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The Journal of Bone and Joint Surgery (American) 84:694-701 (2002)
© 2002 The Journal of Bone and Joint Surgery, Inc.

Specialty Update

What's New in Musculoskeletal Oncology

Mark C. Gebhardt, MD

Mark C. Gebhardt, MD
Department of Orthopaedic Surgery, Massachusetts General Hospital, 55 Fruit Street, GRB 606, Boston, MA 02114. E-mail address: mgebhardt{at}partners.org

The author did not receive grants or outside funding in support of the research or preparation of this manuscript. He did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. A commercial entity paid or directed, or agreed to pay or direct, benefits to research fund, foundation, educational institution, or other charitable or nonprofit organization with which the author is affiliated or associated (Howmedica supports a tumor fellow).

Specialty Update has been developed in collaboration with the Council of Musculoskeletal Specialty Societies (COMSS) of the American Academy of Orthopaedic Surgeons.

Last year, this review focused on novel advances in the biology and prognosis of sarcomas. This year, the focus will be on recent studies of functional outcomes and quality-of-life measures after limb salvage, primarily in the lower extremity. In addition, it will highlight some recent findings regarding soft-tissue sarcomas.

Bone Sarcoma

Limb Salvage
In the past three decades, there have been substantial improvements in the disease outcomes of patients with bone sarcoma. Twenty to thirty years ago, a patient with a high-grade bone sarcoma, such as an osteosarcoma or a Ewing sarcoma, had a 10% to 20% chance of surviving for five years. In most instances, the only form of local control of the tumor was an amputation. Today, as a result of advances in adjuvant chemotherapy, a patient who has osteosarcoma or Ewing sarcoma without metastasis at the time of diagnosis has a 65% to 75% chance of surviving for five years or more. Likewise, the vast majority of patients are being treated with limb preservation techniques. The reconstruction options include the use of allografts, metallic prostheses, and at times composites of both. This apparent advance has been generally heralded as beneficial to patients, but true outcome studies comparing the results of limb salvage with those of amputation, or assessing the differences in outcomes among the various types of prostheses, have been reported only recently. What is apparent is that our ability to assess function, quality of life, and patient acceptance is as primitive as are some of the methods available to us to reconstruct limbs. Nevertheless, we are beginning to understand the long-term outcomes of these limb salvage procedures as we gain experience with the various techniques.

Lane et al. 1 outlined some of the methods at our disposal to assess functional outcomes. One can compare the types and prevalences of complications, as well as the event-free survival rates, associated with allografts and prostheses. This gives some impression of the outcomes of these procedures, and there are many reports in the literature that document such data for a given procedure. Studies that directly compare types of reconstructions are rare. It is important to know the complications of these procedures as they are performed in relatively young patients and in general the prevalence of complications is much higher after limb salvage than it is after amputation. Allografts are associated with high rates of infection, fracture, and nonunion 2-6 , and complications associated with the use of prostheses include aseptic loosening, polyethylene wear, and breakage of the stem of the implant 7,8 . Approximately 60% of limb salvage procedures are followed by a complication, and nearly 75% of these complications require a reoperation 1 .

The experience with gait analysis, measuring muscle strength, and documenting oxygen consumption as a measure of energy expenditure during gait has been reviewed as well. It has been reported that patients with a tumor about the knee have lower energy expenditure following en bloc resection and endoprosthetic reconstruction than do those treated with above-the-knee amputation.

Predicting psychological outcomes is more difficult. Patients who have a good functional outcome after limb salvage generally are satisfied but still have concerns about the durability of the reconstruction. They are at times frustrated by physical limitations in their occupations and in sports. Patients with a less-than-satisfactory outcome following limb salvage often have difficulty making the decision to proceed with amputation. They have concerns about disappointing the surgeon or family members; however, those that do have an amputation following a failed limb-salvage reconstruction are generally satisfied with the outcome and the decision. Patients who have immediate amputation also struggle with thoughts that this might have been avoided, and many have concerns about being able to afford a prosthesis or about the quality of the fit of the prosthesis. Lane et al.1 concluded that, despite advances in limb salvage surgery, patients are confronted with a variety of adaptive challenges related to physical, psychological, social, and vocational issues.

