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Daily treatment with nicotinamide, an active water-soluble form of vitamin B3, failed to reduce the risk of non-melanoma skin cancer in solid-organ transplant recipients with a history of skin cancer, a phase III study in Australia found.

In the ONTRANS trial, the number of new keratinocyte cancers was nearly identical with 12 months of twice-daily nicotinamide compared with placebo (207 vs 210; rate ratio [RR] 1.0, 95% CI 0.8-1.3, P=0.96), reported Diona Damian, PhD, of the University of Sydney at Royal Prince Alfred Hospital, and colleagues in the .

Incidence of basal-cell and squamous-cell carcinomas at 12 months were also no different between the two groups, respectively:

• Basal-cell: 69 vs 59 (RR 1.4, 95% CI 0.8-2.3)
• Squamous-cell: 138 vs 151 (RR 0.9, 95% CI 0.6-1.2)

The study results stand in contrast to the ONTRAC (Oral Nicotinamide to Reduce Actinic Cancer) trial, which showed a 23% lower rate of non-melanoma lesions with nicotinamide in high-risk, immunocompetent participants. But the potential benefit in an immunosuppressed population was unclear, leading to the current trial.

Although ONTRANS (Oral Nicotinamide to Reduce Actinic Cancer After Transplant) was stopped early due to poor recruitment (158 out of a planned 254 participants), "the interpretation of the results is straightforward," wrote David M. Miller, MD, PhD, and Kevin Emerick, MD, both of Harvard Medical School in Boston, in an accompanying the study. "Nicotinamide lacks clinical usefulness in preventing the development of keratinocyte carcinomas in solid-organ transplant recipients."

Yet the prior results in immunocompetent patients has led to widespread use.

"In a involving clinicians, nearly one half of respondents were reported to routinely recommend nicotinamide therapy to solid-organ transplant recipients, even though this population was not represented in the 2015 ONTRAC trial," the editorialists noted. "The lack of a between-group difference with regard to the primary endpoint in the current trial will probably change the practice of many skin-cancer physicians."

Damian's group explained that the necessary immunosuppression to prevent organ rejection is associated with a significantly increased risk of keratinocyte cancer.

Current strategies to reduce skin-cancer morbidity among these patients include the initiation of mTOR inhibitor-based immunosuppressive regimens, as well as the use of chemoprevention with oral retinoids. "Nevertheless," they wrote, "because of cost, adverse effects, and rebound neoplasia, the uptake of systemic retinoids in routine clinical practice has varied."

And while the use of sunscreen is effective in preventing actinic keratosis and squamous-cell carcinoma, "many transplant recipients do not routinely use sunscreen," they observed.

Miller and Emerick pointed out that while immune checkpoint inhibitors have revolutionized the treatment and management of high-risk and advanced melanoma, these therapies must be used with caution in solid-organ transplant patients as they can cause allograft rejection. Thus, "the goal to both minimize risk factors before transplantation and to mitigate the development of keratinocyte carcinomas after transplantation continues," they added.

ONTRANS was a multicenter, double-blind, randomized controlled trial involving 158 solid-organ transplant recipients who had had at least two histologically confirmed keratinocyte cancers in the past 5 years, and who had undergone kidney (45%), liver (28%), or heart or lung (27%) transplantation at least 12 months previously.

Participants were randomly assigned in a 1:1 ratio to either oral nicotinamide (500 mg) or placebo twice daily for 12 months.

Adverse events (AEs) were similar in the two groups, with the most frequent AEs being infections (mostly respiratory, urinary tract, and skin). Three systemic cancers were diagnosed in the placebo group (metastatic squamous-cell carcinoma, lung cancer, and liver angiosarcoma) and one in the nicotinamide group (renal cell carcinoma with fatal post-nephrectomy complications).

As ONTRANS failed to meet its recruitment goal, the trial was underpowered, Damian and colleagues acknowledged. Other limitations cited included that the number of keratinocyte cancers detected was lower than anticipated.

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