Treatment results and prognostic factors in patients

ORIGINAL ARTICLE

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Treatment Results and Prognostic Factors in Patients with Malignant Fibrous Histiocytoma Hsuan-Chih Hsu, Eng-Yen Huang and Chong-Jong Wang From the Department of Radiation Oncology, Chang Gung Memorial Hospital-Kaohsiung, Taiwan

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Correspondence to: Hsuan-Chih Hsu, Department of Radiation Oncology, Chang Gung Memorial Hospital, 123, Ta-Pei Rd, Niao Sung Hsian, Kaohsiung Hsien, Taiwan. Tel: 886-7-7317123 ext. 2600. Fax: 886-7-7322813. E-mail: [email protected]

Acta Oncologica Vol. 43, No. 6, pp. 530 /535, 2004 The objective of this study is to investigate the treatment results, prognostic factors, the role of postoperative radiotherapy, and the usefulness of American Joint Committee on Cancer (AJCC) Staging System (2002) for soft tissue sarcomas in malignant fibrous histiocytoma (MFH). Between November 1987 and December 2000, 76 patients with localized MFH underwent surgery as the primary treatment modality with or without radiotherapy in our institution and were reviewed retrospectively. Patients with regional nodal disease, distant metastases or retroperitoneal disease were excluded from our study. All patients had at least 27 months of follow-up. The 5-year overall survival rate, local control rate, and distant metastasis-free rate were 74), 62), and 87), respectively. In multivariate analysis, AJCC 2002 staging system was the only independent prognostic factor for overall survival rates (p/0.0017). Postoperative radiotherapy was the only significant factor for local control rates (p /0.0024). In conclusion, staging system is a prognostic predictor for overall survival rates and postoperative radiotherapy can improve local control. However, the optimal adjuvant treatment strategy for MFH should still be further explored. Received 2 February 2004 Accepted 8 June 2004

The term ‘soft tissue sarcoma (STS)’ refers to a group of rare malignant neoplasms that arises in the extraskeletal connective tissue (1). However, more than 30 different histologic types of STS have been identified, and the clinical presentation and behavior of each histologic type can vary. In 1964, O’Brien and Stout first recognized malignant fibrous histiocytoma (MFH) as a histologically distinctive type of sarcoma (2). Since the clinicopathologic features of this tumor have been defined, MFH has become the most common type of STS diagnosed in most cancer centers (3 /6). Nevertheless, there have been relatively few studies that examine this type of sarcoma specifically. In the past, adjuvant postoperative radiotherapy has been widely used in MFH but the role of radiotherapy has not been well established. In this study, we retrospectively reviewed the experience of patients with MFH treated at our hospital and wanted to evaluate the treatment results, prognostic factors, role of radiotherapy, and the usefulness of the American Joint Committee on Cancer (AJCC) Staging System (2002) for STS in this disease.

# Taylor & Francis 2004. ISSN 0284-186X DOI: 10.1080u02841860410018421

MATERIAL AND METHODS Patient characteristics Between November 1987 and December 2000, 76 patients with localized MFH underwent surgery as the primary treatment modality with or without radiotherapy in our institution and were analyzed retrospectively. No patient received chemotherapy before or after operation. Patients with regional nodal disease, distant metastases, or retroperitoneal disease were excluded from our study. All retroperitoneal cases were excluded because of their known different behavior and poor outcome in view of their locally advanced presentation. There were 40 men and 36 women (Table I). The age ranged from 18 to 83 years, with a median of 52 years.

Staging Tumors were staged according to the AJCC Staging System (2002) for STS (Table II) (7). The distribution of the 76 patients according to the staging system was as follows: 27 Stage I, 28 Stage II and 21 Stage III (Table I).

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Acta Oncologica 43 (2004)

Malignant fibrous histiocytoma

531

Table I Patient and tumor characteristics by treatment Characteristic

Total Patient no.


