This retrospective analysis evaluated treatment with trabectedin plus pegylated liposomal doxorubicin (PLD) in 34 heavily pretreated patients (median number of previous lines, 3; range, 2-10) with platinum-sensitive relapsed ovarian cancer (ROC) at a single center in Italy.
Trabectedin/PLD treatment consisted of trabectedin administered every 3 weeks as a 3-hour intravenous (i.v.) infusion at a dose of 1.1 mg/m2, immediately after PLD 30 mg/m2 i.v. infusion. Study objectives were the evaluation of the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS).
Three complete responses and 8 partial responses were observed, with an ORR of 32.4% (95% CI, 17.4-50.5%). Median PFS was 6.1 months (95% CI, 4.4-8.9 months). Median OS was 16.3 months (95% CI, 6.8-23.5). Most responses (9 of 11) were found in patients with partially platinum-sensitive disease (ORR 40.9% in this subset; median PFS 6.8 months and median OS 20.8 months). Grade 3 treatment-related adverse events consisted of nausea/vomiting (n = 5; 14.7%), mucositis (n = 2; 5.9%), alanine aminotransferase increase, anemia and neutropenia (n = 1 each; 2.9%).
The overall findings appear consistent with those previously observed in a randomized controlled clinical trial, and support the use of trabectedin/PLD in heavily pretreated patients with platinum-sensitive ROC, especially those with partially platinum-sensitive disease.
Tumori 2015; 101(5): 506 - 510
Article Type: ORIGINAL RESEARCH ARTICLE
AuthorsMaria Ornella Nicoletto, Alessandra Baldoni, Alessandra Casarin, Giovanni Randon, Margherita Nardin, Zora Baretta, Pilar Lardelli, Antonio Nieto, Vicente Alfaro, Claudia Rigamonti, Pier Franco Conte
- • Accepted on 16/05/2015
- • Available online on 18/06/2015
- • Published in print on 09/09/2015
This article is available as full text PDF.
Trabectedin (Yondelis®) is a marine-derived antineoplastic agent that was initially isolated from the Caribbean tunicate
Apart from information obtained in clinical trials, few data are available about the use of trabectedin for ROC in clinical practice. Two retrospective analyses evaluated trabectedin as a single agent in patients with ROC (11, 12), but to date little information is available on the use of trabectedin in combination with PLD. This retrospective analysis was conducted on heavily pretreated patients with platinum-sensitive ROC receiving trabectedin/PLD treatment at a single center in Italy consecutively from May 2012 to January 2015.
Written informed consent to treatment and use of clinical data for scientific purposes was obtained from all patients at the time of chemotherapy administration. Given the retrospective design of this analysis, approval of local ethics committees to retrieve data from clinical charts was not required, but the principles outlined in the Declaration of Helsinki were followed.
Patients were adult women with histologically confirmed epithelial ovarian cancer, previously treated with at least 1 platinum-based regimen, and with radiological evidence of disease progression, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2 and adequate hematological (hemoglobin ≥9 g/dL; absolute neutrophil count ≥1.5 × 109/L; platelets ≥100 × 109/L), renal (serum creatinine ≤1.5 mg/dL) and hepatic function (bilirubin ≤ upper limit of normal [ULN]; aspartate aminotransferase [AST]/alanine aminotransferase [ALT] ≤2.5 × ULN; alkaline phosphatase [AP] ≤2.5 × ULN [if total AP >2.5 × ULN, AP liver fraction and/or gamma glutamyltransferase and/or 5’-nucleotidase had to be ≤ULN], and albumin >25 g/L).
Trabectedin/PLD treatment consisted of trabectedin administered every 3 weeks as a 3-hour intravenous (i.v.) infusion at a dose of 1.1 mg/m2, immediately after i.v. infusion of PLD at a dose of 30 mg/m2. To minimize the risk of PLD infusion reactions, the initial dose was administered at a rate no greater than 1 mg/minute and, if no infusion reaction was observed, subsequent PLD infusions were administered over a 1-hour period. All patients received i.v. prophylactic medication with corticosteroids (dexamethasone 20 mg or equivalent) 30 minutes prior to PLD infusion.
