Download ECOG PS: 0

• B.P., female, 65 yrs, ECOG PS 0
• Medical history: none, medications: none
• December 2012: routine abdominal ultrasound revealed suspicious liver lesions
• December 2012: CT chest/abdomen:
2 liver lesions up to 38 mm
2 pulmonary lesions up to 1cm
thickening of colonic wall (sigma)
• Colonoscopy: non obstructive sigmoid tumor without bleeding signs
• Histology: adenocarcinoma, KRAS WT
MANAGEMENT AND THERAPEUTIC DECISION
DISEASE CHARACTERISTICS
• Colon carcinoma with synchronous liver
and lung metastates (STAGE IV)
• KRAS STATUS: WILD TYPE
• No symptomatic primary tumour for
occlusion and bleeding
PATIENT CHARACTERISTICS
• Age: 65 yrs
• ECOG PS: 0
• Normal blood counts, liver and renal
function tests
1. Disseminated disease, technically ‘never’/unlikely resectable.
2. The aim is prevention of tumour progression and prolongation of life
with minimal treatment burden.
3. Require non-intensive/sequential treatment for “continuum of care”.
4. Because she didn’t receive adjuvant oxaliplatin, she can receive
oxaliplatin in first line.
5. Clinical trials showed an improvement in response rate and PFS with
the addition of anti-EGFR monoclonal antibodies to FOLFOX
FOLFOX+CETUXIMAB
Cycle
Date
Dosage
Toxicity G3-G4
Delay
I
15/01/13
100 %
No
No
II
30/01/13
100 %
No
No
III
14/02/13
100 %
No
No
IV
28/02/13
100 %
No
No
V
11/03/13
100 %
No
No
VI
25/03/13
100 %
No
No
TOX MAX DETECTED: Mucositis G2, Diarrhea G1, Skin toxicity G1
Not dose reduction nor schedule modification
RESTAGING
CT
SCAN
(08/04/13):
disease
progression with increasing of liver nodules and
emerging of new lung nodules
DISEASE CHARACTERISTICS
•
Liver disease incrementation
•
New lung disease
•
No symptomatic primary
tumour for occlusion and
bleeding
•
A Multicenter, Single arm, Open Label Clinical
Trial to Evaluate the Safety and Health-Related
Quality of Life of Aflibercept in Patients with
Metastatic Colorectal Cancer (mCRC) Previously
Treated with an Oxaliplatin-Containing Regimen
Time to progression: 3 months
PATIENT CHARACTERISTICS
•
Age: 65 yrs
•
She remains performance
status ECOG 0
•
RECRUITMENT INTO CLINICAL TRIAL ASQoP
Normal blood counts, liver and
renal function tests
AFLIBERCEPT 4 mg/kg IV+ FOLFIRI q 2 weeks
until disease progression, unacceptable toxicity,
death, investigator’s decision or patient’s refusal
Cycle
Date
Dosage
Toxicity G3-G4
Delay
I
13/05/13
100 %
No
No
II
27/05/13
100 %
Yes
Yes
III
18/06/13
75 %
No
No
IV
02/07/13
75 %
No
No
V
22/07/13
75%
No
No
VI
06/08/13
75%
No
No
• RESTAGING CT SCAN (30/08/13): STABLE DISEASE (SD)
Cycle
Date
Dosage
Toxicity G3-G4
Delay
VII
16/09/13
75 %
No
No
VIII
30/09/13
75 %
No
No
IX
14/09/13
75 %
No
No
X
28/10/13
75 %
No
No
XI
11/11/13
75%
No
No
XII
25/11/13
75%
No
No
• RESTAGING CT SCAN (14/12/13): SD
MANAGEMENT:
TOX MAX DETECTED: neutropenia G2, diarrhea G2
Dose reduction of 25% nor schedule modification
Good tolerability, ECOG PS 1
FROM JANUARY 2014 TO JUNE 2014: 12 CYCLES OF FOLFIRI-AFLIBERCEPT
RESTAGING CT SCAN (11/07/2014): LIVER AND LUNG PROGRESSION DISEASE
DISEASE CHARACTERISTICS
• Liver and lung progression
WHAT TREATMENT SHOULD SHE
RECEIVE NOW?
• No symptomatic primary
tumour for occlusion and
bleeding
• Time to progression: 13
1) BEST SUPPORTIVE CARE
2) REGORAFENIB
months
3) RECHALLENGE FOLFOX
PATIENT CHARACTERISTICS
• Age: 66 yrs
• ECOG PS: 1
• She has received fluorouracil,
oxaliplatin and irinotecan,
cetuximab, aflibercept.
4) CLINICAL TRIALS
WHAT TREATMENT SHOULD SHE RECEIVE
NOW?
