Chicago, 6 giugno 2010VENTURINI: STUDI INDIPENDENTI SU USO FARMACI INNOVATIVI
Studi mirati e indipendenti sull’utilizzo dei farmaci anti-cancro innovativi, per individuare in quali casi sono davvero efficaci e garantirli ai pazienti che ne beneficiano realmente. E’ la proposta rivolta dall’AIOM all’Aifa per coniugare l’accesso alle molecole innovative e costose con la necessità di tenere sotto controllo la spesa, in particolare quella farmaceutica ospedaliera.”Le aziende, una volta ottenuta l’approvazione di un farmaco alla commercializzazione – spiega Marco Venturini, – cercano di registrarlo con più indicazioni possibili, diverse da quella per cui hanno ottenuto l’ok. Ma dopo sono necessari studi per capire quali sono i bersagli ideali contro cui queste molecole funzionano e quali i pazienti giusti a cui darle. Di certo non saranno le farmaceutiche a condurre questi studi, loro hanno interessi diversi”. Da qui, la proposta degli oncologi al direttore generale dell’Aifa, Guido Rasi: “Indirizziamo una parte dei bandi con cui l’Aifa finanzia studi indipendenti, a queste ricerche sull’utilizzo dei farmaci biologici dopo il loro arrivo in commercio. Non si può dare tutto a tutti – sottolinea – ma la terapia giusta al paziente giusto. Altrimenti la personalizzazione delle cure, sempre più mirate a seconda del tipo di tumore del particolare paziente, non vuol dire nulla”.
TUMORE DELL’OVAIO, STUDIO DI FASE III DIMOSTRA UN MIGLIORAMENTO DEL 39% DELLA PFS
Sono stati presentati in plenaria oggi i risultati di uno studio di Fase III che ha dimostrato che le donne con tumore dell’ovaio avanzato precedentemente non trattato che hanno ricevuto un trattamento con bevacizumab in combinazione con la chemioterapia, seguito da una terapia di mantenimento con il solo bevacizumab, hanno avuto un miglioramento del 39% della sopravvivenza senza progressione (PFS) rispetto alla sola chemioterapia. Una valutazione della safety ha individuato eventi avversi in linea con quanto già osservato in altri studi su bevacizumab. Lo studio (chiamato GOG 0218) è stato condotto da un network di ricercatori guidati dal Gynecologic Oncology Group (GOG). Lo studio GOG 0218 ha dimostrato che le donne con tumore ovarico avanzato che hanno ricevuto come trattamento “front-line” bevacizumab in combinazione con chemioterapia (paclitaxel e carboplatino), e hanno proseguito il trattamento con bevacizumab da solo per una durata totale di trattamento fino a 15 mesi, hanno avuto una PFS mediana di 14,1 mesi rispetto ai 10,3 mesi delle donne che hanno ricevuto solo la chemioterapia (hazard ratio = 0.72, p=<0.0001, con una riduzione del 28% del rischio di progressione della malattia o di morte, che corrisponde ad un miglioramento del 39% della possibilità di vivere più a lungo senza che la malattia peggiori). Lo studio ha inoltre valutato l’utilizzo di bevacizumab in combinazione con la chemioterapia ma senza una prosecuzione del trattamento con il solo bevacizumab. Le pazienti che hanno ricevuto questa più breve durata di trattamento con bevacizumab non hanno avuto un aumento statisticamente significativo della PFS rispetto alla sola chemioterapia.
MIELOMA MULTIPLO, CON ACIDO ZOLEDRONICO MIGLIORA LA SOPRAVVIVENZA
Nuovi dati presentati all’ASCO mostrano che in pazienti con mieloma multiplo di nuova diagnosi il trattamento con acido zoledronico associato alla chemioterapia di prima linea rispetto al trattamento con clodronato orale è in grado di aumentare in modo significativo la sopravvivenza globale del 16% (P=0,0118) e la sopravvivenza libera da progressione di malattia del 12% (P=0,0179). In questo studio su quasi 2.000 pazienti, l’aumento della sopravvivenza di 5,5 mesi associato al trattamento con Acido zoledronico è risultato essere indipendente dall’effetto del farmaco sulle complicazioni ossee (anche conosciute come eventi correlati all’apparato scheletrico o SRE)1. Acido zoledronico ha ridotto del 24% e in modo statisticamente significativo il rischio di SRE rispetto a clodronato (P=0,0004), dimostrando di essere superiore rispetto a clodronato nella prevenzione degli SRE.