Davis et al.9 recently developed a patient questionnaireæthe Toronto Extremity Salvage Score (TESS)æas a measure of physical function (disability); it includes questions about activity limitations related to decreased body movement and restrictions in mobility, self-care, and performing daily tasks and routines. Davis et al. used this questionnaire along with the 1987 and 1993 versions of the more traditional Musculoskeletal Tumor Society (MSTS) scoring system and the Short Form-36 (SF-36), which is a generic health-status measure, in a study of ninety-seven patients with a bone or soft-tissu sarcoma in a lower extremity. The TESS was found to be superior to the other scales, but it can be used only to evaluate the domain of physical function. It is an excellent tool with which to assess disability in a clinical trial. The SF-36 is more generic and can be applied to a number of disease states. It measures patients' perceptions of their physical and mental health, but its validity for assessing patients with sarcoma is questionable because of its subscale structure. It does not differentiate upper-extremity from lower-extremity physical function well. Both versions of the MSTS scale reflect the clinician's rather than the patient's assessment of the patient's health, and it is unclear how the functions it measures are defined 9 .

Amputation
There are few studies that directly compare the outcomes of amputation with those of limb salvage. Sometimes limb salvage is not an option because the tumor involves a major nerve or there is a pathological fracture. When limb salvage is possible, the question is whether it is the best choice given the complications and functional limitations following such a procedure and the relatively unrestricted activity allowed by an amputation. Using variables such as age, gender, anatomic site, type of neoplasm, and adjuvant chemotherapy, Davis et al. 10 matched twelve patients who had had an amputation with twenty-four patients treated with limb salvage. The patients had not had a local or distant recurrence for at least one year. The main outcome measure was the TESS, which as noted above is a patient-administered measure of disability (defined as any restriction in, or lack of, the ability to perform an activity in the manner or within the range considered normal for a human being), developed specifically for patients who had a tumor in an extremity. The patients also completed the SF-36 and the Reintegration to Normal Living (RNL) instrument, a measure of handicap (defined as a limitation in, or prevention of, a role that is normal for an individual with a similar age, the same gender, and similar social and cultural circumstances), developed for patients with cancer. The study demonstrated a trend toward more disability following amputation than after limb salvage, as evidenced by lower scores on the TESS and the physical function subscale of the SF-36. In addition, there were differences between the two groups with regard to handicap as measured by the RNL, suggesting that patients with amputation have greater limitations in normal role functions within their family, work, and social environments. The authors' findings coincide with those of others who have shown that patients with limb salvage may have more physical symptoms but patients with amputation tend to have lower self-esteem and more social isolation. More investigation of these issues is needed, however, as neither this study nor others in the literature have had sufficient power to statistically document differences between the groups. A multicenter study is needed to truly document a difference in disability.

In another study, seventy-seven surviving patients who had been treated for a lower-extremity sarcoma of bone over a period of twenty years were retrospectively assessed11. Fifty-two patients had had limb salvage and twenty-five, amputation. The strength of the study was limited because multiple forms of "limb salvage," including endoprosthetic replacements, arthrodeses, and rotationplasties, were employed, and multiple sites, from the pelvis to the ankle, were included. After a median duration of follow-up of ninety-seven months, the functional score according to the 1993 version of the MSTS scale was significantly better (p = 0.0001) in the group treated with limb-sparing than it was for the patients treated with amputation, but the rate of complications was three to four times higher after the limb salvage and endoprosthetic procedures. Thus, this study also showed an advantage to limb salvage but at a clear cost to the patient. Consequently, surgeons need to continue to discuss local control alternatives in detail with their patients.

