S. Huerta1,2, D. H. Wang2, J. Dowell2, W. J. Hittson2, J. R. Torrosi2, H. Illum2 1University Of Texas Soutwhestern,Surgery,Dallas, TX, USA 2North Texas VA Health Care System,Surgery/Hematology Oncology/Radiation Oncolgy,Dallas, TX, USA
Introduction:
Neoajuvant chemoradiation (CRT) is currently the standard of care for patients with rectal cancer. The ability of neoadjuvant CRT to reduce tumor load in rectal cancer is heterogeneous and unpredictable. The nitric oxide (NO) donor DETANONOate reduced tumor load in vitro and in vivo models of rectal cancer subjected to ionizing radiation (IR). Low doses of NO from nitroglycerine (NTG) radio-sensitized breast cancer cells and prostate cancer xenografts. Transcutaneous NTG patches in combination to chemotherapy were safe and effective in patients with lung cancer in clinical trials. Our hypothesis is that NO from NGT can radiosensitize tumors more effectively when added to conventional treatment in patients with rectal cancer.
Methods:
We designed an open label, non-randomized, multi-cohort, dose escalation, Phase I Clincal Trial with primary endpoint to evaluate the safety, tolerability, feasibility and maximum tolerated dose (MTD) of topical nitroglycerin in addition to 5-flourouracil and radiation therapy for neo-adjuvant treatment of loco-regionally advanced operable rectal cancer. A secondary endpoint was rate of pathological complete response (pCR) and tumor response assessed by tumor regression (TGR). Patients were assigned to 4 sequential cohorts (3 each) of escalating dose levels of commercially available nitro glycerin patches (0.2; 0.4; 0.6 and 0.8mg/hour). All patients received radiation therapy [45-50 Gy] in 25-28 fractions to the pelvis along with continuous infusion 5-FU [225mg/m2 / day] for the duration of the radiation therapy. The radiation therapy was planned and delivered as per institutional standard of care.
Results:
From 12/2010 to 8/2014, 15 patients were enrolled in the trial as a dose-escalation protocol. They were all male age (59.9±SD 8.5; range 42-70 years-old). The observed toxicities during the study protocol were mild to moderate and manageable. Four patients developed asymptomatic grade 3 lymphopenia during CRT that resolved promptly upon completion. This was not considered a serious side-effect and was not used for decision making in regards to therapy adjustments or dose-escalation. Two other patients developed grade 3 toxicity (diarrhea and mucositis). These were well managed and were not considered to be related to the NTG patches. Seven patients developed headaches [HA] (5/15 grade I, 1/15 grade II, and 1/15 grade III). One patient in the 0.2 mg dose developed a grade III HA requiring and additional group at this dose. No further grade III HAs were observed following dose escalation. HAs were managed with oral pain medication. Two patients experience pCR (0.2 mg and 0.4 mg), six had a TGR of 1 and three of 2. All of the patients in the 0.6 mg group were down staged from stage III to stage II. Patients in the 8 mg cohort await surgical intervention.
Conclusion:
This data demonstrate that NTG patches can be safely utilized in conjunction with neoadjuvant CRT in patients with rectal cancer.