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Survival of soft tissue sarcoma patients after completing six cycles of first-line anthracycline containing treatment: an EORTC-STBSG database study

Survival of soft tissue sarcoma patients after completing six cycles of first-line anthracycline... Background: Doxorubicin based chemotherapy is standard first line treatment for patients with soft tissue sarcoma. Currently several options to improve survival after doxorubicin based chemotherapy are being studied. This study reports on survival after completing 6 cycles of doxorubicin containing first line treatment, which is important when designing studies trying to improve outcomes of first line treatment. Methods: A retrospective database analysis was performed on 2045 patients from 12 EORTC sarcoma trials (inclusion period 1980–2012) receiving first line doxorubicin based chemotherapy for advanced soft tissue sarcoma in order to establish progression free survival and overall survival after completing 6 cycles of first line doxorubicin based chemo - therapy. Endpoints were overall survival and progression free survival. Factors studied were histologic subtype and type of doxorubicin chemotherapy. Results: 748 of 2045 (36.6%) received at least 6 cycles and did not progress during or at the end of chemotherapy. 475 of 2045 (23.2%) of patients received exactly 6 cycles and did not progress during or at the end of chemotherapy. Median progression free survival after 6 cycles of doxorubicin based chemotherapy was 4.2 months (95% confidence interval 3.7–4.8) and median overall survival 15.7 months (14.0–17.8). Median progression free survival and overall survival from randomisation/registration were 8.7 months (95% confidence interval 8.2–9.1) and 20.1 months (95% confidence interval 18.3–22.3) respectively. Significant differences in progression free survival were found between chemotherapy regimens, but not for overall survival. These data are also reported for patients receiving 7 or more cycles of chemotherapy and for patients with 3 or more cycles of chemotherapy. Conclusion: This large retrospective study is the first to report progression free survival and overall survival after completion of 6 cycles of first line doxorubicin containing chemotherapy. These results are important when designing new studies exploring for example maintenance therapy after doxorubicin based chemotherapy. Keywords: Soft tissue sarcoma, Doxorubicin, Prognosis, Ifosfamide, Overall survival, Progression-free survival Background Soft tissue sarcomas (STS) are a rare group of tumours comprising approximately 1% of all cancers and con- *Correspondence: a.j.gelderblom@lumc.nl Department of Medical Oncology, Leiden University Medical Center, P.O. taining approximately 70 different histological enti - box 9600, 2300 RC Leiden, The Netherlands ties [1]. Clinical behaviour differs between the various Full list of author information is available at the end of the article © The Author(s) 2020. 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The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Verschoor et al. Clin Sarcoma Res (2020) 10:18 Page 2 of 9 histological entities [1]. Surgery is the primary treatment were included in the different studies between 1980 and for localized disease when resection is possible with the 2012) [3, 9–19]. All but one study, included patients with option of adding neo-adjuvant or adjuvant radiotherapy locally advanced or metastatic STS. The study by Stew - [2]. For patients with locally advanced and/or distant ard et al. only included patients with metastatic STS [12]. metastatic disease the goal of treatment is to prolong Patients with at least 1 cycle of treatment were consid- survival and treatment mainly consists of systemic treat- ered for this study. Reasons for exclusion were previ- ment, e.g. cytotoxic drugs and tyrosine kinase inhibitors ous treatment with chemotherapy either as adjuvant or [2]. palliative treatment, patients without data on progres- The current first line chemotherapy consists of anthra - sion and death and patients diagnosed with Gastroin- cycline based chemotherapy either as monotherapy testinal Stromal Tumour (GIST). Among these patients, or combination therapy [3]. Survival remains poor for we focused on patients who did not progress before the patients presenting with incurable disease. Overall sur- end of treatment. End of treatment was considered to vival (OS) with doxorubicin monotherapy is approxi- be 21  days after the date of administration of the last mately 12.8  months and with doxorubicin/ifosfamide treatment (Additional file  1: Figure S1). Analysis was combination therapy approximately 14.3  months [3]. done in three different subgroups: patients who received More recent trials report slightly better median OS for exactly 6 cycles of doxorubicin containing chemotherapy, doxorubicin monotherapy with 17.6  months (GeDDiS), patients with 7 or more cycles and patients with less than 16.9 months (PICASSO III) and 19.0 months (SARC021) 6 cycles who stopped treatment for reasons other than [4–6]. Although the phase II results of the addition of progression. olaratumab to doxorubicin were promising and resulted The EORTC studies 62012, 62061, 62091, 62962 and in a temporary approval by both the U.S. Food and Drug 62971 had treatment regimens including a maximum Administration and the European Medical Agency, the number of 6 cycles of doxorubicin, 62941 7 cycles and results of the phase III ANNOUNCE trial were nega- the other studies aimed for a cumulative dose of 550 mg/ tive and the registration of olaratumab was withdrawn m of doxorubicin allowing for more if the ejection frac- [7, 8]. These phase III results did not show any differ - tion remained within certain limits. ence in overall survival for patients treated with the addi- tion of olaratumab to doxorubicin compared to patients Endpoints with doxorubicin with placebo (median overall survival Endpoints were PFS and OS after completing treatment, 20.4 months (with olaratumab) vs. 19.7 months without) because the aim of the study was to determine PFS and [8]. OS after completion of 6 cycles of doxorubicin contain- Now, other treatment strategies have to be studied to ing treatment in patients who did not have progressive increase the PFS and OS of STS patients including the disease at that time point. PFS was defined as the time addition of maintenance therapy after completing six between end of treatment and progression or death. OS cycles of doxorubicin. In order to assist in the design of was defined as the time between end of treatment and maintenance studies it is important to have survival data death. Also calculated were PFS from date of randomi- of patients after completing six cycles of doxorubicin sation to date of progression or death and OS from date containing treatment and to understand the extent of of randomisation to date of death. Patients progress- the attrition in the number of patients available for study, ing between start of treatment and 21 days after the last indeed the percentage who could possibly benefit from administration date were not considered for the PFS and maintenance therapy by not having progressed before OS after treatment analysis, because only those patients completing 6 cycles of treatment. This study reports who do not have progression before the start of mainte- the OS data of study patients completing six cycles of nance treatment will qualify for maintenance treatment. anthracycline or anthracycline combination therapy in Time on treatment was calculated from date of randomi- the European Organisation for Research and Treatment sation or registration and the end of treatment. of Cancer