Download The concept of maintenance: may we move it to gastric, pancreatic

WCRJ 2016; 3 (2): e713
THE CONCEPT OF MAINTENANCE:
MAY WE MOVE IT TO GASTRIC,
PANCREATIC AND LIVER CANCERS?
G. APRILE, V. FANOTTO, S.K. GARATTINI, C. BOZZA, E. DE CARLO,
C. FONTANELLA, M. BONOTTO, D. BASILE, M. CATTANEO,
M. CASAGRANDE, L. FERRARI, E. ONGARO, G.G. CARDELLINO,
P. ERMACORA, M. GIOVANNONI, N. PELLA, G. FASOLA
Department of Oncology, University and General Hospital, Udine, Italy
Abstract – The significant progresses recently achieved in the treatment of gastric, pancreatic
and liver cancers have led clinicians to evaluate the opportunity to interrupt first-line treatments
before disease progression and to consider maintenance therapies. In colorectal cancer, this strategy
has produced remarkable advances, and patients whose disease is controlled after a few months
of upfront therapy may derive clinical benefit and enjoy improved quality of life from continuing
a less intensive treatment or early shifting to another, well-tolerated regimen. If the concept of
maintenance may be applicable to other gastrointestinal malignancies is currently unknown, but
the evidence is rapidly emerging.
KEYWORDS: Maintenance, Gastric cancer, Pancreatic cancer, Hepatocellular carcinoma.
INTRODUCTION
Maintenance chemotherapy, an important part of
the treatment strategy of metastatic gastrointestinal
tumours, is rapidly evolving. Over the past decade,
three facts have contributed to extend median
overall survival (OS) of gastrointestinal cancer
patients with metastatic disease1: a more profound
understanding of the molecular biology of cancer,
the development of new active drugs and the concept
of a treatment strategy that includes pauses, rechallenges, and maintenance periods. In facts, the
median OS for patients with metastatic colorectal
cancer has surpassed 30 months in molecularly
selected cases2-5, and the median OS of patients
with advanced gastric or pancreatic cancer has
also significantly increased due to the introduction
of novel regimens6,7, second-line treatments8-11,
and target therapies12,13. Despite the extension of
median OS for patients diagnosed with gastric,
pancreatic, or liver cancers, the vast majority of
gastrointestinal tumours still remain incurable in
their advanced phase and the goal of the overall
therapeutic strategy focuses on disease control and
maintenance of good quality of life (QoL).
In the meantime, the paradigm of continuing
first-line therapy until disease progression or intolerable toxicity has been challenged. The introduction of more intense upfront regimens including cytotoxic drugs with potential cumulative
toxicities as well as the survival improvements
gained with the use of novel drugs have turned on
the debate on the optimal upfront treatment duration. In particular, it is unclear if first-line treatment should be better continued until disease progression or rather discontinued after disease control has been achieved (usually after 4 to 6 months)
to offer the patients some period of rest.
Corresponding Author: Giuseppe Aprile, MD; e-mail: [email protected]
1
In this scenario, the example of colorectal
cancer is paradigmatic. A more modern strategy
to manage this disease include an induction
phase with intensive chemotherapy followed by a
maintenance window with a reduced dose of the
same chemotherapy, changed non-cross-resistant
drugs, or modified schedule of treatment14,15.
In facts, the aim of maintenance therapy is to
extend (and reinforce) the favourable results
achieved with first-line induction therapy;
thus, maintenance therapy could only play a
role after a successful first-line treatment (i.e.
complete response, partial response or stable
disease) has been completed15. Moreover, the
substantial toxicity profile of highly active
drugs may be mitigated using maintenance, less
intensive treatment, which may be associated
with improved quality of life. In metastatic
CRC, the continuation of first-line treatment
beyond 4-6 months is supported by limited
evidence15 and the role of maintenance strategy
has been clearly established16. The OPTIMOX-1
trial was the first large study suggesting that
prolonging combination chemotherapy until
disease progression is of limited clinical value17.
