GESTIRE LA TOSSICITÀ
Teresa Troiani MD, PHD
U.O.C. OncoEmatologia
Seconda Università degli Studi di Napoli
Wilson, P. M. et al. Nat. Rev. Clin. Oncol. 2014
Wilson, P. M. et al. Nat. Rev. Clin. Oncol. 2014
Wilson, P. M. et al. Nat. Rev. Clin. Oncol. 2014
5-FU/Capecitabine vs TAS-102
Peters GJ, Nucleotides and Nucleic Acids (2014)
Wilson, P. M. et al. Nat. Rev. Clin. Oncol. 2014
Wilson, P. M. et al. Nat. Rev. Clin. Oncol. 2014
80% of 5FU catabolism is mediated by DPD (dihydropyrimidine dehydrogenase)
The primary catabolite is fluoro-β-alanine, that contributes to:
Neurotoxic events + Cardiotoxic events ++
Hand and foot syndrome +++
Phosphorylation of 5FU leads to the production of FUMP, that contributes to:
Gastrointestinal events +++
S1 , an other oral FP, combining tegafur (a 5FU pro drug),
gimeracil ( CDHP , DPD inhibitor) and oteracil potassium (OPRT
inhibitor), shows reduced incidence of HFS and GI events
5FU Toxicities
Adverse reactions of any grade that occurred in >15% (bars 1) or ≥20% (bars 2) of patients treated with capecitabine or the combination 5- fluorouracil/ leucovorin.
*Statistically significant difference (p < 0.00001 for bars 1 or p < 0.0002 for bars 2).
• Van Cutsem et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 2001
• Twelves C et al. Capecitabine (XelodaTM) improves medical resource use compared with 5-fluorouracil plus leucovorin in a phase III trial conducted in patients with advanced colorectal carcinoma. Eur J Cancer 2001
• Hoff PM al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic col- orectal cancer:
results of a randomized phase III study. J Clin Oncol 2001
Malet Martino et al. The Oncologist 2002
Most common treatment-related clinical adverse events (all grades)
Diarrhoea Stomatitis Hand-foot Nausea Vomiting Alopecia Fatigue syndrome
Pa tients (% )
Xeloda (n=596) 5-FU/LV (n=593)
*
*
*
*
*
*p<0.001 Hoff PM et al. Oncologist 2001;6(Suppl. 4):3–11
100
80
60
40
20
0
60%
50%
Neutropenia:
Xeloda:2.2% FU/LV:21.2%
Most common grade 3/4 treatment-related adverse events
Xeloda (n=596) 5-FU/LV (n=593)
Pa tients (% )
Diarrhoea Stomatitis Hand-foot Nausea Vomiting Neutropenic
syndrome fever/sepsis
*
*
*
*p<0.05
18 16 14 12 10 8 6 4 2 0
Twelves C. Eur J Cancer 2002;38(Suppl. 2):S15–S20
14%
12%
0.2%
3.4%
In an assessment of TAS-102 group after two cycles:
• 53% had a delay of 4 days or more in beginning their next cycle owing to toxicity
• the delay in approximately half of this subgroup extended for 8 days or more.
In the TAS-102 group a total of 73 patients (14%) required dose reductions:
• 53 patients [10%] having a single dose reduction
• 18 [3%] having two reductions
• 2 [<1%] having three reductions)
Adverse events resulted in the withdrawal of 4% of the patients receiving TAS-102 and 2% of the patients receiving placebo.
In TAS-102 group:
• 38% G≥3 neutropenia
• 18% G≥3 anemia
• 5% G≥3 thrombocytopenia
• 2% G≥3 nausea
• 2% G≥3 vomiting
• 3% G≥3 diarrhea
• 7% alopecia
no clinically meaningful differences were noted with respect to the development of serious hepatic or renal dysfunction, anorexia, stomatitis, hand–foot syndrome, or cardiac events.
Mayer RJ et al. NEJM 2015
Xeloda:Diarrhea Any Grade Grade>3
50% 12%
Xeloda:Neutropenia Any Grade NF
2.2% 0.2%
In an assessment of TAS-102 group after two cycles:
• 53% had a delay of 4 days or more in beginning their next cycle owing to toxicity
• the delay in approximately half of this subgroup extended for 8 days or more.
In the TAS-102 group a total of 73 patients (14%) required dose reductions:
• 53 patients [10%] having a single dose reduction
• 18 [3%] having two reductions
• 2 [<1%] having three reductions)
Adverse events resulted in the withdrawal of 4% of the patients receiving TAS-102 and 2% of the patients receiving placebo.
In TAS-102 group:
• 38% G≥3 neutropenia
• 18% G≥3 anemia
• 5% G≥3 thrombocytopenia
• 2% G≥3 nausea
• 2% G≥3 vomiting
• 3% diarrhea
• 7% alopecia
no clinically meaningful differences were noted with respect to the development of serious hepatic or renal dysfunction, anorexia, stomatitis, hand–foot syndrome, or cardiac events.
