PURPOSE:Treatment strategies for osteosarcoma evolving between 1970 and 1999 improved 5-year survival and continue as standard of care today. This report evaluates the impact of these evolving therapies on long-term health outcomes. METHODS:Five-year survivors of childhood osteosarcoma in CCSS treated from 1970 to 1999 were evaluated for late (>5 years from diagnosis) mortality, chronic health conditions (CHCs), and health status using piecewise-exponential and logistical models. Comparisons were made between survivors and siblings without cancer, and among survivors examining historical and current standard chemotherapies (e.g., methotrexate/doxorubicin/cisplatin [MAP] vs. others), specific chemotherapy agents and surgical approaches (amputation vs. limb salvage [LS]). Models were evaluated adjusting for attained age, sex, race, ethnicity, and age at diagnosis. RESULTS:A total of 1257 survivors of osteosarcoma were followed on average for 24.4 years. Twenty-year all-cause late mortality was 13.3% (95% confidence interval [CI]: 11.7%-14.9%) overall and 11.7% (95% CI: 6.9%-16.5%) for the subset treated with MAP plus LS. Survivors were at higher risk of CHCs (rate ratio [RR] 3.7, 95% CI: 3.2-4.3) than the sibling cohort, most notably having more serious cardiac, musculoskeletal, and hearing CHCs. Within the survivor cohort, the risk of severe CHCs was twice as high with MAP versus no chemotherapy (RR 2.1, 95% CI: 1.3-3.4). Compared with primary amputation, serious musculoskeletal CHCs were higher after LS (RR 6.6, 95% CI: 3.6-13.4), without discernable differences in health status. CONCLUSION:Contemporary osteosarcoma therapy with MAP plus LS, while improving 5-year disease-free survival, continues to be associated with a high burden of late mortality, CHCs, and health status limitations.

PURPOSE:Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS:Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS:A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION:Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

