Approach to the care of colorectal cancer survivors

INTRODUCTION — 

The number of long-term survivors of colorectal cancer (CRC) has increased as death rates from CRC have declined progressively in the United States and in many other Western countries. CRC survivors are experiencing normal issues of aging, which may be compounded by the long-term effects of prior cancer and cancer therapy. Long-term CRC survivors are at risk for recurrent CRC, a new primary CRC, other cancers, and both short- and long-term treatment toxicity. Additional issues for cancer survivors include psychological, reproductive, genetic, social, and employment concerns.

This topic review will present an approach to the care of the adult survivor of CRC who completes therapy. An overview of cancer survivorship for primary care and oncology providers and post-treatment surveillance after CRC treatment is discussed separately.

●(See "Overview of cancer survivorship care for primary care and oncology providers".)

●(See "Post-treatment surveillance for colorectal cancer".)

DEFINITION — 

For this overview, we define a CRC survivor as an individual who has completed treatment for CRC (ie, surgery, chemotherapy, and/or radiation therapy) and has no evidence of disease.

There are varying definitions and phases of cancer survivorship. The National Coalition for Cancer Survivorship [1] and the National Cancer Institute define a person as a cancer survivor from the moment of a cancer diagnosis through the balance of his or her life. Others have defined phases of survival in cancer patients, including the acute stage (diagnosis and treatment), extended stage (remission and/or maintenance, with a main focus on surveillance for disease recurrence), and permanent stage (long-term survival or "cure," with a focus on long-term risks of treatment and prevention of subsequent diseases) [2].

GENERAL APPROACH — 

The transition from active treatment to post-treatment care is critical to long-term health. Integral components of CRC survivorship care include the following [3]:

●Surveillance for recurrent or second primary CRC (see 'Surveillance for recurrent disease and second primary tumors' below)

●Prevention of recurrent and new primary cancers and of other late effects

●Assessment of medical and psychosocial late effects and intervention for consequences of cancer and its treatment (see 'Long-term effects of treatment' below)

●Managing comorbid disease in this generally older population

●Encouraging a healthy lifestyle that minimizes cancer risk (see 'Lifestyle modification' below)

●Coordination of care between oncology specialists and primary care providers to ensure that all the survivor's health needs are met (see 'Coordination of care' below)

EPIDEMIOLOGY — 

The number of CRC cancer survivors continues to increase over time [4]. CRC survivors account for 1.4 million (8 percent) of the 18 million cancer survivors living in the United States as of January 2022 [5]. Cancer is largely a disease of older adults, and the majority of cancer survivors in the United States (approximately 67 percent) are over the age of 65 [5]. As a result, CRC survivorship often occurs in a background of comorbid illness [6].

Further details on the epidemiology of colorectal cancer are discussed separately. (See "Epidemiology and risk factors for colorectal cancer", section on 'Epidemiology'.)

OVERVIEW OF TREATMENT

Colon cancer — Treatment for stage I (table 1) disease is surgical resection alone. (See "Overview of the management of primary colon cancer".)

Following curative intent surgery, three to six months of adjuvant chemotherapy is a standard approach for patients with node-positive (stage III (table 1)) colon cancer. The intent of adjuvant chemotherapy is eradication of micrometastases, which decreases disease recurrence and increases cure rates. Further details are discussed separately. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer" and "Adjuvant therapy for resected colon cancer in older adult patients", section on 'Oxaliplatin-based regimens'.)

Although the benefits of adjuvant chemotherapy are less certain for patients with node-negative (stage II) tumors, it is an option for patients with higher-risk disease. Further details are discussed separately. (See "Adjuvant therapy for resected stage II colon cancer".)

Adjuvant radiation therapy (RT) is not routinely used in all patients with resected colon cancer. Further details are discussed separately. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Adjuvant radiation therapy' and "Adjuvant therapy for resected stage II colon cancer", section on 'Adjuvant radiation therapy'.)

Rectal cancer — As with colon cancer, treatment for stage I rectal cancer is surgical resection alone. (See "Overview of the management of rectal adenocarcinoma", section on 'Management according to initial clinical stage'.)

The management of locoregionally advanced rectal cancer is evolving. Management involves a combination of surgery, chemotherapy, and/or radiation therapy (algorithm 1). Further details are discussed separately.

●(See "Neoadjuvant therapy for rectal adenocarcinoma".)

●(See "Adjuvant therapy after neoadjuvant therapy for rectal cancer".)

●(See "Adjuvant therapy for resected rectal adenocarcinoma not treated with neoadjuvant therapy".)

PROGNOSIS AND NATURAL HISTORY — 

The most important prognostic factor for colorectal cancer is disease stage at presentation (figure 1). The five-year overall survival rates for all stages of colon and rectal cancer is approximately 65 percent [7,8]. As an example, five-year survival rates for colon cancer, stratified by stage, in data collected from the Surveillance, Epidemiology, and End Results (SEER) database between 1991 and 2000 were as follows [9] (see "Overview of the management of primary colon cancer", section on 'Prognosis'):

●Stage I (T1-2N0) – 93 percent

●Stage IIA (T3N0) – 85 percent

●Stage IIB (T4N0) – 72 percent

●Stage IIIA (T1-2 N1) – 83 percent

●Stage IIIB (T3-4 N1) – 64 percent

●Stage IIIC (N2) – 44 percent

●Stage IV – 8 percent

However, these survival outcome estimates are problematic in several ways:

●The survival rates depict overall and not cancer-specific survival. Because the incidence of CRC increases with age, there are relevant risks of dying from causes other than CRC.

●Furthermore, in the case of rectal cancer, these survival estimates were derived from studies in which surgical resection was not preceded by neoadjuvant therapy. Outcomes may be better in patients who undergo pathologic staging after preoperative treatment.

