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How did lomustine become standard of care in recurrent glioblastoma?

  • Michael Weller
    Correspondence
    Corresponding author at: Department of Neurology, University Hospital and University of Zurich, Frauenklinikstrasse 26, CH-8091 Zurich, Switzerland.
    Affiliations
    Department of Neurology, Brain Tumor Center & Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland
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  • Emilie Le Rhun
    Affiliations
    Department of Neurology, Brain Tumor Center & Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland

    University of Lille, Inserm, U-1192, F-59000 Lille, France

    CHU Lille, Neuro-Oncology, General and Stereotaxic Neurosurgery Service, F-59000 Lille, France

    Oscar Lambret Center, Neurology, F-59000 Lille, France
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Open AccessPublished:May 04, 2020DOI:https://doi.org/10.1016/j.ctrv.2020.102029

      Highlights

      • Despite limited evidence, lomustine has emerged as standard of care for glioblastoma world-wide.
      • Its activity may be restricted to patients with MGMT promoter-methylated tumors.
      • Lomustine is considered the most active compound of the PCV polychemotherapy protocol.

      Abstract

      Glioblastomas are the most common malignant primary intrinsic brain tumors. Their incidence increases with age, and males are more often affected. First-line management includes maximum safe surgical resection followed by involved-field radiotherapy plus concomitant and six cycles of maintenance temozolomide chemotherapy. Standards of care at recurrence are much less well defined. Minorities of patients are offered second surgery or re-irradiation, but data on a positive impact on survival from randomized trials are lacking. The majority of patients who are eligible for salvage therapy receive systemic treatment, mostly with nitrosourea-based regimens or, depending on availability, bevacizumab alone or in various combinations. In clinical trials, lomustine alone has been increasingly used as a control arm, assigning this drug a standard-of-care position in the setting of recurrent glioblastoma. Here we review the activity of lomustine in the treatment of diffuse gliomas of adulthood in various settings. The most compelling data for lomustine stem from three randomized trials when lomustine was combined with procarbazine and vincristine as the PCV regimen in the newly diagnosed setting together with radiotherapy; improved survival with PCV was restricted to patients with isocitrate dehydrogenase-mutant tumors. No other agent with the possible exception of regorafenib has shown superior activity to lomustine in recurrent glioblastoma, but activity is largely restricted to patients with tumors with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Hematological toxicity, notably thrombocytopenia often limits adequate exposure.

      Keywords

      Introduction

      Lomustine, also known as CCNU (chloroethyl-cyclohexyl-nitrosourea), is an alkylating agent of the nitrosourea family [
      • Nikolova T.
      • Roos W.P.
      • Krämer O.H.
      • Strik H.M.
      • Kaina B.
      Chloroethylating nitrosoureas in cancer therapy: DNA damage, repair and cell death signaling.
      ,
      • Puyo S.
      • Montaudon D.
      • Pourquier P.
      From old alkylating agents to new minor groove binders.
      ,
      • Kaina B.
      • Christmann M.
      DNA repair in personalized brain cancer therapy with temozolomide and nitrosoureas.
      ] (Fig. 1). It is a monofunctional alkylating agent which alkylates DNA and RNA and can cross-link DNA and thus acts in a cell cycle-dependent and -independent manner. One of the most relevant lesions induced by lomustine, the formation of O6-chloroethylguanine, can be reverted by O6-methylguanine DNA methyltransferase (MGMT). Lomustine may also inhibit enzymatic functions by carbamoylation of amino acids but the contribution of this activity to clinical activity remains unknown. As a lipid-soluble drug, it permeates the blood brain barrier well which a priori made it a reasonable candidate for the chemotherapy of intrinsic brain tumors. It is administered orally in six to eight weeks intervals, given its delayed myelosuppressive properties with nadirs at 5 weeks after administration.
      Figure thumbnail gr1
      Fig. 1Chemical structure and major mode of action of the nitrosourea lomustine (adapted from [
      • Puyo S.
      • Montaudon D.
      • Pourquier P.
      From old alkylating agents to new minor groove binders.
      ,
      • Kaina B.
      • Christmann M.
      DNA repair in personalized brain cancer therapy with temozolomide and nitrosoureas.
      ]). A. Chemical structure of lomustine (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea). B-D. Mechanism of DNA crosslinking. Chlorethylation of guanine at the O6 site generates O6-chloroethylguanine by the active metabolite diazohydroxide (B). Intramolecular rearrangement of O6-chloroethylguanine to N1-O6-ethenoguanine (C). Formation of a N1-guanine-N3-cytosine interstrand crosslink (D). Carbamoylation of lysine or arginine residues and thus inactivation of proteins via the active metabolite isocyanate (E).

