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Predicting response to chemotherapy
The prognostic nomogram called Sarculator was used effectively to define a high-risk subgroup of patients likely to benefit from adjuvant chemotherapy, Sandro Pasquali, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy and his colleagues reported at the meeting.
Perioperative chemotherapy was shown to afford no survival advantage over observation in the EORTC 62931 (European Organization for Research and Treatment of Cancer—62931) study of adjuvant doxorubicin plus ifosfamide (Lancet Oncol 2012;13:1045-54). However, subsequent analyses of that data attributed this finding to variations in treatment schedules and the inclusion of low-risk tumors, which may have diluted the effect of chemotherapy, the researchers said in their abstract.
Further, a recent interim report of the ISG-1001 trial showed a survival benefit for patients who received neoadjuvant epirubicin plus ifosfamide therapy for localized high-risk soft-tissue sarcoma of the extremities or trunk wall (Lancet Oncol 2017;18:812-822).
The researchers performed a retrospective analysis of individual data for 290 patients with extremity and trunk wall soft-tissue sarcomas in the EORTC-STBSG 62931 study. The Sarculator was used to calculate 10-year predicted probability of overall survival (pr-OS) for each patient.
Patients were grouped in two categories of predicted overall survival: high predicted survival (over 60%) and low predicted overall survival (60% or less). Overall survival and disease-free survival were calculated at 8 years, the study’s median follow-up.
The 8-year probability of overall survival and disease-free survival was 58% [95% confidence interval (CI): 52–63%] and 51% (95% CI: 46–57%), respectively. In the 290 patients with extremity and trunk wall soft tissue sarcomas, adjuvant chemotherapy was not associated with an overall survival benefit [Hazard ratio (HR) = 0.91, 95%CI 0.63–1.31]. The Sarcolator Nomogram detected 80 patients who were at greater risk of death compared to the 210 patients with higher predicted overall survival. The risk of death was significantly lower with adjuvant chemotherapy in the group with low predicted survival based on the Sarculator Nomogram (HR=0.50, 95%CI 0.30-0.90). Consistently, the risk of recurrence was significantly lower when adjuvant chemotherapy was used in the group with predicted overall survival of less than 60% (HR = 0.49, 95%CI 0.28-0.85) while this difference was not observed in patients with high predicted overall survival (HR = 0.95, 95%CI 0.62-1.44).
Doxorubicin plus dacarbazine deserve evaluation in prospective trials in leiomyosarcoma
Doxorubicin plus dacarbazine appeared to best the outcomes seen with doxorubicin plus ifosfamide and with doxorubicin alone in terms of overall response rate and progression free survival as first-line treatment in patients with advanced leiomyosarcomas, based on a retrospective analysis presented by Lorenzo D’Ambrosio, MD, of the Unitversity of Torino, Italy, and his associates.
As patients in the trial were not randomized to therapy, the researchers used a logistic regression model that accounted for histology, site of primary, age, gender, performance status, tumor extent, and tumor grade. Patients were then matched across the different groups by their propensity scores.The 303 patients, 216 of them women, were enrolled from 18 EORTC STBSG (European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group) sites. Doxorubicin plus dacarbazine was given to 117 patients (39%), doxorubicin plus ifosfamide was given to 71 (23%), and doxorubicin alone was given to 115 (38%). There were no significant differences among the regimens in terms of dose reductions of more than 10%, delays of greater than 72 hours, or granulocyte-colony stimulating factor use.
In the whole population, unadjusted median progression free survival was 9.4 months (95% CI 6.1-9.7 months) for those given doxorubicin plus dacarbazine, 6.8 months (4.5-9.5 months) for those given doxorubicin plus ifosfamide), and 5.4 months (3.8-6.8 months) for those given doxorubicin alone. The respective overall response rates for the three regimens were 36.8%, 21.5%, and 25.9%. When using propensity scores to adjust for lack of randomization, progression free survival was significantly longer with doxorubicin plus dacarbazine [median 9.2 months (95%CI 5.2-9.7 months) than with doxorubicin [median 4.8 months (2.3-6.0 months); HR 0.72 (0.52-0.99)]. The difference was not significant when compared to doxorubicin plus ifosfamide [8.2 months (5.2-10.1 months), HR 1.01 (0.68-1.50)]. Progression free survival did not differ significantly between doxorubicin plus ifosfamide, and doxorubicin [HR 0.71 (0.48-1.06)]. In the same matched population, overall response rates were 30.9%, 19.5%, and 25.6% for doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin, respectively.