Rotationplasty
For children with a bone sarcoma in a lower extremity, rotationplasty offers clear advantages over a proximal thigh amputation or a hip disarticulation because rotationplasty results in a longer lever arm of the thigh and preservation of an actively controlled "knee" joint. Energy expenditure is lower than that following an above-the-knee amputation or a reconstruction with an endoprosthesis. However, the appearance is cosmetically displeasing as the foot and ankle are rotated 180° to create a knee-like joint. Now that experience with expandable and modular prostheses in children and young adults has accumulated, it is unclear whether prostheses can offer better functional outcomes than rotationplasty.

Hillmann et al.12 used the 1993 version of the MSTS scoring system and the core quality-of-life questionnaire (QLQ-36) of the European Organization for Research and Treatment of Cancer (EORTC) to compare the results of thirty-three rotationplasties with those of thirty-four endoprosthetic replacements in patients between the ages of eleven and twenty-four years. The latter instrument includes five functional scales (physical, role, emotional, social, and cognitive), three symptom scales (fatigue, pain, and nausea and vomiting), and a global health and quality-of-life scale. Neither treatment group was dissatisfied with the reconstruction. Patients who had had a rotationplasty had a better score for role functioning (hobbies, work, etc.) and had less restriction relative to activities of daily living than did patients with an endoprosthesis. This difference was primarily due to slight-to-moderate pain noted on the quality-of-life assessment by patients with an endoprosthesis. The patients with an endoprosthesis were more likely to require an assistive device because of quadriceps weakness. The authors noted no psychosocial disadvantage to rotationplasty, and the patients treated with this procedure were very active in sports, whereas the patients with an endoprosthetic replacement led more sedentary lives focused on increasing the longevity of the prosthesis. There may be differences in patient populations with respect to functional goals, expectations, and cosmetic acceptance, so caution should be exercised when generalizing the results. As Hillmann et al. pointed out, the clinician must carefully discuss the options with the patient and family to ensure that the optimum choice is made.

In another study, 133 patients with a high-grade osteosarcoma treated with limb salvage (seventy-nine patients), rotationplasty (twenty-one), or amputation (thirty-three) were followed for a mean of forty-three months13. The limb salvage procedures included thirty-two endoprosthetic reconstructions, thirty-nine allograft procedures, and eight other reconstructions. The authors compared complication rates and scores on the 1993 version of the MSTS scale among the groups and concluded that the functional result of rotationplasty was superior to that of amputation or limb salvage. Twenty of the thirty-two endoprosthetic reconstructions were followed by a major complication, and six of the prostheses were removed. Twenty of the thirty-nine allografts were associated with a major complication, and six had to be removed, primarily because of fracture or infection. Ten of the twenty-one patients with a rotationplasty had a major complication, but none required an amputation. Eight of the thirty-three patients treated with an amputation had a major complication, and three of them required a more proximal amputation. Of the 103 patients who underwent limb reconstruction, sixty-eight (66%) retained the original reconstruction; twenty-three (22%), the second reconstruction; nine (9%), the third; and one, the fourth. These findings substantiate the high complication rate associated with all of these procedures. However, since the study was conducted early in the limb-salvage era, perhaps the reported complication rate was higher than that found today.

In a study by Veenstra et al., quality-of-life questionnaires consisting of the SF-36, the Social Support List, and selected items from the European Organization for Research and Treatment of Cancer (EORTC) questionnaire were completed by thirty-four patients who had had a rotationplasty14. Although the patients' physical function was poorer than that of healthy peers, they wore the prosthesis all day and were generally satisfied with the fit. The levels of psychosocial functioning, general quality of life, and social support were comparable with those of healthy peers. Seventeen of the patients reported no influence on social contacts, whereas nine felt that the rotationplasty had a negative effect.

