Radiation therapy
Whole-abdominal irradiation A study by Hepp et al found whole-abdominal irradiation (WAI) to be an effective adjuvant therapy in patients with optimally debulked tumors. In a series of 60 patients, the 5-year survival rate was 55%, with a median follow-up of 96.5 months. Patients who received chemotherapy (n = 41) fared slightly worse than those who received radiation therapy only. The abdominal control rate was 83%, and the grade 3 and 4 late toxicity rates were 7% and 3%, respectively.
The findings indicate that 5- and 10-year survival rates obtained with WAI are at least equivalent to results obtained using modern systemic agents. However, in view of the recognized limitations of these trials, more rigorously gathered data will be required to establish the role of WAI in these patients.
management of Advanced disease
Surgery
In the majority of cases, surgeons operating on patients with ovarian cancer find obvious evidence of widespread metastatic disease. Ascites is often present, with diffuse peritoneal tumor studding and extensive omental involvement. In such cases, it is still important to document the surgical stage (usually a substage of stage III) and carefully evaluate and describe the extent and location of tumor identified at both the beginning and conclusion of surgery.
Optimal cytoreduction The primary function of surgery in patients with advanced ovarian cancer is cytoreduction or debulking. When surgery is performed by experienced gynecologic cancer surgeons, at least 50% of patients with stage III ovarian cancer can be left with "optimal" residual tumor (ie, ≤ 1 cm). The morbidity associated with such surgery is low, and operative mortality is rare.
Patients with optimally debulked disease have an increased likelihood of achieving a complete clinical response to chemotherapy. Disease progression-free interval, median survival, and long-term survival are all improved in patients who have optimal cytoreduction.
Even among patients with suboptimal residual disease (> 1 cm) after primary surgery, those left with smaller tumor volumes (1 to 2 cm) have a survival advantage over those with a larger residuum. It is thus clear that aggressive surgical cytoreduction, if successful in reducing tumor to small volumes, improves several measures of outcome.
Interval cytoreduction In an EORTC trial, 299 patients with suboptimal advanced ovarian cancer were randomized to receive 6 cycles of cisplatin plus cyclophosphamide with or without interval surgical cytoreduction after the third cycle. Median survival for patients who underwent interval debulking surgery was 27 months, vs 19 months for patients who did not have interval debulking (P = .01). The GOG then completed a randomized trial of interval cytoreduction using a cisplatin-paclitaxel chemotherapy regimen. These results show no benefit for interval cytoreduction (median overall survival, 32 vs 33 months). Taxane-based chemotherapy and more standardized aggressive initial debulking by experienced gynecologic oncologists in the GOG trial have been offered as possible explanations for the discordant outcomes. If an aggressive initial surgical attempt is provided by a gynecologic oncologist, interval surgical cytoreduction cannot be routinely recommended.
Chemotherapy
Two GOG studies have indicated that the major survival benefit of cytoreductive surgery was in those patients who were optimally cytoreduced to no macroscopic residual disease. In the first series, 1,895 patients with stage III disease received cisplatin and paclitaxel in standard IV regimens. Optimal cytoreduction to no macroscopic disease was achieved in 23%. This resulted in significantly better (P < .001) progression-free and overall survival rates (PFS = 33.0 months; OS = 71.9 months) vs patients with residual disease of 0.1 to 1 cm residual disease (PFS = 16.8 months; OS = 42.4 months) or residual disease greater than 1 cm (PFS = 14.1 months; OS = 35.0 months). In a subsequent GOG report on 360 patients with stage IV disease who received cisplatin and paclitaxel in standard IV regimens, 8% were optimally cytoreduced to no macroscopic residual tumor, yielding a PFS of 20.1 months and an OS of 64.1 months. For those patients with residual disease less than or equal to 1 cm, or between 1.1 and 5 cm, PFS and OS rates were similar (PFS = 13.0 months in both groups; OS = 28.7 and 31 months, respectively; Winter WE III et al: J Clin Oncol 25:3621–3627, 2007; Winter WE III et al: J Clin Oncol 26:83–89, 2008).
