COMMENTARY

Alok Khorana: How ASCO 2017 Changed My GI Oncology Practice

Alok A. Khorana, MD

Disclosures

July 10, 2017

For gastrointestinal (GI) cancers, the 2017 meeting of the American Society of Clinical Oncology (ASCO) was truly a practice-changing meeting. Abstracts presented will have an immediate impact on adjuvant therapy in colorectal, gastric, and biliary cancers. There were also several abstracts related to emerging therapeutics in colorectal and upper GI malignancies, but here I will focus on takeaways from ASCO 2017 that will alter clinical practice.

Colorectal Cancer: The IDEA Collaboration

The results of a study conducted by the IDEA collaboration, which focused on duration of adjuvant treatment, was the most discussed trial in GI cancers at ASCO. As background, 6 months of FOLFOX is considered appropriate adjuvant therapy for most patients with stage III colon cancer, on the basis of results of the MOSAIC trial reported more than a decade ago. IDEA was a pooled analysis of concurrently run, similarly (but not identically) designed adjuvant trials in six countries, enrolling nearly 13,000 patients.[1] The results of some of the individual trials were presented separately (eg, IDEA France) as well as in the pooled analysis. The studies were designed for noninferiority, with the upper bound of the confidence interval (CI) of the hazard ratio (HR) designated to be 1.12. The primary endpoint was disease-free survival (DFS), defined as time from enrolment to relapse, second colorectal cancer, and death (all causes). Either FOLFOX or capecitabine/oxaliplatin (CapeOx) was allowed on the basis of physician discretion (but these two treatments were not assigned by randomization); 40% of the population received CapeOx, with contributions to the CapeOx cohort coming disproportionately from the IDEA SCOT trial (conducted in the United Kingdom, Sweden, Denmark, and other countries).

Overall, the 3-year DFS rate was 74.6% in the 3-month group and 75.5% in the 6-month group, with an estimated DFS HR of 1.07 (95% CI, 1.00-1.15). Because this crossed the prespecified upper boundary of 1.12, the study did not meet the threshold for noninferiority—ie, we cannot exclude that 3 months is inferior.

Many have taken to this bottom-line message, including the expert discussant during the ASCO 2017 plenary session, Cathy Eng, MD.

However, there are additional nuances in the results that are worth discussing. As expected, neurotoxicity was higher in the 6-month versus 3-month arm (16% vs 3% FOLFOX, 9% vs 3% CapeOx; P < .0001). The 3-month versus 6-month DFS HRs were 1.16 (95% CI, 1.06-1.26) and 0.95 (95% CI, 0.85-1.06) for FOLFOX- and CapeOx-treated patients, respectively, suggesting that CapeOx might be "okay" for 3 months as an alternative standard. However, as mentioned earlier, because this was not randomized, there are issues related to selection bias.

Risk for recurrence, and therefore benefit from longer chemotherapy, also varied by subgroups. The 3-month versus 6-month DFS HRs were 1.01 (95% CI, 0.90-1.12) in low-risk patients (T1-3 N1) and 1.12 (95% CI, 1.03-1.23) in high-risk patients (T4/N2).

My practice has changed as follows: Generally, I will continue to offer 6 months of FOLFOX. For patients experiencing neuropathy issues, it may be worthwhile to revisit the risk-benefit ratio at the 3-month point. For low-risk patients (T3N1), I will discuss the IDEA results and the pros and cons of a potential 3-month course of therapy.

FLOT for Gastric Perioperative Therapy

The FLOT4-AIO study evaluated the benefit of perioperative FLOT4 (docetaxel 50 mg/m2, oxaliplatin 85 mg/m², leucovorin 200 mg/m², and 5-FU 2600 mg/m² as 24-hour infusion, all d1) compared with the epirubicin/cisplatin/5FU (ECF) regimen for resected gastroesophageal junction/gastric cancers.[2] FLOT improved overall survival (OS) (35 months with ECX/ECF vs 50 months with FLOT; HR 0.77 [95% CI, 0.63-0.94]; P = .012). The 3-year OS rate was 48% with ECF/ECX and 57% with FLOT. FLOT also improved PFS (18 months with ECX/ECF vs 30 months with FLOT; HR 0.75 [95% CI, 0.62-0.91]; P = .004).

Perioperative complications and early mortality were similar. There was more grade 3/4 nausea and vomiting with ECF/ECX and more grade 3/4 neutropenia with FLOT. Rates of curative resection were higher with FLOT than with ECF.

ECF is difficult on patients, and this study will allow us to include patients for perioperative treatment who were previously excluded because of anthracycline-toxicity concerns. FLOT is clearly the new standard of care for perioperative therapy of gastroesophageal junction/gastric cancers, and I have already started recommending it.

Capecitabine as Adjuvant Therapy for Biliary Cancers

BILCAP was a randomized study of adjuvant chemotherapy with capecitabine versus observation in completely resected biliary cancers (including both R0 and margin-positive, or R1, resections).[3] A total of 447 participants were randomly assigned. Primary site included the following: 84 (19%) intrahepatic, 128 (28%) hilar, 156 (35%) extrahepatic completely resected cholangiocarcinoma, and 79 (18%) muscle-invasive gallbladder cancers. By intention-to-treat analysis (n = 447), median OS was 51 months for capecitabine and 36 months for observation, HR 0.80 (95% CI, 0.63-1.04; P = .097). Note that despite the substantial absolute increase in survival, the P value was not significant. However, sensitivity analyses with adjustment for nodal status, grade of disease, and gender produced an HR of 0.71 (95% CI, 0.55-0.92; P < .01). Furthermore, in the per-protocol analysis, median OS was 53 months (95% CI, 40-not reached) for the capecitabine arm and 36 months (95% CI, 30-44) for the observation arm, with an HR of 0.75 (95% CI, 0.58-0.97; P = .028).

The difference in significance between the intention-to-treat and per-protocol analyses may be due to a small number of patients randomly assigned to capecitabine who never received the drug. Toxicity was as anticipated for capecitabine.

Based on these data—and the lack of evidence for current approaches, including adjuvant chemoradiation—I feel very comfortable making 6 months of adjuvant capecitabine my new standard-of-care recommendation for resected biliary cancers.

SIRT Versus Sorafenib in Locally Advanced Hepatocellular Carcinoma

The role of selective internal radiation therapy (SIRT) in advanced hepatocellular carcinoma (HCC) is not fully understood. SIRveNIB was a randomized trial of upfront Y90-based SIRT versus sorafenib in locally advanced HCC, conducted in Asia.[4] OS in the Y90 and sorafenib arms were 8.54 and 10.58 months, respectively (HR 1.17; P = .203), but response rates were higher with SIRT than with sorafenib: 16.5% versus 1.7% (P < .001). If patients do not wish to experience the adverse events associated with sorafenib, SIRT may be considered an alternative option.

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