Dr Sarah Mc Kenna, Consultant Medical Oncologist and Dr Joanne Millar, Consultant Medical Oncologist

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1 Title: Systemic Anti-Cancer Therapy (SACT) Guidelines for Ovarian Cancer Author(s) Ownership: Approval by: Operational Date: Dr Sarah Mc Kenna, Consultant Medical Oncologist and Dr Joanne Millar, Consultant Medical Oncologist NICaN NICaN Drugs and Therapeutics Committee Approval date: 25 th January 2018 Next Review: Version No. 2.1 Supercedes 2.1 Links to other policies NICaN ovarian SACT protocols Date Version Author Comments May 2013 V1.0 Dr Sarah Mc Kenna, Dr Joanne Millar February 2016 October 2017 V2.0 Dr Sarah Mc Kenna, Dr Joanne Millar V2.1 Dr Sarah Mc Kenna, Dr Joanne Millar Final version issued Olaparib added (21/12/17) November 2019 Cisplatin/liposomal doxorubicin, carboplatin/liposomal doxorubicin added. Page 1 of 29

2 Authorisation of Systemic Anti-Cancer therapy (SACT) Guidelines for Ovarian Cancer These SACT guidelines are being submitted by the authors on behalf of the Gynae oncologists group. Page 2 of 29

3 Contents Staging of Ovarian Cancer: FIGO (2013) Early Ovarian Cancer (ie Stage I disease)... 6 Advanced Ovarian Cancer (ie Stage 2-4 disease)... 8 Other treatments you may be asked about:... 9 Relapsed Ovarian Cancer: Principles in Management of Relapsed Ovarian Cancer: Management of Platinum Resistant Ovarian Cancer: Other treatments you may be asked about: Management of Platinum Sensitive Relapse: Other treatments you may be asked about: Treatment at 3 rd and subsequent relapse: Olaparib in BRCA1/2 mutation positive patients responding to 3 rd line platinum based chemotherapy: Management of rarer Ovarian Tumours: Germ Cell Tumours: Low Grade Serous Papillary Ovarian Cancer (LGSP OC): Special considerations: Thromboembolic (VTE) disease and ovarian cancer: HRT and ovarian cancer: Carboplatin allergies: Page 3 of 29

4 Staging of Ovarian Cancer: FIGO (2013). I: confined to ovaries or fallopian tubes IA: tumour limited to 1 ovary (capsule intact) or fallopian tubes; no tumour on ovarian or fallopian tube surface; no malignant cells in the ascites or peritoneal washings. IB: tumour limited to both ovaries (capsule intact) or fallopian tubes; no tumour on ovarian or fallopian tube surface; no malignant cells in the ascites or peritoneal washings. IC: tumour limited to 1 or both ovaries or fallopian tubes with any of the following: ICi: Surgical spill ICii: Capsule rupture before surgery or tumour on ovarian or fallopian tube surface ICiii: Malignant cells in the ascites or peritoneal washings. II: tumour involves 1 or both ovaries or fallopian tubes with pelvic extension (below pelvic brim) or primary peritoneal cancer IIA: extension and/or implants on uterus and/or fallopian tubes and/or ovaries IIB: extension to other pelvic intraperitoneal tissues III: tumour involves 1 or both ovaries or fallopian tubes, or primary peritoneal cancer, with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes. IIIA: positive retroperitoneal lymph nodes only (cytologically or histologically proven) IIIA1(i): metastasis up to 10mm in greatest dimension. IIIA1(ii) metastasis more than 10mm in greatest dimension. Page 4 of 29

5 IIIA2: microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes IIIB: macroscopic peritoneal metastasis beyond the pelvis up to 2cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes IIIC: macroscopic peritoneal metastasis beyond the pelvis more than 2cm in greatest dimension, with or without metastasis to the retro-peritoneal lymph nodes (includes extension of tumour to the capsule of the liver and spleen without parenchymal involvement of either organ) IV: Distant metastasis excluding peritoneal metastases. IVA: pleural effusion with positive cytology IVB: parenchymal metastases and metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity). Page 5 of 29

