RESEARCH ARTICLE For reprint orders, please contact: [email protected]
Trabectedin for advanced soft tissue sarcomas: a single institution experience Ioannis Gounaris*,1, Helen M Hatcher1, Dochka Davidson1, Karen Sherbourne1, Salma Alam1, Kamarul Ahmad Zaki1, Gail Horan1 & Helena M Earl1,2 ABSTRACT Background: We retrospectively analyzed data from patients who had been treated with trabectedin at our institution between April 2009 and August 2011. Patients & Methods: Data from 25 patients with recurrent soft tissue sarcoma (leiomyosarcoma: n = 8; liposarcoma: n = 5) were used to assess the efficacy and safety of trabectedin 1.5 mg/m² given every 3 weeks. Results: Most patients (n = 14) had been heavily pretreated with ≥2 previous chemotherapy lines. Eight (32%) patients achieved a partial response according to dimensional and tumor density changes, and seven (28%) patients had stable disease for ≥3 months (clinical benefit rate = 60%; n = 15). Median progressionfree survival was 6.4 months and overall survival 19.3 months. Common adverse events were fatigue, nausea, anemia and transient transaminase increases. Conclusion: Treatment with trabectedin is effective and well tolerated in heavily pretreated soft tissue sarcoma patients. Tapering dexamethasone courses and switching trabectedin administration to an every 4 weeks schedule effectively dealt with persistent fatigue without compromising effectiveness. Trabectedin (Yondelis®; PharmaMar, Madrid, Spain), is a cytotoxic agent originally isolated from the Caribbean sea squirt Ecteinascidia turbinata and is currently manufactured by total synthesis [1] . It has pleiotropic mechanisms of action, including binding to the DNA minor groove and causing double helix bending towards the major groove [2] , modulating inflammatory responses in the tumor microenvironment [3–5] , and promoting tumor cell differentiation [6–8] . The pivotal registration study of trabectedin (ET-743-STS-201) [101] was a randomized Phase II comparison of two different schedules of trabectedin administered either every 3 weeks (q3w) or weekly in anthracycline- and ifosfamide-pretreated patients with L-sarcomas (leiomyosarcoma [LMS] or liposarcoma [LPS]) [9] . The data from ET-743-STS-201 found that trabectedin 1.5 mg/m² given as a 24-h intravenous infusion q3w regimen provided a superior disease control than weekly trabectedin 0.58 mg/m 2 (3-h infusion for three consecutive weeks in a 4-week cycle) in terms of longer time to progression (TTP; median TTP: 3.7 vs 2.3 months; p = 0.0302) and progression-free survival (PFS; median PFS: 3.3 vs 2.3 months; p = 0.0418). Generally based on these results, in 2007 trabectedin obtained marketing authorization from the European Commission and in many other countries worldwide for the treatment of patients with advanced soft tissue sarcoma (STS) following failure of anthracyclines and ifosfamide, or for those patients who are unsuitable to receive these agents. Noteworthy, retrospective series have reported remarkable efficacy of trabectedin in myxoid liposarcoma (MLS) in particular, with median PFS of 14–17 months in two partially overlapping series [10,11] . However, it should also be noted that trabectedin has also shown activity in unselected patients with recurrent STS treated in three single-arm, Phase II trials [12–14] and in chemotherapy-naive patients with advanced
KEYWORDS
• leiomyosarcoma • liposarcoma • sarcoma • trabectedin • Yondelis
Oncology Centre, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK University of Cambridge Department of Oncology & NIHR Cambridge Biomedical Research Centre, Cambridge, CB2 0QQ, UK *Author for correspondence: Tel.: +44 1223769513; Fax: +44 1223769510; [email protected] 1 2
10.2217/FON.14.10 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(11), 1843–1851
part of
ISSN 1479-6694
1843
RESEARCH ARTICLE Gounaris, Hatcher, Davidson et al. Table 1. Patient and disease characteristics at baseline (n = 25). Characteristics
n (%)
Gender Female Male
17 (68) 8 (32)
Age at study entry (years) Median (range) 60
57 (19–71) 4 (16) 11 (44) 10 (40)
ECOG performance status 0–1 2
23 (92) 2(8)
Histology LMS LPS Synovial sarcoma MMMT Uterine sarcoma (non-LMS) Other
8 (32) 5 (20) 3 (12) 3 (12) 2 (8) 4 (16)
Primary site Abdomen – pelvis Lower extremity Thorax Head and neck
16 (64) 6 (24) 2 (8) 1 (4)
Grade of differentiation 1–2 3 Not recorded
6 (24) 15 (60) 4 (16)
Stage at initial presentation Stage I–III Stage IV
18 (72) 7 (28)
Previous chemotherapy Palliative Adjuvant
22 (88) 12 (48)
Lines of prior chemotherapy 1 2 3
11 (44) 9 (36) 5 (20)
Prior drugs used Anthracyclines Ifosfamide Docetaxel/gemcitabine
25 (100) 21 (84) 7 (28)
Metastatic sites (n) 1 2 ≥3
8 (32) 9 (36) 8 (32)
ECOG: Eastern Cooperative Oncology Group; LMS: Leiomyosarcoma; LPS: Liposarcoma; MMMT: Malignant mixed Müllerian tumor.
