EPITHELIAL OVARIAN CANCER
Executive Summary
Epithelial ovarian cancer is the most common type of ovarian cancer and the most aggressive gynecological malignancy. Approximately 70% of patients are diagnosed at an advanced stage due to the asymptomatic nature of the disease. Early diagnosis is further hindered by the absence of effective screening tests. First-line screening and diagnosis involves gynecologic examination combined with ultrasonography and CA-125 serum level assessment, but the gold standard for conclusive diagnosis and staging remains surgical excision and further histological examination of the excised adnexal mass. Surgery also provides tumor debulking with ultimate goal to perform complete macroscopic tumor resection (optimal cytoreduction) [1]. Initial response to standard primary treatment including surgical cytoreduction and adjuvant platinum-based combined chemotherapy is approximately 80%. A 5-year survival rate is approximately 40% [2].
Public Health Relevance
Epithelial ovarian cancer is not rated as one of the most common human malignancies, but it is a major public health concern due to its disproportionate impact on cancer morbidity and mortality: 238,719 new cases were detected in 2012 [3], an increase in morbidity compared to 225,500 new cases in 2008 [4]. The lifetime risk of epithelial ovarian cancer is approximately 0.7% in sporadic cases and it greatly increases in patients with a familial predisposition (up to 10-40%). The median age at diagnosis for sporadic cancer is 60 years, while predisposed patients may be affected earlier, often in their fifth decade. The age-specific incidence of sporadic disease achieves its peak in people of 75 years and older. Although there has been a statistically significant improvement in treatment results over the last years, ovarian cancer remains the leading cause of gynecologic cancer mortality – 151,905 ovarian cancer-related deaths were registered in 2012.
Nulliparous women and those who have not breastfed are at increased risk for developing ovarian cancer while tubal ligation, oral contraceptives and belonging to African race decreases the risk. Endometriosis is associated with a significantly increased risk of clear-cell, low-grade serous and endometrioid invasive ovarian cancer [5].
The incidence of the disease in developing counties is lower than in developed ones: the incidence of ovarian cancer in South and North America in 2012 was 5.8 and 8.1 per 100,000, respectively. Unfortunately the mortality in developing countries is much higher, probably due to high prevalence of advanced-stage cases and lower level of cancer care.
Requirements for diagnosis, treatment, and monitoring Diagnostics:
At present surgery remains the gold standard for confirming diagnosis and staging ovarian cancer. Laparotomy serves three main purposes in the management of patients with suspected ovarian cancer:
1) to confirm histological type of disease,
2) to determine the extent of disease (staging), which is critical in determining whether postoperative treatment will be necessary, as well as to assess prognosis,
3) to permit debulking of tumor since patients who are optimally cytoreduced (defined as having less than or equal to 1-cm diameter residual tumor) have a better prognosis compared to those with greater amounts of residual disease[6].
Histologic confirmation of the disease should be made on the basis of biopsies of all suspicious sites relevant for staging, such as omentum, mesentery, liver, diaphragm, pelvic and paraaortic lymph nodes [7,8].
Surgery:
As noted above surgery is important in diagnosis, staging, and de-bulking. De-bulking surgery is often done at diagnosis, but can also be performed after 3 or 6 cycles of cyto-reductive chemotherapy.
Testing:
The goal of clinical (preoperative) staging is the confirmation of a malignant adnexal mass, exclusion of another primary tumor, assessment of tumor spread and estimation of possible complications of the disease or further treatment.
Computed tomography (CT-scan) or magnetic resonance imaging (MRI) are standard imaging methods for tumor evaluation and post-operative surveillance. If CT-scan and MRI cannot be used (unavailable in developing countries or a patient has contraindications to contrast agents and ionizing radiation exposure) ultrasonography becomes the method of choice.
The CA-125 serum level should be assessed. CEA assessment is optional (useful to distinguish serous and mucinous ovarian cancer or metastatic spread to ovary of the colon cancer), α -fetoprotein and β-chorionic gonadotropin help to exclude germ cell tumors in women younger than 40 years old. Some other tests should also be done: blood chemistry for the assessment of renal and hepatic functions (liver enzymes, total bilirubin, albumin and creatinine levels), complete blood count.
