Patients diagnosed with stage IV or metastatic ovarian cancer have disease that has spread outside the abdomen or into the liver.
A variety of factors ultimately influence a patient's decision to receive treatment of cancer. The purpose of receiving cancer treatment may be to improve symptoms through local control of the cancer, increase a patient's chance of cure, or prolong a patient's survival. The potential benefits of receiving cancer treatment must be carefully balanced with the potential risks of receiving cancer treatment.
The following is a general overview of the treatment of stage IV ovarian cancer. Circumstances unique to your situation and prognostic factors of your cancer may ultimately influence how these general treatment principles are applied. The information on this Web site is intended to help educate you about your treatment options and to facilitate a mutual or shared decision-making process with your treating cancer physician.
Most new treatments are developed in clinical trials. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of this cancer. Clinical trials are available for most stages of cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. To ensure that you are receiving the optimal treatment of your cancer, it is important to stay informed and follow the cancer news in order to learn about new treatments and the results of clinical trials.
Currently, the standard treatment for stage IV ovarian cancer consists of both surgery and chemotherapy. Unfortunately, less than 10% of patients experience long-term survival following standard treatment. This is because stage IV ovarian cancer is difficult to completely remove with surgery and the currently available chemotherapy is unable to eradiate all of the remaining cancer. Both optimal surgical debulking and platinum-based chemotherapy prolong the time to cancer recurrence and improve overall survival.
Surgical Debulking
During debulking surgery, physicians attempt to remove as much of the ovarian cancer as possible. Debulking is beneficial because it reduces the number of cancer cells that ultimately need to be destroyed by chemotherapy and therefore, decreases the likelihood of the cancer developing a resistance to chemotherapy. Initial debulking surgery in ovarian cancer is currently considered the standard of care because clinical studies have shown that "optimally" debulked patients live longer and have a more prolonged time to cancer recurrence than "suboptimally" debulked patients.
Following surgical debulking, all patients with stage IV ovarian cancer are offered additional treatment. This is because the majority of patients will experience recurrence of their cancer even after complete surgical resection. Nearly all patients with stage IV disease have cancer that was not removed by surgery. An effective treatment is needed to eliminate the remaining cancer in order to improve the outcome achieved with surgical removal of the cancer. Currently, this treatment is chemotherapy.
The combination of surgical debulking and chemotherapy is the standard of care for treatment of stage IV ovarian cancer. There is some controversy, however, regarding the timing of surgical debulking. Some doctors recommend a second or interval surgical debulking procedure after the chemotherapy has a chance to further decrease the amount of cancer.
In 1995, doctors from Europe reported in the New England Journal of Medicine the results of the first significant comparative trial directly evaluating interval surgical debulking as part of an overall treatment plan for women with advanced ovarian cancer. In this clinical study, women with stage IIB to IV ovarian cancer were suboptimally surgically debulked at diagnosis. Patients were initially treated with 3 cycles of chemotherapy and then reevaluated. Patients who had no evidence of progressive cancer either received additional debulking surgery or no additional surgery. All patients were then treated with 3 more cycles of chemotherapy.
Women who underwent interval debulking surgery survived longer and experienced a longer time to cancer recurrence than women not treated with interval debulking surgery. On average, women treated with interval debulking survived 26 months, compared to 20 months and were alive without evidence of cancer recurrence for 18 months, compared to 13 months for women not treated with interval debulking. Two years from treatment, 56% of women treated with interval debulking survived, compared to only 46% not treated with debulking surgery. Approximately 15% of patients experienced complications from the interval debulking surgery, although these complications were minor in nature.
This clinical trial demonstrates that women with stage IIB-IV ovarian cancer treated with interval debulking surgery following initial chemotherapy treatment are more likely to live longer and experience a longer time until cancer recurrence than women not treated with interval debulking surgery. Additional confirmatory studies are ongoing to evaluate the role and timing of interval debulking surgery.