These two issues were addressed in a series of 771 consecutive patients with stages I to IV rectal cancer who were undergoing resection between 1991 and 2008; 296 (38 percent) received some form of neoadjuvant therapy [10]. Ten-year cancer-specific survival rates for patients with stage I, II, III, and IV disease at the time of resection were 89, 80, 63, and 11 percent, respectively. Only approximately one-third of the observed deaths in patients with stages I to III disease were related to rectal cancer. In addition, a substantial number of deaths due to rectal cancer occurred between years 5 and 10 (5-year and 10-year cancer-specific survival 73 versus 66 percent), highlighting the importance of longer follow-up periods to avoid underestimating the real burden of rectal cancer. (See "Pathology and prognostic determinants of colorectal cancer" and "Neoadjuvant therapy for rectal adenocarcinoma", section on 'Prognosis and extent of tumor regression'.)

Despite potentially curative surgery and the use of modern locoregional and systemic therapy, approximately 40 percent of patients who present with stage II or III disease will have a disease recurrence following primary therapy [11,12]. Over 90 percent of recurrences develop within five years, most within the first three years [13].

Most patients who develop recurrent disease will die from it, although a small subset, mainly those with isolated limited metastatic disease to the liver or lungs, may be eligible for additional curative intent surgery:

●Five-year survival rates approaching 40 percent have been reported in patients undergoing partial hepatectomy for limited hepatic metastases (table 2). (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy".)

●Although isolated lung metastases are less common than liver involvement, metastasectomy has also been used to treat carefully selected patients with lung metastases, with five-year survival rates of 35 to 45 percent. (See "Surgical resection of pulmonary metastases: Outcomes by histology" and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques".)

POST-TREATMENT FOLLOW-UP — 

Patients with a history of CRC are recommended to undergo regular follow-up, which includes surveillance for disease recurrence or new primary tumors (polyps and invasive cancers) and evaluation and management of treatment-related late effects.

Surveillance for recurrent disease and second primary tumors — Post-treatment cancer surveillance is recommended for CRC survivors who have undergone definitive curative-intent therapy. The purpose of surveillance is early identification of recurrent disease and screening for second primary cancers and polyps [14]. Further details on post-treatment surveillance after CRC treatment are discussed separately. (See "Post-treatment surveillance for colorectal cancer".)

Long-term effects of treatment — Among patients with CRC, physical health-related quality of life (QOL) is reduced early after treatment but generally returns to normal levels at approximately one year [15]. Most research indicates that overall QOL in long-term CRC survivors five or more years after diagnosis is comparable with that of the general population, although specific impairments may persist for years in the following domains: psychological (distress and depression), social (employment), and physical (bowel problems and fatigue) [16-23].

Furthermore, long-term complications of surgery, late toxicities from chemotherapy and radiation therapy (RT), and comorbidities with advancing age can all be associated with lower QOL among CRC survivors at ≥5 years after diagnosis [18,22,23]. In one study of patients with rectal cancer, a lower QOL was associated with receiving chemoradiotherapy in addition to surgery, having a permanent stoma, or a primary tumor in the lower-third of the rectum [22].

Few professional organizations have developed guidelines for assessing and managing physical and psychosocial long-term and late effects of treatment specifically for CRC survivors. However, guidelines are available from the American Cancer Society [24] and the NCCN [25].

Psychosocial issues — Given the potential for significant psychosocial sequelae, CRC cancer survivors should have regularly scheduled follow-up visits with a health care provider during the first five years of survivorship. (See "Post-treatment surveillance for colorectal cancer".)

Patients with CRC should be routinely screened for psychosocial distress at all stages of disease to facilitate appropriate supportive care. In addition to screening for psychosocial problems, these visits allow health care providers to offer appropriate referrals to mental health, rehabilitation, and social services.

Psychological distress and depression — Following the completion of active anticancer therapies, cancer survivors generally report more psychological distress (including fear of recurrence and death, adjustment to physical changes, alterations in customary social support, social reintegration, and employment and insurance problems) when compared with individuals without a prior history of cancer [26]. Psychological distress can be debilitating and may interfere with long-term health behaviors. Distress levels tend to be highest early in the survivorship phase. For CRC patients specifically, a prospective survey (n >1800) revealed that 7 percent experienced clinically significant psychological distress at 12 months postdiagnosis [27]. The presence of other comorbidities and the lack of social support were independently associated with increased distress.

Depression is common immediately after starting treatment for CRC. In one study of patients with CRC age 65 years or older, 18 percent screened positive for depression within four to six weeks of starting treatment; after a year of follow-up, the prevalence of depression decreased [28]. Female patients, African Americans, people with two or more comorbid conditions, and those with either poor physical or social functioning exhibited worse depressive symptoms.

Over the long term, patients who survive at least five years after a CRC diagnosis continue to experience higher rates of depression when compared with age-matched controls; approximately 14 to 16 percent will screen positive for depression [16,29]. Moreover, in another study, 26 to 44 percent of long-term CRC survivors continued to worry about cancer recurrence, diagnostic tests, or another cancer [30].

These studies suggest that regular psychological distress screening should be performed during the cancer survivorship phase of care to identify CRC survivors who may need specialized psychological interventions.

Social relationships and economic burden — The process of reintegrating into social relationships can be difficult for many survivors; this frequently affects a wide spectrum of social domains, including interactions with spouses and partners, friends, and peers at school or work. Furthermore, survivors shoulder a significant economic burden [31-34]:

●While data specific to CRC are sparse, one study showed that CRC survivors were at higher risk for unemployment when compared with age- and gender-matched healthy adults (59 versus 53 percent for colon and 54 versus 43 percent for rectal cancer, respectively) [31].

●In another prospective cohort study of survivors of CRC or lung cancer, employment declined from 39 percent to 31 percent over the first 15 months after cancer diagnosis, and approximately 17 percent of those who were employed at baseline left the workforce as a result of their cancer [32]. Lower socioeconomic status and advanced age among CRC survivors were associated with significantly higher rates of labor force departure, highlighting the need for attention to these specific subsets of the population.

