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. 2010 May;2(3):175–187. doi: 10.1177/1758834010361333

Practical considerations in ovarian cancer chemotherapy

Mihaela Cristea 1,✉, Ernest Han 2, Lennie Salmon 3, Robert J Morgan 4
PMCID: PMC3126016  PMID: 21789133

Abstract

Epithelial ovarian cancer remains the most lethal gynecologic malignancy despite advances in treatment. The standard management generally involves a combination of surgical tumor debulking and chemotherapy. Over the decades, chemotherapy for ovarian cancer has evolved and currently involves a combination of intravenous platinum and taxane chemotherapy. Over the past decade, three randomized phase III trials have been reported, and all have demonstrated a significant survival advantage for intraperitoneal compared with intravenous chemotherapy. However, there are potential barriers and controversies related to the administration of intraperitoneal chemotherapy in ovarian cancer patients. In this review, we discuss the evolution and current management considerations of chemotherapy for the treatment of epithelial ovarian cancer.

Keywords: ovarian cancer, chemotherapy, intraperitoneal

Overview of ovarian cancer

Ovarian cancer is the fifth most common malignancy in women in the USA and represents the second most common gynecologic cancer, following cancer of the uterine corpus. An estimated 21,550 new diagnoses and an estimated 14,600 deaths from ovarian cancer are expected to occur in the USA in 2009 [American Cancer Society, 2009]. The disease predominantly affects postmenopausal women in their sixth decade. Ovarian cancer is highly curable when it is confined to the ovaries, with an expected 80–95% 5-year survival [American Cancer Society, 2009]. Only about 20% of affected patients are found at this stage, and the diagnosis is often made incidentally during the work-up of another medical condition. Nearly 75% of patients present with advanced stage ovarian cancer and the overall survival (OS) rates are only 20–30% [Herzog, 2006]. The management of ovarian cancer includes aggressive surgery and chemotherapy.

After decades of clinical trials, intravenous (IV) platinum/taxane regimes were accepted in the 1990s as the standard of care for advanced ovarian cancer. It appears, however, that the efficacy of IV chemotherapy has reached a therapeutic plateau. An important improvement in the management of ovarian cancer was introduced by the administration of chemotherapy via the intraperitoneal (IP) route. Several randomized clinical trials were able to demonstrate an improvement in survival from IP versus IV chemotherapy [Armstrong et al. 2006; Markman et al. 2001; Alberts et al. 1996]. More recently, there has been significant interest in improving the tolerability of IP chemotherapy by developing new platinum/taxane regimens or by testing other agents on IP protocols. Other newer approaches to the armamentarium include the development of targeted agents including the angiogenesis inhibitor, bevacizumab, and newer compounds.

History of the modern treatment of ovarian cancer

Similar to other malignancies, the management of ovarian cancer has evolved from single agent to combination chemotherapy. Some of the first drugs used in ovarian cancer included single agent alkylating agents. Subsequently, clinical trials performed in the late 1970s demonstrated that cisplatin was an active chemotherapy in advanced or recurrent ovarian cancer with a single agent response rate in the range of 13–30% [Rossof et al. 1979; Thigpen et al. 1979]. Importantly, the numbers of complete responses and overall response rates doubled compared with earlier single agent trials of non-platinum drugs. Early trials also identified the toxicity profile of this platinum agent including the risk of myelosupression and nephrotoxicity. Subsequently, cisplatin became the primary chemotherapeutic agent defining the comparison arms for many clinical trials in ovarian cancer.

The next generation of research studies evaluating combination chemotherapy with cisplatin plus cyclophosphamide revealed that the time to progression and the duration of survival were markedly improved compared with single agents [Decker et al. 1982]. Adding doxorubicin to the cyclophosphamide plus cisplatin doublet in women with optimally debulked stage III ovarian carcinoma did not result in improved progression-free survival (PFS) (median, 22.7 months and 24.6 months) or OS (median, 31.2 months and 38.9 months) [Omura et al. 1989]. As a result, the standard combination chemotherapy in the late 1980s and early 1990s was cisplatin plus cyclophosphamide.

Carboplatin was introduced in the 1990s as an analog of cisplatin with similar single-agent activity in terms of response and survival rates, but with a significantly improved toxicity profile. The lower incidence of emesis, sensory neuropathy, oto- and nephrotoxicity favored carboplatin; however, myelosuppression was increased compared with cisplatin. Alberts and colleagues conducted a phase III randomized trial in stage III (suboptimal) and stage IV ovarian cancer, comparing cisplatin/cyclophosphamide versus carboplatin/cyclophosphamide [Alberts et al. 1992]. Both arms demonstrated a similar OS (17.4 and 20.0 months for the cisplatin and carboplatin study arms, respectively) and similar response rates including pathologic complete responses. The regimen of carboplatin/cyclophosphamide had a significantly better therapeutic index compared with standard cisplatin/cyclophosphamide. Multiple randomized studies conducted in advanced ovarian cancer and a meta-analysis of these studies confirmed that carboplatin (given as single agent or in combination regimens) had similar survival rates compared with cisplatin [Aabo et al. 1991], alone or in combination.

