SCALOP: Results of a randomized phase II study of induction chemotherapy followed by gemcitabine (G) or capecitabine (Cap) based chemoradiation (CRT) in locally advanced pancreatic cancer (LANPC).

LBA146 Background: CRT with G or 5FU (F) is used to treat LAPC. No multicenter, randomized studies have compared G-CRT vs. F-CRT or the oral fluropyrimidine, Cap-CRT. In the UK, where chemotherapy is traditionally standard of care for LAPC, a trial was conducted to assess the safety, efficacy, and deliverability of G-CRT and Cap-CRT. Methods: Eligibility: histologically proven inoperable LAPC < 7 cm in diameter. Induction chemotherapy: 3 cycles of GEMCAP (G 1,000 mg/m2 days 1, 8, 15; Cap 830 mg/m2 days 1-21 q28 days). Patients with stable/responding disease, tumor diameter ≤ 6cm, and PS 0-1 were eligible for CRT randomisation where patients received a further cycle of GEMCAP followed by either Cap (830 mg/m2 bd weekdays only) or G (300 mg/m2 weekly) with radiation (50.4 Gy/28 fractions). Treatment volume = tumour plus enlarged nodes and margins of 2 cm sup-inf and 1.5 cm radially. Prospective RT quality assurance was mandated. Primary end-point was 9-month PFS (Fleming’s design). Funder: Cancer Research UK (CR UK 07/040). Results: Between July 2009 and October 2011, 114 patients from 28 UK centres were registered of whom 74 patients were randomised. Randomised patient characteristics: median age 64.6; 55.4% male; WHO PS (0:1) 41.9%:58.1%; median tumor diameter 4cm; site (head:body) 85.1%:14.9%. During CRT, more patients in the G arm experienced grade 3/4 haematological (18.4% vs 0%, p=0.007) and non-haematological (26.3% vs 11.1%, p=0.095) toxicity. Both C and G arms passed the primary endpoint with 9-month PFS of 62.9% (80% CIs: 50.6%-73.9%) and 51.4% (80% CIs: 39.4%-63.4%) respectively. OS was significantly superior in the Cap-CRT arm (median OS 15.2 vs 13.4 months, HR=0.50, log rank p=0.025). Conclusions: SCALOP is the largest RCT comparing radio-sensitizers in pancreatic cancer and demonstrates that both G-CRT and Cap-CRT can be delivered safely and effectively. Both regimens met the pre-specified PFS criteria. Compared to G-CRT, Cap-CRT demonstrated significantly better survival and toxicity and should form the template regimen for future trials investigating RT dose escalation and combination with novel radio-sensitizers. Clinical trial information: NCT01032057.

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A phase I study of olaparib in combination with capecitabine-based chemoradiation (CRT) in patients (pts) with locally advanced pancreatic cancer (LAPC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.709 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 709-709

Author(s):

T.R. Jeffry Evans ◽

Martin McKinlay Eatock ◽

Liz-Anne Lewsley ◽

Caroline Kelly ◽

Elaine McCartney ◽

...

Keyword(s):

Partial Response ◽

Induction Chemotherapy ◽

Stable Disease ◽

Excision Repair ◽

Critical Role ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Hair Follicles ◽

