J Thorac Cardiovasc Surg 2000;119:1154-1161
© 2000 The American Association for Thoracic Surgery
EWING SARCOMA OF THE RIB: RESULTS OF AN INTERGROUP STUDY WITH ANALYSIS OF OUTCOME BY TIMING OF RESECTION
Robert C. Shamberger, MD, FACS,
Michael P. LaQuaglia, MD, FACS,
Mark D. Krailo, PhD,
James S. Miser, MD,
Douglas J. Pritchard, MD,
Mark C. Gebhardt, MD, FACS,
John H. Healey, MD,
Nancy J. Tarbell, MD,
Christopher J.H. Fryer, MD,
Paul A. Meyers, MD,
Holcombe E. Grier, MD,
Pediatric Oncology Group Children’s Cancer GroupAddress for correspondence: Robert C. Shamberger, MD, FACS, Department of Surgery, Children’s Hospital, 300 Longwood Ave, Boston, MA 02115 (E-mail: Shamberger@a1.tch.harvard.edu).
From the Departments of Surgery (R.C.S.) and Orthopedic Surgery (M.C.G.) and the Division of Pediatric Hematology/Oncology (H.E.G.) at Children’s Hospital, Boston, Mass; the Dana Farber Cancer Institute (H.E.G.) and Harvard Medical School; the Department of Surgery (M.P.L.), Orthopedic Surgery (J.H.H.), and Pediatrics (P.A.M.) at Memorial Sloan Kettering Cancer Institute, New York, NY; University of Southern California School of Medicine, Los Angeles, Calif (M.D.K.); the Division of Pediatrics, City of Hope, Duarte, Calif (J.S.M.); the Division of Orthopedic Oncology, Mayo Clinic, Rochester, Minn (D.J.P.); the Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School (N.J.T.), Boston, Mass; and the Department of Pediatrics, King Khalid National Guard Hospital, Jeddah, Kingdom of Saudi Arabia (C.J.F.).
This work was supported in part by the following grants from the National Institutes of Health: CA-02649, CA-02971, CA-03161, CA-03526, CA-03750, CA-03888, CA-05436, CA-05587, CA-07306, CA-07431, CA-10198, CA-10382, CA-11233, CA-11796, CA-13539, CA-13809, CA-14560, CA-15525, CA-17829, CA-20320, CA-20549, CA-25408, CA-26044, CA-26126, CA-26270, CA-27678, CA-28383, CA-28439, CA-28476, CA-28851, CA-28882, CA-29013, CA-29139, CA-29293, CA-29314, CA-29691, CA-30969, CA-32053, CA-33587, CA-33603, CA-33625, CA-36015, CA-41573, CA-42764, CA-53128, CA-69177, CA-69428.
Address for reprints: Robert C. Shamberger, MD, FACS (#8850), c/o: Pediatric Oncology Group, 645 North Michigan Ave, Ste 910, Chicago, IL 60611.
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Abstract
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Objective: We sought to establish the outcome and optimal therapeutic sequence for patients with nonmetastatic Ewing sarcoma/primitive neuroectodermal tumor of the chest wall.
Methods: Patients 30 years of age or younger with nonmetastatic Ewing sarcoma/primitive neuroectodermal tumor of the bone were randomly assigned to receive vincristine, doxorubicin, cyclophosphamide, and dactinomycin or those drugs alternating with ifosfamide and etoposide. Local control was obtained with an operation, radiotherapy, or both.
Results: Fifty-three (13.4%) of 393 patients had primary tumors of the chest wall (all rib). Event-free survival at 5 years was 57% for the chest wall compared with 61% for other sites (P > .2). Ifosfamide and etoposide improved outcome in the overall group (5-year event-free survival, 68% vs 54%; P = .002), and a similar trend occurred in chest wall lesions (5-year event-free survival, 64% vs 51%). Patients with chest wall lesions had more attempts at initial surgical resection (30%) than those with other primary tumor sites (8%, P < .01). The attempt at initial resection for chest wall lesions did not correlate with size. Initial resections at other sites were restricted to smaller tumors. Initial resection resulted in negative pathologic margins in 6 of 16 patients, whereas the delayed resection resulted in negative margins in 17 of 24 patients (P = .05). Although there was no difference in survival by timing of the operation in rib lesions, a higher percentage of patients with initial surgical resection received radiation than those with resection after initial chemotherapy (P = .13).
