Publications by authors named "Enrico Cortesi"

158 Publications

Systemic effect of radiotherapy before or after nivolumab in lung cancer: an observational, retrospective, multicenter study.

Tumori 2021 Apr 4:3008916211004733. Epub 2021 Apr 4.

Department of Oncology, San Camillo de Lellis Hospital, Rieti, Italy.

Background: The combination of radiotherapy (RT) and programmed death 1 inhibitors seems to increase antitumor immune responses.

Objective: To assess the outcome and the role of the best combination sequence, i.e. immunotherapy given before, during, and/or after RT, in patients with non-small cell lung cancer (NSCLC).

Methods: We conducted an observational, retrospective analysis of 95 consecutive patients with advanced NSCLC who received any radiotherapy treatment and nivolumab, as clinically indicated. Median overall survival (OS) and the 95% confidence interval (CI) were estimated with the Kaplan-Meier method. Cox model was used to obtain hazard ratio (HR) and associated 95% CI with statistical inference by log-rank statistic.

Results: Median OS was 11.9 months (95% CI, 6.6-17.2). Patients who received radiotherapy during an immune checkpoint inhibitor treatment started more than 60 days before showed a better outcome than patients who started immunotherapy over 60 days after RT ending (HR, 2.90 [1.37-6.12], = 0.005; median OS, 22.4 months vs 8.6 months, = 0.005). Median progression-free survival was 6.3 months (95% CI, 4.6-8.0).

Conclusions: This study shows that combining irradiation with nivolumab for the treatment of advanced NSCLC leads to improved OS. The optimal time window for the combination of RT and immunotherapy seems to play a critical role for therapeutic antitumor response derived by abscopal effect.
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http://dx.doi.org/10.1177/03008916211004733DOI Listing
April 2021

Impact of baseline and on-treatment glycemia on everolimus-exemestane efficacy in patients with hormone receptor-positive advanced breast cancer (EVERMET).

Clin Cancer Res 2021 Mar 30. Epub 2021 Mar 30.

Clinical Oncology, University Hospital of Udine.

Purpose: The mTORC1 inhibitor everolimus (EVE) in combination with the aromatase inhibitor exemestane (EXE) is an effective treatment for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer (HR+/HER2- aBC). However, EVE can cause hyperglycemia and hyperinsulinemia, which could reactivate the PI3K/AKT/mTORC1 pathway and induce tumor resistance to EVE.

Experimental Design: We conducted a multicenter, retrospective, Italian study to investigate the impact of baseline and on-treatment (i.e., during first three months of therapy) blood glucose levels on progression-free survival (PFS) in HR+/HER2- aBC patients treated with EVE-EXE.

Results: We evaluated 809 HR+/HER2- aBC patients treated with EVE-EXE as any-line of therapy for advanced disease. When evaluated as dichotomous variables, baseline and on-treatment glycemia were not significantly associated with PFS. However, when blood glucose concentration was evaluated as a continuous variable, a multivariable model accounting for clinically relevant patient- and tumor-related variables revealed that both baseline and on-treatment glycemia are associated with PFS, and this association is largely attributable to their interaction. In particular, patients who are normoglycemic at baseline and experience on-treatment diabetes have lower PFS compared to patients who are already hyperglycemic at baseline and experience diabetes during EVE-EXE therapy (mPFS 6.34 vs. 10.32 months; HR 1.76; 95% CI 1.15-2.69; p=0.008).

Conclusions: The impact of on-treatment glycemia on the efficacy of EVE-EXE therapy in HR+/HER2 aBC patients depends on baseline glycemia. This study lays the foundations for investigating novel therapeutic approaches to target the glucose/insulin axis in combination with PI3K/AKT/mTORC1 inhibitors in HR+/HER2 aBC patients.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4928DOI Listing
March 2021

Sequencing Life-Prolonging Agents in Castration-Resistant Prostate Cancer Patients: Comparison of Sequences With and Without Radium 223.

Cancer Biother Radiopharm 2021 Mar 25. Epub 2021 Mar 25.

Department of Radiological, Oncological and Anatomo-Pathological Sciences, La Sapienza University, Rome, Italy.

The retrospective studies that have so far described the outcomes of the sequential use of life-prolonging agents (LPAs) did not include metastatic castration-resistant prostate cancer (mCRPC) patients who received radium 223 (RA223) as part of their treatment. Consequently, it is not known whether including RA223 in the therapeutic sequence has an impact on cumulative survival. The aim of this study was to evaluate this impact by comparing the cumulative overall survival (OS) in two series of mCRPC patients sequentially treated with two or three LPAs after first-line docetaxel (DOC), including RA223 and not. The authors retrospectively reviewed the records of mCRPC patients with bone involvement alone who received two or three LPAs (including RA223) after first-line DOC. The control group was a contemporary series of mCRPC patients with bone involvement alone treated with sequences of two or three LPAs other than RA223 after first-line DOC. Median cumulative OS was 40.6 months in the RA223 group of 78 patients and 36.2 months in the non-RA223 group of 186 patients ( = 0.08). OS outcomes were significantly influenced by the number of treatment lines, and baseline Eastern Cooperative Oncology Group performance status (PS) and prostate-specific antigen levels. To the best of the authors' knowledge, this is the first study designed to evaluate the impact of introducing RA223 in the treatment sequences for mCRPC patients, and the results show that its use does not negatively affect cumulative OS.
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http://dx.doi.org/10.1089/cbr.2020.4442DOI Listing
March 2021

The role of opioids in cancer response to immunotherapy.

J Transl Med 2021 03 23;19(1):119. Epub 2021 Mar 23.

Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00185, Rome, Italy.

Background: The response to immunotherapy can be impaired by several factors including external intervention such as drug interactions with immune system. We aimed to examine the immunomodulatory action of opioids, since immune cells express opioid receptors able to negatively influence their activities.

Methods: This observational, multicenter, retrospective study, recruited patients with different metastatic solid tumors, who have received immunotherapy between September 2014 and September 2019. Immunotherapy was administered according to the standard schedule approved for each primary tumor and line of treatment. The concomitant intake of antibiotics, antifungals, corticosteroids and opioids were evaluated in all included patients. The relationship between tumor response to immunotherapy and the oncological outcomes were evaluated. A multivariate Cox-proportional hazard model was used to identify independent prognostic factors for survival.

Results: One hundred ninety-three patients were recruited. Overall, progression-free survival (PFS) and overall survival (OS) were significantly shorter in those patients taking opioids than in those who didn't (median PFS, 3 months vs. 19 months, HR 1.70, 95% CI 1.37-2.09, p < 0.0001; median OS, 4 months vs. 35 months, HR 1.60, 95% CI 1.26-2.02, p < 0.0001). In addition, PFS and OS were significantly impaired in those patients taking corticosteroids, antibiotics or antifungals, in those patients with an ECOG PS ≥ 1 and in patients with a high tumor burden. Using the multivariate analyses, opioids and ECOG PS were independent prognostic factors for PFS, whereas only ECOG PS resulted to be an independent prognostic factor for OS, with trend toward significance for opioids as well as tumor burden.

Discussion: Our study suggests that the concomitant administration of drugs as well as some clinical features could negatively predict the outcomes of cancer patients receiving immunotherapy. In particular, opioids use during immunotherapy is associated with early progression, potentially representing a predictive factor for PFS and negatively influencing OS as well.

Conclusions: A possible negative drug interaction able to impair the immune response to anti-PD-1/PD-L1 agents has been highlighted. Our findings suggest the need to further explore the impact of opioids on immune system modulation and their role in restoring the response to immunotherapy treatment, thereby improving patients' outcomes.
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http://dx.doi.org/10.1186/s12967-021-02784-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988927PMC
March 2021

True conversions from RAS mutant to RAS wild-type in circulating tumor DNA from metastatic colorectal cancer patients as assessed by methylation and mutational signature.

Cancer Lett 2021 Jun 18;507:89-96. Epub 2021 Mar 18.

Cancer Liquid Biopsy Unit, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena, 324, 00161, Rome, Italy. Electronic address:

The paucity of targeted treatments available in patients with RAS mutant colorectal cancers contributes to the poor prognosis of this patient group compared to those with RAS wild-type disease. Recent liquid biopsy-driven studies have demonstrated that RAS mutant clones might disappear in plasma during the clonal evolution of the disease, opening new unforeseen perspectives for EGFR blockade in these patients. Nevertheless, the lack of detection of RAS mutations in plasma might depend on the low amount of released circulating tumor DNA (ctDNA), making it necessary a more accurate selection of patients with true RAS mutation conversions. In this liquid biopsy-based study, we assessed RAS mutational status in initially RAS-mutant patients at the time of progressive disease from any line of therapy and investigated the incidence of true conversions to plasma RAS wild-type, comparing a colon cancer specific methylation profile with a mutational signature of ctDNA. Globally, considering either mutational panel or methylation profile as reliable tests to confirm or exclude the presence of ctDNA, the percentage of "true RAS converters" was 37.5%. In our series we observed a trend toward a better PFS in patients who received anti-EGFR as second or subsequent treatment lines compared to those who did not.
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http://dx.doi.org/10.1016/j.canlet.2021.03.014DOI Listing
June 2021

Total neoadjuvant treatment in locally advanced rectal cancer.

Transl Oncol 2021 May 20;14(5):101044. Epub 2021 Feb 20.

Medical Oncology Department, Policlinico Umberto I, "Sapienza" University of Rome, Italy.

Locally advanced rectal cancer requires a multidisciplinary management, traditionally based on neo-adjuvant (chemo) radiotherapy, conservative surgery with total mesorectal excision and adjuvant chemotherapy. Despite effective in term of local control, this strategy is linked to a high risk of distant metastasis (up to 30%). In this context, recent published randomized phase III clinical trials have tested the potential benefits with a different sequencing and/or intensification of the standard components of the trimodal therapy. Here, we briefly assess the efficacy and discuss the clinical relevance of total neoadjuvant treatment with a focus on indications and results in the short-course radiotherapy followed by chemotherapy use for this setting of patients. Long term results and additional prospective studies are necessary to more accurately estimate the clinical benefit and further establish the role of total neoadjuvant therapy in locally advanced rectal cancer disease.
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http://dx.doi.org/10.1016/j.tranon.2021.101044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907918PMC
May 2021

Sequencing radium 223 and other life-prolonging agents in castration-resistant prostate cancer patients.

Future Oncol 2021 Mar 29;17(7):807-815. Epub 2021 Jan 29.

Department of Radiological, Oncological & Anatomo-Pathological Sciences, La Sapienza University, Viale del Policlinico 155, 00161, Rome, Italy.

Radium 223 (RA223) is currently administered as part of a therapeutic sequence with the other life-prolonging agents (LPAs) for metastatic castration-resistant prostate cancer (mCRPC). We retrospectively reviewed the clinical records of patients who had received at least three LPAs including RA223. Median overall survival (OS) from the start of first-line treatment was 39.8 months, with the patients who completed all six planned courses of RA223 having a longer OS than those who did not (53.2 vs 29.5 months; p < 0.0001). Our study confirms the activity of RA223 regardless of the treatment line in which it is administered and suggests that patient selection plays a central role in maximizing this activity.
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http://dx.doi.org/10.2217/fon-2020-0391DOI Listing
March 2021

Long-term outcome of pemetrexed maintenance for advanced nonsquamous non-small-cell lung cancer: a real-world observational cohort study.

