Radiotherapy and Oncology, 18 (1990) 221-233 Elsevier
221
RADION00706
Treatment of extremity soft tissue sarcomas with surgery and radiotherapy M. R o b i n s o n 1, L. B a I T 2, C. Fisher 3, I. F r y a t t 5, A. Stotter 2, C. H a r m e r 1, E. Wiltshaw 4 and G. W e s t b u r y 2 Departments of ~Radiotherapy, 2Surgery, 3Histopathology, 4Medicine, and 5Computing and Statistics, Sarcoma Unit, Royal Marsden Hospital, London, U.K. (Received 5 April 1989, revision received 29 November 1989, accepted 15 January 1990)
Key words: Extremity; Sarcoma; Radiotherapy; Surgery; Local control; Survival
Summary The results of treatment with a combination of surgery and radiotherapy of 102 patients with nonmetastatic extremity soft tissue sarcoma are reported. Seventy-nine patients were previously untreated and 23 had locally recurrent disease. Sixty-six tumours were situated in the lower limb and 16 in the limb girdles. Fifty-nine were high grade lesions, and 64 were over 5 cm in length. Surgical clearance was "good" (wide or radical) in only 34 cases. Sixty-eight patients received post-operative irradiation, 23 pre-operative irradiation and 11 both pre- and post-operative radiotherapy. Seventeen patients subsequently developed local recurrence and 9 of these remain disease-free after further surgery. Actuarial 5 year local control and disease-free survival rates for new cases were 87 and 65.4 ~o ; and for previously recurrent cases these figures fell to 75 and 54.8~o. Following a univariate analysis of patient, tumour, surgical and radiotherapeutic factors only previous local recurrence (p < 0.1 > 0.05) was found to significantly increase the risk of further local relapse. Multivariate analysis found high tumour grade [relative risk (RR) 8.4], tumour size > 15 cm (RR 3.66), previous local recurrence (RR 6.47) and proximal site (RR 12.7) to be independent poor risk factors for survival.
Introduction Over the last 25 years the management of extremity sarcomas has evolved from radical ablative surgery alone to a policy of limb conservation using a combination of tumour resection and
adjuvant high dose radiotherapy. The success of this approach was reported as early as 1950 by Cade [7]. Simon and Enneking [ 21 ] reported that "adequate" surgery alone results in 98 ~/o local control. This was however at the expense of amputation in
Address for correspondence: M. Robinson, Department of Radiotherapy, Sarcoma Unit, Royal Marsden Hospital, Fulham Rd., London SWJ 6JJ, U.K. 0167-8140/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
222 over 5 0 ~ of cases. All those defined as having "inadequate" surgery failed locally. Lindberg [3] using similar definitions of surgical clearance as the sole treatment modality reported that an intracapsular "shell-out" of tumour resulted in a greater than 90 ~o chance of local recurrence, wide excision 50~o and a radical limb-sparing operation on its own 25~o. The addition of high dose radiotherapy to soft part resection has permitted the practice of limb conservation in the management of limb and limb girdle soft tissue sarcomas in a number of centres [1,4,6,8,10,12,13,17]. The local control rates achieved by this combination have been similar to that from amputation without prejudicing patient survival [ 17]. The goal of combined treatment is a functioning limb without local recurrence. The effect of local recurrence on survival remains uncertain. Some authors [9] associate local recurrence with decreased survival. It has been our finding [23] that local recurrence is an independent poor risk factor in survival. Some important questions concerning the use of radiotherapy in this situation are as yet unanswered. The timing of the radiotherapy in relation to surgery, the extent of surgery required, the extent of apparently normal tissue around the tumour bed to be included in the irradiated volume, and the best dose and fractionation schedule are still unresolved issues. The aim of this study was to review the results of treatment of the 102 cases of limb and limb girdle soft tissue sarcomas treated with curative intent, with both surgery and radiotherapy, by the Sarcoma Unit of the Royal Marsden Hospital over the last 7 years.
Patients and methods
Between 1981 and 1987, 222 patients with soft tissue sarcomas of the limb or limb girdle were treated at the Royal Marsden Hospital. This group does not include patients with desmoids or childhood rhabdomyosarcomas. One hundred and fourteen were treated with surgery alone. Six
were treated with palliative radiotherapy only as surgery was contraindicated because of their general medical condition or the presence of metastases. One hundred and two have been treated by a combination of surgery and radiotherapy. These patients form the basis for this report. No patient is excluded from this series for reasons of inoperability. There were 63 males and 39 females. None had detectable metastases at the time of definitive treatment or had received previous radiotherapy. Computed tomography of the lungs is used routinely in the staging of these patients. Adjuvant systemic chemotherapy was used in only four cases and as a pre-operative intra-arterial infusion with adriamycin in 12 cases [ 14]. In 26 cases the surgery had been performed outside the Royal Marsden Hospital. The median age was 45 years (range 11 to 77).
Surgery The principles of surgical treatment in this Unit have already been described [22]. Where the sarcoma was considered to be operable at referral surgery was usually performed first. Where possible a radical compartmental resection was performed, though for reasons of tumour site and local anatomy this was feasible in less than 15Yo of our patients with limb and limb girdle sarcomas (personal written communication, Stotter, A., July 1988). Surgical clearance was defined using Enneking's criteria [21] and in our series was termed "good" (i.e. radical or wide) in only 34/102 of our cases (Table I). In four cases an excisional biopsy only had been performed by the referring surgeon but further surgery was not considered to be possible without significant functional deficit, and the patients proceeded to radical radiotherapy. At operation, nine tumours were found to be superficial to the deep fascia, 13 both superficial and deep and the remainder deep. Only seven amputations were performed; one was undertaken as primary treatment in another centre before later referral to the Royal Marsden Hospital with a local recurrence; one was a
223 TABLE I Surgical clearance achieved in series of 102 soft tissue s a r c o m a s of limb and limb girdle. Excision biopsy alone Marginal Wide Radical
4 47 21 13
planned amputation of the thumb following preoperative radiotherapy for recurrent disease and the remaining five were required for local recurrence following failure of combined surgery and radiotherapy.
Radiotherapy Post-operative radiotherapy was given to all patients who had high grade tumours and to those with a low/intermediate grade tumour where a wide or radical clearance was not possible, or which recurred after one or more attempts at control by surgery alone. The target volumes have been defined three dimensionally by the routine use of computed tomographic (CT) scans and more recently by the use of magnetic resonance imaging. Two target volumes were defined. The first included all those tissues considered to be at risk of microscopic spread. Where the tumour was intra-compartmental this involved treating the whole compartment. This volume was usually taken to 50 Gy, 2 Gy per fraction, 5 fractions per week. A strip of normal tissue was spared along the length of the irradiated limb and joints were shielded where possible. Where the sarcoma was inoperable at presentation and radiotherapy was given pre-operatively (34 cases), treatment was completed at this dose (or equivalent) or sometimes at 40 Gy in 4 weeks. If the tumour was still inoperable after 50 Gy a further 10 Gy was given and the patient observed. In some sarcomas clinical response was slow and operation was delayed several months. When radiotherapy was given post-operatively (68 patients), the second target volume consisting of the tumour bed and scar with a 2 cm margin
was treated to 10-20 Gy in 5-10 daily 2 Gy fractions to bring the usual total dose to 60 Gy or equivalent in 6 weeks. Following pre-operative irradiation and surgical resection a further 10 Gy in 5 daily fractions was given to 11 patients in whom the resection margin was narrow. Only patients in whom tumour excision was attempted are included in this study. Details of the surgery, timing of radiotherapy, fractionation and range of doses used are given in Tables II and III. Over 50~o of the patients were treated using 2 Gy fractions. However, during the early part of this period there was a study ofhypofractionation using 6.6 Gy fractions given once a week [3]. Post-operatively patients usually received 6 fractions to give a total dose of 39.6 Gy. At present, we are investigating a hyperfractionation protocol using 1.25 Gy twice daily, 5 days a week for 6 weeks. Four patients from this study are included in this report. The radiation technique was selected to tailor T A B L E II Surgical clearance, timing of radiotherapy and fractionation used. Surgical clearance
S t a n d a r d fractionation pre-op
post
pre and post
Excision biopsy Intracapsular Marginal Wide Radical
1 11 4 4
8 26 x × 13 x 6
1× 2 4 2
Total
20
53
9
6.6 Gy weekly Excision biopsy Intracapsular Marginal Wide Radical
-
Total × = Hyperfractionation cases.
2 6 7 2 1
1 1 -
18
2
224 T A B L E III Fraction sizes and range of doses used in treatment of 102 limb and limb girdle sarcomas. Fraction size
No. of patients
Dose range (Gy)
I Shoulder 4 Axilla
1.25 a 1.8 2-2.25 2.25-2.5 3 3.5 4.4
4 4 64 6 2 1 1
62.5-75 60-70 40-66 45-56 50 and 60 42 40
6 Upper a r m 3 Elbow 6 Forearm
Buttock 3 Inguinal 6 Femoral • 2 Thigh
2 Wrist 3 Hand
43
a Twice daily. Popliteal 1 Knee 3
the treatment volume to the target volume. Patients were often immobilized in custom-made casts and the treatment plan produced with the use of CT planning scans, using two or more fields, all of which were usually treated daily (see below). Patients were treated on a 5 MeV linear accelerator sometimes using an extended SSD of 110 cm where field sizes above 40 cm were required. Seventy-nine patients were treated for primary tumours and 23 for locally recurrent disease. Three patients had had more than one recurrence prior to the use of radiotherapy. Five cases were situated at the shoulder girdle, 11 at the pelvic girdle, 20 in the upper limb and 66 in the lower limb (Fig. 1). The median follow-up was 37months (range 101 to 3160 days). All the tumour histology was reviewed by the same pathologist (C.F.).
