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Goenka L, Dubashi B, Kayal S, Rajappa M, Manivannan P, Chakkalakkoombil SV, Gochhait D, Chaturvedula L, Pradeep S, Anandaradje A, Goud AC, Ganesan P. Targeting autophagy in platinum-sensitive relapsed ovarian cancer: randomized phase II trial of hydroxychloroquine with chemotherapy with biomarker correlation. Discov Oncol 2025; 16:203. [PMID: 39969689 PMCID: PMC11839959 DOI: 10.1007/s12672-025-01904-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 02/03/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Autophagy activation contributes to chemotherapy resistance in several cancers, including ovarian cancer. Hydroxychloroquine (HCQ) is an autophagy inhibitor inhibiting the fusion of the autophagosome with the lysosome and has been repurposed as an anti-cancer agent. In this randomized phase II study, we used HCQ in combination with standard chemotherapy in platinum sensitive relapsed ovarian cancer (PSROC) patients. METHODS Patients were randomized in a 1:1 ratio to receive standard chemotherapy (carboplatin with paclitaxel/gemcitabine) with or without HCQ. Those randomized to receive HCQ received additional HCQ 200mg orally twice daily. The primary endpoint was the overall response rate (ORR). Other endpoints included survival outcomes, changes in autophagy biomarkers, toxicity, and quality of life. RESULTS A total of 59 patients were enrolled- chemotherapy + HCQ (N = 28), chemotherapy alone (N = 31), and 56 were evaluable ( received ≥ 3 cycles treatment). The ORR was not superior with the addition of HCQ [85% (22/26) in the experimental arm as compared to 80% (24/30) in the control arm, chi-square test, P = 0.65]. The median progression-free survival was 12 (95% CI, 9.75-14.24) months for the experimental arm and 11 (95% CI, 5.25-16.74) months for the control arm (P = 0.56) , and the median overall survival was 16 (95% CI, 8.54-23.45) months vs. 21 (95% CI, 11.70-30.59 ) months (P = 0.49) respectively. HCQ was well tolerated, with no excess adverse events [21 (75%) in the experimental arm vs. 22 (71%) in the control arm]. There were no substantial differences in the reduction of autophagy biomarker levels and QOL between the control and experimental arms. CONCLUSION Adding HCQ to chemotherapy failed to improve response rates or survival in patients with PSROC. Conducting biomarker-stratified clinical trials might show the potential benefit of HCQ. Trial registration number (TRN): The trial was registered in the Clinical Trial Registry of India ( www.ctri.nic.in ; CTRI/2020/06/025790) on 17th June 2020.
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Affiliation(s)
- Luxitaa Goenka
- Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), 3rdFloor, SSB, JIPMER, Dhanvantari Nagar, Puducherry, 605006, India
| | - Biswajit Dubashi
- Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), 3rdFloor, SSB, JIPMER, Dhanvantari Nagar, Puducherry, 605006, India
| | - Smita Kayal
- Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), 3rdFloor, SSB, JIPMER, Dhanvantari Nagar, Puducherry, 605006, India
| | - Medha Rajappa
- Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, India
| | - Prabhu Manivannan
- Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, India
| | | | - Debasis Gochhait
- Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, India
| | - Latha Chaturvedula
- Department of Obstetrics and Gynaecology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, India
| | - S Pradeep
- Department of Surgical Oncology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, India
| | - Annuja Anandaradje
- Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, India
| | - Alladi Charanraj Goud
- Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), 3rdFloor, SSB, JIPMER, Dhanvantari Nagar, Puducherry, 605006, India
| | - Prasanth Ganesan
- Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), 3rdFloor, SSB, JIPMER, Dhanvantari Nagar, Puducherry, 605006, India.
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Shimoyama S, Okada K, Kimura T, Morohashi Y, Nakayama S, Kemmochi S, Makita-Suzuki K, Matulonis UA, Mori M. FF-10850, a Novel Liposomal Topotecan Achieves Superior Antitumor Activity via Macrophage- and Ammonia-Mediated Payload Release in the Tumor Microenvironment. Mol Cancer Ther 2023; 22:1454-1464. [PMID: 37683276 PMCID: PMC10690090 DOI: 10.1158/1535-7163.mct-23-0099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 08/03/2023] [Accepted: 09/01/2023] [Indexed: 09/10/2023]
Abstract
Topotecan, an approved treatment for refractory or recurrent ovarian cancer, has clinical limitations such as rapid clearance and hematologic toxicity. To overcome these limitations and maximize clinical benefit, we designed FF-10850, a dihydrosphingomyelin-based liposomal topotecan. FF-10850 demonstrated superior antitumor activity to topotecan in ovarian cancer cell line-based xenograft models, as well as in a clinically relevant DF181 platinum-refractory ovarian cancer patient-derived xenograft model. The safety profile was also improved with mitigation of hematologic toxicity. The improved antitumor activity and safety profile are achieved via its preferential accumulation and payload release triggered in the tumor microenvironment. Our data indicate that tumor-associated macrophages internalize FF-10850, resulting in complete payload release. The release mechanism also appears to be mediated by high ammonia concentration resulting from glutaminolysis, which is activated by tumor metabolic reprogramming. In ammonia-rich conditions, FF-10850 released payload more rapidly and to a greater extent than liposomal doxorubicin, a currently approved treatment for ovarian cancer. FF-10850 significantly enhanced antitumor activity in combination with carboplatin or PARP inhibitor without detrimental effects on body weight in murine xenograft models, and demonstrated synergistic antitumor activity combined with anti-PD-1 antibody with the development of tumor antigen-specific immunity. These results support phase I investigation of FF-10850 for the treatment of solid tumors including ovarian cancer (NCT04047251), and further evaluation in combination settings.
