Complications of chemotherapy in neuro-oncology

Handbook of Clinical Neurology, Vol. 105 (3rd series) Neuro-oncology W. Grisold and R. Soffietti, Editors # 2012 Elsevier B.V. All rights reserved

Chapter 57

Complications of chemotherapy in neuro-oncology CHRISTINE MAROSI* Clinical Division of Oncology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria

INTRODUCTION Until recently, the use of chemotherapy in patients with primary brain tumors was a controversial issue. In fact, the debates lasted until the publication of the pivotal study with concomitant and adjuvant chemotherapy with temozolomide, the study from the European Organization for Research and Treatment of Cancer (EORTC 26981/NCIC3), which showed a significant survival benefit without severe loss in quality of life (Stupp et al., 2005). The reservation against the use of chemotherapy in patients with malignant gliomas, the most frequent group of primary brain tumors, was the result of decades of vain effort, using all possible chemotherapeutic drugs, in all thinkable combinations, and by nearly all conceivable application routes and schedules, without clear benefit for the patients, but not without sideeffects, and therefore motivated by the medical principle of primum non nocere. The basic condition for an effective systemic drug therapy against malignant glioma is that the drug is able to cross the blood–brain barrier (BBB). The BBB is a highly complex structure composed by astroglia with tight junctions, a thicker basal lamina with a special composition, and highly specialized endothelia that express efflux pumps and are equipped with an electrical barrier, formed mainly by the protein occludin, all working together to ensure the protection of the inner milieu in the central nervous system (Quencer and Neuwelt, 2002; Neuwelt, 2004; Doolittle et al., 2007). Drugs crossing the BBB have to be nonpolar, small molecules with a molecular weight below 500 Da, to bear no electrical charge, or to be able to use active transport mechanisms, as the BBB is functional in the peripheral growing areas of glioblastoma multiforme (GBM). The requirements for passing the BBB are not

met by the majority of the antineoplastic drugs available, which are mainly water-soluble molecules. However, there is still the brain–tumor barrier to overcome, additionally ‘defended’ by the increased blood flow draining the gliomas and also by the increased intratumoral pressure. Therefore, the spectrum of drugs used in neuro-oncology is narrower than that of cytotoxic drugs available for the treatment of systemic cancer, and defined by the ability to permeate the target. This prerequisite of liposolubility is best achieved by a group of drugs named alkylating agents, which are historically among the first cytotoxic drugs to have been used since the early 1950s. An alkyl is a free radical containing only carbon and hydrogen atoms arranged in a chain. Their general formula is CnH2nþ 1. In medicine and biology, the most prominent use of alkylating agents is the transfer of a methyl group to DNA. Alkylating agents stop tumor growth by crosslinking guanine nucleobases in DNA double-helix strands. This makes the strands unable to uncoil and separate for DNA replication, and thus results in mismatch, single-strand and double-strand breaks, leading to apoptosis, cell death, and resulting in tumor growth arrest. The activity of alkylating agents is cell-cycle independent, although it is more pronounced in rapidly dividing cells. Some alkylating agents are prodrugs, requiring hepatic activation to be converted into the active form; others act directly. Their ability to stop rapidly growing tissues was discovered as a sideeffect of chemical weapons and has been exploited in combination cancer chemotherapies since the 1960s (Halnan, 1999). A dozen alkylating agents, in particular cyclophosphamide, have been used extensively against all tumors, such as breast cancer, lung cancer, gynecological , and sarcomas, mostly in combination with antimetabolites and anthracyclines during the late

*Correspondence to: Christine Marosi, MD, Clinical Division of Oncology, Department of Internal Medicine I, Medical University of Vienna, Wa¨hringer Gu¨rtel 18-20, A – 1090 Vienna, Austria. Tel: þ 43 1 40 400 4429, Fax: þ 43 1 40 400 4451, E-mail: christine. [email protected]

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1960s to the 1990s, until their displacement into secondline or salvage regimens by more modern (i.e., more effective and less toxic) drugs or targeted therapies. In neuro-oncology however, alkylating agents still constitute the backbone of the chemotherapeutic drugs actually in use: ● ● ● ●

Nitrosoureas: BCNU (carmustine), ACNU (nimustine), or CCNU (lomustine) Procarbazine Triazenes: dacarbazine, fotemustine Imidazotetrazines: temozolomide (TMZ).

