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Dose-dense chemotherapy with weekly paclitaxel and 3-weekly carboplatin for recurrent ovarian cancer
Taiwanese Journal of Obstetrics & Gynecology 59 (2020) 21e27
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Original Article
Dose-dense chemotherapy with weekly paclitaxel and 3-weekly carboplatin for recurrent ovarian cancer Wei-Chun Chen a, b, Huei-Jean Huang a, b, Ting-Chang Chang a, b, Hung-Hsueh Chou a, b, * a b
Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Linkou, Taiwan Chang Gung University, College of Medicine, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 23 September 2019
Objective: To analyze the response to dose-dense chemotherapy of weekly paclitaxel and 3-weekly carboplatin in recurrent ovarian cancer, and to report results of literature review. Materials and methods: Patients accepted weekly paclitaxel 80 mg/m2 on day 1, 8, 15 and carboplatin on day1 at area under curve (AUC) 6 every 21 days were reviewed for the response rate, progression-free survival, overall survival, and toxicity during January 2012 to April 2016 in Chang Gung Memorial Hospital at Linkou, Taiwan. Results: Sixteen patients with recurrent ovarian cancer, including 1 platinum-resistant, 7 partially platinum-sensitive, and 8 platinum-sensitive, accepted a median of 6 cycles of chemotherapy (range 3 e10). The overall response rate (ORR) and complete response (CR) rate were 93.8%, and 62.5%, respectively. The median PFS of all patients were 10.9 months (range 4.3e40.5). The median time to response (TTR) was 29.0 days (range 19.6e38.4). The median disease-free survival (DFS) after CR was 5.6 months (range 1.2e34.2). Grade 3 at least toxicity included anemia (6.3%), neutropenia (50%), and thrombocytopenia (18.8%). Twenty-nine articles on phase I, II, III, or retrospective studies of dose-dense chemotherapy with weekly paclitaxel were reviewed. Conclusion: This is the first report using Japanese Gynecologic Oncology Group 3016 protocol, weekly paclitaxel and 3-weely carboplatin, on recurrent ovarian cancer. The current study showed high ORR and CR with tolerable toxicities. Our study suggested dose-dense chemotherapy with paclitaxel, especially combining carboplatin created high efficacy probably by anti-angiogenesis. However, consolidation or maintenance therapy is needed to prolong DFS. © 2020 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Dose-dense chemotherapy Metronomic chemotherapy Weekly paclitaxel Carboplatin Recurrent ovarian cancer
Introduction Of all gynecologic malignancies, ovarian cancer is one of the most prevalent and the leading cause of death. The standard primary treatment for ovarian cancer is cytoreductive surgery and combination chemotherapy with platinum and paclitaxel administered through a conventional 3-weekly or dose-dense schedule [1]. Dose-dense chemotherapy with carboplatin at an area under the curve (AUC) of 6 on day 1 and paclitaxel at 80 mg/
* Corresponding author. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Linkou, #5 Fushing Street, Kwei-Shan, Taoyuan 333, Taiwan. E-mail address: [email protected] (H.-H. Chou).
m2 on days 1, 8, and 15 is superior to 3-weekly carboplatin and paclitaxel in progression-free survival (PFS) and overall survival (OS) as first-line chemotherapy [2]. Approximately 50%e80% of patients obtain a complete response (CR) after operation and firstline chemotherapy [1], but about 70% of them experience recurrent disease that requires salvage chemotherapy [3]. Salvage chemotherapy renders response rate of 47%e67% in patients who are platinum sensitive and 10%e30% in patients who are platinum resistant. Owing to dose-dense chemotherapy resulted in longer survival time, we implemented it to recurrent ovarian cancer as an additional option. The purpose of this retrospective study was to analyze the response to dose-dense chemotherapy with weekly paclitaxel and 3-weekly carboplatin in patients with recurrent ovarian cancer and to review the literature.
https://doi.org/10.1016/j.tjog.2019.10.003 1028-4559/© 2020 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
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W.-C. Chen et al. / Taiwanese Journal of Obstetrics & Gynecology 59 (2020) 21e27
Materials and methods
Response and progress
Patients and study design
The primary outcomes of interest were the response rate (RR), PFS, and OS. Other outcomes included toxicity and safety. The therapeutic response of measurable lesions was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 by CT scans or MRI imaging [5]. For patients without measurable lesions in the imaging study or without an image study after treatment, the response was assessed according to CA-125 values following the Rustin criteria. The overall response rate (ORR) was the summation of CR and partial response (PR), and was calculated from the results of RECIST and CA-125 criteria according to the Gynecological Cancer Intergroup study by Rustin in 2011 [6]. The time to response (TTR) was calculated from the beginning of the salvage treatment to the date when the tumor marker declined to half of its pretreatment level. The PFS was the duration between the beginning of chemotherapy and the occurrence of the first evidence of disease progression, and OS was the length of time between the beginning of chemotherapy and death. Among patients with a CR, disease-free survival (DFS) was calculated from a confirmation of complete remission to disease progression or death.
We retrospectively reviewed our patients with recurrent ovarian, fallopian tube, or peritoneal carcinoma treated with paclitaxel-based dose-dense chemotherapy at Chang Gung Memorial Hospital from January 2012 to January 2016. The patients enrolled in our study satisfied the following conditions: (1) a confirmed pathology of ovarian, fallopian tube, or primary peritoneal carcinoma; (2) recurrence after at least one line of chemotherapy with platinum and taxane; (3) an elevated tumor marker, cancer antigen 125 (CA-125), or recurrent lesions demonstrated by an image study, such as computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET). This retrospective study was conducted with the approval of an institutional review board (IRB) (IRB number 201700944B0). The clinical data included age at diagnosis, the initial stage according to the International Federation of Gynecology and Obstetrics (FIGO) staging system, residual tumors after primary debulking operation, the front-line chemotherapeutic combination, lines of prior chemotherapy, and associated hematologic and nonhematologic adverse events. Levels of the tumor marker CA125 at diagnosis, prior to and during the current salvage chemotherapy, and during follow-up were evaluated. The pathologic reports revealed the primary tumor origin, histologic cell type, and histology grade. The progression-free interval (PFI) was defined as the duration between the last platinum administration of front-line chemotherapy and the first cancer relapse. A patient was defined as platinum resistant if the PFI was less than 6 months, partially platinum sensitive if the PFI was between 6 and 12 months, and platinum sensitive if the PFI was over 12 months. For patients undergoing more than one line of chemotherapy, secondary chemotherapeutic sensitivity was defined on the basis of whether the duration from the last treatment to next recurrence was longer than 6 months. The completeness of cytoreduction (CC) score was defined as follows: CC-0: no visible residual lesions; CC-1: largest residual lesions less than 2.5 mm; CC2: residual lesion size between 2.5 mm and 2.5 cm; CC-3: any residual lesion over 2.5 cm. An optimal debulking operation was defined as all residual lesions less than 1 cm. Chemotherapy regimens Our patients accepted dose-dense chemotherapy with intravenous carboplatin at an AUC of 6 on day 1 and weekly paclitaxel at 80 mg/m2 on days 1, 8, and 15 every 21 days. The duration of therapy depended on the disease status, the patient's response, toxicity, and clinical performance. A complete blood count including a white blood cell count S 2500/uL, absolute neutrophil count S 1500/uL, hemoglobin S 9 g/dL, and platelet count S 100,000/mL was required for chemotherapy. To keep chemotherapy on schedule, leukopenia was corrected with granulocyte colony stimulating factor, and anemia with blood transfusion. Safety and toxicity Safety and adverse events (AEs) were recorded at every visit until 30 days after the last chemotherapy. The patient-based safety and AEs were accessed using the Common Terminology Criteria for Adverse Events, version 4.0 [4]. A routine hematologic evaluation and nonhematologic toxicity assessment were performed before every combined or single-agent chemotherapy.
Literature review We searched for relevant literature in the PubMed and Medline databases by using Medical Subject Headings related to recurrent ovarian cancer, weekly paclitaxel, and dose-dense chemotherapy. Statistical analysis PFS and OS were analyzed and represented using a KaplaneMeier Curve. The differences in PFS and OS among groups were calculated using a log-rank test. The data of patients that were platinum sensitive and those that were platinum resistant were compared through a paired t test and chi-square test. The analyses were considered to be significant when the p value was less than 0.05. Results Patients and treatments From 2012 to April 2016, the data of 18 patients were retrospectively collected at Chang Gung Memorial Hospital in Linkou, Taiwan. Two patients were excluded due to miscoding of disease or nonrecurrent disease, and 16 patients were eligible for the current study. The patient characteristics are shown in Table 1, and the treatment profiles are listed in Table 2. The median age was 53 years (range 32e64). Fourteen patients (93.3%) had high-grade serous carcinomas, 1 had clear cell carcinoma, and 1 was missing data on the cell type due to previous records at a local hospital being unobtainable. All 16 participants had stage 3 (N ¼ 13, 81.3%) or stage 4 disease (N ¼ 3, 19.8%). One (6.3%) patient was platinum resistant and 15 patients were platinum sensitive to the initial chemotherapy, with 7 (43.8%) being partially platinum sensitive and 8 (50%) being platinum sensitive. The number of lines of previous chemotherapy was one regimen for 7 cases (7/16 ¼ 43.5%), two regimens for 4 cases (4/16 ¼ 25%) and more than two regimen for 5 cases (5/16 ¼ 31.3%). Three patients had received hyperthermic intraoperative chemotherapy (HIPEC) at 42 Ce43 C, with 320 mg of paclitaxel and 160 mg of cisplatin for a lavage time of 60 min during their second debulking operations. Seven of the 16 patients (43.8%) had undergone a previous line of chemotherapy within 6 months, and were deemed as secondary platinum
W.-C. Chen et al. / Taiwanese Journal of Obstetrics & Gynecology 59 (2020) 21e27 Table 1 Patient characteristics.
