Acta Oncologica

ISSN: 0284-186X (Print) 1651-226X (Online) Journal homepage: https://www.tandfonline.com/loi/ionc20

Prognostic role of lactate dehydrogenase in solid

tumors: A systematic review and meta-analysis of
76 studies

Fausto Petrelli, Mary Cabiddu, Andrea Coinu, Karen Borgonovo, Mara

Ghilardi, Veronica Lonati & Sandro Barni

To cite this article: Fausto Petrelli, Mary Cabiddu, Andrea Coinu, Karen Borgonovo, Mara Ghilardi,
Veronica Lonati & Sandro Barni (2015) Prognostic role of lactate dehydrogenase in solid tumors:
A systematic review and meta-analysis of 76 studies, Acta Oncologica, 54:7, 961-970, DOI:
10.3109/0284186X.2015.1043026

To link to this article: https://doi.org/10.3109/0284186X.2015.1043026

View supplementary material Published online: 18 May 2015.

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Acta Oncologica, 2015; 54: 961–970

REVIEW ARTICLE

Prognostic role of lactate dehydrogenase in solid tumors:

A systematic review and meta-analysis of 76 studies

FAUSTO PETRELLI, MARY CABIDDU, ANDREA COINU, KAREN BORGONOVO,

MARA GHILARDI, VERONICA LONATI & SANDRO BARNI

Department of Oncology, Medical Oncology Unit, Azienda Ospedaliera Treviglio, Treviglio (BG), Italy

ABSTRACT
Background. In cancer cells, metabolism is shifted to aerobic glycolysis with lactate production coupled with a higher
uptake of glucose as the main energy source. Lactate dehydrogenase (LDH) catalyzes the reduction of pyruvate to form
lactate, and serum level is often raised in aggressive cancer and hematological malignancies. We have assessed the
prognostic value of LDH in solid tumors.
Material and methods. A systematic review of electronic databases was conducted to identify publications exploring
the association of LDH with clinical outcome in solid tumors. Overall survival (OS) was the primary outcome, and
cancer-specific survival (CSS), progression-free survival (PFS), and disease-free survival (DFS) were secondary outcomes.
Data from studies reporting a hazard ratio (HR) and 95% confidence interval (CI) were pooled in a meta-analysis. Pooled
HRs were computed and weighted using generic inverse-variance and random-effect modeling. All statistical tests were
two-sided.
Results. Seventy-six studies comprising 22 882 patients, mainly with advanced disease, were included in the analysis.
Median cut-off of serum LDH was 245 U/L. Overall, higher LDH levels were associated with a HR for OS of 1.7 (95%
CI 1.62–1.79; p ⬍ 0.00001) in 73 studies. The prognostic effect was highest in renal cell, melanoma, gastric, prostate,
nasopharyngeal and lung cancers (all p ⬍ 0.00001). HRs for PFS was 1.75 (all p ⬍ 0.0001).
Conclusions. A high serum LDH level is associated with a poor survival in solid tumors, in particular melanoma, prostate
and renal cell carcinomas, and can be used as a useful and inexpensive prognostic biomarker in metastatic carcinomas.

The different metabolism of cancer compared with that
of normal cells confers a selective advantage for their
proliferation and survival. The use of lactate as an
energy source requires the conversion of lactate into
pyruvate as well as the transport of lactate into and out
of tumor cells by specific transporters.The former path-
way is regulated by lactate dehydrogenase (LDH).
LDHs catalyze the conversion of pyruvate and lactate,
with concomitant conversion of NADH and NAD⫹.
These enzymes are homo- or hetero-tetramers com-
posed of a M and a H protein subunits that are encoded
by LDHA and LDHB genes, respectively. LDHA and
pyruvate dehydrogenase kinase (PDK) are up-regulated
in solid tumors in response to hypoxia in a HIF-1α-
dependent manner. LDHA reducing the pyruvate into
lactate regenerates the NAD⫹ pool necessary to main-
tain an adequate glycolytic process. The combinations
of LDHA and LDHB proteins into tetramers result in
the five major isoforms of LDH, numbered 1–5. LDH-5
has the highest efficiency to catalyze the conversion of
pyruvate to lactate. LDH-5 is mainly localized to the
cytoplasm, where it participates in glucose metabolism.
Expression of LDHA and increased levels of function-
ally active LDH-5 are commonly observed events in
highly invasive hypoxic cancers that are resistant to
chemo- and radiotherapy. Biochemical markers of
tumor burden, such as LDH have been incorporated
into several prognostic scores and staging for renal cell
carcinoma, melanoma and colorectal cancer [1–3]. In
metastatic germ cell tumors, furthermore, LDH is
incorporated in the IGCCCG prognostic classification,
and this possibly aids in guiding treatment and stratify-
ing patients in clinical trials [4].
The significance and magnitude of the prognostic
impact of circulating LDH are, however, unclear.
LDH might be a simple and inexpensive objective
prognostic parameter that could be used in daily
oncologic clinical practice, other than helping to

