62Tubo-Ovarian Cancers: Ovarian, Fallopian Tube, and Primary Peritoneal

CHARACTERISTICS

•   Upon review of pathogenesis for high-grade serous adnexal cancers and reflecting standard clinical practice, ovarian, fallopian tube, and primary peritoneal cancers have now been classified uniformly as high-grade serous tubo-ovarian cancers (HGSTOC). Sex cord stromal and germ cell tumors (GCT) are classified separately and considered to originate from the ovary itself. The more uncommon epithelial subtype origin is undetermined. One in 70 women will develop tubo-ovarian cancer in their lifetime. In 2017, 22,440 new cases are approximated with 14,080 deaths. As awareness has increased regarding the possible origin of HGSTOC, close histolopathologic review can identify the transition within the fallopian tubes from benign to serous carcinoma (Figure 2.3).

•   Serous tubo-ovarian cancer (STOC) is most commonly found in advanced stage: 84% of women present with stage IIIC and 12% to 21% present with stage IV disease. Most women die from bowel complications/obstruction.

        Symptoms include abdominal fullness, dyspepsia, constipation, tenesmus, pelvic fullness or pressure, bloating, and anorexia. Many of these make up the ovarian cancer symptom index.

        The route of spread for tubo-ovarian cancer is primarily transcoelomic. Cancer cells flake off the ovarian/fallopian tube surface and implant throughout the abdomen and pelvis. Other routes of spread are lymphatic and hematogenous.

PRE-TREATMENT WORKUP

•   The pre-treatment workup includes a history and physical examination, lymph node (LN) survey, and laboratory tests, including a CBC, CMP, coagulation profile, CA-125, and other indicated tumor markers. A CXR is recommended in addition to abdominal/pelvic imaging (CT/MRI). Colonoscopy and esophagoduodenoscopy can be considered based on symptoms. Specific attention should be given to pain elicited during the pelvic exam, the presence of a mass that is fixed or solid, the presence of nodularity, and the overall mobility of the rectosigmoid colon and parametrium (Figures 2.4 and 2.5).

TREATMENT

•   Primary treatment can be surgical (PDS-primary surgical debulking) or with neoadjuvant chemotherapy (NACT).

•   Surgery usually consists of an exploratory laparotomy, abdominal cytology, hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and cytoreduction.

•   Patients with evidence of up to stage IIIB cancer should be surgically staged to include peritoneal biopsies and a pelvic and para-aortic lymph node dissection (LND). Three-fourths of advanced-stage cancers will have positive retroperitoneal LN. LN drainage tends to follow the ovarian vessels. Dissection around the high precaval and para-aortic regions is important.

•   The definition of complete debulking is removal of all gross tumor to no residual visible disease (microscopic status): R0. Optimal debulking is removal of all gross tumor to less than 1 cm visible macroscopic disease: R1. Suboptimal resection is defined as remaining visible tumor with a diameter greater than 1 cm: R2.

•   Surgical staging is often inadequate when performed by general surgeons (68%) or general gynecologists (48%), compared to gynecologic oncologists (3%).

•   If neoadjuvant chemotherapy is chosen as primary treatment, surgical debulking should follow after 2–3 cycles of chemotherapy.

HISTOLOGY

•   World Health Organization (WHO) classification of tubo-ovarian tumors:

        Common epithelial

             Serous: high grade and low grade

             Mucinous

             Seromucinous

             Endometrioid

65             Clear cell

             Brenner

             Mixed epithelial

             Undifferentiated

             Mixed mesodermal

             Unclassified

        Sex cord stromal ovarian tumors

             Granulosa stromal cell

                  Granulosa cell

                  Thecoma–fibroma

             Androblastoma: Sertoli–Leydig cell tumors

                  Well-differentiated Pick’s adenoma (Sertoli cell tumor)

                  Intermediate differentiation

                  Poorly differentiated

                  Heterologous elements

             Lipid cell tumors

             Gynandroblastoma

             Unclassified

        Germ cell ovarian tumors

             Dysgerminoma

             Endodermal sinus tumor

             Embryonal carcinoma

             Polyembryoma

             Choriocarcinoma

             Teratoma

                  Immature

                  Mature: dermoid cyst

                  Monodermal: carcinoid, struma ovarii

             Mixed

             Gonadoblastoma

        Soft tissue tumors

        Unclassified

        Metastatic secondary tumors: 5% to 6% of adnexal masses are metastases from the breast, gastrointestinal tract, or urinary tract.

STAGING

FIGO staging was last amended in 2014. Staging is surgical (Table 2.5)

EPITHELIAL TUBO-OVARIAN CANCER

CHARACTERISTICS

•   Risk factors for epithelial ovarian cancer (EOC) include age (median age of 61 years), low or nulliparity, infertility, and genetic risk.

