Optimizing Clinical Care in Patients with Advanced

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May 18, 2011 - Extraskeletal myxoid chondrosarcoma. 3 (8.8). Angiosarcoma. 2 (5.8). Fibrosarcoma. 2 (5.8). Synovial sarcoma. 2 (5.8). Epithelioid sarcoma.

Clinical Study Received: June 1, 2010 Accepted after revision: December 6, 2010 Published online: May 18, 2011

Chemotherapy 2011;57:217–224 DOI: 10.1159/000326466

Optimizing Clinical Care in Patients with Advanced Soft Tissue Sarcoma: A Phase II Study of a New Schedule of High-Dose Continuous Infusion Ifosfamide and Doxorubicin Combination T. De Pas a G. Rosati c G. Spitaleri a C. Boni d A. Tucci e S. Frustaci f R. Scalamogna a D. Radice b S. Boselli a F. Toffalorio a C. Catania a C. Noberasco a A. Delmonte a F. Vecchio a F. de Braud a   

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Divisions of a New Drug Development, and b Epidemiology and Biostatistics, European Institute of Oncology, Milan, c Medical Oncology, Ospedale S. Carlo Unità Potenza, Potenza, d Arcispedale Santa Maria Nuova Azienda Ospedaliera di Reggio Emilia, Reggio Emilia, e Medical Oncology, Ospedale Cardarelli Napoli, Napoli, and f Centro Riferimento Oncologico, Oncologia Medica B, Istituto Nazionale Tumori Aviano, Aviano, Italy  

 

 

 

 

 

Key Words Continuous infusion ⴢ Doxorubicin ⴢ Ifosfamide ⴢ Soft tissue sarcomas

low non-hematological toxicity profile. This regimen attained a high disease control rate with moderate activity. Further investigation into leiomyosarcoma is warranted. Copyright © 2011 S. Karger AG, Basel

Abstract Background: Ifosfamide and doxorubicin combination is an active regimen for patients with advanced soft tissue sarcomas (STS) but is burdened by high toxicity. A phase II trial was designed to assess the activity of continuous infusion ifosfamide and doxorubicin combination. Patients and Methods: Thirty-four chemotherapy-naive patients with advanced STS were treated with ifosfamide (13 g/m2/12 days as continuous infusion) and doxorubicin (75 mg/m2 on day 8) every 28 days with granulocyte colony-stimulating factor. Results: The major toxicity was hematological: grade 3/4 neutropenia, anemia and thrombocytopenia occurred in 63, 30 and 12% of patients, respectively. The disease control rate was 68% and the median time to progression was 7.1 months. Among leiomyosarcomas, 2 partial responses and 4 stable diseases were observed. Conclusions: Our study confirms that the ifosfamide and doxorubicin combination has a very

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Introduction

The outcome of patients with advanced or inoperable soft tissue sarcoma (STS) is still disappointing [1, 2]. Doxorubicin is the standard treatment for advanced disease [3]. Ifosfamide and doxorubicin are the most active drugs in STS, attaining, as a single agent, an overall response rate of 18–20 and 15–35%, respectively [4–6]. Combinations with a standard dose of ifosfamide and doxorubicin have been tested in nonrandomized studies and have reported an increase in overall response rate (up to 50– 60%) [7–13]. However, most of these trials were complicated by serious hematological and non-hematological toxicity affecting the actual benefit of these treatments. Even if these regimens did not demonstrate to improve the overall survival over the monochemotherapy (doxoDr. T. De Pas Istituto Europeo di Oncologia Via Ripamonti 435 IT–20141 Milano (Italia) Tel. +39 02 5748 9482, E-Mail tommaso.de-pas @ ieo.it

