|Ahead of print publication
Prognostic factors and clinical course of extremity soft-tissue sarcomas
Gülsen Pinar Soydemir1, Zümrüt Bahat2, Mustafa Kandaz2, Emine Canyilmaz2, Adnan Yöney2
1 Department of Radiation Oncology, Bakirköy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey
2 Department of Radiation Oncology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
Gülsen Pinar Soydemir,
Department of Radiation Oncology, Bakirköy Dr. Sadi Konuk Education and Research Hospital, Istanbul
Source of Support: None, Conflict of Interest: None
Purpose: Although soft tissue constitutes half of the body weight, soft-tissue sarcomas (STSs) are less common than any other types of tumors.
Materials and Methods: In this retrospective study, the prognostic factors and clinical courses of 64 patients with extremity STSs treated at our clinic between 1996 and 2012 were investigated.
Results: Of the 64 patients included in this study, 35 (55%) were male and 29 (45%) were female. By the end of follow-up, 29 (45%) of the patients remained alive while 35 (55%) deceased. The overall survival (OS) time of the patients was 89.1 months, and their 1-, 3-, 5-, and 10-year survival rates were 82.8%, 69.3%, 51.6%, and 39.4%, respectively. Univariate analysis revealed the following variables as prognostic factors: tumor stage (P < 0.001), surgical method applied (P = 0.009), radiotherapy (RT) application (P = 0.018), RT dose (P < 0.001), and development of metastasis during follow-up (P < 0.001). Multivariate analysis revealed only type of surgery to be a prognostic factor (P = 0.016).
Conclusion: Besides surgery, RT plays a crucial role in the multimodal treatment of STSs and increases local control rates and OS. In our study, stage, surgery, and adjuvant RT were found to be effective factors indicating OS. However, more prospective work in this area is necessary.
Keywords: Radiotherapy, soft-tissue sarcoma, survival
| > Introduction|| |
Although soft tissue constitutes half of the body weight, soft-tissue sarcomas (STSs) are less common than any other types of tumors. STS accounts for 0.7% of all adult cancers and 6.5%–15% of cancers in persons aged below 15 years. The incidence of STS in Turkey is 2.8%.
STS originates from primitive, mesodermal structures and presents various histological subtypes., The most common types of STS in adults are malignant fibrous histiocytoma (MFH, 25%), liposarcoma (10%–17%), and leiomyosarcoma (15%). Rhabdomyosarcoma is common in childhood. The disease also has strong links to genetic diseases such as neurofibromatosis type I, Li–Fraumeni syndrome, and Gardner syndrome.
The peak age was generally 40–60 years. STS is commonly found in extremities (55%), trunk (20%), retroperitoneum (15%), and head/neck (10%).,
STS usually manifests as a painless growing mass; only approximately one-third of STS patients report pain. The major treatment modality of STS is surgery. Depending on its grade and the status of the surgical margin, STS may be treated by radiotherapy (RT) and chemotherapy (CT) to increase local control rates. Adjuvant RT aims to maintain local control and organ functions.
Local invasion and recurrence are frequent. Metastasis is often hematogenously and lymphatically localized to lymph nodes, bones, and lung (most distant metastasis area).
| > Materials and Methods|| |
This retrospective clinical study was conducted with due permission from the Ethics Committee at the Faculty of Medicine in Karadeniz Technical University (2013-72). A total of 64 consecutive patients diagnosed with extremity STS, treated by radiation therapy, and followed up at our clinic between 1996 and 2012 were included in this study.
