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Neoadjuvant Chemotherapy With Doxorubicin and Cisplatin in Malignant Fibrous Histiocytoma of Bone: A European Osteosarcoma Intergroup Study

From the London Regional Cancer Centre, London, Ontario, Canada; Leicester Royal Infirmary, Leicester, University College London Hospitals National Health Service Trust, London, Royal Victoria Infirmary, Newcastle upon Tyne, Royal Orthopaedic Hospital National Health Service Trust, Birmingham, Royal National Orthopedic Hospital, London, and Medical Research Council Cancer Trials Office, Cambridge, United Kingdom; Leiden University Medical Centre, Leiden, the Netherlands; and European Organization for Research and Treatment of Cancer Data Centre, Brussels, Belgium.

Address reprint requests to Vivien H.C. Bramwell, MD, PhD, London Regional Cancer Centre, 790 Commissioners Rd, E, London, Ontario, Canada N6A 4L6; email vbramwell{at}lrcc.on.ca

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: Studies involving small case series have suggested that malignant fibrous histiocytoma of bone (MFH-B) is a chemosensitive tumor and that chemotherapy may improve survival. In this study, we evaluated clinical and pathologic response rates and survival in a series of patients treated with a consistent chemotherapy regimen of doxorubicin and cisplatin (DOX/DDP).

PATIENTS AND METHODS: Study patients were required to have biopsy-proven MFH-B, no previous chemotherapy, and primary or metastatic measurable disease and to be 65 years of age. Treatment consisted of doxorubicin 25 mg/m²/d days 1 through 3 and cisplatin 100 mg/m² by 4-hour intravenous infusion every 3 weeks for six cycles. In patients with operable primary tumors, chemotherapy was planned to start within 42 days of biopsy, with definitive surgery performed after three cycles.

RESULTS: Forty-one patients had operable nonmetastatic limb sarcomas, and 23 (56%) completed six chemotherapy cycles. Limb salvage was possible in 33 patients (80%), and 16 (42%) of 38 assessable specimens showed a good pathologic response ( 90% necrosis). Median time to progression was 56 months, and the 5-year progression-free survival rate was 56% (95% confidence interval [CI], 40% to 72%). Median survival time was 63 months, and the 5-year survival rate was 59% (95% CI, 41% to 77%). Patients with a good pathologic response had longer survival times and times to progression than did those with a poor response. Also treated were two patients with locally recurrent and nine with metastatic disease, and these patients had a median survival time of 17.5 months.

CONCLUSION: Our study suggests that adjuvant or neoadjuvant chemotherapy with DOX/DDP is beneficial in MFH-B. Good pathologic response rates and survivals are quite comparable with those for osteosarcoma, a related bone tumor for which adjuvant or neoadjuvant chemotherapy is an accepted practice.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
MALIGNANT FIBROUS histiocytoma of bone (MFH-B) was recognized as a distinct bone tumor in the early 1970s, being first described by Norman and Feldman¹ as malignant histiocytoma (malignant fibroxanthoma). Histopathologic characteristics include a mixture of spindle shaped fibroblastic cells in a storiform pattern and admixed with mononuclear cells with histiocytic morphology and anaplastic giant cells; and a lack of tumor osteoid or cartilage formation. On the basis of data from four series, the prevalence can be estimated as between 3% and 8% of all bone tumors.^2-5 There seems to be a slight male preponderance, ranging from 1.13:1 to 1.5:1.^3,6-8 The mean age at presentation is higher than in osteogenic sarcoma (OGS), and cases are fairly evenly distributed over the second to sixth decades, with occasional cases in younger or older patients.