●An analysis of the 2008 to 2012 Medical Expenditure Panel Survey examined excess economic burden attributable to cancer (excess annual medical expenditures, productivity loss) for 540 CRC survivors relative to 109,423 individuals without a cancer history [33]. Compared with individuals without a cancer history, non-older-adult CRC survivors experienced annual excess medical expenditures of $8647 (95% CI $4932 to $13,974); for older adult patients the annual excess expenditure was $4913 (95% CI $2768 to $7470). Furthermore, non-older-adult CRC survivors experienced significantly higher rates of employment disability (13.6 versus 4.8 percent) and productivity loss at work (7.2 versus 3.3 days) and at home (4.5 versus 3.3 days).

Issues related to an ostomy — A significant number of CRC patients require diversion of the fecal stream in the form of either a permanent or temporary ostomy as a component of their cancer management. An ostomy has pervasive effects on everyday life (wearing an ostomy bag underneath one's clothing, the possibility of repeated skin irritations and other complications such as leakage and needing to change the pouching system too frequently, difficulties with diet selection and bowel control, as well as reduced social, emotional, sexual, and occupational functioning) that combine to reduce overall functioning and QOL [35-37]. An individual patient's response and subsequent adjustment to intestinal diversion surgery can be highly variable, thus making management and follow-up care challenging. (See "Ileostomy or colostomy care and complications".)

Because ostomies typically result in the loss of control of intestinal contents, including both stool and gas, survivors who are living with ostomies are more likely to experience significant issues with their self-image, comfort with travel and other physical activities, and interpersonal relationships. These issues may contribute to higher rates of depression and decreased overall QOL [20,35,36,38-41]. Therefore, they warrant particular attention during the survivorship phase of cancer care.

Sexual activity is an area of special concern. Ostomy surgery does not typically affect sexual desire or organic sexual function, although injury to pelvic nerves related to rectal dissection or RT may occur. (See 'Sexual dysfunction' below.)

Patients frequently express concerns regarding the psychological aspects of sexual activity, including the partner's response to intimacy. Thus, appropriate counseling in this area is important to the rehabilitation and support of ostomy patients. In general, survivors are advised to empty their pouch and ensure that the pouch is sealed appropriately before engaging in sexual activity. In addition, many patients and partners find it helpful to use special lingerie or cummerbunds to conceal and secure the pouch.

Medical issues

Bowel and anorectal problems — Chronic persistent diarrhea is one of the most common long-term sequelae of treatment for CRC, affecting 49 percent of survivors in one study [16]. Chronic diarrhea limits activities and can negatively affect QOL. Specifically asking about this issue is important because survivors may assume that abnormal bowel symptoms are an inevitable consequence of treatment and not volunteer information about persistent diarrhea at follow-up appointments.

Among patients who undergo low anterior resection (LAR) for rectal cancer, bowel dysfunction is common and can have a profound impact on QOL [42]. Progressively lower surgical anastomoses are associated with a corresponding progressive decline in anorectal function, including increased stool frequency, more incontinence and perianal irritation, decreased stool and flatus discrimination, more incomplete evacuations, and decreased rectal compliance [43]. (See "Surgical treatment of rectal cancer".)

Among patients treated for rectal cancer, rates of bowel and anorectal problems are also higher in irradiated patients, whether RT is administered preoperatively or postoperatively, and they are high in patients receiving chemoradiotherapy as compared with conventional fractionation RT alone [44,45]. The late effects of RT delivered for treatment of rectal cancer can be illustrated by the following data:

●A randomized Dutch trial compared preoperative short-course RT (an approach that is infrequently used in the United States because of higher rates of late gastrointestinal [GI] toxicity) versus surgery alone in 597 patients with rectal cancer [46]. At a median five years of follow-up, the irradiated group had significantly higher rates of fecal incontinence overall (62 versus 38 percent, p <0.001), daily incontinence (14 versus 5 percent), and pad wearing as a result of incontinence (56 versus 33 percent, p <0.001) [46]. Among the 362 patients who did not have a stoma, mean bowel frequency during the day was significantly higher in the irradiated patients (3.69 versus 3.02).

At least in the United States, the more common approach is preoperative standard fractionation RT with concomitant radiosensitizing doses of a fluoropyrimidine. One of the advantages of neoadjuvant as compared with adjuvant chemoradiotherapy is a lower rate of long-term GI toxicity, particularly anastomotic stricture.

●In a matched comparison of patients who did (41 patients) and did not (59 patients) receive chemoradiotherapy after an LAR for rectal cancer, the group that had chemoradiotherapy had more bowel movements per day (median 7 versus 2), more nighttime movements (46 versus 14 percent), more fecal incontinence (occasional 39 versus 7 percent or frequent 17 versus 0 percent), wore a pad more often (41 versus 10 percent), and were more often unable to defer defecation for more than 15 minutes (78 versus 19 percent) [47].

Antidiarrheal medications are common first-line treatment for chronic diarrhea after RT. Dietary adjustments, especially elimination of raw vegetables, may be of benefit [48,49]. Low-fat diets, probiotic supplementation, and elemental diets also may be beneficial among patients treated with pelvic radiation, but the evidence is stronger in preventing acute than chronic diarrhea [50].

Available options for treatment of fecal incontinence include medical therapy to reduce stool frequency and improve stool consistency, biofeedback therapy to improve control of the pelvic floor and abdominal wall musculature, and surgery. (See "Fecal incontinence in adults: Management".)

Urinary dysfunction — The incidence of long-term urinary dysfunction in patients undergoing surgery for rectal cancer depends on the specific operation (rates are higher with abdominoperineal resection as compared with LAR) and the extent of pelvic dissection (rates are lowest in patients undergoing total mesorectal excision [TME] with autonomic nerve preservation). (See "Management of intra-abdominal, pelvic, and genitourinary complications of colorectal surgery", section on 'Urinary dysfunction'.)