Chemotherapy for Stage IV Ovarian Cancer
Regardless of the timing or the necessity of performing interval debulking surgery, combination chemotherapy utilizing one or more anti-cancer drugs is considered "standard" treatment for patients with stage IV ovarian cancer. Clinical trials have demonstrated that for patients with advanced stage ovarian cancer, treatment with combination chemotherapy regimens containing a platinum (Platinol® or Paraplatin®) compound prolongs the duration of survival and prevents more recurrences of cancer compared to treatment with surgery and non-platinum compounds. Current adjuvant chemotherapy typically consists of paclitaxel and a platinum compound administered every 3 weeks for 6-8 cycles.
Unfortunately, fewer than 10% of patients treated with a platinum compound and paclitaxel survive without evidence of cancer recurrence 5 years following treatment. Because many patients still experience recurrence of their cancer following standard therapy, some patients and their doctors consider participation in clinical trials evaluating new treatment approaches as their initial option.
Before deciding to receive adjuvant chemotherapy treatment or to participate in a clinical trial, women should ensure that they understand the answer to 3 questions:
- What is my prognosis (risk of cancer recurrence) without treatment?
- How will my prognosis be improved with treatment?
- What are the risks of treatment?
The combination chemotherapy treatment regimen of cyclophosphamide and Platinol® was the first standard chemotherapy treatment for individuals with advanced ovarian cancer and has been in use for many years. More recently, a new chemotherapy agent, paclitaxel, demonstrated promising anti-cancer activity in the treatment of patients with advanced ovarian cancer.
In order to evaluate whether paclitaxel could be superior to existing chemotherapy treatment approaches, doctors from the Gynecologic Oncology Group performed a clinical study that involved 410 patients with suboptimally debulked ovarian cancers. The patients were randomly assigned to receive treatment with the standard chemotherapy regimen of cyclophosphamide and Platinol® or a new chemotherapy regimen combining paclitaxel with Platinol®. The results of this trial indicated that 73% of patients treated with Platinol® and paclitaxel responded to treatment, compared to only 60% treated with Platinol® and cyclophosphamide. More importantly, patients treated with paclitaxel and Platinol® experienced a longer interval until cancer recurrence and were more likely to be alive 3 years from treatment. However, patients treated with paclitaxel and Platinol® experienced increased side effects including hair loss, suppression of the bone marrow and fever.
The chemotherapy drug Platinol® is associated with significant chemotherapy side effects including nausea, vomiting and nerve damage. A second platinum chemotherapy compound, Paraplatin®, was identified several years ago and appeared to cause fewer side effects than Platinol®. Because of an absence of comparative trials, Paraplatin® was not initially accepted as an equivalent treatment of ovarian cancer.
A large clinical trial conducted in Germany and completed in 1999 compared Platinol® plus paclitaxel to Paraplatin® plus paclitaxel for the treatment of women with advanced ovarian cancer. The results of this clinical trial indicate that there is no significant difference in survival whether paclitaxel is combined with Platinol® or Paraplatin®. Women receiving Platinol®, however, experienced significantly greater side effects from the chemotherapy, including nausea, vomiting and neurological toxicity up to 1 year after treatment. The combination of Paraplatin® plus paclitaxel offers women with ovarian cancer a standard treatment option with fewer side effects than the previous standard of Platinol® and paclitaxel.
The severity of neurotoxicity associated with paclitaxel often prohibits optimal dosing, which may ultimately lead to suboptimal results. Neurotoxicity is the loss of sensation and coordinated movement in extremities, which is permanent and associated with a significant decrease in the quality of life.
