Colorectal Cancer: Management of Stage IV Disease

14513 Background: Role of mainteance therapy after achieving complete response (CR) remain undefined for patients with metasatic colorectal cancer. We studied prognostic and treatment factors including maintenance capecitabine and celecoxib (XCEL) in all 19 unresectable metastatic colorectal cancer patients (pts) who had CR from the prior XCEL study. Methods: Event charts are used to summarize the timeline of the various treatments. Kaplan-Meier survival estimates and univariate log-rank tests were used to evaluate RFS and OS as time from CR. Prognostic and treatment factors included: tumor size, metastasis number (9 solitary disease), site (13 being extrahepatic), stage on diagnosis (stage II versus III/IV), disease free interval prior to stage IV disease, surgery (5 R0, 3 R1–2 resections), lactate dehydrogenase levels, first-line irinotecan chemotherapy, radiation (9 pts ≥ 45 Gy, 3 Pts < 45 Gy), and maintenance XCEL (duration 0–50.3 months). Results: Nine of 19 patients experienced recurrence (median 13 months after CR), and 4 died during the follow-up period (median 31 months after CR). The 2-year RFS for the unresected and R1–2 resected patients was 71% versus 20% for the R0 resected patients (p = 0.07). This paradoxical RFS pattern corresponded to a RFS advantage for maintenance XCEL (p = 0.002), but not any other prognostic or treatment factors. All relapses occurred in situ following discontinuation of XCEL except for the surgical cases. Patients undergoing maintenance XCEL also benefited in OS (p = 0.04). The median OS from XCEL and from onset of metastasis reached 51.9 months (95% CI, 45 months- not reached [NR]) and 73.3 months (95% CI, NR-NR months) respectively. Conclusions: Maintenance XCEL targets colorectal micrometastases and produces a paradoxical RFS and OS advantage among the high-risk unresected/R1–2 resected patients than R0 resected patients. Prospective studies are warranted to validate roles of maintenance XCEL in the treatment of colorectal micrometastases. No significant financial relationships to disclose.

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Role of surgical resection among chemotherapy-treated patients with colorectal cancer stage IV disease: A survival analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.15_suppl.3564 ◽

2011 ◽

Vol 29 (15_suppl) ◽

pp. 3564-3564 ◽

Cited By ~ 2

Author(s):

B. S. Lin ◽

A. Ziogas ◽

T. E. Seery ◽

M. J. Stamos ◽

J. A. Zell

Keyword(s):

Colorectal Cancer ◽

Survival Analysis ◽

Surgical Resection ◽

Stage Iv ◽

Cancer Stage ◽

Stage Iv Disease

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Incidence of peripheral neuropathy in patients with colorectal cancer receiving oxaliplatin alone vs. radiation therapy and oxaliplatin.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e18281 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e18281-e18281

Author(s):

Matthew Blake Lockwood ◽

Krishna Prasad Joshi ◽

James Mobley ◽

Suneetha Sampath ◽

Eric R Siegel ◽

...

Keyword(s):