Recenti Prog Med 2020 12;111(12):761-768

Department of Medical Oncology, Central Hospital of Belcolle, Viterbo, Italy.

Introduction: Pemetrexed maintenance significantly improved progression-free survival (PFS) and overall survival (OS) in advanced nonsquamous non-small-cell lung cancer (NSCLC) patients not progressing after induction chemotherapy.

Objectives: This study is aimed at examine the association of various clinical factor and survival in a real-world cohort analysis.

Materials And Methods: One hundred ninety-four patients were included and classified as "PM" cohort ("Pemetrexed Maintenance", including patients given with pemetrexed maintenance after induction chemotherapy, n=112), and "noPM" cohort ("no Pemetrexed Maintenance" including those discontinuing pemetrexed, n=82).

Results: The median PFS was 8.8 and 5.4 months in the PM and noPM cohorts, respectively (p=0.001). The median OS was 19.6 months in the "PM" cohort and 13.2 months in the "noPM" cohort (p<0.02). In the multivariate analysis, ECOG Performance Status (PS) 0 and maintenance therapy were independently associated with improved PFS and OS. A longer median PFS was reported in patients given ≥5 cycles of pemetrexed maintenance (p<0.01).

Discussion: These results further confirm the survival benefit of pemetrexed maintenance in a real-word population. All eligible advanced NSCLC patients should be strongly considered for at least 5 of pemetrexed maintenance.
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http://dx.doi.org/10.1701/3509.34967DOI Listing
December 2020

Loss of HER2 and decreased T-DM1 efficacy in HER2 positive advanced breast cancer treated with dual HER2 blockade: the SePHER Study.

J Exp Clin Cancer Res 2020 Dec 10;39(1):279. Epub 2020 Dec 10.

Medical Oncology, Paolo Giaccone University Hospital, Palermo, Italy.

Background: HER2-targeting agents have dramatically changed the therapeutic landscape of HER2+ advanced breast cancer (ABC). Within a short time frame, the rapid introduction of new therapeutics has led to the approval of pertuzumab combined with trastuzumab and a taxane in first-line, and trastuzumab emtansine (T-DM1) in second-line. Thereby, evidence of T-DM1 efficacy following trastuzumab/pertuzumab combination is limited, with data from some retrospective reports suggesting lower activity. The purpose of the present study is to investigate T-DM1 efficacy in pertuzumab-pretreated and pertuzumab naïve HER2 positive ABC patients. We also aimed to provide evidence on the exposure to different drugs sequences including pertuzumab and T-DM1 in HER2 positive cell lines.

Methods: The biology of HER2 was investigated in vitro through sequential exposure of resistant HER2 + breast cancer cell lines to trastuzumab, pertuzumab, and their combination. In vitro experiments were paralleled by the analysis of data from 555 HER2 + ABC patients treated with T-DM1 and evaluation of T-DM1 efficacy in the 371 patients who received it in second line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models.

Results: We herein show evidence of lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Lower T-DM1 efficacy was associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. HER2 downregulation at the membrane level was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients. Among the 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis of advanced disease and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p = 0.0006 and 0.03 for OS and PFS2, respectively).

Conclusions: Our data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 in cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.
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http://dx.doi.org/10.1186/s13046-020-01797-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731769PMC
December 2020

Circulating Methylated DNA to Monitor the Dynamics of RAS Mutation Clearance in Plasma from Metastatic Colorectal Cancer Patients.

Cancers (Basel) 2020 Dec 4;12(12). Epub 2020 Dec 4.

Liquid Biopsy Unit, Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.

The clearance of RAS mutations in plasma circulating tumor DNA (ctDNA) from originally RAS-mutant metastatic colorectal cancer (mCRC) has been recently demonstrated. Clinical trials investigating whether RAS mutant mCRC who "convert" to wild-type in plasma might benefit from EGFR blockade are ongoing. Detection of tumor-specific DNA methylation alterations in ctDNA has been suggested as a specific tool to confirm the tumoral origin of cell-free DNA. We monitored RAS clearance in plasma from patients with RAS-mutant mCRC at baseline (pre-treatment) (T0); after 4 months of first-line therapy (T1); at the time of first (T2) and second (T3) progression. A five-gene methylation panel was used to confirm the presence of ctDNA in samples in which RAS mutation clearance was detected. At T1, ctDNA analysis revealed wild-type RAS status in 83% of samples, all not methylated, suggesting at this time point the lack of ctDNA shedding. At T2, ctDNA analysis revealed wild-type RAS status in 83% of samples, of which 62.5% were found methylated. At T3, 50% of wild-type RAS samples were found methylated. Non-methylated samples were found in patients with lung or brain metastases. This five-gene methylation test might be useful to confirm the presence of ctDNA in RAS wild-type plasma samples.
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http://dx.doi.org/10.3390/cancers12123633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761880PMC
December 2020

Baseline CD44v6-positive circulating tumor cells to predict first-line treatment failure in patients with metastatic colorectal cancer.

Oncotarget 2020 Nov 10;11(45):4115-4122. Epub 2020 Nov 10.

Department of Molecular Medicine, Liquid Biopsy Unit, Sapienza University of Rome, Rome, Italy.