1844
Future Oncol. (2014) 10(11)
STS [15] , and that its license is not restricted to specific histological subtypes. The histological heterogeneity of STS, compounded by their rarity, poses particular challenges in personalizing therapy. In the absence of large randomized studies, institutional case series can provide useful insights in the realworld efficacy, toxicity and management of patients receiving novel agents. We present here our single-center experience with 25 patients treated with trabectedin and report encouraging effectiveness and marked improvements in the tolerability of the regimen by careful attention to adjunctive medications and minor schedule modifications. Patients & methods ●●Study design
For this retrospective analysis, outpatient attendance records and the institutional chemotherapy database were searched for all patients commencing chemotherapy with trabectedin for advanced STS between April 2009 (first use) and August 2011 at the Oncology Centre at Addenbrooke’s Hospital (Cambridge, UK). Eligible patients were patients ≥18 years old with unresectable advanced or metastatic, histologically proven STS. All patients were pretreated with combined or sequential cytotoxic regimens that included at least an anthracycline, and had experienced either metastatic relapse or disease progression. As this was a retrospective review of routinely collected clinical data, patient informed consent was not obtained. ●●Treatments
Trabectedin was administered as a 1.5 mg/m2 24-h continuous intravenous (iv.) infusion q3w using a portable infusion pump that enabled convenient outpatient treatment. A maximum of two dose reductions (from 1.5 to ~1.2 then to 1.0 mg/m2) was permitted in cases of toxicities occurring during the previous cycle of therapy. Premedication with dexamethasone 20 mg iv., 30 min prior to trabectedin and growth factor support with pegfilgrastim on day 2 postchemotherapy was mandatory. Dexamethasone 4 mg orally twice daily was given on days 2 and 3 as antiemetic prophylaxis. Treatment with trabectedin was discontinued at progression, in case of unacceptable toxicity or at the patient’s request. For trabectedin administration, the starting dose, number of cycles administered, dose delays, dose reductions, schedule modifications
future science group
Trabectedin for advanced soft tissue sarcomas: a single institution experience and reasons for treatment discontinuation were extracted directly from the relevant reports.
Table 1. Patient and disease characteristics at baseline (n = 25) (cont.).
●●Study evaluations
Characteristics
Response assessment was based on cross-sectional imaging (typically by CT scans of the thorax abdomen and pelvis) every five cycles and clinical assessment before each cycle. Radiological response assessment was based on the reporting radiologist’s overall impression without formal application of the response evaluation criteria in solid tumors (RECIST) or Choi criteria as confirmatory scans were not performed. The cutoff date for this analysis was 23 February 2012. Major clinical toxicities occurring after trabectedin were collected by patient chart review focusing on hematological and nonhematological toxicities and changes in liver function tests. Adverse events (AEs) were graded according to Common Terminology Criteria for Adverse Events v4.0, published 28 May 2009, by the National Cancer Institute [102] . Patient charts were reviewed for data on demographics, diagnosis and previous treatments were extracted.