Colorectal Cancer ◽

Rectal Cancer ◽

Radiation Therapy ◽

Peripheral Neuropathy ◽

Stage Iv ◽

Sensory Neuropathy ◽

Chi Square ◽

Stage Iv Disease ◽

Nerve Fibrosis ◽

Colorectal Cancer Patients

e18281 Background: Peripheral sensory neuropathy (PN) is a known dose limiting toxicity of oxaliplatin, used to treat patients with colorectal cancer. Patients with rectal cancer receive radiation therapy (RT) in addition to oxaliplatin in adjuvant setting. Pelvic radiation causes plexopathy due to demyelination, ischemia due to blood-vessel injury, and nerve fibrosis. To assess if RT increases the incidence of peripheral neuropathy, we conducted an analysis of patients with colorectal cancer treated with oxaliplatin alone vs. oxaliplatin and radiation. Methods: A retrospective analysis of subjects with stages II, III, and IV rectal (R) and colon (C) cancer from 2005 to 2014 was conducted. Only subjects receiving O with or without RT were included. The incidence of PN was compared for increase in subjects receiving both O and RT compared to O alone via one-sided chi-square tests at 5% alpha, both overall and after subgrouping by stage. Results: Out of 261 subjects analyzed, 158 met the study’s criteria. There were 97 C (all received only O) and 61 R (10 received only O; 51 received O+RT). PN occurred in 37% (19/51) of subjects receiving O+RT compared to 22% (24/107) receiving only O ( P= 0.025). In Stage II-III disease, PN occurred at nearly equal rates of 36% (14/39) in subjects receiving O+RT and 33% (16/46) in subjects receiving O only ( P= 0.457). However, in Stage IV disease, PN occurred in 42% (5/12) of subjects receiving O+RT compared to 13% (8/61) of subjects receiving only O ( P= 0.009). Conclusions: In our study, the incidence of PN was higher in subjects receiving both RT and O compared to O alone. Although our study did not show higher PN in stages II and III disease, patients with rectal cancer may have residual neurotoxicity from previous radiation and the subsequent exposure to oxaliplatin may be contributing to the cumulative toxicity. [Table: see text]

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The impact of colorectal cancer screening on incidence and stage IV disease in the Netherlands.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3531 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3531-3531

Author(s):

Myrtle F Krul ◽

Marloes AG Elferink ◽

Niels FM Kok ◽

Evelien Dekker ◽

Iris Lansdorp-Vogelaar ◽

...

Keyword(s):

Colorectal Cancer ◽

The Netherlands ◽

Local Treatment ◽

Stage Iv ◽

Stage I ◽

Crc Screening ◽

Stage Distribution ◽

Incidence And Mortality ◽

Stage Iv Disease ◽

The Impact

3531 Background: Population-based screening for colorectal cancer (CRC) aims to decrease incidence and mortality due to precancerous polyp removal, early detection and early treatment of CRC. In the Netherlands, phased introduction of a biennial fecal immunochemical hemoglobin test started in 2014 for individuals aged 55-75. This evaluation of the national data focuses on the initial effect of CRC screening on incidence and stage distribution and the impact on stage IV disease. Methods: All CRC patients diagnosed in the Netherlands between 2009 and 2018 were selected from the Netherlands Cancer Registry (NCR). Patients were linked to the Dutch national pathology registry (PALGA) to identify screen-detected tumors. Results: The NCR identified 137,717 CRC patients between 2009 and 2018. The incidence within screening age (55-75 yr) of all CRC stages showed an initial peak after introduction of screening in 2014, followed by a continuous decrease for all stages. CRC incidence outside the screening age did not show these explicit changes between 2009 and 2018. In 2018, the incidence of stage IV CRC within screening age was lower than the level at the start of the screening program. Stage distribution within screening age shifted towards earlier stages in the screening period (2014-2018) compared to the period before screening (2009-2012) (stage I: 31% vs. 18%, stage II: 22% vs. 26%, stage III: 29% vs. 31%, Stage IV: 18% vs. 25%, respectively). In the period 2014-2018 and within screening age, the ratio of screen-detected and symptom-detected tumors was highest in stage I (47%:53%) and lowest in stage IV (9%:91%). Screen-detected compared to symptom-detected stage IV patients diagnosed in the period 2014-2018 and within screening age had more frequently single organ metastases (74.5% vs 57.4%, p < 0.001), higher resection rate of the primary tumor (57.5% vs. 41.3%; p < 0.001) and higher local treatment rate of metastases (40.0% vs. 23.4% p < 0.001). The median overall survival of screen-detected stage IV patients was significantly longer than that of symptom-detected stage IV patients (31.0 months (95% CI: 27.7 – 34.3) vs. 15.0 months (95% CI: 14.5 – 15.5), p < 0.001). Conclusions: The initial results of the introduction of CRC screening in the Netherlands showed a favorable trend on CRC incidence and stage distribution. Screen-detected patients with stage IV disease had less extensive disease, resulting in better treatment options and improved survival.