Paclitaxel, an active chemotherapeutic agent introduced in the 1990s, changed the standard of care in ovarian cancer yet again. Two randomized clinical trials comparing cyclophosphamide and cisplatin with paclitaxel and cisplatin demonstrated that the investigational arm had an improved outcome compared with the previous standard combination of cyclophosphamide and cisplatin [Piccart et al. 2000; McGuire et al. 1996]. The first study conducted by the Gynecologic Oncology Group (GOG), randomized 410 women with suboptimally debulked ovarian cancer to cisplatin (75 mg/m2) plus either cyclophosphamide (750 mg/m2) or paclitaxel (135 mg/m2 over 24 h). The response rate (73 versus 60%, p = 0.01), PFS (18 versus 13 months, p < 0.001) and OS (38 versus 24 months, p < 0.001) all favored the cisplatin/paclitaxel arm [McGuire et al. 1996]. The second study was an intergroup European and Canadian randomized clinical trial with broader selection criteria compared with the GOG study. In addition, paclitaxel was delivered as a 3-h rather than a 24-h infusion. This study demonstrated an improved outcome in the paclitaxel group compared with the cyclophosphamide group [Piccart et al. 2000]. This benefit in survival (35.6 versus 25.8 months, p = 0.0016) was seen despite the fact that the study allowed crossover from the cyclophosphamide arm to the paclitaxel arm at progression.

Subsequently, the combination of cisplatin and paclitaxel was compared with carboplatin and paclitaxel, based on the improved toxicity profile of carboplatin compared with cisplatin. A non-inferiority trial conducted by the GOG in patients with optimally debulked stage III ovarian cancer randomized 792 patients to cisplatin 75 mg/m2 plus paclitaxel 135 mg/m2 over 24 h, or carboplatin area under curve (AUC) = 7.5 plus paclitaxel 175 mg/m2 over 3 h [Ozols et al. 2003]. The median PFS and OS were 19.4 and 48.7 months, respectively, for the cisplatin arm compared with 20.7 and 57.4 months, respectively, for the carboplatin arm. The study met its primary non-inferiority end-point and the carboplatin arm was easier to administer and better tolerated compared with the cisplatin arm. Similar results were seen by du Bois and colleagues in a phase III non-inferiority trial comparing paclitaxel plus cisplatin with paclitaxel plus carboplatin in patients with advanced ovarian cancer [du Bois et al. 2003]. These studies supported the combination of platinum plus paclitaxel as the standard of care in advanced ovarian cancer.

Owing to the limited supply of paclitaxel, extensive research was conducted leading to the discovery of docetaxel, a semi-synthetic analog of paclitaxel with pharmacologic and pharmacokinetic advantages over the parent compound. Phase II studies demonstrated that docetaxel is active in ovarian cancer in both taxane naive [Kaye et al. 1997] and paclitaxel-resistant ovarian and primary peritoneal carcinoma [Rose et al. 2003]. A randomized phase III study, Scottish Randomized Trial in Ovarian Cancer (SCOTROC1), compared docetaxel/carboplatin with paclitaxel/carboplatin as initial chemotherapy for stage IC–IV ovarian and/or primary peritoneal cancers [Vasey et al. 2004]. The PFS, which was the primary end-point of the study, was similar in both groups (15.0 months for docetaxel/carboplatin versus 14.8 months for paclitaxel/carboplatin; hazard ratio docetaxel/paclitaxel = 0.97, 95% confidence interval 0.83 to 1.13; p = 0.707). The OS rates at 2 years were comparable in both arms. More grade 3–4 neutropenia was associated with docetaxel while increased grade 2 or higher neurotoxicity was reported with paclitaxel. The authors concluded that docetaxel plus carboplatin represents an alternative first-line chemotherapy regimen for patients with newly diagnosed ovarian cancer.

Further attempts to improve the efficacy of the standard platinum/paclitaxel regimen by utilizing various triplet or sequential doublet chemotherapy failed to demonstrate improved outcomes in patients with advanced ovarian cancer [Bookman et al. 2009]. The Gynecologic Cancer Intergroup randomized 4312 women with stages III or IV ovarian cancer to a five-arm trial. The reference carboplatin/paclitaxel arm was compared with the investigational arms that incorporated gemcitabine, liposomal doxorubicin, or topotecan given concurrently or sequentially with carboplatin/paclitaxel. Each arm received at least four cycles of standard carboplatin/paclitaxel. The primary end-point of this study was OS. All arms had similar PFS and OS values.

