Do you consider FOLFIRINOX dose adjustments for elderly patients with a good performance status in the neoadjuvant setting for resectable pancreatic adenocarcinoma?

This is a question worth revisiting in light of recent data. 

The question assumes that we would prefer to use FOFLIRINOX as peri-operative treatment in resectable PDA and this is commonly the case based on extrapolation from cross-trial comparisons of randomized data evaluating combination therapy in the metastatic and adjuvant settings. 

Sequence of therapy in this setting is also unclear at the current time, though neoadjuvant therapy is attractive as it may be quite challenging to tolerate 6 months of adjuvant therapy after pancreatic resection, and there are other potential putative benefits in initiating systemic therapy without delay for surgery and recovery. The ongoing cooperative group study (Alliance A021806) is asking this question and will hopefully shed more light on this issue. 

We generally start with the doses used in the adjuvant PRODIGE trial (Conroy et al., PMID 30575490) with omission of the 5-FU bolus and 150mg/m2 of Irinotecan but ongoing studies are evaluating the optimal first line regimen for elderly and poor PS patients. 

Notably, the SWOG S1505 study was recently reported (Sohal et al., PMID 33475684). This study randomized 102 resectable patients (centrally confirmed) to perioperative therapy with either mFOLFIRINOX or gem/nab-paclitaxel. The study was designed as a “pick-the-winner” randomized Phase II, and there was no winner as neither arm achieved the desired result compared to historical control. However, this was one of the first comparative studies of these two regimens and in this well done randomized study, almost all important outcomes were similar between the 2 arms with median OS of 23.2 versus 23.6 months in the 2 groups.

Given these results, it remains reasonable to use modified FOLFIRINOX, but if there is concern about tolerability due to age or comorbidities and you feel you can safely give gem/nab-paclitaxel, I would recommend that regimen over further modifying FOLFIRINOX.

If neither regimen can be given safely at recommended doses, I would reconsider whether immediate surgery is an option and if not, would proceed with the regimen and modifications that you use in PS-2 Stage IV patients.

I never use full dose Folfirinox. I have for many years used reduced doses in the neoadjuvant setting, seeing no reason why it should not be better to give when patients tolerate drugs, and from other studies, it has been superior to gemcitabine. Multiple studies have shown modified doses are just as active and patients are not lost as frequently from treatment due to AE.

The biggest change I make is reducing the Camptosar to 100 mg/ m2, a particularly toxic drug and both FU doses by 20%

if the patient tolerates it,  like the myeloma literature in older patients, I gradually increase the FU dose but are timid with Camptosar

 I have had CR at time of resection with this approach 

Unfortunately, the patients we see in community practice are often 15-20 years older than ones studied in clinical trials. Most geriatric lectures or articles that I have read comment on the biologic difference between younger and older patients. More specifically, less muscle, more fat, decreased renal function - all of which contribute to higher drug levels of any medication administered. Although we are trained to avoid dose reductions in potentially curative situations, I would think it reasonable to consider a modest dose reduction for the first course of any neo-adjuvant regimen for a disease that rarely results in cure. Fortunately, there are predictive tools available to estimate patients at highest risk for grade III-VI toxicity. Zhang et al., PMID 31612006