Fabienne Portales

Introduction: Stereotactic MR-guided Adaptive RadioTherapy (SMART) is a novel process to treat pancreatic tumors. We present an update of the data from our prospective registry of SMART for pancreatic tumors. Materials and methods: After the establishment of the SMART indication in a multidisciplinary board, we included all patients treated for pancreatic tumors. Primary endpoints were acute and late toxicities. Secondary endpoints were survival outcomes (local control, overall survival, distant metastasis free survival) and dosimetric advantages of adaptive process on targets volumes and OAR. Results: We included seventy consecutive patients in our cohort between October 2019 and April 2022. The prescribed dose was 50 Gy in 5 consecutive fractions. No severe acute SMART related toxicity was noted. Acute and late Grade ≤ 2 gastro intestinal were low. Daily adaptation significantly improved PTV and GTV coverage as well as OAR sparing. With a median follow-up of 10.8 months since SMART completion, the median OS, 6-months OS, and 1-year OS were 20.9 months, 86.7% (95% CI: (75–93%), and 68.6% (95% CI: (53–80%), respectively, from SMART completion. Local control at 6 months, 1 year, and 2 years were, respectively, 96.8 % (95% CI: 88–99%), 86.5 (95% CI: 68–95%), and 80.7% (95% CI: 59–92%). There was no grade > 2 late toxicities. Locally Advanced Pancreatic Cancers (LAPC) and Borderline Resectable Pancreatic Cancers (BRPC) patients (52 patients) had a median OS, 6-months OS, and 1-year OS from SMART completion of 15.2 months, 84.4% (95% CI: (70–92%)), and 60.5% (95% CI: (42–75%)), respectively. The median OS, 1-year OS, and 2-year OS from initiation of induction chemotherapy were 22.3 months, 91% (95% CI: (78–97%)), and 45.8% (95% CI: (27–63%)), respectively. Twenty patients underwent surgical resection (38.7 % of patients with initially LAPC) with negative margins (R0). Conclusion: To our knowledge, this is the largest series of SMART for pancreatic tumors. The treatment was well tolerated with only low-grade toxicities. Long-term OS and LC rates were achieved. SMART achieved high secondary resection rates in LAPC patients.

Circulating tumor cells (CTCs) are promising diagnostic and prognostic tools for clinical use. In several cancers, including colorectal and breast, the CTC load has been associated with a therapeutic response as well as progression-free and overall survival. However, counting and isolating CTCs remains sub-optimal because they are currently largely identified by epithelial markers such as EpCAM. New, complementary CTC surface markers are therefore urgently needed. We previously demonstrated that a splice variant of CD44, CD44 variable alternative exon 6 (CD44v6), is highly and specifically expressed by CTC cell lines derived from blood samples in colorectal cancer (CRC) patients. Two different approaches—immune detection coupled with magnetic beads and fluorescence-activated cell sorting—were optimized to purify CTCs from patient blood samples based on high expressions of CD44v6. We revealed the potential of the CD44v6 as a complementary marker to EpCAM to detect and purify CTCs in colorectal cancer blood samples. Furthermore, this marker is not restricted to colorectal cancer since CD44v6 is also expressed on CTCs from breast cancer patients. Overall, these results strongly suggest that CD44v6 could be useful to enumerate and purify CTCs from cancers of different origins, paving the way to more efficacious combined markers that encompass CTC heterogeneity.

At time of diagnosis, less than 10% of patients with pancreatic adenocarcinomas (PDAC) are considered to be immediately operable (i.e. resectable). Considering their poor overall survival (OS), only tumours without vascular invasion (NCCN 2017) should be considered for resection, i.e. those for which resection with disease-free margins (R0) is theoretically possible in absence of presurgery treatment. With regard to high R1 rates and undetectable locoregional and/or metastatic spreading prior to surgery explain (at least in part) the observed 1-year relapse and mortality rates of 50 and 25%, respectively. Today, upfront surgery followed by adjuvant chemotherapy is the reference treatment in Europe. The main limitation of the adjuvant approach is the low rate of completion of the full therapeutic sequence. Indeed, only 47 to 60% patients received any adjuvant therapy after resection compared to more than 75% for neoadjuvant therapy. No previous prospective study has compared this approach to a neoadjuvant FOLFIRINOX or FOLFOX chemotherapy for resectable PDAC. PANACHE01-PRODIGE48 is a prospective multicentre controlled randomized non comparative Phase II trial, evaluating the safety and efficacy of two regimens of neo-adjuvant chemotherapy (4 cycles of mFOLFIRINOX or FOLFOX) relative to the current reference treatment (surgery and then adjuvant chemotherapy) in patients with resectable PDAC. The main co-primary endpoints are OS rate at 12 months and the rate of patients undergoing the full therapeutic sequence. The “ideal” cancer treatment for resectable PDAC would have the following characteristics: administration to the highest possible proportion of patients, ability to identify fast-progressing patients (i.e. poor candidates for surgery), a low rate of R1 resections (through optimisation of local disease control), and an acceptable toxicity profile. The neoadjuvant approach may meet all these criteria. With respect to published data on the efficacy of FOLFOX and mFOLFIRINOX, these two regimens are potential candidates for neoadjuvant use in the aim to optimising oncological outcomes in resectable PDAC. ClinicalTrials.gov , NCT02959879 . Trial registration date: November 9, 2016.