This series of randomized phase III studies established carboplatin/paclitaxel as the standard chemotherapy regimen in advanced ovarian cancer and suggested that a plateau has been reached for IV chemotherapy. In patients with advanced ovarian cancer (stages III–IV), six cycles of chemotherapy are recommended [Bertelsen et al. 1999]. Randomized trials have failed to demonstrate an additional benefit from extending the duration of adjuvant chemotherapy to 8–12 cycles, although these trials utilized platinum-based chemotherapy that did not include taxanes.

In high-risk, early stage ovarian cancer such as stage IA or IB (grade 3 or clear cell), stage IC or stage II, 3–6 cycles of carboplatin/paclitaxel are recommended. A randomized phase III GOG trial has shown similar recurrence rates (25.4 versus 20.1%) and 5-year survival (81 versus 83%) in patients receiving three versus six cycles of chemotherapy [Bell et al. 2006]. Greater toxicity was seen with the use of six cycles of chemotherapy, including anemia, neutropenia, and neurotoxicity. In this study, up to 30% of patients had inadequate or incompletely documented surgical staging. Subset analysis based on stage or histologic grade showed similar recurrence rates for both treatment arms. The design of the trial did not allow efficacy analysis based on complete versus incomplete surgical staging. The authors concluded that in patients undergoing complete surgical staging, three cycles of carboplatin/paclitaxel represent a reasonable adjuvant treatment. Three additional cycles of chemotherapy can offer only a modest reduction in the recurrence rate and this should be balanced against the increased toxicity.

Maintenance chemotherapy in patients achieving a complete remission after six cycles of platinum/paclitaxel-based therapy has not been widely adopted in clinical practice, despite randomized data showing an improvement in PFS (28 versus 21 months) in patients receiving 12 versus 3 cycles of monthly maintenance paclitaxel [Markman et al. 2003]. This GOG protocol was discontinued based on an interim analysis showing a statistically significant improvement in PFS. Whether this would translate to improved OS remained an unanswered question as the study closed after only 50% enrollment. The risk of increased neurotoxicity from prolonged exposure to paclitaxel represents a limitation in adopting maintenance paclitaxel. This study has been updated with a reported PFS of 22 versus 14 months for 12 cycles and 3 cycles, respectively. Although the PFS has declined in both treatment arms, the absolute difference (8 versus 7 months) and relative margin (24%) of PFS have improved on long-term follow-up. No survival benefit for the 12 cycles of therapy has emerged [Markman et al. 2009].

More recently, Pecorelli and colleagues reported the results of a randomized trial utilizing six monthly cycles of paclitaxel versus observation and observed no improvement in OS or PFS [Pecorreli et al. 2009]. Other trials have examined maintenance IP cisplatin, IV cisplatin with 5-fluorouracil or epidoxorubicin with similar results [Bolis et al. 2006; Nicoletto et al. 2004; Tournigand et al. 2003]. The new generation of clinical trials is exploring novel agents (CT-2103) or targeted agents (pazopanib) as maintenance therapy in patients who have achieved a complete remission after standard adjuvant chemotherapy [www.clinicaltrials.gov].

Another subject of interest in ovarian cancer involves the timing of chemotherapy in reference to debulking surgery. Two randomized trials have evaluated the role of neoadjuvant chemotherapy followed by interval debulking in patients who did not undergo optimal primary debulking surgery [Rose et al. 2004; Van der Burg et al. 1995]. The Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer (EORTC) demonstrated that interval debulking by an experienced surgeon improved survival in some patients who had undergone suboptimal primary debulking surgery, with residual lesions measuring greater than 1 cm. In this study, patients received three cycles of cyclophosphamide and cisplatin, after which they were randomized to interval debulking surgery versus no surgery followed by three additional cycles of chemotherapy. PFS (18 versus 13 months) and OS (26 versus 20 months) both favored the surgical arm (p = 0.01). These results were not reproduced by GOG 152 [Rose et al. 2004], which also included women with residual disease measuring more than 1 cm after primary debulking surgery and utilized the same treatment schema. A similar time to progression (10.5 versus 10.7 months) and OS (33.9 versus 33.7 months) for the surgical arm and the chemotherapy-only arm, respectively, were observed. The dissimilar outcomes reported by these studies may have been a result of differences in surgical debulking procedures at the time of the primary surgery, the amount of residual disease, and/or the chemotherapy regimens. The GOG study required a maximal upfront surgical effort. Fifty-five percent of the patients had residual tumors measuring 5 cm or less versus one third of the number of patients in the EORTC study. In addition, GOG 152 utilized paclitaxel and cisplatin while the European study predated the use of paclitaxel in ovarian cancer. The authors concluded that patients who had an aggressive attempt of upfront surgery did not benefit from interval debulking.