Other drugs used in neuro-oncology include the alkylating agent-like acting platinum compounds, cisplatin and carboplatin, which are sometimes used in low doses in combination with alkylating agents; the topoisomerase inhibitors derived from camptothecins, irinotecan and, for brain metastases, topotecan; and the podophyllum toxins, etoposide and VM26, pegylated and/or liposomal anthracyclines; and, although it does not penetrate the BBB, the vinca alkaloid vincristine. Targeted therapies, such as tyrosine kinase inhibitors, antibodies directed against membrane-bound receptor molecules, are being used increasingly; their effects and side-effects are reviewed in another chapter. Of note, this chapter focuses on the side-effects and toxicity of the drugs; their efficacy and their potential to prolong survival of patients with brain tumors is the subject of another chapter.

SIDE-EFFECTS OFALKYLATING AGENTS All alkylating agents share a common molecular mechanism of action, which is by nature cytotoxic, mutagenic, and carcinogenic. They differ greatly in their pharmakokinetic features, liposolubility, alkylation sites on DNA, and chemical reactivity, and thus also in the pattern of observed toxicities in clinical use (Yung et al., 2000; Fazeny-Dorner et al., 2003a, b; Piribauer et al., 2003; Brandes et al., 2004a, c, 2006a; Stupp et al., 2005). The effectiveness of alkylating chemotherapy in tumors of glial origin depends on the DNA repair capacity of the individual tumor – more precisely on the intracellular presence of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). The promoter of the gene encoding for MGMT may be silenced by epigenetic methylation; in this case, the tumor responds to alkylating therapy (Esteller et al., 2000; Hegi et al., 2005; Martinez et al., 2007). At the time of writing, it has become clear that prolonged exposure to alkylating drugs does not succeed in depleting MGMT in tumor cells and may therefore produce a response in patients whose tumor cells have an unmethylated MGMT promoter sequence (Reference

Marc. Gilbert et al, ASCO 2011: Trial 0525, oral presentation). Data from a small German study with increased dose intensity of alkylating agents did not support the hypothesis that this regimen was able to produce MGMT depletion in unmethylated tumors, and neither have data from other studies supported this hypothesis so far (Stupp et al., 2005, 2007; Herrlinger et al., 2006). So far, all patients with malignant gliomas are treated with alkylating agents – usually TMZ – knowing that a high proportion of these patients (approximately 60% of those with GBM, a lower proportion in patients with less malignant gliomas) will not respond to this therapy, but will nevertheless suffer the potential side-effects.

Myelosuppression A common feature is myelosuppression, described as a marked to moderate toxicity on white blood cells and platelets, usually with less impact on red blood cells. With nitrosoureas, the onset of myelosuppression is delayed to 4–6 weeks after administration of the drug, preventing therapy intervals shorter than 6–8 weeks. This extraordinary feature of nitrosoureas is undeniably convenient. It allows outpatient treatment with ‘comfortable’ intervals for the patient and the treating physician, who can easily control the swallowing of the medication by the patient. On the other hand, the long treatment intervals bear the inherent disadvantage that many complications can occur between clinic visits. In rare individual patients, the grade of myelotoxicity may be severe, and aplastic anemia and secondary leukemias have been observed in some patients.

Induction of secondary cancer The mutational spectra of alkylating agents on mammalian cells is distinct from that induced in bacterial cells, reflecting the different codon usage by , and differences in DNA repair and replication enzymes. Mutations are induced by busulfan, chlorambucil, cyclophosphamide, dacarbazine, mechlorethamine, melphalan, mitomycin C, nitrosoureas, and thiotepa (Sanderson and Shield, 1996). Although dose-dependent, the relationship is not always linear. The molarities at which alkylating agents induce cell killing and mutations vary over three orders of magnitude. The mutagenic efficiency of alkylating agents also varies, with some agents inducing three times more mutations for equivalent cell killing. The induction of micronuclei, sister chromatid exchanges, or chromosome aberrations is variable, but has been observed for numerous alkylating agents, namely cyclophosphamide, melphalan, and triethylenemelamine. There is insufficient information to determine whether any synergistic effects of alkylating agents used in combination will influence the cytotoxic and mutagenic damage

