Building on the Foundation of 5-FU to Treat Metastatic Colorectal Cancer

Pohl and colleagues have provided a concise overview of current treatment options for metastatic colorectal cancer (mCRC). However, the authors do not provide personal insights as to what direction this burgeoning field will take next. Within the past decade, an abundance of treatment options have emerged. With all available therapies, the median overall survival is reportedly 31.8 months.[1] Yet the 5-year overall survival of a patient with surgically unresectable disease is < 10%, and the duration of treatment is indefinite.

Recent therapeutic development has focused primarily on biologic therapy, which is thought to result in fewer toxicities but has largely remained unproven, since combined treatment with chemotherapy continues to provide the most effective approach for the mCRC patient. Furthermore, single-agent or combined biologic therapy alone has no greater efficacy and may in fact result in significant toxicities.[2] Hence, treatment for the mCRC patient often carries a risk of toxicity, financial burden, and possible psychological strain. We need to identify key predictive and prognostic markers to optimally benefit our patients.

Bevacizumab, FOLFOX, and XELOX
Two signal transduction pathways mentioned by the authors involve the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). Pohl and colleagues highlight the role of the VEGF inhibitor bevacizumab (Avastin) in first- and second-line bevacizumab-naive patients and discuss the original registration trials of AVF2107 and ECOG 3200.[3,4] They briefly mention the results of NO16966 but do not attempt to explain the confounding data.[5,6]

The NO16966 study was originally created as a 2 × 2 international phase III trial to establish noninferiority of FOLFOX (leucovorin, fluorouracil [5-FU], oxaliplatin [Eloxatin]) vs XELOX (capecitabine [Xeloda], oxaliplatin). With the subsequent US Food and Drug Administration (FDA) approval of bevacizumab, NO16966 was amended to be a 2 × 2 placebo-controlled trial with primary endpoints of noninferiority for FOLFOX vs XELOX and superiority of bevacizumab when added to chemotherapy; each primary endpoint was fulfilled. However, when evaluating the benefit of bevacizumab to the specific chemotherapy regimen, the hazard ratio (HR) for progression-free survival was superior only for the XELOX regimen (7.4 vs 9.3 months; HR = 0.77 [97.5% confidence interval (CI) = 0.63–0.94]; P = .0026) in comparison to the FOLFOX regimen (8.6 vs 9.4 months; HR = 0.89 [97.5% CI = 0.73–1.08]; P = .1871). The preliminary findings from this trial resulted in significant concerns about bevacizumab in combination with FOLFOX.

The authors suggest that the response rate and overall survival are consequences of the discontinuation of all chemotherapy, but further elaboration is needed. Other reasons account for this outcome: First, the superior hazard ratio for XELOX/bevacizumab may be a result of the longer progression-free survival in the control arm of FOLFOX vs XELOX resulting in a greater measurable difference. Second, only 29% of bevacizumab patients received treatment until disease progression. Final details of NO16966 are to be published at a later date.

Other Anti-VEGF Therapies
Anti-VEGF therapies discussed by the authors include the oral tyrosine kinase inhibitors (TKI) sunitinib (Sutent) and vatalanib. Sunitinib is a multitargeted TKI currently in phase I/ II development for the treatment of mCRC. Pohl and coauthors state that the reason for the efficacy of sunitinib in metastatic renal cell carcinoma (mRCC), as opposed to less impressive results in mCRC, is unknown. However, they fail to mention the known association between anti-VEGF therapy and mRCC. The transcription factor known as hypoxia-inducible factor (HIF-1α) is normally degraded by the von Hippel-Landau (VHL) protein. However, in the presence of the VHL mutation, HIF-1α degradation is inhibited, resulting in increased VEGF expression, which is likely to account for the single-agent activity of sunitinib and bevacizumab.

The authors suggest that there is a future role for the oral VEGF receptor inhibitor vatalanib in mCRC. Furthermore, high levels of lactate dehydrogenase (LDH) correlated with progression-free survival. However, vatalanib has been extensively evaluated in the first- and second-line settings, failing to fulfill the primary endpoint of progression-free survival. Furthermore, correlation with elevated LDH and progression-free survival was noted on post ad hoc analysis. Elevated LDH levels are nonspecific and not classically viewed as a prognostic indicator in mCRC. Hence, it is unlikely that vatalanib will have a future role in mCRC.