•   Genetic mutations: the BRCA 1 and 2 genes are located on chromosome 17q21 and 13q12-13, respectively. Mutations in these genes can cause autosomal dominant inherited forms of familial cancer and yield a combined 80% overall risk of tubo-ovarian cancer; 11% to 25% of patients of serous TOCs harbor one of these mutations: Rad50/51C/51D, BRIP1, BARD1, CHEK2, MRE11A, MSH2, MLH1, MSH6, PMS2, PPM1Df, POLE, POL-D1, PALB2, 17SNPs, NBN, PALB2, TP53. Hereditary nonpolyposis colon cancer (HNPCC) yields a 10% risk of tubo-ovarian cancer and can present with other cancers such as endometrial cancer (60% risk), colon cancer (60% risk), and urothelial cancers.

•   The use of oral contraceptive pills and pregnancy reduce the overall risk (relative risk [RR] = 0.66). OCPs also reduce risk for HGSTOC in carriers of genetic mutations.

•   10% to 14% of apparent early-stage ovarian cancers are staged IIIA1i/ii (based exclusively on retroperitoneal LN involvement).

•   The ovaries can be “fertile soil” for metastatic disease. Metastatic disease can be distinguished from a primary ovarian tumor by the following: metastatic tumors to the ovaries are bilateral in 77% of cases, have multifocal and nodular implants, and often smaller in size. Primary tumors are commonly larger than 17 cm and usually unilateral (bilateral only in 13%).

•   Terminology has been suggested to distinguish between low-grade and high-grade tubo-ovarian cancers. It is not universally adopted.

        Type I tumors are the low-grade serous tumors. This is distinct from low malignant potential (LMP)/borderline tumors.

             The annual incidence is 3.8%, with an overall survival (OS) of 99 months. Diagnosis is with low mitotic activity (below 12 mitosis/per 10 HPF [high power field]). 99% are found at stage III. Even with six cycles of chemotherapy, 88% of patients had stable disease (a 5% ORR). Nine percent respond to hormonal treatment. Bevacizumab has been shown to provide a sustained complete response (CR) in recurrent disease (1).

             Type I tumors respond to chemotherapy, although not as vigorously as type II because chemoresistance is due to the low growth fraction. In an in vitro chemoresponse profile: 86% of tumors demonstrated a sensitive chemoresponse assay result to at least one agent, 35.7% were pan-sensitive to all seven standard cytotoxic agents: carboplatin, cisplatin, docetaxel, doxorubicin, gemcitabine, paclitaxel, topotecan (2). 23% of low grade (LG)STOC responded in an arbeitsgemeinschaft gynaekologische onkologie (AGO) database (3).

        Type II tumors are the most common type of tubo-ovarian-type cancers, namely high-grade serous. 80% to 90% of HGSTOC respond to standard chemotherapies (Figure 2.6A and B).

PRE-TREATMENT WORKUP

Workup follows the general preoperative/staging workup as described earlier.

HISTOLOGY (Table 2.6)

•   Serous carcinoma is the most common type of EOC. Serous cancers are graded in a two-tiered fashion: low grade and high grade. Immunohistochemistry Profiling for STOC: p53+, WT-1 positive, PAX-8 positive, ER/PR indeterminate, CK7+ (see Figures 2.6A and B)

•   Clear cell carcinoma: these tumors are difficult to treat; 63% are refractory to primary platinum chemotherapy. There is an increased risk of deep vein thrombosis (DVT): 42% versus 18% when compared to serous histologies in one study (4). There is a 15% rate of venous thromboembolism (VTE) during primary treatment, and 9% occurrence at the time of recurrence in another study (5). The OS is approximately 12 months for patients with advanced-stage disease.

•   Mucinous carcinoma tumors are often large and serum CEA can be positive. They have a higher rate of discordance between frozen and final pathology at 34%: 11% were downgraded and 23% were upgraded. This is due in part to their larger size. LN metastases are rare in apparent stage I cancers and an LND can potentially be omitted in these cases without adverse effect on progression-free survival (PFS) or OS (6). Appendectomy is still recommended to ensure primary tumor site identification.

•   Brenner tumors: Brenner tumors of the ovary are relatively uncommon neoplasms, constituting 1.4% to 2.5% of all ovarian tumors. Histologically a Brenner tumor is characterized by varying numbers of rounded nests of transitional or squamous-like epithelium and glandular structures of cylindrical cells within abundant fibrous nonepithelial tissue. Most Brenner tumors are benign, only 2% to 5% being malignant. Malignant components of the tumor show heterogeneous epithelial growth and atypia with intervening stroma, consist of transitional cells, squamous or undifferentiated carcinoma, or a mixture of these types. The criteria proposed by Hull and Campbell in 1973 are as follows (a): frankly malignant histologic features must be present (b), there must be intimate association between the malignant element and a benign Brenner tumor (c), mucinous cystadenomas should preferably be absent or must be well separated from both the benign and the malignant Brenner tumor (d), and stromal invasion by epithelial elements of the malignant Brenner tumor must be demonstrated.

