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Abstract: In this review, we explore the role of stereotactic body radiotherapy (SBRT) and other advanced radiotherapy techniques in the treatment of gastrointestinal malignancies, which primarily involves primary and secondary liver cancers and pancreatic cancers. The review examines radiotherapy in both curative and palliative settings, emphasizing the evolution of SBRT and hypofractionation as alternatives to conventional radiotherapy. We review the recent literature evaluating radiotherapy in the management of unresectable, borderline resectable, and metastatic pancreatic cancer, highlighting recent advances in radiotherapy techniques that aim to improve local control, reduce toxicity, and increase resectability in appropriate patients. For primary liver cancers (hepatocellular carcinoma and cholangiocarcinoma), SBRT has emerged as a potential noninvasive alternative to surgery, particularly in patients with unresectable tumors or those awaiting liver transplantation. The review also provides insights into ongoing clinical trials, comparative studies between SBRT and other local therapies such as radiofrequency ablation, and the use of radiotherapy in managing liver metastases from various primary cancers. Throughout, we emphasize limitations in the available literature and highlight areas of ongoing and future investigation., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Dose escalation radiation therapy such as those delivered by stereotactic body radiation therapy (SBRT) has shown to improve local disease control in multiple types of malignancies. This requires fiducial placement to improve accuracy of treatment and avoid adverse events to adjacent radiosensitive organs during respiration phases. The purpose of this review is to provide updates of recent high-quality articles related to endoscopic ultrasonography (EUS)-guided fiducial placement for gastrointestinal malignancies, particularly in pancreatic cancer, which is expected to be the second leading cause of cancer-related deaths in the USA within this decade., Recent Findings: A recent systematic review and meta-analysis has shown that EUS-guided fiducial placement for gastrointestinal malignancies has excellent technical success and safety profile. Comparative studies of most commercially available fiducial types via a 22-gauge needle system showed that a 0.035 mm diameter and 10 mm long gold fiducial with coiled configuration, hollow core and external helical design might be favoured due to its most balanced performance of visibility, artifact and migration., Summary: A fine balance of performance characteristics of fiducials should be discussed with radiation oncologists to select a suitable and preferred type of fiducials. The comparative studies of other newly developed platinum fiducials and liquid fiducial are pending.

Purpose of Review: Radiation therapy-induced nausea and vomiting (RINV) are common and troublesome symptoms among patients receiving radiation therapy for gastrointestinal cancers. Their impact on function, quality of life and, ultimately, cancer control warrant a review of their incidence, underlying mechanisms, treatments and research themes., Recent Findings: Research in RINV is underrepresented relative to that in chemotherapy-induced nausea and vomiting. The incidence of RINV among patients receiving modern day radiation therapy is questioned and supportive care practice patterns vary among radiation oncologists. Antiemetic guideline recommendations for prophylactic and rescue therapy are based solely on the anatomic region being irradiated and not other patient-related, radiation therapy-related, or organ-specific dosimetric factors that likely modulate the risk of RINV. Dosimetric predictors are likely the most attainable biomarker moving forward, but only early steps have been taken. The small bowel and stomach will be the best first candidates for study among patients with gastrointestinal cancers. Studies of the mechanisms underlying RINV are conspicuously lacking. A new generation of observational studies and therapeutic clinical trials is needed, and more attention must be given to the relative impact of nausea and vomiting on the function and quality of life among specific homogeneous patient populations., Summary: Optimal supportive care strategies for RINV following radiation therapy for gastrointestinal cancers are lacking, and will not be known until future research answers the many open questions regarding the mechanisms underlying RINV, the true incidence and impact of these symptoms among patients and the best way to predict and mitigate them.

