The management of ovarian cancer entails a complex blend of medicaland surgical interventions. Managing patients with recurrent ovariancancer increases the complexity of therapies and adds palliative interventions.The presence of recurrent ovarian cancer is both emotionally andphysically taxing for patients as well as their caregivers. With an increasinglyinformed patient population, a balance must be achieved betweeneasily accessible information enabling patients to know that they nowhave an incurable disease and support for their hopes and desires to stillovercome their cancer. The decision tree in the management of recurrentovarian cancer blends many different factors. This discussion will separatethose factors as if they are pure elements. We will address managementbased on response to primary therapy and time to recurrence, thelocation of recurrence, symptoms of recurrence, the patient’s histopathology,and the patient’s primary stage as it relates to the extent of diseasepresent at the start of chemotherapy.
The management of ovarian cancer entails a complex blend of medical and surgical interventions. Managing patients with recurrent ovarian cancer increases the complexity of therapies and adds palliative interventions. The presence of recurrent ovarian cancer is both emotionally and physically taxing for patients as well as their caregivers. With an increasingly informed patient population, a balance must be achieved between easily accessible information enabling patients to know that they now have an incurable disease and support for their hopes and desires to still overcome their cancer. The decision tree in the management of recurrent ovarian cancer blends many different factors. This discussion will separate those factors as if they are pure elements. We will address management based on response to primary therapy and time to recurrence, the location of recurrence, symptoms of recurrence, the patient’s histopathology, and the patient’s primary stage as it relates to the extent of disease present at the start of chemotherapy.
The incidence of ovarian cancer has remained fairly steady over the past decade, with more than 22,000 newly diagnosed cases predicted in the United States in 2005. Unfortunately, 60% to 70% of women will be diagnosed with advancedstage disease due to lack of specific symptoms as well as effective screening. For these reasons, ovarian cancer is the fifth leading cause of cancerrelated mortality in women, associated with more than 16,000 deaths per year. The current standard of care for women with advanced ovarian cancer is cytoreductive surgery followed by adjuvant platinum-based chemotherapy. The most commonly employed regimen in the United States is carboplatin and paclitaxel, which produces an expected response rate of 70% to 80%.[2,3] Unfortunately, up to 75% of patients with advanced ovarian cancer will develop a recurrence following initial treatment and require subsequent therapy.
A paradigm shift has occurred over the past decade, with many physicians now viewing the treatment of recurrent epithelial ovarian cancer as management of a chronic disease. Certainly there are patients who do well from the start and experience long-term cures or long disease-free intervals. Additionally, there is a small group who progress during first-line chemotherapy and have a relatively short overall survival. However, the majority of women will develop recurrent ovarian cancer at varying intervals, with symptoms that wax and wane in response to repetitive cycles of various chemotherapeutic agents. During the course of their disease, these women will display a variety of symptoms related to disease in their abdomen, as well as more distant sites.
In this article, we will review the literature regarding the management of recurrent disease. Additionally, we will share our own approach to therapeutic decisions based on initial tu- mor characteristics and treatment, symptoms of disease, and toxicities.
Diagnosis of Recurrent Disease
Symptoms of recurrent ovarian cancer are typically vague abdominal complaints, much like those found prior to initial diagnosis. However, most women will be aware of recurrence prior to symptoms due to clinical surveillance schemas that include physical exam, serial CA-125 measurement, and computed tomography (CT) scans. One area of controversy has been the treatment of women with asymptomatic recurrences, either biochemical or based on clinically identifiable tumor. Although most physicians will treat the latter even in asymptomatic women, many physicians struggle with the best time to institute therapy in the setting of an isolated increase in CA-125 levels. Certainly as patients become more informed, they may wish to proceed with aggressive treatment of their disease in the hope that chemotherapy will be able to completely eradicate recurrent small-volume disease.
