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Preoperative accelerated radiotherapy combined with chemotherapy in a defined cohort of patients with high risk soft tissue sarcoma: a Scandinavian Sarcoma Group study

Preoperative accelerated radiotherapy combined with chemotherapy in a defined cohort of patients... Background: We recently reported outcomes from a Scandinavian Sarcoma Group adjuvant study (SSG XX group A) conducted on localized and operable high risk soft tissue sarcoma (STS) of the extremities and trunk wall. SSG XX, group B, comprised of patients in a defined cohort with locally advanced STS considered at high risk for intralesional surgery. These patients received preoperative accelerated radiotherapy, together with neoadjuvant and adjuvant chemotherapy. Herein we report the results of this group B. Methods: Twenty patients with high-grade, locally advanced and deep STS located in lower extremities (n = 12), upper extremities (5) or trunk wall (3) were included. The median age was 59 years and 14 patients were males. The 2 2 treatment regimen consisted of 6 cycles of doxorubicin (60 mg/m ) and ifosfamide (6 g/m ), with three cycles given neoadjuvantly, and preoperative radiotherapy (1, 8 Gyx2/daily to 36 Gy) between cycles 2 and 3. After a repeated MRI surgery was then conducted, and the remaining 3 chemotherapy cycles were given postoperatively at 3 weeks inter- vals. Survival data, local control, toxicity of chemotherapy and postoperative complications are presented. Results: Median follow-up time for metastasis-free survival (MFS) was 2.8 years (range 0.3–10.4). The 5-year MFS was 49.5% (95% confidence interval [CI] 31.7–77.4). The median follow-up time was 5.4 years (range 0.3–10.4) for overall survival (OS). The 5-year OS was 64.0% (95% CI 45.8–89.4). The median tumour size was 13 cm, with undifferentiated pleomorphic sarcoma (n = 10) and synovial sarcoma (n = 6) diagnosed most frequently. All patients completed sur- gery. Resection margins were R0 in 19 patients and R1 in 1 patient. No patients had evidence of disease progression preoperatively. Three patients experienced a local recurrence, in 2 after lung metastases had already been diagnosed. Eleven patients (55%) had postoperative wound problems (temporary in 8 and persistent in 3). Conclusions: Preoperative chemotherapy and radiotherapy were associated with temporary wound-healing prob- lems. Survival outcomes, local control and toxicities were deemed satisfactory when considering the locally advanced sarcoma disease status at primary diagnosis. Trial registration This study was registered at ClinicalTrials.gov Identifier NCT00790244 and with European Union Drug Regulating Authorities Clinical Trials No. EUDRACT 2007-001152-39 *Correspondence: ksh@ous-hf.no Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway 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. Hall et al. Clin Sarcoma Res (2020) 10:22 Page 2 of 9 Keywords: Soft tissue sarcoma, Preoperative, Adjuvant, Chemotherapy, Radiotherapy, Accelerated, Survival, Toxicity Background in Sweden and two in Norway. Most cases were discussed Preoperative chemotherapy (CT) and radiotherapy (RT) at a surgical sarcoma network, a SSG web-based forum have previously been studied as an integrated treatment established to evaluate the risk for intralesional surgery plan for patients with primary soft tissue sarcomas (STS) and the need for preoperative treatment. [1, 2]. Several potential benefits of preoperative chemo-/ A core-needle biopsy or an open surgical biopsy was radiotherapy have been suggested, including an ability to performed for classification of tumour type, grading of assess primary tumour response to a given chemothera- malignancy and histological diagnosis provided by the peutic regimen and to facilitate radical surgical removal, local pathologist. Diagnosis based on fine needle cytol - as well as to initiate earlier systemic treatment to combat ogy alone was not accepted. The SSG Pathology Refer - subclinical metastatic disease. In a recent study the Ital- ence Group later reviewed the morphology in all cases ian and Spanish Sarcoma Groups have shown, such com- according to the WHO-classification and malignancy bined treatment is feasible and safe with limited increase grade, applying the Broders’ system [15–17]. Distinct in wound complications [3]. grading may be unreliable in core-needle biopsies, and According to formal guidelines [4], doxorubicin and the pathologists considered the best assessment to be low ifosfamide are still not regarded as standard treatment grade and high grade, recognising that high grade will in patients with high-grade localised soft-tissue sarcoma, encompass both Broders’ grade 3 and 4. A core needle neither as adjuvant nor neoadjuvant chemotherapy, biopsy does not allow definition of the histological risk despite a demonstrated benefit in several studies [5–10]. factors (vascular invasion, infiltrative growth, necrosis) as Our prospective, non-randomised Scandinavian Sarcoma used in SSGXX, group A [11]. Group (SSG) clinical study, SSG XX, was also designed The following histiotypes were not eligible: extraskel - to investigate the combination of adjuvant doxorubicin etal osteosarcoma or chondrosarcoma, Ewing sarcoma, and ifosfamide in high risk STS [11]. In group A planned rhabdomyosarcoma, Kaposi sarcoma, clear cell sarcoma, for primary surgery, accelerated radiotherapy was sched- alveolar soft part sarcoma, epithelioid sarcoma and radia- uled postoperatively between cycles 3 and 4 with a 5-year tion induced sarcoma. metastasis-free survival of 70.4% and overall survival Mandatory investigations at screening, during treat- 76.1% [11]. The increasing evidence for the benefit of ment and at follow-up visits have previously been pre- adjuvant RT [12, 13] led to the introduction of an acceler- sented [11]. The complete SSG XX protocol is available ated RT administered between courses of chemotherapy on the SSG website [18]. in SSG’s former protocol SSG XIII [14] and pursued also in SSG XX [11]. The SSG XX protocol had a separate Treatment treatment arm (group B) devoted to patients with locally An outline of the treatment, involving scheduling of advanced STS considered to have a high risk for intral- MRI, CT, RT and surgery, is presented in Fig. 1. A maxi- esional surgery. These patients were given both pre- and mum of 28  days was allowed from diagnostic biopsy to postoperative chemotherapy, as well as accelerated RT start of chemotherapy. Doxorubicin 60  mg/m and ifos- before surgery. Here we report our experiences regarding famide 6  g/m were given with a 3  weeks interval for the feasibility and outcomes of this combination. patients < 70  years of age and with doses of 50/5 from age ≥ 70  years. Details of CT and use of granulocyte Methods colony-stimulating factor (G-CSF) have previously been Criteria for inclusion published [11]. The main eligibility criteria for SSG XX, group B were Accelerated RT allowing shortened treatment time was age ≥ 18 to ≤ 75  years, WHO performance status ≤  1, interposed from week 4 to 6, after completion of the two and a locally advanced primary STS of high-grade histol- initial CT cycles and before the 3rd cycle (Fig.  1). This ogy (Grade III or IV in a 4 graded scale) located in the scheduling allowed the maintenance of a high overall extremities or trunk wall. Only patients with a tumour of dose intensity of the CT given. The fractionation sched - anatomical location and/or extension implying an obvi- ule was 1.8 Gy twice daily to 36 Gy, with at least 6 h inter- ous risk for intralesional margins were eligible. Tumour val between the two daily fractions and 5 treatment days size was defined as the longest diameter on MRI at diag - per week. Due to a radiosensitising effect of doxorubicin, nosis. Tumour depth was defined in relation to the deep the minimal interval between doxorubicin (cycle 2) and fascia. The patients were treated at four sarcoma centres RT was set to 7  days. Clinical target volume (CTV) was Hall  et al. Clin Sarcoma Res (2020) 10:22 Page 3 of 9 RT 36 Gy MR I Surgery CT 1CT2 (1.8 x2/d x10d)CT3 CT 4 CT 5 CT 6 01 23 45 67 89 10 11 12 13 14 15 16 17 18 19 20 weeks Fig. 1 Treatment schedule. Chemotherapy (CT ): ≥ 18 and < 70 years of age: Day 1: doxorubicin 60 mg/m , 4-h infusion (IV ); Day 1, 2 and 3: 2 2 ifosfamide 2 g/m /day as 2-h infusion, dose per cycle 6 g/m [with an equal dose of 2-mercaptoethane sulphonate sodium (MESNA)]. ≥ 70 2 2 and ≤ 75 