Interval from last chemotherapy to trabectedin (months)
●●Statistical methods
PFS and overall survival (OS) were estimated using the method of Kaplan and Meier and the log rank test was used to compare survival curves between subgroups; p-values
Trabectedin for advanced soft tissue sarcomas: a single institution experience Ioannis Gounaris*,1, Helen M Hatcher1, Dochka Davidson1, Karen Sherbourne1, Salma Alam1, Kamarul Ahmad Zaki1, Gail Horan1 & Helena M Earl1,2 ABSTRACT Background: We retrospectively analyzed data from patients who had been treated with trabectedin at our institution between April 2009 and August 2011. Patients & Methods: Data from 25 patients with recurrent soft tissue sarcoma (leiomyosarcoma: n = 8; liposarcoma: n = 5) were used to assess the efficacy and safety of trabectedin 1.5 mg/m² given every 3 weeks. Results: Most patients (n = 14) had been heavily pretreated with ≥2 previous chemotherapy lines. Eight (32%) patients achieved a partial response according to dimensional and tumor density changes, and seven (28%) patients had stable disease for ≥3 months (clinical benefit rate = 60%; n = 15). Median progressionfree survival was 6.4 months and overall survival 19.3 months. Common adverse events were fatigue, nausea, anemia and transient transaminase increases. Conclusion: Treatment with trabectedin is effective and well tolerated in heavily pretreated soft tissue sarcoma patients. Tapering dexamethasone courses and switching trabectedin administration to an every 4 weeks schedule effectively dealt with persistent fatigue without compromising effectiveness. Trabectedin (Yondelis®; PharmaMar, Madrid, Spain), is a cytotoxic agent originally isolated from the Caribbean sea squirt Ecteinascidia turbinata and is currently manufactured by total synthesis [1] . It has pleiotropic mechanisms of action, including binding to the DNA minor groove and causing double helix bending towards the major groove [2] , modulating inflammatory responses in the tumor microenvironment [3–5] , and promoting tumor cell differentiation [6–8] . The pivotal registration study of trabectedin (ET-743-STS-201) [101] was a randomized Phase II comparison of two different schedules of trabectedin administered either every 3 weeks (q3w) or weekly in anthracycline- and ifosfamide-pretreated patients with L-sarcomas (leiomyosarcoma [LMS] or liposarcoma [LPS]) [9] . The data from ET-743-STS-201 found that trabectedin 1.5 mg/m² given as a 24-h intravenous infusion q3w regimen provided a superior disease control than weekly trabectedin 0.58 mg/m 2 (3-h infusion for three consecutive weeks in a 4-week cycle) in terms of longer time to progression (TTP; median TTP: 3.7 vs 2.3 months; p = 0.0302) and progression-free survival (PFS; median PFS: 3.3 vs 2.3 months; p = 0.0418). Generally based on these results, in 2007 trabectedin obtained marketing authorization from the European Commission and in many other countries worldwide for the treatment of patients with advanced soft tissue sarcoma (STS) following failure of anthracyclines and ifosfamide, or for those patients who are unsuitable to receive these agents. Noteworthy, retrospective series have reported remarkable efficacy of trabectedin in myxoid liposarcoma (MLS) in particular, with median PFS of 14–17 months in two partially overlapping series [10,11] . However, it should also be noted that trabectedin has also shown activity in unselected patients with recurrent STS treated in three single-arm, Phase II trials [12–14] and in chemotherapy-naive patients with advanced
KEYWORDS
• leiomyosarcoma • liposarcoma • sarcoma • trabectedin • Yondelis
Oncology Centre, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK University of Cambridge Department of Oncology & NIHR Cambridge Biomedical Research Centre, Cambridge, CB2 0QQ, UK *Author for correspondence: Tel.: +44 1223769513; Fax: +44 1223769510; [email protected] 1 2
10.2217/FON.14.10 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(11), 1843–1851
part of
ISSN 1479-6694
1843
RESEARCH ARTICLE Gounaris, Hatcher, Davidson et al. Table 1. Patient and disease characteristics at baseline (n = 25). Characteristics
n (%)
Gender Female Male
17 (68) 8 (32)
Age at study entry (years) Median (range) 60
57 (19–71) 4 (16) 11 (44) 10 (40)
ECOG performance status 0–1 2
23 (92) 2(8)
Histology LMS LPS Synovial sarcoma MMMT Uterine sarcoma (non-LMS) Other
8 (32) 5 (20) 3 (12) 3 (12) 2 (8) 4 (16)
Primary site Abdomen – pelvis Lower extremity Thorax Head and neck
16 (64) 6 (24) 2 (8) 1 (4)
Grade of differentiation 1–2 3 Not recorded
6 (24) 15 (60) 4 (16)
Stage at initial presentation Stage I–III Stage IV
18 (72) 7 (28)
Previous chemotherapy Palliative Adjuvant
22 (88) 12 (48)
Lines of prior chemotherapy 1 2 3
11 (44) 9 (36) 5 (20)
Prior drugs used Anthracyclines Ifosfamide Docetaxel/gemcitabine
25 (100) 21 (84) 7 (28)
Metastatic sites (n) 1 2 ≥3
8 (32) 9 (36) 8 (32)
ECOG: Eastern Cooperative Oncology Group; LMS: Leiomyosarcoma; LPS: Liposarcoma; MMMT: Malignant mixed Müllerian tumor.
