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compared to observation following resection or adjuvant chemotherapy alone and therefore should have a
[49]
role in managing this stage of disease .
The use of intraoperative radiation therapy has been documented, but data is limited to a few case studies
and small case series. One such case utilized a multidisciplinary treatment approach which included upfront
resection with intraoperative radiotherapy followed by adjuvant chemotherapy and radiotherapy. The
[109]
reported patient enjoyed a 40-month survival . A separate case series also documented the use of
intraoperative radiation in two patients with death reported 44 and 22 months post-diagnosis .
[110]
Intraoperative radiation remains a rare treatment in this and other pancreatic diseases.

Use of chemotherapy in advanced disease
Palliative chemotherapy is typically given to patients with locally advanced or metastatic disease. Significant
questions remain regarding what treatment regimen is best for ASCP patients. There are 2 retrospective
multicenter studies and 3 case reports that have documented the response of advanced ASCP to
chemotherapy. Yoshida et al. examined the outcomes of 116 patients with recurrent or metastatic ASCP
who received chemotherapy at 24 Japanese institutions from 2001-2017 . Those receiving combination
[83]
chemotherapy regimens (n = 57) had a trend of increased survival compared to those receiving
monotherapy (n = 59) and a significantly higher disease control rate, and clinical characteristics were well-
balanced between the cohorts. This study was large enough that response to PDAC standards GnP and
FOLFIRINOX could be compared. No difference in median OS, PFS or other clinical parameters of
response was found in the 28 patients receiving GnP versus the 10 treated with FOLFIRINOX, and only 5
patients receiving these treatments survived 18 months or longer. Similarly, a different retrospective
multicenter study reported individual outcomes of 16 ASCP patients receiving chemotherapy for advanced
[111]
disease and identified no statistical or anecdotal evidence for the superiority of a specific regimen . Two
case reports of patients with advanced disease describe rapid disease progression on standard PDAC
regimens, but a third documents a patient achieving a partial response to 5-FU given in combination with
cytokines IFNα and TNFα that allowed for subsequent surgical resection [90,91,112] . There are no reports of
common regimens given for pure squamous cell cancer, such as platinum with taxane being tested in this
tumor type. Current data are unclear on what constitutes an optimal chemotherapy regimen for patients
with advanced ASCP.

Clinical research
Three clinical trials specific for advanced, previously treated ASCP are currently enrolling; these are the first
prospective clinical trials specific for this tumor type [Table 4]. Sequencing of several ASCPs identified
FGFR activation as a lesion that is frequently present in ASCP, and at least one organoid model bearing
FGFR fusion was found to be sensitive to FGFR inhibition with a pharmacologic agent . Based upon this, a
[62]
Phase 2 study of the anti-FGFR drug pemigatinib was recently initiated (NCT05216120). ASCP is now well
understood to have strong overexpression/amplification of MYC. It was recently found that triptolide, the
active ingredient of a Chinese herbal remedy, exhibits anti-cancer efficacy, at least in part, through
inhibition of superenhancer complexes that drive expression of oncogenes like MYC. Treatment with the
triptolide pro-drug minnelide can inhibit activity of MYC and other oncogenic superenhancers . Based
[113]
upon this data, we have initiated a Phase 2 study of Minnelide for ASCP patients, which is currently in
recruitment (NCT04896073) . ASCP has been noted to have expression of PD-L1 in the squamous
[114]
components and a more tumor inflamed phenotype than standard PDAC [51,57,58] . Another Phase 2 study
(NCT05216120) is testing the anti-PD-1 antibody retifanlimab (INCMGA00012) in ASCP patients with
hopes that this tumor type will be more responsive to immunotherapy than PDAC. Results from these
studies of targeted therapies are anxiously awaited.