Primary treatment The results of two randomized trials support a survival advantage for patients treated with combinations of IV platinum and paclitaxel, as compared with those given a platinum plus cyclophosphamide. McGuire et al found a 37- vs 24-month median survival advantage for the platinum-paclitaxel arm. Similarly, an analysis of the intergroup trial by Piccart et al showed an improvement in median survival from 25 to 35 months (P = .001) in favor of the paclitaxel arm. In contrast, the initial analysis of the ICON 3 trial evaluating a control arm (carboplatin or CAP [cyclophosphamide, Adriamycin (doxorubicin), Platinol (carboplatin)] chemotherapy) vs paclitaxel and carboplatin has failed to show a survival advantage for the taxane-containing arm. Many factors in the study have been proposed to explain this difference, and for the present, taxane- and platinum-based therapy remains the standard.
A randomized trial (GOG 158) comparing paclitaxel (175 mg/ m² via a 3-hour infusion) plus carboplatin (dosed to achieve an area under the concentration-time curve [AUC] of 7.5) vs the standard regimen of paclitaxel (135 mg/ m² via a 24-hour infusion) plus cisplatin (75 mg/ m²) in patients with optimally debulked disease showed the shorter schedule with carboplatin to be as effective as the older regimen. Due to its decreased toxicity and ease of administration, the shorter schedule with carboplatin is the preferred treatment.
In addition, the SCOTROC trial suggested that, as primary treatment, docetaxel (Taxotere) and paclitaxel have similar efficacy when combined with carboplatin and that docetaxel produces less neuropathy.
A five-arm international randomized study of primary therapy for patients with stage III or IV disease evaluated carboplatin and paclitaxel as the control arm and studied two triplets (carboplatin + paclitaxel with either gemcitabine [Gemzar] or liposomal doxorubicin [Doxil]) and two sequential doublets (topotecan [Hycamtin]/carboplatin + carboplatin/paclitaxel or carboplatin/gemcitabine + carboplatin/paclitaxel). No difference in progression-free or overall survival rates was seen among the arms, and therefore paclitaxel and carboplatin remains the standard. Based on the variety of phase III trials employing IV paclitaxel and carboplatin therapy following maximal surgical cytoreduction, the expected progression-free and overall survival rates of stage III patients follow: stage III optimal (progression-free survival, 21 to 28 months; overall survival, 52 to 57 months) and stage III suboptimal (progression-free survival, 18 months; overall survival, 38 months).
Neoadjuvant chemotherapy In patients with an inadequate performance status to undergo aggressive primary debulking, a "neoadjuvant" approach with paclitaxel and carboplatin is often considered for several cycles prior to a maximal cytoreductive effort. A large randomized trial reported by Vergote et al evaluated the use of neoadjuvant chemotherapy in 718 patients with stages IIIC–IV ovarian cancer. Patients were randomized to undergo primary debulking followed by 6 courses of paclitaxel and carboplatin chemotherapy (arm A) vs 3 courses of neoadjuvant chemotherapy, interval debulking, and then 3 additional courses (arm B). In the reported data in abstract form, median overall survival was 29 and 30 months for arms A and B, respectively (HR, 0.098; CI: 0.85–1.14); the median progression-free survival was 11 months in both arms (HR, 0.99; CI: 0.87–1.13). The overall survival in both arms was lower than expected, but there was no difference between them. The approach is still controversial, and most gynecologic oncologists still consider primary surgical debulking the standard of care, reserving neoadjuvant therapy only for those patients in whom primary optimal debulking will not be achieved. Further developments in this area will be forthcoming.
