Publications by authors named "Andrés Cervantes"

189 Publications

Radiomics and radiogenomics in head and neck squamous cell carcinoma: Potential contribution to patient management and challenges.

Cancer Treat Rev 2021 Jul 26;99:102263. Epub 2021 Jul 26.

Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain. Electronic address:

The application of imaging biomarkers in oncology is still in its infancy, but with the expansion of radiomics and radiogenomics a revolution is expected in this field. This may be of special interest in head and neck cancer, since it can promote precision medicine and personalization of treatment by overcoming several intrinsic obstacles in this pathology. Our goal is to provide the medical oncologist with the basis to approach these disciplines and appreciate their main uses in clinical research and clinical practice in the medium term. Aligned with this objective we analyzed the most relevant studies in the field, also highlighting novel opportunities and current challenges.
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http://dx.doi.org/10.1016/j.ctrv.2021.102263DOI Listing
July 2021

Retrospective Study of Regorafenib Versus TAS-102 Efficacy and Safety in Chemorefractory Metastatic Colorectal Cancer (mCRC) Patients: A Multi-institution Real Life Clinical Data.

Clin Colorectal Cancer 2021 Jun 10. Epub 2021 Jun 10.

Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", 80131, Naples, Italy. Electronic address:

Introduction: There have been significant developments in colorectal cancer (CRC) research over the last few years, with the introduction of new agents that have been prolonged median overall survival of metastatic colorectal cancer (mCRC). These therapies have improved patient outcomes; however, despite significant progress in strategies for cancer treatment, their use is limited by development of resistant mechanism. Almost 30% of patients with refractory mCRC will remain good candidates for further treatment. Regorafenib and TAS-102 are novel antitumor agents for patients with refractory mCRC. However, it is unclear which patients may derive a survival benefit from these drugs in real-life clinical practice.

Methods: We performed a retrospective analysis evaluating safety and efficacy of TAS-102 and regorafenib in a cohort of refractory mCRC patients, in 3 different centers between January 1 2018 and May 31 2020, with the aim of assessing the optimal sequence treatment for these 2 drugs.

Results: One hundred and forty mCRC patients were included in the analysis. Of these patients, 64 received regorafenib and 76 received TAS-102 as first treatment. After progression, in the regorafenib 24 (37%) patients switched to secondary treatment with TAS-102, instead, in the TAS-102 group, among 76 patients, 29 (45%) patients switched to secondary treatment with regorafenib. Disease control was achieved in 8 (12.5%) of 64 patients in the regorafenib group and 17 (22.4%) of 76 patients in the TAS-102 group. In terms of efficacy, the PFS and OS were similar in both treatment groups for primary and secondary treatments. AEs reported in this analysis were mostly consistent with the known safety profiles of regorafenib and TAS-102 in previous clinical trials.

Conclusion: The present study is the first one to compare the activity of the two agents in a large cohort of chemo-refractory mCRC patients providing more details about the best sequence, to be incorporated in clinical practice.
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http://dx.doi.org/10.1016/j.clcc.2021.06.002DOI Listing
June 2021

Peritoneal invasion and metachronous peritoneal metastases after colon cancer surgery: The role of homogeneous, reliable assessment and confounders.

Eur J Surg Oncol 2021 Jun 29. Epub 2021 Jun 29.

Department of Haematology and Medical Oncology, Hospital Clinico Universitario, University of Valencia, Valencia, Spain.

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http://dx.doi.org/10.1016/j.ejso.2021.06.031DOI Listing
June 2021

First-in-human phase 1 study of budigalimab, an anti-PD-1 inhibitor, in patients with non-small cell lung cancer and head and neck squamous cell carcinoma.

Cancer Immunol Immunother 2021 Jul 3. Epub 2021 Jul 3.

START Madrid-FJD, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain.

Background: Budigalimab is a humanized, recombinant immunoglobulin G1 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We present the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic data from patients enrolled in the head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) expansion cohorts of the phase 1 first-in-human study of budigalimab monotherapy (NCT03000257; registered 15 December 2016).

Patients And Methods: Patients with recurrent/metastatic HNSCC or locally advanced/metastatic NSCLC naive to PD-1/PD-1-ligand inhibitors were enrolled; patients were not selected on the basis of oncogene driver mutations or PD-L1 status. Budigalimab was administered at 250 mg intravenously Q2W or 500 mg intravenously Q4W until disease progression/unacceptable toxicity. The primary endpoints were safety and PK; the secondary endpoint was efficacy. Exploratory endpoints included biomarker assessments.

Results: In total, 81 patients were enrolled (HNSCC: N = 41 [PD-L1 positive: n = 19]; NSCLC: N = 40 [PD-L1 positive: n = 16]); median treatment duration was 72 days (range, 1-617) and 71 days (range, 1-490) for the HNSCC and NSCLC cohorts, respectively. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (HNSCC: n = 9, 22%; NSCLC: n = 5, 13%). Both dosing regimens had comparable drug exposure and increased interferon gamma-induced chemokines, monokine induced by gamma interferon, and interferon-gamma-inducible protein 10. Objective response rates were 13% (90% CI, 5.1-24.5) in the HNSCC cohort and 19% (90% CI, 9.2-32.6) in the NSCLC cohort. Median progression-free survival was 3.6 months (95% CI, 1.7-4.7) and 1.9 months (95% CI, 1.7-3.7) in the HNSCC and NSCLC cohorts.