After these results, two other trials tested
chemotherapy-free intervals during first-line
therapy: the OPTIMOX-2 trial and the COIN
trial. While the COIN trial demonstrated
that intermittent chemotherapy with XELOX
(capecitabine/leucovorin/oxaliplatin) or modified
FOLFOX (5-fluorouracil/leucovorin/oxaliplatin)
for 12 weeks followed by treatment interruption
until disease progression and further 12 weeks
of treatment was non-inferior in terms of OS
to continuous combination chemotherapy until
progression18; the OPTIMOX-2 trial suggested
that a complete interruption of chemotherapy
may be detrimental19. Antiangiogenic drugs have
also been tested in the maintenance setting in a
number of randomized clinical trials enrolling
colorectal cancer patients with advanced disease16.
Although maintenance after first-line therapy
has been studied in lung21,22, breast23, ovarian24,25
and colorectal cancer26,16, its role remains
uncertain in other gastrointestinal cancer. The
aim of this review is to summarize experiences
and evidence of use of maintenance therapy in
non-colorectal metastatic gastrointestinal cancer,
in particular in advanced gastric, pancreatic
and hepatic cancers. There are two different
strategies: A) switch maintenance, where patients
are exposed to new non-cross-resistant cytotoxic
drug or targeted agent that was not included in the
previous induction treatment; and B) continuous
maintenance, where a less-toxic part of the former
regimen is used until disease progression.
2
MAINTENANCE IN ADVANCED
GASTRIC CANCER
Gastric cancer is one of the most common cancers
worldwide, being the third most common cause
of cancer-related death globally1. In the US,
approximately 22,220 patients are diagnosed
annually, of whom 10,990 are expected to die
because of disease progression1. The majority
of patients with gastric cancer were diagnosed
with locally advanced or metastatic disease;
thus, palliative chemotherapy represents the only
therapeutic option, with the purpose of prolonging
survival, relieving symptoms and improving
QoL27-29.
Advanced gastric cancer (AGC) is a chemotherapy-sensitive disease, with various active drug
from different therapy classes. Moreover, two
new drugs have been approved for clinical use.
Trastuzumab, a humanized monoclonal antibody
that blocks HER2 activation, may be used in
first-line in combination with chemotherapy;
ramucirumab, a fully human immunoglobulin G1
monoclonal antibody targeting VEGFR-2, may be
prescribed in pre-treated patients either alone or
combined with single-agent paclitaxel12,13.
Although a large number of trials have been
completed, multiple treatment options, with
different intensity, may be selected as first-line
treatment for advanced disease. Several drugs
have shown good single-agent activity; however,
the response rates range from 10% to 25% and the
median duration of response is relatively short.
Combination chemotherapy is associated with a
statistically significant survival benefit compared
with monotherapy in a meta-analysis of 11 phase II
and III clinical trials with a total of 1,472 patients
(P = 0.001)27. Instead, the role of triplet regimens
has been largely reconsidered because of potential
toxicity and the unclear fitness with a long-term
strategic treatment plan. The meta-analysis also
showed that the combinations of 5-FU and cisplatin
plus anthracycline have a significant survival
benefit compared with the combinations of 5-FU
and cisplatin (p < 0.0001)27. However, even if the
combination of a number of active drugs seems to
be an intriguing possibility due to the demonstrated
benefit in long-term outcome, this strategy also
increases the toxicity rate and eventually leads
to a reduction of treatment compliance30,31. The
prescription of a maintenance therapy after a more
intensive upfront treatment could represent a good
option to keep cancer under control and improve
patients’ QoL.
