Abstract
Inflammatory bowel disease (IBD) is a risk factor for colorectal cancer (CRC). We evaluated chemotherapy tolerance and oncologic outcomes from the medical records of patients with CRC with and without IBD. In this series, patients with CRC with IBD experienced more treatment alterations than those without IBD. Patients with stage IV CRC with IBD had shorter survival than patients without IBD.
Background
Inflammatory bowel disease (IBD), comprising Crohn disease and ulcerative colitis, is a risk factor for colorectal cancer (CRC). Chemotherapy toxicity may exacerbate IBD symptoms and vice versa, but data are limited. We evaluated chemotherapy tolerance and oncologic outcomes in patients with CRC with and without IBD.
Patients and Methods
Medical records of patients with CRC with and without IBD treated between 2008 and 2013 were reviewed. Where possible, patients were matched by age, sex, stage, and diagnosis year. Chemotherapy tolerance and survival outcomes were compared between patients with IBD and without IBD.
Results
A total of 158 subjects with CRC were included: 80 patients had IBD and 78 matched control patients did not have IBD. Between cases and controls, there were no significant differences in demographic data, stage of CRC, and cancer treatments, with equivalent numbers of patients receiving surgery, radiation, and chemotherapy. Patients with IBD experienced more CRC treatment alterations than those without IBD (74% vs. 44%, P = .03), largely due to a higher frequency of treatment delays among patients with IBD. Differences in stage-specific 5-year overall survival (OS) and recurrence-free survival (RFS) in patients with and without IBD were not significant, except for stage IV patients with IBD who had significantly shorter OS than those without IBD. Patients with histologically active IBD did not require more chemotherapy alterations than patients with inactive IBD.
Conclusion
In this series, patients with CRC with IBD experienced more treatment alterations (mostly delays) than those without IBD. Patients with stage IV CRC with IBD had shorter survival than patients without IBD.
Keywords: Chemotherapy treatment alteration, Crohn disease, Overall survival, Recurrence-free survival, Ulcerative colitis
Introduction
Crohn disease (CD) and ulcerative colitis (UC) are chronic inflammatory conditions of the gastrointestinal tract. Together, inflammatory bowel disease (IBD) is estimated to affect more than 0.4% of Europeans and North Americans.1 It is well recognized that patients with IBD are at an increased risk of developing colorectal cancer (CRC), thought to be the result of chronic intestinal inflammation.2–4 In a meta-analysis, quantitative estimates of CRC risk in UC have been reported to be 2% after 10 years, 8% after 20 years, and 18% after 30 years of disease.3 Studies on CRC in UC have noted a high concordance between risk of cancer with the location and extent of disease, with a standardized incidence ratio of 1.7 for proctitis, 2.8 for left-sided colitis, and 14.8 for pancolitis.5 Although more recent studies have demonstrated lower rates of CRC, 1.5 to 2.0 times greater than the general population in North America and in some European countries, all support the strong association between inflammation and cancer development.6
As the population of patients with IBD increases and ages, there is a predictable increase in the risk of sporadic and colitis-associated cancers, especially CRC. Many of these patients will require chemotherapy and/or radiation. Despite the high risk of CRC in IBD, very little is known regarding cancer treatment in patients with IBD.
Several small, retrospective and single-center studies have addressed the effects of cancer treatment on the course of IBD.7,8 However, very few have addressed cancer-specific outcomes, chemotherapy tolerance, and survival in patients with IBD. A study of 19 patients with IBD and gastrointestinal malignancy treated with 5-fluorouracil (5-FU)–based chemotherapy reported an increased risk of severe diarrhea (n = 10, 53%) resulting in discontinuation of therapy in 5 patients and dose reduction in another 5 patients.9 However, a substantial number of patients tolerated chemotherapy without increased difficulty, and patient age, type of IBD, dosing schedule of 5-FU, and the degree of IBD activity were not associated with toxicity.9 Another small study on 8 patients with IBD and gastrointestinal malignancy reported diarrhea as the most common gastrointestinal adverse event, with 38% of patients experiencing more than 7 stools per day over baseline and/or fecal incontinence, all of which occurred in patients with CD.10 Neither of these studies had control groups without IBD, and neither commented on rates of disease recurrence or overall survival (OS).
Given the risk of CRC in patients with IBD, and limited data regarding chemotherapy tolerance and associated cancer outcomes, the aim of the present study was to evaluate chemotherapy tolerance and oncologic outcomes in patients with CRC with and without IBD.
Methods
Patient Population
The electronic medical records of patients with a diagnosis of pathologically confirmed CRC with and without a documented history of IBD treated at The Mount Sinai Hospital, New York, between 2008 and 2013, were reviewed. Patients with IBD (cases) and patients without IBD (controls) were matched by age (within 5 years), sex, stage, and diagnosis year (within 2 years).
