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© 2003 American Society for Clinical Oncology Long-Term Event-Free Survival After Intensive Chemotherapy for Ewing’s Family of Tumors in Children and Young AdultsFrom the Departments of Pediatrics, Surgery, Pathology, Biostatistics, and Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Paul A. Meyers, MD, Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, PO Box 139, 1275 York Ave, New York, NY 10021; e-mail: meyersp{at}mskcc.org.
Purpose: To improve the long-term event-free survival of patients with Ewing’s family of tumors (EFTs) using high-dose, short-term chemotherapy. Patients and Methods: P6 was a prospective study of previously untreated patients with newly diagnosed EFTs. Patients received seven cycles of chemotherapy. Cycles 1, 2, 3, and 6 consisted of cyclophosphamide 2,100 mg/m2/d on days 1 and 2, and a 72-hour continuous infusion of doxorubicin 75 mg/m2 and vincristine 2 mg/m2 starting day 1. Cycles 4, 5, and 7 consisted of 5 consecutive days of ifosfamide 1,800 mg/m2/d and etoposide 100 mg/m2/d. Results: Sixty-eight patients were enrolled from 1991 to 2001 (median age, 18.7 years; range, 3.7 to 39.9 years). At diagnosis, 44 patients had local-regional disease, and 24 had distant metastases. The 4-year event-free survival (EFS) rate for patients with local-regional disease is 82%; overall survival (OS) is 89%. The 4-year EFS rate for patients with distant metastases is 12%; the OS rate is 17.8%. All events occurred within 51 months of diagnosis. Four patients with distant metastases had progressive disease during therapy, and no patient with local-regional disease experienced disease progression during therapy. Conclusion: Sustained EFS and OS can be achieved with intensive chemotherapy in children and young adults with local-regional EFTs. This therapy is relatively ineffective in the treatment of metastatic EFTs.
EWING’S FAMILY of tumors (EFTs) consists of bone and soft tissue sarcomas that primarily affect children and young adults. The treatment of EFTs has improved during the last decade.1 Most recent studies, which used aggressive local control measures and intensive neoadjuvant and adjuvant chemotherapy, report durable remissions in 50% to 80% of patients with local-regional disease.2–13 Large primary tumors with a volume greater than 100 cm3,6,9,10,12,14–20 elevated serum lactate dehydrogenase (LDH) level,9,21,22 tumors of the axial skeleton,10,11,23,24 older age,9,10,22–26 and a poor response to induction chemotherapy9,11–13,17,24 have been associated with worse prognosis among these patients. However, the presence of distant metastases at diagnosis is the most significant adverse prognostic factor for EFTs.2,6,10,11,22–24,27–29 Distant metastases are identified in 20% to 25% of newly diagnosed patients with EFTs.5,10,30,31 Successful treatment of patients with metastatic disease remains a challenge. Most reports cite long-term survival rates of only 9% to 33%.3,5,10,11,30–32 However, patients with metastases limited to the lungs may have a better prognosis than patients with metastatic disease of the bone and bone marrow.10,32–34 Recent strategies, including whole-lung irradiation,30,34,35 dose-intensified chemotherapy,2,7 and high-dose chemotherapy followed by autologous or allogeneic stem-cell transplantation,34,36–39 have done little to improve the prognosis among patients with metastatic disease at presentation. In 1995, we reported successful induction of remission in patients with local-regional disease and good initial responses to dose-intensive chemotherapy in patients with distant metastases.2 A majority of patients with local-regional disease achieved complete remission, although the follow-up time was short. This report includes extended outcome data on 68 newly diagnosed, previously untreated patients with EFTs treated with the P6 protocol at Memorial Sloan-Kettering Cancer Center (MSKCC).
