Pan Arab Journal of Oncology

Pan Arab Journal of Oncology Original Article Retrospective Analysis of Clinicopathologic and Management Aspects of Soft Tissue Sarcoma Tarek Hussein Kamel, Azza Mohamed Adel, Reham Mohamed Faheim, Rana Hegazy Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Ain Shams University ABSTRACT Background: Soft tissue sarcomas (STS) are a group of rare aggressive tumors of mesenchymal origin, separated into over 0 different subtypes by histological and molecular classifications. In this analysis we evaluated the clinicopathologic and management aspects of STS. We analyzed the prognostic and predictive factors affecting both OS &PFS. Patients and methods: Medical records of patients with STS were reviewed retrospectively. Overall survival (OS) and progression free survival (PFS) were estimated and factors potentially influencing these outcomes were analyzed. Keywords Clinicopathologic, Soft Tissue Sarcoma, Prognostic Factors Results: The mean age of patients was 4.0 ± 1.9 years (range 16 4 years). Median OS was.6±. months and median PFS was 10. months. Age was assessed as a predictive factor for OS and patients < 0 years had higher median OS (4. months) compared to patients > 0 years old who had median OS (1. months) with no statistically significance (P = 0.069). Also patients 0 years had median PFS (1.1 months vs 10.1 months) in patients 0 years with no statistically significance on PFS. Type of pathology was also highly significantly correlated to overall survival (P = 0.000), liposarcoma had improved OS (4. months)) compared to other histopathological subtypes. However, it showed no statistically significance to PFS (P= 0.06) with higher median PFS in liposarcoma (. months) compared to other histopathological subtypes. Conclusion: Mean age was found to be 4.9 ±1 years old, with type of pathology. Histopathological subtypes and disease status were assessed as predictive and prognostic factors and were found to be highly correlated to OS. Effect of RTH on OS and PFS is well noted Introduction Soft tissue sarcomas (STS) are a group of rare aggressive tumors of mesenchymal origin, separated into over 0 different subtypes by histological and molecular classifications (1). Treatment planning involving surgeons, radiation oncologists, and medical oncologists with experience in treating sarcoma patients should be the standard of care Chemotherapy is the mainstay of treatment for patients with unresectable metastatic disease, and is usually administered with palliative intent. Although postoperative radiation therapy is not proven to improve the survival, a recent analysis of the Surveillance, Epidemiology and End Result (SEER) noticed survival outcome improvement in patients with high-grade tumors, treated with this combined modality (). 1

Patients and methods Medical records of all patients with histologically confirmed soft tissue sarcoma at clinical oncology department of Ain Shams University between 011 and 017 were retrospectively reviewed, Ninety-Two patients were retained in this analysis. Histological subtypes were pooled for analysis into liposarcoma, leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma (UPS) or other subgroups. Gender, age, tumor grade, histological subgroup, primary tumor site involvement and site of metastases (liver, lung, bone and other ) were assessed as predictive & prognostic factors for OS & PFS. The end points of this study were Overall survival(os) which was defined as the time interval between the date of diagnosis either by biopsy or wide local excision and death due to any cause or last follow up, and Progression free survival (PFS) which was defined as the time interval between the date of definitive surgery and the date of first relapse or metastasis. Results Patients Characteristics As regard age of patients 9 patients were found to be 0 years old, 1 patients were 0 years old, with range of age between 16 4 years. 