BackgroundNivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint–inhibitor antibody, disrupts PD-1–mediated signaling and may restore antitumor immunity. MethodsIn this randomized, open-label, international phase 3 study, we assigned patients with nonsquamous non–small-cell lung cancer (NSCLC) that had progressed during or after platinum-based doublet chemotherapy to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. ResultsOverall survival was longer with nivolumab than with docetaxel. The median overall survival was 12.2 months (95% confidence interval [CI], 9.7 to 15.0) among 292 patients in the nivolumab group and 9.4 months (95% CI, 8.1 to 10.7) among 290 patients in the docetaxel group (hazard ratio for death, 0.73; 96% CI, 0.59 to 0.89; P=0.002). At 1 year, the overall survival rate was 51% (95% CI, 45 to 56) with nivolumab ve...

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Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer

BackgroundOsimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI–sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation–positive advanced non–small-cell lung cancer (NSCLC). MethodsIn this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation–positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival. ResultsThe median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confi...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1713137

Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer

BACKGROUND: In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK ) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. METHODS: We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. RESULTS: The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. CONCLUSIONS: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.) Copyright © 2013 Massachusetts Medical Society.

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1214886

Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer

Bevacizumab plus Irinotecan,Fluorouracil,and Leucovorin for Metastatic Colorectal Cancer

BACKGROUND: The efficacy of the ALK inhibitor crizotinib as compared with standard chemotherapy as first-line treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC) is unknown. METHODS: We conducted an open-label, phase 3 trial comparing crizotinib with chemotherapy in 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease. Patients were randomly assigned to receive oral crizotinib at a dose of 250 mg twice daily or to receive intravenous chemotherapy (pemetrexed, 500 mg per square meter of body-surface area, plus either cisplatin, 75 mg per square meter, or carboplatin, target area under the curve of 5 to 6 mg per milliliter per minute) every 3 weeks for up to six cycles. Crossover to crizotinib treatment after disease progression was permitted for patients receiving chemotherapy. The primary end point was progression-free survival as assessed by independent radiologic review. RESULTS: Progression-free survival was significantly longer with crizotinib than with chemotherapy (median, 10.9 months vs. 7.0 months; hazard ratio for progression or death with crizotinib, 0.45; 95% confidence interval [CI], 0.35 to 0.60; P<0.001). Objective response rates were 74% and 45%, respectively (P<0.001). Median overall survival was not reached in either group (hazard ratio for death with crizotinib, 0.82; 95% CI, 0.54 to 1.26; P=0.36); the probability of 1-year survival was 84% with crizotinib and 79% with chemotherapy. The most common adverse events with crizotinib were vision disorders, diarrhea, nausea, and edema, and the most common events with chemotherapy were nausea, fatigue, vomiting, and decreased appetite. As compared with chemotherapy, crizotinib was associated with greater reduction in lung cancer symptoms and greater improvement in quality of life. CONCLUSIONS: Crizotinib was superior to standard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC. (Funded by Pfizer; PROFILE 1014 ClinicalTrials.gov number, NCT01154140.).

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First-line crizotinib versus chemotherapy in ALK-positive lung cancer