E15048 Background: Efficacy results of Folfox or Folfiri chemotherapies (CT) are not different as 1^st line in mCRC patients, alone or with targeted therapies. No data reported on progression-free survival (PFS) of 1^st line Folfiri after Folfox-based adjuvant CT and of 2^nd line Folfiri-based CT after a Folfox-based 1^st line. The objective was to evaluate the efficacy of a Folfiri-based CT after adjuvant or 1^stline Folfox-based treatment. Methods: 210 of 568 pts from a mCRC database were retrospectively selected and divided in 2 cohorts: pts who received adjuvant Folfox then Folfiri as 1^st line treatment (n = 76, AdjF) and those treated with Folfox as 1^st line treatment then Folfiri 2^nd line (n = 134, FFox). PFS1 was the time from beginning of Folfox to 1^st progression and PFS2 the time from the Irinotecan-based CT to 2^ndprogression. Results: Median age was 62 (22-80). 49.3% pts had synchronous liver (72%) metastases. Primary tumour was right and left colon in 22% and 70% patients. Primary tumour was resected in 91% pts (98.7% and 86.6% in the AdjF and FFox groups, p= 0.003). KRASand BRAF-mutated status were found in 21.8% and 4.7% pts. In the AdjF group, pts received Folfiri as 1^st line combined with Bevacizumab (Beva) or anti-EGFR therapy (Cetuximab or Panitumumab) in 70% and 13% cases. In the FFox group, 1^st line Folfox-based CT was associated with Beva and anti-EGFRs in 7 and 6% pts, and 2^ndline Folfiri-based CT with Beva or Aflibercept in 51 and 4% pts, and with anti-EGFRs in 7.5%. Median duration of a therapeutic line was 5 months (0-29.8). Grade 3-4 toxicities were for the AdjF and FFox groups respectively, diarrhea 13/15%, neutropenia (febrile) 16(7)/37%(1%) and neuropathy 24/18%. Response rates were 55.3% and 68.7% in the AdjF and FFox groups. Median PFS1 were 14 (95%CI:10-16) and 10 (95%CI:8-11) months in the AdjF and FFox groups, and PFS2 10 (95%CI:8-11) and 7 (95%CI:6-9) months, respectively. Median overall survival was 43 (95%CI:39-50) and 33 months (95%CI:26-36) respectively. Conclusions: Results in terms of survival are in favor of the AdjFFox group. It would be interesting to identify a subgroup of pts rapidly progressing after adjuvant Folfox, who might show the same profile than pts in the FFox group.

Purpose This single-arm, phase II trial evaluated nab-paclitaxel monotherapy in pretreated patients with metastatic colorectal cancer (mCRC). Methods Patients with mCRC (RAS wild-type and RAS mutant cohorts) received nab-paclitaxel 125 mg/m² days 1, 8, and 15 (28-day cycle). The primary endpoint was investigator-assessed progression-free survival (PFS) rate at week 8; secondary endpoints included overall survival, overall response rate, and safety. Stage 1 planned enrollment was 15 patients per cohort per Simon 2-stage design. Stage 2 enrollment was to continue unless ≤8 of the first 15 patients per cohort achieved PFS at 8 weeks. Results Stage 1 enrolled 41 patients (RAS wild type: n = 18; RAS mutant: n = 23). In both RAS cohorts, 3 of 15 patients initially enrolled were progression-free at week 8 (20%; 95% CI 4.0–48.0). Median PFS was 8.1 weeks (95% CI 7.7–8.6) and 7.9 weeks (95% CI 7.6–8.0) for RAS wild-type and RAS mutant cohorts, respectively. There were no complete or partial responses. The overall disease control rate was 16% (95% CI 6.0–32.0), and rates were similar in the RAS wild-type and RAS mutant cohorts (18 and 15%, respectively). No new safety signals were reported; the most common grade ≥3 adverse events included neutropenia, asthenia, and peripheral neuropathy. This study did not progress to stage 2 per the preplanned statistical stopping rule. Conclusions In patients with heavily pretreated mCRC, nab-paclitaxel did not demonstrate promising antitumor activity; further assessment of nab-paclitaxel monotherapy in this population of patients is not supported. Trial registration NCT02103062.