Mayer RJ et al. NEJM 2015
Supportive treatment for hematologic toxicities in RECOURSE trial
•
Of 533 pts in the TAS-102 group, 50 (9.4%) received G-CSF vs 0/265 in the pbo group•
more TAS-102 pts also received antianemia products such as epoetin (25 [4.7%] TAS-102 vs 2 [0.3%] pbo).•
The incidence of hematologic toxicities that resulted in dose reductions/delays was 43.0% vs 1.1% for all grades and 29.6% vs 0.8% for Grade ≥ 3, TAS-102 vs pbo, respectively.•
The incidence of febrile neutropenia and hospitalization due to febrile neutropenia was 2.4%.Conclusions: The incidence of hematologic toxicity and consequent use of supportive therapies and use of dose reductions/delays were higher in the TAS-102 group vs pbo group. Low incidence of febrile neutropenia may be related to use of G-CSF, but further analyses to ascertain the role of G-CSF are ongoing. No specific proposal for hematologic toxicity management beyond standard supportive therapies is recommended as institutional or national guidelines are well established.
Meyer et al. E15021 ASCO 2016
NEUTROPENIA FEBBRILE Profilassi primaria
E’ indicata già dal primo ciclo di chemioterapia per prevenire le complicanze della neutropenia
e per mantenere la dose intensity nei trattamenti curativi
NEUTROPENIA FEBBRILE Profilassi secondaria
• E' raccomandata per i pazienti che abbiano avuto un pregresso episodio di NF e per i pazienti per i quali il mantenimento di una corretta intensità di dose (dose dei farmaci e intervallo dei cicli) può influenzare la sopravvivenza libera da malattia o globale (Livello di evidenza 4). In caso contrario, la prima opzione terapeutica è rappresentata da una
riduzione della dose o da un posticipo temporale
NEUTROPENIA FEBBRILE
Utilizzo terapeutico del G-CSF
Yoshino T et al. Clinical colorectal Cancer 2016
Yoshino T et al. Clinical colorectal Cancer 2016
• This was a postmarketing surveillance study; ADR collection was dependent upon spontaneous reporting.
• The number of TAS-102 prescriptions and patients treated with TAS-102 during the study period are only estimated on the basis of a preregistration system, in which registration forms were faxed to the Patient Registration Center from the institute before drug administration
• Because the preregistration by fax was not
mandatory, the precise number of patients could not be determined.
• 370 total ADRs were reported
Yoshino T et al. Clinical colorectal Cancer 2016 Serious neutropenia and FN tended to occur from days 15 to 21 in the first treatment cycle in 12 (75.0%) of 16 patients.
14/16 patients were confirmed to have recovered or were recovering; among them, 64.2% (9 patients) recovered or were recovering around day 6 after onset (median, 7 days; range, 5-20 days).
A detailed investigation report was available in 11 patients: granulocyte-colony stimulating factor (G-CSF) was given to 8 patients (72.7%) and prophylactic and/or therapeutic antibiotics to 10 patients (90.9%).
Death due to infection induced by serious neutropenia was observed in 2 patients—1 experienced FN on day 15 and the other experienced it on day 18.
In 36/52 patients, nonserious neutropenia tended to occur from days 22 to 28 in the first treatment cycle; All patients had recovered or were
recovering with appropriate therapeutic measures. In 23 of the 52 patients (44.2%), neutropenia had resolved or was resolving at around day 7 after the onset (median, 10 days; range, 2-89 days).
Yoshino T et al. Clinical colorectal Cancer 2016 Three ADRs of cardiac disorders were observed in 2 patients
• 1 patient with concurrent cardiac ischemia developed decreased left ventricular function
• 1 patient with a history of myocardial infarction and complications of hypertension, hyperlipidemia and diabetes mellitus, experienced congestive heart failure and atrial fibrillation after receiving TAS- 102
Yoshino T et al. Clinical colorectal Cancer 2016 Interstitial lung disease was observed in 7 patients, including 3 patients with a history of ILD related to previous treatment. All patients were confirmed to have recovered or recovering.
•
Median time to onset was 51 days (range, 22-91 days)•
Median time to recovery was 10 days (range, 7-39 days)Yoshino T et al. Clinical colorectal Cancer 2016
Petrelli et al. BMC Cancer 2016
Petrelli et al. BMC Cancer 2016
• In phase I studies, no cardiotoxic events were reported, including 3 single agent TAS 102 trials and a phase I study of a combination of TAS 102 with a fixed dose of irinotecan (121 patients overall).
• In the phase II trials comparing TAS 102 (at the labeled dose) with
placebo, 112 patients were randomized but no cardiotoxic events were reported.
