Time interval between surgery and start of adjuvant radiotherapy in patients with soft tissue sarcoma: A retrospective analysis of 1131 cases from the French Sarcoma Group

Radiotherapy and Oncology xxx (2016) xxx–xxx

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Original article

Time interval between surgery and start of adjuvant radiotherapy in patients with soft tissue sarcoma: A retrospective analysis of 1131 cases from the French Sarcoma Group q Fourquet Jacques a,⇑, Sunyach Marie-Pierre b, Vilotte Florent c, Le Péchoux Cécile d, Ranchère-Vince Dominique e, Bonvalot Sylvie f,g, Coindre Jean-Michel h, Terrier Philippe i, Meeus Pierre j, Helfre Sylvie k, Martin Etienne l, Vogin Guillaume m, Biau Julian n, Kao William o, Noel Georges p, Ducassou Anne q, Llacer-Moscardo Carmen r, Stoeckle Eberhard s, Penel Nicolas t, Sargos Paul c a Department of Radiation Oncology, Centre Oscar Lambret, Lille; b Department of Radiation Oncology, Centre Léon Bérard, Lyon; c Department of Radiation Oncology, Institut Bergonié, Bordeaux; d Department of Radiation Oncology, Institut Gustave Roussy, Villejuif; e Department of Biopathology, Centre Léon Bérard, Lyon; f Department of Surgery, Institut Gustave Roussy, Villejuif; g Department of Surgery, Institut Curie, Paris; h University of Bordeaux, INSERM U916, Department of Biopathology, Institut Bergonié, Bordeaux; i Department of Pathology, Institut Gustave Roussy, Villejuif; j Department of Surgery, Centre Léon Bérard, Lyon; k Department of Radiation Oncology, Institut Curie, Paris; l Department of Radiation Oncology, Centre Georges-François Leclerc, Dijon; m Department of Radiation Oncology, Institut de Cancérologie de Lorraine, Vandœuvre-lès-Nancy; n Department of Radiation Oncology, Centre Jean Perrin, Clermont-Ferrand; o Department of Radiation Oncology, Centre François Baclesse, Caen; p Department of Radiation Oncology, Centre Paul Strauss, Strasbourg; q Department of Radiation Oncology, Institut Claudius Regaud, IUCT-Oncopole, Toulouse; r Department of Radiation Oncology, Institut du Cancer de Montpellier; s Department of Surgery, Institut Bergonié, Bordeaux; and t Department of Medical Oncology, Centre Oscar Lambret, Lille, France

a r t i c l e

i n f o

Article history: Received 4 March 2016 Received in revised form 2 April 2016 Accepted 20 April 2016 Available online xxxx Keywords: Soft tissue sarcoma Time interval Postoperative radiotherapy

a b s t r a c t Purpose: The aim of this study was to evaluate the impact of the time interval (TI) between surgery and adjuvant radiotherapy (RT) in soft tissue sarcoma (STS). Methods and materials: Data from 1131 patients treated between 1990 and 2014 were retrospectively reviewed. Inclusion criteria were: limb or superficial trunk wall STS (R0 or R1 resection) and adjuvant RT. The impact of TI on 10-year local relapse-free survival (LRFS) and 10-year overall survival (OS) was analyzed using a Log-rank test and then Cox Model. Results: The median TI was 82 days (range, 18–346). With a median follow-up of 235 months (range, 2–296 months), the 10-year LRFS was 57.5% (±2%) and the 10-year OS was 64.2% (±2%). With a TI of 19–39 days, 40–79 days, 80–119 days, and P120 days, 10-year LRFSs were 65.3%, 55.5%, 56.9% and 61.2% (p = 0.465), and 10-year OSs were 72.8%, 60.7%, 66.4% and 62.1% (p = 0.347), respectively. After adjustment for the factors significantly (p 6 0.05) associated with LRFS and OS, TI did not alter LRFS (p = 0.182) either OS (p = 0.335). Conclusions: In this retrospective STS database study, the TI between surgery and start of adjuvant RT did not seem to affect outcomes. Ó 2016 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2016) xxx–xxx

Soft tissue sarcoma (STS) is a rare tumor, accounting for less than 2% of all adult cancers [1]. However, this incidence may be underestimated due to heterogeneity, ubiquitous locations and the complexity of diagnosis needing pathological expertise and sometimes biological molecular confirmatory tests [2–4]. The standard treatment for localized high-grade extremity soft tissue sarcoma (ESTS) is ‘‘large-en bloc resection” combined with radiation

q Presented in oral form at the 18th ECCO–40th ESMO European Cancer Congress, Vienna, Austria, September 25–29, 2015 (abstract number 3402). ⇑ Corresponding author at: Department of Radiation Oncology, Centre Oscar Lambret, 3 rue Frédéric Combemale, 59000 Lille, France. E-mail address: [email protected] (J. Fourquet).