years: doxorubicin 50 mg/m and ifosfamide 5 g/m (given as above). Granulocyte colony-stimulating factor was given routinely after each cycle defined by adding a 2  cm margin in all directions to the The survival analyses were based on follow-up data gross tumour volume (GTV), based on the baseline MRI up to 2  years after the last patient enrolment (which examination. The choice of the conformal radiation treat - occurred on June 30, 2014), at which time the data- ment technique was decided by each centre. base was locked according to the a priori analysis plan. Surgery was planned 3–4  weeks after RT to minimise Patients with no events were censored either at the last the fibrotic tissue response. A preoperative MRI was date of follow-up or at the predefined date of data lock repeated to document any changes in tumour size and (June 30, 2016). extension. Two weeks after surgery, the first of the three A final survival analysis, with use of follow-up data remaining cycles of chemotherapy was given (Fig. 1). until December 31, 2019, is also presented. All patients underwent surgery at a sarcoma centre. At The Kaplan–Meier method was used to estimate MFS that time, their neutrophil levels should be ≥ 1.0 × 10 /l and OS [19]. For the analyses of MFS, patients who were and thrombocytes ≥ 80 × 10 /l. The classification of mar - alive and disease free were censored at the date of the gins, according to the SSG guidelines [18], was coopera- last follow-up, but not later than December 31, 2019. For tively determined by the surgeons and pathologists at the analyses of OS, data for patients who were alive were each sarcoma center. censored at the date of last follow-up, but not later than Details of RT for SSG XX groups A and B combined December 31, 2019. Cox regression analyses to study rel- will be published later, with emphasis on quality assess- ative risks were not performed due to the low number of ment of the radiation dose distributions and target vol- patients. ume definitions in correlation with local recurrences, as The dose intensity of CT was calculated using the well as formal scoring of late effects. method reported in previous studies [11, 14, 20]. Results End‑points Patients The primary end-point was metastasis-free survival The patient demographics, tumour characteristics and (MFS), calculated from the date of CT 1 (first chemo - histological subtypes are shown in Table  1. The timing therapy cycle) until the first of the events of metastasis of various treatments completed by individual patients or death from any cause. Overall survival (OS) was a is shown by case numbers in Fig. 2. Inclusion of patients secondary endpoint defined as the time from CT 1 until (n = 20) in this group with preoperative treatment (group death from any cause. B of SSG XX) was closed in June 2014, when the planned The secondary endpoints also included local recur - number of patients in the postoperative and adjuvant rence, defined as the time from the date of CT 1 to local group A (n = 160) had been fully recruited [11]. recurrence (with death considered a competing event) Nineteen patients had limb-sparing primary surgery; and the proportion of patients with progression of local only in one patient was an amputation deemed necessary disease preoperatively. Lastly, surgical margin status (case 8). Hence, the latter patient was not evaluable for scored as wide, marginal and intralesional, as well as R0, scoring of any wound complications related to RT. This R1 and R2 status, are also reported. patient had a synovial sarcoma (13  cm) located in the distal forearm, with close relation to vessels and nerves, Statistical analyses but after 3 CT cycles and RT, the tumour was unchanged Descriptive analyses were used. Treatment endpoints, as (MRI). He therefore underwent amputation 4 weeks later, well as toxicity from CT and RT, were analysed in all 20 distal to the elbow, with a 5  cm proximal margin from patients who started chemotherapy. the tumour followed by the 3 remaining CT cycles. He Hall et al. Clin Sarcoma Res (2020) 10:22 Page 4 of 9 Table 1 Patients demographic and  tumor characteristics of eligible patients Characteristics Numbers Age at diagnoses (years) Median 59 Range 22–71 Gender Male 14 Female 6 Tumor site Lower extremity (including gluteal and groin) 12 Upper (including shoulder) 5 Trunk wall 3 Location Subcutanous 0 Deep 20 Tumour size (cm) Median 13 Range 7–17 Histopathological subtype Undifferentiated pleomorphic sarcoma 10 Pleomorphic liposarcoma 1 Leiomyosarcoma 1 Synovial sarcoma 6 Malignant peripheral nerve sheath tumor 1 Myxofibrosarcoma 1 developed a solitary pulmonary metastasis (45 mm) that Fig. 2 SSG XX, group B, time schedule for chemotherapy, was surgically removed 3.5  years later and is NED as of radiotherapy and surgery his last follow-up after 8 years. Importantly, none of the 20 patients experienced local tumour progression preoperatively. Resection margins were wide (R0 resection) in 13 patients, marginal (R0) in 6 patients (cases 1, 5, 9, 12, 13 and 16) and intralesional (R1) in 1 (case 2). Metastases‑free and overall survival The analysis according to the described statistical plan in the protocol was done based on the data collected up to a time point exactly 2 years after complete enrolment in the SSG XX trial. By that definition, the data cut-off became June 30, 2016. Later events were therefore not included in this first analysis. As stated above, we also decided to make a later analysis for group B (not done for group A) since several years had elapsed. This analysis included all data up to December 31, 2019. Survival curves for these late analyses only are shown (Figs. 3, 4). Median follow-up of patients in the pre-planned analy- Fig. 3 Metastases-free survival (Kaplan–Meier Curve; % with 95% ses of the primary end-point MFS was 2.1  years (range CI = confidence interval) of 20 patients with high risk soft tissue 0.3–10.4). The estimated MFS rate at 5  years was 44.0% sarcoma and a median follow-up 2.8 years (95% CI 24.4–79.5). For overall survival (OS), the median Hall  et al. Clin Sarcoma Res (2020) 10:22 Page 5 of 9 Table 2 Toxicity according to CTCAE score a b ToxicityAll grades Grade 3–4 Number of patients Number of patients Neutropenia without fever 17 12 Neutropenia with fever 3 3 Thrombocytopenia 16 6 Anaemia 3 3 Wound infection 2 2 Other infections, normal 3 0 ANC Haematuria 3 3 ALAT increased 6 0 Creatinine increased 2 0 Fig. 4 Overall survival (Kaplan–Meier Curve; % with 95% Fever, unspecified 2 0 CI = confidence interval) of 20 patients with high risk soft tissue Pulmonary embolism 1 1 sarcoma and a median follow-up 5.4 years All grades of toxicities occurring in > 1 patient or any grade 3–4 Number of patients with CTCAE toxicities grade 3–4 follow-up time was 3.1 years (range 0.3–10.4). The 5-year estimated OS was 66.7% (95% CI 47.7–93.2). As of the end of 2019, distant metastases had occurred Chemotherapy toxicity in 10 patients (50%), 9 to the lung (cases 2, 7, 8, 9, 10, 11, The CT toxicity was recorded according to Common Ter - 14, 15 and 16) and one to the cerebrum (case 17). Nine minology for Adverse Events (CTCAE), version 3.0. In patients had died (45%), all from sarcoma metastases. general, CT was well tolerated and no worse than in our The median follow-up of patients in this analysis of MFS earlier described larger SSG XX group of patients who was 2.8  years (range 0.3–10.4). The final estimated MFS only underwent postoperative CT and RT [11]. Table  2 rate at 5 years was 49.5% (95% CI 31.7–77.4) (Fig. 3). For presents all toxicities reported in more than one patient overall survival (OS), the median follow-up time was and numbers that had grade 3–4 toxicity. Neutropenia, 5.4 years (range 0.3–10.4). The final estimated 5-year OS without fever and thrombocytopenia, was the most com- was 64% (95% CI 45.8–89.4) (Fig. 4). mon side effect. One case of pulmonary embolism grade 4 was reported as the most serious toxicity. No fatal tox- icities occurred. Chemotherapy cycles and dose intensity Long-term cardiac and renal toxicities were measured Sixteen patients received all the planned 6 cycles, 1 by left ventricular ejection fraction (LVEF) and glomer- patient had 5 cycles, 2 patients 3 cycles and 1 patient had ular filtration rate (GFR), respectively, at several time 2 cycles only (Fig.  2). Median dose intensity for doxoru- points during and after the treatment. The last measure - bicin and ifosfamide combined was only 79.0% (range ments