Administration and Care of Patients:
Anticancer drugs for the treatment of ovarian cancer require peripheral or central venous access. Administration can be performed either in outpatient or in-patient facilities. Antiemetic prophylaxis ideally includes administration of 5HT3-antagonists before the start of chemotherapy. Administration of paclitaxel requires the use of dexamethasone, an H2 blocker, and diphenhydramine to prevent hypersensitivity reaction.
Intravenous vs. Intra-peritoneal Chemotherapy
Chemotherapy is most often administered intravenously, but in some studies, some of the agents are administered intra-peritoneally. In some studies this has been associated with a small improvement in survival outcomes, but is technically very difficult to administer, even in resource-rich settings, and we would not recommend this for routine use in most settings.
Safety monitoring during chemotherapy requires weekly evaluation of complete blood counts. Patients should regularly visit a medical/general oncologist. Efficacy assessment and follow-up after completion of the treatment should be performed using the same methods of tumor size and spread evaluation which had been used initially.
Overview of Regimens
Ovarian cancer is a chemo-sensitive disease; therefore chemotherapy is one of the most important components of the systemic treatment. The following tables include information about administration and dosing of different regimens.
The standard first-line chemotherapy consists of combination of paclitaxel and carboplatin, both administered intravenously every 3 weeks. Patients with early stage IA-IB with low-grade, or well differentiated adenocarcinoma after adequate staging require observation only. In the case of intermediate prognosis, (stage IA-IB and moderately-well differentiated adenocarcinoma after optimal cytoreduction) 4 cycles of paclitaxel and carboplatin every 3 weeks are prescribed. Chemotherapy for advanced ovarian cancer (stage IC-IV) includes 6 cycles of platinum-based regimens, usually paclitaxel and carboplatin or paclitaxel and cisplatin. The combination of paclitaxel and carboplatin is equally effective but is less toxic and less complex to administer.[14]
If taxanes are not available then carboplatin or cisplatin can be given as a single agent, but this is not considered optimal therapy.
Bevacizumab is not recommended as part of the standard regimens since it has not shown an increase in overall survival.
Standard Regimens for First Line Therapy Paclitaxel + Carboplatin or Cisplatin
Carboplatin Intravenous infusion AUC6 Day 1
Paclitaxel Intravenous infusion 175 mg/m2 Day 1
Cisplatin Intravenous infusion 75 mg/m2 Day 1
Second line therapy for patients with recurrent disease after initial chemotherapy
Approximately 80% of patients diagnosed with ovarian epithelial cancer will relapse after first-line platinum-based and taxane-based chemotherapy and may benefit from subsequent therapies [9]. Systemic treatment options for patients with recurrent disease are subdivided in three categories according to the platinum-free interval: platinum-refractory – progressing during therapy, platinum-resistant recurrence – progressing within 6 months after completion of the platinum-based chemotherapy, platinum sensitive – progressing after more than 6 months after completion of the platinum-based chemotherapy. Therapeutic options for second line therapy include combinations of platinum compound plus either paclitaxel, gemcitabine, etoposide or doxorubicin as listed in the tables below. All of them have similar efficacy and the choice will be dependent on patient status and drug availability. Usually 6 cycles of chemo within a 3 week interval is recommended.