Surgery only ()) Surgery/RT ()) p-value Gender Male Female

40 36

23 (51)) 22 (49))

17 (55)) 14 (45))

0.749

Age (yrs) 5/52 /52

38 38

22 (49)) 23 (51))

16 (52)) 15 (48))

0.815

Location Non-extremity 34 Extremity 42

22 (49)) 23 (51))

12 (39)) 19 (61))

0.380

Size (cm) 5/5 5 /10 ]/10

41 21 14

22 (49)) 17 (38)) 6 (13))

19 (61)) 4 (13)) 8 (26))

0.045a

Depth Superficial Deep

25 51

14 (31)) 31 (69))

11 (36)) 20 (64))

0.690

Grade Low High

27 49

21 (47)) 24 (53))

6 (19)) 25 (81))

0.014a

Stage I II III

27 28 21

21 (46)) 12 (27)) 12 (27))

6 (19)) 16 (52)) 9 (29))

0.030a

Surgical margin Negative Positive

61 15

36 (80)) 9 (20))

25 (81)) 6 (19))

0.945

a

Statistically significant.

Surgery and pathologic characteristics All patients underwent complete gross resection of tumor. The specimens relating to the surgical margins were evaluated by pathologists at our hospital. Fifteen patients

(20)) had histologically confirmed positive resection margins. Tumors were diagnosed by the histological criteria for MFH, which have been reported elsewhere (2, 8 /14). A careful pathologic review was carried out to confirm this

Table II American Joint Committee on Cancer Staging System for soft Tissue Sarcomas (2002) T1a T1b T2a T2b N0 N1 M0 M1 G1 G2 G3 G4 Stage Stage Stage Stage

Tumor 5/5 cm in greatest dimension, not involving superficial fascia Tumor 5/5 cm in greatest dimension, deep to or involving superficial fascia Tumor /5 cm in greatest dimension, not involving superficial fascia Tumor /5 cm in greatest dimension, deep to or involving superficial fascia No regional lymph node metastases Regional lymph node metastases No distant metastases Distant metastases Well differentiated Moderately differentiated Poorly differentiated Undifferentiated I T1a, 1b, 2a, 2b N0 M0 G1 /2 G1 Low G2 /3 High II T1a, 1b, 2a N0 M0 G3 /4 III T2b N0 M0 G3 /4 G2 /3 High IV Any T N1 M0 Any G Any G High or low Any T N0 M1 Any G Any G High or low

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H. C. Hsu et al.

histological diagnosis. Low grade corresponds to G1uG2, and high grade corresponds to G3uG4. Low-grade lesions were found in 27 patients (36)) and high-grade lesions were found in 49 patients (64)) (see Table I).


radiation dose (]/61.2 Gy vs. B/61.2 Gy) were evaluated in univariate analysis. The differences between curves were assessed by using the log rank test (17). Multivariate analysis was done by the methods of Cox (18).