Conclusions: The safety, efficacy and biomarker profiles of budigalimab are similar to other PD-1 inhibitors. Development of budigalimab in combination with novel anticancer agents is ongoing.
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http://dx.doi.org/10.1007/s00262-021-02973-wDOI Listing
July 2021

Effects of exogenous α-amylases, glucoamylases, and proteases on ruminal in vitro dry matter and starch digestibility, gas production, and volatile fatty acids of mature dent corn grain.

Transl Anim Sci 2021 Jan 28;5(1):txaa222. Epub 2020 Nov 28.

Department of Animal Sciences, University of Florida, Gainesville, FL.

Two separate experiments were carried out to evaluate the effects of incremental doses of 10 exogenous endo-acting α-amylase and exo-acting glucoamylase; 1LAT (bacterial α-amylase), 2AK, 3AC, 4Cs4, 5Trga, 6Afuga, 7Fvga, and 10Tg (fungal α-amylases, glucoamylases, and α-glucosidase), 8Star and 9Syn (fungal amylase-mixtures; experiment 1) and three exogenous proteases; 11P14L, 12P7L, and 13P30L (bacterial proteases; experiment 2) on in vitro dry matter digestibility (IVDMD) and in vitro starch digestibility (IVSD) of mature dent corn grain using a batch culture system. Incremental doses of the exogenous enzymes (0, 0.25, 0.50, 0.75, and 1.00 mg/g of dried substrate) were applied directly to the substrate (0.5 g of ground corn, 4 mm) in sextuplicate (experiment 1) or quadruplicate (experiment 2) within F57 filter bags, which were incubated at 39 °C in buffered rumen fluid for 7 h. Rumen fluid was collected 2-3 h after the morning feeding from three lactating dairy cows and pooled. Cows were consuming a midlactation total mixed ration (TMR; 1.60 Mcal/kg DM and 15.4%; net energy of lactation and crude protein, respectively). Three independent runs were carried out for each experiment. Data were analyzed as a randomized complete block design using run as the blocking factor. Dose was used as a fixed factor while run was considered a random factor. Linear, quadratic, and cubic orthogonal contrasts were also tested. In experiment 1, enzymes 2AK, 3AC, and 10Tg did not increase ( > 0.10) IVDMD and IVSD, whereas 0.25 mg of enzymes 1LAT, 5Trga, and 8Star increased ( < 0.01) IVDMD by 23%, 47%, and 62% and IVSD by 35%, 41%, and 58%, respectively, compared with the control. Enzymes 4Cs4, 6Afuga, 7Fvga, and 9Syn linearly increased IVDMD and IVSD ( < 0.01). Greatest increases in IVDMD (82.9%) and IVSD (85.9%) resulted with 1 mg of 6Afuga compared to control. In experiment 2, the lowest dose of exogenous proteases 11P14L and 12P7L increased ( < 0.01) IVDMD by 98% and 87% and IVSD by 57% and 64%, respectively, whereas the highest dose of 13P30L increased ( = 0.02) IVDMD by 44.8% and IVSD by 30%, relative to the control. In conclusion, IVSD and IVDMD were increased by one α-amylase, certain glucoamylases, and all proteases tested, with the glucoamylase 6Afuga in experiment 1 and the neutral protease 12P7L in experiment 2, increasing IVDMD and IVSD to the greater extents. Future in vivo studies are required to validate these findings before these enzyme additives can be recommended for improving the digestibility of mature dent corn grain.
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http://dx.doi.org/10.1093/tas/txaa222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205108PMC
January 2021

Epigenetic Mechanisms Are Involved in the Oncogenic Properties of in Colorectal Cancer.

Cancers (Basel) 2021 Mar 21;13(6). Epub 2021 Mar 21.

Institute of Health Research, INCLIVA, 46010 Valencia, Spain.

The gene, which is up-regulated in colorectal cancer, plays a role in cell dissemination and metastasis. It encodes a zinc-finger protein, which interacts with histone methyltransferases G9A and EZH2. The expression of the two major mRNA isoforms 1 (coding for the full protein) and 2 was quantified by RT-qPCR in a cohort of 66 patients. The effects of silencing on the transcriptome of DLD1 and HCT116 cells were analysed by Clariom-S assays and validated by RT-qPCR. The recruitment of methyltransferases and the presence of H3K27me3 were studied by chromatin immunoprecipitation (ChIP). The ratio (isoform 2)/(isoform 1) negatively correlated with the relapsing of disease. The study of the transcriptome of DLD1 and HCT116 cells revealed that many genes affected by silencing are related to cancer. After crossing these results with the list of genes affected by silencing the histone methyltransferases (retrieved in silico), five genes were selected. ChIP analysis revealed that the recruitment of EZH2 is -dependent in , and ; the level of H3K27me3 changes in accordance. G9A also binds and in a -dependent manner. The results highlight the importance of epigenetics in cancer and open a novel therapeutic possibility, as inhibition of histone methyltransferases may reverse the disease-linked histone marks.
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http://dx.doi.org/10.3390/cancers13061433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004037PMC
March 2021

Gut vascular barrier impairment leads to intestinal bacteria dissemination and colorectal cancer metastasis to liver.

Cancer Cell 2021 May 1;39(5):708-724.e11. Epub 2021 Apr 1.

IRCCS Humanitas Research Hospital, via Manzoni 56, Rozzano, Milan 20089, Italy.

