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Survival is influenced by approaches to local treatment of Ewing sarcoma within an international randomised controlled trial: analysis of EICESS-92

Survival is influenced by approaches to local treatment of Ewing sarcoma within an international... Background: Two national clinical trial groups, United Kingdom Children’s Cancer and Leukaemia Group (CCLG) and the German Paediatric Oncology and Haematology Group (GPOH) together undertook a randomised trial, EICESS-92, which addressed chemotherapy options for Ewing’s sarcoma. We sought the causes of unexpected survival differ - ences between the study groups. Methods: 647 patients were randomised. Cox regression analyses were used to compare event-free survival (EFS) and overall survival (OS) between the two study groups. Results: 5-year EFS rates were 43% (95% CI 36–50%) and 57% (95% CI 52–62) in the CCLG and GPOH patients, respectively; corresponding 5-year OS rates were 52% (95% CI 45–59%) and 66% (95% CI 61–71). CCLG patients were less likely to have both surgery and radiotherapy (18 vs. 59%), and more likely to have a single local therapy modal- ity compared to the GPOH patients (72 vs. 35%). Forty-five percent of GPOH patients had pre-operative radiotherapy compared to 3% of CCLG patients. In the CCLG group local recurrence (either with or without metastases) was the first event in 22% of patients compared with 7% in the GPOH group. After allowing for the effects of age, metastases, primary site, histology and local treatment modality, the risk of an EFS event was 44% greater in the CCLG cohort (95% CI 10–89%, p = 0.009), and the risk of dying was 30% greater, but not statistically significant (95% CI 3–74%, p = 0.08). Conclusions: Unexpected differences in EFS and OS occurred between two patient cohorts recruited within an international randomised trial. Failure to select or deliver appropriate local treatment modalities for Ewing’s sarcoma may compromise chances of cure. Trial registration Supported by Deutsche Krebshilfe (Grants No. DKH M43/92/Jü2 and DKH 70-2551 Jü3), and European Union Biomedicine and Health Programme (Grants No. BMH1-CT92-1341 and BMH4-983956), and Cancer Research United Kingdom. Clinical trial information can be found for the following: NCT0000251 Keywords: Ewing sarcoma, Local therapy *Correspondence: jeremy.whelan@nhs.net Department of Oncology, University College Hospitals London NHS Foundation Trust, 250 Euston Road, London NW1 2PG, UK Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 2 of 13 treatment-related morbidity for patients with standard Background risk disease. The overall results of the trial have been Collaboration between national clinical study groups reported [3]. However, we found evidence that EFS and to run large randomised trials is advantageous, espe- overall survival (OS) differed between the CCLG and cially in rare disease settings. It allows rapid accrual of GPOH study groups. Although these data have been larger numbers of patients to provide sufficient power reported in abstract form, this more detailed analysis for robust analyses. Indeed, joint studies may be the retains relevance and influence on practice [4]. only means of effectively answering randomised ques - tions in rare cancers [1, 2]. EICESS-92, a trial developed Patients and methods and completed by the Children’s Cancer and Leukaemia The trial design of EICESS-92 is outlined in Fig.  1, and Group (CCLG, formerly United Kingdom Children’s details are described elsewhere [3]. The study was con - Cancer Study Group, UKCCSG) and the Cooperative fined to patients with primary tumours of bone. Ewing’s Sarcoma Studies (CESS) group of the German Patients with localised tumours of < 100 ml were clas- Paediatric Oncology and Haematology Group (GPOH) sified as standard risk (SR), patients with large localised with associated institutions in Austria, Switzerland and tumours (≥  100  ml), or with metastatic disease, were the Netherlands, addressed two chemotherapy questions classified as high risk (HR). Patients were randomly in patients with Ewing sarcoma (ES). It remains one of assigned to one of two treatment arms. SR-patients the largest randomised studies conducted in this cancer. received four VAIA courses (vincristine, doxorubicin, The primary aims of the trial were to demonstrate an ifosfamide, actinomycin D) followed by ten courses of increase in event-free survival (EFS), and decreased Fig. 1 EICESS 92 consort diagram (from original publication Paulussen et al. [3]) Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 3 of 13 either VAIA or VACA (cyclophosphamide instead of ifos- Table 1 Comparison of patient characteristics between CCLG and GPOH famide) whilst HR-patients were randomised to either fourteen courses of VAIA or fourteen courses of VAIA Number of patients (percent- p value with etoposide (EVAIA) [3]. age) Surgery and/or radiotherapy to the primary tumour CCLG GPOH (‘local therapy’) were scheduled to occur after four cycles N = 210 N = 437 of chemotherapy, at week 12. The choice of local therapy was made by clinicians for individual patients. The proto - Gender col was permissive but indicated that surgery should be Female 84 (40) 177 (40) 0.90 undertaken whenever possible. Preoperative radiother- Male 126 (60) 260 (60) apy (44.8  Gy) was recommended when there was <  50% Age (approx quartiles) (years) reduction of a soft tissue component, evident on repeat 0–9 34 (16) 94 (22) 0.17 imaging after 2 chemotherapy courses. Radiotherapy 10–14 74 (35) 123 (28) (54.4  Gy) replaced surgery for tumours deemed inoper- 15–19 58 (28) 115 (26) able. Post-operative radiotherapy (54.4  Gy) was recom- 20–35 44 (21) 105 (24) mended after intralesional surgery or marginal surgery Primary site with poor response (<  90% necrosis). Postoperative Central axis 84 (40) 236 (54) < 0.001 (0.004) radiotherapy (44.8 Gy) was to be considered for marginal Extremity 115 (55) 197 (45) resections with good response (≥  90% necrosis) or wide Unknown 11 (5) 4 (1) resections with poor response. Hyperfractionated irra- Axial skeletal 26 (12) 89 (20) diation was recommended in these cases. Spine 7 (3 30 (7) In the CESS group, the practice for treating clinical Pelvis 51 (24) 117 (27) teams of routinely seeking advice from clinicians in the Limb proximal 61 (29) 103 (23) central trials office is well established including detailed Limb distal 54 (26) 94 (22) guidance about radiotherapy planning [5]. No similar Unknown 11 (5) 4 (1) process was in place in the UK although the majority Volume of patients selected for surgery by local clinicians were < 100 ml 57 (27) 117 (27) 0.48 (0.97) operated on at four centres only. ≥ 100 ml 149 (71) 304 (69) Unknown 4 (2) 16 (4) Statistical methods Metastases The EICESS database was frozen in March 2007. EFS No 150 (71) 329 (75) 0.27 (0.41) was calculated from the date of randomisation until the Yes 56 (27) 105 (24) date of relapse, death or second malignancy, whichever Unknown 4 (2) 3 (1) occurred first. OS was calculated from the date of ran - Histology domisation until date of death. Patients alive at last fol- Ewing’s sarcoma 140 (67) 261 (60) < 0.001 low-up were censored at date last seen. Kaplan–Meier (< 0.001) Atypical Ewing’s 8 (4) 70 (16) survival curves were examined, and Cox regression mod- PNET 43 (20) 101 (23) elling was used to investigate differences after adjust - Other 6 (3) 5 (1) ing for multiple factors, producing hazard ratios (HR). Unknown 13 (6) 0 (0) Results are also presented separately for patients with Risk group only localised disease. Standard (SR) 53 (25) 102 (23) 0.60 High (HR) 157 (75) 335 (77) Results Trial treatment Between 1992 and 1998, 647 patients were randomised: SR-VACA 27 (13) 52 (12) 0.96 210 CCLG and 437 GPOH (CONSORT diagram Fig.  1). SR-VAIA 26 (12) 50 (11) The median follow-up was 8.5 years. HR-VAIA 76 (36) 164 (38) HR-EVAIA 81 (39) 171 (39) Patient characteristics Histological response These were largely similar between the trial groups, Good 52 (25) [58] 78 (18) [65] < 0.001 [0.33] except that CCLG patients tended to have more extrem- Poor 37 (18) [42] 42 (10) [35] ity tumours (Table  1; 55 vs. 45%), fewer central tumours No surgery 103 (49) 111 (25) (40 vs. 54%), and fewer with atypical Ewing’s sarcoma (4 NA 3 (1) 200 (46) vs. 16%), compared to GPOH patients. Unknown 15 (7) 6 (1) Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 4 of 13 Table 1 continued Table 2 Comparison of local treatment modality in CCLG and GPOH Number of patients (percent- p value age) Number of patients (per- p value centage) CCLG GPOH CCLG GPOH N = 210 N = 437 N = 210 N = 437 No. of chemotherapy cycles received 1–4 18 (8.6) 26 (6.0) 0.32 Local treatment modality 5–9 22 (10.5) 62 (14.2) a Surgery alone 70 (33) 71 (16) < 0.001 10–13 36 (17.10 83 (19.0) Radiotherapy alone 81 (39) 85 (19) 14 131 (62.4) 254 (58.2) Radiotherapy then surgery 6 (3) 195 (45) Unknown 3 (1.4) 12 (2.8) Surgery then radiotherapy 32 (15) 60 (14) p values including unknown data; the p values in brackets exclude unknown None (progressive disease) 18 (9) 7 (2) data Unknown 3 (1) 19 (4) Osteosarcoma or soft tissue Localised disease only NA not applicable, i.e. patients with early radiotherapy before surgery Surgery alone 59 (39) 63 (19) < 0.001 The numbers in square brackets are based only on patients with a good or Radiotherapy alone 53 (35) 55 (17) poor response Radiotherapy then surgery 5 (3) 147 (45) The proportions of patients with bone or bone marrow metastases were similar: 8% GPOH and 5% CCLG Surgery then radiotherapy 24 (16) 47 (14) None (progressive disease) 9 (6) 3 (1) Unknown 0 14 (4) Where histological response data were available for p value for the association between type of local treatment and study group. patients who did not receive pre-operative radiotherapy, The p value is also < 0.001 if ‘none’ or ‘unknown’ are excluded there was no significant difference in the proportion of patients from the two study groups with either a good or to central axis tumours (23 vs. 11%). A similar pattern poor histological response (Table 1, p = 0.33). was seen in GPOH patients, though there was much less of a difference in the proportion who had both Chemotherapy and local therapy therapies depending on whether they had extremity or There was no evidence of a difference in the delivery of central axis tumours (64% vs. 54%). While there was chemotherapy between groups. The number of chemo - no evidence of an association between choice of local therapy cycles received (Table  1) and the median total treatment and either tumour volume (p  =  0.44) or age dose for each cytotoxic drug administered per patient (p = 0.12) in GPOH patients, there was evidence of this were similar. A similar proportion completed all 14 in CCLG patients. Those with a volume <  100  ml were cycles; 62% vs. 58% in the CCLG and GPOH groups, more likely to have surgery alone (47%), and those with respectively (p = 0.30). a volume ≥100  ml tended to have radiotherapy alone. Table  2 shows the type of local therapy used in CCLG Proportionally more patients with volume ≥100  ml and GPOH patients. Most CCLG patients (72%) had received both therapies compared to those with volume a single therapy (surgery alone or