Front-line Bevacizumab in combination with Oxaliplatin, Leucovorin and 5-Fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study

<p>Abstract</p> <p>Purpose</p> <p>To evaluate the efficacy and the toxicity of front line FOLFOX4 combined with bevacizumab in patients with metastatsic CRC (mCRC).</p> <p>Patients and Methods</p> <p>Chemotherapy-naïve patients with mCRC, received bevacizumab (5 mg/kg every 2 weeks d₁), oxaliplatin (85 mg/m²on d₁), leucovorin (200 mg/m²) on days 1 and 2 and 5-Fluorouracil (400 mg/m²as i.v. bolus and 600 mg/m²as 22 h i.v. continuous infusion on days 1 and 2) every 2 weeks.</p> <p>Results</p> <p>Fifty three patients (46 with a PS 0–1) were enrolled. Complete and partial response was achieved in eight (15.1%) and 28 (52.8%) patients, respectively (ORR: 67.9%; 95% C.I.: 53.8%–92%); 11 (20.7%) patients had stable disease and six (11.3%) progressive disease. With a median follow up period of 13.5 months, time to tumor progression was 11 months while the median survival has not yet been reached; the probability of 1-, 2- and 3- year survival was 79.8%, 63.8% and 58.3%, respectively; Two patients relapsed during the follow up period. Eight (15%) patients underwent metastasectomy with R0 resections. Grade 3–4 neutropenia occurred in 15.1% of patients and one (1.9%) of them presented febrile neutropenia. Non-hematologic toxicity included grade 3 diarrhea (7.6%) and grade 2 and 3 neurotoxicity in 16.9 and 15.1% of patients, respectively. One (1.9%) patient presented pulmonary embolism and one (1.9%) cardiac ischaemia. There was one (1.9%) sudden death after the first cycle.</p> <p>Conclusion</p> <p>The combination of FOLFOX4/bevacizumab appears to be highly effective, well tolerated and merits further evaluation in patients with mCRC.</p

Efficacy of the tyrosine kinase inhibitors [ZD 1839 (Gefitinib) and GW572016 (Lapatinib)] on circulating tumor cells in patients with breast cancer