were scheduled, according to the SSG XX proto- 33–86). col, at 10 years after end of treatment. The majority of the For logistical reasons two patients had 3 cycles of CT patients did not show any late cardiac or renal effects, but before RT and three patients received 4 cycles before several data points were missing (i.e. the investigations surgery (Fig.  2). One patient who had surgery after only were not performed). Some patients also had very few, if 2 cycles of CT and RT did not have more CT due to a any, measurements because of rapid disease progression non-healing surgical wound complication (case 15). She dismissing the study-related follow-up. Among the 15 later died of metastases. Two patients who had 3 preop and 16 patients who had at least one measurement of car- erative cycles did not receive postoperative treatment. In diac and renal toxicity, respectively, four patients showed one this was due to cerebral metastases diagnosed shortly a grade 1 cardiac toxicity and just one had grade 1 renal after surgery with rapid clinical deterioration and death toxicity. (case 17), and in the other due to refusal of postoperative CT (case 19). Only 3 patients had their first postoperative cycle as Radiotherapy and toxicity scheduled within 15 days postoperatively (cases 5, 8 and Eighteen patients received the scheduled RT to 36  Gy 14); 10 patients had this cycle between day 15 and 23, 3 preoperatively after 2 cycles without any delays (Fig.  2). patients between day 28 and 34 (cases 3, 10 and 20) and 1 Acute RT toxicity was recorded at each chemotherapy patient at day 68 (case 13). Hall et al. Clin Sarcoma Res (2020) 10:22 Page 6 of 9 cycle until 6  weeks after last cycle. The RTOG Acute of function is the goal and the tumour is located near Radiation Toxicity Scoring was used [21]. critical structures, such as larger vessels and nerves. The Maximum skin toxicity due to RT during the treat- local control rate was deemed satisfactory, as only 3 of ment period was grade 4 in 1 patient (5%), grade 3 in 4 the 20 patients experienced a local recurrence and in patients (20%), grade 2 in 6 patients (30%) and grade 1 in two this occurred after diagnosis of metastatic disease. 5 patients (25%). Scoring 0 was reported for 4 patients. In Nine patients developed pulmonary metastases. Only 2 patients only, toxicity resulted in a delay of CT. Notably, one patient underwent a complete metastasectomy, with very few patients had late radiotoxicity. NED observed after 8  years. The 5-year estimated MFS None of the patients developed a second cancer. and OS rates were 49.5% and 64.0%, respectively. The Italian and Spanish Sarcoma Groups (ISG/GEIS) Local recurrence rate administered neoadjuvant and adjuvant CT with doxoru- Three patients developed a local recurrence (LR). This bicin and ifosfamide to similar patients. They concluded related to one patient with wide margin by primary sur- that CT may be omitted after 3 preoperative cycles, gery of a tumour (12  cm, UPS) in lower extremity that based on their study comparing treatment with 3 pre- developed LR 5.5  years after primary surgery (5.8  years operative cycles only with that of addition of two further after cycle 1) and was salvaged by an uncomplicated re- postoperative cycles [9]. The 10-year overall survival for operation. The patient was NED at follow-up 3  months both treatment arms was about 60% [22]. Interestingly, later (case 3). Furthermore, two patients, both having our survival data seems to be in accordance with the ISG/ 10 cm tumours (synovial sarcoma) in the lower extremi- GEIS trial. In the same study, preoperative RT (44–50 Gy) ties had LR 18  months after primary surgery (20 and was given to 169 patients (from a total of 303 patients) 21  months after cycle 1, respectively). The margins at and wound complications occurred in 13.5% [3]. Gron- primary surgery were wide (R0) and intralesional (R1), chi et al. showed in a recent publication that disease free respectively. Interestingly, both these patients experi- and overall survival by histiotype-tailored neoadjuvant enced LR after first being diagnoses with pulmonary chemotherapy was not superior to anthracycline and metastases (11 months and 4 months, respectively). Both ifosfamide in high-grade STS [23]. Their conclusion was died later of metastases (cases 2 and 11). that doxorubicin and ifosfamide should remain the regi- men to choose whenever neoadjuvant chemotherapy (or Surgical complications adjuvant) is used. No wound healing complications were observed in As already mentioned, the addition of preoperative RT 8 patients. Delayed wound healing in ranges of 2 to to CT is adopted at many centres as part of a multimodal 4  months occurred in 7 patients (cases 9, 11, 12, 13, 14, treatment plan for patients with primary STS [1, 2, 10, 19 and 20) and lasting as long as 6  months in 1 patient 24]. We did not include specific assessment of response (case 5). These patients all had early postoperative infec - into the protocol, neither by radiology nor pathology tions that were treated with antibiotics and wound [18]. It was, however, mandatory to repeat MRI before revisions followed by vacuum pump treatment. One surgery (after 3 preoperative cycles + radiotherapy), but patient needed a skin transplant and healing occurred in the clinical report forms only preoperative tumour at 6 months (case 5). Three patients (cases 6, 15 and 17) progression was registered. Interestingly, no patients had had persistent wounds that did not heal, and two of them preoperative tumour progression after a composite radi- died early due to metastatic disease (cases 15 and 17). ological/clinical evaluation at the local hospital. Further- The third patient (case 6) was NED at last follow-up in more R0 resection margin was obtained in 19 patients (of 2019 but with a still unresolved non-healing wound after 20) which for all practical reasons is an important result, multiple revisions and hyperbaric oxygen treatment. since all eligible patients in SSG XX, group B should have an obvious risk for intralesional surgery. In the ISG/GEIS Discussion study reported above, some cases had positive micro- This study explored the possible benefit of combining scopic margins, despite preoperative CT and RT, but neoadjuvant CT and preoperative, accelerated RT in a this was not associated with an increased risk of distant defined cohort of patients with high-grade STS, where spread or local recurrence [25]. an adequate surgical margin of primary surgery could Several studies have demonstrated no difference in the not a priori be achieved (SSG XX, group B). Interest- rates of local tumour control between pre-and postop- ingly, the surgical margins were in fact intralesional (R1) erative RT [26–29]. The optimal timing of RT is debated in only one patient. This regimen may thus be warranted and depends on factors such as tumour location and for large extremity localised STS and proximally located patient characteristics [30]. In patients where no preop- tumours in the lower extremity/groin, when preservation erative RT has been given, the current consensus is that Hall  et al. Clin Sarcoma Res (2020) 10:22 Page 7 of 9 postoperative RT is indicated in all high-grade STS fol- ifosfamide (5  g/m ) and hyperfractionated radiotherapy lowing marginal and intralesional margin surgery, as (1.5  Gy twice daily/ 42–60  Gy), given as preoperative well as after wide and marginal margin surgery in deep- treatment in 45 patients and as postoperative treatment seated, high-grade tumours [4]. in 44 patients [36]. In that study, the treatment-related The value of preoperative RT for improving survival complication rate was moderate, with a 5-year MFS of of patients with STS remains unproven [27]. O`Sullivan 48% and a local control rate of 81%. The doses of CT and et al. [26] randomised 94 patients to preoperative (50 Gy, the dose per fraction of RT were lower than in our SSG 25 fractions) or postoperative (66  Gy, 33 fractions) RT XX study [11]. In the retrospective study reported [36] and showed a slightly better overall survival in the preop- and in the previous SSG XIII study [14], it was shown erative group after a median follow-up time of 3.3 years. that a low CT dose intensity had a negative impact on However, this benefit was lost after 5  years of follow-up both metastasis-free and overall survival. For inadequate (recurrence-free survival: 58% versus 59%) [31]. The tim - surgical margins, the hyperfractionated RT was given as