RESURGE - Randomized Controlled Comparative Phase II Trial on Surgery for Glioblastoma Recurrence

Background
Glioblastoma is a malignant, locally invasive brain tumor whose prognosis
remains grim despite various intense treatment modalities (Tait et al., 2007).
In the past, radical surgery was met with skepticism due to the aggressive
infiltrative character of the tumor. However, an increasing number of
retrospective studies over the last decade suggest a survival benefit for
surgery (Lacroix et al., 2001; Sanai et al., 2011). A recent post-hoc analysis
of a randomized controlled trial on the use of the surgical adjunct 5-ALA
reported a prolonged overall survival from 11.9 to 16.7 months (evidence level
2a; Stummer et al., 2006; Stummer et al., 2008) after more extensive resection.
Thus, maximal safe resection has become a mainstay of treatment for newly
diagnosed glioblastoma (Mason et al., 2007), followed by adjuvant
radio-chemotherapy (Stupp et al., 2005; Weller, 2011).
Glioblastoma almost invariably recurs after a median of 6.9 months (Stupp et
al., 2005), leaving but few options for further treatment (Stupp et al., 2009).
Recurrence of glioblastoma after surgery and concomitant adjuvant therapy
represents an additional therapeutic challenge and may be treated with
second-line pharmacotherapy. In addition, a second surgery may also be
considered in highly selected patients (Mason et al., 2007).
Rationale
The rationale for surgery - maximum safe resection - is to prolong survival
through reduction of tumor load, and, maybe due to an increased efficacy of
adjuvant treatment (Stummer et al., 2011). However, surgery carries risks of
complications, that may result in a decreased functional and survival outcome
(Hoover et al., 2013). The crucial question therefore is whether, to what
extent, and at what costs in terms of neurological risks a second resection
prolongs survival.
The purpose of the study is to compare the effect of craniotomy and tumor
resection followed by adjuvant second-line therapy to no surgery followed by
second-line therapy on overall survival, neurological status, and quality of
life. Analysis of overall survival will be used to improve sample size
estimation of a subsequent phase III trial for craniotomy and tumor resection
of glioblastoma recurrence in cooperation with the EORTC.

Overall Objective
The purpose of the study is to compare the effect of craniotomy and tumor
resection followed by adjuvant second-line therapy to no surgery followed by
second-line therapy on overall survival, neurological status, and quality of
life. Analysis of overall survival will be used to improve sample size
estimation of a subsequent phase III trial for craniotomy and tumor resection
of glioblastoma recurrence in cooperation with the EORTC.

Primary Objective
The primary objective of this randomized trial is to compare patient survival
after surgery followed by adjuvant second-line therapy to no surgery followed
by second-line therapy in recurrent glioblastoma. An auxiliary objective to
primary objective is to compare the survival of operated patients to control in
the subgroups stratified by extent of resection .

Secondary Objectives
Secondary objectives are:
Assessment of recruitment for all screened patients, comparison of
progression-free survival between treatment arms, evaluation of crossover and
comparison of patient quality of life between treatment arms.

Safety Objectives
Safety objectives are to assess neurological deficits, local infections and
morbidity associated to surgery and hospital stay after surgery and during
follow-up. Total time spent at home, and total time spent outside home at
hospital, rehabilitation or nursing facility will be assessed and compared
between both study arms.

This is a randomized (2:1), parallel-group, controlled, non-blinded,
comparative phase II trial in patients with recurrent glioblastoma. The aim of
the study is to assess the effect of craniotomy and tumor resection followed by
adjuvant second-line therapy versus second-line therapy alone on overall
survival, progression-free survival, neurological status and quality of life.
These results may serve as the basis of a subsequent randomized controlled
phase III trial for craniotomy and tumor resection of glioblastoma recurrence
in cooperation with the EORTC.
All patients presenting at the participating centres with radiological
suspicion of first glioblastoma recurrence will be screened according to the
inclusion criteria. After completed local screening and prior to patient
recruitment the encoded preoperative MRI will be sent by e-mail to the study
eligibility committee which consists of two members of the steering committee
(Prof. Andreas Raabe, Bern and Prof. Luca Regli, Zurich). They will assess the
resectability of the recurrence based on the preoperative MRI within 24h and
they may overrule the local investigator. Study participation will be proposed
to the patient by one of the investigators. Reasons for non-participation for
randomization will be noted for recruitment analysis. Patients participating in
the clinical trial are randomized for surgery followed by adjuvant second-line
therapy (interventional group) or second-line therapy alone (control group) in
a 2:1 ratio. A design with a 2:1 ratio was chosen because patients of the
interventional group are likely to differ in terms of the surgical results:
Based on our own data and the literature (Quick et al., 2014) we assume a 50%
complete resection of enhancing tumor (CRET) rate, leaving the other 50% with
an incomplete resection. According to the literature the extent of resection is
an important predictive factor for overall survival (for initial glioblastoma:
Stummer et al., 2008; for recurrent glioblastoma: Quick et al., 2014). The
trial design with the 2:1 ratio takes the surgical result into account and
permits a comparison between cohorts of complete and incomplete resection of
the interventional group and the control group. Treatment allocation is
balanced for MGMT promoter status and study site at initial diagnosis
(stratification).
Eligible patients who are not willing to be randomized or to participate in the
randomized trial will be asked to give their consent for the participation in
an additional observational arm. In this arm details of treatment,
progression-free survival, overall survival, neurological outcomes and number
of days spent at home/outside home will be assessed, independent of treatment.
Patients allocated to the interventional group are to be operated within 14
days from inclusion and within 21 days from the MRI on which recurrence was
diagnosed and referred to the treating neurooncologist after discharge for
adjuvant second-line therapy as soon as the patient`s condition after surgery
permits. Patients allocated to the control group are to be seen by the treating
neurooncologist following study inclusion and second-line therapy is to be
started within 14 days after study inclusion. Type of (adjuvant) second-line
therapy is determined by the treating neurooncologist according to local and
general guidelines and is not specified by the study protocol. Follow-up visits
consist of a cerebral MRI scan, medical history and physical examination.
Follow-up visits are scheduled every 3 months after study inclusion for up to
24 months (minimal follow-up is 12 months for last patient in) or death.

