Advanced-Stage Ovarian Epithelial Cancer, FTC, and PPC Treatment
Treatment options for patients with all stages of ovarian epithelial cancer, fallopian tube cancer (FTC), and primary peritoneal cancer (PPC) have consisted of surgery followed by platinum-based chemotherapy. Because of high recurrence rates for stage II patients in early-stage disease trials, patients with stage II cancers have been included with patients who have more advanced-stage cancer in Gynecologic Oncology Group (GOG) clinical trials since 2009. Going forward, stage I will remain a separate category for treatment considerations, but high-grade serous stage II cancers are likely to be included with more advanced stages.
The most common approach to advanced ovarian cancer is surgery followed by adjuvant platinum-based chemotherapy. Published trials, most with primary endpoints of progression-free survival (PFS), are listed in Table 7. A PFS endpoint was endorsed by the Gynecologic Cancer InterGroup (GCIC), but subsequently it was questioned in a systematic review and meta-analysis conducted by the GCIC.[1] After a MEDLINE search of randomized clinical trials of newly-diagnosed patients with ovarian epithelial cancer, FTC, or PPC, all studies with a minimum sample of 60 patients published from 2001 through 2016 were used to extract PFS and overall survival (OS) at an individual level. The PFS was mostly based on measurement of CA-125 levels confirmed by radiological examination or by GCIC criteria. Of 17 trials that were individually assessed, five tested the addition of maintenance therapy, seven tested additional induction drugs, and five tested intensification therapy. No poly (ADP-ribose) polymerase (PARP) inhibitor trials were included in this meta-analysis. The analysis concluded that PFS is not an adequate surrogate for OS, but it was limited by the narrow range of treatment effects observed and by poststudy treatments.
Standard Treatment Options for Advanced-Stage Ovarian Epithelial Cancer, FTC, and PPC
Standard treatment options for advanced-stage ovarian epithelial cancer, FTC, and PPC include the following:
- Surgery followed by platinum-based chemotherapy.
- Surgery before or after platinum-based chemotherapy and/or additional consolidation therapy.
- Surgery before or after platinum-based chemotherapy and the addition of bevacizumab to induction therapy and/or consolidation therapy.
- Surgery before or after platinum-based chemotherapy and the addition of PARP inhibitors to induction therapy and/or consolidation therapy.
- Chemotherapy for patients who cannot have surgery (although the impact on OS has not been proven).
Platinum-based chemotherapy is the initial treatment for all patients diagnosed with advanced disease who undergo surgical resection and are staged with cancer that has spread to the pelvic peritoneum (stage II) and beyond (stages III and IV). The role of surgery for patients with stage IV disease is unclear, but in most instances, the bulk of the disease is intra-abdominal, and surgical procedures similar to those used in the management of patients with stage II and III disease are applied.
Surgery has historically been done by open laparotomy performed by gynecologic oncology surgeons, and has included hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and debulking of peritoneal implants (often including resection of the bowel or adjacent organs as needed) to reduce tumor to microscopic, if it can safely be performed.
The volume of disease left at the completion of the primary surgical procedure in GOG studies has been related to patient survival.[2,3,4,5] A literature review showed that patients with optimal cytoreduction had a median survival of 39 months compared with survival of only 17 months in patients with suboptimal residual disease.[2][Level of evidence: 3iA]
However, in an analysis of 2,655 of the 4,312 patients enrolled in the largest GOG study (GOG-0182 [NCT00011986]) (refer to the Surgery followed by platinum-based chemotherapy section of this summary for more information), only cytoreduction to nonvisible disease that is R0 (i.e., complete surgical resection) had an independent effect on survival.[6] The GOG had conducted separate trials to establish a role for intraperitoneal (IP) therapy for women whose disease has been optimally cytoreduced (defined as ≤1 cm residuum) and for those who had suboptimal cytoreductions (>1 cm residuum) (refer to the Surgery before or after platinum-based chemotherapy and/or additional consolidation therapy section of this summary for a review of these trials).
Suboptimally debulked stage III and stage IV patients have inferior 5-year survival rates, but the gap has narrowed in trials that included taxanes and other drugs added to platinums.[7] By contrast, optimally debulked stage III patients treated with a combination of intravenous (IV) taxane and IP platinum plus taxane achieved a median survival of 66 months in a GOG trial.[8][Level of evidence: 1iiA]
Surgery followed by platinum-based chemotherapy
Platinum agents, such as cisplatin or its less-toxic second-generation analog, carboplatin, given either alone or in combination with other drugs, are the foundation of chemotherapy regimens used. Trials by various cooperative groups (conducted from 1999 to 2010) addressed issues of optimal dose intensity [9,10,11] for both cisplatin and carboplatin,[12] schedule,[13] and the equivalent results obtained with either of these platinum drugs, usually in combination with cyclophosphamide.[14]
With the introduction of the taxane paclitaxel, two trials confirmed the superiority of cisplatin combined with paclitaxel when compared with the previous standard treatment of cisplatin plus cyclophosphamide.[15,16] However, two trials that compared single-agent paclitaxel with either cisplatin or carboplatin (ICON3 and GOG-132) failed to confirm such superiority in all outcome parameters (i.e., response, time-to-progression, and survival) (refer to Table 7 for a list of these studies).
Based on the evidence, the initial standard treatment for patients with ovarian cancer is the combination of cisplatin or carboplatin with paclitaxel (defined as induction chemotherapy).