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Table 3 Treatment response related to chemotherapy line and platinum sensitivity.
Characteristics
Number (percentage)
Patients Age at diagnosis (years) Median (Range) Histology HGSC Clear cell carcinoma Uncertain Initial FIGO stage Stage 3 Stage 4 Complete cytoreduction (CC) score CC 0 CC 1 CC 2-3 Uncertain Platinum sensitivity Resistant Sensitive-PFI of 6e12 months Sensitive-PFI of >12 months Prior regimens of chemotherapy 1 2 >2
16
Line of previous C/T 1 2 S3 Platinum sensitivity Resistant PFI 6e12 months PFI > 12 months All
53 (32e64) 14 (87.5) 1 (6.3) 1 (6.3) 13 (81.3) 3 (19.7) 6 2 3 5
Pt No
ORR (%)
CR (%)
PR (%)
SD (%)
PD (%)
7 4 5
6 (85.7) 4 (100) 5 (100)
6 (85.7) 2 (50) 2 (40)
0 2 (50) 3 (60)
0 0 0
1 (14.3) 0 0
1 7 8 16
1 (100) 6 (85.7) 8 (100) 15 (93.8)
1 (100) 4 (57.1) 5 (62.5) 10 (62.5)
0 2 (28.6) 3 (37.5) 5 (31.3)
0 0 0 0
0 1 (14.3) 0 1 (6.25)
C/T: chemotherapy, P-Resistant: platinum-resistant, PFI: progression-free interval, ORR: overall response rate, CR: complete response, PR: partial response, SD: stable disease.
(37.5) (12.5) (18.8) (31.3)
100%, and 100%, and the CR rates were 85.7%, 50%, and 40%, respectively (Table 3). For platinum resistant, partially platinum sensitive, and platinum sensitive patients, the ORRs were 100%, 85.7%, and 100%, and the CR rates were 100%, 57.1%, and 62.5%, respectively. The 5 most heavily pretreated patients had a 100% ORR and a 40% CR rate. The only platinum-resistant patient who had received 4 lines of previous chemotherapy obtained a CR after 10 cycles of current dose-dense chemotherapy. TTRs for complete responders and partial responders were 22 days (range 15e74) and 30 days (range 21e56) (p ¼ 0.856). A decline of CA125 by 50% occurred after the first cycle of dose-dense chemotherapy in most of our patients, as shown in the supplementary material (S1). The OS data are not available yet. The median follow-up time of the alive patients was 22.1 months (range 6.2e51.1). The median PFS of all patients was 10.9 months (range 4.3e40.5), and there was a trend difference (p ¼ 0.049) in favor of platinum-sensitive (median 13.2 months, range 5.4e39.9) rather than partially platinumsensitive (median 7.9 months, range 4.3e16.3) patients. The median OS period from the start of treatment was 21.8 months (95% CI, 12.7e30.8) and 13.0 months (95% CI, 6.6e19.4) for platinumsensitive and partially platinum-sensitive patients, respectively (p ¼ 0.163). Complete responders had a significantly longer median survival time than partial responders, with a PFS of 12.7 months (range 4.9e40.5) versus 6.2 months (range 4.3e13.4) (p ¼ 0.029) (Data shown in supplementary material e S2). The median DFS of
1 (6.2) 7 (43.8) 8 (50.0) 7 (43.8) 4 (25) 5 (31.2)
HGSC: high-grade serous carcinoma, CC: completeness of cytoreduction, CC-0: no visible residual lesions, CC-1: largest residual lesions less than 2.5 mm, CC-2: residual nodular size between 2.5 mm and 2.5 cm, CC-3: any residual lesion over 2.5 cm, PFI: platinum-free interval.
resistant. Among these 7 patients, 5 were the most heavily pretreated, receiving more than 3 lines of chemotherapy. Treatments and response The median number of cycles of dose-dense chemotherapy was 6 (range 3e10), and the total cycle number was 98 in all 16 patients. The median follow-up time was 14.9 months (range 6.2e51.1). At the time of analysis, 7 patients were alive with disease, 2 patients remained alive with no evidence of disease, and 7 patients died of disease. Among the 16 cases, there were 10 CRs (62.5%) and 5 PRs (31.3%), amounting to an ORR of 93.8%. For patients with 1, 2, and more than 2 lines of previous chemotherapy, the ORRs were 85.7%,
Table 2 Patient treatment profiles. Patient Age at diagnosis FIGO stage Histology Gr
CC score Initial PFI month Prior lines of C/T DDC cycle Response TTRy days PFS month OS* month status
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
NA CC2 NA CC3 NA CC3 CC0 CC0 CC1 CC0 CC1 CC0 NA CC0 CC0 NA
56 46 44 54 32 52 58 58 55 58 64 50 57 42 48 49
3 3C 3B 3C 3C 4 3C 3C 3C 3C 4 3C 3C 3C 3C 4
HGSC HGSC NA HGSC HGSC HGSC HGSC HGSC HGSC HGSC HGSC HGSC HGSC HGSC HGSC CLC
3 3 NA 3 3 3 3 3 3 3 3 3 3 3 3 NA
6.3 17.8 8.1 7.5 14.4 10.5 5.6 9.6 22.8 17.2 8.8 26.9 16.3 92.7 28.8 42.3
1 2 3 1 1 1 4 4 2 2 7 2 3 1 1 1
6 10 10 6 5 6 8 3 9 5 6 6 3 5 6 4
PD CR CR CR CR CR CR PR PR PR PR CR PR CR CR CR
15 66 19 21 22 74 21 30 56 43 29 23 52
6.9 31.6 16.5 10.9 17.1 8.5 11.6 4.3 13.4 5.5 8 12.7 6.2 4.9 13.87 40.5
22.1 13.2 12.1 32.2
11.9
20.2 15.1
AWD AWD DOD DOD AWD DOD DOD AWD AWD DOD AWD AWD DOD NED DOD NED
DDC: dose-dense chemotherapy, HGSC: high-grade serous carcinoma, CLC: clear cell carcinoma, CC score: completeness of cytoreduction score, CC-0: no visible residual lesions, CC-1: largest residual lesions less than 2.5 mm, CC-2: residual nodular size between 2.5 mm and 2.5 cm, CC-3: any residual lesion over 2.5 cm, PFI: platinum-free interval, C/T: chemotherapy, PFS: progression-free survival, OS: overall survival, HGSC: high-grade serous carcinoma, HIPEC: hyperthermic intraperitoneal chemotherapy, PD: progressive disease, CR: complete response, PR: partial response, G2/G3/G4: grade 2/grade 3/grade 4, AWD: alive with disease, DOD: died of disease, NED: no evidence of disease, GI: gastrointestinal, NA: not available, *Nine patients were still alive, and the calculated OS values were 6.2, 7.6, 9.5, 13.6, 17.1, 20.7, 22.1, 40.5, and 51.8 months. yThree patients did not have a TTR due to 1 being a non-responder and the other 2 patients having an initial CA-125 within the normal limitation.
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W.-C. Chen et al. / Taiwanese Journal of Obstetrics & Gynecology 59 (2020) 21e27
Table 4 Survival related to previous treatment history. Variants
Numbers
Median PFS (months)
PFS HR (95% CI)
Overall response N (%)
Cytoreduction CC 0 CC 1 at least
6 5
5.5 (4.9e13.9) 10.9 (8.0e31.6) p ¼ 0.415
Reference 0.6 (0.2e2.1) p ¼ 0.420
6 (100) 5 (100)
Prior lines of chemotherapy 1e2 3 at least
11 5
12.7 (4.9e40.5) 8.0 (4.3e16.5) p ¼ 0.221
Reference 2.0 (0.7e6.2) p ¼ 0.230
10 (90.9) 5 (100) p ¼ 0.486
Age at diagnosis 50 years >50 years
7 9
16.5 (4.9e40.5) 8.0 (4.3e13.4) p ¼ 0.003
Reference 8.3 (1.7e41.3) p ¼ 0.010
7 (100) 8 (88.9) p ¼ 0.362
CC: completeness of cytoreduction, CC-0: no visible residual lesions, CC-1: largest residual lesions less than 2.5 mm, CC-2: residual nodular size between 2.5 mm and 2.5 cm, CC-3: any residual lesion over 2.5 cm, PFS: progression-free survival, HR: hazard ratio, CI: confidence interval.