Soft Tissue and Bone Sarcoma Group trial database. Covariates Patients were grouped according to treatment i.e. doxo- 2 2 Methods rubicin 75  mg/m monotherapy, doxorubicin 50  mg/m Patients combined with ifosfamide 5  g/m , doxorubicin 75  mg/ 2 2 The European Organisation for Research and Treatment m combined with ifosfamide 5  g/m and doxorubicin 2 2 of Cancer Soft Tissue and Bone Sarcoma Group study 75  mg/m combined with ifosfamide 10  g/m . The other database contains data from 12 trials studying doxoru- covariate considered in this study was histologic sub- bicin alone or in combination with ifosfamide (patients type. If central pathology review was available the central V erschoor et al. Clin Sarcoma Res (2020) 10:18 Page 3 of 9 pathology diagnosis was used, if it was not present the Baseline characteristics local pathology diagnosis was used. Only histologic sub- Tables  2 and 3 and Additional file  1: Table  S1a–d show types comprising more than ten percent of patients were the characteristics of the included patients. No important considered for separate analysis. differences exist between the different groups. The most common histologic subtype was leiomyosarcoma (31%), Statistics followed by the no longer existing histologic entity malig- PFS and OS were calculated using the Kaplan Meier nant fibrous histiocytoma (MFH) (13%) and synovial sar - method. PFS and OS were compared using a cox propor- coma (10%) (Additional file  1: Table  S3). As none of the tional hazard model. Significance was set at p = 0.05. other subtypes did comprise ten percent of the patients as an entity, these were considered together when his- Results tologic subtype was studied (also MFH was added to In total, 2045 patients were included in this study [PFS the miscellaneous group as this entity no longer exists; from randomisation for the complete population was smaller subgroups would reduce the statistical power). 4.8  months (95% confidence interval 4.4–5.1) and OS from randomisation was 12.4  months (11.9–12.9)]. Patients treated with at least 6 cycles of treatment Almost 50% of patients were treated with doxorubicin Considering the 748 patients with at least 6 cycles of 75  mg/m as monotherapy; the other patients were treatment and without progression before or at the treated with one of the combination regimens (Addi- end of treatment, the median PFS from randomisation tional file  1: Table  S1 shows the distribution of patients was 9.4  months (95% confidence interval: 8.9–9.9) and according to study and treatment regimen. Additional median PFS from end of treatment was 4.3 months (95% file  1: Table S2 shows the number of treatment cycles by confidence interval: 3.8–4.7) (Additional file  1: Table  S4 study). Median time on treatment was 15  weeks, corre- shows the PFS per treatment regimen). PFS for the differ - sponding to a median number of 5 cycles. Of all patients, ent histologies was comparable and is provided in Addi- 43.7% of patients (894) were treated with 6 or more cycles tional file 1: Table S5. of chemotherapy, 70.2% of patients were treated with 3 Median OS from randomisation was 19.5 months (95% or more cycles. Five hundred fifty five patients (27.1%) confidence interval: 18.2–21.3) and median OS from end received exactly 6 cycles of chemotherapy. Median fol- of treatment was 14.5  months (95% confidence interval: low-up for all patients was 4.1 years [Inter quartile range 12.8–16.1) (Additional file  1: Table  S6). The median OS (IQR) 2.5–6.5 years]. Most of the patients receiving more according to histology were approximately the same and than 6 cycles, were included in studies studying the doxo- are provided in Additional file 1: Table S7. 2 2 rubicin 50 mg/m /ifosfamide 5 g/m regimen (Additional file 1: Table S1). Patients treated with exactly 6 cycles of treatment Of these patients with at least 6 cycles of treatment Because longer treatment duration could lead to bias, 748 patients (83.7% of all patients treated with 6 or more we also did the analysis for patients treated with exactly cycles) did not progress before or at the end of treat- 6 cycles. For this analysis, 475 patients were included ment. For exactly 6 cycles, 475 patients (85.6% of patients (85.6% of the total receiving 6 cycles). The median PFS treated with exactly 6 cycles) did not progress before from randomisation was 8.7  months (95% confidence the end of treatment. Table  1 shows the percentage of interval: 8.2–9.1) and the median PFS from end of treat- patients considered for this study per treatment strategy. ment was 4.2  months (95% confidence interval: 3.7–4.8) Table 1 Distribution of patients per treatment strategy and number of cycles Treatment DOX 75 (N = 948) DOX 50—IFO 5 DOX 75—IFO 5 DOX 75—IFO 10 Total (N = 2045) (N = 614) (N = 266) (N = 217) Number of patients with at least 6 cycles 403 (42.5) 270 (44.0) 103 (38.7) 118 (54.4) 895 (43.7) Progression before/at end of treatment 67 (16.6) 55 (20.4) 15 (14.6) 9 (7.6 146 (16.3) No progression before/at end of treatment 336 (83.4) 215 (79.6) 88 (85.4) 109 (92.4) 748 (83.6) Number of patients with less than 6 cycles 545 (57.4) 344 (56.0) 163 (61.3) 99 (45.6) 1151 (56.3) Progression before/at end of treatment 312 (57.2) 175 (50.9) 52 (31.9) 28 (28.3) 567 (49.3) No progression before/at end of treatment 233 (42.8) 168 (49.1) 111 (68.1) 71 (71.7) 584 (50.7) Verschoor et al. Clin Sarcoma Res (2020) 10:18 Page 4 of 9 Table 2 Baseline characteristics Less than 6 cycles Exactly 6 cycles More than 6 cycles Exactly 6 cycles—no PD PD No PD Total PD No PD Total PD No PD Total Treatment before end before end (N =  1151) before end before end (N =  555) before end before end (N =  339) DOX 75 DOX DOX DOX Total of treatment of treatment of treatment of treatment of treatment of treatment (N = 223) 50-IFO 5 75-IFO 5 75-IFO 10 (N = 475) (N = 567) (N = 584) (N = 80) (N = 475) (N = 66) (N = 273) (N = 80) (N = 63) (N = 109) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) Gender Male 273 (48.1) 284 (48.6) 557 (48.4) 45 (56.3) 226 (47.6) 271 (48.8) 26 (39.4) 139 (50.9) 165 (48.7) 102 (45.7) 34 (42.5) 30 (47.6) 60 (55.0) 226 (47.6) Female 294 (51.9) 299 (51.2) 593 (51.5) 35 (43.8) 248 (52.2) 283 (51.0) 40 (60.6) 134 (49.1) 174 (51.3) 121 (54.3) 45 (56.3) 33 (52.4) 49 (45.0) 248 (52.2) Missing 0 (0.0) 1 (0.2) 1 (0.1) 0 (0.0) 1 (0.2) 1 (0.2) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.3) 0 (0.0) 0 (0.0) 1 (0.2) Age < 40 122 (21.5) 124 (21.2) 246 (21.4) 26 (32.5) 125 (26.3) 151 (27.2) 18 (27.3) 80 (29.3) 98 (28.9) 45 (20.2) 23 (28.8) 26 (41.3) 31 (28.4) 125 (26.3) years 40–50 137 (24.2) 122 (20.9) 259 (22.5) 20 (25.0) 115 (24.2) 135 (24.3) 11 (16.7) 64 (23.4) 75 (22.1) 54 (24.2) 15 (18.8) 9 (14.3) 37 (33.9) 115 (24.2) years 50–60 164 (28.9) 170 (29.1) 334 (29.0) 19 (23.8) 148 (31.2) 167 (30.1) 13 (19.7) 73 (26.7) 86 (25.4) 77 (34.5) 19 (23.8) 14 (22.2) 38 (34.9) 148 (31.2) years > = 60 134 (23.6) 156 (26.7) 290 (25.2) 13 (16.3) 85 (17.9) 98 (17.7) 16 (24.2) 49 (17.9) 65 (19.2) 47 (21.1) 21 (26.3) 14 (22.2) 3 (2.8) 85 (17.9) years Missing 10 (1.8) 12 (2.1) 22 (1.9) 2 (2.5) 2 (0.4) 4 (0.7) 8 (12.1) 7 (2.6) 15 (4.4) 0 (0.0) 2 (2.5) 0 (0.0) 0 (0.0) 2 (0.4) Performance status PS 0 223 (39.3) 265 (45.4) 488 (42.4) 38 (47.5) 274 (57.7) 312 (56.2) 25 (37.9) 127 (46.5) 152 (44.8) 132 (59.2) 39 (48.8) 38 (60.3) 65 (59.6) 274 (57.7) PS 1 275 (48.5) 265 (45.4) 540 (46.9) 34 (42.5) 189 (39.8) 223 (40.2) 32 (48.5) 120 (44.0) 152 (44.8) 84 (37.7) 37 (46.3) 24 (38.1) 44 (40.4) 189 (39.8) PS 2 + 67 (11.8) 51 (8.7) 118 (10.3) 8 (10.0) 11 (2.3) 19 (3.4) 9 (13.6) 24 (8.8) 33 (9.7) 7 (3.1) 3 (3.8) 1 (1.6) 0 (0.0) 11 (2.3) Missing 2 (0.4) 3 (0.5) 5 (0.4) 0 (0.0) 1 (0.2) 1 (0.2) 0 (0.0) 2 (0.7) 2 (0.6) 0 (0.0) 1 (1.3) 0 (0.0) 0 (0.0) 