Tumor Diameter ◽

Grade 3

709 Background: Olaparib is a potent inhibitor of PARP-1, which has a critical role in signalling DNA single strand breaks (SSB) as part of the base excision repair pathway, and may have radio-sensitizing effects due to impaired resolution of radiation induced SSB. We hypothesize that O may potentiate the effects of X-CRT in pts with LAPC. Methods: Eligible pts with LAPC, ECOG < 1, tumor diameter < 6cm, with stable disease (SD) or response after 12 weeks’ induction chemotherapy, were treated with 1 of 4 escalating doses of O given bid po starting on day -3, and then in combination with X (830 mg/m2 bid) and radiation (50·4 Gy in 28 fractions) all administered Mon-Fri. Dose limiting toxicities (DLT) were determined on clinical and lab toxicity assessments (NCI-CTC AE v4.03) performed weekly from the start of O until completion of O plus X-CRT (i.e. 6 weeks). Dose escalation continued with a rolling-six design until the Maximum Tolerated Dose (MTD) was reached. Blood samples for PK analyses of O and PD measurement (inhibition of PARP activity) were collected on day -3 (O monotherapy) and during week 1 of O + X-CRT. Results: 18 pts, (9 m, 9 f, ECOG 0/1 [n=6/12]), age range 49-81 (median=70) years, with histologic (14) or cytologic (4) proven LAPC, had received induction chemotherapy with gemcitabine [GEM] (n=2), GEM + X (12), or FOLFIRINOX (3) with partial response (n=4) or stable disease (14). Pts received 50 (3), 100 (4), 150 (6), or 200 (5) mgs bid of O with X+CRT. DLTs were observed in 2 pts (both at 200mgs bid): 1 pt with grade 3 nausea (on optimal anti-emetics) and grade 3 fatigue, 1 pt with grade 3 anorexia. 6 pts were subsequently recruited at 150mgs bid with no DLTs. No pts had complete response, 2 pts had partial response (1 pt each at 100 and 150 mgs bid) and 1 pt (at 100 mgs bid) had progressive disease; the remaining 14 pts had SD. Conclusions: The recommended dose (RP2) of O is 150mgs bid when given in combination with X + CRT in LAPC. Recruitment of up to 12 pts with borderline operable LAPC at the RP2 is ongoing. PK analyses of O, PD studies (PARP inhibition – PBMCs; cytokeratin 18 – serum; γH2AX foci – hair follicles), and exploratory predictive marker studies (tumor – NGS; RNA exome sequencing) are ongoing. Clinical trial information: ISRCTN10361292.

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Phase II Study of Induction Chemotherapy with Gemcitabine plus 5-Fluorouracil Followed by Gemcitabine-Based Concurrent Chemoradiotherapy for Unresectable Locally Advanced Pancreatic Cancer

Tumori Journal ◽

10.1177/030089160609200603 ◽

2006 ◽

Vol 92 (6) ◽

pp. 481-486 ◽

Cited By ~ 11

Author(s):

Ender Kurt ◽

Meral Kurt ◽

Ozkan Kanat ◽

Sibel Kahraman Cetintas ◽

Sevilcan Aygun ◽

...

Keyword(s):

Pancreatic Cancer ◽

Induction Chemotherapy ◽

Concurrent Chemoradiotherapy ◽

External Beam Radiotherapy ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Progression Free Survival ◽

Locally Advanced Pancreatic Cancer ◽

Disease Stabilization ◽

Grade 3

Aims and background To evaluate the efficacy and tolerability of a new treatment approach including induction chemotherapy (CT) and concurrent chemoradiotherapy (CRT) in unresectable, locally advanced pancreatic cancer (LAPC). Patients and methods Twenty-four patients with LAPC were enrolled in the study. They first received induction CT consisting of 5-fluorouracil (5FU) (500 mg/m2) and gemcitabine (1000 mg/m2), which were given weekly for 3 weeks of every 4. Patients showing a response or disease stabilization after 2 cycles of induction CT received CRT consisting of external beam radiotherapy (50.4-54 Gy in fractions of 1.8 Gy/day) and gemcitabine (350 mg/m2, weekly for 6 weeks). Patients without disease progression received 2 additional cycles of CT consisting of 5FU plus gemcitabine with the same doses and schedule as given in the induction CT. Results After the end of the study, 2 (8%) and 5 (21%) patients showed complete and partial responses, respectively. Five patients (21%) had disease stabilization. The grade 3 and 4 toxicities associated with CT were neutropenia (21%) and thrombocytopenia (4%). The grade 3 and 4 toxicities occurring in patients who received CRT were neutropenia (24%), thrombocytopenia (24%), diarrhea (18%), and nausea (12%). The median progression-free survival for all patients was 6 months (95% CI, 3.6-8.4), and the median overall survival was 11 months (95% CI, 8.16-13.84). Conclusions The CRT approach of this study is moderately active and has an acceptable toxicity profile. However, the incor-poration of combination CT into CRT at the present schedule could not produce any additional benefit over CRT alone. Newer agents with more systemic activity are clearly warranted.

