Patients who have been diagnosed with ovarian cancer may have persistent, refractory or recurrent cancer following treatment with surgery and first-line chemotherapy. Persistent cancer refers to residual cancer growths or cells that persist during and following initial treatment. Patients who have achieved complete remission following initial therapy and who subsequently experience a return of cancer cells after treatment are said to have relapsed or recurrent cancer. Patients with ovarian cancer who experience progression or continued growth of the cancer during treatment are said to have refractory cancer. Patients with persistent, recurrent or refractory ovarian cancer can benefit from additional treatment with second-line therapy, which is often referred to as salvage therapy. A patient’s treatment options will differ depending on whether the cancer is persistent, recurrent or refractory.
A variety of factors ultimately influence a patient’s decision to receive second-line treatment of ovarian 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 second-line or salvage treatment of 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.
Recurrent or persistent ovarian cancer may be detected by several methods. Some patients will experience abdominal swelling, pain or symptoms related to the spread of cancer cells (metastases) to the bone, liver, or brain. Other patients may simply have an increase or persistent elevation in the CA-125 level, a blood test commonly used to monitor ovarian cancer activity. When an increase in the CA-125 occurs, most patients will undergo ultrasound or CT scanning of the abdomen and pelvis or other diagnostic procedures in order to determine the location of recurrent cancer. The availability and effectiveness of additional treatment depends on the kind of chemotherapy previously administered, the duration since last treatment and the extent of recurrent cancer.
Despite recent improvements, initial or first-line chemotherapy fails to produce a remission in more than 70% of patients with ovarian cancer. Furthermore, approximately 40-50% of the women who do achieve a remission after first-line chemotherapy will experience a recurrence of cancer within 3 years. Patients who have failed initial surgery and first-line chemotherapy for ovarian cancer are broadly divided into three groups: those with persistent ovarian cancer, recurrent ovarian cancer or refractory ovarian cancer. Currently available salvage chemotherapy can often prolong survival, but is rarely curative. The treatment option that may offer the greatest benefit to patients who wish to pursue aggressive or potentially curative treatments may be participation in clinical studies that are evaluating new and innovative treatment strategies.
Persistent Ovarian Cancer
Patients with persistent ovarian cancer have cancer cells that are detected after initial surgery and first-line chemotherapy. Persistent ovarian cancer is detected either by an elevated CA-125 blood level, abnormal x-rays and CT scans, or with a biopsy performed during second-look laparotomy.
Individuals with persistent ovarian cancer following first-line chemotherapy have a number of treatment options. Additional debulking surgery to remove as much persistent cancer as possible may be considered before resuming further treatment. Further treatment is still necessary since undetectable microscopic deposits of cancer can still exist and cause recurrences even after successful debulking surgery. Patients may elect to receive treatment with additional standard chemotherapy; however, some doctors feel that patients with persistent cancer should receive a different treatment or consider participation in a clinical trial.
Continued Standard Chemotherapy: The standard course of initial chemotherapy is approximately 6 cycles, or about 4 months of treatment. If, after 6 cycles, there is a small amount of persistent cancer, some doctors feel further chemotherapy treatment for 10 or 12 cycles may continue to cause shrinkage of the cancer. Some patients may achieve a complete remission with continued standard chemotherapy.
Second-Line Chemotherapy: Not all patients are able to undergo secondary debulking surgery or are expected to improve with continued treatment with a first-line chemotherapy regimen. Salvage or second-line chemotherapy with other anti-cancer drugs that destroy cancer cells by a different mechanism may provide additional benefit over the continuation of first-line chemotherapy. For more information of available salvage chemotherapy regimens, please see the section on ” Salvage Chemotherapy” below.
Recurrent Ovarian Cancer
Patients with recurrent ovarian cancer have experienced a period of “remission” following initial surgery and first-line chemotherapy, but have subsequently developed a cancer recurrence. Both the effectiveness and type of available therapy depends on the first-line chemotherapy received, the length of time since finishing treatment and the extent of recurrent cancer.
In general, salvage chemotherapy treatment is used to improve a patient’s quality of life by reducing symptoms of recurrent cancer. Certain patients can derive significant benefit from additional treatment. Salvage chemotherapy is typically associated with lower response rates and a shorter duration of remission than first-line chemotherapy. The average duration of survival after recurrence of ovarian cancer is about 12 to 18 months. Fewer than one in ten patients survive beyond 5 years following standard salvage chemotherapy treatment.
The length of time between the completion of first-line chemotherapy and the development of recurrent cancer affects treatment options. Patients who develop recurrent cancer more than 6 months after first-line chemotherapy can experience another remission following treatment with the identical first-line chemotherapy that was previously used. Patients who develop recurrent cancer within 6 months from first-line chemotherapy are less likely to improve with the same anti-cancer drugs and should consider treatment with a different chemotherapy regimen. All patients with recurrent cancer should also consider participating in clinical trials.