6 Medical Management of Epithelial Ovarian Cancer (EOC): Early Ovarian Cancer (ie Stage I disease) Adequate staging surgery (as defined by NICE): midline laparotomy TAH/BSO/infracolic omentectomy biopsy of suspicious peritoneal metastases random biopsy of pelvic and abdominal peritoneum retroperitoneal lymph node assessment (ie direct sampling of nodes if there is a palpable abnormality and random sampling of pelvic and paraaortic nodes if there is no palpable abnormality) 3 patient groups are identified: Patients for whom chemotherapy is likely to be beneficial: Stage I (A-C) and high grade (all clear cell tumours considered high grade) Patients for whom chemotherapy is of uncertain benefit and should be discussed: patients with Stage I(A-C) and Grade II disease who have had suboptimal staging surgery. Patients for whom chemotherapy is unlikely to be of benefit and should not be offered: Stage I (A-C) and Grade I disease Stage I (A-C) and Grade I/II and comprehensive staging (including pelvic and para-aortic lymph node sampling) and no evidence of nodal involvement. Page 6 of 29

7 Chemotherapy: Patients should be offered: Carboplatin AUC 6 for 6 cycles Evidence: 8% improvement in overall survival at 5 yrs Monitoring while on chemotherapy: Baseline CXR and CT scan abdomen and pelvis No need to repeat if normal CA 125 prior to each chemotherapy cycle Dose delays and reductions should be avoided if possible. G-CSF should be used where necessary to maintain dose intensity. Follow-up post chemotherapy: 4 monthly for 2 years 6 monthly for 3 years Patients will be discharged at 5 years: GP will be asked to do an annual CA 125 until 10 years following diagnosis. All patients should be considered for Nurse Led Telephone follow at first review following completion of chemotherapy. Page 7 of 29

8 Advanced Ovarian Cancer (ie Stage 2-4 disease) Timing of chemotherapy: Chemotherapy may be offered: post surgical debulking in neoadjuvant setting in patients: unfit for surgery disease on preoperative assessment not felt to be debulkable Type of Chemotherapy: Standard Chemotherapy: Paclitaxel 175mg/m 2 and Carboplatin AUC 5 for 6 cycle (Note all patients receiving neoadjuvant chemotherapy should be discussed at the gynae MDM following the 3rd cycle of chemo and the discussion documented in the notes). Evidence: 70-80% response to paclitaxel/carboplatin % response to carboplatin Average progression free interval - 1-2yrs Average overall survival 2-3 years BUT small number of long term survivors "Non -Standard" Chemotherapy: There are a number of circumstances in which "non standard" chemotherapy may be considered: 1) Patients 75yrs or, with ECOG performance status 3: Carboplatin AUC 6 3 weekly for 6 cycles 2) Patients in whom it is impossible to predict an accurate GFR due to a low creatinine or large volume ascites Carboplatin 200/400mg depending on patient size and age Page 8 of 29

9 3) Patients with unresolved bowel obstruction. Carboplatin AUC 2 (+/- paclitaxel 80mg/m 2 ) weekly All patients receiving "non standard" regimes should be assessed prior to every cycle for their suitability to switch to "standard" carboplatin and paclitaxel. Monitoring while on chemotherapy: 1) CA125 prior to each chemotherapy cycle 2) At Baseline: CXR CT scan abdomen and pelvis Post 3rd cycle of chemotherapy: CT abdomen and pelvis (only if debulking surgery is being considered) Post 6th cycle chemotherapy: only patients with abnormal baseline CT scans require a CT on completion of chemotherapy Follow-up post chemotherapy: 4 monthly for 2 years 6 monthly for 3 years Annually from year 5 Patients who remain well at 10 years following their original diagnosis may be considered for discharge All patients should be considered for Nurse Led Telephone follow at first review following completion of chemotherapy. Other treatments you may be asked about: Intraperitoneal Chemotherapy: Nine RCTs have examined the value of chemotherapy given intraperitoneally in advanced ovarian cancer. Results suggests that this strategy shows promise but: Page 9 of 29