Computed tomography was performed before RT for planning. The mass or mass bed was fused with magnetic resonance imaging (MRI) present before surgery. The three-dimensional conformal RT or intensity-modulated RT techniques were used for diagnosis. RT area, tumor site, incisional scar, and site of drainage, if present, were considered. The radiation dose was 50 Gy. The clinical target volume (CTV) was considered to be 4 cm from the craniocaudal direction and 2 cm from the mediolateral direction onto the tumor (tumor site). The planned target volume (PTV) safety margin was considered to be CTV + 1 cm. To prevent lymphedema and maintain lymphatic circulation in the extremities, 1–1.5-cm portions of the medial or lateral margin were excluded from the treatment area. After application of a radiation dose of 50 Gy, the PTV was established by providing a margin of 2 cm around the tumor (tumor site). Patients with a negative surgical margin were treated with a radiation dose of 60 Gy, while those with a positive surgical margin were treated with a radiation dose of 66 Gy. Patients with gross illness were treated with radiation doses of 70 Gy or more. During RT, 6–18-mV X-rays were used with either photon with Co-60 or linear accelerators. In addition, for some tumors, electron energies of 6–15 MeV were used.
During treatment, the patients were subjected to weekly physical examinations. Complete blood count and biochemical values were checked, and acute side effects were recorded. All patients and regular controls were followed up every 3 months for 2 years, and then every 6 months, and then annually after 5 years. Physical examinations were performed and the treatment area was assessed by MRI.
General survival time was expressed as the time from date of diagnosis to death or date on which the patient data were updated for surviving patients. Disease-free survival time was expressed as the time from date of diagnosis to development of local recurrence and/or metastasis. Survival analysis was performed using the Kaplan–Meier method. The effects of variables with potential prognostic significance to survival were compared using the log-rank test for univariate analysis and Cox regression for multivariate analysis. P ≤ 0.05 was considered statistically significant, and P < 0.01 was considered extremely significant.
| > Results|| |
Sixty-four patients with extremity STS were involved in this study; 35 (55%) were male and 29 (45%) were female. The mean age of the patients was 54.9 ± 19.6 years (range, 15–85 years). The distribution of patients according to their complaint at admission is as follows: mass in 53 (83%) patients, pain in 5 (8%) patients, neurological symptoms in 4 (6%) patients, and other complaints in 2 (3%) patients. In terms of histological type, the most common tumor type was MFH (31%). In terms of clinical stage, the most common stage was stage II (47%). The tumor grades of the patients were as follows: low grade, 27%; moderate grade, 42%; and high grade, 31%. The patient characteristics are summarized in [Table 1].
|Table 1: Patient characteristics and results of log-rank univariate analysis of overall survival|
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Surgery was performed on 63 (98.5%) of the patients. Specifically, subtotal excision was performed on 2 (3%) patients while total excision was performed on 61 (95%) patients. Only diagnostic biopsy was performed on one patient. When the status of the surgical margins of the patients were evaluated, negative margins were found in 16 (25%) patients, positive margins were found in 10 (16%) patients, close margins were found in 16 (25%) patients, and margins of unknown status were found in 22 (34%) patients. One (2%) of the patients did not consent to RT treatment. Only RT was given to 57 (89%) patients, and 6 (9%) patients received CT. RT was used preoperatively in 3 (%5) patients, postoperatively in 36 (56%) patients (1 patient could not complete the treatment), as treatment for local recurrence in 16 (25%) patients, and palliatively in 8 (13%) patients. One (1%) patient was not treated postoperatively. One (1.5%) patient was treated with RT of 8 Gy, 1 (1.5%) patient was treated with RT of 28 Gy (s/he gave up the treatment voluntarily), 6 (9%) patients were treated with RT of 30 Gy, 9 (14%) patients were treated with RT of <60 Gy, 6 (9%) patients were treated with RT of 60 Gy, 26 (41%) patients were treated with RT of 66 Gy, and 14 (22%) patients were treated with RT of >66 Gy.
