17th Expert Committee on the Selection and Use of Essential Medicines Geneva, 2009

17th Expert Committee on the Selection and Use of Essential Medicines Geneva, 2009

PROPOSAL FOR THE INCLUSION OF IFOSFAMIDE IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES

REPORT FEBRUARY 2008 Yuanyuan Cheng Emily Walkom Discipline of Clinical Pharmacology School of Medicine and Public Health Faculty of Health The University of Newcastle Level 5, Clinical Sciences Building Calvary Mater Newcastle Hospital Waratah, New South Wales AUSTRALIA 2298 TEL +61 2 4921 1856 FAX +61 2 4960 2088

IFOSFAMIDE – February 2008

1.

Summary statement of the proposal for inclusion, change or deletion

Ifosfamide is proposed for inclusion on the World Health Organization’s (WHO) Model List of Essential Medicines for the treatment of individuals with various tumour types, including: soft tissue and bone sarcomas, non-Hodgkin’s lymphoma, cervical cancer, ovarian cancer, and testicular germ cell tumours.

2.

Name of the focal point in WHO submitting or supporting the application

3.

Name of the organization(s) consulted and/or supporting the application

Discipline of Clinical Pharmacology, the University of Newcastle, Clinical Sciences Building, Calvary Mater Newcastle Hospital, Waratah NSW, Australia, 2298.

4.

International non-proprietary name (INN, generic name) of the medicine

Ifosfamide

5.

Dosage form or strength proposed for inclusion

Powder for reconstitution: 1g, 2g

6.

International availability – sources, if possible manufacturers

Ifosfamide is marketed under 11 different trade names in 34 countries worldwide. A detailed list of manufacturers and distributors is presented in Appendix A.

7.

Whether listing is requested as an individual medicine or as an example of a therapeutic group

Listing is requested as an individual medicine

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IFOSFAMIDE – February 2008 8.

Information supporting the pubic health relevance (epidemiological information on disease burden, assessment of current use, target population)

8.1. Disease burden A recent WHO report estimated that 7.6 million people died of cancer in 2005, representing 13% of all deaths worldwide. The report suggests that 84 million people will die of cancer between 2005 and 2015. Cancer is the second leading cause of death in developed countries and among the three leading causes of death in developing countries (Ferlay et al., 2004). More than 70% of cancer deaths occur in low and middle income countries. (WHO Fact Sheet, 2006). Some specific cancer types are more prevalent in developing countries, such as cancers of the stomach, uterine cervix and liver. Other cancer types are more prevalent in the developed world such as cancers of the colorectum and prostate (Stewart & Kleihues, 2003). Advanced screening programs (e.g. for cervical cancer) in developed countries may account for some of the differences in numbers of people with certain cancers compared to developing countries. 8.2. Disease burden in target population and current use Ifosfamide is a bifunctional alkylating agent widely used in the treatment of various neoplasms. Its mechanism of action depends on the ability to alkylate DNA by attaching the N-7 position of guanine with their reactive electrophilic groups (ethyleneimine intermediates), which may result in cytotoxicity and cell death. The pharmacologic features of ifosfamide enable its combination with many other antiblastic agents, and also allow its use in patients who have failed previous treatments (Fulfaro et al., 2003). Tumour types that have been demonstrated to respond to ifosfamide as a single agent or in combination with other agents are germ cell tumours, sarcomas and lymphomas. Antitumour activity has been shown in ovarian and cervical cancers. Some activity has also been seen in lung and breast cancer. (MIMS Australia, 2007). Ifosfamide is currently used in conjunction with other antineoplastic agents for salvage therapy in the treatment of germ cell testicular neoplasms, is usually included as a component of various regimens for bone and soft tissue sarcomas, and is used for initial or secondor third-line therapy in the treatment of various other malignancies including lung cancer, cervical cancer and ovarian cancer (McEvoy, 2006).This submission will focus on the use of ifosfamide for soft tissue and bone sarcomas, non-Hodgkin lymphomas, cervical cancer, ovarian cancer, and testicular germ cell tumours. Soft tissue and bone sarcomas: Sarcomas are a group of rare solid tumours; usually divided into two broad categories: the more frequently occurring sarcomas of soft tissues; and sarcomas of bone, with multiple subtypes in each category. Collectively, sarcomas account for approximately 3

