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ESMO World Congress on Gastrointestinal Cancer 2016
The European Society for Medical Oncology (ESMO) 18th World Congress on Gastrointestinal Cancer (WCGIC), held this year in Barcelona, Spain, from June 29 to July 2, hosted 3,000 oncologists and other medical professionals. With the concurrent release of ESMO’s new consensus guidelines for metastatic colorectal cancer, we focus on related research sessions below.
Analysis of Patients 75 Years of Age And Older in the Open-Label Phase 3b CONSIGN Trial of Regorafenib in Previously Treated Metastatic Colorectal Cancer
The median age at diagnosis for colorectal cancer is 68 years, and one-third of new cases occur in patients 75 years of age or older. Due to concerns about their ability to tolerate anticancer therapies, older patients with colorectal cancer may not receive potentially helpful therapies, Dr. Van Cutsem said. To evaluate the safety of regorafenib in this population, he analyzed a subgroup of patients 75 years of age and older who participated in the international phase 3b CONSIGN study and compared the drug’s effects with those that occurred in the patients younger than 75 years old.
Regorafenib, an oral multikinase inhibitor that blocks the activity of multiple protein kinases involved in oncogenesis, angiogenesis, and the tumor microenvironment, initially proved its efficacy in the phase 3 CORRECT trial. The study, conducted in treatment-refractory metastatic colorectal cancer (mCRC) patients ages 22 to 85 years, demonstrated improved overall survival (the primary endpoint) for regorafenib versus placebo.
The later CONSIGN trial also evaluated the use of regorafenib in treatment-refractory mCRC patients. While investigator-assessed progression-free survival (PFS) data were collected as the only efficacy endpoint, the primary measure was safety. The study included 2,872 patients with mCRC who progressed after standard therapies and had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1. The patients received regorafenib 160 mg daily for the first three weeks of each four-week cycle until disease progression, death, or unacceptable toxicity. Standard therapies included fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and cetuximab/panitumumab in KRAS wild-type patients.
Of the patients assigned to treatment, 268 (9%) were 75 years of age or older (median, 77 years), and 2,604 were younger than 75 years of age (median, 61 years). Compared with the under-75 subgroup, more patients in the 75 years or older subgroup had an ECOG PS of 1; had four or more prior treatment regimens on or after diagnosis of metastatic disease; and had been diagnosed with metastatic disease for 18 months or more.
Treatment duration, median number of cycles, and daily dose were similar in the two subgroups. Most patients had at least one treatment-emergent adverse event (TEAE) (younger than 75 years, 91%; 75 years or older, 91%). Regorafenib-related TEAEs of grade 3 or higher occurred in 56% of the subgroup younger than 75 years versus in 64% of the subgroup older than 75 years. Rates of serious and grade 5 events were similar in the two subgroups. Regorafenib-related TEAEs led to treatment discontinuations in 9% of patients younger than 75 years old and in 12% of patients 75 years of age or older. Grade 3 or higher fatigue and hypertension were numerically higher in the 75 and older subgroup, and the rate of grade 3 or higher hand-foot skin reactions was numerically higher in the younger-than-75 subgroup.
Dr. Van Cutsem said that median PFS was similar in the two groups: 2.7 months for those younger than 75 years old and 2.5 months for those 75 years of age or older.
Summarizing in an interview, he said, “There were no major differences in safety. As long as patients are fit enough, age in itself is not an exclusion criterion for treatment with regorafenib in metastatic colorectal cancer.” He noted that dose reductions and dose interruptions in both subgroups highlight the importance of adverse event management and dose modification.