CD44v6, the CD44 isoform mostly involved in cancer cell migration and invasion, has been identified as a functional biomarker and therapeutic target in colon cancer stem cells. We here provide evidence that baseline CD44v6-positive CTC predict treatment failure in patients with metastatic colorectal cancer undergoing first-line chemotherapy. We suggest that CD44v6-positive CTC can be used to early detect intrinsic drug resistance in this cancer type.
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http://dx.doi.org/10.18632/oncotarget.27794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665234PMC
November 2020

Efficacy and Tolerability of Selective Internal Radiotherapy With Yttrium-90 as Consolidation Treatment After Chemotherapy in Metastatic Colorectal Cancer.

Clin Colorectal Cancer 2020 12 30;19(4):e272-e276. Epub 2020 Jun 30.

Santa Maria Goretti General Hospital, Latina, Italy.

Background: Selective internal radiotherapy (SIRT) with yttrium-90 (Y-90)-labeled resin microspheres may have a role in consolidating the response to chemotherapy in patients with metastatic colorectal cancer unamenable to resection after assessment of the best response to first-line chemotherapy.

Patients And Methods: This was a retrospective analysis of outcomes in patients who had received SIRT as consolidation therapy after one or more lines of chemotherapy. Eligible patients were 18 years or older, had confirmed colorectal liver metastases, and had disease unsuitable for surgical resection or local ablation with curative intent. The primary endpoint was progression-free survival.

Results: Sixty-eight patients with colorectal liver metastases were treated with at least one SIRT procedure after receiving one or more lines of chemotherapy. Median progression-free survival was significantly longer in patients who received SIRT after prior first-line chemotherapy compared to those who received SIRT after two or more lines of chemotherapy (9 vs. 3 months, respectively; hazard ratio = 0.07; 95% confidence interval, 0.02854‒0.2039; P < .001), and in patients with liver-only disease compared to those who had extrahepatic metastases (6.4 vs. 4.1 months, respectively; hazard ratio = 0.57; 95% confidence interval, 0.34-0.95; P = .0318). There were no grade 3 or higher adverse events.

Conclusion: SIRT represents a valid option for the treatment of colorectal liver metastases. Earlier use of SIRT may provide a greater survival benefit compared to that afforded by the procedure when used in salvage settings.
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http://dx.doi.org/10.1016/j.clcc.2020.06.008DOI Listing
December 2020

Cabozantinib After a Previous Immune Checkpoint Inhibitor in Metastatic Renal Cell Carcinoma: A Retrospective Multi-Institutional Analysis.

Target Oncol 2020 08;15(4):495-501

Genitourinary Cancer Unit, Dipartimento di Oncologia Medica, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

Background: Angiogenesis has been recognized as the most important factor for tumor invasion, proliferation, and progression in metastatic renal cell carcinoma (mRCC). However, few clinical data are available regarding the efficacy of cabozantinib following immunotherapy.

Objective: To describe the outcome of cabozantinib in patients previously treated with immunotherapy.

Patients And Methods: Patients with mRCC who received cabozantinib immediately after nivolumab were included. The primary endpoint was to assess the outcome in terms of efficacy and activity.

Results: Eighty-four mRCC patients met the criteria to be included in the final analysis. After a median follow-up of 9.4 months, median overall survival was 17.3 months. According to the IMDC criteria, the rates of patients alive at 12 months in the good, intermediate, and poor prognostic groups were 100%, 74%, and 33%, respectively (p < 0.001). The median progression-free survival (PFS) was 11.5 months (95% CI 8.3-14.7); no difference was found based on duration of previous first-line therapy or nivolumab PFS. The overall response rate was 52%, stable disease was found as the best response in 25.3% and progressive disease in 22.7% of patients. Among the 35 patients with progressive disease on nivolumab, 26 (74.3%) patients showed complete/partial response or stable disease with cabozantinib as best response after nivolumab. The major limitations of this study are the retrospective nature and the short follow-up.

Conclusions: Cabozantinib was shown to be effective and active in patients previously receiving immune checkpoint inhibitors. Therefore, cabozantinib can be considered a valid therapeutic option for previously treated mRCC patients, irrespective of the type and duration of prior therapies.
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http://dx.doi.org/10.1007/s11523-020-00732-yDOI Listing
August 2020

Elective procedures for prostate cancer in the time of Covid-19: a multidisciplinary team experience.

Prostate Cancer Prostatic Dis 2020 May 18:1-3. Epub 2020 May 18.

3Department of Radiology, Oncology and Pathology, Sapienza University of Rome, Rome, Italy.

On March 29th 2020, 97,689 cases of COVID-19 have been diagnosed only in Italy, with 73,880 actually positive cases, a daily increase of 3815 cases, 27,386 hospitalized and 3906 patients in intensive care units, causing a total of 10,779 known deaths. In all urological departments, quickly inpatient and outpatient services have been significantly reduced. Even in this COVID-19 situation, urological neoplasm care must go on, but significant changes need to be made in the way some care is delivered. We compared diagnostic and therapeutic elective procedures requested and performed for PC management from our multidisciplinary team (MDT) during 1 month activity in the highest national level of COVID-19 infection (March 2020) and under restrictions for all the population, with the management performed in a no-COVID-19 month (March 2019) 1 year ago. The only management that did not received a significant reduction are medical therapies for advanced hormone sensitive (HS) or castration resistant (CR) PC. We describe our MDT identifications of elective undeferrable PC management in this COVID-19 time. These suggestions have been considered for a country (ITALY) under a rapid increase of COVID-19 cases and complications, but in a region with an actual lower impact (2914 actual positive and 1079 hospitalized cases) from the infection and in an hospital not completely converted to COVID-19 management. Indications should be different and restricted only to emergencies on the basis of COVID-19 pandemic situation and hospital involvement.
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http://dx.doi.org/10.1038/s41391-020-0240-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233331PMC
May 2020

The Pan-Immune-Inflammation Value is a new prognostic biomarker in metastatic colorectal cancer: results from a pooled-analysis of the Valentino and TRIBE first-line trials.