the patients with a CR was 5.6 months (range 1.2e34.2). Table 4 illustrates the difference in survival rates between categories determined through a log-rank test. Compared with patients aged over 50, patients under 50 had a significantly longer PFS. Safety and adverse events The associated AEs of grade 3 at least are summarized in the supplementary material (S3). In our cohort, the AEs of grade 3 at least were all hematology-related toxicity including 1 case of (6.25%) anemia, 8 (50%) cases of neutropenia, and 8 (30.8%) cases of thrombocytopenia. An episode of grade 2 allergic reaction including generalized rash with pruritus occurred in 1 patient at her sixth cycle of carboplatin treatment and was relieved after discontinuation of medication and steroid administration. One patient abandoned her therapy at the ninth cycle due to suspected drug-related grade 4 liver toxicity, with aspartate aminotransferase at 704 U/L and alanine aminotransferase at 1358 U/L. No grade 5 AEs were recorded in our study. Literature review We reviewed 29 papers about dose-dense chemotherapy using paclitaxel for recurrent ovarian cancer in the literature and classified them into 5 categories (Table 5). These categories were singleagent weekly paclitaxel (N ¼ 11), weekly paclitaxel and weekly carboplatin (N ¼ 7), weekly paclitaxel and 3-weekly or 4-weekly carboplatin (N ¼ 4), weekly paclitaxel and other chemotherapy (N ¼ 2), and weekly paclitaxel and targeted therapy (N ¼ 6). The ORRs of 11 single-agent weekly paclitaxel studies ranged from 20.9% to 68%, and the CR rates ranged from 0% to 27%. The ORRs of 7 weekly paclitaxel and weekly carboplatin studies ranged from 35% to 100%, and the CR rates ranged from 7.8% to 71%. Three studies of weekly paclitaxel (3 weeks on, 1 week off) and 4-weekly carboplatin conducted by Rose, Hoekstra, and Lortholary reported ORRs of 71.5%, 93.3%, and 37%, and CR rates of 53.6%, 86.7%, and 14%, respectively [7e9]. Discussion A higher dose intensity of chemotherapy potentiates tumor killing ability, and this could be achieved by increasing the amount of the drug at each administration or by dose-dense administration at a shorter interval. Two theories explain how dose-dense chemotherapy enhances antitumor activity. The first is based on the log-kill model suggested by Skipper, Schabel, and Wilcox and the growth kinetics model developed by Gompertzian [10]. Skipper, Schabel, and Wilcox suggested that tumors with rapid growth are
more vulnerable to cytotoxic chemotherapy. Gompertzian surmised that tumors grow faster when they are small, and growth slows after they become larger. Dose-dense administration was considered to kill small-volume tumors through frequent exposure to drugs in the sensitive part of cell cycles such as the S phase, to reduce the tumor burden in the G0 phase. The second theory is based on metronomic chemotherapy, stating that frequent lowdose drug administration defers tumor angiogenesis through microtubule disruption and reduction of vascular endothelial growth factor and interleukin-8 [11]. Katsumata et al. reported the results of the Japanese Gynecologic Oncology Group (JGOG) 3016 that dose-dense chemotherapy with carboplatin at an AUC of 6 on day 1 and paclitaxel at 80 mg/m2 on days 1, 8, and 15 was superior to conventional 3-weekly carboplatin and paclitaxel in PFS and OS, exhibiting a 29% lower risk of disease progression and a 25% lower risk of death [12,13]. The cumulative dose of paclitaxel in each cycle, 240 mg/m2 in the JGOG 3016 protocol, is higher than 180 mg/m2 in the conventional 3weekly regimen. Bolis et al., in their phase III trial, did not see the survival benefit of paclitaxel at a dose of 225 mg/m2 over 175 mg/ m2 every 3 weeks [14]. The MITO-7 compared fractionated dose of both carboplatin (AUC2) and paclitaxel (60 mg/m2) given weekly and standard three-weekly regimen to show almost same median progression-free survival (18.3 months vs 17.3 months) [15]. Therefore, we speculate that the survival benefit of the JGOG 3016 protocol in the current study probably resulted from both the higher dose density and increased cumulative paclitaxel dose. For recurrent ovarian cancer, the papers we reviewed also indicated that dose-dense chemotherapy with a combination of carboplatin and paclitaxel generated a higher RR than other regimens. To the best of our knowledge, our study is the first one to use the JGOG 3016 protocol for recurrent ovarian cancer, and the ORR of 93.8% was only next to that reported by Havrilesky (100%). Even the 5 heavily pretreated patients exhibited a 100% ORR and a 40% CR rate. The high RR not only prolonged survival but also improved quality of life by relieving clinical symptoms, including ascites. A recent prospective randomized study, Gynecologic Oncology Group (GOG) 262, enrolled patients after primary debulking surgery to accept 3-weekly conventional regimen or the JGOG 3016 protocol [16]. Participants in both arms were permitted to use bevacizumab. The PFSs were not different between two arms, but were different in the subgroups of patients who did not receive bevacizumab, in favor of the dose-dense arm. These results suggest that dose-dense chemotherapy and bevacizumab benefit patients through a similar mechanism, antiangiogenesis. In the GOG 262 trial, the JGOG 3016 protocol was used for first-line chemotherapy, and the current study as well as the reviewed papers regarding recurrent ovarian cancer might contribute proof to the theory that
W.-C. Chen et al. / Taiwanese Journal of Obstetrics & Gynecology 59 (2020) 21e27
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Table 5 Summary of the reviewed literature and the current study. Author
Regimen
Fennelly, 1997 [17] wkP 40e100 for median 10 cycles Abu-Rustum NR, wkP 60e100 for median 9 cycles 1997 [18] Ota, 2001 [19] wkP 70 for 20 wks (outpatient setting) Havrilesky, 2003 wkP 80 þ wkC AUC2 d1,8,15, q4wk [3]
N
ORR (%)
18 45
4/13 (30) 13 (28.9)
CR (%)
PFS month
OS month
All: 16 (55.2) PR: 1 (12.5) PS: 15 (71.0) 0
All: 11.5 PR: 3.2 PS: 13.7 6
PR: 11.4
All: 15 (24) PR: 3 (13) PS(6e12): 8 (42) PS(>12): 4 (20) 5 (13.65) 2 (6) 12 (48)
11
11 PR8; PS21
All: 24 (82.8) PR: 3 (37.5), PS: 21 (100) 14 (50)
Ghamande, 2003 wkP 80 for 6e8 wks 28 [20] Van der Burg, 2004 wkP 90 þ C AUC 4 d1,8,15,29,36,49 PR23 All: 48 (74) [21] þ6x PC q3wk PPS: 19, PS: 20 PR: 14 (61) PS(6e12): 16 (84) PS(>12): 16 (80) Kita, 2004 [22] wkP 80 d1,8,15, q4wk for 2 þ cycles 37 17 (45.9) Garcia, 2004 [23] wkP 80 þ wkG 1000 d1,8,15 q4wk PR 35 18 (40) Watanabe, 2005 wkP 60 þ wkC AUC2 d1,8,15 q4wk PS 25 22 (88) [24] Rose, 2005 [9] wkP 80 d1,8,15, C AUC 5 d1 q4wk PS 28 20 (71.5) 22 (81) Kikuchi, 2005 [25] wkP 80 þ wkC AUC 2 for median 13 27 courses vs. monthly chemotherapy Dunder, 2005 [26] wkP 80 for 6 wks q8wk for 3 cycles PR/TR 32 10 (31.2) Cohn, 2006 [27] wkP d1,8,15,22; BEV 10 d1, 15; 10 10 (100) q4wk Markman, 2006 wkP 80 d1,8,15 q4wk for 12wks PR/TR 48 10 (20.9) [28] then until PD Le, 2006 [29] wkP 60e80 for 24 wks PR 34 18 (53) Cardron, 2007 [30] wkP 90 þ wkC AUC 4 d1,8 q3wk PR9 All: 19 (66), PR: 3 PPS: 14, PS: 10 (38) PPS: 8 (73), PS: 8 (80) Byrd, 2007 [31] wkP (mean 11 wks; 54% 12 þ wks) 49 RECIST: 14 (28) GCIG: 31 (63) Watari, 2008 [12] wkP 80 d1,8,15 þ wkFU 500 16 wkT/FU: 5 (31.3) d2,9,16; q4wk Linch, 2008 [32] wkP 80e90 d1,8,15 q3w for 24wks 53 RECIST: 22 (42) (median 13 wks) GCIG: 36 (68) 13 (60) Sharma, 2009 [33] wkP 70 þ wkC AUC 3 d1,8,15 q4w 21 Refractory: 1 (25) for 4e6 cycles Refractory: 5, <6m: 7, >6m: 9 <6m: 2 (25), >6m: 5 (50) Hurt, 2009 [34] wkP 60e70 d1,8,15,21; 55 31 (60) BEV 10e15 d1,15, q4wk Hoekstra, 2009 [7] wkP 80 d1,8,15 þ C AUC 5 d1 q4wk PR5; All: 17 (85) PS15 PR: 3 (60), PS: 14 (93.3) PR10; 4 (33) Safra, 2010 [13] wkP80 d3,10,17 þ PS2 Gleevec 300 d1-4,8e11,13e18 q4wk O'malley, 2011 [35] wkP 60e70 d1,8,15,22 vs. Single 29 Single: 14 (48) wkP þ BEV 10e15 d1,15 Combine 41 Combine: 26 (41) Single: 20 (35) All PR/TR Lortholary, 2012 [8] Single: wkP 80 d1,8,15 q4wk C: 19 (37) Single: 56 C: vs. wkP þ C AUC 5 d1 q4wk Topo: vs. wkP þ wkTopo 3 d1,8,15 C: 51, Topo: 57 Topo: 22 (39) q4wk Cadron, 2013 [36] wkP 60 þ wkC AUC 2.7 for 18wks PR: 43 PR: 16 (37) PPS: 14, PS: 6 PPS: 5 (36), PS: 2 (40) Single: 17 (30.2) Poveda, 2015 [37] wkP 80 d1,8,15,22 q4wk All PR Combine: 33 (53.3) vs. wkP þ BEV 10 d1,15 q4wk Single: 55 Combine: 60 Osman, 2016 [38] wkP 80 d1,8,15, q4wk for 6 cycles All PR wkT: 30, wkT: 8 (27) vs. 3wkP 175 d1 q3wk for 6 cycles 3wT: 25 3wT: 4 (25) T: 461 Monk, 2016 [39] wkP 80 d1,8,15 þ weekly P: 458 Trebananib 15 d1,8,15,22 vs wkP þ weekly Placebo, q4wk All: 16 (93.75), Present study wkP 80 d1,8,15 þ C AUC 6 d1 q3wk PR:1 PR: 1 (100) PPS:6 PPS: 5 (83.33), PS:9 PS: 9 (100)
15 (53.6) 8 (29.6)
12 5.7 13.5
8þ
21 13.1
14 48.3
1 (3.1) 8 (80)
10.5 0
2 (4.2) 3 (9) All: 6 (21), PR: 1 (13) PPS: 2 (18),PS: 3 (30)
RECIST: 2 (4) GCIG: 9 (17) 0
13 (25)
6.1 All: 9, PR: 6.75 PPS: 10.5, PS: 12.75
10.43 All: 18 PR: 8
5
12
4.8
13.5
7.9 Refractory: 8.9 <6m: 5.5, >6m: 7.8
13.3 Refractory: 6.7 >6m: 10
7
12
All: 15 (75) All: 13 PR: 2 (40), PS: 13 (86.7) PR: 8, PS: 14 0
6.3
16.5