Rates of long-term urinary incontinence do not seem to be higher in patients who undergo RT in addition to surgery. This was illustrated in a report from the Dutch trial described above in which rates of difficulty with bladder emptying were not significantly different in the groups that did versus did not receive preoperative RT (27 versus 34 percent) [51].

Sexual dysfunction — A wide variety of sexual dysfunctions are experienced by CRC survivors that may impact their QOL. Among men, these include decreased libido, erectile dysfunction (ED), and ejaculatory disorders, including retrograde ejaculations and low or alterations in ejaculation. Among women, specific sexual dysfunctions include decreased libido or sexual desire, dyspareunia, changes in genital arousal and lubrication, and altered orgasms [52,53]. (See "Overview of sexual dysfunction in male cancer survivors" and "Overview of sexual dysfunction in female cancer survivors".)

Prevalence rates for specific sexual dysfunction are difficult to define, in part because of variable methods of data collection and lack of baseline data on sexual activity. A systematic review of sexual function after treatment for rectal cancer concluded that there is a wide range of sexual dysfunction rates in published studies (23 to 69 percent in men and 19 to 62 percent in women), but that, on average, 30 to 40 percent of previously sexually active patients reported sexual inactivity following treatment [54]. A post-treatment reduction in sexual activity of approximately the same magnitude has been noted by others using patient reports of health-related QOL and sexual functioning before and after treatment for rectal cancer [55].

In general, sexual dysfunction is more common in patients treated for rectal than colon cancer [41,56], and in contrast to urinary dysfunction, RT is a major risk factor as illustrated by the following data:

●In a questionnaire study of 241 patients treated with surgery with or without preoperative RT for locally advanced rectal cancer, a median of 4.5 years after surgery, irradiated patients had significantly poorer scores for erectile function, orgasmic function, intercourse satisfaction, and overall satisfaction with sex life compared with those treated without RT [57]. ED was associated with low serum testosterone levels.

●In a study of 990 Dutch patients who underwent TME with or without preoperative RT, among male patients who were sexually active preoperatively, an increase in general sexual dysfunction, ED, and ejaculatory problems were reported by 76, 80, and 72 percent, respectively [58]. Ejaculatory and ED deteriorated over time. Among female patients who were sexually active preoperatively, general sexual dysfunction, dyspareunia, and vaginal dryness were reported by 62, 59, and 57 percent, respectively. Risk factors for increased sexual dysfunction in both men and women included preoperative RT and the presence of a stoma.

Studies show that post-treatment sexual dysfunction is often not addressed either at the time of treatment for CRC or during follow-up care [59-61]. Specifically asking about this issue is important because of its impact on QOL and the availability of specific treatments, particularly for men.

A number of therapies are available to address sexual dysfunction in men. Testosterone replacement therapy may be effective in increasing sexual desire and may improve erectile function in men with low levels of serum testosterone. Oral therapy with a phosphodiesterase-5 inhibitor is considered a first-line approach to treatment of ED. In one study, 79 percent of patients with ED who had undergone rectal excision for rectal cancer and inflammatory bowel disease had a satisfactory response to sildenafil [62]. On the other hand, others report better efficacy for intracavernous pharmacologic therapy than for sildenafil in these patients [63]. (See "Treatment of male sexual dysfunction" and "Overview of sexual dysfunction in male cancer survivors".)

Available treatment options for sexual dysfunction in women are more limited and none have been systematically evaluated in CRC survivors. Water- or silicone-based lubricants during intercourse and vaginal moisturizers can be useful for women with vaginal dryness and dyspareunia. If these are insufficient to alleviate dyspareunia, low-dose vaginal estrogen preparations may be considered. Pelvic floor muscle training and vaginal dilators may be recommended after pelvic RT to prevent vaginal stenosis, but there are few data to support the efficacy of these approaches [64]. There are limited efficacy and safety data for pharmacologic therapy. Management of sexual dysfunction in females and female cancer survivors is addressed in detail separately. (See "Overview of sexual dysfunction in females: Management" and "Overview of sexual dysfunction in female cancer survivors".)

Fatigue — Cancer-related fatigue is a common, distressing, and potentially treatable condition [65,66]. In a study conducted in the Netherlands, of 3739 CRC survivors identified from one city's cancer registry, 39 percent reported fatigue as compared with 22 percent of the normative populations (derived from the CentER panel, an online household panel representative of the Dutch general population, for which annual data collection in 2011 included a fatigue assessment) [66]. Both the prevalence and severity of fatigue were higher in patients who were <5 years since diagnosis compared with those who were ≥5 years.

The most important contributory factors are treatment with cytotoxic chemotherapy or RT, anemia, pain (and its treatment), emotional distress, sleep disturbance, poor nutrition, and other comorbidities. Although most common during active cancer therapy, cancer-related fatigue may affect patients after cancer treatment has been completed. Screening, assessment, and management of fatigue in patients with cancer are addressed separately. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment" and "Cancer-related fatigue: Treatment".)

Side effects related to chemotherapy — Following curative resection, CRC patients who are considered to be at high risk for disease recurrence are frequently offered adjuvant chemotherapy in order to decrease their chance of relapse. Despite the potential survival benefits, chemotherapy also carries the risk for significant toxicities. Chemotherapies that are commonly used in the setting of CRC can be associated with mucositis, emesis, diarrhea, febrile neutropenia, fatigue, hand-foot syndrome, and cardiotoxicity. Fortunately, most of these symptoms are reversible with cessation of the chemotherapy, and late and long-term effects from CRC-specific cytotoxic agents are relatively infrequent with the exception of oxaliplatin-related peripheral neuropathy. (See "Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management" and "Overview of neurologic complications of platinum-based chemotherapy", section on 'Oxaliplatin' and "Toxic erythema of chemotherapy (hand-foot syndrome)", section on 'Hand-foot syndrome'.)