Treatment of cancer in childhood is both a major success of modern medicine and a stark reminder of its limits. In high-income countries, multimodality therapy cures more than 80% of children.1Rodriguez-Galindo C Friedrich P Alcasabas P et al.Toward the cure of all children with cancer through collaborative efforts: pediatric oncology as a global challenge.J Clin Oncol. 2015; 33: 3065-3073Crossref PubMed Scopus (231) Google Scholar In low-income and middle-income countries (LMICs), where most children with cancer live, far fewer children are cured than in high-income countries. Access to essential medicines is one of the key determinants of cancer survival globally. WHO's Essential Medicines List (EML) sets the basic bar that all national governments should meet in provision of medicines.2WHOWHO model list of essential medicines: 19th list. World Health Organization, Geneva2015Google Scholar The revised EML includes an expanded list of core medicines required for multiple malignancies, including the most prevalent paediatric cancers.3WHOThe selection and use of essential medicines. World Health Organization, Geneva2015Google Scholar Ensuring access to such medicines is an explicit component of the broad right to health enshrined in international human rights conventions.4UNInternational covenant on economic, social and cultural rights.http://www.ohchr.org/Documents/ProfessionalInterest/cescr.pdfDate: 16 Dec, 1966Google Scholar The International Society of Paediatric Oncology (SIOP) and Childhood Cancer International (CCI) held a symposium at the 48th SIOP Congress in Dublin, Ireland, on Oct 19, 2016, entitled "Essential medicines for children with cancer: dynamics and challenges". Major challenges and potential solutions related to access to these medicines in LMICs were explored, and priority actions to improve global access were identified. Access to medicines is a complex issue, involving components from drug development to delivery. This joint position statement summarises the symposium's key consensus findings to galvanise the international oncology community to achieve sustained improvements in access to medicines for children with cancer, regardless of disease or geography. The deliberations, situational analysis, and recommendations were framed by four commonly cited core domains of access: availability, accessibility, acceptability, and affordability; we included quality as a fifth domain.5Management Sciences for HealthManaging access to medicines and health technologies. Management Sciences for Health, Arlington2012Google Scholar Availability relates to how medicines are produced and distributed. Barriers to availability include but are not limited to: inadequate drug production, secondary to weak market incentives or poor forecasting of childhood cancer treatment needs; national failures to comply with EML recommendations; and rigid regulatory frameworks governing drug licensing and importation. Accessibility refers to a given medicine's location in relation to the person in need. Cancer medicines are often inaccessible in LMICs because of weak systems of supply management, including poor inventory controls, fractured supply channels, and inadequate infrastructure for proper transport and storage. These complexities are exacerbated by socioeconomic and geographical factors in many LMICs, principally the effects of poverty and rurality on patients' abilities to reach needed medicines. Acceptability considers the design characteristics of existing medicines and how these align with patient and provider expectations and experiences. Medicines for children with cancer are distinct since many require formulation as sterile injectables; consequently, they are complicated to produce, require cold storage, and have short shelf lives. Moreover, they are dosed by weight or body surface area, making it difficult to manufacture vials that minimise waste, or for pills, doses appropriate to varying stages of child development. These characteristics often limit drug acceptability to provider and patient alike, particularly in LMICs. Affordability refers to the relationships between cost, price, and ability to pay and addresses issues related to drug price determination, how medicines are purchased, and the effects of these factors on patient access. Despite the fact that most cytotoxic agents for children are available in generic formulation, cost-related barriers persist. These barriers rest on multiple factors, including national resource constraints and competing health system priorities; small, fragmented markets for paediatric cancer drugs; thin industry profit margins due to patent expiry; and absence of public or employer-based health insurance. Quality incorporates appraisals of drug safety and efficacy and addresses problems related to drug provenance, including counterfeiting, improper production, and inadequate quality surveillance. The capacity for generic production of most essential medicines for children with cancer is a double-edged sword: it lowers prices but diffuses production, complicating assessments of drug origination and thus quality assurances. Such assurances are further compromised in many LMICs by weak or absent pharmacovigilance in the face of decentralised and often labyrinthine systems of drug procurement and supply. Our recommendations to improve global access to childhood cancer medicines are summarised in the panel. Gathering appreciation of the mounting role that cancer will play in global childhood mortality has created a window of opportunity for political action on this issue. SIOP and CCI commit to joint engagement with key academic, policy, advocacy, and industry stakeholders to advance these recommendations. Ongoing efforts include formal collaboration with WHO on iterative updates to the EML for children and plans for cross-sectoral consultation at in-depth symposia during the 2017 SIOP and CCI Annual Congresses in Washington, DC, USA. Only sustained advocacy and effective policies in line with our recommendations will induce real and lasting gains in access to essential medicines for all children with cancer.PanelRecommendations to improve global access to childhood cancer medicinesAvailability•Development of a database listing reliable suppliers of essential medicines for children with cancer•Research to assess and understand barriers to national formulary compliance with EML recommendations across LMICs•WHO-led attempts to harmonise national regulatory regimes through regional collaboration to facilitate pooled procurement•Efforts to develop a not-for-profit capacity for development of off-patent cytotoxic drugs for children, with the potential for global scale-upAccessibility•Human resource investments in paediatric pharmacists, whose scientific and on-the-ground knowledge is crucial to sound policies on supply chain management for antineoplastic drugs•Development of specific guidelines on infrastructural and oversight requirements for injectable chemotherapeutics for children•Formalised voice for childhood cancer experts in national policy making on drug procurement and supplyAcceptability•Development of intrainstitutional and interinstitutional policies to minimise waste of medicines•Regional partnerships with trusted producers to ensure reliable production processes, with a view to minimisation of introduction of potential harmful excipients•Research into patient and provider experiences of use of cancer medicines in LMIC settingsAffordability•Expanded public insurance coverage for essential childhood cancer medicines for children with cancer•Regionally pooled purchasing•Reduction or removal of importation tariffs on childhood cancer medicines•Exploration of innovative financing approaches to provision of off-patent cytotoxic drugsQuality•Development of a WHO-certified list of reputable drug suppliers and formulations to guide national procurement•Improved methods of interinstitutional and health-care user knowledge sharing on drug quality, including through creative uses of mobile technology, to facilitate improved postmarketing quality surveillance•Enhanced training programs for LMIC pharmacists and bedside providers in safe and accurate preparation and administration of chemotherapeutics in children•Expanded research into new, cost-effective, point-of-care quality diagnosticsEML=Essential Medicines List. LMIC=low-income and middle-income country. Availability •Development of a database listing reliable suppliers of essential medicines for children with cancer•Research to assess and understand barriers to national formulary compliance with EML recommendations across LMICs•WHO-led attempts to harmonise national regulatory regimes through regional collaboration to facilitate pooled procurement•Efforts to develop a not-for-profit capacity for development of off-patent cytotoxic drugs for children, with the potential for global scale-up Accessibility •Human resource investments in paediatric pharmacists, whose scientific and on-the-ground knowledge is crucial to sound policies on supply chain management for antineoplastic drugs•Development of specific guidelines on infrastructural and oversight requirements for injectable chemotherapeutics for children•Formalised voice for childhood cancer experts in national policy making on drug procurement and supply Acceptability •Development of intrainstitutional and interinstitutional policies to minimise waste of medicines•Regional partnerships with trusted producers to ensure reliable production processes, with a view to minimisation of introduction of potential harmful excipients•Research into patient and provider experiences of use of cancer medicines in LMIC settings Affordability •Expanded public insurance coverage for essential childhood cancer medicines for children with cancer•Regionally pooled purchasing•Reduction or removal of importation tariffs on childhood cancer medicines•Exploration of innovative financing approaches to provision of off-patent cytotoxic drugs Quality •Development of a WHO-certified list of reputable drug suppliers and formulations to guide national procurement•Improved methods of interinstitutional and health-care user knowledge sharing on drug quality, including through creative uses of mobile technology, to facilitate improved postmarketing quality surveillance•Enhanced training programs for LMIC pharmacists and bedside providers in safe and accurate preparation and administration of chemotherapeutics in children•Expanded research into new, cost-effective, point-of-care quality diagnostics EML=Essential Medicines List. LMIC=low-income and middle-income country. We declare no competing interests. We thank all participants in the joint International Society of Paediatric Oncology-Childhood Cancer International Essential Medicines Symposium at the 48th International Society of Paediatric Oncology Congress in Dublin, Ireland, on Oct 19, 2016, on whose insights and input this position statement is based.

