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Effect of surgical margins on prognosis in aggressive fibromatosis: A single-institutional analysis of 90 patients

Effect of surgical margins on prognosis in aggressive fibromatosis: A single-institutional... ONCOLOGY LETTERS 14: 5129-5134, 2017 Effect of surgical margins on prognosis in aggressive fibromatosis: A single‑institutional analysis of 90 patients 1 1 1 1 2 KAMRAN HARATI , ANAIS JAENISCH , BJÖRN BEHR , OLE GOERTZ , ALI HARATI , 1 3 1 1 TOBIAS HIRSCH , INGO STRICKER , MARCUS LEHNHARDT and ADRIEN DAIGELER 1 2 Department of Plastic Surgery, BG-University Hospital Bergmannsheil, D-44789 Bochum; Department of Neurosurgery, Klinikum Dortmund, D‑44145 Dortmund;  Institute of Pathology, Ruhr-University Bochum, D-44789 Bochum, Germany Received May 12, 2016; Accepted November 17, 2016 DOI: 10.3892/ol.2017.6864 Abstract. The treatment of aggressive fibromatosis poses progression, available treatment alternatives and the decision a therapeutic challenge in an interdisciplinary setting. The of the informed patient. extent of surgical resection is still discussed controversially. The present retrospective analysis aimed to determine Introduction prognostic factors leading to recurrence. Between 2000 and 2014, 114 patients with aggressive fibromatosis were Aggressive bfi romatosis,  also known as desmoid tumor, is a  treated surgically at BG-University Hospital Bergmannsheil semi‑malignant soft tissue neoplasm of clonal myobrfi oblastic  (Bochum, Germany). Univariate and multivariate analyses origin that arises from the musculoaponeurotic structures, were restricted to 90 participants with information available fascial planes and ligaments throughout the body. The inci- on surgical margins at the initial procedure. The median dence is estimated to be 3-4 cases/million people/year in follow-up time was 7.7 years. A total of 45 patients (50%) Europe and the USA, accounting for ~3% of all soft-tissue developed recurrence during follow-up. Primary tumors were tumors analyzed by biopsy (1,2). Aggressive bfi romatosis  can  resected with negative margins (R0) in 50 patients (68%) and occur sporadically or be associated with familial adenomatous with microscopically positive margins (R1) in 28 patients polyposis in Gardner syndrome. Among all cases of sporadic (25%). In addition, tumors in 12 patients (7%) were resected aggressive bfi romatosis,  >70% are associated with β-catenin with macroscopically positive margins at the initial surgical mutations; however, the clinical implication of this finding   procedure. The rates of recurrence-free survival (RFS) after has not been determined completely (3-5). Although aggres- 5 years were 68.8% [95% condfi ence  interval (CI), 53.5‑79.9%]  sive brfi omatosis  does not have the ability to metastasize, it is  in patients with R0-resected primary tumors and 34.1% characterized by locally aggressive growth with destructive (95% CI, 19.9-48.9%) in patients with R1/R2-status (P=0.001). infiltration  of the surrounding tissues and high rates of local  Narrow and wide clear margins within the R0-group were not recurrence despite surgical resection, leading to significant   associated with significantly different outcomes. Adjuvant functional impairments and morbidity. radiation, tumor site and patient age were not associated with Numerous analyses have been conducted to assess the a significant  alteration of RFS. The current results suggest  prognostic factors that affect recurrence-free survival (RFS) that the attainment of microscopically negative surgical in patients with aggressive bfi romatosis ( 1,2,6-16). Among margins at the initial surgical treatment is associated with a these factors, anatomical site, tumor size and patient age are significantly improved prognosis. A conservative surgical considered to be the most signicfi ant  for RFS (10,11). Notably, approach involving the attainment of narrow negative margins the prognostic signicfi ance  of negative surgical margins on  while preserving function should be sought in patients in RFS remains a subject of debate, and inconsistent results have whom tumor resection is indicated. The decision for resection been presented in published studies investigating the clinical should be made interdisciplinary in each case based on tumor signicfi ance  of surgical margins in aggressive bfi romatosis,   questioning the impact of curative surgical resection in general. Prior to 1999, limb-sparing surgical resection with clear margins was considered the therapy of choice in the vast majority of cases, reflecting  the standard approach for the  treatment of soft tissue sarcomas. In 1998 and 1999, the Correspondence to: Dr Kamran Harati, Department of Massachusetts General Hospital and the M.D. Anderson Plastic Surgery, BG-University Hospital Bergmannsheil, Cancer Center (MDACC) reported improved RFS rates Buerkle‑de‑la‑Camp‑Platz 1, D‑44789 Bochum, Germany for patients with negative margins, following analyses of E‑mail: kamran.harati@t‑online.de 92 and 168 patients, respectively (6,7). Shortly afterwards, Key words: fibromatosis, desmoid, recurrence, survival, margin Merchant et al (8) analyzed the outcomes of a series of 105 surgically treated patients with primary disease at the Memorial Sloan-Kettering Cancer Center (MSKCC), and were HARATI et al: SURGICAL MARGINS IN AGGRESSIVE FIBROMATOSIS unable to detect any signicfi ant  effect of positive margins on  (ibuprofen, 1,200-1,800 mg/day; or indomethacin, 150 mg/day. RFS. In 2003, Gronchi et al (10) from the Instituto Nazionale NSAIDs were given for a minimum of three months (range, Tumori (INT) in Milan reported similar observations in 3-14 months). Two patients received tamoxifen following 203 patients. A more recent analysis from the MDACC primary resection. Additionally, 4 patients were treated with in 2007 was unable to reproduce the results from 1999, imatinib and 1 patient with epirubicin. and margin positivity could no longer be substantiated as a significant prognostic factor (17). Thereafter, the MSKCC Histopathological classification. All pathology slides were published its actualized data analyzing 495 patients, revealing analyzed or reviewed for consensus diagnosis by experienced no statistical association between surgical margin status and soft tissue pathologists. RFS (11); however, in the specicfi   subgroup analysis of tumors  measuring <5 cm, R1 margins were found to have an increased Statistical analysis. All patients were retrospectively analyzed risk of local recurrence compared with R0. In 2011, a European  with regard to potential prognostic factors affecting RFS multicenter-based study including 426 patients was unable to (Table I). RFS was defined  as the period of time from the date  determine any signicfi ant  differences in RFS when comparing  of surgery for primary disease to the date of first  recurrence.  