Phase II study of capecitabine-based concomitant chemoradiation followed by durvalumab as a neoadjuvant strategy in locally advanced rectal cancer: the PANDORA trial.

BACKGROUND: This study investigated the efficacy of chemoradiotherapy (CRT) followed by durvalumab as neoadjuvant therapy of locally advanced rectal cancer. PATIENTS AND METHODS: The PANDORA trial is a prospective, phase II, open-label, single-arm, multicenter study aimed at evaluating the efficacy and safety of preoperative treatment with durvalumab (1500 mg every 4 weeks for three administrations) following long-course radiotherapy (RT) plus concomitant capecitabine (5040 cGy RT in 25-28 fractions over 5 weeks and capecitabine administered at 825 mg/m2 twice daily). The primary endpoint was the pathological complete response (pCR) rate; secondary endpoints were the proportion of clinical complete remissions and safety. The sample size was estimated assuming a null pCR proportion of 0.15 and an alternative pCR proportion of 0.30 (α = 0.05, power = 0.80). The proposed treatment could be considered promising if ≥13 pCRs were observed in 55 patients (EudraCT: 2018-004758-39; NCT04083365). RESULTS: Between November 2019 and August 2021, 60 patients were accrued, of which 55 were assessable for the study's objectives. Two patients experienced disease progression during treatment. Nineteen out of 55 eligible patients achieved a pCR (34.5%, 95% confidence interval 22.2% to 48.6%). Regarding toxicity related to durvalumab, grade 3 adverse events (AEs) occurred in four patients (7.3%) (diarrhea, skin toxicity, transaminase increase, lipase increase, and pancolitis). Grade 4 toxicity was not observed. In 20 patients (36.4%), grade 1-2 AEs related to durvalumab were observed. The most common were endocrine toxicity (hyper/hypothyroidism), dermatologic toxicity (skin rash), and gastrointestinal toxicity (transaminase increase, nausea, diarrhea, constipation). CONCLUSION: This study met its primary endpoint showing that CRT followed by durvalumab could increase pCR with a safe toxicity profile. This combination is a promising, feasible strategy worthy of further investigation.

In-vivo evaluations of bone regenerative potential of two novel bioactive glasses.

Due to the aging of population, materials able to repair damaged tissues are needed. Among others, bioactive glasses (BGs) have attracted a lot of interest due to their outstanding properties both for hard and soft tissues. Here, for the first time, two new BGs, which gave very promising results in preliminary in vitro-tests, were implanted in animals in order to evaluate their regenerative potential. The new BGs, named BGMS10 and Bio_MS and containing specific therapeutic ions, were produced in granules and implanted in rabbits' femurs for up to 60 days, to test their biocompatibility and osteoconduction. Additionally, granules of 45S5 Bioglass® were employed and used as a standard reference for comparison. The results showed that, after 30 days, the two novel BGs and 45S5 displayed a similar behavior, in terms of bone amount, thickness of new bone trabeculae and affinity index. On the contrary, after 60 days, 45S5 granules were mainly surrounded by wide and scattered bone trabeculae, separated by large amounts of soft tissue, while in BGMS10 and Bio_MS the trabeculae were thin and uniformly distributed around the BG granules. This latter scenario could be considered as more advantageous, since the features of the two novel BG granules allowed for the neo-formation of a uniformly distributed bony trabeculae, predictive of more favorable mechanical behavior, compared to the less uniform coarse trabeculae, separated by large areas of soft tissue in 45S5 granules. Thus, BGMS10 and Bio_MS could be considered suitable products for tissue regeneration in the orthopedic and dental fields.

Impact of age and gender on the efficacy and safety of upfront therapy with panitumumab plus FOLFOX followed by panitumumab-based maintenance: a pre-specified subgroup analysis of the Valentino study.