Chart Review
Charts were reviewed for patient demographic information, including age at IBD diagnosis; IBD subtype; date of CRC diagnosis; stage of CRC; histologic IBD activity at CRC diagnosis; cancer treatment including surgery, radiotherapy, and chemotherapy; chemotherapy alterations for toxicity, such as treatment delays, discontinuations, dose modifications, and hospitalizations; date of last follow-up, death, or CRC recurrence diagnosis. Reasons for treatment alterations were recorded when available.
Study Objectives
CRC treatment characteristics and outcomes in patients with and without IBD were summarized. The primary objective was to compare the incidence of cancer treatment alterations due to toxicities in patients with CRC with and without IBD. Secondary objectives were stage-specific 5-year OS and recurrence-free survival (RFS) in patients with and without IBD. We also assessed the effect of histopathologic IBD activity on chemotherapy alterations.
Statistical Analyses
The variables are summarized using frequencies, and median and minimum-maximum values. Categorical variables were compared by using χ2 or Fisher exact tests. Continuous variables were compared by using Mann-Whitney U test. OS and RFS were estimated with the use of Kaplan-Meier plots, and log-rank tests were used to compare the outcomes between patients with and without IBD. All reported P values are 2-sided. All analyses were performed in SAS v9.4 statistical software (SAS Institute, Cary, NC).
This study was performed with approval from the Icahn School of Medicine Institutional Review Board, with waiver of consent.
Results
A total of 158 subjects were included in this analysis. There were 80 patients with CRC and IBD. In terms of IBD subtype, 25 (31.25%) had CD and 55 (68.75%) had UC. There were 78 matched controls with CRC who did not have IBD. Between cases and controls, there were no significant differences in basic demographic data, stage of CRC, and cancer treatments with statistically equivalent numbers of patients receiving surgery, radiation, and chemotherapy for their CRC (Table 1). Molecular pathology data were available for 45 patients (28.5%) and there were no differences in mismatch repair protein expression, KRAS or BRAF mutation status between patients with and with IBD. Median duration of IBD at CRC diagnosis was 25 years (range 1–59), and of these patients, 51 (64%) had histologically active IBD at the time of their CRC diagnosis.
Table 1.
Baseline Characteristics in Patients With Colorectal Cancer With and Without Inflammatory Bowel Disease
| IBD, n = 80; 25 CD, 55 UC | Non-IBD, n = 78 | P | |
|---|---|---|---|
| Median age at CRC diagnosis, years | 54 (24–92) | 57 (27–93) | NS |
| Male, n (%) | 48 (60) | 47 (60) | |
| Female, n (%) | 32 (40) | 31 (40) | NS |
| Histologically active IBD at CRC diagnosis, n (%) | |||
| Yes | 51 (64) | N/A | N/A |
| No | 20 (25) | ||
| Unknown | 9 (11) | ||
| Median duration of IBD at CRC diagnosis, years | 25 (1–59) | N/A | N/A |
| CRC stage, n (%) | |||
| I | 29 (36) | 24 (31) | |
| II | 17 (21) | 17 (22) | |
| III | 20 (25) | 24 (31) | |
| IV | 12 (15) | 12 (15) | |
| Unknown | 2 (3) | 1 (1) | NS |
| CRC molecular characteristics, n (%) | |||
| Mismatch repair protein expression | |||
| Deficient | 3 (4) | 6 (8) | |
| Proficient | 17 (21) | 19 (24) | |
| Unknown | 60 (75) | 53 (68) | NS |
| K-ras | |||
| Wild type | 5 (6) | 9 (12) | |
| Mutation | 5 (6) | 1 (1) | |
| Unknown | 70 (88) | 68 (87) | NS |
| BRAF | |||
| Wild type | 4 (5) | 5 (6) | |
| Mutation | 0 (0) | 0 (0) | |
| Unknown | 76 (95) | 73 (94) | NS |
| Cancer treatment | |||
| Surgery | 74 (93) | 75 (96) | |
| Radiotherapy | 13 (31) | 11 (26) | |
| Chemotherapy | 43 (70) | 40 (68) | NS |
Abbreviations: CD = Crohn disease; CRC = colorectal cancer; IBD = inflammatory bowel disease; N/A = not applicable; NS = not significant; UC = ulcerative colitis.
There were also no statistically significant differences in chemotherapy regimens. The patients with and without IBD received fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, anti-EGFR agents, and regional chemotherapy at similar frequencies (Table 2).
Table 2.
