Clinical Oncology (1992) 4:32-35 © 1992 The Royal College of Radiologists
Clinical Oncology
Original Article Intra-arterial Adriamycin, Conventionally Fractionated Radiotherapy and Conservative Surgery for Soft Tissue Sarcomas M. Mason, M. Robinson, C. Harmer and G. Westbury Sarcoma Unit, The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK
Abstract. Thirteen patients with soft tissue sarcomas were treated with a combination of intra-arterial Adriamycin, conventionally fractionated radiotherapy (2 Gy per day), and conservative surgery (trimodal therapy). Severe acute complications occurred in 10 patients: 3 brachial artery thromboses, 6 delayed wound healing, 4 wound infections, and 3 cases of necrosis of the skin plus subcutaneous tissues. Three patients have developed local recurrence. Five patients are alive, 4 of whom are disease-free, and the median follow up time of surviving patients is 56 months. One has significant impairment of limb function due to joint ankylosis. An additional 2 patients were treated with intra-arterial Adriamycin and conservative surgery for local recurrence after previous surgery and radiotherapy; both died of subsequent metastatic disease, one having a further local recurrence. One patient with multifocal angiosarcoma was treated with intra-arterial Adriamycin and radiotherapy but no surgery, and is alive free of disease 49 months later. The combination of radiotherapy and intra-arterial Adriamycin with surgery resulted in significant acute toxicity. This small study has not demonstrated any improvement in local control compared with that expected with conservative surgery and radiotherapy alone. Keywords: Combined modality treatment; Intraarterial chemotherapy; Radiotherapy; Sarcomas
INTRODUCTION In recent years considerable interest has been devoted to the avoidance of amputation in the treatment of soft tissue sarcoma (STS) of the extremities. Local recurrence rates in patients treated with surgery alone are known to depend on the extent of surgical clearance of the tumor, varying from 90% after local excision to less than 10% for amputation. It is clear that other local treatment modalities must be employed in addition to conservaCorrespondence and offprint requests to: Dr M. Mason, Radiotherapy Unit, The Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK.
tire surgery for adequate local control. It is known that the combination of conservative surgery and radiotherapy maintains a functional limb in 85%97% of patients [1-3]. The addition of radiotherapy to surgery is associated with a severe complication rate of less than 10% [1,3], with soft tissue necrosis and bone fracture occurring in less than 2% of patients. In an attempt to improve local control further, Eilber and colleagues [4], treated 105 patients with resectable tumours by a combination of intra-arterial Adriamycin, hypofractionated radiotherapy, and conservative surgery. However, despite their excellent figures for local control, the treatment complications in this series suggested that the toxicity from late normal tissue damage was unacceptably severe. Hypofractionated radiotherapy has been shown to be associated with increased late normal tissue damage [5]. Interaction between Adriamycin and radiotherapy has previously been observed both clinically and radiobiologically [6,7]. It was felt important, therefore, to establish whether the considerable late damage seen in Eilber's first series was due to the fractionation schedule or to the concomitant use of Adriamycin. We decided to evaluate treatment toxicity in a pilot group of patients using conventionally fractionated radiotherapy with intra-arterial Adriamycin and conservative surgery before contemplating a larger prospective study of this approach.
PATIENTS AND METHODS Thirteen patients aged between 20 and 77 years (median 51) with histologically verified STS presenting to the Sarcoma Unit between 1983 and 1985 were treated by intra-arterial Adriamycin, radiotherapy, and conservative surgery. Five of these were referred to the unit with locally recurrent disease after previous surgery. A further 2 patients who had locally recurrent STS after previous conservative surgery and radiotherapy were treated with intra-arterial Adriamycin and conservative surgery without reirradiation. One patient with multifocal angiosarcoma involving bone was considered inoperable and treated with intra-arterial Adriamycin and radiother-
Trimodal Therapy for Soft Tissue Sarcomas
33
Table 1. Patient and tumour characteristics
Table 3. Radiotherapy doses in patients undergoing intra-arterial chemotherapy
Patient Site l 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Thigh
Size (cm) Histology
Grade
12x 12
H
Malignantfibrous histiocytoma Thigh 10x5 Malignantfibrous histiocytoma Thigh 25 x 15 Malignantfibrous histiocytoma Thigh 19x 12 Synovialsarcoma Thigh 10× 12 Synovialsarcoma Thigh 10x6 Synovialsarcoma Thigh 28 x 23 Liposarcoma Thigh 16x 9 Leiomyosarcoma Thigh 10x14 Angiosarcoma Buttock 18x 10 Malignantfibrous histiocytoma Buttock 10× 10 Synovialsarcoma Axilla 23 x 16 Liposarcoma Lower leg Multiple Angiosarcoma Lower leg 5x4 Malignantfibrous histiocytoma Forearm 6x7 Malignantschwannoma Forearm 8x7 Malignantschwannoma
H H H H H I H L L H H L H H L
Dose/Fraction/Time
Number of patients
PrePostoperative operative
65 Gy/32/6.5 weeks 60 Gy/30/6.0 weeks 45 Gy/20/4.0 weeks 44 Gy/22/4.5 weeks 40 Gy/20/4.0 weeks
2 8a 1 1 2
1 5 1 1 2
a
1 2 0 0 0
I patient in this group did not have surgery.