rubicin) [14], they are a suitable choice for patients presenting a bulky disease at diagnosis when there is the need to attain a significant remission of disease and to control disease-related symptoms. Besides, a dose-response relationship has been demonstrated both for doxorubicin and for ifosfamide, at the costs of significantly increased toxicity [15–19]. In detail, in the MD Anderson experience, Benjamin et al. [19] reported increasing response rates with different doses of ifosfamide as a single agent in patients with sarcomas who had failed prior adriamycin-based chemotherapy. The response rate at a standard dose of 10 g/m2 was 21% compared with 14% at a dose of 8 g/m2 and 10% at a dose of 6 g/m2. Continuous infusion of ifosfamide might warrant delivering a higher dose with a low toxicity profile [20–24]. Pharmacological data of ifosfamide demonstrated long-term stability for use in disposable infusion pumps as outpatient treatment. Hematological toxicity was the dose-limiting toxicity, and there was neither urological nor central nervous system toxicity. No recommended way of ifosfamide administration has been approved. We have already performed a dose-finding study to define the maximum tolerated dose of ifosfamide given as a 12-day continuous infusion when combined with a fixed dose of doxorubicin 75 mg/m2 given as a single intravenous bolus injection on day 8, with prophylactic granulocyte colony-stimulating factor (G-CSF) every 4 weeks [25]. The recommended dose was established at 13 g/m2/ 12 days and doxorubicin 75 mg/m2 with an acceptable toxicity. Despite the use of G-CSF, myelosuppression was the dose-limiting toxicity. Major responses were observed at all dose levels (with an overall response rate of 53%). So far, we have carried out this multicenter phase II study to confirm its feasibility and activity in chemotherapy-naive patients with advanced or inoperable STS.

Patients and Methods Patient Selection Patients with histologically proven grade 2–3 metastatic or locally advanced STS, previously untreated with chemotherapy, were eligible for this study. Other inclusion criteria were evaluable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria [26], age 18–70 years old, Eastern Cooperative Oncology Group performance status ^2, and adequate bone marrow (neutrophil count 11,500/mm3, platelets 1100,000/ mm3), kidney (creatinine !1.25 of the upper normal limit and/or creatinine clearance 1 60 ml/min), liver (bilirubin ^1.25 of the upper normal limit, AST and/or ALT ! 2 of the upper normal limit or !3 of the upper normal limit in the presence of tumor involvement in the liver) and heart (left ventricular ejection fraction

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at least 50%, defined by echocardiogram or multiple-gated acquisition scan) function. Patients were included if they had received an isolated perfusion treatment without doxorubicin regimens. The patients could receive radiotherapy for an area !30% of the bone medullary reserve, but these lesions were defined not to be assessable for tumor response. Osteosarcoma, Ewing’s sarcoma, rhabdomyosarcoma, undifferentiated small cell sarcoma, and Kaposi’s sarcoma patients were not eligible. No concurrent radiation, hormonal or experimental therapies were permitted. The local ethic committee approved the protocol, and all patients gave written informed consent. Drug Administration All patients received ifosfamide (13 g/m2/12 days as continuous infusion), sodium-2-mercaptoethanesulfonate (13 g/m2/12 days) and doxorubicin (75 mg/m2 on day 8) every 28 days with GCSF (filgrastim, 300 ␮g/day) through days 14–21 subcutaneously or until neutrophil counts were 11.5 ! 109/l. On an outpatient basis, treatment was administered via a portable pump as a 24hour continuous infusion for 12 consecutive days. Ifosfamide and sodium-2-mercaptoethanesulfonate were diluted in two 7-day disposable elastomer pumps. No prophylactic antiemetic therapy was planned during ifosfamide administration, and oral hydration with at least 2,000 ml/day of liquids was recommended. Doxorubicin (75 mg/m2) was administered as an intravenous bolus injection after prophylactic antiemetic premedication (as physician discretion but recommended use of dexamethasone 8 mg i.v. and granisetron 3 mg i.v.) on day 8. Treatment was administered every 4 weeks until documented disease progression, unacceptable toxicity or patient refusal, up to a maximum of 6 cycles of chemotherapy. During the screening procedure and treatment, a complete blood cell count on days 1, 8, 10 and 12 and biweekly thereafter, serum creatinine on day 8 and a complete chemistry profile on the first day of each cycle were performed. G-CSF (300 ␮g) was routinely administered on days 14–21 or was continued until absolute neutrophil counts were 11.5 ! 109/l. Treatment Evaluations and Dose Modifications At enrolment, patient history was taken and subjects received clinical examination and blood tests, as well as an electrocardiogram, echocardiogram and chest-abdominal CT scan. On day 1 of each cycle, blood tests were performed. On day 8 of each cycle, differential blood count, blood urea nitrogen and creatinine were measured. On days 10, 12, 16 (81 day) and 18 (+1 or 2 days) of each cycle, a differential complete blood count was done. On day 1 of each cycle, chemotherapy was delayed if neutrophils were !1.5 ! 109, platelets ^100 ! 109 and grade 12 nonhematological toxicity occurred. After a 7-day delay, chemotherapy was administered as follows: ifosfamide at 75% of the dose and doxorubicin at 100% of the planned dose were administered if neutrophils were at least 11.0 ! 109 and platelets 175 ! 109, with nausea/vomiting grade ! 2 and grade !1 out of the remaining non-hematological toxicities (except alopecia); in any other case, the patient was excluded from the study. On day 8 of each cycle, ifosfamide was stopped and doxorubicin was continued if the neutrophil count was !1.5 ! 109, platelets were !10 ! 109, and non-hematological toxicity was grade 62. Each subsequent cycle of ifosfamide was administered at 75% of the planned dose if one of the following events happened: at least 7 days of lasting grade

