Adjuvant therapy for elderly patients with stage III colon cancer

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Background

Adjuvant chemotherapy is standard treatment for elderly patients with stage III colon cancer.

The use of single-agent fluoropyrimidines are supported by a pooled analysis[1] of individual patient data from seven phase III randomised controlled trials (RCTs) involving a total of 3351 patients. Included were studies comparing postoperative fluorouracil plus leucovorin (five trials) or fluorouracil plus levamisole (two trials) with surgery alone in patients with stage II or III colon cancer.[1] The study reported a significant positive effect on both overall survival (hazard ratio [HR] 0.76, p < 0.001) and time to tumour recurrence (HR 0.68, p < 0.001), with no significant interaction observed between age and the efficacy of treatment. The incidence of toxic effects was not increased among patients aged over 70 years, except for leukopenia in one study.[1]

The roles of additional agents in adjuvant therapy in the elderly have not been well defined.

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Systematic review evidence

In elderly patients (≥70 years) diagnosed with colon cancer, what is the efficacy of surgery and adjuvant combination chemotherapy (involving either 5-fluorouracil5-fluorouracil is a systemic chemotherapy using fluorouracil. or capecitabine combined with oxaliplatin), compared to surgery with a single chemotherapeutic agent (fluoropyrimidine), in achieving the best outcomes in terms of colorectal cancer mortality, recurrence, quality of life and adverse effects? (ADJ1)

A systematic review was undertaken to evaluate outcomes (cancer-related outcomes, quality of life outcomes and adverse events) for patients with colorectal cancer aged 70 years and over undergoing surgery in combination with either single-agent chemotherapy or combination chemotherapy (oxaliplatin plus either 5-fluoruracil [5FU] or capecitabine).

Three randomised controlled trials (RCTs) were identified that compared adjuvant combination chemotherapy with single chemotherapy in the treatment of Stage II or Stage III colorectal cancer and included elderly patients:

  • The XELOXA study[2][3] compared the combination of oxaliplatin and capecitabine (XELOX) with the combination of leucovorin fluorouracil (FULV) given as either of two regimens. Sub-group analysis was performed for Stage III patients aged 70 years and older (n = 409).[3]
  • The MOSAIC study[4][5][6][7][8] compared the combination of FULV plus oxaliplatin (FOLFOX4) with FULV. Sub-group analysis was performed for Stage II or Stage III patients aged 70 years and older (n = 315).[4][8]
  • The US National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 study4,10,12,13 compared the combination of FULV plus oxaliplatin (FLOX) with FULV. It included sub-group analysis for Stage II or Stage III patients aged 70 years and older (n = 299).[9][7][10]

The search strategy, inclusion and exclusion criteria, and quality assessment are described in detail in the Technical report.

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Addition of oxaliplatin to 5FU-based regimens

In contrast with the efficacy of single-agent fluoropyrimidines as adjuvant treatment in older patients, subset analyses of all three studies combining oxaliplatin with a fluoropyrimidine have not demonstrated any survival advantage from adding oxaliplatin in older patients:

  • In an analysis of 396 patients aged ≥70 enrolled in the NSABP CO7 study[9] there was no advantage from the addition of oxaliplatin for disease free survival at median follow-up of 96 months: HR 1.03 (95% CI 0.77 to 1.36). Similarly, overall survival was not improved: HR 1.18 (95% CI 0.68 to 1.62).
  • The latest analysis of data from 315 patients aged 70 and older from the MOSAIC study[4] show that the addition of oxaliplatin did not improve overall survival at median follow-up of 9.46 years: HR 1.19 (95% CI 0.83 to 1.7).
  • In an analysis of data for 409 patients aged 70 years and older from the XELOXA study,[3] there was no improvement in disease free survival (HR 0.86, 95% CI 0.64 to 1.16) or overall survival (HR 0.98, 95% CI 0.62 to 1.56) at a median follow-up of 74 months.

In a pooled analysis of all three studies[7] (n = 1119) there was no improvement in disease free survival (HR 0.94, 95% CI 0.78 to 1.12) or overall survival (HR 1.04, 95% CI 0.85 to 1.27) in the elderly patients receiving oxaliplatin.

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Understanding the lack of benefit from the addition of oxaliplatin in stage III colon cancer

Oxaliplatin, fluorouracil, and leucovorin are commonly used to treat patients with advanced colorectal cancer. An analysis of the safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly (FOLFOX4) in patients age younger than and at least 70 years[11] reported no impact of age on oxaliplatin benefit. This retrospective analysis of 3742 colorectal cancer patients from four clinical trials, 614 of whom were aged ≥ 70 years, found the relative benefit of FOLFOX4 versus control did not differ by age for response rate, progression free-survival or overall survival.

