Ovarian Cancer – Adjuvant Therapy

1. What every clinician should know

Surgery is the cornerstone of the initial management of epithelial ovarian cancer (EOC), even in advanced stage disease. However, very few women can be effectively treated with surgery alone, and most women will receive adjuvant chemotherapy for the treatment of EOC following initial cytoreductive surgery. Systemic chemotherapy for the initial treatment of EOC will be discussed in this chapter.

2. Diagnosis and differential diagnosis

Ovarian cancer is the most lethal of the gynecologic malignancies, largely attributable to the advanced stage at diagnosis in most patients. Staging for EOC is performed during the initial laparotomy, and consists of:

A thorough inspection of the peritoneal cavity, including paracolic gutters, pelvis, and domes of the diaphragm, and any surface suspicious of harboring tumor metastases should be biopsied or excised. If no suspicious areas are identified, random peritoneal biopsies should be taken from the pelvis, paracolic gutters, and undersurfaces of the diaphragm;
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total abdominal hysterectomy and bilateral salpingo-oophorectomy;
selective bilateral pelvic and aortic lymph node dissections;
omentectomy;
peritoneal washings or aspiration of ascites;
palpation of liver and bowel and biopsy or resection, if indicated.

Stage is determined according to the International Federation of Gynecology and Obstetrics (FIGO) staging system (see Table I). Several factors influence prognosis, in particular, the stage at initial diagnosis, volume of residual disease after initial cytoreductive surgery, inherited BRCA mutation, histologic subtype and grade, and age at diagnosis (see Table II).

Table I.

FIGO stage	Definition	5-Year Survival Rate
I	Tumor confined to the ovaries	>80%
IA	One ovary, capsule intact, no tumor on surface, no malignant cells in ascites or peritoneal washings
IB	Both ovaries involved, capsules intact, no tumor on surface, no malignant cells in ascites or peritoneal washings
IC	Stage IA or IB plus positive ascites or washings, capsule rupture, or tumor on ovarian surface
II	Disease spread confined to the pelvis	60-70%
IIA	Extension or implants on uterus or fallopian tubes, no malignant cells in ascites or peritoneal washings
IIB	Extension or implants on other pelvic organs, no malignant cells in ascites or peritoneal washings
IIC	Stage IIA or IIB with malignant cells in ascites or peritoneal washings
III	Tumor involves one or both ovaries with confirmed peritoneal metastasis outside the pelvis, or positive pelvic, inguinal, or para-aortic lymph nodes
IIIA	Microscopic seeding of the peritoneal surface, negative lymph nodes	30-50%
IIIB	Peritoneal implants <2cm, negative lymph nodes
IIIC	Positive lymph nodes and/or abdominal implants >2cm
IV	Spread to extra-abdominal sites	<20%

Table II.

Better Outcome	Poorer Outcome
Optimal debulking- no visible evidence of disease (only microscopic residual disease)	Suboptimal debulkingStage IV
Younger age at diagnosis	Older age at diagnosis
Lower CA-125	Higher CA-125
Hereditary BRCA mutation	Sporadic
Endometrioid & serous histologies	Clear cell and mucinous histologies

EOC accounts for over 90% of malignant tumors originating in the ovary, and can be classified into distinct histologic subtypes: serous, mucinous, endometrioid, clear cell, transitional cell, mixed, and undifferentiated, with the papillary serous histology accounting for 75% of advanced stage ovarian cancers. In a reflection of the growing evidence that EOC is a heterogeneous group of diseases and that the histological subtypes are biologically and genetically distinct, the Gynecologic Oncology Group (GOG) has started to develop clinical trials for individual histological subtypes. Serous ovarian carcinomas, endometrioid ovarian carcinomas, primary peritoneal carcinomas, and fallopian tube cancers are all managed similarly, and will be the focus of this chapter. Treatment of the less common histological subtypes (low grade/borderline, mucinous, clear cell, germ cell, etc.) will not be addressed here

The extent of surgical resection of macroscopic disease during the initial cytoreductive surgery is a major independent prognostic factor in EOC. The route, duration, and timing of therapy are determined both by the disease stage at diagnosis and the extent of surgical resection (or likelihood of complete resection if neoadjuvant chemotherapy is being considered). Optimal cytoreduction has been defined as no residual tumor larger than 1cm in diameter, but the goal of debulking is to render patients without visible evidence of disease, when possible. Given the significant impact of the initial debulking surgery on clinical outcome, patients who have had only a biopsy or incomplete staging, or incomplete cytoreductive surgery, should be referred to an experienced gynecologic oncologist for consideration of repeat operation. Unlike most other solid tumors, maximal surgical cytoreduction should be attempted even in the presence of widespread disease.

