May 01, 2014 | Cancer Management
By Colleen M. Feltmate, MD, Paul Sabbatini, MD, and Akila N. Viswanathan, MD, MPH
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I SAW THIS IN THE CANCER NETWORK, HOME OF THE JOURNAL ONCOLOGY (from May 2014).
It is a long old read but maybe some will find some useful info:
OVARIAN CANCER
Management of Advanced Disease
Surgery
In the majority of cases (upwards of 75%), 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. Mounting evidence indicates that patients with no visible residual disease have the greatest improvement in outcome, and that this benchmark should represent the standard.
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.
Two GOG studies (Winter et al: J Clin Oncol 2007; Winter et al: J Clin Oncol 2008) have indicated that the major survival benefit of cytoreductive surgery was in those patients who received optimal cytoreduction to no macroscopic residual disease. In the first series, 1,895 patients with stage III disease received cisplatin and paclitaxel in standard intravenous (IV) regimens. Optimal cytoreduction to no macroscopic disease was achieved in 23%. This resulted in significantly better (P < .001) median progression-free survival and overall survival rates (progression-free survival, 33 months; overall survival, 71.9 months) compared with patients with residual disease of 0.1 to 1 cm (progression-free survival, 16.8 months; overall survival, 42.4 months) or residual disease greater than 1 cm (progression-free survival, 14.1 months; overall survival, 35 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 progression-free survival of 20.1 months and an overall survival of 64.1 months. For those patients with residual disease 1 cm or less , or between 1.1 and 5 cm, progression-free survival and overall survival rates were similar (progression-free survival, 13 months in both groups; overall survival, 28.7 and 31 months, respectively).
Interval cytoreduction following suboptimal initial cytoreduction. In an EORTC trial, 299 patients with suboptimal advanced ovarian cancer were randomized to receive six 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 months 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
Primary treatment. The results of two randomized trials support a survival advantage for patients treated with combinations of IV platinum and paclitaxel, compared with those given a platinum plus cyclophosphamide. McGuire et al (N Engl J Med 1996) found a 37-month vs 24-month median survival advantage for the platinum-paclitaxel arm. Similarly, an analysis of the intergroup trial by Piccart et al (J Natl Cancer Inst 2000) showed an improvement in median survival from 25 months 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 cyclophosphamide, Adriamycin [doxorubicin], Platinol [carboplatin] chemotherapy) vs paclitaxel and carboplatin 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 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. Because of its decreased toxicity and ease of administration, the shorter schedule with carboplatin is the preferred treatment.
In addition, the Scottish Randomized Trial in Ovarian Cancer (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 or liposomal doxorubicin [Doxil]) and two sequential doublets (topotecan/carboplatin + carboplatin/paclitaxel or carboplatin/gemcitabine + carboplatin/paclitaxel). No difference in progression-free survival or overall survival rates were 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 survival and overall survival rates for patients with stage III disease are as follows: stage III optimal (progression-free survival, 21 months to 28 months; overall survival, 52 months to 57 months) and stage III suboptimal (progression-free survival, 18 months; overall survival, 38 months).
A randomized trial by Katsumata et al also evaluated paclitaxel and carbolpatin given IV with one arm receiving paclitaxel at 80 mg/m2 weekly vs conventional dosing at 175 mg/m2 every 21 days. Of 631 eligible patients withg stage II–IV disease, the progression interval favored the dose-dense paclitaxel arm at 28 months vs 17 months (hazard ratio [HR] = 0.71; 95% confidence interval [CI], 0.58–0.88; P = .0015). Overall survival at 3 years was also higher for the dose-dense arm (72.1% vs 65.1%; HR = 0.75; 95% CI, 0.57–0.98; P = .03). This finding is currently under evaluation in ongoing cooperative group trials and is not considered standard at this time.
Neoadjuvant chemotherapy (NACT) with interval cytoreductive surgery. In patients with an inadequate performance status to undergo aggressive primary debulking or in whom the level of tumor involvement is not believed to support "optimal cytoreduction," a "neoadjuvant" approach with paclitaxel and carboplatin is often considered for several cycles before 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 six courses of paclitaxel and carboplatin chemotherapy (arm A) or to receive three courses of neoadjuvant chemotherapy, interval debulking, and then three additional courses (arm B). In the reported data, median overall survival was 29 months 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 demonstrated 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 a rate of 24% was shown 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. This prompted evaluation of bevacizumab as part of primary treatment. An important and large first-line chemotherapy trial (GOG 218) 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 (at 15 mg/kg) followed by placebo maintenance; or paclitaxel and carboplatin + bevacizumab (at 15 mg/kg) with bevacizumab maintenance. This trial evaluated toxicity, progression-free survival, 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% to 22% of the bevacizumab-containing arms, and bowel perforations occurred in fewer than 3%. The median progression-free survival was 10.3 months for patients treated with chemotherapy alone vs 14.1 months for those who received extended-schedule bevacizumab (HR = 0.717; 95% CI, 0.625–0.824; P < .001). No difference in overall survival was seen. However, as 40% of patients in the chemotherapy-only arm subsequently received bevacizumab at progression, a potential overall survival would be difficult to demonstrate. The ICON 7 study evaluated paclitaxel and carboplatin with or without bevacizumab (at 7.5 mg/kg) for 12 additional cycles, with recent follow-up showing a progression-free survival advantage in favor of bevacizumab of 21.8 months vs 20.3 months (HR = 0.81; 95% CI, 0.70–0.94; P = .004). A trend toward a survival advantage is seen in patients who entered the study with bulk disease ("high risk") but not in those without bulk disease ("low risk"). No differences in overall survival have emerged. Important differences in this study are the bevacizumab dose; length of administration; and the eligibility criteria, which included high-risk early-stage patients.
