Clinical benefit and tolerability of adjuvant intraperitoneal chemotherapy in patients who have or have not received neoadjuvant chemotherapy for advanced ovarian cancer
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摘要
BACKGROUND Adjuvant chemotherapy using intraperitoneal(IP) treatment has demonstrated survival benefit over intravenous(IV) therapy alone in patients treated with upfront debulking surgery for advanced stage ovarian cancer. Neoadjuvant chemotherapy followed by interim surgery and adjuvant chemotherapy has similar outcome in survival as compared to upfront surgery followed by adjuvant IV chemotherapy. IP chemotherapy has not been widely adopted in clinical practice for a number of reasons. Whether IP chemotherapy delivered in the patients who received neoadjuvant chemotherapy can be well tolerated or confers any clinical benefit has not been well studied.AIM To evaluate the experience of adjuvant IP chemotherapy in the community cancer clinic setting, and the clinical benefit and tolerability of incorporating IP chemotherapy in patients who received neoadjuvant treatment.METHODS We retrospectively evaluated toxicities and outcomes of patients with stage III and IV ovarian cancer diagnosed at our institution between 07/2007 and 07/2015 who received intraperitoneal chemotherapy after cytoreductive surgery(group 1)or after neoadjuvant chemotherapy followed by interim surgery(group 2).RESULTS Thirty eight patients were treated with IP chemotherapy, median age was 54 years old(range 38.6 to 71 years). In group 1(n = 25), 12(48%) of the patients completed 4 or more cycle of IP treatment after upfront debulking surgery; while in group 2(n = 13), 8(61.5%) of the patients completed all 3 cycles of the assigned IP chemotherapy after receiving neoadjuvant IV chemotherapy followed by surgery, and 2(15.4%) more patients tolerated more than 3 cycles. In those patients who did not get planned IP chemotherapy, most of them were treated with substitutional IV chemotherapy, and the completion rate for 6 cycles of IV +IP was 92%. Abdominal pain,(64% in group 1 and 38% in group 2), vomiting,(36% in group 1 and 30.8% in group 2), dehydration(16% in group 1 and 15.4% in group 2), and hypomagnesemia(12% in group 1 and 15.4% in group 2) were the most common adverse effects in all patients, while patients who have received neoadjuvant chemotherapy were more likely to get hypokalemia, fatigue and renal insufficiency. Progression free survival(PFS) was 26.5 mo(95% CI 14.9,38.0) in group 1 and 27.6 mo(95% CI 13.1, 42.1) in group 2. The overall survival was 100.2 mo(95% CI 67.9, 132.5) for group 1 and 68.2 mo(95% CI 32.2, 104.0) for group 2. For the entire cohort, PFS was 26.5 mo(95% CI 15.9, 37.0) and OS was78.8 mo(95% CI 52.3, 105.4).CONCLUSION The use of IP/IV chemotherapy can be safely administrated in the community cancer clinic setting. The use of IP/IV chemotherapy in patients who have received neoadjuvant chemotherapy followed by surgery is feasible and tolerable. Despite various modification of the IP regimen, incorporation of IP chemotherapy in the adjuvant setting appears to be associated with improved PFS and overall survival.