patients with R0 and R1 margins (1). Survival rates were estimated according to the Kaplan-Meier The aforementioned findings  have subsequently subverted  method with respective 95% condfi ence  intervals (CIs), and  the role of surgical resection as an initial treatment step, were compared using the log‑rank test. Multivariate analyses  and have prompted the present review of our institutional were performed using the Cox proportional hazards model. experience. The aim of the current study was to identify the Variables that were associated with P<0.10 in the univariate prognostic indicators of RFS in patients with primary aggres- analysis were included in the multivariate regression to assess sive fibromatosis who underwent surgical resection. The independent prognostic factors for RFS. P<0.05 was consid- analysis focused particularly on the effect of surgical margins ered to indicate a statistically signicfi ant  result. All analyses  on disease outcome. were performed using Stata software (Version 11.2; StataCorp, College Station, TX, USA). Patients and methods Analysis of surgical margins. In order to determine the impact Patients. Between June 2000 and July 2014, 114 patients of surgical resection margins on RFS, the three following vari- with aggressive fibromatosis were treated surgically at ables were analyzed. In ‘margin status after primary resection’ BG-University Hospital Bergmannsheil (Bochum, Germany). (Table II), RFS was assessed with regard to the resection status Of the 114 patients, 82 presented with primary disease in our that was achieved following the resection of the primary tumor institution, while 32 patients were subsequently referred to in our or the referring institution. In those patients with nega- our center following incomplete resection or the diagnosis of tive margins (R0 group) after primary resection, the effect of recurrence ≥3 months after definitive  surgery on the primary  the clear surgical margin width was assessed as ‘distance of tumor performed at other institutions. From this group of closest negative surgical margin at resection of the primary 114 patients, 17 patients were excluded due to the unavailability tumor (R0 group)’ (Table II). The variable ‘margin status of data regarding the surgical margins of the initial surgical after last resection in patients with ≥1 recurrence’ (Table II)  procedure. Furthermore, 7 patients were lost to follow-up. concerned the prognostic influence of the surgical margin Thus, the current analyses were restricted to 90 participants status that was attained at the final  resection of the recurring  with full information available on the surgical margins at the tumor in patients who developed ≥1 recurrence following the  initial procedure. The clinicopathological characteristics of the resection of the primary tumor. patients are summarized in Tables I and II. Patient follow-up information was obtained from our database and from patient Results correspondence. The study was approved by the local ethics committee and all patients provided their written informed Patient characteristics and surgical margins. The median consent. age at the time of initial recurrence was 38.7 years (range, 16.1-74.2 years). The patient group included in the analysis Treatment. The goal of surgical treatment for all patients was consisted of 37 males (41.1%) and 53 females (58.9%). function-preserving and limb-sparing resection of the primary Tumors were located in the lower extremities in 30 patients tumor with clear margins. The indication for adjuvant treat- (33.3%), in the upper extremities in 21 patients (23.3%), in ment was determined at the discretion of the interdisciplinary the intra-abdominal cavity in 14 patients (15.6%), in the head tumor board of our institution or the referring institutions. and neck area in 7 patients (7.8%), and in the supercifi al  trunk  A total of 27 patients received adjuvant radiotherapy in 18 patients (20.0%). During follow-up, 45 patients (50%) following resection of the primary tumor, with a median developed ≥1 recurrence, whereas 23 patients (25.6%) had ≥2  overall dose of 59.7 Gy (range, 50.0-66.0 Gy), and a further local recurrences (range, 2-5 recurrences). Time-to-recurrence 19 patients underwent first adjuvant radiotherapy subse- ranged from 3 months to 14 years (median, 17 months). No quent to an initial recurrence, with a median overall dose patient exhibited multifocal disease. Mortality occurred in 1 of 53.7 Gy (range 50.0-64.0 Gy). Adjuvant non-steroidal (female) patient with 5 recurrences and macroscopic residual anti-inflammatory drugs (NSAIDs) were administered disease subsequent to the last resection, following infiltration   following primary tumor resection in 19 patients, and a further of the internal carotid artery at 6.1 years after the primary 7 patients received NSAIDs following the initial recurrence diagnosis. Only 2 patients had Gardner syndrome. ONCOLOGY LETTERS 14: 5129-5134, 2017 Table I. Results of univariate analyses to determine factors predictive of recurrence-free survival in 90 patients with aggressive fibromatosis. Estimated RFS rate, Total No. of % (95% CI) no. of patients with ----------------------------------------------------------------------------------------------------- P-value Variable  patients  recurrences  1‑year  2‑year  5‑year  (log‑rank) Patient age, years 0.794 <50 61 31 78.5 (65.9-86.9) 70.2 (56.9-80.1) 54.5 (40.4-66.6)   ≥50  29  14  86.2 (67.3‑94.6)  57.7 (37.6‑73.4)  46.6 (27.6‑63.6)  Gender 0.315 Male 37 22 83.5 (67.0-92.2) 72.2 (54.4-84.0) 59.2 (40.7-73.7) Female 53 23 79.2 (65.7-87.9) 62.3 (47.8-73.8) 47.8 (33.6-60.7) Tumor site 0.387 Extremity 51 21 78.4 (64.4-87.4) 58.5 (43.7-70.6) 40.0 (25.9-53.8) 0.074 Abdominal cavity 14 10 85.7 (53.9-96.2) 78.6 (47.2-92.5) 78.6 (47.2-92.5) 0.147   Head/neck  7  3  57.1 (17.2‑83.7)  57.1 (17.2‑83.7)  57.1 (17.2‑83.7)  0.530 Truncal wall 18 11 94.1 (65.0-99.1) 82.4 (54.7-93.9) 63.5 (35.9-81.8) 0.241 Tumor size, cm 0.799 <5 26 15 84.3 (63.3-93.8) 63.5 (41.5-79.1) 59.0 (37.1-75.6)   ≥5  64  30  79.7 (67.6‑87.7)  67.2 (54.2‑77.2)  50.3 (37.2‑62.0)  Previous history of 0.296 trauma at disease site Yes 15 5 80.0 (50.0-93.1) 53.3 (26.3-74.4) 45.7 (20.1-68.3) No 75 40 81.2 (70.3-88.4) 68.9 (57.0-78.1) 53.3 (40.8-64.3) a b c Log‑rank test for equality of survivor functions;  Extremity vs. non-extremity tumors; Abdominal cavity vs. non-abdominal cavity tumors; d e Head/neck vs. non‑head/neck tumors;  Truncal wall vs. Non‑truncal wall tumors. RFS, recurrence‑free survival; CI, confidence interval. Plastic surgical tissue transfer was necessary in 21 patients Univariate analysis identified only the surgical margin following the resection of the primary tumor; specifically,   status attained at the resection of the primary tumor as a 19 patients with soft tissue defects received local afl ps,  while  significant predictor of outcome. Patients who underwent 2 patients with mere skin defects were transplanted with  complete R0 resection of their primary tumor had a signifi - split‑thickness skin grafts. The R0 rates were 52.2% (36/69) for  cantly improved outcome (5-year RFS rate, 68.8%; 95% CI, patients with primary closures and 66.7% (14/21) for patients 53.5-79.9%) when compared with patients in whom incom- who underwent plastic surgical tissue transfer. plete R1 or R2 resection was achieved (5-year RFS rate, 34.1%; 95% CI, 19.9-48.9%; P=0.001 vs. R0) (Table II; Fig. 1A). Follow‑up and survival. As of August 2014 (cut-off date), Furthermore, R0 status was associated with a more favorable the reverse Kaplan-Meier estimate of median follow-up RFS rate when compared only with R1 status (5-year RFS rate, time following primary resection was 7.7 years (95% CI, 28.6%; 95% CI, 13.5-45.6%; P<0.001 vs. R0) (Fig. 1B). R1 and 5.6-8.1 years) (18). The Kaplan-Meier-estimated rates of RFS R2 status had comparably diminished RFS rates (P=0.341). for the entire