Systemic Chemotherapy Regimens in Patients With Colorectal Cancer With and Without Inflammatory Bowel Disease
| Systemic Chemotherapy Regimens | IBD | Non-IBD |
|---|---|---|
| FOLFOX/CAPOX | 24 | 24 |
| FOLFIRI/irinotecan | 8 | 8 |
| 5FU+LV/capecitabine | 11 | 11 |
| Bevacizumab | 7 | 11 |
| Cetuximab/panitumumab | 3 | 2 |
| Regorafenib | 1 | 0 |
| Intraperitoneal mitomycin-C | 1 | 2 |
| Hepatic arterial infusion floxuridine | 1 | 2 |
Abbreviations: 5FU = 5 fluorouracil; IBD = inflammatory bowel disease; LV = leucovorin.
Among patients in whom information was available regarding CRC treatment alteration, significantly more patients with IBD experienced CRC treatment alterations (23/31, 74%) than those without IBD (12/27, 44%; P = .03) (Table 3). This was largely due to a higher frequency of treatment delays among patients with IBD. The most frequently cited reason for treatment alteration was related to gastrointestinal side effects. Details for specific reasons noted in patient charts for treatment delays, discontinuations, dose modifications, and hospitalizations are listed in Table 3.
Table 3.
Cancer Treatment Alterations in Patients With Colorectal Cancer With and Without Inflammatory Bowel Disease
| IBD, n = 80 | Non-IBD, n = 78 | P | |
|---|---|---|---|
| Patients with known cancer treatment alteration data, n (%) | 31 (39) | 27 (35) | >.05 |
| Any treatment alteration, n (%) | |||
| Yes | 23 (74) | 12 (44) | |
| No | 8 (26) | 15 (56) | .03 |
| Dose modification | |||
| N | 7 | 1 | |
| Reasons noted | Diarrhea, peripheral sensory neuropathy, thrombocytopenia, mucositis, ileitis, abdominal pain | Diarrhea, hand-foot skin reaction | |
| Treatment delay | |||
| N | 8 | 4 | |
| Reasons noted | Myelosuppression, body aches/pains, sepsis, diarrhea, enterocutaneous fistulae, bursitis, bowel obstructions, peripheral neuropathy | Folliculitis, myelosuppression, recurrent urinary tract infections | |
| Treatment discontinuation | |||
| N | 7 | 8 | |
| Reasons noted | Severe acne, fluid retention, diarrhea, excessive weight loss, neutropenia, mucositis, peripheral sensory neuropathy, hepatotoxicity | Neuropathy, hypersensitivity reaction, hypertension, hyperbilirubinemia, failure to thrive, hand-foot skin reaction, renal failure | |
| Hospitalization | |||
| N | 6 | 5 | |
| Reasons noted | Diarrhea, peritonitis, sepsis | Hypotension, renal failure, disseminated intravascular coagulation, sepsis |
Abbreviation: IBD = inflammatory bowel disease.
Although there were no statistically significant differences in stage I, II, and III-specific 5-year OS and RFS between patients with CRC with and without IBD (Table 4), there was a trend of worse survival in IBD. Among patients with stage IV CRC, 5-year OS was significantly shorter in patients with IBD compared with patients without IBD (19% vs. 50%, P = .017; Figure 1). Neither IBD activity status (quiescent vs. active) nor the duration of IBD was associated with the frequency of chemotherapy alterations.
Table 4.
Stage-Specific 5-Year Overall Survival and Recurrence Free Survival Between Colorectal Cancer Patients With and Without Inflammatory Bowel Disease
| IBD, n = 80 | Non-IBD, n = 78 | P | |
|---|---|---|---|
| 5-year OS, % | |||
| I | 88 | 100 | NS |
| II | 83 | 100 | NS |
| III | 41 | 75 | NS |
| IV | 19 | 50 | .017 |
| 5-year RFS, % | |||
| I | 89 | 81 | NS |
| II | 59 | 83 | NS |
| III | 60 | 38 | NS |
Abbreviations: IBD = inflammatory bowel disease; NS = not significant; OS = overall survival; RFS = recurrence-free survival.
Figure 1.
Stage-Specific 5-Year Overall Survival Between Patients With Colorectal Cancer With and Without Inflammatory Bowel Disease. Stages I, II, and III P > .05; Stage IV P = .017
Discussion
Few studies have examined the cancer treatment tolerance and outcomes in patients with CRC with IBD, and to date, none have compared this with a matched non-IBD population. In this single-center cohort study, patients with IBD experienced a higher frequency of alterations in cancer treatment compared with patients without IBD, mostly due to delays in their cancer treatment. Given the retrospective nature of this study, data regarding specific reasons for treatment alterations were limited, although gastrointestinal side effects appeared to be more frequently encountered in patients with IBD than without IBD. Moreover, several patients with IBD in this cohort were also noted to experience gastrointestinal fistula during their CRC treatment, none of which were noted in controls.