Multimodality therapy for gastrointestinal (GI) cancers carries considerable risk for toxicity; even single-modality radiation therapy in this population carries with it a daunting side effect profile. Supportive care can certainly mitigate some of the morbidity, but there remain numerous associated acute and late complications that can compromise the therapy and ultimately the outcome. Gastrointestinal cancers inherently occur amid visceral organs that are particularly sensitive to radiotherapy, creating a very narrow therapeutic window for aggressive cell kill with minimal normal tissue damage. Radiation therapy is a critical component of locoregional control, but its use has historically been limited by toxicity concerns, both real and perceived. Fundamental to this is the fact that long-term clinical experience with radiation in GI cancers derives almost entirely from 2-dimensional radiation (plain x-ray-based planning) and subsequently 3-dimensional conformal radiation. The recent use of intensity-modulated photon-based techniques is not well represented in most of the landmark chemoradiation trials. Furthermore, the elusive search for efficacious but tolerable local therapy in GI malignancies raises the possibility that proton radiotherapy's physical and dosimetric differences relative to conventional therapy may make it better suited to the challenge. In many sites, local recurrences after chemoradiation pose a particular challenge, and reirradiation in these sites may be done successfully with proton radiotherapy.

The aim of this paper was to describe the optimized labeling protocol and quality control measures used in the production of [(90)Y]DOTATOC, starting from three different radioactivity levels to treat one, two, or three patients per therapeutic session. We investigated three different starting radioactivity levels. For the low radioactivity preparation we used 5138±280 MBq of [Y] isotope, for the medium radioactivity preparation we used 8893±900 MBq, and for the high radioactivity preparation we used 11250±715 MBq. The radiochemical purity levels for the low radioactivity preparation, medium radioactivity preparation, and high radioactivity preparation were 99.95±0.09, 99.84±0.34, and 99.84±0.53%, respectively, and the radiochemical yields of the labeling procedures were 77.52±1.28, 75.53±3.72, and 78.00±3.20%, respectively. Media fill validation of the process was performed, and the parameters of pH, bacterial endotoxins, sterility, and osmolality were tested at process control. All radiopharmaceutical preparations satisfied the predetermined specifications fixed in our protocol regardless of the starting radioactivity level. The validation of the method guaranteed the safety and quality of the final products, contributing to providing the basis for constructing an informative and successful clinical trial.

Objectives: To investigate the change in creatinine clearance (CrCl) over time following upper abdominal radiation utilizing a dose-volume histogram (DVH) multivariate analysis., Methods: The study population included 125 patients with gastrointestinal malignancy treated with abdominal radiation therapy at our institution between 1994 and 2006, with available creatinine and DVH information. Kidney dose-volume data collected included mean kidney dose, volume of kidney irradiated, V5, V10, and V20 of total kidney volume, and number of mL of kidney greater than and less than 20 Gy., Results: With a median follow-up of 2.4 years, and a mean kidney dose of 16.2 Gy, a significant correlation between decrease in CrCl and irradiated kidney volume observed was noted for all DVH parameters. The strongest correlations were found when using V5, V10, and number of mL of kidney treated to greater than 20 Gy. There was no significant change in number of antihypertensive medications taken by patients over time, and no relationship between outcome variables and pre-existing comorbidities., Conclusions: This is the first study that we are aware of comparing DVH data with measurement of renal toxicity. We show significant correlations between dose and volume irradiated and decline in renal function. This will be clinically useful when determining a treatment plan for patients with borderline preradiation CrCl and provides evidence that minimizing radiation to the kidney could have important clinical ramifications.

Purpose of Review: The present review is timely owing to the previous paucity of biomarkers, particularly functional noninvasive tests, to evaluate the extent and severity of gastrointestinal toxicity in both animal models of chemotherapy and in cancer patients undergoing chemotherapy., Recent Findings: The most recent findings using noninvasive functional biomarkers now allow longitudinal monitoring of the time course of damage and repair that occurs in the gastrointestinal tract following radiotherapy and chemotherapy. This monitoring has in turn enabled collection of objective evidence for efficacy of new antimucositis agents using animal models and, more importantly, for use in future randomized, double-blind, placebo-controlled clinical trials., Summary: In the past 12 months the C sucrose breath test has been applied to a series of animal models of chemotherapeutic damage, showing rapid monitoring of the efficacy of particular bioactive molecules is now possible at different stages of the damage and repair cycle. This biomarker has also been applied to childhood cancer studies of mucositis and now needs to be used in adult cancers for eventual adoption in routine clinical management of mucositis. An exciting possibility would be extension of the biomarker use to predict damage in other regions of the gastrointestinal tract, including oral mucosa.