Standard Regimens for Platinum-sensitive relapse (≥6 months):
Carboplatin Intravenous infusion AUC5 Day 1
Paclitaxel Intravenous infusion 175 mg/m2 Day 1
Cisplatin Intravenous infusion 75 mg/m2 Day 1
Paclitaxel Intravenous infusion 175 mg/m2 Day 1
Carboplatin Intravenous infusion AUC4 Day 1
Gemcitabine Intravenous infusion 1000 mg/m2 Days 1,8
Cisplatin Intravenous infusion 75 mg/m2 Day 1
Etoposide Per os 100 mg 1-7 days
Carboplatin Intravenous infusion AUC5 Day 1
Doxorubicin Intravenous infusion 50 mg/m2 Day 1
Platinum refractory and resistant relapse
In case of platinum resistant relapse treatment is focused on quality of life and control of symptoms. Monotherapy of different non-platinum agents has similar efficacy. Various agents, such as doxorubicin, liposomal doxorubicin, etoposide, gemcitabine, topotecan and
bevacizumab-containing regimens can be utilized in this situation but extension of life is minimal, and these agents are not recommended to be added to the EML for this indication. Other combinations of anticancer drugs (see Table 3) can be used in treating epithelial ovarian cancer. However, some regimens, such as that including bevacizumab, have only shown progression-free survival without evidence supporting overall survival benefit. Thus, the recommendations only consider the standard regimens listed above.
Review of Benefits and Harms Benefits
First line chemotherapy (paclitaxel/platinum) with our without surgery, results in a high remission rate, though as noted below, a high relapse rate. Nonetheless, patients treated with first line therapy have a significant prolongation in survival, and 20% or more are long-term survivors. Therefore the benefit of first-line chemotherapy is significant.
Administration of platinum-based regimens in first-line chemotherapy is highly important and improves progression-free survival up to 18 months and overall survival to 44 months [10]. Median overall survival has improved from 18-24 months two decades ago to 40-60 months and at present the 5-year overall survival is about 44% [10]. There is no benefit from adding a third chemotherapy agent to standard chemotherapy [11].
The risk of recurrence in ovarian cancer after first line therapy is approximately 80% [9].
The probability of response to second-line chemotherapy depends on the progression-free interval after the last dose of the preceding line of chemotherapy. Patients with platinum-resistant ovarian cancer comprise a poor prognosis population, characterized by low response rates (<10%) with short expected overall survival [12]. Administration of doublets does not improve progression-free survival but increases toxicity in contrast with monotherapy with non-platinum agents. For platinum-sensitive ovarian cancer carboplatin doublets is the treatment of choice. The results of the trials, which compared different platinum-based regimens, were controversial in terms of PFS improvement. Nevertheless the overall survival benefit was observed in patients receiving carboplatin and paclitaxel only [13].
Harms and Toxicity Considerations Common
Patients receiving treatment for ovarian cancer experience common drug toxicity reactions. Most patients suffer hematological toxicity from the medication combination including neutropenia, thrombocytopenia, and anemia, all of which are typically rapidly reversible upon discontinuation of agents.[11,13]Paclitaxel can cause hypersensitivity reactions in up to 30% of patients and requires premedication to reduce the risk of these reactions. Paclitaxel frequently causes alopecia and peripheral neuropathy, which is often mild and reversible. [13,15] Cisplatin and carboplatin can cause severe, potentially dose-limiting nausea and vomiting requiring pretreatment with anti-emetics.
Serious
In approximately 10-30% of cases, cisplatin causes nephrotoxicity which may result in electrolyte abnormalities, aggressive IV hydration is necessary to reduce this risk. [13] Doxorubicin is associated with the risk of congestive heart failure, however the risk is small (<1%) in patients receiving <450-500mg/m2 cumulative dose, as in the regimens above.[16]
Systematic Reviews
The following systematic reviews and meta-analyses summarize the literature supporting the use of named regimens:
• Coleman RL et al. Latest research and clinical treatment of advanced-stage epithelial ovarian cancer Nat Rev Clin Oncol. 2013 April ; 10(4): 211–224.
o Available data on second line therapy for recurrent disease is summarized in the tables below from Coleman et al. Stronger data is available for platinum-sensitive disease, where recurrence is documented more than 6 months after platinum-based therapy versus platinum-resistant disease, where recurrence is documented within 6 months of platinum-based therapy. Patients with platinum-sensitive disease have significantly better PFS and OS.
