Pancreatic carcinoma is one of the leading causes of cancer-related mortality. At the time of diagnosis, 30% of patients present with a locally advanced pancreatic carcinoma (LAPC). As circulating ...tumor cells (CTCs) count may be a surrogate of the cancer metastatic abilities, CTC detection rates and prognostic value were studied in a prospective cohort of LAPC patients.
An LAP07 international multicenter randomized study assesses in patients whose LAPC is controlled after 4 months of chemotherapy whether chemoradiotherapy could increase survival versus continuation of chemotherapy. A subgroup of patients included in the LAP07 trial was screened for CTCs (CellSearch®) before the start of the chemotherapy and after 2 months of treatment. Patient characteristics and survival were obtained prospectively and were correlated with CTC detection.
Seventy-nine patients were included. One or more CTCs/7.5 ml were detected in 5% of patients before treatment and in 9% of patients after 2 months of treatment (overall detection rate: 11% of patients). CTC positivity was associated with poor tumor differentiation (P = 0.04), and with shorter overall survival (OS) in multivariable analysis (RR = 2.5, P = 0.01), together with anemia.
The evaluation of micrometastatic disease using CTC detection appears as a promising prognostic tool in LAPC patients.
The role of chemoradiation with systemic chemotherapy compared with chemotherapy alone in locally advanced pancreatic cancer (LAPC) is uncertain.
One hundred and nineteen patients with LAPC, World ...Health Organization performance status of zero to two were randomly assigned to either the induction CHRT group (60 Gy, 2 Gy/fraction; concomitant 5-fluorouracil infusion, 300 mg/m2/day, days 1–5 for 6 weeks; cisplatin, 20 mg/m2/day, days 1–5 during weeks 1 and 5) or the induction gemcitabine group (GEM: 1000 mg/m2 weekly for 7 weeks). Maintenance gemcitabine (1000 mg/m2 weekly, 3/4 weeks) was given in both arms until disease progression or toxicity.
Overall survival was shorter in the CHRT than in GEM arm median survival 8.6 (99% confidence interval 7.1–11.4) and 13 months (8.7–18.1), P = 0.03. One-year survival was, respectively, 32% and 53%. These results were confirmed in a per-protocol analysis for patients who received 75% or more of the planned dose of radiotherapy. More overall grades 3–4 toxic effects were recorded in the CHRT arm, both during induction (36 versus 22%) and maintenance (32 versus 18%).
This intensive induction schedule of CHRT was more toxic and less effective than gemcitabine alone.
Abstract Background Two phase III trials of neoadjuvant treatment in T3-4 rectal cancer established that adding chemotherapy (CRT) to radiotherapy (RT) improves pathological complete response (pCR) ...and local control (LC). We combined trials to assess the clinical benefit of CRT on overall (OS) and progression free survival (PFS) and to explore the surrogacy of pCR and LC. Patients and methods Individual patient data from European Organisation for Research and Treatment of Cancer (EORTC) 22921 (1011 patients) and FFCD 9203 (756 patients) were pooled. Meta-analysis methodology was used to compare neoadjuvant CRT to RT for OS, PFS LC and distant progression (DP). Weighted linear regression was used to estimate trial-level association (surrogacy R2 ) between treatment effects on candidate surrogate (pCR, LC, DP) and OS. Results The median follow-up was 5.6 years. Compared to RT (881 pts), CRT (886 pts) did not prolong OS, DP or PFS. The 5-y OS-rate was 66.3% with CRT versus 65.9% in RT (hazard ratios (HR) = 1.04 {0.88–1.21}). CRT significantly improved LC (HR = 0.54, 95% confidence interval (CI): 0.41–0.72). PFS was validated as surrogate for OS with R2 = 0.88. Neoadjuvant treatment effects on LC ( R2 = 0.17) or DP ( R2 = 0.31) did not predict effects on OS. Conclusion Preoperative CRT does not prolong OS or PFS. pCR or LC do not qualify as surrogate for PFS or OS while PFS is surrogate. Phase III trials should use OS or PFS as primary endpoint.