De Pas et al.  

4 neutropenia, grade 3–4 febrile neutropenia, grade 4 thrombocytopenia or grade 3 with hemorrhage, hemorrhagic cystitis, anticipated interruption of ifosfamide infusion and a delay of 17 days on restarting treatment due to toxicity. Evaluation of Disease Response to treatment was assessed after every 2 cycles of treatment according to standard RECIST criteria [26], and tumor dimensions were assessed using CT scans with contrast enhancement. Follow-up assessments were performed after the first 2 cycles of treatment and then every 2 cycles until disease progression or until the start of another treatment. Toxicity during each treatment cycle was assigned according to the National Cancer Institute Common Toxicity Criteria, version 3.0 (Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Md., USA) [27]. Statistical Methods and Sample Size The primary endpoint of the study was the disease control rate (DCR). Secondary endpoints were time to progression (TTP), overall survival and evaluation of the toxicity profile. The DCR was defined as the proportion of complete response (CR) plus partial response (PR) and stable disease (SD) obtained for at least 6 months. The trial was an exact single-stage phase II design [28, 29] requiring 30 patients in order to decide whether the DCR is ^40 or 660%. We arbitrarily assessed a DCR of 40% referring to the standard treatment [3]. With an estimated drop-out rate of 15%, the total sample size is increased up to 35. In order to reject the hypothesis of a DCR 660%, the absolute number of expected responses (CR, PR and SD) is ^15 with a target power of 0.80. It is our hypothesis that a DCR ^40% is rejected with a target error rate of 0.10, when the number of responses is 616. Categorical variables for patient characteristics at study entry as well as treatment compliance and frequency distribution of toxicity events were tabulated as counts and percentages. Response to treatment either as CR, PR, SD, progressive disease (PD) or DCR was computed as the proportion of the assessable patients and presented in the text with their binomial exact 95% confidence intervals (CIs). Overall survival was defined as the time from the date of the first cycle of chemotherapy to the date of death, or to the date of the last visit for surviving patients. TTP was defined as the time from the date of first cycle of chemotherapy until the date of progression, death or last follow-up, whichever occurred first. Survival probabilities for TTP and overall survival were estimated according to the Kaplan-Meier method [30] and plotted against time.