Purpose: To investigate the effect of gefitinib (an anti-EGFR TKI ) and lapatinib (a dual EGFR and HER2 tyrosine kinase inhibitor) on circulating tumor cells (CTCs) in patients with metastatic breast cancer (MBC).Methods: Seventeen patients with MBC with detectable CTCs after the completion of prior treatment received gefitinib 250 mg/day p.o. Twenty-two patients with HER2-positive CTCs despite disease stabilization or response to prior therapy, received lapatinib 1500 mg daily. The patients received gefitinib or lapatinib in monthly cycles, till disease progression or CTC increase. CTC monitoring was performed by immunofluorescent microscopy using cytospins of peripheral blood mononuclear cells (PBMCs) double stained for HER2 or EGFR and cytokeratin. Results a) Patients who received gefitinib: a median reduction of 96.4 and 94.1 % in CTC count was observed in 11 (64.7 %) and 12 (70.6 %) of patients after the first and the second treatment cycles, respectively. Total CTC numbers declined by 73 and 44 % after the first and second treatment cycles, respectively. In nine patients with EGFR(+)/CK(+) CTCs, gefitinib resulted in a reduction of both EGFR(+) and EGFR(−) CTCs, and after the third course, most detected CTCs were EGFR(−). In two patients, with a sustained decrease in CTC numbers, a PFS of 16.0 and 19.0 months was observed and in one of them, it was associated with clinical objective response.b) Patients who received lapatinib: A total of 120 cycles were administered in 22 patients; median age was 62.5 years, 15 (68.2%) patients were post-menopausal and 20 (90.1%) had HER2-negative primary tumors. At the end of the second course, HER2-positive CTC counts decreased in 76.2% of patients; the median number of HER2-positive CTCs/patient also declined significantly (p=0.013), however the decrease was significant only among patients presenting disease stabilization (p=0.018) but not among those with disease progression during lapatinib treatment. No objective responses were observed. All CTC-positive patients harbored EGFR-positive CTCs on progression compared to 62.5% at baseline (p=0.054). The ratio of EGFR-positive CTCs/total CTCs detected in all patients increased from 17.1% at baseline to 37.6% on progression, whereas the mean percentage of HER2-negative CTCs/patient increased from 2.4% to 30.6% (p=0.03).Conclusion:Treatment-resistant CTCs could be eliminated by gefitinib or lapatinib in MBC, and both EGFR and HER2 expressions on CTCs merit further validation as potential biomarkers for specific and effective targeting of CTCs.Σκοπός: Η μελέτη της επίδραση των gefitinib (αναστολέας της τυροσινικής κινάσης του EGFR ) και lapatinib (διπλoύ αναστολέα των τυροσινικών κινασών των EGFR και HER2) στα κυκλοφορούντα καρκινικά κύτταρα (ΚΚΚ) σε ασθενείς με μεταστατικό καρκίνο του μαστού (ΜΚΜ).Μέθοδοι: Δεκαεπτά ασθενείς με ΜΚΜ και ανιχνεύσιμα ΚΚΚ μετά την ολοκλήρωση της προηγηθείσας θεραπείας έλαβαν gefitinib 250 mg / ημέρα. Είκοσι δύο ασθενείς με ανιχνεύσιμα HER2-θετικά ΚΚΚ μετά από σταθεροποίηση ή ανταπόκριση της νόσου στην προηγούμενη θεραπεία, έλαβαν lapatinib 1500 mg ημερησίως. Οι ασθενείς έλαβαν gefitinib ή lapatinib σε μηνιαίους κύκλους, μέχρι την εξέλιξη της νόσου ή την αύξηση του αριθμού των ΚΚΚ. Η παρακολούθηση των ΚΚΚ έγινε με τη μέθοδο του διπλού ανοσοφθορισμού, χρησιμοποιώντας αντικειμενοφόρες πλάκες μονοπύρηνων περιφερικού αίματος μετά από διπλή χρώση για HER2 ή EGFR και κυτταροκερατίνη. Αποτελέσματα α) Ασθενείς που έλαβαν gefitinib: παρατηρήθηκε διάμεση μείωση κατά 96.4 και 94.1% των ΚΚΚ σε 11 (64,7%) και 12 (70,6%) ασθενείς μετά την ολοκλήρωση του πρώτου και του δεύτερου κύκλου θεραπείας, αντίστοιχα. Ο συνολικός αριθμός των ΚΚΚ μειώθηκε κατά 73 και 44% μετά το πρώτο και δεύτερο κύκλο θεραπείας, αντίστοιχα. Σε εννέα ασθενείς με EGFR (+) ΚΚΚ, η χορήγηση gefitinib οδήγησε σε μείωση των EGFR (+) και EGFR (-) ΚΚΚ, και μετά τον τρίτο κύκλο τα ΚΚΚ που ανιχνεύτηκαν ήταν κυρίως EGFR (-). Σε δύο ασθενείς, με παρατεταμένη μείωση του αριθμού των ΚΚΚ, η διάμεση ελεύθερη προόδου νόσου επιβίωση ήταν 16,0 και 19,0 μήνες και σε μια από αυτές τις ασθενείς, συσχετίστηκε με ανταπόκριση της νόσου.β) Ασθενείς που έλαβαν lapatinib: 120 κύκλοι θεραπείας χορηγήθηκαν σε 22 ασθενείς με διάμεση ηλικία 62,5 έτη. Δεκαπέντε ασθενείς (68,2%) ήταν μετε-εμμηνοπαυσιακές και 20 (90,1%) είχαν HER2-αρνητικούς πρωτοπαθείς όγκους. Μετά το τέλος του δεύτερου κύκλου ο αριθμός των HER2-θετικών ΚΚΚ μειώθηκε σε 76,2% των ασθενών. Ο διάμεσος αριθμός των HER2-θετικών ΚΚΚ/ασθενή μειώθηκε επίσης σημαντικά (p = 0,013), αλλά η μείωση ήταν σημαντική μόνο στις ασθενείς με σταθεροποίηση της νόσου τους (p = 0.018), αλλά όχι στις ασθενείς με εξέλιξη της νόσου κατά τη διάρκεια της θεραπείας με lapatinib. Δεν παρατηρήθηκαν αντικειμενικές ανταποκρίσεις. Όλες οι ασθενείς με ανιχνεύσιμα ΚΚΚ είχαν EGFR-θετικά ΚΚΚ στην πρόοδο σε σύγκριση με το 62,5% κατά την έναρξη της θεραπείας (p = 0,054). Το ποσοστό των EGFR-θετικών ΚΚΚ/συνολικό αριθμό των ΚΚΚ που ανιχνεύτηκαν σε όλες τις ασθενείς αυξήθηκε από 17,1% κατά την έναρξη σε 37,6% στην πρόοδο, ενώ το μέσο ποσοστό των HER2-αρνητικών ΚΚΚ /ασθενή αυξήθηκε από 2,4% σε 30,6% (p = 0,03).Συμπέρασμα: Οι αναστολείς των τυροσινικών κινασών gefitinib ή lapatinib θα μπορούσαν να εξαλείψουν τα ανθεκτικά στη θεραπεία ΚΚΚ σε ασθενείς με μεταστατικό καρκίνο μαστού, και η έκφραση των EGFR και HER2 στα ΚΚΚ χρήζουν περαιτέρω έρευνας ως πιθανοί βιοδείκτες για την αποτελεσματικότερη στόχευση των ΚΚΚ