Vergote and colleagues recently presented the results of a randomized phase III trial [Vergote et al. 2008] in patients with stage IIIC–IV ovarian cancer, which varied from the previous two studies as patients were randomized to receive either primary debulking surgery followed by six cycles of carboplatin/paclitaxel chemotherapy, or interval debulking surgery (which was preceded and followed by three cycles of the same chemotherapy). The authors reported a similar PFS (12 months in both arms) and OS (29 versus 30 months) for the primary- and interval-debulking groups, respectively. There were fewer postoperative complications and deaths in the neoadjuvant group. This study, which had a non-inferiority design, demonstrated that neoadjuvant chemotherapy followed by interval-debulking did not compromise the outcome of patients with stage IIIC–IV ovarian cancer. The neoadjuvant approach was suggested as a feasible option in patients presenting with bulky disease at risk for suboptimal surgery or who do not have access to immediate frontline surgery, but should not be used in patients who have less than stage IIIC ovarian cancer or are candidates for optimal debulking surgery. We eagerly await the results of this study to be published as well as long-term follow-up survival data.

IP chemotherapy

In an attempt to deliver increased concentrations of drugs to the areas of maximal disease, alternative routes of administration of chemotherapy have been investigated including IP chemotherapy administered through surgically placed IP catheters. The IP administration allows very large concentrations of active agents to reach the tumor while attempting to minimize systemic toxicity.

A pharmacologic advantage, defined as the ratio of the peak IP drug level to corresponding plasma values, has been demonstrated for many chemotherapy agents. The IP administration of cisplatin results in a 10–20 fold greater concentration in the IP space compared with that measured in the plasma [Schneider, 1994; Lopez et al. 1985; Casper et al. 1983; Pretorius et al. 1983; Howell et al. 1982; 1983], while for paclitaxel the IP pharmacokinetics demonstrate a 1000-fold greater IP versus IV concentration [Francis et al. 1995; Markman et al. 1992].

Three sequential randomized phase III trials have demonstrated a major improvement in the treatment of advanced ovarian cancer through the utilization of IP chemotherapy [Armstrong et al. 2006; Markman et al. 2001; Alberts et al. 1996]. The evolution of chemotherapy regimens in these IP protocols paralleled that of the development and investigation of IV chemotherapy.

The initial trial reported by Alberts and colleagues in 1996, utilized IV cyclophosphamide administered with IP or IV cisplatin in advanced ovarian cancer patients who had undergone optimal debulking surgery to less than 2 cm residual tumor [Alberts et al. 1996]. At the time this study was conducted, IV cyclophosphamide and cisplatin represented the standard of care. The study demonstrated a survival advantage in patients receiving IP chemotherapy (41 versus 49 months, p = 0.02). The trial had to be extended to 654 patients beyond the initial planned accrual of 400 patients to achieve statistical significant results. Interestingly, in a subanalysis, the median OS was not affected by the extent of residual disease after optimal debulking surgery (microscopic versus 0.5 cm or less versus >0.5–2 cm residual disease) [Alberts et al. 1996]. This observation was unexpected and unexplained based on preclinical and clinical data supporting the use of IP chemotherapy in patients who have low residual volume of disease after initial debulking surgery (<0.5 cm). Early preclinical studies noted that the penetration of IP chemotherapy into tissues was limited [Markman, 2003]. As the standard IV chemotherapy later became paclitaxel and carboplatin, this study was criticized for using a suboptimal chemotherapy regimen. Many questioned whether the benefit of the IP administration of cisplatin could be overcome by the administration of an IV taxane.

A second large phase III study was reported by Markman and colleagues in 2001 in stage III ovarian cancer patients who had undergone optimal debulking surgery to less than 1 cm residual tumor [Markman et al. 2001]. The standard chemotherapy arm used IV paclitaxel and cisplatin, which represented the standard of care at the time that the trial was designed. The investigational arm utilized IV paclitaxel followed by IP cisplatin (100 mg/m2 versus 75 mg/m2 in the IV arm). In addition, the investigational arm had two cycles of moderately high-dose IV carboplatin (AUC 9) with the goal of ‘chemically debulking’ prior to the initiation of paclitaxel and cisplatin. This study demonstrated an improvement in PFS (22 versus 28 months, p = 0.01) and a borderline improvement in OS (52 versus 63 months, p = 0.05) in the investigational arm. The validity of these results was questioned, as only a one-tailed t-test was employed and the OS benefit had been marginal. The increased toxicity associated with the IP arm, with 18% of patients receiving fewer than two courses, prevented the routine use of this regimen despite its proven efficacy. The myelosuppression was attributed mainly to the initial two cycles of carboplatin.

