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3 Giugno 2009

SPECIALE ASCO 2009 – N. 1, 30/05/2009

Orlando, 30 maggio 2009

AL VIA IL 45MO CONGRESSO ASCO: LE CURE PERSONALIZZATE AL CENTRO DELL’ATTENZIONE DI 30.000 ONCOLOGI
Al via a Orlando (Flo) la 45ma edizione del Congresso dell’American Society of Clinical Oncology (ASCO), il piu’ importante appuntamento mondiale per gli specialisti. Sono oltre 30.000 quelli intervenuti quest’anno, piu’ di 4.000 gli abstract presentati.
Il tema a cui e’ dedicato il meeting 2009 e’ la “Personalizing Cancer Care”. “Ogni paziente e’ diverso, dal punto di vista biologico, clinico, economico e sociale – ha commentato Richard L. Schilsky, presidente dell’ASCO -. Solo negli ultimi 10-15 anni si e’ iniziato a capire come si differenziano dal punto di vista istologico tumori simili, in seguito e’ cominciato lo sviluppo di test clinici molecolari che hanno permesso concrete applicazioni nella pratica quotidiana. Ecco perche’ la ricerca traslazionale e trials clinici ben disegnati sono cosi’ cruciali: la ricerca di laboratorio permette di indagare e scoprire le caratteristiche del tumore. Ma per applicare correttamente questi risultati sono necessari test clinici che possano guidare la terapia in modo da produrre i migliori outcome. Migliorare gli outcome attraverso una piu’ accurata selezione dei trattamenti e’ solo uno degli aspetti della personalizing cancer care. Non va sottovalutato il diverso sviluppo di eventi avversi fra paziente e paziente: questa variabilita’ spesso segnala polimorfismi genetici nel metabolismo del farmaco che non possono essere identificati, nella maggior parte dei casi, con un semplice test del sangue. Anche le dosi del farmaco devono essere tarate nella prospettiva di ridurre al minimo le tossicita’. Ma terapia personalizzata significa anche prevenzione e attenzione al “dopo” la malattia. Sempre piu’ pazienti sopravvivono al tumore grazie a terapie piu’ efficaci, bisogna riconoscere pero’ anche l’importanza del supporto sociale, di eventuali comorbilita’, della situazione economica e del livello culturale. Sempre di piu’ “personalizing cancer care” significa come ci relazioniamo con i nostri pazienti, come individui e non come “statistiche’, come persone con una malattia grave che vivono in un contesto sociale che coinvolge familiari, colleghi, amici e gli altri. Come oncologi – ha concluso Schilsky nel suo discorso inaugurale – il nostro focus e’ sempre stato, e deve rimanere, curare il malato, non la malattia. Dobbiamo sempre piu’ attrezzarci per acquisire competenze e rispondere a questo obiettivo nel migliore dei modi”.

IL PRESIDENTE ASCO PLAUDE A OBAMA: “BENE AUMENTO FONDI PER RICERCA”
“La crisi economica non deve fermare la ricerca nella cura del cancro. Dopo anni di robusti investimenti, negli ultimo tempi I finanziamenti sono stati bloccati, con un calo di 500 milioni di dollari nel budget dell’ National Institute of Health dal 2004 al 2008. Per questo – ha commentato Richard L. Schilsky, presidente dell’ASCO – la recente decisione del Presidente Obama di aumentare lo stanziamento per la ricerca e’ fondamentale. Oggi 11 milioni di americani sopravvivono, contro i soli 3 milioni degli anni ’70. E l’incidenza e’ diminuita del 18% negli uomini e del 10% nelle donne rispetto ai primi anni ’90. La priorita’ per l’ASCO e’ ora battersi per la parita’ di accesso alle cure, soprattutto dele minoranze. Esiste un profondo divario negli USA fra chi riesce a curarsi e chi resta escluso. E’ necessaria una profonda riforma del sistema sanitario perche’ tutti possano avere accesso a terapie di qualita’. L’ASCO sta lavorando con l’amministrazione Obama per raggiungere questo obiettivo: aumentare l’assistenza ed eliminare le disparita’. Anche incoraggiando medici appartenenti a minoranze etniche a lavorare in oncologia”.