B
To date, only the role of fluoropyrimidines
as maintenance therapy has been explored in
AGC32-34. The efficacy and safety of capecitabine
THE CONCEPT OF MAINTENANCE: MAY WE MOVE IT TO GASTRIC, PANCREATIC AND LIVER CANCERS?
as maintenance treatment after first-line
chemotherapy in AGC has been evaluated in 287
Chinese patients who had previously received 6
cycles of oxaliplatin and capecitabine as first-line
chemotherapy, without disease progression but
with documented grade 2 or higher neuropathy.
Overall, 222 patients interrupted the treatment and
64 patients received capecitabine as maintenance.
The median PFS was 11.4 months [95%confidence
interval (CI) 10.2-12-2 months] for patients who
received maintenance therapy versus 7.1 months
(95%CI 6.1-8.0 months) for those in the control
group (p < 0.001). The multivariate analysis
showed that the maintenance treatment was an
independent prognostic factor. Moreover, the
safety profile was consistently mild in the phase
of maintenance treatment32. Similar results
emerged from a retrospective Turkish study that
demonstrated a 9-month longer median PFS with
a favourable safety profile for patients exposed to
capecitabine as maintenance therapy33.
In 2015, an Italian study group evaluated the
efficacy and safety of FOLFOX-4 combination
chemotherapy, followed by leucovorin/bolus and
continuous infusion 5-fluorouracil as maintenance chemotherapy in patients older than 74
years diagnosed with AGC and with an impaired
performance status. Overall, 38 patients with no
evidence of disease progression after a maximum
of 6 FOLFOX-4 cycles were enrolled in this study;
they received maintenance treatment with LV/
bolus and continuous infusion 5-FU every 2 weeks
until disease progression or unacceptable toxicity.
After completion of the oxaliplatin-based regimen,
47.3% patients achieved a partial response and
36.8% patients had stable disease. The 6-month
disease-control rate was 47.3% (95%CI 30.9-64.1),
the median PFS was 5.9 months (95%CI 4.7-6.8),
and the median OS was 9.6 months (95%CI 8.111.7). The safety profile was acceptable, with grade
3 neutropenia occurred in 6 patients (15.7%), and
grade 3 anaemia and thrombocytopenia occurred in
2 patients (5.2%)34.
Biologic drugs have also been evaluated as
maintenance therapy for patients with AGC. In
particular, the activity and safety of maintenance
trastuzumab have been explored both in the
pivotal randomized phase III trial12 and in a small
retrospective analysis including HER2 positive
AGC patients who received the HER2 inhibitor
after a first-line doublet or triplet regimen35.
Therefore, patients who have been exposed to
a first-line treatment lasting up to 6 months may
be offered a simplified, less-intense, maintenance
treatment. This could be particularly intriguing
when first-line combination chemotherapy
included oxaliplatin, in order to reduce the risk
of cumulative sensorial neuropathy. Although
first-line treatment for AGC was continued until
progression or toxicity within clinical trials, this
paradigm is shifting towards the possibility of
interrupting first-line treatment after 4 to 6 months
of therapy, and the option of continuing with
the only fluoropyrimidine could be reasonable,
possibly associated with trastuzumab in patients
treated for a HER2 positive disease.
Actually, the median upfront treatment duration
of European patients with AGC seldom exceeds 6
months; consequently, often the treatment does
not exceed this length. Thus, whether to stop or
to mitigate the treatment before progression is not
a frequent question in clinical practice. Generally,
in this case, the decision whether to stop or
continue treatment is clinical, based on a careful
assessment of the risk/benefit analysis. All this
always providing full information to the patient
who needs to be involved in decision-making.
