Stage-based Variation in the Effect of Primary Tumor Side on All Stages of Colorectal Cancer Recurrence and Survival

doi:10.1016/j.clcc.2018.05.008

Clinical Colorectal Cancer

Volume 17, Issue 3, September 2018, Pages e569-e577

https://doi.org/10.1016/j.clcc.2018.05.008 Get rights and content

Abstract

Background

Multiple studies have defined the prognostic and potential predictive significance of the primary tumor side in metastatic colorectal cancer (CRC). However, the currently available data for early-stage disease are limited and inconsistent.

Materials and Methods

We explored the clinicopathologic, treatment, and outcome data from a multisite Australian CRC registry from 2003 to 2016. Tumors at and distal to the splenic flexure were considered a left primary (LP).

Results

For the 6547 patients identified, the median age at diagnosis was 69 years, 55% were men, and most (63%) had a LP. Comparing the outcomes for right primary (RP) versus LP, time-to-recurrence was similar for stage I and III disease, but longer for those with a stage II RP (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.52-0.90; P < .01). Adjuvant chemotherapy provided a consistent benefit in stage III disease, regardless of the tumor side. Overall survival (OS) was similar for those with stage I and II disease between LP and RP patients; however, those with stage III RP disease had poorer OS (HR, 1.30; 95% CI, 1.04-1.62; P < .05) and cancer-specific survival (HR, 1.55; 95% CI, 1.19-2.03; P < .01). Patients with stage IV RP, whether de novo metastatic (HR, 1.15; 95% CI, 0.95-1.39) or relapsed post–early-stage disease (HR, 1.35; 95% CI, 1.11-1.65; P < .01), had poorer OS.

Conclusion

In early-stage CRC, the association of tumor side and effect on the time-to-recurrence and OS varies by stage. In stage III patients with an RP, poorer OS and cancer-specific survival outcomes are, in part, driven by inferior survival after recurrence, and tumor side did not influence adjuvant chemotherapy benefit.

Introduction

Multiple series have demonstrated the prognostic effect of the primary tumor side in patients with metastatic colorectal cancer (mCRC).1, 2, 3, 4 Although multiple clinical, pathologic, and molecular differences have been described when comparing right- versus left-sided cancers, the relative contribution of each to side-based differences in overall survival (OS) for patients with mCRC remains uncertain.

The effect of primary tumor side in early-stage CRC remains relatively underexplored. A recent meta-analysis of 66 studies found improved OS outcomes for early-stage disease patients with a left primary (LP) tumor (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.79-0.84; P < .001).¹ However, stages I, II, and III were combined in that analysis. Three large Surveillance, Epidemiology, and End Results (SEER) program data studies, a German study, and a Canadian population registry study have also evaluated the effect of primary tumor side in early-stage disease.5, 6, 7, 8, 9 Although they mostly found poorer OS for stage III patients with a right primary (RP), conflicting results for those with stage II disease were reported according to primary tumor side, with either no difference or improved OS outcomes with RP disease. Furthermore, these series did not report the recurrence-free survival (RFS) outcomes.

The VICTOR and QUASAR2 studies evaluated the RFS outcomes in a combined analysis of stage II and III colon cancer patients. Although no difference was found in RFS according to primary tumor side, RP patients had inferior OS compared with those with a LP.¹⁰ The investigators concluded that this difference resulted from the effect of the primary tumor side on postrecurrence survival (PRS).¹⁰

Patients with early-stage disease have multiple endpoints of interest, especially because the OS analysis can potentially be confounded by non–cancer-related deaths, the relative benefit of adjuvant therapy, and PRS. To fully understand the effect of tumor side in early-stage CRC, a by-stage analysis that examines the time-to-recurrence (TTR), RFS, PRS and OS is required. We conducted these analyses using a comprehensive clinical registry with prospectively collected data and additional detailed information on known prognostic factors and treatment administered in the adjuvant setting.

Section snippets

Source Data

Using the Australian Comprehensive Cancer Outcomes and Research Database (ACCORD),¹¹ consecutive patients with a diagnosis of all stages of colorectal cancer were identified across 6 Australian hospitals from January 2003 to December 2016. The ACCORD is a dedicated and comprehensive database of prospectively clinician-collected data on clinical characteristics, pathologic information, surgical procedures, systemic treatment where relevant, and long-term outcomes. Patients with multiple primary

General Demographic Data

Of the 6547 eligible patients where initial stage was known, 1104 (17%) had stage I disease, 1916 (29%) had stage II, 1767 (27%) had stage III, and 1513 (23%) had de novo stage IV disease. Across all stages, 4111 (63%) had a LP and 2436 (37%) had an RP, with a significantly greater prevalence of RP tumors (43% vs. 33%; P < .001) among women. Patients with an RP also had a higher median age at diagnosis (72 vs. 67 years; P < .001; Table 1).

Initial Stage I Disease

For patients with initial stage I disease, the relative

Discussion

The prognostic effect of primary tumor side in mCRC has been widely accepted, with patients with RP disease experiencing poorer survival outcomes.¹⁴ More recently, the predictive significance of the primary tumor side has affected clinical practice, owing to a consistent side-based differential response to epidermal growth factor receptor inhibitors.4, 15, 16 The latest National Comprehensive Cancer Network guidelines have recommended against the use of epidermal growth factor receptor

Conclusion

Our results have indicated that the factors that drive recurrence in early-stage CRC are likely distinct, at least in part, from those that drive PRS, rather than the simpler scenario that right-sided cancers have consistently poorer disease biology across all disease stages. To fully understand the contributors to the stage-based variation in outcomes, we suggest that each tumor stage needs to be independently evaluated, with all outcomes (including TTR, OS, and CSS) examined for series in

Disclosure

The authors declare that they have no competing interests.

