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Presurgical Chemotherapy Compared With Immediate Surgery and Adjuvant Chemotherapy for Nonmetastatic Osteosarcoma: Pediatric Oncology Group Study POG-8651

Allen M. Goorin, Douglas J. Schwartzentruber, Meenakshi Devidas, Mark C. Gebhardt, Alberto G. Ayala, Michael B. Harris, Lee J. Helman, Holcombe E. Grier, Michael P. Link

From the Department of Pediatrics, Dana-Farber Cancer Institute; Division of Medicine, Children’s Hospital Boston; Department of Pediatrics, Department of Orthopedic Surgery, Harvard Medical School; and Massachusetts General Hospital, Boston, MA; Surgical Oncology Branch and Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; Department of Statistics, University of Florida, and Pediatric Oncology Group Statistical Office, Gainesville, FL; Department of Surgical Pathology, University of Texas, and M.D. Anderson Cancer Center, Houston, TX; Tomorrows Children’s Institute, Hackensack, and University Medical Center and University of Medicine and Dentistry of New Jersey, Newark, NJ; and Department of Pediatrics, Stanford University School of Medicine, Stanford, CA.

Address reprint requests to Allen M. Goorin, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; email: allen_goorin{at}dfci.harvard.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: Successful therapeutic interventions to prevent disease progression in patients with nonmetastatic osteosarcoma have included surgery with adjuvant chemotherapy. Presurgical chemotherapy has been advocated for these patients because of putative improvement in event-free survival (EFS). The advantages of presurgical chemotherapy include early administration of systemic chemotherapy, shrinkage of primary tumor, and pathologic identification of risk groups. The theoretic disadvantage is that it exposes a large tumor burden to marginally effective chemotherapy. The contribution of chemotherapy and surgery timing has not been tested rigorously.

Patients and Methods: Between 1986 and 1993, we conducted a prospective trial in patients with nonmetastatic osteosarcoma who were assigned randomly to immediate surgery or presurgical chemotherapy. Except for the timing of surgery (week 0 or 10), patients received 44 weeks of identical combination chemotherapy that included high-dose methotrexate with leucovorin rescue, doxorubicin, cisplatin, bleomycin, cyclophosphamide, and dactinomycin.

Results: One hundred six patients were enrolled onto this study. Six were excluded from analysis. Of the remaining 100 patients, 45 were randomly assigned to immediate chemotherapy, and 55 were randomly assigned to immediate surgery. Sixty-seven patients remain disease-free. At 5 years, the projected EFS ± SE is 65% ± 6% (69% ± 8% for immediate surgery and 61% ± 8% for presurgical chemotherapy; P = .8). The treatment arms had similar incidence of limb salvage (55% for immediate surgery and 50% for presurgical chemotherapy).

Conclusion: Chemotherapy was effective in both treatment groups. There was no advantage in EFS for patients given presurgical chemotherapy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
SUCCESSFUL THERAPEUTIC interventions to prevent disease progression in patients with nonmetastatic osteosarcoma have included adjuvant chemotherapy and surgical resection of the primary tumor.^1,2 Presurgical chemotherapy has been recommended for patients with osteosarcoma because several trials that incorporated presurgical chemotherapy resulted in improved outcomes for patients. Investigators have claimed that limb-salvage surgery is facilitated by presurgical chemotherapy. One possible advantage of presurgical chemotherapy is that it immediately treats micrometastatic disease and the primary tumor. In addition, response in the primary tumor may permit safer limb-resection procedures, and presurgical chemotherapy permits identification of risk groups by evaluating pathologic responses of primary tumors after resection.^3–7 Presurgical chemotherapy has been recommended for osteosarcoma, but it exposes a large tumor burden to potentially marginally effective chemotherapy, which may encourage development of distant metastases from chemotherapy-resistant cells. The improved event-free survival (EFS) in early trials that incorporated presurgical chemotherapy might have resulted from the use of more effective chemotherapy regimens or higher dosage chemotherapy, rather than the administration of presurgical chemotherapy per se. The contribution of the timing of chemotherapy and surgery has not been tested rigorously.

