TESTO LABIANCA1pdf - Informazioni sui farmaci

Dott. Labianca, Dott.ssa Tasca Cristina
Dipartimento di Oncologia ed Ematologia, Ospedali Riuniti, Bergamo
Tumori apparato gastrointestinale
Nel corso dell’anno 2009/2010 sono stati pubblicati pochi lavori significativamente “practice changing” relativamente alla terapia
adiuvante del carcinoma del colon retto.
Ancora da approfondire, è lo studio prospettico pubblicato su Jama 2009 nel quale è stata valutata la correlazione tra l’uso dell’acido
acetilsalicilico dopo la diagnosi di cancro del colon-retto e la sopravvivenza globale legata alla malattia, in pazienti affetti da neoplasia
colica iperesprimente COX-2. Tale studio prospettico, valutando una coorte di 1279 pazienti con malattia di stadio I-II-III dopo un followup mediano di 11.8 anni, ha mostrato un ridotto rischio di mortalità globale e di mortalità cancro, specifica specialmente nei pazienti con
tumori che overesprimevano la COX-2.(Abs n.1).
Rimane puramente provocatorio pensare all’ASA come ad una nuova ”target therapy” nonostante le deludenti “performance” di
Bevacizumab (studio NSABPC-08) e Cetuximab (studio USA NO147) che sembrano non funzionare in aggiunta al Folfox-4 nella terapia
adiuvante.
Valida alternativa al Folfox-4 appare essere lo Xelox (per 8 cicli) soprattutto per pazienti in stadio III (ESMO 2009, ASCO 2010).
Ricordiamo che, diversamente da altre schedule contenenti oxaliplatino, secondo l’analisi ACCENT, lo Xelox è utilizzabile anche in
pazienti con età superiore a 70 anni (ASCO GI 2010).
Degno di nota è l’abstract pubblicato su JCO 2009 relativo allo studio CALGB C89803 che ha esaminato 1265 pazienti in stadio III
confrontando lo schema FU/FA bolo+ Irinotecan (IFL) vs FU/FA da solo. Tale protocollo poggia le fondamenta su studi precedenti,
dimostrativi del fatto che i tumore del colon con difetti del sistema DNA MMR presentano caratteristiche cliniche e patologiche distinte,
quali miglior prognosi e ridotta risposta alla chemioterapia con 5-FU. Tale abstract mostra come, nei pazienti affetti da tumore del colon,
l’instabilità micro satellitare secondaria a difetti nel sistema mismatch repair (MMR), sia predittiva di una aumentata risposta, in termini
di DFS a 5 anni, dopo terapia adiuvante con FU, Leucovorin ed Irinotecan. (Abs n.2).
Nello scenario attuale riguardante la terapia adiuvante nel cancro del colon retto spiccano per importanza, i risultati finali di due noti
studi: Petacc 3 e Mosaic. Il primo confronta l’impiego dello schema FU/FA in infusione settimanale o bimensile versus lo stesso regime
associato ad Irinotecan (FOLFIRI). La schedula di combinazione non determina un aumento significativo della DFS a 5 anni (56.7% vs
54.3%) e dell’OS a 5 anni (73.6% vs 71.3%) rispetto al solo deGramont, in pazienti con K colon in stadio III. Inoltre tale combinazione
induce una maggiore incidenza di effetti avversi gastro-intestinali (grado 3-4) e di neutropenia (Abs n.3).
Il secondo studio mostra come l’aggiunta di Oxaliplatino al regime LV5FU2 (FOLFOX-4), confrontato con il solo LV5FU2 (p = 0.002),
aumenta significativamente la DFS a 5 anni (73.3% vs 67.4%) e la OS a 6 anni negli stadi III (72.9% vs 68.7%) in pazienti operati per K
colon in stadio I-II, diventando il regime adiuvante di riferimento per la malattia allo stadio III (Abs n.4). Lo studio ha valutato anche
pazienti in stadio II, nei quali si è osservata una riduzione pari al 5.4% del rischio di recidiva della malattia nei sottogruppi ad alto rischio
(T4, occlusione intestinale, perforazione, G3, invasione vascolare o con un numero < 10 linfonodi esaminati).(Abs n.4)
Le novità relative ai tumori pancreatici riguardano studi volti a dimostrare l’efficacia, negli stadi avanzati della malattia, delle associazioni
tra chemioterapici e farmaci a bersaglio molecolare rispetto al trattamento tradizionale con sola CT (a base di Gemcitabina, in
monoterapia o in associazione).
L’aggiunta di Erlotinib (inibitore orale di EGFR) alla Gemcitabina in uno studio di fase II ha dimostrato un minimo beneficio in termini di
sopravviveva (13 gg) che non consente perciò di raccomandarne l’utilizzo clinico. Sulla scorta dei dati ottenuti e sul modesto risultato
registrato dal regime di combinazione tra Erlotinib e Gemcitabina, possiamo formulare un giudizio di ragionevole dubbio sull’utilità
dell’impiego attuale di questo farmaco. Considerando i pazienti non eleggibili o resistenti alla Gemcitabina in I linea e non valutati per lo
stato mutazionale di K ras è stato condotto uno studio di fase III che prevedeva l’utilizzo di Erlotinib come agente singolo. Tale studio è
stato precocemente chiuso dato che i risultati ottenuti, in termini di PFS e OS, sono scarsi e paragonabili al trattamento con la sola
terapia di supporto. (Abs n.5).
