Radiation therapy and conservative surgery for soft tissue sarcomas of the extremities, torso and head and neck

Annals of Oncology 3 (Suppl. 2): S97-S101, 1992. © 1992 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Radiation therapy and conservative surgery for soft tissue sarcomas of the extremities, torso and head and neck A. De Paoli,1 G. Bertola,2 G. Boz,1 F. Gherlinzoni,3 S. Frustaci,4 G. Fumo,5 R. Innocente,1 M. G. Trovo,1 C. Rossi,2 A. Carbone6 & S. Morassut7 'Radiotherapy Division; 2Surgical Oncology Division, Centro di Riferimento Oncologico (C.R.O.), Aviano; ^Orthopedic Clinic I, Istituti Ortopedici Rizzoli (I.O.R.), Bologna; ^Medical Oncology Division, Centro di Riferimento Oncologico (C.R.O.), Aviano; 5Orthopedic II Division, General Hospital, Pordenone; 6Pathology Division; 7Radiology Department, Centro di Riferimento Oncologico (C.R.O.), Aviano, Italy

Introduction

months (12-72). Three pts. (6.5%) had local failure and 9 (20%) developed distant metastases with local tumor control. All distant metastases occurred in AJC stage IIIB, 9/18 (50%), with an increased frequency by tumor size. Overall local control and disease free survival rates at 5 years (product-limit method) were 93% and 73%, respectively. An evident decrease in disease-free survival rate (33%) was noted for stage IIIB pts. Treatment complications occurred in 11% of pts. and consisted mainly in prolonged wound healing for pts. treated with preoperative radiation therapy. Our experience confirms the high local control rate reported from several Centers with radiation therapy and conservative surgery for soft tissue sarcomas. The incidence of distant metastases for large, high grade lesions is the major problem in these patients.

Key words: radiation therapy, soft tissue sarcoma, conservative surgery

removed as tumor margin during radical resection. So, combined modality therapy reduces the extent of surgical resection, yielding better functional and cosmetic results, and achieves local control rates comparable with those obtained with radical surgery [4]. This expectation has been met at several Centers [6-10]. This report reviews our experience with radiation therapy before or following conservative surgery in the treatment of patients with soft tissue sarcomas of the extremities, torso and head and neck.

Current treatment approaches to primary adult soft tissue sarcomas have changed significantly over the past few decades. Traditionally, the treatment policy has been surgical, usually with amputation for distal extremity primaries or with more ablative procedures (i.e. disarticulation, hemipelvectomy) for proximal extremity tumors [1, 2]. Recently, more conservative procedures have been developed. These include radical compartmental resection [3], radiation therapy and conservative surgery [4], and intra-arterial chemotherapy, radiation therapy and resection [5]. In particular, com- Materials and methods binations of irradiation and surgery have been used increasingly in order to achieve tumor control while re- Between May 1985 and July 1990, 45 patients with primary or reducing the extension of resection compared with radi- current M0 soft tissue sarcomas of the extremities, torso, and head and neck were treated with radiation therapy and surgical resection cal surgery alone. The rationale for combining radiation therapy with at the Centro di Riferimento Oncologico (C.R.O.). This group of patients was selected out of a series of 83 M0 conservative surgery is that moderate doses of radia- patients treated at our Institute during the same period. The median tion should be effective to sterilize microscopic exten- age was 54 years (range 22-79) and the male-female ratio was sion of tumor into grossly normal tissue that should be 1.4:1.0. Patients managed either by radiation therapy alone or radi-

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Summary. Between May 1985 and July 1990, 45 patients (pts.) with primary (39) or recurrent (6) soft tissue sarcomas of the extremities (82%), torso (11%) and head and neck (7%) were treated with radiation therapy and conservative surgery. Seven pts. not amenable to conservative surgery underwent preoperative radiation therapy whereas 38 pts. underwent local excision and post-operative radiation therapy. Out of the 38 pts. managed by postoperative radiation, 24 (63%) showed negative surgical margins and 14 (37%) positive margins, their tumor being adjacent to vital structures. Preoperative radiation allowed conservative surgery in all 7 pts. with initially inoperable tumor; surgical margins were negative in 5 and positive in 2 pts. Twenty-six pts. (58%) had tumor >5 cm (5-24) and 19 (42%) < 5 cm (2.5-4.5) in diameter. High grade tumors (G2-G3) were reported in 41 pts. (90%). In pts. treated postoperatively the radiation dose was 64-66 Gy/32-33 fractions and the pts. treated preoperatively received a dose of 50 Gy/25 fractions. Median follow-up was 33 months and all pts. had a minimum follow-up of 12

