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Taxanes in paediatric oncology: And now?
CANCER TREATMENT REVIEWS (2006) 32, 65–73
www.elsevierhealth.com/journals/ctrv
CONTROVERSY
Taxanes in paediatric oncology: And now? ´ Nicolas Andre
a,b,*
, Christophe Meille
c
a
Department of Paediatric Oncology, EA3286, UFR of Medicine and ‘‘La Timone’’ Children Hospital, Bd. Jean Moulin, 13885 Marseille, Cedex 5, France b FRE – Centre National de la Recherche Scientifique 2737, UFR of Pharmacy, 13885 Marseille, Cedex 5, France c Department of Pharmacokinetics, EA3286, UFR of Pharmacy, 13885 Marseille Cedex 5, France Received 11 October 2005; accepted 15 December 2005
KEYWORDS
Summary Taxanes are a group of anticancer agents that target microtubules, promote their assembly, and stabilize them. The resulting effects are mitotic blockage and induction of apoptosis, whose mechanism of initiation remains to be fully determined. Among adults, taxanes are one of the most powerful and most commonly used anticancer drugs. They show a wide range of activity in malignancies such as breast, ovarian, and lung cancers. In paediatric oncology, pre-clinical and clinical data are quite limited. Six phase I studies, two phase II, and rare case reports have been published. This review will focus on the paediatric pre-clinical and clinical findings with taxanes. Based on data from the literature, we will try to explain the results and foresee the possible use of taxanes in paediatric oncology. Indeed, three main advances have been made regarding taxanes:
Taxanes; Paclitaxel; Docetaxel; Children; Oncology
(1) Increased efficacy when used in multidrug-based chemotherapy regimen. (2) New administration schedules based on anti-angiogenic properties when given at daily very low doses. (3) Development of new taxanes with decreased recognition by Pgp, the product of the MDR1 gene. Thus, although the initial experience with taxanes in paediatric oncology has been disappointing, it may be too early to leave out taxanes and we should further investigate their use among children with cancer. c 2006 Elsevier Ltd. All rights reserved.
Introduction * Corresponding author. Tel.: +33 04 91 83 56 26; fax: +33 04 91 78 20 24. E-mail address: [email protected] (N. Andre ´).
In the last three decades, the prognosis of children with cancer has been significantly improved. Now-
0305-7372/$ - see front matter c 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2005.12.010
66 adays, 70% of children with cancer can be cured. Chemotherapy plays a key role in the treatment of child malignancies, which are particularly chemo-sensitive. Nevertheless, some cancers such as N-myc amplified neuroblastomas, disseminated rhabdomyosarcomas and metastatic osteosarcomas display a 5 year survival rate of less than 50%. Thus, there is a demand for new drugs to keep improving the survival of children with cancer. Taxanes are among the most commonly used anticancer drugs to emerge in the last decades. They are extracted from given parts of yew trees. Paclitaxel was initially identified in 1971,1 and two taxanes are currently available for clinicians: paclitaxel (Taxol) and docetaxel (Taxotere). Although there are several differences in the pharmacokinetics and pharmacologic actions of the two taxanes, they share action mechanisms. Alone or in combination with other anti-cancer agents, paclitaxel is active against a broad range of tumour types, including breast, ovarian, lung, head, and neck cancers.2,3 The range of taxane activity is growing, with confirmed activity in other malignancies that are refractory to conventional chemotherapy, such as previously treated lymphoma, small cell lung cancers, oesophageal, gastric, endometrial, bladder, and germ cell tumours. Nevertheless, despite initial hope among paediatric oncologists,4 the use of taxanes in paediatric oncology has been disappointing. This review will focus on the paediatric pre-clinical and clinical findings with the taxanes. We will explain these results and foresee the use of taxanes in paediatric oncology (Fig. 1).
Figure 1 Taxanes are anticancer drugs obtained from the yew trees: allies for children with cancer?
N. Andre ´, C. Meille
How do they work? Taxanes belong to the class of anti-tubulin agents, but they act differently than previously described anti-tubulin agents.5 Indeed, taxanes bind the beta subunit of tubulin dimers but instead of destabilizing microtubules, they stabilize microtubules by perturbing their dynamics.5 This action induces bundles of microtubules and abnormal mitosis (Fig. 2A and B).6,7 Taxanes can also trigger apoptosis8 (Fig. 2C) but the way taxanes induce cell death is debated.9,10 Indeed, besides its well-described action on microtubules, paclitaxel has an additional mechanism of action.10 It can trigger the activation of several kinases11 and activate gene expression.12 Lately, taxanes have shown other potential targets than microtubules. Paclitaxel can bind to Bcl-213 and mitochondrial tubulin.14,15 So, it has been accepted that taxanes could target mitochondria to activate apoptosis.16 These different properties may explain why the last decade witnessed the emergence of paclitaxel as one of the most powerful compound agents in adult oncology.
Preclinical testing In vitro, several neuroblastoma cell lines are sensitive to taxanes.17–20 A cytotoxic effect occurred at concentrations similar to those achieved in the plasma of patients treated with these agents in initial clinical trials. Docetaxel proved more potent than paclitaxel.18 The authors concluded that the sensitivity of neuroblastoma cell lines to prolonged incubations or daily repeated administrations of taxanes should be assessed in paediatric phase II studies.18 Nevertheless, when neuroblastoma tumours were grafted to nude mice, taxanes displayed little efficacy, particularly when compared to topotecan.21 Hepatoblastoma cell lines obtained from three children were sensitive to paclitaxel.22 Moreover, when hepatoblastoma cell suspensions were transplanted subcutaneously to NMRI nude mice, paclitaxel was efficient in all three hepatoblastoma tumour grafts. After chemotherapy, tumour volume and alpha-fetoprotein levels were significantly reduced.22 Additionally, the activity of paclitaxel was similar to that observed with cisplatin, which was the most potent compound on these cell lines, suggesting an interesting potential of taxanes for this type of tumour. At concentrations achievable in vivo, docetaxel was tested on 20 samples from children with acute lymphoblastic leukaemia (ALL) and acute myeloid
Taxanes in paediatric oncology: And now?
67
Figure 2 Cellular effects of paclitaxel on the SK-N-SH human neuroblastoma cell line. (A) Immunofluorescence staining of alpha-tubulin shows that paclitaxel induces bundles of microtubules (white arrow) in interphasic cells and pseudo asters (grey arrow) in mitotic cells. (B) Mitotic neuroblastoma cell observed with transmission electron microscopy during paclitaxel incubation. Note mitochondria with dark granules and altered structure corresponding to apoptotic mitochondria. Bar = 0.5 lm. (C) Apoptotic bodies (white arrow) evidenced with DAPI staining of DNA in SK-NSH cell line incubated with paclitaxel.
leukaemia (AML).23 Docetaxel was cytotoxic to ALL and AML cells. Its cytotoxic effect was mediated by the induction of apoptosis. Interestingly, docetaxel was consistently more potent than paclitaxel. Authors concluded these results provided the rationale for clinical trials of docetaxel in patients with acute leukaemia. Pre-clinical studies have also shown that paclitaxel and docetaxel were efficient in killing primitive neuroectodermal tumour, glioblastoma, and teratoma cell lines in vitro.17,20 Thus, taxanes are efficient in vitro in several cell lines derived from paediatric tumours. Nevertheless, in a recent review of pre-clinical testing of new agents in paediatric tumour xenograft models, Houghton and al. did not report studies concerning taxanes.24 Thus information remains quite rare.