IFOSFAMIDE – February 2008 1% of all adult malignancies and 15% of paediatric malignancies (National Comprehensive Cancer Network [NCCN], 2007a). Sarcomas are often found in individuals in the “prime of life”, thus the number of years of life lost is great despite the relatively low incidence of these cancers (National Cancer Institute, 2006a). When found within organs, sarcomas are difficult to differentiate from other cancer types, so they are frequently misdiagnosed and highly underreported (National Cancer Institute, 2006a). Based on best available data, the annual incidence of soft tissue sarcomas in the United States for 2007 is estimated to be about 9,220 cases, with an overall mortality rate of approximately 3,560 cases per year (Jemal et al., 2007). Ifosfamide is used as a component of various initial or second-line chemotherapeutic regimens in conjunction with surgery and/or radiation therapy in the treatment of various bone and soft tissue sarcomas in adults and children (McEvoy, 2006). Non-Hodgkin’s lymphoma: Non-Hodgkin’s lymphoma (NHL) comprises of a large group of cancers of the immune system, which can be divided into aggressive (fast-growing) and indolent (slow-growing) types and can be classified as either B-cell or T-cell NHL. B-cell NHLs include Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle cell lymphoma. T-cell NHLs include mycosis fungoides, anaplastic large cell lymphoma, and precursor T-lymphoblastic lymphoma. (National Cancer Institute, 2006b). Prognosis and treatment depends on the stage and type of lymphoma. In the USA, NHL is the fifth leading site of new cancer cases among men and women, accounting for 4% of new cancer cases (Jemal et al., 2007). Worldwide, NHL cases in 2002 accounted for 2.8% of all cancers (Parkin et al., 2005). NHLs are slightly more common in developed countries (50.5% of cases worldwide, Parkin et al.). Age-standardised worldwide incidence and mortality rates per 100,000 population from the GLOBOCAN 2002 database are presented in Table 8.1. Table 8.1

Age-Standardised World incidence and mortality rates/100,000 for Non-Hodgkin’s Lymphoma Worldwide

More developed

Less developed

regions

regions

Males

Females

Males

Females

Males

Females

Incidence

6.1

4.0

10.4

6.5

4.3

2.6

Mortality

3.5

2.3

4.6

2.9

2.8

1.8

Source: Ferlay et al., 2004 (GLOBOCAN 2002 database). In the USA, approximately 750 to 800 children and adolescents younger than 20 years of age are diagnosed with NHL each year; approximately 6% of all childhood cancers diagnosed are NHL (Percy et al., 1999). While NHLs in adults are more commonly of 4

IFOSFAMIDE – February 2008 low or intermediate grade, almost all of those that occur in children can be classified into high-grade categories (Percy et al., 1999). Ifosfamide is not generally used as a first-line treatment for lymphomas, but has been used in the treatment of some types of NHL in children and in conjunction with other antineoplastic agents in the treatment of recurrent or advanced lymphomas (McEvoy, 2006). Cervical cancer: The main cause of cervical cancer has been identified as the human papillomavirus (HPV), which is transmitted through sexual contact. Cervical cancer is the second most common cancer in women worldwide. The majority of cases (e.g. 83% in 2002) occur in developing countries, where cervical cancer is the second most frequent cause of cancer death in women. The substantial decline in incidence and mortality of cervical cancer in developed countries is thought to be a result of effective screening (Parkin et al., 2005). Age-standardised worldwide incidence and mortality rates per 100,000 population from the GLOBOCAN 2002 database are presented in Table 8.2. Ifosfamide has been used as a single agent or in combination with other agents in the treatment of metastatic or recurrent cervical cancer (McEvoy, 2006). Table 8.2

Age-Standardised World incidence and mortality rates/100,000 for Cervical Cancer Worldwide

More developed

Less developed

regions

regions

Incidence

16.2

10.3

19.1

Mortality

9.0

4.0

11.2

Source: Ferlay et al., 2004 (GLOBOCAN 2002 database). Ovarian cancer: Ovarian cancer accounts for approximately 3 percent of all cancers in women and is the fifth leading cause of cancer-related death among women in the United States (Jemal et al., 2007). Ovarian cancer has the highest mortality of all cancers of the female reproductive system. It is often diagnosed at an advanced stage due to the lack of early symptoms and lack of screening tests (National Cancer Institute, 2006c). Age-standardised worldwide incidence and mortality rates per 100,000 population from the GLOBOCAN 2002 database are presented in Table 8.3. Ifosfamide has been used alone or in conjunction with other antineoplastic agents for second-line therapy in patients with advanced or recurrent ovarian cancer (McEvoy, 2006).