The Gynecologic Oncology Group (GOG) is currently conducting a randomized trial evaluating tamoxifen vs thalidomide (Thalomid) in women with biochemical recurrences of ovarian cancer. Although no data are available to date, this is an attractive approach for many clinicians as these drugs are generally well tolerated with limited toxicities. This strategy has the potential to extend the platinumfree interval, which may be beneficial in improving response to subsequent platinum-based regimens.
Management Based on Time to Recurrence
Over the past 2 decades, we have explored many new therapeutic options for the treatment of patients with ovarian cancer. However, two major conceptual changes have greatly influenced our approach to recurrent disease. First, we now tend to treat lower-stage or less residual disease more aggressively in the adjuvant setting, believing that the patient with more favorable disease will benefit more from improved survival rather than less aggressive therapy. Recent data have confirmed that there is a survival advantage in women with advanced disease who are cytoreduced to no gross visible disease compared to those with residual disease of greater than 1 cm, when all are treated with combination chemotherapy.
The other important change has been the concept of recurrent ovarian cancer as a chronic disease. Historically, when a patient developed a recurrence, it was believed that she must be resistant to the last chemotherapy regimen received. Therefore, a different drug with a different mechanism of action was chosen for treatment of the recurrence. The result was often rapid movement through a variety of therapies with their collective toxicities resulting in poor long-term care for the patient. In some patients this may not have made a difference, but for many, opportunities were missed for long-term stabilization of disease with good tolerance to drugs that have limited cumulative toxicity.
Current thinking divides patients into groups based on time from completion of initial therapy. Patients developing recurrent disease less than 6 months after completion of primary platinumbased therapy are typically referred to as platinum-resistant or platinum-refractory.[ 6,7] It is safe to assume that patients in this group have disease that is highly resistant to the therapy already received. In this population, an assessment should be made as to the overall extent of disease, the identification of clear measurable parameters, and then a choice made generally from systemic therapeutic options that are non-platinum-cross-resistant. It is very important to enter many of these patients on clinical trials to help identify new therapeutic strategies.
Patients diagnosed with recurrence after a 1-year disease-free interval are typically referred to as platinum-sensitive and are treated with one or both of the two initial drugs. Data evaluating treatment of primary recurrence with platinum-based regimens have shown that a longer disease-free interval correlates with improved response when rechallenging with platinum. A recent study by Markman et al demonstrated response rates of 33% for those less than 12 months from prior therapy, 55% for those 12 to 18 months from prior therapy, and 75% for those more than 18 months from prior therapy. Objective response rates in women with platinumsensitive ovarian cancer are expected to be 30% to 50% when treated with single-agent platinum, compared to 50% to 80% when treated with combination platinum/paclitaxel.[9-13]
The International Collaborative Ovarian Neoplasm (ICON4) trial compared retreatment with platinum and paclitaxel vs conventional platinumbased regimens in women with a treatment-free interval of more than 6 months. Hazard ratios of 0.82 for 2-year survival (P = .02) and 0.76 for progression-free survival (P = .0004) were noted in women treated with the platinum/paclitaxel regimen. There has been criticism of this study regarding prior exposure to paclitaxel, since the subgroup of patients that appeared to derive the most benefit from combination therapy were those patients who did not receive paclitaxel as part of their primary therapy. However, a combination regimen appears to be a reasonable choice in patients with a treatment-free interval longer than 12 months, but may be of little added benefit in patients recurring 6 to 11 months after platinum-based therapy.
In our practice, patients who experience treatment-free intervals of greater than 6 months are treated in much the same way as noted above. Our choice for initial therapy of recurrent disease is generally one of the drugs used for initial therapy, ie, platinum or paclitaxel. Although patients recurring in the 6-month to 1-year interval probably have relatively resistant disease, we still tend to re-treat with one of the first-line drugs for second-line therapy. The vast majority of patients are given carboplatin because it tends to be a better tolerated drug than paclitaxel and the patient does not lose her hair for a second time. In this setting, the drugs are generally started and continued until there is clear evidence of tumor progression or until an unacceptable toxicity limits the therapy. Often, patients can then be switched to the other drug used for primary therapy, they again respond, and they can be maintained for several additional months.
