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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

44th Annual Meeting of the American Society of Clinical Oncology

Chicago, Illinois / May 30-June 3, 2008

In individuals with advanced brain malignancies, the end point with which to compare strategies continues to be time to progression (TTP) rather than overall survival (OS), but there has been progress toward extending TTP and improving quality of life. In a recently completed phase III study, temozolomide monotherapy was found to be as effective as the combination of procarbazine, vincristine, and CCNU (PVC) but better tolerated. In a three-way comparison, either chemotherapy regimen used upfront produced similar TTP as upfront radiotherapy, suggesting that patients can be spared radiotherapy, according to preference, until progression.

“With regard to PVC and temozolomide, they appear to have equal efficacy but [there is] more toxicity with PVC,” reported Dr. Timothy Cloughesy, Director, Neuro-Oncology Program, University of California, Los Angeles. “There was no loss to providing chemotherapy early. There was basically a median of 18 months that you waited to initiate radiotherapy in the anaplastic astrocytoma arm and greater than four years that one could wait in this population with regard to initiating radiotherapy in the oligo-containing tumours.”

RESCUE Study

The goal of a phase II multicentre Canadian study, called the RESCUE trial, was to evaluate a second-line therapy for patients with malignant glioma who have recurred after an initial standard therapy. No clear second-line therapy exists currently. The genesis of the RESCUE study was a patient who participated in the pivotal NCIC-CTG/EORTC trial that established radiotherapy plus temozolomide (followed by six months of adjuvant temozolomide) as a standard. In this case, the patient responded well to the initial therapy but had a recurrence nine months after completing the adjuvant therapy. When rechallenged with a continuous dose of temozolomide 50 mg/m2, disease control was regained.

On the basis of several subsequent cases that produced similar results, the RESCUE trial was launched to test this approach prospectively, according to lead author Dr. James Perry, Division of Neurology, University of Toronto, Ontario. The primary outcome of the study was six-month PFS with a variety of secondary outcomes, including rate of objective response, OS at 12 months, and safety. For entry, patients with glioblastoma multiforme (GBM) were required to have completed both conventional chemoradiation and at least two courses of adjuvant temozolomide (to avoid patients have the pseudoprogression). Patients with anaplastic glioma were required to have completed at least two courses of temozolomide administered over five days in 28-day courses (5/28). Prior chemotherapy other than temozolomide was not permitted. There were 12 participating Canadian centres.

“We thought this study would be of interest if the progression-free survival (PFS) [at six months] exceeded 20%,” reported Dr. Perry, who indicated that this degree of benefit would provide guidance in a group for which there are little data currently. The study enrolled 120 patients into four groups (Table 1). As in the empiric regimen that launched the study, patients received 50 mg/m2/day temozolomide continuously for up to 12 months.

Table 1. RESCUE Study Cohorts

The results were encouraging. The 20% threshold of PFS at six months that was identified as important in planning the trial was met by three of the four groups. Specifically, the six-month PFS was 28.6% in those with the earliest recurrence (group A), 30.4% in those who failed after stopping adjuvant therapy (group C), and 42.1% in those with anaplastic gliomas (group D). The exception was group B, for which the six-month PFS rate was 9.5%. If all GBMs are considered together, the six-month PFS was 24%.

“The non-hematological toxicities were not very severe. There were a few grade 3 toxicities, but no grade 4 events,” reported Dr. Perry. Regarding hematological toxicities, lymphopenia was the most common, occurring in any grade in almost 50% of patients, 20% of patients had grade 3 lymphopenia, and only one patient had grade 4 lymphopenia (<1%). This high rate of lymphopenia may also seem less severe when it is recognized that 40% of patients had lymphopenia at enrolment (as reported at this point of the study). Moreover, there were no opportunistic infections reported in any patients, even though prophylaxis for Pneumocystis carinii was not mandated and not used at half the centres.

Much of the data analysis for the secondary end points, including survival at 12 months, will be reported at a later date as follow-up continues. One of the most interesting substudies may be a volumetric analysis of brain scans to better quantify the effect of treatment on tumour response over time. However, the primary results of the RESCUE study do provide treatment data for a patient population in whom there has been limited guidance in the past.

