Original article
Clinical
Phase II Study of Metronomic Chemotherapy with Thalidomide, Carboplatin-Vincristine-Fluvastatin in the Treatment of Brain Stem Tumors in Children

https://doi.org/10.1016/j.arcmed.2008.05.008Get rights and content

Background

Brain stem tumors (BST) constitute 20% of all intracranial tumors. Survival for these patients has been very poor worldwide. Four different treatment schemes have been evaluated at our institution, with only a discrete increment in survival when treated with carboplatin-vincristine and fluvastatin (CVF). Low-dose, continuous antiangiogenic treatment has been recently introduced in the treatment of cancer. Our objective was to determine tumor response to metronomic chemotherapy combined with an antiangiogenic drug and fluvastatin and to calculate the survival of pediatric patients with brain stem tumors.

Methods

This was a phase II study. A magnetic resonance (MRI) study was made at inclusion and after the fourth course. Routine laboratory analyses were performed prior to each treatment scheme. Patients received four courses of chemotherapy every 28 days consisting of thalidomide alternating with fluvastatin every 14 days and combined with carboplatin and vincristine every 14 days followed by radiotherapy (56 cGy) and four more courses of the same chemotherapy. Toxicity was evaluated according to Miller criteria.

Results

Nine recently diagnosed BST patients were included. Five patients had low-grade astrocytomas, three patients had glioblastoma multiforme, and one patient presented high-grade astrocytoma. There was a significant reduction in tumor volume and a significant increase in survival at 24 months. Two patients died. Toxicity included carboplatin allergy in one patient, grades 1 and 3 neutropenia in two patients, and grade 4 thrombocytopenia in two patients.

Conclusions

Metronomic treatment with carboplatin and vincristine associated with fluvastatin and thalidomide significantly increased survival of pediatric brain stem tumor patients. Tumor volume showed a significant reduction. Quality of life was also increased. Sample size must be increased in order to make final conclusions.

Introduction

Central nervous system (CNS) tumors are the third most frequent tumors in children. In Mexico, incidence is 17 per million per year, which translates to 560 new cases each year 1, 2. Mortality in these patients is high, exceeding that in other neoplasms in the pediatric population. It has been reported as the sixth cause of death in preschool-age children and the ninth cause of death in school-age children and adolescents 2, 3. New neuroimaging techniques have contributed to an earlier diagnosis, and new chemotherapeutic schemes have increased overall and disease-free survival (1). Mortality in these patients has been reduced by 23% since 1975, in spite of an increment in the number of diagnoses 4, 5.

Brain stem tumors constitute ∼20% of CNS tumors. They present most frequently in children 6 and 7 years old, with no gender difference. Anaplastic astrocytoma and glioblastoma multiforme are the most common histological presentations 3, 6. Brain stem tumors usually infiltrate adjacent tissues; thus, surgical resection is difficult and prognosis worsens as neoplastic bulk cannot be reduced prior to chemotherapy and/or radiotherapy 1, 2.

Many attempts have been made worldwide to improve survival and quality of life in these patients. Post-biopsy radiotherapy, either in dose-escalated or hyperfractionated modality, has not proven effective (7). Since long-term disease control is exceptional when using radiotherapy alone, diverse combinations of radiotherapeutic approaches and infusion of chemotherapeutic agents have been tried. Nevertheless, survival has not substantially improved. In 1999, Allen et al. initiated a phase I protocol in 34 patients with intravenous carboplatin plus hyperfractionated radiotherapy, finding only five long-term survivors (15%) in continuous remission after a mean follow-up period of 79 months (range, 46–104 months) (8). Freeman et al. found that the combination of hyperfractionated radiotherapy plus cisplatinum given by continuous infusion on weeks 1, 3, and 5 of radiotherapy had a detrimental effect on survival compared to hyperfractionated radiotherapy alone (9). In 2003, Marcus et al. reported the results of a phase 1 trial in which etanidazole (escalating dose up to 46.2 g/m2) was combined with hyperfractionated radiation therapy. Median survival was 8.5 months (10). Benesch et al. (11) included 11 children with brain stem gliomas and treated them with intensive induction chemotherapy (ifosfamide [days 1–3], etoposide [days 4–6], methotrexate [days 15 and 22], cisplatin [days 29–31] and cytarabine [days 29–31], separated by a 3-week interval. Maintenance chemotherapy with carmustine, carboplatin and vincristine [8 cycles over a 1-year period] and simultaneous external beam irradiation was administered). Only one third of the children survived at 22, 22, 90, and 92 months, respectively.

In 2004, Bronicser and Gajjar (12) summarized the results of eight different clinical studies for the treatment of diffuse brainstem gliomas, which included phase I and phase II trials. All of them included radiotherapy (Rt) (min 54 cGy, max 72 cGy) and different chemotherapeutic schemes (CBDCA twice a week along with Rt; tamoxifen during and after Rt; high-dose busulfan and tiothepa after Rt; CBDCA prior to and along with Rt; trophosphamide and VP16; CBDCA/VP16/VCR prior to Rt vs. CDDp/cyclo/VP16/VCR prior to Rt; topotecan daily along with Rt and etanidazole along with Rt). Survival was poor in all eight trials. Only topotecan daily along with radiotherapy reported a 53% survival at 1 year, with a median survival of 15 months. Since then, postradiation temozolamide (13), tamoxifen associated with chemotherapy (14) or tipifarnib (15) have not yielded improvement in survival.