Evidence (combination of cisplatin or carboplatin with paclitaxel):
- GOG-132 was widely regarded as showing that sequential treatment with cisplatin and paclitaxel was equivalent to the combination of cisplatin-plus-paclitaxel; however, many patients crossed over before disease progression. Moreover, the cisplatin-only arm was more toxic than the combination of cisplatin (75 mg/m2) and paclitaxel because it utilized a 100 mg/m2 cisplatin dose per cycle.[17]
- The Medical Research Council study (MRC-ICON3) compared carboplatin monotherapy with the combination of carboplatin and paclitaxel. While MRC-ICON3 had fewer early crossovers than GOG-132, it yielded similar outcomes for carboplatin monotherapy, including OS (albeit with less toxicity) compared with the combination treatment.[18]
Since the adoption of the standard combination of platinum plus taxane nearly worldwide, clinical trials have demonstrated the following:
- Noninferiority of carboplatin plus paclitaxel versus cisplatin plus paclitaxel.[15,16,19]
- Noninferiority of carboplatin plus paclitaxel versus carboplatin plus docetaxel.[20]
- No advantage but increased toxic effects of adding epirubicin to the carboplatin plus paclitaxel doublet.[21]
- Noninferiority of carboplatin plus paclitaxel versus sequential carboplatin-containing doublets with either gemcitabine or topotecan; or, triplets with the addition of gemcitabine or pegylated liposomal doxorubicin to the reference doublet as shown below:[22,23]
- From February 2001 to September 2004, 4,312 women with stage III or stage IV ovarian epithelial cancer, FTC, or PPC participating in the GOG-0182 trial were randomly assigned to four different experimental arms or to a reference treatment consisting of carboplatin (area under the curve [AUC], 6) and paclitaxel (175 mg/m2) every 3 weeks for eight cycles.[22] Stratification factors were residual-disease status and the intention to perform interval debulking surgery.
- None of the experimental regimens was inferior.
- Lethal events attributable to treatment occurred in less than 1% of patients without clustering to any one regimen.
- With a median follow-up of 3.7 years, the adjusted relative risk of death ranged from 0.952 to 1.114, with the control arm achieving a PFS of 16.0 months and a median OS of 44.1 months.
Moreover, for the stage III patients who made up 84% to 87% of patients, PFS differences were only noted if surgery achieved R0 resections:[22]
- PFS in patients with residuum larger than 1 cm was 13 months, and OS was 33 months.
- With residuum 1 cm or smaller, PFS was 16 months, and OS was 40 months.
- With R0 resection (e.g., no residuum or microscopic residuum only), PFS was 29 months, and OS was 68 months.
In gynecologic cancer, as opposed to breast cancer, weekly paclitaxel was not explored in phase III trials before 2004. The positive results from the Japanese Gynecologic Oncology Group (JGOG) 3016 study subsequently led to early adoption of divided-dose paclitaxel as the standard treatment, but with only partial confirmation of its superior results.
Evidence (dose-dense [weekly] treatment schedule):
- A JGOG trial (JGOG-3016 [NCT00226915]) accrued 637 patients and randomly assigned them to six to nine cycles of weekly (dose-dense) paclitaxel (80 mg/m2) or to the standard every-21-day schedule of paclitaxel at 180 mg/m2. Both regimens were given with carboplatin (AUC, 6) in every-3-week cycles. The primary study endpoint was PFS with a goal of detecting a PFS increase from 16 months to 21 months in patients receiving the weekly paclitaxel-based regimen.[24,25] Although more toxic, the weekly paclitaxel regimen did not adversely affect quality of life when compared with the intermittent schedule.[26][Level of evidence: 1iiDiii]
Other than ethnicity, this trial population may have differed from GOG and other studies in that patients were younger (average age, 57 years). Twenty percent of patients had stage II disease and 33% of patients had histologies other than high-grade serous or endometrioid cancer. Also, 11% of patients were entered while receiving neoadjuvant treatment, which was an all-inclusive way of assessing treatments other than chemotherapy in first-line settings. The JGOG-3016 study results demonstrated the following:
- At the 1.5-year follow-up after cessation of treatment, patients who received the weekly regimen had a median PFS of 28.0 months (95% confidence interval [CI], 22.3–35.4 months), and patients who received the intermittent regimen had a median PFS of 17.2 months (range, 15.7–21.1 months; hazard ratio [HR], 0.71), favoring the weekly regimen (P = .0015).
- A 2013 update revealed an increase in median survival for patients who received the weekly regimen (median OS, 8.3 years vs. 5.1 years; P = .040); the intermittent regimen results are also noteworthy relative to other clinical trials of weekly dosing schedules.
- In a phase III trial (MITO-7 [NCT00660842]), the outcomes of 406 patients assigned to weekly paclitaxel (60 mg/m2) administered with weekly carboplatin (AUC, 2) were compared with those of 404 patients receiving the conventional every-3-week regimen of paclitaxel and carboplatin.[27][Level of evidence: 1iiA]
- The results failed to confirm the superiority of this weekly schedule (18.3 months PFS for the weekly arm vs. 17.3 months PFS for the standard arm [HR, 0.96; 95% CI, 0.80–1.16]).
- The treatments did not differ in toxic effects. A decrease in quality of life (assessed by the Functional Assessment of Cancer Therapy Ovarian Trial Outcome Index questionnaire) was not seen in the weekly arm compared with the every-3-week arm.
- GOG-0262 (NCT01167712) is a phase III study that compared weekly paclitaxel (80 mg/m2) to every-3-week dosing (175 mg/m2), both with the conventional every-3-week carboplatin (AUC, 6) regimen.[28][Level of evidence: 1iiDiii] An option to give bevacizumab every 3 weeks beginning with cycle two and continuing until cycle six and followed by bevacizumab alone for 1 year, as in GOG-0218, was included for both arms. This option was applied in about 84% of all patients.