STAGING

Follows FIGO and AJCC surgical staging protocols.

•   Upstaging based on LN metastasis has been reviewed in 14 studies. The mean incidence of LN metastases in clinical stages I to II EOC was 14.2% (range 6.1%–29.6%) of which 7.1% were only in the para-aortic region, 2.9% only in the pelvic region, and 4.3% in both the para-aortic and pelvic regions (7). Grade 1 tumors had a mean incidence of LN metastases of 4.0%, grade 2 tumors 16.8%, and grade 3 tumors 20.0%. According to histologic subtype, the highest incidence of LN metastases was found in the serous subtype (23.3%), the lowest in the mucinous subtype (2.6%). Patterns of LN metastases were largely independent of laterality: among those with unilateral lesions and positive nodes, 50% had ipsilateral LN involvement, 40% had bilateral involvement, and 7% to 13% had isolated contralateral positive LN (8).

TREATMENT

Treatment is usually primary surgical staging with debulking if indicated, followed by adjuvant chemotherapy for all tumors staged greater than IA grade 1. Neoadjuvant chemotherapy followed by surgery can be considered for patients who are poor surgical candidates (large pleural effusions with poor ventilation capacity, severe congestive heart failure (CHF), recent myocardial infarction (MI), recent pulmonary embolus) or who have extensive disease that is potentially unresectable (based on operative skill, patient comorbidities, or risk scoring). Optimal debulking to no visible residual disease is the primary goal. Adjuvant chemotherapy treatment should start within 25 days of surgery. Each additional 10% cytoreduction of disease yields a 5.5% increase in median survival (9).

•   Cytoreductive surgery for stage IV TOC can be attempted with 30% achieving optimal cytoreduction; 30% of patients can be expected to have complications (mostly infectious or wound). The preoperative performance status should be two or lower. Bristow et al (10) demonstrated that survival depended on location of the stage IV disease: the median survival for patients with a pleural effusion was 19 months, lung metastasis was 12 months, parenchymal liver metastasis was 18 months, and other extraperitoneal sites were 26 months. If patients had liver metastasis and had optimal intra- and extrahepatic cytoreduction to less than 1 cm, the median OS was 50 months; if there was optimal extrahepatic and suboptimal hepatic resection, the median OS was 27 months; and if there was suboptimal resection at all sites, there was an OS of 8 months.

•   Removal of LNs for advanced-stage disease has been studied (11); 427 patients with stage IIB, IIIC, or IV all underwent optimal surgery, including removal of bulky LNs greater than 1 cm in diameter. Intraoperative randomization was performed and the control arm completed optimal surgery, whereas the treatment arm underwent additional retroperitoneal lymphadenectomy to remove pelvic (at least 25 nodes) and para-aortic (at least 15 nodes) LNs. After surgery, all patients received platinum-based chemotherapy. The 5Y progression free interval (PFI) was 31.2% for the LND group compared to 21.6% for those in the control arm. The LND group was more likely to require blood transfusions, had a longer surgery, and had more postoperative complications. At 68.4 months, 202 of the 427 patients had died. There was no difference in the risk of death: 48.5% of the LND group and 47% of the control group were alive 68.4 months after surgery.

•   Predictive models for optimal surgical cytoreduction

        Different presurgical models have attempted to stratify predictive values of various findings for optimal debulking versus candidacy for neoadjuvant therapy (ascites, carcinomatosis, tumor size, CA-125 level) but the proposed models usually fail with validation sets. False-positive criteria range from 10% to 68% for laboratory, clinical, or radiologic criteria. If there is progressive disease (refractory disease) while on NACT, a change in chemotherapy regimen should be considered. If the tumor has regressed, it is appropriate to surgically assess the patient and attempt surgical debulking.

        A surgical assessment algorithm has been proposed with the potential to categorize patients by location and bulk of disease into theoretically optimally resectable versus not resectable, called: “scope and score” based on the Fagotti score. Care should be taken with this approach as surgeons are passionate about their surgical skill but can vary differently in their opinions and skill sets (12).

             Fagotti score (seven parameters). Laparoscopic evaluation for feasibility of primary debulking surgery (PDS) versus unresectable to optimal disease status. If patients are deemed not optimally resectable, they are thus dispositioned to neoadjuvant chemotherapy (NACT). It was externally validated and modified by Brun (13) (Table 2.7)

•   If tubo-ovarian cancer is diagnosed incidentally after a TH-BSO without staging, surgical staging should be considered within 3 weeks. The risk of undiagnosed higher-stage disease is 22% to 29% (14); 4% to 25% of unstaged clinical stage I ovarian cancers have positive LNs, and the incidence of isolated contralateral positive LNs ranges from 7% to 13%.

