A case of successful resection after FOLFIRINOX in a patient with borderline resectable pancreatic adenocarcinoma

Abstract

Pancreatic adenocarcinoma (PAC), one of the most aggressive human neoplasms, continues to have an exceedingly poor prognosis. With the advance of diagnostic techniques, a distinct subset of pancreatic cancer labeled “borderline resectable pancreatic cancer” has emerged. Optimal treatment of this disease with a multidisciplinary approach including neoadjuvant and adjuvant therapy remains controversial. We describe a case of borderline resectable PAC treated with FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) followed by successful pancreaticoduodenectomy. CT scan demonstrated a pancreatic head tumor attached to the superior mesenteric artery, subsequent to which the patient received FOLFIRINOX. Follow-up images showed no lymph node involvement or metastatic disease, suggesting that radical surgery would be curative. The patient underwent pancreaticoduodenectomy with negative margins and was subsequently diagnosed as Stage III (T3N0M0). Though requiring precise case selection and toxicity management, recent literature suggests that FOLFIRINOX is an effective neoadjuvant regimen in the setting of borderline resectable PAC.

Introduction

Despite advances in surgical technique, imaging technology, chemotherapy, and radiotherapy, pancreatic adenocarcinoma (PAC) still remains one of the most aggressive cancers, causing more than 20,000 deaths every year in Japan. The median 5-year survival is less than 5 % [1, 2]. Complete surgical resection remains the only treatment with curative potential, but only 10–20 % of patients with pancreatic cancer will be candidates for curative resection at diagnosis [3]. Here, we present a patient with borderline resectable PAC who underwent successful resection after neoadjuvant FOLFIRINOX therapy.

Case report

A 73-year-old man was diagnosed with a solid tumor at the pancreatic head after receiving transabdominal ultrasonography for sudden elevations in blood glucose. Histopathological findings from endoscopic ultrasound-guided fine-needle aspiration biopsy revealed PAC. Computed tomography (CT) demonstrated a solid tumor at the pancreatic head with an axial diameter of 3.0 cm, and attachment (<180°) to the superior mesenteric artery (SMA) without compromise of celiac axis (CA) or portal vein (Fig. 1). There was no evidence of lymph node involvement or metastatic disease. CA19-9 was elevated (1263.0 UI/mL). After diagnosis of borderline resectable PAC, the patient was administered 16 cycles of FOLFIRINOX (L-OHP 85, CPT-11 180, l-LV 200 mg/m² day 1, 5-FU 400 mg/m² bolus day 1, 5-FU 2400 g/m² on 46 h infusion every 2 weeks). Bolus 5-FU was discontinued because of the development of Grade 3 fatigue after 2nd cycle. After 7th cycle, he required 20 % dose reduction of L-OHP for Grade 3 peripheral sensory neuropathy, and after 13th cycle the dose had to be reduced by another 20 % due to Grade 3 neuropathy. CA19-9 decreased to 25.6 UI/mL by the end of treatment. Follow-up CT demonstrated no progression in local disease, obscuration of attachment to SMA, and no metastatic disease (Fig. 2). 18F-FDG positron emission tomography (PET) showed no evidence of increased FDG activity in the pancreas (Fig. 3). Ten months after the initial diagnosis, after 6 weeks since last administration of FOLFIRINOX, the patient underwent a subtotal stomach-preserving pancreaticoduodenectomy (SSPPD). Histopathological analysis of the specimen showed a 2.0-cm moderately differentiated tubular adenocarcinoma, and the patient was assessed to be Stage III (T3N0M0) (Figs. 4, 5). Surgical margins were free of disease with all 18 examined lymph nodes being negative. Less than half of carcinoma cells in the focus were viable, and the pretreatment effect was considered to be grade IIb [4].

Fig. 1.

Computed tomography at the time of diagnosis showed the attachment (<180°) of the tumor to the superior mesenteric artery (SMA) (arrow) and also suggested tumor attachment to the root of the right colic artery (RCA)

Fig. 2.

Computed tomography after FOLFIRINOX showed no progression of disease and less compromise of SMA and RCA (arrow)

Fig. 3.

Positron emission tomography (PET) after preoperative chemotherapy showed no evidence of increased FDG activity in pancreas head (arrow)

Fig. 4.

Histopathology review demonstrated moderately differentiated adenocarcinoma consisted with irregular gland formation (arrow). Poorly differentiated adenocarcinoma was recognized in some portions. About 50 % variable residual carcinoma cells were identified

Fig. 5.

Immunohistochemistry showed residual carcinoma which are infiltrating into pancreatic parenchyma

Postoperatively, he was discharged 3 weeks after surgery with no complications. Adjuvant chemotherapy with S-1 (80 mg/body, po bid, day 1–28 every 6 weeks) was started 2 months postoperatively, but stopped due to a keratitis (Grade 3). Currently, the patient continues to do well with no evidence of recurrence after 5 months of follow-up.

