Prognostic relevance of lactate dehydrogenase in advanced pancreatic ductal adenocarcinoma patients
Xiao et al. BMC Cancer
Prognostic relevance of lactate dehydrogenase in advanced pancreatic ductal adenocarcinoma patients
Yuanyuan Xiao 0 2 3
Wen Chen 1
Zhihui Xie 1
Zhenyi Shao 1
Hua Xie 1
Guoyou Qin 0 3 4
Naiqing Zhao 0 3 4
0 Department of Biostatistics, School of Public Health, Fudan University , 130 Dong'an Road, Shanghai , China
1 Information Center, Shanghai Municipal Commission of Health and Family Planning , Shanghai , China
2 School of Public Health, Kunming Medical University , Kunming, Yunnan , China
3 Department of Biostatistics, School of Public Health, Fudan University , 130 Dong'an Road, Shanghai , China
4 Key Lab of Health Technology Assessment, Ministry of Health (Fudan University) , Shanghai , China
Background: The prognostic role of pretreatment serum lactate dehydronegase (LDH) has been well established in many malignant tumors, albeit it remains under-discussed in pancreatic cancer. In the present study, we aimed to assess the association between baseline LDH levels and overall survival (OS) in advanced pancreatic ductal adenocarcinoma (PDAC) patients who did and did not receive subsequent chemotherapy. Methods: In total, 135 retrospectively determined patients with locally advanced or metastatic PDAC, who were diagnosed between 2012 and 2013, were analyzed. Baseline LDH levels were detected within 20 days after histopathological confirmation of the diagnosis. Multivariate Cox proportional hazards regression model was applied to estimate the adjusted hazards ratio (HR) for LDH levels and OS of PDAC. We used restricted cubic spline (RCS) to further investigate dose-effect relationship in the association. Results: Having adjusted for possible confounders, we found that in advanced PDAC patients who went through subsequent chemotherapy, an elevated pretreatment LDH level (≥250 U/L) had an adjusted HR of 2.47 (95% CI = 1.28-4.77) for death, but patients, who did not receive chemotherapy, had no significant HR (adjusted HR = 1.57; 95% CI = 0.83-2.96). RCS fitting results revealed a steep increase in HR for PDAC patients received chemotherapy with a baseline LDH > 500 U/L. Conclusions: Pretreatment LDH levels had noticeable prognostic value in PDAC patients who received subsequent chemotherapy. Tackling elevated LDH levels before the initiation of chemotherapy might be a promising measure for improving OS of patients after treatment for their advanced PDAC. Studies with a large sample size and a prospective design are warranted to substantiate our findings.
Lactate dehydrogenase; Advanced pancreatic ductal adenocarcinoma; Survival analysis; Restricted cubic spline
In metabolic perspective, the most distinctive feature of
cancer cells is the enhanced glycolytic activity even
under sufficient oxygen supply, which is well known as
the “Warburg effect” . As a solid tumor which
featured in hypoxia, some newly uncovered evidence has
suggested that the “Warburg effect” may play a central
role in the initiation, progression, and invasion of
pancreatic cancer .
In the end of glycolysis process, lactate dehydrogenase
(LDH) is involved as the catalyst in transforming pyruvate
into lactate. It has been found that LDHA gene expression
is up-regulated in many human malignant tumors, such as
cancers of the esophagus , stomach , lung ,
colorectum , and more recently, pancreas .
The over-expression of LDHA inevitably promotes the
production of LDH by cancer cells. Thus, the prognostic
value of serum LDH levels in cancer has long been a
topic of considerable research interest. Currently, the
hazardous role of an elevated pretreatment LDH levels
in survival of patients with small-cell lung cancer,
nasopharyngeal cancer, colon cancer, and aggressive lymphoid
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cancers has been well established [8–13]. However, the
association between serum LDH levels and pancreatic
cancer survival has only been discussed at a very limited
scale, although several published studies reached a
consensus in supporting an inverse association [14–19].