• F. A. Raja et al. Optimal first-line treatment in ovarian cancer Ann Oncol (2012) 23 (suppl 10): x118-x127.
o For women with stage Ic and above, clear cell histology, or other high-risk features, adjuvant chemotherapy with carboplatin and paclitaxel is recommended based on ICON 1 and EORTC ACTION trials. Analyzed together, they enrolled >900 patients and showed improvement in RFS (76% vs 65% P = 0.001) and OS (82% ves74% P = 0.008) at 5 years, maintained in 10 year follow-up. Greatest effect of chemotherapy in patients with sub-optimal surgery. No RCT evidence of benefit of adding paclitaxel as compared with carboplatin alone, but it is generally given if available. Mounting evidence that chemotherapy can be given neoadjuvantly with equivalent or improved result compared to adjuvantly. While six cycles of carboplatin are common given, three cycles were shown to be equivalent in GOG 157: RFS at three year follow-up for 6 cycles was 24% lower (HR: 0.761; 95% CI: 0.51-1.13, p=0.18), nearly identical observed death rates (HR: 1.02; 95% CI: 0.662-1.57).
7
Two Tables from Coleman et al 2013
NATURE REVIEWS |CLINICAL ONCOLOGY VOLUME 10| APRIL 2013 | 217
common grade 3 or 4 event (16–17% both cohorts) with peripheral neuropathy (5%) and hand–foot syndrome (4.5%) being more common in the experimental cohort compared to the control. Overall survival has not been reported, but publication is anticipated.
Platinum-sensitive disease
Platinum-sensitive disease is defined as patients whose recurrence is documented greater than 6 months after platinum-based therapy.64,68 These patients have a much
better prognosis than the categories above in terms of longevity, as many will respond to multiple regimens. Generally these patients are treated with a platinum-based combination. Platinum-sensitive disease is a broad category that can be rather heterogeneous, because those who recur just over 6 months after receiving platinum-based therapy can behave more like platinum-resistant patients than those who recur later; response rates and time-to-event data improve incrementally as the time interval from prior chemotherapy until recurrence increases. Thus, some authors have advocated that those who recur earlier, specifically between 6–12 months, be labelled as partially or intermediately sensitive.78 These
patients can be treated in a similar way to platinum-sensitive patients who recur after 12 months; however, some have advocated for the consideration of single-agent therapies used in platinum-resistant disease or non-platinum-based combinations.78
A number of platinum-based combinations can be used in patients with platinum-sensitive disease (Table 4). Often, patients are treated with platinum-based and taxane-platinum-based chemotherapy again; however, concern for cumulative neuropathy can limit this choice.
Furthermore, if the time from previous platinum and taxane treatment has been short, then often a regimen is selected that incorporates an alternative to taxane, such as gemcitabine or PLD. Besides altering the toxi-city profile, a different mechanism of action is invoked by changing the second agent paired with platinum. More recently, with the discovery of other active cytotoxic agents, non-platinum combinations are becoming more common.79 Contemporary trials in platinum-sensitive
disease have incorporated targeted biological agents, as outlined below in the novel agent focus section.
Recurrent disease therapy
Most patients diagnosed with recurrent disease will have a multifocal distribution of implants that mimic their presentation at initial diagnosis. In this respect, it is not difficult to understand clinicians’ and patients’ interest in ‘secondary’ surgical cytoreduction. Unfortunately, despite the significant attention this topic has received from clini-cal investigation, guidance as to its role in the setting of recurrent disease is not clear.18 In addition,
interpreta-tion of the available data is difficult at the minimum, and hazard ous at the extreme, because of the inherent selec-tion bias that exists in reviews of clinical experience at one or more institutions. Even reports that are based on observations of prospectively collected patients cannot be reliably compared to historical observations owing to inability to control for variations in practice patterns, patient selection and assessment models. This situation has placed a premium on phase III investigation, which fortunately is underway.