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Affiliation(s)
| | - Ken Okada
- Bio Science & Engineering Laboratories, FUJIFILM Corporation, Kanagawa, Japan
| | - Toshifumi Kimura
- Bio Science & Engineering Laboratories, FUJIFILM Corporation, Kanagawa, Japan
| | - Yasushi Morohashi
- Bio Science & Engineering Laboratories, FUJIFILM Corporation, Kanagawa, Japan
| | - Shinji Nakayama
- Bio Science & Engineering Laboratories, FUJIFILM Corporation, Kanagawa, Japan
| | - Sayaka Kemmochi
- Bio Science & Engineering Laboratories, FUJIFILM Corporation, Kanagawa, Japan
| | - Keiko Makita-Suzuki
- Bio Science & Engineering Laboratories, FUJIFILM Corporation, Kanagawa, Japan
| | - Ursula A. Matulonis
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Mikinaga Mori
- Bio Science & Engineering Laboratories, FUJIFILM Corporation, Kanagawa, Japan
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Yung MMH, Siu MKY, Ngan HYS, Chan DW, Chan KKL. Orchestrated Action of AMPK Activation and Combined VEGF/PD-1 Blockade with Lipid Metabolic Tunning as Multi-Target Therapeutics against Ovarian Cancers. Int J Mol Sci 2022; 23:ijms23126857. [PMID: 35743298 PMCID: PMC9224484 DOI: 10.3390/ijms23126857] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 06/06/2022] [Accepted: 06/17/2022] [Indexed: 02/06/2023] Open
Abstract
Ovarian cancer is one of the most lethal gynecological malignancies worldwide, and chemoresistance is a critical obstacle in the clinical management of the disease. Recent studies have suggested that exploiting cancer cell metabolism by applying AMP-activated protein kinase (AMPK)-activating agents and distinctive adjuvant targeted therapies can be a plausible alternative approach in cancer treatment. Therefore, the perspectives about the combination of AMPK activators together with VEGF/PD-1 blockade as a dual-targeted therapy against ovarian cancer were discussed herein. Additionally, ferroptosis, a non-apoptotic regulated cell death triggered by the availability of redox-active iron, have been proposed to be governed by multiple layers of metabolic signalings and can be synergized with immunotherapies. To this end, ferroptosis initiating therapies (FITs) and metabolic rewiring and immunotherapeutic approaches may have substantial clinical potential in combating ovarian cancer development and progression. It is hoped that the viewpoints deliberated in this review would accelerate the translation of remedial concepts into clinical trials and improve the effectiveness of ovarian cancer treatment.
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Affiliation(s)
- Mingo M. H. Yung
- Department of Obstetrics & Gynaecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; (M.M.H.Y.); (M.K.Y.S.); (H.Y.S.N.)
| | - Michelle K. Y. Siu
- Department of Obstetrics & Gynaecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; (M.M.H.Y.); (M.K.Y.S.); (H.Y.S.N.)
| | - Hextan Y. S. Ngan
- Department of Obstetrics & Gynaecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; (M.M.H.Y.); (M.K.Y.S.); (H.Y.S.N.)
| | - David W. Chan
- Department of Obstetrics & Gynaecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; (M.M.H.Y.); (M.K.Y.S.); (H.Y.S.N.)
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
- Correspondence: or (D.W.C.); (K.K.L.C.); Tel.: +852-3917-9367 or +852-3943-6053 (D.W.C.); +852-2255-4260 (K.K.L.C.); Fax: +852-2816-1947 or +852-2603-5123 (D.W.C.); +852-2255-0947 (K.K.L.C.)
| | - Karen K. L. Chan
- Department of Obstetrics & Gynaecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; (M.M.H.Y.); (M.K.Y.S.); (H.Y.S.N.)
- Correspondence: or (D.W.C.); (K.K.L.C.); Tel.: +852-3917-9367 or +852-3943-6053 (D.W.C.); +852-2255-4260 (K.K.L.C.); Fax: +852-2816-1947 or +852-2603-5123 (D.W.C.); +852-2255-0947 (K.K.L.C.)
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Zhao LQ, Gao W, Zhang P, Zhang YL, Fang CY, Shou HF. Surgery in platinum-resistant recurrent epithelial ovarian carcinoma. World J Clin Cases 2022; 10:3739-3753. [PMID: 35647161 PMCID: PMC9100723 DOI: 10.12998/wjcc.v10.i12.3739] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 12/24/2021] [Accepted: 03/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Ovarian cancer is one of the three most common malignant tumors of the female reproductive tract and ranks first in terms of mortality among gynecological tumors. Epithelial ovarian carcinoma (EOC) is the most common ovarian malignancy, accounting for 90% of all primary ovarian tumors. The clinical value of cytoreductive surgery in patients with platinum-resistant recurrent EOC remains largely unclear.
AIM To evaluate the feasibility of secondary cytoreductive surgery for treating platinum-resistant recurrent EOC.
METHODS This was a retrospective study of the clinical data of patients with platinum-resistant EOC admitted to the Cancer Hospital of the University of Chinese Academy of Sciences between September 2012 and June 2018. Patient baseline data were obtained from clinical records. Routine follow-up of disease progression was performed as follows. CA125 assessment and physical examination were performed every 3 wk during treatment, including gynecological examination. Imaging assessment was carried out every 12 wk by B-mode ultrasound, computed tomography, or magnetic resonance imaging. The primary outcome was progression-free survival (PFS). Secondary outcomes included overall survival (OS), chemotherapy-free interval (CFI), and complications. Follow-up ended on April 15, 2019.
RESULTS A total of 38 patients were included. R0 resection was achieved in 25 (65.8%) patients and R1/2 in 13 (34.2%). Twenty-five (65.8%) patients required organ resection. Nine (23.7%) patients had operative complications, 36 (94.7%) received chemotherapy, and five (13.2%) had targeted therapy. Median PFS and OS were 10 (95%CI: 8.27-11.73) months and 28 (95%CI: 12.75-43.25) months, respectively; median CFI was 9 (95%CI: 8.06-9.94) months. R0 resection and postoperative chemotherapy significantly prolonged PFS and OS (all P < 0.05), and R0 resection also significantly prolonged CFI (P < 0.05). Grade ≥ 3 complications were observed, including rectovaginal fistula (n = 1), intestinal and urinary fistulas (n = 1), and renal failure-associated death (n = 1). Except for the patient who died after surgery, all other patients with complications were successfully managed. Two patients developed intestinal obstruction and showed improvement after conservative treatment.