To study the effect of the timing of surgery on outcome of patients with nonmetastatic osteosarcoma, a multicenter randomized trial was conducted by the Pediatric Oncology Group (POG). The purpose of this trial was to determine whether chemotherapy administered before definitive resection of primary tumors improved EFS and overall survival compared with traditional resection of the primary tumor followed by adjuvant chemotherapy.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients were enrolled from POG institutions and from the Pediatric Oncology and Surgical Oncology Branches of the National Cancer Institute. Eligible patients were younger than 30 years, were evaluated at participating institutions, and had high-grade nonmetastatic osteosarcoma. Each patient was screened for metastatic disease with computed tomography scan of the chest and radionuclide bone scan within 2 weeks of entry. Patients were eligible for randomized assignment if they had histologic confirmation of high-grade osteosarcoma, no evidence of metastases, a primary tumor in an extremity or expendable bone, no history of cancer, and no prior therapy. To confirm eligibility, pathologic slides from diagnostic biopsies were centrally reviewed. The adequacy of primary surgery also was reviewed centrally using operative reports.

Randomization and Stratification
After eligible patients gave informed consent according to institutional guidelines, treatment was randomly assigned by the POG statistical office. Randomization was balanced for primary site (above knee or elbow), level of serum lactate dehydrogenase (LDH), and intended surgery (amputation v resection).

Therapy and Follow-Up Procedures
After primary tumor biopsies, patients were randomly assigned to receive either immediate intensive presurgical chemotherapy with surgery later or immediate surgery with adjuvant chemotherapy. The chemotherapy regimen was modeled after the adjuvant therapy regimen for osteosarcoma of the Multi-Institutional Osteosarcoma Study (Fig 1).¹ Chemotherapy was initiated within 3 days of random treatment assignment for the initial chemotherapy group, followed by surgery at week 10; chemotherapy was initiated within 21 days after surgery for those treated with immediate surgery. Otherwise, the chemotherapy was identical. High-dose methotrexate (12 g/m² of body-surface area) and leucovorin rescue (15 mg every 6 hours for 10 doses) were administered in weeks 0, 1, 5, 6, 13, 14, 18, 19, 23, 24, 37, and 38 for patients who received presurgical chemotherapy; for patients treated with immediate surgery, this regimen was administered in weeks 3, 4, 8, 9, 13, 14, 18, 19, 23, 24, 37, and 38. Doxorubicin 37.5 mg/m²/d for 2 days and cisplatin 60 mg/m²/d for 2 days were administered in weeks 2, 7, 25, and 28 for the presurgical chemotherapy group and in weeks 5, 10, 25, and 28 for the immediate surgery group. The combination of cyclophosphamide 600 mg/m²/d, bleomycin 15 mg/m²/d, and dactinomycin 0.6 mg/m²/d was administered for 3 days in weeks 15, 31, 34, 39, and 42 for both treatment plans; and a single course of doxorubicin 30 mg/m²/d was administered for 3 consecutive days in week 20 for both groups.

View larger version (12K): [in this window] [in a new window]   Fig 1. Chemotherapy regimen: the timing of surgery was determined by randomization to be performed at either week 0 or week 10; , administration of high-dose methotrexate and leucovorin rescue; AP, doxorubicin and cisplatin administration; BCD, cyclophosphamide, bleomycin, and dactinomycin; and ||, doxorubicin administration.

Statistical Considerations
The study was originally designed to detect a 2-year EFS difference of 15% (better or worse) between arms (65% v 80% or 50% v 65%; 65% was the outcome in our previous trial). Approximately 4 years of accrual (estimated 215 patients) would have allowed an 80% chance of detecting this difference with P = .05. However, because of the difficulty of randomization, actual accrual during the first 2 years was only 20 patients per year. Thus, the study was amended to question only whether preoperative chemotherapy was superior. Power simulations found that with 110 patients, a one-sided (P = .05) log-rank test would have 80% power to detect an increase in 2-year EFS with presurgical chemotherapy from 65% to 80%. The study has a 63% power to detect a 15% poorer income for those treated with delayed surgery compared with those who had immediate surgery (50% v 65%), using a one-sided test of size 5%.