Statistics Results are presented as actuarial local control and disease-free survival rates. The error bars on the graphs represent the 95 ~o confidence intervals of the curve at that point. The number of patients developing local failure and/or distant metastasis are reported. Local control means that the patient has been continuously free of tumour at the primary site, and disease-free survival means that they have been continuously free of disease at all
Calf
11
Shin 2
Foot 6
Fig. 1. The anatomical sites of 102 limb and limb girdle soft tissue sarcomas.
sites. For the purposes of determining actuarial local control rates, patients who had local control but died of distant metastases or intercurrent illness were removed from the analysis at the last TABLE IV Factors assessed for contribution to survival and failure of local control. Age < 40 and < 60 years Sex Tumour size Skin involvement Bone involvement Surgical clearance Upper or lower limb Proximal or distal site Primary or recurrent disease Timing of radiotherapy Radiation field margin: > 5 era, > 10 cm, > 20 cm Radiotherapy dose: > 45 Gy, or > 55 Gy Ret value of radiotherapy schedule Use of intra-arterial adriamycin
225 follow-up examination. Time to local failure was plotted according to a number of patient, tumour and treatment variables and comparisons made between groups using the log-rank method of analysis [ 15]. In looking at disease-free survival, patients who died disease-free were censored at last follow-up examination. Cox regression analysis using the B M D P statistics package was used in an effort to determine the significant factors involved in failure of local tumour control and survival. The patient, tumour and treatment related variables studied are detailed in Table IV. The radiotherapy factors studied included dose in Gray and rets; fraction size and number; timing of radiotherapy in relation to surgery; and an estimate of the margin given the tumour (calculated by subtracting the maximum tumour size from the maximum field size and dividing by 2).
Results
The distribution of histological diagnosis is shown in Table V. Consistent with other contemporary series [ 17,24] there were 33 malignant
TABLE VI Staging of 102 limb and limb girdle soft tissue sarcomas. Stage
No. of patients
1A 1B 1 unknown 2B 3A 3B 3 unknown 4A Grade unknown
5 17 2 12 24 33 1 2 1
fibrous histiocytomas, 23 synovial sarcomas and 24 liposarcomas. Fifty-nine tumours were high grade, 17intermediate and 24 low grade; 2 remained unclassified. Sixty-four of the tumours were more than 5 cm in size. The largest was 30 cm in length. In three cases the size was not documented. The details of the UICC staging of these tumours is given in Table VI. Two patients had enlarged regional lymph nodes at presentation. Both had pre-operative radiotherapy and in one of the cases there was no residual tumour at surgery.
TABLE V Histology of the 102 soft tissue sarcomas. MFH Synovial sarcoma Liposarcoma Myxoid WDLL Pleomorphic NOS Sarcoma NOS Leiomyosarcoma Epithelioid sarcoma Rhabdomyosarcoma Fibrosarcoma Malignant peripheral nerve sheath tumour Haemangiosarcoma Chondrosarcoma Clear cell sarcoma
33 23 24 17 3 2 1 6 4 3 3 2 1 1 1 1
M F H = Malignant fibrous histiocytoma; WDLL = well differentiated lipoma like; NOS = not otherwise specified.
Local control
There have been 15 local recurrences; 10 in the 79 new cases and 5 in the 23 previously recurrent cases. There is no significant difference between the actuarial plots of time to local recurrence of the primary and previously recurrent groups ( p > 0 . 1 ) . At 2years the former showed 92~o local control and the latter only 75 ~o (Fig. 2). One local recurrence occurred after distant relapse, one synchronously and 4 have developed metastases after initial local failure. Only two recurrences occurred close to but outside the irradiated area, the remainder lay within the treatment volume. The details of these patients are shown in Table VII. Of the 15 patients suffering local recurrence 9 have been salvaged without developing metastases following one or more operations. In three cases, further radiotherapy
226 local failure occurred first. In only two patients was local control not eventually achieved. The details of the treatments used for local relapse are detailed in Table VIII. Only three amputations were performed. Two of these 3 patients are disease-free at 11 and 38 months, respectively. The third patient relapsed locally and systemically' 6 months after a hindquarter amputation with marginal clearance. Local control was not achieved by excision biopsy and radiotherapy and the patient died 8 months later.
100-
8
c
p
90-
8o.
l
L
~ 7o. ~
(50-
o c
50-
B 4o. ~a
:30-
g o L a_
_
20-
0
_
Primary
.......
Locally
'H; ......
0
recurrent
*I . . . . . . . 1
""1'"'~*'""1 2
3
Time
since
radiotherapy
RMH
........
~"1 ........... 4
I ~. . . . . . . . . . 5
I'"H*'"~'I 6
7
(years)
Fig. 2. Actuarial plot of time to local recurrence in primary and previously recurrent limb and limb girdle sarcomas.
was given. Six patients have died of metastatic disease. Local control of the primary was achieved in 4 of the 6 patients who developed metastases, was not achieved in one, and was not treated in the remaining case. In only five patients developing metastases has post-radiotherapy TABLE VII Details of the 15 patients suffering local relapse following surgery and radiotherapy.
Site of primary:
Upper limb proximal 2, distal 3 Lower limb proximal 7, distal 3
Initial disease:
Primary 10; previously recurrent 5
Histology:
M F H 4; synovial 4; rhabdomyosarcoma 1; sarcoma NOS 1; haemangiosarcoma 1; fibrosarcoma 1, epithelioid 2; nerve sheath tumour 1
Grade:
High 11; intermediate 1; low 2; unknown 1
Surgical clearance:
Intraeapsular 2; marginal 12; radical 1
Site of recurrence:
In field/adjacent scar 13; marginal 2
Field margins:
Mean 17.2 cm
Rets:
Mean 1775
Number salvaged:
9
MFH = malignant fibrous histiocytoma.
Factors associated with failure of local control Local control of soft tissue sarcomas following combined therapy may be a function of a number of interrelated patient, tumour and treatment factors. However, the small number of local recurrences made an attempt to identify which are most important by Cox regression modelling, impossible. Univariate analysis showed only previous local recurrence (p < 0.1 > 0.05) to be a significant prognostic variable for further local recurrence. Tumour grade (Fig. 3a) did not appear to be important in determining local control. It did significantly influence survival with only a 61% actuarial 5-year survival in those with high grade tumours compared with > 90% in those with low and intermediate grade tumours (log-rank p < 0.1). Size The incidence of local recurrence was not related to increasing tumour size. There was a nonsignificant trend for the reverse to be true (logtrend test p > 0.1). Patients with larger tumours develop metastases earfier, and so less frequently survive to have local recurrences (Fig. 3b). Radiation schedule No relation between dose of radiation in Gray and local control was found. However, different fractionations were used during the period of this study (Table III). Twenty patients were treated with weekly 6.6 Gy fractions. The majority of the patients were treated using 2 Gy fractions daily,
227 TABLE
VIII
Details
of salvage
Surgery
treatment
and
of local recurrences.
DFI
clearance
RXT
CT
(mths)
No.
First relapse
Outcome
LR
(mths) LR
DM
(mths)
(mths)
Excision Intracapsular
9
-
-
0
-
-
64
-
+
2
4
46
Marginal
13
-
+
0
-
-
DF
51
Marginal
32
-
-
0
-
-
DF
11
Marginal
20
-
-
2
4
-
DF
Marginal
5
-
-
0
-
2
Marginal
Marginal
DF
18 + 54
16 + 2
7
-
-
1
2
2
Wide
13
+
-
2a
10
-
DF
+ 8 79
Radical
18
-
-
0
-
-
DF
46
Intracapsular
26
-
-
0
-
-
DF
Marginal
40
-
+
1b
6
6
Radical
31
-
-
0
-
-
None
4
+
-
0
-
0
None
4
-
+
0
-
-
-
-
No treatment
Amputation 11 + 8 DF
38
No surgery
None
12/15 c
Abbreviations: relapse;
DM
DFI
'~ F u r t h e r
XRT;
b Distant
disease
c Metastases
= disease-free
= developing amputation
interval
treatment;
RXT
= radiotherapy;
47 + 3
CT = chemotherapy;
LR = local
metastases. at 60 months
and local recurrence
a t 12 m o n t h s ,
after first RMH
+ 7 DF
for radionecrosis
together
local recurrence
following trauma.