It appears that rotationplasty should remain in our armamentarium. The functional results are reasonable, and there do not appear to be any measurable adverse psychological outcomes.

Prosthetic Reconstruction
A multicenter study was performed to compare the early results of two different types of lower-limb tumor prostheses: the Kotz Modular Femur Tibia Reconstruction System (KMFTR), which is a noncemented, fixed-hinge prosthesis, and the Modular Replacement System (MRS), which is a cemented rotating-hinge prosthesis 15 . Thirty-one KMFTR prostheses and twenty-five MRS prostheses were used for limb salvage after resection of a distal femoral tumor. All patients were followed for a minimum of one year (mean, 35.4 months), all completed questionnaires, and all were assessed prior to any systemic or prosthetic complication. The two groups were comparable with the exception that the average length of bone resection was 2 cm greater in the KMFTR group. The 1987 and 1993 versions of the MSTS, the SF-36, and the TESS were used to measure the outcomes. Overall scores were satisfactory in both groups, but the scores on the 1993 MSTS (p = 0.006) and on the TESS (p = 0.03) were significantly better for the patients treated with the MRS. Activities that patients reported as difficult included kneeling, performing sports activities, gardening, performing strenuous household activities, and ascending or descending stairs or hills. This study was unique in that it was one of the first to address functional issues from the patient's point of view. It was not designed to determine whether one prosthetic design was superior to the other, but factors such as the rotating hinge rather than the fixed hinge and a cemented rather than a noncemented stem could account for the observed differences.

It is interesting to compare the results in the above study with those in another study, of 100 patients treated with a KMFTR after resection of a tumor about the hip or knee 16 . Forty-one of those patients were followed for a median of 127.5 months (fifty-one died and eight were lost to follow-up). The mean score on the 1993 MSTS was 80%, compared with 90.2% for the patients treated with the MRS and 73.1% for the patients treated with the KMFTR in the paper described above 15 . The major complications were aseptic loosening (eleven patients [27% of the forty-one with follow-up]), septic loosening (four patients), and implant fracture (four patients). The Kaplan-Meier estimates of overall prosthetic survival in the 100 patients were 85% at three years, 79% at five years, and 71% at ten years. Ninety-eight percent of the patients retained the limb; one patient had an amputation after a local recurrence, and one had an amputation because of a periprosthetic infection and systemic sepsis.

Allografts
To my knowledge, no recent publication dealing with allografts has directly compared the results with those of other types of reconstruction. One large series of allograft reconstructions in 112 patients treated with neoadjuvant chemotherapy showed promising results 2 . Forty-four arthrodeses, thirty-nine intercalary graft procedures, twenty-two osteoarticular allograft procedures, and seven procedures with an allograft-prosthetic composite were performed. On the basis of a modification of an outcome score described by Mankin17, the functional result was excellent or good in 74% of ninety-two patients available for follow-up. Furthermore, function was satisfactory in 83% of the patients after a secondary operation, which consisted of removal of the graft and replacement with a second graft or prosthesis in four patients. Delayed union occurred in nearly half (49%) of the patients, and a fracture occurred in 27%; there were no deep infections.

In a second series5, osteoarticular allografts were used about the knee after resection of an aggressive benign or a malignant bone tumor in 114 patients (118 allografts), and the results were assessed with use of a radiographic system proposed by the Musculoskeletal Tumor Society. The system is based on eight criteria, including healing of the osteosynthesis sites, fixation of the graft, stability of the joint, and changes in the joint. The authors found an overall five-year rate of survival of the grafts of 73% (76% for distal femoral grafts and 65% for proximal tibial grafts). Sixty-four of the index allografts were still in place, twenty-six had failed, eighteen were in patients who had died, and ten were in patients who had been lost to follow-up. The failures were due to infection (thirteen patients), local recurrence (eight patients), massive resorption (three patients), and fracture (two patients). Seven amputations were performed: one was done because of infection and six, because of local recurrence. The radiographic evaluation showed the joint to be unchanged or to have minor deterioration after 64% of the graft procedures, whereas 22% of the joints had some form of subchondral collapse. Five patients underwent joint replacement with preservation of the initial allograft. Most of the complications occurred in the first four years after the operation, and then the grafts seemed to reach some degree of stability. The authors did not directly compare their results with those of alternative forms of reconstruction, but they concluded that the allograft survival rate of 73% compared favorably with a survival rate for endoprostheses of 67% reported elsewhere18.