      Lomustine in recurrent glioblastoma

      Table 1 summarizes data from all published randomized clinical trials in recurrent glioblastoma that used lomustine as a control arm [
      • Wick W.
      • Puduvalli V.K.
      • Chamberlain M.C.
      • van den Bent M.J.
      • Carpentier A.F.
      • Cher L.M.
      • et al.
      Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma.
      ,
      • Batchelor T.T.
      • Mulholland P.
      • Neyns B.
      • Nabors L.B.
      • Campone M.
      • Wick A.
      • et al.
      Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma.
      ,
      • Taal W.
      • Oosterkamp H.M.
      • Walenkamp A.M.E.
      • Dubbink H.J.
      • Beerepoot L.V.
      • Hanse M.C.J.
      • et al.
      Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial.
      ,
      • Brandes A.A.
      • Carpentier A.F.
      • Kesari S.
      • Sepulveda-Sanchez J.M.
      • Wheeler H.R.
      • Chinot O.
      • et al.
      A phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma.
      ,
      • Wick W.
      • Gorlia T.
      • Bendszus M.
      • Taphoorn M.
      • Sahm F.
      • Harting I.
      • et al.
      Lomustine and bevacizumab in progressive glioblastoma.
      ,
      • Duerinck J.
      • Du Four S.
      • Bouttens F.
      • Andre C.
      • Verschaeve V.
      • Van Fraeyenhove F.
      • et al.
      Randomized phase II trial comparing axitinib with the combination of axitinib and lomustine in patients with recurrent glioblastoma.
      ,
      • Lombardi G.
      • De Salvo G.L.
      • Brandes A.A.
      • Eoli M.
      • Rudà R.
      • Faedi M.
      • et al.
      Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open-label, randomised, controlled, phase 2 trial.
      ,
      • van den Bent M.
      • Eoli M.
      • Sepulveda J.M.
      • Smits M.
      • Walenkamp A.
      • Frenel J.-S.
      • et al.
      INTELLANCE 2/EORTC 1410 randomized phase II study of Depatux-M alone and with temozolomide vs temozolomide or lomustine in recurrent EGFRamplified glioblastoma.
      ]. These trials revealed a low objective response rate to lomustine in the range of 10% and a median progression-free survival that does not exceed 2 months. Progression-free survival at 6 months, a common endpoint in such trials, was in the range of 20% which today is considered a benchmark for planning randomized trials in this setting. The few trials that reported outcome by MGMT promoter methylation status [
      • Taal W.
      • Oosterkamp H.M.
      • Walenkamp A.M.E.
      • Dubbink H.J.
      • Beerepoot L.V.
      • Hanse M.C.J.
      • et al.
      Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial.
      ,
      • Wick W.
      • Gorlia T.
      • Bendszus M.
      • Taphoorn M.
      • Sahm F.
      • Harting I.
      • et al.
      Lomustine and bevacizumab in progressive glioblastoma.
      ,
      • Lombardi G.
      • De Salvo G.L.
      • Brandes A.A.
      • Eoli M.
      • Rudà R.
      • Faedi M.
      • et al.
      Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open-label, randomised, controlled, phase 2 trial.
      ] revealed low activity, if at all, in patients with tumors lacking MGMT promoter methylation.
      Table 1Clinical trials of CCNU in recurrent glioblastoma.
      Trial/referenceResponse rateProgression-free survival (PFS) (months)HRPFS at 6 months (%)HROverall survival (OS) (months)HR
      STEERING

      Wick et al. 2010
      • Wick W.
      • Puduvalli V.K.
      • Chamberlain M.C.
      • van den Bent M.J.
      • Carpentier A.F.
      • Cher L.M.
      • et al.
      Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma.
      Randomized phase III, open label
      Enzastaurin (266)5 responses1.51.28 (0.97–1.70)116.61.20 (0.88–1.65)
      Lomustine (92)4 responses1.6197.1
      REGAL

      Batchelor et al. 2013
      • Batchelor T.T.
      • Mulholland P.
      • Neyns B.
      • Nabors L.B.
      • Campone M.
      • Wick A.
      • et al.
      Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma.
      Randomized phase III, partially blinded
      Cediranib (131)1 CR, 17 PR3.1 (2.7–4.3)1.05 (0.74–1.50), p = 0.901681.43 (0.96–2.13), p = 0.10
      Cediranib plus lomustine (1 2 9)2CR, 19 PR4.2 (2.8–6.7)0.76 (0.53–1.08), p = 0.16359.41.15 (0.77–1.72), p = 0.50
      Lomustine (65)5 PR2.7 (1.4–5.6)259.8
      BELOB