Altri dati relativi all’acido zoledronico si riferiscono al follow-up a cinque anni dello studio di fase III ABCSG-12 (Austrian Breast & Colorectal Cancer Study Group-12) che hanno mostrato che il farmaco, somministrato in associazione alla terapia ormonale postchirurgica, ha prolungato la sopravvivenza libera da malattia del 32% (HR=0,68 [95%CI 0,51-0,91], P=0,009) nelle donne in premenopausa con carcinoma mammario ormono-sensibile (HR+) allo stadio precoce. Questi dati confermano i risultati iniziali dello studio ABCSG-12 presentati all’ASCO 2008, che sono alla base dei dossier approvativi sottoposti negli Stati Uniti e in Europa per l’utilizzo di acido zoledronico nel trattamento adiuvante in donne con carcinoma mammario.
Morgan, G. Evaluating the effects of zoledronic acid (ZOL) on overall survival (OS) in patients (Pts) with multiple myeloma (MM): Results of the Medical Research Council (MRC) Myeloma IX study. Abstract #8021. American Society of Clinical Oncology 2010 Annual Meeting.
FOCUS TUMORE DEL SENO
Nell’ambito degli studi presentati sul tumore del seno sono quattro quelli selezionati dall’ASCO per il loro particolare rilievo:
New Agent, Eribulin, Derived from a Marine Sponge, Increases Survival Among Women with Metastatic Breast Cancer:
A Phase III randomized trial finds that a new chemotherapy agent, eribulin mesylate, extends median overall survival by 2.5 months among women with locally recurrent or metastatic breast cancer who had already been heavily treated with conventional therapies.
Abstract CRA 1004
A phase III study (EMBRACE) of eribulin mesylate versus treatment of physician’s choice in patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline and a taxane.
C. Twelves, D. Loesch, J. L. Blum, L. T. Vahdat, K. Petrakova, P. J. Chollet, C. E. Akerele, S. Seegobin, J. Wanders, J. Cortes, on behalf of the
Study 305 investigators
Background: Eribulin mesylate (E7389; E) is a nontaxane microtubule dynamics inhibitor with a novel mode of action. This study is the first to compare overall survival (OS) with this new chemotherapeutic (CT) agent to real-life choices in heavily pretreated patients (pts) with metastatic breast cancer (MBC).
Methods: Women with locally recurrent or MBC were enrolled in this phase III open-label, randomized, multicenter study. Pts had received 2-5 prior CT (≥2 for advanced disease), including an anthracycline and a taxane, unless contraindicated. Pts were randomized 2:1 to E 1.4 mg/m2 2-5 min IV bolus on days 1 and 8 of a 21-day cycle or treatment of physician’s choice (TPC). TPC was any monotherapy (cytotoxic, hormonal, biologic) or supportive care only. The primary endpoint was OS; secondary endpoints were objective response rate (ORR), and progression-free survival (PFS) by independent review, and duration of response (DOR). Safety and tolerability were assessed. Data are from the final analysis after 422 deaths.
Results: 762 pts were treated (508 E, 254 TPC). Median age was 55.2 (range 27-85), 16% were HER2-positive, 19% triple-negative, 73% received prior capecitabine, median no. of prior CT was 4. Median OS was 13.1 months (mo) for E vs. 10.7 mo for TPC, p=0.04 (primary analysis, stratified log rank test; HR 0.81; 95% CI 0.66, 0.99). Median PFS was 3.7 mo for E and 2.3 mo for TPC p=0.09 (HR 0.85; 95% CI 0.70, 1.03). ORR was 12% (0.4% complete response [CR], 11.5% partial response [PR]) for E and 5% (0 CR; 5% PR) for TPC, p=0.005. Median DOR was 4.1 mo for E (56 responders) vs. 6.7 mo for TPC (11 responders). Grade [G] 3/4 treatment-related adverse events (AEs) of interest for E were asthenia/fatigue (7.6%), neutropenia (44%), peripheral neuropathy (8.4%). 10% of pts experienced treatment-related serious AEs (12% E, 7% TPC).
Conclusions: The study met its primary endpoint with a significant improvement in OS by a median of 2.5 mo with E vs. TPC. E demonstrated a manageable tolerability profile, acceptable for a CT agent used as monotherapy in this late-line setting.