The third study reported by Armstrong and colleagues in 2006 in optimally debulked stage III ovarian cancer patients with less than 1 cm residual tumor, established a new standard of care [Armstrong et al. 2006]. This study randomized patients to IV paclitaxel 135 mg/m2 over 24 h on day 1 followed by IV cisplatin 75 mg/m2 on day 2 versus IP cisplatin 100 mg/m2 on day 2 and IP paclitaxel 60 mg/m2 on day 8. This study demonstrated a significant improvement in OS (49.7 versus 65.6 months, p = 0.03). Fifty-eight percent of patients (119 out of 205) did not complete all six cycles of IP chemotherapy, 34% (40 patients) of whom discontinued treatment primarily due to catheter complications [Walker et al. 2006]. These included catheter infections, catheter blockage, and catheter leaks. Significant neurotoxicity was also observed in this study (19% in IP versus 9% in the IV group). This is in contrast to the Alberts study, where IV use was associated with increased tinnitus, hearing loss, and neuromuscular effects as compared with the IP arm [Alberts et al. 1996]. Although increased toxicity was noted during and following IP chemotherapy in the Armstrong study, the quality-of-life measurements returned to baseline 1 year following treatment.

Despite three phase III trials demonstrating a significant survival advantage with IP compared with IV chemotherapy and a National Cancer Institute clinical alert supporting IP chemotherapy [see http://www.cancer.gov; Trimble and Alvarez, 2006], controversies regarding the use of IP chemotherapy still exist and this route of administration has not gained overwhelming support by the gynecologic and medical oncology community [Ozols et al. 2006]. Some of the barriers to utilizing IP therapy include IP therapy-related side effects, complexity of IP administration, and controversies still related to the clinical survival advantage of IP therapy.

Are there specific populations that are better suited to IP chemotherapy? The first phase III trial involved patients with 2 cm or less residual disease [Alberts et al. 1996], while the other two more recent phase III IP trials enrolled patients with 1 cm or less residual disease [Armstrong et al. 2006; Markman et al. 2001]. With significant improvements in survival noted with IP chemotherapy, it would be interesting to know whether patients with poor prognosis such as suboptimal disease or even stage IV disease would also benefit from IP chemotherapy. Fujiwara and colleagues reported a phase II study using IP carboplatin and IV paclitaxel in ovarian cancer patients with stages II–IV ovarian cancer and residual disease of 2 cm or larger after debulking surgery [Fujiwara et al. 2009]. They noted an 83% response rate and a 25-month median PFS. The median OS had not been reached at the time of publication. Another approach taken by the Southwest Oncology Group (SWOG) was to administer neoadjuvant chemotherapy in women with stage III and IV epithelial ovarian cancer [Tiersten et al. 2009]. Patients then underwent optimal debulking surgery, which was then followed by IV paclitaxel (175 mg/m2) and IP carboplatin (AUC 5) on day 1 and IP paclitaxel (60 mg/m2) on day 8 every 28 days for six cycles. This phase II trial demonstrated a 29- and 34-month median PFS and OS (from the time of starting postoperative chemotherapy), respectively. Of the 26 patients that received IP chemotherapy, 69% were able to complete all six cycles of IP chemotherapy with acceptable toxicities.

Also, there are questions as to whether IP chemotherapy should be offered to all patients. The phase III studies enrolled patients with a GOG or SWOG performance status of greater than or equal to two. Also, the majority of the patients were 70 years of age or younger. Often IP chemotherapy may be avoided in certain patients such as those with advanced age and relatively poor performance status. Further studies are needed to define better the population of patients that may benefit from IP therapy.

With chemotherapy being instilled directly into the peritoneal cavity, there are theoretical concerns about nonspecific elevations of CA125 levels, which may confound our ability to monitor response. Recently, Richardson and colleagues investigated this concern in a retrospective study and noted significantly lower CA125 levels during therapy and a trend of faster time to CA125 normalization and nadir in patients receiving IP as compared with IV chemotherapy [Richardson et al. 2008]. The authors concluded that failure of CA125 to normalize in patients receiving IP chemotherapy may indicate a poor prognosis.

Managing a patient on IP chemotherapy: a nursing perspective

The management of patients with ovarian cancer undergoing IP chemotherapy requires a multidisciplinary approach to ensure the best possible outcomes. Essential to success of any IP chemotherapy program is the education and training of specialized nursing staff that are often the first-line practitioners to encounter and recognize any potential problems with IP administration.

