A multicenter phase 4 geriatric assessment directed trial to evaluate gemcitabine +/− nab-paclitaxel in elderly pancreatic cancer patients (GrantPax)

Background: In the group of elderly patients (≥70 years) with metastatic pancreatic ductal adenocarcinoma (mPDAC), it is not known who benefits from intensive 1st line nab-paclitaxel/gemcitabine (nab-p/gem) combination chemotherapy or who would rather suffer from increased toxicity. We aim to determine whether treatment individualization by comprehensive geriatric assessments (CGAs) improves functional outcome of the patients. Methods/Design: GrantPax is a multicenter, open label phase 4 interventional trial. We use a CGA to stratify elderly patients into three parallel treatment groups (n = 45 per arm): 1) GOGO (nab-p/gem), 2) SLOWGO (gem mono) or 3) FRAIL (best supportive care). After the 1st cycle of chemotherapy (or 4 weeks in FRAIL group) another CGA and safety assessment is performed. CGA-stratified patients may not decline in their CGA performance in response to the first cycle of chemotherapy (primary objective), measured as a loss of 5 points or less in Barthels activities of daily living. Based on the second CGA, patients are re-assigned to their definite treatment arm and undergo further CGAs to monitor the course of treatment. Secondary endpoints include CGA scores during the course of therapy (CGA1–4), response rates, safety and survival rates. Discussion: GrantPax is the first trial implementing a CGA-driven treatment to personalize therapy for elderly patients with pancreatic cancer. This may lead to standardization of therapy decisions for elderly patients and may optimize standard of care for this increasing group of patients. Trial registration: NCT02812992 , registered 24.06.2016

Immunocytochemistry <i>(a)</i> and ELISA assessment <i>(b)</i> of PSC activation.

<p>Increased α-SMA and type-1 collagen protein expression was found on immunocytochemistry after PSCs were exposed both to 21 days of hyperglycemia or 48h of TGF-β1 <b><i>(a)</i>.</b> Increased type-1 and type-3 collagen levels were observed in PSC cell culture supernatant in the ELISA studies, however the increases were statistically only significant after the TGF-β1 treatments both with and without prior CHG exposure, but not after CHG exposure alone <b><i>(b)</i>.</b> Significant differences (p<0.05) are indicated *</p

Proliferation and migration assays of T3M4 cells and the Western blot analyses of key signaling molecules: <i>(a)</i> Sulphorodamine B test.

<p>Proliferation of T3M4 cells incubated with different conditioned PSC culture medium and the CXCR4 inhibitor AMD3100 after 24, 48, 72 and 96 hours of treatment. T3M4 cell proliferation (solid line; untreated control) was increased significantly after incubation with PSC supernatant (dotted line) provided that PSC were prior exposed to CHG. The presence of the CXCR4 inhibitor AMD3100 (dashed line) could partially antagonize this proliferation induction after 96h. <b><i>(b)</i> Migration of T3M4 cancer cells in a wound-healing assay.</b> Substantial effect of hyperglycemia on the migration of cancer cells: a rapid direct effect of elevated glucose level was found. There was no striking effect of conditioned PSC culture mediums on T3M4 cell migration. <b><i>(c)</i> Western blot analyses of key signaling molecules in T3M4 cells.</b> Cancer cells were exposed to hyperglycemia or different conditioned PSC culture medium. Best representative images of key signaling molecules of the cancer cells are indicated in WB membranes. Ponceau staining was used to assess the equal loading of gels. Significant (p<0.05) differences are indicated.*</p

CXCL12 (<i>a</i>) and IGFBP2 (<i>b</i>) protein levels in RLT-PSC cell culture supernatant with ELISA assesment after exposure to hyperglycemia and/or subsequent TGF-β1 treatment.

<p>CXCL12 level was significantly increased in PSC cell culture after exposure to CHG while 48h TGF-β1 treatment with normal glucose concentration also resulted in more than 2-fold increase <b><i>(a</i>)</b>. IGFBP2 protein level was increased in the cell culture medium after exposure to either CHG or TGF-β1. This alteration was only significant when PSCs were exposed to TGF-β1 subsequently after the CHG exposure. <b><i>(b)</i>.</b> Significant differences (p<0.05) are indicated*</p

Summary of signaling pathways induced by chronic hyperglycemia in human pancreatic stellate cells and PaC cells.

<p>These results suggest a role of metabolic factors in PSC activation that may provide profibrogenic stimuli to a lesser extent proliferation signals in these stromal cells. Hyperglycemia also induced a cancer-associated secretion pattern of PSCs that may alter the pancreatic tumor microenvironment. Increased p38 phosphorylation may play an important role and CDC25/SP1 may convey the signals in the PSC nucleus that results in increased secretion of CXCL12 and IGFBP2 that may have an effect on pancreatic cancer cells.</p

Series of Western blot experiments assessing key signaling molecule proteins from cell lysates of RLT-PSC cells.

<p>PSCs were exposed to CHG and/or to subsequent TGF-β1 treatment. Best representative images of key signaling molecules of the stellate cells are indicated in Western blot membranes. Ponceau staining was used to assess the equal loading of gels. Significant (p<0.05)* and highly significant differences (p<0.001)** are marked.</p