|Year : 2017 | Volume
| Issue : 1 | Page : 321-325
Prognostic factors and treatment of patients with advanced synovial sarcoma: A single-center experience
O Ates1, S Aksoy1, H Yeter2, V Sunar1, N Kertmen1, O Dizdar1, A Turker1, A Kars1
1 Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
2 Department of Internal Medicine, Hacettepe University Cancer Institute, Ankara, Turkey
|Date of Web Publication||1-Dec-2017|
Dr. O Ates
Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara
Source of Support: None, Conflict of Interest: None
BACKGROUND: Synovial sarcoma (SS) is a malignant mesenchymal tumor, which comprises 5%–10% of all the sarcomas. There is insufficient information on prognostic factors and salvage treatments of advanced SS. In this study, we aimed to further clarify the clinicopathological features, prognostic factors, and treatment modalities in advanced SS. MATERIALS AND METHODS: A total of 45 SS patients followed up between 2001 and 2015 at our cancer institute, Department of Medical Oncology, were retrospectively evaluated. Eleven patients were initially metastatic, and remaining patients developed metastasis or became inoperable due to locally advanced disease. Overall survival was evaluated by Kaplan–Meier analysis. RESULTS: The median age of patients was 37 (17–70) years and 60% (n = 26) of them were female. SS was most commonly localized in the lower extremity and abdomen-pelvis (29% and 29%, respectively). Median follow-up time was 33 (6–175) months. Patients were treated with a median of two (1–5) line chemotherapies at metastatic stage. Ifosfamide plus adriamycin (IMA) (49%, n = 22) and cisplatin-etoposide (13%, n = 6) were the most often used chemotherapy regimen as first line in metastatic stage. Partial response was obtained in 32% of the patients treated with IMA chemotherapy. Furthermore, median progression-free survival was 6 (1–123) months. Median survival of metastatic stage at diagnosis or in follow-up was 21 months (14–27) and 21 (12–29) months (P = 0.53), respectively. Most metastatic locations were lung (75%) and bone. Factors influencing survival at metastatic stage were evaluated; statistically significant longer survival was observed in patients with lung metastasis, primary tumor size smaller than 10 cm, patients who underwent surgery for the metastasis, and development-to-metastasis period longer than 12 months. CONCLUSION: Median survival of patients in metastatic stage SS was 21 months. Lung was the most common metastatic site.
Keywords: Chemotherapy, locally advanced, metastasis, prognosis, synovial sarcoma
|How to cite this article:|
Ates O, Aksoy S, Yeter H, Sunar V, Kertmen N, Dizdar O, Turker A, Kars A. Prognostic factors and treatment of patients with advanced synovial sarcoma: A single-center experience. Indian J Cancer 2017;54:321-5
|How to cite this URL:|
Ates O, Aksoy S, Yeter H, Sunar V, Kertmen N, Dizdar O, Turker A, Kars A. Prognostic factors and treatment of patients with advanced synovial sarcoma: A single-center experience. Indian J Cancer [serial online] 2017 [cited 2019 Mar 20];54:321-5. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/321/219551
| » Introduction|| |
Synovial sarcoma (SS) is a malignant mesenchymal tumor, which comprises 5%–10% of all sarcomas. Prognosis of SS is poor due to high risk of local recurrence and metastasis. SS occurs predominantly in the young and middle aged. Furthermore, metastatic disease varies from 10% to 50% at presentation and 40%–60% of the patients develop metastases during the course of the disease., The role of adjuvant and neoadjuvant treatment and also treatment of metastatic disease may positively contribute to survival. SS and liposarcoma are two relatively chemosensitive histologies., Several prognostic factors have been identified such as age, tumor size, surgical margins, and histologic subtype for patients with localized disease. There is a paucity of data on prognostic factors of advanced SS. In this study, we aimed to investigate clinicopathologic characteristics, prognostic factors, and treatment modalities in advanced SS.
| » Materials and Methods|| |
A total of 66 patients diagnosed with SS were retrospectively evaluated in our cancer institute department of medical oncology between 2001 and 2015. A total of 21 patients were excluded from the study because these patients did not have a local or distal recurrence. Advanced disease is defined as metastatic disease or locally recurrent disease, which cannot be completely resected locally. A total of 45 patients were enrolled in the study, 11 of them were initially metastatic, and metastases occurred in 29 of the remaining patients. Patients were evaluated in terms of clinicopathological features and treatment modalities such as adjuvant and metastatic lines. After the adjuvant treatment, all patients were followed with computed tomography of the chest and the abdomen (when needed) every 3–4 months for 2 years and then every 6 months for 5 years. After 5 years, the patients were followed up annually. Survival at metastatic stage was evaluated by Kaplan–Meier analysis. P < 0.05 was considered statistically significant. The response to treatments was radiologically evaluated at 2–3-cycle intervals according to revised Response Evaluation Criteria in Solid Tumors Version (RECIST) version 1.1. And also complete remission, progressive disease (PD), and partial response were defined according to RECIST version 1.1. All statistical analyses were performed using SPSS software version 18 (SPSS Inc., Chicago, IL, USA).