BACKGROUND Adjuvant chemotherapy using intraperitoneal(IP) treatment has demonstrated survival benefit over intravenous(IV) therapy alone in patients treated with upfront debulking surgery for advanced stage ovarian cancer. Neoadjuvant chemotherapy followed by interim surgery and adjuvant chemotherapy has similar outcome in survival as compared to upfront surgery followed by adjuvant IV chemotherapy. IP chemotherapy has not been widely adopted in clinical practice for a number of reasons. Whether IP chemotherapy delivered in the patients who received neoadjuvant chemotherapy can be well tolerated or confers any clinical benefit has not been well studied.AIM To evaluate the experience of adjuvant IP chemotherapy in the community cancer clinic setting, and the clinical benefit and tolerability of incorporating IP chemotherapy in patients who received neoadjuvant treatment.METHODS We retrospectively evaluated toxicities and outcomes of patients with stage III and IV ovarian cancer diagnosed at our institution between 07/2007 and 07/2015 who received intraperitoneal chemotherapy after cytoreductive surgery(group 1)or after neoadjuvant chemotherapy followed by interim surgery(group 2).RESULTS Thirty eight patients were treated with IP chemotherapy, median age was 54 years old(range 38.6 to 71 years). In group 1(n = 25), 12(48%) of the patients completed 4 or more cycle of IP treatment after upfront debulking surgery; while in group 2(n = 13), 8(61.5%) of the patients completed all 3 cycles of the assigned IP chemotherapy after receiving neoadjuvant IV chemotherapy followed by surgery, and 2(15.4%) more patients tolerated more than 3 cycles. In those patients who did not get planned IP chemotherapy, most of them were treated with substitutional IV chemotherapy, and the completion rate for 6 cycles of IV +IP was 92%. Abdominal pain,(64% in group 1 and 38% in group 2), vomiting,(36% in group 1 and 30.8% in group 2), dehydration(16% in group 1 and 15.4% in group 2), and hypomagnesemia(12% in group 1 and 15.4% in group 2) were the most common adverse effects in all patients, while patients who have received neoadjuvant chemotherapy were more likely to get hypokalemia, fatigue and renal insufficiency. Progression free survival(PFS) was 26.5 mo(95% CI 14.9,38.0) in group 1 and 27.6 mo(95% CI 13.1, 42.1) in group 2. The overall survival was 100.2 mo(95% CI 67.9, 132.5) for group 1 and 68.2 mo(95% CI 32.2, 104.0) for group 2. For the entire cohort, PFS was 26.5 mo(95% CI 15.9, 37.0) and OS was78.8 mo(95% CI 52.3, 105.4).CONCLUSION The use of IP/IV chemotherapy can be safely administrated in the community cancer clinic setting. The use of IP/IV chemotherapy in patients who have received neoadjuvant chemotherapy followed by surgery is feasible and tolerable. Despite various modification of the IP regimen, incorporation of IP chemotherapy in the adjuvant setting appears to be associated with improved PFS and overall survival.
BACKGROUND Adjuvant chemotherapy using intraperitoneal(IP) treatment has demonstrated survival benefit over intravenous(IV) therapy alone in patients treated with upfront debulking surgery for advanced stage ovarian cancer. Neoadjuvant chemotherapy followed by interim surgery and adjuvant chemotherapy has similar outcome in survival as compared to upfront surgery followed by adjuvant IV chemotherapy. IP chemotherapy has not been widely adopted in clinical practice for a number of reasons. Whether IP chemotherapy delivered in the patients who received neoadjuvant chemotherapy can be well tolerated or confers any clinical benefit has not been well studied.AIM To evaluate the experience of adjuvant IP chemotherapy in the community cancer clinic setting, and the clinical benefit and tolerability of incorporating IP chemotherapy in patients who received neoadjuvant treatment.METHODS We retrospectively evaluated toxicities and outcomes of patients with stage III and IV ovarian cancer diagnosed at our institution between 07/2007 and 07/2015 who received intraperitoneal chemotherapy after cytoreductive surgery(group 1)or after neoadjuvant chemotherapy followed by interim surgery(group 2).RESULTS Thirty eight patients were treated with IP chemotherapy, median age was 54 years old(range 38.6 to 71 years). In group 1(n = 25), 12(48%) of the patients completed 4 or more cycle of IP treatment after upfront debulking surgery; while in group 2(n = 13), 8(61.5%) of the patients completed all 3 cycles of the assigned IP chemotherapy after receiving neoadjuvant IV chemotherapy followed by surgery, and 2(15.4%) more patients tolerated more than 3 cycles. In those patients who did not get planned IP chemotherapy, most of them were treated with substitutional IV chemotherapy, and the completion rate for 6 cycles of IV +IP was 92%. Abdominal pain,(64% in group 1 and 38% in group 2), vomiting,(36% in group 1 and 30.8% in group 2), dehydration(16% in group 1 and 15.4% in group 2), and hypomagnesemia(12% in group 1 and 15.4% in group 2) were the most common adverse effects in all patients, while patients who have received neoadjuvant chemotherapy were more likely to get hypokalemia, fatigue and renal insufficiency. Progression free survival(PFS) was 26.5 mo(95% CI 14.9,38.0) in group 1 and 27.6 mo(95% CI 13.1, 42.1) in group 2. The overall survival was 100.2 mo(95% CI 67.9, 132.5) for group 1 and 68.2 mo(95% CI 32.2, 104.0) for group 2. For the entire cohort, PFS was 26.5 mo(95% CI 15.9, 37.0) and OS was78.8 mo(95% CI 52.3, 105.4).CONCLUSION The use of IP/IV chemotherapy can be safely administrated in the community cancer clinic setting. The use of IP/IV chemotherapy in patients who have received neoadjuvant chemotherapy followed by surgery is feasible and tolerable. Despite various modification of the IP regimen, incorporation of IP chemotherapy in the adjuvant setting appears to be associated with improved PFS and overall survival.