Of the six patients given CT, 2 (33%) were treated preoperatively, 2 (33%) were treated postoperatively, and 2 (33%) were given for treatment of recurrence. For CT, adriamycin + cyclophosphamide was used for 1 (17%) patient, adriamycin + ifosfamide was used for 2 (33%) patients, and other protocols were used for 3 (50%) patients. Decision of postoperative RT was given in close surgical margin (<2 cm) or + margin. Palliative RT was given to treat the symptoms of patients with stage IV tumors. The treatment features are summarized in [Table 2].
|Table 2: Treatment characteristics and results of log-rank univariate analysis of overall survival|
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Thirty-one of the 64 patients developed local recurrence. The surgical margin was positive in 26% of these patients, close in 16%, negative in 23%, and unknown in 35%. Local recurrence developed in 35% of the high-grade patients, 45% of the moderate-grade patients, and 19% of the low-grade patients. In 3% of the patients, metastasis was present at the time of diagnosis. In 55% of the patients followed up after treatment, distant metastasis had developed.
By the end of the follow-up period, 29 (45%) of the patients remained alive while 35 (55%) deceased. The overall survival (OS) time of the patients was 89.1 months, and the 1-, 3-, 5-, and 10-year survival rates were 82.8%, 69.3%, 51.6%, and 39.4%, respectively [Figure 1].
In terms of gender, the median OS and 1-, 3-, and 5-year survival rates for men were 86.6 ± 12.4 (95% confidence interval [CI]: 62.3–110.9) months and 85.7%, 70.5%, and 51.3%, respectively. For women, the corresponding values were 86.2 ± 12.2 (95% CI: 62.3–110.2) months and 79.3%, 67.6%, and 51.7%, respectively. No statistically significant difference was observed between groups (P = 0.860).
In terms of surgery type, the median OS and 1-, 3-, 5-, and 10-year survival rates for gross total excision were 91.2 ± 9.3 (95% CI: 72.9–109.5) months and 85.2%, 71.0%, 52.9%, and 40.4%, respectively. In patients who had undergone applied subtotal excision, the median OS was 21.5 ± 9.5 months (95% CI: 2.7–40.2) and their 1-year survival rate was 50.0%. No patient lived beyond this point. In patients who underwent biopsy, the median survival time was 9.0 months and no patient lived for the past 1 year. A statistically significant difference was noted in the median survival rates among the three groups (P = 0.009).
In terms of tumor stage, the median OS and 1-, 3-, 5-, and 10-year survival rates for stage I tumors were 81.4 ± 15.1 (95% CI: 51.8–111) months and 93.3%, 70.0%, 54.4%, and 31.1%, respectively. For stage II tumors, the corresponding values were 109.2 ± 13.7 months and 90.0%, 76.1%, 63.6%, and 52.5%, respectively. For stage III, the median OS and 1-, 3-, and 5-year survival rates were 50.6 ± 9.1 months and 70.6%, 64.2%, and 32.1% respectively. No patient who lived for the past 10 years after diagnosis. For stage IV tumors, the median OS was 7 months and no patient lived past for the 1 year after diagnosis. A statistically significant difference was noted in the median survival rates among the four groups (P = 0.001).
During univariate analysis, the variables determined as prognostic factors included stage of tumor (P < 0.001), surgical method applied (P = 0.009), RT application (P = 0.018), RT dose (P < 0.001), and development of metastasis during follow-up (P < 0.001). During multivariate analysis, only type of operation was found to be a prognostic factor (P = 0.016) [Table 3].
Dermatitis was observed in the area of treatment in 54 (84%) patients, and edema in the extremities was found in 3 (5%) patients. Of the 54 patients who developed dermatitis, 17 (31%) had a grade I reaction, 29 (54%) had a grade II reaction, and 8 (15%) had a grade III reaction. As side effects following treatment, fibrosis was found in 28 (44%) patients and lymphedema was determined in 4 (6%) patients.
| > Discussion|| |
Surgical excision is the gold standard for treatment of STS. The aim of the surgical treatment is organ preservation and maintenance of maximum organ function, especially in cases with extremity localization. Addition of RT and CT to wide surgical excision has promoted the development of organ-preserving approaches. While the local recurrence rate is about 60%–90% after gross total tumor resection, it is 15%–30% in radical resection and about 10%–20% in compartmental resection. In case of a positive surgical margin in STS, local control rates can be increased with adjuvant treatment.
