Abstract
Introduction
Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard
for muscle-invasive bladder cancer (MIBC), however, NAC confers only a small survival
benefit and new strategies are needed to increase its efficacy. Pre-clinical data
suggest that in response to DNA damage the tumor microenvironment (TME) adopts a paracrine
secretory phenotype dependent on mTOR signaling which may provide an escape mechanism
for tumor resistance, thus offering an opportunity to increase NAC effectiveness with
mTOR blockade.
Patients & Methods
We conducted a phase I/II clinical trial to assess the safety and efficacy of gemcitabine-cisplatin-rapamycin
combination. Grapefruit juice was administered to enhance rapamycin pharmacokinetics
by inhibiting intestinal enzymatic degradation. Phase I was a dose determination/safety
study followed by a single arm Phase II study of NAC prior to radical cystectomy evaluating
pathologic response with a 26% pCR rate target.
Results
In phase I, 6 patients enrolled, and the phase 2 dose of 35 mg rapamycin established.
Fifteen patients enrolled in phase II; 13 were evaluable. Rapamycin was tolerated
without serious adverse events. At the preplanned analysis, the complete response
rate (23%) did not meet the prespecified level for continuing and the study was stopped
due to futility. With immunohistochemistry, successful suppression of the mTOR signaling
pathway in the tumor was achieved while limited mTOR activity was seen in the TME.
Conclusion
Adding rapamycin to gemcitabine-cisplatin therapy for patients with MIBC was well
tolerated but failed to improve therapeutic efficacy despite evidence of mTOR blockade
in tumor cells. Further efforts to understand the role of the tumor microenvironment
in chemotherapy resistance is needed.
Keywords
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Article info
Publication history
Published online: December 22, 2022
Accepted:
December 6,
2022
Received in revised form:
November 2,
2022
Received:
September 12,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Published by Elsevier Inc.