Results

Patient Characteristics We enrolled 34 patients with locally advanced or metastatic STS not suitable for curative surgery. The median age was 49 years (range 24–68), with 16 males and 18 females enrolled. Most of the patients (97%; High-Dose Continuous Infusion of Ifosfamide and Doxorubicin in STS

Table 1. Patient characteristics

Patients Males:females Age, years Median Range ECOG performance status 0 1 2 Stage at enrollment Locally advanced Metastatic disease Both Histology Leiomyosarcoma Uterine Non-uterine Liposarcoma Retroperitoneal undifferentiated Inferior limb myxoid Retroperitoneal pleiomorphic Retroperitoneal well differentiated Extraskeletal myxoid chondrosarcoma Angiosarcoma Fibrosarcoma Synovial sarcoma Epithelioid sarcoma Phyllodes Hemangiopericytoma Gastrointestinal autonomic nerve tumor Mesenchymal sarcoma (NOS) Alveolar sarcoma Grade II III Not available

34 16:18 49 24–68 28 (82.4) 5 (14.7) 1 (2.9) 14 (40.0) 11 (31.4) 10 (28.6) 8 (23.5) 4 4 6 (20.0) 3 1 1 1 3 (8.8) 2 (5.8) 2 (5.8) 2 (5.8) 2 (5.8) 3 (8.8) 1 (2.9) 1 (2.9) 3 (8.8) 1 (2.9) 15 (44) 17 (50) 2 (6)

Figures represent numbers with percentages in parentheses unless otherwise stated. ECOG = Eastern Cooperative Oncology Group; NOS = Not otherwise specified.

33/34) had a good performance status. Only for 2 patients was the score grading not available. The median time from initial diagnosis to study entry was 7 months (range 1–188). At study entry, 20.5% of patients (7/34) had not been previously treated while 23.5% of patients (8/34) had received previous surgery followed by radiotherapy, 52.9% of the patients (18/34) underwent surgery and 2.9% of patients (1/34) radiotherapy only. The most frequent sites of disease were the lung in 20 patients, the liver in 8 patients and bones and soft tissue in 4 patients. Table 1 shows the patient characteristics. Chemotherapy 2011;57:217–224

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Treatment All patients received a total number of 108 cycles of chemotherapy with a median number of 3 cycles per patient (range 1–6). One patient experienced a rapid clinical worsening of the condition during the 1st cycle and died of PD before the end of the 1st cycle; 1 patient developed disease progression after 2 cycles, while 2 others refused to continue treatment because of acute toxicity (grade 2 nausea/vomiting and febrile neutropenia, respectively).

Table 2. Treatment compliance Number of cycles 108 Cycles which required a 7-day delay 16/73 (22) Second cycle 6/31 (19) Third cycle 6/23 (21) Fourth cycle 3/17 (17) Fifth cycle 0/1 Sixth cycle 0/1 Cycles which required a 25% dose reduction 18/73 (24.5) From the second cycle 11/73 (15) From the third cycle 6/42 (14) Cycles which required ifosfamide or doxorubicin omission 5/108 (4) Ifosfamide 1/108 (0.01) Doxorubicin 4/108 (3) Figures in parentheses are percentages.

Toxicity There were no treatment-related deaths. Table 2 shows treatment compliance in detail. Thirty-three patients were evaluable for toxicity. Four (12%) and 17 patients (51.5%) experienced grade 3 and 4 neutropenia, respectively. Four patients (12%) had febrile neutropenia, whereas 1 out of these refused to continue treatment. Eight (24%) and 2 patients (6%) developed grade 3 and 4 anemia, respectively. Three patients (9%) suffered from grade 3 thrombocytopenia. Grade 4 thrombocytopenia occurred only in 1 patient. Non-hematological toxicity was as follows: 3 patients (9%) developed grade 3 vomiting and 1 patient (3%) had grade 3 mucositis. Table 3 summarizes treatment toxicity. Activity The median follow-up was 12.1 months (range 0.6– 74.2). Thirty patients were assessable for activity. None of the patients attained a CR (97.5% one-sided CI 0–11.2). Five patients experienced a PR (16.5%; 95% CI 5.4–33.7). Fifteen patients reached SD 16 months (50%; 95% CI 33.1–69.8). Ten patients experienced PD after the 4th cycle (33.3%; 95% CI 14.2–48.0). DCR (CR + PR + SD 16 months) was 66.5% (95% CI 48.6–83.3). Table 4 shows responses to treatment according to different histologies. The median TTP was 7.1 months (95% CI 4.03–9.13; fig. 1) and median survival was 15.1 (95% CI 8.8–19.9; fig.  2). Among the 8 patients with leiomyosarcoma, 2 had PR and

