*Hee Jun Lee and Hee Seung Kim contributed equally to this work.
The purpose of this study is to evaluate the efficacy and toxicity of oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX-4) chemotherapy in heavily pretreated patients with recurrent epithelial ovarian cancer (EOC).
Clinical data were reviewed in 28 patients who received FOLFOX-4 as more than the second-line chemotherapy, consisting of 85 mg/m2 of oxaliplatin as a 2-hour infusion, 200 mg/m2 of leucovorin as a 2-hour infusion, and bolus 400 mg/m2 on day 1, followed by a 22-hour infusion of 600 mg/m2 of 5-fluorouracil for two consecutive days every three weeks. In addition, its efficacy and toxicity were compared with those reported in in three previous relevant studies.
A total of 128 cycles of FOLFOX-4 were administered with the median number of five cycles (range, 1 to 10 cycles). In nine patients with measurable disease, complete response (CR) and partial response (PR) were observed in 0 (0%) and two (22.2%) patients, whereas in 19 patients with non-measurable disease, CR and PR were observed in 0 (0%) and five (26.3%) patients. Among all patients, grade 3 anemia, neutropenia, and thrombocytopenia were observed in two (7.1%), three (10.7%), and one (3.6%) patient, and grade 3 fatigue, nausea and vomiting, and peripheral neuropathy were observed in one (3.6%), two (7.1%), and three (10.7%) patients. In addition, median values of time to progressive disease and chemotherapy-specific survival were three months (range, 0 to 10 months) and nine months (range, 4 to 24 months).
FOLFOX-4 is feasible as salvage chemotherapy with acceptable toxicity for heavily pretreated patients with recurrent EOC.
Epithelial ovarian cancer (EOC) is the second most common malignancy of the female genital tract [
When EOC recurs after primary treatment, the second-line chemotherapy is different between platinum-sensitive and platinum-resistant diseases. Patients with platinum-sensitive disease, who relapse later than six months after primary treatment, can be treated again with taxane- and platinum-based chemotherapy, whereas different cytotoxic drugs, including topotecan, gemcitabine, and pegylated liposomal doxorubicin are administered to those with platinum-resistant disease, which are known to show a relatively low response rate of 15% to 35% [
When compared with carboplatin and cisplatin, oxaliplatin, a diaminocyclohexane, platinum derivative, has different cytotoxic effects and various intracellular targets [
FOLFOX-4 is currently one of the most efficient chemotherapeutic regimens for treatment of colon and breast cancers [
The current study is a retrospective review, which enrolled patients who received FOLFOX-4 as salvage chemotherapy for treatment of recurrent EOC. Approval by the Institutional Review Board of Seoul National University Hospital was obtained in advance. Because this study was a retrospective review of medical records, informed consent was waived.
All data were acquired from a database of heavily pretreated patients with recurrent EOC between January 2002 and February 2011. The eligibility criteria were as follows: patients with histological confirmation of EOC; those with Eastern Cooperative Oncology Group performance status of 0 to 1; those who underwent cytoreductive surgery followed by taxane- and platinum-based chemotherapy as primary treatment; those who received FOLFOX-4 for treatment of recurrent disease as more than the second-line chemotherapy; those without other combined malignancies; those with adequate hepatic, renal, and bone marrow functions.
FOLFOX-4 consisted of 85 mg/m2 of oxaliplatin as a 2-hour infusion on day 1, 200 mg/m2 of LV as a 2-hour infusion on day 1, and bolus 400 mg/m2 of 5-FU on day 1, followed by a 22-hour infusion of 600 mg/m2 of 5-FU for two consecutive days every three weeks. Chemotherapy was terminated when progressive disease (PD) developed, chemotherapy-induced toxicities were uncontrolled by conservative treatment such as granulocyte colony stimulating factor, or the treatment schedule was delayed by more than two weeks.