- Overall, the weekly paclitaxel regimen failed to prolong PFS compared with the every-3-week regimen (14.7 months vs. 14.0 months), with an HR for progression or death of 0.89 (95% CI, 0.74–1.06).
- However, among patients not receiving bevacizumab, the weekly paclitaxel arm had significantly prolonged PFS (14.2 months vs. 10.3 months), with an HR of 0.62 (95% CI, 0.40–0.95; P = .03)
- The weekly paclitaxel regimen had a higher rate of grade 3 or 4 anemia (36% vs. 16%) and grade 2 to 4 sensory neuropathy (26% vs. 18%).
- ICON8 (NCT01654146) is another phase III trial that compared weekly paclitaxel with every-3-week dosing, with another arm that compared weekly paclitaxel with weekly carboplatin (AUC, 2 ˣ 6 cycles).[29]
- This large study did not demonstrate any significant differences between the arms.
- A separate quality-of-life study found no difference in global quality of life among the three groups at a 9-month cross-sectional analysis, although the weekly paclitaxel schedules scored significantly lower in longitudinal analyses.[30]
Table 7. Selected Phase III Studies of Intravenous Adjuvant Therapy for Advanced Ovarian Cancer After Initial Surgery
| Trial |
Treatment Regimens |
No. of Patients |
Progression-free Survival (mo) |
Overall Survival (mo) |
| AUC = area under the curve; EORTC = European Organization for Research and Treatment of Cancer; Est = estimated; GOG = Gynecologic Oncology Group; ICON = International Collaboration on Ovarian Neoplasms; JGOG = Japanese Gynecologic Oncology Group; MITO = Multicentre Italian Trials in Ovarian cancer; MRC = Medical Research Council; No. = number; NR = not reported. |
| a Control arms are bolded. |
| b Statistically inferior result (P < .001–< .05). |
| c Optimally debulked only. |
| d Every 3 weeks for six cycles unless specified. |
| e JGOG-3016 included stage II patients. |
| f Estimated from the curve. |
| GOG-111 (1990–1992)a[31] |
Paclitaxel (135 mg/m2, 24 h) and cisplatin (75 mg/m2) |
184 |
18 |
38 |
| Cyclophosphamide (750 mg/m2) and cisplatin (75 mg/m2) |
202 |
13b |
24b |
| EORTC-55931 |
Paclitaxel (175 mg/m2, 3 h) and cisplatin (75 mg/m2) |
162 |
15.5 |
35.6 |
| Cyclophosphamide (750 mg/m2) and cisplatin (75 mg/m2) |
161 |
11.5b |
25.8b |
| GOG-132 (1992–1994) |
Paclitaxel (135 mg/m2, 24 h) and cisplatin (75 mg/m2) |
201 |
14.2 |
26.6 |
| Cisplatin (100 mg/m2) |
200 |
16.4 |
30.2 |
| Paclitaxel (200 mg/m2, 24 h) |
213 |
11.2b |
26 |
| MRC-ICON3[18] |
Paclitaxel (175 mg/m2, 3 h) and carboplatin (AUC, 6) |
478 |
17.3 |
36.1 |
| Carboplatin (AUC, 6) |
943 |
16.1 |
35.4 |
| Paclitaxel (175 mg/m2, 3 h) and carboplatin (AUC, 6) |
232 |
17 |
40 |
| Cyclophosphamide (500 mg/m2) and doxorubicin (50 mg/m2) and cisplatin (50 mg/m2) |
421 |
17 |
40 |
| GOG-158 (1995–1998)c |
Paclitaxel (135 mg/m2, 24 h) and cisplatin (75 mg/m2)d |
425 |
14.5 |
48 |
| Paclitaxel (175 mg/m2, 3 h) and carboplatin (AUC, 6) |
415 |
15.5 |
52 |
| JGOG-3016 (2002–2004)e |
Paclitaxel (180 mg/m2) and carboplatin (AUC, 6)d |
319 |
17.5 |
62.2 |
| Paclitaxel (80 mg/m2) and carboplatin (AUC, 6) |
312 |
28.5 |
100.5 |
| MITO-7[27,32] |
Paclitaxel (175 mg/m2) and carboplatin (AUC, 6)d |
404 |
17.3 |
NR |
| Paclitaxel (60 mg/m2) and carboplatin (AUC, 6) |
406 |
18.3 |
NR |
| GOG-0262[28] |
Paclitaxel (80 mg/m2) and carboplatin (AUC, 6) plus optional bevacizumab cycles 2–6, and every 3 wk until progression |
346 |
14.7 |
Est 42 |
| Paclitaxel (175 mg/m2) and carboplatin (AUC, 6) (× 6 cycles) plus optional bevacizumab cycles 2–6, and every 3 wk until progression |
346 |
14.0 |
Est 42 |
| GOG-218 |
Paclitaxel (175 mg/m2) and carboplatin (AUC, 6) (× 6 cycles) and placebo cycles 2–22 |
625 |
10.3 |
39.3 |
| Paclitaxel (175 mg/m2) and carboplatin (AUC, 6) (× 6 cycles) and bevacizumab cycles 2–6, and placebo cycles 7–22 |
625 |
11.2 |
38.7 |
| Paclitaxel (175 mg/m2) and carboplatin (AUC, 6) (× 6 cycles) and bevacizumab cycles 2–22 |
623 |
14.1 |
39.7 |
| ICON7[33] |
Paclitaxel (175 mg/m2) and carboplatin (AUC, 5 or 6) and bevacizumab (7.5 mg/kg) (× 6 cycles) and bevacizumab alone cycles 7–18 |
764 |
19.0 |
45.5 |
| Paclitaxel (175 mg/m2) and carboplatin (AUC, 5 or 6) (× 6 cycles) |
764 |
17.3 |
44.6 |
| ICON8[29] |
Paclitaxel (175 mg/m2) and carboplatin (AUC, 5 or 6) (× 6 cycles) |
522 |
17.8 |
41f |
| Paclitaxel (80 mg/m2 weekly) and carboplatin (AUC, 5 or 4) (× 6 cycles) |
523 |
20.8 |
41f |
| Paclitaxel (80 mg/m2 weekly) and carboplatin (AUC, 2 weekly) (× 6 cycles) |
521 |
21.0 |
41f |
Surgery before or after platinum-based chemotherapy and/or additional consolidation therapy
The pharmacologic basis for the delivery of anticancer drugs by the IP route was established in the late 1970s and early 1980s. When several drugs were studied, mostly in the setting of minimal residual disease at reassessment after patients had received their initial chemotherapy, cisplatin alone and in combination received the most attention. Favorable outcomes from IP cisplatin were most often seen when tumors had shown responsiveness to platinum therapy and with small-volume tumors (usually defined as tumors <1 cm).[34]
In the 1990s, randomized trials were conducted to evaluate whether the IP route would prove superior to the IV route. IP cisplatin was the common denominator of these randomized trials.