Innovativo, e ancora tutto da validare, è invece lo studio di fase II che valuta l’utilizzo del vaccino GI-400 (farmaco biologico) come
terapia adiuvante in pazienti operati per carcinoma del pancreas con K-ras mutato, tenendo in considerazione sia che il 90% circa dei
pazienti con tumore del pancreas sono portatori di mutazioni dell'ongene Ras sia l'alto tasso di recidiva di malattia dopo un trattamento
chemioterapico standard con Gemcitabina. L'analisi in cieco relativa ai dati di sicurezza per i primi 100 pazienti in combinazione
(Gemcitabina+GI-4000 vs Gemcitabina da sola) sono confrontabili con i dati pubblicati relativi alla sola Gem (Abs n.6).
Anche l'utilizzo di Axitinib (inibitore selettivo di VEGF) valutato da uno studio di fase III, non ha dato benefici in termini di OS. Dopo un
analisi ad interim pre-pianificata, lo studio che valutava Gemcitabina plus Axitinib vs Gemcitabina plus placebo è stato chiuso, e
l'interruzione di Axitinib è stata raccomandata. Si sono registrati, infatti, molteplici effetti collaterali di grado 3-4 (trombocitopenia,
anoressia, ipertensione, astenia, incremento dei livelli di ormone tiroidostimolante) senza incrementi in termini di OS mediana (7.4 mesi
nel braccio sperimentale vs 8.2 nel braccio di controllo, rispettivamente) (Abs n.7).
Negativo è anche il risultato dello studio di fase III, denominato CALGB 80303, che ha valutato l'associazione tra Bevacizumab plus
Gemcitabina non ottenendo alcun vantaggio in terminin di OS (HR=1.03).
Deludente il tentativo di utilizzare Trastuzumab e Capecitabina in pazienti con carcinoma pancreatico metastatico iperesprimente HER2
(fattore di crescita epidermoidale di tipo 2). Se, infatti, HER2 è iperespresso nell’80% dei pazienti, in solo 11% vi è amplificazione
genica. In considerazione di ciò, e degli scarsi risultanti relativi in termini di PFS e OS, è possibile concludere per una non efficacia del
trattamento combinato con Capecitabina plus Trastuzumab in pazienti con tumore del pancreas metastatico (Abs n.8).
Questi risultati negativi sono da analizzare considerando che la terapia anti-angiogenetica dà risultati se utilizzata nelle prime fasi di
sviluppo tumorale, e non in fase avanzata. Altrettanto importante è considerare il complesso sistema di segnali del processo
angiogenetico e l’eventuale presenza di K-ras mutato, e ciò rende necessaria una terapia multi target e non solo una terapia basata su
VEGF o VEGFR.
Altro studio rilevante, il CONKO-004, presentato all’ESMO/ECCO 2009 riguarda l’associazione tra Enoxaparina (LMWH) e
chemioterapia sistemica palliativa (GEM in monoterapia o in associazione a CDDP/5-FU/Acido folinico) nel carcinoma pancreatico
metastatico (APC), che tradizionalmente è la neoplasia con maggiore rischio di eventi tromboembolici venosi (Abs n.9).
Si è visto come l’uso profilattico di Enoxaparina combinato alla CT, in pazienti con APC mai trattati precedentemente, sia efficace e
sicuro per la prevenzione primaria di sVTE (riduzione degli eventi trombotici da 15% nel gruppo di osservazione a 5% nel gruppo
trattato con Enoxaparina). Non si è verificato un incremento del rischio di emorragie severe. Restiamo in attesa dei risultati definitivi
relativamente a OS e TTP che, attualmente, non sembrano differire nei due gruppi studiati.
Argomento poco trattato negli ultimi anni dagli oncologi, ma meritevole di attenzione, è quello relativo alla terapia loco-regionale nei
tumori gastroenterici. Nella pratica clinica tutti i trattamenti loco regionali (chirurgia, radioterapia, radiofrequenza, alcolizzazione,
chemioembolizzazione) sono strettamente limitati dal numero e dalle dimensioni delle lesioni. Particolare interesse desta la terapia
intrarteriosa epatica (HAI) che, sfruttando la notevole vascolarizzazione arteriosa delle lesioni epatiche, siano esse neoplasie primitive,
recidive o metastasi, permette l’utilizzo di pompe impiantabili per l’infusione di agenti neoplastici quali le fluoro piridine ed in particolare il
nuovo farmaco FUDR, utilizzato da solo o in associazione a chemioterapia.
Un recente studio di fase I apparso su JCO 2009 ha dimostrato come l’utilizzo di floxuridina intrarteriosa/desametasone plus
chemioterapia sistemica con Oxaliplatino ed Irinotecan abbia un alto tasso di conversione alla resezione, pari al 47% dei paziente
studiati, che presentavano metastasi epatiche non operabili da neoplasia colica (RC nell’8%, RP nel 84%) (Abs n.10).
Diversi sono stati gli studi clinici randomizzati di confronto tra l’infusione arteriosa epatica e la chemioterapia sistemica, entrambi con
fluoropirimidine, per il trattamento delle metastasi epatiche non resecabili da carcinoma del colon-retto. Una sintesi quantitativa dei
risultati di tali studi mostra un tasso di risposta globale del 42% per la terapia intrarteriosa e del 18.4% per la terapia sistemica mentre il
tempo mediano di sopravvivenza globale è pari a 15.9 e 12.4 mesi, rispettivamente. Nonostante l’alto tasso di risposte ottenuto dal
trattamento intrarterioso rispetto a quello sistemico, non si ha alcun vantaggio in termini si sopravvivenza. Per tale motivo gli autori di
tale studio non consigliano tale approccio nella pratica clinica (Abs n.11).