The role of bevacizumab in primary treatment Bevacizumab (Avastin) has shown activity in patients with recurrent ovarian cancer. Response rates of 16% and 21% have been reported when it is used as a single agent and of 24% when it is used in conjunction with oral cyclophosphamide. The progression-free intervals across trials range from 4.4 months to 7.2 months, and the median overall survival ranges from 10.7 months to 17 months. An important and large first-line chemotherapy trial was reported at ASCO 2010. This trial randomized patients with stages III and IV ovarian cancer following surgical debulking to receive paclitaxel and carboplatin + placebo followed by placebo maintenance (total therapy, 15 months), paclitaxel and carboplatin + bevacizumab followed by placebo maintenance, or paclitaxel and carboplatin + bevacizumab with bevacizumab maintenance. This trial evaluated toxicity, progression-free, and overall survival. A total of 1,873 patients were enrolled in the study. The baseline clinical characteristics were well balanced. Adverse events were typical of those seen in other bevacizumab-containing studies. Hypertension was seen in 16%–22% of the bevacizumab-containing arms, and bowel perforations occurred in <>
As a result of these preliminary data, there are many questions to consider. They will be answered in time with additional studies or clarified once details are available. Will there be an overall survival benefit? If not, is a strategy that prolongs only progression-free survival sufficient? How long should bevacizumab be given? Should it be continued longer than 15 months, until disease progression, or for life? What happens when bevacizumab is discontinued? Is the phenotype of relapsed disease on bevacizumab more aggressive? Is there rebound at its discontinuation? Finally, is the "cure" proportion improved with prolonged bevacizumab use?
Intraperitoneal chemotherapy
The randomized study by Armstrong et al employed intraperitoneal (IP) therapy as part of primary treatment. They showed a median overall survival of 65.6 months for the IP arm vs 49 months in the IV group. This finding represents the largest difference to date between two treatment arms in any study evaluating primary therapy. The study is the third in a series of studies supporting the IP administration of primary chemotherapy to optimally debulked stage III patients.
The first study by Alberts et al predated paclitaxel and carboplatin use and simply asked the question of whether the IV or IP administration of cisplatin was better, showing an advantage for the latter (median overall survival, 49 vs 41 months; P = .02) This first IP study has been criticized because it does not contain paclitaxel and thus does not reflect contemporary treatment.
Early treatment of relapse immediately after testing positive for elevated CA-125 levels in women with ovarian cancer in clinical complete remission does not improve survival over delaying treatment until the occurrence of clinical symptoms of relapse such as pelvic pain or bloating. This was according to data presented at ASCO 2009. In this study, investigators compared overall survival between 265 women with ovarian cancer in remission after initial chemotherapy who began second-line chemotherapy after experiencing a rise in CA-125 level, and 264 women with rising CA-125 level whose treatment was delayed until symptoms of relapse appeared. Second-line chemotherapy was started in the early treatment group a median 5 months before the delayed treatment group. At the time the study was presented, overall survival was the same between both groups (HR, 1.01, 95% CI: 0.82–1.25: P = .91). Researchers concluded that there was no survival benefit from early treatment based on a raised serum marker level alone. They added that consequently, there was no value in the routine measurement of CA-125 levels in the follow-up of ovarian cancer patients (Rustin GJ et al: J Clin Oncol 27[18S]: abstract P1, 2009).
The second study by Markman et al included paclitaxel, but the experimental arm not only included IP delivery of cisplatin but also added high-dose IV carboplatin in an attempt to "chemically debulk" the tumor prior to IP administration. The Markman study, while also showing an advantage for the IP-containing experimental arm (overall survival, 52 vs 63 months; P = .05), was criticized because more than one variable was changed and the benefit could not be directly attributed to IP therapy.
As previously discussed, the third and well-designed trial by Armstrong et al showed a median overall survival of 65.6 months for the IP arm vs 49 months for the IV group. This study used IV paclitaxel (135 mg/ m²) over 24 hours on day 1, IP cisplatin (100 mg/ m²) on day 2, and IP paclitaxel (60 mg/ m²) on day 8 for 6 total cycles. Due to increased toxicity in the IP arm (metabolic, neuropathy), only 42% of patients completed all 6 cycles. However, a quality-of-life analysis at 12 months showed no difference between the IP and IV groups, suggesting the toxicity was reversible.
The general consensus opinion is that patients with stage III optimally debulked disease should be offered IP primary therapy. Studies are under way to modulate the regimen in an attempt to preserve the benefit and lessen toxicity. Initial modifications have included changing the IV paclitaxel to 135 mg/ m² over 3 hours on day 1 and lowering the IP cisplatin dose to 75 mg/ m² on day 2. If toxicity becomes prohibitive for a given patient, therapy is completed using IV paclitaxel and carboplatin. For patients not suited for IP treatment or for suboptimally debulked stage III patients or those with stage IV disease, IV paclitaxel with carboplatin also remains the standard. The next logical step to be addressed in upcoming cooperative groups is how to combine IP therapy with bevacizumab-containing treatment while also reducing the toxicity of IP therapy.