group were 52.2% (95% CI, 40.9-62.3) at 5 years Notably, surgical margin width did not inufl ence  the RFS rates  and 42.7% (95% CI, 28.8-55.9) at 10 years. in patients who underwent an R0 resection of their primary tumor (≤1 vs. >1 mm, P=0.301; and ≤5 vs. >5 mm, P=0.245)]  Univariate analysis of survival. In the entire series, patient (Table II; Fig. 1C). age and gender were not found to be signicfi ant  predictors of  However, surgical margins exhibited prognostic signifi - RFS (Table I). Similar to findings  in previous studies (1,17), cance at the resection of the primary tumor only; patients who tumors arising in the extremities appeared to have a poorer developed ≥1 recurrence did not gain a survival benetfi   from an  prognosis compared with lesions at other sites [5-year RFS R0 resection of the recurring tumor (5-year RFS rate, 77.9%; rates, 40.0% (95% CI, 25.9-53.8%) vs. 68.0% (95% CI, 95% CI, 54.5-90.2%) compared with an R1/2 resection of the 50.4‑80.4%), respectively]; however, this survival distribu- recurring tumor (5-year RFS rate, 50.2%; 95% CI, 24.0-71.6%; tion failed to reach statistical significance  in the univariate  P=0.269 vs. R0) (Table II; Fig. 1D). analysis (P=0.074). In contrast to the results of previous Regarding adjuvant treatment modalities, radiation treatment studies, tumor size did not exhibit any effect on RFS in the did not result in an improved outcome compared with no radia- present series. tion treatment [5-year RFS rates, 48.4% (95% CI, 27.8-66.3%) vs. HARATI et al: SURGICAL MARGINS IN AGGRESSIVE FIBROMATOSIS Table II. Univariate analyses of recurrence-free survival with respect to treatment characteristics. Estimated RFS Total No. rate, % (95% CI) no. of of patients ----------------------------------- ------------------------------------------------------------ P-value Variable  patients  with recurrences  1‑year  2‑year  5‑year  (log‑rank) Margin status after primary resection R0 50 34 87.9 (75.0-94.4) 75.5 (60.8-85.3) 68.8 (53.5-79.9) R1/2 40 11 72.5 (55.9-83.7) 55.0 (38.5-68.8) 34.1 (19.9-48.9) 0.001 R1 28 7 71.4 (50.9-84.6) 46.4 (27.6-63.3) 28.6 (13.5-45.6) <0.001 R2 12 4 75.0 (40.8-91.2) 75.0 (40.8-91.2) 47.6 (18.2-72.4) 0.341 Distance of closest negative surgical margin at resection of the primary tumor (R0 group), mm   ≤1  26  16  84.4 (63.7‑93.9)  76.2 (54.4‑88.6)  62.9 (40.5‑78.8)  0.301   >1  24  18  91.7 (70.6‑97.8)  75.0 (52.6‑87.9)  75.0 (52.6‑87.9)    ≤5  44  31  88.5 (74.6‑95.1)  79.1 (63.6‑88.5)  71.5 (55.2‑82.7)  0.245   >5  6  3  83.3 (27.3‑97.5)  50.0 (11.1‑80.4)  50.0 (11.1‑80.4)  Wound closure after 0.069 primary resection Primary closure 69 31 78.1 (66.4-86.2) 60.2 (47.6-70.7) 47.0 (34.4-58.6) Non-primary closure 21 14 90.5 (67.0-97.5) 85.7 (62.0-95.2) 69.3 (43.6-85.1) (plastic surgical tissue transfer) Adjuvant radiotherapy 0.861 Yes 27 13 81.5 (61.1-91.8) 73.9 (52.9-86.6) 48.4 (27.8-66.3) No 63 32 80.8 (68.7-88.6) 63.0 (49.8-73.7) 54.4 (41.1-65.9) Adjuvant NSAID treatment 0.080 Yes 19 7 73.7 (47.9-88.1) 47.4 (24.4-67.3) 36.8 (16.5-57.5) No 71 38 83.0 (72.1-90.0) 71.5 (59.4-80.6) 56.9 (44.0-67.8) Margin status after 0.269 last resection in patients with ≥1 recurrence R0 25 11 87.6 (66.3-95.8) 77.9 (54.5-90.2) 77.9 (54.5-90.2) R1/R2 20 12 89.2 (63.1-97.2) 77.6 (50.7-91.0) 50.2 (24.0-71.6) a b c d e f Log‑rank test for equality of survivor functions;  R0 vs. R1/2; R0 vs. R1; R1 vs. R2; ≤1 vs. >1 mm; ≤5 vs. >5 mm. RFS, recurrence‑free  survival; CI, confidence interval; NSAID, non‑steroidal anti‑inflammatory drug. 54.4% (95% CI, 41.1-65.9%), respectively; P=0.861). Adjuvant Discussion treatment with NSAIDs was associated with a marginally diminished RFS rate when compared with untreated patients In the present study, the surgical margin status attained at [5-year RFS rates, 36.8% (95% CI, 16.5-57.5%) vs. 56.9% (95% the resection of the primary tumor was the only factor that CI, 44.0‑67.8%), respectively; P=0.080] (Table II). exhibited prognostic significance in the analysis of RFS; patients with R0 margins after primary resection had a Multivariate analysis of survival. The only significant  prog- signicfi antly  improved RFS rate compared with patients who  nostic factor for RFS according to the Cox model was the underwent R1 or R2 resections. Notably, narrow and wide margin status attained at the primary resection (Table III); negative margins had similar outcomes within the R0-resected the hazard ratio for recurrence was 2.73 (95% CI, 1.52-4.91; subset, supporting a surgical approach aiming to achieve P=0.001) for patients with positive margins (R1/R2) vs. more conservative resections, rather than radical and wide R0-resected patients. All other variables failed to reach statis- excisions. In the entirety of the present series of patients, 6 out tical signicfi ance in the multivariate analysis. of 50 patients within the R0 subgroup underwent resections ONCOLOGY LETTERS 14: 5129-5134, 2017 Table III. Results of multivariate analysis on recurrence-free survival according to Cox proportional hazards model. Category (reference) Hazard ratio 95% CI P-value Margin status after primary resection: R1/R2 (vs. R0) 2.73 1.52-4.91 0.001 Tumor site: Extremity (vs. non-extremity) 1.66 0.83-3.32 0.153 Wound closure at primary resection: Primary (vs. non-primary) 1.38 0.64-2.96 0.411 Adjuvant NSAID treatment: Yes (vs. no) 1.93 0.88-4.23 0.101 CI, confidence interval; NSAID, non‑steroidal anti‑inflammatory drug. Figure 1. Effects of surgical margins on recurrence‑free survival following resection in patients with aggressive bfi romatosis.  Kaplan‑Meier curves show the  comparison of (A) R0 vs. R1/2 status, (B) R0 vs. R1 status, and (C) close vs. wide surgical margins (≤5 vs. >5 cm) following the primary resection, as well as  (D) R0 vs. R1/2 status following final resection in patients with ≥1 recurrence. with margins of >5 mm of healthy tissue, reflecting  a less  markedly higher compared with that in the present study,  radical treatment policy. In the cases with positive margins, which reported a 5-year RFS rate of only 52.2% (95% CI, tumors had infiltrated critical anatomical structures, such 40.9-62.3%) for the entire series. As three out of the four as large nerves of the extremities, or were too advanced and centers pooled the RFS rates of R0 and R1 patients, only the widespread for complete resection, which would have resulted MDACC data can be compared; the MDACC study reported a in functional loss and increased morbidity. Taken together,  5-year RFS rate of 75% for R1/R2-resected patients, which is these findings  suggest that a less radical surgical approach  markedly higher than that in the current series, which reported  with function-sparing resections should be employed when a rate of 34.1% (95% CI, 19.9-48.9%) for the corresponding feasible, without leaving microscopic or macroscopic positive patient group. This observation leads to the question of why margins. However, surgical margins did not inufl ence  RFS in  patients with positive margins had such poorer outcomes in the patients in whom tumors had recurred. current series compared with other studies. In contrast to the current findings,  none of the large retro- A potential reason for this may be related to the adjuvant spective studies previously conducted by the MDACC, MSKCC, treatments administered to patients with positive margins. INT and the French Sarcoma Group were able to determine a