Abstract Objective To assess the impact of primary tumour resection on overall survival (OS) of patients diagnosed with stage IV colorectal cancer (CRC). Design Among the 294 patients with ...non-resectable colorectal metastases enrolled in the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 phase III trial, which compared different first-line single-agent chemotherapy regimens, 216 patients (73%) presented with synchronous metastases at study entry and constituted the present study population. Potential baseline prognostic variables including prior primary tumour resection were assessed by univariate and multivariate Cox analyses. Progression-free survival (PFS) and OS curves were compared with the logrank test. Results Among the 216 patients with stage IV CRC (median follow-up, 33 months), 156 patients (72%) had undergone resection of their primary tumour prior to study entry. The resection and non-resection groups did not differ for baseline characteristics except for primary tumour location (rectum, 14% versus 35%; p = 0.0006). In multivariate analysis, resection of the primary was the strongest independent prognostic factor for PFS (hazard ratio (HR), 0.5; 95% confidence interval CI, 0.4–0.8; p = 0.0002) and OS (HR, 0.4; CI, 0.3–0.6; p < 0.0001). Both median PFS (5.1 4.6–5.6 versus 2.9 2.2–4.1 months; p = 0.001) and OS (16.3 13.7–19.2 versus 9.6 7.4–12.5; p < 0.0001) were significantly higher in the resection group. These differences in patient survival were maintained after exclusion of patients with rectal primary ( n = 43). Conclusion Resection of the primary tumour may be associated with longer PFS and OS in patients with stage IV CRC starting first-line, single-agent chemotherapy.
Palliative care (PC) is integrated into standard oncology care. However, its clinical impact at the end of life remains unclear in pancreatic adenocarcinoma (PA). We aimed to describe the end-of-life ...care pathway and to assess whether PC referral influences survival after chemotherapy discontinuation (CD) among advanced PA patients.
This retrospective single-centre observational study was conducted among deceased patients with advanced PA who had received chemotherapy between January 1, 2016, and December 31, 2021. Baseline characteristics, the timing of PC referral and events after CD were collected. The primary outcome was time from CD to death.
Among the 148 included patients, 53.4% (n = 79) received PC, mostly late after the CD (n = 133, 89.9%), 16.9% (n = 25) received chemotherapy in the last 14 days of life and 75.6% died at the hospital. None received PC in the 8 weeks following the diagnosis. PC referral significantly increased PC department admissions (p < 0.001) and decreased medical unit admissions (p < 0.001). The median survival after the CD was 35 days (IQR: 19–64.5). PC referral was associated with increased survival after CD (HR: 0.65 0.47–0.90, p = 0.010, Cox) and after adjusting (HR: 0.65 0.42–0.99, p = 0.045, Cox).
The study suggests that PC may be associated with longer survival after CD in advanced PA patients. However, PC is underused, and patients are referred late in their care pathway.
This randomised, open-label, phase I/II study evaluated the efficacy and safety of nintedanib, an oral, triple angiokinase inhibitor, combined with chemotherapy, relative to bevacizumab plus ...chemotherapy as first-line therapy in patients with metastatic colorectal cancer (mCRC).
Patients with histologically confirmed mCRC (adenocarcinoma), an Eastern Cooperative Oncology Group performance status ≤2 and adequate organ function were included. Patients were randomised 2:1 to receive nintedanib 150 mg or 200 mg b.i.d. plus mFOLFOX6 (oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2 or d,l-leucovorin 400 mg/m2, 5-fluoruracil bolus 400 mg/m2 followed by 2400 mg/m2, every 2 weeks) or bevacizumab (5 mg/kg every 2 weeks) plus mFOLFOX6. During phase I, patients underwent a 3 + 3 dose-escalation schema to determine the maximum tolerated dose (MTD) of nintedanib in combination with mFOLFOX6. The primary end point was progression-free survival (PFS) rate at 9 months. Objective response (OR) was a secondary end point.
The nintedanib recommended phase II dose was 200 mg b.i.d. plus mFOLFOX6 based on safety data from phase I (n = 12). Of 128 patients randomised in the phase II part, 126 received treatment (nintedanib plus mFOLFOX6, n = 85; bevacizumab plus mFOLFOX6, n = 41). PFS at 9 months was 62.1% with nintedanib and 70.2% with bevacizumab difference: -8.1% (95% confidence interval -27.8 to 11.5). Confirmed ORs were recorded in 63.5% and 56.1% of patients in the nintedanib and bevacizumab groups, respectively. The incidence of adverse events (AEs) considered related to treatment was 98.8% with nintedanib and 97.6% with bevacizumab; the incidence of serious AEs was 37.6% with nintedanib and 53.7% with bevacizumab. The pharmacokinetics of nintedanib and the components of mFOLFOX6 were unaffected by their combination.
Nintedanib in combination with mFOLFOX6 showed efficacy as first-line therapy in patients with mCRC with a manageable safety profile and further studies in this population are warranted.