Radiation therapy as a single modality
In ovarian cancer, no prospective randomized trial has compared WAI, performed with modern techniques and equipment, with a paclitaxel-containing chemotherapy regimen. It has been demonstrated that the ability of WAI to sterilize macroscopic deposits of ovarian carcinoma is limited. Patients with any site of residual disease > 1 cm have compromised outcomes. The limited radiation tolerance of the abdominal organs also limits the radiation dose. Chemotherapy remains the standard of care for the adjuvant treatment of ovarian cancer.
Chemotherapy plus radiation therapy
Sequential combined-modality therapy (CMT) employing chemotherapy and irradiation has been shown in randomized trials to significantly increase survival over patients treated with chemotherapy alone. A phase III prospective randomized trial in patients with stage III ovarian cancer from the SNG showed a significant 20% improvement in 5-year progression-free survival for patients treated with chemotherapy and WAI vs chemotherapy alone.
In another European study, 64 of 94 patients with stages IC–IV disease who had undergone "radical" surgery and had no evidence of gross residual disease after 6 courses of chemotherapy (carboplatin, epirubicin, and prednimustine) were randomized to receive either consolidation WAI (30 Gy), followed by a boost to the para-aortic region and pelvis (12.0 and 21.6 Gy, respectively), or no further therapy. Relapse-free survival rates were significantly higher in patients who received adjuvant chemoradiation therapy than in those who received adjuvant chemotherapy only (2- and 5-year relapse-free survival rates, 68% vs 56% and 49% vs 26%, respectively); the same was true of overall survival rates (2- and 5-year overall survival rates, 87% vs 61% and 59% vs 33%, respectively). The differences between the two treatment groups were more pronounced in patients with stage III disease (2- and 5-year relapse-free survival rates, 77% vs 54% and 45% vs 19%, respectively; 2- and 5-year overall survival rates, 88% vs 58% and 59% vs 26%, respectively).
Einhorn et al, from the Karolinska Hospital in Stockholm, treated 75 patients with stages IIB–IV ovarian carcinoma with combined surgery, chemotherapy, and WAI to 40 Gy, utilizing a "six-field" approach. Outcomes were compared with those of 98 patients treated in subsequent years with only surgery and chemotherapy. After different prognostic factors were controlled statistically, it was found that patients who received WAI had a significantly better survival rate than those who did not. The authors suggest that, given the results of this and other studies combined with the limited success of modern combination chemotherapy regimens, the role of abdominal radiation therapy should be further investigated in a prospective fashion.
Despite these successful European trials, the regimen of chemotherapy and radiation in the up-front management of stage III ovarian cancer has not been implemented in the United States due to many factors. Paclitaxel-based chemotherapy provides a significant benefit for patients, as does IP chemotherapy. The use of radiation may increase potential bowel toxicity, particularly IP chemotherapy, and in some patients may cause bone marrow suppression, which theoretically may hinder future administration of chemotherapy.
TABLE 4Possible prognostic factors for salvage radiation therapy following chemotherapy
Recurrent disease
Patients who respond to primary chemotherapy with paclitaxel and platinum agents and who relapse ≥ 6 months after the completion of treatment often have additional responses when retreated with the same agents. Response rates to repeat treatment with carboplatin are ~30% in those patients who relapse 12 months after primary therapy and 57% if the relapses occur > 24 months after primary therapy. In addition, a plethora of new agents have demonstrated modest phase II activity in patients with refractory disease.
Topotecan has received FDA approval for the treatment of patients with refractory disease (Table 3). An oral preparation is in phase III trials.
An open, randomized study compared topotecan (1.5 mg/m²/d for 5 days) with paclitaxel (175 mg/ m² q21d) in 226 women whose ovarian cancer had recurred after first-line platinum therapy. There were no statistically significant differences between the treatment groups with respect to response rate (20.5% vs 14.0%), response duration (25.9 vs 21.6 weeks), or median survival (63 vs 53 weeks).