Br J Cancer 2020 08 19;123(3):403-409. Epub 2020 May 19.

Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.

Background: Immune-inflammatory biomarkers (IIBs) showed a prognostic relevance in patients with metastatic CRC (mCRC). We aimed at evaluating the prognostic power of a new comprehensive biomarker, the Pan-Immune-Inflammation Value (PIV), in patients with mCRC receiving first-line therapy.

Methods: In the present pooled-analysis, we included patients enrolled in the Valentino and TRIBE trials. PIV was calculated as: (neutrophil count × platelet count × monocyte count)/lymphocyte count. A cut-off was determined using the maximally selected rank statistics method. Generalised boosted regression (GBR), the Kaplan-Meier method and Cox hazards regression models were used for survival analyses.

Results: A total of 438 patients were included. Overall, 208 patients (47%) had a low-baseline PIV and 230 (53%) had a high-baseline PIV. Patients with high PIV experienced a worse PFS (HR, 1.66; 95% CI, 1.36-2.03, P < 0.001) and worse OS (HR, 2.01; 95% CI, 1.57-2.57; P < 0.001) compared to patients with low PIV. PIV outperformed the other IIBs in the GBR model and in the multivariable models.

Conclusion: PIV is a strong predictor of survival outcomes with better performance than other well-known IIBs in patients with mCRC treated with first-line therapy. PIV should be prospectively validated to better stratify mCRC patients undergoing first-line therapy.
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http://dx.doi.org/10.1038/s41416-020-0894-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403416PMC
August 2020

The Agnostic Role of Site of Metastasis in Predicting Outcomes in Cancer Patients Treated with Immunotherapy.

Vaccines (Basel) 2020 Apr 28;8(2). Epub 2020 Apr 28.

Department of Clinical and molecular oncology, University of Rome "Sapienza", 00185 Rome, Italy.

Immune checkpoint inhibitors have revolutionized treatment and outcome of melanoma and many other solid malignancies including non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Unfortunately, only a minority of patients have a long-term benefit, while the remaining demonstrate primary or acquired resistance. Recently, it has been demonstrated that the prevalence of programmed death-ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs) varies based on the anatomical site of metastases. In particular, liver seems to have more immunosuppressive microenvironment while both the presence of lymph nodal disease and lung metastases seem to have the highest prevalence of PD-L1 and TILs. The aim of the present study is to investigate the possible role of site of metastases as a predictive factor for response or resistance to immunotherapy in several types of cancer. In this multicenter retrospective study, we enrolled patients with metastatic NSCLC, melanoma, RCC, urothelial, merkel carcinoma, and colon cancer who received immunotherapy from April 2015 to August 2019. Major clinicopathological parameters were retrieved and correlated with patients' survival outcomes in order to assess their prognostic value and build a useful tool to assist in the decision-making process. A total of 291 patients were included in this study. One hundred eighty-seven (64%) patients were male and 104 (36%) female. The tumor histology was squamous NSCLC in 56 (19%) patients, non-squamous NSCLC in 99 (34%) patients, melanoma in 101 (35%) patients, RCC in 28 (10%) patients, and other tumors in the remaining 7 (2%) patients. The number of metastatic sites was 1 in 103 patients (35%), 2 in 104 patients (36%) and 3 in 84 patients (29%). Out of 183 valuable patients, the entity of response was complete response (CR), partial response (PR), stable disease (SD), and progression disease (PD) in 15, 53, 31, and 79 patients, respectively. Using an univariate analysis (UVA), tumor burden ( = 0.0004), the presence of liver ( = 0.0009), bone ( = 0.0016), brain metastases ( < 0.0001), the other metastatic sites ( = 0.0375), the number of metastatic sites ( = 0.0039), the histology ( = 0.0034), the upfront use of immunotherapy ( = 0.0032), and Eastern Cooperative Oncology Group (ECOG) Perfomance status (PS) ≥ 1 ( < 0.0001) were significantly associated with poor overall survival (OS). Using a multivariate analysis (MVA) the presence of liver ( = 0.0105) and brain ( = 0.0026) metastases, the NSCLC diagnosis ( < 0.0001) and the ECOG PS ( < 0.0001) resulted as significant prognostic factors of survival. Regarding the progression free survival (PFS), using a UVA of the tumor burden ( = 0.0004), bone ( = 0.0098) and brain ( = 0.0038) metastases, the presence of other metastatic sites ( = 0.0063), the number of metastatic sites ( = 0.0007), the histology ( = 0.0007), the use of immunotherapy as first line ( = 0.0031), and the ECOG PS ≥ 1 ( ≤ 0.0001) were associated with a lower PFS rate. Using an MVA, the presence of brain ( = 0.0088) and liver metastases ( = 0.024) and the ECOG PS ( < 0.0001) resulted as predictors of poor PFS. Our study suggests that the site of metastases could have a role as prognostic and predictive factor in patients treated with immunotherapy. Indeed, regardless of the histology, the presence of liver and brain metastases was associated with a shorter PFS and OS, but these results must be confirmed in further studies. In this context, a deep characterization of microenvironment could be crucial to prepare patients through novel strategies with combination or sequential immunotherapy in order to improve treatment response.
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http://dx.doi.org/10.3390/vaccines8020203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349154PMC
April 2020

Status of correlation between BMI and response to immunocheck-point inhibitor in advanced non-small-cell lung cancer.