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A Critical Overview of Systematic Reviews of Chemotherapy for Advanced and Locally Advanced Pancreatic Cancer using both AMSTAR2 and ROBIS as Quality Assessment Tools

Reviews on Recent Clinical Trials ◽

10.2174/1574887115666200902111510 ◽

2020 ◽

Vol 15 ◽

Author(s):

Amit Dang ◽

Surendar Chidirala ◽

Prashanth Veeranki ◽

BN Vallish

Keyword(s):

Pancreatic Cancer ◽

High Risk ◽

Systematic Reviews ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Risk Of Bias ◽

Low Risk ◽

Locally Advanced Pancreatic Cancer ◽

Grade 3 ◽

Critical Overview

Background: We performed a critical overview of published systematic reviews (SRs) of chemotherapy for advanced and locally advanced pancreatic cancer, and evaluated their quality using AMSTAR2 and ROBIS tools. Materials and Methods: PubMed and Cochrane Central Library were searched for SRs on 13th June 2020. SRs with metaanalysis which included only randomized controlled trials and that had assessed chemotherapy as one of the treatment arms were included. The outcome measures, which were looked into, were progression-free survival (PFS), overall survival (OS), and adverse events (AEs) of grade 3 or above. Two reviewers independently assessed all the SRs with both ROBIS and AMSTAR2. Results: Out of the 1,879 identified records, 26 SRs were included for the overview. Most SRs had concluded that gemcitabine-based combination regimes, prolonged OS and PFS, but increased the incidence of grade 3-4 toxicities, when compared to gemcitabine monotherapy, but survival benefits were not consistent when gemcitabine was combined with molecular targeted agents. As per ROBIS, 24/26 SRs had high risk of bias, with only 1/26 SR having low risk of bias. As per AMSTAR2, 25/26 SRs had critically low, and 1/26 SR had low, confidence in the results. The study which scored ‘low’ risk of bias in ROBIS scored ‘low confidence in results’ in AMSTAR2. The inter-rater reliability for scoring the overall confidence in the SRs with AMSTAR2 and the overall domain in ROBIS was substantial; ROBIS: kappa=0.785, SEM=0.207, p<0.001; AMSTAR2: kappa=0.649, SEM=0.323, p<0.001. Conclusion: Gemcitabine-based combination regimens can prolong OS and PFS but also worsen AEs when compared to gemcitabine monotherapy. The included SRs have an overall low methodological quality and high risk of bias as per AMSTAR2 and ROBIS respectively.

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Irreversible Electroporation (IRE) in Locally Advanced Pancreatic Cancer: A Review of Current Clinical Outcomes, Mechanism of Action and Opportunities for Synergistic Therapy

Journal of Clinical Medicine ◽

10.3390/jcm10081609 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1609

Author(s):

Zainab L. Rai ◽

Roger Feakins ◽

Laura J. Pallett ◽

Derek Manas ◽

Brian R. Davidson

Keyword(s):

Pancreatic Cancer ◽

Mechanism Of Action ◽

Locally Advanced ◽

Irreversible Electroporation ◽

Advanced Pancreatic Cancer ◽

Standard Of Care ◽

Locally Advanced Pancreatic Cancer ◽

Animal Data ◽

Standard Of Care Treatment ◽

Apoptosis And Necrosis

Locally advanced pancreatic cancer (LAPC) accounts for 30% of patients with pancreatic cancer. Irreversible electroporation (IRE) is a novel cancer treatment that may improve survival and quality of life in LAPC. This narrative review will provide a perspective on the clinical experience of pancreas IRE therapy, explore the evidence for the mode of action, assess treatment complications, and propose strategies for augmenting IRE response. A systematic search was performed using PubMed regarding the clinical use and safety profile of IRE on pancreatic cancer, post-IRE sequential histological changes, associated immune response, and synergistic therapies. Animal data demonstrate that IRE induces both apoptosis and necrosis followed by fibrosis. Major complications may result from IRE; procedure related mortality is up to 2%, with an average morbidity as high as 36%. Nevertheless, prospective and retrospective studies suggest that IRE treatment may increase median overall survival of LAPC to as much as 30 months and provide preliminary data justifying the well-designed trials currently underway, comparing IRE to the standard of care treatment. The mechanism of action of IRE remains unknown, and there is a lack of data on treatment variables and efficiency in humans. There is emerging data suggesting that IRE can be augmented with synergistic therapies such as immunotherapy.

