Surgery for Locally Unresectable Pancreatic Cancer

Pancreatic cancer (PC) has a rising incidence and remains associated with one of the mostchallenging prognosis in oncology, with a 5-years survival around 11% and merely 4% of patients alive at 10 years. About one third of PC patients is diagnosed with locally advanced (LAPC) stage of disease, with a primary tumor that is considered unresectable (in the absence of metastatic disease) due to the local involvement of major vessels and is typically treated with palliative chemotherapy or best supportive care, with the aim to prolong survival while maintaining acceptable quality of life (QoL). However, the introduction of novel induction chemotherapy regimens has improved the clinical outcome of these patients in recent years. The preferred induction regimen for patients with favorable performance status (ECOG 0-1) has become modified 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin [(m)FOLFIRINOX], with gemcitabine + nab-paclitaxel (GEMNabP) as a more tolerable alternative. In this scenario, the resection of apparently unresectable PC following induction chemotherapy, although somewhat controversial, has emerged as an important development for selected patients. In this regard, the National Comprehensive Cancer Network (NCCN) guidelines recommends 4 to 6 months of induction combination chemotherapy followed by conventional radiotherapy (CRT) or stereotactic body radiation therapy (SBRT) for selected patients without systemic metastases, followed by consideration for surgical resection if feasible, with adjuvant chemotherapy if clinically indicated. Surgical resection can be usually achieved in about 25% of LAPC patients after chemotherapy with modern regimens, and in the context of multidisciplinary management at high-volume centers with high expertise. Resection is associated with encouraging results in terms of median overall survival (OS), reaching 20 to 40 months, and with 5-years survival around 20%. To achieve surgical radicality, venous resection, arterial divestment or even arterial resection could be necessary. In recent multicentric series, patients receiving R0 portal vein (PV)/superior mesenteric vein (SMV) resection had a median OS of 24 months and a 20% 5-year OS 16, and patients requiring major arterial reconstruction and/or periarterial divestment had in-hospital mortality rates of 4-5%, median OS of 13.7-20.1 months, and 5-year OS of 12.5-13.7%. Despite the encouraging survival outcomes, based on both remarkable advances in surgical technique at high-volume centers and the use of modern combination chemotherapy regimens and chemo-radiation, aggressive surgery for LAPC after induction chemotherapy remains a controversial topic for several aspects:

• Most of the available literature consists of retrospective studies, without intention-to-treat design and with clear selection bias for best responders after induction therapy, who are selected for surgery. Other studies reported similar survival outcomes in non-resected LAPC patients who had a good radiographic and serologic response after first line chemotherapy. While standard dose RT appeared ineffective in patients who have not undergone resection, RT with dose intensification and ablative intent might enable improvements in local control in LAPC patients, and SBRT seems to successfully achieve local control while also improving QoL.
• Most series considered locally advanced and borderline resectable PC as a single entity or did not distinguish between arterial resection of common hepatic artery (CHA)/celiac trunk (CA) or superior mesenteric artery (SMA), despite clear differences in terms of prognosis and perioperative complexity. Surgery for LAPC is feasible and safe only at high-volume centers with dedicated programs, and arterial resections are technically demanding procedures with a long learning curve (esteemed around 15 procedures).
• Quality of life (QoL) and patient reported outcomes (PROMS) were seldom verified and put in the context of the relatively modest survival of resected LAPC patients. Despite improvements in recent years, arterial divestment or resections may not only increase significantly perioperative morbidity and mortality, but also imply life-long consequences such as diarrhea, due to nerve plexus dissection, and diabetes, as total pancreatectomy is often required. Despite its technical complexity, there is no high-level evidence supporting the benefit of aggressive surgery for LAPC after induction chemotherapy.

The aim of the present study is to evaluate survival and QoL outcomes in a cohort of patients affected by LAPC and selected for surgical exploration and radical resection after disease non progression during induction chemotherapy at leading expert centers.

Inclusion criteria

• Patients older than 18 years
• Patients able to give informed consent
• Histologically confirmed pancreatic adenocarcinoma
• LAPC stage according to NCCN10 at diagnosis (Figure 1)
• Received at least 4 months of induction chemotherapy
• RECIST 1.1 stable disease (SD) or partial response (PR) after induction therapy
• Patient considered eligible for radical resection by local MDT

Exclusion criteria

• Informed consent withdrawal
• Presence of tumor characteristics precluding surgery
• Presence of patient significant comorbidities precluding surgery
• Unavailable pre-induction therapy abdominal imaging
• Pathological confirmation of any tumor different from PDAC