Because published studies generally focused on advanced
pancreatic cancer patients who received palliative
chemotherapy, it is not clear whether the prognostic relevance of
baseline LDH levels also exists in patients who are
precluded from chemotherapy, which is another issue of
potential clinical relevance, albeit it has never been
In the present study, we aimed to assess the
association between baseline LDH levels and overall survival
(OS) in advanced pancreatic ductal adenocarcinoma
(PDAC) patients who did and did not receive
chemotherapy. Moreover, we further analyzed the dose-effect
relationship in the association between LDH and OS of
The study population consisted of 135 PDAC patients
diagnosed between January 1, 2012 and December 31,
2013. All patients were retrospectively determined in a
mega population-based electronic inpatients database
originated from Shanghai metropolitan area, China.
Other than histopathological confirmation, inclusion
criteria for PDAC patients were: 1) locally advanced or
metastasis occurred, already missed the opportunity for
curative operation; 2) survival length, defined as time
interval between the date of diagnosis and the date of
death, surpassed 30 days; 3) vital information for
analysis, such as age, sex, baseline (defined as within 20 days
after PDAC confirmation) serum LDH and albumin test
results, and chemotherapy regimens, was complete.
The outcome of interest was OS, and the date of death
for PDAC patients was acquired through external
matching with death registration system. The deadline
of matching was set as January 31, 2015. The study
protocol was reviewed and approved by Institutional
Research Ethics Board of Fudan University, because of
the retrospective nature, plus no individually identifiable
or sensitive information was involved, informed consents
from all patients had been waived.
General characteristics of 135 PDAC patients we studied
are described in Table 1. The mean age of patients was
65.56 years, with a standard deviation of 10.91 years. The
numbers of males and females were comparable. The
longest survival length of PDAC patients was 965 days,
and the shortest was 31 days. The median survival time
was 214 days. Means of baseline LDH and albumin
levels were 216.04 units/liter (U/L) and 38.61 g/L,
respectively. Overall, 68 patients received subsequent
Subsequent chemotherapy (Yes)
Other chemotherapy regimen
chemotherapy, which accounted for 50.37%. Among the
68 patients who received chemotherapy, over 90%
received gemcitabine alone or in combination with
other agents and over 80% (N = 116) died before the
pre-designated matching deadline.
Variables and definitions
A normal level of serum LDH is usually defined as less
than 250 U/L. We used this cutoff-value to dichotomize
PDAC patients into “normal LDH” and “elevated LDH”
groups based on the baseline test results. Baseline serum
albumin levels were defined as “normal” (≥35 g/L) and
“decreased” (<35 g/L) accordingly. Palliative
chemotherapy was defined as the administration of one or
more following medications that are commonly used
for treatment of PDAC in China: gemcitabine,
nabPaclitaxel, 5-fluorouracil, Irinotecan, and Oxaliplatin.
Descriptive statistics were used to illustrate or compare
characteristics within or between PDAC patients from
different baseline LDH groups. Multivariate Cox
proportional hazards regression model was applied to estimate
the adjusted hazards ratio associated with LDH levels.
Finally, considering the arbitrariness which might have
been introduced by pre-designated cutoff for baseline
LDH levels, a continuous variable, as well as the
possibility of nonlinear relationship, we adopted restrictive
cubic spline (RCS) to discuss the dose-effect relationship
in the association between LDH and death hazards in
PDAC patients who did and did not receive
chemotherapy separately. We chose three knots to fit RCS: the 5th,
50th, and 95th percentiles of LDH levels.
All statistical analyses were executed by SAS (version
9.2, SAS Institute Inc., Cary, NC, USA), and the
significance level for test or inference was set as two-tailed
Overall survival of PDAC patients with different baseline
By applying the aforementioned cutoffs for LDH and
albumin levels, 30 (22.22%) patients recorded an
elevated baseline LDH level, while 26 (19.26%) presented
decreased baseline albumin level. There are significant
distributional differences in age at diagnosis and
albumin levels between PDAC patients with normal and
elevated baseline LDH levels, and the OS was
comparatively inferior for PDAC patients with elevated LDH
levels (Table 2).