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Colorectal cancer (CRC) is the third most commonly diagnosed malignant tumor and the fourth leading cause of cancer death in the world, accounting for about 1.4 million new cases and almost 700,000 deaths [1]. The studies of changes in colorectal cancer incidence over time showed a significant increase over decades [2]. With all the advances in modern medicine, colorectal cancer still occupies one of the leading positions, remaining the third common oncological disease in men and second in women worldwide [3,4].
Colorectal cancer (CRC) is the third most commonly diagnosed malignant tumor. The problem of mCRC is urgent due to both an increase in the number of metastatic tumors and the implementation of high-tech treatment methods that have significantly improved the results of a 5-year survival.
The research used the method of experiment and observation. Current study included data of 332 patients with CRC who received comprehensive treatment from 2014 to 2018 in oncology centers of the Republic of Kazakhstan. The patients were treated according to the clinical protocols for the treatment of oncological diseases approved in the Republic of Kazakhstan, including surgical treatment, as well as chemotherapy and radiation therapy, depending on the stage and localization of the process. A comprehensive treatment also included surgical treatment, chemotherapy, targeted chemotherapy and, in some cases, radiation therapy for rectal cancer. The diagnosis was confirmed morphologically in all patients; process dissemination was recorded using standard examination methods. Among the patients, women prevailed – 182 (54.8%) women and 150 men (45.2%) were included; the Caucasian race prevailed – 170 (51.2%) patients and 162 (48.8%) patients were of the Asian race. The mean age of the patients at the time of treatment was 56.4 ± 0.6 years (from 25 to 79 years). Histologically, adenocarcinoma prevailed represented by glandular – in 95.6%, mucous – in 2.9% and trabecular – in 1.5% of cases. A comprehensive treatment was used in 209 (63.0%) patients and other types of treatment were used in 123 (37.0%) patients (PCT, stoma + PCT). Radiation therapy was administered to 13 (3.9%) patients diagnosed with rectal cancer.
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Recently, Karim et al utilized data from the province of Ontario, Canada, and found no significant difference in survival when comparing left and right early-stage CRC.17 Although the prognostic and predictive role of the primary tumor side in metastatic CRC is well-known, there is limited information in the early-stage CRC.10,11,16-21 Heterogeneity across the available studies in terms of population and treatment is significant and could justify conflicting results.
The impact of sidedness in the high-risk stage II colorectal cancer (CRC) setting is uncertain. Although controversial, available data suggest a possible modest benefit of adjuvant chemotherapy (CT) in the adjuvant scenario. The aim of this study is to analyze the overall survival (OS) and recurrence-free survival (RFS) according to the tumor side.
In this single-center retrospective cohort, we analyzed patients treated between January 2011 and December 2018. We evaluated OS and RFS of high-risk patients according to the tumor side and considering adjuvant CT exposure and clinical and molecular features.
A total of 1047 patients with stage II CRC were evaluated. Of these, 540 had high-risk criteria and microsatellite stability (MSS) or unknown status. One hundred fifty-seven (29%) patients had right-sided tumors, and 352 (65.2%) had left-sided tumors. Most patients received adjuvant CT, and the majority of them had T3 stage tumors, ≥ 12 lymph node resection, left tumor, MSS, and moderate differentiation. OS did not differ according to tumor side (5-year OS rates: 81.9% for right-sided tumors vs. 83% for left-sided tumors; hazard ratio, 0.91; 95% confidence interval, 0.55-1.53; P = .744). Adjuvant CT was associated with a superior RFS and OS, with 5-year OS rates of 87.7% versus 76.1% in the no-adjuvant group (hazard ratio, 0.46; 95% CI, 0.28-0.73; P = .001).
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Consecutive patients who underwent curative resection of colon cancer (2006-2013) were identified from a prospective database and retrospectively analyzed. Risk for recurrence, overall survival, and survival after recurrence (SAR) were compared between left- and right-sided tumors using the log-rank test, and multivariable Cox proportional hazards regression.
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Original StudyStage-based Variation in the Effect of Primary Tumor Side on All Stages of Colorectal Cancer Recurrence and Survival

Abstract

Background

Materials and Methods

Results

Conclusion

Introduction

Section snippets

Source Data

General Demographic Data

Initial Stage I Disease

Discussion

Conclusion

Disclosure

Ann Oncol

Eur J Cancer

Lancet Oncol

J Chronic Dis

Eur J Surg Oncol

Eur J Cancer

J Gastrointest Surg

Comparison of 17,641 patients with right- and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival

Dis Colon Rectum

Is there a difference in survival between right- versus left-sided colon cancers?

Ann Surg Oncol

Adjuvant chemotherapy for stage II right-sided and left-sided colon cancer: analysis of SEER-Medicare data

Ann Surg Oncol

Original Study
Stage-based Variation in the Effect of Primary Tumor Side on All Stages of Colorectal Cancer Recurrence and Survival