BACKGROUND: The safety and efficacy outcome of elderly metastatic colorectal cancer (mCRC) patients fit enough to receive combination chemotherapy plus biological agents is an issue of growing interest. Also, gender-specific differential toxicity and efficacy of anti-epidermal growth factor receptor (EGFR)-based upfront treatments need to be explored. PATIENTS AND METHODS: Valentino was a multicenter, randomized, phase II trial, investigating two panitumumab-based maintenance strategies following first-line panitumumab plus FOLFOX in RAS wild-type mCRC patients. We carried out a subgroup analysis, aimed at assessing the differences in efficacy, safety and quality of life (QoL) according to age (<70 versus ≥70 years) and gender (male versus female). Efficacy endpoints were progression-free survival (PFS), overall survival (OS) and overall response rate (ORR); safety endpoints were rates of any grade and grade 3/4 adverse events (AEs). RESULTS: No significant differences in terms of PFS, OS and ORR were observed between patients aged <70 or ≥70 years and the effect of the maintenance treatment arm on survival outcomes was similar in the two subgroups. The safety profile of both induction and maintenance treatment and the impact on QoL were similar in elderly and younger patients. No significant differences in PFS, OS, ORR or clinical benefit rate were observed according to gender. A significantly higher rate of overall grade 3/4 AEs (P = 0.008) and of grade 3/4 thrombocytopenia (P = 0.017), any grade and grade 3/4 neutropenia (P < 0.0001) and any grade conjunctivitis (P = 0.033) was reported in female as compared to male patients. Conversely, we reported a significantly higher incidence of any grade skin rash (P = 0.0007) and hypomagnesemia (P = 0.029) in male patients. CONCLUSIONS: The upfront choice of an anti-EGFR-based doublet chemotherapy followed by a maintenance strategy represents a valuable option in RAS wild-type mCRC irrespective of gender and age, though a careful evaluation of patients to maximize the risk/benefit ratio is warranted.

Molecular determinants of clinical outcomes with pembrolizumab versus paclitaxel in a randomized, open-label, phase III trial in patients with gastroesophageal adenocarcinoma.

BACKGROUND: In the phase III KEYNOTE-061 trial (NCT02370498), pembrolizumab did not significantly improve overall survival versus paclitaxel as second-line therapy for gastric/gastroesophageal junction (GEJ) adenocarcinoma with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors. The association of tissue tumor mutational burden (tTMB) status and clinical outcomes was determined, including the relationship with CPS and microsatellite instability-high (MSI-H) status. PATIENTS AND METHODS: In patients with whole exome sequencing (WES) data [420/592 (71%); pembrolizumab, 218; paclitaxel, 202], the association of tTMB with objective response rate (ORR; logistic regression), progression-free survival (PFS; Cox proportional hazards regression), and overall survival (OS; Cox proportional hazards regression) were measured using one-sided (pembrolizumab) and two-sided [paclitaxel] P values. tTMB was also evaluated using FoundationOne®CDx [205/592 (35%)]. Prespecified equivalent cut-offs of 175 mut/exome for WES and 10 mut/Mb for FoundationOne®CDx were used. RESULTS: WES-tTMB was significantly associated with ORR, PFS, and OS in pembrolizumab-treated (all P < 0.001) but not paclitaxel-treated patients (all P > 0.6) in univariate analysis. The area under the receiver operating characteristics curve for WES-tTMB and response was 0.68 [95% confidence interval (CI) 0.56-0.81] for pembrolizumab and 0.51 (95% CI 0.39-0.63) for paclitaxel in univariate analysis. There was low correlation between WES-tTMB and CPS in both treatment groups (r ≤ 0.16). WES-tTMB remained significantly associated with all clinical endpoints with pembrolizumab after adjusting for CPS and with PFS and OS after excluding known MSI-H tumors (n = 26). FoundationOne®CDx-tTMB demonstrated a positive association with ORR, PFS, and OS in pembrolizumab-treated patients (all P ≤ 0.003) but not PFS or OS in paclitaxel-treated patients (P > 0.1). CONCLUSION: This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and efficacy with pembrolizumab but not paclitaxel in patients with gastric/GEJ adenocarcinoma in a randomized setting. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status.

