The Role of Multimodality Therapy in Soft-tissue Sarcoma
MURRAY F. BRENNAN, M.D.,* EPHRAIM S. CASPER, M.D.,t LOUIS B. HARRISON, M.D.,* MAN H. SHIU, M.D.,* JEFFREY GAYNOR, PH.D.,§ and STEVEN 1. HAJDU, M.D.1I
Soft-tissue sarcomas are uncommon malignancies. The development during a period of 8 years, in one institution, of a prospective data base incorporating more than 1600 patients with these tumors is described. The most common sites for occurrence are the extremities, but they can occur in any of the soft tissues of the body. Liposarcoma and leiomyosarcoma are the most common histopathologic conditions identified. Prognostic factors for both recurrence and survival include site, histopathology, size, grade, and adequacy of resection. A prospective randomized trial of the use of adjuvant radiation by the brachytherapy technique in extremity lesions has shown a decrease in local recurrence, but no impact on survival. Eligible patients not randomized to the trial show no difference in local recurrence or survival, regardless of whether they received adjuvant radiation.
OFT-TISSUE SARCOMAS are ubiquitous neoplasms that arise in the soft, or connective, tissues of the body. They are diverse in histology and occur at any site throughout the body. Most of them predominate in the extremities. Soft-tissue sarcomas in children, especially the most common form, rhabdomyosarcoma, have been prototypes for multimodality therapy.' Children previously treated only by radical and mutilating surgery can now be treated by more function-sparing procedures, chemotherapy and radiation therapy, with the chance for long-term, disease-free survival.2 The challenge to transfer to adults the improved results seen in children has been one of frustration. The present report documents some of our experiences with these neoplasms and focuses on a recent prospective randomized trial to control local recurrence, by the addition of adjuvant radiation therapy using the brachytherapy technique, in patients with adult extremity soft-tissue tumors. S
Presented at the 11 1 th Annual Meeting of the American Surgical Association, April 1 1-13, 1991, Boca Raton, Florida. Supported by National Cancer Institute grant CA 47179 (to Murray F. Brennan). Address reprint requests to Murray F. Brennan, M.D., Chairman, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021.
From the Departments of Surgery,* Medicine,t Radiation
Oncology,4 Biostatistics,§ and Pathology, || Memorial Sloan-
Kettering Cancer Center, New York, New York
Materials and Methods In 1982 we began a prospective database at Memorial Sloan-Kettering Cancer Center (MSKCC) for all adult (age more than 16 years) patients admitted and treated for soft-tissue sarcoma. This database has been used for the development of prospective evaluations of the management of these tumors and the correlation of clinical and biologic parameters for outcome and survival. All patient tissue biopsies and tumor resections have been reviewed by a single pathologist. All patients have been reviewed and staged on a weekly basis as to extent of disease, and multiple demographic features have been recorded. These include factors known to influence outcome, such as age; sex; tumor site, size, depth, histopathologic grade, and type; and presence or absence of metastasis. A prospective randomized study of the benefit of brachytherapy (BRT) was begun in July 1982 and is reported here as of closure in July 1987. Patients were ineligible if they had received previous radiation therapy or chemotherapy or if they were foreign nationals, for whom long-term follow-up might be difficult. All patients with localized extremity or superficial truncal lesions were considered eligible, providing they had a limb-sparing operation that would completely remove all gross disease without tumor violation and without the need for resection of major vessels, nerves, or bone. Patients were included if they presented either with a primary untreated but biopsied lesion, or with a locally recurrent but nonmetastatic tumor. All patients had a tissue diagnosis of soft-tissue sarcoma before entrance into the trial. Signed informed consent was obtained before operation and intraoperative randomization was performed once
328
MULTIMODALITY THERAPY FOR SOFT-TISSUE SARCOMA
'v o l. _214 -N o. 3
329 The margin of resection of any tumor situated within 1 mm of an inked surface margin of the surgical specimen was considered microscopically positive.