radiotherapy alone); <  100  ml (21 vs. 10%). In the CCLG group there was a whilst most GPOH patients had both radiotherapy and clear trend with age; the proportions receiving sin- surgery (59%), which was mainly radiotherapy followed gle modality treatment were 94% (age 0–9  years), 75% by surgery (45%). Only 18% of CCLG patients had both (age 10–14  years), 68% (age 15–19  years) and 59% (age radiotherapy and surgery. A similar pattern was seen for 20–35 years), indicating that older patients tended to be patients without metastatic disease. given both therapies. Patient characteristics were examined which might influence the selection of local treatment (Table  3). Overall outcome Many patients with metastatic disease were treated Appendix Table  6 shows the distribution of events and with radiotherapy alone in both trial groups, though deaths by trial group. The CCLG cohort had more local the percentage was higher in CCLG patients. A sub- relapses (with or without metastatic disease) than GPOH; stantial proportion of CCLG patients with central axis 22 vs. 7%. Appendix Tables  7, 8 show the distribution of tumours had radiotherapy alone (62%), while those with events according to local therapy. Figure 2 shows EFS and extremity tumours tended to have surgery alone. CCLG OS according to trial group. Both outcomes were poorer patients were more likely to have both radiotherapy in the CCLG patients. and surgery if they had extremity tumours compared Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 5 of 13 Table 3 Association between the choice of local modality treatment and specified patient characteristics Number of patients (percentage), excluding missing data CCLG GPOH N None RT alone Surgery alone RT and surgery N None RT alone Surgery alone RT and surgery Disease Localised 150 9 (6) 53 (35) 59 (39) 29 (19) 315 3 (1) 55 (17) 63 (20) 194 (62) Metastatic 56 9 (16) 27 (48) 11 (20) 9 (16) 101 4 (4) 30 (30) 8 (8) 59 (58) Localised extremity disease 91 5 (5) 18 (20) 46 (50) 22 (24) 155 1 (1) 8 (5) 44 (28) 102 (66) Localised pelvic disease 31 0 24 (77) 6 (19) 1 (3) 79 1 (1) 27 (36) 7 (9) 39 (53) Primary site Central axis 84 9 (11) 52 (62) 14 (17) 9 (11) 226 4 (2) 73 (32) 22 (10) 127 (56) Extremity 115 7 (6) 28 (24) 54 (47) 26 (23) 189 3 (2) 11 (6) 48 (25) 127 (67) Volume (ml) < 100 57 5 (9) 19 (33) 27 (47) 6 (10) 111 3 (3) 26 (23) 16 (14) 66 (59) ≥ 100 146 13 (9) 61 (42) 40 (27) 32 (22) 292 4 (1) 54 (18) 52 (18) 182 (62) Age (years) 0–9 34 0 10 (29) 22 (65) 2 (6) 92 1 (1) 18 (20) 22 (24) 51 (55) 10–14 74 5 (7) 32 (43) 24 (32) 13 (18) 118 0 30 (25) 11 (9) 77 (65) 15–19 56 5 (9) 25 (45) 13 (23) 13 (23) 111 3 (3) 21 (19) 21 (19) 66 (59) 20–35 43 8 (19) 14 (33) 11 (26) 10 (23) 97 3 (3) 16 (16) 17 (18) 61 (63) Chi square tests were used to examine the association between each factor and choice of local therapy, excluding those who received no local treatment (‘None’ in the table) CCLG: disease (p = 0.04); primary site (p < 0.001); volume (p = 0.01); age (p = 0.01) GPOH: disease (p = 0.002); primary site (p < 0.001); volume (p = 0.44); age (p = 0.12) N total number of patients RT radiotherapy Differences in survival between the trial groups allowing ratios were: 1.47 (95% CI 1.11–1.96) and 1.52 (95% CI for specified factors 1.11–2.07) for those with localised disease only. For those The risk of having an event or dying for CCLG patients with metastatic disease, the HRs for EFS and OS were: compared to GPOH was examined using Cox regres- 1.20 (95% CI 0.82–1.74) and 1.22 (95% CI 0.82–1.80) sion modelling. Overall, the chance of having an event based on all patients, and 0.98 (95% CI 0.65–1.48) and (relapse, death or second malignancy) was increased by 1.01 (0.66–1.57) based on those who had local therapies. 42% (HR 1.42, 95% CI 1.13–1.77, p = 0.002) in the CCLG In an analysis in which only patients that had a local group compared to the GPOH group. The CCLG group recurrence (with or without distant recurrence) were had an increased risk of dying of 45% (HR 1.45, 95% CI counted as an event (all other events censored at the 1.14–1.86, p = 0.003) in comparison to the GPOH group time when they occurred), an excess risk was still found (Appendix Table  9). The table also shows that the excess in CCLG patients compared to GPOH. The hazard ratios risk (42% EFS, and 45% OS) did not materially change, were: 3.46 (95% CI 2.19–5.47) unadjusted, and 3.47 (95% even after allowing for several prognostic factors: age, CI 2.00–6.01), allowing for age, primary site, histology metastatic disease status, primary site or histology. The and local treatment. association between outcome and study group was very Appendix Table  9 also shows hazard ratios for CCLG similar when only examining patients with non-met - compared to GPOH patients only among those who astatic disease. Combined local treatment seemed to received local treatment. The HRs were 1.22 and 1.28 have an effect on OS (reducing the excess risk from 45 to for EFS and OS, respectively. These estimates were 30%) but not EFS. When several prognostic factors were somewhat lower than those in all patients (and only just allowed for together, there was still an increased risk missed statistical significance, due to being based on a among CCLG patients: 44% for EFS (HR 1.44, p = 0.009) smaller number of patients), indicating that the differ - and 30% for OS (HR 1.30, p  =  0.08, which was not sta - ence between the HRs based on all patients and those tistically significant). We further examined the effect based only on those who had local treatment is largely separately among patients with localised disease only and due to excluding those with progressive disease or miss- those with metastatic disease. The EFS and OS hazard ing data on local therapy. The EFS HR of 1.22 reduced Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 6 of 13 (Table  4), CCLG patients were 67% more likely to have Event-free survival an event (p = 0.03) and 65% more likely to die (p = 0.05). The adjusted point estimates were similar but were not UKCCSG statistically significant (p  = 0.07 for both EFS and OS). To GPOH further consider different numbers of CCLG and GPOH patients who received radiotherapy then surgery or vice versa, Table  4 shows HRs within in each subgroup: there was still evidence of an excess risk among CCLG patients. Appendix Table  10 is only based on patients HR 1.42 95% CI (1.13-1.77) 0 without metastatic disease: the conclusions were similar 0 5 10 15 to Table  4. Appendix Table  11 is based only on patients Number of years since randomisation with metastatic disease: it is difficult to make any reliable No. at risk: conclusions because of the smaller patient numbers. UKCCSG 210 87 26 GPOH 437 22264 Local treatment and timing of treatment Overall survival GPOH patients were more likely to have “early” local therapy, i.e. within 12  weeks of starting chemother- apy, compared to CCLG patients: 43% (176/407) vs. 9% (17/180), p  <  0.001. This is consistent with the greater use of pre-operative radiotherapy. GPOH patients were also less likely to have “late” local therapy, i.e. more than 15  weeks from start of chemotherapy; 20% (82/407), vs. 32% (57/180) p  =  0.004. There was an association HR 1.45 95% CI (1.14-1.86) between clinical outcome and the length of time from the 0 5 10 15 start of chemotherapy to the start of local therapy (con- Number of years since randomisation sidered as a continuous variable). For every increase of No. at risk: 4 weeks, the risk of an (EFS) event increased by 27% (HR UKCCSG 210 106 38 1.27, 95% CI 1.05–1.53) among patients who had pre- GPOH 437 26181 operative radiotherapy; 14% (HR 1.14, 95% CI 1.02–1.27) Fig. 2 Event-free and overall survival for CCLG and GPOH patients. among those who had surgery, with or without subse- 5-year EFS rates: CCLG 43% (95% CI, 36–50%); GPOH 57% (95% CI quent radiotherapy; and 7% (HR 1.07, 95% CI 0.96–1.19) 52–62). 5-year OS rates: CCLG 52% (95% CI 45–59%); GPOH 66% (95% among those who had radiotherapy alone. CI 61–71). 10-year EFS rates: CCLG 41% (95% CI 35–48); GPOH 51% (95% CI 46–56). 10-year OS rates: CCLG 49% (95% CI 42–56); GPOH Appendix Table  12 examines the influence of type of 60% (95% CI 55–65) local treatment and its timing (in all patients and only those with localised disease). Either factor reduced the HRs for EFS and OS to a similar extent. In the multivari- ate model they were each independent prognostic fac- to 1.14 after allowing for the type of local treatment, i.e. tors. However, Table 4 and Appendix Table 10 show that it is partly explained by differences in the local therapy when the data were presented by type of treatment, the administered (consistent with Table 2) further indicating timing had some effect but it still did not largely explain the influence of local treatments on survival outcomes. the difference between CCLG and GPOH outcomes (sur - When we examined the effect of different local treat - gery with or without radiotherapy). ment modalities on outcomes, there was no evidence of a difference between CCLG and GPOH patients for Localised extremity tumours either EFS or OS among those who received radiother- Table  5 shows the hazard ratios comparing CCLG with apy alone (Table  4). This is not surprising given that the GPOH, according to primary site. When 253 patients proportions with a local relapse (with or without metas- with localised extremity tumours were examined, statis- tases) were not very different: 22% CCLG vs. 16% GPOH tically significant survival differences remained between (Appendix Table  7, 8). The risk of an event or death was the two study groups. There was a 68% increase in the moderately higher in the CCLG group among patients death rate among CCLG patients compared to those in who had surgery alone (excess risk: EFS 31% and OS 50%, GPOH, after allowing for local therapy and other factors though neither were statistically significant). However, (Table 5, p = 0.05). The 5-year survival rates were: GPOH among patients who had both radiotherapy and surgery 81% (95% CI 75–87%), and CCLG 62% (95% CI 52–72%). Percentage alive Percentage alive Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 7 of 13 Table 4 Hazard ratios (CCLG vs. GPOH) according to local treatment modality Local treatment modality Subdivision of RT and surgery group None Radiotherapy (RT) alone Surgery alone RT and surgery RT then surgery Surgery then RT N = 23 N = 164 N = 138 N = 289 N = 201 N = 88 No. events EFS 21 105 53 131 93 38 OS 19 92 41 109 79 30 Unadjusted EFS 20 (2.64–161) 0.86 (0.58–1.26) 1.31 (0.76–2.25) 1.67 (1.05–2.66) 2.22 (0.81–6.07) 1.99 (1.05–3.78) OS 1.50 (0.56–3.96) 0.95 (0.63–1.44) 1.50 (0.81–2.80) 1.65 (1.00–2.74) 1.96 (0.72–5.37) 2.10 (1.02–4.30) Adjusted for age, metastatic disease, primary site and histology EFS 53 (4.0–477) 0.92 (0.62–1.38) 1.24 (0.70–2.20) 1.82 (1.12–2.94) 2.40 (0.84–6.84) 2.50 (1.24–5.06) OS 2.09 (0.64–6.79) 1.06 (0.69–1.63) 1.41 (0.73–2.74) 1.81 (1.07–3.05) 2.21 (0.77–6.35) 2.76 (1.26–6.05) Adjusted for age, metastatic disease, primary site, histology and time between the start of chemotherapy and starting local treatment EFS 0.91 (0.60–1.38) 1.24 (0.70–2.19) 1.61 (0.96–2.70) 1.98 (0.70–5.60) 2.83 (1.30–6.16) OS 1.04 (0.67–1.63) 1.43 (0.73–2.78) 1.68 (0.97–2.91) 1.94 (0.68–5.58) 3.39 (1.42–8.06) Hazard ratios greater than 1 indicate that CCLG patients had a higher risk of having an event or dying compared to GPOH patients Based on data excluding patients with unknown primary site because there were so few EFS event-free survival; OS overall survival Table 5 Hazard ratios (CCLG vs. GPOH) according to primary site and localised disease No. events Unadjusted Adjusted for age, metastatic disease, histology and local treatment Hazard ratio 95% CI p value Hazard ratio 95% CI p value Central axis All (n = 320) EFS 177 1.48 (1.08–2.03) 0.02 1.27 (0.89–1.82) 0.19 OS 154 1.47 (1.05–2.06) 0.03 1.20 (0.82–1.75) 0.36 Localised (n = 220) EFS 102 1.47 (0.97–2.24) 0.07 1.33 (0.82–2.16) 0.24 OS 87 1.46 (0.93–2.30) 0.10 1.15 (0.69–1.92) 0.58 Extremity All (n = 312) EFS 140 1.56 (1.12–2.18) 0.009 1.75 (1.18–2.60) 0.005 OS 112 1.69 (1.17–2.45) 0.006 1.59 (1.02–2.46) 0.04 Localised (n = 253) EFS 99 1.68 (1.13–2.50) 0.01 1.56 (1.00–2.43) 0.05 OS 75 1.86 (1.18–2.93) 0.007 1.68 (1.00–2.81) 0.05 Pelvic disease All (n = 168) EFS 100 1.36 (0.90–2.05) 0.14 1.05 (0.65–1.70) 0.84 OS 90 1.32 (0.85–2.04) 0.21 0.98 (0.60–1.62) 0.94 Localised (n = 107) EFS 56 1.22 (0.69–2.15) 0.51 0.98 (0.51–1.89) 0.96 OS 51 1.17 (0.64–2.14) 0.61 1.01 (0.51–2.03) 0.97 Hazard ratios greater than 1 indicate that CCLG patients had a higher risk of having an event or dying compared to GPOH patients Hazard ratios for localised disease were not adjusted for metastatic disease EFS event-free survival; OS overall survival Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 8 of 13 There were no differences in the baseline patient char - adolescents and young adults [12, 13]. The main influ - acteristics or number of chemotherapy cycles received, ences on continued survival disparity are attributable to except a slight excess of atypical ES in GPOH; 15% lack of health-care resources and access to modern treat- (24/162) vs. 5% (5/91) in CCLG. For patients with local- ments, lack of specialised centres with multidisciplinary ised extremity tumours, combined modality treatment teams, delayed diagnosis and treatment and poor man- was used more frequently in GPOH patients than CCLG agement of treatment, and drug toxicity. However, this patients (66% vs. 24%) whereas a greater proportion of is unlikely to fully account for the wide range in survival CCLG patients were treated with radiotherapy alone from ES reported here. (20% vs. 5%). More CCLG patients had a local recur- Given that all patients were treated according to a rence, with or without metastatic disease (16% vs. 3%). common protocol, the substantial survival differences between national study groups in this randomised trial Central axis and pelvic tumours are striking. Survival for the entire group of 647 patients Among patients with central axis tumours, the HRs for exceeded 60% but this disguises the 14% inferior 5  year both EFS and OS reduced after allowing for several fac- survival of the cohort of patients recruited through tors, and most of the reduction was due to adjusting for the CCLG. The inferior outcome was not obviously local treatment, indicating that this does have a role. A accounted for by differences in baseline characteristics, more pronounced reduction was seen for patients with delivery of chemotherapy or follow up. Differences were pelvic disease (HRs: EFS 1.05, OS 0.98). Patients with found in management of the primary tumour and in the localised pelvic tumours had a similar survival whether rates of local recurrence associated with different treat - treated in the CCLG or GPOH: the 5-year OS rates were ment modalities. We believe that this evidence provides 52 and 56%, respectively (p = 0.65), and the adjusted OS support that variations in local therapy influence survival. HR was 1.01, 95% CI 0.51–2.03 (Table 5), allowing for the It is possible that inherent differences in health care different local treatment modalities used between the delivery systems between the two study groups may have two cohorts. Radiotherapy alone was the local treatment contributed to survival differences. No differences were modality used in 77% (24/31) CCLG patients compared found in the tumour volume and the frequency of pres- to 34% (27/79) GPOH patients. Surgery combined with entation with metastases between the two study groups, radiotherapy was only used for 3% of CCLG patients factors which might indicate systematic delays in diagno- (1/31) compared to 49% of GPOH patients (39/79). A sis in one study group compared to the other. Likewise, survival advantage seemed evident for patients with there was no indication of a systematic difference in the localised pelvic tumours selected for surgery, compared way chemotherapy was delivered. to those who had radiotherapy alone (hazard ratio 0.50, Approaches to local tumour control were clearly differ - 95% CI 0.28–0.88, p = 0.016). ent between the two groups, including the timing of local treatments, but they did not explain all of the difference, Discussion particularly when patients had surgery. Primary tumour The EICESS-92 clinical trial revealed unexpected dif - control in ES can be achieved with surgery, radiotherapy ferences in survival between cohorts of ES patients or a combination of both. The choice is based on balanc - from two countries. Differences in mortality from can - ing the differing morbidities of the two modalities for cer between countries are well documented in Europe, each individual patient. The optimal approach for local especially for common cancers [6, 7]. These differences control remains a topic of debate. The relative merits of in outcome have also been reported for rare cancers [8, surgery and radiotherapy have been debated but conclu- 9]. Survival in the UK is lower for some cancers than in sions are often obscured by patient selection which biases other Western European and Nordic countries. Expla- comparison [5, 14–17]. Tumours that are inoperable and nations for these differences may include: registry data thus treated by radiotherapy alone are often associated being unrepresentative or containing artefact; differences with other adverse features such as large volume [18–21]. in population health or use of health resources; differ - The greater incidence of local relapse in CCLG patients ences in stage of cancer at diagnosis and variable access indicates that both selection of patients for, and delivery to optimal treatment or expertise [10]. Within EURO- of, surgery and radiotherapy may have been sub-optimal. CARE 3, which examined registry data for 20 European While not specific to Ewing sarcoma, there is a gen - countries, 5-year survival from ES ranged from 31 to 86% eral consensus on the relevance of centralization to high for the period 1990–1994 [11]. The EUROCARE-5 study volume centres and networks for sarcoma, especially for investigated whether survival differences among Euro - diagnosis and surgery [22, 23]. The degree of centralisa - pean countries had changed further from 1999 to 2007 tion and the process of decision-making about local ther- and found persisting inequalities both for children and apy differed between the two study groups in EICESS-92. Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 9 of 13 Ideally, the optimal local treatment for an individual results from this trial, the UK has initiated a system for patient should be decided through consideration of centralised national review and guidance on local treat- patient characteristics, the potential benefit and harm ment decision making for ES. This system is currently of the treatment options, and patient preference. In the undergoing evaluation. CESS group, treatment took place in three hundred or Authors’ contributions more centres, most of which treat relatively few patients. JW, AMCT, AH, RG, AC, DS, JB, IL and MP contributed to discussion, interpreta- However, each centre was familiar with accessing special- tion and appraisal of the presented data. All but AH and JB participated in the EICESS 92 study. AH undertook the statistical analysis. JW and AH drafted ist guidance from the trial headquarters. This extended the manuscript. HJ and AC critically appraised the manuscript and were joint to a centralised system of advice for local therapy plan- chairman of the EICESS 92 study. All authors read and approved the final ning [5]. A consequence is likely to have been consider- manuscript. able consistency of local treatment approach within the Author details majority of the GPOH cohort. In contrast, although sur- 1 Department of Oncology, University College Hospitals London NHS Founda- gery for bone sarcomas took place mainly in four centres tion Trust, 250 Euston Road, London NW1 2PG, UK. Cancer Research UK and UCL Clinical Trials Centre, University College London, London, UK. Chil- in the UK, advice about local tumour management was dren’s Cancer and Leukaemia Group Data Centre, Cancer Studies and Molecu- only sought on an ad hoc basis and there was no similar 4 lar Medicine, University of Leicester, Leicester, UK. The Royal Orthopaedic system for any degree of central treatment planning. Hospital, Birmingham, UK. Queen Elizabeth II Hospital, Birmingham, UK. 6 7 University Hospital Essen, Essen, Germany. Vestische Kinder- und Jugendk- The EICESS-92 trial is an example of how collaboration linik Datteln, University Witten/Herdecke, Datteln, Germany. Department between national clinical study groups is required to run of Pediatric Hematology and Oncology, University Children’s Hospital Münster, large randomised trials with sufficient power for robust Münster, Germany. Northern Institute for Cancer Research, Newcastle Uni- versity, Newcastle upon Tyne, UK. University of Leeds and Leeds Community analyses in rare cancers. It is acknowledged that the work Healthcare Trust, Leeds, UK. has been delayed in its publication but it has been revis- ited to coincide with a strong current focus and drive for Acknowledgements We are grateful for the support given to this project by staff at the CCLG Data international consensus on the role of surgery and radio- Centre in Leicester, especially Claire Weston and Carolyn Douglas. This work therapy in ES. was undertaken in part at UCLH/UCL who received a proportion of funding The low rates of local recurrence evident with patients from the Department of Health’s NIHR Biomedical Research Centres funding scheme. undergoing combined modality treatment and the Presented in part at ASCO Annual Meeting, Atlanta, June 2006. enhanced survival for a cohort of patients, more of whom underwent surgical resection and received radiother- Competing interests apy, indicates that clinicians should always consider this The authors declare they have no competing interests. option. Nevertheless, this must be balanced against the additional late effects, including second malignancies, Availability of data and materials Not applicable. which are associated with the use of radiotherapy in ES. Consent for publication Conclusion Not applicable. In summary, unexpected differences in survival between Ethics approval and consent to participate cohorts of patients within the same randomised trial have EICESS-92 was approved by the appropriate ethics committees and institu- been