A Phase III Skin Cancer Chemoprevention Study of DFMO: Long-term Follow-up of Skin Cancer Events and Toxicity

1Carbone Cancer Center, University of Wisconsin-Madison.
Cancer Prevention Research (Impact Factor: 4.44). 10/2012; 5(12). DOI: 10.1158/1940-6207.CAPR-12-0233
Source: PubMed


Decreasing the incidence of non-melanoma skin cancer (NMSC) is of great importance in regards to future healthcare services. Given the previously reported preventive effects of α-difluoromethylornithine (DFMO) in skin and colon cancer trials, we determined appropriate cause to update the clinical data on the subjects from the recently reported Randomized, Double-Blind, Placebo-Controlled Phase III Skin Cancer Prevention Study of DFMO. Our intention was to retrospectively assess the further incidence of skin cancer, other malignancies, and adverse events of patients accrued to our phase III skin cancer prevention study of DFMO. Clinical records of 209 UW Health subjects were reviewed, and 2092.7 person years of on study (884.3 person years) and post study (1208.4 person years) follow-up for these patients were assessed for new NMSC events and recurrence rates from the on study period, the post study period, and the two study periods combined. No evidence of increased significant diagnoses or serious adverse events was observed in the DFMO participants. The initially observed, marginally significant reduction (p=0.069) in NMSC rates for DFMO subjects relative to placebo continued without evidence of rebound. Event rates after discontinuation from study for total NMSCs (DFMO 0.236 NMSC/person/year, placebo 0.297, p=0.48) or the subtypes of BCCs (DFMO 0.179 BCC/person/year, placebo 0.190, p=0.77) and SCCs (DFMO 0.057 SCC/person/year, placebo 0.107, p=0.43) are listed. Follow-up data revealed a persistent but insignificant reduction in new NMSCs occurring in DFMO subjects without evidence of latent or cumulative toxicity relative to placebo subjects.

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    • "Please cite this article in press as: Marta Cristina Filipe Simões, João José Simões Sousa, Alberto António Caria Canelas Pais, Skin cancer and new treatment perspectives: A review, Cancer Letters (2014), doi: 10.1016/j.canlet.2014.11.001 [131] [132] [133] [134] and DL-α-tocopherol [135] [136]. Nonetheless, α-difluoromethylornithine and DL-α-tocopherol recently failed to demonstrate any relevant protective effect [126] [136]. "
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    • "These results are evident by the multiple clinical trials for the prevention of NMSCs in humans using COX-2 inhibitor, celecoxib [16] or an ODC inhibitor, DFMO [17], [18]. Clearly, blockade of these molecular targets singly by administering inhibitors of these molecular targets showed a modest success in reducing SCC development in humans [19], [20]. Recently, Meyskens et al. [21] have shown that combined administration of DFMO and sulindac (COX inhibitor) reduced the recurrence of all colorectal adenomas by 70% in resected adenoma patients. "
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    ABSTRACT: Non-melanoma skin cancer (NMSC) is the most common type of skin cancer in Caucasian populations. Its increasing incidence has been a major public health concern. Elevated expressions of ODC and COX-2 are associated with both murine and human NMSCs. Inhibition of these molecular targets singly employing their respective small molecule inhibitors showed limited success. Here, we show that combined blockade of ODC and COX-2 using their potent inhibitors, DFMO and diclofenac respectively abrogates growth of A431 epidermal xenograft tumors in nu/nu mice by more than 90%. The tumor growth inhibition was associated with a diminution in the proliferation and enhancement in apoptosis. The proliferation markers such as PCNA and cyclin D1 were reduced. TUNEL-positive apoptotic cells and cleaved caspase-3 were increased in the residual tumors. These agents also manifested direct target-unrelated effects. Reduced expression of phosphorylated MAPKAP-2, ERK, and Akt (ser(473) & thr(308)) were noticed. The mechanism by which combined inhibition of ODC/COX attenuated tumor growth and invasion involved reduction in EMT. Akt activation by ODC+COX-2 over-expression was the key player in this regard as Akt inhibition manifested effects similar to those observed by the combined inhibition of ODC+COX-2 whereas forced over-expression of Akt resisted against DFMO+diclofenac treatment. These data suggest that ODC+COX-2 over-expression together leads to pathogenesis of aggressive and invasive cutaneous carcinomas by activating Akt signaling pathway, which through augmenting EMT contributes to tumor invasion.
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    ABSTRACT: In this issue (beginning on page 1368), Kreul and colleagues report a retrospective review of long-term efficacy and toxicity for subjects participating in a phase III study of difluoromethylornithine (DFMO) for prevention of nonmelanoma skin cancer (NMSC). They conclude that those treated with DFMO had a nonsignificant, persistent decrease in NMSC after completion of treatment and that treatment with DFMO did not result in late toxicity after the discontinuation of treatment. We review the data on DFMO as a chemopreventive agent for skin and other cancers, discuss the necessary qualities of a cancer chemopreventive agent, and reflect on the requirements for a well-conducted cancer chemoprevention study, including the rationale for long-term follow-up in cancer prevention studies. Cancer Prev Res; 5(12); 1341-4. ©2012 AACR.
    Cancer Prevention Research 12/2012; 5(12):1341-4. DOI:10.1158/1940-6207.CAPR-12-0429 · 4.44 Impact Factor
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