Oxaliplatin-induced peripheral neuropathy — Oxaliplatin is associated with a cumulative, dose-limiting, late-onset symmetric distal (stocking-glove pattern) axonal neuropathy, typically without motor involvement. Up to 90 percent of patients receiving a six-month course of an oxaliplatin-containing adjuvant chemotherapy regimen develop a neuropathy during treatment; neuropathy is generally reversible, although it may take several years. As an example, in one systematic review of 27 studies, the pooled prevalence of persistent chemotherapy-induced peripheral neuropathy (CIPN) of any grade at 6, 12, 24, and 36 months after oxaliplatin-containing chemotherapy was 58, 45, 32, and 24 percent, respectively [67]. The average prevalence of CIPN decreased by 26 percent per year after chemotherapy (pooled relative risk 0.74, 95% CI 0.72-0.75). Symptoms may include numbness, tingling, and cold-induced pain. Persisting neuropathy symptoms, especially pain, can negatively impact QOL [68,69]. (See "Overview of neurologic complications of platinum-based chemotherapy", section on 'Cumulative sensory neuropathy'.)

Most patients do not require specific treatment. Regular physical activity should be encouraged [70]. For patients with a persisting painful neuropathy, treatment with duloxetine may be beneficial [71]. Other anticonvulsants and antidepressants have been effective in other types of neuropathic pain, but have not yet proven effective for treating chemotherapy-induced peripheral neuropathy. Although proof of benefit has not been provided, scrambler therapy and acupuncture may diminish established neuropathy symptoms and appear to be reasonably safe. These approaches are discussed in more detail separately. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy".)

Complications due to radiation therapy — In addition to bowel and anorectal problems discussed above, other complications related to RT include chronic radiation proctitis, pelvic fractures, and second malignancies. (See 'Bowel and anorectal problems' above.)

Chronic radiation proctitis — Patients treated with pelvic RT for rectal cancer may develop chronic radiation proctitis, a delayed response to RT that is caused by atrophy and fibrosis of the irradiated intestinal epithelium [72,73]. Symptoms usually develop approximately one year after radiation exposure and may include diarrhea, rectal urgency and/or pain, obstruction, and bleeding. (See "Radiation proctitis: Clinical manifestations, diagnosis, and management", section on 'Clinical manifestations'.)

CRC survivors should be educated about symptoms of proctitis and the need to seek appropriate medical attention if symptoms develop. If radiation proctitis is suspected, referral to a gastroenterologist is appropriate. Although mucosal biopsies are not diagnostic, they can help to exclude other causes of proctitis such as infection or inflammatory bowel disease.

High-quality evidence for the optimal management of these patients is sparse. Typically, management is tailored to the specific pattern of symptoms and its intensity. Specific therapy may not be necessary in those who have only mild symptoms such as occasional hematochezia or mild tenesmus. Stool softeners are a conservative first-line treatment for relieving mild obstructive symptoms that are due to radiation-induced strictures.

Diagnosis and management of chronic radiation proctitis are discussed in detail separately. (See "Radiation proctitis: Clinical manifestations, diagnosis, and management".)

Pelvic fractures — Pelvic RT may predispose to bone loss and a heightened risk of bone fracture. Most of the data are in men receiving RT for prostate cancer. (See "External beam radiation therapy for localized prostate cancer", section on 'Insufficiency fractures'.)

There are some data in patients treated for rectal cancer. A large, retrospective cohort study of older women undergoing treatment for rectal, anal, or cervical cancer showed that survivors of rectal cancer were significantly more likely to have a pelvic fracture if they received RT as a component of therapy than if they did not (cumulative five-year fracture rate, 11.2 versus 8.7 percent); 90 percent of the fractures were hip fractures [74]. The use of combined modality therapy may increase the effect of RT on bone density; the use of other medications and estrogen deficiency may further contribute [75]. (See "Screening for osteoporosis in postmenopausal women and men" and "Osteoporotic fracture risk assessment" and "Epidemiology and etiology of premenopausal osteoporosis" and "Etiology of osteoporosis in men" and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in men".)

CRC survivors who have received pelvic RT should undergo long-term monitoring of bone density, appropriate medical treatment for osteopenia and osteoporosis, and careful evaluation if symptoms suggesting fractures develop. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women" and "Evaluation and treatment of premenopausal osteoporosis" and "Treatment of osteoporosis in men".)

Second malignancies — Radiation-associated secondary malignancies are a known but infrequent complication of pelvic irradiation [76,77]. Most of the data are in men treated for prostate cancer. (See "External beam radiation therapy for localized prostate cancer", section on 'Secondary malignancies'.)

Few studies have assessed the risk of a second cancer in patients treated with RT before or after surgery for rectal cancer, with varying results [78-82]. Some have found an increased risk of developing a second cancer after RT [79,81], while others have not [78,80,82]. As examples:

●No increased risk of second cancers after RT in patients receiving short-course RT for rectal cancer was shown in an analysis of the Dutch TME trial in which 1530 individuals with rectal cancer were randomly assigned to preoperative short-course RT (25 Gy in 5 fractions) versus no RT. At a median follow-up of 14 years, there was no significant difference in the number of secondary cancers in irradiated compared with nonirradiated patients (10-year rates of secondary malignancies 14.8 versus 15.3 percent) [78].

●On the other hand, an increased risk of second cancers following standard conventional fractionation RT was suggested in one analysis of 1599 patients treated with either preoperative (5 X 5 Gy fractions) or postoperative RT (30 X 2 Gy fractions for stage II or III disease) or surgery alone in the Swedish and Uppsala rectal cancer trials [79]. Compared with nonirradiated patients, a significant increased risk for second cancers in irradiated patients was seen in organs within or adjacent to the irradiated volume (relative risk [RR] 2.04, 95% CI 1.10-3.79) but not outside the irradiated volume (RR 1.78, 95% CI 0.97-3.27). The increase in second cancers among those receiving RT could not be attributed to one or a few specific cancer types. An important point, however, is that in the Swedish Rectal Cancer Trial 20 percent of the irradiated patients developed either a local recurrence or a second cancer compared with 31 percent of the nonirradiated patients (RR 0.55, 95% CI 0.44-0.70), suggesting that while there is a higher risk of second cancers, there is also a lower risk of local recurrences following RT.