ing of RT did not affect local control, but more patients a split-course procedure [36]. Their relatively high local had wound complications in the preoperative RT group recurrence rate might underscore the findings of Jebsen than in the postoperative group [26]. Other researchers et  al. [14], who showed that split-course RT to a greater have also reported increased risk of wound complications total radiation dose could not compensate for poor surgi- [1, 32]. Nevertheless, preoperative RT is preferred by cal margins. many due to its more favourable long-term risk profile, More recently, Spalec et  al. showed in a prospective with less fibrosis, joint stiffness and oedema [31, 33, 34]. study of 30 patients with borderline resectable STS that The temporary nature of wound complications also moti - radiotherapy with 5 fractions of 5 Gy combined with pre- vates preoperative RT [30]. operative chemotherapy was feasible [37]. R0 resection In the recently reported phase 3 study by ISG/GEIS, margin was obtained in 15 of the 23 patients and R1 in where preoperative RT was combined with doxorubicin 7 patients who had limb-sparing surgery. By pathological and ifosfamide (3 cycles), the incidence of wound com- evaluation of the removed tumours < 50% stainable cells plications was 17% whereas it was 10% with neoadju- was found in 14 patients. Good early tolerance of the vant CT, alone or combined with postoperative RT [3]. treatment was reported. In our present study, 11 of 20 patients had wound com- The non-randomised design and the low sample num - plications, but these were mostly of short duration. Pos- ber in our study limit the interpretation of the results. sibly, our 3 additional cycles postoperatively might have The study strengths were the prospective design and the increased the toxicity. One factor to be kept in mind is strict high risk inclusion criteria. We believe that our that the acute toxicity profile associated with preopera - findings may add valuable information for clinical teams tive RT may be mitigated by experienced surgeons using treating this particular and challenging group of STS techniques such as free and pedicle flaps for high-risk patients. locations. Therefore, these patients should be referred to specialised centres [25, 35]. All patients in our study were Conclusions treated by experienced sarcoma surgeons. A low local recurrence rate (3 of 20 patients) with an For preoperative RT a dose of 50  Gy in 1.8–2  Gy in acceptable 5-year estimated MFS (49.5%) and OS (64.0%) once-daily fractions over 5–6 weeks is the usual delivery rate were demonstrated in a very high risk group of STS schedule [4, 35]. Accelerated RT (36  Gy, 20 fractions of patients (SSG XX, group B). Only one patient required 1.8 Gy per fraction, twice daily, 5 days per week) is equiv- an amputation. A combined preoperative CT and RT alent to a total dose of about 50 Gy [18]. The accelerated approach resulted in almost all operations rendering RT interposed between CT cycles was used in SSG`s for- adequate surgical margins. Wound healing problems mer adjuvant protocol, SSG XIII [14] and subsequently occurred in several patients but were mostly of a tempo- in SSG XX where higher CT doses were given (group A) rary nature. From these results we recommend preopera- [11]. Acceptable treatment-related morbidity was dem- tive chemotherapy and radiotherapy to be considered for onstrated [11, 14]. In the current study we evaluated selected high risk patients after careful evaluation by a accelerated RT in a preoperative setting in highly selected multidisciplinary team. Referral of STS patients to spe- patients (group B). Accelerated radiotherapy interposed cialised centres is always recommended, and this is par- between CT cycles may allow the maintenance of a high ticularly important in high-grade locally advanced cases. overall dose intensity of the CT given as evident for both group A [11] and group B. Abbreviations In a retrospective study, 89 patients with localised high MFS: Metastasis-free survival; OS: Overall survival; LR: Local recurrence; RT: risk STS had six courses of doxorubicin (50  mg/m ) and Radiotherapy; CT: Chemotherapy; MRI: Magnetic resonance imaging; SSG: Hall et al. Clin Sarcoma Res (2020) 10:22 Page 8 of 9 Scandinavian Sarcoma Group; STS: Soft tissue sarcoma; WHO: World Health 4. Casali PG, Abecassis N, Aro HT, Bauer S, Biagini R, Bielack S, et al. Soft Organization; NED: No evidence of disease. tissue and visceral sarcomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl Acknowledgements 4):iv51–67. The authors specially thank Eva-Mari Olofsson at the SSG secretariat for help 5. Pervaiz N, Colterjohn N, Farrokhyar F, Tozer R, Figueredo A, Ghert M. A with data management and secretarial assistance. The SSG Pathology Group is systematic meta-analysis of randomized controlled trials of adjuvant greatly acknowledged for ensuring the morphology. chemotherapy for localized resectable soft-tissue sarcoma. Cancer. 2008;113(3):573–81. Authors’ contributions 6. Woll PJ, Reichardt P, Le Cesne A, Bonvalot S, Azzarelli A, Hoekstra HJ, et al. KSH, ME, ØSB, CT, HB conceived and designed the study. KSH, ME, ØSB, BB, Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim EL, HH, KP, NJ acquired the data. OH performed the statistical analysis. KSH, for resected soft-tissue sarcoma (EORTC 62931): a multicentre ran- ØSB, ME wrote the manuscript. KSH, ØSB, ME, BB, CT, HB, OH, EL, HH, KP, NJ domised controlled trial. Lancet Oncol. 2012;13(10):1045–54. contributed to the interpretation of data, revised the manuscript carefully, 7. Frustaci S, Gherlinzoni F, De Paoli A, Bonetti M, Azzarelli A, Comandone approved its final version and gave consent for publication. All authors read A, et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the and approved the final manuscript. extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol. 2001;19(5):1238–47. Funding 8. Petrioli R, Coratti A, Correale P, D’Aniello C, Grimaldi L, Tanzini G, et al. The study was supported by the Swedish Cancer Society and the National Adjuvant epirubicin with or without ifosfamide for adult soft-tissue Advisory Unit for Sarcoma in Norway. sarcoma. Am J Clin Oncol. 2002;25(5):468–73. 9. Gronchi A, Frustaci S, Mercuri M, Martin J, Lopez-Pousa A, Verderio P, et al. Availability of data and materials Short, full-dose adjuvant chemotherapy in high-risk adult soft tissue The presented data are available from the corresponding author. sarcomas: a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. J Clin Oncol. 2012;30(8):850–6. Ethics approval and consent to participate 10. Gronchi A, Ferrari S, Quagliuolo V, Broto JM, Pousa AL, Grignani G, et al. Written informed consent was obtained from all patients. The study was Histotype-tailored neoadjuvant chemotherapy versus standard chemo- approved by the ethical committees, for Norway reference number: therapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an 2.2007.107 and for Sweden reference number: Dnr 223/2007. international, open-label, randomised, controlled, phase 3, multicentre trial. Lancet Oncol. 2017;18(6):812–22. Consent for publication 11. Sundby Hall K, Bruland ØS, Bjerkehagen B, Zaikova O, Engellau J, Hagberg Written informed consent was obtained from all patients. O, et al. Adjuvant chemotherapy and postoperative radiotherapy in high- risk soft tissue sarcoma patients defined by biological risk factors—A Competing interests Scandinavian Sarcoma Group study (SSG XX). Eur J Cancer. 2018;99:78–85. The authors declare that they have no competing interests. 12. Trovik CS, Bauer HC, Berlin O, Tukiainen E, Erlanson M, Gustafson P, et al. Local recurrence of deep-seated, high-grade, soft tissue sarcoma: 459 Author details patients from the Scandinavian Sarcoma Group Register. Acta Orthop Department of Oncology, The Norwegian Radium Hospital, Oslo University Scand. 2001;72(2):160–6. Hospital, Oslo, Norway. Institute for Clinical Medicine, Faculty of Medicine, 13. Jebsen NL, Trovik CS, Bauer HC, Rydholm A, Monge OR, Hall KS, et al. University of Oslo, Oslo, Norway. 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Randomized Clinical Trial: three versus five cycles of full-dose epirubicin Neoadjuvant chemotherapy in high-risk soft tissue sarcomas: final results plus ifosfamide. J Clin Oncol. 2015;33(31):3628–34. Hall  et al. Clin Sarcoma Res (2020) 10:22 Page 9 of 9 of a randomized trial from Italian (ISG), Spanish (GEIS), French (FSG), and 32. Pisters PW. Preoperative chemotherapy and split-course radiation therapy Polish (PSG) sarcoma groups. J Clin Oncol. 