Due to the known complications associated with paclitaxel, researchers continue to evaluate different chemotherapy combinations. Recently, researchers from Scotland conducted a multi-center clinical trial comparing paclitaxel/Paraplatin® to the combination of Taxotere® /Paraplatin®. Over 1,000 women with advanced stage ovarian cancer were treated with Paraplatin® combined with either Taxotere® or paclitaxel following surgery. Anti-cancer responses were achieved in 62% of patients receiving paclitaxel, compared to 65% of patients receiving Taxotere®. Early withdrawal from this trial due to side effects of chemotherapy occurred in 12% of patients receiving paclitaxel, versus only 8% of patients receiving Taxotere®. Neurotoxicity following treatment occurred in 80% of patients who received paclitaxel, compared with only 40% of patients who received Taxotere®. Low levels of blood cells were more common with the Taxotere® regimen; however, physicians reported that these patients were adequately managed. One year following treatment, cancer-free survival was equal between the two groups of patients. These results appear to suggest that Taxotere® may be substituted for paclitaxel to reduce side effects without compromising survival; however physicians conducting this trial are waiting for more long-term outcomes.
Despite the development of several new chemotherapy drugs over the past few years, there is no substantial evidence that any of the treatments have increased the number of women cured of ovarian cancer. Some individuals will choose to receive "standard treatment" with paclitaxel and Paraplatin®. For others, participation in clinical studies evaluating novel treatment approaches will be more appealing and may offer the best hope for improving the treatment of ovarian cancer.
Novel Treatment Approaches for Patients with Metastatic Ovarian Cancer
The following are all novel treatment strategies for treatment of ovarian cancer. They are currently being evaluated alone or in combination in clinical studies. Given the poor outcomes of treatment for ovarian cancer, the greatest benefit to patients wishing to pursue aggressive or potentially curative treatments may be participation in clinical studies that combine more than one of the following treatment strategies.
New Chemotherapy Regimens: Adjuvant chemotherapy with a platinum and taxane is currently the standard treatment for stage II ovarian cancer. Several new chemotherapy drugs including Doxil® and Hycamtin® show promising anti-cancer activity when used for the treatment of more advanced ovarian cancer. Development of new multi-drug chemotherapy treatment regimens that incorporate these or other additional anti-cancer therapies for use as adjuvant treatment is an active area of clinical research.
Doxil® provides a different anti-cancer effect than paclitaxel and platinum compounds. In addition, two design modifications of this drug augment the potency of its anti-cancer effects. Doxil® has a slow-release mechanism, meaning small doses of the active drug are constantly being delivered in the body. Additionally, it has been designed to stay in an active form (versus being broken down by the body) for a longer period of time, thereby leading to increased concentrations of the drug in cancer cells.
A clinical trial directly comparing Doxil® and Hycamtin® in recurrent ovarian cancer has demonstrated that Doxil® has significant anti-cancer activity with fewer side effects than Hycamtin®. Clinical trials incorporating Doxil® and other anti-cancer agents into adjuvant treatment regimens are ongoing.
Higher-Dose Chemotherapy: Since conventional-dose chemotherapy appears to cure some women with ovarian cancer and since more chemotherapy kills more cancer cells, the delivery of very high doses of chemotherapy may be able to destroy enough cancer to improve a patient's chance of cure.
Several clinical trials have been performed that evaluate modest increases in the chemotherapy dose of Platinol® and/or cyclophosphamide. Results of these trials have been inconsistent with only 3 of 9 trials demonstrating improved patient outcomes with higher dose therapy. Because the dose of chemotherapy has only been increased 2 to 3 times over standard doses, some doctors believe that an even larger increase in dose will be necessary in order to achieve a more consistent improvement in survival. They advocate utilizing "dose-dense" therapy and/or high-dose chemotherapy and stem cell transplant.
Dose-Dense Treatment: Rapid administration of several different single chemotherapy compounds at the maximum tolerated dose allows higher doses of chemotherapy to be delivered and may prevent cancer cells from developing chemotherapy resistance.