Nonostante ciò, sulla scorta degli ottimi risultati in termini di risposta clinica è stato condotto uno studio di fase I che ha determinato la
dose massima di CT sistemica (Oxaliplatino, 5-FU, LV) da associare insieme all’infusione intrarteriosa epatica di FUDR e
Desametasone intrarterioso, nella terapia adiuvante post-resezione chirurgica dei secondarismi epatici. I risultati di tale studio mostrano
la fattibilità e l’efficacia dell’utilizzo di Oxaliplatino a 85 mg/mq, 5-FU in ic a 2000 mg/mq con LV a 400 mg/mq associato a HAI
FUDR/DEX con sopravvivenza a 4 anni pari a 88% e sopravvivenza libera da malattia pari al 50% (Abs n.12)
Studi di fase I sono stati condotti con l’obiettivo di valutare fattibilità, efficacia e stabilire la massima dose tollerata e la durata
dell’infusione intrarteriosa epatica anche di altri agenti antineoplastici, come ad esempio la Gemcitabina, sia in pazienti con metastasi
epatiche non recabili di K colon sia in pazienti affetti da neoplasia epatica primitiva (epatocarcinoma). La Gemcitabina per infusione
intrarteriosa è stata ben tollerata anche a dosi superiori e a durata maggiore rispetto alla dose raccomandata di 1.0000 mg/mq in 30
minuti (Abs n.13).
Nel carcinoma del retto la chirurgia è sempre stato il trattamento di prima scelta gravato, però, da alti tassi di recidive loco regionali e
dati di sopravvivenza globale scoraggianti. L’aggiunta di chemio-radioterapia upfront ha migliorato i risultati riguardanti il controllo loco
regionale della malattia. L’ipotesi che l’aggiunta di ipertermia alla RT pre-operatoria fosse efficace ha spinto diversi autori a quantificare
il potenziale effetto della termo-radioterapia vs CT-RT, in termini di RC patologiche, OS e tossicità. Studi di fase II e III di confronto tra
sola RT preoperatoria vs RT+ipertermia neoadiuvante hanno evidenziato una maggiore risposta nei pazienti trattati con la combinazione
dei due trattamenti, con uguale tollerabilità ma con un non rilevante aumento della sopravvivenza (Abs n.14).Alla luce di tali studi è
possibile affermare che l’approccio locoregionale, soprattutto la terapia intrarteriosa epatica, nelle neoplasie del tratto GE è applicabile
in pochi casi selezionati Per il futuro si auspica alla costituzione di trails comprendenti un maggior numero di pazienti e il confronto con
schemi di terapia sistemica che prevedano l’utilizzo di farmaci biologci di ultima generazione.
Bibliografia
1. Chan AT et al. Uso dell’aspirina e sopravvivenza dopo una diagnosi di cancro colon rettale. Jama, 2009; 302(6):649-59
CONTEXT: Aspirin reduces risk of colorectal neoplasia in randomized trials and inhibits tumor growth and metastases in
animal models. However, the influence of aspirin on survival after diagnosis of colorectal cancer is unknown. OBJECTIVE: To
examine the association between aspirin use after colorectal cancer diagnosis on colorectal cancer-specific and overall
survival. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 1279 men and women diagnosed with stage
I, II, or III colorectal cancer. Participants were enrolled in 2 nationwide health professional cohorts in 1980 and 1986 prior to
diagnosis and followed up through June 1, 2008. MAIN OUTCOME MEASURE: Colorectal cancer-specific and overall
mortality. RESULTS: After a median follow-up of 11.8 years, there were 193 total deaths (35%) and 81 colorectal cancerspecific deaths (15%) among 549 participants who regularly used aspirin after colorectal cancer diagnosis, compared with
287 total deaths (39%) and 141 colorectal cancer-specific deaths (19%) among 730 participants who did not use aspirin.
Compared with nonusers, participants who regularly used aspirin after diagnosis experienced a multivariate hazard ratio (HR)
for colorectal cancer-specific mortality of 0.71 (95% confidence interval [CI], 0.53-0.95) and for overall mortality of 0.79 (95%
CI, 0.65-0.97). Among 719 participants who did not use aspirin before diagnosis, aspirin use initiated after diagnosis was
associated with a multivariate HR for colorectal cancer-specific mortality of 0.53 (95% CI, 0.33-0.86). Among 459 participants
with colorectal cancers that were accessible for immunohistochemical assessment, the effect of aspirin differed significantly
according to cyclooxygenase 2 (COX-2) expression (P for interaction = .04). Regular aspirin use after diagnosis was
associated with a lower risk of colorectal cancer-specific mortality among participants in whom primary tumors overexpressed
COX-2 (multivariate HR, 0.39; 95% CI, 0.20-0.76), whereas aspirin use was not associated with lower risk among those with
primary tumors with weak or absent expression (multivariate HR, 1.22; 95% CI, 0.36-4.18). CONCLUSION: Regular aspirin
use after the diagnosis of colorectal cancer is associated with lower risk of colorectal cancer-specific and overall mortality,
especially among individuals with tumors that overexpress COX-2.
2.
Bertagnolli MM et al. L’instabilità micro satellitare predice un’aumentata risposta alla terapia adiuvante con Iriontecan,
Fluorouracile e Leucovorin nel cancro del colon allo stadio III: CALGB Protocol 89803. JCO 2009; 27(11):1814-21
PURPOSE: Colon cancers exhibiting DNA mismatch repair (MMR) defects demonstrate distinct clinical and pathologic
features, including better prognosis and reduced response to fluorouracil (FU) -based chemotherapy. This prospective study
investigated adjuvant chemotherapy containing FU and irinotecan in patients with MMR deficient (MMR-D) colon cancers.