Evidence (surgery followed by IP chemotherapy):
- The use of IP cisplatin as part of the initial approach in patients with stage III optimally debulked ovarian cancer is supported principally by the results of three randomized clinical trials (SWOG-8501, GOG-0114, and GOG-0172 [NCT00003322]).[8,35,36] These studies tested the role of IP drugs (IP cisplatin in all three studies and IP paclitaxel in the last study) against the standard IV regimen.
- In the three studies, superior PFS and OS favoring the IP arm were documented.
Specifically, the most recent study, GOG-0172, demonstrated the following:[8][Level of evidence:1iiA]
- A median survival of 66 months for patients on the IP arm versus 50 months for patients who received IV administration of cisplatin and paclitaxel (P = .03).
- Toxic effects were greater in the IP arm because of the cisplatin dose per cycle (100 mg/m2); sensory neuropathy resulted from the additional IP chemotherapy and from the systemic administration of paclitaxel.
- The rate of completion of six cycles of treatment was also less frequent in the IP arm (42% vs. 83%) because of the toxic effects and catheter-related problems.
An updated combined analysis of GOG-0114 and GOG-0172 included 876 patients with a median follow-up of 10.7 years and reported the following results.[37]
- Median survival with IP therapy was 61.8 months (95% CI, 55.5–69.5) compared with 51.4 months (95% CI, 46.0–58.2) for IV therapy.
- IP therapy was associated with a 23% decreased risk of death (adjusted hazard ratio [AHR], 0.77; 95% CI, 0.65–0.90; P = .002).
- IP therapy improved the survival of patients with gross residual (≤1 cm) disease (AHR, 0.75; 95% CI, 0.62–0.92; P = .006).
- Risk of death decreased by 12% for each cycle of IP chemotherapy completed (AHR, 0.88; 95% CI, 0.83–0.94; P < .001).
- Factors associated with poorer survival included clear and mucinous versus serous histology (AHR, 2.79; 95% CI, 1.83–4.24; P < .001), gross residual versus no visible disease (AHR, 1.89; 95% CI, 1.48–2.43; P < .001), and fewer versus more cycles of IP chemotherapy (AHR, 0.88; 95% CI, 0.83–0.94; P < .001).
- Younger patients were more likely to complete the IP regimen, with a 5% decrease in probability of completion with each year of age (odds ratio, 0.95; 95% CI, 0.93–0.96; P < .001).
- A Cochrane-sponsored meta-analysis of all randomized IP-versus-IV trials showed an HR of 0.79 for disease-free survival and 0.79 for OS, favoring the IP arms.[38]
- In another meta-analysis of seven randomized trials assessing IP versus systemic chemotherapy conducted by Cancer Care of Ontario, the relative ratio (RR) of disease progression at 5 years based on the three trials that reported this endpoint was 0.91 (95% CI, 0.85–0.98), and the RR of death at 5 years based on six trials was 0.88 (95% CI, 0.81–0.95) for the IP route.[39]
- In the subsequent IP trial (GOG-252), modifications of the IP regimen used in GOG-0172 were made to improve its tolerability (e.g., to reduce by ≥25% the total 3-hour amount of cisplatin given; and, to shift from the less practical 24-hour IV administration of paclitaxel to a 3-hour IV administration).[40]
In this study, 1,560 patients were randomly assigned to receive six cycles of IV paclitaxel (80 mg/m2 once per week with IV carboplatin [AUC, 6] every 3 weeks) versus IV paclitaxel (80 mg/m2 once per week with IP carboplatin [AUC, 6] [the IP carboplatin arm]) versus once-every-3-weeks IV paclitaxel (135 mg/m2 over 3 hours on day 1, IP cisplatin 75 mg/m2 on day 2, and IP paclitaxel 60 mg/m2 on day 8 [the IP cisplatin arm]). The last regimen was the modified IP superior arm of GOG-0172. All participants received bevacizumab (15 mg/kg IV every 3 weeks in cycles 2−22) and bevacizumab (15 mg/kg every 3 weeks) was added to all three arms.
- The median PFS duration was 24.9 months in the IV carboplatin arm, 27.4 months in the IP carboplatin arm, and 26.2 months in the IP cisplatin arm.