Nevertheless, adjuvant treatment modalities were not less predictive role of positive surgical margins (1,8,10,17). A mere intense in the current patient population: From the 45 patients descriptive comparison of the four studies mentioned with the with positive margins at our center, 23 (51.2%) received present study does not allow a further explanation for these adjuvant treatment (15 radiation only, 2 NSAIDs only, 2 contrasting results. Notably, a signicfi ant  difference regarding  tamoxifen only, and 4 combined treatment). The frequency of the RFS rates obtained between the different studies can be adjuvant treatment was similar in the MDACC series, in which detected: The overall 5-year RFS rates for patients treated 36 (52.9%) out of 68 patients with positive margins received surgically in the MDACC (80%) and in the INT (76%) were adjuvant therapy. HARATI et al: SURGICAL MARGINS IN AGGRESSIVE FIBROMATOSIS 3. Dômont J, Salas S, Lacroix L, Brouste V, Saulnier P, Terrier P, A final  potential explanation for the low RFS rates in the  Ranchère D, Neuville A, Leroux A, Guillou L, et al: High present study may be found in the time point of recurrence frequency of beta-catenin heterozygous mutations in detection. It must be noted that patients at our institution extra‑abdominal fibromatosis:  A potential molecular tool for  disease management. Br J Cancer 102: 1032-1036, 2010. are intensely followed-up with contrast-enhanced magnetic 4. Mullen JT, DeLaney TF, Rosenberg AE, Le L, Iafrate AJ, resonance imaging assessments every 3 months in the Kobayashi  W,  Szymonifka  J,  Yeap  BY,  Chen  YL,  first  2 years, and then every 6 months for ≥3 further years,  Harmon DC, et al: β-Catenin mutation status and outcomes in sporadic desmoid tumors. Oncologist 18: 1043-1049, 2013. enabling the detection of recurrences relatively rapidly and 5. Lazar AJ, Tuvin D, Hajibashi S, Habeeb S, Bolshakov S,  prior to the development of symptoms. However, we are Mayordomo‑Aranda  E,  Warneke  CL,  Lopez‑Terrada  D,  unable to determine the true reason for these marked outcome  Pollock RE and Lev D: Specific  mutations in the beta‑catenin  gene (CTNNB1) correlate with local recurrence in sporadic differences between the studies. desmoid tumors. Am J Pathol 173: 1518-1527, 2008. In conclusion, the data from the present study suggest 6. Spear MA, Jennings LC, Mankin HJ, Spiro IJ, Springfield DS,   an improved outcome for patients with completely resected Gebhardt MC, Rosenberg AE, Efird JT and Suit HD: Individualizing management of aggressive bfi romatoses . Int J primary tumors. Tumor biology may dictate the outcome; Radiat Oncol Biol Phys 40: 637-645, 1998. however, given the diminished outcome of patients retaining 7. Ballo MT, Zagars GK, Pollack A, Pisters PW and Pollack RA:  positive margins, surgical efforts must aim for function-sparing Desmoid tumor: Prognostic factors and outcome after surgery, radiation therapy, or combined surgery and radiation therapy. resections with negative margins wherever feasible. In this J Clin Oncol 17: 158-167, 1999. context, close negative margins, even those <1 mm, appear to 8. Merchant NB, Lewis JJ, Woodruff JM, Leung DH and be adequate. However, it cannot be retrospectively concluded Brennan MF: Extremity and trunk desmoid tumors: A multifac- torial analysis of outcome. Cancer 86: 2045-2052, 1999. whether the R0 resection itself or the characteristic of ‘R0 9. Lewis JJ, Boland PJ, Leung DH, Woodruff JM and Brennan MF: resectability’ at the initial surgical procedure leads to the The enigma of desmoid tumors. Ann Surg 229: 866-873, 1999. improved outcome; it is probable that tumors that cannot be 10. Gronchi A, Casali PG, Mariani L, Lo Vullo S, Colecchia M, Lozza L, Bertulli R, Fiore M, Olmi P, Santinami M and Rosai J: completely resected have more aggressive biological features Quality of surgery and outcome in extra-abdominal aggressive than completely resectable tumors, thus impairing the outcome bfi romatosis:  A series of patients surgically treated at a single  more substantially. Subsequently, a positive margin status institution. J Clin Oncol 21: 1390-1397, 2003. 11. Crago AM, Denton B, Salas S, Dufresne A, Mezhir JJ, could be a result, rather than a cause, of biological aggressive- Hameed M, Gonen M, Singer S and Brennan MF: A prognostic ness, and it may not itself inufl ence the outcome directly. nomogram for prediction of recurrence in desmoid bfi romatosis . Finally, the time point of surgical resection must be Ann Surg 258: 347-353, 2013. 12. Colombo C, Miceli R, Le Péchoux C, Palassini E, Honoré C, addressed. As proposed by the European Organisation Stacchiotti S, Mir O, Casali PG, Dômont J, Fiore M, et al: for Research and Treatment of Cancer (EORTC) in 2015, Sporadic extra abdominal wall desmoid-type fibromatosis: a wait-and-see strategy for ~1 or 2 years appears to be Surgical resection can be safely limited to a minority of patients. Eur J Cancer 51: 186-192, 2015. reasonable for patients with asymptomatic primary tumors 13. Bonvalot S, Ternès N, Fiore M, Bitsakou G, Colombo C,  at non-critical sites as a frontline approach, and can Honoré C, Marrari A, Le Cesne A, Perrone F, Dunant A and prevent unnecessary resections that may result in lifelong Gronchi A: Spontaneous regression of primary abdominal wall desmoid tumors: More common than previously thought. Ann morbidity (19,20). Currently, a prospective observational study Surg Oncol 20: 4096-4102, 2013. (NCT01801176) by the Institut Gustave Roussy is underway 14. Briand S, Barbier O, Biau D, Bertrand-Vasseur A, Larousserie F, to assess the outcome of different treatment arms formulating Anract P and Gouin F: Wait-and-see policy as a first-line management for extra-abdominal desmoid tumors. J Bone Joint the role of the wait-and-see policy in more detail. To date, Surg Am 96: 631-638, 2014. the EORTC recommends a surgical resection in cases of 15. Eastley N, Aujla R, Silk R, Richards CJ, McCulloch TA, Esler CP progression if the expected postoperative functional impair- and Ashford RU: Extra-abdominal desmoid fibromatosis-a sarcoma unit review of practice, long term recurrence rates and ment is limited. However, as this can be highly subjective, the survival. Eur J Surg Oncol 40: 1125-1130, 2014. postoperative consequences must be clearly discussed with 16. Shin SH, Ko KR, Cho SK, Choi YL and Seo SW: Surgical each patient before decisions are made. outcome of desmoid tumors: Adjuvant radiotherapy delayed the recurrence, but did not affect long-term outcomes. J Surg Oncol 108: 28-33, 2013. Acknowledgements 17. Lev D, Kotilingam D, Wei C, Ballo MT, Zagars GK, Pisters PW, Lazar AA, Patel SR, Benjamin RS and Pollock RE: Optimizing treatment of desmoid tumors. J Clin Oncol 25: 1785-1791, 2007. The current study was supported by a FoRUM grant (grant 18. Schemper M and Smith TL: A note on quantifying follow-up in no. K090-15) from Ruhr-University Bochum (Bochum, studies of failure time. Control Clin Trials 17: 343-346, 1996. Germany). 19. Gronchi A, Colombo C, Le Péchoux C, Dei Tos AP, Le Cesne A, Marrari A, Penel N, Grignani G, Blay JY, Casali PG, et al: Sporadic desmoid‑type bfi romatosis:  A stepwise approach to a  References non-metastasising neoplasm-a position paper from the Italian and the French Sarcoma Group. Ann Oncol 25: 578-583, 2014. 20. Kasper B, Baumgarten C, Bonvalot S, Haas R, Haller F, 1. Salas S, Dufresne A, Bui B, Blay JY, Terrier P, Ranchere-Vince D, Hohenberger P, Moreau G, van der Graaf WT and Gronchi A; Bonvalot S, Stoeckle E, Guillou L, Le Cesne A, et al: Prognostic Desmoid Working Group: Management of sporadic desmoid-type factors influencing progression-free survival determined from bfi romatosis:  A European consensus approach based on patients'  a series of sporadic desmoid tumors: A wait-and-see policy and professionals' expertise-a sarcoma patients EuroNet and according to tumor presentation. J Clin Oncol 29: 3553-3558, 2011. European organisation for research and treatment of cancer/Soft 2. de Camargo VP, Keohan ML, D'Adamo DR, Antonescu CR, tissue and bone sarcoma group initiative. Eur J Cancer 51: Brennan MF, Singer S, Ahn LS and Maki RG: Clinical outcomes 127-136, 2015. of systemic therapy for patients with deep bfi romatosis  (desmoid  tumor). Cancer 116: 2258-2265, 2010. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Oncology Letters Pubmed Central

