6. Platin Duyarlılığı Birincil tedavi Birincil tedavinin bitmesi 0 . ay 6. ay 12. ay Yanıtsız Dirençli Duyarlı Herzog TJ: Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options
7. Tedavi Kararı Platinum Sensitive Platinum Refractory/Resistant Kemoterapi duyarlı Kemoterapiye yanıtsız / dirençli Birinci basamak kemoterapi sonrası tedavi > 6 ay Platin içeren ikili < 6 ay Platin olmayan tek ilaç Alışılmış uygulama Monk BJ: Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options
8. Hastalıksız sürenin KT yanıtına etkisi Blackledge G, et al. Br J Cancer . 1989;59:650-653. Zaman aralığı (ay) Platin cevabı , % Diğer ilaçlara yanıt , % 0-6 10 15 7-12 29 20 13-18 63 30 19-24 94 30
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10. Over kanserinde FDA onaylı ilaçlar 1978 S isplatin K arboplatin Altretamine Pa k lita ks el Topote k an Lipo z omal do ks orubi s in ( hızlandırılmış ) Lipo z omal do ks orubicin ( tam ) Gem s itabin ( karboplatinle birlikte ) 2006 1989 1990 1992 1996 1999 2005 2009 Monk BJ: Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options
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15. Platine Karşılık İkili İlaç P: Platin grubu ilaç, T: Paklitaksel, C: Karboplatin, PLD: Lipozomal doksorubisin, G:Gemsitabin PFS: İlerlemesiz sağkalım, OS: Toplam sağkalım * : p= 0.02 ICON 4 / AGO-OVAR 2.2 AGO-OVAR 2.5 SWOG Tedavi P+T krş P C+G krş C C+PLD krş C Hasta sayısı 802 356 61 Yanıt %66 krş %54 %47.2 krş %30.9 %67 krş %32 PFS 13 ay krş 10 ay 8.6 ay krş 5.8 ay 12 ay krş 8 ay OS 29 ay krş 24 ay* 18 ay krş 17.3 ay 26 ay krş 18 ay
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18. GCIG CALYPSO Araştırması Platine duyarlı nüks over kanseri hastaları PLD 30 mg/m 2 + K arboplatin AUC 5 28 günde bir x 6 Paclita ks el 175 mg/m 2 + K arboplatin AUC 5 21 günde bir x 6 ClinicalTrials.gov. NCT00538603. R A S T G E L E D A Ğ I T Thigpen JT: Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options
20. GOG-213 ClinicalTrials.gov. NCT00565851. PI: Coleman Evet Hayır Cerrahi Cerrahi yok K arboplatin P a k lita ks el K arboplatin Pa k lita ks el Beva s izumab Beva s izumab Kemoterapi alıp almayacağı Rastgele dağıt Cerrahi adayı mı? Nüks ov e r, Primer peritoneal , ve Fallop tüp kanserleri Tümörsüz sağkalım süresi ≥ 6 ay Rastgele dağıt Herzog TJ: Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options
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25. Hastalıksız sürenin KT yanıtına etkisi Blackledge G, et al. Br J Cancer . 1989;59:650-653. Zaman aralığı (ay) Platin cevabı , % Diğer ilaçlara yanıt , % 0-6 10 15 7-12 29 20 13-18 63 30 19-24 94 30
26. Platine Dirençli Hastalıkta FDA Onaylı Tek İlaç Tedaviler 1. O’Byrne KJ, et al. ASCO 2002. Abstract 808. 2. Gordon AN, et al. J Clin Oncol. 2001;19:3312-3322. 3. ten Bokkel Huinink, et al. Ann Oncol. 2004;15:100-103. Monk BJ: Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options İlaç Uygulama Çalışma Yanıt , % Pegile Liposomal Doksorubisin 4 haftada bir, 1 gün O’Byrne [1] 17.8 Gordon [2] 19.7 Topotecan 3 haftada bir, 5 gün ten Bokkel Huinink [3] 20.5 Gordon 17.0
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29. PLD + Gemsitabin birlikteliği platine dirençli hastalıkta etkili mi, değil mi? 28 gün 25 (1) 1000 (1+8) 17 %28.6 35 Karaoglu, ark. 2009 25 (1+15) 30(1) 25 (1) PLD mg/m2, (günler) 2000 (1+15) 650 (1+8) 650 (1+8) G mg/m2, (günler) 17 15.8 8.4 OS (ay) 28 gün 28 gün 28 gün Döngü süresi, %28 %33 %22 TY + KY 18 31 33 n Tas, ark. 2008 Petru, ark. 2006 Skarlos, ark. 2005