• In the phase III study by Mayer et al. n = 3 and n = 2 cardiac events
(cardiac ischemia) were recorded in the experimental and control arms respectively, with no rate of cardiac arrhythmia observed. The rate of cardiotoxicity is 0.5 %
• That represents from 2 to 40-fold numerically less frequent of that reported with 5FU in literature.
A potential limitation of our observation is that the patients who had
cardiotoxicity during previous treatments might have been excluded from TAS102 trials, which enrolled patients heavely pretreated with many previous lines of therapies.
Petrelli et al. BMC Cancer 2016
• The exact pathophysiology of these events is not well known, but a cardiac vasospasm seems the main events associated with cardiotoxicity.
• The role of the 5FU metabolites: in particular 5FU is catabolized to alpha-fluoro- beta-alanine (FBAL) and subsequently to fluoroacetate, the latter suspect in particular as a cardiotoxic substance.
• Recently, Italian authors analyzed human cardiomyocytes and endothelial cells to evaluate the effect of 5FU. They observed autophagic features with reactive oxygen species (ROS) elevation as an endothelial response and induction of a senescent phenotype on both cell types treated with 5FU . By these data and owing to the relative mis- understanding of exact mechanisms involved in the cardiotoxicity of 5FU, there is a rationale for using different inhibitors of thymidylate synthase (TS), commonly prescribed in clinical practice, in particular, raltitrexed. Animal studies of myocardium damage after 5FU administration showed that multifocal hemorrhages, myofiber necrosis, inflammatory reactions including perivascular involvement, pericarditis, valvulitis and vascular changes, were observed.
Petrelli et al. BMC Cancer 2016
Possible mechanisms of reduced cardio-toxic events in patients treated with TAS 102 :
1. Differential activation of cell death and autophagy. Autophagic features at the ultrastructural and molecular levels, in particular in 5-FU exposed cardiomyocytes and endothelial cells can be observed. Conversely, TFT is more potent than 5FU, because it induces higher levels of cell death and does not elicit an autophagic survival response in the cancer cell lines.
2. Different oncological target (DNA damage and synthesis) for TAS 102 itself compared to 5FU or capecitabine: TF-TMP (tri-fluorothymidine monophosphate) and TF-TTP (tri-fluorothymidine triphosphate) vs FdUMP (fluorodeoxyuridine monophosphate) and FdUTP (fluorodeoxyuridine triphosphate).
3. Different incorporation in tissues. The incorporation of FTD into DNA in tumor tissues is significantly higher than its incorporation into DNA in normal tissues, thus sparing cardiovascular tissues.
4. Different metabolism. TAS 102 is not catabolized by dihydropyridine dehydrogenase (DPD), that is predominantly expressed in the liver and inactivates more than 80 % of administered 5FU, with consequently reduced formation of cardiotoxyc metabolits eg. FBAL and F-citrate. F-citrate inhibits the Krebs cycle by inhibition of aconitase, limiting the cellular production of adenosine triphosphate (ATP). Fluoroacetate is known to be highly cardiotoxic and neurotoxic.
Petrelli et al. BMC Cancer 2016
•
Drug pharmacokinetics was evaluated using a randomized, single-dose, two-treatment (fed versus fasting), two- period, two- sequence cross-over design, followed by repeated administration.•
16 patients were given single doses of TAS-102 (35 mg ⁄ m2) in the pharmacokinetic phase and received twice-daily doses of TAS-102 in 28-day cycles in the repeated administration phase for evaluating efficacy and safety.Yoshino T et al. Cancer Science 2016
•
As TAS-102 is given orally, assessment of the effect of food on the pharmacokinetics of its constituents is required.•
The primary objective of this study was to assess the effect of food on the pharmacokinetics of FTD and TPI after a single oral administration of TAS-102.•
The secondary objective was to investigate the efficacy and safety of repeated TAS-102 administration.•
A high-fat, high-calorie meal was used to evaluate the maximal effect of food intake on pharmacokinetics.Yoshino T et al. Clinical colorectal Cancer 2016
•
Food showed no effect on the area under the curve from 0 to 12 h or 0 h–infinity values of trifluridine following administration of TAS-102 under fasting and fed conditions, whereas those of tipiracil hydrochloride decreased by approximately 40%.•
Maximum concentrations of both drugs decreased by approximately 40%, indicating that food influenced the absorption and bioavailability of trifluridine and tipiracil hydrochloride, respectively.•
During the repeated administration, stable disease was observed in nine patients with rectal, small-cell lung, breast, thymic, duodenal and prostate cancers.•
Major adverse events were neutropenia, leukopenia, anemia, and nausea. G4 neutropenia were resolved by prolongation of the washout period (n = 5 ⁄ 5 patients), and reduction of TAS-102 dose (n = 4 ⁄ 5 patients) or administration of GCSF or both (n = 3 ⁄ 5 patients). No febrile neutropenia was observed in any patient in the study.(no. JapicCTI-111482).