10 strategy is only useful in patients with disease < 2cm in maximum diameter. no trials thus far have used standard IV paclitaxel/carboplatin as the control arm significant local and systemic toxicities with this approach Summary: Intra-peritoneal chemotherapy is not currently recommended outside a clinical trial. Bevacizumab: Bevacizumab is a humanized monoclonal antibody to vascular endothelial growth factor A. Two large RCTs have examined the utility of adding bevacizumab to standard paclitaxel and carboplatin in patients with advanced ovarian cancer. Both studies demonstrated an improvement in mpfs (2 months and 4 months) with some suggestion that the drug may be more effective in patients with suboptimally de-bulked disease. Neither study demonstrated an improvement in OS. The addition of bevacizumab was associated with significant toxicity including increased bleeding, hypertension and thromboembolic events. Summary: Bevacizumab has a license in this setting in Europe. Bevacizumab has not been approved by NICE in this setting. Bevacizumab was originally not approved by SMC in this setting. However following a re-submission under the end of life and ultra-orphan drugs procedure, bevacizumab in combination with paclitaxel and carboplatin is now available in patients with Stage IV disease. Bevacizumab remains on the CDF for use in combination with paclitaxel and carboplatin in patients with sub-optimally de-bulked ovarian cancer for patients in England and Wales. Page 10 of 29

11 Relapsed Ovarian Cancer: Definitions: 2 patients groups are defined: Platinum Resistant - relapse 6mths after completion of platinum based therapy Platinum Sensitive - relapse > 6 months after platinum based chemotherapy Principles in Management of Relapsed Ovarian Cancer: Requirements for Treatment: to be considered for chemotherapy the following conditions must be met: ECOG PS 2 Functioning gut Timing of Chemotherapy: Optimal timing of chemotherapy is uncertain. Consider chemotherapy when: patient has "significant" disease on CT scan and/or symptoms are developing. Page 11 of 29

12 Management of Platinum Resistant Ovarian Cancer: Patients in this group have a poor outlook and the value of further chemotherapy is uncertain. Many of the trials used as evidence for the treatment of these patients, have a mixed population of those with platinum resistant and platinum sensitive disease. The applicability of results from such trials to this poor risk sub population is uncertain. In all cases, the main focus of treatment should be on optimisation of symptom control. Any decision to proceed with chemotherapy, must be individualised and involve a careful discussion with the patient regarding the paucity of evidence and possibly detrimental effect on quality of life. Where available patients should be considered for clinical trials. Chemotherapy: Patients who had carboplatin and paclitaxel as initial chemotherapy: Patients with neuropathy Grade 1: paclitaxel weekly 80mg/m 2 Patients with neuropathy > Grade 1: liposomal doxorubicin 50mg/m 2 4 weekly (consider starting at 40mg/m 2 if ECOG PS =2) Evidence: response rates 10-20% effect on survival uncertain Monitoring while on chemotherapy: Repeat CT scan abdomen and pelvis after 6 cycles of paclitaxel (or 2 cycles of liposomal doxorubicin) Proceed to 18 cycles of paclitaxel (or 6 cycles of liposomal doxorubicin) if response demonstrated. Page 12 of 29

13 Patients who had carboplatin as initial chemotherapy: Paclitaxel 80mg/m 2 weekly Evidence - response rate 10-20% effect on survival uncertain Monitoring while on chemotherapy: Repeat CT scan abdomen and pelvis after 6 cycles Proceed to 18 cycles if response demonstrated Follow-up after chemotherapy: Review 3 monthly Discuss referral to palliative care team Hormonal Therapy: Letrozole 2.5mg mane Evidence - response rate variably reported probably approximately 10% effect on survival uncertain but durable responses seen occasionally. Monitoring while on hormonal therapy: Clinical monitoring only. Page 13 of 29