- For the subgroup of 1,380 patients with stage II/III and residual disease of 1 cm or less, the median PFS was 26.9 months in the IV carboplatin arm, 28.7 months in the IP carboplatin arm, and 27.8 months in the IP cisplatin arm.
- The median PFS for patients with stage II/III disease and no residual tumor was 35.9, 38.8, and 35.5 months, respectively.
- The median OS for all enrolled patients was 75.5, 78.9, and 72.9 months, respectively; the median OS for patients with stage II/III disease with no gross residual tumor was 98.8 months, 104.8 months, and not reached, respectively.
- This study concluded that, compared with the IV carboplatin reference arm, PFS was not significantly increased with either IP regimen when combined with bevacizumab.[40][Level of evidence: 1iiDiii]
Surgery before or after platinum-based chemotherapy and the addition of bevacizumab to induction and/or consolidation therapy
Two phase III studies compared the outcome of standard primary cytoreductive surgery with that of neoadjuvant chemotherapy followed by interval cytoreductive surgery; both studies (described below) demonstrated that PFS and OS were noninferior with the use of primary cytoreductive surgery.[41,42]
Evidence (chemotherapy followed by surgery):
- Between 1998 and 2006, a study led by the European Organization for the Research and Treatment of Cancer (EORTC) Gynecological Cancer Group, together with the National Cancer Institute of Canada Clinical Trials Group (EORTC-55971 [NCT00003636]), included 670 women with stages IIIC and IV ovarian epithelial cancer, FTC, and PPC.[41][Level of evidence: 1iiA] The women were randomly assigned to undergo primary debulking surgery followed by at least six courses of platinum-based chemotherapy or to receive three courses of neoadjuvant platinum-based chemotherapy followed by interval debulking surgery, and at least three more courses of platinum-based chemotherapy.
Methods included efforts to ensure accuracy of diagnosis (e.g., rule out peritoneal carcinomatosis of gastrointestinal origin) and stratification by largest preoperative tumor size (excluding ovaries) (<5 cm, >5 cm–10 cm, >10 cm–20 cm, or >20 cm). Other stratification factors included institution, method of biopsy (i.e., image-guided, laparoscopy, laparotomy, or fine-needle aspiration), and tumor stage (i.e., stage IIIC or IV). The primary endpoint of the study was OS, with primary debulking surgery considered the standard.[41][Level of evidence: 1iiA]
- Median OS for primary debulking surgery was 29 months, compared with 30 months for patients assigned to neoadjuvant chemotherapy.
- The HRdeath in the group assigned to neoadjuvant chemotherapy followed by interval debulking, as compared with the group assigned to primary debulking surgery followed by chemotherapy, was 0.98 (90% CI, 0.84–1.13; P = .01 for noninferiority).[41][Level of evidence: 1iiA]
- Perioperative and postoperative morbidity and mortality were higher in the primary debulking surgery group (7.4% severe hemorrhage and 2.5% deaths, compared with 4.1% severe hemorrhage and 0.7% deaths in the neoadjuvant group).
- The strongest independent predictor of prolonged survival was the absence of residual tumor after surgery.
- The subset of patients achieving optimal cytoreduction (≤1 cm residuum), whether after primary debulking surgery or after neoadjuvant chemotherapy followed by interval debulking surgery, had the best median OS.
- Between 2004 and 2010, a group of 87 hospitals in the United Kingdom and New Zealand enrolled 550 women with stage III or IV ovarian epithelial cancer and randomly assigned them to undergo primary cytoreductive surgery followed by six cycles of chemotherapy or primary (neoadjuvant) chemotherapy for three cycles, followed by surgery and three additional cycles of chemotherapy. In contrast to the EORTC study, the chemotherapy consisted of conventional carboplatin (AUC, 5 or AUC, 6) and paclitaxel (175 mg/m2, in 76% of patients), or carboplatin alone (23% of patients), or nonpaclitaxel chemotherapy (1% of patients).[42][Level of evidence: 1iiA]
A minimization method was used to randomly assign patients in a 1:1 ratio.[43] Participants were stratified by randomizing center, largest radiologic tumor, and prespecified chemotherapy regimen. The primary endpoint was to establish noninferiority, with the upper bound of a one-sided 90% CI for the HRdeath at less than 1.18.
- As of May 2014, 451 deaths had occurred, and the HRdeath favored neoadjuvant chemotherapy, with the upper bound of the one-sided 90% CI of 0.98 (95% CI, 0.72‒1.05).
- The most common grade 3 or 4 postoperative adverse event was hemorrhage in both groups, with 8 women (3%) having this problem with primary cytoreductive surgery versus 14 (6%) in the neoadjuvant chemotherapy group. Grade 3 and 4 toxic events from chemotherapy occurred in 110 (49%) of 225 women randomly assigned to primary cytoreductive surgery and in 102 (40%) of the 253 women receiving neoadjuvant chemotherapy, with one fatal event of neutropenic sepsis occurring in the primary chemotherapy group.
These studies and additional observational and partially published phase III studies have led to the publication of a Clinical Practice Guideline on behalf of the Society of Gynecologic Oncology and the American Society of Clinical Oncology.[44]
Hyperthermic peritoneal chemotherapy (HIPEC) is another pharmacologically based modality to enhance the antitumor effects via direct drug delivery to peritoneal surfaces. It was initially tested against mucinous tumors of gastrointestinal origin.[45] Increasingly, HIPEC is being applied to ovarian cancers, with considerable variation in patient selection, drugs administered, and time at target temperatures (most often 30 minutes at 42°C). The role of HIPEC remains experimental in the treatment of patients with high-grade serous ovarian cancers.
