Timeliness of Adjuvant Chemotherapy for Stage III Adenocarcinoma of the Colon: A Measure of Quality of Care

doi:10.1016/j.clcc.2013.08.002

Clinical Colorectal Cancer

Volume 12, Issue 4, December 2013, Pages 275-279

Presented in part at the ASCO Quality Care Symposium, 2012, San Diego, California

https://doi.org/10.1016/j.clcc.2013.08.002 Get rights and content

Abstract

Background

Findings from multiple clinical trials established AC as a standard of care for stage III colon cancer. However, there is no recommended standard time for delivery of AC. We explored the timeliness of AC with FOLFOX as a predictor of recurrence and its role as a quality indicator in patients with stage III colon cancer.

Patients and Methods

We conducted a retrospective analysis of patients with colon cancer who received AC at Los Angeles County Hospital and Norris Cancer Center between 2003 and 2011. Time to recurrence (TTR) was the primary end point of the study, Kaplan-Meier curves and log-rank tests were used to assess the association between timing of the AC and TTR.

Results

We identified 102 patients with stage III colon cancer who had received AC. With a median follow-up of 3.2 years, time from surgery to AC was not a predictor of recurrence (P = .19). However, there was a nonsignificant trend toward higher risk of systemic recurrence when the delay of AC was more than 12 weeks (P = .068). Additionally, a significant association was found between age, race, type of hospital, and timeliness of AC.

Conclusion

To date, our study is the largest data set to assess the timeliness of FOLFOX as a predictor of outcome in stage III colon cancer. Because FOLFOX is the current standard for AC for colon cancer, we report a trend toward worse outcome when FOLFOX is delayed more than 12 weeks. This result, thus supports quality measures to assess the timeliness of AC in stage III colon cancer and might have a meaningful effect on the care of patients with colon cancer.

Introduction

Colorectal cancer is the third most commonly diagnosed cancer, accounting for approximately 10% of all cancer deaths in the United States.¹ In 2013, approximately 103,000 colon cancer cases will be diagnosed in the United States, of which close to 37% will present as stage III disease.²

Surgical resection followed by adjuvant chemotherapy is the standard treatment for stage III colon cancer. Adjuvant chemotherapies include 5-FU (fluorouracil) and LV (leucovorin) or capecitabine, with or without oxaliplatin. The 2 modern trials of adjuvant chemotherapy for colon cancer include MOSAIC (Multi-center International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) and NSABP (National Surgical Adjuvant Breast and Bowel Project) C-07 trials. Both of the trials evaluated the benefit of the addition of oxaliplatin to 5-FU and LV compared with 5-FU and LV alone, showing significant improvement in disease-free and overall survival in stage III colon cancer.3, 4 The patients started adjuvant chemotherapy within 56 days of surgical resection and both trials provided convincing evidence for the benefit of adjuvant chemotherapy in stage III colon cancer.

Currently no guidelines exist for when chemotherapy should start after surgical resection. Delay of chemotherapy beyond 8 weeks has been associated with a higher risk of death and recurrence in the patients who received 5-FU only chemotherapy.5, 6, 7 A systematic review and metaanalysis have shown that relative overall survival decreases by 14% for every 4-week delay in initiation of adjuvant chemotherapy with 5-FU.⁸ The significance of these studies suggests that timeliness of adjuvant chemotherapy after surgery has clinical implications, and delays in adjuvant chemotherapy can result in inferior outcome and should be avoided. However, to our knowledge, the significance of delays in administration of oxaliplatin-based regimens in stage III colon cancer is unexplored. Furthermore, many of the existing studies are based on administrative data in which there is information regarding the initiation of chemotherapy and no information regarding completion of chemotherapy. Considering that patients who had delays in initiation of chemotherapy might also be at higher risk for dose reduction, dose delays and early termination of chemotherapy might confound the final conclusion.

In 2007, the National Quality Forum endorsed a measure submitted by the Commission of Cancer that adjuvant chemotherapy should be administered within 120 days of diagnosis of stage III colon cancer.⁹

In the present investigation, we explored the timeliness of adjuvant chemotherapy with Oxaliplatin/5-Fluorouracil/Leucovorin (FOLFOX) for stage III colon cancer in patients who received adjuvant chemotherapy at our institution.

