NEOADJUVANT CHEMOTHERAPY FOR PANCREATIC CANCER

For the first time, neoadjuvant chemotherapy has been shown to improve survival in patients with resectable pancreatic ductal adenocarcinoma (PDAC).

The finding comes from a Japanese study, which used perioperative chemotherapy with neoadjuvant gemcitabine and S-1 (Taiho Pharmaceutical), as well as adjuvant S-1.

The 2-year overall survival rates were 63.7% for the group who received neoadjuvant therapy, compared with 52.5% for those who had upfront surgery.

Based on these findings, lead investigator Michiaki Unno, MD, PhD, Tohoku University Graduate School of Medicine in Sendai, Japan, commented that "neoadjuvant therapy could be a new standard for patients with resectable pancreatic ductal adenocarcinoma."

However, one of the drugs used in this study, S-1, is currently available only in certain parts of the world — Japan and several East Asian countries, as well as some European countries — but not in the United States. S-1 is a combination of three compounds: tegafur (a prodrug of 5-fluorouracil [5FU] ), gimeracil, and oteracil potassium.

The new results were presented here at the Gastrointestinal Cancers Symposium (GICS) 2019.

Current Management  

Currently, the standard of care for patients with resectable or borderline resectable pancreatic adenocarcinoma is surgery followed by adjuvant chemotherapy. Neoadjuvant therapy is a potential approach, but its use has not been supported by the literature.

However, at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO), findings from a phase 3 trial showed that chemoradiotherapy before surgery improved survival in pancreatic cancer patients, as compared with patients who went straight to surgery. However, the authors emphasized that those findings were preliminary, and that final results are needed before definitive conclusions can be drawn.

S1 has previously been shown to significantly increase overall survival in pancreatic cancer patients as compared with gemcitabine.

In addition, an earlier phase 2 trial (Prep-01) showed that neoadjuvant S-1 combined with gemcitabine improved overall survival. Based on these results, the larger phase 2/3 trial (Prep-02/JSAP-05) trial was conducted to confirm these findings.

Significant Survival Benefit

The study included 364 previously untreated patients with pancreatic ductal adenocarcinoma who were enrolled in 57 centers in Japan and randomized to either neoadjuvant chemotherapy using gemcitabine and S1, or upfront surgery.

Gemcitabine was given at a dose of 1 g/m² on days 1 and 8 and oral S-1 at a dose of 40 mg/m² twice daily on days 1 through 14; patients received 2 cycles of this regimen.

In addition, S-1 was given as adjuvant therapy for 6 months in the cohort with curative resection and within 10 weeks after surgery in both groups.

The phase 2 part of the study was designed to confirm if the experimental group had a sufficient resection rate to proceed to phase 3. The preplanned criteria was met, as the rate of successful resection was high following neoadjuvant chemotherapy (93% vs 82% in the upfront surgery group).

For phase 3, the primary endpoint was overall survival, and secondary endpoints included adverse events, resection rate, recurrence, and nodal metastases.

"The study demonstrated a significant survival benefit with neoadjuvant therapy," said Unno.

The median overall survival was 36.7 months in patients who received the neoadjuvant protocol, as compared with 26.6 months for those who underwent upfront surgery (hazard ratio [HR] 0.72; P = .015).

When looking at secondary outcomes, lymph node metastasis was significantly decreased in the neoadjuvant group vs upfront surgery (59.6% vs 81.5%). Recurrence rates were similar for both groups, but metastasis to the liver was significantly higher in the upfront surgery group (47.4% vs 30%, P = .01).

Grade 3 and 4 adverse events were experienced by 72.8% of the cohort receiving neoadjuvant therapy (48.8% grade 3 and 23.8% grade 4), and were primarily hematologic. There was no perioperative mortality in either treatment group.

Unlikely to Change Treatment

In a discussion of the study, Andrew Zhu, MD, PhD, director of liver cancer research at Massachusetts General Hospital, Boston, noted that based on the data presented, he concurs that it "provides another viable option for Japanese patients."

However, the findings are unlikely to change treatment in the United States and Europe, where different chemotherapy regimens are used, he explained.

"I think this is a well-conducted study, but some data clarification is needed," said Zhu, adding that, for example, the difference between chemotherapy regimens in both groups makes it more difficult to address the sequence.

It is also unknown how many patients received additional chemotherapy, or what the difference in disease-free survival was in both groups, he pointed out. Thus, the results need to be interpreted with caution.

"There are also unanswered questions," said Zhu, such as what is the best neoadjuvant chemotherapy regimen or if perioperative chemotherapy can be moved to total neoadjuvant therapy in resectable PDAC.

Studies are currently underway to evaluate neoadjuvant or perioperative treatment with regimens such as FOLFIRINOX compared with gemcitabine plus nab-paclitaxel, or in combination with stereotactic body radiotherapy.

Unno has received honoraria from Asahi Kasei, Boston Scientific, Chugai Pharma, Covidien/Medtronic, Daiichi Sankyo, Eisai, Johnson & Johnson, Merck Serono, Nobelpharma, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Takeda, Teijin Pharma, and Yakult Honsha. He has also received research funding from Asahi Kasei (Inst), Chugai Pharma (Inst), Pfizer (Inst), Taiho Pharmaceutical (Inst), Takeda (Inst), and Yakult Honsha (Inst).

Zhu has disclosed relationships with AstraZeneca, Merck, Bristol Myers Squibb, Roche/Genentech, Bayer, Eisai, Exelixis, and Lilly.

Gastrointestinal Cancers Symposium (GICS) 2019: Abstract 189. Presented January 18, 2019.