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IFOSFAMIDE – February 2008 Table 8.2

Age-Standardised World incidence and mortality rates/100,000 for Ovarian Cancer Worldwide

More developed

Less developed

regions

regions

Incidence

6.6

10.2

5.0

Mortality

4.0

5.7

2.9

Source: Ferlay et al., 2004 (GLOBOCAN 2002 database). Testicular germ cell tumours: Testicular cancer is a highly treatable, often curable, cancer that usually develops in young and middle-aged men. Over 90% of cancers of the testis develop in germ cells. The two main types of germ cell tumour are seminomas or nonseminomas (American Cancer Society, 2006). It is estimated that there will be 7,920 new cases and 380 deaths due to testicular cancer in the USA in 2007 (Ries et al., 2007). Ifosfamide is considered by most clinicians to be the standard initial salvage (i.e., second-line) regimen in patients with recurrent testicular cancer, but is also used as a third-line treatment (McEvoy, 2006).

9.

Treatment details (dosage regimen, duration, reference to existing WHO and other clinical guidelines, need for special diagnostic or treatment facilities and skills)

9.1. Dosage regimen and duration Ifosfamide is given intravenously, either by injection as a solution diluted to less than 4%, or by infusion. Dosage of ifosfamide must be based on the clinical and haematologic response and tolerance of the patient (McEvoy, 2006). Dosage regimens include: • total dose of 8 to 12g/m2 divided over 3 to 5 days, with the course repeated at 2 to 4 week intervals; • total dose of 6g/m2 divided over 5 days, repeated every 3 weeks; • doses of 5 to 6g/m2, to a maximum of 10g, given as a single 24-hour infusion, repeated at 3 to 4 week intervals (Sweetman, 2007). Cycles of therapy are repeated as necessary depending on the patient’s response (McEvoy, 2006). Similar levels of toxicity have been noted in higher total doses of ifosfamide given by continuous infusion compared with short IV infusion, but the most effective dosage schedule has not been determined (McEvoy, 2006).

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IFOSFAMIDE – February 2008 Patients should be adequately hydrated prior to and during treatment with ifosfamide to minimize urotoxicity (2 litres of oral or IV fluid daily). In addition, a uroprotective agent such as mesna should be administered during therapy to decrease the risk of bladder toxicity (e.g. hemorrhagic cystitis; McEvoy, 2006). 9.2. Reference to existing WHO and other clinical guidelines The National Comprehensive Cancer Network (NCCN) has produced a series of clinical practice guidelines with generally accepted or recommended chemotherapy regimens (NCCN, 2007a, 2007b, 2007c, 2007d, 2007e, 2007f). The regimens that include ifosfamide for the treatment of the cancer subtypes of interest in the current report are detailed in Table 9.2. Table 9.2 Recommended chemotherapy regimens that include ifosfamide (NCCN, 2007) Tumour type

Chemotherapy regimens

Soft tissue sarcoma

Ifosfamide (single agent) AIM (doxorubicin, ifosfamide, mesna) MAID (mesna, doxorubicin, ifosfamide, dacarbazine) Ifosfamide, epirubicin, Mesna

Bone sarcoma

Should include at least two of the following: doxorubicin, cisplatin, ifosfamide, high-dose methotrexate, and growth factors

Non-Hodgkin’s

Second-line therapy for diffuse large B-Cell lymphomas and

lymphoma

peripheral T-cell lymphomas: ICE (ifosfamide, carboplatin, etoposide) ± rituximab MINE (mesna, ifosfamide, mitoxantrone, etoposide) ± rituximab

Cervical cancer

Second-line therapy: ifosfamide (single agent)

Ovarian cancer

Recurrence regimens: Ifosfamide (single agent) TIP (paclitaxel, ifosfamide, cisplatin) VIP (etoposide, ifosfamide, cisplatin) VeIP (vinblastine, ifosfamide, cisplatin) Paclitaxel/Ifosfamide

