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Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:

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Page 1: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:
Page 2: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:
Page 3: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:

• 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

Page 4: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:
Page 5: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:

• Presentation at diagnosis1:– 45% with localized disease– 25% with locally advanced disease– 20–30% metastatic disease

• 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.

Page 6: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:

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

RT vs. observation 72 Kjaer (1987) negative

MPA 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- vs. observation 247 Pizzocaro (2001) negative

IFN- NL vs. observation 283 Messing (2003) negative

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)

s.c. IL-2 + IFN- + 5-FU vs. observation 203 Atzpodien (2005) negative

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

Aut. tumour-derived HSP-96-peptide complexvs. observation

918 Wood C (2008) negative

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

s.c. IL-2 + IFN- + 5-FU vs. observation 550 Aitchinson (2012) negative

Girentuximab (anti-CAIX MoAb) vs. observation

856 Belldegrun (2013) negative

Page 7: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:

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

RT vs. observation 72 Kjaer (1987) negative

MPA 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- vs. observation 247 Pizzocaro (2001) negative

IFN- NL vs. observation 283 Messing (2003) negative

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)

s.c. IL-2 + IFN- + 5-FU vs. observation 203 Atzpodien (2005) negative

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

Aut. tumour-derived HSP-96-peptide complexvs. observation

918 Wood C (2008) negative

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

s.c. IL-2 + IFN- + 5-FU vs. observation 550 Aitchinson (2012) negative

Girentuximab (anti-CAIX MoAb) vs. observation

856 Belldegrun (2013) negative

Page 8: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:

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

Page 9: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:

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

ASSURE (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

Closed at enrolment;no data available yet

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

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

Closed at enrolment;no data available yet

EVEREST (SWOG)Everolimus vs. placebo (days 1-42; treatment repeats every 6 weeks for 9 courses)

1218 Pathologically intermediate high-risk or very high-risk.

Primary end-point: DFS

Not yet enrolling(US only)

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

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

Closed at enrolment;no data available yet

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 0-1Primary end-point: DFS

Enrolling(Japan only)

Page 10: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:

• To 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 mandatory

Page 11: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:
Page 12: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:

Pro Cons

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

Potential for higher incidence of wound complications

Incorporates cytoreductive surgery to examine tissue before and after therapy for endpoint targets

Local tumor progression in non-responders 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

Page 13: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:

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

Sorafenib treatment

Page 14: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:

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

Level II thrombus Level I thrombus

Sunitinib treatment(4 cycles)

Page 15: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:

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

Baseline 8 Weeks of therapy

Bevacizumab treatment

Page 16: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:

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

Primary Tumor Regressionn=45 (%)

>20% growth 1 (2)

10-20% growth 2 (4)

0-10% growth 19 (42)

1-10% shrinkage 13 (29)

11-20% shrinkage 7 (16)

20-30% shrinkage 3 (7)

Page 17: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:

CG Wood, personal communication

Page 18: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:

CG Wood, personal communication

Pre-Surgical Therapy

Immediate Surgery Total 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) 0.91

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) 0.95 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

Page 19: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:

CG Wood, personal communication

Univariate analysis Odds Ratio 95 % CI P

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

Superficial Wound Healing 12.91 2.78, 60.06 0.001*

Chylous Ascites 0.57 0.11, 2.90 0.49

Page 20: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:

CG Wood, personal communication

• *Adjusted for:– Pre-operative albumin– Smoking status (never, current, former)– Pre-operative hemoglobin– Laparoscopic vs open surgery– ECOG performance status– Body mass index– Age

Odds Ratio* 95% CI p-value

Superficial Wound Healing 19.7 2.13, 181.88 <0.01

Page 21: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:

Withheld treatment for at least 2 or 3 half-lives before and after surgery

Max

imum

resp

onse

Days after wounding (log scale)

I. inflammation

II. cell proliferationand matrix deposition

III. matrix remodelling

● Bleeding

● Coagulation

● Platelet activation

● Complement activation

● Granulocytes

● Phagocytosis

● Fibroplasia

● Angiogenesis

● Re-epithelization

● Extracelluar matrix sythesis

● Collagens

● Fibronectin

● Proteoglicans● Macrophages

● Cytokines

Stages of wound healingStages of wound healing

Extracellular matrixsynthesis, degradationand remodelling

Tensile strength

Cellularity

Vascularity

Consider drug half-life

Temsirolimus: 17 hrs

Sorafenib: 24-48 hrs

Sunitinib: 60-110 hrs

Bevacizumab: 14-21 days

Pazopanib: 30.9 hrs

Page 22: Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy:

CG Wood, personal communication

• Present, initial, body of evidencewould suggest that

significant primary tumor downstagingwill not be realized with the current generation

of targeted therapy agents