For potentially curable treatment of resectable pancreatic cancer, adjuvant therapy remains the standard “for now,” but evidence is growing that neoadjuvant therapy may be more beneficial, at least in certain patient subsets, according to Thomas Seufferlein, MD, PhD, Professor of Medicine at the University of Ulm in Germany.

At the European Society for Medical Oncology (ESMO) 2017 Congress, Dr. Seufferlein described the efficacy of neoadjuvant therapy but acknowledged several questions remain.¹ Neoadjuvant therapy will not reach its full potential until these issues are clarified.

Pros and Cons, in Brief

Phase III trials have shown that adjuvant chemotherapy improves 5-year survival in resectable pancreatic cancer; however, many patients never receive it. There has been no upfront evaluation of adjuvant therapy’s efficacy, and current protocols are of less benefit in patients with positive margins, involved lymph nodes, and high T stage.

Neoadjuvant therapy can address some of these shortcomings. For one thing, it treats the disease early, when micrometastases are just becoming established. Efficacy can be evaluated promptly (after surgery), and it can downsize large tumors, allowing more R0 resections. Most patients are able to actually receive treatment, and there may be a survival benefit, the latest studies suggest.

But the neoadjuvant strategy also has its limitations, Dr. Seufferlein acknowledged. It requires a cytologic or histologic diagnosis of cancer, which depends on tumor biopsy (rather than “liquid” sampling), and the optimal protocols and schedules are yet to be established. While most patients can undergo neoadjuvant therapy, 20% will have disease progression during it, although this is a group of patients who “probably would not have benefited otherwise,” he said.

What Adjuvant Treatment Can Achieve

In 2004, the ESPAC-1 trial demonstrated that adjuvant chemotherapy with fluorouracil (5-FU) can achieve 5-year overall survival of 21%, vs 8% for observation.² The study also showed no benefit to radiation. “Adjuvant chemotherapy (without radiation) is beneficial and improves survival,” Dr. Seufferlein said.

The debate then focused on determining the best drugs in this setting: gemcitabine or 5-FU plus leucovorin. A comparison of the two in ESPAC-3 found no differences in progression-free or overall survival; both regimens doubled the overall survival rate.³ Next, long-term survival data were provided by the German CONKO-001 trial, which showed that treatment with gemcitabine led to a 10-year disease-free survival rate approaching 20% and overall survival exceeding 15%.⁴ “This is a low figure, but still, with adjuvant gemcitabine there are patients who do benefit and may be cured,” he commented.

Subsequent ESPAC trial analyses also confirmed that chemotherapy can be initiated any time up to 12 weeks postoperatively, without compromising efficacy.⁵ What is most important is the completion of six cycles, he emphasized.

Adjuvant treatment is the standard after resection of pancreatic adenocarcinoma, and the standard is getting better.
— Thomas Seufferlein, MD, PhD

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“So, adjuvant treatment is the standard after resection of pancreatic adenocarcinoma, and the standard is getting better,” he said, specifically pointing to the addition of capecitabine to gemcitabine in improving outcomes. In the 2017 ESPAC-4 study, this combination improved overall survival, vs gemcitabine alone (hazard ratio [HR] = 0.82; P = .032).^6,7 Median survival reached 28 months with gemcitabine/capecitabine.

“But in Japan, these would not be such good data,” he continued, since Asian patients respond best to S-1, an oral 5-FU prodrug that has not been approved by the U.S. Food and Drug Administration. In the phase III JASPAC 01 trial, adjuvant chemotherapy with S-1 produced a 5-year overall survival rate of 43.6%, vs 24.2% for gemcitabine (HR = 0.60; P < .0001) and was relatively well tolerated.⁸

“This overall survival rate has not been seen before,” he commented. “But because of differences in metabolism, S-1 is not as effective in Western populations.”

The envelope is being pushed further by ongoing studies, including APACT, which is evaluating gemcitabine plus nab-paclitaxel (Abraxane) vs gemcitabine alone, and comparisons of FOLFIRINOX and FOLFOXIRI (both of which include 5-FU, leucovorin, irinotecan, and oxaliplatin) vs gemcitabine in Europe.

What Adjuvant Therapy Cannot Achieve

Despite the proven benefits of adjuvant chemotherapy, a number of problems make it a far-from-perfect treatment for pancreatic cancer, Dr. Seufferlein said.

Some 30% to 50% of eligible patients never actually receive adjuvant chemotherapy, mostly due to postoperative complications.^9-11 Moreover, a number of patient subsets do not benefit much, even with combinations, he pointed out. This includes patients with high-grade tumors, positive lymph nodes, stage III disease (and some with stage II), and positive surgical margins.

