Radiation and Immunotherapy in Upper Gastrointestinal Cancers: The Current State of Play.

Radiotherapy remains one of the contemporary cornerstones of cancer treatment in the neoadjuvant, curative, adjuvant and palliative settings, either in isolation or as a multimodal approach. Moreover, recent advances in targeted immune checkpoint therapy have firmly established immunotherapy as the fourth pillar in cancer therapy alongside surgery, chemotherapy and notably radiotherapy. There is emerging evidence to suggest both radioresistance and reduced efficacy of immune checkpoint blockade (ICB) are potentiated by the tumour microenvironment (TME) and in fact modulating aspects of this immunosuppressive milieu is instrumental to unlocking anti-tumour immunity. The response rates of Upper Gastrointestinal (UGI) malignancies to ICB remains modest at 10-15%, compared to melanoma at 20-40%. Harnessing the effects of radiotherapy through remodelling of the TME using ICB as a radiosensitisor is an avenue showing promise. Here we explore the rationale behind combining radiotherapy with ICB, as a symbiotic relationship in shifting the balance in favour of anti-tumour immunity. We discuss the effects of radiotherapy on immunogenic cell death, the concept of the abscopal effect, the importance of the cGAS STING pathway, and their relevance in the context of the tumour microenvironment. Furthermore, dosing and timing of radiotherapy and ICB is now being evaluated for its synergistic effects on host tumour immunity, and we review the ongoing efforts and current available literature for single agent and dual agent ICB in combination multimodal therapy for both locally advanced operable and metastatic disease of the upper gastrointestinal tract.

Radiation-induced damage in the upper gastrointestinal tract: clinical presentation, diagnostic tests and treatment options.

Radiation-induced damage of the upper gastrointestinal (GI) tract results from radiation of GI tumors or structures adjacent to the GI tract. Radiation-induced damages of the upper GI tract may be acute or delayed, and ranges from lack of appetite, mucosal inflammation (i.e. esophagitis, gastritis, duodenitis) to ulcers, which may be complicated by perforation, penetration, bleeding and stenosis. Radiation-related factors as well as individual patient predisposing factors may increase susceptibility to post-radiation damage. High quality evidence for the treatment of radiation-induced GI damage is scarce and the management is often extrapolated from studies on GI lesions of different etiology. Treatment depends on severity and localization of the radiation-induced damage, and ranges from supportive and dietary measures to endoscopic interventions or surgery. Modern radiation techniques may decrease the incidence and severity of the radiation-induced upper gastrointestinal disease.

Radiation-Related Risk of Cancers of the Upper Digestive Tract among Japanese Atomic Bomb Survivors.

As a follow-up to the comprehensive work on solid cancer incidence in the Life Span Study (LSS) cohort of atomic bomb survivors between 1958 and 1998, we report here on updated radiation risk estimates for upper digestive tract cancers. In this study, we added 11 years of follow-up (1958-2009), used improved radiation dose estimates, considered effects of smoking and alcohol consumption and performed dose-response analyses by anatomical sub-site. In examining 52 years'worth of data, we ascertained the occurrence of 394 oral cavity/pharyngeal cancers, 486 esophageal cancers and 5,661 stomach cancers among 105,444 subjects. The radiation risk for oral cavity/pharyngeal cancer, other than salivary gland, was elevated but not significantly so. In contrast, salivary gland cancer exhibited a strong linear dose response with excess relative risk (ERR) of 2.54 per Gy [95% confidence interval (CI): 0.69 to 6.1]. Radiation risk decreased considerably with increasing age at time of exposure (-66% per decade, 95% CI: -88% to -32%). The dose response for esophageal cancer was statistically significant under a simple linear, linear-quadratic and quadratic model. Both linear-quadratic and quadratic models described the data better than a simple linear model and, of the two, the quadratic model showed a marginally better fit based on the Akaike Information Criteria. Sex difference in linear ERRs was not statistically significant; however, when the dose-response shape was allowed to vary by sex, statistically significant curvature was found among males, with no evidence of quadratic departure from linearity among females. The risk for stomach cancer increased significantly with dose and there was little evidence for quadratic departure from linearity among either males or females. The sex-averaged ERR at age 70 was 0.33 per Gy (95% CI: 0.20 to 0.47). The ERR decreased significantly (-1.93 power of attained age, 95% CI: -2.94 to -0.82) with increasing attained age, but not with age at exposure, and was higher in females than males (P = 0.02). Our results are largely consistent with the results of prior LSS analyses. Salivary gland, esophageal and stomach cancers continue to show significant increases in risk with radiation dose. Adjustment for lifestyle factors had almost no impact on the radiation effect estimates. Further follow-up of the LSS cohort is important to clarify the nature of radiation effects for upper digestive tract cancers, especially for oral cavity/pharyngeal and esophageal cancers, for which detailed investigation for dose-response shape could not be conducted due to the small number of cases.

How Sensitive Is the Upper Gastrointestinal Tract to 90Y Radioembolization? A Histologic and Dosimetric Analysis in a Porcine Model.

