terapia neoadiuvante e adiuvante c. porta.ppt [modalità ... · •presentation 1at diagnosis : –...

• Adjuvant therapy:

– Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back

• Neo‐adjuvant therapy:

– Treatment given as a first step to shrink a tumor before the main treatment, which is usually surgery, is given

NCI Dictionary of Cancer Terms

• Presentation at diagnosis1:

– 45% with localized disease– 25% with locally advanced disease– 20–30% metastatic disease

• 33% of patients treated for localized disease will• 33% of patients treated for localized disease will develop metastatic disease2

1. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2009;2. Flanigan RC et al. Curr Treat Options Oncol 2003;4:385–90.

Closed adjuvant trials N Author (year) Outcome of the study

RT vs. observation 72 Kjaer (1987) negative

MPA vs observation 136 Pizzocaro (1987) negativeMPA vs. observation 136 Pizzocaro (1987) negative

Aut. tumor vaccine + BCG vs. observation 43 Adler (1987) negative

Aut. tumor vaccine ± BCG vs. observation 120 Galligioni (1996) negative

UFT vs. observation 71 Naito (1997) negative

IFN‐α vs. observation 247 Pizzocaro (2001) negative

IFN‐α NL vs. observation 283 Messing (2003) negativeg ( ) g

HD IL‐2 vs. observation 69 Clark (2003) negative

Autologous tumor vaccine vs. observation 553 Jocham (2004) positive in terms of PFS (p=0.02)

2 b i 203 A di (2005) is.c. IL‐2 + IFN‐α + 5‐FU vs. observation 203 Atzpodien (2005) negative

s.c. IL‐2 + IFN‐α vs. observation 310 Passalacqua (2007) negative

Aut. tumour‐derived HSP‐96‐peptide complex 918 Wood C (2008) negativevs. observation

Thalidomide vs. observation 46* Margulis (2009) negative*trial stopped due to inefficacy

b i hi ( ) is.c. IL‐2 + IFN‐α + 5‐FU vs. observation 550 Aitchinson (2012) negative

Girentuximab (anti‐CAIX MoAb) vs. observation

856 Belldegrun (2013) negative

Massari F, et al. Clin Genitourin Cancer 2013 (E‐pub ahead of print)

Ongoing adjuvant trials

SORCE (MRC/EORTC)Sorafenib 1 year (+ 2 years placebo) vs. Sorafenib 3 years vs. placebo 3 years

1656 Leibovich score of 3 to 8.Primary end‐point: DFS

Closed at enrolment;no data available yet

SS ( COG) 923 3b 0 Cl d lASSURE (ECOG)Sunitinib 1 year vs. Sorafenib 1 year vs. placebo 1 year

1923 T3b‐4 N0, T1‐4 N+, or T1‐4 with positive margins or

vascular invasion)Primary end‐point: DFS


S‐TRAC (Pfizer)Sunitinib 1 year vs. placebo 1 year

856 High risk according to UISS.Primary end‐point: DFS


EVEREST (SWOG)Everolimus vs placebo (days 1 42; treatment

1218 Pathologically intermediate high risk or very high risk

Not yet enrolling(US only)Everolimus vs. placebo (days 1‐42; treatment

repeats every 6 weeks for 9 courses)high‐risk or very high‐risk.Primary end‐point: DFS

(US only)

VEG113387 PROTECT study (GSK)Pazopanib 1 year vs. placebo 1 year

1500 Intermediate and high risk.Primary end‐point: DFS


NCT01599754 (SFJ Pharmaceuticals)Axitinib 3 yeas vs. placebo 3 years

592 pT2 or higher, pNx pN0 or pN1, M0, Fuhrman G3‐4 and

ECOG PS 0‐1

Enrolling(Japan only)

ECOG PS 0‐1Primary end‐point: DFS

• To date, no treatment emerged as a standard of care inTo date, no treatment emerged as a standard of care in this setting

• Presently, patients should be thus offered just obser‐vation

• Enrollment into well‐desigend and adequately con‐ducted RCTs is mandatoryducted RCTs is mandatory

Pro ConsPro Cons

Litmus test for patients who will do well Therapy may impact wound healing and recovery

Potential for higher incidence ofPotential for higher incidence of wound complications

Incorporates cytoreductive surgery to i i b f d f h

Local tumor progression in non‐d i l i f hexamine tissue before and after therapy

for endpoint targetsresponders increases complexity of the surgery

More “ectomies”= Worse outcome

May see responses in the primary tumor not seen before

Timing is everythingWhy interrupt a therapeutic response?Who wants to operate on therapy refractory disease?