An International, Randomized Noninferiority Trial Comparing Three Versus Six Months of Oxaliplatin-Based Adjuvant Chemotherapy For Colon Cancer: Compliance and Safety Of the Phase 3 Japanese ACHIEVE Trial
While oxaliplatin/fluoropyrimidine chemotherapy (5-fluoropyrimidine and leucovorin [5-FU/LV] or capecitabine) is an established adjuvant treatment for colon cancer, neurotoxicity from oxaliplatin is cumulative, dose limiting, and potentially irreversible. Some research has shown, however, that limiting infusional 5-FU to three months instead of bolus 5-FU/LV for six months retains efficacy with significantly lower incidence of adverse events.1,2
The International Duration Evaluation of Adjuvant Chemotherapy Collaboration was established to test whether three-month oxaliplatin-based adjuvant treatment is noninferior in terms of disease-free survival to six-month treatment in patients with stage 3 colon cancer, with less toxicity. It includes six ongoing clinical studies worldwide from which data will be pooled. Among them, the ACHIEVE trial is comparing three- versus six-month oxaliplatin-based therapy.
ACHIEVE subjects (N = 1,277) had curatively resected stage 3 colon cancer (including rectosigmoid cancer) and performance status of 0–1. Patients who received prior oxaliplatin chemotherapy were excluded. Patients received either a modified (m) FOLFOX6 or XELOX regimen (25%/75%) for six months (n = 635) or three months (n = 642). Median age was approximately 67 years, and approximately 50% of the patients were men. The tumor site was the colon in about three-quarters of patients, and was rectosigmoid in the remainder.
Treatment completion rates were higher in the three-month treatment arm than in the six-month arm (86% versus 61%). Nonhematological adverse events were more common with the six-month regimen (mFOLFOX6, 48%, versus XELOX, 41%) than with the three-month regimen (mFOLFOX6, 35%, versus XELOX, 27%; P < 0.0001). Grade 2 or higher hand-foot syndrome was more common with the six-month regimen (mFOLFOX6, 3%, versus XELOX, 15%) than with the three-month regimen (mFOLFOX6, 1%, versus XELOX, 7%; P < 0.0002). Grade 2 or higher neuropathy was reported more frequently with the six-month treatment (mFOLFOX6, 36%, versus XELOX, 37%) than with the three-month treatment (mFOLFOX6, 11%, versus XELOX, 14%; P < 0.0001). There was one treatment-related death due to duodenal perforation in the six-month mFOLFOX6 arm.
Among grade 3 or higher hematological adverse events, neutropenia was more frequent with the six-month regimen (mFOLFOX6, 34%, versus XELOX, 15%) than with the three-month regimen (mFOLFOX6, 27%, versus XELOX, 10%; P < 0.0036). One case of febrile neutropenia was observed in the six-month arm.
Looking at the two 5-FU backbones, Dr. Eto noted that leukopenia and neutropenia rates (grade 3 or above) were higher for mFOLFOX, and thrombocytopenia and nonhematological adverse events were more common for XELOX. Neuropathy (grade 2 or higher) was similar (approximately 25%) for both mFOLFOX6 and XELOX. Overall, multivariate and univariate analyses showed that adverse events of grade 3 or higher were significantly more common with the six-month regimen, with mFOLFOX6, with older age, with higher body surface area, with lower baseline renal function, and among women.
ACHIEVE results showed that while both mFOLFOX6 and XELOX were safe and well tolerated, treatment-emergent adverse events were significantly lower in the three-month arm than in the six-month arm. Treatment compliance was lower in the standard six-month arm, Dr. Eto added.
Efficacy findings are not expected to be available until the 2017 American Society of Clinical Oncology annual meeting.
Evaluation of Depth of Response Within a Volumetric Model in Patients With Metastatic Colorectal Cancer: Results of the SIRFLOX Study
In a prior report of phase 3 SIRFLOX trial data,3 adding selective internal radiotherapy (SIRT) to first-line modified (m) FOLFOX6 with or without bevacizumab did not improve progression-free survival (PFS) in metastatic colorectal cancer (mCRC). PFS for those with liver metastases, however, was longer with SIRT by 7.9 months (20.5 months with SIRT versus 12.6 months without; 31% risk reduction; P = 0.002).