surgery was classified according to the definitions of Enneking and co-workers [8] as radical, wide, marginal, or intracapsular. Late normal tissue damage was assessed using criteria previously described [5]. The presence of discolouration, induration, pain, impairment of joint m o v e m e n t , distal o e d e m a , and wound b r e a k d o w n was judged by clinical examination. Each was graded as slight, moderate, or severe. All surviving patients have been followed for a minimum of 52 months (range 52-76, median 56).
H, high; I, intermediate; L, low. apy alone. Sites of disease and histology are shown in Table 1. Metastatic disease at the time of presentation was excluded by computerized t o m o g r a p h y of the thorax. Intra-arterial Adriamycin was administered preoperatively as a continuous infusion over 3 days. Arterial catheters were inserted under local anaesthetic and their positions checked daily with fiuorescein angiography. The dose varied according to site: for femoral infusions a dose of 90 mg was administered but for infusions through smaller vessels it was reduced as shown in Table 2. R a d i o t h e r a p y was given preoperatively in 10 patients and postoperatively in 3. The original treatment intent was radical radiotherapy to at least 60 Gy in 30 fractions over 6 weeks or equivalent. In 4 patients treated preoperatively, lower doses were employed as shown in Table 3. In 3 of these radiotherapy was truncated because the primary tumour, previously judged to be inoperable, had regressed sufficiently to permit conservative surgery. In the fourth, radiotherapy was discontinued at 40 Gy due to extensive necrosis of skin and subcutaneous tissues. In 7 patients the tumour was judged to be fixed at the time of presentation and therefore inoperable using conservative techniques. These patients all underwent preoperative radiotherapy. The extent of Table 2. Doses of Adriamycin used for 16 intra-arterial infusions Site of Catheter
Total dose (mg) Number of patients
Common femoral Superficial femoral External Iliac Profunda femoris Subclavian Proximal popliteal Internal Iliac
90 90 90 60 60 60 45 30 30
Brachial
6 1 2 1 1 1 1 1 2
RESULTS The acute complications of trimodal treatment are shown in Table 4. Of the group of 13 patients treated with trimodal therapy, a total of 9 developed severe acute complications defined as arterial thrombosis or delayed wound healing (due to wound infection or necrosis). Three patients developed brachial artery thromboses. Two of these received the infusion into the brachial artery and the third into the subclavian artery with the catheter inserted via the brachial artery. All 3 patients underwent successful emergency embolectomy. Four patients developed transient skin erythema in the region being perfused. Six patients experienced delay in wound healing after surgery, 3 of these with wound infection, 2 with necrosis of skin plus subcutaneous tissues, and 1 with both infection and necrosis. R a d i o t h e r a p y was preoperative in all but one patient. Three patients were treated to 45 Gy or less, and 3 to 60 G y or more. Of the 3 patients treated with only 2 modalities, one (treated with intra-arterial Adriamycin and surgery) experienced delayed wound healing and skin erythema, but neither of the remaining 2 patients suffered acute complications. Fifteen patients underwent excision of the primary tumour. The extent of surgical clearance was judged to be radical in 2, wide in 6, and marginal in 7. Table 4. Acute complications of trimodal therapy Complication
Number of patients
Wound infection Delayed wound healing Necrosis of skin and subcutaneous tissues Lymphoedema Brachial artery thrombosis Skin rash in perfused limb
4 6 3 2 3 4
34
M . M a s o n et al.
Histological examinations of the resected specimens showed 'extensive' or 'total' necrosis in 7 patients, 6 of whom had received preoperative radiotherapy. Four patients developed local recurrence between 10 and 29 months after therapy. Their treatment was trimodal in 3 and surgery plus intra-arterial chemotherapy in 1. Three of these patients with local recurrence have subsequently died. A further 7 patients have died with metastatic disease without local recurrence. The 6 remaining patients are alive and disease-free with a median follow-up of 56 months. Late normal tissue damage was assessed in these 6 surviving patients and is summarized in Table 5. Four of the 6 have undergone a full functional assessment as part of another study [9]. Only one patient had functional impairment severe enough to restrict his normal activity. This was a patient with local recurrence within the radiation field after trimodal therapy and who is currently alive with disease. Patient 13 was treated with radiotherapy and intraarterial chemotherapy only, but the remaining patients in Table 5 were treated with trimodal therapy. T a b l e 5. L a t e N o r m a l T i s s u e D a m a g e in 6 s u r v i v i n g p a t i e n t s Patient no. 5
8
9
13
Discolouration
+
-
+ +
+/-
Induration
-
+
+ +
+/-
Pain
-
+
+ +
+/-
+ +
+/-
-
+
+/-
-
14
15
Wound breakdown Limitation of movement Distal oedema -, none; +/-,
slight; + , m o d e r a t e ; + + ,
severe.