Tumor response was assessed every three cycles by repeating baseline assessments using imaging studies (computed tomography, magnetic resonance imaging) according to the Response Evaluation Criteria in Solid Tumors (RECIST) for patients with measurable disease [
For survival analysis, time to progressive disease (TTPD) was defined as the time lapse from the beginning of FOLFOX-4 chemotherapy to the date of proven PD. Chemotherapy-specific survival (CSS) was calculated as the time lapse from the beginning of FOLFOX-4 chemotherapy to the date of cancer-related death or the end of the study. Overall survival (OS) was defined as the time lapse from the date of diagnosis to the date of cancer-related death or the end of the study. TTPD, CSS, and OS were evaluated using the Kaplan-Meier method with the log-rank test. Statistical analyses were performed using SPSS ver. 19.0 (SPSS Inc., Chicago, IL). Finally, we compared the efficacy and toxicity of FOLFOX-4 chemotherapy between the current study and three previous relevant studies [
A total of 28 heavily pretreated patients with recurrent EOC were enrolled in the current study. Their clinicopathologic characteristics are shown in
In evaluation of tumor response according to the RECIST criteria for nine patients with measurable disease, CR, PR, SD, and PD were observed in 0 (0%), two (22.2%), two (22.2%), and five (55.6%) patients, respectively. In 19 patients with non-measurable disease, 0 (0%), five (26.3%), four (21.1%), and 10 (52.6%) patients showed CR, PR, SD, and PD (
In regard to hematological toxicity, two (7.1%), three (10.7%), and one (3.6%) patients showed grade 3 anemia, neutropenia, and thrombocytopenia. In addition, grade 3 fatigue, nausea and vomiting, and peripheral neuropathy were observed as non-hematological toxicity in one (3.6%), two (7.1%), and three (10.7%) patients, respectively (
The efficacy of FOLFOX-4 has been investigated as salvage chemotherapy in previous studies [
Three drugs consisting of FOLFOX-4 have been studied extensively for efficacy in previous studies. Oxaliplatin is known to have relative non-cross-resistance with cisplatin or carboplatin [
Nevertheless, the synergic efficacy and toxicity by the combination of oxaliplatin, LV and 5-FU for treatment of recurrent EOC are still unclear. In the current study, overall response rates were 22.2% (CR, 0; PR, 2) in nine patients with measurable disease, and 26.3% (CR, 0; PR, 5) in 19 patients with non-measurable disease. In addition, clinical benefit rates, including CR, PR, and SD were 44.4% and 47.4% in patients with measurable and non-measurable diseases, respectively. In terms of survival and toxicity, FOLFOX-4 chemotherapy showed an adequate survival benefit (TTPD, 3 months; CSS, 9 months; OS, 40 months), and its toxicity was acceptable (0-10.7%) without treatment-related death. These findings indicate that FOLFOX-4 chemotherapy is feasible as a salvage treatment for heavily pretreated patients with recurrent EOC.
For clarification of the efficacy and toxicity of FOLFOX-4 chemotherapy in treatment of EOC, we compared our results with those reported in three previous relevant studies (
In addition, we found that the median TTPD and CSS were similar between the current study and the three previous studies (TTPD, 3 months vs. 4-4.8 months; CSS, 9 months vs. approximately 10 months) [
Through our experience and review of previous relevant studies, we found that FOLFOX-4 chemotherapy was efficient in heavily pretreated patients with EOC. In addition, its toxicity was acceptable, and manageable by supportive care. Thus, FOLFOX-4 chemotherapy should be considered as feasible for treatment of recurrent EOC in patients with heavily pretreated EOC, and its efficacy and toxicity should be approved by relevant clinical trials in the near future.
This research was supported by a grant (nos. 04-2012-0890; 03-2012-0170) from the Seoul National University Hospital (SNUH) research fund.
Conflict of interest relevant to this article was not reported.
Kaplan-Meier survival analysis with the log-rank test for (A) time to progressive disease, (B) chemotherapy-specific survival, and (C) overall survival in 28 patients with recurrent epithelial ovarian cancer who received oxaliplatin, leucovorin, and 5-fluoleurouracil (FOLFOX-4) chemotherapy.
Characteristics of patients
Characteristic | No. (%) |
---|---|
Median age (range, yr) | 61 (46-79) |
Menopause | |
Yes | 21 (75.0) |
No | 7 (25.0) |
ECOG performance status | |
0 | 17 (60.7) |
1 | 11 (39.3) |
FIGO stage | |
IIB | 1 (3.6) |
IIC | 1 (3.6) |
IIIA | 1 (3.6) |
IIIB | 1 (3.6) |
IIIC | 19 (67.7) |
IV | 5 (17.9) |
Histology | |
Serous | 21 (75.0) |
Non-serous | 7 (25.0) |
Median follow-up (range, mo) | 34 (10-95) |
Treatment time for FOLFOX-4 | |
3rd line | 4 (14.3) |
4th line | 7 (25.0) |
5th line | 8 (28.6) |
6th to 9th line | 9 (32.1) |
Cycles of FOLFOX-4 | |
1 | 2 (7.1) |
2 | 7 (25.0) |
3 | 4 (14.3) |
4 | 3 (10.7) |
5-9 | 12 (42.9) |
ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics; FOLFOX-4, oxaliplatin, leucovorin, and 5-fluorouracil.
