NEW YORK CITY—With a growing number of available agents for metastatic colorectal cancer (CRC), first-line treatment decisions have become more variable and complex.
Oncologists specializing in this patient population have moved away from the one-size-fits-all approach. “Improvements in systematic therapies, coupled with improved imaging, surgical techniques, locoregional therapies, improved understanding of molecular markers, tumor sidedness, and an awareness that some patients can in fact be cured pushes us all to apply more intense strategic thinking to managing our patients with metastatic CRC,” according to John L. Marshall, MD, Director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancer, and Chief of the Division of Hematology/Oncology, Medstar Georgetown University Hospital, Washington, D.C.
During his discussion, “Multidisciplinary, Front-line Treatment Planning for Metastatic CRC,” at the Chemotherapy Foundation Symposium, held Nov. 8-10, Marshall emphasized the impact of collaborative care on outcomes for this patient population.
Evolution of Treatment
The management and treatment of colorectal cancer continues to develop with each new discovery.
“The full FDA approval of irinotecan in 1998, when I was a fellow, marked the first approval of a new chemotherapy drug for advanced colon cancer in 4 decades. This was followed by the approvals of capecitabine, oxaliplatin, bevacizumab, and cetuximab,” Marwan G. Fakih, MD, Professor, Department of Medical Oncology and Therapeutics Research; Associate Director for Clinical Investigations, Comprehensive Cancer Center; and Co-Director, Gastrointestinal Cancer Program, City of Hope Comprehensive Cancer Center in Duarte, Calif., wrote previously in Oncology Times. “Many additional agents have been approved since, which adds more complexity to the treatment of advanced colorectal cancer. It's been exciting to participate in the birth of new treatment algorithms for CRC and watch survival steadily improve.”
With a shift towards precision medicine, oncologists across disciplines and disease type are seeking ways to identify which patients will respond best to which treatment; and colorectal cancer is no exception. “Since the 1990s, microsatellite instability (MSI) has served as a useful marker in CRC, especially for stage II and III patients. More recently, MSI has been shown to predict clinical benefit to checkpoint inhibitor immunotherapy (N Engl J Med 2015;372(26):2509-2520),” noted Fakih.
However, MSI is not a prognostic tool for all patients. As Fakih reported in Oncology Times, MSI-high patients account for about 15 percent of all cases of CRC (Gastroenterology 2010;138(6);2073-2087.e3), and only about 4 percent of stage IV patients (Br J Cancer 2009;100:266-273).
During his presentation, Marshall highlighted another important discovery with significant clinical implications. A retrospective analysis of data from the phase III CALGB/SWOG 80405 found the location of the primary tumor within the colon predicts survival and may help inform optimal treatment selection for patients with metastatic disease (ASCO 2016; Abstract 3504). The data show that patients whose primary tumors originate on the left side of the colon survive significantly longer (median OS=33.3 months) than those whose tumors originate on the right side (19.4 months).
“While previous studies had suggested that tumor location may impact clinical colorectal cancer outcomes, the effect we observed in this analysis appears to be far greater than we expected,” said lead study author Alan P. Venook, MD, Professor of Medicine at the University of California, San Francisco, in a statement. “These findings will likely change the way we approach colorectal cancer treatment and research, even as we seek to more deeply understand the biology driving the difference in outcomes between right- and left-sided cancers.”
With an increased number of therapeutic options, effective care and treatment of metastatic CRC depends on the work of professionals across the health care continuum.
“Cancer is complicated,” Marshall noted. “If you look at who is involved in metastatic management, it's not just one surgeon; you need liver, lung, peritoneal, and colorectal surgeons.”
In addition to the oncologist and the surgeon, the multidisciplinary team should include radiology as well as radiation oncology. “You need outstanding gastrointestinal support as well as interventional radiology and therapeutic pathology,” Marshall said during his presentation. “And last, but not least, you need an engaged patient who can really understand the complexity and the strategy you are about to present.”
It is also the role of the oncologist to assess the patient's goals and determine what kind of support system they have, he emphasized.
Basics of Disease Management
When managing metastatic CRC, Marshall first considers surgery because it does “cure some with stage IV colorectal cancer.” However, he cautioned, the more metastases the less likely that this will be the case.
Radiofrequency ablation (RFA) can be beneficial; however, radiation therapy and embolization are not Marshall's treatment of choice. “When ranking for patients, I think surgery is best, followed by RFA, and then radiation therapy and embolization would be down the list for curative therapies.”
In terms of perioperative chemotherapy, Marshall acknowledges a lack of supporting research. “Very little evidence, if any, supports the role of perioperative chemotherapy; while there are some patients that may benefit, there is not significant evidence that it has the adjuvant effect like we have in stage II and III disease.”
Role of Neoadjuvant Chemotherapy
What should oncologists consider when determining the value of neoadjuvant chemotherapy for their patients?
According to Marshall, “those patients who respond to preoperative chemotherapy have better outcomes. We are treating that microscopic, metastatic disease early and it may decrease the surgical complications.”
However, he cautioned, there can be negatives to this approach. This can cause hepatotoxicity and there are complications. Additionally, Marshall noted, we can see complete responses that could hide metastatic sites and make it difficult for the surgeon to find the root.”
Therefore, oncologists should consider the pros and cons of neoadjuvant chemotherapy as they develop treatment plans for their patients.
Resectable vs. Non-Resectable
Marshall notes that the first step for any oncologist treating metastatic patients is to classify them as “resectable right now,” “maybe resectable later,” and “likely never resectable.”
For patients who are resectable, Marshall emphasized the importance of getting the best imaging possible, such as a PET scan. Then you would proceed with pre- or postoperative chemotherapy. “You have to make some decisions,” he noted. “You have to decide in a multidisciplinary fashion: Is this one surgery? Is it a staged procedure? And you have decide if radiation is necessary.”
Among patients with metastatic CRC who may become resectable, the decision-making becomes more complex, according to Marshall. “Get your best imaging at baseline,” he said. “You need to know right/left, you need to know their molecular profile (i.e., RAS/BRAF/MSI).”
Marshall emphasized when determining treatment for these patients it is important to not use too much chemotherapy because it will ruin your process and you will reassess in about 2-3 months.
For patients who fall into the never-resectable category, it is important for oncologists to know right/left as well as molecular profiling (i.e., HER2/MSI/BRAF/RAS). “The goal here is not how much chemotherapy, but how little,” noted Marshall. “The goal is to determine what is the least amount of chemotherapy you can give to keep this patient going with a good quality of life.
“Also, you should keep checking back around locoregional therapy,” he continued. “And, I would think about removing the primary,” he continued. “This is a controversial topic because we do not know definitely why this might be positive, but lots of metadata shows it improves outcomes. We didn't believe left/right before; maybe we should consider removing the primary forward.”
As Marshall concluded his presentation, he urged attendees to remember to treat their patients as they would like to be treated, and he reminded fellow oncologists that the goal is to try and cure their patients, “but more importantly know when you cannot.”
Catlin Nalley is associate editor.