Surgery must take place between day 1 and 14 after study inclusion and within
21 days from the MRI on which recurrence was diagnosed. The modalities of
surgery and the choice of pre- and intra- operative technical adjuncts is at
the treating neurosurgery discretion and recorded in the electronic case report
forms (eCRFs). However, some form of intra-operative resection control (iMRI or
intra- operative fluorescence) and function control (electrophysiology) should
be available to the surgeon and used when warranted. Patients will be seen
after surgery by the treating neurooncologist to discuss modalities of adjuvant
second-line therapy. Type of adjuvant second-line therapy is not stipulated by
the study protocol. Modalities of pharmacotherapy, administered doses, duration
of treatment, adverse events and further therapies are reported on the eCRFs by
the neurooncologist.

Benefits of surgery for recurrent glioblastoma
The aim of surgery at glioblastoma recurrence is to prolong survival through
reduction of tumor load. Retrospective single center studies suggest
comparatively long survival times after re-operation. A recent report observed
a mean survival after re-operation of 13.5 months (Quick et al., 2014). Of
note, patients who received a complete resection of enhancing tumor (CRET) at
recurrence had a longer survival than those who received an incomplete
resection (15.3 months versus 8.6 months, respectively). The yet largest
retrospective report stratified all glioblastoma patients who underwent tumor
resection according to the number of resections received and found mean overall
survival times of 6.8, 15.5 and 22.4 months for 1, 2 and 3 resections,
respectively (p<0.05, 578 patients, Chaichana et al., 2013). A multicenter,
retrospective investigation on >500 patients reports a mean overall survival of
>25 months in patients with repeat surgery (Ringel et al., unpublished
results). These relatively long survival times appear favorable compared to
patients who did not receive surgery at recurrence (Stupp et al., 2005).
However, these data are non-controlled.
A meta-analysis of 300 patients in eight EORTC randomized controlled trials on
second-line pharmacotherapy showed identical survival rates for patients with
and without surgery at recurrence (median survival 7.1 months after recurrence
for both subgroups, Figure 1). However, only a minority of patients (n=20)
underwent resection and the extent of resection is unknown (Gorlia et al.,
2012).
Risks of surgery for recurrent glioblastoma
Wound healing difficulties, cerebrospinal fluid leaks, hydrocephalus requiring
ventriculo-peritoneal shunt implantation, infections, edema and neurological
deficits have all been described as morbidity of initial and repeated surgery
(Samis Zella et al., 2014). Surgically acquired major permanent neurological
deficits have become an unlikely event at the first resection (3.8%, Schucht et
al., 2012). Whether a surgery for recurrent glioblastoma represents a higher
risk of permanent neurological deficit is unclear. A recent report found
identical rates of 13% for new motor and speech deficits following primary and
repeated surgery (Chaichana et al., 2013). Gempt et al. (2013) observed a
higher rate of neurological deficits of 16% (2/25) after recurrent surgery
compared to 7% (6/84) after initial surgery, presumably due to a higher rate of
postoperative ischemic changes (80% vs 31% for recurrent vs. initial surgery,
p<0.01). Similarly, Hoover et al. (2013) found a higher incidence of
neurological deficits in patients after repeated surgery (12.1% vs. 4.8% at
first surgery) and a higher risk for overall complications (including
neurological deficits, wound problems and systemic complications) of 27.0%
after repeated surgery compared to 12.8% after first surgery (p=0.0068).
Dutzmann et al. (2012) also compared complications of initial and repeat
surgeries, and found the risk for new neurological deficits to be similar
(10.0% and 10.6% for initial and repeat surgeries, respectively). The same
group recently published a retrospective analysis on 40 patients with recurrent
glioblastoma deemed eligible for a gross total resection (Quick et al., 2014).
12.5% showed a new or worsening of an already existing neurological deficit, 5%
suffered from postoperative cerebrospinal fluid fistula leading to wound
revision, and 2.4% had a wound infection. Chang et al. (2003) observed a higher
rate of 18% worsened neurological status after repeat surgery compared to 8%
after initial surgery in (91 and 408 patients, respectively; p = 0.007).
Systemic infections (4.4%) were also more frequent after repeated than after
initial surgery (0%, P<0.0001).
Risks of surgery may negatively impact its benefit for survival
Surgically acquired neurological deficits lead to decreased life expectancy in
addition to the obvious loss of quality of life (McGirt et al., 2009). A single
center report retrospectively stratified patients according to treatment at
recurrence, and found mean survival duration after recurrence of 5, 6, 9 and 14
months for palliative treatment, surgery only, chemotherapy only and surgery
plus chemotherapy, respectively (De Bonis et al., 2013). Surgery alone did not
provide a survival benefit, which might at least partially be due to a high
rate of patients who did not receive adjuvant second-line therapy after surgery
due to major surgical morbidity (48%).