DISCUSSION STS is an aggressive malignancy which will recur if local therapy is inadequate. There have been a number of published series showing that local control rates of 85% can be achieved for limb sarcomas by conservative surgery combined with radical irradiation [2,3]. A recent retrospective analysis of our experience suggested that patients with extremity sarcomas who had a local recurrence were 4.5 times more likely to die from their disease [10]. However, any further improvement in local control achieved by the use of new techniques is likely to be small, requiring a randomized trial with large numbers of patients to demonstrate it. Given the rarity of STS, this is unlikely to be achieved. Initial reports of resectable tumours treated with intra-arterial Adriamycin, conservative surgery, and radiotherapy suggested that this was an effective combination, with limb salvage rates of 90% [4,11]. However, 4 of 61 patients with STS in Eilber's initial series developed a fracture of the adjacent long bone, a complication never encountered in this unit, although mentioned in the Lindberg et al. series [1]. Four patients in Eilber's initial series of 105 patients
with bone and soft tissue sarcomas required amputation for complications arising from treatment [11]. However, in his trimodal approach the radiotherapy comprised 10 fractions of 3.5 Gy. Thus, not only was chemotherapy introduced, but the irradiation was simultaneously altered from conventional treatment. In an attempt to reduce the morbidity the radiotherapy was reduced to 17.5 Gy in 5 fractions but this led to a 12% local recurrence rate in the 137 patients in which it was employed [12]. The dose was subsequently increased to 28 Gy in 8 fractions. The complication rate was not significantly different between these 3 groups [13] and the overall limb salvage rate was 98% [13,14]. In a previous attempt in our unit to improve local control of STS, once-weekly large fractions of radiotherapy were used (hypofractionation) as an adjunct to limb conserving surgery. Unfortunately an unacceptable level of late normal tissue damage resulted without observable benefit [5]. We have therefore returned to the use of conventional daily fractions of 2 Gy. It might be anticipated that standard fractionation would be associated with less late normal tissue damage than large fraction irradiation when used in a trimodal approach. In our study, trimodal therapy was employed in a group of patients most of whom already had adverse prognostic features with regard to local control: 5 were treated for local recurrence following previous surgery and 7 had tumours fixed to bone. Three of 13 patients treated with trimodal therapy suffered a further local recurrence despite this aggressive approach (2 for local recurrence and 1 with a fixed tumour). These results suggest that any inherent advantage for trimodal therapy over surgery plus radical radiotherapy might be difficult to prove. One of the patients treated with intra-arterial Adriamycin and surgery without radiotherapy also developed further local recurrence. Despite the length of time that has elapsed since the introduction of intra-arterial chemotherapy [1517] and the preliminary in vitro studies which suggested that Adriamycin and radiation acted on mammalian cells by different mechanisms [6], the underlying basis for combined chemotherapy and radiotherapy is poorly understood. It is still not resolved whether such combinations act synergistically or whether their effects are merely additive, but it is noteworthy that a number of clinical trials have failed to demonstrate an advantage for the use of combined radiotherapy plus chemotherapy for a variety of tumours at different sites [18]. One possible advantage for intra-arterial chemotherapy is that a 6-fold increase in drug concentration may be achieved in the arterial supply to the tumour compared with the same dose given intravenously [14]. Eilber has, however, carried out a randomized trial of intravenous versus intra-arterial Adriamycin in the treatment of extremity sarcomas, and this failed to demonstrate any advantage in terms of local control by the use of intra-arterial Adriamycin [19]. Moreover, there has been a lack of demonstrable benefit in several studies of adjuvant chemotherapy [20,21]. In agreement with the published series [4,11,12,14] the acute toxicity of trimodal therapy in this study is considerable. This, combined with the complexity of