14 Other treatments you may be asked about: Bevacizumab: Aurelia - an open label RCT examined the effect of adding bevacizumab to standard chemotherapy (liposomal doxorubicin, paclitaxel weekly or topotecan) in patients with platinum resistant/refractory ovarian cancer. Results show a modest improvement in median OS with the addition of bevacizumab (13.3 v s 16.6months). However looking at the paclitaxel v s paclitaxel/bevacizumab group specifically, a very significant improved mos was observed (13.2 v s 22.4months, p=0.174) Summary: Bevacizumab has a license in this indication. Under the end of life and ultra-orphan drug process, the SMC has approved bevacizumab in combination with paclitaxel weekly in patients with platinum resistant/refractory ovarian cancer. NICE have not approved bevacizumab in this setting. Bevacizumab is not available on the CDF for this indication. Page 14 of 29

15 Management of Platinum Sensitive Relapse: Secondary debulking surgery Secondary de-bulking surgery should be considered for all patients. Those most likely to be suitable are those with: a good performance status absence of ascites complete resection at first surgery limited number of disease sites operable disease as assessed radiologically Evidence: DESKTOP III study randomised patents with platinum sensitive relapsed ovarian cancer and a positive AGO score (ECOG PS 0, ascites <500ml and complete cytoreduction at initial surgery) between secondary de-bulking and chemotherapy or chemotherapy only. An improvement in mpfs was observed in patients undergoing surgery in addition to chemotherapy (19.5 v s 14months). The benefit was confined to those patients who were optimally debulked. The data is not mature for OS analysis. All patients who may be suitable should be discussed at the Gynae MDM Patients who have had secondary debulking may have immediate further platinum based chemotherapy or may delay chemotherapy until there is further evidence of disease progression. Page 15 of 29

16 Chemotherapy Chemotherapy: For patients who are not surgical candidates or who elect to have chemotherapy after surgery 1) Carboplatin AUC 5 and liposomal doxorubicin (PLD) 30mg/m 2 Q 4/52 for 6 cycles Evidence: Response rates >30% - dependant on specific platinum free interval Median PFS: 11.3months, Median OS: 30 months Monitoring while on chemotherapy: Repeat CT scan abdomen and pelvis after 2 cycles Proceed to 6 cycles if response demonstrated 2) Patients with cardiac dysfunction or other contraindication to PLD: Paclitaxel 175mg/m 2 and carboplatin AUC5 Q 3/52 for 6 cycles Evidence: response rates >30% - dependant on specific platinum free interval mpfs 13mths mos 29mths (versus 24months with carboplatin alone) Monitoring while on chemotherapy: Repeat CT scan after 2 cycles Proceed to 6 cycles if response demonstrated 3) Some patients with platinum sensitive relapse may not be suitable doublet therapy (Patients >75yrs or with ECOG PS = 2) Carboplatin AUC6 Q 3/52 for 6 cycles Evidence: response rates >30% - dependant on specific platinum free interval Median OS 24mths Page 16 of 29

17 Monitoring while on chemotherapy: Repeat CT scan after 2 cycles Proceed to 6 cycles if response demonstrated Other treatments you may be asked about: Bevacizumab: OCEANS was a Phase III randomised double blind placebo controlled study of chemotherapy with or without bevacizumab in patients with platinum resistant ovarian cancer. Patients with platinum sensitive relapsed ovarian cancer were randomised to receive carboplatin and gemcitabine alone or with bevacizumab. The addition of bevacizumab improved mpfs (8.4 v s 12.4 months) but no difference in mos was noted (33.6 v s 32.9months). Summary: Bevacizumab has a license for use in this indication. Bevacizumab has not been approved by NICE or SMC for use in this indication. Olaparib: SOLO 2 was a double blind randomised placebo controlled phase III trial. Patients with known germline or somatic BRCA1/2 mutations who had responded to platinum based chemotherapy for relapsed disease were randomised to olaparib (300mg BD) or placebo. mpfs was significantly longer in the olaparib group (19.1 v s 5.5months). Overall survival data is not yet available. This mirrors the previous registration phase II RCT, where patients with platinum sensitive ovarian cancer were randomised to olaparib or placebo. In the subset of patients with proven BRCA1 or 2 mutations, an improvement on mpfs was noted in the olaparib treated group (11.2 v s 4.3 mths) An improvement on mos was not seen. Page 17 of 29