'Highly' Platinum-Sensitive Disease
Patients who recur 3 or 4 years out from primary therapy are generally assessed with an eye to retreatment as if in primary treatment mode. Workup of these patients should include assessment of the extent of disease, followed by debulking in some cases and then primary multiagent chemotherapy.
Various groups have evaluated the role of secondary cytoreduction. Recent studies have shown that a survival benefit can be achieved when patients have more than a 24-month disease-free interval and are cytoreduced to microscopic disease.[12,13] Eisenkop and colleagues also showed a 25-month survival advantage in patients achieving optimal secondary cytoreduction to microscopic disease prior to salvage chemotherapy (P = .005) and a 2-month survival advantage for women whose largest tumor measured < 10 cm (P = .04). We tend to use secondary cytoreduction in women with a disease-free interval longer than 24 months with few masses present on exam and/or CT scan. We also rechallenge these pa- tients with front-line chemotherapy, for which expected response rates are greater than 70%.
Beyond Platinum and Paclitaxel
Today, many options exist for the treatment of recurrent ovarian cancer. Although platinum and paclitaxel remain the standards for primary therapy for ovarian cancer in the United States, many other compounds have been shown to possess activity against the disease. A selected list of these compounds can be found in Table 1.[10,15-34] When considering which of these agents to use when platinum and/or paclitaxel has been used as first-, second-, or even thirdline chemotherapy, we tend to balance the chances of a good response with the possibility of new or additive toxicities. Additionally, many of the trials referred to in Table 1 had a significant number of patients who exhibited stable disease as their best response to therapy. The goal of disease stabilization with limited toxicity may be a reasonable approach in certain patients who have minimal symptoms from their disease.
An excellent example of this approach is a heavily pretreated patient who we have begun treating with liposomal doxorubicin (Doxil), with good results. Previous studies have shown response rates ranging from 10% to 26%,[22,23,35] but an additional 30% to 40% of patients may have stable disease while on therapy. Combining this drug's excellent tolerability and safety profile with its high response and disease stabilization rates, patients can continue on therapy for prolonged periods with monthly infusions of 20 to 40 mg/m2.[36,37] Using this approach, we have had several patients who have been on liposomal doxorubicin for more than 24 months. Controversy exists regarding an appropriate time to stop such therapy, but we believe that choosing agents with few or tolerable toxicities that can be given on a convenient schedule over a prolonged period of time is an acceptable way to manage recurrent disease. Additionally, we have found that most patients are unwilling to stop taking the agent once clinical tumor progression has ceased, particularly if they remain asymptomatic.
Several other options exist for treatment in recurrent ovarian cancer including the topoisomerase inhibitors etoposide and topotecan (Hycamtin), the microtubule stabilizer docetaxel (Taxotere), and the nucleoside analog gemcitabine (Gemzar). Although response rates to these and other drugs range from 10% to 47%, it is difficult to tell which drug(s) will offer which patient the best response.[16-20,29,30,38] Importantly, none of these drugs are cross-resistant to platinum, and therefore, they have the potential to induce responses or disease stabilization even in patients that have been refractory to platinum-based therapy.
As discussed previously, the ICON4 trial showed progression-free and overall survival benefits for patients treated with combination platinumbased regimens for platinum-sensitive disease. While this is the first time that this finding has been identified in a prospective randomized fashion, other authors have shown similar benefits with other combinations.