Trimodal Therapy for Soft Tissue Sarcomas the technique of intra-arterial chemotherapy, r e n d e r s it u n s u i t a b l e for use o u t s i d e s p e c i a l i z e d centres. In t h e p r e s e n t series 7 5 % of t h e p a t i e n t s experienced acute complications, often requiring h o s p i t a l i z a t i o n f o r f u r t h e r surgical i n t e r v e n t i o n in t h e f o r m o f e m b o l e c t o m y o r skin grafting. This c o m p a r e s u n f a v o u r a b l y with o u r p r e v i o u s l y r e p o r t e d series [3,22] w h e r e m a j o r c o m p l i c a t i o n s in p a t i e n t s n o t r e c e i v i n g c h e m o t h e r a p y w e r e s e e n in o n l y 6 % of p a t i e n t s t r e a t e d with 2 G y p e r d a y a n d in 13% of p a t i e n t s t r e a t e d with a high d o s e , h y p e r f r a c t i o n a t e d r e g i m e n . T h e t r e a t m e n t of t h e s e o f t e n large t u m o u r s is a s s o c i a t e d with a significant m o r b i d i t y a n d t h e r e is e v i d e n c e t h a t this m a y b e i n c r e a s e d b y the c o n c o m i t a n t use o f c h e m o t h e r a p y . C h a n g a n d c o l l e a g u e s [23] r e p o r t e d t h a t 3 0 % o f t h e i r p a t i e n t s with high g r a d e e x t r e m i t y STS t r e a t e d b y s u r g e r y , r a d i o t h e r a p y , a n d adjuvant chemotherapy experienced major wound c o m p l i c a t i o n s . T h e y also c o n c l u d e d t h a t t h e a d d i t i o n o f c h e m o t h e r a p y to s u r g e r y with o r w i t h o u t r a d i o therapy increased the incidence of joint contractures. It is i m p o s s i b l e to d r a w a n y firm conclusions r e g a r d i n g late n o r m a l tissue d a m a g e a f t e r t r i m o d a l t h e r a p y f r o m t h e small n u m b e r o f surviving p a t i e n t s , p a r t i c u l a r l y as t h e single p a t i e n t with significant f u n c t i o n a l l i m b i m p a i r m e n t also s u f f e r e d local r e c u r r e n c e , m a k i n g it difficult to s e p a r a t e t r e a t m e n t a n d d i s e a s e - r e l a t e d factors. In t h e r e m a i n i n g p a t i e n t s , late n o r m a l tissue d a m a g e was u n r e m a r k a b l e . T h e i n c r e a s e in c o m p l i c a t i o n s a n d t h e failure of i n t r a - a r t e r i a l A d r i a m y c i n to i m p r o v e local c o n t r o l m e a n t h a t t h e use o f t h e s e a g e n t s s h o u l d be confined to a c o n t r o l l e d trial.
References 1. Lindberg RD, Martin RG, Romsdahi MM, et al. Conservative surgery and postoperative radiotherapy in 300 adults with soft tissue sarcomas. Cancer 1981; 47:2391-7. 2. Suit HD, Mankin HJ, Wood WC, et al. Treatment of the patient with stage M0 soft tissue sarcoma. J Clin Oncol 1988; 6:854-62. 3. Robinson M, Barr L, Fisher C, et al. Treatment of soft tissue sarcomas with surgery and radiotherapy. Radiother Oncol 1990; 18:221-33. 4. Eilber FR, Mirra JJ, Grant TT, et al. Is amputation neccessary for sarcomas? A seven year experience with limb salvage. Ann Surg 1980; 192:431-8. 5. Ashby MA, Ago CT, Harmer CL. Hypofractionated radio-
35 therapy for sarcomas. Int J Radiat Oncol Biol Phy 1986; 12:13-7. 6. Belli JA, Piro AJ. The interaction between radiation and Adriamycin damage in mammalian cells. Cancer Res 1977 37:1624-30. 7. Cassaday JR, Richter MP, Piro AJ, et al. Radiation-Adriamycin interactions: preliminary clincial observations. Cancer 1975; 36:946-9. 8. Enneking WF, Spanier SS, Malawer MM. The effect of the anatomic setting on the result of surgical procedures for soft parts sarcoma of the thigh. Cancer 1981; 47:1005-22. 9. Robinson MH, Eeles R, Spruce L, et al. Limb conservation. Is it worthwhile? Proceedings of the British Oncological Association [abstract]. Br J Cancer 1990; 62 Suppl XI:9. 10. Stotter AT, A'Hern RP, Fisher C, et al, The influence of local recurrence of extremity soft tissue sarcoma on metastasis and survival. Cancer 1990; 66:1119-29. 11. Eilber FR. Perfusion chemotherapy. In: Baker LH, editor. Soft tissue sarcomas. Boston: Martinus Nijhoff, 1983:101-7. 12. Eilber FR, Giuliano A, Huth J, et al. Neoadjuvant chemotherapy, radiation, and limited surgery for high grade soft tissue sarcoma of the extremity. Dev Oncol 1988; 55:115-22. 13. Giuliano AE, Eilber FR. Complications of limb salvage for soft-tissue sarcoma of the extremity [abstract]. Am J Clin Oncol 1987; 10:108. 14. Huth JF, Eilber FR. Preoperative intra-arterial chemotherapy. Cancer Treat Res 1989; 44:103--10. 15. Klopp CT, Alford TC, Bateman J, et al. Fractionated intraarterial cancer chemotherapy with methyl bis-amine hydrochloride: a preliminary report. Ann Surg 1950; 132:822--32. 16. Di Pietro S, De Palo GM, Molinari R, et al. Clinical trials with Adriamycin by prolonged arterial infusion. Tumori 1970; 56:233-44. 17. Haskell CM, Silverstein MJ, Rangel DM, et al. Multimodality cancer therapy in man: a pilot study of Adriamycin by arterial infusion. Cancer 1974; 33:1485-90. 18. Tannock IF. Combined modality treatment with radiotherapy and chemotherapy. Radiother Oncol 1989; 16:93-101. 