Tumor location and tumor characteristics


Tumors were located on the upper extremity in 12 patients (16)), the lower extremity in 30 patients (40)), head and neck in 11 patients (14)), trunk in 11 patients (14)), pelvis in 6 patients (8)), and others in 6 patients (8)). Tumor size was 5/5 cm in 41 patients (54)), between 5 cm and 10 cm in 21 patients (28)) and ]/10 cm in 14 patients (18)). Tumors were located superficial to the investing muscular fascia in 25 patients (33)) and deep to or involving it in 51 patients (67)) (Table I). Radiotherapy There was no consensus on the indication for postoperative radiotherapy for patients with MFH at our hospital. It depended on the decisions of different surgeons. Thirty-one of the 76 patients (41)) were treated with megavoltage equipment, including 60Co gamma rays, 6 /10 MV photons or 9 /15 MeV electrons combined with surgery. Radiation techniques were dependent on the location and size of disease. The irradiated fields encompassed the tumor bed with a generous margin 5 cm to 7 cm superior and inferior and 2 cm to 3 cm laterally. No attempt had been made to encompass the entire muscle or anatomical compartment. The radiation dose ranged from 46.8 to 66.6 Gy, 1.8 /2 Gy per fraction, with a median dose of 61.2 Gy. Duration of the external beam ranged from 37 /73 days (median 55 days). The interval between surgery and the start of radiation ranged from 21 to 80 days (median 33 days). Follow-up Patients had follow-up in the Radiation Oncology Department at 1 /3 month intervals during the first 2 years and every 4 /6 months between the second and fifth posttreatment years; after 5 years, patients were seen annually. All patients had at least 27 months of follow-up. The range of follow-up for all patients was 27 /188 months (median, 93 months). Statistics The balance between patient and tumor characteristics for various groups of patients was evaluated with the x2uFisher’s exact test (15). We retrospectively evaluated overall survival rate, local control rate, and distant metastasis-free rate that were determined by the Kaplan /Meier method (16). Several prognostic factors including gender, age, tumor location (non-extremity vs. extremity), tumor size (5/5 vs. 5 /10 vs. ]/10), depth (superficial vs. deep), grade (low vs. high), stage (stage I vs. II vs. III), surgical margins (negative vs. positive), radiation (yes vs. no), and

RESULTS The 76 patients who had complete surgical resection of MFH were analyzed for several factors, including patient and tumor characteristics, surgical findings, and pathological assessments (Table I). The data were displayed with regard to whether or not adjuvant radiotherapy was administered, because there were two principal treatments administered in this series, that is, ‘surgery alone’ versus ‘surgery and radiotherapy’. As shown in Table I, the two groups were well balanced with regard to gender, age, depth, surgical margins, and tumor locations. The most notable difference between these two groups was the tendency for patients receiving irradiation to have a more advanced stage, a factor of definite prognostic significance (Table III). Overall survival rate The 5-year overall survival rate for the all series was 74). In univariate analysis, grade, stage, and radiation dose were significant factors. The respective 5-year overall survival rates were 88) and 62) for low grade and high grade tumor (p /0.0244); 88), 79) and 54) for patients with stage I, II and III (p /0.0008); 79) and 57) for patients receiving radiation dose ]/61.2 Gy and B/61.2 Gy (p /0.0274) (Table III). The other prognostic factors did not significantly impact on overall survival rates. Multivariate analysis. All prognostic factors were tested by a Cox regression analysis. Only stage (I vs. II vs. III) (OR 2.65, 95) CI 1.44 /4.88, p/0.0017) was found to significantly influence overall survival rates (Table IV). Local control rate Of 76 patients, 28 patients (37)) had local failures. The median time for developing local recurrence was 22 months (range: 4 /124 months). Isolated local recurrences were observed in 22 patients (29)), isolated metastatic disease without local recurrence in 4 patients (5)), and combined local and metastatic disease in 6 patients (8)). The 5-year local control rate for all patients was 62). In univariate analysis, irradiation was the only significant prognostic factor in local control. The respective 5-year local control rates were 64) and 60) for low grade and high grade tumor (p /0.9203); 64), 67), and 51) for patients with stage I, II and III (p /0.4901); 85) and 44) for patients receiving irradiation and not receiving irradiation (p /0.0011) (Fig. 1) (see Table III). Multivariate analysis. Only radiation (yes vs. no) (OR 0.25, 95) CI 0.10 /0.61, p/0.0024) was found to significantly influence local control rates (see Table IV).