引文
1 Siegel RL,Miller KD,Jemal A.Cancer statistics,2015.CA Cancer J Clin 2015;65:5-29[PMID:25559415 DOI:10.3322/caac.21254]
2 Surveillance,Epidemiology,and End Results Program.Cancer Stat Facts:Ovarian Cancer,2016.Available from:URL:http://seer.cancer.gov/statfacts/html/ovary.html
3 Alberts DS,Liu PY,Hannigan EV,O'Toole R,Williams SD,Young JA,Franklin EW,Clarke-Pearson DL,Malviya VK,DuBeshter B.Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer.N Engl J Med 1996;335:1950-1955[PMID:8960474 DOI:10.1056/NEJM199612263352603]
4 Armstrong DK,Bundy B,Wenzel L,Huang HQ,Baergen R,Lele S,Copeland LJ,Walker JL,Burger RA;Gynecologic Oncology Group.Intraperitoneal cisplatin and paclitaxel in ovarian cancer.N Engl JMed 2006;354:34-43[PMID:16394300 DOI:10.1056/NEJMoa052985]
5 Markman M.Hyperthermic intraperitoneal chemotherapy in the management of ovarian cancer:A critical need for an evidence-based evaluation.Gynecol Oncol 2009;113:4-5[PMID:19176238 DOI:10.1016/j.ygyno.2008.12.022]
6 Jaaback K,Johnson N.Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer.Cochrane Database Syst Rev 2006;CD005340[PMID:16437527 DOI:10.1002/14651858.CD005340.pub2]
7 Tewari D,Java JJ,Salani R,Armstrong DK,Markman M,Herzog T,Monk BJ,Chan JK.Long-term survival advantage and prognostic factors associated with intraperitoneal chemotherapy treatment in advanced ovarian cancer:a gynecologic oncology group study.J Clin Oncol 2015;33:1460-1466[PMID:25800756 DOI:10.1200/JCO.2014.55.9898]
8 Wright AA,Cronin A,Milne DE,Bookman MA,Burger RA,Cohn DE,Cristea MC,Griggs JJ,Keating NL,Levenback CF,Mantia-Smaldone G,Matulonis UA,Meyer LA,Niland JC,Weeks JC,O'Malley DM.Use and Effectiveness of Intraperitoneal Chemotherapy for Treatment of Ovarian Cancer.J Clin Oncol2015;33:2841-2847[PMID:26240233 DOI:10.1200/JCO.2015.61.4776]
9 Burger RA,Brady MF,Bookman MA,Fleming GF,Monk BJ,Huang H,Mannel RS,Homesley HD,Fowler J,Greer BE,Boente M,Birrer MJ,Liang SX;Gynecologic Oncology Group.Incorporation of bevacizumab in the primary treatment of ovarian cancer.N Engl J Med 2011;365:2473-2483[PMID:22204724 DOI:10.1056/NEJMoa1104390]
10 Perren TJ,Swart AM,Pfisterer J,Ledermann JA,Pujade-Lauraine E,Kristensen G,Carey MS,Beale P,Cervantes A,Kurzeder C,du Bois A,Sehouli J,Kimmig R,St?hle A,Collinson F,Essapen S,Gourley C,Lortholary A,Selle F,Mirza MR,Leminen A,Plante M,Stark D,Qian W,Parmar MK,Oza AM;ICON7Investigators.A phase 3 trial of bevacizumab in ovarian cancer.N Engl J Med 2011;365:2484-2496[PMID:22204725 DOI:10.1056/NEJMoa1103799]
11 Pimenta L,Dornelas M,Cezana L.Weekly vs.Every-3-Week Paclitaxel for Ovarian Cancer.N Engl JMed 2016;374:2602-2603[PMID:27355551 DOI:10.1056/NEJMc1603849]