One of the combinations receiving significant attention is that of gemcitabine and platinum. Gemcitabine is a nucleoside analog that inhibits DNA synthesis by causing premature nucleoside substitution-based chain termination as well as other mechanisms. This combination has been shown to possess synergistic activity in vitro that may be at least partly due to reversal of ERCC1-induced platinum resistance. Several trials have shown objective response rates ranging from 55% to 64% when carboplatin and gemcitabine are used both in platinum-sensitive and platinum-resistant populations, and this combination has been associated with quicker palliation of symptoms and longer time to progression.[33,34,40-42]
However, this improvement in activity comes at the cost of toxicity, with as many as 78% of patients exhibiting grade 3/4 bone marrow toxicity. Heavily pretreated patients have more frequent grade 3/4 toxicities and often require growth factor support and/or blood transfusions. Nevertheless, due to its high response rate, we are using this palliative regimen, particularly in highly symptomatic patients with gastrointestinal complaints.
Although most clinicians tend to consider mostly cytotoxic therapy for recurrent ovarian cancer, several hormonal options have shown benefit in clinical trials. Tamoxifen, megestrol acetate, and some of the more recently applied aromatase inhibitors are less likely to produce complete responses but have the potential for prolonged disease stabilization. Response rates to tamoxifen have ranged from 13% to 18%, with an additional 30% to 40% achieving stable disease in a platinum-resistant setting.[27,28]
It is probably worthwhile to check the primary tumor for estrogen/progesterone receptors, although one can with great reliability assume that mucinous tumors and most clear cell tumors will not show significant receptor expression and therefore tend to respond poorly to hormonal therapy. We feel that the patient who has progressive disease after two or three prior courses of chemotherapy and who is fortunate enough to be feeling well is an excellent candidate for hormonal therapy. Again, in a patient with no symptoms, it may be appropriate to simply stabilize disease. Under these circumstances, most patients would be happy to begin a nontoxic therapy in hopes of preventing progressive disease.
Management Based on Location of Recurrence
As a rule, ovarian cancer tends to recur in the abdomen. Patients with recurrence in the abdomen may present similar to patients with primary disease, with abdominal aching and symptoms of increased gas, bloating, or nausea. When these signs initially appear, we usually first place the patient on a low-residue diet (Table 2) to try to forestall any obstructive symptoms. This approach often allows us to initiate the next course of chemotherapy, frequently producing enough of a response to avoid complete obstruction. The initiation of a low-residue diet also puts a degree of control back in the patient's hands, as she learns what she can do to prevent a more complete obstruction.
A GI series or CT scan is often done to first identify and then to try to localize the site of obstruction. CT has the added advantage of being able to assess the volume and site(s) of disease. When deciding on various modes of therapy, it is extremely important to integrate the acute event with overall disease status. The earlier an obstruction occurs in a patient's disease course or the more distal the obstruction is, the more likely a surgical intervention will be considered.
Malignant Bowel Obstruction
Options for management of malignant bowel obstruction include medical therapy, surgical bypass or excision of the obstruction, intraluminal stenting, and, occasionally, localized radiation therapy. All of these options must be considered in light of the patient's age and overall medical status. For example, if the patient has received a number of therapies and the recurrence is very proximal, it may be that a decompressing gastrostomy is the only reasonable choice. In properly chosen patients, this may be just as successful at palliating symptoms with fewer complications and may offer the patient equal quality of life and survival when compared to open surgical procedures such as intestinal bypass or ostomy formation. Placement of a gastrostomy tube can occasionally be accompanied by a liquid diet. In the obstructed patient who has been documented to have a very slowly progressive tumor that is not causing other symptoms, the use of home parenteral nutrition may be appropriate.
The development of recurrent ascites will usually require initial paracentesis and then the initiation of second-, third-, or fourth-line chemotherapy, whatever the case may be. Ascites is usually a good marker of tumor response, as chemoresponsiveness is usually accompanied by either marked slowing or reversal of ascites formation. Occasionally patients with late-stage disease will develop recurrent ascites requiring paracentesis every 7 to 10 days. We place a Tenckhoff catheter in these patients so that they can manage the problem themselves.[ 48] Most patients appreciate this intervention because it gives them some control and eliminates multiple trips to the hospital.