CONCLUSION Secondary cytoreductive surgery is feasible for treating platinum-resistant recurrent EOC. These findings provide important references for the selection of clinical therapeutic regimens.
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Affiliation(s)
- Ling-Qin Zhao
- Department of Gynecologic Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, Zhejiang Province, China
| | - Wen Gao
- Department of Gynecologic Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, Zhejiang Province, China
| | - Ping Zhang
- Department of Gynecologic Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, Zhejiang Province, China
| | - Ying-Li Zhang
- Department of Gynecologic Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, Zhejiang Province, China
| | - Chen-Yan Fang
- Department of Gynecologic Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, Zhejiang Province, China
| | - Hua-Feng Shou
- Department of Gynecology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
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Olesen KD, Larsen ATR, Jensen LH, Steffensen KD, Søndergaard SR. Treosulfan in platinum-resistant ovarian cancer. Int J Gynecol Cancer 2021; 31:1045-1051. [PMID: 34006568 DOI: 10.1136/ijgc-2021-002395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 04/28/2021] [Accepted: 04/30/2021] [Indexed: 11/03/2022] Open
Abstract
OBJECTIVES Treosulfan is offered as last-line treatment in patients with end-stage ovarian cancer. This retrospective study aimed to evaluate the response rates, overall survival, and adverse events of treosulfan in this patient population. METHODS The study included patients with end-stage platinum-resistant ovarian cancer treated with treosulfan from October 2015 to October 2020 at the Department of Oncology, Lillebaelt Hospital, University Hospital of Southern Denmark, Vejle, Denmark. Patients were included for treatment if their cancer had progressed and if other treatment options were limited. Patients receiving treosulfan as first-line treatment were excluded from the study. Response rates were evaluated according to the combined criteria of CA125 and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Kaplan-Meier survival analyses were used to illustrate progression-free and overall survival. Adverse events were graded 1-5 according to the Common Terminology Criteria for Adverse Events version 5.0. RESULTS Sixty-seven patients with a median age of 72 years (range 33-92) were identified. Sixty-three (94%) patients were diagnosed with serous adenocarcinoma. Fifty-seven (85%) patients were Federation of International Gynecology and Obstetrics (FIGO) stage III or IV at the time of diagnosis. The median number of treatments prior to treosulfan treatment was 3 (range 1-8). One patient had a complete response (2%), eight patients had a partial response (13%), and 22 patients (35%) had stable disease as the best response. The median duration of response (complete or partial) was 239 days (range 43-572). Median progression-free survival was 63 days (95% CI 41 to 77). The most common adverse events were anemia (83%), fatigue (83%), anorexia (62%), nausea (57%), and constipation (41%). CONCLUSIONS Treosulfan is an alternative for the treatment of relapsed ovarian cancer when other treatment options are limited, with response rates of approximately 15%. In general, the treatment was well tolerated. Taking the mild adverse events and the response rates into account, palliative treosulfan mainly seems beneficial for patients with performance status 0-1.
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Affiliation(s)
- Katrine Dam Olesen
- Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark .,Department of Oncology, Lillebælt Hospital, University Hospital of Southern Denmark, Vejle, Denmark
| | - Anja Tolstrup Rædkjær Larsen
- Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.,Department of Oncology, Lillebælt Hospital, University Hospital of Southern Denmark, Vejle, Denmark
| | - Lars Henrik Jensen
- Department of Oncology, Lillebælt Hospital, University Hospital of Southern Denmark, Vejle, Denmark.,Institute of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Karina Dahl Steffensen
- Department of Oncology, Lillebælt Hospital, University Hospital of Southern Denmark, Vejle, Denmark.,Institute of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Stine Rauff Søndergaard
- Department of Oncology, Lillebælt Hospital, University Hospital of Southern Denmark, Vejle, Denmark.,Institute of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
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Cui Q, Hu Y, Ma D, Liu H. A Retrospective Observational Study of Anlotinib in Patients with Platinum-Resistant or Platinum-Refractory Epithelial Ovarian Cancer. Drug Des Devel Ther 2021; 15:339-347. [PMID: 33536747 PMCID: PMC7850384 DOI: 10.2147/dddt.s286529] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/22/2020] [Indexed: 12/31/2022] Open
Abstract
Objective Anlotinib, an oral small-molecular tyrosine kinase inhibitor (TKI) on tumor angiogenesis and growth, has a wide spectrum of inhibitory effects on targets such as vascular endothelial growth factor receptors 2/3 (VEGFR2/3), etc. The efficacy and safety of anlotinib in the treatment of platinum-resistant or platinum-refractory ovarian cancer were evaluated. Patients and Methods Patients with platinum-resistant or platinum-refractory ovarian cancer that treated with anlotinib in the Affiliated Cancer Hospital of Zhengzhou University from May 2018 to March 2020 were included. Medical records were reviewed in terms of objective response, survival outcomes, and safety. Results A total of 38 patients were analyzed. The median progression-free survival and the median overall survival were 7.7 months (95% CI: 6.7–8.7) and 16.5 months (95% CI: 13.3–19.7), respectively. About 17 patients received anlotinib monotherapy, and the median progression-free survival was 7.7 months (95% CI: 6.3–9.1). A total of 19 cases received anlotinib plus chemotherapy with a median progression-free survival of 8.0 months (95% CI: 4.8–11.2). A total of 2 cases received anlotinib plus anti-PD-1 antibody pembrolizumab, and 1 case had partial response, the other progressive disease. The objective response rate was 42.1% while the disease control rate was 86.8%. A total of 5 patients experienced dose reduction from 12 mg to 10 mg because of adverse effects. The most common adverse effects were hypertension (31.6%), fatigue (28.9%), anorexia (26.3%) and hand-foot syndrome (23.7%). No treatment-related deaths were recorded. Conclusion Anlotinib produced moderate improvements in progression-free survival and overall survival in patients with platinum-resistant or platinum-refractory ovarian cancer. It indicates that anlotinib maybe a new treatment option for patients with platinum-resistant or platinum-refractory ovarian cancer.
