The Contemporary Role of the Use of Radiation Herapy in the Management of Sarcoma

PRACTICAL RADIATION ONCOLOGY FOR THE SURGICAL ONCOLOGIST

THE CONTEMPORARY ROLE OF THE USE OF RADIATION THERAPY IN THE MANAGEMENT OF SARCOMA Anita Mahajan, MD

Approximately 6600 new cases of soft-tissue sarcoma were diagnosed in the United States in 1997 and approximately 4100 deaths resulted from this d i a g n ~ s i sThis . ~ ~ rare group of tumors comprises only 0.48% of all diagnosed malignancies in the United States and accounts for 0.75% of cancer deaths per year.51 Soft-tissue sarcomas arise from cells of mesenchymal origin and are subclassified by the presumed cell of origin.ls The most common histologic subtypes are malignant fibrous histiocytoma (22%-28%), liposarcoma (13%-23%), leiomyosarcoma (10%-20%), and fibrosarcoma (4%Anatomically, sarcomas can arise in any site in which muscle, 11%).30,57,89 fat, fibrous tissues, blood vessels, or supporting cells of the peripheral nervous system exist. The most common anatomic sites of primary involvement are lower extremity (45%),trunk (17%),upper extremity (14%), retroperitoneum (12%),and head and neck (10%).58,65,78,89 The most common presenting sign is a painless mass first noted for a median time of 4 months before diagnosis.39Symptoms may reflect local invasion of the bone or neurovascular structures. Metastatic disease is present in 6% to 20% at time of diagnosis 39,66,89 The most common site of hematogenous spread is lung, followed by bone, liver, and skin. Lymph node involvement is found in approximately 6% of cases and is most common in clear

From the Department of Radiation Oncology, Tufts University School of Medicine, New England Medical Center, Boston, Massachusetts SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 9 NUMBER 3 JULY 2000

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MAHAJAN

cell sarcoma, epithelioid sarcoma, angiosarcoma, rhabdomyosarcoma, and synovial s a r ~ o m a . ~ ~ , ~ ~ Historically, the approach to the treatment of soft-tissue sarcoma has been amputation. Over the last 50 years, however, multimodality approaches using combinations of surgery, radiotherapy, and, more recently, chemotherapy have been studied. This article summarizes the recent data that investigate the contemporary role of radiation therapy in the treatment of soft-tissue sarcomas. Emphasis is placed on the importance of the early evaluation by a multidisciplinary team that consists of a surgical oncologist, radiation oncologist, medical oncologist, pathologist, radiologist, and physiotherapist. Most of this article concentrates on the management of high-grade soft-tissue extremity sarcomas. Retroperitoneal sarcomas and low-grade sarcomas are addressed briefly. PROGNOSTIC FACTORS

Prognostic factors have been evaluated in several different institutional retrospective reviews.1r38,55,83,ss In all of these studies the histologic grade, tumor depth, and tumor size were related to metastatic rate and survival. Local control was affected by surgical margin status as well as the status at presentation of primary versus recurrent tumors. It should be emphasized that independent risk factors have been identified for local recurrence versus metastatic recurrence. A summary of some large studies can be found in Tables 1 to 3. Table 1. PROGNOSTIC FACTORS RELATED TO LOCAL CONTROL 5-Year Local Control

age <50 >50 size <5 cm 5-9 cm 210 cm superficial deep grade 1 2 3

margin

+

primary recurrent bone/NV

+

lymph node

+

Coindre et all2 n = 546

Pisters et a155 n = 1041

Vraa et als5 n = 316

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Table 2. PROGNOSTIC FACTORS RELATED TO DISTANT METASTASIS 5-Year Distant Control

Coindre et allz n = 546

Pisters et aIs5 n = 1041

age <50 >50 size <5 cm 5-9 cm 210 cm upper extremity lower extremity superficial deep grade 1 "

L

3 margin

+

bone/NV

+

lymph node

+-

STAGING

The current American Joint Commission of Cancer (AJCC)staging of soft-tissue sarcoma is shown in Box 1.The 1997staging system, compared with the 1992 one, incorporates the location of the tumor with respect to the superficial fascia as staging parameter. Accordingly, the stage grouping has been r n ~ d i f i e d .The ~ , ~majority ~ of the literature cited in this article refers to the older staging system. Table 3. PROGNOSTIC FACTORS RELATED TO SURVIVAL 5-Year Overall Survival

age <50 >50 size <5 cm 5-9 cm 210 cm upper extremity lower extremity trunk superficial deep grade 1 " L 3 margin + -

lymph node

+-

Coindre et all2 n = 546

Vraa et alas n = 316

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MAHAJAN

Box 1. 1997 AJCC Staging System for Soft-Tissue Sarcoma Primary Tumor (T) TX primary tumor cannot be assessed TO no evidence of primary tumor TI tumor 5 cm or less in greatest diameter T l a superficial tumor T I b deep tumor T2 tumor more than 5 cm in greatest diameter T2a superficial tumor T2b deep tumor Note: Superficial tumor is located exclusively above the superficial fascia without invasion of the fascia; deep tumor is located either exclusively beneath the superficial fascia or superficial to the fascia with invasion of or through the fascia or superficial and beneath the fascia. Retroperitoneal, mediastinal, and pelvic sarcomas are classified as deep tumors. Regional Nodes (N) NX regional lymph nodes cannot be assessed NO no regional lymph node metastasis N1 regional lymph node metastasis Distant Metastasis (M) MX distant metastasis cannot be assessed MO no distant metastasis MI distant metastasis Stage Grouping Stage I A (low grade, small superficial, deep) B (low grade, large, superficial)