49 patients (.%) was found to have Extremity STS, patients (.6%) with head and neck,17 patients with trunk (1.4%), patients with retroperitoneal STS (.6%), patients with chest STS (.6%), patients with visceral STS (.1%). Tumor grade was 10. % for GI, 1.% GII and 7.6% for GIII. In this series 4 patients had liposarcoma (6.1%), 1 patients with leiomyosarcoma (1%), 11 patients with spindle cell sarcoma NOS (1%), patients with Dermatofibrosarcoma protuberance (.7%), patients with synovial sarcoma (.4%), and patients with other histological subtypes (4.7%). Localized disease was found in 64 patients (69.6%), patients were metastatic (0.4%) with the lung being the most common site of metastasis (1 patients), patients had locally recurrent disease Treatment Characteristics Most patients had wide local excision (77.1%) with 7% had adequate margin, 1 patients had no surgery only biopsied, patients had amputation and only one patient had palliative surgery. EBRT was delivered to 49 patients (. %) received with dose ranging from 0 to 66 Gy. Two patients (4 %) received preoperative RTH, 4 (69.%) patients had post-operative RTH,1 patients (6.7%) received palliative RTH either to bone or brain. Most of the patients received DCRT, few people received D. Energy was missed from patients files. CTH was delivered to 9 patients (1.%). All of 9 patients received 1 st line regimen, 17 patients (.6%) received second line and 9 patients (1%) received third line Age 0 0 Range Gender Female Male Comorbidities Yes No FH First degree Second degree NO FH Table 1. Patients Characteristics Tumor Site Extremities Head & Neck Trunk Retroperitoneal Chest Visceral Histological Subtype Liposarcoma Leiomyosarcoma Spindle Cell Sarcoma NOS Dermatofibrosarcoma protuberance Synovial Sarcoma Others Grade I II III Stage I II III IV NA Histological Subtype Liposarcoma Leiomyosarcoma Spindle Cell Sarcoma NOS Dermatofibrosarcoma protuberance Synovial Sarcoma Others Classification Localized Metastatic Synchronous Lung Bone Brain Liver Other Metachronous Lung Bone Brain Liver Other Locally recurrent 9 1 16 4 41 1 1 71 49 17 4 1 11 10 9 1 4 4 1 11 64 14 10 6 14 11 4 44... 77......6 1.4.6.6.1 6.1 1.0 1.0.7.4 4.7 10. 1. 7.6 14.1.9 7. 0.4 4. 6.1 1.0 1.0.7.4 4.7 69.6 0.4 0 71.4 1.4.7 7.1 4. 46.4 7. 1.4 14.. 1.4 SD= Standard Deviation, FH = Family History, NOS= Not Otherwise Specified

Table. Summarize lines of treatment used Line of treatment Surgery NO WLE Amputation Palliative RTH Pre-op Post-Op Palliative CTH 1st Line nd line rd line Type of CTH UK Single Combination No of patients 1 71 1 49 4 1 9 9 17 9 1 11 (%) 16. 77.1.4 1.. 4 69. 6.7 1. 100.0.6 1.0.40 7.90 79.0 10.0 Targeted WLE= Wide local excision, RTH= Radiotherapy, Pre-op= preoperative, Post-op= postoperative, CTH= Chemotherapy, UK= Unknown Disease outcome and patient survival In our series OS and PFS were calculated to patients, the median OS was.6±. months. Median PFS was 10. months. Prognostic & Predictive Factors Many factors were tested to find out if they can potentially influence OS and PFS. Discussion e In our series, a total of patients with STS were included in, clinico-pathological data were investigated and reported in our results, many variables were evaluated as prognostic and predictive factors and correlated with overall survival and progression free survival. In our analysis, the mean age was (4. ± 1.9) with range (16-4 years). Median OS was.6±. months and median PFS was 10. months. Age was assessed as a predictive