Conclusions: Although rib primary tumors are significantly larger than tumors found in other sites, their outcome is similar. We favor delayed resection whenever possible to minimize the number of patients requiring radiation therapy.
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Introduction
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Ewing sarcoma is the most frequent chest wall tumor occurring in children and adolescents. It is an extremely aggressive tumor, and management requires intensive local therapy with surgical resection, radiotherapy, or both, as well as adjuvant chemotherapy to prevent or treat metastases. Local recurrence in this tumor has been frequent. An intergroup study with two new agents in the treatment of this tumor recently has been completed. We have reviewed the patients in this study with chest wall tumors because particular consideration is required for treatment of this location. Radiation administered to the chest is less well tolerated than that administered to other sites because of exposure to the heart and lungs. Also, the ribs have often been considered as expendable bones in contrast to the central axial skeleton and certain long bones of the extremities.
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Methods
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Patients and therapeutic plan
Intergroup study INT-0091 (CCG 7881, POG 8850) was opened to all member institutions of the Children’s Cancer Group and the Pediatric Oncology Group in December 1988 and closed in November 1992. Patients accrued to this study were 30 years of age or less at diagnosis, with a primary bone tumor that had a histologic diagnosis of Ewing sarcoma, peripheral neuroectodermal tumor, or primitive sarcoma of bone. Prior anticancer therapy other than an operation to obtain a diagnosis was not allowed. To retain eligibility, protocol chemotherapy had to start within 1 month of the diagnostic biopsy. Patients, guardians, or both had to give informed written consent according to institutional guidelines to participate.
Patients were randomized at study entry to receive standard chemotherapy with doxorubicin, vincristine, cyclophosphamide, and dactinomycin or to receive the experimental therapy consisting of those 4 drugs alternating with courses of ifosfamide and etoposide. Randomization was stratified into groups according to the presence of metastases. Details of the chemotherapy regimens are presented elsewhere.
1 This report is restricted to patients without metastatic disease at diagnosis.
Local control measures consisted of either radiation therapy, an operation, or both. The protocol called for delivery of local control at 12 weeks. The treating physicians decided which local control modality to use in each case, and this factor was not a randomized variable; the protocol allowed an operation for tumors deemed to be resectable. For patients receiving radiotherapy alone, the initial tumor volume (soft tissue and osseous extent of tumor) with a 3-cm margin was treated to 4500 cGy. This was followed by a reduction in treatment volume to the postchemotherapy, preradiotherapy extent of tumor for an additional 1080 cGy, resulting in a total dose of 5580 cGy. Patients with residual tumor after an operation also were irradiated after these dose-volume guidelines for gross residual disease and 4500 cGy with a 1-cm margin for microscopic disease. The protocol allowed for attempted surgical resection before the start of chemotherapy and after consultation with the study chair and surgical members of the study committee.
Estimation of size of tumor at diagnosis
The 3 largest perpendicular measures of the patient’s primary tumor, as determined by computed tomography, were to be supplied at the time of study entry. For patients for whom all 3 measurements were reported, tumor volume was estimated by the product of the 3 perpendicular measures. If one or more of the measurements were not available, the tumor volume was not estimated.
Statistical analysis
Adverse event-free survival (EFS) was defined to be the time from study entry until disease progression, diagnosis of a second malignant neoplasm, death, or last patient contact when an event was considered to have occurred, whichever came first. Otherwise, the patient was censored at the date of last contact. Data current to December 1997 were used in the analysis.
For a patient to be considered capable for evaluation for local control, the individual must have started maintenance after all local interventions were completed. Adverse EFS after local control was defined to be the time from the start of maintenance therapy until disease progression, diagnosis of a second malignant neoplasm, death, or last patient contact, whichever came first. If the patient experienced disease progression, diagnosis of a second malignant neoplasm or death after an event was considered to have occurred. Otherwise, the patient was censored at the date of last contact.
The survivor functions for EFS and EFS after local control were estimated by the method of Kaplan and Meier. 2 Risk for adverse event was compared across groups defined by treatment or prognostic factors by the log-rank statistic. 2 The patient’s randomized treatment assignment was used in all comparisons involving regimen. Hazard ratios (HRs) and associated confidence intervals (CIs) were estimated by the proportional hazards regression model. 2
The proportional hazards regression model was used to determine, for patients with rib primary tumors, which factors were independently prognostic for outcome. All factors that were significant at the .10 level in univariate analyses, as well as the randomized regimen, were selected for inclusion in a backward stepwise model. Age and tumor volume were selected by this screening process. The absolute value of age and tumor volume were used. Modifying these effects with quadratic terms did not significantly improve fit. A multiplicative interaction term for age and tumor volume was included in the regression model used to start the backward stepwise procedure. Terms that were significant at the .05 level or less in the final model were considered independently prognostic for risk of adverse events.