Clinical testing Phase I trials In children, 6 phase I trials have determined the maximum tolerated doses (MTD) and dose-limiting
toxicities (DLT) of taxanes by testing different schedules of administration. Four of them studied paclitaxel and two others docetaxel. Data are summarized in Table 1.
Paclitaxel A phase I trial of paclitaxel in children with refractory solid tumours from the Paediatric Oncology Group (POG)25 showed that the recommended dose for phase II trials was 350 mg/m2 when administered as a 24-h infusion every 3 weeks. DLT was neurotoxic and toxicity was not significantly correlated with dosage. In contrast, toxicity correlates better with paclitaxel systemic exposure, evaluated by the area under curve (AUC). The authors attributed this to the saturable distribution and elimination mechanisms of paclitaxel.26 Responses were documented in 4 out of the 31 (13%) children in that study. Among the responses, one complete response was noted in a patient with papillary serous carcinoma. In seven children with refractory leukaemia, a phase I study on escalation targeting a systemic exposure to paclitaxel was performed to integrate the inter-individual pharmacokinetic variability
68 Table 1
N. Andre ´, C. Meille Phase I trials of taxanes in children
Author Anticancer (reference) agent tested
MTD Number Schedule of administration of patients
Limiting toxicity
Response number of CR, PR, SD and histology
Hurwitz25
Paclitaxel
31
24-h infusion/ 21 days
350 mg/m2
Neurological
1 CR (papillary serous carcinoma) 2 PR (rhabdomyosarcoma, hepatocellular carcinoma) 9 SD (3 Ewing tumours, 2 osteosarcomas, 2 synovialosarcoma, 1 glioma, 1 intrathoracic chordoma)
Doz28
Paclitaxel
16
3-h infusion/ 21 days
No
Neurological
0 CR 1 PR (rhabdomyosarcoma) 1 SD (rhabdomyosarcoma)
Woo27
Paclitaxel
7
24-h infusion/ 21 days
target AUC 31– 45 mM h
Mucous
0 CR 1 PR (leukaemia) SD: Not mentioned
Liu31
paclitaxel & radiotherapy
11
24-h infusion times 6 days
4 mg/m2/day
Hayashi32
Paclitaxel
16
3-h infusion twice weekly · 6/28 days
50 mg/m2/ dose
Haematological
Blaney33
Docetaxel
44
1-h infusion/ 21 days
125 mg/m2/ dose
Haematological, 1 CR general (rhabdomyosarcoma) 1 PR (PNET) 4 SD (3 PNET, 1 colon carcinoma)
Siebel34
Docetaxel 17 and filgrastim
1-h infusion/ 21 day 5 lg/kg/day
185 mg/m2/ dose
Dermatologic
2 PR: glioma 0 CR 0 PR 3 SD (2 osteosarcomas, 1 ependymoma)
0 CR 1 PR (colon carcinoma) SD: not mentioned
Abbreviations: CR = complete response, PR = rartial response, SD = stable disease.
along the escalation process.27 AUCs were lower than those expected from phase I studies in children with solid tumours. Mucositis was the DLT exposure limiting toxicity. The efficacy was very low: peripheral blast count did not decrease in two patients, but it declined in five patients three days after the first course. Six out of the seven patients endured a worsening of their leukaemia within 20 days. Only one patient was eligible for a second course. The phase I study conducted by the Socie ´te ´ Franc ¸aise d’Oncologie Pe ´diatrique (SFOP) sought to determine the MTD and the pharmacokinetics of paclitaxel in children with cancer when adminis-
tered in 3-h infusion every 3 weeks.28 Seventeen children with various solid tumours were included. One treatment-related death occurred just after the infusion at the highest dosage, and the investigators did not recommend this schedule of administration. No dose-limiting haematological toxicity was observed. Nevertheless, because of its low aqueous solubility, paclitaxel requires a pharmaceutical vehicle: cremophor EL. It is a purified polyoxyethylated castor oil probably involved in paclitaxel toxicity.28 Thus, it is difficult to discriminate the respective roles of paclitaxel and cremophor EL in the observed toxicity. One partial response was observed in a patient with embryonal
Taxanes in paediatric oncology: And now? rhabdomyosarcoma. Stable disease was observed after 2 courses at 350 mg/m2 in one patient with alveolar rhabdomyosarcoma. Disease progression was observed in the 12 other assessable patients. In the same study, the pharmacokinetics of paclitaxel showed specific characteristics; clearance appeared to decrease as the dosage increased and the maximum concentration and AUC increased more than in proportion to the dose. As in the study of Hurwitz et al.25 these results suggest that paclitaxel pharmacokinetics is non-linear when the drug is administered as a 3-h infusion in children. However, although it has been proposed that paclitaxel’s nonlinear pharmacokinetics is due to saturable distribution and elimination processes,26 recent reports strongly suggest that the non-linearity results from the entrapment of paclitaxel in its vehicle.29,30 This effect makes it difficult to use the clearance as parameter for drug exposure, as the actual exposure to unbound paclitaxel fraction depends on the plasma level of cremophor EL. Another phase I study by Liu and al. investigated the association of radiotherapy with increased paclitaxel dose among 11 children suffering from brain tumours. Paclitaxel was given as a 24-h infusion 7 days a week.31 These authors showed the feasibility of such an association and recommended that paclitaxel should be given at doses of 4 mg/m2 /day for 6 weeks. The dose-limiting toxicity was severe constipation. The underlying mechanism suspected is autonomic neuropathy. In this trial, two patients achieved partial remissions. Lastly, Hayashi and al.32 reported the results of a phase I trial from the POG in which paclitaxel was administered as a 3-h infusion, twice weekly. Sixteen assessable patients were enrolled. In this case study, neutropenia was the DLT dose-limiting toxicity. With this schedule, the MTD of paclitaxel was 50 mg/m2/dose. No response was observed. Docetaxel In 1997, the Children’s Cancer Group (CCG) published the results of the first phase I trial of docetaxel. It was administered as a 1-h infusion every three weeks in children with refractory solid tumours.33 Forty-four children received 103 courses of docetaxel. The MTD according to previous treatment (heavy vs. less heavy) were respectively 65 and 125 mg/m2. A complete response was observed in a patient with rhabdomyosarcoma. A partial response and two minimal responses were observed in three patients with peripheral primitive neuroectodermal tumour. Three out of the four responding patients were treated at doses superior or equal to 100 mg/m2. With this schedule of administration, the DLT was neutropenia, and neuropathy
69 was uncommon. The toxicity profile in children is similar to the one in adults. As neutropenia was the DLT of docetaxel in children, a collaborative Paediatric Oncology Branch, National Cancer Institute and Children’s Cancer Group Trial set up another phase I trial of docetaxel. It was administered as an intravenous infusion for 1 h every 21 days with filgrastim (G-CSF 5 lg/ kg/day) support.34 Seventeen patients were included. DLT were generalized erythematous desquamating skin rash and myalgias. Filgrastim support proved efficient, as neutropenia was not dose limiting anymore and allowed an increase in MTD (185 mg/m2), which is 50% higher than the MTD of docetaxel without growth factor. Only one minor response was observed in a patient with a colon cancer. Nevertheless, as 9 patients out of the 17 patients included had osteosarcomas, data about potential efficacy may not be representative in this study. Thus, from phase I trials of taxanes, we learned that – Several administration schedules can be performed: a 1-h or 24-h infusion every three weeks, a 3-h infusion twice weekly, and a continuous infusion for 6 days – Administrations can be safely repeated – Limiting toxicity depends on the schedule of administration – Responses and stabilization were observed in respectively 5% and 15% of the patients with various types of cancer.