18 Summary: Olaparib is licensed as maintenance treatment in patients with proven somatic or germline BRCA1/2 mutations following response to 2 nd or subsequent platinum based chemotherapy. NICE guidance approve use of olaparib following response to 3 rd or subsequent platinum based chemotherapy in patients with proven somatic or germline BRCA1/2 mutations. SMC approves use of olaparib in licensed indication (ie patients with proven somatic or germline BRCA1/2 mutations and following response to 2 nd line platinum based therapy). Rucaparib: Study 10 and ARIEL 2 were phase 2 studies examining the activity of rucaparib in patients with BRCA1/2 mutations whose disease had progressed after 2 lines of chemotherapy. Response rates were 54% with a median duration of response of 9.2 months. Summary: Rucaparib has FDA approval for use in patients with a BRCA1/2 mutation and progressing after 2 lines of chemotherapy. Rucaparib does not yet have a license for use in the UK. Niraparib: NOVA was a double blind randomised placebo controlled phase III trial. Patients with relapsed ovarian cancer which had responded to 2 nd or subsequent line platinum based chemotherapy were randomised to niraparib 300mg daily or placebo. mpfs was significantly longer in the group with BRCA1/2 mutations (5 v s 21mths. P<0.0001), and also the patients without BRCA1/2 mutations (3.9 v s 9.3mths, p<0.0001). Summary Niraparib has FDA approval for use in all patients with EOC patients demonstrating a response to 2 nd or subsequent line platinum based chemotherapy. Niraparib does not yet have a license for use in UK. Page 18 of 29

19 Treatment at 3 rd and subsequent relapse: In patients relapsing after 2nd and subsequent lines of chemotherapy the chances of response to chemotherapy becomes progressively smaller and a decision to treat has to be carefully weighed against the potential negative impact on quality of life related to chemotherapy side effects. A decision to proceed with chemotherapy in these circumstances needs individual consideration and must be made by the supervising consultant. There are some general considerations: Requirements for Treatment: to be considered for chemotherapy the following conditions must be met: ECOG PS 2 Functioning gut Timing of Chemotherapy: Optimal timing of chemotherapy is uncertain. Consider chemotherapy when: patient has "significant" disease on CT scan and/or symptoms are developing. 2 patient cohorts are identified: Platinum resistant: Chemotherapy Apply same treatment considerations and decisions as those presenting after first line chemotherapy with platinum resistant disease. Treatment options include: Paclitaxel 80mg/m 2 weekly Etoposide 50mg/m 2 PO daily D1-21 of a 28 day cycle. Liposomal doxorubicin 50mg/m 2 q 4/52 (only for patients who have not received this in the second line setting) Monitoring while on chemotherapy: Repeat CT scan after 2 cycles Proceed to 6 cycles if response demonstrated Page 19 of 29

20 Hormonal Therapy: Letrozole 2.5mg mane Evidence - response rate variably reported probably approximately 10% effect on survival uncertain but durable responses seen occasionally. Monitoring while on hormonal therapy: Clinical monitoring only. Platinum sensitive: Treatment options include: Carboplatin AUC 6 q 3/52 X 6 cycles Paclitaxel 80mg/m 2 weekly Etoposide 50mg/m 2 PO daily D1-21 of a 28 day cycle. Liposomal doxorubicin 50mg/m 2 q 4/52 (only for patients who have not received this in the second line setting) (There is no evidence for doublet therapy in the 3 rd line setting) Monitoring while on chemotherapy: Repeat CT scan after 2 cycles Proceed to 6 cycles if response demonstrated Page 20 of 29