Qualitative characteristics were compared across subgroups by means of the exact conditional test of proportions. 3 In particular, tumor size was classified as above or below median and compared across groups defined by site of primary tumor.
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Results
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Three hundred ninety-three eligible patients with nonmetastatic Ewing sarcoma were entered on the study. Fifty-three patients had a primary tumor located in the ribs, and 340 had primary tumors located at other sites. There were no sternal primary tumors.
Two hundred twenty-six patients had sufficient data submitted to estimate tumor volume. Patients without tumor volume calculated were distributed similarly across the various primary tumor sites when compared with patients with known volumes. Rib lesions were significantly larger than tumors at some other sites and most closely resembled pelvic tumors in volume (Table I).
Two patients did not have any data submitted to describe the surgical procedures performed as part of protocol therapy. These individuals are excluded from subsequent analyses.
Sixteen patients with rib primary tumors had an attempt to resect the tumor before the start of chemotherapy. Patients with rib primary tumors were significantly more likely to have initial surgical excision attempted when compared with patients with tumors of other sites (30% vs 8%, P < .01). Attempts at initial resection for chest wall lesions were not associated with size of tumor, as assessed by largest diameter in contrast to tumors at other sites, where initial resections were done only rarely in large tumors (Table II).
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Table II. Relationship of primary tumor site and size by largest tumor dimension to likelihood of initial attempt at resection
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Data from the local pathologist were available for 16 of the initial resections. Sixty-two percent (10/16) were determined to have tumor at the margin of resection. Data from the local pathologist was available for 24 of the 30 patients who underwent an operation after induction therapy. Tumor was found at the margin of resection in 7 (29%) of these patients (P = .05).
The type of local therapy delivered after induction as it relates to initial local therapy is demonstrated in Table III. Patients who had an initial resection were more likely to receive radiation therapy than those who had resections after initial chemotherapy, although this was not significant at the .05 level (P = .13).
The 5-year EFS for all 393 patients with nonmetastatic disease was 61% (95% CI, 55%-66%; Fig 1). EFS at 5 years was 57% for the chest wall compared with 61% at all other sites (HR for chest wall tumor, 0.88; 95% CI, 0.56-1.4; P = .6). Ifosfamide and etoposide significantly improved outcome in the overall group (5-year EFS, 68% vs 54% for standard chemotherapy; HR, 0.61; 95% CI, 0.44-0.84; P = .002); the same trend was seen for chest wall lesions but did not reach statistical significance (5-year EFS, 64% vs 51% for standard chemotherapy; HR, 0.61; 95% CI, 0.27-1.4; P = .2). The site of the primary tumor was associated with risk for adverse event. Patients with rib primary tumors had outcomes comparable with those of patients with primary tumors in the femur or humerus and outcomes superior to those of patients with pelvic primary tumors (Fig 2; HR for femur or humerus primary tumor, 0.84; HR for pelvic primary tumor, 1.3; HR for any other site, 0.69; P = .03). Patients with rib lesions of volume greater than the median for this site were at increased risk for an adverse event (Fig 3; HR, 3.3; 95% CI, 1.0-11), as were older patients (Fig 4; HR for patients 10-17 years of age, 2.4; HR for patients 18 years or older, 7.8; P = .03). Risk for an adverse event was not related to an initial attempt at resection (Fig 5; HR, 0.72; 95% CI, 0.28-1.8; P = .5). The type of local control measures also was not related to EFS after local control (Fig 6; HR for operation, 0.35; HR for operation plus radiation therapy, 0.48; P = .3).
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Fig. 1. Kaplan-Meier estimate of EFS for all patients with nonmetastatic disease at study entry (n = 393).
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Fig. 2. Kaplan-Meier estimates of EFS for patients with nonmetastatic disease at study entry according to site of primary tumor (P = .03): ribs (n = 53), humerus or femur (n = 100), pelvis (n = 93), or other site (n = 147).
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Fig. 3. Kaplan-Meier estimates of EFS for patients with nonmetastatic rib primary tumors according to estimated tumor volume (P = .03): 419 cm3 or less or greater than 420 cm3.