- never locally controlled
after that.
a t 15 m o n t h s .
although four received twice daily fractionation. There is no significant difference between the hypofractionated group and the others in local progression-free survival (Fig. 3c). Without the benefit of a multivariate analysis it is not possible to draw any conclusions about the influence of radiation dosage on tumour control. Only 9 patients had skin involvement at presentation and 7 relapsed locally within 39 months. Local control was also worse in the 12 patients given intra-arterial adriamycin but this is probably a function of patient selection as it was only patients with large high grade tumours who were offered this treatment. The timing of radiotherapy (pre-, post- or pre- and post-surgery) was based upon tumour operability at presentation. It is therefore not possible to determine the influence
of this timing upon subsequent local control. There was, however, no significant difference between the plots of local recurrence-free survival for these groups. Survival Overall, 15 patients with primary tumours and 7 with recurrent tumours died. Twenty-one and six respectively, developed metastases. One patient developed lymph node involvement during radiotherapy, and two others 5 and 8 months after treatment. The 5 year actuarial survival of primary and recurrent groups was 77 and 64.3~o, respectively (Fig. 4). The corresponding disease-free survivals were 65.4 and 54.8~o. A multivariate analysis of the prognostic fac-
228 Limb
100 "
and
limb
girdle
sarcoma
(primary
v local
rec)
90-
~ 80u
70-
o
60-
70-
50-
50-
B 4o. ~ ~
2010.
2
b
30-
~-
,
60-
- .......
High Intermediate
-.-.-,_
LOW
L a
0
"~"'""'1
...........
0
I
1
..... """1
2
Time
since
4030-
........... 3
RMH
I ...... '""1' ...... ""1'"'"'""1 4 5 6
radiotherapy
Primary
20-
- ....
0
(years)
0
.......... I ........... I ........... I ........... I'",', 1 2 3 4
90.
Limb
8 80. 70"
L 5 ~)
50"
2o
(years)
radiotherapy
and limb
girdle
sarcoma
(grade)
90-
.... .... i ........... [............
80.~
7060-
"t 30.
~
RMH
100 -
40. -
since
..... I ........... I" ......... I 5 6 7
Fig. 4. Actuarial survival of patients with primary and previously recurrent limb and limb girdle sarcomas.
100 •
60.
recurrent
10-
7
Time
L L 2
Locally
t ~ no
50. _
10 cm
30.
0
o
b
'"."'""1
...........
1 Time
I'"'""'"1
2 since
.....
'"'"1"'"'"'"1"
3 RMH
4
radiotherapy
.........
5
I ...........
I
6
7
o.
2010.
(years)
..... -.-,-
High Intermediate LOW
a
. . . . . . . . . . . I . . . . . . . . . . . I . . . . . . . . . . . I . . . . . . . . . . . I "~ . . . . . . . . . I ~'t~ . . . . . . . I . . . . . . . . . . . I 1 2 3 4 5 6 7 Time
since
RMH
radiotherapy
(years)
100Limb
90-
,~
80.
~) L_
70-
o
60-
oc
50-
"5 >,
40-
..... ,._.. ....
...............
,. . . . . . . . . . . . . .
and
limb
girdle
(size)
sarcoma
1009080-
.........
,> 7 0 -
i
6o50-
3o. 2
(L
_ _ .......
2o-
4o-
Hypotractionation Other
3o10-
{2.
c
20"
0 0
1 Time
2 since RMH
4
5
radiotherapy
3
(years)
6
7
Fig. 3. Time to local recurrence for 102 extremity sarcomas plotted by (a)tumour grade (high intermediate, low) (b) tumour size ( < 5 cm vs, 5-10 cm vs. > 10 cm); (c) fractionation (6.6 Gy weekly vs. other).
..... .....
< 5crn 5-10 cm > 10 cm
10-
b " ......... I'" ........ I,. ......... I', ......... I ........... I ........... i ........... I 0 1 2 3 4 5 6 7 Time
since
RMH
radiotherapy
(years)
Fig. 5. Survival plotted according to (a) tumour grade (b) tumour size.
229 TABLE IX The independent prognostic factors for survival determined by multivariate analysis. Model
Log likelihood
Reduction in LL
3(2
p
Original 4 ~ + diameter > 15 cm + radiotherapy post-surgery + >15cm+XRT post-surgery
78.78 76.41
2.37
4.75
0.029
76.71
2.07
4.04
0.041
76.33
2.45
4.9
0.086
Co-factors Low grade Intermediate grade High grade Distal Proximal or girdle No local recurrence Prior local recurrence Tumour diameter < 15 cm Diameter > = 15 cm
Relative risk (95~o limits) 1 1.74 (0.23-13.3) 8.4 (1.74-40.5) 1 12.7 (2.6-61.8) 1 6.47 (2.16-19.4) 1 3.66 (1.22-11.0)
a High grade, intermediate grade, site distal and local recurrence.
tors relating to survival was also carried out. The significant tumour-related factors were grade, previous local recurrence, distal site of tumour, and tumour diameter > 15 cm (Table IX). Patients with high grade tumours were more likely to die from their sarcomas (Fig. 5a) as were those with previous local recurrence (Fig. 4) and large ( > 15 cm) tumours (Fig. 5b). Those with distal tumours had a decreased risk of death. Fitting four co-factors: high grade, intermediate grade, site distal and previous local recurrence to a proportional hazard model gives a reduction in the log likelihood from 92.49 to 78.78. The fitting of other co-factors gives no further significant reduction in log likelihood with the exception of diameter > 15 cm and timing of radiotherapy. Further analysis shows that tumour diameter > 15 cm and timing of radiotherapy are not independent co-factors. Inclusion of tumour size instead of the timing of radiotherapy results in a marginally better model. This confirms that the group receiving pre-operative radiotherapy probably did worse because they were selected for this treatment on the basis of their inoperability.
The same factors making surgery difficult are shown to predict for poor survival i.e. large, fixed, proximal tumours.
Complications Surgical and radiotherapy complications are detailed in Table X according to fractionation regime used. There were two major infections, and seven major wound breakdowns requiring surgical intervention. Two patients had a major bleed from a femoral artery blow-out and one, treated outside the Royal Marsden, eventually required an above knee amputation. One other amputation was performed for a t r o p h i c ulcer distal to the treated area. Five of 20 patients receiving post-operative weekly fractions of 6.6 Gy developed major complications due to their radiotherapy. In contrast, only 8 of the 82 patients receiving more standard fractionation developed major complications (chi-squared test p = 0.066). Of these eight, six had been treated with high dose pre-operative radiotherapy (2 with an added post-operative boost) and 2 with the
230 TABLE
X
Complications
of surgery and radiotherapy
according
timing of radiotherapy
and fractionation
schedule.
Standard
Weekly
Pre-op
Post-op
Minor
Major
Post-op
Minor
Major
Minor
Major
Surgical Infection
6 x ×
1
3
1
1
Collection
1x
2 ×, +
-
1
-
1
Wound
3 +
4 x x ×
2
3
-
-
breakdown
-
Haemorrhage
-
1+
-
1
-
-
Contracture
-
-
1
-
-
-
1
1
-
1x
-
-
-
-
1
-
-
Foot drop
.
Stiff shoulder
-
Pulmonary
-
-
1x
.
-
1x
-
embolus
Coronary Urinary
retention
.
.
.
-
.
1 .
.
.
Radiotherapy Oedema
-
1
-
-
4
-
Induration
-
-
2
-
1
-
Fibrosis
-
-
4
-
1
2
Pain
.
Contracture
1x
.
.
.
-
1
-
1
1
3
-
Limited movement
2 x
1
2
-
1
2
Ankylosis
-
1
1
1
1
-
Wound
-
2 +
1
-
-
-
1
.
14
15
14
9
breakdown
Amputation Total
x
= Intra-arterial
17
2 .
. 12
.
adriamycin.
+ = Pre and post-operative
radiotherapy.
addition of intra-arterial adriamycin. The small numbers of patients in each group make firm conclusions difficult, but the use of high dose postoperative radiotherapy with 2 Gy fractions seems to be associated with a low major complication rate.