The high prices of cancer drugs are affecting the care of patients with cancer and our health care system.1 In the United States, the average price of new cancer drugs increased 5- to 10-fold over 15 years, to more than $100,000 per year in 2012. A study by Howard et al2 documented the escalation in cancer drug prices by an average of $8500 a year over the past 15 years. The cost of drugs for each additional year lived (after adjusting for inflation) has increased from $54,000 in 1995 to $207,000 in 2013.

CORRESPONDING AUTHOR: P. Michael Link, Research Group Climate Change and Security, Center for Earth System Analysis and Sustainability, University of Hamburg, Grindelberg 7 #2014, D-20144 Hamburg, Germany, E-mail: michael.link@uni-hamburg.de

Pediatric follicular lymphoma (pFL) is a rare neoplasm with features differing from follicular lymphoma arising in adults. Here, we describe a rare case of pFL that showed morphologic features partially overlapping with progressive transformation of germinal centers and reactive follicular hyperplasia. As typical of pFL, neoplastic B cells within follicles did not express B-cell leukemia/lymphoma 2 (BCL2). However, this case showed additional distinctive abnormal findings, which contributed to the diagnosis: (1) diffuse and uniform staining of immunoglobulin M (IgM) on cells within and outside of follicles, (2) abnormally dim expression of CD21 on follicular dendritic cells, and (3) expression of human germinal center–associated lymphoma (HGAL) and LIM domain only 2 (LMO2) on B cells in interfollicular and follicular areas. This case demonstrates the utility of these abnormal features, which can be seen in adult- or usual-type follicular lymphoma, in the diagnosis of pFL. Further studies are necessary to evaluate the significance of these findings in other cases of pFL.

Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) is a rare disorder, constituting less than 1% of primary cutaneous lymphomas. Most cases occur in adults and may present as plaques or nodules with ulceration. Here we describe an unusual case of PCGD-TCL in a 3-year-old boy who presented with asymptomatic subcutaneous nodules. To our knowledge, this report represents one of the youngest reported patients with gamma-delta lymphoma/lymphoproliferative disorder. In addition, our patient has an indolent clinical presentation with greater than 1 year clinical follow-up. Because gamma-delta T-cell lymphomas are exceedingly rare in children, we acknowledge that the clinical course/outcome in young patients is still unclear. We hope to add to the recognition that PCGD-TCLs demonstrate a wide clinical spectrum of disease with relatively indolent presentations in some cases.

Objective: To examine inpatient utilization of pediatric cancer specialty centers (PCSCs) by pediatric oncology patients. Study Design: We performed a retrospective (1999 to 2010) population-based analysis of oncology hospitalizations for pediatric patients aged 0 through 18 years using the California Office of Statewide Health Planning and Development database. Logistic regression examined hospitalization at 29 PCSCs and variables of age, sex, tumor type, payer, race, income, and distance to admission site. Results: Analysis of 103,961 pediatric oncology discharges revealed that 93% occurred at PCSCs. These sites experienced a 20% increase in pediatric oncology discharges, conversely non-PCSCs exhibited a 70% decrease (P<0.0001). Multivariate analyses revealed increased utilization with young age (odds ratio [OR], 4.58; 95% CI, 3.88-5.42), African American (OR, 1.26; 95% CI, 1.11-1.43), and middle income (OR, 1.36; 95% CI, 1.29-1.45). Decreased utilization was seen for females (OR, 0.88; 95% CI, 0.84-0.93) and Hispanics (OR, 0.72; 95% CI, 0.68-0.77). Payer and proximity were not significantly associated with change in utilization. Tumor types less likely to utilize a PCSC included germ cell, solid, and central nervous system tumors. Adolescents were >3 times less likely to be treated at a PCSC. Conclusions: Inpatient pediatric oncology care in California has become increasingly regionalized with the vast majority of patients accessing PCSCs. However, variability in hospitalizations of adolescent patients and children not treated in PCSCs deserve further evaluation.

A previous US study reported poorer survival in children with acute lymphoblastic leukemia (ALL) exposed to extremely low-frequency magnetic fields (ELF–MF) above 0.3 μT, but based on small numbers. Data from 3073 cases of childhood ALL were pooled from prospective studies conducted in Canada, Denmark, Germany, Japan, UK and US to determine death or relapse up to 10 years from diagnosis. Adjusting for known prognostic factors, we calculated hazard ratios (HRs) and 95% confidence intervals (CI) for overall survival and event-free survival for ELF–MF exposure categories and by 0.1 μT increases. The HRs by 0.1 μT increases were 1.00 (CI, 0.93–1.07) for event-free survival analysis and 1.04 (CI, 0.97–1.11) for overall survival. ALL cases exposed to >0.3 μT did not have a poorer event-free survival (HR=0.76; CI, 0.44–1.33) or overall survival (HR=0.96; CI, 0.49–1.89). HRs varied little by subtype of ALL. In conclusion, ELF–MF exposure has no impact on the survival probability or risk of relapse in children with ALL.

Posterior fossa syndrome (PFS), also known as cerebellar affective syndrome, is characterized by emotional lability and decreased speech production following injury or surgery to the cerebellum. Rarely, oculomotor dysfunction has been described in association with PFS. Here, we report a case of complete ocular paresis associated with PFS in an 11-year-old male following medulloblastoma resection.

