Download Chemotherapy Dosing in Special Populations Sabine Kaestner MSci Pharm, PhD

Chemotherapy Dosing in
Special Populations
Sabine Kaestner
MSci Pharm, PhD
Plymouth Hospitals Trust
Plymouth, UK
[email protected]
1
Disclosure
„
Sabine Kaestner, MSci Pharm, PhD has
no real or apparent conflicts of interest to
report
2
Learning Objectives
„
„
Indicate which patient-related factors may affect the
pharmacokinetics (PK) and pharmacodynamics (PD)
of cancer chemotherapy drugs in special populations
„
„
Assess and discuss the potential clinical impact of
different approaches to chemotherapy dose
modifications in special populations
„
„
Identify sources for inaccuracies and errors in
chemotherapy dosage calculations/modifications
3
Lecture Outline
„
Dosing of chemotherapy drugs:
Background
„
Chemotherapy dosing in
• Amputees
•
•
•
Obese patients
Elderly
Pregnant patients
4
Dosing of Chemotherapy Drugs:
Background
5
Cancer Chemotherapy
„
Characteristics
• Narrow therapeutic window
• Intrapatient variability
Therapeutic & toxic effects
• Interpatient variability
Patient-specific doses …
6
Cancer Chemotherapy
… but treatment effects difficult to measure
„
„
Disease progression
„
„
Drugs in combinations
„
„
What should be measured?
– Tumour regression
– Disease-free or overall survival
– Surrogate markers (PK)
„
„
Follow-up?
7
Chemotherapy Dose
„
„
Traditionally based on body surface area (BSA)
•
•
•
Used for interspecies scaling
Often poorly correlated with drug clearance
Generally fails to reduce PK variability, some
exceptions
• Does not account for several factors affecting drug
clearance
„
„
Calvert-formula for carboplatin dose an exception
Kaestner SA, Sewell GJ. Clin Oncol (R Coll Radiol). 2007;19:23-37.
8
BSA vs Drug Clearance:
5-Fluorouracil (5-FU)
9
Chemotherapy Dose Modifications
„
Dose reductions or delays, because of
• Excessive toxicity
• Hepatic and renal impairment
• Age or obesity
• Previous chemotherapy treatment
„
Dose escalations??
• Not as common
• Potential for underdosing
Bonadonna G, et al. N Engl J Med. 1995;332:901-6.
10
Chemotherapy Dosing
in Amputees
11
Chemotherapy Dose
„
Various approaches
• Standard BSA dosing
„
„
Pre-amputation height and weight?
• Dose modification based on BSA reduction
„
„
Formulae to subtract area of appropriate limb
• Dose modification based on weight reduction
O’Marcaigh AS, et al. J Pediatr Hematol Oncol. 1995;17:172-5.
Colangelo PM, et al. Am J Hosp Pharm. 1984;41:2650-5.
12
Any Evidence Supporting Dose
Modifications?
„
No evidence
„
No common guidelines regarding dose
modifications
• Need for trials and standardisation
„
Amputation clearly not the only factor
• Young, old, comorbidities, medications,
pharmacogenetics …
„
Use professional judgement?
13
PK in Amputees
„
„
Drug distribution
•
•
•
„
„
Change in body composition
↓ Size of vascular system
Cardiac output may change
Drug metabolism (and excretion) unlikely to
change
Note: renal function estimates based on serum
creatinine inaccurate in amputees
Duong CD, Loh JY. J Oncol Pharm Pract. 2006;12:223-36.
14
Chemotherapy Dosing in
Obese Patients
15
Obesity and Cancer
„
„
„
„
„
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Overweight/obesity (body mass index [BMI]
> 25 and 30 kg/m22) ⇒ ↑ cancer risk
• UK study, 1.2 million women
Lack of physical activity ⇒ ↑ breast cancer risk
Increasing BMI associated with poorer cancer
survival
• Due to delayed diagnoses or insufficient
treatment?
Reeves GK, et al. BMJ. 2007;335:1134. Epub.
Tao MH, et al. Am J Epidemiol. 2006;163:101-7.
16
Dose Modifications in Obesity
„
„
Obesity associated with large first-cycle dose
reductions
„
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Reluctance to prescribe full doses due to fear of
excessive toxicity
„
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Doses rarely escalated in subsequent cycles
⇒ Potential for underdosing (should not reduce
< 85% of standard dose intensity [DI])
„
„
No evidence
Griggs JJ, et al. Arch Intern Med. 2005;165:1267-73.
