Glioblastoma (GBM) is the most common malignant brain tumor (48.3% of malignant tumors).1
It has a predilection for Caucasian men with a mean age of 65.1, 2 There are
approximately 13,000 new diagnoses of GBM made every year in the United States.1 Patients
have an average survival of 12-15 months, with a 5-year survival rate of 6.8% despite
various treatments.1 If the prognosis at the time of initial diagnosis is grim, it is
even worse at the time of recurrence. Recurrence after the initial resection, which can
be symptomatic or discovered on surveillance MRI imaging, occurs in nearly all patients,
usually within the first year, even when the initial management is aggressive.3-6 There
is no standard way to care for recurrent GBM patients and treatment may include one or
more of the following: repeat surgery, radiation therapy, or second-line chemotherapy.7
Repeat surgical management carries a greater risk of wound infection and cerebrospinal
fluid leak than the initial surgery, especially in patients who received radiation.8 When
maximal resection was attempted at the time of the initial procedure, the second surgery
is more at risk of neurological injury. Repeat surgical management often also entails a
delay in the initiation of further chemotherapy, as these agents are not administered
peri-operatively because of potentially deleterious effects on wound healing.
Nonetheless, despite, or because of the desperate setting, patients and surgeons are
often pressed to consider repeat surgery, which is performed in at least 10-30% of
patients.9 Repeat surgical treatment may be more favorable with younger age (<60 years),
and preoperative Karnofsky performance status (KPS) of at least 70.9 Median survival
following repeat resection varies between 13-54 weeks,10, 11 but all reports suffer from
the limitations of retrospective studies, the most obvious being selection bias in terms
of patient age, functional status, tumor location and size.11, 12 Yet, despite favorable
biases some studies report no improvement in terms of survival or quality of life.13, 14
Two recent systematic meta-analyses of case series offer conflicting conclusions about
the merit of re-operation.15, 16
If the intent of repeat surgery is to improve quality and quantity of life, there is no
level 1 evidence it is effective.3, 16, 17 Thus repeat surgery should be considered the
experimental arm of a randomized trial designed in the best interest of the patient,
being only offered as a 50% chance, always balanced by a 50% chance of being allocated
non-surgical care, or a chance to escape what could turn out to be unnecessary or harmful
surgery.18 For patients may be better served by being free to pursue other life
priorities in the company of loved ones rather than being scheduled to endure repeat
craniotomy and multiple clinical or research follow-up visits. There is sufficient
community equipoise to support the conduct of such a randomized trial.19
Tria Design:
The trial is a simple, all-inclusive, prospective, multicenter, randomized care trial18
that allocates 1:1 re-operation (or not) for patients with recurrent Glioblastoma. The
primary outcome is overall survival. Secondary outcomes include standard peri-operative
safety outcomes and (a notion of) 'quality survival', or survival at home, measured by
counting days of survival minus days in hospital/nursing home/palliative care setting.
Blinding is not feasible; treatment allocation will not be masked. The trial allows for
pre-randomization.22 The burden of the proof of benefit is on surgery. While some
patients allocated non-surgical management may still want surgery, and some patients
allocated surgery may prefer non-surgical management, we feel participating patients will
be better informed by the discussion around trial participation.
Hypothesis:
Patients with recurrent Glioblastoma, at the time they are considered for repeat
resection, who undergo repeat resection for the GBM, will experience an increase in
median overall survival from 6 to 9 months.