Discussion
In 1950, Cade reported that "radiation has given results when used in combination with surgery better than surgery alone, however extensive the surgery". Since that time there have been a number of published series reporting the results of combining surgery and radiotherapy. In general,
these reports show 85-95% local control at 2-5years [1,4,6,8,10,12,13,17] with a similar proportion of conserved limbs, and about 70~o 5-year disease-free survival. Eilber and Morton [10] reported the use of regional intra-arterial adriamycin and a short course of radiotherapy pre-operatively. They achieved 97 ~o limb salvage with only 8~o local recurrences in a series of resectable tumours, although they were obliged to reduce the dose of radiotherapy because of high initial complication rates. The advantage of this approach over conventional surgery and radiotherapy is unproven since the entry criterion of resectability excludes some unfavourable tumours. Similar results have been achieved without
231 standardisation of surgery and with the use of different radiotherapy schemes. There is considerable variation in the volumes treated by radiotherapists with some centres, including our own, favouring treating the whole anatomical compartment in the first phase whereas others give a smaller margin to the tumour in the phase I volume [17]. Indeed, Shiu [20] has reported excellent results using an interstitial 192Ir implant at the time of the operation as the sole form of radiotherapy. The timing of the radiotherapy also varies from centre to centre. Suit [25] and Barkley [4] favour the use of pre-operative radiotherapy, particularly for large tumours. We prefer post-operative radiotherapy where it is judged possible to perform a satisfactory surgical clearance at presentation. If not, pre-operative radiotherapy is given and time allowed for tumour regression before resection. A post-operative boost is given if the surgical margins are unsatisfactory. This boost may be given by external beam radiotherapy or interstitial 192Ir implant. Our figures, namely a local control rate of 92 ~o at 2 years in previously untreated cases and of 75 To in locally recurrent cases, are similar to those reported from other major centres [1,4,6,8,10,12,13,17]. This suggests that the variations in both the timing and the techniques of radiotherapy practised in different institutions are not significantly important. However, the use of pre-operative radiotherapy can cause fixed inoperable tumours to become resectable and thus increase the number of patients suitable for limb conservation. This must be taken into consideration in comparing results from different centres. We have shown that patients with initially fixed inoperable tumours have a particularly poor prognosis making limb conservation even more valuable for these patients. The aim of this study was to identify some of the factors involved in failure of local control and survival. The number of recurrences is small and the factors involved in local recurrence are all interrelated. Only previous local recurrence was found to be significantly associated with further
local recurrence in our study. This does not rule out the likelihood that other factor are also important. Suit [25] has reported grade as well as size as a prognostic factor in local control - and survival as we also find. We have not confirmed the importance of tumour grade in local recurrence in our series. No one histological diagnosis predominated in the patients with local recurrence. It is unclear whether soft tissue sarcomas exhibit any clinically useful dose-response relationship to radiation. It is our policy to give 60 Gy to the tumour bed and other centres give a similar dose [13,24]. There is no evidence from clinical work that use of higher doses reduces local recurrence rates. Carabell and Goodman [8] considered that the dose-response relationship in soft tissue sarcoma is probably fairly flat. Lindberg [13] reported similar local control with fewer complications on reducing the dose used from 75 to 60 Gy. In fact, better local control was seen in a small group of patients with poor prognosis tumours given 50 Gy in 5 weeks as pre-operative radiotherapy. Thirteen of the 24 patients achieving local control with pre-operative radiotherapy in Suit's series [24] had received less than 50 Gy. In our study dose, recorded as either Gray or in rets received was not a factor in local control. This study reinforces the difficulties inherent in trying to derive a dose-response relationship from retrospective studies, where the doses used are often determined by certain selection criteria. Although the dose-response of sarcomas is uncertain it is established that morbidity increases over 60 Gy and particularly with doses above 75 Gy [ 10,19]. One method of giving an increased effective tumour dose without increasing late damage is by using hyperfractionation. We are at present using such a schedule and will assess whether this results in improved local control and/or a change in morbidity. Our previous study [3] of large fractions of 6.6 Gy given once a week for 6 weeks produced no apparent benefit in tumour control but did increase morbidity. Large fractions are no longer used except for convenience in a palliative situation.
232 In summary, control of local disease is possible, even following relapse, in most patients without resorting to amputation. The safety of the limb conservation approach is confirmed. The major problem in the management of soft tissue sarcoma remains systemic dissemination. Some small trials have suggested increased survival with the use of adjuvant chemotherapy in high grade soft tissue sarcomas [ 17,16], but larger trials have not confirmed this. The latest report from the E O R T C suggests improved local control in the patients with non-extremity tumours receiving adjuvant combination chemotherapy, but no survival advantage [ 5 ]. The evidence for the role of adjuvant chemotherapy in the management of adult extremity soft tissue sarcomas outside a trial situation is not strong, and its routine use is not part of our present treatment policy.
6
7 8 9
10
11
12
Acknowledgements Thanks to Nicky McKean and Sheila Macmillan for their help in entering and updating the data on the Sarcoma Unit database.
13
14
References 1 Abbatucci, J. S., Boulier, N., de Ranieri, J., Mandard, A. M. Tanguy, A. and Busson, A. Radiotherapy as an integrated part of the treatment of soft tissue sarcomas. Radiother. Oncol. 2: 115-121, 1984. 2 Antman, K., Suit, H.D. and Amato, D. Preliminary results of randomized trial of adjuvant doxorubicin for sarcomas: lack of apparent difference between treatment groups. J. Clin. Oncol. 2: 601-608, 1984. 3 Ashby, M.A., Ago, C.T. and Harmer, C.L. Hypofractionated radiotherapy for sarcomas. Int. J. Radiat. Oncol. Biol. Phys. 12: 13-17, 1986. 4 Barkley, Jr., H.T., Martin, R.G., Romsdahl, M.M. Lindberg, R. and Zagars, G.K. Treatment of soft tissue sarcomas by preoperative irradiation and conservative surgical resection. Int. J. Radiat. Oncol. Biol. Phys. 14: 693-699, 1988. 5 Bramwell, V., Rouesse, J., Steward, W., Santoro, A., Buesa, J., Stafford-Koops, H., Wagener, T., Somers, R., Ruka, W. and Markham, D. European experience of adjuvant chemotherapy for soft tissue sarcoma: interim
15
16
17
18
report of a randomised trial of cyvadic versus control. Dev. Oncol. 55: 156-163, 1988. Brennan, M.F., Shui, M.H., Collin, L., Hilaris, B., Magill, G., Lane, J., Godbold, J. and Hajdu, S.I. Extremity soft tissue sarcomas. Cancer Treat. Symp. 3: 71-81, 1985. Cade, S. Soft tissue tumours, their natural history and treatment. Proc. R. Soc. Med. 44: 19-36, 1950. Carabell, S. C. and Goodman, R.L. Radiation therapy for soft tissue sarcomas. Semin. Oncol. 8: 201-206, 1981. Collin, C. F., Friedrich, C., Godbold, J., Hajdu, S. and Brennan, M.F. Prognostic factors for local recurrence and survival in patients with localized extremity softtissue sarcoma. Semin. Surg. Oncol. 4: 30-37, 1988. Eilber, F. R., Giuliano, A. E., Huth, J. F., Mirra, J. and Morton, D.L. Limb salvage for high-grade soft tissue sarcomas of the extremity: experience at the University of California, Los Angeles. Cancer Treat. Symp. 3: 49-57, 1985. Eilber, F. R., Giuliano, A. E., Huth, J. F. and Morton, D.L. A randomized prospective trial using postoperative adjuvant chemotherapy (adriamycin) in high-grade extremity soft-tissue sarcoma. Am. J. Clin. Oncol (CCT). 11: 39-45, 1988. Lindberg, R. D., Martin, R. G., Romsdahl, M. M. and Barkley, Jr., H.T. Conservative surgery and postoperative radiotherapy in 300 adults with soft tissue sarcomas. Cancer 47: 2391-2397, 1981. Lindberg, R.D. Treatment of localized soft tissue sarcomas in adults at M. D. Anderson hospital and Tumor Institute. Cancer Treat. Symp. 3: 59-65, 1985. Mason, M., Harmer, C. L. and Westbury, G. Late normal tissue damage following intra-arterial adriamycin plus radiotherapy and conservation surgery for soft tissue sarcomas. (Abstr.). Br. J. Cancer. 56: 878, 1987. Peto, R., Pike, M., Armitage, P., Breslow, N. E., Cox, D. R., Howard, S. V., Mantel, N., McPherson, K., Peto, J. and Smith, P.G. Design and analysis of randomized clinical trials requiring prolonged observation of each patient: analysis and examples. Br. J. Cancer 35: 1-39, 1977. Picci, P., Bacci, G., Gherlinzoni, F., Capanna, R., Mercuri, M., Ruggieri, P., Baldini, N., Avella, M., Pignatti, G. and Manfrini, M. Results of a randomized trial for the treatment of localized soft tissue tumors (STS) of the extremities in adult patients. Dev. Oncol. 55: 144-148, 1988. Porter, D.A., Kinsella, T., Glatstein, E., Wesley, R., White, D.E., Seipp, C.A., Chang, A. E., Lack, E.E., Costa, J. and Rosenberg, S.A. High grade soft tissue sarcomas of the extremities. Cancer 58: 190-205, 1986. Rosenberg, S.A. Prospective randomized trials demonstrating the efficacy of adjuvant chemotherapy in adult patients with soft tissue sarcomas. Cancer Treat. Rep. 68: 1067-1078, 1984.
233 19 Salinas, R., Hussey, D.H., Fletcher, G.H., Lindberg, R. D., Martin, R. G., Peters, L.J. and Sinkovics, J. G. Experience with fast neutron therapy for locally advanced sarcomas. Int. J. Radiat. Oncol. Biol. Phys. 6: 267-272, 1980. 20 Shiu, M. H., Turnbull, A. D., Nori, D., Hajdu, S. and Hilaris, B. Control of locally advanced extremity soft tissue sarcomas by function-savingresection and brachytherapy. Cancer 53: 1385-1392, 1984. 21 Simon, M. A., and Enneking, W.F. The management of soft tissue sarcomas of the extremities. J. Bone Joint Surg. 58: 317-327, 1976. 22 Stotter, A. T., McLean, N. R., Fallowfield, M. E., Breach, N. M. and Westbury, G. Reconstruction after excision
of soft tissue sarcomas of the limbs and trunk. Br. J. Surg. 75: 774-778, 1988. 23 Stotter, A.T., A'Hern, R.P., Fallowfield, M.E. and Westbury G. The influence of local recurrence of extremity soft tissue sarcomas on metastasis and survival. Cancer, in press, 1990. 24 Suit, H. D., Mankin, H. J. and Wood, W.C. Pre-operative, intra-operative, and post-operative radiation in the treatment of primary soft tissue sarcoma. Cancer 55: 2659-2667, 1985. 25 Suit, H.D., Mankin, H.J., Wood, W.C., Gebhardt, M. C., Harman, D. C., Rosenberg, A., Tepper, J. E. and Rosenthal, D. Treatment of the patient with stage Mo soft tissue sarcoma. J. Clin. Oncol. 6: 854-862, 1988.