As with OGS, these tumors show a predilection for long bones, but 25% to 30% of tumors occur in the axial skeleton. The majority are intramedullary in origin, but periosteal variants have been described. They may arise as primary (de novo) or as secondary tumors, from benign bone lesions such as giant cell tumor, fibrous dysplasia, Paget's disease, bone infarcts or cysts, or osteomyelitis. A number of these secondary tumors arise as a result of previous irradiation.⁹ As may be expected, secondary tumors tend to occur more frequently in the older population, and there is evidence that these patients have worse outcomes.^3,6

Because of comparable occurrence rates for p53 mutations, as assessed by polymerase chain reaction–single-stranded conformational polymorphism sequencing analysis, and the absence of p16^INK4A mutations in both MFH-B as well as malignant fibrous histiocytoma of soft tissues and OGS, a role for p53 mutations in the tumorigenesis of these sarcomas has been suggested.¹⁰ In contrast with malignant fibrous histiocytoma of soft tissue, a heavily disputed entity and presumably an admixture of several distinct but hitherto unrecognized tumor types,¹¹ MFH-B is a homogeneous malignant bone tumor that is well recognized, although several morphologically similar malignant spindle cell tumors exist, such as leiomyosarcoma, and must be ruled out during diagnosis.

The aggressive potential of MFH-B is reflected in the survival figures. In Table 1, we have summarized outcomes for six series of patients with mostly high-grade MFH-B.^2,3,5,6,8,12 The 5-year survival rates range between 34% and 57%. Some of the variation in these figures may be attributable to variable criteria for histologic diagnosis, the presence of a few low-grade tumors, or, in later series, inclusion of some patients receiving chemotherapy. Survival figures are substantially lower at 10 years, probably reflecting some late relapses and deaths.

In classic OGS, adjuvant combination chemotherapy has resulted in consistent 5-year survival rates of 60% or better in several large studies.¹³ This contrasts with survival rates of less than 20% for patients treated with surgery alone.¹⁴ With intensive preoperative chemotherapy, high rates of histologic necrosis ( 90%; "good response") have been reported in 20% to 60% of patients and seem to predict a favorable outcome.¹⁵ This success in patients with OGS, together with the known chemosensitivity of Ewing's sarcoma of bone, has prompted oncologists to explore the use of chemotherapy in other bone sarcomas.

At the time this study was initiated (1988), there were some published data on the use of adjuvant chemotherapy in MFH-B but most reports were anecdotal.^16-19 However, three studies involving small series^3,20,21 suggested the efficacy of chemotherapy.

Thus it seemed that MFH-B might respond to chemotherapy in a way similar to the way that OGS responds. In addition, the possibility that other rarer spindle cell sarcomas of bone might be responsive to chemotherapy warranted further study. The optimum therapeutic regimen could not be determined from the data from these limited series, but doxorubicin (DOX), cisplatin (DDP) and high-dose methotrexate (HDMTX) appeared to be active agents. The European Osteosarcoma Intergroup (EOI) has considerable experience with treatment with a combination of DOX and DDP in primary osteosarcoma. In a randomized study, this combination therapy was shown to be superior to a similar regimen incorporating HDMTX,²² and in a subsequent study it was proven to have efficacy similar to that of a complex multiagent regimen.²³

Even with international collaboration, it is difficult to undertake and complete randomized trials of new treatment options in rare tumors in a timely fashion. The purpose of this nonrandomized study was to measure efficacy and outcome in patients with primary, nonmetastatic MFH-B treated with a consistent regimen of chemotherapy (DOX/DDP) known to be effective in classic OGS. Efficacy also was evaluated in patients with measurable locally recurrent and/or metastatic disease.

Little is known about the activity of chemotherapy in patients with rarer histologic subtypes (eg, fibrosarcoma, leiomyosarcoma, and angiosarcoma of bone) and patients with sarcomas arising in abnormal bone (eg, fibrous dysplasia, bone infarcts, Paget's disease, and irradiated bone), and therefore such patients were included in this study. Results in these patients are the subject of another report (Nooij et al, manuscript in preparation). The first 46 patients with all histologic types were described in a preliminary report.²⁴

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Study Population
Patients with biopsy-proven primary limb MFH-B, potentially resectable, who had no evidence of metastases and who were 65 years of age or younger, were eligible for this study. Patients with locally recurrent or metastatic disease also were eligible but are described separately. All patients were required to have assessable (usually primary tumor) and/or measurable disease. For patients receiving preoperative chemotherapy, it was recommended that this be instituted within 28 days from the date of biopsy (later amended to 42 days). Additional requirements at entry were adequate renal function (serum creatinine level of < 150 fmol/L), hepatic function (serum bilirubin level of < 20 fmol/L), and bone marrow reserve (WBC count of > 4 x 10⁹/L and platelet count of > 100 x 10⁹/L). Informed consent was obtained according to local institutional policies. Patients who had received previous chemotherapy or radiotherapy for sarcoma were not eligible, nor were those with other malignancies. Patients who had undergone previous amputation or definitive surgery for their primary tumors were not eligible. Additional exclusion criteria were concomitant disease that prevented intensive chemotherapy and a World Health Organization (WHO) performance status of 2.

