Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy

PURPOSE Risk-reducing surgery for cancer prevention in solid tumors is a pressing clinical topic because of the increasing availability of germline genetic testing. We examined the short- and long-term outcomes of risk-reducing total gastrectomy (RRTG) and its lesser-known impacts on health-related quality of life (QOL) in individuals with hereditary diffuse gastric cancer syndrome. METHODS Individuals who underwent RRTG as part of a single-institution natural history study of hereditary gastric cancers were examined. Clinicopathologic details, acute and chronic operative morbidity, and health-related QOL were assessed. Validated questionnaires were used to determine QOL scores and psycho-social-spiritual measures of healing. RESULTS One hundred twenty-six individuals underwent RRTG because of a pathogenic or likely pathogenic germline CDH1 variant between October 2017 and December 2021. Most patients (87.3%; 110/126) had pT1aN0 gastric carcinoma with signet ring cell features on final pathology. Acute (<30 days) postoperative major morbidity was low (5.6%; 7/126) and nearly all patients (98.4%) lost weight after total gastrectomy. At 2 years after gastrectomy, 94% (64/68) of patients exhibited at least one chronic complication (ie, bile reflux, dysphagia, and micronutrient deficiency). Occupation change (23.5%), divorce (3%), and alcohol dependence (1.5%) were life-altering consequences attributed to total gastrectomy by some patients. In patients with a median follow-up of 24 months, QOL scores decreased at 1 month after gastrectomy and returned to baseline by 6-12 months. CONCLUSION RRTG is associated with life-changing adverse events that should be discussed when counseling patients with CDH1 variants about gastric cancer prevention. The risks of cancer-prevention surgery should not only be judged in the context of likelihood of death due to disease if left untreated, but also based on the real consequences of organ removal.


INTRODUCTION
Prophylactic surgery is a cancer-prevention strategy applied to individuals at risk for developing solid tumors because of pathogenic or likely pathogenic (P/LP) germline gene variants.It is necessary not only to understand surgical risks and alternatives to surgery, such as enhanced surveillance, but also to incorporate lifetime cancer risk estimates when developing a personalized management strategy.1][12] For example, multiple studies have demonstrated that body image and sexual wellbeing were negatively affected after mastectomy. 11,124][15] However, the physical and psychosocial impacts of risk-reducing surgery for other solid tumors is not well known.
Loss-of-function mutations in the tumor suppressor gene CDH1 are causally linked to hereditary diffuse gastric cancer (HDGC) and hereditary lobular breast cancer, 16,17 making this a unique cohort for which there are potentially two indications for risk-reducing surgery.A minority of HDGC cases are attributed to germline variants in CTNNA1. 18,19Riskreducing total gastrectomy (RRTG) is recommended to germline CDH1 P/LP variant carriers because the estimated lifetime risk of diffuse-type gastric cancer is 25%-42%, with some population estimates as high as 80%. 20,21Although recent studies have demonstrated that endoscopic surveillance with random and targeted biopsies can be a reasonable alternative to surgery in some patients, the long-term safety of surveillance is not yet known. 22,23Attempts to risk-stratify individuals on the basis of genotype or family cancer history to help guide clinical management have not been successful. 24,257][28] Although short-term operative risks and early recovery patterns have been described, the long-term consequences of total gastrectomy remain ill defined.In healthy individuals with germline CDH1 variants and an otherwise normal life expectancy, the best estimates of individuals' lifetime risks of HDGC versus the long-term QOL outcomes and psychosocial implications of total gastrectomy are critical to consider to inform preoperative decision making most appropriately.We sought to examine the physical and psychosocial impacts of RRTG in individuals with CDH1 P/LP variants.With a focus on short-and long-term outcomes that encompass both physical health and QOL, we aimed to shed light on the diversity of personal consequences that may guide counseling for risk-reducing surgery and aid decision making.