Lung Cancer Manag 2020 Feb 25;9(2):LMT26. Epub 2020 Feb 25.

Medical Oncology Unit, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.

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http://dx.doi.org/10.2217/lmt-2019-0016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186849PMC
February 2020

Fracture risk and survival outcomes in metastatic castration-resistant prostate cancer patients sequentially treated with abiraterone acetate and RADIUM-223.

Eur J Nucl Med Mol Imaging 2020 10 5;47(11):2633-2638. Epub 2020 Apr 5.

Department of Radiological, Oncological and Anatomo-Pathological Sciences, Sapienza University, Rome, Italy.

Purpose: To evaluate the fracture risk and survival outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) who received sequentially abiraterone acetate (AA) and radium 223 [223Ra]RaCl in the daily clinical practice.

Materials: We retrospectively reviewed the records of mCRPC patients who received [223Ra]RaCl immediately after progressing during an AA treatment line in everyday clinical practice.

Results: We reviewed data of a consecutive series of 94 mCRPC patients. Most of the patients (85.1%) received [223Ra]RaCl as second- or third-line treatment. [223Ra]RaCl treatment was well-tolerated; there were only four cases of grade 3 anaemia, two cases of grade 3 leukopenia and one case of grade 3 neutropenia. The overall fracture rate is 2.1%; one fracture was recorded during the course of [223Ra]RaCl treatment, and one was recorded 1 month after its end. The fractures both occurred at metastatic sites. Median OS from [223Ra]RaCl start was more than 14 months regardless of the treatment line when [223Ra]RaCl was administered.

Conclusion: The findings of this study show that the treatment with [223Ra]RaCl immediately after AA was active and safe with a very low risk of a fracture. Thus, the present observational report makes a valuable contribution to the current debate concerning the risks and benefits of including [223Ra]RaCl in the therapeutic algorithm.
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http://dx.doi.org/10.1007/s00259-020-04796-wDOI Listing
October 2020

Impact of BMI on HER2+ metastatic breast cancer patients treated with pertuzumab and/or trastuzumab emtansine. Real-world evidence.

J Cell Physiol 2020 11 15;235(11):7900-7910. Epub 2020 Jan 15.

Medical Oncology Unit, Belcolle Hospital, Viterbo, Italy.

Body mass index (BMI) is a main indicator of obesity and its association with breast cancer is well established. However, little is known in the metastatic setting, especially in HER2-positive patients. We assessed the influence of BMI on clinical outcomes of patients treated with pertuzumab and/or trastuzumab emtansine (T-DM1) for HER2+ metastatic breast cancer (mBC). BMI was addressed as a categorical variable, being classified on the basis of the following ranges, that is, 18.5-24.9, 25-29.9, and 30.0-34.9, namely, normal weight, overweight, and Class I obesity. The outcomes chosen were progression-free survival to first-line chemotherapy (PFS1) and overall survival (OS). Overall (N = 709), no impact of BMI was observed on PFS1 (p = .15), while BMI ≥ 30 was associated with worse OS (p = .003). In subjects who progressed to first line (N = 575), analyzing data across PFS1 quartiles and strata of disease burden, BMI predicted lower PFS1 in patients within the I PFS1 quartile and with the lowest disease burden (p = .001). Univariate analysis showed a detrimental effect of BMI ≥ 30 on OS for women within the I PFS1 quartile (p = .03). Results were confirmed in multivariate analysis. According to PFS1 quartiles a higher percentage of patients with high BMI and low disease burden progressed within 6 months of therapy. The effect of BMI on prognosis was also confirmed in multivariate analysis of OS for overall population. In our cohort, a BMI ≥ 30 correlated with worse OS in patients with HER2+ mBC who received pertuzumab and/or T-DM1 but had no impact on PFS to first line. BMI predicted worse I PFS1 quartile.
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http://dx.doi.org/10.1002/jcp.29445DOI Listing
November 2020

'Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation' by Braaten : another point of view.

Ann Rheum Dis 2020 Jan 6. Epub 2020 Jan 6.

Arthritis Center, Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università di Roma, Sapienza University of Rome, Roma, Italy.

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http://dx.doi.org/10.1136/annrheumdis-2019-216867DOI Listing
January 2020

Immune-related adverse events correlate with clinical outcomes in NSCLC patients treated with nivolumab: The Italian NSCLC expanded access program.

Lung Cancer 2020 02 20;140:59-64. Epub 2019 Dec 20.

Biostatistical Unit, Regina Elena National Cancer Institute, IRCCS, Rome, Italy.

Objectives: The incidence of any and of severe-grade immune-related adverse events (irAEs) with second-line nivolumab monotherapy is 31-65 % and 2-5 % respectively. While potentially serious and even fatal, in the absence of an appropriate therapy, such events might be indicators of the activation of the immune system and, potentially, of efficacy.

Materials And Methods: We collected the records of 1959 non-small-cell lung cancer (NSCLC) patients treated with nivolumab in the Italian expanded access program, and we registered the appearance of any and of severe grade irAEs. We retrospectively searched for correlations between toxicity and efficacy parameters by using Cox's regression analysis.

Results: Overall, 342 (17.8%) patients developed an irAE of any grade. We observed that patients developing irAE of any grade achieved a significantly higher response rate (RR 27.2% vs 15.2%; p < 0.0001), disease control rate (DCR 60.5% vs 40.2%; p < 0.0001), median progression-free survival (mPFS 6.0 months [95% CI 4.9-7.1] vs 3.0 [95% CI: 2.8-3.2], p < 0.0001) and median overall survival (mOS 16.7 months [95% CI: 13.5-19.9] vs 9.4 [95% CI: 8.4-10.4], p < 0.00001) compared to patients who did not. At multivariate analysis the development of an irAE remained an independent indicator of nivolumab efficacy (HR 1.44 [95% CI: 1.22-1.71] p < 0.0001).

