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Single Center Experience of a New Intensive Induction Therapy for Ewing’s Family of Tumors: Feasibility, Toxicity, and Stem Cell Mobilization Properties

From the Meyerstein Institute of Oncology, Middlesex Hospital, University College London Hospitals National Health Service Trust, London, United Kingdom; and Royal National Orthopaedic Hospital, Stanmore, London, United Kingdom.

Address reprint requests to J.S. Whelan, MD, Meyerstein Institute of Oncology, Middlesex Hospital, University College London Hospitals National Health Service Trust, Mortimer St, London W1T 3AA; email: jeremy.whelan{at}uclh.org.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: To examine the feasibility, tolerability, and toxicity of an intensified induction regimen (vincristine, ifosfamide, doxorubicin, and etoposide [VIDE]) in patients with newly diagnosed Ewing’s family of tumors (EFT); to assess ability to maintain dose-intensity, and predictability of peripheral-blood stem cell mobilization.

Patients and Methods: Thirty patients were treated with vincristine 1.4 mg/m² (maximum 2 mg) on day 1, doxorubicin 20 mg/m², ifosfamide 3 g/m² plus mesna and etoposide 150 mg/m² on days 1 to 3. Cycles were given every 21 days for up to six cycles.

Results: One-hundred and seventy cycles of VIDE were given. The median treatment interval was 21 days (21 to 42) and nadir count: hemoglobin 8.3 (6.3 to 11.9), neutrophils 0.045 (0.0 to 2.1), and platelets 45 (3 to 343). There were 96 episodes of infection requiring hospitalization (56%). Growth factor support reduced infectious complications by 34%. Etoposide dose was reduced, or omitted, in 24% of cycles. Four patients did not complete six cycles due to unacceptable toxicity and one patient progressed on treatment. Twenty patients underwent peripheral-blood stem cell harvesting, 15 after cycle 3, and five after cycle 4. Median CD34⁺ yield was 4.6 x 10⁶/kg per patient (1.8 to 14.5). Overall response to treatment, measured in 24 patients, was 88%. Seven of 11 patients undergoing surgery achieved greater than 90% necrosis of tumor (64%).

Conclusion: VIDE is an effective induction regimen with substantial but acceptable toxicity that allows predictable mobilization of stem cells. Maintenance of dose-intensity is feasible in the majority of patients. Growth factors play a role in maintaining dose-intensity and reduce infectious complications.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
IN 1921, James Ewing described a small round cell tumor arising in bone, which principally occurred in children and teenagers.¹ His accurate description of the clinical features of the disease that carries his name has now been expanded to include extraosseous and peripheral neuroectodermal tumors (PNET), which are histologically similar to Ewing’s sarcoma of bone² and demonstrate the same rearrangement of chromosome 22 in more than 95% of tumors, most commonly as t(11;22).^3,4 Because they share many clinical and pathological features, these tumors are classified as the Ewing’s family of tumors (EFT).

Before the use of chemotherapy, the long-term outlook for patients with Ewing’s sarcoma was poor with a 5-year survival of less than 20% despite good local control of disease.⁵ The use of chemotherapy has improved prognosis, and with aggressive multimodality treatment, overall long-term survival now approaches 60%.^6–9 Initial trials using vincristine, doxorubicin, dactinomycin, and cyclophosphamide showed improved survival in studies in Europe ET-1,⁸ CESS-81⁹ and the United States IESS-1.⁷ Single agent data show alkylating agents and anthracyclines to be the most effective chemotherapeutic drugs.

