Recent Progress in the Diagnosis and Treatment of Ovarian Cancer

Treatment of Early Stage (Stages I and II) EOC

Specific ovarian carcinoma treatment recommendations are dependent on the stage of the disease and extent of surgical debulking. Approximately 25% of women with ovarian cancer have disease confined to one or both ovaries (FIGO stage I) or to the pelvis (FIGO stage II). Even among this good-prognosis group, the failure rate is high enough to warrant adjuvant chemotherapy in most patients.

Data from 2 parallel, randomized European clinical trials in early ovarian cancer, the International Collaborative Ovarian Neoplasm trial 1 (ICON1) and Adjuvant Chemotherapy in Ovarian Neoplasm (ACTION), have been combined for analysis. Both trials compared a platinum-containing adjuvant chemotherapy regimen with observation after surgery. With over 4 years of median follow-up of over 900 patients, the hazard ratio for recurrence-free survival is 0.64 (95% confidence interval [95% CI], 0.50-0.82; P = .001) in favor of adjuvant chemotherapy, and the hazard ratio for OS is 0.67 (95% CI, 0.50-0.90; P = .008) in favor of adjuvant chemotherapy. A subgroup analysis suggested that the benefits of chemotherapy were primarily in nonoptimally staged patients, underscoring the prognostic importance and clinical relevance of surgical staging in early ovarian cancer.⁶²

The GOG has attempted to precisely define the subgroups of patients with early ovarian cancer that would benefit from adjuvant therapy and determine the optimal form of therapy for these patients. Studies over the past 3 decades have shown that patients with stage IA or IB disease (limited to one or both ovaries with no ascites and negative peritoneal washings) and with well- or moderately differentiated histology have a 5-year disease-free survival (DFS) rate of 91% and a 5-year OS rate of 94% with surgery alone; thus, this subset of patients does well and is generally not treated with adjuvant therapy. It is, however, critical that these patients are fully staged. Studies have documented that almost one-third of apparent early stage patients will have more advanced stage disease when full staging is done. In contrast, chemotherapy improves progression-free survival (PFS) for patients with stage IA or IB poorly differentiated disease, stage IC, or stage II disease, and these patients should receive adjuvant chemotherapy.⁶³

The rarity of early stage ovarian cancer has made it difficult to perform studies in this group of patients. The most recently reported phase 3 study in this population (GOG protocol 157) compared 3 versus 6 cycles of paclitaxel and carboplatin.⁶⁴ The 5-year probability of recurrence was 20.1% for 6 cycles versus 25.4% for 3 cycles, a 24% reduction in recurrence risk. However, the OS was similar for both regimens and the decrease in recurrence risk did not reach statistical significance. A subsequent unplanned analysis of patients from this trial showed that those with high-grade serous histology had a significantly lower risk of recurrence with 6 compared with 3 cycles. Based on these reports of this study, most recommend a minimum of 3 cycles of paclitaxel and carboplatin for patients with early stage disease who are treated with adjuvant chemotherapy and many recommend 6 cycles for those with high-grade serous cancers.

Treatment of Advanced Stage (Stages III and IV) EOC

Approximately 75% of women with ovarian carcinoma present with stage III or IV disease. As previously mentioned, prognosis correlates with the extent of residual disease after primary debulking surgery. Although this is best documented in patients with stage III disease, even patients with stage IV disease have an improved prognosis with optimal debulking (no residual implant greater than 1 cm). It is clear that this is a continuum, with those with the least tumor burden after surgery having the best prognosis and with prognosis worsening as the diameter of the smallest residual lesion increases.³³

It has been recognized that not all patients can be optimally debulked at initial surgery. This has led to alternate approaches to achieve optimal surgical status. One of these is the administration of chemotherapy before definitive surgery, an approach referred to as neoadjuvant chemotherapy. A recent randomized trial compared primary debulking surgery followed by platinum-based chemotherapy with neoadjuvant platinum-based chemotherapy followed by interval debulking surgery in stage IIIC or IV EOC.⁶⁵ The findings from this trial were that neoadjuvant chemotherapy was not inferior to primary debulking surgery; however, the median OS of the 2 groups (30 months and 29 months, respectively) is inferior to the findings from GOG trials in this same population. Given the large body of literature demonstrating the survival benefit for cytoreduction, the inability to reliably predict preoperatively which patients will not be able to be cytoreduced, and the inferior outcome of both arms on this study, neoadjuvant chemotherapy remains controversial.