Metastasis is facilitated by the formation of a "premetastatic niche," which is fostered by primary tumor-derived factors. Colorectal cancer (CRC) metastasizes mainly to the liver. We show that the premetastatic niche in the liver is induced by bacteria dissemination from primary CRC. We report that tumor-resident bacteria Escherichia coli disrupt the gut vascular barrier (GVB), an anatomical structure controlling bacterial dissemination along the gut-liver axis, depending on the virulence regulator VirF. Upon GVB impairment, bacteria disseminate to the liver, boost the formation of a premetastatic niche, and favor the recruitment of metastatic cells. In training and validation cohorts of CRC patients, we find that the increased levels of PV-1, a marker of impaired GVB, is associated with liver bacteria dissemination and metachronous distant metastases. Thus, PV-1 is a prognostic marker for CRC distant recurrence and vascular impairment, leading to liver metastases.
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http://dx.doi.org/10.1016/j.ccell.2021.03.004DOI Listing
May 2021

Circulating Tumor DNA Detection by Digital-Droplet PCR in Pancreatic Ductal Adenocarcinoma: A Systematic Review.

Cancers (Basel) 2021 Feb 27;13(5). Epub 2021 Feb 27.

Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain.

Pancreatic cancer (PC) is one of the most devastating malignant tumors, being the seventh leading cause of cancer-related death worldwide. Researchers and clinicians are endeavoring to develop strategies for the early detection of the disease and the improvement of treatment results. Adequate biopsy is still challenging because of the pancreas's poor anatomic location. Recently, circulating tumor DNA (ctDNA) could be identified as a liquid biopsy tool with huge potential as a non-invasive biomarker in early diagnosis, prognosis and management of PC. ctDNA is released from apoptotic and necrotic cancer cells, as well as from living tumor cells and even circulating tumor cells, and it can reveal genetic and epigenetic alterations with tumor-specific and individual mutation and methylation profiles. However, ctDNA sensibility remains a limitation and the accuracy of ctDNA as a biomarker for PC is relatively low and cannot be currently used as a screening or diagnostic tool. Increasing evidence suggests that ctDNA is an interesting biomarker for predictive or prognosis studies, evaluating minimal residual disease, longitudinal follow-up and treatment management. Promising results have been published and therefore the objective of our review is to understand the current role and the future perspectives of ctDNA in PC.
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http://dx.doi.org/10.3390/cancers13050994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956845PMC
February 2021

Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial.

Lancet Oncol 2021 01 7;22(1):29-42. Epub 2020 Dec 7.

Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands. Electronic address:

Background: Systemic relapses remain a major problem in locally advanced rectal cancer. Using short-course radiotherapy followed by chemotherapy and delayed surgery, the Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation (RAPIDO) trial aimed to reduce distant metastases without compromising locoregional control.

Methods: In this multicentre, open-label, randomised, controlled, phase 3 trial, participants were recruited from 54 centres in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, and the USA. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, had a biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocarcinoma, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for chemotherapy, and could be assessed for staging within 5 weeks before randomisation. Eligible participants were randomly assigned (1:1), using a management system with a randomly varying block design (each block size randomly chosen to contain two to four allocations), stratified by centre, ECOG performance status, cT stage, and cN stage, to either the experimental or standard of care group. All investigators remained masked for the primary endpoint until a prespecified number of events was reached. Patients allocated to the experimental treatment group received short-course radiotherapy (5 × 5 Gy over a maximum of 8 days) followed by six cycles of CAPOX chemotherapy (capecitabine 1000 mg/m orally twice daily on days 1-14, oxaliplatin 130 mg/m intravenously on day 1, and a chemotherapy-free interval between days 15-21) or nine cycles of FOLFOX4 (oxaliplatin 85 mg/m intravenously on day 1, leucovorin [folinic acid] 200 mg/m intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m intravenously and fluorouracil 600 mg/m intravenously for 22 h on days 1 and 2, and a chemotherapy-free interval between days 3-14) followed by total mesorectal excision. Choice of CAPOX or FOLFOX4 was per physician discretion or hospital policy. Patients allocated to the standard of care group received 28 daily fractions of 1·8 Gy up to 50·4 Gy or 25 fractions of 2·0 Gy up to 50·0 Gy (per physician discretion or hospital policy), with concomitant twice-daily oral capecitabine 825 mg/m followed by total mesorectal excision and, if stipulated by hospital policy, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4. The primary endpoint was 3-year disease-related treatment failure, defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death, assessed in the intention-to-treat population. Safety was assessed by intention to treat. This study is registered with the EudraCT, 2010-023957-12, and ClinicalTrials.gov, NCT01558921, and is now complete.

Findings: Between June 21, 2011, and June 2, 2016, 920 patients were enrolled and randomly assigned to a treatment, of whom 912 were eligible (462 in the experimental group; 450 in the standard of care group). Median follow-up was 4·6 years (IQR 3·5-5·5). At 3 years after randomisation, the cumulative probability of disease-related treatment failure was 23·7% (95% CI 19·8-27·6) in the experimental group versus 30·4% (26·1-34·6) in the standard of care group (hazard ratio 0·75, 95% CI 0·60-0·95; p=0·019). The most common grade 3 or higher adverse event during preoperative therapy in both groups was diarrhoea (81 [18%] of 460 patients in the experimental group and 41 [9%] of 441 in the standard of care group) and neurological toxicity during adjuvant chemotherapy in the standard of care group (16 [9%] of 187 patients). Serious adverse events occurred in 177 (38%) of 460 participants in the experimental group and, in the standard of care group, in 87 (34%) of 254 patients without adjuvant chemotherapy and in 64 (34%) of 187 with adjuvant chemotherapy. Treatment-related deaths occurred in four participants in the experimental group (one cardiac arrest, one pulmonary embolism, two infectious complications) and in four participants in the standard of care group (one pulmonary embolism, one neutropenic sepsis, one aspiration, one suicide due to severe depression).