17
Dose Modifications in Obesity
„
Examples of different approaches
•
•
•
•
•
BSA doses “capped” at 2.0 - 2.2 m22
BSA based on lean body mass (LBM) or ideal
body weight (IBW)
BSA based on average between actual weight
and IBW
Cap according to BMI
Reduce dose empirically
⇒ Varies between
prescribers/institutions
Baker SD, et al. J Natl Cancer Inst. 1995;87:333-4.
Green B, Duffull SB. Br J Clin Pharmacol. 2004;58:119-33.
18
Considerations
„
„
Use of total body weight: up to 25% - 30% dose
increases
„
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BSA does not reflect body composition
„
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What contributes to the large BSA?
• Patient 1
Weight: 95 kg Height: 160 cm
⇒ BSA: 2 m22 BMI: 37 kg/m22
• Patient 2
Weight: 80 kg Height: 180 cm
⇒ BSA: 2 m22 BMI: 25 kg/m22
19
What Are the Clinical Outcomes?
„
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Full doses do not seem to increase toxicity in obese
„
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Full doses may even give reduced toxicity
compared with in non-obese
„
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Therapeutic effects
• May diminish beneficial impact of adjuvant
chemotherapy
• Use of actual body weight associated with improved
overall survival
• More studies needed
Poikonen P, et al. Acta Oncol. 2001;40:67-71.
20
Is There a Better Approach?
„
„
PK alterations in obesity
• Drug distribution
„
„
Body composition
„
„
↑ Alpha 1-acid glycoprotein
• Metabolism
„
„
Phase 1 processes
– Activity or amount of selected CYP450 enzymes
may be elevated
„
„
Phase 2 processes
– ↑ Glucuronidation and sulfation
Baker SD, et al. J Natl Cancer Inst. 1995;87:333-4; Morgan DJ, Bray KM. Clin Pharmacokinet. 1994;26:292-307;
Blouin RA, et al. Clin Pharm. 1987;6:706-14.
21
Is There a Better Approach?
„
PK alterations in obesity
• Excretion
„
„
↑ Glomerular filtration and tubular secretion
Note: Renal function estimates may be inaccurate
in obese
„
„
„
„
Serum creatinine alone not useful
Lack of PK data for cytotoxic drugs in obesity
Herrington JD, et al. Cancer Chemother Pharmacol. 2006;57:241-7.
22
PK of Selected Cytotoxic Drugs
„
Recent report for drugs with different
elimination pathways
Elimination
Pathway
Clearance in
Obese
Cisplatin
Renal tubular secretion (unbound)
↑
Paclitaxel
CYP2C8, CYP3A4
↑
Troxacitabine
Renal filtration
↑
Carboplatin
Renal filtration
↔
Docetaxel
CYP3A4
↔
Drug
Irinotecan/SN-38 hCE2/CYP3A4/UGT1A1
↔
Topotecan
Renal tubular secretion
↔
Doxorubicin
Aldoketoreductases
Sparreboom A, et al. J Clin Oncol. 2007;25:4707-13.
↔ men
↓ women
23
Conclusions
„
„
Various factors may alter drug clearance in
obesity
„
„
Large potential for underdosing with “capped”
doses and additional errors may be introduced
„
„
More studies needed, but …
• All obese are not the same
• Impact of obesity “itself” unlikely to override factors
known to influence drug disposition
„
„
e.g. pharmacogenetics (DPD and UGT1A1 enzymes)
24
Chemotherapy Dosing
in the Elderly
25
Cancer and Age
„
When are we classified as “elderly” patients?
„
Diagnosis and treatment complicated by
background pathophysiology, comorbidity, etc.
„
Ageing alters biology of cancer
• DNA damage
• Host antitumour response
„
„
60% of new cancer diagnoses in patients >65 y.
Yancik R. Cancer. 1997;80:1273-83.
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Treatment Considerations
Age
“Poor prognosis”
“Poor tolerance”
„
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Ageing and treatment response
• Cancer cells less aggressive, more resistant, less responsive
„
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PK and PD may increase susceptibility to adverse effects (AEs)
• Reduced clearance
• Vulnerability and comorbidity, e.g.
„„
„„
„„
„„
cardiovascular
cardiovascular
hepatic
hepatic
renal
renal
nervous
nervous &
& respiratory
respiratory systems
systems
27
Treatment Considerations
28
Treatment Considerations
⇒ “Is it worth it?”
„
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Benefit varies with likelihood of cancer-related death
„
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Quality of life?
„
„
Life expectancy often underestimated
(UK data):
Remaining years
Age
Male
Female
65
16.9
19.7
75
10.2
12.2
85
5.5
6.5
The Office for National Statistics. Available at: www.statistics.gov.uk/StatBase/Product.asp?vlnk=14459.