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Fig. 4. Kaplan-Meier estimates of EFS for patients with nonmetastatic rib primary tumors according to age at study entry (P = .01): 10 years or younger (n = 19), 10 to 17 years (n = 30), or older than 17 years (n = 4).
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Fig. 5. Kaplan-Meier estimates of EFS for patients with nonmetastatic rib primary tumors according to whether the operation was conducted before the start of systemic chemotherapy (P = .5): yes (n = 16) versus no (n = 35).
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Fig. 6. Kaplan-Meier estimates of EFS after local control for patients with nonmetastatic rib primary tumors according to type of local control (P = .3): radiation therapy (n = 14), an operation (n = 18), or radiation therapy and an operation (n = 12).
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The backward stepwise model demonstrated that both increased tumor volume and increased age were factors independently associated with elevated risk for adverse events in patients with rib primary tumors. There was no evidence of an interaction between the two factors.
Complete data regarding the surgical resection was available on 34 patients. The magnitude of chest wall resection is shown in Table IV. Prosthetic mesh was used for reconstruction in 19 children (polytetrafluoroethylene,* 9 children; Marlex mesh [Bard Implants, Billerica, Mass], 6 children; Prolene mesh [Ethicon, Inc, Somerville, NJ], 2 children; Vicryl mesh [Ethicon], 2 children; and dural graft, 1 child). In 1 child a prosthetic sandwich reconstruction was performed, and in another child a frozen rib allograft was placed. A lung was adherent to the mass in 18 patients, and a wedge resection was performed in 15 patients. Adherent diaphragm was resected in 9 patients, and in all cases primary closure was possible. Muscle flap rotation was performed in 4 patients (pectoral muscle, 1 patient; latissimus dorsi muscle, 3 patients).
Few complications were reported. Only 2 were reported in the 16 attempted resections before chemotherapy. Both patients had intraoperative hemorrhage. There was 1 incident of intraoperative hemorrhage and 1 incident of delayed wound healing among the resections attempted after induction chemotherapy.
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Discussion
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In this large study of primitive neuroectodermal tumor and Ewing sarcoma of bone, rib primary tumors did as well or better than primary tumors of similar size at other sites. As in other sites, outcome correlated with size and age, as well as whether the patient received the experimental therapy, although the latter did not reach statistical significance for the rib lesions. Surgeons are more likely to attempt an initial resection for patients with rib primary tumors. In contrast to other sites, initial resection of the ribs was attempted, even with very large primary tumors.
Should one attempt initial resection in Ewing sarcoma/primitive neuroectodermal tumor of the ribs? We found no difference in eventual outcome for patients who had initial resection compared with those who had initial biopsy only, but the numbers are limited in this study. Importantly, however, more patients with an initial attempt at resection required eventual radiation therapy than those patients who had their resection after initial shrinkage of the tumor with chemotherapy. Radiation therapy has special side effects in the chest, where large volumes of lung may be damaged with the required high doses of radiation therapy. 4 In addition, the heart may be in the field, and radiation to the heart is believed to add toxicity to the damage caused by an essential chemotherapeutic agent for this disease, doxorubicin. 5,6 Finally, the risk of second malignant neoplasms after radiation therapy in Ewing sarcoma is quite high (10%-30%). 7-9
We therefore agree with Rao and others, who believe that initial attempts at resection should rarely be done in Ewing sarcoma/primitive neuroectodermal tumor of the chest wall. 10-12 After initial chemotherapy, the tumors are generally smaller and the margins of involvement are better defined, resulting in an increased proportion of resections with negative microscopic margins, as was found in this study. A limited number of children will require radiation therapy because of paravertebral involvement, size of the lesion, apical location of the tumor, or incomplete resection of the tumor at a delayed operation. EFS for patients without metastases now is nearly 60%, regardless of the form of local treatment. Any therapy that might lead to long-term side effects, such as radiation, should be avoided if possible, and this can best be achieved by use of initial chemotherapy before attempted resection.
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Acknowledgments
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We thank the investigators of the Pediatric Oncology Group and the Children’s Cancer Group and the many pathologists, surgeons, pediatricians, radiation oncologists, and other health professionals who managed the children entered into this study.
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References
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Received for publication April 27, 1999. Revisions requested Aug 24, 1999; revisions received Jan 12, 2000. Accepted for publication Feb 7, 2000.
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Abstract
Introduction