Single: 5 (17) Combine: 14 (34) Single: 3 (5) C: 7 (14) Topo: 6 (10)
Single: 6.2 Combine: 13.2 Single: 3.7 C: 4.8, Topo: 5.4 p ¼ 0.46
Single 9.1 Combine: 20.6 Single: 19.9 C: 15.2, Topo: 18.6 p ¼ 0.29
PR: 1 (6.2) PPS: 1 (7.1), PS: 1 (20)
PR: 6 PPS: 6, PS: 11
PR: 9 PS: 10, PS: 14
Single: 3.9 Combine: 10.4 with signifikance wkT: 7, 3wT: 4.5 p ¼ 0.02 T: 7.4, P: 5.4 p < 0.001
Single: 13.2 Combine: 22.4 with no significance wkT: 15.5, 3wT: 12.5 p ¼ 0.03 T: 19.3, P: 18.3 p < 0.52
All: 10.90, PR: 11.60 PPS: 6.93, PS: 13.43
All: 13.28, PR: 32.23 PPS: 9.50, PS: 20.23
wkT: 2 (7) 3wT: 0
All: 10 (62.5), PR: 1 (100) PPS: 3 (50), PS: 6 (66.67)
ORR: overall response rate, CR: complete response, PFS: progression-free survival, OS: overall survival, wkP: weekly paclitaxel, wkC: weekly carboplatin, qXw: q X week, wkG: weekly gemcitabine, wkFU: weekly 5-FU, SD: stable disease, PD: progressive disease, wkTopo: weekly topotecan, BEV: bevacizumab, PR: platinum-resistant, PPS: partially platinum-sensitive, PS: platinum-sensitive.
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increasing chemotherapeutic density through dose-dense administration generates an antiangiogenesis effect. Although the current dose-dense chemotherapy results in a high CR rate of 62.5%, the DFS of 5.6 months is still not satisfactory, and further prolonged therapy or maintenance therapy is required to consolidate satisfactory results. Several poly ADP- ribose polymerase inhibitors (PARPi) are used to extend the duration of response to chemotherapy, expressed as prolonged PFS [40]. Thus, patients in our study with high response may have chance to accept maintenance treatment with PARPi to prolonged PFS. Conclusion Although our retrospective study comprised small sample size, it achieved a high ORR (93.8%) and CR rate (62.5%), with tolerable toxicities. The findings of our report and the literature review suggest that dose-dense administration with paclitaxel, especially in combination with carboplatin, resulted in a highly favorable treatment response, probably through a mechanism of antiangiogenesis. However, consolidation therapy or maintenance therapy is required to prolong DFS. Prospective trials of a larger scale are necessary to validate our findings. Declaration of Competing Interest None. Acknowledgements This work was supported by the Chang-Gung Memorial Hospital integrated research project [CORPG3G0371]. The results of the current study were presented at the annual meeting of the Taiwan Association of Obstetrics and Gynecology, 2017. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.tjog.2019.10.003. References [1] Silverberg E, Boring CC, Squires TS. Cancer statistics, 1990. CA Cancer J Clin 1990;40:9e26. [2] Katsumata N, Yasuda M, Isonishi S, Takahashi F, Michimae H, Kimura E, et al. Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol 2013;14:1020e6. [3] Havrilesky LJ, Alvarez AA, Sayer RA, Lancaster JM, Soper JT, Berchuck A, et al. Weekly low-dose carboplatin and paclitaxel in the treatment of recurrent ovarian and peritoneal cancer. Gynecol Oncol 2003;88:51e7. [4] Enteprise Vocabulary Services NCI. NCI common terminology criteria for adverse events (CTCAE). 2010. [5] Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228e47. [6] Rustin GJ, Vergote I, Eisenhauer E, Pujade-Lauraine E, Quinn M, Thigpen T, et al. Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer 2011;21:419e23. [7] Hoekstra AV, Hurteau JA, Kirschner CV, Rodriguez GC. The combination of monthly carboplatin and weekly paclitaxel is highly active for the treatment of recurrent ovarian cancer. Gynecol Oncol 2009;115:377e81. [8] Lortholary A, Largillier R, Weber B, Gladieff L, Alexandre J, Durando X, et al. Weekly paclitaxel as a single agent or in combination with carboplatin or weekly topotecan in patients with resistant ovarian cancer: the CARTAXHY randomized phase II trial from Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO). Ann Oncol 2012;23:346e52.
[9] Rose PG, Smrekar M, Fusco N. A phase II trial of weekly paclitaxel and every 3 weeks of carboplatin in potentially platinum-sensitive ovarian and peritoneal carcinoma. Gynecol Oncol 2005;96:296e300. [10] Norton L, Simon R, Brereton HD, Bogden AE. Predicting the course of Gompertzian growth. Nature 1976;264:542e5. [11] Miller KD, Sweeney CJ, Sledge Jr GW. Redefining the target: chemotherapeutics as antiangiogenics. J Clin Oncol 2001;19:1195e206. [12] Watari H, Hosaka M, Mitamura T, Moriwaki M, Ohba Y, Todo Y, et al. Weekly paclitaxel/5-fluorouracil followed by platinum retreatment for patients with recurrent ovarian cancer: a single institution experience. Eur J Gynaecol Oncol 2008;29:573e7. [13] Safra T, Andreopoulou E, Levinson B, Borgato L, Pothuri B, Blank S, et al. Weekly paclitaxel with intermittent imatinib mesylate (Gleevec): tolerance and activity in recurrent epithelial ovarian cancer. Anticancer Res 2010;30: 3243e7. [14] Bolis G, Scarfone G, Polverino G, Raspagliesi F, Tateo S, Richiardi G, et al. Paclitaxel 175 or 225 mg per meters squared with carboplatin in advanced ovarian cancer: a randomized trial. J Clin Oncol 2004;22:686e90. [15] Pignata S, Scambia G, Katsaros D, Gallo C, Pujade-Lauraine E, Placido SD, et al. Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 2014;15:396e405. [16] Chan JK, Brady MF, Penson RT, Huang H, Birrer MJ, Walker JL, et al. Weekly vs. every-3-week paclitaxel and carboplatin for ovarian cancer. N Engl J Med 2016;374:738e48. [17] Fennelly D, Aghajanian C, Shapiro F, O'Flaherty C, McKenzie M, O'Connor C, et al. Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol 1997;15:187e92. [18] Abu-Rustum NR, Aghajanian C, Barakat RR, Fennelly D, Shapiro F, Spriggs D. Salvage weekly paclitaxel in recurrent ovarian cancer. Semin Oncol 1997;24. S15-62-s15-67. [19] Ota S, Sugiyama T, Komai K, Hirai N, Kumagai S, Ushijima K, et al. Weekly 1 hour paclitaxel infusion in patients with recurrent gynecological tumors: a pilot study. Jpn J Clin Oncol 2001;31:395e8. [20] Ghamande S, Lele S, Marchetti D, Baker T, Odunsi K. Weekly paclitaxel in patients with recurrent or persistent advanced ovarian cancer. Int J Gynecol Cancer 2003;13:142e7. [21] Burg MEVD, Vergote I, Burger CW, Gaast A. Phase II study of weekly paclitaxel carboplatin in the treatment of progressive ovarian cancer. J Clin Oncol 2004;22:5058. [22] Kita T, Kikuchi Y, Takano M, Suzuki M, Oowada M, Konno R, et al. The effect of single weekly paclitaxel in heavily pretreated patients with recurrent or persistent advanced ovarian cancer. Gynecol Oncol 2004;92: 813e8. [23] Garcia AA, O'Meara A, Bahador A, Facio G, Jeffers S, Kim DY, et al. Phase II study of gemcitabine and weekly paclitaxel in recurrent platinum-resistant ovarian cancer. Gynecol Oncol 2004;93:493e8. [24] Watanabe Y, Nakai H, Ueda H, Hoshiai H. Evaluation of weekly low-dose paclitaxel and carboplatin treatment for patients with platinum-sensitive relapsed ovarian cancer. Gynecol Oncol 2005;96:323e9. [25] Kikuchi A, Sakamoto H, Yamamoto T. Weekly carboplatin and paclitaxel is safe, active, and well tolerated in recurrent ovarian cancer cases of Japanese women previously treated with cisplatin-containing multidrug chemotherapy. Int J Gynecol Cancer 2005;15:45e9. [26] Dunder I, Berker B, Atabekoglu C, Bilgin T. Preliminary experience with salvage weekly paclitaxel in women with advanced recurrent ovarian carcinoma. Eur J Gynaecol Oncol 2005;26:79e82. [27] Cohn DE, Valmadre S, Resnick KE, Eaton LA, Copeland LJ, Fowler JM. Bevacizumab and weekly taxane chemotherapy demonstrates activity in refractory ovarian cancer. Gynecol Oncol 2006;102:134e9. [28] Markman M, Blessing J, Rubin SC, Connor J, Hanjani P, Waggoner S. Phase II trial of weekly paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian and primary peritoneal cancers: a Gynecologic Oncology Group study. Gynecol Oncol 2006;101:436e40. [29] Le T, Hopkins L, Baines KA, Rambout L, Al Hayki M, Kee Fung MF. Prospective evaluations of continuous weekly paclitaxel regimen in recurrent platinumresistant epithelial ovarian cancer. Gynecol Oncol 2006;102:49e53. [30] Cadron I, Leunen K, Amant F, Van Gorp T, Neven P, Vergote I. The "Leuven" dose-dense paclitaxel/carboplatin regimen in patients with recurrent ovarian cancer. Gynecol Oncol 2007;106:354e61. [31] Byrd L, Thistlethwaite FC, Clamp A, Ton C, Hasan J, Jayson GC. Weekly paclitaxel in the treatment of recurrent ovarian carcinoma. Eur J Gynaecol Oncol 2007;28:174e8. [32] Linch M, Stavridi F, Hook J, Barbachano Y, Gore M, Kaye SB. Experience in a UK cancer centre of weekly paclitaxel in the treatment of relapsed ovarian and primary peritoneal cancer. Gynecol Oncol 2008;109:27e32. [33] Sharma R, Graham J, Mitchell H, Brooks A, Blagden S, Gabra H. Extended weekly dose-dense paclitaxel/carboplatin is feasible and active in heavily pretreated platinum-resistant recurrent ovarian cancer. Br J Cancer 2009;100: 707e12. [34] Hurt JD, Richardson DL, Seamon LG, Fowler JF, Copeland LJ, Cohn DE, et al. Sustained progression-free survival with weekly paclitaxel and bevacizumab in recurrent ovarian cancer. Gynecol Oncol 2009;115:396e400.