Correspondence: F. Petrelli, Department of Oncology, Medical Oncology Unit, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047, Treviglio (BG),
Italy. Tel: ⫹ 39 0363424420. Fax: ⫹ 39 0363424380. E-mail: faupe@libero.it

(Received 28 February 2015 ; accepted 14 April 2015)

ISSN 0284-186X print/ISSN 1651-226X online © 2015 Informa Healthcare
DOI: 10.3109/0284186X.2015.1043026
962 F. Petrelli et al.
stratify patients in clinical trials. The aim of this study
was to summarize all data to quantify the prognostic
value of LDH on the clinical outcome in various solid
tumors, using standard meta-analysis techniques.
Material and methods
This analysis was conducted in line with the Pre-
ferred Reporting Items for Systematic Reviews and
Meta-Analyses guidelines [5].
Search methods and criteria for selecting studies for this
review
An electronic search of PubMed, EMBASE,
SCOPUS, Web of Science, CINAHL and the Coch-
rane Register of Controlled Trials was performed.
Search terms included: (“neoplasms”[MeSH Terms]
OR “neoplasms”[All Fields] OR “cancer”[All Fields])
AND (LDH[All Fields] OR (“l-lactate dehydro-
genase”[MeSH Terms] OR (“l-lactate”[All Fields]
AND “dehydrogenase”[All Fields]) OR “l-lactate
dehydrogenase”[All Fields] OR (“lactate”[All Fields]
AND “dehydrogenase”[All Fields]) OR “lactate
dehydrogenase ” [All Fields])) AND ( “ mortality ”
[Subheading] OR “mortality”[All Fields] OR
“survival”[All Fields] OR “survival”[MeSH Terms])
AND (multivariate[All Fields] OR (cox[All Fields]
AND (“regression (psychology)”[MeSH Terms] OR
(“regression”[All Fields] AND “(psychology)”[All
Fields]) OR “regression (psychology)”[All Fields]
OR “regression”[All Fields]))) AND (hazard[All
Fields] AND (“Ratio (Oxf)”[Journal] OR “ratio”[All
Fields])). Citation lists of retrieved articles were
screened manually to ensure the sensitivity of the
search strategy.
Inclusion criteria for the primary analysis were as
follows: 1) studies published in complete papers and
in the English language, of (at least 10) adult patients
with solid tumors reporting on the prognostic impact
of serum LDH; and 2) availability of a hazard ratio
(HR) and 95% confidence interval (CI) for overall
survival (OS). For a secondary analysis, studies pro-
viding an HR for cancer-specific survival (CSS),
progression-free survival (PFS) or time to progres-
sion, and disease-free survival (DFS), were included
as well. Duplicate publications were excluded. Two
reviewers (F. Petrelli, M. Cabiddu) evaluated inde-
pendently all of the titles identified by the search
strategy. The results were then pooled, and all poten-
tially relevant publications were retrieved in full. The
same two reviewers then evaluated the complete
articles for eligibility. To avoid inclusion of duplicated
or overlapping data, we compared author names and
institutions where patients were recruited and if sub-
stantial doubts remained, the study reporting fewer
patients was not included in the analysis.
Data extraction
OS was the primary outcome of interest. CSS, PFS,
and DFS were secondary outcomes. The following
details were extracted: name of first author, type of
study, year of publication, number of patients
included in the analysis, disease site, disease stage
(non-metastatic, metastatic, mixed [non-metastatic
and metastatic]), cut-off defining high LDH, and
HRs for OS, PFS, DFS, or CSS as applicable. HRs
were extracted only from multivariable analyses.
When two or more HRs were reported for different
cut-off values, only those above the median LDH
value for that study were considered.
Data collection and statistical analysis
The meta-analysis was conducted initially for all
included studies for each of the endpoints of interest.
Subgroup analyses were conducted for disease site
and stage of disease only for the primary outcome.
Extracted data were aggregated into a meta-analysis
using RevMan 5.3 software (Cochrane Collabora-
tion, Copenhagen, Denmark). Estimates of HRs
were weighted and pooled using the generic inverse-
variance and random-effect model [6]. Analyses were
conducted for all studies, and differences between
diseases were assessed using methods described by
Deeks et al. [7]. Meta-regression analysis was per-
formed to evaluate the effect of LDH cut-off level
(when available) on the HR for OS. Publication bias
for the primary endpoint was assessed by visual
inspection of the funnel plot. Heterogeneity was
assessed with the use of the Cochran Q and I2 sta-
tistics. All statistical tests were two-sided, and statis-
tical significance was defined as p ⬍ 0.05.
Results
Seventy-six studies [8–83] with a total of 22 882
patients were included (Figure 1). Characteristics of
the included studies are shown in (Supplementary
Table I available online at http://informahealthcare.
com/doi/abs/10.3109/0284186X.2015.1043026);
most (95%) were published in the last decade. Among
trials, eight studies regarded gastrointestinal malig-
nancies (4 biliopancreatic, 2 gastric, 1 colorectal and
1 neuroendocrine cancers), seven head and neck can-
cers, seven lung cancers, 12 melanomas, one sarcoma,
one thymic carcinoma, one mesothelioma, one breast
cancer, four mixed or unknown primaries, 16 prostate
cancers, 15 renal cell carcinomas and three testicular
cancers. Number of patients ranged from 35 to 2425.
In all trials patients with mainly metastatic or locally
advanced unresectable disease were included (only
5 trials included stage I–III cancers).