Doxorubicin is the most widely used anthracycline and has a steep dose-response curve. In a review of drugs active against Ewing’s sarcoma, doxorubicin dose-intensity was found to be the single most important determinant to influence survival.¹⁰ The dose of doxorubicin varies between regimens, with up to 90 mg/m² being used.¹¹ In most, however, the anthracycline is alternated with actinomycin-D, thereby reducing dose-intensity. In IESS-II, patients receiving higher doxorubicin dose-intensity showed a significantly better outcome when compared with patients treated with alternating courses of doxorubicin and actinomycin-D.¹²

Ifosfamide and cyclophosphamide show the highest activity among the alkylating agents, and their use at higher doses has been aided by the availability of mesna to prevent urothelial toxicity.¹³ The addition of ifosfamide to standard regimens, including cyclophosphamide, has been shown to be beneficial, particularly when given early in treatment.^14,15 In ET-2,¹⁶ substitution of ifosfamide for cyclophosphamide and an increase in dose-intensity of doxorubicin, was associated with a 20% improvement in survival in patients treated with combination induction therapy.

Etoposide has been shown to be an active agent in Ewing’s sarcoma¹⁷ and has been used successfully in combination with ifosfamide, initially in patients with recurrent disease,¹⁸ and with higher activity in patients with newly diagnosed disease.¹⁹ The contribution of etoposide when added to doxorubicin and ifosfamide is as yet undetermined but has been addressed in the EICESS 92 study.²⁰

Results of these trials have identified a number of factors that indicate an adverse prognosis.^11,21,22 Most important is the presence of distant metastases as diagnosis, with bone metastases and bone marrow involvement conferring a worse prognosis than the presence of pulmonary metastases. Also, the site of disease is important with pelvic and axial tumors faring worse than extremity limb tumors. In addition, the size of the tumor at diagnosis alters outcome with smaller tumors (< 100 mL), although unusual, conferring a better outcome. Histological response to chemotherapy is increasingly recognized as another factor providing powerful prognostic information.^9,23–25

A number of strategies have been used to improve outcome in patients with poor prognosis. These have included intensive induction regimens and the use of high-dose myeloablative chemotherapy with stem cell support.^26–30 All the trials, however, are nonrandomized with small numbers of patients. Further information from larger trials is necessary.

Thus, important questions in the development of new therapeutic strategies in EFT include whether more intensive treatments will improve outcome for those with metastatic or poorly responsive disease, and whether such factors can be used prospectively to adjust therapy.

The purpose of this report is to describe the feasibility of an intensified induction regimen of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE), in preparation for its use in a cooperative group randomized study. Ifosfamide and doxorubicin are given in 3-weekly cycles at doses based on previous European trials. The addition of etoposide intensifies the regimen with greater risk of significant toxicity due to increased myelosupression, thus tolerability and ability to maintain dose-intensity needs to be assessed. In addition, the phase III study addresses the role of high-dose chemotherapy in patients with poor prognostic features. Therefore, the efficacy and predictability of VIDE for mobilization of peripheral-blood stem cells was also assessed.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection
Between January 1998 and June 1999, thirty patients aged 7 to 36 years with previously untreated EFT were treated with VIDE chemotherapy at the London Bone and Soft Tissue Tumour Service (London, UK). Patients over 13 years of age were treated by a medical oncologist, with patients between 13 and 20 years of age being treated on a specialist adolescent unit. Children under 13 years of age were cared for by pediatric oncologists.

Histological Diagnosis
The diagnosis of EFT was based on specimens obtained from needle or open surgical biopsy. Histological examination was carried out on routinely processed, paraffin-embedded sections of the biopsies stained with hematoxylin and eosin (H&E). To confirm the diagnosis, a panel of immunocytochemical markers were applied to unstained sections mounted on vectabond-coated slides. The antibodies included CD99 (MIC 2), CD45 (LCA), S100, Desmin, Synaptophysin, and MNF116. All specimens were reviewed at The Royal National Orthopaedic Hospital (Stanmore, UK).

Staging
Diagnostic investigations before treatment included a plain radiograph in two planes, and magnetic resonance imaging (MRI) or computerized tomography (CT) of the primary site, with estimation of tumor volume.

Staging investigations included a plain chest radiograph, thoracic CT scan with 1-cm intervals, and whole body technetium (^99mTc) bone scan. If equivocal areas of increased uptake were found on bone scanning, the presence of metastases was confirmed by MRI. Bilateral iliac crest bone marrow aspiration and trephine were taken (distant from the site of the primary tumor or known metastases). These underwent routine cytological and histological analysis.