      Taal et al. 2014
      • Taal W.
      • Oosterkamp H.M.
      • Walenkamp A.M.E.
      • Dubbink H.J.
      • Beerepoot L.V.
      • Hanse M.C.J.
      • et al.
      Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial.
      Randomized phase II, open labelORR
      Bevacizumab (50)38 (24–53)3 (3–4)16 (7–27)8 (6–9)
      Bevacizumab plus lomustine (90 mg/m2) (44)34 (20–51)4 (3–8)41 (26–55)11 (8–12)
      Lomustine (46)5 (1–17)1 (1–3)13 (5–24)8 (6–11)
      Bevacizumab
      MGMT unmethylated (24)8 (1–23)1
      MGMT methylated (18)33 (14–55)0.43 (0.21–0.85)
      Bevacizumab plus lomustine (90/110 mg/m2)
      MGMT unmethylated (26)23 (9–40)
      MGMT methylated (11)62 (38–79)0.41 (0.22–0.77)
      Lomustine
      MGMT unmethylated (20)01
      MGMT methylated (23)26 (11–45)0.56 (0.37–0.77)
      Brandes et al. 2016
      • Brandes A.A.
      • Carpentier A.F.
      • Kesari S.
      • Sepulveda-Sanchez J.M.
      • Wheeler H.R.
      • Chinot O.
      • et al.
      A phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma.
      Randomized phase II, partially blinded
      Galunisertib (40))2 PR1.8 (1.6–3.0)15 (5–28)8.0 (5.7–11.7)0.93 (0.58–1.49)
      Galunisertib plus lomustine (79)1 CR1.8 (1.7–1.8)6 (2–13)6.7 (5.3–8.5)1.13 (0.78–1.65)
      Lomustine plus placebo (39)None1.9 (1.7–1.9)6 (1–18)7.5 (5.6–10.3)
      Wick et al. 2017
      • Wick W.
      • Gorlia T.
      • Bendszus M.
      • Taphoorn M.
      • Sahm F.
      • Harting I.
      • et al.
      Lomustine and bevacizumab in progressive glioblastoma.
      Randomized phase III, open label
      Bevacizumab plus lomustine (288)5 CR, 103 PR4.2 (3.7–4.3)0.49 (0.39–0.61), p < 0.0019.1 (8.1–10.1)0.95 (0.74–1.21), p = 0.65
      Lomustine (149)1 CR, 18 PR1.5 (1.5–2.5)8.6 (7.6–10.4)
      Bevacizumab plus lomustine
      MGMT unmethylated (102)3.0 (2.8–3.7)12.7 (7.1–19.9)8.0 (6.9–9.1)
      MGMT methylated (78)6.9 (5.6–8.3)58.4 (46.9–68.7)12.6 (10.6–16.1)
      Lomustine
      MGMT unmethylated (44)1.5 (1.4–1.5)2.3 (0.2–10.4)7.2 (4.8–8.6)
      MGMT methylated (46)3.0 (1.6–5.1)30.4 (18.0–43.9)10.4 (8.3–13.5)
      Duerinck et al. 2018
      • Duerinck J.
      • Du Four S.
      • Bouttens F.
      • Andre C.
      • Verschaeve V.
      • Van Fraeyenhove F.
      • et al.
      Randomized phase II trial comparing axitinib with the combination of axitinib and lomustine in patients with recurrent glioblastoma.
      Randomized phase II, open label, glioblastoma at first or later relapses
      Axitinib (50)3 CR, 11 PR2.9 (2.6–2.8)26 (13–38)12.4 (4.7–16.3)
      Axitinib plus lomustine (29)11 PR3 (1.4–4.7)24 (8–39)11.7 (7.9–15.6)
      REGOMA

      Lombardi et al. 2018
      • Lombardi G.
      • De Salvo G.L.
      • Brandes A.A.
      • Eoli M.
      • Rudà R.
      • Faedi M.
      • et al.
      Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open-label, randomised, controlled, phase 2 trial.
      Randomized phase II, open label
      Regorafenib (59)1 CR, 2 PR2 (1.9–3.6)0.65 (0.45–0.95)16.9 (8.7–27.5)7.4 (5.8–12.0)0.50 (0.33–0.75). p = 0.0009
      Lomustine (60)1 CR, 1 PR1.9 (1.8–2.1)8.3 (3.1–17.0)5.6 (4.7–7.3)
      Regorafenib
      MGMT unmethylated (30)0.43 (0.23–0.80)

      p = 0.028
      MGMT methylated (29)0.57 (0.33–0.97)

      p = 0.015
      Lomustine

      MGMT unmethylated (32)