COMPLICATIONS OF CHEMOTHERAPY IN NEURO-ONCOLOGY equally. However, there are numerous reports of secondary leukemias following the treatment of gliomas, which are the earliest occurring secondary malignancies observed in time (Cohen et al., 1976; Robustelli della Cuna et al., 1982; Genot et al., 1983; Rosner, 1983; Kempin et al., 1984; Pedersen-Bjergaard et al., 1985; Preussmann, 1986; Perry et al., 1998; Gill et al., 2007; Izaki et al., 2007). After the atomic bombs dropped on Hiroshima and Nagasaki, the incidence of leukemia among survivors peaked 5–10 years after exposure, followed by an increased rate of solid tumors starting 10–15 years after exposure and increasing for up to 30 years after radiation exposure (Yasui and Tahara, 2000; Matsuo et al., 2005). After treatment with radiation or alkylating agents, the delay between exposure and clinical occurrence of secondary malignancy seems to be shorter than in the A-bomb survivor population. Analysis of the secondary cancer rate in children treated for Ewing’s sarcoma showed that leukemias occurred from 1.5 to 8 years after treatment, whereas solid tumors were found 7–11 years after radiotherapy (Kodym, 2002). In a survey of more than 9000 survivors of childhood cancer, Tucker et al. (1987) found secondary leukemias in 22 individuals, compared with 1.5 expected based on general population rates. Alkylating agents increased the relative risk of secondary leukemia by 4.8, with a strong dose– response relationship (Tucker et al., 1987). The secondary leukemias bear characteristic chromosomal aberrations involving chromosomes 5 and 7, and respond poorly to therapy (Neugut et al., 1990). In December 2007, Schering Plough reported that after a postmarketing experience of more than 240 000 subjects treated with TMZ, the risk of developing myelodysplastic syndrome/myelodysplasia was estimated as 3.7 per 100 000, and the risk of leukemia was 7 per 100 000 (Schering Plough Investigator brochure SCH 52365, Temozolomide, December 2007, p. 192).

Impact on fertility Treatment with alkylating agents may cause loss of fertility in both sexes and premature menopause in women to a greater extent than other cytotoxic drugs (Byrne et al., 1992; Chiarelli et al., 1999; Aubard et al., 2000; von der Weid, 2008). In women the menstrual cycle can be greatly affected during and for several months after chemotherapy, or even indefinitely, and men may experience erectile dysfunction and other sexual problems to a variable degree. Both sexes need to practise active contraception during and for 2–3 months after chemotherapy. These issues should be actively addressed by the treating oncologist, and patients should be encouraged to ask questions and seek professional counseling.

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Pulmonary fibrosis Pulmonary fibrosis has been observed after prolonged application of nitrosoureas, in particular with BCNU after exceeding a cumulative dose of 1000 mg/m2. This toxicity may be more common in children than in adult patients (O’Driscoll et al., 1995; Mertens et al., 2002). Symptoms of an alveolar–interstitial pneumonitis develop progressively, often years after the treatment. During the acute phase, severe pulmonary fibrosis with prominent hyperplasia of alveolar macrophages and type II pneumocytes may be seen. Lung function tests show a restrictive pattern. In long-term surviving children, pulmonary toxicity was the cause of death in 47% (Holoye et al., 1976; Lieberman et al., 1980; Fauroux et al., 1994; O’Driscoll et al., 1995; Shen et al., 2004). After BCNU treatment, a high rate of symptomatic restrictive pulmonary disease was observed in the German–Austrian Glioma trial, reaching up to 12% per year, with 4% of deaths due to pulmonary fibrosis. This prompted the executive committee of the NOA-1 trial to substitute BCNU with ACNU, which had shown no pulmonary toxicity in more than 100 patients with glioma whose pulmonary function had been closely monitored (Weller et al., 2003). In fact, in the NOA-1 trial, no pulmonary toxicity recorded, despite survival reaching the longest duration in patients with malignant gliomas published so far.

Nausea and vomiting Induction of nausea and vomiting after the administration of alkylating agents was a very common and burdensome side-effect of these drugs. Most of them are quoted in the median to mild emetogenic category of cytotoxic drugs. Nausea and vomiting have usually been preventable, and thus manageable, since the availability of potent antiemetic drugs, either serotonin antagonists or tachykinin receptor antagonists, which can be administered before the onset of chemotherapy.

TOXICITIES OF THE DRUGS USED MOST FREQUENTLY IN NEURO-ONCOLOGY Table 57.1 gives an overview of the toxicities of the cytotoxic regimens used for patients with high-grade gliomas as first-line therapy (Levin et al., 2000; Grossman et al., 2003; Fazeny-Dorner et al., 2003b; Piribauer et al., 2003; Weller et al., 2003; Stupp et al., 2005); Table 57.2 shows the toxicities of regimens used in patients with recurrent tumors (Yung et al., 2000; Brandes et al., 2004a, b, c; Schmidt et al., 2006; Tang et al., 2006; Chamberlain et al., 2008); and Table 57.3 summarizes the toxicities encountered with TMZ in different schedules.