Overall survival comparisons were weakened by a shorter median follow-up in the doxorubicin plus dacarbazine groups (32 months) compared to the doxorubicin plus ifosfamide group (50 months) and the doxorubicin group (46 months). With this limit, patients in the doxorubicin plus dacarbazine arm had longer overall survival [median 36.8 (27.9-47.2) months] when compared to both doxorubicin plus ifosfamide [21.9 (16.7-33.4), HR 0.65 (0.40-1.06); and doxorubicin arms 30.3 (21.0-36.3) months, HR 0.66 (0.43-0.99).
Subsequent treatments were well balanced across arms. None of the selected factors for multivariate analysis (age, sex, ECOG performance status, histotype, site of primary tumor, tumor grade, and tumor extent) significantly affected the progression free survival and overall survival associated with the treatments.
Olaratumab in combination with doxorubicin plus ifosfamide
Olaratumab at 15 mg/kg has been shown to be safe in combination with doxorubicin plus ifosfamide in a Phase 1b study (NCT03283696), reported Sebastian Bauer, MD, of the West German Cancer Center, University of Duisburg-Essen, Essen, Germany, and his colleagues.
Given that 8 of 10 evaluable patients have completed the drug-limiting toxicity period without drug-limiting toxicities at the 15 mg/kg dose level of olaratumab, the study has proceeded to the next cohort. In those patients, an olaratumab loading dose of 20 mg/kg will be evaluated in cycle 1, followed by 15 mg/kg of olaratumab in subsequent cycles with the same doses of doxorubicin plus ifosfamide, the researchers wrote in their abstract.
The phase 1 trial enrolled 16 patients with advanced or metastatic soft tissue sarcomas and no prior lines of systemic therapy and ECOG performance status 0-1. Adequate follow up data was available for 10 patients.
Olaratumab, (Lartruvo), which binds platelet-derived growth factor receptor alpha (PDGFRα), was given at 15 mg/kg in combination with doxorubicin (75 mg/m2 on days 1-3) and ifosfamide (10 g/m2 on days 1-4) followed by mandatory granulocyte-colony-stimulating factor therapy in cycles 1-6 on a 21-day cycle. Doxorubicin was allowed to be administered by continuous infusion or bolus administration and with cardiac protection. Mesna dosing was at least 60% of the ifosfamide dose.
Two of the 10 patients had dose-limiting toxicities; one had Grade 4 febrile neutropenia and the other had Grade 3 febrile neutropenia and Grade 3 mucositis. Common related adverse events occurring in over 30% of patients included fatigue, anemia, neutropenia, thrombocytopenia, constipation, and nausea. One patient discontinued study treatment due to progressive disease, and all others were on study treatment as of data cutoff. Among 7 patients evaluated for tumor response assessment, 3 patients had a partial response according to RECIST and 3 further patients had stabilized disease as best overall response for a disease control rate of 86%.
Anthracycline-based regimen excels in FIGO-1 uterine leiomyosarcoma
Future trials to assess the efficacy of adjuvant chemotherapy in uterine leiomyosarcoma should incorporate anthracyclines, according to Roberta Sanfilippo, MD, of Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, and her colleagues.
Disease-free survival was extended in patients with uterine leiomyosarcomas treated with anthracycline-based regimens as compared to gemcitabine and docetaxel, based on a retrospective analysis reported at the meeting by Dr. Sanfilippo.
They reviewed all patients with FIGO stage I uterine leiomyosarcomas who underwent hysterectomy with or without oophorectomy and were treated with adjuvant chemotherapy with either anthracycline-based or gemcitabine-based chemotherapy at two Italian centers.
Of 145 patients, 97 were treated with an anthracycline-based regimen and 48 with gemcitabine and docetaxel. The median number of cycles of anthracycline based regimen received was 4 (range 2-6) and with gemcitabine and docetaxel was 5 (range 3-7). Disease free survival was 31 months in patients treated with anthracycline-based chemotherapy and 19 months in patients treated with gemcitabine and docetaxel.