we could determine that all gross tumor could be resected. Tumor violation was an intraoperative exclusion, as was the failure to remove the tumor completely as judged by the operating surgeon. Extracapsular excision, in which a defined gross margin of normal tissue could not be obtained, was acceptable. Stratification was used before randomization for known prognostic vanrables previously identified.34 These included tumor presentation (prmarv or recurrent), tumor size (less than or more than 5 cm), tumor depth (superficial or deep), and tumor grade (high or low). Once randomized, afterloading catheters were placed in the tumor bed, and on the fifth to sixth postoperative day, these catheters were loaded with Inrdium192 sources. A total dose of approximately 4200 to 4500 cGy was delivered in 4 to 6 days to the isodose contour that incorporated the target volume determined at the time of operation.5'6 Patients with high-grade tumors were eligible to receive postoperative chemotherapy as part of a further randomized trial of the benefits of adjuvant chemotherapy, with Adriamycin (Adria Laboratories, Dublin, OH) given by either the bolus or continuous-infusion technique.7 Patient follow-up examinations were performed everv 3 months for the first 3 years, then everv 6 months thereafter. All nonrandomized patients were followed in the same manner as those who were randomized.
Statistical evaluation includes the use of chi square, Kaplan-Meier survival curves, and log-rank analysis, performed where indicated.
Results From 1982 through 1990, we admitted 1685 adults who were more than 16 years old with soft-tissue sarcoma. Most tumors (50%) occurred in the extremities (Fig. 1). The most common histopathologic diagnosis was liposarcoma, followed by leiomyosarcoma and malignant fibrous histiocvtoma (MFH) (Fig. 2). In the extremities and superficial trunk, liposarcoma and MFH were most common, whereas in the retroperitoneum and visceral tissues, leiomyosarcoma predominated. Survival rate based solely on site and individual histopathology are shown in Figures 3 and 4. Because tumor grade and site are so important, we documented outcome based on high-grade status alone within a single site, the extremity (Fig. 5). Between 1982 and 1987, 997 patients were admitted to MSKCC; of 225 eligible patients, 126 were randomized in the trial of BRT. Failure to randomize was due primarily to patient refusal to accept entrance into an 'ex-
Soft Tlssue Sarcoma Site
lower extremity
i FIG. 1. Site of sarcoma in 1685 patients admitted from 1982 to 1990.
672 (40%)
upper extremity 179 (11%) Y other
head & neck
retro/intra-abdom. 242 (14%)
/visceral trunc a 229 (14%)
IMSKCC 7/2/82 - 7/2/90 I
.
86 (6%)
n
-
1685
gen ito u r in a r y 107 (6%)
92 (6%)
78
(6%)
330 330
BRENNAN AND OTHERS
Ann. Surg. * September 1991
BRENNAN AND OTHERS
Ann. Surg. . September
Soft Tissue Sarcoma Histology
lelomyosarcoma (108r°°
301
liposarooma
..:-......
MFH
34 (2%)
271 (16%)
_ rhabdomyosarooma angiosarooms 377(% (2 ) \igS S pin d~spinle cell other .........t ohondrosarooma 42(2%) S N 42 (2s)
o°the8r
143 (6%)
^
MPNT 84 (6%) embryonal rhabdo.
f lbrosarcoms fibrosaroomasynovial 142 (5%) 136 (8%)
MSKCC 7/2/82 - 7/2/90
n
a
FIG. 2. Histopathology of soft-tissue sarcoma for 1685 patients with soft-tissue sarcoma, admitted from 1982 to 1990.
8
1685
Primary Soft Tissue Sarcoma Survival by Site Proportion Surviving
FIG. 3. Survival by site: extremity lesions have a better overall prognosis than reoperitoneal lesions (p < 0.0001) for patients presenting with localized disease, for whom complete follow-up is avail-
I~~~~~~~~~~~~~~~~~~~~~
able.
,-0
20
40
60
80
Time (Months) -
MSKCC 7/1/82
-
7/1/90
extremity (n-676) n
*
1200
+ retroper. (n-179)
100
Vol. 214oNo. 3
331
MULTIMODALITY THERAPY FOR SOFT-TISSUE SARCOMA
Soft Tissue Sarcoma Histopathology lelomyo vreus:
lipo - p-.02
Proportion Surviving
I1
MFH
-p-.002
0.8
FIG. 4. Survival by histopathology for patients with primary (nonmetastatic) tumors at presentation.
0.4-
0.2
.
O 0
10
20
30
Iclomyo. (162)
+
- T8S (96)
40 Months
50
liposarcoma (329) other (406)
80
70
80
lMFH (207)
MSKCC 7/1/82 - 7/1/90 ns1200
Extremity Soft Tissue Sarcoma
Proportion Surviving 0.5 0.84
0.7 _ FIG. 5. Extremity soft-tissue sarcoma. Patients with pri-
mary localized lesions at presentation. Influence of grade is shown.