GI-2 GI-2

Tla-b T2a

NO NO

MO

Stage II A (low grade, large, deep) B (high grade, small, superficial, deep) C (high grade, large, superficial)

GI-2 G3-4 G3-4

T2b Tla-b T2a

NO NO NO

MO MO MO

Stage Ill (high grade, large, deep)

G3-4

T2b-b

NO

MO

any G any G

any T any T

N1 any N

MO MI

Stage IV (any metastasis)

MO

LIMB SALVAGE

Pathologic evaluation has shown that malignant sarcoma cells infiltrate well beyond the pseudocapsule of the grossly evident lesion; therefore, a generous margin of normal tissue must be removed with the tumor to ensure adequate microscopic margins. This finding is supported by the decrease in local recurrence rates seen after increasingly radical surgeries, as shown in Table 4. Amputation has the lowest rate of recurrence and

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THE USE OF RADIATION THERAPY IN THE MANAGEMENT OF SARCOMA

simple excision the highest. Wide local excision has an intermediate local recurrence rate that can be reduced further with the use of adjuvant radiation therapy. Use of this regimen has the added benefit of functional limb preservation. Cade9addressed this approach in 1951, at which time he concluded "that amputation was indicated in less than a quarter of the total number" of patients with soft-tissue sarcoma. He reported that of 128 patients treated in one of three ways-(1) wide excision with preoperative and postoperative radiotherapy, (2) amputation, alone or with radiation, (3) radiation alone-61%, 38%, and 19%, respectively, were alive at the time of the analysis. Of note, 6 of the 22 patients treated with radiation alone had local control, indicating radiosensitivity of sarcoma cells. Evaluation of 653 patients treated at the Memorial Hospital and the James Ewing Hospital in New York supported these results. Because of the favorable results seen in the combined treatment regimen, it was recommended that a prospective trial be designed to investigate the use of radiation therapy in the treatment of soft-tissue sarcomas.45 Between 1975 and 1981, the National Cancer Institute (NCI) ran a randomized controlled evaluation between the limb-sparing surgery plus radiation versus amputation. The results revealed no significant difference in the 5-year disease-free survival rates (78% versus 71%) or the overall survival rates (88% versus 83%)between the two In this study there is a suggestion for a higher local control in the amputation arm (100%versus 82%;P = 0.006); however, this did not diminish the overall survival rate. The concept of limb salvage has been supported by many other retrospective studies from various institutions, as summarized in Table 5. RADIATION TECHNIQUE

The goal of radiotherapy given in combination with surgery is the optimization of local control with the best functional outcome for the paTable 4. LOCAL FAILURE RATES AFTER INCREASINGLY AGGRESSIVE SURGICAL PROCEDURES Simple Excision

Wide Local Excision

Compartmental Excision

Author

P'oI

WI

(%I

Shieber & Graham71 Abbas et all Harrison et alZ9 Azzarelli4 Shiu et a172 Karakousis & Drisc011~~ Rydholm et aP7 Cantin et allo Rosenberg et alG4

90 65

39 36

Amputation

("/.I 8

33

31 25 13 7

7 0

Table 5. LOCAL CONTROL RATES AND SURVIVAL RATES AFTER LIMB CONSERVING SURGERY WITH PREOPERATIVE OR POSTOPERATIVE RADIOTHERAPY FOR INTERMEDIATE-AND HIGH-GRADE SOFT-TISSUE SARCOMAS

Dose Author

Lindberg et a14' Zagars et a19' Suit et also Potter et aF8 Keus et alS4 Karakousis et alS3 Vraa et alR5 Coindre et all2 Williard et alR9 Le Pechow et a137

Center

Years

Number

MDACC MDACC MGH NCI Neth. CI Ros. Park Aarhus France MSKCC IGR

1963-1977 1966-1991 1971-1985 1975-1982 1977-1983 1977-1994 1979-1993 1980-1989 1982-1990 1984-1993

190 271 220 123 117 46 50 316 557 45

(GY) 65-75 50-65 60-68 63 60 60 50 50 + BRT 55-70

5 yr Local Control (%)

5 yr DiseaseFree Survival (%)

5 yr Overall Survival

61 55 70 65

65 69

75 77 86 92 81 76 88 71 85 75

CI = Cancer institute; BRT = brachytherapy; IGR = Institute Gustave Roussy; MDACC = M. D. Anderson Cancer Center; MGH MSKCC = Memorial Sloan-KetteringCancer Center; NCI = National Cancer Institute; BRT = brachytherapy.

78 42 =

Po)

77 70 55 80 65 62

Massachusetts GeneralHospital;

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tient. It is extremely important for the surgeon to discuss the locations for the incision and drain sites with the radiation oncologist before surgery. Before planning irradiation for a sarcoma, the preoperative imaging scans (ideally CT and MR scans), the surgical operative note, and postoperative imaging should be evaluated. Volume and Dose