Phase II trials A phase II study was initiated by the Paediatric Oncology Group (POG) in children with progressing or relapsing brain tumours.35 Paclitaxel was administered according to the recommendations of the phase I trial from Hurwitz et al.25 Seventy-three patients have been included. Tolerance proved good. One complete response and three partial responses were observed. For 22 patients, disease stabilized for at least 2 months. Nevertheless, according to the authors, the lack of significant response did not allow recommending paclitaxel in the treatment of paediatric cerebral tumours. The POG also conducted a study of paclitaxel, topotecan, and topotecan-cyclophosphamide in children newly diagnosed with stage IV neuroblastomas.36 One hundred patients were enrolled among whom 33 received paclitaxel 350 mg/m2 intravenously for 24 h every 14–21 days. Objective responses (defined as complete responses + partial responses + mixed responses) were documented in
70 25% of the patients treated with paclitaxel. Twelve children had progressive disease during the paclitaxel up-front therapy. Four patients had grade 3–4 allergic reactions to paclitaxel. In agreement with tumour xenograft experiments,21 topotecan administered alone induced more responses than paclitaxel. Miscellaneous Besides well-designed studies, several papers report single cases or small series of patients treated with paclitaxel. Thus, taxanes alone or in combination with other anticancer agents with has shown activity in patients with neuroblastoma,37 Wilms’ tumours,38–40 multifocal juvenile granulosa cell tumour of the ovary,41 non-Hodgkin’s intestinal lymphoma.42
Why such limited success? Based on these data, no phase III studies have been conducted and there are currently no indications to use taxanes in paediatric oncology. It remains unknown why taxanes have such a low efficacy among children with solid tumours, known to be very sensitive to chemotherapy. Several answers can be given. First, solid tumours in children can have distinct histological origins from those in adults. Lots of adult tumours are carcinomas which are quite rarely seen in children. The efficacy of taxanes may depend on the histological characteristics of the tumours; they may be more efficient in carcinomas such as ovarian, breast, lung, head and neck carcinomas.43–46 Second, phase I studies can be performed in adults who never received or received little chemotherapy. In paediatric oncology, phase I studies are usually performed in patients previously heavily treated. These treatments include high-dose and multi-regimen chemotherapy inducing the selection of highly resistant cancer cells clones among patients with relapsing or refractory disease. Furthermore, previous treatment regimens commonly include anti-tubulin agents such as vincristine, which is used, for instance, in the treatment of nephroblastoma, neuroblastoma, lymphoma, and rhabdomyosarcoma. Resistance to taxanes47 can be related to acquired cross-resistance towards anti-tubulin agents or other anticancer agents. Several mechanisms can explain resistance. Multidrugresistant (MDR) phenotype is frequently encountered. It is mediated by a drug
N. Andre ´, C. Meille efflux pump, the Pgp a 170-kDATP-binding transport protein encoded by the MDR1 gene.47 Besides, changes in the subtypes of tubulin isotypes48 and modifications of microtubule dynamics49 are resistance factors that are specific to anti-tubulin agents. Lastly, resistance can also be mediated by changes in the apoptotic pathways such as increased expression of bcl-2.10 These molecular changes in the tumour may explain the poor preliminary results obtained in paediatric phase I and II trials.
And now? The experimentation of new drugs in paediatric oncology faces several problems.24 One is that only few patients are eligible for phase I trials. Consequently, only a small fraction of the new drugs tested for cancer indications in adults can be evaluated in children. Considering the arrival of new agents with new mechanisms of action, is it rational to further test paclitaxel in a clinical setting given the results obtained so far among children? On the other hand, the knowledge we accumulate from extensive basic research as well as from clinical research in adults raises hopes of new uses of paclitaxel that should not be neglected by paediatric oncologists. Three main advances have been made in the field of taxanes: (A) increased efficacy when used in multidrug-based chemotherapy regimen, (B) metronomic dosing, i.e., a less toxic administration schedule, and (C) development of new taxanes.
Taxanes in association with other anticancer agents Taxanes exhibit synergic toxicity when combined with other anticancer agents.2,43–46 Such associations contain traditional anticancer agents such as platinum compounds, doxorubicin, other anti-tubulin agents, or new agents such as trastuzamab (Herceptin), or gemcitabine (Gemzar). For children, Surico et al.37 Ramanathan38 or Italiano39 suggested that the association of paclitaxel with cisplatin is efficient against highly resistant neuroblastomas and Wilms’ tumours, respectively. These are the first lines of evidence on the interest of combining taxanes with other anticancer agents in paediatric oncology. Multiagent chemotherapy regimens containing taxanes could therefore be evaluated in children in phase I, phase II, or ‘‘up-front’’ trials.
Taxanes in paediatric oncology: And now?