3. Management

Adjuvant chemotherapy

While a number of chemotherapeutic agents are active in the treatment of EOC, numerous studies have shown the superiority of the combination of a platinum agent and a taxane, usually paclitaxel, following initial surgical cytoreduction, and this has become the standard of care for the treatment of EOC. The stage at diagnosis and extent of surgical cytoreduction determine the treatment duration and route. It is therefore critical that patients receive comprehensive surgical staging, because as many as one third of apparent early stage patients are discovered to have a more advanced stage after undergoing complete staging surgery.

Adjuvant chemotherapy for early stage (stage I and stage II) epithelial ovarian cancer

Although prognosis is generally better for patients with stage I or II disease (Table I), the recurrence rate is significant enough to recommend adjuvant chemotherapy in most patients. Patients with well- or moderately well-differentiated stage IA or IB disease have an excellent prognosis and are the only group for whom adjuvant chemotherapy has not consistently shown a benefit.

Two large multi-institutional European trials, Adjuvant Chemotherapy in Ovarian Neoplasm (ACTION) and International Collaborative Ovarian Neoplasm trial 1 (ICON1), compared adjuvant platinum-based chemotherapy versus observation in early stage EOC.

After a median of 10.1 years of follow-up in the ACTION trial, recurrence free survival was improved in the group who received chemotherapy versus observation (70% versus 62%). However, the overall survival difference was not statistically significant. A subgroup analysis showed that the benefit of adjuvant therapy appeared to be limited to patients who had received less than complete surgical staging.
In ICON1, a difference in both recurrence-free and overall survival was observed in the group who received chemotherapy. However in a subset analysis, only women with high risk early stage disease benefitted from adjuvant chemotherapy.
In a combined analysis of both studies, the 5 year overall survival favored adjuvant chemotherapy over observation (82% versus 74%).

The optimal duration of adjuvant chemotherapy in early stage EOC has not been established. In GOG protocol 157, patients with stage I or II optimally cytoreduced EOC received either three or six cycles of carboplatin and paclitaxel. The recurrence rate was 24% lower for patients treated with six cycles of chemotherapy, however the difference was not statistically significant. A subsequent unplanned analysis revealed that those with high-grade serous histology had a significantly lower risk of recurrence with six cycles of adjuvant therapy as compared to three cycles.

Whether patients can be treated with single agent chemotherapy versus a doublet has not been determined, however, most would recommend treatment similar to advanced stage disease. GOG protocol 175 showed no benefit to the addition of weekly maintenance low dose paclitaxel to three cycles of paclitaxel and carboplatin in early stage disease. Therefore, at this time, patients with high risk early stage disease (defined as poorly differentiated stage IA or IB, or any grade stage IC or stage II disease, or clear cell carcinoma) are recommended to undergo a minimum of three cycles of paclitaxel and carboplatin. An additional three cycles of therapy may be considered for those with high-grade serous carcinoma. It should be noted that current GOG trials for advanced stage disease include stage II patients.

Adjuvant chemotherapy for advanced stage epithelial ovarian cancer

The majority of women with EOC present with stage III or IV disease. All patients with EOC, even those with stage IV disease, have an improved prognosis with optimal cytoreductive surgery. The standard of care for the treatment of advanced stage EOC is maximal cytoreductive surgery followed by at least six cycles of a platinum/taxane combination regimen (see Table III). The choice of platinum agent may be based on side effect profile rather than efficacy, as several studies have shown that cisplatin and carboplatin are therapeutically equivalent in advanced EOC. Cisplatin is associated with greater nephrotoxicity, neurotoxicity (including ototoxicity), and chemotherapy associated nausea/vomiting, while carboplatin causes more severe myelosuppression, particularly thrombocytopenia.

Table III.