Recurrence of ovarian cancer in the pelvis can be associated with special management issues. In addition to causing obstruction of the rectum or rectosigmoid as mentioned above, pelvic recurrences often erode into the apex of the vagina, causing bleeding and an unpleasant odor. Additionally, progressive disease in this area can lead to rectovaginal or vesicovaginal fistula and/or ureteral obstruction.
Regardless of the complication, management is always undertaken with regard to the overall status of the patient's disease. At one extreme, for example, a fistula will prompt urinary diversion or colostomy, while at the other extreme, the patient consuming very little orally can be managed with diapers or catheters associated with absorptive dressings. Tumor eroding into the apex of the vagina will respond like tumor in other areas to successful chemotherapy. However, this development is more often an accompaniment of later-stage disease, when the tumor has become less responsive to chemotherapy. Odor can be nicely managed by 250 to 500 mg of oral metronidazole per day.
An upper vaginal recurrence is also a good area to treat with local radiation therapy, which almost invariably results in tumor shrinkage and good palliation of bleeding or drainage. Radiation may also play a role in recurrences on the pelvic sidewall, which tend to be quite painful and the cause of disturbing symptoms such as lymphedema or venous thrombosis. When ureteral obstruction is present, management will again be based on symptoms and the expected potential for response to radiation or cytotoxic chemotherapy. Pain and infection will generally require nephrostomy, with possible internalization of a stent in antegrade fashion.
Chest recurrences are most frequently pleural-based and fluid-producing. Tapping the fluid for relief of symptoms and then treating with chemotherapy is generally our selected approach. We prefer not to use sclerosing techniques if the effusion is still responsive to chemotherapy. However, once chemotherapy proves ineffective in controlling the effusion, either sclerosis is attempted or a Pleurex catheter placed so that patients may drain the chest cavity themselves at home.
The physician needs to keep fairly aggressive with this complication of recurrent disease because if the lung remains in the contracted state due to the effusion for too long, the coating of tumor on the visceral pleura will become too thick and the lung will not be able to expand with drainage of the fluid. As with most neoplasms in the otherwise healthy patient, a solitary late parenchymal recurrence should always be considered for possible resection. However, under most circumstances the parenchymal metastasis will be multiple when investigated by positron-emission tomography (PET) or CT scan and will therefore be managed more appropriately with systemic therapy.
Although metastases to the central nervous system are historically infrequent in recurrent ovarian cancer, patients are now living long enough to develop such tumor spread. Metastases to the brain will almost always occur after pulmonary disease is present. In the absence of symptoms, radiotherapeutic strategies will generally be the central form of management. Patients presenting with headache, seizures, or nausea and vomiting due to pressure symptoms will benefit from rapid institution of steroid therapy followed by radiation therapy. For solitary lesions, consideration should be given to a primary surgical approach, again taking into account the patient's overall disease status. Small retrospective studies suggest that craniotomy followed by whole-brain irradiation and/ or chemotherapy may provide a longer overall survival.[52,53]
Management Based on Primary Stage
Although most clinical decisions will be based on prior therapy and any treatment-free interval, the primary stage of a patient's cancer can affect the management of recurrent disease in a variety of ways. First, primary stage can affect interpretation of a patient's tumor markers. A patient initially diagnosed with earlystage disease that recurs may not have as much information on the utility of the particular tumor marker compared to patients with more advanced disease. This is particularly true in patients with negative or unknown markers preoperatively.
Primary stage secondarily affects residual disease on starting therapy, which may have an impact on initial clinical response and the overall time to recurrence. It is quite possible that a patient with an early-stage tumor and no residual disease recurring after 12 months may be chemoresistant in much the same way as a patient with optimally debulked advanced-stage disease who recurs within 4 months after a complete clinical response. Standard definitions of platinum resistance as they relate to choice of subsequent therapy may not apply in this setting.
