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MEDITERRANEAN SCHOOL OF ONCOLOGY
Ritmi circadiani e qualità di vita: actigrafia e nuovi orizzonti nel
carcinoma della mammella
Roma, 28 Novembre 2008
Cronomodulazione e farmaci orali
Giuseppe Tonini
[email protected]
Oncologia Medica
Universita’ Campus Bio-Medico, Roma
Chronobiology

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
Chronobiology is the study of the temporal relationships of
biological phenomena
Rhythms that fluctuate on a 24-hour time scale are known
as circadian rhythms.
The best-known circadian rhythms
 body temperature
 hormone secretion
 metabolism
 sleep/wake cycle
Physiology of Circadian Rhythmicity

Prominent daily variations also occur in



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endocrine,
thermoregulatory,
cardiac,
pulmonary,
renal,
gastrointestinal,
neurobehavioral functions
Harrison
3
Circadian rhytms in colorectal cancer
patients
Mormont MC et al, Chronobiol Int 2002
Properties of circadian rythms

Ubiquitous (cyanobacterias, plants, rodents,
humans)

Endogenous (persist in the absence of
environmental cycles)

Circadian clock genes
Circadian gene expression
In vitro circadian expression of cell
cycle genes
Delaunay F et al, J Biol Chem 2001
Functional classes of cycling transcripts in
cultured rat fibroblasts
Delaunay F et al, J Biol Chem 2001
Chronobiology: implications for cancer therapy

Chronotherapy aims to adapt the timing of drug
administration according to the circadian
rhythms of cancer and normal cells.

Administration of drug at a circadian time when it
is best tolerated can achieve best antitumour
activity.
Mormont and Levi, Cancer 2003
Chronobiology: implications for cancer therapy
Circadian rhythms in anticancer drug tolerability in laboratory mice or rats. The
least toxic dosing time is indicated as a function of the rest-activity cycle.
Mormont and Levi, Cancer 2003
How administer chronotherapy: the
multichannel pump
 Centralized programmation
 Any modulation of delivery rate
 4 reservoirs (100-2000 ml)
 Rates from 1 to 3000 ml/h
 Safeties
 Alarms
 Very expensive!!!!
New advances in chronotherapy
Phase I, II, III trials are on-going
and the results are interesting!!!!
Oxaliplatin and capecitabine
in vitro synergistic effect
Chronomodulated Capecitabine
Capecitabine
Weekly infusion of oxaliplatin

Phase II studies with weekly or biweekly oxaliplatin have
demonstrated low levels of toxicity and high clinical activity
(Rosati G, Ann Oncol. 2001 and Oncology, 2004; Santini D, Medical Oncology,
2004; Scheithauer W, Ann Oncol, 2003; Kemeny N, Ann Oncol, 2002; Chao Y et
al, Br J cancer, 2004)

The weekly oxaliplatin schedule leads to a higher dose-density
and a higher total dose administered (Rosati G, Ann Oncol. 2001;
Santini D, Medical Oncology, 2004)