Topotecan has efficacy comparable to that of paclitaxel in this setting and is being evaluated in combination with platinum and other agents.
Liposomal doxorubicin also has received FDA approval for the treatment of patients with metastatic platinum- and paclitaxel-refractory disease. A randomized trial by Gordon et al compared liposomal doxorubicin with topotecan in this setting; similar response rates, time to disease progression, and overall survival (60.0 vs 56.7 weeks) were seen with these two agents.
Other agents Phase II trials have demonstrated the activity of other agents in patients with recurrent ovarian cancer. They include gemcitabine, vinorelbine, oral altretamine (Hexalen), oral etoposide, irinotecan, and bevacizumab. In general, these agents have similar response rates, ranging from 10% to 15% in patients with platinum-resistant disease and 30% in patients with platinum-sensitive disease, with a median duration of response ranging from 4 to 8+ months. With the judicious selection and dosing of available agents to keep symptoms from disease and treatment to a minimum, a good quality of life can be maintained throughout much of the disease course.
A randomized ICON 4/AGO-OVAR 2.2 study addressed the issue of using single-agent carboplatin vs paclitaxel with carboplatin for patients with platinum-sensitive recurrent disease (defined generally as patients relapsing more than 6 months from prior platinum therapy). Both progression-free (HR, 0.76; 95% CI: 0.66–0.80; P = .0004) and 1-year overall survival rates (50% vs 40%) favored combination therapy. An AGO study evaluating carboplatin vs carboplatin with gemcitabine in a similar population was reported. This study likewise showed an improved response rate (47.2% vs 30.9%; P = .0016) and disease progression-free survival (8.6 vs 5.8 months; P = .0031) favoring the combination.
Preliminary results of the CALYPSO study have been reported in abstract form in the platinum-sensitive population. This study compared paclitaxel and carboplatin with liposomal doxorubicin and carboplatin. It showed an extended progression-free survival favoring the liposomal doxorubicin and carboplatin combination, from 9.4 months to 11.3 months (HR, 0.82; 95% CI: 0.72–0.94). Taken together, these data at a minimum suggest a benefit for platinum-based combination therapy over single-agent carboplatin in patients with platinum-sensitive recurrence. Survival data from the CALYPSO study are not yet mature.
The role of antivascular agents in recurrent disease
The single-agent and combination chemotherapy response rates for bevacizumab in patients with recurrent disease are reviewed in the section justifying the clinical trials and evaluating its potential use in the first-line setting. Several large important phase III studies are also ongoing in patients with platinum-sensitive recurrent disease (defined as > 6 months from prior platinum treatment). The GOG trial (NCT0056551) is randomizing recurrent patients to a secondary debulking or not and then to paclitaxel and carboplatin with or without bevacizumab. Primary objectives are to determine whether secondary surgical cytoreduction followed by adjuvant chemotherapy with or without bevacizumab prolongs overall survival. Bevacizumab continues in responders to evaluate the potential benefit of maintenance. Secondary objectives are to evaluate progression-free survival and quality of life, with a planned enrollment of 660 patients.
The ICON 6 study (NCT00544973) is evaluating patients with paclitaxel and carboplatin with or without AZ2171 (cediranib) and includes both a concurrent arm as well as a concurrent approach followed by maintenance therapy. Primary endpoints are safety, progression-free survival, and overall survival, with a planned enrollment estimate of 2,000 patients. Finally, the OCEANS study (NCT00434642) is evaluating the use of gemcitabine and carboplatin with or without bevacizumab in patients with platinum-sensitive disease. The primary endpoint is progression-free survival, with secondary endpoints to include overall survival and safety, particularly characterizing the incidence of gastrointestinal perforation. Planned enrollment is 440 patients.
Salvage and palliative radiotherapy after chemotherapy
In the setting of small-volume residual disease detected after chemotherapy, external-beam irradiation has been used with some success. Favorable experiences with salvage radiation therapy in chemotherapy-refractory ovarian carcinomas continue to be reported. Table 4 lists possible prognostic variables in these patients.