IV Regimen	Predominant Complications
Paclitaxel 175mg/m2 IV over 3 hours followed by carboplatin AUC 5-7.5 IV over 1 hour Day 1; repeat every 3 weeks x 6 cycles	Sensory peripheral neuropathy
Docetaxel 60-75mg/m2 IV over 1 hour followed by carboplatin AUC 5-6 IV over 1 hour Day 1. Repeat every 3 weeks x 6 cycles.	Neutropenia
Dose dense paclitaxel 80mg/m2 IV over 1 hour days 1, 8, and 15 and carboplatin AUC 6 IV over 1 hour Day 1. Repeat every 3 weeks x 6 cycles.	Increased discontinuation of therapy secondary to hematologic toxicities
IP Regimen
Paclitaxel 135mg/m2 IV continuous infusion over 24h Day 1; cisplatin 75-100mg/m2 IP Day 2 after completion of IV paclitaxel; paclitaxel 60mg/m2 IP Day 8, repeat every 3 weeks x 6 cycles	Leukopenia, infection, fatigue, renal toxicity, electrolyte abnormalities, abdominal discomfort, neurotoxicity, inability to complete regimen because of toxicity, catheter complications, N/V/dehydration, abdominal pain
Alternate Outpatient IP regimen
Paclitaxel 135mg/m2 IV over 3h Day 1; cisplatin 75-100mg/m2 IP Day 2; paclitaxel 60mg/m2 IP Day 8, repeat every 3 weeks x 6 cycles	Similar to above but lower overall rate and severity of toxicities

Paclitaxel has been the taxane of choice for the treatment of advanced EOC. However, docetaxel may be substituted for paclitaxel based on the Scottish Randomised Trial in Ovarian Cancer (SCOTROC) study that showed similar efficacy between docetaxel/carboplatin as compared to paclitaxel/carboplatin. Docetaxel was associated with less neuropathy, but greater chemotherapy induced nausea/vomiting, myelosuppression, diarrhea, and hypersensitivity reactions. The substitution of docetaxel, while not standard, may be an attractive therapeutic option for patients at high risk of developing peripheral neuropathy (e.g., patients with diabetes).

An alternative strategy using dose-dense weekly paclitaxel plus carboplatin every three weeks was initially evaluated by the Japanese Gynecologic Oncology Group (JGOG). This resulted in an 11 month improvement in PFS and an improvement in three year OS (72% vs. 65%) compared to standard every 3 week paclitaxel dosing. After long-term follow-up, median overall survial was improved inthe weekly paclitaxel group (100.5 vs 62.2 months, hazard ratio 0.79, p 0.039). The dose-dense weekly paclitaxel reigmen was also evaluated in GOG protocol 262 presented at ESGO 2013. This study compared every 3 week versus dose dense weekly paclitaxel combined with carboplatin with or without bevacizumab (see more regarding bevacizumab below). When comparing the patients who did not choose bevacizumab, median PFS was improved in the dose-dense weekly paclitaxel arm compared to conventional 3 week dosing (14.2 vs 10.3 months, HR 0.596, p 0.033). This regimen is considered an acceptable alternative regimen by the NCCN guidelines committee. However, this regimen is associated with increased hematologic toxicities, which led a larger proportion of patients on the dose-dense weekly paclitaxel arm to discontinue therapy in the JGOG study.

Addition of Bevacizumab to adjuvant chemotherapy

Angiogenesis and angiogenic factors (i.e. VEGF) play a role in the growth of ovarian tumors. Bevacizumab, a monoclonal antibody recognizing VEGF-A, is associated with tumor response and delayed disease progression in patients with recurrent ovarian cancer. The role of bevacizumab in addition to chemotherapy has been evaluated in three multi-center randomized phase III trials (GOG 218, ICON7, and GOG 262). In GOG 218 and ICON7, bevacizumab was given during, and for up to 18 months following, chemotherapy. Both studies showed a statistically significant improvement in median PFS (~4 months) for bevacizumab following chemotherapy, but neither trial reported an improvement in overall survival for a bevacizumab-containing arm. A subset analysis of ICON7 suggested an improvement in overall survival in patients at high risk for progression (i.e. FIGO stage IV disease or FIGO stage III disease and >1.0 cm of residual disease after debulking surgery). In GOG 262, patients who opted to receive bevacizumab did not receive further benefit from dose-dense weekly paclitaxel. The addition of bevacizumab dose increase toxicity particularly grade 2 or higher hypertension and bowel perforation.