patients with cancer have an elevated risk of thromboembolic events especially in the venous system, as widely documented in literature2• Rare cases concern the arterial system1•10. About 90% of cancer patients have abnormal clotting: higher platelets aggregation; higher activity of procoagulant factors such as prothrombinase and factor X; lower activity of anticoagulant factors. The risk of arterial thromboses increases when antiblastic chemotherapy is administered. Cases are reported in patients treated with platinumderived compounds4•6•7, bleomycin6, vinca alcaloids8 and tamoxifen3• Wall et al. 11 , from Cancer and Leukemia Group B (CALGB), evaluated the association between arterial thromboembolic events and chemotherapy administration. They observed 13 (1.3%) arterial thrombosis after chemotherapy in 1,014 patients with breast cancer stage II and III (TNM). These events happened early in the course of therapy and affected both peripheral and cerebral circulation. We present a case of a white female with small cell lung cancer, who at day 9 after the first cycle of chemotherapy with cisplatin and etoposide developed an acute arterial obstruction of the upper left limb. A 49-year-old white female smoking about 30 cigarettes a day, with a familiar history of hypertrigliceridemia, with previous aspecific pleuritis, duodenal ulceration, appendicectomy, hysterectomy and monolateral ovariectomy, with any impairment of cardiovascular system, was hospitalized because of thoracic pain and dry cough. The electrocardiogram was normal, as well as haemostasis and lipidic balance, a stress test was broken off at 60 W for sudden thoracic pain and dyspnea. RX revealed a left pulmonary mass: an eventual fibrobronchoscopy showed an almost full obstruction of the left common upper-anterior broncus. Biopsy revealed a small cell lung cancer. Whole-body bone scanning and whole-body CT evidenced three left pulmonary metastasis, 4 cm, 3 cm and 2.5 cm respectively. An ecocardiography was performed, showing a The patient was admitted at our day-hospital. Chemotherapy consisted of cisplatin 100 mg/m2 d 1 + etoposide 100 mg/m2 d 1-2-3 q28w, with previous administration of ranitidine, desametasone, ondansetron and with G-CSF support. At day 6 after treatment the patient felt paresthesias at the second and third finger of the upper right limb, with spontaneous resolution after 20 minutes. More ,~e­ vere symptoms appeared 24 hours later at the upper left limb, with severe pain and cyanosis. She was hospitalized and after a Doppler ultrasonography and an arteriography diagnosis was made of acute obstruction of the left axillary artery, extending to omeral and radio-ulnar arteries. An embolectomy of omeral, ulnar and radial arteries was performed, with systemic heparin administration followed by warfarin from day 3 after intervention. No postsurgical complications ensued, therefore the second cycle of chemotherapy was administered at day 28. Although rare, arterial thrombosis in cancer patients after chemotherapy have to be carefully considered and evaluated for the additional risk. Among the mechanisms considered for arterial thromboembolic events in the cancer population there are: 1) sympathetic nervous system stimulation because of tumor infiltration of a nervous plexus, with spasm of arterial wall muscular cells; 2) intraarterial precipitation of crioglobulins and other proteins; 3) tumoral invasion of arteries with distal embolization; 4) state of hypercoagulability. Edwards et al. 5 use heparin to prevent arterial thrombosis and this procedure is also reported by other authors9. Further evaluation is necessary to find valid markers in order to identify the patients who are at higher risk to develop a thrombotic event. These selected patients could be considered for a preventive treatment with he-, parin.

Acute arterial thrombosis in a patient with small cell lung cancer after a cycle of chemotherapy with cisplatin and etoposide.

Background: Bevacizumab plus chemotherapy prolongs progression-free survival (PFS) and overall survival (OS) in metastatic colorectal cancer (mCRC). Although there is strong evidence to suggest that the mutational status of the K-ras oncogene has a role as a predictive factor for activity in patients treated with cetuximab and panitumumab, few data have been obtained in patients treated with bevacizumab. We conducted an additional retrospective analysis to investigate the prognostic value of K-ras mutation relative to mCRC first-line treatment with bevacizumab. Materials and methods: A total of 108 patients were retrospectively reviewed. K-ras status was assessed in the overall population by sequencing. Statistical association for PFS and OS was analyzed using the Kaplan–Meier method, and the prognostic role of K-ras was determined using the logrank test. Results: Median PFS was 10 months both for patients with wild-type (WT) K-ras and mutated (MT) K-ras (hazard ratio [HR] 0.94, P=0.75); neither difference in median OS was significant (27 months WT K-ras versus 26 months MT K-ras, HR 0.92; P=0.70). A further analysis was carried out in the two groups according to metastatic sites. No statistically significant differ ence in terms of PFS and OS was demonstrated between WT K-ras and MT K-ras with liver metastases only and in those with extrahepatic disease. Conclusion: Although further study is required, our results seem to confirm that K-ras muta tion does not have a prognostic role in mCRC patients receiving first-line treatment with

/pdf/metastatic-colorectal-cancer-first-line-treatment-with-57opvlprje.pdf

Metastatic colorectal cancer first-line treatment with bevacizumab: the impact of K-ras mutation.