0.3 0.2 0.1
p . 0.001
80
40
20
0
80
Months
--high grade (417) MSKCC 7/82
-
7/90
n
*
617
1 low grade (200#
100
BRENNAN AND OTHERS
332
Ann. Surg. * September 1991
Soft Tissue Sarcoma Randomized Trial of Adjuvant Brachytherapy
FIG. 6. Schematic showing randomization of patients for
adjuvant brachytherapy.
MSKCC 7/1/82 - 7/1/87
periment.' Of those patients not randomized, approximately 25% received BRT and 75% did not (Fig. 6). Follow-up data dates from March 1, 1991, with a median of 40.75 months for all patients, and 46.5 months for survivors.
The appropriateness of our preoperative stratifications indicated in Table 1, showing patients equally distributed between the two groups according to risk factors. The differences between the numbers entered for the two groups was a consequence of our initial expectation that we would need 250 patients to show effectiveness, and because of multiple prerandomization stratifications, group allocation was performed such that a balance for each stratum would be achieved when 30 patients were entered into each stratum. The fact that 30 patients were not entered into every stratum at the time of closure confirmed the appropriateness of the stratification strategy but resulted in a slight disparity in the total number of patients in each group. The patients were equally distributed by histopathologic diagnosis (Table 2). There were no differences within the two groups between patients with high-grade lesions who received adjuvant Adriamycin, and no difference in the number with positive microscopic margins (Table 3). As expected, nonrandomized patients who received BRT had a greater proportion of large, deep, high-grade lesions than those not receiving BRT (Table 4).
The results of the impact on local recurrence are illustrated in Figure 7, in which any local recurrence is demonstrated to be diminished by the addition of BRT. This is true also when local-only recurrence is examined (Fig. 8). No effect on survival has yet been demonstrated (Fig. 9). Interestingly subset analysis, analyzing only high-grade
are
TABLE 1. Soft-tissue Sarcoma: Randomized Trial ofAdjuvant
Brachytherapy Patient and Tumor Characteristics Age
BRT (n = 56)
no BRT (n = 70)
>50
33 59%
39 56%
5 cm 50 5 cm
MURRAY F. BRENNAN, M.D.,* EPHRAIM S. CASPER, M.D.,t LOUIS B. HARRISON, M.D.,* MAN H. SHIU, M.D.,* JEFFREY GAYNOR, PH.D.,§ and STEVEN 1. HAJDU, M.D.1I
Soft-tissue sarcomas are uncommon malignancies. The development during a period of 8 years, in one institution, of a prospective data base incorporating more than 1600 patients with these tumors is described. The most common sites for occurrence are the extremities, but they can occur in any of the soft tissues of the body. Liposarcoma and leiomyosarcoma are the most common histopathologic conditions identified. Prognostic factors for both recurrence and survival include site, histopathology, size, grade, and adequacy of resection. A prospective randomized trial of the use of adjuvant radiation by the brachytherapy technique in extremity lesions has shown a decrease in local recurrence, but no impact on survival. Eligible patients not randomized to the trial show no difference in local recurrence or survival, regardless of whether they received adjuvant radiation.
OFT-TISSUE SARCOMAS are ubiquitous neoplasms that arise in the soft, or connective, tissues of the body. They are diverse in histology and occur at any site throughout the body. Most of them predominate in the extremities. Soft-tissue sarcomas in children, especially the most common form, rhabdomyosarcoma, have been prototypes for multimodality therapy.' Children previously treated only by radical and mutilating surgery can now be treated by more function-sparing procedures, chemotherapy and radiation therapy, with the chance for long-term, disease-free survival.2 The challenge to transfer to adults the improved results seen in children has been one of frustration. The present report documents some of our experiences with these neoplasms and focuses on a recent prospective randomized trial to control local recurrence, by the addition of adjuvant radiation therapy using the brachytherapy technique, in patients with adult extremity soft-tissue tumors. S
Presented at the 11 1 th Annual Meeting of the American Surgical Association, April 1 1-13, 1991, Boca Raton, Florida. Supported by National Cancer Institute grant CA 47179 (to Murray F. Brennan). Address reprint requests to Murray F. Brennan, M.D., Chairman, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021.