W.-C. Chen et al. / Taiwanese Journal of Obstetrics & Gynecology 59 (2020) 21e27 [35] O'Malley DM, Richardson DL, Rheaume PS, Salani R, Eisenhauer EL, McCann GA, et al. Addition of bevacizumab to weekly paclitaxel significantly improves progression-free survival in heavily pretreated recurrent epithelial ovarian cancer. Gynecol Oncol 2011;121:269e72. [36] Cadron I, Abdulkadir L, Despierre E, Berteloot P, Neven P, Leunen K, et al. The "Leuven" paclitaxel/carboplatin weekly regimen in patients with recurrent ovarian cancer, a retrospective study. Gynecol Oncol 2013;128:34e7. [37] Poveda AM, Selle F, Hilpert F, Reuss A, Savarese A, Vergote I, et al. Bevacizumab combined with weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan in platinum-resistant recurrent ovarian cancer: analysis by chemotherapy cohort of the randomized phase III AURELIA trial. J Clin Oncol 2015;33:3836e8.
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[38] Osman MA, Elkady MS, Nasr KE. Weekly paclitaxel versus three-weekly paclitaxel in recurrent platinum-resistant epithelial ovarian and peritoneal cancers: a phase III study. Clin Med Insights Oncol 2016;10:35e41. [39] Monk BJ, Poveda A, Vergote I, Raspagliesi F, Fujiwara K, Bae DS, et al. Final results of a phase 3 study of trebananib plus weekly paclitaxel in recurrent ovarian cancer (TRINOVA-1): long-term survival, impact of ascites, and progression-free survival-2. Gynecol Oncol 2016;143:27e34. [40] Mittica G, Ghisoni E, Giannone G, Genta S, Aglietta M, Sapino A, et al. PARP inhibitors in ovarian cancer. Recent Pat Anti-Cancer Drug Discov 2018;13: 392e410.
Contents lists available at ScienceDirect
Taiwanese Journal of Obstetrics & Gynecology journal homepage: www.tjog-online.com
Original Article
Dose-dense chemotherapy with weekly paclitaxel and 3-weekly carboplatin for recurrent ovarian cancer Wei-Chun Chen a, b, Huei-Jean Huang a, b, Ting-Chang Chang a, b, Hung-Hsueh Chou a, b, * a b
Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Linkou, Taiwan Chang Gung University, College of Medicine, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 23 September 2019
Objective: To analyze the response to dose-dense chemotherapy of weekly paclitaxel and 3-weekly carboplatin in recurrent ovarian cancer, and to report results of literature review. Materials and methods: Patients accepted weekly paclitaxel 80 mg/m2 on day 1, 8, 15 and carboplatin on day1 at area under curve (AUC) 6 every 21 days were reviewed for the response rate, progression-free survival, overall survival, and toxicity during January 2012 to April 2016 in Chang Gung Memorial Hospital at Linkou, Taiwan. Results: Sixteen patients with recurrent ovarian cancer, including 1 platinum-resistant, 7 partially platinum-sensitive, and 8 platinum-sensitive, accepted a median of 6 cycles of chemotherapy (range 3 e10). The overall response rate (ORR) and complete response (CR) rate were 93.8%, and 62.5%, respectively. The median PFS of all patients were 10.9 months (range 4.3e40.5). The median time to response (TTR) was 29.0 days (range 19.6e38.4). The median disease-free survival (DFS) after CR was 5.6 months (range 1.2e34.2). Grade 3 at least toxicity included anemia (6.3%), neutropenia (50%), and thrombocytopenia (18.8%). Twenty-nine articles on phase I, II, III, or retrospective studies of dose-dense chemotherapy with weekly paclitaxel were reviewed. Conclusion: This is the first report using Japanese Gynecologic Oncology Group 3016 protocol, weekly paclitaxel and 3-weely carboplatin, on recurrent ovarian cancer. The current study showed high ORR and CR with tolerable toxicities. Our study suggested dose-dense chemotherapy with paclitaxel, especially combining carboplatin created high efficacy probably by anti-angiogenesis. However, consolidation or maintenance therapy is needed to prolong DFS. © 2020 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Dose-dense chemotherapy Metronomic chemotherapy Weekly paclitaxel Carboplatin Recurrent ovarian cancer
Introduction Of all gynecologic malignancies, ovarian cancer is one of the most prevalent and the leading cause of death. The standard primary treatment for ovarian cancer is cytoreductive surgery and combination chemotherapy with platinum and paclitaxel administered through a conventional 3-weekly or dose-dense schedule [1]. Dose-dense chemotherapy with carboplatin at an area under the curve (AUC) of 6 on day 1 and paclitaxel at 80 mg/
* Corresponding author. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Linkou, #5 Fushing Street, Kwei-Shan, Taoyuan 333, Taiwan. E-mail address: [email protected] (H.-H. Chou).
m2 on days 1, 8, and 15 is superior to 3-weekly carboplatin and paclitaxel in progression-free survival (PFS) and overall survival (OS) as first-line chemotherapy [2]. Approximately 50%e80% of patients obtain a complete response (CR) after operation and firstline chemotherapy [1], but about 70% of them experience recurrent disease that requires salvage chemotherapy [3]. Salvage chemotherapy renders response rate of 47%e67% in patients who are platinum sensitive and 10%e30% in patients who are platinum resistant. Owing to dose-dense chemotherapy resulted in longer survival time, we implemented it to recurrent ovarian cancer as an additional option. The purpose of this retrospective study was to analyze the response to dose-dense chemotherapy with weekly paclitaxel and 3-weekly carboplatin in patients with recurrent ovarian cancer and to review the literature.
https://doi.org/10.1016/j.tjog.2019.10.003 1028-4559/© 2020 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
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Materials and methods
Response and progress
Patients and study design
The primary outcomes of interest were the response rate (RR), PFS, and OS. Other outcomes included toxicity and safety. The therapeutic response of measurable lesions was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 by CT scans or MRI imaging [5]. For patients without measurable lesions in the imaging study or without an image study after treatment, the response was assessed according to CA-125 values following the Rustin criteria. The overall response rate (ORR) was the summation of CR and partial response (PR), and was calculated from the results of RECIST and CA-125 criteria according to the Gynecological Cancer Intergroup study by Rustin in 2011 [6]. The time to response (TTR) was calculated from the beginning of the salvage treatment to the date when the tumor marker declined to half of its pretreatment level. The PFS was the duration between the beginning of chemotherapy and the occurrence of the first evidence of disease progression, and OS was the length of time between the beginning of chemotherapy and death. Among patients with a CR, disease-free survival (DFS) was calculated from a confirmation of complete remission to disease progression or death.