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Immunomagnetic Enrichment and Detection of Micrometastases in Colorectal Cancer: Correlation With Established Clinical Parameters

Journal of Clinical Oncology ◽

10.1200/jco.2002.02.152 ◽

2002 ◽

Vol 20 (21) ◽

pp. 4338-4343 ◽

Cited By ~ 21

Author(s):

Martin R. Weihrauch ◽

Edmund Skibowski ◽

Thomas C. Koslowsky ◽

Wilfried Voiss ◽

Daniel Re ◽

...

Keyword(s):

Colorectal Cancer ◽

Bone Marrow ◽

Cancer Patients ◽

Stage Iv ◽

Stage I ◽

Clinical Parameters ◽

Uicc Stage ◽

Detection Rates ◽

Stage Iv Disease ◽

Colorectal Cancer Patients

PURPOSE: Micrometastatic disease in bone marrow is of prognostic significance in colorectal cancer patients. However, detection rates of standard immunocytology are relatively low. We used magnetic activated cell sorting (MACS), a highly sensitive method, to increase detection rates and correlated the presence of cytokeratin (CK)-expressing cells with clinical parameters. PATIENTS AND METHODS: Bone marrow was obtained from 51 consecutive patients with newly diagnosed colorectal adenocarcinoma who underwent primary surgery and 18 control subjects. International Union Against Cancer (UICC) stage I disease was diagnosed in 11 patients, stage II disease was diagnosed in 14 patients, stage III disease was diagnosed in 12 patients, and stage IV disease was diagnosed in 14 patients. CK-positive cells were enriched and stained with magnetically labeled CAM 5.2 antibodies directed to CK 7 and 8. RESULTS: CK-positive cells were found in 33 (65%) patients and were absent in 18 (35%). Four of 11 (36%) patients with UICC stage I disease, nine of 14 (64%) with stage II diease, eight of 12 (67%) with stage III disease, and 12 of 14 (86%) with stage IV disease were CK-positive. Epithelial cells were more frequently found in pT3/4 (72%) than in pT1/2 (36%) tumors (P = .026), but there was no difference for lymph node status. CK-positive patients had a higher chance for elevated carcinoembryonic antigen (85% v 15%, P = NS) and CA 19-9 levels (92% v 8%, P = .019). There were no significant differences in CA 72-4, sex, age, tumor grading, or tumor localization regarding the presence of CK-positive cells. All control subjects were CK-negative. CONCLUSION: In searching for micrometastases in colorectal cancer patients, we have achieved high detection rates by using MACS. The presence of these cells correlated significantly with tumor stage, tumor extension, and the tumor marker CA 19-9.

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A metagene of NRF2 expression is a prognostic biomarker in all stage colorectal cancer

10.1101/690974 ◽

2019 ◽

Cited By ~ 1

Author(s):

Séan M. O’Cathail ◽

Chieh-Hsi Wu ◽

Annabelle Lewis ◽

Chris Holmes ◽

Maria A Hawkins ◽

...

Keyword(s):

