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ALHulais et al. J Cancer Metastasis Treat 2019;5:3 I http://dx.doi.org/10.20517/2394-4722.2018.71 Page 15 of 23

showed that celecoxib attenuated metastasis and tumorigenesis by inhibiting the synthesis of PGE2, thereby
[84]
down-regulating the WNT/LGR5 pathway activity, including for colorectal CSCs . Hence, celecoxib has
shown a range of highly beneficial and intriguing properties as an effective anticancer drug in animal tumor
models and provides an example of a drug affecting the WNT/LGR5 signaling pathway in CSCs to prevent
CSC survival and metastasis.

Clinical studies of colorectal cancer patients receiving treatment with celecoxib over the long-term for
several years have been successfully completed [211-214] . In most of these studies, celecoxib was used in
combination with chemotherapy and showed significant improvements with inclusion of celecoxib, resulting
in decreased rates of metastases and incidence of recurrence. In a large trial from 2006, the results of the
Adenoma Prevention with Celecoxib (APC study) showed that continued dosing (400 mg) of celecoxib
daily in patients diagnosed with colorectal polyposis and treated over prolonged periods of three years
significantly decreased the recurrence of adenoma and advanced adenoma, when compared to placebo [215] . In
follow-up studies, it was reported that although the effects of celecoxib diminished two years after treatment
was halted, there was still a considerable treatment benefit at five years [216,217] . Overall, the risk for advanced
adenoma relative to placebo was lowered by 52% on low-dose 200 mg bi-daily (vs. 57% at 3 years) and 51% on
high-dose 400 mg bi-daily (vs. 66% at 3 years) [217] . Hence, long term use of celecoxib has consistently proven
to significantly lower the formation of advanced colorectal cancers in such studies.

We have previously extensively reviewed the outcomes of human clinical trials with celecoxib to treat cancer
and which have often shown that sustained, long-term use over several years provided significant benefits in
[23]
terms of patient outcomes, particularly against metastatic recurrence of cancers . To summarize from the
trial outcomes, unfortunately many such clinical trials underway during the last decade suffered from being
prematurely terminated because of the growing recognition at the time of cardiotoxic side effects associated
with the use of certain COX-2 inhibitors (coxibs), such as Vioxx (rofecoxib) [218] . Although this resulted in
a total ban for Vioxx, elevated cardiotoxicity was ruled out for celecoxib in 2015, when it was approved by
the USFDA after it was found to be as safe as ibuprofen or naproxen [219] . As an example of one prematurely
terminated study, a Phase II trial was reported in 2018 concerning the effects of celecoxib (400 mg twice
daily, every day) plus or minus chemotherapy with IFL (irenotecan, 5-fluorouracil (FU), and leucovorin;
each cycle comprising IFL over 4 weeks then 2 weeks with no IFL) for previously untreated or unresectable
metastatic CRC confirmed by biopsy [155] .

Unfortunately, because the Phase II trial was prematurely terminated, only short-term use of celecoxib in
patients could be analyzed with follow up to 2 years, and which would not be expected to show significant
effects based on the earlier findings outlined above. This Phase II study was further complicated by a protocol
variation with the inclusion of 81mg aspirin added with celecoxib to mitigate against possible cardiotoxicity
in the high-risk cardiovascular subjects. This trial was limited to a median of three treatment cycles (a total
of ~ 20 weeks of daily celecoxib). Nevertheless, the results showed promise in that PFS and overall survival
(OS) of patients was improved at 8.7 and 19.7 months, respectively when compared to the historical IFL
alone treated controls of 7 and 15 months. After modifying the study protocol, the overall survival was ~91%
at one year and 50% at 2 years (median OS = 24.2 months), and the authors could not exclude the possibility
of added survival benefit with celecoxib slowing progression of disease. A larger, multicentred Phase III trial
(Alliance/SWOG C80702) is underway with FOLFOX (5-FU + oxaliplatin + folinic acid = leucovorin) every
2 weeks for 24 weeks, plus celecoxib (400mg daily treatment extended to 3 years) with longer term follow-up
to include 6-year survival and will complete in December 2019.

CONCLUSION
Based on the supportive findings reviewed here, the importance of cytotoxic drugs targeting the CSC
population has become self-evident, with significant ramifications for the future of anticancer drug design