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The incidence of pancreatic cancer in the U.S. has been on the rise since the early 2000s, with an estimated 64,050 new cases diagnosed in 2023 and 50,550 deaths, according to statistics from the . The overall 5-year survival rate is 10%.

Resectable pancreatic ductal adenocarcinoma accounts for more than 90% of pancreatic cancer diagnoses. At the time of diagnosis, , while slightly more than 28% of cases are locally advanced or are regional disease considered borderline resectable.

consists of either neoadjuvant chemoradiation followed by pancreaticoduodenectomy (NACRT) or upfront pancreaticoduodenectomy and adjuvant chemotherapy (USR). (NCCN) recommend use of either approach, but studies aimed at ending this ambiguity have been met with varying results.

A series of recent analyses comparing the cost effectiveness of the two approaches may provide new insight into the best treatment strategy in resectable pancreatic cancer. The results showed that NACRT prior to surgery -- despite being more expensive than USR -- was favored in 94.3% of 100,000 random-sampling simulations.

"NACRT should be considered in all patients unless there is an absolute contraindication," concluded Simran Arjani, MD, of Rutgers New Jersey Medical School in Newark, and co-authors, writing in .

The team used a decision tree populated with Medicare reimbursement costs, and morbidity and mortality data for quality-adjusted life-years (QALYs) were used to calculate the incremental cost-effectiveness ratio (ICER) -- the primary outcome. In a theoretical cohort with a base case modeled on a 65-year-old male, half of patients received neoadjuvant fluorouracil, irinotecan, oxaliplatin, and leucovorin (FOLFIRINOX)–based chemoradiation followed by surgical resection, while the other half received upfront resection followed by adjuvant FOLFIRINOX–based chemotherapy.

The analyses showed that NACRT followed by resection was $6,840.96 [all costs in USD] more expensive than USR followed by adjuvant therapy but yielded 0.14 more QALYs. The ICER was $48,130. When the ICER was compared with a predetermined willingness-to-pay threshold of $100,000 per QALY gained, the ICER favored NACRT.

"This may be inconsequential to some patients and extremely important to others," Arjani and co-authors pointed out.

Although have improved, thanks to novel combination therapies such as FOLFIRINOX and gemcitabine plus nab-paclitaxel, the toxicity associated with NACRT can potentially delay curative surgery, putting patients with resectable disease at risk.

For this reason, the use of NACRT should still be discussed, the investigators said. "The results of this study and those in the published literature emphasize the role of resection rates after NACRT, which is a surrogate for both chemo-responsiveness of the disease and treatment toxicity."

In the future, the ability to identify chemoresponsive disease will define treatment decision-making, the researchers predicted. "Work in to identify resistance or susceptibility to chemotherapy drugs has the potential to maximize treatment benefits and minimize treatment-related toxicity."

In the following interview, Arjani, who is now a resident in internal medicine at Montefiore Medical Center in the Bronx, New York, elaborated on the study results.

Have your findings resolved any of the ambiguity surrounding current NCCN guidelines for the management of resectable pancreatic cancer?

Arjani: Our study alone cannot resolve the ambiguity in the guidelines. However, it contributes to the growing body of literature in favor of neoadjuvant therapy while providing a unique cost-based perspective. In the absence of our ability to predict response to chemotherapy, neoadjuvant therapy should at least be considered in all patients with resectable pancreatic cancer.

You referred to "an absolute contraindication" to the use of NACRT. What was this?

Arjani: We were referring to poor functional status. Although first-line chemotherapy regimens for pancreatic cancer are improving, they remain fairly toxic and the patient who is too fragile to withstand chemo or its side effects is not a candidate for NACRT. If this type of patient can tolerate surgery, early resection may confer better survival.

Are the side effect profiles of newer chemotherapies of concern?

Arjani: Our ability to provide symptom-based treatment has improved with time and is driving any improvements in chemo tolerability. However, the current literature does not conclusively differentiate between the toxicity of the two main first-line regimens, FOLFIRINOX and gemcitabine with nab-paclitaxel. Both are more effective than the gemcitabine-only regimen that preceded them, but they are also more toxic.

What did your study indicate about the clinical scenarios in which upfront surgery became cost effective?

Arjani: The one-way sensitivity analyses showed that upfront surgery was only cost effective if the percentage of patients able to proceed to surgery after NACRT dropped to 21% or less as a result of poor performance status or the progression of disease. Similarly, upfront surgery became cost effective if 85.4% of patients or less were resectable in the operating room after NACRT. Two-way sensitivity analyses were in alignment with these results.

You found that NACRT was associated with 0.14 more QALYs than USR, but also with significantly increased costs. What are the clinical implications for the low-income patient?

Arjani: Taking into consideration a standard willingness-to-pay (WTP) set in cost-effectiveness analyses of $100,000 USD per QALY gained, we conducted an analysis to determine how changing this WTP affected our outcomes. We found that at a WTP of less than approximately $62,000 USD, upfront surgery became the preferred treatment. These results can only be hypothesis-generating, as the probabilities, costs, and survival in this model may not reflect those of a resource-poor environment. That being said, in such a situation, surgery may be the preferred first step.

What's next for your research?

Arjani: Our team, led by Dr. Ravi J. Chokshi, [Division of Surgical Oncology at Rutgers] continues to analyze ambiguities and changes in our current oncologic practice guidelines through a cost-effectiveness lens.

Any other comments?

Arjani: Thank you for the opportunity to share and discuss our study, as well as the role cost plays in cancer treatment strategies.

Read the study here.