Nutrition and health-related quality of life after multimodality treatment of gastroesophageal cancer

Background: Gastroesophageal cancer (GEC) is notorious for causing extreme weight loss and symptoms contributing to weight loss are often the first sign of the disease. Malnutrition is not only associated with increased morbidity and mortality but does also impact on eligibility for multimodality treatment which might further deteriorate nutritional status and exacerbate weight loss. While nutrition is a key component in the standardized postoperative recovery protocol, nutritional route is not included due to lack of scientific evidence. At Karolinska University Hospital patients undergoing esophagectomy routinely receive a nutritional jejunostomy. Potential advantages of this approach were evaluated in study I. Quality of life measurements does not only assessing overall quality of life but also assess nutritional aspects. Study II assess effects of neoadjuvant treatment on Health-Related Quality of Life (HRQL) while study IV evaluates HRQL on time-to-surgery from neoadjuvant chemoradiotherapy (nCRT). Study III is a pilot-study for pharmacological treatment of nutritional issues in patients operated for GEC where HRQL serves as a secondary outcome.

Aim: The overall aim of this thesis was to investigate measures involved in the multimodal treatment of GEC to improve nutritional aspects and HRQL, enhancing understanding and treatment and ultimately contributing to reduce morbidity and mortality.

Method and results: Study I examined 1871 patients who underwent GEC surgery in Sweden between 2006 and 2017. Multivariable logistic regression showed that postoperative complications were more common in patients with a nutritional jejunostomy (39.0% vs. 44.4%, p=0.019). A sub-analysis demonstrated benefit of jejunostomy among patients with postoperative leakage (OR 0.19 for Clavien-Dindo score ≥ IIIb, range 0.04- 0.94). Study II evaluated the effects of neoadjuvant therapy vs. surgery alone in 361 patients undergoing curatively intended GEC surgery at Karolinska University Hospital between 2013 and 2020. Multivariable linear regression demonstrated less pain and fewer problems related to eating restrictions in patients assigned to neoadjuvant treatment (-11, p=0.004, - 12, p=0.005). Study III assessed safety and tolerability of Octreotide LAR depot, 10mg, administered intramuscularly at 7 days, 1 month and 2 months postoperatively. The study included 20 patients (10 gastrectomy, 10 esophagectomy) and was conducted from September 2021 to October 2023. Of the 20 participants, 19 (95%) completed the treatment. Mild to moderate adverse events were reported in 12 participants (60%). Two patients experienced serious adverse events, although none attributed to the exposure. Study IV was a secondary endpoint analysis within a multicenter randomized controlled trial, in which patients were randomized between standard time-to-surgery (4-6 weeks) and prolonged time-to-surgery (10-12 weeks). Among the 192 patients who completed at least one HRQL-questionnaire, 95 (49%) were assigned to the prolonged time-to-surgery. Preoperatively, after nCRT, patients in the prolonged time-to-surgery group reported better HRQL compared to those in the standard time-to-surgery group, but postoperatively no clinically significant differences were found.

Conclusions: The studies included in this thesis demonstrates beneficial use of selective jejunostomy and improved preoperative HRQL after neoadjuvant treatment compared to surgery alone. It demonstrates tolerability of Sandostatin LAR depot, which might potentially mitigate the undesired postoperative weight-loss in patients with GEC. Finally, the results demonstrates that postoperative HRQL is unaffected by time-to-surgery after esophagectomy for cancer.

List of scientific papers

I. Holmén A, Hayami M, Szabo E, Rouvelas I, Agustsson T, Klevebro F. Nutritional jejunostomy in esophagectomy for cancer, a national register-based cohort study of associations with postoperative outcomes and survival. Langenbecks Arch Surg. 2021 Aug;406(5):1415-1423. https://doi.org/10.1007/s00423-020-02037-0

Il. Holmen A, Jebril W, Ida S, Agustsson T, Lampi M, Rouvelas I, Sunde B, Klevebro F. Effects of neoadjuvant therapy on health-related quality of life for patients with gastroesophageal cancer. Eur J Surg Oncol. 2023 Nov;49(11):107008. https://doi.org/1016/j.ejso.2023.107008

III. Holmén A, Lampi M, Rouvelas I, Sunde B, Agustsson T, Lindberg G, Klevebro F. Postoperative Treatment with Octreotide in Patients with Gastroesophageal Cancer: An Open-Label Phase 2 Study. [Submitted]

IV. Holmen A, Murad F, Nilsson K, Rouvelas I, Lindblad M, Szabo E, Halldestam I, Smedh U, Wallner B, Johansson J, Johnsen G, Aahlin E.K, Johannsessen H-O, Alexandersson von Döbeln G, Hjortland G.O, Wang N, Shang Y, Borg D, Quaas A, Bertella I, Bruns C, Schröder W, Nilsson M, Klevebro F, Sunde B. Health-related quality of life comparing standard and prolonged time-to-surgery after neoadjuvant chemoradiotherapy for esophageal cancer - results from the multicenter, randomized, controlled NeoRes II trial. [Manuscript]