The primary end point of this study was EFS. All eligible patients were included in the analysis. Patients were analyzed as randomized, irrespective of actual treatment received. Outcome according to treatment actually administered was also analyzed. Time to an adverse event was defined as time from the date of randomization until recurrence of tumor at any site, second malignancy, or death from any cause. Patients who did not have adverse events were censored at the date of last contact. Survival and EFS estimates were computed by the Kaplan-Meier⁸ method, with SEs determined according to Peto et al.^9,10 Surgical complications were analyzed with the Fisher’s exact test.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Between October 1986 and November 1993, 106 patients were enrolled onto the study. Six patients were excluded from the analysis. Five were ineligible (one patient had a wrong diagnosis, one patient had metastasis at diagnosis, two patients had low-grade periosteal osteosarcomas, and one patient had no pathologic confirmation), and one patient was excluded because he was not randomly assigned to treatment. Among 100 eligible patients remaining, 45 were randomly assigned to presurgical chemotherapy and 55 were assigned to immediate surgery. The difference in number of patients randomly assigned to the two treatment plans was influenced by the stratifications that included the surgical procedure planned, serum LDH, and the location of primary tumor.

Characteristics of randomly assigned patients are listed in Table 1. There was a preponderance of male subjects in each group, and most patients were older than 12 years. Most tumors were in the femur and tibia in both groups. There was one patient with a lesion in the talus in the immediate surgery group and one patient with a metatarsal lesion in the presurgical chemotherapy group. Fifty-one percent of patients in the presurgical chemotherapy group were intended to have limb-resection surgery and 49% were intended to have amputations, compared with 53% intended to have limb-resection surgery and 47% intended to have amputations in the immediate surgery group. The average annual accrual was 15 patients. The study accrued patients for 7 years. Accrual in the last 2 years of the trial was nine and eight patients, respectively. Thirty-seven institutions registered patients on this trial, and three institutions enrolled eight or more patients.

Among 55 patients treated with immediate surgery, 39 remain disease-free, and 15 developed distant relapses. Three patients with distant relapses developed pulmonary relapses after resection of primary tumors but before receiving any chemotherapy. There was one toxic death from bronchiolitis obliterans, which was most likely caused by bleomycin toxicity.

EFS
Sixty-seven patients remain disease-free. The projected overall 5-year EFS ± SE is 65% ± 6% (Fig 2). EFS by randomized treatment is shown in Fig 3A. The five-year EFS ± SE is 69% ± 8% for patients randomly assigned to immediate surgery and 61% ± 8% for patients randomly assigned to presurgical chemotherapy. There was insufficient evidence to show improvement in EFS for the presurgical chemotherapy group (one-sided log-rank, P = .8).

View larger version (11K): [in this window] [in a new window]   Fig 2. Event-free survival and survival for all eligible patients. Numbers on the curves represent patients still at risk.

View larger version (14K): [in this window] [in a new window]   Fig 3. (A) Event-free survival (EFS) and (B) survival according to assigned treatment. Numbers on the curves represent patients still at risk. There was insufficient evidence to show improvement in EFS (P = .6) or survival (P = .8) for the presurgical chemotherapy group.

When analyzed according to treatment actually administered, the results were not different. Five patients randomly assigned to immediate surgery were initially treated with chemotherapy: two because no allografts were available for reconstructive surgery, one because of pathologic fracture through the tumor, one by physician’s choice, and one at the patient’s request. Thus, 50 patients were treated with each approach.

Surgical Outcome
Surgical data forms were available for 97 of 100 eligible patients. Among patients assigned to presurgical chemotherapy, 50% had limb-sparing surgery. Four patients initially deemed eligible for limb-sparing surgery had amputations after presurgical chemotherapy, three by patient choice and one because of disease progression. However, two patients assessed initially as requiring amputations were able to have limb-sparing surgery because of tumor regression after presurgical chemotherapy.

