Dissertation committee:
Μιχάλης Κουτσιλιέρης, Καθηγητής, Ιατρική, ΕΚΠΑ
Μαρία Λυμπέρη-Κυριακοπούλου, Καθηγήτρια, Ιατρική, ΕΚΠΑ
Χρήστος Κόνσουλας, Αν. Καθηγητής, Ιατρική, ΕΚΠΑ
Ελένη Κοτσιφάκη, Αν. Καθηγήτρια, Ιατρική, ΕΚΠΑ
Κλειώ Μαυραγάνη, Επικ. Καθηγήτρια, Ιατρική, ΕΚΠΑ
Αθανάσιος Αρμακόλας, Επικ. Καθηγητής, Ιατρική, ΕΚΠΑ
Αναστάσιος Φιλίππου, Επικ. Καθηγητής, Ιατρική, ΕΚΠΑ
Summary:
Background: Lung cancer is the most common cause of cancer and responsible for 28% of all deaths associated with cancer. Approximately 80% of lung cancer cases are non-small cell lung cancer (NSCLC). One of the cytotoxic agents most commonly used in the treatment of epithelial malignancies is cisplatin. However, its severe side effects and resistance to administration have impeded the clinical use of cisplatin. Lipoplatin is a new liposomal cisplatin, designed to reduce cisplatin toxicities without reduce efficacy.
Purpose: The analysis and assessment of radiological findings, which mainly based the evaluation of response to chemotherapy (according to RECIST 1.1 criteria) and correlation with the histological type of cancer in a phase II prospective, randomized, comparative, open label study and compare the efficacy and safety of Lipoplatin-gemcitabine versus cisplatin-gemcitabine combination as first line treatment in advanced NSCLC. Secondary endpoints of the study is the ORR, DCR, PFS, duration of the response and OS.
Patients and methods: The study was performed in Metaxa hospital (2nd pathological clinic, investigator: Dr. Nikolaos Milonakis). Inclusion criteria included: age >18 years, with histologically or cytologicaly confirmed diagnosis of stage IIIb/IV; ECOG performance status 0-1; at least one measurable lesion as defined by the RECIST criteria; adequate bone marrow/liver/renal function; ability to comply with the protocol. Exclusion criteria included prior chemotherapy for NSCLC; other neoplasms; major surgery or radiotherapy within 3 weeks of study commencement; recent myocardial infarction or severe heart disease; autoimmune disease; pregnancy and lactation. Patients with brain metastases were eligible at least 1 month after the completion of radiotherapy and only if the lesion was evaluated as controlled. Patients randomized to arm A, received Lipoplatin 120mg/m2 as 6-h (intravenous) IV infusion on days 1,8 and 15 of 21-day cycle, followed by gemcitabine 1000mg/m2 as 30-min IV infusion on daye 1 and 8 of the cycle; there is no pre- or post-hydration. Patients randomized to arm B received cisplatin 100mg/m2 as 2-h (intravenous) IV infusion on day 1 of a 21-day cycle, with pre-hydration and forced diuresis, followed by gemcitabine 1000mg/m2 as 30 min (intravenous) IV infusion on day 1 and 8 of the cycle.
The clinical evaluation of the patient will be: before starting treatment, weekly evaluation (7th day after each injection), after 3 and 6 cycles of treatment and every 3 months for life. The patients were assessed by complete physical examination, including neurogical examination, electrocardiogram, disease evaluation by appropriate radiological techniques, (chest X-rays, CT scan of the chest, abdomen and brain, bone scan), complete blood cell count, serum chemistries and creatinine clearance. All imaging exams will be carried out according to normal internationals protocols, not necessarily at preselected centers since the introduction and monitoring of patients in the study will preformed in any center.
Results: The evaluation of the study effectiveness was based on the imaging findings using RECIST 1.1 criteria. Partial response (PR) after three complete cycles showed in 31.7% of patients in arm A and 25.6% in B respectively. Stable disease on the other hand was achieved in 39% patients in the arm A compared to 30.8% patients in the arm B. DCR was 71% and 59% for arm A and B respectively. A preliminary efficacy of Lipogem versus Cisgem in the adenocarcinoma histological subtype of NSCLC showed 16.7% versus 45.8% PD. Treatment in arm A was better tolerated with myelotoxicity and a transient mild elevation of serum creatinine as the dominant side effects; the only grade 4 adverse event was neutropenia noted in 2% of the patients. There was a significant reduction in nephrotoxicity in the Lipogem arm (0% versus 5% grade III) as well nausea and vomiting (2% versus 12% grade III).
Conclusion: Lipoplatin has shown to have lower toxicity, mainly nephrotoxicity, as well as higher efficacy than cisplatin, when combined with gemcitabine in advanced NSCLC. There were no associated deaths, or life-threating adverse events. Particularly relevant is that Lipoplatin is administered without pre- or post-hydration, on an outpatients basis. The higher response, although statistically insignificant because of the small patient sample, as well as the reduced overall toxicity are proposed to arise from the ability of the Lipoplatin nanoparticles to preferentially attack tumor cell and tumor cell vasculature compared to normal tissue. In addition, Lipoplatine in the adenocarcinoma histological subtype of NSCLC has a statistically significant response versus cisplatin.
Keywords:
Non Small Cell Lung Cancer (NSCLC), Cisplatin, Lipoplatin, Computed Tomography, RECIST