PATIENTS AND METHODS: Cancer and Leukemia Group B 89803 randomly assigned 1,264 patients with stage III colon
cancer to postoperative weekly bolus FU/leucovorin (LV) or weekly bolus irinotecan, FU, and LV (IFL). The primary end point
was overall survival; disease-free survival (DFS) was a secondary end point. Tumor expression of the MMR proteins, MLH1
and MSH2, was determined by immunohistochemistry (IHC). DNA microsatellite instability was also assessed using a panel
of mono- and dinucleotide markers. Tumors with MMR defects were those demonstrating loss of MMR protein expression
(MMR-D) and/or microsatellite instability high (MSI-H) genotype. RESULTS: Of 723 tumor cases examined by genotyping and
IHC, 96 (13.3%) were MMR-D/MSI-H. Genotyping results were consistent with IHC in 702 cases (97.1%). IFL-treated patients
with MMR-D/MSI-H tumors showed improved 5-year DFS as compared with those with mismatch repair intact tumors (0.76;
95% CI, 0.64 to 0.88 v 0.59; 95% CI, 0.53 to 0.64; P = .03). This relationship was not observed among patients treated with
FU/LV. A trend toward longer DFS was observed in IFL-treated patients with MMR-D/MSI-H tumors as compared with those
receiving FU/LV (0.57; 95% CI, 0.42 to 0.71 v 0.76; 95% CI, 0.64 to 0.88; P = .07; hazard ratio interaction between tumor
status and treatment, 0.51; likelihood ratio P = .117). CONCLUSION: Loss of tumor MMR function may predict improved
outcome in patients treated with the IFL regimen as compared with those receiving FU/LV.
3.
Van Cutsem E et al. Trial randomizzato di fase III di confronto tra 5FU infusionale/LV ogni 2 settimane da solo o con
Irinotecan nel trattamento adiuvante del cancro del colon allo stadio III: PETACC-3. JCO, 2009; 27(19):3117-25.
Background: Infused irinotecan regimens have improved survival in metastatic CRC. This international, multicenter, openlabel, randomized, prospective trial of adjuvant chemotherapy with IF vs. F was designed to confirm these results in pts with
stage III colon cancer. Pts were given IF (Arm A) or F (Arm B) in 4 cycles of 3 infusions every 2 weeks (de Gramont regimen)
or 4 cycles of the AIO regimen. Irinotecan was given as 180 mg/m2 per dose in the de Gramont regimen, and as 80 mg/m2 in
the AIO regimen. Methods: Inclusion criteria were WHO performance status <2, and stage III disease (UICC criteria).
Exclusion criteria were prior treatment with chemotherapy, and rectal cancer. The primary endpoint is the comparison of 3year disease-free survival in stage III pts who received IF vs. F in the de Gramont regimen, using the log-rank test. A total of
2014 Stage III pts were to be randomized in order to obtain the 452 events calculated to guarantee 90% power to detect an
increase in 3 yr DFS from 70% to 77% in Arm A (hazard ratio 1.36). The DFS and RFS curves will also be estimated using
Kaplan-Meier methodology. Cox models will be used to analyze the influence of selected variables. Secondary endpoints
include relapse-free survival, overall survival, safety, and potential prognostic markers. Results: Between Jan 2000 and April
2002, 2124 pts from 28 countries were randomized and 2101 pts treated. Tumor blocks from 1500 pts were collected for
translational research. The two arms were well balanced - median age 60 (19–76), 55% male, 99% WHO PS <2. Median
follow-up was 31 months. Selected grade 3/4 toxicities (%) in Arms A/B respectively were: myelosuppresion (1 vs. 0.3%)
diarrhea (12 vs. 6%), venous thrombosis (7 vs. 5%), infection (2 vs. 0.2%). Conclusions: The primary endpoint will be
analyzed before March 25, 2005 and will be presented at the ASCO meeting.
4.
Andrè T et al. Aumento della sopravvivenza globale con Oxaliplatino, Fluorouracile e Leucovorin nel trattamento adiuvante
del cancro del colon allo stadio II o III nel trial MOSAIC. JCO, 2009; 27 (19): 3109-16.
PURPOSE Three-year disease-free survival (DFS) was significantly improved in patients who had undergone resection with
curative intent for stage II or III colon cancer who received bolus plus continuous-infusion fluorouracil plus leucovorin
(LV5FU2) with the addition of oxaliplatin (FOLFOX4). Final results of the study, including 6-year overall survival (OS) and 5year updated DFS, are reported. PATIENTS AND METHODS A total of 2,246 patients were randomly assigned to receive
LV5FU2 or FOLFOX4 for 6 months. The primary end point was DFS. Secondary end points were OS and safety. Results
Five-year DFS rates were 73.3% and 67.4% in the FOLFOX4 and LV5FU2 groups, respectively (hazard ratio [HR] = 0.80;
95% CI, 0.68 to 0.93; P = .003). Six-year OS rates were 78.5% and 76.0% in the FOLFOX4 and LV5FU2 groups, respectively
(HR = 0.84; 95% CI, 0.71 to 1.00; P = .046); corresponding 6-year OS rates for patients with stage III disease were 72.9%
and 68.7%, respectively (HR = 0.80; 95% CI, 0.65 to 0.97; P = .023). No difference in OS was seen in the stage II population.
The incidence of second noncolorectal cancers was 5.5% and 6.1% in the FOLFOX4 and LV5FU2 groups, respectively.
Among patients receiving oxaliplatin, the frequency of grade 3 peripheral sensory neuropathy was 1.3% 12 months after
treatment and 0.7% at 48 months. CONCLUSION Adding oxaliplatin to LV5FU2 significantly improved 5-year DFS and 6-year
OS in the adjuvant treatment of stage II or III colon cancer and should be considered after surgery for patients with stage III
disease.
5.
Iyer RV et al. Studio di fase II di erlotinib in pazienti con carcinoma del pancreas avanzato, refrattario al trattamento
chemioterapico con Gemcitabina. ASCO GI 2010-Abstract numero:258.