Figure 1. Study flow diagram of included studies.
Overall survival
Seventy-three studies reported HR for OS. Forty-
one studies did not specify a numerical cut-off used
for multivariate analysis; conversely, in 34 studies a
predefined cut-off was reported (median: 245 U/L).
Twelve of the eligible 73 studies (16%) reported a
non-statistically significant HR.
Overall, LDH level was associated with a HR for
OS of 1.7 (95% CI 1.62–1.79; p ⬍ 0.00001; I2 ⫽ 92%,
p for heterogeneity ⬍ 0.00001, random-effect model).
The effect of LDH level on OS among disease
subgroups is shown in Figure 2. The prognostic effect
of serum LDH, among subgroups with two or more
studies, was highest in renal cell carcinoma (HR ⫽ 2.08;
95% CI 1.74–2.5, p ⬍ 0.00001), followed by mela-
noma (HR ⫽ 1.97; 95% CI 1.59–2.43, p ⬍ 0.00001),
gastric cancer (HR ⫽ 1.91; 95% CI 1.38–2.63,
p ⬍ 0.0001), prostate cancer (HR ⫽ 1.9; 95% CI
1.58–2.29, p ⬍ 0.00001), nasopharyngeal carcinoma
Prognostic role of LDH in solid tumors 963
(HR ⫽ 1.74; 95% CI 1.52–1.99, p ⬍ 0.00001), and
lung cancer (HR ⫽ 1.54; 95% CI 1.33–1.78,
p ⬍ 0.00001). The HR for the subgroup of mixed
solid tumors series or unknown primary was 1.74
(95% CI 1.4–2.15, p ⬍ 0.00001). Differences between
disease subgroups were statistically significant (p for
subgroup difference ⬍ 0.00001). Neuroendocrine
tumors, breast cancer, thymic carcinoma, mesothe-
lioma, testicular and colorectal cancer, and sarcoma
data were provided only in one paper each.
For the 15 disease-site subgroups analyzed, there
was statistically significant heterogeneity among trials
of biliopancreatic cancer, renal cell carcinoma, pros-
tate cancer, and melanoma, whereas heterogeneity
among other trials was non-statistically significant.
The scatter plot for the meta-regression is shown in
(Supplementary Figure 1 available online at http://
informahealthcare.com/doi/abs/10.3109/0284186X.
2015.1043026). Overall, there was a nearly statistically
significant association between LDH cut-off and the
HR for OS (p ⫽ 0.11). There was evidence of signifi-
cant publication bias, with several studies reporting
significantly higher results than expected (Figure 3).
Cancer-specific survival
Few studies reported this data, so a formal meta-
analysis was not performed.
Progression-free survival or time to progression
Thirteen trials reported HRs for PFS or TTP. Over-
all, a high LDH level was associated with a poor PFS
(HR ⫽ 1.75, 95% CI 1.31–2.33, p ⬍ 0.0001; I2 ⫽ 86%,
p for heterogeneity ⬍ 0.0001, random-effect model).
Disease-free survival
Only two studies including nasopharyngeal cancer
patients reported HRs for DFS. A high LDH con-
centration was associated with a lower DFS as mul-
tivariate analysis (HR ⫽ 1.68, 95% CI 1.24–2.27,
p ⫽ 0.001; I2 ⫽ 47%, p for heterogeneity ⫽ 0.16, fixed
effect model).
Discussion
Several studies have suggested that elevated LDH is
both a hallmark of aggressive carcinomas and lym-
phomas and associated with an unfavorable outcome.
Indeed, LDH levels are actually included in the
TNM staging system for melanoma [3], defining the
M1c subgroup that is associated with a five-year OS
of 10%. LDH is also considered with respect to the
risk status of testicular cancer, in particular meta-
static non-seminoma germ cell tumors [84].
964 F. Petrelli et al.
Hazard Ratio Hazard Ratio
Study or Subgroup log[Hazard Ratio] SE Weight IV, Random, 95% CI Year IV, Random, 95% CI
1.1.1 Pancreatic-biliary
Masaki 2005 0.01 0.003 4.7% 1.01 [1.00, 1.02] 2005
Furuse 2009 0.615 0.304 0.6% 1.85 [1.02, 3.36] 2009
Nakai 2010 0.255 0.115 2.4% 1.29 [1.03, 1.62] 2010
Haas 2013 0.191 0.192 1.3% 1.21 [0.83, 1.76] 2013
Subtotal (95% CI) 9.0% 1.19 [0.96, 1.48]
Heterogeneity: Tau² = 0.03; Chi² = 9.38, df = 3 (P = 0.02); I² = 68%
Test for overall effect: Z = 1.59 (P = 0.11)