Efficacy of FOLFOX-4 chemotherapy in 28 heavily pretreated patients with recurrent epithelial ovarian cancer
No. | Age |
FIGO |
Histology | Prior chemotherapy | Treatment time |
Cycles of |
Tumor |
---|---|---|---|---|---|---|---|
1 | 69 | IV | Serous | T/C×9 → T/C×9 → D/C×7 → WT×5 |
8 | 5 | Partial |
2 | 62 | IIIC | Serous | T/C×6 → To×6 → G/P×6 → PLD×4 → D/C×6 | 6 | 2 | Progressive |
3 | 48 | IIIC | Serous | T/C×6 → D/P×6 → To/P×6 → G×4 | 5 | 2 | Progressive |
4 | 65 | IIIC | Serous | T/C×9 → To/P×9 → G×1 | 4 | 10 | Partial |
5 | 46 | IIIC | Serous | T/C×9 → G/C×9 → D/P×3 → To×4 | 5 | 3 | Progressive |
6 | 48 | IV | Mucinous | T/C×9 → G/C×2 | 3 | 3 | Progressive |
7 | 63 | IIIC | Serous | T/C×9 → T/C×6 → G/C×3 → To×2 | 5 | 4 | Partial |
8 | 57 | IIIC | Serous | T/C×9 → G/C×4 → To×3 | 4 | 4 | Stable |
9 | 53 | IIIC | Undifferentiated | T/C×9 → G/P×6 → To×3 | 4 | 10 | Stable |
10 | 69 | IIB | Serous | T/C×6 → T/C×6 → G/P×6 → D×6→ To/P×9 | 6 | 1 | Progressive |
11 | 60 | IIIA | Endometrioid | T/C×6 → G/P×6 | 3 | 7 | Stable |
12 | 63 | IIIC | Serous | T/C×6 → D/C×6 → G/C×6 → To×6 → E×6 |
8 | 7 | Stable |
13 | 78 | IIIC | Mucinous | T/C×9 → G/P×4 | 3 | 1 | Progressive |
14 | 47 | IV | Serous | T/C×3 → D/C×6 → G×4 → To×3 → G/P×3 |
9 | 2 | Progressive |
15 | 56 | IV | Serous | T/C×7 → G/P×7 → To×3 | 4 | 7 | Partial |
16 | 64 | IIIC | Serous | T/C×9 → G/P×6 → To/P×3 → To/C×9 | 5 | 2 | Progressive |
17 | 69 | IV | Serous | T/C×9 → To/P×6 → D/C×4 → G/C×2 | 5 | 4 | Progressive |
18 | 50 | IIIC | Serous | T/C×6 → T×6 → D/P×3 → To×2 → G/C×6 |
9 | 4 | Progressive |
19 | 60 | IIIC | Endometrioid | T/C×3 → To/P×3 → Cy/P×1 → G/P×6 → D×1 | 6 | 9 | Partial |
20 | 67 | IIIC | Serous | T/C×9 → To×6 → G/C×6 → To×12 → D×2 |
8 | 7 | Stable |
21 | 54 | IIIC | Endometrioid | T/C×7 → Do/P×4 → G/P×1 | 4 | 3 | Progressive |
22 | 60 | IIIC | Endometrioid | T/C×6 → G/C×6→ To/P×6 → WT×3 |
7 | 7 | Stable |
23 | 59 | IIIC | Serous | T/C×9 → D/P×6 → To/P×6 → G×3 | 5 | 5 | Progressive |
24 | 69 | IIIC | Serous | T/C×9 → To/P×9 | 3 | 2 | Progressive |
25 | 79 | IIC | Serous | T/C×6 → D/C×9 → To×3 → G/P×4 | 5 | 2 | Progressive |
26 | 50 | IIIB | Serous | T/C×9 → To/P×6 → D/C×4 | 4 | 7 | Partial |
27 | 70 | IIIC | Serous | T/C×9 → D/C×3 → To×9 → To/P×6 | 5 | 6 | Partial |
28 | 60 | IIIC | Serous | T/C×9 → To/P×3 → G/C×3 | 4 | 2 | Progressive |
FOLFOX-4, oxaliplatin, leucovorin, and 5-fluorouracil; FIGO, International Federation of Gynecology and Obstetrics criteria for ovarian cancer; T, paclitaxel; C, carboplatin; D, docetaxel; WT, weekly paclitaxel; To, topotecan; P, cisplatin; G, gemcitabine; WI, weekly irinotecan; PLO, pegylated liposomal doxorubicin; E, etoposide; Cy, cyclophosphamide; Do, doxorubicin. a)Tumor response according to the Response Evaluation Criteria in Solid Tumors.