Conclusions: This report, performed in Caucasian NSCLC patients, showed that the appearance of irAEs correlated with outcome.
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http://dx.doi.org/10.1016/j.lungcan.2019.12.014DOI Listing
February 2020

Thyroid disorders in programmed death 1 inhibitor-treated patients: Is previous therapy with tyrosine kinase inhibitors a predisposing factor?

Clin Endocrinol (Oxf) 2020 03 1;92(3):258-265. Epub 2020 Jan 1.

Department of Experimental Medicine, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.

Background: Programmed death 1 (PD-1) inhibitors are frequently associated with thyroid-related adverse events (TAEs), but many aspects remain unclear. This study aims to evaluate the incidence and characteristics of such events and to find any predictive factor for its development.

Methods: We retrospectively analysed data from patients with advanced solid tumours (non-small-cell lung carcinoma, renal cell carcinoma, metastatic melanoma) treated with PD-1 inhibitors (nivolumab, pembrolizumab) in Oncology Unit B, Policlinico Umberto I of Rome, from June 2015 to December 2018. All patients underwent baseline thyroid function evaluations repeated monthly.

Results: The cohort consisted of 126 patients (66.7% male, mean age 66.4 ± 9.7 years). One hundred and seven received nivolumab and 19 pembrolizumab. Twenty-three per cent of patients experienced TAEs (mainly CTCAE grade 1), with hypothyroidism in 15.1% (subclinical: 11.9%, overt: 3.2%) and hyperthyroidism in 8.0% (subclinical: 4.8%, overt: 3.2%). Median time to TAE onset was 8.7 ± 6.8 weeks (10.4 ± 7.6 weeks for hypothyroidism, 5.4 ± 3.0 weeks for hyperthyroidism). Most TAEs (89.7%) appeared within the first 3 months, none after 8 months. Most hypothyroid patients (63.2%) had previously been treated with a tyrosine kinase inhibitor (TKI). Logistic regression analysis showed that pretreatment with a TKI was a major predisposing factor for the development of hypothyroidism (OR 9.2, 95% CI: 1.4-59.9, P = .020).

Conclusions: TAEs are common during anti-PD-1 therapy and usually occur within the first 3 months of treatment. This is the first study evaluating the impact of previous oncologic therapies on TAEs, identifying TKI as a major risk factor for the development of hypothyroidism in patients treated with anti-PD-1.
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http://dx.doi.org/10.1111/cen.14135DOI Listing
March 2020

Real-life results from the overall population and key subgroups within the Italian cohort of nivolumab expanded access program in non-squamous non-small cell lung cancer.

Eur J Cancer 2019 12 28;123:72-80. Epub 2019 Oct 28.

Oncology Unit, Policlinico Umberto I, Roma, Italy.

Background: Nivolumab was the first immune checkpoint inhibitor approved for previously treated advanced non-small cell lung cancer (NSCLC). Before its introduction in the market, nivolumab was made available to NSCLC patients through an expanded access program (EAP). Here we present the Italian cohort of patients with non-squamous NSCLC enrolled in a worldwide nivolumab EAP, with subgroup analyses involving elderly patients, patients with central nervous system (CNS) metastases and patients receiving nivolumab beyond progression.

Methods: Pretreated patients with advanced non-squamous NSCLC received nivolumab at 3 mg/kg every 2 weeks up to 24 months. Efficacy data (investigator-assessed tumour response, progression date and survival) and safety data were collected.

Findings: 1588 patients were treated across 153 Italian centres. Overall response rate and disease control rate were 18% and 44%, respectively; median overall survival (OS) was 11.3 months (95% CI: 10.2-12.4). Elderly patients (≥70 n = 522; ≥75 n = 232) achieved outcomes similar to the global study population; patients with CNS metastases (n = 409) had an OS of 8.6 months (95% CI: 6.4-10.8), and a 1-year OS rate of 43%. Nivolumab was administered beyond progression to 276 patients (26%), 57 of whom achieved subsequent disease control; the median OS of patients receiving nivolumab beyond progression was 16.2 months (95% CI: 14.0-18.4), while 1-year OS rate was 62%.

Interpretation: To date, this is the largest clinical experience with nivolumab in a real-world setting. Our data support its use in clinical practice for pretreated non-squamous NSCLC, including patients with older age or CNS metastases.
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http://dx.doi.org/10.1016/j.ejca.2019.09.011DOI Listing
December 2019

Adjuvant chemotherapy in resected colon cancer: When, how and how long?

Surg Oncol 2019 Sep 2;30:100-107. Epub 2019 Jul 2.

Department of Radiology, Oncology and Pathology, Policlinico Umberto, I Sapienza University of Rome, Italy.