therapy (RT). Adjuvant RT could be omitted in some cases of superficial, low grade and small size STS [5,6]. Indeed, when added to conservative surgery, RT showed a significant benefit for local control in three randomized trials [7–9]. The timing of this RT remains a matter of debate because a randomized study of preoperative versus postoperative RT in the treatment of ESTS did not find differences in local control or overall survival [10]. However, this study demonstrated that postoperative RT was associated with more late toxicities (such as joint stiffness, fibrosis or edema) whereas preoperative RT was associated with more early wound complications after surgery [10,11]. Because of the high rate of wound complications in the preoperative arm (35% vs 17%, p = 0.01), the trial was closed after the preplanned interim analysis.

http://dx.doi.org/10.1016/j.radonc.2016.04.037 0167-8140/Ó 2016 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Fourquet J et al. Time interval between surgery and start of adjuvant radiotherapy in patients with soft tissue sarcoma: A retrospective analysis of 1131 cases from the French Sarcoma Group. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.04.037

2

Timing of adjuvant RT in STS

In everyday practice, a large portion of STS cases underwent surgery before being referred to expert centers, and then these cases could not be considered for formal preoperative RT. Therefore, RT is currently most frequently delivered as an adjuvant therapy. The time interval (TI) between surgery and RT in STS is a major concern for several reasons. First, the standard of care involves several different treatment schedules that should be perfectly coordinated. Secondly, the prognostic value of this TI is not well established because there are three retrospective studies that have been published to date [12–14]. Two of these included a small number of patients [12–13], and the third one included a heterogeneous population [14]. Consequently, the impact of TI on cancer control is still based on expert opinion [15]. Finally, this question is often unanswered in daily clinical practice, mainly for patients who have a long TI between surgery and RT for various causes (e.g., delay in referral, wound complications and adjuvant chemotherapy). Therefore, we performed this retrospective study to assess the impact of TI between surgery and postoperative RT on outcomes of adult patients with a localized STS.

Methods and materials French Sarcoma Group database and inclusion criteria Patients included in this study were all enrolled in the retrospective French Sarcoma Group (FSG) database, also known as Conticabase, which is now interconnected with other databases in SarcomaBCB (https://conticabase.sarcomabcb.org). Each patient with a STS can be included in this multicenter database after signing an informed consent sheet. All of the cases are centrally reviewed by the members of the pathology committee of the FSG and data are updated every two years with an unlimited follow-up. The inclusion criteria of the present study were as follows: age P18 years old, STS included in the Conticabase, tumors located in the extremities and superficial trunk, primary treatment as curative intent and adjuvant radiotherapy delivered. The exclusion criteria were as follows: metastasis at diagnosis, initial treatment of a local recurrence, adjuvant brachytherapy, neoadjuvant chemotherapy or radiotherapy and a R2 surgery.

Patients, tumors and treatment characteristics From January 1990 to April 2014, 1131 patients who met the inclusion criteria were included in the database. They were treated in 15 French sarcoma reference centers. In each center, a physician reviewed the patient files and checked the recorded data. The following variables were considered for analysis: TI between surgery and RT; patient characteristics (i.e., gender, age, previous cancer, and hereditary predisposition); tumor characteristics (i.e., histological grade, tumor size, tumor depth, histological subtype, tumor site, vessel tumor emboli, bone, cutaneous, muscular or neurovascular invasion and multifocality); treatment characteristics (i.e., first surgery outside the reference center, margins status, RT total dose, postoperative chemotherapy, time to first consultation in the reference center, TI between the histological diagnosis and the first surgery).Histological tumor types and subtypes were classified according to the World Health Organization (WHO) classification of tumors [16]. The Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system [17] was applied. Tumor depth was superficial or deep according to the involvement of the muscle fascia. Margin status was established using the recommendations from the FSG, meaning a collegial process with surgical and pathological reports [18]. The results were finally reported with the Union Internationale Contre le Cancer (UICC) R system: R0 (complete microscopic excision), R1 (microscopic

