Chemotherapy for Locally Advanced Pancreatic Cancer: The Dilemma of David Versus Goliath After NEOPAN - To the Editor

Sep 30, 2026

Uploaded by Hazel

Letter to the editor analyzing the challenging NEOPAN PRODIGE 29-UCGI 26 trial in locally advanced pancreatic cancer. Discusses the trial’s design target for mPFS, the borderline separation without a clear overall survival advantage, and how postprogression chemotherapy patterns may influence endpoints like PFS. Highlights equally low resection rates and argues the treatment goal should shift toward palliation. Reviews toxicity reporting gaps (G-CSF and neurotoxicity) and questions age stratification thresholds, then outlines next steps including more intensive regimens, molecular stratification, and emerging agents.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages3

Reading Time8 min

AccessFree to download

Correspondence

NEOPAN trial design and interpretation

Postprogression therapy impact on outcomes

Resection rates and treatment goals

Toxicity reporting considerations (G-CSF and neurotoxicity)

Age stratification considerations

Implications for next steps and future research

Correspondence Chemotherapy for Locally Advanced Pancreatic Cancer: The Dilemma of David Versus Goliath After NEOPAN TO THE EDITOR: The challenging PRODIGE 29-UCGI 26 (NEOPAN) trial1 was conducted in a population where randomized evidence is critically needed. NEOPAN represents a cornerstone for both future research and clinical practice in the management of locally advanced pancreatic cancer (LAPC) . Some aspects merit further discussion to best interpret its results and guide the ongoing update of international guidelines. NEOPAN was designed to detect a 3-month improvement in median progression-free survival (mPFS), from 5 to 8 months. This was a reasonable target, particularly in light of the phase III CONKO-007 trial interim analysis, which also reported an 8-month mPFSin the chemotherapy-alone arm, approximately 84% of whom received ﬂuorouracil, oxaliplatin, and irinotecan (FOLFIRINOX).2 However, with the beneﬁt of hindsight, the observed advantage was statistically signiﬁcant but did not clearly cross the efﬁcacy boundary: the trial arms slightly overperformed, especially for gemcitabine, as the observed mPFS gain was from 7.7 to 9.7 months in the experimental arm. Moreover, this PFS beneﬁt did not translate into an overall survival (OS) advantage, which may prompt discussion regarding the clinical impact of the ﬁndings. It is important to note that the study was not powered to detect differences in this outcome and many factors may explain the lack of OS beneﬁt. Among patients receiving postprogression chemotherapy, 56% of those deemed ﬁt for modiﬁed FOLFIRINOX (mFOLFIRINOX) but randomly assigned to gemcitabine were treated with second-line, multiagent, non–gemcitabinebased regimens (mFOLFIRINOX, FOLFOX, or FOLFIRI), whereas 44% of those in the mFOLFIRINOX arm received gemcitabine monotherapy at progression. In this regard, an analysis of PFS1 1 PFS2 or of PFSratio,3 reﬂecting the impact of subsequent therapies, would be informative. Importantly, NEOPAN reported equally low resection rates, accurately mirroring real-world practice. Given that longterm survival in LAPC is primarily driven by surgical resection,2,4,5 when this is not achievable, the therapeutic goal should shift toward palliation with the least possible harm. In this context, treatment toxicity is crucial. NEOPAN provides reassuring evidence on the tolerability of mFOLFIRINOX when administered in experienced centers. However, an acknowledged limitation is the lack of information regarding granulocyte colony-stimulating factor (G-CSF) use. Given that grade ≥3 neutropenia was more frequent in the gemcitabine monotherapy arm, it is reasonable to infer that prophylactic G-CSF was used routinely with mFOLFIRINOX. This consideration is relevant when compared with once weekly regimens, which are often subject to treatment delays because of neutropenia, potentially affecting their efﬁcacy. Another key missing data point concerns neurotoxicity, which often limits oxaliplatin use and likely contributed to its lower dose intensity in NEOPAN. Recent evidence suggests that maintaining at least 80% relative dose intensity may be important for efﬁcacy of triplet regimens.6 Therefore, stating that mFOLFIRINOX was better tolerated than gemcitabine monotherapy, without reporting these key toxicity data, may be misleading. Age stratiﬁcation is another key consideration. Although the trial enrolled patients age up to 84 years—rarely candidates for triplet regimens in routine practice—the use of a 60-year cutoff is difﬁcult to interpret, particularly given the seemingly greater beneﬁt of mFOLFIRINOX in older patients. Analyses with age as a continuous variable and in narrower bands (eg, 5-year intervals) would offer clearer insight. Notably, ongoing trials in LAPC adopting mFOLFIRINOX (eg, ClinicalTrials.gov identiﬁer: NCT06897644) require TRIBE7-like criteria, with an upper age cutoff of 75 years and an Eastern Cooperative Oncology Group performance status

FAQs

What primary endpoints were targeted and how did NEOPAN perform on progression-free survival?

NEOPAN was designed to improve median progression-free survival from 5 to 8 months. The observed mPFS gain was statistically significant but did not clearly cross the efficacy boundary, with a rise from 7.7 to 9.7 months in the experimental arm.

Why might NEOPAN not show an overall survival advantage?

The study was not powered to detect differences in overall survival. The letter also notes many factors, including how postprogression chemotherapy was delivered across treatment arms, may explain the lack of OS benefit.

Which toxicity-related data gaps could affect the interpretation of tolerability?

The letter emphasizes missing information on granulocyte colony-stimulating factor (G-CSF) use and lacks detailed neurotoxicity reporting. These omissions may complicate comparisons between mFOLFIRINOX and gemcitabine monotherapy and could influence dose intensity assessments.

Sep 30, 2026

Uploaded by Hazel