Francesca Di Fabio

The predictive value of 18F-FDG-PET early evaluation in patients with metastatic gastric adenocarcinoma treated with chemotherapy plus cetuximab

BackgroundThe aim of the study was to evaluate whether the therapy-induced reduction of the 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) maximum standardized uptake value in patients with advanced gastric adenocarcinoma treated with chemotherapy plus cetuximab could predict the objective response and outcome early during the treatment.MethodsThe study was performed as a part of a phase II trial evaluating cetuximab plus the leucovorin/5-fluorouracil/irinotecan (FOLFIRI) regimen. The objective response was evaluated according to the response evaluation criteria in solid tumors (RECIST) every 6 weeks. The early metabolic response evaluated by 18F-FDG-PET was assessed according to our own evaluated cutoff value (<35%) after receiver operating characteristic (ROC) analysis.ResultsTwenty of 22 patients had positive baseline 18F-FDG-PET. The best RECIST response was: complete response (CR), 3; partial response (PR), 9; stable disease (SD), 8. Twelve patients (60%) were classified as metabolic responders and 8 (40%) as nonresponders. At the median follow-up time of 11 months, median time to disease progression (TTP) and overall survival (OS) for early metabolic responders versus nonresponders were 11 versus 5 months (P = 0.0016) and 16 versus 6 months (P = 0.1493), respectively.ConclusionThe early metabolic response evaluated by 18F-FDG-PET predicted the clinical outcome in this series of patients with advanced gastric cancer treated with chemotherapy plus cetuximab.

Prospective phase II study of single-agent gemcitabine in untreated elderly patients with stage IIIB/IV non-small-cell lung cancer.

The purpose of this study was to evaluate the efficacy and tolerability of single-agent gemcitabine in untreated elderly patients with stage IIIb/IV non–small-cell lung cancer (NSCLC). Since April 1997, 46 consecutive patients have been enrolled in this multicenter study. Gemcitabine 1,000 mg/m2 was administered as a 30-minute intravenous infusion on days 1, 8, and 15 every 28 days. Primary patient characteristics were: male/female 38/8; median age 73 years (range: 70–82 years); median Karnofsky performance status (PS) 90 (range: 70–100); stage IIIb 61% and stage IV 39%; histotype: epidermoid 48%, adenocarcinoma 43%, and large cell carcinoma 9%. No complete response was observed, but 10 (21.7%) patients achieved partial response (PR) (95% confidence limits: 11–36%), 27 (58.7%) had stable disease (SD), and 7 (15%) progressed early (at the first evaluation). The median duration of PR and SD was 8 months (range: 4–23+ months) and 4 months (range: 2–9 months), respectively. Subjective response evaluating PS and symptoms such as dyspnea, pain, and cough was evaluated in 40 patients; 11 (27.5%) improved, 15 (37.5%) remained stable, and 14 (35%) worsened. The median time to progression was 4 months, the median survival was 9 months, and 1-year survival was 44%. After a median follow-up of 10.5 months, 14 patients are still alive. There were no grade 4 toxicities. Grade 3 neutropenia and thrombocytopenia occurred in 19% and 2% of patients, respectively. Nonhematologic toxicities were mild. Grade I/II side effects of nausea/vomiting, transient fever, increase of hepatic transaminases, transient peripheral edema at lower extremity (not related to cardiac or renal disease or phlebothrombosis) were reported. This phase II study confirms the activity and favorable toxicity profile of single-agent gemcitabine in the treatment of elderly patients with advanced NSCLC.

Panitumumab in combination with infusional oxaliplatin and oral capecitabine for conversion therapy in patients with colon cancer and advanced liver metastases. The MetaPan study.

Preoperative chemotherapy improves the outcome in patients with colorectal cancer with liver metastases. In the current study, the authors evaluated the activity of a conversion treatment with the combination of capecitabine plus oxaliplatin (XELOX) used in association with panitumumab in patients with unresectable, liver‐only, metastatic colon cancer.

Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S) trial: Comparison of a sequential treatment with irinotecan (CPT-11) plus 5-fluorouracil (5-FU)/folinic acid (LV) followed by docetaxel and cisplatin versus a 5-FU/LV regimen as postoperative treatment for radically resected gastric cancer.

