Good afternoon

MODERATOR
Dr KIRAN HY
READER

PRESENTER
DR. JOMI PORINCHU
PG STUDENT

The purpose of adjuvant chemotherapy is to treat latent tumor

cells that cannot be seen macroscopically after completion of
first-line therapy.
Yasunao Kogashiwa, Naoyuki Kohno
 Contents
Introduction Classification

Historic milestones Individual drugs

Prognostic factors in planning Chemotherapy approaches

Chemoprevention
Chemotherapy
Complications

Conclusion
 Introduction
The pre and post 1991 era!!!! German chemist Paul Ehrlich

A Landmark study Cooperative

Studies Program of the Department of
Veteran Affairs Laryngeal Cancer Study
Group demonstrated larynx preservation
and equivalent survival between
chemotherapy vs. surgery + post-surgery
radiation.
N ENG J Med 1991; 324: 1685-1690
Early 20th century

Mustard gas was used in chemical warfare

Very low white blood cell counts

1940s, several patients with advanced

lymphomas

Their improvement, although temporary, was

remarkable
 1940 beginning of anti-neoplastic chemotherapy

1950-1959 - search of new agents

Better alkylating agents

Heidelberger- 5-FU

1960-1969 - Wide spread interest

Combination therapy evolved (1965)

New clinical trials

Cure of childhood leukemia

1970-1979 - decade of cure

Multi drug therapies in solid tumors
INDICATIONS
 Principles of
Chemotherapy
Chemotherapy for H&N cancer differs in 2 fundamental
respects from regional T/t

Chemotherapy reaches tumors cells throughout the body

Administered in widely varying treatment schedules ranging from

a brief single treatment course to extended treatment programs

Goal : to eliminate as many cancer cells as possible by selectively

killing them with drugs while sparing normal tissues

 Principles Of
Chemotherapy
(cell kill hypothesis)
1. A single cancer cell can multiply and eventually kill the
host

2. Survival and ability to respond to chemotherapy are

inversely related to the numbers of viable tumor cells

3. Generally a direct relationship exists between the dose

of a drug and its ability to kill tumor cells

4. A given dose of drug will kill a constant fraction of

tumor cells regardless of the number present prior to
therapy.
 Gompertzian growth model..
Initial tumour growth- 1st order, with later
growth being much slower.
Cell cycle
Basic Concepts of
Chemotherapy
Prognostic factors in planning
chemotherapy
 i on
i f c at
a s s
Cl
 Classification
A. Drugs acting directly on cells (cytotoxic
drugs)
- Alkylating agents
- Anti-metabolites
- Vinca alkaloids
- Taxanes
- Epipodophyllotoxin
- Camptothecin analogues
- Antibiotics
- Miscellaneous
 CYTOTOXIC DRUGS
1. Alkylating agents-

Nitrogen mustards : Cyclophosphamide

Ifosfamide,
Chlorambucil,
Melphalan
Mechlorethamine
Ethylenimine : Thiotepa, hexamethylmelamine
Alkyl sulfonate : Busulfan
Nitrosoureas : Lomustine, streptozocin,
Carmustine
Triazine : Dacarbazine, temozolomide
 CYTOTOXIC DRUGS
2. Antimetabolites
Folic acid analogs : Methotrexate- (Mtx)
Purine analogs : 6- Mercaptopurine (6-MP),

6-Thioguanine (6-TG),
Azathioprine, pentostatin
cladribine
Pyrimidine analogs : 5-Fluorouracil (5-FU)
Floxuridine
Cytarabine(cytosine arabinoside)
gemcitabine
 CYTOTOXIC DRUGS
3. Natural products :
Vinca alkaloids : Vincristine (Oncovin),
Vinblastine

Taxanes : Paclitaxel, Docetaxel

Epipodophyllotoxin : Etoposide, teniposide

Camptothecin analogues :Topotecan, Irinotecan

 CYTOTOXIC DRUGS
Antibiotics :
Actinomycin (Dactinomycin)
Doxorubicin
Daunorubicin (Rubidomycin)
Mitoxantrone
Bleomycins ,
Mitomycin C
Mithramycin (Plicamycin)