UN PAZIENTE SU DIECI E’ PREOCCUPATO DEI COSTI DELLA TERAPIA

Ricercatori statunitensi dell’Harvard Medical School hanno analizzato l’ansia dei pazienti rispetto ai costi della terapia e se questa preoccupazione spinga loro ad adottare comportamenti per “risparmiare” (non seguire la prescrizione, saltare le dosi o utilizzarne meno rispetto a quella raccomandata, ecc), tali da rivelarsi dannosi per la riuscita della terapia. La ricerca, presentata all’ASCO da Deborah Scrag, ha preso in esame 409 pazienti con colonretto metastatico in cura con bevacizumab e/o cetuximab nell’ambito di uno studio promosso dal National Cancer Institute e che necessitavano di terapie di supporto(antiemetici, antibiotici, ecc.).
I risultati principali dello studio dimostrano che:
– Il 10% dei pazienti e’ preoccupato dai costi delle terapie di supporto
– Circa il 15% dei pazienti ha adottato strategie di risparmio durante I primi tre mesi del trial, come non seguire la terapia, assumere una dose minore di quella raccomdata o “tagliare” sui costi delle terapie di supporto
– Solo il 12% dei pazienti ha riferito di aver discusso con il proprio medico riguardo al costo della terapia
Abstract 9503
Clinical trial participants’ strategies for coping with prescription drug costs: a companion study to CALGB 80405
D. Schrag, M. Naughton, A. Kesselheim, L. Archer, D. Niedzwiedcki, D. Romanus, R. Goldberg, A. Venook, Cancer and Leukemia Group B; Dana-Farber Cancer Institute, Boston, MA; Wake Forest University, Winston-Salem, NC; Brigham and Women’s Hospital, Boston, MA; CALGB, Chicago, IL; University of North Carolina, Chapel Hill, NC; University of California at San Fransisco, San Fransisco, CA

VACCINO TERAPEUTICO PER IL MELANOMA
Presentati oggi all’ASCO i risultati di uno studio randomizzato di fase III che dimostra come il vaccino terapeutico si riveli promettente per i malati con melanoma avanzato. La ricerca, condotta dall’equipe del prof. Patrick Hwu, direttore del dipartimento del Melanoma all’M.D. Anderson Cancer Centre con il Goshen Centre for Cancer Care dell’Indiana (diretto dal prof. Douglas Schwartzentruber), e’ uno studio di fase III che ha coinvolto 185 pazienti reclutati in 21 centri negli USA. Tutti avevano un melanoma metastatico ed erano stratificati per metastasi cutanee, un noto indicatore di risposta all’interleuchina-2 (IL2). I pazienti sono stati randomizzati per ricevere solo IL-2 o IL-2 piu’ vaccino. Chi ha ricevuto il vaccino ha mostrato un significativo tasso di risposta, 22.1%, e di sopravvivenza libera da progressione, 2.9 mesi. I dati in chi non ha ricevuto il vaccino sono stati rispettivamente 9.7% e 1.6 mesi. La mediana di sopravvivenza per chi ha ricevuto il vaccino mostra inoltre un trend positivo, 17.6 mesi vs. 12.8. Il vaccino e’ un peptide, identificato come gp100:209-217 (200M) che agisce stimolando le cellule T dei pazienti, che ne controllano la risposta immunitaria.
Abstract 9011
A phase III multi-institutional randomized study of immunization with gp 100:209-217 (210M) peptide followed by high-dose IL2 compared with high-dose IL-2 alone in patients with metastatic melanoma
D. J. Schwartzentruber, D. Lawson, J. Richards, R. M. Conry, D. Miller, J. Triesman, F. Gailani, L. B. Riley, D. Vena, P. Hwu; Center for Cancer Care, Goshen, IN; Winship Cancer Institute, Emory University, Atlanta, GA; Lutheran General Hospital Cancer Care Center, Park Ridge, IL; UAHSF Comprehensive Cancer Center, Birmingham, AL; James Graham Brown Cancer Center, Louisville, KY; Medical Consultants, Milwaukee, WI; Riverside Creek Medical Center, Riverside, CA; St. Luke’s Hospital, Bethlehem, PA; The EMMES Corporation, Rockville, MD; M. D. Anderson Cancer Center, Houston, TX