Prior to infusing the chemotherapy through the peritoneal port, the patients are premedicated and placed in a semi-Fowler’s position (the patient’s head is elevated 30° to 45° with the knees either bent or straight). The chemotherapy is warmed to body temperature to minimize cramping and shivering during the administration. The infusion time may range from 30 min to 2 h, based on the patient’s tolerance. Fluids should be infused as quickly as possible using gravity only. The optimal infusion volume is 2 L in order to perfuse the peritoneum. Patients should turn from side to side every 15 min for 1–2 h and alternate the Trendelenburg position with reverse Trendelenburg position for 15 min as long as tolerated during the infusion for effective absorption and distribution to the abdominal cavity.

Several complications may occur during the IP administration of chemotherapy and fluids. Abdominal discomfort may be prompted by rapid fluid instillation into the peritoneum and it can be improved by mild analgesics and/or by repositioning the patients. Respiratory distress may arise due to the sudden rise in intra-abdominal pressure. Elevating the head of the bed, assessing the vital signs and stopping the infusion may be necessary. The patients should be monitored for hypersensitivity reactions. Other symptoms such as nausea, diarrhea, cramping, and gastric symptoms may occur and can be treated symptomatically as necessary.

New directions in ovarian cancer treatment

In recent years, novel chemotherapeutic agents have been evaluated in ovarian cancer in an attempt to identify those agents associated with enhanced efficacy and reduced toxicity compared with standard combinations. The taxanes have played a major role in the treatment of ovarian cancer. A disadvantage of current taxane formulations has been the poor solubility of these compounds requiring the use of solvents such as Cremophor EL and polysorbate 80 for paclitaxel and docetaxel, respectively. Both solvents can contribute to acute hypersensitivity reactions and peripheral neuropathies. New taxane hydro-soluble formulations have been developed in order to overcome some of the side effects associated with the standard solvents [Hennenfent and Govindan, 2006].

CT-2103 is an investigational chemotherapeutic taxane that links paclitaxel to a biodegradable, water-soluble polymer of glutamic acid, a naturally occurring amino acid. CT-2103 does not require antihistamine and steroid premedications and can be safely administered intravenously over 10 min. Sabbatini and colleagues reported a phase II clinical trial enrolling 99 patients with recurrent platinum-sensitive and platinum-refractory ovarian cancer [Sabbatini et al. 2004]. An overall response rate of 10% was seen and the median time to disease progression was 2 months. Higher response rates were seen in platinum-sensitive patients (14%) and in patients who had received up to two prior regimens (28% and 10% in platinum-sensitive and platinum-resistant patients, respectively). CT-2103 had no evidence of activity in patients with truly taxane-refractory disease. Neurotoxicity was higher than predicted, with grade 2/3 neuropathy reported in 30% of patients. Most of the hypersensitivity reactions were mild and responded to standard premedications. The authors concluded that CT-2103 is active in ovarian cancer, but should be studied in patients who had received less prior therapy.

Currently, the GOG is conducting a phase III clinical trial of maintenance single-agent paclitaxel, CT-2103, or placebo, for 12 months in women with advanced ovarian cancer who achieve a complete clinical response to primary platinum/taxane chemotherapy. The primary objective of this study is the OS.

Another taxane of interest in ovarian cancer is nab-paclitaxel, which is a novel formulation of albumin-bound paclitaxel, combining a protein with the chemotherapeutic agent in particle form. This composition provides increased intratumoral concentration of the drug by a receptor-mediated transport process across the endothelial cell wall, thereby breaching the blood/tumor interface. Nab-paclitaxel has demonstrated activity in patients with metastatic breast cancer [Gradishar et al. 2005; Blum et al. 2004; Ibrahim et al. 2002].

Teneriello and colleagues conducted a phase II study in platinum-sensitive patients with recurrent ovarian cancer [Teneriello et al. 2007]. Forty-seven patients were enrolled on this study. Nab-paclitaxel was administered intravenously at 260 mg/m2 over 30 min every 3 weeks until disease progression, up to a maximum of six cycles. The overall response rate was 50%. Higher responses were seen in patients with biochemical relapse (64%) versus patients with measurable disease.