19. Eilber FR, Giuliano AE, Huth JF, et al. Intravenous (IV) vs. intra-arterial (IA) Adriamycin, 2800 rad irradiation and surgical excision for extremity soft tissue sarcomas; a randomised prospective trial. Proc ASCO 1990; 9:309. 20 Blackledge G, Van Oosterom A, Mouridsen HT, et al. The place of chemotherapy in the management of soft tissue sarcoma: experiences of the EORTC Soft Tissue and Bone Sarcoma Group. Clin Oncol 1989; 1:106--9. 21. Eilber FR, Guiliano AE, Huth JF, et al. A randomized prospective trial using postoperative adjuvant chemotherapy (Adriamycin) in high grade extremity soft tissue sarcoma. Am J Clin Oncol 1988; 11:3%45. 22. Robinson M, Cassoni A, Harmer C, et al. Hyperfractionated high dose radiotherapy in extremity soft tissue sarcomas. Proceedings of the British Oncological Association [abstract]. Br J Cancer 1990; 62 Suppl XI:20. 23. Chang AE, Steinberg SM, Culnane M, et al. Functional and psychological effects of multimodality limb-sparing therapy in patients with soft tissue sarcomas. J Clin Oncol 1989; 7:121% 28.
Receivedfor publication January 1991 Accepted July 1991
Clinical Oncology
Original Article Intra-arterial Adriamycin, Conventionally Fractionated Radiotherapy and Conservative Surgery for Soft Tissue Sarcomas M. Mason, M. Robinson, C. Harmer and G. Westbury Sarcoma Unit, The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK
Abstract. Thirteen patients with soft tissue sarcomas were treated with a combination of intra-arterial Adriamycin, conventionally fractionated radiotherapy (2 Gy per day), and conservative surgery (trimodal therapy). Severe acute complications occurred in 10 patients: 3 brachial artery thromboses, 6 delayed wound healing, 4 wound infections, and 3 cases of necrosis of the skin plus subcutaneous tissues. Three patients have developed local recurrence. Five patients are alive, 4 of whom are disease-free, and the median follow up time of surviving patients is 56 months. One has significant impairment of limb function due to joint ankylosis. An additional 2 patients were treated with intra-arterial Adriamycin and conservative surgery for local recurrence after previous surgery and radiotherapy; both died of subsequent metastatic disease, one having a further local recurrence. One patient with multifocal angiosarcoma was treated with intra-arterial Adriamycin and radiotherapy but no surgery, and is alive free of disease 49 months later. The combination of radiotherapy and intra-arterial Adriamycin with surgery resulted in significant acute toxicity. This small study has not demonstrated any improvement in local control compared with that expected with conservative surgery and radiotherapy alone. Keywords: Combined modality treatment; Intraarterial chemotherapy; Radiotherapy; Sarcomas
INTRODUCTION In recent years considerable interest has been devoted to the avoidance of amputation in the treatment of soft tissue sarcoma (STS) of the extremities. Local recurrence rates in patients treated with surgery alone are known to depend on the extent of surgical clearance of the tumor, varying from 90% after local excision to less than 10% for amputation. It is clear that other local treatment modalities must be employed in addition to conservaCorrespondence and offprint requests to: Dr M. Mason, Radiotherapy Unit, The Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK.
tire surgery for adequate local control. It is known that the combination of conservative surgery and radiotherapy maintains a functional limb in 85%97% of patients [1-3]. The addition of radiotherapy to surgery is associated with a severe complication rate of less than 10% [1,3], with soft tissue necrosis and bone fracture occurring in less than 2% of patients. In an attempt to improve local control further, Eilber and colleagues [4], treated 105 patients with resectable tumours by a combination of intra-arterial Adriamycin, hypofractionated radiotherapy, and conservative surgery. However, despite their excellent figures for local control, the treatment complications in this series suggested that the toxicity from late normal tissue damage was unacceptably severe. Hypofractionated radiotherapy has been shown to be associated with increased late normal tissue damage [5]. Interaction between Adriamycin and radiotherapy has previously been observed both clinically and radiobiologically [6,7]. It was felt important, therefore, to establish whether the considerable late damage seen in Eilber's first series was due to the fractionation schedule or to the concomitant use of Adriamycin. We decided to evaluate treatment toxicity in a pilot group of patients using conventionally fractionated radiotherapy with intra-arterial Adriamycin and conservative surgery before contemplating a larger prospective study of this approach.
