Phase I dose escalation trial of nitroglycerin in addition to 5-fluorouracil and radiation therapy for neoadjuvant treatment of operable rectal cancer.

BACKGROUND: Nitric oxide donors decreased cell survival in vitro and tumor load in vivo in models of rectal cancer subjected to ionizing radiation. Nitroglycerin (NTG) transdermal patches, added to chemotherapy, have been shown to improve outcomes in lung cancer patients. METHODS: This open-label, nonrandomized, multicohort, dose escalation, phase I trial had a primary endpoint to evaluate the safety, tolerability, feasibility, dose-limiting toxicity and maximum tolerated dose of topical NTG in addition to 5-fluorouracil and radiation therapy for neoadjuvant treatment of locoregionally advanced operable rectal cancer. The secondary endpoint was rate of pathologic complete response (pCR). Patients were assigned to 3 sequential cohorts of escalating dose levels of commercially available NTG patches (0.2, 0.4, and 0.6 mg/h), each cohort was intended to consist of 3 patients. RESULTS: Thirteen patients were enrolled in the trial as specified in the dose escalation protocol. They were all male with a median age of 59.4 ± 2.5 (SEM) years. The observed toxicities were mild to moderate and manageable. Four patients developed asymptomatic grade 3 lymphopenia during the chemoradiation that resolved promptly upon completion. One patient had a non-ST segment elevation MI and 1 patient developed diarrhea. None of these toxicities were attributed to NTG except for 1 patient who developed a grade 3 headache. This required an additional group of patients at the same dose and no other patient experienced headaches. pCR was 17%. CONCLUSION: NTG patches are well-tolerated and it is feasible to proceed with a phase II trial at the maximum dose examined (0.6 mg/h).

Stereotactic body radiation therapy: normal tissue and tumor control effects with large dose per fraction.

Stereotactic body radiation therapy (SBRT) is a potent noninvasive means of administering high radiation doses to demarcated tumor deposits in extracranial locations. The treatments use image guidance and related advanced treatment delivery technologies for the purpose of escalating the radiation dose to the tumor, while sharply minimizing the radiation doses to surrounding normal tissues. The local tumor control outcomes for SBRT have been higher than any previously published for the radiotherapy of frequently occurring carcinomas. In addition, the pattern, timing and severity of the toxicities have been very different than from those seen with conventional radiotherapy. These issues pose challenges to our understanding of the radiobiological mechanisms and the optimal uses of SBRT. In this review, the clinical characteristics and outcomes of SBRT are presented in the context of their possible underlying mechanisms. While some of these considerations remain theoretical, they may outline at least qualitative understandings of the observed clinical effects, and motivate continuing research into the effects of SBRT that guide its most effective use in the clinic.

Optimizing dose and fractionation for stereotactic body radiation therapy. Normal tissue and tumor control effects with large dose per fraction.

Stereotactic body radiation therapy (SBRT) is a potent noninvasive means of administering high-dose radiation to demarcated tumor deposits in extracranial locations. The treatments use image guidance and related treatment delivery technology for the purpose of escalating the radiation dose to the tumor itself with as little radiation dose to the surrounding normal tissue as possible. The local tumor control for SBRT has been higher than anything previously published for radiotherapy in treating typical carcinomas. In addition, the pattern, timing and severity of toxicity have been very different than what was seen with conventional radiotherapy. In this review, the clinical characteristics and outcomes of SBRT are presented in the context of their underlying mechanisms. While much of the material is unproven and speculative, it at least qualitatively searches for understanding as to the biological basis for the observed clinical effects. Hopefully, it will serve as a motivation for more sophisticated biological research into the effects of SBRT.