Several trials have been initiated by our group since 1991. The first experience with post-surgical radiotherapy (54 cGy) followed by chemotherapy with BCNU (120 mg/m2 on day 1, every 6 weeks for 12 months), procarbazine (100 mg/m2 for 14 days every month for 12 months), and vincristine (2 mg/m2 every 6 weeks for 12 months) had a 5-year survival of 29% (unpublished data). In 1994 a new protocol was initiated including four courses of neoadjuvant ifosfamide, carboplatin, and etoposide (ICE) followed by hyperfractionated radiotherapy and four more courses of ICE. Initial tumor reduction was observed after two courses of chemotherapy, but progressive disease was found after the fourth course. Survival in these patients was poor, achieving only 20% at 18 months (16). A new attempt to improve survival of these patients included four courses of carboplatin (350 mg/m2 on days 1 and 2), vincristine (2 mg/m2 on day 1) and fluvastatin (8 mg/kg/day from days 1–14) every 4 weeks, followed by hyperfractionated radiotherapy (54 cGy). Fifteen patients with low-grade astrocytomas of the brain stem were included with a 20% survival at 12 months. More recently, we tried four courses of neoadjuvant ICE chemotherapy associated with temozolamide (200 mg/m2 for 5 days) every 4 weeks followed by hyperfractionated radiotherapy (54 cGy). Four high-grade astrocytoma brain stem patients were included with a 30% survival at 18 months (unpublished data).

Recent investigations in the field of cancer have introduced new therapeutic approaches such as the administration of antiangiogenic drugs based on the hypothesis that tumor survival depends on the generation of new vessels inside the tumor, which assure its nutrient and oxygen distribution as well as its toxin excretion. Inhibition of this process, especially when targeted to specific stages of cancer, may contribute to the prevention of angiogenic switch in premalignant lesions as well as intervening in the rapid expansion of small tumors or inducing the regression of large end-stage cancers (17). More than 75 antiangiogenic compounds have entered clinical trials. Most of them have included patients with advanced disease resistant to standard therapies. Preliminary results of the clinical studies suggest that single-agent antiangiogenic therapy is poorly active in advanced tumors.

Some cytotoxic drugs have been found to have antiangiogenic properties when administered in a low-continuous dosage. Thus, a new logic in the administration of chemotherapy that involves the administration of drugs at constant intervals without rest periods (metronomic scheduling) in combination with other cytotoxic drugs targeting distinct aspects of the tumor's functionality has been proposed as promising in the treatment of cancer (18).

Research in animals combining antiangiogenic drugs and cytotoxic chemotherapy (19) suggests that brain tumor stem-like cells found a significant reduction in tumor sphere-forming units and suggests that antiangiogenic therapy may act as a chemosensitizer of brain tumor stem-like cells, representing a new possible mechanism to explain the ability of antiangiogenic therapy to enhance the efficacy of chemotherapy.

Few clinical investigations have been done regarding the treatment of intracranial tumors in children and adults with a metronomic approach. In 2002, Sterba et al. (20) reported the results of combined radiotherapy and temozolamide (90 mg/m2/day for 42 days) in eight children with poor prognosis brain tumors. Complete response was found in two medulloblastoma patients. In 2005, Herrlinger et al. (21) reported a 0% survival at 6 months when treating patients with cyclophosphamide (100 mg daily) and methotrexate (5 mg twice weekly) in 10 relapsed glioblastoma adult patients. In 2006, Kong et al. (22) report a 58.3% survival at 3 months (median overall survival of 11 months) when administering metronomic temozolamide (daily dose of 40 mg/m2) in 12 temozolamide-refractory glioblastoma patients. More recently, Kesari et al. (23) tried low-dose etoposide alternating with cyclophosphamide every 21 days, in combination with daily thalidomide and celecoxib in adult patients with recurrent malignant gliomas. For glioblastoma multiforme patients, median overall survival was 21 weeks, whereas anaplastic glioma patients had a median overall survival of 41.5 weeks. Although these authors conclude that this metronomtic regimen did not significantly improve overall survival in these heavily pretreated patients, they suggest that further studies using metronomic chemotherapy combined with more potent antiangiogenic agents in patients with less advanced disease must be conducted.