PATIENTS AND METHODS Thirteen patients aged between 20 and 77 years (median 51) with histologically verified STS presenting to the Sarcoma Unit between 1983 and 1985 were treated by intra-arterial Adriamycin, radiotherapy, and conservative surgery. Five of these were referred to the unit with locally recurrent disease after previous surgery. A further 2 patients who had locally recurrent STS after previous conservative surgery and radiotherapy were treated with intra-arterial Adriamycin and conservative surgery without reirradiation. One patient with multifocal angiosarcoma involving bone was considered inoperable and treated with intra-arterial Adriamycin and radiother-
Trimodal Therapy for Soft Tissue Sarcomas
33
Table 1. Patient and tumour characteristics
Table 3. Radiotherapy doses in patients undergoing intra-arterial chemotherapy
Patient Site l 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Thigh
Size (cm) Histology
Grade
12x 12
H
Malignantfibrous histiocytoma Thigh 10x5 Malignantfibrous histiocytoma Thigh 25 x 15 Malignantfibrous histiocytoma Thigh 19x 12 Synovialsarcoma Thigh 10× 12 Synovialsarcoma Thigh 10x6 Synovialsarcoma Thigh 28 x 23 Liposarcoma Thigh 16x 9 Leiomyosarcoma Thigh 10x14 Angiosarcoma Buttock 18x 10 Malignantfibrous histiocytoma Buttock 10× 10 Synovialsarcoma Axilla 23 x 16 Liposarcoma Lower leg Multiple Angiosarcoma Lower leg 5x4 Malignantfibrous histiocytoma Forearm 6x7 Malignantschwannoma Forearm 8x7 Malignantschwannoma
H H H H H I H L L H H L H H L
Dose/Fraction/Time
Number of patients
PrePostoperative operative
65 Gy/32/6.5 weeks 60 Gy/30/6.0 weeks 45 Gy/20/4.0 weeks 44 Gy/22/4.5 weeks 40 Gy/20/4.0 weeks
2 8a 1 1 2
1 5 1 1 2
a
1 2 0 0 0
I patient in this group did not have surgery.
surgery was classified according to the definitions of Enneking and co-workers [8] as radical, wide, marginal, or intracapsular. Late normal tissue damage was assessed using criteria previously described [5]. The presence of discolouration, induration, pain, impairment of joint m o v e m e n t , distal o e d e m a , and wound b r e a k d o w n was judged by clinical examination. Each was graded as slight, moderate, or severe. All surviving patients have been followed for a minimum of 52 months (range 52-76, median 56).
H, high; I, intermediate; L, low. apy alone. Sites of disease and histology are shown in Table 1. Metastatic disease at the time of presentation was excluded by computerized t o m o g r a p h y of the thorax. Intra-arterial Adriamycin was administered preoperatively as a continuous infusion over 3 days. Arterial catheters were inserted under local anaesthetic and their positions checked daily with fiuorescein angiography. The dose varied according to site: for femoral infusions a dose of 90 mg was administered but for infusions through smaller vessels it was reduced as shown in Table 2. R a d i o t h e r a p y was given preoperatively in 10 patients and postoperatively in 3. The original treatment intent was radical radiotherapy to at least 60 Gy in 30 fractions over 6 weeks or equivalent. In 4 patients treated preoperatively, lower doses were employed as shown in Table 3. In 3 of these radiotherapy was truncated because the primary tumour, previously judged to be inoperable, had regressed sufficiently to permit conservative surgery. In the fourth, radiotherapy was discontinued at 40 Gy due to extensive necrosis of skin and subcutaneous tissues. In 7 patients the tumour was judged to be fixed at the time of presentation and therefore inoperable using conservative techniques. These patients all underwent preoperative radiotherapy. The extent of Table 2. Doses of Adriamycin used for 16 intra-arterial infusions Site of Catheter
Total dose (mg) Number of patients
Common femoral Superficial femoral External Iliac Profunda femoris Subclavian Proximal popliteal Internal Iliac
90 90 90 60 60 60 45 30 30
Brachial
6 1 2 1 1 1 1 1 2
RESULTS The acute complications of trimodal treatment are shown in Table 4. Of the group of 13 patients treated with trimodal therapy, a total of 9 developed severe acute complications defined as arterial thrombosis or delayed wound healing (due to wound infection or necrosis). Three patients developed brachial artery thromboses. Two of these received the infusion into the brachial artery and the third into the subclavian artery with the catheter inserted via the brachial artery. All 3 patients underwent successful emergency embolectomy. Four patients developed transient skin erythema in the region being perfused. Six patients experienced delay in wound healing after surgery, 3 of these with wound infection, 2 with necrosis of skin plus subcutaneous tissues, and 1 with both infection and necrosis. R a d i o t h e r a p y was preoperative in all but one patient. Three patients were treated to 45 Gy or less, and 3 to 60 G y or more. Of the 3 patients treated with only 2 modalities, one (treated with intra-arterial Adriamycin and surgery) experienced delayed wound healing and skin erythema, but neither of the remaining 2 patients suffered acute complications. Fifteen patients underwent excision of the primary tumour. The extent of surgical clearance was judged to be radical in 2, wide in 6, and marginal in 7. Table 4. Acute complications of trimodal therapy Complication