Abstract Response evaluation in solid tumours currently uses radiological imaging techniques to measure changes under treatment. Imaging requires a well-defined anatomical lesion to be viewed and ...relies on the measurement of a reduction in tumour size during treatment as the basis for presumed clinical benefit. However, with the development of anti-angiogenesis agents, anatomical imaging has became inappropriate as certain tumours would not reduce in size. Functional studies are therefore necessary and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), DCE-computed tomography (CT) and DCE-ultrasonography (US) are currently being evaluated for monitoring treatments. Diffusion-weighted MR imaging (DW-MRI) and magnetic resonance spectroscopy (MRS) are also capable of detecting changes in cell density and metabolite content within tumours. In this article, we review anatomical and functional criteria currently used for monitoring therapy. We review the published data on DCE-MRI, DCE-CT, DCE-US, DW-MRI and MRS. This literature review covers the following area: basic principles of the technique, clinical studies, reproducibility and repeatability, limits and perspectives in monitoring therapy. Anatomical criteria such as response evaluation criteria in solid tumours (RECIST) will require adaptation to employ not only new tools but also different complementary techniques such as functional imaging in order to monitor therapeutic effects of conventional and new anti-cancer agents.
Abstract Background FOLFIRINOX is a polychemotherapy regimen currently used to treat inoperable pancreatic cancer in patients with a good performance status (PS). FOLFIRINOX lengthens overall ...survival time (OS), but no specific data are available in elderly patients. Methods All cases of inoperable pancreatic adenocarcinoma in patients over 70 years old treated with FOLFIRINOX were retrospectively reviewed between 2008 and 2015 in five institutions in France. The primary objective was to evaluate the safety and efficacy of FOLFIRINOX in the elderly. Results Forty-two patients with a median age of 73 years (range: 70–79) and a median PS of 1 (range: 0–2) were included. 88% of patients treated with FOLFIRINOX were enrolled between 2012 and 2015. 24 patients (57%) needed a primary dose reduction but this did not impact OS (median OS 11.7 months (6.9–16.4) compared to 16.6 months (0.37–32.8) without dose reduction, p = 0.69). Twelve patients (29%) experienced grade 3 toxicity. Sensory neuropathy occurred most often (56%). Primary prophylaxis with granulocyte colony stimulating factor (GCSF) was administered to 14 patients (33%). One treatment-related death occurred (septic shock), although this patient had not had primary prophylaxis with GCSF. Median follow-up was 86 months. Median OS was 11.6 months (95%CI: 8.9–14.3). Conclusion Median OS observed in the elderly was similar to OS previously reported in younger patients in the ACCORD 11 trial. FOLFIRINOX is effective in selected, fit elderly patients but with greater grade 3 neurotoxicity. Primary dose reduction and primary GCSF prophylaxis may control tolerance.
After surgical resection of pancreatic ductal adenocarcinoma (PDAC), patients are predominantly treated with adjuvant chemotherapy, commonly consisting of gemcitabine (GEM)-based regimens or the ...modified FOLFIRINOX (mFFX) regimen. While mFFX regimen has been shown to be more effective than GEM-based regimens, it is also associated with higher toxicity. Current treatment decisions are based on patient performance status rather than on the molecular characteristics of the tumor. To address this gap, the goal of this study was to develop drug-specific transcriptomic signatures for personalized chemotherapy treatment.
We used PDAC datasets from preclinical models, encompassing chemotherapy response profiles for the mFFX regimen components. From them we identified specific gene transcripts associated with chemotherapy response. Three transcriptomic artificial intelligence signatures were obtained by combining independent component analysis and the least absolute shrinkage and selection operator-random forest approach. We integrated a previously developed GEM signature with three newly developed ones. The machine learning strategy employed to enhance these signatures incorporates transcriptomic features from the tumor microenvironment, leading to the development of the ‘Pancreas-View’ tool ultimately clinically validated in a cohort of 343 patients from the PRODIGE-24/CCTG PA6 trial.
Patients who were predicted to be sensitive to the administered drugs (n = 164; 47.8%) had longer disease-free survival (DFS) than the other patients. The median DFS in the mFFX-sensitive group treated with mFFX was 50.0 months stratified hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.21-0.44, P < 0.001 and 33.7 months (stratified HR 0.40, 95% CI 0.17-0.59, P < 0.001) in the GEM-sensitive group when treated with GEM. Comparatively patients with signature predictions unmatched with the treatments (n = 86; 25.1%) or those resistant to all drugs (n = 93; 27.1%) had shorter DFS (10.6 and 10.8 months, respectively).
This study presents a transcriptome-based tool that was developed using preclinical models and machine learning to accurately predict sensitivity to mFFX and GEM.
•Transcriptomic signatures were developed for key pancreatic cancer drugs to enable personalized treatment.•The Pancreas-View tool integrates four drug signatures to assist informed therapeutic decisions.•Signatures accurately identify high responder patients, indicative of improved DFS and cancer-specific survival.•Clinical validation involving a cohort of 343 patients confirms the efficacy of this signature approach.•Transcriptomic signatures that integrate predictors from preclinical models and machine learning offer a rationalized treatment strategy.
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