Section snippets

Materials and Methods

This study was conducted at the Hospital de Pediatría, Centro Médico Nacional Siglo XXI (CMN SXXI) of the Instituto Mexicano del Seguro Social (IMSS) in Mexico City. We included all patients from March 2005–January 2008, 17 years of age or younger, with a newly diagnosed brain stem tumor, who proved to have normal hepatic and renal function tests. We excluded undernourished or dehydrated patients. Informed consent was obtained from patients’ guardians. The protocol was approved by the local

Results

Nine patients were included. There were five females and four males with a female:male ratio of 1.25:1. Median age was 50 months (min 23, max 144); two patients were 36 months of age or younger. Median lag time was 60 days (min 16, max 300); four patients had a final diagnosis after 30 days of their first symptomatology. Five patients had low-grade astrocytomas, three presented glioblastoma multiforme, and one had a high-grade astrocytoma. At inclusion, six patients had a normal body mass

Discussion

Survival of children with various neoplasms including supra- and infratentorial tumors has increased in the last decades 1, 2 due to the introduction of new cytotoxic drugs, the comprehension of drug distribution within the tumor, and the mechanisms of drug resistance, initiation of other modalities of drug administration (localized, intra-arterial, cerebrospinal fluid, chemotherapy-impregnated polymer implantation, etc.), understanding of psychopathological mechanisms of cancer, knowledge

References (35)

  • J. Allen et al.

    A phase I/II study of carboplatin combined with hyperfractionated radiotherapy for brainstem gliomas

    Cancer

    (1999)
  • M. Benesch et al.

    Outcome and long-term side effects after synchronous radio-chemotherapy for childhood brain stem gliomas

    Pediatr Neurosurg

    (2001)
  • A. Bronicser et al.

    Supratentorial high-grade astrocytoma and diffuse brainstem glioma: two challenges for the pediatric oncologist

    Oncologist

    (2004)
  • A. Bronicser et al.

    Role of temozolamide after radiotherapy for newly diagnosed diffuse brainstem glioma in children: results of a multiinstitutional study (SJHG-98)

    Cancer

    (2005)
  • M.M. de Aquino-Gorayeb et al.

    Treatment of childhood diffuse brain stem tumors: comparison of results in different treatment modalities

    Clin Transl Oncol

    (2006)
  • M. Fouladi et al.

    Children's Oncology Group

    Cancer

    (2007)
  • E. López-Aguilar et al.

    Preirradiation ifosfamide, carboplatin and etoposide for the treatment of high grade astrocytomas in children

    Child Nerv Syst

    (2003)
  • Cited by (47)

    • A Combined Hypofractionated Volumetric Modulated Arc Radiotherapy, Radio-Sensitising and Adjuvant Metronomic Chemotherapy Treatment for Canine Stage IV Nasal Tumours With Intracranial Extension

      2022, Topics in Companion Animal Medicine
      Citation Excerpt :

      The technical difficulties with conformal radiation therapy of stage IV nasal tumours were addressed using VMAT. Carboplatin was selected as a radiosensitiser due to its specific putative effect on the tumour and on the brain, even if little data regarding metronomic chemotherapy with carboplatin is available in human medicine.36-39,41 In this study, the rationale for the chosen metronomic carboplatin protocol was based on trying to limit toxicity and chemoresistance via frequent administration of the chemotherapeutic agent at a very low dose.

    • Statins as adjuvants in the treatment of ovarian cancer: Controversy and misunderstanding

      2021, European Journal of Pharmacology
      Citation Excerpt :

      Regarding the doses of statins that have been used in cancer patients, Knox et al. (2005) in a Phase I clinical trial used a high dose of lovastatin: 7.5 mg/kg/day for 21 days with a week of rest. A dose of fluvastatin of 8 mg/kg/day was administered to children for 14 days every four weeks (López-Aguilar et al., 2008) and Garwood et al. (2010) used it at 80 mg/day for 3–6 weeks. Han et al. (2011), used 40 mg/day of simvastatin during the entire course of chemotherapy, and Lee et al. (J. Lee et al., 2014a), administered this drug at 80 mg/day for alternating cycles every 14 days.

    • Repurposing old drugs as new inhibitors of the ubiquitin-proteasome pathway for cancer treatment

      2021, Seminars in Cancer Biology
      Citation Excerpt :

      Numerous clinical trials have been performed in cancer patients using statins alone or in combination with other agents (https://clinicaltrials.gov/ct2/results?term = statin + AND + cancer &Search = Search). Although statin monotherapy did not give impressive results [241–243], the combination therapy of statins with other agents have shown more promising results [244–248]. Thus, repurposing statins as anticancer agents provides an encouraging strategy for cancer treatment.

    • Old wine in new bottles: Drug repurposing in oncology

      2020, European Journal of Pharmacology
      Citation Excerpt :

      However, using very small phase II study (n = 9), the appropriate combination of chemotherapeutic agents every 28 days consisting of thalidomide alternating with fluvastatin every 14 days, combined with carboplatin and vincristine every 14 days, and finally followed by radiotherapy and four more courses of the same chemotherapy, has increased survival of paediatric brain stem tumour patients (López-Aguilar et al., 2008). With respect to the toxicity of the therapy applied, the side effects included carboplatin allergy in one patient, grades I and III neutropenia in two patients, and grade IV thrombocytopenia in two patients (López-Aguilar et al., 2008). Lung cancer: As far as NSCLC is concerned, the preliminary data have suggested further investigation of the combination treatment with thalidomide, carboplatin and paclitaxel in chemotherapy-naive cancer patients (Merchant et al., 2000).

    View all citing articles on Scopus
    View full text