      MGMT methylated (27)
      van den Bent et al. 2019
      • van den Bent M.
      • Eoli M.
      • Sepulveda J.M.
      • Smits M.
      • Walenkamp A.
      • Frenel J.-S.
      • et al.
      INTELLANCE 2/EORTC 1410 randomized phase II study of Depatux-M alone and with temozolomide vs temozolomide or lomustine in recurrent EGFRamplified glioblastoma.
      Randomized phase II, open label, EGFR-amplified glioblastoma
      ABT-414 (86)2 PR1.97.91.04 (0.73–1.49, p = 0.83
      ABT-414 plus temozolomide (88)5 PR2.79.60.71 (0.50–1.02), p = 0.62
      Lomustine or temozolomide (86)1 PR1.98.2
      Abbreviations: ND no data, OS overall survival, PFS progression-free survival, TMZ temozolomide.
      Overall survival from randomization in all trials was in the range of 6–9 months and differences in overall survival between trials are probably largely driven by patient selection. None of the experimental agents was superior to lomustine with the possible exception of regorafenib, however, the REGOMA trial was a medium-sized phase II trial and several prognostic factor imbalances favored the regorafenib group: patients were on steroids less frequently, were younger, had more often MGMT promoter-methylated tumors, and had a longer progression-free survival with first-line therapy. Furthermore, cross-trial comparison indicates particularly poor outcome with lomustine in the REGOMA trial [
      • Lombardi G.
      • De Salvo G.L.
      • Brandes A.A.
      • Eoli M.
      • Rudà R.
      • Faedi M.
      • et al.
      Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open-label, randomised, controlled, phase 2 trial.
      ]. While this observation is held as an argument against the validity of the data from the REGOMA trial, it is still a randomized clinical trial, and enrollment of a poor prognosis patient population is probably a better explanation for this poorer outcome.
      Quite obviously, the one trial that is missing is a simple comparison of lomustine with placebo or best standard of care to demonstrate that lomustine has indeed activity in recurrent glioblastoma. In that regard, a small Belgian trial on axitinib comes closest to such a design because the combination of lomustine with axitinib was compared with axitinib alone [
      • Duerinck J.
      • Du Four S.
      • Bouttens F.
      • Andre C.
      • Verschaeve V.
      • Van Fraeyenhove F.
      • et al.
      Randomized phase II trial comparing axitinib with the combination of axitinib and lomustine in patients with recurrent glioblastoma.
      ]. Somewhat unexpectedly, this trial indicated no additional activity of lomustine in this setting of combination with axitinib. One may speculate whether this even reflects partially antagonistic activity of axitinib and lomustine, either on a biochemical level or at the level of lomustine penetration to the tumor tissue. Anyhow, this trial has received very little attention, probably because of small sample size, because of the mixing of axitinib-treated patients from various stages of the trial, and because of a mixed population of patients with first and later recurrences of glioblastoma.

      Lomustine in newly diagnosed glioblastoma?

      No contemporary trial has explored whether the addition of lomustine to standard of care radiotherapy would improve outcome in subsets of gliomas of adulthood. One might speculate that similar results as obtained with temozolomide in glioblastoma should also possibly be achieved with a nitrosourea compound. Yet, the disappointing results with lomustine as part of the PCV regimen in a historical United Kingdom trial do not support this expectation (see below) [
      • Medical Research Council Brain Tumor Working Party
      Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council trial.
      ]. Conversely, the CeTeG trial renewed interest in lomustine as part of the management in the first-line setting (see below) [
      • Herrlinger U.
      • Tzaridis T.
      • Mack F.
      • Steinbach J.P.
      • Schlegel U.
      • Sabel M.
      • et al.
      Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial.
      ].

      Lomustine as part of the PCV regimen

      Undoubtedly the most convincing efficacy data for lomustine have been generated when the drug was used in combination with another alkylating agent, procarbazine, and the antimitotic agent, vincristine, as the PCV protocol. This protocol was first used in unselected brain tumor patients in 1975, based on single agent and preclinical data, and was not felt to be superior to carmustine at the time [
      • Gutin P.H.
      • Wilson C.B.
      • Kumar A.R.
      • Boldrey E.B.
      • Levin V.
      • Powell M.
      • et al.
      Phase II study of procarbazine, CCNU, and vincristine combination chemotherapy in the treatment of malignant brain tumors.
      ]. The most commonly used version of PCV today includes lomustine given at 110 mg/m2 p.o. on day 1, procarbazine given at 60 mg/m2 p.o. on days 8–21, and vincristine given at 1.4 mg/m2 at days 8 and 29 of a six-to-eight week cycle. Of note, two negative clinical trials conducted in the United Kingdom used a different regimen that uses lomustine at 100 mg/m2 p.o. on day 1, procarbazine at 100 mg/m2 p.o. on days 1–10, and vincristine at 1.5 mg/m2 on day 1 of a six week cycle [
      • Medical Research Council Brain Tumor Working Party
      Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council trial.
      ,
      • Brada M.
      • Stenning S.
      • Gabe R.
      • Thompson L.C.
      • Levy D.
      • Rampling R.
      • et al.
      Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma.
      ]. Vincristine is commonly capped at a total dose of 2 mg.
      The PCV regimen has demonstrated superiority when combined with radiotherapy over radiotherapy alone in three randomized clinical trials of lower (II/III) WHO grade gliomas (Table 2) [
      • Medical Research Council Brain Tumor Working Party
      Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council trial.
      ,
      • Brada M.
      • Stenning S.
      • Gabe R.
      • Thompson L.C.
      • Levy D.
      • Rampling R.
      • et al.
      Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma.
      ,
      • Cairncross G.
      • Wang M.
      • Shaw E.
      • Jenkins R.
      • Brachman D.
      • Buckner J.
      • et al.
      Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402.
      ,
      • van den Bent M.J.
      • Brandes A.A.
      • Taphoorn M.J.B.
      • Kros J.M.
      • Kouwenhoven M.C.M.
      • Delattre J.-Y.
      • et al.
      Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951.
      ,
      • Buckner J.C.
      • Shaw E.G.
      • Pugh S.L.
      • Chakravarti A.
      • Gilbert M.R.
      • Barger G.R.
      • et al.
      Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma.
      ]. Subgroup analyses from these trials allowed to conclude that PCV is most active in 1p19q-codeleted tumors (oligodendrogliomas) followed by isocitrate dehydrogenase (IDH) mutant astrocytomas whereas activity in IDH wild-type tumors remains uncertain. This is because the latter tumors were underrepresented in the three clinical trials and because prior studies of PCV in the newly diagnosed or recurrent setting of mostly IDH wild-type (presumably) gliomas in the United Kingdom had not demonstrated superiority when PCV was combined with radiotherapy over radiotherapy alone in the newly diagnosed setting, or over temozolomide alone in the recurrent setting (Table 2). It has remained an area of controversy to date to what extent procarbazine and vincristine contribute to the efficacy of the PCV regimen.
      Table 2Randomized clinical trials of PCV polychemotherapy in patients with diffuse gliomas of WHO grades II-IV.
      Progression-free survival (PFS) [years]Overall survival (OS) [years]
      BR05