Enzymes : L-Asparaginase

Biological response modifiers: interferon- alfa, interleukin 2

 CYTOTOXIC DRUGS

4. Miscellaneous agents
Substituted urea - Hydroxyurea

methylhydrazine derivative - Procarbazine

Platinum coordination complexes - Cisplatin ,

Carboplatin

Adrenocortical suppressant -
Mitotane,aminoglutethimide

Tyrosine kinase inhibitor - imatinib

 CLASSIFICATION
B. Drugs altering hormonal milieu
Adrenocortico-steroids Prednisone

Estrogens diethylstilbestrol, ethinyl estradiol

Anti estrogen Tamoxifen

Antiandrogen Flutamide

5- reductase inhibitor Finasteride

GnRH analogues Leuprolide,

Progestins Hydroxyprogesterone

Androgens Testosterone propionate

 Chemotherapeutic agents with
activity in head and neck
cancers
Agent Mechanism Toxicity
Alkylators
Cyclophosphamide DNA cross-linker nausea, cystitis,

Ifosfamide Myelosuppression,
cystitis, confusion,
alopecia
Antimetabolities
Methotrexate Binds dihydrofolate Mucositis,
reductase Myelosuppression
5-Fluorouracil Inhibits thymidylate Mucositis,
synthetase myelosuppression,dia
rrhea
Antibiotics
Bleomycin Scission of DNA Pulmonary fibrosis,
rash, Mucositis
Adriamycin DNA intercalator Cardiotoxicity,
mucositis,
 Chemotherapeutic agents with
activity in head and neck
cancers
Agent Mechanism Toxicity
Vinca Alkaloids
Vincristine Mitotic arrest Neurotoxicity,
myelosuppression alopecia
Vinblastine

Miscellaneous
Cisplatin DNA Nephrotoxicity, vomiting,
Carboplatin intercalator otoxicity, neuropathy
Myelosuppression
Taxanes
Paclitaxel Microtubule Myelosuppression, neuropathy
docetaxel stabilizer Edema, neutropenia,,
neuropathy

METHOTREXATE
One of the oldest and highly efficacious

antineoplastic drugs.

Most widely used drug in palliative therapy in

recurrent and metastatic HNSCC

Folic acid analog that is S-phase specific

Least toxic

Cytotoxic effects - can be by administration

of reduced folates which can be converted to

tetrahydrofolate
Mechanism of action
 Uses
Highly effective in maintaining remission in children with
acute lymphoblastic leukemia.
Useful in SCCHN and other malignancies, rheumatoid
arthritis, psoriasis and as immunosuppressant.
Response rates -vary between 8% and 50%, averaging 30%.
 Dosage
IM or SC, IV or oral routes.

Weekly or biweekly preferred schedule.

40 to 60 mg/m2 weekly in 2 divided doses

moderate-dose range (250 to 500 mg/m2

IV).
high-dose range (5 to 10 gm/m2) - followed
by leucovorin rescue.
J Clin Oncol 2007; 25: 1378-1384
Levitt et al

J Clin Oncol 2007; 25: 1378-1384

 Folate Trap

Methionine
synthase

DHF
Toxicity
 CISPLATIN
Most active agent in HNSCC

inorganic metal coordination complex

major anti-tumor activity Response

rates ranging from 20-50%

Inhibits DNA synthesis by binding to DNA to cause

inter-strand and intra-strand cross-linking.
Mechanism of action
PHARMACOKINETIC DATA

Bioavailability - complete
Protein binding - > 95%
Half-life - 30-100 hours
Excretion - Renal
 Dosage
IV route
requires hydration and diuresis - prevent renal tubular
damage.
80 to 120 mg/sq.m every 3 or 4 weeks by IV infusion with
mannitol diuresis or by 24-hour infusion.
Continuous infusion increases exposure (compare to bolus
dose)
 Dose response
same response rate as methotrexate- approximately
30%,
duration of response -4 months.

comparison of 60 mg/m2 and 120 mg/m2 Veronesi et

al(1986)
no difference in response rates.

Forastiere et al - pilot trial evaluating 200 mg/m2

73% response rate or double that expected with

conventional dosing.
 TOXICITY OF CISPLATIN
Renal dysfunction

Nausea and vomiting

Hematologic toxicity, -neutropenia and

thrombocytopenia

Anemia - result of Bone Marrow suppression

Electrolyte imbalance - because of renal wasting.

Peripheral neuropathypredominantly sensory

Ototoxicity - 4000 to 8000 Hz range.