Anti-EGFR Therapies
The authors provide a broad overview of anti-EGFR therapy with a focus on combined biologic therapy. The PACCE trial was based on the BOND-2 study demonstrating that combined biologic therapy with or without chemotherapy was feasible and efficacious.[7] The authors provide two potential reasons for the unfavorable outcome of PACCE vs BOND-2: (1) tumor differentiation in treatment-naive vs the pretreated patient population, and (2) change in chemotherapy sensitivity.

Although these explanations are plausible, additional factors must account for the disappointing outcome. The BOND-2 trial was a small phase II study and likely accrued a very select patient population. Furthermore, multiple phase II studies were completed regarding the efficacy and safety of chemotherapy plus cetuximab (Erbitux). Little evidence supported the combination of panitumumab (Vectibix) and chemotherapy prior to PACCE, emphasizing the importance of phase II clinical trials.

Predictive Markers
A critical area of scientific development that is being incorporated into daily practice and deserves greater elaboration than the authors provide is the role of predictive markers. As they note, a surrogate marker of efficacy for anti-VEGF therapy has not been established. However, K-ras mutations are present in approximately 40% of all mCRC patients. A mutation in the K-ras oncogene may impede efficacy of anti-EGFR therapy by dysregulation of the downstream MAPK/MEK/ERK pathways. Initial studies of single-agent cetuximab in the presence of a K-ras mutation showed the mutation in 0% of patients who responded to the drug, compared with 68.4% of nonresponders. Consequently, the mutation had a negative impact on overall survival (6.9 vs 16.3 months, respectively).[8]

The role of K-ras as a predictive marker was confirmed in the large phase III registration trial of panitumumab vs best supportive care.[9] The use of panitumumab in the patient with a K-ras mutation is no better than best supportive care alone (7.4 vs 7.3 weeks, respectively). Hence, the use of anti-EGFR therapy should be discouraged in a K-ras mutant patient, to prevent unnecessary toxicities and expense.

In the future, all patients are to be tested for K-ras in the United Kingdom. Preliminary results of multiple phase II/III studies indicate the predictive role of K-ras holds true in combination with chemotherapy.[10-12] Additional studies are ongoing.

Conclusions
We are at the threshold of discovery in the treatment of colorectal cancer. Pohl and colleagues have simply touched upon the future of metastatic colorectal cancer treatment. Our current therapies have clearly afforded our patients improved survival, but treatment choices have been commonly provided with little knowledgeof the underlying tumor biology. Future treatment will be guided by the molecular characteristics of the tumor such as the status of K-ras, amphiregulin, epiregulin, PTEN, and other features.

To many, the provision of 5-FU may seem archaic, but 5-FU remains an integral part of our therapies, providing moderate response at the cost of minimal toxicities in comparison to oxaliplatin, bevacizumab, cetuximab, and panitumumab. Therefore, rather than being “a long way from 5-FU,” I would maintain that current treatment approaches continue to build upon the foundation of 5-FU. We are at the forefront of novel approaches to therapeutic decision-making.

The main article can be found here:
Targeting Metastatic Colorectal Cancer in 2008: A Long Way From 5-FU

Disclosures:

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Grothey A, Sugrue M, Hedrick E, et al, and the BRiTE Study Investigators: Association between exposure to bevacizumab (BV) beyond first progression (BBP) and overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC): Results from a large observational study (BRiTE) (abstract 4036). J Clin Oncol 25(18S):172s, 2007.

2. Hecht J: An interim analysis of efficacy and safety from a randomized controlled trial of panitumumab with chemotherapy plus bevacizumab (bev) in metastatic colorectal cancer (mCRC). Programs and abstracts of the 9th World Congress on Gastrointestinal Cancer; Barcelona, Spain; June 27-30, 2007.

3. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004.

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