Trial Design
The primary objective of the study was to assess the therapeutic activity of DOX/DDP chemotherapy in patients with MFH-B. For patients with operable primary tumors with no evidence of metastases, the primary outcome measurements were clinical and pathologic response, and secondary measurements were duration of progression-free and overall survival. An additional objective was to assess the acute and chronic toxicity of DOX/DDP chemotherapy in this group of patients, who were expected to have a higher median age than patients with classic OGS.

In patients with operable (usually extremity) lesions who received neoadjuvant therapy, response was assessed after the third course of chemotherapy and definitive surgery was to be performed approximately 9 to 10 weeks after the start of chemotherapy. Chemotherapy was planned to recommence 14 days (maximum, 28 days) after surgery.

Therapeutic Regimen
The regimen was identical to that used in previous EOI studies of OGS.^22,23 This regimen comprised six cycles at 3-week intervals of DOX 25 mg/m² days 1 through 3 by intravenous bolus and DDP 100 mg/m² day 1 by 4-hour intravenous infusion at 3-week intervals. Hydration and electrolyte support were used and have been described previously.²²

Dose Modifications
The doses of DOX plus DDP were reduced by 15% in patients with WHO grade 3 hematologic toxicity and by 30% in cases of grade 4 toxicity and/or serious infection or bleeding. The DOX dose was reduced by 20% in patients with grade 3 or 4 mucositis. Doses were not adjusted for reversible renal toxicity, but DDP was not given if the serum creatinine level remained above 150 fmol/L.

Chemotherapy was delayed until hematologic recovery (WBC count of > 3 x 10⁹/L, granulocyte count of > 1.5 x 10⁹/L, and platelet count of > 100 x 10⁹/L), with repeat blood cell counts performed at weekly intervals and doses dictated by nadir hematologic values. Chemotherapy was discontinued if recovery was not apparent after 3 weeks.

Pretreatment and Follow-Up Investigations
Initial patient evaluations comprised history and physical examination, which included tumor measurement; determination of performance status; complete blood cell count; determination of serum creatinine level and creatinine clearance; measurement of electrolytes; liver function tests; determination of alkaline phosphatase, calcium, and magnesium levels; electrocardiography; chest radiography; computed tomography (CT) of the lungs, radiography of affected bone; and bone scintigraphy. More detailed assessment of the primary tumor by CT, magnetic resonance imaging, or angiography was recommended if these methods were available, particularly for patients who were treated with limb salvage surgery. Audiometry, measurement of nuclear medicine cardiac ejection fractions, and EDTA renal clearance tests were optional. Blood counts were required before each chemotherapy cycle and between 9 and 16 days after DOX/DDP therapy. Biochemical tests and clinical tumor measurement were performed before each cycle of chemotherapy. Chest radiography, lung CT, bone scintigraphy, and primary tumor radiologic investigations were repeated immediately before surgery.

After the completion of chemotherapy, patients were followed at 6-week intervals for a further 12 months, at 2-month intervals for 18 months, at 3-month intervals up to 5 years, and thereafter at investigators' discretion until death. Patients will be followed to determine long-term toxicity (eg, cardiac toxicity, renal toxicity, and secondary malignancies).

Central Pathology Review
Central review was performed by a panel of pathologists with established experience in bone tumor pathology. Review of biopsy material to verify the diagnosis of MFH-B was a requirement to confirm patient eligibility. The same panel studied histologic changes in operative specimens. The methodology used was described previously.^22,25 Eight pathologists from six European countries used a simple reproducible method for assessing the postchemotherapy response of the resected specimen. The tumor was resected longitudinally in a plane through its widest part. An entire slab of this cut surface was divided into individually labeled blocks, decalcified, cut, and stained for histologic examination. A clear lead-acetate sheet with 2 x 2-mm squares was placed over the slides, and each square was assessed for tumor viability, tumor damage, or tumor necrosis. The total number of squares in each category was then used to calculate the percentage of the specimen that contained viable, damaged, or necrotic tumor.

