Comorbidity and Colorectal Cancer

Comorbidity is defined as the presence of one or more disorders in addition to colorectal cancer. Comorbidity plays a role in a patient’s individual risk of mortality and morbidity and may influence tolerance to cancer therapy. A comorbidity assessment is necessary to answer the following questions: Is the patient’s remaining life expectancy likely to be limited by the colorectal cancer or by another comorbid medical condition [1]? Will the comorbid condition(s) affect treatment tolerance? What are the interactions between the comorbid medical conditions and colorectal cancer?

The severity of comorbidity is associated with survival in cancer patients, independent of cancer stage [2]. Not surprisingly, it has been shown that the prognostic importance of overall comorbidity depends on the mortality burden of the index cancer: Comorbidities seem to have the greatest prognostic impact among groups with the highest survival rate and least impact in groups with the lowest survival rate [3]. In some cases, cancer treatment may do more harm than good if tumor complications are unlikely to occur during the patient’s remaining lifetime. As previously mentioned, the majority of patients with colorectal cancer are older than 65 years. It has been estimated that the median number of comorbid conditions in older patients with colorectal cancer is four [4]. In a retrospective study based on cancer registry data, it was found that comorbidity had a substantial influence on colorectal cancer survival [4]. Approximately 18 % of deaths in the study cohort of 29,733 patients with a primary diagnosis of stage 1–3 colorectal cancer aged 67 years or older were attributable to chronic heart failure, chronic obstructive pulmonary disease, or diabetes mellitus. The authors point out that the effect of comorbidity is comparable with the effect of advanced-stage cancer because the predicted 5-year survival in a patients with stage I cancer and comorbidity was approximately 50 %. In comparison, the 5-year survival was approximately 78 % in an older patients with stage I cancer without comorbidity.

The influence of comorbidity on treatment and outcomes in older patients with cancer is not well understood. Some studies indicate that a few specific diseases matter [5], but the overall burden of disease may be even more important [6]. Unfortunately, in the majority of surgical publications, neither specific comorbidities nor the severity of comorbidities are registered preoperatively. Instead, American Society of Anesthesiologists physical status class (ASA class) is employed as a sole measure of comorbidity. ASA class only distinguishes between no systemic disease, mild systemic disease, and severe systemic disease. We will take a closer look at some studies that did measure comorbidity in older patients with colorectal cancer. Zingmond and colleagues studied predictors of serious medical and surgical complications after colorectal resections in 56,621 patients identified from the California hospital discharge database [7]. Independent predictors of serious medical complications were greater age, higher Charlson comorbidity index (CACI) score [8], and emergency surgery, while independent predictors of serious surgical complications were tumor location, greater age, and higher CACI score. Ouellette and colleagues evaluated CACI as a predictor of morbidity and mortality in 239 patients with colorectal carcinoma [9]. They found that CACI correlated with a longer length of stay, perioperative mortality, and overall mortality. However, in that study, CACI did not predict the severity of complications. In a retrospective registry study by Rabeneck and colleagues, 30-day mortality in older patients following surgery for colorectal carcinoma in the veteran affairs health-care system was studied [10]. On a side note, the multivariate analyses were not corrected for emergency versus elective procedures. The study found that predictors of 30-day mortality after rectal and colon cancer resections were age >65 years, comorbidity, and marital status. A study by Rutten and colleagues about total mesorectal excision and age used comorbidity data to show that comorbidity increased with increasing age up to 85–89 years, but they did not study the impact of comorbidity on postoperative morbidity or mortality [11]. Tan and colleagues studied a population of 121 octogenarians undergoing colorectal cancer surgery. In multivariate analyses, ASA class III and CACI scores over 5 were independent predictors of morbidity. Of note, only 13 (12.4 %) of their patients were ASA class III, and the majority of their octogenarians were actually ASA class I. In the preoperative assessment of cancer patients (PACE) study, the association between geriatric domains (activities of daily living (ADL), cognition, depression, and comorbidity), performance status, and fatigue and surgical outcomes in a sample of 460 older cancer patients was studied [12]. The majority of patients had breast cancer (47 %), while 31 % had colorectal cancer. PACE did not include nutritional data. Independent predictors of surgical morbidity were found to be fatigue and dependency in IADL. Comorbidity, measured by Satariano’s index of comorbidities, did not predict postoperative morbidity. In a large study including 84,524 patients in France, 30-day postoperative mortality after CRC resection was independently associated with age 70 years or more, respiratory comorbidity, vascular comorbidity, neurologic comorbidity, emergency surgery, synchronous liver metastases, and preoperative malnutrition [13].