On the other hand, Neoptolemos et al showed that with adjuvant chemotherapy, median overall survival can reach 41.0 months for patients with well-differentiated tumors, 58.0 months for patients with node-negative disease, and 34.6 months for those with negative margins. Median overall survival was not reached in patients with stage I disease.⁷

What Neoadjuvant Therapy Can Offer

Neoadjuvant therapy can address some of the shortcomings of adjuvant therapy, said Dr. Seufferlein. By definition, it is the earliest possible treatment and thus addresses early micrometastases; dangerous “cancer-initiating cells” can be present even in small tumors prior to surgery. “A 2-cm tumor has a 70% chance of having micrometastases,” he noted. “If you treat late, you may not get disease control. Neoadjuvant treatment just might increase the survival of these patients.”

But to achieve pathologic complete response and R0 resections, and thus to improve survival, “we have to be efficient in the neoadjuvant setting and have a powerful chemotherapy,” he added. With increasingly effective regimens, R0 resection rates have increased to more than 90%, and median survival, which ranged from 23 to 31 months in prior studies, has not been reached in some recent trials.

In a 2016 meta-analysis of FOLFIRINOX therapy, 26% of patients with locally advanced disease were able to undergo resection; median progression-free survival was 15 months, and median overall survival was 24 months,¹² which is double the 1-year median survival achieved with older regimens.

UNANSWERED QUESTIONS ABOUT NEOADJUVANT THERAPY FOR PANCREATIC CANCER

Best tools for establishing diagnosis
Preferred regimen
Duration of treatment
Optimal disease subtype
Best benefit/risk ratio for patients

Also, a propensity score–matched analysis of 15,237 stage I/ II patients from the National Cancer Database who underwent resection with curative intent, either by upfront resection or by neoadjuvant chemotherapy followed by surgery has been published.¹³ The analysis showed that patients who underwent neoadjuvant therapy tended to have more T0 or T1 tumors, fewer lymph node metastases, and clearer resection margins—“and this seemed to translate into improved survival,” Dr. Seufferlein noted. Median overall survival was 21 months for upfront surgery, 23 months for upfront surgery plus adjuvant chemotherapy, and 26 months for neoadjuvant therapy. Hazard ratios were 0.72 (P < .01) and 0.83 (P < .01) when upfront surgery was followed by chemotherapy.

Drawbacks and Uncertainties

A prerequisite for neoadjuvant chemotherapy is tumor biopsy, which is required for a definitive diagnosis. In 25% of patients, this is not achieved, even with ultrasound guidance. Since only about one-third of patients have mutations that are concordant between tumor and plasma/serum, “liquid biopsies” cannot currently be used instead.

Also, neoadjuvant therapy carries a higher risk for toxicity than does adjuvant therapy, he said, citing rates of 8% to 22% from various studies. But this is mostly manageable, and the greatest risks are limited to patients whose disease is initially considered unresectable, he pointed out. Finally, because staging tools are imprecise, approximately one in five patients with disease initially deemed resectable does not undergo the surgery, Dr. Seufferlein added.

Issues yet to be settled include the following: preferred regimen -(FOLFIRINOX, gemcitabine/nab-paclitaxel, others?), duration of treatment (number of cycles, postoperative treatment?), and optimal disease subtype. “There will be no one-size-fits-all. We need randomized trials,” he said. ■

DISCLOSURE: Dr. Seufferlein has received honoraria from Amgen, Bayer, Merck, Sanofi, Celgene, and Shire; he is on the advisory boards of Lilly, Amgen, Bayer, Celgene, and Merck-Serono; and has received research support from Boehringer Ingelheim, Sanofi, and Celgene.

REFERENCES

1. Seufferlein T: Pancreatic cancer: Neoadjuvant vs adjuvant. ESMO 2017 Congress. Educational session. Presented September 9, 2017.

2. Neoptolemos JP, et al: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350:1200-1210, 2004.

3. Neoptolemos JP, et al: Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection. JAMA 304:1073-1081, 2010.

4. Oettle H, et al: Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer. JAMA 310:1473-1481, 2013.

5. Valle JW, et al: Optimal duration and timing of adjuvant chemotherapy after definitive surgery for ductal adenocarcinoma of the pancreas. J Clin Oncol 32:504-512, 2014.

6. Neoptolemos JP, et al: Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4). Lancet 389:1011-1024, 2017.

7. Neoptolemos JP, et al: Comparison of adjuvant gemcitabine and capecitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4). Lancet 389:1011-1024, 2017.

8. Uesaka K, et al: Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer. Lancet 388:248-257, 2016.

9. Mayo SC, et al: Management of patients with pancreatic adenocarcinoma. J Am Coll Surg 214:33-45, 2012.

10. Aloia TA, et al: Delayed recovery after pancreaticoduodenectomy. J Am Coll Surg 204:347-355, 2007.

11. Tzeng CW, et al: Treatment sequencing for resectable pancreatic cancer. J Gastrointest Surg 18:16-24, 2014.