1.1.2 Gastric
Sougioultzis 2011 0.542 0.129 2.1% 1.72 [1.34, 2.21] 2011
Zhao 2014 0.907 0.273 0.7% 2.48 [1.45, 4.23] 2014
Subtotal (95% CI) 2.8% 1.91 [1.38, 2.63]
Heterogeneity: Tau² = 0.02; Chi² = 1.46, df = 1 (P = 0.23); I² = 32%
Test for overall effect: Z = 3.93 (P < 0.0001)

1.1.3 Colorectal
Chibaudel 2011 0.588 0.11 2.5% 1.80 [1.45, 2.23] 2011
Subtotal (95% CI) 2.5% 1.80 [1.45, 2.23]
Heterogeneity: Not applicable
Test for overall effect: Z = 5.35 (P < 0.00001)

1.1.4 Neuroendocrine
Yamaguchi 2014 0.43 0.19 1.3% 1.54 [1.06, 2.23] 2014
Subtotal (95% CI) 1.3% 1.54 [1.06, 2.23]
Heterogeneity: Not applicable
Test for overall effect: Z = 2.26 (P = 0.02)

1.1.5 Nasopharyngeal
Zhou 2011 1.111 0.317 0.6% 3.04 [1.63, 5.65] 2011
Li 2012 0.507 0.238 0.9% 1.66 [1.04, 2.65] 2012
Jin 2013 0.464 0.079 3.2% 1.59 [1.36, 1.86] 2013
Wan 2013 0.966 0.305 0.6% 2.63 [1.45, 4.78] 2013
Tian 2013 0.737 0.318 0.6% 2.09 [1.12, 3.90] 2013
Zeng 2014 0.522 0.179 1.4% 1.69 [1.19, 2.39] 2014
Wei 2014 0.545 0.176 1.4% 1.72 [1.22, 2.44] 2014
Subtotal (95% CI) 8.7% 1.74 [1.52, 1.99]
Heterogeneity: Tau² = 0.00; Chi² = 6.53, df = 6 (P = 0.37); I² = 8%
Test for overall effect: Z = 8.03 (P < 0.00001)

