Abstract
Background:
Colitis-associated Cancers (CAC) are a catastrophic complication of Inflammatory Bowel Disease (IBD); at diagnosis, CAC is frequently at an advanced stage. Although the genomic alterations (GA) in CAC are different from sporadic colorectal cancer (CRC), the same systemic therapies are used. We compared clinically relevant outcomes using standard care systemic chemotherapy of Stage IV CAC versus a matched patient control cohort of Stage IV CRC patients.
Methods:
A retrospective matched cohort design was used.18 cases with Stage IV CAC (7 UC; 11 CD) and 18 CRC were identified. GA analysis was available for all patients. Outcome endpoints included response rate and response duration, Progression-free Survival (PFS), and Overall Survival.
Results:
While the response rates were similar (CAC 35.7% vs CRC 57.1%, p=0.45), the median duration of response for CAC was significantly shorter (1.4 months vs. CRC 11.8 months, p=0.006). There was no difference in dose density of first line therapy between cohorts, suggesting that shorter response duration was due to more rapid development of chemotherapy resistance. Median OS was significantly shorter for CAC patients (13 vs 27.6 months), p=0.034. As expected, there was a difference in the spectrum of GA between CAC and CRC cohorts. However, GA associated with poor prognosis (eg B-Raf) were no more frequent in the CAC cohort.
Conclusions:
Clinically meaningful outcomes of duration of response and overall survival are worse for CAC vs sporadic CRC patients treated with FOLFOX or FOLFIRI as first therapy for metastatic disease.
Keywords: Colitis-associated Cancers, Chemotherapy, Colitis-associated cancers Genomics Alterations Analysis
Precis:
Standard of care colorectal cancer chemotherapy regimens are less effective in colitis associated cancers than for matched control cohort sporadic colorectal cancer patients. Testing newer agents in these patients, including those targeting genomic alterations found in CAC, should be a priority.
INTRODUCTION
The global incidence of inflammatory bowel disease (IBD) has markedly increased over the last several decades; it is estimated that there are currently 3.1 million adults in the United States who have been diagnosed with IBD 1. Patients with Crohn’s Disease (CD) or Ulcerative Colitis (UC) have a markedly increased risk of developing cancers of the colon or rectum or, for Crohn’s Disease, of the small bowel 2. Colitis-associated cancers (CAC) are a catastrophic complication of IBD. Patients with CAC are frequently diagnosed with advanced stage malignancies, perhaps due to delayed recognition of the developing cancer as symptoms such as rectal bleeding or change in bowel habits are attributed to underlying IBD.
There is currently little available data regarding the effectiveness of systemic therapy in patients with metastatic CAC compared to the larger population of patients with sporadic colorectal cancer (CRC). We and others recently reported that CAC, which develops in an inflammatory milieu, has a spectrum of genomic alterations (GA) different from that of sporadic colorectal cancer. 3 However, currently CAC patients are treated with the same therapies as patients with sporadic CRC, such as FOLFOX or FOLFIRI (fluorocuracil, leucovorin and oxaliplatin or irinotecan) chemotherapy regimens.
We analyzed matched cohorts of patients with metastatic CAC and metastatic CRC to compare outcomes to standard first-line chemotherapy. The genomic alterations analyses of each cohort were examined to further explore correlations and possible mechanisms underlying differences in outcomes between the two groups.
METHODS
Patient Selection
A retrospective matched cohort design was used for this study. CAC cases were first identified by querying a prospectively-maintained dataset of CAC cases seen at Memorial Sloan Kettering Cancer Center (MSK) from 2000 to 2018, in whom a genomic analysis of tumor specimens had been performed. All cases were reviewed by a medical oncologist (R.Y., D.K.). A total of 18 cases with metastatic CAC (7 UC; 11 CD) were identified. The original pathology was reviewed by a MSK pathologist (L.T.), and the diagnosis of both colitis and carcinoma confirmed. The electronic medical records of 500 potential control patients with metastatic sporadic CRC or small bowel cancer, who had also undergone next generation sequencing of a tumor sample, were screened for eligibility to serve as matched cases. 4. In addition to complete records for the demographic and clinical data and genomic alterations analysis, eligibility requirements included availability of the complete first line chemotherapy doses administered, availability of the images to allow independent radiology assessment of response to therapy, and the absence of other malignancy during the time of treatment for metastatic CRC.
Each CAC case was matched 1:1 to a sporadic colorectal or small bowel cancer case as described in Statistical Methods. Because CAC patients might have active IBD, which might affect the use of agents such as fluorouracil or irinotecan (increased risk of bowel toxicity) we also assessed the doses of the regimen administered over the first 8 cycles (16 weeks) of treatment. We were thus able to evaluate any differences in the dose density of chemotherapy delivered across cohorts that might confound the exposure/outcome relationship of interest (response rate, response duration, and survival).