Testicular germ cell

First-line: 2 cycles of chemotherapy

tumour

VelP (paclitaxel/ifosfamide/cisplatin); or TIP (vinblastine/ifosfamide/cisplatin) Second-line (salvage therapy): (VeIP) Vinblastine 0.11 mg/kg IV per day for 2 days, ifosfamide 1200 mg/m2 IV daily for 5 days, mesna 400 mg/m2 IV every 8h x 5 days, and cisplatin 20 mg/m2 IV daily for 5 days; OR (TIP) Paclitaxel 250 mg/m2 IV day 1, followed by ifosfamide 1500mg/m2 and cisplatin 25 mg/m2 IV daily on days 2-5, mesna 500 mg/m IV before, and then 4 and 8 h after each dose of ifosfamide

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IFOSFAMIDE – February 2008 9.3. Need for special diagnostic or treatment facilities and skills Because of the carcinogenic potential of ifosfamide, precautions for handling and preparing solutions of cytotoxic drugs must be observed, and the drug must be used only under constant supervision by clinicians experienced in handling cytotoxic drugs. (McEvoy, 2006). Whilst undergoing a chemotherapy regimen including ifosfamide, regular monitoring is required to manage side-effects. Urinalysis is recommended prior to each dose of ifosfamide (McEvoy, 2006) to monitor for bladder toxicity. Regular monitoring of renal function is also required, particularly in the case of long-term treatment or in children. Glomerular and tubular kidney function must be evaluated and checked before commencement of therapy, as well as during and after treatment. Since use of ifosfamide is associated with myelosuppression, leucocyte, erythrocyte and platelet counts should be carried out prior to each administration and at appropriate intervals, if necessary daily (MIMS Australia, 2007).

10.

Summary of comparative effectiveness in a variety of clinical settings

10.1. Identification of clinical evidence (search strategy, systematic reviews identified, reasons for selection/exclusion of particular data) Medline (1966-2007), Embase (1980-2007), the Cochrane Controlled Clinical Trials Register (till 2007) and the Cochrane Database of Systematic Reviews (till 2007) were searched for randomised clinical trial reports and systematic reviews on ifosfamide used as a single agent or in combination in the treatment of soft tissue sarcomas, non-Hodgkin’s lymphoma, cervical cancer, ovarian cancer and testicular germ cell tumours. The following terms were applied in the literature review: ifosfamide or iphosphamide or Ifex or Mitoxana and “randomized controlled trial” or “random allocation” or “double blind procedure” or “single blind procedure” or “clinical trials” or “comparative studies” or “meta-analysis” or “systematic review” or “synthesis” or “guidelines”. Reference lists of retrieved papers were searched for further relevant studies 10.2. Summary of available estimates of comparative effectiveness Ifosfamide in soft tissue and bone sarcomas Soft tissue sarcoma Doxorubicin and ifosfamide are the mainstays in the treatment of advanced soft tissue sarcomas. The use of doxorubicin is considered an acceptable standard of care in patients with metastatic or inoperable soft tissue sarcoma. As a single agent given in metastatic disease, doxorubicin induces response rates of approximately 16%-27%, with median overall survival ranging from 7.7 to 12.0 months. Ifosfamide also shows 8