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Affiliation(s)
- Qingli Cui
- Department of Integrated Traditional and Western Medicine, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou City, Henan Province, People's Republic of China
| | - Yanhui Hu
- Department of Integrated Traditional and Western Medicine, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou City, Henan Province, People's Republic of China
| | - Dongyang Ma
- Department of Integrated Traditional and Western Medicine, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou City, Henan Province, People's Republic of China
| | - Huaimin Liu
- Department of Integrated Traditional and Western Medicine, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou City, Henan Province, People's Republic of China
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Armstrong DK, Alvarez RD, Bakkum-Gamez JN, Barroilhet L, Behbakht K, Berchuck A, Chen LM, Cristea M, DeRosa M, Eisenhauer EL, Gershenson DM, Gray HJ, Grisham R, Hakam A, Jain A, Karam A, Konecny GE, Leath CA, Liu J, Mahdi H, Martin L, Matei D, McHale M, McLean K, Miller DS, O'Malley DM, Percac-Lima S, Ratner E, Remmenga SW, Vargas R, Werner TL, Zsiros E, Burns JL, Engh AM. Ovarian Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021; 19:191-226. [PMID: 33545690 DOI: 10.6004/jnccn.2021.0007] [Citation(s) in RCA: 403] [Impact Index Per Article: 100.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country's fifth most common cause of cancer mortality in women. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. These NCCN Guidelines discuss cancers originating in the ovary, fallopian tube, or peritoneum, as these are all managed in a similar manner. Most of the recommendations are based on data from patients with the most common subtypes─high-grade serous and grade 2/3 endometrioid. The NCCN Guidelines also include recommendations specifically for patients with less common ovarian cancers, which in the guidelines include the following: carcinosarcoma, clear cell carcinoma, mucinous carcinoma, low-grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord-stromal, and malignant germ cell tumors. This manuscript focuses on certain aspects of primary treatment, including primary surgery, adjuvant therapy, and maintenance therapy options (including PARP inhibitors) after completion of first-line chemotherapy.
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Affiliation(s)
| | | | | | | | | | | | - Lee-May Chen
- 7UCSF Helen Diller Family Comprehensive Cancer Center
| | | | | | | | | | - Heidi J Gray
- 12Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | | | | | | | | | | | | | - Joyce Liu
- 19Dana-Farber/Brigham and Women's Cancer Center
| | - Haider Mahdi
- 20Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | - Lainie Martin
- 21Abramson Cancer Center at the University of Pennsylvania
| | - Daniela Matei
- 22Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | | | - David M O'Malley
- 26The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | | | | | | | - Roberto Vargas
- 20Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
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Miller EM, Samec TM, Alexander-Bryant AA. Nanoparticle delivery systems to combat drug resistance in ovarian cancer. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2020; 31:102309. [PMID: 32992019 DOI: 10.1016/j.nano.2020.102309] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 09/04/2020] [Accepted: 09/17/2020] [Indexed: 12/17/2022]
Abstract
Due to the lack of early symptoms and difficulty of accurate diagnosis, ovarian cancer is the most lethal gynecological cancer faced by women. First-line therapy includes a combination of tumor resection surgery and chemotherapy regimen. However, treatment becomes more complex upon recurrence due to development of drug resistance. Drug resistance has been linked to many mechanisms, including efflux transporters, apoptosis dysregulation, autophagy, cancer stem cells, epigenetics, and the epithelial-mesenchymal transition. Thus, developing and choosing effective therapies is exceptionally complex. There is a need for increased specificity and efficacy in therapies for drug-resistant ovarian cancer, and research in targeted nanoparticle delivery systems aims to fulfill this challenge. Although recent research has focused on targeted nanoparticle-based therapies, few of these therapies have been clinically translated. In this review, non-viral nanoparticle delivery systems developed to overcome drug-resistance in ovarian cancer were analyzed, including their structural components, surface modifications, and drug-resistance targeted mechanisms.
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Affiliation(s)
- Emily M Miller
- Nanobiotechnology Laboratory, Department of Bioengineering, Clemson University, Clemson, SC
| | - Timothy M Samec
- Nanobiotechnology Laboratory, Department of Bioengineering, Clemson University, Clemson, SC
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Armstrong DK, Alvarez RD, Bakkum-Gamez JN, Barroilhet L, Behbakht K, Berchuck A, Berek JS, Chen LM, Cristea M, DeRosa M, ElNaggar AC, Gershenson DM, Gray HJ, Hakam A, Jain A, Johnston C, Leath CA, Liu J, Mahdi H, Matei D, McHale M, McLean K, O'Malley DM, Penson RT, Percac-Lima S, Ratner E, Remmenga SW, Sabbatini P, Werner TL, Zsiros E, Burns JL, Engh AM. NCCN Guidelines Insights: Ovarian Cancer, Version 1.2019. J Natl Compr Canc Netw 2020; 17:896-909. [PMID: 31390583 DOI: 10.6004/jnccn.2019.0039] [Citation(s) in RCA: 187] [Impact Index Per Article: 37.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years from diagnosis. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. The best outcomes are observed in patients whose primary treatment includes complete resection of all visible disease plus combination platinum-based chemotherapy. Research efforts are focused on primary neoadjuvant treatments that may improve resectability, as well as systemic therapies providing improved long-term survival. These NCCN Guidelines Insights focus on recent updates to neoadjuvant chemotherapy recommendations, including the addition of hyperthermic intraperitoneal chemotherapy, and the role of PARP inhibitors and bevacizumab as maintenance therapy options in select patients who have completed primary chemotherapy.