1 (0.2) V erschoor et al. Clin Sarcoma Res (2020) 10:18 Page 5 of 9 Table 3 Tumour and treatment characteristics Less than 6 cycles Exactly 6 cycles More than 6 cycles Exactly 6 cycles—no PD PD No PD Total PD No PD Total PD No PD Total Treatment before end before end (N = 1151) before end before end (N = 555) before end before end (N = 339) DOX 75 DOX DOX DOX Total of treatment of treatment of treatment of treatment of treatment of treatment (N = 223) 50-IFO 5 75-IFO 5 75-IFO 10 (N = 475) (N = 567) (N = 584) (N = 80) (N = 475) (N = 66) (N = 273) (N = 80) (N = 63) (N = 109) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) Histopathological grading Grade I 38 (6.7) 30 (5.1) 68 (5.9) 6 (7.5) 52 (10.9) 58 (10.5) 8 (12.1) 24 (8.8) 32 (9.4) 26 (11.7) 12 (15.0) 8 (12.7) 6 (5.5) 52 (10.9) and II Grade III 331 (58.4) 366 (62.7) 697 (60.6) 46 (57.5) 331 (69.7) 377 (67.9) 33 (50.0) 152 (55.7) 185 (54.6) 158 (70.9) 38 (47.5) 33 (52.4) 102 (93.6) 331 (69.7) Missing 198 (34.9) 188 (32.2) 386 (33.5) 28 (35.0) 92 (19.4) 120 (21.6) 25 (37.9) 97 (35.5) 122 (36.0) 39 (17.5) 30 (37.5) 22 (34.9) 1 (0.9) 92 (19.4) Site of primary tumour Other 284 (50.1) 257 (44.0) 541 (47.0) 32 (40.0) 245 (51.6) 277 (49.9) 26 (39.4) 106 (38.8) 132 (38.9) 130 (58.3) 40 (50.0) 17 (27.0) 58 (53.2) 245 (51.6) Extremities 129 (22.8) 143 (24.5) 272 (23.6) 27 (33.8) 152 (32.0) 179 (32.3) 17 (25.8) 73 (26.7) 90 (26.5) 76 (34.1) 15 (18.8) 12 (19.0) 49 (45.0) 152 (32.0) Missing 154 (27.2) 184 (31.5) 338 (29.4) 21 (26.3) 78 (16.4) 99 (17.8) 23 (34.8) 94 (34.4) 117 (34.5) 17 (7.6) 25 (31.3) 34 (54.0) 2 (1.8) 78 (16.4) Histology Leiomyo- 192 (33.9) 180 (30.8) 372 (32.3) 23 (28.8) 128 (26.9) 151 (27.2) 25 (37.9) 79 (28.9) 104 (30.7) 66 (29.6) 25 (31.3) 13 (20.6) 24 (22.0) 128 (26.9) sarcoma Synovial 32 (5.6) 59 (10.1) 91 (7.9) 10 (12.5) 71 (14.9) 81 (14.6) 6 (9.1) 29 (10.6) 35 (10.3) 37 (16.6) 8 (10.0) 7 (11.1) 19 (17.4) 71 (14.9) sarcoma Other 315 (55.6) 317 (54.3) 632 (54.9) 44 (55.0) 266 (56.0) 310 (55.9) 35 (53.0) 151 (55.3) 186 (54.9) 119 (53.4) 42 (52.5) 40 (63.5) 65 (59.6) 266 (56.0) Missing 28 (4.9) 28 (4.8) 56 (4.9) 3 (3.8) 10 (2.1) 13 (2.3) 0 (0.0) 14 (5.1) 14 (4.1) 1 (0.4) 5 (6.3) 3 (4.8) 1 (0.9) 10 (2.1) Prior surgery No surgery 60 (10.6) 57 (9.8) 117 (10.2) 10 (12.5) 19 (4.0) 29 (5.2) 3 (4.5) 25 (9.2) 28 (8.3) 8 (3.6) 11 (13.8) 0 (0.0) 0 (0.0) 19 (4.0) Non 104 (18.3) 77 (13.2) 181 (15.7) 18 (22.5) 23 (4.8) 41 (7.4) 10 (15.2) 64 (23.4) 74 (21.8) 11 (4.9) 12 (15.0) 0 (0.0) 0 (0.0) 23 (4.8) optimal surgery Complete 155 (27.3) 128 (21.9) 283 (24.6) 13 (16.3) 66 (13.9) 79 (14.2) 35 (53.0) 106 (38.8) 141 (41.6) 42 (18.8) 24 (30.0) 0 (0.0) 0 (0.0) 66 (13.9) surgery Unknown 248 (43.7) 322 (55.1) 570 (49.5) 39 (48.8) 367 (77.3) 406 (73.2) 18 (27.3) 78 (28.6) 96 (28.3) 162 (72.6) 33 (41.3) 63 (100.0) 109 (100.0) 367 (77.3) Prior radiotherapy No 435 (76.7) 390 (66.8) 825 (71.7) 58 (72.5) 279 (58.7) 337 (60.7) 43 (65.2) 191 (70.0) 234 (69.0) 115 (51.6) 57 (71.3) 41 (65.1) 66 (60.6) 279 (58.7) Yes 119 (21.0) 171 (29.3) 290 (25.2) 19 (23.8) 153 (32.2) 172 (31.0) 23 (34.8) 82 (30.0) 105 (31.0) 66 (29.6) 22 (27.5) 22 (34.9) 43 (39.4) 153 (32.2) Missing 13 (2.3) 23 (3.9) 36 (3.1) 3 (3.8) 43 (9.1) 46 (8.3) 0 (0) 0 (0) 0 (0) 42 (18.8) 1 (1.3) 0 (0.0) 0 (0.0) 43 (9.1) Primary site involved No 195 (34.4) 219 (37.5) 414 (36.0) 35 (43.8) 244 (51.4) 279 (50.3) 36 (54.5) 112 (41.0) 148 (43.7) 122 (54.7) 42 (52.5) 22 (34.9) 58 (53.2) 244 (51.4) Yes 310 (54.7) 288 (49.3) 598 (52.0) 37 (46.3) 192 (40.4) 229 (41.3) 25 (37.9) 133 (48.7) 158 (46.6) 86 (38.6) 38 (47.5) 17 (27.0) 51 (46.8) 192 (40.4) Missing 62 (10.9) 77 (13.2) 139 (12.1) 8 (10.0) 39 (8.2) 47 (8.5) 5 (7.6) 28 (10.3) 33 (9.7) 15 (6.7) 0 (0.0) 24 (38.1) 0 (0.0) 39 (8.2) Verschoor et al. Clin Sarcoma Res (2020) 10:18 Page 6 of 9 Table 3 (continued) Less than 6 cycles Exactly 6 cycles More than 6 cycles Exactly 6 cycles—no PD PD No PD Total PD No PD Total PD No PD Total Treatment before end before end (N = 1151) before end before end (N = 555) before end before end (N = 339) DOX 75 DOX DOX DOX Total of treatment of treatment of treatment of treatment of treatment of treatment (N = 223) 50-IFO 5 75-IFO 5 75-IFO 10 (N = 475) (N = 567) (N = 584) (N = 80) (N = 475) (N = 66) (N = 273) (N = 80) (N = 63) (N = 109) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) Metastatic site involved No 79 (13.9) 99 (17.0) 178 (15.5) 10 (12.5) 49 (10.3) 59 (10.6) 10 (15.2) 45 (16.5) 55 (16.2) 22 (9.9) 14 (17.5) 5 (7.9) 8 (7.3) 49 (10.3) Yes 426 (75.1) 408 (69.9) 834 (72.5) 62 (77.5) 387 (81.5) 449 (80.9) 51 (77.3) 200 (73.3) 251 (74.0) 186 (83.4) 66 (82.5) 34 (54.0) 101 (92.7) 387 (81.5) Missing 62 (10.9) 77 (13.2) 139 (12.1) 8 (10.0) 39 (8.2) 47 (8.5) 5 (7.6) 28 (10.3) 33 (9.7) 15 (6.7) 0 (0.0) 24 (38.1) 0 (0.0) 39 (8.2) V erschoor et al. Clin Sarcoma Res (2020) 10:18 Page 7 of 9 (Additional file  1: Table  S8). A significant effect of treat - well-established concept in colorectal cancer, non-small ment on PFS was found, patients receiving doxorubicin cell lung cancer and ovarian cancer [20–22]. Progression monotherapy had a worse PFS compared to patients after first-line treatment can result in a deterioration in receiving doxorubicin 75  mg/m combined with ifos- performance status making it difficult or impossible to famide 10  g/m combination therapy [p = 0.021 and administer second-line treatment. Maintenance treat- p = 0.036 respectively, as already reported by Judson et al. ment is intended to improve OS by prolonging the pro- [3]]. In this analysis, no significant effect of histology on gression-free survival after first-line treatment by direct PFS was found (Additional file 1: Table S9). continuation of chemotherapy. In STS, this is even more Median OS from randomisation for these patients was a problem, because doxorubicin is first-line treatment 20.1 months (95% confidence interval: 18.3–22.3 months) and has a maximum safe cumulative dose of 450  mg/m and median OS from end of treatment was 15.7  months (6 cycles), although even at this dose there is evidence of (95% confidence interval: 14.0–17.8). There was no statis - cardiac damage in a significant percentage of patients. tically significant effect of treatment regimen or histology Administration of higher cumulative doses, e.g. 600 mg/ on OS (Additional file 1: Tables S10 and S11). m (8 cycles) as in the olaratumab study, is only possi- ble with the co-administration of the cardioprotective Patients treated with less than 6 cycles and no progressive agent cardioxane since the risk of cardiotoxicity at this disease dose without cardioprotection is in the region of 50%. An The progression-free survival for patients treated with alternative to doxorubicin would be the use of liposomal less than 6 cycles of doxorubicin-containing treatment doxorubicin, which does not have the cardiotoxic poten- regimens was 3.8  months (95% confidence interval tial of doxorubicin [16]. When considering maintenance 3.5–4.3  months) from randomisation (Additional file  1: treatment, one needs to take into account the risks of this Table S12). OS was 10.0 months (95% confidence interval therapy and the loss in quality of life caused by the main- 9.1–10.8 months) (Additional file  1: Table S14). As there tenance treatment. Drugs that have some proven util- can be a bias due to the number of cycles given, no for- ity against sarcomas and could be used in maintenance mal statistical comparisons were done. The median pro - treatment include pazopanib and trabectedin, which are gression-free survival and OS for the different treatment both well-tolerated [23–25]. Although the concept of regimens are shown in Additional file  1: Tables S13 and maintenance treatment after doxorubicin is attractive, S15 respectively, but