Despite the uncertainty, most practitioners strongly advocate that secondary cytoreduction has a place
Table 3 | Most-frequently used agents in platinum-resistant disease
Agent Response
rate (%) PFS (months) Overall(months) survival Side effects Comments
Pegylated liposomal doxorubicin71,72
10–20 3–4 10–12 Hand–foot syndrome;
mucositis Most frequently prescribed as every 4 weeks schedule Topotecan71,73 12–18 3–4 10–12 Myelosuppression Daily for 5 days or weekly
administration used
Docetaxel70 22 3.5 12.7 Myelosuppression Single GOG trial with very good results
Gemcitabine72,126 15 4–5 11.8–12.7 Myelosuppression Also data with platinums in resistant
disease;127 approved for
platinum-sensitive disease with carboplatin Pemetrexed128 15–21 2.9 11.4 Myelosuppression Not approved in ovarian cancer
Etoposide129,130 6–27 4–5 10–11 Myelosuppression Activity, dose and population dependent
Paclitaxel74–77 10–30 4–6 13 Myelosuppression;
neuropathy Usually administered weekly in this setting Nab-paclitaxel131 23 4–5 17.4 Myelosuppression;
neuropathy
Not approved in ovarian cancer
Bevacizumab93 21 4.7 17 Hypertension;
proteinuria; thrombosis Not approved in ovarian cancer in the USA; pivotal phase II supporting phase III front-line and recurrence investigation
Chemotherapy* ± bevacizumab68
13 vs 31 3.4 vs 6.7
Pending Adding bevacizumab increased hypertension; proteinuria
Overall survival pending; bevacizumab not approved in ovarian cancer
*Allowable chemotherapy regimens in this study were paclitaxel (weekly), pegylated liposomal doxorubicin; topotecan (two infusion styles: weekly, daily for 5 days). Abbreviations: GOG, Gynecologic Oncology Group; PFS, progression-free survival.
REVIEWS
© 2013 Macmillan Publishers Limited. All rights reserved among carefully selected patients.80 One clear factor in
the consideration for surgical intervention in medically fit patients is their underlying potential to respond to adjuvant therapy. Although this is an imperfect science, the probability of responding to secondary chemo-therapy seems to be a positively sloped linear relation-ship with treatment and platinum-free interval.77 In this regard, patients with long treatment or platinum-free intervals (>24 months from first-line treatment comple-tion) have anticipated outcomes, such as response rate, PFS and overall survival similar to those with treatment-naive disease.81The impact of even a subtotal resection may have merit in this situation.82,83 However, given that the median PFS from most phase III front-line trials ranges between 10 and 24 months, the majority of candi-dates with recurrent disease will fall into a category of intermediate and largely unknown potential chemo-sensitivity. In a multivariate analysis of overall survival of 46 women undergoing secondary cytoreduction for recurrent disease,84 time to recurrence of 24 months or longer, and resection to no visible residual disease were the only independent predictors of survival. The optimal resection rate (complete resection to no visible disease) in this study was 41%. In a prospective study of 106 patients with recurrence 6 months or longer after primary treatment,85 82% of the patients were rendered free of visible tumour. In the multivariate analysis,84 four variables were independent predictors of survival: disease-free interval, residual disease after secondary surgery, administration of chemotherapy before second-ary surgery, and size of recurrent tumour. The authors concluded that complete resection can be obtained in most selected patients and the procedure should be considered before the administration of second-line chemotherapy. The vast majority of published series on the topic have reiterated the importance of treatment or platinum-free interval and post-operative disease resi-duum on treatment ‘success’;1 suggesting that patient and perioperative co-factors can be identified within indivi-dual series. Nevertheless, patient selection tools with sufficient external validity are problematic and limited.