In summary, the available evidence clearly indicates that comorbidity is an independent contributing factor for adverse outcomes after CRC surgery, both when studying the comorbidity burden as well as independent comorbidities. Thus, all studies examining outcomes after CRC surgery should include data regarding comorbidity beyond ASA class. Furthermore, because comorbidity impacts on surgical mortality, morbidity, and survival, there is an obvious need to incorporate a pretreatment comorbidity assessment in all older patients with colorectal cancer.

Adjuvant chemotherapy is indicated in patients with stage III colon cancer in order to eradicate potential residual micrometastatic disease following surgical resection. It has been shown in numerous studies that the receipt of chemotherapy varies with age and comorbidity. Specific comorbidities that are associated with decreased likelihood of receiving chemotherapy are congestive heart failure, chronic obstructive pulmonary disease, and diabetes [14]. More studies looking at the impact of comorbidity on receipt of chemotherapy and chemotherapy toxicity in this patient population are warranted.

Disability and Geriatric Syndromes

In older patients in general, optimizing functional status is one of the major treatment goals. This is also important in all phases of care of older patients with cancer. Being hospitalized is an event that frequently precipitates disability [15]. However, surgical studies dealing with treatment for CRC in older patients rarely include information about preoperative physical function or the adverse effect of surgery on physical function. The most commonly used outcome measures in the surgical literature are postoperative mortality, postoperative morbidity, and survival – thus disregarding one of the main treatment goals: optimizing functional status. It has been shown that seriously ill patients are willing to undergo burdensome treatment for the sake of survival, but not if the consequence is disability or cognitive decline [16]. About one-third of patients older than 70 years of age experience hospitalization-associated disability (defined as the loss of ability to complete one of the basic ADLs needed to live independently: bathing, dressing, rising from a bed or chair, using the toilet, eating, or walking across a room). In clinical practice, the recognition of limitations in functional status is mandatory in order to prevent and manage disability postoperatively. Furthermore, functional status is a powerful predictor of postoperative outcomes [6, 9, 12, 17–19]. Measuring preoperative functional status is particularly important in older surgical patients, where the proportion of patients with disabilities is higher than in younger patient cohorts. Furthermore, functional status is one of the most powerful predictors of survival in general [20] and thus need to be incorporated in an overall treatment plan weighing risks and benefits for cancer patients.

The long-term effects of treatment for CRC on disability have been evaluated in population-based studies. Hewitt and colleagues found that cancer survivors in general were more likely to report limitations of ADLs or instrumental ADLs and functional disabilities than individuals without a history of cancer [21]. This effect was less evident for men with a history of CRC. Lawrence and colleagues studied the effect of abdominal surgery on functional status [22]. They found that potentially modifiable independent predictors of ADL and IADL recovery were preoperative physical conditioning and depression, in addition to serious postoperative complications. The clinical course of functional recovery varied across different measures, and protracted disability at 6 months after operation was substantial.

The term “geriatric syndromes” is used by geriatricians to highlight the unique features of health conditions that are commonly seen in older people. Examples of geriatric syndromes are falls, frailty, functional decline, delirium, and incontinence. These syndromes are difficult to capture in established disease categories. For research purposes, the concept of geriatric syndromes is still poorly defined. A common feature of geriatric syndromes is that they are multifactorial [23]. Multiple organ systems are involved, and the chief complaint may not necessarily involve the site of the physiological insult. Instead, the symptoms arise from the organ with the least physiological reserves. This may be illustrated with a clinical example commonly seen: An older patient develops delirium because of a urinary tract infection (UTI). Even though the pathology is located in the bladder, the patient presents with disorganized thinking and inattention instead of frequent and painful voiding. Delirium in the course of an infection or after surgery is often seen in patients with limited cognitive reserves. Delirium cannot be explained by a single cause (UTI), but it occurs because the patient has impairments in multiple domains. Due to impairments such as comorbidities, cognitive impairment, and limited social support, the patient is vulnerable, and the UTI may be viewed as a precipitating event that then triggers the syndrome of delirium. This way of thinking is useful for understanding how to prevent disability and geriatric syndromes in older patients undergoing treatment for CRC. Surgery and subsequent hospitalization lead to functional loss, and several factors contribute to this negative spiral. A first step for successful prevention is the identification of pretreatment determinants of vulnerability, such as higher age (especially age over 85 years), poor mobility, comorbidity, cognitive dysfunction, dependency in ADLs and IADLs, depression, and geriatric syndromes. These factors are assessed through a geriatric assessment (Chap. 5). The next step is to minimize the surgical trauma, for example, through the enhanced recovery after surgery (ERAS) principles proposed by Kehlet and colleagues [24], or by choosing minimally invasive surgery when possible. Postoperatively, factors such as early ambulation, early nutrition, and early return to home may facilitate recovery. It is important to avoid enforced dependence, a disturbing environment (distortion of the night-day cycle, frequent personnel changes, noisy environment), and polypharmacy. A planned discharge from the hospital is easier when an early assessment of post-discharge needs is performed, thus avoiding a rushed planning immediately before discharge, which increases the risk of overlooking important factors that may contribute to rehospitalization.