Radiographic Analysis
The study radiologists were blinded to the study cohort (CAC vs Sporadic CRC) to minimize information bias while determining response. Baseline and follow-up scans from initiation of frontline treatment were reviewed by MSK radiologists (D.B., V.P.). Treatment response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 5 Best overall response was further dichotomized using the categorical RECIST measures as either response (complete response plus partial response) or non-response (stable disease and progression of disease).
Genomic Analysis
Either the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) 6 or the Foundation Medicine next-generation sequencing assays were used to analyze the genomic alterations present in each patient’s tumor. Over 340 genes were systematically analyzed to explore differences between the genomic configuration of the sporadic and colitis-associated cancer matched pairs.
Statistical Methods
Each CAC case was matched 1:1 to a sporadic colorectal or small bowel cancer case based on four variables: age (<40 vs ≥40), location of primary tumor (small bowel, right side or left colon) metachronous or synchronous metastatic disease, and regimen of first line metastatic cancer treatment (FOLFOX or FOLFIRI). The matching was conducted using the %gmatch SAS macro (SAS version 9.2, SAS Institute, Cary, NC).
Disease and treatment characteristics were summarized according to CAC and CRC using frequencies and percentages for categorical variables and medians and ranges for continuous variables. Exact McNemar’s test was used to examine the association between best response and genetic profiles between the paired CAC and CRC groups. One pair was excluded from each of the MYC, APC, and TP53 analyses due to incomplete mutational data. Duration of response was estimated among patients who achieved partial or complete response according to RECIST criteria. It was calculated from date of best response until the date of progression disease and estimated using Kaplan-Meier methods.
Overall survival and progression-free survival were calculated from date of first treatment until first progression or death (for PFS) or to the date of death or last follow-up (OS). For the PFS outcome, patients who stopped therapy to allow surgery were followed until their date of first POD, or death whichever occurred first. OS and PFS were estimated using Kaplan-Meier methods and compared between CAC versus sporadic CRC patients using a partial likelihood function for the Cox model under an independent working correlation assumption with a robust sandwich variance estimator to account for the matching. To account for differences due to undergoing surgery, we further adjusted for surgery by including it as time-dependent covariate in the Cox model. Actual doses of the components of FOLFOX or FOLFIRI delivered over 8 cycles were compared between the CAC and CRC groups using a multivariate multi distant test.7 All statistical analyses were performed using SAS Version 9.3 (SAS Institute, INC., Cary, NC, USA) or R Version 3.3.0 (R Foundation for Statistical Computing, Vienna, Austria). All P-values were two sided. P-values were considered to indicate statistical significance.
The study was performed under MSK approved Institutional Review Board/Privacy Board protocols.
RESULTS
Patient Characteristics are shown in Table 1. The median age at diagnosis of CAC was 52 years, substantially younger than the median age of diagnosis of patients with sporadic CRC in the United States 8. This may reflect the younger age of patients with colitis associated cancers. While the median age in the control sporadic CRC cohort is similar, as control cohort patients were matched by age, it is also not substantially different from the median age of metastatic CRC patients seen at MSK, a tertiary referral center4 Other known prognostic factors such as location of the primary tumor site (small bowel-right colon versus left colon), and synchronous versus metachronous diagnosis of metastatic disease were also matched between the CRC and CAC cohorts (Table 1). The FOLFOX regimen was used in slightly more patients than FOLFIRI.
Table 1.
Patient Characteristics
| Characteristics | CRC (n=18) | CAC (n=18) |
|---|---|---|
| Median age at diagnosis (range) | 52 (29–80) | 51.5 (25–78) |
| Gender (M:F) | 12:6 | 9:9 |
| Tumor differentiation | ||
| moderate | 11 (61%) | 10 (55%) |
| poor | 7 (39%) | 8 (44.4) |
| Metastatic disease onset | ||
| synchronous | 11 (61.1) | 11 (61.1) |
| metachronous | 7 (38.9) | 7 (38.9) |
| Primary site of tumor | ||
| right colon | 6 (33.3) | 6 (33.3) |
| left colon | 9 (50) | 9 (50) |
| small intestine | 3 (16.7) | 3 (16.7) |
| Liver metastases only | ||
| no | 12 (66.7) | 13 (72.2) |
| yes | 6 (33.3) | 5 (27.8) |
| First Systemic treatment | ||
| FOLFOX +/− bevacizumab | 9 (50) | 9 (50) |
| FOLFIRI +/− bevacizumab | 6 (33.3) | 6 (33.3)4 |
| 5FU/LV | 2 (11.1) | 2 (11.1) |
| HAI pump + FOLFOX | 1 (5.6) | 1 (5.6) |
Dose density of chemotherapy and toxicity: We evaluated the dose density of oxaliplatin, irinotecan, and fluorouracil delivered during the first 8 weeks of therapy between the two cohorts. For this analysis, we used the recommended standard of care dosing schedules for FOLFOX and for FOLFIRI. 9,10 Full doses of each regimen were assumed to be able to be delivered for the first 8 weeks of treatment. Decreases in dose or deletion of an individual agent were at the discretion of the treating physician and were not mandated.