Pemetrexed is a novel folate antimetabolite that has been evaluated in ovarian cancer. The GOG conducted a phase II clinical trial with single-agent pemetrexed in patients with persistent or recurrent platinum-resistant ovarian cancer after one prior chemotherapy regimen [Miller et al. 2008]. This study utilized a higher dose of pemetrexed (900 mg/m2) compared with the standard dose of 500 mg/m2. The overall response rate was 21% with a median duration of response of 6.8 months. The PFS was approximately 3.0 months and the OS was 11.4 months. The most common treatment-related toxicities included myelosuppression (neutropenia 42%, leukopenia 25%, and anemia), and constitutional symptoms in 15%. This study demonstrated that pemetrexed has activity comparable with other agents in recurrent platinum-resistant ovarian carcinoma. A European study compared the safety and efficacy of standard 500 mg/m2 versus high-dose 900 mg/m2 pemetrexed in a randomized phase II study conducted in patients with platinum-resistant epithelial ovarian cancer [Vergote et al. 2009]. Both arms demonstrated a similar overall response rate (9.3 versus 10.4%, respectively), PFS and OS. The toxicity profile favored the standard pemetrexed arm, suggesting that the standard dose of 500 mg/m2 should be used in other ovarian cancer studies. A phase II study evaluating pemetrexed plus carboplatin in patients with recurrent platinum-sensitive ovarian cancer [Matulonis et al. 2008], demonstrated an overall response rate of 51.1%, which was comparable with previous reports for paclitaxel/carboplatin and gemcitabine/carboplatin in this patient population [Pfisterer et al. 2006; Parmar et al. 2003]. Only partial responses were observed with pemetrexed and carboplatin, while complete responses were noted in the ICON 4 and AGO study. This was an unexplained finding. The efficacy and favorable toxicity profile of pemetrexed/carboplatin suggest that this regimen is a reasonable option in patients with recurrent platinum-sensitive ovarian cancer and further testing of this platinum doublet may be warranted.

Targeted agents have been explored in ovarian cancer in monotherapy studies and combination studies with chemotherapy. Anti-angiogenic agents, including anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (bevacizumab) and VEGF receptor small-molecule kinase inhibitors (i.e. cediranib, pazopanib, sunitinib and sorafenib) are showing promise in numerous phase II clinical trials [Matulonis et al. 2009; Garcia et al. 2008; Matei et al. 2008; Richardson et al. 2008; Buckstein et al. 2007; Cannistra et al. 2007; Friedlander et al. 2007]. There are several ongoing randomized phase III trials using anti-angiogenic agents in combination with chemotherapy [Varughese et al. 2009]. These studies are being conducted both in first-line setting (GOG 218 and ICON 7) and in platinum-sensitive relapsed ovarian cancer (GOG 213 and the Ovarian Cancer Evaluation of Avastin and Safety-AVF4095s (OCEANS) trial). The chemotherapy regimens utilized in these trials include carboplatin/paclitaxel (GOG 218, ICON 7 and GOG 213) and carboplatin/gemcitabine (OCEANS trial). Bevacizumab, 15 mg/kg or 7.5 mg/kg is administered every 21 days during chemotherapy. In some of the treatment arms, maintenance bevacizumab is continued after completing the chemotherapy for a total of 15 months. Except for GOG 213, the primary end-point of these studies is PFS. Whether maintenance bevacizumab beyond chemotherapy can improve PFS or OS remains an unanswered question. GOG 218, which is a three-arm study, was designed to answer this question. All patients received six cycles of carboplatin/paclitaxel. Bevacizumab is combined with chemotherapy in two arms, but only one arm continued bevacizumab beyond chemotherapy. This study recently closed to accrual in June 2009. Currently, the GOG is implementing a new IP phase III protocol, GOG 252 in optimally debulked stage II and III ovarian cancer patients, which includes the following arms: (a) paclitaxel 80 mg/m2 IV weekly and carboplatin AUC = 6 IV on day 1; (b) paclitaxel 80 mg/m2 IV weekly, and carboplatin AUC = 6 IP on day 1; (c) paclitaxel 135 mg/m2 IV over 3 h on day 1, cisplatin 75 mg/m2 IP on day 2, and paclitaxel 60 mg/m2 IP on day 8 [see Walker, 2009; www.cancer.gov]. This is repeated every 3 weeks for six cycles. Bevacizumab is also incorporated into each arm but its use will be contingent on the results of GOG 218.

Poly (ADP-ribose) polymerase (PARP) inhibitors are promising anticancer agents in ovarian cancer. PARP 1 is an enzyme which has a role in the repair of single-stranded DNA breaks [Schreiber et al. 2006]. In the absence of PARP 1 activity, these breaks can interfere with DNA replication and cause the accumulation of double-stranded DNA (dsDNA) breaks. BRCA 1 and BRCA 2 are components of the homologous recombination, which is a repair pathway for dsDNA breaks. Women with BRCA-associated ovarian cancer seem to be particularly sensitive to PARP inhibitors. This was first demonstrated by a phase I clinical trial [Fong et al. 2008; 2009]. The study was initially open to patients with advanced solid tumors but in the expansion phase only patients with BRCA 1 or BRCA 2 mutations were enrolled. Significant activity to olaparib (AZD2281) was seen only in mutation carriers. Twelve of the 19 (63%) patients with BRCA-associated ovarian, breast, or prostate cancers had a clinical benefit from treatment with olaparib, defined as radiologic and/or tumor-marker responses or stable disease for a period of 4 months or more. This agent has a favorable toxicity profile. Most side effects included grade 1 or 2 nausea, fatigue, vomiting, and anorexia. A low incidence of myelosuppression was seen.