Table 3. Frequency distribution of toxicity events in 33 patients according to the National Cancer Institute Common Toxicity Criteria, version 3.0

CTCAE version 3.0

Toxicities Nausea/vomiting Neutropenia Leukopenia Anemia Alopecia Thrombocytopenia Asthenia Mucositis Constipation Paresthesias Fever Diarrhea

Grade 1

Grade 2

Grade 3

Grade 4

Any grade

12 (36.3) 1 (3) 0 5 (15) 4 (12) 8 (24) 7 (21) 3 (9) 5 (15) 3 (9) 3 (9) 1 (3)

12 (36.3) 2 (6) 4 (12) 6 (18) 14 (42.5) 4 (12) 3 (9) 5 (15) 1 (3) 1 (3) 0 0

3 (9) 4 (12) 5 (15) 8 (24) 0 3 (9) 0 1 (3) 0 0 0 0

0 17 (51.5) 15 (45.5) 2 (6) 0 1 (3) 0 0 0 0 0 0

27 (81.8) 24 (72.5) 24 (72.5) 21 (63.0) 18 (54.5) 16 (48) 10 (30) 9 (27) 6 (18) 4 (12) 3 (9) 1 (3)

Figures in parentheses are percentages. CTCAE = Common Terminology Criteria for Adverse Events.

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De Pas et al.  

4 experienced SD. The median TTP was 14 months (range 2–30); among the patients with uterine and non-uterine leiomyosarcoma, the median TTP was 9 months (range 2–30) and 16.5 months (range 13–27), respectively. We did not record a significant difference in TTP after grading distribution among patients with leiomyosarcoma.

Discussion

Table 4. Response to treatment according to disease histology Patients PR SD PD Not evaluable Leiomyosarcoma Liposarcoma Chondrosarcoma Angiosarcoma Fibrosarcoma Synovial sarcoma Epitheliod sarcoma Phyllodes Hemangiopericytoma Gastrointestinal autonomic nerve tumor Mesenchymal sarcoma (NOS) Alveolar sarcoma

1.0

1.0

0.9

0.9

0.8 0.7 0.6 0.5 0.4 0.3 0.2

8 6 3 2 2 2 2 3 1 1 3 1

2 0 0 0 1 0 0 0 1 1 0 0

4 3 3 1 1 1 1 1 0 0 0 0

2 1 0 1 0 1 0 2 0 0 3 0

0 2 0 0 0 0 1 0 0 0 0 1

NOS = Not otherwise specified.

Survival probability (95% CI)

Survival probability (95% CI)

The continuous infusion of high-dose ifosfamide is an attempt to improve the drug safety profile, and thus, possibly optimize clinical care in patients with STS. Although the drug is given over 12 days, ifosfamide can be administered on an outpatient basis, and so far, hospitalization can be avoided. No need of intravenous hydration is another selling point of this schedule. Our study confirms the good toxicity profile of a regimen combined with full-dose doxorubicin. Neutropenia was by far the most relevant toxicity of this schedule even if a low rate of febrile neutropenia was recorded. Sixty-three percent of patients experienced a grade 3–4 neutropenia (51.5% grade 4). Table 5 depicts other trials investigating highdose ifosfamide in comparison to our trial [11, 31–34]. Comparing our findings with others, we observe that our incidence of grade 3–4 neutropenia was inferior, except for the trial by Palumbo et al. [11, 32–35]. The percentage of grade 3–4 neutropenia in the previous trials was as fol-

