Radiation-induced bystander effects are defined as biological effects expressed after irradiation by cells whose nuclei have not been directly irradiated. These effects include DNA damage, chromosomal instability, mutation, and apoptosis. There is considerable evidence that ionizing radiation affects cells located near the site of irradiation, which respond individually and collectively as part of a large interconnected web. These bystander signals can alter the dynamic equilibrium between proliferation, apoptosis, quiescence or differentiation. The aim of this review is to examine the most important biological effects of this phenomenon with regard to areas of major interest in radiotherapy. Such aspects include radiation-induced bystander effects during the cell cycle under hypoxic conditions when administering fractionated modalities or combined radio-chemotherapy. Other relevant aspects include individual variation and genetics in toxicity of bystander factors and normal tissue collateral damage. In advanced radiotherapy techniques, such as intensity-modulated radiation therapy (IMRT), the high degree of dose conformity to the target volume reduces the dose and, therefore, the risk of complications, to normal tissues. However, significant doses can accumulate out-of-field due to photon scattering and this may impact cellular response in these regions. Protons may offer a solution to reduce out-of-field doses. The bystander effect has numerous associated phenomena, including adaptive response, genomic instability, and abscopal effects. Also, the bystander effect can influence radiation protection and oxidative stress. It is essential that we understand the mechanisms underlying the bystander effect in order to more accurately assess radiation risk and to evaluate protocols for cancer radiotherapy.

BACKGROUND: Patients with rectal cancer who achieve complete clinical response after neoadjuvant chemoradiation have been managed by organ-preserving strategies and acceptable long-term outcomes. Controversy still exists regarding optimal timing for the assessment of tumor response after neoadjuvant chemoradiation. OBJECTIVE: The purpose of this study was to estimate the time interval for achieving complete clinical response using strict endoscopic and clinical criteria after a single neoadjuvant chemoradiation regimen. DESIGN: This was a retrospective review of consecutive patients managed by 54-Gy and consolidation 5-fluorouracil–based chemotherapy. Assessment of response was performed at 10 weeks after radiation. Patients with suspected complete clinical response were offered watch-and-wait strategy and reassessment every 6 to 8 weeks until achievement of strict criteria of complete clinical response or overt residual cancer. SETTINGS: This study was conducted at a single tertiary care center. PATIENTS: Patients with complete clinical response who underwent a successful watch-and-wait strategy until last follow-up were eligible. Dates of radiation completion and achievement of strict endoscopic and clinical criteria (mucosal whitening, teleangiectasia, and no ulceration or irregularity) were recorded. Patients with incomplete response or with initial complete clinical response followed by local recurrence or regrowth were excluded. MAIN OUTCOMES MEASURES: The distribution of time intervals between completion of radiation and achievement of strict complete clinical response was measured. Patients who achieved early complete clinical response (≤16 wk) were compared with late complete clinical response (>16 wk). RESULTS: A total of 49 patients achieved complete clinical response and were successfully managed nonoperatively. A median interval of 18.7 weeks was observed for achieving strict complete clinical response. Only 38% of patients achieved complete clinical response between 10 and 16 weeks from radiation completion. Patients with earlier cT status (cT2/T3a) achieved a complete clinical response significantly earlier when compared with those patients with more advanced disease (T3b-d/4; 19 vs 26 wk; p = 0.03). LIMITATIONS: This was a retrospective study with a small sample size. CONCLUSIONS: Assessment at 10 to 16 weeks may detect a minority of patients who achieve complete clinical response without additional recurrence after neoadjuvant chemoradiation. Patients suspected for a complete clinical response should be considered for reassessment beyond 16 weeks before definitive management when considered for a watch and wait strategy. See Video Abstract at http://links.lww.com/DCR/A901.

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Nonoperative management of patients with complete clinical response following chemoradiation results in better anorectal function in comparison with patients with near-complete response managed by transanal endoscopic microsurgery. In the absence of clinically detectable residual cancer, this latter approach may result in significant worsening of anorectal function.