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Table 57.1 Toxicity of first-line chemotherapy regimens FazenyDorner et al., 2003b

Stupp et al., 2005 RT

No. of patients

F/D

284 IþII

149 IþII 24 22 12 7 24 – – –

286 IþII 27 5 1

IIIþIV 0 0 0

1 1 21 5

0 2 14 <1

2 38 9

12 7 13 4

5 3

<1 <1

12 28

3 2

IIIþIV 1 7 7

0 25

Grossman et al., 2003 CCNU

IIIþIV 1 7 1 21 7 1 – – 1 0

BCNU

IþII 8 14

IIIþIV 5 6

19

7

0

0

0 7

0 3

110 IþII, NR

MRC, 2001 PCV

IIIþ IV 1 26 26 32 5

2

335 IþII 21.8 37.5

IIIþIV 1.3 7.4

11.8

6.6

11.3 41.8

0.5 24.8

Levin et al., 2000

Weller et al., 2003

PCV

PCVDFMO

ACNU þ VM26

ACNUþ Ara C

138 IIIþIV 4.3 20.7 17.6

134 IIIþIV 6.6 17.6 22.9

148 IIIþIV 2* 17*

134 2* 41*

34.4 1.4 1.5

11* 7

41* 4

2*

2*

5.7 1.5 0.7

Values are percentages. *toxicities in % per cycle. ACNU, nimustine; adj, adjuvant; Ara C, cytosine arabinoside; conc, concomitant; DFMO, difluoromethylornithine; F/D, Fotemustine/Dacarbacine; MRC, Medical Research Council; NR, not reported; PCV, procarbazine, CCNU, and vincristine; RT, radiotherapy; TMZ, temozolomide; VM-26, Teniposide.

C. MAROSI

Anemia Leukopenia Granulocytopenia Lymphopenia Thrombocytopenia Infection Fatigue Other constitutional Rash Nausea and vomiting

TMZ conc þ adj

Piribauer et al., 2003

Table 57.2 Toxicity of chemotherapy regimens in patients with recurrent malignant gliomas

Anemia Leukopenia Neutropenia Lymphopenia Thrombocytopenia Infection Fatigue Rash Constitutional other Nausea and vomiting Pulmonary Hepatic Constipation Diarrhea Neurological

Brandes et al., 2004c

Schmidt et al., 2006

BCNU

PCV

PCV

40 IþII 5

IIIþIV 5

37 IþII 16

IIIþIV 0

17

13.8

45.9

16.2

36

29

42.4

8

0

1.7

5.4

2.7

8.6 5 10

1.7 8.6 5

24.3 0 16.2

5.4 2.7 11

86 IþII 2.3 57

TMZ

IIIþIV 2.4 15

29

17.4

8

9.3

5 (allergy) 16.3

9.3

Chamberlain et al., 2008

Brandes et al., 2004b

PCZ

CPT11

BCNU þ CPT11

Tamoxifen þ carboplatin

110

22 AO IþII 0

IIIþIV 0

42 IþII 7

IIIþIV 0

19

19

26.2

2.4

27 IþII 52 49 23

0

52

3

60 19

19 0

49

0

34

0

Yung et al., 2000

110 IþII 3 2 4

IIIþIV 0 2 5

8 1 34 12 47 2

4 0 4

1 0 3

10 0 3 0

4 1 25 15

5 0 4 1

4 1 0

38 2

4 0 1

9.5 41

46 29.7

2.7

43*

Values are percentages. *polyneuropathies. PCV, procarbazine, CCNU, and vincristine; TMZ, temozolomide; BCNU, carmustine; CPT11: irinotecan.

14

19

28.6 19

9.5 2.4

69

7

Tang et al., 2006

41*

IIIþIV 0 0 0

COMPLICATIONS OF CHEMOTHERAPY IN NEURO-ONCOLOGY

No. of patients

Brandes et al., 2004a

877

Table 57.3 Side-effects of temozolomide in different regimens Stupp et al., 2005 TMZ þ RT þ conc

RT

No. of patients Anemia Leukopenia Granulocytopenia Lymphopenia Thrombocytopenia infection Fatigue Other constitutional Rash Nausea and vomiting Constipation Transaminases Lung

Yung et al., 2000

Wick et al., 2007

Brandes et al., 2006b

Perry et al., 2008*

Kong et al., 2006

TMZ 7/14

TMZ 21/28

TMZ 28/28

TMZ TMZ metronomic ‘Tegwondo’

90 IþII 25 26.6 13.3 27.5 11.7

12 IIIþIV 0 0 0 0 0

TMZ adj

TMZ conc þ adj

TMZ 5/28

223 IþII

284 IþII

IIIþIV 1 7 7

110 IþII 3 2 4

286 IþII 27 5 1

287 IIIþIV IþII IIIþIV 0 51 <1 0 27 3 0 14 4

1 1 21 5

0 2 14 <1

8 1 26 7

3 3 7 2

2 25 4

11 5 6 2

2 38 9

12 7 13 4

8 1 34 12

5 3

<1 <1

9 13

1 <1

5 18

2 1

12 28

3 2

1.7 3

5.7 16.2

-

0

4

0 6

2

47 2

1 0

24 18

3 3

5.7

-

3 0 0

0 0 0

IIIþIV 2 5 4

90 IIIþIV IþII 0 2 5 7.6 1.6 10 5.9 0 3 0

IIIþIV

1.2 1.8 10.4

33 IþII 18

IIIþIV 3

17

13.8

36 12{ (opp)

