AREAS OF CONFUSION IN ONCOLOGY
Adjuvant Chemotherapy for Stage II Colon Cancer
By Scott Kopetz, MD1, Daniela Freitas, MD2, Aknar F.C. Calabrich, MD2, Paulo M. Hoff, MD, FACP3 |
March 1, 2008
1Assistant Professor, Department of Gastrointestinal Medical Oncology
The University of Texas, M.D. Anderson Cancer Center, Houston, Texas
2Centro de Oncologia, Hospital Sírio-Libanês
3Executive Director, Centro de Oncologia, Hospital Sírio-Libanês, Medical Oncology, University of São Paulo, Brazil, São Paulo, Brazil
Dilemmas in Clinical Decision-Making: A Case Example
Based on these data, guidelines have been developed that define a consensus group of high-risk features for stage II colon cancer.[27,50] These expert panel recommendations recognize that the benefit of adjuvant therapy for stage II patients is unknown and suggest enrollment in a clinical trial, if possible. Patient-physician decision-making is encouraged after a discussion of the risks and potential benefits of adjuvant therapy.
The National Comprehensive Cancer Network clinical practice guidelines define high-risk stage II disease as being characterized by at least one of the following factors: T4 tumor; poor histologic grade (undifferentiated or poorly differentiated); lymphovascular involvement; bowel obstruction at presentation; T3 lesion with localized perforation or close, indeterminate, or positive margins; and inadequately sampled lymph nodes (defined as fewer than 12 nodes analyzed). According to these guidelines, patients with high-risk disease should be considered for adjuvant chemotherapy. There is no evidence, however, that the factors associated with poorer prognosis are predictive of response to treatment.
The guidelines developed by ASCO are similar but also list neural invasion as a high-risk feature. The possible absolute benefit of adjuvant chemotherapy for stage II patients is estimated in this guideline as a 2% to 4% increase in the 5-year survival rate. The consensus opinion was that the direct evidence does not yet support the use of adjuvant chemotherapy for high-risk stage II patients, but that indirect evidence based on inadequate sample size in prior negative trials and the established benefit for stage III patients may support treatment of selected patients.
On the basis of these criteria, high-risk features are found in the majority of stage II patients. In the subset of stage II patients enrolled in the MOSAIC trial, 64% were characterized as high risk. Specifically, 19% had T4 lesions, 34% had inadequate lymph node sampling (defined as fewer than 10 lymph nodes in this study), 17% had bowel obstruction, 9% had perforation, and the high-risk pathologic findings of poor differentiation and vascular invasion were seen in 10% and 4% of patients, respectively.
Other high-risk models have been suggested. For example, the Petersen prognostic model defines high risk as either tumor perforation or more than one of the following: peritoneal involvement, vascular invasion, and positive surgical margins. In an independent validation cohort of 1,625 stage II patients, this model demonstrated a significant difference in 5-year survival rate for high-risk vs low-risk patients (45% vs 70%, respectively, P < .01).
In addition to the well-recognized pathologic and clinical high-risk characteristics, molecular markers can also provide prognostic information. Several molecular markers are being prospectively validated and are reviewed here. The ASCO recommendations on the use of markers in colon cancer provide a more definitive review of this topic.
• Microsatellite Instability—Microsatellite instability (MSI) is a measure of DNA repair mechanisms that when disrupted lead to replication errors in repetitive nucleotide regions (called microsatellites). MSI is classically associated with the familial hereditary nonpolyposis colorectal cancer syndrome, although it is also present in a minority of sporadic colon cancers. The presence of MSI has been associated with better outcomes in stage II and III patients. Studies to determine the impact of MSI status on response to 5-FU are few in number but appear to suggest a lack of benefit from 5-FU adjuvant therapy.[54,55]
• 18q LOH—Loss of heterozygosity on the long arm of chromosome 18 (18q LOH) is a common finding in tumors arising from the chromosomal instability pathway. The deleted in colon cancer (DCC) protein is encoded on this chromosome, and in stage II colon cancer, 18q LOH is associated with a worse prognosis in two retrospective studies.[56,57] Similar studies have used the presence or absence of DCC staining to evaluate 18q status, with mixed results. These markers require prospective validation before they can be recommended for use in determining the prognosis of stage II colon cancer. One study in high-risk stage II and stage III patients suggested a benefit from 5-FU adjuvant chemotherapy in patients with retention of both alleles of 18q, but the study design was unable to separate the predictive and prognostic roles of 18q LOH.