2064 Background: Thymomas are rare slowly growing neoplasms, associated with myasthenia gravis, hypogammaglobulinemia and pure red-cell aplasia. Its malignant behavior is indicated by micro- or macroscopic invasion of tumor capsule or sorrounding organs. About 40% of thymomas are invasive and some well encapsulated tumor recur years after surgical resection. The 5 years survival rate in patients with noninvasive thymomas is 70 - 85% and decreases at 50 - 67% for invasive thymomas with the worst trend for stage IV (23%). Recurrence rate is usually low (2%) for stage I encapsulated thymomas while for stage II and III is approximately 28% and it seems to decrease at 5% when thymectomy is followed by RT. Thymomas have a high content of somatostatin receptors so they could show an elevated Indium-labeled octreotide (111In-DTPA-D - Phe - octreotide) uptake when OCTREOSCAN is performed. Methods: We tested 29 patients (pts) (tab.1) whose CT showed thymoma’s relapse and 27.5% (n=8) resulted scintigraphically posit...

Targeting the therapy: Octreotide in thymoma relapse

Aim: The effect of KRAS status on response to bevacizumab plus chemotherapy in metastatic colorectal cancer is still unclear. We aimed to evaluate the overall clinical response to such a therapy in clinical practice and assess the role of KRAS status on therapy response. Patients & methods: This was a retrospective study enrolling 108 metastatic colorectal cancer patients. KRAS mutation analysis was performed by PCR. Results: Overall, 41.7% of patients had stable disease, 39.8% a partial response, 3.7% a complete response and 14.8% disease progression. Both clinical benefit and objective response rate tended to be higher in patients with only hepatic metastases than those with extrahepatic or multiple metastases. Response to therapy would appear to be independent of KRAS status, but larger studies are needed. Conclusion: Bevacizumab plus chemotherapy provides clinical benefit and objective response rate in patients with metastatic colorectal cancer independently of KRAS expression, especially in those pat...

Bevacizumab plus chemotherapy in metastatic colorectal cancer patients treated in clinical practice.

839 Background: X (Xeloda) is the reference treatment in anthracycline- and taxane-pretreated MBC, based on consistent high activity, a good safety profile with little myelosuppression and no alopecia, and evidence that its addition to docetaxel extends survival. Tolerability and efficacy also make X an interesting drug in elderly pts with hormone-refractory disease. Methods: Between May 2002 and Sep 2003, 18 elderly MBC pts received X 1000 mg/m2 twice daily on days 1–14, every 3 weeks. Study objectives were efficacy and safety of X and its impact on quality of life (QoL), assessed via the Clinical Benefit Response (CBR) every third cycle of treatment. Results: Pt characteristics were: median age 70 years (range 68–73); median ECOG PS 1 (range 0–2); 100% with visceral metastases and 53% with >2 metastatic sites. All pts had received prior adjuvant chemotherapy and at least one previous hormonal therapy for advanced disease. A total of 142 cycles were administered (median 6 cycles per pt). After 3 cycles, ...

Flavia Longo

Papers

Acute arterial thrombosis in a patient with small cell lung cancer after a cycle of chemotherapy with cisplatin and etoposide.

Metastatic colorectal cancer first-line treatment with bevacizumab: the impact of K-ras mutation.

Targeting the therapy: Octreotide in thymoma relapse

Bevacizumab plus chemotherapy in metastatic colorectal cancer patients treated in clinical practice.

Capecitabine (X) in elderly patients (pts) with hormone-refractory metastatic breast cancer (MBC)