The benefit of adjuvant chemotherapy has been clearly established in the adjuvant setting for node-positive colon cancer. A number of trials in the adjuvant setting have analyzed the efficacy of multiple-agent combinations, including irinotecan, oxaliplatin, bevacizumab and cetuximab. Only oxaliplatin added to fluorouracil/capecitabine has been shown to be superior beyond a fluropyrimidine alone in the adjuvant setting. As such, standard treatment options include fluorouracil (FU) or capecitabine with or without oxaliplatin. However, oxaliplatin is associated with cumulative dose-dependent neurotoxicity, characterized by distal or perioral paresthesias or dysesthesias; for this reason, in this review we discuss the results of the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) trial. The IDEA trail is the largest prospective clinical trial ever conducted in colorectal cancer, wherein patients were treated with either 3 months or 6 months of adjuvant chemotherapy. In the era of cancer gene expression-based subtyping, the Colorectal Cancer Subtyping Consortium has proposed a four-subgroup molecular classification system for colorectal cancer, consisting of CMS1 (immune), CMS2 (canonical), CMS3 (metabolic) and CMS4 (mesenchymal). In this review, we present and analyze the available data on efficacy and toxicity of the combination regimen approved for treatment of resected colon cancer, and discuss the questions of when, how and how long we need to treat such patients.
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http://dx.doi.org/10.1016/j.suronc.2019.06.003DOI Listing
September 2019

Commentary on: "Randomized Phase II Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: CAO/ARO/AIO-12".

Int J Colorectal Dis 2019 09 12;34(9):1617-1618. Epub 2019 Aug 12.

Medical Oncology Unit B, Policlinico Umberto I, "Sapienza" University of Rome, Viale Regina Elena 326, Rome, Italy.

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http://dx.doi.org/10.1007/s00384-019-03364-5DOI Listing
September 2019

Distinct HR expression patterns significantly affect the clinical behavior of metastatic HER2+ breast cancer and degree of benefit from novel anti-HER2 agents in the real world setting.

Int J Cancer 2020 04 7;146(7):1917-1929. Epub 2019 Aug 7.

Department of Medical Oncology, Policlinico Universitario "A. Gemelli", Rome, Italy.

We analyzed data from 738 HER2-positive metastatic breast cancer (mbc) patients treated with pertuzumab-based regimens and/or T-DM1 at 45 Italian centers. Outcomes were explored in relation to tumor subtype assessed by immunohistochemistry (IHC). The median progression-free survival at first-line (mPFS1) was 12 months. Pertuzumab as first-line conferred longer mPFS1 compared to other first-line treatments (16 vs. 9 months, p = 0.0001), regardless of IHC subtype. Median PFS in second-line (mPFS2) was 7 months, with no difference by IHC subtype, but it was more favorable with T-DM1 compared to other agents (7 vs. 6 months, p = 0.03). There was no PFS2 gain in patients with tumors expressing both hormonal receptors (HRs; p = 0.17), while a trend emerged for tumors with one HR (p = 0.05). Conversely, PFS2 gain was significant in HRs-negative tumors (p = 0.04). Median overall survival (mOS) was 74 months, with no significant differences by IHC subtypes. Survival rates at 2 and 3 years in patients treated with T-DM1 in second-line after pertuzumab were significantly lower compared to pertuzumab-naïve patients (p = 0.01). When analyzed by IHC subtype, the outcome was confirmed if both HRs or no HRs were expressed (p = 0.02 and p = 0.006, respectively). Our results confirm that HRs expression impacts the clinical behavior and novel treatment-related outcomes of HER2-positive tumors when treatment sequences are considered. Moreover, multivariate analysis showed that HRs expression had no effect on PFS and OS. Further studies are warranted to confirm our findings and clarify the interplay between HER2 and estrogen receptor pathways in HER2-positive (mbc) patients.
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http://dx.doi.org/10.1002/ijc.32583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027476PMC
April 2020

Incidence of portal hypertension in patients exposed to oxaliplatin.

Dig Liver Dis 2019 09 15;51(9):1348-1350. Epub 2019 Jul 15.

Dipartimento di Medicina Traslazionale e di Precisione, "Sapienza" University of Rome, Italy Hypertension, "Sapienza" University of Rome, Italy.

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http://dx.doi.org/10.1016/j.dld.2019.06.020DOI Listing
September 2019

Cabozantinib in Renal Cell Carcinoma With Brain Metastases: Safety and Efficacy in a Real-World Population.

Clin Genitourin Cancer 2019 08 13;17(4):291-298. Epub 2019 May 13.

Medical Oncology Department, Genitourinary Cancer Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy. Electronic address:

Background: Cabozantinib showed efficacy and manageable toxicity in patients with metastatic renal cell carcinoma (mRCC). In this study we aimed to describe the safety and to collect evidence on the potential efficacy of cabozantinib in mRCC patients with brain metastases (BM) in a real-world experience.

Materials And Methods: We retrospectively collected data of patients treated with cabozantinib within the Italian Managed Access Program. Patients were selected for the presence of BM before the start of treatment and for at least 1 previous tyrosine kinase inhibitor (TKI) treatment regimen for metastatic disease. Safety data were reported, and overall response rate (ORR), brain-specific response, progression-free survival (PFS), and median overall survival (OS) were analyzed.

Results: Overall, 12 patients treated with cabozantinib were evaluated. Any grade adverse events (AEs) accounted for 92%, Grade 3/4 AEs rated at 36% with no major neurological side effects. The most common AEs included hypertension (33%), fatigue (24%), aminotransferase elevation (25%), hypothyroidism (16%), and gastrointestinal toxicity (16%). The ORR was 50% with a disease control rate of 75%. All 5 patients treated with a combined systemic and brain-directed approach obtained intracranial disease control, without increased toxicity. Median PFS and median OS were 5.8 and 8.8 months, respectively. Comparable safety and tolerability results for other TKI regimens were reported from the literature.

Conclusion: Cabozantinib showed safety, acceptable tolerability, and promising antitumor activity in a population of mRCC patients with BM from a real-world experience. A combined modality approach for renal cell carcinoma with BM, whenever feasible, could be recommended to improve oncological outcomes.
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http://dx.doi.org/10.1016/j.clgc.2019.05.002DOI Listing
August 2019