That is also clearly revealed in prospective randomized studies in which the effectiveness of adjuvant RT was compared with that of surgery alone and RT given following surgery., In a study conducted by Yang et al., the local control rate was reported to be 95% in group treated with RT, and this rate is reported to be 60% in the control group in low-grade patients (P = 0.016). In general, patient groups on which surgery alone was carried out reported a local recurrence rate of about 30%–50%. With application of RT, these rates decreased to 7%–15% in the general patient population and 20%–25% in head/neck tumors. In our research, the local recurrence rate was found to be 48%. This rate is consistent with the literature.
Marginal excision is not sufficient for the treatment of sarcoma, and local likelihood of local recurrence can be as high as 60%–90%., When an ideal wide surgical margin is obtained, this rate decreases to about 10%., In radical excision, recurrence rates range from 5% to 20%., In our study, local recurrence at the site of operation was observed in 26% of the patients on which total excision was carried out.
Atean et al. found local recurrence rates to be 11.5%. In a study conducted by Pisters et al. comprising 1041 cases, the local recurrence rate was 26%. In our study, 23% patients exhibited local recurrence following RT. This rate was found to be consistent with previous reports in the literature.
Status of the surgical margin is an independent prognostic factor for local control. Eroǧlu et al. found a local recurrence rate of 21.6%. In a study conducted by Youssef et al., local control was found to be 78% in cases with negative and close surgical margins and 52% (P = 0.04) in positive cases. In our study, the finding that local recurrence is not significantly related to the surgical margin may be due to the high ratio of patients with unknown status of the surgical margin.
In many studies, high grades were reported to be a factor determining local recurrence. In our research, local recurrence was found in 19% of the low-grade patients, 45% of the moderate-grade patients, and 35% of the high-grade patients. Although local recurrence was observed more commonly in moderate- and high-grade patients compared with low-grade patients, no statistical significance was determined among these groups.
The effect of tumor size on local control is controversial, and some studies reveal this effect only via univariate analysis, not multivariate analysis. In our study, the effect of tumor size on local control could not be found.
Coindre et al. reported deeper tumoral locations as a negative factor in terms of local control. In our study, when the tumoral location was examined in patients who had developed local recurrence, 45% of the tumors were found to be superficially located while 55% were deeply located. However, no statistical significance influencing survival was found.
In a study conducted by Yıldız et al., no significant effect of local recurrence on survival was revealed. In our study, while the average general survival time was found to be 92.1 ± 13.7 months in patients who did not develop local recurrence, the average general survival time was 84.7 ± 10.7 months in patients who developed local recurrence. No statistically significant difference between groups was found.
Atean et al. reported acute toxicities on the skin of RT-treated patients but did not observe grade IV side effects. In our study, acute dermatitis was found in 84% of the patients and edema on the treated extremities was observed in 5% of the patients. Of the acute dermatitis cases, 31% was grade I, 54% was grade II, and 15% was grade III. As a chronic side effect, fibrosis in 44% of the patients and lymphedema in 6% of the patients were observed.
Metastasis most commonly occurs in the lungs with rates of 65%–70%., The most common subtypes of tumor to metastasize in the lungs are MFH, liposarcoma, and leiomyosarcoma.,, In a study conducted by Billingsley et al., the rate of distant metastasis was 23%, and 73% of the patients who developed metastasis were reported to have pulmonary involvement. In our study, distant organ metastasis developed in 55% of the followed up patients. Of the metastases found, 71% occurred in the lungs, 17% occurred in the bones, 6% occurred in the brain, and 6% occurred in the lymph nodes.