ALK+ anaplastic large cell lymphoma (ALCL) is usually a disease of young patients. We investigated phosphatidylinositol‐3 kinase (PI3K)/Akt pathway‐associated factors in pediatric cases and cell lines.

Interview with Dr. Bruce Chabner on shortages of generic drugs and possible solutions. (10:16)Download Among the generic drugs in short supply is mechlorethamine, part of a standard regimen for pediatric Hodgkin's lymphoma. The Pediatric Hodgkin Lymphoma Consortium has substituted cyclophosphamide, which is less effective and increases the risk of complications.

10003 Background: Second malignant neoplasms (SMN) are a known complication of Hodgkin disease (HD) treatment. While it is theorized that lower radiation doses may be associated with lower SMN risk, long-term follow-up of children treated with low-dose radiation is lacking. We report the occurrence of SMN among pediatric HD survivors treated at Stanford with chemotherapy and low-dose radiation from 1970 to 1990. Methods: Patients received 6 cycles of MOPP (mechlorethamine, vincristine, prednisone, procarbazine) with 15–25.5 Gy radiation ± 10 Gy boost or 3 MOPP and 3 ABVD cycles (doxorubicin, bleomycin, vinblastine, dacarbazine) with 15 Gy radiation ± 10 Gy boost. Follow-up was obtained through 9/1/2007. Standardized incidence ratios (SIRs) and absolute excess risk (AER) for SMN were calculated using the SEER9 database (1973–2004). Cumulative SMN incidence was determined by the Kaplan-Meier method. Univariate associations were evaluated with the chi-square test or t-test. Multivariate analysis was performed with Cox proportional hazards regression using chronological age as the time scale. Results: One hundred ten of 112 patients achieved remission; median follow-up is 20.6 years. Four patients developed secondary leukemia. Fifteen patients developed 17 secondary solid tumors (5 thyroid carcinomas, 6 breast carcinomas, 4 sarcomas, 1 bladder paraganglioma, 1 melanoma) at a median of 15.4 years. All solid tumors except the melanoma occurred within or at the margin of radiation fields, ranging in dose from 15–26.5 Gy. There were no cases of lung, gastric, or colorectal carcinoma. Cumulative incidence of any SMN is 17% (95%CI 10.5–26.7) at 20 years following HD diagnosis. The SIR for any SMN is 22.9 (95%CI 14.2–35) with an AER of 93.7 cases per 10,000 person-years. In univariate analysis, older age at HD diagnosis (>11 years) and female gender were associated with SMN (p<0.05). In multivariate analysis, there were no statistically significant associations. Conclusions: The incidence of SMN in pediatric HD survivors is elevated following treatment with chemotherapy and low-dose radiation. Sarcomas, breast, and thyroid carcinomas occurred with similar frequency and latency as found in studies of HD survivors who received high-dose radiation. No significant financial relationships to disclose.

PurposeThe American Society of Clinical Oncology (ASCO) Cancer Research Committee designed a qualitative research project to assess the attitudes of cancer researchers and compliance officials regarding compliance with the US Privacy Rule and to identify potential strategies for eliminating perceived or real barriers to achieving compliance.MethodsA team of three interviewers asked 27 individuals (13 investigators and 14 compliance officials) from 13 institutions to describe the anticipated approach of their institutions to Privacy Rule compliance in three hypothetical research studies.ResultsThe interviews revealed that although researchers and compliance officials share the view that patients' cancer diagnoses should enjoy a high level of privacy protection, there are significant tensions between the two groups related to the proper standards for compliance necessary to protect patients. The disagreements are seen most clearly with regard to the appropriate definition of a "future research use" of protected health information in biospecimen and data repositories and the standards for a waiver of authorization for disclosure and use of such data.ConclusionASCO believes that disagreements related to compliance and the resulting delays in certain projects and abandonment of others might be eased by additional institutional training programs and consultation on Privacy Rule issues during study design. ASCO also proposes the development of best practices documents to guide 1) creation of data repositories, 2) disclosure and use of data from such repositories, and 3) the design of survivorship and genetics studies.