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Affiliation(s)
| | | | | | | | | | | | | | - Lee-May Chen
- UCSF Helen Diller Family Comprehensive Cancer Center
| | | | | | - Adam C ElNaggar
- St. Jude Children's Research Hospital/The University of Tennessee Health Science Center
| | | | - Heidi J Gray
- University of Washington/Seattle Cancer Care Alliance
| | | | | | | | - Charles A Leath
- University of Alabama at Birmingham Comprehensive Cancer Center
| | - Joyce Liu
- Dana-Farber/Brigham and Women's Cancer Center
| | - Haider Mahdi
- Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | - Daniela Matei
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | - David M O'Malley
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
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Santangelo G, Caruso G, Palaia I, Tomao F, Perniola G, Di Donato V, Fischetti M, Muzii L, Benedetti Panici P. The emerging role of precision medicine in the treatment of ovarian cancer. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2020. [DOI: 10.1080/23808993.2020.1777854] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Giusi Santangelo
- Department of Maternal and Child Health and Urological Sciences, Sapienza University, Rome, Italy
| | - Giuseppe Caruso
- Department of Maternal and Child Health and Urological Sciences, Sapienza University, Rome, Italy
| | - Innocenza Palaia
- Department of Maternal and Child Health and Urological Sciences, Sapienza University, Rome, Italy
| | - Federica Tomao
- Department of Maternal and Child Health and Urological Sciences, Sapienza University, Rome, Italy
| | - Giorgia Perniola
- Department of Maternal and Child Health and Urological Sciences, Sapienza University, Rome, Italy
| | - Violante Di Donato
- Department of Maternal and Child Health and Urological Sciences, Sapienza University, Rome, Italy
| | - Margherita Fischetti
- Department of Maternal and Child Health and Urological Sciences, Sapienza University, Rome, Italy
| | - Ludovico Muzii
- Department of Maternal and Child Health and Urological Sciences, Sapienza University, Rome, Italy
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Gilbert L, Ramanakumar AV, Festa MC, Jardon K, Zeng X, Martins C, Shbat L, Alsoud MA, Borod M, Wolfson M, Papaioannou I, Basso O, Sampalis J. Real-world direct healthcare costs of treating recurrent high-grade serous ovarian cancer with cytotoxic chemotherapy. J Comp Eff Res 2020; 9:537-551. [PMID: 32223298 PMCID: PMC11864079 DOI: 10.2217/cer-2020-0032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 03/06/2020] [Indexed: 11/21/2022] Open
Abstract
Aim: To describe the direct healthcare costs associated with repeated cytotoxic chemotherapy treatments for recurrent high-grade serous cancer (HGSC) of the ovaries. Patients & methods: Retrospective review of 66 women with recurrent stage III/IV HGSC ovarian cancer treated with repeated lines of cytotoxic chemotherapy in a Canadian University Tertiary Center. Results: Mean cost of treatment of first relapse was CAD$52,227 increasing by 38% for two, and 86% for three or more relapses with median overall survival of 36.0, 50.7 and 42.8 months, respectively. In-hospital care accounted for 71% and chemotherapy drugs accounted for 17% of the total costs. Conclusion: After the third relapse of HGSC, cytotoxic chemotherapy did not prolong survival but was associated with substantially increased healthcare costs.
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Affiliation(s)
- Lucy Gilbert
- McGill UniversityHealth Center, Gynecologic Cancer Services, Cancer CareMission, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada
- McGill University, Department of Obstetrics & Gynecology, 1001 Decarie Boulevard, Montreal, QC, H4A 3 J1, Canada
- Clinical Oncology Department, Tanta University, Egypt
| | - Agnihotram V Ramanakumar
- Research Institute of The McGill University Health Center, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada
| | - Maria Carolina Festa
- McGill UniversityHealth Center, Gynecologic Cancer Services, Cancer CareMission, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada
- McGill University, Department of Obstetrics & Gynecology, 1001 Decarie Boulevard, Montreal, QC, H4A 3 J1, Canada
| | - Kris Jardon
- McGill UniversityHealth Center, Gynecologic Cancer Services, Cancer CareMission, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada
- McGill University, Department of Obstetrics & Gynecology, 1001 Decarie Boulevard, Montreal, QC, H4A 3 J1, Canada
- Clinical Oncology Department, Tanta University, Egypt
| | - Xing Zeng
- McGill UniversityHealth Center, Gynecologic Cancer Services, Cancer CareMission, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada
- McGill University, Department of Obstetrics & Gynecology, 1001 Decarie Boulevard, Montreal, QC, H4A 3 J1, Canada
- Clinical Oncology Department, Tanta University, Egypt
| | - Claudia Martins
- McGill UniversityHealth Center, Gynecologic Cancer Services, Cancer CareMission, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada
- McGill University, Department of Obstetrics & Gynecology, 1001 Decarie Boulevard, Montreal, QC, H4A 3 J1, Canada
- Clinical Oncology Department, Tanta University, Egypt
| | - Layla Shbat
- McGill UniversityHealth Center, Gynecologic Cancer Services, Cancer CareMission, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada
- McGill University, Department of Obstetrics & Gynecology, 1001 Decarie Boulevard, Montreal, QC, H4A 3 J1, Canada
| | - Marwa Abo Alsoud
- McGill UniversityHealth Center, Gynecologic Cancer Services, Cancer CareMission, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada
- McGill University, Department of Obstetrics & Gynecology, 1001 Decarie Boulevard, Montreal, QC, H4A 3 J1, Canada
- Clinical Oncology Department, Tanta University, Egypt
| | - Manuel Borod
- Clinical Oncology Department, Tanta University, Egypt
- McGill University Health Center, Supportive & Palliative Care Services, Cancer Care Mission, 1001 Decarie Boulevard, Montreal, QC, H4A 3 J1, Canada