||Discuss adjuvant chemotherapy with all stage II colon cancer patients whose comorbidities do not preclude treatment.
||Gauge patient interest in participating in the decision-making process.
||Evaluate clinical and pathologic features that may predict a higher rate of recurrence.
||As appropriate, relay risks and estimated benefits of treatment using “number needed to treat” language, while acknowledging uncertainty in the degree of benefit. Alternatively, online numeracy guides may aid in the discussion of the benefits of treatment.
||For patients who receive adjuvant chemotherapy, reevaluate risks and benefits with the patient as appropriate during the course of treatment.
• Other Molecular Marker Considerations—Other markers, such as mutations in p53, PIK3CA, and KRAS and expression of vascular endothelial growth factor, lactate dehydrogenase, and telomerase, have been shown to have prognostic significance in preliminary studies in early-stage colon cancer. Further validation is required before they can be utilized in the clinic, however.
Molecular markers may not be independent of histologic markers. For example, a tumor lymphocytic infiltrate is associated with better outcomes and is seen more frequently in MSI tumors. Similarly, 18q LOH appears to be necessary for vascular invasion. Success in advancing molecular techniques will require that they show improvement in prognostic ability over current pathologic techniques.
Prognostic factors are frequently reported, but it is much more complicated to determine factors predictive of efficacy after treatment. Separation of the predictive and prognostic characteristics of a marker requires samples from both treated and untreated patients. This is a critical limitation of many studies, as markers denoting poor prognosis do not always predict response to therapy. For example, patients with stage II/III colorectal cancer lacking a particular epithelial growth factor receptor polymorphism have worse overall survival but also a decreased sensitivity to chemotherapy. Likewise, stage II/III patients with tumors expressing low levels of dihydropyrimidine dehydrogenase had worse overall survival if they received surgery alone but a greater relative benefit from oral 5-FU adjuvant chemotherapy.
• Multiple-Marker Models—Given the complexities of cancer, a single molecular marker is unlikely to completely distinguish high- and low-risk patients. As a result, there has been significant interest in prognostic models that incorporate multiple molecular features, such as genetic microarrays and multiplexed PCR assays. In one study in stage II colon cancer, a 23-gene signature was found to confer 13-fold higher odds of relapse than a good prognostic signature. A second study produced a 43-gene set that segregated stage II and III patients into good- and poor-prognosis groups with corresponding 5-year overall survival rates of 65% and 30%, respectively. In both studies, validation was limited to a small sample set, and further external validation is needed.
A similar approach is being taken by the NSABP using PCR techniques, which can be performed using paraffin(Drug information on paraffin)-embedded tissues. Moving these platforms into the clinic requires additional work to generate a laboratory test certified for clinical use, and ideally, a robust determination of the critical components of the predictive panel. In addition, the information obtained from the gene arrays must be shown to be independent from previously established clinicopathologic factors.[59,67]
ECOG 5202 Study
In a current GI Intergroup trial, E5202, patients are being prospectively selected for adjuvant therapy on the basis of MSI and 18q status. Poor-prognosis patients, defined as those with 18q loss of heterozygosity and either MSS (microsatellite stable) or MSI-Low (low levels of microsatellite instability not meeting the formal MSI definition) status, will be treated with FOLFOX-based regimens identical to that in the ongoing NSABP C-08 trial. Conversely, patients with a good prognosis (retained 18q heterozygosity or MSI [denoted as MSI-High]) will be observed only (Figure 2). In addition, tumor banking is incorporated in this study to allow for the future evaluation of molecular prognostic models, including DNA microarray studies.