From 1991 to 2001, 68 patients with newly diagnosed, previously untreated EFTs were enrolled onto this phase II, single-arm, nonrandomized evaluation of the P6 protocol. A one-sided stopping rule was used to evaluate the first 36 patients. The results of the interval evaluation were reported previously2 and were sufficient to continue the study. All patients diagnosed during the enrollment period were eligible. Pathologic confirmation of the diagnosis was obtained before study entry. All tumors demonstrated histologic,1 immunohistochemical,40,41 and, in selected cases, molecular genetic42 findings consistent with the diagnosis of EFTs. The P6 protocol (Institutional Review Board number 90–062) was approved by the MSKCC Institutional Review Board, and signed informed consent was obtained from all patients or legal guardians before initiation of treatment. Pretreatment extent of disease evaluation for each patient included computed tomography (CT) and/or magnetic resonance imaging of the primary site; CT of the chest (and/or abdomen and pelvis, when appropriate); a technetium-99m bone scan; and pathologic, histochemical, and, in selected cases, molecular evaluation of bone marrow aspirates and biopsies from multiple sites. Patients with local-regional disease had tumors confined to the region of the primary site of disease. Patients with distant metastases had radiographic or pathologic evidence of tumor at any site distant from the primary site. The P6 protocol was originally designed as a regimen for the treatment of patients whose initial presentation conferred an inferior prognosis, on the basis of either the presence of distant metastases or the size and/or site of the primary tumor for patients with local-regional disease. When initiated, the protocol eligibility criteria restricted entry to patients whose primary tumor volume was greater than 100 cm3 (calculated as described previously15). There were no severe toxicities observed in the initial cohort; in September of 1995, the eligibility criteria were expanded to allow for all patients with EFTs. Seventeen of 42 patients with local-regional disease were enrolled before this amendment.
Therapy
Two days of high-dose cyclophosphamide and 3 days of continuous-infusion doxorubicin with vincristine (HDCAV) were given during cycles 1, 2, 3, and 6 (Table 1  lists the specific doses and schedule). The initial protocol called for a vincristine dose of 3 mg/m2/cycle or 0.1 mg/kg/cycle, whichever was lower (maximum dose, 3.0 mg). In addition, a bolus dose of 1.5 mg/m2 was given on day 9 of the cycle. Because of the unexpected high incidence of grade 3 and 4 neurotoxicities among the first 17 patients, the bolus dose was eliminated from the protocol, and the 72-hour infusion dose was decreased to 2 mg/m2/cycle or 0.067 mg/kg/cycle, whichever was lower (maximum dose, 2.0 mg). Cycles 4, 5, and 7 consisted of ifosfamide and etoposide given as 1-hour infusions on 5 consecutive days. Cyclophosphamide and ifosfamide were given with vigorous hydration, antiemetics, and an equivalent daily dose of mesna administered as a continuous 24-hour intravenous infusion. When possible, surgical resection was scheduled after recovery from course 3 and radiotherapy (RT) was scheduled after completion of all chemotherapy. Gross total resection (GTR) is defined as the surgical excision of the entire visible tumor, regardless of the presence of microscopic disease at the margins. If a GTR was not possible after cycle 3 of chemotherapy, local control with surgery and/or RT was reserved until after the completion all chemotherapy, and was prescribed as indicated by the size and location of the primary tumor, and by the presence of any residual disease. In general, 45 to 50.4 Gy was administered for microscopic margins, and 55.8 Gy was administered for gross disease.5,7,31,33 All patients underwent GTR, RT, or both. Patients received periodic extent-of-disease evaluations. These evaluations included CT or magnetic resonance imaging of the primary site; CT of the chest, abdomen, and pelvis; and, when bone marrow disease was present at diagnosis, bone marrow aspirations until results were negative for disease. When possible, a GTR was performed after cycle 3 of chemotherapy and the specimens obtained were evaluated for degree of necrosis. The antitumor effect of the chemotherapy is defined, for the primary tumor only, as follows: for a complete response (CR), there was no detectable tumor; for a very good partial response (VGPR), greater than 90% of the tumor was necrotic; for a partial response, greater than 50% of the tumor was necrotic; and in patients with stable disease, less than 50% of the tumor was necrotic. Progressive disease was defined as any radiographic evidence of a significant (> 25%) increase in the tumor size or appearance of new metastatic lesions. Patients who underwent surgical resections at diagnosis and patients with unresectable primary tumors were not assessed for histologic response. Nine patients with either a poor response to chemotherapy or with inadequate local control were removed from the protocol and given high-dose chemotherapy with autologous stem-cell rescue. Although event-free at the time of the autologous bone marrow rescue, these patients were all thought to be at extremely high risk for relapse. Data from these patients were published previously,38 and because autologous bone marrow rescue has not been shown to alter prognosis, these patients are included in this report.