Goodman and Gilmans Pharmacological basis of therapeutics 10 th edition 2001
 CARBOPLATIN
MOA similar to cisplatin

Renal toxicity, ototoxicity & neurotoxicity

are rare & less emetogenic potential
Dose-limiting toxicity is myelosuppression

Can be administered in outpatient-

without need for hydration
Not as active as cisplatin- 14-30% RR
Reserved for pts with renal impairment or
preexisting peripheral neuropathy.
 TAXANES
Act by stabilizing microtubules by binding to B-subunit
of tubulin, thereby inhibiting microtubule de-
polymerization, which results in a cell cycle arrest at
G2/M phase

Response rates of approximately 30% to 40%

Paclitaxel- 135- 250 mg/m2 given over 3- 24 hrs

Docetaxel- 75mg/m2 over 1 hour every 3 wks

 Toxicity..
PACLITAXEL DOCETAXEL
Myelosuppression Myelosuppressio
Hypersensitivity n
Peripheral neuropathy Neutropenia
Myalgia/arthralgia Capillary leak
syndrome

Potent radiosensitizers because G2/M is

the cellular phase at which cells exhibit
greatest radiosensitivity- Chemoradiation
regimen
 BLEOMYCIN
Anti-neoplastic antibiotic- binds between opposing
strands of DNA generating oxygen free-radicals &
produces DNA strand breaks.

Conventional dose- 10 to 20 units/m2 twice weekly im or

iv

Advantage- is not associated with myelosuppression

RR 15-20% avg. 21%

 Toxic effects
Fever or chills
Anaphylactic reaction
Alopecia
Skin toxicity- erythema, thickening & hyper pigmentation
Stomatitis
Pulmonary toxicity
Pneumonitis
Dry cough
Pulmonary fibrosis
Hypoxia
 TOPICAL BLEOMYCIN

Double-blind RCT 22 patients oral

leukoplakia/erythroplakia - topical
bleomycin vs placebo
Bleomycin 1% in dimethylsulphoxide
(DMSO) - 5 minutes for 14 consecutive
days.
Results : pts Bleomycin -
decrease - clinical size of the lesion
and histological reduction in dysplasia was
seen
 5-FLUOROURACIL
Fluorouracil (5-FU or f5U) is a drug that is a pyrimidine analog
Antimetabolite- exerts its cytotoxic effects in several different ways
Single agent RR 15%
PHARMACOKINETIC DATA
Bioavailability- 28 to 100%
Protein binding -8 to 12%
Metabolism- Intracellular and hepatic
Half-life- 10 to 20 minutes
Excretion- Renal
 Toxic reactions
Diarrhea

Stomatitis

Myelosuppression

Nausea, vomiting

Alopecia

Hyper-pigmentation

Maculo-papular rashes
 As combination

therapy
Kish et al showed synergy with cisplatin-
RR-70%- assumed increasing importance in
the management of HNSCC

As potent radiation sensitizer concurrent

radiotherapy advanced SCCHN, rectum,
esophagus, lung
Topical premalignant keratosis of skin
 CYCLOPHOSPHAMIDE
Inhibit cell cycle at any stage( Not
phase specific)
Activated in the liver by
microsomal enzymes
MOA : Cross-links DNA strands,
preventing further division
Orally or iv
Iv- as a single dose of 500 to 1500
mg repeated every 3 or 4 weeks
RR- 25-30%
Hydrate pts well before & after

Prominent immunosuppressant
property
 Side effects
Bone marrow Cessation of menses
suppression
Permanent infertility
Nausea & vomiting
Acute hemorrhagic
Alopecia
cystitis
Ridging of nails
Haematuria
Azoospermia
Fibrotic bladder

Bladder carcinoma
 Uses
As a single agent lymphoma Burkitts lymphoma, chronic
leukemias

As combination breast cancer and lymphomas Non

Hodgkins Lymphoma, carcinoma of lung, breast, cervix, head
and neck, ovary, neuroblastoma, retinoblastoma

As immunosuppressant prevent organ rejection

transplantation
 VINCA ALKALOIDS
Disrupts microtubular spindle
formation- mitotic arrest in metaphase
Vinblastine- 0.1- 0.15 mg/kg iv weekly
3 does
Toxic reactions
Myelosuppression
Alopecia
Myalgias
Vincristine - 1.0 to 1.5 mg/m once or
twice monthly
Toxic reactions
Peripheral neuropathy
Constipation
Alopecia
No myelosuppressive effects
 Chemotherapy Approaches