Because dose-dense treatment can cause severed side effects, time-staggered delivery of the chemotherapy agents may decrease the risk of side effects caused by combination chemotherapy, while maintaining optimal anti-cancer effects. One recent clinical trial evaluated a treatment regimen that involved 3 chemotherapy agents delivered in a time-staggered manner for patients with advanced ovarian cancer. The regimen consisted of 4 courses of Platinol® and Hycamtin® followed by 4 courses of Platinol® and paclitaxel. (Patients underwent surgery prior to chemotherapy or in between courses.) Nearly 80% of the women in this trial achieved a complete or partial disappearance of their cancer following treatment. This treatment was generally well tolerated; however, there was one treatment related death.
High-Dose Chemotherapy and Autologous Stem Cell Transplant: Chemotherapy targets and kills rapidly dividing cells such as cancer cells. High- dose chemotherapy (HDC) kills more cancer cells than lower-dose conventional chemotherapy. Unfortunately, HDC also kills more normal cells, especially the blood-producing stem cells in the bone marrow. Stem cells are immature cells produced in the bone marrow, which is the spongy material inside bones. Stem cells eventually become either red blood cells, which provide oxygen to tissues, white blood cells, which fight infection; or platelets, which aid in blood clotting.
HDC destroys cancer as well as bone marrow stem cells. When bone marrow is destroyed, stem cell stores are depleted, which leads to low levels of circulating blood cells. When these cells reach critically low levels, complications such as anemia, infection and bleeding can occur. As these complications could result in death, it is imperative to restore stem cell levels as quickly as possible. Stem cell transplantation is an attempt to restore the blood-producing stem cells after HDC has reduced them to dangerously low levels. In autologous stem cell transplantation, the patient's own stem cells are collected before chemotherapy treatment, frozen, and infused back into the patient after treatment to “rescue” the bone marrow.
Researchers from the Autologous Blood and Marrow Transplant Registry evaluated over 400 women with advanced ovarian cancer who received HDC and autologous stem cell transplantation as part of their treatment. Two years following treatment, the overall survival rate for patients in this study was 35%. There was a subgroup of these patients who had a survival rate of 55% after two years. These women were younger and in otherwise good health, possessed a certain microscopic type of cancer cell (non-clear cell) and were treated with HDC and stem cell transplantation during their first remission. The results from this study indicate patients with advanced ovarian cancer who undergo HDC and autologous stem cell transplant may experience improved survival times, particularly when this treatment strategy is used early in a patient's treatment course.
Neoadjuvant Chemotherapy (before Surgery): Neoadjuvant refers to the administration of anti-cancer chemotherapy prior to surgery. When surgery is performed after chemotherapy treatment, it is referred to as interval debulking. 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.
Researchers from Germany recently conducted a clinical trial evaluating neoadjuvant chemotherapy in 63 patients with stage III ovarian cancer and ascites. Patients were divided into two groups: one group (control group) received standard therapy consisting of debulking surgery followed by chemotherapy, while the other group (treatment group) received three cycles of neoadjuvant chemotherapy followed by standard debulking surgery and chemotherapy.
The rate of complete cancer removal was 32% in the group of patients who received neoadjuvant chemotherapy, compared to only 13% in the group of patients who only received standard debulking surgery and chemotherapy. Importantly, this transferred into improved survival, with patients who received neoadjuvant therapy surviving on average 42 months after treatment, compared to only 23 months for patients who received standard debulking surgery and chemotherapy. There was no difference between the two groups in time spent in surgery, blood transfusion requirements, side effects or mortality during surgery. The results of this clinical trial suggest that neoadjuvant chemotherapy may significantly improve survival in patients with stage III ovarian cancer. More research is currently underway to confirm these results in larger clinical trials.
Intraperitoneal Therapy: Another treatment approach currently under evaluation is the use of intraperitoneal therapy for patients with advanced ovarian cancer. This treatment approach delivers the therapy directly into the abdominal cavity, where there is the greatest number of cancer cells. Intraperitoneal therapy involves the delivery of therapy 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 inch. In an attempt to improve survival rates, chemotherapy, biological response modifiers and other agents are being tested in clinical trials evaluating intraperitoneal therapy.