The radiation volume should encompass all sites of possible tumor extension for the first 45 to 50 Gy and then should be followed by a reduced field volume that gives a boost dose for the highest risk areas. The boost dose depends on the status of the pathologic margins. If the margins are microscopically positive, then a total dose of 65 to 70 Gy is recommended. For gross residual tumor the dose must be escalated to 70 to 75 Gy. If the margins were negative a total dose of 60 to 63 Gy may be sufficient. An analysis from the Fox Chase Cancer Center suggests that all soft-tissue sarcomas should have more than 62.5 Gy total dose for adequate local control.19Higher doses are definitely associated with a higher risk of morbidity. Lindberg et a141did not detect a reduction of local control when doses were decreased from 65 to 70 Gy to 60 to 65 Gy. The National Comprehensive Care Network (NCCN) guidelines suggest total doses of 64 to 66 Gy with negative margins, 68 Gy with microscopic positive margins, and 70 to 76 Gy with grossly positive margins.14 In the case of postoperative irradiation the initial field encompasses all of the surgical bed with a margin. The recommended margin depends on the grade, size, and anatomic location of the tumor. Most centers recommend between 5 and 15 cm of normal tissue margin for the first 45 to 50 Gy. Generally, if a joint space is near the primary site and it is not involved, the margin can be smaller in that direction. The axial margin is approximately 2 cm on the involved muscle. Care should be taken to avoid treating the full diameter of the adjacent bone if it is not necessary. If there is a postoperative hematoma, it should be covered fully with the initial field because there is a high-risk of tumor seeding in the hematoma. Additionally, any scars related to the surgery, biopsy, or drain sites require coverage. This highlights the need to keep incisions and the resulting scars parallel to the axis of the limb to avoid the need for circumferential irradiation of an extremity. A longitudinal strip of normal tissue always should be maintained outside of the irradiation field to avoid radiationrelated edema of extremity. Bolus is used to decrease the effect of skin sparing of megavoltage photons. The energy used should be low enough to avoid too much skin sparing but high enough to allow adequate penetration to the tumor. The most common energies used are between cobalt 60 and 10 mV photons. Postoperatively, 3 to 4 weeks of healing time is recommended before starting the irradiation. For preoperative irradiation the principles are the same; however, the planning is done with the tumor in situ, which may allow more accurate determination of the planning target volume. Only the biopsy scar re-

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MAHAJAN

quires coverage, which emphasizes the need for a carefully placed incision for tissue evaluation. Typically 45 to 50 Gy is given in 1.8 to 2 Gy fractions preoperatively and a postoperative boost of 10 to 15 Gy is given depending on the pathologic findings. Usually the surgery takes place 2 to 3 weeks after the irradiation to allow adequate resolution of the acute side effects of the irradiation but before significant fibrosis has occurred. Hyperfractionated irradiation has been evaluated for improving local control by Le Pechoux et alS7and Frezza et aLZ2From 1984 to 1993, 62 patients were treated with postoperative irradiation after limb conservation surgery in the first study. Seventeen patients received 45 Gy over 3 weeks in a 1.5-Gy twice a day regimen. The daily doses were separated by at least 6 hours. The remaining 45 patients were treated with a conventional dose of 50 Gy plus a boost of 5 to 20 Gy. There did not appear to be a difference with the hyperfractionated irradiation (HFRT) when comparing local control (75% at 5 years) or long-term morbidity. The authors believed that the HFRT dose may have been too low for an adequate compari~on.~~ In the Italian study, 1.6 Gy was given twice a day to 24 patients with soft-tissue sarcoma preoperatively. Complications were reduced when compared with the previously used treatment regimen of 3 Gy/fraction. The ultimate effect was to reduce the interval to surgery.22

Radiographic Imaging An MR image obtained preoperatively aids immensely in establishing the tumor geometry. MR imaging is more accurate than CT in evaluating the anatomic compartment and individual muscle involvement using the T2-weighted spin echo sequences as well as the difference between vascular structures and tumor using the TI-weighted series.l'~~~ Both CT and MR imaging were equal in evaluating the maximal tumor diameter, detection of tumor depth, delineation of tumor, and neurovascular, osseous, and articular relationship^.^^,'^ This information allows decisions to be made about operability as well as the target volume for irradiation.

Immobilization and Treatment Planning The set-up for limb irradiation requires an accurate, reproducible immobilization technique that allows adequate exposure for the site of interest while allowing minimal normal tissue exposure, such as the contralateral leg. Immobilization is commonly achieved with the use of Alpha Cradle molding material, with which an individualized form is made to hold the patient in place from day to day. Conventionally the field arrangement is an anterior and posterior pair of beams that covers the target volume. Currently, with the availability of three-dimensional treatment planning, other field arrangements that may allow better target coverage and less normal tissue irradiation are possible. This technology allows better visualization of the target volume in the treatment position so that

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511

any rotation of the limb required for repositioning the patient from the diagnostic radiographic evaluations can be appreciated and accounted for while designing a treatment plan. Noncoplanar plans as well as wedges and compensators are used to optimize the dosimetry. It is important to keep the maximum doses away from potential pressure bearing areas such as the knees or the buttocks to minimize tissue morbidity. Inverse planning systems that use intensity-modulated irradiation are currently available and may be useful to deliver dose where critical structures such as bowel, kidney, and liver would otherwise limit the dose. In this type of planning system, the radiation oncologist is able to enter his or her requirement for tumor dose and control probabilities and normal tissue tolerance, and a planning computer searches millions of iterations to provide the best treatment plan to conform to the requirements entered.

PREOPERATIVE VERSUS POSTOPERATIVE IRRADIATION

There has been an ongoing debate about the relative merits of either preoperative or postoperative irradiation in high-grade sarcomas. The benefits of both modalities can be seen in Table 6. The general trend has been to offer preoperative irradiation where limb salvage surgery would be difficult without significant morbidity; for instance, if there is involvement of the neurovascular bundle or extensive involvement near the joint spaces. The possible reduction of tumor size may decrease the extent of surgical resection required. At the Massachusetts General Hospital the Table 6. SUMMARY OF THEORETIC ADVANTAGES AND DISADVANTAGES OF PREOPERATIVE AND POSTOPERATIVE IRRADIATION FOR HIGH-GRADE SOFT-TISSUE SARCOMAS

preoperative irradiation

postoperative irradiation

Advantages

Disadvantages

volume of irradiation decreased48 late radiation damage less because decreased volume tumor in place for planning increased oxygen delivery no delay in irradiation no surgical transplant of cells potentially less extensive surgery patient may be more compliant because surgery is later surgery is immediate no delay in wound healing pathologic specimen unaltered for analysis response to chemotherapy can be evaluated if used preoperatively

delay in wound healing pretreatment pathology specimen usually small chemotherapy response not clear

volume of irradiation increased decreased oxygenation for irradiation patient may be less compliant because surgery already performed

rate of preoperative irradiation has increased over time in the treatment of large extremity sarcomas. Neilsen et a148showed in 26 patients that the field sizes required to treat the lesions preoperatively were less than those required postoperatively. They also found that fewer joints were included in the preoperative field. Two patients required full circumferential limb irradiation in the preoperative field, whereas four required it in the postoperative field.48Of note, the same margin requirements around the target volume were maintained in designing the preoperative and postoperative volumes.

