Obstetrics and Gynecology

Ovarian Cancer - Treatment options for recurrent cancer

Recurrent Ovarian Cancer (Including Fallopian Tube and Primary Peritoneal Cancer)

1. What every clinician should know

The contemporary management of recurrent ovarian, primary peritoneal, or fallopian cancers has continued to evolve and now offers women the hope of extended survival with an improved quality of life, although cure remains elusive once disease recurs. Unfortunately, up to 70% of patients who originally presented with advanced ovarian cancer will recur.

Recurrence of ovarian cancer may occur via a variety of presentations, as disease may be either silent or symptomatic. The confirmation of recurrence is frustrating for patient and physician alike as the response to front-line therapy after initial surgery is often complete, and thus patients are encouraged by the achievement of a complete remission with no evidence of any active disease, only to be disappointed once again.

Generally patients are followed every 3 months for the first 2 years and then every 6 months for at least 5 years following the end of initial chemotherapy. While there are established risk factors for recurrence such as stage and grade of tumor, the outcome or prediction of recurrence can not be made with certainty for any single patient. Some patients with apparent good prognosis disease will recur, and some patients with poor prognosis disease will never recur after initial adjuvant treatment. Patients who do not respond to front-line treatment are technically considered to have persistent, not recurrent, disease; yet many of the treatment options are similar for both groups.

2. Diagnosis and differential diagnosis

Diagnosis of recurrence is usually based upon developing symptoms or the detection of a rising CA-125 value. When symptoms progress or CA-125 levels increase substantially (at least two times the upper limits of normal), imaging studies are generally ordered. Most common is CT scan, but PET scan alone or preferably with CT as well as MRI or U/S may be preferred in some cases.

Some have questioned the value of routinely following CA-125 values as there is one study that has shown that no survival improvement was demonstrated when patients were randomized to withholding CA-125 results and treating only if symptoms occurred thereby triggering imaging versus active treatment of rising values even if the patient has no symptoms or significant disease on imaging studies. In fact, more chemotherapy was administered in the CA-125 knowledgeable group, but quality of life was worse, presumably secondary to side effects from chemotherapy, and survival was not improved. Despite this data, most patients in the U.S. still have CA-125 values checked during surveillance.

The reliability of elevated CA-125 using GCIG criteria reliably predicts recurrent disease in the vast majority of patients. Not all epithelial ovarian cancers express CA-125; thus, this marker is not as effective when not elevated at the time of original diagnosis. It also important to realize that occasionally patients may have a false positive result as a result of poor clearance due to kidney or liver disease or inflammation in the peritoneal cavity that can result in modest rises in markers. Nonetheless, if the trend continues to elevate, the chances of a false positive result diminish precipitously. Other newer markers can also be used, such as HE4 in surveillance for recurrent ovarian cancer.

Establishing recurrent disease is most often via imaging after the patient has increased symptoms such as pain, bloating, early satiety, or change in urinary or bowel habits, or has an elevated serum tumor marker upon routine surveillance. Biopsy is generally not necessary for confirmation unless a patient has had other malignancies or a lesion on scan is not clearly defined. Rising CA-125 values generally pre-date radiographic confirmation by approximately 3 months.

3. Management

A. When should therapies be initiated?

Therapy is generally initiated immediately if imaging shows significant disease, any solid organ involvement or impending bowel obstruction. Otherwise, the timing of initiation of treatment for recurrent ovarian cancer can be individualized.

B. What should the therapy for recurrent cancer be?

Treatment of recurrence must address the goals of extending survival, mitigating symptoms and optimizing quality of life. Treatment of patients with recurrent ovarian cancer has largely been empiric, and there have been limited data available that clearly establishes the preferred choice, combinations and sequence of the ever-expanding array of therapeutic options available. Recent trials and guideline generation have offered clinical guidance for the treatment of recurrent ovarian cancer.

Current management of recurrent ovarian cancer usually is dictated by the interval of time until recurrence of disease is diagnosed. Patients are classified into platinum sensitive, platinum resistant or platinum refractory subgroups.

Platinum sensitivity status has been defined by the length of time from which a patient had been treated with front-line therapy, with 6 months marking the delineation between the sensitive and resistant patients. Those patients who demonstrate progression of tumor during front-line therapy are defined as having platinum refractory disease.

The 6-month delineation between platinum sensitive and platinum resistant disease is based upon the changes in response rates when patients were compared before and after this arbitrary cutoff. Patients who recur just after 6 months from platinum-treatment cessation may respond in a similar manner to a patient whose tumor is platinum resistant compared with a patient whose tumor recurs after 12 or more months. The response rates to platinum re-challenge rise significantly after 12 months from the time of front-line therapy.