Interpretation: The observed decreased probability of disease-related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting. Therefore, the experimental treatment can be considered as a new standard of care in high-risk locally advanced rectal cancer.

Funding: Dutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network.
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http://dx.doi.org/10.1016/S1470-2045(20)30555-6DOI Listing
January 2021

Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer.

Cancers (Basel) 2020 Dec 3;12(12). Epub 2020 Dec 3.

Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010 Valencia, Spain.

Most clinical practice guidelines recommend a selective approach for rectal cancer after clinical staging. In low-risk patients, upfront surgery may be an appropriate option. However, in patients with MRI-defined high-risk features such as extramural vascular invasion, multiple nodal involvement or T4 and/or tumors close to or invading the mesorectal fascia, a more intensive preoperative approach is recommended, which may include neoadjuvant or preoperative chemotherapy. The potential benefits include better compliance than postoperative chemotherapy, a higher pathological complete remission rate, which facilitates a non-surgical approach, and earlier treatment of micrometastatic disease with improved disease-free survival compared to standard preoperative chemoradiation or short-course radiation. Two recently reported phase III randomized trials, RAPIDO and PRODIGE 23, show that adding neoadjuvant chemotherapy to either standard short-course radiation or standard long-course chemoradiation in locally advanced rectal cancer patients reduces the risk of metastasis and significantly prolongs disease-related treatment failure and disease-free survival. This review discusses these potentially practice-changing trials and how they may affect our current understanding of treating locally advanced rectal cancers.
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http://dx.doi.org/10.3390/cancers12123611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761666PMC
December 2020

Neoadjuvant treatment for locally advanced unresectable and borderline resectable pancreatic cancer: oncological outcomes at a single academic centre.

ESMO Open 2020 11;5(6):e000929

CIBERONC, Instituto de Salud Carlos III, Madrid, Comunidad de Madrid, Spain; Department of Medical Oncology, University of Valencia, Valencia, Spain. Electronic address:

Introduction: Pancreatic cancer (PC), even in the absence of metastatic disease, has a dismal prognosis. One-third of them are borderline resectable (BRPC) or locally advanced unresectable PC (LAUPC) at diagnosis. There are limited prospective data supporting the best approach on these tumours. Neoadjuvant chemotherapy (ChT) is being increasingly used in this setting.

Methods: This is a retrospective series of consecutive patients staged as BRPC or LAUPC after discussion in the multidisciplinary board (MDB) at an academic centre. All received neoadjuvant ChT, followed by chemoradiation (ChRT) in some cases, and those achieving enough downstaging had a curative-intent surgery. Descriptive data about patient's characteristics, neoadjuvant treatments, toxicities, curative resections, postoperative complications, pathology reports and adjuvant treatment were collected. Overall survival (OS) and progression-free survival was calculated with Kaplan-Meier method and log-rank test.

Results: Between August 2011 and July 2019, 49 patients fulfilled the inclusion criteria, and all of them received neoadjuvant ChT. Fluorouracil+folinic acid, irinotecan and oxaliplatin was the most frequently used scheme (77%). The most prevalent grade 3 or 4 toxicities were neutropenia (26.5%), neurotoxicity (12.2%), diarrhoea (8.2%) and nausea (8.2%). 18 patients (36.7%) received ChRT thereafter. In total, 22 patients (44,9%) became potentially resectable and 19 of them had an R0 or R1 pancreatic resection. One was found to be unresectable at surgery and two refused surgery. A vascular resection was required in 7 (35%). No postoperative deaths were observed. Postoperative ChT was given to 12 (66.7%) of resected patients. Median OS of the whole cohort was 24,9 months (95% CI 14.1 to 35.7), with 30.6 months for resected and 13.1 months for non-resected patients, respectively (p<0.001).

Conclusion: A neoadjuvant approach in BRPC and LAUPC was well tolerated and allowed a curative resection in 38.8% of them with a potential improvement on OS.
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http://dx.doi.org/10.1136/esmoopen-2020-000929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684818PMC
November 2020

Addition of nivolumab to chemotherapy in patients with advanced gastric cancer: a relevant step ahead, but still many questions to answer.

ESMO Open 2020 11;5(6):e001107

Department of Medical Oncology, Biomedical Research institute INCLIVA, University of Valencia, Valencia, Comunitat Valenciana, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Comunidad de Madrid, Spain. Electronic address:

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http://dx.doi.org/10.1136/esmoopen-2020-001107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677349PMC
November 2020

Aurora kinases in ovarian cancer.

ESMO Open 2020 10;5(5):e000718

Department of Medical Oncology, Hospital Clinico Universitario of Valencia, Biomedical Research Institute INCLIVA, CIBERONC and University of Valencia, Valencia, Spain.

Aurora kinases (AURK) are key regulators of the mitotic spindle formation. AURK is frequently overexpressed in ovarian cancer and this overexpression has been frequently associated with prognosis in these tumours. Interestingly, AURK have been shown to interact with DNA repair mechanisms and other cell cycle regulators. These functions have brought light to Aurora family as a potential target for anticancer therapy. In the last years, two clinical trials with different AURK inhibitors have shown activity in epithelial and clear-cell ovarian cancer. Although there is a lack of predictive factors of AURK inhibition activity, recent trials have identified some candidates. This review will focus in the functions of the AURK family, its role as prognostic factor in epithelial ovarian cancer and potential clinical implications.
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http://dx.doi.org/10.1136/esmoopen-2020-000718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580081PMC
October 2020

Association of Bevacizumab Plus Oxaliplatin-Based Chemotherapy With Disease-Free Survival and Overall Survival in Patients With Stage II Colon Cancer: A Secondary Analysis of the AVANT Trial.