As a result of these data, there are many questions to consider regarding bevacizumab use in the first-line setting. Key questions are: Will there be an overall survival benefit in prolonged follow-up? 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? Finally, is the proportion with "cure" improved by prolonged bevacizumab?
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 for 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 (to be discussed further below) in a series of studies supporting the IP administration of primary chemotherapy to optimally debulked stage III patients.
The first study (Alberts et al: N Engl J Med 1996) 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 months 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.
The second study, by Markman et al (J Clin Oncol 2003), 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 before IP administration. The Markman study, while also showing an advantage for the IP-containing experimental arm (overall survival, 52 months 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 six total cycles. Because of increased toxicity in the IP arm (metabolic, neuropathy), only 42% of patients completed all six 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 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 patients with suboptimally debulked stage III disease or those with stage IV disease, IV paclitaxel with carboplatin also remains the standard. The next logical step, which is being addressed in the cooperative groups with ongoing trials, 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 of greater than 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 employing chemotherapy and irradiation has been shown in randomized trials to significantly increase survival compared with use of chemotherapy alone. A phase III prospective randomized trial in patients with stage III ovarian cancer from the Swedish-Norwegian Group showed a significant 20% improvement in 5-year progression-free survival for patients treated with chemotherapy and WAI vs chemotherapy alone. Similarly, a study in stage I–II clear cell carcinoma patients showed a 20% survival advantage for the use of radiation after carboplatin and paclitaxel chemotherapy.
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 six 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 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-year and 5-year relapse-free survival rates, 68% vs 56% and 49% vs 26%, respectively); the same was true of overall survival rates (2-year 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-year and 5-year relapse-free survival rates, 77% vs 54% and 45% vs 19%, respectively; 2-year and 5-year overall survival rates, 88% vs 58% and 59% vs 26%, respectively).
Einhorn et al (Radiother Oncol 1999), from the Karolinska Hospital in Stockholm, treated 75 patients with stages IIB–IV ovarian carcinoma with combined surgery, chemotherapy, and WAI to 40 Gy, using 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 because of 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.
Recurrent disease
Patients who progress on primary platinum treatment are classified as refractory. Patients who respond (approximately 70%) and then have a recurrence are generally categorized into those who relapse 6 months or less from prior therapy (considered platinum-resistant) or those who relapse more than 6 months after treatment (considered platinum-sensitive).
Data presented by Rustin et al at the 2009 ASCO meeting indicate that in women whose ovarian cancer is in clinical complete remission, early treatment of relapse immediately after the patient tests positive for elevated CA-125 levels does not improve survival over delaying treatment until clinical symptoms of relapse occur, such as pelvic pain or bloating. In their study, these investigators compared overall survival in 265 women with ovarian cancer in remission after initial chemotherapy who began second-line chemotherapy after experiencing a rise in CA-125 level with overall survival in 264 women with rising CA-125 levels whose treatment was delayed until symptoms of relapse appeared. Second-line chemotherapy was started in the early-treatment group a median of 5 months before it was started in 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 routine measurement of CA-125 levels in the follow-up of ovarian cancer patients.
Platinum-resistant recurrence. For platinum-resistant patients, a series of agents have demonstrated modest activity, and they are chosen on the basis of schedule and expected toxicity. Doublets have not been shown to be more effective than sequential single agents for patients with platinum-refractory or platinum-resistant disease. Topotecan and liposomal doxorubicin have FDA approval as single agents for ovarian cancer patients with recurrence.
TABLE 3: Chemotherapy regimens for ovarian carcinoma
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%), response duration (25.9 weeks vs 21.6 weeks), or median survival (63 weeks vs 53 weeks). Liposomal doxorubicin was then compared with topotecan in patients with metastatic platinum- and paclitaxel-refractory disease in a randomized trial by Gordon et al, which showed similar response rates, time to disease progression, and median survival (60 weeks vs 56.7 weeks) in the overall population.