The graft survival in the above study was in contrast to that in a smaller study of seventeen allografts about the knee and shoulder after resection of a high-grade bone sarcoma in children reported by Rödl et al.19. Only seven of the fifteen patients followed for at least five years or until graft removal had a functional allograft in place. Loss of the graft was due to fracture in seven patients and to infection in one. These patients had a second reconstruction (seven with a prosthesis and one with an allograft), so all patients retained the limb. The authors concluded that, although the patients with a graft in place at five years had good function, the high failure rate made the use of an allograft an unacceptable alternative.

Currently, the issue of whether allografts or endoprostheses offer superior outcomes in all patients is unresolved. Both options remain in the armamentarium of the tumor surgeon. As experience is gained, the specific indications for one or the other type of reconstruction are becoming better defined.

Upper Extremity
Most of the above studies focused on the lower extremity. At last year's meeting of the Musculoskeletal Tumor Society, early experience with the use of a metallic scapular prosthesis to restore shoulder function following scapular and rotator cuff resection was presented 20 . This constrained prosthesis relies on periscapular muscles to restore scapulothoracic and glenohumeral motion following resection of a scapular tumor. The cases of three patients were presented, and the authors reported that a stable shoulder girdle could be restored following total scapular resection. The prosthesis works best if the deltoid, trapezius, rhomboid, latissimus dorsi, and serratus anterior muscles can be retained. Although this prosthesis offers the promise of superior function in a limited patient population, it has not yet been shown to offer better function than scapulectomy when similar muscles can be retained. A second presentation at this meeting, however, did compare the results of replacement with a total scapular prosthesis with those of scapulectomy in twenty-two patients in whom a malignant scapular tumor had been resected with preservation of the axillary nerve 21 . Patients treated with a prosthesis had better results than those treated with a scapulectomy in terms of the active range of motion and scores for pain, strength, stability, acceptance, and function according to the upper-extremity MSTS scoring system. The cosmetic appearance was also better after the treatment with the prosthesis. This and other types of shoulder reconstruction may be of value in a select group of patients with a malignant tumor involving the scapula, but the results are preliminary.

Overview
In summary, investigators recently have begun to assess the functional outcomes and quality of life after limb salvage and amputation following resection of bone and soft-tissue sarcomas, but considerable progress still needs to be made both in reconstruction techniques and in assessing outcomes. This area continues to be a topic of intense interest for orthopaedic oncologists, and this field is a major component of the meetings of many of the tumor societies, including the Musculoskeletal Tumor Society, the International Symposium on Limb Salvage, the European Musculo-Skeletal Oncology Society, and the Connective Tissue Oncology Society. Studies have shown that we are only beginning to understand how to assess outcomes after limb salvage and amputation for the treatment of bone sarcomas. Only a limited number of studies have directly compared one reconstruction technique with another for the same type and location of tumor, and surgeons are currently left to individualize options for a given patient after explaining the alternatives to the patient and the family. With better studies, more optimal outcome tools, and longer follow-up of patients who have survived after treatment of sarcoma, it is hoped that this process will become more objective.