Eliminates unnecessary and morbid surgery in patients who don’t respond

Sorafenib treatment

Escudier B, et al. ECCO 13 – the European Cancer Conference, Paris, October 30‐November 3, 2005; abs.794.

Sunitinib treatment(4 cycles)( y )

Level II thrombus Level I thrombusLevel II thrombus

Shuch B, et al. BJU Int 2008;102:692‐696

Baseline 8 Weeks of therapyBaseline 8 Weeks of therapy

Bevacizumab treatment

Jonasch E, et al. J Clin Oncol 2009;27:4076‐81

Primary Tumor Regressionn=45 (%)

h ( )>20% growth 1 (2)

10‐20% growth 2 (4)

0 10% growth 19 (42)0‐10% growth 19 (42)

1‐10% shrinkage 13 (29)

11‐20% shrinkage 7 (16)11 20% shrinkage 7 (16)

20‐30% shrinkage 3 (7)

Van der Veldt AAM, et al. Clin Cancer Res 2008;14:2431‐6; Thomas AA, et al. J Urol 2009;181:518‐23;Jonasch E, et al. J Clin Oncol 2009;27:4076‐81

CG Wood, personal communication

Pre‐Surgical Immediate Total p

Therapy SurgeryTotal p

Overall 25 (43.1) 28 (28.7) 54 (33.5) 0.048

Peri‐operative Death 1 (1.7) 2 (2.0) 3 (1.9) 0.91Peri operative Death 1 (1.7) 2 (2.0) 3 (1.9) 0.91

Readmission to Hospital 6 (10.3) 11 (11.0) 17 (10.8) 0.90

Bleeding 1 (1.7) 2 (2.0) 3 (1.9) 0.91

Thromboembolic 5 (8.6) 5 (5.0) 10 (6.3) 0.36

Cardiac 1 (1.7) 3 (3.0) 4 (2.5) 0.63

Gastrointestinal 5 (8.6) 9 (8.9) 14 (8.8) 0.95Gastrointestinal 5 (8.6) 9 (8.9) 14 (8.8) 0.95

Infection 4 (6.9) 6 (5.9) 10 (6.3) 0.81

Superficial Wound Healing 12 (20.7) 2 (2.0) 14 (8.8) <0.001

Fascial dehiscence 2 (3.5) 0 (0.0) 2 (1.3) 0.06

Chylous Ascites 2 (3.5) 6 (5.9) 8 (5.0) 0.49


Univariate analysis Odds Ratio 95 % CI Py

Overall Complications 1.98 1.00, 3.89 0.049*

Peri‐operative Death 0.87 0.08, 9.79 0.91

Readmission to Hospital 0.93 0.33, 2.67 0.90

Bleeding 0.87 0.08, 9.79 0.91

Thromboembolic 1.81 0.50, 6.54 0.37

Cardiac 0.57 0.06, 5.64 0.63

Gastrointestinal 0.96 0.31, 3.03 0.95

Infection 1.17 0.32, 4.34 0.81

S fi i l W d H liSuperficial Wound Healing 12.91 2.78, 60.06 0.001*

Chylous Ascites 0.57 0.11, 2.90 0.49


Odds Ratio* 95% CI p valueOdds Ratio* 95% CI p‐value

Superficial Wound Healing

19.7 2.13, 181.88 <0.01

• *Adjusted for:

Wound Healing

– Pre‐operative albumin– Smoking status (never, current, former)

Pre operative hemoglobin– Pre‐operative hemoglobin– Laparoscopic vs open surgery– ECOG performance status– Body mass index– Age


Stages of wound healingConsider drug half‐life

I. inflammation

II. cell proliferationand matrix deposition

III. matrix remodelling

Consider drug half life

Temsirolimus: 17 hrs

Sorafenib: 24‐48 hrs● Fibroplasia

● Angiogenesis

R ith li ti

Sorafenib: 24 48 hrs

Sunitinib: 60‐110 hrs

Bevacizumab: 14‐21 daysnse

● Granulocytes

● Phagocytosis

● Re‐epithelization

● Extracelluar matrix sythesis Extracellular matrix

synthesis degradation

y

Pazopanib: 30.9 hrs

Withheld treatment for mum

respon ● Bleeding

● Coagulation

● Platelet activation

● Collagens

● Fibronectin● Macrophages

synthesis, degradationand remodelling

Tensile strength

CellularityWithheld treatment for at least 2 or 3 half‐lives before and after surgery

Maxim

Days after wounding (log scale)

● Platelet activation

● Complement activation

● Proteoglicans● Cytokines

Cellularity

Vascularity

• Present, initial, body of evidencewould suggest that

significant primary tumor downstagingsignificant primary tumor downstaging

will not be realized with the current generation

of targeted therapy agents


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