Trabectedin and low-dose radiotherapy
Trabectedin concurrent with low-dose radiotherapy is being examined as an option for patients with pulmonary metastatic soft tissue sarcoma (NCT02275286).
In a phase 1 study, long-lasting dimensional responses were seen in 71% of the irradiated lesions showed. Based on those results, trabectedin (Yondelis) at 1.5 mg/m 2 will be the recommended dose for phase 2, according to Javier Martín-Broto, MD, of the Institute of Biomedicine Research (IBIS)-University Hospital Virgen del Rocio/CSIC/University of Seville, Spain, and his colleagues.
For the study, trabectedin was given along with radiotherapy (30 Gy) in 10 fractions (3 Gy/fraction). Three dose levels of trabectedin were administered: -1 (1.1 mg/m 2), 1 (1.3 mg/m 2) and 2 (1.5 mg/m 2). Dose-limiting toxicity was defined as grade 3 or greater events excluding grade 3/4 neutropenia lasting less than 5 days, grade 3 transaminitis if it did not lead to trabectedin delay, and grade 3/4 nausea/vomiting due to inadequate prophylaxis.
Ten of the 18 patients enrolled had synovial sarcoma; 3 had undifferentiated pleomorphic sarcomas and the other patients had either myxoid liposarcoma, dedifferentiated liposarcoma, G3 not otherwise specified sarcoma, leiomyosarcoma, and malignant peripheral nerve sheath tumor.
Patients received a median of 1 prior line of chemotherapy (range: 0-3). Twelve patients received trabectedin at dose level 1 and 6 patients at dose level 2. Grade 3/4 adverse events were neutropenia, seen in 8 patients; alanine aminotransferase (ALT) elevation, seen in 2 patients; gamma-glutamyl transferase (GGT) elevation, seen in 2 patients; anemia, seen in 2 patients; febrile neutropenia, seen in 1 patient; and pneumonitis, seen in 1 patient.
There were two dose-limiting toxicities: transient grade 4 ALT elevation at the level 1 dose and grade 4 neutropenia for more than 5 days at the level 2 dose.
Based on central radiological review of 17 evaluable patients, 2 patients achieved complete response, 3 had partial responses, 6 had stable disease, and 6 had progressive disease. The local review reported complete responses in 2 patients, partial responses in 5, stable disease in 4, and progressive disease in 6.
On the irradiated lesions, 4 had complete responses, 8 had partial responses, 4 had stable disease, and 1 had progressive disease. With a median follow-up of 18 months, median progression-free survival was 2.83 months (95%CI: 2.3-3.3 months). Thirteen patients have died, with a median overall survival of 8.77 months (95%CI: 3.6-13.9) and a 12-month overall survival rate of 48%.
Predicting response to chemotherapy
The prognostic nomogram called Sarculator was used effectively to define a high-risk subgroup of patients likely to benefit from adjuvant chemotherapy, Sandro Pasquali, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy and his colleagues reported at the meeting.
Perioperative chemotherapy was shown to afford no survival advantage over observation in the EORTC 62931 (European Organization for Research and Treatment of Cancer—62931) study of adjuvant doxorubicin plus ifosfamide (Lancet Oncol 2012;13:1045-54). However, subsequent analyses of that data attributed this finding to variations in treatment schedules and the inclusion of low-risk tumors, which may have diluted the effect of chemotherapy, the researchers said in their abstract.
Further, a recent interim report of the ISG-1001 trial showed a survival benefit for patients who received neoadjuvant epirubicin plus ifosfamide therapy for localized high-risk soft-tissue sarcoma of the extremities or trunk wall (Lancet Oncol 2017;18:812-822).
The researchers performed a retrospective analysis of individual data for 290 patients with extremity and trunk wall soft-tissue sarcomas in the EORTC-STBSG 62931 study. The Sarculator was used to calculate 10-year predicted probability of overall survival (pr-OS) for each patient.
Patients were grouped in two categories of predicted overall survival: high predicted survival (over 60%) and low predicted overall survival (60% or less). Overall survival and disease-free survival were calculated at 8 years, the study’s median follow-up.