Colorectal Cancer ◽

Poor Prognosis ◽

Prognostic Biomarker ◽

Molecular Taxonomy ◽

Disease Free Survival ◽

Stage Iv ◽

Stage I ◽

Braf V600e ◽

Stage Iv Disease ◽

Nrf2 Expression

ABSTRACTObjectiveNrf2 overexpression confers poor prognosis in some cancers but its role in colorectal cancer (CRC) is unknown. Due to its role as a transcription factor we hypothesise a metagene of NRF2 regulated genes could act as a prognostic biomarker in CRC.DesignUsing known NRF2 regulated genes, we defined an NRF2 metagene to represent the pathway expression using principal component analysis and Cox proportional hazard models. The NRF2 metagene was validated in four independent datasets, including the recently profiled MRC FOCUS randomised controlled trial.Results36 genes comprised the final prognostic metagene in the training set. 1,360 patients were included in the validation analyses. High NRF2 metagene expression is associated with worse disease free survival (DFS) and overall survival (OS) outcomes in stage I/II/III disease and worse OS in stage IV disease. In multivariate analyses, NRF2 expression remained significant when adjusted for known prognostic factors of adjuvant chemotherapy and stage in stage I/II/III disease, as well as BRAF V600E mutation and sidedness in stage IV disease. NRF2 metagene expression exhibits variation within each of the Consensus Molecular Subtypes (CMS) but high expression is particularly enriched in CMS 4.ConclusionWe demonstrate in a large scale analysis that NRF2 expression is a novel biomarker of poor prognosis across all stages of colorectal cancer. Higher expression observed in CMS 4 further refines the molecular taxonomy of colorectal cancer.

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Conditional survival analysis of stage IV colorectal cancer patients living >24 months.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.3566 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 3566-3566

Author(s):

Nadia Dawn Ali ◽

Shadi Zandieh ◽

Kristen Donohue ◽

Chunxia Chen ◽

Dirk Moore ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Median Overall Survival ◽

Survival Curve ◽

Stage Iv ◽

Conditional Survival ◽

Prognostic Information ◽

Curative Intent ◽

Cancer Management ◽

Stage Iv Colorectal Cancer

3566 Background: The overall survival of patients with stage IV colorectal cancer (both in unresectable and resectable settings) has been increasing over recent decades due to improvements in chemotherapy, liver surgery and other liver-directed therapies. As a result of more patients living longer, there is a need to refine prognostic information to more accurately predict survival to assist multi-disciplinary cancer management teams in treatment decisions but also for patient quality of life. Methods: We performed a retrospective analysis of all patients with stage IV colorectal cancer seen at Rutgers Cancer Institute of New Jersey between Jan 1, 2005 to March 10, 2015 by ICD-9 code (N = 318 patients). This included patients who were deemed unresectable and patients who were resected with curative intent. Our study population was patients with documented survival for > 24 months (N = 158). Variables gathered included patient demographics, disease related (primary location, KRAS status, metastasis location, interval to metastases) and treatment related (chemotherapy regimens, radiation and surgery) data. Survival curve estimates are conditional on having survived 24 months. Results: Complete data was available for 125 patients (75 were resected for cure and 50 were not). Median overall survival of resected patients was not reached. The median overall survival of non-resected patients was 75.9 months. Univariate and multivariate analysis for surgery and non-surgery groups was performed. No statistically significant covariates were found beyond surgical resectability. The conditional survival probabilities of living 1, 2 or 3 years longer after 24 months of survival are 91.7%, 71.6% and 51.6% respectively in the patients with unresectable disease, and 98.1%, 92.2% and 88.8% in patients who were able to be resected with curative intent. Conclusions: These results indicate that patients who survive 24 months with stage IV colorectal cancer have an excellent prognosis. For patients who are unresectable and survive 24 months, this study suggests that they may benefit from resection of remaining metastatic sites if feasible. For resected patients this information may propose a possible benefit from repeat metastasectomy.

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Nrf2 metagene as a prognostic biomarker across all stages of colorectal cancer (CRC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.557 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 557-557

Author(s):

Sean Micheal O'Cathail ◽

Chieh-Hsi Wu ◽

Annabelle Lewis ◽

Tim Maughan ◽

Maria A Hawkins

Keyword(s):