Effect of surgical margins on prognosis in aggressive fibromatosis: A single-institutional analysis of 90 patients

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ONCOLOGY LETTERS 14: 5129-5134, 2017 Effect of surgical margins on prognosis in aggressive fibromatosis: A single‑institutional analysis of 90 patients 1 1 1 1 2 KAMRAN HARATI , ANAIS JAENISCH , BJÖRN BEHR , OLE GOERTZ , ALI HARATI , 1 3 1 1 TOBIAS HIRSCH , INGO STRICKER , MARCUS LEHNHARDT and ADRIEN DAIGELER 1 2 Department of Plastic Surgery, BG-University Hospital Bergmannsheil, D-44789 Bochum; Department of Neurosurgery, Klinikum Dortmund, D‑44145 Dortmund;  Institute of Pathology, Ruhr-University Bochum, D-44789 Bochum, Germany Received May 12, 2016; Accepted November 17, 2016 DOI: 10.3892/ol.2017.6864 Abstract. The treatment of aggressive fibromatosis poses progression, available treatment alternatives and the decision a therapeutic challenge in an interdisciplinary setting. The of the informed patient. extent of surgical resection is still discussed controversially. The present retrospective analysis aimed to determine Introduction prognostic factors leading to recurrence. Between 2000 and 2014, 114 patients with aggressive fibromatosis were Aggressive bfi romatosis,  also known as desmoid tumor, is a  treated surgically at BG-University Hospital Bergmannsheil semi‑malignant soft tissue neoplasm of clonal myobrfi oblastic  (Bochum, Germany). Univariate and multivariate analyses origin that arises from the musculoaponeurotic structures, were restricted to 90 participants with information available fascial planes and ligaments throughout the body. The inci- on surgical margins at the initial procedure. The median dence is estimated to be 3-4 cases/million people/year in follow-up time was 7.7 years. A total of 45 patients (50%) Europe and the USA, accounting for ~3% of all soft-tissue developed recurrence during follow-up. Primary tumors were tumors analyzed by biopsy (1,2). Aggressive bfi romatosis  can  resected with negative margins (R0) in 50 patients (68%) and occur sporadically or be associated with familial adenomatous with microscopically positive margins (R1) in 28 patients polyposis in Gardner syndrome. Among all cases of sporadic (25%). In addition, tumors in 12 patients (7%) were resected aggressive bfi romatosis,  >70% are associated with β-catenin with macroscopically positive margins at the initial surgical mutations; however, the clinical implication of this finding   procedure. The rates of recurrence-free survival (RFS) after has not been determined completely (3-5). Although aggres- 5 years were 68.8% [95% condfi ence  interval (CI), 53.5‑79.9%]  sive brfi omatosis  does not have the ability to metastasize, it is  in patients with R0-resected primary tumors and 34.1% characterized by locally aggressive growth with destructive (95% CI, 19.9-48.9%) in patients with R1/R2-status (P=0.001). infiltration  of the surrounding tissues and high rates of local  Narrow and wide clear margins within the R0-group were not recurrence despite surgical resection, leading to significant   associated with significantly different outcomes. Adjuvant functional impairments and morbidity. radiation, tumor site and patient age were not associated with Numerous analyses have been conducted to assess the a significant  alteration of RFS. The current results suggest  prognostic factors that affect recurrence-free survival (RFS) that the attainment of microscopically negative surgical in patients with aggressive bfi romatosis ( 1,2,6-16). Among margins at the initial surgical treatment is associated with a these factors, anatomical site, tumor size and patient age are significantly improved prognosis. A conservative surgical considered to be the most signicfi ant  for RFS (10,11). Notably, approach involving the attainment of narrow negative margins the prognostic signicfi ance  of negative surgical margins on  while preserving function should be sought in patients in RFS remains a subject of debate, and inconsistent results have whom tumor resection is indicated. The decision for resection been presented in published studies investigating the clinical should be made interdisciplinary in each case based on tumor signicfi ance  of surgical margins in aggressive bfi romatosis,   questioning the impact of curative surgical resection in general. Prior to 1999, limb-sparing surgical resection with clear margins was considered the therapy of choice in the vast majority of cases, reflecting  the standard approach for the  treatment of soft tissue sarcomas. In 1998 and 1999, the Correspondence to: Dr Kamran Harati, Department of Massachusetts General Hospital and the M.D. Anderson Plastic Surgery, BG-University Hospital Bergmannsheil, Cancer Center (MDACC) reported improved RFS rates Buerkle‑de‑la‑Camp‑Platz 1, D‑44789 Bochum, Germany for patients with negative margins, following analyses of E‑mail: kamran.harati@t‑online.de 92 and 168 patients, respectively (6,7). Shortly afterwards, Key words: fibromatosis, desmoid, recurrence, survival, margin Merchant et al (8) analyzed the outcomes of a series of 105 surgically treated patients with primary disease at the Memorial Sloan-Kettering Cancer Center (MSKCC), and were HARATI et al: SURGICAL MARGINS IN AGGRESSIVE FIBROMATOSIS unable to detect any signicfi ant  effect of positive margins on  (ibuprofen, 1,200-1,800 mg/day; or indomethacin, 150 mg/day. RFS. In 2003, Gronchi et al (10) from the Instituto Nazionale NSAIDs were given for a minimum of three months (range, Tumori (INT) in Milan reported similar observations in 3-14 months). Two patients received tamoxifen following 203 patients. A more recent analysis from the MDACC primary resection. Additionally, 4 patients were treated with in 2007 was unable to reproduce the results from 1999, imatinib and 1 patient with epirubicin. and margin positivity could no longer be substantiated as a significant prognostic factor (17). Thereafter, the MSKCC Histopathological classification. All pathology slides were published its actualized data analyzing 495 patients, revealing analyzed or reviewed for consensus diagnosis by experienced no statistical association between surgical margin status and soft tissue pathologists. RFS (11); however, in the specicfi   subgroup analysis of tumors  measuring <5 cm, R1 margins were found to have an increased Statistical analysis. All patients were retrospectively analyzed risk of local recurrence compared with R0. In 2011, a European  with regard to potential prognostic factors affecting RFS multicenter-based study including 426 patients was unable to (Table I). RFS was defined  as the period of time from the date  determine any signicfi ant  differences in RFS when comparing  of surgery for primary disease to the date of first  recurrence.  