In 90Y radioembolization, nontarget embolization to the stomach or small bowel can result in gastrointestinal injury, a rare but difficult to manage clinical complication. However, dosimetric thresholds for toxicity to these tissues from radioembolization have never been evaluated in a controlled setting. We performed an analysis of the effect of 90Y radioembolization in a porcine model at different absorbed-dose endpoints. METHODS: Six female pigs underwent transfemoral angiography and infusion of 90Y-resin microspheres into arteries supplying part of the gastric wall. Esophagogastroduodenoscopy was performed after 4 wk to assess interim gastrointestinal health. Animals were monitored for side effects for 9 wk after 90Y infusion, after which they were euthanized and their upper gastrointestinal tracts were excised for analysis. Histologic sections were used to map microsphere location, and a microdosimetric evaluation was performed to determine the absorbed-dose profile within the gastrointestinal wall. RESULTS: 90Y radioembolization dosages from 46.3 to 105.1 MBq were infused, resulting in average absorbed doses of between 35.5 and 91.9 Gy to the gastric wall. No animal exhibited any signs of pain or gastrointestinal distress through the duration of the study. Excised tissue showed 1-2 small (<3.0 cm2) healed or healing superficial gastric lesions in 5 of 6 animals. Histologic analysis demonstrated that lesion location was superficial to areas of abnormally high microsphere deposition. An analysis of microsphere deposition patterns within the gastrointestinal wall indicated a high preference for submucosal deposition. Dosimetric evaluation at the luminal mucosa performed on the basis of microscopic microsphere distribution confirmed that 90Y dosimetry techniques conventionally used in hepatic dosimetry provide a first-order estimate of absorbed dose. CONCLUSION: The upper gastrointestinal tract may be less sensitive to 90Y radioembolization than previously thought. Lack of charged-particle equilibrium at the luminal mucosa may contribute to decreased toxicity of 90Y radioembolization compared with external-beam radiation therapy in gastrointestinal tissue. Clinical examples of injury from 90Y nontarget embolization have likely resulted from relatively large 90Y activities being deposited in small tissue volumes, resulting in absorbed doses in excess of 100 Gy.

Effectiveness of coil embolization in angiographically detectable versus non-detectable sources of upper gastrointestinal hemorrhage.

PURPOSE: To determine whether the effectiveness of arterial embolization in patients with acute upper gastrointestinal hemorrhage is related to the visualization of contrast medium extravasation at angiography. MATERIALS AND METHODS: Transcatheter embolization was performed in 108 patients who experienced acute upper gastrointestinal hemorrhage during a 5-year period. Patient charts were retrospectively reviewed. Thirty-six patients who underwent embolization after angiography demonstrated active contrast medium extravasation from an involved artery. Seventy-two patients underwent embolization in the absence of contrast medium extravasation into a bowel lumen. Embolization technique, requirement for further blood products, need for further surgery, and 30-day mortality were recorded. RESULTS: The gastroduodenal artery (GDA) was embolized in 26 of the 36 patients (72%) with extravasation, and the left gastric artery was embolized in 10 (28%). The GDA was embolized in 64 of the 72 patients (89%) without extravasation, and the left gastric artery was embolized in 13 (18%). After embolization, 23 of the 36 patients (64%) with extravasation and 44 of the 72 (61%) without extravasation required additional blood product transfusions. Seven of the 36 patients (19%) with extravasation and 16 of the 72 (22%) without extravasation required subsequent surgery secondary to bleeding. Thirty-day hemorrhage-related mortality was 17% (six of 36 patients) in the positive extravasation group and 22% (16 of 72 patients) in the negative extravasation group. The treatment success rate was 44% (16 of 36 patients) in the positive extravasation group and 44% (32 of 72 patients) in the negative extravasation group. CONCLUSIONS: In patients with acute upper gastrointestinal hemorrhage, arterial embolization is equally effective in patients who demonstrate active contrast medium extravasation at angiography as in those who do not show contrast extravasation.

Radiation therapy and upper gastrointestinal tract: esophageal, gastric, and pancreatic cancer. Toward new standards?

PURPOSE OF REVIEW: To emphasize the role and place of chemoradiation in the treatment of patients with upper gastrointestinal tract cancer. RECENT FINDINGS: For esophagus cancer, in resectable stages IIA to IIB, squamous cell types, surgery remains standard treatment, and preoperative chemoradiation is investigational. After the results of two randomized trials conducted in France and Germany, however, chemoradiation alone is challenging surgery. In adenocarcinomas, preoperative chemoradiation is under investigation. In both types, new studies incorporating targeted therapies to chemoradiation are starting. For gastric cancer, chemoradiation after operation is standard of care in the United States but is still discussed in Europe. Preoperative chemoradiation is in current development, and future trials will compare preoperative strategies and strategies after operation. For pancreatic cancer, after a curative resection, chemoradiation in the United States and chemotherapy in Europe are standard of care, respectively. An ongoing European trial is comparing these two strategies after operation. SUMMARY: Recommendations are issued from the analysis of recently published clinical trials. New areas of development are discussed.

[Clinical study on treatment of patients with upper digestive tract malignant tumors of middle and late stage with Ginkgo biloba exocarp polysaccharides capsule preparation].

OBJECTIVE: To observe the clinical efficacy of Ginkgo biloba exocarp polysaccharides (GBEP) capsule preparation in treating upper digestive tract malignant tumors of middle and late stage. METHODS: Eighty-six patients of the upper digestive tract malignant tumors were treated with GBEP capsule preparation taken orally. The clinical symptoms and the qualities of life of the patients with single GBEP and combined with operation, radiotherapy or intervention chemotherapy were observed. The tumor size was measured by electronic gastroscope before and after treatment with single GBEP. Objective response rate (RR) of the tumor was calculated. The survival period of patient was observed. The changes of blood routine examination in the patients treated with radiotherapy were observed. RESULTS: GBEP preparation could markedly improve the patients'clinical symptoms. Karnofsky scoring of the patients markedly increased after treatment. There were 2 CR (complete response, 6.3%), 22 PR (partial response, 68.8%)and 5 SD (stable disease, 15.6%) of 32 cases with single GBEP preparation. The survival periods of the 32 cases were markedly prolonged. The preparation could relieve the inhibited hematopietic function and the weight loss due to radiotherapy. CONCLUSION: GBEP capsule preparation has some definite therapeutic effects on upper digestive tract malignant tumors of middle and late stage.