•   The timing of ovarian cyst rupture can make a difference. According to one study (15), preoperative cyst rupture had a larger influence on PFS than intraoperative cyst rupture. For preoperative cyst rupture, the hazard ratio (HR) for OS was 2.65 versus 1.64 for intraoperative cyst rupture (16).

•   Tumor biology: the impact of disease distribution in stage III ovarian cancer patients was evaluated (17): 417 patients from three randomized Gynecologic Oncology Group (GOG) trials who were microscopically cytoreduced and given adjuvant IV platinum/paclitaxel were reviewed. Patients were divided into three groups based on preoperative disease burden: minimal disease (MD) was defined by pelvic tumor and retroperitoneal metastasis; abdominal peritoneal disease (APD) was considered disease limited to the pelvis, retroperitoneum, lower abdomen, and omentum; and upper abdominal disease (UAD) was considered disease affecting the diaphragm, spleen, liver, or pancreas. The median OS was not reached in MD patients, 80 months in the APD group, and 56 months in the UAD group (p < 0.05). The 5Y survival (YS) was 67% for MD group, 63% for APD and 45% for UAD. In multivariate analysis, the UAD group had a significantly worse prognosis than MD and APD both individually and combined (PFS HR 1.44; p = 0.008 and OS HR 1.77; p = 0.0004). Thus, it is suggested that there is a biological difference in ovarian cancer patients proportional to the amount of disease at presentation.

CHEMOTHERAPY FOR EPITHELIAL TUBO-OVARIAN CANCER

•   First-line chemotherapy involves platinum-based chemotherapy regimens with a taxane. Single-agent platinum regimens can be considered in older or compromised patients.

•   Second-line agents are used when cancer recurs after first-line therapy has been given.

        Platinum-sensitive and platinum-resistant disease. This is defined based on disease recurrence in relation to the 6 month time period following completion of first-line platinum-based chemotherapy.

             Platinum sensitive disease: tumor has recurred but more than 6 months has elapsed since primary treatment with platinum-containing regimens. Second line chemotherapy with platinum-based regimens should be used.

             Platinum resistance is defined as: disease recurrence occurring less than 6 months after completion of primary platinum-based treatment. If recurrence occurs at less than 6 months, non–platinum-based salvage therapies should be used.

             Platinum refractory is defined as: patients who have progressive disease while on chemotherapy.

             Response rates for second-line chemotherapy depend on the time to recurrence after primary chemotherapy. The longer the interval from primary therapy, the better the response rate: 6 to 12 months, 27%; 13 to 24 months, 33%; greater than 24 months, 59%

•   Neoadjuvant chemotherapy is chemotherapy given prior to surgery. Surgery is usually attempted after two to three cycles of chemotherapy. This has been shown to reduce the radical nature of surgery with a decreased risk of colostomy and hemorrhage.

•   Consolidation: chemotherapy that is used after primary or adjuvant chemotherapy to decrease the chance of cancer recurrence in patients with complete clinical remission (CCR). This is usually a short duration of treatment.

•   Maintenance: chemotherapy that is used after primary or adjuvant chemotherapy to decrease the chance of cancer recurrence in patients with CCR. This is usually of a longer duration than consolidation therapy.

•   Intraperitoneal (IP) chemotherapy: chemotherapy is administered directly into the abdominal cavity. IP chemotherapy using platinum and taxane regimens is indicated for optimally debulked patients stage II or higher.

•   Intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC): heated cytotoxic regimens are administered at the time of primary or recurrent debulking surgery and circulated intraperitoneally for a specific amount of time.

        Benefits:

             A high volume of chemotherapy can be delivered, and a homogeneous distribution can be achieved. This is often not practical in conventional IP therapy, because of abdominal distension and pain, but it is feasible in HIPEC, since the patient is under anesthesia.

               There is no interval between cytoreduction and chemotherapy. The cytotoxic therapy is applied at the time of minimal disease manifestation, and there are no adhesions that might alter the distribution of the drug.

             Hyperthermia (>41°C) has a pharmacokinetic benefit. Several studies have convincingly shown that hyperthermia can increase both the tumor penetration of cisplatin as well as DNA crosslinking.

             High concentrations of chemotherapy can be achieved in the IP compartment with low systemic exposure—in a single intraoperative treatment.

             There is the mechanical continuous flow of perfusion solution.

        Many combinations of cytotoxic agents have been used:

             Single agents to include: carboplatin 800 mg/m² for 60 to 120 minutes at 41°C to 43°C; oxaliplatin 460 mg/m² for 30 minutes; cisplatin 100 mg/m² for 90 minutes at 41°C to 43°C.