LBA4001 Background: Following radical resection of gastric or gastroesophageal junction (GEJ) adenocarcinoma, a meta-analysis and randomized studies demonstrated better survival in pts treated with fluoropyrimidine regimens compared to surgery alone. ITACA-S trial is a no-profit, multicenter, randomized, open-label, superiority phase III study aimed at evaluating whether a more intensive postoperative chemotherapy improves efficacy, when replace fluoropyrimidine. METHODS Pts radically resected for gastric or GEJ adenocarcinoma, with ≥D1-lymphadenectomy, node involvement (pN+) or pN0 with pT2b-3-4; within 3-8 weeks after surgery were eligible. Treatment consisted in CPT-11 180 mg/m2 on d1, LV 100 mg/m2 d1-2, 5-FU 400-600 mg/m2 d1-2, q14; for 4 cycles (FOLFIRI regimen) followed by docetaxel 75 mg/m2 d1, cisplatin 75 mg/m2 d1, q 21; for 3 cycles (arm A) vs. LV 100 mg/m2 d1-2, 5-FU 400-600 mg/m2 d1-2, q 14 for 9 cycles (arm B). The primary hypothesis on disease-free survival (DFS) requires 636 events (first recurrence or death) to detect an hazard ratio (HR) of 0.80, with 2-sided 5% significance level for the log-rank test and a power of 80%. RESULTS From February 2005 to August 2009, 1,106 pts were randomized and 1,100 were analyzed (562 arm A, 538 arm B; 6 major violations) by 123 Italian centers. By March 2012, with a median follow-up of 49 months (quartile range: 36-62) we observed 558 events for DFS (HR 0.98; 95%CI 0.83-1.16;p=0.83) accounting for 88% of the target number and 440 deaths (HR: 1.00; 95%CI 0.83-1.20;p=0.98). Toxicity was consistent with literature. Given the data observed, both under the original hypothesis and the current trend, the probability to reach a statistically significant results at the target events is <0.0001. CONCLUSIONS Adjuvant chemotherapy in gastric cancer with more intensive regimen did not result in a significant prolongation of DFS and OS when compared to bolus/infusion FU/LV regimen.

Cigarettes smoking habit may reduce benefit from cetuximab-based treatment in advanced colorectal cancer patients

Background: NF-κB is one of the nuclear effectors of EGFR activation. There are reports showing that NF-κB expression and activity is enhanced after nicotine treatment. Some data demonstrated that NF-κB activation plays a role in the induction of resistance to cetuximab and irinotecan in advanced colorectal tumors. The aim of this study was to evaluate the effect of cigarette smoking on cetuximab efficacy in advanced colorectal cancer patients. Methods: We retrospectively analysed the smoking habits of 200 patients treated with a variety of anticancer regimens containing cetuximab for advanced colorectal cancer. All patients were irinotecan-resistant and received an oxaliplatin-based first line treatment. We divided our patient population as follows: no previous smoking habit, previous smokers (any number of cigarettes), current smokers of less of 10 cigarettes/day, current smokers of more than 10 cigarettes/day. Results: Out of 200 patients 58 declared a history of cigarette smoking, 108 patients never smoked and the remaining 44 patients were cigarette smokers during cetuximab-based anticancer therapy. Of the 44 smokers, 18 smoked more than 10 cigarettes per day. No statistically significant differences in terms of response rate (RR) and time to progression (TTP) were identified between previous smokers and never smokers. RR in actual smokers was 13.6% and was lower than RR reported for non-smokers (27.1%; p = 0.023). In addition, the median TTP was 5.5 months in the non-smokers versus 2.8 months in the current smokers (p < 0.0001). A difference in terms of overall survival (OS) was detected between the two groups (p = 0.03). Comparing smokers of more than 10 cigarettes per day and smokers of less than 10 cigarettes per day no differences were detected in RR, TTP or OS. Conclusions: Our results suggest that cigarette smoking during anticancer treatment with a cetuximab-based regimen may be responsible for a decrease in RR and lead to a lower TTP.

18FDG-PET evaluation correlates better than CT with pathological response in a metastatic colon cancer patient treated with bevacizumab-based therapy.