12 Vergote I,TropéCG,Amant F,Kristensen GB,Ehlen T,Johnson N,Verheijen RH,van der Burg ME,Lacave AJ,Panici PB,Kenter GG,Casado A,Mendiola C,Coens C,Verleye L,Stuart GC,Pecorelli S,Reed NS;European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group;NCIC Clinical Trials Group.Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer.N Engl J Med 2010;363:943-953[PMID:20818904 DOI:10.1056/NEJMoa0908806]
13 Mackay H,Gallagher CJ,Parulekar WR,Ledermann JA,Armstrong DK,Gourley C,Romero I,Feeney A,Bessette P,Hall M,Weberpals JI,Hall G,Lau SK,Gauthier P,Fung-Kee-Fung M,Eisenhauer EA,Winch C,Tu D,Provencher DM.OV21/PETROC:A randomized Gynecologic Cancer Intergroup(GCIG)phase II study of intraperitoneal(IP)versus intravenous(IV)chemotherapy following neoadjuvant chemotherapy and optimal debulking surgery in epithelial ovarian cancer(EOC).J Clin Oncol 2016;34:LBA5503
14 Vergote I,Rustin GJ,Eisenhauer EA,Kristensen GB,Pujade-Lauraine E,Parmar MK,Friedlander M,Jakobsen A,Vermorken JB.Re:new guidelines to evaluate the response to treatment in solid tumors[ovarian cancer].Gynecologic Cancer Intergroup.J Natl Cancer Inst 2000;92:1534-1535[PMID:10995813 DOI:10.1093/jnci/92.18.1534]
15 Konner JA,Grabon DM,Gerst SR,Iasonos A,Thaler H,Pezzulli SD,Sabbatini PJ,Bell-McGuinn KM,Tew WP,Hensley ML,Spriggs DR,Aghajanian CA.Phase II study of intraperitoneal paclitaxel plus cisplatin and intravenous paclitaxel plus bevacizumab as adjuvant treatment of optimal stage II/IIIepithelial ovarian cancer.J Clin Oncol 2011;29:4662-4668[PMID:22067389 DOI:10.1200/JCO.2011.36.1352]
16 Genentech Inc.Avastin prescribing information,2018.Available from:URL:https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125085s0169lbl.pdf
17 Katsumata N,Yasuda M,Takahashi F,Isonishi S,Jobo T,Aoki D,Tsuda H,Sugiyama T,Kodama S,Kimura E,Ochiai K,Noda K;Japanese Gynecologic Oncology Group.Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer:a phase 3,open-label,randomised controlled trial.Lancet 2009;374:1331-1338[PMID:19767092 DOI:10.1016/S0140-6736(09)61157-0]
18 Walker J,Brady MF,DiSilvestro PA,Fujiwara K,Alberts D,Zheng W,Tewari K,Cohn DE,Powell M,Van Le L,Rubin S,Davidson SA,Gray HJ,Waggoner S,Myers T,Aghajanian C,Secord AA,Mannel RS.A phase III trial of bevacizumab with IV versus IP chemotherapy for ovarian,fallopian tube,and peritoneal carcinoma:An NRG Oncology Study.Gynecologic Oncology 2016;141:208[DOI:10.1016/j.ygyno.2016.04.535]
19 van Driel WJ,Koole SN,Sikorska K,Schagen van Leeuwen JH,Schreuder HWR,Hermans RHM,de Hingh IHJT,van der Velden J,Arts HJ,Massuger LFAG,Aalbers AGJ,Verwaal VJ,Kieffer JM,Van de Vijver KK,van Tinteren H,Aaronson NK,Sonke GS.Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer.N Engl J Med 2018;378:230-240[PMID:29342393 DOI:10.1056/NEJMoa1708618]
20 Spriggs DR,Zivanovic O.Ovarian Cancer Treatment-Are We Getting Warmer?N Engl J Med 2018;378:293-294[PMID:29342385 DOI:10.1056/NEJMe1714556]