JAMA Netw Open 2020 10 1;3(10):e2020425. Epub 2020 Oct 1.

Department of Medical Oncology, Franco-British Hospital-Fondation Cognacq-Jay, Levallois-Perret, France.

Importance: In the pivotal Bevacizumab-Avastin Adjuvant (AVANT) trial, patients with high-risk stage II colon cancer (CC) had 5-year and 10-year overall survival (OS) rates of 88% and 75%, respectively, with adjuvant fluorouracil and oxaliplatin-based chemotherapy; however, the trial did not demonstrate a disease-free survival (DFS) benefit of adding bevacizumab to oxaliplatin-based chemotherapy in stage III CC and suggested a detrimental effect on OS. The Long-term Survival AVANT (S-AVANT) study was designed to collect extended follow-up for patients in the AVANT trial.

Objective: To explore the efficacy of adjuvant bevacizumab combined with oxaliplatin-based chemotherapy in patients with high-risk, stage II CC.

Design, Setting, And Participants: This prespecified secondary end point analysis of the AVANT and S-AVANT studies included 573 patients with curatively resected high-risk stage II CC and at least 1 of the following criteria: stage T4, bowel obstruction or perforation, blood and/or lymphatic vascular invasion and/or perineural invasion, age younger than 50 years, or fewer than 12 nodes analyzed. The AVANT study was a multicenter randomized stage 3 clinical trial. Data were collected from December 2004 to February 2019, and data for this study were analyzed from March to September 2019.

Intervention: Patients were randomly assigned to receive 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4), FOLFOX4 with bevacizumab, or capecitabine and oxaliplatin (XELOX) with bevacizumab.

Main Outcomes And Measures: The primary end points of this secondary analysis were DFS and OS in patients with high-risk stage II CC.

Results: The AVANT study included 3451 patients, of whom 573 (16.6%) had high-risk stage II CC (192 [33.5%] randomized to FOLFOX4 group; 194 [33.9%] randomized to FOLFOX4 with bevacizumab group; 187 [32.6%] randomized to XELOX with bevacizumab group). With a median (interquartile range) age of 57.0 (47.2-65.7) years, the study population comprised 325 men (56.7%) and 248 women (43.3%). After a median (interquartile range) follow-up of 6.9 (6.1-11.3) years, the 3-year DFS and 5-year OS rates were 88.2% (95% CI, 83.7%-93.0%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 group, 86.6% (95% CI, 81.8%-91.6%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 with bevacizumab group, and 86.7% (95% CI, 81.8%-91.8%) and 93.2% (95% CI, 89.6%-97.0%) in the XELOX with bevacizumab group, respectively. The DFS hazard ratio was 0.94 (95% CI, 0.59-1.48; P = .78) for FOLFOX4 with bevacizumab vs FOLFOX4 and 1.07 (95% CI, 0.69-1.67; P = .76) for XELOX with bevacizumab vs FOLFOX4. The OS hazard ratio was 0.92 (95% CI, 0.55-1.55; P = .76) for FOLFOX4 with bevacizumab vs FOLFOX4 and 0.85 (95% CI, 0.50-1.44; P = .55) for XELOX with bevacizumab vs FOLFOX4.

Conclusions And Relevance: In this secondary analysis of data from the AVANT trial, adding bevacizumab to oxaliplatin-based chemotherapy was not associated with longer DFS or OS in patients with high-risk stage II CC. The findings suggest that the definition of high-risk stage II CC needs to be revisited.

Trial Registration: ClinicalTrial.gov Identifiers: AVANT (NCT00112918); S-AVANT (NCT02228668).
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http://dx.doi.org/10.1001/jamanetworkopen.2020.20425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573695PMC
October 2020

In the literature: October 2020.

ESMO Open 2020 10;5(5)

Department of Medical Oncology, Biomedical Research Institute INCLIVA, CiberOn, University of Valencia, Valencia, Spain

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http://dx.doi.org/10.1136/esmoopen-2020-001048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549462PMC
October 2020

Precision Medicine to Treat Advanced Gastroesophageal Adenocarcinoma: A Work in Progress.

J Clin Med 2020 Sep 22;9(9). Epub 2020 Sep 22.

Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Blasco Ibañez 17, 46010 Valencia, Spain.

Gastroesophageal adenocarcinoma (GEA) represents a heterogeneous disease and, when diagnosed as locally advanced or metastatic, it is characterized by poor prognosis. During the last few years, several molecular classifications have been proposed to try to personalize treatment for those patients diagnosed with advanced disease. Nevertheless, despite the great effort, precision medicine is still far from being a reality. The improvement in the molecular analysis due to the application of high throughput technologies based on DNA and RNA sequencing has opened a novel scenario leading to the personalization of treatment. The possibility to target epidermal growth factor receptor (HER)2, Claudine, Fibroblast Growth Factor Receptors (FGFR), and other alterations with a molecular matched therapy could significantly improve clinical outcomes over advanced gastric cancer patients. On the other hand, the development of immunotherapy could also represent a promising strategy in a selected population. In this review, we sought to describe the novel pathways implicated in GEA progression and the results of the molecular matched therapies.
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http://dx.doi.org/10.3390/jcm9093049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564841PMC
September 2020

Detection of postoperative plasma circulating tumour DNA and lack of CDX2 expression as markers of recurrence in patients with localised colon cancer.