New schedules of administration There is currently no consensus regarding the optimum schedule of administration of taxanes. Hayashi suggested32 that a protracted schedule of frequent repetitive doses might accommodate the phase specificity of the drug, but additional studies are required to determine if this kind of administration of paclitaxel is better than less frequent administration. Recent pre-clinical studies have shown that frequent administration in vivo of low doses of chemotherapeutic drugs (‘‘metronomic’’ dosing) can affect tumour endothelium and inhibit tumour angiogenesis.50 Prolonged exposure to low drug concentrations seems to be the most suitable approach to make the most of the anti-angiogenic potential of taxanes in vitro and in tumour xenograft models.51 Compared with other types of normal cells, activated endothelial cells are more sensitive, or even selectively sensitive, to protracted low-dose chemotherapy.52,53 Thus, paclitaxel is active on endothelial cells at concentrations one thousand times lower than on tumour cells. Furthermore, at low doses, some anticancer agents may have a different mechanism of action. Indeed, Pasquier et al. recently showed that very low doses of paclitaxel paradoxically increased the dynamicity of microtubules.54 Metronomic dosing also reduces significant side effects, even during prolonged chronic treatment, thus creating a potential therapeutic window.10 Thus, despite the lack of clinical data, the experimental anti-angiogenic properties of both paclitaxel and docetaxel provide a basis for novel therapeutic approaches.
71 with respect to subcutaneous administration.56 Furthermore, patients could take these agents at home, saving hospitalization costs and providing increased comfort.
Conclusion So far, clinical trials revealed no indications for the use of taxanes in paediatric oncology. There is a striking difference in the value of taxanes in children compared to those in adults, for whom taxanes represent a major advance in anticancer treatment. As we have shown here, the potential use of paclitaxel in paediatrics has not been fully evaluated. As fundamental research gives us a better understanding of taxane-induced anticancer properties, the anti-angiogenic properties of taxanes or their association with other anticancer agents may studies in paediatric oncology.
Search strategy and selection criteria We identified articles for this review through searches of Pub Med/MEDLINE using the search terms ‘‘taxanes’’ or ‘‘paclitaxel’’ or ‘‘docetaxel’’ and ‘‘children’’, and from the reference lists of relevant articles. Only articles published in English were included. Conference abstracts were excluded.
Conflicts of interest None.
New taxanes
Acknowledgements
The development of new taxanes should also be considered. Several new taxanes are currently studied in clinical trials: BMS 184476, BMS 188797, BMS 275183, IDN 5109/BAY 598862, RPR 109881A, and RPR 116258. All these compounds share the same feature, that is, decreased recognition by Pgp.55 Thus, intracellular concentrations of these taxanes are higher. By overcoming MDR, secondgeneration taxanes show no difference in cytotoxicity against drug-sensitive cell lines compared to drug-resistant cell lines. Moreover, some of the new taxanes, like IDN 5390, appear particularly interesting as they show excellent oral bioavailability.56 Oral IDN 5390 maintained substantial efficacy against human tumour xenografts, including paclitaxel-resistant tumours, without loss of potency
We thank Pr A. Iliadis from the Department of Pharmacokinetics, EA3286, UFR of Pharmacy and Pr J.L. Bernard from the Paediatric Oncology Department, EA3286, UFR of Medicine and ‘‘La Timone’’ Children Hospital for their advice. CM is the recipient of a grant from the Acade ´mie de Me ´decine.
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N. Andre ´, C. Meille 23. Consolini R, Pui CH, Behm FG, Raimondi SC, Campana D. In vitro cytotoxicity of docetaxel in childhood acute leukemias. J Clin Oncol 1998;16:907–13. 24. Houghton PJ, Adamson PC, Blaney S, Fine HA, Gorlick R, Haber M, et al. Testing of new agents in childhood cancer preclinical models: meeting summary. Clin Cancer Res 2002;8:3646–57. 25. Hurwitz CA, Relling MV, Weitman SD, Ravindranath Y, Vietti DR, Strother DR, et al. Phase I trial of paclitaxel in children with refractory solid tumors: a Paediatric Oncology Group Study. J Clin Oncol 1993;11:2324–9. 26. Sonnichsen DS, Hurwitz CA, Pratt CB, Shuster JJ, Relling MV. Saturable pharmacokinetics and paclitaxel pharmacodynamics in children with solid tumors. J Clin Oncol 1994;12:532–8. 27. Woo MH, Relling MV, Sonnichsen DS, Rivera GK, Pratt CB, Pui CH, et al. Phase I targeted systemic exposure study of paclitaxel in children with refractory acute leukemias. Clin Cancer Res 1999;5:543–9. 28. Doz F, Gentet JC, Pein F, Frappaz D, Chastagner P, Moretti S, et al. Phase I trial and pharmacological study of a 3-hour paclitaxel infusion in children with refractory solid tumours: a SFOP study. Br J Cancer 2001;84:604–10. 29. Sparreboom A, Van Zuylen L, Brouwer E, Loss WJ, de Bruijn H, Gelderblom H, et al. Cremophor EL-mediated alteration of paclitaxel distribution in human blood : clinical pharmacokinetic implications. Cancer Res 1999;59:1454–7. 30. Gelderblom H, Verweij J, Nooter K, Sparreboom A. Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer 2001;37: 1590–8. 31. Liu L, Vapiwala N, Munoz LK, Winick NJ, Weitman S, Strauss LC, et al. A phase I study of cranial radiation therapy with concomitant continuous infusion paclitaxel in children with brain tumors. Med Pediatr Oncol 2001;37:390–2. 32. Hayashi RJ, Blaney S, Sullivan J, Weitman S, Vietti T, Bernstein ML. Paediatric Oncology Group Study Phase 1 study of Paclitaxel administered twice weekly to children with refractory solid tumors: a paediatric oncology group study. J Pediatr Hematol Oncol 2003;25:539–42. 33. Blaney SM, Seibel NL, O’Brien M, Reaman GH, Berg SL, Adamson PC, et al. Phase I trial of docetaxel administered as a 1-hour infusion in children with refractory solid tumors: a collaborative paediatric branch, National Cancer Institute and Children’s Cancer Group trial. J Clin Oncol 1997;15: 1538–43. 34. Seibel NL, Blaney SM, O’Brien M, Krailo M, Hutchinson R, Mosher RB, et al. Phase I trial of docetaxel with filgrastim support in paediatric patients with refractory solid tumors: a collaborative Paediatric Oncology Branch, National Cancer Institute and Children’s Cancer Group trial. Clin Cancer Res 1999;5:733–7. 35. Hurwitz CA, Strauss LC, Kepner J, Kretschmar C, Harris MB, Friedman H, et al. Paclitaxel for the treatment of progressive or recurrent childhood brain tumors: a paediatric oncology phase II study. J Pediatr Hematol Oncol 2001;23:277–81. 36. Kretschmar CS, Kletzel M, Murray K, Thorner P, Joshi V, Marcus R, et al. Response to paclitaxel, topotecan, and topotecan-cyclophosphamide in children with untreated disseminated neuroblastoma treated in an upfront phase II investigational window: a paediatric oncology group study. J Clin Oncol 2004;22:4119–26. 37. Surico G, Muggeo P, De Leonardis F, Rigillo N. New paclitaxel–cisplatin based chemotherapy regimen for advanced stage, recurrent, or refractory neuroblastomapreliminary report. Med Pediatr Oncol 2003;40:130–2.