A clinical trial conducted by the U.S. Intergroup directly compared intravenous cyclophosphamide-Platinol® to intravenous cyclophosphamide and intraperitoneal Platinol® in patients with optimally debulked stage III ovarian cancer. Patients treated with intraperitoneal Platinol® were more likely to survive without evidence of cancer recurrence an average of 8 months longer than patients treated with standard intravenous Platinol®. A second clinical trial has directly compared intravenous paclitaxel-Platinol® to the combination of intravenous paclitaxel-Paraplatin® followed by intraperitoneal Platinol® in patients with optimally debulked stage III disease. Preliminary results suggest that the addition of intraperitoneal Platinol® improved the chance of being free of cancer by several months. Patients who receive the intraperitoneal chemotherapy have more side effects, including low blood counts and infections.
Biological Response Modifiers: Biological response modifiers are naturally occurring or synthesized substances that direct, facilitate or enhance the body's normal immune defenses and are being evaluated as intraperitoneal therapy. Biologic response modifiers include interferons, interleukins, vaccines and monoclonal antibodies.
Interferon Gamma: In 1996, doctors in France observed that patients with ovarian cancer whose cancer had progressed following chemotherapy responded to intraperitoneal interferon gamma. In that clinical trial, 32% of patients experienced an anti-cancer response and 23% of these were complete responses. All responses were documented by a second-look surgical operation.
Doctors in Austria have recently reported the results from another clinical trial evaluating intraperitoneal administration of interferon gamma. In this study, 148 patients with stage IC-IIIC ovarian cancer were treated with Platinol® and cyclophosphamide and then randomly assigned to receive either gamma interferon 6 days out of each monthly cycle of chemotherapy or to receive no further treatment. Complete anti-cancer responses were observed in 68% of patients who received gamma interferon and more than half of the patients who received gamma interferon were alive without cancer progression three years following treatment, compared to only 38% of patients who received no gamma interferon. This study shows that gamma interferon improves the efficacy of primary chemotherapy for patients with advanced ovarian cancer. Undoubtedly, gamma interferon will be evaluated in combination with newer drug regimens that include paclitaxel and Paraplatin®.
Proleukin® Therapy: Proleukin® is a biological modifier that has been used extensively to treat others cancers. Recently, phase I studies in women with ovarian cancer whose disease progressed following Platinol®-based chemotherapy have established a dose and schedule of Proleukin® that can be administered intraperitoneally. In this phase I study, 6 of 35 women (17%) achieved a complete remission and the overall response rate was 26% with intraperitoneal Proleukin® alone. Several trials are now ongoing to confirm this observation and to use this approach for consolidation treatment after achieving a complete remission.
Ethyol®: Because chemotherapy produces significant side effects, there is great interest in developing compounds that protect normal cells from chemotherapy damage. An additional advantage of reducing chemotherapy side effects is that the maximum amount of chemotherapy can be utilized to treat the cancer, as side effects often necessitate a dose reduction. Ethyol® is a compound that protects some organs from side effects of chemotherapy drugs and has been approved by the Food and Drug Administration for use with Platinol®. Clinical trials are evaluating the use of Ethyol® in combination with other chemotherapy agents in patients with advanced ovarian cancer.
Consolidative Radiation Therapy: Common treatments utilized after successful surgical debulking include radiation therapy that is delivered to the entire abdomen from an external machine or the administration of a radioactive suspension directly into the abdomen. For a variety of reasons, primary chemotherapy drugs after surgical debulking have replaced radiation therapy since chemotherapy appears to be more effective for treating larger deposits of cancer with less severe side effects. Some centers are investigating whether the addition of radiation therapy after chemotherapy can improve cure rates in comparison to chemotherapy alone. The use of radiation therapy for patients who appear to have responded completely to surgical debulking and chemotherapy is an area of active investigation.