Pretreatment Investigations
Blood investigations including complete blood count and differential, lactate dehydrogenase, renal and liver function, and calcium were measured. A multigated radionucleotide angiography scan (MUGA) was performed to determine resting left ventricular ejection fraction (LVEF) and was required to be more than 50%, with normal pump function. EDTA creatinine clearance was performed to determine a glomerular filtration rate of more than 60 mL/min/1.73 m².

Treatment
Induction (VIDE). Treatment consisted of chemotherapy with vincristine 1.4 mg/m² (maximum 2 mg) on day 1, doxorubicin 20 mg/m², ifosfamide 3 mg/m² (with 3 g/m² mesna as a 24-hour infusion), and etoposide 150 mg/m², all given on days 1 to 3. Cycles were given every 21 days, or on hematological recovery with a neutrophil count of greater than 1 x 10⁹/L, and platelet count of more than 80 x 10⁹/L, to a maximum of six cycles.

Further Treatment
Patients presenting with localized disease received consolidation chemotherapy with VAI (vincristine on day 1, dactinomycin 0.75 mg/m² and ifosfamide 3g/m² [with 3g/m² mesna] days 1 and 2) every 21 days (with same hematological criteria) to a maximum of eight cycles.

Patients with metastatic disease at presentation were considered for high-dose chemotherapy with busulphan 600 mg/m² (150 mg/m² days -6 to -3) and melphalan 140 mg/m² (day 2) with peripheral-blood stem cell rescue (day 0) after one or more cycles of VAI chemotherapy (Fig 1).

View larger version (18K): [in this window] [in a new window]   Fig 1. Chemotherapy schedule for patients with EFT. VIDE, vincristine 1.4mg/m2, ifosfamide 9g/m2, doxorubicin 60 mg/m2, etoposide 450 mg/m2; VAI, vincristine 1.4mg/m2, actinomycin D 1.5 mg/m2, ifosfamide 6g/m2; HD, busulphan 600 mg/m2, melphalan 140mg/m2 with peripheral blood stem cell support; RT, radiotherapy.

Local Therapy
Definitive local therapy was scheduled according to modality. Surgery was scheduled to be performed in patients with readily resectable primary tumors on completion of induction therapy. In patients with disease not amenable to surgery, radiotherapy was given concurrently with consolidation chemotherapy (VAI).

In patients with metastatic disease undergoing high-dose chemotherapy, radiotherapy was administered when appropriate to the primary site 2 months after recovery from high-dose treatment.

Peripheral-Blood Stem Cell Harvesting
Peripheral-blood stem cells were mobilized with the use of granulocyte-colony-stimulating factor (G-CSF), with Lenograstin (Chugai-Granocyte) or Filgrastin (Amgen), 5 µg/kg, given daily starting 24 hours after completion of chemotherapy, following the third or fourth cycle of VIDE. Patients had a daily complete blood count from day 9 and stem cell harvesting was attempted on day 14 if the total WBC count was more than 3.0 x 10⁹/L or delayed until this value reached. G-CSF was continued until harvesting was completed. Harvesting was considered successful if CD34⁺ cell count was more than 2 x 10⁶/kg.

Patients with bone marrow involvement at diagnosis had a repeat bone marrow aspirate and trephine before cycle 3. Harvesting was only performed if no evidence of tumor cells were demonstrated by histological or cytological analysis.