21 Olaparib in BRCA1/2 mutation positive patients responding to 3 rd line platinum based chemotherapy: Patients with BRCA1/2 germline or somatic mutations AND whose disease has responded to 3 rd line platinum based chemotherapy: Olaparib 400mg PO BD as maintenance Evidence: 7 month improvement in mpfs no survival data yet. Monitoring while on Olaparib: Repeat CT scan every 3 cycles. Continue treatment until progression Page 21 of 29

22 Management of rarer Ovarian Tumours: Germ Cell Tumours: These patients should be referred to the germ cell team. Low Grade Serous Papillary Ovarian Cancer (LGSP OC): These are a relatively rare subset of epithelial ovarian cancer. They are characterised by a resistance to chemotherapy and a relatively long natural history in contrast to the more commonly occurring high grade serous ovarian cancers. Optimal treatment algorithms have not been established. Response rates to chemotherapy are low and so chemotherapy is of uncertain benefit. Anti-oestrogen therapies have shown some activity in this disease. A retrospective cohort study examined the effect of anti-oestrogen therapy in patients with LGSP OC following debulking surgery. mpfs was significantly longer in the group of patients who were given maintenance anti-oestrogen therapy (64.9 v s 26.4mths. p <0.001). This effect was particularly marked in patients with optimally de-bulked disease (81.1 v s 29.9months. p<0.001) mpfs was similar between the 2 groups (103 v s 116 months). However, in the sub-group of patients with optimally de-bulked disease a very significant improvement in survival was noted in those on maintenance anti-oestrogen therapy. (191.3 v s 106 months. P 0.04) Summary: The relative rarity of this disease and lack of trial evidence make development of treatment algorithms difficult. In general terms patients should be considered for de-bulking surgery where possible. Consideration should be given to use of anti-oestrogen therapy (usually letrozole 2.5mg mane). Current evidence suggests that this may be particularly important in the sub group of patients whose disease has been optimally de-bulked. Page 22 of 29

23 Special considerations: Thromboembolic (VTE) disease and ovarian cancer: VTE disease is a common complication of ovarian cancer and its treatment. Patients developing VTE while at diagnosis or while on treatment for ovarian cancer should generally remain on therapeutic enoxaparin for 6 months. At 6 months the use of anticoagulation need to be re-evaluated: for patients in whom there is no evidence of residual disease consideration can be given to stopping enoxaparin. Patients with ongoing cancer (ie those who did not have a complete response to treatment) should generally be recommended to continue with enoxaparin at a reduced dose of 1mg/kg. For those who find the injections particularly onerous consideration may be given to substituting enoxoparin with apixaban 2.5mg BD For patients with relapsed ovarian cancer and a history of VTE who are not currently on anti-coagulant therapy and in whom more chemotherapy is planned, consideration should be given to commencing prophylactic enoxaparin. HRT and ovarian cancer: Women premenopausal at time of diagnosis: No evidence of adverse effect Consider HRT for patients for: 1) Management of acute menopausal symptoms 2) For patients with early stage disease to prevent long term complications of early menopause (these patients should be referred to the HRT clinic in the RVH) Women post menopausal at diagnosis: Little evidence to guide decision Probably safe for short term use in patients with troublesome acute symptoms. Preference should be given to topical HRT for patients whose main problem is vaginal dryness Page 23 of 29