patients with R0 and R1 margins (1). Survival rates were estimated according to the Kaplan-Meier The aforementioned findings  have subsequently subverted  method with respective 95% condfi ence  intervals (CIs), and  the role of surgical resection as an initial treatment step, were compared using the log‑rank test. Multivariate analyses  and have prompted the present review of our institutional were performed using the Cox proportional hazards model. experience. The aim of the current study was to identify the Variables that were associated with P<0.10 in the univariate prognostic indicators of RFS in patients with primary aggres- analysis were included in the multivariate regression to assess sive fibromatosis who underwent surgical resection. The independent prognostic factors for RFS. P<0.05 was consid- analysis focused particularly on the effect of surgical margins ered to indicate a statistically signicfi ant  result. All analyses  on disease outcome. were performed using Stata software (Version 11.2; StataCorp, College Station, TX, USA). Patients and methods Analysis of surgical margins. In order to determine the impact Patients. Between June 2000 and July 2014, 114 patients of surgical resection margins on RFS, the three following vari- with aggressive fibromatosis were treated surgically at ables were analyzed. In ‘margin status after primary resection’ BG-University Hospital Bergmannsheil (Bochum, Germany). (Table II), RFS was assessed with regard to the resection status Of the 114 patients, 82 presented with primary disease in our that was achieved following the resection of the primary tumor institution, while 32 patients were subsequently referred to in our or the referring institution. In those patients with nega- our center following incomplete resection or the diagnosis of tive margins (R0 group) after primary resection, the effect of recurrence ≥3 months after definitive  surgery on the primary  the clear surgical margin width was assessed as ‘distance of tumor performed at other institutions. From this group of closest negative surgical margin at resection of the primary 114 patients, 17 patients were excluded due to the unavailability tumor (R0 group)’ (Table II). The variable ‘margin status of data regarding the surgical margins of the initial surgical after last resection in patients with ≥1 recurrence’ (Table II)  procedure. Furthermore, 7 patients were lost to follow-up. concerned the prognostic influence of the surgical margin Thus, the current analyses were restricted to 90 participants status that was attained at the final  resection of the recurring  with full information available on the surgical margins at the tumor in patients who developed ≥1 recurrence following the  initial procedure. The clinicopathological characteristics of the resection of the primary tumor. patients are summarized in Tables I and II. Patient follow-up information was obtained from our database and from patient Results correspondence. The study was approved by the local ethics committee and all patients provided their written informed Patient characteristics and surgical margins. The median consent. age at the time of initial recurrence was 38.7 years (range, 16.1-74.2 years). The patient group included in the analysis Treatment. The goal of surgical treatment for all patients was consisted of 37 males (41.1%) and 53 females (58.9%). function-preserving and limb-sparing resection of the primary Tumors were located in the lower extremities in 30 patients tumor with clear margins. The indication for adjuvant treat- (33.3%), in the upper extremities in 21 patients (23.3%), in ment was determined at the discretion of the interdisciplinary the intra-abdominal cavity in 14 patients (15.6%), in the head tumor board of our institution or the referring institutions. and neck area in 7 patients (7.8%), and in the supercifi al  trunk  A total of 27 patients received adjuvant radiotherapy in 18 patients (20.0%). During follow-up, 45 patients (50%) following resection of the primary tumor, with a median developed ≥1 recurrence, whereas 23 patients (25.6%) had ≥2  overall dose of 59.7 Gy (range, 50.0-66.0 Gy), and a further local recurrences (range, 2-5 recurrences). Time-to-recurrence 19 patients underwent first adjuvant radiotherapy subse- ranged from 3 months to 14 years (median, 17 months). No quent to an initial recurrence, with a median overall dose patient exhibited multifocal disease. Mortality occurred in 1 of 53.7 Gy (range 50.0-64.0 Gy). Adjuvant non-steroidal (female) patient with 5 recurrences and macroscopic residual anti-inflammatory drugs (NSAIDs) were administered disease subsequent to the last resection, following infiltration   following primary tumor resection in 19 patients, and a further of the internal carotid artery at 6.1 years after the primary 7 patients received NSAIDs following the initial recurrence diagnosis. Only 2 patients had Gardner syndrome. ONCOLOGY LETTERS 14: 5129-5134, 2017 Table I. Results of univariate analyses to determine factors predictive of recurrence-free survival in 90 patients with aggressive fibromatosis. Estimated RFS rate, Total No. of % (95% CI) no. of patients with ----------------------------------------------------------------------------------------------------- P-value Variable  patients  recurrences  1‑year  2‑year  5‑year  (log‑rank) Patient age, years 0.794 <50 61 31 78.5 (65.9-86.9) 70.2 (56.9-80.1) 54.5 (40.4-66.6)   ≥50  29  14  86.2 (67.3‑94.6)  57.7 (37.6‑73.4)  46.6 (27.6‑63.6)  Gender 0.315 Male 37 22 83.5 (67.0-92.2) 72.2 (54.4-84.0) 59.2 (40.7-73.7) Female 53 23 79.2 (65.7-87.9) 62.3 (47.8-73.8) 47.8 (33.6-60.7) Tumor site 0.387 Extremity 51 21 78.4 (64.4-87.4) 58.5 (43.7-70.6) 40.0 (25.9-53.8) 0.074 Abdominal cavity 14 10 85.7 (53.9-96.2) 78.6 (47.2-92.5) 78.6 (47.2-92.5) 0.147   Head/neck  7  3  57.1 (17.2‑83.7)  57.1 (17.2‑83.7)  57.1 (17.2‑83.7)  0.530 Truncal wall 18 11 94.1 (65.0-99.1) 82.4 (54.7-93.9) 63.5 (35.9-81.8) 0.241 Tumor size, cm 0.799 <5 26 15 84.3 (63.3-93.8) 63.5 (41.5-79.1) 59.0 (37.1-75.6)   ≥5  64  30  79.7 (67.6‑87.7)  67.2 (54.2‑77.2)  50.3 (37.2‑62.0)  Previous history of 0.296 trauma at disease site Yes 15 5 80.0 (50.0-93.1) 53.3 (26.3-74.4) 45.7 (20.1-68.3) No 75 40 81.2 (70.3-88.4) 68.9 (57.0-78.1) 53.3 (40.8-64.3) a b c Log‑rank test for equality of survivor functions;  Extremity vs. non-extremity tumors; Abdominal cavity vs. non-abdominal cavity tumors; d e Head/neck vs. non‑head/neck tumors;  Truncal wall vs. Non‑truncal wall tumors. RFS, recurrence‑free survival; CI, confidence interval. Plastic surgical tissue transfer was necessary in 21 patients Univariate analysis identified only the surgical margin following the resection of the primary tumor; specifically,   status attained at the resection of the primary tumor as a 19 patients with soft tissue defects received local afl ps,  while  significant predictor of outcome. Patients who underwent 2 patients with mere skin defects were transplanted with  complete R0 resection of their primary tumor had a signifi - split‑thickness skin grafts. The