Soft-Tissue Restoration

Often ignored is the issue of motor power following limb salvage. In one interesting study, gait analysis after resection and prosthetic reconstruction for the treatment of distal femoral tumors showed that nine patients who had had resection of the vastus lateralis and intermedius had better gait performance than did seven patients who had had resection of the vastus medialis, although both groups had good functional outcomes 22 . There was no substantial difference in strength, indicating that these differences would not have been detected by manual motor-testing alone. The decision regarding how much tissue to resect depends on the extent of tumor involvement, but these findings suggest that if the surgeon has a choice of biopsy placement it is better to use a lateral approach so that more of the vastus medialis can be preserved at the time of resection.

Muscle transposition can be employed to restore quadriceps function following resection of tumors about the knee. One study showed that a gastrocnemius flap could be used, alone or augmented with transfer of the pes anserinus, to increase the strength of the extensor mechanism following extra-articular resection combined with endoprosthetic reconstruction23. The results were better in seven patients with distal femoral resection than they were in two patients with proximal tibial resection. Innervated free tissue transfer was employed in another study consisting primarily of patients with soft-tissue sarcoma24. That study did not include any formal functional analysis, but the authors observed that function improved after recovery of the implanted muscle flap, suggesting that the innervated transplants functioned. It is not clear that the function observed with that approach is superior to that achieved with a lesser extent of resection and radiation therapy (to preserve functioning muscles), but the approach opens the possibility of using innervated muscle transfer in selected patients.

It is necessary to find better methods of attaching muscles to implants. A preliminary study at the meeting of the Musculoskeletal Tumor Society introduced the possibility of using tantalum implants to allow soft-tissue growth into tumor prostheses 25 . This study of six lower-extremity reconstructions showed early success with this type of material, and it provided promise for developing better methods of incorporating metallic prostheses and host tissues.

Soft-Tissue Sarcoma

Classification
This review will focus on a few selected areas from the many recent reports dealing with soft-tissue sarcoma. The classification of soft-tissue sarcomas has dramatically changed in the last thirty years. Experienced pathologists using histological analysis, electron microscopy, and immunohistochemistry have developed a sophisticated system for classification of soft-tissue sarcomas on the basis of the presumed cell of origin (lineage). In this classification system, malignant fibrous histiocytoma is considered the most common form of soft-tissue sarcoma, but there is disagreement about the criteria on which this diagnosis should be based. Several experienced pathologists question the validity of this entity and its subtypes (myxoid, giant cell, inflammatory, and angiomatoid malignant fibrous histiocytoma). A group of investigators retrospectively analyzed malignant fibrous histiocytomas of various subtypes in 100 consecutive patients to see if specific lines of differentiation were present 26 . They defined specific histopathological criteria for the reclassification of these tumors and correlated the findings with clinical stage and outcome. Thirty-nine tumors were originally classified as myxoid malignant fibrous histiocytoma, and sixty-one were originally classified as storiform-pleomorphic malignant fibrous histiocytoma. In eighty-four of the 100 tumors, a specific line of differentiation could be detected, most commonly high-grade myxofibrosarcoma or high-grade leiomyosarcoma.

These investigators also compared stage-II and III myogenic sarcomas (leiomyosarcoma, rhabdomyosarcoma, pleomorphic myogenic sarcoma, and myogenic spindle-cell sarcoma), as classified according to the system of the American Joint Commission, with other sarcomas and found that the myogenic tumors were associated with a worse five-year metastasis-free survival rate (0.45) than the nonmyogenic tumors were (0.73) (p = 0.006). Although this was a small sample of patients and the authors did not control for tumor size, they concluded that the careful classification of this group of sarcomas is not merely an academic exercise but rather may allow identification of prognostic groups and potentially identify patients who need more (or less) aggressive therapy. When all of these tumors are lumped into a single category (malignant fibrous histiocytoma), such prognostic information is lost. The authors also pointed out that existing data support the contention that pleomorphic sarcomas have divergent outcomes. For example, dedifferentiated liposarcomas are associated with a metastatic risk of <25% and high-grade myxofibrosarcomas are associated with a metastatic risk of 35% to 40% in the first five years, whereas pleomorphic rhabdomyosarcomas are associated with an even higher risk. The authors believed that the use of the term malignant fibrous histiocytoma should be minimized. It will probably take some time for this concept to be confirmed and accepted by the clinical community because malignant fibrous histiocytoma is now used ubiquitously. However, the data and the rationale are compelling.