lows: Reichardt et al. [11] reported 100% (83% grade 4); Le Cesne et al. [34] 92%, with 16.6% febrile neutropenia; Lòpez-Pousa et al. [33] 79% (67% grade 4), with 20% febrile neutropenia; Palumbo et al. [32] 34% (13% grade 4); Patel et al. [35] reported 94% (doxorubicin 75 mg/m2 – ifosfamide 10 mg/m2 trial) and 100% febrile neutropenia (doxorubicin 90 mg/m2 – ifosfamide 10 mg/m2 trial), respectively. Non-hematological toxicity was negligible: neither renal nor neurological toxicity was observed, with nephro-

0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

0.1

0

0 0

12

24 36 48 Overall survival (months)

60

72

Fig. 1. Overall survival in evaluable patients with STS (median

15.2 months; 95% CI 8.8–19.9).

High-Dose Continuous Infusion of Ifosfamide and Doxorubicin in STS

0

12 24 36 48 Progression-free survival (months)

60

Fig. 2. TTP in evaluable patients with STS (median 7.1 months; 95% CI 4.0–9.1).

Chemotherapy 2011;57:217–224

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Table 5. Dose-intensive chemotherapy phase II trials

Author

Patients

Regimen

mTTP months

OOR (CR)

DCR (SD)

Reichardt et al. [11], 1998

46

NR

52 (22)

78 (26)

Patel et al. [35], 1998

16

Epi 45 mg/m2 days 2–3, Ifo 2.5 g/m2 days 1–5 G-CSF every 3 weeks Doxo 75 mg/m2 days 1–3, Ifo 2 g/m2 days 1–5, every 3 weeks or Doxo 90 mg/m2 days 1–3, Ifo 2.5 g/m2 days 1–4, every 3 weeks Epi 55 mg/m2 days 1–2, Ifo 2,5 g/m2 days 1–4 G-CSF every 3 weeks Doxo 75 mg/m2 day 1, Ifo 5 g/m2 day 1, every 3 weeks Liposomal daunorubicin 50 mg/m2 day 1 + Ifo 5 g/m2 day 1 + G-CSF, every 4 weeks Doxo 50 mg/m2 day 1, Ifo 12 g/m2 days 1–5, GM-CSF every 4 weeks –

NR

69 (19)

94 (25)

NR

59 (0)

89 (30)

NR

59 (13)

95 (36)

7.2

23 (3)

70 (47)

6

31 (3)

31 (17)

9

42 (0.01)

79 (37)

7.1

16.5 (0)

66.5 (50)

17 Palumbo et al. [32], 1999

39

Le Cesne et al. [34], 2000

133

Siehl et al. [31], 2005

37

LÓpez-Pousa et al. [33], 2006 This study

64 34

mTTP = Median TTP; OOR = overall response rate; Epi = epidoxorubicin; Ifo = ifosfamide; NR = not reported; Doxo = doxorubicin; GM-CSF = granulocyte macrophage colony-stimulating factor.

toxicity checked only on day 8 and prior to the next cycle. Hematological toxicity was the main toxicity in all the trials; non-hematological toxicity occurred in a low rate of patients, but sometimes, it was significant (e.g., neurological, renal, cardiological toxicity). In details, neurological toxicity was reported by Siehl et al. [31] (grade 2), Reichardt et al. [11] (any grade), López-Pousa et al. [33] and Patel et al. [35] (^ grade 3). Renal toxicity occurred in the following trials: Reichardt (grade 1–2), Palumbo and López-Pousa (grade 1–2), Patel (grade 3 bladder toxicity) [11, 32, 33, 35]. Moreover, these 3 trials recorded a reversible arrhythmia, a grade 2 myocardial failure and a heart-related death, respectively [11, 34, 35]. Except for 2 studies (Siehl, López-Pousa), all the trials used high doses of ifosfamide every 3 weeks, unlike our trial, which used a schedule of 28 days (ifosfamide 3 g/m2/ week). This could explain the reduced toxicity recorded in our trial. Indeed, the incidence of cardiotoxicity could be reduced combining ifosfamide with pegylated liposomal doxorubicin, as has been demonstrated in other tumors [36, 37]. The study met the first endpoint attaining a high DCR. The observed median TTP (7 months) was similar to that of other trials. Nonetheless, we observed a moderate activity in terms of tumor response with a rather low 16% 222