| » Results|| |
The median age of the patients at presentation was 37 (17–70) years. [Table 1] lists the general characteristics of the patients. Sixty percent of the patients (n = 27) were female. A remarkable number of the patients had SS in the lower extremity and abdomen-pelvis (29% and 29%, respectively). Tumor size ranged between 2 and 17 cm with a median of 7 cm. The majority of the patients had T2 (73%) tumor with a lymph node involvement rate of 29%. The rates of Stage 3 and 4 patients were 44% and 25%, respectively. Epithelial membrane antigen and CK immunohistochemically staining were positive in 75% and 56% of the samples, respectively. Translocation t (X: 18) was determined in 11 patients. Biphasic and monophasic subtypes of SS were seen in 10 (22%) each of the patients and also three (n = 7%) patients expressed poorly differentiated types.
Treatment and survival
A total of 38 patients underwent surgery and 14 of these patients had positive surgical margins (microscopic [r1] in nine and macroscopic [r2] in five patients). Adjuvant chemotherapy and radiotherapy were delivered in 56% (n = 19) and 47% (n = 16) of patients, respectively. Fifty percent of those in the chemotherapy group (50%, (n=17)) were treated with ifosfamide plus adriamycin (IMA) combination as adjuvant treatment.
Median follow-up time was 33 (6–175) months. Recurrence occurred in 34 patients, systemic metastasis in 18, and local recurrence only in five patients. Local recurrence with systemic metastasis occurred in 11 patients [Table 1]. Locally recurring tumors were unresectable in six patients. The most frequent metastatic sites were the lung (n = 29, 64%), lymph nodes (n = 3, 6%), and bones (n = 2, 4%) [Table 1]. Furthermore, five (10%) patients had other metastatic sites together with the lung. Resection of the recurrent lesions was done in 22 patients and 10 (29%) underwent metastasectomy. Furthermore, palliative radiotherapy was delivered to nine (20%) patients for recurrent disease. Median overall survival of SS was 48 (26–69) months from diagnosis. Survival rates at 3 and 5 years were 53% and 27%, respectively.
Median survival of patients with metastatic disease at presentation and of those developing metastatic disease later in the follow-up was similar, 21 months (14–27) and 21 months (12–29) (P = 0.53), respectively. Patients with metastases received a median of two (1–5) lines' chemotherapies. The combinations used in the first line consisted of IMA (49%, n = 22) in almost half of the patients, followed by cisplatin-etoposide in 13% (n = 6) and vincristine, adriamycin, and cyclophosphamide (VAC), ifosfamide, mesna, etoposide (IMET) in the rest. Best response achieved with IMA regimen was PR in 7 (32%) patients, standard deviation (SD) and PD were obtained in 4 (18%) and 11 (50%) of the patients, respectively. Median progression-free survival was 6 (1–123) months. Response to cisplatin-etoposide combination was negligible; SD was obtained in 67% (n = 4) and 33% (n = 2) of the patients had PD.
Objective response rate (ORR) in patients treated with nonifosfamide-based regimens was 14%. SD and PD rates were 43% each. There was no statistically significant ORR difference between regimens with/without ifosfamide in the first line.
Pazopanib (15%) and gemcitabine-docetaxel combination (13%) were the most commonly used second-line regimens in the metastatic setting. The PR rate with pazopanib regimen was 29% and 57% and 14% of the patients had SD or PD, respectively. PR, SD, and PD rates were 33%, 50%, and 17% in patients treated with gemcitabine-docetaxel regimen, respectively.
Various factors with an impact on survival of metastatic disease were evaluated by univariate analysis; metastasis to lung, primary tumor smaller than 10 cm, complete resection of the metastatic disease, and development-to-metastasis time longer than 12 months were associated with a longer survival [Table 2]. There was no statistically significant difference in terms of age at diagnosis (<30 vs. ≥30), adjuvant chemotherapy, or radiotherapy implementation including radiation therapy (RT) for local recurrence.