Taxanes in paediatric oncology: And now? 38. Ramanathan RK, Rubin JT, Ohori NP, Belani CP. Dramatic response of adult wilms tumor to paclitaxel and cisplatin. Med Pediatr Oncol 2000;34:296–8. 39. Italiano A, Sirvent N, Michiels JF, Peyrade F, Otto J, Thyss A. Tumour response to paclitaxel in an adult with relapsed nephroblastoma. Lancet Oncol 2005;6:252–3. 40. Woo MH, Gregornik D, Shearer PD, Meyer WH, Relling MV. Pharmacokinetics of paclitaxel in an anephric patient. Cancer Chemother Pharmacol 1999;43:92–6. 41. Erdreich-Epstein A, Monforte HL, Lavey RS, Joshi S, Phillips JG, Villablanca JG. Successful multimodality therapy of recurrent multifocal juvenile granulosa cell tumor of the ovary. J Pediatr Hematol Oncol 2002;24:229–33. 42. Berrak SG, Turkkan E, Canpolat C, Iskit S, Dagli T, Abacioglu U. Partial intestinal obstruction due to childhood refractory non-Hodgkin’s lymphoma, successfully treated with taxol. Eur J Pediatr Surg 2003;13:276–9. 43. Du Bois A, Pfisterer J. Future options for first-line therapy of advanced ovarian cancer. Int J Gynecol Cancer 2005; 15(Suppl 1):42–50. 44. Trudeau M, Sinclair SE, Clemons M. Breast Cancer Disease Site Group. Neoadjuvant taxanes in the treatment of nonmetastatic breast cancer: a systematic review. Cancer Treat Rev 2005;31:283–302. 45. Chu Q, Vincent M, Logan D, Mackay JA, Evans WK. Lung Cancer Disease Site Group of Cancer Care Ontario’s Program in Evidence-based Care. Taxanes as first-line therapy for advanced non-small cell lung cancer: A systematic review and practice guideline. Lung Cancer 2005;50:355–74. 46. Schrijvers D, Vermorken JB. Taxanes in the treatment of head and neck cancer. Curr Opin Oncol 2005;17: 218–24. 47. Dumontet C, Sikic BI. Mechanisms of action of and resistance to antitubulin agents: microtubule dynamics, drug transport, and cell death. J Clin Oncol 1999;17:1061–70.
73 48. Orr GA, Verdier-Pinard P, McDaid H, Horwitz SB. Mechanisms of Taxol resistance related to microtubules. Oncogene 2003;22:7280–95. 49. Goncalves A, Braguer D, Kamath K, Martello L, Briand C, Horwitz S, et al. Resistance to Taxol in lung cancer cells associated with increased microtubule dynamics. Proc Natl Acad Sci U S A 2001;98:11737–42. 50. Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 2000;105:1045–7. 51. Bocci G, Nicolaou KC, Kerbel RS. Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective anti-angiogenic window for various chemotherapeutic drugs. Cancer Res 2002;62: 6938–43. 52. Belotti D, Vergani V, Drudis T, Borsotti P, Pitelli MR, Viale G, et al. The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Cancer Res 1996;2:1843–9. 53. Pasquier E, Carre M, Pourroy B, Camoin L, Rebai O, Briand C, et al. Antiangiogenic activity of paclitaxel is associated with its cytostatic effect, mediated by the initiation but not completion of a mitochondrial apoptotic signaling pathway. Mol Cancer Therap 2004;3:1301–10. 54. Pasquier E, Honore S, Pourroy B, Jordan MA, Lehmann M, Briand C, et al. Antiangiogenic concentrations of paclitaxel induce an increase in microtubule dynamics in endothelial cells but not in cancer cells. Cancer Res 2005;65:2433–40. 55. Ferlini C, Ojima I, Distefano M, Gallo D, Riva A, Morazzoni P, et al. Second generation taxanes: from the natural framework to the challenge of drug resistance. Curr Med Chem Anti-Cancer Agents 2003;3:133–8. 56. Pratesi G, Laccabue D, Lanzi C, Cassinelli G, Supino R, Zucchetti M, et al. IDN 5390: an oral taxane candidate for protracted treatment schedules. Br J Cancer 2003;88: 965–72.
www.elsevierhealth.com/journals/ctrv
CONTROVERSY
Taxanes in paediatric oncology: And now? ´ Nicolas Andre
a,b,*
, Christophe Meille
c
a
Department of Paediatric Oncology, EA3286, UFR of Medicine and ‘‘La Timone’’ Children Hospital, Bd. Jean Moulin, 13885 Marseille, Cedex 5, France b FRE – Centre National de la Recherche Scientifique 2737, UFR of Pharmacy, 13885 Marseille, Cedex 5, France c Department of Pharmacokinetics, EA3286, UFR of Pharmacy, 13885 Marseille Cedex 5, France Received 11 October 2005; accepted 15 December 2005
KEYWORDS
Summary Taxanes are a group of anticancer agents that target microtubules, promote their assembly, and stabilize them. The resulting effects are mitotic blockage and induction of apoptosis, whose mechanism of initiation remains to be fully determined. Among adults, taxanes are one of the most powerful and most commonly used anticancer drugs. They show a wide range of activity in malignancies such as breast, ovarian, and lung cancers. In paediatric oncology, pre-clinical and clinical data are quite limited. Six phase I studies, two phase II, and rare case reports have been published. This review will focus on the paediatric pre-clinical and clinical findings with taxanes. Based on data from the literature, we will try to explain the results and foresee the possible use of taxanes in paediatric oncology. Indeed, three main advances have been made regarding taxanes:
Taxanes; Paclitaxel; Docetaxel; Children; Oncology
(1) Increased efficacy when used in multidrug-based chemotherapy regimen. (2) New administration schedules based on anti-angiogenic properties when given at daily very low doses. (3) Development of new taxanes with decreased recognition by Pgp, the product of the MDR1 gene. Thus, although the initial experience with taxanes in paediatric oncology has been disappointing, it may be too early to leave out taxanes and we should further investigate their use among children with cancer. c 2006 Elsevier Ltd. All rights reserved.
Introduction * Corresponding author. Tel.: +33 04 91 83 56 26; fax: +33 04 91 78 20 24. E-mail address: [email protected] (N. Andre ´).