IFOSFAMIDE – February 2008 activity against advanced soft tissue sarcoma with response rates of approximately 25% and a median overall survival of 1 year in metastatic disease. The use of doxorubicin is mainly limited by side effects of myelosuppression and cardiomyopathy, while ifosfamide is limited by leucopenia after the introduction of mesna. Unfortunately, there are no randomised studies comparing doxorubicin and ifosfamide when given as a single agent. Nevertheless, given the apparent equivalent clinical efficacy in advanced soft tissue sarcomas, ifosfamide appears as a valid alternative in patients for whom doxorubicin is contraindicated (Sleijfer et al., 2005). Treatment strategies for metastatic soft tissue sarcoma summarized in a review by Spira et al. (2002) included the addition of ifosfamide as palliative therapy in selected patients with inoperable disease. The first-line treatment for younger patients with good performance status was a bolus of ifosfamide and doxorubicin in combination with granulocyte-colony stimulating factor (G-CSF), however, for older patients or those with a poor performance status, the single-agent doxorubicin therapy or best supportive care was recommended. Numerous drug combinations have been explored for their efficacy and activity in advanced soft tissue sarcoma. To evaluate the effect of ifosfamide-containing chemotherapy in patients with locally advanced or metastatic soft tissue sarcomas, Verma et al. (2006) conducted a meta-analysis based on three randomised controlled trials (RCTs) comparing a combination chemotherapy regimen including ifosfamide with a similar regimen with no ifosfamide. Based on 1612 eligible patients, the pooled analysis of objective tumour response from the relevant chemotherapy regimens of the three trials detected a significant difference between ifosfamide-containing chemotherapy and non-ifosfamide-containing chemotherapy, favouring the ifosfamide-containing regimen (RR=1.52, 95% CI: 1.11, 2.08) (Figure 10.1). The higher response, however, was not translated into increased survival (RR=0.98, 95% CI: 0.85, 1.13) (Figure 10.2). The median survival of all treatment arms ranged between 8.4 and 13 months.

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IFOSFAMIDE – February 2008 Figure 10.1 Meta-analysis of published tumour response data from randomized controlled trials of ifosfamide-containing chemotherapy versus non-ifosfamide-containing chemotherapy (random effects model).

Source: Verma et al., 2006

Figure 10.2 Meta-analysis of published one-year mortality data from randomized controlled trials of ifosfamide-containing chemotherapy versus non-ifosfamide-containing chemotherapy (random effects model)

Source: Verma et al., 2006 In light of the above meta-analysis, the practice guideline established by Cancer Care Ontario suggested that “In patients with metastatic soft tissue sarcoma, the addition of ifosfamide to standard first-line doxorubicin containing regimens is not recommended over single-agent doxorubicin. However, in patients with symptomatic, locally-advanced, or inoperable soft tissue sarcoma, in whom tumour response might potentially result in reduced symptomatology or render a tumour resectable, it is reasonable to use ifosfamide in combination with doxorubicin” (Verma et al., 2006). The place of ifosfamide in the chemotherapy for soft tissue sarcoma has been further confirmed by the newly revised National Comprehensive Cancer Network (NCCN) Practice Guidelines for soft tissue sarcoma, in which the combination of epirubicin, ifosfamide and mesna was added as an option for systemic therapy (NCCN, 2007a). 10

IFOSFAMIDE – February 2008 Bone sarcoma The three most common bone sarcomas are: osteosarcoma 35%-45%, chondrosarcoma 22%-30%, and Ewing’s sarcoma 15%-16% (Longhi et al., 2005; NCCN, 2007b). The introduction of chemotherapy has improved cure rates up to 70% in osteosarcoma and Ewing’s sarcoma (Bacci et al., 2003; Longhi et al., 2005). Cytotoxic agents which have shown activity against osteosarcoma include doxorubicin, cisplatin, high dose methotrexate (HDMTX), bleomycin, cyclophosphamide, and dactinomycin (Bacci et al., 2001; Goorin et al., 2003). The inclusion of ifosfamide in the combination chemotherapies has demonstrated a 5-year overall survival rate of 58% - 77% (Zalupski et al., 2004; Ferrari et al., 2005). However, in a randomized trial investigating the inclusion of ifosfamide (I) and/or muramyl tripeptide (MTP) with the standard chemotherapy of cisplatin, doxorubicin, and HDMTX in osteosarcoma patients, event-free survival (EFS) rate was not improved with the incorporation of ifosfamide (5-year EFS: I + standard chemotherapy 56%; standard chemotherapy 64%). The addition of MTP had no impact on EFS (with MTP 63%; without MTP 64%), while the addition of both ifosfamide and MTP suggested a possible increase in EFS (with I + MTP 72%; without I + MTP 64%). The authors suggested that the underpowered analysis of the four arms of the trial may have masked any benefit of adding ifosfamide to the standard therapy regimen (Meyers et al., 2005). Another randomized trial, however, demonstrated that preoperative etoposide-ifosfamide plus HDMTX led to significantly more good histologic responses than doxorubicin plus HDMTX (56% vs 39%, p=0.009) in osteosarcoma patients. EFS was numerically higher in the etoposide-ifosfamide arm than in the doxorubicin arm (3-year EFS, 69% vs 62%, p>0.05). The lack of statistical significance may be due to the small sample size (118 in the etoposide-ifosfamide arm and 116 in the doxorubicin arm) and the relatively short follow-up (Le Deley et al., 2007). The standard chemotherapy protocol for Ewing’s sarcoma was originally based on four drugs: vincristine, doxorubicin, cyclophosphamide, and dactinomycin (VACD), which resulted in a 5-year disease-free survival (DFS) of 30-60% (Cangir et al., 1990; Nesbit et al., 1990). The combination of ifosfamide and etoposide (I+E) has shown effectiveness in untreated patients with Ewing’s sarcoma with an overall response rate of 96% (Meyer et al., 1992). More recently, a randomized trial was carried out in the US to investigate the clinical efficacy of adding I+E to the standard VACD regimen in patients with newly diagnosed disease. Significant benefits in EFS and overall survival for patients with nonmetastatic Ewing’s sarcoma were reported (Grier et al., 2003). However, in an Italian trial of neoadjuvant chemotherapy for Ewing’s sarcoma, the involvement of I+E in the conventional VACD maintenance phase seemed to confer no advantages. The different outcomes observed in the two trials might be due to the differences in schedule and number of cycles of I+E delivered, as a delayed administration and fewer cycles of I+E were performed in the Italian trial (Bacci et al.,