The following terms were used to categorize chemotherapy effect: no tumor, totally necrotic tumor, nonneoplastic reparative tissue; D1 (acellular fibrotic hyalinized tissue containing widely scattered pleomorphic or pyknotic cells), D2 (acellular fibrotic tissue with moderate numbers of scattered bizarre cells), D3 (moderately large numbers of pleomorphic and bizarre cells showing nuclear and cytoplasmic changes more in keeping with damaged tumor cells than with cells found in an untreated sarcoma); and viable, undamaged tumor similar to the original biopsy specimen. The categories of no tumor and D1 were incorporated to constitute the category of 90% necrosis. The categories of D2, D3, and viable, undamaged tumor were incorporated to form the category of < 90% necrosis.

Response Criteria
The circumference of the limb and primary tumor length were recorded, and the treating physician was asked to categorize response as complete remission, improvement, no change, or disease progression. Accurate clinical measurement of two perpendicular diameters was not thought to be possible because changes in tumor masses could be obscured by factors such as postbiopsy edema, hematoma, and muscle wasting. Components such as pain relief and reduction of inflammatory signs were taken into account, but the final categorization was essentially subjective. Response was assessed after three cycles of DOX/DDP chemotherapy, immediately before definitive surgery. Because primary progression (clinical or radiologic) was difficult to assess and can be mimicked by edema, it was not regarded as an indication to stop or alter chemotherapy postoperatively.

Response in cases of measurable metastatic disease was assessed using International Union Against Cancer criteria.

Statistical Methods
For patients presenting with operable tumors, response to neoadjuvant chemotherapy, based on clinical and radiologic evaluation, was the primary end point. For patients who presented with inoperable or metastatic disease, response to chemotherapy, based on clinical and radiologic evaluation, was the primary end point. Pathologic response to chemotherapy and time to progression were assessed as secondary end points for patients with operable nonmetastatic disease; duration of survival and side effects were assessed as secondary end points for all patients. Time to progression and overall survival were measured from the date of start of chemotherapy. Patients who died without disease progression were censored at the time of death in the time-to-progression analysis.

The study was designed to document a response rate of 40% in the patients with operable nonmetastatic disease. The two-step Gehan design was used. If no responses were documented in the first nine patients, that particular study had to be closed, as the possibility of achieving a response rate of more than 40% was excluded (P = .01). If at least one response was noted, at least 15 additional patients were added, to allow estimation of response rate with a standard error of less than 10%. Additional patients were consequently added to narrow the confidence interval (CI) for response rate and survival estimates. Patients presenting with inoperable recurrent or metastatic disease were simultaneously registered onto the trial so that the response rate to chemotherapy could be documented in those cases. Response rates and 95% CIs were estimated using the Fisher's exact method.²⁶ Survival and progression-free rates were estimated using the Kaplan-Meier method.²⁷ The standard error of the 5-year estimates was computed using the Greenwood formula.²⁸

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Between April 1988 and October 1996, a total of 108 patients were registered onto the whole study. Two patients were excluded because pathologic material was not available for central review. Through pathologic review, 15 patients were shown to have pathologies that made them ineligible for the study (osteosarcoma, 11; soft tissue sarcoma, two; chondrosarcoma, one; metastatic carcinoma, one). Of the remaining 91 cases, 53 were confirmed to be MFH-B and 38 were other spindle cell sarcomas of bone and are the subject of a separate report (Nooij et al, manuscript in preparation). Table 2 lists reassignments made after central pathology review. One further patient, who had no assessable or measurable disease, was ineligible, leaving the 52 patients who are the subject of this report.

Contributing groups were the Medical Research Council, United Kingdom (31 patients), the United Kingdom Children's Cancer Study Group (five patients), the European Organization for Research and Treatment of Cancer (13 patients) and the Canadian Sarcoma Group (three patients) (contributors are listed in the Appendix). For further analysis, patients were divided into two categories: those with resectable nonmetastatic disease (41 patients) and those with recurrent inoperable or metastatic disease (11 patients). Patient characteristics and the major outcomes (response to chemotherapy and survival) are reported separately for those two groups. However, they were combined when we were determining compliance with chemotherapy and toxicity.

