Stacey A. Cohen, MD, associate professor, the Clinical Research Division, Fred Hutchinson Cancer Center, assistant professor, the Division of Oncology, the University of Washington, discusses the evaluation of the role of circulating tumor DNA (ctDNA) to determine the benefit of chemotherapy in colorectal cancer (CRC).

At the 2022 ESMO Congress, investigators presented real-world data from a retrospective analysis evaluating whether ctDNA is a reliable predictor of cancer recurrence in patients with resected stage I to III CRC.

Investigators observed the relationship between ctDNA status and the use of chemotherapy to evaluate the role of ctDNA as a prognostic and predictive factor, Cohen says. In patients who were ctDNA negative, there was not a clear benefit from chemotherapy; however, this was not a large pool of patients, and it remains too early to determine whether patients who are ctDNA negative require chemotherapy, Cohen explains.

Further investigation of ctDNA’s role in making chemotherapy decisions in required, particularly in patients with stage II CRC, Cohen adds. Additional research will aim to answer questions about chemotherapy and longitudinal ctDNA monitoring, Cohen continues. More robust conclusions can be made as datasets grow, and studying ctDNA in a real-world setting will better reflect a larger variety of patients and the heterogeneity of CRC, Cohen concludes.

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Stacey A. Cohen, MD, discusses the evaluation of the role of circulating tumor DNA to determine the benefit of chemotherapy in colorectal cancer.


Dr. Cohen on the Use of ctDNA for Chemotherapy Decisions in CRC

Stacey A. Cohen, MD, physician, Seattle Cancer Care Alliance, associate professor, Division of Medical Oncology, University of Washington (UW) School of Medicine, physician, UW Medicine, associate professor, Clinical Research Division, Fred Hutchinson Cancer Research Center, discusses the shortcomings of clinical trials evaluating cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer (CRC).

Studies evaluating cytoreductive surgery and HIPEC have been incongruent in terms of how the cytoreductive surgeries are performed, the types of chemotherapies used, and how long the chemotherapy is administered to patients, Cohen says. Moreover, these factors could impact survival for this population.

Some data indicate that cytoreductive surgery is the most meaningful step of treatment for eligible patients, and that HIPEC may offer additive benefits, Cohen explains. Ultimately, the inconsistency within these studies calls attention to the need for careful patient selection and a comprehensive understanding of available literature to inform individual treatment plans, Cohen concludes. 

Stacey A. Cohen, MD, discusses the shortcomings of clinical trials evaluating cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in colorectal cancer.


Dr. Cohen on the Shortcomings of Trials Evaluating Cytoreductive Surgery and HIPEC in CRC 

Stacey A. Cohen, MD, physician, Seattle Cancer Care Alliance, associate professor, Division of Medical Oncology, University of Washington (UW) School of Medicine, physician, UW Medicine, associate professor, Clinical Research Division, Fred Hutchinson Cancer Research Center, discusses the importance of patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer (CRC).

Intravenous chemotherapy does not uniformly penetrate the peritoneal cavity, Cohen says. However, patients with peritoneal disease and CRC can have local metastatic spread that differs from the blood-based metastatic spread observed with other visceral sites. 

These patients can undergo cytoreductive surgery with the goal of removing all visible sites of disease. Scoring systems are used before and after surgery to determine how much disease the patient has initially and the completeness of the surgery, respectively, Cohen explains.

Additionally, patients whose cytoreductive surgery completely removes visible disease may undergo HIPEC to decrease or eliminate microscopic disease, Cohen says. However, patient selection and discussion with a multidisciplinary tumor board involving medical oncology, surgical oncology, radiology, and pathology is critical to ensure patients are fit for this aggressive treatment approach, Cohen concludes.

Stacey A. Cohen, MD, discusses the importance of patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in colorectal cancer.



Dr. Cohen on the Importance of Patient Selection for HIPEC Surgery in CRC 

Stacey A. Cohen, MD, physician, Seattle Cancer Care Alliance, associate professor, Division of Medical Oncology, University of Washington (UW) School of Medicine, physician, UW Medicine, associate professor, Clinical Research Division, Fred Hutchinson Cancer Research Center, discusses tailoring treatment approaches to individual subtypes in colorectal cancer (CRC).

Certain subtypes of CRC are indicated for targeted therapy, whereas others predict for a lack of response to specific therapeutic options, Cohen says. Moreover, each subgroup is associated with a different prognosis, so it is important to understand the disease state prior to making clinical decisions.

For example, a patient with a peritoneal malignancy has a worse prognosis compared with a patient with standard-risk CRC, Cohen explains. Moreover, the presence of a 

 mutation confers poor outcomes. As such, a patient that has a 

-positive peritoneal malignancy should be treated with a BRAF targeted agent. Additionally, if the patient has good tumor biology and responds to initial therapy, they may not require more aggressive therapy with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy surgery, Cohen concludes.

Stacey A. Cohen, MD, discusses tailoring treatment approaches to individual subtypes in colorectal cancer.