The 8-year probability of overall survival and disease-free survival was 58% [95% confidence interval (CI): 52–63%] and 51% (95% CI: 46–57%), respectively. In the 290 patients with extremity and trunk wall soft tissue sarcomas, adjuvant chemotherapy was not associated with an overall survival benefit [Hazard ratio (HR) = 0.91, 95%CI 0.63–1.31]. The Sarcolator Nomogram detected 80 patients who were at greater risk of death compared to the 210 patients with higher predicted overall survival. The risk of death was significantly lower with adjuvant chemotherapy in the group with low predicted survival based on the Sarculator Nomogram (HR=0.50, 95%CI 0.30-0.90). Consistently, the risk of recurrence was significantly lower when adjuvant chemotherapy was used in the group with predicted overall survival of less than 60% (HR = 0.49, 95%CI 0.28-0.85) while this difference was not observed in patients with high predicted overall survival (HR = 0.95, 95%CI 0.62-1.44).
Doxorubicin plus dacarbazine deserve evaluation in prospective trials in leiomyosarcoma
Doxorubicin plus dacarbazine appeared to best the outcomes seen with doxorubicin plus ifosfamide and with doxorubicin alone in terms of overall response rate and progression free survival as first-line treatment in patients with advanced leiomyosarcomas, based on a retrospective analysis presented by Lorenzo D’Ambrosio, MD, of the Unitversity of Torino, Italy, and his associates.
As patients in the trial were not randomized to therapy, the researchers used a logistic regression model that accounted for histology, site of primary, age, gender, performance status, tumor extent, and tumor grade. Patients were then matched across the different groups by their propensity scores.The 303 patients, 216 of them women, were enrolled from 18 EORTC STBSG (European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group) sites. Doxorubicin plus dacarbazine was given to 117 patients (39%), doxorubicin plus ifosfamide was given to 71 (23%), and doxorubicin alone was given to 115 (38%). There were no significant differences among the regimens in terms of dose reductions of more than 10%, delays of greater than 72 hours, or granulocyte-colony stimulating factor use.
In the whole population, unadjusted median progression free survival was 9.4 months (95% CI 6.1-9.7 months) for those given doxorubicin plus dacarbazine, 6.8 months (4.5-9.5 months) for those given doxorubicin plus ifosfamide), and 5.4 months (3.8-6.8 months) for those given doxorubicin alone. The respective overall response rates for the three regimens were 36.8%, 21.5%, and 25.9%. When using propensity scores to adjust for lack of randomization, progression free survival was significantly longer with doxorubicin plus dacarbazine [median 9.2 months (95%CI 5.2-9.7 months) than with doxorubicin [median 4.8 months (2.3-6.0 months); HR 0.72 (0.52-0.99)]. The difference was not significant when compared to doxorubicin plus ifosfamide [8.2 months (5.2-10.1 months), HR 1.01 (0.68-1.50)]. Progression free survival did not differ significantly between doxorubicin plus ifosfamide, and doxorubicin [HR 0.71 (0.48-1.06)]. In the same matched population, overall response rates were 30.9%, 19.5%, and 25.6% for doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin, respectively.
Overall survival comparisons were weakened by a shorter median follow-up in the doxorubicin plus dacarbazine groups (32 months) compared to the doxorubicin plus ifosfamide group (50 months) and the doxorubicin group (46 months). With this limit, patients in the doxorubicin plus dacarbazine arm had longer overall survival [median 36.8 (27.9-47.2) months] when compared to both doxorubicin plus ifosfamide [21.9 (16.7-33.4), HR 0.65 (0.40-1.06); and doxorubicin arms 30.3 (21.0-36.3) months, HR 0.66 (0.43-0.99).
Subsequent treatments were well balanced across arms. None of the selected factors for multivariate analysis (age, sex, ECOG performance status, histotype, site of primary tumor, tumor grade, and tumor extent) significantly affected the progression free survival and overall survival associated with the treatments.
Olaratumab in combination with doxorubicin plus ifosfamide
Olaratumab at 15 mg/kg has been shown to be safe in combination with doxorubicin plus ifosfamide in a Phase 1b study (NCT03283696), reported Sebastian Bauer, MD, of the West German Cancer Center, University of Duisburg-Essen, Essen, Germany, and his colleagues.