Disclosures: Christopher Twelves, Consultant or Advisory Role, Eisai, Expert Testimony, Eisai; Joanne Blum, Consultant or Advisory Role, Eisai; Linda Vahdat, Consultant or Advisory Role, BMSO, Eisai, Research Funding, BMSO, Eisai, Research Funding, ImClone Systems; Corina Akerele, Employment/Leadership Position, Eisai; Seth Seegobin, Employment/Leadership Position, Eisai; Jantien Wanders, Employment/Leadership Position, Eisai; Javier Cortes, Consultant or Advisory Role, Eisai.
*Abstract presented or published pursuant to an exception to the ASCO Conflict of Interest Policy.
Breast Cancers that Spread to the Liver May Change Biology, Impacting Treatment Effectiveness:
A retrospective study of women with metastatic breast cancer showed that the biological characteristics of their primary tumors – including estrogen, progesterone, and HER2 status – often changes when the cancer spread to the liver, requiring a change in therapy for many women.
Abstract: CRA 1008
Should liver metastases of breast cancer be biopsied to improve treatment choice?
M. A. Locatelli, G. Curigliano, L. Fumagalli, V. Bagnardi, G. Aurilio, P. Della Vigna, L. Monfardini, S. Giudici, G. Viale, A. Goldhirsch
Background: Decision making on systemic treatment of women with metastatic breast cancer is based on features like estrogen receptor (ER), progesterone receptor (PgR), and HER2 status assessed on the primary tumor. We evaluated the concordance of receptor status between primary tumor and liver metastases (mts) and its impact on treatment choice.
Methods: We retrospectively analyzed a database including ultrasound guided liver biopsies performed from 1995 to 2008. All tissue samples, both from primary tumor and liver mts, were analyzed for ER, PgR and HER2 status. Clinical and biological data were obtained from medical charts. Differences between proportions were evaluated using the Pearson chi-square test.
Results: We identified 255 consecutive patients (pts) with matched primary and liver tissue samples. Median time from primary diagnosis to liver biopsy was 3.4 years (range 0-18.3 years). Changes in ER status were observed in 41/255 pts (16.0%). 16/58 pts (27.6%) changed from ERnegative to ER-positive and 25/197 pts (12.7%) changed from ER-positive to ER-negative (p=0.0066). Changes in PgR status were observed in 76/255 pts (29.8%). 18/91 pts (19.8%) changed from PgR-negative to -positive and 58/164 pts (64.6%) from PgR-positive to PgR-negative (p <0.0001). 12/52 pts (23.1%) changed from ER- and PgR-negative to ER- or PgR-positive (group A) and 27/203 pts (13.3%) changed from ER- or PgR-positive to ER- and PgR-negative (group B) (p=0.087). In the group A the treatment of 4/12 pts (33.3%) was changed after biopsy: 2/4 started endocrine treatment (HT) and 2/4 stopped it. In group B the treatment of 18/27 pts (66.6%) was changed after biopsy: 17/18 stopped HT.
Changes in HER2 status were observed in 22/167 pts (13.1%): 6/116 pts (5.1%) changed from HER2-negative to HER2-positive and 16/51 pts (31.4%) changed from HER2-positive to negative (p=<0.0001). In this group pts started and/or stopped a trastuzumab containing treatment after biopsy.
Conclusions: There was a discordance in receptor status between primary tumor and liver mts, which led to change in therapy for 48/255 of pts (18.8 %). Biopsy of metastases for reassessment of biological features should be considered in all pts when safe and easy to perform, since it is likely to impact treatment choice.
Removing Axillary Lymph Nodes Based on Metastases in the Sentinel Node Does Not Improve Survival in Early Breast Cancer:
Removing additional axillary (underarm) lymph nodes to look for breast cancer in women with limited disease spread in the sentinel node does not improve survival, according to results from a Phase III study. These findings are important because many physicians routinely remove multiple axillary nodes in women with micrometastases in the sentinel lymph node, which increases the risk of side effects, such as pain and swelling.
Abstract: CRA 506
ACOSOG Z0011: A randomized trial of axillary node dissection in women with clinical T1-2 N0 M0 breast cancer who have a positive sentinel node.
A. E. Giuliano, L. M. McCall, P. D. Beitsch, P. W. Whitworth, M. Morrow, P. W. Blumencranz, A. M. Leitch, S. Saha, K. Hunt, K. V. Ballman
Background: Sentinel node biopsy (SNB) eliminates the need for axillary dissection (ALND) in patients whose sentinel node (SN) is tumorfree. However, completion ALND remains the gold standard for patients with a tumor-involved sentinel node. ALND achieves regional control, but its effect on survival remains controversial. The main objective of ACOSOG Z0011 was to compare outcomes of patients with hematoxylin and eosin (H&E) detected metastasis in SN managed with or without ALND and no axillary irradiation.