Predictive role of microsatellite instability for PD-1 blockade in patients with advanced gastric cancer: a meta-analysis of randomized clinical trials.

BACKGROUND: Several post hoc analyses of randomized controlled trials (RCTs) suggested the importance of microsatellite instability (MSI) as a positive predictive factor to immunotherapy in patients with advanced gastric cancer (GC); however, individually these have low statistical power. METHODS: RCTs investigating treatment with or without an anti-programmed cell death protein 1 (PD-1) agent for advanced GC and providing outcome according to MSI status were selected. The hazard ratio (HR) and the odds ratio were used to compare the treatment effect on survival outcomes and tumor response, respectively, for anti-PD-1-based therapy compared with standard therapy. Evidence for treatment effect by MSI status was evaluated by a test of interaction. RESULTS: The phase III KEYNOTE-062, CheckMate-649, JAVELIN Gastric 100 and KEYNOTE-061 trials were included. A total of 2545 patients with evaluable MSI status were included and 123 (4.8%) had MSI-high cancers. The HR for overall survival benefit with anti-PD-1-based regimens was 0.34 (95% CI: 0.21-0.54) for MSI-high cancers versus 0.85 [95% confidence interval (CI): 0.71-1.00] for microsatellite stable. The treatment effect was significantly different in the two subgroups (P for interaction 0.003). In the MSI-high subgroup, the HR for progression-free survival was 0.57 (95% CI: 0.33-0.97; P = 0.04) and the odds ratio for response was 1.76 (95% CI: 1.10-2.83; P = 0.02). CONCLUSIONS: Patients with MSI-high GC should be regarded as a specific and highly immunosensitive population worthy of dedicated clinical trials.

The prognostic impact of primary tumour location in patients with stage II and stage III colon cancer receiving adjuvant therapy. A GISCAD analysis from three large randomised trials.

PURPOSE: Because the role of the primary tumour location in the adjuvant setting has not been clearly established in colon cancer, we analysed the clinical outcome according to the primary tumour location from three Italian trials assessing adjuvant therapy in colon cancer. PATIENTS AND METHODS: Overall survival (OS) and disease-free survival (DFS) were assessed globally and in each trial, according to right-sided, transverse and left-sided primary colon cancer. Analysis was planned to provide overall and stage-specific results. RESULTS: Individual data of 5239 patients were included in this analysis. The right-sided tumours were 1540 (29%), tumours originating in the transverse were 815 (16%) and left-sided tumours were 2884 (55%). At the multivariate analysis, DFS findings from the comparison of the right-sided versus left-sided tumours (hazard ratio [HR] = 1.00; 95% confidence interval [CI] = 0.89-1.14) were not statistically associated with clinical outcomes in the overall population. On the contrary, OS findings, from the comparison of the right-sided versus left-sided tumours, were significantly associated with outcomes (HR = 1.20; 95% CI = 1.04-1.39). In stage II patients, there was no difference in terms of DFS and OS among the three different tumour locations, whereas in stage III patients, the left-sided tumours showed an improved prognosis in terms of OS (HR: 1.36 95% CI = 1.14-1.62, p < 0.001). CONCLUSION: This is the largest analysis demonstrating a prognostic effect of the tumour location on patients with colon cancer receiving adjuvant chemotherapy. Nevertheless, the effect is limited to OS in stage III colon cancer. In stage II tumours, the primary location has a lesser impact. The transverse tumours should be prognostically considered in between the right-sided and left-sided tumours.

Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients bearing MGMT methylation.