Background: Erlotinib + G is effective in pts with APC. The effect of erlotinib alone in pts ineligible for or refractory to G was
tested. Methods: Eligibility-Pts with APC, 0/1 prior therapy. Endpoints-Primary: progression free survival (PFS), secondary:
RECIST response rate (RR), overall survival (OS), quality of life (QOL) (EORTC PAN26 tool) and toxicity. Clinical outcomes
were correlated with smoking status, steady state concentrations of erlotinib in week 3 of treatment, rash development and kras mutation status of tumors. Treatment: erlotinib 150 mg POqd for 3 week cycles with restaging q6 weeks. Statistical
methods used- Kaplan-Meier method, log-rank test, Cox proportional hazards model and the Wilcoxon rank sum test. Results:
Eighteen pts were enrolled, 15 are evaluable for response (3 symptomatic deterioration). Pt characteristics: Median age 64.5
yrs (range 48-84 yrs) sex M/F:9/9; ECOG performance 0/1/2:13/3/2; stage III/IV:0/18. Prior therapy 0/1: 4(22%)/14 (78%).
Median cycles: 2 (range 0.24-4.6). Median PFS:1.38 months (95% CI: 1.35- 1.41). The study was closed before accrual of the
planned 34 pts, as these findings are consistent with that expected from supportive care alone. Median OS:3.1 months (95%
CI: 2.8-4.3); best responses: stable disease = 4/18 (22%), progression = 11/18 (61%) and nonevaluable = 3/18 (16%). Median
disease control time (DCT): 9.3 weeks. Current/past/never smokers (n = 6/10/2) had a PFS of 1.3, 1.4 and 4.2 months,
respectively. Past/current smokers had lower steady state concentrations of OSI 774 and OSI 420 than never smokers (all
however within the wide range from population PK studies). QOL scores (baseline and post-therapy) had no association with
OS (p value = 0.11) or PFS (p value = 0.21). Due to inadequate tissue in 8 of the first 9 tumor blocks tested, k-ras mutation
status assessment was not done. No grade 3 or 4 treatment related toxicities were seen. Fatigue, anorexia, nausea, diarrhea
and anemia were frequent grade 1/2 events (n > 5). Rash was infrequent in this population (grade 1/2: n = 3/4). Conclusions:
In this APC population, clinical benefit rate of erlotinib (CR + PR + SD) is 22% with median DCT of 9.3 weeks. As expected
PFS and OS were short.
6.
Richards DA et al. Studio di fase II randomizzato di terapia adiuvante di pazienti operati per carcinoma del pancreas con
mutazione dir as, trattati con gemcitabina e GI-4000 e gemcitabina agente singolo: analisi di sicurezza nei primi 100 pazienti.
ASCO GI 2010-Abstract numero:229.
Background: Patients with resected pancreas cancer have a high relapse rate despite standard adjuvant treatment with
gemcitabine. Approximately 90% of pancreas tumors harbor a mutation in the Ras oncogene. GI- 4000 is a series of 4 whole,
heat-inactivated recombinant S. cerevisiae yeast, each engineered to express a different mutated Ras oncoprotein. GI-4000
exhibited an excellent safety profile when administered as a single agent in a phase 1 clinical trial. Methods: The study
population includes patients with resected pancreas cancer who have a product-related Ras mutation and an R0 or R1
resection by Whipple procedure. Patients were randomized 1:1 to receive GI-4000 or placebo weekly for 3 weeks starting 21-
35 days post surgery, monthly during 6 months of gemcitabine therapy, and monthly as a monotherapy thereafter until
recurrence, death, or discontinuation. Gemcitabine was administered at 1,000mg/m2 for 6 cycles. Results: The median age is
61 years; 60% of the study population is male, and resection status is R0 77% or R1 23%. The median exposure to
gemcitabine is 6 cycles. The median exposure to study drug (GI-4000 or placebo) is 11 doses/35 weeks. 33% of patients had
a total of 57 treatment emergent SAEs (5% [thought to be] related to GI-4000, 7% [thought to be] related to gemcitabine). 35
deaths and 2 discontinuations due to AE have been reported. Treatment emergent SAEs occurring in > 2% of the population
include: small intestinal obstruction and abdominal abscess. Treatment emergent grade 3-4 AEs occurring in > 5% of the
population: anemia, neutropenia, abdominal pain, and fatigue. There have been an equivalent number of discontinuations,
serious adverse events, adverse events, and deaths compared to published data. Conclusions: The blinded pooled safety
data for the first 100 treated patients in adjuvant combination (gemcitabine plus GI-4000 and gemcitabine alone) compares
well to published data for gemcitabine alone. Based on quarterly Bayesian analyses, enrollment may be expanded to up to
200 subjects. Unblinded safety and efficacy data results will be available upon completion of the trial.
7.
Kindler HL et al. A double-blinded, placebo-controlled, randomized, phase III study of Axitinib (AG-013736; A) plus
gemcitabine vs. gemcitabine plus placebo in advanced pancreatic cancer patient. European Journal of Cancer Supplements,
Vol 7 N°2, September 2009, Page 361.
Background: A is an oral, potent, selective inhibitor of vascular endothelial growth factor receptors1, 2, 3. In a randomized,
phase II trial of G +/− A in PC pts, there was a non-statistically significant gain in overall survival (OS) in pts treated with A+G
compared with G (6.9 vs. 5.6 months; Spano et al. Lancet 2008). These data led to an international, double-blind,
placebocontrolled, randomized, phase III trial of A+G vs. P+G in advanced PC pts
(NCT00219557; Sponsor: Pfizer Oncology)
Material and Methods: Eligible pts had no prior chemotherapy, ECOG performance status (PS) 0/1, no tumor invasion of
adjacent organs, no recent thrombosis, and no bleeding risk. Primary endpoint: OS.
Stratification: disease extent (locally advanced vs. metastatic). Statistics:90% power to detect a death hazard ratio of _0.73 for
G+A with a 1-sided 0.025 false-positive error rate. Pts were randomized in a 1:1 ratio to receive G 1,000 mg/m2 over 30
minutes on days 1, 8, 15, Q28 days, and either A 5 mg or P orally BID. CT scans were obtained Q8 weeks.