Pisters et al. conducted a study comprising 1041 cases and determined a 5-year survival rate of 76%. In the study conducted by Demiral et al., the 5-year general survival rate was found to be 58%. The average general survival time in our study was 89.1 ± 9.2 months, and the 1-, 3-, and 5-year general survival rates were 82.8%, 69.3%, and 51.6%, respectively.
Kattan et al. postoperatively evaluated 2163 patients in MSKCC and found that histopathological subtype could be a significant determining factor in sarcoma-specific death. When considering the general survival for the most common histological subtypes, the average general survival time for MFH was 90.2 ± 10.6 months, the average general survival time for liposarcoma was 69.7 ± 18.1 months, and the average general survival time for leiomyosarcoma was 92.8 ± 21.1 months. No significant difference among the three groups was found.
Pisters et al. demonstrated a significant relationship between status of the surgical margin and general survival. In our study, no statistically significant difference was found among groups in terms of surgical margin (P = 0.540). The difference between studies may be attributed to incomplete data on the surgical margin of all patients and an insufficient number of cases in this work.
In a study conducted by Gustafson and Arner, the survival time was reported to decrease significantly with increasing tumor stage. In our study, the 5-year general survival time for patients with stage I STS was 54.4% in stage I, that for patients with stage II STS was 63.6%, and that for patients with stage III STS was 32.1%. The average general survival time of patients with stage IV STS was 5.0 months; in fact, no patient with this tumor stage remained alive for the past 1 year after diagnosis. A significant relationship was found between the tumor stage of patients at the time of diagnosis and survival (P < 0.001).
In a study conducted by O'Sullivan et al. that compared preoperative and postoperative RT, preoperative treatment revealed a slightly significant improvement in general survival compared with postoperative treatment. In our study, a statistically significant difference was found between RT type and survival (P = 0.018).
The first study to show that RT dosage was a prognostic factor influencing local control in extremity STSs was reported by the Fox Chase Cancer Center. In our study, the average general survival time of patients treated with RT doses of 30 Gy and less was 26.6 ± 15.5 months, that of patients treated with RT doses of 30–60 Gy was 75.5 ± 4.7 months, that of patients treated with RT doses of 60 Gy was 125.5 ± 16.2 months, that of patients treated with RT doses of 66 Gy was 97.8 ± 10.3 months, and that of patients treated with RT doses of 70 Gy or more was 90.0 months. A statistically significant difference was observed among the treatment groups (P < 0.001).
In a study conducted by Demiral et al., development of distant metastasis was determined to be a prognostic factor that decreased general survival. In our study, the average general survival time among patients without distant metastasis was 149.5 months, and the 5-year general survival rate of these patients was 87.8%. Of the patients with distant metastasis, the average general survival time was 40.7 months, and the 5-year general survival rate was 23.7%. The difference observed between these two groups was statistically significant (P < 0.001).
| > Conclusion|| |
Besides surgery, RT plays a crucial role in the multimodality treatment of STS to increase local control rates and OS. In our study, stage, surgery, and adjuvant RT were found to be effective in OS. However, more prospective work in this area is necessary.
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Conflicts of interest
There are no conflicts of interest.
| > References|| |
Kebudi R, Agaoglu FY. Çocukluk çaǧı rabdomiyosarkoma – dışı yumuşak doku sarkomaları. Klin Gelişim 2007;20:95-108.
Mann GB, Lewis JJ, Brennan MF. Adult soft tissue sarcoma. Aust N Z J Surg 1999;69:336-43.
Salo JC, Lewis JJ, Woodruff JM, Leung DH, Brennan MF. Malignant fibrous histiocytoma of the extremity. Cancer 1999;85:1765-72.
Singer S. Soft tissue sarcomas. In: Townsend CM, Beauschamp RD, Evers BM, Mattox KL, editors. Sabiston Textbook of Surgery. 18th
ed. Philadelphia, PA: Sounders Elsevier; 2007. p. 786-99.
