Since radiotherapy for localized muscle-invasive bladder cancer is associated with a
relatively high rate of local recurrence, much effort was put to enhance the efficacy of
radiotherapy by concurrent chemotherapy. For a long time, cisplatin was considered as the
drug of choice in chemoradiotherapy in bladder cancer, although only one randomized trial
has compared these two approaches in bladder cancer (Coppin et al., 1996). In that study, 99
patients were randomly assigned to undergo radiotherapy with or without cisplatin, followed
by elective cystectomy or further radiotherapy. The concurrent cisplatin group had improved
pelvic control of locally advanced bladder cancer with preoperative or definitive radiation,
but has not been shown to improve overall survival. The concern of potential toxicities is also
a problem.
In the Bladder Cancer 2001 (BC2001) trial, the investigators tested if the concurrent use
of a non-platinum regimen, fluorouracil and mitomycin C would be more efficacious than
radiotherapy alone in 360 bladder cancer patients. At 2 years, rates of locoregional disease -
free survival were 67% in the chemoradiotherapy group and 54% in the radiotherapy group.
Five-year rates of overall survival were 48% in the chemoradiotherapy group and 35% in the
radiotherapy group (James et al., 2012). Grade 3 or 4 adverse events were slightly more
common in the chemoradiotherapy group than in the radiotherapy group during treatment
(36.0% vs. 27.5%, P=0.07) The fluorouracil and mitomycin C combination is obviously not
optimal because patient in study group still have 8.5% increase of high-grade toxicities
(although statistically insignificant).
Despite our preclinical data is very inspiring, the potential enhancement of toxicities
by concurrent use of afatinib and radiation is also a big concern. According to the data
in phase I study, the mean Cmax of afatinib after 4-week use of 50mg once daily dose in
5 patients was 66.8(ng/mL) (Murakami et al., 2012) which is equivalent to 138 nM. This
concentration is below most concentration we used in this study. For example, in clonogenic
assay we used 200-1000nM in murine bladder cancer model and 100-500nM in human
bladder cancer model. If future clinical trial of concurrent administration of afatinib and
radiotherapy is planned, the dose must be carefully titrated to ensure the safety in bladder
cancer patients.
In addition, although in animal study we didn’t observe severe diarrhea or weight loss in
mice, the potential additive gastrointestinal toxicity is also important. In LUX-Lung 3
phase III clinical trial of afatinib or cisplatin plus pemetrexed in patients with metastatic lung
adenocarcinoma with EGFR mutations, 95.2% of patients receiving afatinib have diarrhea.
(14.4% ≥ Grade 3), compared with 15.3% all grade diarrhea in chemotherapy group (Sequist
et al., 2013) Similarly, In LUX-Lung 6 phase III clinical trial of afatinib versus cisplatin plus
gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung
cancer harboring EGFR mutations, 88.3% of patients receiving afatinib have diarrhea. (5.4%
Grade 3), compared with 10.6% all grade diarrhea in chemotherapy group (Y. L. Wu et al.,
2014). On the other hand, in Bladder Cancer 2001 trial of radiotherapy with or without
chemotherapy in muscle-invasive bladder cancer, 9.6% in chemoradiotherapy group and
2.7% in radiotherapy group have Grade 3-5 gastrointestinal toxicity (James et al., 2012),
indicating chemotherapeutic agents as radiosensitizers may enhance the already existed risk
of diarrhea. Therefor the handling of potential gastrointestinal toxicity is very important for
further radiosensitizing studies.
Despite the challenges in designing clinical trial of afatinib as radiosensitizer in bladder
cancer, my PhD study provided many precious data for future preclinical and clinical studies.
In 2015 ASCO Annual meeting, Powles et al. reported a phase II/III, double-blind,
randomized trial comparing maintenance lapatinib versus placebo after first line
chemotherapy in HER1/2 positive metastatic bladder cancer patients. (abstr 4505) Although
maintenance lapatinib does not improve outcomes in EGFR or HER2 positive bladder cancer
patients, this is the first personalized randomized trial in metastatic urothelial carcinoma. It
also showed that EGFR and HER2 are still considered important pathways in bladder cancer
therapy, but the selection of appropriate patients may be required to achieve good result.
Just like lapatinib failed to demonstrate radiosensitizing activity in our screening study
but afatinib successes, we need more well-designed study to examine the clinical potential of
new generation EGFR inhibitor like afatinib in bladder cancer treatment.
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