Palliative chemotherapy

Induction chemotherapy

Concomitant chemoradiotherapy

Adjuvant chemotherapy

Combination therapy

Chemoprevention

Intralesional chemotherapy

Topical chemotherapy
 PALLIATIVE
CHEMOTHERAPY
Used in management of H&N cancers that are
recurrent, metastatic, unresectable & considered
incurable
Goal- QOL- pain, preserving or improving
organ function & preventing obstruction of airway
or esophagus
In some instances survival may be prolonged,
survival is not the 1 goal of palliative therapy
median survival rate is 4 months
 Single agent- Methotrexate therapy (standard for head and neck)

- well tolerated, convenient, and inexpensive.

Multi-agent chemotherapy- CISPLATIN & FU has demonstrated

response rates (30% to 50%) & may slightly prolong survival-
toxic, convenient & expensive (Regime of choice pt. good
performance status )

New therapeutic regimens- taxanes, vinca alkaloids in single & multi-

agent trials
COMBINATION THERAPY
Designing Drug Cominations
COMBINATION THERAPY
In 1982, investigators at Wayne State University-
first to report on results of a 2 drug combination
of CDDP with 5-FU- overall response of 89%

Jacobs et al response rates were higher for

cisplatin in combination with 5-FU compared with
either single agent(32% vs. 17% and 13%)

Forastiere et al single agent MTX with CDDP/5-

FU or CARBO/ 5-FU superior response rates of
combination was clear but with increased toxicity
 Novel combinations
Colevas et.al

Shin et al

Gaspar et al

Since currently used standard chemotherapy

options in HNSCC are all palliative, both single
agent and combination of drugs may be
appropriate, the choice of treatment should depend
on a balance between efficacy and toxicity.
 INDUCTION
CHEMOTHERAPY
Advantages
drug conc. in tumor because of intact vascular supply

in tumor size- extent of surgery or make a non-

resectable tumor resectable organ preservation

Eradication of micro-metastatic disease

Can be given in higher doses & is better tolerated prior

to definitive loco-regional therapy .

Chemosensitive tumors- better prognosis

 Disadvantages
Delay in potentially curative surgery or
radiotherapy
Patients may refuse further T/t
morbidity & cost of T/t
 Licitra et al 195 patients with resectable OC tumors- 3
cycles of CDDP and 5- FU followed by surgery-
induction chemotherapy did not improve long term
outcome, however, it may allow less aggressive surgery
or spare radiation to the oral cavity in select patients
J Clin Oncol 2003; 21(2): 327-33

Grau et al in a prospective trial of induction

chemotherapy for patients with resectable or
unresectable stage III or IV OC cancer. 66% of patients
responded and of 46 patients who were considered
inoperable, 34 were able to undergo complete resection
after induction chemotherapy.
Oncology 2002; 63: 338-45
 In 1985, the Department of Vetran Affairs Laryngeal Cancer Study Group
initiated a landmark multicenter randomized trial of induction chemotherapy
followed by definitive RT vs. total laryngectomy.

Based on currently available information, except for preservation of the

larynx, induction chemotherapy for HNSCC should be limited to therapeutic
trials & has no identified place in standard H&N oncologic therapy
Induction chemotherapy continues to
remain a nonstandard treatment approach.
Phase III trials have, as yet, not defined the
role of induction chemotherapy, in
improving outcome.
 CONCURRENT
CHEMORADIOTHERAPY
First used in 1962
CCR has demonstrated improvements in clinical
outcome in resectable and unresectable locally
advanced HNSCC.
Improved local & regional control, disease free survival
and overall survival.
Mechanism for interaction b/w cytotoxic drugs &
radiation that results in additive or synergistic
phenomenon rests on several mechanisms
The net effect is to improve cellular cytotoxicity
 Mechanisms
Spatial co-operation : radiation to control locoregional disease &
chemotherapy systemically to control micrometastatic disease
Chemotherapy ability of radiotherapy damaged tumor cells to repair
Improved blood supply to tumor with cytoreduction-improved tumor
tissue oxygenation and radiosensitivity
Specific chemotherapeutic drugs (fluorouracil, cisplatin, and taxanes)
induce cell cycle arrest at the G2 checkpoint, where the cell is most
radiosensitive
Non-overlapping toxicity : chemotherapy & radiotherapy have
different mechanisms of toxicity, which are additive to tumor but less to
normal tissues
It has selective cytoprotective properties for normal tissues- allowing
radiation doses
 Single agents &
radiotherapy.
Methotrexate + radiotherapy
Methotrexate- S-phase block of cell cycle- accumulation of cells in G I
phase- radiosensitivity