residual disease) or R2 (macroscopic residual disease) [18]. Institutional board approval was obtained for this study. Statistical analysis The TI was considered to be the interval, in days, between the first surgical excision and the first day of RT. It was analyzed as a continuous variable and as a categorical variable. For the categorical data, the population sample was divided into four groups according to quartiles: group A (18–39 days between surgery and RT), group B (40–79 days), group C (80–119 days) and group D (P120 days). The impact of TI between surgery and RT was analyzed first for the whole population (N = 1131) and then with a subgroup named ‘‘optimal management” (n = 714). In this subgroup, patients had a margin status R0 and received a RT total dose P50 Gy. The local recurrence-free survival (LRFS) rate and overall survival (OS) rate were calculated using the Kaplan–Meier method. This impact has been analyzed in univariate analysis on LRFS and OS using a Logrank test when TI was categorical data and a univariate Cox model when TI was continuous data. Then, a multivariate analysis was performed with other significant (p < 0.05) predictive factors identified in univariate analysis for LRFS and OS, using a Cox model. After adjustment to these predictive factors, the impact of TI was analyzed for LRFS and OS using a Cox model. For the ‘‘optimal management” subgroup, the same analyses were performed. All analyses were performed using the IBM SPSS Statistics 13.0 software. Results Main characteristics of the study population The main characteristics of the study population are summarized in Table 1. The median age was 60 years (range, 19–100 years). Ninety-six patients (8.3%) had a previous cancer and 16 (1.4%) had a type 1 neurofibromatosis. The median tumor size was 80 mm (range, 2–450 mm). Most of the patients had muscular involvement (598 patients, 52.9%) and had no cutaneous, bone or neuro-vascular invasion (526 patients, 46.5%; 779 patients, 68.9%; and 732 patients, 64.7%, respectively). Nine hundred and sixty patients (84.9%) had a unifocal tumor. The median RT dose was 54 Gy (range, 11–74 Gy). The main characteristics of patients in ‘‘optimal management” subgroup are presented in Supplemental data, Table 1. TI The median TI between surgery and RT was 82 days (range, 18– 346 days). There were 55 patients (4.9%) in the group A TI category, 358 patients (31.7%) in group B, 241 patients (21.3%) in group C and 222 patients (19.6%) in group D. The mean TI was 96 days (standard deviation, 51; Supplemental data, Fig. 1). The median follow-up time was 235 months (range, 2–296 months). Survival In the whole study population (N = 1,131), 363 patients had a local recurrence and 291 patients died. The five- and 10-year LRFS were 70.9% and 57.5%, respectively. The five- and 10-year OS were 78.1% and 64.2%, respectively. The median LRFS was 149 months (range, 127–170 months). The median OS was 216 months (range, 146–285 months). In the ‘‘optimal management” subgroup (n = 714), 210 patients had a local recurrence and 172 patients died. The five- and 10-year LRFS were 74.5% and 60.1%, respectively. The five- and 10-year OS

Please cite this article in press as: Fourquet J et al. Time interval between surgery and start of adjuvant radiotherapy in patients with soft tissue sarcoma: A retrospective analysis of 1131 cases from the French Sarcoma Group. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.04.037

3

J. Fourquet et al. / Radiotherapy and Oncology xxx (2016) xxx–xxx Table 1 Main population characteristics (N = 1131). Variables Sex Age, years

Histological grade (FNCLCC)

Tumor size, mm

Tumor depth

Histologic subtype

Tumor site

Vessel tumor emboli

Surgery outside RC Margin status

RT dose, Gy

Chemotherapy

Male Female Unknown 19–44 45–59 60–69 P70 Unknown 1 2 3 Unknown 650 51–80 81–140 >140 Unknown Superficial Deep Liposarcoma UPS Myxofibrosarcoma Leiomyosarcoma Synovialosarcoma MPNST Other Lower limb Upper limb Thoracic wall Abdominal wall Unknown Yes No Yes No Unknown R0 R1 Unknown 11–49 50–59.6 P60 Unknown Yes No

n

%

597 534 55 241 284 232 319 21 270 398 442 39 313 251 266 262 1 167 963 374 252 158 145 78 33 91 720 191 208 12 249 28 854 543 588 1 762 368 57 73 675 326 3 95 1033

52.8 47.2 4.9 21.3 25.1 20.5 28.2 1.8 23.9 35.2 39.1 3.4 27.7 22.2 23.5 23.2 0.1 14.8 85.1 33.1 22.3 13.9 12.9 6.9 2.9 8.0 63.7 16.9 18.4 1.0 22.0 2.5 75.5 48.0 52.0 0.1 67.4 32.5 5.0 6.5 59.7 28.8 0.3 8.4 91.3