R0 rates were 52.2% (36/69) for  cantly improved outcome (5-year RFS rate, 68.8%; 95% CI, patients with primary closures and 66.7% (14/21) for patients 53.5-79.9%) when compared with patients in whom incom- who underwent plastic surgical tissue transfer. plete R1 or R2 resection was achieved (5-year RFS rate, 34.1%; 95% CI, 19.9-48.9%; P=0.001 vs. R0) (Table II; Fig. 1A). Follow‑up and survival. As of August 2014 (cut-off date), Furthermore, R0 status was associated with a more favorable the reverse Kaplan-Meier estimate of median follow-up RFS rate when compared only with R1 status (5-year RFS rate, time following primary resection was 7.7 years (95% CI, 28.6%; 95% CI, 13.5-45.6%; P<0.001 vs. R0) (Fig. 1B). R1 and 5.6-8.1 years) (18). The Kaplan-Meier-estimated rates of RFS R2 status had comparably diminished RFS rates (P=0.341). for the entire group were 52.2% (95% CI, 40.9-62.3) at 5 years Notably, surgical margin width did not inufl ence  the RFS rates  and 42.7% (95% CI, 28.8-55.9) at 10 years. in patients who underwent an R0 resection of their primary tumor (≤1 vs. >1 mm, P=0.301; and ≤5 vs. >5 mm, P=0.245)]  Univariate analysis of survival. In the entire series, patient (Table II; Fig. 1C). age and gender were not found to be signicfi ant  predictors of  However, surgical margins exhibited prognostic signifi - RFS (Table I). Similar to findings  in previous studies (1,17), cance at the resection of the primary tumor only; patients who tumors arising in the extremities appeared to have a poorer developed ≥1 recurrence did not gain a survival benetfi   from an  prognosis compared with lesions at other sites [5-year RFS R0 resection of the recurring tumor (5-year RFS rate, 77.9%; rates, 40.0% (95% CI, 25.9-53.8%) vs. 68.0% (95% CI, 95% CI, 54.5-90.2%) compared with an R1/2 resection of the 50.4‑80.4%), respectively]; however, this survival distribu- recurring tumor (5-year RFS rate, 50.2%; 95% CI, 24.0-71.6%; tion failed to reach statistical significance  in the univariate  P=0.269 vs. R0) (Table II; Fig. 1D). analysis (P=0.074). In contrast to the results of previous Regarding adjuvant treatment modalities, radiation treatment studies, tumor size did not exhibit any effect on RFS in the did not result in an improved outcome compared with no radia- present series. tion treatment [5-year RFS rates, 48.4% (95% CI, 27.8-66.3%) vs. HARATI et al: SURGICAL MARGINS IN AGGRESSIVE FIBROMATOSIS Table II. Univariate analyses of recurrence-free survival with respect to treatment characteristics. Estimated RFS Total No. rate, % (95% CI) no. of of patients ----------------------------------- ------------------------------------------------------------ P-value Variable  patients  with recurrences  1‑year  2‑year  5‑year  (log‑rank) Margin status after primary resection R0 50 34 87.9 (75.0-94.4) 75.5 (60.8-85.3) 68.8 (53.5-79.9) R1/2 40 11 72.5 (55.9-83.7) 55.0 (38.5-68.8) 34.1 (19.9-48.9) 0.001 R1 28 7 71.4 (50.9-84.6) 46.4 (27.6-63.3) 28.6 (13.5-45.6) <0.001 R2 12 4 75.0 (40.8-91.2) 75.0 (40.8-91.2) 47.6 (18.2-72.4) 0.341 Distance of closest negative surgical margin at resection of the primary tumor (R0 group), mm   ≤1  26  16  84.4 (63.7‑93.9)  76.2 (54.4‑88.6)  62.9 (40.5‑78.8)  0.301   >1  24  18  91.7 (70.6‑97.8)  75.0 (52.6‑87.9)  75.0 (52.6‑87.9)    ≤5  44  31  88.5 (74.6‑95.1)  79.1 (63.6‑88.5)  71.5 (55.2‑82.7)  0.245   >5  6  3  83.3 (27.3‑97.5)  50.0 (11.1‑80.4)  50.0 (11.1‑80.4)  Wound closure after 0.069 primary resection Primary closure 69 31 78.1 (66.4-86.2) 60.2 (47.6-70.7) 47.0 (34.4-58.6) Non-primary closure 21 14 90.5 (67.0-97.5) 85.7 (62.0-95.2) 69.3 (43.6-85.1) (plastic surgical tissue transfer) Adjuvant radiotherapy 0.861 Yes 27 13 81.5 (61.1-91.8) 73.9 (52.9-86.6) 48.4 (27.8-66.3) No 63 32 80.8 (68.7-88.6) 63.0 (49.8-73.7) 54.4 (41.1-65.9) Adjuvant NSAID treatment 0.080 Yes 19 7 73.7 (47.9-88.1) 47.4 (24.4-67.3) 36.8 (16.5-57.5) No 71 38 83.0 (72.1-90.0) 71.5 (59.4-80.6) 56.9 (44.0-67.8) Margin status after 0.269 last resection in patients with ≥1 recurrence R0 25 11 87.6 (66.3-95.8) 77.9 (54.5-90.2) 77.9 (54.5-90.2) R1/R2 20 12 89.2 (63.1-97.2) 77.6 (50.7-91.0) 50.2 (24.0-71.6) a b c d e f Log‑rank test for equality of survivor functions;  R0 vs. R1/2; R0 vs. R1; R1 vs. R2; ≤1 vs. >1 mm; ≤5 vs. >5 mm. RFS, recurrence‑free  survival; CI, confidence interval; NSAID, non‑steroidal anti‑inflammatory drug. 54.4% (95% CI, 41.1-65.9%), respectively; P=0.861). Adjuvant Discussion treatment with NSAIDs was associated with a marginally diminished RFS rate when compared with untreated patients In the present study, the surgical margin status attained at [5-year RFS rates, 36.8% (95% CI, 16.5-57.5%) vs. 56.9% (95% the resection of the primary tumor was the only factor that CI, 44.0‑67.8%), respectively; P=0.080] (Table II). exhibited prognostic significance in the analysis of RFS; patients with R0 margins after primary resection had a Multivariate analysis of survival. The only significant  prog- signicfi antly  improved RFS rate compared with patients who  nostic factor for RFS according to the Cox model was the underwent R1 or R2 resections. Notably, narrow and wide margin status attained at the primary resection (Table III); negative margins had similar outcomes within the R0-resected the hazard ratio for recurrence was 2.73 (95% CI, 1.52-4.91; subset, supporting a surgical approach aiming to achieve P=0.001) for patients with positive margins (R1/R2) vs. more conservative resections, rather than radical and wide R0-resected patients. All other variables failed to reach statis- excisions. In the entirety of the present series of patients, 6 out tical signicfi ance in the multivariate analysis. of 50 patients within the R0 subgroup underwent resections ONCOLOGY LETTERS 14: 5129-5134, 2017 Table III. Results of multivariate analysis on recurrence-free survival according to Cox proportional hazards model. Category (reference) Hazard ratio 95% CI P-value Margin status after primary resection: R1/R2 (vs. R0) 2.73 1.52-4.91 0.001 Tumor site: Extremity (vs. non-extremity) 1.66 0.83-3.32 0.153 Wound closure at primary resection: Primary (vs. non-primary) 1.38 0.64-2.96 0.411 Adjuvant NSAID treatment: Yes (vs. no) 1.93 0.88-4.23 0.101 CI, confidence interval; NSAID, non‑steroidal anti‑inflammatory drug. Figure 1. Effects of surgical margins on recurrence‑free survival following resection in patients with aggressive bfi romatosis.  