Modifications for Toxicity
Chemotherapy was delayed for up to 1 week without modification if the absolute neutrophil count (ANC) was less than 1 x 10⁹/L or the platelet count was less than 80 x 10⁹/L on day 21. Patients were not routinely treated with growth factor support unless large volume disease, pelvic disease, or poor performance status was thought to substantially increase the risk of neutropenic complications. If an episode of febrile neutropenia requiring hospitalization was experienced, additional cycles were administered with G-CSF 5 µg/kg, given for 10 days starting 24 hours after completion of chemotherapy. Dose modifications were made according to toxicities. If further episodes of febrile neutropenia, grade 3 to 4 mucositis or gastrointestinal toxicity, or thrombocytopenia requiring platelet support (grade 4) were experienced, etoposide dose was reduced to 80%. Thereafter, omission of etoposide was considered. Vincristine was reduced by 50% for patients with evidence of grade 2 peripheral neuropathy and withheld if ongoing thereafter. Toxicities were scored in accordance with the revised National Cancer Institute common toxicity criteria grading (version 2.0).³¹

Radiological Response Evaluation
Imaging of the primary tumor by MRI or CT scanning was carried out after two or more cycles of treatment to assess tumor response, and aid decisions regarding local therapy, and again before the definitive local treatment.

Radiological Response Criteria
Response was assessed according to standard criteria.

Histological Response
Resected tumors were examined histologically to assess completeness of excision and tumor response to chemotherapy. A slab, including the resection margins, was prepared from the specimen through the plane of maximum tumor diameter, which was then submitted for decalcification or routine processing. Response to chemotherapy was assessed by estimating the percent necrosis of tumor surface represented in the processed slab. Greater than 90% necrosis of tumor indicated a good response while less than 90% necrosis represented a poor response.³²

Assessment of Toxicity
A repeat MUGA scan was carried out after completion of treatment (doxorubicin dose ± 360 mg/m²) to assess short-term cardiac toxicity. Urea and electrolytes were measured before each cycle of treatment. Glomerular filtration rate was not routinely remeasured until after completion of VIDE unless a rise in serum creatinine of more than 10% was noted.

Written informed consent was obtained from all patients undergoing treatment. For patients younger than 16 years of age, written informed consent was obtained from parents or legal guardian and verbal assent obtained from the patient.

	RESULTS

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Patient Characteristics
Median age at diagnosis was 17 years (range 7 to 36). Male to female ratio was 2:1. Disease was localized in 19 patients (63%) and metastatic in 11 patients (37%). Three of 11 patients with metastatic disease had involvement of two or more sites. Nine of 24 (38%) patients assessable for tumor volume had primary tumors less than 100 mL (Table 1).

Treatment Interval
Treatment interval was assessable for 167 cycles of treatment and included the interval from cycles of treatment to surgery. For these cycles, time to operation was used as assessment. The interval was maintained without significant delay (up to 3 days) in 128 cycles (77%). Treatment delays of less than 1 week were encountered in 26 cycles (16%). Nine cycles (5%) were delayed up to 2 weeks. In three cycles, this was due to ongoing sepsis; in another, the patient required treatment for a perianal fissure. One cycle was delayed to allow planned collection of stem cells, another for radiotherapy planning, and three cycles were delayed for planning of surgery. Four cycles (2%) were delayed up to 21 days. In one cycle, this was as a result of poor wound healing from surgery undertaken before commencement of chemotherapy and another because of ongoing sepsis. The other two cycles involved delays for surgery.

Treatment Duration
Four patients did not complete six cycles of VIDE chemotherapy due to toxicity. One patient experienced two episodes of severe (grade 3 and 4) febrile neutropenia in addition to severe chronic Clostridium difficile infection, which necessitated termination of treatment after two cycles. A second patient presented with a large pelvic tumor (4,900 mL) with renal failure secondary to chronic obstructive uropathy. Despite reversal of the obstruction, chemotherapy was complicated by severe renal tubular and parenchymal toxicity, together with grade 3 febrile neutropenia and grade 4 thrombocytopenia, and had to be terminated after three cycles of treatment. Two patients, aged 22 and 23 years, with localized disease underwent surgery after five cycles of treatment due to cumulative bone marrow toxicity. Postoperatively, they continued with consolidation treatment.