identified and are national in origin. It appears that tional review boards. Informed consent was obtained from all patients or guardians. less aggressive methods of local control have resulted in a higher rate of local recurrence and this was associated Funding with a higher risk of metastatic disease and subsequent Supported by Deutsche Krebshilfe (Grants No. DKH M43/92/Jü2 and DKH 70-2551 Jü3), and European Union Biomedicine and Health Programme death. These data reinforce the importance of careful (Grants No. BMH1-CT92-1341 and BMH4-983956), and Cancer Research United planning of treatment for local tumour control in ES and Kingdom. that radiotherapy alone should be discouraged when sur- gical resection can be undertaken. International clinical Appendix trials may offer opportunities to explore the impact of See Tables 6, 7, 8, 9, 10, 11 and 12. different treatment approaches. As a consequence of the Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 10 of 13 Table 6 Number of patients and events according to trial group Number of patients (percentage) CCLG GPOH Total N = 210 N = 437 First events (total) 119 (57) 204 (47) 323 Death-treatment related 1 (0.5) 3 (1) 4 Disease progression 3 (1) 12 (3) 15 Unknown cause 3 (1) 1 (0.2) 3 Distant metastases 66 (31) 148 (34) 214 [Distant metastases in those with metastatic disease at baseline] [25 (12%)] [57 (13%)] [82] Local relapse 29 (14) 13 (3) 42 Local and distant relapse 16 (8) 18 (4) 34 Relapse (unspecified site) 0 4 (1) 4 Second malignancy 2 (1) 5 (1) 7 All deaths 105 (50) 168 (38) 273 As a percentage of the number of patients from either CCLG or GPOH Table 7 Distribution of first events by treatment modality: CCLG patients Local treatment modality, N (%) Total Surgery alone RT alone RT then surgery Surgery then RT None Unknown N = 70 N = 81 N = 6 N = 32 N = 18 N = 3 No event 41 (59) 31 (38) 2 (33) 14 (44) 0 2 (67) 90 Local recurrence 5 (7.1) 12 (15) 1 (17) 1 (3.1) 10 (56) 0 29 Distant recurrence 18 (26) 28 (35) 1 (17) 13 (41) 5 (28) 1 (33) 66 Local and distant 3 (4.3) 6 (7.4) 2 (33) 3 (9.4) 2 (11) 0 13 Relapse-unspecified 0 0 0 0 0 0 0 Second malignancy 1 (1.4) 1 (1.2) 0 0 0 0 2 Death—no relapse 2 (2.9) 3 (3.7) 0 1 (3.1) 1 (5.6) 0 7 All deaths 24 (34) 45 (56) 4 (67) 15 (47) 16 (89) 1 (33) 105 RT radiotherapy Table 8 Distribution of first events by treatment modality: GPOH patients Local treatment modality, N (%) Total Surgery alone RT alone RT then surgery Surgery then RT None Unknown N = 71 N = 85 N = 195 N = 60 N = 7 N = 19 No event 46 (65) 30 (35) 106 (54) 38 (63) 1 (14) 12 (63) 233 Local recurrence 3 (4.2) 3 (3.5) 3 (1.5) 4 (6.7) 0 0 13 Distant recurrence 19 (27) 36 (42) 71 (36) 16 (27) 2 (29) 4 (21) 148 Local and distant 2 (2.8) 10 (12) 4 (2.0) 1 (1.7) 0 1 (5.3) 18 Relapse-unspecified 0 1 (1.2) 2 (1.0) 0 0 1 (5.3) 4 Second malignancy 1 (1.4) 2 (2.4) 2 (1.0) 0 0 0 5 Death—no relapse 0 3 (3.5) 7 (3.6) 1 (1.7) 4 (57) 1 (5.3) 16 All deaths 18 (25) 47 (55) 75 (38) 17 (28) 6 (86) 5 (26) 158 To one decimal place if < 10% RT radiotherapy Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 11 of 13 Table 9 Hazard ratios for comparing CCLG and GPOH patients EFS OS HR (95% CI) p value HR (95% CI) p value All patients Unadjusted 1.42 (1.13–1.77) 0.002 1.45 (1.14–1.86) 0.003 Unadjusted HR, in localised disease only 1.47 (1.11–1.96) 0.007 1.52 (1.11–2.07) 0.009 Adjusted for risk group and trial treatment 1.43 (1.14–1.79) 0.002 1.49 (1.17–1.91) 0.001 Adjusted for each of the following factors separately Age 1.45 (1.15–1.81) 0.001 1.47 (1.15–1.88) 0.002 Metastatic disease 1.38 (1.10–1.73) 0.005 1.42 (1.11–1.81) 0.005 Primary site 1.48 (1.18–1.86) <0.001 1.52 (1.19–1.95) 0.001 Histology 1.41 (1.12–1.77) 0.004 1.44 (1.12–1.85) 0.004 Local treatment modality 1.45 (1.12–1.89) 0.006 1.30 (0.98–1.72) 0.07 Adjusted for age, metastatic disease, primary site, histology and local tr eatment 1.44 (1.10–1.89) 0.009 1.30 (0.97–1.74) 0.08 Adjusted HR, in localised disease only 1.48 (1.05–2.09) 0.026 1.29 (0.88–1.89) 0.19 Only patients who had local therapy; excluding progressive disease (n = 25) and where it was not known whether local therapy was given or not n = 22) Unadjusted 1.22 (0.96–1.55) 0.11 1.28 (0.99–1.67) 0.06 Adjusted for type of local treatment 1.14 (0.87–1.51) 0.34 1.25 (0.92–1.68) 0.15 Adjusted for time between the start of chemotherapy and starting local treatment 1.12 (0.87–1.44) 0.37 1.18 (0.90–1.55) 0.22 Adjusted for age, metastatic disease, primary site, histology, local treatment, and time between 1.13 (0.84–1.50) 0.42 1.25 (0.91–1.71) 0.17 the start of chemotherapy and starting local treatment Hazard ratios greater than 1 indicate that CCLG patients had a higher risk of having an event or dying compared to GPOH patients EFS event-free survival; OS overall survival Using Cox regression modelling (age as a continuous variable). Missing data for the other variables were included as a separate category, but excluding these from the analyses did not materially change the hazard ratio estimates in the table Includes categories for no local therapy and missing data Surgery alone, radiotherapy alone, surgery then radiotherapy, radiotherapy then surgery Table 10 Hazard ratios (CCLG vs. GPOH) according to local treatment modality, among patients with localised disease only Local treatment modality Subdivision of RT and surgery group Radiotherapy (RT) alone Surgery alone RT and surgery RT then surgery Surgery then RT N = 108 N = 119 N = 221 N = 152 N = 69 No. events EFS 62 42 83 61 22 OS 53 33 66 49 17 Unadjusted EFS 0.89 (0.54–1.46) 1.44 (0.78–2.64) 1.66 (0.94–2.96) 2.44 (0.76–7.81) 2.36 (1.02–5.45) OS 0.99 (0.56–1.64) 1.74 (0.86–3.51) 1.60 (0.84–3.06) 2.70 (0.84–8.73) 2.03 (0.78–5.28) Adjusted for age, primary site and histology EFS 0.98 (0.58–1.66) 1.51 (0.78–2.94) 1.65 (0.91–2.99) 2.39 (0.71–8.05) 2.12 (0.83–5.40) OS 1.10 (0.62–1.95) 1.94 (0.89–4.25) 1.50 (0.77–2.93) 3.10 (0.90–10.70) 1.74 (0.60–5.08) Adjusted for age, primary site, histology and time between the start of chemotherapy and starting local treatment EFS 0.95 (0.54–1.67) 1.48 (0.76–2.89) 1.48 (0.81–2.69) 1.69 (0.50–5.68) 2.10 (0.82–5.41) OS 1.03 (0.55–1.90) 1.92 (0.87–4.24) 1.39 (0.71–2.74) 2.49 (0.72–8.58) 1.74 (0.59–5.10) Hazard ratios greater than 1 indicate that CCLG patients had a higher risk of having an event or dying compared to GPOH patients Based on data excluding patients with unknown primary site because there were so few EFS event-free survival; OS overall survival Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 12 of 13 Table 11 Hazard ratios (CCLG vs. GPOH) according to local treatment modality, among patients with metastatic disease only Local treatment modality Radiotherapy (RT) alone Surgery alone RT and surgery N = 56 N = 19 N = 66 No. events EFS 43 11 48 OS 39 8 43 Unadjusted EFS 0.79 (0.43–1.44) 0.79 (0.24–2.61) 2.01 (0.89–4.54) OS 0.92 (0.49–1.74) 0.71 (0.18–2.85) 1.98 (0.88–4.47) Adjusted for age, primary site, histology and time between the start of chemotherapy and starting local treatment EFS 0.81 (0.44–1.67) Too few patients to allow for other factors reliably 2.51 (0.89–7.06) OS 1.01 (0.50–2.01) 2.54 (0.90–7.20) Hazard ratios greater than 1 indicate that CCLG patients had a higher risk of having an event or dying compared to GPOH patients Based on data excluding patients with unknown primary site because there were so few EFS event-free survival; OS overall survival Table 12 Hazard ratios for comparing CCLG and GPOH patients, after examining local treatment and time to local treat- ment EFS OS HR (95% CI) p value HR (95% CI) p value All patients Unadjusted 1.22 (0.96–1.56) 0.10 1.29 (0.99–1.68) 0.055 Adjusted for local treatment 1.14 (0.87–1.51) 0.34 1.25 (0.93–1.68) 0.15 Adjusted for between the start of chemotherapy and starting local treatment 1.13 (0.88–1.45) 0.34 1.19 (0.91–1.56) 0.20 Adjusted for both local treatment and timing 1.11 (0.84–1.47) 0.46 1.21 (0.90–1.65) 0.21 Localised disease only Unadjusted 1.31 (0.97–1.76) 0.08 1.39 (1.00–1.93) 0.048 Adjusted for local treatment 1.22 (0.87–1.72) 0.25 1.30 (0.89–1.90) 0.17 Adjusted for between the start of chemotherapy and starting local treatment 1.18 (0.87–1.60) 0.30 1.24 (0.88–1.74) 0.21 Adjusted for local treatment and the time between the start of chemotherapy and starting 1.14 (0.81–1.62) 0.45 1.20 (0.82–1.77) 0.35 local treatment Metastatic disease only Unadjusted 0.98 (0.65–1.48) 0.93 1.01 (0.66–1.57) 0.94 Adjusted for local treatment 0.98 (0.61–1.56) 0.93 1.11 (0.68–1.81) 0.69 Adjusted for between the start of chemotherapy and starting local treatment 0.95 (0.62–1.45) 0.81 1.00 (0.64–1.57) 0.98 Adjusted for both local treatment and timing 0.99 (0.61–1.60) 0.97 1.14 (0.69–1.89) 0.60 Type of local treatment and time to local treatment seem to be independent factors. In the Cox regression which contains both of them, the p values for each variable are: All patients EFS: local treatment (p < 0.0001); time to local treatment (p < 0.001) All patients OS: local treatment (p < 0.0001); time to local treatment (p < 0.001) Patients with localised disease only, EFS: local treatment (p = 0.002); time to local treatment (p = 0.002) Patients with localised disease only OS: local treatment (p = 0.002; time to local treatment (p = 0.004) Surgery alone, radiotherapy alone, surgery then radiotherapy, radiotherapy then surgery Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 13 of 13 P, Sánchez-Pérez MJ, Sant M, Santaquilani M, Stiller C, Tavilla A, Trama A, Publisher’s Note Visser O, Peris-Bonet R, EUROCARE Working Group. Childhood cancer sur- Springer Nature remains neutral with regard to jurisdictional claims in pub- vival in Europe 1999–2007: results of EUROCARE-5–a population-based lished maps and institutional affiliations. study. Lancet Oncol. 2014;15:35–47. 13. Trama A, Botta L, Foschi R, Ferrari A, Stiller C, Desandes E, Maule MM, Mer- Received: 14 December 2017 Accepted: 7 February 2018 letti F, Gatta G, EUROCARE-5 Working Group. Survival of European adoles- cents and young adults diagnosed with cancer in 2000–07: population- based data from EUROCARE-5. Lancet Oncol. 2016;17:896–906. 14. Schuck A, Ahrens S, Paulussen M, Kuhlen M, Konemann S, Rube C, Winkel- mann W, Kotz R, Dunst J, Willich N, Jurgens H. Local therapy in localized References Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, 1. Gaspar N, Hawkins DS, Dirksen U, Lewis IK, Ferrari S, Le Deley MC, Kovar and EICESS 92 trials. Int J Radiat Oncol Biol Phys. 2003;55:168–77. J, Grimer R, Whelan J, Claude L, Delattre O, Paulussen M, Picci P, Sundby 15. Miller BJ, Gao Y, Duchman KR. Does surgery or radiation provide the best Hall K, van den Berg H, Ladenstein R, Michon J, Hiorth L, Judson I, overall survival in Ewing Sarcoma? 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CARENet Working Group. Treatment challenges in and outside a network 8. Gatta G, Trama A, Capacaccia R, RARECARENet Working Group. Epidemi- setting: soft tissue sarcomas. Eur J Surg Oncol. 2017;19:30705–9. ology of rare cancers and inequalities in oncologic outcomes. Eur J Surg Oncol. 2017;19:685–6. 9. Gatta G, Capocaccia R, Botta L, Mallone S, De Angelis R, Ardanaz E, Comber H, Dimitrova N, Leinonen MK, Siesling S, van der Zwan JM, Van Eycken L, Visser O, Zakelj MP, Anderson LA, Bella F, Kaire I, Otter R, Stiller Submit your next manuscript to BioMed Central CA, Trama A, RARECAREnet Working Group. Burden and centralised treat- and we will help you at every step: ment in Europe of rare tumours: results of RARECAREnet—a population- based study. Lancet Oncol. 2017;18:1022–39. • We accept pre-submission inquiries 10. Coleman MP, Gatta G, Verdecchia A, Esteve J, Sant M, Storm H, Allemani • Our selector tool helps you to find the most relevant journal C, Ciccolallo L, Santaguilani M, Berrino F, EUROCARE Working Group. • We provide round the clock customer support EUROCARE-3 summary: cancer survival in Europe at the end of the 20th century. Ann Oncol. 2003;14:128–49. • Convenient online submission 11. Gatta G, Capocaccia R, De Angelis R, Stiller C, Coebergh JW, EUROCARE • Thorough peer review Working Group. Cancer survival in European adolescents and young • Inclusion in PubMed and all major indexing services adults. Eur J Cancer. 2003;39:2600–10. 12. Gatta G, Botta L, Rossi S, Aareleid T, Bielska-Lasota M, Clavel J, Dimitrova • Maximum visibility for your research N, Jakab Z, Kaatsch P, Lacour B, Mallone S, Marcos-Gragera R, Minicozzi Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Sarcoma Research Springer Journals