Background: Non-randomized studies showed that temozolomide (TMZ) achieves an average 10% response rate in heavily pretreated metastatic colorectal cancer (mCRC) patients with promoter methylation of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT). In this phase II trial, irinotecan and temozolomide (TEMIRI) combination regimen was assessed in irinotecan-sensitive, MGMT methylated/microsatellite stable (MSS) pretreated mCRC patients. Patients and methods: Key inclusion criteria were centrally confirmed MGMT methylation by methylation-specific PCR, MSS mCRC, progression after at least two prior chemotherapy regimens for advanced disease and irinotecan-free interval >3 months. TEMIRI (TMZ 150 mg/m2 on days 1-5 plus irinotecan 100 mg/m2 on days 1, 15 q28 days) was administered for six cycles, followed by maintenance with TMZ. The primary end point was overall response rate (ORR). Exploratory translational analyses included MGMT immunohistochemistry (IHC) and methyl-BEAMing (MB). Results: Between December 2014 and June 2017, 25 patients were enrolled. The primary end point was met, since six patients achieved a partial response [ORR 24%, 95% confidence interval (CI) 11% to 43%]. At a median follow-up of 15.6 months, median progression-free survival (mPFS) and overall survival (mOS) were 4.4 and 13.8 months, respectively. Only four (16%) patients had ≥ grade 3 (CTCAE 4.0) adverse events. All patients whose cancer was MGMT-positive IHC were non-responders. Consistently, patients with MGMT-negative/low tumors had a significantly longer mPFS than others (6.9 versus 2.0 months; hazard ratio = 0.29, 95% CI 0.02-0.41; P = 0.003) and a non-significant trend for longer mOS. MB testing showed similar accuracy. Conclusions: TEMIRI regimen is a safe and active option in pre-treated, irinotecan-sensitive mCRC patients with MGMT methylation.

RET fusions in a small subset of advanced colorectal cancers at risk of being neglected.

Background: Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC). Patients and methods: In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: (i) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811), (ii) cohorts screened at two Italian and one South Korean Institutions and (iii) Foundation Medicine Inc. database. Next-generation sequencing data were analyzed for RET rearranged cases. Results: RET fusions were more frequent in older patients (median age of 66 versus 60 years, P = 0.052), with ECOG PS 1-2 (90% versus 50%, P = 0.02), right-sided (55% versus 32%, P = 0.013), previously unresected primary tumors (58% versus 21%, P < 0.001), RAS and BRAF wild-type (100% versus 40%, P < 0.001) and MSI-high (48% versus 7%, P < 0.001). Notably, 11 (26%) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement. At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 versus 38.0 months, HR: 4.59; 95% CI, 3.64-32.66; P < 0.001). In the multivariable model, RET rearrangements were still associated with shorter OS (HR: 2.97; 95% CI, 1.25-7.07; P = 0.014), while primary tumor location, RAS and BRAF mutations and MSI status were not. Conclusions: Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.

Variant alleles in factor V, prothrombin, plasminogen activator inhibitor-1, methylenetetrahydrofolate reductase and risk of thromboembolism in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab.

Single-nucleotide polymorphisms (SNPs) related to hereditary thrombophilia were investigated as risk factors for thromboembolism in cancer patients. Their effect in metastatic colorectal cancer (mCRC) has never been explored so far. Our aim was to analyse the effect of coagulation factor V (FVL G1691A), prothrombin (PT G20210A), methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and plasminogen activator inhibitor type 1 (PAI-1 5G/4G) allelic variants in this setting. Fifty-two patients treated with first-line chemotherapy plus bevacizumab who developed a thromboembolic event in their lifetime were initially genotyped. A contemporary cohort of 127 patients who did not experience any thromboembolic event was also analysed. DNA was extracted from peripheral blood and genotypes were determined by real-time PCR, using LightSNiP (TIB MOLBIOL) on LightCcler 480 (Roche). The association between thromboembolism and SNPs was investigated by univariable and multivariable analyses. All SNPs were in Hardy-Weinberg equilibrium (χ2 test P>0.20). FVL G1691A and PT G20210A were present only in heterozygosis in 4 (2.2%) and 7 (3.9%) patients, respectively; MTHFR C677T in homozygosis in 29 (16.2%), MTHFR A1298C in homozygosis in 13 (7.3%); PAI-1 5G/4G in 98 (54.7%) and 4G/4G in 41 (23%) patients. At univariable analysis, treatment duration was significantly associated with thromboembolism (P<0.001), whereas gender, age, obesity, platelets count and chemotherapy backbone were not. Similarly, FVL G1691A and PT G20210A as well as MTHFR C677T and PAI-1 4G allele were significantly associated, whereas MTHFR A1298C was not. At multivariable model including PT G20210A, MTHFR C677T and PAI-1 4G (age, obesity, treatment duration and chemotherapy backbone were included as adjustment factors), the three SNPs were significantlty associated with higher risk of thromboembolism (P=0.025, <0.0001 and P=0.033, respectively). Further validation studies are warranted in order to design a prospective trial of thromboprophylaxis in mCRC patients with high-risk genotypes.