In a report of 20 patients who received multiple chemotherapy regimens for recurrent disease located in the pelvis, surgical debulking of the recurrent mass was followed by postoperative radiation therapy to 50.4 Gy. Patients who were able to have complete debulking and radiation had a 3-year overall survival of 50%, a disease-free survival of 72%, and local relapse-free survival of 89%; those with residual disease had corresponding values of 19%, 22%, and 42%, respectively. Radiation therapy should be considered for patients with localized recurrence of ovarian cancer who have failed to respond to multiple chemotherapy regimens, given the general sensitivity of ovarian cancer to radiation therapy.
Sedlacek et al described 27 patients who had not responded to aggressive cytoreductive surgery followed by multiple-drug platinum-based chemotherapy and who received WAI (30 to 35 Gy at 100 to 50 cGy/fraction, with a pelvic boost to a total dose of 45 Gy). The 5-year survival rate was 15%. The extent of residual disease at the initiation of radiation therapy strongly correlated with the length of survival.
Baker et al analyzed the efficacy of salvage WAI in 47 patients with ovarian cancer who had not responded to one or more chemotherapy regimens. Actuarial 4-year survival and disease-free survival rates were 48% and 37%, respectively, in patients with microscopic residual disease, vs 11% and 5%, respectively, in patients with macroscopic residual disease. In addition, patients with disease limited to the pelvis after laparotomy (including gross disease) had a 4-year actuarial survival rate of 60% and a disease-free survival rate of 54%, as compared with 16% and 4%, respectively, in patients with upper abdominal involvement.
This finding was confirmed by Firat and Erickson, who described their experience with selective radiotherapy in 28 patients with recurrent or persistent disease involving the vagina and/or rectum. Pelvic radiotherapy was uniformly successful in palliating vaginal bleeding. Furthermore, there were eight long-term survivors (five with no evidence of disease), implying that pelvic radiotherapy alone can be effective salvage therapy, particularly when there is no extrapelvic disease.
Fujiwara and colleagues reported high rates of objective and symptomatic responses using local radiotherapy in 20 patients (42 evaluable lesions) with recurrent ovarian cancer following chemotherapy. Lymph node metastases appeared to be particularly responsive.
Tinger et al reported an overall response rate of 73% in 80 patients with advanced and recurrent disease treated with palliative intent. Responses were maintained until death in all but 10 patients. Toxicity was limited, and there was no grade 4 toxicity. It was suggested that response rate, survival, and toxicity with palliative radiotherapy compared favorably with those of second- and third-line chemotherapies.
Based on these and other studies, certain treatment guidelines can be suggested:
• Palliation of vaginal bleeding, pelvic pain, or bowel or bladder blockage due to tumor compression may be feasible.
• Salvage radiation therapy may also be considered in selected patients after a localized pelvic recurrence following maximal debulking.
Novel approaches
The randomized trials evaluating the role of antivascular strategies in patients with ovarian cancer are all nearing completion, and results will be available soon to guide their use in both the primary and recurrent settings. Other clinical trials evaluating PARP (poly [ADP-ribose] polymerase) inhibitors and other targeted agents are ongoing, and clinical trial participation should be supported whenever possible.
High-dose chemotherapy In a trial conducted largely in patients with platinum-resistant (66%) and bulky disease (61%), the median progression-free and overall survival intervals were short (7 and 13 months, respectively) in those treated with high-dose chemotherapy and stem cell support, suggesting no benefit. There is no role for high-dose chemotherapy in the standard management of patients with epithelial ovarian cancer.
Treatment recommendations and unresolved issues
For advanced ovarian cancer, current front-line management should incorporate a taxane with platinum-based therapy, utilizing an IV and/or IP route. Results also support the use of a taxane and platinum-based therapy in patients with high-risk early-stage disease.
Issues that are evolving include (1) considering a variety of IP doses and schedules to reduce the toxicity of this approach, which has been shown to prolong overall survival; (2) the role of maintenance or consolidation treatment with standard chemotherapy or with novel agents following primary therapy; (3) the optimal use of platinum vs nonplatinum agents, and whether they should be used as single agents or in combination, for patients with recurrent disease; and (4) the role of novel drugs, notably bevacizumab and other antivascular agents, in both the adjuvant and recurrent-disease settings.