Among patients assigned to immediate surgery, 55% had limb-sparing surgery. Two patients assessed initially as eligible for limb-sparing surgery had amputations, one because of disease progression during preoperative evaluation and the other was converted to amputation during surgery.

Outcome According to Pathologic Response to Presurgical Chemotherapy
Forty-two (93%) of 45 patients in the presurgical chemotherapy arm had central pathology review of resected surgical specimens after presurgical chemotherapy. Specimens from 26 of the patients (62%) showed less than 10% residual viable tumor, and 14 specimens (33%) showed less than 2% residual viable tumor after this chemotherapy regimen. Among the 26 patients who had less than 10% residual viable tumor in their resected specimens after presurgical chemotherapy, six patients experienced relapse and 20 patients remain disease-free, for a projected overall 5-year EFS ± SE of 73% ± 8% (Fig 4A). Among 16 patients who had 10% residual viable tumor, nine experienced relapse, for a 5-year EFS ± SE of 44% ± 15%. This difference is statistically significant (P = .027).

View larger version (14K): [in this window] [in a new window]   Fig 4. Event-free survival comparing pathologic response at (A) less than 10% residual viable tumor versus 10% residual viable tumor and (B) less than 2% residual viable tumor versus 2% residual viable tumor. Numbers on the curves represent patients still at risk.

Among 26 patients with less than 10% residual viable tumor, 20 remain alive (5-year survival ± SE, 77% ± 9%), compared with 12 of 16 patients with 10% residual viable tumor (5-year survival ± SE, 80% ± 12%; P = .896; Fig 5A). The 5-year survival ± SE is 86% ± 10% for the patients with less than 2% residual viable tumor, compared with 74% ± 10% for patients with 2% residual viable tumor (P = .34; Fig 5B).

View larger version (13K): [in this window] [in a new window]   Fig 5. Survival comparing pathologic response at (A) less than 10% residual viable tumor versus 10% residual viable tumor and (B) less than 2% residual viable tumor versus 2% residual viable tumor. Numbers on the curves represent patients still at risk.

Toxicity
There were three deaths attributable to chemotherapy. Otherwise, the toxic effects associated with this regimen were moderate, readily manageable, and reversible. Two patients who developed congestive heart failure from doxorubicin died while they were receiving therapy without evidence of disease. A third patient died of bronchiolitis obliterans. Patients spent considerable time in the hospital during chemotherapy. The most frequently observed toxic effect was neutropenia, which was seen in 89% of the patients receiving the presurgical chemotherapy treatment plan and 93% in the immediate surgery arm. Infections were also common, with 33% of patients having significant infections. Elevations of serum AST were commonly found, usually after courses of high-dose methotrexate, but were reversible. One patient had significant hearing loss. Other neurologic toxicities were related to administration of high-dose methotrexate and included seizures or migraine headaches in four patients. There were renal complications from the combination of cisplatin and high-dose methotrexate; primarily, these were abnormalities of serum electrolytes including sodium, potassium, calcium, and magnesium. Mucositis, nausea, and vomiting were common and troublesome complications. As anticipated, no significant differences in toxicity by treatment arm were observed.