Efficacy of Lapatinib in Therapy-Resistant HER2-Positive Circulating Tumor Cells in Metastatic Breast Cancer.

To evaluate the efficacy of lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, in therapy-resistant HER2-positive CTCs in metastatic breast cancer (MBC).Patients with MBC and HER2-positive CTCs despite disease stabilization or response to prior therapy, received lapatinib 1500 mg daily in monthly cycles, till disease progression or CTC increase. CTC monitoring was performed by immunofluorescent microscopy using cytospins of peripheral blood mononuclear cells (PBMCs) double stained for HER2 or EGFR and cytokeratin.A total of 120 cycles were administered in 22 patients; median age was 62.5 years, 15 (68.2%) patients were post-menopausal and 20 (90.1%) had HER2-negative primary tumors. At the end of the second course, HER2-positive CTC counts decreased in 76.2% of patients; the median number of HER2-positive CTCs/patient also declined significantly (p = 0.013), however the decrease was significant only among patients presenting disease stabilization (p = 0.018) but not among those with disease progression during lapatinib treatment. No objective responses were observed. All CTC-positive patients harbored EGFR-positive CTCs on progression compared to 62.5% at baseline (p = 0.054). The ratio of EGFR-positive CTCs/total CTCs detected in all patients increased from 17.1% at baseline to 37.6% on progression, whereas the mean percentage of HER2-negative CTCs/patient increased from 2.4% to 30.6% (p = 0.03).The above results indicate that lapatinib is effective in decreasing HER2-positive CTCs in patients with MBC irrespectively of the HER2 status of the primary tumor and imply the feasibility of monitoring the molecular changes on CTCs during treatment with targeted agents.Clinical trial.gov NCT00694252

Salvage treatment in metastatic breast cancer with weekly paclitaxel and bevacizumab

Weekly paclitaxel (P) in combination with bevacizumab (B) is an effective regimen as initial treatment of metastatic breast cancer (MBC). We investigated in a phase II study the activity of the same regimen as salvage therapy in MBC. Pretreated women with MBC received weekly P (90 mg/m(2) days 1, 8, 15) and B (10 mg/kg days 1, 15) every 28 days. B could continue after discontinuing P until disease progression. This was second-line chemotherapy for 30% and third-line or more for 70% of patients. A total of 40 patients were enrolled. Median age: 61 (range 32-80) years; postmenopausal: 80%; baseline ECOG performance status &lt; 2 in 80% of patients. Two patients (5%) achieved complete response, 10 (25%) partial response (overall response rate 30%; 95% CI 15.8-44.2), and 10 (25%) stable disease. The response rate was 28% for the patients who had previously received taxanes. After a median follow-up of 20.6 months, the median time to progression was 4.8 months (95% CI 1.7-7.8), median survival 13.0 months (95% CI 10.3-15.7), and the probability of 1-year survival 55.5%. Main grade 3-4 toxicities were neutropenia 42.5%, febrile neutropenia 5%, and asthenia 10%. There was one toxic death due to sepsis. The PB regimen is well tolerated and active as salvage therapy in pretreated women with MBC. It could be an effective option even for patients exposed to taxanes during prior treatments

Waterfall plot of the % change in HER2-positive CTC numbers in patients treated with lapatinib (n = 20) after the completion of the first treatment cycle as compared to the baseline; in one patient no information on CTC counts was available.

<p>Waterfall plot of the % change in HER2-positive CTC numbers in patients treated with lapatinib (n = 20) after the completion of the first treatment cycle as compared to the baseline; in one patient no information on CTC counts was available.</p

A representative picture of CTCs detected on a patient’s cytospin.

<p>Cells were double stained using A45 B/B3 (green), HER2 (red) antibodies, and DAPI (blue) and evaluated by immunofluorescence microscopy. Presented is a HER2-negative CTC in comparison with two HER2-positive CTCs.</p