Dose Reduction
The dose of ifosfamide was reduced in six cycles (3%), and doxorubicin dose was reduced in four cycles of treatment (2%). The dose of etoposide was reduced to 80% in 18 cycles (11%), to 70% in two cycles (1%), and omitted in 20 cycles (12%). Fifteen patients (50%) had either dose reduction or omission of etoposide. Vincristine was reduced to 1 mg in five cycles of treatment and omitted in nine cycles.

Toxicities
Grade 3 or 4 neutropenia was observed in 155 cycles (97%) and grade 3 or 4 thrombocytopenia in 87 cycles (54%). There were 104 episodes of infection (61%), eight were classified grade 1 to 2, 95 grade 3, and one grade 4. There were no toxic deaths. Infection requiring admission to hospital was seen in 56% (61 of 109) of cycles in patients with localized disease and 57% (35 of 61) of cycles in patients with metastatic disease. Eight episodes of infection were not associated with neutropenia and were treated with oral antibiotics in an outpatient setting. Infectious complications requiring hospitalization were increased in patients with primary pelvic disease, occurring in 24 of 31 cycles (77%). Grade 3 and 4 anemia was seen in 61 cycles (36%; Table 2).

Growth Factors
Eighteen of 30 patients commenced treatment without growth factor support. There was a high rate of infectious complications with 16 of 18 (89%) patients requiring hospitalization. In the other 12 patients treated with growth factor support, 8 (67%) required hospitalization for febrile neutropenia.

Overall, the use of growth factor support had a significant effect on infectious complications with a reduction in infection requiring hospitalization of 34%. Grade 4 thrombocytopenia was more frequent in cycles treated with growth factor support. This may in part be explained by their greater use later on in treatment when cumulative toxicity is more significant (Table 3).

Collection of Peripheral-Blood Stem Cells
Twenty patients underwent peripheral-blood stem cell collection, nine with metastatic disease at diagnosis and 11 with localized tumors (Table 4). Two additional patients with pelvic and metastatic disease, who experienced severe toxicity with VIDE, terminated chemotherapy after two and three cycles of treatment and were thus not eligible for harvesting. Eight patients, all with localized disease, were not considered for stem cell harvesting as only those with metastatic disease were considered for harvesting at the beginning of the study. From May 1998, however, all patients older than 13 years of age and children younger than 13 years of age with metastatic disease or pelvic tumors were considered for harvesting.

Details of Harvesting
Fifteen patients were harvested after cycle 3 and five patients after cycle 4. A total of 26 harvests were performed.

Fifteen patients were successfully harvested over 1 day, with a median WBC of 17.3 x 10⁹/L (3.8 to 41.3), yielding a median CD34⁺ count of 6.2 x 10⁶/kg (1.8 to 14.5). Ten of these patients were harvested on day 14 (67%), two on day 15, two on day 16, and one on day 19. Four patients were harvested over 2 days (one starting on day 14, two on day 15, and one on day 16), and one patient who failed harvest over 2 days after cycle 3 was successfully harvested over 3 days with cycle 4. Apart from one patient who was harvested on day 19, harvests carried out on day 14 yielded the highest median CD34⁺ count (Table 5). Overall, the median CD34⁺ yield was 4.6 x 10⁶/kg per patient. Collections of adequate CD34⁺ were cultured, yielding a median colony-forming unit-granulocyte macrophase (CFU-GM) culture of 49.05 x 10⁴/kg.

Local Treatment
Surgery. Fourteen patients underwent surgery as treatment for the primary site of disease. Two patients had surgery before commencing chemotherapy, both of whom had radiotherapy after VIDE, one as definitive treatment and one as adjuvant. Twelve patients had surgery after VIDE. Four patients underwent surgery after 5 cycles of treatment, six patients after 6 cycles, and two patients after 7 cycles of chemotherapy (Table 6). One patient had an incomplete excision and underwent radical local radiotherapy after high-dose therapy. Two patients had a marginal excision. One received adjuvant radiotherapy, and one had no further local therapy.

Four further patients underwent radical radiotherapy to the site of primary tumor. Two patients underwent radiotherapy 2 months after completion of high-dose chemotherapy, and two patients underwent radical radiotherapy after chemotherapy had been terminated due to toxicity.

