Testing the Efficacy of Topical Calcipotriene Plus 5-Fluorouracil Combination to Activate the Immune System Against Precancerous Skin Lesions in Organ Transplant Recipients

Inclusion Criteria:

* Patients who had received a kidney or lung transplant \>= 2 years before enrollment in the study with a stable status of transplanted graft (participants must have visited their transplant specialist within 6 months before enrolling to the study, documenting stable graft safety). The target population includes patients who are on tacrolimus and/or MMF without voriconazole as their immunosuppressive regimen.
* Presence of four to fifteen clinically typical, visible, and discrete AKs in 25 cm\^2 on any of the following anatomical sites: upper extremities, face, and/or scalp.
* Age of at least 18 years. Because no dosing or adverse event (AE) data are currently available on the use of calcipotriene plus 5-FU in participants \<18 years of age, children and adolescents are excluded from this study but will be eligible for future pediatric trials, if applicable.
* Karnofsky performance status \>= 60%.
* Leukocytes \>= 3,000/microliter and \< 12000/ microliter.
* Absolute neutrophil count \>= 1,000/microliter.
* Platelets \>= 100,000/microliter.
* Creatinine =\< 1.5 × institutional upper limit of normal.
* Baseline respiratory requirement for lung transplant recipients:

  * Respiratory rate within 12-18/min
  * PO2 saturation within 90-100mmHg
* Female participants must be non-reproductive potential (i.e., post-menopausal by a history of age \> 50 years old and no menses for \>= 1 year without an alternative medical cause; OR history of hysterectomy, history of bilateral tubal ligation, or history of bilateral oophorectomy) OR must have a negative urine pregnancy test. The effects of calcipotriene plus 5-FU on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because of unknown teratogenic effect, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately.
* Ability and willingness to participate in the study.

Exclusion Criteria:

* OTRs with any sign of organ rejection are not eligible.
* Patients who received any systemic cancer therapy or radiation within =\< 1 year (y) of study enrollment, or have a diagnosis requiring them to receive such treatment(s) are excluded.
* Patients with known dihydropyrimidine dehydrogenase deficiency (due to the higher risk of 5-FU toxicity).
* Patients with known history of hypercalcemia or vitamin D toxicity.
* History of treatment with calcipotriene plus 5-FU within one year before enrollment in the study.
* The treatment area is within 5 cm of an incompletely healed wound or a suspected basal cell or squamous cell carcinoma.
* The treatment area contained hypertrophic and hyperkeratotic lesions, cutaneous horns, or lesions that had not responded to repeated cryotherapy.
* Participants may not be receiving any other investigational agents.
* History of allergic reactions attributed to compounds of similar chemical or biological composition to calcipotriene and or 5-FU
* Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnant women are excluded from this study because there is an unknown but potential risk for teratogenic or abortifacient effects. Also, there is unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with calcipotriene plus 5-FU, breastfeeding should be discontinued if the mother is treated.
* Participants who are HIV-positive will be excluded from the study. There is a higher risk of organ rejection in HIV-positive patients, and also a higher risk of developing skin cancer, related to their infection-associated immunosuppressed state and drug-induced immunosuppression for preventing organ rejection. In addition, considering HIV's adverse effects on CD4+ T cell function and the fact that the topical medication in this study is specifically designed to target CD4+ T cells, we plan to exclude HIV positive patients in order to avoid this confounding factor on the primary endpoint of the study.
* Participants with known history of chronic hepatitis B, or hepatitis C will be excluded from the study in order to avoid confounding an existing condition with an immune response to the study agents.