Recurrence after 6 Months from Therapy
Patients who develop recurrent cancer more than 6 months after first-line chemotherapy or have not been treated with platinum and taxane chemotherapy have a good chance of improving with these drugs. Debulking surgery to remove as much cancer as possible may be considered before resuming chemotherapy treatment. The length of time between the completion of first-line chemotherapy and the development of recurrent disease can help determine whether additional treatment with a taxane and platinum will be effective in shrinking recurrent cancers. Over half of patients who develop a recurrence longer than 12 months from initial treatment are likely to improve with further chemotherapy, compared with less than half of patients who develop a recurrence between 6 and 12 months from initial treatment.
Not all patients will improve following re-treatment with taxane and platinum chemotherapy. Some patients are also unable to receive these anti-cancer drugs due to limiting side effects. Patients unlikely to benefit are typically offered salvage or second-line chemotherapy with one or more of many available anti-cancer drugs. They may also consider participating in a clinical trial.
For individuals with recurrent ovarian cancer, Doxil®, Hycamtin® and Gemzar® chemotherapy have been shown to be effective in producing responses and prolonging survival time. Recent findings of a comparison study of Hycamtin® and Doxil® suggest that Doxil® improves survival in selected patients, is more convenient to receive and is associated with fewer side effects than Hycamtin®.
Researchers from 71 different medical centers treated 474 women with ovarian cancer that had recurred after platinum-based chemotherapy. Patients received treatment with either Hycamtin® or Doxil®. In patients with platinum-resistant disease, the response rates were 7% in those receiving Hycamtin® and 12% in those receiving Doxil®. The average survival time was 51 weeks for Hycamtin® and 53 weeks for Doxil®. However, patients with cancer that was still responsive to platinum survived on average 83 weeks if treated with Doxil®, compared to 63 weeks if treated with Hycamtin®.
The side effects of the treatments were also quite different. Hycamtin® produced more severe damage to the bone marrow, causing lower blood cell counts than Doxil®; therefore, patients receiving Hycamtin® were more likely to require additional treatment with growth factors and to receive blood and platelet transfusions. Twenty-five percent of patients treated with Doxil® had severe tingling, burning, redness, swelling and blistering of the hands and were also more likely to develop mouth sores, but were much less likely to experience hair loss. Three patients treated with Hycamtin®, compared with no patients in the Doxil® group, died of treatment-related complications. The researchers noted that Doxil® was easier to administer, with only 6 infusions over 6 months compared with 40 infusions of Hycamtin®, and that patients taking this agent were better able to maintain a “normal” life during treatment.
Gemzar® is another chemotherapy agent that has been reported to produce anti-cancer responses in 11%-28% of patients with recurrent ovarian cancer. Although single agent Gemzar® appears very active, combinations of other chemotherapy drugs and Gemzar® have even greater anti-cancer activity.
Recurrence within 6 Months from Therapy
Patients who develop recurrent cancer within 6 months from first-line therapy are less likely to improve with additional treatment that utilizes the same first-line chemotherapy drugs. In general, patients with recurrent ovarian cancer that occurs shortly after initial therapy have few standard treatment options. Most patients will have already received taxane and platinum chemotherapy, and are considered resistant to these drugs. Certain patients can derive significant benefit from additional treatment with salvage or second-line chemotherapy or from participation in a clinical trial designed to evaluate promising new treatment strategies.
Role of Surgery
Typically, women who have ovarian cancer are initially treated with surgery, followed by chemotherapy or radiation therapy. If the cancer recurs (returns) after treatment, a combination of chemotherapy drugs is often used to increase survival time and relieve the symptoms of the cancer. More recently, researchers in California have reported that the use of a second surgery plus chemotherapy (and radiation therapy in some) to treat recurrent ovarian cancer may prolong survival times.
In this clinical study, 106 women who experienced a recurrence of ovarian cancer 6 months or more after their initial treatment received additional therapy. The treatment for recurrent cancer consisted of a second surgery to remove all visible cancer. In addition, 40% of the patients received chemotherapy before the surgery, and the other 60% received chemotherapy after the surgery. Some patients also received radiation therapy after the surgery. The results of this study showed that surgeons were able to remove all visible cancer in 82% of patients. After the surgery, 3% of patients had small amounts of residual cancer remaining and 15% had large amounts of residual cancer remaining. The average survival time with this treatment regimen was 36 months, with a 5-year survival rate of 28%. Women who had a long interval between initial treatment and the cancer recurrence had better outcomes, as did those who had only small amounts of visible cancer at the time of the second treatment. Side effects of treatment included 2 deaths from treatment-related complications.
The researchers concluded that women who have a second surgery to treat recurrent ovarian cancer appear to have a longer survival time than those who receive only chemotherapy and/or radiation therapy without additional surgery.
A number of newer chemotherapy drugs have demonstrated an ability to kill cancer cells even when first-line chemotherapy is ineffective. Salvage chemotherapy may consist of single chemotherapy drugs or combinations of anti-cancer therapies. When one chemotherapy drug stops killing cancer cells, sometimes switching to a different anti-cancer drug is effective. In general, the chances of remission become smaller and smaller as drugs are changed, yet the potential side effects continue to increase with each new drug.