Local Control Local failure rates have been reported by Suit et aln,79to be lower in preoperatively treated patients, especiallyin tumors larger than 5 cm: 80% to 100%versus 50% to 90%.There has been no statistical improvement in overall survival rate because these patients continue to have a high systemic recurrence rate. Pollack et a1 retrospectively reviewed data from 453 patients treated at the M.D. Anderson Cancer Center. The patients were divided into three groups: (1)preoperative irradiation to 50 Gy (n = 128), (2) postoperative irradiation to a mean dose of 64 Gy (n = 165), (3) irradiation with a gross total excision performed before evaluation at M.D. Anderson Cancer Center (n = 160). At 10 years, the local control of the preoperative group and postoperative groups were 88%and 67%,respectively ( P = 0.01).56These data would support the effect of lower doses needed preoperatively theoretically because of enhanced oxygen delivery before surgery to the target area.

Complication Rates Complication rates have been evaluated in the literature. In particular, studies have shown that some degree of wound healing delay occurs in 16% to 37% of patients who receive preoperative i r r a d i a t i ~ n .Sec~,~~ ondary surgery was required in 16.5% (n = 33) of patients, of whom six Factors that increase delay in wound healpatients required amputati~n.~ ing include the width of skin excision, a history of smoking, diabetes, vascular disease, lower extremity site, advanced age of patient, use of brachytherapy boost, and twice a day fractionati~n.~,~~ It should be emphasized that meticulous surgical technique reduces the complication rates with preoperative irradiation. In particular, elimination of dead space, closure under no tension, minimal undermining of skin flaps, use of myocutaneous flaps, and free flaps to aid closure and removal of drains only when drainage is less than 15 mL/d improves outcome^.^ Lindberg et al's41 evaluation of postoperative complications revealed a 6.5% incidence of acute and late toxicities. Extensive soft-tissue necrosis that required amputation, fracture, fibrosis, nerve or vascular damage, and

THE USE OF RADIATION THERAPY IN THE MANAGEMENT OF SARCOMA

513

edema was seen. These particular complications also could occur with preoperative irradiation with the same frequency. A recent prospective trial conducted by the National Cancer Institute of Canada compared preoperative and postoperative irradiation in the curative management of extremity soft-tissue sarcoma. In this trial the primary objective was to compare wound healing complications in the two groups. Eligibility included the need for surgery and irradiation for management. Stratification was by tumor size, less than or more than 10 cm. One hundred ninety patients were accrued from 1994 to 1997. The study was closed early because of highly statistically significant differences in the interim analysis. Thirty-five percent of patients treated with preoperative irradiation had complications versus 17% in the postoperative group (P = 0.01). Other significant factors included volume of tissue resected and lower limb involvement. With 1.9 years of median follow-up, six patients have relapsed locally. Metastatic and survival results are the same. The authors concluded that local anatomic factors should be considered in the scheduling of the irradiation and surgery.50It should be noted that these results confirm the findings of the previously mentioned retrospective analyses. THE ROLE OF BRACHYTHERAPY

Brachytherapy is an irradiation technique that involves the use of intraoperative placement of catheters directly on the surgical bed through which treatment with radioactive isotopes is delivered postoperatively. Normal tissues are spared maximally. Theoretical advantages of this technique over the standard external beam radiotherapy are listed in Table 7. These benefits may be of particular importance in pediatric patients, in whom the decreased volume of irradiated normal tissue is especially de~irable.~~ The typical target volume used for brachytherapy treatment consists of the surgical bed after removal of the tumor with a 2- to 4-cm margin inferior and superior to the tumor, 1.5- to 2-cm margin medial and lateral to the tumor. The catheters are then placed 1 to 2 cm apart, usually in a Table 7. SUMMARY OF THEORETIC BENEFITS OF BRACHYTHERAPY VERSUS EXTERNAL BEAM IRRADIATION IN THE MANAGEMENT OF HIGH-GRADE SOFT-TISSUE SARCOMAS Advantages

external beam irradiation brachytherapy

large margin can be encompassed, including scars no irradiation to staff decreased treatment time decreased volume of normal tissue irradiation low dose rate may be beneficial