1. BEST SUPPORTIVE CARE
14%
2. REGORAFENIB
41%
3. RECHALLENGE FOLFOX
12%
4. CLINICAL TRIALS
33%
020
1) Regorafenib in 2014 was in Cnn prescription range.
2) It is unlikely that she would benefit from further chemotherapy.
3) The aim is abrogation of further progression, low toxicity most relevant, tumour
shrinkage is less relevant.
4) Because she is well and has a good performance status, she should be considered for
a clinical trial.
Prot. CAPmetro+PPI: “ASSOCIATION BETWEEN PROTON-PUMP INHIBITORS (PPI) and
METRONOMIC CAPECITABINE (mCAP) AS SALVAGE TREATMENT FOR PATIENTS WITH
ADVANCED GASTRO-INTESTINAL TUMOURS: A RANDOMIZED PHASE II STUDY”, EudraCT
Numer: 2013-001096-20
Pretreated patients with
advanced gastro-intestinal cancer.
N = 66
Randomization 1:1
METRONOMIC
CAPECITABINE
METRONOMIC
CAPECITABINE+
RABEPRAZOLE 1,5 MG/KG
BID
Primary end point:
• Safety
• 3-months progression-free survival
(PFS)
Secondary end points:
• clinical benefit rate
• overall survival (OS)
• the pharmacokinetics of capecitabine
monotherapy and in combination with
rabeprazole
WHICH IS THE MOST APPROPRIATE PRIMARY
ENDPOINT
IN
CLINICAL
TRIALS
WITH
METRONOMIC CHEMOTHERAPY?
1. Clinical benefit
75%
2. Safety
17%
3. PFS
6%
4. OS
1%
020
HOW MUCH MEDICATION WOULD YOU RECOMMEND
(POSOLOGY)?
1) Capecitabine 500 mg x 2 daily, continuosly
2) Capecitabine 500 mg x 2 daily, days 1-28 every 5 weeks
3) Capecitabine 1250 mg/mq daily, continuosly
4) Capecitabine 1500 mg daily, continuosly
HOW MUCH MEDICATION WOULD YOU
RECOMMEND (POSOLOGY)?
1. Capecitabine 500 mg x 2 daily,
continuosly
2. Capecitabine 500 mg x 2 daily,
days 1-28 every 5 weeks
3. Capecitabine 1250 mg/mq
daily, continuosly
4. Capecitabine 1500 mg daily,
continuosly
020
25%
4%
12%
59%
HOW MUCH MEDICATION WOULD YOU RECOMMEND
(POSOLOGY)?
1) Capecitabine 500 mg x 2 daily, continuosly
2) Capecitabine 500 mg x 2 daily, days 1-28 every 5 weeks
3) Capecitabine 1250 mg/mq daily, continuosly
4) Capecitabine 1500 mg daily, continuosly
CAPECITABINE 1500 MG DAILY,
CONTINUOSLY
ASSOCIATION BETWEEN PROTON-PUMP INHIBITORS (PPI) AND METRONOMIC CAPECITABINE (mCAP) AS SALVAGE TREATMENT FOR
PATIENTS WITH ADVANCED GASTRO-INTESTINAL TUMOURS:A RANDOMIZED PHASE II STUDY
Milano Annalisa1, D’Antonio Chiara1, Roberto Michela1, Falcone Rosa1, Di Pietro Francesca Romana1, Durante Valeria1,
Romiti Adriana1, Fais Stefano2, Marchetti Paolo1
1Sapienza
University, Sant’Andrea Hospital, Rome Italy; 2National Istitute of Health, Rome Italy
INTRODUCTION
Highly proliferating tumor cells produce large amounts of H+ through anaerobic
glycolysis and proton flow regulators as V-ATPase are responsible for the pH gradient
between intracellular and extracellular environment, typical of the malignant cells1.
Several researches have shown that acidification of tumor microenvironment is the
basis for tumor invasiveness, ability to metastasize and cytotoxic agents resistance2.
Therefore proton pump inhibitors (PPI) could be used to increase the chemosensitivity
of cancer cells3 4. We previously demonstrated that capecitabine (mCAP) at
metronomic dosage (1500 mg/die) is moderately active and well-tolerated as salvage
chemotherapy in patients with metastatic colorectal cancer5. The aim of this
comparative, phase II study was to evaluate safety and activity of mCAP alone or
combined with rabeprazole6 in pretreated patients with advanced gastro-intestinal
cancer.