Section snippets

Patient Selection

We performed a retrospective study of patients with stage III colon cancer who received their adjuvant chemotherapy at Los Angeles County-University of Southern California Medical Center (LAC-USC) and Norris Cancer Center between 2003 and 2011. Patients were identified from our administrative records. Demographic and tumor characteristics (tumor location, tumor stage, node stage) and treatment-related information (type and date of surgery, and type, date, and number of cycles of adjuvant

Results

Patient demographic and tumor characteristics are presented in Table 1. One hundred and two patients were included for analysis with the median follow-up time of 3.2 years (range, 0.5-9.5 years). The median age of the cohort was 58 years (range, 27-85 years), with only 25 patients older than the age of 65 years.

Ninety-three patients completed adjuvant chemotherapy within 6 months and 9 patients had incomplete chemotherapy. One patient received 1 cycle of chemotherapy, 2 patients received 2

Discussion

We investigated the significance of the time to start of adjuvant chemotherapy as a predictor of recurrence in patients with stage III colon cancer. This is one of the largest reports to investigate time of adjuvant chemotherapy in patients receiving FOLFOX in the adjuvant setting for stage III colon cancer.

Although no association was found between time from surgery to adjuvant therapy and TTR for local and systemic recurrences, delays of > 12 weeks were predictive of systemic recurrence.

Conclusion

Our results show that patients with stage III colon cancer who started adjuvant chemotherapy > 12 weeks after resection have a higher risk for systemic recurrence. Our findings are relevant to the current practice of adjuvant chemotherapy with FOLFOX for stage III colon cancer, and suggest that timeliness of adjuvant chemotherapy after surgery should be a quality measure. The accountability now shifts to institutions that should evaluate and redefine interventions to overcome barriers that

Disclosure

The authors have stated that they have no conflicts of interest.

References (20)

I. Chau et al.
A randomised comparison between 6 months of bolus fluorouracil/leucovorin and 12 weeks of protracted venous infusion fluorouracil as adjuvant treatment in colorectal cancer
Ann Oncol
(2005)
S. Bayraktar et al.
Timing of adjuvant and neoadjuvant therapy in colorectal cancers
Clin Colorectal Cancer
(2010)
W. Lee et al.
Socioeconomic factors impact colon cancer outcomes in diverse patient populations
J Gastrointest Surg
(2012)
R. Siegel et al.
Cancer statistics, 2013
CA Cancer J Clin
(2013)
Fast Stats: an interactive tool for access to SEER cancer statistics. Available at:...
T. Andre et al.
Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial
J Clin Oncol
(2009)
G. Yothers et al.
Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses
J Clin Oncol
(2011)
P.M. Czaykowski et al.
Adjuvant chemotherapy for stage III colon cancer: does timing matter?
Dis Colon Rectum
(2011)
D. Hershman et al.
Timing of adjuvant chemotherapy initiation after surgery for stage III colon cancer
Cancer
(2006)
J.J. Biagi et al.
Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis
JAMA
(2011)

There are more references available in the full text version of this article.

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Original studyTimeliness of Adjuvant Chemotherapy for Stage III Adenocarcinoma of the Colon: A Measure of Quality of Care

Abstract

Background

Patients and Methods

Results

Conclusion

Introduction

Section snippets

Patient Selection

Results

Discussion

Conclusion

Disclosure

Ann Oncol

Clin Colorectal Cancer

J Gastrointest Surg

Cancer statistics, 2013

CA Cancer J Clin

Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial

J Clin Oncol

Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses

J Clin Oncol

Adjuvant chemotherapy for stage III colon cancer: does timing matter?

Dis Colon Rectum

Timing of adjuvant chemotherapy initiation after surgery for stage III colon cancer

Cancer

Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis

JAMA

Original study
Timeliness of Adjuvant Chemotherapy for Stage III Adenocarcinoma of the Colon: A Measure of Quality of Care