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Metastatic Colorectal Cancer: Treatment Challenges, Progress, and Advice With Chiara Cremolini, MD

Chiara Cremolini, MD

Colorectal cancer is the third leading cause of cancer death and the fourth most common diagnosed cancer in the world. Often, this disease is left undiagnosed until it reaches an advanced stage. Unfortunately, late-stage metastatic colorectal cancer has a poor prognosis with a 5-year survival rate of only 12%. In an interview with i3 Health, Chiara Cremolini, MD, provides insights on the challenges of treating patients with metastatic colorectal cancer, explains how metastatic colorectal cancer treatment is evolving, and gives advice to oncologists with patients with metastatic colorectal cancer.

What are the most challenging aspects of treating patients with metastatic colorectal cancer?

Chiara Cremolini, MD: Life expectancy for metastatic colorectal cancer patients has increased in the last few years thanks to the availability of both systemic therapies and locoregional procedures. The introduction of targeted agents, mostly antiangiogenic drugs and the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, prolonged the overall survival of affected patients, but positive predictors of benefit from targeted drugs are still lacking with the exception of microsatellite instability for checkpoint inhibitors.

While new targeted approaches are currently under investigation, these new options on the horizon (eg, BRAF + EGFR inhibitors, anti-HER2 strategies, NTRK inhibitors, KRAS G12C inhibitors) may be beneficial for small subgroups of patients based on their molecular characteristics. The main reasons for these partially disappointing results from the targeted philosophy should be probably searched in the intrinsic heterogeneity of metastatic colorectal cancer and the lack of a predominantly driver pathway in the vast majority of tumors. For these reasons, the role of chemotherapy is still crucial in the management of metastatic colorectal cancer patients and the choice of the first-line therapy is of paramount importance since it may substantially affect the subsequent steps of the therapeutic route. Moreover, the weight of the upfront treatment on the long-term outcome of these patients is well established, proving the significance of considering a good start to treatment as a very important objective of oncologists' treatment choices.

How do you foresee the treatment of metastatic colorectal cancer evolving?

Dr. Cremolini: Immunotherapy has entered the clinical scenario of metastatic colorectal cancer for the small subgroup of microsatellite-instable tumors. One of the most compelling needs is bringing immunotherapy to the vast majority of microsatellite-stable metastatic colorectal cancers. To this purpose, strategies to make initially cold tumors responsive to the action of immune checkpoint inhibitors are under investigation with some preliminary promising results though. The combination of checkpoint inhibitors with antiangiogenic agents has provided successful results in several solid malignancies. Recently, signals of activity for the combination of an anti-PD-1 with the multityrosine kinase inhibitor regorafenib, able to inhibit tumor-associated macrophages with immune-suppressive effect, were demonstrated.

The combination of a checkpoint inhibitor with first-line chemotherapy and the antiangiogenic bevacizumab is under investigation in a phase 2 randomized study by GONO named AtezoTRIBE that is probably the "last call" for the investigation of this strategy. Finally, a very intriguing tool for driving therapeutic choices in metastatic colorectal cancer is the quantitative and qualitative analysis of circulating tumor DNA (ctDNA) in liquid biopsies. The comprehensive assessment of a tumor's molecular characteristics through a non-invasive procedure may provide useful information to build a step-by-step molecularly informed continuum of care. The possibility of also detecting the minimal residual disease following radical surgical procedures is of paramount interest to identify the so-called "molecularly metastatic disease" and to early treat patients who will experience disease relapse though in the absence of macroscopically evident disease.

Any advice for community oncologists who see patients with metastatic colorectal cancer?

Dr. Cremolini: We recommend choosing the first-line therapy of metastatic colorectal cancer patients considering that it may substantially affect their prognosis. Investing in the "best" first-line therapy has a clear impact on patients' long-term outcome. Considering that the optimal integration of systemic and locoregional treatments may lead to a small but not negligible fraction of these patients to be cured though affected by an advanced disease, being more "aggressive" in this setting is justified also at the price of a relative increase in the probability of experiencing some adverse events.

About Dr. Cremolini

Chiara Cremolini, MD, of Azienda Ospedaliero-Universitaria Pisana has authored or co-authored 344 publications on colorectal cancer. Dr. Cremolini is currently working on two projects at the moment regarding single nucleotide polymorphism (SNPs) in colorectal cancer and dihydropyrimidine dehydrogenase (DPYD) and fluoropyrimidines toxicity.

For More Information

Cremolini C, Antoniotti C, Rossini D, et al (2020). Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicenter, open-label, phase 3, randomized, controlled trial. Lancet Oncol. [Epub ahead of print] DOI:10.1016/S1470-2045(19)30862-9

Rawla P, Sunkara T & Barsouk A (2019). Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors. Prz Gastroenterol, 14(2):89-103. DOI:10.5114/pg.2018.81072

Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health. 

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