Dose density was calculated as previously described. There were no significant differences in dose density for any of the components of either FOLFOX or FOLFIRI in patients with sporadic colorectal cancer versus the CAC cohort (p =0.46). This indicates that the two cohorts were able to receive equal doses of cytotoxic chemotherapy. There was also no difference in the number of patients in whom a biological agent either bevacizumab or an EGFR targeting agent was used. 3 of 18 CAC patients received bevacizumab as part of their first line therapy; 5 of 18 sporadic CRC patients received this agent. EGFR antagonists were not given as part of first line therapy in either cohort.
Response to first-line chemotherapy: Shown in table 2 are response rates by cohort as independently assessed by the reference radiologists. There was no difference in overall best response rate (PR+CR) to first-line therapy between cohorts: the CR+PR rate was 35.7% (5/14) for the CAC cohort and 57.1% for the Sporadic CRC cohort (8/14) (p =0.45). Note that in 4 CAC cases, the reference radiologists assessed disease as evaluable but not measurable, so that these patients were not included in the objective response assessment. By subtype of IBD, the CR/PR response rates were 3/10 (30%, 95% CI 6.7–65%) for Crohn’s Disease CAC, and 2/4 (50%, 95% CI 6.7–93%) for Ulcerative Colitis CAC. The overall CR plus PR response rate is similar to that reported for first line therapy in Stage IV CRC patients. 9,10.
Table 2:
Objective Response to First Line Chemotherapy
| Response (%) | Sporadic CRC | CAC | |
|---|---|---|---|
| Complete Response | 2 (14%) | 1 (7%) | |
| Partial Response | 6 (43%) | 4(29%) | |
| Total Response (CR+PR) | 8 (57%) | 5 (36%) | |
| Stable | 5 (36%) | 6 (42%) | |
| Progression of Disease | 1 (7%) | 3 (22%) | |
| Not Evaluable | 0 | 4 * |
Response assessment by Independent Radiology Review using RECIST 1.1
Evaluable but not measurable disease for Response; Evaluable for Progression-Free Survival
Median Duration of Response and Progression Free Survival: While the objective tumor response rate was similar between the two cohorts, the median duration of response was only 1.4 (95%CI: <1 to 5.3) months for CAC cases compared to 11.8 [95%CI: 3.4–21.0] (p =0.006) months for CRC patients. Progression free survival (PFS) was shorter for patients with CAC (median PFS for CAC pts: 4 months [95%CI: 1.7–7.7] vs CRC: 10.5 months [95%CI: 4.4–17.6]). At a 6 month timepoint, 38% [95%CI: 17%−60%] and 72% [95%CI: 45%−87%] for CAC, and CRC patients respectively had PFS. After accounting for surgery, the risk of progression or death was nearly 2-fold higher for patients with CAC versus CRC patients (HR: 1.98 [95%CI: 0.90–4.3],p=0.085), but the difference did not reach statistical significance.
Overall Survival: Median OS was significantly shorter for CAC patients versus those with sporadic colorectal cancer: median OS was 13.5 months [95%CI: 6–21.5] for the CAC cohort patients versus 27.6 months [95%CI: 13.2–36.9, p=0.034] for sporadic small intestine and CRC patients. After controlling for surgery, the risk of overall mortality was 2.06 for CAC vs sporadic CRC, p=0.079.
We evaluated the spectrum of genomics alterations of the two cohorts (Figure 3). Recurrent genomic alterations shared by the sporadic and colitis-associated cancer cases included alterations in KRAS (p > 0.95), MYC (p = 0.63) and TP53 (p = 0.11). However, APC (p < 0.01) mutations were significantly less common in CAC than in CRC. We observe 8 discordant pairs in which all 8 CAC cases were APC WT, while their matched CRC controls were APC mutation. Unique GAs observed in CAC included IDH1 R132C and FGFR2-TACC2 fusion. While there were fewer BRAF mutations in the CAC cohort than in the CRC cohort, this difference was not statistically significant (p = 0.6). One pair was excluded from each of the MYC, APC, and TP53 analyses due to incomplete mutational data. The MSK IMPACT assay includes ERCC2, a gene associated with resistance to platinum compounds in bladder cancer. 11 None of the CAC nor of the CRC cases had an ERCC2 mutation.
Figure 3.