Treatment of Optimally Debulked Disease

The long-term OS rate for women with optimally debulked stage III disease is approximately 25%; thus, a small but appreciable cure rate is found in women treated with aggressive initial surgery followed by platinum-based chemotherapy. After surgery, all women should receive at least 6 cycles of platinum-based therapy with either cisplatin or carboplatin in combination with a taxane, usually paclitaxel. If cisplatin is used, patients require careful monitoring of renal function, electrolytes, and neurologic status. Because nephrotoxicity and neurotoxicity are cumulative, cisplatin dosing should be modified early if there is an indication of renal dysfunction or progressive sensory neuropathy. Based on the results of GOG protocol 158, systemic treatment with carboplatin and 3-hour paclitaxel is equivalent to cisplatin and 24-hour paclitaxel, with an improved toxicity profile.⁶⁶ Carboplatin and paclitaxel thus have widespread acceptance as initial chemotherapy for ovarian cancer.

For women with optimally debulked ovarian cancer, a major controversy concerns the route, intravenous (iv) or intraperitoneal (ip), by which chemotherapy is optimally administered. Three randomized trials comparing iv with ip chemotherapy have shown a clinical benefit for use of the ip approach. The first trial, led by the Southwest Oncology Group, used iv cyclophosphamide in combination with cisplatin administered either ip or iv. This study showed a survival advantage for the group receiving ip cisplatin (49 months vs 41 months; P = .02; relative risk [RR] = 0.76), and there was a significant reduction in sensory neuropathy with ip therapy.⁶⁷ The second study compared a standard iv paclitaxel and cisplatin regimen with 2 cycles of high-dose carboplatin iv at an area under the curve (AUC) of 9 followed by 6 cycles of iv paclitaxel and ip cisplatin. This study showed an improvement in PFS (28 months vs 22 months; P = .01; RR = 0.78) and OS (63 months vs 52 months; P = .05; RR = 0.81) for the ip regimen.⁶⁸ The third study compared the same standard iv paclitaxel and cisplatin regimen with an intensive regimen of iv paclitaxel with ip cisplatin and ip paclitaxel. This study also showed an improvement in PFS (24 months vs 18 months; P = .05; RR = 0.80) and OS (66 months vs 50 months; P = .03; RR = 0.75) for the ip regimen.⁶⁹ The latter 2 studies showed increased toxicity for the ip regimen compared with the iv regimen and fewer patients were able to complete assigned ip therapy compared with those assigned to iv therapy. Current efforts are focusing on ways to improve the tolerability of ip administration using contemporary supportive care measures, modification of the treatment regimens, and use of carboplatin in place of cisplatin for ip administration. It should be noted that the use of ip therapy for suboptimally debulked and stage IV disease has not been widely accepted. Most such patients will still receive iv systemic therapy.

Treatment of Suboptimally Debulked Stage III and IV Disease

Women who have residual disease larger than 1 cm after initial debulking surgery have a substantially worse prognosis than those with optimally debulked disease. Nevertheless, a small proportion of these women will have long-term DFS. In contrast, women with disease outside the abdominal cavity or in the liver parenchyma, making them stage IV, have a worse prognosis and rarely have a long-term DFS. In addition to residual tumor volume, other factors associated with a poor prognosis include advanced age, mucinous or clear cell histology, and the presence of ascites.

Evidence clearly demonstrates that chemotherapy prolongs survival in women with stage III disease, whether optimally or suboptimally debulked, and possibly in stage IV disease. Thus, women in these disease categories should be encouraged to receive chemotherapy as a treatment option after surgery. Although there are many active agents for the treatment of ovarian cancer, the standard of care is combination therapy that includes a taxane and a platinum compound, usually carboplatin and paclitaxel.

Fifteen years ago, combination chemotherapy with paclitaxel plus cisplatin as administered in GOG protocol 111 became the standard of care for patients with advanced ovarian cancer.⁷⁰ The superiority of this regimen over the older cyclophosphamide and cisplatin regimen was confirmed in a European Organization for Research and Treatment of Cancer (EORTC) study.⁷¹ The latter trial used 3-hour paclitaxel with cisplatin and demonstrated an increased incidence of high-grade neurotoxicity. Based on the notable differences in neurotoxicity between these 2 trials, the standard of care is to use a prolonged 24-hour paclitaxel infusion when combined with cisplatin to decrease neurotoxicity.