      MRC Brain Tumor Working Party 2001
      • Medical Research Council Brain Tumor Working Party
      Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council trial.
      Randomized, open label, phase III, newly diagnosed WHO grade III/IV astrocytomaRT (339)RT → PCV (335)RT (339)RT → PCV (335)HR (95% CI)P
      No dataNo data9.510.00.95 (0.81–1.11)0.50
      Brada et al. 2010
      • Brada M.
      • Stenning S.
      • Gabe R.
      • Thompson L.C.
      • Levy D.
      • Rampling R.
      • et al.
      Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma.
      Randomized, open label, phase III, recurrent high-grade gliomaPCV (224)TMZ 5/23 (112) or TMZ 21/7 (111)HR (95% CI)PPCV (224)TMZ 5/23 (112) or TMZ 21/7 (111)HR (95% CI)P
      3.64.70.89 (0.73–1.08)0.236.77.20.91 (0.74–1.11)0.35
      RTOG 9402

      Cairncross et al. 2013
      • Cairncross G.
      • Wang M.
      • Shaw E.
      • Jenkins R.
      • Brachman D.
      • Buckner J.
      • et al.
      Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402.
      Randomized, open label, phase III, newly diagnosed anaplastic oligodendroglioma or oligoastrocytomaRT (14 3)PCV → RT (148)HR (95% CI)PRT (143)PCV → RT (148)HR (95% CI)P
      All patients (291)No update in 2013No update in 20134.74.60.79 (0.6–1.4)
      1p/19q-codeleted (126)2.98.40.47 (0.3–0.72)7.314.70.59 (0.37–0.95)
      1p/19q-non-codeleted (137)11.20.81 (0.56–1.16)2.72.60.85 (0.58–1.23)
      EORTC 26951

      Van den Bent et al. 2013
      • van den Bent M.J.
      • Brandes A.A.
      • Taphoorn M.J.B.
      • Kros J.M.
      • Kouwenhoven M.C.M.
      • Delattre J.-Y.
      • et al.
      Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951.
      Randomized, open label, phase III, newly diagnosed anaplastic oligodendroglioma or oligoastrocytomaRT (183)RT → PCV (185)HR (95% CI)RT (183)RT → PCV (185)HR (95% CI)
      All patients (368)1.12.00.66 (0.52–0.83)2.53.50.75 (0.6–0.95)
      1p/19q-codeleted (80)4.213.10.42 (0.24–0.74)9.3Not reached0.56 (0.31–1.03)
      1p/19q-non-codeleted (236)0.71.20.73 (0.56–0.97)1.82.10.83 (0.62–1.1)
      RTOG 9802