E15708 Background: Pancreatic cancer (PC) has a poor prognostic. Only patients who undergo a complete R0 surgery have longer survival rates. Treatment of locally-advanced (LA) and borderline (BL) PC is controversial. Folfirinox is considered as a standard first-line treatment in metastatic patients. The aim of our study was to evaluate the impact of Folfirinox in LA and BL PC. Methods: We performed a retrospective analysis of prospectively-collected data from LA and BL PC patients treated with original Folfirinox in our institution between January 2010 and February 2015. Results: 35 patients were enrolled, 20 (57.1%) pancreatic head adenocarcinoma, 19 (54.3%) LA and 16 (45.7%) BL PC. There were 54.3% male, median age was 60 [44-74]. OMS was 0, 1, 2 for 21 (61.8%), 11 (32.4%), 2 (5.9%) patients. Median CA19.9 level was 5N [1-33]. All patients had Folfirinox in first-line followed by radiochemotherapy (RTCT) in 23 (65.7%) patients, with Gemzar and Xeloda in 21 and 2 patients. Median number of chemotherapy cycles was 4 [1-13]. The grade 3-4 toxicity rate was 17.1% (n = 6), mainly digestive (67%), hematologic (16.7%), none neurologic. There was no toxic death. 17 (46%) patients underwent surgery, 7 LA and 10 BL, with a R0 resection in 13 patients, mainly 8 PT3 (57.1%), no PT0, and 14N+. The morbidity rate was 40%, including 3 fistulae and 2 hemorrhages. Median overall survival was 24 months (95%CI: 14-44): 53 (95%CI: 26-.) and 12 months (95%CI: 9-19) in surgery vs no-surgery patients (p< 0.001). Progression-free survival was 13.9 months (95%CI: 11.2-17.1): 16.2 (95%CI: 13.7-25.3) and 9.5 (95%CI: 7.4-15.9) months in surgery vsno-surgery patients. 13 patients were still alive at the time of analysis, with a median follow-up of 44 months (95%CI: 7-53). 30 patients had disease progression, locally, distant or both in 7 (24.1%), 20 (69.0%) and 3 (13.1%) patients. Weight loss, OMS status, abdominal pain and CA19.9 level at diagnosis were not correlated with better survival. Conclusions: Folfirinox, followed or not by RTCT, as inductive treatment for LA and BL PC is feasible with acceptable toxicity, and allowed resectability in 37.1% patients, and thus a longer survival. Further studies are needed to confirm these encouraging results.

E15688 Background: FOLFIRINOX (FFX) and nab-paclitaxel/gemcitabine (AG) showed significant improvement in efficacy compared to gemcitabine alone in metastatic pancreatic cancer (mPC). Alternating AG and FFX may overcome resistance to primary therapy and delay tumor progression. We designed a multicenter phase I-II trial with a new sequential regimen of AG followed by FFX in first-line treatment of mPC. The phase I primary objective was to determine the recommended AG and FFX doses. Primary endpoint was to determine the dose-limiting toxicities (DLTs). The phase II will assess the efficacy of the recommended doses. Methods: AG and FFX were administered sequentially, each AG cycle followed by a FFX cycle. Dose-escalation is shown in the table below. Chemotherapeutic agents were administered according to standard practice, except for Gemcitabine (10 mg/m²/min). Results: From September 2013 to October 2015, 33 mPC patients were included: 7, 6 and 7 patients in levels 1, 2a and 2b, respectively, and 13 in level 3. 31 patients were evaluable for tolerance (2 not evaluable at levels 1 and 2b). Patients’ characteristics at baseline were: male 54.8%, median age 61 years (42-75), ECOG PS 0 (35.5%) or 1 (64.5%). Five DLTs were reported: 1, 2 and 2 in levels 2a, 2b and 3, respectively. All DLTs were grade 4 transient, asymptomatic neutropenia with spontaneous resolution. They occurred at treatment initiation, probably due to the absence of prophylactic GCSF treatment during AG administration. There was no limiting neurotoxicity. Promising efficacy results (response and survival) will be presented at the meeting. Conclusions: This new regimen alternating AG and FFX shows acceptable toxicity and promising efficacy results.The recommended dose (level 3) is being confirmed in a 12 patient-expansion cohort before starting the phase II accrual. Supporter: This project is supported by CELGENE. The authors thank the participating teams. Clinical trial information: NCT01964287.