HER2 loss in HER2-positive gastric or gastroesophageal cancer after trastuzumab therapy: Implication for further clinical research.

Mechanisms of acquired resistance to trastuzumab-based treatment in gastric cancer are largely unknown. In this study, we analyzed 22 pairs of tumor samples taken at baseline and post-progression in patients receiving chemotherapy and trastuzumab for advanced HER2-positive [immunohistochemistry (IHC) 3+ or 2+ with in-situ hybridization (ISH) amplification] gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over-expression were defined as post-trastuzumab IHC score <3+ and absence of ISH amplification, and IHC "downscoring" from 2+/3+ to 0/1+, respectively. HER2 IHC was always performed, while ISH was missing in 3 post-progression samples. Patients with initial HER2 IHC score 3+ and 2+ were 14 (64%) and 8 (36%), respectively. Loss of HER2 positivity and HER2 over-expression was observed in 32 and 32% samples, respectively. The chance of HER2 loss was not associated with any of the baseline clinicopathological variables. The only exception was in patients with initial IHC score 2+ versus 3+, for both endpoints of HER2 positivity (80 vs. 14%; p = 0.008) and HER2 over-expression (63 vs. 14%; p = 0.025). As already shown in breast cancer, loss of HER2 may be observed also in gastric cancers patients treated with trastuzumab-based chemotherapy in the clinical practice. This phenomenon may be one of the biological reasons explaining the failure of anti-HER2 second-line strategies in initially HER2-positive disease.

Phase III trial comparing 3-6 months of adjuvant FOLFOX4/XELOX in stage II-III colon cancer: safety and compliance in the TOSCA trial.

BACKGROUND: Six months of oxaliplatin-based adjuvant chemotherapy is standard of care for radically resected stage III colon cancer and an accepted option for high-risk stage II. A shorter duration of therapy, if equally efficacious, would be advantageous for patients and Health-Care Systems. PATIENTS AND METHODS: TOSCA ['Randomized trial investigating the role of FOLFOX-4 or XELOX (3 versus 6 months) regimen duration and bevacizumab as adjuvant therapy for patients with stage II/III colon cancer] is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III radically resected colon cancer to receive 3 months (arm 3 m) versus 6 months (arm 6 m) of FOLFOX4/XELOX. Primary end-point was relapse-free survival. We present here safety and compliance data. RESULTS: From June 2007 to March 2013, 3759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX4 and 36% XELOX in either arm. Treatment completion rate without any modification was 35% versus 12% and with delays or dose reduction 52% versus 44% in arm 3 and 6 m. Treatment was permanently discontinued in 8% (arm 3 m) and 33% (arm 6 m). In arm 6 m, 50% of patients discontinuing treatment did so after completing 80% of planned program. Grade 3+ toxicities were higher in arm 6 m than that in 3 m. Grade 2+ neuropathy was 31.2% versus 8.8% (P < 0.0001) while grade 3+ was 8.4 versus 1.3 (P < 0.0001), in arm 3 and 6 m. Seven deaths within 30 days from last treatment administration in arm 6 m and three deaths in arm 3 m were observed (0.3% versus 0.1%, P = 0.34). CONCLUSIONS: TOSCA is the first trial comparing 3 versus 6 months of adjuvant chemotherapy completing accrual within the international initiative of treatment duration evaluation (International Duration Evaluation of Adjuvant, IDEA). High compliance to treatment in control arm will allow a correct assessment of potential differences between the two treatment durations. CLINICALTRIALSGOV REGISTRATION NUMBER: NCT00646607.