Abbreviations: FNCLCC, Federation Nationale des Centres de Lutte Contre le Cancer; MPNST, Malignant Peripheral Nerve Sheath Tumor; RC, Reference Center; RT, Radiotherapy; UPS, Undifferentiated Pleomorphic Sarcoma.

were 80.2% and 66.2%, respectively. The median LRFS was 152 months (range, 109–212 months). The median OS had not been reached at the time of analysis. Impact of the TI between surgery and RT in univariate analysis on the whole population The TI as continuous variable was not associated with LRFS in the univariate analysis (hazard ratio [HR] = 0.99; 95% confidence

interval [CI], 0.99–1.01; p = 0.43). As categorical data, the TI was also not associated with LRFS (Table 2 and Fig. 1A, p = 0.465). The TI was not associated with OS as continuous data (HR = 0.99; 95% CI, 0.98–1.01, p = 0.301) or categorical data (Table 2 and Fig. 1B, p = 0.347).

Prognostic factors for LRFS and OS (univariate and multivariate analyses) The factors associated with LRFS in univariate analysis are presented in Table 3. Eight factors were significantly associated with LRFS: margin status, gender, age, tumor grade, tumor size, histological subtype, vessel tumor emboli and RT dose. These parameters were included in a multivariate analysis, and the following variables were statistically associated with LRFS (Table 3): margin status, gender, age, tumor grade, tumor size, RT dose. Previous cancer, hereditary predisposition, tumor depth, tumor site, muscular, cutaneous, bone or neuro-vascular invasion, multifocality, time to first consultation in the reference center, TI between the histological diagnosis and the first surgery, first surgery outside the reference center and postoperative chemotherapy were not significantly associated with LRFS on either univariate or multivariate analysis. Regarding the OS, results of the univariate and multivariate analyses are shown in Table 4. Seven factors were significantly associated with OS in univariate analysis: gender, age, tumor grade, tumor size, histological subtype, vessel tumor emboli and RT dose. In multivariate analysis, gender, age, histological grade, tumor size, RT dose and vessel tumor emboli were associated with OS. Previous cancer, hereditary predisposition, tumor depth, tumor site, muscular, cutaneous, bone or neuro-vascular invasion, multifocality, time to first consultation in the reference center, TI between the histological diagnosis and the first surgery, margin status, first surgery outside the reference center and postoperative chemotherapy were not associated with OS on either univariate or multivariate analysis.

Impact of the TI between surgery and RT in multivariate analysis on the whole population In multivariate analysis for LRFS (i.e., margin status, gender, age, histological grade, tumor size, RT dose) and OS (i.e., gender, age, histological grade, tumor size, RT dose and vessel tumor emboli), TI before the start of RT did not significantly alter either LRFS (p = 0.182) or OS (p = 0.335); Table 5.

Impact of the TI between surgery and RT in the ‘‘optimal management” subgroup (n = 714) In univariate analysis, TI was not associated with LRFS (p = 0.352) or with OS (p = 0.325; Supplemental data, Table 2). TI did not also affect LRFS and OS in multivariate analysis (see Supplemental data, Table 3).

Table 2 Impact of the TI (categorical data) on LRFS and OS for the whole population in univariate analysis. TI category (days)

A (18–39) B (40–79) C (80–119) D (P120)

LRFS

OS

Five-year (%)

10-year (%)

HR (95% CI)

p

Five-year (%)

10-year (%)

HR (95% CI)

p

76.5 69.6 69.9 72.6

65.3 55.5 56.9 61.2

0.83 (0.49–1.69) 1.19 (0.87–1.63) 1.18 (0.84–1.66) REF

0.465

80.4 75.6 78.8 81.1

72.8 60.7 66.4 62.1

0.81 (0.45–1.45) 1.28 (0.91–1.79) 1.06 (0.73–1.56) REF

0.347

Abbreviations: CI, Confidence Interval; HR, Hazard Ratio; LRFS, Local Recurrence Free Survival; OS, Overall Survival; REF, REFERENCE; TI, Time Interval

Please cite this article in press as: Fourquet J et al. Time interval between surgery and start of adjuvant radiotherapy in patients with soft tissue sarcoma: A retrospective analysis of 1131 cases from the French Sarcoma Group. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.04.037

4

Timing of adjuvant RT in STS

B 1.00

Local relapse free survival

0.90

0.90

0.80

0.80

0.70

0.70 Probability

Probability

A 1.00

0.60 0.50 0.40

0.60 0.50 0.40 0.30

0.30 0.20

0.20

Time interval surgery−radiotherapy (days) :