Disadvantages

prolonged treatment time more normal tissue treated small margins around high-risk areas are irradiated exposure of staff to radiation

single plane along the area of concern. The catheters are usually placed perpendicular to the axis of the incision to minimize the distortion of the closure. The catheters can be fixed with absorbable sutures to the tumor bed and are secured to the skin using buttons and nonabsorbable sutures. A drain is usually place to minimize the possibility of a seroma. Planning radiographs are then obtained with dummy catheters in place. Loading with the radioactive sources takes place to deliver the irradiation at the isodose curve that best covers the catheters at 40 to 60 cGy/h. In the treatment of high-grade sarcoma, brachytherapy can be used deliver dose either for a postoperative boost with preoperative or postoperative external beam radiotherapy plan or as a single modality. The total dose delivered varies according to the particular goal of the implant. The duration of the implant is proportional to the total dose and dose rate. When used in combination with external beam irradiation, the brachytherapy dose is between 15 and 25 Gy. For definitive treatment after surgery the dose delivered is between 42 and 45 Gy. It is recommended to load the catheters no sooner than the sixth postoperative day to minimize the risk of wound healing problem^.^ A randomized trial of adjuvant brachytherapy was carried out at Memorial Sloan-Kettering Cancer Center.53In this trial, 164 patients treated between 1982 and 1992 were randomized intraoperatively either to adjuvant brachytherapy or to no adjuvant treatment. Eligible patients included persons with completely resected, localized, superficial trunk sarcomas or Dersons with localized extremitv lesions that could be resected completeG by a limb-sparing procedure. The brachytherapy was designed to deliver 42 to 45 Gy over 4 to 6 days with iridium 92. Local recurrences were noted in 13 patients treated with brachytherapy, compared with 25 in the no adjuvant treatment arm ( P < 0.04). Analysis of local control showed that the benefit was restricted to those patients with high-grade tumors.54Correlation between implant dosimetry and the location of the failures revealed that most failures were in field. Aee older than 60 vears was found to be the only prognostic factor relatedvto local failure.'size, location, histologic margin, depth, and primary versus recurrent presentation had no effect on local recurrences. There was no statistically significant difference in freedom from metastatis or disease-specific survival. Complications seen in the brachytherapy group included delayed healing of the surgical wound. Initially the radiation sources were loaded on the first postoperative day, but it was noted on an early analysis that 11 of 23 patients had moderate and major wound complications. Subsequently, loading has occurred after the postoperative day, and since the change in policy only 3 patients in each study arm have developed major or moderate wound complications. Habrand et alZ8reported their experience of brachytherapy in sarcoma treatment at the Institut Gustave Roussy. In their review they concluded that high-dose brachytherapy with conservative surgery is highly effective in small and mid-size lesions located in the extremity and in the head and neck. In the truncal and recurrent tumors, however, they suggested that local control may be improved using a combination of external beam irradiation and possibly chemotherapy.

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Combinations of external beam irradiation and brachvtherawv have been studied. Schray et a170 reported a review of 63 patients in whom implant doses of 15 to 20 Gy were given in combination with external beam doses of 45 to 50 Gy. External beam irradiation was given preoperatively in larger tumors or in tumors near neurovascular bundles. Analysis of local recurrence revealed a 4% rate ( n = 56) in patients treated with a primary diagnosis versus a 33% rate ( n = 9) in patients being treated with a recurrent lesion. Five percent ( n = 40) of vatients had wound healing complications noted with postoperative external beam irradiation versus 25% ( n = 16) in patients treated with preoperative external beam i r r a d i a t i ~ nUse . ~ ~ of a brachytherapy boost has been advocated to improve local control in patients with positive surgical margin^.^ Local control was better (90% versus 59%) and wound healing was equivalent (38% versus 26%) in a study from Memorial Sloan-Kettering Cancer Center in which brachytherapy and postoperative external beam irradiation were compared with brachytherapy alone in cases in which surgical margins were p ~ s i t i v e . ~ Gemer et alZ3proposed that the 65 Gv treatment volume calculated from the dosimetry of the brachytherapy implant and the external beam plan should be larger than the excised tumor volume. Preplanning the brachytherapy plan is highly recommended to achieve this goal. High-dose-rate (HDR)brachytherapy is becoming more available and does have some advantages, in particular enhanced radiation protection for the staff. Koizumi et a136published a series of 14 patients with softtissue and bone tumors who were treated with HDR brachvtherawv. The I J treatments were started between days 4 and 13 after surgery. A total dose of 40 to 50 Gy was given in seven to ten fractions over 4 to 7 days in a twice a day regimen. The dose was prescribed to 5 or 10 mm from the sources. Ultimate local control was seen in 50%. No infection or delayed wound healing was seen. One peripheral nerve palsy was d e ~ c r i b e d . ~ ~ -I

l i

I

'

I

I

J

LOW-GRADE SARCOMAS

One of the established prognostic factors for soft-tissue sarcomas is the grade of the lesion. The grade and histologic subtype of the tumor must be established by an experienced pathologist accustomed to classifying such malignancies. Factors that help establish the grade include differentiation of the tumor, presence and amount of necrosis, and most importantly, the number of mitoses.84Disagreement over the specific type and grade has been studied and suggests that peer review is important for standardizing care and establishing accurate diagnosis because treatment recommendations are markedly different for low-grade versus highgrade lesions.59 Low-grade sarcomas are generally known to have a better overall prognosis than high-grade sarcomas. Adjuvant therapy after surgical resection with negative microscopic margins is not routinely recommended.43Situations in which adjuvant radiotherapy would decrease lo-

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MAHAJAN

cal recurrence include those with tumor recurrence or positive margins.43 Pisters et a154found that adjuvant brachytherapy after complete resection of low-grade sarcomas involving the extremity or superficial trunk did not reduce local recurrence rates and they do not recommend it in this setting.