A subsequent study, GOG protocol 132, compared treatment with high-dose cisplatin (100 mg/m²) as a single agent with high-dose paclitaxel (200 mg/m²/24 hours) as a single agent, versus paclitaxel (135 mg/m²/24 hours) followed by cisplatin (75 mg/m²) (combination arm). All regimens were given every 3 weeks for 6 cycles to women with suboptimally debulked stage III or stage IV disease.⁷² The results of this trial failed to demonstrate the same median PFS for the same population of women treated with the same combination arm in GOG protocol 111 (14 months vs 18 months). Furthermore, women who received cisplatin as a single agent or in combination with paclitaxel had no significant difference in PFS (16 months and 14 months, respectively), whereas women receiving paclitaxel alone had an inferior PFS (11 months). This is the only study in the current era using a non–platinum-containing treatment for newly diagnosed patients, and it demonstrates the superiority of platinum-based therapies. Interestingly, the survival of the 3 arms was similar. A possible explanation for this is that patients who discontinued treatment on the cisplatin arm (largely due to toxicity) went on to treatment with paclitaxel before disease progression, and patients on the paclitaxel alone arm who discontinued therapy (largely due to inferior disease outcome) went on to platinum therapy without disease progression. Although this was not specifically tested in this trial, this would suggest that “sequential” therapy may provide equivalent survival to combination therapy. It was noted that more patients in the combination arm were able to complete all 6 cycles of therapy and that toxicity in the combination arm was less toxic than cisplatin alone. Thus, the combination was considered the treatment of choice.

Docetaxel was examined as a replacement for paclitaxel in the Scottish Randomized Trial in Ovarian Cancer (SCOTROC) study. This study compared carboplatin at an AUC of 5 with either paclitaxel at a dose of 175 mg/m²/3 hours or docetaxel at a dose of 75 mg/m²/1 hour. There were no differences in PFS (14.8 months vs 15 months) or in 2-year survival (68.8% vs 64.2%) for paclitaxel/carboplatin compared with docetaxel/carboplatin, respectively.⁷³ There were more myelosuppression and hypersensitivity reactions on the docetaxel arm and more neurotoxicity and arthralgias/myalgias on the paclitaxel arm. The conclusion from the study was that docetaxel/carbopaltin was an alternative first-line chemotherapy regimen for ovarian cancer.

More recently, the GOG and the GCIG evaluated the addition of a third drug to the paclitaxel/carboplatin backbone for the initial therapy of ovarian cancer. More than 4000 women with newly diagnosed stage III or IV ovarian cancer were randomized to receive carboplatin/paclitaxel or 1 of 4 experimental regimens containing a third drug: a triplet of carboplatin/paclitaxel and gemcitabine, a triplet of carboplatin/paclitaxel and liposomal doxorubicin, a sequential doublet of carboplatin/topotecan followed by carboplatin/paclitaxel, or a sequential doublet of gemcitabine/carboplatin followed by carboplatin/paclitaxel. There was no difference in median PFS (range 15.3 months to 16.4 months) or median OS (range 39.1 months to 42.8 months) for any of the experimental regimens compared with carboplatin/paclitaxel.⁷⁴

Some controversy exists regarding the appropriate doses of carboplatin and paclitaxel to use in this setting. The above trials have used carboplatin at an AUC ranging from 4 to 7.5 and paclitaxel at a dose of 150 to 175 mg/m² over 3 hours or 135 mg/m² over 24 hours. Although some argued that there is a dose-response effect of carboplatin, the overall comparable results from these trials argue against this point. Most now use an AUC of 6 for initial chemotherapy.

In a study from the Japanese GOG, dose-dense, weekly paclitaxel with every-3-week carboplatin has been shown to improve both PFS (28 months vs 17 months; P = .0015) and 3-year OS (72% vs 65%; P = .03) when compared with standard therapy given every 3 weeks.⁷⁵ However, the dose-dense regimen is more toxic, and patients discontinued dose-dense paclitaxel therapy more often than did those receiving standard therapy. This regimen is now being compared with an ip cisplatin regimen and an ip carboplatin regimen in GOG protocol 252.

A summary of preferred primary adjuvant chemotherapy regimens for EOC is shown in Table 4.