Comparison of efficacy and toxicity of FOLFOX-4 in recurrent epithelial ovarian cancer
Characteristic | Sundar et al. [12] | Pectasides et al. [13] | Rosa et al. [14] | Current study | |||
---|---|---|---|---|---|---|---|
Study design | Prospective | Prospective | Retrospective | Retrospective | |||
No. of patients | 27 | 38 | 14 | 28 | |||
FIGO stage | |||||||
I | 0 (0) | 0 (0) | 2 (14.3) | 0 (0) | |||
II | 2 (7.4) | 14 (36.8) | 0 (0) | 2 (7.1) | |||
III | 16 (59.3) | 18 (47.4) | 11 (78.6) | 21 (75.0) | |||
IV | 9 (33.3) | 3 (7.9) | 1 (7.1) | 5 (17.9) | |||
Unknown | 0 (0) | 3 (7.9) | 0 (0) | 0 (0) | |||
Tumor response | WHO | Rustin | WHO criteiria | RECIST | Rustin | RECIST | Rustin |
criteria | criteria | (n=38) | criteria | criteria | criteria | criteria | |
(n=20) | (n=25) | (n=14) | (n=14) | (n=9) | (n=19) | ||
CR or 75% response | 3 (15.0) | 12 (48.0) | 3 (7.9) | 2 (14.3) | 4 (28.6) | 0 (0) | 0 (0) |
PR or 50% response | 3 (15.0) | 2 (8.0) | 8 (21.1) | 2 (14.3) | 2 (14.3) | 2 (22.2) | 5 (26.3) |
Overall response | 6 (30.0) | 14 (56.0) | 11 (29.0) | 4 (28.6) | 6 (42.9) | 2 (22.2) | 5 (26.3) |
Median TTPD (mo) | 4 | 4.8 | – | 3 | |||
Median CSS (mo) | 10 | 10.1 | – | 9 | |||
Median no. of prior |
1 (1-2) | 1 (1-3) | 5 (3-10) | 5 (2-8) | |||
Median cycles of |
7 (2-12) | 4 (1-8) | 8 (2-11) | 5 (1-10) | |||
Grade 3 or 4 toxicity | |||||||
Anemia | 1 (3.7) | 4 (10.6) | 0 (0) | 2 (7.1) | |||
Leukopenia | 0 (0) | – | 0 (0) | 0 (0) | |||
Neutropenia | 4 (14.8) | 11 (29.0) | 1 (7.1) | 3 (10.7) | |||
Thrombocytopenia | 3 (11.1) | 8 (20.8) | 1 (7.1) | 1 (3.6) | |||
Abdominal discomfort | – | – | 0 (0) | 0 (0) | |||
Anorexia | – | 3 (7.9) | 0 (0) | 0 (0) | |||
Constipation | 0 (0) | – | 0 (0) | 0 (0) | |||
Diarrhea | 1 (3.7) | 3 (11.5) | 0 (0) | 0 (0) | |||
Fatigue | – | 3 (7.9) | 0 (0) | 1 (3.6) | |||
Nausea and vomiting | 0 (0) | 4 (10.5) | 0 (0) | 2 (7.1) | |||
Mucositis | – | 4 (10.5) | 0 (0) | 0 (0) | |||
Peripheral neuropathy | – | 6 (15.8) | 2 (14.3) | 3 (10.7) | |||
Peripheral edema | – | – | 0 (0) | 0 (0) | |||
Hypokalemia | 0 (0) | – | 0 (0) | 0 (0) |
Values are presented as number (%). FOLFOX-4, oxaliplatin, leucovorin, and 5-fluorouracil; FIGO, International Federation of Gynecology and Obstetrics; WHO, World Health Organization; RECIST, Response Evaluation Criteria in Solid Tumors; CR, complete response; PR, partial response; TTPD, time to progressive disease; CSS, chemotherapy-specific survival.
Summary of tumor responses
No. of patients (%) |
Total (%) | ||
---|---|---|---|
Patients with |
Patients with |
||
Complete response | 0 (0) | 0 (0) | 0 (0) |
Partial response | 2 (22.2) | 5 (26.3) | 7 (25.0) |
Stable disease | 2 (22.2) | 4 (21.1) | 6 (21.4) |
Partial disease | 5 (55.6) | 10 (52.6) | 15 (53.6) |
Total | 9 (100) | 19 (100) | 28 (100) |
RECIST, Response Evaluation Criteria in Solid Tumors.