Results: 632 pts were enrolled from 7/07 to 10/08. At the time of the pre-specified interim analysis, data from 630 pts were
available. Based on the interim analysis after 223 deaths had occurred, the Independent Data Monitoring Committee in 1/09
determined that the futility boundary
had been crossed. Pts on treatment were notified and unblinded, and discontinuation of A was recommended. Pt
characteristics (314 A+G/316 P+G): male 61%/60%; median age 61/62 years; PS 1 52%/49%; stage IV disease 80%/79%.
Median time on treatment: 2.7/2.8 months (mo). Median follow-up: 5.6/5.6 mo. Median OS: intent-to-treat population 7.4/8.2
mo (95% CI: 6.2−9.5/6.9−10.4 mo); locally advanced disease 9.0/10.6 mo (95% CI: 7.3−10.1/9.9–not available); metastatic
disease 6.9/6.9 (95% CI:5.6−10.2/6.2−8.2). Overall death hazard ratio: 1.06 (95% CI: 0.82−1.38).
Deaths as of 1/09: 112/111 pts. Of the 613 pts evaluable for toxicity, grade 3/4 toxicity included (% pts A+G/P+G): neutropenia
13%/12%; thrombocytopenia 12%/7%; anemia 3%/8%; fatigue 8%/7%; anorexia 6%/4%; hypertension 7%/2%; asthenia
6%/2%; gastrointestinal bleeding2%/2%; gastrointestinal perforation 1%/1%; pulmonary embolism 2%/2%;deep vein
thrombosis 1%/2%; cerebrovascular accident 0.3%/0.3%;proteinuria 1%/0%. Thyroid-stimulating hormone levels were
obtained in 217 pts; of 197 pts with normal baseline values, elevations _5 mU/mL occurred in 36%/8% of pts.
Conclusion: The addition of A to G does not increase survival in pts with advanced PC.
8.
Geissler M et al. Trastuzumab e Capecitabina in pazienti con tumore del pancreas metastatico con iperespressione di HER2:
studio multicentrico di fase II del gruppo AIO per studio tumore del pancreas (su patrocinio del gruppo Tedesco AIO[AIO PK0204]). ASCO GI 2010-Abstract numero:200.
Background: In metastatic pancreatic cancer (mPaCa) overexpression of the human epidermal growth factor receptor 2
(HER2) has been reported in up to 82% of cases, suggesting its use as a therapeutic target. Therefore, the study was
conducted to determine the efficacy and toxicity of capecitabine (CAP) and TRAS in pts with mPaCa. Methods: Eligible pts
had histologically confirmed mPaCa. The primary endpoint was PFS at 12 weeks. Pts with mPaCa immunohistochemically
overexpressing HER2 grade 3 or grade 2 with gene amplification (FISH) received TRAS 4 mg/kg initially followed by weekly 2
mg/kg combined with CAP 1250 mg/m2 bid day 1-14, q21. The study with planned 37 pts was prematurely closed due to
unexpected low HER2 expression. Results: Between May 1994 and February 1998 a total of 212 pts with a median age 64
years (range 38-86) were centrally screened for HER2 expression. In 207 pts the tumor specimens could be assessed for
HER2 expression and gene amplification: By IHC 83 (40%) were grade 0, 71 (34%) grade 1, 31 (15%) grade 2, and 22 (11%)
grade 3, respectively. One IHC grade 2 and all IHC grade 3 specimens showed gene amplification by FISH. From the 23 pts
with HER2 gene amplification 17 could be assessed for response to treatment and toxicity in an intention-to treat analysis.
Reported grade 3/4 toxicities in 88 cycles of chemotherapy were: leucopenia 6%, diarrhea 6%, nausea 6%, hand-foot
syndrome 6%. There was no TRAS-attributable cardiac toxicity. 23.5% of treated patients were progression free at 12 weeks,
the median overall survival was 211 days. Conclusions: In conctrast to previous findings, this multicenter study demonstrated
HER2 overexpression and gene amplification in only 11% of pts with mPaCa. This discrepancy can be explained by the use
of centrally reviewed standardized HER2 test methods and the examination of a large unselected cohort in the present study.
Although the therapy was well tolerated, PFS and OS did not perform favourably compared to standard gemcitabine
chemotherapy. Due to the low HER-2 overexpression found in this study we do not recommend further evaluation of antiHER2 treatment in pts with mPaCa.
9.
Pelzer U et al. Successful prevention of symptomatic thromboembolic evets by the low molecular weight heparin enoxaparin
in patients with advanced pancreatic cancer-results of CONKO 004 trial. European Journal of Cancer Supplements, Vol 7
N°2, September 2009, Page 365.
Objective: Patients (pts) with advanced pancreatic cancer (APC) are at increased risk for potentially letal venous
thromboembolic events (VTE).
There are conflicting data about the efficacy and safety of low molecular weight heparin (LMWH) used in different dosages for
prevention of VTE in various cancers. LMWH are also under discussion to improve overall survival (OS) in malignancy. Our
pilot study proved the feasibility of the LMWH enoxaparin (E) added to chemotherapy in pts with APC. So we consequently
started this open, prospective, randomized, multicenter study (CONKO 004) to investigate the value of E in pts with APC.
Methods: Chemotherapy naive pts with histologically or cytologically confirmed APC were randomized to receive or not to
receive LMWH (E 1 mg/kg once daily) simultaneously to palliative systemic chemotherapy.
Primary endpoint of this trial was the reduction of symptomatic VTE (sVTE). Toxicity, time to progression (TTP) and OS were
among the secondary endpoints of the study. This trial was approved by the ethics committees of the participating centers.