In the last three decades, the prognosis of children with cancer has been significantly improved. Now-
0305-7372/$ - see front matter c 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2005.12.010
66 adays, 70% of children with cancer can be cured. Chemotherapy plays a key role in the treatment of child malignancies, which are particularly chemo-sensitive. Nevertheless, some cancers such as N-myc amplified neuroblastomas, disseminated rhabdomyosarcomas and metastatic osteosarcomas display a 5 year survival rate of less than 50%. Thus, there is a demand for new drugs to keep improving the survival of children with cancer. Taxanes are among the most commonly used anticancer drugs to emerge in the last decades. They are extracted from given parts of yew trees. Paclitaxel was initially identified in 1971,1 and two taxanes are currently available for clinicians: paclitaxel (Taxol) and docetaxel (Taxotere). Although there are several differences in the pharmacokinetics and pharmacologic actions of the two taxanes, they share action mechanisms. Alone or in combination with other anti-cancer agents, paclitaxel is active against a broad range of tumour types, including breast, ovarian, lung, head, and neck cancers.2,3 The range of taxane activity is growing, with confirmed activity in other malignancies that are refractory to conventional chemotherapy, such as previously treated lymphoma, small cell lung cancers, oesophageal, gastric, endometrial, bladder, and germ cell tumours. Nevertheless, despite initial hope among paediatric oncologists,4 the use of taxanes in paediatric oncology has been disappointing. This review will focus on the paediatric pre-clinical and clinical findings with the taxanes. We will explain these results and foresee the use of taxanes in paediatric oncology (Fig. 1).
Figure 1 Taxanes are anticancer drugs obtained from the yew trees: allies for children with cancer?
N. Andre ´, C. Meille
How do they work? Taxanes belong to the class of anti-tubulin agents, but they act differently than previously described anti-tubulin agents.5 Indeed, taxanes bind the beta subunit of tubulin dimers but instead of destabilizing microtubules, they stabilize microtubules by perturbing their dynamics.5 This action induces bundles of microtubules and abnormal mitosis (Fig. 2A and B).6,7 Taxanes can also trigger apoptosis8 (Fig. 2C) but the way taxanes induce cell death is debated.9,10 Indeed, besides its well-described action on microtubules, paclitaxel has an additional mechanism of action.10 It can trigger the activation of several kinases11 and activate gene expression.12 Lately, taxanes have shown other potential targets than microtubules. Paclitaxel can bind to Bcl-213 and mitochondrial tubulin.14,15 So, it has been accepted that taxanes could target mitochondria to activate apoptosis.16 These different properties may explain why the last decade witnessed the emergence of paclitaxel as one of the most powerful compound agents in adult oncology.
Preclinical testing In vitro, several neuroblastoma cell lines are sensitive to taxanes.17–20 A cytotoxic effect occurred at concentrations similar to those achieved in the plasma of patients treated with these agents in initial clinical trials. Docetaxel proved more potent than paclitaxel.18 The authors concluded that the sensitivity of neuroblastoma cell lines to prolonged incubations or daily repeated administrations of taxanes should be assessed in paediatric phase II studies.18 Nevertheless, when neuroblastoma tumours were grafted to nude mice, taxanes displayed little efficacy, particularly when compared to topotecan.21 Hepatoblastoma cell lines obtained from three children were sensitive to paclitaxel.22 Moreover, when hepatoblastoma cell suspensions were transplanted subcutaneously to NMRI nude mice, paclitaxel was efficient in all three hepatoblastoma tumour grafts. After chemotherapy, tumour volume and alpha-fetoprotein levels were significantly reduced.22 Additionally, the activity of paclitaxel was similar to that observed with cisplatin, which was the most potent compound on these cell lines, suggesting an interesting potential of taxanes for this type of tumour. At concentrations achievable in vivo, docetaxel was tested on 20 samples from children with acute lymphoblastic leukaemia (ALL) and acute myeloid
Taxanes in paediatric oncology: And now?
67
Figure 2 Cellular effects of paclitaxel on the SK-N-SH human neuroblastoma cell line. (A) Immunofluorescence staining of alpha-tubulin shows that paclitaxel induces bundles of microtubules (white arrow) in interphasic cells and pseudo asters (grey arrow) in mitotic cells. (B) Mitotic neuroblastoma cell observed with transmission electron microscopy during paclitaxel incubation. Note mitochondria with dark granules and altered structure corresponding to apoptotic mitochondria. Bar = 0.5 lm. (C) Apoptotic bodies (white arrow) evidenced with DAPI staining of DNA in SK-NSH cell line incubated with paclitaxel.
leukaemia (AML).23 Docetaxel was cytotoxic to ALL and AML cells. Its cytotoxic effect was mediated by the induction of apoptosis. Interestingly, docetaxel was consistently more potent than paclitaxel. Authors concluded these results provided the rationale for clinical trials of docetaxel in patients with acute leukaemia. Pre-clinical studies have also shown that paclitaxel and docetaxel were efficient in killing primitive neuroectodermal tumour, glioblastoma, and teratoma cell lines in vitro.17,20 Thus, taxanes are efficient in vitro in several cell lines derived from paediatric tumours. Nevertheless, in a recent review of pre-clinical testing of new agents in paediatric tumour xenograft models, Houghton and al. did not report studies concerning taxanes.24 Thus information remains quite rare.
Clinical testing Phase I trials In children, 6 phase I trials have determined the maximum tolerated doses (MTD) and dose-limiting
toxicities (DLT) of taxanes by testing different schedules of administration. Four of them studied paclitaxel and two others docetaxel. Data are summarized in Table 1.
Paclitaxel A phase I trial of paclitaxel in children with refractory solid tumours from the Paediatric Oncology Group (POG)25 showed that the recommended dose for phase II trials was 350 mg/m2 when administered as a 24-h infusion every 3 weeks. DLT was neurotoxic and toxicity was not significantly correlated with dosage. In contrast, toxicity correlates better with paclitaxel systemic exposure, evaluated by the area under curve (AUC). The authors attributed this to the saturable distribution and elimination mechanisms of paclitaxel.26 Responses were documented in 4 out of the 31 (13%) children in that study. Among the responses, one complete response was noted in a patient with papillary serous carcinoma. In seven children with refractory leukaemia, a phase I study on escalation targeting a systemic exposure to paclitaxel was performed to integrate the inter-individual pharmacokinetic variability
68 Table 1
N. Andre ´, C. Meille Phase I trials of taxanes in children
Author Anticancer (reference) agent tested
MTD Number Schedule of administration of patients
Limiting toxicity
Response number of CR, PR, SD and histology
Hurwitz25
Paclitaxel
31
24-h infusion/ 21 days
350 mg/m2
Neurological
1 CR (papillary serous carcinoma) 2 PR (rhabdomyosarcoma, hepatocellular carcinoma) 9 SD (3 Ewing tumours, 2 osteosarcomas, 2 synovialosarcoma, 1 glioma, 1 intrathoracic chordoma)
Doz28
Paclitaxel
16
3-h infusion/ 21 days
No
Neurological
0 CR 1 PR (rhabdomyosarcoma) 1 SD (rhabdomyosarcoma)
Woo27
Paclitaxel
7
24-h infusion/ 21 days
target AUC 31– 45 mM h
Mucous
0 CR 1 PR (leukaemia) SD: Not mentioned
Liu31
paclitaxel & radiotherapy
11
24-h infusion times 6 days
4 mg/m2/day
Hayashi32
Paclitaxel
16
3-h infusion twice weekly · 6/28 days
50 mg/m2/ dose
Haematological
Blaney33
Docetaxel
44
1-h infusion/ 21 days
125 mg/m2/ dose
Haematological, 1 CR general (rhabdomyosarcoma) 1 PR (PNET) 4 SD (3 PNET, 1 colon carcinoma)
Siebel34
Docetaxel 17 and filgrastim
1-h infusion/ 21 day 5 lg/kg/day
185 mg/m2/ dose
Dermatologic
2 PR: glioma 0 CR 0 PR 3 SD (2 osteosarcomas, 1 ependymoma)
0 CR 1 PR (colon carcinoma) SD: not mentioned
Abbreviations: CR = complete response, PR = rartial response, SD = stable disease.