0.10 0.00 0

A B C D

Overall survival

2

4

6

A: <40d

B: 40−79d

C: 80−119d

D: ≥120d

8 Years

Number at risk (number of events) 54 (6) 46 (3) 41 (4) 31 (1) 357 (43) 289 (39) 182 (14) 115 (10) 240 (34) 183 (20) 114 (9) 70 (3) 220 (18) 180 (25) 99 (7) 61 (6)

23 69 47 36

10

(2) (5) (4) (1)

20 43 30 20

12

(1) (6) (4) (2)

14 26 14 10

14

(1) (1) (2) (0)

11 11 6 3

Time interval surgery−radiotherapy (days) :

0.10 0.00 0

16

(0) (0) (0) (0)

A B C D

4 6 3 1

2

4

6

A: <40d

B: 40−79d

C: 80−119d

D: ≥120d

8 Years

Number at risk (number of events) 54 (5) 47 (3) 42 (4) 32 (0) 357 (31) 300 (35) 195 (14) 124 (11) 240 (23) 193 (16) 124 (7) 79 (4) 220 (14) 184 (12) 114 (10) 68 (9)

25 76 53 39

10

(1) (4) (2) (2)

22 50 35 22

12

(0) (6) (3) (1)

17 31 18 12

14

(2) (2) (1) (0)

13 14 9 5

16

(0) (0) (0) (0)

5 6 4 3

Fig. 1. Kaplan–Meier curves according to TI categories on the whole population (univariate analysis) for (A) LRFS (p = 0.465) and (B) OS (p = 0.347).

Table 3 Factors associated with LRFS in univariate and multivariate analyses. Variables

Univariate analysis HR (95% CI)

Sex Female Male Age (continuous data) Histological grade FNCLCC 1 2 3 Tumor size, mm 650 51–80 81–140 >140 Histological subtype Leiomyosarcoma Liposarcoma MPNST Myxofibrosarcoma Synovialosarcoma Other UPS Vessel tumor emboli No Yes Margin status R0 R1 RT dose, Gy 11–49 50–59.6 P60

Multivariate analysis p

aHR (95% CI)

p

0.71 (0.57–0.88) REF 1.34 (1.25–1.45)

0.002

0.30 (0.19–0.47) 0.76 (0.59–0.97) REF

0.0001 0.032

0.64 (0.44–0.92) 0.91 (0.64–1.29) 0.99 (0.71–1.39) REF

0.016 0.612 0.973

0.73 (0.50–1.08)

0.120

1.22 (0.75–1.98)

0.419

0.020 0.78 (0.63–0.96) REF 1.37 (1.25–1.51)

0.0001 0.0001

0.21 (0.14–0.30) 0.55 (0.44–0.69) REF

0.0001

0.0001 0.81 (0.59–1.11) 1.24 (0.91–1.69) 1.43 (1.06–1.94) REF 0.0001 1.05 0.38 0.63 0.82 0.56 0.72 REF

(0.77–1.43) (0.28–0.52) (0.33–1.17) (0.58–1.14) (0.36–0.88) (0.48–1.07)

REF 0.049

0.53 (0.30–0.93) REF

0.79 (0.44–1.44) REF

0.450

0.75 (0.52–0.91) REF

0.003

0.67 (0.37–0.89)

0.002

0.002 0.69 (0.56–0.86) REF 0.0001 0.81 (0.54–1.22) 0.62 (0.49–0.77) REF

REF

Abbreviations: aHR, adjusted Hazard Ratio; CI, Confidence Interval; FNCLCC, Federation Nationale des Centres de Lutte Contre le Cancer; HR, Hazard Ratio; MPNST, Malignant Peripheral Nerve Sheath Tumor; REF, REFERENCE; RT, Radiotherapy; UPS, Undifferentiated Pleomorphic Sarcoma. p are significant (p < 0.05) values.

Discussion This study suggested a lack of prognostic value for the TI between surgery and start of adjuvant RT in localized adult STS. Indeed, this TI was not significantly associated with an increased risk of local recurrence in univariate analysis, whether it was analyzed as continuous data (p = 0.430) or categorical data (p = 0.465). After adjustment for the other predictive factors that were independently correlated with LRFS in multivariate analysis (i.e., margin status, gender, age, histological FNCLCC grade, tumor size, RT dose), the TI did not significantly affect local control as well (p = 0.182). We have found similar and consistent results for the