Matched analysis of Genomics alterations in patients with metastatic disease
DISCUSSION
Our matched case cohort analysis suggests that patients with metastatic colon or small bowel CAC treated with standard of care cytotoxic systemic regimens have a worse outcome than patients with sporadic small intestinal or colorectal cancer. Median duration of response, PFS and OS are shorter in patients with CAC. The median duration of OS in the sporadic CRC cohort is consistent, although somewhat shorter, than OS in recent large prospective trials of chemotherapy in Stage IV CRC 12. While the objective response rate to standard cytotoxic regimens was similar between the two cohorts, resistance appears to develop more rapidly in CAC than in sporadic cancer cases: there was a striking difference in median duration of response of 1.4 vs 11.8 months. Rapid development of resistance may underlie the poorer overall survival of the CAC cohort.
The spectrum of genomic alterations between the two cohorts is different, as expected from our and others previous studies of CAC.13 However, the incidence of known poor prognosis alterations, such as BRAF mutations, was if anything more frequent in the sporadic CRC cohort. APC alterations, which have been associated with better prognosis, were significantly less common in CAC versus sporadic small intestine and CRC cases. Whether GA distinct to CAC, such IDH1 mutations and FGFR fusions, play a role in the more rapid development of primary resistance has not yet been elucidated. Additional studies evaluating resistance pathways are needed to identify potential targets to increase the duration of response and survival in CAC patients.
We recognize that the small number of CAC patients available in our study limits the power of the observations regarding PFS and OS. However, the risk of progression or death was nearly 2-fold higher for the CAC cohort than the CRC cohort after controlling for surgical intervention, and the survival differences are striking. Our findings are consistent with those of two other reports. Axelrad et al evaluated chemotherapy tolerance and outcomes to systemic therapy in patients with CAC and a matched control group of sporadic colon cancer patients 14. 12 of the 80 CAC patients had stage IV disease, as did 12 of 80 CRC matched controls. Overall survival was analyzed by stage; rate of response to chemotherapy and progression free survival were not reported. For all patients (both those receiving adjuvant therapy, the majority, as well as those with stage IV disease) FOLFOX or a variant was the most commonly used regimen. 5-year overall survival was significantly shorter in stage IV CAC patients than in stage IV sporadic CRC (19% versus 50%). The very high 5-year overall survival for the stage IV sporadic CRC patients may reflect a substantial percentage who underwent surgical resection of metastatic disease. Median survival for both CAC and sporadic CRC was well above that expected for patients with stage IV advanced unresectable colorectal cancer again suggesting that an intervention in addition to systemic chemotherapy was performed. The authors noted that for the subgroup of patients in whom there was information regarding delays or alterations in treatment, these occurred substantially more frequently in patients with CAC than in those with sporadic CRC. However, a dose density analysis as we have performed was not reported; we did not find a difference in dose density for CAC patients that would explain the worse outcome for patients with CAC. Nio et al evaluated the efficacy and safety of chemotherapy in Japanese CAC patients 15. 13 of the 29 patients were treated for advanced metastatic disease. A control group of sporadic CRC patients was not evaluated. For this stage IV metastatic disease cohort, FOLFOX with or without bevacizumab or cetuximab was used in the majority of patients. 2 of 13 patients had complete or partial remissions; median progression free survival was 182 days and median overall survival was 315 days, similar to PFS and OS seen in our study.
In summary, while the overall number of patients for which data are available is limited, stage IV CAC patients appear to have progression free and overall survival that is worse than that of patients with stage IV sporadic colorectal cancer. Our study suggests that a shorter duration of response to standard of care chemotherapy regimens may underlie shorter overall survival in CAC. A better understanding of the events leading to resistance to systemic therapy and the development of newer regimens more effectively targeting the genomic alterations seen in CAC may lead to improved outcome.
Figure 1.
Overall Survival – CAC Cases vs CRC Controls
Figure 2:
Progression Free Survival
Clinical Teaching Points:
For patients with metastatic Colitis Associated Cancers, standard of care chemotherapy regimens used for palliation are less effective than the same regimens used in patients with sporadic colorectal cancer. While objective response rates are similar, time to progression of disease and overall survival are inferior to these outcome measures in patients with sporadic colorectal cancer, suggesting more rapid time to resistance.
Colorectal and small bowel cancers developing in patients with Inflammatory Bowel Disease have a spectrum of genomic alterations which are different to those of patients with sporadic colorectal cancer. Whether this difference in the spectrum of genomic alterations underlies more rapid development of resistance to cytotoxic chemotherapy is not yet known.
Acknowledgments
Supported in part by grants from the Crohn’s and Colitis Foundation, the Lostritto Family Foundation, the James and Sigrid Mueller Fund, and NIH/NCI Cancer Center Support Grant P30 CA008748
Footnotes
There are no conflicts of interest for any of the authors.
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