A Decade of Progress for Patients With Metastatic Colorectal Cancer: A New Decade in Which Obstacles Loom

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Al B. Benson III
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Remarkably, within a little more than a decade, there has been a transformation in the therapeutic approach to patients with colorectal cancer from a 1-drug strategy, albeit administered in multiple different schedules plus leucovorin, to an 8-drug armamentarium that includes hundreds of different possible schedules and sequences. This multiagent phenomenon has produced tangible benefit for many patients with metastatic colorectal cancer. For these patients, median survival has extended from significantly less than 1 year to more than 2 years. In some cases, patients with resectable metastatic disease have seen a long-term survival gain. Patients with stage III colon cancer also have experienced improved outcomes with the addition of oxaliplatin to a fluoropyrimidine. Disappointingly, however, attempts to build on treatment advances with the other new agents available did not improve survival. This lack of improvement poses critical and unanswered questions about possible biologic differences, for example, between those with microscopic versus macroscopic disease.

The past decade also has enriched our understanding of colorectal cancer biology and the vast complexity of signaling pathways, although understanding in colorectal cancer lags behind that in breast and other cancers for which researchers now have an array of different molecular targets as templates for drug development. Importantly, international clinical trials in colorectal cancer provided a mechanism to create extensive tumor repositories from which, most notably, the KRAS story has unfolded and is still evolving. These clinical studies provide the opportunity to unmask other potentially significant mutations and molecular associations.

In this special issue of JNCCN, multiple articles integrate a spectrum of treatment approaches, strategies, and challenges, reflecting comprehensive care for patients with metastatic colorectal cancer. An article from Dr. Deeb and colleagues discusses KRAS and multigene assays, including their current and potential uses in colorectal cancer. But first, the case report by colorectal cancer experts at the City of Hope Comprehensive Cancer Center provides a multidisciplinary review of the optimal management of the patient with synchronous metastatic rectal cancer, often the topic of considerable debate at tumor boards around the country. The emphasis on multidisciplinary collaboration and coordination is critical for the care of these individuals, as is highlighted in this case report and discussion.

An article from Drs. Ciombor and Bekaii-Saab at The Ohio State University Comprehensive Cancer Center summarizes the array of treatment opportunities for patients with metastatic colorectal cancer. This article also addresses future research opportunities to tackle unanswered questions. Dr. Grem, from the University of Nebraska Medical Center, discusses sequencing of treatment in advanced unresectable disease, with an emphasis on achieving the balance between efficacy and toxicity and the management strategies required.

Finally, Drs.Vergo and Cullinan from the Section of Palliative Care at Dartmouth-Hitchcock Medical Center discuss the growing emphasis on the early introduction of palliative care for patients with advanced disease, and offer their insights on focusing on the symptoms, social, spiritual, and emotional needs of our patients, and when primary palliative care may be insufficient and referral to specialty palliative care is recommended. Our inability to cure most patients with metastatic colorectal cancer warrants attention to the importance of integrating specialty palliative care as an essential strategy

The past few years of colorectal cancer clinical research have produced measured, incremental gains in developing treatment strategies principally based on currently available agents. These advances also include a proof of principle that continuing an antiangiogenic sequential approach for patients with metastatic disease progression can provide a degree of benefit for some, as yet undefined, subsets of patients. Within the last year, the FDA approved bevacizumab and ziv-aflibercept for treatment after first progression, and regorafenib for patients with refractory disease. Although clearly a proof of principle, our ability to appropriately select patients for antiangiogenesis therapy remains elusive. This problem is confounded by the significant costs of prolonged antiangiogenesis treatment, the risk of toxicity, and exposure for individuals unlikely to benefit.

Determining the best way to develop a new paradigm for colorectal cancer research that embraces laboratory, imaging, and clinical science is a daunting challenge, but it is essential if we are to take the next leap forward in therapeutic advances. Many in the gastrointestinal research community agree that one of the most pressing issues is the need to develop standardized, widely available genomic platforms from which subsets of patients may be selected for innovative clinical trial designs that incorporate multiple “buckets” linked to a particular molecular or genomic profile targeted by a specific agent or combination.

This research concept will require a fusion of partners and stakeholders from government, industry, payers, investigators, institutions, and patients and their advocates to overcome the challenges associated with patient recruitment to biologically directed clinical research requiring tissue acquisition; reimbursement and cost; collaboration among multiple industry partners; regulatory issues; informatics; and real-time, validated, and reproducible laboratory platforms. Given the current economic climate and rapidly evolving world of oncologic care delivery, without the will and perseverance of all stakeholders, the next generation of advances to truly improve outcomes for patients with colorectal cancer will be at best delayed because we failed to maximize the tremendous opportunities that current and future technology afford.

Al B. Benson III, MD, is a Professor of Medicine at Northwestern University’s Feinberg School of Medicine and Associate Director for Clinical Investigations at the Robert H. Lurie Comprehensive Cancer Center among other professional roles, including attending physician at Northwestern Memorial Hospital.

Dr. Benson earned his medical degree at the State University of New York at Buffalo after which he completed an internal medicine residency and a medical oncology fellowship at the University of Wisconsin Hospitals.

Dr. Benson is active on numerous professional committees, often as an officer. He received the ASCO Statesman Award and has served on a number of committees. In addition, he is a member of several medical societies and is a past president of the Illinois Medical Oncology Society and a member and past chair of the Board of Directors of NCCN. He serves on several NCCN panels, is the past president of the International Society of GI Oncology (ISGIO), and past president of the Association of Community Cancer Centers (ACCC).

Dr. Benson’s research is primarily in the areas of gastrointestinal cancer and other clinical trials, biologic therapies, and cancer guideline development. He has authored or coauthored numerous reports, reviews, and book chapters, and his research has been awarded funding from a variety of sources, including the NIH.

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