221
RADION00706
Treatment of extremity soft tissue sarcomas with surgery and radiotherapy M. R o b i n s o n 1, L. B a I T 2, C. Fisher 3, I. F r y a t t 5, A. Stotter 2, C. H a r m e r 1, E. Wiltshaw 4 and G. W e s t b u r y 2 Departments of ~Radiotherapy, 2Surgery, 3Histopathology, 4Medicine, and 5Computing and Statistics, Sarcoma Unit, Royal Marsden Hospital, London, U.K. (Received 5 April 1989, revision received 29 November 1989, accepted 15 January 1990)
Key words: Extremity; Sarcoma; Radiotherapy; Surgery; Local control; Survival
Summary The results of treatment with a combination of surgery and radiotherapy of 102 patients with nonmetastatic extremity soft tissue sarcoma are reported. Seventy-nine patients were previously untreated and 23 had locally recurrent disease. Sixty-six tumours were situated in the lower limb and 16 in the limb girdles. Fifty-nine were high grade lesions, and 64 were over 5 cm in length. Surgical clearance was "good" (wide or radical) in only 34 cases. Sixty-eight patients received post-operative irradiation, 23 pre-operative irradiation and 11 both pre- and post-operative radiotherapy. Seventeen patients subsequently developed local recurrence and 9 of these remain disease-free after further surgery. Actuarial 5 year local control and disease-free survival rates for new cases were 87 and 65.4 ~o ; and for previously recurrent cases these figures fell to 75 and 54.8~o. Following a univariate analysis of patient, tumour, surgical and radiotherapeutic factors only previous local recurrence (p < 0.1 > 0.05) was found to significantly increase the risk of further local relapse. Multivariate analysis found high tumour grade [relative risk (RR) 8.4], tumour size > 15 cm (RR 3.66), previous local recurrence (RR 6.47) and proximal site (RR 12.7) to be independent poor risk factors for survival.
Introduction Over the last 25 years the management of extremity sarcomas has evolved from radical ablative surgery alone to a policy of limb conservation using a combination of tumour resection and
adjuvant high dose radiotherapy. The success of this approach was reported as early as 1950 by Cade [7]. Simon and Enneking [ 21 ] reported that "adequate" surgery alone results in 98 ~/o local control. This was however at the expense of amputation in
Address for correspondence: M. Robinson, Department of Radiotherapy, Sarcoma Unit, Royal Marsden Hospital, Fulham Rd., London SWJ 6JJ, U.K. 0167-8140/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
222 over 5 0 ~ of cases. All those defined as having "inadequate" surgery failed locally. Lindberg [3] using similar definitions of surgical clearance as the sole treatment modality reported that an intracapsular "shell-out" of tumour resulted in a greater than 90 ~o chance of local recurrence, wide excision 50~o and a radical limb-sparing operation on its own 25~o. The addition of high dose radiotherapy to soft part resection has permitted the practice of limb conservation in the management of limb and limb girdle soft tissue sarcomas in a number of centres [1,4,6,8,10,12,13,17]. The local control rates achieved by this combination have been similar to that from amputation without prejudicing patient survival [ 17]. The goal of combined treatment is a functioning limb without local recurrence. The effect of local recurrence on survival remains uncertain. Some authors [9] associate local recurrence with decreased survival. It has been our finding [23] that local recurrence is an independent poor risk factor in survival. Some important questions concerning the use of radiotherapy in this situation are as yet unanswered. The timing of the radiotherapy in relation to surgery, the extent of surgery required, the extent of apparently normal tissue around the tumour bed to be included in the irradiated volume, and the best dose and fractionation schedule are still unresolved issues. The aim of this study was to review the results of treatment of the 102 cases of limb and limb girdle soft tissue sarcomas treated with curative intent, with both surgery and radiotherapy, by the Sarcoma Unit of the Royal Marsden Hospital over the last 7 years.
Patients and methods
Between 1981 and 1987, 222 patients with soft tissue sarcomas of the limb or limb girdle were treated at the Royal Marsden Hospital. This group does not include patients with desmoids or childhood rhabdomyosarcomas. One hundred and fourteen were treated with surgery alone. Six
were treated with palliative radiotherapy only as surgery was contraindicated because of their general medical condition or the presence of metastases. One hundred and two have been treated by a combination of surgery and radiotherapy. These patients form the basis for this report. No patient is excluded from this series for reasons of inoperability. There were 63 males and 39 females. None had detectable metastases at the time of definitive treatment or had received previous radiotherapy. Computed tomography of the lungs is used routinely in the staging of these patients. Adjuvant systemic chemotherapy was used in only four cases and as a pre-operative intra-arterial infusion with adriamycin in 12 cases [ 14]. In 26 cases the surgery had been performed outside the Royal Marsden Hospital. The median age was 45 years (range 11 to 77).
Surgery The principles of surgical treatment in this Unit have already been described [22]. Where the sarcoma was considered to be operable at referral surgery was usually performed first. Where possible a radical compartmental resection was performed, though for reasons of tumour site and local anatomy this was feasible in less than 15Yo of our patients with limb and limb girdle sarcomas (personal written communication, Stotter, A., July 1988). Surgical clearance was defined using Enneking's criteria [21] and in our series was termed "good" (i.e. radical or wide) in only 34/102 of our cases (Table I). In four cases an excisional biopsy only had been performed by the referring surgeon but further surgery was not considered to be possible without significant functional deficit, and the patients proceeded to radical radiotherapy. At operation, nine tumours were found to be superficial to the deep fascia, 13 both superficial and deep and the remainder deep. Only seven amputations were performed; one was undertaken as primary treatment in another centre before later referral to the Royal Marsden Hospital with a local recurrence; one was a
223 TABLE I Surgical clearance achieved in series of 102 soft tissue s a r c o m a s of limb and limb girdle. Excision biopsy alone Marginal Wide Radical
4 47 21 13
planned amputation of the thumb following preoperative radiotherapy for recurrent disease and the remaining five were required for local recurrence following failure of combined surgery and radiotherapy.
Radiotherapy Post-operative radiotherapy was given to all patients who had high grade tumours and to those with a low/intermediate grade tumour where a wide or radical clearance was not possible, or which recurred after one or more attempts at control by surgery alone. The target volumes have been defined three dimensionally by the routine use of computed tomographic (CT) scans and more recently by the use of magnetic resonance imaging. Two target volumes were defined. The first included all those tissues considered to be at risk of microscopic spread. Where the tumour was intra-compartmental this involved treating the whole compartment. This volume was usually taken to 50 Gy, 2 Gy per fraction, 5 fractions per week. A strip of normal tissue was spared along the length of the irradiated limb and joints were shielded where possible. Where the sarcoma was inoperable at presentation and radiotherapy was given pre-operatively (34 cases), treatment was completed at this dose (or equivalent) or sometimes at 40 Gy in 4 weeks. If the tumour was still inoperable after 50 Gy a further 10 Gy was given and the patient observed. In some sarcomas clinical response was slow and operation was delayed several months. When radiotherapy was given post-operatively (68 patients), the second target volume consisting of the tumour bed and scar with a 2 cm margin
was treated to 10-20 Gy in 5-10 daily 2 Gy fractions to bring the usual total dose to 60 Gy or equivalent in 6 weeks. Following pre-operative irradiation and surgical resection a further 10 Gy in 5 daily fractions was given to 11 patients in whom the resection margin was narrow. Only patients in whom tumour excision was attempted are included in this study. Details of the surgery, timing of radiotherapy, fractionation and range of doses used are given in Tables II and III. Over 50~o of the patients were treated using 2 Gy fractions. However, during the early part of this period there was a study ofhypofractionation using 6.6 Gy fractions given once a week [3]. Post-operatively patients usually received 6 fractions to give a total dose of 39.6 Gy. At present, we are investigating a hyperfractionation protocol using 1.25 Gy twice daily, 5 days a week for 6 weeks. Four patients from this study are included in this report. The radiation technique was selected to tailor T A B L E II Surgical clearance, timing of radiotherapy and fractionation used. Surgical clearance
S t a n d a r d fractionation pre-op
post
pre and post
Excision biopsy Intracapsular Marginal Wide Radical
1 11 4 4
8 26 x × 13 x 6
1× 2 4 2
Total
20
53
9
6.6 Gy weekly Excision biopsy Intracapsular Marginal Wide Radical
-
Total × = Hyperfractionation cases.