PATIENTS AND METHODS
This is a single centre, open label, randomized phase II study to determine safety and
activity of mCAP (1500 mg/die, continuosly) combined with Rabeprazole (1.5 mg/kg
bis in die for 3 days a week) compared to mCAP alone. The maximum administered
dose of Rabeprazole was 120 mg/day, as for the treatment of Zollinger Ellison
Syndrome. Inclusion criteria were: diagnosis of advanced or metastatic
gastrointestinal tumors, at least one previous line of treatment, performance status
(ECOG) ≤ 2, life expectancy > 3 months, adequate organ (liver, kidney, heart and bone
marrow) function. This trial is registered at EU Clinical Trials Register, EUdract
number 2013-001096-20.
RESULTS
Forty-one metastatic gastrointestinal cancer patients have been recruited (median of
previous chemotherapy regimens: 2). There was no difference in demographic
parameters distribution in the two treatment arms. All patients were evaluable for
response at 12 weeks. Six (29%) patients treated with mCAP and four (20%) patients
treated with mCAP+PPI had clinical benefit, defined as the sum of complete responses
(CR), partial responses (PR) and stabilization of disease (SD). No grade 4 toxicity
occurred (table).
Median PFS was 15 weeks in both treatment arms; median OS was 26 and 29 weeks in
mCAP and mCAP+PPI arm respectively (Figure).
mCAP
N (%)
mCAP+PPI
N (%)
21 (51)
20 (49)
68 (4584)
68 (56-85)
SEX:
Female
Male
9 (43)
12 (57)
7 (35)
13 (65)
ECOG PS:
0
>1
7 (33)
14 (67)
9 (45)
11 (55)
LOCALIZATION:
Upper GI-cancer
Lower GI-cancer
2 (10)
19 (90)
1 (5)
19 (95)
N= 41
AGE,years
Median (range)
METASTASIS
Hepatic
Lung
Other
HAEMATOLOGICAL
TOXICITY G3-G4
16 (76)
12 (57)
2 (9)
9 (45)
11 (55)
5 (25)
CONCLUSIONS
In this preliminary analysis comparable tolerability and
activity were observed in the two treatment arms. mCAP
could be considered for patients who cannot bear more
intensive treatments. A pharmacokinetic study to evaluate
the influence of high-dose PPI on absorption, distribution
and effects of mCAP is ongoing .
2 (11)
0
NONHAEMATOLOGICAL
TOXICITY G3-G4
4 (22)
3 (15)
RESPONSE RATE
PR
SD
PD
NA (NOT
AVAILABLE)
0
6 (29)
13 (62)
2 (9)
1 (5)
3 (15)
16 (80)
TABLE:clinocopathologic features of patients
REFERENCES
1) Tredan O et al. J Natl Cancer Inst 2007; 99:1441-54
2) Spugnini EP et al. Biochim Biophys Acta. 2014 Oct 20.
pii: S0005-736(14)00350-2
3) Fais S et al. Cancer Res 2007; 67:10627-30
4) Lindner K et al. J Exp Clin Cancer Res 2014; 33(1):73
5) Romiti et al. Med Oncol. 2015;32(3):54
6) Gu M et al. Oncol Lett 2014;8(4):1739-44
ASSOCIATION BETWEEN PROTON-PUMP INHIBITORS (PPI) AND METRONOMIC CAPECITABINE (mCAP) AS SALVAGE TREATMENT FOR
PATIENTS WITH ADVANCED GASTRO-INTESTINAL TUMOURS:A RANDOMIZED PHASE II STUDY
Milano Annalisa1, D’Antonio Chiara1, Roberto Michela1, Falcone Rosa1, Di Pietro Francesca Romana1, Durante Valeria1,
Romiti Adriana1, Fais Stefano2, Marchetti Paolo1
1Sapienza
University, Sant’Andrea Hospital, Rome Italy; 2National Istitute of Health, Rome Italy
INTRODUCTION
Highly proliferating tumor cells produce large amounts of H+ through anaerobic
glycolysis and proton flow regulators as V-ATPase are responsible for the pH gradient
between intracellular and extracellular environment, typical of the malignant cells1.
Several researches have shown that acidification of tumor microenvironment is the
basis for tumor invasiveness, ability to metastasize and cytotoxic agents resistance2.
Therefore proton pump inhibitors (PPI) could be used to increase the chemosensitivity
of cancer cells3 4. We previously demonstrated that capecitabine (mCAP) at
metronomic dosage (1500 mg/die) is moderately active and well-tolerated as salvage
chemotherapy in patients with metastatic colorectal cancer5. The aim of this
comparative, phase II study was to evaluate safety and activity of mCAP alone or
combined with rabeprazole6 in pretreated patients with advanced gastro-intestinal
cancer.