Platinum refractory disease

Patients with refractory disease show evidence of a lack of response to front-line therapy, most often in the form of progressive disease. These patients generally exhibit poor objective responses to almost all agents available for re-treatment and the choice of therapy depends upon patient wishes and comorbidities.

Patients that develop platinum refractory disease are good candidates for clinical trials in that new active agents may potentially be identified. Furthermore, a thorough discussion with the patient and her family is necessary to communicate the overall poor prognosis and the low likelihood of identifying an agent that will impart an objective response of any significant duration. Some patients may opt to continue active treatment while others may choose supportive care. In the event that patients are treated with a chemotherapeutic and develop stable disease, it may be prudent to continue with treatment until demonstrable evidence of progression of disease.

Platinum resistant disease

Patients who are defined as having platinum resistance disease develop objective evidence of recurrent disease within 6 months of previous platinum-based therapy. Technically, to be defined as resistant, these patients should be re-challenged with platinum and in turn show a lack of clinical response.

Due to the poor response rates to re-challenging these patients, most clinicians omit re-challenging with platinums and move directly to other therapies. If an agent is found to result in stable disease with mitigation or elimination of symptoms, these patients are likely deriving clinical benefit despite showing now objective evidence of response. Thus these patients may benefit from continued treatment until progression.

The most common treatments for platinum resistant disease are listed in Table I .

Table I.

Common treatments for platinum resistant disease

Therapy options

Three novel agents with unique cytotoxic mechanisms of action have been the most commonly utilized choices in the platinum resistant setting. Two of these agents, pegylated liposomal doxorubicin (PLD) and topotecan, are FDA approved for the treatment of recurrent ovarian cancer. PLD is currently the most frequently utilized of all the options in this setting, yet drug shortages in 2011 and beyond have changed prescribing. The third agent, gemcitabine, has been granted approval only in combination with platinum in the platinum sensitive group, but has been used in combination as well as a single agent in resistant disease.

PLD

PLD consists of doxorubicin that is encapsulated in liposomes and then pegylated or coated with polyethylene glycol. These two processes effect a marked reduction in the cardiac toxicity associated with doxorubicin while prolonging the half-life of the PLD compound such that less frequent dosing is necessary.

In phase II trials, PLD has been shown to have a 14-20% response rate when used as a single agent in patients with recurrent disease. The pivotal phase III randomized trial compared PLD to topotecan and demonstrated a similar response rate and time to progression. Updated survival analysis in this trial noted that patients receiving PLD had an overall survival advantage compared with those treated with topotecan due to the significant survival advantage of PLD seen in patients with platinum-sensitive disease. Survival was not statistically different between agents for those with platinum-resistant disease.

The FDA approved dose for PLD of 50mg/M2 administered every 4 weeks has most commonly been reduced to 40 mg/M2 to decrease the incidence of the two most common significant toxicities: palmer-plantar erythrodysthesia (PPE) and mucositis.

Topotecan

Topotecan is a semi-synthetic derivative of campothecin. Its mechanism of action is as a direct inhibitor of topoisomerase I. This enzyme is critical in the DNA replication process, and inhibition of this enzyme by topotecan results in single and double strand DNA breaks that accumulate and result in apoptotic cell death. Topotecan showed response rates of 14–18% in patients clinically defined as platinum-resistant or platinum-refractory. Significantly, up to nearly 50% of patients demonstrated stable disease in most studies.

The drug has been administered using an on-label 5-day schedule with 30-minute, intravenous (IV) bolus infusions of 1.5 mg/m 2 repeated every 21 days. The dose-limiting toxicity associated with this schedule has been significant neutropenia. Lower doses of topotecan to reduce the incidence of grade 3 and 4 neutropenia that can approach 80% with the traditional dosing schedule have been investigated. The results of these studies demonstrated that the dose of topotecan could be lowered to 1.25 or even 1.0 mg/m 2 without significantly compromising efficacy while decreasing the incidence of toxicity.

Although, these data were based on a 5-day infusion every 3 weeks, phase II data has suggested that weekly topotecan at 4 mg/m 2 is tolerable and efficacious. This weekly regimen is associated with less myelosuppression, but equivalent antitumor activity has not been uniformly seen across trials as some have shown decreased efficacy especially in terms of response with the weekly schedule. Others have explored the use of a 3-day infusion schedule at a dose of 2.0 mg/m 2 with mixed results in terms of efficacy, but with a decrease in the toxicity as well. Currently, the weekly schedule seems to be most utilized despite the concerns with decreased response.