We retrospectively reviewed our patients with recurrent ovarian, fallopian tube, or peritoneal carcinoma treated with paclitaxel-based dose-dense chemotherapy at Chang Gung Memorial Hospital from January 2012 to January 2016. The patients enrolled in our study satisfied the following conditions: (1) a confirmed pathology of ovarian, fallopian tube, or primary peritoneal carcinoma; (2) recurrence after at least one line of chemotherapy with platinum and taxane; (3) an elevated tumor marker, cancer antigen 125 (CA-125), or recurrent lesions demonstrated by an image study, such as computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET). This retrospective study was conducted with the approval of an institutional review board (IRB) (IRB number 201700944B0). The clinical data included age at diagnosis, the initial stage according to the International Federation of Gynecology and Obstetrics (FIGO) staging system, residual tumors after primary debulking operation, the front-line chemotherapeutic combination, lines of prior chemotherapy, and associated hematologic and nonhematologic adverse events. Levels of the tumor marker CA125 at diagnosis, prior to and during the current salvage chemotherapy, and during follow-up were evaluated. The pathologic reports revealed the primary tumor origin, histologic cell type, and histology grade. The progression-free interval (PFI) was defined as the duration between the last platinum administration of front-line chemotherapy and the first cancer relapse. A patient was defined as platinum resistant if the PFI was less than 6 months, partially platinum sensitive if the PFI was between 6 and 12 months, and platinum sensitive if the PFI was over 12 months. For patients undergoing more than one line of chemotherapy, secondary chemotherapeutic sensitivity was defined on the basis of whether the duration from the last treatment to next recurrence was longer than 6 months. The completeness of cytoreduction (CC) score was defined as follows: CC-0: no visible residual lesions; CC-1: largest residual lesions less than 2.5 mm; CC2: residual lesion size between 2.5 mm and 2.5 cm; CC-3: any residual lesion over 2.5 cm. An optimal debulking operation was defined as all residual lesions less than 1 cm. Chemotherapy regimens Our patients accepted dose-dense chemotherapy with intravenous carboplatin at an AUC of 6 on day 1 and weekly paclitaxel at 80 mg/m2 on days 1, 8, and 15 every 21 days. The duration of therapy depended on the disease status, the patient's response, toxicity, and clinical performance. A complete blood count including a white blood cell count S 2500/uL, absolute neutrophil count S 1500/uL, hemoglobin S 9 g/dL, and platelet count S 100,000/mL was required for chemotherapy. To keep chemotherapy on schedule, leukopenia was corrected with granulocyte colony stimulating factor, and anemia with blood transfusion. Safety and toxicity Safety and adverse events (AEs) were recorded at every visit until 30 days after the last chemotherapy. The patient-based safety and AEs were accessed using the Common Terminology Criteria for Adverse Events, version 4.0 [4]. A routine hematologic evaluation and nonhematologic toxicity assessment were performed before every combined or single-agent chemotherapy.
Literature review We searched for relevant literature in the PubMed and Medline databases by using Medical Subject Headings related to recurrent ovarian cancer, weekly paclitaxel, and dose-dense chemotherapy. Statistical analysis PFS and OS were analyzed and represented using a KaplaneMeier Curve. The differences in PFS and OS among groups were calculated using a log-rank test. The data of patients that were platinum sensitive and those that were platinum resistant were compared through a paired t test and chi-square test. The analyses were considered to be significant when the p value was less than 0.05. Results Patients and treatments From 2012 to April 2016, the data of 18 patients were retrospectively collected at Chang Gung Memorial Hospital in Linkou, Taiwan. Two patients were excluded due to miscoding of disease or nonrecurrent disease, and 16 patients were eligible for the current study. The patient characteristics are shown in Table 1, and the treatment profiles are listed in Table 2. The median age was 53 years (range 32e64). Fourteen patients (93.3%) had high-grade serous carcinomas, 1 had clear cell carcinoma, and 1 was missing data on the cell type due to previous records at a local hospital being unobtainable. All 16 participants had stage 3 (N ¼ 13, 81.3%) or stage 4 disease (N ¼ 3, 19.8%). One (6.3%) patient was platinum resistant and 15 patients were platinum sensitive to the initial chemotherapy, with 7 (43.8%) being partially platinum sensitive and 8 (50%) being platinum sensitive. The number of lines of previous chemotherapy was one regimen for 7 cases (7/16 ¼ 43.5%), two regimens for 4 cases (4/16 ¼ 25%) and more than two regimen for 5 cases (5/16 ¼ 31.3%). Three patients had received hyperthermic intraoperative chemotherapy (HIPEC) at 42 Ce43 C, with 320 mg of paclitaxel and 160 mg of cisplatin for a lavage time of 60 min during their second debulking operations. Seven of the 16 patients (43.8%) had undergone a previous line of chemotherapy within 6 months, and were deemed as secondary platinum
W.-C. Chen et al. / Taiwanese Journal of Obstetrics & Gynecology 59 (2020) 21e27 Table 1 Patient characteristics.
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Table 3 Treatment response related to chemotherapy line and platinum sensitivity.
Characteristics
Number (percentage)
Patients Age at diagnosis (years) Median (Range) Histology HGSC Clear cell carcinoma Uncertain Initial FIGO stage Stage 3 Stage 4 Complete cytoreduction (CC) score CC 0 CC 1 CC 2-3 Uncertain Platinum sensitivity Resistant Sensitive-PFI of 6e12 months Sensitive-PFI of >12 months Prior regimens of chemotherapy 1 2 >2
16
Line of previous C/T 1 2 S3 Platinum sensitivity Resistant PFI 6e12 months PFI > 12 months All
53 (32e64) 14 (87.5) 1 (6.3) 1 (6.3) 13 (81.3) 3 (19.7) 6 2 3 5
Pt No
ORR (%)
CR (%)
PR (%)
SD (%)
PD (%)
7 4 5
6 (85.7) 4 (100) 5 (100)
6 (85.7) 2 (50) 2 (40)
0 2 (50) 3 (60)
0 0 0
1 (14.3) 0 0
1 7 8 16
1 (100) 6 (85.7) 8 (100) 15 (93.8)
1 (100) 4 (57.1) 5 (62.5) 10 (62.5)
0 2 (28.6) 3 (37.5) 5 (31.3)
0 0 0 0
0 1 (14.3) 0 1 (6.25)
C/T: chemotherapy, P-Resistant: platinum-resistant, PFI: progression-free interval, ORR: overall response rate, CR: complete response, PR: partial response, SD: stable disease.
(37.5) (12.5) (18.8) (31.3)
100%, and 100%, and the CR rates were 85.7%, 50%, and 40%, respectively (Table 3). For platinum resistant, partially platinum sensitive, and platinum sensitive patients, the ORRs were 100%, 85.7%, and 100%, and the CR rates were 100%, 57.1%, and 62.5%, respectively. The 5 most heavily pretreated patients had a 100% ORR and a 40% CR rate. The only platinum-resistant patient who had received 4 lines of previous chemotherapy obtained a CR after 10 cycles of current dose-dense chemotherapy. TTRs for complete responders and partial responders were 22 days (range 15e74) and 30 days (range 21e56) (p ¼ 0.856). A decline of CA125 by 50% occurred after the first cycle of dose-dense chemotherapy in most of our patients, as shown in the supplementary material (S1). The OS data are not available yet. The median follow-up time of the alive patients was 22.1 months (range 6.2e51.1). The median PFS of all patients was 10.9 months (range 4.3e40.5), and there was a trend difference (p ¼ 0.049) in favor of platinum-sensitive (median 13.2 months, range 5.4e39.9) rather than partially platinumsensitive (median 7.9 months, range 4.3e16.3) patients. The median OS period from the start of treatment was 21.8 months (95% CI, 12.7e30.8) and 13.0 months (95% CI, 6.6e19.4) for platinumsensitive and partially platinum-sensitive patients, respectively (p ¼ 0.163). Complete responders had a significantly longer median survival time than partial responders, with a PFS of 12.7 months (range 4.9e40.5) versus 6.2 months (range 4.3e13.4) (p ¼ 0.029) (Data shown in supplementary material e S2). The median DFS of
1 (6.2) 7 (43.8) 8 (50.0) 7 (43.8) 4 (25) 5 (31.2)
HGSC: high-grade serous carcinoma, CC: completeness of cytoreduction, CC-0: no visible residual lesions, CC-1: largest residual lesions less than 2.5 mm, CC-2: residual nodular size between 2.5 mm and 2.5 cm, CC-3: any residual lesion over 2.5 cm, PFI: platinum-free interval.