“We believe that continuously delivered temozolomide is active at first progression despite prior exposure to temozolomide concurrent with radiotherapy. It appears to be active not only as a rechallenge after a treatment break but also just as a schedule change from standard five-day treatment to continuous treatment,” Dr. Perry stated. “It appears to be well tolerated with non-hematological toxicities, with lymphopenia as the main hematological toxicity.” Overall, Dr. Perry concluded, “The efficacy here, in terms of PFS at six months, appears to be comparable to or maybe slightly better than other conventional agents used as second-line therapies such as the nitrosureas.”

Next steps include studies that will evaluate dose intensity and studies to determine whether temozolomide might serve as the backbone for second-line therapies. According to Dr. Perry, “Temozolomide is really the backbone of our upfront therapies and we have numerous temozolomide studies upfront, and this might be a suitable thing for the future [in second-line therapy] with other cytotoxic agents or with novel targeted therapies.”

Radiochemotherapy Strategies in Anaplastic Gliomas

Dr. Cloughesy introduced the discussion of the latebreaker phase III NOA-04 study of sequential radiochemotherapy of anaplastic glioma with PVC or temozolomide. In this ambitious German multicentre study of 319 randomized patients, a variety of important questions (Table 2) were posed, according to lead author Dr. Wolfgang Wick, Department of Neuro-Oncology, German Cancer Research Centre, University of H
Table 2. Questions

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In this somewhat complex but influential trial, anaplastic glioma patients were randomized to begin therapy with radiation or with chemotherapy. Those in the chemotherapy arm were further randomized to temozolomide (eight four-week cycles of 200 mg/m2 on days 1 to 5) or to PVC (six cycles of 110 mg/m2 CCNU on day 1, 60 mg/m2 procarbazine on days 8 to 21, and 2 mg vincristine on days 8 and 29). In addition, the relative effect of each strategy for the primary outcome of TTF was evaluated for the patients who entered the study with histologies of astrocytoma (52.6%), oligoastrocytoma (33.2%) or oligodendroglioma (14.2%). Furthermore, outcome was evaluated in those with adequate tissue samples for presence of methylated methyl-guanyl, methyl-transferase (MGMT) and 1p/q19, both of which have been identified as prognostically important in previous studies.

In what was described as a relatively typical anaplastic glioma population, the average age was 45. About 65% of the population was male. Slightly more than 40% tested positive for loss of heterozygosity on chromosomes 1p and q19 (LOH 1p/q19) and slightly less than 60% tested positive for MGMT methylation. Slightly less than half had complete resections of tumour. The remaining had partial resections.

Study Findings

When upfront radiotherapy was compared to upfront chemotherapy, the median TTF was almost indistinguishable with median rates of 42.7 months and 43.8 months, respectively. Within the chemotherapy arm, a comparison of the two treatment strategies also found them statistically comparable, although Dr. Wick reported that the median TTF of 47 months on temozolomide was numerically longer than the median TTF of 38.8 months on PVC. The relative tolerability also favoured single-agent temozolomide over PVC on a numerical basis (statistical differences were not provided). In particular, the rate of grade 3 or 4 hematological toxicity was 17.4% in the PVC group vs. 4% in the temozolomide group. Infection rates were also higher on PVC than on temozolomide or radiotherapy (4% vs. 1% vs. 0%). Radiotherapy was free of hematological toxicities of any kind.

“The treatment-related discontinuations were 0% in the radiotherapy arm and 9% in the chemotherapy arm, and this was basically due to PVC discontinuations,” Dr. Wick reported.

When histologies were compared, there was “a huge increase” in risk for an accelerated TTF in patients with an anaplastic astrocytoma relative to either of the oligoastrocytomas, producing a hazard ratio (HR) of 3.3 (P<0.0001). However, there was no increased hazard for an oligoastrocytoma relative to an oligodendroglioma (HR 1.0). As reported in previous studies, lack of LOH 1p/19q (HR 3.3; P=0.0129) and absence of MGMT hypermethylation (HR 2.98; P<0.0001) were both associated with more rapid TTF.