Resectable Nonmetastatic MFH-B
Patient characteristics. The group of 41 patients with resectable nonmetastatic MFH-B included 26 males and 15 females. Median age was 42 years (range, 14 to 62 years). Performance status was high (WHO grade 0 or 1) in 31 patients, and in the remainder it was poorer because of symptoms of the primary tumor rather than comorbid disease. In 30 patients, primary tumors were located in the lower limb (femur, 20; tibia, 10). There were four pelvic tumors and seven tumors in the upper limb (humerus, six; radius, one).

Chemotherapy. Chemotherapy was started within 42 days of biopsy in 33 patients, with the remaining eight patients starting therapy at a median of 59 days after biopsy (range, 44 to 131 days). Twenty-three patients (56%) completed six cycles of chemotherapy, and therapy was stopped because of primary tumor progression in three patients, because of toxicity or refusal to continue in 13, and for other reasons (surgical complications, lack of response) in two.

Table 3 shows the timing of and reasons for stopping chemotherapy (also included are data from the 11 patients with recurrent inoperable or metastatic disease). Toxicities leading to discontinuation of chemotherapy included neutropenic sepsis, thrombocytopenia, reduced renal function, and psychiatric problems. Protocol dose reductions were necessary for one cycle in 15 patients, two cycles in 12 patients, and three cycles in two patients, and four cycles in two patients. The mean total dose of DOX administered was 296 mg/m² (range, 100 to 667 mg/m²), 65.7% of the projected dose (450 mg/m²). The mean total dose of DDP given was 392 mg/m² (range, 75 to 630 mg/m²), 65.3% of the projected dose (600 mg/m²).

Side effects of chemotherapy for all 52 patients are summarized in Table 4, shown as the maximal toxicity occurring over all cycles. Myelosuppression was severe, with WHO grade 3 or 4 neutropenia occurring in 65% of cases and grade 3 or 4 thrombocytopenia occurring in 46% of cases. Myelosuppression was associated with significant infection (grade 3 or 4) in 19% of patients, but there were no toxic deaths. Oral toxicity was the other major side effect (grade 3 or 4 oral toxicity occurred in 15% of cases), and most patients had severe alopecia. Significant cardiac toxicity was not noted, and although 12% of patients developed renal abnormalities, only one developed grade 3 toxicity.

Surgery. For the 41 patients with localized disease, the timing of surgery relative to chemotherapy was quite variable. Eighteen patients (44%) received three cycles of chemotherapy preoperatively and three cycles postoperatively as planned. Surgery was performed after one cycle of chemotherapy in three patients, after two cycles in three patients, and after three cycles in six patients; in these cases, chemotherapy was then discontinued. One patient had surgery after completion of chemotherapy. The remaining nine patients had other sequences of chemotherapy and surgery. One further patient received additional cycles of ifosfamide chemotherapy before surgery, because of primary progression after three cycles of DOX/DDP therapy, and went on to have conservative surgery and a bone graft (data not included in Tables 5 and 6).

Types of surgery performed are listed in Table 5. There were few postoperative complications; they included deep wound infection (one patient), superficial wound infection (three patients), skin necrosis of flaps (two patients), and neurologic damage, hematoma, gangrenous cholitis, and prosthetic instability (one patient each). There were no postoperative deaths.

In 34 patients, surgical margins were judged adequate. Locoregional radiotherapy was administered to all six patients with inadequate margins (in one case before surgery), and in two of these cases additional nonprotocol chemotherapy was given.

Response to chemotherapy. The association between clinical and pathologic response is shown in Table 6. Data from one patient, who received nonprotocol therapy with ifosfamide before surgery, are not included in this table. Clinical response was not recorded in seven patients, and pathologic response could not be reviewed in two patients. Twenty (60%) of 33 patients evaluated showed a complete (four patients) or partial (16 patients) clinical response. Pathologic response data were not available in two of these responding cases, but 13 (72%) of 18 of the remaining patients also showed a good pathologic response. One patient with a good pathologic response showed no change clinically, and another patient with a good pathologic response was shown clinically to have progressive disease. Overall, a good pathologic response to chemotherapy occurred in 16 (42%) of the 38 patients with specimens available for review. The good pathologic response rate was 40% (95 CI, 25% to 57%) if all 40 patients were included.