Experience with HIPEC spans more than two decades after initial publications that have since been summarized.[46] Evidence for its use in ovarian cancer includes a randomized study.
- The final results of a phase III, open-label Dutch study (NCT00426257) have been published. The study was performed in eight hospitals and included 245 patients with newly diagnosed ovarian cancer who were at least stable after receiving three cycles of carboplatin (AUC, 5–6) and paclitaxel 175 mg/m2, both of which were given by IV every 3 weeks.[47] Randomization took place at the time of surgery, and patients were assigned to undergo either cytoreductive surgery without HIPEC (n = 123) or with HIPEC (n = 122). All patients subsequently received three additional cycles of IV chemotherapy. The study was reported with a median follow-up of 4.7 years, after the surgical intervention. HIPEC consisted of perfusion of the abdominal cavity with cisplatin 100 mg/m2 in heated saline at 40°C (104°F) that was maintained for 60 minutes. Sodium thiosulfate was given at the start of the perfusion as an IV bolus of 9 g/m2 in 200 mL followed by continuous infusion IV (12 g/m2 in 1L) for 6 hours.[48]
- After a median follow-up of 4.7 years, 209 of the 245 patients had a recurring disease event or died. In an intention-to-treat analysis, 110 of 123 patients in the surgery group and 99 of 122 patients in the HIPEC group had such an event (HR, 0.66; 95% CI, 0.50–0.87; P = .003).
- The median recurrence-free survival was 3.5 months longer in the HIPEC group (14.2 months vs. 10.7 months).
- In the surgery group, 76 of 123 patients (62%) had died, but in the HIPEC group, 61 of 122 patients (50%) had died at the time of publication (HR, 0.67; 95% CI, 0.48–0.94; P = .02) with median OS of 33.9 months in the surgery group and 45.7 months in the HIPEC group.
- In the two groups, patient characteristics were mostly balanced with regard to age (median age, 61 years in both groups), histologic cell type in patients with high-grade serous ovarian carcinoma (87% in the surgery group and 92% in the HIPEC group), residual disease after surgery, and the number of patients completing adjuvant chemotherapy after surgery (90% in the surgery group and 94% in the HIPEC group).
In the institutions that have experience performing HIPEC, adverse events were comparable in the two groups. Patients in the HIPEC group had higher incidences of ileus (3% vs. 8%), fever (8% vs. 12%), and thromboembolic events (2% vs. 6%), but in that group, there were smaller differences in electrolyte changes (5% vs. 6%) and neuropathy (27% vs. 31%) than in patients in the surgery group, and both groups of patients had added IV chemotherapy. The use of sodium thiosulfate most likely accounts for this favorable safety profile vis-à-vis cisplatin, which was given as part of HIPEC in a published phase I trial.[49] HIPEC should be considered an option for patients who receive neoadjuvant therapy if they have access to a surgical team who has experience performing HIPEC.
Two phase III trials (GOG-0218 [NCT00262847] and ICON7 [NCT00483782]) have evaluated the role of bevacizumab in first-line therapy for ovarian epithelial cancer, FTC, and PPC after surgical cytoreduction.[50,51] Both trials showed a modest improvement in PFS when bevacizumab was added to initial chemotherapy and continued every 3 weeks for 16 and 12 additional cycles, as a maintenance phase.
Evidence (surgery followed by chemotherapy and bevacizumab):
- GOG-0218 was a double-blinded, randomized, controlled trial that included 1,873 women with stage III or IV disease, all of whom received chemotherapy—carboplatin (AUC, 6) and paclitaxel (175 mg/m2 for six cycles). Forty percent of the women had suboptimally resected stage III disease, and 26% had stage IV disease. The primary endpoint of the study was PFS.[50][Level of evidence:1iDiii] Participants were randomly assigned to receive the following:
- Chemotherapy plus placebo (cycles 2–22) (the control group).
- Chemotherapy plus bevacizumab (15 mg/kg cycles 2–6), followed by placebo (cycles 7–22) (the bevacizumab-initiation group).
- Chemotherapy plus bevacizumab (15 mg/kg cycles 2–22) (the bevacizumab-throughout group).
Results from the trial demonstrated the following:
- There was no difference in PFS between the control group and the bevacizumab-initiation group.
- There was a statistically significant increase in PFS in the bevacizumab-throughout group when compared with the control group (14.1 months vs. 10.3 months), with an HRdisease progression ordeath of 0.717 in the bevacizumab-throughout group (95% CI, 0.625–0.824; P < .001).
- Median OS was 39.3 months for the control group, 38.7 months for the bevacizumab-initiation group, and 39.7 months for the bevacizumab-throughout group.
- Quality of life was not different between the three groups. Hypertension of grade 2 or higher was more common with bevacizumab than with placebo.
- There were more treatment-related deaths in the bevacizumab-throughout arm (10 of 607, 2.3%) than in the control arm (6 of 601, 1.0%).
- ICON7 randomly assigned 1,528 women after initial surgery to chemotherapy—carboplatin (AUC, 5 or 6) plus paclitaxel (175 mg/m2 for six cycles)—or to chemotherapy plus bevacizumab (7.5 mg/kg for six cycles), followed by bevacizumab alone for an additional 12 cycles. Nine percent of patients had early-stage, high-grade tumors; 70% had stage IIIC or IV disease; and 26% had more than 1 cm of residual tumor before initiating chemotherapy. PFS was the main outcome measure.[51][Level of evidence: 1iiDiii]
- Median PFS was 17.3 months in the control group and 19 months in the bevacizumab group. HRdisease progression ordeath in the bevacizumab group was 0.81 (95% CI, 0.70–0.94; P = .004).