Statistical Methods
From May 1990 to February 2001, 68 patients with newly diagnosed EFTs were enrolled onto the P6 protocol. The characteristics of all patients are listed in Table 2  . Forty-four patients (65%) had local-regional disease and 24 (35%) patients had distant metastases at diagnosis. Forty-two patients (62%), 17 (71%) with distant metastases and 25 (57%) with local-regional disease, were male. Twenty-six (38%) patients, seven (29%) with distant metastases and 19 (43%) with local-regional disease, were female. The EFS and OS for all patients are shown in Figure 1A. The EFS for all patients enrolled onto the P6 protocol is 55% (95% CI, 43.4% to 68.3% at 4 years). The OS for all patients enrolled onto the P6 protocol is 61% (95% CI, 50% to 75% at 4 years).
Local-Regional Disease The median age at diagnosis was 16.8 years for patients with local-regional disease (range, 6 to 32.9 years). The median follow-up time for surviving patients was 4.1 years from the initiation of therapy (range, 0.7 to 8.5 years). The 4-year EFS and OS are 82% and 89%, respectively (Figs 1B and 1C). There were eight events (Table 3). Three patients developed treatment-related myelodysplasia or acute myelogenous leukemia while in remission (10, 15, and 51 months from diagnosis, respectively). Five patients experienced relapse 7, 12, 15, 19, and 32 months from diagnosis, respectively. The median time to relapse was 15 months. No patients with local-regional disease had progression of their disease while receiving therapy.
Primary sites of disease in patients with local-regional disease are listed in Table 2 . There were eight tumors (18%) less than 100 cm3 at diagnosis, 31 tumors (70%) greater than 100 cm3, and five tumors (11%) for which accurate tumor measurements in three dimensions were not available. LDH (normal range is 60 to 200 U/L) ranged from 0 to 200 U/L in 20 (45%) patients and 200 to 300 U/L in 11 (25%) patients, was greater than 300 U/L in four patients (9%), and was not evaluated before the initiation of therapy in nine patients (20%). The median LDH at diagnosis was 193 U/L (Table 4).
Local control—local-regional disease. Fifteen patients (34%) with local-regional disease received RT to the primary site before an event (Table 5 ). Doses ranged from 36 to 54 Gy in 14 of 15 patients. One patient received 12 Gy brachytherapy to a chest wall primary tumor after an incomplete surgical resection. Thirty patients (68%) underwent GTR a median of 2.6 months after the initiation of therapy. Five patients (three with an intra-abdominal primary tumor, one with a pelvic primary tumor, and one with a chest wall primary tumor) had a GTR as a diagnostic procedure before referral for the P6 protocol. Five patients experienced relapse of disease: three in the lungs, one in the bone and bone marrow, and one at the primary site of disease. The patient who experienced relapse at the site of an intra-abdominal primary tumor had a GTR as a diagnostic procedure and no RT.