Outcome. Two patients were never rendered free of disease by protocol treatment. One with a pelvic tumor showed local progression after two cycles of chemotherapy, had a marginal resection, experienced a rapid local recurrence, which was treated by palliative radiotherapy, and died shortly thereafter. A second patient developed lung and bone metastases during protocol chemotherapy, and these metastases responded to ifosfamide chemotherapy. The primary tumor was resected and the patient was alive 5.3 years from the start of chemotherapy, after multiple treatments for metastases. Four patients showed local recurrence after completion of protocol treatment, and two of those patients have died. Only one of these patients was considered to have had inadequate margins after surgery. Twelve patients developed metastases, six in lung only, one in bone only, two in lung and bone, and the remainder at multiple sites.

Median duration of follow-up was 5.2 years. Nineteen patients' disease progressed (median time to progression, 56 months), and the progression-free survival rate at 5 years was 56% (95% CI, 40% to 72%) (Fig 1). Thirteen patients died from progressive sarcoma and two from other causes (pancreatic carcinoma and septicemia associated with urinary infection). The median survival time was 63 months, with 59% (95% CI, 41% to 77%) surviving at 5 years (Fig 2).

View larger version (11K): [in this window] [in a new window]   Fig 1. Time to disease progression.

View larger version (11K): [in this window] [in a new window]   Fig 2. Overall survival.

Overall survival of and time to progression for nonmetastatic patients who underwent surgery are shown in Figs 3 and 4. In our study, patients with a good pathologic response had longer survivals and times to progression than did poor responders. No statistical comparison was made, because of the potential biases and the very low power of such an analysis.

View larger version (11K): [in this window] [in a new window]   Fig 3. Overall survival, by pathologic response.

View larger version (11K): [in this window] [in a new window]   Fig 4. Time to disease progression, by pathologic response.

Recurrent Inoperable or Metastatic MFH-B
Eleven patients had metastatic (nine patients) or locally recurrent inoperable (two patients) disease. Eight patients had lung metastases (one also had bone metastases), and one had nodal metastases. There were five men and six women in this group of patients, and the median age was 31 years (range, 18 to 64 years). All had an adequate performance status (WHO grade 0 in three patients, grade 1 in six patients, and grade 2 in two patients). Primary locations were femur (six patients), pelvis (three patients), tibia (one patient), and patella (one patient).

Only five patients completed all of the planned chemotherapy cycles; therapy was stopped in four patients because of primary progression and in two because of lack of response. Overall clinical response for the nine patients with metastatic disease was as follows: complete response in one patient, partial response in four patients (three patients' disease subsequently progressed), stabilization of disease in three patients, and progression of disease in one patient.

Five of the patients with metastases had operable tumors. Three with a partial clinical response (one showing a good pathologic response) to chemotherapy and one with stable disease underwent surgery; three patients had prosthetic placement, and no reconstruction was necessary in one patient. Surgical margins were adequate in three patients and inadequate in one patient with a partial response. There were no surgical complications. One patient with an operable tumor did not undergo surgery, for religious reasons. The two patients presenting with local recurrence did not undergo further surgery.

In nine of these 11 patients with recurrent or metastatic MFH-B, the disease progressed, and seven of the 11 patients died (one from viral pneumonia). The median survival time was 17.5 months (Fig 2).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
MFH-B is an aggressive bone sarcoma that shares many clinical features as well as similarities in tumorigenesis with classic high-grade OGS. However, it is very difficult (more so than in OGS) to obtain an unbiased estimate of outcome for patients with MFH-B presenting without metastatic disease who receive only locoregional therapy. In retrospective reviews, survival data obtained from pathology files for bone tumors seen at large centers (see Table 1) may be influenced by patterns of referral, differing pathologic criteria for diagnosis, inconsistent inclusion of low-grade tumors, variations in locoregional management, and inclusion of some patients receiving systemic therapy. Case reports accompanied by literature reviews^29,30 may also be affected by variable quality of literature searches, publication bias, and an inability to verify histologic classification and clinical details. Thus, although our study findings are consistent with findings presented in many recent reports^12,31-34 that support the use of adjuvant chemotherapy, conclusive evidence could only be provided by a randomized trial. The logistics of conducting such a study are formidable. Over a 12-year period, the large Rizzoli Institute in Bologna documented only 51 patients eligible to receive chemotherapy,³⁴ and in this EOI study, we registered only 41 patients with localized disease over 8 years.

