Gastric Cancer Clinical Trial
Official title:
Limited Versus Extended Lymphadenectomy in High Risk Elderly With Gastric Adenocarcinoma: a Randomized Controlled Trial
Background: Literature often shows limited and discordant data regarding the prognostic
value of age in gastric-cancer patients. Generally, disease-specific survival does not seem
to be worse in the elderly when compared with younger patients, and therefore gastrectomy
with extended lymphadenectomy for non-early tumors is considered the "standard" surgical
therapy for all of operable patients, despite any age- or comorbidity-related limitations.
Recent trials reported a survival benefit for extended nodal dissection compared with the
more limited method, but some Authors found age (and comorbidities) to be a relevant
predictor of postoperative complications, conditioning the safety of the surgical procedure
itself.
Methods/Design: The LELEGA Trial (Limited versus Extended Lymphadenectomy in high risk
Elderly with Gastric Adenocarcinoma) is a randomized, clinical multicenter trial. All
patients >75 years and with Charlson Comorbidity Score >5 with resectable M0 gastric cancer
are eligible for inclusion and randomization. The primary endpoint is 5-year
Disease-Specific Survival (DSS). Secondary endpoints include 5-year Overall Survival (OS)
and postoperative complications classified according to Clavien-Dindo. Assuming an alpha
(two-sided) of 5%, 232 patients per group are necessary to achieve an 80% power to detect a
13% survival difference (from 56% to 69%) between groups.
Discussion: LELEGA trial is a prospective, multicenter randomized study to define optimal
extent of lymphadenectomy (extended versus limited) in elderly and high-comorbidity gastric
cancer patients.
Background Although worldwide incidence of gastric cancer has decreased, it still remains
the fourth most common type of cancer and the second leading cause of cancer-related death,
with a growing prevalence in the elderly owing to increased life expectancy. The Literature
often shows limited and discordant data regarding the prognostic value of age in
gastric-cancer patients. Generally, disease-specific survival does not seem to be worse in
the elderly when compared with younger patients. This evidence leads to the standardization
of surgery in gastric cancer patients, whatever the age (and comorbidity). Gastrectomy with
extended lymphadenectomy for non-early tumors is considered the "standard" surgical therapy
for operable patients, despite any age- or comorbidity-related limitations. Following the
initial doubts concerning its safety in the first randomized controlled studies, extended
lymphadenectomy in gastric-cancer surgery now shows good results. Recent trials, minimizing
the impact of nodal dissection on early postoperative outcome, showed a survival benefit for
extended nodal dissection compared with the more limited method, particularly in advanced
stages. Some of these studies showed age (and comorbidities) to be a relevant predictor of
postoperative complications, conditioning the safety of the surgical procedure itself.
In a retrospective multicenter study, we examined 1.322 non-metastatic gastric-cancer
patients that underwent curative gastrectomy with D2 versus D1 lymphadenectomy from January
2000 to December 2009. Postoperative complications, overall survival (OS), and
disease-specific survival (DSS) according to age and the Charlson Comorbidity Score (CCS)
were analyzed in relation to the extent of lymphadenectomy.
Postoperative morbidity was 30.4%. Complications were more frequent in high-morbidity
elderly patients, and, although general morbidity rates after D2 and D1 lymphadenectomy were
similar (29.9% and 33.2%, respectively), they also increased following D2 in high-morbidity
elderly patients (39.6%). D2-lymphadenectomy significantly improved 5-year OS and DSS (48.0%
vs. 37.6% in D1, p<0.001 and 72.6% vs. 58.1% in D1, p<0.001, respectively) in all patients.
In elderly patients, this benefit was present only in 5-year DSS. D2 nodal dissection
induced better 5-year OS and DSS rates in elderly patients with positive nodes (29.7% vs.
21.2% in D1, p=0.008 and 47.5% vs. 30.6% in D1, p=0.001, respectively), although it was
present only in DSS when high-morbidity elderly patients were considered.
Even if promising, these results are derived by a retrospective study with some unavoidable
biases: particularly, the selection bias depending on the choice of surgeons to perform a D1
in most elderly considered in the analysis (23.8% vs 14.4% of D1 in younger patients,
p<0.001) and the unmeasurable effect of the adjuvant treatments.
Hence, a phase-III randomized controlled trial could be useful to obtain reliable data about
relevant topic.
Rationale With the aging of world population, in next years we will have to face with a
greater number of elderly patients. Actually, also concerning gastric cancer, this part of
population is usually excluded from clinical trial, and hence guidelines are not "tested"
for them. Many retrospective studies (including our retrospective analysis on a very large
series) did not solve any doubt about short-term outcomes and survival benefit of D2
gastrectomy in high-risk elderly patients. Evident methodological limitations limit the
relevance of their conclusions. Firstly, the retrospective design of these studies implies
non-homogeneous groups, unavoidably influenced by the different cut-offs used for "elderly"
definition and by the surgeons' choice with particular regard to lymphadenectomy. Secondly,
they often did not consider any adjuvant therapy: although analysis would have been
influenced by the administration of different regimens with different schedules, survival
might have been modified, thus conditioning the interpretation of results. According the
results of these retrospective reports extended lymphadenectomy confirmed its efficacy in
determining better survival rates in gastric cancer patients. However, after extended nodal
dissection OS in high-morbidity elderly patients, even with nodal involvement, does not
present undoubted benefits. Most of these studies did not have sufficient power to validate
their conclusions.
In conclusion, this prospective randomized multicenter trial will test the effect of
extension of lymphadenectomy on the particular setting of high-risk elderly patients in the
attempt to identify those patients most likely to benefit from aggressive radical surgery
with acceptable perioperative risk.
STUDY DESIGN This is a multicenter, open randomized trial
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