98

Table 1. Patient characteristics. 45 54 (28-79)

N. of patients Age (yrs.) Sex

- Males - Females

26 (58%) 19(42%)

Primary tumor Recurrent tumor

39 (86%) 6(14%)

Site -

Upper extremity Lower extremity Torso Head and neck

12 (26%) 25 (56%) 5(11%) 3 (7%)

Histologic type - Liposarcoma - MFH - Synovial sarcoma - Malignant schwannoma - Other

11 (24%) 10(22%) 5 (11%) 4 (9%) 15 (34%)

Stage (AJC) - IA - IB - IIA - IIB - IHA - 1IIB - IVA

(G1T1N0M0) (G1T2N0M0) (G2T1N0M0) (G2T2N0M0) (G3T1N0M0) (G3T2N0M0) (Gl-3, T l - 2 , Nl, MO)

Treatment - Local excision and postoperative radiotherapy - Preoperative radiotherapy and local excision

[12]. Two or 3 target volumes were usually defined for treatment planning which were to include at first the high risk areas for tumor spreading and finally the tumor or tumor bed only. Patients were immobilized in a simple and reproducible treatment position which also allowed normal tissues, which did not need to be irradiated, to be moved out from the radiation field. Customized immobilization devices, wedge filters or compensating filters were frequently used. The initial treatment volume received approximately a dose of 50 Gy given at 2 Gy per fraction, 5 fractions per week. For patients treated postoperatively radiation was continued up to 64-66 Gy, whereas patients treated preoperatively received a dose of 50 Gy. In this last group of patients, a postoperative boost of 14-16 Gy was planned when the resulting surgical margins were positive. There was no consistent plan for adjuvant chemotherapy. Six patients received chemotherapy (Doxorubicin and Ifosfamide), 2 of them preoperatively. Results are reported as causes of failure, local control and disease-free survival rates. Survival analyses were performed using the Kaplan-Meier product-limit method [13].

Results Up to July 30, 1991, the median follow-up was 33 months, and all patients had a minimum follow-up of 12 months (12-72). Of the 45 patients treated, 3 (6.5%) had local failure and 9 (20%) developed distant metastases with control of the primary tumor. Two of the 3 patients who failed locally also had distant metastases, 1 patient before and the other one at the time of diagnosis of local failure. Overall local control and disease free survival rates were 93% and 73%, respectively. Causes of failure and estimated 5-year results are reported in Table 2. Patients with high grade sarcomas and tumor size >5 cm (stage Illb) demonstrated an evident decrease in disease-free survival rate (33%) whereas local control was slightly influenced (80%). In particular, increasing size of high grade tumors was clearly related to the frequency of distant metastases. Data on the incidence of distant metastases as a function of tumor size in

Table 2. Causes of failure and 5-year results according to AJC stage.a Stage

1 (2%) 3 (7%) 2 (4%) 5(11%) 16(36%) 18 (40%)

LF C ± DM"

DM d

Local control (%)

IA IB IIA IIB IUA

1 3 2

5

IVA

16 18 —

Total

45

IIIB

1 3 2 5 15 7 —

_ _ 1 2 —

33

3

(73.5%) (6.5%) 0

38 (84%) 7(16%)

N. pts. NED"

b c a

9 9

Diseasefree survival (%)

92 80 —

100 100 100 100 92 33 —

93

73

100 100 100

100

(20%)

Data estimated by Kaplan-Meier product-limit method. NED = No evidence of disease. LF = Local failure. DM = Distant metastases.

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cal surgery, patients aged 16 or younger, patients under 30 years of age with diagnosis of rhabdomyosarcoma, patients with sarcomas of the pelvic, abdominal or thoracic cavities and retroperitoneal tissue were excluded from our analysis. Patient characteristics are reported in Table 1. This series includes patients whose tumors were considered to be not amenable to conservative surgery, but which were rendered amenable to conservative resection as a result of preoperative irradiation; so, all patients treated with radiation therapy and conservative surgical resection are included in this study. All patients underwent radiation therapy at our Institute, whereas some patients underwent surgery in referring hospitals. However, a re-excision of operative bed was planned at our Surgical Department for patients in whom adequacy of previous surgery, performed elsewhere, was dubious. Surgical procedure was designed to remove all gross disease and, when possible, lesions were excised with margins of normal surrounding tissue. Although the specific procedures performed varied according to site and extent of the primary tumor, gross disease was completely resected in all cases. Surgical margins were scored according to histologic evaluation of inked margins. For patients who underwent surgery in outside hospitals, assessment of surgical margins was obtained by careful review of operative and pathologic reports. Margins were scored as negative when tumor was removed as a single piece and was not visualized during surgical procedure. Surgical margins for the patients who underwent re-excision of operative bed were also scored as negative if there was no evidence of tumor in the margins of the second resected specimen. The histologic slides of all patients were reviewed by our pathologist. Patients were staged according to the current American Joint Committee Staging System [11]. Radiation therapy was given with external photon beam using a 6 or 8 MeV Linear Accelerator; the treatment techniques employed were in accordance with the guidelines reported by Tepper et al.