| | - Michael Wolfson
- University of Ottawa, Department of Epidemiology & Community Medicine, 600 Peter Morand Crescent, Ottawa, Canada, K1G 5Z3, Canada
| | - Ioanna Papaioannou
- JSS Medical Research, 9400 Henri-Bourassa West, Montreal, QC, H4S 1N8, Canada
| | - Olga Basso
- Research Institute of The McGill University Health Center, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada
- Department of Epidemiology, Biostatistics, & Occupational Health, McGill University, 1020 Pine Avenue West, Montreal, QC, H3A 1A2, Canada
| | - John Sampalis
- JSS Medical Research, 9400 Henri-Bourassa West, Montreal, QC, H4S 1N8, Canada
- McGill University, Faculty of Medicine, Department of Surgery, Division of Surgical Research, 1650 Cedar Avenue, Montreal, QC, H3G 1A4, Canada
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12
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Gupta S, Nag S, Aggarwal S, Rauthan A, Warrier N. Maintenance therapy for recurrent epithelial ovarian cancer: current therapies and future perspectives - a review. J Ovarian Res 2019; 12:103. [PMID: 31685032 PMCID: PMC6827246 DOI: 10.1186/s13048-019-0579-0] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 10/10/2019] [Indexed: 12/20/2022] Open
Abstract
Epithelial ovarian cancer (EOC) is usually diagnosed late at an advanced stage. Though EOC initially responds to treatment, the recurrence rate is pretty high. The efficacy of different targeted therapies reduces with each recurrence. Hence there is need of effective maintenance therapy in recurrent EOC. Recently, polyADP-ribose polymerase (PARP) inhibitors (PARPi) have been approved both for initial treatment of EOC and as its maintenance treatment. PARPi have also been found to act regardless of BRCA status or homologous recombination (HR) deficiency. Several trials testing PARPi early in maintenance therapy are in progress and their results will shed light on the optimal timing of maintenance therapy that gives the most benefit with least toxicity. Right patient selection for maintenance treatment is also a challenge. Hence, though PARPi are emerging as a promising maintenance treatment in recurrent EOC with prolongation of progression free survival (PFS), results from further trials and overall survival (OS) data from current trials are awaited to fulfill the gaps in understanding the role of this pathway in treatment of EOC. This review discusses the current therapies for EOC, challenges in the treatment of recurrent EOC, recent developments and trials in recurrent EOC maintenance with special focus on PARPi and future perspectives.
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Affiliation(s)
- Sudeep Gupta
- Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial Centre, Room 305, 3rd Floor, Paymaster Shodhika, Navi Mumbai, Mumbai, 410210, India.
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Ringley JT, Moore DC, Patel J, Rose MS. Poly (ADP-ribose) Polymerase Inhibitors in the Management of Ovarian Cancer: A Drug Class Review. P & T : A PEER-REVIEWED JOURNAL FOR FORMULARY MANAGEMENT 2018; 43:549-556. [PMID: 30186027 PMCID: PMC6110640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
OBJECTIVE To review the pharmacology, safety, efficacy, and role of poly adenosine diphosphate [ADP]-ribose polymerase (PARP) inhibitors in the treatment and maintenance of relapsed, advanced ovarian cancer. SUMMARY A total of 3 phase 2 trials and 2 phase 3 trials were reviewed that evaluated the safety and efficacy of oral niraparib, olaparib, and rucaparib in patients with ovarian cancer. Progression-free survival (PFS) was evaluated in the maintenance setting for niraparib and olaparib, resulting in a PFS of 21.0 months and 8.4 months, respectively. Olaparib and rucaparib were evaluated in the treatment setting, producing a PFS of 9.4 months and 12.8 months, respectively. PFS was higher in patients with BRCA mutation when compared to patients with BRCA wild-type in both the maintenance and treatment setting across all trials evaluated. Niraparib, olaparib, and rucaparib were found to be relatively well tolerated in clinical trials, with the most common adverse events being anemia, fatigue, and nausea. CONCLUSION PARP inhibitors appear to be a safe and effective new option in the treatment and maintenance of relapsed, advanced BRCA1/2 mutant ovarian cancer. This drug class will likely have an expanding role in ovarian cancer as further trial results are published.
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Arora E, Masab M, Jindal V, Riaz I, Gupta S, Varadi G. Role of Poly Adenosine Diphosphate Ribose Polymerase Inhibitors in Advanced Stage Ovarian Cancer. Cureus 2018; 10:e2685. [PMID: 30050740 PMCID: PMC6059530 DOI: 10.7759/cureus.2685] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Ovarian cancer is one of the leading causes of death from gynecologic cancers. In this present era of cancer treatment, therapeutic options for patients with advanced or recurrent ovarian cancer are limited. The present standard of care treatment for advanced ovarian cancer is a platinum-based doublet chemotherapy (paclitaxel and carboplatin with or without bevacizumab) after a maximum attempt of surgical cytoreduction. However, there are no promising options for the management of patients with ovarian cancer refractory to the platinum-based chemotherapy. Therefore, newer, safe, and more effective treatment modalities are required for patients with advanced or recurrent ovarian cancer. Poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors have shown an impressive safety profile and anti-tumor efficacy in patients with breast cancer 1 and 2 (BRCA1 and BRCA2) gene-mutated ovarian cancer who were previously treated with the standard of care chemotherapy. We have done a detailed review of the literature to emphasize the role of PARP inhibitors in the treatment of advanced or relapsed ovarian cancer.