ONCOLOGI POCO ATTENTI AL MANTENIMENTO DELLA FERTILITA’ DEI MALATI
Porre attenzione a preservare la fertilita’ dei pazienti oncologici sottoposti a chemioterapia non e’ una delle priorita’ per il medico: i malati raramente vengono informati e ancora meno vengono indirizzati verso specialisti del settore in tempo utile per prevenire eventuali problemi futuri. Lo rivela un’indagine del Moffitt Cancer Centre Institute di Miami presentata oggi al Congresso. Sono stati coinvolti 613 oncologi: se la maggioranza degli specialisti dichiara di discutere il problema con il paziente in eta’ fertile, solo uno su 4 lo ha poi indirizzato verso centri specializzati o ha consegnato materiale informativo. Lo studio sottolinea come meno del 50% dei pazienti riceva un’adeguata informazione sui rischi per la fertilita’ prima di iniziare un trattamento di chemioterapia. Inoltre il 38% degli oncologi afferma di non conoscere le line guida per la tutela della fertilita’ emanate dall’ASCO nel 2006.
Abstract CRA 9508
National survey of physicians practice patterns: Fertility preservation and cancer patients
G. Quinn, S. T. Vadaparampil, P. Jacobsen, J. Lee, J. Lancaster, G. Bepler, D. L. Keefe, T. L. Albrecht

SPECIALE WOMEN’S CANCER
Fra le piu’ rilevanti novita’ presentate all’ASCO nell’ambito dei tumori femmili 4 studi sono ritenuti fra i piu’ meritevoli di attenzione:
No survival advantage to treating ovarian cancer relapse based on rising CA125 levels, compared with waiting for symptoms
A study featured in ASCO’s plenary session reports that starting treatment immediately for an ovarian cancer relapse based on CA125 protein levels found in the blood does not improve overall survival, compared with delaying treatment until symptoms arise. The findings should allow women to avoid the anxiety and cost associated with frequent blood testing and the toxicity of early treatment.
A randomized trial in ovarian cancer (OC) of early treatment of relapse based on CA125 level alone versus delayed treatment based on conventional clinical indicators (MRC OV05/EORTC 55955 trials)
G. J. Rustin, M. E. van der Burg, on behalf of MRC and EORTC collaborators
Background: Serum CA125 often rises several months before women with OC have symptoms or clinical signs of relapse. OV05/55955 was designed to determine whether there were benefits from early treatment based on a confirmed elevation of CA125 levels versus delaying treatment until clinically indicated. Methods: Women with OC in clinical complete remission after first line platinum-based chemotherapy and a normal CA125 were registered. CA125 was measured every 3 months but patients and investigators were blinded to the results, which were only monitored by the trials units. If CA125 levels exceeded twice the upper limit of normal, patients were randomized to either immediate treatment or to remain having blinded CA125 measurements with treatment commencing when clinical or symptomatic recurrence appeared. Patients in both arms were treated according to standard local practice. The primary outcome measure was overall survival. The study was designed to detect a 10% improvement in 2-year overall survival in the immediate treatment arm with at least 85% power and 5% significance level (2-sided). Results: 1442 patients were registered from 59 sites in 10 countries between 1996 and 2005. Randomization closed on 31March 2008 with 527 patients (264 immediate and 263 delayed) randomized and when the targeted number of events (deaths) were reached. 915 patients have not been randomized due to: no CA125 rise and no relapse (48%); relapse with or without CA125 rise (30%); death (6%); patient withdrawal (14%); or other reasons (2%). For randomized patients baseline characteristics were well balanced between the groups. Median age at registration was 61 years; 81% were FIGO stage III/IV. Second-line chemotherapy started a median of 5 months earlier in the immediate arm. With a median follow up of 49 months from randomization and a total of 351 deaths, there was no evidence of a difference in overall survival between the immediate and delayed arms, hazard ratio 1.01, 95% CI 0.82-1.25, p = 0.91. Conclusions: There is no survival benefit from early treatment based on a raised serum marker level alone, and therefore no value in the routine measurement of CA125 in the follow-up of ovarian cancer patients

