The optimal treatment for locally advanced esophageal cancer is trimodality therapy (surgery, radiation, and chemotherapy) or chemoradiation. However, locoregional failure is at least 50%. A major past study (Intergroup 0123) attempted to escalate the radiation dose from 50.4 Gy to 64.8 Gy but this showed no difference in survival. However, many of these deaths occurred at or before even 50.4 Gy was delivered, so perhaps modern RT techniques (IMRT and/or protons) can allow for safer delivery of higher doses of RT. These techniques allow for dose escalation in the form of an SIB. 

The present study is a phase I/II trial evaluating the safety and efficacy of an SIB approach for unresectable locoregionally advanced esophageal patients, which entailed delivery of 50.4 Gy to subclinical areas at risk and 63.0 Gy to the gross tumor and involved nodes, all given in 28 fractions.  

46 patients received this therapy, either with protons or photons. 24% of patients were ultimately able to receive surgery. No patients experienced grade 4 or 5 toxicity. There were 10 acute grade 3 events which included esophagitis, dysphagia, and anorexia. There were 3 late esophageal strictures. The actuarial local recurrence risks were 22%, 30%, and 33% at 6 months, 1 year, and 2 years, respectively. 33% of patient experienced local failure and the medial overall survival was 21.5 months. An exploratory analysis suggested that this local control compares favorably with standard radiation approaches. These findings are encouraging and support the initiation of larger trials to further study the safety and efficacy of this approach. 

Reference (PubMed Link): Chen D, Menon H, Verma V, et al. Results of a phase 1/2 trial of chemoradiotherapy with simultaneous integrated boost of radiotherapy dose in unresectable locally advanced esophageal cancer. JAMA Oncol 2019.

Key Institution: MD Anderson Cancer Center, Houston, Texas
Keywords: Unresectable esophageal cancer, simultaneous integrated boost 

NBTXR3 is a spherical nanoparticle composed of crystalline hafnium oxide with a negatively charged phosphate coating. The particles can be administered into the tumor. Initial phase I trial evaluated dose escalation to obtain an optimal dose. Patients then received pre-operative radiotherapy followed by surgical resection. Initial studies showed a 40% tumor shrinkage with median residual tumor cells 26%. This trial concluded that the optimal nanoparticle volume was 10% of tumor size. The present trial then evaluated the use of NBTXR3 + RT versus RT alone followed by surgery for both groups. The pathologic complete response (CR) rate was 16% in NBTXR3 + RT versus 8% in RT alone. There was an absolute improvement in R0 resection of 12% (77% vs 64%, p=0.04). There were no significant differences in toxicity between the two groups. Overall, this is a new technology that requires ongoing study to further establish its value. This study did not show a survival benefit, but long-term follow-up will confirm whether this benefit exists.

Reference (PubMed Link): Bonvalot S, Rutkowski PL, Thariat J, et al. Nbtxr3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (act.In.Sarc): A multicentre, phase 2-3, randomised, controlled trial. Lancet Oncol 2019;20:1148-1159.

Key Institution: Multi-Center International Trial (Nanobiotix)
Keywords: Nanoparticles, sarcoma, radiosensitizer

Immunotherapy continues to revolutionize the treatment of metastatic cancer with expanding applications across many tumor types. There is significant interest in combining radiation therapy with immunotherapy to potentially enhance immune responses and trigger abscopal effects. While there is some thought that SBRT may be particularly effective at triggering immune responses when compared with conventional fractionation, the safety of combining SBRT with immunotherapy and the number of lesions that should be treated remains unclear. In this prospective phase I trial of patients who had progressed on standard therapies, SBRT followed by pembrolizumab appeared to be safe. The overall response rate was encouraging in this population of patients not selected forPD-L1 expression, providing preliminary support for tumor debulking with SBRT and possible evidence of synergism. Furthermore, the correlation of interferon-gamma gene expression after SBRT with the development of abscopal responses suggests that this maybe a helpful biomarker for future studies. Ultimately, the progression-free and overall survival in this heterogenous group of patients with metastatic disease remains poor, and this approach will need to be tested in randomized trials.

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