It has been postulated that the mere presence of underlying IBD yields gastrointestinal mucosa more vulnerable to the toxic effects of chemotherapy.11 In this series, IBD activity, based on histologic confirmation from endoscopic or surgical assessments, was not associated with a significant difference in treatment alteration. This is consistent with data from a previous study in which the degree of IBD activity was not significantly associated with the development of severe diarrhea with 5-FU chemotherapy.9 In addition, studies have demonstrated a therapeutic benefit of cytotoxic chemotherapies on the course of IBD, which may directly impact the relationship between IBD activity and specific gastrointestinal chemotherapy toxicities.7 However, histologic IBD activity may not reflect the clinical course of IBD, and prospective studies are required to validate this measure.
Although there exists no method for distinguishing gastrointestinal side effects of cancer treatment from IBD-associated complications, the present data suggest that gastrointestinal complications during CRC treatment in patients with IBD are secondary to exacerbation of IBD. However, future studies, ideally prospective in nature, are required to help address this. Expert opinion has suggested treating patients with IBD who experience diarrhea during chemotherapy with aminosalicylates (eg, mesalamine) and avoiding immunosuppressive drugs, such as corticosteroids, thiopurines, and tumor necrosis factor–alpha antagonists, to prevent profound hematologic toxicities.11
In the present series, there were no significant differences in 5-year OS or RFS between patients with IBD and without IBD with stage I to III CRC. However, survival was shorter in patients with stage IV with IBD compared with patients without IBD. Our study is consistent with previous reports of shorter survival in patients with IBD compared with those without IBD.12–14 In a series of 33 patients with UC and CRC, 5-year OS was 39%, significantly less than the 59% 5-year OS rate in 133 sporadic CRC controls (hazard ratio 1.83, P = .03).12 In all of these previous single-center series, patients were not matched by cancer treatment. In contrast, several other studies have demonstrated comparable OS rates in patients with IBD and patients with sporadic cancer.15–19
There are several limitations to the current study inherent to its retrospective design. The observed association of IBD and treatment alterations and OS could be due to the presence of other factors that contribute to CRC development and to individualized decision-making in the management of cancer in patients with IBD. As both cases and controls received similar chemotherapies and rates of radiation, we did not examine the impact of specific chemotherapy regimens, chemotherapy dosing protocols, or radiation dosing protocols on specific toxicities. Furthermore, our definition of active IBD was limited to patients with histologic evidence for active disease at their CRC diagnosis, which may not have fully captured all patients with active IBD or clinically relevant IBD, as we did not include a clinical surrogate for this analysis. In addition, the relatively small sample size suggests that our retrospective data may not be generalizable to other clinical settings.
Despite these limitations, this is one of the largest studies examining the impact of IBD on cancer treatment tolerance and oncologic outcomes in CRC. Larger studies may help clarify the trend of worse survival in patients with IBD and stages I to III CRC. In addition, future prospective studies in patients with IBD with cancer may provide insights into the best treatment regimens that maximize therapeutic benefit, minimize toxicity, and optimally improve cancer outcomes.
Clinical Practice Points.
Patients with IBD are at an increased risk of developing CRC, thought to be the result of chronic intestinal inflammation. As the population of patients with IBD increases and ages, there is a predictable increase in the risk of sporadic and colitis-associated cancers, especially CRC. Many of these patients will require cancer treatment.
Our study was conducted to describe CRC treatment characteristics and outcomes in patients with and without IBD, to compare the incidence of cancer treatment alterations due to toxicities in patients with CRC with and without IBD, to calculate stage-specific 5-year OS and RFS in patients with and without IBD, and to assess the effect of histopathologic IBD activity on chemotherapy alterations.
Consistent with some existing literature, our study showed that patients with IBD experienced more CRC treatment alterations than those without IBD, largely due to a higher frequency of treatment delays. Differences in stage-specific 5-year OS and RFS in patients with IBD trended to be shorter than those without IBD, with those with stage IV having statistically significantly shorter OS than those without IBD. Patients with histologically active IBD did not require more chemotherapy alterations than patients with inactive IBD.
Our study is one of the largest examining the impact of IBD on cancer treatment tolerance and oncologic outcomes in CRC. Our data suggest that gastrointestinal complications during CRC treatment in patients with IBD are secondary to exacerbation of IBD. Prospective studies in patients with IBD with cancer may provide further insights into the best treatment regimens that maximize therapeutic benefit and minimize toxicity.
Acknowledgments
This research was supported in part by the Chemotherapy Foundation.
Footnotes
Disclosure
The authors have stated that they have no conflicts of interest.
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