Hydroxyurea + radiotherapy
Kills cells in S-phase & synchronizes cells into more radiosensitive G,
phase

Bleomycin + radiotherapy
Enhanced effects- interference with cellular repair after irradiation

5-FU + radiotherapy
5-FU - active radiosensitizer for pts with H&N cancer
 ADJUVANT
CHEMOTHERAPY
Adjuvant chemotherapy after primary surgery
has been shown to be effective .

Despite surgery & RT

Only 30% survival rate 5 years

Approx. 20% develop metastatic disease

Further 10-20% develop a 2 nd primary tumor

Goals : to eradicate sites of micrometastases.

reduce risk of loco regional recurrence.

 Advantages over Neoadjuvant
treatment
Surgery is not delayed

Neoadjuvant therapy can blur margins of disease

Neoadjuvant therapy- symptom relief- pt refusal to surgery,

decrease compliance

High- risk pts (those with extracapsular extension, carcinoma

in situ or close surgical margins)- benefit from adjuvant
chemotherapy with local control
Although there appears to be some in incidence of
distant metastases, adjuvant therapy has not been
demonstrated to improve survival .
 Topical chemotherapy
Actinic keratotic lesions- 5% fluorouracil cream

Superficial basal cell carcinomas

Not effective for invasive lesions

Needless delay in definitive therapy

 Sequential chemotherapy
Induction CT + CRT
Strong biologic rationale
Immediate period after completion of IC may be
biologically critical time.
Considering Gompertzian kinetics model- when
tumor volume is low the proliferation of cancer
cell is more rapid. With this model in mind, the
addition of a non-cross resistant therapy with
minimal delay should improve loco-regional
control
Docetaxel, cisplatin, & 5-FU (TPF) superior to classic comb.
of cisplatin & 5 FU

Sequential treatment represents an improvement over

treatment with either induction chemotherapy or
chemoradiotherapy and may represent the future of
treatment for locally advanced SCCHN.
 Chemoprevention
Chemoprevention involves the administration of a
natural or man-made agent to retard or prevent the
development or progression of cancer (M. Sporn,
1976)

Primary: Prevention of cancer in healthy individuals

Secondary: Prevention of cancer in patients with
pre-malignant lesions
Tertiary: Prevention of second cancer in patients
who had cancer
Chemoprevention
Chemopreventive agents
Retinoids and Non Retinoids
Retinoids: Natural derivatives & synthetic analogues of Vit. A
(Retinol, Retinal, retinyl esters, all-trans-retinoic acid, and their
metabolites)

Non Retinoids: -carotene, Vit E, selenium, aspirin & COX-2

inhibitors

Potential New Agents :

Vitamin D analogs
5-reductase inhibitors
Matrix metalloproteinase inhibitor
 Allergic Reactions
Hypersensitivity, anaphylaxis, drug
reaction.

Overactive or misdirected immune response

that results in local tissue injury or changes
throughout the body in response to a
foreign substance

Management
Epinephrine

Antihistamines

Corticosteroids
 Nausea and vomiting

Emesis is mediated mainly by several neurotransmitters

in GIT & CNS including serotonin, dopamine, &
aminobutyric acid which act directly/ indirectly on
centre that controls emesis

Treatment
Antagonist of 5-hydroxytryptamine 3 receptors (5-HT3R) + oral
dexamethasone: prevent acute emesis after use of high or moderately high
emetogenic agents

New antiemetic agent- Palonosetron- higher binding affinity for 5-HT3R and a
terminal half-life of elimination at least 4 times longer than any other antagonist
 Emetogenic potential of chemotherapy agents
High
>50 mg/m2 cisplatin
>500 mg/m2 dacarbazine
>1500 mg/m2 cyclophosphamide
Moderately high
<50 mg/m2 cisplatin
>1000 mg/m2 methotrexate
>60 mg/m2 doxorubicin
Moderate
>370 mg/m2 bolus fluorouracil
750 mg/m2 cyclophosphamide
2501000 mg/m2 methotrexate
2060 mg/m2 doxorubicin
80120 mg/m2 intravenous etoposide
 Diarrhoea
Severe diarrhoea dehydration, renal failure
Diarrhoea + severe neutropenia Gram-negative sepsis
contributed to incidence of mortality within 60 days.