Toward the molecular dissection of peritoneal pseudomyxoma.

BACKGROUND: Outcome of pseudomyxoma peritonei (PMP) after cytoreductive surgery (CRS) and hypertermic intraperitoneal chemotherapy (HIPEC) is heterogeneous even after adjusting for clinico-pathological prognostic variables. The identification of additional prognostic or even predictive biomarkers is an unmet clinical need. PATIENTS AND METHODS: Forty patients with mucinous appendiceal tumors and PMP were clinically eligible and had evaluable tumor samples obtained after CRS and HIPEC. We carried out next-generations sequencing (NGS) of 50 gene's hotspot regions contained in the Hotspot Cancer Panel v2 using the Ion Torrent Personal Genome Machine platform (Life Technologies). RESULTS: KRAS and GNAS mutations were found in 72% and 52%, and their allelic frequency was below 10% in 55% and 43% of samples, respectively. KRAS and GNAS mutations were associated with worse progression-free survival (PFS) at univariate analysis (P = 0.006 and 0.011, respectively). At multivariate analysis, only KRAS mutations were independently associated with PFS (P = 0.012); GNAS mutations were not-being significantly associated with other poor prognostic features such as incomplete cytoreduction or KRAS mutations. Validation of results was carried out in an independent bi-institutional cohort of 25 patients and the prognostic effect of KRAS mutations was again confirmed in the multivariate model (P = 0.029). NGS approach allowed the discovery of other potentially druggable mutations such as those in PI3K, AKT, LKB1, FGFR3 and PDGFRA. CONCLUSIONS: Given the homogeneity of this series and the sensitivity of NGS in this low-cellularity tumor, we demonstrated for the first time a poor prognostic role of KRAS mutations.

BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis.

BACKGROUND: While the negative prognostic role of BRAF V600E mutation in metastatic colorectal cancer (mCRC) is well established, the impact of BRAF codons 594 and 596 mutations, occurring in <1% of CRCs, is completely unknown. The present work aims to describe clinical, pathological and molecular features and prognosis of BRAF codons 594 and 596 mutant mCRCs, compared with BRAF V600E mutant and wild-type ones. PATIENTS AND METHODS: Patients treated for mCRC at three Italian Institutions between October 2006 and October 2014, with available KRAS and NRAS codon 12, 13, 59, 61, 117 and 146 and BRAF codon 594, 596 and 600 mutational status, as detected by means of direct sequencing or matrix assisted laser desorption ionization time-of-flight MassArray, were included. RESULTS: Ten patients bearing BRAF codons 594 or 596 mutated tumors were identified and compared with 77 and 542 patients bearing BRAF V600E mutated and BRAF wild-type tumors, respectively. While BRAF V600E mutated tumors were more frequently right-sided, mucinous and with peritoneal spread, BRAF 594 or 596 mutated were more frequently rectal, nonmucinous and with no peritoneal spread. All BRAF 594 or 596 mutated tumors were microsatellite stable. Patients with BRAF codons 594 or 596 mutated tumors had markedly longer overall survival (OS) when compared with BRAF V600E mutated [median OS: 62.0 versus 12.6 months; hazard ratio: 0.36 (95% confidence interval 0.20-0.64), P = 0.002], both at univariate and multivariate analyses. CONCLUSIONS: BRAF codon 594 or 596 mutated mCRCs are different from BRAF V600E ones in terms of molecular features, pathological characteristics and clinical outcome. This is consistent with preclinical evidences of a kinase inactivating effect of these mutations. The role of CRAF in transducing the intracellular signal downstream BRAF 594 or 596 mutated proteins opens the way to further preclinical investigation.

Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer.

BACKGROUND: Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. PATIENTS AND METHODS: Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m(2) day 1, LV 100 mg/m(2) as 2 h infusion and 5-FU 400 mg/m(2) as bolus, days 1 and 2 followed by 600 mg/m(2)/day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). RESULTS: From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85-1.17; P = 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82-1.18; P = 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively. CONCLUSIONS: A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01640782.

Activity of temozolomide in patients with advanced chemorefractory colorectal cancer and MGMT promoter methylation.

BACKGROUND: No evidence-based treatment options are available for patients with advanced colorectal cancer (CRC) progressing after standard therapies. MGMT is involved in repair of DNA damage and MGMT promoter methylation may predict benefit from alkylating agents such as temozolomide. The aim of our study was to evaluate the activity of temozolomide in terms of response rate in patients with metastatic CRC and MGMT methylation, after failure of approved treatments. PATIENTS AND METHODS: Patients were enrolled in a monocentre, open-label, phase II study and treated with temozolomide at a dose of 150 mg/m2/day for 5 consecutive days in 4-weekly cycles. The treatment was continued for at least six cycles or until progressive disease. RESULTS: Thirty-two patients were enrolled from August 2012 to July 2013. Treatment was well tolerated with one grade 4 thrombocytopenia and no other grade≥3 toxicities. No complete response occurred. The objective response rate was 12%, reaching the pre-specified level for promising activity. Median progression-free survival and overall survival were 1.8 and 8.4 months, respectively. Patients with KRAS, BRAF and NRAS wild-type CRC showed significantly higher response when compared with those with any RAS or BRAF mutation (44% versus 0%; P=0.004). TP53 status had no influence on the primary end point. CONCLUSIONS: Temozolomide is tolerable and active in heavily pre-treated patients with advanced CRC and MGMT promoter methylation. Further studies in biomolecularly enriched populations or in a randomized setting are necessary to demonstrate the efficacy of temozolomide after failure of standard treatments.

Lack of KRAS, NRAS, BRAF and TP53 mutations improves outcome of elderly metastatic colorectal cancer patients treated with cetuximab, oxaliplatin and UFT.

There is conflicting evidence on the predictive role of KRAS status when cetuximab is added to oxaliplatin-based regimens. This study investigated the impact of KRAS, NRAS, BRAF, PI3KCA and TP53 status on outcome of elderly metastatic colorectal cancer patients enrolled in TEGAFOX-E (cetuximab, oxaliplatin and oral uracil/ftorafur--UFT) phase II study. Twenty-eight patients were enrolled and all were evaluable for safety and activity. Twenty-three specimens were analysed for KRAS, BRAF, NRAS, PI3KCA and TP53 mutational status by means of polymerase chain reaction and correlated with objective response, progression-free survival and overall survival. An evident increase of response rate was noted in KRAS/NRAS wild-type cases (70 versus 33%, P = 0.198). KRAS/NRAS wild-type status showed an independent association with a longer progression-free survival (44 versus 9 weeks, P = 0.009). Considering the combined assessment of BRAF, KRAS/NRAS and TP53, a trend towards an increase of response rate was noted in patients without mutations (83 versus 33%, P = 0.063). Moreover, patients with all wild-type genes had significantly longer progression-free survival than patients with any mutation (48 versus 10 weeks, P = 0.007). As a single biomarker, only KRAS/NRAS proteins maintained an independent value for outcome prediction. Patients with KRAS/NRAS, BRAF and TP53 wild-type tumours could derive the maximal benefits from treatment with cetuximab, oxaliplatin and UFT.

Lack of Bax expression is associated with irinotecan-based treatment activity in advanced colorectal cancer patients.