The discordance between the outcome data for the addition of oxaliplatin for the treatment of elderly patients in the adjuvant setting, versus the metastatic setting, remains largely unexplained. In the MOSAIC trial, the incidence of second cancers was significantly different between the elderly and the younger patients (11.0% versus 4.0%; p = 0.001) but not in the 5FU-alone arm (6.3% versus 5.3%; p = 0.16).[8] In elderly patients treated with FOLFOX4, the median overall survival after recurrence was 3.6 months, compared with 13.7 months in patients treated with 5FU. However, no excess of second cancers or shorter post recurrence survival was reported in the other studies, and the observations from the MOSAIC trial could not fully explain a failure of oxaliplatin to improve outcomes in older patients.

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Evidence summary and recommendations

Evidence summary Level References
In elderly patients (≥ 70 years) following surgery for stage III colon cancer, subset analyses of three randomised controlled trials found no survival benefit from the addition of oxaliplatin to a fluoropyrimidine containing adjuvant chemotherapy (involving either 5-fluorouracil5-fluorouracil is a systemic chemotherapy using fluorouracil. or capecitabine), compared to adjuvant chemotherapy with a fluoropyrimidine alone. I, II [7], [9], [2], [4]
Consensus-based recommendationA recommendation formulated in the absence of quality evidence, after a systematic review of the evidence was conducted and failed to identify admissible evidence on the clinical question.Question mark transparent.png

Elderly patients (≥ 70 years) with stage III colon cancer who are fit for adjuvant chemotherapy should receive 6 months of a single-agent fluoropyrimidine (either 5FU or capecitabine).

Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

The addition of oxaliplatin to adjuvant fluoropyrimidine-based therapy in elderly patients (≥ 70 years) with stage III colon cancer did not improve survival outcomes.

Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

The combination of oxaliplatin and fluoropyrimidine-based therapy in the metastatic setting provides a similar benefit in elderly patients and younger patients. The discordance between the adjuvant and metastatic setting remain unexplained.

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Considerations in making these recommendations

While oxaliplatin-based treatment provides a similar advantage for older and younger patients with metastatic disease, the data do not support this approach in older patients in the adjuvant setting. Therefore, oxaliplatin-based therapy cannot be recommended for older patients.

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Health system implications

Clinical practice

The recommendation would not change current practice.

Resourcing

The recommendation has no implications for resourcing.

Barriers to implementation

No barriers to the implementation of this recommendation are envisaged.

Next section: adjuvant therapy for stage II colon cancer

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References

  1. 1.01.11.2 Sargent DJ, Goldberg RM, Jacobson SD, Macdonald JS, Labianca R, Haller DG, et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 2001 Oct 11;345(15):1091-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11596588.
  2. 2.02.1 Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol 2011 Apr 10;29(11):1465-71 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21383294.
  3. 3.03.13.2 Schmoll HJ, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, et al. Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer: Final Results of the NO16968 Randomized Controlled Phase III Trial. J Clin Oncol 2015 Nov 10;33(32):3733-40 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26324362.
  4. 4.04.14.24.3 André T, de Gramont A, Vernerey D, Chibaudel B, Bonnetain F, Tijeras-Raballand A, et al. Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Outcomes According to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study. J Clin Oncol 2015 Dec 10;33(35):4176-87 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26527776.
  5. André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004 Jun 3;350(23):2343-51 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15175436.
  6. André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, 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 Jul 1;27(19):3109-16 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19451431.
  7. 7.07.17.27.3 McCleary NJ, Meyerhardt JA, Green E, Yothers G, de Gramont A, Van Cutsem E, et al. Impact of age on the efficacy of newer adjuvant therapies in patients with stage II/III colon cancer: findings from the ACCENT database. J Clin Oncol 2013 Jul 10;31(20):2600-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23733765.
  8. 8.08.18.2 Tournigand C, André T, Bonnetain F, Chibaudel B, Lledo G, Hickish T, et al. Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly patients (between ages 70 and 75 years) with colon cancer: subgroup analyses of the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer trial. J Clin Oncol 2012 Sep 20;30(27):3353-60 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22915656.
  9. 9.09.19.2 Yothers G, O'Connell MJ, Allegra CJ, Kuebler JP, Colangelo LH, Petrelli NJ, 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 Oct 1;29(28):3768-74 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21859995.
  10. Kuebler JP, Colangelo L, O'Connell MJ, Smith RE, Yothers G, Begovic M, et al. Severe enteropathy among patients with stage II/III colon cancer treated on a randomized trial of bolus 5-fluorouracil/leucovorin plus or minus oxaliplatin: a prospective analysis. Cancer 2007 Nov 1;110(9):1945-50 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17853393.
  11. Goldberg RM, Tabah-Fisch I, Bleiberg H, de Gramont A, Tournigand C, Andre T, et al. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol 2006 Sep 1;24(25):4085-91 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16943526.
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Appendices


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