Phase II trials have demonstrated the activity of other agents in patients with recurrent ovarian cancer. They include gemcitabine, vinorelbine, oral altretamine, oral etoposide, irinotecan, bevacizumab and, recently, pemetrexed. 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 months to 8 or more 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.
Platinum-sensitive recurrence. A randomized ICON 4/Arbeitsgemeinschaft Gynaekologische Onkologie Studiengrappe Ovarialkarzinom (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 survival (HR = 0.76; 95% CI, 0.66–0.8; 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 months vs 5.8 months; P = .0031) favoring the combination.
Results of the CALYPSO study have been reported 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; P = .005). Additional follow-up showed no difference in overall survival between the two arms. 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; there was no difference in overall survival (31.5 months for both groups; P = .987), suggesting equivalence of the paclitaxel and carboplatin regimens in terms of efficacy. The benefits of the nontaxane doublets for platinum-sensitive recurrence (ie, with gemcitabine or liposomal doxorubicin) include the lack of worsening neuropathy and no alopecia, making these attractive alternatives in this patient population.
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 patients with recurrent disease 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 is continued 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 treated with paclitaxel and carboplatin with or without AZ2171 (cediranib) and includes both a concurrent arm and a concurrent approach followed by maintenance therapy. Primary end points are safety, progression-free survival, and overall survival, with a planned enrollment estimate of 2,000 patients. The OCEANS study, with 484 patients enrolled, evaluated use of gemcitabine and carboplatin with or without bevacizumab in patients with platinum-sensitive disease, with continued administration of bevacizumab until progression or toxicity. The primary end point was progression-free survival; secondary end points included overall survival and safety, particularly characterizing the incidence of gastrointestinal perforation. Preliminary results were presented at ASCO 2011. The arms were well balanced. Efficacy outcomes favored the bevacizumab arm, with response rates of 79% vs 57% (P < .0001) and progression-free survival of 12.4 months vs 8.4 months (HR = 0.484; 95% CI, 0.388–0.605; P < .0001). All subgroups (platinum-free interval, age, performance status, and presence or absence of cytoreductive surgery) showed similar benefit. A difference in overall survival was not noted. Toxicity was as seen in previous studies, with hypertension and proteinuria being the most common (but manageable) toxicities; no bowel perforations were seen. The combination of gemcitabine and carboplatin with bevacizumab followed by bevacizumab maintenance showed a progression-free survival benefit over gemcitabine and carboplatin alone. The AURELIA study, a phase III trial in patients with recurrent planinum-resistent disease receiving bevacizumab in combination with paclitaxel, topotecan, or liposomal doxorubicin showed a significant improvement in progression-free survival (3.4 months vs 6.7 months). While both the OCEANS and AURELIA studies demonstrated improved progression-free survival, this did not translate to improved overall survival.
Sidebar: The AURELIA trial, reported in abstract form at ASCO 2012, included 361 patients with platinum-resistant disease. The patients were randomized to receive either paclitaxel, liposomal doxorubicin, or topotecan with or without bevacizumab. Response rate and progression-free survival (HR = 0.48; 95% CI, 0.38–0.61; P < .001) were significantly improved in patients who received bevacizumab in conjunction with chemotherapy compared with those who did not receive bevacizumab (Pujade-Lauraine E et al: J Clin Oncol 30(S):abstract LBA5002, 2012).
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 patients with chemotherapy-refractory ovarian carcinomas continue to be reported. Table 4 lists possible prognostic variables in these patients.
TABLE 4: Possible prognostic factors for salvage radiation therapy following chemotherapy
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 (ASCO 1997, abstract 1263) 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 150 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%, compared with 16% and 4%, respectively, in patients with upper abdominal involvement.
This finding was confirmed by Firat and Erickson (Gynecol Oncol 2001), 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 (Int J Gynecol Cancer 2002) 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 (Int J Radiat Oncol Biol Phys 2001) 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.
On the basis of 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 select 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 guide their use in both the primary and recurrent settings. Emerging data are confirming the activity of PARP inhibitors in patients with ovarian cancer. Approximately 10% to 15% of patients with ovarian cancer are known to be deficient in homologous recombination repair, because of germline BRCA1 or BRCA2 mutations. Up to 50% of all patients are, however, likely deficient because of somatically acquired mutations, epigenetic inactivation, or BRCA1- or BRCA2-independent defects in addition. Olaparib, as one example, has shown single-agent response rates ranging from 28% to 41%, depending on dose and BRCA status. A recent trial assessed the activity of olaparib vs placebo in patients with platinum-sensitive recurrence returning to complete remission or partial remission after treatment. This maintenance trial enrolled 265 patients and administered oral olaparib at 40
Recurrence - Is it really a case of 'when' or could it be 'if'.
De bulking operation, advice please
Ovarian Cancer Modulator
3rd line treatment and platinum resistant
Interesting news re Olaparib 