The weekly oxaliplatin schedule may lead to a better and more
continous synergistic action with capecitabine administered for
14 days
Toxicity and efficacy of chronomodulated chemotherapy
Metastatic colorectal cancer
(Folinic Acid, 5-FU, Oxaliplatin)
Infusion flow
Constant
Chrono
p
Toxicity
Oral mucositis gr 3-4
Neuropathy gr 2-3
Responding rate
74%
31%
30%
14%
<10-4
16%
<10-2
51%
<10-3
Lévi et al. JNCI 1994 ; Lancet 1997 ; Lancet Onc 2001
Chronotherapy trials in metastatic breast cancer
Author
Phase
Regimen
Pts
Results
DepresBrummer et
al (1995)
I
Mitoxantrone, 5FU/AF
18
Neutropenia
was the
most frequent toxicity
(G3: 4 pts; G4: 7 pts),
G3 mucositis: 1 pts; No
G3/4 diarrhea, nausea,
or vomiting.
Coudert et al
(2008)
I
Vinorelbine. 5FU (8 chrono
schedules)
90
No significant results
regarding an optimal
time
for
vinorelbine
administration
Experiences of chronomodulated
chemotherapy at Campus BioMedico
Continuous infusion of oxaliplatin plus chronomodulated
capecitabine in 5-fluorouracil- and irinotecan-resistant
advanced colorectal cancer patients.
Santini D, Vincenzi B, La Cesa A, Caricato M, Schiavon G, Spalletta B, Di Seri
M, Coppola R, Rocci L and Tonini G.
Oncology. 2005;69(1):27-34.
Chronomodulated administration of oxaliplatin plus
capecitabine (XELOX) as first line chemotherapy in advanced
colorectal cancer patients: phase II study.
Santini D, Vincenzi B, Schiavon G, Di Seri M, Virzi V, Spalletta B, Caricato M,
Coppola R and Tonini G.
Cancer Chemother Pharmacol. 2007 Apr;59(5):613-20.
Treatment schedule
Chronomodulated XELOX
C.I. Oxaliplatin (70 mg/mq)
Chronomodulated
Capecitabine (2000 mg/mq)
1
8
8 a.m.-8 p.m.
8 a.m.-8 p.m.
X
X
15
21
X
Treatment schedule
Capecitabine chronomodulation
50%
45%
40%
35%
30%
25%
20%
15%
10%
5%
0%
% dose
8 a.m.
6 p.m.
11 p.m.
Patients characteristics
Number of patients (%)
62 (100%)
First line
26
Other lines
36
1-2 previous lines
Median age, years (range)
16-20
65 (32-77)
Male/Female
32/30
ECOG 0/1/2
36/22/4
Colon/rectal (%)
68/32
Single/> 1 metastatic sites (%)
48/52
>2 metastatic sites(%)
27.1%
Metastatic sites (%)
liver/lung
68.7/47.9
Best confirmed responses in first line chemotherapy
(% patients)
N Pts (%)
26
%
cCR
2
7.7%
cPR
15
57.7%
RR%
17
65,4%
cSD
7
26.9%
cPD
2
7.7%
D Stab.
24
92.3%
Best confirmed responses in other lines of
chemotherapy (% patients)
N Pts (%)
36
(100%)
CR
0
(0%)
PR
11
(30.6%)
SD
13
(36.1%)
PD
12
(33.3%)
CR-PR
11
(30.6%)
Disease stabilization
24
(66.6%)
(CR-PR-SD)
Survival data in first line chemotherapy
N Pts 26
Months (95% C.I.)
Progression free survival
9.66 (6.88 - 12.45)
Median survival
19.74 (15.92–23.56)
1-year survival rate
84.6% (22 Pts)
Survival data in other lines of chemotherapy
N Pts
36
Months (range)
Progression free survival
6.7 (4.9-8.4)
Median survival
11.3 (6.6-13.1)
1-year survival rate
53.8%
Safety results (after dose reduction)
toxicity per patient (47 patients)
NCI  Gr 3
Thrombocytopenia
Neutropenia
% patients
0
6.1
Febrile neutropenia
0
Anemia
0
Asthenia
21.2
Diarrhea
12.1
Stomatitis
3
Vomiting
6.1
Hand foot syndrome
3.0
Alopecia (Gr2)
3.0
Liver
3.0
Conclusions
With high activity and good tolerability, chronomodulated
XELOX compares favorably with standard XELOX
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High RR% in first and other lines
TTP in first line comparable with the best schedules
Favorable median survival
Responses in oxaliplatin-pretreated patients
Low incidence of severe neurotoxicity and hand foot
syndrome
Low incidence of severe diarrhea after dose reduction of
capecitabine
Bevacizumab plus chronomodulated
capecitabine as first-line advanced colorectal
cancer patients.
(Unpublished data)
Schedule
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Oxaliplatin: 70m/mq (gg 1-8q21)

Bevacizumab: 7,5 mg/mq (gg1q21)