Triple agent combination regimens

Several strategies to enhance the response to standard combination therapy have been used. Triplet combination regimens and sequential doublet therapy have been evaluated to determine whether efficacy could be improved by the addition of agents to the standard combination of paclitaxel and carboplatin for the initial therapy of EOC. While the addition of agents to the carboplatin/paclitaxel backbone for initial therapy was feasible, this strategy has not provided any PFS or OS advantage, and in some cases resulted in increased toxicity. At this time, combination therapy with a platinum and taxane remains the standard of care.

Intraperitoneal chemotherapy

Women with optimally resected disease are potentially eligible for treatment with intraperitoneal (IP) chemotherapy. Because EOC stays confined to the peritoneal cavity for the majority of the natural course of the disease, regional therapy through IP administration of chemotherapy has been studied as an alternative to the standard systemic (IV) therapeutic route. Three randomized trials comparing IV with IP chemotherapy have shown a clinical benefit for the IP approach.

In the most recent study (GOG 172), which compared the combination of IV paclitaxel plus IP cisplatin and paclitaxel versus IV cisplatin and paclitaxel (the regimen described in Table III), median overall survival was increased by 16 months in those who received IP therapy. Based on the results of this study, the National Cancer Institute (NCI) released a statement recommending strong consideration for using IP therapy in women with optimally cytoreduced advanced ovarian cancer. The NCCN advises that IP therapy may also be considered for patients with stage II disease, although there is no randomized data in this population.

Special considerations for IP therapy

IP chemotherapy is associated with significant toxicities, including increased rates of myelosuppression, infection, fatigue, renal toxicity, abdominal discomfort, neurotoxicity, metabolic abnormalities, catheter complications, and chemotherapy associated nausea, vomiting, and dehydration. Because of the toxicity of the regimen, only 42% of patients assigned to IP chemotherapy on trial GOG 172 were able to complete six cycles of therapy. Despite this, there was still a significant improvement in disease free recurrence and overall survival.

In a separate quality of life (QOL) analysis, patients who received IP therapy had a worse QOL during therapy, but there was no difference one year after completion of treatment. However, the IP route of therapy has not been universally accepted, and approaches to improve tolerability through adjustments in the treatment regimen and enhancing supportive measures are currently being evaluated. IP chemotherapy can be successfully given with a reasonable toxicity profile when patients are appropriately selected and the therapy is performed at an experienced center with the assistance of a skilled and dedicated support staff.

IP therapy may not be appropriate for patients with a poor performance status, significant comorbidities, or hepatic/renal dysfunction. Patients being considered for IP therapy may undergo placement of the IP catheter during the initial cytoreductive surgery. Data from GOG 172 indicate that patients who underwent a large bowel resection at initial surgery had a higher rate of IP catheter complications or malfunction. Therefore, in patients who undergo a bowel resection, IP catheter placement may be delayed.

Patients undergoing IP therapy should be monitored carefully for dehydration, electrolyte abnormalities, myelosuppression, hepatic and renal toxicity, and neuropathy. Intravenous hydration should be given before and after IP chemotherapy. Additional IV fluid and electrolyte replacement in the week after IP cisplatin can further improve tolerance and minimize toxicities.

Catheter complications may be addressed by support staff familiar in handling catheter obstructions and minimizing catheter related infections.

When to initiate therapy

Regardless of whether IP or IV chemotherapy is selected, therapy is initiated ideally within four to six weeks of surgery, once the patient has fully recovered from the cytoreductive surgery. Patients who have evidence of rapid recurrence of ascites after initial surgery are believed to benefit from starting chemotherapy earlier.

Duration of therapy

Extending treatment duration beyond six cycles of chemotherapy does not improve response or prolong survival. The NCCN guidelines recommend no more than six to eight cycles of combination chemotherapy for initial treatment.

Follow up surveillance

Disease recurrence may be suggested by the development of new symptoms, rising CA-125 serum concentration, or evidence of recurrence by CT scan. Timing of initiation of second-line therapy is controversial.

Treatment of suboptimally cytoreduced EOC

Patients who have residual unresectable disease after initial surgery (suboptimal resection with > 1cm residual disease) should receive an IV platinum/taxane regimen ( Table III). Completion surgery to remove remaining disease (interval debulking) may be considered after three to six cycles of chemotherapy. Postoperative chemotherapy should be given, to complete a total of six cycles of therapy. For patients who undergo completion surgery after six cycles of chemotherapy, further postoperative chemotherapy, usually for three more cycles, can be considered. Any patient with suspected potentially resectable disease should undergo surgical cytoreduction.

