The combined use of temozolamide and lomustine (CCNU) has extended survival by more than 50% for one category of patients with glioblastoma in a small study reported in the Journal of Clinical Oncology, now available online, published ahead of print.
“We were stunned” by the data showing 50% of the whole cohort surviving more than two years, chief investigator Ulrich Herrlinger, MD, Professor of Clinical Neuro-Oncology at the University of Bonn Medical School, said in an interview.
Reflecting on the findings, however, Martin J. van den Bent, MD, of the European Organization for Research and Treatment of Cancer (EORTC) and Professor of Oncology at the Daniel Den Hoed Cancer Center at Erasmus Medical Center in Rotterdam, cautioned, however, that although the data are of interest as the first signs of clinical activity, the study is still very small: “We don't know to what extent biases have played a role in getting this result,” he noted.
The prospective study looked at long-term survival among patients newly diagnosed with glioblastoma between March 2002 and December 2003 among whom 31 received oral CCNU at 100 mg/m2 on Day 1 followed by temozolamide at 100 mg/m2 on Days 2 through 6 each week, continued for a maximum of six weeks.
An additional group of eight patients received an intensified regimen in which the CCNU dose was raised to 110 mg/m2 and the temozolomide was given at a dose of 150 mg/m2 for six courses. All patients received standard surgery plus radiotherapy (60 Gy) to the tumor site only.
The median overall survival was 23.1 months for the whole cohort, with 47% of the patients surviving for two years and 18.5% for four years. But after a median follow-up of 41.5 months the median overall survival had not been reached in the patients who had received the intensified regimen and was significantly higher than in the standard group (22.6 months).
Four out of eight patients receiving the intensified regimen were alive at 56 months, two of them without any recurrence, and the investigators noted that methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter in tumor tissue was associated with a much longer median overall survival of 34.4 months compared with only 12.5 months in patients without such methylation.
Dr. Herrlinger noted that since MGMT is an enzyme that detoxifies the DNA changes brought about by temozolomide, when it is methylated the detoxification should be low, so temozolomide is expected to have a good effect in patients who have a methylated MGMT promoter. But, on the other hand, in patients with a non-methylated MGMT promoter there should be high MGMT expression in the tumor cell and high detoxification, reducing the anti-neoplastic benefit of temozolomide.
“And that's what we saw in our group,” Dr. Herrlinger said. “This has been demonstrated previously for standard temozolomide therapy, and we were able to show this also happens in our temozolomide-plus-lomustine therapy”.
Side effects on the therapy included thrombocytopenia, leucopenia, and risk of infection. Two patients died. And the German team reported an increase from 16% to 57% in the incidence of World Health Organization Grade 4 hemotoxicity in the intensified group compared with patients receiving the standard doses.
But the gains demonstrated in this study have prompted the investigators to launch a Phase III study comparing the combination of lomustine plus temozolomide versus temozolomide alone; and Dr. Herrlinger suggested that young patients with newly diagnosed glioblastoma without any concomitant disease could be treated off-study with this combination:
“Clinicians have to keep in mind that this still remains experimental. But we in Bonn, at least, are giving this combination therapy to some of our patients.”
He and his colleagues concluded that the combination may add a survival benefit, but with greater risk of acute toxicity. The JCO article states that the improvement in survival “might be the best rate ever observed in a glioblastoma analysis,” and that: “it does not appear to be bias driven.”
Furthermore, the long-term survivors in the study were not particularly young: The median age was 57. The authors acknowledge that second resections and multiple salvage therapies might also have influenced overall survival to some extent in addition to the change in therapy.
No Control Group
But Dr. van den Bent urged caution in assessing the value of data from such a small study, which was also less conclusive because it lacked a control group. And he noted, “One argument why this combination may not hit a home run comes from a French study published in 2005 by Oliver Chinot, MD, and colleagues, who looked at temozolomide in combination with BCNU. Although the study [Annals of Oncology 2005,16:1177–1184] saw interesting improvements in survival, there were no hints of such magnificent long-term survival.”
Dr. van den Bent also said that he considers temozolomide and lomustine to be “old fashioned” drugs that work with long-established mechanisms of action and have already been investigated in many trials in various combinations: “And so far none of these trials has ever suggested that we might cure the patients with those kinds of agents.”
He added that for glioblastoma he thinks another class of agents is needed that interfere with basic metabolic pathways distinguishing these tumors. And multiple drugs may be needed to target several molecular mechanisms.
“The problem is we don't have a clue what kind of basic mechanisms should be stopped, or what kind of proteins should be blocked or stimulated in order to obtain such results—we simply do not know enough about glioblastoma,” he concluded.
Meanwhile, Dr. van den Bent said he is eagerly awaiting the outcome of the 1,200-patient RTOG 0525 study being conducted by Marl R. Gilbert, MD, and colleagues of the Department of Neurology at the University of Texas M. D. Anderson Cancer Center, looking at standard-dose versus intensified temozolomide, with both regimens allocated to two treatment groups: MGMT methylated or non-methylated. The four patient groups, he said, are big enough to power the analysis needed to yield evidence about whether temozolomide at higher density could deplete MGMT better and improve outcomes.