Extending Outcomes for Pancreas Cancer Patients With Nominal Oligometastatic Disease (EXPAND): A Randomized Phase III Trial

Inclusion Criteria: Age 18 Histologically or cytologically confirmed pancreatic ductal adenocarcinoma. Histologic / cytologic confirmation of pancreatic ductal adenocarcinoma may come from the primary tumor (i.e., via FNA at initial diagnosis). Histological/pathologic confirmation of distant metastatic disease is not required if clinical and radiographic consensus is that the patient has distant metastatic disease. Eastern Cooperative Oncology Group (ECOG) performance status ≤2 Candidate for MDT (including radiation therapy, surgical resection, ablation, and embolization) to all sites of disease including oligometastatic sites and if present intact primary / regional nodal disease. Between one and five distant metastatic lesions, counted as follows: each lesion (not site) will be counted as one, with the exception of metastatic lymph node stations, which will collectively count as one lesion. Regional nodal stations will be counted as a collective single lesion if present. All progressive lesions must be amenable to local therapy as noted in criterion 4.2.1.4 above. Counting of oligometastatic nodal disease will be based on nodal chains. A nodal chain will be considered a single metastatic lesion if the presence of that node results in the patient as having M1 disease per the TNM staging system, AJCC version 8.0. In addition, one of the following criteria must be met: a) ≥1 LN meets radiologic criteria for metastatic disease via RECIST 1.1 (short axis ≥15mm), b) pathologic assessment has confirmed the presence of metastatic cancer cells, and/or c) the LN exhibits imaging signal characteristic of a metastatic lesion (e.g. FDG avidity, contrast enhancement, etc.). In the event of ambiguity or equivocal findings, the principal investigator or co-principal investigator will make a final determination of whether criteria are met. The following caveats apply: In patients with a LN exhibiting a short axis ≥15mm and who have other diagnoses that can produce enlarged LNs (e.g. indolent CLL, sarcoidosis, etc…) or a prior history of benign enlarged LNs will not be considered to have metastatic disease per the discretion of the treating physician. LN chains that occur bilaterally will be considered separate metastatic sites. For example, left axilla LNs will counted separately from right axilla LNs. The following midline LN chains will be counted as 1 metastatic site: mediastinal, para-aortic, mesenteric. The following bilateral LN chains will be counted as 1 metastatic site for unilateral involvement, and 2 for bilateral for involvement: preauricular, cervical and occipital, supraclavicular, infraclavicular, pectoral, axillary, hilar, epitrochlear and brachial, iliac, inguinal and femoral, popliteal. Baseline imaging must include a scan done within 4 weeks prior to randomization, demonstrating oligometastatic disease by RECIST (v1.1) criteria compared to pre-baseline imaging. Baseline imaging must be done within 4 weeks prior to randomization, and the following imaging is required: PET/CT scan or CT scan of the chest/abdomen/pelvis. MRI may be substituted as indicated (i.e., CT scan of chest plus MRI abdomen/pelvis). Diagnostic laparoscopy may be indicated prior to enrollment if any concern for peritoneal disease / carcinomatosis is present, at the investigator's discretion. Presence of peritoneal carcinomatosis will exclude the patient from this trial as below. Indications for peritoneal carcinomatosis may include findings concerning for but not definitive for peritoneal disease on diagnostic imaging, elevated CA-19-9, and clinical symptoms concerning for peritoneal disease. Patients referred for the study that require immediate MDT can receive treatment to CNS lesions or other symptomatic lesions prior to randomization, but these lesions will be counted towards the total number of oligometastatic lesions. Patients with \>5 discrete metastatic sites previously with subsequent 'induction' of oligometastatic disease (\<=5 discrete sites; induction via response to systemic therapy) may be eligible if 5 or fewer metastatic disease sites have been present / noted radiographically for a minimum of 6 months, and pending principal investigator review/discretion. Females of childbearing potential must not be breast feeding and must have a negative serum or urine pregnancy test and must agree to use adequate contraception from the time of screening until 3 months after discontinuation of the study medication. Acceptable methods of contraception include total and true sexual abstinence, tubal ligation, hormonal contraceptives that are not prone to drug-drug interactions (IUS Levonorgestrel Intra Uterine System (Mirena), Medroxyprogesterone injections (Depo-Provera), copper-banded intra-uterine devices, and vasectomized partner. All hormonal methods of contraception should be used in combination with the use of a condom by their sexual male partner. Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12 months with no menses without an alternative medical cause). Women will be considered post-menopausal if they have been amenorrheic for the past 12 months without an alternative medical cause. The following age-specific requirements must also apply: Women \< 50 years old: they would be considered post-menopausal if they have been amenorrheic for the past 12 months or more following cessation of exogenous hormonal treatments. The levels of Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) must also be in the post-menopausal range (as per the institution). Women ≥ 50 years old: they would be consider post-menopausal if they have been amenorrheic for the past 12 months or more following cessation of all exogenous hormonal treatments, or have had radiation-induced oophorectomy with the last menses \> 1 year ago, or have had chemo