Tumor response and PFS were assessed according to the Response Evaluation Criteria in Solid Tumors, RECIST v.1.1 (13). Patients were also followed up for OS analysis. PFS and OS were calculated from the first day of trabectedin/PLD treatment to the date of disease progression or death.
The safety of trabectedin/PLD treatment was evaluated by recording of adverse events (AEs), laboratory test results, physical examinations and vital signs. AEs and laboratory abnormalities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), v.3.0.
Descriptive statistics were used for this retrospective analysis. Noncontinuous variables are described in frequency tables using counts and percentages. Continuous variables are described by median, minimum and maximum. The binomial exact estimator and its 95% CI was calculated for the evaluation of categorical efficacy variables (e.g., RECIST response). The Kaplan-Meier method was used for time-to-event variables (PFS and OS). Exploratory log-rank tests were utilized to estimate the relationship of time-to-event variables (PFS and OS) with tumor grade, histology,
Thirty-four patients with ROC were treated with trabectedin/PLD in the evaluated period. Their main demographic and baseline characteristics are shown in
Demographic and baseline characteristics (n = 34)
|UK = unknown.|
|aAdenocarcinoma not otherwise specified (NOS), clear cell, endometrioid (n = 4), mucinous, primitive peritoneal and yolk sac tumor.|
|bResidual tumor <1 cm.|
|cResidual tumor ≥1 cm (n = 7) or localized peritoneal seeding (n = 2).|
|Age (years)||Median (range)||60 (26-79)|
|Time from diagnosis (months)||Median (range)||30.0 (11.0-124.9)|
|Histological type||Serous adenocarcinoma||23||67.6|
|Tumor grade at diagnosis||2||5||14.7|
|Residual tumor||Optimally debulked <1b||25||73.5|
|Number of previous lines of chemotherapy||Median (range)||3 (2-10)|
|Platinum-free interval (months)||6-12||22||64.7|
The evaluated population had been heavily pretreated; the median number of previous chemotherapy lines was 3 (range, 2-10 lines), and 41.2% of patients had received 4 or more lines. Most patients (64.7%) had partially platinum-sensitive disease (i.e., PFI was 6-12 months) (
The median number of trabectedin/PLD cycles received per patient was 5 (range, 1-16), although those patients less heavily pretreated were able to receive trabectedin/PLD for longer periods: patients with 2 prior chemotherapy lines had a median of 9 cycles administered.
Response to treatment
Thirty-one patients were evaluable for response (
Response rate according to RECIST (n = 34)
|RECIST = Response Evaluation Criteria in Solid Tumors; CI = confidence interval.|
|Objective response rate, % (95% CI)||32.4 (17.4-50.5)|
Median PFS was 6.1 months (95% CI 4.4-8.9). The PFS rates at 6 and 12 months were 52.5% and 12.4%, respectively (
Progression-free survival (n = 30)
|CI = confidence interval; PFS = progression-free survival.|
|Censored, n (%)||8 (26.7%)|
|Median (95% CI) (months)||6.1 (4.4-8.9)|
|PFS at 6 months, % (95% CI)||52.5% (33.5-71.5)|
|PFS at 12 months, % (95% CI)||12.4% (0-27.5)|
Kaplan-Meier plot of progression-free survival (PFS) according to the number of previous chemotherapy lines received. Data shown are medians (95% CI). C = censored; CI = confidence interval; N = number of patients; n.r. = not reached.
The majority of patients were alive at the time of this retrospective analysis (58% of patients censored) and therefore OS data were very immature. Median OS was 16.3 months (95% CI 6.8-23.5). The OS rates at 6 and 12 months were 76.3% and 68.9%, respectively. A statistically significant difference (p = 0.0318) was found according to the number of previous chemotherapy lines (
Kaplan-Meier plot of overall survival (OS) according to the number of previous chemotherapy lines received. Data shown are medians (95% CI). C = censored; CI = confidence interval; N = number of patients; n.r. = not reached.