99 persisting seroma complicated by infection and ulceration requiring surgical treatment, in the other one. Overall incidence of complications was 5/45 (11%). Although none of the patients developed major edema or fibrosis, mild edema and/or fibrosis was noted during follow-up in 8 patients (18%). However, functional and cosmetic results in all patients were considered to be good by the participating clinicians. Discussion

The results reported from this series of patients appear to reproduce the high rate of local control that can be achieved with a combination of radiation therapy and conservative surgery in the treatment of soft tissue sarcomas. In fact, the local control rates are reported to range from 85% and 95% in several experiences employing such function sparing procedures [6-10]. These results are equivalent to those reported with radical, often ablative, surgery in other series of patients [14]. In our experience, conservative surgery consisted of resection of all gross disease with a margin of surrounding normal tissue, when possible. In no case were either compartmental resection or muscle group excision from insertion to insertion performed. Surgical margins were negative in 29 (65%) and positive, in at least one portion of the operative specimen, in 16 (35%) patients. Historically, marginal and wide procedures for high grade lesions have resulted in local recurrence rates of 90% and 50% respectively, when irradiation was not used [3]. We reported a 96.5% local control rate for patients with negative and 87.5% for patients with positive margins after pre- or postoperative radiation therapy. Most patients (91%) had high grade tumors. Results in patients with positive margins are usually less satisfactory, in particular for large, high grade tumors treated with post-operative radiation [4, 7, 15]. Our local control data (93%) reported after marginal procedures might depend on the small number of patients treated, and the few local recurrences occurred at the present follow-up. Better results are expected in patients with negative margins; wide excision is recommended when surgery is planned as a first step of treatment [6]. To date, in our series no patient with negative surgiTable 3. Distant metastases rate versus tumor size in patients with cal margins recurred locally after post-operative radialocal control. tion. These results support our attempt to perform, Size (mm) Gl G2-3 when possible, wide surgical excision and, for patients referred from outside hospitals after dubious adequacy DM (%) DM (%) N. pts. N. pts. of previous surgical procedure, re-excision of surgical _ bed. Fifty percent of patients who underwent re-opera3 <25 0 0 1 14 26-50 0 0 tion showed residual tumor in the surgical specimen. 3 0 12 51-100 25 These findings are reported also from other authors 4 0 101-150 50 who recommend re-resection of the tumor bed follow0 3 151-200 67 ing resection by non-oncologic surgeons. [16]. 0 2 >200 100 In the present series of patients, 7/45 (15.5%) had 4 0 Total 38 24 tumor not amenable to conservative surgery (because

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patients who achieved local control are reported in Table 3. The 3 patients who had local failure had a primary tumor (no patient with recurrent tumor relapsed) and the site of disease was the lower extremity (knee in two patients and thigh in one patient, respectively). Two of these patients were treated with preoperative radiation therapy. Thus, 2 out of 7 patients (28.5%) with initially inoperable tumors with conservative surgery, failed after preoperative irradiation and only 1 out of 38 (2.5%) failed after local excision and postoperative radiation therapy. These patients had surgical salvage with amputation and 2 developed lung metastases. Out of the 38 patients managed by postoperative radiation therapy, 16 (42%) had re-excision of tumor bed before treatment because of dubious adequacy of previous surgery and 8 of them (50%) showed residual tumor in the resected specimen. Definitive surgical margins were negative in 24 patients (63%), whereas they were positive in 14 (37%) because of tumor proximity to adjacent vital structures. Local control was achieved in all 24 patients with negative margins and in 13/14 patients (93%) with positive margins. For patients treated with preoperative radiation, surgical margins resulted negative in 5 and positive in 2 patients, respectively. Patients with positive margins received postoperative boost to the tumor bed with a radiation dose of 16 Gy. Local control was achieved in 5/7 patients (71.5%); surgical margins were negative in 1 and positive in the other one of the relapsed patients. Overall local control rate by surgical margins for all groups of patients resulted in 28/29 (96.5%) when margins were negative and 14/16 (87.5%) when margins were positive. Treatment complications consisted mainly in wound problems for patients treated with preoperative radiation. These complications occurred in 3 of the 7 patients (43%) treated preoperatively and consisted of prolonged wound healing (>6 months) also requiring surgical procedure. Two of these patients had large, high grade sarcomas and also received chemotherapy in the preoperative treatment. Other complications were reported in 2 patients treated with postoperative radiation. These included bone fracture in 1 patient, and