METHODS
Individuals enrolled in a natural history study of hereditary gastric cancers (ClinicalTrials.govidentifier: NCT03030404) and who harbored a CDH1 P/LP germline variant were eligible for this retrospective analysis.Patients with CTNNA1 variants were excluded.All individuals received counseling for management of gastric cancer risk, including international consensus recommendations for RRTG and the option for annual endoscopic surveillance for those who declined, delayed, or were medically unfit for surgery. 18Individuals who elected for RRTG underwent a standardized preoperative evaluation by a registered dietitian, a clinical pharmacist, a gastroenterologist, and a surgical oncologist.A licensed clinical social worker evaluated patient employment/insurance status, mental health history, alcohol and drug use, and presence of social support system.RRTG was ascribed to individuals without gross findings of gastric cancer at the time of screening esophagogastroduodenoscopy.Operations were standardized and performed by the same surgeon (J.L.D.) with a D1 (perigastric) lymphadenectomy and Roux-en-Y esophagojejunostomy using a 50-cm retro-colic Roux limb.Postoperative adverse events were recorded according to the classification by Dindo et al. 29 Acute morbidity was recorded at 30 days postoperatively and throughout the follow-up period.Postgastrectomy clinical evaluations and nutritional assessments were performed at 1, 3, 6, and 12 months postoperatively and annually thereafter.
Comprehensive clinical questionnaires were administered to individuals with a minimum of 2 years of postgastrectomy follow-up.The National Institutes of Health Healing Experience of All Life Stressors (NIH-HEALS) questionnaire was completed by patients before surgery and at 1, 3, 6, 12, and 24 months after RRTG to assess psycho-social-spiritual healing. 30Subscores were calculated as previously described. 30The Functional Assessment of Cancer Therapy-General (FACT-G) and Gastric (FACT-Ga) questionnaires were used to assess QOL after RRTG. 31QOL measures were determined by calculating physical, social, emotional, and functional well-being scores, and a gastric cancer-specific subscore.Three scores were calculated: FACT-Gastric Trial Outcome Index (TOI), FACT-G, and FACT-Ga as previously described. 31,32We analyzed data from patients who completed baseline surveys and at least one postgastrectomy time point, and excluded those without baseline surveys.One-way analyses of variance were performed to compare scores at baseline and postgastrectomy time points using GraphPad Prism Version 9.3.1 (GraphPad Software, Inc, San Diego, CA).All research-related clinical care was provided at NIH Clinical Center, Bethesda, MD.This study was approved by the institutional review board of the NIH, and all patients provided informed written consent.

RESULTS
Physical and psychosocial outcomes in 126 consecutive individuals undergoing RRTG between October 2017 and December 2021 were analyzed.Most individuals were female (75%) and White (97%) and had a median age of 43 years (range, 19-71) at operation (Table 1 A1, online only).Seven patients exhibited a large gene deletion, two had a start-loss variant, and one had a large duplication variant.
Upper endoscopy was performed before surgery in all patients except one who previously underwent Roux-en-Y gastric bypass (RYGB).Random endoscopic gastric biopsies revealed occult, microscopic foci of signet ring cell carcinomas in approximately half (47.2%, 59/125) of the patients, which is consistent with the disease phenotype. 22,23tal gastrectomy was conducted with an open surgical approach in all but two cases.Median operative duration was 168 minutes (range, 111-373 minutes) with a median estimated blood loss of 50 mL.A concurrent procedure (eg, cholecystectomy) was performed in 21.4% of cases.Gross pathologic examination revealed normal-appearing gastric mucosa in all patients.Pathologic diagnosis of T1aN0 gastric carcinoma with signet ring cell features was  1).There were no cancer recurrences or cancer-related deaths during the follow-up period.

Postgastrectomy GI Symptoms
Many of the classic postgastrectomy syndromes are the consequence of stomach removal and loss of the antireflux mechanism, food storage capacity, and hormone signaling. 33ile reflux was the most pervasive GI symptom, reported by 73.5% (50/68) of patients with a minimum of 2 years of follow-up (Table 3).Bile reflux was classified as mild, moderate, severe, or very severe. 34  intensive nutrition education and frequent counseling by a registered dietitian.

