Evolving Adjuvant Treatment Landscape in GI Cancers

Targeted Therapies in Oncology, June 2018, Volume 7, Issue 6

Things are looking up in the world of adjuvant therapy for patients with gastrointestinal cancers, according to Diane Reidy-Lagunes, MD. During her presentation, Reidy-Lagunes outlined the current state-of-the-art in GI cancer care, with findings from pivotal studies in gastric, pancreatic, biliary, and colorectal cancers.

Diane Reidy-Lagunes, MD

Things are looking up in the world of adjuvant therapy for patients with gastrointestinal (GI) cancers, according to Diane Reidy-Lagunes, MD.

“The landscape is changing,” said Reidy-Lagunes, a medical oncologist at Memorial Sloan Kettering Cancer Center, during a presentation at the 3rd Annual School of Gastrointestinal Oncology™, hosted by Physicians’ Education Resource®. “We are making strides to [improve both] the quantity and quality of life.”

During her presentation, Reidy-Lagunes outlined the current state-of-the-art in GI cancer care, with findings from pivotal studies in gastric, pancreatic, biliary, and colorectal cancers.


Results from the FLOT4 clinical trial suggest that the FLOT (fluorouracil/leucovorin, oxaliplatin, and docetaxel [Taxotere]) regimen should be the adjuvant treatment of choice in gastric cancer over epirubicin/cisplatin/fluorouracil (ECF) or epirubicin/cisplatin/oxaliplatin (ECX).1“FLOT is now the standard of care,” Reidy-Lagunes said. “ECF and ECX…should go in the waste bin of oncologic history. We no longer use epirubicin-based therapies for preoperative treatment in gastric cancer.”

In the randomized, multicenter, phase III trial, patients with resectable gastric cancer or adenocarcinoma of the gastroesophageal junction type I to III were assigned to FLOT (n = 356) or ECF/ECX (n = 360).

ECF was the previous standard of care based on results from the MAGIC trial, which was published in 2006.

In FLOT4, overall survival (OS) was superior for patients assigned to FLOT compared with ECF/ECX (50 vs 35 months; HR, 0.77; 95% CI, 0.63-0.94; log-rankP= .012). OS rates in the FLOT arm are projected to be superior at 2 years (68% vs 59%), 3 years (57% vs 48%), and 5 years (45% vs 36%).

Grade 3/4 diarrhea, infections, and neutropenia occurred more frequently in the FLOT arm, but the ECF/ECX arm had higher rates of grade 3/4 vomiting (2% vs 8%) and nausea (7% vs 16%). The 2 groups had nearly identical rates of serious adverse events (AEs), serious AEs related to treatment, and toxic deaths. Reidy-Lagunes added that there was no difference in operative morbidity/mortality between the treatment groups.


Gemcitabine has been the backbone for both metastatic and adjuvant treatment since the 1990s, Reidy-Lagunes said. The advent of FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) gave patients with metastatic disease who had a good performance status a new treatment option, and results published in 2017 did the same in the adjuvant setting.

“We have a lot more work to do in the world of pancreas cancer, but ESPAC4—at least incrementally—improved the overall survival,” she said.

This phase III, open-label, randomized trial was conducted in Europe and the United Kingdom. Adult patients who underwent complete macroscopic resection for ductal adenocarcinoma of the pancreas were randomly assigned to receive either 1000 mg/m2 of gemcitabine once weekly for 3 weeks of a 4-week cycle (n = 366) or 1000 mg/m2of gemcitabine on days 1, 8, and 15 plus 1660 mg/m2of daily oral capecitabine (Xeloda) for 21 days followed by 7 days off (n = 362). Patients were treated for up to 6 cycles.2

The median OS for gemcitabine alone was 25.5 months (95% CI, 22.7-27.9) versus 28.0 months (95% CI, 23.5-31.5) for the combination (HR, 0.82; 95% CI, 0.68-0.98;P= .032).

The incremental benefit for median OS is not very impressive, according to Reidy-Lagunes, but there is a clear separation in survival curves from 4 to 5 years. Investigators need to define the population that will derive the most benefit from gemcitabine/ capecitabine, but a subgroup benefits from doublet treatment compared with single-agent treatment, she said.

“In the world of pancreatic cancer, [patients] with earlier stage disease can do a lot better if you get those therapies,” she said. “Lymph node—negative? Absolutely. Those are the ones where you can really make a difference and help in pancreas cancer.”

Reidy-Lagunes suggested that results to be presented at the 2018 ASCO Annual Meeting of modified FOLFIRINOX versus gemcitabine in the adjuvant setting could lead to a new standard of care in this setting. And indeed, results of the study were positive in favor of modified FOLFIRINOX.


“We know that biliary cancers, unfortunately, portend a poor prognosis. The overall survival at 1 year is only 22%,” Reidy-Lagunes said, adding that 5-year OS falls to 9%. “Only 15% to 20% of our patients are surgical candidates, and because they’re so rare, we end up lumping all these different biliary cancers together, which we know genetically and clinically is probably not the best thing to do.”

She called the results from BILCAP—a randomized, controlled, open-label trial comparing 8 cycles of capecitabine with observation after resection for patients with biliary tract cancer—a game changer.

Investigators randomly assigned 223 patients to 1250 mg/m2 of capecitabine twice-daily on days 1 to 14 of a 3-week cycle for up to 24 weeks. A total of 224 patients were randomly assigned to observation. The intent-to-treat analysis included all patients.3

“[Median] overall survival was 51 months for the capecitabine arm versus 36 months, which is pretty impressive for the world of [gastrointestinal] cancers,” she said. “Now capecitabine in the adjuvant setting for biliary cancers is the standard of care.”