24 Consideration should also be given to "non hormonal " measures to alleviate hot flushes. Options include: Venlafaxine 37.5mg mane for 1 week. If flushes are still ongoing or incompletely settled after 1 week venlafaxine can be increased to 75mg. If flushes do not improve after a week venlafaxine is ineffective and should be stopped. Gabapentin 300mg TID (300mg Day 1; 300mg BD Day 2; 300mg TID thereafter) Carboplatin allergies: Carboplatin allergies are well described typically in patients receiving 2nd and subsequent lines of carboplatin chemotherapy. While desensitization protocols have been described their efficacy is uncertain. Our management of carboplatin allergy is as follows: Patient should NOT receive further carboplatin Options for patients allergic to carboplatin: Cisplatin 100mg/m 2 Q 3 weeks. The prescription option "Cisplatin in those allergic to carboplatin" should be used Oxaliplatin 130MG/m 2 Q 3 weeks. (consider reducing to 100mg/m 2 ) for cycle 1. The prescription option "Oxaliplatin in those allergic to carboplatin" should be used Cisplatin 75mg/m 2 can be substituted for carboplatin in those with an allergy to carboplatin and receiving with carboplatin/liposomal doxorubicin or carboplatin/paclitaxel Patients should be counselled that there is some cross reactivity between the 2 drugs and a proportion of patients may also develop a reaction to cisplatin or oxaliplatin. All patients receiving cisplatin or oxaliplatin after a carboplatin allergy should be premedicated with H1/H2 blockade, steroids and anti-histamines (as per RIOSH prescription.) Page 24 of 29

25 References: Guidelines NICE Clinical Guideline 122, Ovarian Cancer: recognition and initial management. SIGN Management of Ovarian Cancer. NCCN Practice Guidelines in Oncology Ovarian Cancer. V Sources Seminal Papers International Collaborative Ovarian Neoplasm trial 1: a randomised trial of adjuvant chemotherapy in women with early-stage ovarian cancer. Colombo et al. J Natl Cancer Inst Jan 15;95(2) Impact of adjuvant chemotherapy and surgical staging in early-stage ovarian cancer: European Organisation for Research and Treatment of Cancer-Adjuvant Chemotherapy in Ovarian Neoplasm. Trimbos et al. J Natl Cancer Inst Jan 15;(95(2): International Collaborative Ovarian Neoplasm trial 1 and Adjuvant Chemotherapy in Ovarian Neoplasm Trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian cancer. Trimbos et al. J Natl Cancer Inst Jan 15;95(2): Cyclophosphamide and Cisplatin compared with Paclitaxel and Cisplatin in patients with Stage III and Stage IV ovarian cancer. Mc Guire et al. N Engl J Med Jan 4;334(1)1-6 Randomised intergroup trial of Cisplatin-Paclitaxel versus Cisplatin- Cyclphosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst May 3;92(9): A randomized clinical trial of Cisplatin/Paclitaxel versus Carboplatin/Paclitaxel as first-line treatment of ovarian cancer. du Bois et al. J Natl Cancer Inst Sep 3;95(17); Page 25 of 29

26 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. Ozols et al. J Clin Oncol Sep 1;21(17): Early versus delayed treatment of relapsed ovarian cancer (MRC0vo5)-a randomised trial. Rustin et al. Lancet 376(9747) ,2010. Recurrent epithelial ovarian carcinoma: a randomised phase III study of pegylated liposomal doxorubicin versus topotecan. Gordon AN et al. J Clin Oncol Jul 15;19(14): Phase II trial of weekly single-agent Paclitaxel in platinum/paclitaxel refractory ovarian cancer. Markman et al. J Clin Oncol May 1;20(9): Phase II trial of weekly paclitaxel (80mg/M 2 ) in platinum and paclitaxelresistant ovarian cancer and primary peritoneal cancers: a Gynecologic Oncology Group Study. Markman et al Gynecol Oncol Jun;101(3) Antioestrogen therapy is active in selected ovarian cancer cases: the use of Letrozole in ER positive patients. Smyth JF et al. Clin Cancer Res Jun 15;13(12): Efficacy of Letrozole in the treatment of recurrent platinum and taxane resistant high grade cancer of the ovary or peritoneum. Ramirez et al. Gynecol Oncol 2008 Jul;110(1):56-9. The role of secondary cytoreduction in the management of the first relapse in epithelial ovarian cancer. Oksefjell H et al Feb;20(2): Cytoreductive surgery for patients with recurrent epithelial ovarian cancer. Tebes SJ et al. Gynecol Oncol Sep;106: Randomised Controlled Phase III study evaluating the impact of secondary debulking in recurrent ovarian cancer AGO DESKTOP III/ENGOT OV20. Du Bois et al. J Clin Oncol. 2017; 35(suppl abstr 5501) Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer:the ICON4/AGO- OVAR-2.2 trial. Parman MK et al. Lancet.2003 Jun 21;361(9375) Page 26 of 29