Dr. Cohen on Tailoring Treatment to Individual Subtypes in CRC 

Stacey A. Cohen, MD, physician, Seattle Cancer Care Alliance, associate professor, Division of Medical Oncology, University of Washington (UW) School of Medicine, physician, UW Medicine, associate professor, Clinical Research Division, Fred Hutchinson Cancer Research Center, discusses the standardization of triplet-based chemotherapy regimens in colorectal cancer (CRC).

Data evaluating triplet-based chemotherapy strategies in CRC have largely demonstrated improved progression-free survival (PFS) with triplet combinations vs doublet combinations, Cohen explains. However, it was unclear whether the triplet regimens extended overall survival (OS) long-term compared with doublets, given that the 3-drug combinations were associated with increased toxicity, Cohen says.

Data from the phase 3 TRIBE2 study (NCT02339116), which compared upfront FOLFOXIRI plus bevacizumab (Avastin), followed by reintroduction with FOLFOXIRI plus bevacizumab at progression vs modified FOLFOX6 (mFOLFOX6) plus bevacizumab, followed by FOLFIRI plus bevacizumab in patients with metastatic CRC, showed improved PFS and OS with the FOLFOXIRI-based approach, Cohen explains.

The findings of TRIBE2 resulted in the standardization of the FOLFOXIRI-based treatment regimen for patients with CRC and the approach is being utilized with increasing frequency, Cohen says. Moreover, patients with peritoneal disease, who are expected to have poor prognoses, can receive triplet regimens the TRIBE2 data and the other studies, Cohen concludes.

Stacey A. Cohen, MD, discusses the standardization of triplet-based chemotherapy regimens in colorectal cancer. 

 Dr. Cohen on the Standardization of Triplet Chemotherapy in CRC

Stacey A. Cohen, MD, physician, Seattle Cancer Care Alliance, associate professor, Division of Medical Oncology, University of Washington (UW) School of Medicine, physician, UW Medicine, and associate professor, Clinical Research Division, Fred Hutchinson Cancer Research Center, discusses the clinical implications of the ongoing GALAXY trial (UMIN000039205), part of the CIRCULATE-Japan project, in colorectal cancer (CRC).

Early results from the study, which is monitoring ctDNA status in patients with stage II to stage IV CRC who are undergoing surgical resection, showed a minimal difference in disease-free survival (DFS) among patients who were preoperatively ctDNA negative vs positive, according to Cohen. Although ctDNA did not provide prognostic insight when examined in patients before surgery, those found to be ctDNA negative after surgery did have better outcomes, Cohen explains. As such, there is evidence to support that ctDNA status can provide insight into which patients are more likely to experience recurrence or worse outcomes, Cohen says. Still, how to optimally treat patients with CRC based on their ctDNA status remains unclear, Cohen notes.

The goal of treating, and hopefully curing, patients with CRC is to do so with minimal toxicity and intervention, Cohen adds. For example, some patients may only require surgery plus short-course chemotherapy, although others with more aggressive disease may require more intense treatment. As such, utilizing ctDNA can help to stratify those patients and determine a treatment strategy that is more tailored to their disease type, Cohen says.

Additionally, more research efforts are needed to ensure that the correct patient populations are being matched to the correct treatments, Cohen adds. As more data become available, it is evident that not all patients with CRC should be treated with the same approaches. Utilizing new prognostic markers can help to do this moving forward, Cohen concludes.

Stacey A. Cohen, MD, discusses the clinical implications of the ongoing GALAXY trial, part of the CIRCULATE-Japan project, in colorectal cancer.


Dr. Cohen on the Clinical Implications of the GALAXY Trial in CRC

Stacey A. Cohen, MD, physician, Seattle Cancer Care Alliance, associate professor, Division of Medical Oncology, University of Washington (UW) School of Medicine, physician, UW Medicine, associate professor, Clinical Research Division, Fred Hutchinson Cancer Research Center, discusses the preliminary results of the ongoing GALAXY trial (UMIN000039205), part of the CIRCULATE-Japan project, in colorectal cancer (CRC).

Initial data from molecular subgroup analyses of the GALAXY trial, which were presented during the 2021 

ESMO World Congress on Gastrointestinal Cancer

, reported that the patients enrolled on the trial were stratified by stage, and then further stratified by frequency of circulating tumor DNA (ctDNA) detection, Cohen says. As anticipated, it was seen that a higher frequency of ctDNA was detected in patients with later-stage disease, which echoed the results of previous studies, Cohen adds.

The results of a multivariate analysis noted that ctDNA positivity was associated with a higher likelihood of recurrence, Cohen continues. Additionally, ctDNA positivity was correlated with higher T- and N-stage CRC, Cohen says. Finally, ctDNA positivity was less associated with common molecular biomarkers, such as 

 mutations, and microsatellite instability–high status, Cohen concludes. 

Stacey A. Cohen MD, discusses the preliminary results of the ongoing GALAXY trial, part of the CIRCULATE-Japan project, in colorectal cancer.

Stacey A. Cohen, MD

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