Capecitabine: 1750 mg/mq (gg1-14q21):
¼ h 8, ¼ h 18, ½ h 23.
Patients’ characteristics
Total
19
Median Age
57
100%
Primary Tumor
Colon
10
52,6%
Rectal
9
47,4%
1
9
47,4%
2
5
26,3%
≥3
5
26,3%
Liver
13
Abdominal Lymph nodes
7
Lung
6
Peritoneum
5
Number of metastatic sites
Metastasis localization
Toxicity
Toxicity
Pts (%)
Grade 1
Grade 2
Grade 3
Grade 4
Any Grade
Hematological
Anemia
6 (31,5)
1 (5,3)
1 (5,3)
0
8 (42,1)
Leucopenia
3 (15,8)
1 (5,3)
0
0
4 (21)
Neutropenia
0
4 (21)
1 (5,3)
0
5 (26,3)
4 (21)
0
1 (5,3)
0
5 (26,3)
Thrombocytopenia
Non Hematological
Nausea/vomiting
4 (21)
5 (26,4)
0
0
9 (47,4)
Stomatitis
10 (52,6)
1 (5,3)
1 (5,3)
0
12 (63,2)
Neurotoxicity
14 (73,6)
3 (15,8)
1 (5,3)
0
18 (92,7)
Diarrhea
7 (36,8)
2 (10,6)
3 (15,8)
0
12 (63,2)
Asthenia
7 (36,8)
7 (36,8)
2 (10,6)
0
16 (84,2)
H-F syndrome
6 (13,1)
1 (2,2)
0
0
7 (15,3)
Hepatotoxicity
1 (5,2)
3 (15,8)
1 (5,3)
1 (5,3)
6 (31,4)
Efficacy
Pts (%)
1 (8,4%)
5 (41,6%)
3 (25%)
3 (25%)
CR
PR
SD
PD
Response Duration
Median 7 months
95% C.I. 4,987-9,899
TTP
Median 9 months
95% C.I. 8,101-9,899
OS
Not reached
RR
6 (50%)
DCR
9 (75%)
Phase I study of intermittent and
chronomodulated oral therapy with capecitabine
in patients with advanced and/or metastatic
cancer.
Santini D, Vincenzi B, Schiavon G, La Cesa A, Gasparro S, Vincenzi A and Tonini G.
BMC Cancer. 2006; 24;6:42
Schedules and end-points
Schedule:
Capecitabine 1500-2750 mg/mq (gg1-14q21): ¼
h 8, ¼ h 18, ½ h 23.
Endpoints:
• Maximum-tolerated dose
• Dose-limiting toxicities
• Safety
Patients’ characteristics
Results
 Most common toxicities: fatigue, diarrhoea and hand foot
syndrome.
 Only 1/9 pts treated at capecitabine dose of 2,750 mg/m2
had DLT toxicities (fatigue G4).
 No other episodes of DLT were observed at the same dose steps
and at lower doses of capecitabine.
 The dose of 2,750 mg/m2 is recommended for further study.
 Tumor responses were observed in patients with metastatic breast
(6 PR) and colorectal cancer (3 PR).
Conclusions
Conclusions
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
Circadian rhythms modulate cell functions
relevant for:
- anticancer agent pharmacology
- Cancer processes
New advances in cancer chronotherapy :
• Programmable drug delivery devices
• Relevance shown in Phase I, II & III clinical
trials
Conclusions

In our experience chronomodulated chemotherapy is
effective and well tolerated

Our results clearly highlight the need for new trials to
verify the real clinical impact of this new way of
chronomodulated capecitabine administration in
combination with other active drugs in solid tumors.
Oncologia Medica
Università Campus Bio-Medico, Roma
Giuseppe Tonini
Daniele Santini
Bruno Vincenzi
Annalisa La Cesa
Claudia Grilli
Sara Galluzzo
Simona Gasparro
Vladimir Virzì
Gaia Schiavon
Valentina Leoni
Marianna Silletta
Francesco Pantano
Maria Elisabetta Fratto
Alice Calvieri
Olga Venditti
Chiara Spoto
Salvatore Intagliata
Calogero Gucciardino
Laura Rocci
Federica Uzzalli
Marzia Mazzaroni