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Chemotherapy Dosage
„
„
Underrepresentation in clinical trials
Lack of evidence
„
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Age >65 years frequently associated with no
chemotherapy or reduced doses
„
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Chronological age alone does not
• Contraindicate chemotherapy
• Justify empiric dose reductions
„
„
Elderly a more heterogeneous
population than young
Griggs JJ, et al. Arch Intern Med. 2005;165:1267-73.
30
A Multidisciplinary Assessment
Concomitant medications and interactions
Compliance
Functional status
Social support
Histological diagnosis
Life expectancy
Clinical stage
Comorbidity
Nutritional status
Physiological functions
Performance status
Psychological status
Alternatives to
chemotherapy
Likely response to treatment
Aim of chemotherapy
Basic screening tools have been evaluated
Aapro MS. J Clin Oncol. 2005;23:2121-2; COIN Guidelines. Clin Oncol (R Coll Radiol). 2001;13:S211.
31
PK in Elderly: General Changes
„
Bioavailability and distribution
• ↓ Gastrointestinal absorption and motility
• ↓ Lean body mass
• ↑ Adipose tissue
• ↓ Albumin (15%–20%)
• Haemoglobin?
Hurria A, Lichtman SM. Cancer Control. 2007;14:32-43; Wildiers H, et al. Clin Pharmacokinet. 2003;42:1213-42.
32
PK in Elderly: General Changes
„
Metabolism and excretion
• ↓ Hepatic volume and perfusion
• Phase 1 reactions modified
„
„
↓ Some CYP450 activity
• ↔ Phase 2 reactions
• ↓ Renal filtration
(1 mL/min/year >40 y in the majority)
Note: Serum creatinine for estimating renal function
inaccurate in elderly
Aapro MS. J Clin Oncol. 2005;23:2121-2; Hurria A, Lichtman SM. Cancer Control. 2007;14:32-43;
Wildiers H, et al. Clin Pharmacokinet. 2003;42:1213-42; Lichtman SM, Villani G. Cancer Control. 2000;7:548-56;
Marx GM, et al. Ann Oncol. 2004;15:291-5.
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Chemotherapy PK/PD in Elderly
„
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PK and PD data exist for selected drugs
„
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Most studies find no significant difference in PK
„
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PD may differ independently of PK
„
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Few drug doses may have to be adjusted purely
based on age
„
„
Observations not always consistent
• Study inclusion criteria?
⇒ Some examples
34
Chemotherapy PK/PD in Elderly
Drug
Dose
Modification
Age-Related
PK?
CL ↓/↔
F?
Comments
Myelosuppression ↑, non-PK related
Etoposide
Age
Renal imp.
Gemcitabine
Hepatic imp.
Renal imp.
Methotrexate
Age?
Renal imp.
CL ↓
Toxicity may be increased. Folinic acid rescue
important.
5-FU
Renal imp.
CL ↔
Stomatitis risk ↑
Capecitabine
Renal imp.
CL ↔
F↔
Topotecan
Renal imp.
Irinotecan
Plasma
proteins?
Vinorelbine
Severe hepatic
imp.
CL ↓/↔
−
CL ↔
Temozolomide
Minimal toxicity in elderly
CL ↔
Diarrhoea risk ↑
Favourable toxicity profile
Myelosuppression ↑, non-PK related
Imp. = impairment, CL = clearance, F = bioavailability, 5-FU = 5-fluorouracil
Hurria A, Lichtman SM. Cancer Control. 2007;14:32-43; Wildiers H, et al. Clin Pharmacokinet. 2003;42:1213-42;
35
Lichtman SM, Villani G. Cancer Control. 2000;7:548-56.
Chemotherapy PK/PD in Elderly
Drug
Dose
Modification
Age-Related
PK?
CL ↓/↔
Comments
Cardiotoxicity ↑. Often avoided, great care
needed (esp. with trastuzumab).
Add dexrazoxane. Liposomal formulations
may be beneficial.
Doxorubicin
Hepatic imp.
Idarubicin
Renal imp.
Epirubicin
Hepatic imp.
Mitoxantrone
Hepatic imp.
CL ↔
Paclitaxel
Docetaxel
Hepatic imp.
CL ↓/↔
Cisplatin
Age?
Renal imp.
Plasma proteins
CL ↓
Enhanced toxicity. Age an independent
factor for CL ↓
Carboplatin
Renal imp.
CL ↔
Care when using serum creatinine-based
formulae
Oxaliplatin
Renal imp.
Erythrocytes?