●An elevated risk for second gynecologic malignancies of the uterine corpus (adjusted HR [aHR] 3.06, 95% CI 2.14-4.37) and ovarian cancer (aHR 2.08, 95% CI 1.22-3.56) in radiated as compared with nonirradiated individuals was noted in a population-based cohort study of 20,142 women diagnosed with locoregional rectal cancer between 1973 and 2015 and reported to the Surveillance, Epidemiology, and End Results database [81]. Notably, while the risk for uterine cancer after RT increased with age at rectal cancer diagnosis, and decreased with longer latency since rectal cancer diagnosis, the opposite was found for ovarian cancer: risk decreased with older age since rectal cancer diagnosis and increased with longer latency since rectal cancer diagnosis.

Diabetes and obesity — A higher risk of CRC in patients with diabetes has been well documented and attributed, in part, to common risk factors, including obesity, lack of physical activity, and diet. (See "Epidemiology and risk factors for colorectal cancer", section on 'Diabetes mellitus and insulin resistance'.)

Increasing evidence suggests that the incidence of both diabetes and obesity may be higher after diagnosis and treatment of CRC:

●In an analysis of population-based data from Ontario, Canada, 39,707 incident cases of CRC dating from April 2002 to March 2010 were compared with 198,535 age- and sex-matched control subjects without CRC [83]. During a mean follow-up of 4.8 years, the rate of developing diabetes was 53 percent higher among patients with CRC compared with those without a diagnosis of CRC in the first year postdiagnosis (hazard ratio [HR] 1.53, 95% CI 1.42-1.64), and it remained increased in the fifth year (HR 1.19, 95% CI 1.05-1.35). Similar results were seen even in patients who did not receive adjuvant chemotherapy, arguing against a role for CRC treatment late effects [84].

●Similarly, a higher risk for both diabetes and obesity was noted in a population-based cohort analysis of 7114 CRC survivors who were matched (for birth year, sex, and birth state) with a general population cohort of 25,979 individuals from the Utah Population Database [85]. Across time periods of 1 to 5, 5 to 10, and >10 years postdiagnosis, risks for diabetes and obesity were significantly higher for the CRC survivors. The risk for obesity was higher at 5 to 10 years postdiagnosis than it was at 1 to 5 years (HR 1.50 [95% CI 1.16-1.95] versus 1.40 [95% CI 1.66-2.18]).

These data suggest that active screening for diabetes and counseling for potentially modifiable risk factors may be warranted for this high-risk group.

Cardiovascular disease — Patients treated for CRC are more likely than individuals without a history of cancer to develop cardiovascular disease. This was shown in an analysis derived from the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database in which 72,408 individuals over the age of 65 diagnosed and treated for stage I to III CRC between 2000 and 2011 (27 percent of whom received some form of adjuvant chemotherapy and 12 percent of whom received RT) were compared with a matched cohort of 72,408 Medicare patients without cancer [86]. At a median follow-up of eight years, the 10-year cumulative incidence of new-onset cardiovascular disease and heart failure was significantly higher in patients treated for CRC (57 and 55 percent compared with 22 and 18 percent for control, respectively). Risk increased with age and was influenced by exposure to fluoropyrimidines and preexisting comorbidities. Patients who received capecitabine rather than fluorouracil had a significantly higher risk for heart failure (two years or more since diagnosis; HR 1.57, 95% CI 1.36-1.81) but a significantly lower risk of cardiovascular disease (HR 0.72, 95% CI 0.62-0.84). Among the CRC survivors, factors that contributed to the accelerated time to heart failure and cardiovascular disease included African American race/ethnicity and RT. In addition, there were significant interactions between chemotherapy and diabetes for accelerated time to heart failure and between hypertension and chemotherapy for accelerated time to cardiovascular disease.

These findings provide evidence to support close medical surveillance for heart failure and cardiovascular disease in older CRC cancer survivors, particularly those with preexisting hypertension and diabetes.

The increased cardiovascular disease risk in CRC survivors relative to the general population is likely attributable to multiple shared risk factors, many of which are precursors or consequences of obesity. Clinical care guidelines recommend that clinicians counsel patients with CRC regarding the association between obesity and cardiovascular disease risk [24], although this recommendation is based exclusively on expert opinion, and the evidence to support this recommendation is weak. A population-based retrospective cohort study of 2839 patients diagnosed with stage I to III CRC between 2006 and 2011 at an integrated health system in North America examined the association between body composition and post-treatment cardiovascular events [87]. The median age at diagnosis was 62, although the range was 19 to 80. The cumulative incidence of a major adverse cardiovascular event 10 years after diagnosis of CRC was 19 percent. Body mass index (BMI) was not correlated with the risk of a major adverse cardiovascular event (contrasting BMI categories of ≥35 kg/m² versus 18.5 to 29 kg/m², the HR was 1.23, 95% CI 0.85-1.77). By contrast, visceral adiposity (as assessed by CT scan) was associated with excess risk (HR 1.54, 95% CI 1.02-2.31), but subcutaneous adiposity was not (HR contrasting the highest versus lowest quintile 1.15, 95% CI 0.78-1.69). The association of visceral, but not subcutaneous, adipose tissue area with major adverse cardiovascular events is consistent with broad evidence associating visceral adiposity with the pathogenesis of multiple chronic diseases. This finding also suggests that assessing BMI alone may have limited use for determining cardiovascular risk in this patient population. (See "Obesity in adults: Prevalence, screening, and evaluation", section on 'Waist circumference'.)

GENETIC ISSUES — 

Although most CRCs are sporadic, specific genetic disorders have been identified, mostly autosomal dominant, that are associated with a very high risk of developing the disease. Familial adenomatous polyposis (FAP) and Lynch syndrome (hereditary nonpolyposis CRC) are the most common of the familial CRC syndromes, but together these two conditions account for only approximately 5 percent of CRC cases. (See "Epidemiology and risk factors for colorectal cancer", section on 'Hereditary CRC syndromes' and "Clinical manifestations and diagnosis of familial adenomatous polyposis" and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis".)

