All aspects of this case, including initial staging, location of the primary tumor, and genetic analysis, must be considered in understanding the favorable outcome for this patient. To the authors’ knowledge, only Schneitler et al. have detailed a similar course in 2 patients with PDAC of the tail responding to FOLFIRINOX and having successful R0 resections. However, both of these patients had liver metastases (that resolved) and follow-up CT showed new retroperitoneal LN metastasis within 1 year for one patient7. There are also numerous studies and reports on borderline or unresectable locally advanced carcinomas responsive to neoadjuvant chemotherapy, but are limited in the case of definitive metastases and identifying characteristics towards successful tumor regression and resection789101112. Metastatic tumor regression has been documented in the presence of BRCA mutations, or in response to immune- and/or targeted therapy, but the clinical application is limited to a small subset of patients and is not applicable to ours13141516.
For patients with a high-performance status capable of tolerating the toxicity, FOLFIRINOX has been shown increase median overall survival in metastatic disease1. The goal is to control the tumor to an operable burden to achieve complete resection. There are no clinical trials supporting surgical resection in metastatic disease, but there are numerous individual reports of attempting resection, most often of the liver, in highly selected patients with varying results1,17,18. Disease recurrence is 70% following curative resection in metastatic PDAC and has only been found consistently beneficial in the setting of lung metastases1. A meta-analysis in 2010 identified resection rates in initially unresectable staging to be 70% after neoadjuvant chemotherapy with a 5-year survival rate comparable to patients capable of immediate resection. However, this included locally advanced and metastatic cancer and was before the introduction of FOLFIRINOX as the standard chemotherapy regimen. Overall, what has continued to stand true is that even in the case of favorable response to neoadjuvant therapy, surgery is riskier due to more extensive resection, as was required in our patient1,19. Notably, Jang et al. identified low contrast enhancement of soft tissue contacting major vasculature to be significantly associated with R0 resection after neoadjuvant FOLFIRINOX8.
Consideration must also be made towards the location of the primary tumor affecting the prognosis when treated with FOLFIRINOX. A retrospective study by Lorgis et al. describes a primary tumor of the body or tail to be more responsive than that of the pancreatic head, with increased median overall survival of 12 months in metastatic PDAC20. However, this difference in response was not identified in previous clinical trial21. The latter only included patients with excellent performance status, where 38% of patients had a primary tumor of the pancreatic head, whereas most other trials describe about 70%2021. This is notable because incidence rates of pancreatic cancer in the body and tail are ever rising7.
These uncertainties are due to, in large part, a budding understanding of pancreatic cancer biology. Through the known distinct developmental pathways of the pancreatic head, body, and tail, varying malignant potential may arise among the individual cellular environments7. In this patient, NGS did not return significant or targetable markers. However, of note, KRAS is mutated in 95% of patients, with the most common being G12D being 42%. There are phase I/II trials in place with KRAS-targeted therapeutics, but little definitive data is present. If recurrence occurs in this patient, as recurrence does occur in 70–80% of patients following surgical resection, use of a KRAS-targeted therapies may be a potential option1.
Overall, barring clear availability for targeted therapies, a metastatic PDAC of the tail may be considered to have a better prognosis than previously considered. FOLFIRINOX is the ideal treatment if the patient has a high-performance status, and PRODIGE 35 recommends 8 minimum cycles. However, in our case, the patient only tolerated 6 cycles and was still highly responsive, which speaks to the receptiveness of primary tail tumors. Even though the patient had increasing levels of CA 19 − 9 prior to resection (Table 1.), the primary had shrunk to 2.1 cm on imaging with no radiographic evidence of recurrence. Despite a stage IV diagnosis, the primary tumor was resected in order to mitigate the risk for mutation and progression. Although rare, greater hope for patients with PDAC of the tail with favorable tumor biology responsive to FOLFIRINOX may contribute to increased surgical resection rates and improve survival rates.