Treatment
Treatment of high-grade soft-tissue sarcomas in adults has been frustrating because the dramatic improvements in the survival of children with osteosarcoma that has resulted from the use of adjuvant and neoadjuvant chemotherapy have not been witnessed in adults with soft-tissue sarcoma. In fact, few studies have convincingly demonstrated an advantage to using chemotherapy for patients with non-rhabdomyosarcoma soft-tissue sarcoma, although at most centers it is believed to be beneficial for patients with a large high-grade sarcoma, for which the prognosis is especially poor. The response of osteosarcoma to chemotherapy and the prognosis can be assessed by evaluating tumor necrosis histologically following induction (neoadjuvant) chemotherapy. A high percentage of necrosis (>95% to 98%) predicts a good outcome and presumably drug sensitivity of the osseous tumor. Similar data with regard to soft-tissue sarcomas in adults have been lacking.

Two recent studies have shown that neoadjuvant therapy can affect necrosis in soft-tissue sarcomas. In the first study, a series of protocols was used over a twenty-three-year period in a total of 496 patients with intermediate or high-grade soft-tissue sarcoma in an extremity 27 . The protocols included doxorubicin-based chemotherapy with varying doses of radiation (17 to 35 Gy), and later intra-arterial cisplatin and ifosfamide were added. There was a strong association between tumor necrosis and outcome. Patients with >95% tumor necrosis had significantly lower five and ten-year rates of local recurrence (6% and 11%, respectively) than did those with <95% necrosis (17% and 23%, respectively) (p = 0.0018). Similarly, the five and ten-year survival rates for patients with >95% necrosis were significantly higher (80% and 71%, respectively) than those for patients with <95% necrosis (62% and 55%, respectively) (p = 0.001). Furthermore, the addition of ifosfamide increased the percentage of patients with >95% necrosis from 13% (without ifosfamide) to 48% (with ifosfamide). This increase was associated with a substantially improved survival rate (0.03), although the patients had not been randomized to the two treatment groups and the ifosfamide-treated patients had a mean duration of follow-up of 4.5 years compared with eight years for the other patients. Nevertheless, these data suggest that tumor necrosis may be as important a factor in the prognosis for soft-tissue sarcomas as it is in the prognosis for bone sarcomas. The relative importance of radiation and chemotherapy in achieving tumor necrosis is uncertain, since patients received both modalities, but the observation that ifosfamide substantially increased the percentage of patients with a high degree of tumor necrosis suggests that the chemotherapy is more important in this regard. Another issue raised, but not answered, in this study is whether the route of administration of the chemotherapy (intra-arterial or intravenous) is important. The observation that the highest percentage of necrosis was achieved by the protocol that included intravenous doxorubicin, cisplatin, and ifosfamide as well as 28 Gy of irradiation suggests that the intraarterial route is not necessary.