Other trials testing maintenance therapy in
gastric cancer are ongoing. MANTRA is an
Italian phase II randomized study that compares
regorafenib to placebo in patients with no evidence
of progressive disease after a first-line platinum
and fluoropyrimidine-based chemotherapy for
HER2-ngeative locally advanced or metastatic
gastric or gastroesophageal junction (GEJ)
cancer. The primary endpoint is PFS, defined as
the time from random assignment to progressive
disease or death. Secondary endpoints are OS,
safety, RR, and quality of life. After achieving
disease control after platinum compounds and
fluoropyrimidine-based regimes (up to 6 cycles
of cisplatin and 5-fluorouracil or capecitabine,
up to 12 cycles of FOLFOX, or up to 8 cycles of
XELOX) patients will be randomly assigned to
receive either placebo or regorafenib at the oral
dose of 160 mg on days 1-21 every 4 weeks, until
intolerance or disease progression36. JAVELIN
Gastric 100 is a phase III multicentric openlabel trial that investigates maintenance therapy
in a similar patients’ setting. After completing
an induction phase encompassing a combination
of oxaliplatin and a fluoropyrimidine for three
months, patients are randomized to either a
maintenance phase with avelumab at the dose of
10 mg/kg or to continuing the same chemotherapy
doublet until disease progression, unacceptable
toxicity, or consent withdrawal. The co-primary
endpoints of the study are overall survival and
progression-free survival37.
ARMANI is a randomized, open-label,
multicenter phase III trial that tests standard
doses of ramucirumab plus paclitaxel as switchmaintenance therapy aiming at demonstrating a
prolonged PFS in the experimental arm38.
3
MAINTENANCE IN ADVANCED
PANCREATIC CANCER
Pancreatic cancer is a leading cause of cancerrelated death in Western Countries1. Gemcitabine
has been considered the treatment’s cornerstone
of palliative chemotherapy in advanced
pancreatic cancer (APC) for over 15 years39, since
gemcitabine-based combinations only minimally
improved survival compared to gemcitabine
alone40, 41. Recently, combination regimens such
as FOLFIRINOX (5-FU/leucovorin/oxaliplatin/
irinotecan)7, PEFG (cisplatin/epirubicin/5-FUgemcitabine)42, and gemcitabine-nabpaclitaxel6
have emerged as new effective options for
patients with advanced disease. In the randomized
PRODIGE 4/ACCORD 11 trial, median OS
was longer for patients exposed to the triplet
regimen compared to that reported for those
treated with gemcitabine alone (median OS 11.1
vs. 6.8 months, p < 0.001). Also, a significant
clinical benefit was achieved in the experimental
arm (p < 0.001). However, the safety profile
and the burden of related toxicities probably
restrict the use of FOLFIRINOX to younger and
fit patients. The combination of nabpaclitaxel
and gemcitabine showed a significant survival
gain over gemcitabine alone (8.7 months vs. 6.6
months, p < 0.001) and significantly improved the
secondary endpoints with a better safety profile
than FOLFIRINOX. Thus, over the last 3 years
the median OS of APC has doubled from the 6
months of gemcitabine alone to the 9-11 months
of combination therapy and this new setting of
treatments, characterized by effective upfront
chemotherapy regimen and the possibility of
prolonged control of disease, could justify the
approach of maintenance in pancreatic cancer.
Reasonable options to be explored in this setting
are represented by fluoropyrimidine monotherapy
and targeted therapies. The effectiveness
and tolerability of maintenance capecitabine
administered to patients with advanced disease
who had received the first-line FOLFIRINOX
and without signs of progression after 4 cycles
were studied in a retrospective analysis of 103
metastatic patients. In this study, 31 patients were
initially treated with a minimum of four cycles
of FOLFIRINOX and, if the disease was not
progressed, they received capecitabine 2,000 mg/
sqm day 1-14 q21; upon progression patients could
be retreated with FOLFIRINOX. Median OS was
19 months with survival rates of 74% at 1 year
and 24% at 2 years. Median PFS was 11 months,
and after disease progression, FOLFIRINOX was
administered to 14 patients owing a prolonged
disease control43.
4
Another therapeutic strategy to prolong disease
control without impacting on quality of life is the
use of a sequential, not cross-resistant scheme.