PATIENTS AND METHODS
This is a single centre, open label, randomized phase II study to determine safety and
activity of mCAP (1500 mg/die, continuosly) combined with Rabeprazole (1.5 mg/kg
bis in die for 3 days a week) compared to mCAP alone. The maximum administered
dose of Rabeprazole was 120 mg/day, as for the treatment of Zollinger Ellison
Syndrome. Inclusion criteria were: diagnosis of advanced or metastatic
gastrointestinal tumors, at least one previous line of treatment, performance status
(ECOG) ≤ 2, life expectancy > 3 months, adequate organ (liver, kidney, heart and bone
marrow) function. This trial is registered at EU Clinical Trials Register, EUdract
number 2013-001096-20.
RESULTS
Forty-one metastatic gastrointestinal cancer patients have been recruited (median of
previous chemotherapy regimens: 2). There was no difference in demographic
parameters distribution in the two treatment arms. All patients were evaluable for
response at 12 weeks. Six (29%) patients treated with mCAP and four (20%) patients
treated with mCAP+PPI had clinical benefit, defined as the sum of complete responses
(CR), partial responses (PR) and stabilization of disease (SD). No grade 4 toxicity
occurred (table).
mCAP
N (%)
mCAP+PPI
N (%)
21 (51)
20 (49)
68 (4584)
68 (56-85)
SEX:
Female
Male
9 (43)
12 (57)
7 (35)
13 (65)
ECOG PS:
0
>1
7 (33)
14 (67)
9 (45)
11 (55)
LOCALIZATION:
Upper GI-cancer
Lower GI-cancer
2 (10)
19 (90)
1 (5)
19 (95)
N= 41
AGE,years
Median (range)
METASTASIS
Hepatic
Lung
Other
HAEMATOLOGICAL
TOXICITY G3-G4
16 (76)
12 (57)
2 (9)
9 (45)
11 (55)
5 (25)
CONCLUSIONS
In this preliminary analysis comparable tolerability and
activity were observed in the two treatment arms. mCAP
could be considered for patients who cannot bear more
intensive treatments. A pharmacokinetic study to evaluate
the influence of high-dose PPI on absorption, distribution
and effects of mCAP is ongoing .
2 (11)
0
NONHAEMATOLOGICAL
TOXICITY G3-G4
4 (22)
3 (15)
RESPONSE RATE
PR
SD
PD
NA (NOT
AVAILABLE)
0
6 (29)
13 (62)
2 (9)
1 (5)
3 (15)
16 (80)
TABLE:clinocopathologic features of patients
REFERENCES
1) Tredan O et al. J Natl Cancer Inst 2007; 99:1441-54
2) Spugnini EP et al. Biochim Biophys Acta. 2014 Oct 20.
pii: S0005-736(14)00350-2
3) Fais S et al. Cancer Res 2007; 67:10627-30
4) Lindner K et al. J Exp Clin Cancer Res 2014; 33(1):73
5) Romiti et al. Med Oncol. 2015;32(3):54
6) Gu M et al. Oncol Lett 2014;8(4):1739-44
WHAT IS THE MOST FREQUENT SIDE
EFFECT OF mCAP IN YOUR CLINICAL
PRACTICE?
1. HFS
54%
2. Anemia
4%
3. Diarrhea
16%
4. Asthenia
25%
010
Cycle
Date
Dosage
Toxicity G3-G4
Delay
I
13/09/14
100 %
No
No
II
11/10/14
100 %
No
No
III
08/11/14
100 %
No
No
IV
02/01/15
100 %
No
No
V
30/01/15
100 %
No
No
VI
27/02/15
100 %
No
No
VII
24/04/15
100 %
No
No
VIII
22/05/15
100 %
No
No
IX
19/06/15
100 %
No
No
X
14/08/15
100 %
No
No
XI
11/09/15
100 %
No
No
XII
09/10/15
100 %
No
No
XIII
4/12/15
100 %
No
No
XIV
04/01/16
100 %
No
No
TOX MAX DETECTED: HFS G2, Anemia G1, Asthenia G1
Not dose reduction nor schedule modification
+3
+6
+12
0
+3
+6
+9
Folfox‐Cetuximab
TTP
Folfiri‐Aflibercept
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
METRONOMIC CAPECITABINE
•
METRONOMIC CAPECITABINE HAS FAVORABLE TOXICITY PROFILE
WITHOUT ANY OCCURENCES OF SEVERE ADVERSE EVENTS.
•
METRONOMIC CAPECITABINE SHOWS MODERATE ACTIVITY.
•
THE COST OF THE THERAPY IS FINANCIALLY SUSTAINABLE.
•
METRONOMIC CAPECITABINE IS A THERAPEUTIC CHANCE FOR
PATIENTS INELIGIBLE FOR INTENSIVE STANDARD TREATMENTS.