1.1.6 Lung
Ando 2004 0.449 0.483 0.3% 1.57 [0.61, 4.04] 2004
de Jong 2007 0.3 0.1 2.7% 1.35 [1.11, 1.64] 2007
Almasi 2012 0.693 0.261 0.8% 2.00 [1.20, 3.34] 2012
Lee 2014 1.319 0.634 0.2% 3.74 [1.08, 12.96] 2014
Kang 2014 0.41 0.171 1.5% 1.51 [1.08, 2.11] 2014
Wang 2014 0.594 0.114 2.4% 1.81 [1.45, 2.26] 2014
Ulas 2014 0.27 0.138 2.0% 1.31 [1.00, 1.72] 2014
Subtotal (95% CI) 9.8% 1.54 [1.33, 1.78]
Heterogeneity: Tau² = 0.01; Chi² = 8.06, df = 6 (P = 0.23); I² = 26%
Test for overall effect: Z = 5.70 (P < 0.00001)

1.1.7 Renal cell

Atzpodien 2003 0.262 0.134 2.0% 1.30 [1.00, 1.69] 2003
Peccatori 2005 0.888 0.335 0.5% 2.43 [1.26, 4.69] 2005
Donskov 2006 1.131 0.37 0.4% 3.10 [1.50, 6.40] 2006
Escudier 2007 0.519 0.189 1.3% 1.68 [1.16, 2.43] 2007
Richey 2010 0.438 0.194 1.3% 1.55 [1.06, 2.27] 2010
Vermaat 2010 1.281 0.383 0.4% 3.60 [1.70, 7.63] 2010
Culp 2010 0.507 0.141 1.9% 1.66 [1.26, 2.19] 2010
Abel 2011 0.884 0.333 0.5% 2.42 [1.26, 4.65] 2011
Patil 2011 0.658 0.109 2.5% 1.93 [1.56, 2.39] 2011
Armstrong 2012 1.033 0.171 1.5% 2.81 [2.01, 3.93] 2012
Kamba 2014 1.176 0.551 0.2% 3.24 [1.10, 9.54] 2014
Cetin 2014 0.801 0.374 0.4% 2.23 [1.07, 4.64] 2014
Atkinson 2014 1.115 0.342 0.5% 3.05 [1.56, 5.96] 2014
Amato 2014 1.91 0.663 0.1% 6.75 [1.84, 24.77] 2014
Subtotal (95% CI) 13.6% 2.08 [1.74, 2.50]
Heterogeneity: Tau² = 0.05; Chi² = 28.03, df = 13 (P = 0.009); I² = 54%
Test for overall effect: Z = 7.90 (P < 0.00001)

1.1.8 Testicular
Gerlinger 2010 1.224 0.354 0.5% 3.40 [1.70, 6.81] 2010
Subtotal (95% CI) 0.5% 3.40 [1.70, 6.81]
Heterogeneity: Not applicable
Test for overall effect: Z = 3.46 (P = 0.0005)