ESMO Open 2020 09;5(5):e000847

Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain. Electronic address:

Background: Colon cancer (CC) is a heterogeneous disease. Novel prognostic factors beyond pathological staging are required to accurately identify patients at higher risk of relapse. Integrating these new biological factors, such as plasma circulating tumour DNA (ctDNA), CDX2 staining, inflammation-associated cytokines and transcriptomic consensus molecular subtypes (CMS) classification, into a multimodal approach may improve our accuracy in determining risk of recurrence.

Methods: One hundred and fifty patients consecutively diagnosed with localised CC were prospectively enrolled in our study. ctDNA was tracked to detect minimal residual disease by droplet digital PCR. CDX2 expression was analysed by immunostaining. Plasma levels of cytokines potentially involved in disease progression were measured using ELISAs. A 96 custom gene panel for nCounter assay was used to classify CC into colorectal cancer assigner and CMS.

Results: Most patients were classified into CMS4 (37%) and CMS2 (28%), followed by CMS1 (20%) and CMS3 (15%) groups. CDX2-negative tumours were enriched in CMS1 and CMS4 subtypes. In univariable analysis, prognosis was influenced by primary tumour location, stage, vascular and perineural invasion together with high interleukin-6 plasma levels at baseline, tumours belonging to CMS 1 vs CMS2 +CMS3, ctDNA presence in plasma and CDX2 loss. However, only positive ctDNA in plasma samples (HR 13.64; p=0.002) and lack of CDX2 expression (HR 23.12; p=0.001) were found to be independent prognostic factors for disease-free survival in the multivariable model.

Conclusions: ctDNA detection after surgery and lack of CDX2 expression identified patients at very high risk of recurrence in localised CC.
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http://dx.doi.org/10.1136/esmoopen-2020-000847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513635PMC
September 2020

Trends and outcome of neoadjuvant treatment for rectal cancer: A retrospective analysis and critical assessment of a 10-year prospective national registry on behalf of the Spanish Rectal Cancer Project.

Eur J Surg Oncol 2021 02 18;47(2):276-284. Epub 2020 Aug 18.

Colorectal Unit, Hospital Universitario y Politecnico La Fe, University of Valencia, Spain. Electronic address:

Introduction: Preoperative treatment and adequate surgery increase local control in rectal cancer. However, modalities and indications for neoadjuvant treatment may be controversial. Aim of this study was to assess the trends of preoperative treatment and outcomes in patients with rectal cancer included in the Rectal Cancer Registry of the Spanish Associations of Surgeons.

Method: This is a STROBE-compliant retrospective analysis of a prospective database. All patients operated on with curative intention included in the Rectal Cancer Registry were included. Analyses were performed to compare the use of neoadjuvant/adjuvant treatment in three timeframes: I)2006-2009; II)2010-2013; III)2014-2017. Survival analyses were run for 3-year survival in timeframes I-II.

Results: Out of 14,391 patients,8871 (61.6%) received neoadjuvant treatment. Long-course chemo/radiotherapy was the most used approach (79.9%), followed by short-course radiotherapy ± chemotherapy (7.6%). The use of neoadjuvant treatment for cancer of the upper third (15-11 cm) increased over time (31.5%vs 34.5%vs 38.6%,p = 0.0018). The complete regression rate slightly increased over time (15.6% vs 16% vs 18.5%; p = 0.0093); the proportion of patients with involved circumferential resection margins (CRM) went down from 8.2% to 7.3%and 5.5% (p = 0.0004). Neoadjuvant treatment significantly decreased positive CRM in lower third tumors (OR 0.71, 0.59-0.87, Cochrane-Mantel-Haenszel P = 0.0008). Most ypN0 patients also received adjuvant therapy. In MR-defined stage III patients, preoperative treatment was associated with significantly longer local-recurrence-free survival (p < 0.0001), and cancer-specific survival (p < 0.0001). The survival benefit was smaller in upper third cancers.

Conclusion: There was an increasing trend and a potential overuse of neoadjuvant treatment in cancer of the upper rectum. Most ypN0 patients received postoperative treatment. Involvement of CRM in lower third tumors was reduced after neoadjuvant treatment. Stage III and MRcN + benefited the most.
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http://dx.doi.org/10.1016/j.ejso.2020.04.056DOI Listing
February 2021

Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer.

Br J Cancer 2020 11 11;123(11):1590-1598. Epub 2020 Sep 11.

Sarah Cannon Research Institute/Tennessee Oncology, Drug Development Unit, 250 25th Ave., North Nashville, TN, 37203, USA.

Background: This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours.

Methods: Eligible patients received increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD × 3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD × 5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5 mg QD (39 patients), 40 mg QW (26 patients) or 30 mg QW (17 patients).

Results: Maximum tolerated doses of sapanisertib were 6 mg QD, 40 mg QW, 9 mg QD × 3dQW and 7 mg QD × 5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD × 3dQW/QD × 5dQW); expansion phase doses of 5 mg QD and 30 mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers.

Conclusions: Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer.

Clinical Trial Registration: ClinicalTrials.gov, NCT01058707.
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http://dx.doi.org/10.1038/s41416-020-01041-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686313PMC
November 2020

How we treat metastatic colorectal cancer.