Four patients did not undergo local treatment. This was due to progression of disease while undergoing consolidation treatment in two patients, and renal toxicity preventing further treatment in one patient. The fourth patient had multiple sites of metastases from a primary tumor arising in C5 to T1 vertebrae and underwent high-dose treatment. One additional patient who progressed on VIDE underwent surgery after second line treatment.

Additional Therapy
Consolidation treatment. Twenty patients underwent further treatment with VAI chemotherapy as consolidation.

High-dose treatment. Patients with metastatic disease at diagnosis were considered for high-dose chemotherapy if in complete remission or with minimal stable disease based on CT or MRI after induction therapy. Six of 11 patients with metastatic disease at diagnosis underwent treatment with busulphan/melphalan supported by peripheral-blood stem cells. One patient with a large localized chest wall tumor that was treated with primary surgery also underwent high-dose treatment. Three patients who presented with metastatic disease terminated treatment early due to toxicity, and two patients progressed while undergoing consolidation therapy.

In seven patients undergoing high-dose treatment, recovery of hematopoesis was with a median neutrophil recovery to more than 0.5 x 10⁹/L of 11 days (11 to 13 days), and platelet recovery to more than 50 x 10⁹/L of 16 days (15 to 44 days). The most frequent toxicity was grade 4 mucositis and febrile neutropenia lasting a median of 7 days (range 5 to 10 days). There were no toxic deaths.

Radiological Response Evaluation
Two patients underwent excision of the primary tumor before chemotherapy and therefore, they were not evaluable for radiological response. One patient with multifocal bone disease at diagnosis was assessed by positron emission tomography (PET) scanning. This method of assessment has not been fully evaluated in EFTs, and although improvement was noted, response could not be quantified. Three patients had incomplete imaging, which did not allow accurate assessment of response. Twenty-four patients were evaluable for measurement of tumor volumes and radiological response of the primary tumor to treatment with VIDE. Twenty-one patients (88%) had a partial response, six with complete resolution of extraosseous disease, two patients (8%) had stable disease, and one patient progressed on treatment (4%).

Histological Response
Histological response was evaluable in eleven patients undergoing surgery. The final patient underwent extracorporeal radiotherapy to the excised tibia, which was then used as an arthrodesis and thus was not evaluable for histological response to treatment. In seven of the eight patients with a complete resection of tumor, histological analysis showed greater than 90% necrosis of tumor (good response). The eighth patient showed 85% necrosis. The three patients with marginal/incomplete excisions all had less than 90% necrosis of tumor (poor response; Table 6).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Ahead of a cooperative European study examining the role of VIDE in all patients and contribution of high-dose busulphan/melphalan with peripheral-blood stem cell support in patients with high risk disease, we undertook a nonrandomized pilot study to examine the feasibility and tolerance of an intensive induction regimen with a particular emphasis on ability to maintain dose/time intensity, the role of growth factors, and collection of peripheral-blood stem cells.

The toxicity encountered with VIDE chemotherapy was substantial but, in almost all situations, predictable and manageable. The most common toxicity was hematological with 97% cycles documenting grade 3 or 4 neutropenia. This was complicated by febrile neutropenia requiring admission in 56% of cycles, grade 3 to 4 anemia in 36% of cycles and grade 4 thrombocytopenia in 27% of cycles. These toxicities are manageable but require close liaison with the local multidisciplinary team and good local supportive care facilities. Ready access to inpatient and outpatient facilities in a population comprising pediatric and adult patients is essential.

The regimen was generally well tolerated by patients with both localized and metastatic disease, but infectious complications were more frequent in those with primary pelvic disease. Other common toxicities included mild peripheral neuropathy (up to grade 2) in six patients (20%), which was reversible on dose reduction or termination of vincristine. There were no toxic deaths.