RETROPERITONEAL SARCOMAS Retroperitoneal sarcomas comprise less than 3% of all soft-tissue sarcomas. There appear to be two peaks of age at diagnosis, one in the first decade and the second in the sixth decade.87Diagnosis is usually delayed until symptoms related to compression of normal structures occur. Hematogenous metastases are uncommon at presentation. CT and MR imaging evaluation are helpful in determining the extent of involvement. The primary modality of treatment consists of surgical debulking. Resectability has improved over time because of better surgical technique. Recently the NCI reported a 73% resectability rate in selected patients.73 Involvement of the large vessels, spinal cord, or nerve plexus renders a patient's tumor unresectable. If a patient has peritoneal seeding or hematogenous spread, resection is not curative. Adjuvant radiotherapy is advocated in most high-grade lesions because of the infiltrative nature of these tumors. Ideally, the radiotherapist should be present at the time of resection to aid in planning the postoperative irradiation and to guide the placement of clips intraoperatively. Preoperative irradiation may be useful to decrease potential seeding and to aid resection. Additionally, having the tumor in situ facilitates the localization of the sarcoma, and the tumor itself may be pushing radiosensitive normal tissues out of the way. The same principles outlined in the previous section are required to plan irradiation for retroperitoneal sarcomas. The additional factor in this location is the recognition of radiosensitive normal tissues: the kidneys, liver, small bowel, and stomach. One whole kidney should be limited to less than 18 Gy. The whole liver should receive less than 30 Gy. A small portion of the small intestine may receive 54 Gy. Doses higher than these could increase complication rates precipitously. 45 Gy is the recommended dose in the preoperative setting. If the surgical margins are close or positive, further irradiation as a 15-Gy intraoperative or postoperative boost should be considered. Postoperatively, doses are limited to 50 to 55 Gy, usually because of small bowel and stomach dose tolerance. Prediction of cure is related to the degree of resection and tumor grade. In a study by Jaques et a13' on 114 patients, despite the fact that 59% had a complete resection, almost half of those patients had a local recurrence, and in 75% of those patients the local recurrence was the first site of failure. Median survival times were related to the extent of surgery: complete resection, 60 months; partial resection, 24 months; and biopsy only, 12 months. These results would indicate a role for radiotherapy to

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improve local control. No randomized study has been conducted to show the effect of regional adjuvant irradiation. The NCI has conducted two randomized studies on retroperitoneal sarcomas. The first study (1977-1981) examined the effect of chemotherapy after surgery and postoperative radiation, 45 Gy in 23 to 30 fractions followed by a boost of 9 Gy in 5 fractions in 37 patients. In this study, 7 patients received an intraoperative radiotherapy (IORT) boost of 20 Gy using 11 MeV electrons followed by external beam irradiation of 35 Gy. Chemotherapy was instituted 3 days before the irradiation and consisted of doxorubicin and cyclophosphamide followed by high-dose methotrexate. The patients who received the IORT also were given a preirradiation dose of misonidazole, a radiosensitizer. Of interest, one cycle of chemotherapy was given during irradiation without a planned break. The actuarial survival rate was 23% at 5 years. Disease-specific survival rate was 31% at 5 years. The grade correlated with survival: grade 1,100%; grade 2,87%; and grade 3,28%. No benefit of adjuvant chemotherapy could be identified in this study. There was a high rate of enteritis, and four deaths were related to therapy. Of the 16 patients who had recurrences, only 1 was in the field of radiation. Eight patients developed peritoneal seeding, and 6 had hematogenous spread of disease.25 From 1980 to 1985, a second study randomized 35 patients to either 20 Gy IORT with 35 to 40 Gy external beam or standard postoperative irradiation of 50 to 55 Gy. Adjuvant chemotherapy also was given in a randomized fashion to the two arms between 1980 and 1981. There was no difference in survival identified between the two groups. Acute and chronic enteritis was reduced in the IORT arm (3 versus 19 patients) but 4 patients (versus 1 in the nonIORT arm) developed lumbosacral or femoral neuropathies in this arm. Fistula formation was more common in the standard treatment arm (6 versus 0). The recommendation resulting from this finding was to limit the dose to 20 Gy or less when a large peripheral nerve is in the IORT field. The conclusion of this study was that the use of IORT minimized complications but led to no improvement in overall ~ u r v i v a l .Gunderson ~ ~ , ~ ~ et a127reported on 20 patients treated with external beam irradiation (45-60 Gy) and IORT (10-20 Gy). Only one patient developed a severe neuropathy, and one patient required surgery for a small bowel obstruction. To minimize potential morbidities, use of organ displacement has been advocated. Omental slings, polyglycolic acid mesh slings, tissue expanders, and gel implants have been used to suspend or displace bowel away from the area receiving irradiation. Ritter et a1'j2describe a system in which a polyglycolic acid mesh sheet is stapled or sewn to the abdominal or thoracic wall and a silicone-shelled breast implant is placed in the pocket, which is then filled with saline to the desired capacity.This system may result in easier removal of the implant upon completion of the therapy because of decreased adhesions between the implant and the normal tissues. This technique could lead to decreased rates of long-term complications such as enterocutaneous fistula formation. The mesh eventually would be absorbed ~pontaneously.~~

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MORBIDITY AND FUNCTIONAL OUTCOME

