It is the consensus of the reference committee to use a starting dose of 110 mg/m2 in this patient population based on the dose of lomustine used in recent clinical trials and due to toxicity concerns in these heavily pre-treated patients.
There is no standard systemic therapy available for recurrent glioblastoma, although nitrosoureas are commonly used at recurrence. Chemotherapy with single agent nitrosourea therapy may achieve similar tumour control rates as compared with temozolomide.rr
While there are no clinical trials comparing lomustine monotherapy to best supportive care (BSC), lomustine has been widely used as a comparator arm in a number of recent clinical trials in recurrent glioblastoma. The studies are summarised in the table below:
Source |
Study & year published |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase II trials |
Taal et al. 2014r (BELOB) |
Yes
(comparator arm) |
Yes |
Arm 1: lomustine (PO) 110 mg/m2 d1 q6w
Arm 2: bevacizumab (IV) 10 mg/kg, d1 q2w
Arm 3: lomustine (PO) 110 mg/m2 d1 q6w and bevacizumab (IV) 10 mg/kg d1 q2w (lomustine dose subsequently reduced to 90 mg/m2) |
Phase III trials |
Wick et al 2010r |
Yes
(comparator arm) |
Yes
(within dose range) |
Enzastaurin (PO) 500 mg/d (with 1,125 mg loading dose day 1) vs.
Lomustine (PO) 100 - 130 mg/m2 d1 q6w |
|
Batchelor at al 2013r
(REGAL) |
Yes
(comparator arm) |
Yes |
Arm 1: cediranib (PO) 30 mg daily
Arm 2: cediranib (PO) 20 mg daily plus lomustine (PO) 110 mg/m2 d1 q6w
Arm 3: lomustine (PO) 110 mg/m2 d1 q6w plus placebo |
|
Wick et al 2017r
(EORTC 21601) |
Yes
(comparator arm) |
Yes |
Lomustine (PO) 90 mg/m2 d1 q6w plus bevacizumab (IV) 10 mg/kg d1 q2w
vs
Lomustine (PO) 110 mg/m2 d1 q6w |
Guidelines |
Date published/revised |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
2018 |
Yes |
Yes (within dose range) |
NCCN chemotherapy template dose:
Lomustine (PO) 100 - 130 mg/m2 |
BCCA |
April 2017 |
Yes |
Yes |
Lomustine (PO) 110 mg/m2 (for patients who have received prior alkylators e.g temozolomide) or 130 mg/m2 |
CCO |
April 2016 |
Yes |
No |
Lomustine (PO) 130 mg/m2 |
ESMO clinical practice guidelines |
Stupp 2014r |
Yes |
N/A |
No doses given |
Efficacy
A summary of the efficacy results from the clinical trials is shown in the table below
Study |
Treatment arms and number of patients |
Median PFS |
Median OS |
Summary |
Wick et al 2010r |
Enzastaurin (n=174) |
1.5 months
(HR vs Lom 1.28, p = 0.08) |
6.6 months
(HR vs Lom 1.2, p = 0.25) |
Enzastaurin did not have superior efficacy compared to lomustine monotherapy |
Lomustine (n=92) |
1.6 months |
7.1 months |
Batchelor et al 2013r |
Cediranib (n=131) |
92 days
(HR vs Lom 1.05, p=0.90) |
8 months
(HR vs Lom 1.43, p=0.10) |
Cediranib monotherapy or combination therapy did not improve PFS or OS compared with lomustine alone |
Cediranib + Lom (n=129) |
125 days
(HR vs Lom 0.76, p=0.16) |
9.4 months
(HR vs Lom 1.15, p=0.50) |
Lom + placebo (n=65) |
82 days |
9.8 months |
Taal et al 2014r |
Lomustine (n=46) |
1 month (95% CI 1-3) |
8 months (95% CI, 6-11) |
Combination of bevacizumab and lomustine may have more activity than either drug administered alone. Further investigation in a phase III trial required |
Bevacizumab (n=50) |
3 months (95% CI 3-4) |
8 months (95% CI, 6-9) |
Lom + Bev (n=52) |
4 months (95% CI, 3-8) |
12 months (95% CI, 8-13) |
Wick et al 2017r |
Lom + Bev (n= 288) |
4.2 months
(HR vs Lom 0.49, p <0.001) |
9.1 months
(HR vs Lom 0.95, p=0.65) |
Combination therapy with lomustine and bevacizumab, despite prolonged PFS, did not confer a survival advantage over lomustine monotherapy |
Lomustine (n=149) |
1.5 months |
8.6 months |
Toxicity
The most frequently reported adverse events associated with lomustine are haematological (thrombocytopenia, neutropenia and leukopenia).
In the clinical trial of enzastaurin compared to lomustine by Wick et al, twelve patients discontinued enzastaurin because of adverse events and four patients discontinued lomustine. There was no significant difference in the incidence of serious AEs between the arms except for neutropenia, thrombocytopenia, and leukopenia which occurred more frequently in the lomustine arm. There were eleven patients (6.6%) on enzastaurin and four patients (4.8%) on lomustine who died from treatment. Four of the eleven deaths on enzastaurin were related to AEs and one related to a drug-related cerebral haemorrhage. All four deaths on lomustine were related to disease progression.r
© Journal of Clinical Oncology 2010