No grade 4 treatment-related AEs were reported. Grade 3 treatment-related AEs included nausea/vomiting (n = 5; 14.7%), mucositis (n = 2; 5.9%), ALT increase, anemia and neutropenia (n = 1 each; 2.9%) (
Treatment-related adverse events (worst grade per patient; n = 34)
|NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events.|
|Alanine aminotransferase increase||-||-||1||2.9|
|Intolerance to antiemetics||1||2.9||-||-|
|Sensorial peripheral neuropathy||2||5.9||-||-|
This retrospective analysis evaluated the efficacy and safety outcomes of the trabectedin/PLD combination when used in patients with ROC in daily clinical practice. This analysis was conducted in patients with platinum-sensitive disease (64.7% had partially platinum-sensitive disease) and showed ORR = 32.4%, median PFS = 6.1 months and median OS = 16.3 months. In the pivotal OVA-301 trial, data obtained from the platinum-sensitive subset of patients showed ORR = 35.3%, median PFS = 9.2 months and median OS = 27.0 months (
Efficacy outcomes in patients with platinum-sensitive relapsed ovarian cancer treated with trabectedin 1.1 mg/m2 plus PLD 30 mg/m2 3-hour q3wk infusion.
|First author (year)||Type of study||No.||Number of previous lines (median, range)||Platinum-sensitive, n (%)||Cycles, median (range)||ORR (%)||Median PFS (months)||Median OS (months)|
|ORR = objective response rate; OS = overall survival; PFI = platinum-free interval; PFS = progression-free survival; PLD = pegylated liposomal doxorubicin; q3wk = every 3 weeks.|
|aPlatinum-sensitive disease (PFI >6 months) and partially platinum-sensitive disease (PFI 6-12 months).|
|bNo data on pretreatment were available, but the inclusion criteria of this study allowed only 1 previous line of treatment.|
|cThe majority of patients were alive at the time of this retrospective analysis (58% of patients censored) and therefore OS data were very immature.|
|Monk (2010, 2012) (9, 10)||Phase III clinical trial, randomized Independent review||337||1b||278 (64.7%)||6 (1-21)||35.3%||NA||9.2||7.4||27.0||NA|
|Current study||Single-center retrospective analysis||34||3 (2-10)||34 (100.0%)||5 (1-16)||32.4%||40.9%||6.1||6.8||16.3c||20.8c|
In the present single-center study, patients with partially platinum-sensitive disease obtained more clinical benefit in terms of ORR, PFS and OS. This is an expected finding as previous studies showed that the efficacy of the trabectedin/PLD combination appears particularly optimized in the partially platinum-sensitive ROC population (7, 15, 16).
The safety profile was as expected for trabectedin/PLD treatment; no new safety signals were reported. The median number of cycles received per patient was similar to that reported in the pivotal OVA-301 trial in a less heavily pretreated population (
In conclusion, this retrospective analysis shows that trabectedin/PLD is an effective treatment for ROC patients in daily clinical practice, especially patients with partially platinum-sensitive disease. Our findings were consistent with those of a previous randomized trial and further support that trabectedin/PLD maintains antitumor activity when administered as a third or further chemotherapy line.
- Nicoletto, Maria Ornella [PubMed] [Google Scholar] 1, * Corresponding Author (email@example.com)
- Baldoni, Alessandra [PubMed] [Google Scholar] 1
- Casarin, Alessandra [PubMed] [Google Scholar] 1
- Randon, Giovanni [PubMed] [Google Scholar] 1
- Nardin, Margherita [PubMed] [Google Scholar] 1
- Baretta, Zora [PubMed] [Google Scholar] 1
- Lardelli, Pilar [PubMed] [Google Scholar] 2
- Nieto, Antonio [PubMed] [Google Scholar] 2
- Alfaro, Vicente [PubMed] [Google Scholar] 2
- Rigamonti, Claudia [PubMed] [Google Scholar] 3
- Conte, Pier Franco [PubMed] [Google Scholar] 1
Medical Oncology Unit, Istituto Oncologico Veneto IOV-IRCCS, Padua - Italy
Clinical R&D Department, PharmaMar, Colmenar Viejo, Madrid - Spain
Medical Affairs Department, PharmaMar Italy, Milan - Italy