2 6 7 2 1
1 1 -
18
2
224 T A B L E III Fraction sizes and range of doses used in treatment of 102 limb and limb girdle sarcomas. Fraction size
No. of patients
Dose range (Gy)
I Shoulder 4 Axilla
1.25 a 1.8 2-2.25 2.25-2.5 3 3.5 4.4
4 4 64 6 2 1 1
62.5-75 60-70 40-66 45-56 50 and 60 42 40
6 Upper a r m 3 Elbow 6 Forearm
Buttock 3 Inguinal 6 Femoral • 2 Thigh
2 Wrist 3 Hand
43
a Twice daily. Popliteal 1 Knee 3
the treatment volume to the target volume. Patients were often immobilized in custom-made casts and the treatment plan produced with the use of CT planning scans, using two or more fields, all of which were usually treated daily (see below). Patients were treated on a 5 MeV linear accelerator sometimes using an extended SSD of 110 cm where field sizes above 40 cm were required. Seventy-nine patients were treated for primary tumours and 23 for locally recurrent disease. Three patients had had more than one recurrence prior to the use of radiotherapy. Five cases were situated at the shoulder girdle, 11 at the pelvic girdle, 20 in the upper limb and 66 in the lower limb (Fig. 1). The median follow-up was 37months (range 101 to 3160 days). All the tumour histology was reviewed by the same pathologist (C.F.).
Statistics Results are presented as actuarial local control and disease-free survival rates. The error bars on the graphs represent the 95 ~o confidence intervals of the curve at that point. The number of patients developing local failure and/or distant metastasis are reported. Local control means that the patient has been continuously free of tumour at the primary site, and disease-free survival means that they have been continuously free of disease at all
Calf
11
Shin 2
Foot 6
Fig. 1. The anatomical sites of 102 limb and limb girdle soft tissue sarcomas.
sites. For the purposes of determining actuarial local control rates, patients who had local control but died of distant metastases or intercurrent illness were removed from the analysis at the last TABLE IV Factors assessed for contribution to survival and failure of local control. Age < 40 and < 60 years Sex Tumour size Skin involvement Bone involvement Surgical clearance Upper or lower limb Proximal or distal site Primary or recurrent disease Timing of radiotherapy Radiation field margin: > 5 era, > 10 cm, > 20 cm Radiotherapy dose: > 45 Gy, or > 55 Gy Ret value of radiotherapy schedule Use of intra-arterial adriamycin
225 follow-up examination. Time to local failure was plotted according to a number of patient, tumour and treatment variables and comparisons made between groups using the log-rank method of analysis [ 15]. In looking at disease-free survival, patients who died disease-free were censored at last follow-up examination. Cox regression analysis using the B M D P statistics package was used in an effort to determine the significant factors involved in failure of local tumour control and survival. The patient, tumour and treatment related variables studied are detailed in Table IV. The radiotherapy factors studied included dose in Gray and rets; fraction size and number; timing of radiotherapy in relation to surgery; and an estimate of the margin given the tumour (calculated by subtracting the maximum tumour size from the maximum field size and dividing by 2).
Results
The distribution of histological diagnosis is shown in Table V. Consistent with other contemporary series [ 17,24] there were 33 malignant
TABLE VI Staging of 102 limb and limb girdle soft tissue sarcomas. Stage
No. of patients
1A 1B 1 unknown 2B 3A 3B 3 unknown 4A Grade unknown
5 17 2 12 24 33 1 2 1
fibrous histiocytomas, 23 synovial sarcomas and 24 liposarcomas. Fifty-nine tumours were high grade, 17intermediate and 24 low grade; 2 remained unclassified. Sixty-four of the tumours were more than 5 cm in size. The largest was 30 cm in length. In three cases the size was not documented. The details of the UICC staging of these tumours is given in Table VI. Two patients had enlarged regional lymph nodes at presentation. Both had pre-operative radiotherapy and in one of the cases there was no residual tumour at surgery.
TABLE V Histology of the 102 soft tissue sarcomas. MFH Synovial sarcoma Liposarcoma Myxoid WDLL Pleomorphic NOS Sarcoma NOS Leiomyosarcoma Epithelioid sarcoma Rhabdomyosarcoma Fibrosarcoma Malignant peripheral nerve sheath tumour Haemangiosarcoma Chondrosarcoma Clear cell sarcoma
33 23 24 17 3 2 1 6 4 3 3 2 1 1 1 1
M F H = Malignant fibrous histiocytoma; WDLL = well differentiated lipoma like; NOS = not otherwise specified.
Local control
There have been 15 local recurrences; 10 in the 79 new cases and 5 in the 23 previously recurrent cases. There is no significant difference between the actuarial plots of time to local recurrence of the primary and previously recurrent groups ( p > 0 . 1 ) . At 2years the former showed 92~o local control and the latter only 75 ~o (Fig. 2). One local recurrence occurred after distant relapse, one synchronously and 4 have developed metastases after initial local failure. Only two recurrences occurred close to but outside the irradiated area, the remainder lay within the treatment volume. The details of these patients are shown in Table VII. Of the 15 patients suffering local recurrence 9 have been salvaged without developing metastases following one or more operations. In three cases, further radiotherapy
226 local failure occurred first. In only two patients was local control not eventually achieved. The details of the treatments used for local relapse are detailed in Table VIII. Only three amputations were performed. Two of these 3 patients are disease-free at 11 and 38 months, respectively. The third patient relapsed locally and systemically' 6 months after a hindquarter amputation with marginal clearance. Local control was not achieved by excision biopsy and radiotherapy and the patient died 8 months later.
100-
8
c
p
90-
8o.
l
L
~ 7o. ~
(50-
o c
50-
B 4o. ~a
:30-
g o L a_
_
20-
0
_
Primary
.......
Locally
'H; ......
0
recurrent
*I . . . . . . . 1
""1'"'~*'""1 2
3
Time
since
radiotherapy
RMH
........
~"1 ........... 4
I ~. . . . . . . . . . 5
I'"H*'"~'I 6
7
(years)
Fig. 2. Actuarial plot of time to local recurrence in primary and previously recurrent limb and limb girdle sarcomas.
was given. Six patients have died of metastatic disease. Local control of the primary was achieved in 4 of the 6 patients who developed metastases, was not achieved in one, and was not treated in the remaining case. In only five patients developing metastases has post-radiotherapy TABLE VII Details of the 15 patients suffering local relapse following surgery and radiotherapy.
Site of primary:
Upper limb proximal 2, distal 3 Lower limb proximal 7, distal 3
Initial disease:
Primary 10; previously recurrent 5
Histology:
M F H 4; synovial 4; rhabdomyosarcoma 1; sarcoma NOS 1; haemangiosarcoma 1; fibrosarcoma 1, epithelioid 2; nerve sheath tumour 1
Grade:
High 11; intermediate 1; low 2; unknown 1
Surgical clearance:
Intraeapsular 2; marginal 12; radical 1
Site of recurrence:
In field/adjacent scar 13; marginal 2
Field margins:
Mean 17.2 cm
Rets:
Mean 1775
Number salvaged:
9
MFH = malignant fibrous histiocytoma.
Factors associated with failure of local control Local control of soft tissue sarcomas following combined therapy may be a function of a number of interrelated patient, tumour and treatment factors. However, the small number of local recurrences made an attempt to identify which are most important by Cox regression modelling, impossible. Univariate analysis showed only previous local recurrence (p < 0.1 > 0.05) to be a significant prognostic variable for further local recurrence. Tumour grade (Fig. 3a) did not appear to be important in determining local control. It did significantly influence survival with only a 61% actuarial 5-year survival in those with high grade tumours compared with > 90% in those with low and intermediate grade tumours (log-rank p < 0.1). Size The incidence of local recurrence was not related to increasing tumour size. There was a nonsignificant trend for the reverse to be true (logtrend test p > 0.1). Patients with larger tumours develop metastases earfier, and so less frequently survive to have local recurrences (Fig. 3b). Radiation schedule No relation between dose of radiation in Gray and local control was found. However, different fractionations were used during the period of this study (Table III). Twenty patients were treated with weekly 6.6 Gy fractions. The majority of the patients were treated using 2 Gy fractions daily,
227 TABLE
VIII
Details
of salvage
Surgery
treatment
and
of local recurrences.
DFI
clearance
RXT
CT
(mths)
No.
First relapse
Outcome
LR
(mths) LR
DM
(mths)
(mths)
Excision Intracapsular
9
-
-
0
-
-
64
-
+
2
4
46
Marginal
13
-
+
0
-
-
DF
51
Marginal
32
-
-
0
-
-
DF
11
Marginal
20
-
-
2
4
-
DF
Marginal
5
-
-
0
-
2
Marginal
Marginal
DF
18 + 54
16 + 2
7
-
-
1
2
2
Wide
13
+
-
2a
10
-
DF
+ 8 79
Radical
18
-
-
0
-
-
DF
46
Intracapsular
26
-
-
0
-
-
DF
Marginal
40
-
+
1b
6
6
Radical
31
-
-
0
-
-
None
4
+
-
0
-
0
None
4
-
+
0
-
-
-
-
No treatment
Amputation 11 + 8 DF
38
No surgery
None
12/15 c
Abbreviations: relapse;
DM
DFI
'~ F u r t h e r
XRT;
b Distant
disease
c Metastases
= disease-free
= developing amputation
interval
treatment;
RXT
= radiotherapy;
47 + 3
CT = chemotherapy;
LR = local
metastases. at 60 months
and local recurrence
a t 12 m o n t h s ,
after first RMH
+ 7 DF
for radionecrosis
together
local recurrence
following trauma.