FIRGEM, a phase II randomized trial, assigned
98 patients to first-line therapy alternating
4 cycles of a modified FOLFIRI regimen
(FOLFIRI3) with 2 months of gemcitabine given
as maintenance therapy versus gemcitabine
alone until progression. The median OS was
3 months longer in the maintenance arm (11
months in the FIRGEM regimen vs. 8.2 months
in the gemcitabine group). Overall, the FIRGEM
strategy allows using oxaliplatin in second-line of
treatment44.
The role of 5-fluorouracil and leucovorin (5-FU/
LV) as maintenance therapy will be explored in
PANOPTIMOX trial that is still recruiting: patients
are randomized to receive FOLFIRINOX regimen
as reference regimen versus FOLFIRINOX
regimen for 8 cycles with 5-FU/LV in maintenance
versus FIRGEM regimen45.
Angiogenic inhibitors have also been tested as
maintenance therapy in patients with metastatic
pancreatic cancer. Based on preclinical data
showing its activity in murine models46, sunitinib
was compared to placebo in PACT-1247. Patients
without disease progression after 6 months of any
gemcitabine-based first-line chemotherapy were
randomly assigned to observation or sunitinib at
the flat continuous dose of 37.5 mg daily. The trial
met its primary endpoint showing a PFS rate at 6
months of 22% in the experimental arm (vs. 3.6% in
the control arm). Although not practice-changing,
this trial offered a proof of concept of the potential
role of angiogenic inhibitors for maintenance
therapy in metastatic pancreatic cancer.
Despite the aggressiveness of this disease
may limit the window of opportunity for using
a maintenance treatment, a growing interest in
this subject is emerging, mainly because of the
current availability of more effective multidrug
regimens. Metformin, an oral hypoglycaemic
agent, may contribute to achieve disease control
inhibiting EGFR and m-TOR pathways48 and,
based on preclinical studies, it appears to
potentially inhibit pancreatic cancer cell lines49;
as a result, confirmatory clinical trials have
provided contradictory results50. An ongoing trial
is randomizing patients with metastatic pancreatic
cancer who have received FOLFIRINOX or
a gemcitabine-containing regimen and have
responded or achieved stable disease to metformin
or metformin plus rapamycin51.
Ganitumab (AMG 479), a monoclonal antibody
against insulin-like growth factor 1 receptor, was
studied as maintenance therapy after combination
therapy with gemcitabine and radiation therapy,
THE CONCEPT OF MAINTENANCE: MAY WE MOVE IT TO GASTRIC, PANCREATIC AND LIVER CANCERS?
resulting in a good and manageable safety profile52.
However, the negative survival results of phase III trial
of gemcitabine plus ganitumab53 seem to minimize
the future role of this compound in this disease.
The molecular classifications of pancreatic
cancer could also lead to target new pathways
and to extend maintenance options54. Whether
in the near future new maintenance therapies
will be tested in specific molecular subgroups of
pancreatic cancer is of extreme interest. Olaparib,
a Poly ADP ribose polymerase inhibitor, is
currently being studied as maintenance therapy
in metastatic pancreatic cancer patients with
germline mutation of BRCA 1/255.
MAINTENANCE THERAPY
IN HCC
Despite the remarkable worldwide incidence and
prevalence of liver cancers1, the median survival
for patients with the unresectable or metastatic
disease is limited to only few months. The reasons
for these discouraging results are attributed to the
lack of effective treatment options for patients
with advanced disease, being sorafenib, a multikinase inhibitor that targets vascular endothelial
growth factor (VEGFR), the only available
evidence-based systemic treatment. However, a
press release by Bayer has recently announced
that the RESORCE trial testing regorafenib in
patients with HCC whose disease had progressed
after treatment with sorafenib56.
In this general panorama, finding new
effective therapies is mandatory for improving
survival of HCC. Moreover, it is also necessary
to preserve the liver function while arresting the
disease evolution. Systemic therapy following
interventional procedures may be considered
a maintenance therapy. Some authors have
analyzed the impact of treating with maintenance
interferon (IFN) patients who underwent liver
resection or TACE in order to reduce the risk
of disease recurrence. A meta-analysis57 of 10
trials with a total of 1,029 subjects treated with a
locoregional procedure, either TACE or surgical
resection, compared the outcomes of patients who
received IFN after procedure versus placebo only.
