An Education Session on Friday, May 29, “Treating Newly Diagnosed Metastatic Colorectal Cancer: The Role of Chemotherapy, Ablation, Intra-arterial Therapy, and Surgery,” demonstrated that multidisciplinary management is imperative to achieve an optimal treatment outcome.
Speakers included session Chair Cathy Eng, MD, of The University of Texas MD Anderson Cancer Center; Thomas Bachleitner-Hofmann, MD, of the Medical University of Vienna; and Stephen Barnett Solomon, MD, of Memorial Sloan Kettering Cancer Center. Their presentations focused on questions related to specific patient cases, and attendees were asked to vote on treatment options at each stage of decision making in the cases. Presenters reviewed prior research, as well as trials underway that can be expected to provide further answers to these treatment questions.
The speakers emphasized that RAS mutation analysis should be ordered for all patients with newly diagnosed metastatic colorectal cancer. The goals of therapy should be identified early, including whether the tumor is resectable or borderline resectable, and whether palliative treatment is indicated. Therapy sequence must be based on the patient’s symptoms, and the primary tumor should be evaluated for patency of the lumen. All patients should be encouraged to enroll in clinical trials, when possible, to aid in treatment advances, the speakers said.
Colorectal cancer is the third most common cancer in men and the second most common in women, and remains a “very deadly disease,” Dr. Eng, session chair, said during her introduction. Worldwide, there are 1.23 million cases, and 608,700 people die each year of the disease. In the United States, the incidence rate projected for 2015 is 136,700 cases and 49,700 deaths. Screening is still underutilized, she said.
Molecular Testing Essential
The first case presented was a 56-year-old man with a 3-month history of blood-tinged stools daily. A colonoscopy revealed a nonobstructing sigmoid colon cancer occupying 60% of the lumen. His hemoglobin was 10.9 g/dL; mean corpuscular volume, 75; and carcinoembryonic antigen (CEA), 38 ng/mL. CT/MRI imaging revealed oligometastatic disease with a 3-cm tumor in segment II of the liver.
When asked to vote on the appropriate first step for this patient, approximately 38% of the audience voted for systemic therapy, and 32% proposed molecular testing.
Dr. Eng argued that molecular testing should be the first step for this patient, including tests for KRAS, NRAS, and BRAF mutations. Systemic chemotherapy should begin after the patient’s molecular markers have been identified, she said.
Evidence-Based Medicine for Neoadjuvant Therapy
Dr. Bachleitner-Hofmann discussed the role of evidence-based medicine for neoadjuvant therapy and reviewed research related to chemotherapy with FOLFOX for resectable liver metastases in patients with colorectal cancer.
The EORTC 40983 trial—a randomized, controlled, parallel-group, phase III study performed in Europe, Australia, and Hong Kong—included 364 patients with colorectal cancer and up to four liver metastases. Patients were assigned to either perioperative FOLFOX4 plus surgery or to surgery alone.
In the report on the updated long-term results published in Lancet Oncology in 2013, there was no difference in overall survival (OS) with the addition of perioperative chemotherapy with FOLFOX4 compared with surgery alone. The study investigators noted that the previously observed benefit in progression-free survival (PFS) “means that perioperative chemotherapy with FOLFOX4 should remain the reference treatment for this population of patients.”
Dr. Bachleitner-Hofmann said that this trial was not powered to detect differences in OS, and that only 63% of patients received adjuvant chemotherapy.
Results of the new EPOC randomized controlled trial, published in Lancet Oncology in 2014, evaluated the addition of cetuximab to FOLFOX in patients with KRAS exon 2 wild type (WT) resectable colorectal liver metastases. Patients in the trial received either chemotherapy alone or chemotherapy with cetuximab. At an overall median follow-up of 20.7 months, PFS was significantly shorter in the chemotherapy plus cetuximab group (hazard ratio [HR] 1.48, 95% CI [1.04, 2.12]; p = 0.03).
In a trial by Ye et al., published in Journal of Clinical Oncology in 2013, patients with unresectable colorectal liver metastases were randomly assigned to treatment with FOLFOX/FOLFIRI with or without cetuximab. Patients treated with chemotherapy plus cetuximab had increased OS (HR 0.54, 95% CI [0.33, 0.89]; p = 0.013).
“We are all awaiting results of the BOS-2 (EORTC trial 40091) trial,” Dr. Bachleitner-Hofmann said. The trial is now recruiting patients to investigate the efficacy of FOLFOX alone, FOLFOX plus bevacizumab, and FOLFOX plus panitumumab in patients with resectable liver metastases. Results of the phase II randomized trial are expected in 2017. Primary outcomes measures include PFS at 1 year and increase in PFS at 1 year in each arm of the trial.