along the escalation process.27 AUCs were lower than those expected from phase I studies in children with solid tumours. Mucositis was the DLT exposure limiting toxicity. The efficacy was very low: peripheral blast count did not decrease in two patients, but it declined in five patients three days after the first course. Six out of the seven patients endured a worsening of their leukaemia within 20 days. Only one patient was eligible for a second course. The phase I study conducted by the Socie ´te ´ Franc ¸aise d’Oncologie Pe ´diatrique (SFOP) sought to determine the MTD and the pharmacokinetics of paclitaxel in children with cancer when adminis-
tered in 3-h infusion every 3 weeks.28 Seventeen children with various solid tumours were included. One treatment-related death occurred just after the infusion at the highest dosage, and the investigators did not recommend this schedule of administration. No dose-limiting haematological toxicity was observed. Nevertheless, because of its low aqueous solubility, paclitaxel requires a pharmaceutical vehicle: cremophor EL. It is a purified polyoxyethylated castor oil probably involved in paclitaxel toxicity.28 Thus, it is difficult to discriminate the respective roles of paclitaxel and cremophor EL in the observed toxicity. One partial response was observed in a patient with embryonal
Taxanes in paediatric oncology: And now? rhabdomyosarcoma. Stable disease was observed after 2 courses at 350 mg/m2 in one patient with alveolar rhabdomyosarcoma. Disease progression was observed in the 12 other assessable patients. In the same study, the pharmacokinetics of paclitaxel showed specific characteristics; clearance appeared to decrease as the dosage increased and the maximum concentration and AUC increased more than in proportion to the dose. As in the study of Hurwitz et al.25 these results suggest that paclitaxel pharmacokinetics is non-linear when the drug is administered as a 3-h infusion in children. However, although it has been proposed that paclitaxel’s nonlinear pharmacokinetics is due to saturable distribution and elimination processes,26 recent reports strongly suggest that the non-linearity results from the entrapment of paclitaxel in its vehicle.29,30 This effect makes it difficult to use the clearance as parameter for drug exposure, as the actual exposure to unbound paclitaxel fraction depends on the plasma level of cremophor EL. Another phase I study by Liu and al. investigated the association of radiotherapy with increased paclitaxel dose among 11 children suffering from brain tumours. Paclitaxel was given as a 24-h infusion 7 days a week.31 These authors showed the feasibility of such an association and recommended that paclitaxel should be given at doses of 4 mg/m2 /day for 6 weeks. The dose-limiting toxicity was severe constipation. The underlying mechanism suspected is autonomic neuropathy. In this trial, two patients achieved partial remissions. Lastly, Hayashi and al.32 reported the results of a phase I trial from the POG in which paclitaxel was administered as a 3-h infusion, twice weekly. Sixteen assessable patients were enrolled. In this case study, neutropenia was the DLT dose-limiting toxicity. With this schedule, the MTD of paclitaxel was 50 mg/m2/dose. No response was observed. Docetaxel In 1997, the Children’s Cancer Group (CCG) published the results of the first phase I trial of docetaxel. It was administered as a 1-h infusion every three weeks in children with refractory solid tumours.33 Forty-four children received 103 courses of docetaxel. The MTD according to previous treatment (heavy vs. less heavy) were respectively 65 and 125 mg/m2. A complete response was observed in a patient with rhabdomyosarcoma. A partial response and two minimal responses were observed in three patients with peripheral primitive neuroectodermal tumour. Three out of the four responding patients were treated at doses superior or equal to 100 mg/m2. With this schedule of administration, the DLT was neutropenia, and neuropathy
69 was uncommon. The toxicity profile in children is similar to the one in adults. As neutropenia was the DLT of docetaxel in children, a collaborative Paediatric Oncology Branch, National Cancer Institute and Children’s Cancer Group Trial set up another phase I trial of docetaxel. It was administered as an intravenous infusion for 1 h every 21 days with filgrastim (G-CSF 5 lg/ kg/day) support.34 Seventeen patients were included. DLT were generalized erythematous desquamating skin rash and myalgias. Filgrastim support proved efficient, as neutropenia was not dose limiting anymore and allowed an increase in MTD (185 mg/m2), which is 50% higher than the MTD of docetaxel without growth factor. Only one minor response was observed in a patient with a colon cancer. Nevertheless, as 9 patients out of the 17 patients included had osteosarcomas, data about potential efficacy may not be representative in this study. Thus, from phase I trials of taxanes, we learned that – Several administration schedules can be performed: a 1-h or 24-h infusion every three weeks, a 3-h infusion twice weekly, and a continuous infusion for 6 days – Administrations can be safely repeated – Limiting toxicity depends on the schedule of administration – Responses and stabilization were observed in respectively 5% and 15% of the patients with various types of cancer.