resistant. Among these 7 patients, 5 were the most heavily pretreated, receiving more than 3 lines of chemotherapy. Treatments and response The median number of cycles of dose-dense chemotherapy was 6 (range 3e10), and the total cycle number was 98 in all 16 patients. The median follow-up time was 14.9 months (range 6.2e51.1). At the time of analysis, 7 patients were alive with disease, 2 patients remained alive with no evidence of disease, and 7 patients died of disease. Among the 16 cases, there were 10 CRs (62.5%) and 5 PRs (31.3%), amounting to an ORR of 93.8%. For patients with 1, 2, and more than 2 lines of previous chemotherapy, the ORRs were 85.7%,
Table 2 Patient treatment profiles. Patient Age at diagnosis FIGO stage Histology Gr
CC score Initial PFI month Prior lines of C/T DDC cycle Response TTRy days PFS month OS* month status
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
NA CC2 NA CC3 NA CC3 CC0 CC0 CC1 CC0 CC1 CC0 NA CC0 CC0 NA
56 46 44 54 32 52 58 58 55 58 64 50 57 42 48 49
3 3C 3B 3C 3C 4 3C 3C 3C 3C 4 3C 3C 3C 3C 4
HGSC HGSC NA HGSC HGSC HGSC HGSC HGSC HGSC HGSC HGSC HGSC HGSC HGSC HGSC CLC
3 3 NA 3 3 3 3 3 3 3 3 3 3 3 3 NA
6.3 17.8 8.1 7.5 14.4 10.5 5.6 9.6 22.8 17.2 8.8 26.9 16.3 92.7 28.8 42.3
1 2 3 1 1 1 4 4 2 2 7 2 3 1 1 1
6 10 10 6 5 6 8 3 9 5 6 6 3 5 6 4
PD CR CR CR CR CR CR PR PR PR PR CR PR CR CR CR
15 66 19 21 22 74 21 30 56 43 29 23 52
6.9 31.6 16.5 10.9 17.1 8.5 11.6 4.3 13.4 5.5 8 12.7 6.2 4.9 13.87 40.5
22.1 13.2 12.1 32.2
11.9
20.2 15.1
AWD AWD DOD DOD AWD DOD DOD AWD AWD DOD AWD AWD DOD NED DOD NED
DDC: dose-dense chemotherapy, HGSC: high-grade serous carcinoma, CLC: clear cell carcinoma, CC score: completeness of cytoreduction score, CC-0: no visible residual lesions, CC-1: largest residual lesions less than 2.5 mm, CC-2: residual nodular size between 2.5 mm and 2.5 cm, CC-3: any residual lesion over 2.5 cm, PFI: platinum-free interval, C/T: chemotherapy, PFS: progression-free survival, OS: overall survival, HGSC: high-grade serous carcinoma, HIPEC: hyperthermic intraperitoneal chemotherapy, PD: progressive disease, CR: complete response, PR: partial response, G2/G3/G4: grade 2/grade 3/grade 4, AWD: alive with disease, DOD: died of disease, NED: no evidence of disease, GI: gastrointestinal, NA: not available, *Nine patients were still alive, and the calculated OS values were 6.2, 7.6, 9.5, 13.6, 17.1, 20.7, 22.1, 40.5, and 51.8 months. yThree patients did not have a TTR due to 1 being a non-responder and the other 2 patients having an initial CA-125 within the normal limitation.
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Table 4 Survival related to previous treatment history. Variants
Numbers
Median PFS (months)
PFS HR (95% CI)
Overall response N (%)
Cytoreduction CC 0 CC 1 at least
6 5
5.5 (4.9e13.9) 10.9 (8.0e31.6) p ¼ 0.415
Reference 0.6 (0.2e2.1) p ¼ 0.420
6 (100) 5 (100)
Prior lines of chemotherapy 1e2 3 at least
11 5
12.7 (4.9e40.5) 8.0 (4.3e16.5) p ¼ 0.221
Reference 2.0 (0.7e6.2) p ¼ 0.230
10 (90.9) 5 (100) p ¼ 0.486
Age at diagnosis 50 years >50 years
7 9
16.5 (4.9e40.5) 8.0 (4.3e13.4) p ¼ 0.003
Reference 8.3 (1.7e41.3) p ¼ 0.010
7 (100) 8 (88.9) p ¼ 0.362
CC: completeness of cytoreduction, CC-0: no visible residual lesions, CC-1: largest residual lesions less than 2.5 mm, CC-2: residual nodular size between 2.5 mm and 2.5 cm, CC-3: any residual lesion over 2.5 cm, PFS: progression-free survival, HR: hazard ratio, CI: confidence interval.
the patients with a CR was 5.6 months (range 1.2e34.2). Table 4 illustrates the difference in survival rates between categories determined through a log-rank test. Compared with patients aged over 50, patients under 50 had a significantly longer PFS. Safety and adverse events The associated AEs of grade 3 at least are summarized in the supplementary material (S3). In our cohort, the AEs of grade 3 at least were all hematology-related toxicity including 1 case of (6.25%) anemia, 8 (50%) cases of neutropenia, and 8 (30.8%) cases of thrombocytopenia. An episode of grade 2 allergic reaction including generalized rash with pruritus occurred in 1 patient at her sixth cycle of carboplatin treatment and was relieved after discontinuation of medication and steroid administration. One patient abandoned her therapy at the ninth cycle due to suspected drug-related grade 4 liver toxicity, with aspartate aminotransferase at 704 U/L and alanine aminotransferase at 1358 U/L. No grade 5 AEs were recorded in our study. Literature review We reviewed 29 papers about dose-dense chemotherapy using paclitaxel for recurrent ovarian cancer in the literature and classified them into 5 categories (Table 5). These categories were singleagent weekly paclitaxel (N ¼ 11), weekly paclitaxel and weekly carboplatin (N ¼ 7), weekly paclitaxel and 3-weekly or 4-weekly carboplatin (N ¼ 4), weekly paclitaxel and other chemotherapy (N ¼ 2), and weekly paclitaxel and targeted therapy (N ¼ 6). The ORRs of 11 single-agent weekly paclitaxel studies ranged from 20.9% to 68%, and the CR rates ranged from 0% to 27%. The ORRs of 7 weekly paclitaxel and weekly carboplatin studies ranged from 35% to 100%, and the CR rates ranged from 7.8% to 71%. Three studies of weekly paclitaxel (3 weeks on, 1 week off) and 4-weekly carboplatin conducted by Rose, Hoekstra, and Lortholary reported ORRs of 71.5%, 93.3%, and 37%, and CR rates of 53.6%, 86.7%, and 14%, respectively [7e9]. Discussion A higher dose intensity of chemotherapy potentiates tumor killing ability, and this could be achieved by increasing the amount of the drug at each administration or by dose-dense administration at a shorter interval. Two theories explain how dose-dense chemotherapy enhances antitumor activity. The first is based on the log-kill model suggested by Skipper, Schabel, and Wilcox and the growth kinetics model developed by Gompertzian [10]. Skipper, Schabel, and Wilcox suggested that tumors with rapid growth are
more vulnerable to cytotoxic chemotherapy. Gompertzian surmised that tumors grow faster when they are small, and growth slows after they become larger. Dose-dense administration was considered to kill small-volume tumors through frequent exposure to drugs in the sensitive part of cell cycles such as the S phase, to reduce the tumor burden in the G0 phase. The second theory is based on metronomic chemotherapy, stating that frequent lowdose drug administration defers tumor angiogenesis through microtubule disruption and reduction of vascular endothelial growth factor and interleukin-8 [11]. Katsumata et al. reported the results of the Japanese Gynecologic Oncology Group (JGOG) 3016 that dose-dense chemotherapy with carboplatin at an AUC of 6 on day 1 and paclitaxel at 80 mg/m2 on days 1, 8, and 15 was superior to conventional 3-weekly carboplatin and paclitaxel in PFS and OS, exhibiting a 29% lower risk of disease progression and a 25% lower risk of death [12,13]. The cumulative dose of paclitaxel in each cycle, 240 mg/m2 in the JGOG 3016 protocol, is higher than 180 mg/m2 in the conventional 3weekly regimen. Bolis et al., in their phase III trial, did not see the survival benefit of paclitaxel at a dose of 225 mg/m2 over 175 mg/ m2 every 3 weeks [14]. The MITO-7 compared fractionated dose of both carboplatin (AUC2) and paclitaxel (60 mg/m2) given weekly and standard three-weekly regimen to show almost same median progression-free survival (18.3 months vs 17.3 months) [15]. Therefore, we speculate that the survival benefit of the JGOG 3016 protocol in the current study probably resulted from both the higher dose density and increased cumulative paclitaxel dose. For recurrent ovarian cancer, the papers we reviewed also indicated that dose-dense chemotherapy with a combination of carboplatin and paclitaxel generated a higher RR than other regimens. To the best of our knowledge, our study is the first one to use the JGOG 3016 protocol for recurrent ovarian cancer, and the ORR of 93.8% was only next to that reported by Havrilesky (100%). Even the 5 heavily pretreated patients exhibited a 100% ORR and a 40% CR rate. The high RR not only prolonged survival but also improved quality of life by relieving clinical symptoms, including ascites. A recent prospective randomized study, Gynecologic Oncology Group (GOG) 262, enrolled patients after primary debulking surgery to accept 3-weekly conventional regimen or the JGOG 3016 protocol [16]. Participants in both arms were permitted to use bevacizumab. The PFSs were not different between two arms, but were different in the subgroups of patients who did not receive bevacizumab, in favor of the dose-dense arm. These results suggest that dose-dense chemotherapy and bevacizumab benefit patients through a similar mechanism, antiangiogenesis. In the GOG 262 trial, the JGOG 3016 protocol was used for first-line chemotherapy, and the current study as well as the reviewed papers regarding recurrent ovarian cancer might contribute proof to the theory that