2 Surveillance,Epidemiology,and End Results Program.Cancer Stat Facts:Ovarian Cancer,2016.Available from:URL:http://seer.cancer.gov/statfacts/html/ovary.html
3 Alberts DS,Liu PY,Hannigan EV,O'Toole R,Williams SD,Young JA,Franklin EW,Clarke-Pearson DL,Malviya VK,DuBeshter B.Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer.N Engl J Med 1996;335:1950-1955[PMID:8960474 DOI:10.1056/NEJM199612263352603]
4 Armstrong DK,Bundy B,Wenzel L,Huang HQ,Baergen R,Lele S,Copeland LJ,Walker JL,Burger RA;Gynecologic Oncology Group.Intraperitoneal cisplatin and paclitaxel in ovarian cancer.N Engl JMed 2006;354:34-43[PMID:16394300 DOI:10.1056/NEJMoa052985]
5 Markman M.Hyperthermic intraperitoneal chemotherapy in the management of ovarian cancer:A critical need for an evidence-based evaluation.Gynecol Oncol 2009;113:4-5[PMID:19176238 DOI:10.1016/j.ygyno.2008.12.022]
6 Jaaback K,Johnson N.Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer.Cochrane Database Syst Rev 2006;CD005340[PMID:16437527 DOI:10.1002/14651858.CD005340.pub2]
7 Tewari D,Java JJ,Salani R,Armstrong DK,Markman M,Herzog T,Monk BJ,Chan JK.Long-term survival advantage and prognostic factors associated with intraperitoneal chemotherapy treatment in advanced ovarian cancer:a gynecologic oncology group study.J Clin Oncol 2015;33:1460-1466[PMID:25800756 DOI:10.1200/JCO.2014.55.9898]
8 Wright AA,Cronin A,Milne DE,Bookman MA,Burger RA,Cohn DE,Cristea MC,Griggs JJ,Keating NL,Levenback CF,Mantia-Smaldone G,Matulonis UA,Meyer LA,Niland JC,Weeks JC,O'Malley DM.Use and Effectiveness of Intraperitoneal Chemotherapy for Treatment of Ovarian Cancer.J Clin Oncol2015;33:2841-2847[PMID:26240233 DOI:10.1200/JCO.2015.61.4776]
9 Burger RA,Brady MF,Bookman MA,Fleming GF,Monk BJ,Huang H,Mannel RS,Homesley HD,Fowler J,Greer BE,Boente M,Birrer MJ,Liang SX;Gynecologic Oncology Group.Incorporation of bevacizumab in the primary treatment of ovarian cancer.N Engl J Med 2011;365:2473-2483[PMID:22204724 DOI:10.1056/NEJMoa1104390]
10 Perren TJ,Swart AM,Pfisterer J,Ledermann JA,Pujade-Lauraine E,Kristensen G,Carey MS,Beale P,Cervantes A,Kurzeder C,du Bois A,Sehouli J,Kimmig R,St?hle A,Collinson F,Essapen S,Gourley C,Lortholary A,Selle F,Mirza MR,Leminen A,Plante M,Stark D,Qian W,Parmar MK,Oza AM;ICON7Investigators.A phase 3 trial of bevacizumab in ovarian cancer.N Engl J Med 2011;365:2484-2496[PMID:22204725 DOI:10.1056/NEJMoa1103799]
11 Pimenta L,Dornelas M,Cezana L.Weekly vs.Every-3-Week Paclitaxel for Ovarian Cancer.N Engl JMed 2016;374:2602-2603[PMID:27355551 DOI:10.1056/NEJMc1603849]