Kaplan‑Meier curves show the  comparison of (A) R0 vs. R1/2 status, (B) R0 vs. R1 status, and (C) close vs. wide surgical margins (≤5 vs. >5 cm) following the primary resection, as well as  (D) R0 vs. R1/2 status following final resection in patients with ≥1 recurrence. with margins of >5 mm of healthy tissue, reflecting  a less  markedly higher compared with that in the present study,  radical treatment policy. In the cases with positive margins, which reported a 5-year RFS rate of only 52.2% (95% CI, tumors had infiltrated critical anatomical structures, such 40.9-62.3%) for the entire series. As three out of the four as large nerves of the extremities, or were too advanced and centers pooled the RFS rates of R0 and R1 patients, only the widespread for complete resection, which would have resulted MDACC data can be compared; the MDACC study reported a in functional loss and increased morbidity. Taken together,  5-year RFS rate of 75% for R1/R2-resected patients, which is these findings  suggest that a less radical surgical approach  markedly higher than that in the current series, which reported  with function-sparing resections should be employed when a rate of 34.1% (95% CI, 19.9-48.9%) for the corresponding feasible, without leaving microscopic or macroscopic positive patient group. This observation leads to the question of why margins. However, surgical margins did not inufl ence  RFS in  patients with positive margins had such poorer outcomes in the patients in whom tumors had recurred. current series compared with other studies. In contrast to the current findings,  none of the large retro- A potential reason for this may be related to the adjuvant spective studies previously conducted by the MDACC, MSKCC, treatments administered to patients with positive margins. INT and the French Sarcoma Group were able to determine a Nevertheless, adjuvant treatment modalities were not less predictive role of positive surgical margins (1,8,10,17). A mere intense in the current patient population: From the 45 patients descriptive comparison of the four studies mentioned with the with positive margins at our center, 23 (51.2%) received present study does not allow a further explanation for these adjuvant treatment (15 radiation only, 2 NSAIDs only, 2 contrasting results. Notably, a signicfi ant  difference regarding  tamoxifen only, and 4 combined treatment). The frequency of the RFS rates obtained between the different studies can be adjuvant treatment was similar in the MDACC series, in which detected: The overall 5-year RFS rates for patients treated 36 (52.9%) out of 68 patients with positive margins received surgically in the MDACC (80%) and in the INT (76%) were adjuvant therapy. HARATI et al: SURGICAL MARGINS IN AGGRESSIVE FIBROMATOSIS 3. Dômont J, Salas S, Lacroix L, Brouste V, Saulnier P, Terrier P, A final  potential explanation for the low RFS rates in the  Ranchère D, Neuville A, Leroux A, Guillou L, et al: High present study may be found in the time point of recurrence frequency of beta-catenin heterozygous mutations in detection. It must be noted that patients at our institution extra‑abdominal fibromatosis:  A potential molecular tool for  disease management. Br J Cancer 102: 1032-1036, 2010. are intensely followed-up with contrast-enhanced magnetic 4. Mullen JT, DeLaney TF, Rosenberg AE, Le L, Iafrate AJ, resonance imaging assessments every 3 months in the Kobayashi  W,  Szymonifka  J,  Yeap  BY,  Chen  YL,  first  2 years, and then every 6 months for ≥3 further years,  Harmon DC, et al: β-Catenin mutation status and outcomes in sporadic desmoid tumors. Oncologist 18: 1043-1049, 2013. enabling the detection of recurrences relatively rapidly and 5. Lazar AJ, Tuvin D, Hajibashi S, Habeeb S, Bolshakov S,  prior to the development of symptoms. However, we are Mayordomo‑Aranda  E,  Warneke  CL,  Lopez‑Terrada  D,  unable to determine the true reason for these marked outcome  Pollock RE and Lev D: Specific  mutations in the beta‑catenin  gene (CTNNB1) correlate with local recurrence in sporadic differences between the studies. desmoid tumors. Am J Pathol 173: 1518-1527, 2008. In conclusion, the data from the present study suggest 6. Spear MA, Jennings LC, Mankin HJ, Spiro IJ, Springfield DS,   an improved outcome for patients with completely resected Gebhardt MC, Rosenberg AE, Efird JT and Suit HD: Individualizing management of aggressive bfi romatoses . Int J primary tumors. Tumor biology may dictate the outcome; Radiat Oncol Biol Phys 40: 637-645, 1998. however, given the diminished outcome of patients retaining 7. 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Gronchi A, Casali PG, Mariani L, Lo Vullo S, Colecchia M, Lozza L, Bertulli R, Fiore M, Olmi P, Santinami M and Rosai J: completely resected have more aggressive biological features Quality of surgery and outcome in extra-abdominal aggressive than completely resectable tumors, thus impairing the outcome bfi romatosis:  A series of patients surgically treated at a single  more substantially. Subsequently, a positive margin status institution. J Clin Oncol 21: 1390-1397, 2003. 11. Crago AM, Denton B, Salas S, Dufresne A, Mezhir JJ, could be a result, rather than a cause, of biological aggressive- Hameed M, Gonen M, Singer S and Brennan MF: A prognostic ness, and it may not itself inufl ence the outcome directly. nomogram for prediction of recurrence in desmoid bfi romatosis . Finally, the time point of surgical resection must be Ann Surg 258: 347-353, 2013. 12. Colombo C, Miceli R, Le Péchoux C, Palassini E, Honoré C, addressed. As proposed by the European Organisation Stacchiotti S, Mir O, Casali PG, Dômont J, Fiore M, et al: for Research and Treatment of Cancer (EORTC) in 2015, Sporadic extra abdominal wall desmoid-type fibromatosis: a wait-and-see strategy for ~1 or 2 years appears to be Surgical resection can be safely limited to a minority of patients. Eur J Cancer 51: 186-192, 2015. reasonable for patients with asymptomatic primary tumors 13. Bonvalot S, Ternès N, Fiore M, Bitsakou G, Colombo C,  at non-critical sites as a frontline approach, and can Honoré C, Marrari A, Le Cesne A, Perrone F, Dunant A and prevent unnecessary resections that may result in lifelong Gronchi A: Spontaneous regression of primary abdominal wall desmoid tumors: More common than previously thought. Ann morbidity (19,20). Currently, a prospective observational study Surg Oncol 20: 4096-4102, 2013. (NCT01801176) by the Institut Gustave Roussy is underway 14. Briand S, Barbier O, Biau D, Bertrand-Vasseur A, Larousserie F, to assess the outcome of different treatment arms formulating Anract P and Gouin F: Wait-and-see policy as a first-line management for extra-abdominal desmoid tumors. J Bone Joint the role of the wait-and-see policy in more detail. To date, Surg Am 96: 631-638, 2014. the EORTC recommends a surgical resection in cases of 15. Eastley N, Aujla R, Silk R, Richards CJ, McCulloch TA, Esler CP progression if the expected postoperative functional impair- and Ashford RU: Extra-abdominal desmoid fibromatosis-a sarcoma unit review of practice, long term recurrence rates and ment is limited. However, as this can be highly subjective, the survival. Eur J Surg Oncol 40: 1125-1130, 2014. postoperative consequences must be clearly discussed with 16. Shin SH, Ko KR, Cho SK, Choi YL and Seo SW: Surgical each patient before decisions are made. outcome of desmoid tumors: Adjuvant radiotherapy delayed the recurrence, but did not affect long-term outcomes. J Surg Oncol 108: 28-33, 2013. Acknowledgements 17. Lev D, Kotilingam D, Wei C, Ballo MT, Zagars GK, Pisters PW, Lazar AA, Patel SR, Benjamin RS and Pollock RE: Optimizing treatment of desmoid tumors. J Clin Oncol 25: 1785-1791, 2007. The current study was supported by a FoRUM grant (grant 18. Schemper M and Smith TL: A note on quantifying follow-up in no. K090-15) from Ruhr-University Bochum (Bochum, studies of failure time. Control Clin Trials 17: 343-346, 1996. Germany). 19. Gronchi A, Colombo C, Le Péchoux C, Dei Tos AP, Le Cesne A, Marrari A, Penel N, Grignani G, Blay JY, Casali PG, et al: Sporadic desmoid‑type bfi romatosis:  A stepwise approach to a  References non-metastasising neoplasm-a position paper from the Italian and the French Sarcoma Group. 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Oncology LettersPubmed Central

Published: Sep 1, 2017

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