Neoadjuvant chemotherapy was administered to 23% (n = 10) of the patients. Eight patients among them were treated with IMA chemotherapy [Table 1]. Four patients underwent neoadjuvant RT. Surgery was performed in nine patients after the neoadjuvant treatment.
| » Discussion|| |
SS is a rare disease with poor prognosis. Due to its rarity, there exists no consensus, yet on prognostic factors in localized as well as in metastatic SS. In the current study, we retrospectively reviewed the data of 45 patients with advanced SS. In advanced disease, patients with lung metastasis, primary tumor smaller than 10 cm, time-to-metastasis longer than 12 months, and who underwent metastasectomy were found to have longer survival [Table 2].
Metastatic disease varies from 10% to 50% at presentation and total of 40%–60% of the patients develop metastases during the course of the disease., In this study, a total of 11 patients had metastatic disease at presentation (24%) and the remaining 29 patients developed metastatic disease later in follow-up (85%). This was higher than the literature. In our study, median survival of patients with metastatic disease was 21 months. There are conflicting reports in the literature, whereas in earlier studies, median survivals are around 12 months.,, In more recent studies, longer median survivals are reported., This might be explained by surgical interventions for metastases, new radiotherapy techniques, and availability of new drugs (e.g., pazopanib).
Lung was the most common location of metastases for SS patients. This was 75% (n = 34) in our patients. Patients with lung metastases only were reported to have better survival. This finding is in accordance with our study that median survival of patients with lung only metastasis was better compared to other sites (23 vs. 17 months P = 0.04). Pulmonary metastasectomy has generally been observed to prolong the survival; a similar improvement was present in our series., However, this was not confirmed by a larger study.
Local recurrence rate is also high in SS between 10% and 50% in various studies., In our study, local recurrence rate was 47% at a median duration of 12 months. This rate is higher compared to previous reports. This might be explained by the higher rate of positive surgical margins (31%) in our study. Adjuvant radiotherapy and chemotherapy were less commonly delivered in our institute; this may have contributed to the high local recurrence rate.
Patients with a diagnosis to metastasis interval shorter than 12 months had a poor prognosis similar to the previous reports.,,,
Adjuvant chemotherapy reduces local recurrence and metastasis and provides a survival advantage in soft tissue sarcomas (STSs). Chemotherapy options are limited in metastatic STS. SS and liposarcoma are two relatively chemosensitive STS histologies.,,, Ifosfamide, dacarbazine, and doxorubicin have proven activity as monotherapy., Response rate to first-line chemotherapy is approximately 25% in metastatic STS., Karavasilis et al. reported ORR of 33% and 53% in STS and SS, respectively. Attempts to increase the activity with chemotherapy combinations have been disappointing, and an optimal combination is still not defined due to the rarity of the disease. While ORR of doxorubicin and dacarbazine (DTIC) combination was 17%, ORR of doxorubicin, ifosfamide, and dacarbazine combination was 25%. The response rate to cyclophosphamide, vincristine, doxorubicin, and DTIC (cyclophosphamide, vincristine, doxorubicin, and dacarbazine) was 20%, which was equal to single-agent doxorubicin. Combination of mesna, doxorubicin, ifosfamide, and dacarbazine (32%) seems superior to the doxorubicin. In our study, ORR to first-line IMA was 31% in the metastatic setting. Furthermore, ORR of all treatment groups in metastatic stage was 20% (rate of SD was 24%) similar to reports in medical literature. The second-line chemotherapies used in SS had lower activities. There are various studies with different ORR. Response rate of gemcitabine-docetaxel as a second line was reported to 6%–20% in studies involving patients with heterogeneous STS., In patients with SS, second-line gemcitabine-docetaxel ORR was 54%., In our study, ORR to gemcitabine-docetaxel was 33% in second line.
A relatively low number of patients, retrospective design, and intrinsic selection bias are the main limitations of our study. Furthermore, our study groups are nonselective, and chemotherapy regimens delivered to patients are heterogeneous.
| » Conclusion|| |
Median survival of metastatic stage SS was 21 months. Lung was the most common metastatic site. Nonpulmonary metastasis, time to metastasis shorter than 12 months, primary tumor size bigger than 10 cm, and ineligibility to undergo metastasectomy were poor prognostic factors in advanced SS.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Brennan M, Alektiar K, Maki R. Sarcomas of the soft tissue and bone. Cancer: Principles and Practice of Oncology.2001;2:1841-90.
Krieg AH, Hefti F, Speth BM, Jundt G, Guillou L, Exner UG, et al.
Synovial sarcomas usually metastasize after >5 years: A multicenter retrospective analysis with minimum follow-up of 10 years for survivors. Ann Oncol 2011;22:458-67.
Bergh P, Meis-Kindblom JM, Gherlinzoni F, Berlin O, Bacchini P, Bertoni F, et al.
Synovial sarcoma: Identification of low and high risk groups. Cancer 1999;85:2596-607.