2020;38(19):2178–86. for patients with localized soft tissue sarcomas: home run, base hit, or 24. Pasquali S, Palassini E, Stacchiotti S, Casali PG, Gronchi A. Neoadjuvant strike out? J Clin Oncol. 2006;24(4):549–51. treatment: a novel standard? Curr Opin Oncol. 2017;29(4):253–9. 33. Davis AM, O’Sullivan B, Turcotte R, Bell R, Catton C, Chabot P, et al. Late 25. 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Individualised risk assessment for local recurrence and distant 37. Spalek M, Koseła-Paterczyk H, Borkowska A, Wągrodzki M, Szumera- metastases in a retrospective transatlantic cohort of 687 patients with Ciećkiewicz A, Cieszanowski A, et al. OC-0069 5x5 Gy with chemotherapy high-grade soft tissue sarcomas of the extremities: a multistate model. in borderline resectable soft tissue sarcomas: early results of a trial. BMJ Open. 2017;7(2):e012930. Radiother Oncol. 2019;133:S31–2. 30. Lansu J, Groenewegen J, van Coevorden F, van Houdt W, van Akkooi ACJ, van Boven H, et al. Time dependent dynamics of wound complications Publisher’s Note after preoperative radiotherapy in Extremity Soft Tissue Sarcomas. Eur J Springer Nature remains neutral with regard to jurisdictional claims in pub- Surg Oncol. 2019;45(4):684–90. lished maps and institutional affiliations. 31. O’Sullivan B, Davis AM, Turcotte R, Wunder J, Catton C, Kandel R, et al. Five years results of a randomized phase III trial of pre-operative vs post- operative radiotherapy in extremity soft tissue sarcoma. J Clin Oncol. 2004;22(14 suppl):9007. Ready to submit your research ? Choose BMC and benefit from: fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Sarcoma Research Springer Journals

Preoperative accelerated radiotherapy combined with chemotherapy in a defined cohort of patients with high risk soft tissue sarcoma: a Scandinavian Sarcoma Group study

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Abstract

Background: We recently reported outcomes from a Scandinavian Sarcoma Group adjuvant study (SSG XX group A) conducted on localized and operable high risk soft tissue sarcoma (STS) of the extremities and trunk wall. SSG XX, group B, comprised of patients in a defined cohort with locally advanced STS considered at high risk for intralesional surgery. These patients received preoperative accelerated radiotherapy, together with neoadjuvant and adjuvant chemotherapy. Herein we report the results of this group B. Methods: Twenty patients with high-grade, locally advanced and deep STS located in lower extremities (n = 12), upper extremities (5) or trunk wall (3) were included. The median age was 59 years and 14 patients were males. The 2 2 treatment regimen consisted of 6 cycles of doxorubicin (60 mg/m ) and ifosfamide (6 g/m ), with three cycles given neoadjuvantly, and preoperative radiotherapy (1, 8 Gyx2/daily to 36 Gy) between cycles 2 and 3. After a repeated MRI surgery was then conducted, and the remaining 3 chemotherapy cycles were given postoperatively at 3 weeks inter- vals. Survival data, local control, toxicity of chemotherapy and postoperative complications are presented. Results: Median follow-up time for metastasis-free survival (MFS) was 2.8 years (range 0.3–10.4). The 5-year MFS was 49.5% (95% confidence interval [CI] 31.7–77.4). The median follow-up time was 5.4 years (range 0.3–10.4) for overall survival (OS). The 5-year OS was 64.0% (95% CI 45.8–89.4). The median tumour size was 13 cm, with undifferentiated pleomorphic sarcoma (n = 10) and synovial sarcoma (n = 6) diagnosed most frequently. All patients completed sur- gery. Resection margins were R0 in 19 patients and R1 in 1 patient. No patients had evidence of disease progression preoperatively. Three patients experienced a local recurrence, in 2 after lung metastases had already been diagnosed. Eleven patients (55%) had postoperative wound problems (temporary in 8 and persistent in 3). Conclusions: Preoperative chemotherapy and radiotherapy were associated with temporary wound-healing prob- lems. Survival outcomes, local control and toxicities were deemed satisfactory when considering the locally advanced sarcoma disease status at primary diagnosis. Trial registration This study was registered at ClinicalTrials.gov Identifier NCT00790244 and with European Union Drug Regulating Authorities Clinical Trials No. EUDRACT 2007-001152-39 *Correspondence: ksh@ous-hf.no Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway 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. Hall et al. Clin Sarcoma Res (2020) 10:22 Page 2 of 9 Keywords: Soft tissue sarcoma, Preoperative, Adjuvant, Chemotherapy, Radiotherapy, Accelerated, Survival, Toxicity Background in Sweden and two in Norway. Most cases were discussed Preoperative chemotherapy (CT) and radiotherapy (RT) at a surgical sarcoma network, a SSG web-based forum have previously been studied as an integrated treatment established to evaluate the risk for intralesional surgery plan for patients with primary soft tissue sarcomas (STS) and the need for preoperative treatment. [1, 2]. Several potential benefits of preoperative chemo-/ A core-needle biopsy or an open surgical biopsy was radiotherapy have been suggested, including an ability to performed for classification of tumour type, grading of assess primary tumour response to a given chemothera- malignancy and histological diagnosis provided by the peutic regimen and to facilitate radical surgical removal, local pathologist. Diagnosis based on fine needle cytol - as well as to initiate earlier systemic treatment to combat ogy alone was not accepted. The SSG Pathology Refer - subclinical metastatic disease. In a recent study the Ital- ence Group later reviewed the morphology in all cases ian and Spanish Sarcoma Groups have shown, such com- according to the WHO-classification and malignancy bined treatment is feasible and safe with limited increase grade, applying the Broders’ system [15–17]. Distinct in wound complications [3]. grading may be unreliable in core-needle biopsies, and According to formal guidelines [4], doxorubicin and the pathologists considered the best assessment to be low ifosfamide are still not regarded as standard treatment grade and high grade, recognising that high grade will in patients with high-grade localised soft-tissue sarcoma, encompass both Broders’ grade 3 and 4. A core needle neither as adjuvant nor neoadjuvant chemotherapy, biopsy does not allow definition of the histological risk despite a demonstrated benefit in several studies [5–10]. factors (vascular invasion, infiltrative growth, necrosis) as Our prospective, non-randomised Scandinavian Sarcoma used in SSGXX, group A [11]. Group (SSG) clinical study, SSG XX, was also designed The following histiotypes were not eligible: extraskel - to investigate the combination of adjuvant doxorubicin etal osteosarcoma or chondrosarcoma, Ewing sarcoma, and ifosfamide in high risk STS [11]. In group A planned rhabdomyosarcoma, Kaposi sarcoma, clear cell sarcoma, for primary surgery, accelerated radiotherapy was sched- alveolar soft part sarcoma, epithelioid sarcoma and radia- uled postoperatively between cycles 3 and 4 with a 5-year tion induced sarcoma. metastasis-free survival of 70.4% and overall survival Mandatory investigations at screening, during treat- 76.1% [11]. The increasing evidence for the benefit of ment and at follow-up visits have previously been pre- adjuvant RT [12, 13] led to the introduction of an acceler- sented [11]. The complete SSG XX protocol is available ated RT administered between courses of chemotherapy on the SSG website [18]. in SSG’s former protocol SSG XIII [14] and pursued also in SSG XX [11]. The SSG XX protocol had a separate Treatment treatment arm (group B) devoted to patients with locally An outline of the treatment, involving scheduling of advanced STS considered to have a high risk for intral- MRI, CT, RT and surgery, is presented in Fig. 1. A maxi- esional surgery. These patients were given both pre- and mum of 28  days was allowed from diagnostic biopsy to postoperative chemotherapy, as well as accelerated RT start of chemotherapy. Doxorubicin 60  mg/m and ifos- before surgery. Here we report our experiences regarding famide 6  g/m were given with a 3  weeks interval for the feasibility and outcomes of this combination. patients < 70  years of age and with doses of 50/5 from age ≥ 70  years. Details of CT and use of granulocyte Methods