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Salleh et al. J Cancer Metastasis Treat 2020;6:31 I http://dx.doi.org/10.20517/2394-4722.2020.70 Page 5 of 9

demonstrated that patients receiving modified-FOLFIRINOX therapy had decreased levels of CA 19-9
and that this decrease in CA 19-9 was found to be associated with a significantly longer median OS of
[29]
[30]
patients . In another study, Aoki et al. determined the prognostic significance of decreased CA 19-9
after receiving neoadjuvant therapy in patients with PDAC. The authors found no increase in CA 19-9
levels in patients receiving neoadjuvant therapy and that the responder group demonstrated a lower risk of
[30]
hepatic recurrence compared to the non-responder group . Overall, these studies indicate the importance
of evaluating CA 19-9 levels as a prognostic biomarker in monitoring the response to treatments for PDAC.

[31]
Chiorean et al. conducted a randomized phase III trial (MPACT) to evaluate the effect of weekly nab-
paclitaxel plus gemcitabine over gemcitabine alone on CA 19-9 levels at eight-week intervals as a predictor
of OS in metastatic pancreatic cancer patients. The authors observed that patients treated with nab-
paclitaxel plus gemcitabine had better outcomes compared with gemcitabine alone and that the improved
outcomes were associated with decreased levels of CA 19-9 compared to increased or static levels. In the
same context, there was a statistically significant survival advantage for patients receiving nab-paclitaxel
[31]
plus gemcitabine vs. gemcitabine alone . In addition, an abrupt decrease in CA 19-9 levels was observed
[31]
in each of the two treatment arms during the initial eight weeks period of treatment . Moreover,
[31]
prolonged OS and PFS has also been found to be associated with a decline in CA 19-9 levels . Overall,
these findings confirmed the applicability of CA 19-9 as an early biomarker to access the anti-tumour
efficacy of therapeutic agents for metastatic pancreatic cancer patients.

Advantages of serum CA 19-9 levels as a biomarker for defining the surgical resectability in
PDAC patients
Given that the CA 19-9 levels were positively correlated with the OS, several studies evaluated an
association between CA 19-9 and tumour resectability. While surgical resection remains one of the
potential curative options for PDAC, many cases are not amenable to surgical resection at the time of
evaluation [32-35] . For that reason, identifying unresectable patients preoperatively is vital to avoid undesired
surgery [32-35] . For this reason, the use of serum CA 19-9 levels pre-operatively has been extensively evaluated
to determine resectability in pancreatic cancer patients [32,33,36-40] .

[40]
Heger et al. investigated the dynamics of CA 19-9 levels during neoadjuvant treatment (NT) in order
to predict resectability and survival. The authors noticed a significant correlation between the reduced
levels of CA 19-9 with resectability and OS. Importantly, a significant difference in CA 19-9 levels was
observed following the treatment with FOLFIRINOX (FOL) as patients treated with this regimen had a
[40]
significantly higher resection rate compared to those treated by gemcitabine-based NT . Furthermore, the
combination of NT and FOL was found to be associated with a significantly improved survival rate among
[40]
resected pancreatic cancer patients . This study corroborates findings by Bolton et al. who delineated
[41]
their experience and correlated the findings between borderline resectable pancreatic cancer (BRPC) vs.
initially resectable pancreatic cancer (IRPC) patients receiving neoadjuvant therapy. While no significant
differences were observed in the OS responses between IRPC and BRPC prior to multiagent neoadjuvant
[41]
therapy, BRPC patients treated with neoadjuvant therapy experienced increased OS . Also, patients with
a high College of American Pathologists (CAP) score or a less than 50% increase in CA19-9 levels had
[41]
longer survival than patients with a low CAP score and > 50% CA19-9 levels . Importantly, compared to
all other treatments, FOLFIRINOX treatment followed by neoadjuvant therapy significantly improved the
[41]
survival response in BRPC patients . Overall, these findings indicate that multiagent neoadjuvant therapy
is associated with an increased survival rate, which is correlated with a decrease in CA 19-9 levels when
compared to other neoadjuvant therapies.

[42]
Notably, these findings appear to be consistent with the studies by van Veldhuisen et al. , who evaluated
the diagnostic accuracy of serum CA 19-9 in combination with RECIST-response on CT imaging to predict
the resectability of locally advanced pancreatic cancer (LAPC) following induction chemotherapy. The