Maintenance Therapy

Although achieving a cure for advanced ovarian cancer is extremely rare, the majority of patients do achieve a complete clinical remission after initial cytoreductive surgery and combination chemotherapy. The ability to achieve a complete remission, which is uncommon in other advanced epithelial cancers, provides a unique opportunity to capitalize on this finite period with innovative consolidation and maintenance strategies. Clinical trials have studied consolidation therapies involving high-dose chemotherapy with stem cell transplantation and ip administration of antibodies conjugated with a variety of radioisotopes, while maintenance therapies have focused on the prolonged use of single-agent chemotherapy, ip chemotherapy, hormonal therapy, and vaccines. Thus far, none of these interventions has shown an improvement in OS.⁶⁶

Results of a phase 3 trial led by the Southwest Oncology Group/GOG sparked controversy because it showed that a maintenance strategy of 12 monthly cycles of single-agent paclitaxel delivered to women who attained a complete response to primary platinum-paclitaxel chemotherapy significantly improved PFS, compared with delivery of 3 cycles of the same treatment regimen. The trial was unable to demonstrate an OS advantage, although a subset of the patients with a low CA 125 baseline did exhibit an improvement in survival.⁶⁸ Among the unanswered questions regarding this trial is whether the clinical benefit justifies the prolonged use of the agent with its inherent toxicities. Concerns about toxicity would lessen if a definitive OS benefit was shown.

Due to the promising results as a second-line treatment strategy (which will be discussed later), coupled with its favorable toxicity profile, the use of bevacizumab has emerged as an attractive choice as a maintenance strategy. Based on the results of prior single-agent phase 2 bevacizumab trials, the GOG performed a randomized, double-blinded, 3-arm phase 3 trial comparing the standard primary chemotherapy regimen of carboplatin/paclitaxel versus carboplatin/paclitaxel plus bevacizumab with chemotherapy versus carboplatin/paclitaxel plus bevacizumab with chemotherapy and bevacizumab continued for 1 year after the completion of chemotherapy. Results were recently presented and demonstrated that chemotherapy plus concurrent and maintenance bevacizumab prolongs PFS⁷⁶; however, to date there is no survival difference between the 3 arms. We await mature survival data to determine if there is an impact of the addition of bevacizumab on survival.

There is a clear need for additional clinical trials to assess whether the clinical benefits such as quality of life, symptom control, and survival advantages outweigh the added exposure to the side effects of the agents or treatments used in the maintenance or consolidation setting.

Duration of Therapy and Evaluation of the Patient Receiving Therapy

Before treatment, levels of the ovarian tumor marker CA 125 should be measured and, if elevated, should be used as adjunctive evidence of response to therapy. Levels should be measured routinely during the course of treatment. A consistent rise in CA 125 can be used as a measure of failure of treatment in the absence of radiographic and clinical changes. Like-wise, a linear fall in serum levels of CA 125 can be used as a measure of treatment success. Levels of carcinoembryonic antigen and CA 19-9 may be elevated in women with mucinous carcinomas and may be potentially useful in following the course of the disease.

Treatment should consist of 6 to 8 cycles of chemotherapy. Residual disease should be measured before beginning therapy by visual inspection at the time of surgery, by computed tomography (CT) scan if bulk disease remains, or by physical examination when appropriate. The role of positron emission tomography (PET) scanning is currently being investigated.

Recurrent EOC may be suspected by the development of new symptoms, the radiographic detection of an asymptomatic disease recurrence by CT scans, or a rising serum concentration of CA 125, which may predate radiographic disease progression by many months. Timing of second-line therapy is controversial. Immediate institution of therapy is indicated for symptomatic women, with the specific goal being symptom palliation. In contrast, the optimal timing of second-line therapy for an asymptomatic woman with recurrent disease (typically detected because of an asymptomatic rise in the serum level of CA 125) has been controversial.