Lynch syndrome is more common than FAP and accounts for approximately 3 to 5 percent of all colonic adenocarcinomas. The term Lynch syndrome denotes families who have been genetically determined to have a disease-causing defect in one of the mismatch repair (MMR) genes. The biologic footprint of a defect in MMR capacity is high levels of microsatellite instability (MSI). MSI testing of CRCs is routinely used to help establish the diagnosis of Lynch syndrome. Some institutions perform MSI testing or immunohistochemistry testing for MMR proteins in CRCs in young patients (diagnosed prior to age 50 years) or in those who meet the Bethesda criteria (table 3). At other institutions, universal testing of all CRCs for MSI is practiced and is endorsed in guidelines from the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology, and others [88-90]. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis" and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Cancer screening and management".)

Extracolonic cancers are very common in Lynch syndrome, particularly endometrial carcinomas, which may occur in up to 60 percent of female mutation carriers in some families. Other sites at increased risk of neoplasm formation include the ovary, stomach, small bowel, hepatobiliary system, brain, and renal pelvis or ureter.

The development of one or more of these cancers in a family member of a CRC survivor may prompt consideration for genetic testing. Family history is seldom updated regularly during follow-up. However, regularly updating a three-generation family history pedigree from cancer survivors can be valuable to help determine the potential risk for cancer in family members as well as the survivor's own risk of subsequent cancers that may be associated with a previously unrecognized hereditary syndrome.

LIFESTYLE MODIFICATION — 

The role of lifestyle modification (eg, diet, exercise, smoking cessation) and the use of aspirin/nonsteroidal inflammatory drugs (NSAIDs) in preventing a cancer recurrence is often a topic of interest to cancer survivors. (See "The roles of diet, physical activity, and body weight in cancer survivors".)

Diet and exercise — Numerous observational studies indicate an association between lifestyle factors (obesity, physical activity, diet) and the risk of a first diagnosis of CRC. (See "Epidemiology and risk factors for colorectal cancer", section on 'Protective factors'.)

Data from prospective observational studies suggest that dietary factors may influence outcomes in some patients with CRC. In addition, higher levels of physical activity have been associated with a reduced risk of CRC-specific and overall mortality and have a beneficial impact on fatigue, quality of life, and functional status. Despite the lack of evidence from randomized controlled trials confirming these observations, updated 2013 American Society of Oncology (ASCO) guidelines for follow-up care, surveillance, and secondary prevention for survivors of CRC endorse counseling patients on maintaining healthy body weight, being physically active, and eating a healthy diet [91]. The roles of diet, physical activity, and body weight in cancer survivors are discussed separately. (See "The roles of diet, physical activity, and body weight in cancer survivors".)

A benefit for increasing fiber intake on CRC outcomes was suggested in a study of 1575 health care professionals with stage I to III CRC [92]. Patients who increased their fiber intake after diagnosis had a lower mortality, and each 5 g/day increase in intake was associated with a 19 percent lower CRC-specific mortality (95% CI 7 to 28 percent) and a 14 percent reduction in all-cause mortality (95% CI 8 to 19 percent). Benefit was shown for cereal fiber but not fruit fiber.

Given the lack of randomized trials that have tested the impact of higher fiber intake in individuals with early-stage CRC, the benefit of fiber for CRC recurrence remains unclear.

Nevertheless, it seems reasonable to suggest that patients increase their fiber intake following diagnosis and treatment of CRC. The harm of additional fiber intake is low or nonexistent, and other data in the nutritional epidemiology literature are also supportive of dietary fiber for positive health benefits (cholesterol, cardiovascular disease, insulin resistance), even in a general population. (See "The roles of diet, physical activity, and body weight in cancer survivors", section on 'Colorectal cancer' and "Healthy diet in adults", section on 'Fiber'.)

Aspirin and other NSAIDs — Observational studies suggest that use of aspirin and other nonsteroidal inflammatory drugs (NSAIDs) may improve survival among patients receiving treatment for early colon cancer [93]. However, randomized trials confirming the benefit of aspirin are necessary prior to the routine use of aspirin in CRC survivors, given the potential for harm (eg, gastrointestinal bleeding). (See "Adjunctive therapy for non-metastatic treated colorectal cancer: Aspirin, NSAIDs, and vitamin D".)

Alcohol and tobacco use — Excess alcohol intake has been linked to an elevated risk for CRC, although its influence on survival after a diagnosis of CRC is unclear [94]. Furthermore, cigarette smoking (especially postdiagnosis smoking) has been associated with an increased risk for and mortality from CRC [95-100]. Survivors should be encouraged to quit smoking and use alcohol in moderation, if they drink. Guidelines for diet and physical activity for cancer prevention from the American Cancer Society suggest it is best not to drink alcohol, and those who do should limit their consumption [101]. (See "Epidemiology and risk factors for colorectal cancer", section on 'Other risk factors' and "Epidemiology and risk factors for colorectal cancer", section on 'Alcohol'.)

Changing long-term health behaviors — Survivors with unhealthy lifestyles can be motivated to make behavioral improvements. There have been at least four published randomized trials of health behavior interventions specifically for CRC survivors [102-105]. Although the results of three early trials were promising, two were limited by small sample size, methodologic issues, and a focus exclusively on exercise [103,104], while a third targeted only older CRC survivors and limited outcome assessment to intake of fruits and vegetables and physical activity.

Multiple unhealthy behaviors can co-occur, and few studies have addressed whether an intervention can address multiple behaviors simultaneously [102,106]. In one randomized study focusing on CRC survivors, a six-month duration of telephone-delivered health coaching sessions focusing on physical activity, weight management, dietary habits, and alcohol and smoking cessation led to significant changes in physical activity, body mass index, and intake of total and saturated fat compared with usual care [102]. Unfortunately, the intervention did not result in changes in fruit and fiber intake, alcohol intake, smoking at 6 or 12 months, or sedentary behavior at 12 months [102,107]. (See "The roles of diet, physical activity, and body weight in cancer survivors".)