Doxil®: By packaging the anti-cancer drug doxorubicin in tiny liposomes, the drug is less likely to be broken down by the body and is more likely to reach cancer cells. A number of clinical studies have evaluated the use of Doxil® in patients who are resistant to paclitaxel and Platinol® chemotherapy. Doxil® has been directly compared to Hycamtin® and found to have equivalent or improved survival with fewer side effects than Hycamtin®
Gemzar®: Gemzar® has demonstrated significant anti-cancer activity in patients who are resistant to taxanes and platinum chemotherapy. Gemzar® appears to have similar anti-cancer activity to Doxil® and Hycamtin®, but may be associated with fewer side effects. Additionally, the combination of Gemzar® and Platinol® appears to kill more cancer cells than each drug given alone. Doctors have reported that the combination has produced a partial or complete disappearance of cancer in 69% of patients.
Etoposide: Etoposide is an anti-cancer drug that can be taken orally. In a clinical trial conducted by the Gynecologic Oncology Group, over 25% of patients whose cancer was resistant to Platinol® experienced a remission following treatment with etoposide.
Hycamtin®: A number of clinical studies have evaluated the use of Hycamtin® in patients who are resistant to Platinol®. About 14% of Platinol®-resistant patients achieved remission following treatment with Hycamtin®, indicating that it might be an effective treatment option for these patients.
In a clinical study conducted in Europe, Hycamtin® was directly compared with paclitaxel in patients who were resistant to Platinol®. Hycamtin® was at least as effective as paclitaxel for killing cancer cells and producing cancer shrinkage. Over half of the patients who received Hycamtin® survived at least one year from the start of the clinical trial.
Strategies to Improve Treatment
The following are all new treatment strategies for treatment of ovarian cancer. Clinical trials are currently underway to evaluate these strategies alone or in combination. 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.
Phase I Trials: New chemotherapy drugs continue to be developed and evaluated in patients with recurrent cancers in phase I clinical trials. The purpose of phase I trials is to evaluate new drugs in order to determine the best method for administering the drug and whether the drug has any anti-cancer activity in patients.
Monoclonal Antibodies: Monoclonal antibodies can be produced in a laboratory and are able to identify specific proteins on the surface of certain cells and bind to them. This binding action stimulates the immune system to attack and kill the cells to which the monoclonal antibody is bound.
OvaRex® is a monoclonal antibody that has been designed to identify and bind to CA 125, a protein found on the surface of most ovarian cancer cells. Researchers from the Vancouver Cancer Center recently conducted a clinical trial evaluating OvaRex® in 13 patients with advanced ovarian cancer who had failed multiple treatments. Over half of the patients in this study demonstrated a significant immune response to treatment. Following treatment with OvaRex®, one patient survived more than 18 months and two patients are still alive after almost two years.
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. Dose-dense treatment approaches are being evaluated in clinical trials.
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.
Since 1983, physicians in France have been evaluating high-dose chemotherapy as a treatment for ovarian cancer and recently presented their cumulative experience in utilizing this treatment. In this clinical study, 181 women with advanced stage III or IV ovarian cancer were treated with high-dose chemotherapy after primary debulking surgery and 6 cycles of platinum chemotherapy. Several different high-dose chemotherapy regimens were utilized. The treatment was reasonably well tolerated, with a mortality rate of 2.5%. At 5 years from initiation of treatment, 36% of patients survived and 23% survived without evidence of cancer progression. Patients who achieved optimal surgical debulking and were subsequently treated with high-dose chemotherapy had a 5-year survival rate of 51%. The researchers concluded that high-dose chemotherapy treatment for ovarian cancer is feasible, safe and may be superior to conventional chemotherapy treatment approaches.
Doctors at MD Anderson Cancer Center in Texas recently reported the results of a clinical trial designed to incorporate Hycamtin® into a high-dose chemotherapy treatment regimen that also utilized cyclophosphamide and Alkeran®. In this treatment program, patients whose cancer had returned or progressed following initial treatment for ovarian cancer were enrolled to determine the optimal dose of Hycamtin® that could be delivered in combination with cyclophosphamide and Alkeran®. All patients received the high-dose chemotherapy treatment supported by peripheral blood stem cells with acceptable side effects. Almost 92% of these patients who had previously failed therapy experienced a partial or complete disappearance of their cancer following treatment. This represents significant anti-cancer activity and the physicians will continue to evaluate the 3-drug combination of Hycamtin®, cyclophosphamide and Alkeran® in patients with advanced ovarian cancer. The doctors in France, as well as other countries, are currently conducting clinical trials that directly compare high-dose chemotherapy to standard or conventional-dose chemotherapy treatment programs.
Biological Modifier Therapy: Biological response modifiers are naturally occurring or synthesized substances that direct, facilitate or enhance the body’s normal immune defenses. Biologic response modifiers include interferons, interleukins, vaccines and monoclonal antibodies. In an attempt to improve survival rates, these and other agents are being tested alone or in combination with chemotherapy in clinical trials.
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 (into the abdominal cavity). 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.
Nolvadex®: Nolvadex® is a hormonal agent that blocks some of the actions of the female hormone estrogen. Some patients who are resistant to Platinol® will experience cancer shrinkage with Nolvadex®. The advantage of Nolvadex® is that it is taken by mouth and has minimal side effects.
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