Dr. Eng reviewed trial data related to treatment options according to RAS status. The FIRE-3 phase III study compared FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab as first-line treatment for metastatic colorectal cancer. The updated data from the trial showed that the proportion of patients with all-RAS status who achieved an objective response did not significantly differ between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab groups. Patients with RAS WT tumors had a median OS of 33.1 months with FOLFIRI plus cetuximab, compared with 25.6 months with FOLFIRI plus bevacizumab (HR 0.70; p = 0.011).
In patients with a RAS mutation, however, no difference was observed between the regimens. OS was 16.4 months and 20.6 months, respectively (HR 1.20; p = 0.57). OS for patients with a BRAF mutation was 12.3 months with FOLFIRI plus cetuximab and 13.7 months with FOLFIRI plus bevacizumab (HR 0.87; p = 0.65).
The TRIBE phase III trial, published in New England Journal of Medicine in 2014, looked at the efficacy of FOLFIRI plus bevacizumab compared with FOLFOXIRI plus bevacizumab. The primary endpoint was PFS. Results showed that FOLFOXIRI plus bevacizumab resulted in an improved outcome compared with FOLFIRI plus bevacizumab.
Dr. Solomon reviewed the options for catheter-directed therapies, including intra-arterial hepatic chemotherapy, chemoembolization, and radioembolization. Radioembolization, he said, can deliver 120 Gy to the tumor without reaching normal liver toxicity. It, therefore, selectively targets liver tumor cells with a lethal radiation dose while, at the same time, minimizing radiation exposure to the normal liver parenchyma.
Primary Tumor Resection
Dr. Bachleitner-Hofmann discussed factors to consider regarding resection when a patient has a primary tumor that is asymptomatic and the metastatic disease is unresectable. The risks of primary tumor–associated complications include bleeding, obstruction, and perforation. The rationale for resection of the primary tumor would be to avoid complications and cure the patient if metastases become resectable.
However, the drawbacks of resection are many, he said. Upfront resection delays administration of chemotherapy, and chemotherapy can address systemic disease, as well as the primary tumor. Complications can further delay or even preclude the administration of chemotherapy. The rate of major complications in primary resection of stage IV colorectal cancer is 11.8%, and the rate of minor complications is 20.6%.
A study by Poultsides et al. published in Journal of Clinical Oncology in 2009 looked at a cohort of 233 patients with stage IV colorectal cancer without surgical resection of the asymptomatic primary tumor. Eighty-nine percent of the patients never had a complication. For the 11% who had a primary tumor complication, 4% were treated with a nonsurgical intervention, such as a stent or external beam radiation therapy, and 7% were treated with a resection, bypass, or ostomy.
A 2012 Cochrane review looked at data from seven nonrandomized studies with a total of 1,086 patients to determine whether there is an improvement in OS following resection of a primary cancer in patients with unresectable stage IV colorectal cancer and an asymptomatic primary tumor that is treated with chemotherapy/radiotherapy. The review included 722 patients treated with surgery and 364 who did not have surgery.
The review concluded that resection of the primary tumor in patients who are asymptomatic and treated with chemotherapy/radiotherapy is not associated with a consistent improvement in OS. Moreover, resection does not significantly reduce the risk of complications from the primary tumor (such as obstruction, perforation, or bleeding). “Yet there is enough doubt with regard to the published literature to justify further clinical trials in this area. The results from an ongoing high-quality randomized controlled trial will help to answer this question,” the article stated.
A SEER database analysis of primary tumor resection in a population-based cohort of patients with unresectable stage IV metastatic colorectal cancer, published in Annals of Surgery in 2014, concluded that palliative primary tumor resection was associated with improved OS and cancer-specific survival. The data indicated that the number of surgeries decreased between 1998 and 2009, and the number of patients not receiving surgery increased. Elderly patients, in particular, were offered surgery less frequently. Also, the efficacy of newer chemotherapy regimens improved during that time period.
The authors concluded that “the dogma that an asymptomatic primary tumor never should be resected in patients with unresectable colorectal cancer metastases must be questioned.”
Results are anticipated from a number of ongoing trials that may help clarify some of the treatment options for patients, including CAIRO4, SYNCHRONOUS, CLIMAT-PRODIGE 30, and GRECCAR 8.
Watch the entire session, on the ASCO Virtual Meeting website.