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Affiliation(s)
- Ena Arora
- Obstetrics and Gynecology, Civil Hospital Chandigarh, Chandigarh, IND
| | - Muhammad Masab
- Internal Medicine, Albert Einstein Medical Center, New York, USA
| | - Vishal Jindal
- Internal Medicine, St. Vincent Hospital Worcester, Worcester, USA
| | - Iqra Riaz
- Department of Medicine, Mayo Hospital, King Edward Medical University, Lahore, Pakistan
| | - Sorab Gupta
- Hematology and Oncology, Albert Einstein Medical Center, New York, USA
| | - Gabor Varadi
- Hematology and Oncology, Albert Einstein Medical Center, New York, USA
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Cortez AJ, Tudrej P, Kujawa KA, Lisowska KM. Advances in ovarian cancer therapy. Cancer Chemother Pharmacol 2018; 81:17-38. [PMID: 29249039 PMCID: PMC5754410 DOI: 10.1007/s00280-017-3501-8] [Citation(s) in RCA: 393] [Impact Index Per Article: 56.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 12/11/2017] [Indexed: 02/06/2023]
Abstract
Epithelial ovarian cancer is typically diagnosed at an advanced stage. Current state-of-the-art surgery and chemotherapy result in the high incidence of complete remissions; however, the recurrence rate is also high. For most patients, the disease eventually becomes a continuum of symptom-free periods and recurrence episodes. Different targeted treatment approaches and biological drugs, currently under development, bring the promise of turning ovarian cancer into a manageable chronic disease. In this review, we discuss the current standard in the therapy for ovarian cancer, major recent studies on the new variants of conventional therapies, and new therapeutic approaches, recently approved and/or in clinical trials. The latter include anti-angiogenic therapies, polyADP-ribose polymerase (PARP) inhibitors, inhibitors of growth factor signaling, or folate receptor inhibitors, as well as several immunotherapeutic approaches. We also discuss cost-effectiveness of some novel therapies and the issue of better selection of patients for personalized treatment.
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Affiliation(s)
- Alexander J Cortez
- Maria Skłodowska-Curie Institute - Oncology Center, Gliwice Branch, Wybrzeże Armii Krajowej 15, Gliwice, 44-100, Poland
| | - Patrycja Tudrej
- Maria Skłodowska-Curie Institute - Oncology Center, Gliwice Branch, Wybrzeże Armii Krajowej 15, Gliwice, 44-100, Poland
| | - Katarzyna A Kujawa
- Maria Skłodowska-Curie Institute - Oncology Center, Gliwice Branch, Wybrzeże Armii Krajowej 15, Gliwice, 44-100, Poland
| | - Katarzyna M Lisowska
- Maria Skłodowska-Curie Institute - Oncology Center, Gliwice Branch, Wybrzeże Armii Krajowej 15, Gliwice, 44-100, Poland.
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16
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Cerrato A, Morra F, Celetti A. Use of poly ADP-ribose polymerase [PARP] inhibitors in cancer cells bearing DDR defects: the rationale for their inclusion in the clinic. J Exp Clin Cancer Res 2016; 35:179. [PMID: 27884198 PMCID: PMC5123312 DOI: 10.1186/s13046-016-0456-2] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 11/09/2016] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND DNA damage response (DDR) defects imply genomic instability and favor tumor progression but make the cells vulnerable to the pharmacological inhibition of the DNA repairing enzymes. Targeting cellular proteins like PARPs, which cooperate and complement molecular defects of the DDR process, induces a specific lethality in DDR defective cancer cells and represents an anti-cancer strategy. Normal cells can tolerate the DNA damage generated by PARP inhibition because of an efficient homologous recombination mechanism (HR); in contrast, cancer cells with a deficient HR are unable to manage the DSBs and appear especially sensitive to the PARP inhibitors (PARPi) effects. MAIN BODY In this review we discuss the proof of concept for the use of PARPi in different cancer types and the success and failure of their inclusion in clinical trials. The PARP inhibitor Olaparib [AZD2281] has been approved by the FDA for use in pretreated ovarian cancer patients with defective BRCA1/2 genes, and by the EMEA for maintenance therapy in platinum sensitive ovarian cancer patients with defective BRCA1/2 genes. BRCA mutations are now recognised as the molecular targets for PARPi sensitivity in several tumors. However, it is noteworthy that the use of PARPi has shown its efficacy also in non-BRCA related tumors. Several trials are ongoing to test different PARPi in different cancer types. Here we review the concept of BRCAness and the functional loss of proteins involved in DDR/HR mechanisms in cancer, including additional molecules that can influence the cancer cells sensitivity to PARPi. Given the complexity of the existing crosstalk between different DNA repair pathways, it is likely that a single biomarker may not be sufficient to predict the benefit of PARP inhibitors therapies. Novel general assays able to predict the DDR/HR proficiency in cancer cells and the PARPi sensitivity represent a challenge for a personalized therapy. CONCLUSIONS PARP inhibition is a potentially important strategy for managing a significant subset of tumors. The discovery of both germline and somatic DNA repair deficiencies in different cancer patients, together with the development of new PARP inhibitors that can kill selectively cancer cells is a potent example of targeting therapy to molecularly defined tumor subtypes.
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17
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Suh CH, Tirumani SH, Keraliya A, Kim KW, Ramaiya NH, Shinagare AB. Molecular targeted therapy in gynaecologic malignancies: primer for radiologists. Br J Radiol 2016; 89:20160086. [PMID: 27331884 DOI: 10.1259/bjr.20160086] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
The identification of characteristic genetic alteration in gynaecological malignancies has opened the door for molecular targeted therapy. The purpose of this review is to provide a primer for the radiologist on these agents with emphasis on the role of imaging in treatment response assessment and drug toxicities. The use of targeted therapy in gynaecological malignancies will likely increase in the future and make the role of the radiologist critical in response assessment and detection of toxicities.