533

Table III The results of univariate analysis in different prognostic factors Variables

End point


Overall survival Local control Distant metastasis free (p-value) (p-value) (p-value) Gender (male vs. female) Age ( 5/52 vs. /52) Location (Non-extremity vs. extremity) Size ( 5/5 vs. 5 /10 vs. ]/10) Depth (superficial vs. deep) Grade (low vs. high) Stage I vs. II vs. III Margin (negative vs. positive) RT (yes vs. no) Dose (]/61.2 Gy vs. B/61.2 Gy)

0.9961 0.3464 0.5902

0.7468 0.6840 0.3288

0.5537 0.7665 0.2520

0.1512 0.0511 0.0244a 0.0008a 0.3143 0.2489 0.0274a

0.3021 0.0532 0.9203 0.4901 0.2971 0.0011a 0.1928

0.0317a 0.0149a 0.6519 0.0170a 0.1158 0.6601 0.1955

a


Distant metastasis-free rate All patients had the 5-year distant metastasis-free rate of 87). Univariate analysis revealed significant correlation for tumor size, depth, and stage. The respective 5-year distant metastasis-free rates were 97), 76), and 74) for tumor size 5/5 cm, 5 /10 cm, and ]/10 cm (p /0.0317); 100) and 81) for patients with superficial and deep tumor (p /0.0149); 92), 96), and 67) for patients with stage I, II and III (p /0.0170) (Table III). Multivariate analysis. No prognostic factor was found to significantly influence distant metastasis-free rate (see Table IV). To date, distant metastases have developed in 10 patients (13)). Only one of the 10 patients had multiple distant metastatic sites including lung and brain. Lung metastases were the most common and occurred in 8 of 10 patients (80)). Bone metastasis occurred in one patient and one patient developed liver metastasis. The discovery of distant

metastases after treatment ranged from 7 to 76 months (median, 13 months). DISCUSSION In our retrospective study, 76 patients with localized MFH underwent surgery as the primary treatment modality with or without radiotherapy. No patients received chemotherapy. The 5-year overall survival rate, local control rate, and distant metastasis-free rate were 74), 62), and 87), respectively. Our treatment results are in accord with the study by Pezzi et al., in which the 5-year survival rate was 67.2) and local control rate was 72) (19). On reviewing the literature, few studies reported information on the management of MFH although it had become the most common subtype of STS in most cancer centers. In 2002, Belal et al. (20) reported 92 patients with localized MFH who underwent surgery as the primary treatment modality with or without (pre- or postoperative) RT anduor

Table IV The results of multivariate analysis in different prognostic factors Variables

End point Overall survival Local control Distant metastasis free (p-value) (p-value) (p-value)

Gender (male vs. female) Age ( 5/52 vs. /52) Location (Non-extremity vs. extremity) Size ( 5/5 vs. 5 /10 vs. ]/10) Depth (superficial vs. deep) Grade (low vs. high) Stage I vs. II vs. III Margin (negative vs. positive) RT (yes vs. no) Dose (]/61.2 Gy vs. B/61.2 Gy) a


0.8426 0.3538 0.6391

0.9009 0.8621 0.2767

0.3815 0.5738 0.6421

0.6644 0.2838 0.6423 0.0017a 0.5532 0.5413 0.7359

0.2000 0.0513 0.2133 0.1468 0.0774 0.0024a 0.4544

0.0866 0.9604 0.9574 0.8741 0.3370 0.5490 0.8548

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H. C. Hsu et al.


1.0

Local control rate

0.8

0.6

Post−op RT (+)

0.4

p = 0.0011

0.2 Post−op RT (−) 0.0 0

24

48

72

96

120

144

168

192


Months

Fig. 1. Local control rates according to postoperative radiotherapy status.