Different strategies have been assessed in an effort to address this deficiency. Radiological evaluation has been frequently cited by investigators, but predictive criteria identifying optimal candidates are poorly reproducible
between institutions.82 Endoscopic evaluation, similar to that used by clinicians to identify appropri ate candi-dates for primary cytoreduction, has also been used. Benedetti-Panici and colleagues reported that no visible residual disease was achieved in 79% of patients prescreened by imaging and exam who subsequently underwent pre resection endoscopy.86 As in other trials, patient selection was tightly controlled with 60% of the operative sample presenting with solitary recurrence masses. The AGO identified a panel of features in their initial retrospective study on the topic (DESKTOP I trial),87 and validated their predictive model in a sub-sequent study.88 They found that patients who had a performance status of 0 or 1, with early stage disease, or had no visible tumour residuum following initial surgi-cal cyto reduction and no ascites were likely (>67%) to have a complete surgical cytoreduction. Currently, the criteria are being used to determine eligibility for a phase III trial (DESKTOP III89) currently underway. Another phase III study (GOG-21390) is being conducted to evaluate not only surgical cytoreduction, but also adjuvant chemotherapy in platinum-sensitive patients. In this trial, eligi bility for secondary surgery is limited to measurable disease, treatment-free interval of greater than 6 months and investigator opinion of complete cytoreduction. A third randomized phase III trial is also recently underway using the iMODEL scoring system for eligibility.81,91 This trial will randomize eligible patients (score of ≤4.7) to secondary cytoreduction followed by chemotherapy versus chemotherapy alone. Each of these phase III studies are targeting overall survival as their primary end point.
A large, multicentre-collected data set of in divi dual patients undergoing secondary cytoreduction was interro gated for prognostic and selection criteria character istics.83,92 In the first report, platinum-free interval, ascites, recurrent disease distribution, and post- operative primary residual disease were independently predictive of overall survival. From weighted scoring in a nomogram, low-risk and high-risk cohorts could be discriminated (low-risk = score 0–2 versus high-risk = score 3–8, HR = 3.65, 95% CI 3.05–4.4).83 In the second report aimed at candidate selection (removing secondary cytoreduction outcome) the risk model added FIGO stage, performance status, and CA-125 level.92 The
Table 4 | Pivotal clinical trials in the platinum-sensitive recurrent setting
Study Agents RR
(%) PFS (months) PFS HRs Overall survival (months) Overall survival HRs
ICON 4
(n = 802)132 Carboplatin*Carboplatin + paclitaxel 5466 129 0.76P <0.001 2429 0.82P = 0.02 AGO (n = 366)133 Carboplatin Gemcitabine + carboplatin 31 47 5.8 8.6 0.72 P = 0.003 17.3 18 0.96 P = 0.73 CALYPSO (n = 976)134 Carboplatin + paclitaxel Carboplatin + PLD —— 9.411.3 0.82P = 0.005 31.5 0.99P = 0.87 OCEANS
(n = 484)135 Gemcitabine + carboplatin + placeboGemcitabine + carboplatin + bevacizumab 5779 12.48.4 0.48P <0.0001 35.233.3 1.03P = 0.84 Immature data
*Other non-taxane combinations were allowed. Abbreviations: HR, hazard ratio; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; RR, response rate.
Recommendations
The reviewers recommend the incorporation of epithelial ovarian cancer treatment options into the WHO Model List of Essential Medicines, and recommend specifically that cisplatin and gemcitabine be added to the core Essential Medicines List.
Additions proposed for Section 8.2 of the EML
Cisplatin* Gemcitabine
*Carboplatin is currently in the WHO Essential Medicines List for Adults (2013, 18th Edition).
Next to Carboplatin in the list is a symbol that indicates that the listing of the drug indicates “similar clinical performance within a pharmacological class. The listed medicine should be the example of the class for which there is the best evidence for effectiveness and safety. In some cases, this may be the first medicine that is licensed for marketing; in other instances, subsequently licensed compounds may be safer or more effective. Where there is no difference in terms of efficacy and safety data, the listed medicine should be the one that is generally available at the lowest price, based on international drug price information sources. Not all square boxes are applicable to medicine selection for children — see the second EMLc for details. Therapeutic equivalence is only indicated on the basis of reviews of efficacy and safety and when consistent with WHO clinical guidelines. National lists should not use a similar symbol and should be specific in their final selection, which would depend on local availability and price.” The present proposal calls for the explicit addition of Cisplatin to the EML given its distinct use in the treatment of a number of cancers.
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