Accurate pathologic diagnosis is critical in any study of MFH-B. For this multicenter study, the method of biopsy was not recorded, and it is likely that both needle and open biopsy techniques were used. However, van der Bijl et al³⁵ showed that Jamshidi trocar biopsy is a reliable technique in patients with bone tumors, with 95% diagnostic accuracy in 258 patients. A strength of this study was central pathology review, and only those cases confirmed as MFH-B cases were included. As shown in Table 2, 13 tumors categorized by local pathologists as MFH-B were reclassified as ineligible for study (seven cases) or other spindle cell sarcomas of bone (six cases) and are being reported on separately (Nooij et al, manuscript in preparation). In addition, two cases categorized by local pathologists as other spindle cell sarcomas were recategorized as MFH-B.

In 1984, investigators at the M.D. Anderson Cancer Center²⁰ reported significantly improved 2-year relapse-free survival (RFS) and overall survival rates (45% and 58%, respectively) for 24 patients with MFH-B who received a variety of chemotherapy regimens, compared with rates (11% and 28%, respectively) for 36 patients receiving locoregional treatment only. However, Patel et al,³⁶ presenting updated results for a subset of 15 patients who received chemotherapy, noted that only four patients were long-term survivors (75 to 140 months), and median RFS and overall survival times were 19 and 23 months, respectively.

In two small studies with short follow-up and in which DOX-based neoadjuvant chemotherapy was given, 10 of 12 patients³² and seven of nine patients³¹ survived for more than 2 years. Ham et al³³ reported that all 10 patients with MFH-B treated at their center with an intensive HDMTX-based regimen were surviving disease-free at a median follow-up of 9.8 years. However, four of five patients who could not tolerate this regimen or received other chemotherapy had died of sarcoma. Yokoyama et al¹² reported that in their series of 34 patients with MFH-B, six patients with adequate surgical margins who received intensive chemotherapy (DOX/HDMTX and vincristine) were relapse-free for more than 5 years.

Waddell et al³⁷ also reported favorable results (57% RFS and overall survival at 30 months) from a regimen of DOX/DDP similar to ours. However, direct comparisons are limited by the fact that only nine of the 17 cases of high-grade, nonmetastatic, non-OGS tumors were MFH-B.

Many studies of OGS have demonstrated that neoadjuvant chemotherapy can cause significant necrosis in primary tumors. Good response has been reported in 20% to 60% of cases depending on the regimen used and seems to predict a better outcome.¹⁵ In this study of MFH-B, a good response was evident in 42% of the 38 assessable tumors and predicted a better progression-free survival and improved overall survival (Figs 3 and 4). Johnson et al³¹ and Earl et al³² reported similar rates of good response in their small series: 44% (four of nine patients) and 47% (seven of 15 patients), respectively. In contrast, in their much larger series of 51 patients, Picci et al³⁴ found a lower rate of good response (27%), but they also found that this correlated with improved disease-free survival (P = .04).

The EOI has considerable experience in the use of DOX/DDP therapy in classic OGS, and it is worth comparing some of the clinical features and outcomes described in the reports of two osteosarcoma studies^22,23 and the current study of MFH-B (Table 7) (although it must be acknowledged that these are not randomized comparisons). Our MFH-B patients were older, and fewer patients completed the full six cycles of chemotherapy. Given that there were no major differences in reported clinical and pathologic response rates between these studies that might have led to premature discontinuation of chemotherapy, this may be because of increased toxicity or poorer tolerance in older patients. This explanation is suggested by the lower mean total doses of DOX and DDP administered in this study compared with those in the previous osteosarcoma studies. Five-year overall survival rates, 64% and 55% for OGS and 59% for MFH-B, are quite similar among the three studies (Table 7).