This issue was directly addressed in a prospective trial of 1442 women with EOC in complete clinical remission with a normal CA 125 level after surgical cytoreduction and first-line platinum-based chemotherapy.⁷⁷ Serum CA 125 levels were assayed every 3 months, but both patients and investigators were blinded to the results. Women who remained asymptomatic but whose CA 125 levels exceeded twice the upper limit of normal (n = 527) were randomly assigned to immediate treatment or to continued blinding of the CA 125 results with treatment delayed until the time of a clinical or symptomatic recurrence. Although chemotherapy was initiated a median of 5 months earlier in the immediate treatment arm, at a median follow-up of 57 months from randomization, this did not contribute to improved survival (hazard ratio for death with immediate vs delayed treatment, 1.00; 95% CI, 0.82-1.22) or a longer remission duration. Furthermore, immediate treatment had an adverse impact on quality of life. It should be noted that the median time to randomization of patients was approximately 9 months, indicating that this is an early recurrence population. It is not clear if patients with later recurrence might benefit from the earlier identification of recurrence that might allow for surgical cytoreduction of recurrent disease (see below) or more aggressive, multidrug therapies. Nonetheless, the value of routine monitoring of serum CA 125 levels in the follow-up of ovarian cancer patients is challenged by these results. Although the data from this trial provide reassurance that there is no apparent benefit to early detection and treatment of recurrence based upon intensive CA 125 surveillance, there may be specific subgroups of patients who might benefit. Thus, the impact of these results on clinical practice and on guidelines for post-treatment surveillance remain to be determined.

Treatment of Recurrent EOC

Once recurrent ovarian cancer is diagnosed, the goals of therapy should be carefully reviewed. In the recurrent setting, excessively aggressive therapy can limit future treatment options and impair quality of life. Patients may be under the impression that aggressive treatment can still result in cure. Unfortunately, the cumulative experience with recurrent ovarian cancer is that, although it is highly treatable, it is generally not curable. Patients with an early platinum-resistant recurrence rarely achieve a complete response from any therapy and will likely be on some type of treatment for the majority of their remaining life. Even patients who recur late and respond completely to second-line therapy will have a second remission that is shorter than the first in more than 95% of cases.⁷⁸ The goals of treatment of recurrent ovarian cancer are thus to prolong survival, to delay time to progression, to control disease-related symptoms, to minimize treatment-related symptoms, and to maintain or improve quality of life.

Patients with recurrent disease are commonly characterized as platinum sensitive or platinum resistant. Although this definition is useful for clinical trial purposes and to determine the optimal approach to treatment, it does have limitations. The definition of platinum-resistant disease includes patients who progress while receiving initial chemotherapy (sometimes called platinum-refractory) or within 6 months of completing initial platinum-based chemotherapy. This definition has been used to determine eligibility for clinical trials, most of which require disease that is measurable using traditional imaging modalities such as CT. Thus, most of the data regarding the efficacy of treatment in this group of patients are limited to those meeting these criteria. Patients who are determined to recur based solely on more sensitive criteria such as CA 125 or PET imaging generally have lower volume disease and may have different response characteristics than those with larger volume, traditionally measurable disease.

Treatment of Platinum-Sensitive Recurrent EOC

Platinum-sensitive patients are defined by recurrence 6 or more months after the completion of initial chemotherapy. Platinum-sensitive disease is a spectrum ranging from relatively less platinum-sensitive patients who recur shortly after the 6-month benchmark to those recurring more than 12 to 18 months after completing initial treatment. A common observation is that the response to platinum retreatment increases with a longer interval from prior platinum treatment. Because there are compelling data that cytoreductive surgery improves survival for patients with newly diagnosed ovarian cancer, the issue of surgery is appropriate to address in a highly platinum-sensitive recurrent patient with potentially resectable disease. The majority of ovarian cancer recurrences are within the abdomen and thus potentially amenable to cytoreductive surgery. However, the benefit of secondary cytoreduction in women with a documented or suspected recurrence of EOC is unclear because of the lack of randomized trial data examining this issue.

Secondary cytoreductive surgery can be considered for patients who recur after an at least 6-month disease-free interval.⁷⁹ When selecting patients for secondary cytoreduction, the most significant preoperative factors are the disease-free interval and success of a prior cytoreductive effort. In general, patients who are further out from completion of their chemotherapy (more than 12 months) and who have limited sites of disease and an absence of signs of carcinomatosis on imaging are more likely to benefit from secondary cytoreduction. Once secondary cytoreductive surgery is attempted, the most important factor for improved survival is optimal cytoreduction. Review of outcomes after secondary cytoreductive surgery showed that the survival of patients with optimal debulking (less than 1 cm) was 16 to 61 months versus 8 to 27 months in those with suboptimal cytoreduction.^80,81 More recently, a retrospective analysis of 240 patients showed that only those with complete tumor resection, with no visible residual disease, had an improved outcome after secondary cytoreductive surgery.⁸² Those with any visible residual disease fared no better than patients who did not have surgery. Secondary cytoreductive surgery for recurrent, platinum-sensitive ovarian cancer is being prospectively evaluated in 2 randomized trials: GOG protocol 213 and AGO-OVAR DESKTOP III.