Treatment
Main aim should be to volume of diarrhoea, treat dehydration
aggressively
Antibiotics if symptoms persist or if there is accompanying
neutropenia
High-dose Loperamide- an initial dose of 4 mg followed by 2 mg
every 2 h until there has been 12 h without loose motions
 Mucositis
Mucositis & xerostomia are most common oral
complications of nonsurgical therapy of cancer

Significantly affects quality of life in terms of pain,

ability to eat, swallow & talk.

Require an interruption of therapy or lead to dose of

cancer therapy or T/t delay.

In presence of neutropenia, mucositis predisposes to

septicemia, bacteremia & fungemia
 Rx
Anti-inflammatory agents

Anti-microbial agents

Biologic response modifiers

Cytokines such as IL-1, IL-11 & KGF
Thalidomide, an angiogenesis-inhibiting drug, also acts against TNF.
GM-CSF

Cytoprotective agents( Amifostine)

primarily free radical scavengers or antioxidants
 Bone marrow suppression
Anemia
Erythropoietin (EPO): stimulates production of red blood cells in the bone marrow
SC or IV
Side effects: headache, hypertension, arthralgia (bone or joint pain), diarrhea,
nausea, fatigue
Neutropenia
G-CSF (granulocyte-colony-stimulating factor): stimulates production
of white blood cells in the bone marrow
SC or IV
Common side effect: bone pain
Do not give < 24 hrs before or after chemotherapy, or within 12 hours of radiation
Thrombocytopenia
GM-CSF
Stimulates neutrophils and platelets
Platelet transfusion to keep platelet count >20,000
Infections
Alopecia

Bleeding
 Future.
Gene therapy
By inserting TNF, IL-2 & other cytokine
genes into tumor cells, increase their
immune recognition and destruction by
tumor infiltrating lymphocytes.

Introduction of multidrug resistant gene

into bone marrow- render them less
susceptible to myleosuppressant drug-
thus limit toxicity of many anticancer drug
Targeted Therapy
EGFR involved in development & progression of
HNSCC, ass. with poor prognosis
Anti-EGFR monoclonal antibody Cetuximab- first
targeted therapy
Improve survival and locoregional control when added to
RT .
Considered standard approach for patients with
compromised performance status/significant
comorbidities that preclude platinum based therapy.
Role in aggressive , concurrent CRT under evalution
Anti-angiogenesis with Bevacizumab(anti-VEGF)

Inhibits growth of new tumor blood vessels and

normalize tumor vasculature, thereby boosting drug
delivery when used in combination with cytotoxics.
For metastatic HNSCC under investigation.
Bevacizumab + Erlotinib- promising results
Bevacizumab + CT/CRT- under evaluation
 Conclusion

Chemotherapy is a specialized area of medical

practice, and cytotoxic drugs should only be prescribed
with relevant expertise. Chemotherapy should only be
administered in settings where there are necessary
support staff and facilities available.
It is still, however important for specialists in
other disciplines to know the basics about chemotherapy
who refer patients for treatment
 References
Principles and Practice of Head and Neck Surgery
and Oncology Second Edition Paul Q. Montgomery,
Peter H. Rhys Evans, Patrick J. Gullane
Chemoradiation Therapy: The Evolving Role in Head
and Neck Cancer and Its Application to Oral Cavity
Tumors- Oral Maxillofacial Surg Clin N Am 18 (2006)
605614 Barbara A. Murphy, Anthony Cmelak,
Principles of Oral Maxillofacial Surgery, Vol-1, Larry J.
Peterson
Head & Neck Surgery: Stell & Maran
Cancer of oral cavity: Jatin Shah
Cancer of the Head and Neck . Eugene Myers et al.
Handbook of Chemotherapy. Roland Skeel
THANK YOU