3549 Background: The two-stage surgical resection (TSR) of bilobar colorectal liver metastases (CRLM) is widely used and has shown encouraging survival results. The risk of drop-out after the first-stage hepatectomy remains high and associated with poor survival rates. Our objective was to evaluate the predictive factors of long-term survival, based on the pathologic response to an intensified systemic chemotherapy administered preoperatively. Methods: Data from 899 patients treated for CRLM in our institution were collected prospectively between January 2003 and August 2013. We evaluated the pathologic response to preoperative chemotherapy, and its impact on the second-stage completion and on survival. The Tumour Regression Grade (TRG), the Blazer grade, and the modified-TRG were used to classify patients as responders (TRG and mTRG 1-3, Blazer 0-1) or non-responders (TRG and mTRG 4-5, Blazer 2) after the first stage Results: Sixty-seven patients were eligible for the TSR first stage. All patients underwent an intensified chemotherapy in combination with a biotherapy (Bevacizumab or Cetuximab) in 38cases. Responders in the three classifications (TRG: p = 0.033; mTRG: p = 0.03, Blazer: p = 0.005), and initial metastases number (p = 0.001) were independent predictive factors for the second-stage completion. Triple chemotherapy was significantly associated with responders in the three classifications (TRG and mTRG: 73.7% versus 26.3% p < 0.0001 ; Blazer : 84.2% versus 15.8% p = 0.001). Median overall survival (OS) of patients who completed TSR was significantly different (44, 84 versus 18,39 months; p < 0.0001). Conclusions: A good pathologic response to intensified preoperative chemotherapy is associated with completion of the second stage of TSR, and thus with a longer survival. Knowing this response before the first-stage resection may allow avoiding useless resections for patients who will not benefit from this strategy. Updated relapse-free survival and OS and particular patterns of pathologic response will be presented for this meeting.

2073 Background: Brain metastases (BM) are quite rare and not well-documented in gastro-intestinal (GI) cancers. This prospective multicenter cohort study aimed to assess the overall survival (OS) in GI cancer patients with BM. Methods: From 2012 to 2014, 147 patients with synchronous or metachronous BM from histologically-proven GI primary tumors (PT) from 15 French centers were included. OS was defined as the time from BM diagnosis until death. Results: Patients were mainly women (64.6%); median age was 65.5 [28-92]. Histology was adenocarcinoma in 138 pts (95.8%). PT sites were mainly colorectal (71.9%), gastroesophageal (GE) (17.1%), biliary tract (7.6%). Initial staging was T3-T4 in 87 pts (65.5%), positive nodal status in 74 pts (55.2%). 61 pts (44.5) were M0, 75 pts (55.6%) were metastatic with 1, 2 or 3 sites in 42.2%, 36.3% and 21.5 %. Extra-cerebral metastases (ECM) were mostly lung (63.7%) and liver (59.3%). Median time between PT diagnosis and BM occurrence was 25.9 months [1.3-243.2]. 89 pts (60.5%) had PT or ECM progression. BM were unilateral in 62.5% patients, cerebral, cerebellar or both in 59.3%, 12.1% and 28.6%, respectively. BM management was anti-oedematic agents in 120 pts (84.5%), surgery in 25 pts (17.6%), whole-brain or stereotaxic radiotherapy in respectively 78 (54.1%) and 23 pts (16.0%). After a median follow-up of 28.7 months [0-32], median OS was 6.6 months [4.5-8.3]. Median OS was significantly higher in patients who underwent BM surgery, 12.1 (95%CI: 7.2-18.0) vs 4.6 (95%CI: 3.6-7.2) months (p= 0.010), in patients with WHO performance status 0-1 (8.4; 95%CI: 6.6-11.3) vs 2 (3.3; 95%CI: 2.4-5.9) (p= 0.001), and for cerebral (8.7; 95%CI: 5.9-12.3) vs cerebellar (4.6; 95%CI: 1.3-7.2) vs both (3.7; 95%CI: 2.4-7.5) localization (p= 0.013). In multivariate analysis, only BM localization was a significant prognostic factor for OS (HR = 1.7 and 1.8 for cerebellar and both localizations, p= 0.0168). Conclusions: Our study confirms that BM surgery improves poor survival of GI cancer patients with BM. Management and treatment of BM should be discussed in multidisciplinary meetings in regards of the prognostic factors identified, especially BM localization and PS. Authors thank the GERCOR for operational support.