Methods: Clinically node-negative patients who underwent SN biopsy and had 1 or 2 SN with metastases detected by H&E were randomized to ALND or no further axillary specific treatment. All patients were treated with lumpectomy and opposing tangential field irradiation. Adjuvant systemic therapy was at the discretion of their physicians. Overall survival (OS), disease-free survival (DFS), and locoregional control were evaluated.
Results: 446 patients were randomized to SNB alone and 445 to SNB plus ALND. Patients treated with SNB alone were similar to those treated with SNB + ALND with respect to age, tumor size, Bloom-Richardson score, estrogen receptor status, adjuvant systemic therapy, tumor type, and T stage. Patients randomized to SNB alone had a median of two lymph nodes removed whereas patients randomized to ALND had a median of 17 lymph nodes removed. 17.6% of ALND patients had 3 or more involved nodes compared to 5.0% of SNB patients (p < 0.001). Median follow-up is 6.2 years. 5-year in-breast recurrence after ALND was 3.7% compared to 2.1% for SNB (p = 0.16) while 5-year nodal recurrence was 0.6% compared to 1.3% (p = 0.44) respectively. The five-year OS for patients undergoing SNB + ALND is 91.9% compared to 92.5% for SNB alone (p = 0.24), and DFS is 82.2% compared to 83.8% respectively (p = 0.13).
Conclusions: Despite the widely held belief that ALND improves survival, no significant difference was recognized by this study of SN nodepositive women. Although the study closed early because of low accrual/event rate, it is the largest phase III study of ALND for node-positive women, and it demonstrates no trend toward clinical benefit of ALND for patients with limited nodal disease.
Disclosures: Peter Blumencranz, Honoraria, ACOSOG, Research Funding, ACOSOG; A. Leitch, Research Funding, ACOSOG, NSABP; Sukamal Saha, Employment/Leadership Position, Audit Committee.
Using Immunohistochemistry Testing to Identify Breast Cancer Micrometastases in the Sentinel Node and Bone Marrow Does Not Help Predict Survival:
A large observational trial of women with earlystage breast cancer who had breast-sparing surgery (lumpectomy) showed that using immunohistochemistry (IHC) to detect micrometastases in sentinel lymph nodes and the bone marrow does not predict overall survival and should not be used to guide treatment decisions. Micrometastases are smaller, hidden pockets of metastatic disease that may be missed by standard pathology.
Abstract CRA 504
ACOSOG Z0010: A multicenter prognostic study of sentinel node (SN) and bone marrow (BM) micrometastases in women with clinical T1/T2 N0 M0 breast cancer.
R. Cote, A. E. Giuliano, D. Hawes, K. V. Ballman, P. W. Whitworth, P. W. Blumencranz, D. S. Reintgen, M. Morrow, A. M. Leitch, K. Hunt
Background: SN biopsy (SNB) with immunohistochemistry (IHC) of histologically negative SN identifies metastases (mets) not seen by
standard histology. The impact of IHC-detected BM mets has been reported in several large single-institution studies. 5,539 patients (pts) were entered into this prospective multicenter observational study to determine the clinical significance of SN and BM mets.
Methods: Patients underwent lumpectomy and SNB with bilateral iliac crest BM aspiration. BM and histologically negative SN were evaluated with IHC in a central laboratory (results not clinically reported). Overall survival (OS), disease-free survival, and locoregional recurrence were determined. Results with OS (the primary endpoint) are reported here.
Results: SN were successfully identified in 5,184 of 5,485 pts (94.5%). Histologic SN mets were found in 1,239 pts (23.9%). IHC detected an additional 350 pts (10.5%) with SN mets. BM mets were identified by IHC in 105 of 3491 examined (3.0%). 5-yr overall survival is shown in the Table. BM IHC positivity significantly predicted decreased OS (p=0.015). A multivariable analysis that included SN and BM status, ER, PR, grade, size, and age showed that neither IHC detected mets in SN (p=0.66) or BM (p=0.08) were independent predictors of OS, although BM status showed a strong trend.
Conclusions: The detection of BM mets by IHC in pts with clinical T1/2 N0M0 breast cancer identifies those pts at significantly increased risk for death; the impact of BM mets on outcome supports and confirms prior studies. In this study, SN IHC-detected mets appear to have no significant impact on OS. The routine examination of SN by IHC is not supported in this patient population by this study.
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