarian cancer include oral agents such as sorafenib, sunitinib, and thalidomide. These agents may be given as monotherapy or in combination with chemotherapy as well.
HER2 is a cell surface receptor found on many cells. It is over-expressed on 20% of breast cancers and 15 to 30% of ovarian cancers. Several anti-HER2 therapies are approved in the U.S. for the treatment of breast cancer. These include the monoclonal antibody trastuzumab and lapatinib, which is a HER-2 tyrosine kinase inhibitor. Both of these agents are currently under investigation in ovarian cancer.
Vorinostat and belinostat are histone deacetylase inhibitors. Histone deacetylases breakdown proteins inside of cells. Many cancers have more histone deacetylases than normal cells, which leads to altered protein metabolism, resistance to apoptosis (cell death).
Vorinostat and belinostat lead to accumulation of acetylated histone proteins, which results in cell cycle arrest and apoptosis. These drugs are being studied as treatment options for many solid tumors, including ovarian cancer.