Around 20–30% of patients with hepatic metastasis from colorectal cancer can undergo liver resection, but the increased response rate obtained with the addition of monoclonal antibodies to chemotherapy regimens could result in a higher rate of liver surgery. In this report we describe the case of a patient who underwent a liver resection after neoadjuvant treatment with capecitabine, oxaliplatin and bevacizumab and who achieved a complete pathological response of the liver metastasis. A preoperative CT scan demonstrated a partial response to the treatment while 18FDG-PET scan correctly evaluated the complete pathological response in the liver and detected an active interaortocaval lymph node metastasis. New specific studies are required to evaluate the imaging response in metastatic colorectal cancer patients especially after treatment with new, targeted agents.

Multimodal sequential approach in colorectal cancer liver metastases: hepatic resection after yttrium-90 selective internal radiation therapy and cetuximab rescue treatment

Synchronous or metachronous liver metastases occur in up to one-third of patients with colorectal cancer and are associated with a poor prognosis. Many evidences have shown that surgical resection can be curative, with 5-year survival rates ranging from 37% to 50%, but many patients are ineligible for surgery because of multiple liver lesions, bilobar distribution of liver metastases, or the presence of widespread extrahepatic disease. The management of unresectable liver metastases includes many therapeutic options such as systemic chemotherapy, selective internal radiation therapy (SIRT) with yttrium-90 (Y-90), targeted therapy, and surgery. These treatments can be integrated into a sequential multimodal approach to increase the resection rate. We present a case in which such an approach was put into practice. The favorable result suggests that SIRT, along with systemic chemotherapy and surgery, is a valid treatment option for unresectable colorectal liver metastases.

Observational study on quality of life, safety, and effectiveness of first‐line cetuximab plus chemotherapy in KRAS wild‐type metastatic colorectal cancer patients: the ObservEr Study

Cetuximab improves efficacy when added to chemotherapy for metastatic colorectal cancer (mCRC). Effective management of skin reactions from cetuximab improves quality of life (QoL), and treatment compliance in clinical trials. No data are available from real‐world settings. The ObservEr observational, multicenter, prospective study evaluated QoL, the incidence of skin reactions, and management of chemotherapy plus cetuximab in first‐line for mCRC. The primary endpoint was QoL measured with the Dermatology Life Quality Index (DLQI) and EORTC QLQ‐C30. Secondary endpoints were the incidence of skin and serious adverse events, median overall and progression‐free survival, tumor response, and resection rates. Between May 2011 and November 2012, 228 patients with KRASwt mCRC were enrolled at 28 Italian centers, 225 evaluable, median age 65 years. QoL did not change during treatment and was not affected by the choice of prophylactic or reactive skin management. The incidence of cetuximab‐specific grade ≥3 skin reactions was 14%, with no grade 4/5 events. Skin reactions correlated with survival (P = 0.016), and their incidence was influenced by chemotherapy regimen (oxaliplatin vs. irinotecan—Incidence rate ratio [IRR] 1.72, P < 0.0001) and gender (male vs. female—IRR 1.38, P = 0.0008). Compliance at first postbaseline evaluation was 97.75%. Median overall survival was 23.6 months, median progression‐free survival 8.3 months. Cetuximab plus chemotherapy did not compromise QoL in the routine clinical setting when patients receive close monitoring plus prophylactic or reactive management of skin reactions. We observed the same correlation between overall survival (OS) and skin reactions reported in controlled clinical trials, also in this setting.

Activity and Safety of Cetuximab Plus Modified FOLFOXIRI Followed by Maintenance With Cetuximab or Bevacizumab for RAS and BRAF Wild-type Metastatic Colorectal Cancer: A Randomized Phase 2 Clinical Trial