Results: The study was closed after recruitment of 312 pts in January 2009 according to a predefined event rate of sVTE.
After a median follow-up of 30.4 weeks (w) the ITT-analysis resulted in a significant risk reduction of sVTE from 15% (22/152)
in the observation group (O) to 5% (8/160) in the E group. The median time to sVTE in the E group was 19.6 [1.1;33]
w versus 11.4 [0.4;45.4] w in the observation group. Major bleeding rates were 9.9% for O and 6.3% for E. In each group
there was one tumorrelated fatal hemorrhage. The preliminary data analysis (OS 208/312 pts; TTP 230/312 pts) illustrates no
significant difference in OS (O:29w vs.
E:31w) and TTP (O:19w vs. E:22w).
Conclusions: The prophylactic use of enoxaparin in pts with APC is effective and safe for the primary prevention of sVTE
applied simultaneously to chemotherapy. Definitive results on OS and TTP are pending.
10. Kemeny NE et al. Conversion to resectability using hepatic artery infusion plus sistemi chemotherapy for the treatment of
unresectable liver metastases from colorectal carcinoma. JCO 2009; 27: 3465-71.
PURPOSE To determine the conversion to resectability in patients with unresectable liver metastases from colorectal cancer
treated with hepatic arterial infusion (HAI) plus systemic oxaliplatin and irinotecan (CPT-11). PATIENTS AND METHODS
Forty-nine patients with unresectable liver metastases (53% previously treated with chemotherapy) were enrolled onto a
phase I protocol with HAI floxuridine and dexamethasone plus systemic chemotherapy with oxaliplatin and irinotecan. Results
Ninety-two percent of the 49 patients had complete (8%) or partial (84%) response, and 23 (47%) of the 49 patients were able
to undergo resection in a group of patients with extensive disease (73% with > five liver lesions, 98% with bilobar disease,
86% with > or = six segments involved). For chemotherapy-naïve and previously treated patients, the median survival from
the start of HAI therapy was 50.8 and 35 months, respectively. The only baseline variable significantly associated with a
higher resection rate was female sex. Variables reflecting extensive anatomic disease, such as number of lesions or number
of vessels involved, were not significantly associated with the probability of resection. CONCLUSION The combination of
regional HAI floxuridine/dexamethasone and systemic oxaliplatin and irinotecan is an effective regimen for the treatment of
patients with unresectable liver metastases from colorectal cancer, demonstrating a 47% conversion to resection (57% in
chemotherapy-naïve patients). Future randomized trials should compare HAI plus systemic chemotherapy with systemic
therapy alone to assess the additional value of HAI therapy in converting patients with hepatic metastases to resectability.
11. Mocellin S et al. Fluoropyrimidine-HAI (hepatic arterial infusion) versus systemic chemotherapy for unresectable liver
metastases from colorectal cancer. Cochrane Database Syst Rev 2009 Jul 8 ; (3): CD007823
BACKGROUND: Although locoregional treatments such as hepatic arterial infusion (HAI) claim the advantage of delivering
higher doses of anticancer agents directly into the metastatic organ as compared to systemic chemotherapy (SCT), the
benefit in terms of overall survival (OS) is unclear. We quantitatively summarized the results of randomised controlled trials
(RCT) comparing HAI to SCT for the treatment of unresectable liver metastatic disease from colorectal cancer (CRC).
OBJECTIVES: The aim of this work is to quantitatively summarize the results of RCT comparing HAI to SCT for the treatment
of unresectable hepatic metastases from CRC. SEARCH STRATEGY: A systematic review of reports published until
September 2008 on the findings of RCT that compared HAI to SCT for the treatment of unresectable CRC liver metastases
was performed by searching the MEDLINE, Embase, Cancerlit, Cochrane and GoogleScholar electronic databases as well as
other databanks collecting information on clinical trials. SELECTION CRITERIA: Inclusion criteria were patients with
unresectable CRC liver metastases enrolled in RCT comparing HAI to SCT. The outcome measures were tumor response
rate and overall survival. DATA COLLECTION AND ANALYSIS: Two authors independently carried out study selection and
assessment of methodological quality. A third author performed a concordance analysis in order to unravel potential
systematic biases. MAIN RESULTS: Ten RCT were identified that met the eligibility criteria. HAI regimens were based on
floxuridine (FUDR), 5-fluorouracil or either one of these two fluoropyrimidines in eight and one RCT, respectively. SCT
consisted of FUDR or 5-fluorouracil in three and seven RCT, respectively. By pooling the summary data, tumor response rate
resulted 42.9% and 18.4% for HAI and SCT, respectively (RR = 2.26; 95% CI, 1.80 to 2.84; P < 0.0001). Mean weighted
median OS times were 15.9 and 12.4 months for HAI and SCT, respectively: the meta-risk of death was not statistically
different between the two treatment groups (HR = 0.90; 95% CI, 0.76 to 1.07; P = 0.24). AUTHORS' CONCLUSIONS:
Currently available evidence does not support the clinical or investigational use of fluoropyrimidine-based HAI alone for the
treatment of patients with unresectable CRC liver metastases: in fact, the greater tumor response rate obtained with this HAI
regimen does not translate into a survival advantage over fluoropyrimidine alone SCT.
12. Kemeny N et al Phase I trial of adjuvant hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexametasone plus
systemic oxaliplatin, 5-FU and leucovorin in patients with resected liver metastases from colorectal cancer. Ann Oncology
2009; 20(7): 1236-41. Epub 2009 Feb 20.