Phase II trials A phase II study was initiated by the Paediatric Oncology Group (POG) in children with progressing or relapsing brain tumours.35 Paclitaxel was administered according to the recommendations of the phase I trial from Hurwitz et al.25 Seventy-three patients have been included. Tolerance proved good. One complete response and three partial responses were observed. For 22 patients, disease stabilized for at least 2 months. Nevertheless, according to the authors, the lack of significant response did not allow recommending paclitaxel in the treatment of paediatric cerebral tumours. The POG also conducted a study of paclitaxel, topotecan, and topotecan-cyclophosphamide in children newly diagnosed with stage IV neuroblastomas.36 One hundred patients were enrolled among whom 33 received paclitaxel 350 mg/m2 intravenously for 24 h every 14–21 days. Objective responses (defined as complete responses + partial responses + mixed responses) were documented in
70 25% of the patients treated with paclitaxel. Twelve children had progressive disease during the paclitaxel up-front therapy. Four patients had grade 3–4 allergic reactions to paclitaxel. In agreement with tumour xenograft experiments,21 topotecan administered alone induced more responses than paclitaxel. Miscellaneous Besides well-designed studies, several papers report single cases or small series of patients treated with paclitaxel. Thus, taxanes alone or in combination with other anticancer agents with has shown activity in patients with neuroblastoma,37 Wilms’ tumours,38–40 multifocal juvenile granulosa cell tumour of the ovary,41 non-Hodgkin’s intestinal lymphoma.42
Why such limited success? Based on these data, no phase III studies have been conducted and there are currently no indications to use taxanes in paediatric oncology. It remains unknown why taxanes have such a low efficacy among children with solid tumours, known to be very sensitive to chemotherapy. Several answers can be given. First, solid tumours in children can have distinct histological origins from those in adults. Lots of adult tumours are carcinomas which are quite rarely seen in children. The efficacy of taxanes may depend on the histological characteristics of the tumours; they may be more efficient in carcinomas such as ovarian, breast, lung, head and neck carcinomas.43–46 Second, phase I studies can be performed in adults who never received or received little chemotherapy. In paediatric oncology, phase I studies are usually performed in patients previously heavily treated. These treatments include high-dose and multi-regimen chemotherapy inducing the selection of highly resistant cancer cells clones among patients with relapsing or refractory disease. Furthermore, previous treatment regimens commonly include anti-tubulin agents such as vincristine, which is used, for instance, in the treatment of nephroblastoma, neuroblastoma, lymphoma, and rhabdomyosarcoma. Resistance to taxanes47 can be related to acquired cross-resistance towards anti-tubulin agents or other anticancer agents. Several mechanisms can explain resistance. Multidrugresistant (MDR) phenotype is frequently encountered. It is mediated by a drug
N. Andre ´, C. Meille efflux pump, the Pgp a 170-kDATP-binding transport protein encoded by the MDR1 gene.47 Besides, changes in the subtypes of tubulin isotypes48 and modifications of microtubule dynamics49 are resistance factors that are specific to anti-tubulin agents. Lastly, resistance can also be mediated by changes in the apoptotic pathways such as increased expression of bcl-2.10 These molecular changes in the tumour may explain the poor preliminary results obtained in paediatric phase I and II trials.
And now? The experimentation of new drugs in paediatric oncology faces several problems.24 One is that only few patients are eligible for phase I trials. Consequently, only a small fraction of the new drugs tested for cancer indications in adults can be evaluated in children. Considering the arrival of new agents with new mechanisms of action, is it rational to further test paclitaxel in a clinical setting given the results obtained so far among children? On the other hand, the knowledge we accumulate from extensive basic research as well as from clinical research in adults raises hopes of new uses of paclitaxel that should not be neglected by paediatric oncologists. Three main advances have been made in the field of taxanes: (A) increased efficacy when used in multidrug-based chemotherapy regimen, (B) metronomic dosing, i.e., a less toxic administration schedule, and (C) development of new taxanes.
Taxanes in association with other anticancer agents Taxanes exhibit synergic toxicity when combined with other anticancer agents.2,43–46 Such associations contain traditional anticancer agents such as platinum compounds, doxorubicin, other anti-tubulin agents, or new agents such as trastuzamab (Herceptin), or gemcitabine (Gemzar). For children, Surico et al.37 Ramanathan38 or Italiano39 suggested that the association of paclitaxel with cisplatin is efficient against highly resistant neuroblastomas and Wilms’ tumours, respectively. These are the first lines of evidence on the interest of combining taxanes with other anticancer agents in paediatric oncology. Multiagent chemotherapy regimens containing taxanes could therefore be evaluated in children in phase I, phase II, or ‘‘up-front’’ trials.
Taxanes in paediatric oncology: And now?
New schedules of administration There is currently no consensus regarding the optimum schedule of administration of taxanes. Hayashi suggested32 that a protracted schedule of frequent repetitive doses might accommodate the phase specificity of the drug, but additional studies are required to determine if this kind of administration of paclitaxel is better than less frequent administration. Recent pre-clinical studies have shown that frequent administration in vivo of low doses of chemotherapeutic drugs (‘‘metronomic’’ dosing) can affect tumour endothelium and inhibit tumour angiogenesis.50 Prolonged exposure to low drug concentrations seems to be the most suitable approach to make the most of the anti-angiogenic potential of taxanes in vitro and in tumour xenograft models.51 Compared with other types of normal cells, activated endothelial cells are more sensitive, or even selectively sensitive, to protracted low-dose chemotherapy.52,53 Thus, paclitaxel is active on endothelial cells at concentrations one thousand times lower than on tumour cells. Furthermore, at low doses, some anticancer agents may have a different mechanism of action. Indeed, Pasquier et al. recently showed that very low doses of paclitaxel paradoxically increased the dynamicity of microtubules.54 Metronomic dosing also reduces significant side effects, even during prolonged chronic treatment, thus creating a potential therapeutic window.10 Thus, despite the lack of clinical data, the experimental anti-angiogenic properties of both paclitaxel and docetaxel provide a basis for novel therapeutic approaches.
71 with respect to subcutaneous administration.56 Furthermore, patients could take these agents at home, saving hospitalization costs and providing increased comfort.
Conclusion So far, clinical trials revealed no indications for the use of taxanes in paediatric oncology. There is a striking difference in the value of taxanes in children compared to those in adults, for whom taxanes represent a major advance in anticancer treatment. As we have shown here, the potential use of paclitaxel in paediatrics has not been fully evaluated. As fundamental research gives us a better understanding of taxane-induced anticancer properties, the anti-angiogenic properties of taxanes or their association with other anticancer agents may studies in paediatric oncology.
Search strategy and selection criteria We identified articles for this review through searches of Pub Med/MEDLINE using the search terms ‘‘taxanes’’ or ‘‘paclitaxel’’ or ‘‘docetaxel’’ and ‘‘children’’, and from the reference lists of relevant articles. Only articles published in English were included. Conference abstracts were excluded.
Conflicts of interest None.
New taxanes
Acknowledgements
The development of new taxanes should also be considered. Several new taxanes are currently studied in clinical trials: BMS 184476, BMS 188797, BMS 275183, IDN 5109/BAY 598862, RPR 109881A, and RPR 116258. All these compounds share the same feature, that is, decreased recognition by Pgp.55 Thus, intracellular concentrations of these taxanes are higher. By overcoming MDR, secondgeneration taxanes show no difference in cytotoxicity against drug-sensitive cell lines compared to drug-resistant cell lines. Moreover, some of the new taxanes, like IDN 5390, appear particularly interesting as they show excellent oral bioavailability.56 Oral IDN 5390 maintained substantial efficacy against human tumour xenografts, including paclitaxel-resistant tumours, without loss of potency
We thank Pr A. Iliadis from the Department of Pharmacokinetics, EA3286, UFR of Pharmacy and Pr J.L. Bernard from the Paediatric Oncology Department, EA3286, UFR of Medicine and ‘‘La Timone’’ Children Hospital for their advice. CM is the recipient of a grant from the Acade ´mie de Me ´decine.
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