Survival is influenced by approaches to local treatment of Ewing sarcoma within an international randomised controlled trial: analysis of EICESS-92

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Copyright © 2018 by The Author(s)
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Biomedicine; Cancer Research; Oncology; Surgical Oncology
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Abstract

Background: Two national clinical trial groups, United Kingdom Children’s Cancer and Leukaemia Group (CCLG) and the German Paediatric Oncology and Haematology Group (GPOH) together undertook a randomised trial, EICESS-92, which addressed chemotherapy options for Ewing’s sarcoma. We sought the causes of unexpected survival differ - ences between the study groups. Methods: 647 patients were randomised. Cox regression analyses were used to compare event-free survival (EFS) and overall survival (OS) between the two study groups. Results: 5-year EFS rates were 43% (95% CI 36–50%) and 57% (95% CI 52–62) in the CCLG and GPOH patients, respectively; corresponding 5-year OS rates were 52% (95% CI 45–59%) and 66% (95% CI 61–71). CCLG patients were less likely to have both surgery and radiotherapy (18 vs. 59%), and more likely to have a single local therapy modal- ity compared to the GPOH patients (72 vs. 35%). Forty-five percent of GPOH patients had pre-operative radiotherapy compared to 3% of CCLG patients. In the CCLG group local recurrence (either with or without metastases) was the first event in 22% of patients compared with 7% in the GPOH group. After allowing for the effects of age, metastases, primary site, histology and local treatment modality, the risk of an EFS event was 44% greater in the CCLG cohort (95% CI 10–89%, p = 0.009), and the risk of dying was 30% greater, but not statistically significant (95% CI 3–74%, p = 0.08). Conclusions: Unexpected differences in EFS and OS occurred between two patient cohorts recruited within an international randomised trial. Failure to select or deliver appropriate local treatment modalities for Ewing’s sarcoma may compromise chances of cure. Trial registration Supported by Deutsche Krebshilfe (Grants No. DKH M43/92/Jü2 and DKH 70-2551 Jü3), and European Union Biomedicine and Health Programme (Grants No. BMH1-CT92-1341 and BMH4-983956), and Cancer Research United Kingdom. Clinical trial information can be found for the following: NCT0000251 Keywords: Ewing sarcoma, Local therapy *Correspondence: jeremy.whelan@nhs.net Department of Oncology, University College Hospitals London NHS Foundation Trust, 250 Euston Road, London NW1 2PG, UK Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 2 of 13 treatment-related morbidity for patients with standard Background risk disease. The overall results of the trial have been Collaboration between national clinical study groups reported [3]. However, we found evidence that EFS and to run large randomised trials is advantageous, espe- overall survival (OS) differed between the CCLG and cially in rare disease settings. It allows rapid accrual of GPOH study groups. Although these data have been larger numbers of patients to provide sufficient power reported in abstract form, this more detailed analysis for robust analyses. Indeed, joint studies may be the retains relevance and influence on practice [4]. only means of effectively answering randomised ques - tions in rare cancers [1, 2]. EICESS-92, a trial developed Patients and methods and completed by the Children’s Cancer and Leukaemia The trial design of EICESS-92 is outlined in Fig.  1, and Group (CCLG, formerly United Kingdom Children’s details are described elsewhere [3]. The study was con - Cancer Study Group, UKCCSG) and the Cooperative fined to patients with primary tumours of bone. Ewing’s Sarcoma Studies (CESS) group of the German Patients with localised tumours of < 100 ml were clas- Paediatric Oncology and Haematology Group (GPOH) sified as standard risk (SR), patients with large localised with associated institutions in Austria, Switzerland and tumours (≥  100  ml), or with metastatic disease, were the Netherlands, addressed two chemotherapy questions classified as high risk (HR). Patients were randomly in patients with Ewing sarcoma (ES). It remains one of assigned to one of two treatment arms. SR-patients the largest randomised studies conducted in this cancer. received four VAIA courses (vincristine, doxorubicin, The primary aims of the trial were to demonstrate an ifosfamide, actinomycin D) followed by ten courses of increase in event-free survival (EFS), and decreased Fig. 1 EICESS 92 consort diagram (from original publication Paulussen et al. [3]) Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 3 of 13 either VAIA or VACA (cyclophosphamide instead of ifos- Table 1 Comparison of patient characteristics between CCLG and GPOH famide) whilst HR-patients were randomised to either fourteen courses of VAIA or fourteen courses of VAIA Number of patients (percent- p value with etoposide (EVAIA) [3]. age) Surgery and/or radiotherapy to the primary tumour CCLG GPOH (‘local therapy’) were scheduled to occur after four cycles N = 210 N = 437 of chemotherapy, at week 12. The choice of local therapy was made by clinicians for individual patients. The proto - Gender col was permissive but indicated that surgery should be Female 84 (40) 177 (40) 0.90 undertaken whenever possible. Preoperative radiother- Male 126 (60) 260 (60) apy (44.8  Gy) was recommended when there was <  50% Age (approx quartiles) (years) reduction of a soft tissue component, evident on repeat 0–9 34 (16) 94 (22) 0.17 imaging after 2 chemotherapy courses. Radiotherapy 10–14 74 (35) 123 (28) (54.4  Gy) replaced surgery for tumours deemed inoper- 15–19 58 (28) 115 (26) able. Post-operative radiotherapy (54.4  Gy) was recom- 20–35 44 (21) 105 (24) mended after intralesional surgery or marginal surgery Primary site with poor response (<  90% necrosis). Postoperative Central axis 84 (40) 236 (54) < 0.001 (0.004) radiotherapy (44.8 Gy) was to be considered for marginal Extremity 115 (55) 197 (45) resections with good response (≥  90% necrosis) or wide Unknown 11 (5) 4 (1) resections with poor response. Hyperfractionated irra- Axial skeletal 26 (12) 89 (20) diation was recommended in these cases. Spine 7 (3 30 (7) In the CESS group, the practice for treating clinical Pelvis 51 (24) 117 (27) teams of routinely seeking advice from clinicians in the Limb proximal 61 (29) 103 (23) central trials office is well established including detailed Limb distal 54 (26) 94 (22) guidance about radiotherapy planning [5]. No similar Unknown 11 (5) 4 (1) process was in place in the UK although the majority Volume of patients selected for surgery by local clinicians were < 100 ml 57 (27) 117 (27) 0.48 (0.97) operated on at four centres only. ≥ 100 ml 149 (71) 304 (69) Unknown 4 (2) 16 (4) Statistical methods Metastases The EICESS database was frozen in March 2007. EFS No 150 (71) 329 (75) 0.27 (0.41) was calculated from the date of randomisation until the Yes 56 (27) 105 (24) date of relapse, death or second malignancy, whichever Unknown 4 (2) 3 (1) occurred first. OS was calculated from the date of ran - Histology domisation until date of death. Patients alive at last fol- Ewing’s sarcoma 140 (67) 261 (60) < 0.001 low-up were censored at date last seen. Kaplan–Meier (< 0.001) Atypical Ewing’s 8 (4) 70 (16) survival curves were examined, and Cox regression mod- PNET 43 (20) 101 (23) elling was used to investigate differences after adjust - Other 6 (3) 5 (1) ing for multiple factors, producing hazard ratios (HR). Unknown 13 (6) 0 (0) Results are also presented separately for patients with Risk group only localised disease. Standard (SR) 53 (25) 102 (23) 0.60 High (HR) 157 (75) 335 (77) Results Trial treatment Between 1992 and 1998, 647 patients were randomised: SR-VACA 27 (13) 52 (12) 0.96 210 CCLG and 437 GPOH (CONSORT diagram Fig.  1). SR-VAIA 26 (12) 50 (11) The median follow-up was 8.5 years. HR-VAIA 76 (36) 164 (38) HR-EVAIA 81 (39) 171 (39) Patient characteristics Histological response These were largely similar between the trial groups, Good 52 (25) [58] 78 (18) [65] < 0.001 [0.33] except that CCLG patients tended to have more extrem- Poor 37 (18) [42] 42 (10) [35] ity tumours (Table  1; 55 vs. 45%), fewer central tumours No surgery 103 (49) 111 (25) (40 vs. 54%), and fewer with atypical Ewing’s sarcoma (4 NA 3 (1) 200 (46) vs. 16%), compared to GPOH patients. Unknown 15 (7) 6 (1) Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 4 of 13 Table 1 continued Table 2 Comparison of local treatment modality in CCLG and GPOH Number of patients (percent- p value age) Number of patients (per- p value centage) CCLG GPOH CCLG GPOH N = 210 N = 437 N = 210 N = 437 No. of chemotherapy cycles received 1–4 18 (8.6) 26 (6.0) 0.32 Local treatment modality 5–9 22 (10.5) 62 (14.2) a Surgery alone 70 (33) 71 (16) < 0.001 10–13 36 (17.10 83 (19.0) Radiotherapy alone 81 (39) 85 (19) 14 131 (62.4) 254 (58.2) Radiotherapy then surgery 6 (3) 195 (45) Unknown 3 (1.4) 12 (2.8) Surgery then radiotherapy 32 (15) 60 (14) p values including unknown data; the p values in brackets exclude unknown None (progressive disease) 18 (9) 7 (2) data Unknown 3 (1) 19 (4) Osteosarcoma or soft tissue Localised disease only NA not applicable, i.e. patients with early radiotherapy before surgery Surgery alone 59 (39) 63 (19) < 0.001 The numbers in square brackets are based only on patients with a good or Radiotherapy alone 53 (35) 55 (17) poor response Radiotherapy then surgery 5 (3) 147 (45) The proportions of patients with bone or bone marrow metastases were similar: 8% GPOH and 5% CCLG Surgery then radiotherapy 24 (16) 47 (14) None (progressive disease) 9 (6) 3 (1) Unknown 0 14 (4) Where histological response data were available for p value for the association between type of local treatment and study group. patients who did not receive pre-operative radiotherapy, The p value is also < 0.001 if ‘none’ or ‘unknown’ are