Adjuvant chemotherapy for stage II colon cancer with poor prognostic features: the controversy is still open

Erika Martinelli

Colorectal cancer (CRC) is the third most common cancer worldwide and surgery is the cornerstone treatment in locoregional disease (stage I, II and III). The aim of adjuvant therapy is to eradicate residual micrometastasis thus improving the cure rate in early stage. It has clearly evolved, as evidenced by the variety of drugs and delivery methods which have been studied over the years.

The additional survival benefit of chemotherapy is stage specific and this has been clearly demonstrated in stage III with the use of oxaliplatin and fluoropyrimidine (intravenous infusion, bolus or oral).

The use of adjuvant chemotherapy in stage II colorectal cancer remains controversial in the oncology community. Inadequate numbers of randomised stage II patients in large studies and the preferential enrolment of “higher-risk” patients (T4 tumours, lymphovascular invasion, high-grade histology, presentation with obstruction/perforation, or inadequate lymph node sampling) have resulted in little hard evidence. Clinical trials suggest that use of 5-fluorouracil-based chemotherapy has a low survival benefit with a gain of only a few percent in absolute risk. The addition of oxaliplatin to fluorouracil shows a trend toward improvement in disease-free survival at 5 years in patients with “high risk” stage II colorectal cancer. Despite its uncertain impact on survival, adjuvant chemotherapy is commonly administered.

The report of O’Connor and colleagues attempts to clarify this issue. Specifically, the manuscript describes the effectiveness of chemotherapy in improving overall survival after surgical resection in patients with stage II disease with no poor prognostic features, stage II disease with any poor prognostic features, and stage III disease.

The data were extracted from the SEER (Surveillance, Epidemiology and End Results)-Medicare registry linked to Medicare claims files.  This database describes treatment and outcomes among Medicare beneficiaries older than 65 years in real-world conditions in contrast to selected populations enrolled in randomised clinical trials. A total of 43032 patients with colorectal cancer diagnosed between 1992 and 2005  were identified. Among these 24847 patients were diagnosed with stage II cancer, 75% with one or more poor prognostic feature. Adjuvant chemotherapy was administered in 20% of this subgroup of patients (3834). Kaplan-Meier survival analysis with propensity-score weighting was used to compare 5-year overall survival between treated and untreated patients in each stage group.

No differences in 5-years survival were detected in the group with stage II disease and any poor prognostic features, whether treated with chemotherapy or not (56.7% versus 56.1%); nor for the stage II disease population with no poor prognostic features (70.0% versus 69.5%). However, patients with stage III disease derived significant survival benefit from chemotherapy (48.9% versus 35.3). It is important to note that the study population is older than 65 years, although the analysis does not exclude a potential benefit from adjuvant treatment in younger people. Moreover, median age for colorectal cancer diagnosis is 70 years, hence these patients represent a more real-world age distribution.

The authors conclude that the lack of benefit from chemotherapy must be considered in treatment decisions in patients over 65 years with colon cancer, with any possible survival benefit likely to be less than 2% at 5 years.

Therefore, it is crucial to identify new prognostic tools, going beyond the already assessed clinicopathologic features, which could identify a specific group of high risk patients who might benefit from chemotherapy. Identification of the highest-risk subset for adjuvant therapy still needs improvement.

Source: O’Connor E et al. Journal of Clinical Oncology (2011),  Volume 29, Number 25: 3381-338

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