      Buckner et al. 2016
      • Buckner J.C.
      • Shaw E.G.
      • Pugh S.L.
      • Chakravarti A.
      • Gilbert M.R.
      • Barger G.R.
      • et al.
      Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma.
      Randomized, open label, phase III, WHO grade II oligodendroglioma, oligoastrocytoma, astrocytomaRT (126)RT → PCV (125)HR (95% CI)PRT (126)RT → PCV (125)HR (95% CI)P
      All patients (251)4 (3.1–5.5)10.4 (6.1-not reached)0.50 (0.36–0.68)<0.0017.813.30.59 (0.42–0.83)0.03
      Patients with IDH1R132H-mutant tumors (71)0.32 (0.17–0.62)<0.0010.42 (0.20–0.86)0.02
      Vincristine does not cross the blood brain barrier, accordingly, it has been repeatedly proposed to omit this drug from the PCV regimen, assuming that it cannot reach its target, and also because of significant toxicity in terms of peripheral neuropathy upon prolonged use. No clinical trial has compared PCV with a PC regimen, that has e.g., been used in large tumors then referred to as gliomatosis cerebri [
      • Glas M.
      • Bähr O.
      • Felsberg J.
      • Rasch K.
      • Wiewrodt D.
      • Schabet M.
      • et al.
      NOA-05 phase 2 trial of procarbazine and lomustine therapy in gliomatosis cerebri.
      ] and the patient numbers required to demonstrate that vincristine can be safely omitted would probably be enormous. Yet, two retrospective case series have not reported inferior outcome with a PC regimen as opposed to PCV in oligodendroglial tumors [
      • Vesper J.
      • Graf E.
      • Wille C.
      • Tilgner J.
      • Trippel M.
      • Nikkhah G.
      • et al.
      Retrospective analysis of treatment outcome in 315 patients with oligodendroglial brain tumors.
      ,
      • Webre C.
      • Shonka N.
      • Smith L.
      • Liu D.
      • De Groot J.
      PC or PCV, that is the question: primary anaplastic oligodendroglial tumors treated with procarbazine and CCNU with and without vincristine.
      ].
      Procarbazine is another alkylating agent chemically related to temozolomide that has inferior activity in recurrent glioblastoma as a single agent compared with temozolomide [
      • Yung W.K.
      • Albright R.E.
      • Olson J.
      • Fredericks R.
      • Fink K.
      • Prados M.D.
      • et al.
      A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse.
      ]. Accordingly, there was a rationale to improve PCV by replacing procarbazine by temozolomide and by omitting vincristine to design a novel alkylator combination for newly diagnosed glioblastoma [
      • Herrlinger U.
      • Rieger J.
      • Koch D.
      • Loeser S.
      • Blaschke B.
      • Kortmann R.-D.
      • et al.
      Phase II trial of lomustine plus temozolomide chemotherapy in addition to radiotherapy in newly diagnosed glioblastoma: UKT-03.
      ,
      • Glas M.
      • Happold C.
      • Rieger J.
      • Wiewrodt D.
      • Bähr O.
      • Steinbach J.P.
      • et al.
      Long-term survival of patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide.
      ]. UKT-03 was a small phase II trial that was in part designed to overcome MGMT-mediated chemoresistance, assuming that exposure to temozolomide for five days directly after lomustine intake might deplete MGMT and thus improve the efficacy of lomustine. However, compared with historical controls, this small trial appeared to indicate no benefit in MGMT promoter unmethylated glioblastoma, but rather a strong survival signal in patients with MGMT promoter methylated glioblastoma. Accordingly, this combination was taken forward to a randomized phase III trial, CeTeG, in this subset of patients. While patient numbers were small and while there were imbalances of prognostic factors of patients at three sites, there was still overall a signal of prolonged survival for the temozolomide-lomustine combination over standard of care [
      • Herrlinger U.
      • Tzaridis T.
      • Mack F.
      • Steinbach J.P.
      • Schlegel U.
      • Sabel M.
      • et al.
      Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial.
      ]. The idea of combing temozolomide with lomustine has also been adopted for pediatric malignant gliomas) [
      • Jakacki R.I.
      • Yates A.
      • Blaney S.M.
      • Zhou T.
      • Timmerman R.
      • Ingle A.M.
      • et al.
      A phase I trial of temozolomide and lomustine in newly diagnosed high-grade gliomas of childhood.
      ,
      • Jakacki R.I.
      • Cohen K.J.
      • Buxton A.
      • Krailo M.D.
      • Burger P.C.
      • Rosenblum M.K.
      • et al.
      Phase 2 study of concurrent radiotherapy and temozolomide followed by temozolomide and lomustine in the treatment of children with high-grade glioma: a report of the Children’s Oncology Group ACNS0423 study.
      ].
      The efficacy signal with combining temozolomide and lomustine in the CeTeG trial [
      • Herrlinger U.
      • Tzaridis T.
      • Mack F.
      • Steinbach J.P.
      • Schlegel U.
      • Sabel M.
      • et al.
      Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial.
      ] suggests that there may be true synergistic activities of different alkylating agents that warrant further study [
      • Kaina B.
      • Christmann M.
      DNA repair in personalized brain cancer therapy with temozolomide and nitrosoureas.
      ,
      • Fu D.
      • Calvo J.A.
      • Samson L.D.
      Balancing repair and tolerance of DNA damage caused by alkylating agents.
      ]. This is because simply doubling the dose of temozolomide in the newly diagnosed setting, as explored in the RTOG 0525 trial, had no effect at all on progression-free or overall survival [
      • Gilbert M.R.
      • Wang M.
      • Aldape K.D.
      • Stupp R.
      • Hegi M.E.
      • Jaeckle K.A.
      • et al.
      Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial.
      ].