100 which report grade and size to be the principal indicators for metastatic potential in patients with soft tissue sarcomas [6,10,15]. These indicators may be useful for the selection of patients in further clinical trials with systemic adjuvant chemotherapy which remains, at the present, one of the major points of investigation for soft tissue sarcomas. In summary, our experience appears to reproduce the high local control rate reported from several Centers with radiation therapy and conservative surgery for soft tissue sarcomas. Morbidity of treatment is demonstrably acceptable and functional and cosmetic results have been considered to be good in all patients. The incidence of distant metastases for large, high grade lesions represents the major problem for these patients.

Acknowledgement

The authors would like to thank Mrs. Michilin Daniela for her assistance in the preparation of this manuscript.

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of locally advanced or critical site of disease) and were treated with preoperative radiation. All patients underwent conservative resection after radiotherapy and 5/7 (71.4%) have local control of disease. Experiences from several Centers demonstrated the efficacy of this approach with higher local control rates for large tumors when compared to postoperative radiation [6, 8, 10]. Owing to the limited number of patients treated in our series, indications cannot be drawn to evaluate this approach. However, the results reported in these 7 patients are encouraging and are a valid indication to continue this approach for large, inoperable, or borderline operable lesions. Our group of patients presented with tumor in the extremity, torso, and head and neck. Analysis of results according to tumor location is still untimely because of the small number of lesions in some sites, such as torso and head and neck region. However, it is interesting to note that the combination of radiation therapy and conservative surgery can be used in a wide spectrum of tumor sites. This is an important aspect when effective function sparing procedures in the treatment of soft tissue sarcomas are compared. In fact, radical-compartmental resection can be employed only in intracompartmental tumors [3,17] and the combination of radiation, intra-arterial chemotherapy and surgery is safely feasible only for lower extremity localizations [5, 18]. Treatment complications represent a critical point in the evaluation of the efficacy of a function sparing procedure. We reported an overall 11% incidence of complications. These consisted in significant wound problems in 3 out of the 7 patients (43%) treated preoperatively, whereas complications were noted in only 2 of the 38 patients (5%) treated with postoperative radiation (infected sarcoma with ulceration and bone fracture, respectively). Delay in wound healing represented a major problem in several experiences when doses of preoperative radiation of about 50 Gy, as in our study, were used. The incidence of these complications has been reported to range from 16% to 60% [10, 19, 20]. On the other hand, such dose level of radiation, has been demonstrated to be effective to allow conservative surgery in most patients with initially inoperable tumors and to achieve a high rate of local control. Efforts to minimize delay in wound healing consisting in more limited surgical procedures, to fill the space left after resection of large tumors by muscle flaps, closure without tension and longer drain decompression have been demonstrated to be effective and are highly recommended [6]. Analysis of failure documented in our series a high incidence of distant metastases limited to patients with high grade, large size tumors. Disease-free survival at 5 years was 33% for stage IIIB. Nine out of 18 patients (50%) with stage IIIB developed distant metastases and an increasing frequency by tumor size was noted (Table 3). These data are confirmed in several experiences

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19. Ball RS, O'Sullivan B, Langer F et al. Complications and functional results after limb-salvage surgery and radiotherapy for difficult mesenchymal neoplasms: a prospective analysis. Canad J Surg 1989; 32: 69-73. 20. Bryant MH, Schray MF, Martinez AM et al. Pre- and/or postoperative irradiation combined with limb-sparing surgery for soft tissue sarcomas of the extremities. Proc. 7th Annual Meeting E.S.T.R.O., Den Haag, September 1988; 203. P 988.

Correspondence to: Dr. Antonino De Paoli Radiotherapy Division Centro di Riferimento Oncologico 33081 Aviano (PN), Italy

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