BACKGROUND: The purpose of the study was to determine the maximum tolerated dose of systemic oxaliplatin (oxal), 5fluorouracil (5-FU) and leucovorin (LV) that could be administered with hepatic arterial infusion (HAI) of floxuridine (FUDR)
and dexamethasone (Dex) in the adjuvant setting after hepatic resection. METHODS: Thirty-five patients with resected liver
metastases were entered into a phase I trial using HAI FUDR/Dex with escalating doses of oxal and 5-FU. RESULTS: The
initial dose of HAI FUDR was fixed at 0.12 mg/kg x pump volume divided by pump flow rate plus Dex infused over the first 2
weeks of a 5-week cycle. Systemic chemotherapy was delivered on days 15 and 29 with the doses of oxal escalated from 85
to 100 mg/m2 and the 5-FU 48-h continuous infusion doses from 1000 to 2000 mg/m2. The LV dose was fixed at 400 mg/m).
Dose-limiting toxic effects were diarrhea, 8.5%, and elevated bilirubin, 8.5%. With a median follow-up of 43 months, the 4year survival and progression-free survival were 88% and 50%, respectively. CONCLUSIONS: Adjuvant therapy after liver
resection with HAI FUDR/Dex plus systemic oxal at 85 mg/m2 and 5-FU by continuous infusion at 2000 g/m2 with LV at 400
mg/m2 is feasible and appears effective. Randomized studies comparing this regimen to systemic FOLFOX are suggested.
13. Tse AN et al. A phase I study of gemcitabine given via intrahepatic pump for primary or metastatic hepatic malignancies.
Cancer Chemoter Pharmacol 2009; 64 (5): 935-44.
PURPOSE: To determine the maximum tolerated dose and duration of hepatic arterial infusion (HAI) gemcitabine in patients
with unresectable hepatic metastases from colorectal cancer or primary hepatic malignancies. METHODS: Patients received
weekly gemcitabine via the side-port of an implantable HAI pump for 3 weeks in a 28-day cycle. During the dose escalation
phase, increasing doses of HAI gemcitabine (800, 1,000, 1,200, and 1,500 mg/m(2)) were given at a fixed dose-rate of 10
mg/(m(2) min). This was followed by the infusion duration escalation (IDE) phase, in which HAI gemcitabine at 1,000 mg/m(2)
was given over increasing lengths of time (200, 300, and 400 min). To estimate hepatic drug extraction, the pharmacokinetics
of HAI gemcitabine was compared with those of intravenous gemcitabine given at the same dose-rate to the same patient in
the IDE phase. RESULTS: Twenty-eight of 30 patients were evaluable. HAI gemcitabine was well tolerated up to 1,500
mg/m(2) given at 10 mg/(m(2) min) and up to 1,000 mg/m(2) infused over 400 min. There were no protocol-defined doselimiting toxicities. One patient with cholangiocarcinoma had a partial response. Hepatic extraction of gemcitabine seems
highly variable among patients and does not correlate with the length of HAI infusion. CONCLUSIONS: Hepatic arterial
infusion of gemcitabine given at doses higher or longer than the recommended systemic dose of 1,000 mg/m(2) over 30 min
is well tolerated. For future studies, we recommend an infusion of 1,500 mg/m(2) at a fixed dose-rate of 10 mg/(m(2) min).
14. De Haas-Kock DFM et al. Ccomitant hyperthermia and radiation therapy for treating locally advanced rectal cancer. Cochrane
Database Syst Rev 2010 Issue 3: CD006269.
BACKGROUND: Surgery has been the treatment of choice for patients with rectal cancer. For locally advanced cancer results
were poor, with high rates of locoregional recurrences and poor overall survival data. Adding (chemo)radiotherapy upfront
improved results mainly in locoregional control. Adding hyperthermia to radiotherapy preoperatively might have an equivalent
beneficial effect. OBJECTIVES: To quantify the potential beneficial effect of thermo radiation compared to chemo-radiation
with respect to pathological complete responses, overall survival and toxicity in rectal cancer therapy. SEARCH STRATEGY:
We identified the relevant phase II and III randomised controlled trials in any language trough electronic searches May 2007
of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2007), the Cochrane
Colorectal Cancer Groups Specialised Register, MEDLINE (from 1966), EMBASE (from 1974), CINAHL (from 1982).
Furthermore, various trial databases were searched for the identification of recent completed and ongoing trials (metaRegister
of Controlled Trials, Cancer Research UK, Cancer.gov, The Eastern Cooperative Oncology Group Trials Database). All
studies identified until May 2007 were considered for inclusion in the present study. SELECTION CRITERIA: Only phase II
and III randomised controlled clinical trials were included in the analysis. DATA COLLECTION AND ANALYSIS: All identified
studies were assessed by two independent reviewers. A weighted estimate of the treatment effect was computed for 2, 3, 4
and 5-year survival, for local tumour recurrence, severe acute and late toxicity and complete tumour response (CR). CR was
defined either clinically by disappearance of all pretreatment signs of local tumour or pathologically by microscopically free
margins. The risk ratio (RR) and hazard ratio (HR) were used. Analyses were performed with the Reference Manager
(RevMan). MAIN RESULTS: Six RCTs published between 1990 and 2007 were identified. A total number of 520 patients was
treated, 258 in the radiotherapy only arm (RT) and 262 in the radiotherapy-hyperthermia arm (RHT). Four studies (424
patients) reported overall survival (OS) rates. After 2 years, OS was significantly better in the RHT group (HR 2.06; 95% CI
1.33-3.17; p=.001), but this difference disappeared after a longer period (3, 4 and 5 year OS). All but one studies reported CR
rates. A significant higher CR rate was observed in the RHT group (RR 2.81; 95% CI 1.22-6.45; p=.01). Only 2 studies
reported on acute toxicity. In these 2 studies no significant differences were observed between the RT and the RHT group.
Late toxicity data were not reported. AUTHORS' CONCLUSIONS: Further studies are needed to compare chemoradiation
versus thermoradiation versus chemoradiation plus hyperthermia in well selected/conducted and quality controlled
randomised trials.
A&S Anno 2010 n.1