A study of the percentage of tumor necrosis achieved by neoadjuvant chemotherapy alone was also reported 28 . The median duration of follow-up was five years. A selected group of thirty-three patients was treated with one of two different chemotherapy regimens with intravenous and intra-arterial routes of administration. Some patients seen during the period of study were excluded from the analysis because radiation therapy was also deemed to be necessary. Initially, the chemotherapy protocol was used for patients with an intermediate or high-grade sarcoma in an extremity only when amputation was thought to be the sole option for local control, but subsequently the protocol was employed for all patients with a large high-grade sarcoma. Group 1 (eighteen patients) was treated with intravenous doxorubicin and intra-arterial cisplatin, whereas Group 2 (fifteen patients) also received intravenous ifosfamide. Both groups received postresection chemotherapy as well. Two patients (in Group 1) required amputation, and no patient had a positive margin. More than 95% necrosis was achieved in twenty-two (76%) of twenty-nine patients. (Four patients who had undergone subtotal resection prior to the neoadjuvant chemotherapy had no tumor to assess.) The median percentage of necrosis was 95% in Group 1 and 98% in Group 2. The overall survival rate was 88% (95% confidence interval, 0.75 to 1.00) at five and ten years. The disease-free survival rate was 80% (95% confidence interval, 0.68 to 0.93) at five and ten years. Two patients had locally recurrent disease, and one of them died. This work is very preliminary, and only a small group of selected patients was analyzed over a long time-period, but the authors believed that neoadjuvant chemotherapy alone is sufficient to achieve a high degree of necrosis and to allow limb-salvage surgery without the addition of radiation. Since neither this study nor the one described above 27 was controlled or randomized, the issue of whether neoadjuvant chemotherapy improves survival compared with that achieved with postoperative adjuvant chemotherapy alone, or whether radiation is necessary, remains unresolved.

Data presented at the seventh annual conference of the Connective Tissue Oncology Society (CTOS) in November 2001 showed that a protocol of intravenous MAID ( m esna, A driamycin [doxorubicin], i fosfamide, and d acarbazine) chemotherapy interdigitated with radiotherapy followed by surgical resection and postoperative chemotherapy in forty-eight patients increased overall and disease-free survival compared with that of forty-eight historical controls 29 . The five-year rate of local control was 92% for patients treated with MAID and 86% for control patients (p = 0.1155). The rates of metastasis-free survival were 75% and 44% (p = 0.0016), respectively, and the overall survival rates were 70% and 42% (p = 0.0002), respectively. Obviously a direct, randomized comparison would be ideal, but these studies suggest that neoadjuvant chemotherapy and radiotherapy is of benefit in patients with a large high-grade sarcoma in an extremity.

An exciting development in the treatment of soft-tissue sarcoma discussed at this year's CTOS meeting dealt with a tumor outside the realm of orthopaedics. However, the biological implications are intriguing and it exemplifies how future therapies for sarcomas will likely be based on molecular alterations in tumors. Gastrointestinal stromal tumors are rare mesenchymal tumors of the gastrointestinal tract characterized by cell-surface expression of the tyrosine kinase KIT (CD117). The primary treatment is surgical, and the tumors are resistant to chemotherapy and radiation. The transmembrane receptor tyrosine kinase KIT is believed to be crucial to the pathogenesis of the tumor. Recently, in vitro exposure of gastrointestinal stromal tumors to the signal transduction inhibitor imatinib mesylate (formerly STI571 30 ; Novartis Pharmaceuticals, East Hanover, New Jersey), which blocks the tyrosine kinase activity of KIT, was shown to cause rapid inhibition of ligand-independent KIT phosphorylation, decreased cellular proliferation, and induction of apoptosis 31 . A study of the safety and effectiveness of this therapy in a large group of patients with advanced soft-tissue sarcomas, including gastrointestinal stromal tumors, was reported previously 32 . At the CTOS meeting, two groups of investigators presented evidence of a role for KIT in gastrointestinal stromal tumors. Demetri reported a partial response in 75% of patients who had a gastrointestinal stromal tumor with exon 11 mutations and stabilization of the disease in 20% 33 . Verweij presented the results of a phase-2 EORTC study showing a benefit of treatment with imatinib mesylate in 85% to 90% of patients who had a gastrointestinal stromal tumor with c-KIT mutations, but the drug was not active in non-gastrointestinal stromal tumors 34 . These results show the potential for the development of anticancer drugs on the basis of specific molecular abnormalities present in cancers.

The continued study of outcomes, methods of limb reconstruction, and biology of sarcomas will improve our ability to treat affected patients. Important work has taken place in recent years, and more exciting findings should be forthcoming.

References

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