Objectives: Neuroendocrine tumors (NETs) are uncommon malignancies with variable natural history and often indolent biological behavior. Over the past decade, novel treatment approaches have been developed. The purpose of this study was to review the experience at the Princess Margaret Hospital in treating patients with NET over the past decade., Methods: The Princess Margaret Hospital Cancer Registry identified 193 patients with NET of the gastrointestinal tract or unknown primary who had their initial visits between 1992 and 2002. A retrospective chart review was performed., Results: The median follow-up duration was 22.6 months. Demographics of the entire cohort of 193 patients were: male, 53%; mean age, 56 years; age-adjusted Charlson score 0, 71%. Anatomic distribution of the primary location revealed that 35% were from the foregut, 40% from midgut, 11% from hindgut, and 14% from unknown origin. Pathological distribution demonstrated that 72% were NET/carcinoids, 21% were islet cell tumors, and 6% were small cell carcinomas. At presentation, 53% of patients had distant metastases and 46% had loco-regional disease. Curative surgery was performed in 35% of the cohort, whereas radiotherapy and chemotherapy of any intent were delivered to 13% and 34%, respectively. For the entire cohort, 5-year survival was 58% (95% confidence interval, 50%-67%). In multivariate analysis, age, location of primary, and curative intent of surgery were independent predictors of survival. Of patients who underwent curative surgery, 86% were alive at 5 years., Conclusion: Patients with NET who are offered curative surgery have a good outcome. Distant metastases are commonly found at presentation and portend a worse prognosis. These patients should be evaluated by a multidisciplinary team regarding new approaches to surgery and other therapies.

Purpose of Review: Health-related quality-of-life studies are now recognized as critical to understand the burden of disease and treatments on patients' well being. Significant advances have been recently achieved in gastrointestinal cancers, including the development and clinical use of new robust quality-of-life instruments. We review recent literature to evaluate whether quality-of-life assessment contributes to optimal patient information and helps treatment choices., Recent Findings: Treatments of gastrointestinal cancers have changed in the last few years with increasing use of multimodal therapies and advances in surgical techniques, especially for low-lying rectal cancers. Concurrent to the development of sphincter-saving procedures, however, the long-term consequences of a permanent stoma on quality of life have been debated. Results of new palliative treatments should also be considered looking at preservation or improvement of quality of life and not only prolongation of life., Summary: Gastrointestinal malignancies impact strongly on patient quality of life due to the aggressiveness of the treatments. Short-term negative effects of surgery and specific deficits in survivors were recently described in gastrointestinal cancers. Baseline quality-of-life data predict length of survival in hepatocarcinoma and metastatic colorectal cancer. Generally, quality-of-life results help to fully inform the patients of the advantages or disadvantages of therapeutic options, including adjuvant and palliative treatments.

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.

Purpose: Preclinical studies have demonstrated significant synergistic tumor cell death when gemcitabine is combined with radiation therapy. The optimal mode for concomitant delivery of drug and radiation therapy remains to be determined. A phase I/II study was undertaken to establish the maximum tolerated dose of infusional gemcitabine when combined with radiation therapy in advanced gastrointestinal malignancies and to assess the response to treatment., Materials and Methods: Twenty-five patients with advanced or recurrent gastrointestinal malignancy were entered in this dose-escalation study. The initial dose of gemcitabine was 50 mg/m2 as a 24-hour continuous intravenous infusion given weekly x 3 with concurrent radiation therapy. The patients were given a week off chemotherapy after the third injection. The radiation therapy was continued during that week. Gemcitabine was thereafter resumed weekly for another 3 weeks or until the patient completed the radiation therapy (whichever was earlier). Five patients were treated at each dose level. The dose of the drug was escalated in increments of 50 mg/m2 if the toxicity was acceptable at the previous level until the maximum tolerated dose was established. Thirteen patients with advanced unresectable colorectal cancer and 12 patients with advanced unresectable pancreaticobiliary cancers were enrolled on the study. Radiation was delivered at 180 cGy/fraction to a total dose of 4000 cGy +/- boost. Because toxicity was severe at the 150 mg/m2 dose level, three additional patients were entered at this dose level. The dose was then dropped to 125 mg/m2, and five more patients were entered at this dose level. Two additional patients were then added in order to assess toxicity. Patient follow-up ranged from 4 to 22 months, and the median was 8 months., Results: All patients were evaluable for toxicity. The doses of 50 and 100 mg/m2 were well tolerated, but at 150 mg/m2, six of eight patients experienced grade 3 or greater toxicity. The dose was de-escalated to 125 mg/m2, and three of seven patients showed grade 3 diarrhea and weight loss. Clinical tumor response was evaluable in 20 patients. Ten patients had a complete clinical response (50%), five patients had a partial response (25%), three patients had no response, and two patients had progression of disease. No patients experienced late toxicities related to either gemcitabine administration or radiation therapy. Twelve patients are currently alive., Conclusion: Based on these results, it appears that the maximum tolerated dose for weekly 24-hour infusion of gemcitabine combined with radiation therapy is 100 mg/m2. Gemcitabine appears to be a potent radiation sensitizer, and when combined with radiation therapy, it has shown encouraging tumor responses. In this study, we found an overall response rate of 75% in patients with locally advanced stage of disease. Further evaluation of gemcitabine at 100 mg/m2 is being undertaken in preparation for a confirmatory multi-institutional phase II study.