did not differ. maintenance studies had trouble recruiting due to the temporary registration and availability of olaratumab Discussion in most of the western world. Probably, these trials will In this study, we report the progression-free and OS of now recruit more easily, because olaratumab failed in the patients completing 6 cycles of doxorubicin based chem- phase III trial. For designing future studies of mainte- otherapy who did not progress before completion of this nance therapy in STS, data on PFS and OS in this setting treatment. Knowledge of the PFS and OS of patients are essential. completing 6 cycles of doxorubicin without progressive It is important to realise that of all patients included in disease is essential for planning maintenance studies with the database, only 43.7% received 6 cycles or more and cytotoxic chemotherapy or tyrosine kinase inhibitors. It only 83.7% of these did not progress before the end of is also important to know what percentage of the total treatment (36.6% of all patients). Patients treated with number of patients receiving systemic therapy is likely to more than 6 cycles have a similar OS as patients receiv- be available for such trials. ing exactly 6 cycles of doxorubicin, but patients receiving The prognosis of patients with metastatic STS remains less than 6 cycles without progressive disease at the end poor, with a median OS of 12.8–14.3 months respectively of treatment have a worse survival. Based on this data- in a recently reported study of first-line doxorubicin base study we roughly estimate that only one third of all versus doxorubicin/ifosfamide [3]. More recent studies patients (all patients receiving 6 or more cycles and no show a median OS around 18  months [4–6]. Although progressive disease at end of treatment) will qualify for the addition of olaratumab to doxorubicin seemed to be maintenance treatment. promising based on the phase II data, the confirmatory The PFS of 8.7  months and the OS of 20.1  months phase III trial, ANNOUNCE, did not show any benefit from randomisation is much longer than the mean OS of the addition of olaratumab to doxorubicin (median of patients included in first line studies. Of course, this overall survival 20.4 versus 19.7  months) [7, 8]. Now, is an expected difference because responding patients one of the other strategies that could be explored to will have a better prognosis compared to patients not improve the OS of STS patients is the addition of main- responding to chemotherapy. On the other hand, this tenance therapy after first-line chemotherapy. This is a improved survival should be accounted for when Verschoor et al. Clin Sarcoma Res (2020) 10:18 Page 8 of 9 planning maintenance studies and single arm phase II Supplementary information studies. Supplementary information accompanies this paper at https ://doi. org/10.1186/s1356 9-020-00137 -5. One of the major limitations of this study is the long interval between the first included patient and the last Additional file 1. Additional Tables. included patient. Ifosfamide was already available in the early years of this study, but trabectedin, pazopanib and gemcitabine/docetaxel are new second or later Abbreviations GIST: Gastro-intestinal stromal tumour; IQR: Interquartile range; MFH: Malig- line treatments prolonging PFS and/or OS [19, 23, 26]. nant fibrous histiocytoma; OS: Overall survival; PFS: Progression free survival; These new second line treatments will cause bias when STS: Soft tissue sarcoma. comparing older regimens like doxorubicin 50  mg/m Acknowledgements combined with ifosfamide 5  g/m to newer regimens This publication was supported by the EORTC Cancer Research Fund. like doxorubicin 75  mg/m combined with ifosfamide 10  g/m . The improved supportive care over the years Authors’ contributions Study design: AJV, SL, HG; Data acquisition: SM, MT, IJ, EW, HG, ALC; Statisti- will increase this bias somewhat further. cal analysis and interpretation: AJV, SL, HG; Manuscript preparation: AJV, HG; In this study, treatment regimen had only a signifi - Manuscript editing and review: All authors; All authors read and approved the cant effect on PFS, with doxorubicin 75  mg/m com- final manuscript. bined with ifosfamide 10 g/m having the best PFS. No Funding significant effect on OS was found, but a trend towards This work was financially supported by the European Organisation for an increase in OS was found for patients with doxoru- Research and Treatment of Cancer unconditionally. bicin/ifosfamide combination therapy, which is more or Data availability less comparable with our study on this regimen, show- The data used in this manuscript is available on request. The data is stored at ing only a very little improvement in OS compared with EORTC. For conditions and procedures to assess the data: https ://www.eortc .org/data-shari ng/ doxorubicin 75  mg/m monotherapy [3]. The increase in PFS without an increase in OS in this study could Ethics approval and consent to participate be the effect of sequentially using these agents com - All patients consented to participate in the different trials. For all studies, ethi- cal approval was provided by the medical ethical committees of the different pared to using them concurrently. For other tumours participating hospitals. Information about the ethics approval is provided in like colorectal cancer it has been shown that sequen- the manuscripts of the individual studies. tial treatment is comparable to concurrent treatment Consent for publication [27]. Second, as the study design selects for respond- Not applicable. ing patients, the difference in OS between this study and the EORTC 62012 study could be caused by the Competing interest AJV, SL, SM, IJ, MT and HG have nothing to disclose. ALC reports personal fees increased response rate with doxorubicin/ifosfamide. from Pharmamar, Lilly, Novartis and Amgen, all outside the submitted work. Importantly, this study shows no effect of histology EW reports personal fees from Novartis, Lilly, Nanobiotix, Bayer, PharmaMar, on the outcome of patients, although the number of Milestone, Menarini and New Oncology, all outside the submitted work. separately studied subtypes was small. This is in con - Author details trast to earlier studies, showing a better survival in for 1 Department of Medical Oncology, Leiden University Medical Centre, example synovial sarcoma [28]. These differences could Albinusdreef 2, 2333 ZA Leiden, The Netherlands. European Organisation for Research and Treatment of Cancer, Avenue Emmanuel Mounier 83/11, be caused by the low number of included patients in 1200 Brussels, Belgium. Institute of Cancer Research and the Royal Marsden this study, or by the exclusion of patients with progres- 4 NHS Foundation Trust, 123 Old Brompton Road, London SW7 3RP, UK. Institut sion during treatment, thereby selecting for responding Bergonié, 229 Cours de l’Argonne, 33000 Bordeaux, France. Gerhard Domagk Institute of Pathology, University Hospital Muenster, Domagkstraße 17, patients. 48149 Muenster, Germany. Institut Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France. Department of Medical Oncology, Leiden University Medical Center, P.O. box 9600, 2300 RC Leiden, The Netherlands. Conclusions Received: 20 January 2020 Accepted: 14 August 2020 This is the first study reporting the progression-free survival and OS of patients completing 6 cycles of doxorubicin containing treatment without progres- sive disease before completion of treatment. These data References are important for future study design and daily patient 1. Fletcher CDM, Bridge JA, Hogendoorn PC, Mertens F. WHO Classification of tumours of soft tissue and bone. 4th ed. Lyon: IARC press; 2013. care as one of the ways forwards to improve survival 2. Casali PG, Abecassis N, Bauer S, Biagini R, Bielack S, Bonvalot S, et al. in advanced STS could be maintenance treatment for Soft tissue and visceral sarcomas: ESMO–EURACAN Clinical Prac- the minority of patients whose disease is sensitive to tice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Supplement_4):iv51–iv67. chemotherapy. V erschoor et al. Clin Sarcoma Res (2020) 10:18 Page 9 of 9 3. 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Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/ CAELYX) versus doxorubicin in the treatment of advanced or metastatic http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Sarcoma Research Springer Journals