The benefit of adjuvant 5-FU chemotherapy for stage II colon cancer has not been robustly demonstrated, with most trials and meta-analyses demonstrating trends toward improved outcomes that do not meet statistical significance. In multiple trials, however, the relative benefit of treatment with 5-FU adjuvant chemotherapy is similar for stage II and III patients, with relative risk reductions of 15% to 20% with 5-FU treatment. This credibly implies that stage II patients derive benefit from adjuvant treatment, but that the degree of benefit is too small to observe given the size of previous clinical trials.
For patients with low-risk stage II cancer, the small-interval benefit from treatment is balanced by the fixed risks of severe toxicity and death from chemotherapy. Although the decision regarding adjuvant treatment needs to be individualized, observation only is an acceptable option for these patients. For the patient with high-risk stage II disease, the benefit from chemotherapy is greater and outweighs the risks associated with chemotherapy in most situations.
Quantitating the degree of benefit is helpful for some patients with sufficient numeric literacy. Using the “number needed to treat” method of communicating absolute benefit is preferred in patient discussions, as it avoids the use of relative benefits.[68,69] The number of stage II patients needed to treat to prevent one recurrence or death is 25 to 50 patients, at the cost of a severe adverse event in every 6 patients treated and death due to treatment in every 100 to 200 patients treated. For high-risk stage II patients, the number needed to treat to prevent one death or recurrence is likely in the range of 15 to 30. For stage II patients without high-risk features, it can be implied that the number needed to treat to prevent one recurrence or death is greater than 50.
Alternatively, two freely available online numeracy guides have been developed for adjuvant chemotherapy for colon cancer. Adjuvant! Online (www.adjuvantonline.com) incorporates more prognostic characteristics, allows alteration of the underlying assumptions of benefit, and provides a graphic display of benefit designed to be shared with patients. The Mayo Clinic calculator (www.mayoclinic.com/calcs) relies on fixed assumptions of benefit for stage II patients and is supported by a peer-reviewed publication describing its validation methods.
Although not studied in stage II patients, capecitabine has been demonstrated to be at least equivalent to intravenous 5-FU regimens in stage III and IV patients , and it is an appropriate single-agent treatment option to discuss with the patient. Inclusion of oxaliplatin into the adjuvant regimen increases the uncertainty regarding the degree of benefit from the treatment and increases the toxicities associated with treatment. As in the prior 5-FU trials, the relative benefit of treatment with oxaliplatin in the two recent adjuvant trials is remarkably similar for stage II and III disease. As a result, treatment with an oxaliplatin/5-FU combination cannot be viewed as the new standard but is reasonable for select stage II patients.
The list of potential prognostic factors dramatically outpaces our ability to prospectively validate them and determine whether they will translate into factors predictive of response to chemotherapy. Molecular markers are under investigation and should not be used to guide current clinical decision-making. Similarly, microarray-based assays for stage II colon cancer will require extensive prospective validation prior to implementation, but they offer the potential to improve patient selection for adjuvant therapy.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
A 70-year-old man with hypertension presented to his primary care physician with anemia and fatigue, prompting a colonoscopy, which demonstrated a nonobstructing sigmoid adenocarcinoma. He underwent a left hemicolectomy, which identified a moderately differentiated adenocarcinoma invading through the muscularis propria (T3) without lymphovascular invasion. Ten lymph nodes were evaluated, without evidence of tumor involvement.
How should we treat this stage II colon cancer patient? There are no consistent data on the benefit of adjuvant chemotherapy in stage II patients, although the cumulative evidence suggests a small benefit for fluorouracil/leucovorin chemotherapy.
How does the limited number of evaluated lymph nodes impact the treatment recommendation? It may represent inadequate surgical resection, incomplete pathologic evaluation, or a paucity of pericolonic regional lymph nodes in this patient.
What risk factors, if any, should influence the treatment recommendation? Several “high-risk” features have been proposed, including inadequate sampling of the lymph nodes, with varying amounts of supporting data.
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