Neoadjuvant therapy

Optimal debulking surgery may not be feasible at initial surgery for all patients. Tumor bulk and location may make optimal debulking at initial surgery challenging, and some patients may not be good operative candidates because of comorbidities, poor performance status, or massive ascites. Neoadjuvant chemotherapy followed by debulking surgery may be considered to improve the likelihood that an optimal surgery can be performed.

In a randomized trial, primary debulking surgery (PDS) followed by six cycles of platinum-based chemotherapy was compared with three cycles of neoadjuvant platinum-based chemotherapy (NACT) followed by interval debulking surgery (IDS) and three more cycles of chemotherapy in patients with stage IIIC or IV EOC. The trial determined that the progression free and overall survival with NACT and IDS was not inferior to PDS followed by chemotherapy. NACT increased the likelihood that an optimal surgical cytoreduction could be performed, and complete resection of macroscopic disease, whether with PDS or after NACT, improves outcomes.

It should be noted that only 40% of patients randomized to PDS had initial optimal cytoreduction. Furthermore, the median overall survival of 30 months in the two groups was inferior to the survival expected based on data from similar populations in GOG trials. Because of this, the use of neoadjuvant chemotherapy is still controversial. In the United States, surgical cytoreduction remains the treatment choice, when feasible. NACT may be considered for patients with bulky stage IIIC/IV disease who are unlikely to have successful debulking and for those who are not surgical candidates. Before initiation of chemotherapy, the pathologic diagnosis should be confirmed by FNA, biopsy, or paracentesis. For patients who have interval debulking after neoadjuvant chemotherapy, post-operative chemotherapy should be re-initiated within four to six weeks of surgery.

Maintenance and consolidation therapy

Although the majority of patients with advanced ovarian cancer achieve a complete clinical remission after cytoreductive surgery and combination chemotherapy, few will experience long-term remission. The use of maintenance and consolidation chemotherapy during complete clinical remission to improve outcomes has shown minimal benefit, except for extended therapy with paclitaxel. In GOG 178, patients in complete clinical remission after initial paclitaxel and carboplatin received either 3 or 12 additional monthly cycles of paclitaxel. PFS was extended by eight months (22 vs. 14 months) in the extended dosing arm, although OS was not improved.

A second randomized trial evaluating single-agent paclitaxel every three weeks for six cycles versus observation showed no significant improvement in PFS or OS. Thus the benefit of maintenance paclitaxel is unclear and is currently under investigation in GOG 212. Until further data is available, the possible benefit needs to be weighed against the risk of toxicity with prolonged therapy (particularly neurotoxicity).

4. Complications

Diagnosis/staging/surgical resection

Many women do not undergo an adequate staging and debulking operation. Women suspected of having ovarian cancer should be referred to a gynecologic oncologist experienced in the treatment of ovarian cancer.

Histology

Determining the histological subtype of ovarian cancer is essential to determining prognosis and can assist in selecting the appropriate chemotherapeutic regimen.

Complications of chemotherapy

The combination of paclitaxel and carboplatin does not typically cause significant neutropenic complications, thus routine primary prophylaxis with GCSF is not indicated. Dose reductions may be required for prolonged or febrile neutropenia, liver dysfunction, or renal toxicity.

Complications of IP therapy

Women who are unable to tolerate IP therapy should complete therapy with IV combination therapy.

Persistent or progressive disease during initial therapy

Patients with evidence of persistent or progressive disease during initial therapy should be treated with second-line therapy. Timing of initiation of chemotherapy for asymptomatic patients with a consistent rise in CA-125 is controversial.

Role of clinical trials

All patients with EOC should be encouraged to participate in clinical trials throughout the course of their diagnosis and treatment.

5. What is the evidence for specific management and treatments recommended

Jelovac, D, Armstrong, DK. “Recent progress in the diagnosis and treatment of ovarian cancer”. CA Cancer J Clin. vol. 61. 2011 May-Jun. pp. 183-203. (In this comprehensive review, the authors discuss the risk factors, genetics, and epidemiology behind epithelial ovarian cancer in addition to the recent advances in diagnosis, staging, and treatment.)

“National Comprehensive Cancer Network (NCCN) guidelines”. (The NCCN clinical practice guidelines provide a multi-center evidence-based consensus on the approach to diagnosis and treatment of ovarian cancer. Treatment of the less common ovarian histological subtypes is included.)