Survival of soft tissue sarcoma patients after completing six cycles of first-line anthracycline containing treatment: an EORTC-STBSG database study

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Abstract

Background: Doxorubicin based chemotherapy is standard first line treatment for patients with soft tissue sarcoma. Currently several options to improve survival after doxorubicin based chemotherapy are being studied. This study reports on survival after completing 6 cycles of doxorubicin containing first line treatment, which is important when designing studies trying to improve outcomes of first line treatment. Methods: A retrospective database analysis was performed on 2045 patients from 12 EORTC sarcoma trials (inclusion period 1980–2012) receiving first line doxorubicin based chemotherapy for advanced soft tissue sarcoma in order to establish progression free survival and overall survival after completing 6 cycles of first line doxorubicin based chemo - therapy. Endpoints were overall survival and progression free survival. Factors studied were histologic subtype and type of doxorubicin chemotherapy. Results: 748 of 2045 (36.6%) received at least 6 cycles and did not progress during or at the end of chemotherapy. 475 of 2045 (23.2%) of patients received exactly 6 cycles and did not progress during or at the end of chemotherapy. Median progression free survival after 6 cycles of doxorubicin based chemotherapy was 4.2 months (95% confidence interval 3.7–4.8) and median overall survival 15.7 months (14.0–17.8). Median progression free survival and overall survival from randomisation/registration were 8.7 months (95% confidence interval 8.2–9.1) and 20.1 months (95% confidence interval 18.3–22.3) respectively. Significant differences in progression free survival were found between chemotherapy regimens, but not for overall survival. These data are also reported for patients receiving 7 or more cycles of chemotherapy and for patients with 3 or more cycles of chemotherapy. Conclusion: This large retrospective study is the first to report progression free survival and overall survival after completion of 6 cycles of first line doxorubicin containing chemotherapy. These results are important when designing new studies exploring for example maintenance therapy after doxorubicin based chemotherapy. Keywords: Soft tissue sarcoma, Doxorubicin, Prognosis, Ifosfamide, Overall survival, Progression-free survival Background Soft tissue sarcomas (STS) are a rare group of tumours comprising approximately 1% of all cancers and con- *Correspondence: a.j.gelderblom@lumc.nl Department of Medical Oncology, Leiden University Medical Center, P.O. taining approximately 70 different histological enti - box 9600, 2300 RC Leiden, The Netherlands ties [1]. Clinical behaviour differs between the various Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Verschoor et al. Clin Sarcoma Res (2020) 10:18 Page 2 of 9 histological entities [1]. Surgery is the primary treatment were included in the different studies between 1980 and for localized disease when resection is possible with the 2012) [3, 9–19]. All but one study, included patients with option of adding neo-adjuvant or adjuvant radiotherapy locally advanced or metastatic STS. The study by Stew - [2]. For patients with locally advanced and/or distant ard et al. only included patients with metastatic STS [12]. metastatic disease the goal of treatment is to prolong Patients with at least 1 cycle of treatment were consid- survival and treatment mainly consists of systemic treat- ered for this study. Reasons for exclusion were previ- ment, e.g. cytotoxic drugs and tyrosine kinase inhibitors ous treatment with chemotherapy either as adjuvant or [2]. palliative treatment, patients without data on progres- The current first line chemotherapy consists of anthra - sion and death and patients diagnosed with Gastroin- cycline based chemotherapy either as monotherapy testinal Stromal Tumour (GIST). Among these patients, or combination therapy [3]. Survival remains poor for we focused on patients who did not progress before the patients presenting with incurable disease. Overall sur- end of treatment. End of treatment was considered to vival (OS) with doxorubicin monotherapy is approxi- be 21  days after the date of administration of the last mately 12.8  months and with doxorubicin/ifosfamide treatment (Additional file  1: Figure S1). Analysis was combination therapy approximately 14.3  months [3]. done in three different subgroups: patients who received More recent trials report slightly better median OS for exactly 6 cycles of doxorubicin containing chemotherapy, doxorubicin monotherapy with 17.6  months (GeDDiS), patients with 7 or more cycles and patients with less than 16.9 months (PICASSO III) and 19.0 months (SARC021) 6 cycles who stopped treatment for reasons other than [4–6]. Although the phase II results of the addition of progression. olaratumab to doxorubicin were promising and resulted The EORTC studies 62012, 62061, 62091, 62962 and in a temporary approval by both the U.S. Food and Drug 62971 had treatment regimens including a maximum Administration and the European Medical Agency, the number of 6 cycles of doxorubicin, 62941 7 cycles and results of the phase III ANNOUNCE trial were nega- the other studies aimed for a cumulative dose of 550 mg/ tive and the registration of olaratumab was withdrawn m of doxorubicin allowing for more if the ejection frac- [7, 8]. These phase III results did not show any differ - tion remained within certain limits. ence in overall survival for patients treated with the addi- tion of olaratumab to doxorubicin compared to patients Endpoints with doxorubicin with placebo (median overall survival Endpoints were PFS and OS after completing treatment, 20.4 months (with olaratumab) vs. 19.7 months without) because the aim of the study was to determine PFS and [8]. OS after completion of 6 cycles of doxorubicin contain- Now, other treatment strategies have to be studied to ing treatment in patients who did not have progressive increase the PFS and OS of STS patients including the disease at that time point. PFS was defined as the time addition of maintenance therapy after completing six between end of treatment and progression or death. OS cycles of doxorubicin. In order to assist in the design of was defined as the time between end of treatment and maintenance studies it is important to have survival data death. Also calculated were PFS from date of randomi- of patients after completing six cycles of doxorubicin sation to date of progression or death and OS from date containing treatment and to understand the extent of of randomisation to date of death. Patients progress- the attrition in the number of patients available for study, ing between start of treatment and 21 days after the last indeed the percentage who could possibly benefit from administration date were not considered for the PFS and maintenance therapy by not having progressed before OS after treatment analysis, because only