excluded there was no significant difference in the proportion of patients from the two study groups with either a good or to central axis tumours (23 vs. 11%). A similar pattern poor histological response (Table 1, p = 0.33). was seen in GPOH patients, though there was much less of a difference in the proportion who had both Chemotherapy and local therapy therapies depending on whether they had extremity or There was no evidence of a difference in the delivery of central axis tumours (64% vs. 54%). While there was chemotherapy between groups. The number of chemo - no evidence of an association between choice of local therapy cycles received (Table  1) and the median total treatment and either tumour volume (p  =  0.44) or age dose for each cytotoxic drug administered per patient (p = 0.12) in GPOH patients, there was evidence of this were similar. A similar proportion completed all 14 in CCLG patients. Those with a volume <  100  ml were cycles; 62% vs. 58% in the CCLG and GPOH groups, more likely to have surgery alone (47%), and those with respectively (p = 0.30). a volume ≥100  ml tended to have radiotherapy alone. Table  2 shows the type of local therapy used in CCLG Proportionally more patients with volume ≥100  ml and GPOH patients. Most CCLG patients (72%) had received both therapies compared to those with volume a single therapy (surgery alone or radiotherapy alone); <  100  ml (21 vs. 10%). In the CCLG group there was a whilst most GPOH patients had both radiotherapy and clear trend with age; the proportions receiving sin- surgery (59%), which was mainly radiotherapy followed gle modality treatment were 94% (age 0–9  years), 75% by surgery (45%). Only 18% of CCLG patients had both (age 10–14  years), 68% (age 15–19  years) and 59% (age radiotherapy and surgery. A similar pattern was seen for 20–35 years), indicating that older patients tended to be patients without metastatic disease. given both therapies. Patient characteristics were examined which might influence the selection of local treatment (Table  3). Overall outcome Many patients with metastatic disease were treated Appendix Table  6 shows the distribution of events and with radiotherapy alone in both trial groups, though deaths by trial group. The CCLG cohort had more local the percentage was higher in CCLG patients. A sub- relapses (with or without metastatic disease) than GPOH; stantial proportion of CCLG patients with central axis 22 vs. 7%. Appendix Tables  7, 8 show the distribution of tumours had radiotherapy alone (62%), while those with events according to local therapy. Figure 2 shows EFS and extremity tumours tended to have surgery alone. CCLG OS according to trial group. Both outcomes were poorer patients were more likely to have both radiotherapy in the CCLG patients. and surgery if they had extremity tumours compared Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 5 of 13 Table 3 Association between the choice of local modality treatment and specified patient characteristics Number of patients (percentage), excluding missing data CCLG GPOH N None RT alone Surgery alone RT and surgery N None RT alone Surgery alone RT and surgery Disease Localised 150 9 (6) 53 (35) 59 (39) 29 (19) 315 3 (1) 55 (17) 63 (20) 194 (62) Metastatic 56 9 (16) 27 (48) 11 (20) 9 (16) 101 4 (4) 30 (30) 8 (8) 59 (58) Localised extremity disease 91 5 (5) 18 (20) 46 (50) 22 (24) 155 1 (1) 8 (5) 44 (28) 102 (66) Localised pelvic disease 31 0 24 (77) 6 (19) 1 (3) 79 1 (1) 27 (36) 7 (9) 39 (53) Primary site Central axis 84 9 (11) 52 (62) 14 (17) 9 (11) 226 4 (2) 73 (32) 22 (10) 127 (56) Extremity 115 7 (6) 28 (24) 54 (47) 26 (23) 189 3 (2) 11 (6) 48 (25) 127 (67) Volume (ml) < 100 57 5 (9) 19 (33) 27 (47) 6 (10) 111 3 (3) 26 (23) 16 (14) 66 (59) ≥ 100 146 13 (9) 61 (42) 40 (27) 32 (22) 292 4 (1) 54 (18) 52 (18) 182 (62) Age (years) 0–9 34 0 10 (29) 22 (65) 2 (6) 92 1 (1) 18 (20) 22 (24) 51 (55) 10–14 74 5 (7) 32 (43) 24 (32) 13 (18) 118 0 30 (25) 11 (9) 77 (65) 15–19 56 5 (9) 25 (45) 13 (23) 13 (23) 111 3 (3) 21 (19) 21 (19) 66 (59) 20–35 43 8 (19) 14 (33) 11 (26) 10 (23) 97 3 (3) 16 (16) 17 (18) 61 (63) Chi square tests were used to examine the association between each factor and choice of local therapy, excluding those who received no local treatment (‘None’ in the table) CCLG: disease (p = 0.04); primary site (p < 0.001); volume (p = 0.01); age (p = 0.01) GPOH: disease (p = 0.002); primary site (p < 0.001); volume (p = 0.44); age (p = 0.12) N total number of patients RT radiotherapy Differences in survival between the trial groups allowing ratios were: 1.47 (95% CI 1.11–1.96) and 1.52 (95% CI for specified factors 1.11–2.07) for those with localised disease only. For those The risk of having an event or dying for CCLG patients with metastatic disease, the HRs for EFS and OS were: compared to GPOH was examined using Cox regres- 1.20 (95% CI 0.82–1.74) and 1.22 (95% CI 0.82–1.80) sion modelling. Overall, the chance of having an event based on all patients, and 0.98 (95% CI 0.65–1.48) and (relapse, death or second malignancy) was increased by 1.01 (0.66–1.57) based on those who had local therapies. 42% (HR 1.42, 95% CI 1.13–1.77, p = 0.002) in the CCLG In an analysis in which only patients that had a local group compared to the GPOH group. The CCLG group recurrence (with or without distant recurrence) were had an increased risk of dying of 45% (HR 1.45, 95% CI counted as an event (all other events censored at the 1.14–1.86, p = 0.003) in comparison to the GPOH group time when they occurred), an excess risk was still found (Appendix Table  9). The table also shows that the excess in CCLG patients compared to GPOH. The hazard ratios risk (42% EFS, and 45% OS) did not materially change, were: 3.46 (95% CI 2.19–5.47) unadjusted, and 3.47 (95% even after allowing for several prognostic factors: age, CI 2.00–6.01), allowing for age, primary site, histology metastatic disease status, primary site or histology. The and local treatment. association between outcome and study group was very Appendix Table  9 also shows hazard ratios for CCLG similar when only examining patients with non-met - compared to GPOH patients only among those who astatic disease. Combined local treatment seemed to received local treatment. The HRs were 1.22 and 1.28 have an effect on OS (reducing the excess risk from 45 to for EFS and OS, respectively. These estimates were 30%) but not EFS. When several prognostic factors were somewhat lower than those in all patients (and only just allowed for together, there was still an increased risk missed statistical significance, due to being based on a among CCLG patients: 44% for EFS (HR 1.44, p = 0.009) smaller number of patients), indicating that the differ - and 30% for OS (HR 1.30, p  =  0.08, which was not sta - ence between the HRs based on all patients and those tistically significant). We further examined the effect based only on those who had local treatment is largely separately among patients with localised disease only and due to excluding those with progressive disease or miss- those with metastatic disease. The EFS and OS hazard ing data on local therapy. The EFS HR of 1.22 reduced Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 6 of 13 (Table  4), CCLG patients were 67% more likely to have Event-free survival an event (p = 0.03) and 65% more likely to die (p = 0.05). The adjusted point estimates were similar but were not UKCCSG statistically significant (p  = 0.07 for both EFS and OS). To GPOH further consider different numbers of CCLG and GPOH patients who received radiotherapy then surgery or vice versa, Table  4 shows HRs within in each subgroup: there was still evidence of an excess risk among CCLG patients. Appendix Table  10 is only based on patients HR 1.42 95% CI (1.13-1.77) 0 without metastatic disease: the conclusions were similar 0 5 10 15 to Table  4. Appendix Table  11 is based only on patients Number of years since randomisation with metastatic disease: it is difficult to make any reliable No. at risk: conclusions because of the smaller patient numbers. UKCCSG 210 87 26 GPOH 437 22264 Local treatment and timing of treatment Overall survival GPOH patients were more likely to have “early” local therapy, i.e. within 12  weeks of starting chemother- apy, compared to CCLG patients: 43% (176/407) vs. 9% (17/180), p  <  0.001. This is consistent with the greater use of pre-operative radiotherapy. GPOH patients were also less likely to have “late” local therapy, i.e. more than 15  weeks from start of chemotherapy; 20% (82/407), vs. 32% (57/180) p  =  0.004. There was an association HR 1.45 95% CI (1.14-1.86) between clinical outcome and the length of time from the 0 5 10 15 start of chemotherapy to the start of local therapy (con- Number of years since randomisation sidered as a continuous variable). For every increase of No. at risk: 4 weeks, the risk of an (EFS) event increased by 27% (HR UKCCSG 210 106 38 1.27, 95% CI 1.05–1.53) among patients who had pre- GPOH 437 26181 operative radiotherapy; 14% (HR 1.14, 95% CI 1.02–1.27) Fig. 2 Event-free and overall survival for CCLG and GPOH patients. among those who had surgery, with or without subse- 5-year EFS rates: CCLG 43% (95% CI, 36–50%); GPOH 57% (95% CI quent radiotherapy; and 7% (HR 1.07, 95% CI 0.96–1.19) 52–62). 5-year OS rates: CCLG 52% (95% CI 45–59%); GPOH 66% (95% among those who had radiotherapy alone. CI 61–71). 10-year EFS rates: CCLG 41% (95% CI 35–48); GPOH 51% (95% CI 46–56). 10-year OS rates: CCLG 49% (95% CI 42–56); GPOH Appendix Table  12 examines the influence of type of 60% (95% CI 55–65) local treatment and its timing (in all patients and only those with localised disease). Either factor reduced the HRs for EFS and OS to a similar extent. In the multivari- ate model they were each independent prognostic fac- to 1.14 after allowing for the type of local treatment, i.e. tors. However, Table 4 and Appendix Table 10 show that it is partly explained by differences in the local therapy when the data were presented by type of treatment, the administered (consistent with Table 2) further indicating timing had some effect but it still did not largely explain the influence of local treatments on survival outcomes. the difference between CCLG and GPOH outcomes (sur - When we examined the effect of different local treat - gery with or without radiotherapy). ment modalities on outcomes, there was no evidence of a difference between CCLG and GPOH patients for Localised extremity tumours either EFS or OS among those who received radiother- Table  5 shows the hazard ratios comparing CCLG with apy alone (Table  4). This is not surprising given that the GPOH, according to primary site. When 253 patients proportions with a local relapse (with or without metas- with localised extremity tumours were examined, statis- tases) were not very different: 22% CCLG vs. 16% GPOH tically significant survival differences remained between (Appendix Table  7, 8). The risk of an event or death was the two study groups. There was a 68% increase in the moderately higher in the CCLG group among patients death rate among CCLG patients compared to those in who had surgery alone (excess risk: EFS 31% and OS 50%, GPOH, after allowing for local therapy and other factors though neither were