Adjuvant Chemotherapy Advances Boost Outcomes in GI Malignancies

Diane Reidy-Lagunes, MD

Improved chemotherapy combination regimens are enhancing outcomes for patients across a range of gastrointestinal (GI) cancers, according to Diane Reidy-Lagunes, MD, who reviewed practice-changing findings during a presentation at the 3rd Annual School of Gastrointestinal Oncology™ (SOGO^®).

“The landscape is changing,” said Reidy-Lagunes, associate deputy physician in chief of clinical operations at Memorial Sloan Kettering Cancer Center in New York, New York. “We are making strides to [improve both] the quantity and quality of life.”

Evolving Options in Gastric Cancer

Reidy-Lagunes outlined the current state-of-the-art GI care during her presentation at SOGO^®, which Physicians’ Education Resource^® hosted April 28 in New York City. She detailed findings from pivotal studies in gastric, pancreatic, biliary, and colorectal cancers to give her audience an overview of the field.In gastric cancer, 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-rank P = .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%). “OS unquestionably was improved on the FLOT arm,” Reidy-Lagunes said. “All the way out to 5 years, you could still see that difference.”

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.

New Standard in Pancreatic Setting

There was no difference in operative morbidity/mortality between the treatment groups, Reidy-Lagunes added. Furthermore, there were no differences in terms of complications, death at 30 or 90 days, or number of hospitalization days.The 5-year survival rate for stage Ia pancreatic cancer is 14%, dropping to 3% for stage III disease and about 1% for stage IV, according to the American Cancer Society. The disease accounts for 3% of all cancers but 7% of cancer deaths.²

That does not mean there is no hope for these patients, Reidy-Lagunes said—gemcitabine has been the backbone for both metastatic and adjuvant treatment since the 1990s. The advent of FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) gave patients with metastatic disease who had a good performance status a new 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,” Reidy-Lagunes said. This phase III, open-label, randomized trial was conducted at 92 hospitals 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/m² of gemcitabine on days 1, 8, and 15 plus 1660 mg/m² of oral capecitabine (Xeloda) administered daily for 21 days followed by 7 days off (n = 362). Patients were treated for up to 6 cycles.³

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.”

That combination may soon be supplanted in the adjuvant setting by a modified FOLFIRINOX (mFOLFIRINOX) regimen, based on the results of PRODIGE 24/CCTG PA.6 study presented at the American Society of Clinical Oncology Annual Meeting (ASCO 2018).⁴ Patients with nonmetastatic pancreatic ductal adenocarcinoma and good performance status who had undergone surgical resection with no tumor residue were randomized 1:1 to receive mFOLFIRINOX or gemcitabine for 6 months.

The mFOLFIRINOX regimen consisted of oxaliplatin, leucovorin, and irinotecan administered intravenously (IV) at day 1, followed by 5-fluorouracil via continuous IV infusion over 46 hours, for 12 two-week cycles. Gemcitabine was administered via IV on days 1, 8, and 15 every 28 days for 6 cycles.

The median OS was nearly 20 months longer with mFOLFIRINOX than with gemcitabine: 54.4 versus 35.0 months, which represents a 36% reduction in the risk of death (HR, 0.64; 95% CI, 0.48-0.86; P = .003).⁴ The median disease-free survival was 21 months with mFOLFIRINOX versus 12.8 months with gemcitabine (HR, 0.58; 95% CI, 0.46-0.73; P <.001).

OS Benefit in Biliary Tract Cancer

“FOLFIRINOX was more toxic than gemcitabine but it’s still a safe regimen with manageable toxicities,” said lead author Thierry Conroy, MD, a medical oncologist and director of the Institut de Cancerologie de Lorraine in Nancy, France. “The FOLFIRINOX regimen should be considered the new standard of care after pancreatic cancer resection in patients with good performance status.”“We know that biliary cancers, unfortunately, portend a pretty poor prognosis. The overall survival at 1 year is [just] 22%,” Reidy-Lagunes said, adding that 5-year OS falls to 9%. “[Just] 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.”

Results from a previous meta-analysis retrospectively showed that chemotherapy, radiotherapy, or chemoradiation after resection helps patients do better. “Doing something is the right thing to do,” she said.

Reidy-Lagunes 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, and 224 patients were randomly assigned to observation. The intent-to-treat analysis included all patients.⁵

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

The 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 0.70 (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%). Regarding the 93 serious AEs reported, 32% of patients experienced ≥1 serious AE; no treatment-related deaths were noted.

Table. Disease-Free Survival Results in IDEA Trial

CAPOX indicates capecitabine and oxaliplatin; DFS, disease-free survival; FOLFOX, 5-fluorouracil, leucovorin and oxaliplatin; HR, hazard ratio; T, tumor stage; N, nodal status.

Colon Cancer Debate Over Duration

Capecitabine did not reduce quality of life, Reidy-Lagunes said, adding that the drug should serve as the control arm for adjuvant trials in the patient population going forward.Chemotherapy regimens have been part of the adjuvant treatment paradigm for colon cancer for approximately 30 years, with the standard for patients with stage II or III disease evolving to bolus plus continuous infusion fluorouracil with leucovorin (LV5FU2). In the MOSAIC trial, investigators sought to determine whether adding oxaliplatin (FOLFOX4) would further improve outcomes.

Final results demonstrated better outcomes among patients who received LV5FU2 (n = 1123) versus FOLFOX4 (n = 1123), but the OS results were unimpressive, Reidy-Lagunes said. The HR for survival for FOLFOX4 was 1.00 (95% CI, 0.71- 1.42; P = .996) in patients with stage II disease, and there was just a 4.4% difference in survival favoring the regimen in patients with stage III disease (HR, 0.80; 95% CI, 0.66-0.98; P = .029).⁶

Unlike in pancreas cancer, FOLFOX (5-fluorouracil plus leucovorin and oxaliplatin) works better in patients with more advanced disease, Reidy-Lagunes 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 months 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.⁷

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 (Table).⁸ “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 [rate] was 85%,” she said. 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). “It’s a modest separation, but it’s there,” she said. “It looks like 3 months is not equivalent to 6 months in the high-risk patients.”

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. “Most of the data suggest that neuropathy starts around cycle 8 or 9, and that’s the permanent neuropathy that we worry about.”

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.”

References

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2. American Cancer Society. Key statistics for pancreatic cancer. cancer.org/cancer/pancreatic-cancer/about/key-statistics.html. Updated January 4, 2018. Accessed May 18, 2018.
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8. 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.