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35. Over Kanserinde Bevasizumab’lı Faz II Çalışmalar 1. Cannistra SA, et al. J Clin Oncol. 2007;25:5180-5186. 2. Burger RA, et al. J Clin Oncol. 2007;25:5165-5175. 3. Garcia AA, et al. J Clin Oncol. 2008;26:76-82. *GOG. Monk BJ: Ovarian Cancer: Recent Developments in the Standard of Care and Emerging Options Cannistra ve a rk [1] Burger ve ark [2] * Garcia ve ark [3] Hasta sayısı , 44 62 70 Önceki KT sayısı , % 2: 52 3: 48 1: 34 2: 66 Ortanca : 2 Aralık : 1-3 Yanıt oranı , % 16 (PR) 18 (PR) 3 (CR) 24 (PR) GI delinme , % 11 0 6 Arteri ye l tromboemboli , % 7 0 4 Ölüm , % 7 0 4
mos, months. This slide displays a timeline of platinum sensitivity.
Patients with ovarian cancer who recur within less than 6 months after therapy are termed either “platinum resistant” or “platinum refractory.” They are called platinum refractory if they do not respond to platinum-based chemotherapy and platinum resistant if their disease recurs within this interval. Patients are referred to as being platinum sensitive if their disease recurs after 6 months. I would like to propose that these patients are not only resistant to platinum therapy but also to chemotherapy. The issue is not just platinum sensitivity; it is also chemotherapy sensitivity.
This slide shows the data on which those observations were based. In the 0-6–month period, alternative treatments appear to be better, and during that time, there were few alternative treatments. In the 7-12–month period, retreatment with a platinum-based regimen is better in terms of response rate, and then the further out you get, the greater the advantage for using retreatment with a platinum‑based regimen.
CR, complete response; DFI, disease-free interval; PR, partial response; SD, stable disease The NCCN guidelines for treating patients with recurrent ovarian cancer are based on this 6‑month time point, but the guidelines are rather vague. For example, the second row of the graphic in the slide, “recurrence regimen (typically in nonplatinum)” implies that the regimen does not have to be a nonplatinum regimen. Therefore, treating a patient who has a platinum-free interval of 5.5 months with platinum again would adhere to the NCCN guidelines. In the 6- to 12-month interval, there is some leeway. If there is a focal recurrence, a secondary cytoreduction should be considered; however, randomized trials are needed to confirm this paradigm. Certainly, patients who are highly platinum-sensitive at over 12 months, at least at the current status, would be retreated with platinum, perhaps a platinum combination.
FDA, US Food and Drug Administration. Currently, 7 drugs are approved by the US Food and Drug Administration for use in ovarian cancer. Of these, 3 drugs are commonly used in the upfront setting: cisplatin, carboplatin, and paclitaxel. Altretamine, an alkylating agent, is really of historical importance. Other novel nonplatinum drugs are also available: topotecan was approved in 1996; liposomal doxorubicin gained full approval in 1999; and the latest drug, gemcitabine, was approved with carboplatin in 2006.
OS, overall survival; PFS, progression-free survival. The gemcitabine/carboplatin combination yielded a better result: 47 vs 31% for the carboplatin-alone group; however, this patient population was less favorable than the population in ICON 4, so these trials cannot be compared.
AUC, area under the curve; PFS, progression-free survival. These findings prompted this randomized European trial, comparing PLD/carboplatin vs paclitaxel/carboplatin. Recent findings indicate that there was a survival advantage for PLD/carboplatin vs paclitaxel/carboplatin in this trial.