Given that 8 of 10 evaluable patients have completed the drug-limiting toxicity period without drug-limiting toxicities at the 15 mg/kg dose level of olaratumab, the study has proceeded to the next cohort. In those patients, an olaratumab loading dose of 20 mg/kg will be evaluated in cycle 1, followed by 15 mg/kg of olaratumab in subsequent cycles with the same doses of doxorubicin plus ifosfamide, the researchers wrote in their abstract.
The phase 1 trial enrolled 16 patients with advanced or metastatic soft tissue sarcomas and no prior lines of systemic therapy and ECOG performance status 0-1. Adequate follow up data was available for 10 patients.
Olaratumab, (Lartruvo), which binds platelet-derived growth factor receptor alpha (PDGFRα), was given at 15 mg/kg in combination with doxorubicin (75 mg/m2 on days 1-3) and ifosfamide (10 g/m2 on days 1-4) followed by mandatory granulocyte-colony-stimulating factor therapy in cycles 1-6 on a 21-day cycle. Doxorubicin was allowed to be administered by continuous infusion or bolus administration and with cardiac protection. Mesna dosing was at least 60% of the ifosfamide dose.
Two of the 10 patients had dose-limiting toxicities; one had Grade 4 febrile neutropenia and the other had Grade 3 febrile neutropenia and Grade 3 mucositis. Common related adverse events occurring in over 30% of patients included fatigue, anemia, neutropenia, thrombocytopenia, constipation, and nausea. One patient discontinued study treatment due to progressive disease, and all others were on study treatment as of data cutoff. Among 7 patients evaluated for tumor response assessment, 3 patients had a partial response according to RECIST and 3 further patients had stabilized disease as best overall response for a disease control rate of 86%.
Anthracycline-based regimen excels in FIGO-1 uterine leiomyosarcoma
Future trials to assess the efficacy of adjuvant chemotherapy in uterine leiomyosarcoma should incorporate anthracyclines, according to Roberta Sanfilippo, MD, of Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, and her colleagues.
Disease-free survival was extended in patients with uterine leiomyosarcomas treated with anthracycline-based regimens as compared to gemcitabine and docetaxel, based on a retrospective analysis reported at the meeting by Dr. Sanfilippo.
They reviewed all patients with FIGO stage I uterine leiomyosarcomas who underwent hysterectomy with or without oophorectomy and were treated with adjuvant chemotherapy with either anthracycline-based or gemcitabine-based chemotherapy at two Italian centers.
Of 145 patients, 97 were treated with an anthracycline-based regimen and 48 with gemcitabine and docetaxel. The median number of cycles of anthracycline based regimen received was 4 (range 2-6) and with gemcitabine and docetaxel was 5 (range 3-7). Disease free survival was 31 months in patients treated with anthracycline-based chemotherapy and 19 months in patients treated with gemcitabine and docetaxel.
Trabectedin and low-dose radiotherapy
Trabectedin concurrent with low-dose radiotherapy is being examined as an option for patients with pulmonary metastatic soft tissue sarcoma (NCT02275286).
In a phase 1 study, long-lasting dimensional responses were seen in 71% of the irradiated lesions showed. Based on those results, trabectedin (Yondelis) at 1.5 mg/m 2 will be the recommended dose for phase 2, according to Javier Martín-Broto, MD, of the Institute of Biomedicine Research (IBIS)-University Hospital Virgen del Rocio/CSIC/University of Seville, Spain, and his colleagues.
For the study, trabectedin was given along with radiotherapy (30 Gy) in 10 fractions (3 Gy/fraction). Three dose levels of trabectedin were administered: -1 (1.1 mg/m 2), 1 (1.3 mg/m 2) and 2 (1.5 mg/m 2). Dose-limiting toxicity was defined as grade 3 or greater events excluding grade 3/4 neutropenia lasting less than 5 days, grade 3 transaminitis if it did not lead to trabectedin delay, and grade 3/4 nausea/vomiting due to inadequate prophylaxis.
Ten of the 18 patients enrolled had synovial sarcoma; 3 had undifferentiated pleomorphic sarcomas and the other patients had either myxoid liposarcoma, dedifferentiated liposarcoma, G3 not otherwise specified sarcoma, leiomyosarcoma, and malignant peripheral nerve sheath tumor.