Radiation-induced changes of the endocervical glandular epithelium have not been well characterized. Ten specimens (nine from hysterectomy, one from biopsy) from patients with therapeutic radiation to the pelvis for genitourinary or gastrointestinal cancer were examined by histological, immunohistochemical, flow cytometry and image cytometry analysis, and comparison was made to 10 cases of adenocarcinoma in situ (ACIS) of the cervix. Patients ranged from 34 to 68 years of age and received at least 3600 cGy total dosage to the pelvis. Hysterectomy or biopsy was performed six weeks to 17.5 years after completion of radiotherapy. Gross examination of the hysterectomy specimen revealed fibrosis, induration, stenosis, surface irregularity or an unremarkable cervix. Microscopic examination of endocervical glandular epithelium showed sparse, widely spaced glands which were tubular or dilated. Epithelium was simple cuboidal or flattened and consisted of large cells with at most a slight increase in N/C ratio, well-defined intercellular borders and eosinophilic or finely vacuolated cytoplasm. Nuclei frequently showed loss of polarity, one or two prominent eosinophilic nucleoli, and evenly dispersed chromatin; only occasional hyperchromatic cells were seen. Rare scattered cells were immunoreactive for carcinoembryonic antigen in seven of nine cases. One case was hyperdiploid by both flow cytometry and image cytometry. The remaining cases were diploid by flow cytometry and either diploid (five cases) or hypodiploid (four cases) by image cytometry. These findings indicate that pelvic radiation therapy causes characteristic histologic changes in endocervical glandular epithelium that are distinct from those of ACIS of the cervix. Cytoplasmic CEA staining frequently is focally positive and does not allow distinction from ACIS.

Perioperative adjuvant treatment with chemotherapy or radiation therapy has been investigated for colon, rectal, gastric, esophageal, and pancreatic cancers. To date, conclusive benefit had been shown only for colon and rectal cancers. Demonstration that adjuvant therapy can result in reductions in tumor recurrence and cancer death after surgery for large bowel cancer is a major therapeutic advancement, and current clinical trials may yield further incremental improvements. Standard recommendations for adjuvant treatment exist for patients with colorectal cancers who do not take part in these clinical studies. Several factors complicate the assessment of adjuvant therapy for gastric, esophageal, and pancreatic cancers. Some regimens have appeared to offer promise of improved postsurgical outcome, but no adjuvant treatment has established benefit in these sites.

During the past year, little of finite value has been published to change the approach to combined treatment modalities for the patient with gastrointestinal cancer. The value of adding other modalities to surgery to improve the cure rate has been marginal. Neoadjuvant and adjuvant treatment appear to be making inroads into the treatment of esophagus cancer, and newer development of less toxic treatment offers promise for the future. In stomach cancer, combined modality treatment is only of value for patients with locally advanced disease. In the United States, adjuvant chemotherapy is accepted as being of value for patients with colon cancer, and adjuvant treatment with both radiotherapy and chemotherapy is considered to be best for patients with surgically treatable rectum cancer. Primary liver cancer continues to offer a challenge for combined modality treatment, but a call for prospective, randomized control trials seems to be in order.