- never locally controlled
after that.
a t 15 m o n t h s .
although four received twice daily fractionation. There is no significant difference between the hypofractionated group and the others in local progression-free survival (Fig. 3c). Without the benefit of a multivariate analysis it is not possible to draw any conclusions about the influence of radiation dosage on tumour control. Only 9 patients had skin involvement at presentation and 7 relapsed locally within 39 months. Local control was also worse in the 12 patients given intra-arterial adriamycin but this is probably a function of patient selection as it was only patients with large high grade tumours who were offered this treatment. The timing of radiotherapy (pre-, post- or pre- and post-surgery) was based upon tumour operability at presentation. It is therefore not possible to determine the influence
of this timing upon subsequent local control. There was, however, no significant difference between the plots of local recurrence-free survival for these groups. Survival Overall, 15 patients with primary tumours and 7 with recurrent tumours died. Twenty-one and six respectively, developed metastases. One patient developed lymph node involvement during radiotherapy, and two others 5 and 8 months after treatment. The 5 year actuarial survival of primary and recurrent groups was 77 and 64.3~o, respectively (Fig. 4). The corresponding disease-free survivals were 65.4 and 54.8~o. A multivariate analysis of the prognostic fac-
228 Limb
100 "
and
limb
girdle
sarcoma
(primary
v local
rec)
90-
~ 80u
70-
o
60-
70-
50-
50-
B 4o. ~ ~
2010.
2
b
30-
~-
,
60-
- .......
High Intermediate
-.-.-,_
LOW
L a
0
"~"'""'1
...........
0
I
1
..... """1
2
Time
since
4030-
........... 3
RMH
I ...... '""1' ...... ""1'"'"'""1 4 5 6
radiotherapy
Primary
20-
- ....
0
(years)
0
.......... I ........... I ........... I ........... I'",', 1 2 3 4
90.
Limb
8 80. 70"
L 5 ~)
50"
2o
(years)
radiotherapy
and limb
girdle
sarcoma
(grade)
90-
.... .... i ........... [............
80.~
7060-
"t 30.
~
RMH
100 -
40. -
since
..... I ........... I" ......... I 5 6 7
Fig. 4. Actuarial survival of patients with primary and previously recurrent limb and limb girdle sarcomas.
100 •
60.
recurrent
10-
7
Time
L L 2
Locally
t ~ no
50. _
10 cm
30.
0
o
b
'"."'""1
...........
1 Time
I'"'""'"1
2 since
.....
'"'"1"'"'"'"1"
3 RMH
4
radiotherapy
.........
5
I ...........
I
6
7
o.
2010.
(years)
..... -.-,-
High Intermediate LOW
a
. . . . . . . . . . . I . . . . . . . . . . . I . . . . . . . . . . . I . . . . . . . . . . . I "~ . . . . . . . . . I ~'t~ . . . . . . . I . . . . . . . . . . . I 1 2 3 4 5 6 7 Time
since
RMH
radiotherapy
(years)
100Limb
90-
,~
80.
~) L_
70-
o
60-
oc
50-
"5 >,
40-
..... ,._.. ....
...............
,. . . . . . . . . . . . . .
and
limb
girdle
(size)
sarcoma
1009080-
.........
,> 7 0 -
i
6o50-
3o. 2
(L
_ _ .......
2o-
4o-
Hypotractionation Other
3o10-
{2.
c
20"
0 0
1 Time
2 since RMH
4
5
radiotherapy
3
(years)
6
7
Fig. 3. Time to local recurrence for 102 extremity sarcomas plotted by (a)tumour grade (high intermediate, low) (b) tumour size ( < 5 cm vs, 5-10 cm vs. > 10 cm); (c) fractionation (6.6 Gy weekly vs. other).
..... .....
< 5crn 5-10 cm > 10 cm
10-
b " ......... I'" ........ I,. ......... I', ......... I ........... I ........... i ........... I 0 1 2 3 4 5 6 7 Time
since
RMH
radiotherapy
(years)
Fig. 5. Survival plotted according to (a) tumour grade (b) tumour size.
229 TABLE IX The independent prognostic factors for survival determined by multivariate analysis. Model
Log likelihood
Reduction in LL
3(2
p
Original 4 ~ + diameter > 15 cm + radiotherapy post-surgery + >15cm+XRT post-surgery
78.78 76.41
2.37
4.75
0.029
76.71
2.07
4.04
0.041
76.33
2.45
4.9
0.086
Co-factors Low grade Intermediate grade High grade Distal Proximal or girdle No local recurrence Prior local recurrence Tumour diameter < 15 cm Diameter > = 15 cm
Relative risk (95~o limits) 1 1.74 (0.23-13.3) 8.4 (1.74-40.5) 1 12.7 (2.6-61.8) 1 6.47 (2.16-19.4) 1 3.66 (1.22-11.0)
a High grade, intermediate grade, site distal and local recurrence.
tors relating to survival was also carried out. The significant tumour-related factors were grade, previous local recurrence, distal site of tumour, and tumour diameter > 15 cm (Table IX). Patients with high grade tumours were more likely to die from their sarcomas (Fig. 5a) as were those with previous local recurrence (Fig. 4) and large ( > 15 cm) tumours (Fig. 5b). Those with distal tumours had a decreased risk of death. Fitting four co-factors: high grade, intermediate grade, site distal and previous local recurrence to a proportional hazard model gives a reduction in the log likelihood from 92.49 to 78.78. The fitting of other co-factors gives no further significant reduction in log likelihood with the exception of diameter > 15 cm and timing of radiotherapy. Further analysis shows that tumour diameter > 15 cm and timing of radiotherapy are not independent co-factors. Inclusion of tumour size instead of the timing of radiotherapy results in a marginally better model. This confirms that the group receiving pre-operative radiotherapy probably did worse because they were selected for this treatment on the basis of their inoperability.
The same factors making surgery difficult are shown to predict for poor survival i.e. large, fixed, proximal tumours.
Complications Surgical and radiotherapy complications are detailed in Table X according to fractionation regime used. There were two major infections, and seven major wound breakdowns requiring surgical intervention. Two patients had a major bleed from a femoral artery blow-out and one, treated outside the Royal Marsden, eventually required an above knee amputation. One other amputation was performed for a t r o p h i c ulcer distal to the treated area. Five of 20 patients receiving post-operative weekly fractions of 6.6 Gy developed major complications due to their radiotherapy. In contrast, only 8 of the 82 patients receiving more standard fractionation developed major complications (chi-squared test p = 0.066). Of these eight, six had been treated with high dose pre-operative radiotherapy (2 with an added post-operative boost) and 2 with the
230 TABLE
X
Complications
of surgery and radiotherapy
according
timing of radiotherapy
and fractionation
schedule.
Standard
Weekly
Pre-op
Post-op
Minor
Major
Post-op
Minor
Major
Minor
Major
Surgical Infection
6 x ×
1
3
1
1
Collection
1x
2 ×, +
-
1
-
1
Wound
3 +
4 x x ×
2
3
-
-
breakdown
-
Haemorrhage
-
1+
-
1
-
-
Contracture
-
-
1
-
-
-
1
1
-
1x
-
-
-
-
1
-
-
Foot drop
.
Stiff shoulder
-
Pulmonary
-
-
1x
.
-
1x
-
embolus
Coronary Urinary
retention
.
.
.
-
.
1 .
.
.
Radiotherapy Oedema
-
1
-
-
4
-
Induration
-
-
2
-
1
-
Fibrosis
-
-
4
-
1
2
Pain
.
Contracture
1x
.
.
.
-
1
-
1
1
3
-
Limited movement
2 x
1
2
-
1
2
Ankylosis
-
1
1
1
1
-
Wound
-
2 +
1
-
-
-
1
.
14
15
14
9
breakdown
Amputation Total
x
= Intra-arterial
17
2 .
. 12
.
adriamycin.
+ = Pre and post-operative
radiotherapy.
addition of intra-arterial adriamycin. The small numbers of patients in each group make firm conclusions difficult, but the use of high dose postoperative radiotherapy with 2 Gy fractions seems to be associated with a low major complication rate.