Platinum-based combination therapy has become the standard of care for patients recurring more than 6 months after initial therapy, based on several recent phase 3 randomized trials comparing single-agent platinum agents with platinum-based combinations.

The first study, the ICON4/AGO-OVAR 2.2 trial, compared platinum without a taxane (largely single-agent carboplatin) with paclitaxel plus platinum (largely paclitaxel plus carboplatin) and showed an improvement in response rate (54% vs 66%), time to disease progression (9 months vs 12 months), 1-year PFS (40% vs 50%), median survival (24 months vs 29 months), and 2-year survival (50% vs 57%) for the combination arm.⁸³ Some question the results of this study because the majority of patients had not received a prior taxane with initial therapy.

A second study, AGO-OVAR 2.5, randomized platinum-sensitive patients to carboplatin (AUC of 4 on day 1) with gemcitabine (at a dose of 1000 mg/m² on days 1 and 8) or carboplatin alone (AUC of 5).⁸⁴ Compared with single-agent carboplatin, the combination arm had an improved response rate (31% vs 47%; P = .0016) and an improved PFS (5.8 months vs 8.6 months; P = .0031). However, there were no significant differences in OS for the 2 arms (17.3 months vs 18 months). The improved outcome for the gemcitabine and carboplatin arm provides an alternative to taxane/carboplatin therapy with less neurotoxicity and alopecia, toxicities that can negatively impact quality of life for many patients.

In CALYPSO, the GCIG compared paclitaxel (175 mg/m²) and carboplatin (AUC of 5) every 3 weeks with pegylated liposomal doxorubicin (30 mg/m²) and carboplatin (AUC of 5) every 4 weeks in patients with recurrent, platinum-sensitive ovarian cancer. The primary endpoint was PFS and the pegylated liposomal doxorubicin/carboplatin arm showed superiority compared with the paclitaxel/carboplatin arm (11.3 months vs 9.4 months; P = .005).⁸⁵ This study showed more myelosuppression, mucositis, and hand-foot syndrome in patients treated with pegylated liposomal doxorubicin/carboplatin and more alopecia, neuropathy, and hypersensitivity/allergic reactions in patients treated with paclitaxel/carboplatin. Overall, there were fewer drug-related adverse events and less early termination of therapy in the pegylated liposomal doxorubicin/carboplatin arm.

The development of carboplatin hypersensitivity reactions frequently occurs in patients receiving platinum-based therapy for recurrent disease. In a retrospective single-institution review, hypersensitivity reaction was reported in 24 of 205 (12%) patients with ovarian cancer treated with carboplatin.⁸⁶ Subsequently, multiple reports have been published documenting effective carboplatin desensitization protocols.^87-93 Several of these include the use of oral, nonsedating antihistamines; oral corticosteroids; and/or nonsteroidal anti-inflammatory drugs beginning 2 to 3 days before and continuing 2 to 3 days after carboplatin. In addition, iv H1 and H2 histamine blockers and corticosteroids are given before carboplatin, which is administered as a slow infusion with a gradually increasing rate, usually over 4 to 24 hours. The extra effort of desensitization should be limited to patients who are responding to or who still have the potential for a significant response to carboplatin.

The recommendations for the treatment of patients with recurrent, platinum-sensitive ovarian cancer are summarized in Table 5.

Treatment of Recurrent Platinum-Resistant EOC

Most patients with recurrent ovarian cancer will eventually develop platinum-resistant disease. In general, platinum-resistant patients will be treated with sequential single agents rather than combination therapy. Table 6 lists common chemotherapy agents used in the treatment of recurrent platinum-resistant ovarian cancer.

Topotecan was first used as a “daily × 5” regimen using the drug for 5 consecutive days on a 3-week schedule.⁹⁴ This regimen, although effective, results in a high degree of myelosuppression and is poorly tolerated past second- or third-line therapy. More recently, weekly topotecan has been documented to be active in platinum-resistant disease, with response rates ranging from 9% to 20%.^95-97 The weekly topotecan regimen has much less myelosuppression and alopecia than the “daily × 5” regimen, and is better tolerated as treatment in more heavily pretreated patients. The weekly topotecan regimen has not been directly compared with the “daily × 5” regimen to formally compare efficacy; however, the improved tolerance of the weekly regimen has led to the more common use of this schedule and allows the use of topotecan in more heavily pretreated patients.