1.1.9 Prostate
D'amico 2005 1.03 0.173 1.5% 2.80 [2.00, 3.93] 2005
George 2005 0.3 0.156 1.7% 1.35 [0.99, 1.83] 2005
Taplin 2005 0.473 0.118 2.3% 1.60 [1.27, 2.02] 2005
Humphrey 2006 0.306 0.172 1.5% 1.36 [0.97, 1.90] 2006
Saito 2007 0.482 0.236 0.9% 1.62 [1.02, 2.57] 2007
Scher 2009 1.335 0.225 1.0% 3.80 [2.44, 5.91] 2009
Coumans 2010 0.187 0.24 0.9% 1.21 [0.75, 1.93] 2010
Yamada 2011 0.902 0.39 0.4% 2.46 [1.15, 5.29] 2011
Kume 2011 0.358 1.087 0.1% 1.43 [0.17, 12.04] 2011
Narita 2012 1.806 0.666 0.1% 6.09 [1.65, 22.45] 2012
Armstrong 2013 0.56 0.246 0.9% 1.75 [1.08, 2.84] 2013
Omlin 2013 0.555 0.139 1.9% 1.74 [1.33, 2.29] 2013
Sonpavde 2014 1.051 0.113 2.4% 2.86 [2.29, 3.57] 2014
Halabi 2014 0.336 0.096 2.8% 1.40 [1.16, 1.69] 2014
Templeton 2014 0.924 0.213 1.1% 2.52 [1.66, 3.82] 2014
Ferraldeschi 2014 0.464 0.237 0.9% 1.59 [1.00, 2.53] 2014
Subtotal (95% CI) 20.4% 1.90 [1.58, 2.29]
Heterogeneity: Tau² = 0.09; Chi² = 58.03, df = 15 (P < 0.00001); I² = 74%
Test for overall effect: Z = 6.82 (P < 0.00001)

1.1.10 Melanoma
Franzke 1998 0.494 0.132 2.1% 1.64 [1.27, 2.12] 1998
Chiarion-Sileni 2003 1.163 0.222 1.0% 3.20 [2.07, 4.94] 2003
Schmidt 2005 1.03 0.123 2.2% 2.80 [2.20, 3.56] 2005
Soubrane 2005 0.52 0.174 1.5% 1.68 [1.20, 2.37] 2005
Schmidt 2007 0.788 0.195 1.2% 2.20 [1.50, 3.22] 2007
Neuman 2008 0.351 0.126 2.2% 1.42 [1.11, 1.82] 2008
Staudt 2010 1.988 0.347 0.5% 7.30 [3.70, 14.41] 2010
Jakob 2012 1.012 0.2 1.2% 2.75 [1.86, 4.07] 2012
Weide 2012 0.47 0.106 2.6% 1.60 [1.30, 1.97] 2012
Wevers 2013 0.329 0.315 0.6% 1.39 [0.75, 2.58] 2013
Gray 2014 0.399 0.102 2.7% 1.49 [1.22, 1.82] 2014
Gaudy-Marqueste 2014 -0.144 0.341 0.5% 0.87 [0.44, 1.69] 2014
Subtotal (95% CI) 18.2% 1.97 [1.59, 2.43]
Heterogeneity: Tau² = 0.10; Chi² = 55.47, df = 11 (P < 0.00001); I² = 80%
Test for overall effect: Z = 6.28 (P < 0.00001)

1.1.11 Sarcoma
Gonzalez-Billalabeitia 2009 2.239 0.862 0.1% 9.38 [1.73, 50.83] 2009
Subtotal (95% CI) 0.1% 9.38 [1.73, 50.83]
Heterogeneity: Not applicable
Test for overall effect: Z = 2.60 (P = 0.009)

1.1.12 Mixed or unknown

Lagerwaard 1999 0.438 0.082 3.2% 1.55 [1.32, 1.82] 1999
Trivanovic 2009 0.793 0.229 1.0% 2.21 [1.41, 3.46] 2009
Tredan 2011 0.47 0.164 1.6% 1.60 [1.16, 2.21] 2011
Pinato 2014 1.163 0.422 0.3% 3.20 [1.40, 7.32] 2014
Subtotal (95% CI) 6.0% 1.74 [1.40, 2.15]
Heterogeneity: Tau² = 0.02; Chi² = 4.71, df = 3 (P = 0.19); I² = 36%
Test for overall effect: Z = 5.03 (P < 0.00001)

1.1.13 Mesothelioma
Najmi 2014 0.01 0.005 4.7% 1.01 [1.00, 1.02] 2014
Subtotal (95% CI) 4.7% 1.01 [1.00, 1.02]
Heterogeneity: Not applicable
Test for overall effect: Z = 2.00 (P = 0.05)

1.1.14 Thymic carcinoma

Wu 2014 1.025 0.361 0.4% 2.79 [1.37, 5.66] 2014
Subtotal (95% CI) 0.4% 2.79 [1.37, 5.66]
Heterogeneity: Not applicable
Test for overall effect: Z = 2.84 (P = 0.005)