PARP inhibitors show promise for hard-to-treat breast cancers:
Two studies, including one featured in ASCO’s plenary session, report promising data on a new class of targeted drugs called PARP inhibitors. The plenary study reports that women with hard-to-treat “triple-negative” breast cancer who received the PARP inhibitor BSI-201 along with conventional chemotherapy had better outcomes than women who received chemotherapy alone. A second study reports that women with BRCAdeficient advanced breast cancer experienced tumor shrinkage after receiving the PARP inhibitor
olaparib as a single agent.

Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer

A. Tutt, M. Robson, J. E. Garber, S. Domchek, M. W. Audeh, J. N. Weitzel, M. Friedlander, J. Carmichael
Background: Olaparib (AZD2281; KU-0059436) is a novel, orally active PARP inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. A phase I trial identified 400 mg bd as the maximum tolerated dose (MTD) with an initial signal of efficacy in BRCA-deficient ovarian cancers (ASCO 2008; abst 5510). The primary aim of this study was to test the efficacy of olaparib in confirmed BRCA1/BRCA2 carriers with advanced refractory breast cancer. The secondary aim was to assess safety and tolerability in this population. Methods: In an international, multicenter, proof-of-concept, single-arm, phase II study, two sequential patient (pt) cohorts received continuous oral olaparib in 28-day cycles initially at the MTD, 400 mg bd (27 pts), and subsequently at 100 mg bd, a previously identified PARP inhibitory dose (27 pts). Eligibility criteria included confirmed BRCA1/BRCA2 mutation and recurrent, measurable chemotherapy-refractory breast cancer. The primary efficacy endpoint was best objective response rate (ORR; RECIST) post baseline. Progression-free survival (PFS) and clinical benefit rate were secondary endpoints. All adverse events were reported using CTCAE v3. Results: On November 20, 2008, 54 pts exposed to a median of three prior lines of chemotherapy, had been enrolled. 27 pts were dosed at 400 mg bd (18 BRCA1 deficient and 9 BRCA2 deficient), and 24 of these had databased RECIST assessments. The ORR (currently based on unconfirmed responses) was 38% (9/24) (400 mg bd). Causallyrelated toxicity was mainly mild (grade 1-2) in severity; 9/27 pts (33%) had fatigue; 7/27 (26%) had nausea; 4/27 (15%) had vomiting; and 1/27 (4%) had anemia. Causally-related grade 3 or higher toxicities were seen in 5 pts (19%) with fatigue (3 pts), nausea (2 pts), and anemia (1 pt). 27 pts were treated in the subsequent 100 mg bd cohort where no data are currently available. Conclusions: Olaparib at 400 mg bd is well tolerated and highly active in advanced chemotherapy-refractory BRCA-deficient breast cancer. Toxicity in BRCA1/BRCA2 carriers was similar to that reported previously in non-carriers. This first study with olaparib in BRCA-deficient breast cancers provides positive proof-of-concept for high activity and tolerability of a genetically defined targeted therapy. Disclosures: Andrew Tutt,,Employment or Leadership Position,Institute of Cancer ResearchMark Robson,,Research Funding,KudosSusan Domchek,,Research Funding,AstraZenecaM Audeh,,Consultant or Advisory Role, AstraZenecaJeffrey Weitzel,,Honoraria,Myriad GeneticsJames Carmichael,,Employment or Leadership Position,AstraZenecaJames Carmichael,,Stock Ownership,AstraZeneca

Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple negative breast cancer (TNBC): Results of a randomized phase II trial
J. O’Shaughnessy, C. Osborne, J. Pippen, M. Yoffe, D. Patt, G. Monaghan, C. Rocha, V. Ossovskaya, B. Sherman, C. Bradley
Background: TNBC is an aggressive breast cancer subtype that shares molecular and pathologic features with BRCA1-related breast cancers. BRCA-deficient cells are sensitive to inhibition of PARP1, a critical enzyme of cell proliferation and DNA repair, and thus represent a rational target of PARP inhibitor-based cancer therapy. The objectives of this study were to evaluate BSI-201, a potent PARP1 inhibitor, in combination with gemcitabine/carboplatin (G/C) in subjects with metastatic TNBC. Methods: Eligible subjects had measurable disease and had ≤2 prior cytotoxic regimens for ER-, PR-, and HER2-negative metastatic breast cancer. Patients were randomized (1:1) to G/C alone or G/C + BSI-201. Gemcitabine (1000 mg/m2) and carboplatin (AUC=2) were given on days 1 and 8, and BSI-201 (5.6 mg/kg; iv; biweekly) on days 1, 4, 8, and 11 every 21 days. Endpoints were clinical benefit rate (CBR = CR + PR + SD ≥6 months), progression-free survival (PFS) and overall survival (OS). Results: Analyses of the first 86 of a planned 120 patients showed that BSI-201 + G/C had improved CBR, median PFS, and median OS, compared with G/C alone. The frequency and nature of adverse events (AEs) did not differ betweearms. Conclusions: This preliminary analysis demonstrates that BSI-201 + G/C significantly improves CBR, PFS and OS, compared with G/C alone. BSI-201 + G/C was well tolerated, with BSI-201 adding no significant toxicity to G/C. Updated CBR, PFS, and OS for all 120 patients and exploratory correlative analyses of PARP expression and clinical response will be presented.Disclosures: Christine Rocha,,Employment or Leadership Position,BiPar Sciences. Inc,Valeria Ossovskaya, Employment or Leadership Position,BiPar Sciences, InccBarry Sherman,,Employment or Leadership Position,BiPar Sciences, Inc.Charles Bradley,,Employment or Leadership Position,BiPar Sciences, Inc.

Gemcitabine plus chemoradiation improves cervical cancer survival
Adding the drug gemcitabine to cisplatin-based chemotherapy and radiation therapy extends overall survival among women with locally advanced cervical cancer. This study was primarily conducted in developing countries, where cervical cancer screening programs are limited.

A phase III study comparing concurrent gemcitabine (Gem) plus cisplatin (Cis) and radiation followed by adjuvant Gem plus Cis versus concurrent Cis and radiation in patients with stage IIB to IVA carcinoma of the cervix
A. Dueñas-González, J. J. Zarba, J. C. Alcedo, P. Pattarunataporn, S. Beslija, F. Patel, L. Casanova, H. Barraclough, M. Orlando
Background: Cervical cancer is the second-most common cancer among women worldwide, in both incidence and mortality. Current standard therapy for locally advanced disease consists of concurrent Cis and external-beam radiation (XRT). This multi-center, open-label, randomized, phase 3 trial aimed to improve outcomes, capitalizing on the synergistic activity of Gem, Cis, XRT, and the potential value of adjuvant therapy. Methods: Eligible patients (pts) with bulky stage IIB to IVA, 18-70 years of age, chemo- and radiotherapy naïve, with a Karnofsky Performance Status score ≥70, were randomized to Arm A: Cis 40 mg/m2 followed by Gem 125 mg/m2 weekly x 6 doses with concurrent XRT (50.4 Gy: in 28 fractions: 1.8 Gy/day, 5 days/week), followed by brachytherapy (brachy) (30-35 Gy) and then 2 adjuvant 21-day cycles of Gem (1,000 mg/m2 on Days 1 and 8) plus Cis (50 mg/m2 on Day 1); or Arm B: Cis 40 mg/m2 weekly x 6 doses with concurrent XRT followed by brachy, given as in Arm A. Primary endpoint waprogression-free survival (PFS) at 3 years, compared between arms using Kaplan-Meier methods and a Z-statistic. Results: 515 pts were enrolled between 5/02 and 3/04 (259 pts Arm A, 256 pts Arm B). Median age was 46 years; stage IIB/IIIB/IVA in 61/37/2% of pts. Compliance in the concurrent and brachy phase was >90% for both arms; adjuvant cycles were completed by >75% of pts in Arm A. PFS at 3 years was 74% in Arm A compared to 65% in Arm B, resulting in a statistically significant improvement (p = 0.029). Overall survival (log-rank p= 0.0224) and time to progressive disease (log-rank p = 0.0008) were also significantly improved. Significantly more pts in Arm A experienced grade 3/4 toxicities (86.5%), compared to pts in Arm B (46.3%; Fisher’s p < 0.001). In Arm A, 2 pts died due to causes probably related to treatment compared to 0 pts in Arm B. Conclusions: This novel regimen of concurrent Gem plus Cis and XRT followed by brachy and adjuvant Gem plus Cis significantly improved outcomes in
pts with locally advanced carcinoma of the cervix, at the expense of increased but acceptable toxicity, compared to the current standard of care. Disclosures: Alfonso Dueñas-González,,Honoraria,Eli LillyHelen Barraclough,,Employment or Leadership Position,Eli Lilly and CompanyHelen Barraclough,,Stock Ownership,Eli Lilly and CompanyMauro Orlando,,Employment or Leadership Position,Eli Lilly and CompanyMauro Orlando,,Stock Ownership,Eli Lilly and Company