      Tolerability and safety of lomustine

      Lomustine is an emetogenic chemotherapeutic agent that requires standard antiemetic agent prophylaxis which is commonly sufficiently active. The clinically most relevant toxicities documented in clinical trials are summarized in Table 3 [
      • Wick W.
      • Puduvalli V.K.
      • Chamberlain M.C.
      • van den Bent M.J.
      • Carpentier A.F.
      • Cher L.M.
      • et al.
      Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma.
      ,
      • Batchelor T.T.
      • Mulholland P.
      • Neyns B.
      • Nabors L.B.
      • Campone M.
      • Wick A.
      • et al.
      Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma.
      ,
      • Taal W.
      • Oosterkamp H.M.
      • Walenkamp A.M.E.
      • Dubbink H.J.
      • Beerepoot L.V.
      • Hanse M.C.J.
      • et al.
      Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial.
      ,
      • Brandes A.A.
      • Carpentier A.F.
      • Kesari S.
      • Sepulveda-Sanchez J.M.
      • Wheeler H.R.
      • Chinot O.
      • et al.
      A phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma.
      ,
      • Duerinck J.
      • Du Four S.
      • Bouttens F.
      • Andre C.
      • Verschaeve V.
      • Van Fraeyenhove F.
      • et al.
      Randomized phase II trial comparing axitinib with the combination of axitinib and lomustine in patients with recurrent glioblastoma.
      ,
      • Lombardi G.
      • De Salvo G.L.
      • Brandes A.A.
      • Eoli M.
      • Rudà R.
      • Faedi M.
      • et al.
      Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open-label, randomised, controlled, phase 2 trial.
      ,
      • van den Bent M.
      • Eoli M.
      • Sepulveda J.M.
      • Smits M.
      • Walenkamp A.
      • Frenel J.-S.
      • et al.
      INTELLANCE 2/EORTC 1410 randomized phase II study of Depatux-M alone and with temozolomide vs temozolomide or lomustine in recurrent EGFRamplified glioblastoma.
      ]. Thrombocytopenia emerges as the most important toxicity overall and often requires dose reductions, delays of cycles or even discontinuation of treatment. Neutropenia and lymphocytopenia are comparably less frequent and less severe. Despite this toxicity profile, myelodysplastic syndromes and leukemia are rare as sequelae of lomustine chemotherapy presumably because the limited life expectancy of glioma patients reduces the risk of complications that may occur years after exposure [
      • Baehring J.M.
      • Marks P.W.
      Treatment-related myelodysplasia in patients with primary brain tumors.
      ], yet, given the increasing use of the PCV regimen in patients with lower WHO grade tumors with a median survival of 15–20 years, the incidence of such delayed haematological complications may increase.
      Table 3Toxicity of lomustine in clinical trials in recurrent glioblastoma.
      Trial/referenceHematological toxicityNon-hematological toxicity
      Thrombocytopenia

      Grades 1–2
      Thrombocytopenia

      Grades 3–4
      Neutropenia

      Grades 1–2
      Neutropenia

      Grades 3–4
      Lymphopenia

      Grades 1–2
      Lymphopenia

      Grades 3–4
      Liver enzymes

      Grades 1–2
      Liver enzymes

      Grades 3–4
      Respiratory toxicity

      Grades 1–2
      Respiratory toxicity

      Grades 3–4
      Comments
      STEERING

      Wick et al. 2010
      • Wick W.
      • Puduvalli V.K.
      • Chamberlain M.C.
      • van den Bent M.J.
      • Carpentier A.F.
      • Cher L.M.
      • et al.
      Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma.
      Grade 2 onlyGrade 2 onlyGrade 2 only
      Enzastaurin (167)4 (2)1 (1)1 (1)000
      Lomustine (84)9 (11)21 (25)4 (5)17 (20)2 (2)0
      REGAL

      Batchelor et al. 2013
      • Batchelor T.T.
      • Mulholland P.
      • Neyns B.
      • Nabors L.B.
      • Campone M.
      • Wick A.
      • et al.
      Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma.
      Cediranib (128)2 (2)1 (1)3 (2)4 (3)4 (3) PE
      Cediranib plus lomustine (123)47 (38)25 (20)5 (4)14 (11)6 (5) PE
      Lomustine (64)14 (22)2 (3)5 (8)04 (6) PE
      BELOB

      Taal et al. 2014
      • Taal W.
      • Oosterkamp H.M.
      • Walenkamp A.M.E.
      • Dubbink H.J.
      • Beerepoot L.V.
      • Hanse M.C.J.
      • et al.
      Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial.
      Randomized phase II, open labelOnly while blood cell count available
      Bevacizumab (50)49 (98)1 (2)50 (100)05 (10)2 (4)
      Bevacizumab plus lomustine (9o mg/m2) (44)40 (91)4 (9)41 (93)3 (7)15 (34)0
      Lomustine (44)37 (81)9 (19)38 (82)8 (17%)1 (2)0
      Brandes et al. 2016
      • Brandes A.A.
      • Carpentier A.F.
      • Kesari S.
      • Sepulveda-Sanchez J.M.
      • Wheeler H.R.
      • Chinot O.
      • et al.
      A phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma.
      Randomized phase II, partially blinded
      Galunisertib (40)2 (5)02 (0)001 (3)
      Galunisertib plus lomustine (78)16 (21)6 (8)4 (5)6 (8)2 (3)7 (9)
      Lomustine (39)10 (26)5 (13)4 (10)2 (5)2 (5)0
      Duerinck et al. 2018
      • Duerinck J.
      • Du Four S.
      • Bouttens F.
      • Andre C.
      • Verschaeve V.
      • Van Fraeyenhove F.
      • et al.
      Randomized phase II trial comparing axitinib with the combination of axitinib and lomustine in patients with recurrent glioblastoma.
      Randomized phase II, open label, glioblastoma at first or later relapses
      Axitinib03 (6)03 (6)
      Axitinib plus lomustine10 (34)9 (31)6 (21)3 (10)
      REGOMA