Patients received a median of 1 prior line of chemotherapy (range: 0-3). Twelve patients received trabectedin at dose level 1 and 6 patients at dose level 2. Grade 3/4 adverse events were neutropenia, seen in 8 patients; alanine aminotransferase (ALT) elevation, seen in 2 patients; gamma-glutamyl transferase (GGT) elevation, seen in 2 patients; anemia, seen in 2 patients; febrile neutropenia, seen in 1 patient; and pneumonitis, seen in 1 patient.
There were two dose-limiting toxicities: transient grade 4 ALT elevation at the level 1 dose and grade 4 neutropenia for more than 5 days at the level 2 dose.
Based on central radiological review of 17 evaluable patients, 2 patients achieved complete response, 3 had partial responses, 6 had stable disease, and 6 had progressive disease. The local review reported complete responses in 2 patients, partial responses in 5, stable disease in 4, and progressive disease in 6.
On the irradiated lesions, 4 had complete responses, 8 had partial responses, 4 had stable disease, and 1 had progressive disease. With a median follow-up of 18 months, median progression-free survival was 2.83 months (95%CI: 2.3-3.3 months). Thirteen patients have died, with a median overall survival of 8.77 months (95%CI: 3.6-13.9) and a 12-month overall survival rate of 48%.
Predicting response to chemotherapy
The prognostic nomogram called Sarculator was used effectively to define a high-risk subgroup of patients likely to benefit from adjuvant chemotherapy, Sandro Pasquali, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy and his colleagues reported at the meeting.
Perioperative chemotherapy was shown to afford no survival advantage over observation in the EORTC 62931 (European Organization for Research and Treatment of Cancer—62931) study of adjuvant doxorubicin plus ifosfamide (Lancet Oncol 2012;13:1045-54). However, subsequent analyses of that data attributed this finding to variations in treatment schedules and the inclusion of low-risk tumors, which may have diluted the effect of chemotherapy, the researchers said in their abstract.
Further, a recent interim report of the ISG-1001 trial showed a survival benefit for patients who received neoadjuvant epirubicin plus ifosfamide therapy for localized high-risk soft-tissue sarcoma of the extremities or trunk wall (Lancet Oncol 2017;18:812-822).
The researchers performed a retrospective analysis of individual data for 290 patients with extremity and trunk wall soft-tissue sarcomas in the EORTC-STBSG 62931 study. The Sarculator was used to calculate 10-year predicted probability of overall survival (pr-OS) for each patient.
Patients were grouped in two categories of predicted overall survival: high predicted survival (over 60%) and low predicted overall survival (60% or less). Overall survival and disease-free survival were calculated at 8 years, the study’s median follow-up.
The 8-year probability of overall survival and disease-free survival was 58% [95% confidence interval (CI): 52–63%] and 51% (95% CI: 46–57%), respectively. In the 290 patients with extremity and trunk wall soft tissue sarcomas, adjuvant chemotherapy was not associated with an overall survival benefit [Hazard ratio (HR) = 0.91, 95%CI 0.63–1.31]. The Sarcolator Nomogram detected 80 patients who were at greater risk of death compared to the 210 patients with higher predicted overall survival. The risk of death was significantly lower with adjuvant chemotherapy in the group with low predicted survival based on the Sarculator Nomogram (HR=0.50, 95%CI 0.30-0.90). Consistently, the risk of recurrence was significantly lower when adjuvant chemotherapy was used in the group with predicted overall survival of less than 60% (HR = 0.49, 95%CI 0.28-0.85) while this difference was not observed in patients with high predicted overall survival (HR = 0.95, 95%CI 0.62-1.44).
Doxorubicin plus dacarbazine deserve evaluation in prospective trials in leiomyosarcoma
Doxorubicin plus dacarbazine appeared to best the outcomes seen with doxorubicin plus ifosfamide and with doxorubicin alone in terms of overall response rate and progression free survival as first-line treatment in patients with advanced leiomyosarcomas, based on a retrospective analysis presented by Lorenzo D’Ambrosio, MD, of the Unitversity of Torino, Italy, and his associates.