Several groups have evaluated quality of life with limb conservation. The NCI group retrospectively analyzed information on 152 patients who received treatment between 1975 and 1986. Overall, 84% of the patients were noted to be ambulating without assistive devices and with mild or no pain. Limb contracture was noted in 20%of patients and was correlated to irradiation of a joint space. Higher doses (more than 63 Gy/1.8 Gy fractions) given before 1980, were correlated with chronic pain, edema, decrease in muscle strength, decreased range of motion, and skin telangiectasias. Radiation fields more than 35 cm contributed to edema and decreased strength. Lower extremity lesions were more frequently associated with chronic edema, infection, and ulceration, especially when more than 75%of the diameter of the extremity was irradiated.76Fractures, all of which did heal, were noted in 6% of the total number of patients e ~ a l u a t e dLin . ~ ~et a140studied 12 patients who developed fractures after limb conservation treatment for soft-tissue sarcoma. Interestingly, all of these patients had excision of the periosteum at the time of resection. In an analysis of 54 patients with lower extremity sarcomas treated with limb conservation, 78% patients walked normally, 15% needed an assistive device, and 7% needed a joint support. Thirty percent of the patients had detectable lymphedema, but only 2 patients needed compression stockings. Sixty-eight percent of the patients reported excellent function. In conclusion, the authors found that despite a significant loss of range of motion and muscle power, patients retained excellent limb function and quality of life.63These outcomes also are supported by a study by Keus et a1.34Bell et a16found that poor functional outcome was related to large tumor size, postoperative complications, and neural sacrifice. Talbert et a18' reviewed the experience at M.D. Anderson Cancer Center with respect to soft-tissue sarcomas of the wrist, hand, ankle, and foot and found that conservation surgery with radiation therapy was a feasible treatment with a high rate of disease control and functional limb preservation. In general it is recommended to keep the total dose a low as possible, use CT-based treatment planning to design volumes for irradiation as optimally as possible, avoid joint spaces if possible, and to avoid full circumference limb irradiation. It appears, however, that despite a certain amount of unavoidable measurable morbidity, the quality of life as reported by patients is excellent in most patients who are treated with limb conservation. CHEMOTHERAPY

The role of chemotherapy in primary treatment of sarcoma is not well established. In an adjuvant setting results are mixed. A meta-analysis suggests an improved survival at 5 years.82Another study shows reduced .~ studies show prolocal recurrence but no change in s ~ r v i v a l Other

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519

longation of disease-frees u r ~ i v a l All . ~ ~of, these ~ ~ studies had doxorubicinbased regimens. Neo-adjuvant combined therapy with radiotherapy and chemotherapy has been investigated regarding the endpoints of improving local control and increasing disease-free survival. The radiation therapy oncology group (RTOG) is conducting a phase I1 trial using a combination of mesna, Adriamycin, ifosfamide, and DTIC (dacarbazine) (MAID), with irradiation based on results from the MassachusettsGeneral Hospital suggesting an 81% versus 38% disease-free rate at 5 years in patients who received MAID and radiotherapy versus radiotherapy alone.75An improved complete response rate has been reported by Eilber et all7 using high-dose ifosfamide, Adriamycin, and cisplatinum with irradiation (3.5 Gy x 8). Of 41 patients with gross tumor at start of treatment, an optimistic 49% pathologic complete response rate has been seen.17Neoadjuvant chemotherapy (Adriamycin/ifosfamide) with an accelerated hyperfractionated course of irradiation (1.5-1.6 Gy twice a day to 60 to 64 Gy) has been shown to have 96% resectability with 18% downstaging in a group of patients with locally advanced soft-tissuesarcomas. Local control remains 100%;overall survival rate was 83% at 3 years.69 IMPROVING STANDARD RADIOTHERAPY

Several different techniques to improve local control with radiotherapy have been studied using radiobiologic principles. Goffman et alZ6used iododeoxyuridine (IUDR) with HFRT to treat 36 patients with unresectable tumors. In this study an overall local control rate of 60% was seen. Tumors from 5 to 9 cm had 66% control and those between 15 and 19 cm were controlled 57% of the time. The radiotherapy was delivered at 1.5 Gy twice a day with IUDR infusions planned for two blocks of 14 days. Many patients did not receive the full dose of IUDR because of thrombocytopenia. The mean overall survival of the patients with no metastases was 23 months.26Sondak et a174used a similar strategy for preoperative treatment. In this study resection of locally advanced soft-tissue sarcomas became possible and those sarcomas that were resected with negative margins had excellent local control.74 Razoxane is another radiation sensitizer that blocks dividing cells in the G2 or G2/M phase of the cell cycle, which is the most sensitive phase to irradiation. This drug in conjunction with radiotherapy was studied in a group of 144 patients with soft-tissue sarcomas, including patients with locally advanced, recurrent, or metastatic disease. All patients were given 56 to 60 Gy of irradiation depending on the state of resection. They were randomized to receive razoxane beginning 5 days before irradiation and then concomitantly with the radiotherapy. In the postoperative group there was no difference in local control or survival. In the group with gross disease, the response rate with razoxane was 74% versus 49%.Local control rate was also higher: 64% versus 30%.The acute toxicity was higher, but long-term morbidity was the same.61

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Isolated limb perfusion with tumor necrosis factor and melphalan with or without interferon gamma has been studied.15,16,42,49,86 Results suggest increased resectability with acceptable morbidity. Hyperthermia has been used with radiation with or without chemotherapy to improve control in large sarcomas that may have had some form of previous treatment.20,47 Nakano et a147noted that although there was not a dramatic visible response to hyperthermia with irradiation, pathologically a fibrous layer was found around the tumor that could possibly improve resectability. In this study no local failures were found despite the large size of the primaries. Limb salvage rate was 92%. Neutron irradiation has been studied in the hopes of taking advantage of the greater relative biologic effectiveness of neutrons versus photons. Two clinical studies have suggested that neutron irradiation may result in better resectability for high-and low- to intermediate-grade sarc o m a ~ .Data ~ ~ ,are ~ ~limited because of the lack of availability of neutron treatment facilities. CONCLUSIONS Progress has been made in the treatment of high-grade soft-tissue sarcoma. Use of multimodality therapy makes limb salvage possible with good local control and excellent functional outcome. Carefully planned radiotherapy should be an integral component of the treatment regimen to optimize the functional outcome of the patient. Early involvement of all the involved disciplines allows the best overall treatment strategy to be designed. A pattern-of-care study showed a decrease in the number of amputations performed over time: a 35% rate in 1988 compared with an 11% rate in 1993.57Despite the increased use of wide local excision as a primary modality, this study noted no change in the frequency of the use of adjuvant or neoadjuvant radiotherapy (35%)between the two study eras. Because it is clear that the use of radiotherapy results in improved local control, the author suggests that radiotherapy is being underused. This conclusion is supported by the frequency of local failures noted in this study (15%-18%) versus that seen in major sarcoma centers (5%-lo%), where adjuvant radiation is routinely used in high-risk patients.57 Improvements in radiotherapy techniques using conformal planning systems to spare normal structures may decrease the morbidities currently seen. Use of systemic radiosensitizers and chemotherapy may further reduce local failure and improve quality of life and, ultimately, the quantity of life. References 1. Abbas J, Holyoke E, Moore R, et al: The surgical treatment and outcome of soft-tissue sarcoma. Arch Surg 116:765,1981