CL ↔
Lack of nephrotoxicity, lower haematotoxicity
than cis/carbo
CL ↔
Myelosuppression ↑, mesna
Cyclophosphamide
-
CL ↔
Well tolerated
Well tolerated, esp. weekly
Favourable toxicity profile
Care if concurrent treatment with other
neurotoxic drugs
Hurria A, Lichtman SM. Cancer Control. 2007;14:32-43; Wildiers H, et al. Clin Pharmacokinet. 2003;42:1213-42;
36
Lichtman SM, Villani G. Cancer Control. 2000;7:548-56.
Supportive Therapy
„
„
Crucial for treatment completion
„
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Hydration status important
• Poor hydration may lead to reduced clearance
„
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Prophylactic haematopoietic growth factors (GFs)
often recommended
• Do not have to compromise DI
• Cost-effective
• Results in non-haematologic dose-limiting toxicity,
e.g. gastrointestinal, neuropathy, and mucositis
Repetto L, et al. Eur J Cancer. 2003;39:2264-72.
Wildiers H, et al. Clin Pharmacokinet. 2003;42:1213-42.
37
Conclusions
„
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„
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„
„
„
„
„
„
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„
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Poor prognostic outcomes not universal
Age not contraindication for treatment
Response poor in frail but other elderly should be
treated as younger patients
Dose reduction = simplistic approach
Dose optimisation through full geriatric
assessment
May start with lower dose but should
escalate if well tolerated
Treat complications early
Balducci L. Cancer Control. 2001;8:1-25.
38
Chemotherapy Dosing in
Pregnant Patients
39
Cancer During Pregnancy
„
„
Estimated to complicate 0.02 to 0.1%
of pregnancies
∼10% of those <40 y diagnosed with
breast cancer are pregnant
„
Increasing incidence expected as women
delay childbearing
„
Common cancers: cervical, breast,
lymphoma, and malignant melanoma
Cancer in pregnancy. Available at: www.motherisk.org; Woo JC, et al. Arch Surg. 2003;138:91-9.
40
Treatment Goals
„
„
Limited knowledge about effect of cancer on
pregnancy and vice versa
„
„
Goals
• Save the mother’s life
• Treat curable malignant disease
• Protect the foetus and newborn from harmful
treatment effects
• Retain the mother’s reproductive system intact
for future pregnancies
41
Options
„
„
Termination of pregnancy
• Treatment formerly considered indication
for abortion
• Not effective intervention (no survival benefit)
„
„
Some exceptions
„
„
Continuation of pregnancy with modified
treatment regimens
„
„
Postpone treatment until after delivery
• Close monitoring of tumour growth
Berry DL, et al. J Clin Oncol. 1999;17:855-61.
42
Risks
„
„
Continuation of pregnancy with treatment
• Which modifications?
• Risks to the foetus
• Increased risk of miscarriage, prematurity, stillbirth
„
„
Continuation of pregnancy without treatment
• Therapeutic delay
„
„
May not be disadvantage in ER+ breast cancer
• Metastasis risk in both mother and foetus
Pereg D, et al. Haematologica. 2007;92:1230-7.
43
Treatment Options
„
Surgery
„
Chemotherapy
• Modified schedule
• Supportive care, e.g.
„
„
„
Antiemetics
„
„
Lack of data using GFs
Radiotherapy contraindicated
44
Potential Adverse Effects
„
„
“Life-saving vs life-threatening”
„
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Potential direct effects on foetus
•
•
•
•
Malformations
Neurologic development
Intrauterine death
miscarriage/stillbirth
Intrauterine growth retardation and/or prematurity
Effects on physical (e.g. heart, kidney) and mental
development
Epstein RJ. BMC Cancer. 2007;7:92. Epub; Cancer in pregnancy. Available at: www.motherisk.org
45
Potential Adverse Effects
„
„
Potential effects on newborn/long-term
• “Normal” chemotherapy AEs
„
„
Haematologic toxicity
– infectious complications
– haemorrhage
•
•
•
„
„
Alopecia
„
„
Ototoxicity
„
„
Cardiotoxicity
Respiratory complications
Secondary malignancies
Infertility
Cardonick E, et al. Lancet Oncol. 2004;5:283-91; Cancer in pregnancy. Available at: www.motherisk.org
46
Chemotherapy Modifications
„
Timing of treatment
„
Choice of drugs
„
Dosage
„
Scheduling
47
Timing of Treatment
„
„
No chemotherapy during first trimester
• Teratogenic during organogenesis ∼ 8 weeks
• Malformation risk 10% with single agent,
25% with combinations
• Eyes, genitals and CNS remain vulnerable
„
„
Second and third trimesters
• Reduced hazard to foetus
• “Planned” timing of delivery
„
„
„
„
account for expected bone marrow depression
Contraindicated during breast-feeding
Cardonick E, et al. Lancet Oncol. 2004;5:283-91; Cancer in pregnancy. Available at: www.motherisk.org
48
Choice of Drugs
„
„
Characteristics affecting placental transfer
• Lipophilicity, molecular weight, protein binding
• P-glycoprotein and CYPs?