The prospective, open-label SIRFLOX trial included 530 patients with nonresectable liver-only or liver-dominant mCRC who had no prior chemotherapy for advanced disease (performance status 0–1). Patients with limited extrahepatic metastases and/or a single anatomical area of less than 2 cm in diameter lymph node involvement were allowed. Among patients randomized 1:1 to SIRT (n = 267) delivered via yttrium-90 microspheres (SIR-Spheres, Sirtrex), the objective response rate (ORR) in the liver was significantly higher with SIRT added (78.7% versus 68.8%; P = 0.042), and in the overall population, the complete response rate (CR) was higher with SIRT added (4.5% versus 1.5%; P = 0.054). (Bevacizumab was also administered at the investigator’s discretion per institutional practice.)
Based on SIRFLOX data, Dr. Heinemann related SIRT’s impact on hepatic depth of response (DpR) versus chemotherapy alone to baseline tumor burden and to effects on ORR and CR. Ultimately, this analysis will test the relationship between DpR and oveall survival (OS). DpR is based on measures of tumor load at baseline and on the tumor load nadir after treatment. DpR, unlike the Response Evaluation Criteria in Solid Tumors (also known as RECIST), captures postprogression survival until the tumor load becomes lethal, he said.
Investigators stratified patients into two groups: those with a baseline tumor load of 12% or less (239 patients) or greater than 12% (245 patients) in the liver. Mean liver involvement was approximately 18%. Extrahepatic disease was present in about 40% of patients and was the primary tumor in situ in approximately 45%.
The addition of SIRT in patients with 12% or less baseline tumor burden did not improve DpR (P = 0.763, 8.1% difference favoring chemotherapy alone), although time to nadir was 23.5 days longer with SIRT added (243 days; P = 0.152). In the greater than 12% tumor burden group, however, DpR was improved by 20.3% (P = 0.003) with SIRT added (77.5% with SIRT added versus 57.2% for chemotherapy alone). In addition, time to nadir was 102 days longer in the SIRT-added group (298 days versus 196 days; P = 0.001).
PFS in the liver in the 12% or less tumor burden group was extended by 2.9 months with SIRT added (15.1 months versus 12.2 months; P = 0.112). In the greater than 12% tumor burden group, PFS with SIRT was 14.1 months longer (27.2 months versus 13.1 months; P = 0.003). Hepatic ORRs in the 12% or less tumor burden group were similar at about 84%, but CRs were significantly more common with SIRT added (11.3% versus 1.7%; P = 0.003). In the greater than 12% tumor burden group, ORR was significantly higher with SIRT added (88.2% versus 67.2%; P = 0.022). CRs were low and similar (0.8% for chemotherapy alone versus 0% with SIRT added; P = 0.303).
Addressing the observation that SIRT has a greater effect in patients with higher tumor burdens, Dr. Heinemann said in an interview, “Without going back to animal studies, we can only speculate about the exact biology, but maybe because the tumor vasculature in larger metastases is well developed, it may be more able to trap the SIRT microspheres than the very small metastases.”
He emphasized that this study is the first in mCRC to evaluate the effects of initial tumor burden on treatment outcomes. Asked if SIRT could be recommended for first-line treatment outside of a clinical trial, he said, “We have a very interesting hypothesis and very interesting data, but we don’t recommend SIRT for first-line use in the absence of survival data.”
“These findings provide additional evidence to support the benefit of SIRT in patients with metastatic colorectal cancer,” he concluded.
ESMO Consensus Guidelines for the Management Of Patients With Metastatic Colorectal Cancer
“Management of metastatic colorectal cancer is becoming more complex. It requires a strategic approach and evidence-based patient selection for the best treatment options,” Dr. Van Cutsem said in his introduction to his oral presentation on the updated consensus guidelines for metastatic colorectal cancer (mCRC). While the last decade has seen better outcomes for patients with mCRC, it remains unclear which advances and strategic changes in treatment and management have been responsible for the improvements. Potential factors include changes in patient clinical presentation because of earlier detection of metastatic disease or closer follow-up after primary tumor resection; improvements in efficacy and administration of systemic therapies; increases in treatments aimed at facilitating resection of metastases for cure or durable relapse-free survival, including use of other ablative techniques; and “continuum of care” strategies coupled with early integration of optimal supportive care. The new guidelines aim at combining what is thought to be contributing to recent outcomes gains, and offer strategies and the evidence supporting them.