OS: no significant prognostic value of the TI before starting RT in univariate analysis (p = 0.301 when TI is a continuous data, p = 0.347 when TI is a categorical data) or after adjustment to the other variables correlated with OS in the multivariate model (i.e., gender, age, histological FNCLCC grade, tumor size, vessel tumor emboli, and RT dose; p = 0.335). In the ‘‘optimal management” subgroup, which means a R0 resection and a RT dose P50 Gy, the TI does not significantly alter LRFS or OS. Only the comparison between group C (80–119 days between surgery and RT) and group D TI category (P120 days) showed a significant association with a worse LRFS after adjustment for the other prognostic factors (HR = 1.69; 95% CI, 1.05–2.69, p = 0.026). However, given the large

Please cite this article in press as: Fourquet J et al. Time interval between surgery and start of adjuvant radiotherapy in patients with soft tissue sarcoma: A retrospective analysis of 1131 cases from the French Sarcoma Group. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.04.037

5

J. Fourquet et al. / Radiotherapy and Oncology xxx (2016) xxx–xxx Table 4 Factors associated with OS in univariate and multivariate analyses. Variables

Univariate analysis

Multivariate analysis

HR (95% CI) Sex Female Male Age (continuous data) Histological grade FNCLCC 1 2 3 Tumor size, mm 650 51–80 81–140 >140 Histological subtype Leiomyosarcoma Liposarcoma MPNST Myxofibrosarcoma Synovialosarcoma Other UPS Vessel tumor emboli No Yes RT dose, Gy 11–49 50–59.6 P60

p

aHR (95% CI)

p

0.65 (0.50–0.83) REF 1.41 (1.29–1.53)

0.001

0.20 (0.11–0.35) 0.72 (0.48–1.04) REF

0.0001 0.079

0.41 (0.27–0.62)

0.0001

0.007 0.72 (0.57–0.91) REF 1.45 (1.34–1.58)

0.0001 0.0001

0.16 (0.10–0.25) 0.50 (0.39–0.65) REF

0.0001

0.0001 0.59 (0.41–0.85) 1.07 (0.76–1.50) 1.39 (1.01–1.92) REF

REF 0.001

1.27 0.43 0.77 0.85 0.64 0.75 REF

(0.90–1.78) (0.31–0.60) (0.40–1.49) (0.58–1.24) (0.39–1.05) (0.48–1.17)

0.89 (0.57–1.37)

0.597

REF 0.008

0.39 (0.22–0.67) REF

0.57 (0.29–0.90) REF

0.020

0.70 (0.48–0.91)

0.008

0.021 0.87 (0.55–1.35) 0.68 (0.53–0.87) REF

REF

Abbreviations: aHR, adjusted Hazard Ratio; CI, Confidence Interval; FNCLCC, Federation Nationale des Centres de Lutte Contre le Cancer; HR, Hazard Ratio; MPNST, Malignant Peripheral Nerve Sheath Tumor; REF, REFERENCE; RT, Radiotherapy; UPS, Undifferentiated Pleomorphic Sarcoma. p are significant (p < 0.05) values.

Table 5 Impact of the TI (categorical data) on LRFS and OS for the whole population in multivariate analysis. TI category (days)

A (18–39) B (40–79) C (80–119) D (P120)

LRFS

OS

aHR (95% CI)

p

aHR (95% CI)

p

0.81 (0.46–1.41) 1.15 (0.82–1.62) 1.34 (0.93–1.93) REF

0.182

0.74 (0.40–1.36) 1.08 (0.75–1.58) 1.20 (0.79–1.82) REF

0.335

Abbreviations: aHR, adjusted Hazard Ratio; CI, Confidence Interval; LRFS, Local Recurrence Free Survival; OS, Overall Survival; REF, REFERENCE.

number of statistical tests carried out (almost 80 tests), Bonferroni’s correction should be applied to avoid a risk-a inflation, and therefore the p-value should be <0.00063 to be regarded as statistically significant. Overall, the TI was not significantly associated with OS and LRFS in this study. The five- and 10-year LRFS in our study (70.9% and 57.5%, respectively) may be low when compared to other published prognostic studies [12–14,19–28]. In these studies, the five- and 10year LRFS were approximately 80% and 75%, respectively, or even more in the most recent studies [25–28].However, in these studies, the R0 resection rate, which is the most important factor for local control and is widely described in the literature [14,19–28], was higher than in our study (approximately 80% versus 67% in the present study) and can explain these results. In addition, it should be noted that the population in this study was a non-selected population having undergone the first surgery in a reference center in only 52% of the cases. The very long follow-up (median follow up = 235 months) can also be responsible for the additional local recurrences that were diagnosed. The five- and 10-year OS (78.1% and 64.2%, respectively in our study) strongly depended on the percentage of grade 3 tumors. It has been extensively shown in