Number of patients
Wound infection Delayed wound healing Necrosis of skin and subcutaneous tissues Lymphoedema Brachial artery thrombosis Skin rash in perfused limb
4 6 3 2 3 4
34
M . M a s o n et al.
Histological examinations of the resected specimens showed 'extensive' or 'total' necrosis in 7 patients, 6 of whom had received preoperative radiotherapy. Four patients developed local recurrence between 10 and 29 months after therapy. Their treatment was trimodal in 3 and surgery plus intra-arterial chemotherapy in 1. Three of these patients with local recurrence have subsequently died. A further 7 patients have died with metastatic disease without local recurrence. The 6 remaining patients are alive and disease-free with a median follow-up of 56 months. Late normal tissue damage was assessed in these 6 surviving patients and is summarized in Table 5. Four of the 6 have undergone a full functional assessment as part of another study [9]. Only one patient had functional impairment severe enough to restrict his normal activity. This was a patient with local recurrence within the radiation field after trimodal therapy and who is currently alive with disease. Patient 13 was treated with radiotherapy and intraarterial chemotherapy only, but the remaining patients in Table 5 were treated with trimodal therapy. T a b l e 5. L a t e N o r m a l T i s s u e D a m a g e in 6 s u r v i v i n g p a t i e n t s Patient no. 5
8
9
13
Discolouration
+
-
+ +
+/-
Induration
-
+
+ +
+/-
Pain
-
+
+ +
+/-
+ +
+/-
-
+
+/-
-
14
15
Wound breakdown Limitation of movement Distal oedema -, none; +/-,
slight; + , m o d e r a t e ; + + ,
severe.
DISCUSSION STS is an aggressive malignancy which will recur if local therapy is inadequate. There have been a number of published series showing that local control rates of 85% can be achieved for limb sarcomas by conservative surgery combined with radical irradiation [2,3]. A recent retrospective analysis of our experience suggested that patients with extremity sarcomas who had a local recurrence were 4.5 times more likely to die from their disease [10]. However, any further improvement in local control achieved by the use of new techniques is likely to be small, requiring a randomized trial with large numbers of patients to demonstrate it. Given the rarity of STS, this is unlikely to be achieved. Initial reports of resectable tumours treated with intra-arterial Adriamycin, conservative surgery, and radiotherapy suggested that this was an effective combination, with limb salvage rates of 90% [4,11]. However, 4 of 61 patients with STS in Eilber's initial series developed a fracture of the adjacent long bone, a complication never encountered in this unit, although mentioned in the Lindberg et al. series [1]. Four patients in Eilber's initial series of 105 patients
with bone and soft tissue sarcomas required amputation for complications arising from treatment [11]. However, in his trimodal approach the radiotherapy comprised 10 fractions of 3.5 Gy. Thus, not only was chemotherapy introduced, but the irradiation was simultaneously altered from conventional treatment. In an attempt to reduce the morbidity the radiotherapy was reduced to 17.5 Gy in 5 fractions but this led to a 12% local recurrence rate in the 137 patients in which it was employed [12]. The dose was subsequently increased to 28 Gy in 8 fractions. The complication rate was not significantly different between these 3 groups [13] and the overall limb salvage rate was 98% [13,14]. In a previous attempt in our unit to improve local control of STS, once-weekly large fractions of radiotherapy were used (hypofractionation) as an adjunct to limb conserving surgery. Unfortunately an unacceptable level of late normal tissue damage resulted without observable benefit [5]. We have therefore returned to the use of conventional daily fractions of 2 Gy. It might be anticipated that standard fractionation would be associated with less late normal tissue damage than large fraction irradiation when used in