12 Vergote I,TropéCG,Amant F,Kristensen GB,Ehlen T,Johnson N,Verheijen RH,van der Burg ME,Lacave AJ,Panici PB,Kenter GG,Casado A,Mendiola C,Coens C,Verleye L,Stuart GC,Pecorelli S,Reed NS;European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group;NCIC Clinical Trials Group.Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer.N Engl J Med 2010;363:943-953[PMID:20818904 DOI:10.1056/NEJMoa0908806]
13 Mackay H,Gallagher CJ,Parulekar WR,Ledermann JA,Armstrong DK,Gourley C,Romero I,Feeney A,Bessette P,Hall M,Weberpals JI,Hall G,Lau SK,Gauthier P,Fung-Kee-Fung M,Eisenhauer EA,Winch C,Tu D,Provencher DM.OV21/PETROC:A randomized Gynecologic Cancer Intergroup(GCIG)phase II study of intraperitoneal(IP)versus intravenous(IV)chemotherapy following neoadjuvant chemotherapy and optimal debulking surgery in epithelial ovarian cancer(EOC).J Clin Oncol 2016;34:LBA5503
14 Vergote I,Rustin GJ,Eisenhauer EA,Kristensen GB,Pujade-Lauraine E,Parmar MK,Friedlander M,Jakobsen A,Vermorken JB.Re:new guidelines to evaluate the response to treatment in solid tumors[ovarian cancer].Gynecologic Cancer Intergroup.J Natl Cancer Inst 2000;92:1534-1535[PMID:10995813 DOI:10.1093/jnci/92.18.1534]
15 Konner JA,Grabon DM,Gerst SR,Iasonos A,Thaler H,Pezzulli SD,Sabbatini PJ,Bell-McGuinn KM,Tew WP,Hensley ML,Spriggs DR,Aghajanian CA.Phase II study of intraperitoneal paclitaxel plus cisplatin and intravenous paclitaxel plus bevacizumab as adjuvant treatment of optimal stage II/IIIepithelial ovarian cancer.J Clin Oncol 2011;29:4662-4668[PMID:22067389 DOI:10.1200/JCO.2011.36.1352]
16 Genentech Inc.Avastin prescribing information,2018.Available from:URL:https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125085s0169lbl.pdf
17 Katsumata N,Yasuda M,Takahashi F,Isonishi S,Jobo T,Aoki D,Tsuda H,Sugiyama T,Kodama S,Kimura E,Ochiai K,Noda K;Japanese Gynecologic Oncology Group.Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer:a phase 3,open-label,randomised controlled trial.Lancet 2009;374:1331-1338[PMID:19767092 DOI:10.1016/S0140-6736(09)61157-0]
18 Walker J,Brady MF,DiSilvestro PA,Fujiwara K,Alberts D,Zheng W,Tewari K,Cohn DE,Powell M,Van Le L,Rubin S,Davidson SA,Gray HJ,Waggoner S,Myers T,Aghajanian C,Secord AA,Mannel RS.A phase III trial of bevacizumab with IV versus IP chemotherapy for ovarian,fallopian tube,and peritoneal carcinoma:An NRG Oncology Study.Gynecologic Oncology 2016;141:208[DOI:10.1016/j.ygyno.2016.04.535]
19 van Driel WJ,Koole SN,Sikorska K,Schagen van Leeuwen JH,Schreuder HWR,Hermans RHM,de Hingh IHJT,van der Velden J,Arts HJ,Massuger LFAG,Aalbers AGJ,Verwaal VJ,Kieffer JM,Van de Vijver KK,van Tinteren H,Aaronson NK,Sonke GS.Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer.N Engl J Med 2018;378:230-240[PMID:29342393 DOI:10.1056/NEJMoa1708618]
20 Spriggs DR,Zivanovic O.Ovarian Cancer Treatment-Are We Getting Warmer?N Engl J Med 2018;378:293-294[PMID:29342385 DOI:10.1056/NEJMe1714556]