Gene Therapy: Gene therapy involves the manipulation of genes in order to correct or override the abnormal alterations that cause cancer. This can be accomplished by replacing or inactivating a dysfunctional gene or replacing or inserting a functional gene.
Many different types of cancers develop due to a mutation (alteration) in a certain gene called the p53 gene. This gene, sometimes called the “cell suicide” gene, keeps normal cell replication under strict control. If there is an abnormality in a cell, the p53 gene normally stops replication of this damaged cell, thereby inhibiting further progression to cancer. However, in cells that have a mutation within their p53 gene, there is no restraint on abnormal replication, leading to uncontrolled, rapid growth of the cells - the hallmark trait of cancer.
Researchers from the University of Iowa have reported that using gene therapy in select patients with recurrent ovarian cancer may significantly improve survival. In a recent clinical trial, 36 patients with advanced ovarian cancer received gene therapy treatment involving a manipulated virus to deliver a functional p53 gene. All of the patients had received multiple courses of standard treatment prior to these clinical trials. Patients in the trial received multiple courses of gene therapy in combination with chemotherapy. Almost half of the patients who received gene therapy showed a significant regression of their cancer. One-quarter of the patients were still alive almost 20 months following treatment. This appears to be a significant improvement in survival over standard therapies for patients with recurrent ovarian cancer. Future clinical trials will be conducted to directly compare this gene therapy strategy to current standard treatments for ovarian cancer, in order to further define treatment outcomes.
Epidermal Growth Factor Receptor (EGFR) Inhibitors: Epidermal growth factor receptors (EGFR) are small proteins that are found on the surface of all cells. EGFR binds exclusively to small proteins circulating in the blood called growth factors. The binding action between EGFR and growth factors stimulates biological processes within the cell to promote growth of a cell in a strictly controlled manner. However, in many cancer cells, EGFR is either abundantly overexpressed or the EGFR biological processes that normally stimulate cell growth are constantly active, leading to the uncontrolled and excessive growth of the cancer cell.
EGFR inhibitors block the EGFR pathway, thereby halting excessive cellular growth by inhibiting the EGFR process within a cell. Several EGFR inhibitors have been developed and are currently being evaluated in clinical trials. OSI-774 is a novel therapeutic agent that blocks the EGFR pathway. Clinical trials are currently underway evaluating OSI-774 in a variety of cancers. Recently, a multi-institutional clinical trial was conducted evaluating OSI-774 in 30 patients with advanced ovarian cancer who had stopped responding to standard therapies. All patients in this study overexpressed EGFR. Eight weeks following treatment with OSI-774, 15 patients achieved a stabilization of their cancer and 3 patients achieved a 50% or greater reduction in their cancer. These results indicate that OSI-774 has anti-cancer activity when used as a single agent in some patients with advanced ovarian cancer.
Combined Approaches: Combining one or more new strategies may offer the greatest hope for patients. For example, a patient could receive dose-dense induction chemotherapy, followed by interval debulking and high-dose chemotherapy and autologous stem cell transplant, which together should produce the highest chance of achieving a complete remission. Patients in remission could then receive additional treatment with anti-cancer agents, such as maintenance chemotherapy or other biologic agents. Many combinations are being evaluated in clinical trials.
When Deciding on Treatment, Patients Should Ask the Following Questions:
Is there any evidence that the new treatment may be an improvement over conventional treatment? Since over 50% of patients with stage IV disease may experience cancer recurrence, it may not be useful to compare the response rate to chemotherapy, the average duration of survival or time to relapse.
Instead, when evaluating treatment strategies, patients may want to compare the percentage of patients surviving with or without relapse 3-5 years from treatment to determine whether a treatment is truly more effective.
What is known about the risks or side effects of the new treatment? It is important to understand that patients experience more side effects with each treatment they receive. Since few patients with metastatic cancer are cured with standard initial treatment, prolonging the decision to receive a new treatment may result in greater side effects and a lesser chance of benefit.
|
