Key points

Introduction

Approximately 60% of all cancers and 70% of cancer mortality occurs in individuals aged 65 years or older, defining cancer as a disease of older adults. For esophagogastric (EG) cancers, the median age of diagnosis is 67 years and nearly 30% of patients are 75 years or older. However, despite the demographic shifts, older patients with EG cancers are less likely to be recommended for surgery and less likely to receive chemotherapy compared with younger patients, irrespective of tumor stage. Recent trials in neoadjuvant therapy have clearly shown decreases in recurrence and improvements in overall survival; however, combined modality treatments with chemotherapy and radiation are often not recommended for most elderly patients with localized esophageal cancer.

Clearly, patient-related factors, such as comorbidities, functional status, and limited social support, affect the ability to deliver and tolerate treatment and thus have a direct effect on the survival of older adults. However, there are data that elderly patients have a lower likelihood of being offered treatment based on age alone. This finding is not surprising given the underrepresentation of elderly patients in clinical trials and the limited information to guide oncologists on the management of this population. This review evaluates the current knowledge and the remaining challenges in optimally managing elderly patients with esophagogastric cancer.

Introduction

Approximately 60% of all cancers and 70% of cancer mortality occurs in individuals aged 65 years or older, defining cancer as a disease of older adults. For esophagogastric (EG) cancers, the median age of diagnosis is 67 years and nearly 30% of patients are 75 years or older. However, despite the demographic shifts, older patients with EG cancers are less likely to be recommended for surgery and less likely to receive chemotherapy compared with younger patients, irrespective of tumor stage. Recent trials in neoadjuvant therapy have clearly shown decreases in recurrence and improvements in overall survival; however, combined modality treatments with chemotherapy and radiation are often not recommended for most elderly patients with localized esophageal cancer.

Clearly, patient-related factors, such as comorbidities, functional status, and limited social support, affect the ability to deliver and tolerate treatment and thus have a direct effect on the survival of older adults. However, there are data that elderly patients have a lower likelihood of being offered treatment based on age alone. This finding is not surprising given the underrepresentation of elderly patients in clinical trials and the limited information to guide oncologists on the management of this population. This review evaluates the current knowledge and the remaining challenges in optimally managing elderly patients with esophagogastric cancer.

Assessment of the geriatric patient with esophagogastric cancer

Advanced age alone should not preclude patients from receiving standard anticancer therapy. We should acknowledge that older patients have unique issues that require careful consideration, including age and life expectancy, functional status, risk of treatment-related morbidity, competing comorbidities, and desire to receive therapy. However, functional, not chronologic, age should guide treatment decisions. Fit older patients may derive the same benefit from aggressive treatments as younger patients. Age-specific modifications of some treatment paradigms, however, may be appropriate, as therapy tolerance and risk of toxicities vary according to patient age and burden of comorbidities.

Conventional performance status measures, such as the Karnofsky Performance Status (KPS) or the Eastern Cooperative Oncology Group (ECOG) performance status are used to predict treatment toxicity and survival in oncology, regardless of a patient’s age. However, these tools were validated in younger patients and do not address the diversity of health issues of the geriatric cancer population.

Comprehensive geriatric assessment (CGA) has the potential to identify those at risk for treatment complications and functional disability, and to provide an opportunity to implement interventions and support before, during, and after treatment. Geriatricians perform a multidisciplinary assessment that measures independent clinical predictors of morbidity and mortality in older adults ( Table 1 ). This assessment has only recently been evaluated in the oncology setting. One such cancer-specific CGA tool has been developed by Hurria and colleagues. This tool is designed to be mainly self-administered by the patient and feasible in the setting of an outpatient oncology clinic. The Council on Aging Research Group used this tool in a multicenter prospective study to develop a predictive model for chemotherapy toxicity in patients 65 years or older. The model identified age 72 years or older, tumor type (gastrointestinal or genitourinary cancers), polychemotherapy, anemia, creatinine clearance, and geriatric assessment variables (hearing, number of falls, and functional status) as risk factors for toxicity. The CGA tool consisting of 11 questions, including 5 geriatric assessment questions and 6 questions captured in routine daily practice, was recently externally validated and shows it is possible to predict chemotherapy toxicity in adults ( Table 2 ). A high score, 10 to 19 points, was associated with high risk (70.2%, P <.001) of developing grade 3 to 5 toxicity in the validation cohort. Interestingly, physician-rated KPS was not predictive of chemotherapy toxicity in either the developmental or validation cohorts.

There are ongoing multicenter studies evaluating the efficacy of this tool in predicting toxicity among patients with specific tumor types and treatment regimens. CGAs are being implemented and studied in the preoperative setting to predict and stratify older patients at risk for surgical complications and mortality. Further work needs to be done to implement such tools and could potentially affect the choice of treatment regimens. However, these types of models only just start to improve our understanding of how to best assess and risk-stratify our geriatric patients, and to help determine appropriate treatment plans that go beyond just numeric patient age.

Surgery for esophageal cancer

The only predominant curative approach for esophagogastric cancer is surgical resection. Esophagectomy is a complex, invasive procedure with potentially high rates of morbidity and mortality. This risk of the increased postsurgical morbidity in older patients has been debated in the literature and appears to be closely related to hospital volume, surgical expertise, and patient selection. Single-institution reports have demonstrated that esophagectomy can be performed safely in patients 80 years and older ; however, most of the data suggest that older patients are at increased risk for pulmonary and cardiovascular complications. Nationally, mortality risk has been shown to significantly increase proportionally with age: 8.8% of patients aged 65 to 69 years, 13.4% of patients aged 70 to 79, and 19.9% of patients aged 80 years or older.