Bristow, RE, Tomacruz, RS, Armstrong, DK, Trimble, EL, Montz, FJ. “Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis”. J Clin Oncol. vol. 20. 2002. pp. 1248-1259. (This meta-analysis demonstrates the important role of surgical cytoreduction for all stages of EOC.)

Colombo, N, Pecorelli, S. “What have we learned from ICON1 and ACTION”. Int J Gynecol Cancer. vol. 13. 2003. pp. 140-143. (The authors perform a combined analysis of two large European multi-center trials assessing the efficacy of adjuvant therapy for early stage EOC.)

Ozols, RF, Bundy, BN, Greer, BE. “Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study”. J Clin Oncol. vol. 21. 2003. pp. 3194-3200. (This study demonstrates the relative therapeutic equivalence of cisplatin and carboplatin.)

Vasey, PA, Jayson, GC, Gordon, A. “Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma”. J Natl Cancer Inst. vol. 96. 2004. pp. 1682-1691. (This large phase III trial demonstrated similar efficacy of docetaxel–carboplatin as compared to paclitaxel– carboplatin as first-line chemotherapy for stage Ic–IV epithelial ovarian or primary peritoneal cancer.)

Katsumata, N, Yasuda, M, Takahashi, F, Katsumata, N, Yasuda, M, Isonishi, S. “Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial”. Lancet. vol. 374. 2009. pp. 1331-1338. (These trials from the JGOG showed improved disease-free and overall survival in patients treated with dose-dense paclitaxel with carboplatin, albeit with an increase in chemotherapy-associated toxicities.)

Perren, TJ, Swart, AM, Pfisterer, J, Burger, RA, Brady, MF, Bookman, MA. “ICON7 Investigators. A phase 3 trial of bevacizumab in ovarian cancer”. N Engl J Med. vol. 365. 2011 Dec 29. pp. 2484-2496. (These trials evaluated the addition of bevacizumab to standard front-line adjuvant therapy. Both show a modest improvement in PFS without significant improvement in OS, except in patients with high-risk of progression in the ICON7 study.)

Armstrong, DK, Bundy, B, Wenzel, L, Huang, HQ, Baergen, R, Lele, S, Copeland, LJ, Walker, JL, Burger, RA. “Gynecologic Oncology Group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer”. N Engl J Med. vol. 354. 2006 Jan 5. pp. 34-43. (This phase III trial (GOG 172) showed a substantial improvement in disease-free and overall survival with the combination of IV paclitaxel and IP paclitaxel and cisplatin. This trial prompted the recommendation of the NCI to discuss IP therapy with all patients newly diagnosed with advanced EOC.)

Jaaback, K, Johnson, N. “Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer”. Cochrane Database Syst Rev. 2006 Jan 25. pp. CD005340(This meta-analysis of randomized control trials of IP therapy for women with newly diagnosed EOC showed an improvement in overall and progression free survival across eight studies (including GOG 172).)

Bertelsen, K, Grenman, S, Rustin, GJ. “How long should first-line chemotherapy continue”. Ann Oncol. vol. 10. 1999. pp. 17-20. (This short review focuses on the studies that have defined the duration of therapy in EOC. The majority of studies were performed before the current standard of care was defined.)

Vergote, I, Trope, CG, Amant, F. “Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer”. N Engl J Med. vol. 363. 2010. pp. 943-953. (Recent multi-center European trial showing that neoadjuvant chemotherapy followed by interval surgical cytoreduction is not inferior to standard initial cytoreduction followed by adjuvant chemotherapy for the treatment of stage IIIC or IV EOC.)

Markman, M, Liu, PY, Moon, J. “Impact on survival of 12 versus 3 monthly cycles of paclitaxel (175 mg/m2) administered to patients with advanced ovarian cancer who attained a complete response to primary platinum-paclitaxel: follow-up of a Southwest Oncology Group and Gynecologic Oncology Group phase 3 trial”. Gynecol Oncol. vol. 14. 2009. pp. 195-198. (In this Phase III trial, maintenance paclitaxel resulted in an improved disease-free survival compared to observation alone in women who had a complete clinical remission after initial therapy.)

Hope, JM, Blank, SV. “Current status of maintenance therapy for advanced ovarian cancer”. Int J Womens Health. vol. 1. 2010 Aug 9. pp. 173-80. (The authors review the current data for maintenance therapy in advanced EOC.)

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