DISCUSSION
Hereditary cancer syndromes present unique opportunities for cancer prevention and challenging decisions for health care providers and patients alike.We elucidated the burden of total gastrectomy for prevention of advanced gastric cancer in individuals with CDH1 P/LP variants.Although occult, early-stage signet ring cell carcinoma is a common finding at RRTG, additional research is needed to elucidate the mechanisms by which some of these lesions will progress to advanced cancer and others will not. 40,41Until accurate cancer risk stratification is available, the risk reduction achieved with RRTG is absolute, albeit consequential.Nearly all patients in this study exhibited at least one chronic sequela of RRTG.With no gastric cancer recurrence or cancer-related deaths in this cohort, we demonstrated the magnitude of acute and chronic effects of RRTG on physical and psychosocial well-being and persistent health changes in multiple body systems.Although the rate of major postoperative complications was low, which speaks to the safety of the operation, nearly all patients experienced the enduring consequences of RRTG that included micronutrient deficiencies, fatigue, dysphagia, bile reflux, and depression.
One aim of this study was to improve our understanding of postgastrectomy outcomes with validated QOL surveys.We found that physical, social, emotional, and functional wellbeing scores significantly decreased in the first month after surgery, then returned to baseline by 6 months, which is similar to previous QOL studies in patients undergoing TG. 42,43 This suggests that resources should be focused on optimizing recovery in the immediate postoperative period.However, we found that QOL questionnaires did not capture many of the challenges faced by patients months after RRTG.Although Worster et al 43 found physical and functional QOL scores returned to baseline by 12 months after gastrectomy, intrusive GI symptoms, such as diarrhea, strict dietary restrictions, and reflux persisted.Muir et al 42 also found QOL scores decreased immediately after gastrectomy, returned to baseline by 12 months, yet declined again at 24 months.In their study, pain, fatigue, insomnia, dyspnea, and loss of appetite were the most common complaints after gastrectomy.Chronic fatigue and weight loss affecting body image have also been reported after gastrectomy. 44Despite potential lifelong morbidity, most patients who undergo RRTG report being satisfied with their decision. 27,45Although QOL assessment tools can be helpful, they are unlikely to capture the complete experience in patients undergoing RRTG.In the current study, one in four patients changed jobs after gastrectomy.Reasons for job change included inability to perform similar occupation tasks as presurgery, chronic   FACT-G and FACT-Ga questionnaires included 27 and 46 items, respectively, scored on a five-point Likert scale from not at all (0) to very much (4).The FACT-Ga TOI was calculated by adding physical and functional well-being scores.The FACT-G total score included physical, social, emotional, and functional well-being scores.The FACT-Ga total score combined the FACT-G score with a 19-item gastric cancer subscale.Examples of physical, social, emotional, and functional well-being items were "I have a lack of energy," "I get emotional support from my family," "I worry that my condition will get worse," and "I am able to enjoy life," respectively.The 19-item gastric cancer subscale score included disease-specific questions such as "I am bothered by reflux or heartburn" and "My digestive problems interfere with my usual activities."(A) FACT-G, (B) FACT-Ga, and (C) TOI scores were calculated in 54 patients with germline CDH1 variants at baseline and 1, 3, 6, 12, and 24 months after risk-reducing total gastrectomy.NIH-HEALS questionnaire included 35 items scored on a five-point Likert scale from strongly disagree (1) to strongly agree (5) with four items reverse scored (6, 23, 28, and 34).(D) Total score and subscores (E) connection to a higher power, community, and family, (F) reflection and introspection or the ability to find meaning and purpose in activities that connect mind and body, and (G) trust and acceptance that caregivers, friends, and family will respond when needs arise were calculated.Examples of questionnaire items included "My situation strengthened my connection to a higher power" for the connection factor, "I gain awareness from self-reflection" for the reflection and introspection factor, and "I am content with my life" for the trust and acceptance factor.(D) Total score and (E-G) subscores were calculated in 54 patients with germline CDH1 variants at baseline and 1, 3, 6, 12, and 24 months after risk-reducing total gastrectomy.*P ≤ .05,**P ≤ .01,***P ≤ .001.FACT-G, Functional Assessment of Cancer Therapy General; FACT-Ga, Functional Assessment of Cancer Therapy-Gastric; NIH-HEALS, National Institutes of Health Healing Experience of All Life Stressors; TOI, Trial Outcome Index.
fatigue, and persistent postoperative GI symptoms such as nausea and poor oral intake.These data are consistent with a report by Hallowell et al 44 demonstrating that patients undergoing TG can experience negative financial consequences because of the inability to return to work or to work full time.Our findings emphasize the importance of access to medical care and health insurance for management of long-term sequelae after RRTG.
The impact of elevated cancer risk because of germline gene mutations and recommendation for risk-reducing surgery are major stressors for individuals and families.Many patients we surveyed had a concurrent diagnosis of mental illness, with anxiety being the most common.Although we did not compare patient-reported anxiety presurgery and postsurgery, multiple studies have shown that presurgery anxiety was significantly reduced postoperatively in women at high risk for breast cancer who underwent bilateral prophylactic mastectomy (BPM). 10,46,47McCarthy and colleagues demonstrated that women who underwent BPM with reconstruction had higher psychosocial well-being scores, yet lower physical well-being scores of the chest and upper body, at 1 and 2 years postoperatively. 10BPM can also negatively affect women's self-esteem and body image, further impairing personal views about sexuality and sex life. 46,47Interestingly, women who underwent psychological consultation before BPM had improved psychosocial outcomes and a more positive body image. 48,49This underscores the importance of formal preoperative psychosocial assessment and interdisciplinary management of individuals being considered for risk-reducing surgery.
In conclusion, risk-reducing surgery for prevention of cancer is associated with a myriad of physical and psychosocial sequelae that may vary greatly by organ system.For individuals at risk for diffuse gastric cancer, an interdisciplinary clinical team is crucial to properly prepare and care for patients who elect for total gastrectomy.A thorough consideration of surgical morbidity and the purported benefits of cancer risk reduction are vital to fully inform all patients with hereditary cancer syndromes who are considering surgery.Alternatives to surgery, such as enhanced surveillance, warrant counseling about risks of a missed cancer diagnosis or development of incurable cancer.For CDH1 variant carriers, the long-term sequelae of total gastrectomy, not just acute operative risk, should be given equal consideration as the chance of developing advanced gastric cancer.