Tan and colleagues examined the Nationwide Inpatient Sample database for the presence of geriatric events after surgery in patients older than 65. These events included dehydration, delirium, falls, fractures, failure to thrive, and pressure ulcers, which are not commonly reported in the surgical literature. A quarter of all patients undergoing stomach cancer surgery experience a geriatric event, with even higher rates seen in those 75 years and older (data were not provided for esophageal cancer surgery). These geriatric events were associated with prolonged hospitalization (odds ratio [OR] 5.97; 95% confidence interval [CI] 5.16–5.80), higher cost (OR, 4.97; 95% CI 4.58–5.39), lower likelihood of discharge to home (OR 0.27; 95% CI 0.26–0.29), and higher likelihood of death during the index hospitalization (OR 3.22; 95% CI 2.94–3.53) compared with patients who did not experience such events. This is consistent with the surgical literature reporting higher postoperative complications and longer hospitalizations in older patients.

As part of the consideration in determining the optimal approach in elderly patients, the relative benefit of surgery needs to be considered in the context of the high proportion of patients developing metastatic disease within the first 2 years of diagnosis, even with initial presentation of localized disease. Surgery remains the mainstay of early-stage T1 and node-negative esophagogastric cancer. However, the risk of metastatic disease development escalates to reach 60% or higher in patients with T2 or higher T-stage disease, and node positivity at surgery portends a risk in excess of 70% to 80% to develop metastatic disease.

Therefore, the role of esophagectomy in an elderly patient needs to be considered carefully in a select group of robust individuals based on assessment of their physiologic and functional status. These patients may be best served by referral to a high-volume center with appropriate expertise. Preoperative CGA to identify and prevent potential complications specific to older patients, such as early mobilization, avoidance of polypharmacy, and early recognition of postoperative delirium may reduce both cardiopulmonary and geriatric-specific complications and optimize treatment outcomes. Postoperative management of elderly surgical patients needs to be specialized to avoid geriatric events, including delirium, malnutrition, pressure ulcers, falls, infection, functional decline, and polypharmacy. With adequate and collaborative perioperative care between the surgical and geriatric teams, the risk of morbidity and mortality for older patients may be mitigated.

Neoadjuvant chemoradiation

For locally advanced esophagogastric cancers (T3 or node-positive disease), preoperative chemoradiation (CRT) has become an accepted standard treatment. The Chemoradiotherapy for Esophageal Cancer followed by Surgery Study (CROSS) randomized 368 patients with esophageal and gastroesophageal junction cancers to surgery alone or weekly carboplatin and paclitaxel for 5 weeks with concurrent radiotherapy followed by surgery. The CRT arm showed a significant improvement in median survival of 49 months versus 24 months compared with surgery alone. The long-term follow-up data show 14% improvements in 5-year survival in the CRT group compared with surgery alone, as well as significantly lower rates of locoregional and distant progression. Toxicity data show that the treatment can be well tolerated with low rates of grade 3 or 4 toxicity in the CRT arm. However, the median age of the patients in the CROSS trial was 60 years (range 36–79 years), with more than 80% of patients having a World Health Organization performance status score of 0. There is no subset analysis provided for age, making it difficult to generalize the findings to a geriatric patient population.

There are few small, mostly retrospective, studies focused on older patients who have received preoperative chemoradiation followed by esophagectomy. Fogh and colleagues reported no significant difference in mortality in patients older than 70 years compared with younger patients (7% vs 5%) but reported higher rates of cardiac arrhythmias and pulmonary complications requiring intubation in the older patients undergoing surgery. Similar data were reported by Ruol and colleagues, who showed no difference in mortality rates in patients older than 70 years compared to those younger than 70 years old receiving neoadjuvant chemoradiation with 5-fluorouracil (5-FU)/cisplatin with 45 to 50 Gy of radiation followed by esophagectomy. The study was limited by the small number of older patients (n = 31). This study showed similar median survival rates in the older and younger patients (23.1 vs 23.7 months) with similar partial complete response (pCR) rates (26% vs 23%). Older patients had significantly higher rates of cardiovascular complications, with 22% of patients experiencing a myocardial infarction, severe arrhythmia, pulmonary edema, or pulmonary embolism compared with 5% of younger patients ( P = .003).

These studies suggest that a select group of older patients who are good surgical candidates appear to tolerate neoadjuvant treatment with no significant increase in mortality compared with younger patients, but higher rates of cardiopulmonary complications are seen. The limitations of these data are the retrospective nature of the studies and they do not include data on quality of life and functional recovery after treatment.

Definitive Chemoradiation as an Alternative to Surgery

There are many more elderly patients who are not good candidates for esophagectomy on the basis of frailty, medical comorbidities, advanced age, or patient preference. Definitive chemoradiation is an alternative for such patients who can potentially achieve long-term disease control. It is an accepted practice for squamous cell histology. The data are limited but there are studies suggesting that chemoradiotherapy is not only feasible in elderly patients with esophageal cancer, but also those with good functional status can obtain comparable benefit seen in younger patients ( Table 3 ). For elderly, frail patients, this approach of definitive chemoradiation can provide fair rates of clinical complete response of approximately 50% to 60% with median 2-year survival rates of 30% to 40%.

Table 3

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