Grimer RJ. On the effect of setting of a positive surgical margin in soft tissue sarcoma. Cancer 2014;120:2803-5.
Pisters PW, Harrison LB, Leung DH, Woodruff JM, Casper ES, Brennan MF. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996;14:859-68.
Yang JC, Chang AE, Baker AR, Sindelar WF, Danforth DN, Topalian SL, et al.
Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16:197-203.
Ozturk R. Cerrahi teknikler. In: Engin K, Saglik Y, Aydinli U, editors. Kemik ve Yumuşak Doku Tümörleri. 1st
edn. Ankara: Derman Publishers; 2005. p. 635-704.
Demiralp B. Soft tissue sarcomas. Turk Klin J Surg Med Sci 2006;2:49-57.
Atean I, Pointreau Y, Rosset P, Garaud P, De-Pinieux G, Calais G. Prognostic factors of extremity soft tissue sarcoma in adults. A single institutional analysis. Cancer Radiother 2012;16:661-6.
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.
Eroǧlu A, Ünal E, Kocaoǧlu H. Soft tissue sarcomas. Turk J Surg 1999;4:237-44.
Youssef E, Fontanesi J, Mott M, Kraut M, Lucas D, Mekhael H, et al.
Long-term outcome of combined modality therapy in retroperitoneal and deep-trunk soft-tissue sarcoma: Analysis of prognostic factors. Int J Radiat Oncol Biol Phys 2002;54:514-9.
Coindre JM, Terrier P, Bui NB, Bonichon F, Collin F, Le Doussal V, et al.
Prognostic factors in adult patients with locally controlled soft tissue sarcoma. A study of 546 patients from the French Federation of Cancer Centers Sarcoma Group. J Clin Oncol 1996;14:869-77.
Yıldız C, Erler K, Bilgiç S, Atesalp AS, Basbozkurt M. The effects of surgical margins on local control and survival in extremity soft tissue sarcomas. Acta Orthop Traumatol Turc 2003;37:359-67.
Billingsley KG, Burt ME, Jara E, Ginsberg RJ, Woodruff JM, Leung DH, et al.
Pulmonary metastases from soft tissue sarcoma: Analysis of patterns of diseases and postmetastasis survival. Ann Surg 1999;229:602-10.
Gadd MA, Casper ES, Woodruff JM, McCormack PM, Brennan MF. Development and treatment of pulmonary metastases in adult patients with extremity soft tissue sarcoma. Ann Surg 1993;218:705-12.
Billingsley KG, Lewis JJ, Leung DH, Casper ES, Woodruff JM, Brennan MF. Multifactorial analysis of the survival of patients with distant metastasis arising from primary extremity sarcoma. Cancer 1999;85:389-95.
Demiral AN, Şen M, Çetinayak O, Bayman E, Havitçioǧlu H, Manisalı M, et al
. Prognostic factors in soft tissue sarcoma patients treated with postoperative radiotherapy. Turk J Oncol 2006;21:119-124.
Kattan MW, Leung DH, Brennan MF. Postoperative nomogram for 12-year sarcoma-specific death. J Clin Oncol 2002;20:791-6.
Gustafson P, Arner M. Soft tissue sarcoma of the upper extremity: Descriptive data and outcome in a population-based series of 108 adult patients. J Hand Surg Am 1999;24:668-74.
O'Sullivan B, Davis AM, Turcotte R, Bell R, Catton C, Chabot P, et al.
Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: A randomised trial. Lancet 2002;359:2235-41.
Fein DA, Lee WR, Lanciano RM, Corn BW, Herbert SH, Hanlon AL, et al.
Management of extremity soft tissue sarcomas with limb-sparing surgery and postoperative irradiation: Do total dose, overall treatment time, and the surgery-radiotherapy interval impact on local control? Int J Radiat Oncol Biol Phys 1995;32:969-76.
[Table 1], [Table 2], [Table 3]