factor for OS and patients < 0 years had higher median OS (4. months) compared to patients > 0 years old who had median OS (1. months) with no statistically significance (P = 0.069) this is due to limited number of patients. Also patients 0 years had median PFS (1.1 months vs 10.1 months) in patients 0 years with no statistically significance on PFS. Type of pathology was also highly significantly correlated to overall survival (P = 0.000), liposarcoma had improved OS (4. months)) compared to other histopathological subtypes. However, it showed no statistically significance to PFS (P= 0.06) with higher median PFS in liposarcoma (. months) compared to other histopathological subtypes. In EORTC series of,1 patients with follow-up data, the median survival time was 1 weeks. A univariate analysis demonstrated a highly significant favorable prognostic value of young age, good performance status, absence of liver and bone metastases, low histopathologic grade. Patients with liposarcoma and those with synovial sarcoma had a significantly better survival time (Van Glabbeke et al, 1999). Although tumor grade is well known as a determinant factor of PFS. In our series tumor grade was evaluated in relation to OS & PFS and was found to be non-significant (P= 0.716& 0.47). (Coindre JM, et al 001), This could be attributed to most of patients in our analysis had high-grade tumors. In our analysis, type of surgery was correlated to OS and those patients who had WLE had better overall survival (.months) compared to those who didn t do surgery (7.1 months) with non -significant (P = 0.09) this is probably due to higher number of patients underwent WLE in contrast to no surgery and this emphasis the effect of limb sparing surgery on OS. Figure 1. Kaplan Meier Plot of OS & PFS in months. Extent of surgical margins was evaluated as predictive factor on OS, patients with inadequate margins had OS (47.6 months vs 0.4 months) in patients with adequate margins but with statistically not significant (P= 0.47). Also this is due lower number

Age (yrs) Total No. Table. Predictive Factors Analysis for OS OS 9% Confidence Interval Log rank test (months) Median Lower Bound Upper Bound X P-value Sig. < 0 yrs 4.00 7.40 7.1 > 0 yrs 40 1.00.000 7.46 Gender Female 41.0 0.1 46.4 Male 1 1.10.74 7.6 Comorbidities No 71 7.00.466 46.4 Yes 1 14.00.000 9.191 Site Extremities 49 7.00.616 1.4 Head & Neck 7 47.470 - - Trunk 17 0.470 1.90 4.0 Retroperitoneal 4.000.000 14. Visceral 14.00 - - Chest 9.70 4.79 14.61 Margin Adequate 4 0.470 1.74 9.16 Inadequate 11 47.670.967 69.7 NA 7 - - LNs No 1.600.97 4. Yes 11.0.764 7.96 Grade I 11 47.470 9.4 6.616 II 9 Not reached Synovial Sarcoma Not reached - - Others.0 4.4.06 S= Significant, NS= Non-Significant, HS= Highly Significant of patients and lack of documentation of surgical margins details www.amaac.org Atean et al. reported that the extent of free resection margin Pan Arab Journal of Oncology/Supplement /November 01 4 - - III 0.470 4.19 6.71 Pathology Liposarcoma 4 4.00 1.460 6.140 Spindle Cell Sarcoma NOS 11.100.6 10.64 Leiomyosarcoma 1 9.70 0.000 1.76 DFSP 1.0 0.000 4.744.1 0.069 NS.097 0.14 NS 1.164.1 NS.7 0.741 NS 0.16 0.47 NS 0. 0.1 NS 0.667 0.716 NS. 0.000 HS