Importance The combination of a triple-drug chemotherapy regimen with an anti–epidermal growth factor receptor (EGFR) agent as a first-line treatment of metastatic colorectal cancer (mCRC) showed promising activity along with safety concerns in single-arm phase 2 trials. The role of maintenance following chemotherapy and anti-EGFR and the optimal regimen to be adopted are not established. Objectives To evaluate the activity and safety of cetuximab plus modified FOLFOXIRI (mFOLFOXIRI) and explore the role of maintenance with cetuximab or bevacizumab in RAS and BRAF wild-type mCRC. Design, Setting, and Participants In a prospective, noncomparative, open-label, multicenter, randomized phase 2 trial, patients aged 18 to 75 years with unresectable, previously untreated RAS and BRAF wild-type (before amendment, KRAS wild-type) mCRC were recruited from 21 oncology units in Italy from October 19, 2011, to March 1, 2015 (followed up through May 31, 2017). In total, 323 patients were screened and 143 were randomized to 2 treatment arms to receive as a first-line induction a regimen of mFOLFOXIRI plus cetuximab followed by cetuximab (arm A) or bevacizumab (arm B) until disease progression. Primary analyses were conducted in a modified intention-to-treat population. Interventions mFOLFOXIRI plus cetuximab repeated every 2 weeks for up to 8 cycles, followed by maintenance with cetuximab or bevacizumab until disease progression. Main Outcomes and Measures The primary end point was the 10-month progression-free rate (PFR); secondary end points included progression-free and overall survival, response rate, rate of metastases resection, and adverse events. Results Of 143 patients randomized, 116 (81.1%) (median [interquartile range (IQR)] age, 59.5 [53-67] years; 34 [29.3%] women) had RAS and BRAF wild-type mCRC. At a median (IQR) follow-up of 44.0 (30.5-52.1) months, 10-month PFRs were 50.8% (90% CI, 39.5%-62.2%) in arm A and 40.4% (90% CI, 29.4%-52.1%) in arm B. The overall response rate was 71.6% (95% CI, 62.4%-79.5%). Main grade 3/4 adverse events were neutropenia (occurring in 36 patients [31%]), diarrhea (in 21 patients [18%]), skin toxic effects (in 18 patients [16%]), asthenia (in 11 patients [9%]), stomatitis (in 7 patients [6%]), and febrile neutropenia (in 3 patients [3%]). Conclusions and Relevance Although neither of the 2 arms met the primary end point, the findings indicate that a 4-month induction regimen of mFOLFOXIRI plus cetuximab is feasible and provides relevant activity results, leading to a high surgical resection rate. Trial Registration clinicaltrials.gov Identifier: NCT02295930

Heterogeneity in the colorectal primary tumor and the synchronous resected liver metastases prior to and after treatment with an anti-EGFR monoclonal antibody

Molecular heterogeneity between primary tumors (PTs) and synchronous resected liver metastasis in colorectal cancer (CRC) has potential relevance in treatment strategies. Next-generation sequencing (NGS) may be able to increase the chances of identifying multiple molecular driver alterations, calling for therapy. The aim of the present study was to evaluate mutations in PT and synchronous resected liver metastases for patients with Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) exon 2 wild-type metastatic (m)CRC who underwent chemotherapy (CT) featuring an anti-epidermal growth factor receptor (EGFR) monoclonal antibody. Genomic analysis was performed on 54 lesions from 7 patients with mCRC. For each patient, a PT biopsy or a surgical specimen was obtained prior to CT, and the PT and all liver metastases resected following CT were analyzed. DNA libraries were generated using the Ion AmpliSeq Colon and Lung Cancer Panel, assessing the most frequent somatic mutations in 22 genes involved in colon tumorigenesis, and sequencing was performed on an Ion Personal Genome Machine system. A partial response was achieved in all the patients, with a median progression free survival time of 11 months (range, 3-21 months). All the patients were subjected to surgical liver metastasis resection. The median overall survival time was 31 months (range, 4-46 months). Molecular analysis of the genes correlated with the target therapy, suggesting significant intratumor heterogeneity, as revealed by the different mutational landscape of certain PTs and synchronous resected liver metastases following systemic therapy when compared with the PT prior to treatment. In particular, the loss and acquisition of mutations in KRAS, neuroblastoma RAS viral oncogene homolog (NRAS), tumor protein p53 (TP53), the p110α catalytic subunit of phosphoinositide 3-kinase (PIK3CA), F-box/WD repeat-containing protein 7 (FBXW7) and phosphatase and tensin homolog (PTEN) were observed. In addition, one patient developed a mucinous pattern following systemic CT. Taken together, the results of the present study demonstrated that intratumor heterogeneity is likely to affect the response to therapy, and to drive acquired resistance to targeted agents. The preliminary data also suggest a potential role for NGS in the evaluation of biological drug resistance, affecting future sequential treatment strategies.