Twenty-five patients (83%) completed 6 cycles of VIDE. Treatment interval was maintained without significant delay (up to 3 days) in 80% and up to 1 week in 95% of cycles. The use of growth factor support enabled maintenance of dose-intensity in 82 cycles (48%). Growth factors were shown to be useful in reducing infective complications, if used with the first cycle of treatment and with ongoing treatment. There was, however, an increased incidence of thrombocytopenia requiring platelet support.

Dose reduction due to hematological toxicity was necessary in 15 patients. Because anthracyclines and alkylating agents are of such importance in EFT, the aim was to maintain doses of doxorubicin and ifosfamide as long as possible. The results show that this was feasible, with doxorubicin dose maintained in 98% of cycles and ifosfamide dose maintained in 97% of cycles.

A recent experience at St Jude’s Children’s Hospital (Memphis, TN) showed that a dose-intensive induction regimen produced favorable response rates and was feasible for three cycles of treatment before local therapy with radiotherapy.³³ The induction regimen consisted of ifosfamide 2 g/m² (day 1 to 3), etoposide 150 mg/m² (day 1 to 3), cyclophosphamide 1.5 g/m² (day 5), and doxorubicin 45 mg/m² (day 5) given three weekly. The VIDE regimen uses higher doses of doxorubicin (60 mg/m²) and ifosfamide (9 g/m²) but no cyclophosphamide and equivalent etoposide doses. The hematological toxicity experienced with VIDE was comparable to that of the St Jude induction regimen. We found it was feasible to prolong an intensive induction regimen to 6 cycles with little increase in toxicity, with 83% of patients tolerating 6 cycles of treatment. At St Jude, after treatment of the primary tumor with radiotherapy, an attempt was made to increase dose-intensity with ifosfamide 2 g/m² (day 1 to 5) with etoposide 150 mg/m² (day 1 to 5), and cyclophosphamide 1.0 or 1.5 g/m² (day 1 and 2) with doxorubicin 60 mg/m² (day 1) alternating three weekly. This was only feasible in 25% of patients and lends support to the idea that if dose-intensity is to be attempted, it should be undertaken on commencement of chemotherapy before cumulative bone marrow and local treatment toxicity makes it difficult.

Local treatment was scheduled to begin on completion of the induction regimen. When surgery was used as the treatment of the primary tumor, we found it was feasible to plan this to occur after the sixth cycle of treatment. The logistics of planning of concurrent radiotherapy were more complex, and the timing of radiotherapy commencement more variable. In the majority of patients, it was given concurrently with consolidation therapy.

Mobilization and harvesting of stem cells is possible and predictable in patients treated with VIDE. The procedure was successful in all patients in whom it was attempted and equally practical in those with localized and metastatic disease. This is important because long-term survival of patients with adverse prognostic factors remains poor with conventional chemotherapy. There is some evidence of efficacy of high-dose busulphan/melphalan treatment with stem cell support in patients with EFTs.²⁹ These trials, however, are nonrandomized and involve only small numbers of patients. A large European multinational randomized study to assess the role of high-dose treatment in patients with high-risk disease has now begun. It is thus important that the induction regimen allows predictable mobilization of peripheral-blood stem cells so that practical considerations do not interfere with treatment.

Radiological response evaluation assessed by MRI in 24 patients showed an overall response rate of 88% to induction therapy, and histological response in 11 patients undergoing surgery showed greater than 90% necrosis in the 7 of 11 evaluable resection specimens (64%).

In conclusion, VIDE is a dose-intense induction regimen that has substantial but acceptable toxicity. Maintenance of dose-intensity is feasible in the majority of patients for six cycles of treatment, and the treatment interval is sustainable. Growth factors play a role in maintaining dose-intensity, reduce the incidence of infectious complications, and enable consistent mobilization of peripheral-blood stem cells in all patients. Preliminary results show good radiological and histological response rates. Complex and intensive regimens such as this require familiarity, and good supportive care facilities are essential. Care must be taken if considering administration outside specialist centers.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted April 24, 2000; accepted May 2, 2003.

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