Surgical Complications
Surgical data forms were not available for three patients (one patient in the presurgical chemotherapy group and two patients in the immediate surgery group). Fifteen early (< 30 days) and late ( 30 days) wound complications occurred in 12 of 44 assessable patients assigned to presurgical chemotherapy, and 22 complications were observed in 15 of 53 assessable patients assigned to immediate surgery (Table 2). The incidence of complications was not different between treatments; however, patients undergoing limb-sparing surgery had more complications. Twenty-one (41%) of 51 patients who had limb-sparing surgery had wound complications, compared with six (13%) of 46 patients who had amputations (P = .0029, Fisher’s exact). There were late complications from 38 to 2,405 days after surgery in the presurgical chemotherapy group and from 54 to 1,541 days after surgery in the immediate surgery group. To manage surgical complications, 15 surgical procedures (including two amputations) were performed in the group assigned to presurgical chemotherapy, and 18 surgical procedures (including three amputations) were performed in the immediate surgery group.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Accrual was poor because of bias (primarily among surgeons) that patients had improved survival with presurgical chemotherapy. That bias proved to be unfounded. Most investigators now recommend presurgical chemotherapy for patients with osteosarcoma. The justification is based on prognostic information that can be obtained from histologic assessment of the resection specimen after presurgical chemotherapy and the belief that presurgical chemotherapy improves the surgical outcome for patients who are candidates for limb-sparing surgery. However, no improvement in overall outcome (EFS or survival) can be expected from this approach. Neither the administration of presurgical chemotherapy nor immediate surgery prevents early disease progression in some patients. In our study, early (presurgical) administration of chemotherapy may have contributed to disease progression in six patients by delaying definitive surgery. However, immediate resection of primary tumor, before any chemotherapy, necessitated delay in initiation of chemotherapy to allow for wound healing. Three patients developed distant metastatic disease during that interval. Thus, different problems are associated with each strategy. The toxicities experienced by patients were similar whether or not they received presurgical chemotherapy. Two percent of patients developed congestive heart failure during chemotherapy, which is an unfortunate but predictable complication at the dosage of doxorubicin they received.¹⁴

Both strategies resulted in similar proportions of patients who were able to undergo limb-salvage surgery and similar incidences of postsurgical complications were observed with each treatment. About half of the patients had limb-resection surgery. Acceptable rates of local control of disease were observed with each treatment approach because there was only one local recurrence. As might be anticipated, patients who had amputations suffered fewer complications at 24 months, compared with those who had limb-salvage surgery.

The preoperative chemotherapy given in this trial was quite effective. Most patients had favorable chemotherapy effects in the primary tumor; 63% of patients had less than 10% residual viable tumor, and 33% had less than 2% residual viable tumor, which compares favorably with results from other presurgical chemotherapy regimens.^3,5–7,13 Favorable (< 10% residual viable tumor) and very favorable (< 2% residual viable tumor) responses in primary tumors were associated with superior EFS. However, that has not yet translated into a survival advantage.

Improvements in EFS with multiagent chemotherapy and surgery of the primary tumor of 50% to 80% have been reported in single-institution and group studies.^{1–3,5,7,12,13,15–25} The EFS values of the multi-institution studies are in the lower range of 50% to 65%. The 5-year EFS of 65% (5-year overall survival, 78%) in this POG study is excellent for a multi-institutional trial and is similar to the outcome for the patients randomly assigned to receive similar adjuvant chemotherapy in the previous POG study.¹ The current study has extended follow-up (and the survival curves are quite stable).

Chemotherapy before resection of primary tumors is used currently as a strategy for treatment of carefully selected patients with various other cancers, including breast cancer,^26,27 rhabdomyosarcoma,^28,29 bladder carcinoma,³⁰ laryngeal cancer,³¹ Ewing sarcoma,³² and soft tissue sarcoma,³³ because of putative improvement in outcomes.³⁴ Although presurgical chemotherapy does permit identification of risk groups by tumor response in osteosarcoma,^3,5–7,13 it does not seem to improve outcome for patients with nonmetastatic disease. Refinements in therapy for patients with osteosarcoma are needed because almost one third of patients relapse with current therapy. With the use of presurgical chemotherapy, patients spend considerable time in the hospital, the toxicity of the chemotherapy is significant, and the late effects of the therapy are just becoming known.

	NOTES

 
Supported in part by grant nos. CA-03161, CA-05587, CA-11233, CA-15525, CA-15898, CA-20549, CA-25408, CA-28383, CA-28439, CA-28476, CA-29139, CA-29293, CA-30969, CA-32053, CA-33587, CA-33603, CA-33625, CA-41573, CA-69177, and CA-69428 from the National Institutes of Health, Bethesda, MD.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted August 27, 2001; accepted January 3, 2003.

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