Table. Predictive Factors Analysis for OS continued d Classification Metastatic.40.000 6.996 Localized 64.600 0.660 0.40 Metastatic Synchronous 14 7.170 4.717 9.6 Metachronous 14 47.670 4.741 60.99 Surgery Biopsy only 16 7.170.04 11.9 WLE 71.0 7.69 49.41 Amputation 1.00.0 4.10 RTH No 4 10.100 4.4 1.76 Yes 49 47.470 4.66 70.74 CTH Total No. No 6 0.470 9.6 1.7 Yes 9.0 6.10 0.0 S= Significant, NS= Non-Significant, HS= Highly Significant OS 9% Confidence Interval Log rank test (months) Median Lower Bound Upper Bound X P-value Sig. 0.44 0.06 NS e 11.1 0.001 S 4.7.09 NS f 17.71 0.000 HS 1.6 0.66 NS is related to the outcome (DSS and DFS). The impact of resection margin status on local control was demonstrated by other investigators. However, the effect of positive margin and local recurrence as independent prognostic factors for metastasis-free survival and OS is still a matter of debate (Pisters PW, et al 1996). In contrast, recent reports argued that surgical excision with negative margins not only improves local control but also enhances OS (Dickinson I.C, et al 006). Our results also showed that patients who received RTH had better overall survival (47.4 months vs 10.1 months) in those who didn t receive (P = 0.000), also the effect of RTH on PFS was addressed and patients who received RTH had better PFS than those who didn t (14. months vs months) with statistically significant P= 0.00). In 010 SEER analysis was conducted to determine the effect of radiation therapy on overall survival among patients with primary soft tissue sarcomas, of this cohort 47 % of patients received RTH the -year overall survival was 7% in patients who received radiation therapy vs. 6% for those who did not receive radiation therapy (p < 0.001) (Koshy M, et al 010). As regard CTH either single or combination, our analysis showed that patients who received CTH showed median survival (. months vs 0.4 months) in those who didn t receive CTH with no statistically significance (P= 0.66)). Also CTH didn t show any statistically significance when correlated to PFS (median PFS 7.1 months vs 1.1 months in patients who didn t receive; P= 0.0) this can be justified by the lack of details on response after each CTH line and the each progression happened after. In a randomized control phase III trial assessing whether dose intensification of doxorubicin with ifosfamide improves survival of patients with advanced soft-tissue sarcoma compared with doxorubicin alone (Judson I, et al 014). There was no significant difference in overall survival between groups (median overall survival 1 months in the doxorubicin group vs 14 months in the doxorubicin and ifosfamide group; p=0 076). Median PFS was significantly higher (7 4 months for the doxorubicin an ifosfamide group vs 4.6 months for the doxorubicin group; p=0 00). More patients in the doxorubicin and ifosfamide group than in the doxorubicin group had an overall response rate (6% vs 14%; p<0 0006) (Judson I, et al 014).

Age (yrs) < 0 yrs 1.170.9 0.4 > 0 yrs 40 10.100 6.1 1. Gender Female 41 17.70 6.66.174 Male 1 10.100 7.0 1.9 Comorbidities No 71 10.0 7.44 1.6 Yes 1 9.10 0.000 4.60 Site Extremities 49 11.100.9 19.4 Head & Neck 7 7.100 1.64 1.66 Trunk 17 14.0 7.044 1.616 Retroperitoneal 4.000 0.000 14. Visceral.070 - - Chest 6.000 1.7 10.4 Margin Adequate 4 1.10 0.664.96 Inadequate 11.470.000 1.94 NA 7 - - - LNs No 1 1.10 7.60 16.900 Yes 11 6.100.67. Grade I 11 17.70.79 1.61 II 9 11.100 4.10 1.00 III 10.100 6.01 1.99 Pathology Total No. Table 4. Prognostic Factors Analysis for PFS Liposarcoma 4.00.000 46.71 Spindle Cell Sarcoma NOS 11 6.100 1.09 11.111 Leiomyosarcoma 1.070 0.000 11.09 DFSP 9.100.7 1.7 Synovial Sarcoma 6.400 1.7 10.96 Others 16.70 10.967 1.7 S= Significant, NS= Non-Significant, HS= Highly Significant OS 9% Confidence Interval Log rank test (months) Median Lower Bound Upper Bound X P-value Sig. 1.49 0. NS 1.614 0.04 NS 0.01 0.914 NS.9 0.0 NS 0.6 0.67 NS.76 0.016 NS 1.07 0.47 NS 11.90 0.06 NS 6