29 3{

Strick, pers. comm

IIIþIV 0.8 4.2 5.8 21.6 5

25.5

1.6

27 IþII 1 7 0 2 4 2 11 0

IIIþIV 1 1 1 21 1 0 0 0

Values are percentages. *Preliminary data from Perry et al. (2010). 5/28: TMZ 200 mg/m2, days 1–5, repeated every 28 days; 7/14: TMZ 150 mg/m2, days 1–7, repeated every 14 days; 21/28: TMZ 75 mg/m2, days 1–21, repeated every 28 days; concomitant TMZ: 75 mg/m2, days 1–42. 28/28: TMZ 50 mg/ m2, days 1–28, repeated every 28 days; Tegwondo: ‘Temodal on working days’ 100 mg/m2, days 1–5, Monday to Friday, repeated every week. adj, adjuvant; conc, concomitant; RT, radiotherapy; TMZ, temozolomide.

COMPLICATIONS OF CHEMOTHERAPY IN NEURO-ONCOLOGY

ACNU, BCNU, and CCNU ACNU (nimustine), BCNU (carmustine), and CCNU (lomustine) are nitrosourea drugs that have been used for the treatment of brain tumors for more than 40 years. Their most prominent side-effect is the delayed myelosuppression, with the nadir occurring 5–6 weeks after drug administration. This long delay to the occurrence of the dose-limiting side-effects of leukocytopenia and thrombocytopenia demands special attention for the controls, and complicates the use of drug combinations. In combination with VM-26, treatment with ACNU induced the longest period of median survival duration ever reported in patients with newly diagnosed GBM in the NOA-1 trial, with 4–5% of patients surviving beyond 5 years (Weller et al., 2003). In a survey of nitrosourea efficacy in high-grade glioma, summarizing 504 cohorts with more than 24 000 patients, Wolff et al. (2008) calculated that the greatest survival gain was achieved with ACNU (8.9 months), followed by CCNU (5.3 months) and fotemustine (2.0 months, but only three cohorts), whereas BCNU provided no survival gain (Wolff et al., 2008). The occurrence of pulmonary toxicity with potential fatal pulmonary fibrosis should be kept in mind; it is most pronounced for BCNU, less for ACNU and CCNU.

Fotemustine Fotemustine (diethyl-1-(3-(2-chloroethyl)-3-nitrosoureido)ethylphosphonate) is a nitrosourea compound with enhanced lipophilia and therefore favorable tissue distribution in cerebral tumor lesions. Fotemustine in solution requires protection from light. The nadir of myelosuppression occurs after 3 weeks, facilitating combination regimens. So far, there have been no reports of pulmonary toxicity (Frenay et al., 1991, 2000; Fazeny-Dorner et al., 2003a, b).

Procarbazine Procarbazine (p-toluoamide, Natulan, or Benzamide) is a prodrug that requires metabolic activation by cytochrome P450 in the liver or by reaction with molecular oxygen. It is not active in hypoxic milieu (Rutishauser and Bollag, 1967). Procarbazine and its metabolites are highly reactive molecules. Their metabolism can follow several pathways, ending with methyl radicals, methane, alcohol, aldehyde, and acid (Baggiolini et al., 1965). Thus, many drug interactions can occur with procarbazine, including enzyme induction of antiepileptic drugs and many other drugs metabolized by the cytochrome P450 system. Some 25–75% of procarbazine is excreted by the urinary tract.

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From in vitro and animal experiments, mutagenic, carcinogenic, and sterilizing side-effects of procarbazine have been well documented. The LD50 in mice is 700 mg/kg and in rats 1400 mg/kg after single-dose exposure, both more than 100 times higher than the doses used in humans. In humans, the dose-limiting toxicity is myelosuppression, mostly granulocytopenia with the risk of neutropenic fever, thrombocytopenia, nausea and vomiting, and allergic reactions. For decades, procarbazine has been widely used, mainly for the treatment of Hodgkin’s disease, malignant lymphomas, small-cell lung cancer, and brain tumors. In addition, procarbazine may cause influenzalike symptoms, depression, difficulty sleeping or nightmares in 10–30% of patients treated. More rarely, it can interact with alcohol, certain other drugs, and some foods, mainly ‘tyramine’-containing foods such as mature cheeses, yeast or meat extracts, smoked sausage, over-ripe fruit, alcoholic beverages and nonalcoholic beers, all foods that have been fermented, pickled, smoked, ‘hung’, or ‘matured’. In a multicenter randomized study of patients with recurrent glioblastoma, procarbazine was compared with TMZ (Yung et al., 2000). The proportion of patients who were free from progression 6 months after the start of therapy was 8% for PCZ and 21% for TMZ. Of note, in this trial the patients’ quality of life (QoL) was recorded prospectively; QoL was stable or increased in patients treated with TMZ, but decreased in all categories for patients treated with procarbazine (Yung et al., 2000; Macdonald et al., 2005).