colony-stimulating factor (G-CSF) have previously been Criteria for inclusion published [11]. The main eligibility criteria for SSG XX, group B were Accelerated RT allowing shortened treatment time was age ≥ 18 to ≤ 75  years, WHO performance status ≤  1, interposed from week 4 to 6, after completion of the two and a locally advanced primary STS of high-grade histol- initial CT cycles and before the 3rd cycle (Fig.  1). This ogy (Grade III or IV in a 4 graded scale) located in the scheduling allowed the maintenance of a high overall extremities or trunk wall. Only patients with a tumour of dose intensity of the CT given. The fractionation sched - anatomical location and/or extension implying an obvi- ule was 1.8 Gy twice daily to 36 Gy, with at least 6 h inter- ous risk for intralesional margins were eligible. Tumour val between the two daily fractions and 5 treatment days size was defined as the longest diameter on MRI at diag - per week. Due to a radiosensitising effect of doxorubicin, nosis. Tumour depth was defined in relation to the deep the minimal interval between doxorubicin (cycle 2) and fascia. The patients were treated at four sarcoma centres RT was set to 7  days. Clinical target volume (CTV) was Hall  et al. Clin Sarcoma Res (2020) 10:22 Page 3 of 9 RT 36 Gy MR I Surgery CT 1CT2 (1.8 x2/d x10d)CT3 CT 4 CT 5 CT 6 01 23 45 67 89 10 11 12 13 14 15 16 17 18 19 20 weeks Fig. 1 Treatment schedule. Chemotherapy (CT ): ≥ 18 and < 70 years of age: Day 1: doxorubicin 60 mg/m , 4-h infusion (IV ); Day 1, 2 and 3: 2 2 ifosfamide 2 g/m /day as 2-h infusion, dose per cycle 6 g/m [with an equal dose of 2-mercaptoethane sulphonate sodium (MESNA)]. ≥ 70 2 2 and ≤ 75 years: doxorubicin 50 mg/m and ifosfamide 5 g/m (given as above). Granulocyte colony-stimulating factor was given routinely after each cycle defined by adding a 2  cm margin in all directions to the The survival analyses were based on follow-up data gross tumour volume (GTV), based on the baseline MRI up to 2  years after the last patient enrolment (which examination. The choice of the conformal radiation treat - occurred on June 30, 2014), at which time the data- ment technique was decided by each centre. base was locked according to the a priori analysis plan. Surgery was planned 3–4  weeks after RT to minimise Patients with no events were censored either at the last the fibrotic tissue response. A preoperative MRI was date of follow-up or at the predefined date of data lock repeated to document any changes in tumour size and (June 30, 2016). extension. Two weeks after surgery, the first of the three A final survival analysis, with use of follow-up data remaining cycles of chemotherapy was given (Fig. 1). until December 31, 2019, is also presented. All patients underwent surgery at a sarcoma centre. At The Kaplan–Meier method was used to estimate MFS that time, their neutrophil levels should be ≥ 1.0 × 10 /l and OS [19]. For the analyses of MFS, patients who were and thrombocytes ≥ 80 × 10 /l. The classification of mar - alive and disease free were censored at the date of the gins, according to the SSG guidelines [18], was coopera- last follow-up, but not later than December 31, 2019. For tively determined by the surgeons and pathologists at the analyses of OS, data for patients who were alive were each sarcoma center. censored at the date of last follow-up, but not later than Details of RT for SSG XX groups A and B combined December 31, 2019. Cox regression analyses to study rel- will be published later, with emphasis on quality assess- ative risks were not performed due to the low number of ment of the radiation dose distributions and target vol- patients. ume definitions in correlation with local recurrences, as The dose intensity of CT was calculated using the well as formal scoring of late effects. method reported in previous studies [11, 14, 20]. Results End‑points Patients The primary end-point was metastasis-free survival The patient demographics, tumour characteristics and (MFS), calculated from the date of CT 1 (first chemo - histological subtypes are shown in Table  1. The timing therapy cycle) until the first of the events of metastasis of various treatments completed by individual patients or death from any cause. Overall survival (OS) was a is shown by case numbers in Fig. 2. Inclusion of patients secondary endpoint defined as the time from CT 1 until (n = 20) in this group with preoperative treatment (group death from any cause. B of SSG XX) was closed in June 2014, when the planned The secondary endpoints also included local recur - number of patients in the postoperative and adjuvant rence, defined as the time from the date of CT 1 to local group A (n = 160) had been fully recruited [11]. recurrence (with death considered a competing event) Nineteen patients had limb-sparing primary surgery; and the proportion of patients with progression of local only in one patient was an amputation deemed necessary disease preoperatively. Lastly, surgical margin status (case 8). Hence, the latter patient was not evaluable for scored as wide, marginal and intralesional, as well as R0, scoring of any wound complications related to RT. This R1 and R2 status, are also reported. patient had a synovial sarcoma (13  cm) located in the distal forearm, with close relation to vessels and nerves, Statistical analyses but after 3 CT cycles and RT, the tumour was unchanged Descriptive analyses were used. Treatment endpoints, as (MRI). He therefore underwent amputation 4 weeks later, well as toxicity from CT and RT, were analysed in all 20 distal to the elbow, with a 5  cm proximal margin from patients who started chemotherapy. the tumour followed by the 3 remaining CT cycles. He Hall et al. Clin Sarcoma Res (2020) 10:22 Page 4 of 9 Table 1 Patients demographic and  tumor characteristics of eligible patients Characteristics Numbers Age at diagnoses (years) Median 59 Range 22–71 Gender Male 14 Female 6 Tumor site Lower extremity (including gluteal and groin) 12 Upper (including shoulder) 5 Trunk wall 3 Location Subcutanous 0 Deep 20 Tumour size (cm) Median 13 Range 7–17 Histopathological subtype Undifferentiated pleomorphic sarcoma 10 Pleomorphic liposarcoma 1 Leiomyosarcoma 1 Synovial sarcoma 6 Malignant peripheral nerve sheath tumor 1 Myxofibrosarcoma 1 developed a solitary pulmonary metastasis (45 mm) that Fig. 2 SSG XX, group B, time schedule for chemotherapy, was surgically removed 3.5  years later and is NED as of radiotherapy and surgery his last follow-up after 8 years. Importantly, none of the 20 patients experienced local tumour progression preoperatively. Resection margins were wide (R0 resection) in 13 patients, marginal (R0) in 6 patients (cases 1, 5, 9, 12, 13 and 16) and intralesional (R1) in 1 (case 2). Metastases‑free and overall survival The analysis according to the described statistical plan in the protocol was done based on the data collected up to a time point exactly 2 years after complete enrolment in the SSG XX trial. By that definition, the data cut-off became June 30, 2016. Later events were therefore not included in this first analysis. As stated above, we also decided to make a later analysis for group B (not done for group A) since several years had elapsed. This analysis included all data up to December 31, 2019. Survival curves for these late analyses only are shown (Figs. 3, 4). Median follow-up of patients in the pre-planned analy- Fig. 3 Metastases-free survival (Kaplan–Meier Curve; % with 95% ses of the primary end-point MFS was 2.1  years (range CI = confidence interval) of 20 patients with high risk soft tissue 0.3–10.4). The estimated MFS rate at 5  years was 44.0% sarcoma and a median follow-up 2.8 years (95% CI 24.4–79.5). For overall survival (OS), the median Hall  et al. Clin Sarcoma Res (2020) 10:22 Page 5 of 9 Table 2 Toxicity according to CTCAE score a b ToxicityAll grades Grade 3–4 Number of patients Number of patients Neutropenia without fever 17 12 Neutropenia with fever 3 3 Thrombocytopenia 16 6 Anaemia 3 3 Wound infection 2 2 Other infections, normal 3 0 ANC Haematuria 3 3 ALAT increased 6 0 Creatinine increased 2 0 Fig. 4 Overall survival (Kaplan–Meier Curve; % with 95% Fever, unspecified 2 0 CI = confidence interval) of 20 patients with high risk soft tissue Pulmonary embolism 1 1 sarcoma and a median follow-up 5.4 years All grades of toxicities occurring in > 1 patient or any grade 3–4 Number of patients with CTCAE toxicities grade 3–4 follow-up time was 3.1 years (range 0.3–10.4). The 