A phase II trial of the oral PARP inhibitor, olaparib (AZD2281), in BRCA-deficient advanced ovarian cancer was reported at the annual meeting of the American Society of Clinical Oncology in 2009 [Audeh et al. 2009]. This study enrolled patients with chemotherapy-refractory BRCA-associated ovarian cancer. The study design included two patient cohorts treated with olaparib, 400 mg twice daily (33 patients), and 100 mg twice daily (24 patients). Patients received continuous oral olaparib in 28-day cycles. The rationale for the treatment dose and schedule was based on the phase I study mentioned above. At the interim analysis, the overall response rate (ORR), which represented the primary efficacy end-point, was 33% at 400 mg twice daily and 12.5% at 100 mg twice daily. The clinical benefit rate (ORR and/or confirmed ≥50% decline in CA125) was 57.6% at 400 mg twice daily and 16.7% at 100 mg twice daily. Olaparib was well tolerated with primarily grade 1/2 toxicity observed.

Multiple PARP inhibitors, including AGO14699 (Pfizer), AZD2281 (AstraZeneca), ABT-888 (Abbott) and BSI-201 (Bi Par) are undergoing evaluation on phase I and phase II clinical trials. These studies will explore PARP inhibitors as monotherapy and in combination with chemotherapy. For some of these agents, the best treatment schedule (intermittent versus continuous administration) and the most effective dose have yet to be defined. In ovarian cancer, these agents are being assessed both in BRCA-associated and sporadic ovarian cancer. It remains unclear whether PARP inhibitors will benefit women with platinum-sensitive versus platinum-refractory ovarian cancer since two clinical trials have suggested opposite results [Audeh et al. 2009; Fong et al. 2009]. The number of patients on those trials was low and definitive conclusions could not be reached. The ongoing clinical trials may define the target populations of women with ovarian cancer that would benefit from PARP inhibitors.

Conclusions

Significant progress has been made in the treatment of advanced ovarian cancer. Table 1 shows an algorithm for clinical decision-making in the treatment of ovarian cancer. After decades of clinical trials, combination chemotherapy with a platinum/taxane doublet was accepted as the standard regimen in advanced ovarian cancer and suggested that a plateau has been reached for IV chemotherapy. Several randomized clinical trials have demonstrated a survival advantage for the administration of IP chemotherapy. The need to select the patients and potential catheter-related complications limits the accessibility of IP chemotherapy. New taxane formulations with an improved toxicity profile, as well as novel chemotherapy and targeted agents will provide new directions in the treatment of ovarian cancer.

Table 1.

Key points in clinical decision-making for treating ovarian cancer.

• Patients with ovarian cancer should undergo aggressive surgery performed by a surgeon trained in gynecologic oncology.
• In high-risk, early-stage ovarian cancer such as stage IA or IB (grade 3 or clear cell), stage IC or stage II, 3–6 cycles of carboplatin/paclitaxel are recommended.
• In patients with advanced ovarian cancer (stages III– IV), six cycles of carboplatin/paclitaxel are recommended.
• In good-performance patients with optimally debulked stage III ovarian cancer, treated at institutions that can prove intraperitoneal chemotherapy, patients should be advised that a significant survival advantage has been demonstrated for intraperitoneal compared with intravenous chemotherapy.
• Maintenance chemotherapy in patients achieving a complete remission after six cycles of platinum/paclitaxel-based therapy has been shown to improve progression-free survival but not the overall survival. This benefit should be balanced against the risk of increased neurotoxicity from prolonged exposure to paclitaxel.
• The role of neoadjuvant chemotherapy followed by interval debulking in patients who did not undergo optimal primary debulking surgery remains controversial.
• In patients with stage IIIC–IV ovarian cancer, interval debulking surgery preceded and followed by three cycles of carboplatin/paclitaxel may provide similar outcomes compared with primary debulking surgery followed by six cycles of carboplatin/paclitaxel, although long-term follow-up is needed.
• It is important to encourage eligible patients to enter clinical trials.
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Acknowledgments

This work was supported in part by National Cancer Institute Cancer Center Support Grant CA 33572.

Conflict of interest statement

Mihaela Cristea, NCCN grant: ‘Phase I trial of intraperitoneal nab-paclitaxel (Abraxane®) in the treatment of advanced malignancies primarily confined to the peritoneal cavity’.

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