From the Departments of Surgery,* Medicine,t Radiation
Oncology,4 Biostatistics,§ and Pathology, || Memorial Sloan-
Kettering Cancer Center, New York, New York
Materials and Methods In 1982 we began a prospective database at Memorial Sloan-Kettering Cancer Center (MSKCC) for all adult (age more than 16 years) patients admitted and treated for soft-tissue sarcoma. This database has been used for the development of prospective evaluations of the management of these tumors and the correlation of clinical and biologic parameters for outcome and survival. All patient tissue biopsies and tumor resections have been reviewed by a single pathologist. All patients have been reviewed and staged on a weekly basis as to extent of disease, and multiple demographic features have been recorded. These include factors known to influence outcome, such as age; sex; tumor site, size, depth, histopathologic grade, and type; and presence or absence of metastasis. A prospective randomized study of the benefit of brachytherapy (BRT) was begun in July 1982 and is reported here as of closure in July 1987. Patients were ineligible if they had received previous radiation therapy or chemotherapy or if they were foreign nationals, for whom long-term follow-up might be difficult. All patients with localized extremity or superficial truncal lesions were considered eligible, providing they had a limb-sparing operation that would completely remove all gross disease without tumor violation and without the need for resection of major vessels, nerves, or bone. Patients were included if they presented either with a primary untreated but biopsied lesion, or with a locally recurrent but nonmetastatic tumor. All patients had a tissue diagnosis of soft-tissue sarcoma before entrance into the trial. Signed informed consent was obtained before operation and intraoperative randomization was performed once
328
MULTIMODALITY THERAPY FOR SOFT-TISSUE SARCOMA
'v o l. _214 -N o. 3
329 The margin of resection of any tumor situated within 1 mm of an inked surface margin of the surgical specimen was considered microscopically positive.
we could determine that all gross tumor could be resected. Tumor violation was an intraoperative exclusion, as was the failure to remove the tumor completely as judged by the operating surgeon. Extracapsular excision, in which a defined gross margin of normal tissue could not be obtained, was acceptable. Stratification was used before randomization for known prognostic vanrables previously identified.34 These included tumor presentation (prmarv or recurrent), tumor size (less than or more than 5 cm), tumor depth (superficial or deep), and tumor grade (high or low). Once randomized, afterloading catheters were placed in the tumor bed, and on the fifth to sixth postoperative day, these catheters were loaded with Inrdium192 sources. A total dose of approximately 4200 to 4500 cGy was delivered in 4 to 6 days to the isodose contour that incorporated the target volume determined at the time of operation.5'6 Patients with high-grade tumors were eligible to receive postoperative chemotherapy as part of a further randomized trial of the benefits of adjuvant chemotherapy, with Adriamycin (Adria Laboratories, Dublin, OH) given by either the bolus or continuous-infusion technique.7 Patient follow-up examinations were performed everv 3 months for the first 3 years, then everv 6 months thereafter. All nonrandomized patients were followed in the same manner as those who were randomized.
Statistical evaluation includes the use of chi square, Kaplan-Meier survival curves, and log-rank analysis, performed where indicated.
Results From 1982 through 1990, we admitted 1685 adults who were more than 16 years old with soft-tissue sarcoma. Most tumors (50%) occurred in the extremities (Fig. 1). The most common histopathologic diagnosis was liposarcoma, followed by leiomyosarcoma and malignant fibrous histiocvtoma (MFH) (Fig. 2). In the extremities and superficial trunk, liposarcoma and MFH were most common, whereas in the retroperitoneum and visceral tissues, leiomyosarcoma predominated. Survival rate based solely on site and individual histopathology are shown in Figures 3 and 4. Because tumor grade and site are so important, we documented outcome based on high-grade status alone within a single site, the extremity (Fig. 5). Between 1982 and 1987, 997 patients were admitted to MSKCC; of 225 eligible patients, 126 were randomized in the trial of BRT. Failure to randomize was due primarily to patient refusal to accept entrance into an 'ex-
Soft Tlssue Sarcoma Site
lower extremity
i FIG. 1. Site of sarcoma in 1685 patients admitted from 1982 to 1990.
672 (40%)
upper extremity 179 (11%) Y other
head & neck
retro/intra-abdom. 242 (14%)
/visceral trunc a 229 (14%)
IMSKCC 7/2/82 - 7/2/90 I
.