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2. Alekhteyar K, Leung D, Brennan M: The effect of combined external beam radiotherapy and brachytherapy on local control and wound complications in patients with highgrade soft tissue sarcomas of the extremity with positive microscopic margin. Int JRadiat Oncol Biol Phys 36:321, 1996 3. Arbeit J, Hilaris B, Brennan M: Wound complications in the multimodality treatment of extremity and superficial trunk sarcomas. J Clin Oncol5:480,1987 4. Azzarelli A: Surgery in soft tissue sarcomas. Eur J Cancer 29A:618,1993 5. Bears 0, Henson D, Hutter R, et al: Manual for Staging Cancer, American Joint Commission on Cancer. Philadelphia, JB Lippincott, 1992 6. Bell R, O'Sullivan B, Davis A, et al: Functional outcome in patients treated with surgery and irradiation for soft tissue tumours. J Surg Oncol48:224,1991 7. Bramwell V, Rouesse J, Steward W, et al: Adjuvant CYVADIC chemotherapy for adult soft tissue sarcoma: Reduced local recurrence but no improvement in survival: A study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol12:1137,1994 8. Bujko K, Suit H, Springfield D, et al: Wound healing after pre-operative irradiation for sarcoma of the soft tissues. Surg Gynaecol Obstet 176:124,1993 9. Cade S: Soft tissue tumours: Their natural history and treatment. Proceedings of the Royal Society of Medicine 46:19, 1951 10. Cantin J, McNeer G, Chu F, et al: The problem of local recurrence after treatment of soft tissue sarcoma. Ann Surg 168:47,1968 11. Chang A, Matory Y, Dwyer A, et al: Magnetic resonance imaging versus computed tomography in the evaluation of soft tissue tumors of the extremities. Ann Surg 205:340, 1987 - - -. 12. Coindre J-M, Terrier P, Nguyen B, et al: Prognostic factors in adult patients with locally controlled soft tissue sarcoma: A study of 546 patients from the French Federation of Cancer Centers Sarcoma Group. J Clin Oncol14:869,1996 13. Demas B, Heelan R, Lane J, et al: Soft-tissue sarcomas of the extremities:Comparison of MR and CT in determining the extent of disease. AJR Am J Roentgen01 150:615,1988 14. Demetri G, Pollock R, et al: NCCN Sarcoma Practice Guidelines. Oncology 3:1, 1998 15. Eggermont A, Koops H, Klausner J, et al: Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcoma. Ann Surg 224756,1996 16. Eggermont A, Schraffordt H, Klausner J, et al: Limb salvage by isolated limb perfusion (ILP) with TNF and melphalan in patients with locally advanced soft tissue sarcomas: Outcome of 270 ILPs in 246 patients. J Clin Oncol18:535a, 1999 17. Eilber F, Eckhardt J, Rosen G, et al: Improved complete response rate with neoadjuvant chemotherapy and radiation for high grade soft tissue sarcoma. J Clin Oncol13:473,1994 18. Enzinger E, Weiss S, General considerations. In Enzinger E, Weiss S (eds): Soft Tissue Tumors. St. Louis, CV Mosby, 1996, p4. 19. Fein D, Lee W, Lanciano R, et al: Management of extremity soft tissue sarcomas with limb-sparing surgery and postoperative irradiation: Do total dose, overall treatment time, and the surgery-radiotherapy interval impact on local control? Int J Radiat Oncol Biol Phvs 32:969,1995 20. ~ e ~ e r b a nT,d ~teevesR, Wiedemann G, et al: Local hyperthermia, radiation, and chemotherapy in locally advanced malignancies. Oncology 53:214, 1996 21. Fleming I, Cooper J, Henson D, et al: AJCC Cancer Staging Manual. Philadelphia, Lippincott-Raven, 1997 22. Frezza G, Barbieri E, Ammendolia I, et al: Surgery and radiation therapy in the treatment of soft tissue sarcoma of extremities. Ann Oncol3:S93, 1992 23. Gemer L, Trowbridge D, Neff J, et al: Local recurrence of soft tissue sarcoma following brachytherapy. Int J Radiat Oncol Biol Phys 20:587,1991 24. Glenn J, Kinsella T, Glatstein E, et al: A randomized, prospective trial of adjuvant chemotherapy in adults with soft tissue sarcomas of the head and neck, breast and trunk. Cancer 55:1206,1985 25. Glenn J, Sindelar W, Kinsella T, et al: Results of multimodality therapy of resectable softtissue sarcomas of the retroperitoneum. Surgery 97:316,1985 26. Goffman T, Tochner Z, Glatstein E: Primary treatment of large and massive adult sarcomas with iododeoxyuridine and aggressive hyperfractionated irradiation. Cancer 67:572, 1991

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Address reprint requests to Anita Mahajan, MD Department of Radiation Oncology New England Medical Hospital 750 Washington Street, Box 359 Boston, MA 02111