ESMO Open 2020 08;4(Suppl 2):e000813

Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Campania, Italy. Electronic address:

Colorectal cancer is the second leading cause of cancer-related death worldwide. About 20% of patients suffer from metastatic disease at diagnosis, while about one-third of patients treated with curative intent relapsed. In these patients, an accurate staging allows to plan a treatment strategy within a multidisciplinary team in order to achieve predefined goals. Patient's clinical features, tumour characteristics and molecular profile ( and microsatellite instability (MSI) status) should be considered during the treatment choice. Combination of chemotherapy (fluoropyrimidines, oxaliplatin and irinotecan) plus biological agents (antiepidermal growth factor receptor or antiangiogenic drugs) in addition to surgery, could give a chance of cure in resectable or potentially resectable tumours. However, in never resectable tumours, disease control and prolonging survival should be the goal to achieve simultaneously with control of symptoms. In addition to standard therapies, especially in case of unresectable oligometastatic disease, several local ablative treatment are available. In later lines, when improving quality of life become predominant, regorafenib and trifluridine/tipiracil demonstrated survival benefit, while re-challenge therapies represent an option only in selected patients. In patients with -mutant tumour or with MSI, new therapies showed survival gain and probably will be a new piece in the treatment algorithm.
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http://dx.doi.org/10.1136/esmoopen-2020-000813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451280PMC
August 2020

In the literature: August 2020.

ESMO Open 2020 08;5(4)

Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain

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http://dx.doi.org/10.1136/esmoopen-2020-000909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437707PMC
August 2020

In the literature: June 2020.

ESMO Open 2020 07;5(4)

Department of Medical Oncology, Biomedical Research Institute INCLIVA, CiberOn, University of Valencia, Valencia, Spain

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http://dx.doi.org/10.1136/esmoopen-2020-000832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7342860PMC
July 2020

Computational Evaluation and In Vitro Validation of New Epidermal Growth Factor Receptor Inhibitors.

Curr Top Med Chem 2020 ;20(18):1628-1639

ProtoQSAR SL, European Center for Innovative Companies (CEEI), Valencia Technology Park, Avenida Benjamin Franklin 12, 46980 Paterna, Valencia, Spain.

Background: The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein that acts as a receptor of extracellular protein ligands of the epidermal growth factor (EGF/ErbB) family. It has been shown that EGFR is overexpressed by many tumours and correlates with poor prognosis. Therefore, EGFR can be considered as a very interesting therapeutic target for the treatment of a large variety of cancers such as lung, ovarian, endometrial, gastric, bladder and breast cancers, cervical adenocarcinoma, malignant melanoma and glioblastoma.

Methods: We have followed a structure-based virtual screening (SBVS) procedure with a library composed of several commercial collections of chemicals (615,462 compounds in total) and the 3D structure of EGFR obtained from the Protein Data Bank (PDB code: 1M17). The docking results from this campaign were then ranked according to the theoretical binding affinity of these molecules to EGFR, and compared with the binding affinity of erlotinib, a well-known EGFR inhibitor. A total of 23 top-rated commercial compounds displaying potential binding affinities similar or even better than erlotinib were selected for experimental evaluation. In vitro assays in different cell lines were performed. A preliminary test was carried out with a simple and standard quick cell proliferation assay kit, and six compounds showed significant activity when compared to positive control. Then, viability and cell proliferation of these compounds were further tested using a protocol based on propidium iodide (PI) and flow cytometry in HCT116, Caco-2 and H358 cell lines.

Results: The whole six compounds displayed good effects when compared with erlotinib at 30 μM. When reducing the concentration to 10μM, the activity of the 6 compounds depends on the cell line used: the six compounds showed inhibitory activity with HCT116, two compounds showed inhibition with Caco-2, and three compounds showed inhibitory effects with H358. At 2 μM, one compound showed inhibiting effects close to those from erlotinib.

Conclusion: Therefore, these compounds could be considered as potential primary hits, acting as promising starting points to expand the therapeutic options against a wide range of cancers.
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http://dx.doi.org/10.2174/1568026620666200603122726DOI Listing
May 2021

Unintentional injection of a dexamethasone implant into the crystalline lens: a case report.

Arq Bras Oftalmol 2020 06 29;83(3):246-249. Epub 2020 May 29.

Retina Department, Asociación para Evitar la Ceguera en México, Hospital Dr. Luis Sanchez Bulnes, Mexico City, Mexico.

The intravitreal dexamethasone implant is a sustained-release anti-inflammatory drug system that releases 0.7 mg of dexamethasone into the vitreous cavity. The following case report describes a rare complication: accidental injection of the dexamethasone implant into the crystalline lens. A 73-year-old woman was diagnosed with central retina vein occlusion and cystoid macular edema. Initial tSreatment included three monthly intravitreal doses of anti-vascular endothelial growth factor treatment, which was not successful. Treatment was then modified to an intravitreal dexamethasone implant. Ten weeks later, the implant was observed in the posterior cortex of the crystalline lens. Because no improvement had occurred, the patient underwent phacoemulsification surgery, during which part of the lens migrated into the vitreous cavity. Therefore, 23-gauge pars plana complete vitrectomy was performed with trans-surgical administration of intravitreal aflibercept. Crystalline lens injury due to an intravitreal dexamethasone implant is a rare complication and typically results from the injection procedure. Immediate surgical or conservative approaches should be considered on an individual basis.
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http://dx.doi.org/10.5935/0004-2749.20200066DOI Listing
June 2020

A phase 1b study of the MET inhibitor capmatinib combined with cetuximab in patients with MET-positive colorectal cancer who had progressed following anti-EGFR monoclonal antibody treatment.

Invest New Drugs 2020 12 14;38(6):1774-1783. Epub 2020 May 14.

Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

Background Overcoming resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) in patients with KRAS wildtype (WT) metastatic colorectal cancer (mCRC) could help meet the needs of patients with limited treatment options. Methods In this phase 1b study, patients with N/KRAS WT, MET-positive mCRC who had progressed following anti-EGFR mAb treatment received escalating oral doses of capmatinib (150, 300, and 400 mg) twice daily plus weekly intravenous cetuximab (at the approved dose). The primary objective was to establish a recommended dose for expansion (RDE) of capmatinib in combination with cetuximab. Safety, preliminary activity, pharmacokinetics, and pharmacodynamics were also explored. Results Thirteen patients were enrolled. No patients experienced a dose-limiting toxicity at investigated doses; the RDE was established as capmatinib 400 mg twice daily plus cetuximab. All patients experienced adverse events (AEs) suspected to be related to the study treatment. Five patients (38.5%) reported study-drug-related AEs of grade 3/4 in severity. No patients achieved a complete or partial response according to RECIST v1.1; however, tumor shrinkage of 29-44% was observed in 4 patients. Conclusions Capmatinib plus cetuximab was well tolerated. Preliminary signs of activity were observed. Further investigation is warranted to obtain efficacy data and refine predictive biomarkers of response. Clinical trial registration NCT02205398.
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http://dx.doi.org/10.1007/s10637-020-00928-zDOI Listing
December 2020

Editorial debate: Challenges we oncologists, working within a universal healthcare system, have to face in these hard times.

ESMO Open 2020 05;5(3):e000800

Dept. Medical Oncology, Biomedical Research institute INCLIVA, University of Valencia, Valencia, Spain. Electronic address:

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http://dx.doi.org/10.1136/esmoopen-2020-000800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211068PMC
May 2020

Personalized Medicine: Recent Progress in Cancer Therapy.

Cancers (Basel) 2020 Apr 19;12(4). Epub 2020 Apr 19.

Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain.

Translational research has revolutionized how we develop new treatments for cancer patients. The change from an organ-centric concept guiding treatment choice towards deep molecular analysis, driving a personalized approach, is one of the most important advances of modern oncology. Several tools such as next generation sequencing and RNA sequencing have greatly improved the capacity to detect predictive and prognostic molecular alterations. Detection of gene mutations, amplifications, and fusions has therefore altered the history of several diseases in both a localized and metastatic setting. This shift in perspective, in which attention is focused on the specific molecular alterations of the tumor, has opened the door to personalized treatment. This situation is reflected in the increasing number of basket trials selecting specific molecular targets. Nonetheless, some weaknesses need to be addressed. The complexity of cancer cells enriched with concomitant molecular alterations complicates identification of the driver. Moreover, tumor heterogeneity could be responsible for the lack of benefit when targeted agents are used. In light of this, there is growing interest in the role of multidisciplinary committees or molecular tumor boards to try to enhance selection. The aim of this review is to critically analyze the evolution of cancer treatment towards a precision approach, underlining some recent successes and unexpected failures.
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http://dx.doi.org/10.3390/cancers12041009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226371PMC
April 2020

In the literature: April 2020.

ESMO Open 2020 Apr;5(2)

Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain

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http://dx.doi.org/10.1136/esmoopen-2020-000749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204796PMC
April 2020

Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer - Results of the international randomized RAPIDO-trial.

Radiother Oncol 2020 06 30;147:75-83. Epub 2020 Mar 30.

Department of Medical Oncology, University of Groningen, University Medical Center Groningen, The Netherlands. Electronic address:

Background: Preoperative chemoradiotherapy (CRT) followed by total mesorectal excision is widely accepted as the standard of care for high-risk rectal cancer. Adjuvant chemotherapy is advised in several international guidelines, although the survival benefit remains unclear and compliance is poor. The current multidisciplinary approach has led to major improvements in local control, yet the occurrence of distant metastases has not decreased accordingly. The combination of short-course radiotherapy (SCRT) and chemotherapy in the waiting period before surgery might have several benefits, including higher compliance, downstaging and better effect of systemic therapy.

Methods: This is an investigator-initiated, international multicentre randomized phase III trial. High-risk rectal cancer patients were randomized to SCRT followed by chemotherapy (6 cycles CAPOX or alternatively 9 cycles FOLFOX4) and subsequent surgery, or long-course radiotherapy (25-28 × 2-1.8 Gy) with concomitant capecitabine followed by surgery and optional postoperative chemotherapy (8 cycles CAPOX or 12 cycles FOLFOX4) according to local institutions' policy. The primary endpoint is time to disease-related treatment failure. Here, we report the compliance, toxicity and postoperative complications in both study groups.

Findings: Between June 2011 and June 2016, 920 patients were enrolled. Of these, 901 were evaluable (460 in the experimental arm and 441 in the standard arm). All patients in the experimental arm received 5 × 5 Gy radiotherapy, and 84% of all patients received at least 75% of the prescribed chemotherapy. In the standard arm, the compliance for CRT was 93% and 58% for postoperative chemotherapy. Toxicity ≥grade 3 occurred in 48% of patients in the experimental arm, compared to 25% of patients in the standard arm during preoperative treatment and 35% of patients during postoperative chemotherapy. No statistically significant differences in surgical procedures or postoperative complications were observed.

Interpretation: High compliance (84%) of preoperative systemic treatment could be achieved with the experimental approach. Although considerable toxicity was observed during preoperative therapy, this did not lead to differences in surgical procedures or postoperative complications. Longer follow-up time is needed to assess the primary endpoint and related outcomes.
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http://dx.doi.org/10.1016/j.radonc.2020.03.011DOI Listing
June 2020
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