Gemcitabine

The nucleoside analogue gemcitabine initially received an indication in pancreatic cancer and has been utilized in several malignancies including ovarian carcinoma. When utilized in platinum-paclitaxel refractory or resistant ovarian cancer, a 16% objective response rate with median duration of response of 4 months was achieved.

Gemcitabine is well tolerated and does not exhibit cumulative myelosuppression, and it is given as a weekly regimen at doses ranging from 800 to 1,200 mg/m 2. Combination data with PLD or platinum has demonstrated some impressive response rates in platinum resistant patients with responses in the 40% range. The Gynecologic Oncology Group (GOG) completed a trial that exhibited only a 16% response rate in platinum resistant patients when treated with a combination of cisplatinum and gemcitabine, but the progression free survival (PFS) appeared impressive.

Other agents

A number of other agents are available for the treatment of ovarian cancer. Weekly paclitaxel is a frequently utilized option, and response rates compare favorably to other options for these patients. One of the most active single agents in platinum resistant disease is a novel taxane compound, docetaxel, which has shown significant activity with impressive single agent response rates

One well done study by the Gynecologic Oncology Group(GOG) exhibited a 22% response. Hexamethylmelamineis also FDA approved for recurrent ovarian cancer and has demonstrated activity in patients with platinum and/or paclitaxel resistant disease. In a GOG study, however, it was noted to have very limited activity in patients with relapsed platinum-refractory ovarian cancer.

Oral etoposide has been noted to have significant activity in platinum-resistant ovarian cancer. In a GOG study where patients received a starting dose of 50 mg/m 2 for 21 days, the investigators noted a complete response of 7% and a partial response of nearly 20%, for an overall response rate of 27%. Higher cumulative doses and prolonged therapy increase the risk of myelodysplastic syndromes and acute leukemias. These concerns are of less importance in these poor prognosis patients with platinum-resistant disease.

Ifosfamide, an alkylating agent, is administered at a dose of 1.0 or 1.2 g/m 2 for 5 days plus 200 mg/m 2 or 240 mg/m 2 in combination with mesna for uroprotection against hemorrhagic cystitis. In one trial, this regimen produced a response rate of 12% in platinum-refractory patients. Other agents such as tamoxifen demonstrate response rates of 10-15% in those with platinum-resistant ovarian carcinomas. In platinum-resistant patients, weekly vinorelbine administered at a dose of 25 mg/m 2 intravenously was noted to have a response rate of approximately 20%.

Bevacizumab, an anti-angiogenesis agent, is not yet approved for treatment of ovarian cancer in the U.S., but this compound has shown promise in patients with recurrent disease. In one GOG study with a mixture of platinum resistant and sensitive patients, a response rate of 21% and no progression of disease in over 40% of patients at 6 months was observed. This compound is especially effective at targeting ascites and pleural effusions. Data on combinations of bevacizumab with chemotherapeutics such as low dose cyclophosphamide has shown activity as well. Side effects are discussed below.

Another agent not approved for ovarian cancer, yet with demonstrated activity is pemetrexed, an antifolate that inhibits multiple enzymes in the DNA synthesis pathway. Synergy between platinum and pemetrexed has been documented. To estimate the anti-tumor activity and toxicity of pemetrexed in patients with persistent or recurrent platinum-resistant epithelial ovarian or primary peritoneal cancer who have failed on higher priority treatment protocols, a multicenter cooperative group phase II trial was conducted by the GOG. Pemetrexed 900 mg/m 2 was administered as an IV infusion over 10 minutes every 21 days and continued until disease progression or unacceptable adverse effects.

A total of 51 patients were enrolled and received 259 cycles (median: 4; range 1-19) of pemetrexed. 40% of patients received 6 or more cycles. There was 1 CR and 9 PR (21% ORR) with a median duration of response of 6.8 months. An additional 35% had stable disease for 4.1 months. Thirty-eight percent had progressive disease. The median PFS was 3+ months with OS 11.4+ months. The treatment was well tolerated; grade 3/4 toxicities included neutropenia (42%), leukopenia (25%), anemia (15%), and constitutional symptoms (15%). No treatment-related deaths were reported.

Hormonal agents, including tamoxifen, have shown activity in recurrent ovarian cancer, especially in patients with psammoma carcinomas. These agents can result in anti-angiogenic effects and are well tolerated.

Platinum sensitive disease

The treatment approach for patients who recur more than six months after having received primary platinum therapy, defined as platinum sensitive disease, is usually combination chemotherapy. This combination includes a platinum agent.