FIG 3 .
FIG 3. FACT-G and FACT-Ga questionnaires included 27 and 46 items, respectively, scored on a five-point Likert scale from not at all (0) to very much(4).The FACT-Ga TOI was calculated by adding physical and functional well-being scores.The FACT-G total score included physical, social, emotional, and functional well-being scores.The FACT-Ga total score combined the FACT-G score with a 19-item gastric cancer subscale.Examples of physical, social, emotional, and functional well-being items were "I have a lack of energy," "I get emotional support from my family," "I worry that my condition will get worse," and "I am able to enjoy life," respectively.The 19-item gastric cancer subscale score included disease-specific questions such as "I am bothered by reflux or heartburn" and "My digestive problems interfere with my usual activities."(A) FACT-G, (B) FACT-Ga, and (C) TOI scores were calculated in 54 patients with germline CDH1 variants at baseline and 1, 3, 6, 12, and 24 months after risk-reducing total gastrectomy.NIH-HEALS questionnaire included 35 items scored on a five-point Likert scale from strongly disagree (1) to strongly agree (5) with four items reverse scored(6, 23, 28, and 34).(D) Total score and subscores (E) connection to a higher power, community, and family, (F) reflection and introspection or the ability to find meaning and purpose in activities that connect mind and body, and (G) trust and acceptance that caregivers, friends, and family will respond when needs arise were calculated.Examples of questionnaire items included "My situation strengthened my connection to a higher power" for the connection factor, "I gain awareness from self-reflection" for the reflection and introspection factor, and "I am content with my life" for the trust and acceptance factor.(D) Total score and (E-G) subscores were calculated in 54 patients with germline CDH1 variants at baseline and 1, 3, 6, 12, and 24 months after risk-reducing total gastrectomy.*P ≤ .05,**P ≤ .01,***P ≤ .001.FACT-G, Functional Assessment of Cancer Therapy General; FACT-Ga, Functional Assessment of Cancer Therapy-Gastric; NIH-HEALS, National Institutes of Health Healing Experience of All Life Stressors; TOI, Trial Outcome Index.
39ruction due to internal hernia in one patient 3.5 months after gastrectomy, and one patient who underwent exploratory laparoscopy for recurrent abdominal pain and had multiple sites of incidental small bowel intussusception.Of all 126 patients, 14 patients (11.1%) developed incisional hernias postoperatively, 13 of whom underwent operative repair.Psychosocial Sequelae of RRTGRRTG imparts lifestyle changes and psychosocial costs that are not well characterized.In patients with a minimum of 24 months of follow-up, 22% (15/68) reported a preoperative diagnosis of generalized anxiety disorder, depression, or bipolar disorder.Anxiety specifically related to the diagnosis of CDH1 P/LP variant was self-reported in four patients.Five patients reported a new diagnosis of depression or anxiety after total gastrectomy.Fifteen (75%; 15/20) were managed with prescription medications.Diagnosis of a P/LP gene mutation can affect family dynamics, employment, insurability, and interpersonal relationships.39Aftertotal gastrectomy, many patients (23.5%; 16/68) reported an employment change during the follow-up period.Occupational changes were often attributed to the inability to perform work because of persistent GI symptoms after gastrectomy, such as nausea, fatigue, and inability to tolerate oral intake or eat frequent meals while working.Two patients changed jobs to have better access to medical care FIG 2. Schematic demonstrating the chronic sequelae and impact on multiple organ systems after riskreducing total gastrectomy.increased from 1 month to 6 months (P 5 .05)and 1 month to 12 months (P < .001)after gastrectomy.Before RRTG, 54 patients completed the NIH-HEALS and FACT-G/Ga surveys and 36, 32, 21, 27, and 11 patients completed the survey at 1, 3, 6, 12, and 24 months, respectively.There was no difference in the overall NIH-HEALS score at baseline compared with 1, 3