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Advanced pancreatic cancer: The standard of care and new opportunities

Oncology Reviews ◽

10.4081/oncol.2018.370 ◽

2018 ◽

Cited By ~ 2

Author(s):

Amrallah A. Mohammad

Keyword(s):

Pancreatic Cancer ◽

Mortality Rate ◽

Cancer Treatment ◽

Molecular Analysis ◽

Therapeutic Approach ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Standard Of Care

Presentation of pancreatic cancer is localized, locally advanced or metastatic. With the later represented the main bulk (more than 80%). Despite the significant innovation in molecular analysis and therapeutic approach in many types of cancer in the last two decades, still the outcome of advanced pancreatic cancer is disappointing and the mortality rate approximately unchanged. In this mandated review we intended to highlight the standard of care and emerging agents for advanced pancreatic cancer treatment.

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Prognostic impact of chemoradiation-related lymphopenia in patients with locally advanced pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.439 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 439-439

Author(s):

Daniel W Kim ◽

Grace Lee ◽

Colin D. Weekes ◽

David P. Ryan ◽

Aparna Raj Parikh ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cox Model ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Pancreatic Head ◽

Locally Advanced Pancreatic Cancer ◽

Ductal Adenocarcinoma ◽

Prognostic Impact ◽

Entire Cohort ◽

Grade 3

439 Background: Chemoradiation (CRT) induced lymphopenia is common and associated with poorer survival in multiple solid malignancies. The objective of this study was to evaluate the prognostic impact of lymphopenia in patients with nonmetastatic, unresectable pancreatic ductal adenocarcinoma (PDAC) treated by neoadjuvant FOLFIRINOX (5-fluorouracil [5FU]/leucovorin/irinotecan/oxaliplatin) followed by CRT. We hypothesized that severe lymphopenia would correlate with worse survival. Methods: The inclusion criteria for this single-institution retrospective study were: 1) biopsy-proven diagnosis of unresectable PDAC, 2) absence of distant metastasis, 3) receipt of neoadjuvant FOLFIRINOX followed by CRT, and 4) absolute lymphocyte count (ALC) available prior to and two months after initiating CRT. In general, CRT consisted of 5FU or capecitabine and RT with 58.8 Gy over 28 fractions. Lymphopenia was graded according to CTCAE v5.0. The primary variable of interest was lymphopenia at two months, dichotomized by ALC of < 0.5/μl (Grade 3 lymphopenia). The primary endpoint was overall survival (OS). Cox modeling and Kaplan-Meier methods were used to perform survival analyses. Results: A total of 138 patients were identified. Median follow-up for the entire cohort was 16 months. Median age was 65. Fifty-six percent were female, 86% were Caucasian, and 97% had ECOG ≤1. Median tumor size was 3.8 cm. Tumor location was pancreatic head in 63%, body in 22%, tail in 8%, and neck in 7%. Median baseline ALC for the entire cohort was 1.5 k/ul. Two months after initiating CRT, 106 (77%) had severe (Grade 3 or worse) lymphopenia. While there were no significant differences in baseline patient or disease characteristics, patients with severe lymphopenia received higher doses of RT with longer duration of treatment compared to those without severe lymphopenia. On multivariable Cox model, severe lymphopenia at two months was significantly associated with increased hazards of death (HR = 4.00 [95% CI 2.03-7.89], p < 0.001). Greater number of neoadjuvant FOLFIRINOX cycles received prior to CRT was associated with lower hazards of death (HR = 0.84 [95% CI 0.77-0.92], p < 0.001). The 12-month OS was 73% vs. 90% in the cohort with vs. without severe lymphopenia, respectively (log-rank p < 0.001). Conclusions: Treatment-related lymphopenia is common and severe lymphopenia may be a prognostic marker of poorer survival in locally advanced pancreatic cancer. Closer observation in high-risk patients and minimization of RT dose and duration are potential approaches to mitigating CRT-related lymphopenia. Our findings also suggest an important role of the host immunity in pancreatic cancer outcomes, supporting the ongoing efforts of immunotherapy trials in pancreatic cancer.

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