Distant Metastases Twenty-four patients had distant metastases at diagnosis (Table 2 ). The median age at diagnosis was 22.7 years (range, 9.0 to 39.9 years). The EFS and OS at 4 years from the initiation of therapy were 12% and 17.8%, respectively (Figs 1B and 1C). The median follow-up time for the four surviving patients was 81.6 months (range, 24 to 107 months). Primary sites of disease are listed in Table 2. Six patients (25%) had distant metastases to only the lungs, whereas the remaining 18 patients (75%) had some combination of metastases to lung, bone marrow, and/or bone. One patient, with a primary tumor in the femur, had metastases to brain parenchyma. Fourteen patients (58%) had primary tumors with accurate size measurement in three dimensions. Only one patient had a tumor less than 100 cm3, and 13 patients (54%) had tumors larger than 100 cm3 at diagnosis (Table 4). The mean size of the primary tumor at diagnosis was 868 cm3 (range, 17.6 to 3,990 cm3). Serum LDH at diagnosis ranged from 0 to 200 U/L in one patient (4%), 200 to 300 U/L in nine patients (38%), greater than 300 U/L in 11 patients (46%), and was not evaluated before the initiation of therapy in three patients (13%).
Twenty of 24 patients (83%) experienced an event (Table 3 Local control—metastatic disease. Nine patients (38%) with distant metastases received 30 to 54 Gy RT to the primary site before an event. Two of these patients received pulmonary RT in addition to RT for the primary site of disease. Two patients with pulmonary metastases but no other significant metastatic disease received pulmonary RT only. GTR was possible in 12 patients (50%) at a median of 3.2 months from diagnosis. Five patients (21%) had unresectable primary tumors (four pelvic and one spinal) and received RT alone. Four patients experienced progressive disease prior to surgical resection. Three patients (with a spinal, chest wall, and extremity primary tumor, respectively) had a GTR at diagnosis, before referral for P6 therapy, and no subsequent local control measure before an event. Twelve patients experienced relapse: five in lung only, four in lung plus another metastatic site, one in the CNS, and two in the primary site. Both patients who relapsed in the primary site had an extensive surgical resection of the primary tumor after cycle 3 of chemotherapy with no subsequent RT.
Response to Therapy
Autologous stem-cell rescue. Nine patients (one with local-regional disease and eight with distant metastases) with disease not amenable to either GTR or RT (n = 7), or with poorly responsive disease (n = 2), received myeloablative chemotherapy with autologous stem-cell rescue in addition to the P6 protocol. Only two of these patients (one with local-regional disease and one with distant metastases) survived disease free; five experienced disease relapse and died with progressive disease, and three died as a result of complications associated with the high-dose chemotherapy. Prognostic features. The presence of metastatic disease at diagnosis clearly was a poor prognostic feature (P < .0001). As stated, the pathologic response to therapy did not predict outcome in this report. In addition, univariate analysis did not identify any statistically significant prognostic value in either the size of the tumor (< or > 100 cm3) or the site of the primary tumor (axial skeleton v the extremity). Among the patients with metastatic disease, lung-only metastases did not predict an improved EFS or OS (P = .2). By univariate analysis, a serum LDH greater than 200 U/L (P = .011) and older age (by the Cox regression model) are both predictive of a poor EFS and OS. However, multivariate analysis of age, LDH, and metastatic disease demonstrates that metastatic disease at diagnosis is the only significant prognostic variable in this study.