Colorectal Cancer ◽

Transcription Factor ◽

Prognostic Biomarker ◽

Stage Iv ◽

Stage I ◽

Braf V600e ◽

Candidate Gene Approach ◽

Metastatic Focus ◽

Stage Iv Disease ◽

Nrf2 Expression

557 Background: Keap1/Nrf2 is an important intracellular canonical stress response pathway, with Nrf2 acting as a potent transcription factor. Lung cancer is known to acquire constitutive activation of the pathway thus promoting survival, resisting chemo-radiation and dysregulating metabolism. Mechanisms of pathway activation include methylation of KEAP1, somatic mutation and direct activation by KRAS, BRAF and MYC. Its role in CRC is unknown. Due to its role as a transcription factor, activated in many ways, we hypothesise a metagene of Nrf2 regulated genes would act as a prognostic biomarker in CRC. Methods: Using a candidate gene approach and publicly available data (GSE17536), we derived and trained a 36 gene metagene to aggregate Nrf2 pathway expression, using principal component analysis and cox proportional hazard models. GSE14333 was used for validation in stage I/II/III CRC. The first line metastatic FOCUS trial was used for validation in Stage IV disease. Results: 601 patients are included in the validation analysis. Nrf2 metagene expression is associated with worse DFS outcomes in stage I/II/III disease in Cox PH model comparisons (LRT, p = 0.00175) and worse OS in stage IV disease (LRT, p = 0.00574). On multivariate analysis, Nrf2 expression remained significant when adjusted for known prognostic factors of adjuvant chemotherapy and Duke’s stage in stage I/II/III disease (ANOVA, p = 0.03), BRAF V600E and sidedness in stage IV disease (ANOVA, p = 0.00255). Using the median cut point, high expression has a HR 2.36 (C.I 1.27-4.38) in stage I/II/III disease and HR 1.39 (C.I 1.12-1.72) in metastatic disease. Conclusions: Nrf2 expression is a novel, robust prognostic biomarker of poor prognosis across all stages of colorectal cancer. Greater understanding of its mechanistic role could lead to targeted strategies to improve outcomes in CRC. [Table: see text]

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Patterns of Care and Costs for Older Patients With Colorectal Cancer at the End of Life: Descriptive Study of the United States and Canada

JCO Oncology Practice ◽

10.1200/jop.19.00061 ◽

2020 ◽

Vol 16 (1) ◽

pp. e1-e18 ◽

Cited By ~ 1

Author(s):

Karen E. Bremner ◽

K. Robin Yabroff ◽

Diarmuid Coughlan ◽

Ning Liu ◽

Christopher Zeruto ◽

...

Keyword(s):

Colorectal Cancer ◽

United States ◽

End Of Life ◽

Care Delivery ◽

Stage Iv ◽

Cancer Registries ◽

The United States ◽

Hospitalization Costs ◽

Stage Iv Disease ◽

Medicare Patients

PURPOSE: End-of-life (EOL) cancer care is costly, with challenges regarding intensity and place of care. We described EOL care and costs for patients with colorectal cancer (CRC) in the United States and the province of Ontario, Canada, to inform better care delivery. METHODS: Patients diagnosed with CRC from 2007 to 2013, who died of any cancer from 2007 to 2013 at age ≥ 66 years, were selected from the US SEER cancer registries linked to Medicare claims (n = 16,565) and the Ontario Cancer Registry linked to administrative health data (n = 6,587). We estimated total and resource-specific costs (2015 US dollars) from public payer perspectives over the last 360 days of life by 30-day periods, by stage at diagnosis (0-II, III, IV). RESULTS: In all months, especially 30 days before death, higher percentages of SEER-Medicare than Ontario patients received chemotherapy (15.7% v 8.0%), and imaging tests (39.4% v 31.1%). A higher percentage of Ontario patients were hospitalized (62.5% v 51.0%), but 43.2% of hospitalized SEER-Medicare patients had intensive care unit (ICU) admissions versus 17.9% of hospitalized Ontario patients. Cost differences between cohorts were greater for patients with stage IV disease. In the last 30 days, mean total costs for patients with stage IV disease were $15,881 (SEER-Medicare) and $12,034 (Ontario) versus $19,354 and $17,312 for stage 0-II. Hospitalization costs were higher for SEER-Medicare patients ($11,180 v $9,434), with lower daily hospital costs in Ontario ($1,067 v $2,004). CONCLUSION: These findings suggest opportunities for reducing chemotherapy and ICU use in the United States and hospitalizations in Ontario.

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