PCV PCV is a combination regimen of procarbazine, CCNU, and vincristine, used widely for the treatment of gliomas following publication of a randomized trial conducted by the Northern California Oncology Group, which compared PCV and BCNU as adjuvant treatment in patients with GBM and anaplastic astrocytoma (AA) after radiation therapy. In this trial, patients with AA survived for a median of 82 weeks with BCNU and for 157 weeks with PCV. Procarbazine, CCNU, and vincristine are administered in various regimens, two of which are: ● ● ●

Procarbazine 100 mg/m2 orally on days 1–10 or 60 mg/m2 orally on days 8–21 CCNU 100 mg/m2 orally on day 1 or 110 mg/m2 orally on day 1 Vincristine 1.5 mg/m2 intravenously on day 1 or 1.4 mg/m2 intravenously on days 8 and 29.

The duration of a cycle is 42 days (6 weeks). The sideeffects are the cumulative adverse effects as observed

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with PCZ and CCNU, and distal small-fiber neuropathy, mainly sensory neuropathy of fingers and feet due to vincristine, affecting 40–50% of patients after a cumulative dose of 8 mg vincristine in adults (Windebank and Grisold, 2008), and occasionally abdominal cramps and pain. In 1999, Prados et al. analysed the Radiation Therapy Oncology Group database to validate the effects of PCV on survival in patients with AA and found no survival advantage in comparison with BCNU. In 2007, Taphoorn et al. evaluated health-related QoL prospectively in 368 patients with anaplastic oligodendrogliomas treated either by radiotherapy or with PCV. They found that loss of appetite and drowsiness were aggravated by PCV in comparison with irradiation, but that there were no differences in the two arms on long-term follow-up.

Vincristine Vincristine is a cytotoxic alkaloid derived from a tropical shrub, the Madagscar periwinkle (Vinca rosea Linnei). It binds to tubulin monomers and prevents the formation of the microtubules of the mitotic spindle. It is used mainly for the treatment of lymphatic neoplasias, breast and lung cancer, and does not appear to penetrate the adult BBB, making any potential benefit for this drug in the treatment of primary brain tumors highly questionable.

Temozolomide TMZ, an oral alkylating imidazotetrazine, is currently the most widely used drug in patients with primary brain tumors. TMZ concomitant to radiotherapy and followed by adjuvant treatment is the current standard therapy in newly diagnosed glioblastoma. According to the investigator’s brochure, from December 2007 nearly 250 000 patients had been treated with TMZ. TMZ is licensed in the USA, Canada, European Union, Israel, Japan, and many other countries for the treatment of patients with newly diagnosed and recurrent high-grade malignant gliomas, and in 20 countries worldwide for the treatment of patients with metastatic melanoma. For an alkylating agent, TMZ shows a low toxicity profile. Of note, there is an increased risk of hematotoxicity in women, and in both sexes after the age of 70 years. There is no reported clinical experience on the use of TMZ in children younger than 3 years of age. In pediatric patients, the rates of thrombocytopenia and leukopenia are somewhat higher than in adult patients: grade III or IV thrombocytopenia in 26%, neutropenia in 20%, and lymphopenia in 39% of