The hazard ratio (HR) for survival was 0.81 (95% CI, 0.63-1.04;P= .097). After controlling for prognostic factors such as gender, disease grade, and nodal status, the HR was 0.7 (95% CI, 0.55- 0.91;P= .007). Median recurrence-free survival also favored the experimental arm at 24.6 versus 17.6 months (HR, 0.76; 95% CI, 0.58-0.99;P= .039).

Plantar palmar erythema (21%) was the most common grade 3/4 AE with capecitabine, followed by fatigue (8%) and diarrhea (8%). Overall, 93 serious AEs were reported, and 32% of patients experienced ≥1 serious AE; no treatment-related deaths were noted.

The drug should serve as the control arm for adjuvant trials in this patient population going forward, Reidy-Lagunes said.


Although physicians discuss the importance of the MOSAIC trial comparing fluorouracil and leucovorin (n = 1123) versus FOLFOX4 (5-fluorouracil, folinic acid, and oxaliplatin; n = 1123) for patients with stage II/III colon cancer, the OS results were unimpressive, Reidy-Lagunes said. The HR for survival was 1.00 (95% CI, 0.71-1.42;P= .996) in patients with stage II disease, and a 4.4% difference in survival favored FOLFOX4 in patients with stage III disease (HR, 0.80; 95% CI, 0.66-0.98;P= .029).4

Unlike in pancreas cancer, FOLFOX works better in patients with more advanced disease, she said: “The incremental value of adding oxaliplatin to a [patient with stage] IIIc is a lot better than [it is for] patients with IIIa or IIIb. If you have a 50% to 60% chance of recurrence with IIIc disease, the incremental benefit of adding oxaliplatin is about 50%, whereas in stage IIIa or IIIb, it may be on the order of 20% or 30%.”

The IDEA trial, an analysis of pooled data from 6 randomized, phase III trials involving approximately 13,000 patients, evaluated 3 versus 6 months of adjuvant FOLFOX or CAPOX (capecitabine and oxaliplatin) in patients with stage III colon cancer. Investigators sought to establish noninferiority for disease-free survival (DFS) with a shorter course of chemotherapy.5

At 3 years, the DFS rate was 74.6% in the 3-month group compared with 75.5% in the 6-month group (HR, 1.07; 95% CI, 1.00-1.15). The results were controversial because the prespecified endpoint set noninferiority at 1.12, according to Reidy-Lagunes. “By the statistical prespecified endpoint, this study was not noninferior, meaning that there was a difference between 3 versus 6 months,” she said, “even though if you look at the curves, the curves don’t separate.”

When patients were stratified into low-risk (tumor stage [T] 1-3 and nodal status [N] 1 disease) and high-risk (T4 or N2) groups for each treatment, again, there was little difference for 3 months of treatment versus 6 months. “However, when you compare the overall survival for the low-risk [patients], those in the CAPOX [arm] looked like they did a little better— their overall survival was 85%,” she said.

In the FOLFOX arm, 3-year DFS in the low-risk group was 81.9% for 3 months and 83.5% for 6 months. Three-year DFS was 85.0% in the low-risk group assigned to 3 months of CAPOX compared with 83.1% for the 6-month regimen (TABLE). The CAPOX regimen delivers more oxaliplatin earlier in the course of treatment, which could explain why those patients appeared to do better, Reidy-Lagunes said.

In high-risk patients, 3-year DFS was nearly identical for the 3- and 6-month CAPOX regimens (64.1% vs 64.0%, respectively). However, 6 months of FOLFOX showed a slight advantage compared with 3 months (64.7% vs 61.5%, respectively).

Although DFS outcomes are generally similar between the 3- and 6-month groups, patients on the longer course suffered significantly more neuropathy, which Reidy-Lagunes said can first appear as many as 3 months after the end of treatment and continue for years. “Across the board, patients who were on treatment for 6 months had much more neuropathy, which can be permanent in some patients,” she said.

For her next patient with T4 or N2 disease, Reidy-Lagunes said, she would recommend a 6-month course of FOLFOX. For patients with T1-3, N1 disease, she would offer 3 months of CAPOX or FOLFOX: “The data suggest CAPOX may be more reliable.


  1. Al-Batran SE, Homann N, Schmalenberg H, et al. Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): a multicenter, randomized phase 3 trial.J Clin Oncol.2017;35(suppl 15; abstr 4004). ascopubs.org/doi/ abs/10.1200/JCO.2017.35.15_suppl.4004.
  2. Neoptolemos JP, Palmer DH, Ghaneh P, et al; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial.Lancet.2017;389(10073):1011-1024. doi: 10.1016/S0140-6736(16)32409-6.
  3. Primrose JN, Fox RP, Palmer DH, et al. Adjuvant capecitabine for biliary tract cancer: the BILCAP randomized study.J Clin Oncol.2017;35(suppl; abstr 4006). meetinglibrary.asco.org/record/144518/abstract.
  4. André T, Boni C, Mounedji-Boudiaf L, et al; Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.N Engl J Med.2004;350(23):2343-2351. doi: 10.1056/NEJMoa032709.
  5. Meyerhardt JA. Is three months a good IDEA? Presented at: 2017 American Society of Clinical Oncology Annual Meeting; June 2-6, 2017; Chicago, IL. meetinglibrary.asco.org/record/147268/video.