Classification Metastatic 6.100.44.6 Localized 64 16.70.9.947 Metastatic Metachronous 14 10.00 1.19.07 Synchronous 14.000 7.707 1.69 Surgery Biopsy only 16.00 0.0 10.0 WLE 71 14.0 6.94 1.676 Amputation.100.000 1.047 RTH No 4.00 0.000 11.747 Yes 49 14.0 9.174 19.46 CTH Table 4. Prognostic Factors Analysis for PFS continued Total No. No 6 1.170 4.1 0.14 Yes 9 7.170 4.66 9.67 S= Significant, NS= Non-Significant, HS= Highly Significant d OS 9% Confidence Interval Log rank test (months) Median Lower Bound Upper Bound X P-value Sig. 10.07 0.00 S.67 0.067 NS 17.06 0.000 HS 9.97 0.00 S.909 0.0 NS e f In 017 a subgroup analysis a subgroup analysis of the EORTC 601 study, a Phase III trial of doxorubicin versus doxorubicin ifosfamide chemotherapy in 4 patients with advanced soft tissue sarcoma (STS). Analysis of the main study showed that combination chemotherapy improved tumor response and progression-free survival, but differences in overall survival (OS) were not statistically significant. The study analyzed factors prognostic for tumor response and OS, and assessed histological subgroup and tumor grade as predictive factors to identify patients more likely to benefit from combination chemotherapy (RJ Young, et al 017). Conclusion Soft tissue sarcoma is a heterogeneous group of rare tumors, a total of patients were analyzed between 011 to 017. Median age was found to be 4.9 ±1 years old, with median OS was.6±. months and median PFS was 10. months. Histopathological subtypes and type of metastasis were assessed as prognostic factors and were found to be highly correlated to OS. Tumor grade is a strong predictor for PFS but our series showed no significance, possibly due to more number of high grade tumors. Effect of RTH on OS and PFS is well noted. Extent of surgical margin could be a predictive factor for OS and also Prognostic factor of PFS. References 1. Fletcher CDM, Bridge JA, Hogendoorn PCW, et al. WHO classification of tumours of soft tissue and bone. 4th ed. Lyon: IARC; 01.. Koshy M, Rich SE, Mohiuddin MM. Improved survival with radiation therapy in high-grade soft tissue sarcomas of the extremities: a SEER analysis. Int J Radiat Oncol Biol 7

Phys 010; 77: 0 9.. Van Glabbeke M1, van Oosterom AT, Oosterhuis JW, Mouridsen H, Crowther D, Somers R, Verweij J, Santoro A, Buesa J, Tursz T. Prognostic Factors for the Outcome of Chemotherapy in Advanced Soft Tissue Sarcoma: An Analysis of,1 Patients Treated With Anthracycline- Containing First-Line Regimens A European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol. 1999; 17(1):10-7. 4. Coindre JM, Terrier P, Guillou L, Le Doussal V, Collin F, Ranchère D, et al. Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 140 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer 001; 91:1914 6.. Pisters P, Leung D, Woodruff J, Shi W, Brennan M. Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol 1996; 14: 1679 9. 6. Dickinson IC, Whitwell DJ, Battistuta D, Thompson B, Strobel N, Duggal A, et al. Surgical margin and its influence on survival in soft tissue sarcoma. ANZ J Surg 006; 76:104 9. 7. Judson I, Verweij J, Gelderblom H, Hartmann JT, Schöffski P, Blay JY, Kerst JM, Sufliarsky J, Whelan J, Hohenberger P, Krarup-Hansen A, Alcindor T, Marreaud S, Litière S, Hermans C, Fisher C, Hogendoorn PC, dei Tos AP, van der Graaf WT. European Organisation and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first -line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase trial. Lancet Oncol. 014; 1(4):41-.. Robin J. Young, Saskia Litière, Michela Lia, Pancras C.W. Hogendoorn, Cyril Fisher, Gunhild Mechtersheimer, Søren Daugaard, Raf Sciot, Françoise Collin, Christina Messiou, Viktor Grünwald, Alessandro Gronchi, Winette van der Graaf, Eva Wardelmann & Ian Judson (017) Predictive and prognostic factors associated with soft tissue sarcoma response to chemotherapy: a subgroup analysis of the European Organisation for Research and Treatment of Cancer