FT, fallopian tube; PI, primary investigator; PPT, primary peritoneal; TFI, treatment-free interval. GOG 213 is an interesting study because it looks at 2 aspects: secondary cytoreduction and the role of biologics.
AUC, area under the concentration curve; GI, gastrointestinal; OS, overall survival; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; PFS, progression-free survival. The phase III OCEANS trial is also evaluating bevacizumab, this time in combination with carboplatin and gemcitabine in platinum-sensitive patients. This trial originally started out as a randomized phase II that morphed into a phase III study, and data are anticipated in 2010.
Chemo, chemotherapy. The ICON6 trial is evaluating the antiangiogenic agent cediranib, which is orally administered, and, like the GOG 218 trial, is being conducted among patients with platinum-sensitive recurrent ovarian cancer and consists of 3 treatment arms.
PLD, pegylated doxorubicin. The slide displays the paradigm that is most often used in the treatment of ovarian cancer today in the recurrent disease setting. We look at the patient’s response to frontline treatment and how long since that frontline treatment before recurrence develops, and we define the patient’s disease as being either chemosensitive or chemoresistant. If she is chemosensitive, she is retreated with a platinum‑based doublet, and if she is chemoresistant, then she is treated with alternative agents. Single agents are usually used because there is no evidence that a combination regimen offers an advantage in the chemoresistant setting, and certainly not platinum.
This slide shows the data on which those observations were based. In the 0-6–month period, alternative treatments appear to be better, and during that time, there were few alternative treatments. In the 7-12–month period, retreatment with a platinum-based regimen is better in terms of response rate, and then the further out you get, the greater the advantage for using retreatment with a platinum‑based regimen.
FDA, US Food and Drug Administration; PLD, pegylated liposomal doxorubicin. When we counsel a patient with platinum-resistant recurrent ovarian cancer on treatment options, she will ask, “What is the chance that this therapy is going to work?” The answer is 17% to 20%, as shown by the data from the trials listed in the slide. The ten Bokkel Huinink study was a phase II trial, whereas the O’Byrne and Gordon studies were phase III trials. Pegylated liposomal doxorubicin (PLD) is generally given at a dose of 50 mg/m^2 every 4 weeks, although 40 mg/m^2 also may be given. Topotecan is generally given at a dose of 1.5 mg/m^2 every 5 days, weekly, or at 1.25 mg/m^2 for 5 days.
CRs, complete responses; GI, gastrointestinal; PRs, partial responses. Since that report 3 carefully performed phase II trials of single-agent bevacizumab have been conducted in predominantly platinum-resistant recurrent ovarian cancer. As mentioned, the response rates of topotecan and PLD (17% to 20%) are in the same range as the response rates of bevacizumab in these studies. The concern with bevacizumab is gastrointestinal perforations, and the risk of this is approximately twice the rate observed in patients with cancers other than ovarian. Therefore, if the risk of gastrointestinal perforations is 1% to 2% in colon cancer patients, this risk is approximately 4% in ovarian cancer patients.
The GOG has screened 38 agents to identify those that are active in recurrent ovarian cancer. Only 3 agents have been identified to have activity in this setting: weekly paclitaxel, pemetrexed, and docetaxel.
This slide shows the agents currently being evaluated for ovarian cancer in phase III trials.
Phenoxodiol is a compound that has the potential to reverse platinum resistance. It has been shown to sensitize cells due to Fas-mediated apoptosis and restore sensitivity in docetaxel-resistant epithelial ovarian cancer cells.
BRCP, breast cancer resistance protein; CR, complete response; GI, gastrointestinal; MDR, multidrug resistance; MRP, multidrug resistance protein; PR, partial response. Karenitecin is a novel camptothecins that is highly lipophilic. A phase II trial evaluating karenitecin in the third-line setting was negative. The response rate was 12%.
EOC, epithelial ovarian cancer; OS, overall survival; PFS, progression-free survival. Based on this result, a large, randomized phase III was launched to evaluate karenitecin vs the standard camptothecin topotecan in the second- and third-line settings. The trial is ongoing.