27 Pegylated Liposomal Doxorubicin and Carboplatin compared with Paclitaxel and Carboplatin for patients with platinum sensitive ovarian cancer. Pujade-Lauraine E. et al. J Clin Oncol July 10 28(20) Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. Ledermann et al. NEJM 2012;366: Olaparib tablets as maintenance treatment in patients with platinum sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double blind randomised placebo controlled phase III trials. Pujade-Lauraine E. et al. Lancet Oncology vol 18 (9) p Supportive papers ICON 7. A Phase III trial of Bevacizumab in ovarian cancer. Perren et al. NEJM 2011; 365: Bevacizumab combined with chemotherapy for platinum resistant ovarian cancer the Aurelia open label randomised phase II trial. Pujade-Lauraine E. et al. J Clin Oncol. 2014:32(13): Final overall survival and safety analysis of OCEANS: a Phase III trial of chemotherapy with or without Bevacizumab in patients with platinum sensitive relapsed ovarian cancer. Aghajanian C. et al. Gynecol Oncol Oct 139(1) 10-6 Oxaliplatin or Paclitaxel in patients with platinum pretreated advanced ovarian cancer: A randomised Phase II study of the EORTC gynaecological group. Piccart et al. J Clin Oncol 18(6) ;2000. Estrogen replacement therapy for ovarian canner survivors-a randomised controlled trial. Guidozzi et al. Cancer 1999 Sept 15;86(6) : Gabapentin for hot flushes in 420 women with breast cancer: a randomised double-blind placebo controlled trial. Pandya KJ et al. Lancet (9488): Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Loprinzi et al.lancet Dec 16; 356(9247): Page 27 of 29

28 The dilemna of Carboplatin-associated hypersensitivity reactions in ovarian cancer management. Markman M. Gynecol Oncol Nov;107(2):163-5 Use of Cisplatin without desensitisation after Carboplatin hypersensitivity reaction in epithelial ovarian and primary peritoneal cancer. Callahan MB et al. Am J Obstet Gynecol Aug;197(2):199 Hormonal maintenance for woman with low grade serous papillary ovarian cancer. Gershenson et al. J Clin Oncol Technology appraisals NICE technology appraisal guidance (TA55): Guidance on the use of Paclitaxel in the treatment of ovarian cancer (updated 2005) NICE technology appraisal (TA284): Bevacizumab in combination with Paclitaxel and Carboplatin for first line treatment of ovarian cancer. NICE technology appraisal guidance (TA285): Bevacizumab in combination with Gencitabine and Carboplatin for treating the first recurrence of platinum sensitive ovarian cancer NICE technology appraisal guidance (TA389): Topotecan, Pegylated Liposomal Doxorubicin, Paclitaxel, Trabectidin and Gemcitabine for treatment of relapsed ovarian cancer NICE technology appraisal guidance (TA381): Olaparib for maintenance treatment of relapsed platinum sensitive BRCA mutation positive ovarian cancer after response to 2 nd or subsequent line platinum based chemotherapy Databases Cochrane Database of Systematic Reviews 2012, Issue 3. Winter-Roach et al. Adjuvant chemotherapy for early stage ovarian cancer: recognition and initial management Page 28 of 29

29 Cochrane Database of Systematic Reviews 2013, Issue 7. Laurie TA et al. Pegylated Liposomal Doxorubicin for Relapsed Ovarian Cancer. Page 29 of 29