„
„
Long t½½ of drug/metabolites a disadvantage
„
„
Cytotoxic drugs from all classes have
• Been used successfully in adjuvant chemotherapy
„
„
Follow-up?
• Induced all types of toxicity
Cardonick E, et al. Lancet Oncol. 2004;5:283-91; Cancer in pregnancy. Available at: www.motherisk.org
49
Choice of Drugs
„
„
Standard or modified regimens, may exclude certain
drugs
Examples
•
•
•
•
Some antimetabolites considered especially toxic
Trastuzumab avoided (anhydramnios common AE)
Doxorubicin or epirubicin preferable to idarubicin
CAF; cyclophosphamide 500 mg/m22, doxorubicin 50
mg/m22, 5-FU 1,000 mg/m22 used successfully in breast
cancer
• FOLFOX6 in rectal cancer: oxaliplatin 85 mg/m22, fol. acid
400 mg/m22, 5-FU 400 mg/m22 + 2,400 mg/m22 46 h infusion
Berry DL, et al. J Clin Oncol.1999;17:855-61. Epstein RJ. BMC Cancer. 2007;7:92 epub.
Gensheimer M, et al. Cancer Chemother Pharmacol. 2008; Mar 21. [Epub ahead of print].
50
Dosage and Scheduling
„
„
Lack of data
„
„
May try weekly schedules
„
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Standard doses, but … inadequate or excessive?
• Adjust for continuous change in body weight?
„
„
Anecdotal evidence of increased toxicity
postpartum
„
„
Reduced dose
„
„
What about PK?
Cardonick E, et al. Lancet Oncol. 2004;5:283-91.
suboptimal effect? Resistance?
51
PK and PD in Pregnancy
„
Clinical and PK studies difficult
„
Changes during pregnancy
• Hormonal
• Bioavailability and distribution
• Metabolism and excretion
52
Bioavailability and Distribution
„
„
↓ Gastric emptying/motility
„
„
↑ Body water and adipose tissue
„
„
↑ Cardiac output
„
„
↓ Albumin concentration (haemodilution)
„
„
An additional compartment: amniotic fluid
Anger GJ, Piquette-Miller M. Clin Pharmacol Ther. 2008;83:184-7.
FDA: PK in pregnancy. Available at: http://www.fda.gov/cder/guidance/5917dft.htm.
53
Metabolism and Excretion
„
„
Phase 1 processes
• ↑ CYP3A4 activity and amount
• ↑ CYP2D6 activity
• ↓ CYP1A2 activity
„
„
Phase 2 processes
• Conjugating enzyme activity altered
• e.g. ↑ glucuronidation
„
„
↑ Hepatic blood flow
„
„
↑ Renal blood flow (50%−80%)
Anger GJ, Piquette-Miller M. Clin Pharmacol Ther. 2008;83:184-7.
FDA: PK in pregnancy. Available at: http://www.fda.gov/cder/guidance/5917dft.htm.
54
Conclusions
„
„
Termination of pregnancy does not (in general)
improve maternal prognosis
However,
„
„
Still lack of information on optimal dosing
strategies and benefits/risks with chemotherapy
„
„
Impossible to predict risks to mother and
foetus/child
„
„
Each new case must be treated individually
55
Overall Conclusions
„
„
Various factors may influence chemotherapy PK and PD in
the special populations discussed
„
„
Put potential effects of these factors into context of
• Pre-existing
Pre-existing intraintra- and
and interpatient
interpatient variabilities
variabilities (enzyme
(enzyme activity,
activity,
pharmacogenetics,
pharmacogenetics, etc.)
etc.)
• Tumour
Tumour PK/biology
PK/biology and
and drug
drug resistance
resistance
• Concomitant
Concomitant medications
medications and
and illnesses
illnesses
„
„
Customary dosing approaches may result in suboptimal
treatment outcomes
„
„
Modern strategies desirable, e.g.
• Combinations
Combinations of
of population
population data
data and
and patient-specific
patient-specific data
data in
in
Bayesian
Bayesian approaches
approaches
• TDM?
TDM?
56