Pegylated liposomal doxorubicin also has documented efficacy, with response rates ranging from 12% to 26% in patients with recurrent, platinum-resistant ovarian cancer.^94,98-100 It has unique toxicities of hand-foot syndrome and mucositis, although these toxicities are not common and do not usually limit therapy. The convenience of the once-every-28 days treatment schedule and the relative lack of myelosuppression make this a favored regimen in the treatment of recurrent disease. Pegylated liposomal doxorubicin and topotecan have been compared in a randomized phase 3 trial and showed similar response rates in patients with platinum-resistant disease, with no significant differences in response, PFS, or OS.⁹⁴

Gemcitabine has been studied as a single agent in platinum-resistant disease with response rates of 11% to 17%.^101-103 It has also has been compared with pegylated liposomal doxorubicin in a randomized phase 3 trial in patients who recurred within 12 months of the completion of initial chemotherapy.¹⁰⁰ In this trial, 56% of patients were platinum refractory, having developed disease recurrence within 6 months of completing initial chemotherapy. Compared with pegylated liposomal doxorubicin, the gemcitabine arm had an improved response rate (29% vs 16%); however, this did not reach statistical significance (P = .06). The median PFS was 20 weeks for gemcitabine and 16 weeks for pegylated liposomal doxorubicin (P = .4). In spite of the higher response rate and PFS for the gemcitabine arm, the pegylated liposomal doxorubicin arm had an improved median OS compared with the gemcitabine arm (55 weeks vs 60 weeks), which reached statistical significance (P = .048).

Oral etoposide has significant activity in platinum-refractory ovarian cancer, with documented response rates from 6% to 32%.^104-106 However, it is not commonly used, possibly because of secondary hematologic malignancies associated with its use.¹⁰⁷ In GOG trials, 3 of 150 patients treated with oral etoposide (2%) developed secondary myelodysplastic syndrome or acute myelogenous leukemia within 18 months of therapy.

Alternative taxanes have been shown to be active in platinum- and paclitaxel-resistant ovarian cancer. Weekly paclitaxel, docetaxel, and nanoparticle albumin-bound paclitaxel are all active.^108,109 This would indicate that resistance to the standard, every-3-weeks paclitaxel regimen does not necessarily confer resistance to paclitaxel administration, resulting in different exposures, or to an alternative taxane, docetaxel. Based on these studies, retreatment with an alternative taxane is reasonable to consider in platinum- and paclitaxel-resistant ovarian cancer.

Targeted Therapies

The major focus of current clinical trials for the treatment of recurrent ovarian cancer is the use of targeted biologic agents. Targeted agents that are documented to be effective in recurrent disease will then be candidates for study in front-line therapy. Although several families of agents have been studied in recurrent ovarian cancer, the greatest success to date has been with the use of agents that target the vascular endothelial growth factor (VEGF) pathway.

Hormonal Therapies

Hormone therapy with tamoxifen, aromatase inhibitors (eg, letrozole), or fulvestrant is associated with low objective response rates (10%); however, occasional patients experience a dramatic tumor marker response, and some women have prolonged periods of stable disease. The efficacy of tamoxifen was explored in a Cochrane review that included 623 women from 11 nonrandomized series; 1 non-randomized phase 2 study; and 1 randomized trial comparing tamoxifen alone, in combination with medroxyprogesterone, or with medroxyprogesterone alone in women with recurrent EOC.¹³⁰ Overall, 60 women (9.6%) achieved an objective response to tamoxifen alone, although the range within individual studies was 0% to 56%. An additional 32% achieved stable disease for periods of longer than 4 weeks. When compared with chemotherapy (either weekly paclitaxel or pegylated doxorubicin), chemotherapy showed a small but statistically significant improvement in PFS.¹³¹

The aromatase inhibitor letrozole was studied in a phase 2 trial in women with estrogen receptor-positive EOC. In this trial, only 3 of 33 evaluable patients had a radiographic partial response, but 42% had stable disease for at least 12 weeks.¹³²

The pure antiestrogen fulvestrant showed a modest degree of antitumor efficacy in a phase 2 trial in which 26 heavily pretreated women (median, 5 prior chemotherapy regimens) with estrogen receptor-positive EOC received fulvestrant. Half of the patients had stabilization of disease, but none had objective responses.¹³³

Although there are no rigorous clinical trial data, there are anecdotal reports of increased response rates and prolonged responses of low-grade ovarian cancers to hormonal therapies.