those patients completing 6 cycles of treatment. This study reports who do not have progression before the start of mainte- the OS data of study patients completing six cycles of nance treatment will qualify for maintenance treatment. anthracycline or anthracycline combination therapy in Time on treatment was calculated from date of randomi- the European Organisation for Research and Treatment sation or registration and the end of treatment. of Cancer Soft Tissue and Bone Sarcoma Group trial database. Covariates Patients were grouped according to treatment i.e. doxo- 2 2 Methods rubicin 75  mg/m monotherapy, doxorubicin 50  mg/m Patients combined with ifosfamide 5  g/m , doxorubicin 75  mg/ 2 2 The European Organisation for Research and Treatment m combined with ifosfamide 5  g/m and doxorubicin 2 2 of Cancer Soft Tissue and Bone Sarcoma Group study 75  mg/m combined with ifosfamide 10  g/m . The other database contains data from 12 trials studying doxoru- covariate considered in this study was histologic sub- bicin alone or in combination with ifosfamide (patients type. If central pathology review was available the central V erschoor et al. Clin Sarcoma Res (2020) 10:18 Page 3 of 9 pathology diagnosis was used, if it was not present the Baseline characteristics local pathology diagnosis was used. Only histologic sub- Tables  2 and 3 and Additional file  1: Table  S1a–d show types comprising more than ten percent of patients were the characteristics of the included patients. No important considered for separate analysis. differences exist between the different groups. The most common histologic subtype was leiomyosarcoma (31%), Statistics followed by the no longer existing histologic entity malig- PFS and OS were calculated using the Kaplan Meier nant fibrous histiocytoma (MFH) (13%) and synovial sar - method. PFS and OS were compared using a cox propor- coma (10%) (Additional file  1: Table  S3). As none of the tional hazard model. Significance was set at p = 0.05. other subtypes did comprise ten percent of the patients as an entity, these were considered together when his- Results tologic subtype was studied (also MFH was added to In total, 2045 patients were included in this study [PFS the miscellaneous group as this entity no longer exists; from randomisation for the complete population was smaller subgroups would reduce the statistical power). 4.8  months (95% confidence interval 4.4–5.1) and OS from randomisation was 12.4  months (11.9–12.9)]. Patients treated with at least 6 cycles of treatment Almost 50% of patients were treated with doxorubicin Considering the 748 patients with at least 6 cycles of 75  mg/m as monotherapy; the other patients were treatment and without progression before or at the treated with one of the combination regimens (Addi- end of treatment, the median PFS from randomisation tional file  1: Table  S1 shows the distribution of patients was 9.4  months (95% confidence interval: 8.9–9.9) and according to study and treatment regimen. Additional median PFS from end of treatment was 4.3 months (95% file  1: Table S2 shows the number of treatment cycles by confidence interval: 3.8–4.7) (Additional file  1: Table  S4 study). Median time on treatment was 15  weeks, corre- shows the PFS per treatment regimen). PFS for the differ - sponding to a median number of 5 cycles. Of all patients, ent histologies was comparable and is provided in Addi- 43.7% of patients (894) were treated with 6 or more cycles tional file 1: Table S5. of chemotherapy, 70.2% of patients were treated with 3 Median OS from randomisation was 19.5 months (95% or more cycles. Five hundred fifty five patients (27.1%) confidence interval: 18.2–21.3) and median OS from end received exactly 6 cycles of chemotherapy. Median fol- of treatment was 14.5  months (95% confidence interval: low-up for all patients was 4.1 years [Inter quartile range 12.8–16.1) (Additional file  1: Table  S6). The median OS (IQR) 2.5–6.5 years]. Most of the patients receiving more according to histology were approximately the same and than 6 cycles, were included in studies studying the doxo- are provided in Additional file 1: Table S7. 2 2 rubicin 50 mg/m /ifosfamide 5 g/m regimen (Additional file 1: Table S1). Patients treated with exactly 6 cycles of treatment Of these patients with at least 6 cycles of treatment Because longer treatment duration could lead to bias, 748 patients (83.7% of all patients treated with 6 or more we also did the analysis for patients treated with exactly cycles) did not progress before or at the end of treat- 6 cycles. For this analysis, 475 patients were included ment. For exactly 6 cycles, 475 patients (85.6% of patients (85.6% of the total receiving 6 cycles). The median PFS treated with exactly 6 cycles) did not progress before from randomisation was 8.7  months (95% confidence the end of treatment. Table  1 shows the percentage of interval: 8.2–9.1) and the median PFS from end of treat- patients considered for this study per treatment strategy. ment was 4.2  months (95% confidence interval: 3.7–4.8) Table 1 Distribution of patients per treatment strategy and number of cycles Treatment DOX 75 (N = 948) DOX 50—IFO 5 DOX 75—IFO 5 DOX 75—IFO 10 Total (N = 2045) (N = 614) (N = 266) (N = 217) Number of patients with at least 6 cycles 403 (42.5) 270 (44.0) 103 (38.7) 118 (54.4) 895 (43.7) Progression before/at end of treatment 67 (16.6) 55 (20.4) 15 (14.6) 9 (7.6 146 (16.3) No progression before/at end of treatment 336 (83.4) 215 (79.6) 88 (85.4) 109 (92.4) 748 (83.6) Number of patients with less than 6 cycles 545 (57.4) 344 (56.0) 163 (61.3) 99 (45.6) 1151 (56.3) Progression before/at end of treatment 312 (57.2) 175 (50.9) 52 (31.9) 28 (28.3) 567 (49.3) No progression before/at end of treatment 233 (42.8) 168 (49.1) 111 (68.1) 71 (71.7) 584 (50.7) Verschoor et al. Clin Sarcoma Res (2020) 10:18 Page 4 of 9 Table 2 Baseline characteristics Less than 6 cycles Exactly 6 cycles More than 6 cycles Exactly 6 cycles—no PD PD No PD Total PD No PD Total PD No PD Total Treatment before end before end (N =  1151) before end before end (N =  555) before end before end (N =  339) DOX 75 DOX DOX DOX Total of treatment of treatment of treatment of treatment of treatment of treatment (N = 223) 50-IFO 5 75-IFO 5 75-IFO 10 (N = 475) (N = 567) (N = 584) (N = 80) (N = 475) (N = 66) (N = 273) (N = 80) (N = 63) (N = 109) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) Gender Male 273 (48.1) 284 (48.6) 557 (48.4) 45 (56.3) 226 (47.6) 271 (48.8) 26 (39.4) 139 (50.9) 165 (48.7) 102 (45.7) 34 (42.5) 30 (47.6) 60 (55.0) 226 (47.6) Female 294 (51.9) 299 (51.2) 593 (51.5) 35 (43.8) 248 (52.2) 283 (51.0) 40 (60.6) 134 (49.1) 174 (51.3) 121 (54.3) 45 (56.3) 33 (52.4) 49 (45.0) 248 (52.2) Missing 0 (0.0) 1 (0.2) 1 (0.1) 0 (0.0) 1 (0.2) 1 (0.2) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.3) 0 (0.0) 0 (0.0) 1 (0.2) Age < 40 122 (21.5) 124 (21.2) 246 (21.4) 26 (32.5) 125 (26.3) 151 (27.2) 18 (27.3) 80 (29.3) 98 (28.9) 45 (20.2) 23 (28.8) 26 (41.3) 31 (28.4) 125 (26.3) years 40–50 137 (24.2) 122 (20.9) 259 (22.5) 20 (25.0) 115 (24.2) 135 (24.3) 11 (16.7) 64 (23.4) 75 (22.1) 54 (24.2) 15 (18.8) 9 (14.3) 37 (33.9) 115 (24.2) years 50–60 164 (28.9) 170 (29.1) 334 (29.0) 19 (23.8) 148 (31.2) 167 (30.1) 13 (19.7) 73 (26.7) 86 (25.4) 77 (34.5) 19 (23.8) 14 (22.2) 38 (34.9) 148 (31.2) years > = 60 134 (23.6) 156 (26.7) 290 (25.2) 13 (16.3) 85 (17.9) 98 (17.7) 16 (24.2) 49 (17.9) 65 (19.2) 47 (21.1) 21 (26.3) 14 (22.2) 3 (2.8) 85 (17.9) years Missing 10 (1.8) 12 (2.1) 22 (1.9) 2 (2.5) 2 (0.4) 4 (0.7) 8 (12.1) 7 (2.6) 15 (4.4) 0 (0.0) 2 (2.5) 0 (0.0) 0 (0.0) 2 (0.4) Performance status PS 0 223 (39.3) 265 (45.4) 488 (42.4) 38 (47.5) 274 (57.7) 312 (56.2) 25 (37.9) 127 (46.5) 