Discussion
In 1950, Cade reported that "radiation has given results when used in combination with surgery better than surgery alone, however extensive the surgery". Since that time there have been a number of published series reporting the results of combining surgery and radiotherapy. In general,
these reports show 85-95% local control at 2-5years [1,4,6,8,10,12,13,17] with a similar proportion of conserved limbs, and about 70~o 5-year disease-free survival. Eilber and Morton [10] reported the use of regional intra-arterial adriamycin and a short course of radiotherapy pre-operatively. They achieved 97 ~o limb salvage with only 8~o local recurrences in a series of resectable tumours, although they were obliged to reduce the dose of radiotherapy because of high initial complication rates. The advantage of this approach over conventional surgery and radiotherapy is unproven since the entry criterion of resectability excludes some unfavourable tumours. Similar results have been achieved without
231 standardisation of surgery and with the use of different radiotherapy schemes. There is considerable variation in the volumes treated by radiotherapists with some centres, including our own, favouring treating the whole anatomical compartment in the first phase whereas others give a smaller margin to the tumour in the phase I volume [17]. Indeed, Shiu [20] has reported excellent results using an interstitial 192Ir implant at the time of the operation as the sole form of radiotherapy. The timing of the radiotherapy also varies from centre to centre. Suit [25] and Barkley [4] favour the use of pre-operative radiotherapy, particularly for large tumours. We prefer post-operative radiotherapy where it is judged possible to perform a satisfactory surgical clearance at presentation. If not, pre-operative radiotherapy is given and time allowed for tumour regression before resection. A post-operative boost is given if the surgical margins are unsatisfactory. This boost may be given by external beam radiotherapy or interstitial 192Ir implant. Our figures, namely a local control rate of 92 ~o at 2 years in previously untreated cases and of 75 To in locally recurrent cases, are similar to those reported from other major centres [1,4,6,8,10,12,13,17]. This suggests that the variations in both the timing and the techniques of radiotherapy practised in different institutions are not significantly important. However, the use of pre-operative radiotherapy can cause fixed inoperable tumours to become resectable and thus increase the number of patients suitable for limb conservation. This must be taken into consideration in comparing results from different centres. We have shown that patients with initially fixed inoperable tumours have a particularly poor prognosis making limb conservation even more valuable for these patients. The aim of this study was to identify some of the factors involved in failure of local control and survival. The number of recurrences is small and the factors involved in local recurrence are all interrelated. Only previous local recurrence was found to be significantly associated with further
local recurrence in our study. This does not rule out the likelihood that other factor are also important. Suit [25] has reported grade as well as size as a prognostic factor in local control - and survival as we also find. We have not confirmed the importance of tumour grade in local recurrence in our series. No one histological diagnosis predominated in the patients with local recurrence. It is unclear whether soft tissue sarcomas exhibit any clinically useful dose-response relationship to radiation. It is our policy to give 60 Gy to the tumour bed and other centres give a similar dose [13,24]. There is no evidence from clinical work that use of higher doses reduces local recurrence rates. Carabell and Goodman [8] considered that the dose-response relationship in soft tissue sarcoma is probably fairly flat. Lindberg [13] reported similar local control with fewer complications on reducing the dose used from 75 to 60 Gy. In fact, better local control was seen in a small group of patients with poor prognosis tumours given 50 Gy in 5 weeks as pre-operative radiotherapy. Thirteen of the 24 patients achieving local control with pre-operative radiotherapy in Suit's series [24] had received less than 50 Gy. In our study dose, recorded as either Gray or in rets received was not a factor in local control. This study reinforces the difficulties inherent in trying to derive a dose-response relationship from retrospective studies, where the doses used are often determined by certain selection criteria. Although the dose-response of sarcomas is uncertain it is established that morbidity increases over 60 Gy and particularly with doses above 75 Gy [ 10,19]. One method of giving an increased effective tumour dose without increasing late damage is by using hyperfractionation. We are at present using such a schedule and will assess whether this results in improved local control and/or a change in morbidity. Our previous study [3] of large fractions of 6.6 Gy given once a week for 6 weeks produced no apparent benefit in tumour control but did increase morbidity. Large fractions are no longer used except for convenience in a palliative situation.
232 In summary, control of local disease is possible, even following relapse, in most patients without resorting to amputation. The safety of the limb conservation approach is confirmed. The major problem in the management of soft tissue sarcoma remains systemic dissemination. Some small trials have suggested increased survival with the use of adjuvant chemotherapy in high grade soft tissue sarcomas [ 17,16], but larger trials have not confirmed this. The latest report from the E O R T C suggests improved local control in the patients with non-extremity tumours receiving adjuvant combination chemotherapy, but no survival advantage [ 5 ]. The evidence for the role of adjuvant chemotherapy in the management of adult extremity soft tissue sarcomas outside a trial situation is not strong, and its routine use is not part of our present treatment policy.
6
7 8 9
10
11
12
Acknowledgements Thanks to Nicky McKean and Sheila Macmillan for their help in entering and updating the data on the Sarcoma Unit database.
13
14
References 1 Abbatucci, J. S., Boulier, N., de Ranieri, J., Mandard, A. M. Tanguy, A. and Busson, A. Radiotherapy as an integrated part of the treatment of soft tissue sarcomas. Radiother. Oncol. 2: 115-121, 1984. 2 Antman, K., Suit, H.D. and Amato, D. Preliminary results of randomized trial of adjuvant doxorubicin for sarcomas: lack of apparent difference between treatment groups. J. Clin. Oncol. 2: 601-608, 1984. 3 Ashby, M.A., Ago, C.T. and Harmer, C.L. Hypofractionated radiotherapy for sarcomas. Int. J. Radiat. Oncol. Biol. Phys. 12: 13-17, 1986. 4 Barkley, Jr., H.T., Martin, R.G., Romsdahl, M.M. Lindberg, R. and Zagars, G.K. Treatment of soft tissue sarcomas by preoperative irradiation and conservative surgical resection. Int. J. Radiat. Oncol. Biol. Phys. 14: 693-699, 1988. 5 Bramwell, V., Rouesse, J., Steward, W., Santoro, A., Buesa, J., Stafford-Koops, H., Wagener, T., Somers, R., Ruka, W. and Markham, D. European experience of adjuvant chemotherapy for soft tissue sarcoma: interim
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16
17
18
report of a randomised trial of cyvadic versus control. Dev. Oncol. 55: 156-163, 1988. Brennan, M.F., Shui, M.H., Collin, L., Hilaris, B., Magill, G., Lane, J., Godbold, J. and Hajdu, S.I. Extremity soft tissue sarcomas. Cancer Treat. Symp. 3: 71-81, 1985. Cade, S. Soft tissue tumours, their natural history and treatment. Proc. R. Soc. Med. 44: 19-36, 1950. Carabell, S. C. and Goodman, R.L. Radiation therapy for soft tissue sarcomas. Semin. Oncol. 8: 201-206, 1981. Collin, C. F., Friedrich, C., Godbold, J., Hajdu, S. and Brennan, M.F. Prognostic factors for local recurrence and survival in patients with localized extremity softtissue sarcoma. Semin. Surg. Oncol. 4: 30-37, 1988. Eilber, F. R., Giuliano, A. E., Huth, J. F., Mirra, J. and Morton, D.L. Limb salvage for high-grade soft tissue sarcomas of the extremity: experience at the University of California, Los Angeles. Cancer Treat. Symp. 3: 49-57, 1985. Eilber, F. R., Giuliano, A. E., Huth, J. F. and Morton, D.L. A randomized prospective trial using postoperative adjuvant chemotherapy (adriamycin) in high-grade extremity soft-tissue sarcoma. Am. J. Clin. Oncol (CCT). 11: 39-45, 1988. Lindberg, R. D., Martin, R. G., Romsdahl, M. M. and Barkley, Jr., H.T. Conservative surgery and postoperative radiotherapy in 300 adults with soft tissue sarcomas. Cancer 47: 2391-2397, 1981. Lindberg, R.D. Treatment of localized soft tissue sarcomas in adults at M. D. Anderson hospital and Tumor Institute. Cancer Treat. Symp. 3: 59-65, 1985. Mason, M., Harmer, C. L. and Westbury, G. Late normal tissue damage following intra-arterial adriamycin plus radiotherapy and conservation surgery for soft tissue sarcomas. (Abstr.). Br. J. Cancer. 56: 878, 1987. Peto, R., Pike, M., Armitage, P., Breslow, N. E., Cox, D. R., Howard, S. V., Mantel, N., McPherson, K., Peto, J. and Smith, P.G. Design and analysis of randomized clinical trials requiring prolonged observation of each patient: analysis and examples. Br. J. Cancer 35: 1-39, 1977. Picci, P., Bacci, G., Gherlinzoni, F., Capanna, R., Mercuri, M., Ruggieri, P., Baldini, N., Avella, M., Pignatti, G. and Manfrini, M. Results of a randomized trial for the treatment of localized soft tissue tumors (STS) of the extremities in adult patients. Dev. Oncol. 55: 144-148, 1988. Porter, D.A., Kinsella, T., Glatstein, E., Wesley, R., White, D.E., Seipp, C.A., Chang, A. E., Lack, E.E., Costa, J. and Rosenberg, S.A. High grade soft tissue sarcomas of the extremities. Cancer 58: 190-205, 1986. Rosenberg, S.A. Prospective randomized trials demonstrating the efficacy of adjuvant chemotherapy in adult patients with soft tissue sarcomas. Cancer Treat. Rep. 68: 1067-1078, 1984.
233 19 Salinas, R., Hussey, D.H., Fletcher, G.H., Lindberg, R. D., Martin, R. G., Peters, L.J. and Sinkovics, J. G. Experience with fast neutron therapy for locally advanced sarcomas. Int. J. Radiat. Oncol. Biol. Phys. 6: 267-272, 1980. 20 Shiu, M. H., Turnbull, A. D., Nori, D., Hajdu, S. and Hilaris, B. Control of locally advanced extremity soft tissue sarcomas by function-savingresection and brachytherapy. Cancer 53: 1385-1392, 1984. 21 Simon, M. A., and Enneking, W.F. The management of soft tissue sarcomas of the extremities. J. Bone Joint Surg. 58: 317-327, 1976. 22 Stotter, A. T., McLean, N. R., Fallowfield, M. E., Breach, N. M. and Westbury, G. Reconstruction after excision
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