Frustaci S, De Paoli A, Bidoli E, La Mura N, Berretta M, Buonadonna A, et al.
Ifosfamide in the adjuvant therapy of soft tissue sarcomas. Oncology 2003;65 Suppl 2:80-4.
Frustaci S, Gherlinzoni F, De Paoli A, Bonetti M, Azzarelli A, Comandone A, et al.
Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: Results of the Italian randomized cooperative trial. J Clin Oncol 2001;19:1238-47.
Van Glabbeke M, van Oosterom AT, Oosterhuis JW, Mouridsen H, Crowther D, Somers R, et al.
Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: An analysis of 2,185 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;17:150-7.
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 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer 2001;91:1914-26.
Bauer HC, Trovik CS, Alvegård TA, Berlin O, Erlanson M, Gustafson P, et al.
Monitoring referral and treatment in soft tissue sarcoma: Study based on 1,851 patients from the Scandinavian Sarcoma Group Register. Acta Orthop Scand 2001;72:150-9.
Ferrari A, De Salvo GL, Dall'Igna P, Meazza C, De Leonardis F, Manzitti C, et al.
Salvage rates and prognostic factors after relapse in children and adolescents with initially localised synovial sarcoma. Eur J Cancer 2012;48:3448-55.
Spurrell EL, Fisher C, Thomas JM, Judson IR. Prognostic factors in advanced synovial sarcoma: An analysis of 104 patients treated at the Royal Marsden Hospital. Ann Oncol 2005;16:437-44.
Pack GT, Ariel IM. Synovial sarcoma (malignant synovioma); a report of 60 cases. Surgery 1950;28:1047-84.
Pastorino U, Buyse M, Friedel G, Ginsberg RJ, Girard P, Goldstraw P, et al.
Long-term results of lung metastasectomy: Prognostic analyses based on 5206 cases. J Thorac Cardiovasc Surg 1997;113:37-49.
Pisters PW, Leung DH, Woodruff J, Shi W, Brennan MF. Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol 1996;14:1679-89.
van Geel AN, Pastorino U, Jauch KW, Judson IR, van Coevorden F, Buesa JM, et al.
Surgical treatment of lung metastases: The European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group study of 255 patients. Cancer 1996;77:675-82.
Trassard M, Le Doussal V, Hacène K, Terrier P, Ranchère D, Guillou L, et al.
Prognostic factors in localized primary synovial sarcoma: A multicenter study of 128 adult patients. J Clin Oncol 2001;19:525-34.
Casson AG, Putnam JB, Natarajan G, Johnston DA, Mountain C, McMurtrey M, et al.
Five-year survival after pulmonary metastasectomy for adult soft tissue sarcoma. Cancer 1992;69:662-8.
Sleijfer S, Ouali M, van Glabbeke M, Krarup-Hansen A, Rodenhuis S, Le Cesne A, et al.
Prognostic and predictive factors for outcome to first-line ifosfamide-containing chemotherapy for adult patients with advanced soft tissue sarcomas: An exploratory, retrospective analysis on large series from the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG). Eur J Cancer 2010;46:72-83.
Verazin GT, Warneke JA, Driscoll DL, Karakousis C, Petrelli NJ, Takita H. Resection of lung metastases from soft-tissue sarcomas. A multivariate analysis. Arch Surg 1992;127:1407-11.
Karavasilis V, Seddon BM, Ashley S, Al-Muderis O, Fisher C, Judson I. Significant clinical benefit of first-line palliative chemotherapy in advanced soft-tissue sarcoma: Retrospective analysis and identification of prognostic factors in 488 patients. Cancer 2008;112:1585-91.
Santoro A, Tursz T, Mouridsen H, Verweij J, Steward W, Somers R, et al.
Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: A randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 1995;13:1537-45.
Kaya AO, Büyükberber S, Ozkan M, Alkis N, Sevinc A, Ozdemir NY, et al.
Efficacy and toxicity of gemcitabine plus docetaxel combination as a second line therapy for patients with advanced stage soft tissue sarcoma. Asian Pac J Cancer Prev 2012;13:463-7.
Schmitt T, Kosely F, Wuchter P, Schmier JW, Ho AD, Egerer G. Gemcitabine and docetaxel for metastatic soft tissue sarcoma – A single center experience. Oncol Res Treat 2013;36:415-20.
Yetisyigit T, Arpaci E, Seber ES, Kucukoner M, Kos FT, Sonmez OU, et al.
Salvage treatment experience in advanced synovial sarcoma: A multicenter retrospective analysis of the Anatolian Society of Medical Oncology. Asian Pac J Cancer Prev 2013;14:5185-8.
[Table 1], [Table 2]