The question is, should these patients also be retreated with a taxane in addition to the platinum agent? A second question is, should all patients be treated preferentially with a platinum-based regimen or should some patients be treated with non-platinum compounds at the time of first recurrence? If so, who are the best candidates for treatment with a non-platinum agent? The common platinum-based combinations are listed in Table II .

Table II.

Platinum sensitive: Major phase III trials

Several large randomized trials have examined the role of platinum-based combination therapy versus single agent platinum in platinum sensitive patients. The results of these trials have established that there is a benefit to adding a second active agent to those patients who have an adequate performance status. The first trial was conducted by the ICON4 AGO OVAR 2.2 investigators and compared platinum versus platinum and a taxane. This trial, known as ICON 4, showed a statistically improved progression-free and overall survival.

Analysis of this phase III trial revealed significant methodological problems due to subgroup heterogeneity as entry criteria and assessment of response differed among the three groups that enrolled patients. Nonetheless, the importance of the survival advantage demonstrated in this trial cannot be completely discounted, and the platinum-based doublet should serve as the control arm in future trials. The median treatment-free interval for both arms of the trial exceeded 12 months in 75% of cases. Thus the advantage of combination therapy in patients who recur 6-12 months after primary treatment is not clearly established in this study.

The Intergroup trial was principally conducted by the AGO (ArbeitsgemeinschaftGynakologischeOnkologie), and showed that there was a progression-free survival advantage in using platinum in combination with gemcitabine versus using platinum alone. In this trial, there was a progression-free survival benefit for the combination even in the 6-12 month cohort.

Unfortunately, the methodology of that study precluded assessment of overall survival as an endpoint, as it was under-powered to assess this end point, but there was no trend toward any significant improvement in overall survival. In addition, greater toxicity was demonstrated with the combination. The incidence of grade 3/4 neutropenia, thrombocytopenia and anemia was statistically significantly greater in the combination treatment group.

These studies certainly provide evidence that support primary re-treatment with platinum-based compounds. However, the applicability of these trials to all patients with platinum sensitive disease may not be completely valid. The majority of the patients in the ICON4 trial had long platinum free intervals. Thus it may not be necessary to treat those with shorter platinum free intervals with platinum.

It may be possible to achieve the same efficacy by sequencing platinum and other agents without the increase in toxicities observed with platinum-based combination therapy. What these trials have done is establish a new standard. The current convention is to prescribe platinum-based combination therapy for all patients with platinum free intervals of greater than 12 months and for most who recur between 6 and 12 months. Those who are 6-12 months from prior treatment have tumor responses that are not so superior to that of single agents. Thus monotherapy may be considered as an option for those who recur closer to 6 months from prior treatment.

Further trials have tried to define the best option for the second agent that is paired with platinum. The CALYPSO trial compared carboplatin/paclitaxel versus carboplatin/PLD in platinum sensitive patients and found a modest but statistically improved PFS favoring the PLD cohort. No difference in OS was seen, but the investigators concluded that the toxicity and quality of life overall appeared to favor the PLD group as well.

The latest data to be presented combined a targeted anti-angiogenic agent with a platinum/gemcitabine chemotherapy backbone in patients with platinum sensitive disease. The trial compared chemotherapy alone with carboplatin (AUC 4)/gemcitabine (1000 mg days 1 and 8) versus the same regimen plus bevacizumab 15 mg/kg with chemotherapy and until progression. The primary end-point PFS differed by four months (12.4 vs. 8.4), favoring the bevacizumab treated cohort. Additionally the response rate was higher as well (79% vs. 57%). Toxicity was increased with greater hypertension and proteinuria, but no new safety signals were raised as the bevacizumab regimen was well tolerated. GOG 213, besides assessing the value of secondary cytoreduction in platinum sensitive patients, compared the value of adding bevacizumab to carboplatin and paclitaxel chemotherapy in a randomized fashion.

The decision for retreatment versus novel agent administration depends upon multiple factors, including toxicity from prior therapy, patient performance status and co-morbidities, symptoms of recurrence and goals of therapy. Patients with platinum sensitive disease are excellent candidates for clinical trials. This subgroup of patients has been the cornerstone of new drug development, since they have significant and well-characterized response rates that serve as benchmarks for comparison to potentially new active compounds.

Targeted agents

The concept that one can specifically target a molecule, protein or pathway that is over-expressed or up-regulated in cancer, but not in normal tissues, is appealing theoretically. To that end, a large number of compounds have been tested in patients with ovarian cancer.