statistically significant). However, (Table 5, p = 0.05). The 5-year survival rates were: GPOH among patients who had both radiotherapy and surgery 81% (95% CI 75–87%), and CCLG 62% (95% CI 52–72%). Percentage alive Percentage alive Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 7 of 13 Table 4 Hazard ratios (CCLG vs. GPOH) according to local treatment modality Local treatment modality Subdivision of RT and surgery group None Radiotherapy (RT) alone Surgery alone RT and surgery RT then surgery Surgery then RT N = 23 N = 164 N = 138 N = 289 N = 201 N = 88 No. events EFS 21 105 53 131 93 38 OS 19 92 41 109 79 30 Unadjusted EFS 20 (2.64–161) 0.86 (0.58–1.26) 1.31 (0.76–2.25) 1.67 (1.05–2.66) 2.22 (0.81–6.07) 1.99 (1.05–3.78) OS 1.50 (0.56–3.96) 0.95 (0.63–1.44) 1.50 (0.81–2.80) 1.65 (1.00–2.74) 1.96 (0.72–5.37) 2.10 (1.02–4.30) Adjusted for age, metastatic disease, primary site and histology EFS 53 (4.0–477) 0.92 (0.62–1.38) 1.24 (0.70–2.20) 1.82 (1.12–2.94) 2.40 (0.84–6.84) 2.50 (1.24–5.06) OS 2.09 (0.64–6.79) 1.06 (0.69–1.63) 1.41 (0.73–2.74) 1.81 (1.07–3.05) 2.21 (0.77–6.35) 2.76 (1.26–6.05) Adjusted for age, metastatic disease, primary site, histology and time between the start of chemotherapy and starting local treatment EFS 0.91 (0.60–1.38) 1.24 (0.70–2.19) 1.61 (0.96–2.70) 1.98 (0.70–5.60) 2.83 (1.30–6.16) OS 1.04 (0.67–1.63) 1.43 (0.73–2.78) 1.68 (0.97–2.91) 1.94 (0.68–5.58) 3.39 (1.42–8.06) Hazard ratios greater than 1 indicate that CCLG patients had a higher risk of having an event or dying compared to GPOH patients Based on data excluding patients with unknown primary site because there were so few EFS event-free survival; OS overall survival Table 5 Hazard ratios (CCLG vs. GPOH) according to primary site and localised disease No. events Unadjusted Adjusted for age, metastatic disease, histology and local treatment Hazard ratio 95% CI p value Hazard ratio 95% CI p value Central axis All (n = 320) EFS 177 1.48 (1.08–2.03) 0.02 1.27 (0.89–1.82) 0.19 OS 154 1.47 (1.05–2.06) 0.03 1.20 (0.82–1.75) 0.36 Localised (n = 220) EFS 102 1.47 (0.97–2.24) 0.07 1.33 (0.82–2.16) 0.24 OS 87 1.46 (0.93–2.30) 0.10 1.15 (0.69–1.92) 0.58 Extremity All (n = 312) EFS 140 1.56 (1.12–2.18) 0.009 1.75 (1.18–2.60) 0.005 OS 112 1.69 (1.17–2.45) 0.006 1.59 (1.02–2.46) 0.04 Localised (n = 253) EFS 99 1.68 (1.13–2.50) 0.01 1.56 (1.00–2.43) 0.05 OS 75 1.86 (1.18–2.93) 0.007 1.68 (1.00–2.81) 0.05 Pelvic disease All (n = 168) EFS 100 1.36 (0.90–2.05) 0.14 1.05 (0.65–1.70) 0.84 OS 90 1.32 (0.85–2.04) 0.21 0.98 (0.60–1.62) 0.94 Localised (n = 107) EFS 56 1.22 (0.69–2.15) 0.51 0.98 (0.51–1.89) 0.96 OS 51 1.17 (0.64–2.14) 0.61 1.01 (0.51–2.03) 0.97 Hazard ratios greater than 1 indicate that CCLG patients had a higher risk of having an event or dying compared to GPOH patients Hazard ratios for localised disease were not adjusted for metastatic disease EFS event-free survival; OS overall survival Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 8 of 13 There were no differences in the baseline patient char - adolescents and young adults [12, 13]. The main influ - acteristics or number of chemotherapy cycles received, ences on continued survival disparity are attributable to except a slight excess of atypical ES in GPOH; 15% lack of health-care resources and access to modern treat- (24/162) vs. 5% (5/91) in CCLG. For patients with local- ments, lack of specialised centres with multidisciplinary ised extremity tumours, combined modality treatment teams, delayed diagnosis and treatment and poor man- was used more frequently in GPOH patients than CCLG agement of treatment, and drug toxicity. However, this patients (66% vs. 24%) whereas a greater proportion of is unlikely to fully account for the wide range in survival CCLG patients were treated with radiotherapy alone from ES reported here. (20% vs. 5%). More CCLG patients had a local recur- Given that all patients were treated according to a rence, with or without metastatic disease (16% vs. 3%). common protocol, the substantial survival differences between national study groups in this randomised trial Central axis and pelvic tumours are striking. Survival for the entire group of 647 patients Among patients with central axis tumours, the HRs for exceeded 60% but this disguises the 14% inferior 5  year both EFS and OS reduced after allowing for several fac- survival of the cohort of patients recruited through tors, and most of the reduction was due to adjusting for the CCLG. The inferior outcome was not obviously local treatment, indicating that this does have a role. A accounted for by differences in baseline characteristics, more pronounced reduction was seen for patients with delivery of chemotherapy or follow up. Differences were pelvic disease (HRs: EFS 1.05, OS 0.98). Patients with found in management of the primary tumour and in the localised pelvic tumours had a similar survival whether rates of local recurrence associated with different treat - treated in the CCLG or GPOH: the 5-year OS rates were ment modalities. We believe that this evidence provides 52 and 56%, respectively (p = 0.65), and the adjusted OS support that variations in local therapy influence survival. HR was 1.01, 95% CI 0.51–2.03 (Table 5), allowing for the It is possible that inherent differences in health care different local treatment modalities used between the delivery systems between the two study groups may have two cohorts. Radiotherapy alone was the local treatment contributed to survival differences. No differences were modality used in 77% (24/31) CCLG patients compared found in the tumour volume and the frequency of pres- to 34% (27/79) GPOH patients. Surgery combined with entation with metastases between the two study groups, radiotherapy was only used for 3% of CCLG patients factors which might indicate systematic delays in diagno- (1/31) compared to 49% of GPOH patients (39/79). A sis in one study group compared to the other. Likewise, survival advantage seemed evident for patients with there was no indication of a systematic difference in the localised pelvic tumours selected for surgery, compared way chemotherapy was delivered. to those who had radiotherapy alone (hazard ratio 0.50, Approaches to local tumour control were clearly differ - 95% CI 0.28–0.88, p = 0.016). ent between the two groups, including the timing of local treatments, but they did not explain all of the difference, Discussion particularly when patients had surgery. Primary tumour The EICESS-92 clinical trial revealed unexpected dif - control in ES can be achieved with surgery, radiotherapy ferences in survival between cohorts of ES patients or a combination of both. The choice is based on balanc - from two countries. Differences in mortality from can - ing the differing morbidities of the two modalities for cer between countries are well documented in Europe, each individual patient. The optimal approach for local especially for common cancers [6, 7]. These differences control remains a topic of debate. The relative merits of in outcome have also been reported for rare cancers [8, surgery and radiotherapy have been debated but conclu- 9]. Survival in the UK is lower for some cancers than in sions are often obscured by patient selection which biases other Western European and Nordic countries. Expla- comparison [5, 14–17]. Tumours that are inoperable and nations for these differences may include: registry data thus treated by radiotherapy alone are often associated being unrepresentative or containing artefact; differences with other adverse features such as large volume [18–21]. in population health or use of health resources; differ - The greater incidence of local relapse in CCLG patients ences in stage of cancer at diagnosis and variable access indicates that both selection of patients for, and delivery to optimal treatment or expertise [10]. Within EURO- of, surgery and radiotherapy may have been sub-optimal. CARE 3, which examined registry data for 20 European While not specific to Ewing sarcoma, there is a gen - countries, 5-year survival from ES ranged from 31 to 86% eral consensus on the relevance of centralization to high for the period 1990–1994 [11]. The EUROCARE-5 study volume centres and networks for sarcoma, especially for investigated whether survival differences among Euro - diagnosis and surgery [22, 23]. The degree of centralisa - pean countries had changed further from 1999 to 2007 tion and the process of decision-making about local ther- and found persisting inequalities both for children and apy differed between the two study groups in EICESS-92. Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 9 of 13 Ideally, the optimal local treatment for an individual results from this trial, the UK has initiated a system for patient should be decided through consideration of centralised national review and guidance on local treat- patient characteristics, the potential benefit and harm ment decision making for ES. This system is currently of the treatment options, and patient preference. In the undergoing evaluation. CESS group, treatment took place in three hundred or Authors’ contributions more centres, most of which treat relatively few patients. JW, AMCT, AH, RG, AC, DS, JB, IL and MP contributed to discussion, interpreta- However, each centre was familiar with accessing special- tion and appraisal of the presented data. All but AH and JB participated in the EICESS 92 study. AH undertook the statistical analysis. JW and AH drafted ist guidance from the trial headquarters. This extended the manuscript. HJ and AC critically appraised the manuscript and were joint to a centralised system of advice for local therapy plan- chairman of the EICESS 92 study. All authors read and approved the final ning [5]. A consequence is likely to have been consider- manuscript. able consistency of local treatment approach within the Author details majority of the GPOH cohort. In contrast, although sur- 1 Department of Oncology, University College Hospitals London NHS Founda- gery for bone sarcomas took place mainly in four centres tion Trust, 250 Euston Road, London NW1 2PG, UK. Cancer Research UK and UCL Clinical Trials Centre, University College London, London, UK. Chil- in the UK, advice about local tumour management was dren’s Cancer and Leukaemia Group Data Centre, Cancer Studies and Molecu- only sought on an ad hoc basis and there was no similar 4 lar Medicine, University of Leicester, Leicester, UK. The Royal Orthopaedic system for any degree of central treatment planning. Hospital, Birmingham, UK. Queen Elizabeth II Hospital, Birmingham, UK. 6 7 University Hospital Essen, Essen, Germany. Vestische Kinder- und Jugendk- The EICESS-92 trial is an example of how collaboration linik Datteln, University Witten/Herdecke, Datteln, Germany. Department between national clinical study groups is required to run of Pediatric Hematology and Oncology, University Children’s Hospital Münster, large randomised trials with sufficient power for robust Münster, Germany. Northern Institute for Cancer Research, Newcastle Uni- versity, Newcastle upon Tyne, UK. University of Leeds and Leeds Community analyses in rare cancers. It is acknowledged that the work Healthcare Trust, Leeds, UK. has been delayed in its publication but it has been