122 pediatric subjects in a study of the Children’s Oncology Group with the 5/28 regimen (Nicholson et al., 2007). Under physiological conditions, TMZ converts spontaneously to the active metabolite MTIC (5-(3-methyltriazen-1-yl)imidazole-4-carboxamide). It has favorable pharmacokinetic properties with a small intersubject variability for area under the curve (AUC) values. TMZ does not accumulate and reaches 30% of plasma levels in cerebrospinal fluid. The metabolites of TMZ are mainly excreted renally, after glucuronization in the liver. In patients with impaired hepatic function up to Child grade I–II (serum albumin no lower than 30 g/L, with no or reversible ascites), dose modification is not required. No data are available for patients with hepatic failure and Child grade higher than II. Similarly, no dose adjustments are needed for patients with impaired renal function, although there are no data on patients with terminal renal insufficiency. These favorable pharmacokinetic properties have facilitated the multitude of schedules explored for TMZ so far (see Table 57.3) (Yung et al., 2000; Stupp et al., 2005; Baruchel et al., 2006; Brandes et al., 2006b; Herrlinger et al., 2006; Kong et al., 2006; Wick et al., 2007). The main toxicity of TMZ is myelosuppression, the severity of which varies according to the dosage schedule (see Table 57.3), but generally reaches clinical significance in only a small proportion of treated patients. With increasing duration of TMZ administration, the rate of lymphopenia, selective for CD4 lymphocytes, increases – up to 47% encountered in the 21/28 schedule (Brandes et al., 2006b). When the CD4 count drops below 200/mm3 or the total lymphocyte number is less than 400/mm3, there is a significant risk of opportunistic infections, such as Pneumocystis carinii pneumonia, herpes zoster, Kaposi sarcoma, or reactivation of herpes or hepatitis B infection. Ganiere et al. (2006) reported a patient who suffered from several simultaneous opportunistic infections. Thus, in analogy to patients with HIV/AIDS, P. carinii prophylaxis with trimethoprim or monthly pentamidine inhalations is strongly recommended during concomitant chemotherapy and/or for patients with lymphocyte counts below the above-mentioned limits. Routine prophylaxis for all patients during concomitant treatment has been recommended; this has to be weighed against the 6–8% rate of complications with trimethoprim, which may also rarely cause bone marrow aplasia by itself (Kocak et al., 2006). In all clinical trials with TMZ reported so far, the rate of neutropenic infections was about 1–3%. In addition, with prolonged duration of TMZ administration, increased rates of pruritus and pruritic rashes have been observed, in up to 15% of patients. This dermatological complication can even cause a dose-limiting

COMPLICATIONS OF CHEMOTHERAPY IN NEURO-ONCOLOGY toxicity and requires treatment with antihistamines and (topical) steroids (J. Pichler, personal communication). In animal experiments, fatal effects after a single dose of TMZ were observed with doses ranging from 1000 to 2000 mg/m2 in rats and mice. In humans, there have been numerous reports of unintentional overdoses and adverse events, including myelotoxicity and, occasionally, neutropenic fever and sepsis. There are five reports of fatal overdose, all in women aged 41–53 years, compatible with the increased hematotoxicity seen in women. These overdoses reported with fatal outcome were 200 mg/m2 for 30 days, 320 mg for 22 days, 1250 mg on days 1–5, and 2000 mg on days 1–5, that is, two to five times the range of normal doses. Furthermore, there are reports of several cases of secondary leukemia and myelodysplastic syndrome following treatment with TMZ (De Vita et al., 2005; Noronha et al., 2006). Thus, even though the toxicity of TMZ may be low for an alkylating agent, this does no mean that there is no risk.

OTHER CYTOTOXIC DRUGS USED IN NEURO-ONCOLOGY Cisplatin and carboplatin Cisplatin and carboplatin act by crosslinking DNA, mostly by forming intrastrand crosslinks with purine bases, by means of a mechanism closely related to that of alkylating agents. In carboplatin, two chlorine groups are substituted by cyclobutane dicarboxylate, resulting in a lower reactivity with DNA, although the same products are formed. Both drugs have been in use for the treatment of solid tumors since the late 1980s. Cisplatin causes a heavy burden of side-effects, besides its undeniable efficacy in antitumoral therapy. Of note, cisplatin is one of the drugs with the highest emetogenic potential, requiring careful antiemetic prophylaxis with 5-HT3 antagonists, corticosteroids, and, when needed, tachykinin antagonists to manage nausea and vomiting. In the treatment of primary brain tumors, the platinum doses usually used are much lower than those in lung or ovarian cancer, 20 mg/m2 per cycle instead of 70–100 mg/m2 per cycle (Stewart et al., 1984; Follezou et al., 1989; Mahaley et al., 1989; Newton et al., 1989; Lord and Coleman, 1991; Kiu et al., 1995; Frenay et al., 2000, 2005; Gilbert et al., 2000; Zustovich et al., 2007). Other, potentially doselimiting, side-effects of ciplatin, namely peripheral neurotoxicity, ototoxicity with progressive hearing loss, and nephrotoxicity, also have to be considered, even when lower doses of cisplatin are used. Of note, adequate hydration of patients and evaluation of renal

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function before patients are chosen for the treatment with platinum-based drugs are mandatory. Compared with cisplatin, the side-effects of carboplatin are considerably reduced, but there is more hematotoxicity. Both drugs have been used by intravenous infusion, as well as by intra-arterial injection. The latter did not fulfil the expectations of higher efficacy and was hampered by occasional severe ocular complications and more complicated handling (Wu et al., 1997; Tfayli et al., 1999).