For subsequent chemotherapy, we sketched
KaplanMeier survival curves with regard to baseline LDH
levels: for both groups of patients, an elevated baseline
LDH level was associated with significantly
compromised OS (Fig. 1).
Independent association between baseline LDH levels
and OS of PDAC
The serum LDH level is also an indicator of liver
function, and because of anatomic vicinity, advanced
pancreatic cancer usually metastases to the liver, leading to
a decreased liver function in turn . Therefore, when
constructing multivariate Cox model, we further
included the serum albumin level, a more sensitive indicator
of liver function to adjust for possible confounding. Cox
model fitting results are enumerated in Table 3. For
advanced PDAC patients who underwent subsequent
palliative chemotherapy, univariate Cox model found
that pretreatment LDH level was significantly
associated with deteriorated survival (crude HR = 2.34; 95%
CI = 1.23–4.45), and this notable association was
maintained in the multivariate model: compared with
patients having a normally ranged LDH level, an elevated
LDH level was associated with an HR of 2.47 (95%
CI = 1.28–4.77). For PDAC patients who did not
accept chemotherapy, initially a prominent association
between baseline LDH levels and OS has been discerned
(crude HR = 1.91; 95% CI = 1.04–3.47), but after
adjustment for possible confounders, this association was
insignificant (adjusted HR = 1.57; 95% CI = 0.83–2.96).
Dose-response association between baseline LDH and OS
RCS fitting results disclosed that, in general, the
doseresponse trend between pretreatment LDH levels and
HR was less apparent. In advanced PDAC patients who
received chemotherapy, LDH levels higher than 500 U/L
were associated with a significantly increased HR. On
the contrary, in PDAC patients who did not receive
chemotherapy, the change of baseline LDH levels
showed an insignificant influence on OS (Fig. 2).
In the present study, we discussed the influence of LDH
levels measured right after cancer diagnosis on OS of
patients with advanced PDAC. Based on multivariate
Cox model and RCS, we observed that, for patients who
received subsequent palliative chemotherapy, an elevated
baseline LDH level was associated with nearly 2.5 folds
hazards of death, whereas for patients who did not
receive chemotherapy, this association was not
Serum LDH levels are widely accepted as indicators of
tissue breakdown. In cancer patients, because of
enhanced proliferation capacity, the cycle of cancer cells
will be shortened, which in turn causes an increased risk
of necrosis. Besides, vicinal normal tissues can be
encroached upon and destructed by cancer cells . All
these mechanisms, along with enhanced glycolysis, may
collectively contribute to increased serum LDH levels in
cancer patients. In this sense, LDH levels can actually
partly reflect tumor burden. It has been suggested that,
high concentration of lactate can promote tumor
progression and metastasis through up-regulation of tumor
growth factors, such as vascular endothelial growth factor
and hypoxia-inducible factor 1α, or through the direct
enhancement of cellular motility . More recently,
Rong et al. found that LDH directly promotes the
growth of pancreatic cancer cells . Thus, it is reasonable
to suspect that the significant inverse association between
baseline LDH levels and survival we found in advanced
PDAC patients who received chemotherapy can partly be
attributed to tumor burden or pro-progression nature of
LDH. As to the reason that why this association was not
Table 2 Distributional differences in general characteristics for PDAC patients of different baseline LDH levels
Age at diagnosis (Yrs, mean, std.)