Sentinel node biopsy is an effective option for early-stage cervical cancer:
Most women with early stage cervical cancer can safely undergo sentinel node biopsy – a technique in which only one or two lymph nodes are removed to determine whether cancer has spread – in lieu of the traditional, more invasive pelvic lymph node removal, which can lead to more significant side effects. Sentinel node biopsy was also as effective for detecting cancer spread to atypical areas of the pelvis.

Impact of sentinel lymph node biopsy on staging of early cervical cancer. Results of a prospective, multicenter study
F. Lecuru, A. Bats, P. Mathevet, D. Querleu, E. Leblanc, P. Morice, E. Darai, H. Marret, C. Collin, G. Chatellier, F. Gilaizeau
Background: 10% to 15% of patients with pN0 early cervical cancer experience recurrences. This may be related either to nodes missed by the dissection or located outside the dissection field or to failed diagnosis of node metastases. The objective of this study was to measure the benefits from sentinel node (SN) detection in terms of nodes collected from unusual territories and of detected micrometastases and isolated tumor cells (ITCs). Methods: 145 patients who had stage Ia1- Ib1 epidermoid cancer or adenocarcinoma or adenosquamous cancer were included in a multicenter study (January 2005 – June 2007). Noninclusion criteria were age<18 years, pregnancy, and previous treatment. SNs were identified by combined technetium and blue-dye labeling in the pelvic and para-aortic territories. Slices were cut 200 μm apart. At each level, HES staining and labeling with anti-cytokeratin antibodies (AE1-AE3) were performed. SNs in an unusual territory were defined as SNs outside the ilio-obturator region. ITC was definedas size <0.2 mm, micrometastasis as size 0.2 to 2mm, and macrometastases as size >2 mm. The study was funded by the French National Institute of Cancer and reviewed by an IRB. Results: 17 patients were excluded for major protocol deviations, leaving 128 patients for the per protocol analysis. One or more SNs were detected in 98.4% of patients (95%CI, 94.4 to 99.9%). The 430 detected SNs were located as follows: external iliac, 80.5 %; common iliac, 8.6%; presacral and paraaortic, 5.5%; and parametrial, 4.9 %. SN detection identified at least one SN in an unusual territory in 48/128 (37.5%) patients. There were 26 positive SNs in 21(16.4%) patients of whom 8 (38%) had macrometastases, 7 (33%) micrometastases, and 6 (29%) ITCs. Of these 26 nodes, 7 (27%) were detected only byimmunohistochemistry (6/128 patients : 4.6%). There was no false-negative No node metastases were found in 104/128 (81.2%) patients. Conclusions: SN detection supplied additional information in 39.8% of patients (51/128), either showing that drainage occurred via unusual pathways or detecting cancer spread via immunohistochemistry. Node dissection could have been avoided in the 104/128 patients with negative nodes, potentially decreasing treatment-associated morbidity.

Fonte ASCO
Supplemento ad AIOM News
Editore Intermedia
Direttore responsabile Mauro Boldrini
TORNA INDIETRO