COORDINATION OF CARE — 

Little is known about whether follow-up care is best provided by specialists or generalists as CRC survivors transition from active treatment to survivorship. Only two prospective trials have addressed the utility of generalist versus specialist care in CRC survivors:

●In an Australian trial that randomly assigned 203 patients with colon cancer to follow-up by general practitioners or surgeons, there were no differences between the groups in disease recurrence, time to detection, all-cause mortality, quality of life (QOL), anxiety, depression, or patient satisfaction [108]. In a later analysis, patients' ability to choose the setting of follow-up also had no influence on health-related QOL compared with random allocation to general practitioner or surgeon [15]. With regards to patterns of surveillance care, general practitioners ordered more fecal occult blood tests than surgeons, whereas more colonoscopies were performed in the surgeon-led group.

●Using a 2X2 factorial design, a Dutch trial randomly assigned 303 patients receiving primary surgical treatment for stage I to III colon or rectal cancer to survivorship care overseen by a surgeon or a general practitioner, with a second randomization for access versus no access to a web-based e-Health self-management tool (Oncokompass [109]) that aims to increase knowledge about the effects of cancer on patients and facilitate access to supportive care [110]. In interim analyses at the 12-month follow-up, there were no important differences in QOL or symptom burden between patients whose survivorship care was led by their generalist or their surgeon, and access to Oncokompass also did not affect QOL. Few patients received adjuvant chemotherapy, and thus, this subgroup of patients provided little data. Further, information about other clinically relevant outcomes, including preferences of both patients and clinicians for care, recurrence detection, mortality, and guideline adherence were not presented. The study is planned for a five-year follow-up.

In general, CRC survivors who are followed by primary care providers tend to receive more preventive care and appropriate care for comorbid conditions than do patients who are seen by specialists alone [111]. Furthermore, because many cancer survivors are older adults, primary care providers may be better equipped to address recommended chronic disease care that is often not addressed among cancer survivors [112]. Yet, most primary care providers encounter few such patients in their practices; they may be unaware of or unprepared to handle potential long-term complications of treatment [113,114] or be unaware of recommendations for post-treatment surveillance from organizations such as the American Society of Clinical Oncology (ASCO), among others.

A shared care model that involves coordinated care between primary care and specialists may optimize adherence to guidelines for recommended follow-up care in cancer survivors along with general preventive and chronic disease care, although there is low-quality evidence to support benefit from such a model of care for patients with chronic diseases. A variety of care models have been proposed to coordinate follow-up between specialists and primary care providers, and the concept of shared care is supported by the Institute of Medicine and ASCO [115,116]. The roles and responsibilities for survivorship care should be well delineated for both patients and their providers. Communication between the primary care provider and subspecialists is vital given that uncertainties about clinician roles and responsibilities can lead to deficiencies in care [117,118]. (See "Overview of cancer survivorship care for primary care and oncology providers", section on 'Coordination of care'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Colorectal cancer" and "Society guideline links: Neuropathic pain".)

SUMMARY AND RECOMMENDATIONS

●Definition – Colorectal cancer (CRC) survivors are defined as individuals who have completed treatment for CRC and have no evidence of disease. (See 'Definition' above.)

●General approach – The care of CRC survivors includes surveillance for recurrent or second primary CRC, assessing and treating psychosocial and medical consequences of cancer and its therapy, managing comorbid disease in this generally older population, encouraging healthy lifestyles that minimize cancer risk, and coordinating care between oncology specialists and primary care providers. (See 'General approach' above and 'Coordination of care' above.)

●Surveillance for recurrent disease and second primary tumors

•Most CRC recurrences occur within the first five years after diagnosis. (See 'Prognosis and natural history' above.)

•Post-treatment cancer surveillance is recommended for CRC survivors who have undergone definitive curative-intent therapy. The purpose of surveillance is early identification of recurrent disease and screening for second primary cancers and polyps. Further details on post-treatment surveillance after CRC treatment are discussed separately. (See "Post-treatment surveillance for colorectal cancer".)

●Psychosocial issues – CRC survivors should be regularly screened for psychosocial distress often associated with survivorship, including depression, employment issues, and issues related to an ostomy. (See 'Psychosocial issues' above.)

●Medical issues – Other common medical issues in CRC survivors include bowel problems and fatigue. CRC survivors may also be at a higher risk for diabetes and cardiovascular disease. Urinary incontinence and sexual dysfunction are more common in survivors of rectal cancer. (See 'Medical issues' above.)

●Treatment-related complications

•Chemotherapy – Chemotherapy that is commonly used to treat non-metastatic CRC include fluorouracil, capecitabine, and oxaliplatin. The most common long-term effect of chemotherapy is oxaliplatin-induced peripheral neuropathy; the 1 percent of patients with chronic severe painful neuropathy may require treatment with opioids, antidepressants, or anticonvulsants. (See 'Side effects related to chemotherapy' above.)

•Radiation therapy – Complications of radiation therapy include radiation proctitis; bowel, bladder, and sexual dysfunction; increased risk for pelvic fracture; and radiation-associated secondary malignancies. (See 'Complications due to radiation therapy' above and 'Medical issues' above.)

●Lifestyle modifications – All CRC cancer survivors should be encouraged to pursue a healthy lifestyle that includes (see 'Lifestyle modification' above):

•Following a healthy diet and avoiding weight gain

•Exercise

•Avoiding or minimizing alcohol intake

•Refraining from smoking

Observational studies suggest that use of aspirin and other nonsteroidal inflammatory drugs may improve survival among patients receiving treatment for early colon cancer. However, randomized trials confirming the benefit of aspirin are necessary prior to the routine use of aspirin in CRC survivors, given the potential for harm (eg, gastrointestinal bleeding).