revis- ited to coincide with a strong current focus and drive for Acknowledgements We are grateful for the support given to this project by staff at the CCLG Data international consensus on the role of surgery and radio- Centre in Leicester, especially Claire Weston and Carolyn Douglas. This work therapy in ES. was undertaken in part at UCLH/UCL who received a proportion of funding The low rates of local recurrence evident with patients from the Department of Health’s NIHR Biomedical Research Centres funding scheme. undergoing combined modality treatment and the Presented in part at ASCO Annual Meeting, Atlanta, June 2006. enhanced survival for a cohort of patients, more of whom underwent surgical resection and received radiother- Competing interests apy, indicates that clinicians should always consider this The authors declare they have no competing interests. option. Nevertheless, this must be balanced against the additional late effects, including second malignancies, Availability of data and materials Not applicable. which are associated with the use of radiotherapy in ES. Consent for publication Conclusion Not applicable. In summary, unexpected differences in survival between Ethics approval and consent to participate cohorts of patients within the same randomised trial have EICESS-92 was approved by the appropriate ethics committees and institu- been identified and are national in origin. It appears that tional review boards. Informed consent was obtained from all patients or guardians. less aggressive methods of local control have resulted in a higher rate of local recurrence and this was associated Funding with a higher risk of metastatic disease and subsequent Supported by Deutsche Krebshilfe (Grants No. DKH M43/92/Jü2 and DKH 70-2551 Jü3), and European Union Biomedicine and Health Programme death. These data reinforce the importance of careful (Grants No. BMH1-CT92-1341 and BMH4-983956), and Cancer Research United planning of treatment for local tumour control in ES and Kingdom. that radiotherapy alone should be discouraged when sur- gical resection can be undertaken. International clinical Appendix trials may offer opportunities to explore the impact of See Tables 6, 7, 8, 9, 10, 11 and 12. different treatment approaches. As a consequence of the Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 10 of 13 Table 6 Number of patients and events according to trial group Number of patients (percentage) CCLG GPOH Total N = 210 N = 437 First events (total) 119 (57) 204 (47) 323 Death-treatment related 1 (0.5) 3 (1) 4 Disease progression 3 (1) 12 (3) 15 Unknown cause 3 (1) 1 (0.2) 3 Distant metastases 66 (31) 148 (34) 214 [Distant metastases in those with metastatic disease at baseline] [25 (12%)] [57 (13%)] [82] Local relapse 29 (14) 13 (3) 42 Local and distant relapse 16 (8) 18 (4) 34 Relapse (unspecified site) 0 4 (1) 4 Second malignancy 2 (1) 5 (1) 7 All deaths 105 (50) 168 (38) 273 As a percentage of the number of patients from either CCLG or GPOH Table 7 Distribution of first events by treatment modality: CCLG patients Local treatment modality, N (%) Total Surgery alone RT alone RT then surgery Surgery then RT None Unknown N = 70 N = 81 N = 6 N = 32 N = 18 N = 3 No event 41 (59) 31 (38) 2 (33) 14 (44) 0 2 (67) 90 Local recurrence 5 (7.1) 12 (15) 1 (17) 1 (3.1) 10 (56) 0 29 Distant recurrence 18 (26) 28 (35) 1 (17) 13 (41) 5 (28) 1 (33) 66 Local and distant 3 (4.3) 6 (7.4) 2 (33) 3 (9.4) 2 (11) 0 13 Relapse-unspecified 0 0 0 0 0 0 0 Second malignancy 1 (1.4) 1 (1.2) 0 0 0 0 2 Death—no relapse 2 (2.9) 3 (3.7) 0 1 (3.1) 1 (5.6) 0 7 All deaths 24 (34) 45 (56) 4 (67) 15 (47) 16 (89) 1 (33) 105 RT radiotherapy Table 8 Distribution of first events by treatment modality: GPOH patients Local treatment modality, N (%) Total Surgery alone RT alone RT then surgery Surgery then RT None Unknown N = 71 N = 85 N = 195 N = 60 N = 7 N = 19 No event 46 (65) 30 (35) 106 (54) 38 (63) 1 (14) 12 (63) 233 Local recurrence 3 (4.2) 3 (3.5) 3 (1.5) 4 (6.7) 0 0 13 Distant recurrence 19 (27) 36 (42) 71 (36) 16 (27) 2 (29) 4 (21) 148 Local and distant 2 (2.8) 10 (12) 4 (2.0) 1 (1.7) 0 1 (5.3) 18 Relapse-unspecified 0 1 (1.2) 2 (1.0) 0 0 1 (5.3) 4 Second malignancy 1 (1.4) 2 (2.4) 2 (1.0) 0 0 0 5 Death—no relapse 0 3 (3.5) 7 (3.6) 1 (1.7) 4 (57) 1 (5.3) 16 All deaths 18 (25) 47 (55) 75 (38) 17 (28) 6 (86) 5 (26) 158 To one decimal place if < 10% RT radiotherapy Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 11 of 13 Table 9 Hazard ratios for comparing CCLG and GPOH patients EFS OS HR (95% CI) p value HR (95% CI) p value All patients Unadjusted 1.42 (1.13–1.77) 0.002 1.45 (1.14–1.86) 0.003 Unadjusted HR, in localised disease only 1.47 (1.11–1.96) 0.007 1.52 (1.11–2.07) 0.009 Adjusted for risk group and trial treatment 1.43 (1.14–1.79) 0.002 1.49 (1.17–1.91) 0.001 Adjusted for each of the following factors separately Age 1.45 (1.15–1.81) 0.001 1.47 (1.15–1.88) 0.002 Metastatic disease 1.38 (1.10–1.73) 0.005 1.42 (1.11–1.81) 0.005 Primary site 1.48 (1.18–1.86) <0.001 1.52 (1.19–1.95) 0.001 Histology 1.41 (1.12–1.77) 0.004 1.44 (1.12–1.85) 0.004 Local treatment modality 1.45 (1.12–1.89) 0.006 1.30 (0.98–1.72) 0.07 Adjusted for age, metastatic disease, primary site, histology and local tr eatment 1.44 (1.10–1.89) 0.009 1.30 (0.97–1.74) 0.08 Adjusted HR, in localised disease only 1.48 (1.05–2.09) 0.026 1.29 (0.88–1.89) 0.19 Only patients who had local therapy; excluding progressive disease (n = 25) and where it was not known whether local therapy was given or not n = 22) Unadjusted 1.22 (0.96–1.55) 0.11 1.28 (0.99–1.67) 0.06 Adjusted for type of local treatment 1.14 (0.87–1.51) 0.34 1.25 (0.92–1.68) 0.15 Adjusted for time between the start of chemotherapy and starting local treatment 1.12 (0.87–1.44) 0.37 1.18 (0.90–1.55) 0.22 Adjusted for age, metastatic disease, primary site, histology, local treatment, and time between 1.13 (0.84–1.50) 0.42 1.25 (0.91–1.71) 0.17 the start of chemotherapy and starting local treatment Hazard ratios greater than 1 indicate that CCLG patients had a higher risk of having an event or dying compared to GPOH patients EFS event-free survival; OS overall survival Using Cox regression modelling (age as a continuous variable). Missing data for the other variables were included as a separate category, but excluding these from the analyses did not materially change the hazard ratio estimates in the table Includes categories for no local therapy and missing data Surgery alone, radiotherapy alone, surgery then radiotherapy, radiotherapy then surgery Table 10 Hazard ratios (CCLG vs. GPOH) according to local treatment modality, among patients with localised disease only Local treatment modality Subdivision of RT and surgery group Radiotherapy (RT) alone Surgery alone RT and surgery RT then surgery Surgery then RT N = 108 N = 119 N = 221 N = 152 N = 69 No. events EFS 62 42 83 61 22 OS 53 33 66 49 17 Unadjusted EFS 0.89 (0.54–1.46) 1.44 (0.78–2.64) 1.66 (0.94–2.96) 2.44 (0.76–7.81) 2.36 (1.02–5.45) OS 0.99 (0.56–1.64) 1.74 (0.86–3.51) 1.60 (0.84–3.06) 2.70 (0.84–8.73) 2.03 (0.78–5.28) Adjusted for age, primary site and histology EFS 0.98 (0.58–1.66) 1.51 (0.78–2.94) 1.65 (0.91–2.99) 2.39 (0.71–8.05) 2.12 (0.83–5.40) OS 1.10 (0.62–1.95) 1.94 (0.89–4.25) 1.50 (0.77–2.93) 3.10 (0.90–10.70) 1.74 (0.60–5.08) Adjusted for age, primary site, histology and time between the start of chemotherapy and starting local treatment EFS 0.95 (0.54–1.67) 1.48 (0.76–2.89) 1.48 (0.81–2.69) 1.69 (0.50–5.68) 2.10 (0.82–5.41) OS 1.03 (0.55–1.90) 1.92 (0.87–4.24) 1.39 (0.71–2.74) 2.49 (0.72–8.58) 1.74 (0.59–5.10) Hazard ratios greater than 1 indicate that CCLG patients had a higher risk of having an event or dying compared to GPOH patients Based on data excluding patients with unknown primary site because there were so few EFS event-free survival; OS overall survival Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 12 of 13 Table 11 Hazard ratios (CCLG vs. GPOH) according to local treatment modality, among patients with metastatic disease only Local treatment modality Radiotherapy (RT) alone Surgery alone RT and surgery N = 56 N = 19 N = 66 No. events EFS 43 11 48 OS 39 8 43 Unadjusted EFS 0.79 (0.43–1.44) 0.79 (0.24–2.61) 2.01 (0.89–4.54) OS 0.92 (0.49–1.74) 0.71 (0.18–2.85) 1.98 (0.88–4.47) Adjusted for age, primary site, histology and time between the start of chemotherapy and starting local treatment EFS 0.81 (0.44–1.67) Too few patients to allow for other factors reliably 2.51 (0.89–7.06) OS 1.01 (0.50–2.01) 2.54 (0.90–7.20) Hazard ratios greater than 1 indicate that CCLG patients had a higher risk of having an event or dying compared to GPOH patients Based on data excluding patients with unknown primary site because there were so few EFS event-free survival; OS overall survival Table 12 Hazard ratios for comparing CCLG and GPOH patients, after examining local treatment and time to local treat- ment EFS OS HR (95% CI) p value HR (95% CI) p value All patients Unadjusted 1.22 (0.96–1.56) 0.10 1.29 (0.99–1.68) 0.055 Adjusted for local treatment 1.14 (0.87–1.51) 0.34 1.25 (0.93–1.68) 0.15 Adjusted for between the start of chemotherapy and starting local treatment 1.13 (0.88–1.45) 0.34 1.19 (0.91–1.56) 0.20 Adjusted for both local treatment and timing 1.11 (0.84–1.47) 0.46 1.21 (0.90–1.65) 0.21 Localised disease only Unadjusted 1.31 (0.97–1.76) 0.08 1.39 (1.00–1.93) 0.048 Adjusted for local treatment 1.22 (0.87–1.72) 0.25 1.30 (0.89–1.90) 0.17 Adjusted for between the start of chemotherapy and starting local treatment 1.18 (0.87–1.60) 0.30 1.24 (0.88–1.74) 0.21 Adjusted for local treatment and the time between the start of chemotherapy and starting 1.14 (0.81–1.62) 0.45 1.20 (0.82–1.77) 0.35 local treatment Metastatic disease only Unadjusted 0.98 (0.65–1.48) 0.93 1.01 (0.66–1.57) 0.94 Adjusted for local treatment 0.98 (0.61–1.56) 0.93 1.11 (0.68–1.81) 0.69 Adjusted for between the start of chemotherapy and starting local treatment 0.95 (0.62–1.45) 0.81 1.00 (0.64–1.57) 0.98 Adjusted for both local treatment and timing 0.99 (0.61–1.60) 0.97 1.14 (0.69–1.89) 0.60 Type of local treatment and time to local treatment seem to be independent factors. In the Cox regression which contains both of them, the p values for each variable are: All patients EFS: local treatment (p < 0.0001); time to local treatment (p < 0.001) All patients OS: local treatment (p < 0.0001); time to local treatment (p < 0.001) Patients with localised disease only, EFS: local treatment (p = 0.002); time to local treatment (p = 0.002) Patients with localised disease only OS: local treatment (p = 0.002; time to local treatment (p = 0.004) Surgery alone, radiotherapy alone, surgery then radiotherapy, radiotherapy then surgery Whelan et al. Clin Sarcoma Res (2018) 8:6 Page 13 of 13 P, Sánchez-Pérez MJ, Sant M, Santaquilani M, Stiller C, Tavilla A, Trama A, Publisher’s Note Visser O, Peris-Bonet R, EUROCARE Working Group. Childhood cancer sur- Springer Nature remains neutral with regard to jurisdictional claims in pub- vival in Europe 1999–2007: results of EUROCARE-5–a population-based lished maps and institutional affiliations. study. 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Journal

Clinical Sarcoma ResearchSpringer Journals

Published: Mar 30, 2018

References