the literature that histological grade (whatever grading system used) is the most important variable for OS in soft tissue sarcoma [14,19–28,29].In the study of Gronchi et al., where the percentage of FNCLCC grade 3 tumors was approximately comparable to those in the present study (42.7% versus 39.1%, respectively), the fiveyear disease-specific mortality was 82% (95% CI, 80–85%) [25]. Although the comparison is difficult because of the heterogeneity of the studies, the main characteristics of our study population (i.e., equilibrated sex ratio; median age of 60 years; large and deep tumors; and most common location, lower limb) seem to be found often in the other studies [1,2,14,19,30]. In this study we have also identified major prognostic factors that were clearly demonstrated in the literature: surgical margin status for the LRFS, histological grade and tumor size for the OS [19,29]. The impact of the TI between surgery and postoperative RT has mainly been studied in breast and head and neck cancer. Several reviews based on large retrospective studies demonstrated that a delay in postoperative RT could significantly alter local control in breast and head and neck cancer [31–33]. However, in STS, this topic has been explored very little and there is little evidence available [12–14]. In a retrospective small study (58 patients treated between 1981 and 1998) with a short follow-up (median followup, 49.5 months) published in 2002, Schwartz et al. found that a postoperative radiation delay P4 months was associated with inferior local disease control [13]. However, caution should be taken with these results because of the small sample size and short follow-up. In addition, there has been no multivariate analysis taking into account the confounding factors and the two groups (one defined as ‘‘short delay” with a TI < 4 months and the other defined as ‘‘long delay” with a TI P 4 months) were significantly (p < 0.05) unbalanced regarding high histological grades (47% in the ‘‘long delay” group versus 19%) and chemotherapy (97% in the ‘‘long delay” group versus 47%). The largest retrospective study available from the MD Anderson Cancer Center was published in 2004, with

Please cite this article in press as: Fourquet J et al. Time interval between surgery and start of adjuvant radiotherapy in patients with soft tissue sarcoma: A retrospective analysis of 1131 cases from the French Sarcoma Group. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.04.037

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Timing of adjuvant RT in STS

799 patients treated between 1960 and 2000 and a median followup of 145 months [14].All of the patients were irradiated at MD Anderson; there was a central pathological diagnosis and quality treatment review. However, inclusion criteria were large with various tumor sites (retroperitoneal sarcoma, 6%; head and neck, 11%), local recurrence (18%) and pediatric sarcoma. According to our results, authors reported that the TI did not significantly affect the LRFS (p = 0.23). The main limitation of this study was the retrospective nature of this work with inherent biases of the methodology. However, it is difficult to improve the level of evidence because a randomized study is not possible for ethical reasons, as a treatment delay is not considered in the best interest of the patient. A prospective database could be considered but it requires excessive time and resources regarding the required sample size and appropriate follow-up. Another limitation is that this work is a database study for which we have acknowledged several missing data, especially the precise reason(s) for delaying the start of RT (curative intentreoperation? Wound complications? Delay to expert Centre referral?). Then, the long treatment period, more than twenty years, with the evolution of knowledge during this time can be considered as another study limitation. However, this sarcoma database provides good quality data with professional management and regular data updating based for the evolution of knowledge, especially concerning pathological data. For example, there is no malignant fibrous histiocytoma in this database (it was approximately 30% of the histological subtypes in the past) because they all have been reclassified (mainly as undifferentiated pleomorphic sarcoma). Lastly, the interdisciplinary management of these patients had changed during the study period, especially regarding the indication of adjuvant chemotherapy that could delay the start of adjuvant RT. The present report did not explore the role of high-volume centers, this major issue requires additional analysis that are presently ingoing. In conclusion, in this retrospective database study, the TI between surgery and start of adjuvant RT did not seem to affect the outcomes for adult patients with a localized superficial trunk or extremity STS. To the best of our knowledge, this is the largest study with the most homogeneous population. Because of the limitations of this study, we cannot give any strong recommendation for daily practice; however, the TI between surgery and RT in soft tissue sarcoma should not be a sufficient criterion to refute indicated radiotherapy. RT should be administered as early as possible when healing is obtained, especially for patients at high risk of local recurrence. This study is warranted to be confirmed by other large database studies. A very interesting point that could be investigated in another study is the impact of the TI between surgery and RT on outcomes for STS among patients who suffered from a local relapse.

Funding sources INCa (Institut National du Cancer) subvention BCB INCa 2012162.