             Cisplatin 350 mg/m² and alpha-interferon 5 million IU/m² and for 90 minutes at 43°C to 44°C; cisplatin 100 mg/m² and mitomycin C 15 mg/m² for 60 minutes at 41°C to 43°C; paclitaxel 60 to 75 mg/m² and cisplatin 100 mg/m² or doxorubicin 0.1 mg/kg (if platinum resistant) for 120 minutes at 40°C to 43°C.

        However, the absence of sufficient levels of scientific evidence to support the use of HIPEC in patients with tubo-ovarian cancer with peritoneal dissemination does not allow a general recommendation outside of clinical trials.

TREATMENT BY STAGE

•   Stage IA grade 1 tumors: surgery is definitive. If fertility preservation is a concern, consider leaving the uterus and contralateral tube and ovary.

•   Stage IA, grade 2 or 3 and stage IB and IC, any grade: primary treatment is surgery. If fertility is a concern, consider leaving the uterus and contralateral tube and ovary. Adjuvant chemotherapy is platinum based with a taxane for three to six cycles.

•   Stages II, III, IV: either NACT or PDS may be offered. NACT has been shown to offer lower peri- and postoperative morbidity but PDS may offer superior survival (18).

        Primary treatment is surgery (PDS). Adjuvant chemotherapy is platinum based with a taxane for six cycles. This can be administered IV or IP/IV.

        Consideration can be given to neoadjuvant chemotherapy for:

             The medically unfit or high perioperative risk patient.

             Per surgical risk assessment score (Fagotti).

SECOND-LOOK LAPAROTOMY

•   Second-look laparotomy is the pathological surgical assessment for residual disease after primary adjuvant chemotherapy in a patient with a clinical complete response. It is used to guide decisions for either continuing chemotherapy, changing chemotherapy, or discontinuing chemotherapy. It can also be used to guide treatment in patients who were suboptimally debulked, or who were primarily unstaged. Routine second-look laparotomy is not the current standard of care; 40% of second-look patients are pathologically positive, and of those who are negative, 50% will recur (see Table 2.8) (19).

RECURRENCE

•   Most recurrences occur within the first 2 years. The risk of recurrence for a grade 1, stage I ovarian cancer is less than 10%. The risk of recurrence for stage III ovarian cancer is much higher, over 50%.

SECONDARY CYTOREDUCTION

•   Secondary cytoreduction is the removal of gross recurrent disease after primary or secondary chemotherapy. There are some criteria attributed to Chi, which help stratify patients as appropriate surgical candidates. These are based on time, location, and number of recurrent tumor sites. If the recurrence occurs at greater than 30 months from primary chemotherapy, secondary cytoreduction can be attempted regardless of number of involved sites. If the interval is less than 30 months, and there are one to two sites of recurrence, cytoreduction can again be attempted. If there is carcinomatosis, ascites, or the patient is platinum resistant, it is often not wise to attempt secondary cytoreduction. For those who had less than 0.5 cm of residual disease after secondary cytoreduction, an improvement in OS to 56 months was seen versus 27 months for those who were suboptimally debulked. The overall success at secondary optimal cytoreduction ranges between 24% and 84% (20).

CEREBELLAR DEGENERATION

•   Cerebellar degeneration can occur from antibodies to ovarian cancer. This is called paraneoplastic cerebellar degeneration. The incidence is 2:1,000 patients with gynecologic cancers. There are two main antibodies: the anti-Yo antibody reacts against the Purkinje cells and the anti-Hu antibody reacts against all neurons.

SURVIVAL

•   Relative survival

•   2 YS: 65%; 5 YS: 44%; 10 YS: 36% (21) (Tables 2.9 and 2.10)

•   10 YS: 31% of women survive more than 10 years. Younger age, early stage, low grade, and nonserous histology are significant predictors of long-term survival. One third of those who survived to 10 years had stages III or IV per 1989 staging, 16% of patients with late-stage serous cancer survived more than 10 years (22).

SURVIVAL CARE

•   Follow-up:

        Every 3 months for 2 years

        Every 6 months up to 5 years

        Annually for subsequent visits

•   At each visit:

        Physical and pelvic examination

        Symptom review

        Consider CA-125: discussion should be held with the patient regarding surveillance with tumor markers. Rustin et al demonstrated no improvement in survival when tumor markers were followed. Patients had a poorer quality of life with additional unsuccessful cycles of chemotherapy given based on laboratory data. Assessment of symptoms, along with physical examination, can guide the clinician regarding when to order lab tests, imaging, and when to initiate second-line chemotherapy (23).

•   CT imaging: CT cannot often detect subcentimeter disease.