5-year estimated OS was 66.7% (95% CI 47.7–93.2). As of the end of 2019, distant metastases had occurred Chemotherapy toxicity in 10 patients (50%), 9 to the lung (cases 2, 7, 8, 9, 10, 11, The CT toxicity was recorded according to Common Ter - 14, 15 and 16) and one to the cerebrum (case 17). Nine minology for Adverse Events (CTCAE), version 3.0. In patients had died (45%), all from sarcoma metastases. general, CT was well tolerated and no worse than in our The median follow-up of patients in this analysis of MFS earlier described larger SSG XX group of patients who was 2.8  years (range 0.3–10.4). The final estimated MFS only underwent postoperative CT and RT [11]. Table  2 rate at 5 years was 49.5% (95% CI 31.7–77.4) (Fig. 3). For presents all toxicities reported in more than one patient overall survival (OS), the median follow-up time was and numbers that had grade 3–4 toxicity. Neutropenia, 5.4 years (range 0.3–10.4). The final estimated 5-year OS without fever and thrombocytopenia, was the most com- was 64% (95% CI 45.8–89.4) (Fig. 4). mon side effect. One case of pulmonary embolism grade 4 was reported as the most serious toxicity. No fatal tox- icities occurred. Chemotherapy cycles and dose intensity Long-term cardiac and renal toxicities were measured Sixteen patients received all the planned 6 cycles, 1 by left ventricular ejection fraction (LVEF) and glomer- patient had 5 cycles, 2 patients 3 cycles and 1 patient had ular filtration rate (GFR), respectively, at several time 2 cycles only (Fig.  2). Median dose intensity for doxoru- points during and after the treatment. The last measure - bicin and ifosfamide combined was only 79.0% (range ments were scheduled, according to the SSG XX proto- 33–86). col, at 10 years after end of treatment. The majority of the For logistical reasons two patients had 3 cycles of CT patients did not show any late cardiac or renal effects, but before RT and three patients received 4 cycles before several data points were missing (i.e. the investigations surgery (Fig.  2). One patient who had surgery after only were not performed). Some patients also had very few, if 2 cycles of CT and RT did not have more CT due to a any, measurements because of rapid disease progression non-healing surgical wound complication (case 15). She dismissing the study-related follow-up. Among the 15 later died of metastases. Two patients who had 3 preop and 16 patients who had at least one measurement of car- erative cycles did not receive postoperative treatment. In diac and renal toxicity, respectively, four patients showed one this was due to cerebral metastases diagnosed shortly a grade 1 cardiac toxicity and just one had grade 1 renal after surgery with rapid clinical deterioration and death toxicity. (case 17), and in the other due to refusal of postoperative CT (case 19). Only 3 patients had their first postoperative cycle as Radiotherapy and toxicity scheduled within 15 days postoperatively (cases 5, 8 and Eighteen patients received the scheduled RT to 36  Gy 14); 10 patients had this cycle between day 15 and 23, 3 preoperatively after 2 cycles without any delays (Fig.  2). patients between day 28 and 34 (cases 3, 10 and 20) and 1 Acute RT toxicity was recorded at each chemotherapy patient at day 68 (case 13). Hall et al. Clin Sarcoma Res (2020) 10:22 Page 6 of 9 cycle until 6  weeks after last cycle. The RTOG Acute of function is the goal and the tumour is located near Radiation Toxicity Scoring was used [21]. critical structures, such as larger vessels and nerves. The Maximum skin toxicity due to RT during the treat- local control rate was deemed satisfactory, as only 3 of ment period was grade 4 in 1 patient (5%), grade 3 in 4 the 20 patients experienced a local recurrence and in patients (20%), grade 2 in 6 patients (30%) and grade 1 in two this occurred after diagnosis of metastatic disease. 5 patients (25%). Scoring 0 was reported for 4 patients. In Nine patients developed pulmonary metastases. Only 2 patients only, toxicity resulted in a delay of CT. Notably, one patient underwent a complete metastasectomy, with very few patients had late radiotoxicity. NED observed after 8  years. The 5-year estimated MFS None of the patients developed a second cancer. and OS rates were 49.5% and 64.0%, respectively. The Italian and Spanish Sarcoma Groups (ISG/GEIS) Local recurrence rate administered neoadjuvant and adjuvant CT with doxoru- Three patients developed a local recurrence (LR). This bicin and ifosfamide to similar patients. They concluded related to one patient with wide margin by primary sur- that CT may be omitted after 3 preoperative cycles, gery of a tumour (12  cm, UPS) in lower extremity that based on their study comparing treatment with 3 pre- developed LR 5.5  years after primary surgery (5.8  years operative cycles only with that of addition of two further after cycle 1) and was salvaged by an uncomplicated re- postoperative cycles [9]. The 10-year overall survival for operation. The patient was NED at follow-up 3  months both treatment arms was about 60% [22]. Interestingly, later (case 3). Furthermore, two patients, both having our survival data seems to be in accordance with the ISG/ 10 cm tumours (synovial sarcoma) in the lower extremi- GEIS trial. In the same study, preoperative RT (44–50 Gy) ties had LR 18  months after primary surgery (20 and was given to 169 patients (from a total of 303 patients) 21  months after cycle 1, respectively). The margins at and wound complications occurred in 13.5% [3]. Gron- primary surgery were wide (R0) and intralesional (R1), chi et al. showed in a recent publication that disease free respectively. Interestingly, both these patients experi- and overall survival by histiotype-tailored neoadjuvant enced LR after first being diagnoses with pulmonary chemotherapy was not superior to anthracycline and metastases (11 months and 4 months, respectively). Both ifosfamide in high-grade STS [23]. Their conclusion was died later of metastases (cases 2 and 11). that doxorubicin and ifosfamide should remain the regi- men to choose whenever neoadjuvant chemotherapy (or Surgical complications adjuvant) is used. No wound healing complications were observed in As already mentioned, the addition of preoperative RT 8 patients. Delayed wound healing in ranges of 2 to to CT is adopted at many centres as part of a multimodal 4  months occurred in 7 patients (cases 9, 11, 12, 13, 14, treatment plan for patients with primary STS [1, 2, 10, 19 and 20) and lasting as long as 6  months in 1 patient 24]. We did not include specific assessment of response (case 5). These patients all had early postoperative infec - into the protocol, neither by radiology nor pathology tions that were treated with antibiotics and wound [18]. It was, however, mandatory to repeat MRI before revisions followed by vacuum pump treatment. One surgery (after 3 preoperative cycles + radiotherapy), but patient needed a skin transplant and healing occurred in the clinical report forms only preoperative tumour at 6 months (case 5). Three patients (cases 6, 15 and 17) progression was registered. Interestingly, no patients had had persistent wounds that did not heal, and two of them preoperative tumour progression after a composite radi- died early due to metastatic disease (cases 15 and 17). ological/clinical evaluation at the local hospital. Further- The third patient (case 6) was NED at last follow-up in more R0 resection margin was obtained in 19 patients (of 2019 but with a still unresolved non-healing wound after 20) which for all practical reasons is an important result, multiple revisions and hyperbaric oxygen treatment. since all eligible patients in SSG XX, group B should have an obvious risk for intralesional surgery. In the ISG/GEIS Discussion study reported above, some cases had positive micro- This study explored the possible benefit of combining scopic margins, despite preoperative CT and RT, but neoadjuvant CT and preoperative, accelerated RT in a this was not associated with an increased risk of distant defined cohort of patients with high-grade STS, where spread or local recurrence [25]. an adequate surgical margin of primary surgery could Several studies have demonstrated no difference in the not a priori be achieved (SSG XX, group B). Interest- rates of local tumour control between pre-and postop- ingly, the surgical margins were in fact intralesional (R1) erative RT [26–29]. The optimal timing of RT is debated in only one patient. This regimen