W.-C. Chen et al. / Taiwanese Journal of Obstetrics & Gynecology 59 (2020) 21e27
25
Table 5 Summary of the reviewed literature and the current study. Author
Regimen
Fennelly, 1997 [17] wkP 40e100 for median 10 cycles Abu-Rustum NR, wkP 60e100 for median 9 cycles 1997 [18] Ota, 2001 [19] wkP 70 for 20 wks (outpatient setting) Havrilesky, 2003 wkP 80 þ wkC AUC2 d1,8,15, q4wk [3]
N
ORR (%)
18 45
4/13 (30) 13 (28.9)
CR (%)
PFS month
OS month
All: 16 (55.2) PR: 1 (12.5) PS: 15 (71.0) 0
All: 11.5 PR: 3.2 PS: 13.7 6
PR: 11.4
All: 15 (24) PR: 3 (13) PS(6e12): 8 (42) PS(>12): 4 (20) 5 (13.65) 2 (6) 12 (48)
11
11 PR8; PS21
All: 24 (82.8) PR: 3 (37.5), PS: 21 (100) 14 (50)
Ghamande, 2003 wkP 80 for 6e8 wks 28 [20] Van der Burg, 2004 wkP 90 þ C AUC 4 d1,8,15,29,36,49 PR23 All: 48 (74) [21] þ6x PC q3wk PPS: 19, PS: 20 PR: 14 (61) PS(6e12): 16 (84) PS(>12): 16 (80) Kita, 2004 [22] wkP 80 d1,8,15, q4wk for 2 þ cycles 37 17 (45.9) Garcia, 2004 [23] wkP 80 þ wkG 1000 d1,8,15 q4wk PR 35 18 (40) Watanabe, 2005 wkP 60 þ wkC AUC2 d1,8,15 q4wk PS 25 22 (88) [24] Rose, 2005 [9] wkP 80 d1,8,15, C AUC 5 d1 q4wk PS 28 20 (71.5) 22 (81) Kikuchi, 2005 [25] wkP 80 þ wkC AUC 2 for median 13 27 courses vs. monthly chemotherapy Dunder, 2005 [26] wkP 80 for 6 wks q8wk for 3 cycles PR/TR 32 10 (31.2) Cohn, 2006 [27] wkP d1,8,15,22; BEV 10 d1, 15; 10 10 (100) q4wk Markman, 2006 wkP 80 d1,8,15 q4wk for 12wks PR/TR 48 10 (20.9) [28] then until PD Le, 2006 [29] wkP 60e80 for 24 wks PR 34 18 (53) Cardron, 2007 [30] wkP 90 þ wkC AUC 4 d1,8 q3wk PR9 All: 19 (66), PR: 3 PPS: 14, PS: 10 (38) PPS: 8 (73), PS: 8 (80) Byrd, 2007 [31] wkP (mean 11 wks; 54% 12 þ wks) 49 RECIST: 14 (28) GCIG: 31 (63) Watari, 2008 [12] wkP 80 d1,8,15 þ wkFU 500 16 wkT/FU: 5 (31.3) d2,9,16; q4wk Linch, 2008 [32] wkP 80e90 d1,8,15 q3w for 24wks 53 RECIST: 22 (42) (median 13 wks) GCIG: 36 (68) 13 (60) Sharma, 2009 [33] wkP 70 þ wkC AUC 3 d1,8,15 q4w 21 Refractory: 1 (25) for 4e6 cycles Refractory: 5, <6m: 7, >6m: 9 <6m: 2 (25), >6m: 5 (50) Hurt, 2009 [34] wkP 60e70 d1,8,15,21; 55 31 (60) BEV 10e15 d1,15, q4wk Hoekstra, 2009 [7] wkP 80 d1,8,15 þ C AUC 5 d1 q4wk PR5; All: 17 (85) PS15 PR: 3 (60), PS: 14 (93.3) PR10; 4 (33) Safra, 2010 [13] wkP80 d3,10,17 þ PS2 Gleevec 300 d1-4,8e11,13e18 q4wk O'malley, 2011 [35] wkP 60e70 d1,8,15,22 vs. Single 29 Single: 14 (48) wkP þ BEV 10e15 d1,15 Combine 41 Combine: 26 (41) Single: 20 (35) All PR/TR Lortholary, 2012 [8] Single: wkP 80 d1,8,15 q4wk C: 19 (37) Single: 56 C: vs. wkP þ C AUC 5 d1 q4wk Topo: vs. wkP þ wkTopo 3 d1,8,15 C: 51, Topo: 57 Topo: 22 (39) q4wk Cadron, 2013 [36] wkP 60 þ wkC AUC 2.7 for 18wks PR: 43 PR: 16 (37) PPS: 14, PS: 6 PPS: 5 (36), PS: 2 (40) Single: 17 (30.2) Poveda, 2015 [37] wkP 80 d1,8,15,22 q4wk All PR Combine: 33 (53.3) vs. wkP þ BEV 10 d1,15 q4wk Single: 55 Combine: 60 Osman, 2016 [38] wkP 80 d1,8,15, q4wk for 6 cycles All PR wkT: 30, wkT: 8 (27) vs. 3wkP 175 d1 q3wk for 6 cycles 3wT: 25 3wT: 4 (25) T: 461 Monk, 2016 [39] wkP 80 d1,8,15 þ weekly P: 458 Trebananib 15 d1,8,15,22 vs wkP þ weekly Placebo, q4wk All: 16 (93.75), Present study wkP 80 d1,8,15 þ C AUC 6 d1 q3wk PR:1 PR: 1 (100) PPS:6 PPS: 5 (83.33), PS:9 PS: 9 (100)
15 (53.6) 8 (29.6)
12 5.7 13.5
8þ
21 13.1
14 48.3
1 (3.1) 8 (80)
10.5 0
2 (4.2) 3 (9) All: 6 (21), PR: 1 (13) PPS: 2 (18),PS: 3 (30)
RECIST: 2 (4) GCIG: 9 (17) 0
13 (25)
6.1 All: 9, PR: 6.75 PPS: 10.5, PS: 12.75
10.43 All: 18 PR: 8
5
12
4.8
13.5
7.9 Refractory: 8.9 <6m: 5.5, >6m: 7.8
13.3 Refractory: 6.7 >6m: 10
7
12
All: 15 (75) All: 13 PR: 2 (40), PS: 13 (86.7) PR: 8, PS: 14 0
6.3
16.5
Single: 5 (17) Combine: 14 (34) Single: 3 (5) C: 7 (14) Topo: 6 (10)
Single: 6.2 Combine: 13.2 Single: 3.7 C: 4.8, Topo: 5.4 p ¼ 0.46
Single 9.1 Combine: 20.6 Single: 19.9 C: 15.2, Topo: 18.6 p ¼ 0.29
PR: 1 (6.2) PPS: 1 (7.1), PS: 1 (20)
PR: 6 PPS: 6, PS: 11
PR: 9 PS: 10, PS: 14
Single: 3.9 Combine: 10.4 with signifikance wkT: 7, 3wT: 4.5 p ¼ 0.02 T: 7.4, P: 5.4 p < 0.001
Single: 13.2 Combine: 22.4 with no significance wkT: 15.5, 3wT: 12.5 p ¼ 0.03 T: 19.3, P: 18.3 p < 0.52
All: 10.90, PR: 11.60 PPS: 6.93, PS: 13.43
All: 13.28, PR: 32.23 PPS: 9.50, PS: 20.23
wkT: 2 (7) 3wT: 0
All: 10 (62.5), PR: 1 (100) PPS: 3 (50), PS: 6 (66.67)
ORR: overall response rate, CR: complete response, PFS: progression-free survival, OS: overall survival, wkP: weekly paclitaxel, wkC: weekly carboplatin, qXw: q X week, wkG: weekly gemcitabine, wkFU: weekly 5-FU, SD: stable disease, PD: progressive disease, wkTopo: weekly topotecan, BEV: bevacizumab, PR: platinum-resistant, PPS: partially platinum-sensitive, PS: platinum-sensitive.
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W.-C. Chen et al. / Taiwanese Journal of Obstetrics & Gynecology 59 (2020) 21e27
increasing chemotherapeutic density through dose-dense administration generates an antiangiogenesis effect. Although the current dose-dense chemotherapy results in a high CR rate of 62.5%, the DFS of 5.6 months is still not satisfactory, and further prolonged therapy or maintenance therapy is required to consolidate satisfactory results. Several poly ADP- ribose polymerase inhibitors (PARPi) are used to extend the duration of response to chemotherapy, expressed as prolonged PFS [40]. Thus, patients in our study with high response may have chance to accept maintenance treatment with PARPi to prolonged PFS. Conclusion Although our retrospective study comprised small sample size, it achieved a high ORR (93.8%) and CR rate (62.5%), with tolerable toxicities. The findings of our report and the literature review suggest that dose-dense administration with paclitaxel, especially in combination with carboplatin, resulted in a highly favorable treatment response, probably through a mechanism of antiangiogenesis. However, consolidation therapy or maintenance therapy is required to prolong DFS. Prospective trials of a larger scale are necessary to validate our findings. Declaration of Competing Interest None. Acknowledgements This work was supported by the Chang-Gung Memorial Hospital integrated research project [CORPG3G0371]. The results of the current study were presented at the annual meeting of the Taiwan Association of Obstetrics and Gynecology, 2017. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.tjog.2019.10.003. References [1] Silverberg E, Boring CC, Squires TS. Cancer statistics, 1990. CA Cancer J Clin 1990;40:9e26. [2] Katsumata N, Yasuda M, Isonishi S, Takahashi F, Michimae H, Kimura E, et al. Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol 2013;14:1020e6. [3] Havrilesky LJ, Alvarez AA, Sayer RA, Lancaster JM, Soper JT, Berchuck A, et al. Weekly low-dose carboplatin and paclitaxel in the treatment of recurrent ovarian and peritoneal cancer. Gynecol Oncol 2003;88:51e7. [4] Enteprise Vocabulary Services NCI. NCI common terminology criteria for adverse events (CTCAE). 2010. [5] Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228e47. [6] Rustin GJ, Vergote I, Eisenhauer E, Pujade-Lauraine E, Quinn M, Thigpen T, et al. Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer 2011;21:419e23. [7] Hoekstra AV, Hurteau JA, Kirschner CV, Rodriguez GC. The combination of monthly carboplatin and weekly paclitaxel is highly active for the treatment of recurrent ovarian cancer. Gynecol Oncol 2009;115:377e81. [8] Lortholary A, Largillier R, Weber B, Gladieff L, Alexandre J, Durando X, et al. Weekly paclitaxel as a single agent or in combination with carboplatin or weekly topotecan in patients with resistant ovarian cancer: the CARTAXHY randomized phase II trial from Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO). Ann Oncol 2012;23:346e52.
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