Discussion

The overall 5-year survival rate of pancreatic cancer has remained very poor in spite of the combination of surgery, chemotherapy, and radiation therapies [5]. Although margin-free resection is the only potentially curative technique for managing PAC, most patients are diagnosed with advanced disease; as such, only 10–20 % patients are candidates for curable resection at the time of diagnosis [6]. Even with margin-free resection, however, the recurrence rate is extremely high compared with other solid cancers, and the median survival of patients who receive surgical treatment followed by adjuvant therapy is approximately 20 months [7]. The strongest prognostic indicators for long-term patient survival are negative margin status, tumor DNA content, tumor size, and absence of lymph node metastases [8].

With recent advances in imaging and surgical techniques, the distinct subset of “borderline resectable pancreatic cancer” has emerged [9]. How best to treat this group using a multidisciplinary approach including neoadjuvant and adjuvant therapy is a topic of great interest. Although individual institutions typically have their own defining criteria for borderline resectable tumors, among which there remain numerous subtle differences, there is a general consensus that this group of tumors includes those with encasement of a short segment of the hepatic artery, without evidence of tumor extension to the CA and/or tumor abutment of the SMA involving 180° or less of the artery circumference. The relationship between tumor and superior mesenteric vein–portal vein (SMV-PV) varies by the guideline referenced. For example, the National Comprehensive Cancer Network and American Hepato-Pancreato-Biliary Association/Society of Surgical Oncology guidelines both take a conservative view of the tumor–vein relationship, stating that any impingement or narrowing of the SMV-PV should be considered borderline resectable [9–12].

It still remains controversial whether patients with resectable disease should undergo surgery or preoperative chemotherapy first. Neoadjuvant therapy for borderline resectable PAC is being widely investigated as a potential strategy for down staging initially unresectable tumors, allowing for more successful margin-negative resection. Although there is no high-level evidence supporting neoadjuvant therapy for patients with borderline resectable disease, there is a general consensus in the USA that these patients, having the high possibility of radiographically occult metastatic disease, should not be taken directly to the operating theater without induction therapy, in order to prevent margin-positive outcomes. Preoperative therapy offers several potential benefits including delivery of pharmacotherapy to intact and well-vascularized tissues, tumor downsizing, and maximizing the potential for margin-negative resection. Neoadjuvant therapy also offers the benefit of higher rates of treatment completion, as a reported 24 % of post-operative patients never receive planned adjuvant therapy due to post-surgical complications [13]. Several groups have reported that patients completing preoperative regimens demonstrate lower incidence of margin-positive resection and local recurrence [14, 15]. An added putative benefit of neoadjuvant therapy is selection for surgery of those patients with more stable disease or disease that is more responsive to therapy. A potential risk involving surgical delay is disease progression during the period of preoperative therapy, which could result in a squandered opportunity for surgical intervention. However, it has also been shown that disease progression during the neoadjuvant therapy is less common than previously reported data in which less than 50 % of patients with borderline resectable disease completed whole therapy including successful surgery [12].

Currently, there is insufficient evidence to select specific neoadjuvant regimens, so optimal regimens in this setting remain unclear. Neoadjuvant therapy regimens are often similar to those used in locally advanced and metastatic disease. The results of the ACCORD4/Partenariat de Recherche en Oncologie Digestive (PRODIGE) 11 trial have had considerable influence on the management of patients with metastatic PAC [16]. These results suggest that effective preoperative therapy with FOLFIRINOX may be an important key to managing borderline resectable disease; several retrospective but promising clinical studies (Table 1) involving the application of neoadjuvant FOLFIRINOX have already been reported.

Table 1.

Summary of select clinical trials with neoadjuvant FOLFIRINOX

Reference	Type of study	n	Resection rate (%)	R0 resection rate (%)
Ferrone et al. [17]	Retrospective	47	85	88
Paniccia et al. [18]	Retrospective	20	85	100
Christians et al. [19]	Retrospective	18	67	100
Hosein et al. [20]	Retrospective	18	56	80

In this report, we have demonstrated that preoperative FOLFIRINOX followed by pancreaticoduodenectomy can be safely performed, and our experience suggests that it might improve treatment outcomes. Initially, we did not plan to perform surgery after chemotherapy, so FOLFIRINOX therapy administered in this case may not precisely be called neoadjuvant chemotherapy. Furthermore, we recognize that optimal number of cycles of preoperative treatment and timing of surgery remain debatable. However, similar to previously reported cases, our experience suggests that FOLFIRINOX is a useful preoperative treatment regimen in this setting as long as chemotherapy-related toxicity does not delay or compromise surgical resection. A common concern with FOLFIRINOX followed by surgery is the potential for cumulative toxicity. In our case, side effects were safely managed with antiemetic support and dose reductions. During surgery, we found fibrotic change and adhesions around the pancreatic head (Fig. 6). Although these warranted care, we felt that they did not make the procedure particularly more complicated or dangerous. Selecting appropriate cases, it seems feasible to use FOLFIRINOX as neoadjuvant therapy for borderline resectable disease. Further studies are needed to confirm whether FOLFIRINOX may have a role as a routine neoadjuvant agent.

Fig. 6.

Fibrotic changes identified around the SMA (arrow)

In conclusion, we herein report a precious case of borderline resectable PAC that successfully underwent curative resection after preoperative FOLFIRINOX therapy.