“We did a CART (Classification and Regression Tree) analysis to have a sense for the risk hierarchy and we found that MGMT (methylation) is probably the most valuable factor for a good prognosis, and this is about as important as a favourable histology [having an oligodendroglial component], and both are much more important than detecting 1p/q19 in the tumour tissue,” Dr. Wick told delegates. “Interestingly—and this has not been suggested by all previous studies—there was a good correlation between MGMT methylation and 1p/q19 in the oligodendroglial tumours, which is not the case in astrocytic tumours.”

When the radiotherapy and chemotherapy arms were compared for progression-free survival (PFS), a secondary end point, and OS, there was also no difference observed between the arms. Specifically, the median PFS was 30.6 and 31.6 months, respectively. When the separate histologies were evaluated, the efficacy of radiotherapy and chemotherapy were again similar. Of interest was the fact that the PFS for astrocytomas was 18.2 months on chemotherapy vs. 10.8 months on radiotherapy. Although this was not statistically different, Dr. Wick suggested that the results clearly refute critics who would doubt chemotherapy as an upfront replacement for radiotherapy. In both oligoastrocytoma and oligodendroglial tumours, the median PFS was approximately 52 months whether patients received radiotherapy or chemotherapy. The median OS in both groups was similar and exceeds 60 months.

EGFR Vaccine Combination Strategy

In fact, this latter approach was the subject of another phase II trial which specifically evaluated a vaccine targeted at variant III of the epidermal growth factor receptor (EGFRvIII) in combination with temozolomide. Called CDX-110, the vaccine’s specificity for this tumour-specific gene mutation, which is not expressed on any normal tissues but is widely expressed in GBMs, has a number of potential advantages. One is that EGFRvIII expression is not only associated with tumourgenicity but also with resistance to conventional treatments.

In an update of current experience, Dr. John H. Sampson, Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, reported that there are now two studies that have suggested a survival advantage over matched controls when the vaccine is given in combination with temozolomide after tumour resection. He reported on the results of ACT II, which is a multicentre study evaluating 21 patients on EGFRvIII vaccine.

“The OS in the ACT II trial is 33 months,” reported Dr. Sampson. “Using the matched cohorts, this is a statistically significant meaningful increase in median survival [15.2 months; P=0.0097].” One of the most supportive findings is growing evidence for a correlation between the maximum antibody titre produced by the vaccine and the prolongation of TTF. Although this correlation has not yet reached statistical significance due to small numbers in the study, Dr. Sampson predicted that titres might help clinicians predict responders and non-responders.

In the current treatment schema, patients are initiated on the first dose of vaccine 20 days after patients have started on radiotherapy and temozolomide. The vaccine is administered in three doses separated by two weeks between each dose. Patients also receive granulocyte macrophage colony-stimulating factor (GM-CSF) with the vaccine. Temozolomide is then administered in a monthly cycle with additional vaccinations.

Adverse events associated with the vaccine in the ACT II study were characterized as “minimal,” with the most common involving skin reactions at the injection site. Two patients were taken off the study due to allergic reactions.

“Overall, EGFRvIII appears to be a unique antigen-specific target that appears to be amenable to immunotherapy,” Dr. Sampson remarked. According to studies to date, the evidence that it is compatible with chemotherapy can be derived from the observation that “temozolomide appears to dramatically enhance immunogenicity.” He noted that the activity now seen repeatedly in independent studies has provided the basis for a phase III trial that is now in late stages of development.

Summary

The incremental progress in the treatment of brain malignancies is being built on the established efficacy of existing agents. While resection followed by radiotherapy and chemotherapy remains the standard first-line therapy in many of the most common malignancies, the recent data suggesting that temozolomide can be employed effectively in second-line treatment of patients already exposed to this compound provide a structure on which to look for regimens that can further delay disease progression. The greatest promise may be in combining standard chemotherapies such as temozolomide with novel agents directed at molecular targets in order to achieve longer and perhaps indefinite disease control.