      Lombardi et al. 2018
      • Lombardi G.
      • De Salvo G.L.
      • Brandes A.A.
      • Eoli M.
      • Rudà R.
      • Faedi M.
      • et al.
      Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open-label, randomised, controlled, phase 2 trial.
      Randomized phase II, open label
      Regorafenib (59)12 (20)1 (2)1 (2)1 (2)2 (3)3 (5)6 (10)2 (4)
      Lomustine (60)18 (30)8 (13)4 (7)7 (12)2 (3)8 (13)1 (2)2 (3)
      van den Bent et al. 2019
      • van den Bent M.
      • Eoli M.
      • Sepulveda J.M.
      • Smits M.
      • Walenkamp A.
      • Frenel J.-S.
      • et al.
      INTELLANCE 2/EORTC 1410 randomized phase II study of Depatux-M alone and with temozolomide vs temozolomide or lomustine in recurrent EGFRamplified glioblastoma.
      Randomized phase II, open label, EGFR-amplified glioblastoma
      ABT-414 (84)01 (1)5 (6)0010 (12)33 (39)06 (7)0
      ABT-414 plus temozolomide (88)54 (61)7 (8)14 (16)3 (3)35 (40)26 (30)49 (56)015 (17)5 (6) (2 PE)
      Lomustine (56)36 (64)14 (25)14 (25)10 (18)25 (45)18 (32)19 (34)2 (4)9 (16)3 (5) (all PE)Unclear whether seen with lomustine or temozolomide
      Abbreviations: ND no data, OS overall survival, PFS progression-free survival, TMZ temozolomide.
      Non-haematological toxicities are of less concern, although liver toxicity remains an issue notably in combination with other potentially hepatotoxic drugs. Pulmonary fibrosis, a potentially life threatening toxicity associated with nitrosourea treatment, has not been documented to be a toxicity of concern in clinical trials where toxicity was carefully documented. The absence of relevant rates of severe pulmonary toxicity does not justify to monitor lung function in otherwise asymptomatic patients when planning clinical trials with lomustine.

      Conclusions

      Lomustine probably remains the most widely used drug second only to temozolomide in the treatment of gliomas. Despite all limitations summarized above, it is defined as the main standard of care for recurrent glioblastoma in Europe, where bevacizumab is not approved, in the EANO guideline [
      • Weller M.
      • van den Bent M.
      • Tonn J.C.
      • Stupp R.
      • Preusser M.
      • Cohen-Jonathan-Moyal E.
      • et al.
      European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas.
      ], and also in the Adaptive Global Innovative Learning Environment for Glioblastoma (AGILE) consortium [
      • Alexander B.M.
      • Ba S.
      • Berger M.S.
      • Berry D.A.
      • Cavenee W.K.
      • Chang S.M.
      • et al.
      Adaptive global innovative learning environment for glioblastoma: GBM AGILE.
      ]. Moreover, lomustine is likely the key component of the PCV regimen which has become standard of care in most lower WHO grade gliomas with IDH mutation.
      There is little doubt that exposure to lomustine could be improved in patients with lomustine-sensitive tumors like oligodendrogliomas or MGMT promoter-methylated glioblastoma if the key toxicities where mitigated. One such avenue would be the administration of drugs like romiplostim, a thrombopoietin receptor agonist recently shown to allow adequate exposure to temozolomide in patients with newly diagnosed glioblastoma experiencing severe thrombocytopenia [
      • Le Rhun E.
      • Devos P.
      • Houillier C.
      • Cartalat S.
      • Chinot O.
      • Di Stefano A.L.
      • et al.
      Romiplostim for temozolomide-induced thrombocytopenia in glioblastoma: The PLATUM trial.
      ]. For clinical trials in recurrent glioblastoma, while lomustine remains the standard of care, differential sample size calculations and outcome expectations based on the rate of patients with MGMT promoter-methylated tumors enrolled into the trial should be considered.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Declaration of Competing Interest

      MW has received research grants from Abbvie, Adastra, Dracen, Merck, Sharp & Dohme (MSD), Merck (EMD) and Novocure, and honoraria for lectures or advisory board participation or consulting from Abbvie, Basilea, Bristol Meyer Squibb (BMS), Celgene, Medac, Merck, Sharp & Dohme (MSD), Merck (EMD), Novocure, Orbus, Roche and Tocagen.
      ELR has received honoraria for lectures or advisory board from Tocagen, Abbvie, Daiichy Sankyo.

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