Baseline albumin (Deceased, %)
Subsequent chemotherapy (Yes, %)
Fig. 1 Kaplan-Meier curves illustrating overall survival status by baseline LDH levels in two groups of advanced PDAC patients. a PDAC patients
with chemotherapy; b PDAC patients withoutchemotherapy
Fig. 2 RCS fitting results for baseline LDH and OS in two groups of advanced PDAC patients. a chemotherapy group; b non-chemotherapy group
recognizable in patients who did not receive
chemotherapy, the most likely explanation is that, usually an
end-stage disease and exhausted physical status are
major hurdles that may prevent cancer patients from
chemotherapy; therefore, in this group of patients, the
plummeting health would inundate a comparatively
weak influence of LDH in survival, if it indeed
High serum LDH levels have been found to be
associated with resistance to chemotherapy in many types of
cancer, such as cancers of the colorectum [23, 24],
breasts , and lung [26, 27], just to name a few. A
popular theory for this phenomenon is that stromal cells
inversely transform lactate into pyruvate, which fuels
progression of cancer cells and strengthens their resistance
to chemotherapeutic agents [1, 28]. One previously
published in vitro study clearly demonstrated that, novel LDH
inhibitors exhibited synergistic cytotoxic activity with
gemcitabine . Therefore, it might be true that the
association between elevated pretreatment LDH levels
and deteriorated survival in advanced PDAC patients
who went through chemotherapy was actually the
association between enhanced chemoresistance and
increased hazards of death.
Nevertheless, either way suggests the promising role of
baseline LDH levels in individualized treatment of
PDAC: for patients who are designated for chemotherapy,
tackling elevated LDH levels before treatment may
alleviate tumor stress and improve the efficacy of
chemotherapeutic agents, thus gain survival benefit in the
end. Currently, various effective LDH inhibitors are
already available, and the inhibition of LDH has
minimum impact on normal tissues and presents no major
side effects [29–31]. More importantly, the reduction in
LDH activity has been proved an effective
antiproliferation measure for several other types of cancer
in vivo [32, 33]. For PDAC patients who are not suitable
for chemotherapy, based on current evidence, the
therapeutic value of LDH inhibition cannot be concluded yet.
Although the acceptance of chemotherapy can be an
ideal surrogate for the disease stage and physical
performance status, there lies a possibility that cost concern
prevented some eligible PDAC patients from this
available but expensive treatment, and this situation could
introduce bias to the association between baseline LDH
levels and OS in patients who did not receive
chemotherapy. Nonetheless, this bias tended to derail the
association away from the null, and even so, we still
concluded an insignificant association in this group of
Several limitations of the present study should be
considered. At first, the risk of selection bias cannot be
eliminated as we only chose advanced PDAC patients
whose vital information was complete. Besides, although
when estimating the association between baseline LDH
levels and PDAC survival, we have successfully
controlled for multiple possible confounders, residual
confounding effect undoubtedly existed, and its extent is
hard to estimate. Finally, all patients were originated
from a localized region in China, thus the generalization
of our study results should be made with caution. For
future studies, from the genetic perspective, the
association between LDH gene expression and OS of both
advanced and resectable PDAC patients is a promising
topic that deserves additional investigation. It is critically
important to unveil the possible underlying mechanisms
of our findings and to successfully implement effective
intervention measures in improving the prognosis of
In this retrospective study, we assessed the association
between LDH levels measured right after cancer
diagnosis and OS in a group of advanced PDAC patients. We
found that an elevated pretreatment LDH level was
associated with significantly deteriorated survival in PDAC
patients who received subsequent chemotherapy, but
this association was not statistically significant in PDAC
patients who did not receive chemotherapy. Our
findings suggest that, for PDAC patients, before the
initiation of chemotherapy, tackling the enhanced LDH
activity may ultimately improve survival. Prospective
cohorts are warranted to validate our findings.
HR: Hazard ratio; LDH: Lactate dehydrogenase; OS: Overall survival;
PDAC: Pancreatic ductal adenocarcinoma; RCS: Restricted cubic spline
Availability of data and materials
The datasets analyzed during the current study are not publicly available due
to confidentiality agreement, but are available from the corresponding author
on reasonable request.
YX and NZ conceptualized the study. WC, ZX, ZS, and HX collected and
sorted the data. YX, NZ, and GQ performed data analysis. YX drafted the
manuscript, NZ, GQ, WC, ZX, ZS, and HX critically revised the paper. All
authors had read and approved the final manuscript.
Ethics approval and consent to participate
This study was approved by Institutional Research Ethics Board of Fudan
University. Because of the retrospective nature, plus no individually identifiable
or sensitive information was involved, informed consents from all patients had
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