Authors’ disclosures of potential conflicts of interest The authors indicated no potential conflict of interest relevant to the study. Acknowledgments SarcomaBCB team management (Jean-Baptiste Courrèges, Françoise Ducimetière, Thomas Gaudin, Antoine Giraud, Myriam Jean-Denis, Arnaud Malfilatre, Nouria Mesli).

All of the people who helped us in each sarcoma reference center: Institut Bergonié (Guy Kantor, Binh Bui), Centre Léon Bérard (Jean-Yves Blay), Institut Curie (Marick Laé, Sophie Piperno-Neumann), Centre Antoine Lacassagne (Isabelle Peyrottes, Juliette Thariat), Centre Oscar Lambret (Abel Cordoba, Eric Lartigau, Emmanuelle Tresch), Centre Georges-François Leclerc (Françoise Colin, Geneviève Laporte), Institut de Cancérologie de l’Ouest site René Gauducheau (Emmanuelle Bompas, Augustin Mervoyer), Institut Claudius Regaud, IUCT-Oncopole, Toulouse (Martine Delannes, Sophie Le Guellec), Institut du Cancer de Montpellier (Marie-Christine Château), Institut de Cancérologie de l’Ouest site Paul Papin (Hadji Hamidou, Isabelle Valo), Centre François Baclesse (Corinne Delcambre, Delphine Lerouge), Centre Jean Perrin (Jacques Olivier Bay, Michel Lapeyre), Institut de Cancérologie de Lorraine (Jean-Christophe Faivre) and CHU de Strasbourg (Jean-Emmanuel Kurtz). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2016.04. 037. References [1] Clark MA, Fisher C, Judson I, Thomas JM. Soft-tissue sarcomas in adults. N Engl J Med 2005;353:701–11. [2] Ducimetière F, Lurkin A, Ranchère-Vince D, et al. Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing. PLoS ONE 2011;6: e20294. [3] Mastrangelo G, Coindre JM, Ducimetière F, et al. Incidence of soft tissue sarcoma and beyond: a population-based prospective study in 3 European regions. Cancer 2012;118:5339–48. [4] Stiller CA, Trama A, Serraino D, et al. Descriptive epidemiology of sarcomas in Europe: report from the RARECARE project. Eur J Cancer 2013;49:684–95. [5] ESMO/European Sarcoma Network Working Group. Soft tissue and visceral sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014;25. iii102-12.. [6] PDQ Adult Treatment Editorial Board. Adult Soft Tissue Sarcoma Treatment (PDQÒ): Health Professional Version. In: PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002. Available from: http://www.ncbi.nlm.nih.gov/books/NBK66046. [7] Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 1982;196:305–15. [8] Pisters PW, Harrison LB, Leung DH, Woodruff JM, Casper ES, Brennan MF. Longterm results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996;14:859–68. [9] Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16:197–203. [10] O’Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 2002;359:2235–41. [11] Davis AM, O’Sullivan B, Turcotte R, et al. Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol 2005;75:48–53. [12] Fein DA, Lee WR, Lanciano RM, et al. Management of extremity soft tissue sarcomas with limb-sparing surgery and postoperative irradiation: do total dose, overall treatment time, and the surgery-radiotherapy interval impact on local control? Int J Radiat Oncol Biol Phys 1995;32:969–76. [13] Schwartz DL, Einck J, Hunt K, et al. The effect of delayed postoperative irradiation on local control of soft tissue sarcomas of the extremity and torso. Int J Radiat Oncol Biol Phys 2002;52:1352–9. [14] Ballo MT, Zagars GK, Cormier JN, et al. Interval between surgery and radiotherapy: effect on local control of soft tissue sarcoma. Int J Radiat Oncol Biol Phys 2004;58:1461–7. [15] FNCLCC. Standards, Options et Recommandations 2006 pour la prise en charge des patients adultes atteints de sarcome des tissus mous, de sarcome utérin ou de tumeur stromale gastro-intestinale. 1995. [16] Fletcher C, Bridge J, Hogendoorn P, Mertens F. World Health Organization classification of tumours of soft tissue and bone. 4th ed. Lyon: IARC Press; 2013. [17] Trojani M, Contesso G, Coindre JM, et al. Soft-tissue sarcomas of adults; study of pathological prognostic variables and definition of a histopathological grading system. Int J Cancer 1984;33:37–42.

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Please cite this article in press as: Fourquet J et al. Time interval between surgery and start of adjuvant radiotherapy in patients with soft tissue sarcoma: A retrospective analysis of 1131 cases from the French Sarcoma Group. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.04.037