DE Foliart*,1, BH Pollock2, G Mezei3, R Iriye4, JM Silva4, KL Ebi5, L Kheifets6, MP Link7, R Kavet3 Correction to: British Journal of Cancer (2006) 94, 161–164. doi: 10.1038/6602916 Owing to an author error, the legend to Figure 1 was incorrect. The correct legend is given below. DE Foliart, BH Pollock, G Mezei, R Iriye, JM Silva, KL Ebi, L Kheifets, MP Link, R Kavet

8514 Background: Limited information exists regarding risk of t-MDS/AML after Ewing’s sarcoma. Methods: We followed a cohort of 578 individuals less than 30 years of age, diagnosed with Ewing’s sarcoma, PNET or primitive sarcoma of bone between 1988 and 1994 (treated according to a therapeutic protocol: CCG-7881/POG-8850) to determine the incidence of t-MDS/AML and associated risk factors. Between 1988 and 1992, all patients were assigned randomly to standard chemotherapy with doxorubicin (dox), vincristine (VCR), cyclophosphamide (CPM), and dactinomycin (DACT) (Regimen A: n=262) or experimental therapy consisting of these four drugs in alternation with Ifosfamide (I) and etoposide (E) (Regimen B: n=256). Between 1992 and 1994, patients with metastatic disease were nonrandomly assigned to Regimen C (n=60). Cumulative therapeutic exposures were: Regimen A: CPM:20.4 g/2, dox:375 mg/m2; Regimen B: CPM:9.6 g/m2, dox:375 mg/2, E:5 g/m2, I:90 mg/2; Regimen C: CPM:17.6 g/m2, dox:450 mg/m2, E:5 g/m2, I:140 g/m2. Results: Median age at diagnosis (dx) was 12.0 yr. Eleven patients developed t-MDS/AML [Regimen A (n=3), Regimen B (n=2), Regimen C (n=6)] at a median of 3 yr., with a cumulative incidence of 2% at 5 years. Magnitude of risk by regimen is shown in the Table. Multiple regression analysis revealed that Regimen C (RR=15.9, 95% CI, 3.8–65.8), but not Regimen B (RR=0.6, 95% CI, 0.1–3.7) was associated with an increased risk of developing t-MDS/t-AML when compared with Regimen A. Age at diagnosis, gender, and use of radiation therapy for local control did not increase the risk of t-MDS/AML. Conclusions: The risk of t-MDS/AML after Ewing’s sarcoma is not increased after exposure to ifosfamide at a dose of 90 g/m2, or etoposide at 5 g/m2, when compared to those not exposed to ifosfamide or etoposide, but that the risk increases dramatically after exposure to ifosfamide at cumulative doses of 140 g/m2. No significant financial relationships to disclose.

PURPOSE To determine whether the addition of ifosfamide and/or muramyl tripeptide (MTP) encapsulated in liposomes to cisplatin, doxorubicin, and high-dose methotrexate (HDMTX) could improve the probability for event-free survival (EFS) in newly diagnosed patients with osteosarcoma (OS). PATIENTS AND METHODS Six hundred seventy-seven patients with OS without clinically detectable metastatic disease were treated with one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and HDMTX and underwent definitive surgical resection of the primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 double dagger 2 factorial design. The primary end point for analysis was EFS. RESULTS Patients treated with the standard arm of therapy had a 3-year EFS of 71%. We could not analyze the results by factorial design because we observed an interaction between the addition of ifosfamide and the addition of MTP. The addition of MTP to standard chemotherapy achieved a 3-year EFS rate of 68%. The addition of ifosfamide to standard chemotherapy achieved a 3-year EFS rate of 61%. The addition of both ifosfamide and MTP resulted in a 3-year EFS rate of 78%. CONCLUSION The addition of ifosfamide in this dose schedule to standard chemotherapy did not enhance EFS. The addition of MTP to chemotherapy might improve EFS, but additional clinical and laboratory investigation will be necessary to explain the interaction between ifosfamide and MTP.