Even though a disproportionate number of patients with tumor volumes greater than 100 cm3 and patients with tumors of the axial skeleton were enrolled onto the study, excellent long-term disease-free survival and OS rates are observed in patients with local-regional disease treated with short-duration, dose-intensified chemotherapy according to the MSKCC P6 protocol. Unfortunately, the survival for patients with metastatic disease at diagnosis remains poor. More than half of the patients with distant metastases who were assessed for a pathologic response to the initial three cycles of HDCAV demonstrated a CR or VGPR. However, these responses were short-lived. Local control measures are an important component of therapy for patients with EFTs.9,11,16,27,46–52 After cycle 3 of chemotherapy, 56 patients (82%) underwent either GTR, RT, or both. RT is more commonly reserved for tumors that respond poorly to neoadjuvant therapy, are in surgically inaccessible areas, or are surgically resected with suboptimal results. Accordingly, 35% of the patients in this study received RT before their first event. It is possible that the high local control rate in this study contributed to the good outcome among patients with local-regional disease. One theoretical advantage to dose-intensified chemotherapy is the induction of a more rapid response, allowing for early and effective local control. More than 60% of the patients underwent an extensive surgical resection of the primary tumor after the third cycle of HDCAV. Twenty-eight (67%) of these patients demonstrated a CR or VGPR to the first three cycles of HDCAV. The presence of metastatic disease at diagnosis appears to be the overwhelming prognostic indicator in this study, and it predicts a significant reduction in survival among patients with EFT. Older patients and patients with an LDH greater than 200 U/L at diagnosis also appear to have a worse prognosis. However, the average age and serum LDH are higher in the subgroup of patients with distant metastases. By multivariate analysis, the only significant prognostic indicator is the presence of metastatic disease at diagnosis. Survival among patients with distant metastases treated on the P6 protocol is similar to that in previous reports.3,5,10,11,30–32 Before 1979, there were no long-term survivors among patients with metastatic EFTs. In 1987, Hayes et al28 reported some long-term survivors among patients with distant metastases treated with intermediate-dose multiagent chemotherapy. Subsequent studies using various combinations, doses, and schedules of cyclophosphamide, doxorubicin, actinomycin, vincristine, ifosfamide, etoposide, and fluorouracil have failed to significantly improve the prognosis of these patients.2–5,23,28,30,31,33,53 However, among the subgroup of patients with distant metastases, those with disease metastatic only to lung may have a better prognosis.10,32–34 Only six such patients are included in this study, and any potential survival advantage among these patients did not reach statistical significance. This report includes patients who were removed from the P6 protocol and treated with myeloablative therapy and autologous stem-cell transplantation. At the time these patients were treated, myeloablative therapy was thought to have potential benefit as consolidative therapy. Subsequent reports suggest that the high-dose strategy employed does not alter the poor prognosis for patients with metastatic disease.34,36–46 Consequently, these patients are included in this analysis. Kushner et al54 previously reported five patients with therapy-related acute myelogenous leukemias (tAML) among 86 patients (5.8%) after treatment with the P6 protocol. One of those patients is included in the current report—the other patient with EFTs was not enrolled on the protocol—along with two additional patients with tAML. This does not represent an increase in the overall incidence of tAML among patients treated with dose-intensified chemotherapy, but it does confirm the risk. In summary, the long-term survival of 68 patients with EFTs treated with dose-intensified chemotherapy is reported. Patients with local-regional disease at diagnosis have a high EFS rate (82% at 4 years) after treatment with the MSKCC P6 protocol. This rate may be particularly notable because the initial cohort of patients with local-regional disease was restricted to those patients with an unfavorable prognosis by virtue of a large primary tumor volume. There have been no late events in the patients with local-regional disease, and these survival rates seem to be durable. Patients with detectable metastatic disease at diagnosis have significantly worse prognosis, with a 4-year EFS rate of 12% and OS rate of 17.8%. These data are consistent with other protocols for metastatic disease and represent continued deficiencies in available therapy for metastatic EFT. Novel therapies are clearly needed for the successful treatment of this disease. In addition, although the survival data among patients with local-regional disease are promising, three of these patients developed secondary malignancies. Dose-intensified chemotherapy may favorably influence disease-free survival among patients with local-regional disease, but the risk of secondary malignancies among these patients is a source of concern. These data emphasize the importance of identifying those patients who may benefit from less exposure to chemotherapy.
The authors indicated no potential conflicts of interest.
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54. Kushner BH, Heller G, Cheung NK, et al: High risk of leukemia after short-term dose-intensive chemotherapy in young patients with solid tumors. J Clin Oncol 16:3016–3020, 1998 Submitted October 4, 2002; accepted June 23, 2003. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