- Grade 3 or higher adverse events were more common in the bevacizumab group, with an increase in bleeding, hypertension (grade 2 or higher), thromboembolic events (grade 3 or higher), and gastrointestinal perforations.
- Quality of life was not different between the two groups.
- In 2015, the ICON7 authors reported an updated survival analysis.[33]
- There was no significant difference with 44.6 months (95% CI, 43.2–45.9) in patients on standard chemotherapy versus 45.5 months (44.2–46.7) in patients receiving bevacizumab with the chemotherapy induction, and then completing 1 year of bevacizumab maintenance (log-rank P = .85).
These two studies supported U.S. Food and Drug Administration (FDA) approval of bevacizumab in the first-line setting, both during induction and as consolidation therapy, after bevacizumab first gained approval in the platinum-resistant setting (AURELIA [NCT00976911] trial).
Surgery before or after platinum-based chemotherapy and the addition of poly (ADP-ribose) polymerase (PARP) inhibitors to induction and/or consolidation therapy
PARP is a family of enzymes involved in base-excision repair of DNA single-strand breaks. In patients with homologous recombination deficiency, including patients with germline BRCA1 or BRCA2 (gBRCA) mutations or with nongermline homologous recombination deficiency–positive tumors, the inhibition of PARP results in the production of double-strand breaks of DNA. Human DNA repair mechanisms largely rely on one intact copy of the gene. Cells with a double-strand break are usually targeted for cell death. This susceptibility of BRCA-deficient or BRCA-mutant cells to PARP inhibition,[52,53] has spurred the clinical development of this class of agents. Initially, these agents were tested in women who had been pretreated with chemotherapy. (Refer to the Bevacizumab, other targeted drugs, and poly [ADP-ribose] polymerase [PARP] inhibitors with or without chemotherapy section of this summary for more information.)
Evidence (surgery before or after chemotherapy and PARP inhibitors):
- A double-blind phase III trial (SOLO-1) (NCT01844986) compared maintenance olaparib (300 mg tablets bid) with a placebo in patients with newly diagnosed, high-grade serous or endometrioid advanced ovarian cancer with mutations of BRCA1, BRCA2, or both, who had a complete or partial clinical response after platinum-based chemotherapy.[54] The study of 391 randomly assigned patients ran from September 2013 to March 2015. Of those patients, 260 were assigned to receive olaparib, and 131 patients were assigned to receive a placebo. All but three patients had germline mutations in BRCA1 (n = 191) or BRCA2 (n = 66). The analysis of the primary endpoint was stopped after 2 years if there was no evidence of disease or was continued until investigator-assessed disease progression. Patients with partial responses at 2 years were permitted to receive the intervention in a blinded manner. Crossover was not specified, but after discontinuation, patients could receive treatments at the discretion of the investigator. The primary endpoint was PFS, which was defined as from the time of randomization to objective disease progression on imaging (q 12 weeks up to 3 years), or death from any cause.
- After a median follow-up of 41 months, the risk of disease progression or death was 70% lower with olaparib than with a placebo (Kaplan-Meier estimates of PFS at 3 years, 60% vs. 27%; HR, 0.3; 95% CI, 0.23–0.41; P < .001).
- Grades 3 and 4 adverse events were present in 39% of the patients who received olaparib versus 18% who received a placebo. The most common events with olaparib were fatigue, vomiting, and anemia. Drug discontinuation occurred in 12% of the patients who received olaparib versus 2% who received a placebo.
- No significant changes in quality of life occurred in either group.[54][Level of evidence: 1iiDiii]
- The results of an updated analysis indicated that the risk of disease progression or death was reduced as follows:[55]
- By 69% with olaparib (HR, 0.31; 95% CI, 0.21–0.46) compared with 63% with placebo (HR, 0.37; 95% CI, 0.24–0.58) in patients undergoing upfront or interval surgery;
- By 56% with olaparib (HR, 0.44; 95% CI, 0.25–0.77) compared with 67% with placebo (HR, 0.33; 95% CI, 0.23–0.46) in patients with residual or no residual disease after surgery;
- By 66% with olaparib (HR, 0.34; 95% CI, 0.24–0.47) compared with 69% with placebo (HR, 0.31; 95% CI, 0.18–0.52) in women with clinical complete response or partial response at baseline; and
- By 59% with olaparib (HR, 0.41; 95% CI, 0.30–0.56) compared with 80% with placebo (HR 0.20; 95% CI, 0.10–0.37) in patients with a BRCA1 or BRCA2 mutation.
- A double-blind phase III trial (PRIMA [NCT02655016]) compared maintenance niraparib (300 mg tablets once daily and later amended to 200 mg in women <77 kg and/or baseline platelet count <150,000/µL) versus placebo in patients with high-grade serous ovarian cancer before the last cycle of platinum-based chemotherapy.[56] Homologous recombination deficiency as determined by myChoice (Myriad) was present in 50.9% of patients. In a 2:1 randomization (niraparib, n = 487; placebo, n = 246) from June 2016 to May 2018, patients were assigned for comparison of primary endpoints of PFS for homologous recombination deficiency (50.9%) and for the overall population.
- At a median follow-up of 13.8 months, the risk of progression in the homologous recombination deficiency population had an HR of 0.43 (95% CI, 0.31−0.59; P < .001) corresponding to a median PFS of 21.9 months versus 10.4 months favoring the drug compared with the placebo. In the overall population selected for this trial, the HR was 0.62, which corresponded to a median PFS of 13.8 months versus 8.2 months (95% CI, 0.50−0.76; P < .001).