The recurrence rates of HCC in IFN maintenance
group were significantly lower with an odds ratio
(OR) of 0.66 (95% CI, 0.50-0.86; p = 0.02), the
beneficial effect of maintenance strategy was
more evident after TACE (OR 0.54; 95% CI, 0.330.86, p = 0.01). Moreover, also the death rates
were significantly reduced in the IFN group (OR
0.42; 95% CI, 0.32-0.56; p < 0.00001). Similar
results were showed in a later analysis58. These
data support IFN as a maintenance strategy to
reduce recurrence rate and improve survival of
HCC after an interventional procedure.
Based on the data demonstrating that procedure
such as three-dimensional conformal radiation
therapy (3DCRT)/intensity-modulated radiation
therapy (IMRT) combined with TACE can
improve outcomes in local control and survival of
locally advanced HCC, sorafenib has been added
to prevent intra-hepatic spread of liver metastases.
An ongoing phase I/II trial is enrolling patients
to receive TACE plus 3DCRT/IMRT followed
by sorafenib at the dose of 400 mg twice a day
continuously given for 12 months unless intolerable
toxicities and/or tumour progression58. Aim of this
study is to demonstrate superiority of the addition
of sorafenib to the above-cited strategy in terms
of time to progression (TTP), PFS, and OS in
comparison to historical data. Also, the biological
response modifiers (BRMs) have been tested
as maintenance therapy for HCC. For example,
BRMs were given in combination with 5-FU after
percutaneous ethanol injection (PEI), trans-catheter
arterial embolization (TAE) or arterial infusion of
antitumor agents (AI). However, this strategy did
not show to improve outcomes59.
Recently, some studies combined standard
sorafenib with doxorubicin or gemcitabine60,61.
Based on the results of a recent retrospective study
focused on the GEMOX regimen (gemcitabine/
oxaliplatin) that showed an objective response
rate (ORR) of 22% and an OS of 11 months62, a
prospective study adding sorafenib to this regimen
was conducted. In this open-label prospective trial
patients with advanced HCC received GEMOX
in combination with sorafenib up to 6 cycles
and patients without progression where further
treated with sorafenib maintenance until disease
progression. The ORR registered was 26.5%,
median TTP was 10.3 months, and median OS was
15.7 months. The preliminary data suggested that
GEMOX plus sorafenib followed by maintenance
sorafenib was effective and manageable; however,
further confirmatory analyses are required.
Developing maintenance strategies for HCC
patients could be important to improve both
recurrence-free survival after local treatment
and overall survival together with the attempt of
preserving hepatic function from the toxicities that
may be caused by a prolonged maximal therapy.
Most of the maintenance trials address the issue of
prolonging the benefit of interventional procedure
rather than depotentiating or maintaining the
benefit gained with a systemic treatment. The
future is exciting, but still we have a long way to
go.
5
CONCLUSIONS
Since the aims of palliative treatment remain to
prolong survival, control symptoms and preserve
an adequate quality of life, it seems reasonable
to stop any intense first-line treatment after 4 to
6 months as long as an adequate disease control
has been achieved. Thereafter, a less-intense
treatment may be useful to reinforce the clinical
results while ensuring an optimal quality of life.
The interest in maintenance strategy, which has
been largely adopted in treating colorectal cancer
patients with advanced disease, is growing in
other gastrointestinal cancers for at least two
main reasons. Firstly , maintenance therapy has
a more favourable tolerability profile that may
favour long-term treatment strategies. Secondly,
it may create a window of opportunity for novel
drugs to be tested. Still, the future is uncertain,
but it looks certainly promising.
Conflict of Interests:
The Authors declare that they have no conflict of
interests.
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