86 (6%)
n
-
1685
gen ito u r in a r y 107 (6%)
92 (6%)
78
(6%)
330 330
BRENNAN AND OTHERS
Ann. Surg. * September 1991
BRENNAN AND OTHERS
Ann. Surg. . September
Soft Tissue Sarcoma Histology
lelomyosarcoma (108r°°
301
liposarooma
..:-......
MFH
34 (2%)
271 (16%)
_ rhabdomyosarooma angiosarooms 377(% (2 ) \igS S pin d~spinle cell other .........t ohondrosarooma 42(2%) S N 42 (2s)
o°the8r
143 (6%)
^
MPNT 84 (6%) embryonal rhabdo.
f lbrosarcoms fibrosaroomasynovial 142 (5%) 136 (8%)
MSKCC 7/2/82 - 7/2/90
n
a
FIG. 2. Histopathology of soft-tissue sarcoma for 1685 patients with soft-tissue sarcoma, admitted from 1982 to 1990.
8
1685
Primary Soft Tissue Sarcoma Survival by Site Proportion Surviving
FIG. 3. Survival by site: extremity lesions have a better overall prognosis than reoperitoneal lesions (p < 0.0001) for patients presenting with localized disease, for whom complete follow-up is avail-
I~~~~~~~~~~~~~~~~~~~~~
able.
,-0
20
40
60
80
Time (Months) -
MSKCC 7/1/82
-
7/1/90
extremity (n-676) n
*
1200
+ retroper. (n-179)
100
Vol. 214oNo. 3
331
MULTIMODALITY THERAPY FOR SOFT-TISSUE SARCOMA
Soft Tissue Sarcoma Histopathology lelomyo vreus:
lipo - p-.02
Proportion Surviving
I1
MFH
-p-.002
0.8
FIG. 4. Survival by histopathology for patients with primary (nonmetastatic) tumors at presentation.
0.4-
0.2
.
O 0
10
20
30
Iclomyo. (162)
+
- T8S (96)
40 Months
50
liposarcoma (329) other (406)
80
70
80
lMFH (207)
MSKCC 7/1/82 - 7/1/90 ns1200
Extremity Soft Tissue Sarcoma
Proportion Surviving 0.5 0.84
0.7 _ FIG. 5. Extremity soft-tissue sarcoma. Patients with pri-
mary localized lesions at presentation. Influence of grade is shown.
0.3 0.2 0.1
p . 0.001
80
40
20
0
80
Months
--high grade (417) MSKCC 7/82
-
7/90
n
*
617
1 low grade (200#
100
BRENNAN AND OTHERS
332
Ann. Surg. * September 1991
Soft Tissue Sarcoma Randomized Trial of Adjuvant Brachytherapy
FIG. 6. Schematic showing randomization of patients for
adjuvant brachytherapy.
MSKCC 7/1/82 - 7/1/87
periment.' Of those patients not randomized, approximately 25% received BRT and 75% did not (Fig. 6). Follow-up data dates from March 1, 1991, with a median of 40.75 months for all patients, and 46.5 months for survivors.
The appropriateness of our preoperative stratifications indicated in Table 1, showing patients equally distributed between the two groups according to risk factors. The differences between the numbers entered for the two groups was a consequence of our initial expectation that we would need 250 patients to show effectiveness, and because of multiple prerandomization stratifications, group allocation was performed such that a balance for each stratum would be achieved when 30 patients were entered into each stratum. The fact that 30 patients were not entered into every stratum at the time of closure confirmed the appropriateness of the stratification strategy but resulted in a slight disparity in the total number of patients in each group. The patients were equally distributed by histopathologic diagnosis (Table 2). There were no differences within the two groups between patients with high-grade lesions who received adjuvant Adriamycin, and no difference in the number with positive microscopic margins (Table 3). As expected, nonrandomized patients who received BRT had a greater proportion of large, deep, high-grade lesions than those not receiving BRT (Table 4).
The results of the impact on local recurrence are illustrated in Figure 7, in which any local recurrence is demonstrated to be diminished by the addition of BRT. This is true also when local-only recurrence is examined (Fig. 8). No effect on survival has yet been demonstrated (Fig. 9). Interestingly subset analysis, analyzing only high-grade
are
TABLE 1. Soft-tissue Sarcoma: Randomized Trial ofAdjuvant
Brachytherapy Patient and Tumor Characteristics Age
BRT (n = 56)
no BRT (n = 70)
>50
33 59%
39 56%
5 cm 50 5 cm