77EPITHELIAL TUBO-OVARIAN CANCER NOTABLE TRIALS

•   Primary Adjuvant Chemotherapy Trials

        ICON 1: this trial evaluated 477 patients who had early ovarian cancer “staged” with hysterectomy, bilateral salpingo-oophorectomy, and recommended omentectomy. Eligibility was if the treating physician was uncertain whether the patient required chemotherapy. 93% of patients were “stage I.” Patients were randomized between no further treatment (NFT) and single-agent carboplatin (AUC 5); cisplatin, doxorubicin, cyclophosphamide (CAP); or another platinum regimen. Histology was: 32% serous, 15% clear cell, 23% mucinous. Most patients were apparent stage I; however, there were 7% of patients with stage II or III disease; 70% were grade 2 or 3. At 51 months, the OS was 79% in the chemotherapy arm versus 70% in the NFT arm. The 5Y PFS was 73% in the chemotherapy group versus 62% in the NFT group. For clinical stage I disease that did not get staged, there was a 38% recurrence rate without further treatment and a 30% death rate. Chemotherapy had an HR of 0.66 for survival (24).

        ACTION: this trial ran concurrently with ICON 1. 30% of 448 patients were comprehensively staged. Patients were randomized to observation or to chemotherapy. Chemotherapy consisted of four to six cycles of single-agent platinum or a platinum-containing regimen. 40% of patients were stage IA or IB and 60% had grade 1 or grade 2 disease. The 5 YS in the observation and adjuvant chemotherapy arms were 75% and 85%. Patients who received chemotherapy had a better recurrence-free survival (RFS; HR 0.63). In nonoptimally staged patients, the adjuvant chemotherapy group had an improved OS and RFS (HR 1.75 and HR 1.78, respectively). Among patients in the observation arm, optimal staging provided an improvement in OS and RFS (HR 2.31 and HR 1.82, respectively). There was no benefit seen from adjuvant chemotherapy in the optimally staged patients. This suggests that in the suboptimally staged group, there were undiagnosed higher-staged patients who benefited when given chemotherapy. A 10Y follow-up found support for most of the original conclusions, except that OS after optimal surgical staging was improved, now among patients who received adjuvant chemotherapy (HR of death 1.89) (25,26).

        ICON 2: this trial evaluated 1,526 eligible surgically staged patients who needed primary adjuvant chemotherapy. Patients were staged I to IV and were randomized to single-agent platinum-based chemotherapy or CAP. This trial was stopped early due to the availability of taxanes. These patients were then grouped into the control arm of ICON 3 as their outcomes were statistically nonsignificant with an OS HR of 1.0. The median survival in both groups was 33 months and the 2 YS was 60% for both arms. CAP was more toxic (27).

        ICON 3: this trial evaluated 274 eligible surgically staged patients stages I to IV, 20% of whom were stages I and II. Patients were randomized between a paclitaxel–carboplatin doublet versus the ICON 2 group of single-agent carboplatin or CAP. The OS was 36 months for carboplatin–paclitaxel and 35 months for the control groups of single-agent carboplatin and CAP. The PFS were 17 months versus 16 months for the control arm. There were a lot of confounding factors in this study: a large number of patients were deemed to have recurrent disease based on elevated CA-125 levels prior to showing clinical recurrence. In addition, 30% of those who did not get paclitaxel as primary treatment received paclitaxel as second-line treatment (28).

        ICON 4: this trial evaluated 802 eligible patients with recurrent platinum-sensitive ovarian cancer; 75% recurred more than 12 months following initial therapy. Patients were randomized to paclitaxel 175 to 185 mg/m² and cisplatin 50 mg/m² or carboplatin AUC 5 versus single-agent cisplatin 75 mg/m² or carboplatin AUC 5. The doublet therapy showed a statistically significant improvement over the single-agent group with a median PFS of 13 months versus 10 months (HR 0.76; p = 0.0004). The doublet therapy showed an improvement in median survival by 5 months (29 months versus 24 months; HR of 0.82, p = 0.02). This translated to a 2 YS of 57% versus 50% and a 1Y PFS of 50% versus 40%. Criticisms of this trial were that 75% of patients were in a good prognosis group. This is essentially a trial of platinum-sensitive disease (28).

        ICON 5/GOG 182 EORTC 55012: this trial evaluated 4,312 surgically staged stage III and IV patients for primary adjuvant therapy. The control arm was the doublet of carboplatin AUC 6 and paclitaxel 175 mg/m² administered for eight cycles. The experimental arms consisted of carboplatin–paclitaxel–gemcitabine as sequential doublets or in triplicate, for a total of eight cycles, or carboplatin–paclitaxel–topotecan as sequential doublets for a total of eight cycles, and carboplatin–paclitaxel–liposomal doxorubicin as a triplicate regimen for eight cycles. There was no difference in median PFS or OS with the PFS in the control arm being 16 months and the OS being 44 months, both in the optimally and suboptimally debulked patients. The median PFS for patients with suboptimal, gross optimal (<1 cm residual), and microscopic residual disease were 13, 16, and 29 months, respectively, and the median OS rates were 33, 40, and 68 months, respectively (29).