may thus be warranted and depends on factors such as tumour location and for large extremity localised STS and proximally located patient characteristics [30]. In patients where no preop- tumours in the lower extremity/groin, when preservation erative RT has been given, the current consensus is that Hall  et al. Clin Sarcoma Res (2020) 10:22 Page 7 of 9 postoperative RT is indicated in all high-grade STS fol- ifosfamide (5  g/m ) and hyperfractionated radiotherapy lowing marginal and intralesional margin surgery, as (1.5  Gy twice daily/ 42–60  Gy), given as preoperative well as after wide and marginal margin surgery in deep- treatment in 45 patients and as postoperative treatment seated, high-grade tumours [4]. in 44 patients [36]. In that study, the treatment-related The value of preoperative RT for improving survival complication rate was moderate, with a 5-year MFS of of patients with STS remains unproven [27]. O`Sullivan 48% and a local control rate of 81%. The doses of CT and et al. [26] randomised 94 patients to preoperative (50 Gy, the dose per fraction of RT were lower than in our SSG 25 fractions) or postoperative (66  Gy, 33 fractions) RT XX study [11]. In the retrospective study reported [36] and showed a slightly better overall survival in the preop- and in the previous SSG XIII study [14], it was shown erative group after a median follow-up time of 3.3 years. that a low CT dose intensity had a negative impact on However, this benefit was lost after 5  years of follow-up both metastasis-free and overall survival. For inadequate (recurrence-free survival: 58% versus 59%) [31]. The tim - surgical margins, the hyperfractionated RT was given as ing of RT did not affect local control, but more patients a split-course procedure [36]. Their relatively high local had wound complications in the preoperative RT group recurrence rate might underscore the findings of Jebsen than in the postoperative group [26]. Other researchers et  al. [14], who showed that split-course RT to a greater have also reported increased risk of wound complications total radiation dose could not compensate for poor surgi- [1, 32]. Nevertheless, preoperative RT is preferred by cal margins. many due to its more favourable long-term risk profile, More recently, Spalec et  al. showed in a prospective with less fibrosis, joint stiffness and oedema [31, 33, 34]. study of 30 patients with borderline resectable STS that The temporary nature of wound complications also moti - radiotherapy with 5 fractions of 5 Gy combined with pre- vates preoperative RT [30]. operative chemotherapy was feasible [37]. R0 resection In the recently reported phase 3 study by ISG/GEIS, margin was obtained in 15 of the 23 patients and R1 in where preoperative RT was combined with doxorubicin 7 patients who had limb-sparing surgery. By pathological and ifosfamide (3 cycles), the incidence of wound com- evaluation of the removed tumours < 50% stainable cells plications was 17% whereas it was 10% with neoadju- was found in 14 patients. Good early tolerance of the vant CT, alone or combined with postoperative RT [3]. treatment was reported. In our present study, 11 of 20 patients had wound com- The non-randomised design and the low sample num - plications, but these were mostly of short duration. Pos- ber in our study limit the interpretation of the results. sibly, our 3 additional cycles postoperatively might have The study strengths were the prospective design and the increased the toxicity. One factor to be kept in mind is strict high risk inclusion criteria. We believe that our that the acute toxicity profile associated with preopera - findings may add valuable information for clinical teams tive RT may be mitigated by experienced surgeons using treating this particular and challenging group of STS techniques such as free and pedicle flaps for high-risk patients. locations. Therefore, these patients should be referred to specialised centres [25, 35]. All patients in our study were Conclusions treated by experienced sarcoma surgeons. A low local recurrence rate (3 of 20 patients) with an For preoperative RT a dose of 50  Gy in 1.8–2  Gy in acceptable 5-year estimated MFS (49.5%) and OS (64.0%) once-daily fractions over 5–6 weeks is the usual delivery rate were demonstrated in a very high risk group of STS schedule [4, 35]. Accelerated RT (36  Gy, 20 fractions of patients (SSG XX, group B). Only one patient required 1.8 Gy per fraction, twice daily, 5 days per week) is equiv- an amputation. A combined preoperative CT and RT alent to a total dose of about 50 Gy [18]. The accelerated approach resulted in almost all operations rendering RT interposed between CT cycles was used in SSG`s for- adequate surgical margins. Wound healing problems mer adjuvant protocol, SSG XIII [14] and subsequently occurred in several patients but were mostly of a tempo- in SSG XX where higher CT doses were given (group A) rary nature. From these results we recommend preopera- [11]. Acceptable treatment-related morbidity was dem- tive chemotherapy and radiotherapy to be considered for onstrated [11, 14]. In the current study we evaluated selected high risk patients after careful evaluation by a accelerated RT in a preoperative setting in highly selected multidisciplinary team. Referral of STS patients to spe- patients (group B). Accelerated radiotherapy interposed cialised centres is always recommended, and this is par- between CT cycles may allow the maintenance of a high ticularly important in high-grade locally advanced cases. overall dose intensity of the CT given as evident for both group A [11] and group B. Abbreviations In a retrospective study, 89 patients with localised high MFS: Metastasis-free survival; OS: Overall survival; LR: Local recurrence; RT: risk STS had six courses of doxorubicin (50  mg/m ) and Radiotherapy; CT: Chemotherapy; MRI: Magnetic resonance imaging; SSG: Hall et al. Clin Sarcoma Res (2020) 10:22 Page 8 of 9 Scandinavian Sarcoma Group; STS: Soft tissue sarcoma; WHO: World Health 4. Casali PG, Abecassis N, Aro HT, Bauer S, Biagini R, Bielack S, et al. Soft Organization; NED: No evidence of disease. tissue and visceral sarcomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl Acknowledgements 4):iv51–67. The authors specially thank Eva-Mari Olofsson at the SSG secretariat for help 5. Pervaiz N, Colterjohn N, Farrokhyar F, Tozer R, Figueredo A, Ghert M. A with data management and secretarial assistance. The SSG Pathology Group is systematic meta-analysis of randomized controlled trials of adjuvant greatly acknowledged for ensuring the morphology. chemotherapy for localized resectable soft-tissue sarcoma. Cancer. 2008;113(3):573–81. Authors’ contributions 6. Woll PJ, Reichardt P, Le Cesne A, Bonvalot S, Azzarelli A, Hoekstra HJ, et al. KSH, ME, ØSB, CT, HB conceived and designed the study. KSH, ME, ØSB, BB, Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim EL, HH, KP, NJ acquired the data. OH performed the statistical analysis. KSH, for resected soft-tissue sarcoma (EORTC 62931): a multicentre ran- ØSB, ME wrote the manuscript. KSH, ØSB, ME, BB, CT, HB, OH, EL, HH, KP, NJ domised controlled trial. Lancet Oncol. 2012;13(10):1045–54. contributed to the interpretation of data, revised the manuscript carefully, 7. Frustaci S, Gherlinzoni F, De Paoli A, Bonetti M, Azzarelli A, Comandone approved its final version and gave consent for publication. All authors read A, et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the and approved the final manuscript. extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol. 2001;19(5):1238–47. Funding 8. Petrioli R, Coratti A, Correale P, D’Aniello C, Grimaldi L, Tanzini G, et al. The study was supported by the Swedish Cancer Society and the National Adjuvant epirubicin with or without ifosfamide for adult soft-tissue Advisory Unit for Sarcoma in Norway. sarcoma. Am J Clin Oncol. 2002;25(5):468–73. 9. Gronchi A, Frustaci S, Mercuri M, Martin J, Lopez-Pousa A, Verderio P, et al. 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Five years results of a randomized phase III trial of pre-operative vs post- operative radiotherapy in extremity soft tissue sarcoma. J Clin Oncol. 2004;22(14 suppl):9007. Ready to submit your research ? Choose BMC and benefit from: fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions

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Clinical Sarcoma Research – Springer Journals

Published: Dec 1, 2020

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