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IFOSFAMIDE – February 2008 1998). The incorporation of I+E has not improved outcomes in patients with metastatic disease (Grier et al., 2003; Miser et al., 2004). The NCCN Guidelines for bone cancer recommend that neoadjuvant and adjuvant chemotherapy are effective for localized osteosarcoma at diagnosis and cytotoxic agents should include at least two of the following drugs: doxorubicin, cisplatin, ifosfamide and high-dose methotrexate. For Ewing’s sarcoma, the Guideline suggests that chemotherapy should include a combination of at least three of the agents: ifosfamide and/or cyclophosphamide, etoposide, doxorubicin and vincristine (NCCN, 2007b). Ifosfamide in non-Hodgkin’s lymphoma RCHOP (Rituximab + cyclophosphamide, doxorubicin, vincristine, prednisone) is the current standard treatment for non-Hodgkin’s lymphoma (NHL). Various non-cross-resistant compounds have been investigated in patients with recurrent or refractory NHL, including ifosfamide-containing regimens such as ICE (ifosfamide, carboplatin, etoposide) and MIME (mesna, ifosfamide, mitoxantrone, etoposide). A systematic review identified 22 phase II studies (1210 patients overall; individual trials from 20–208 patients) using 15 different combinations of cytotoxic drugs in conventional dose second line therapy for NHL (Kimby et al., 2001). The most common drugs tested in these trials were etoposide (20 studies), ifosfamide (14 studies), and methotrexate (11 studies). All 22 studies revealed similar results, with second line combination chemotherapy frequently inducing remission in patients with relapsed or refractory aggressive NHL. The review found that overall 60–70% of patients with relapsed disease showed objective tumour responses. Complete remission was seen in 20–40% of patients. However, these responses were frequently short-lived with a maximum of 10% of responders remaining disease free after 3–5 years. In a review conducted by the Italian Society of Hematology (SIE) that aimed to develop clinical practice guidelines for the treatment of nodal diffuse large B-cell NHL, ifosfamide-containing regimens proved to be effective in relapsed NHL patients (Barosi et al., 2006). The addition of rituximab (R) in the second line therapy in non-controlled trials was also explored. Patients under 65 years old and with good performance status achieved a 5-year event-free survival of 35-60% after high-dose chemotherapy (HDT)/autologous stem cell transplantation (ASCT). A pooled analysis of 3 phase II trials of 150 refractory or relapsed patients receiving ICE followed by HDT/ASCT showed a 4-year overall survival of 27% and a 4-year progression-free survival of 20%. Both reviews were unable to conclude that any particular second line chemotherapy regimen was superior to the others.

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IFOSFAMIDE – February 2008 Based on the systematic literature review, the SIE recommended that at first relapse, patients should receive non-cross-reactive chemotherapies, for example, ICE, DHAP (dexamethasone, cisplatin, cytarabine), MIME, HDS (high-dose sequential) with or without rituximab followed, in eligible patients (