Topoisomerase inhibitors TOPOTECAN

AND IRINOTECAN

Topotecan and irinotecan inhibit the enzyme topoisomerase I, whereas etoposide (VP16, Vepesid) and teniposide (VM26) inhibit topoisomerase II. Both enzymes catalyze and guide the unraveling of DNA, before DNA replication. All are derived from plants. Their rate of penetration through the BBB is less than 10% of the plasma levels, due to protein binding.

TOPOTECAN Topotecan (Hycamptin) is used mainly for the treatment of lung and ovarian cancer. The main side-effects are myelotoxicity with febrile neutropenia, diarrhea, nausea and vomiting, and mucositis (de Jonge et al., 2000; Markman et al., 2000). An oral formulation is now available.

IRINOTECAN Irinotecan (CPT11) is a semisynthetic topoisomerase I inhibitor that was used mainly in the treatment of colonic cancer. The inhibition of topoisomerase I by the active metabolite SN-38 eventually leads to inhibition of both DNA replication and transcription.The active metabolite is in turn inactivated in the liver by glucuronidation by the enzyme UGT1A1. Persons with an inherited specific variant of the glucuronating enzyme, called *28 variant, who express less UGT1A1 enzyme in their liver are at higher risk of developing severe side-effects after administration of irinotecan, namely severe diarrhea and neutropenia (de Chaisemartin and Loriot, 2005; Braun et al., 2007; Gamelin et al., 2007). CPT11 has shown activity against glioma cell lines and in animal models of malignant glioma (Nakatsu et al., 1997; Kamiyama et al., 2005), and possibly also has interesting synergistic effects with TMZ that were finally reproducible in patients in early phase I (Houghton et al., 2000; Reardon et al., 2005; Vredenburgh et al., 2007; Sathornsumetee et al., 2008). More recently, irinotecan (at a low dose of 125 mg/m2 every 2 weeks) was used in combination with the

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antibody against vascular endothelial growth factor receptor, bevacizumab, in patients with recurrent highgrade glioma, yielding impressive results: 57–86% of partial remissions seen by magnetic resonance imaging (Vredenburgh et al., 2007; Sathornsumetee et al., 2008) and a progression-free survival rate of about 46%. These encouraging results have to be confirmed in further trials and lead to more basic research on the mechanisms of action of antiangiogeneic agents. However, in the dosages used for the combination with bevacizumab, irinotecan is usually well tolerated and causes neither significant diarrhea nor hematotoxicity.

anthracyclines as well as pegylated forms that can penetrate into gliomas become available. Moreover, in vitro, long-term exposure to doxorubicin is able to decrease the proliferative potential of glioma stem cells (Eramo et al., 2006). Several small studies on pegylated and/or liposomal anthracyclines in recurrent malignant gliomas have shown efficacy in patients with tumors refractory to alkylating agents (Eramo et al., 2006; Glas et al., 2007; Wagner et al., 2008). As well as hematological side-effects, the pattern of side-effects consists of the risk of hand–foot syndrome and a remote risk of cardiotoxicity in the doses administered (Massing and Fuxius, 2000; Rahman et al., 2007).

ETOPOSIDE Etoposide is an inhibitor of the enzyme topoisomerase II, derived from Podophyllum peltatum, the mayapple, a perennial herbaceous plant. Etoposide can be administered either as intravenous infusion or in oral form. Hematotoxicity, nausea and vomiting, alopecia, and a persistent metallic taste are the main side-effects of the oral form. Given as infusion, etoposide may cause hypotension, pain and burning at the injection site, and fever. Etoposide has been used extensively for the treatment of primary brain tumors, also by the intraarterial route (Madajewicz et al., 1991; Newton and Newton, 1995; Ciesielski and Fenstermaker, 1999; Wolff et al., 2000; Schuller et al., 2001; Kesari et al., 2007; Terasaki et al., 2008).

TENIPOSIDE Teniposide (VM26, Vumon R) is the second podophyllotoxin used in cancer therapy. It is insoluble in water and ether, slightly soluble in methanol, and very soluble in acetone and dimethylformamide. The side-effects are similar to those of etoposide, with more emphasis on hematotoxicity and mucositis (Weller et al., 2003).

Anthracyclines Anthracyclines are a class of potent and widely used cytotoxic drugs, derived from antibiotics that inhibit DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand. They create ironmediated free oxygen radicals, damaging the DNA and cell membranes, and inhibit topoisomerase II. Therefore, they are used to treat leukemias and a wide range of solid tumors, such as lung cancer, breast cancer, gynecological cancers, and sarcomas. Anthracyclines do not cross the BBB and are substrates for the multidrug resistance protein-1 (P-glycoprotein 1). Therefore, this group of cytotoxic drugs did not appear suitable for the treatment of malignant glioma. However, interest is increasing, as liposome-coated

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