EPITHELIAL OVARIAN CANCER

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. 1

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. 2

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/m 2 Day 1 Cisplatin Intravenous infusion 75 mg/m 2 Day 1 Paclitaxel Intravenous infusion 175 mg/m 2 Day 1 3

Second line therapy for patients with recurrent disease after initial chemotherapy Approximately 80% of patients diagnosed with ovarian epithelial cancer will relapse after firstline 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/m 2 Day 1 Cisplatin Intravenous infusion 75 mg/m 2 Day 1 Paclitaxel Intravenous infusion 175 mg/m 2 Day 1 Carboplatin Intravenous infusion AUC4 Day 1 Gemcitabine Intravenous infusion 1000 mg/m 2 Days 1,8 Cisplatin Intravenous infusion 75 mg/m 2 Day 1 Etoposide Per os 100 mg 1-7 days Carboplatin Intravenous infusion AUC5 Day 1 Doxorubicin Intravenous infusion 50 mg/m 2 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. 4

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/m 2 cumulative dose, as in the regimens above.[16] 5

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). 6

Two Tables from Coleman et al 2013 REVIEWS EVIEWS Table 3 Most-frequently used agents in platinum-resistant disease Agent Response rate (%) PFS (months) Overall survival (months) Side effects Pegylated liposomal 10 20 3 4 10 12 Hand foot syndrome; doxorubicin 71,72 mucositis Comments Most frequently prescribed as every 4 weeks schedule Topotecan 71,73 12 18 3 4 10 12 Myelosuppression Daily for 5 days or weekly administration used Docetaxel 70 22 3.5 12.7 Myelosuppression Single GOG trial with very good results Gemcitabine 72,126 15 4 5 11.8 12.7 Myelosuppression Also data with platinums in resistant disease; 127 approved for platinumsensitive disease with carboplatin Pemetrexed 128 15 21 2.9 11.4 Myelosuppression Not approved in ovarian cancer Etoposide 129,130 6 27 4 5 10 11 Myelosuppression Activity, dose and population dependent Paclitaxel 74 77 10 30 4 6 13 Myelosuppression; neuropathy Nab-paclitaxel 131 23 4 5 17.4 Myelosuppression; neuropathy Bevacizumab 93 21 4.7 17 Hypertension; proteinuria; thrombosis Chemotherapy* 13 vs 31 3.4 ± bevacizumab 68 vs 6.7 Pending Adding bevacizumab increased hypertension; proteinuria Usually administered weekly in this setting Not approved in ovarian cancer Not approved in ovarian cancer in the USA; pivotal phase II supporting phase III front-line and recurrence investigation 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. common grade 3 or 4 event (16 17% both cohorts) with Furthermore, if the time from previous platinum and peripheral Table 4 Pivotal neuropathy clinical trials (5%) in and the hand foot platinum-sensitive syndrome recurrent taxane settingtreatment has been short, then often a regimen (4.5%) Study being more Agents common in the experimental cohort RR compared to the control. Overall survival has not been (%) is PFS selected that PFS incorporates HRs Overall an survival alternative Overall to taxane, such (months) as gemcitabine or PLD. (months) Besides altering survival the HRs toxicity reported, ICON 4 but publication Carboplatin* is anticipated. 54 9 profile, a 0.76 different mechanism 24 of action 0.82 is invoked by (n = 802) 132 Carboplatin + paclitaxel 66 changing 12 the P second <0.001 agent 29 paired with platinum. P = 0.02 More Platinum-sensitive AGO Carboplatin disease 31 recently, 5.8 with 0.72 the discovery 17.3 of other active 0.96cytotoxic Platinum-sensitive (n = 366) 133 Gemcitabine disease + carboplatin is defined as patients whose 47 recurrence CALYPSO is documented Carboplatin + paclitaxel greater than 6 months after platinum-based (n = 976) 134 Carboplatin therapy. 64,68 + PLD These patients have a much better OCEANS prognosis Gemcitabine than the + categories carboplatin + above placeboin terms 57 of agents, 8.6 non-platinum P = 0.003 combinations 18 are becoming P = 0.73 more common. 9.4 79 Contemporary 0.82 31.5trials in platinum-sensitive 0.99 disease 11.3 have P incorporated = 0.005 targeted biological P = 0.87 agents, as outlined 8.4 below 0.48 in the novel 35.2agent focus section. 1.03 longevity, (n = 484) 135 as many Gemcitabine will respond + carboplatin to multiple + bevacizumab regimens. 79 12.4 P <0.0001 33.3 P = 0.84 Generally these patients are treated with a platinumbased Recurrent disease therapy Immature data *Other combination. non-taxane combinations Platinum-sensitive were allowed. Abbreviations: disease HR, hazard is a broad ratio; PFS, progression-free Most patients survival; diagnosed PLD, pegylated with liposomal recurrent doxorubicin; disease RR, response will have rate. category that can be rather heterogeneous, because those who recur just over 6 months after receiving platinumbased a multifocal distribution of implants that mimic their presentation at initial diagnosis. In this respect, it is not among therapy carefully can selected behave patients. more like One platinum-resistant clear factor difficult between to institutions. understand clinicians Endoscopic and evaluation, patients interest similar in patients the consideration than those for who surgical recur intervention later; response in medically rates and secondary to that used surgical by clinicians cytoreduction. identify Unfortunately, appropri despite candidates significant for primary attention cytoreduction, this topic has has received also been from used. clini- time-to-event fit patients is their data underlying improve incrementally potential to as respond the time to the interval adjuvant from therapy. prior Although chemotherapy this is an imperfect until recurrence science, increases. the probability Thus, some of responding authors have to advocated secondary that chemotherapy recur seems earlier, to be specifically a positively between sloped 6 12 linear months, relation- be those who labelled ship with as treatment partially or and intermediately platinum-free sensitive. interval. 77 78 In These this patients regard, patients can be treated with long in a treatment similar way or platinum-free to sensitive intervals (>24 patients months who from recur first-line after 12 treatment months; however, completion) have anticipated advocated outcomes, for the consideration such as response of single- rate, some agent PFS and therapies overall survival used in similar platinum-resistant to those with treatmentnaive disease. 81 The impact combinations. of even 78 a subtotal resection disease or non-platinum-based may A have number merit of in platinum-based this situation. 82,83 combinations However, given that can be the used median in patients PFS from with most platinum-sensitive phase III front-line disease trials (Table ranges between 4). Often, 10 patients and 24 months, are treated the majority with platinumbasedates with and taxane-based recurrent disease chemotherapy will fall into again; a category however, of of candical Benedetti-Panici investigation, guidance and colleagues as to its role reported in the setting that no of recurrent visible residual disease disease not was clear. achieved 18 In addition, in 79% interpretation prescreened of the available by imaging data is and difficult exam at who the minimum, subsequently and of patients hazard underwent ous at pre the resection extreme, endoscopy. because of the As inherent other selection patient bias selection that exists was in tightly reviews controlled of clinical with experience 60% of the at trials, one operative or more sample institutions. presenting Even with reports solitary that are recurrence based on observations masses. The AGO of prospectively identified a collected panel of features patients in cannot their be initial reliably retrospective compared study to historical on the observations topic (DESKTOP owing I to trial), inability and to validated control for their variations predictive in practice model in patterns, a subsequent selection study. 88 and They assessment found that models. patients This who situation had a patient has performance placed a premium status of 0 on or phase 1, with III early investigation, stage disease, which or fortunately had no visible underway. tumour residuum following initial surgical Despite cyto reduction the uncertainty, and no most ascites practitioners were likely strongly (>67%) 7

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, 18 th 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. 8

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