1.1.15 Breast
Liu 2014 0.351 0.14 1.9% 1.42 [1.08, 1.87] 2014
Subtotal (95% CI) 1.9% 1.42 [1.08, 1.87]
Heterogeneity: Not applicable
Test for overall effect: Z = 2.51 (P = 0.01)

Total (95% CI) 100.0% 1.70 [1.62, 1.79]

Heterogeneity: Tau² = 0.01; Chi² = 922.95, df = 72 (P < 0.00001); I² = 92%
Test for overall effect: Z = 20.98 (P < 0.00001) 0.02 0.1 1 10 50
Test for subgroup differences: Chi² = 335.54, df = 14 (P < 0.00001), I² = 95.8% Favours low LDH Favours high LDH

Figure 2. Forest plots showing hazard ratio for overall survival for LDH greater than or less than the cut-off for overall studies and by
disease subgroups.

We performed a meta-analysis of 76 studies found a consistent impact of elevated LDH on sur-

involving 22 882 patients with solid tumors in order vival (HR ⫽ 1.7) among various disease subgroups,
to assess the prognostic effect of serum LDH. We and mainly in advanced disease stages. High serum

SE(log[Hazard Ratio])
0
0.5
1.5
2
0.02 0.1
Subgroups
Pancreatic-biliary
Gastric
Colorectal
Neuroendocrine
Figure 3. Funnel plot of hazard ratio for overall survival for serum LDH level (horizontal axis) and the standard error (SE) for the hazard
ratio (vertical axis). Each study is represented by one circle. The vertical line represents the pooled effect estimate.
LDH was also associated with a reduced PFS in 13
trials. As expected, the magnitude of the effect on OS
was the greatest in melanoma and renal cell carcinoma
other than metastatic (castration-resistant) prostate
cancer. The burden of the data considered (about
50% of the included studies) concerns these neoplas-
tic diseases, in which hypoxia and angiogenic factors
play a crucial role. In particular, in renal cell carci-
noma, a five-parameter-based prognostic score pro-
vided by the Memorial Sloan-Kettering Cancer
Center that is commonly used in patients with meta-
static disease includes LDH levels and correlates these
with outcomes in patients treated in various clinical
trials before and after the era of targeted therapy
[85,86]. The present analysis mainly covered patients
with advanced tumors, which confirms that the prog-
nostic role of LDH currently seems to be confined to
only highly proliferative and metastatic cancers. We
focused on solid tumors, because the prognostic role
of LDH in hematological disease is well known, espe-
cially in high-grade lymphoma where it is elevated in
almost 50% of patients [87]. The novelty of our data
is that it particularly relates to prostate cancer, where
the role of LDH as a prognostic factor has not yet
been fully demonstrated. Several papers reporting the
role of inflammation parameters (neutrophil-lympo-
cyte ratio and C-reactive protein) other than bone-
related biomarkers (e.g. alkaline phosphatase) have
recently been published [88–94]. In particular, LDH
seems to be associated with a poor prognosis in met-
astatic, castration-resistant prostate cancer, and could
thus be valuable for identifying patients who are suit-
able for the earlier use of chemotherapy. Data on
LDH levels and inflammatory parameters could be
useful when starting therapy for prostate cancer and
Prognostic role of LDH in solid tumors 965
Hazard Ratio
1 10 50
Nasopharyngeal Prostate Mesothelioma
Lung Melanoma Thymic carcinoma
Renal cell Sarcoma Breast
Testicular Mixed or unknown
the other metastatic malignancies examined in this
meta-analysis. It is possible that C-reactive protein
reflects the enhanced immune response elicited by a
tumor, which is more intense when tissue necrosis
(and so LDH) and inflammation are high, as occurs
with more aggressive cancer subtypes.
That lactates play a role in cancer cells is unsurpris-
ing, and LDH concentrations in human serum during
neoplastic conditions can be regarded as a marker of
(cancer) the metabolic activity and avid glucose uptake
of cells. Tumor hypoxia actually induces, among other
things, the expression of a hypoxia-inducible factor
(HIF), which is a transcription factor that initiates a
range of activities, including angiogenesis and various
prosurvival mechanisms [95]. In terms of tumor growth,
the local blood supply becomes inadequate, thus requir-
ing angiogenesis and leading to hypoxia. The metabo-
lism of cells is consecutively shifted towards the
anerobic glycolytic pathway (e.g. from glucose to
lactate) through the enhanced expression of glycolytic
enzymes and glucose transporters. This is coupled with