The group from Bologna also compared outcomes for OGS and MFH-B treated with similar chemotherapy regimens (Table 8). Picci et al³⁴ described outcomes for patients presenting at the Rizzoli Institute with OGS or MFH-B and treated with three different, consecutive chemotherapy regimens between 1982 and 1994. Bacci et al^38,39 compared outcomes for patients with OGS and MFH-B, treated with HDMTX/DOX/DDP therapy (1986 to 1990) or HDMTX/DOX/DDP/ifosfamide therapy (1991 to 1994). In contrast with the EOI, the Rizzoli group documented significantly lower rates (Table 8) of good histologic response to the same chemotherapy regimens, for MFH-B compared with OGS. However, as in our study, clinical response, rates of limb salvage, and survival were quite similar for the two groups of tumors. All of these nonrandomized comparisons are subject to bias and determinations should be interpreted with caution.

As a primary bone tumor, in general MFH-B has been treated with regimens known to be active in OGS. An alternative approach would be to use a combination, such as DOX/ifosfamide, which is commonly used to treat soft tissue sarcomas. Ifosfamide is an active drug in both soft tissue and bone sarcomas.⁴⁰ There are few data on the use of ifosfamide in MFH-B. One of our patients developed lung and bone metastases during DOX/DDP chemotherapy, and these metastases responded to ifosfamide therapy. The Rizzoli group incorporated ifosfamide into their most recent combination regimen for MFH-B,³⁹ but it is difficult to determine, through comparisons between sequential nonrandomized studies, whether there was additional benefit. The EOI is considering incorporating ifosfamide into the DOX/DDP regimen for their next MFH-B protocol.

In conclusion, our study supports others in the literature that suggest that adjuvant or neoadjuvant chemotherapy is beneficial in MFH-B. Good pathologic response rates and survival figures are quite comparable with those for OGS, a related bone tumor for which adjuvant or neoadjuvant chemotherapy is the accepted practice.^13,15 Given the rate of good pathologic response, DOX/DDP therapy seems an effective regimen with an acceptable 5-year survival rate. Although at least one group^33,41 has stated that HDMTX is a critical component of effective adjuvant chemotherapy for MFH-B, our data suggest that this remains unproven.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The following physicians contributed patients to this European Osteosarcoma Intergroup study:

United Kingdom and Canada (data submitted to the Medical Research Council Cancer Trials Office, Cambridge): R. Souhami, R. Sweetnam, M. Hams (Middlesex and University College Hospitals, London); M. Ostrowski, R. Sneath (Royal Orthopaedic Hospital, Birmingham); S. Kaye, D.L. Hamblin (Western Infirmary, Glasgow); W. Steward, F. Madden, M. Green (Royal Infirmary, Leicester); J. Roberts, A. Cross (General Hospital, Newcastle); N. Blechan, P. Scott (Addenbrooks Hospital, Cambridge); P. Daley, B. Hurson (St. James Hospital, Dublin); G. Mead, S. Wood (Royal South Hants Hospital, Southampton); I. Manifold, M. Robson (Weston Park Hospital, Sheffield); D. Crowther (Christie Hospital, Manchester); C. Bailey, R. Conmer (Cookridge Hospital, Leeds); G. Rustin, S. Cannon (Mount Vernon Hospital, London); N. Hodson (Royal Sussex County Hospital, Brighton); P. Harper (Guy's Hospital, London); V. Bramwell (London Regional Cancer Centre, Ontario, Canada).

Continental Europe (data submitted to the European Organization for Research and Treatment of Cancer Data Centre, Brussels, Belgium): M. Nooij, A. Taminiau (University Medical Center, Leiden, the Netherlands); A. Fernandes, S. Pires (Francisco Gentil Hospital (Lisbon, Portugal); A. Bosley, C. Chatelain (University Clinic of Mont Goudinne, Yvoir, Belgium).

	ACKNOWLEDGMENTS

 
Supported in part by grants no. SU10 CA11488-18 through ZU10 CA11488-28 from the National Cancer Institute (Bethesda, MD). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

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Submitted February 12, 1999; accepted June 9, 1999.

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