As patients in the trial were not randomized to therapy, the researchers used a logistic regression model that accounted for histology, site of primary, age, gender, performance status, tumor extent, and tumor grade. Patients were then matched across the different groups by their propensity scores.The 303 patients, 216 of them women, were enrolled from 18 EORTC STBSG (European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group) sites. Doxorubicin plus dacarbazine was given to 117 patients (39%), doxorubicin plus ifosfamide was given to 71 (23%), and doxorubicin alone was given to 115 (38%). There were no significant differences among the regimens in terms of dose reductions of more than 10%, delays of greater than 72 hours, or granulocyte-colony stimulating factor use.
In the whole population, unadjusted median progression free survival was 9.4 months (95% CI 6.1-9.7 months) for those given doxorubicin plus dacarbazine, 6.8 months (4.5-9.5 months) for those given doxorubicin plus ifosfamide), and 5.4 months (3.8-6.8 months) for those given doxorubicin alone. The respective overall response rates for the three regimens were 36.8%, 21.5%, and 25.9%. When using propensity scores to adjust for lack of randomization, progression free survival was significantly longer with doxorubicin plus dacarbazine [median 9.2 months (95%CI 5.2-9.7 months) than with doxorubicin [median 4.8 months (2.3-6.0 months); HR 0.72 (0.52-0.99)]. The difference was not significant when compared to doxorubicin plus ifosfamide [8.2 months (5.2-10.1 months), HR 1.01 (0.68-1.50)]. Progression free survival did not differ significantly between doxorubicin plus ifosfamide, and doxorubicin [HR 0.71 (0.48-1.06)]. In the same matched population, overall response rates were 30.9%, 19.5%, and 25.6% for doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin, respectively.
Overall survival comparisons were weakened by a shorter median follow-up in the doxorubicin plus dacarbazine groups (32 months) compared to the doxorubicin plus ifosfamide group (50 months) and the doxorubicin group (46 months). With this limit, patients in the doxorubicin plus dacarbazine arm had longer overall survival [median 36.8 (27.9-47.2) months] when compared to both doxorubicin plus ifosfamide [21.9 (16.7-33.4), HR 0.65 (0.40-1.06); and doxorubicin arms 30.3 (21.0-36.3) months, HR 0.66 (0.43-0.99).
Subsequent treatments were well balanced across arms. None of the selected factors for multivariate analysis (age, sex, ECOG performance status, histotype, site of primary tumor, tumor grade, and tumor extent) significantly affected the progression free survival and overall survival associated with the treatments.
Olaratumab in combination with doxorubicin plus ifosfamide
Olaratumab at 15 mg/kg has been shown to be safe in combination with doxorubicin plus ifosfamide in a Phase 1b study (NCT03283696), reported Sebastian Bauer, MD, of the West German Cancer Center, University of Duisburg-Essen, Essen, Germany, and his colleagues.
Given that 8 of 10 evaluable patients have completed the drug-limiting toxicity period without drug-limiting toxicities at the 15 mg/kg dose level of olaratumab, the study has proceeded to the next cohort. In those patients, an olaratumab loading dose of 20 mg/kg will be evaluated in cycle 1, followed by 15 mg/kg of olaratumab in subsequent cycles with the same doses of doxorubicin plus ifosfamide, the researchers wrote in their abstract.
The phase 1 trial enrolled 16 patients with advanced or metastatic soft tissue sarcomas and no prior lines of systemic therapy and ECOG performance status 0-1. Adequate follow up data was available for 10 patients.
Olaratumab, (Lartruvo), which binds platelet-derived growth factor receptor alpha (PDGFRα), was given at 15 mg/kg in combination with doxorubicin (75 mg/m2 on days 1-3) and ifosfamide (10 g/m2 on days 1-4) followed by mandatory granulocyte-colony-stimulating factor therapy in cycles 1-6 on a 21-day cycle. Doxorubicin was allowed to be administered by continuous infusion or bolus administration and with cardiac protection. Mesna dosing was at least 60% of the ifosfamide dose.