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overall response rate in comparison with the other trials (table 5) [11, 31–35]. Again, this could be related to a lower ifosfamide dose intensity (3 g/m2/week). Antitumor activity was encouraging in the leiomyosarcoma subgroup. Though the small number of patients cannot allow us to reach definitive conclusions, among the 8 patients with advanced leiomyosarcoma, we recorded 2 PR and 4 SD (16 months). These results are of major interest in light of the previous data. The Mayo Clinic 1993 trial that investigated the 7.5 mg/m2 ifosfamidebased combination demonstrated a lower response rate in their subpopulation with leiomyosarcoma (14%) [38]. A review of 2,185 patients from the European Organization for Research and Treatment of Cancer showed that there is evidence that some histological subtypes are more sensitive to chemotherapy than others: response rates for leiomyosarcoma were lower than for synovial sarcoma, reporting progression-free survival rates at 3 months of 44 and 77%, respectively [39]. Lately, an exploratory analysis of 1,337 patients with SFS treated in 1 of 10 prospective European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group trials confirmed that leiomyosarcomas had a lower chance to respond to ifosfamide compared with synovial sarcomas [40]. Among the trials included in that analysis, only 3 De Pas et al.  

studies had used higher doses of ifosfamide: 3 ! 3 g/m2/ day, 9 g/m2 continuously over 3 days, and 12 g/m2 continuously over 3 days, respectively. Only the response rate was correlated with the ifosfamide dose, which has no impact on the overall survival. This could be due to the fact that the majority of patients treated with ifosfamide at doses !9 g/m2 received it in combination with doxorubicin. Unfortunately, an analysis comparing the response rate in leiomyosarcomas and the ifosfamide doses was not carried out. Though the use of ifosfamide in patients with leiomyosarcoma is a matter of discussion, other trials suggested that higher doses of ifosfamide combined with full-dose anthracyclines reached a favorable outcome in this set of patients: Reichardt et al. [11] (12.5 g/m2 ifosfamide) observed 3 PR out of 5 patients with leiomyosarcoma; Palumbo et al. [32] (ifosfamide administered up to 10 g/m2) attained 1 CR, 3 PR, 6 SD out of 10 patients with leiomyosarcoma; López-Pousa et al. [33] (12 g/m2 ifosfamide) reached 8 out of 14 responses in this subset of patients. Nonetheless, the French sarcoma group has recently published a retrospective analysis of 147 patients with

metastatic leiomyosarcoma treated with a doxorubicinbased regimen (of which 53% contained ifosfamide). The combined regimen did not improve the outcome, and multivariate analysis showed that progression-free survival was improved with a doxorubicin dose 160 mg/ m2/3 weeks and that the addition of ifosfamide worsened the overall survival [41]. Unfortunately, the dose of ifosfamide administered in the different regimens was not reported. Altogether, these results confirm that the use of ifosfamide in STS should be addressed to specific subhistologies. So far, this schedule should be mainly addressed to ifosfamide-sensitive entities (e.g., synovial sarcoma, dedifferentiated liposarcoma), meanwhile the use of ifosfamide in other entities (e.g., lyposarcoma, leiomyosarcoma) remains to be debated. In conclusion, a 12-day continuous infusion of highdose ifosfamide combined with full doses of doxorubicin is feasible and well tolerated, with a very low non-hematological toxicity profile. This regimen attained a promising DCR in patients with STS and showed encouraging activity in the leiomyosarcoma subset.

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