A number of promising compounds such as epidermal growth factor receptor (EGFR) inhibitors, Poly (ADP-ribose) polymerase (PARP) inhibitors, and anti-angiogenics, among many others, are in development. PARP inhibitors have shown excellent responses in both platinum resistant and sensitive patients, even in patients who lacked BRCA mutations. These agents, however, are not yet clinically available.

Inhibiting angiogenesis is a rational strategy in the treatment of ovarian cancer as this is a vascular endothelial growth factor (VEGF) driven tumor. The anti-angiogenic compound furthest in development for ovarian cancer is bevacizumab, which binds VEGF ligand.

The results of GOG 170-D included 62 platinum sensitive and platinum resistant patients with recurrent or persistent epithelial ovarian or primary peritoneal cancer. Bevacizumab was administered at a dose of 15mg/kg IV every 3 weeks until disease progression or toxicity was reached. The overall objective response rate was 21%, and 55% of the patients were assessed as having had stable disease. The six months progression free survival (PFS) was 40%. Toxicity assessment revealed four patients with grade 3/4 gastrointestinal events, with one patient having a small bowel obstruction. Grade 3 hypertension was observed in four patients. Three patients developed venous thromboembolism.

A second phase II trial reported a 28% response rate and a 55% stable disease rate with the use of bevacizumab in combination with metronomic (low dose) cyclophosphamide in 29 patients treated with bevacizumab at a dose of 10 mg/m2 IV on days 1, 8, 15 and then every two weeks plus cyclophosphamide 50 mg orally every day. Cannistra reported the results from a multi-center, single-arm Phase II trial evaluating bevacizumab in platinum refractory /resistant ovarian cancer patients. Due to an unexpectedly high level of bowel perforations (5 of 44 patients or 11%), enrollment was suspended.

The phase III OCEANS trial seen in Table II showed adding bevacizumab to carboplatin/gemcitabine improved PFS and response. Further affimative data is seen in the AURELIA trial in platinum resistant p.

The role of surgery in recurrent ovarian cancer

The concept of performing surgery in patients who have recurrent ovarian cancer has been controversial and often vexing as different investigators have used different definitions in reporting their findings. Some have confused secondary cytoreduction with second-look, a procedure to determine disease status for patients with no clinical evidence of disease following front-line therapy. Defining clear benefit from either procedure has been difficult in high quality studies. Clearly those who are poor candidates are those patients in whom there is a short treatment-free interval and who have evidence of multifocal disease or ascites.

Several trials have shown clinical benefit for secondary cytoreduction in those patients who have had the longest treatment-free intervals usually exceeding 12 months or longer, and their radiographic findings have been limited to isolated masses. Such patients should be counseled to consider the option of reoperation as removal of these tumors may improve survival. Prospective data is being collected in trials in Europe to assess the ability to determine prognostic factors that predict successful selection of patients for secondary cytoreduction and to see if there is a survival advantage. GOG 213 also will report on the value of secondary cytoreduction in platinum sensitive patients upon completion of this portion of the trial.

7. What is the evidence for specific management and treatment recommendations?

Herzog, TJ. "Recurrent ovarian cancer: How important is it to treat to disease progression?". Clin Cancer Res. vol. 10. 2004. pp. 7439-49.

Herzog, TJ. "The current treatment of recurrent ovarian cancer". Curr Oncol Rep. vol. 8. 2006. pp. 448-54.

Gordon, AN, Tonda, M, Sun, S, Rackoff, W. "Doxil Study 30-49 Investigators. Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian cancer". Gynecol Oncol. vol. 95. 2004 Oct. pp. 1-8.

Parmar, MK, Ledermann, JA, Colombo, N, du Bois, A, Delaloye, JF. "ICON and AGO Collaborators. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial". Lancet. vol. 361. 2003. pp. 2099-106.

Pujade-Lauraine, E, Wagner, U, Aavall-Lundqvist, E, Gebski, V, Heywood, M. "Pegylated liposomal Doxorubicin and Carboplatin compared with Paclitaxel and Carboplatin for patients with platinum-sensitive ovarian cancer in late relapse". J Clin Oncol. vol. 28. 2010 Jul. pp. 3323-9.

Pfisterer, J, Plante, M, Vergote, I, du Bois, A, Hirte, H. "AGO-OVAR; NCIC CTG; EORTC GCG. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCICCTG, and the EORTC GCG". J Clin Oncol. vol. 24. 2006. pp. 4699-707.

Aghajanian. "OCEANS: A randomized, double-blinded, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer". J Clin Oncol. vol. 29. 2011. pp. LBA5007.

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