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Affiliation(s)
- Chong Hyun Suh
- 1 Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.,2 Department of Radiology, Namwon Medical Center, Namwon-Si, Jeollabuk-Do, Republic of Korea
| | - Sree H Tirumani
- 3 Department of Imaging, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.,4 Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Abhishek Keraliya
- 3 Department of Imaging, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.,4 Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Kyung Won Kim
- 1 Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Nikhil H Ramaiya
- 3 Department of Imaging, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.,4 Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Atul B Shinagare
- 3 Department of Imaging, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.,4 Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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Yung MMH, Ngan HYS, Chan DW. Targeting AMPK signaling in combating ovarian cancers: opportunities and challenges. Acta Biochim Biophys Sin (Shanghai) 2016; 48:301-17. [PMID: 26764240 PMCID: PMC4886241 DOI: 10.1093/abbs/gmv128] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 10/29/2015] [Indexed: 12/25/2022] Open
Abstract
The development and strategic application of effective anticancer therapies have turned out to be one of the most critical approaches of managing human cancers. Nevertheless, drug resistance is the major obstacle for clinical management of these diseases especially ovarian cancer. In the past years, substantial studies have been carried out with the aim of exploring alternative therapeutic approaches to enhance efficacy of current chemotherapeutic regimes and reduce the side effects caused in order to produce significant advantages in overall survival and to improve patients' quality of life. Targeting cancer cell metabolism by the application of AMP-activated protein kinase (AMPK)-activating agents is believed to be one of the most plausible attempts. AMPK activators such as 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside, A23187, metformin, and bitter melon extract not only prevent cancer progression and metastasis but can also be applied as a supplement to enhance the efficacy of cisplatin-based chemotherapy in human cancers such as ovarian cancer. However, because of the undesirable outcomes along with the frequent toxic side effects of most pharmaceutical AMPK activators that have been utilized in clinical trials, attentions of current studies have been aimed at the identification of replaceable reagents from nutraceuticals or traditional medicines. However, the underlying molecular mechanisms of many nutraceuticals in anticancer still remain obscure. Therefore, better understanding of the functional characterization and regulatory mechanism of natural AMPK activators would help pharmaceutical development in opening an area to intervene ovarian cancer and other human cancers.
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Affiliation(s)
- Mingo M H Yung
- Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Hextan Y S Ngan
- Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - David W Chan
- Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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Liu Y, Ren Z, Xu S, Bai H, Ma N, Wang F. Low-dose-intensity bevacizumab with weekly irinotecan for platinum- and taxanes-resistant epithelial ovarian cancer. Cancer Chemother Pharmacol 2015; 75:645-51. [PMID: 25599660 PMCID: PMC4341009 DOI: 10.1007/s00280-015-2680-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 01/08/2015] [Indexed: 11/27/2022]
Abstract
PURPOSE The purpose of this study was to evaluate the safety and efficacy of low-dose-intensity bevacizumab and weekly irinotecan as salvage treatment for patients with platinum- and taxanes-resistant advanced epithelial ovarian cancer. METHODS Fifty-two patients with platinum- and taxanes-resistant advanced epithelial ovarian cancer received bevacizumab 5 mg/Kg days 1 and 15; irinotecan 60 mg/m(2) days 1, 8 and 15. The combined therapy was repeated every 28 days, up to six cycles. RESULTS A total of 230 cycles of bevacizumab combined with irinotecan were administrated to 52 patients. Among the 52 patients, 22 patients achieved partial response (42.3 %); 12 patients had stable disease (23.1 %) and 18 patients experienced disease progression (34.6 %). The median progression-free survival and the median overall survival were 8.0 months (95 % confidence interval: 6.74-9.26 months) and 13.8 months (95 % confidence interval: 11.97-15.63 months), respectively. The most frequent grade 3-4 hematologic toxicities were neutropenia (11.5 %) and thrombocytopenia (3.8 %). The non-hematologic toxicities included grade 3 diarrhea (3.8 %) and hypertension (3.8 %). Two patients (3.8 %) were confirmed with deep vein thrombosis. Febrile neutropenia, symptomatic cardiac dysfunction and gastrointestinal perforation were not observed in this study. CONCLUSIONS The combination of low-dose-intensity bevacizumab and weekly irinotecan was an effective and safe regimen for patients with platinum- and taxanes-resistant epithelial ovarian cancer.
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Affiliation(s)
- Ying Liu
- Department of Oncology, Henan Cancer Hospital, Zhengzhou University Affiliated Cancer Hospital, Zhengzhou, Henan, China,
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Abstract
ObjectiveThe aim of this study was to evaluate the effectiveness and safety of percutaneous interstitial implantation with125I seed under computed tomographic (CT) guidance for recurrent ovarian cancer (ROC).Materials and MethodsA retrospective review was performed on 17 patients with ROC who were treated with125I seed brachytherapy. Treatment planning system was used preoperatively to determine the estimated seeds number and distribution;125I seeds were implanted into recurrent lesions under CT guidance. Therapeutic effectiveness and complications were noted during follow-up time.ResultsMonths are counted from the time of125I seed brachytherapy, and the median duration of follow-up was 10.5 months (3-23 months). The objective response rates after 1, 3, 6, 12, and 18 months were 76.5%, 75.0%, 61.5%, 42.9%, and 40%, respectively. The pain relief rate was 61.5%, and the general living quality was improved dramatically. The median progression-free survival time was 5.4 months, the median overall survival time was 11.3 months, and the 1-year survival rate was 41.2%. Complications in this study were very mild; severe adverse events such as massive bleeding, intestinal fistula, and treatment-related deaths did not occur.ConclusionsOur initial experience showed that CT-guided125I seed interstitial implantation is safe and feasible in the treatment of patients with ROCs after multiple therapies.
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Salvage chemotherapy with docetaxel and pegylated liposomal doxorubicin in pretreated patients with platinum- and taxane-sensitive ovarian cancer: a multicenter phase II trial of the Hellenic Oncology Research Group (HORG). Cancer Chemother Pharmacol 2014; 73:819-25. [DOI: 10.1007/s00280-014-2411-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Accepted: 02/06/2014] [Indexed: 10/25/2022]
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Bronte G, Cicero G, Sortino G, Pernice G, Catarella MT, D'Alia P, Cusenza S, Lo Dico S, Bronte E, Sprini D, Midiri M, Firenze A, Fiorentino E, Bazan V, Rolfo C, Russo A. Immunotherapy for recurrent ovarian cancer: a further piece of the puzzle or a striking strategy? Expert Opin Biol Ther 2013; 14:103-14. [DOI: 10.1517/14712598.2014.859671] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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