The previous “ESMO Clinical Practice Guidelines” report, published in 2014, was a nine-page document. The 2016 consensus guidelines now span 37 pages and list 21 specific recommendation areas.
The first eight areas range across tissue handling, selection, and biomarker testing. For example, testing to determine RAS mutational status is recommended for all patients at the time of diagnosis and should include at least KRAS exons 2, 3, and 4 (codons 12, 13, 59, 61, 117, and 146) and NRAS exons 2, 3, and 4 (codons 12, 13, 59, 61, and 117). In addition, BRAF status testing for prognostic assessment (and/or potential selection for clinical trials) is strongly recommended. Microsatellite instability testing, which can assist clinicians in genetic counseling and offers strong predictive value for the use of immune checkpoint inhibitors, is an emerging biomarker, but is not yet mandatory. Testing for biomarkers such as EGFR or HER2, while emerging in use, is not yet recommended as routine for patient management.
The ninth recommendation area covers emerging technologies, such as circulating tumor cell number and liquid circulating tumor DNA biopsies, reserved for research settings.
Specific treatment strategies enter at the 10th recommendation, which covers oligometastatic disease, followed by recommendations regarding perioperative treatment and conversion therapy for potentially resectable patients.
A striking change in the new guidelines is the emphasis given to ablative therapies, which in the 2014 practice guidelines was limited to a short paragraph and a few mentions. In the 2016 consensus paper, ablative techniques are introduced in the 13th guideline on conversion strategies, and are covered in detail throughout the 16th recommendation. The ablation techniques span thermal, chemo, and radiofrequency ablation, and include stereotactic body radiation therapy and selective internal radiation therapy. The radioembolization recommendation for liver-limited disease is expanded beyond yttrium-90 microspheres to include chemoembolization. Under the “local and ablative treatment” heading, the 2016 paper includes cytoreduction surgery and hyperthermic intraperitoneal chemotherapy.
The remaining recommendations encompass first-line (according to targeted agent used), maintenance, second-line, and third-line therapies.
Discussing innovations in pharmacotherapy for third-line therapy, Dr. Van Cutsem said that trifluridine/tipiracil is now recommended for patients pretreated with fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, and for RAS wild-type patients with EGFR antibodies. Trifluridine/tipiracil was approved in late 2015 in the United States for mCRC patients who have been treated previously with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biologic product, and, if the patient is RAS wild-type, an anti-EGFR monoclonal antibody.
“These recommendations should help us to fine-tune and improve our strategies, and guide treatment options in order to improve outcomes,” Dr. Van Cutsem concluded.
The complete guidelines are available at: https://annonc.oxfordjournals.org/content/early/2016/07/07/annonc.mdw235.full.pdf+html.
- Saini A, Norman AR, Cunningham D, et al. Twelve weeks of protracted venous infusion of fluorouracil (5-FU) is as effective as 6 months of bolus 5-FU and folinic acid as adjuvant treatment in colorectal cancer. Br J Cancer 2003;88;(12):1859–1865.
- Chau I, Norman AR, Cunningham D, et al. A randomised comparison between 6 months of bolus fluorouracil/leucovorin and 12 weeks of protracted venous infusion fluorouracil as adjuvant treatment in colorectal cancer. Ann Oncol 2005;16;(4):549–557.Epub 2005 Feb 2.
- Gibbs P, Heinemann V, Sharma NK, et al. SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 ± bevacizumab (bev) versus mFOLFOX6 + selective internal radiation therapy ± bev in patients with metastatic colorectal cancer.
Presentation at American Society of Clinical Oncology Annual Meeting Chicago, Illinois May 29–June 2, 2015Abstract published in J Clin Oncol2015;33(15)(suppl):3502 Available at: http://ascopubs.org/action/redirect?url=http%3A%2F%2Fjco.ascopubs.org%2Fcgi%2Fcontent%2Fabstract%2F33%2F15_suppl%2F3502&sid=d3ae7e6b-4eec-45ec-8d58-8778eb47a12f. Accessed August 4, 2016.