a trimodal approach. In our study, trimodal therapy was employed in a group of patients most of whom already had adverse prognostic features with regard to local control: 5 were treated for local recurrence following previous surgery and 7 had tumours fixed to bone. Three of 13 patients treated with trimodal therapy suffered a further local recurrence despite this aggressive approach (2 for local recurrence and 1 with a fixed tumour). These results suggest that any inherent advantage for trimodal therapy over surgery plus radical radiotherapy might be difficult to prove. One of the patients treated with intra-arterial Adriamycin and surgery without radiotherapy also developed further local recurrence. Despite the length of time that has elapsed since the introduction of intra-arterial chemotherapy [1517] and the preliminary in vitro studies which suggested that Adriamycin and radiation acted on mammalian cells by different mechanisms [6], the underlying basis for combined chemotherapy and radiotherapy is poorly understood. It is still not resolved whether such combinations act synergistically or whether their effects are merely additive, but it is noteworthy that a number of clinical trials have failed to demonstrate an advantage for the use of combined radiotherapy plus chemotherapy for a variety of tumours at different sites [18]. One possible advantage for intra-arterial chemotherapy is that a 6-fold increase in drug concentration may be achieved in the arterial supply to the tumour compared with the same dose given intravenously [14]. Eilber has, however, carried out a randomized trial of intravenous versus intra-arterial Adriamycin in the treatment of extremity sarcomas, and this failed to demonstrate any advantage in terms of local control by the use of intra-arterial Adriamycin [19]. Moreover, there has been a lack of demonstrable benefit in several studies of adjuvant chemotherapy [20,21]. In agreement with the published series [4,11,12,14] the acute toxicity of trimodal therapy in this study is considerable. This, combined with the complexity of
Trimodal Therapy for Soft Tissue Sarcomas the technique of intra-arterial chemotherapy, r e n d e r s it u n s u i t a b l e for use o u t s i d e s p e c i a l i z e d centres. In t h e p r e s e n t series 7 5 % of t h e p a t i e n t s experienced acute complications, often requiring h o s p i t a l i z a t i o n f o r f u r t h e r surgical i n t e r v e n t i o n in t h e f o r m o f e m b o l e c t o m y o r skin grafting. This c o m p a r e s u n f a v o u r a b l y with o u r p r e v i o u s l y r e p o r t e d series [3,22] w h e r e m a j o r c o m p l i c a t i o n s in p a t i e n t s n o t r e c e i v i n g c h e m o t h e r a p y w e r e s e e n in o n l y 6 % of p a t i e n t s t r e a t e d with 2 G y p e r d a y a n d in 13% of p a t i e n t s t r e a t e d with a high d o s e , h y p e r f r a c t i o n a t e d r e g i m e n . T h e t r e a t m e n t of t h e s e o f t e n large t u m o u r s is a s s o c i a t e d with a significant m o r b i d i t y a n d t h e r e is e v i d e n c e t h a t this m a y b e i n c r e a s e d b y the c o n c o m i t a n t use o f c h e m o t h e r a p y . C h a n g a n d c o l l e a g u e s [23] r e p o r t e d t h a t 3 0 % o f t h e i r p a t i e n t s with high g r a d e e x t r e m i t y STS t r e a t e d b y s u r g e r y , r a d i o t h e r a p y , a n d adjuvant chemotherapy experienced major wound c o m p l i c a t i o n s . T h e y also c o n c l u d e d t h a t t h e a d d i t i o n o f c h e m o t h e r a p y to s u r g e r y with o r w i t h o u t r a d i o therapy increased the incidence of joint contractures. It is i m p o s s i b l e to d r a w a n y firm conclusions r e g a r d i n g late n o r m a l tissue d a m a g e a f t e r t r i m o d a l t h e r a p y f r o m t h e small n u m b e r o f surviving p a t i e n t s , p a r t i c u l a r l y as t h e single p a t i e n t with significant f u n c t i o n a l l i m b i m p a i r m e n t also s u f f e r e d local r e c u r r e n c e , m a k i n g it difficult to s e p a r a t e t r e a t m e n t a n d d i s e a s e - r e l a t e d factors. In t h e r e m a i n i n g p a t i e n t s , late n o r m a l tissue d a m a g e was u n r e m a r k a b l e . T h e i n c r e a s e in c o m p l i c a t i o n s a n d t h e failure of i n t r a - a r t e r i a l A d r i a m y c i n to i m p r o v e local c o n t r o l m e a n t h a t t h e use o f t h e s e a g e n t s s h o u l d be confined to a c o n t r o l l e d trial.
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Receivedfor publication January 1991 Accepted July 1991