        ICON 7/AGO-OVAR 11: this trial evaluated 1,528 eligible patients stages I to IV, of whom 26% were suboptimally debulked. The control arm was carboplatin AUC 5 or 6 and paclitaxel 175 mg/m² IV every 3 weeks for six cycles. The experimental arm consisted of carboplatin and paclitaxel at the same doses with the addition of bevacizumab at 7.5 mg/kg IV every 3 weeks for six cycles, with maintenance bevacizumab continued for an additional 12 cycles or until progression of disease. Median follow-up was 48.9 months. At 42 months, PFS was 22.4 months without bevacizumab versus 24.1 months with bevacizumab (p = 0.04 log rank). In high-risk patients, the PFS was 14.5 months versus 18.1 months with bevacizumab and median OS was 28.8 versus 36.6 months with bevacizumab. At 48.9 months though, no difference in PFS was seen. For the entire population at 48.9 months, the restricted mean survival time (RMST; OS) demonstrated an improvement of only 0.9 months from 44.6 to 45.5 months (95% confidence interval [CI] log rank p = 0.85, pH test p = 0.02) with bevacizumab—not significant (NS). In a subgroup analysis, RMST for the poor prognosis group (stage IV, inoperable stage III [6%], and suboptimally debulked >1 cm stage III) demonstrated a 4.8-month RMST improvement from 34.5 to 39.3 months (log rank p = 0.03 PH test = 0.007). In the average prognosis group, the RMST was 49.7 months versus 48.4 months (p = 0.2) in the bevacizumab group. No benefit from bevacizumab was seen in low-grade serous tumors, clear cell tumors, or low-stage high-risk patients (stage I–IIA clear cell or G3). Hypertension attributed to bevacizumab was seen in 18% of patients who received bevacizumab versus 2% of patients in the control arm. Bowel perforation was seen in 10 patients in the bevacizumab group versus three patients in the control arm (30,31).

        GOG 1: 86 evaluable surgical stage I patients were randomized to observation, whole pelvic radiation therapy (WP-XRT), or melphalan chemotherapy. Recurrence was 17% in the observation group, 30% in those irradiated, and 6% in those who received chemotherapy. Recurrence was related to grade: grade 1, 11%; grade 2, 22%; grade 3, 27% (32).

        GOG 111: this trial evaluated 386 eligible suboptimally debulked stage III and IV patients. Patients with greater than 1 cm residual disease were randomly assigned to receive cisplatin 75 mg/m² and cyclophosphamide 750 mg/m² or cisplatin 75 mg/m² and 24-hour paclitaxel 135 mg/m². Overall response rate in the first arm was 73% compared to 60%. PFS was longer in the paclitaxel-containing arm at 17.9 months versus 12.9 months. OS was longer in the paclitaxel arm at 37.5 months compared to 24.4 months (33).

        OV-10: this trial evaluated cyclophosphamide and cisplatin versus 3-hour paclitaxel and cisplatin in 680 eligible patients with stage IIB, IIC, III, or IV disease, who were optimally and suboptimally debulked. The ORR was 58.6% in the cisplatin and paclitaxel arm versus 44.7% in the cyclophosphamide and cisplatin arm. The PFS was 15.5 months versus 11.5 months favoring the paclitaxel arm and the OS was 35.6 months versus 25.8 months, again, all favoring paclitaxel (34).

        GOG 132: this trial evaluated 648 suboptimal stage III and any stage IV patients. There were three arms: a doublet of cisplatin and paclitaxel dosed at 75 and 135 mg/kg; single-agent paclitaxel dosed at 200 mg/kg; and single-agent cisplatin dosed at 100 mg/kg. The PFS, respectively, were 14 months, 11 months, and 16 months. The OS, respectively, were 26 months, 26 months, and 30 months. The response rates were, respectively, 67%, 67%, and 47% (35).

        GOG 157: this trial evaluated three versus six cycles of paclitaxel and carboplatin in 427 eligible patients staged IAG3, IBG3, IC, and II. The primary endpoint was recurrence rate. 457 patients were registered, 213 in each arm. Of these, 70% were stage I, 30% were stage II, and there were 30% clear cell cancers in each arm. The recurrence rate was 27.4% for three cycles versus 19% for six cycles (95% CI: 0.53–1.13). The probability of surviving 5 years was 81% for three cycles versus 83% for six cycles (95% CI: 0.66–1.57). The HR for recurrence was 0.74, p = 0.18 (NS). Criticisms of the study were: insufficient power to detect a difference, and only 29% (126) of patients were staged appropriately. Chan updated the data in 2006 and found a benefit to six cycles of chemotherapy specifically for serous tumors with a 5Y RFS of 83% compared to 60% in those who received six versus three cycles of chemotherapy, respectively (p = 0.007). Those with serous tumors had a significantly lower risk of recurrence after six versus three cycles of chemotherapy (HR 0.33; 95% CI: 0.14–0.77; p = 0.04) in contrast to nonserous tumors (HR 0.94; 95% CI: 0.60–1.49) (36,37).