chemotherapy. The data showed that the use of adjuvant RT (pre- or postoperative) was associated with a decreased risk of local recurrence but no survival benefits. In our retrospective study, postoperative RT could improve local control rates in univariate (p /0.0011) and multivariate analysis (p /0.0024) even though there was a tendency for the postoperative RT group to have a more advanced stage. Therefore, we confirmed the role of postoperative RT in improving local control but the benefits in increasing overall survival rates and distant metastasis-free rates were worthy of further investigation in randomized trials. With regard to the postoperative radiation dose for STS, many centers consider 60 Gy as a standard treatment dose (21). In 2002, Belal et al. (20) reported that radiation dose ]/50 Gy was significant factor for relapse-free survival in univariate (p /0.0004) and multivariate analysis (p /0.0005). In the current study, univariate analysis revealed that patients who received 61.2 Gy or more have better overall survival rates compared with those who received less than 61.2 Gy (p /0.0274). We could not make any conclusions about optimal radiation dose in so few cases. In previous studies, a microscopic positive margin was found to be associated with a higher risk of local failure (4 /6, 20). Fagundes et al. (4) found a correlation of local failure with positive surgical margin: of 23 patients with positive margins, 9 (39)) had local recurrence, whereas 1 of 11 patients (9)) with negative margins had local recurrence. Belal et al. (20) reported that the 5-year relapse free survival for patients with negative pathologic margins was 55), in comparison with 24) for those with positive tumor margins (p /0.0006). However, in multivariate analysis, surgical margin was not a significant factor for relapse-free survival. In our study, surgical margin had borderline influence on local control rate (p/0.0774) in

multivariate analysis, but no statistical significance. Further analyzing our data, 42 (69)) of 61 patients who had negative surgical margins were staged as advanced stage (II/III). Maybe the staging confounded the influence of surgical margins on local control. Patients with MFH have been staged by the same staging system used for STS, the AJCC classification. Few studies, however, have definitely validated the prognostic usefulness of this classification for patients with MFH. In 1999, Salo et al. reported 239 patients with localized MFH of the extremity who underwent complete gross resection of the disease and were followed prospectively. Patients were staged according to the AJCC 1997 staging system for STS. Log rank survival analysis showed significant differences in disease specific survival between stage I, II and III (22). In our study, tumors were staged by the AJCC 2002 staging system for STS. The differences between these two staging systems were that T2bG1 2N0M0 belonged to stage II in AJCC 1997, but belonged to stage I in AJCC 2002. Our data showed that the AJCC 2002 staging system was a significant factor for overall survival rates (p /0.0008) and distant metastasis-free rates (p /0.0170) in univariate analysis and correlated with overall survival rates (p/ 0.0017) in multivariate analysis. As regards stage, we concluded that the more advanced the stage of the disease, the worse the survival rate. Adjuvant chemotherapy for rhabdomyosarcoma, osteosarcoma, and Ewing’s sarcoma is established, but remains controversial in other adult sarcomas (23). Some randomized clinical studies showed a clear advantage in overall or disease-free survival (24 /27), whereas others showed no benefit of adjuvant chemotherapy (28 /32). In 2000, the Sarcoma Meta-analysis Collaboration (SMAC) Meta-analysis Group published a meta-analysis, based on individual data on 1,568 patients from 14 trials of doxorubicin-based adjuvant chemotherapy (33). They found that doxorubicinbased adjuvant chemotherapy appeared to significantly improve time to local and distant recurrence and overall recurrence-free survival in adults with localized resectable STS. There was some evidence of a trend towards improved overall survival. Until now, no consensus on treatment of STS has been reached. Several randomized trials are still under investigation. In prior studies, factors of prognostic importance in patients with MFH of the extremity were associated with size, depth, and grade (22). The AJCC 2002 staging system for STS has focused on the above factors. Our study demonstrated again that the staging system was an important prognostic predictor in overall survival rates. The relationship between stage and prognosis for MFH had some therapeutic implications. Adding more aggressive chemotherapy to those patients with advanced stage was worthy of further investigation.


CONCLUSION The AJCC 2002 staging system is a prognostic predictor for overall survival rates in patients with MFH who underwent surgery as the primary treatment modality with or without radiotherapy. The role of postoperative RT in improving local control was confirmed in our study, but the benefits in increasing overall survival rates and distant metastasis-free rates are worthy of further investigation in randomized trials. Until now, no consensus on treatment of MFH has been reached. Adding chemotherapy to those patients with advanced stage is worth further investigation.


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