- Grade 3 or higher adverse events, none fatal, consisted of anemia in 31% of patients, thrombocytopenia in 28.7% of patients, and neutropenia in 12.8% of patients; 58 of 307 discontinuations of niraparib were caused by adverse events versus 5 of 175 discontinuations of the placebo.
- VELIA/GOG-3005 (NCT02470585), a phase III placebo-controlled study, assessed the efficacy of oral veliparib added to first-line induction chemotherapy with carboplatin/paclitaxel and continued as maintenance chemotherapy.[57] The study randomly assigned 1,140 patients in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance, chemotherapy plus veliparib followed by placebo maintenance, and chemotherapy plus veliparib induction and maintenance (labeled as ‘veliparib throughout'). Doses of veliparib were 150 mg twice daily during induction, and patients who completed six cycles without progression received single-agent veliparib (or matching placebo) at 300 mg twice daily for 2 weeks (labeled as the transition period), and if no dose-limiting side effects were noted, escalated to 400 mg twice daily for an additional 30 cycles of 3 weeks of oral drug. The study accrued patients from July 2015 to July 2017, and the data was analyzed at a median 28 months duration of follow-up. As in the PRIMA study above, efficacy analyses were performed in three sequential inclusive populations: 1) the BRCA mutation cohort, 2) the homologous recombination deficiency cohort (that included the preceding cohort), and 3) the intention-to-treat population.
- At a median follow-up of 28 months, the BRCA-mutation cohort experienced a PFS of 34.7 months with veliparib throughout versus 22.0 months in the chemotherapy-only arm (induction veliparib added without veliparib maintenance was not compared). This corresponded to an HR of 0.44 (95% CI, 0.28−0.68; P < .001).
- For the homologous recombination deficiency population, PFS occurred at a median of 31.9 months for the veliparib throughout arm versus 20.5 months for the chemotherapy-alone arm, with an HR of 0.57 (95% CI, 0.43−0.76; P < .001).
- In the overall population selected, the median PFS was 23.5 months for the veliparib throughout arm versus 17.3 months for the chemotherapy-alone arm, corresponding to an HR of 0.68 (95% CI, 0.56−0.83; P < .001).
- Veliparib contributed to a higher rate of anemia and thrombocytopenia when combined with chemotherapy, and contributed overall to nausea and fatigue. Adverse events unrelated to progression during the maintenance phase lead to drug discontinuation in 82 patients. Forty of 377 patients going onto maintenance therapy in the veliparib throughout cohort withdrew consent for the trial drug, 22 patients in the chemotherapy-plus-placebo cohort of 371 patients withdrew consent for the trial drug, and 24 patients in the veliparib only as maintenance (not further analyzed in the comparisons) cohort of 383 patients withdrew consent for the trial drug.
- PAOLA1 (NCT02477644), a placebo-controlled trial, compared first-line chemotherapy with carboplatin/paclitaxel followed by bevacizumab maintenance for 2 years, to the inclusion of olaparib versus placebo in the maintenance phase.[58] This study included 537 patients who were assessed for BRCA mutations (including somatic mutations) and a nonhomologous recombination deficiency cohort.
- PFS in the 29% of patients with BRCA mutations was 37.2 months for bevacizumab-plus-olaparib group versus 21.7 months for the bevacizumab-alone maintenance group, which corresponded to an HR of 0.31.
- For the non-BRCA population, the HR was 0.71, which corresponded to a median PFS of 18.9 months versus 16.0 months.
- For the overall population, the HR was 0.59, which corresponded to a PFS of 22.1 months for the bevacizumab-plus-olaparib group versus 16.6 months for the bevacizumab-alone maintenance group.
Other consolidation and/or maintenance therapy trials
Phase III trials of consolidation and/or maintenance therapy have been carried out with cytotoxic drugs, small molecules,[59] vaccines,[60] and radioimmunoconjugates [61] with negative results. Extending duration of paclitaxel has resulted in modest lengthening of PFS in randomized trials.[62,63]
Trials ongoing with antiangiogenic drugs (other than bevacizumab) and PARP inhibitors are described in the Treatment Options under Clinical Evaluation section that follows.
Treatment Options Under Clinical Evaluation
Trials are ongoing with antiangiogenic drugs (other than bevacizumab) and with PARP inhibitors. PARP is a family of enzymes involved in base-excision repair of DNA single-strand breaks. In patients with homologous recombination deficiency, including patients with germline BRCA1 or BRCA2 (gBRCA) mutations or with nongermline homologous recombination deficiency–positive tumors, inhibition of PARP results in production of double-strand breaks of DNA. Human DNA repair mechanisms largely rely on one intact copy of the gene; cells with a double-strand break are usually targeted for cell death. This susceptibility of BRCA-deficient or BRCA-mutant cells to PARP inhibition [52,53] has spurred the clinical development of this class of agents. Sensitivity to platinum compounds is a feature of homologous recombination deficiency, and a population of platinum-sensitive patients is expected to be homologous recombination deficiency enriched and most likely to benefit from PARP inhibition. Several of these drugs have been studied in ovarian cancer as monotherapy or drug combinations and have demonstrated activity in the recurrent setting, with olaparib, rucaparib, and niraparib achieving FDA approval with varying indications. (Refer to the Recurrent or Persistent Ovarian Epithelial Cancer, FTC, and PPC Treatment section of this summary for more information.) Phase III studies are ongoing with these three agents after first-line treatments, and also with a fourth drug, veliparib, which is not otherwise commercially available.
Information about ongoing clinical trials is available from the NCI website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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