Frailty is a geriatric syndrome that attracts special attention from researchers and clinicians who deal with older patients. Frailty describes “an elderly patient who is at heightened vulnerability to adverse health status change because of a multisystem reduction in reserve capacity,” but after years of debate, it remains controversial how to identify frailty in an individual patient [25]. Treatment modalities such as surgery and chemotherapy put a cancer patient at risk of complications and toxicity, and identifying frailty is thus particularly important in older patients with cancer. Within geriatric oncology, a frailty definition derived from criteria first described by Winograd and later modified by Balducci has been proposed [26]. Based on a geriatric assessment (GA), an older adult is considered frail when fulfilling any of the following criteria: dependency in activities of daily living (ADL), three or more comorbid illnesses, the presence of geriatric syndromes (e.g., dementia, malnutrition, depression, delirium, and falls), or age >85 years. This may be considered a multicomponent phenotype of frailty, and deficits across different health domains, such as clinical, psychological, and functional, are expected to predict treatment tolerance and life expectancy. Rockwood and colleagues have proposed an approach to defining frailty where accumulation of deficits is counted. The more deficits you have, the frailer you are [27]. In Rockwood’s definition, a frailty index is constructed based on a GA [28]. Within the geriatric and biogerontological literature, a widely accepted definition of frailty is based on data from more than 5,000 community dwelling individuals aged 65 years and older who participated in the cardiovascular health study [29]. The physical phenotype of frailty (PF) is defined as fulfilling at least three of the following five criteria: unintentional weight loss, exhaustion, slow walking speed, low physical activity, and weakness. This approach to defining frailty disregards comorbidity and cognition. A physiologic loss of reserves is identified through clusters of physical impairments. PF predicts incident falls, hospitalizations, worsening mobility, and deaths in large cohorts [29, 30]. Two studies have looked at whether PF predicts postoperative complications after CRC surgery, and the results were conflicting [31, 32]. To my knowledge, no studies have specifically studied the impact of PF on chemotherapy toxicity in older patients with CRC.

Dementia is a geriatric syndrome that impacts delivery of care for CRC. Little data is available, but a few studies have specifically investigated how a diagnosis of dementia influences CRC diagnosis, treatment, and survival. In one study, based on cancer registry data, patients with a mental disorder had a greater likelihood of being diagnosed at an unknown stage or being diagnosed at autopsy [33]. Thirteen percent of patients with a diagnosis of dementia in that study did not receive any treatment for their CRC, and for patients with stage III CRC, 79 % did not receive adjuvant chemotherapy. Less than 10 % of the patients in the study had dementia, and registry data must be interpreted with caution because dementia is under diagnosed in the elderly. In another study from 2004, also based on cancer registry data from the USA, Gupta and colleagues reported that patients with dementia were twice as likely to be diagnosed with colon cancer after death [34]. They also found that patients with stage I to III disease were half as likely to undergo surgical resection for their colon carcinoma.

Conclusion

For older patients with CRC, there is a large body of evidence indicating that comorbidity, disability, and geriatric syndromes impact on diagnosis, treatment, toxicity, morbidity, and survival. If these factors are not taken into consideration, there is a risk of both overtreatment and under-treatment. A geriatric assessment involves these important patient factors and allows for individualized treatment decisions.