Two of the 10 patients had dose-limiting toxicities; one had Grade 4 febrile neutropenia and the other had Grade 3 febrile neutropenia and Grade 3 mucositis. Common related adverse events occurring in over 30% of patients included fatigue, anemia, neutropenia, thrombocytopenia, constipation, and nausea. One patient discontinued study treatment due to progressive disease, and all others were on study treatment as of data cutoff. Among 7 patients evaluated for tumor response assessment, 3 patients had a partial response according to RECIST and 3 further patients had stabilized disease as best overall response for a disease control rate of 86%.
Anthracycline-based regimen excels in FIGO-1 uterine leiomyosarcoma
Future trials to assess the efficacy of adjuvant chemotherapy in uterine leiomyosarcoma should incorporate anthracyclines, according to Roberta Sanfilippo, MD, of Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, and her colleagues.
Disease-free survival was extended in patients with uterine leiomyosarcomas treated with anthracycline-based regimens as compared to gemcitabine and docetaxel, based on a retrospective analysis reported at the meeting by Dr. Sanfilippo.
They reviewed all patients with FIGO stage I uterine leiomyosarcomas who underwent hysterectomy with or without oophorectomy and were treated with adjuvant chemotherapy with either anthracycline-based or gemcitabine-based chemotherapy at two Italian centers.
Of 145 patients, 97 were treated with an anthracycline-based regimen and 48 with gemcitabine and docetaxel. The median number of cycles of anthracycline based regimen received was 4 (range 2-6) and with gemcitabine and docetaxel was 5 (range 3-7). Disease free survival was 31 months in patients treated with anthracycline-based chemotherapy and 19 months in patients treated with gemcitabine and docetaxel.
Trabectedin and low-dose radiotherapy
Trabectedin concurrent with low-dose radiotherapy is being examined as an option for patients with pulmonary metastatic soft tissue sarcoma (NCT02275286).
In a phase 1 study, long-lasting dimensional responses were seen in 71% of the irradiated lesions showed. Based on those results, trabectedin (Yondelis) at 1.5 mg/m 2 will be the recommended dose for phase 2, according to Javier Martín-Broto, MD, of the Institute of Biomedicine Research (IBIS)-University Hospital Virgen del Rocio/CSIC/University of Seville, Spain, and his colleagues.
For the study, trabectedin was given along with radiotherapy (30 Gy) in 10 fractions (3 Gy/fraction). Three dose levels of trabectedin were administered: -1 (1.1 mg/m 2), 1 (1.3 mg/m 2) and 2 (1.5 mg/m 2). Dose-limiting toxicity was defined as grade 3 or greater events excluding grade 3/4 neutropenia lasting less than 5 days, grade 3 transaminitis if it did not lead to trabectedin delay, and grade 3/4 nausea/vomiting due to inadequate prophylaxis.
Ten of the 18 patients enrolled had synovial sarcoma; 3 had undifferentiated pleomorphic sarcomas and the other patients had either myxoid liposarcoma, dedifferentiated liposarcoma, G3 not otherwise specified sarcoma, leiomyosarcoma, and malignant peripheral nerve sheath tumor.
Patients received a median of 1 prior line of chemotherapy (range: 0-3). Twelve patients received trabectedin at dose level 1 and 6 patients at dose level 2. Grade 3/4 adverse events were neutropenia, seen in 8 patients; alanine aminotransferase (ALT) elevation, seen in 2 patients; gamma-glutamyl transferase (GGT) elevation, seen in 2 patients; anemia, seen in 2 patients; febrile neutropenia, seen in 1 patient; and pneumonitis, seen in 1 patient.
There were two dose-limiting toxicities: transient grade 4 ALT elevation at the level 1 dose and grade 4 neutropenia for more than 5 days at the level 2 dose.
Based on central radiological review of 17 evaluable patients, 2 patients achieved complete response, 3 had partial responses, 6 had stable disease, and 6 had progressive disease. The local review reported complete responses in 2 patients, partial responses in 5, stable disease in 4, and progressive disease in 6.
On the irradiated lesions, 4 had complete responses, 8 had partial responses, 4 had stable disease, and 1 had progressive disease. With a median follow-up of 18 months, median progression-free survival was 2.83 months (95%CI: 2.3-3.3 months). Thirteen patients have died, with a median overall survival of 8.77 months (95%CI: 3.6-13.9) and a 12-month overall survival rate of 48%.