152 (44.8) 132 (59.2) 39 (48.8) 38 (60.3) 65 (59.6) 274 (57.7) PS 1 275 (48.5) 265 (45.4) 540 (46.9) 34 (42.5) 189 (39.8) 223 (40.2) 32 (48.5) 120 (44.0) 152 (44.8) 84 (37.7) 37 (46.3) 24 (38.1) 44 (40.4) 189 (39.8) PS 2 + 67 (11.8) 51 (8.7) 118 (10.3) 8 (10.0) 11 (2.3) 19 (3.4) 9 (13.6) 24 (8.8) 33 (9.7) 7 (3.1) 3 (3.8) 1 (1.6) 0 (0.0) 11 (2.3) Missing 2 (0.4) 3 (0.5) 5 (0.4) 0 (0.0) 1 (0.2) 1 (0.2) 0 (0.0) 2 (0.7) 2 (0.6) 0 (0.0) 1 (1.3) 0 (0.0) 0 (0.0) 1 (0.2) V erschoor et al. Clin Sarcoma Res (2020) 10:18 Page 5 of 9 Table 3 Tumour and treatment characteristics Less than 6 cycles Exactly 6 cycles More than 6 cycles Exactly 6 cycles—no PD PD No PD Total PD No PD Total PD No PD Total Treatment before end before end (N = 1151) before end before end (N = 555) before end before end (N = 339) DOX 75 DOX DOX DOX Total of treatment of treatment of treatment of treatment of treatment of treatment (N = 223) 50-IFO 5 75-IFO 5 75-IFO 10 (N = 475) (N = 567) (N = 584) (N = 80) (N = 475) (N = 66) (N = 273) (N = 80) (N = 63) (N = 109) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) Histopathological grading Grade I 38 (6.7) 30 (5.1) 68 (5.9) 6 (7.5) 52 (10.9) 58 (10.5) 8 (12.1) 24 (8.8) 32 (9.4) 26 (11.7) 12 (15.0) 8 (12.7) 6 (5.5) 52 (10.9) and II Grade III 331 (58.4) 366 (62.7) 697 (60.6) 46 (57.5) 331 (69.7) 377 (67.9) 33 (50.0) 152 (55.7) 185 (54.6) 158 (70.9) 38 (47.5) 33 (52.4) 102 (93.6) 331 (69.7) Missing 198 (34.9) 188 (32.2) 386 (33.5) 28 (35.0) 92 (19.4) 120 (21.6) 25 (37.9) 97 (35.5) 122 (36.0) 39 (17.5) 30 (37.5) 22 (34.9) 1 (0.9) 92 (19.4) Site of primary tumour Other 284 (50.1) 257 (44.0) 541 (47.0) 32 (40.0) 245 (51.6) 277 (49.9) 26 (39.4) 106 (38.8) 132 (38.9) 130 (58.3) 40 (50.0) 17 (27.0) 58 (53.2) 245 (51.6) Extremities 129 (22.8) 143 (24.5) 272 (23.6) 27 (33.8) 152 (32.0) 179 (32.3) 17 (25.8) 73 (26.7) 90 (26.5) 76 (34.1) 15 (18.8) 12 (19.0) 49 (45.0) 152 (32.0) Missing 154 (27.2) 184 (31.5) 338 (29.4) 21 (26.3) 78 (16.4) 99 (17.8) 23 (34.8) 94 (34.4) 117 (34.5) 17 (7.6) 25 (31.3) 34 (54.0) 2 (1.8) 78 (16.4) Histology Leiomyo- 192 (33.9) 180 (30.8) 372 (32.3) 23 (28.8) 128 (26.9) 151 (27.2) 25 (37.9) 79 (28.9) 104 (30.7) 66 (29.6) 25 (31.3) 13 (20.6) 24 (22.0) 128 (26.9) sarcoma Synovial 32 (5.6) 59 (10.1) 91 (7.9) 10 (12.5) 71 (14.9) 81 (14.6) 6 (9.1) 29 (10.6) 35 (10.3) 37 (16.6) 8 (10.0) 7 (11.1) 19 (17.4) 71 (14.9) sarcoma Other 315 (55.6) 317 (54.3) 632 (54.9) 44 (55.0) 266 (56.0) 310 (55.9) 35 (53.0) 151 (55.3) 186 (54.9) 119 (53.4) 42 (52.5) 40 (63.5) 65 (59.6) 266 (56.0) Missing 28 (4.9) 28 (4.8) 56 (4.9) 3 (3.8) 10 (2.1) 13 (2.3) 0 (0.0) 14 (5.1) 14 (4.1) 1 (0.4) 5 (6.3) 3 (4.8) 1 (0.9) 10 (2.1) Prior surgery No surgery 60 (10.6) 57 (9.8) 117 (10.2) 10 (12.5) 19 (4.0) 29 (5.2) 3 (4.5) 25 (9.2) 28 (8.3) 8 (3.6) 11 (13.8) 0 (0.0) 0 (0.0) 19 (4.0) Non 104 (18.3) 77 (13.2) 181 (15.7) 18 (22.5) 23 (4.8) 41 (7.4) 10 (15.2) 64 (23.4) 74 (21.8) 11 (4.9) 12 (15.0) 0 (0.0) 0 (0.0) 23 (4.8) optimal surgery Complete 155 (27.3) 128 (21.9) 283 (24.6) 13 (16.3) 66 (13.9) 79 (14.2) 35 (53.0) 106 (38.8) 141 (41.6) 42 (18.8) 24 (30.0) 0 (0.0) 0 (0.0) 66 (13.9) surgery Unknown 248 (43.7) 322 (55.1) 570 (49.5) 39 (48.8) 367 (77.3) 406 (73.2) 18 (27.3) 78 (28.6) 96 (28.3) 162 (72.6) 33 (41.3) 63 (100.0) 109 (100.0) 367 (77.3) Prior radiotherapy No 435 (76.7) 390 (66.8) 825 (71.7) 58 (72.5) 279 (58.7) 337 (60.7) 43 (65.2) 191 (70.0) 234 (69.0) 115 (51.6) 57 (71.3) 41 (65.1) 66 (60.6) 279 (58.7) Yes 119 (21.0) 171 (29.3) 290 (25.2) 19 (23.8) 153 (32.2) 172 (31.0) 23 (34.8) 82 (30.0) 105 (31.0) 66 (29.6) 22 (27.5) 22 (34.9) 43 (39.4) 153 (32.2) Missing 13 (2.3) 23 (3.9) 36 (3.1) 3 (3.8) 43 (9.1) 46 (8.3) 0 (0) 0 (0) 0 (0) 42 (18.8) 1 (1.3) 0 (0.0) 0 (0.0) 43 (9.1) Primary site involved No 195 (34.4) 219 (37.5) 414 (36.0) 35 (43.8) 244 (51.4) 279 (50.3) 36 (54.5) 112 (41.0) 148 (43.7) 122 (54.7) 42 (52.5) 22 (34.9) 58 (53.2) 244 (51.4) Yes 310 (54.7) 288 (49.3) 598 (52.0) 37 (46.3) 192 (40.4) 229 (41.3) 25 (37.9) 133 (48.7) 158 (46.6) 86 (38.6) 38 (47.5) 17 (27.0) 51 (46.8) 192 (40.4) Missing 62 (10.9) 77 (13.2) 139 (12.1) 8 (10.0) 39 (8.2) 47 (8.5) 5 (7.6) 28 (10.3) 33 (9.7) 15 (6.7) 0 (0.0) 24 (38.1) 0 (0.0) 39 (8.2) Verschoor et al. Clin Sarcoma Res (2020) 10:18 Page 6 of 9 Table 3 (continued) Less than 6 cycles Exactly 6 cycles More than 6 cycles Exactly 6 cycles—no PD PD No PD Total PD No PD Total PD No PD Total Treatment before end before end (N = 1151) before end before end (N = 555) before end before end (N = 339) DOX 75 DOX DOX DOX Total of treatment of treatment of treatment of treatment of treatment of treatment (N = 223) 50-IFO 5 75-IFO 5 75-IFO 10 (N = 475) (N = 567) (N = 584) (N = 80) (N = 475) (N = 66) (N = 273) (N = 80) (N = 63) (N = 109) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) Metastatic site involved No 79 (13.9) 99 (17.0) 178 (15.5) 10 (12.5) 49 (10.3) 59 (10.6) 10 (15.2) 45 (16.5) 55 (16.2) 22 (9.9) 14 (17.5) 5 (7.9) 8 (7.3) 49 (10.3) Yes 426 (75.1) 408 (69.9) 834 (72.5) 62 (77.5) 387 (81.5) 449 (80.9) 51 (77.3) 200 (73.3) 251 (74.0) 186 (83.4) 66 (82.5) 34 (54.0) 101 (92.7) 387 (81.5) Missing 62 (10.9) 77 (13.2) 139 (12.1) 8 (10.0) 39 (8.2) 47 (8.5) 5 (7.6) 28 (10.3) 33 (9.7) 15 (6.7) 0 (0.0) 24 (38.1) 0 (0.0) 39 (8.2) V erschoor et al. Clin Sarcoma Res (2020) 10:18 Page 7 of 9 (Additional file  1: Table  S8). A significant effect of treat - well-established concept in colorectal cancer, non-small ment on PFS was found, patients receiving doxorubicin cell lung cancer and ovarian cancer [20–22]. Progression monotherapy had a worse PFS compared to patients after first-line treatment can result in a deterioration in receiving doxorubicin 75  mg/m combined with ifos- performance status making it difficult or impossible to famide 10  g/m combination therapy [p = 0.021 and administer second-line treatment. Maintenance treat- p = 0.036 respectively, as already reported by Judson et al. ment is intended to improve OS by prolonging the pro- [3]]. In this analysis, no significant effect of histology on gression-free survival after first-line treatment by direct PFS was found (Additional file 1: Table S9). continuation of chemotherapy. In STS, this is even more Median OS from randomisation for these patients was a problem, because doxorubicin is first-line treatment 20.1 months (95% confidence interval: 18.3–22.3 months) and has a maximum safe cumulative dose of 450  mg/m and median OS from end of treatment was 15.7  months (6 cycles), although even at this dose there is evidence of (95% confidence interval: 14.0–17.8). There was no statis - cardiac damage in a significant percentage of patients. tically significant effect of treatment regimen or histology Administration of higher cumulative doses, e.g. 600 mg/ on OS (Additional file 1: Tables S10 and S11). m (8 cycles) as in the olaratumab study, is only possi- ble with the co-administration of the cardioprotective Patients treated with less than 6 cycles and no progressive agent cardioxane since the risk of cardiotoxicity at this disease dose without cardioprotection is in the region of 50%. An The progression-free survival for patients treated with alternative to doxorubicin would be the use of liposomal less than 6 cycles of doxorubicin-containing treatment doxorubicin, which does not have the cardiotoxic poten- regimens was 3.8  months (95% confidence interval tial of doxorubicin [16]. When considering maintenance 3.5–4.3  months) from randomisation (Additional file  1: treatment, one needs to take into account the risks of this Table S12). OS was 10.0 months (95% confidence interval therapy and the loss in quality of life caused by the main- 9.1–10.8 months) (Additional file  1: Table S14). As there tenance treatment. Drugs that have some proven util- can