Management Based on Primary Therapy
Patients with primary therapy that did not include surgery must be evaluated for treatment options based on the time from initial therapy as well as the pattern of recurrent disease. Ovarian cancer is a special disease in that it often spreads in a pattern that is amenable to debulking surgery and, most importantly, is responsive to chemotherapy. Patients with platinum-refractory disease, whether previously operated on or not, will not likely benefit from debulking surgery unless they have a slow-growing well-differentiated carcinoma or a tumor of low malignant potential. Conversely, patients with late recurrences, regardless of the primary treatment modality, are potentially good candidates for surgery as described previously.
When radiation therapy-especially whole-abdominal irradiation-has been part of primary therapy, the management of recurrent disease is significantly altered. Marrow toxicity from chemotherapies will be increased, resulting in the need to reduce initial dosages. Radiation therapy to the abdomen also has a profound effect on the ability to perform surgery in the future. The risk of any surgery is significantly increased due to the risk of postoperative fistula formation. Loops of adherent bowel are often dependent upon each other for survival, and apparent successful separation reveals itself to be unsuccessful when one of the loops fistulizes postoperatively from lack of blood supply. This is a devastating complication for somebody who already has recurrent disease.
Therefore, the necessity of all surgical interventions must be given the greatest consideration, and every effort should be made for that surgery to be as limited as possible in patients who have had pelvic and especially abdominal radiation therapy. One can always define special circumstances in which surgery might make sense, but special circumstances are generally quite uncommon.
Management Based on Histopathology
As a general rule, the more educated your patient is about her cancer, the easier it will be to manage the disease under all circumstances. Patient education is a physician's responsibility. It is important to let patients know what you are thinking about their disease. Emphasizing the good aspects and providing them with hope early on in the disease course is perfectly acceptable. Patients are well aware that they can die of cancer. However, it is more than reasonable to make patients aware when they have a tumor with an adverse histology.
A good example is when the patient has been diagnosed with an advanced mucinous malignancy. Most of these tumors will be nonovarian in origin, but when their origin is or appears to be ovarian, response rates are low and steadily progressive disease is more the rule than the exception. An initial aggressive surgical attempt in a patient with a mucinous tumor may be the best option since a slow growth rate may be present, particularly in well-differentiated mucinous tumors. However, once the cancer has demonstrated resistance to platinum and taxanes, it may be wise to rapidly move to more traditional GI tract agents such as fluorouracil (5-FU) or, more recently, irinotecan (Camptosar).
Clear cell tumors also show higher in vitro resistance to standard cytotxic agents and clinically respond more poorly to chemotherapy. Higher expression of ERCC1 in clear cell carcinomas leads one to consider the addition of gemcitabine to treatment regimens for these patients, as this agent has been associated with a better response in ERCC1-positive tumors. Again, with appropriate upfront education, choices of agents and patient acceptance of management will generally be easier from a discussion standpoint when the disease is recurrent, although the medical management will be nonetheless difficult.
The management of women with recurrent ovarian cancer is a challenging and multifaceted task. Balancing a patient's hopes for cure with the reality of the disease, toxicity of the treatment, and desired quality of life can be difficult even for the most experienced clinician. Future management will likely include new classes of drugs including small-molecule inhibitors alone or in combination with traditional cytotoxic compounds. We are already seeing more clinical trials with these types of compounds that target specific points in cancer cell signaling. Adding these agents to our armamentarium for cancer treatment may offer new hope, but will likely increase the complexity of decision-making and the toxicity of continued therapy.
It is important to keep in mind that we must design our initial management of a cancer based on our knowledge of the natural history of the particular tumor. Once we have information as to the behavior of the cancer in a given patient, however, especially if outside the usual parameters of the natural history of that disease, it is the behavior in that patient that must take precedence for future therapeutic decisions.
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