BACKGROUND: Currently, first-line chemotherapy in advanced colorectal cancer is not tailored on predictive biomarkers. Bax proapoptotic protein may correlate to chemosensitivity and differential response to irinotecan or oxaliplatin-based combinations. METHODS: Bax expression was assessed by immunohistochemistry in 49 advanced colorectal cancer patients enrolled at our institution from 2002 to 2004 within a multicenter, phase II, randomized trial of first-line UFT/leucovorin/irinotecan (TEGAFIRI) versus UFT/leucovorin/oxaliplatin (TEGAFOX). RESULTS: Bax-positive and negative samples were 49 and 51 %. Response was significantly lower in Bax positive (25 %) as compared to Bax negative (56 %) (Odds ratio = 0.26; p = 0.03). No significant difference was noted in TEGAFOX subgroup; in TEGAFIRI arm, responses were lower in Bax positive (18 %) than Bax negative (67 %) (Odds ratio = 0.11; p = 0.03). No difference in terms of progression-free and overall survival was observed according to Bax. CONCLUSION: Bax-negative colorectal cancer may identify a specific phenotype of patients with significantly higher chance to respond to doublet irinotecan-based chemotherapy.

PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients.

BACKGROUND: It has been reported that KRAS mutations (and to a lesser extent KRAS mutations with the BRAF V600E mutation) negatively affect response to anti-epidermal growth factor receptor (EGFR) mAbs in metastatic colorectal cancer (mCRC) patients, while the biological impact of the EGFR pathway represented by PI3K/PTEN/AKT on anti-EGFR treatment is still not clear. PATIENTS AND METHODS: We analysed formalin-fixed samples from a cohort of 32 mCRC patients treated with cetuximab by means of EGFR immunohistochemistry, EGFR and PTEN FISH analysis, and KRAS, BRAF, PI3KCA, and PTEN genomic sequencing. RESULTS: Ten (31%) of 32 patients showed a partial response to cetuximab and 22 (69%) did not [nonresponder (NR)]. EGFR immunophenotype and FISH-based gene status did not predict an anti-EGFR mAb response, whereas KRAS mutations (24%) and PI3K pathway activation, by means of PI3KCA mutations (13%) or PTEN mutation (10%)/loss (13%), were significantly restricted to, respectively, 41% and 37% of NRs. CONCLUSION: These findings suggested that KRAS mutations and PI3KCA/PTEN deregulation significantly correlate with resistance to cetuximab. In line with this, patients carrying KRAS mutations or with activated PI3K profiles can benefit from targeted treatments only by switching off molecules belonging to the downstream signalling of activated EGFR, such as mammalian target of rapamycin.

Capecitabine plus oxaliplatin and irinotecan regimen every other week: a phase I/II study in first-line treatment of metastatic colorectal cancer.

BACKGROUND: A phase I/II study was performed to determine the safety and activity of a capecitabine plus oxaliplatin and irinotecan (COI) regimen using capecitabine concurrently with oxaliplatin and irinotecan in previously untreated patients with metastatic colorectal cancer. PATIENTS AND METHODS: Patients received irinotecan on day 1, oxaliplatin (85 mg/m(2)) on day 2 and capecitabine (1000 mg/m(2) orally twice daily) on days 2-6 of a biweekly schedule. Three dose levels ranging from 150 to 180 mg/m(2) were explored for irinotecan in sequential cohorts of three to six patients. Once the recommended dose was determined, a total of 28 eligible patients were planned at this dose level. RESULTS: Thirty-eight patients received a median of six cycles. The recommended phase II dose of irinotecan was 180 mg/m(2). Toxicity was manageable: the most common severe toxicities were diarrhoea (24%) and nausea (16%). Of 27 assessable patients treated at the recommended dose, 17 achieved a partial response (overall response rate (ORR) 63%; 95% confidece interval (CI), 44 to 78%), with eight patients undergoing liver metastasectomy. Estimated progression-free survival and overall median survival were 8.5 and 23.5 months, respectively. CONCLUSIONS: Biweekly COI is feasible and active. Tolerability and ease of administration make the regimen well suited for downsizing hepatic colorectal metastases before curative surgery.