         GOG 158: this trial compared 792 optimally cytoreduced stage III ovarian cancer patients to 24-hour paclitaxel and cisplatin versus 3-hour paclitaxel and carboplatin. This was designed as a noninferiority study and there was provision for second-look laparotomy, which about 50% chose to do (Greer et al subset analysis proved that second-look laparotomy was not beneficial). 85% were able to receive all six cycles. The PFS was 19 months for paclitaxel and cisplatin and 20 months for paclitaxel and carboplatin. The OS was 48 months for paclitaxel cisplatin and 57 months for paclitaxel carboplatin. The RR of recurrence was 0.88 (95% CI: 0.75–1.03), and the RR for the OS was 0.84 (95% CI: 0.7–1.02) favoring carboplatin and paclitaxel. The carboplatin arm had less myelotoxicity and electrolyte problems, with similar neurotoxicity (19,38).

        GOG 218: this randomized trial evaluated 1,873 staged III or IV suboptimally debulked patients with a control arm of carboplatin and paclitaxel. The investigational arms consisted of carboplatin and paclitaxel with either bevacizumab for 5 months during primary therapy or an extended dosing of bevacizumab after six initial cycles of carboplatin, paclitaxel, and bevacizumab for a total of 18 cycles. The PFS was, respectively, 10.3, 11.2, and 14.1 months; the PFS HR was 0.91/0.72. The OS, respectively, was 39.9, 38.7, and 39.7 months; OS HR was 1.036/0.92. Maximum separation of the PFS occurred at 15 months and the curves merged 9 months later. The degree of neutropenia was associated with a greater PFS and OS (HR 0.76 and 0.73, respectively) (39).

        SCOTROC 1: this trial evaluated 1,077 patients with stage IC to IV disease and randomized them to docetaxel 75 mg/m² versus paclitaxel at 175 mg/m² each with carboplatin at an AUC of 5 for six cycles. The PFS was 15 months versus 14.8 months. Docetaxel was found to not be inferior. The OS was 64.2% versus 68.9%, respectively (40).

        OCTAVIA: this single-arm study evaluated 189 patients treated with primary adjuvant bevacizumab plus weekly paclitaxel and every 21 days carboplatin. For patients with stage IIB to IV or grade 3/clear-cell stage I/IIA, bevacizumab was dosed at 7.5 mg/kg on day 1; paclitaxel at 80 mg/m² on days 1, 8, 15; and carboplatin at an AUC 6 on day 1 IV every 21 days for six to eight cycles, followed by single-agent maintenance bevacizumab to total 1 year. 74% of the patients had stage IIIC/IV disease. The primary objective was PFS. Patients received a median of six chemotherapy and 17 bevacizumab cycles. At the predefined cutoff 24 months after last patient enrollment, 99 patients (52%) had progressed and 19 (10%) had died, all from ovarian cancer. The median PFS was 23.7 months (95% CI: 19.8–26.4 months), 1Y PFS rate was 85.6%, response evaluation criteria in solid tumors (RECIST) response rate was 84.6%, and median response duration was 14.7 months. Most patients (≥90%) completed at least six chemotherapy cycles. Grade ≥3 peripheral sensory neuropathy occurred in 5% and febrile neutropenia in 0.5%. There was one case of gastrointestinal perforation (0.5%) and no treatment-related deaths (41).

        AGO-OVAR 9: This was a randomized phase III front-line chemotherapy trial by the Gynecologic Cancer InterGroup (GCIG) for previously untreated patients with stages I to IV epithelial ovarian cancer. 1,742 patients were randomly allocated to receive a combination of paclitaxel, carboplatin, and gemcitabine (TCG) or paclitaxel and carboplatin (TC). TC was given day 1 every 21 days for a planned minimum of six courses. Gemcitabine was given on days 1 and 8 of each cycle in the TCG arm. The median PFS for the TCG arm vs TC arm was 17.8 months and 19.3 months, respectively (HR 1.18; 95% CI: 1.06–1.32; p = 0.0044). The median OS for TCG and TC arm was 49.5 months and 51.5 months, respectively. Patients on the TCG arm experienced more grade 3 to 4 hematologic toxicity and fatigue compared to patients treated on the TC arm. Quality of life analysis showed a disadvantage in the TCG arm (42).

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