a reduced dependence on the oxidative pathway. Can-
cers are also able to produce lactate due to increased
glycolytic activity, regardless of oxygen availability (the
so-called Warburg effect), which is a phenomenon that
was first described about a century ago as being a con-
sequence of energy requests from tumor cells. Lactate
which is the end product of glycolysis from pyruvate, is
produced in large amounts in highly aggressive tumors
in response to the specific characteristics of the microen-
vironment and the genetic features of neoplastic cells.
Importantly, lactate also constitutes an alternative met-
abolic source for cancer cells [96–98]. The LDH-A
gene promoter possesses two conserved hypoxia
response elements containing functionally-essential
966 F. Petrelli et al.
binding sites for HIF-1 with the consensus sequence
5´-RCGTG-3´, which may strongly suggest an oxygen-
dependent regulation of LDH-5 activity [99].
Recently, high LDH levels have been found to
predict the response to anti-angiogenetic agents,
such as bevacizumab and sorafenib. In two papers,
Scartozzi et al. examined this predictive role, dem-
onstrating that: 1) in subjects with high serum LDH,
bevacizumab confers a higher RR in colorectal
cancer; and 2) in hepatocellular carcinoma treated
with sorafenib, LDH levels seem to predict clinical
outcomes in terms of PFS and OS [100,101].
This meta-analysis does, however, have some
limitations. First, only published data, as opposed to
individual patient data, have been collected. Second,
we found evidence of high heterogeneity among the
trials, as well as a significant publication bias, with
a larger number of trials than expected reporting a
significantly higher effect of LDH levels. Further-
more, we only included studies reporting HRs, while
more than 20 publications reporting on the prognos-
tic value of LDH were excluded (e.g. because only
odds ratios, relative risk for survival, or p for sig-
nificance were reported), possibly introducing bias.
It is notable that almost all of the excluded papers
(the majority analyzing genitourinary tumors, sarco-
mas, melanomas and lung cancers) presented a sig-
nificant association with outcome, thus reducing the
risk that could have changed the final results. Many
other case series, however, were excluded because
serum LDH data was unavailable in the population
analyzed. Third, LDH is influenced by other non-
neoplastic conditions, including heart failure, hypo-
thyroidism, anemia, and lung or liver disease, which
may have influenced the serum concentrations. Most
of the studies included in this meta-analysis did not
explicitly control for such different, benign condi-
tions that may have affected LDH levels. Finally, a
cut-off value associated with a significantly worse
OS cannot be defined, even if the median of the
reported cut-off values is the common upper normal
limit used in most laboratories (245 U/L). Unfortu-
nately, only about 50% of the papers considered
provided details of such a cut-off point, and the
metaregression for correlations of serum cut-off
levels with HRs was not significant. However, to our
knowledge, this is the first meta-analysis to system-
atically confirm the poor prognostic value of high
LDH concentrations in solid tumors. It also involves
22 961 patients included in 76 published studies,
mainly concerning genitourinary and melanoma
tumors. The value of the analysis does, however,
remain confined to advanced tumors with locally
advanced and metastatic disease, and its significance
with respect to the early stages of disease requires
further evaluation.
Recent in vitro studies have shown that inhibiting
LDHA expression may lessen invasiveness and the
metastatic potential of cancer cells by reducing their
proliferation capacity and reversing their resistance
to chemotherapy [102–110]. LDH can thus be
regarded as an ideal target for anticancer therapies.
In conclusion, serum LDH is associated with poor
survival with respect to many solid tumors, and could
be used as a cost-effective prognostic biomarker in
terms of prognostic scores before treating advanced
disease and enrolling patients in prospective trials.
The evaluation of LDH as a therapeutic target is also
warranted, and is the subject of ongoing trials.
Declaration of interest: The authors report no
conflicts of interest. The authors alone are respon-
sible for the content and writing of the paper.
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