1844
Future Oncol. (2014) 10(11)
STS [15] , and that its license is not restricted to specific histological subtypes. The histological heterogeneity of STS, compounded by their rarity, poses particular challenges in personalizing therapy. In the absence of large randomized studies, institutional case series can provide useful insights in the realworld efficacy, toxicity and management of patients receiving novel agents. We present here our single-center experience with 25 patients treated with trabectedin and report encouraging effectiveness and marked improvements in the tolerability of the regimen by careful attention to adjunctive medications and minor schedule modifications. Patients & methods ●●Study design
For this retrospective analysis, outpatient attendance records and the institutional chemotherapy database were searched for all patients commencing chemotherapy with trabectedin for advanced STS between April 2009 (first use) and August 2011 at the Oncology Centre at Addenbrooke’s Hospital (Cambridge, UK). Eligible patients were patients ≥18 years old with unresectable advanced or metastatic, histologically proven STS. All patients were pretreated with combined or sequential cytotoxic regimens that included at least an anthracycline, and had experienced either metastatic relapse or disease progression. As this was a retrospective review of routinely collected clinical data, patient informed consent was not obtained. ●●Treatments
Trabectedin was administered as a 1.5 mg/m2 24-h continuous intravenous (iv.) infusion q3w using a portable infusion pump that enabled convenient outpatient treatment. A maximum of two dose reductions (from 1.5 to ~1.2 then to 1.0 mg/m2) was permitted in cases of toxicities occurring during the previous cycle of therapy. Premedication with dexamethasone 20 mg iv., 30 min prior to trabectedin and growth factor support with pegfilgrastim on day 2 postchemotherapy was mandatory. Dexamethasone 4 mg orally twice daily was given on days 2 and 3 as antiemetic prophylaxis. Treatment with trabectedin was discontinued at progression, in case of unacceptable toxicity or at the patient’s request. For trabectedin administration, the starting dose, number of cycles administered, dose delays, dose reductions, schedule modifications
future science group
Trabectedin for advanced soft tissue sarcomas: a single institution experience and reasons for treatment discontinuation were extracted directly from the relevant reports.
Table 1. Patient and disease characteristics at baseline (n = 25) (cont.).
●●Study evaluations
Characteristics
Response assessment was based on cross-sectional imaging (typically by CT scans of the thorax abdomen and pelvis) every five cycles and clinical assessment before each cycle. Radiological response assessment was based on the reporting radiologist’s overall impression without formal application of the response evaluation criteria in solid tumors (RECIST) or Choi criteria as confirmatory scans were not performed. The cutoff date for this analysis was 23 February 2012. Major clinical toxicities occurring after trabectedin were collected by patient chart review focusing on hematological and nonhematological toxicities and changes in liver function tests. Adverse events (AEs) were graded according to Common Terminology Criteria for Adverse Events v4.0, published 28 May 2009, by the National Cancer Institute [102] . Patient charts were reviewed for data on demographics, diagnosis and previous treatments were extracted.
Interval from last chemotherapy to trabectedin (months)
●●Statistical methods
PFS and overall survival (OS) were estimated using the method of Kaplan and Meier and the log rank test was used to compare survival curves between subgroups; p-values