be a bias due to the number of cycles given, no for- ity against sarcomas and could be used in maintenance mal statistical comparisons were done. The median pro - treatment include pazopanib and trabectedin, which are gression-free survival and OS for the different treatment both well-tolerated [23–25]. Although the concept of regimens are shown in Additional file  1: Tables S13 and maintenance treatment after doxorubicin is attractive, S15 respectively, but did not differ. maintenance studies had trouble recruiting due to the temporary registration and availability of olaratumab Discussion in most of the western world. Probably, these trials will In this study, we report the progression-free and OS of now recruit more easily, because olaratumab failed in the patients completing 6 cycles of doxorubicin based chem- phase III trial. For designing future studies of mainte- otherapy who did not progress before completion of this nance therapy in STS, data on PFS and OS in this setting treatment. Knowledge of the PFS and OS of patients are essential. completing 6 cycles of doxorubicin without progressive It is important to realise that of all patients included in disease is essential for planning maintenance studies with the database, only 43.7% received 6 cycles or more and cytotoxic chemotherapy or tyrosine kinase inhibitors. It only 83.7% of these did not progress before the end of is also important to know what percentage of the total treatment (36.6% of all patients). Patients treated with number of patients receiving systemic therapy is likely to more than 6 cycles have a similar OS as patients receiv- be available for such trials. ing exactly 6 cycles of doxorubicin, but patients receiving The prognosis of patients with metastatic STS remains less than 6 cycles without progressive disease at the end poor, with a median OS of 12.8–14.3 months respectively of treatment have a worse survival. Based on this data- in a recently reported study of first-line doxorubicin base study we roughly estimate that only one third of all versus doxorubicin/ifosfamide [3]. More recent studies patients (all patients receiving 6 or more cycles and no show a median OS around 18  months [4–6]. Although progressive disease at end of treatment) will qualify for the addition of olaratumab to doxorubicin seemed to be maintenance treatment. promising based on the phase II data, the confirmatory The PFS of 8.7  months and the OS of 20.1  months phase III trial, ANNOUNCE, did not show any benefit from randomisation is much longer than the mean OS of the addition of olaratumab to doxorubicin (median of patients included in first line studies. Of course, this overall survival 20.4 versus 19.7  months) [7, 8]. Now, is an expected difference because responding patients one of the other strategies that could be explored to will have a better prognosis compared to patients not improve the OS of STS patients is the addition of main- responding to chemotherapy. On the other hand, this tenance therapy after first-line chemotherapy. This is a improved survival should be accounted for when Verschoor et al. Clin Sarcoma Res (2020) 10:18 Page 8 of 9 planning maintenance studies and single arm phase II Supplementary information studies. Supplementary information accompanies this paper at https ://doi. org/10.1186/s1356 9-020-00137 -5. One of the major limitations of this study is the long interval between the first included patient and the last Additional file 1. Additional Tables. included patient. Ifosfamide was already available in the early years of this study, but trabectedin, pazopanib and gemcitabine/docetaxel are new second or later Abbreviations GIST: Gastro-intestinal stromal tumour; IQR: Interquartile range; MFH: Malig- line treatments prolonging PFS and/or OS [19, 23, 26]. nant fibrous histiocytoma; OS: Overall survival; PFS: Progression free survival; These new second line treatments will cause bias when STS: Soft tissue sarcoma. comparing older regimens like doxorubicin 50  mg/m Acknowledgements combined with ifosfamide 5  g/m to newer regimens This publication was supported by the EORTC Cancer Research Fund. like doxorubicin 75  mg/m combined with ifosfamide 10  g/m . The improved supportive care over the years Authors’ contributions Study design: AJV, SL, HG; Data acquisition: SM, MT, IJ, EW, HG, ALC; Statisti- will increase this bias somewhat further. cal analysis and interpretation: AJV, SL, HG; Manuscript preparation: AJV, HG; In this study, treatment regimen had only a signifi - Manuscript editing and review: All authors; All authors read and approved the cant effect on PFS, with doxorubicin 75  mg/m com- final manuscript. bined with ifosfamide 10 g/m having the best PFS. No Funding significant effect on OS was found, but a trend towards This work was financially supported by the European Organisation for an increase in OS was found for patients with doxoru- Research and Treatment of Cancer unconditionally. bicin/ifosfamide combination therapy, which is more or Data availability less comparable with our study on this regimen, show- The data used in this manuscript is available on request. The data is stored at ing only a very little improvement in OS compared with EORTC. For conditions and procedures to assess the data: https ://www.eortc .org/data-shari ng/ doxorubicin 75  mg/m monotherapy [3]. The increase in PFS without an increase in OS in this study could Ethics approval and consent to participate be the effect of sequentially using these agents com - All patients consented to participate in the different trials. For all studies, ethi- cal approval was provided by the medical ethical committees of the different pared to using them concurrently. For other tumours participating hospitals. Information about the ethics approval is provided in like colorectal cancer it has been shown that sequen- the manuscripts of the individual studies. tial treatment is comparable to concurrent treatment Consent for publication [27]. Second, as the study design selects for respond- Not applicable. ing patients, the difference in OS between this study and the EORTC 62012 study could be caused by the Competing interest AJV, SL, SM, IJ, MT and HG have nothing to disclose. ALC reports personal fees increased response rate with doxorubicin/ifosfamide. from Pharmamar, Lilly, Novartis and Amgen, all outside the submitted work. Importantly, this study shows no effect of histology EW reports personal fees from Novartis, Lilly, Nanobiotix, Bayer, PharmaMar, on the outcome of patients, although the number of Milestone, Menarini and New Oncology, all outside the submitted work. separately studied subtypes was small. This is in con - Author details trast to earlier studies, showing a better survival in for 1 Department of Medical Oncology, Leiden University Medical Centre, example synovial sarcoma [28]. These differences could Albinusdreef 2, 2333 ZA Leiden, The Netherlands. European Organisation for Research and Treatment of Cancer, Avenue Emmanuel Mounier 83/11, be caused by the low number of included patients in 1200 Brussels, Belgium. Institute of Cancer Research and the Royal Marsden this study, or by the exclusion of patients with progres- 4 NHS Foundation Trust, 123 Old Brompton Road, London SW7 3RP, UK. Institut sion during treatment, thereby selecting for responding Bergonié, 229 Cours de l’Argonne, 33000 Bordeaux, France. Gerhard Domagk Institute of Pathology, University Hospital Muenster, Domagkstraße 17, patients. 48149 Muenster, Germany. Institut Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France. Department of Medical Oncology, Leiden University Medical Center, P.O. box 9600, 2300 RC Leiden, The Netherlands. 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