Short summary

Combination chemotherapy (e.g. FOLFIRINOX, Gem-Abraxane, Gem-Cap, Gem-S1) is standard of care in patients with LAPC but more and more scientific studies point to the fact that patients without sign of progressive disease (PD) will benefit from additional radiotherapy and especially SBRT. SBRT is a Phase I/II trial. In SBRT patients will be treated with 50 Gy in 5 fractions within a total of 7 - 8 days or with 60 Gy in 8 fractions in 10-13 days. The primary efficacy variable is resection rate for all patients starting SBRT.   

Rationale

Patients with pancreatic cancer (PC) are often divided in three major clinical groups, resectable disease (rPC), locally advanced (LAPC) disease, and metastatic disease (mPC). Perhaps a fourth group should be added because a large proportion of patients never receive any active therapy (1). The prognosis for all three groups is dismal. Even for patients with rPC, the expected median survival (mOS) based on randomized study data is around 20-24 months and for patients with LAPC less than 12 months. LAPC is often a mix of borderline and never-resectable tumours. Multimodality treatment might downstage these tumours to allow a potential radical resection, especially in the borderline group

The traditional two main parameters used for evaluating tumour vessel encasement are; the grade of the circumferential involvement and the length that the tumour is in contact with vessels (Figure 1). The importance of both grade and length of such encasements probably differs from arteries to veins in the pancreatic region. For instance a <50% circumferential involvement in a short vein segment is easy to deal with for the trained surgeon, whereas a corresponding involvement of arteries makes it less likely to achieve a R0 resection. It is possible that also periarterial stranding has to be taken into account. Moreover, venous narrowing or complete obstruction might jeopardize surgical resection. 

About 30-40% of the patients have LAPC at the time of diagnosis, with extensive tumour growth over the adjacent organs particularly due to vascular involvement of the tumour - venous and/or arterial, but without evidence of distant metastases. These tumours are usually considered not resectable due to the fact that complete surgical excision with negative pathologic margins is not possible using standard surgical procedures, with a survival no different than that in metastatic disease. In some of these patients, however, radical (R0) resection may be achieved after pre-operative oncological therapy with the aim to downstage or down-size the primary tumour (2). The results following resection of LAPC with venous and arterial resection and reconstruction are conflicting, and the data are hampered by the lack of prospective studies with strict definitions regarding both the diagnosis and definition of LAPC. Thus, the recent interest in a neoadjuvant approach to LAPC is faced with two important issues that need careful consideration before embarking on major prospective studies: 1) How is LAPC defined? and 2) How is LAPC diagnosed?

Description of the cohort

STUDY POPULATION

Inclusion criteria

• LAPC (Karolinska Type A-D) 

• Cytologically or histologically verified adenocarcinoma/carcinoma

• Prior combination chemotherapy for 2-6 months (unless contraindicated) and no sign of progressive disease

• The patient is medically operable (i.e. no co-morbidity which can preclude anaesthe-sia or surgery) 

• WHO performance status 0-1

• Age ? 18 years 

• Adequate hepatic function: bilirubin <3.0 x UNL, PP% 0,5 - 1,3, APTT < 1,5 x UNL

Patients with obstruction of bile duct or gut must be drained before start of therapy

• Oral and written informed consent must be obtained prior to registration with planned date of first treatment within 14 days from registration.

Exclusion criteria

• M1 disease

• Prior radiotherapy to abdominal cavity

• Pregnancy or breast-feeding. Fertile patients must use adequate contraceptives

• Severe uncontrolled concomitant illness (e.g. clinically significant cardiac disease or myocardial infarction within 12 months)

Data and biological material

First diagnosis of primary tumor (biopsy/cytology)

Tumor stage at primary diagnosis - AJCC 8th ed.

Karolinska classification 

Reason for non-resectability

First line therapy

Performance Status before SBRT

Pt. weight before SBRT

Progression of disease in SBRT 

Bloodsamples

Biological material is collected in the form of blood/biospecimens.

Publications associated with the project

Publication will be prepared by the Sponsor-Investigator who will also decide who will be the first author. The protocol committee writes the first and final version. Regardless of positive, negative, or inconclusive results the trial will be made publicly available through conferences and/or international, scientific journals.