Role of Neoadjuvant Therapy in Pancreatic Cancer 'Unproven'

Liam Davenport

July 10, 2017

BARCELONA  — Although good evidence supports adjuvant therapy after resection in patients with locally advanced pancreatic cancer, the role of neoadjuvant therapy in borderline resectable cases is less clear.

This was the conclusion from Jean-Luc Van Laethem, MD, PhD, Erasme University Hospital (ULB), Brussels, Belgium, who reviewed the subject here at the 19th World Congress on Gastrointestinal Cancer (WCGC).

Patients with resectable pancreatic ductal adenocarcinoma experience significant survival benefits with adjuvant chemotherapy, he said.

However, he continued, the use of neoadjuvant or induction therapy is not currently supported by the literature as a standard therapeutic option, apart from potentially in certain cases, and many questions over its use remain to be addressed.

Current Clinical Landscape

Dr Van Laethem started his review by highlighting that, in the current clinical landscape for pancreatic cancer, approximately 15% to 20% of cases are resectable, with an estimated survival with optimal therapy of up to 28 months.

A further 15% to 20% of pancreatic cancers are locally advanced, with an estimated survival of up to 15 months.

However, up to 70% of all pancreatic cancer cases are metastatic and are associated with a survival of up to 12 months.

"But there is a borderline between localized and locally advanced cases called borderline resectable diseases," he said, adding that choosing the optimal therapy for these cases is "a little bit confusing."

Dr Van Laethem emphasized that initial decision-making in these patients "of course should be multidisciplinary and rely on multislice CT [computed tomography] scanning to decide if we go to surgery or not, based on the resectability criteria."

He said that, for resectable cases, treatment can begin with neoadjuvant therapy before surgery and then adjuvant therapy or can proceed directly to surgery, followed by adjuvant therapy.

For borderline operable cases, in which a grade of R0 "is unlikely," patients can receive induction therapy before dissection of the tumor is attempted, or surgeons can go for upfront, or "risky," surgery, he said.

"The third situation is a tumor that will probably never be resectable and then we go for induction chemo and chemoradiation," Dr Van Laethem said. After this, surgeons can attempt "improbable" surgery.

He noted that the most recent practice guidelines for pancreatic cancer have concluded that high, grade I evidence supports the use of adjuvant chemotherapy, resulting in A or strong recommendations.

However, for neoadjuvant/induction therapy, only low, grade IV evidence is available, and any recommendations are B or moderate/borderline.

Numerous Trials of Adjuvant Therapy

Dr Van Laethem highlighted the fact that numerous trials have studied adjuvant chemotherapy in pancreatic cancer, most of which have reported significant improvements in 2-year survival rates.

The most notable recent study was the European Study Group for Pancreatic Cancer (ESPAC) 4 trial, in which 722 patients with pancreatic ductal adenocarcinoma who had undergone curative resection were randomly assigned to gemcitabine or gemcitabine plus capecitabine. Survival significantly improved with combination therapy.

However, Dr Van Laethem pointed out that although the study met its primary endpoint, there were methodologic issues, overlapping confidence intervals for median overall survival, short follow-up of the last patients to be enrolled, and no differences in disease-free survival, among other problems.

Consequently, he said that mature data are " eagerly awaited" and that while gemcitabine plus capecitabine is a new treatment option in pancreatic cancer, it is "not a new standard."

To those ends, several ongoing phase 3 trials are studying adjuvant therapy in pancreatic cancer, including PACT-15, PRODIGE 24/ACCORD 24, RTOG 0848, and APACT.

Dr Van Laethem said that although surgery plus adjuvant chemotherapy is considered the standard in resectable pancreatic cancer, recent findings have indicated that around 25% of patients die within the first year of follow-up, 50% experience recurrence, and up to 40% do not complete adjuvant chemotherapy.

It is therefore clear that "better patient selection is needed," he said.

Neoadjuvant Therapy

Neoadjuvant therapy given pre- or perioperatively aims to increase resectability, target occult disease, allow early intervention, and avoid treatment delays. This therapy also offers a "unique window" to allow patients with rapid progression to avoid ineffective surgery and permits the study of the effects of therapy on tumor biology.

However, Dr Van Laethem underlined that this relies on appropriate clinical selection, technical preparation of the patient, vascular staging, the assessment of molecular prognostic factors, and the appropriate selection of treatment based on such factors.

The meta-analyses available so far on the use of neoadjuvant therapy in pancreatic ductal adenocarcinoma have suggested that it is effective in only a minority of unresectable patients and that only patients with locally advanced disease are likely to benefit.

Dr Van Laethem said that nevertheless many potential confounding factors may have affected the results, including differences in both the regimens used and the types of studies included in the meta-analyses, the number of patients in individual trials, the resectability criteria used, and the lack of a control group in most trials.

Therefore, many questions remain over neoadjuvant/induction therapy, including the type of chemotherapy to be used, whether to combine it with radiation therapy, and the sequencing of treatments, particularly over whether to start with chemotherapy or chemoradiation.

Nevertheless, a study has shown that combining FOLFIRINOX (folinic acid, fluorouracil, irinotecan, oxaliplatin) with chemoradiation is both feasible and active in locally advanced pancreatic cancer and improves objective response rates and disease control rates.

To further explore whether chemoradiation is required after induction chemotherapy, patient selection, and the treatment modalities to be used, there are several ongoing and planned randomized controlled trials.

Emerging data from these trials suggest that nab-paclitaxel plus gemcitabine is as effective as neoadjuvant therapy in patients with resectable or borderline resectable pancreatic cancer. However, it is essential that tumor response, based on levels of circulating markers and imaging assessments, is evaluated early to differentiate between responders and nonresponders.

Best Available Evidence

Dr Van Laethem concluded that the best available evidence indicates the current standard is to use adjuvant chemotherapy with gemcitabine after R0/R1 resection, while gemcitabine plus capecitabine remains "a new option."

In contrast, adjuvant chemoradiation is not standard therapy and should be used only in selected cases. He said that there is also no current standard adjuvant therapy for metastatic pancreatic ductal adenocarcinoma.

Although neoadjuvant/induction therapy is not standard treatment for potentially resectable tumors, Dr Van Laethem summarized, emerging evidence supports its use in "specific cases," such as patients suspected of having extrapancreatic disease and cases in which it is not clear that the patient can undergo surgery.

However, the overall evidence is low grade, and many questions remain, including the extent of the effect on survival outcomes and the role of chemoradiotherapy, which may be answered by ongoing trials.

After the presentation, session co-chair Thomas Seufferlein, MD, Department of Internal Medicine, Ulm University, German, thanked Dr Van Laethem for "this excellent, comprehensive overview."

He said, "One quick question from my side: You have a proportion of patients progressing under neoadjuvant treatment, maybe 20%.…They are not eligible for surgery anymore because they are progressing. Do you see that as a problem, or do you see it as a chance to learn the tumor biology and that maybe these patients would not have benefited? What is your view?"

Dr Van Laethem replied that he sees it as a chance to learn about the tumor biology because a patient with metastatic disease "is not a good candidate" for surgery.

No funding was reported. Dr Van Laethem has disclosed no relevant financial relationships.

19th World Congress on Gastrointestinal Cancer (WCGC). No abstract available. Presented June 28, 2017.

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